Clinical Score to Differentiate Scrub Typhus and Dengue: A Tool to Differentiate Scrub Typhus and Dengue.

PubMed

Mitra, Shubhanker; Gautam, Ira; Jambugulam, Mohan; Abhilash, Kundavaram Paul Prabhakar; Jayaseeelan, Vishalakshi

2017-01-01

Dengue and scrub typhus share similar clinical and epidemiological features, and are difficult to differentiate at initial presentation. Many places are endemic to both these infections where they comprise the majority of acute undifferentiated febrile illnesses. We aimed to develop a score that can differentiate scrub typhus from dengue. In this cross-sectional study, 188 cases of scrub typhus and 201 cases of dengue infection who presented to the emergency department or medicine outpatient clinic from September 2012 to April 2013 were included. Univariate followed by multivariate logistic regression analysis was performed to identify clinical features and laboratory results that were significantly different between the two groups. Each variable was assigned scores based on the strength of association and receiver operating characteristics area under the curve (ROC-AUC) was generated and compared. Six scoring models were explored to ascertain the model with the best fit. Model 2 was developed using the following six variables: oxygen saturation (>90%, ≤90%), total white blood cell count (<4000, 4001-7000 and >7000 cells/cumm), hemoglobin (≤14 and >14 g/dL), total bilirubin (<2 and ≥2 mg/dL), serum glutamic oxaloacetic transaminase (>200 and ≥200 IU/dL), and altered sensorium (present or absent). Each variable was assigned scores based on its strength of association. The AUC-ROC curve (95% confidence interval) for model 2 was 0.84 (0.79-0.89). At the cut off score of 13, the sensitivity and specificity were 85% and 77% respectively, with a higher score favoring dengue. In areas of high burden of ST and dengue, model 2 (the "clinical score to differentiate scrub typhus and dengue fever") is a simple and rapid clinical scoring system that may be used to differentiate scrub typhus and dengue at initial presentation.

Clinical profile and outcome of children with scrub typhus from Chennai, South India.

PubMed

Ganesh, Ramaswamy; Suresh, Natarajan; Pratyusha, L L; Janakiraman, Lalitha; Manickam, Mani; Andal, A

2018-06-01

Scrub typhus is an acute febrile illness caused by Orientia tsutsugamushi. We prospectively studied the clinico-laboratory profile and outcome of 358 children aged 1 day to 18 years diagnosed with scrub typhus from Chennai, South India. All children (100%) had fever. Eschar was seen in 67%. All children were treated with oral doxycycline and those with complications were treated with intravenous chloramphenicol/azithromycin. Rapid defervescence (within 48 h) after initiation of doxycline was seen in 306 (85%) and 52 (14.5%) developed complications. Multivariate logistic regression analysis revealed that children who had an elevated aspartate amino transferase (> 120 IU/L) and the presence of thrombocytopenia (platelet count less than 1 lac cells/mm 3 ) at admission had high risk of developing complications. The overall mortality rate in this series was 0.8%. Our 4-year study highlights the clinico-laboratory profile of Scrub typhus in children from Chennai, South India. Early recognition and prompt treatment reduces the complication and mortality. What is Known: • Scrub typhus is endemic to tsutsugamushi triangle, a geographical triangle extending from northern Japan in the east to Pakistan and Afghanistan in the west and northern Australia in the south. • There is paucity of data regarding its clinico-laboratory profile in neonates as well as its predictors of outcome. What is New: • Children who had an elevated AST and the presence of thrombocytopenia at admission had high risk of developing complications.

Between bacteriology and virology: the development of typhus vaccines between the First and Second World Wars.

PubMed

Weindling, P

1995-01-01

This paper provides an overview of the development of typhus vaccines between the first and second world wars. It is shown that there was a shift in the classification of the causal Rickettsiae from being classed as bacteria to being conceptualised as a type of virus. This 'paradigm switch' stimulated interest in the possibility of producing an effective medicine.

High seroprevalence of antibodies against spotted fever and scrub typhus bacteria in patients with febrile Illness, Kenya.

PubMed

Thiga, Jacqueline W; Mutai, Beth K; Eyako, Wurapa K; Ng'ang'a, Zipporah; Jiang, Ju; Richards, Allen L; Waitumbi, John N

2015-04-01

Serum samples from patients in Kenya with febrile illnesses were screened for antibodies against bacteria that cause spotted fever, typhus, and scrub typhus. Seroprevalence was 10% for spotted fever group, <1% for typhus group, and 5% for scrub typhus group. Results should help clinicians expand their list of differential diagnoses for undifferentiated fevers.

Diagnostic validation of selected serological tests for detecting scrub typhus.

PubMed

Koraluru, Munegowda; Bairy, Indira; Varma, Muralidhar; Vidyasagar, Sudha

2015-07-01

Clinical diagnosis of scrub typhus is often difficult because the symptoms are very similar to those of other febrile illness such as dengue, leptospirosis, malaria and other viral hemorrhagic fevers. Though better diagnostic tests are available for rickettsial diseases and scrub typhus elsewhere, the Weil-Felix test is still commonly used in India, mainly because microimmunofluorescence assays (M-IFA) were not available in India till recently and relevant staff had insufficient training. The present study was performed to investigate the performance of M-IFA, IgM ELISA, and Weil-Felix test on 546 non-repeated serum samples from subjects suspected of having scrub typhus. One hundred and forty-three of these 546 samples were positive by M-IFA; these cases were also confirmed clinically to have scrub typhus based on their dramatic responses to doxycycline therapy. IgM ELISA was positive in 122 of the 143 M-IFA positive cases and the Weil-Felix test in 96. Though the Weil-Felix test is a heterophile agglutination test, it was found in this study to have good specificity but far too little sensitivity to use as a routine diagnostic test. IgM ELISA can be a good substitute for M-IFA. Incorporation of multiple prototype antigens on M-IFA slides is likely one of the reasons for its superior performance. As newer and better diagnostic assays become available for scrub typhus diagnosis in developed countries, it will be imperative to also use such tests in other endemic countries to prevent over- or under-diagnosis of scrub typhus. © 2015 The Societies and Wiley Publishing Asia Pty Ltd.

Eradication of typhus exanthematicus in Bosnia and Herzegovina.

PubMed

Puvacić, Zlatko; Beslagić, Edina; Zvizdić, Sukrija; Puvacić, Sandra; Ravlija, Jelena; Hamzić, Sadeta

2006-02-01

Typhus exanthematicus in Bosnia and Herzegovina held in endemic areas from which especially quickly began spread after 1945. That year, in 1945, one hundred epidemics of typhus fever appeared, with the highest incidence rate in Europe of 215.04 per 1,000. Directions of unique program in the world were to eradicate lice of the body, but also establish monitoring of the recidivism, Brill-Zinsser disease. Since 1971, typhus exanthematicus (classical typhus) hasn't appeared in Bosnia and Herzegovina, so epidemic typhus can considered as an eradicated communicable disease.

Development of life stages of Leptotrombidium imphalum and Leptotrombidium chiangraiensis (Acari: Trombiculidae) uninfected and infected with the scrub typhus rickettsia, Orientia tsustugamushi

USDA-ARS?s Scientific Manuscript database

Leptotrombidium chiangraiensis Tanskul and Linthicum and Leptotrombidium imphalum Vercammen-Grandjean are important vectors of scrub typhus in ricefield habitats in northern Thailand. The developmental biology of all stages of the life cycle of two generations of mites infected with Orientia tsutsug...

Hemorrhagic Transformation of Scrub Typhus Encephalitis: A Rare Entity.

PubMed

Kim, H-C; Yoon, K-W; Yoo, D-S; Cho, C-S

2015-12-01

Central nervous system (CNS) involvement of scrub typhus infection is well known. Most CNS involvement of scrub typhus infection present as meningitis or encephalitis. We report on a patient suffering from hemorrhagic transformation of intracranial lesions caused by Orientia tsutsugamushi. A 53-year-old female farmer who was infected by scrub typhus was treated with doxycycline and recovered from the systemic illness. However, headache persisted. Brain radiologic studies revealed acute intracranial hemorrhage and enhancing lesion, which implied a CNS involvement. Hemorrhagic transformation of encephalitis by scrub typhus is very rare complication and to our best knowledge, this is the first report of hemorrhagic transformation of scrub typhus encephalitis. Clinician should consider the possibility of hemorrhagic transformation of encephalitis in cases of scrub typhus infection.

[An outbreak of epidemic louse-borne typhus in Tokyo 1914: a study on the prevention of epidemics].

PubMed

Watanabe, Mikio

2002-12-01

In 1914, the third year of the Taisho era, a period of democracy and prosperity of Japan, Tokyo was attached by an outbreak of epidemic louse-borne typhus. The number of patients was 4,119 and number of deaths was 778 (mortality rate of 18.9%) in Tokyo and 7,309 patients had been suffering from typhus fever that year in Japan. Many possible causes of the outbreak were suspected by the Health Authority of the Home Office, but these were not confirmed. One of the most likely reasons is the poor and congested living conditions of seasonal construction workers. Laborers had moved from the northwest region of Japan where typhus fever had developed occasionally in those days. Some of the laborers probably brought pathogenic germs with lice. The main preventive method for epidemic louse-borne typhus was isolation of patients and disinfecting of the areas. Kitasato Shibasaburou proposed the improvement of residential conditions of workers to prevent the prevalence of disease, but the proposal was not accepted because of financial reasons of the government. Recurrence of the outbreak did not occur in the following years. However, a huge outbreak of typhus fever with 32,366 patients and 3,351 deaths, was documented in 1946, amidst the disordered conditions of Japan after World War II.

Climate variability, animal reservoir and transmission of scrub typhus in Southern China

PubMed Central

Li, Xiaoning; Ma, Yu; Tao, Xia; Wu, Xinwei

2017-01-01

Objectives We aimed to evaluate the relationships between climate variability, animal reservoirs and scrub typhus incidence in Southern China. Methods We obtained data on scrub typhus cases in Guangzhou every month from 2006 to 2014 from the Chinese communicable disease network. Time-series Poisson regression models and distributed lag nonlinear models (DLNM) were used to evaluate the relationship between risk factors and scrub typhus. Results Wavelet analysis found the incidence of scrub typhus cycled with a period of approximately 8–12 months and long-term trends with a period of approximately 24–36 months. The DLNM model shows that relative humidity, rainfall, DTR, MEI and rodent density were associated with the incidence of scrub typhus. Conclusions Our findings suggest that the incidence scrub typhus has two main temporal cycles. Determining the reason for this trend and how it can be used for disease control and prevention requires additional research. The transmission of scrub typhus is highly dependent on climate factors and rodent density, both of which should be considered in prevention and control strategies for scrub typhus. PMID:28273079

Climate variability, animal reservoir and transmission of scrub typhus in Southern China.

PubMed

Wei, Yuehong; Huang, Yong; Li, Xiaoning; Ma, Yu; Tao, Xia; Wu, Xinwei; Yang, Zhicong

2017-03-01

We aimed to evaluate the relationships between climate variability, animal reservoirs and scrub typhus incidence in Southern China. We obtained data on scrub typhus cases in Guangzhou every month from 2006 to 2014 from the Chinese communicable disease network. Time-series Poisson regression models and distributed lag nonlinear models (DLNM) were used to evaluate the relationship between risk factors and scrub typhus. Wavelet analysis found the incidence of scrub typhus cycled with a period of approximately 8-12 months and long-term trends with a period of approximately 24-36 months. The DLNM model shows that relative humidity, rainfall, DTR, MEI and rodent density were associated with the incidence of scrub typhus. Our findings suggest that the incidence scrub typhus has two main temporal cycles. Determining the reason for this trend and how it can be used for disease control and prevention requires additional research. The transmission of scrub typhus is highly dependent on climate factors and rodent density, both of which should be considered in prevention and control strategies for scrub typhus.

Use of a Sensitive Microplate Enzyme-Linked Immunosorbent Assay in a Retrospective Serological Analysis of a Laboratory Population at Risk to Infection with Typhus Group Rickettsiae

DTIC Science & Technology

1980-01-01

Rocky Mountain spotted fever (3, 12, 20, 30), typhus, and scrub typhus rickettsiae. In a sum- and scrub typhus (38). Many, however, were mary and...and M. J. Synder. 197ti murine typhus in sera from Indonesians. Trans. R. ’.oc. Prompt confirmation of Rocky Mountain spotted fever "Trop. Med Hyg

Rickettsia Felis in Xenopsylla Cheopis, Java, Indonesia

DTIC Science & Technology

2006-08-01

Sardjono TW, Yanuwiadi B, Hernowati TE, et al. Seroepidemiological evidence for murine and scrub typhus in Malang, Indonesia. Am J Trop Med Hyg. 1997;57...and Allen L. Richards* Rickettsia typhi and R. felis, etiologic agents of murine typhus and fleaborne spotted fever, respectively, were detected in...Indonesia and nat- urally occurring R. felis in Oriental rat fleas. Murine typhus (endemic typhus , fleaborne typhus ),caused by Rickettsia typhi, is

Spatiotemporal Dynamics of Scrub Typhus Transmission in Mainland China, 2006-2014

PubMed Central

Hu, Wen-Biao; Haque, Ubydul; Weppelmann, Thomas A.; Wang, Yong; Liu, Yun-Xi; Li, Xin-Lou; Sun, Hai-Long; Sun, Yan-Song; Clements, Archie C. A.; Li, Shen-Long; Zhang, Wen-Yi

2016-01-01

Background Scrub typhus is endemic in the Asia-Pacific region including China, and the number of reported cases has increased dramatically in the past decade. However, the spatial-temporal dynamics and the potential risk factors in transmission of scrub typhus in mainland China have yet to be characterized. Objective This study aims to explore the spatiotemporal dynamics of reported scrub typhus cases in mainland China between January 2006 and December 2014, to detect the location of high risk spatiotemporal clusters of scrub typhus cases, and identify the potential risk factors affecting the re-emergence of the disease. Method Monthly cases of scrub typhus reported at the county level between 2006 and 2014 were obtained from the Chinese Center for Diseases Control and Prevention. Time-series analyses, spatiotemporal cluster analyses, and spatial scan statistics were used to explore the characteristics of the scrub typhus incidence. To explore the association between scrub typhus incidence and environmental variables panel Poisson regression analysis was conducted. Results During the time period between 2006 and 2014 a total of 54,558 scrub typhus cases were reported in mainland China, which grew exponentially. The majority of cases were reported each year between July and November, with peak incidence during October every year. The spatiotemporal dynamics of scrub typhus varied over the study period with high-risk clusters identified in southwest, southern, and middle-eastern part of China. Scrub typhus incidence was positively correlated with the percentage of shrub and meteorological variables including temperature and precipitation. Conclusions The results of this study demonstrate areas in China that could be targeted with public health interventions to mitigate the growing threat of scrub typhus in the country. PMID:27479297

Spatiotemporal Dynamics of Scrub Typhus Transmission in Mainland China, 2006-2014.

PubMed

Wu, Yi-Cheng; Qian, Quan; Soares Magalhaes, Ricardo J; Han, Zhi-Hai; Hu, Wen-Biao; Haque, Ubydul; Weppelmann, Thomas A; Wang, Yong; Liu, Yun-Xi; Li, Xin-Lou; Sun, Hai-Long; Sun, Yan-Song; Clements, Archie C A; Li, Shen-Long; Zhang, Wen-Yi

2016-08-01

Scrub typhus is endemic in the Asia-Pacific region including China, and the number of reported cases has increased dramatically in the past decade. However, the spatial-temporal dynamics and the potential risk factors in transmission of scrub typhus in mainland China have yet to be characterized. This study aims to explore the spatiotemporal dynamics of reported scrub typhus cases in mainland China between January 2006 and December 2014, to detect the location of high risk spatiotemporal clusters of scrub typhus cases, and identify the potential risk factors affecting the re-emergence of the disease. Monthly cases of scrub typhus reported at the county level between 2006 and 2014 were obtained from the Chinese Center for Diseases Control and Prevention. Time-series analyses, spatiotemporal cluster analyses, and spatial scan statistics were used to explore the characteristics of the scrub typhus incidence. To explore the association between scrub typhus incidence and environmental variables panel Poisson regression analysis was conducted. During the time period between 2006 and 2014 a total of 54,558 scrub typhus cases were reported in mainland China, which grew exponentially. The majority of cases were reported each year between July and November, with peak incidence during October every year. The spatiotemporal dynamics of scrub typhus varied over the study period with high-risk clusters identified in southwest, southern, and middle-eastern part of China. Scrub typhus incidence was positively correlated with the percentage of shrub and meteorological variables including temperature and precipitation. The results of this study demonstrate areas in China that could be targeted with public health interventions to mitigate the growing threat of scrub typhus in the country.

An Overview of Epidemic Typhus in the World and Iran during the 19th and 20th Centuries.

PubMed

Azizi, Mohammad Hossein; Bahadori, Moslem; Azizi, Farzaneh

2016-10-01

The present article provides a concise historical review on classical epidemic typhus (exanthemata typhus) in the world as well its outbreaks in Iran mainly during the 19th and 20th centuries. Typhus is still a potential public health threat under certain conditions, despite the fact that nowadays, efficient antibiotics are accessible and sanitary conditions which lead to typhus outbreaks have improved significantly.

Scrub Typhus Outbreak in a Remote Primary School, Bhutan, 2014.

PubMed

Tshokey, Tshokey; Graves, Stephen; Tshering, Dorji; Phuntsho, Kelzang; Tshering, Karchung; Stenos, John

2017-08-01

Scrub typhus in Bhutan was first reported in 2009. We investigated an outbreak of scrub typhus in a remote primary school during August-October 2014. Delay in recognition and treatment resulted in 2 deaths from meningoencephalitis. Scrub typhus warrants urgent public health interventions in Bhutan.

Epidemic typhus meningitis in the southwestern United States.

PubMed

Massung, R F; Davis, L E; Slater, K; McKechnie, D B; Puerzer, M

2001-03-15

A patient residing in New Mexico had murine typhus diagnosed. A novel molecular assay was performed at the Centers for Disease Control and Prevention, and Rickettsia prowazekii, the agent of epidemic typhus, was found, rather than R. typhi. To our knowledge, this is the first reported case of epidemic typhus confirmed by means of polymerase chain reaction--based testing of cerebrospinal fluid, and it introduces a novel assay for the molecular diagnosis of both epidemic and murine typhus.

Clinical and Epidemiological Characteristics of Scrub Typhus and Murine Typhus among Hospitalized Patients with Acute Undifferentiated Fever in Northern Vietnam

PubMed Central

Hamaguchi, Sugihiro; Cuong, Ngo Chi; Tra, Doan Thu; Doan, Yen Hai; Shimizu, Kenta; Tuan, Nguyen Quang; Yoshida, Lay-Myint; Mai, Le Quynh; Duc-Anh, Dang; Ando, Shuji; Arikawa, Jiro; Parry, Christopher M.; Ariyoshi, Koya; Thuy, Pham Thanh

2015-01-01

A descriptive study on rickettsiosis was conducted at the largest referral hospital in Hanoi, Vietnam, to identify epidemiological and clinical characteristics of specific rickettsiosis. Between March 2001 and February 2003, we enrolled 579 patients with acute undifferentiated fever (AUF), excluding patients with malaria, dengue fever, and typhoid fever, and serologically tested for Orientia tsutsugamushi and Rickettsia typhi. Of the patients, 237 (40.9%) and 193 (33.3%) had scrub and murine typhus, respectively, and 149 (25.7%) had neither of them (non–scrub and murine typhus [non-ST/MT]). The proportion of murine typhus was highest among patients living in Hanoi whereas that of scrub typhus was highest in national or regional border areas. The presence of an eschar, dyspnea, hypotension, and lymphadenopathy was significantly associated with a diagnosis of scrub typhus (OR = 46.56, 10.90, 9.01, and 7.92, respectively). Patients with murine typhus were less likely to have these findings but more likely to have myalgia, rash, and relative bradycardia (OR = 1.60, 1.56, and 1.45, respectively). Scrub typhus and murine typhus were shown to be common causes of AUF in northern Vietnam although the occurrence of spotted fever group rickettsiae was not determined. Clinical and epidemiological information may help local clinicians make clinical diagnosis of specific rickettsioses in a resource-limited setting. PMID:25778504

Acute pancreatitis associated with scrub typhus.

PubMed

Sv, Padmavathi Devi; M, Aruna; Kumar, Anil Cv; Krishna Reddy, Hari; Bl, Sangeetha; Siva Kumar, V

2017-01-01

Scrub typhus, or tsutsugamushi fever, is a zoonosis of rural Asia and the western Pacific islands. The causative organism, Orientia (formerly Rickettsia) tsutsugamushi, is transmitted to humans by the bite of a larval Leptotrombidium mite (chigger). Scrub typhus may have gastrointestinal presentations, such as acute acalculous cholecystitis, duodenal ulcer perforation, peritonitis and gastric ulceration. Acute pancreatitis with scrub typhus has been reported rarely. We report a patient of scrub typhus complicated by acute pancreatitis and acute kidney injury. © The Author(s) 2016.

Control of typhus fever in Finland during World War II.

PubMed

Laurent, Helene

2009-12-01

The article describes the measures taken against the threat of typhus epidemic in Finland during the Second World War. Comparisons between countries at war and their different typhus prevention methods are made. The main method of typhus prevention in Finland consisted of regular sauna bathing, which was culturally acceptable and very efficient when combined with heating of the clothing. The Finnish troops remained virtually louse-free by ecological and traditional methods, and thus the spread of typhus fever in the army could be prevented.

Scrub typhus: Clinical spectrum and outcome.

PubMed

Venkategowda, Pradeep M; Rao, S Manimala; Mutkule, Dnyaneshwar P; Rao, Mallela V; Taggu, Alai N

2015-04-01

Scrub typhus is one of the differential diagnoses for fever with thrombocytopenia. ARDS associated with Scrub typhus has high morbidity and mortality. To evaluate clinical features, lab values, and outcome in patients with scrub typhus and comparison in patients with or without ARDS. A prospective observational study was conducted on 109 patients with febrile illness and thrombocytopenia during a period of 12 months. All 109 patients were tested with both Immune-chromatography test and Weil felix test. Patients having either Immune-chromatography test/Weil felix test positive have been included and considered as scrub typhus positive whereas negative for both Immune-chromatography and Weil felix test were excluded. Clinical features, lab parameters, and outcome were evaluated in all patients with scrub typhus. Statistical analysis used in this study was T-test. Among 58 patients who were included (After exclusion of 51 patients among total of 109 patients) 34 patients had no ARDS and 24 patients had ARDS. The clinical feature like dyspnoea, cough, low blood pressure (MAP<65 mmHg), IVC collapsibility (by ultrasound) and laboratory parameters like decreased Hemoglobin, Hematocrit, Serum albumin, and increased serum creatinine, serum total bilirubin, SGOT, SGPT, LDH, CPK, and serum lactate were statistically significant (P < 0.0001) in scrub typhus patients group with ARDS. The higher titers of Weil-felix can be correlated with more severe form of disease according to our observation. All 34 Scrub typhus patients without ARDS recovered completely. Among 24 Scrub typhus patients with ARDS, 22 patients recovered, and 2 patients died. Scrub typhus is an important differential diagnosis in a patients having fever with thrombocytopenia. Scrub typhus associated with ARDS has high morbidity and mortality. Early diagnosis and treatment with doxycycline can prevent the occurrence of ARDS.

Serological differentiation of murine typhus and epidemic typhus using cross-adsorption and Western blotting.

PubMed

La Scola, B; Rydkina, L; Ndihokubwayo, J B; Vene, S; Raoult, D

2000-07-01

Differentiation of murine typhus due to Rickettsia typhi and epidemic typhus due to Rickettsia prowazekii is critical epidemiologically but difficult serologically. Using serological, epidemiological, and clinical criteria, we selected sera from 264 patients with epidemic typhus and from 44 patients with murine typhus among the 29,188 tested sera in our bank. These sera cross-reacted extensively in indirect fluorescent antibody assays (IFAs) against R. typhi and R. prowazekii, as 42% of the sera from patients with epidemic typhus and 34% of the sera from patients with murine typhus exhibited immunoglobulin M (IgM) and/or IgG titers against the homologous antigen (R. prowazekii and R. typhi, respectively) that were more than one dilution higher than those against the heterologous antigen. Serum cross-adsorption studies and Western blotting were performed on sera from 12 selected patients, 5 with murine typhus, 5 with epidemic typhus, and 2 suffering from typhus of undetermined etiology. Differences in IFA titers against R. typhi and R. prowazekii allowed the identification of the etiological agent in 8 of 12 patients. Western blot studies enabled the identification of the etiological agent in six patients. When the results of IFA and Western blot studies were considered in combination, identification of the etiological agent was possible for 10 of 12 patients. Serum cross-adsorption studies enabled the differentiation of the etiological agent in all patients. Our study indicates that when used together, Western blotting and IFA are useful serological tools to differentiate between R. prowazekii and R. typhi exposures. While a cross-adsorption study is the definitive technique to differentiate between infections with these agents, it was necessary in only 2 of 12 cases (16.7%), and the high costs of such a study limit its use.

Serological Differentiation of Murine Typhus and Epidemic Typhus Using Cross-Adsorption and Western Blotting

PubMed Central

La Scola, Bernard; Rydkina, Lena; Ndihokubwayo, Jean-Bosco; Vene, Sirkka; Raoult, Didier

2000-01-01

Differentiation of murine typhus due to Rickettsia typhi and epidemic typhus due to Rickettsia prowazekii is critical epidemiologically but difficult serologically. Using serological, epidemiological, and clinical criteria, we selected sera from 264 patients with epidemic typhus and from 44 patients with murine typhus among the 29,188 tested sera in our bank. These sera cross-reacted extensively in indirect fluorescent antibody assays (IFAs) against R. typhi and R. prowazekii, as 42% of the sera from patients with epidemic typhus and 34% of the sera from patients with murine typhus exhibited immunoglobulin M (IgM) and/or IgG titers against the homologous antigen (R. prowazekii and R. typhi, respectively) that were more than one dilution higher than those against the heterologous antigen. Serum cross-adsorption studies and Western blotting were performed on sera from 12 selected patients, 5 with murine typhus, 5 with epidemic typhus, and 2 suffering from typhus of undetermined etiology. Differences in IFA titers against R. typhi and R. prowazekii allowed the identification of the etiological agent in 8 of 12 patients. Western blot studies enabled the identification of the etiological agent in six patients. When the results of IFA and Western blot studies were considered in combination, identification of the etiological agent was possible for 10 of 12 patients. Serum cross-adsorption studies enabled the differentiation of the etiological agent in all patients. Our study indicates that when used together, Western blotting and IFA are useful serological tools to differentiate between R. prowazekii and R. typhi exposures. While a cross-adsorption study is the definitive technique to differentiate between infections with these agents, it was necessary in only 2 of 12 cases (16.7%), and the high costs of such a study limit its use. PMID:10882661

Meteorological factors and risk of scrub typhus in Guangzhou, southern China, 2006–2012

PubMed Central

2014-01-01

Background Scrub typhus is becoming the most common vector born disease in Guangzhou, southern China. In this study, we aimed to examine the effect of weather patterns on the incidence of Scrub typhus in the subtropical city of Guangzhou for the period 2006–2012, and assist public health prevention and control measures. Methods Scrub typhus reported cases during the period of 2006–2012 in Guangzhou were obtained from National Notifiable Disease Report System (NNDRS). Simultaneous meteorological data including temperature, relative humidity, atmospheric pressure, sunshine, and rainfall were obtained from the documentation of the Guangzhou Meteorological Bureau. A negative binomial regression was used to identify the relationship between meteorological variables and scrub typhus. Results Annual incidence rates of scrub typhus from 2006 to 2012 were 3.25, 2.67, 3.81, 4.22, 4.41, 5.12, and 9.75 (per 100 000) respectively. Each 1°C rise in temperature corresponded to an increase of 14.98% (95% CI 13.65% to 16.33%) in the monthly number of scrub typhus cases, while a 1 hPa rise in atmospheric pressure corresponded to a decrease in the number of cases by 8.03% (95% CI −8.75% to −7.31%). Similarly, a 1 hour rise in sunshine corresponded to an increase of 0.17% or 0.54%, and a 1 millimeter rise in rainfall corresponded to an increase of 0.05% or 0.10%, in the monthly number of scrub typhus cases, depending on the variables considered in the model. Conclusion Our study provided evidence that climatic factors were associated with occurrence of scrub typhus in Guangzhou city, China. Temperature, duration of sunshine, and rainfall were positively associated with scrub typhus incidence, while atmospheric pressure was inversely associated with scrub typhus incidence. These findings should be considered in the prediction of future patterns of scrub typhus transmission. PMID:24620733

Seroprevalence of Scrub Typhus, Typhus, and Spotted Fever Among Rural and Urban Populations of Northern Vietnam.

PubMed

Trung, Nguyen Vu; Hoi, Le Thi; Thuong, Nguyen Thi Hong; Toan, Tran Khanh; Huong, Tran Thi Kieu; Hoa, Tran Mai; Fox, Annette; Kinh, Nguyen van; van Doorn, H Rogier; Wertheim, Heiman F L; Bryant, Juliet E; Nadjm, Behzad

2017-05-01

AbstractRickettsial infections are recognized as important causes of fever throughout southeast Asia. Herein, we determined the seroprevalence to rickettsioses within rural and urban populations of northern Vietnam. Prevalence of individuals with evidence of prior rickettsial infections (IgG positive) was surprisingly low, with 9.14% (83/908) testing positive to the three major rickettsial serogroups thought to circulate in the region. Prevalence of typhus group rickettsiae (TG)-specific antibodies (6.5%, 58/908) was significantly greater than scrub typhus group orientiae (STG)- or spotted fever group rickettsiae (SFG)-specific antibodies ( P < 0.05). The majority of TG seropositives were observed among urban rather than rural residents ( P < 0.05). In contrast, overall antibody prevalence to STG and SFG were both very low (1.1%, 10/908 for STG; 1.7%, 15/908 for SFG), with no significant differences between rural and urban residents. These results provide data on baseline population characteristics that may help inform development of Rickettsia serological testing criteria in future clinical studies.

Molecular epidemiology and genetic diversity of Orientia tsutsugamushi from patients with scrub typhus in 3 regions of India.

PubMed

Varghese, George M; Janardhanan, Jeshina; Mahajan, Sanjay K; Tariang, David; Trowbridge, Paul; Prakash, John A J; David, Thambu; Sathendra, Sowmya; Abraham, O C

2015-01-01

Scrub typhus, an acute febrile illness that is widespread in the Asia-Pacific region, is caused by the bacterium Orientia tsutsugamushi, which displays high levels of antigenic variation. We conducted an investigation to identify the circulating genotypes of O. tsutsugamushi in 3 scrub typhus-endemic geographic regions of India: South India, Northern India, and Northeast India. Eschar samples collected during September 2010-August 2012 from patients with scrub typhus were subjected to 56-kDa type-specific PCR and sequencing to identify their genotypes. Kato-like strains predominated (61.5%), especially in the South and Northeast, followed by Karp-like strains (27.7%) and Gilliam and Ikeda strains (2.3% each). Neimeng-65 genotype strains were also observed in the Northeast. Clarifying the genotypic diversity of O. tsutsugamushi in India enhances knowledge of the regional diversity among circulating strains and provides potential resources for future region-specific diagnostic studies and vaccine development.

Severe Fever with Thrombocytopenia Syndrome in Patients Suspected of Having Scrub Typhus.

PubMed

Wi, Yu Mi; Woo, Hye In; Park, Dahee; Lee, Keun Hwa; Kang, Cheol-In; Chung, Doo Ryeon; Peck, Kyong Ran; Song, Jae-Hoon

2016-11-01

To determine prevalence of severe fever with thrombocytopenia syndrome in South Korea, we examined serum samples from patients with fever and insect bite history in scrub typhus-endemic areas. During the 2013 scrub typhus season, prevalence of this syndrome among patients suspected of having scrub typhus was high (23.0%), suggesting possible co-infection.

Neuropsychiatric Manifestations of Scrub Typhus.

PubMed

Mahajan, Sanjay K; Mahajan, Sanyam K

2017-01-01

Scrub typhus is caused by Orientia tsutsugamushi characterized by focal or disseminated vasculitis and perivasculitis which may involve the lungs, heart, liver, spleen and central nervous system. It was thought to have been eradicated from India. Recently it is being reported from many areas of India. The clinical picture and severity of the symptoms varies widely. The neurological manifestations of scrub typhus are not uncommon but are diverse. Meningoencephalitis is classical manifestation of scrub typhus but cerebellitis, cranial nerve palsies, plexopathy, transverse myelitis, neuroleptic malignant syndrome and Guillan-Barré syndrome are other manifestations reported in literature. The availability of literature on the neurological manifestations of scrub typhus is limited to case reports mainly. This article reviews various neurological manifestations of scrub typhus reported in literature.

Neuropsychiatric Manifestations of Scrub Typhus

PubMed Central

Mahajan, Sanjay K.; Mahajan, Sanyam K.

2017-01-01

Scrub typhus is caused by Orientia tsutsugamushi characterized by focal or disseminated vasculitis and perivasculitis which may involve the lungs, heart, liver, spleen and central nervous system. It was thought to have been eradicated from India. Recently it is being reported from many areas of India. The clinical picture and severity of the symptoms varies widely. The neurological manifestations of scrub typhus are not uncommon but are diverse. Meningoencephalitis is classical manifestation of scrub typhus but cerebellitis, cranial nerve palsies, plexopathy, transverse myelitis, neuroleptic malignant syndrome and Guillan-Barré syndrome are other manifestations reported in literature. The availability of literature on the neurological manifestations of scrub typhus is limited to case reports mainly. This article reviews various neurological manifestations of scrub typhus reported in literature. PMID:28694624

Murine and epidemic typhus rickettsiae: how close is their relationship?

PubMed Central

Woodward, T. E.

1982-01-01

Typhus fever has occurred globally as epidemic and endemic disorders. In 1910, Brill reported a typhus-like illness which Zinsser and others determined to be recurrent epidemic typhus fever. Maxcy, in 1926, proposed rodents and fleas as reservoir and vector, respectively, of endemic typhus, which Dyer confirmed in 1930. Animals experimentally infected with epidemic typhus (Rickettsia prowazeki) are immune to murine typhus (Rickettsia typhi) and vice versa. Similar solid cross-immunity exists for humans. The two diseases are clinically similar in pathologic and serologic reactions. Human epidemic typhus presumably involved a man-louse-man cycle without an animal reservoir. This concept is now questioned. Antibodies to R. prowazeki have been reported in livestock in Africa, rats in Manila, and from flying squirrels and humans in the United States. R. prowazeki was recovered from blood specimens of goats, sheep, from ixodid ticks, louse, and flea-ectoparasites of flying squirrels, and tissues of flying squirrels. More than 20 cases of squirrel-related acute epidemic typhus have been reported in the United States. R. prowazeki has not been recovered from human cases. Chemical studies of R. prowazeki and R. typhi show genetic similarities but differences in genome size and degree of hybridization suggest that interconversions between the two agents do not occur rapidly in nature. It is proposed that, with time, their relatedness will become even closer. PMID:6817526

The History of Epidemic Typhus.

PubMed

Angelakis, Emmanouil; Bechah, Yassina; Raoult, Didier

2016-08-01

Epidemic typhus caused by Rickettsia prowazekii is one of the oldest pestilential diseases of humankind. The disease is transmitted to human beings by the body louse Pediculus humanus corporis and is still considered a major threat by public health authorities, despite the efficacy of antibiotics, because poor sanitary conditions are conducive to louse proliferation. Epidemic typhus has accompanied disasters that impact humanity and has arguably determined the outcome of more wars than have soldiers and generals. The detection, identification, and characterization of microorganisms in ancient remains by paleomicrobiology has permitted the diagnosis of past epidemic typhus outbreaks through the detection of R. prowazekii. Various techniques, including microscopy and immunodetection, can be used in paleomicrobiology, but most of the data have been obtained by using PCR-based molecular techniques on dental pulp samples. Paleomicrobiology enabled the identification of the first outbreak of epidemic typhus in the 18th century in the context of a pan-European great war in the city of Douai, France, and supported the hypothesis that typhus was imported into Europe by Spanish soldiers returning from America. R. prowazekii was also detected in the remains of soldiers of Napoleon's Grand Army in Vilnius, Lithuania, which indicates that Napoleon's soldiers had epidemic typhus. The purpose of this article is to underscore the modern comprehension of clinical epidemic typhus, focus on the historical relationships of the disease, and examine the use of paleomicrobiology in the detection of past epidemic typhus outbreaks.

Scrub Typhus - A Major Cause of Pediatric Intensive Care Admission and Multiple Organ Dysfunction Syndrome: A Single-Center Experience from India.

PubMed

Giri, Prabahs Prasun; Roy, Joydeb; Saha, Agnisekhar

2018-02-01

Scrub typhus has been globally recognized as an emerging infectious disease contributing significantly to pyrexia of unknown origin (PUO) and a potential cause of multiorgan dysfunction syndrome (MODS). We studied the incidence of scrub typhus as a cause of pediatric intensive care unit (PICU) admission and MODS in our hospital and its clinical and laboratory characteristics to measure the incidence of MODS caused by scrub typhus. This study was done in a pediatric teaching hospital in Kolkata, India. Records of patients admitted with PUO from March 2012 to December 2015 were reviewed. Rathi-Goodman-Aghai scoring system was used to identify potential ST patients and confirmed by serological testing. Clinical characteristics, laboratory findings, and treatment response were noted of those needing PICU admissions. Ninety-seven cases of scrub typhus have been identified during that period. PICU admission was needed in 30 of them (31%) which contributed 8.43% of total PICU admissions. Among these 30 patients, 16 (53%) developed MODS which contributed 18.29% of total MODS admitted in PICU. Septic shock was the most common manifestation in as many as 18 (60%) patients followed by encephalopathy in 13 (43%). Patients were treated with either doxycycline alone or in combination with azithromycin. Mean time to complete defervescence was 32 h after first dose of doxycycline. The outcome was excellent without a single mortality. Scrub typhus is an important cause of MODS in this part of the world, especially in fevers associated with features as identified and not responding to conventional antibiotics.

Scrub Typhus Incidence Modeling with Meteorological Factors in South Korea.

PubMed

Kwak, Jaewon; Kim, Soojun; Kim, Gilho; Singh, Vijay P; Hong, Seungjin; Kim, Hung Soo

2015-06-29

Since its recurrence in 1986, scrub typhus has been occurring annually and it is considered as one of the most prevalent diseases in Korea. Scrub typhus is a 3rd grade nationally notifiable disease that has greatly increased in Korea since 2000. The objective of this study is to construct a disease incidence model for prediction and quantification of the incidences of scrub typhus. Using data from 2001 to 2010, the incidence Artificial Neural Network (ANN) model, which considers the time-lag between scrub typhus and minimum temperature, precipitation and average wind speed based on the Granger causality and spectral analysis, is constructed and tested for 2011 to 2012. Results show reliable simulation of scrub typhus incidences with selected predictors, and indicate that the seasonality in meteorological data should be considered.

Scrub Typhus Incidence Modeling with Meteorological Factors in South Korea

PubMed Central

Kwak, Jaewon; Kim, Soojun; Kim, Gilho; Singh, Vijay P.; Hong, Seungjin; Kim, Hung Soo

2015-01-01

Since its recurrence in 1986, scrub typhus has been occurring annually and it is considered as one of the most prevalent diseases in Korea. Scrub typhus is a 3rd grade nationally notifiable disease that has greatly increased in Korea since 2000. The objective of this study is to construct a disease incidence model for prediction and quantification of the incidences of scrub typhus. Using data from 2001 to 2010, the incidence Artificial Neural Network (ANN) model, which considers the time-lag between scrub typhus and minimum temperature, precipitation and average wind speed based on the Granger causality and spectral analysis, is constructed and tested for 2011 to 2012. Results show reliable simulation of scrub typhus incidences with selected predictors, and indicate that the seasonality in meteorological data should be considered. PMID:26132479

Multiple eschars in scrub typhus: a case report.

PubMed

Koraluru, Munegowda; Nandigam, Manideep; Bairy, Indira; Vidyasagar, Sudha; Varma, Muralidhar

2017-01-01

Eschar in scrub typhus aids in early diagnosis and institution of appropriate therapy; however, the eschar positivity rates vary greatly in endemic regions. Multiple eschars in scrub typhus are a rare presentation. Our patient presented with fever and multiple eschars and was empirically started on doxycycline. Nested polymerase chain reaction from all the four eschars and from EDTA blood were positive for 56-kDa type-specific antigen which is specific for Orientia tsutsugamushi The patient recovered completely after 7 days of antibiotic treatment. He was from an area where scrub typhus was not observed previously. An eschar in an acute febrile patient from the "tsutsugamushi triangle" is a valuable sign in scrub typhus diagnosis. A search for multiple eschars in scrub typhus must be made by clinicians. © The Author(s) 2016.

An outbreak investigation of scrub typhus in Western Province, Solomon Islands, 2014.

PubMed

Marks, Michael; Joshua, Cynthia; Longbottom, Jenny; Longbottom, Katherine; Sio, Alison; Puiahi, Elliot; Jilini, Greg; Stenos, John; Dalipanda, Tenneth; Musto, Jennie

2016-01-01

To identify the etiology and risk factors of undifferentiated fever in a cluster of patients in Western Province, Solomon Islands, May 2014. An outbreak investigation with a case control study was conducted. A case was defined as an inpatient in one hospital in Western Province, Solomon Islands with high fever (> 38.5 °C) and a negative malaria microscopy test admitted between 1 and 31 May 2014. Asymptomatic controls matched with the cases residentially were recruited in a ratio of 1:2. Serum samples from the subjects were tested for rickettsial infections using indirect micro-immunofluorescence assay. Nine cases met the outbreak case definition. All cases were male. An eschar was noted in five cases (55%), and one developed pneumonitis. We did not identify any environmental factors associated with illness. Serum samples of all five follow-up cases (100%) had strong-positive IgG responses to scrub typhus. All but one control (10%) had a moderate response against scrub typhus. Four controls had low levels of antibodies against spotted fever group rickettsia, and only one had a low-level response to typhus group rickettsia. This outbreak represents the first laboratory-confirmed outbreak of scrub typhus in the Western Province of Solomon Islands. The results suggest that rickettsial infections are more common than currently recognized as a cause of an acute febrile illness. A revised clinical case definition for rickettsial infections and treatment guidelines were developed and shared with provincial health staff for better surveillance and response to future outbreaks of a similar kind.

Successfully Managed Acute Transverse Myelitis Related to Scrub Typhus and Serial Image Findings

PubMed Central

Yun, Jae Sung; Song, Ji Soo; Choi, Eun Jung; Hwang, Jeong-Hwan; Lee, Chang-Seop; Park, Eun Hae

2017-01-01

Central nervous system involvement manifesting as meningitis or meningoencephalitis is a known complication of scrub typhus, but very few spinal cord lesions such as acute transverse myelitis (ATM) have been reported in association with this disease. Scrub typhus patients with a spinal lesion present with neurologic symptoms including dysuria, motor, and sensory weakness. Herein, we describe a rare case of ATM associated with scrub typhus. Clinical characteristics, cerebrospinal fluid cytology, Orientia tsutsugamushi serum antibody titer, and serial magnetic resonance imaging scans resulted in a diagnosis of ATM associated with scrub typhus. PMID:28115665

Successfully Managed Acute Transverse Myelitis Related to Scrub Typhus and Serial Image Findings.

PubMed

Yun, Jae Sung; Song, Ji Soo; Choi, Eun Jung; Hwang, Jeong-Hwan; Lee, Chang-Seop; Park, Eun Hae

2017-03-01

AbstractCentral nervous system involvement manifesting as meningitis or meningoencephalitis is a known complication of scrub typhus, but very few spinal cord lesions such as acute transverse myelitis (ATM) have been reported in association with this disease. Scrub typhus patients with a spinal lesion present with neurologic symptoms including dysuria, motor, and sensory weakness. Herein, we describe a rare case of ATM associated with scrub typhus. Clinical characteristics, cerebrospinal fluid cytology, Orientia tsutsugamushi serum antibody titer, and serial magnetic resonance imaging scans resulted in a diagnosis of ATM associated with scrub typhus.

Clinico - Laboratory Profile of Scrub Typhus - An Emerging Rickettsiosis in India.

PubMed

Narayanasamy, Dinesh Kumar; Arunagirinathan, Arul Kumaran; Kumar, Revathi Krishna; Raghavendran, V D

2016-11-01

To study the clinical and laboratory profile of pediatric scrub typhus in rural south India. This is a descriptive study of the clinical and laboratory features of 117 children with IgM ELISA proven scrub typhus out of 448 children, who were admitted in the Pediatric ward of a tertiary care hospital, during the study period of November 2014 through March 2015. Fever was present in all 117 children, with mean duration of fever at admission as 9 d. Gastrointestinal tract was the most commonly affected system, seen in 51 % of children. Cough (82 %), myalgia (70 %), vomiting (68 %), headache (45 %) and pain abdomen (42 %) were the most common symptoms of scrub typhus. Hepatomegaly (70), splenomegaly (53 %), pallor (50 %) and eschar (41 %) were the common clinical findings in children with scrub typhus. Out of 49 children with eschar, 32 were associated with regional lymphadenopathy, which was commonly seen in axillary, neck and groin regions. Leucocytosis (50 %), anemia (56 %), increased SGOT / SGPT (47 %), thrombocytopenia (41 %), hypoalbuminemia (40 %) and hyponatremia (40 %) were the common lab features. Shock (46 %), myocarditis (24 %) and pneumonia (16 %) were the common complications seen in these children. This study showed that early treatment for scrub typhus results in a good outcome in terms of early recovery and nil mortality. Regional lymphadenopathy is a marker of hidden or developing eschar. Total count and differential count should be interpreted on the background of the duration of fever. Since IgM ELISA, which is diagnostic of scrub typhus may not be widely available, any febrile child coming from rural area with hepatosplenomegaly, pallor, eschar, generalised / regional lymphadenopathy, anemia, leucocytosis, thrombocytopenia and increased Aspartate transaminase (AST) /Alanine aminotransferase (ALT) should be started on empirical Doxycycline or Azithromycin in order to prevent life threatening complications secondary to delay in therapy.

A Spatiotemporal Database to Track Human Scrub Typhus Using the VectorMap Application

PubMed Central

Kelly, Daryl J.; Foley, Desmond H.; Richards, Allen L.

2015-01-01

Scrub typhus is a potentially fatal mite-borne febrile illness, primarily of the Asia-Pacific Rim. With an endemic area greater than 13 million km2 and millions of people at risk, scrub typhus remains an underreported, often misdiagnosed febrile illness. A comprehensive, updatable map of the true distribution of cases has been lacking, and therefore the true risk of disease within the very large endemic area remains unknown. The purpose of this study was to establish a database and map to track human scrub typhus. An online search using PubMed and the United States Armed Forces Pest Management Board Literature Retrieval System was performed to identify articles describing human scrub typhus cases both within and outside the traditionally accepted endemic regions. Using World Health Organization guidelines, stringent criteria were used to establish diagnoses for inclusion in the database. The preliminary screening of 181 scrub typhus publications yielded 145 publications that met the case criterion, 267 case records, and 13 serosurvey records that could be georeferenced, describing 13,739 probable or confirmed human cases in 28 countries. A map service has been established within VectorMap (www.vectormap.org) to explore the role that relative location of vectors, hosts, and the pathogen play in the transmission of mite-borne scrub typhus. The online display of scrub typhus cases in VectorMap illustrates their presence and provides an up-to-date geographic distribution of proven scrub typhus cases. PMID:26678263

A Spatiotemporal Database to Track Human Scrub Typhus Using the VectorMap Application.

PubMed

Kelly, Daryl J; Foley, Desmond H; Richards, Allen L

2015-12-01

Scrub typhus is a potentially fatal mite-borne febrile illness, primarily of the Asia-Pacific Rim. With an endemic area greater than 13 million km2 and millions of people at risk, scrub typhus remains an underreported, often misdiagnosed febrile illness. A comprehensive, updatable map of the true distribution of cases has been lacking, and therefore the true risk of disease within the very large endemic area remains unknown. The purpose of this study was to establish a database and map to track human scrub typhus. An online search using PubMed and the United States Armed Forces Pest Management Board Literature Retrieval System was performed to identify articles describing human scrub typhus cases both within and outside the traditionally accepted endemic regions. Using World Health Organization guidelines, stringent criteria were used to establish diagnoses for inclusion in the database. The preliminary screening of 181 scrub typhus publications yielded 145 publications that met the case criterion, 267 case records, and 13 serosurvey records that could be georeferenced, describing 13,739 probable or confirmed human cases in 28 countries. A map service has been established within VectorMap (www.vectormap.org) to explore the role that relative location of vectors, hosts, and the pathogen play in the transmission of mite-borne scrub typhus. The online display of scrub typhus cases in VectorMap illustrates their presence and provides an up-to-date geographic distribution of proven scrub typhus cases.

Status epilepticus in scrub typhus.

PubMed

Kalita, Jayantee; Mani, Vinita E; Bhoi, Sanjeev K; Misra, Usha K

2016-07-01

Scrub typhus is an emerging infection, and there is little information about status epilepticus (SE) in scrub typhus. We report the clinical spectrum and outcome of SE in scrub typhus. In a 3-year prospective hospital-based observational study, all scrub typhus patients with SE were included. Scrub typhus was diagnosed by immunochromatography assay. SE was defined if convulsions lasted longer than 5 min. The patients' demographic, clinical, computed tomography (CT), magnetic resonance imaging (MRI), and electroencephalography (EEG) findings were noted. Response to antiepileptic drugs (AEDs) and outcome at 1 month and 1 year were recorded. Between 2012 and 2014, there were 66 patients with scrub typhus admitted with central nervous system (CNS) involvement, 10 (15.2%) of whom had SE (generalized convulsions in 5, secondary generalized in one). The median age of the patients was 34 (range 18-71) years and seven were female. The duration of SE ranged between 10 min and 48 h. SE responded to one AED in five patients, two AEDs in three patients, and more than two AEDs in two patients. Cranial MRI findings were normal. All patients recovered completely with doxycycline by 1 month and AED was withdrawn by 8 months in all. Although 15% patients with scrub typhus may have SE, they have good outcome. Wiley Periodicals, Inc. © 2016 International League Against Epilepsy.

A comparative study of hepatitis caused by scrub typhus and viral hepatitis A in South Korea.

PubMed

Lee, Jun; Kim, Dong-Min; Yun, Na Ra; Byeon, Yu Mi; Kim, Young Dae; Park, Chan Guk; Kim, Man Woo; Han, Mi Ah

2011-11-01

We compared clinical features and laboratory findings of 104 patients with hepatitis A and 197 patients with scrub typhus. Nausea, vomiting, abdominal pain, hepatomegaly, and jaundice were common in patient with hepatitis A, and fever and headache were significantly more common in patients with scrub typhus. At presentation, an alanine aminotransferase (ALT) level ≥ 500 U/L was observed in 1% of scrub typhus patients and in 87.5% of hepatitis A patients (P < 0.001). A bilirubin level ≥ 1.3 mg/dL was observed in 16.8% of scrub typhus patients and 90.4% of hepatitis A patients. The ALT:lactate dehydrogenase ratio was ≤ 5 in 97.4% of the patients with scrub typhus and > 5 in 95.2% of those with hepatitis A (P < 0.001). Fever, headache, rash, and eschar are findings that indicate scrub typhus. An ALT level ≥ 500 U/L (adjusted odds ratio = 0.011) a bilirubin level ≥ 1.3 (adjusted odds ratio = 0.024), an ALT:lactate dehydrogenase ratio > 5, and hepatomegaly are indications of viral hepatitis A.

A Comparative Study of Hepatitis Caused by Scrub Typhus and Viral Hepatitis A in South Korea

PubMed Central

Lee, Jun; Kim, Dong-Min; Yun, Na Ra; Byeon, Yu Mi; Kim, Young Dae; Park, Chan Guk; Kim, Man Woo; Han, Mi Ah

2011-01-01

We compared clinical features and laboratory findings of 104 patients with hepatitis A and 197 patients with scrub typhus. Nausea, vomiting, abdominal pain, hepatomegaly, and jaundice were common in patient with hepatitis A, and fever and headache were significantly more common in patients with scrub typhus. At presentation, an alanine aminotransferase (ALT) level ≥ 500 U/L was observed in 1% of scrub typhus patients and in 87.5% of hepatitis A patients (P < 0.001). A bilirubin level ≥ 1.3 mg/dL was observed in 16.8% of scrub typhus patients and 90.4% of hepatitis A patients. The ALT:lactate dehydrogenase ratio was ≤ 5 in 97.4% of the patients with scrub typhus and > 5 in 95.2% of those with hepatitis A (P < 0.001). Fever, headache, rash, and eschar are findings that indicate scrub typhus. An ALT level ≥ 500 U/L (adjusted odds ratio = 0.011) a bilirubin level ≥ 1.3 (adjusted odds ratio = 0.024), an ALT:lactate dehydrogenase ratio > 5, and hepatomegaly are indications of viral hepatitis A. PMID:22049041

[The mathematical modelling of the possible morbidity from epidemic louse-borne typhus under current conditions].

PubMed

Lukin, E P; Mikhaĭlov, V V; Oleĭchik, V L; Solodiankin, A I

1996-01-01

On the basis of their earlier formula for modeling the possible development of the epidemic process of louse-borne exanthematous typhus the authors have calculated the probability of the development of such process for high indices (10 -- 12 % of convalescents with louse contamination rate among them reaching 20 -- 40 %) characterizing this process. The number of sources of this infection (primary patients), as well as the rate of increase and scale of louse contamination of the population, are of prime importance for the prognostication of the development of the epidemic.

Seroprevalence of Scrub Typhus, Typhus, and Spotted Fever Among Rural and Urban Populations of Northern Vietnam

PubMed Central

Trung, Nguyen vu; Hoi, Le Thi; Thuong, Nguyen Thi Hong; Toan, Tran Khanh; Huong, Tran Thi Kieu; Hoa, Tran Mai; Fox, Annette; van Kinh, Nguyen; van Doorn, H. Rogier; Wertheim, Heiman F. L.; Bryant, Juliet E.; Nadjm, Behzad

2017-01-01

Rickettsial infections are recognized as important causes of fever throughout southeast Asia. Herein, we determined the seroprevalence to rickettsioses within rural and urban populations of northern Vietnam. Prevalence of individuals with evidence of prior rickettsial infections (IgG positive) was surprisingly low, with 9.14% (83/908) testing positive to the three major rickettsial serogroups thought to circulate in the region. Prevalence of typhus group rickettsiae (TG)–specific antibodies (6.5%, 58/908) was significantly greater than scrub typhus group orientiae (STG)– or spotted fever group rickettsiae (SFG)–specific antibodies (P < 0.05). The majority of TG seropositives were observed among urban rather than rural residents (P < 0.05). In contrast, overall antibody prevalence to STG and SFG were both very low (1.1%, 10/908 for STG; 1.7%, 15/908 for SFG), with no significant differences between rural and urban residents. These results provide data on baseline population characteristics that may help inform development of Rickettsia serological testing criteria in future clinical studies. PMID:28500808

Tsutsugamushi Disease (Scrub Typhus) Meningoencephalitis in North Eastern India: A Prospective Study.

PubMed

Sharma, S R; Masaraf, H; Lynrah, K G; Lyngdoh, M

2015-01-01

Scrub typhus is rampant in northern, eastern, and southern India. Central nervous system involvement in the form of meningitis or meningoencephalitis is common in scrub typhus. As specific laboratory methods remain inadequate or inaccessible in developing countries, prompt diagnosis is often difficult. The aim of this study was to characterize neurological complications in scrub typhus from northeastern region of India. We did a prospective study of scrub meningoencephalitis at North Eastern Indira Gandhi Regional Institute of Medical Sciences among patients admitted to hospital between October 2009 and November 2011. The diagnosis was made based on the clinical pictures, presence of an eschar, and a positive Weil-Felix test (WFT) with a titer of >1:160 and if required a positive scrub IgM enzyme-linked immunosorbent assay. Lumbar puncture was performed in patients with headache, nuchal rigidity, altered sensorium or cranial nerve deficits, and magnetic resonance imaging (MRI) brain performed if needed. Twenty-three patients of scrub typhus meningitis that were serologically confirmed were included in the study. There were 13 males and 10 females. Fever ≥1 week was the most common manifestation (39.1%). Interestingly, none had an eschar. Median cerebrospinal fluid (CSF) cell count, lymphocyte percentage, CSF protein, CSF glucose/blood glucose, CSF ADA were 17 cells/μL, 90%, 86 mg/dL, 0.6605 and 3.6 U/mL, respectively. All patients were treated with doxycycline. There was no mortality in our study. Absence of Eschar does not rule out scrub typhus. Clinical features and CSF findings can mimic tuberculous meningitis so misdiagnosis may lead to unwarranted prolonged empirical antituberculous therapy in cases of lymphocytic meningoencephalitis. Delay in treatment can be potentially fatal. WFT still serves as a useful and affordable diagnostic tool for this disease in resource-poor countries.

Immune thrombocytopenia with multi-organ dysfunction syndrome as a rare presentation of scrub typhus: a case report.

PubMed

Ittyachen, Abraham M; Abraham, Saramma P; Krishnamoorthy, Smitha; Vijayan, Anuroopa; Kokkat, Jayamohan

2017-10-06

Scrub typhus is an acute infectious illness caused by Orientia tsutsugamushi. It is endemic to a part of the world known as the "tsutsugamushi triangle". Humans are accidental hosts in this zoonotic disease. About a third of patients admitted with scrub typhus have evidence of multi-organ dysfunction. Multi-organ dysfunction secondary to scrub typhus carries a high mortality rate. We report a 65-year old lady who was admitted in a Tertiary Care Center in the state of Kerala in India, with 7 day history of fever, myalgia and reduced urine output. Head to foot examination revealed the presence of an eschar on her chest. One week prior to the onset of her illness she had gone trekking through a hilly forest area. She was clinically suspected to have scrub typhus, which was later confirmed with laboratory tests. She developed multi-organ dysfunction syndrome secondary to this illness. Though there was an improvement in the multi-organ dysfunction, thrombocytopenia alone failed to improve. Bone marrow study was done which was suggestive of immune thrombocytopenia. Patient was given a course of steroids with which the thrombocytopenia improved. Failure of platelet count to normalize even after there has been a general improvement of other markers of multi-organ dysfunction in scrub typhus should prompt the clinician to consider other potential causes of thrombocytopenia. An unusual finding as this calls for further research to understand the molecular mechanisms behind such an event. Further, considering the close similarity in clinical presentation of several tropical illnesses, meticulous history taking and a detailed physical examination needs to be emphasized.

Bayesian spatial modelling and the significance of agricultural land use to scrub typhus infection in Taiwan.

PubMed

Wardrop, Nicola A; Kuo, Chi-Chien; Wang, Hsi-Chieh; Clements, Archie C A; Lee, Pei-Fen; Atkinson, Peter M

2013-11-01

Scrub typhus is transmitted by the larval stage of trombiculid mites. Environmental factors, including land cover and land use, are known to influence breeding and survival of trombiculid mites and, thus, also the spatial heterogeneity of scrub typhus risk. Here, a spatially autoregressive modelling framework was applied to scrub typhus incidence data from Taiwan, covering the period 2003 to 2011, to provide increased understanding of the spatial pattern of scrub typhus risk and the environmental and socioeconomic factors contributing to this pattern. A clear spatial pattern in scrub typhus incidence was observed within Taiwan, and incidence was found to be significantly correlated with several land cover classes, temperature, elevation, normalized difference vegetation index, rainfall, population density, average income and the proportion of the population that work in agriculture. The final multivariate regression model included statistically significant correlations between scrub typhus incidence and average income (negatively correlated), the proportion of land that contained mosaics of cropland and vegetation (positively correlated) and elevation (positively correlated). These results highlight the importance of land cover on scrub typhus incidence: mosaics of cropland and vegetation represent a transitional land cover type which can provide favourable habitats for rodents and, therefore, trombiculid mites. In Taiwan, these transitional land cover areas tend to occur in less populated and mountainous areas, following the frontier establishment and subsequent partial abandonment of agricultural cultivation, due to demographic and socioeconomic changes. Future land use policy decision-making should ensure that potential public health outcomes, such as modified risk of scrub typhus, are considered.

Typhus fever: an overlooked diagnosis.

PubMed

Mazumder, Ramendra N; Pietroni, Mark A C; Mosabbir, Nadira; Salam, M A

2009-06-01

A case of typhus fever is presented. On admission, the clinical diagnosis was typhoid fever. Forty-eight hours after admission, the presence of subconjunctival haemorrhage, malena, and jaundice raised the possibility of a different aetiology, the two most likely differentials being dengue and typhus. Finally, a co-infection of typhoid and typhus was discovered. This uncommon clinical scenario should be taken into account in the management of patients with high fever on admission being treated as a case of typhoid fever.

ACUTE CHOLECYSTITIS AS AN UNUSUAL PRESENTATION OF SCRUB TYPHUS: A REPORT OF TWO CASES AND REVIEW OF THE LITERATURE.

PubMed

Charoenphak, Sirima; Rattanawong, Pattara; Sungkanuparph, Somnuek

2017-01-01

Scrub typhus rarely presents with acute cholecystitis. We present 2 cases of scrub typhus with cholecystitis. The first patient is a 62 year old female who presented to the hospital with fever and body aches for 1 week and right upper quadrant abdominal pain for 3 days. She gave a history of an insect bite 2 weeks previously. She was diagnosed as having acute cholecystitis and underwent cholecystectomy. She continued with fever post-operatively and physical examination revealed an eschar. She had an immunofluorescence assay (IFA) performed that revealed a high IgM titer for Orientia tsutsugamushi. She was diagnosed as having scrub typhus, treated with doxycycline and she recovered completely. The second patient also presented to the hospital with a 1 week history of fever and upper quadrant abdominal pain. She was diagnosed with having cholecystitis. Her symptoms did not improve with intravenous antibiotics and further investigation revealed elevated titers for O. tsutsugamushi and Leptospira interrogans. She was diagnosed as having a co-infection of scrub typhus and leptospirosis and treated with doxycycline. She recovered completely. Patients from scrub typhus endemic regions who present with acute cholecystitis but do not respond to traditional treatment should be tested for scrub typhus and leptospirosis and should have a careful admission physical examination looking for eschar formation, since scrub typhus may present with acute cholecystitis.

Estimating the burden of scrub typhus: A systematic review.

PubMed

Bonell, Ana; Lubell, Yoel; Newton, Paul N; Crump, John A; Paris, Daniel H

2017-09-01

Scrub typhus is a vector-borne zoonotic disease that can be life-threatening. There are no licensed vaccines, or vector control efforts in place. Despite increasing awareness in endemic regions, the public health burden and global distribution of scrub typhus remains poorly known. We systematically reviewed all literature from public health records, fever studies and reports available on the Ovid MEDLINE, Embase Classic + Embase and EconLit databases, to estimate the burden of scrub typhus since the year 2000. In prospective fever studies from Asia, scrub typhus is a leading cause of treatable non-malarial febrile illness. Sero-epidemiological data also suggest that Orientia tsutsugamushi infection is common across Asia, with seroprevalence ranging from 9.3%-27.9% (median 22.2% IQR 18.6-25.7). A substantial apparent rise in minimum disease incidence (median 4.6/100,000/10 years, highest in China with 11.2/100,000/10 years) was reported through passive national surveillance systems in South Korea, Japan, China, and Thailand. Case fatality risks from areas of reduced drug-susceptibility are reported at 12.2% and 13.6% for South India and northern Thailand, respectively. Mortality reports vary widely around a median mortality of 6.0% for untreated and 1.4% for treated scrub typhus. Limited evidence suggests high mortality in complicated scrub typhus with CNS involvement (13.6% mortality), multi-organ dysfunction (24.1%) and high pregnancy miscarriage rates with poor neonatal outcomes. Scrub typhus appears to be a truly neglected tropical disease mainly affecting rural populations, but increasingly also metropolitan areas. Rising minimum incidence rates have been reported over the past 8-10 years from countries with an established surveillance system. A wider distribution of scrub typhus beyond Asia is likely, based on reports from South America and Africa. Unfortunately, the quality and quantity of the available data on scrub typhus epidemiology is currently too limited for any economical, mathematical modeling or mapping approaches.

Characteristics of scrub typhus, murine typhus, and Q fever among elderly patients: Prolonged prothrombin time as a predictor for severity.

PubMed

Chang, Ko; Lee, Nan-Yao; Ko, Wen-Chien; Lin, Wei-Ru; Chen, Yen-Hsu; Tsai, Jih-Jin; Chen, Tun-Chieh; Lin, Chun-Yu; Chang, Ya-Ting; Lu, Po-Liang

2017-06-22

The clinical manifestations of scrub typhus, murine typhus and acute Q fever in the elderly are not clear. We conducted a retrospective study to identify the characteristics of the elderly aged ≥65 years with a comparison group aged 18-64 years among patients with scrub typhus, murine typhus, or acute Q fever who were serologically confirmed at three hospitals in Taiwan during 2002-2011. Among 441 cases, including 187 cases of scrub typhus, 166 acute Q fever, and 88 murine typhus, 68 (15.4%) cases were elderly patients. The elderly had a higher severe complication rate (10.3% vs. 3.5%, p = 0.022), but did not have a significantly higher mortality rate (1.47% vs. 0.54%, p = 0.396). Compared with those without severe complications, we found the elderly (p = 0.022), dyspnea (p = 0.006), less relative bradycardia (p = 0.004), less febrile illness (p = 0.004), prolonged prothrombin time (PT) (p = 0.002), higher levels of initial C-reactive protein (p = 0.039), blood leukocyte counts (p = 0.01), and lower platelet counts (p = 0.012) are significantly associated with severe complications. Only prolonged prothrombin time was associated with severe complications in multivariate analysis (p = 0.018, CI 95% 0.01-0.66). Among clinical symptoms and laboratory data, multivariate analysis revealed chills was less frequently occurred in the elderly (p = 0.012, 95% confidence interval [CI]: 1.33-9.99). The elderly cases with scrub typhus, murine typhus, or acute Q fever would be more likely to have severe complications, for which prothrombin time prolongation is an important predictor for severe complications. Copyright © 2017. Published by Elsevier B.V.

Estimating the burden of scrub typhus: A systematic review

PubMed Central

Bonell, Ana; Lubell, Yoel; Newton, Paul N.; Crump, John A.

2017-01-01

Background Scrub typhus is a vector-borne zoonotic disease that can be life-threatening. There are no licensed vaccines, or vector control efforts in place. Despite increasing awareness in endemic regions, the public health burden and global distribution of scrub typhus remains poorly known. Methods We systematically reviewed all literature from public health records, fever studies and reports available on the Ovid MEDLINE, Embase Classic + Embase and EconLit databases, to estimate the burden of scrub typhus since the year 2000. Findings In prospective fever studies from Asia, scrub typhus is a leading cause of treatable non-malarial febrile illness. Sero-epidemiological data also suggest that Orientia tsutsugamushi infection is common across Asia, with seroprevalence ranging from 9.3%–27.9% (median 22.2% IQR 18.6–25.7). A substantial apparent rise in minimum disease incidence (median 4.6/100,000/10 years, highest in China with 11.2/100,000/10 years) was reported through passive national surveillance systems in South Korea, Japan, China, and Thailand. Case fatality risks from areas of reduced drug-susceptibility are reported at 12.2% and 13.6% for South India and northern Thailand, respectively. Mortality reports vary widely around a median mortality of 6.0% for untreated and 1.4% for treated scrub typhus. Limited evidence suggests high mortality in complicated scrub typhus with CNS involvement (13.6% mortality), multi-organ dysfunction (24.1%) and high pregnancy miscarriage rates with poor neonatal outcomes. Interpretation Scrub typhus appears to be a truly neglected tropical disease mainly affecting rural populations, but increasingly also metropolitan areas. Rising minimum incidence rates have been reported over the past 8–10 years from countries with an established surveillance system. A wider distribution of scrub typhus beyond Asia is likely, based on reports from South America and Africa. Unfortunately, the quality and quantity of the available data on scrub typhus epidemiology is currently too limited for any economical, mathematical modeling or mapping approaches. PMID:28945755

Co-infection of scrub typhus and leptospirosis in patients with pyrexia of unknown origin in Longding district of Arunachal Pradesh in 2013.

PubMed

Borkakoty, Biswajyoti; Jakharia, Aniruddha; Biswas, Dipankar; Mahanta, Jagadish

2016-01-01

Scrub typhus and leptospirosis are bacterial zoonotic disease causing high morbidity and mortality. The seasonal outbreak of pyrexia is common in Arunachal Pradesh (AP); many times the disease remains undiagnosed. An outbreak of pyrexia of unknown origin (PUO) occurred in Longding district of Arunachal Pradesh in 2013, with 108 deaths, which was investigated to elucidate the cause of illness. Blood samples from the affected region with acute pyrexia were collected, and screened for the malaria parasite, scrub typhus IgM and leptospira IgM. Scrub typhus IgM was reactive in 97% (30/31), and 25% (8/31) cases were co-infected with leptospira. Incidentally, scrub typhus reactive (67%) and leptospira co-infection (62.7%) were higher in females. Record of previous 3 years (2011-2013) from Longding, Community Health Centre showed an increase in indoor pyrexia cases by 2-fold or more during October and November. The present study is the first report of co-infection of scrub typhus with leptospirosis from Northeast India. Medical officers in this region should take scrub typhus and leptospirosis in their differential diagnosis of patients with PUO for early diagnosis and effective treatment.

Meteorological factors affecting scrub typhus occurrence: a retrospective study of Yamagata Prefecture, Japan, 1984-2014.

PubMed

Seto, J; Suzuki, Y; Nakao, R; Otani, K; Yahagi, K; Mizuta, K

2017-02-01

Climate change, by its influence on the ecology of vectors might affect the occurrence of vector-borne diseases. This study examines the effects of meteorological factors in Japan on the occurrence of scrub typhus, a mite-borne zoonosis caused by Orientia tsutsugamushi. Using negative binomial regression, we analysed the relationships between meteorological factors (including temperature, rainfall, snowfall) and spring-early summer cases of scrub typhus in Yamagata Prefecture, Japan, during 1984-2014. The average temperature in July and August of the previous year, cumulative rainfall in September of the previous year, snowfall throughout the winter, and maximum depth of snow cover in January and February were positively correlated with the number of scrub typhus cases. By contrast, cumulative rainfall in July of the previous year showed a negative relationship to the number of cases. These associations can be explained by the life-cycle of Leptotrombidium pallidum, a predominant vector of spring-early summer cases of scrub typhus in northern Japan. Our findings show that several meteorological factors are useful to estimate the number of scrub typhus cases before the endemic period. They are applicable to establish an early warning system for scrub typhus in northern Japan.

Increased level and interferon-γ production of circulating natural killer cells in patients with scrub typhus.

PubMed

Kang, Seung-Ji; Jin, Hye-Mi; Cho, Young-Nan; Kim, Seong Eun; Kim, Uh Jin; Park, Kyung-Hwa; Jang, Hee-Chang; Jung, Sook-In; Kee, Seung-Jung; Park, Yong-Wook

2017-07-01

Natural killer (NK) cells are essential immune cells against several pathogens. Not much is known regarding the roll of NK cells in Orientia tsutsugamushi infection. Thus, this study aims to determine the level, function, and clinical relevance of NK cells in patients with scrub typhus. This study enrolled fifty-six scrub typhus patients and 56 health controls (HCs). The patients were divided into subgroups according to their disease severity. A flow cytometry measured NK cell level and function in peripheral blood. Circulating NK cell levels and CD69 expressions were significantly increased in scrub typhus patients. Increased NK cell levels reflected disease severity. In scrub typhus patients, tests showed their NK cells produced higher amounts of interferon (IFN)-γ after stimulation with interleukin (IL)-12 and IL-18 relative to those of HCs. Meanwhile, between scrub typhus patients and HCs, the cytotoxicity and degranulation of NK cells against K562 were comparable. CD69 expressions were recovered to the normal levels in the remission phase. This study shows that circulating NK cells are activated and numerically increased, and they produced more IFN-γ in scrub typhus patients.

Increased level and interferon-γ production of circulating natural killer cells in patients with scrub typhus

PubMed Central

Cho, Young-Nan; Kim, Seong Eun; Kim, Uh Jin; Park, Kyung-Hwa; Jang, Hee-Chang; Jung, Sook-In; Kee, Seung-Jung

2017-01-01

Background Natural killer (NK) cells are essential immune cells against several pathogens. Not much is known regarding the roll of NK cells in Orientia tsutsugamushi infection. Thus, this study aims to determine the level, function, and clinical relevance of NK cells in patients with scrub typhus. Methodology/Principal findings This study enrolled fifty-six scrub typhus patients and 56 health controls (HCs). The patients were divided into subgroups according to their disease severity. A flow cytometry measured NK cell level and function in peripheral blood. Circulating NK cell levels and CD69 expressions were significantly increased in scrub typhus patients. Increased NK cell levels reflected disease severity. In scrub typhus patients, tests showed their NK cells produced higher amounts of interferon (IFN)-γ after stimulation with interleukin (IL)-12 and IL-18 relative to those of HCs. Meanwhile, between scrub typhus patients and HCs, the cytotoxicity and degranulation of NK cells against K562 were comparable. CD69 expressions were recovered to the normal levels in the remission phase. Conclusions This study shows that circulating NK cells are activated and numerically increased, and they produced more IFN-γ in scrub typhus patients. PMID:28750012

Rapid Increase in Scrub Typhus Incidence in Mainland China, 2006-2014.

PubMed

Wu, Yi-Cheng; Qian, Quan; Magalhaes, Ricardo J Soares; Han, Zhi-Hai; Haque, Ubydul; Weppelmann, Thomas A; Hu, Wen-Biao; Liu, Yun-Xi; Sun, Yan-Song; Zhang, Wen-Yi; Li, Shen-Long

2016-03-01

Scrub typhus is a vector-borne disease, which has recently reemerged in China. In this study, we describe the distribution and incidence of scrub typhus cases in China from 2006 to 2014 and quantify differences in scrub typhus cases with respect to sex, age, and occupation. The results of our study indicate that the annual incidence of scrub typhus has increased during the study period. The number of cases peaked in 2014, which was 12.8 times greater than the number of cases reported in 2006. Most (77.97%) of the cases were reported in five provinces (Guangdong, Yunnan, Anhui, Fujian, and Shandong). Our study also demonstrates that the incidence rate of scrub typhus was significantly higher in females compared to males (P < 0.001) and was highest in the 60-69 year age group, and that farmers had a higher incidence rate than nonfarmers (P < 0.001). Different seasonal trends were identified in the number of reported cases between the northern and southern provinces of China. These findings not only demonstrate that China has experienced a large increase in scrub typhus incidence, but also document an expansion in the geographic distribution throughout the country. © The American Society of Tropical Medicine and Hygiene.

Scrub typhus as a possible aetiology of Guillain-Barré syndrome: two cases.

PubMed

Lee, M-S; Lee, J-H; Lee, H-S; Chang, H; Kim, Y-S; Cho, K-H; Ahn, S-H; Song, J-H; Yoo, M; Han, J-K; Park, H-Y

2009-09-01

Neurological complications of scrub typhus are reported to be rare. Peripheral nervous system involvement has been reported in only one case. We present two cases of Guillan-Barré syndrome (GBS) associated with scrub typhus. In both cases, the findings of an elevated indirect immunofluorescent antibody titer for Orientia tsutsugamushi and nerve conduction study showing sensory-motor polyneuropathy, have led us to believe that scrub typhus could be one of the antecedent illnesses associated with GBS.

Typhus Fever: An Overlooked Diagnosis

PubMed Central

Mazumder, Ramendra N.; Mosabbir, Nadira; Salam, M.A.

2009-01-01

A case of typhus fever is presented. On admission, the clinical diagnosis was typhoid fever. Forty-eight hours after admission, the presence of subconjunctival haemorrhage, malena, and jaundice raised the possibility of a different aetiology, the two most likely differentials being dengue and typhus. Finally, a co-infection of typhoid and typhus was discovered. This uncommon clinical scenario should be taken into account in the management of patients with high fever on admission being treated as a case of typhoid fever. PMID:19507758

Activation of the coagulation cascade in patients with scrub typhus.

PubMed

Lee, Hee-Jeong; Park, Chi-Young; Park, Sang-Gon; Yoon, Na-Ra; Kim, Dong-Min; Chung, Choon-Hae

2017-09-01

This retrospective study aimed to evaluate the levels of coagulation factors and presence of disseminated intravascular coagulation (DIC) in patients with scrub typhus. We included patients confirmed to have scrub typhus at the Chosun University Hospital between September 2004 and December 2009. The DIC scores were evaluated in 365 patients and 36 healthy controls. The median concentrations of fibrinogen, d-dimer, and fibrin/fibrinogen degradation products (FDP) were compared between patients and healthy controls (p<0.001 for all tests). Patients with scrub typhus had longer prothrombin time and lower platelet counts than the controls. Major bleeding was observed in 18/365 patients with scrub typhus. Fifty-one (14.0%) patients presented with severe complications of scrub typhus. Overt DIC and thrombocytopenia (<100,000 platelets/mm 3 ) were observed more frequently in patients with bleeding and severe illness. Furthermore, median platelet counts were low in both groups. Approximately 2.7% (n=10) and 16.4% (n=60) patients with scrub typhus had overt DIC, as defined by the International Society on Thrombosis and Hemostasis DIC score (DIC1) and the DIC-scoring template with a fibrinogen/C-reactive protein-ratio (DIC2), respectively. Three (16.7%) and 10 (55.6%) patients with bleeding had overt DIC, as defined by the DIC1 and DIC2, respectively. Seven (13.7%) and 26 (51%) patients with severe illness had overt DIC, as defined by DIC1 and DIC2, respectively. In conclusion, activation of the coagulation system is an important feature of scrub typhus and is correlated with severe disease, including bleeding. This is the first study to report a relationship between DIC and scrub typhus. Copyright © 2017 Elsevier Inc. All rights reserved.

Identification of factors for physicians to facilitate early differential diagnosis of scrub typhus, murine typhus, and Q fever from dengue fever in Taiwan.

PubMed

Chang, Ko; Lee, Nan-Yao; Ko, Wen-Chien; Tsai, Jih-Jin; Lin, Wei-Ru; Chen, Tun-Chieh; Lu, Po-Liang; Chen, Yen-Hsu

2017-02-01

Dengue fever, rickettsial diseases, and Q fever are acute febrile illnesses with similar manifestations in tropical areas. Early differential diagnosis of scrub typhus, murine typhus, and Q fever from dengue fever may be made by understanding the distinguishing clinical characteristics and the significance of demographic and weather factors. We conducted a retrospective study to identify clinical, demographic, and meteorological characteristics of 454 dengue fever, 178 scrub typhus, 143 Q fever, and 81 murine typhus cases in three Taiwan hospitals. Case numbers of murine typhus and Q fever correlated significantly with temperature and rainfall; the scrub typhus case number was only significantly related with temperature. Neither temperature nor rainfall correlated with the case number of dengue fever. The rarity of dengue fever cases from January to June in Taiwan may be a helpful clue for diagnosis in the area. A male predominance was observed, as the male-to-female rate was 2.1 for murine typhus and 7.4 for Q fever. Multivariate analysis revealed the following six important factors for differentiating the rickettsial diseases and Q fever group from the dengue fever group: fever ≥8 days, alanine aminotransferase > aspartate aminotransferase, platelets >63,000/mL, C-reactive protein >31.9 mg/L, absence of bone pain, and absence of a bleeding syndrome. Understanding the rarity of dengue in the first half of a year in Taiwan and the six differentiating factors may help facilitate the early differential diagnosis of rickettsial diseases and Q fever from dengue fever, permitting early antibiotic treatment. Copyright © 2015. Published by Elsevier B.V.

Rickettsial Illnesses as Important Causes of Febrile Illness in Chittagong, Bangladesh

PubMed Central

Kingston, Hugh W.; Hossain, Mosharraf; Leopold, Stije; Anantatat, Tippawan; Tanganuchitcharnchai, Ampai; Sinha, Ipsita; Plewes, Katherine; Maude, Richard J.; Chowdhury, M.A. Hassan; Paul, Sujat; Uddin, Rabiul Alam Mohammed Erfan; Siddiqui, Mohammed Abu Naser; Zahed, Abu Shahed; Abu Sayeed, Abdullah; Rahman, Mohammed Habibur; Barua, Anupam; Uddin, Mohammed Jasim; Sattar, Mohammed Abdus; Dondorp, Arjen M.; Blacksell, Stuart D.; Day, Nicholas P.J.; Ghose, Aniruddha; Hossain, Amir

2018-01-01

We conducted a yearlong prospective study of febrile patients admitted to a tertiary referral hospital in Chittagong, Bangladesh, to assess the proportion of patients with rickettsial illnesses and identify the causative pathogens, strain genotypes, and associated seasonality patterns. We diagnosed scrub typhus in 16.8% (70/416) and murine typhus in 5.8% (24/416) of patients; 2 patients had infections attributable to undifferentiated Rickettsia spp. and 2 had DNA sequence–confirmed R. felis infection. Orientia tsutsugamushi genotypes included Karp, Gilliam, Kato, and TA763-like strains, with a prominence of Karp-like strains. Scrub typhus admissions peaked in a biphasic pattern before and after the rainy season, whereas murine typhus more frequently occurred before the rainy season. Death occurred in 4% (18/416) of cases; case-fatality rates were 4% each for scrub typhus (3/70) and murine typhus (1/28). Overall, 23.1% (96/416) of patients had evidence of treatable rickettsial illnesses, providing important evidence toward optimizing empirical treatment strategies. PMID:29553921

Clinical Evaluation of Rapid Diagnostic Test Kit for Scrub Typhus with Improved Performance.

PubMed

Kim, Young-Jin; Park, Sungman; Premaratna, Ranjan; Selvaraj, Stephen; Park, Sang-Jin; Kim, Sora; Kim, Donghwan; Kim, Min Soo; Shin, Dong Hoon; Choi, Kyung-Chan; Kwon, Soon-Hwan; Seo, Wonjun; Lee, Nam Taek; Kim, Seung-Han; Kang, Heui Keun; Kim, Yoon-Won

2016-08-01

Diagnosis of scrub typhus is challenging due to its more than twenty serotypes and the similar clinical symptoms with other acute febrile illnesses including leptospirosis, murine typhus and hemorrhagic fever with renal syndrome. Accuracy and rapidity of a diagnostic test to Orientia tsutsugamushi is an important step to diagnose this disease. To discriminate scrub typhus from other diseases, the improved ImmuneMed Scrub Typhus Rapid Diagnostic Test (RDT) was evaluated in Korea and Sri Lanka. The sensitivity at the base of each IgM and IgG indirect immunofluorescent assay (IFA) in Korean patients was 98.6% and 97.1%, and the specificity was 98.2% and 97.7% respectively. The sensitivity and specificity for retrospective diagnosis at the base of IFA in Sri Lanka was 92.1% and 96.1%. ImmuneMed RDT was not reactive to any serum from seventeen diseases including hemorrhagic fever with renal syndrome (n = 48), leptospirosis (n = 23), and murine typhus (n = 48). ImmuneMed RDT shows superior sensitivity (98.6% and 97.1%) compared with SD Bioline RDT (84.4% at IgM and 83.3% at IgG) in Korea. The retrospective diagnosis of ImmuneMed RDT exhibits 94.0% identity with enzyme-linked Immunosorbent assay (ELISA) using South India patient serum samples. These results suggest that this RDT can replace other diagnostic tests and is applicable for global diagnosis of scrub typhus. This rapid and accurate diagnosis will be beneficial for diagnosing and managing scrub typhus.

Predictors of Severity in Pediatric Scrub Typhus.

PubMed

Narayanasamy, Dinesh Kumar; Arun Babu, Thirunavukkarasu; Vijayadevagaran, Vijayasankar; Kittu, Devi; Ananthakrishnan, Shanthi

2018-01-24

To identify the factors that can predict the severity of scrub typhus in children. This prospective study was conducted at a tertiary care teaching hospital between November 2014 to October 2016. All children <12y of age admitted with fever for more than 7d and positive IgM ELISA for scrub typhus were included in the study. These children were followed during the hospital course and their laboratory results, response to treatment and complications were documented. Cases of 'severe scrub typhus' were identified based on criteria from published adult and pediatric studies. Out of 930 children with fever for more than 7d, IgM ELISA for scrub typhus was positive in 230 children. Ninety one (40.6%) cases fulfilled the criteria of 'severe scrub typhus' in children. Out of 45 factors, 27 potential factors were studied. The multivariate analysis identified 5 factors, breathlessness (OR: 6.85, 95%CI: 2.69 to 9.87), altered sensorium (OR: 11.48, 95% CI 3.43 to 10.19), leucocytosis (OR: 3.38, 95% CI 1.12 to 10.16), hypoalbuminemia (OR: 10.78, 95% CI 2.66 to 48.76), and hyponatremia (OR: 10.08, 95% CI 2.11 to 23.42) to be significantly associated with the 'severe scrub typhus' cases. Breathlessness, altered sensorium, leucocytosis, hypoalbuminemia, and hyponatremia predict severity in childhood scrub typhus. Presence of these factors should alert the treating physician regarding the need for intensive monitoring, treatment or referral.

Diagnostic accuracy of a loop-mediated isothermal PCR assay for detection of Orientia tsutsugamushi during acute Scrub Typhus infection.

PubMed

Paris, Daniel H; Blacksell, Stuart D; Nawtaisong, Pruksa; Jenjaroen, Kemajittra; Teeraratkul, Achara; Chierakul, Wirongrong; Wuthiekanun, Vanaporn; Kantipong, Pacharee; Day, Nicholas P J

2011-09-01

There is an urgent need to develop rapid and accurate point-of-care (POC) technologies for acute scrub typhus diagnosis in low-resource, primary health care settings to guide clinical therapy. In this study we present the clinical evaluation of loop-mediated isothermal PCR assay (LAMP) in the context of a prospective fever study, including 161 patients from scrub typhus-endemic Chiang Rai, northern Thailand. A robust reference comparator set comprising following 'scrub typhus infection criteria' (STIC) was used: a) positive cell culture isolate and/or b) an admission IgM titer ≥1∶12,800 using the 'gold standard' indirect immunofluorescence assay (IFA) and/or c) a 4-fold rising IFA IgM titer and/or d) a positive result in at least two out of three PCR assays. Compared to the STIC criteria, all PCR assays (including LAMP) demonstrated high specificity ranging from 96-99%, with sensitivities varying from 40% to 56%, similar to the antibody based rapid test, which had a sensitivity of 47% and a specificity of 95%. The diagnostic accuracy of the LAMP assay was similar to realtime and nested conventional PCR assays, but superior to the antibody-based rapid test in the early disease course. The combination of DNA- and antibody-based detection methods increased sensitivity with minimal reduction of specificity, and expanded the timeframe of adequate diagnostic coverage throughout the acute phase of scrub typhus.

Reemerging threat of epidemic typhus in Algeria.

PubMed

Mokrani, K; Fournier, P E; Dalichaouche, M; Tebbal, S; Aouati, A; Raoult, D

2004-08-01

We report a case of epidemic typhus in a patient from the Batna region of Algeria, who presented with generalized febrile exanthema. The clinical diagnosis was confirmed by serological cross-adsorption followed by Western blotting. Our report emphasizes the threat of epidemic typhus in the highlands of Algeria.

Murine Typhus, Reunion, France, 2011–2013

PubMed Central

Camuset, Guillaume; Socolovschi, Cristina; Moiton, Marie-Pierre; Kuli, Barbara; Foucher, Aurélie; Poubeau, Patrice; Borgherini, Gianandrea; Wartel, Guillaume; Audin, Héla; Raoult, Didier; Filleul, Laurent; Parola, Philippe; Pagès, Fréderic

2015-01-01

Murine typhus case was initially identified in Reunion, France, in 2012 in a tourist. Our investigation confirmed 8 autochthonous cases that occurred during January 2011–January 2013 in Reunion. Murine typhus should be considered in local patients and in travelers returning from Reunion who have fevers of unknown origin. PMID:25625653

Scrub typhus in the northern provinces of Vietnam: an observational study of admissions to a national referral hospital.

PubMed

Nadjm, Behzad; Thuy, Pham T; Trang, Van D; Ha, Le Dang; Kinh, Nguyen V; Wertheim, Heiman F

2014-11-01

Scrub typhus is a common cause of fever in parts of South East and Southern Asia. Little is known about the disease burden in Vietnam. A 2-year observational study of scrub typhus at a tertiary referral hospital in northern Vietnam was carried out. Diagnosis was based on a single serological test in patients with suggestive clinical symptoms. Scrub typhus was diagnosed in 3.5% (251/7226) of admissions. Cases occurred throughout the year, with incidence highest in the summer. Although complications were common, mortality was low (1.2%; 3/251). These data suggest that scrub typhus is common, with a seasonal distribution in northern Vietnam. © The Author 2014. Published by Oxford University Press on behalf of Royal Society of Tropical Medicine and Hygiene.

A review of the global epidemiology of scrub typhus.

PubMed

Xu, Guang; Walker, David H; Jupiter, Daniel; Melby, Peter C; Arcari, Christine M

2017-11-01

Scrub typhus is a serious public health problem in the Asia-Pacific area. It threatens one billion people globally, and causes illness in one million people each year. Caused by Orientia tsutsugamushi, scrub typhus can result in severe multiorgan failure with a case fatality rate up to 70% without appropriate treatment. The antigenic heterogeneity of O. tsutsugamushi precludes generic immunity and allows reinfection. As a neglected disease, there is still a large gap in our knowledge of the disease, as evidenced by the sporadic epidemiologic data and other related public health information regarding scrub typhus in its endemic areas. Our objective is to provide a systematic analysis of current epidemiology, prevention and control of scrub typhus in its long-standing endemic areas and recently recognized foci of infection.

A review of the global epidemiology of scrub typhus

PubMed Central

Xu, Guang; Jupiter, Daniel; Melby, Peter C.; Arcari, Christine M.

2017-01-01

Scrub typhus is a serious public health problem in the Asia-Pacific area. It threatens one billion people globally, and causes illness in one million people each year. Caused by Orientia tsutsugamushi, scrub typhus can result in severe multiorgan failure with a case fatality rate up to 70% without appropriate treatment. The antigenic heterogeneity of O. tsutsugamushi precludes generic immunity and allows reinfection. As a neglected disease, there is still a large gap in our knowledge of the disease, as evidenced by the sporadic epidemiologic data and other related public health information regarding scrub typhus in its endemic areas. Our objective is to provide a systematic analysis of current epidemiology, prevention and control of scrub typhus in its long-standing endemic areas and recently recognized foci of infection. PMID:29099844

Comparison of Scrub Typhus Meningitis with Acute Bacterial Meningitis and Tuberculous Meningitis.

PubMed

Kakarlapudi, Svas Raju; Chacko, Anila; Samuel, Prasanna; Verghese, Valsan Philip; Rose, Winsley

2018-01-15

To compare scrub typhus meningitis with bacterial and tuberculous meningitis. Children aged <15 years admitted with meningitis were screened and those who fit criteria for diagnosis of scrub typhus meningitis (n=48), bacterial meningitis (n=44) and tuberculous meningitis (n=31) were included for analysis. Clinical features, investigations and outcomes were compared between the three types of meningitis. Mean age, duration of fever at presentation, presence of headache and, altered sensorium and presence of hepatomegaly/splenomegaly were statistically significantly different between the groups. Scrub typhus had statistically significant thrombocytopenia, shorter hospital stay and a better neurological and mortality outcome. Sub-acute presentation of meningitis in older age group children, and good outcome is associated with scrub typhus when compared to bacterial and tuberculous meningitis.

Epidemiology of scrub typhus and the eschars patterns in South Korea from 2008 to 2012.

PubMed

Park, Ji-Hyuk; Kim, Sun-Ja; Youn, Seung-Ki; Park, Kisoo; Gwack, Jin

2014-01-01

In South Korea, scrub typhus is the most common acute febrile illness in autumn. We analyzed scrub typhus cases reported from 2008 to 2012 to describe the epidemiology of scrub typhus as well as eschar patterns. A total of 30,478 cases were reported from 2008 to 2012; the incidence rates were higher in the southern and western regions of South Korea. The common clinical symptoms of confirmed scrub typhus cases from 2010 to 2012 were fever/chills (95.2%), eschars (78.9%), and myalgia (61.7%). The primary sites of eschars were the lower extremities (19.0%), abdomen/waist (13.4%), and axilla (11.5%) in men and the shoulder/frontal chest (15.1%), lower extremities (14.5%), and abdomen/waist (13.6%) in women. Regardless of gender, eschars tended to be more on the lower extremities among the leisure activities group. Among the occupational farm work group, who usually lived in rural areas, eschars appeared most frequently on the abdomen/waist in men and on the shoulder/frontal chest in women. Eschar patterns were influenced by gender and activities. These results could facilitate the prevention of scrub typhus and clarify the current status of scrub typhus in South Korea.

Activation, Impaired Tumor Necrosis Factor-α Production, and Deficiency of Circulating Mucosal-Associated Invariant T Cells in Patients with Scrub Typhus.

PubMed

Kang, Seung-Ji; Jin, Hye-Mi; Won, Eun Jeong; Cho, Young-Nan; Jung, Hyun-Ju; Kwon, Yong-Soo; Kee, Hae Jin; Ju, Jae Kyun; Kim, Jung-Chul; Kim, Uh Jin; Jang, Hee-Chang; Jung, Sook-In; Kee, Seung-Jung; Park, Yong-Wook

2016-07-01

Mucosal-associated invariant T (MAIT) cells contribute to protection against certain microorganism infections. However, little is known about the role of MAIT cells in Orientia tsutsugamushi infection. Hence, the aims of this study were to examine the level and function of MAIT cells in patients with scrub typhus and to evaluate the clinical relevance of MAIT cell levels. Thirty-eight patients with scrub typhus and 53 health control subjects were enrolled in the study. The patients were further divided into subgroups according to disease severity. MAIT cell level and function in the peripheral blood were measured by flow cytometry. Circulating MAIT cell levels were found to be significantly reduced in scrub typhus patients. MAIT cell deficiency reflects a variety of clinical conditions. In particular, MAT cell levels reflect disease severity. MAIT cells in scrub typhus patients displayed impaired tumor necrosis factor (TNF)-α production, which was restored during the remission phase. In addition, the impaired production of TNF-α by MAIT cells was associated with elevated CD69 expression. This study shows that circulating MAIT cells are activated, numerically deficient, and functionally impaired in TNF-α production in patients with scrub typhus. These abnormalities possibly contribute to immune system dysregulation in scrub typhus infection.

Differential diagnosis of scrub typhus meningitis from tuberculous meningitis using clinical and laboratory features.

PubMed

Valappil, Ashraf V; Thiruvoth, Sohanlal; Peedikayil, Jabir M; Raghunath, Praveenkumar; Thekkedath, Manojan

2017-12-01

The involvement of the central nervous system in the form of meningitis or meningoencephalitis is common in scrub typhus and is an important differential diagnosis of other lymphocytic meningitis like tuberculous meningitis (TBM). The aim of this study was to identify the clinical and laboratory parameters that may be helpful in differentiating scrub typhus meningitis from TBM. We compared of the clinical and laboratory features of 57 patients admitted with scrub typhus meningitis or TBM during a 3-year period. Patients who had abnormal cerebrospinal fluid (CSF) and positive scrub typhus enzyme-linked immunosorbent assay serology (n=28) were included in the scrub typhus meningitis group, while the TBM group included those who satisfied the consensus diagnostic criteria of TBM (n=29). Compared with the TBM group, the mean duration of symptoms was less in patients with scrub typhus meningitis, who also had a lower magnitude of neurological deficits, such as altered mental status and cranial nerve and motor deficits. Patients with scrub typhus meningitis had a lower CSF white blood-cell count (WBC) than the TBM group (130.8±213 195±175 cells/mm 3 , P=0.002), lower CSF protein elevation (125±120 vs. 195.2±108.2mg/dl, P=0.002), and higher CSF sugar (70.1±32.4 vs. 48.7±23.4mg/dl, P=0.006). Features predictive of the diagnosis of scrub typhus meningitis included the absence of neurological impairment at presentation, blood serum glutamic-oxaloacetic transaminase>40 international units (IU)/L, serum glutamic-pyruvic transaminase>60 IU/L, total blood leukocyte count>10,000/mm 3 , CSF protein<100mg/dl, CSF sugar>50mg/dl, CSF WBC<100 cells/mm 3 . All patients with scrub typhus meningitis recovered completely following doxycycline therapy CONCLUSIONS: This study suggests that, clinical features, including duration of fever, neurological deficits at presentation and laboratory parameters such as CSF pleocytosis,CSF protein elevation, CSF sugar levels and liver enzyme values are helpful in differentiating scrub typhus meningitis from tuberculous meningits. These features with scrub IgM serology may be helpful in identifying patients with scrub meningitis and in avoiding prolonged empirical antituberculous therapy in cases of lymphocytic meningitis. Copyright © 2017 Elsevier B.V. All rights reserved.

[Spatio-temporal distribution of scrub typhus and related influencing factors in coastal beach area of Yancheng, China].

PubMed

Chen, Y Z; Li, F; Xu, H; Huang, L C; Gu, Z G; Sun, Z Y; Yan, G J; Zhu, Y J; Tang, C

2016-02-01

In order to provide better programs on monitoring, early warning and prevention of Scrub Typhus in the coastal beach area, temporal-spatial distribution characteristics of scrub typhus were summarized. Relationships between temporal-spatial clustering of Scrub Typhus, meteorological factors, rodent distribution and the biological characteristics in coastal beach area of Yancheng city, were studied. Reports on network-based Scrub Typhus epidemics and information on population, weather situation through monitoring those stations, from 2005 to 2014 were collected and processed, in the coastal beach area of Yancheng city. Distribution, density of the population concerned and seasonal fluctuation on rodents were monitored in coastal beach area, from April 2011 to December, 2013. METHODS as descriptive statistics, space-time permutation scantistics, autocorrelation and Cross-correlation analysis etc, were used to analyze the temporal-spatial distribution of Scrub Typhus and correlation with rodent distribution, density fluctuation and meteorological indexes. Zero-inflated Pearson (ZIP) regression model was contributed according to the distribution of related data. All methods were calculated under Excel 2003, SPSS 16.0, Mapinfo 11.0, Satscan 9.0 and Stata/SE 10.0 softwares. (1) The incidence of Scrub Typhus was gradually increasing and the highest incidence of the year was seen in 2014, as 5.81/10 million. There was an autumn peak of Scrub typhus, with the highest incidence rate as 12.02/10 million in November. The incidence rate of Scrub typhus appeared high in Binhai, Dafeng and Xiangshui, with the average incidence rates appeared as 3.30/10 million, 3.21/10 million and 2.79/10 million, respectively. There were 12 towns with high incidence rates in the coastal beach area, with incidence rate showed between 4.41/10 and 10.03/10 million. (2) There were three incidence clusters of Scrub typhus seen in 25 towns, between October 2012 and November 2012 in Dongtai, Dafeng, Sheyang areas and 5 towns between October and November, 2014 in Xiangshui area, together with another 6 towns in November of 2006, in Binhai area. (3) Apodemus agrarius appeared the dominant species in the coastal area, with the constituent ratio as 89.19%. The rodent density appeared two peaks in winter and summer in 2011 and 2013. The winter peak was seen in January and the summer peak lasting for 5-8 months. Scrub Typhus was seen 10-11 months in a year and the incidence was increasing, parallel with the peak of the rodent density. The peak incidence of Scrub Typhus showed a temperature/rainfall-related peak. Rodent density, temperature, rainfalls were correlated with the incidence of Scrub Typhus, under the Cross correlation analysis. Rains, Mean minimum temperature of a 3-month lagging were directly correlated but the duration of sunshine and relative humidity were negatively correlated with the incidence of Scrub Typhus, under the Zero-inflated Pearson (ZIP) regression model. Temporal-spatial clustering and factors as media creature and weather condition of Scrub Typhu were discovered, which provided evidence for effective measures on prevention and control of the disease.

Cytokine network in scrub typhus: high levels of interleukin-8 are associated with disease severity and mortality.

PubMed

Astrup, Elisabeth; Janardhanan, Jeshina; Otterdal, Kari; Ueland, Thor; Prakash, John A J; Lekva, Tove; Strand, Øystein A; Abraham, O C; Thomas, Kurien; Damås, Jan Kristian; Mathews, Prasad; Mathai, Dilip; Aukrust, Pål; Varghese, George M

2014-02-01

Scrub typhus, caused by Orientia tsutsugamushi, is endemic in the Asia-Pacific region. Mortality is high if untreated, and even with treatment as high as 10-20%, further knowledge of the immune response during scrub typhus is needed. The current study was aimed at comparing plasma levels of a variety of inflammatory mediators in scrub typhus patients and controls in South India in order to map the broader cytokine profile and their relation to disease severity and clinical outcome. We examined plasma levels of several cytokines in scrub typhus patients (n = 129) compared to healthy controls (n = 31) and infectious disease controls (n = 31), both in the acute phase and after recovery, by multiplex technology and enzyme immunoassays. Scrub typhus patients were characterized by marked changes in the cytokine network during the acute phase, differing not only from healthy controls but also from infectious disease controls. While most of the inflammatory markers were raised in scrub typhus, platelet-derived mediators such as RANTES were markedly decreased, probably reflecting enhanced platelet activation. Some of the inflammatory markers, including various chemokines (e.g., interleukin-8, monocyte chemoattractant peptide-1 and macrophage inflammatory protein-1β) and downstream markers of inflammation (e.g., C-reactive protein and pentraxin-3), were also associated with disease severity and mortality during follow-up, with a particular strong association with interleukin-8. Our findings suggest that scrub typhus is characterized by a certain cytokine profile that includes dysregulated levels of a wide range of mediators, and that this enhanced inflammation could contribute to disease severity and clinical outcome.

Bevacizumab in choroidal neovascularization secondary to Indian tick typhus: A rare case report.

PubMed

Ijeri, Raghavendra; Beladiya, Gautam; Bhomaj, Sharad

2016-10-01

Tick typhus causes hemorrhagic lesions over the skin. Retina also shows hemorrhages and exudates. Many cases have been reported in western literature about this condition. To our best of knowledge, this is the first case report of tick typhus in India which was also associated with inflammatory choroidal neovascularization.

Epidemic typhus imported from Algeria.

PubMed

Niang, M; Brouqui, P; Raoult, D

1999-01-01

We report epidemic typhus in a French patient returning from Algeria. The diagnosis was confirmed by serologic testing and the isolation of Rickettsia prowazekii in blood. Initially the patient was thought to have typhoid fever. Because body lice are prevalent in industrialized regions, the introduction of typhus to pediculosis-endemic areas poses a serious public health risk.

Clinical and laboratory features of murine typhus in central Tunisia: a report of seven cases.

PubMed

Letaïef, A Omezzine; Kaabia, N; Chakroun, M; Khalifa, M; Bouzouaia, N; Jemni, L

2005-11-01

Murine or endemic typhus, caused by Rickettsia typhi, has been reported in all continents. In the 1970s, no cases of murine typhus were diagnosed in Tunisia. The clinico-epidemiological characteristics of seven cases of murine typhus diagnosed at our hospitals since 1993 are reported. Diagnosis was confirmed by indirect fluorescence assay detecting specific R. typhi antibodies. Murine typhus occurred in all ages from 18-80 years during the hot season in rural areas. Clinical features were: sudden onset of fever and absence of eschar in all cases, with maculo-papular rash (five cases), prostration (four cases), meningism (three cases) and pneumonia (four cases). Frequent laboratory findings were moderate thrombopenia (four cases) and elevated transaminases (four cases). Before the results of serology, clinical diagnoses were Mediterranean Spotted Fever (four cases), Q fever (one case), pneumonia (one case), and lymphocytic meningitis (one case). Serology confirmed all diagnoses with cross-reactivity with Rickettsia conorii. Murine typhus exists in Tunisia and its prevalence is underestimated. Further, more specific studies are needed to evaluate the true prevalence.

The Correlation of Endoscopic Findings and Clinical Features in Korean Patients with Scrub Typhus: A Cohort Study.

PubMed

Lee, Jun; Kim, Dong-Min; Yun, Na Ra; Kim, Young Dae; Park, Chan Guk; Kim, Man Woo

2016-01-01

Scrub typhus is an infectious disease caused by Orientia tsutsugamushi-induced systemic vasculitis, but the involvement of the gastrointestinal tract and the endoscopic findings associated with scrub typhus are not well understood. We performed a prospective study and recommend performing esophagogastroduodenoscopy (EGD) for all possible scrub typhus patients, regardless of gastrointestinal symptoms. Gastrointestinal symptoms, endoscopic findings and clinical severity based on organ involvement and ICU admission were analyzed. Gastrointestinal symptoms occurred in up to 76.4% of scrub typhus patients. The major endoscopic findings were ulcers (43/127, 33.9%). Interestingly, 7.1% (9/127) of the patients presented with esophageal candidiasis. There was no correlation between the presence or absence of gastrointestinal symptoms and the endoscopic grade (P = 0.995). However, there was a positive correlation between the clinical severity and the endoscopic findings (P = 0.001). Sixty-three percent of the patients presented with erosion or ulcers on prospectively performed endoscopic evaluations, irrespective of gastrointestinal symptoms. Gastrointestinal symptoms did not reflect the need for endoscopy. Scrub typhus patients could have significant endoscopic abnormalities even in the absence of gastrointestinal symptoms.

[Epidemic typhus in Africa].

PubMed

Ndihokubwayo, J B; Raoult, D

1999-01-01

Epidemic typhus is caused by a small strictly intracellular virus named Rickettsia prowazekii, a member of the Rickettsial family. It is transmitted to man by the body louse, Pediculus humanus. Although now rare in Western countries, exanthematic typhus remains common in the Southern hemisphere due to poverty, inadequate clothing hygiene, and poor socioeconomic conditions. In Africa, outbreaks have historically occurred in Burundi, Rwanda, southwest Ouganda, and Ethiopia. The largest outbreak of epidemic typhus since the World War II was reported in Burundi where ongoing civil war since October 1993 has forced 10 p. 100 of the population of Burundi to live in cold, promiscuity, and malnutrition of makeshift refugee camps. The purpose of this report based on our two-year experience working with this unfortunate population is to describe the characteristics of this disease in Africa where the epidemic form had become rare until recently. Indeed political unrest as well as numerous civil wars are now epidmiological factors favorizing outbreaks of epidemic typhus at any time. This overview also provides an opportunity to recall epidemiological, bacteriological, and clinical aspects of typhus as well as diagnosis and treatment of the disease in the context of Africa.

[Epidemic typhus in tropical Africa. A reemerging disease that is severe but curable].

PubMed

Zoguéreh, D D; Ndihokubwayo, J B; Simboyinuma, A

2000-01-01

In tropical regions of Africa, frequently subject to social and political upheavals, there is an ever-present threat of typhus epidemics, as shown by the recent typhus outbreak in Burundi in 1997. Epidemic typhus should be systematically suspected in certain epidemiological conditions: famine, war, high-density populations (refugee camps, prisons), the presence of body louse in the clothing, and in the presence of certain clinical findings: severe infectious syndrome (temperature above 38 C), severe pain and muscle weakness, with coughing and severe neurological signs. The rapid diagnosis and treatment of typhus are essential. The prognosis has improved, thanks to the specific antibiotics that are currently available, particularly doxycycline, prescribed as a single oral dose of 200 mg for adults or of 100 mg for children. However, the prognosis still depends to a large extent on the speed of diagnosis. Typhus epidemics could be effectively predicted and limited if the measures for control of the body louse recommended by the World Health Organization were applied in the areas with the most favorable epidemiological conditions.

Effect of Latitude and Seasonal Variation on Scrub Typhus, South Korea, 2001–2013

PubMed Central

Jeung, Ye Sul; Kim, Choon-Mee; Yun, Na Ra; Kim, Seok-Won; Han, Mi Ah; Kim, Dong-Min

2016-01-01

In South Korea, scrub typhus is one of the most common rickettsial diseases. The number of scrub typhus patients has increased in South Korea, a total of 69,210 cases were reported from 2001 to 2013. The seasonality and relation of scrub typhus cases to latitude were analyzed in this article using data obtained from the National Notifiable Diseases Surveillance System website of the Korea Centers for Disease Control and Prevention. The incidence of scrub typhus tended to increase in the later months of the year, especially in October–December. In general, lower latitudes were associated with a later peak incidence. Our results suggest for the first time that the monthly observed incidence tended to increase in the later months of the year as the latitude decreased, and on a yearly basis in Korea. PMID:26503283

Renal Manifestation in Scrub Typhus during a Major Outbreak in Central Nepal.

PubMed

Sedhain, A; Bhattarai, G R

2017-01-01

Renal involvement and acute kidney injury (AKI) are common clinical manifestations seen in scrub typhus, a vector-borne tropical disease. There are no data on renal manifestation in scrub typhus in Nepal. We conducted a prospective study to analyze the incidence, urinary abnormalities, course, severity, outcome, and the predictors of AKI in patients with scrub typhus during a major outbreak in Central Nepal. Total 1398 patients admitted with acute febrile illness were subjected for Scrub Typhus Detect™ Immunoglobulin M (IgM) enzyme-linked immunosorbent assay (ELISA) test, of which 502 (35.90%) patients tested positive and were included in the study. Mean age of the patients was 30.37 ± 18.81 years (range, 1-79 years) with 26.29% in the pediatric age group. Female-to-male ratio was 1.26:1. Mean duration of fever was 6.8 ± 3.1 days. Mean IgM ELISA value for scrub typhus was 2.17 ± 1.70 without difference in AKI and non-AKI groups (2.17 ± 1.76 vs. 2.16 ± 1.62; P = 0.94). Urinary abnormalities were seen in 42.3% of patients. Mean serum creatinine was 1.37 ± 0.69 mg/dl with significant difference in two groups (1.85 ± 0.87 vs. 1.03 ± 0.17; P = 0.003). AKI was seen in 35.8% of patients with majority having Stage 1 AKI (68.3%) followed by Stage 2 (34.1%) and Stage 3 (1.2%). Hemodialysis was required for 3.94% of patients. In 54% of patients, AKI occurred in fifth and sixth day of fever. ICU admission was required for 18.73% of patients and 8.57% required ventilator support. Mortality rate was 1.79%, which was higher among patients with AKI (2.96% vs. 1.0%; P = 0.106). Multivariate analysis revealed that the presence of pneumonia, shock, and acute respiratory distress syndrome predicted the development of AKI.

Prevalence of scrub typhus in pyrexia of unknown origin and assessment of interleukin-8, tumor necrosis factor-alpha, and interferon-gamma levels in scrub typhus-positive patients.

PubMed

Rizvi, Meher; Sultan, Asfia; Chowdhry, Madhav; Azam, Mohd; Khan, Fatima; Shukla, Indu; Khan, Haris M

2018-01-01

Scrub typhus is lesser known cause of fever of unknown origin in India. Even if there have been reports documenting the prevalence of scrub typhus in different parts of India, it is still an unknown entity, and clinicians usually do not consider it as differential diagnosis. The present study was performed to document the prevalence of scrub typhus among febrile patients in western part of Uttar Pradesh and to assess the clinical profile of infected patients on the one hand and knowledge, attitude, and practices among clinicians on the other. A total of 357 adult patients with fever of more than 5-day duration were recruited. All patients underwent complete physical examination, and detailed clinical history was elicited as per predesigned pro forma. After primary screening to rule out malaria, enteric fever, and leptospirosis infection, secondary screening for scrub typhus was done by rapid screen test and IgM ELISA. Scrub typhus infection was positive in 91 (25.5%) cases. The most common symptoms among the patients were fever (100%), pain in abdomen (79.1%), pedal edema 56 (61.5%), rash 44 (48.3%), headache 44 (48.3%), vomiting 42 (46.1%), constipation 33 (36.2%), cough 28 (30.7%), and lymphadenopathy 20 (21.9%). The median values of interleukin-8, interferon-gamma, and tumor necrosis factor-alpha in healthy controls were 15.54 pg/ml, 7.77 pg/ml, and 54.1 pg/ml, respectively, while the median values of these cytokines in scrub typhus-positive patients were 21.04 pg/ml, 8.74 pg/ml, and 73.8 pg/ml, respectively. Our results highlight that scrub typhus infection is an important cause of pyrexia of unknown origin, and active surveillance is necessary to assess the exact magnitude and distribution of the disease.

Serosurveillance of Scrub Typhus in Small Mammals Collected from Military Training Sites near the DMZ, Northern Gyeonggi-do, Korea, and Analysis of the Relative Abundance of Chiggers from Mammals Examined

DTIC Science & Technology

2010-09-01

Korean J Paras/to/. Vol. 48, No. 3: 237-243, September 2010 DOl: JO.J3471kjp.2010.48.J.237 Serosurveillance of Scrub Typhus in Small Mammals...65th Medical BrigadeAJSAMEDDAC-Korea, Unit# 15281, APO AP 96205-5281, USA Abstract: Comprehensive quarterly serosurveillance on scrub typhus in small...rarely observed (prevalence < 1 0%). In contrast to previous surveys, higher chigger indices of the primary scrub typhus vectors, L. pallidum (165.4

Comparative Evaluation of Serological and Molecular Methods for the Diagnosis of Scrub Typhus in Indian Settings.

PubMed

Gupta, Nitin; Chaudhry, Rama; Kabra, Sushil K; Lodha, Rakesh; Mirdha, Bijay Ranjan; Das, Bimal Kumar; Dey, Aparajit Ballay; Sreenivas, Vishnubhatla

2017-03-24

The major brunt of scrub typhus is borne by developing countries like India but the disease remains neglected. The rapid progression of this infection to serious complications and associated mortality calls for improved diagnostics. The immunoglobulin (Ig)M immunofluorescence assay (IFA), with all of its limitations remains the gold standard. Of 218 suspected cases from patients enrolled in a 2-year study, 30 cases of scrub typhus were detected by IgM IFA, using a 1:64 dilution. The sensitivities of the IgM enzyme-linked immunosorbent assay, IgM rapid flow assay (RFA), and IgG RFA were found to be 97%, 87%, and 77%, respectively. Their respective specificities were 100%, 100%, and 92%, respectively. The sensitivity and specificity of a nested PCR assay targeting a gene encoding a 56-kDa protein were found to be 50% and 100%, respectively.

STUDIES ON SCRUB TYPHUS

PubMed Central

Smadel, Joseph E.; Rights, Fred L.; Jackson, Elizabeth B.

1946-01-01

A complement-fixing antigen specific for scrub typhus occurs in the body fluids and tissues of infected mice, white rats, and cotton rats. The specific serological substance is demonstrable only in those animals which develop a rapidly fatal disease after an incubation period of a few days. Such an experimental infection is induced in mice and rats by the intravenous injection of suspensions of yolk sac rich in R. orientalis. Ether extraction is an important step in the preparation of a complement-fixing antigen from tissues of mice dying with scrub typhus. The Imphal No. 8 and Calcutta strains of R. orientalis are indistinguishable on the basis of complement fixation and cross-immunity tests. The complement-fixing antigen in body fluids of infected mice and rats and in our preparations of tissues from such animals occurs as a soluble antigen. Under the proper conditions the soluble antigen can be stored or dehydrated without loss of serological activity. PMID:19871518

[Epidemics and disease during the Revolution Period in Mexico].

PubMed

Sanfilippo-Borrás, José

2010-01-01

The health condition in Mexico was bad around de beginning of the revolutionary period. The movement of troops led the development of epidemics like yellow fever, typhus, smallpox, and influenza that were enhance with natural disasters and hunger in whole country, from cost to cost and in the north big cities like Monterrey, Guadalajara and Saltillo. Doctor Liceaga conducted a well planned campaign against yellow fever eradicating water stagnant deposits in order to combat the vector transmission, the Aedes aegypti, mosquito with satisfactory results. The first smallpox epidemic in the XX Century in Mexico was in 1916. The Mexican physicians used the smallpox vaccine against this epidemic. An American physician named Howard Taylor Ricketts arrived to Mexico for studying the typhus transmission. Accidentally he had been infected and finally, he died from typhus. Definitively, the epidemics predominate along de revolutionary period in Mexico.

Activation, Impaired Tumor Necrosis Factor-α Production, and Deficiency of Circulating Mucosal-Associated Invariant T Cells in Patients with Scrub Typhus

PubMed Central

Won, Eun Jeong; Cho, Young-Nan; Jung, Hyun-Ju; Kwon, Yong-Soo; Kee, Hae Jin; Ju, Jae Kyun; Kim, Jung-Chul; Kim, Uh Jin; Jang, Hee-Chang; Jung, Sook-In; Kee, Seung-Jung; Park, Yong-Wook

2016-01-01

Background Mucosal-associated invariant T (MAIT) cells contribute to protection against certain microorganism infections. However, little is known about the role of MAIT cells in Orientia tsutsugamushi infection. Hence, the aims of this study were to examine the level and function of MAIT cells in patients with scrub typhus and to evaluate the clinical relevance of MAIT cell levels. Methodology/Principal Findings Thirty-eight patients with scrub typhus and 53 health control subjects were enrolled in the study. The patients were further divided into subgroups according to disease severity. MAIT cell level and function in the peripheral blood were measured by flow cytometry. Circulating MAIT cell levels were found to be significantly reduced in scrub typhus patients. MAIT cell deficiency reflects a variety of clinical conditions. In particular, MAT cell levels reflect disease severity. MAIT cells in scrub typhus patients displayed impaired tumor necrosis factor (TNF)-α production, which was restored during the remission phase. In addition, the impaired production of TNF-α by MAIT cells was associated with elevated CD69 expression. Conclusions This study shows that circulating MAIT cells are activated, numerically deficient, and functionally impaired in TNF-α production in patients with scrub typhus. These abnormalities possibly contribute to immune system dysregulation in scrub typhus infection. PMID:27463223

Scrub Typhus: An Emerging Neglected Tropical Disease in Nepal.

PubMed

Upadhyaya, B P; Shakya, G; Adhikari, S; Rijal, N; Acharya, J; Maharjan, L; Marasini, B R

2016-05-01

Scrub typhus is a neglected tropical disease and is under reported from Nepal. The objective of this study was to investigate the sero-epidemiology of scrub typhus in patients suffering from acute febrile illness. A total of 434 specimens collected from July to November 2015 at National Public Health Laboratory (NPHL) were investigated for detection of immunoglobulin M (IgM) antibody to Orientiatsutsugamushi.The Scrub Typhus Detect TM kit (InBios, USA) was used to detect the antibodies to O.tsutsugamushi in human serum. Randomly selected 10% positive specimens were used for confirmation by dot- enzyme-linked immunosorbent assay and indirect immunofluorescence assay. Of the total, 175 (40.3%) were positive for IgM antibodies to O. tsutsugamushi. Positive results of scrub typhus were highest among female in 11-20 year followed by males in 41-50 years age group. The IgM antibodies to O. tsutusugamushi were positive in specimens of various geographical regions including 30 districts of Nepal. Positive cases were found in various ecological regions of Nepal. Scrub typhus is one of the neglected tropical diseases in Nepal. Patients with acute febrile illness should be investigated for scrub typhus with high priority. There is an urgent need of reliable and affordable diagnostic tests at all level of health facilities of Nepal. Surveillance and public health awareness about the disease transmission and preventive measures needs to be initiated.

Fatal Flea-Borne Typhus in Texas: A Retrospective Case Series, 1985-2015.

PubMed

Pieracci, Emily G; Evert, Nicole; Drexler, Naomi A; Mayes, Bonny; Vilcins, Inger; Huang, Philip; Campbell, Jill; Behravesh, Casey Barton; Paddock, Christopher D

2017-05-01

AbstractFlea-borne (murine) typhus is a global rickettsiosis caused by Rickettsia typhi . Although flea-borne typhus is no longer nationally notifiable, cases are reported for surveillance purposes in a few U.S. states. The infection is typically self-limiting, but may be severe or life-threatening in some patients. We performed a retrospective review of confirmed or probable cases of fatal flea-borne typhus reported to the Texas Department of State Health Services during 1985-2015. When available, medical charts were also examined. Eleven cases of fatal flea-borne typhus were identified. The median patient age was 62 years (range, 36-84 years) and 8 (73%) were male. Patients presented most commonly with fever (100%), nausea and vomiting (55%), and rash (55%). Respiratory (55%) and neurologic (45%) manifestations were also identified frequently. Laboratory abnormalities included thrombocytopenia (82%) and elevated hepatic transaminases (63%). Flea or animal contact before illness onset was frequently reported (55%). The median time from hospitalization to administration of a tetracycline-class drug was 4 days (range, 0-5 days). The median time from symptom onset to death was 14 days (range, 1-34 days). Flea-borne typhus can be a life-threatening disease if not treated in a timely manner with appropriate tetracycline-class antibiotics. Flea-borne typhus should be considered in febrile patients with animal or flea exposure and respiratory or neurologic symptoms of unknown etiology.

Differences in agricultural activities related to incidence of scrub typhus between Korea and Japan.

PubMed

Ma, Chang-Jin; Oh, Gyung-Jae; Kang, Gong-Unn; Lee, Jeong Mi; Lee, Da-Un; Nam, Hae-Sung; Ryu, So Yeon; Lee, Young-Hoon

2017-01-01

The purpose of this study was to establish a basis for improving or strengthening the preventive strategy against scrub typhus in Korea by comparing and analyzing the difference of prevention behaviors contributing to the occurrence of scrub typhus in Japan and Korea. The survey was carried out in Jeollabuk-do, which is a high risk and high incidence area, and Fukuoka Prefecture, which is a high risk and low incidence area. The study included 406 Korean farmers and 216 Japanese farmers. Data were collected through face-to-face surveys by interviewers who had completed standardized education. Korean farmers have a higher percentage of agricultural working posture that involved contact with weeds than Japanese farmers (p<0.05). The frequency and proportion of weeding were lower in Korean farmers than in Japanese farmers (p<0.05). The level of knowledge about scrub typhus was significantly higher among Korean farmers than among Japanese farmers (p<0.05). Mostly, the behavior of agriculture work was more appropriate for Japanese farmers than for Korean farmers (p<0.05). The total average level of agricultural work was lower in Korea than in Japan, lower in men than women, and lower in part-time farmers than full-time farmers (p<0.05). This study suggests that it is reasonable to develop and provide a program that can improve the level of preventive behavior taking into consideration the characteristics of the subject in order to reduce the incidence of diseases in high-risk areas for scrub typhus.

Differences in agricultural activities related to incidence of scrub typhus between Korea and Japan

PubMed Central

2017-01-01

OBJECTIVES The purpose of this study was to establish a basis for improving or strengthening the preventive strategy against scrub typhus in Korea by comparing and analyzing the difference of prevention behaviors contributing to the occurrence of scrub typhus in Japan and Korea. METHODS The survey was carried out in Jeollabuk-do, which is a high risk and high incidence area, and Fukuoka Prefecture, which is a high risk and low incidence area. The study included 406 Korean farmers and 216 Japanese farmers. Data were collected through face-to-face surveys by interviewers who had completed standardized education. RESULTS Korean farmers have a higher percentage of agricultural working posture that involved contact with weeds than Japanese farmers (p<0.05). The frequency and proportion of weeding were lower in Korean farmers than in Japanese farmers (p<0.05). The level of knowledge about scrub typhus was significantly higher among Korean farmers than among Japanese farmers (p<0.05). Mostly, the behavior of agriculture work was more appropriate for Japanese farmers than for Korean farmers (p<0.05). The total average level of agricultural work was lower in Korea than in Japan, lower in men than women, and lower in part-time farmers than full-time farmers (p<0.05). CONCLUSIONS This study suggests that it is reasonable to develop and provide a program that can improve the level of preventive behavior taking into consideration the characteristics of the subject in order to reduce the incidence of diseases in high-risk areas for scrub typhus. PMID:29121711

Association of Drought with Typhus Epidemics in Central Mexico

NASA Astrophysics Data System (ADS)

Acuna-Soto, R.; Stahle, D.; Villanueva Diaz, J.; Therrell, M.

2007-05-01

Typhus is an acute infectious disease caused by the bacteria Rickettsia prowazekii, which is transmitted among humans by the body lice (Pediculus humanus corporis). The disease is highly contagious and transmission is favored in populations living in crowded conditions. Under these circumstances, typhus transmission is facilitated by factors that favor the colonization and proliferation of body lice such as absence of personal hygiene and wearing the same clothes for long periods of time. Historically, periods of war and famine were associated with devastating epidemics with high mortality rates in many parts of the world. Central Mexico has a long record of typhus epidemics. In this region, at > 2000 meters above sea level, the disease was endemic and occurred with a seasonal pattern in winter, with occasional large epidemics. Recently, we completed a chronology of epidemics in Mexico. A total of 22 well-defined major typhus epidemics were identified between 1650 and 1920. All of them caused periods of increased mortality that lasted 2 - 4 years (more than one standard deviation from the previous ten year period). The record of typhus epidemics was evaluated against the tree-ring record of Cuauhtmoc La Fragua, Puebla. This chronology, based on Douglas fir, has demonstrated to be a faithful record of precipitation in central Mexico. The results indicate that a statistically significant drought (t test, p < .05) prevailed during the first year of all 22 large outbreaks of typhus in recent Mexican history. No distinction is made between times of peace and war. This indicates that drought alone was capable of inducing the social conditions for increased transmission of typhus in pre-industrial central Mexico.

Seroprevalence of Scrub Typhus Infection in Arunachal Pradesh, India.

PubMed

Jakharia, Aniruddha; Borkakoty, Biswajyoti; Biswas, Dipankar; Yadav, Kaushal; Mahanta, Jagadish

2016-10-01

Scrub typhus is a major reason for febrile illness, caused by a bacterium Orientia tsutsugamushi, a rickettsial pathogen. Few outbreaks of scrub typhus have been reported from Arunachal Pradesh in recent past. However, there is lack of seroprevalence data from the region. In this regard, this study was undertaken using archival serum sample available from seven districts of Arunachal Pradesh. This serological study was conducted in Regional Medical Research Center for NE Region, Dibrugarh. Reactivity to IgG class of antibodies against scrub typhus was done using Scrub typhus detect IgG ELISA kit as per manufacturer's protocol. Seroprevalence of scrub typhus in seven districts of Arunachal Pradesh was found to be 40% (120/300). The age-specific scrub typhus seroprevalence rose steadily from 5.6% in children <10 years of age to 61.8% in persons aged ≥40 years (p = 0.0001). Prevalence is lowest in Papumpare (25.9%) and highest in East Siang (72.5%) (p = 0.0001). The seroprevalence in males and females was very similar, however, the female prevalence increases from age group ≥30 years (p = 0.053). Moreover, among the farmers, the seroprevalence is higher (58.3%) (p = 0.0001). As clinical symptoms overlap with other viral/bacterial infections, scrub typhus infection should be considered in differential diagnosis of any acute febrile illness in this part of the country. In view of the high prevalence, empirical therapy of doxycycline/azithromycin may be done in cases of undiagnosed fever. Active surveillance has to be done to understand exact magnitude, epidemiological aspects, and distribution of vector and disease of this reemerging neglected tropical disease.

Predictors of acute myocarditis in complicated scrub typhus: an endemic province in the Republic of Korea.

PubMed

Chin, Jung Yeon; Kang, Ki-Woon; Moon, Kyung Min; Kim, Jongwoo; Choi, Yu Jeong

2018-03-01

Scrub typhus is known as a self-limited infectious disease. Cardiac complication is uncommon and usually not life-threatening. Until now, few cases of fulminant myocarditis by scrub typhus have been reported. So, we investigated incidence and predictors of acute myocarditis in severe scrub typhus. We retrospectively reviewed 89 patients among 91 scrub typhus confirmed patients who examined an echocardiogram and cardiac biomarkers from 2005 to 2015 in the intensive care unit at our hospital. We excluded two patients who didn't have electrocardiography. Patients were divided into two groups and compared between scrub typhus with (n = 13) and without (n = 76) acute myocarditis. Age, sex, and underlying diseases were similar between the groups. The existence of eschar and duration of general ache and fever were similar between the groups. However, patients with acute myocarditis had more elevated total bilirubin, high incidence of ST elevations and paroxysmal atrial fibrillation (PAF) than those without acute myocarditis. Receiver operating characteristic analysis showed that the PAF was a predictor of myocarditis with a sensitivity of 70% and specificity of 84%. Predictive power of combination of ST-segment elevation and PAF was significantly associated with myocarditis in the multivariate analysis (odds ratio, 1.57; 95% confidence interval [CI], 1.21 to 11.7; p = 0.041) and area under the curve was 0.947 (95% CI, 0.878 to 0.983; p < 0.001). Acute myocarditis with scrub typhus may be more common than previously reported. Patients with high bilirubin and PAF are at increased risk of acute myocarditis with scrub typhus. These patients warrant closer follow-up and echocardiogram would be needed.

Differential patterns of endothelial and leucocyte activation in ‘typhus-like’ illnesses in Laos and Thailand

PubMed Central

Paris, D H; Jenjaroen, K; Blacksell, S D; Phetsouvanh, R; Wuthiekanun, V; Newton, P N; Day, N P J; Turner, G D H

2008-01-01

Scrub typhus is responsible for a large proportion of undifferentiated fevers in south-east Asia. The cellular tropism and pathophysiology of the causative agent, Orientia tsutsugamushi, remain poorly understood. We measured endothelial and leucocyte activation by soluble cell adhesion molecule enzyme-linked immunosorbent assays in 242 Lao and Thai patients with scrub or murine typhus, leptospirosis, dengue, typhoid and uncomplicated falciparum malaria on admission to hospital. Soluble E-selectin (sE-selectin) levels were lowest in dengue, sL-selectin highest in scrub typhus with a high sE-selectin to sL-selectin ratio in leptospirosis patients. In scrub typhus patients elevated sL-selectin levels correlated with the duration of skin rash (P = 0·03) and the presence of eschar (P = 0·03), elevated white blood cell (WBC) count (P = 0·007), elevated lymphocyte (P = 0·007) and neutrophil counts (P = 0·015) and elevated levels of sE-selectin correlated with the duration of illness before admission (P = 0·03), the presence of lymphadenopathy (P = 0·033) and eschar (P = 0·03), elevated WBC (P = 0·005) and neutrophil counts (P = 0·0003). In comparison, soluble selectin levels in murine typhus patients correlated only with elevated WBC counts (P = 0·03 for sE-selectin and sL-selectin). Soluble intercellular adhesion molecule-1 and soluble vascular adhesion molecule-1 levels were not associated significantly with any clinical parameters in scrub or murine typhus patients. The data presented suggest mononuclear cell activation in scrub typhus. As adhesion molecules direct leucocyte migration and induce inflammatory and immune responses, this may represent O. tsutsugamushi tropism during early dissemination, or local immune activation within the eschar. PMID:18505434

Differential patterns of endothelial and leucocyte activation in 'typhus-like' illnesses in Laos and Thailand.

PubMed

Paris, D H; Jenjaroen, K; Blacksell, S D; Phetsouvanh, R; Wuthiekanun, V; Newton, P N; Day, N P J; Turner, G D H

2008-07-01

Scrub typhus is responsible for a large proportion of undifferentiated fevers in south-east Asia. The cellular tropism and pathophysiology of the causative agent, Orientia tsutsugamushi, remain poorly understood. We measured endothelial and leucocyte activation by soluble cell adhesion molecule enzyme-linked immunosorbent assays in 242 Lao and Thai patients with scrub or murine typhus, leptospirosis, dengue, typhoid and uncomplicated falciparum malaria on admission to hospital. Soluble E-selectin (sE-selectin) levels were lowest in dengue, sL-selectin highest in scrub typhus with a high sE-selectin to sL-selectin ratio in leptospirosis patients. In scrub typhus patients elevated sL-selectin levels correlated with the duration of skin rash (P = 0.03) and the presence of eschar (P = 0.03), elevated white blood cell (WBC) count (P = 0.007), elevated lymphocyte (P = 0.007) and neutrophil counts (P = 0.015) and elevated levels of sE-selectin correlated with the duration of illness before admission (P = 0.03), the presence of lymphadenopathy (P = 0.033) and eschar (P = 0.03), elevated WBC (P = 0.005) and neutrophil counts (P = 0.0003). In comparison, soluble selectin levels in murine typhus patients correlated only with elevated WBC counts (P = 0.03 for sE-selectin and sL-selectin). Soluble intercellular adhesion molecule-1 and soluble vascular adhesion molecule-1 levels were not associated significantly with any clinical parameters in scrub or murine typhus patients. The data presented suggest mononuclear cell activation in scrub typhus. As adhesion molecules direct leucocyte migration and induce inflammatory and immune responses, this may represent O. tsutsugamushi tropism during early dissemination, or local immune activation within the eschar.

Predictors of acute myocarditis in complicated scrub typhus: an endemic province in the Republic of Korea

PubMed Central

Chin, Jung Yeon; Kang, Ki-Woon; Moon, Kyung Min; Kim, Jongwoo; Choi, Yu Jeong

2018-01-01

Background/Aims Scrub typhus is known as a self-limited infectious disease. Cardiac complication is uncommon and usually not life-threatening. Until now, few cases of fulminant myocarditis by scrub typhus have been reported. So, we investigated incidence and predictors of acute myocarditis in severe scrub typhus. Methods We retrospectively reviewed 89 patients among 91 scrub typhus confirmed patients who examined an echocardiogram and cardiac biomarkers from 2005 to 2015 in the intensive care unit at our hospital. We excluded two patients who didn’t have electrocardiography. Patients were divided into two groups and compared between scrub typhus with (n = 13) and without (n = 76) acute myocarditis. Results Age, sex, and underlying diseases were similar between the groups. The existence of eschar and duration of general ache and fever were similar between the groups. However, patients with acute myocarditis had more elevated total bilirubin, high incidence of ST elevations and paroxysmal atrial fibrillation (PAF) than those without acute myocarditis. Receiver operating characteristic analysis showed that the PAF was a predictor of myocarditis with a sensitivity of 70% and specificity of 84%. Predictive power of combination of ST-segment elevation and PAF was significantly associated with myocarditis in the multivariate analysis (odds ratio, 1.57; 95% confidence interval [CI], 1.21 to 11.7; p = 0.041) and area under the curve was 0.947 (95% CI, 0.878 to 0.983; p < 0.001). Conclusions Acute myocarditis with scrub typhus may be more common than previously reported. Patients with high bilirubin and PAF are at increased risk of acute myocarditis with scrub typhus. These patients warrant closer follow-up and echocardiogram would be needed. PMID:28226202

Cytokine Network in Scrub Typhus: High Levels of Interleukin-8 Are Associated with Disease Severity and Mortality

PubMed Central

Astrup, Elisabeth; Janardhanan, Jeshina; Otterdal, Kari; Ueland, Thor; Prakash, John A. J.; Lekva, Tove; Strand, Øystein A.; Abraham, O. C.; Thomas, Kurien; Damås, Jan Kristian; Mathews, Prasad; Mathai, Dilip; Aukrust, Pål; Varghese, George M.

2014-01-01

Background Scrub typhus, caused by Orientia tsutsugamushi, is endemic in the Asia-Pacific region. Mortality is high if untreated, and even with treatment as high as 10–20%, further knowledge of the immune response during scrub typhus is needed. The current study was aimed at comparing plasma levels of a variety of inflammatory mediators in scrub typhus patients and controls in South India in order to map the broader cytokine profile and their relation to disease severity and clinical outcome. Methodology/Principal Findings We examined plasma levels of several cytokines in scrub typhus patients (n = 129) compared to healthy controls (n = 31) and infectious disease controls (n = 31), both in the acute phase and after recovery, by multiplex technology and enzyme immunoassays. Scrub typhus patients were characterized by marked changes in the cytokine network during the acute phase, differing not only from healthy controls but also from infectious disease controls. While most of the inflammatory markers were raised in scrub typhus, platelet-derived mediators such as RANTES were markedly decreased, probably reflecting enhanced platelet activation. Some of the inflammatory markers, including various chemokines (e.g., interleukin-8, monocyte chemoattractant peptide-1 and macrophage inflammatory protein-1β) and downstream markers of inflammation (e.g., C-reactive protein and pentraxin-3), were also associated with disease severity and mortality during follow-up, with a particular strong association with interleukin-8. Conclusions/Significance Our findings suggest that scrub typhus is characterized by a certain cytokine profile that includes dysregulated levels of a wide range of mediators, and that this enhanced inflammation could contribute to disease severity and clinical outcome. PMID:24516677

Sylvatic typhus associated with flying squirrels (Glaucomys volans) in New York State, United States.

PubMed

Prusinski, Melissa A; White, Jennifer L; Wong, Susan J; Conlon, Maureen A; Egan, Christina; Kelly-Cirino, Cassandra D; Laniewicz, Brian R; Backenson, P Bryon; Nicholson, William L; Eremeeva, Marina E; Karpathy, Sandor E; Dasch, Gregory A; White, Dennis J

2014-04-01

Sylvatic typhus is an infrequent, potentially life-threatening emerging zoonotic disease. In January of 2009, the New York State Department of Health was notified of a familial cluster of two suspected cases. Due to the paucity of typhus cases in New York, epidemiologic and environmental investigations were conducted to establish rickettsial etiology and determine potential sources of infection. Patients presented with symptoms consistent with typhus, and serologic testing of each patient confirmed infection with typhus group rickettsiae. Serologic analysis of blood obtained from southern flying squirrels (Glaucomys volans) captured from the attic crawlspace above an enclosed front porch of the cases' residence indicated evidence of infection with Rickettsia prowazekii, with 100% seroprevalence (n=11). Both patients reported spending significant time on the porch and hearing animal activity above the ceiling prior to onset of illness, implicating these flying squirrels as the likely source of infection.

Scrub Typhus: An Emerging Threat

PubMed Central

Chakraborty, Sayantani; Sarma, Nilendu

2017-01-01

Scrub typhus is caused by Orientia tsutsugamushi (formerly Rickettsia) and is transmitted to humans by an arthropod vector of the Trombiculidae family (Leptotrombidium deliense and L. akamushi). It is the most common re-emerging Rickettsial infection in India and many other South East Asian countries. In fact, scrub typhus is confined geographically to the Asia Pacific region, a billion people are at risk and nearly a million cases are reported every year. Scrub typhus appears particularly to be distributed in the tsutsugamushi triangle which is distributed over a very wide area of 13 million km2 bound by Japan in the east, through China, the Philippines, tropical Australia in the south, and west through India, Pakistan, possibly to Tibet to Afghanistan, and southern parts of the USSR in the north. Eschar is the characteristic lesion that starts as a vesicular lesion at the site of mite feeding. Later, an ulcer forms with black necrotic center and an erythematous border along with regional lymphadenopathy. Other features are fever, maculopapular rash starting from the trunk, and spreading to the limbs. It may affect the central nervous system, cardiovascular system, renal, respiratory, and gastrointestinal systems. Serious complication in the form of myocarditis, pneumonia, meningoencephalitis, acute renal failure, gastrointestinal bleeding, and even acute respiratory distress syndrome may develop. Tetracycline or chloramphenicol remains the main stay of therapy. PMID:28979009

A murine model of infection with Rickettsia prowazekii: implications for pathogenesis of epidemic typhus.

PubMed

Bechah, Yassina; Capo, Christian; Grau, Georges E; Raoult, Didier; Mege, Jean-Louis

2007-06-01

Epidemic typhus remains a major disease threat, furthermore, its etiologic agent, Rickettsia prowazekii, is classified as a bioterrorism agent. We describe here a murine model of epidemic typhus that reproduced some features of the human disease. When BALB/c mice were inoculated intravenously with R. prowazekii (Breinl strain), they survived but did not clear R. prowazekii infection. Immunohistological analysis of tissues and quantitative PCR showed that R. prowazekii was present in blood, liver, lungs and brain 1 day after infection and persisted for at least 9 days. Importantly, infected mice developed interstitial pneumonia, with consolidation of the alveoli, hemorrhages in lungs, multifocal granulomas in liver, and hemorrhages in brain, as seen in humans. Circulating antibodies directed against R. prowazekii were detected at day 4 post-infection and steadily increased for up to 21 days, demonstrating that R. prowazekii lesions were independent of humoral immune response. R. prowazekii-induced lesions were associated with inflammatory response, as demonstrated by elevated levels of inflammatory cytokines including interferon-gamma, tumor necrosis factor and the CC chemokine RANTES in the lesions. We concluded that the BALB/c mouse strain provides a useful model for studying the pathogenic mechanisms of epidemic typhus and its control by the immune system.

Typhus Exanthematicus in Romania During the Second World War (1940-1945) Reflected by Romanian Medical Journals of the Time.

PubMed

Jeican, Ionuţ Isaia; Botiş, Florin Ovidiu; Gheban, Dan

2015-01-01

This article provides a picture of exanthematic Typhus in Romania during the Second World War: epidemiological aspects of this disease in the inner zone and in the zone of military operations, as well as information about the diagnosis, treatment and prophylaxis of the Typhus in our country during this period.

Severe interstitial pneumonia due to murine typhus in a patient returning from Bali.

PubMed

Malheiro, Luís; Ceia, Filipa; Alves, João; Carvalho, Ana Cláudia; Sobrinho-Simões, Joana; Sousa, Rita; Sarmento, António; Santos, Lurdes

2017-01-01

Murine typhus has been increasingly reported as a cause of fever in returning travelers from Southeast Asia. We report a case of a previously healthy traveler returning from Bali with an non-specific febrile illness which quickly progressed to a severe form of interstitial pneumonia. After a careful epidemiological evaluation and laboratory analysis, murine typhus was diagnosed.

Typhus syncopalis: an epidemic in Connecticut in 1823.

PubMed

Leng, Shirie C

2012-10-01

In 1825 Dr. Thomas Miner wrote about an epidemic that occurred in Middletown, Connecticut in 1823. He called this disease "Typhus syncopalis," sinking typhus, or New England spotted fever. Differences in the understanding of disease processes in the early 19th century preclude a definitive modern equivalent fortyphus syncopalis. In addition, there are disagreements among Dr. Miners' contemporaries with regard to fever classification systems. Examination of the symptoms and physical findings as described by Dr. Miner suggest the presence of encephalitis or meningitis as well as a syndrome resembling a shock-like state. Based on symptom comparisons, this paper suggests that typhus syncopalis was likely meningococcemia caused by Neisseria meningiditis.

Some Practical Considerations in the Control of Louse-borne Typhus Fever in Great Britain in the Light of Experience in Russia, Poland, Rumania and China

PubMed Central

Mackenzie, Melville D.

1941-01-01

This paper deals with some aspects of the control of louse-borne typhus fever. The epidemic form is associated with famine and overcrowding. In producing an epidemic in a hitherto endemic area malnutrition is of greater importance than over-crowding; another factor which brings this about is widespread movement of civil or military population thus bringing non-immunes into a district where typhus is endemic. Endemic typhus usually occurs in the early months of the year, whilst the epidemic form may appear at any time. Conditions under which epidemic typhus occurs favour the outbreak of other diseases so that an uncomplicated case is rarely seen. Louse-borne typhus fever lasts from twelve to sixteen days. The incubation period is usually twelve to fourteen days, though it may be from five to twenty-one days. The onset is sudden, but is often preceded by malaise and a rise of temperature. Two common initial symptoms are acute frontal or occipital headache and bronchitis. The first sign may be mental confusion or delirium. Acute delirium is usually present after the first week. PMID:19992447

Scrub typhus: radiological and clinical findings in abdominopelvic involvement.

PubMed

Kim, Kun Yung; Song, Ji Soo; Park, Eun Hae; Jin, Gong Yong

2017-03-01

To describe the clinical and radiological findings of abdominopelvic involvement in scrub typhus. Abdominopelvic computed tomography (CT) of 78 patients with scrub typhus were evaluated by two readers. The presence of gallbladder wall thickening, arterial inhomogeneous enhancement of the liver, periportal edema, splenic infarction, hepatomegaly, splenomegaly, ascites, pleural effusion, and sites of lymphadenopathy were evaluated. Patients were divided into four clinical subgroups according to laboratory findings. Association between imaging findings and subgroups was analyzed by Chi squared test or Fisher's exact test. The most common CT finding was hepatomegaly (74.4%), followed by splenomegaly (66.7%). The majority of patients had at least three areas of abdominopelvic lymphadenopathy (71.8%). Pelvic lymphadenopathy was most commonly seen when eschar was found in the ipsilateral lower extremity (left, n = 5/7; right, n = 8/13). Significant association between hepatic dysfunction and perigastric lymphadenopathy was documented (p = 0.03). Scrub typhus has a spectrum of variable clinical and radiological findings mimicking those of acute hepatitis. Diffuse abdominopelvic lymphadenopathy involving the retroperitoneum and pelvic area may aid in early diagnosis of scrub typhus. Perigastric lymphadenopathy could be a sign of severe scrub typhus combined with hepatic dysfunction.

Molecular characterization of Orientia tsutsugamushi serotypes causing scrub typhus outbreak in southern region of Andhra Pradesh, India.

PubMed

Usha, K; Kumar, E; Kalawat, Usha; Kumar, B Siddhartha; Chaudhury, A; Gopal, D V R Sai

2016-10-01

Scrub typhus is a vector-borne zoonotic infection caused by Orientiatsutsugamushi. Local epidemiology of the circulating serotypes of scrub typhus is not available from most parts of India. We conducted this study for the diagnosis of scrub typhus using IgM ELISA and to detect O. tsutsugamushi serotypes circulating in southern Andhra Pradesh, India. Samples were collected from patients clinically suspected to have scrub typhus and were subjected to IgM ELISA to measure IgM antibodies against O. tsutsugamushi. Nested polymerase chain reaction (PCR) was performed targeting strain-specific regions in ELISA-positive samples. Of a total of 663 samples, 258 (38.91%) were found to be positive by IgM ELISA. Serotypes could be detected in 230 (34.69%) samples only. Only two serotypes, Karp and Kawasaki, were found in the serum samples, with the former being predominant. The dual infection of Karp and Kawasaki serotypes was found in seven patients. Other serotypes such as Gilliam, Kuroki and Kato were not detected in the samples. The nested PCR products proved useful in presumptively identifying the endemic O. tsutsugamushi serotypes. The present study could be significant in understanding scrub typhus epidemiology in this region.

Scrub typhus associated hepatic dysfunction and abdominal CT findings

PubMed Central

Park, Man Je; Lee, Hyoun Soo; Shim, Sang Goon; Kim, So Hee

2015-01-01

Objective: This retrospective study investigated abnormal hepatic dysfunction and abdominal computed tomography (CT) findings in scrub typhus. Methods: Three hundred forty nine adult patients were diagnosed with scrub typhus. Ninety four underwent abdominal CT. The CT images were reviewed by the attending radiologist. Patient data of history, symptoms, signs, and results of laboratory tests were collected from the electronic medical records. Results: In 349 patients with scrub typhus, elevation of aspartate aminotransferase (78.5%) and alanine aminotransferase (63.0%) were dominant compared to alkaline phosphatase (27.2%) and total bilirubin (16.1%). Abdominal CT findings of 94 patients were, in descending order of frequency, enlarged lymph node (53.2%), inhomogeneous enhancement of liver (47.9%), splenomegaly (46.8%), ascites (28.7%), low attenuation of periportal areas (27.7%), gallbladder wall thickening (17.0%), and splenic infarct (6.4%). Also, the level of aspartate aminotransferase tended to be elevated according to the number of CT findings (P= 0.028) Conclusions: We found that abdominal CT manifestations of scrub typhus with elevated aminotransferases were varied and not specific. However, knowledge of these findings may evoke the recognition of scrub typhus by clinicians in endemic areas. PMID:26101478

The Correlation of Endoscopic Findings and Clinical Features in Korean Patients with Scrub Typhus: A Cohort Study

PubMed Central

Lee, Jun; Kim, Dong-Min; Yun, Na Ra; Kim, Young Dae; Park, Chan Guk; Kim, Man Woo

2016-01-01

Scrub typhus is an infectious disease caused by Orientia tsutsugamushi-induced systemic vasculitis, but the involvement of the gastrointestinal tract and the endoscopic findings associated with scrub typhus are not well understood. We performed a prospective study and recommend performing esophagogastroduodenoscopy (EGD) for all possible scrub typhus patients, regardless of gastrointestinal symptoms. Gastrointestinal symptoms, endoscopic findings and clinical severity based on organ involvement and ICU admission were analyzed. Gastrointestinal symptoms occurred in up to 76.4% of scrub typhus patients. The major endoscopic findings were ulcers (43/127, 33.9%). Interestingly, 7.1% (9/127) of the patients presented with esophageal candidiasis. There was no correlation between the presence or absence of gastrointestinal symptoms and the endoscopic grade (P = 0.995). However, there was a positive correlation between the clinical severity and the endoscopic findings (P = 0.001). Sixty-three percent of the patients presented with erosion or ulcers on prospectively performed endoscopic evaluations, irrespective of gastrointestinal symptoms. Gastrointestinal symptoms did not reflect the need for endoscopy. Scrub typhus patients could have significant endoscopic abnormalities even in the absence of gastrointestinal symptoms. PMID:27195943

Scrub typhus islands in the Taiwan area and the association between scrub typhus disease and forest land use and farmer population density: geographically weighted regression.

PubMed

Tsai, Pui-Jen; Yeh, Hsi-Chyi

2013-04-29

The Taiwan area comprises the main island of Taiwan and several small islands located off the coast of the Southern China. The eastern two-thirds of Taiwan are characterized by rugged mountains covered with tropical and subtropical vegetation. The western region of Taiwan is characterized by flat or gently rolling plains. Geographically, the Taiwan area is diverse in ecology and environment, although scrub typhus threatens local human populations. In this study, we investigate the effects of seasonal and meteorological factors on the incidence of scrub typhus infection among 10 local climate regions. The correlation between the spatial distribution of scrub typhus and cultivated forests in Taiwan, as well as the relationship between scrub typhus incidence and the population density of farm workers is examined. We applied Pearson's product moment correlation to calculate the correlation between the incidence of scrub typhus and meteorological factors among 10 local climate regions. We used the geographically weighted regression (GWR) method, a type of spatial regression that generates parameters disaggregated by the spatial units of analysis, to detail and map each regression point for the response variables of the standardized incidence ratio (SIR)-district scrub typhus. We also applied the GWR to examine the explanatory variables of types of forest-land use and farm worker density in Taiwan in 2005. In the Taiwan Area, scrub typhus endemic areas are located in the southeastern regions and mountainous townships of Taiwan, as well as the Pescadore, Kinmen, and Matou Islands. Among these islands and low-incidence areas in the central western and southwestern regions of Taiwan, we observed a significant correlation between scrub typhus incidence and surface temperature. No similar significant correlation was found in the endemic areas (e.g., the southeastern region and the mountainous area of Taiwan). Precipitation correlates positively with scrub typhus incidence in 3 local climate regions (i.e., Taiwan's central western and southwestern regions, and the Kinmen Islands). Relative humidity correlates positively with incidence in Southwestern Taiwan and the Kinmen Islands. The number of wet days correlates positively with incidence in Southwestern Taiwan. The duration of sunshine correlates positively with incidence in Central Western Taiwan, as well as the Kinmen and Matou Islands. In addition, the 10 local climatic regions can be classified into the following 3 groups, based on the warm-cold seasonal fluctuations in scrub typhus incidence: (a) Type 1, evident in 5 local climate regions (Taiwan's northern, northwestern, northeastern, and southeastern regions, as well as the mountainous area); (b) Type 2 (Taiwan's central western and southwestern regions, and the Pescadore Islands); and (c) Type 3 (the Kinmen and Matou Islands). In the GWR models, the response variable of the SIR-district scrub typhus has a statistically significantly positive association with 2 explanatory variables (farm worker population density and timber management). In addition, other explanatory variables (recreational forests, natural reserves, and "other purpose" areas) show positive or negative signs for parameter estimates in various locations in Taiwan. Negative signs of parameter estimates occurred only for the explanatory variables of national protectorates, plantations, and clear-cut areas. The results of this study show that scrub typhus in Taiwan can be classified into 3 types. Type 1 exhibits no climatic effect, whereas the incidence of Type 2 correlates positively with higher temperatures during the warm season, and the incidence of Type 3 correlates positively with higher surface temperatures and longer hours of sunshine. The results also show that in the mountainous township areas of Taiwan's central and southern regions, as well as in Southeastern Taiwan, higher SIR values for scrub typhus are associated with the following variables: farm worker population density, timber management, and area type (i.e., recreational forest, natural reserve, or other purpose).

Scrub typhus islands in the Taiwan area and the association between scrub typhus disease and forest land use and farmer population density: geographically weighted regression

PubMed Central

2013-01-01

Background The Taiwan area comprises the main island of Taiwan and several small islands located off the coast of the Southern China. The eastern two-thirds of Taiwan are characterized by rugged mountains covered with tropical and subtropical vegetation. The western region of Taiwan is characterized by flat or gently rolling plains. Geographically, the Taiwan area is diverse in ecology and environment, although scrub typhus threatens local human populations. In this study, we investigate the effects of seasonal and meteorological factors on the incidence of scrub typhus infection among 10 local climate regions. The correlation between the spatial distribution of scrub typhus and cultivated forests in Taiwan, as well as the relationship between scrub typhus incidence and the population density of farm workers is examined. Methods We applied Pearson’s product moment correlation to calculate the correlation between the incidence of scrub typhus and meteorological factors among 10 local climate regions. We used the geographically weighted regression (GWR) method, a type of spatial regression that generates parameters disaggregated by the spatial units of analysis, to detail and map each regression point for the response variables of the standardized incidence ratio (SIR)-district scrub typhus. We also applied the GWR to examine the explanatory variables of types of forest-land use and farm worker density in Taiwan in 2005. Results In the Taiwan Area, scrub typhus endemic areas are located in the southeastern regions and mountainous townships of Taiwan, as well as the Pescadore, Kinmen, and Matou Islands. Among these islands and low-incidence areas in the central western and southwestern regions of Taiwan, we observed a significant correlation between scrub typhus incidence and surface temperature. No similar significant correlation was found in the endemic areas (e.g., the southeastern region and the mountainous area of Taiwan). Precipitation correlates positively with scrub typhus incidence in 3 local climate regions (i.e., Taiwan’s central western and southwestern regions, and the Kinmen Islands). Relative humidity correlates positively with incidence in Southwestern Taiwan and the Kinmen Islands. The number of wet days correlates positively with incidence in Southwestern Taiwan. The duration of sunshine correlates positively with incidence in Central Western Taiwan, as well as the Kinmen and Matou Islands. In addition, the 10 local climatic regions can be classified into the following 3 groups, based on the warm-cold seasonal fluctuations in scrub typhus incidence: (a) Type 1, evident in 5 local climate regions (Taiwan’s northern, northwestern, northeastern, and southeastern regions, as well as the mountainous area); (b) Type 2 (Taiwan’s central western and southwestern regions, and the Pescadore Islands); and (c) Type 3 (the Kinmen and Matou Islands). In the GWR models, the response variable of the SIR-district scrub typhus has a statistically significantly positive association with 2 explanatory variables (farm worker population density and timber management). In addition, other explanatory variables (recreational forests, natural reserves, and “other purpose” areas) show positive or negative signs for parameter estimates in various locations in Taiwan. Negative signs of parameter estimates occurred only for the explanatory variables of national protectorates, plantations, and clear-cut areas. Conclusion The results of this study show that scrub typhus in Taiwan can be classified into 3 types. Type 1 exhibits no climatic effect, whereas the incidence of Type 2 correlates positively with higher temperatures during the warm season, and the incidence of Type 3 correlates positively with higher surface temperatures and longer hours of sunshine. The results also show that in the mountainous township areas of Taiwan’s central and southern regions, as well as in Southeastern Taiwan, higher SIR values for scrub typhus are associated with the following variables: farm worker population density, timber management, and area type (i.e., recreational forest, natural reserve, or other purpose). PMID:23627966

[Epidemiology of scrub typhus and influencing factors in Yunnan province, 2006-2013].

PubMed

Sun, Y; Shi, C; Li, X L; Fang, L Q; Cao, W C

2018-01-10

Objective: To understand the epidemiological characteristics of scrub typhu s and influencing factors in Yunnan province, and provide further information for the prevention and control of scrub typhus. Methods: Based on the incidence data of scrub typhus reported in Yunnan from 2006 to 2013, the epidemiological characteristics of scrub typhus were analyzed and related environmental factors were identified with panel negative binomial regression model. Results: A total of 8 980 scrub typhus cases were reported during 2006-2013 in Yunnan. The average annual incidence was 2.46/100 000, with an uptrend observed. Natural focus expansion was found, affecting 71.3% of the counties in 2013. The epidemic mainly occurred in summer and autumn with the incidence peak during July-October. The annual incidence was higher in females than in males. More cases occurred in children and farmers, the proportions of cases in farmers and pre-school aged children showed an obvious increase. Panel negative binomial regression model indicated that the transmission risk of scrub typhus was positive associated with monthly temperature and monthly relative humidity. Furthermore, an "U" pattern between the risk and the increased coverage of cropland and grassland as well as an "inverted-U" pattern between the risk and increased coverage of shrub were observed. Conclusion: It is necessary to strengthen the scrub typhus surveillance in warm and moist areas as well as the areas with high coverage of cropland and grassland in Yunnan, and the health education in children and farmers who are at high risk.

Fatal Flea-Borne Typhus in Texas: A Retrospective Case Series, 1985–2015

PubMed Central

Pieracci, Emily G.; Evert, Nicole; Drexler, Naomi A.; Mayes, Bonny; Vilcins, Inger; Huang, Philip; Campbell, Jill; Behravesh, Casey Barton; Paddock, Christopher D.

2017-01-01

Flea-borne (murine) typhus is a global rickettsiosis caused by Rickettsia typhi. Although flea-borne typhus is no longer nationally notifiable, cases are reported for surveillance purposes in a few U.S. states. The infection is typically self-limiting, but may be severe or life-threatening in some patients. We performed a retrospective review of confirmed or probable cases of fatal flea-borne typhus reported to the Texas Department of State Health Services during 1985–2015. When available, medical charts were also examined. Eleven cases of fatal flea-borne typhus were identified. The median patient age was 62 years (range, 36–84 years) and 8 (73%) were male. Patients presented most commonly with fever (100%), nausea and vomiting (55%), and rash (55%). Respiratory (55%) and neurologic (45%) manifestations were also identified frequently. Laboratory abnormalities included thrombocytopenia (82%) and elevated hepatic transaminases (63%). Flea or animal contact before illness onset was frequently reported (55%). The median time from hospitalization to administration of a tetracycline-class drug was 4 days (range, 0–5 days). The median time from symptom onset to death was 14 days (range, 1–34 days). Flea-borne typhus can be a life-threatening disease if not treated in a timely manner with appropriate tetracycline-class antibiotics. Flea-borne typhus should be considered in febrile patients with animal or flea exposure and respiratory or neurologic symptoms of unknown etiology. PMID:28500797

Risk factors associated with severe scrub typhus in Shandong, northern China.

PubMed

Zhang, Luyan; Zhao, Zhongtang; Bi, Zhenwang; Kou, Zengqiang; Zhang, Meng; Yang, Li; Zheng, Li

2014-12-01

The aim of this study was to identify risk factors associated with severe scrub typhus, in order to provide a reference for clinical decision-making. A case-control study was conducted of scrub typhus patients who presented at local hospitals between 2010 and 2013. In total, 46 patients with severe scrub typhus complications (cases) and 194 without severe complications (controls) were included. There were significant differences in the duration of illness before effective antibiotic therapy, lymphadenopathy, rash, blood platelet count, white blood cell (WBC) count, percentage neutrophils, and percentage lymphocytes between the case and control groups. Multivariate analysis demonstrated that the following four factors were significantly associated with the severe complications of scrub typhus: (1) duration of illness before effective antibiotic therapy (odds ratio (OR) 2.287, 95% confidence interval (CI) 1.096-4.770); (2) the presence of a rash (OR 3.694, 95% CI 1.300-10.495); (3) lymphadenopathy (OR 2.438, 95% CI 1.090-5.458); (4) blood platelet count <100×10(9)/l (OR 2.226, 95% CI 1.002-4.946). This study indicates that improved diagnosis and timely treatment are important factors for the prevention of severe scrub typhus. When scrub typhus patients present with a rash, lymphadenopathy, or blood platelet count <100×10(9)/l, clinicians should be alert to the appearance of severe complications. Copyright © 2014 The Authors. Published by Elsevier Ltd.. All rights reserved.

Problem Oriented Differential Diagnosis of Tropical Diseases

DTIC Science & Technology

1989-09-01

glomerulonephritis. 13. Varicella ( chicken pox ): rare complication. II. Nephrotic syndrome A distinctive lesion associated with nephrotic syndrome in West...hypersensitivity reactions, Stevens-Johnson syndrome, toxic nephrosis, and hypoglycemia. Studies in Mexico have shown that bismuth subsalicylate tablets are...typhus fever 7 14 Murine typhus 14 26 Q fever 10 21 Rickettsial pox 3 14 Rocky mountain spotted fever 6 21 Scrub typhus 2 10 Tick-borne rickettsioses

Typhus Exanthematicus in Romania During the Second World War (1940–1945) Reflected by Romanian Medical Journals of the Time

PubMed Central

JEICAN, IONUŢ ISAIA; BOTIŞ, FLORIN OVIDIU; GHEBAN, DAN

2015-01-01

This article provides a picture of exanthematic Typhus in Romania during the Second World War: epidemiological aspects of this disease in the inner zone and in the zone of military operations, as well as information about the diagnosis, treatment and prophylaxis of the Typhus in our country during this period. PMID:26528054

Q Fever, Scrub Typhus, and Rickettsial Diseases in Children, Kenya, 2011-2012.

PubMed

Maina, Alice N; Farris, Christina M; Odhiambo, Antony; Jiang, Ju; Laktabai, Jeremiah; Armstrong, Janice; Holland, Thomas; Richards, Allen L; O'Meara, Wendy P

2016-05-01

To increase knowledge of undifferentiated fevers in Kenya, we tested paired serum samples from febrile children in western Kenya for antibodies against pathogens increasingly recognized to cause febrile illness in Africa. Of patients assessed, 8.9%, 22.4%, 1.1%, and 3.6% had enhanced seroreactivity to Coxiella burnetii, spotted fever group rickettsiae, typhus group rickettsiae, and scrub typhus group orientiae, respectively.

[Current problems in the laboratory control of louse-borne typhus infection in Ukraine].

PubMed

Klymchuk, M D

1996-01-01

Surveys designed to study spread of typhus infection (persistent form and Brill's disease), and state of laboratory diagnosis in Ukraine showed an important role the laboratory diagnosis plays in the system of epidemiological surveillance aimed at preventing epidemic typhus. Main trends of activities on perfection of the system of laboratory control of the infection under present-day conditions are outlined.

Murine typhus in two travelers returning from Bali, Indonesia: an underdiagnosed disease.

PubMed

Takeshita, Nozomi; Imoto, Kazuya; Ando, Shuji; Yanagisawa, Kunio; Ohji, Goh; Kato, Yasuyuki; Sakata, Akiko; Hosokawa, Naoto; Kishimoto, Toshio

2010-01-01

Two Japanese travelers from Bali were diagnosed with murine typhus in Japan during the same period. Although one had only mild illness, the other experienced liver and kidney dysfunction. Murine typhus may be missed not only in endemic areas around the world, but also in travelers, especially those returning from marine resorts in these areas. © 2010 International Society of Travel Medicine.

Endemic Scrub Typhus in South America.

PubMed

Weitzel, Thomas; Dittrich, Sabine; López, Javier; Phuklia, Weerawat; Martinez-Valdebenito, Constanza; Velásquez, Katia; Blacksell, Stuart D; Paris, Daniel H; Abarca, Katia

2016-09-08

Scrub typhus is a life-threatening zoonosis caused by Orientia tsutsugamushi organisms that are transmitted by the larvae of trombiculid mites. Endemic scrub typhus was originally thought to be confined to the so called "tsutsugamushi triangle" within the Asia-Pacific region. In 2006, however, two individual cases were detected in the Middle East and South America, which suggested that the pathogen was present farther afield. Here, we report three autochthonous cases of scrub typhus caused by O. tsutsugamushi acquired on Chiloé Island in southern Chile, which suggests the existence of an endemic focus in South America. (Funded by the Chilean Comisión Nacional de Investigación Científica y Tecnológica and the Wellcome Trust.).

VARIATION IN MORBIDITY AND MORTALITY OF MURINE TYPHUS INFECTION IN MICE WITH CHANGES IN THE ENVIRONMENTAL TEMPERATURE

PubMed Central

Moragues, Vicente; Pinkerton, Henry

1944-01-01

Murine typhus rickettsiae injected intraperitoneally in mice of the dba strain caused a uniformly fatal rickettsial peritonitis if the animals were kept at a room temperature ranging from 65–73°F. or from 70–80°F. With an environmental temperature range of 85–98°F., a mortality of less than 25 per cent was observed. By utilizing different strains of mice and controlling the environmental temperature, conditions may be created under which murine typhus will have any desired degree of mortality. Such conditions have obvious advantages for the evaluation of therapeutic measures in typhus infection. PMID:19871351

The genotypes of Orientia tsutsugamushi, identified in scrub typhus patients in northern Vietnam.

PubMed

Nguyen, Hang L K; Pham, Hang T T; Nguyen, Tinh V; Hoang, Phuong Vm; Le, Mai T Q; Takemura, Taichiro; Hasebe, Futoshi; Hayasaka, Daisuke; Yamada, Akio; Hotta, Kozue

2017-03-01

There are an estimated one million patients with scrub typhus in the Asia-Pacific region. There are few reports describing the incidence of scrub typhus in Vietnam. Blood samples collected from 63 patients clinically diagnosed as having scrub typhus from July 2015 to September 2016 were subjected to genotyping of Orientia tsutsugamushi. Of these patients, 42 (67%) tested positive for O. tsutsugamushi, and the most common genotype was identified to be Karp (55%). Other genotypes, TA763, Gilliam type in Japan variant, and Kato were also found in 17%, 17% and 12% of patients, respectively. To better understand the epidemiological landscape of scrub typhus in Vietnam, a countrywide study is needed. LC110330-LC110333, LC110336-LC110351 and LC214804-LC214825. © The Author 2017. Published by Oxford University Press on behalf of Royal Society of Tropical Medicine and Hygiene. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Epidemiological, clinical and laboratory profile of scrub typhus cases detected by serology and RT-PCR in Kumaon, Uttarakhand: a hospital-based study.

PubMed

Rawat, Vinita; Singh, Rajesh Kumar; Kumar, Ashok; Saxena, Sandip R; Varshney, Umesh; Kumar, Mukesh

2018-04-01

We analysed the epidemiology, clinical and laboratory data of the 168 scrub typhus cases confirmed by a combination of any one of the following: real time polymerase chain reaction (RT-PCR) and/or immunofluorescence assay (IFA) (IgM and/or IgG). The peak season for scrub typhus was from July to October. By multivariate binary logistic regression analysis, the risk of scrub typhus was about four times in those working in occupation related to forest work. Major clinical manifestations were fever (100%), myalgia (65%), cough (51%) and vomiting (46%); major complications were meningitis/meningoencephatilitis (12.5%) and multi-organ failure (MOF) and pneumonia (5.3% each). Laboratory investigations revealed raised aminotranferase levels and thrombocytopenia in most confirmed cases. We conclude that scrub typhus is an important cause of febrile illness in the Kumaon hills of Uttarakhand where this disease had not previously been considered to exist.

[Typhus fever morbidity among the military personnel and civilians in the regions around Volga river during World War I].

PubMed

Raĭkova, S V; Zav'ialov, A I

2013-07-01

The article is concerned to the materials about epidemiologic situation of typhus fever in the regions around Volga river (Saratovsky, Samarsky and others) during World War I (1914-1918) among the military personnel of the Russian army and among the civilians. The main reasons for spread of infection, ways of the transmission, and also measures for decreasing of level of morbidity on the different stages of evacuation of patients with typhus fever in the safer hospitals are shown. The most important methods of fighting against epidemic of typhus fever were: isolation of patients in separate special hospitals, desincection and disinfection measures in the foci of infection and organization appropriate sanitary conditions for military man in the army and among civilians. Acquired valuable experience of territorial and military doctors during the period of epidemic of typhus fever allowed receiving complex effective antiepidemic measures of fighting and prevention from this disease.

[Case of imported scrub typhus contracted in Myanmar].

PubMed

Matsumura, Yasufumi; Shimizu, Tsunehiro

2009-05-01

Scrub typhus is widespread in rural south and southeastern Asia and the western Pacific. The scrub typhus incidence is the highest among vector-borne diseases in Japan, but imported cases are extremely rare. A 49-year-old man admitted for persistent fever, headache, and rash after returning from Myanmar had been exposed to mosquito and tick bites while doing a 12-day forest inventory in Myanmar. On admission, he had a generalized maculopapular rash but no apparent eschars characteristic of scrub typhus. Blood examination and abdominal ultrasonography showed elevated liver enzymes, thrombocytopenia, and hepatosplenomegaly. Repeated blood smears and blood cultures were negative for malaria infection and bacteremia. Dengue fever was denied by both PCR and serology. The patient deteriorated on the ninth day and suffered complications of rhabdomyolysis, pneumonia, and enteritis. Based on a tentative diagnosis of typhoid fever or rickettiosis, we administratered ceftriaxone and minocycline, which dramatically reduced clinical signs and symptoms. After discharge on day 19, immunofluorescence assay showed significantly increased antibodies for Orienta tsutsugamushi serotype Gilliam, first discovered in Myanmar. All serological results were negative for other rickettioses, leptospirosis and Q fever. Given the many travelers from Japan visiting endemic scrub typhus areas, we must recognize cases of imported scrub typhus among those travelers with fever and rash returning from endemic areas.

Nested polymerase chain reaction on blood clots for gene encoding 56 kDa antigen and serology for the diagnosis of scrub typhus.

PubMed

Prakash, J A J; Kavitha, M L; Mathai, E

2011-01-01

Scrub typhus is a zoonotic illness endemic in the Asia-Pacific region. Early diagnosis and appropriate management contribute significantly to preventing adverse outcomes including mortality. Serology is widely used for diagnosing scrub typhus. Recent reports suggest that polymerase chain reaction (PCR) could be a rapid and reliable alternative. This study assessed the utility of these tests for scrub typhus diagnosis. Nested PCR to detect the 56 kDa antigen gene of O. tsutsugamushi was performed on blood clots from 87 individuals with clinically suspected scrub typhus. Weil-Felix test and scrub typhus IgM ELISA were performed on serum samples from the same patients. As a gold standard reference test was not available, latent class analysis (LCA) was used to assess the performance of the three tests. The LCA analysis showed the sensitivity of Weil-Felix test, IgM ELISA and PCR to be 59%, 100% and 58% respectively. The specificity of ELISA was only 73%, whereas those of the Weil-Felix test and PCR were 94% and 100% respectively. Nested PCR using blood clots while specific, lacked sensitivity as compared to IgM ELISA. In resource-poor settings Weil-Felix test still remains valuable despite its moderate sensitivity.

Clinical proteomic analysis of scrub typhus infection.

PubMed

Park, Edmond Changkyun; Lee, Sang-Yeop; Yun, Sung Ho; Choi, Chi-Won; Lee, Hayoung; Song, Hyun Seok; Jun, Sangmi; Kim, Gun-Hwa; Lee, Chang-Seop; Kim, Seung Il

2018-01-01

Scrub typhus is an acute and febrile infectious disease caused by the Gram-negative α-proteobacterium Orientia tsutsugamushi from the family Rickettsiaceae that is widely distributed in Northern, Southern and Eastern Asia. In the present study, we analysed the serum proteome of scrub typhus patients to investigate specific clinical protein patterns in an attempt to explain pathophysiology and discover potential biomarkers of infection. Serum samples were collected from three patients (before and after treatment with antibiotics) and three healthy subjects. One-dimensional sodium dodecyl sulphate-polyacrylamide gel electrophoresis followed by liquid chromatography-tandem mass spectrometry was performed to identify differentially abundant proteins using quantitative proteomic approaches. Bioinformatic analysis was then performed using Ingenuity Pathway Analysis. Proteomic analysis identified 236 serum proteins, of which 32 were differentially expressed in normal subjects, naive scrub typhus patients and patients treated with antibiotics. Comparative bioinformatic analysis of the identified proteins revealed up-regulation of proteins involved in immune responses, especially complement system, following infection with O. tsutsugamushi , and normal expression was largely rescued by antibiotic treatment. This is the first proteomic study of clinical serum samples from scrub typhus patients. Proteomic analysis identified changes in protein expression upon infection with O. tsutsugamushi and following antibiotic treatment. Our results provide valuable information for further investigation of scrub typhus therapy and diagnosis.

Scrub typhus re-emergence in India: Contributing factors and way forward.

PubMed

Ranjan, Jai; Prakash, John Antony Jude

2018-06-01

Scrub typhus is a mite borne infectious disease which has re-emerged in India in the 3rd millennium after years of quiescence. In this review, the authors hypothesize the various factors responsible for resurgence of this disease. The main drivers that could have contributed to the upsurge in scrub typhus cases in past two decades are changes in land use land cover (LULC) and urbanisation which are; as a result of the population explosion, causing a strain on sanitation and also increased diversion of forest land for agricultural use. In addition, the availability of better tests, changes in antimicrobial use, climate change also could have impacted the epidemiology, which is showing an upward trend as is evidenced by increasing reports and concomitant publications from India on scrub typhus. Scrub typhus cases are supposed to increase in the coming years as factors like global warming, urbanisation, changes in LULC and rise in AMR (anti-microbial resistance) will be difficult or impossible to control. Therefore, increasing awareness of public and health care professionals regarding scrub typhus coupled with availability of rapid diagnostic assays and implementation of appropriate treatment protocols for control of AFI (acute febrile illness) especially at the community level will help mitigate the scenario in the long run. Copyright © 2018. Published by Elsevier Ltd.

Epidemic characteristics and spatio-temporal patterns of scrub typhus during 2006-2013 in Tai'an, Northern China.

PubMed

Zheng, L; Yang, H-L; Bi, Z-W; Kou, Z-Q; Zhang, L-Y; Zhang, A-H; Yang, L; Zhao, Z-T

2015-08-01

Tai'an, a famous cultural tourist district, is a new endemic foci of scrub typhus in northern China. Frequent reports of travel-acquired cases and absence of effective vaccine indicated a significant health problem of scrub typhus in Tai'an. Thus, descriptive epidemiological methods and spatial-temporal scan statistics were used to describe the epidemic characteristics and detect the significant clusters of the high incidence of scrub typhus at the town level in Tai'an. Results of descriptive epidemiological analysis showed a total of 490 cases were reported in Tai'an with the annual average incidence ranging from 0·48 to 2·27/100 000 during 2006-2013. Females, the elderly and farmers are the high-risk groups. Monthly changes of scrub typhus cases indicated an obvious epidemic period in autumn. Spatial-temporal distribution analysis, showed significant clusters of high incidence mainly located in eastern and northern Tai'an. Our study suggests that more effective, targeted measures for local residents should be implemented in the eastern and northern areas of Tai'an in autumn. Meanwhile, it may prove beneficial for health policy makers to advise travellers to take preventive measures in order to minimize the risk of infection of scrub typhus in Tai'an.

The clinical characteristics of pleural effusion in scrub typhus.

PubMed

Kim, Hyung Ho; Chung, Jong-Hoon; Kim, Dong-Min; Yun, Na Ra; Lee, Jun; Kwon, Yong Eun; Yoon, Sung Ho; Lee, Seung Il; Han, Mi Ah

2016-06-11

The aim of this study is to identify the factors associated with the occurrence of pleural effusion and to investigate the characteristics of pleural effusion in scrub typhus. We conducted a retrospective analysis of the medical records of scrub typhus patients between January 2004 and December 2011 at Chosun University Hospital in South Korea. A total of 445 scrub typhus patients were divided into the following two groups: without (n = 352) or with pleural effusion (n = 93). The data of 18 scrub typhus patients who underwent thoracentesis were summarized. Multivariate analysis demonstrated that the following factors were associated with the occurrence of pleural effusion in scrub typhus: older age (odds ratio [OR] = 1.029, P = 0.037, confidence interval [CI] = 1.002-1.056); male gender (OR = 1.924, P = 0.020, CI = 1.109-3.340); presence of heart failure (OR = 2.628, P = 0.039, CI = 1.052-6.565); and lower albumin (OR = 0.107, P ≤ 0.001, CI = 0.058-0.196). Most pleural effusion presentations were bilateral (88 %) and small (91 %). The effusion had transudate characteristics in 7 patients and exudate characteristics in 11 patients based on Light's criteria. This study provided the first data regarding the following four independent risk factors associated with the occurrence of pleural effusion: older age; male gender; the presence of heart failure; and lower albumin. The pleural effusion presentations in scrub typhus patients were bilateral and small in most cases, with transudate and/or exudate characteristics.

Scrub typhus in rural Rajasthan and a review of other Indian studies.

PubMed

Masand, Rupesh; Yadav, Ritesh; Purohit, Alok; Tomar, Balvir Singh

2016-05-01

Scrub typhus is an acute febrile illness which has been reported from various parts of India with Rajasthan recently joining the list of affected states. To report a series of paediatric scrub typhus cases from rural Rajasthan. Retrospective review of children with scrub typhus admitted to the wards and paediatric intensive care unit (PICU) of a tertiary-care hospital. The study was undertaken over an 8-month period from May to December 2013. All patients with a clinical presentation and/or serological confirmation of scrub typhus who tested negative for malaria, enteric fever, dengue, leptospirosis and urinary tract infection (UTI) were included. A range of investigations were undertaken including IgM-ELISA for scrub typhus, followed by appropriate medical management. Thirty patients satisfied the inclusion criteria. The mean (SD, range) age of the patients was 8·56 (3·43, 3-16) years. The most common clinical features were fever (n = 30, 100%), headache (n = 20, 66%), myalgia (n = 15, 50%), hepatosplenomegaly (n = 18, 60%) and pallor (n = 5, 16%). Typical features such as eschar and rash were observed in only one (3·3%) and three (10%) patients, respectively; none had generalised lymphadenopathy or conjunctival congestion. IgM-ELISA for scrub typhus was positive in 28 patients (93·3%) and 27 responded to doxycycline within 24-72 hours. One of the three patients who required PICU support responded to intravenous chloramphenicol and, of the other two (6·6%), one died of acute respiratory distress syndrome and the other owing to acute renal failure. A high index of suspicion is essential for early diagnosis and prevention of complications in scrub typhus together with prompt referral from rural areas to a higher centre. Awareness of the disease manifestations may further help to prevent excessive investigations in patients presenting with non-specific febrile illness and reduce the economic burden to the family and society in resource-constrained settings.

Scrub typhus in rural Rajasthan and a review of other Indian studies.

PubMed

Masand, Rupesh; Yadav, Ritesh; Purohit, Alok; Tomar, Balvir Singh

2016-01-09

Scrub typhus is an acute febrile illness which has been reported from various parts of India with Rajasthan recently joining the list of affected states. To report a series of paediatric scrub typhus cases from rural Rajasthan. Retrospective review of children with scrub typhus admitted to the wards and paediatric intensive care unit (PICU) of a tertiary-care hospital. The study was undertaken over an 8-month period from May to December 2013. All patients with a clinical presentation and/or serological confirmation of scrub typhus who tested negative for malaria, enteric fever, dengue, leptospirosis and urinary tract infection (UTI) were included. A range of investigations were undertaken including IgM-ELISA for scrub typhus, followed by appropriate medical management. Thirty patients satisfied the inclusion criteria. The mean (SD, range) age of the patients was 8·56 (3·43, 3-16) years. The most common clinical features were fever (n = 30, 100%), headache (n = 20, 66%), myalgia (n = 15, 50%), hepatosplenomegaly (n = 18, 60%) and pallor (n = 5, 16%). Typical features such as eschar and rash were observed in only one (3·3%) and three (10%) patients, respectively; none had generalised lymphadenopathy or conjunctival congestion. IgM-ELISA for scrub typhus was positive in 28 patients (93·3%) and 27 responded to doxycycline within 24-72 hours. One of the three patients who required PICU support responded to intravenous chloramphenicol and, of the other two (6·6%), one died of acute respiratory distress syndrome and the other owing to acute renal failure. A high index of suspicion is essential for early diagnosis and prevention of complications in scrub typhus together with prompt referral from rural areas to a higher centre. Awareness of the disease manifestations may further help to prevent excessive investigations in patients presenting with non-specific febrile illness and reduce the economic burden to the family and society in resource-constrained settings.

A Systematic Review of Mortality from Untreated Scrub Typhus (Orientia tsutsugamushi).

PubMed

Taylor, Andrew J; Paris, Daniel H; Newton, Paul N

2015-01-01

Scrub typhus, a bacterial infection caused by Orientia tsutsugamushi, is increasingly recognized as an important cause of fever in Asia, with an estimated one million infections occurring each year. Limited access to health care and the disease's non-specific symptoms mean that many patients are undiagnosed and untreated, but the mortality from untreated scrub typhus is unknown. This review systematically summarizes the literature on the untreated mortality from scrub typhus and disease outcomes. A literature search was performed to identify patient series containing untreated patients. Patients were included if they were symptomatic and had a clinical or laboratory diagnosis of scrub typhus and excluded if they were treated with antibiotics. The primary outcome was mortality from untreated scrub typhus and secondary outcomes were total days of fever, clinical symptoms, and laboratory results. A total of 76 studies containing 89 patient series and 19,644 patients were included in the final analysis. The median mortality of all patient series was 6.0% with a wide range (min-max) of 0-70%. Many studies used clinical diagnosis alone and had incomplete data on secondary outcomes. Mortality varied by location and increased with age and in patients with myocarditis, delirium, pneumonitis, or signs of hemorrhage, but not according to sex or the presence of an eschar or meningitis. Duration of fever was shown to be long (median 14.4 days Range (9-19)). Results show that the untreated mortality from scrub typhus appears lower than previously reported estimates. More data are required to clarify mortality according to location and host factors, clinical syndromes including myocarditis and central nervous system disease, and in vulnerable mother-child populations. Increased surveillance and improved access to diagnostic tests are required to accurately estimate the untreated mortality of scrub typhus. This information would facilitate reliable quantification of DALYs and guide empirical treatment strategies.

Characterization of the rhesus macaque (Macaca mulatta) scrub typhus model: Susceptibility to intradermal challenge with the human pathogen Orientia tsutsugamushi Karp

PubMed Central

Sunyakumthorn, Piyanate; Somponpun, Suwit J.; Im-erbsin, Rawiwan; Anantatat, Tippawan; Jenjaroen, Kemajittra; Dunachie, Susanna J.; Lombardini, Eric D.; Burke, Robin L.; Blacksell, Stuart D.; Jones, James W.; Mason, Carl J.; Richards, Allen L.; Day, Nicholas P. J.

2018-01-01

Background Scrub typhus is an important endemic disease in tropical Asia caused by Orientia tsutsugamushi for which no effective broadly protective vaccine is available. The successful evaluation of vaccine candidates requires well-characterized animal models and a better understanding of the immune response against O. tsutsugamushi. While many animal species have been used to study host immunity and vaccine responses in scrub typhus, only limited data exists in non-human primate (NHP) models. Methodology/Principle findings In this study we evaluated a NHP scrub typhus disease model based on intradermal inoculation of O. tsutsugamushi Karp strain in rhesus macaques (n = 7). After an intradermal inoculation with 106 murine LD50 of O. tsutsugamushi at the anterior thigh (n = 4) or mock inoculum (n = 3), a series of time course investigations involving hematological, biochemical, molecular and immunological assays were performed, until day 28, when tissues were collected for pathology and immunohistochemistry. In all NHPs with O. tsutsugamushi inoculation, but not with mock inoculation, the development of a classic eschar with central necrosis, regional lymphadenopathy, and elevation of body temperature was observed on days 7–21 post inoculation (pi); bacteremia was detected by qPCR on days 6–18 pi; and alteration of liver enzyme function and increase of white blood cells on day 14 pi. Immune assays demonstrated raised serum levels of soluble cell adhesion molecules, anti-O. tsutsugamushi-specific antibody responses (IgM and IgG) and pathogen-specific cell-mediated immune responses in inoculated macaques. The qPCR assays detected O. tsutsugamushi in eschar, spleen, draining and non-draining lymph nodes, and immuno-double staining demonstrated intracellular O. tsutsugamushi in antigen presenting cells of eschars and lymph nodes. Conclusions/Significance These data show the potential of using rhesus macaques as a scrub typhus model, for evaluation of correlates of protection in both natural and vaccine induced immunity, and support the evaluation of future vaccine candidates against scrub typhus. PMID:29522521

[Petechial typhus in Napoleonic Italy. Scientific debate and the role of Giovanni Rasori].

PubMed

Sabbatani, Sergio

2006-12-01

During the Napoleonic wars, an epidemic recrudescence of petechial typhus was observed throughout Europe. In Italy, the epidemic first broke out in Genoa, in 1799, coming from southern France, during the sieges of the Austro-Hungarian army. Giovanni Rasori, a young Republican physician and man of the sciences, supported the besieged and contributed to defend the city. From the beginning, Rasori identified the cause of the epidemic in petechial typhus, being able to evaluate its clinical presentation, and developed a pathogenetic theory, known as contrastimulus. At that time, this theory obtained some success, though opposed by the academic establishment in Lombardy. In this article, we present the medical and philosophical ideas which, in the period between the 18th and 19th century, pervaded medical Italian culture. Furthermore, a biographic profile of Giovanni Rasori is described, a courageous scientist who did not disdain to take part in political and cultural Italian life during a historical period that was to become important for the future fortunes of Italy.

Entomology with the U.S. Marines in Vietnam - Some Lessons Learned

DTIC Science & Technology

2008-11-16

these areas, and capability of individual commands. malaria, dengue, encephalitis, plague, This included the provision of scrub typhus and filariasis...any, probably due to the large, mobile was not available at the time. About 22 parasite reservoir (NVA, VC & local cases of scrub typhus occurred in...of light traps was November in Danang. often a challenge. Their use in the Filariasis, Scrub Typhus & Plague. "bush" was not feasible for security

Hemorrhagic Fever With Renal Syndrome (Korean Hemorrhagic Fever).

DTIC Science & Technology

1992-04-30

serologically in 1990 and 1991 were 1,043 and 956, respectively and large outbreaks of scrub typhus, murine typhus, leptospirosis and spotted fever...and leptospirosis occured during epidemic season of HFRS in 1986 and nos. of confirmed patients serologically at our laboratory were 215 and 64, respn...ctive’ly. It ,"’s demonstrated that fieia mice and wild rats are reservoir hosts of HFRS, scrub typhus and leptospirosis in Korea. Global distribution

A stranger to our camps: Typhus in American history.

PubMed

Humphreys, Margaret

2006-01-01

Medical observers during the American Civil War were happily surprised to find that typhus fever rarely made an appearance, and was not a major killer in the prisoner-of-war camps where the crowded, filthy, and malnourished populations appeared to offer an ideal breeding ground for the disease. Through a review of apparent typhus outbreaks in America north of the Mexican border, this article argues that typhus fever rarely if ever extended to the established populations of the United States, even when imported on immigrant ships into densely populated and unsanitary slums. It suggests that something in the American environment was inhospitable to the extensive spread of the disease, most likely an unrecognized difference in the North American louse population compared to that of Europe.

The history of epidemic typhus.

PubMed

Raoult, Didier; Woodward, Theodore; Dumler, J Stephen

2004-03-01

Few infectious diseases have influenced human civilization to the same degree as louse-transmitted typhus. Rickettsia prowazekii continues to strikes tens to hundreds of thousands of persons who live with war, famine, crowding, and in squalid conditions associated with social unrest, with mortality rates in excess of 10% to 15%. Historical documents confirm that such devastation has been a continuous feature of human existence to the extent that typhus has been a major determinant in the outcome of many wars, altering human history in its wake-despite incomplete knowledge of its precise origin. In the twenty-first century, circumstances are still conductive for outbreak; the emerging threat of bioterrorism raises justifiable concerns that typhus could affect civilization just as greatly in the future as it has in the past.

Typhus, yellow fever and Medicine in Mexico during the French intervention

PubMed

Gerardo-Ramírez, Monserrat; Zavaleta-Castro, Jesús; Gómez-Quiroz, Luis Enrique

2018-01-01

French intervention in Mexico (1861-1867) is particularly full of episodes of patriotic heroism in terms of military, politic and, even, religious affairs, however this history is also rich in episodes related to diseases and the evolution of Mexican scientific medicine practice, epidemics such as typhus (nowadays knows as rickettsiosis), yellow fever, or cholera. Principally, this context outlined the Mexican history and influenced the course of the nation. The epidemics served as fertile land for the development of medicine science leading by prominent physicians, particularly by doctor Miguel Francisco Jiménez. Copyright: © 2018 SecretarÍa de Salud.

Human louse-transmitted infectious diseases.

PubMed

Badiaga, S; Brouqui, P

2012-04-01

Several of the infectious diseases associated with human lice are life-threatening, including epidemic typhus, relapsing fever, and trench fever, which are caused by Rickettsia prowazekii, Borrelia recurrentis, and Bartonella quintana, respectively. Although these diseases have been known for several centuries, they remain a major public health concern in populations living in poor-hygiene conditions because of war, social disruption, severe poverty, or gaps in public health management. Poor-hygiene conditions favour a higher prevalence of body lice, which are the main vectors for these diseases. Trench fever has been reported in both developing and developed countries in populations living in poor conditions, such as homeless individuals. In contrast, outbreaks of epidemic typhus and epidemic relapsing fever have occurred in jails and refugee camps in developing countries. However, reports of a significantly high seroprevalence for epidemic typhus and epidemic relapsing fever in the homeless populations of developed countries suggest that these populations remain at high risk for outbreaks of these diseases. Additionally, experimental laboratory studies have demonstrated that the body louse can transmit other emerging or re-emerging pathogens, such as Acinetobacter baumannii and Yersinia pestis. Therefore, a strict survey of louse-borne diseases and the implementation of efficient delousing strategies in these populations should be public health priorities. © 2012 The Authors. Clinical Microbiology and Infection © 2012 European Society of Clinical Microbiology and Infectious Diseases.

Urbanization of Scrub Typhus Disease in South Korea

PubMed Central

Park, Sang-Won; Ha, Na-Young; Ryu, Boyeong; Bang, Ji Hwan; Song, Hoyeon; Kim, Yuri; Kim, Gwanghun; Oh, Myoung-don; Cho, Nam-Hyuk; Lee, Jong-koo

2015-01-01

Background Scrub typhus is an endemic disease in Asia. It has been a rural disease, but indigenous urban cases have been observed in Seoul, South Korea. Urban scrub typhus may have a significant impact because of the large population. Methods Indigenous urban scrub typhus was epidemiologically identified in Seoul, the largest metropolitan city in South Korea, using national notifiable disease data from 2010 to 2013. For detailed analysis of clinical features, patients from one hospital that reported the majority of cases were selected and compared to a historic control group. Chigger mites were prospectively collected in the city using a direct chigger mite-collecting trap, and identified using both phenotypic and 18S rDNA sequencing analyses. Their infection with Orientia tsutsugamushi was confirmed by sequencing the 56-kDa antigen gene. Results Eighty-eight cases of urban scrub typhus were determined in Seoul. The possible sites of infection were mountainous areas (56.8%), city parks (20.5%), the vicinity of one’s own residence (17.0%), and riversides (5.7%). Eighty-seven chigger mites were collected in Gwanak mountain, one of the suspected infection sites in southern Seoul, and seventy-six (87.4%) of them were identified as Helenicula miyagawai and eight (9.2%) as Leptotrombidium scutellare. Pooled DNA extracted from H. miyagawai mites yielded O. tsutsugamushi Boryong strain. Twenty-six patients from one hospital showed low APACHE II score (3.4 ± 2.7), low complication rate (3.8%), and no hypokalemia. Conclusions We identified the presence of indigenous urban scrub typhus in Seoul, and a subgroup of them had mild clinical features. The chigger mite H. miyagawai infected with O. tsutsugamushi within the city was found. In endemic area, urban scrub typhus needs to be considered as one of the differential febrile diseases and a target for prevention. PMID:26000454

Significance of major international seaports in the distribution of murine typhus in Taiwan.

PubMed

Kuo, Chi-Chien; Wardrop, Nicola; Chang, Chung-Te; Wang, Hsi-Chieh; Atkinson, Peter M

2017-03-01

International seaports are hotspots for disease invasion and pathogens can persist in seaports even after ports are abandoned. Transmitted by fleas infected by Rickettsia typhi, murine typhus, a largely neglected and easily misdiagnosed disease, is known to occur primarily in large seaports. However, the significance of seaports in the occurrence of murine typhus has never been validated quantitatively. We studied the spatial distribution of murine typhus, a notifiable disease, in Taiwan. We investigated whether risk of infection was correlated with distance to international seaports and a collection of environmental and socioeconomic factors, using a Bayesian negative binomial conditionally autoregressive model, followed with geographically weighted regression. Seaports that are currently in use and those that operated in the 19th century for trade with China, but were later abandoned due to siltation were analyzed. A total of 476 human cases of murine typhus were reported during 2000-2014 in the main island of Taiwan, with spatial clustering in districts in southwest and central-west Taiwan. A higher incidence rate (case/population) was associated with a smaller distance to currently in-use international seaports and lower rainfall and temperature, but was uncorrelated with distance to abandoned ports. Geographically weighted regression revealed a geographic heterogeneity in the importance of distance to in-use seaports near the four international seaports of Taiwan. Our study suggests that murine typhus is associated with international seaports, especially for those with large trading volume. Thus, one of the costs of global trade in Taiwan might be elevated risks of murine typhus. Globalization has accelerated the spread of infectious diseases, but the burden of disease varies geographically, with regions surrounding major international seaports warranting particular surveillance.

Significance of major international seaports in the distribution of murine typhus in Taiwan

PubMed Central

Wardrop, Nicola; Chang, Chung-Te; Wang, Hsi-Chieh; Atkinson, Peter M.

2017-01-01

Background International seaports are hotspots for disease invasion and pathogens can persist in seaports even after ports are abandoned. Transmitted by fleas infected by Rickettsia typhi, murine typhus, a largely neglected and easily misdiagnosed disease, is known to occur primarily in large seaports. However, the significance of seaports in the occurrence of murine typhus has never been validated quantitatively. Methodology/Principal findings We studied the spatial distribution of murine typhus, a notifiable disease, in Taiwan. We investigated whether risk of infection was correlated with distance to international seaports and a collection of environmental and socioeconomic factors, using a Bayesian negative binomial conditionally autoregressive model, followed with geographically weighted regression. Seaports that are currently in use and those that operated in the 19th century for trade with China, but were later abandoned due to siltation were analyzed. A total of 476 human cases of murine typhus were reported during 2000–2014 in the main island of Taiwan, with spatial clustering in districts in southwest and central-west Taiwan. A higher incidence rate (case/population) was associated with a smaller distance to currently in-use international seaports and lower rainfall and temperature, but was uncorrelated with distance to abandoned ports. Geographically weighted regression revealed a geographic heterogeneity in the importance of distance to in-use seaports near the four international seaports of Taiwan. Conclusions/Significance Our study suggests that murine typhus is associated with international seaports, especially for those with large trading volume. Thus, one of the costs of global trade in Taiwan might be elevated risks of murine typhus. Globalization has accelerated the spread of infectious diseases, but the burden of disease varies geographically, with regions surrounding major international seaports warranting particular surveillance. PMID:28264003

Serological Diagnosis of Acute Scrub Typhus in Southern India: Evaluation of InBios Scrub Typhus Detect IgM Rapid Test and Comparison with other Serological Tests.

PubMed

Anitharaj, Velmurugan; Stephen, Selvaraj; Pradeep, Jothimani; Park, Sungman; Kim, Seung-Han; Kim, Young Jin; Kim, Eun-Ye; Kim, Yoon-Won

2016-11-01

Scrub Typhus (ST) is being reported from different parts of India in the recent past. However, the diagnosis and confirmation of ST cases require specific serological and molecular diagnostic tests. Both rapid and conventional ELISA tests need to be properly evaluated. Evaluation of a new ST IgM Immunochromatography (ICT) test kit (InBios Scrub Typhus Detect IgM Rapid Test) and compare it with another rapid kit, conventional ELISA kit and Weil-Felix (WF) test. This prospective study was carried out in Mahatma Gandhi Medical College and Research Institute, Puducherry, during November 2015 to June 2016. Clinically suspected 220 ST patients were examined by a new kit, InBios Scrub Typhus Detect IgM Rapid Test, taking the conventional InBios Scrub Typhus Detect IgM ELISA as reference. Additional comparison was made with ImmuneMed Scrub Typhus Rapid, and WF test (single OXK titers ≥1:320). Statistical analysis was performed (Chi-square, Spearman's correlation and Kappa) using IBM SPSS Statistics 17 for Windows (SPSS Inc; Chicago, USA). Percentage Sensitivity, Specificity, Positive Predictive and Negative Predictive Values for InBios, ImmuneMed and WF were 99.25, 93.02, 95.68, 98.77; 94.87, 94.19, 96.21, 92.05 and 50.38, 95.51, 94.29, 56.67 respectively. A total of 134 patients were positive in reference standard InBios IgM ELISA. This new rapid ST IgM kit validated for the first time in India, showed good sensitivity and specificity. As a Point-of-Care (PoC) test, the kit would be helpful in both urban and remote rural parts of India.

Serological Diagnosis of Acute Scrub Typhus in Southern India: Evaluation of InBios Scrub Typhus Detect IgM Rapid Test and Comparison with other Serological Tests

PubMed Central

Anitharaj, Velmurugan; Pradeep, Jothimani; Park, Sungman; Kim, Seung-Han; Kim, Young Jin; Kim, Eun-Ye; Kim, Yoon-Won

2016-01-01

Introduction Scrub Typhus (ST) is being reported from different parts of India in the recent past. However, the diagnosis and confirmation of ST cases require specific serological and molecular diagnostic tests. Both rapid and conventional ELISA tests need to be properly evaluated. Aim Evaluation of a new ST IgM Immunochromatography (ICT) test kit (InBios Scrub Typhus Detect IgM Rapid Test) and compare it with another rapid kit, conventional ELISA kit and Weil-Felix (WF) test. Materials and Methods This prospective study was carried out in Mahatma Gandhi Medical College and Research Institute, Puducherry, during November 2015 to June 2016. Clinically suspected 220 ST patients were examined by a new kit, InBios Scrub Typhus Detect IgM Rapid Test, taking the conventional InBios Scrub Typhus Detect IgM ELISA as reference. Additional comparison was made with ImmuneMed Scrub Typhus Rapid, and WF test (single OXK titers ≥1:320). Statistical analysis was performed (Chi-square, Spearman’s correlation and Kappa) using IBM SPSS Statistics 17 for Windows (SPSS Inc; Chicago, USA). Results Percentage Sensitivity, Specificity, Positive Predictive and Negative Predictive Values for InBios, ImmuneMed and WF were 99.25, 93.02, 95.68, 98.77; 94.87, 94.19, 96.21, 92.05 and 50.38, 95.51, 94.29, 56.67 respectively. A total of 134 patients were positive in reference standard InBios IgM ELISA. Conclusion This new rapid ST IgM kit validated for the first time in India, showed good sensitivity and specificity. As a Point-of-Care (PoC) test, the kit would be helpful in both urban and remote rural parts of India. PMID:28050364

Scrub typhus

PubMed Central

Rapsang, Amy G; Bhattacharyya, Prithwis

2013-01-01

Scrub typhus is an acute febrile illness caused by orientia tsutsugamushi, transmitted to humans by the bite of the larva of trombiculid mites. It causes a disseminated vasculitic and perivascular inflammatory lesions resulting in significant vascular leakage and end-organ injury. It affects people of all ages and even though scrub typhus in pregnancy is uncommon, it is associated with increased foetal loss, preterm delivery, and small for gestational age infants. After an incubation period of 6-21 days, onset is characterized by fever, headache, myalgia, cough, and gastrointestinal symptoms. A primary papular lesion which later crusts to form a flat black eschar, may be present. If untreated, serious complications may occur involving various organs. Laboratory studies usually reveal leukopenia, thrombocytopenia, deranged hepatic and renal function, proteinuria and reticulonodular infiltrate. Owing to the potential for severe complications, diagnosis, and decision to initiate treatment should be based on clinical suspicion and confirmed by serologic tests. A therapeutic trial of tetracycline or chloramphenicol is indicated in patients in whom the diagnosis of scrub typhus is suspected. The recommended treatment regimen for scrub typhus is doxycycline. Alternative regimens include tetracycline, chloramphenicol, azithromycin, ciprofloxacin, rifampicin, and roxithromycin. Treatment of pregnant women with azithromycin was successfully done without relapse and with favorable pregnancy outcomes. Hence, early diagnosis and treatment are essential in order to reduce the mortality and the complications associated with the disease. We searched the English-language literature for reports of scrub typhus in children, pregnant women, and non-pregnant patients with scrub typhus, using the MEDLINE/PubMed database, which includes citations from 1945 to the present time. We used the search terms ‘scrub typhus’, ‘scrub typhus’ and ‘pregnancy’, ‘scrub typhus’ and ‘children’, ‘scrub typhus’ and ‘complications’, ‘scrub typhus’ and ‘treatment’. PMID:23825810

Urbanization of scrub typhus disease in South Korea.

PubMed

Park, Sang-Won; Ha, Na-Young; Ryu, Boyeong; Bang, Ji Hwan; Song, Hoyeon; Kim, Yuri; Kim, Gwanghun; Oh, Myoung-don; Cho, Nam-Hyuk; Lee, Jong-koo

2015-05-01

Scrub typhus is an endemic disease in Asia. It has been a rural disease, but indigenous urban cases have been observed in Seoul, South Korea. Urban scrub typhus may have a significant impact because of the large population. Indigenous urban scrub typhus was epidemiologically identified in Seoul, the largest metropolitan city in South Korea, using national notifiable disease data from 2010 to 2013. For detailed analysis of clinical features, patients from one hospital that reported the majority of cases were selected and compared to a historic control group. Chigger mites were prospectively collected in the city using a direct chigger mite-collecting trap, and identified using both phenotypic and 18S rDNA sequencing analyses. Their infection with Orientia tsutsugamushi was confirmed by sequencing the 56-kDa antigen gene. Eighty-eight cases of urban scrub typhus were determined in Seoul. The possible sites of infection were mountainous areas (56.8%), city parks (20.5%), the vicinity of one's own residence (17.0%), and riversides (5.7%). Eighty-seven chigger mites were collected in Gwanak mountain, one of the suspected infection sites in southern Seoul, and seventy-six (87.4%) of them were identified as Helenicula miyagawai and eight (9.2%) as Leptotrombidium scutellare. Pooled DNA extracted from H. miyagawai mites yielded O. tsutsugamushi Boryong strain. Twenty-six patients from one hospital showed low APACHE II score (3.4 ± 2.7), low complication rate (3.8%), and no hypokalemia. We identified the presence of indigenous urban scrub typhus in Seoul, and a subgroup of them had mild clinical features. The chigger mite H. miyagawai infected with O. tsutsugamushi within the city was found. In endemic area, urban scrub typhus needs to be considered as one of the differential febrile diseases and a target for prevention.

Scrub typhus in Uttarakhand & adjoining Uttar Pradesh: Seasonality, clinical presentations & predictors of mortality.

PubMed

Bhargava, Anurag; Kaushik, Reshma; Kaushik, Rajeev Mohan; Sharma, Anita; Ahmad, Sohaib; Dhar, Minakshi; Mittal, Garima; Khanduri, Sushant; Pant, Priyannk; Kakkar, Rajesh

2016-12-01

Scrub typhus is a re-emerging mite-borne rickettsiosis, which continues to be underdiagnosed, with lethal consequences. The present study was conducted to determine the seasonality, clinical presentation and predictors of mortality in patients with scrub typhus at a tertiary care teaching hospital in northern India. Scrub typhus was suspected in patients attending the hospital as per the standard case definition and serological evidence was obtained by performing an IgM ELISA. A total of 284 patients with scrub typhus from urban and rural areas were seen, predominantly from July to November. The most common clinical presentation was a bilateral community-acquired pneumonia (CAP), which resembled pneumonia due to atypical pathogens and often progressed to acute respiratory distress syndrome (ARDS). An acute undifferentiated febrile illness (AUFI) or a febrile illness associated with altered sensorium, aseptic meningitis, shock, abdominal pain, gastrointestinal bleeding or jaundice was also seen. Eschars were seen in 17 per cent of patients, and thrombocytopenia, transaminitis and azotaemia were frequent. There were 24 deaths (8.5%) caused predominantly by ARDS and multi-organ dysfunction. The mortality in patients with ARDS was high (37%). ARDS [odds ratio (OR)=38.29, 95% confidence interval (CI): 9.93, 147.71] and acute kidney injury (OR=8.30, 95% CI: 2.21, 31.21) were the major predictors of death. The present findings indicate that scrub typhus may be considered a cause of CAP, ARDS, AUFI or a febrile illness with multisystem involvement, in Uttarakhand and Uttar Pradesh, especially from July to November. Empiric therapy of CAP may include doxycycline or azithromycin to ensure coverage of underlying unsuspected scrub typhus.

Leptospirosis Scrub Typhus and Colorado Tick Fever Like Disease in Korea

DTIC Science & Technology

1991-01-24

leptospirosis in humanm, serological surveys will also be done in bovine and swine populations to assess the distribution, serotypes and prevalence of...34AD-A2 35 000 AD______ GRANT NO: DAND17-88-Z-8042 TITLE: LEPTOSPIROSIS , SCRUB TYPHUS AND COLORADO TICK FEVER LIKE DISEASE IN KOREA PRINCIPAL...21702-5012 63807A 63807D809 AN A315678 11. TITLE (Inc•ude Security Classfication) LEPTOSPIROSIS , SCRUB TYPHUS AND COLORADO TICK FEVER LIKE DISEASE IN

[Poland: cholera to typhus, 1831-1950].

PubMed

Balinska, M A

1999-12-01

In this article devoted to Poland's direct and indirect role in the elaboration of contemporary international health structures and to her reputation as an epidemic reservoir of Europe, we consider how Poland came to be perceived as the cordon sanitaire of the West. Traditionally seen as upholding Western values, in the 19th and 20th centuries the country became increasingly associated with "Eastern plagues"-cholera and then typhus-coming from Russia and which could spread to the rest of Europe if Poland did not manage to contain them. When Poland was reconstituted as a nation-state in 1918, the new country won international recognition through her successful attempts to contain a typhus epidemic sweeping westwards from Russia. The Polish government convened the first European, League sponsored, health conference following the First World War. A Polish doctor, L. RAJCHMAN, was chosen to head up the League of Nations Health Organisation (forerunner of the WHO) and later (1946) founded UNICEF. Finally, we examine the key issue of exanthematous typhus in both world wars, exemplifying how a disease can come to be "ideologized", in this case by Nazi Germany. Typhus was the pretext used- in the name of "public health"-for segregating Polish citizens of Jewish origin and even killing them. Paradoxically, typhus was in the process of being eradicated when the war began and German policy of mass resettlements, sequestration, and starvation only spurred the epidemic they supposedly wished to control.

Epidemiology of Spotted Fever Group and Typhus Group Rickettsial Infection in the Amazon Basin of Peru

DTIC Science & Technology

2010-01-01

MediCine and Hyg1cne Epidemiology of Spotted Fever Group and Typhus Group Rickettsial Infection in the Amazon Basin of Peru Brett M. Forshey, Allison...approximately 4% of acute febrile episodes detected in Iquitos, a city located in the Amazon region of northeast- ern Peru , could be attributed to SFGR...2010 to 00-00-2010 4. TITLE AND SUBTITLE Epidemiology Of Spotted Fever Group And Typhus Group Rickettsial Infection In The Amazon Basin Of Peru 5a

Clinical and paraclinical profile, and predictors of outcome in 90 cases of scrub typhus, Meghalaya, India.

PubMed

Sivarajan, Sunuraj; Shivalli, Siddharudha; Bhuyan, Debomallya; Mawlong, Michael; Barman, Rittwick

2016-10-05

India is an integral component of "tsutsugamushi triangle" which depicts a part of the globe endemic to scrub typhus. Owing to frequent outbreaks witnessed in different parts of the country in the recent past, scrub typhus is described as a re-emerging infectious disease in India. The present study aimed to study the clinical and paraclinical profile, complications and predictors of outcome among 90 cases of scrub typhus diagnosed in a hospital of north-eastern India from Sept 2011 to Aug 2012. A longitudinal study was conducted in a hospital of Meghalaya, India between Sept 2011 and Aug 2012. Diagnosis of scrub typhus was arrived by SD BIOLINE tsutsugamushi (solid phase immunochromatographic assay) rapid diagnostic test for antibodies (IgM, IgG or IgA). Descriptive analyses of age, gender, geographic area, symptoms and signs, treatment, laboratory findings, complications, and outcome were conducted. Relative risk (RR) with 95 % confidence interval (CI) was computed for Multiple Organ Dysfunction Syndrome (MODS) and mortality. Binary logistic regression was applied to the significant correlates (P < 0.05) on univariate analysis to identify the predictors of MODS and mortality in scrub typhus. As many as 662 clinically suspected scrub typhus patients were tested and 90 (13.6 %) were diagnosed to have scrub typhus. Out of 90 patients, 52.2 % (n = 47) were males and their mean (SD) age was 36.29 (13.38) years. Fever of <7 days (n = 75, 83.3 %), myalgia (n = 56, 62.2 %), pain abdomen (n = 24, 26.7 %), headache (n = 24, 26.7 %), nausea/vomiting (n = 21, 23.3 %), dry cough (n = 21, 23.3 %), hepatomegaly (n = 24, 26.7 %), splenomegaly (n = 22, 24.4 %), and lymphadenopathy (n = 20, 22.2 %) were the predominant clinical features. Eschar was seen in 10 patients (11.1 %). One third (n = 30) of the patients developed at least one systemic complication. Acute hepatitis (n = 15, 16.7 %), pneumonitis (n = 14, 15.6 %), and acute kidney injury (n = 11, 12.2 %) were the common complications. MODS was seen in 14.4 % (n = 13) and 38.5 % (n = 5) of the patients with MODS died. Overall, case fatality rate was 5.15 % (n = 5). On univariate analysis, platelets <100 000/mm 3 , serum creatinine >1.5 mg/dl, and transaminase (AST, ALT or both) >500 U/L were associated with MODS (P < 0.001) and mortality (P < 0.05). In addition, serum bilirubin >3 mg/dl was also associated with MODS (P < 0.001). On applying binary logistic regression, serum creatinine >1.5 mg/dl was a predictor of MODS (OR: 76.1, 95 % CI: 4.9-1175.6) and mortality (OR: 18.03, 95 % CI: 1.38-235.1). In this study setting, approximately one-seventh (13.6 %) of the acute undifferentiated febrile illness were due to scrub typhus. Systemic complications were common (33.3 %). Serum creatinine >1.5 mg/dl was a predictor of MODS and mortality.

Development of Recombinase Polymerase Amplification Assays for Detection of Orientia tsutsugamushi or Rickettsia typhi.

PubMed

Chao, Chien-Chung; Belinskaya, Tatyana; Zhang, Zhiwen; Ching, Wei-Mei

2015-01-01

Sensitive, specific and rapid diagnostic tests for the detection of Orientia tsutsugamushi (O. tsutsugamushi) and Rickettsia typhi (R. typhi), the causative agents of scrub typhus and murine typhus, respectively, are necessary to accurately and promptly diagnose patients and ensure that they receive proper treatment. Recombinase polymerase amplification (RPA) assays using a lateral flow test (RPA-nfo) and real-time fluorescent detection (RPA-exo) were developed targeting the 47-kDa gene of O. tsutsugamushi or 17 kDa gene of R. typhi. The RPA assay was capable of detecting O. tsutsugamushi or R. typhi at levels comparable to that of the quantitative PCR method. Both the RPA-nfo and RPA-exo methods performed similarly with regards to sensitivity when detecting the 17 kDa gene of R. typhi. On the contrary, RPA-exo performed better than RPA-nfo in detecting the 47 kDa gene of O. tsutsugamushi. The clinical performance of the O. tsutsugamushi RPA assay was evaluated using either human patient samples or infected mouse samples. Eight out of ten PCR confirmed positives were determined positive by RPA, and all PCR confirmed negative samples were negative by RPA. Similar results were obtained for R. typhi spiked patient sera. The assays were able to differentiate O. tsutsugamushi and R. typhi from other phylogenetically related bacteria as well as mouse and human DNA. Furthermore, the RPA-nfo reaction was completed in 20 minutes at 37°C followed by a 10 minute incubation at room temperature for development of an immunochromatographic strip. The RPA-exo reaction was completed in 20 minutes at 39°C. The implementation of a cross contamination proof cassette to detect the RPA-nfo fluorescent amplicons provided an alternative to regular lateral flow detection strips, which are more prone to cross contamination. The RPA assays provide a highly time-efficient, sensitive and specific alternative to other methods for diagnosing scrub typhus or murine typhus.

Development of Recombinase Polymerase Amplification Assays for Detection of Orientia tsutsugamushi or Rickettsia typhi

PubMed Central

Chao, Chien-Chung; Belinskaya, Tatyana; Zhang, Zhiwen; Ching, Wei-Mei

2015-01-01

Sensitive, specific and rapid diagnostic tests for the detection of Orientia tsutsugamushi (O. tsutsugamushi) and Rickettsia typhi (R. typhi), the causative agents of scrub typhus and murine typhus, respectively, are necessary to accurately and promptly diagnose patients and ensure that they receive proper treatment. Recombinase polymerase amplification (RPA) assays using a lateral flow test (RPA-nfo) and real-time fluorescent detection (RPA-exo) were developed targeting the 47-kDa gene of O. tsutsugamushi or 17 kDa gene of R. typhi. The RPA assay was capable of detecting O. tsutsugamushi or R. typhi at levels comparable to that of the quantitative PCR method. Both the RPA-nfo and RPA-exo methods performed similarly with regards to sensitivity when detecting the 17 kDa gene of R. typhi. On the contrary, RPA-exo performed better than RPA-nfo in detecting the 47 kDa gene of O. tsutsugamushi. The clinical performance of the O. tsutsugamushi RPA assay was evaluated using either human patient samples or infected mouse samples. Eight out of ten PCR confirmed positives were determined positive by RPA, and all PCR confirmed negative samples were negative by RPA. Similar results were obtained for R. typhi spiked patient sera. The assays were able to differentiate O. tsutsugamushi and R. typhi from other phylogenetically related bacteria as well as mouse and human DNA. Furthermore, the RPA-nfo reaction was completed in 20 minutes at 37oC followed by a 10 minute incubation at room temperature for development of an immunochromatographic strip. The RPA-exo reaction was completed in 20 minutes at 39oC. The implementation of a cross contamination proof cassette to detect the RPA-nfo fluorescent amplicons provided an alternative to regular lateral flow detection strips, which are more prone to cross contamination. The RPA assays provide a highly time-efficient, sensitive and specific alternative to other methods for diagnosing scrub typhus or murine typhus. PMID:26161793

Development of a rapid and visual nucleotide detection method for a Chinese epidemic strain of Orientia tsutsugamushi based on recombinase polymerase amplification assay and lateral flow test.

PubMed

Qi, Yong; Yin, Qiong; Shao, Yinxiu; Cao, Min; Li, Suqin; Chen, Hongxia; Shen, Wanpeng; Rao, Jixian; Li, Jiameng; Li, Xiaoling; Sun, Yu; Lin, Yu; Deng, Yi; Zeng, Wenwen; Zheng, Shulong; Liu, Suyun; Li, Yuexi

2018-05-01

Orientia tsutsugamushi is an obligate intracellular pathogen that causes scrub typhus. Diagnosing scrub typhus remains a challenge, and a sensitive, specific, simple, and rapid diagnostic test is still needed. A recombinase polymerase amplification (RPA) assay combined with a lateral flow (LF) test targeting the 56-kDa gene of a Karp-like strain of O. tsutsugamushi was developed and optimized. The detection limits, sensitivity, specificity, and simulative clinical performance were evaluated. Primers and probe were screened to establish the RPA assay, and the reaction conditions were optimized. The detection limit was 10 copies/reaction in detecting plasmid DNA and 12 copies/reaction in detecting genomic DNA. The RPA-LF method could differentiate O. tsutsugamushi from other phylogenetically related bacteria. The sensitivity was 100% and specificity was over 90%, when evaluated using infected animal samples or simulative clinical samples. Furthermore, the method was completed in 20min at 37°C followed by a 3-5min incubation at room temperature for the development of an immunochromatographic strip, and the results could be determined visually. This method is promising for wide-ranging use in basic medical units considering that it requires minimal instruments and infrastructure and is highly time-efficient, sensitive, and specific for diagnosing scrub typhus. Copyright © 2018 The Authors. Published by Elsevier Ltd.. All rights reserved.

Single-nucleotide polymorphisms in Toll-like receptor (TLR)-2, TLR4 and heat shock protein 70 genes and susceptibility to scrub typhus.

PubMed

Janardhanan, Jeshina; Joseph Martin, Sherry; Astrup, Elisabeth; Veeramanikandan, R; Aukrust, Pål; Abraham, Ooriapadickal C; Varghese, George M

2013-11-01

Scrub typhus is a highly prevalent bacterial infection in India and South Asia that is caused by Orientia tsutsugamushi. The innate immune response to infections is modulated by Toll-like receptors (TLRs) and heat shock proteins (HSPs). This study was done to assess the prevalence and possible association of TLR and HSP polymorphisms in scrub typhus. TLR4 Asp299Gly, TLR4 Thr399Ile, TLR2 Arg753Gln and HSP70-2 A1267G are single-nucleotide polymorphisms (SNPs) that may modulate their activities, and these SNPs were assessed in 137 scrub typhus patients and 134 controls by PCR restriction fragment length polymorphism. We found that the two TLR4 mutations, TLR4 D299G and TLR4T399I, were present in 19.5% and 22% of the study population, respectively, and was in significant linkage disequilibrium with a D' of 0.8. The TLR2 mutation was found to be rare, whereas the HSP A>G mutation was very common (77.5%). Compared with the controls, the prevalence of heterozygous genotype of the TLR4D299G SNP, but not any of the other SNPs, was significantly higher among scrub typhus patients. Further studies using a larger sample size and more candidate genes may better enable in determining the role of these associations in susceptibility and severity of scrub typhus.

[BRILL-ZINSER DISEASE AS A CONSEQUENCE OF RICKETTSIA PROWAZEKII PERSISTENCE IN PREVIOUSLY ILL WHO HAVE HAD EPIDEMIC TYPHUS (EPIDEMIOLOGIC ASPECTS)].

PubMed

Tarasevich, I V; Shpynov, S N; Pantyukhina, A N

2015-01-01

Materials, that summarize data of original research and scientific literature on epidemiology and problems of persistence during epidemic typhus, whose causative agent (Rickettsia prowazekii) is reactivated in the organism of the previously ill and is manifested as Brill-Zinser disease, are presented. A retrospective analysis was carried out with the data obtained by Russian (All-Union) Centre for Rickettsioses during study of epidemiologic examination maps of 5705 typhus nidi and results of 19 463 blood sera analysis during study of immunologic structure of population in the territories of the former USSR for the period from 1970 to 1992. A decrease of epidemic typhus morbidity and an increase of the fraction of Brill-Zinser disease took place as a result of pediculosis corporis control. In separate territories specific weight of Brill-Zinser disease was 48% in 1952, up to 80% in 1969, and from 1977 all the ill were previously ill. However, during the perestroika period and afterwards, due to a reduction of economic and hygienic living conditions, appearance of refugees, the immune structure regarding typhus began to change. Due to the buildup of the population migration process and the presence of risk groups (refugees, homeless) among population of regions, where local wars are waged, the enhancement of methods of epidemic typhus and Brill-Zinser disease diagnostics and pediculosis corporis eradication is necessary. Study of R. prowazekii by molecular-genetics methods is necessary for complete understanding of its mechanism of persistence.

[The role of Turkish physicians in the vaccination against typhus during the years of World War I].

PubMed

Karatepe, Mustafa

2008-04-01

During the years of World War I, several severe typhus epidemics were seen in Erzurum and nearby cities. A total of 164 health officers, 125 of whom were physicians, struggled against the epidemic in the region but also they lost their lives due to typhus. Vaccination against typhus was one of the means of fighting the epidemic. However, there were some claims that a small group of Turkish physicians injected typhus-contaminated serum into Armenian civilians during World War I, and that this should be accepted as a form of biological warfare against Armenian civilians. The purpose of this article is to set out how, by whom, and on whom, and under what conditions the typhus vaccination was applied in order to reveal the truth in terms of the evidence found in historical documents. The typhus vaccine was prepared from blood taken from febrile patients affected by the disease. After the blood of the patients were defibrinated and inactivated at 60 degrees C for an hour, it was used. As the amount of blood needed to prepare the vaccine was so great, the amount of available vaccine was always insufficient to meet the demand. Hence, the prepared vaccine was only applied to those which had the higher risk of contracting typhus such as physicians and nurses. The vaccine prepared by The Third Army Health Commander Dr. Tevfik Salim was first applied to nine officers, five of whom were physicians, and among whom were Dr. Haydar Cemal and Dr. Salahattin on March 28, 1915 in Hasankale, Erzurum. Furthermore, the same vaccine was applied to people in the vicinity by Dr. Alaattin in Erzurum, Dr. Abdulhalim Asim in Bayburt, Dr. Izak in Sivas and Dr. Mihran in Hasankale. Ali Ihsan Sabis and Fevzi Cakmak, who were high ranking officers, were among those who volunteered to have the vaccination. The Third Army Health Commander Dr. Tevfik Salim ordered that the vaccine should not be applied without blood inactivation. Despite this order, Dr. Hamit Osman, who had a mental illness, applied the vaccination without inactivating the blood to some people. Among those were physicians of the Red Crescent Hospital together with soldiers who were nursing in the hospitals in Erzincan. Dr. Hamdi Suat inactivated the blood by leaving it at -16 degrees C for 24-48 hours, and instead of giving a single dose, he applied three-doses with 3-day-intervals, followed by a one more dose, which he called "the vaccine for absolute immunization" to the same people after 10-23 days. This "vaccine for absolute immunization" was actually typhus-contaminated blood which had not been inactivated. It should be noted that he injected himself with the same form of vaccine. In his article published in German in 1916 and in Turkish in 1917, he stated that he injected "the vaccine for absolute immunization" to some subjects 'condemned to death'. Dr. Haydar Cemal claimed, in a newspaper dated December 23, 1918, that the people reported as subjects 'condemned to death' were indeed Armenians, and that the innocent Armenians marked out for deportation were inoculated with the blood of typhus fever patients, and that he eyewitnessed all these events. As a result of his claims, the Interior Ministry demanded an immediate investigation, and at the end of that investigation it was understood that Dr. Haydar Cemal and Dr. Hamdi Suat had never worked together in Erzincan at the time Dr. Haydar Cemal claimed. All the claims were refuted by the investigating committee and nobody was charged. During a severe typhus epidemic, Turkish physicians injected the typhus vaccine for the purpose of "saving a life from the fire". The typhus vaccine was prepared using the available scientific knowledge of the time. No racial or religious discrimination against the people vaccinated had been proved. According to the sources, the claim that some Turkish physicians used the blood of patients with typhus as a means of biological warfare does not reflect the historical truth.

Scrub typhus in South India: clinical and laboratory manifestations, genetic variability, and outcome.

PubMed

Varghese, George M; Janardhanan, Jeshina; Trowbridge, Paul; Peter, John V; Prakash, John A J; Sathyendra, Sowmya; Thomas, Kurien; David, Thambu S; Kavitha, M L; Abraham, Ooriapadickal C; Mathai, Dilip

2013-11-01

This study sought to document the clinical and laboratory manifestations, genetic variability, and outcomes of scrub typhus, an often severe infection caused by Orientia tsutsugamushi, in South India. Patients admitted to a large teaching hospital with IgM ELISA-confirmed scrub typhus were evaluated. Clinical examination with a thorough search for an eschar, laboratory testing, chest X-ray, and outcome were documented and analyzed. Additionally, a 410-bp region of the 56-kDa type-specific antigen gene of O. tsutsugamushi was sequenced and compared with isolates from other regions of Asia. Most of the 154 patients evaluated presented with fever and non-specific symptoms. An eschar was found in 86 (55%) patients. Mild hepatic involvement was seen in most, with other organ involvement including respiratory, cardiovascular, and renal. Multi-organ dysfunction was noted in 59 (38.3%), and the fatality rate was 7.8%. Hypotension requiring vasoactive agents was found to be an independent predictor of mortality (p<0.001). The phylogeny of 26 samples showed 17 (65%) clustering with the Kato-like group and eight (31%) with the Karp-like group. The presentation of scrub typhus can be variable, often non-specific, but with potentially severe multi-organ dysfunction. Prompt recognition is key to specific treatment and good outcomes. Further study of the circulating strains is essential for the development of a successful vaccine and sensitive point-of-care testing. Copyright © 2013 International Society for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.

Scrub typhus: audit of an outbreak.

PubMed

Krishna, Mani Ram; Vasuki, B; Nagaraju, K

2015-06-01

To document the epidemiological, clinical and laboratory profile of all children with scrub typhus at a tertiary care centre in Chennai between September 2010 and June 2011. The case records of all children admitted and diagnosed with scrub typhus between September 2010 and June 2011 were analysed to look for salient clinical and laboratory parameters. During the study period, 52 children were admitted with scrub typhus in the authors' hospital. The presenting complaints included fever in all cases. Other symptoms included swelling of legs (50 %) and vomiting (45 %). 13 % presented with CNS symptoms. The commonest physical findings included eschar (67 %), hepatomegaly (94 %), splenomegaly (73 %) and third spacing (67 %). Salient lab parameters included packed cell volume (PCV) <30 (48 %), leucocytosis (56 %), positive C-reactive protein (CRP) (92 %), hypoalbuminemia (79 %). Common complications included acute kidney injury (10 %) and peripheral gangrene (4 %). There was no mortality in the present case series. The clinical profile of children with scrub typhus in a tertiary care centre is reported. Eschar and hepatosplenomegaly with a high CRP value is helpful in diagnosis. All patients responded well to the treatment.

Prevalence and risk factors for scrub typhus in South India.

PubMed

Trowbridge, Paul; P, Divya; Premkumar, Prasanna S; Varghese, George M

2017-05-01

To determine the prevalence and risk factors of scrub typhus in Tamil Nadu, South India. We performed a clustered seroprevalence study of the areas around Vellore. All participants completed a risk factor survey, with seropositive and seronegative participants acting as cases and controls, respectively, in a risk factor analysis. After univariate analysis, variables found to be significant underwent multivariate analysis. Of 721 people participating in this study, 31.8% tested seropositive. By univariate analysis, after accounting for clustering, having a house that was clustered with other houses, having a fewer rooms in a house, having fewer people living in a household, defecating outside, female sex, age >60 years, shorter height, lower weight, smaller body mass index and smaller mid-upper arm circumference were found to be significantly associated with seropositivity. After multivariate regression modelling, living in a house clustered with other houses, female sex and age >60 years were significantly associated with scrub typhus exposure. Overall, scrub typhus is much more common than previously thought. Previously described individual environmental and habitual risk factors seem to have less importance in South India, perhaps because of the overall scrub typhus-conducive nature of the environment in this region. © 2017 John Wiley & Sons Ltd.

Distribution of Eschar in Pediatric Scrub Typhus.

PubMed

Rose, Winsley; Rajan, Roshni J; Punnen, Anu; Ghosh, Urmi

2016-10-01

Identifying an eschar in scrub typhus is useful for initiation of prompt and appropriate antibiotic therapy. The distribution of eschars in all children <15 years of age admitted with confirmed scrub typhus over a 5 year period is described. Of 431 children admitted with scrub typhus, eschars were present in 176 (40.8%) children with the following distribution: head, face and neck, 33 (19.1%); axillae, 37 (21%); chest and abdomen, 21 (11.9%); genitalia, inguinal region and buttocks, 58 (33%); back, 8 (4.5%); upper extremities, 13 (7.4%); and lower extremities, 5 (2.8%). The commonest sites of eschars were scrotum (27 of 106; 25.5%) and axillae (15 of 106; 14.2%) in males and axillae (22 of 70; 31.4%) and groin (16 of 70; 22.9%) in females. Eschars were seen within skin folds in 100 of 176 (56.8%) children. Children should be carefully examined for the presence of eschar especially in the skin folds of the genitalia, axillae and groin to make an early diagnosis of scrub typhus. © The Author [2016]. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Diagnostic evaluation of rapid tests for scrub typhus in the Indian population is needed.

PubMed

Shivalli, Siddharudha

2016-05-12

Owing to frequent outbreaks witnessed in different parts of the country in the recent past, scrub typhus is being described as a re-emerging infectious disease in India. Differentiating scrub typhus from other endemic diseases like malaria, leptospirosis, dengue fever, typhoid, etc. is difficult due to overlapping clinical features and a lower positivity for eschars in Asian populations. Hence, the diagnosis heavily relies on laboratory tests. Costs and the need of technical expertise limit the wide use of indirect immunoperoxidase or immunofluorescence assays, ELISA and PCR. The Weil-Felix test is the most commonly used and least expensive serological test, but lacks both sensitivity and specificity. Hence, the diagnosis of scrub typhus is often delayed or overlooked. With due consideration of the cost, rapidity, single test result and simplicity of interpretation, rapid diagnostic tests have come into vogue. However, evaluation of rapid diagnostic tests for scrub typhus in the Indian population is needed to justify or discourage their use. Research studies are needed to find the most suitable test in terms of the rapidity of the result, simplicity of the procedure, ease of interpretation and cost to be used in the Indian populace.

[Petechial typhus. History of men, armies and pedicula].

PubMed

Sabbatani, Sergio

2006-09-01

Since the Classical age, humankind has had to cope with petechial typhus, especially during wars and famine. Epidemics chiefly occurred during sieges and followed the paths of armies, when infected soldiers transmitted the infection to populations with whom they came into contact. Winter exacerbated the disease due to the use of unhygienic woollen clothes that allowed the spread of pediculosis. It was only in the early 18th century that petechial typhus outbreaks diminished thanks to the use of Marseille soap and to the new custom of changing clothing at bedtime. In many military campaigns, deaths from typhus were higher than those due to war wounds: recent studies established that the French defeat during the Napoleonic Russian military campaign has to be attributed more to typhus than to the military superiority of the enemy. Indeed, the contagion is estimated to have affected 80% of the 600,000 troops involved. The role of Pediculus as a vehicle of infection established in 1909 by Charles Nicolle, microbiological isolation performed by Howard Ricketts and Stanislaus von Prowazck, and finally the advent of antibiotic therapy, all laid the basis for controlling the disease in the 20th century.

Detection of a typhus group Rickettsia in Amblyomma ticks in the state of Nuevo Leon, Mexico.

PubMed

Medina-Sanchez, Aaron; Bouyer, Donald H; Alcantara-Rodriguez, Virginia; Mafra, Claudio; Zavala-Castro, Jorge; Whitworth, Ted; Popov, Vsevolod L; Fernandez-Salas, Ildefonso; Walker, David H

2005-12-01

The state of Nuevo Leon, Mexico has had outbreaks of typhus group rickettsiosis, most recently recognized in 1997. Evaluation of the sera of 345 patients with a dengue-like illness revealed that 25.5% had antibodies reactive with typhus group rickettsiae and 16% had antibodies to Rickettsia parkeri. Rickettsiae were detected by PCR and shell-vial isolations in the field-collected Amblyomma ticks. Molecular characterization by DNA sequence analysis of the gltA, ompB, and 17-kDa gene identified the organisms to be R. prowazekii.

THE EXPERIMENTAL INFECTION OF THE HUMAN BODY LOUSE, PEDICULUS HUMANUS CORPORIS, WITH MURINE AND EPIDEMIC LOUSE-BORNE TYPHUS STRAINS

PubMed Central

Snyder, J. C.; Wheeler, C. M.

1945-01-01

Experiments are described which demonstrate that human body lice (Pediculus humanus corporis), were infected experimentally with murine and epidemic louse-borne strains of typhus fever by feeding on suitably prepared rabbits. Details of the two methods of infection, the "bleb technique" and the "I.V. technique," are presented. It is concluded that the experimental infection of human lice with typhus can be accomplished very easily and rapidly with these methods. The possible applications of the method are discussed. PMID:19871482

Preclinical models used for immunogenicity prediction of therapeutic proteins.

PubMed

Brinks, Vera; Weinbuch, Daniel; Baker, Matthew; Dean, Yann; Stas, Philippe; Kostense, Stefan; Rup, Bonita; Jiskoot, Wim

2013-07-01

All therapeutic proteins are potentially immunogenic. Antibodies formed against these drugs can decrease efficacy, leading to drastically increased therapeutic costs and in rare cases to serious and sometimes life threatening side-effects. Many efforts are therefore undertaken to develop therapeutic proteins with minimal immunogenicity. For this, immunogenicity prediction of candidate drugs during early drug development is essential. Several in silico, in vitro and in vivo models are used to predict immunogenicity of drug leads, to modify potentially immunogenic properties and to continue development of drug candidates with expected low immunogenicity. Despite the extensive use of these predictive models, their actual predictive value varies. Important reasons for this uncertainty are the limited/insufficient knowledge on the immune mechanisms underlying immunogenicity of therapeutic proteins, the fact that different predictive models explore different components of the immune system and the lack of an integrated clinical validation. In this review, we discuss the predictive models in use, summarize aspects of immunogenicity that these models predict and explore the merits and the limitations of each of the models.

Immunogenicity of therapeutic proteins: the use of animal models.

PubMed

Brinks, Vera; Jiskoot, Wim; Schellekens, Huub

2011-10-01

Immunogenicity of therapeutic proteins lowers patient well-being and drastically increases therapeutic costs. Preventing immunogenicity is an important issue to consider when developing novel therapeutic proteins and applying them in the clinic. Animal models are increasingly used to study immunogenicity of therapeutic proteins. They are employed as predictive tools to assess different aspects of immunogenicity during drug development and have become vital in studying the mechanisms underlying immunogenicity of therapeutic proteins. However, the use of animal models needs critical evaluation. Because of species differences, predictive value of such models is limited, and mechanistic studies can be restricted. This review addresses the suitability of animal models for immunogenicity prediction and summarizes the insights in immunogenicity that they have given so far.

Clinical Profile of Scrub Typhus in Pregnancy in Sub-Himalayan Region.

PubMed

Kumar, Ritesh; Thakur, Surinder; Bhawani, Rajesh; Kanga, Anil; Ranjan, Asha

2016-10-01

Scrub typhus is rare in pregnancy, but it has now become an important cause of febrile illness in pregnancy in sub-Himalayan region of India. Only a few case reports have been published so far, and they show adverse maternal and fetal outcomes. No consensus has been reached till now regarding treatment. All the pregnant patients irrespective of period of gestation admitted with febrile illness with positive IgM ELISA for scrub typhus with or without eschar were included. The clinical profile was observed using a detailed history of symptoms, travel, recreation, agricultural activities, treatment record prior to admission, and a detailed examination, and the treatment outcome was noted. Fever workup including cultures, CXR, CSF analysis, serology for scrub was done. IgM scrub typhus was done by kit method manufactured by InBios Intertational, Inc. We observed in total 14 pregnant patients out of which eight were in the the second trimester and six were in the third trimester. The clinical features of the disease observed for pregnant females were the same as for nonpregnant females. There was no difference in the severity of scrub typhus between pregnant and nonpregnant women. No mortality was found in these patients. On follow-up, they had normal peripartum and postpartum periods. All were treated with azithromycin 500 mg once a day for 5 days. Although rare, scrub typhus should be considered in differential diagnosis of fever in pregnant patients especially in scrub season. Azithromycin should be the drug of choice in pregnancy as it has no adverse effect on fetus and pregnancy outcome.

A comparative hospital-based observational study of mono- and co-infections of malaria, dengue virus and scrub typhus causing acute undifferentiated fever.

PubMed

Ahmad, S; Dhar, M; Mittal, G; Bhat, N K; Shirazi, N; Kalra, V; Sati, H C; Gupta, V

2016-04-01

Positive serology for dengue and/or scrub typhus infection with/without positive malarial smear (designated as mixed or co-infection) is being increasingly observed during epidemics of acute undifferentiated febrile illnesses (AUFIs). We planned to study the clinical and biochemical spectrum of co-infections with Plasmodium sp., dengue virus and scrub typhus and compare these with mono-infection by the same organisms. During the period from December 2012 to December 2013, all cases presenting with AUFIs to a single medical unit of a referral centre in Garhwal region of the north Indian state of Uttarakhand were retrospectively selected and categorised aetiologically as co-infections, malaria, dengue or scrub typhus. The groups thus created were compared in terms of demographic, clinical, biochemical and outcome parameters. The co-infection group (n = 49) was associated with milder clinical manifestations, fewer, milder and non-progressive organ dysfunction, and lesser need for intensive care, mechanical ventilation and dialysis as compared to mono-infections. When co-infections were sub-grouped and compared with the relevant mono-infections, there were differences in certain haematological and biochemical parameters; however, this difference did not translate into differential outcomes. Scrub typhus mono-infection was associated with severe disease in terms of both morbidity and mortality. Malaria, dengue and scrub typhus should be routinely tested in all patients with AUFIs. Co-infections, whether true or due to serological cross-reactivity, appear to be a separate entity so far as presentation and morbidity is concerned. Further insight is needed into the mechanism and identification of the protective infection.

Scrub typhus caused by Orientia tsutsugamushi Kawasaki-related genotypes in Shandong Province, northern China.

PubMed

Zhang, Luyan; Bi, Zhenwang; Kou, Zengqiang; Yang, Huili; Zhang, Aihua; Zhang, Shoufeng; Meng, Xiangpeng; Zheng, Li; Zhang, Meng; Yang, Hui; Zhao, Zhongtang

2015-03-01

Orientia tsutsugamushi, the causative agent of scrub typhus, is an obligate intracellular bacterium and characterized by dramatic genetic diversity. To elucidate the genotypes of O. tsutsugamushi populating in patients in Shandong Province, a new epidemic zone in China, we sequenced partial of the 56-kDa type-specific antigen gene (TSA) and identified the genotypes of 43 O. tsutsugamushi samples from human patients confirmed with scrub typhus from 2010 to 2013. All of the 43 sequences are in the same clade, 39 of them are in one branch and the other four sequences, nominated as SH1002, SH1306, SH1309, and SH1307 are in four separate branches. To clarify the clinical characterizations caused by Kawasaki-related genotypes, we studied the clinical profiles of these 43 scrub typhus patients. Most patients (88.1%) were farmers lived in rural areas. They presented with fever (100.0%), headache (79.1%), dizziness (32.6%), generalized myalgia (48.8%), fatigue (53.5%), anorexia (53.5%), facial flushing (23.3%), conjunctival congestion (11.6%), skin rashes (58.1%) and lymphadenopathy (23.3%). Eschar (97.7%) was quite common in patients, which provided doctors with a luminous clue for diagnosis of scrub typhus. Thrombocytopenia was seen in 23.1% of patients, and three patients (7.0%) had bronchopneumonia. There was no death report in Shandong Province during the study period. The present study provides beneficial data for clinical, serological, and molecular diagnosis of scrub typhus infections, and also provides foundations for subsequent studies. Copyright © 2015 Elsevier B.V. All rights reserved.

Molecular detection of Orientia tsutsugamushi from suspected scrub typhus cases.

PubMed

Srinivasan, Seethalakshmi; Menon, Thangam

2017-01-01

Scrub typhus is an acute febrile illness caused by Orientia tsutsugamushi. The disease is under-diagnosed in India, because of low index of suspicion and also due to its nonspecific presentation, and lack of confirmatory diagnostic tests. This study was undertaken to diagnose scrub typhus in patients with undifferentiated fevers by serology and molecular methods. A total of 68 blood samples were collected from patients clinically suspected to have scrub typhus. After transportation to the laboratory, the serum was separated from the blood and subjected to rapid card test. The ethylenediaminetetraacetic acid blood samples were subjected to DNA extraction using QIAamp DNA Mini Kit followed by nested polymerase chain reaction (nPCR). 24/68 (35.29%) cases showed the presence of antibody against scrub typhus by serology. 6/68 (8.8%) patients showed the presence of outer membrane protein antigen gene 56 kDa by nPCR. 5/24 serology positive cases showed the presence of 56 kDa outer membrane protein antigen gene by nPCR. A large number of cases positive by serology were negative by PCR which may indicate a low sensitivity of this test either due to low copy numbers or due to excess host DNA. Delay in treatment may increase disease severity and leads to higher mortality. Thus, molecular methods of diagnosis may aid in the early diagnosis of infection and enable prompt treatment. This is the first report on the diagnosis of scrub typhus in the suburbs of Chennai using molecular methods and reemphasizes the need for increased awareness of rickettsial infections in rural areas.

Effects of clarithromycin treatment in scrub typhus in children: comparison with chloramphenicol and azithromycin.

PubMed

Lee, Min; Kim, June; Jo, Dae Sun

2017-04-01

Chloramphenicol and tetracycline are not recommended for treating scrub typhus in pediatric patients because of potential side effects, such as aplastic anemia or tooth discoloration. While clarithromycin has recently been used in adults, few reports have been published on its effects in pediatric patients. We report the clinical profiles of pediatric scrub typhus and the effects of clarithromycin on scrub typhus in children. We retrospectively analyzed medical records of 56 children with scrub typhus who were admitted between 2004 and 2013 to Chonbuk National University Hospital, Jeonju, Korea. Cases were divided into 3 groups based on thetreatment drug (chloramphenicol, azithromycin, and clarithromycin). We compared their clinical manifestations and laboratory findings. All patients exhibited fever and rash. Other common clinical manifestations were eschars (66%), lymphadenopathy (48%), upper respiratory symptoms (42%), abdominal pain (32%), and hepatosplenomegaly (14%). Elevated levels of C-reactive protein, erythrocyte sedimentation rates, aspartate transaminase, and alanine transaminase were detected in 95%, 96%, 84%, and 77% of patients, respectively. Additionally, decreased platelet and white blood cell levels were observed in 43% and 36% of patients, respectively. There were no statistical differences between the treatment groups in mean age ( P =0.114) or sex ( P =0.507). However, time to defervescence after the treatments differed significantly, being the shortest in the clarithromycin group ( P =0.019). All patients recovered without complications related to the disease or drugs. Clarithromycin was as effective as chloramphenicol and azithromycin in pediatric scrub typhus patients and may be used as a first-line treatment drug.

Seroepidemiology of rickettsial infections in Northeast India.

PubMed

Khan, Siraj Ahmed; Bora, Trishna; Chattopadhyay, Suchismita; Jiang, Ju; Richards, Allen L; Dutta, Prafulla

2016-08-01

Resurgence of scrub typhus was reported in Northeast India in 2010 after a gap of 67 years since World War II. However, the presence of other rickettsial infections remained unknown from this region. A seroepidemiological investigation was undertaken in the scrub typhus affected areas from 2013-2015 in Assam, Arunachal Pradesh and Nagaland to assess the exposure to other rickettsial diseases besides scrub typhus. Samples were collected from people residing in scrub typhus reporting areas. Serology was performed by an indirect ELISA for the three rickettsial agents' viz., scrub typhus group orientiae (STGO), spotted fever group rickettsiae (SFGR) and typhus group rickettsiae (TGR). A sample with total net absorbance ≥1.000 was considered as positive. An entomological survey was also carried out in the affected areas. Overall, 1265 human blood samples were collected, of which 30.8% (n=390), 13.8% (175) and 4.2% (53) had antibodies against STGO, SFGR and TGR respectively. Presence of antibodies against more than one of the rickettsial groups was also detected. Among the arthropods collected, chiggers of Leptotrombidium deleinse, fleas belonging to Ctenocephalides felis and Pulex irritans, ticks belonging to Rhipicephalus microplus, Haemaphysalis spp. were predominant. Candidatus Rickettsia senegalensis was detected in C. felis. Our findings confirm wide circulation of rickettsial infections and their probable vectors in the northeast region of India.Accession numbers: KU163367, KU163368, KU499847, KU499848. © The Author 2016. Published by Oxford University Press on behalf of Royal Society of Tropical Medicine and Hygiene. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Scrub typhus cases in a teaching hospital in Penghu, Taiwan, 2006-2010.

PubMed

Wang, Ying-Chuan; Chen, Po-Chuan; Lee, Kwai-Fong; Wu, Yu-Cheng; Chiu, Chun-Hsiang

2013-03-01

Scrub typhus is a mite-borne infectious disease caused by Orientia tsutsugamushi (previously called Rickettsia tsutsugamushi). The severity of this disease varies from only mild symptoms to death, and its manifestations are nonspecific. Therefore, clinicians may not correctly diagnose scrub typhus early enough for successful treatment. Reports of infections in travelers returning from Asia to their home countries are increasingly common. Thus, it is important that even clinicians in nonepidemic regions be alert for this disease. Here we describe the epidemiological aspects and clinical manifestations of scrub typhus encountered at a teaching hospital in Penghu, Taiwan, over the past 5 years. A total of 126 patients were confirmed to be positive for scrub typhus at the hospital from 2006 to 2010. All cases were confirmed by the Centers for Disease Control and Prevention or its contract laboratory through pathogen isolation and an indirect immunofluorescence assay. Medical records of these patients were reviewed, and demographic and clinical characteristics, laboratory data, seasonal data, geographic distribution, complications, and outcome were analyzed. The incidence of scrub typhus peaked in individuals aged 0-10 and 51-60 years, with the highest incidence among those ≤10 years of age. No significant difference was noted between sexes. Fever was the most common symptom (93.6%), followed by chills (23.8%), cough (18.3%), and headache (14.3%). Eschars were observed in 78 (61.9%) patients, with the axilla being the most frequent site (n=17; 21.8%). Most patients were retirees (n=63; 50%), followed by students (n=16; 12.7%). Patients were more likely to live in rural areas than urban areas. Scrub typhus was epidemic in the spring (April to June) and fall (October to December) in a bimodal distribution similar to that observed in Japan. Leukocytosis was not common, but most patients had abnormal C-reactive protein levels, thrombocytopenia, and elevated liver function test results. Residents of Penghu, particularly Makung City and Husi Township, as well as travelers to the region during the spring and fall seasons should be educated about the signs and symptoms of scrub typhus. All physicians who come into contact with individuals residing in or traveling to or from epidemic regions should remain alert about the manifestations of this disease.

[The eagle and the louse: typhus in the Grand Army].

PubMed

Ducoulombier, Henri

2014-01-01

How is it that lice, such a common parasite, have shaken the Napoleonic empire? This paper, based on medical literature and on proven facts, is going to tell the history of such a "war pestilence", a "contagious typhus".

Scrub typhus causing neonatal hepatitis with acute liver failure-A case series.

PubMed

Vajpayee, Shailja; Gupta, R K; Gupta, M L

2017-05-01

Neonatal hepatitis with acute liver failure due to varied etiology including various infections is reported in the past. Scrub typhus as a cause of neonatal hepatitis has rarely been reported in literature. A high index of clinical suspicion is required for early diagnosis and timely treatment. Severity and prognosis of the disease varies widely because several different strains of Orientia tsutsugamushi exist with different virulence. Delayed diagnosis can result in complication and significant morbidity and mortality. Here, we report three cases of neonatal hepatitis with acute liver failure caused by scrub typhus to increase awareness.

Autochthonous epidemic typhus associated with Bartonella quintana bacteremia in a homeless person.

PubMed

Badiaga, Sékéné; Brouqui, Philippe; Raoult, Didier

2005-05-01

Trench fever, a louse-borne disease caused by Bartonella quintana, is reemerging in homeless persons. Epidemic typhus is another life-threatening louse-borne disease caused by Rickettsia prowazekii and known to occur in conditions of war, famine, refugee camps, cold weather, poverty, or lapses in public health. We report the first case of seroconversion to R. prowazekii in a homeless person of Marseilles, France. This was associated with B. quintana bacteremia. Although no outbreaks of typhus have been notified yet in the homeless population, this disease is likely to reemerge in such situation.

Comparison of minocycline and azithromycin for the treatment of mild scrub typhus in northern China.

PubMed

Zhao, Minxing; Wang, Ting; Yuan, Xiaoyu; Du, Weiming; Lin, Miaoxin; Shen, Yanbo

2016-09-01

Scrub typhus, caused by Orientia tsutsugamushi, has recently emerged in northern China where the disease had not been known to exist. Although doxycycline and azithromycin are the recommended agents for the treatment of scrub typhus, clinical responses depend both on the susceptibilities of various O. tsutsugamushi strains and the severity of the disease. A retrospective analysis was conducted on patients diagnosed with mild scrub typhus from August 2013 to January 2016 in the Affiliated Hospital of Nantong University, northern China. A total of 40 patients who received minocycline treatment and 34 patients who received azithromycin treatment were included in the analysis. All patients except one defervesced within 120 h after initiating antimicrobial therapy. Kaplan-Meier curves in association with log-rank test showed that the median time to defervescence was significantly shorter for the minocycline-treated group than the azithromycin-treated group (P = 0.003). There were no serious adverse events during treatment. No relapse occurred in either group during the 1-month follow-up period. In conclusion, both minocycline and azithromycin are effective and safe for the treatment of mild scrub typhus, but minocycline is more active than azithromycin against O. tsutsugamushi infection acquired in northern China. Copyright © 2016 Elsevier B.V. and International Society of Chemotherapy. All rights reserved.

Medical science in the light of the Holocaust: Departing from a post-war paper by Ludwik Fleck.

PubMed

Hedfors, Eva

2008-04-01

In scholarly debates, Ludwik Fleck's post-war paper 'Problemy naukoznawstwa [Problems of the Science of Science]', published in 1946, has been taken unanimously to illustrate the epistemology expounded in his monograph Genesis and Development of a Scientific Fact. The paper has also been seen to support parts of the received view of Fleck, notably that he manufactured an anti-typhus vaccine while imprisoned in Buchenwald. However, a different narrative emerges when comparing Fleck's paper with other accounts, also published in 1946 and written by other prisoners alluded to by Fleck in his paper. The situation is further complicated by four papers, published in prestigious scientific journals between 1942 and 1945, by the German medical leader of the typhus studies accounted for by Fleck. In addition, a thus-far neglected paper by Fleck, published in 1946 and summarizing his observations on typhus, discloses his role in the Buchenwald studies. Despite the obvious difficulties with tracing the history behind these works, notably the one on Nazi science, the contention is that what was attempted in Buchenwald in the name of science amounted to pseudoscience. This conclusion is amply supported not only by the accounts given by Fleck's fellow prisoners, but also by his own post-war paper on typhus. Based on the above findings, it is suggested that the mythology about Fleck, established in the 1980s, has been accomplished by a selective reading of his papers and also that the role played by Fleck was more complex than has so far been contemplated.

Clinical significance of NGAL and KIM-1 for acute kidney injury in patients with scrub typhus.

PubMed

Sun, In O; Shin, Sung Hye; Cho, A Young; Yoon, Hyun Ju; Chang, Mi Yok; Lee, Kwang Young

2017-01-01

The aim of this study is to investigate the clinical significance of neutrophil gelatinase-associated lipocalin (NGAL) and kidney injury molecule-1 (KIM-1) for acute kidney injury (AKI) in patients with scrub typhus. From 2014 to 2015, 145 patients were diagnosed with scrub typhus. Of these, we enrolled 138 patients who were followed up until renal recovery or for at least 3 months. We measured serum and urine NGAL and KIM-1 levels and evaluated prognostic factors affecting scrub typhus-associated AKI. Of the 138 patients, 25 had scrub typhus-associated AKI. The incidence of AKI was 18.1%; of which 11.6%, 4.3%, and 2.2% were classified as risk, injury, and failure, respectively, according to RIFLE criteria. Compared with patients in the non-AKI group, patients in the AKI group were older and showed higher total leukocyte counts and hypoalbuminemia or one or more comorbidities such as hypertension (72% vs 33%, p<0.01), diabetes (40% vs 14%, p<0.01), or chronic kidney disease (32% vs 1%, p<0.01). In addition, serum NGAL values (404± 269 vs 116± 78 ng/mL, P<0.001), KIM-1 values (0.80± 0.52 vs 0.33± 0.68 ng/mL, P<0.001), urine NGAL/creatinine values (371± 672 vs 27± 39 ng/mg, P<0.001) and urine KIM-1/creatinine values (4.04± 2.43 vs 2.38± 1.89 ng/mg, P<0.001) were higher in the AKI group than in the non-AKI group. By multivariate logistic regression, serum NGAL and the presence of chronic kidney disease were significant predictors of AKI. Serum NGAL might be an additive predictor for scrub typhus-associated AKI.

Lateral Flow Rapid Test for Accurate and Early Diagnosis of Scrub Typhus: A Febrile Illness of Historically Military Importance in the Pacific Rim.

PubMed

Chao, Chien-Chung; Zhangm, Zhiwen; Weissenberger, Giulia; Chen, Hua-Wei; Ching, Wei-Mei

2017-03-01

Scrub typhus (ST) is an infection caused by Orientia tsutsugamushi. Historically, ST was ranked as the second most important arthropod-borne medical problem only behind malaria during World War II and the Vietnam War. The disease occurs mainly in Southeast Asia and has been shown to emerge and reemerge in new areas, implying the increased risk for U.S. military and civilian personnel deployed to these regions. ST can effectively be treated by doxycycline provided the diagnosis is made early, before the development of severe complications. Scrub Typhus Detect is a lateral flow rapid test based on a mixture of recombinant 56-kDa antigens with broad reactivity. The performance of this prototype product was evaluated against indirect immunofluorescence assay, the serological gold standard. Using 249 prospectively collected samples from Thailand, the sensitivity and specificity for IgM was found to be 100% and 92%, respectively, suggesting a high potential of this product for clinical use. This product will provide a user friendly, rapid, and accurate diagnosis of ST for clinicians to provide timely and accurate treatments of deployed personnel. Reprint & Copyright © 2017 Association of Military Surgeons of the U.S.

Survey of three bacterial louse-associated diseases among rural Andean communities in Peru: prevalence of epidemic typhus, trench fever, and relapsing fever.

PubMed

Raoult, D; Birtles, R J; Montoya, M; Perez, E; Tissot-Dupont, H; Roux, V; Guerra, H

1999-08-01

Typhus and other louse-transmitted bacterial infections in Peruvian sierra communities are known to occur but have not recently been assessed. In this study, 194 of 1,280 inhabitants of four villages in Calca Province in the Urubamba Valley were included. Thirty-nine (20%) of the 194 volunteers had antibodies to Rickettsia prowazekii, whereas 24 (12%) had antibodies to Bartonella quintana and 2 against Borrelia recurrentis. There was a significant correlation between the presence of infesting ectoparasites and antibodies to R. prowazekii, as well as between antibodies to R. prowazekii and ectoparasite infestation and fever in the previous 6 months. The proportion of inhabitants infested with ectoparasites was significantly higher in the highest-altitude village than in the other three villages. Two volunteers' antibody levels suggested a recent typhus infection, but only B. quintana DNA was amplified from lice. Epidemic typhus remains extant in the area, and B. quintana infections were encountered and documented for the first time in South America.

Epidemic typhus.

PubMed

Bechah, Yassina; Capo, Christian; Mege, Jean-Louis; Raoult, Didier

2008-07-01

Epidemic typhus is transmitted to human beings by the body louse Pediculus humanus corporis. The disease is still considered a major threat by public-health authorities, despite the efficacy of antibiotics, because poor sanitary conditions are conducive to louse proliferation. Until recently, Rickettsia prowazekii, the causal agent, was thought to be confined to human beings and their body lice. Since 1975, R prowazekii infection in human beings has been related to contact with the flying squirrel Glaucomys volans in the USA. Moreover, Brill-Zinsser disease, a relapsed form of epidemic typhus that appears as sporadic cases many years after the initial infection, is unrelated to louse infestation. Stress or a waning immune system are likely to reactivate this earlier persistent infection, which could be the source of new epidemics when conditions facilitate louse infestation. Finally, R prowazekii is a potential category B bioterrorism agent, because it is stable in dried louse faeces and can be transmitted through aerosols. An increased understanding of the pathogenesis of epidemic typhus may be useful for protection against this bacterial threat.

Surveillance of potential hosts and vectors of scrub typhus in Taiwan.

PubMed

Kuo, Chi-Chien; Lee, Pei-Lung; Chen, Chun-Hsung; Wang, Hsi-Chieh

2015-12-01

Scrub typhus is a lethal infectious disease vectored by larval trombiculid mites (i.e. chiggers) infected with Orientia tsutsugamushi (OT) and recent decades have witnessed an emergence of scrub typhus in several countries. Identification of chigger species and their vertebrate hosts is fundamental for the assessment of human risks to scrub typhus under environmental changes, but intensive and extensive survey of chiggers and their hosts is still lacking in Taiwan. Chiggers were collected from shrews and rodents in nine counties of Taiwan and were assayed for OT infections with nested polymerase chain reaction (PCR). PCR products were further sequenced to reveal probable OT strains. Rodents were assessed for OT exposure by immunofluorescent antibody assay. Lastly, incidence rate of scrub typhus in each county was associated with loads and prevalence of chigger infestations, seropositivity rate in rodents, and OT positivity rate in chiggers. Rattus losea was the most abundant (48.7% of 1,285 individuals) and widespread (occurred in nine counties) small mammal species and hosted the majority of chiggers (76.4% of 128,520 chiggers). Leptotrombidium deliense was the most common (64.9% of all identified chiggers) and widespread (occurred in seven counties) chigger species but was replaced by Leptotrombidium pallidum or Leptotrombidium scutellare during the cold seasons in two counties (Matsu and Kinmen) where winter temperatures were lower than other study sites. Seropositivity rate for OT exposure in 876 assayed rodents was 43.0% and OT positivity rate in 347 pools of chiggers was 55.9%, with 15 OT strains identified in the 107 successfully sequenced samples. Incidence rate of scrub typhus was positively correlated with chigger loads, prevalence of chigger infestations, seropositivity rate but not OT positivity rate in chiggers. Our study reveals R. losea as the primary host for chiggers and there exists a geographical and seasonal variation in chigger species in Taiwan. It also emphasizes the importance of recognition of chigger vectors and their vertebrate hosts for a better prediction of human risks to scrub typhus under rapid environmental changes.

Prospective evaluation of commercial antibody-based rapid tests in combination with a loop-mediated isothermal amplification PCR assay for detection of Orientia tsutsugamushi during the acute phase of scrub typhus infection.

PubMed

Blacksell, Stuart D; Paris, Daniel H; Chierakul, Wirongrong; Wuthiekanun, Vanaporn; Teeratakul, Achara; Kantipong, Pacharee; Day, Nicholas P J

2012-03-01

Samples from 160 prospectively recruited febrile patients with typhus-like illness in an area of Thailand (Chiang Rai, northern Thailand) where scrub typhus is endemic were used to evaluate the diagnostic capabilities of four rapid immunochromatographic tests (ICTs) for the detection of Orientia tsutsugamushi IgM and total antibodies during acute scrub typhus infection. Of the 160 cases, 54 (34%) had been confirmed to have scrub typhus using the reference scrub typhus infection criteria (STIC), i.e., positive cell culture isolation, an admission IgM antibody titer of ≥1:12,800, a 4-fold rising IgM antibody titer, and/or positivity for ≥2 out of 3 PCR gene targets). The ICTs gave the following sensitivities and specificities: the Panbio IgM ICT, 46% (95% confidence interval [CI], 33 to 60) and 95% (95% CI, 89 to 98), respectively; the Standard Diagnostics IgM ICT, 68% (95% CI, 60 to 75) and 73% (95% CI, 68 to 78), respectively; the AccessBio IgM ICT, 56% (95% CI, 48 to 63) and 90% (95% CI, 87 to 94), respectively; and the AccessBio total antibody ABt ICT, 61% (95% CI, 53 to 68) and 68% (95% CI, 63 to 73), respectively. An isothermal loop amplification (LAMP) PCR assay for scrub typhus demonstrated a sensitivity of 52% (95% CI, 38 to 66) and a specificity of 94% (95% CI, 88 to 98). This study has revealed the diagnostic limitations of antibody-based assays in an acute care setting. However, the combination of ICTs with LAMP usually increased sensitivity with a minimal reduction in specificity. The best combination, the Panbio IgM ICT and LAMP, resulted in a sensitivity of 67% (95% CI, 53 to 79) and a specificity of 91% (95% CI, 83 to 95). The combination of antibody-based assays with DNA- or antigen-based tests shows promise for improved diagnostic sensitivity.

Detection of antibodies against spotted fever group Rickettsia (SFGR), typhus group Rickettsia (TGR), and Coxiella burnetii in human febrile patients in the Philippines.

PubMed

Camer, Gerry Amor; Alejandria, Marissa; Amor, Miguel; Satoh, Hiroshi; Muramatsu, Yasukazu; Ueno, Hiroshi; Morita, Chiharu

2003-02-01

A total of 157 sera from febrile patients in the Philippine General Hospital in Manila, Luzon, and the Northern Samar Provincial Hospital, the Philippines, were used. Serum antibodies against spotted fever group Rickettsia (SFGR) and typhus group Rickettsia (TGR) were detected by indirect immunofluorescence test. Antibody positive rates were 1.3% for SFGR (Rickettsia japonica) and 2.5% for TGR (R. typhus), respectively. Rickettsial antibodies in humans in the Philippines were found for the first time. These results underscore the need for further epidemiological study of clinical rickettsioses in the Philippines.

Early Diagnosis of Scrub Typhus with a Rapid Flow Assay Using Recombinant Major Outer Membrane Protein Antigen (r56) of Orientia tsutsugamushi

PubMed Central

Ching, W.-M.; Rowland, D.; Zhang, Z.; Bourgeois, A. L.; Kelly, D.; Dasch, G. A.; Devine, P. L.

2001-01-01

The variable 56-kDa major outer membrane protein of Orientia tsutsugamushi is the immunodominant antigen in human scrub typhus infections. We developed a rapid immunochromatographic flow assay (RFA) for the detection of immunoglobulin M (IgM) and IgG antibodies to O. tsutsugamushi. The RFA employs a truncated recombinant 56-kDa protein from the Karp strain as the antigen. The performance of the RFA was evaluated with a panel of 321 sera (serial bleedings of 85 individuals suspected of scrub typhus) which were collected in the Pescadore Islands, Taiwan, from 1976 to 1977. Among these 85 individuals, IgM tests were negative for 7 cases by both RFA and indirect fluorescence assay (IFA) using Karp whole-cell antigen. In 29 cases specific responses were detected by the RFA earlier than by IFA, 44 cases had the same detection time, and 5 cases were detected earlier by IFA than by RFA. For IgG responses, 4 individuals were negative with both methods, 37 cases exhibited earlier detection by RFA than IFA, 42 cases were detected at the same time, and 2 cases were detected earlier by IFA than by RFA. The sensitivities of RFA detection of antibody in sera from confirmed cases were 74 and 86% for IgM and IgG, respectively. When IgM and IgG results were combined, the sensitivity was 89%. A panel of 78 individual sera collected from patients with no evidence of scrub typhus was used to evaluate the specificity of the RFA. The specificities of the RFA were 99% for IgM and 97% for IgG. The sensitivities of IFA were 53 and 73% for IgM and IgG, respectively, and were 78% when the results of IgM and IgG were combined. The RFA test was significantly better than the IFA test for the early detection of antibody to scrub typhus in primary infections, while both tests were equally sensitive with reinfected individuals. PMID:11238230

Outcome of Intravenous Azithromycin Therapy in Patients with Complicated Scrub Typhus Compared with That of Doxycycline Therapy Using Propensity-Matched Analysis

PubMed Central

Jang, Mi-Ok; Jang, Hee-Chang; Kim, Uh Jin; Ahn, Joon Hwan; Kang, Seung-Ji; Jung, Sook-In; Shin, Hee-Young

2014-01-01

There are no well-matched, controlled studies comparing azithromycin with doxycycline for the treatment of complicated scrub typhus. A retrospective propensity score-matched case-control study was performed for patients who presented with complicated scrub typhus and were treated with doxycycline or azithromycin between 2001 and 2011. Data on comorbidities, clinical manifestations, laboratory studies, treatments, and outcomes were extracted for analysis. The clinical characteristics and outcomes of the azithromycin-treated group (n = 73) were compared to those of the doxycycline-treated group (n = 108). Of 181 patients, 73 from each group were matched by propensity scores. There were no significant differences in baseline characteristics between the matched groups. The treatment success and survival rates were not significantly different (89% [65/73 patients] versus 96% [70/73 patients] and 96% [70/73 patients] versus 96% [70/73 patients], respectively [P > 0.05]). No difference was observed in the time to defervescence or length of hospital stay between the two groups (P > 0.05). In complicated scrub typhus patients (n = 181), multivariate analysis showed that only APACHE II score was an independent risk factor for mortality (95% confidence interval, 1.11 to 1.56; P < 0.001). Our data suggest that outcomes of azithromycin therapy are comparable to those of doxycycline therapy in patients with complicated scrub typhus. PMID:24366734

Flying Squirrel–associated Typhus, United States

PubMed Central

Krebs, John W.; Comer, James A.; Sumner, John W.; Rushton, Thomas C.; Lopez, Carlos E.; Nicholson, William L.; Rooney, Jane A.; Lance-Parker, Susan E.; McQuiston, Jennifer H.; Paddock, Christopher D.; Childs, James E.

2003-01-01

In March 2002, typhus fever was diagnosed in two patients residing in West Virginia and Georgia. Both patients were hospitalized with severe febrile illnesses, and both had been recently exposed to or had physical contact with flying squirrels or flying squirrel nests. Laboratory results indicated Rickettsia prowazekii infection. PMID:14609478

Diversification of Orientia tsutsugamushi genotypes by intragenic recombination and their potential expansion in endemic areas

PubMed Central

Kim, Gwanghun; Ha, Na-Young; Min, Chan-Ki; Kim, Hong-Il; Yen, Nguyen Thi Hai; Lee, Keun-Hwa; Oh, Inbo; Kang, Jae-Seung; Choi, Myung-Sik; Kim, Ik-Sang

2017-01-01

Background Scrub typhus is a mite-borne febrile disease caused by O. tsutsugamushi infection. Recently, emergence of scrub typhus has attracted considerable attention in several endemic countries in Asia and the western Pacific. In addition, the antigenic diversity of the intracellular pathogen has been a serious obstacle for developing effective diagnostics and vaccine. Methodology/Principal findings To understand the evolutionary pathway of genotypic diversification of O. tsutsugamushi and the environmental factors associated with the epidemiological features of scrub typhus, we analyzed sequence data, including spatiotemporal information, of the tsa56 gene encoding a major outer membrane protein responsible for antigenic variation. A total of 324 tsa56 sequences covering more than 85% of its open reading frame were analyzed and classified into 17 genotypes based on phylogenetic relationship. Extensive sequence analysis of tsa56 genes using diverse informatics tools revealed multiple intragenic recombination events, as well as a substantially higher mutation rate than other house-keeping genes. This suggests that genetic diversification occurred via frequent point mutations and subsequent genetic recombination. Interestingly, more diverse bacterial genotypes and dominant vector species prevail in Taiwan compared to other endemic regions. Furthermore, the co-presence of identical and sub-identical clones of tsa56 gene in geographically distant areas implies potential spread of O. tsutsugamushi genotypes. Conclusions/Significance Fluctuation and diversification of vector species harboring O. tsutsugamushi in local endemic areas may facilitate genetic recombination among diverse genotypes. Therefore, careful monitoring of dominant vector species, as well as the prevalence of O. tsutsugamushi genotypes may be advisable to enable proper anticipation of epidemiological changes of scrub typhus. PMID:28248956

Scrub Typhus Leading to Acute Encephalitis Syndrome, Assam, India.

PubMed

Khan, Siraj A; Bora, Trishna; Laskar, Basanta; Khan, Abdul M; Dutta, Prafulla

2017-01-01

To determine the contribution of Orientia tsutsugamushi, the agent of scrub typhus, as a cause of acute encephalitis syndrome (AES) in Assam, India, we conducted a retrospective study of hospital patients with symptoms of AES during 2013-2015. Our findings suggest that O. tsutsugamushi infection leads to AES and the resulting illness and death.

Diagnosis of Queensland tick typhus and African tick bite fever by PCR of lesion swabs.

PubMed

Wang, Jin Mei; Hudson, Bernard J; Watts, Matthew R; Karagiannis, Tom; Fisher, Noel J; Anderson, Catherine; Roffey, Paul

2009-06-01

We report 3 cases of Queensland tick typhus (QTT) and 1 case of African tick bite fever in which the causative rickettsiae were detected by PCR of eschar and skin lesions in all cases. An oral mucosal lesion in 1 QTT case was also positive.

A case series of possibly recrudescent Orientia tsutsugamushi infection presenting as pneumonia.

PubMed

Im, Jae-Hyoung; Baek, Ji Hyeon; Lee, Jin-Soo; Chung, Moon-Hyun; Lee, Sun Myoung; Kang, Jae-Seung

2014-01-01

Orientia tsutsugamushi remains latent in humans after scrub typhus. Pneumonia occurs as a complication of scrub typhus in the late-phase disease. However, pneumonia may also occur as a presenting manifestation of O. tsutsugamushi infection. We reviewed the cases of 3 patients with atypical pneumonia who presented at our hospital and were later confirmed to have O. tsutsugamushi infection by serology, nested polymerase chain reaction (PCR), and cell culture. All patients were young adults with no history of scrub typhus, and none claimed to have recently been exposed to areas where scrub typhus is endemic. Two cases occurred in non-outbreak seasons. Furthermore, eschar was not observed. Pneumonia was documented within 4 days after fever onset. The immunoglobulin (Ig) G antibody titers against O. tsutsugamushi were higher than the IgM titers, although the serologic test results were less helpful in the diagnosis. Nested PCR and cell culture of blood specimens confirmed the diagnosis of O. tsutsugamushi infection. These findings suggest that pneumonia can occur as a result of recrudescence of latent O. tsutsugamushi infection.

Clinical manifestations of scrub typhus.

PubMed

Rajapakse, Senaka; Weeratunga, Praveen; Sivayoganathan, Sriharan; Fernando, Sumadhya Deepika

2017-02-01

The mite-borne rickettsial zoonosis scrub typhus is widely prevalent in parts of Southeast and Far East Asia, and northern Australia. The disease is an acute febrile illness, associated with rash and often an eschar, which responds dramatically to treatment with antibiotics. In some cases it results in a serious illness leading to multiple organ involvement and death. The disease manifestations are thought to result from a systemic vasculitis, caused by both direct effects of the organisms as well as an exaggerated immune response, although little is understood about its pathogenesis. A wide spectrum of clinical manifestations, affecting nearly every organ system, have been described with scrub typhus. Some of these manifestations are serious and life threatening. In this systematic review, we summarise the typical and atypical manifestations of scrub typhus reported in the literature. Awareness of these unusual manifestations will hopefully guide clinicians towards diagnosing the condition early, and initiating early appropriate antibiotics and other supportive measures. © The Author 2017. Published by Oxford University Press on behalf of Royal Society of Tropical Medicine and Hygiene. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Persistence of Orientia tsutsugamushi in humans.

PubMed

Chung, Moon-Hyun; Lee, Jin-Soo; Baek, Ji-hyeon; Kim, Mijeong; Kang, Jae-Seung

2012-03-01

We investigated the persistence of viable Orientia tsutsugamushi in patients who had recovered from scrub typhus. Blood specimens were available from six patients with scrub typhus who were at 1 to 18 months after the onset of the illness. The EDTA-treated blood specimens were inoculated into ECV304 cells, and cultures were maintained for 7 months. Sequencing of the 56-kDa type-specific antigen gene of O. tsutsugamushi was performed to ascertain the homology of isolates. O. tsutsugamushi was isolated from all six patients, and nucleotide sequences of isolates serially collected from each patient were identical in all five patients in whom nucleotide sequences were compared. One patient relapsed 2 days after completion of antibiotic therapy; two patients complained of weakness for 1 to 2.5 months after the illness; one patient underwent coronary angioplasty 6 months later; and one patient suffered from a transient ischemic attack 8 months later. This finding suggests that O. tsutsugamushi causes chronic latent infection, which may be associated with certain clinical illnesses, preceded by scrub typhus. Antibiotic therapy abates the symptoms of scrub typhus, but does not eradicate O. tsutsugamushi from the human body.

Scrub typhus masquerading as HELLP syndrome and puerperal sepsis in an asymptomatic malaria patient.

PubMed

Karim, Habib Md Reazaul; Bhattacharyya, Prithwis; Kakati, Sonai Datta; Borah, Tridip Jyoti; Yunus, Md

2016-01-01

Scrub typhus and malaria can involve multiple organ systems and are notoriously known for varied presentations. However, clinical malaria or scrub typhus is unusual without fever. On the other hand, altered sensorium with or without fever, dehydration, hemorrhage and hemolysis may lead to low blood pressure. Presence of toxic granules and elevated band forms in such patients can even mimic sepsis. When such a patient is in the peripartum period, it creates a strong clinical dilemma for the physician especially in unbooked obstetric cases. We present such a case where a 26-year-old unbooked female presented on second postpartum day with severe anemia, altered sensorium, difficulty in breathing along with jaundice and gum bleeding without history of fever. Rapid diagnostic test for malaria was negative and no eschar was seen. These parameters suggested a diagnosis of HELLP (Hemolysis, Elevated Liver enzymes, Low Platelet) syndrome with or without puerperal sepsis. Subsequently she was diagnosed as having asymptomatic malaria and scrub typhus and responded to the treatment of it. The biochemical changes suggestive of HELLP syndrome also subsided. We present this case to emphasize the fact that mere absence of fever and eschar does not rule out scrub typhus. It should also be considered as a differential diagnosis in patients with symptoms and signs suggesting HELLP syndrome. Asymptomatic malaria can complicate case scenario towards puerperal sepsis by giving false toxic granules and band form in such situations.

Diagnostic performance of serological tests to detect antibodies against acute scrub typhus infection in central India.

PubMed

Pote, Kiran; Narang, Rahul; Deshmukh, Pradeep

2018-01-01

Differentiating scrub typhus from other acute febrile illness is difficult due to non specificity of clinical symptoms and relative absence of eschar in Indian population. The diagnosis thus relies mainly on laboratory tests. Antibody based serological tests are mainstay of scrub typhus diagnosis. Here, we evaluated the diagnostic performance of IgM ELISA, IgM IFA and ICT to detect antibodies against O. tsutsugamushi in acute serum of febrile patients. The serum samples from 600 randomly selected patients suffering from acute undifferentiated fever were tested by all the three tests mentioned above. We used latent class analysis to generate unbiased results as all the tests for scrub typhus diagnosis are imperfect and none of them can be considered as reference standard. We found that IgM ELISA with cutoff titer 0.5 OD has high diagnostic accuracy (sensitivity 99.9% and specificity 99.15) than IgM IFA (sensitivity 96.8% and specificity 99.7%) for scrub typhus diagnosis. ICT used in our study had very high specificity 100% but low sensitivity (38%) which would limit its use for acute serum samples. ICT being a screening or point of care test, has to be more sensitive while some compromise with specificity is affordable. Hence, optimal cutoff for ICT should be evaluated under different settings. IgM ELISA being simple and affordable could be an alternative diagnostic test to IgM IFA which is subjective and costly.

[The epidemic typhus of 1813/14 in the area of lower Franconia].

PubMed

Vasold, Manfred

2004-01-01

When Napoleon left for Moscow, in June 1812, he marched at the head of a huge army, perhaps more than half a million men strong. Roughly one fifth of them survived and came back to Germany at the turn of 1812/13. The "Grande Armée" had been subject to open battles and guerilla warfare, but even more to the ravages of hunger and infectious disease - it was epidemic typhus that killed off the soldiers. On their way back to France, the soldiers carried that disease to some areas of Germany, esp. those along the Main river. In late winter of 1813 some parts of Franconia suffered terribly. The epidemic subsided in summer 1813 when the lice - typhus is a louse-born disease - were less and better under control. But again in the winter of 1813/14, after the battle of Leipzig (Oct. 1813), a murderous epidemic of typhus broke out and killed very many people in cities like Wurzburg, Aschaffenburg, and Mainz. Mortality rose to a high percentage. Some contemporary German doctors had a rough idea that the carrier of the disease must be in the clothes. According to very conservative estimates one out of ten Germans fell sick, and ten percent of the sick died of typhus, a quarter of a million out of 23 million people. German historiography normally does not mention this epidemic in history text-books, so this epidemic is rather unknown.

Coincidence between geographical distribution of Leptotrombidium scutellare and scrub typhus incidence in South Korea.

PubMed

Roh, Jong Yul; Song, Bong Gu; Park, Won Il; Shin, Eun Hee; Park, Chan; Park, Mi-Yeoun; Chang, Kyu Sik; Lee, Wook Gyo; Lee, Hee Il; Shin, E-Hyun

2014-01-01

To clarify the geographical distribution of scrub typhus vectors in Korea, a survey of larval trombiculid mites was conducted from 2005 to 2007 by collecting wild small mammals twice a year (spring and autumn) at 24 sites nationwide. A total of 67,325 mites representing 4 genera and 14 species were collected from 783 trapped rodents, corresponding to a chigger index (number of chigger mites per rodent) of 86.0. The predominant mite species were Leptotrombidium pallidum (52.6%), Leptotrombiduim scutellare (27.1%), Leptotrombidium palpale (8.2%), Leptotrombidium orientale (5.6%), and Neotrombicula tamiyai (1.7%). However, the proportions of L. scutellare in southern areas, including endemic provinces such as Jeollabuk-Do (34.3%), Jeollanam-Do (49.0%), and Gyeongsangnam-Do (88%), were relatively higher than in central Korean regions where L. pallidum was predominant. In autumn, the ratio of L. scutellare increased to 42% while the ratio of L. pallidum decreased. The geographical distribution map of the L. scutellare chigger index was identical to the incidence pattern of scrub typhus, whereas those of overall mites and L. pallidum showed no relationship with case incidence patterns. Distribution mapping analysis shows an identical geographical distribution of L. scutellare and epidemic incidence of scrub typhus in South Korea. L. pallidum could be another vector at all other parts of the Korean peninsula, including the eastern and northern regions that have a low level of scrub typhus incidence.

Nursing typhus victims in the Second World War, 1942-1944: a discussion paper.

PubMed

Brooks, Jane

2014-07-01

This article explores the care British nurses provided to victims of typhus during the Second World War. Typhus is associated with poverty and overcrowding. During wars in the pre-antibiotic era, civilians were particularly susceptible to epidemics, which military governments feared would spread to their troops. This discussion paper draws on archival data from three typhus epidemics in the Second World War to examine the expert work of British nurses in caring for victims during these potential public health disasters. The published sources for the paper include material from nursing and medical journals published between 1940-1947. Archival sources come from the National Archives in Kew, the Wellcome Library and the Army Medical Services Museum, between 1943-1945. Of particular interest is the correspondence with Dame Katharine Jones from nurses on active service overseas. Whilst epidemics of typhus are now rare, nurses in the present day may be required to care for the public in environments of extreme poverty and overcrowding, where life-threatening infectious diseases are prevalent. This article has demonstrated that it is possible for expert and compassionate nursing to alleviate suffering and prevent death, even when medical technologies are unavailable. Expert and compassionate care, adequate nutrition and hydration and attention to hygiene needs are crucial when there are limited pharmacological treatments and medical technologies available to treat infectious diseases. The appreciation of this could have implications for nurses working in current global conflicts. © 2013 John Wiley & Sons Ltd.

[Clinical features of four atypical pediatric cases of endemic typhus with pneumonia].

PubMed

Liu, Jin-rong; Xu, Bao-ping; Li, Shao-gang; Liu, Jun; Tian, Bao-lin; Zhao, Shun-ying

2013-10-01

To analyze clinical manifestations, treatment and prognosis of 4 cases with endemic typhus. The clinical data of four endemic typhus patients in prognosis were retrospectively analyzed. These four atypical cases of endemic typhus with pneumonia were treated in our department from October 2011 to March 2012. They were all male, with an age range of 15 months to 7 years. The four patients had long history, mild respiratory symptom and no improvement was found after treatment with cephalosporins. There were no evidences of bacterial, viral, or fungal infections and we thought they might have infection with other pathogen. Three were from rural areas. Routine blood tests, Weil-Felix reaction, blood smear (Giemsa staining) , and indirect immunofluorescence assay were performed. Blood smear and IFA tests showed evidences for endemic typhus. The clinical presentations were atypical, the patients had no headache, but all had fever, rash, and pneumonia of varying severity. None of the patients had a severe cough, but bronchial casts were observed in one case. Recurrent fever was reported in three cases. Physical examinations showed no eschars, but one patient had a subconjunctival hemorrhage, and one had skin scratches, cervical lymphadenopathy, pleural effusion, pericardial effusion, and cardiac dilatation. Two patients had remarkably increased peripheral blood leukocyte counts; both these patients also had high alanine aminotransferase (ALT) levels and one had a high C-reactive protein (CRP) level. Weil-Felix testing was negative or the OX19 titer was low. The peripheral blood smear (Giemsa stain) showed intracellular pathogens in all four cases. After combined therapy with doxycycline and macrolide antibiotics, all four patients recovered well. The endemic typhus children often come from rural areas. The clinical presentations were atypical, they usually have no headache, but have fever (often Periodic fever) , rash, and pneumonia of varying severity in these four cases. Combined therapy with doxycycline and macrolide antibiotics was effective in all four patients.

Chest radiographic manifestations of scrub typhus.

PubMed

Abhilash, Kpp; Mannam, P R; Rajendran, K; John, R A; Ramasami, P

2016-01-01

Respiratory system involvement in scrub typhus is seen in 20-72% of patients. In endemic areas, good understanding and familiarity with the various radiologic findings of scrub typhus are essential in identifying pulmonary complications. Patients admitted to a tertiary care center with scrub typhus between October 2012 and September 2013 and had a chest X ray done were included in the analysis. Details and radiographic findings were noted and factors associated with abnormal X-rays were analyzed. The study cohort contained 398 patients. Common presenting complaints included fever (100%), generalized myalgia (83%), headache (65%), dyspnea (54%), cough (24.3%), and altered sensorium (14%). Almost half of the patients (49.4%) had normal chest radiographs. Common radiological pulmonary abnormalities included pleural effusion (14.6%), acute respiratory distress syndrome (14%), airspace opacity (10.5%), reticulonodular opacities (10.3%), peribronchial thickening (5.8%), and pulmonary edema (2%). Cardiomegaly was noted in 3.5% of patients. Breathlessness, presence of an eschar, platelet counts of <20,000 cells/cumm, and total serum bilirubin >2 mg/dL had the highest odds of having an abnormal chest radiograph. Patients with an abnormal chest X-ray had a higher requirement of noninvasive ventilation (odds ratio [OR]: 13.98; 95% confidence interval CI: 5.89-33.16), invasive ventilation (OR: 18.07; 95% CI: 6.42-50.88), inotropes (OR: 8.76; 95% CI: 4.35-17.62), higher involvement of other organ systems, longer duration of hospital stay (3.18 ± 3 vs. 7.27 ± 5.58 days; P< 0.001), and higher mortality (OR: 4.63; 95% CI: 1.54-13.85). Almost half of the patients with scrub typhus have abnormal chest radiographs. Chest radiography should be included as part of basic evaluation at presentation in patients with scrub typhus, especially in those with breathlessness, eschar, jaundice, and severe thrombocytopenia.

Abundance & distribution of trombiculid mites & Orientia tsutsugamushi, the vectors & pathogen of scrub typhus in rodents & shrews collected from Puducherry & Tamil Nadu, India.

PubMed

Candasamy, Sadanandane; Ayyanar, Elango; Paily, Kummankottil; Karthikeyan, Patricia Anitha; Sundararajan, Agatheswaran; Purushothaman, Jambulingam

2016-12-01

Human cases of scrub typhus are reported every year from Puducherry and adjoining areas in southern India. However, information on the presence of causative agent, Orientia tsutsugamushi, and its vectors is lacking. Hence, the objective of the study was to find out the vector as well as pathogen distribution in rodents and shrews present in the scrub typhus-reported areas in southern India. Trombiculid mites were collected by combing rats and shrews collected using Sherman traps and identified to species level following standard taxonomical keys. The serum samples of the animals were used for Weil-Felix test and the clots containing blood cells were used for DNA extraction and polymerase chain reaction (PCR). A total of 181 animals comprising four rodent species and one shrew species were collected from 12 villages. High proportion of chiggers was collected from the shrew, Suncus murinus (79.1%) and Rattus rattus (47.6%). A total of 10,491 trombiculid mites belonging to nine species were collected. Leptotrombidium deliense, the known vector of scrub typhus pathogen, was the predominant species (71.0%) and the chigger (L. deliense) index was 41.1 per animal. Of the 50 animals screened for the pathogen, 28 showed agglutination against OX-K in Weil-Felix test indicating the presence of antibodies against O. tsutsugamushi, the causative agent of scrub typhus. PCR carried out with the DNA extracted from blood samples of two of the animals were positive for GroEl gene of O. tsutsugamushi. L. deliense index was well above the critical limit of chigger load, indicating that all the villages were receptive for high risk of transmission of scrub typhus to human. Pathogen positivity was higher among animals collected from villages recorded for higher chigger indices due to active transmission between the chigger mites and reservoir host animals. The results are suggestive of routine vector/pathogen surveillance at hot spots to initiate timely preventive measures.

Rickettsioses in Europe.

PubMed

Portillo, Aránzazu; Santibáñez, Sonia; García-Álvarez, Lara; Palomar, Ana M; Oteo, José A

2015-01-01

Bacteria of the genera Rickettsia and Orientia (family rickettsiaceae, order rickettsiales) cause rickettsioses worldwide, and are transmitted by lice, fleas, ticks and mites. In Europe, only Rickettsia spp. cause rickettsioses. With improvement of hygiene, the risk of louse-borne rickettsiosis (epidemic typhus) is low in Europe. Nevertheless, recrudescent form of Rickettsia prowazekii infection persists. There could be an epidemic typhus outbreak if a body lice epidemic occurs under unfavorable sanitary conditions. In Europe, endemic typhus or Rickettsia typhi infection, transmitted by rats and fleas, causes febrile illness. At the beginning of this century, flea-borne spotted fever cases caused by Rickettsia felis were diagnosed. Flea-borne rickettsiosis should be suspected after flea bites if fever, with or without rash, is developed. Tick-borne rickettsioses are the main source of rickettsia infections in Europe. Apart from Rickettsia conorii, the Mediterranean Spotted Fever (MSF) agent, other Rickettsia spp. cause MSF-like: Rickettsia helvetica, Rickettsia monacensis, Rickettsia massiliae or Rickettsia aeschlimannii. In the 1990s, two 'new' rickettsioses were diagnosed: Lymphangitis Associated Rickettsiosis (LAR) caused by Rickettsia sibirica mongolitimonae, and Tick-Borne Lymphadenopathy/Dermacentor-Borne-Necrosis-Erythema-Lymphadenopathy/Scalp Eschar Neck Lymphadenopathy (TIBOLA/DEBONEL/SENLAT), caused by Rickettsia slovaca, Candidatus Rickettsia rioja and Rickettsia raoultii. Lastly, European reports about mite-borne rickettsiosis are scarce. Copyright © 2015 Institut Pasteur. Published by Elsevier Masson SAS. All rights reserved.

Newly Recognized Pediatric Cases of Typhus Group Rickettsiosis, Houston, Texas, USA

PubMed Central

Erickson, Timothy; da Silva, Juliana; Nolan, Melissa S.; Marquez, Lucila; Munoz, Flor M.

2017-01-01

An increase in typhus group rickettsiosis and an expanding geographic range occurred in Texas, USA, over a decade. Because this illness commonly affects children, we retrospectively examined medical records from 2008–2016 at a large Houston-area pediatric hospital and identified 36 cases. The earliest known cases were diagnosed in 2011. PMID:29148369

[Typhus in Mexico City in 1915].

PubMed

Rodríguez, Martha Eugenia

2016-01-01

The year 1915 was particularly difficult; it was characterized by droughts, famines, and outbreaks of diseases including typhus.This text exposes its spread in Mexico City as well as the measures implemented to combat it, carried out before knowing the etiology of the illness, focused on cleaning up the environment and the measures undertaken afterwards with the aim of delousing people.

Medical Surveillance Monthly Report (MSMR). Volume 2, Number 11, November 2015

DTIC Science & Technology

2015-11-01

encounters within 2 weeks Typhoid fever 002.0 once per 360 days 1 inpatient Typhus fever 080, 081.x once per lifetime 1 inpatient, 2 outpatient encounters...Tuberculosis 49 18 36.7 3 1 33.3 NR NR NR NR NR NR Tularemia 2 1 50.0 0 0 * 1 1 100.0 0 0 * Typhoid fever 4 0 0.0 0 0 * NR NR NR NR NR NR Typhus fever 2 1 50.0 0...Tularemia 1 1 100.0 0 0 * 1 1 100.0 0 0 * Typhoid fever 3 0 0.0 0 0 * NR NR NR NR NR NR Typhus fever 2 0 0.0 0 0 * 0 0 * 0 0 * Vaccine, adverse event 1

2012 AAPS National Biotech Conference Open Forum: a perspective on the current state of immunogenicity prediction and risk management.

PubMed

Rajadhyaksha, Manoj; Subramanyam, Meena; Rup, Bonnie

2013-10-01

The immunogenicity profile of a biotherapeutic is determined by multiple product-, process- or manufacturing-, patient- and treatment-related factors and the bioanalytical methodology used to monitor for immunogenicity. This creates a complex situation that limits direct correlation of individual factors to observed immunogenicity rates. Therefore, mechanistic understanding of how these factors individually or in concert could influence the overall incidence and clinical risk of immunogenicity is crucial to provide the best benefit/risk profile for a given biotherapeutic in a given indication and to inform risk mitigation strategies. Advances in the field of immunogenicity have included development of best practices for monitoring anti-drug antibody development, categorization of risk factors contributing to immunogenicity, development of predictive tools, and development of effective strategies for risk management and mitigation. Thus, the opportunity to ask "where we are now and where we would like to go from here?" was the main driver for organizing an Open Forum on Improving Immunogenicity Risk Prediction and Management, conducted at the 2012 American Association of Pharmaceutical Scientists' (AAPS) National Biotechnology Conference in San Diego. The main objectives of the Forum include the following: to understand the nature of immunogenicity risk factors, to identify analytical tools used and animal models and management strategies needed to improve their predictive value, and finally to identify collaboration opportunities to improve the reliability of risk prediction, mitigation, and management. This meeting report provides the Forum participant's and author's perspectives on the barriers to advancing this field and recommendations for overcoming these barriers through collaborative efforts.

DDT - A Brief History and Status

EPA Pesticide Factsheets

DDT was the first of the modern synthetic insecticides, developed in the 1940s. It helped control diseases such as typhus and malaria. Enviromental concerns led to its cancellation in the 1970s. It still has limited indoor use in Africa to prevent malaria.

Severe scrub typhus infection: Clinical features, diagnostic challenges and management

PubMed Central

Peter, John Victor; Sudarsan, Thomas I; Prakash, John Anthony J; Varghese, George M

2015-01-01

Scrub typhus infection is an important cause of acute undifferentiated fever in South East Asia. The clinical picture is characterized by sudden onset fever with chills and non-specific symptoms that include headache, myalgia, sweating and vomiting. The presence of an eschar, in about half the patients with proven scrub typhus infection and usually seen in the axilla, groin or inguinal region, is characteristic of scrub typhus. Common laboratory findings are elevated liver transaminases, thrombocytopenia and leukocytosis. About a third of patients admitted to hospital with scrub typhus infection have evidence of organ dysfunction that may include respiratory failure, circulatory shock, mild renal or hepatic dysfunction, central nervous system involvement or hematological abnormalities. Since the symptoms and signs are non-specific and resemble other tropical infections like malaria, enteric fever, dengue or leptospirosis, appropriate laboratory tests are necessary to confirm diagnosis. Serological assays are the mainstay of diagnosis as they are easy to perform; the reference test is the indirect immunofluorescence assay (IFA) for the detection of IgM antibodies. However in clinical practice, the enzyme-linked immuno-sorbent assay is done due to the ease of performing this test and a good sensitivity and sensitivity when compared with the IFA. Paired samples, obtained at least two weeks apart, demonstrating a ≥ 4 fold rise in titre, is necessary for confirmation of serologic diagnosis. The mainstay of treatment is the tetracycline group of antibiotics or chloramphenicol although macrolides are used alternatively. In mild cases, recovery is complete. In severe cases with multi-organ failure, mortality may be as high as 24%. PMID:26261776

A study of muscle involvement in scrub typhus.

PubMed

Kalita, Jayantee; Misra, Usha K; Mani, Vinita E; Mahadevan, Anita; Shankar, Susrala K

2015-01-15

Patients with scrub typhus often complain of myalgia, but a comprehensive study on muscle dysfunction is lacking. We therefore report the clinical, electromyographic and muscle biopsy findings in patients with scrub typhus. Consecutive patients with scrub typhus were included, and their clinical and laboratory findings were noted. The patients with myalgia or weakness and elevated serum creatine kinase (CK) were considered to have muscle involvement. Electromyography (EMG) and muscle biopsy were done in some patients. Patients were treated with doxycycline 200mg daily for 7 days, and their clinical and biochemical outcome on discharge and one month were evaluated. 13 out of 33 (39.4%) patients had muscle involvement and their CK levels ranged between 287 and 3166 (859 ± 829) U/L. EMG revealed short duration polyphasic potentials, and muscle histopathology revealed evidence of vasculitis. There were significant correlations between severity of weakness and CK levels (r = -0.6; p < 0.001), platelet counts (r = 0.4; p = 0.04), duration of illness (r = -0.4; p = 0.01) and disability on discharge (r = -0.4; p = 0.04). Patients with muscle involvement had more severe illness evidenced by a lower Glasgow Coma Scale score (p < 0.001), thrombocytopenia (p = 0.05) and greater disability on discharge (p = 0.007), when compared to those without muscle involvement. All the patients had complete recovery following doxycycline therapy, and CK levels also normalized. Muscle dysfunction was present in 39% patients with scrub typhus. Although muscle histopathology showed evidence of vasculitis, patients responded to doxycycline. Copyright © 2014 Elsevier B.V. All rights reserved.

Inactivation of SAM-Methyltransferase is the Mechanism of Attenuation of a Historic Louse Borne Typhus Vaccine Strain

PubMed Central

Liu, Yan; Wu, Bin; Weinstock, George; Walker, David H.; Yu, Xue-jie

2014-01-01

Louse borne typhus (also called epidemic typhus) was one of man's major scourges, and epidemics of the disease can be reignited when social, economic, or political systems are disrupted. The fear of a bioterrorist attack using the etiologic agent of typhus, Rickettsia prowazekii, was a reality. An attenuated typhus vaccine, R. prowazekii Madrid E strain, was observed to revert to virulence as demonstrated by isolation of the virulent revertant Evir strain from animals which were inoculated with Madrid E strain. The mechanism of the mutation in R. prowazekii that affects the virulence of the vaccine was not known. We sequenced the genome of the virulent revertant Evir strain and compared its genome sequence with the genome sequences of its parental strain, Madrid E. We found that only a single nucleotide in the entire genome was different between the vaccine strain Madrid E and its virulent revertant strain Evir. The mutation is a single nucleotide insertion in the methyltransferase gene (also known as PR028) in the vaccine strain that inactivated the gene. We also confirmed that the vaccine strain E did not cause fever in guinea pigs and the virulent revertant strain Evir caused fever in guinea pigs. We concluded that a single nucleotide insertion in the methyltransferase gene of R. prowazekii attenuated the R. prowazekii vaccine strain E. This suggested that an irreversible insertion or deletion mutation in the methyl transferase gene of R. prowazekii is required for Madrid E to be considered a safe vaccine. PMID:25412248

Inactivation of SAM-methyltransferase is the mechanism of attenuation of a historic louse borne typhus vaccine strain.

PubMed

Liu, Yan; Wu, Bin; Weinstock, George; Walker, David H; Yu, Xue-Jie

2014-01-01

Louse borne typhus (also called epidemic typhus) was one of man's major scourges, and epidemics of the disease can be reignited when social, economic, or political systems are disrupted. The fear of a bioterrorist attack using the etiologic agent of typhus, Rickettsia prowazekii, was a reality. An attenuated typhus vaccine, R. prowazekii Madrid E strain, was observed to revert to virulence as demonstrated by isolation of the virulent revertant Evir strain from animals which were inoculated with Madrid E strain. The mechanism of the mutation in R. prowazekii that affects the virulence of the vaccine was not known. We sequenced the genome of the virulent revertant Evir strain and compared its genome sequence with the genome sequences of its parental strain, Madrid E. We found that only a single nucleotide in the entire genome was different between the vaccine strain Madrid E and its virulent revertant strain Evir. The mutation is a single nucleotide insertion in the methyltransferase gene (also known as PR028) in the vaccine strain that inactivated the gene. We also confirmed that the vaccine strain E did not cause fever in guinea pigs and the virulent revertant strain Evir caused fever in guinea pigs. We concluded that a single nucleotide insertion in the methyltransferase gene of R. prowazekii attenuated the R. prowazekii vaccine strain E. This suggested that an irreversible insertion or deletion mutation in the methyl transferase gene of R. prowazekii is required for Madrid E to be considered a safe vaccine.

Studies on Typhus and Spotted Fever

DTIC Science & Technology

1979-02-01

thawing caused no detectaule loss of ricket - tsial infectivity. Accordingly, the longterm survival of typhus organisms at -700 C in these and other...or even qualitative,differentiation between a specific action on intracellular ricket - tsiae and selective cytotoxicity directed against infected...study of the cell envelopes of Rickettsia prowazekii, Rickettsia ricket ii, and Rickettsia tsutsugamushi. Infect. Immun. 21: 1020-1uZ3 (1978). 8

The Economic and Quality of Life Impact of Remote Technologies on High Risk Patients and Their Caregivers

DTIC Science & Technology

2009-01-01

leptospirosis in South Vietnam. A study in 150 patients. Annals of Internal Medicine. 1973 Aug;79(2):167-73. 3. Berman SJ, Kundin WD. Scrub typhus in South...Berman SJ. Scrub typhus . In: Hoeprich PD, Jordan MC, Ronald AR, eds. Infectious Diseases 5th ed. Philadelphia: JB Lippincott, 1994. Chapter 113

Seroepidemiology of spotted fever group and typhus group rickettsioses in humans, South Korea.

PubMed

Jang, Won-Jong; Choi, Yeon-Joo; Kim, Jong-Hyun; Jung, Kwang-Don; Ryu, Ji-Sun; Lee, Seung-Hyun; Yoo, Cheon-Kwon; Paik, Hyung-Suk; Choi, Myung-Sik; Park, Kyung-Hee; Kim, Ik-Sang

2005-01-01

The prevalence of spotted fever group (SFG) and typhus group (TG) rickettsioses was investigated in 3,362 sera by immunofluorescence assay. The serum samples were obtained from patients with acute febrile episodes in South Korea from December 1992 to November 1993. The number of polyvalent positive sera against SFG rickettsial agents at the level of 1: 40 dilution was 269 (8%) in Rickettsia sibirica, 482 (14.34%) in R. conorii, and 546 (16.24%) in R. akari. Many of the positive sera contained immunoglobulin (Ig) M antibodies rather than IgG antibodies. These results strongly suggest that SFG rickettsioses are prevalent in Korea. For TG rickettsial agents, the number of positive sera was 1,096 (32.60%) in R. typhi and 951 (28.29%) in R. prowazekii. Only a few epidemic typhus positive sera contained IgM antibodies. The result suggests that recent and/or primary infections of epidemic typhus were very rare in Korea during the said period. Among seven patients who had high titers (1:5,120) of IgG antibody to R. prowazekii, six were over 50 years old. The result suggests that Brill-Zinsser disease was prevalent in Korea.

Indian tick typhus presenting with gangrene: a case report from an urban slum of Delhi.

PubMed

Kumar, Manish; Singh, Raghvendra; Yadav, Mukesh

2014-01-01

Indian Tick Typhus has been rarely reported in children from Delhi. A 10-y-old male child from Delhi presented with fever, non specific gastrointestinal symptoms, petechial rash and gangrene of all the toes. Possibility of rickettsial infection was entertained after the child failed to improve with best of the antibiotics. Sample for serology for rickettsial infection was sent and Doxycycline was started empirically. He became afebrile within 72 h of starting Doxycycline. Later, diagnosis of Indian Tick Typhus was confirmed on the basis of IgM positivity against Rickettsia conori. Possibility of rickettsial infection should be entertained in children with history of fever and skin rash, especially if the child fails to improve with a course of antibiotics and common infectious etiologies have been ruled out.

Jail fever (epidemic typhus) outbreak in Burundi.

PubMed

Raoult, D; Roux, V; Ndihokubwayo, J B; Bise, G; Baudon, D; Marte, G; Birtles, R

1997-01-01

We recently investigated a suspected outbreak of epidemic typhus in a jail in Burundi. We tested sera of nine patients by microimmunofluorescence for antibodies to Rickettsia prowazekii and Rickettsia typhi. We also amplified and sequenced from lice gene portions specific for two R. prowazekii proteins: the gene encoding for citrate synthase and the gene encoding for the rickettsial outer membrane protein. All patients exhibited antibodies specific for R. prowazekii. Specific gene sequences were amplified in two lice from one patient. The patients had typical clinical manifestations, and two died. Molecular techniques provided a convenient and reliable means of examining lice and confirming this outbreak. The jail-associated outbreak predates an extensive ongoing outbreak of louse-borne typhus in central eastern Africa after civil war and in refugee camps in Rwanda, Burundi (1), and Zaire.

Jail fever (epidemic typhus) outbreak in Burundi.

PubMed Central

Raoult, D.; Roux, V.; Ndihokubwayo, J. B.; Bise, G.; Baudon, D.; Marte, G.; Birtles, R.

1997-01-01

We recently investigated a suspected outbreak of epidemic typhus in a jail in Burundi. We tested sera of nine patients by microimmunofluorescence for antibodies to Rickettsia prowazekii and Rickettsia typhi. We also amplified and sequenced from lice gene portions specific for two R. prowazekii proteins: the gene encoding for citrate synthase and the gene encoding for the rickettsial outer membrane protein. All patients exhibited antibodies specific for R. prowazekii. Specific gene sequences were amplified in two lice from one patient. The patients had typical clinical manifestations, and two died. Molecular techniques provided a convenient and reliable means of examining lice and confirming this outbreak. The jail-associated outbreak predates an extensive ongoing outbreak of louse-borne typhus in central eastern Africa after civil war and in refugee camps in Rwanda, Burundi (1), and Zaire. PMID:9284381

Protein-protein conjugate nanoparticles for malaria antigen delivery and enhanced immunogenicity

PubMed Central

Scaria, Puthupparampil V.; Jones, David S.; Barnafo, Emma; Fischer, Elizabeth R.; Anderson, Charles; MacDonald, Nicholas J.; Lambert, Lynn; Rausch, Kelly M.; Narum, David L.

2017-01-01

Chemical conjugation of polysaccharide to carrier proteins has been a successful strategy to generate potent vaccines against bacterial pathogens. We developed a similar approach for poorly immunogenic malaria protein antigens. Our lead candidates in clinical trials are the malaria transmission blocking vaccine antigens, Pfs25 and Pfs230D1, individually conjugated to the carrier protein Exoprotein A (EPA) through thioether chemistry. These conjugates form nanoparticles that show enhanced immunogenicity compared to unconjugated antigens. In this study, we examined the broad applicability of this technology as a vaccine development platform, by comparing the immunogenicity of conjugates prepared by four different chemistries using different malaria antigens (PfCSP, Pfs25 and Pfs230D1), and carriers such as EPA, TT and CRM197. Several conjugates were synthesized using thioether, amide, ADH and glutaraldehyde chemistries, characterized for average molecular weight and molecular weight distribution, and evaluated in mice for humoral immunogenicity. Conjugates made with the different chemistries, or with different carriers, showed no significant difference in immunogenicity towards the conjugated antigens. Since particle size can influence immunogenicity, we tested conjugates with different average size in the range of 16–73 nm diameter, and observed greater immunogenicity of smaller particles, with significant differences between 16 and 73 nm particles. These results demonstrate the multiple options with respect to carriers and chemistries that are available for protein-protein conjugate vaccine development. PMID:29281708

A century of typhus, lice and Rickettsia.

PubMed

Andersson, J O; Andersson, S G

2000-03-01

At the beginning of the 20th century, it was discovered at the Pasteur Institute in Tunis that epidemic typhus is transmitted by the human body louse. The complete genome sequence of its causative agent, Rickettsia prowazekii, was determined at Uppsala University in Sweden at the end of the century. In this mini-review, we discuss insights gained from the genome sequence of this fascinating and deadly organism.

Incidence, risk factors and clinical outcomes of acute kidney injury associated with scrub typhus: a retrospective study of 510 consecutive patients in South Korea (2001-2013).

PubMed

Hwang, Kyungo; Jang, Ha Nee; Lee, Tae Won; Cho, Hyun Seop; Bae, Eunjin; Chang, Se-Ho; Park, Dong Jun

2017-03-15

Renal involvement in scrub typhus ranges from simple urinary abnormalities to acute kidney injury (AKI) leading to death. This study evaluated the incidence, predictors and prognosis of AKI associated with scrub typhus according to the RIFLE (risk, injury, failure, loss, end-stage kidney disease) criteria. We retrospectively evaluated the medical records of patients diagnosed with scrub typhus from January 2001 to November 2013 in Gyeongsang National University Hospital. During the study period, 510 patients were diagnosed with scrub typhus and the incidence of AKI was 35.9%. There were 132 (25.9%) patients at risk, 37 (7.3%) with injury and 14 (2.7%) with failure. In comparison with the non-AKI group, the AKI group was older (73.9 vs 63.4 years, p<0.001) and had more comorbidities such as hypertension, diabetes mellitus and chronic kidney disease (CKD). AKI frequently occurs in hypertensive patients taking angiotensin receptor blockers or ACE inhibitors (p=0.002), and in patients with diabetes with higher glycated haemoglobin levels (p=0.033). Haematuria and proteinuria were more frequent in the AKI group. There was no relationship between the severity of proteinuria and occurrence of AKI. Intensive care unit admission and death were more frequent in the AKI group. The renal function of most patients with AKI recovered without sequelae, except for 1 patient who had underlying CKD. Multivariate analysis showed that age, presence of CKD, serum albumin level and time to hospital presentation after symptom onset were independent predictors of AKI in patients with scrub typhus. Our current results suggest that the presence of underlying CKD, older age, lower serum albumin level and time to hospital presentation after symptom onset were important risk factors to determine occurrence of AKI. Whether earlier diagnosis and treatment in patients with the above risk factors reduce the incidence and severity of AKI deserves to be investigated. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.

[Spatial analysis of autumn-winter type scrub typhus in Shandong province, 2006-2014].

PubMed

Yang, H; Bi, Z W; Kou, Z Q; Zheng, L; Zhao, Z T

2016-05-01

To discuss the spatial-temporal distribution and epidemic trends of autumn-winter type scrub typhus in Shandong province, and provide scientific evidence for further study for the prevention and control of the disease. The scrub typhus surveillance data during 2006-2014 were collected from Shandong Disease Reporting Information System. The data was analyzed by using software ArcGIS 9.3(ESRI Inc., Redlands, CA, USA), GeoDa 0.9.5-i and SatScan 9.1.1. The Moran' s I, log-likelihood ratio(LLR), relative risk(RR)were calculated and the incidence choropleth maps, local indicators of spatial autocorrelation cluster maps and space scaning cluster maps were drawn. A total of 4 453 scrub typhus cases were reported during 2006-2014, and the annual incidence increased with year. Among the 17 prefectures(municipality)in Shandong, 13 were affected by scrub typhus. The global Moran's I index was 0.501 5(P<0.01). The differences in local Moran' s I index among 16 prefectures were significant(P<0.01). The " high-high" clustering areas were mainly Wulian county, Lanshan district and Juxian county of Rizhao, Xintai county of Tai' an, Gangcheng and Laicheng districts of Laiwu, Yiyuan county of Zibo and Mengyin county of Linyi. Spatial scan analysis showed that an eastward moving trend of high-risk clusters and two new high-risk clusters were found in Zaozhuang in 2014. The centers of the most likely clusters were in the south central mountainous areas during 2006-2010 and in 2012, eastern hilly areas in 2011, 2013 and 2014, and the size of the clusters expanded in 2008, 2011, 2013 and 2014. One spatial-temporal cluster was detected from October 1, 2014 to November 30, 2014, the center of the cluster was in Rizhao and the radius was 222.34 kilometers. A positive spatial correlation and spatial agglomerations were found in the distribution of autumn-winter type scrub typhus in Shandong. Since 2006, the epidemic area of the disease has expanded and the number of high-risk areas has increased. Moreover, the eastward moving and periodically expanding trends of high-risk clusters were detected.

Optimal Cutoff and Accuracy of an IgM Enzyme-Linked Immunosorbent Assay for Diagnosis of Acute Scrub Typhus in Northern Thailand: an Alternative Reference Method to the IgM Immunofluorescence Assay

PubMed Central

Blacksell, Stuart D.; Tanganuchitcharnchai, Ampai; Jintaworn, Suthatip; Kantipong, Pacharee; Richards, Allen L.; Day, Nicholas P. J.

2016-01-01

The enzyme-linked immunosorbent assay (ELISA) has been proposed as an alternative serologic diagnostic test to the indirect immunofluorescence assay (IFA) for scrub typhus. Here, we systematically determine the optimal sample dilution and cutoff optical density (OD) and estimate the accuracy of IgM ELISA using Bayesian latent class models (LCMs). Data from 135 patients with undifferentiated fever were reevaluated using Bayesian LCMs. Every patient was evaluated for the presence of an eschar and tested with a blood culture for Orientia tsutsugamushi, three different PCR assays, and an IgM IFA. The IgM ELISA was performed for every sample at sample dilutions from 1:100 to 1:102,400 using crude whole-cell antigens of the Karp, Kato, and Gilliam strains of O. tsutsugamushi developed by the Naval Medical Research Center. We used Bayesian LCMs to generate unbiased receiver operating characteristic curves and found that the sample dilution of 1:400 was optimal for the IgM ELISA. With the optimal cutoff OD of 1.474 at a sample dilution of 1:400, the IgM ELISA had a sensitivity of 85.7% (95% credible interval [CrI], 77.4% to 86.7%) and a specificity of 98.1% (95% CrI, 97.2% to 100%) using paired samples. For the ELISA, the OD could be determined objectively and quickly, in contrast to the reading of IFA slides, which was both subjective and labor-intensive. The IgM ELISA for scrub typhus has high diagnostic accuracy and is less subjective than the IgM IFA. We suggest that the IgM ELISA may be used as an alternative reference test to the IgM IFA for the serological diagnosis of scrub typhus. PMID:27008880

Differences in the clinical presentation and the frequency of complications between elderly and non-elderly scrub typhus patients.

PubMed

Jang, Mi-Ok; Kim, Ji Eun; Kim, Uh Jin; Ahn, Joon Hwan; Kang, Seung-Ji; Jang, Hee-Chang; Jung, Sook-In; Park, Kyung-Hwa

2014-01-01

Age can affect the clinical features and severity of infectious disorders, such as scrub typhus. We performed this study to examine differences between elderly and non-elderly scrub typhus patients, and to identify risk factors predictive of disease outcomes. This retrospective study included patients admitted to a tertiary hospital with scrub typhus between 2001 and 2011. A total of 615 patients were enrolled in this study, 328 of which were >65 years of age. Of the elderly patients, 46.0% (151/328) experienced at least one complication compared to only 23.0% (66/287) in younger patients. A linear trend was observed between age and complication rates (p=0.002). The most common complication in elderly patients was acute kidney injury (75, 22.9%). Treatment failure was reported in 10 elderly patients (3.0%) compared to one non-elderly patient (0.3%). Mental confusion and dyspnea of clinical manifestations at admission were common in elderly patients. Frequency of fever, rash, and eschar were similar in both groups. The following four factors were significantly associated with severe scrub typhus in elderly patients: (1) white blood cell (WBC) counts>10,000/mm(3) (OR=2.569, CI=1.298-5.086), (2) MDRD GFR<60mL/min (OR=3.525, CI=1.864-6.667), (3) albumin≤3.0g/dL (OR=4.976, CI=2.664-9.294), and (4) acute physiology and chronic health evaluation II (APACHE II) score>10 points (OR=3.304, CI=1.793-60.87). Complications and mortality were more common in elderly patients, often associated with delays in diagnosis and treatment. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

Establishment of a novel endothelial target mouse model of a typhus group rickettsiosis: evidence for critical roles for gamma interferon and CD8 T lymphocytes.

PubMed

Walker, D H; Popov, V L; Feng, H M

2000-09-01

A mouse model of typhus rickettsiosis that reproduces the hematogenous dissemination to the critical target organs, including brain, lungs, heart, and kidneys, primary endothelial and, to a lesser degree, macrophage intracellular rickettsial infection, and typical vascular-based lesions of louse-borne typhus and murine typhus was established. Intravenous inoculation of C3H/HeN mice with Rickettsia typhi caused disease with a duration of the incubation period and mortality rate that were dependent on the infective dose of rickettsiae. Lethal infection was associated with high concentrations of R. typhi in the lungs and brain, despite a brisker humoral immune response to the rickettsiae than in the sublethal infection. Gamma interferon and CD8 T lymphocytes were demonstrated to be crucial to clearance of the rickettsiae and recovery from infection in experiments in which specific monoclonal antibodies were administered to deplete these components. Death of animals depleted of gamma interferon or CD8 T lymphocytes was associated with overwhelming rickettsial infection demonstrated by titers of infectious rickettsiae and by immunohistochemistry. An effective antirickettsial immune response was associated with elevated serum concentrations of IL-12 on Day 5 and increased secretion of IL-12 by concanavalin-A-stimulated spleen cells on Day 5. Evidence for transient suppression of the immune response consisted of marked reduction in the secretion of IL-2 and IL-12 by concanavalin-A-stimulated spleen cells on Days 10 and 15. This model offers excellent opportunities for study of attenuation and pathogenetic mechanisms of typhus rickettsiae, which are established biologic weapons of potential use in bioterrorism.

Murine Typhus

PubMed Central

Dzul-Rosado, Karla R; Zavala Velázquez, Jorge Ernesto; Zavala-Castro, Jorge

2012-01-01

Rickettsia typhi: is an intracellular bacteria who causes murine typhus. His importance is reflected in the high frequency founding specific antibodies against Rickettsia typhi in several worldwide seroepidemiological studies, the seroprevalence ranging between 3-36%. Natural reservoirs of R. typhi are rats (some species belonging the Rattus Genus) and fleas (Xenopsylla cheopis) are his vector. This infection is associated with overcrowding, pollution and poor hygiene. Typically presents fever, headache, rash on trunk and extremities, in some cases may occur organ-specific complications, affecting liver, kidney, lung or brain. Initially the disease is very similar to other diseases, is very common to confuse the murine typhus with Dengue fever, therefore, ignorance of the disease is a factor related to complications or non-specific treatments for the resolution of this infection. This paper presents the most relevant information to consider about the rickettsiosis caused by Rickettsia typhi. PMID:24893060

Diagnosis of scrub typhus.

PubMed

Janardhanan, Jeshina; Trowbridge, Paul; Varghese, George M

2014-12-01

Scrub typhus is an acute febrile illness that, if untreated, can result in considerable morbidity and mortality. One of the primary reasons for delays in the treatment of this potentially fatal infection is the difficulty in diagnosing the condition. Diagnosis is often complicated because of the combination of non-specific symptoms that overlap with other infections commonly found in endemic areas and the poor available diagnostics. In the majority of the endemic settings, diagnosis still relies on the Weil-Felix test, which is neither sensitive nor specific. Other methods of testing have become available, but at this time, these remain insufficient to provide the rapid point-of-care diagnostics that would be necessary to significantly change the management of this infection by providers in endemic areas. This article reviews the currently available diagnostic tools for scrub typhus and their utility in the clinical setting.

Cluster of Sylvatic Epidemic Typhus Cases Associated with Flying Squirrels, 2004–2006

PubMed Central

Chapman, Alice S.; Swerdlow, David L.; Dato, Virginia M.; Anderson, Alicia D.; Moodie, Claire E.; Marriott, Chandra; Amman, Brian; Hennessey, Morgan; Fox, Perry; Green, Douglas B.; Pegg, Eric; Nicholson, William L.; Eremeeva, Marina E.

2009-01-01

In February 2006, a diagnosis of sylvatic epidemic typhus in a counselor at a wilderness camp in Pennsylvania prompted a retrospective investigation. From January 2004 through January 2006, 3 more cases were identified. All had been counselors at the camp and had experienced febrile illness with myalgia, chills, and sweats; 2 had been hospitalized. All patients had slept in the same cabin and reported having seen and heard flying squirrels inside the wall adjacent to their bed. Serum from each patient had evidence of infection with Rickettsia prowazekii. Analysis of blood and tissue from 14 southern flying squirrels trapped in the woodlands around the cabin indicated that 71% were infected with R. prowazekii. Education and control measures to exclude flying squirrels from housing are essential to reduce the likelihood of sylvatic epidemic typhus. PMID:19624912

Cluster of sylvatic epidemic typhus cases associated with flying squirrels, 2004-2006.

PubMed

Chapman, Alice S; Swerdlow, David L; Dato, Virginia M; Anderson, Alicia D; Moodie, Claire E; Marriott, Chandra; Amman, Brian; Hennessey, Morgan; Fox, Perry; Green, Douglas B; Pegg, Eric; Nicholson, William L; Eremeeva, Marina E; Dasch, Gregory A

2009-07-01

In February 2006, a diagnosis of sylvatic epidemic typhus in a counselor at a wilderness camp in Pennsylvania prompted a retrospective investigation. From January 2004 through January 2006, 3 more cases were identified. All had been counselors at the camp and had experienced febrile illness with myalgia, chills, and sweats; 2 had been hospitalized. All patients had slept in the same cabin and reported having seen and heard flying squirrels inside the wall adjacent to their bed. Serum from each patient had evidence of infection with Rickettsia prowazekii. Analysis of blood and tissue from 14 southern flying squirrels trapped in the woodlands around the cabin indicated that 71% were infected with R. prowazekii. Education and control measures to exclude flying squirrels from housing are essential to reduce the likelihood of sylvatic epidemic typhus.

Studies on Typhus and Spotted Fever.

DTIC Science & Technology

1986-09-01

Rocky Mountain spotted fever , scrub typhus, trench fever, R. prowazekil, R. mooseri, R. Canada, R...rickettsia- static action: erythromycin and rifampin. Although erythromycin aiready had proven to be unreliable in the treatment of Rocky Mountain spotted fever , the...DC. 9. DuPont, H. L., R. B. Hornick, A. T. Dawkins, G. G. heiner. I. B. Fabrikant, C. L. Wisseman. Jr, and T. E. Woodward. 1VU1. Rocky Mountain spotted fever :

Risk of Relapse Associated with Doxycycline Therapy for Scrub Typhus

DTIC Science & Technology

1981-01-01

143150-9 202 Rickettsiae ard Rickettsial Diseases I. INTRODUCTION Chloramphenicol (Chloromycetin) or oxytetracycline (Terra- mycin) are the drugs...doses of oxytetracycline in a double blind, randomized trial conducted in a population of scrub typhus patients who were exposed in the Pescadores... oxytetracycline , 500 mg every 6 hrs for 7 days (OXY, 23 patients). Drug and placebo were manufactured in such a way and administered every 6 hrs for 7

Factory-Based Permethrin Impregnation of Uniforms: Residual Activity against Aedes aegypti and Ixodes ricinus in Battle Dress Uniforms Worn under Field Conditions, and Cross-Contamination during the Laundering and Storage Process

DTIC Science & Technology

2006-06-01

fever, relapsing fever, scrub typhus , and visceral leishmaniasis were either principal or contributing factors affecting overall mortal- ity and...human health. In 26 of 52 retro- spectively analyzed wars from 480 BC to 2002 AD, vector-borne diseases like plague, louse-borne typhus , malaria, yellow

Clinical Predictors of Multiple Organ Dysfunction Syndromes in Pediatric patients with Scrub Typhus.

PubMed

Zhao, Dongying; Zhang, Yongjun; Yin, Zhaoqing; Zhao, Jing; Yang, Defeng; Zhou, Qun

2017-06-01

Scrub typhus can produce multiple organ dysfunction syndrome (MODS). Early recognition of the patients at risk of MODS would be helpful in providing timely management and reducing the mortality. In all, 449 children with scrub typhus were enrolled at three hospitals in Yunnan, China from January 2010 to January 2015. The patients' clinical status of organ system dysfunction was evaluated on the day of discharge from hospital by using standard criteria. The patients were classified into MODS present (64 cases, 14.3%) or MODS absent (385 cases, 85.7%). Multivariate logistic regression analyses revealed that the prognostic factors for MODS included skin rash (odds ratio, OR = 3.3, p = 0.037), time interval form treatment to defervescence (OR = 1.2, p = 0.035), hemoglobin (OR = 0.54, p = 0.041), platelet counts (OR = 0.06, p < 0.001), aspartate-aminotransferase (OR = 4.7, p = 0.011) and total bilirubin (OR = 2.3, p = 0.013). By describing risk factors resulting in MODS in pediatric scrub typhus, our study provides clinicians with important information to improve the clinical monitoring and prognostication of MODS. © The Author [2016]. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Scrub Typhus: A Clinico-Laboratory Differentiation of Children with and without Meningitis.

PubMed

Bhat, Nowneet Kumar; Pandita, Neerul; Saini, Manju; Dhar, Minakshi; Ahmed, Sohaib; Shirazi, Nadia; Wasim, Sanober; Shirke, Rupali; Chandar, Vipan

2016-06-01

Neurological involvement in the form of meningitis or meningoencephalitis, although well documented in scrub typhus, has not been extensively studied in the pediatric population. We report the clinical and laboratory profile of 96 children with scrub typhus and compared those with and without meningitis. Twenty seven (28%) children had clinical and laboratory evidence of meningitis. The most frequent presenting features were fever (100%), meningeal signs (66.6%), nausea and vomiting (56.3%), seizures (55.5%) and altered sensorium (51.8%). The children with meningitis presented early and had significantly lower respiratory and renal impairments when compared with the non-meningitis group. Cerebrospinal fluid (CSF) analysis revealed elevated total leukocyte count (86.73 ± 94.50 cells/mm(3)), mononuclear pleocytosis (lymphocyte percentage of 76.85 ± 15.86), elevated proteins (108.33 ± 52.63 mg%) and normal CSF glucose (64.18 ± 15.92 mg%). We conclude that meningitis is a common and early complication of childhood scrub typhus. The CSF reveals a lymphocytic pleocytosis, raised proteins and a normal glucose level. These children respond promptly to appropriate antibiotics as do children without meningitis. © The Author [2016]. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Reports of Military Observers Attached to the Armies in Manchuria during the Russo-Japanese War. Part 2

DTIC Science & Technology

1906-10-01

pressure, almost petechial in character, as if there was a slight admixture of typhus infection. Such cases were always serious. Typhoid fever is not rare...of typhoid fever , 15 of typhus, and 9 of recurrent fever . The number of typhoid- fever cases, how- ever, rapidly increased up to 951 on August 26...east of Lake Baikal (about 570,000 men), was as follows: Dysentery....................... ............... Typhoid fever

Sacral Herpes Zoster Associated with Voiding Dysfunction in a Young Patient with Scrub Typhus.

PubMed

Hur, Jian

2015-06-01

When a patient presents with acute voiding dysfunction without a typical skin rash, it may be difficult to make a diagnosis of herpes zoster. Here, we present a case of scrub typhus in a 25-year-old man with the complication of urinary dysfunction. The patient complained of loss of urinary voiding sensation and constipation. After eight days, he had typical herpes zoster eruptions on the sacral dermatomes and hypalgesia of the S1-S5 dermatomes. No cases of dual infection with varicella zoster virus and Orientia tsutsugamushi were found in the literature. In the described case, scrub typhus probably induced sufficient stress to reactivate the varicella zoster virus. Early recognition of this problem is imperative for prompt and appropriate management, as misdiagnosis can lead to long-term urinary dysfunction. It is important that a diagnosis of herpes zoster be considered, especially in patients with sudden onset urinary retention.

Sacral Herpes Zoster Associated with Voiding Dysfunction in a Young Patient with Scrub Typhus

PubMed Central

2015-01-01

When a patient presents with acute voiding dysfunction without a typical skin rash, it may be difficult to make a diagnosis of herpes zoster. Here, we present a case of scrub typhus in a 25-year-old man with the complication of urinary dysfunction. The patient complained of loss of urinary voiding sensation and constipation. After eight days, he had typical herpes zoster eruptions on the sacral dermatomes and hypalgesia of the S1-S5 dermatomes. No cases of dual infection with varicella zoster virus and Orientia tsutsugamushi were found in the literature. In the described case, scrub typhus probably induced sufficient stress to reactivate the varicella zoster virus. Early recognition of this problem is imperative for prompt and appropriate management, as misdiagnosis can lead to long-term urinary dysfunction. It is important that a diagnosis of herpes zoster be considered, especially in patients with sudden onset urinary retention. PMID:26157595

Investigation of the role of Blankaartia acuscutellaris (Acari: Trombiculidae) as a vector of scrub typhus in central Thailand.

PubMed

Frances, S P; Watcharapichat, P; Phulsuksombati, D; Tanskul, P

2001-12-01

Monthly collections of rodents were conducted in Phitsanulok Province, central Thailand in 1993 to investigate the role of the mite Blankaartia acuscurellaris as a vector of scrub typhus. Overall, a total of 41 rodents were collected and examined for the presence of the red colored larvae of B. acuscutellaris and yellow larvae of Leptotrombidium deliense and Ascoshoengastia sp. A total of 787 B. acuscutellaris and 1390 yellow larvae were placed into pools, triturated and isolation of Orientia tsutsugamushi attempted in laboratory mice. The sera of 8 of the collected rodents had elevated antibodies to O. tsutsugamushi indicating active infections; however, O. tsutsugamushi was not isolated from rodent tissues or pools of larvae. The results of this survey suggest that B. acuscutellaris may not be an important vector of scrub typhus, but more studies are needed in endemic areas.

[Sanitary and epidemiological supply for the Russian Army during the First World War (1914-1918)].

PubMed

gorelova, L E; Loktev, A E

2014-02-01

At the beginning of the First World War the most typical diseases in the Russian Army were typhoid, typhus, diphtheria, cholera, smallpox and other infectious diseases. At the beginning of the First World War the level of infectious morbidity was significantly low, but further increased and pandemic risk arose. Servicemen were mostly ill with typhus, relapsing fever, flux, cholera, smallpox and typhoid. The highest mortality rate was registered in patients with cholera, typhus and typhoid. According the prewar deployment program of the Russian Army anti-epidemiologic facilities were established. By the end of war were established 110 sanitary-and-hygienic and 90 disinfection units. However, organization of anti-epidemiologic security was unsatisfactory. Due to lack of specialists and equipment anti-epidemiologic facilities of units were under strength. Commanders of sanitary units and sanitary service had not enough resources for operational service in the Forces and facilities of rear area.

A Case Report and Literature Review of Scrub Typhus With Acute Abdomen and Septic Shock in a Child-The Role of Leukocytoclastic Vasculitis and Granulysin.

PubMed

Chang, Po-Hsiung; Cheng, Yu-Pin; Chang, Po-Sheng; Lo, Chiao-Wei; Lin, Lung-Huang; Lu, Chin-Fang; Chung, Wen-Hung

2018-04-24

Scrub typhus is becoming a clinically important cause of acute undifferentiated febrile illness in Taiwan. The incubation period is between 6 and 21 days after exposure. It is transmitted by chiggers (larva of trombiculid mite) in long grasses and in dirt-floor homes, with infection characterized by a flu-like illness of fever, headache, and myalgia lasting approximately 1 week. It has various systemic manifestations, including GI symptoms. In some, the illness progresses to multiorgan dysfunction syndrome and death. We report on a 13-year-old boy who lived in Taipei City and who had initially tentative diagnosis of acute pyrexia of unknown origin with high fever up to 40.3°C for 1 week, but later had thrombocytopenia and diffuse abdominal pain with peritoneal sign suspected acute appendicitis. During the clinical course, septic shock and disseminated intravascular coagulopathy (DIC) were noted. There were skin rash in his trunk and extremities and an eschar with black crust surrounded by a scaling erythematous rim on his right buttock. In addition, we got the information of his travel history in Green Island and Orchid Island for 10 days.With the correct antibiotics, vancomycin, meropenem, and doxycycline, the patient was getting better and corresponding with high level of granulysin and tumor necrosis factor-alpha. The diagnosis of scrub typhus was confirmed by the biopsy of eschar and high quantitative real-time polymerase chain reaction values of Orientia tsutsugamushi (16sRNA and 56 kDa) tested by Centers for Disease Control and Prevention, Taiwan. Histopathological findings of the eschar revealed the leukocytoclastic vasculitis, crust and thrombus formation with many gram-negative microorganisms, O. tsutsugamushi demonstrated by 47 kDa monoclonal antibody immunohistochemical stain and electromicroscopy. After the careful selection of appropriate antibiotics including meropenem, vancomycin, and doxycycline, he recovered and was subsequently discharged 7 days after admission. This case highlights that scrub typhus infection can mimic acute abdomen and septic shock with DIC. This rare presentation of acute abdomen and septic shock with thrombocytopenia and DIC caused by scrub typhus should remind physicians to be alert to the possibility of acute abdomen and febrile illness resulting from scrub typhus.

ORFeome Phage Display.

PubMed

Zantow, Jonas; Moreira, Gustavo Marçal Schmidt Garcia; Dübel, Stefan; Hust, Michael

2018-01-01

ORFeome phage display allows the efficient functional screening of entire proteomes or even metaproteomes to identify immunogenic proteins. For this purpose, randomly fragmented, whole genomes or metagenomes are cloned into a phage-display vector allowing positive selection for open reading frames (ORF) to improve the library quality. These libraries display all possible proteins encoded by a pathogen or a microbiome on the phage surface. Consequently, immunogenic proteins can be selected from these libraries using disease-related immunoglobulins from patient serum. ORFeome phage display in particular allows the identification of immunogenic proteins that are only expressed in the host-pathogen interaction but not in cultivation, as well as the detection of very low expressed and very small immunogens and immunogenic proteins of non-cultivable organisms. The identified immunogenic proteins are potential biomarkers for the development of diagnostic assays or vaccines. These articles will give an introduction to ORFeome phage-display technology and give detailed protocols to identify immunogenic proteins by phage display.

The inducers of immunogenic cell death for tumor immunotherapy.

PubMed

Li, Xiuying

2018-01-01

Immunotherapy is a promising treatment modality that acts by selectively harnessing the host immune defenses against cancer. An effective immune response is often needed to eliminate tumors following treatment which can trigger the immunogenicity of dying tumor cells. Some treatment modalities (such as photodynamic therapy, high hydrostatic pressure or radiotherapy) and agents (some chemotherapeutic agents, oncolytic viruses) have been used to endow tumor cells with immunogenicity and/or increase their immunogenicity. These treatments and agents can boost the antitumor capacity by inducing immune responses against tumor neoantigens. Immunogenic cell death is a manner of cell death that can induce the emission of immunogenic damage-associated molecular patterns (DAMPs). DAMPs are sufficient for immunocompetent hosts to trigger the immune system. This review focuses on the latest developments in the treatment modalities and agents that can induce and/or enhance the immunogenicity of cancer cells.

Direct evidence of Rickettsia typhi infection in Rhipicephalus sanguineus ticks and their canine hosts.

PubMed

Dzul-Rosado, Karla; Lugo-Caballero, Cesar; Tello-Martin, Raul; López-Avila, Karina; Zavala-Castro, Jorge

2017-01-01

Murine typhus is a rickettsiosis caused by Rickettsia typhi , whose transmission is carried out by rat fleas in urban settlements as classically known, but it also has been related to cat fleas in a sub-urban alternative cycle that has been suggested by recent reports. These studies remarks that in addition to rats, other animals like cats, opossums and dogs could be implied in the transmission of Rickettsia typhi as infected fleas obtained from serologically positive animals have been detected in samples from endemic areas. In Mexico, the higher number of murine typhus cases have been detected in the Yucatan peninsula, which includes a great southeastern region of Mexico that shows ecologic characteristics similar to the sub-urban alternative cycle recently described in Texas and California at the United States. To find out which are the particular ecologic characteristics of murine typhus transmission in this region, we analyzed blood and Rhipicephalus sanguineus ticks obtained from domestic dogs by molecular approaches, demonstrating that both samples were infected by Rickettsia typhi . Following this, we obtained isolates that were analyzed by genetic sequencing to corroborate this infection in 100% of the analyzed samples. This evidence suggests for the first time that ticks and dogs could be actively participating in the transmission of murine typhus, in a role that requires further studies for its precise description.

[Struggle against typhus in the Caucasian front during the 1st World War].

PubMed

Karatepe, Mustafa

2002-01-01

As an infectious disease, typhus has triggered many epidemics during the course of wars and caused thousands of death all through the ages. The French physician Charles Nicolle (1886-1936) defined its agent as a louse transferring the disease from man to man in 1909 and was awarded the Nobel Prize in 1928. Many cases were reported during the 1st World War both in the European and the Ottoman armies; and one of the most severe epidemics broke in the Caucasian front; a great number of civilians and soldiers died at winter in 1914 and 1915. Lice had to be destroyed in order to prevent the epidemic, but etuves in the Caucasian front was too few to achieve it. Clothes were cleansed in ovens by means of a method proposed by Dr. Abdülkadir Noyan (1886-1977). On March 28, 1915 the first typhus vaccination, obtained from the infected blood of the patients, was applied by Dr. Tevfik Salim (Saklam) (1882-1963). In 1916 Dr. Ahmet Fikri Tüzer discovered a disinfection apparatus called "buğu sandiği" (vapour box) which was widely used in the Caucasian front after 1917. This apparatus was highly useful in controlling the typhus epidemics. 164 health officers lost their lifes in the Caucasian front between 1914-1918, in addition, 7310 military casualties were recorded from 1915 to the end of the war.

Temporal changes in prevalence of scrub typhus rickettsia (Orientia tsutsugamushi) infecting the eggs of Leptotrombidium imphalum (Acari: Trombiculidae).

PubMed

Kollars, T M; Kengluecha, A; Khlaimanee, N; Tanskul, P

2001-01-01

Eggs from seven colony lines of the chigger mite Leptotrombidium imphalum (Vercammen-Grandjean & Langston) were examined for infection with Orientia tsutsugamushi (Hyashi), the etiologic agent of scrub typhus. The polymerase chain reaction (PCR) using primers OtP 56.809 and OtM 56.1221, which amplify a 291 bp region of the P56 gene of O. tsutsugamushi, was used to detect scrub typhus within single eggs. All seven chigger mite lines produced infected eggs with varying rates of infection (Li1 = 8.1%, n = 124; Li2 = 45.6%, n = 90; Li3 = 30.1%, n = 144; Li4 = 31.7%, n = 145; Li5 = 21.3%, n = 136; Li6 = 41.6% n = 77; Li7 = 22.5%, n = 110). The 3 wk with the highest infection rates for each line using Fourier analysis were as follows: Li1 = 2, 7, 14; Li2 = 4, 6, 12; Li3 = 3, 6, 12; Li4 = 4, 6, 12; Li5 = 5, 7, 14; Li7 = 4, 6, 12. Li6 only had nine measurements over time; therefore, Li6 was excluded from individual analysis. Infection rates of scrub typhus in eggs occurred in a 2-wk 2-d cycle, using Fourier analysis of combined data. Not only did infection rates vary among the progeny of females, but temporal variation also occurred.

The formulation and immunogenicity of therapeutic proteins: Product quality as a key factor.

PubMed

Richard, Joel; Prang, Nadia

2010-08-01

The formation of anti-drug antibodies represents a risk that should be assessed carefully during biopharmaceutical drug product (DP) development, as such antibodies compromise safety and efficacy and may alter the pharmacokinetic properties of a compound. This feature review discusses immunogenicity issues in biopharmaceutical DP development, with a focus on product quality. Excipient-induced and aggregate-induced immunogenicity are reviewed based on the concepts of 'aggregation-competent' species and 'provocative' aggregates. In addition, the influence of formulation parameters, such as particulates and contaminants appearing in the DP during processing and storage, on aggregate-induced immunogenicity are presented, including the role of fill-and-finish equipments and the effect of interactions with container materials. Furthermore, methods to detect and quantify aggregation and precursor conformational changes in a protein formulation are reviewed, and immunological mechanisms that may lead to aggregate-induced immunogenicity are proposed and discussed.

Immunogenicity of therapeutics: a matter of efficacy and safety.

PubMed

Nechansky, Andreas; Kircheis, Ralf

2010-11-01

The unwanted immunogenicity of therapeutic proteins is a major concern regarding patient safety. Furthermore, pharmacokinetic, pharmacodynamic and clinical efficacy can be seriously affected by the immunogenicity of therapeutic proteins. Authorities have fully recognized this issue and demand appropriate and well-characterized assays to detect anti-drug antibodies (ADAs). We provide an overview of the immunogenicity topic in general, the regulatory background and insight into underlying immunological mechanisms and the limited ability to predict clinical immunogenicity a priori. Furthermore, we comment on the analytical testing approach and the status-quo of appropriate method validation. The review provides insight regarding the analytical approach that is expected by regulatory authorities overseeing immunogenicity testing requirements. Additionally, the factors influencing immunogenicity are summarized and key references regarding immunogenicity testing approaches and method validation are discussed. The unwanted immunogenicity of protein therapeutics is of major concern because of its potential to affect patient safety and drug efficacy. Analytical testing is sophisticated and requires more than one assay. Because immunogenicity in humans is hardly predictable, assay development has to start in a timely fashion and for clinical studies immunogenicity assay validation is mandatory prior to analyzing patient serum samples. Regarding ADAs, the question remains as to when such antibodies are regarded of clinical relevance and what levels are, if at all, acceptable. In summary, the detection of ADAs should raise the awareness of the physician concerning patient safety and of the sponsor/manufacture concerning the immunogenic potential of the drug product.

Acute undifferentiated fever in India: a multicentre study of aetiology and diagnostic accuracy.

PubMed

Mørch, Kristine; Manoharan, Anand; Chandy, Sara; Chacko, Novin; Alvarez-Uria, Gerardo; Patil, Suvarna; Henry, Anil; Nesaraj, Joel; Kuriakose, Cijoy; Singh, Ashita; Kurian, Siby; Gill Haanshuus, Christel; Langeland, Nina; Blomberg, Bjørn; Vasanthan Antony, George; Mathai, Dilip

2017-10-04

The objectives of this study were to determine the proportion of malaria, bacteraemia, scrub typhus, leptospirosis, chikungunya and dengue among hospitalized patients with acute undifferentiated fever in India, and to describe the performance of standard diagnostic methods. During April 2011-November 2012, 1564 patients aged ≥5 years with febrile illness for 2-14 days were consecutively included in an observational study at seven community hospitals in six states in India. Malaria microscopy, blood culture, Dengue rapid NS1 antigen and IgM Combo test, Leptospira IgM ELISA, Scrub typhus IgM ELISA and Chikungunya IgM ELISA were routinely performed at the hospitals. Second line testing, Dengue IgM capture ELISA (MAC-ELISA), Scrub typhus immunofluorescence (IFA), Leptospira Microscopic Agglutination Test (MAT), malaria PCR and malaria immunochromatographic rapid diagnostic test (RDT) Parahit Total™ were performed at the coordinating centre. Convalescence samples were not available. Case definitions were as follows: Leptospirosis: Positive ELISA and positive MAT. Scrub typhus: Positive ELISA and positive IFA. Dengue: Positive RDT and/or positive MAC-ELISA. Chikungunya: Positive ELISA. Bacteraemia: Growth in blood culture excluding those defined as contaminants. Malaria: Positive genus-specific PCR. Malaria was diagnosed in 17% (268/1564) and among these 54% had P. falciparum. Dengue was diagnosed in 16% (244/1564). Bacteraemia was found in 8% (124/1564), and among these Salmonella typhi or S. paratyphi constituted 35%. Scrub typhus was diagnosed in 10%, leptospirosis in 7% and chikungunya in 6%. Fulfilling more than one case definition was common, most frequent in chikungunya where 26% (25/98) also had positive dengue test. Malaria and dengue were the most common causes of fever in this study. A high overlap between case definitions probably reflects high prevalence of prior infections, cross reactivity and subclinical infections, rather than high prevalence of coinfections. Low accuracy of routine diagnostic tests should be taken into consideration when approaching the patient with acute undifferentiated fever in India.

Elevated levels of von Willebrand factor and high mobility group box 1 (HMGB1) are associated with disease severity and clinical outcome of scrub typhus.

PubMed

Chen, Hongliu; Ning, Zong; Qiu, Ying; Liao, Yuanli; Chang, Haihua; Ai, Yuanyuan; Wei, Yinghua; Deng, Yiming; Shen, Ying

2017-08-01

This study aimed to investigate whether von Willebrand factor (vWF) and high mobility group box 1 (HMGB1) are associated with the severity and clinical outcome of scrub typhus and to seek novel biomarkers for surveillance and prediction of the prognosis of this infection. Serum concentrations of vWF and HMGB1 were measured twice by ELISA for scrub typhus patients (n=103), once prior to doxycycline therapy and then on day 7 of doxycycline therapy; concentrations were measured once for healthy controls (n=32). Among the total 103 patients enrolled, 38 had disease complicated by multiple organ dysfunction syndrome (MODS). Serum concentrations of vWF and HMGB1 were significantly higher in all the patients than in the healthy controls, both prior to doxycycline treatment and on day 7 of doxycycline treatment (p<0.01). Furthermore, serum levels of vWF, HMGB1, and creatinine (SCr) in the patients with MODS increased distinctly, while the platelet (PLT) count diminished markedly compared to the levels in patients without MODS (p<0.01). The concentration of vWF was positively correlated with that of HMGB1 (r=0.764, p<0.001) and SCr (r=0.528, p<0.001), but negatively correlated with the PLT count (r=-0.632, p<0.001). Both HMGB1 and vWF were significantly associated with mortality in scrub typhus (area under the curve (AUC)=0.864, p=0.001, and AUC=0.862, p=0.001, respectively). Elevated levels of vWF and HMGB1 are associated with the severity and clinical outcome of scrub typhus. These represent possible new biomarkers for use in the assessment and prognostic prediction of this infection. Copyright © 2017 The Author(s). Published by Elsevier Ltd.. All rights reserved.

Clinical profile and improving mortality trend of scrub typhus in South India.

PubMed

Varghese, George M; Trowbridge, Paul; Janardhanan, Jeshina; Thomas, Kurien; Peter, John V; Mathews, Prasad; Abraham, Ooriapadickal C; Kavitha, M L

2014-06-01

Scrub typhus, a bacterial zoonosis caused by Orientia tsutsugamushi, may cause multiorgan dysfunction syndrome (MODS) and is associated with significant mortality. This study was undertaken to document the clinical and laboratory manifestations and complications and to study time trends and factors associated with mortality in patients with scrub typhus infection. This retrospective study, done at a university teaching hospital, included 623 patients admitted between 2005 and 2010 with scrub typhus. The diagnosis was established by a positive IgM ELISA and/or pathognomonic eschar with PCR confirmation where feasible. The clinical and laboratory profile, course in hospital, and outcome were documented. Factors associated with mortality were analyzed using multivariate logistic regression analysis. The most common presenting symptoms were fever (100%), nausea/vomiting (54%), shortness of breath (49%), headache (46%), cough (38%), and altered sensorium (26%). An eschar was present in 43.5% of patients. Common laboratory findings included elevated transaminases (87%), thrombocytopenia (79%), and leukocytosis (46%). MODS was seen in 34% of patients. The overall case-fatality rate was 9.0%. Features of acute lung injury were observed in 33.7%, and 29.5% required ventilatory support. On multivariate analysis, shock requiring vasoactive agents (relative risk (RR) 10.5, 95% confidence interval (CI) 4.2-25.7, p<0.001), central nervous system (CNS) dysfunction (RR 5.1, 95% CI 2.4-10.7, p<0.001), and renal failure (RR 3.6, 95% CI 1.7-7.5, p=0.001) were independent predictors of mortality. Over 4 years, a decreasing trend was observed in the mortality rate. Scrub typhus can manifest with potentially life-threatening complications such as lung injury, shock, and meningoencephalitis. MODS occurred in a third of our patients. The overall case-fatality rate was 9%, with shock, renal failure, and CNS associated with a higher mortality. Copyright © 2014 The Authors. Published by Elsevier Ltd.. All rights reserved.

Tick-borne typhus fever of northern Asia: some characteristics of the pathogenesis.

PubMed

Nelyubov, M V

2002-09-01

Morphological changes in the viscera of albino mice were studied over the course of North Asia typhus fever. In general, the microcirculatory bed in the studied organs (brain, liver, spleen, peritoneum, and testicle) corresponded to angioparalytical capillary and venular hyperemia. Macrophagic reaction (proliferation of stellate macrophages) transformed into granulomatous reaction in the course of the experiment. Macrophagic reaction of the spleen was characterized by blurred follicular pattern. In the testes a tendency to the loss of normal spermatogenesis was observed.

[Exanthematic typhus epidemic in Chile (1932-1939)].

PubMed

Laval, Enrique

2013-06-01

After the great epidemic of the exanthematic typhus of 1918-1919 in Chile, there was a gradual decrease in the number of cases , until it became endemic around 1926. Starting in 1932 and until 1939 a new epidemic outbreak occured that prompted researchers to its study supported by the new clinical and technological advances of this period. Subsequently, two important events occured: the erradication of the vector ( human louse) by means of effective insecticides and the discovery of an effective antibiotic treatment.

Queensland tick typhus: three cases with unusual clinical features.

PubMed

Wilson, P A; Tierney, L; Lai, K; Graves, S

2013-07-01

Queensland tick typhus (QTT), caused by Rickettsia australis, is usually a relatively mild illness but can occasionally be severe. We describe three cases of probable QTT with unusual clinical features, namely splenic infarction, fulminant myopericarditis and severe leukocytoclastic vasculitis. QTT may present with uncommon clinical features in addition to the more common manifestations. A high index of suspicion enables specific antibiotic therapy that may hasten recovery. © 2013 The Authors; Internal Medicine Journal © 2013 Royal Australasian College of Physicians.

Nanosecond-Pulsed DBD Plasma-Generated Reactive Oxygen Species Trigger Immunogenic Cell Death in A549 Lung Carcinoma Cells through Intracellular Oxidative Stress

PubMed Central

Lin, Abraham; Truong, Billy; Patel, Sohil; Kaushik, Nagendra; Choi, Eun Ha; Fridman, Gregory; Fridman, Alexander; Miller, Vandana

2017-01-01

A novel application for non-thermal plasma is the induction of immunogenic cancer cell death for cancer immunotherapy. Cells undergoing immunogenic death emit danger signals which facilitate anti-tumor immune responses. Although pathways leading to immunogenic cell death are not fully understood; oxidative stress is considered to be part of the underlying mechanism. Here; we studied the interaction between dielectric barrier discharge plasma and cancer cells for oxidative stress-mediated immunogenic cell death. We assessed changes to the intracellular oxidative environment after plasma treatment and correlated it to emission of two danger signals: surface-exposed calreticulin and secreted adenosine triphosphate. Plasma-generated reactive oxygen and charged species were recognized as the major effectors of immunogenic cell death. Chemical attenuators of intracellular reactive oxygen species successfully abrogated oxidative stress following plasma treatment and modulated the emission of surface-exposed calreticulin. Secreted danger signals from cells undergoing immunogenic death enhanced the anti-tumor activity of macrophages. This study demonstrated that plasma triggers immunogenic cell death through oxidative stress pathways and highlights its potential development for cancer immunotherapy. PMID:28467380

Use of Prior Vaccinations for the Development of New Vaccines

NASA Astrophysics Data System (ADS)

Etlinger, H. M.; Gillessen, D.; Lahm, H.-W.; Matile, H.; Schonfeld, H.-J.; Trzeciak, A.

1990-07-01

There is currently a need for vaccine development to improve the immunogenicity of protective epitopes, which themselves are often poorly immunogenic. Although the immunogenicity of these epitopes can be enhanced by linking them to highly immunogenic carriers, such carriers derived from current vaccines have not proven to be generally effective. One reason may be related to epitope-specific suppression, in which prior vaccination with a protein can inhibit the antibody response to new epitopes linked to the protein. To circumvent such inhibition, a peptide from tetanus toxoid was identified that, when linked to a B cell epitope and injected into tetanus toxoid-primed recipients, retained sequences for carrier but not suppressor function. The antibody response to the B cell epitope was enhanced. This may be a general method for taking advantage of previous vaccinations in the development of new vaccines.

Flinders Island Spotted Fever Rickettsioses Caused by “marmionii” Strain of Rickettsia honei, Eastern Australia

PubMed Central

Unsworth, Nathan B.; Graves, Stephen R.; Faa, Antony G.; Cox, G. Erika; Dyer, John R.; Boutlis, Craig S.; Lane, Amanda M.; Shaw, Matthew D.; Robson, Jennifer; Nissen, Michael D.

2007-01-01

Australia has 4 rickettsial diseases: murine typhus, Queensland tick typhus, Flinders Island spotted fever, and scrub typhus. We describe 7 cases of a rickettsiosis, with an acute onset and symptoms of fever (100%), headache (71%), arthralgia (43%), myalgia (43%), cough (43%), maculopapular/petechial rash (43%), nausea (29%), pharyngitis (29%), lymphadenopathy (29%), and eschar (29%). Cases were most prevalent in autumn and from eastern Australia, including Queensland, Tasmania, and South Australia. One patient had a history of tick bite (Haemaphysalis novaeguineae). An isolate shared 99.2%, 99.8%, 99.8%, 99.9%, and 100% homology with the 17 kDa, ompA, gltA, 16S rRNA, and Sca4 genes, respectively, of Rickettsia honei. This Australian rickettsiosis has similar symptoms to Flinders Island spotted fever, and the strain is genetically related to R. honei. It has been designated the “marmionii” strain of R. honei, in honor of Australian physician and scientist Barrie Marmion. PMID:17553271

Flinders Island spotted fever rickettsioses caused by "marmionii" strain of Rickettsia honei, Eastern Australia.

PubMed

Unsworth, Nathan B; Stenos, John; Graves, Stephen R; Faa, Antony G; Cox, G Erika; Dyer, John R; Boutlis, Craig S; Lane, Amanda M; Shaw, Matthew D; Robson, Jennifer; Nissen, Michael D

2007-04-01

Australia has 4 rickettsial diseases: murine typhus, Queensland tick typhus, Flinders Island spotted fever, and scrub typhus. We describe 7 cases of a rickettsiosis with an acute onset and symptoms of fever (100%), headache (71%), arthralgia (43%), myalgia (43%), cough (43%), maculopapular/petechial rash (43%), nausea (29%), pharyngitis (29%), lymphadenopathy (29%), and eschar (29%). Cases were most prevalent in autumn and from eastern Australia, including Queensland, Tasmania, and South Australia. One patient had a history of tick bite (Haemaphysalis novaeguineae). An isolate shared 99.2%, 99.8%, 99.8%, 99.9%, and 100% homology with the 17 kDa, ompA, gltA, 16S rRNA, and Sca4 genes, respectively, of Rickettsia honei. This Australian rickettsiosis has similar symptoms to Flinders Island spotted fever, and the strain is genetically related to R. honei. It has been designated the "marmionii" strain of R. honei, in honor of Australian physician and scientist Barrie Marmion.

Flea-Borne Rickettsioses in the North of Caldas Province, Colombia

PubMed Central

Montoya, Viviana; Martínez, Alejandra; Mercado, Marcela; De la Ossa, Alberto; Vélez, Carolina; Estrada, Gloria; Pérez, Jorge E.; Faccini-Martínez, Alvaro A.; Labruna, Marcelo B.; Valbuena, Gustavo

2013-01-01

Abstract Rickettsia typhi and R. felis are the etiological agents of murine typhus and flea-borne spotted fever, respectively. Both are emerging acute febrile zoonotic diseases for which fleas are vectors; they also have similar clinical characteristics and global distribution. In 2005, we identified the circulation of murine typhus in 6 towns within the mountainous coffee-growing area north of Caldas, Colombia. We now report the specific seroprevalence against R. typhi and R. felis, and associated risk factors in 7 towns of this province. The combined seroprevalence against the 2 flea-borne rickettsioses is the highest yet reported in the literature: 71.7% (17.8% for R. felis, 25.2% for R. typhi, and 28.7% for both). We also report a prospective analysis of 26 patients with a febrile illness compatible with rickettsioses, including murine typhus; 9 of these patients had a rickettsiosis. This supports our sero-epidemiological results and highlights the diagnostic complexity of febrile syndromes in this region. PMID:23473218

[The 1817 outbreak of louse-borne typhus in the Leghorn area (Tuscany): relationship between Authorities, public Health and medical doctrine

PubMed

Ruggi, Giovanni; Carneglia, Luca

2002-01-01

The authors recall the louse-borne typhus that took place in Leghorn in 1817. They analyse its causes and the health measures adopted to face it. Out of the historical reconstruction, there arise some issues on both the coming up again of such risk and the role played by health measures. Data concern the chronicles and the medical literature of those days. The method adopted implies comparison between historical circumstances, medical debate and provisions: in 1817 an epidemic of typhus exanthematicus caused hundreds of deaths and gave rise to much medical controversy incapable, however, of improving the existing knowledge. The analysis show a lack of health protection programs and a fallacious medical approach which did not help understand the relationship between pediculosis and disease. Following the health risks posed by migration pressures, this study stresses the importance of keeping the health agents' freedom of judgment away from political and administrative authority.

Multispacer typing of Rickettsia prowazekii enabling epidemiological studies of epidemic typhus.

PubMed

Zhu, Yong; Fournier, Pierre-Edouard; Ogata, Hiroyuki; Raoult, Didier

2005-09-01

Currently, there is no tool for typing Rickettsia prowazekii, the causative agent of epidemic typhus, currently considered a potential bioterrorism agent, at the strain level. To test if the multispacer typing (MST) method could differentiate strains of R. prowazekii, we amplified and sequenced the 25 most variable intergenic spacers between the R. prowazekii and R. conorii genomes in five strains and 10 body louse amplicons of R. prowazekii from various geographic origins. Two intergenic spacers, i.e., rpmE/tRNA(fMet) and serS/virB4, were variable among tested R. prowazekii isolates and allowed identification of three and two genotypes, respectively. When the genotypes obtained from the two spacers were combined, we identified four different genotypes. MST demonstrated that several R. prowazekii strains circulated in human body lice during an outbreak of epidemic typhus in Burundi. This may help to discriminate between natural and intentional outbreaks. Our study supports the usefulness of MST as a versatile method for rickettsial strain genotyping.

Scrub Typhus in Northeastern Thailand: Eschar Distribution, Abnormal Electrocardiographic Findings, and Predictors of Fatal Outcome.

PubMed

Thipmontree, Wilawan; Tantibhedhyangkul, Wiwit; Silpasakorn, Saowaluk; Wongsawat, Ekkarat; Waywa, Duangdao; Suputtamongkol, Yupin

2016-10-05

Scrub typhus is endemic in Thailand. Of the 495 patients with acute undifferentiated fever studied in Maharat Nakhon Ratchasima Hospital, Nakhon Ratchasima, Thailand, from June 1, 2011, to December 31, 2012, 146 patients (29.5%) had confirmed scrub typhus. The majority of cases were male, farmers, with the mean (±standard deviation) age of 54.1 ± 15.2 years. A total of 59 patients (40.4%) had eschar lesion. The commonest sites for an eschar in male patients were the perineum, inguinal, and buttock area; whereas in females, it was the head and neck area. Abnormal electrocardiogram was found in 39 of 79 patients (49.4%) with sinus tachycardia being the most frequent finding (17, 21.5%). A total of 73 patients (50%) had at least one complication. Myocarditis was the cause of complete heart block in a scrub typhus patient, and he fully recovered after receiving intravenous chloramphenicol treatment. The case fatality rate was 6.2% (nine deaths).The independent predictors for fatal outcome were age over 65 years (odds ratio [OR] = 14.49, 95% confidence interval [CI] = 1.26-166.44, P = 0.03), acute kidney injury (OR = 12.75, 95% CI = 1.77-92.07, P = 0.01), and hyperbilirubinemia (OR = 24.82, 95% CI = 2.12-286.61, P = 0.01). Early diagnosis and prompt appropriate treatment can improve the patient's outcome. © The American Society of Tropical Medicine and Hygiene.

Increased endothelial and macrophage markers are associated with disease severity and mortality in scrub typhus.

PubMed

Otterdal, Kari; Janardhanan, Jeshina; Astrup, Elisabeth; Ueland, Thor; Prakash, John A J; Lekva, Tove; Abraham, O C; Thomas, Kurien; Damås, Jan Kristian; Mathews, Prasad; Mathai, Dilip; Aukrust, Pål; Varghese, George M

2014-11-01

Scrub typhus is endemic in the Asia-Pacific region. Mortality is high even with treatment, and further knowledge of the immune response during this infection is needed. This study was aimed at comparing plasma levels of monocyte/macrophage and endothelial related inflammatory markers in patients and controls in South India and to explore a possible correlation to disease severity and clinical outcome. Plasma levels of ALCAM, VCAM-1, sCD163, sCD14, YKL-40 and MIF were measured in scrub typhus patients (n = 129), healthy controls (n = 31) and in infectious disease controls (n = 31), both in the acute phase and after recovery, by enzyme immunoassays. Patients had markedly elevated levels of all mediators in the acute phase, differing from both healthy and infectious disease controls. During follow-up levels of ALCAM, VCAM-1, sCD14 and YKL-40 remained elevated compared to levels in healthy controls. High plasma ALCAM, VCAM-1, sCD163, sCD14, and MIF, and in particular YKL-40 were all associated with disease severity and ALCAM, sCD163, MIF and especially YKL-40, were associated with mortality. Our findings show that scrub typhus is characterized by elevated levels of monocyte/macrophage and endothelial related markers. These inflammatory markers, and in particular YKL-40, may contribute to disease severity and clinical outcome. Copyright © 2014 The British Infection Association. Published by Elsevier Ltd. All rights reserved.

Quantitative and volume, conductivity and scatter changes in leucocytes of patients with acute undifferentiated febrile illness: a pilot study.

PubMed

Kalra, Varun; Ahmad, Sohaib; Shrivastava, Vikas; Mittal, Garima

2016-05-01

A single diagnostic test for acute undifferentiated febrile illnesses (AUFI) is elusive. This pilot study was undertaken on the premise that leucocytes, being the main cells of defence, undergo quantitative, structural and functional changes in AUFI. We evaluated the potential of volume, conductivity and scatter (VCS) parameters of leucocytes, generated with the haemogram report by the Coulter auto-analyzer, in differentiating the common etiologies of AUFI. The haematological and VCS data obtained from 800 controls and 200 cases of AUFI (50 cases each of acute malaria, dengue, scrub typhus and enteric fever) were retrieved for analysis. The cases and controls differed significantly with respect to relative numbers and the VCS parameters of neutrophils, lymphocytes and monocytes (p<0.05). The neutrophil and lymphocyte were significantly voluminous in acute malaria and scrub typhus as compared to dengue and enteric fevers (p<0.05). Enteric fever significantly enhanced the conductivity of neutrophils as compared to other subgroups while lymphocyte conductivity significantly differed from dengue and scrub typhus. Lymphocyte and neutrophil scatter values in malaria and scrub typhus were comparable but differed significantly from that in enteric fever. Etiology-specific changes occur in leucocytes, both in numbers and their VCS properties which can be identified without additional cost. © The Author 2016. Published by Oxford University Press on behalf of Royal Society of Tropical Medicine and Hygiene. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

A RICKETTSIAL INFECTION IN CANADIAN VOLES

PubMed Central

Baker, James A.

1946-01-01

From apparently normal voles captured on Grosse Isle, Province of Quebec, Canada, an infective agent has been grown in embryonated eggs, and by inoculation an inapparent infection was established in voles, mice, guinea pigs, hamsters, and rats. No growth of the agent was obtained in the absence of living cells, and the manner of its development in the yolk sac of embryonated eggs, as well as morphological, epidemiological, and pathogenic features, indicates a rickettsial nature. The inability to transmit infection by either cage or intrauterine contact points to a vector, and mites are shown to have a probable part in the epidemiology. Mice infected with the vole agent resist lethal doses of the Karp strain of scrub typhus, and certain epidemiological, morphological, and immunological features support the relationship indicated by the mouse tests. It is therefore concluded that voles on this island have an inapparent infection due to a rickettsia that may be related to the rickettsia of scrub typhus. PMID:19871552

Analysis of the cross-reactivity of various 56 kDa recombinant protein antigens with serum samples collected after Orientia tsutsugamushi infection by ELISA.

PubMed

Chao, Chien-Chung; Huber, Erin S; Porter, Terrisita B; Zhang, Zhiwen; Ching, Wei-Mei

2011-06-01

Orientia tsutsugamushi, the etiologic agent of scrub typhus, has a highly expressed and immunodominant 56-kD outer membrane protein. This protein is one of the leading candidates for diagnosis and vaccine development for scrub typhus. Previous studies using recombinant 56-kD protein (r56s) derived from Karp strain (Kpr56) in a mouse model have shown good homologous protection but only moderate to poor heterologous protection. We evaluated the cross-reactivity of recombinant 56-kD proteins from Karp, Kato, Gilliam, TA763, and three chimeric 56-kD proteins. Not all r56s are equally reactive with strain-specific serum samples. These data provide a first glance of how reactive these r56s are toward the antiserum of different strains and which r56 exhibits the broadest reactivity. A formulation of this combination has the potential to provide broad protection against the heterologous challenge and to be used in a highly sensitive diagnostic assay.

Endoscopic Characteristics Comparison of Helicobacter pylori and Orientia tsutsugamushi Infection

PubMed Central

Kim, Dong-Min; Yun, Na Ra; Sul, Hyoung; Kim, Choon-Mee

2017-01-01

Abstract Background Aside from Helicobacter pylori, another cause for the development or worsening of gastrointestinal ulcers is scrub typhus, an acute febrile disease caused by Orientia tsutsugamushi. We aimed to compare the endoscopic characteristics of peptic ulcers caused by these infectious agents. Methods This retrospective case–control study involved patients who underwent upper gastrointestinal endoscopy at Chosun University Hospital in Korea. Results In total, 141 patients with peptic ulcer were included in the study. Compared with patients with O. tsutsugamushi infection (n = 62; age, 63.8 ± 12.1 years; male sex, 42%), those with H. pylori infection (n = 79; age, 53.0 ± 14.8 years; male sex, 81%) were younger and more likely to be male (P < 0.001 for both). Patients with O. tsutsugamushi infection were more likely to have multiple lesions (40/62, 64.5% vs. 37/79, 46.8%; P = 0.042) and irregular-shaped lesions (27/62, 43.6% vs. 20/79, 25.3%; 
P = 0.031). Patients with H. pylori infection had higher incidence of hemorrhagic ulcers (26/79, 32.9% vs. 8/62, 12.9%; P = 0.007), and lesions occurred most often in the duodenum (43.0%), followed by the antrum (36.7%), body (34.2%), and angle (12.7%) of the stomach. In patients with O. tsutsugamushi infection, lesions occurred most often in the antrum (70.97%) of the stomach. In both groups, gastric ulcer lesions occurred most often in the antrum, followed by the body and angle of the stomach (36.7% vs. 70.97%, 34.2% vs. 22.6%, and 12.7% vs. 14.5% for gastric ulcers associated with H. pylori and O. tsutsugamushi infection, respectively). Patients with O. tsutsugamushiinfection had significantly higher incidence of ulcers on the antrum (70.97% vs. 36.7%, P < 0.001) and the greater curvature (45.2% vs. 24.0%, P = 0.012). Finally, 35.5% of patients with gastric ulcer caused by scrub typhus also had duodenal ulcer. Conclusion This is the first study to compare endoscopic features of peptic ulcers caused by H. pylori and O. tsutsugamushi. Peptic ulcers in patients with H. pylori infection occurred predominantly in the antrum/body/lesser curvature and presented with single, round/oval lesions, while ulcers in patients with scrub typhus occurred predominantly in the antrum/greater curvature and presented with multiple, irregular lesions. Scrub typhus should be considered as a cause of duodenal ulcer in scrub typhus-endemic areas. Disclosures All authors: No reported disclosures.

Application of M13 phage display for identifying immunogenic proteins from tick (Ixodes scapularis) saliva.

PubMed

Becker, Martin; Felsberger, André; Frenzel, André; Shattuck, Wendy M C; Dyer, Megan; Kügler, Jonas; Zantow, Jonas; Mather, Thomas N; Hust, Michael

2015-05-30

Ticks act as vectors for a large number of different pathogens, perhaps most notably Borrelia burgdorferi, the causative agent of Lyme disease. The most prominent tick vector in the United States is the blacklegged tick, Ixodes scapularis. Tick bites are of special public health concern since there are no vaccines available against most tick-transmitted pathogens. Based on the observation that certain non-natural host animals such as guinea pigs or humans can develop adaptive immune responses to tick bites, anti-tick vaccination is a potential approach to tackle health risks associated with tick bites. The aim of this study was to use an oligopeptide phage display strategy to identify immunogenic salivary gland proteins from I. scapularis that are recognized by human immune sera. Oligopeptide libraries were generated from salivary gland mRNA of 18 h fed nymphal I. scapularis. Eight immunogenic oligopeptides were selected using human immune sera. Three selected immunogenic oligopeptides were cloned and produced as recombinant proteins. The immunogenic character of an identified metalloprotease (MP1) was validated with human sera. This enzyme has been described previously and was hypothesized as immunogenic which was confirmed in this study. Interestingly, it also has close homologs in other Ixodes species. An immunogenic protein of I. scapularis was identified by oligopeptide phage display. MP1 is a potential candidate for vaccine development.

Immunogenicity assessment during the development of protein therapeutics.

PubMed

Rosenberg, Amy S; Sauna, Zuben E

2018-05-01

Here we provide a critical review of the state of the art with respect to non-clinical assessments of immunogenicity for therapeutic proteins. The number of studies on immunogenicity published annually has more than doubled in the last 5 years. The science and technology, which have reached a critical mass, provide multiple of non-clinical approaches (computational, in vitro, ex vivo and animal models) to first predict and then to modify or eliminate T-cell or B-cell epitopes via de-immunization strategies. We discuss how these may be used in the context of drug development in assigning the immunogenicity risk of new and marketed therapeutic proteins. Protein therapeutics represents a large share of the pharma market and provide medical interventions for some of the most complex and intractable diseases. Immunogenicity (the development of antibodies to therapeutic proteins) is an important concern for both the safety and efficacy of protein therapeutics as immune responses may neutralize the activity of life-saving and highly effective protein therapeutics and induce hypersensitivity responses including anaphylaxis. The non-clinical computational tools and experimental technologies that offer a comprehensive and increasingly accurate estimation of immunogenic potential are surveyed here. This critical review also discusses technologies which are promising but are not as yet ready for routine use. Published 2017. This article is a U.S. Government work and is in the public domain in the USA.

Salk's HIV immunogen: an immune-based therapy in human trials since 1988.

PubMed

Jonas Salk, the developer of the first polio vaccine, has created a therapeutic vaccine for HIV which helps the immune system fight disease progression. Salk uses inactivated HIV-1 virus combined with Incomplete Freund's Adjuvant (IFA) in the vaccine preparation. The resulting HIV-1 immunogen was first studied in 1987, and since then, 235 seropositive individuals have received inoculations without serious adverse effects. Data from the first 25 subjects indicate that immunization with the HIV-1 immunogen results in improvement of cell-mediated response against the virus, a slower increase in the amount of virus present, and a reduced rate of clinical progression. Subsequent studies also show that higher doses of immunogen may produce stronger cell-mediated responses and high HIV-DTH (delayed-type hypersensitivity responsiveness immunogen) is associated with better outcome. Additional trials of HIV-1 immunogen are awaiting Food and Drug Administration approval.

[Some information regarding the historical development of typhoid fever in Chile].

PubMed

Laval, Enrique

2017-10-01

During the historical development of typhoid fever in Chile, its confusion with other infectious diseases is particularly noteworthy, especially with murine typhus, a problem that was mainly resolved during the 1918 epidemic. The importance of chloramphenicol treatment is also highlighted, which meant an enormous improvement in typhoid/paratyphoid fevers, in combination with public health and health education actions that allowed to almost eliminate these infectious diseases in our country.

Hemorrhagic Fever with Renal Syndrome (Korean Hemorrhagic Fever)

DTIC Science & Technology

1990-06-29

particles were used for a rapid serologic diagnostic test for HFRS. ’te-re were 430 cases of HFRS in Korea in 1989 and large outbreaks of scrub typhus...almost same as in 1988. A simple and rapid serologic diagnostic test for hantavirus infection was developed by high density particle agglutination...infection and HFRS b) serologic relation cif hantaviruses isolated from the different parts of the world c) development of a simple serologic diagnostic

Modulating Vaccinia Virus Immunomodulators to Improve Immunological Memory

PubMed Central

Torres, Alice A.; Smith, Geoffrey L.

2018-01-01

The increasing frequency of monkeypox virus infections, new outbreaks of other zoonotic orthopoxviruses and concern about the re-emergence of smallpox have prompted research into developing antiviral drugs and better vaccines against these viruses. This article considers the genetic engineering of vaccinia virus (VACV) to enhance vaccine immunogenicity and safety. The virulence, immunogenicity and protective efficacy of VACV strains engineered to lack specific immunomodulatory or host range proteins are described. The ultimate goal is to develop safer and more immunogenic VACV vaccines that induce long-lasting immunological memory. PMID:29495547

Rickettsia australis and Queensland Tick Typhus: A Rickettsial Spotted Fever Group Infection in Australia.

PubMed

Stewart, Adam; Armstrong, Mark; Graves, Stephen; Hajkowicz, Krispin

2017-07-01

Rickettsia australis , the etiologic agent of Queensland tick typhus (QTT), is increasingly being recognized as a cause of community-acquired acute febrile illness in eastern Australia. Changing human population demographics, climate change, and increased understanding of expanding vector distribution indicate QTT is an emerging public health threat. This review summarizes the epidemiology, pathogenesis, clinical features, treatment principles, and future directions of this disease. Increased recognition of QTT will enable consideration of and prompt treatment of R. australis infection by clinicians in Australia.

Hermann Mooser, Typhus, Warsaw 1941.

PubMed

Lindenmann, Jean

2002-01-01

Hermann Mooser (1891-1971), a Swiss rickettsiologist, sent his friend Peyton Rous (1879-1970) of the Rockefeller Institute (New York) a telegram on November 3, 1941, asking for financial help for the manufacture of typhus vaccine in Zurich for the Warsaw Ghetto. His explanatory letter from November 4 reached Rous too late to have any influence on the negative decision (by the Rockefeller Foundation and the American Red Cross) in this matter. Contrary to Weindling's affirmation Mooser was neither in Warsaw in 1941, nor was he a member of the Swiss Sanitary Missions to the eastern front.

Modulating immunogenic properties of HIV-1 gp41 membrane-proximal external region by destabilizing six-helix bundle structure

DOE Office of Scientific and Technical Information (OSTI.GOV)

Banerjee, Saikat; Shi, Heliang; Habte, Habtom H.

The C-terminal alpha-helix of gp41 membrane-proximal external region (MPER; {sup 671}NWFDITNWLWYIK{sup 683}) encompassing 4E10/10E8 epitopes is an attractive target for HIV-1 vaccine development. We previously reported that gp41-HR1-54Q, a trimeric protein comprised of the MPER in the context of a stable six-helix bundle (6HB), induced strong immune responses against the helix, but antibodies were directed primarily against the non-neutralizing face of the helix. To better target 4E10/10E8 epitopes, we generated four putative fusion intermediates by introducing double point mutations or deletions in the heptad repeat region 1 (HR1) that destabilize 6HB in varying degrees. One variant, HR1-∆10-54K, elicited antibodies inmore » rabbits that targeted W672, I675 and L679, which are critical for 4E10/10E8 recognition. Overall, the results demonstrated that altering structural parameters of 6HB can influence immunogenic properties of the MPER and antibody targeting. Further exploration of this strategy could allow development of immunogens that could lead to induction of 4E10/10E8-like antibodies. - Highlights: • Four gp41 MPER-based immunogens that resemble fusion intermediates were generated. • C-terminal region of MPER that contains 4E10/10E8 epitopes was highly immunogenic. • Altering 6HB structure can influence immunogenic properties of the MPER. • Induced antibodies targeted multiple residues critical for 4E10/10E8 binding. • Development of immunogens based on fusion intermediates is a promising strategy.« less

Use of eschar swabbing for the molecular diagnosis and genotyping of Orientia tsutsugamushi causing scrub typhus in Quang Nam province, Vietnam.

PubMed

Le Viet, Nhiem; Laroche, Maureen; Thi Pham, Hoa L; Viet, Nho L; Mediannikov, Oleg; Raoult, Didier; Parola, Philippe

2017-02-01

Scrub typhus is a rickettsiosis which is caused by Orientia tsutsugamushi and occurs throughout the Asia-Pacific region. Molecular diagnosis of rickettsioses using eschar swabs has recently emerged, and may be very useful for the diagnosis of these diseases in tropical settings. Quantitative polymerase chain reaction (qPCR) was used to detect O. tsutsugamushi DNA in whole blood and eschar swab specimens of 67 patients who were clinically suspected of scrub typhus in Quang Nam province, Vietnam. Among the 20 patients for whom both eschar and whole blood were obtained, 17 (85%) of the eschar specimens and 5 (25%) of the whole blood specimens tested positive for O. tsutsugamushi. Genetic analysis of the 56-kDa TSA gene sequences demonstrated that the 14 sequences obtained in this study, including 12 eschar swabs and 2 whole blood specimens, were related to 4 groups: Karp, Kawasaki, Gilliam (JG-v and TG-v) and TA716. The majority (9/14; 64.4%) of contemporary O. tsutsugamushi genotypes in Quang Nam province were related to the Karp group. These results suggest that polyclonal antigen pools used for serological testing in the future should contain at least Karp, Kawasaki, Gilliam and TA716 antigens for Vietnamese patients, as well as patients who have traveled to Vietnam. qPCR after eschar swabbing should be considered for molecular diagnosis of scrub typhus in endemic patients as well as in travelers, since it is easy to perform and appears very useful for the rapid detection of Orientia tsutsugamushi in the early phase of infection.

Identification of immunogenic polypeptides from a Mycoplasma hyopneumoniae genome library by phage display.

PubMed

Kügler, Jonas; Nieswandt, Simone; Gerlach, Gerald F; Meens, Jochen; Schirrmann, Thomas; Hust, Michael

2008-09-01

The identification of immunogenic polypeptides of pathogens is helpful for the development of diagnostic assays and therapeutic applications like vaccines. Routinely, these proteins are identified by two-dimensional polyacrylamide gel electrophoresis and Western blot using convalescent serum, followed by mass spectrometry. This technology, however, is limited, because low or differentially expressed proteins, e.g. dependent on pathogen-host interaction, cannot be identified. In this work, we developed and improved a M13 genomic phage display-based method for the selection of immunogenic polypeptides of Mycoplasma hyopneumoniae, a pathogen causing porcine enzootic pneumonia. The fragmented genome of M. hyopneumoniae was cloned into a phage display vector, and the genomic library was packaged using the helperphage Hyperphage to enrich open reading frames (ORFs). Afterwards, the phage display library was screened by panning using convalescent serum. The analysis of individual phage clones resulted in the identification of five genes encoding immunogenic proteins, only two of which had been previously identified and described as immunogenic. This M13 genomic phage display, directly combining ORF enrichment and the presentation of the corresponding polypeptide on the phage surface, complements proteome-based methods for the identification of immunogenic polypeptides and is particularly well suited for the use in mycoplasma species.

Aleuria Aurantia Lectin (AAL)-Reactive Immunoglobulin G Rapidly Appears in Sera of Animals following Antigen Exposure

PubMed Central

Chen, Songming; Lu, Chen; Gu, Hongbo; Mehta, Anand; Li, Jianwei; Romano, Patrick B.; Horn, David; Hooper, D. Craig; Bazemore-Walker, Carthene R.; Block, Timothy

2012-01-01

We have discovered an Aleuria Aurantia Lectin (AAL)-reactive immunoglobulin G (IgG) that naturally occurs in the circulation of rabbits and mice, following immune responses induced by various foreign antigens. AAL can specifically bind to fucose moieties on glycoproteins. However, most serum IgGs are poorly bound by AAL unless they are denatured or treated with glycosidase. In this study, using an immunogen-independent AAL-antibody microarray assay that we developed, we detected AAL-reactive IgG in the sera of all animals that had been immunized 1–2 weeks previously with various immunogens with and without adjuvants and developed immunogen-specific responses. All of these animals subsequently developed immunogen-specific immune responses. The kinetics of the production of AAL-reactive IgG in mice and rabbits were distinct from those of the immunogen-specific IgGs elicited in the same animals: they rose and fell within one to two weeks, and peaked between four to seven days after exposure, while immunogen-specific IgGs continued to rise during the same period. Mass spectrometric profiling of the Fc glycoforms of purified AAL-reactive IgGs indicates that these are mainly comprised of IgGs with core-fucosylated and either mono-or non-galactosylated Fc N-glycan structures. Our results suggest that AAL-reactive IgG could be a previously unrecognized IgG subset that is selectively produced at the onset of a humoral response. PMID:23024749

[The North African plague and Charles Nicolle's theory of infectious diseases].

PubMed

Ben, Néfissa Kmar; Moulin, Anne Marie

2010-01-01

Many infectious diseases were described in North Africa in 18th-19th centuries by European travellers. Most of them were allegedly imported by new migrant populations coming from sub-Saharan, European or Middle East countries. Plague outbreaks have been described since the Black Death as diseases of the Mediterranean harbours. Charles Nicolle and his collaborators at the Pasteur Institute were witnesses to the extinction of plague and typhus fever in Tunisia. Both could be considered as endemo-epidemic diseases propagated by ancient nomad communities for centuries. Typhus was exported to other countries; plague was imported by Mediterranean travellers but also hid in unknown wild-animal reservoirs. The role of the bite of a rat's flea was not confirmed and the pneumonic form might have prevailed in the medieval North African cities. Association between plague, typhus, flu and other causes of immune deficiencies could explain the high morbidity and mortality caused by plague in the past. The authors comment the local history of plague at the light of the evolutionary laws of infectious disease proposed by Charles Nicolle in 1930.

HIV-1 broadly neutralizing antibody precursor B cells revealed by germline-targeting immunogen

DOE PAGES

Jardine, Joseph G.; Kulp, Daniel W.; Havenar-Daughton, Colin; ...

2016-03-25

Induction of broadly neutralizing antibodies (bnAbs) is a major HIV vaccine goal. Germline-targeting immunogens aim to initiate bnAb induction by activating bnAb germline precursor B cells. Critical unmet challenges are to determine whether bnAb precursor naïve B cells bind germline-targeting immunogens and occur at sufficient frequency in humans for reliable vaccine responses. We employed deep mutational scanning and multi-target optimization to develop a germline-targeting immunogen (eOD-GT8) for diverse VRC01-class bnAbs. We then used the immunogen to isolate VRC01-class precursor naïve B cells from HIV-uninfected donors. Frequencies of true VRC01-class precursors, their structures, and their eOD-GT8 affinities support this immunogen asmore » a candidate human vaccine prime. Lastly, these methods could be applied to germline targeting for other classes of HIV bnAbs and for Abs to other pathogens.« less

HIV-1 broadly neutralizing antibody precursor B cells revealed by germline-targeting immunogen

DOE Office of Scientific and Technical Information (OSTI.GOV)

Jardine, Joseph G.; Kulp, Daniel W.; Havenar-Daughton, Colin

Induction of broadly neutralizing antibodies (bnAbs) is a major HIV vaccine goal. Germline-targeting immunogens aim to initiate bnAb induction by activating bnAb germline precursor B cells. Critical unmet challenges are to determine whether bnAb precursor naïve B cells bind germline-targeting immunogens and occur at sufficient frequency in humans for reliable vaccine responses. We employed deep mutational scanning and multi-target optimization to develop a germline-targeting immunogen (eOD-GT8) for diverse VRC01-class bnAbs. We then used the immunogen to isolate VRC01-class precursor naïve B cells from HIV-uninfected donors. Frequencies of true VRC01-class precursors, their structures, and their eOD-GT8 affinities support this immunogen asmore » a candidate human vaccine prime. Lastly, these methods could be applied to germline targeting for other classes of HIV bnAbs and for Abs to other pathogens.« less

HIV-1 broadly neutralizing antibody precursor B cells revealed by germline-targeting immunogen.

PubMed

Jardine, Joseph G; Kulp, Daniel W; Havenar-Daughton, Colin; Sarkar, Anita; Briney, Bryan; Sok, Devin; Sesterhenn, Fabian; Ereño-Orbea, June; Kalyuzhniy, Oleksandr; Deresa, Isaiah; Hu, Xiaozhen; Spencer, Skye; Jones, Meaghan; Georgeson, Erik; Adachi, Yumiko; Kubitz, Michael; deCamp, Allan C; Julien, Jean-Philippe; Wilson, Ian A; Burton, Dennis R; Crotty, Shane; Schief, William R

2016-03-25

Induction of broadly neutralizing antibodies (bnAbs) is a major HIV vaccine goal. Germline-targeting immunogens aim to initiate bnAb induction by activating bnAb germline precursor B cells. Critical unmet challenges are to determine whether bnAb precursor naïve B cells bind germline-targeting immunogens and occur at sufficient frequency in humans for reliable vaccine responses. Using deep mutational scanning and multitarget optimization, we developed a germline-targeting immunogen (eOD-GT8) for diverse VRC01-class bnAbs. We then used the immunogen to isolate VRC01-class precursor naïve B cells from HIV-uninfected donors. Frequencies of true VRC01-class precursors, their structures, and their eOD-GT8 affinities support this immunogen as a candidate human vaccine prime. These methods could be applied to germline targeting for other classes of HIV bnAbs and for Abs to other pathogens. Copyright © 2016, American Association for the Advancement of Science.

Immunogenicity of biotherapy used in psoriasis: the science behind the scenes.

PubMed

Jullien, Denis; Prinz, Jörg C; Nestle, Frank O

2015-01-01

A potential limitation in the use of biologic drugs used to treat psoriasis is the development of anti-drug antibodies (ADAs). Many factors contribute to this unwanted immune response, from the product itself, to its mode of administration, the underlying disease, and patient characteristics. ADAs may decrease the efficacy of biologic drugs by neutralizing them or modifying their clearance and may account for hypersensitivity reactions. This article reviews the scientific basis of immunogenicity and the mechanisms by which it affects clinical outcomes. It also considers testing for immunogenicity and how biologic therapy of psoriasis may be tailored on the basis of immunogenicity.

Chigger (Acarina:Trombiculidae) surveys of the west coast beaches of Sabah and Sarawak.

PubMed

Dohany, A L; Phang, O W; Rapmund, G

1977-06-01

Leptotrombidium (Leptotrombidium) arenicola Traub, a vector of scrub typhus, had previously been found to occur in the coastal vegetation behind the edge of open sand along the beaches of Peninsular Malaysia. Surveys of the west coast beaches of Sabah and Sarawak were conducted to determine if this species occurs in similar habitat in East Malaysia on the island of Borneo. Leptotrombidium (L.) arenicola was not collected from the eighteen sites studied. Of the 11,982 mite larvae collected, 55 per cent were L.(L.) deliense (Walch), a well-known, widespread vector of scrub typhus.

Serological Surveillance of Scrub Typhus, Murine Typhus, and Leptospirosis in Small Mammals Captured at Firing Points 10 and 60, Gyeonggi Province, Republic of Korea, 2001-2005

DTIC Science & Technology

2010-01-01

Province, Republic of Korea, 2001-2005 5a. CONTRACT NUMBER 5b. GRANT NUMBER 5c. PROGRAM ELEMENT NUMBER 6. AUTHOR (S) 5d. PROJECT NUMBER 5e. TASK...rodent-borne disease surveillance, including rodent bionom- ics, ecology, and hantaviruses , conducted at other U.S. and Korean operated military...2005 as described by O’Guinn et al (2008), as a result of a hantavirus case reported in October 2000 in a U.S. soldier who trained at these sites

Evaluation of a broad-ranging and convenient enzyme-linked immunosorbent assay using the lysate of infected cells with five serotypes of Orientia tsutsugamushi, a causative agent of scrub typhus.

PubMed

Ogawa, Motohiko; Satoh, Masaaki; Saijo, Masayuki; Ando, Shuji

2017-01-05

Scrub typhus is a mite-borne rickettsiosis caused by infection of Orientia tsutsugamushi, which is endemic to several Asia-Pacific Rim countries, including Japan. Although micro-indirect immunofluorescent assay (micro-IFA) is the standard method for the serological diagnosis of scrub typhus, enzyme-linked immunosorbent assay (ELISA) is considered to be more objective, by providing digitized results as opposed to being subject to the judgment of the evaluator as in micro-IFA. Therefore, the aim of this study was to develop a broad-ranging ELISA using the five major prevalent serotypes of O. tsutsugamushi in Japan as the antigens. Furthermore, in contrast to previous studies that used purified microorganisms via ultracentrifugation, we directly used the infected cells, and evaluated the diagnostic accuracy of this simplified method to that of micro-IFA. Evaluation of paired patient sera against the five serotypes showed that the accuracy of ELISA relative to micro-IFA was 87.4 and 79.5% for immunoglobulin (Ig)M and IgG assays, respectively, at the optimized cut-off value. Further evaluation of patient sera against the expected serotype of the infecting strain showed that the accuracy of ELISA compared to micro-IFA increased to 100 and 97.4% in the IgM and IgG assays, respectively. This suggests that use of the five prevalent serotypes contributed to the increase of the accuracy of ELISA. When applying the criteria of serological diagnosis for paired sera samples to ELISA, all 19 patients were diagnosed as positive; a ≥4-fold elevation of the antibody titer was observed in 15 of 19 patients that were positive, and very high antibody titers were observed in both paired sera samples of the remaining four patients. In addition, all samples of healthy subjects and patients with other types of rickettsiosis were diagnosed as negative using these criteria. Our results suggest the excellent performance of the new broad-ranging and convenient ELISA, which appears to be applicable for the diagnosis of scrub typhus patients infected with the wide variety of prevalent strains in Japan. Furthermore, the ELISA is more objective than the micro-IFA, and can therefore provide more accurate diagnoses in Japan.

Impact of product-related factors on immunogenicity of biotherapeutics.

PubMed

Singh, Satish Kumar

2011-02-01

All protein therapeutics have the potential to be immunogenic. Several factors, including patient characteristics, disease state, and the therapy itself, influence the generation of an immune response. Product-related factors such as the molecule design, the expression system, post-translational modifications, impurities, contaminants, formulation and excipients, container, closure, as well as degradation products are all implicated. However, a critical examination of the available data shows that clear unequivocal evidence for the impact of these latter factors on clinical immunogenicity is lacking. No report could be found that clearly deconvolutes the clinical impact of the product attributes on patient susceptibility. Aggregation carries the greatest concern as a risk factor for immunogenicity, but the impact of aggregates is likely to depend on their structure as well as on the functionality (e.g., immunostimulatory or immunomodulatory) of the therapeutic. Preclinical studies are not yet capable of assessing the clinically relevant immunogenicity potential of these product-related factors. Simply addressing these risk factors as part of product development will not eliminate immunogenicity. Minimization of immunogenicity has to begin at the molecule design stage by reducing or eliminating antigenic epitopes and building in favorable physical and chemical properties. Copyright © 2010 Wiley-Liss, Inc.

Development of a strategy and computational application to select candidate protein analogues with reduced HLA binding and immunogenicity.

PubMed

Dhanda, Sandeep Kumar; Grifoni, Alba; Pham, John; Vaughan, Kerrie; Sidney, John; Peters, Bjoern; Sette, Alessandro

2018-01-01

Unwanted immune responses against protein therapeutics can reduce efficacy or lead to adverse reactions. T-cell responses are key in the development of such responses, and are directed against immunodominant regions within the protein sequence, often associated with binding to several allelic variants of HLA class II molecules (promiscuous binders). Herein, we report a novel computational strategy to predict 'de-immunized' peptides, based on previous studies of erythropoietin protein immunogenicity. This algorithm (or method) first predicts promiscuous binding regions within the target protein sequence and then identifies residue substitutions predicted to reduce HLA binding. Further, this method anticipates the effect of any given substitution on flanking peptides, thereby circumventing the creation of nascent HLA-binding regions. As a proof-of-principle, the algorithm was applied to Vatreptacog α, an engineered Factor VII molecule associated with unintended immunogenicity. The algorithm correctly predicted the two immunogenic peptides containing the engineered residues. As a further validation, we selected and evaluated the immunogenicity of seven substitutions predicted to simultaneously reduce HLA binding for both peptides, five control substitutions with no predicted reduction in HLA-binding capacity, and additional flanking region controls. In vitro immunogenicity was detected in 21·4% of the cultures of peptides predicted to have reduced HLA binding and 11·4% of the flanking regions, compared with 46% for the cultures of the peptides predicted to be immunogenic. This method has been implemented as an interactive application, freely available online at http://tools.iedb.org/deimmunization/. © 2017 John Wiley & Sons Ltd.

Technology evaluation: C242-DM1, ImmunoGen Inc.

PubMed

Smith, S

2001-04-01

C242-DM1 is a tumor-activated immunotoxin under development by GlaxoSmithKline plc (formerly SmithKline Beecham plc), under licence from ImmunoGen Inc, as a potential treatment for colon tumor. It consists of a colon cancer-specific humanized antibody, C242, conjugated to the maytansine derivative DM1. In preclinical studies, C242-DM1 caused complete tumor regression in animal models of both human pancreatic and non-small cell lung cancer (NSCLC) at non-toxic doses. C242-DM1 has also been evaluated in an immunoconjugate combination with J-591 (Cornell University). The J591-DM1 immunoconjugate demonstrated effective, antigen-specific delivery of a highly cytotoxic drug to PSMA-positive Pca cells in vitro and in vivo with low systemic toxicity. Results from studies in monkeys showed that C242-DM1 had no significant toxicity or side effects, when administered at doses higher than those that were previously shown to completely eradicate human colon tumors in mice [271420]. ImmunoGen acquired the right to evaluate, and an option to license, technology related to maytansines from Takeda. In February 1999, ImmunoGen and SmithKline Beecham signed a US $45 million development and commercialization agreement for C242-DM1 [313493]. In August 1997, Immunogen received an SBIR grant to advance development of huC242-DM1 [258356]. EP-00425235, held by ImmunoGen, covers conjugated forms of ansamitocin (maytansine) derivatives. Takeda holds several patents for the production of ansamitocin and its analogs, the first one being JP-53124692.

Rickettsial infections--a threat to travellers?

PubMed

Rolain, Jean-Marc; Jensenius, Mogens; Raoult, Didier

2004-10-01

Recent developments in cell-culture techniques and molecular methods have led to the description of several new rickettsial diseases. An update on these new infections should be of interest to health workers with patients who are international travellers. Epidemic typhus was reported last year in the United States when an outbreak of murine typhus was recorded in Hawaii. Among spotted fever group rickettsioses, African tick bite fever is now probably the most common rickettsial infection in Africa with numerous cases also reported in international travellers. For the first time the Astrakhan fever rickettsia has been described outside Europe, in a French patient returning from Chad. Similarly, the first case of Rickettsia sibirica mongolotimonae infection in Africa was reported in 2004. Finally, a newly recognized agent of a spotted fever rickettsiosis, Rickettsia parkeri, has been reported in the United States during 2004. Because results of serological testing are only presumptive, sophisticated methods are crucial for the diagnosis and description of new rickettsial diseases, especially in atypical cases. Modern diagnostic tools include cross-adsorption assays, Western blot testing, and cell-culture and molecular-biological methods.

Scrub typhus and spotted fever among hospitalised children in South India: Clinical profile and serological epidemiology.

PubMed

Kalal, B S; Puranik, P; Nagaraj, S; Rego, S; Shet, A

2016-01-01

Rickettsial infections are re-emerging. In India, they are now being reported from several areas where they were previously unknown. The objective of this study was to describe the epidemiology, clinical profile and outcome of serologically-confirmed scrub typhus and spotted fever among children in a tertiary care hospital in Bengaluru. Hospitalised children aged <18 years, with clinical features suggestive of rickettsial disease admitted between January 2010 and October 2012 were included prospectively. Diagnosis was based on scrub typhus and spotted fever-specific IgM and IgG by enzyme-linked immunosorbent assay (ELISA). Of 103 children with clinical features suggestive of rickettsial illness, ELISA test confirmed 53 cases for scrub typhus, 23 cases for spotted fever group and 14 with mixed infection. The average age was 7.3 (±3.9) years and 44 (71.0%) children were male. Majority of cases were from Karnataka (50%), Andhra Pradesh (32.3%) and Tamil Nadu (17.7%). Common clinical features included fever (100%, average duration 11 days), nausea and vomiting (44%), rash (36%); eschar was rare. Compared to the ELISA test, Weil-Felix test (OX-K titre of 1:80) had a sensitivity and specificity of 88.7% and 43.9%, respectively. Treatment with chloramphenicol or doxycycline was given to the majority of the children. Complications included meningoencephalitis (28%), shock (10%), retinal vasculitis (10%) and purpura fulminans (7%). These findings suggest that the burden of rickettsial infection among children in India is high, with a substantially high complication rate. Rickettsial-specific ELISA tests can help in early diagnosis and early institution of appropriate treatment that may prevent life-threatening complications.

Use of eschar swabbing for the molecular diagnosis and genotyping of Orientia tsutsugamushi causing scrub typhus in Quang Nam province, Vietnam

PubMed Central

Le Viet, Nhiem; Laroche, Maureen; Thi Pham, Hoa L.; Viet, Nho L.; Mediannikov, Oleg; Raoult, Didier; Parola, Philippe

2017-01-01

Background Scrub typhus is a rickettsiosis which is caused by Orientia tsutsugamushi and occurs throughout the Asia-Pacific region. Molecular diagnosis of rickettsioses using eschar swabs has recently emerged, and may be very useful for the diagnosis of these diseases in tropical settings. Methodology/Principal findings Quantitative polymerase chain reaction (qPCR) was used to detect O. tsutsugamushi DNA in whole blood and eschar swab specimens of 67 patients who were clinically suspected of scrub typhus in Quang Nam province, Vietnam. Among the 20 patients for whom both eschar and whole blood were obtained, 17 (85%) of the eschar specimens and 5 (25%) of the whole blood specimens tested positive for O. tsutsugamushi. Genetic analysis of the 56-kDa TSA gene sequences demonstrated that the 14 sequences obtained in this study, including 12 eschar swabs and 2 whole blood specimens, were related to 4 groups: Karp, Kawasaki, Gilliam (JG-v and TG-v) and TA716. The majority (9/14; 64.4%) of contemporary O. tsutsugamushi genotypes in Quang Nam province were related to the Karp group. Conclusions These results suggest that polyclonal antigen pools used for serological testing in the future should contain at least Karp, Kawasaki, Gilliam and TA716 antigens for Vietnamese patients, as well as patients who have traveled to Vietnam. qPCR after eschar swabbing should be considered for molecular diagnosis of scrub typhus in endemic patients as well as in travelers, since it is easy to perform and appears very useful for the rapid detection of Orientia tsutsugamushi in the early phase of infection. PMID:28241043

Mosaic vaccines elicit CD8+ T cell responses in monkeys that confer immune coverage of diverse HIV strains

DOE Office of Scientific and Technical Information (OSTI.GOV)

Fischer, Will; Korber, Bette

2009-01-01

Creation of a successful HIV vaccine will require the development of a strategy to generate cellular immunity with sufficient cross-clade breadth to deal with the extreme genetic diversity of the virus. Polyvalent mosaic immunogens derived from in silica recombination of natural strains of HIV are designed to induce cellular immune responses that maximally cover the sequence diversity of circulating virus isolates. Immunization of rhesus monkeys with plasmid DNA and recombinant vaccinia virus vaccine constructs expressing either consensus immunogens or polyvalent mosaic immunogens elicited a CD4+ T lymphocyte-biased response with comparably broad epitope-specific total T lymphocyte specificities. However, immunization with themore » mosaic immunogens induced HIV-specific CD8+ T lymphocyte responses with markedly greater depth and breadth. Therefore, the use of polyvalent mosaic immunogens is a promising strategy for a global vaccine for HIV.« less

Key points in evaluating immunogenicity of pandemic influenza vaccines: A lesson from immunogenicity studies of influenza A(H1N1)pdm09 vaccine.

PubMed

Ohfuji, Satoko; Kobayashi, Masayuki; Ide, Yuichiro; Egawa, Yumi; Saito, Tomoko; Kondo, Kyoko; Ito, Kazuya; Kase, Tetsuo; Maeda, Akiko; Fukushima, Wakaba; Hirota, Yoshio

2017-09-18

Immunogenicity studies on pandemic influenza vaccine are necessary to inform rapid development and implementation of a vaccine during a pandemic. Thus, strategies for immunogenicity assessment are required. To identify essential factors to consider when evaluating the immunogenicity of pandemic influenza vaccines using the experience in Japan with the influenza A(H1N1)pdm09 vaccine. We conducted a search of observational studies using PubMed and IchushiWeb. Search terms included "influenza vaccine AND (immunogenicity OR immune response) AND Japan AND (2009 OR pdm09) NOT review," and was limited to studies conducted in humans. A total of 33 articles were identified, of which 16 articles met the inclusion criteria. Immunogenicity of the commercially available influenza A(H1N1)pdm09 vaccine satisfied the international criteria for influenza vaccine immunogenicity in all study populations. The most remarkable immune response was observed in junior high school students, while the lowest immune response was observed in hematological malignancy patients. Similar to immunogenicity studies on seasonal influenza vaccines, factors such as patient background (e.g., age, underlying condition, pre-vaccination titer, body mass index, etc.) and study procedure (e.g., concurrent measurement of pre- and post-vaccination antibody titer, effects of infection during the study period) may have affected the assessment of immunogenicity to the influenza A(H1N1)pdm09 vaccine. In addition, prior vaccination with the seasonal influenza vaccine may inhibit antibody induction by the influenza A(H1N1)pdm09 vaccine. This review discusses factors and strategies that must be considered and addressed during immunogenicity assessments of pandemic influenza vaccines, which may provide useful information for future influenza pandemics. Copyright © 2017 The Author(s). Published by Elsevier Ltd.. All rights reserved.

Approaches to Mitigate the Unwanted Immunogenicity of Therapeutic Proteins during Drug Development.

PubMed

Salazar-Fontana, Laura I; Desai, Dharmesh D; Khan, Tarik A; Pillutla, Renuka C; Prior, Sandra; Ramakrishnan, Radha; Schneider, Jennifer; Joseph, Alexandra

2017-03-01

All biotherapeutics have the potential to induce an immune response. This immunological response is complex and, in addition to antibody formation, involves T cell activation and innate immune responses that could contribute to adverse effects. Integrated immunogenicity data analysis is crucial to understanding the possible clinical consequences of anti-drug antibody (ADA) responses. Because patient- and product-related factors can influence the immunogenicity of a therapeutic protein, a risk-based approach is recommended and followed by most drug developers to provide insight over the potential harm of unwanted ADA responses. This paper examines mitigation strategies currently implemented and novel under investigation approaches used by drug developers. The review describes immunomodulatory regimens used in the clinic to mitigate deleterious ADA responses to replacement therapies for deficiency syndromes, such as hemophilia A and B, and high risk classical infantile Pompe patients (e.g., cyclophosphamide, methotrexate, rituximab); novel in silico and in vitro prediction tools used to select candidates based on their immunogenicity potential (e.g., anti-CD52 antibody primary sequence and IFN beta-1a formulation); in vitro generation of tolerogenic antigen-presenting cells (APCs) to reduce ADA responses to factor VIII and IX in murine models of hemophilia; and selection of novel delivery systems to reduce in vivo ADA responses to highly immunogenic biotherapeutics (e.g., asparaginase). We conclude that mitigation strategies should be considered early in development for biotherapeutics based on our knowledge of existing clinical data for biotherapeutics and the immune response involved in the generation of these ADAs.

Development of an FHbp-CTB holotoxin-like chimera and the elicitation of bactericidal antibodies against serogroup B Neisseria meningitidis.

PubMed

Price, Gregory A; Bash, Margaret C

2018-01-29

The Neisseria meningitidis factor H binding protein (FHbp) is an important virulence factor and vaccine antigen contained in both USA licensed serogroup B meningococcal vaccines. Recent studies in human factor H (hFH) transgenic mice suggest that hFH-FHbp interactions lower FHbp-elicited immunogenicity. To provide tools with which to characterize and potentially improve FHbp immunogenicity, we developed an FHbp-cholera holotoxin-like chimera vaccine expression system in Escherichia coli that utilizes cholera toxin B (CTB) as both a scaffold and adjuvant for FHbp. We developed FHbp-CTB chimeras using a wild-type (WT) FHbp and a low hFH-binding FHbp mutant R41S. Both chimeras bound to G M1 ganglioside and were recognized by the FHbp-specific monoclonal antibody JAR4. The R41S mutant had greatly reduced hFH binding compared to the WT FHbp-CTB chimera. WT and R41S FHbp-CTB chimeric antigens were compared to equimolar amounts of FHbp admixed with CTB or FHbp alone in mouse immunogenicity studies. The chimeras were significantly more immunogenic than FHbp alone or mixed with CTB, and elicited bactericidal antibodies against a panel of MenB isolates. This study demonstrates a unique and simple method for studying FHbp immunogenicity. The chimeric approach may facilitate studies of other protein-based antigens targeting pathogenic Neisseria and lay groundwork for the development of new protein based vaccines against meningococcal and gonococcal disease. Published by Elsevier Ltd.

Accuracy of Conventional PCR Targeting the 16S rRNA Gene with the Ot-16sRF1 and Ot-16sRR1 Primers for Diagnosis of Scrub Typhus: a Case-Control Study

PubMed Central

Kim, Choon-Mee; Cho, Min Keun; Yun, Na-Ra; Kim, Seok Won; Jang, Sook Jin; Ahn, Young-Joon; Lim, Donghoon

2015-01-01

We retrospectively evaluated the accuracy of conventional PCR targeting the 16S rRNA gene (16S C-PCR) using the Ot-16sRF1/Ot-16sRR1 primers for diagnosing scrub typhus. The diagnosis of Orientia tsutsugamushi infection by 16S C-PCR presented an increased sensitivity of 87.0% and specificity of 100% compared with those obtained with other targets and is thus a simple and clinically useful method with good diagnostic accuracy. PMID:26491185

Revisiting doxycycline in pregnancy and early childhood--time to rebuild its reputation?

PubMed

Cross, Ruby; Ling, Clare; Day, Nicholas P J; McGready, Rose; Paris, Daniel H

2016-01-01

Doxycycline is highly effective, inexpensive with a broad therapeutic spectrum and exceptional bioavailability. However these benefits have been overshadowed by its classification alongside the tetracyclines - class D drugs, contraindicated in pregnancy and in children under 8 years of age. Doxycycline-treatable diseases are emerging as leading causes of undifferentiated febrile illness in Southeast Asia. For example scrub typhus and murine typhus have an unusually severe impact on pregnancy outcomes, and current mortality rates for scrub typhus reach 12-13% in India and Thailand. The emerging evidence for these important doxycycline-treatable diseases prompted us to revisit doxycycline usage in pregnancy and childhood. A systematic review of the available literature on doxycycline use in pregnant women and children revealed a safety profile of doxycycline that differed significantly from that of tetracycline; no correlation between the use of doxycycline and teratogenic effects during pregnancy or dental staining in children was found. The change of the US FDA pregnancy classification scheme to an evidence-based approach will enable adequate evaluation of doxycycline in common tropical illnesses and in vulnerable populations in clinical treatment trials, dosage-optimization pharmacokinetic studies and for the empirical treatment of undifferentiated febrile illnesses, especially in pregnant women and children.

T-cell dependent immunogenicity of protein therapeutics: Preclinical assessment and mitigation.

PubMed

Jawa, Vibha; Cousens, Leslie P; Awwad, Michel; Wakshull, Eric; Kropshofer, Harald; De Groot, Anne S

2013-12-01

Protein therapeutics hold a prominent and rapidly expanding place among medicinal products. Purified blood products, recombinant cytokines, growth factors, enzyme replacement factors, monoclonal antibodies, fusion proteins, and chimeric fusion proteins are all examples of therapeutic proteins that have been developed in the past few decades and approved for use in the treatment of human disease. Despite early belief that the fully human nature of these proteins would represent a significant advantage, adverse effects associated with immune responses to some biologic therapies have become a topic of some concern. As a result, drug developers are devising strategies to assess immune responses to protein therapeutics during both the preclinical and the clinical phases of development. While there are many factors that contribute to protein immunogenicity, T cell- (thymus-) dependent (Td) responses appear to play a critical role in the development of antibody responses to biologic therapeutics. A range of methodologies to predict and measure Td immune responses to protein drugs has been developed. This review will focus on the Td contribution to immunogenicity, summarizing current approaches for the prediction and measurement of T cell-dependent immune responses to protein biologics, discussing the advantages and limitations of these technologies, and suggesting a practical approach for assessing and mitigating Td immunogenicity. © 2013. Published by Elsevier Inc. All rights reserved.

Approaches to the induction of HIV broadly neutralizing antibodies.

PubMed

Moore, Penny L; Williamson, Carolyn

2016-11-01

A vaccine that elicits antibody responses that can neutralize the diversity of HIV clades has not yet been achieved, and is a major focus of HIV vaccine research. Here, we provide an update on the barriers to eliciting such antibodies, and how advances in immunogen design may circumvent these roadblocks, focusing on data published in the last year. Studies of how broadly neutralizing antibodies (bNAbs) develop in HIV-infected donors continue to produce key insights, suggesting that for some viral targets there are common pathways to developing breadth. Germline-targeting strategies, that aim to recruit rare precursors of bNAbs, have shown promise in immunogenicity studies, and structural biology has led to advances in immunogen design. Mapping of strain-specific tier 2 vaccine responses has highlighted the challenges that remain in driving antibodies toward breadth. Elucidation of the HIV envelope structure, together with an understanding of how bNAbs emerge in vivo has guided the design of new immunogens and vaccine strategies that show promise for eliciting protective antibodies.

Immunogenicity of HPV prophylactic vaccines: Serology assays and their use in HPV vaccine evaluation and development.

PubMed

Pinto, Ligia A; Dillner, Joakim; Beddows, Simon; Unger, Elizabeth R

2018-01-17

When administered as standard three-dose schedules, the licensed HPV prophylactic vaccines have demonstrated extraordinary immunogenicity and efficacy. We summarize the immunogenicity of these licensed vaccines and the most commonly used serology assays, with a focus on key considerations for one-dose vaccine schedules. Although immune correlates of protection against infection are not entirely clear, both preclinical and clinical evidence point to neutralizing antibodies as the principal mechanism of protection. Thus, immunogenicity assessments in vaccine trials have focused on measurements of antibody responses to the vaccine. Non-inferiority of antibody responses after two doses of HPV vaccines separated by 6 months has been demonstrated and this evidence supported the recent WHO recommendations for two-dose vaccination schedules in both boys and girls 9-14 years of age. There is also some evidence suggesting that one dose of HPV vaccines may provide protection similar to the currently recommended two-dose regimens but robust data on efficacy and immunogenicity of one-dose vaccine schedules are lacking. In addition, immunogenicity has been assessed and reported using different methods, precluding direct comparison of results between different studies and vaccines. New head-to-head vaccine trials evaluating one-dose immunogenicity and efficacy have been initiated and an increase in the number of trials relying on immunobridging is anticipated. Therefore, standardized measurement and reporting of immunogenicity for the up to nine HPV types targeted by the current vaccines is now critical. Building on previous HPV serology assay standardization and harmonization efforts initiated by the WHO HPV LabNet in 2006, new secondary standards, critical reference reagents and testing guidelines will be generated as part of a new partnership to facilitate harmonization of the immunogenicity testing in new HPV vaccine trials. Copyright © 2018 Elsevier Ltd. All rights reserved.

Multivalent Immunogenic Vaccines for Treating Prostate and Breast Cancer | NCI Technology Transfer Center | TTC

Cancer.gov

Researchers at the NCI have developed a treatment for prostate and breast cancer using multivalent peptides derived from TARP, the T cell receptor gamma alternate reading frame protein. These immunogenic peptides from TARP elicit an immune response, triggering T cells to kill only the cancer cells within a patient. NCI seeks licensees or co-development partners to commercialize this invention.

Reporting, Visualization, and Modeling of Immunogenicity Data to Assess Its Impact on Pharmacokinetics, Efficacy, and Safety of Monoclonal Antibodies.

PubMed

Passey, Chaitali; Suryawanshi, Satyendra; Sanghavi, Kinjal; Gupta, Manish

2018-02-26

The rapidly increasing number of therapeutic biologics in development has led to a growing recognition of the need for improvements in immunogenicity assessment. Published data are often inadequate to assess the impact of an antidrug antibody (ADA) on pharmacokinetics, safety, and efficacy, and enable a fully informed decision about patient management in the event of ADA development. The recent introduction of detailed regulatory guidance for industry should help address many past inadequacies in immunogenicity assessment. Nonetheless, careful analysis of gathered data and clear reporting of results are critical to a full understanding of the clinical relevance of ADAs, but have not been widely considered in published literature to date. Here, we review visualization and modeling of immunogenicity data. We present several relatively simple visualization techniques that can provide preliminary information about the kinetics and magnitude of ADA responses, and their impact on pharmacokinetics and clinical endpoints for a given therapeutic protein. We focus on individual sample- and patient-level data, which can be used to build a picture of any trends, thereby guiding analysis of the overall study population. We also discuss methods for modeling ADA data to investigate the impact of immunogenicity on pharmacokinetics, efficacy, and safety.

Identification of immunogenic proteins and evaluation of four recombinant proteins as potential vaccine antigens from Vibrio anguillarum in flounder (Paralichthys olivaceus).

PubMed

Xing, Jing; Xu, Hongsen; Wang, Yang; Tang, Xiaoqian; Sheng, Xiuzhen; Zhan, Wenbin

2017-05-31

Vibrio anguillarum is a severe bacterial pathogen that can infect a wide range of fish species. Identification of immunogenic proteins and development of vaccine are essential for disease prevention. In this study, immunogenic proteins were screened and identified from V. anguillarum, and then protective efficacy of the immunogenic proteins was evaluated. Immunogenic proteins in V. anguillarum whole cell were detected by Western blotting (WB) using immunized flounder (Paralichthys olivaceus) serum, and then identified by Mass spectrometry (MS). The recombinant proteins of four identified immunogenic proteins were produced and immunized to fish, and then percentages of surface membrane immunoglobulin-positive (sIg+) cells in peripheral blood lymphocytes (PBL), total antibodies, antibodies against V. anguillarum, antibodies against recombinant proteins and relative percent survival (RPS) were measured, respectively. The results showed that five immunogenic proteins, VAA, Groel, OmpU, PteF and SpK, were identified; their recombinant proteins, rOmpU, rGroel, rSpK and rVAA, could induce the proliferation of sIg+ cells in PBL and production of total antibodies, antibodies against V. anguillarum and antibodies against the recombinant proteins; their protection against V. anguillarum showed 64.86%, 72.97%, 21.62% and 78.38% RPS, respectively. The results revealed that the immunoproteomic technique using fish anti-V. anguillarum serum provided an efficient way to screen the immunogenic protein for vaccine antigen. Moreover, the rVAA, rGroel and rOmpU had potential to be vaccine candidates against V. anguillarum infection. Copyright © 2017 Elsevier Ltd. All rights reserved.

THE EFFECT OF X-RAY IRRADIATION ON THE RESISTANCE OF WHITE MICE TO B. TYPHI ABDOMINALIS (in Russian)

DOE Office of Scientific and Technical Information (OSTI.GOV)

Alexeva, O.G.

1957-01-01

White mice were sensitized by intraperitoneal injection of 2.5 million B. typhi abdominalis Felix Ty/sub 2/ or 50 million B. dysenteria Flexner No. 26-w. Four days later they were subjected to total x-ray irradiation with a LD 10/13 dose (300 r). Experiments on 250 mice showed that in irradiated mice the biologic effect of a sensibilizing dose increases from DL 18/13 to DL 48/13 for typhus and from DL 3/13 to DL24/13 for dysentery. Mice sensitized with B. typhus abdominalis and irradiated died after periods typical for radiation sickness, but developed also bacteriemia pointing to a complicated pathologic process. Themore » degree of active antityphus immunization developed after sensibilization by the stated method was determined by intraperitoneal inoculation of 2 DCL (200 million) on the 1, 3, 5, 7, 10, 20, 30 day after irradiation with 300r. Experiments on 600 mice have shown that the earlier developed immunity does not change during the first days of radiation sickness. During the III period of radiation sickness (3-1Oth days) and in the reparation period (20--30th days) the survival of experimental mice is 40--45% less than of the unirradiated controls. The reduced tension of active immunity is also manifested by inhibition of phagocytosis in vivo, accumulation of enormous amounts of bacteria in the place of injection, and, protracted bacteriemia. (tr-auth)« less

Molecular evidence of Rickettsia typhi infection in dogs from a rural community in Yucatán, México.

PubMed

Martínez-Ortiz, Daly; Torres-Castro, Marco; Koyoc-Cardeña, Edgar; López, Karina; Panti-May, Alonso; Rodríguez-Vivas, Iván; Puc, Adriano; Dzul, Karla; Zavala-Castro, Jorge; Medina-Barreiro, Anuar; Chablé-Santos, Juan; Manrique-Saide, Pablo

2016-02-23

Rickettsia typhi causes murine or endemic typhus, which is transmitted to humans primarily through flea bites contaminated with feces. Synanthropic and domestic animals also contribute to the infection cycle of R. typhi. Cases of murine typhus in humans were reported in the rural community of Bolmay, Yucatán, México, between 2007 and 2010.  To identify the presence of R. typhi and estimate the frequency of infection in dogs from Bolmay, México, a locality with previous reports of murine typhus in humans.  Whole blood samples were taken from 128 dogs. Total DNA was extracted for use in the polymerase chain reaction (PCR) to amplify fragments of the 17 kDa and omp B genes and confirms the presence of Rickettsia spp. The reaction products were sequenced, and alignment analysis was performed using the BLAST tool.  The frequency of R. typhi infection in dogs was 5.5 % (7/128). The alignment identified 99% and 100% homology to the R. typhi 17 kDa and omp B genes, respectively.  We confirmed the presence of R. typhi in dogs in the studied community but at a low frequency. However, there is potential risk of transmission to humans.

Jakub Penson and his studies on acute renal failure during typhus epidemics in Warsaw Ghetto.

PubMed

Rutkowski, Boleslaw

2004-01-01

In the Warsaw Ghetto established by the German Nazis as a special district for Polish Jews in 1940 there were two typhus epidemics. Many patients affected by this disease (1500 during the first and 6500 during second epidemic) were treated at The Department of Infectious Disease of Czyste Hospital headed by Dr Jakub Penson--a Polish physician of Jewish origin. A heroic group of 20 physicians not only treated patients in these tragic circumstances, but also performed in defiance of Nazi prohibition, scientific studies on the clinical course of typhus with special attention on hyperazotemia and renal complication. The results of their observations were presented in 1941-42 during clinical meetings in Czyste Hospital and later published by Penson in 1946 in the Polish Physicians Weekly. Among other clinical statements a description of acute renal failure of extrarenal origin, caused by dehydration and toxic influence of primary disease seems the most important one. It has to be taken into account that acute renal failure appearing during Crush Syndrome was described by Bywaters in 1941. Jakub Penson survived the German Nazi occupation and later become a head of the Internal Medicine Department in Gdansk Medical University and one of the precursors of clinical nephrology in Poland.

Revisiting doxycycline in pregnancy and early childhood – time to rebuild its reputation?

PubMed Central

Cross, Ruby; Ling, Clare; Day, Nicholas P. J.; McGready, Rose; Paris, Daniel H.

2016-01-01

ABSTRACT Introduction: Doxycycline is highly effective, inexpensive with a broad therapeutic spectrum and exceptional bioavailability. However these benefits have been overshadowed by its classification alongside the tetracyclines – class D drugs, contraindicated in pregnancy and in children under 8 years of age. Doxycycline-treatable diseases are emerging as leading causes of undifferentiated febrile illness in Southeast Asia. For example scrub typhus and murine typhus have an unusually severe impact on pregnancy outcomes, and current mortality rates for scrub typhus reach 12-13% in India and Thailand. The emerging evidence for these important doxycycline-treatable diseases prompted us to revisit doxycycline usage in pregnancy and childhood. Areas Covered: A systematic review of the available literature on doxycycline use in pregnant women and children revealed a safety profile of doxycycline that differed significantly from that of tetracycline; no correlation between the use of doxycycline and teratogenic effects during pregnancy or dental staining in children was found. Expert Opinion: The change of the US FDA pregnancy classification scheme to an evidence-based approach will enable adequate evaluation of doxycycline in common tropical illnesses and in vulnerable populations in clinical treatment trials, dosage-optimization pharmacokinetic studies and for the empirical treatment of undifferentiated febrile illnesses, especially in pregnant women and children. PMID:26680308

Molecular Pathogenesis of Rickettsioses and Development of Novel Anti-Rickettsia Treatment by Comginatorial Peptide-Based Libraries

DTIC Science & Technology

2005-02-01

in many parts of the world and include Rocky Mountain spotted fever (the most common rickettsiosis in the US), epidemic and endemic typhus (1-4). The... Mountain spotted fever and other rickettsioses. In: Schaecter M, Engleberg NC, Eisenstein BI, MedoffG, editors. Mechanisms of microbial disease. Baltimore...Brouqui P, editors. Rickettsiae and rickettsial diseases at the turn of the millenium. Paris: Elsevier; 1999. p. 274-277. 3. Walker DH. Rocky

Protection of Military Personnel Against Vector-Borne Diseases: A Review of Collaborative Work of the Australian and US Military Over the Last 30 Years.

PubMed

Frances, Stephen P; Edstein, Michael D; Debboun, Mustapha; Shanks, G Dennis

2016-01-01

Australian and US military medical services have collaborated since World War II to minimize vector-borne diseases such as malaria, dengue, and scrub typhus. In this review, collaboration over the last 30 years is discussed. The collaborative projects and exchange scientist programs have resulted in mutually beneficial outcomes in the fields of drug development and personal protection measures against vector-borne diseases.

[Dr. Elizabeth Ross: heroine and victim of the World War I in Serbia].

PubMed

Mikić, Želimir; Lešić, Aleksandar

2012-01-01

At the beginning of 1915, several months after the World War I started, Serbia was in an extremely difficult situation.The country was war-ravaged, full of sick and wounded soldiers, there was a desperate shortage of doctors, nurses and other medical personnel, and the epidemic of typhus fever exploded and violently attacked the entire country. At that time, however, a number of both foreign allied medical missions and individual volunteers, from various countries, mostly from Great Britain, came to Serbia to help. Among them mostly were women, and they were of enormous support to Serbia in that grave situation. It is estimated that there were more than 600 foreign women volunteers in Serbia at that time and that 22 of them died there. Dr. Elizabeth Ross was one of those brave volunteers who came to Serbia early in 1915. That noble Scottish lady doctor was born in 1878 and finished her medical studies at the University of Glasgow in 1901. After graduation she worked in various places in Great Britain until 1909, when she went to Persia (Iran), where she worked until the beginning of the so called Great War. When she heard of the urgent need in Serbia she left Persia as soon as she could and volunteered to serve in Serbia. She came to Kragujevac at the beginning of January 1915, where she worked at the First Military Reserve Hospital, which at that time was actually a typhus hospital. Working there intensively and devotedly for several weeks under shocking conditions she contracted typhus herself and died there on her 37th birthday on February 14th, 1915. She was buried in Kragujevac, next to two British ladies who also died in Serbia of typhus. Her grave was restored in 1980 when the town of Kragujevac started holding commemorations at the graveside every February 14th at noon to honor her and all other brave and noble women who lost their lives helping Serbia at that unfortunate time.

Antibody prevalence and factors associated with exposure to Orientia tsutsugamushi in different aboriginal subgroups in West Malaysia.

PubMed

Tay, Sun Tee; Mohamed Zan, Hafizatul Anis; Lim, Yvonne A L; Ngui, Romano

2013-01-01

Limited data is available on the current status of scrub typhus infection in the aboriginal population in Malaysia. This study was aimed to provide recent data on the degree of exposure of 280 individuals from seven aboriginal subgroups to Orientia tsutsugamushi (causative agent of scrub typhus) in West Malaysia. The environment, socioeconomic and behavioural risk factors associated with the disease were also investigated. The antibody prevalence to O. tsutsugamushi ranged from 0 to 36.4% in seven subgroups, with high prevalence rates noted in subgroups involved in agricultural activity and the lowest prevalence rates noted in subgroups whose main occupations were associated to fishing. Univariate analysis indicated populations with age above 18 years (OR = 1.15, 95% CI = 1.02-1.30, P = 0.015), working (OR = 1.99, 95% CI = 1.01-3.92, P = 0.044), working at agriculture area (OR = 1.18, 95% CI = 0.98-1.42, P = 0.031), receiving household income less than US$ 166.7 (RM500) per month (OR = 2.43, 95% CI = 1.16-5.11, P = 0.016) and having close contact with animal pets (OR = 4.06, 95% CI = 1.20-13.76, P = 0.016) are significantly associated with exposure to O. tsutsugamushi. Multivariate analysis confirms that participants who are above 18 years old, receiving household income less than US$ 166.7 (RM500) per month and having close contact with animal pets are 3.6 times (95% CI = 1.81-7.03, P<0.001), 1.3 times (95% CI = 1.14-1.64, P = 0.002) and 1.2 times (95% CI = 1.05-1.06, P = 0.006) more likely to have exposure to O. tsutsugamushi, respectively. The present study indicates that scrub typhus is still an important disease in the aboriginal population in Malaysia. Awareness about the disease and education on the preventive measures are important in reducing the risk of acquiring scrub typhus in the population studied.

High seroprevalence of Mycoplasma pneumoniae IgM in acute Q fever by enzyme-linked immunosorbent assay (ELISA).

PubMed

Lai, Chung-Hsu; Chang, Lin-Li; Lin, Jiun-Nong; Chen, Wei-Fang; Kuo, Li-Li; Lin, Hsi-Hsun; Chen, Yen-Hsu

2013-01-01

Q fever is serologically cross-reactive with other intracellular microorganisms. However, studies of the serological status of Mycoplasma pneumoniae and Chlamydophila pneumoniae during Q fever are rare. We conducted a retrospective serological study of M. pneumoniae and C. pneumoniae by enzyme-linked immunosorbent assay (ELISA), a method widely used in clinical practice, in 102 cases of acute Q fever, 39 cases of scrub typhus, and 14 cases of murine typhus. The seropositive (57.8%, 7.7%, and 0%, p<0.001) and seroconversion rates (50.6%, 8.8%, and 0%, p<0.001) of M. pneumoniae IgM, but not M. pneumoniae IgG and C. pneumoniae IgG/IgM, in acute Q fever were significantly higher than in scrub typhus and murine typhus. Another ELISA kit also revealed a high seropositivity (49.5%) and seroconversion rate (33.3%) of M. pneumoniae IgM in acute Q fever. The temporal and age distributions of patients with positive M. pneumoniae IgM were not typical of M. pneumoniae pneumonia. Comparing acute Q fever patients who were positive for M. pneumoniae IgM (59 cases) with those who were negative (43 cases), the demographic characteristics and underlying diseases were not different. In addition, the clinical manifestations associated with atypical pneumonia, including headache (71.2% vs. 81.4%, p=0.255), sore throat (8.5% vs. 16.3%, p=0.351), cough (35.6% vs. 23.3%, p=0.199), and chest x-ray suggesting pneumonia (19.3% vs. 9.5%, p=0.258), were unchanged between the two groups. Clinicians should be aware of the high seroprevalence of M. pneumoniae IgM in acute Q fever, particularly with ELISA kits, which can lead to misdiagnosis, overestimations of the prevalence of M. pneumoniae pneumonia, and underestimations of the true prevalence of Q fever pneumonia.

High Seroprevalence of Mycoplasma pneumoniae IgM in Acute Q Fever by Enzyme-Linked Immunosorbent Assay (ELISA)

PubMed Central

Lai, Chung-Hsu; Chang, Lin-Li; Lin, Jiun-Nong; Chen, Wei-Fang; Kuo, Li-Li; Lin, Hsi-Hsun; Chen, Yen-Hsu

2013-01-01

Q fever is serologically cross-reactive with other intracellular microorganisms. However, studies of the serological status of Mycoplasma pneumoniae and Chlamydophila pneumoniae during Q fever are rare. We conducted a retrospective serological study of M. pneumoniae and C. pneumoniae by enzyme-linked immunosorbent assay (ELISA), a method widely used in clinical practice, in 102 cases of acute Q fever, 39 cases of scrub typhus, and 14 cases of murine typhus. The seropositive (57.8%, 7.7%, and 0%, p<0.001) and seroconversion rates (50.6%, 8.8%, and 0%, p<0.001) of M. pneumoniae IgM, but not M. pneumoniae IgG and C. pneumoniae IgG/IgM, in acute Q fever were significantly higher than in scrub typhus and murine typhus. Another ELISA kit also revealed a high seropositivity (49.5%) and seroconversion rate (33.3%) of M. pneumoniae IgM in acute Q fever. The temporal and age distributions of patients with positive M. pneumoniae IgM were not typical of M. pneumoniae pneumonia. Comparing acute Q fever patients who were positive for M. pneumoniae IgM (59 cases) with those who were negative (43 cases), the demographic characteristics and underlying diseases were not different. In addition, the clinical manifestations associated with atypical pneumonia, including headache (71.2% vs. 81.4%, p=0.255), sore throat (8.5% vs. 16.3%, p=0.351), cough (35.6% vs. 23.3%, p=0.199), and chest x-ray suggesting pneumonia (19.3% vs. 9.5%, p=0.258), were unchanged between the two groups. Clinicians should be aware of the high seroprevalence of M. pneumoniae IgM in acute Q fever, particularly with ELISA kits, which can lead to misdiagnosis, overestimations of the prevalence of M. pneumoniae pneumonia, and underestimations of the true prevalence of Q fever pneumonia. PMID:24147043

New Genotypes of Orientia tsutsugamushi Isolated from Humans in Eastern Taiwan

PubMed Central

Lin, Chin-Hui; Chen, Tren-Yi; Chen, Li-Kuang

2012-01-01

Scrub typhus, an acute febrile illness, is caused by the obligate intracellular bacterium Orientia tsutsugamushi. In our study, O. tsutsugamushi was rapidly detected and typed by polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP) analysis of the 56-kDa type-specific antigen (TSA) gene. To investigate the genotypes of clinical variants of O. tsutsugamushi, we collected 3223 blood samples from eastern Taiwanese patients with suspected scrub typhus from 2002 to 2008. In total, 505 samples were found to be positive for scrub typhus infection by PCR, and bacteria were isolated from 282 of them. Four prototype genotype strains (Karp, Kato, Kawasaki and Gilliam) and eleven different Taiwanese genotype isolates (Taiwan-A, -B, -C, -D, -E, -G, -H, -J, -N, -O and -P) were identified by RPLF analysis. Taiwan-H, the major genotype in eastern Taiwan, exhibited prevalence and isolation rates of 47.3% (239/505) and 42.6% (120/282), respectively. We also assessed the genetic relatedness of the 56-kDa TSA gene among eight Taiwan-H isolates, thirteen other Taiwanese isolates and 104 DNA sequences deposited in the GenBank database using MEGA version 5.0 and PHYLIP version 3.66. We found that the Taiwan-H isolates formed into a new cluster, which was designated the Taiwan Gilliam-variant (TG-v) cluster to distinguish it from the Japanese Gilliam-variant (JG-v) cluster. According to Simplot analysis, TG-v is a new recombinant strain among Gilliam, Ikeda and Kato. Moreover, the Gilliam-Kawasaki cluster had the highest percentage of RFLP cases and was the most frequently isolated type in eastern Taiwan (50.1%, 253/505; 44.0%, 124/282). These findings shed light on the genetic evolution of O. tsutsugamushi into different strains and may be useful in vaccine development and epidemic disease control in the future. PMID:23071693

Oligopeptide M13 Phage Display in Pathogen Research

PubMed Central

Kügler, Jonas; Zantow, Jonas; Meyer, Torsten; Hust, Michael

2013-01-01

Phage display has become an established, widely used method for selection of peptides, antibodies or alternative scaffolds. The use of phage display for the selection of antigens from genomic or cDNA libraries of pathogens which is an alternative to the classical way of identifying immunogenic proteins is not well-known. In recent years several new applications for oligopeptide phage display in disease related fields have been developed which has led to the identification of various new antigens. These novel identified immunogenic proteins provide new insights into host pathogen interactions and can be used for the development of new diagnostic tests and vaccines. In this review we focus on the M13 oligopeptide phage display system for pathogen research but will also give examples for lambda phage display and for applications in other disease related fields. In addition, a detailed technical work flow for the identification of immunogenic oligopeptides using the pHORF system is given. The described identification of immunogenic proteins of pathogens using oligopeptide phage display can be linked to antibody phage display resulting in a vaccine pipeline. PMID:24136040

Oligopeptide m13 phage display in pathogen research.

PubMed

Kügler, Jonas; Zantow, Jonas; Meyer, Torsten; Hust, Michael

2013-10-16

Phage display has become an established, widely used method for selection of peptides, antibodies or alternative scaffolds. The use of phage display for the selection of antigens from genomic or cDNA libraries of pathogens which is an alternative to the classical way of identifying immunogenic proteins is not well-known. In recent years several new applications for oligopeptide phage display in disease related fields have been developed which has led to the identification of various new antigens. These novel identified immunogenic proteins provide new insights into host pathogen interactions and can be used for the development of new diagnostic tests and vaccines. In this review we focus on the M13 oligopeptide phage display system for pathogen research but will also give examples for lambda phage display and for applications in other disease related fields. In addition, a detailed technical work flow for the identification of immunogenic oligopeptides using the pHORF system is given. The described identification of immunogenic proteins of pathogens using oligopeptide phage display can be linked to antibody phage display resulting in a vaccine pipeline.

Elicitation of Robust Tier 2 Neutralizing Antibody Responses in Nonhuman Primates by HIV Envelope Trimer Immunization Using Optimized Approaches.

PubMed

Pauthner, Matthias; Havenar-Daughton, Colin; Sok, Devin; Nkolola, Joseph P; Bastidas, Raiza; Boopathy, Archana V; Carnathan, Diane G; Chandrashekar, Abishek; Cirelli, Kimberly M; Cottrell, Christopher A; Eroshkin, Alexey M; Guenaga, Javier; Kaushik, Kirti; Kulp, Daniel W; Liu, Jinyan; McCoy, Laura E; Oom, Aaron L; Ozorowski, Gabriel; Post, Kai W; Sharma, Shailendra K; Steichen, Jon M; de Taeye, Steven W; Tokatlian, Talar; Torrents de la Peña, Alba; Butera, Salvatore T; LaBranche, Celia C; Montefiori, David C; Silvestri, Guido; Wilson, Ian A; Irvine, Darrell J; Sanders, Rogier W; Schief, William R; Ward, Andrew B; Wyatt, Richard T; Barouch, Dan H; Crotty, Shane; Burton, Dennis R

2017-06-20

The development of stabilized recombinant HIV envelope trimers that mimic the virion surface molecule has increased enthusiasm for a neutralizing antibody (nAb)-based HIV vaccine. However, there is limited experience with recombinant trimers as immunogens in nonhuman primates, which are typically used as a model for humans. Here, we tested multiple immunogens and immunization strategies head-to-head to determine their impact on the quantity, quality, and kinetics of autologous tier 2 nAb development. A bilateral, adjuvanted, subcutaneous immunization protocol induced reproducible tier 2 nAb responses after only two immunizations 8 weeks apart, and these were further enhanced by a third immunization with BG505 SOSIP trimer. We identified immunogens that minimized non-neutralizing V3 responses and demonstrated that continuous immunogen delivery could enhance nAb responses. nAb responses were strongly associated with germinal center reactions, as assessed by lymph node fine needle aspiration. This study provides a framework for preclinical and clinical vaccine studies targeting nAb elicitation. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

Using Fitness Landscapes for Rational Hepatitis C Immunogen Design

NASA Astrophysics Data System (ADS)

Hart, Gregory; Ferguson, Andrew

2015-03-01

Hepatitis C virus afflicts 170 million people worldwide, 2-3% of the global population. Prophylactic vaccination offers the most realistic and cost effective hope of controlling this epidemic, particularly in the developing world where expensive drug therapies are unavailable. Despite 20 years of research, the high mutability of the virus, and lack of knowledge of what constitutes effective immune responses, have impeded development of an effective vaccine. Coupling data mining of sequence databases with the Potts model, we have developed a computational approach to systematically identify viral vulnerabilities and perform rational design of vaccine immunogens. We applied our approach to the nonstructural proteins NS3, NSA, NSA, and NSB which are crucial for viral replication.The predictions of our model are in good accord with experimental measurements and clinical observations, and we have used our model to design immunogen candidates to elicit T-cell responses against vulnerable regions of theseviral proteins.

Immunogenicity of biologically-derived therapeutics: assessment and interpretation of nonclinical safety studies.

PubMed

Ponce, Rafael; Abad, Leslie; Amaravadi, Lakshmi; Gelzleichter, Thomas; Gore, Elizabeth; Green, James; Gupta, Shalini; Herzyk, Danuta; Hurst, Christopher; Ivens, Inge A; Kawabata, Thomas; Maier, Curtis; Mounho, Barbara; Rup, Bonita; Shankar, Gopi; Smith, Holly; Thomas, Peter; Wierda, Dan

2009-07-01

An evaluation of potential antibody formation to biologic therapeutics during the course of nonclinical safety studies and its impact on the toxicity profile is expected under current regulatory guidance and is accepted standard practice. However, approaches for incorporating this information in the interpretation of nonclinical safety studies are not clearly established. Described here are the immunological basis of anti-drug antibody formation to biopharmaceuticals (immunogenicity) in laboratory animals, and approaches for generating and interpreting immunogenicity data from nonclinical safety studies of biotechnology-derived therapeutics to support their progression to clinical evaluation. We subscribe that immunogenicity testing strategies should be adapted to the specific needs of each therapeutic development program, and data generated from such analyses should be integrated with available clinical and anatomic pathology, pharmacokinetic, and pharmacodynamic data to properly interpret nonclinical studies.

[Analysis of epidemic features of scrub typhus between year 2006 and 2010 in Shandong province, China].

PubMed

Ding, Lei; Li, Zhong; Wang, Xian-jun; Ding, Shu-jun; Zhang, Meng; Zhao, Zhong-tang

2012-04-01

To explore the epidemic features of scrub typhus between year 2006 and 2010 in Shandong Province. Based on the data collected through Diseases Reporting Information System between year 2006 and 2010 in Shandong province, 1291 cases of scrub typhus were selected. The study described the population distribution features of the scrub typhus patients, and explored the temporal and spatial distribution features of the disease by applying the methods of spatial thematic mapping, inverse distance weighted, spatial autocorrelation analysis, spatial clustering analysis, temporal clustering analysis and spatial variation analysis in temporal trends based on Geographic Information software (ArcGIS 9.3) and Spatial Clustering Software (SatScan 7.0). The onset age of the 1291 patients ranged between 1 and 92 years old.639 out of 1291 patients were over 55 years old, accounting for 49.5%.640 patients were male and the other 651 patients were female, occupying 49.6% and 50.4% respectively. The gender ratio was 1:1.02. Patients were found in farmers, workers, students and preschool children. However, most of the cases were farmers, up to 84.8% (1095/1291). Global Moran's I index was 0.324 (P < 0.01). The local Moran's I index in 8 locations were proved to have statistical significance (P < 0.01); all of which were H-H clustering areas. Gangcheng (38 cases), Laicheng (154 cases), Xintai (160 cases) and Donggang (105 cases) were important locations, whose local Moran's I index were 2.111, 1.642, 1.277 and 0.775 respectively. The clustering period of scrub typhus in respective year were as follows: 2006.09.23 - 2006.11.20 (202 cases), 2007.10.02 - 2007.11.11 (197 cases), 2008.09.30 - 2008.11.07 (302 cases), 2009.09.25 - 2009.11.10 (204 cases), and 2010.10.05 - 2010.11.13 (226 cases), whose RR values were separately 45.55, 34.60, 50.64, 53.09 and 79.84 (P < 0.01). Two spatial clustering area were found in the study, one was the area centered Taian and Xintai with radiation radius at 58.28 km (542 cases) and the other one was the area centered Rizhao and Donggang with radiation radius at 22.68 km (134 cases), whose RR values were 4.52 and 3.96 (P < 0.01). The spatial features of the two clustering areas were inland low hills area and coastal hills area. The highest annual growth rate of the disease was 45.04%, found in the area centered Linyi and Mengyin counties, with the radiation radius at 45.82 km. The RR value was 3.68 (P < 0.01). The majority of the scrub typhus patients were middle-aged and elderly farmers. The epidemic peak was between the last 10 days of September and the first 10 days of November. A positive spatial correlation of the disease was found; and most cases clustered in inland low hills area and costal hills area; especially the area around Linyi and Mengyin, with the highest annual growth rates of the disease.

Can dendritic cells improve whole cancer cell vaccines based on immunogenically killed cancer cells?

PubMed Central

Cicchelero, Laetitia; Denies, Sofie; Devriendt, Bert; de Rooster, Hilde; Sanders, Niek N

2015-01-01

Immunogenic cell death (ICD) offers interesting opportunities in cancer cell (CC) vaccine manufacture, as it increases the immunogenicity of the dead CC. Furthermore, fusion of CCs with dendritic cells (DCs) is considered a superior method for generating whole CC vaccines. Therefore, in this work, we determined in naive mice whether immunogenically killed CCs per se (CC vaccine) elicit an antitumoral immune response different from the response observed when immunogenically killed CCs are associated with DCs through fusion (fusion vaccine) or through co-incubation (co-incubation vaccine). After tumor inoculation, the type of immune response in the prophylactically vaccinated mice differed between the groups. In more detail, fusion vaccines elicited a humoral anticancer response, whereas the co-incubation and CC vaccine mainly induced a cellular response. Despite these differences, all three approaches offered a prophylactic protection against tumor development in the murine mammary carcinoma model. In summary, it can be concluded that whole CC vaccines based on immunogenically killed CCs may not necessarily require association with DCs to elicit a protective anticancer immune response. If this finding can be endorsed in other cancer models, the manufacture of CC vaccines would greatly benefit from this new insight, as production of DC-based vaccines is laborious, time-consuming and expensive. PMID:26587315

Preclinical evaluation of a Haemophilus influenzae type b conjugate vaccine process intended for technology transfer.

PubMed

Hamidi, Ahd; Verdijk, Pauline; Kreeftenberg, Hans

2014-01-01

Introduction of Haemophilus influenzae type b (Hib) vaccine in low- and middle-income countries has been limited by cost and availability of Hib conjugate vaccines for a long time. It was previously recognized by the Institute for Translational Vaccinology (Intravacc, originating from the former Vaccinology Unit of the National Institute of Public Health [RIVM] and the Netherlands Vaccine Institute [NVI]) that local production of a Hib conjugate vaccine would increase the affordability and sustainability of the vaccine and thereby help to speed up Hib introduction in these countries. A new affordable and a non-infringing production process for a Hib conjugate vaccine was developed, including relevant quality control tests, and the technology was transferred to a number of vaccine manufacturers in India, Indonesia, and China. As part of the Hib technology transfer project managed by Intravacc, a preclinical toxicity study was conducted in the Netherlands to test the safety and immunogenicity of this new Hib conjugate vaccine. The data generated by this study were used by the technology transfer partners to accelerate the clinical development of the new Hib conjugate vaccine. A repeated dose toxicity and local tolerance study in rats was performed to assess the reactogenicity and immunogenicity of a new Hib conjugate vaccine compared to a licensed vaccine. The results showed that the vaccine was well tolerated and immunogenic in rats, no major differences in both safety and immunogenicity in rats were found between the vaccine produced according to the production process developed by Intravacc and the licensed one. Rats may be useful to verify the immunogenicity of Hib conjugate vaccines and for preclinical evaluation. In general, nonclinical evaluation of the new Hib conjugate vaccine, including this proof of concept (safety and immunogenicity study in rats), made it possible for technology transfer partners, having implemented the original process with no changes in the manufacturing process and vaccine formulation, to start directly with phase 1 clinical trials.

Immunogenicity of biologics in inflammatory bowel disease

PubMed Central

Vermeire, Séverine; Gils, Ann; Accossato, Paola; Lula, Sadiq; Marren, Amy

2018-01-01

Crohn’s disease and ulcerative colitis are chronic inflammatory disorders of the gastrointestinal tract. Treatment options include biologic therapies; however, a proportion of patients lose response to biologics, partly due to the formation of anti-drug antibodies (ADAbs). Concomitant immunosuppressive agents reduce the development of ADAbs. This review article aims to assess the immunogenicity of biologic therapies and their clinical implications. A comprehensive literature search was conducted for articles published January 2009 to August 2015 reporting immunogenicity to adalimumab (ADM), certolizumab pegol (CZP), golimumab, infliximab (IFX), ustekinumab, and vedolizumab in inflammatory bowel disease (IBD). Eligible articles were reviewed and quality assessed by independent reviewers. Overall, 122 publications reporting 114 studies were assessed. ADAbs were reported for all agents, but the percentage of patients developing ADAbs was extremely variable, with the highest (65.3%) being for IFX administration to patients with IBD. ADAb presence was frequently associated with a reduction in primary efficacy and a loss of response, and, for IFX, an increase in adverse events (AEs). Lower serum levels of ADM, CZP and IFX were seen in ADAbs-positive rather than ADAbs-negative patients; pharmacokinetic data were unavailable for other therapies. Little information was available regarding the timing of ADAb development; studies reported their detection from as early as 10–14 days up to months after treatment initiation. Biologic therapies carry an intrinsic risk of immunogenicity, although reported rates of ADAbs vary considerably. The clinical implications of immunogenicity are a concern for effective treatment; further research, particularly into the more recently approved biologics, is required. PMID:29383030

The Optimisation of the Expression of Recombinant Surface Immunogenic Protein of Group B Streptococcus in Escherichia coli by Response Surface Methodology Improves Humoral Immunity.

PubMed

Díaz-Dinamarca, Diego A; Jerias, José I; Soto, Daniel A; Soto, Jorge A; Díaz, Natalia V; Leyton, Yessica Y; Villegas, Rodrigo A; Kalergis, Alexis M; Vásquez, Abel E

2018-03-01

Group B Streptococcus (GBS) is the leading cause of neonatal meningitis and a common pathogen in livestock and aquaculture industries around the world. Conjugate polysaccharide and protein-based vaccines are under development. The surface immunogenic protein (SIP) is a conserved protein in all GBS serotypes and has been shown to be a good target for vaccine development. The expression of recombinant proteins in Escherichia coli cells has been shown to be useful in the development of vaccines, and the protein purification is a factor affecting their immunogenicity. The response surface methodology (RSM) and Box-Behnken design can optimise the performance in the expression of recombinant proteins. However, the biological effect in mice immunised with an immunogenic protein that is optimised by RSM and purified by low-affinity chromatography is unknown. In this study, we used RSM for the optimisation of the expression of the rSIP, and we evaluated the SIP-specific humoral response and the property to decrease the GBS colonisation in the vaginal tract in female mice. It was observed by NI-NTA chromatography that the RSM increases the yield in the expression of rSIP, generating a better purification process. This improvement in rSIP purification suggests a better induction of IgG anti-SIP immune response and a positive effect in the decreased GBS intravaginal colonisation. The RSM applied to optimise the expression of recombinant proteins with immunogenic capacity is an interesting alternative in the evaluation of vaccines in preclinical phase, which could improve their immune response.

Rickettsial Infections and Fever, Vientiane, Laos

PubMed Central

Phongmany, Simaly; Rolain, Jean-Marc; Phetsouvanh, Rattanaphone; Blacksell, Stuart D.; Soukkhaseum, Vimone; Rasachack, Bouachanh; Phiasakha, Khamphong; Soukkhaseum, Surn; Frichithavong, Khamthavi; Chu, Vang; Keolouangkhot, Valy; Martinez-Aussel, Bertrand; Chang, Ko; Darasavath, Chirapha; Rattanavong, Oudayvone; Sisouphone, Siho; Mayxay, Mayfong; Vidamaly, Sisouphane; Parola, Philippe; Thammavong, Chanpheng; Heuangvongsy, Mayboun; Syhavong, Bounkong; Raoult, Didier; White, Nicholas J.

2006-01-01

Rickettsial diseases have not been described previously from Laos, but in a prospective study, acute rickettsial infection was identified as the cause of fever in 115 (27%) of 427 adults with negative blood cultures admitted to Mahosot Hospital in Vientiane, Laos. The organisms identified by serologic analysis were Orientia tsutsugamushi (14.8%), Rickettsia typhi (9.6%), and spotted fever group rickettsia (2.6% [8 R. helvetica, 1 R. felis, 1 R. conorii subsp. indica, and 1 Rickettsia "AT1"]). Patients with murine typhus had a lower frequency of peripheral lymphadenopathy than those with scrub typhus (3% vs. 46%, p<0.001). Rickettsioses are an underrecognized cause of undifferentiated febrile illnesses among adults in Laos. This finding has implications for the local empiric treatment of fever. PMID:16494751

[Epidemics in the news in Portugal: cholera, plague, typhus, influenza and smallpox, 1854-1918].

PubMed

de Almeida, Maria Antónia Pires

2014-01-01

In severe health crisis like those of 1854-1856, 1899 and 1918, especially in Porto, where cholera morbus, the bubonic plague, typhus fever, pneumonic influenza and smallpox killed high percentages of the population, the images of the epidemics in the press enable us to identify the scientific knowledge in a country considered peripheral, but which had studies and personnel specialized at the most advanced levels for the time. A database of 6,700 news items and announcements reveals the medical and pharmaceutical knowledge of the second half of the nineteenth and early twentieth centuries, the way it was transmitted and disclosed to the public and the solutions offered by the health authorities. Hygiene was consistently highlighted in the news and announcements.

Post hoc assessment of the immunogenicity of bioengineered factor VIIa demonstrates the use of preclinical tools.

PubMed

Lamberth, Kasper; Reedtz-Runge, Stine Louise; Simon, Jonathan; Klementyeva, Ksenia; Pandey, Gouri Shankar; Padkjær, Søren Berg; Pascal, Véronique; León, Ileana R; Gudme, Charlotte Nini; Buus, Søren; Sauna, Zuben E

2017-01-11

Immunogenicity is an important consideration in the licensure of a therapeutic protein because the development of neutralizing anti-drug antibodies (ADAs) can affect both safety and efficacy. Neoantigens introduced by bioengineering of a protein drug are a particular cause for concern. The development of a bioengineered recombinant factor VIIa (rFVIIa) analog was discontinued after phase 3 trials because of the development of ADAs. The unmodified parent molecule (rFVIIa), on the other hand, has been successfully used as a drug for more than two decades with no reports of immunogenicity in congenital hemophilia patients with inhibitors. We used computational and experimental methods to demonstrate that the observed ADAs could have been elicited by neoepitopes in the engineered protein. The human leukocyte antigen type of the patients who developed ADAs is consistent with this hypothesis of a neoepitope-driven immune response, a finding that might have implications for the preclinical screening of therapeutic protein analogs. Copyright © 2017, American Association for the Advancement of Science.

Clinical concerns of immunogenicity produced at cellular levels by biopharmaceuticals following their parenteral administration into human body.

PubMed

Tamilvanan, Shunmugaperumal; Raja, Natarajan Livingston; Sa, Biswanath; Basu, Sanat Kumar

2010-08-01

Similar to the low molecular weight traditional drugs, biopharmaceuticals are capable of producing not only therapeutic effects but also side effects provided if the dose of these compounds exceeds certain concentration and/or if the exposure duration of these compounds at subtoxic doses is being lengthened. In addition, a major drawback of biopharmaceuticals is the risk of antibody formation. Following the administration of biopharmaceuticals into human body, the formation of antidrug-antibody (ADA) or neutralizing antibody and other general immune system effects (including allergy, anaphylaxis, or serum sickness) are of clinical concern regarding therapeutic efficacy and patient safety. For example, drug-induced neutralizing antibodies to erythropoietin (EPO) result in pure red cell aplasia, whereas drug-induced acquired anti-factor VIII antibodies worsen the pathology associated with hemophilia. Since most of the already developed or under development biopharmaceuticals are to some extent immunogenic, the regulatory agencies insist to conduct potential ADA formation during the drug development process itself. This review encompasses a short overview on the clinical concerns of immunogenicity produced at cellular levels by growth hormone, interferon-alpha, EPO, factor VIII, and factor IX following their parenteral administration into human body. Clinical concerns related to immunogenicity produced by the biosimilar versions of these drugs are also presented wherever possible.

Immunogenic Peptides (Vaccines) for the Treatment of Prostate and Breast Cancer | NCI Technology Transfer Center | TTC

Cancer.gov

Researchers at the NCI have developed a novel treatment for prostate and breast cancer using synthetic peptides derived from TARP, the T cell receptor gamma alternate reading frame protein. These immunogenic peptides from TARP elicit an immune response, triggering T cells to kill only the cancer cells within a patient.

Accuracy of AccessBio Immunoglobulin M and Total Antibody Rapid Immunochromatographic Assays for the Diagnosis of Acute Scrub Typhus Infection

DTIC Science & Technology

2010-02-01

archived samples, we assessed the diagnostic capacity of a rapid immunochromatographic test (ICT) for the detection of Orientia tsutsugamushi IgM and...illness in the Asia-Pacific region. As very few health facilities have accessible accurate diagnostic tests , the diagnosis of scrub fever must be based...develop- ment of rapid , diagnostic tests by the use of immunochromato- graphic test (ICf) technologies has provided a mechanism for point-of-care

From the bench to clinical practice: understanding the challenges and uncertainties in immunogenicity testing for biopharmaceuticals

PubMed Central

Gunn, G. R.; Sealey, D. C. F.; Jamali, F.; Meibohm, B.; Ghosh, S.

2016-01-01

Summary Unlike conventional chemical drugs where immunogenicity typically does not occur, the development of anti‐drug antibodies following treatment with biologics has led to concerns about their impact on clinical safety and efficacy. Hence the elucidation of the immunogenicity of biologics is required for drug approval by health regulatory authorities worldwide. Published ADA ‘incidence’ rates can vary greatly between same‐class products and different patient populations. Such differences are due to disparate bioanalytical methods and interpretation approaches, as well as a plethora of product‐specific and patient‐specific factors that are not fully understood. Therefore, the incidence of ADA and their association with clinical consequences cannot be generalized across products. In this context, the intent of this review article is to discuss the complex nature of ADA and key nuances of the methodologies used for immunogenicity assessments, and to dispel some fallacies and myths. PMID:26597698

Factors contributing to the immunogenicity of meningococcal conjugate vaccines

PubMed Central

Bröker, Michael; Berti, Francesco; Costantino, Paolo

2016-01-01

ABSTRACT Various glycoprotein conjugate vaccines have been developed for the prevention of invasive meningococcal disease, having significant advantages over pure polysaccharide vaccines. One of the most important features of the conjugate vaccines is the induction of a T-cell dependent immune response, which enables both the induction of immune memory and a booster response after repeated immunization. The nature of the carrier protein to which the polysaccharides are chemically linked, is often regarded as the main component of the vaccine in determining its immunogenicity. However, other factors can have a significant impact on the vaccine's profile. In this review, we explore the physico-chemical properties of meningococcal conjugate vaccines, which can significantly contribute to the vaccine's immunogenicity. We demonstrate that the carrier is not the sole determining factor of the vaccine's profile, but, moreover, that the conjugate vaccine's immunogenicity is the result of multiple physico-chemical structures and characteristics. PMID:26934310

Ticks and Tickborne Diseases Affecting Military Personnel

DTIC Science & Technology

1989-09-01

36 Rocky Mountain Spotted Fever ........................ 38 Boutonneuse Fever ...40 Siberian Tick Typhus ................................ 40 Tularemia ........................................... 41 Colorado Tick Fever ...42 Tickborne Relapsing Fever ........................... 43 Tickborne Encephalitis .............................. 43 Crimean

FDA advisory committees meet January 26 on Salk HIV-1 immunogen.

PubMed

1995-01-06

Two advisory committees of the Food and Drug Administration (FDA) will meet to consider future trials of the HIV-1 immunogen developed by Dr. Jonas Salk. The Immune Response Corporation has already conducted several studies of the immunogen, and has found improvement in various immunological and other blood tests, and no adverse effects. However, the studies have not been large enough to show conclusively that the treatment has clinical benefit in delaying disease progression. The new, larger trials are intended to demonstrate a delay in disease progression and validate the use of blood-test markers of disease progression for studying an immune-based treatment.

RNActive® Technology: Generation and Testing of Stable and Immunogenic mRNA Vaccines.

PubMed

Rauch, Susanne; Lutz, Johannes; Kowalczyk, Aleksandra; Schlake, Thomas; Heidenreich, Regina

2017-01-01

Developing effective mRNA vaccines poses certain challenges concerning mRNA stability and ability to induce sufficient immune stimulation and requires a specific panel of techniques for production and testing. Here, we describe the production of stabilized mRNA with enhanced immunogenicity, generated using conventional nucleotides only, by introducing changes to the mRNA sequence and by complexation with the nucleotide-binding peptide protamine (RNActive® technology). Methods described here include the synthesis, purification, and protamine complexation of mRNA vaccines as well as a comprehensive panel of in vitro and in vivo methods for evaluation of vaccine quality and immunogenicity.

An update on safety and immunogenicity of vaccines containing emulsion-based adjuvants.

PubMed

Fox, Christopher B; Haensler, Jean

2013-07-01

With the exception of alum, emulsion-based vaccine adjuvants have been administered to far more people than any other adjuvant, especially since the 2009 H1N1 influenza pandemic. The number of clinical safety and immunogenicity evaluations of vaccines containing emulsion adjuvants has correspondingly mushroomed. In this review, the authors introduce emulsion adjuvant composition and history before detailing the most recent findings from clinical and postmarketing data regarding the effects of emulsion adjuvants on vaccine immunogenicity and safety, with emphasis on the most widely distributed emulsion adjuvants, MF59® and AS03. The authors also present a summary of other emulsion adjuvants in clinical development and indicate promising avenues for future emulsion-based adjuvant development. Overall, emulsion adjuvants have demonstrated potent adjuvant activity across a number of disease indications along with acceptable safety profiles.

Factors influencing preclinical in vivo evaluation of mumps vaccine strain immunogenicity

PubMed Central

Halassy, B; Kurtović, T; Brgles, M; Lang Balija, M; Forčić, D

2015-01-01

Immunogenicity testing in animals is a necessary preclinical assay for demonstration of vaccine efficacy the results of which are often the basis for the decision whether to proceed or withdraw the further development of the novel vaccine candidate. However, in vivo assays are rarely, if at all, optimized and validated. Here we clearly demonstrate the importance of in vivo assay (mumps virus immunogenicity testing in guinea pigs) optimization for gaining reliable results and the suitability of Fractional factorial design of experiments (DoE) for such a purpose. By the use of DoE with resolution IV (2IV(4-1)) we clearly revealed that the parameters significantly increasing assay sensitivity were interval between animal immunizations followed by the body weight of experimental animals. The quantity (0 versus 2%) of the stabilizer (fetal bovine serum, FBS) in the sample was shown as non-influencing parameter in DoE setup. However, the separate experiment investigating only the FBS influence, and performed under other parameters optimally set, showed that FBS also influences the results of immunogenicity assay. Such finding indicated that (a) factors with strong influence on the measured outcome can hide the effects of parameters with modest/low influence and (b) the matrix of mumps virus samples to be compared for immunogenicity must be identical for reliable virus immunogenicity comparison. Finally the 3 mumps vaccine strains widely used for decades in the licensed vaccines were for the first time compared in an animal model, and results obtained were in line with their reported immunogenicity in human population supporting the predictive power of the optimized in vivo assay. PMID:26376015

Factors influencing preclinical in vivo evaluation of mumps vaccine strain immunogenicity.

PubMed

Halassy, B; Kurtović, T; Brgles, M; Lang Balija, M; Forčić, D

2015-01-01

Immunogenicity testing in animals is a necessary preclinical assay for demonstration of vaccine efficacy the results of which are often the basis for the decision whether to proceed or withdraw the further development of the novel vaccine candidate. However, in vivo assays are rarely, if at all, optimized and validated. Here we clearly demonstrate the importance of in vivo assay (mumps virus immunogenicity testing in guinea pigs) optimization for gaining reliable results and the suitability of Fractional factorial design of experiments (DoE) for such a purpose. By the use of DoE with resolution IV (2IV((4-1))) we clearly revealed that the parameters significantly increasing assay sensitivity were interval between animal immunizations followed by the body weight of experimental animals. The quantity (0 versus 2%) of the stabilizer (fetal bovine serum, FBS) in the sample was shown as non-influencing parameter in DoE setup. However, the separate experiment investigating only the FBS influence, and performed under other parameters optimally set, showed that FBS also influences the results of immunogenicity assay. Such finding indicated that (a) factors with strong influence on the measured outcome can hide the effects of parameters with modest/low influence and (b) the matrix of mumps virus samples to be compared for immunogenicity must be identical for reliable virus immunogenicity comparison. Finally the 3 mumps vaccine strains widely used for decades in the licensed vaccines were for the first time compared in an animal model, and results obtained were in line with their reported immunogenicity in human population supporting the predictive power of the optimized in vivo assay.

Use of In Vitro Assays to Assess Immunogenicity Risk of Antibody-Based Biotherapeutics

PubMed Central

Joubert, Marisa K.; Deshpande, Meghana; Yang, Jane; Reynolds, Helen; Bryson, Christine; Fogg, Mark; Baker, Matthew P.; Herskovitz, Jonathan; Goletz, Theresa J.; Zhou, Lei; Moxness, Michael; Flynn, Gregory C.; Narhi, Linda O.; Jawa, Vibha

2016-01-01

An In Vitro Comparative Immunogenicity Assessment (IVCIA) assay was evaluated as a tool for predicting the potential relative immunogenicity of biotherapeutic attributes. Peripheral blood mononuclear cells from up to 50 healthy naïve human donors were monitored up to 8 days for T-cell proliferation, the number of IL-2 or IFN-γ secreting cells, and the concentration of a panel of secreted cytokines. The response in the assay to 10 monoclonal antibodies was found to be in agreement with the clinical immunogenicity, suggesting that the assay might be applied to immunogenicity risk assessment of antibody biotherapeutic attributes. However, the response in the assay is a measure of T-cell functional activity and the alignment with clinical immunogenicity depends on several other factors. The assay was sensitive to sequence variants and could differentiate single point mutations of the same biotherapeutic. Nine mAbs that were highly aggregated by stirring induced a higher response in the assay than the original mAbs before stirring stress, in a manner that did not match the relative T-cell response of the original mAbs. In contrast, mAbs that were glycated by different sugars (galactose, glucose, and mannose) showed little to no increase in response in the assay above the response to the original mAbs before glycation treatment. The assay was also used successfully to assess similarity between multiple lots of the same mAb, both from the same manufacturer and from different manufacturers (biosimilars). A strategy for using the IVCIA assay for immunogenicity risk assessment during the entire lifespan development of biopharmaceuticals is proposed. PMID:27494246

Immunogenicity and Safety of the New Inactivated Quadrivalent Influenza Vaccine Vaxigrip Tetra: Preliminary Results in Children ≥6 Months and Older Adults

PubMed Central

Montomoli, Emanuele; Torelli, Alessandro; Gianchecchi, Elena

2018-01-01

Since the mid-1980s, two lineages of influenza B viruses have been distinguished. These can co-circulate, limiting the protection provided by inactivated trivalent influenza vaccines (TIVs). This has prompted efforts to formulate quadrivalent influenza vaccines (QIVs), to enhance protection against circulating influenza B viruses. This review describes the results obtained from seven phase III clinical trials evaluating the immunogenicity, safety, and lot-to-lot consistency of a new quadrivalent split-virion influenza vaccine (Vaxigrip Tetra®) formulated by adding a second B strain to the already licensed TIV. Since Vaxigrip Tetra was developed by means of a manufacturing process strictly related to that used for TIV, the data on the safety profile of TIV are considered supportive of that of Vaxigrip Tetra. The safety and immunogenicity of Vaxigrip Tetra were similar to those of the corresponding licensed TIV. Moreover, the new vaccine elicits a superior immune response towards the additional strain, without affecting immunogenicity towards the other three strains. Vaxigrip Tetra is well tolerated, has aroused no safety concerns, and is recommended for the active immunization of individuals aged ≥6 months. In addition, preliminary data confirm its immunogenicity and safety even in children aged 6–35 months and its immunogenicity in older subjects (aged 66–80 years). PMID:29518013

Expression and immunogenicity of novel subunit enterovirus 71 VP1 antigens

DOE Office of Scientific and Technical Information (OSTI.GOV)

Xu, Juan; Department of Microbiology and Immunology, Nanjing Medical University; Wang, Shixia

Highlights: Black-Right-Pointing-Pointer EV71 is a major emerging infectious disease in many Asian countries. Black-Right-Pointing-Pointer Inactivated EV71 vaccines are in clinical studies but their safety and efficacy are unknown. Black-Right-Pointing-Pointer Developing subunit based EV71 vaccines is significant and novel antigen design is needed. Black-Right-Pointing-Pointer DNA immunization is an efficient tool to test the immunogenicity of VP1 based EV71 vaccines. Black-Right-Pointing-Pointer Multiple VP1 antigens are developed showing immunogenic potential. -- Abstract: Hand, foot, and mouth disease (HFMD) is a common viral illness in young children. HFMD is caused by viruses belonging to the enterovirus genus of the picornavirus family. Recently, enterovirus 71more » (EV71) has emerged as a virulent agent for HFMD with severe clinical outcomes. In the current report, we conducted a pilot antigen engineering study to optimize the expression and immunogenicity of subunit VP1 antigen for the design of EV71 vaccines. DNA immunization was adopted as a simple technical approach to test different designs of VP1 antigens without the need to express VP1 protein in vitro first. Our studies indicated that the expression and immunogenicity of VP1 protein can be improved with alternated VP1 antigen designs. Data presented in the current report revealed novel pathways to optimize the design of VP1 antigen-based EV71 vaccines.« less

77 FR 8263 - Prospective Grant of Exclusive License: The Development of Anti-mesothelin Targeted Immunotoxins...

Federal Register 2010, 2011, 2012, 2013, 2014

2012-02-14

... ``Pseudomonas Exotoxin A with Less Immunogenic B Cell Epitopes'' [HHS Ref. E-263-2011/0-US-01], US Patent application 61/495,085 entitled ``Pseudomonas Exotoxin A with Less Immunogenic T Cell Epitopes'' [HHS Ref. E... Immunotoxin in Which All B-Cell Epitopes Have Been Removed and Which Has High Cytotoxic Activity'' [HHS Ref. E...

Canarypox virus expressing infectious bursal disease VP2 protein as immunogen for chickens

PubMed Central

Zanetti, Flavia Adriana; Grand, María Daniela Conte; Mitarotonda, Romina Cristina; Taboga, Oscar Alberto; Calamante, Gabriela

2014-01-01

Canarypox viruses (CNPV) carrying the coding sequence of VP2 protein from infectious bursal disease virus (IBDV) were obtained. These viruses were able to express VP2 protein in vitro and to induce IBDV-neutralizing antibodies when inoculated in specific pathogen-free chickens demonstrating that CNPV platform is usefulness to develop immunogens for chickens. PMID:24948937

Epitope-Specific Evolution of Human B Cell Responses to Borrelia burgdorferi VlsE Protein from Early to Late Stages of Lyme Disease.

PubMed

Jacek, Elzbieta; Tang, Kevin S; Komorowski, Lars; Ajamian, Mary; Probst, Christian; Stevenson, Brian; Wormser, Gary P; Marques, Adriana R; Alaedini, Armin

2016-02-01

Most immunogenic proteins of Borrelia burgdorferi, the causative agent of Lyme disease, are known or expected to contain multiple B cell epitopes. However, the kinetics of the development of human B cell responses toward the various epitopes of individual proteins during the course of Lyme disease has not been examined. Using the highly immunogenic VlsE as a model Ag, we investigated the evolution of humoral immune responses toward its immunodominant sequences in 90 patients with a range of early to late manifestations of Lyme disease. The results demonstrate the existence of asynchronous, independently developing, Ab responses against the two major immunogenic regions of the VlsE molecule in the human host. Despite their strong immunogenicity, the target epitopes were inaccessible to Abs on intact spirochetes, suggesting a lack of direct immunoprotective effect. These observations document the association of immune reactivity toward specific VlsE sequences with different phases of Lyme disease, demonstrating the potential use of detailed epitope mapping of Ags for staging of the infection, and offer insights regarding the pathogen's possible immune evasion mechanisms. Copyright © 2016 by The American Association of Immunologists, Inc.

Influence of Oxidation and Multimerization on the Immunogenicity of a Thioredoxin-L2 Prophylactic Papillomavirus Vaccine

PubMed Central

Seitz, Hanna; Dantheny, Tatiana; Burkart, Frank; Ottonello, Simone

2013-01-01

Current commercial prophylactic human papillomavirus (HPV) vaccines are based on virus-like particles assembled from the major capsid protein L1 and show excellent safety and efficacy profiles. Still, a major limitation is their rather narrow range of protection against different HPV types. In contrast, the minor capsid protein L2 contains a so-called major cross-neutralizing epitope that can induce broad-range protective responses against multiple HPV types. This epitope is conserved among different papillomaviruses (PV) and contains two cysteine residues that are present in the L2 proteins of all known PV types. The main challenge in developing L2-directed vaccines is to overcome the intrinsically low immunogenicity of the L2 protein. Previously, we developed a recombinant L2-based prototype vaccine by inserting peptide epitopes spanning the cross-neutralizing L2 sequence into a bacterial thioredoxin (Trx) scaffold. These antigens induced high-titer neutralizing antibodies in mice. Here, we address the question of whether Trx scaffold multimerization may further enhance the immunogenicity of the TrxL2 vaccine. We also demonstrate that the oxidation state of the conserved cysteine residues is not essential for vaccine functionality, but it contributes to immunogenicity. PMID:23677323

Development of designed site-directed pseudopeptide-peptido-mimetic immunogens as novel minimal subunit-vaccine candidates for malaria.

PubMed

Lozano, José Manuel; Lesmes, Liliana P; Carreño, Luisa F; Gallego, Gina M; Patarroyo, Manuel Elkin

2010-12-06

Synthetic vaccines constitute the most promising tools for controlling and preventing infectious diseases. When synthetic immunogens are designed from the pathogen native sequences, these are normally poorly immunogenic and do not induce protection, as demonstrated in our research. After attempting many synthetic strategies for improving the immunogenicity properties of these sequences, the approach consisting of identifying high binding motifs present in those, and then performing specific changes on amino-acids belonging to such motifs, has proven to be a workable strategy. In addition, other strategies consisting of chemically introducing non-natural constraints to the backbone topology of the molecule and modifying the α-carbon asymmetry are becoming valuable tools to be considered in this pursuit. Non-natural structural constraints to the peptide backbone can be achieved by introducing peptide bond isosters such as reduced amides, partially retro or retro-inverso modifications or even including urea motifs. The second can be obtained by strategically replacing L-amino-acids with their enantiomeric forms for obtaining both structurally site-directed designed immunogens as potential vaccine candidates and their Ig structural molecular images, both having immuno-therapeutic effects for preventing and controlling malaria.

Identification of In Vivo-Expressed Immunogenic Proteins by Serological Proteome Analysis of the Bacillus anthracis Secretome▿ †

PubMed Central

Chitlaru, Theodor; Gat, Orit; Grosfeld, Haim; Inbar, Itzhak; Gozlan, Yael; Shafferman, Avigdor

2007-01-01

In a previous comparative proteomic study of Bacillus anthracis examining the influence of the virulence plasmids and of various growth conditions on the composition of the bacterial secretome, we identified 64 abundantly expressed proteins (T. Chitlaru, O. Gat, Y. Gozlan, N. Ariel, and A. Shafferman, J. Bacteriol. 188:3551-3571, 2006). Using a battery of sera from B. anthracis-infected animals, in the present study we demonstrated that 49 of these proteins are immunogenic. Thirty-eight B. anthracis immunogens are documented in this study for the first time. The relative immunogenicities of the 49 secreted proteins appear to span a >10,000-fold range. The proteins eliciting the highest humoral response in the course of infection include, in addition to the well-established immunogens protective antigen (PA), Sap, and EA1, GroEL (BA0267), AhpC (BA0345), MntA (BA3189), HtrA (BA3660), 2,3-cyclic nucleotide diesterase (BA4346), collagen adhesin (BAS5205), an alanine amidase (BA0898), and an endopeptidase (BA1952), as well as three proteins having unknown functions (BA0796, BA0799, and BA0307). Of these 14 highly potent secreted immunogens, 11 are known to be associated with virulence and pathogenicity in B. anthracis or in other bacterial pathogens. Combining the results reported here with the results of a similar study of the membranal proteome of B. anthracis (T. Chitlaru, N. Ariel, A. Zvi, M. Lion, B. Velan, A. Shafferman, and E. Elhanany, Proteomics 4:677-691, 2004) and the results obtained in a functional genomic search for immunogens (O. Gat, H. Grosfeld, N. Ariel, I. Inbar, G. Zaide, Y. Broder, A. Zvi, T. Chitlaru, Z. Altboum, D. Stein, S. Cohen, and A. Shafferman, Infect. Immun. 74:3987-4001, 2006), we generated a list of 84 in vivo-expressed immunogens for future evaluation for vaccine development, diagnostics, and/or therapeutic intervention. In a preliminary study, the efficacies of eight immunogens following DNA immunization of guinea pigs were compared to the efficacy of a PA DNA vaccine. All eight immunogens induced specific high antibody titers comparable to the titers elicited by PA; however, unlike PA, none of them provided protection against a lethal challenge (50 50% lethal doses) of virulent B. anthracis strain Vollum spores. PMID:17353282

Deer ticks (image)

MedlinePlus

Diseases are often carried by ticks, including Rocky Mountain Spotted Fever, Colorado Tick Fever, Lyme disease, and tularemia. Less common or less frequent diseases include typhus, Q-fever, relapsing fever, viral encephalitis, hemorrhagic fever, ...

Typhus

MedlinePlus

... R, Blaser MJ, eds. Mandell, Douglas, and Bennett's Principles and Practice of Infectious Diseases, Updated Edition . 8th ... R, Blaser MJ, eds. Mandell, Douglas, and Bennett's Principles and Practice of Infectious Diseases, Updated Edition . 8th ...

iVAX: An integrated toolkit for the selection and optimization of antigens and the design of epitope-driven vaccines.

PubMed

Moise, Leonard; Gutierrez, Andres; Kibria, Farzana; Martin, Rebecca; Tassone, Ryan; Liu, Rui; Terry, Frances; Martin, Bill; De Groot, Anne S

2015-01-01

Computational vaccine design, also known as computational vaccinology, encompasses epitope mapping, antigen selection and immunogen design using computational tools. The iVAX toolkit is an integrated set of tools that has been in development since 1998 by De Groot and Martin. It comprises a suite of immunoinformatics algorithms for triaging candidate antigens, selecting immunogenic and conserved T cell epitopes, eliminating regulatory T cell epitopes, and optimizing antigens for immunogenicity and protection against disease. iVAX has been applied to vaccine development programs for emerging infectious diseases, cancer antigens and biodefense targets. Several iVAX vaccine design projects have had success in pre-clinical studies in animal models and are progressing toward clinical studies. The toolkit now incorporates a range of immunoinformatics tools for infectious disease and cancer immunotherapy vaccine design. This article will provide a guide to the iVAX approach to computational vaccinology.

Trial Watch: Immunogenic cell death inducers for anticancer chemotherapy.

PubMed

Pol, Jonathan; Vacchelli, Erika; Aranda, Fernando; Castoldi, Francesca; Eggermont, Alexander; Cremer, Isabelle; Sautès-Fridman, Catherine; Fucikova, Jitka; Galon, Jérôme; Spisek, Radek; Tartour, Eric; Zitvogel, Laurence; Kroemer, Guido; Galluzzi, Lorenzo

2015-04-01

The term "immunogenic cell death" (ICD) is now employed to indicate a functionally peculiar form of apoptosis that is sufficient for immunocompetent hosts to mount an adaptive immune response against dead cell-associated antigens. Several drugs have been ascribed with the ability to provoke ICD when employed as standalone therapeutic interventions. These include various chemotherapeutics routinely employed in the clinic (e.g., doxorubicin, epirubicin, idarubicin, mitoxantrone, bleomycin, bortezomib, cyclophosphamide and oxaliplatin) as well as some anticancer agents that are still under preclinical or clinical development (e.g., some microtubular inhibitors of the epothilone family). In addition, a few drugs are able to convert otherwise non-immunogenic instances of cell death into bona fide ICD, and may therefore be employed as chemotherapeutic adjuvants within combinatorial regimens. This is the case of cardiac glycosides, like digoxin and digitoxin, and zoledronic acid. Here, we discuss recent developments on anticancer chemotherapy based on ICD inducers.

Universal immunogenicity validation and assessment during early biotherapeutic development to support a green laboratory.

PubMed

Bautista, Ami C; Zhou, Lei; Jawa, Vibha

2013-10-01

Immunogenicity support during nonclinical biotherapeutic development can be resource intensive if supported by conventional methodologies. A universal indirect species-specific immunoassay can eliminate the need for biotherapeutic-specific anti-drug antibody immunoassays without compromising quality. By implementing the R's of sustainability (reduce, reuse, rethink), conservation of resources and greener laboratory practices were achieved in this study. Statistical analysis across four biotherapeutics supported identification of consistent product performance standards (cut points, sensitivity and reference limits) and a streamlined universal anti-drug antibody immunoassay method implementation strategy. We propose an efficient, fit-for-purpose, scientifically and statistically supported nonclinical immunogenicity assessment strategy. Utilization of a universal method and streamlined validation, while retaining comparability to conventional immunoassays and meeting the industry recommended standards, provides environmental credits in the scientific laboratory. Collectively, individual reductions in critical material consumption, energy usage, waste and non-environment friendly consumables, such as plastic and paper, support a greener laboratory environment.

Reducing V3 Antigenicity and Immunogenicity on Soluble, Native-Like HIV-1 Env SOSIP Trimers.

PubMed

Ringe, Rajesh P; Ozorowski, Gabriel; Rantalainen, Kimmo; Struwe, Weston B; Matthews, Katie; Torres, Jonathan L; Yasmeen, Anila; Cottrell, Christopher A; Ketas, Thomas J; LaBranche, Celia C; Montefiori, David C; Cupo, Albert; Crispin, Max; Wilson, Ian A; Ward, Andrew B; Sanders, Rogier W; Klasse, P J; Moore, John P

2017-08-01

Native-like trimers of the SOSIP design are being developed as immunogens in human immunodeficiency virus type 1 (HIV-1) vaccine development programs. These trimers display the epitopes for multiple broadly neutralizing antibodies (bNAbs) but can also expose binding sites for some types of nonneutralizing antibodies (non-NAbs). Among the latter are epitopes in the gp120 V3 region that are highly immunogenic when SOSIP trimers are evaluated in animal models. It is presently uncertain whether antibodies against V3 can interfere with the induction of NAbs, but there are good arguments in favor of suppressing such "off-target" immune responses. Accordingly, we have assessed how to minimize the exposure of V3 non-NAb epitopes and thereby reduce their immunogenicity by introducing N -glycans within the V3 region of BG505 SOSIP trimers. We found that inserting glycans at positions 306 and 314 (termed M1 and M7) markedly reduced V3 antigenicity while improving the presentation of trimer apex bNAb epitopes. Both added glycans were shown to be predominantly of the Man 6 GlcNAc 2 form. The additional introduction of the E64K ground-state stabilizing substitution markedly reduced or ablated soluble CD4 (sCD4) induction of non-NAb epitopes in V3 and/or associated with the coreceptor binding site. When a V3 glycan- and E64K-modified trimer variant, BG505 SOSIP.664-E64K.M1M7, was tested in rabbits, V3 immunogenicity was eliminated while the autologous NAb response was unchanged. IMPORTANCE Trimeric proteins are being developed for future HIV-1 vaccine trials in humans, with the goal of eliciting broadly active neutralizing antibodies (NAbs) that are active against a wide variety of circulating strains. In animal models, the present generation of native-like trimer immunogens, exemplified by the BG505 SOSIP.664 construct, induces narrow-specificity antibodies against the neutralization-resistant (tier-2), sequence-matched virus and more broadly active antibodies against sequence-divergent atypically neutralization-sensitive (tier-1) viruses. A concern in the trimer immunogen design field has been whether the latter off-target antibodies might interfere with the induction of the more desired responses to tier-2 epitopes. Here, we have inserted two glycans into the dominant site for tier-1 NAbs, the gp120 V3 region, to block the induction of off-target antibodies. We characterized the new trimers, tested them as immunogens in rabbits, and found that the blocking glycans eliminated the induction of tier-1 NAbs to V3-epitopes. Copyright © 2017 Ringe et al.

Reducing V3 Antigenicity and Immunogenicity on Soluble, Native-Like HIV-1 Env SOSIP Trimers

PubMed Central

Ringe, Rajesh P.; Ozorowski, Gabriel; Rantalainen, Kimmo; Struwe, Weston B.; Matthews, Katie; Torres, Jonathan L.; Yasmeen, Anila; Cottrell, Christopher A.; Ketas, Thomas J.; LaBranche, Celia C.; Montefiori, David C.; Cupo, Albert; Crispin, Max; Wilson, Ian A.; Ward, Andrew B.; Sanders, Rogier W.; Klasse, P. J.

2017-01-01

ABSTRACT Native-like trimers of the SOSIP design are being developed as immunogens in human immunodeficiency virus type 1 (HIV-1) vaccine development programs. These trimers display the epitopes for multiple broadly neutralizing antibodies (bNAbs) but can also expose binding sites for some types of nonneutralizing antibodies (non-NAbs). Among the latter are epitopes in the gp120 V3 region that are highly immunogenic when SOSIP trimers are evaluated in animal models. It is presently uncertain whether antibodies against V3 can interfere with the induction of NAbs, but there are good arguments in favor of suppressing such “off-target” immune responses. Accordingly, we have assessed how to minimize the exposure of V3 non-NAb epitopes and thereby reduce their immunogenicity by introducing N-glycans within the V3 region of BG505 SOSIP trimers. We found that inserting glycans at positions 306 and 314 (termed M1 and M7) markedly reduced V3 antigenicity while improving the presentation of trimer apex bNAb epitopes. Both added glycans were shown to be predominantly of the Man6GlcNAc2 form. The additional introduction of the E64K ground-state stabilizing substitution markedly reduced or ablated soluble CD4 (sCD4) induction of non-NAb epitopes in V3 and/or associated with the coreceptor binding site. When a V3 glycan- and E64K-modified trimer variant, BG505 SOSIP.664-E64K.M1M7, was tested in rabbits, V3 immunogenicity was eliminated while the autologous NAb response was unchanged. IMPORTANCE Trimeric proteins are being developed for future HIV-1 vaccine trials in humans, with the goal of eliciting broadly active neutralizing antibodies (NAbs) that are active against a wide variety of circulating strains. In animal models, the present generation of native-like trimer immunogens, exemplified by the BG505 SOSIP.664 construct, induces narrow-specificity antibodies against the neutralization-resistant (tier-2), sequence-matched virus and more broadly active antibodies against sequence-divergent atypically neutralization-sensitive (tier-1) viruses. A concern in the trimer immunogen design field has been whether the latter off-target antibodies might interfere with the induction of the more desired responses to tier-2 epitopes. Here, we have inserted two glycans into the dominant site for tier-1 NAbs, the gp120 V3 region, to block the induction of off-target antibodies. We characterized the new trimers, tested them as immunogens in rabbits, and found that the blocking glycans eliminated the induction of tier-1 NAbs to V3-epitopes. PMID:28539451

Antibody Prevalence and Factors Associated with Exposure to Orientia tsutsugamushi in Different Aboriginal Subgroups in West Malaysia

PubMed Central

Tay, Sun Tee; Mohamed Zan, Hafizatul Anis; Lim, Yvonne A. L.; Ngui, Romano

2013-01-01

Background Limited data is available on the current status of scrub typhus infection in the aboriginal population in Malaysia. This study was aimed to provide recent data on the degree of exposure of 280 individuals from seven aboriginal subgroups to Orientia tsutsugamushi (causative agent of scrub typhus) in West Malaysia. The environment, socioeconomic and behavioural risk factors associated with the disease were also investigated. Methods/Findings The antibody prevalence to O. tsutsugamushi ranged from 0 to 36.4% in seven subgroups, with high prevalence rates noted in subgroups involved in agricultural activity and the lowest prevalence rates noted in subgroups whose main occupations were associated to fishing. Univariate analysis indicated populations with age above 18 years (OR = 1.15, 95% CI = 1.02–1.30, P = 0.015), working (OR = 1.99, 95% CI = 1.01–3.92, P = 0.044), working at agriculture area (OR = 1.18, 95% CI = 0.98–1.42, P = 0.031), receiving household income less than US$ 166.7 (RM500) per month (OR = 2.43, 95% CI = 1.16–5.11, P = 0.016) and having close contact with animal pets (OR = 4.06, 95% CI = 1.20–13.76, P = 0.016) are significantly associated with exposure to O. tsutsugamushi. Multivariate analysis confirms that participants who are above 18 years old, receiving household income less than US$ 166.7 (RM500) per month and having close contact with animal pets are 3.6 times (95% CI = 1.81–7.03, P<0.001), 1.3 times (95% CI = 1.14–1.64, P = 0.002) and 1.2 times (95% CI = 1.05–1.06, P = 0.006) more likely to have exposure to O. tsutsugamushi, respectively. Conclusion The present study indicates that scrub typhus is still an important disease in the aboriginal population in Malaysia. Awareness about the disease and education on the preventive measures are important in reducing the risk of acquiring scrub typhus in the population studied. PMID:23936576

The Epidemiology and Characteristics of Q fever and Co-infections with Scrub Typhus, Murine Typhus or Leptospirosis in Taiwan: A Nationwide Database Study.

PubMed

Lai, C-H; Sun, W; Lee, C-H; Lin, J-N; Liao, M-H; Liu, S-S; Chang, T-Y; Tsai, K-F; Chang, Y-C; Lin, H-H; Chen, Y-H

2017-11-01

Q fever (QF) is a worldwide zoonosis associated with outbreaks. Only a few nationwide studies regarding the surveillance and epidemiology of human QF have been reported. Although QF is endemic in Taiwan, a nationwide database investigation of the epidemiology and characteristics of QF and its associations with scrub typhus (ST), murine typhus (MT) and leptospirosis (LS) has never been reported. We analysed nationwide databases of suspected QF, ST, MT and LS cases from October 2007 to December 2014 obtained from the Centers for Disease Control, Taiwan. A total of 468 (4.2%) QF cases were identified among 11 109 suspected QF cases. QF cases were mainly distributed in the southern and Kaohsiung-Pingtung regions but rarely in the eastern region. Compared to non-QF cases, QF cases had significantly higher percentages of males (88.7 versus 66.2%) and high-risk occupations (farming, animal husbandry or veterinary medicine) (16.2 versus 10.5%). But the percentages of specific animal contact, including cattle (0.6 versus 0.8%) and goats (0.9 versus 1.0%), were low in both. The majority of suspected QF cases (89.4%) were simultaneously suspected with ST, MT or LS, and the combinations of suspected diseases differed between regions. The number of suspected QF cases from the eastern region decreased since 2009, which was not observed in other regions. A total of 1420 (12.8%) cases had confirmed diseases, including QF (453, 4.1%), QF+ST (7, 0.06%), QF+MT (4, 0.04%), QF+LS (4, 0.04%), MT (186, 1.7%), ST (545, 4.9%), ST+LS (11, 0.1%) and LS (210, 1.9%). Compared to cases of unknown disease, QF cases had larger percentages of high-risk occupations (16.2 versus 9.6%) but similar histories of animal contact (29.8 versus 25.1%). QF is an endemic disease in southern Taiwan. It is difficult to differentiate QF from ST, MT or LS only by high-risk occupations and history of animal contact, and co-infection of QF with these diseases should be considered. © 2016 Blackwell Verlag GmbH.

Chicken IgY Fc expressed by Eimeria mitis enhances the immunogenicity of E. mitis.

PubMed

Qin, Mei; Tang, Xinming; Yin, Guangwen; Liu, Xianyong; Suo, Jingxia; Tao, Geru; Ei-Ashram, Saeed; Li, Yuan; Suo, Xun

2016-03-21

Eimeria species are obligate intracellular apicomplexan parasites, causing great economic losses in the poultry industry. Currently wild-and attenuated- type anticoccidial vaccines are used to control coccidiosis. However, their use in fast growing broilers is limited by vaccination side effects caused by medium and/or low immunogenic Eimeria spp. There is, therefore, a need for a vaccine with high immunogenicity for broilers. The avian yolk sac IgY Fc is the avian counterpart of the mammalian IgG Fc, which enhances immunogenicity of Fc-fusion proteins. Here, we developed a stable transgenic Eimeria mitis expressing IgY Fc (Emi.chFc) and investigated whether the avian IgY Fc fragment enhances the immunogenicity of E. mitis. Two-week-old broilers were immunized with either Emi.chFc or wild type Eimeria and challenged with wild type E. mitis to analyze the protective properties of transgenic Emi.chFc. Chickens immunized with Emi.chFc had significantly lower oocyst output, in comparison with PBS, mock control (transgenic E. mitis expressing HA1 from H9N2 avian influenza virus) and wildtype E. mitis immunized groups after challenge, indicating that IgY Fc enhanced the immunogenicity of E. mitis. Our findings suggest that IgY Fc-expressing Eimeria may be a better coccidiosis vaccine, and transgenic Eimeria expressing Fc-fused exogenous antigens may be used as a novel vaccine-delivery vehicle against a wide variety of pathogens.

Enhancing efficiency and quality of statistical estimation of immunogenicity assay cut points through standardization and automation.

PubMed

Su, Cheng; Zhou, Lei; Hu, Zheng; Weng, Winnie; Subramani, Jayanthi; Tadkod, Vineet; Hamilton, Kortney; Bautista, Ami; Wu, Yu; Chirmule, Narendra; Zhong, Zhandong Don

2015-10-01

Biotherapeutics can elicit immune responses, which can alter the exposure, safety, and efficacy of the therapeutics. A well-designed and robust bioanalytical method is critical for the detection and characterization of relevant anti-drug antibody (ADA) and the success of an immunogenicity study. As a fundamental criterion in immunogenicity testing, assay cut points need to be statistically established with a risk-based approach to reduce subjectivity. This manuscript describes the development of a validated, web-based, multi-tier customized assay statistical tool (CAST) for assessing cut points of ADA assays. The tool provides an intuitive web interface that allows users to import experimental data generated from a standardized experimental design, select the assay factors, run the standardized analysis algorithms, and generate tables, figures, and listings (TFL). It allows bioanalytical scientists to perform complex statistical analysis at a click of the button to produce reliable assay parameters in support of immunogenicity studies. Copyright © 2015 Elsevier B.V. All rights reserved.

Immunogenicity, safety, and efficacy of abatacept administered subcutaneously with or without background methotrexate in patients with rheumatoid arthritis: results from a phase III, international, multicenter, parallel-arm, open-label study.

PubMed

Nash, Peter; Nayiager, Sauithree; Genovese, Mark C; Kivitz, Alan J; Oelke, Kurt; Ludivico, Charles; Palmer, William; Rodriguez, Cristian; Delaet, Ingrid; Elegbe, Ayanbola; Corbo, Michael

2013-05-01

To evaluate the impact of concomitant methotrexate (MTX) on subcutaneous (SC) abatacept immunogenicity, and to assess safety and efficacy. This phase III, open-label study had a 4-month short-term (ST) period and an ongoing long-term extension (LTE) period. Rheumatoid arthritis patients were stratified to receive SC abatacept (125 mg/week) with (combination) or without MTX (monotherapy), with no intravenous loading dose; patients receiving monotherapy could add MTX in the LTE period. Immunogenicity (percentage of anti-abatacept antibody-positive patients) was assessed. ST and LTE period data are reported, including efficacy through LTE month 14 and safety through LTE month 20. Ninety-six of 100 enrolled patients completed the ST period; 3.9% (combination) and 4.1% of patients (monotherapy) developed transient immunogenicity, and no patients were antibody positive at month 4. Serious adverse events (SAEs) were reported in 3.9% (combination) and 6.1% of patients (monotherapy); 5.9% (combination) and 8.2% of patients (monotherapy) experienced SC injection reactions, and all were mild in intensity. Mean 28-joint Disease Activity Score (DAS28) changes were -1.67 (95% confidence interval [95% CI] -2.06, -1.28; combination) and -1.94 (95% CI -2.46, -1.42; monotherapy) at month 4. Ninety patients entered and were treated in the LTE period; 83.3% (75 of 90) remained ongoing at month 24. One LTE-treated patient (1.1%) developed immunogenicity, 14.4% of patients experienced SAEs, and no SC injection reactions were reported. For patients entering the LTE period, mean DAS28 changes from baseline were -1.84 (95% CI -2.23, -1.34; combination) and -2.86 (95% CI -3.46, -2.27; monotherapy) at month 18. SC abatacept did not elicit immunogenicity associated with loss of safety or efficacy, either with or without MTX. Copyright © 2013 by the American College of Rheumatology.

Ehrlichiosis

MedlinePlus

... cause a number of serious diseases worldwide, including Rocky Mountain spotted fever and typhus . All of these diseases are spread ... cases. Sometimes, the disease may be mistaken for Rocky Mountain spotted fever. The symptoms are often mild, but people are ...

[Correlations between climate change-related infectious diseases and meteorological factors in Korea].

PubMed

Kim, Si Heon; Jang, Jae Yeon

2010-09-01

Infectious diseases are known to be affected by climate change. We investigated if the infectious diseases were related to meteorological factors in Korea. Scrub typhus, hemorrhagic fever with renal syndrome (HFRS), leptospirosis, malaria and Vibrio vulnificus sepsis among the National Notifiable Infectious Diseases were selected as the climate change-related infectious diseases. Temperature, relative humidity and precipitation were used as meteorological factors. The study period was from 2001 through 2008. We examined the seasonality of the diseases and those correlations with meteorological factors. We also analyzed the correlations between the incidences of the diseases during the outbreak periods and monthly meteorological factors in the hyper-endemic regions. All of the investigated diseases showed strong seasonality; malaria and V. vulnificus sepsis were prevalent in summer and scrub typhus, HFRS and leptospirosis were prevalent in the autumn. There were significant correlations between the monthly numbers of cases and all the meteorological factors for malaria and V. vulnificus sepsis, but there were no correlation for the other diseases. However, the incidence of scrub typhus in hyper-endemic region during the outbreak period was positively correlated with temperature and humidity during the summer. The incidences of HFRS and leptospirosis had positive correlations with precipitation in November and temperature and humidity in February, respectively. V. vulnificus sepsis showed positive correlations with precipitation in April/May/July. In Korea, the incidences of the infectious diseases were correlated with meteorological factors, and this implies that the incidences could be influenced by climate change.

Laboratory evaluation of aromatic essential oils from thirteen plant species as candidate repellents against Leptotrombidium chiggers (Acari: Trombiculidae), the vector of scrub typhus.

PubMed

Eamsobhana, Praphathip; Yoolek, Adisak; Kongkaew, Wittaya; Lerdthusnee, Kriangkrai; Khlaimanee, Nittaya; Parsartvit, Anchana; Malainual, Nat; Yong, Hoi-Sen

2009-03-01

Scrub typhus, a rickettsial disease transmitted by several species of Leptotrombidium chiggers (larvae), is endemic in many areas of Asia. The disease is best prevented by the use of personal protective measures, including repellents. In this study commercially produced aromatic, essential oils of 13 plant species and ethanol (control) were tested in the laboratory for repellency against host-seeking chiggers of Leptotrombidium imphalum Vercammen-Grandjean and Langston (Acari: Trombiculidae). A rapid, simple and economic in vitro test method was used by exposing the chigger for up to 5 min. Repellency was based on relative percentages of chiggers attracted to test and control substances. Four of the 13 essential oils showed promise as effective repellent against L. imphalum chiggers. Syzygium aromaticum (clove) oil exhibited 100% repellency at 5% concentration (dilution with absolute ethanol), whereas Melaleuca alternifolia (tea tree) oil exhibited 100% repellency at 40% concentration. Undiluted oils of Zingiber cassamunar (plai) and Eucalyptus globules (blue gum) exhibited 100% repellency. Of the remaining nine essential oils, only 100% Pelargonium graveolens (geranium) exhibited >50% repellency (viz. 57%). Styrax torkinensis (benzoin) oil did not exhibit any repellency. These findings show that several aromatic, essential oils of plants may be useful as chigger repellent for the prevention of scrub typhus. Syzygium aromaticum oil may be safer and more economical to prevent chigger attacks than commercially available synthetic chemicals, such as DEET that may have harmful side effects.

[Little known activity of the Czestochowa typhus Institute in 1943 and 1944].

PubMed

Aramowicz, P; Fijałek, J; Lutrzykowski, A

1996-01-01

In 1921 Prof. Rudolf Weigl started manufacturing on an industrial scale a typhus vaccine. Until the beginning of World War Two he organised five companies called Weigl Institute. During the Soviet occupation the Lvov plant became the Lvov Sanitary and Bacteriological Institute and after the town was taken over by the German Army on 1st July 1941, Prof. Weigl became a head of research of the Military Typhus Institute. It consisted of four sections for manufacturing the vaccine. All the produce was mainly despatched to the Russian front and only very little reached the civilians. In November and December 1943 the plant was moved to Czestochowa into a main building in Wilsona str. and two four storey others in Jasnogórska str. Its head became a German doctor Mozer (witness test). It is difficult to state numbers the plant employed there being no data left but according to employees still alive there must have been about a hundred lab. staff and two hundred feeders. The plant was divided into "breeding", "preparatory" and "liofilisation" sections. "The breeding" was for feeders and breeding lice. Cages containing about 30,000 lice were fastened to voluntary feeders for each feeding. Next "loaders" covered a so-called key board with 20 insects and infectors introduced and pressurised solution containing live rickets into a louse intestine. After a six or seven day passage, lice ware dried and their intestines prepared to produce liofilizeate all the staff and their families were inoculated. ...

Isolation and Characterization of Orientia tsutsugamushi from Rodents Captured following a Scrub Typhus Outbreak at a Military Training Base, Bothong District, Chonburi Province, Central Thailand

DTIC Science & Technology

2011-01-01

pended in M199 medium (Grand Island Biological Company [GIBCO), Grand Island, NY), and subsequently exposed to 3,000-rad irradiation in 60Co gamma... irradiator (Atomic Energy of Canada, Ltd., Ottawa, Canada). Irradiated L-929 cells were dispensed into three 50-cm2 flasks to develop a monolayer...monolayers of irradiated L-929 cells. Inoculated cells were incubated at room temperature for 1 hour on a shaker and then the BHI supernatant was dis

HIV-1 Immunogen: an overview of almost 30 years of clinical testing of a candidate therapeutic vaccine.

PubMed

Graziani, Gina M; Angel, Jonathan B

2016-07-01

Although current antiretroviral therapy (ART) has transformed HIV infection into a chronic, manageable disease, ART does not cure HIV infection. Furthermore, the majority of the world's infected individuals live in resource-limited countries in which access to ART is limited. Thus, the development of an effective therapeutic HIV vaccine would be an invaluable treatment alternative. Developed by the late Dr. Jonas Salk, HIV-1 Immunogen (Remune®) is a candidate therapeutic vaccine that has been studied in thousands of HIV-infected individuals in more than a dozen clinical trials during almost three decades. This Drug Evaluation, which summarizes the results of these trials that have shown the vaccine to be safe and immunogenic, also discusses the contradictory and controversial conclusions drawn from the phases 2, 2/3 and 3 trials that assessed the clinical efficacy of this vaccine. Given the lack of unequivocal clinical benefits of HIV-1 Immunogen despite almost 30 years of extensive testing, it does not appear, in our view, that this vaccine is a clinically effective immunotherapy. However, inclusion of this vaccine in the newly proposed 'Kick/Shock and Kill' strategy for HIV eradication, or use as a prophylactic vaccine, could be considered for future trials.

Immunogenicity and protective efficacy of rotavirus VP8* fused to cholera toxin B subunit in a mouse model.

PubMed

Xue, Miaoge; Yu, Linqi; Jia, Lianzhi; Li, Yijian; Zeng, Yuanjun; Li, Tingdong; Ge, Shengxiang; Xia, Ningshao

2016-11-01

In attempts to develop recombinant subunit vaccines against rotavirus disease, it was previously shown that the N-terminal truncated VP8* protein, VP8-1 (aa26-231), is a good vaccine candidate when used for immunization in combination with Freund's adjuvant. However, this protein stimulated only weak immune response when aluminum hydroxide was used as an adjuvant. In this study, the nontoxic B subunit of cholera toxin (CTB) was employed as intra-molecular adjuvant to improve the immunogenicity of VP8-1. Both, the N-terminal and C-terminal fusion proteins, were purified to homogeneity, at which stage they formed pentamers, and showed significantly higher immunogenicity and protective efficacy than a VP8-1/aluminum hydroxide mixture in a mouse model. Compared to VP8-1-CTB, CTB-VP8-1 showed higher binding activity to both, GM1 and the conformation sensitive neutralizing monoclonal antibodies specific to VP8. More importantly, CTB-VP8-1 elicited higher titers of neutralizing antibodies and conferred higher protective efficacy than VP8-1-CTB. Therefore, the protein CTB-VP8-1, with enhanced immunogenicity and immunoprotectivity, could be considered as a viable candidate for further development of an alternative, replication-incompetent, parenterally administered vaccine against rotavirus disease.

An immunogen synthesis strategy for the development of specific anti-deoxynivalenol monoclonal antibodies.

PubMed

Sanders, Melanie; Guo, Yirong; Iyer, Abhishek; García, Yara Ruiz; Galvita, Anastasia; Heyerick, Arne; Deforce, Dieter; Risseeuw, Martijn D P; Van Calenbergh, Serge; Bracke, Marc; Eremin, Sergei; Madder, Annemieke; De Saeger, Sarah

2014-01-01

An immunogen synthesis strategy was designed to develop anti-deoxynivalenol (DON) monoclonal antibodies with low cross-reactivity against structurally similar trichothecenes. A total of eight different DON immunogens were synthesised, differing in the type and position of the linker on the DON molecule. After immunisation, antisera from mice immunised with different DON immunogens were checked for the presence of relevant antibodies. Then, both homologous and heterologous enzyme-linked immunosorbent assays (ELISAs) were performed for hybridoma screening. Finally, three monoclonal antibodies against DON and its analogues were generated. In addition, monoclonal antibody 13H1 could recognise DON and its analogues in the order of HT-2 toxin > 15-acetyldeoxynivalenol (15-ADON) > DON, with IC₅₀ ranging from 1.14 to 2.13 µg ml⁻¹. Another monoclonal antibody 10H10 manifested relatively close sensitivities to DON, 3-acetyldeoxynivalenol (3-ADON) and 15-ADON, with IC₅₀ values of 22, 15 and 34 ng ml⁻¹, respectively. Using an indirect ELISA format decreases the 10H10 sensitivity to 15-ADON with 92%. A third monoclonal antibody 2A9 showed to be very specific and sensitive to 3-ADON, with IC₅₀ of 0.38 ng ml⁻¹. Using both 2A9 and 10H10 monoclonal antibodies allows determining sole DON contamination.

Protein instability and immunogenicity: roadblocks to clinical application of injectable protein delivery systems for sustained release.

PubMed

Jiskoot, Wim; Randolph, Theodore W; Volkin, David B; Middaugh, C Russell; Schöneich, Christian; Winter, Gerhard; Friess, Wolfgang; Crommelin, Daan J A; Carpenter, John F

2012-03-01

Protein instability and immunogenicity are two main roadblocks to the clinical success of novel protein drug delivery systems. In this commentary, we discuss the need for more extensive analytical characterization in relation to concerns about protein instability in injectable drug delivery systems for sustained release. We then will briefly address immunogenicity concerns and outline current best practices for using state-of-the-art analytical assays to monitor protein stability for both conventional and novel therapeutic protein dosage forms. Next, we provide a summary of the stresses on proteins arising during preparation of drug delivery systems and subsequent in vivo release. We note the challenges and difficulties in achieving the absolute requirement of quantitatively assessing the degradation of protein molecules in a drug delivery system. We describe the potential roles for academic research in further improving protein stability and developing new analytical technologies to detect protein degradation byproducts in novel drug delivery systems. Finally, we provide recommendations for the appropriate approaches to formulation design and assay development to ensure that stable, minimally immunogenic formulations of therapeutic proteins are created. These approaches should help to increase the probability that novel drug delivery systems for sustained protein release will become more readily available as effective therapeutic agents to treat and benefit patients. Copyright © 2011 Wiley Periodicals, Inc.

Perspectives on Subcutaneous Route of Administration as an Immunogenicity Risk Factor for Therapeutic Proteins.

PubMed

Hamuro, Lora; Kijanka, Grzegorz; Kinderman, Francis; Kropshofer, Harald; Bu, De-Xiu; Zepeda, Monica; Jawa, Vibha

2017-10-01

An increasing number of therapeutic proteins are being developed for delivery through the subcutaneous (SC) route of administration. Relative to intravenous (IV) administration, the SC route offers more convenience to patients, flexibility in dosing, and potential to reduce health care costs. There is a perception that SC administration can pose a higher immunogenicity risk than IV administration for a given protein. To evaluate whether there is a difference in therapeutic protein immunogenicity associated with administration routes, a more detailed understanding of the interactions with the immune system by each route is needed. Few approved therapeutic proteins have available clinical immunogenicity data sets in the public domain that represent both IV and SC administration routes. This has prevented a direct comparison of the 2 routes of administration across a large sample size. Of the 6 marketed products where SC and IV route-related incidences of anti-drug antibody (ADA) were available, 4 were associated with higher immunogenicity incidence with SC. In other cases, there was no apparent difference between the SC and IV routes. Overall, the ADA incidence was low (<15%) with no impact on safety or efficacy. The challenges associated with identifying specific risk factors unique to SC administration are discussed. Copyright © 2017 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.

Native-like aggregates of Factor VIII (FVIII) are immunogenic von Willebrand Factor deficient and hemophilia A mice

PubMed Central

Pisal, Dipak S.; Kosloski, Matthew P.; Middaugh, C. Russell; Bankert, Richard B.; Balu-Iyer, Sathy V.

2013-01-01

The administration of recombinant Factor VIII (FVIII) is the first line therapy for Hemophilia A (HA), but 25–35% of patients develop an inhibitory antibody response. In general, the presence of aggregates contributes to unwanted immunogenic responses against therapeutic proteins. FVIII has been shown to form both native-like and non-native aggregates. Previously, we showed that non-native aggregates of FVIII are less immunogenic compared to the native protein. Here we investigated the effect of native-like aggregates of FVIII on immunogenicity in HA and von Willebrand Factor knockout (vWF−/−) mice. Mice immunized with native-like aggregates showed significantly higher inhibitory antibody titers compared to animals that received native FVIII. Following re-stimulation in vitro with native FVIII, the activation of CD4+ T cells isolated from mice immunized with native-like aggregates is ~4 fold higher than mice immunized with the native protein. Furthermore, this is associated with increases in the secretion of pro-inflammatory cytokines IL-6 and IL-17 in the native-like aggregate treatment group. The results indicate that the native-like aggregates of FVIII are more immunogenic than native FVIII for both the B cell and T cell responses. PMID:22388918

Stability of the Rabbit Immunogenic Marker of RA 27/3 Rubella Vaccine Virus After Human Passage

PubMed Central

Linnemann, Calvin C.; Hutchinson, Leslie; Rotte, Thomas C.; Hegg, Marion E.; Schiff, Gilbert M.

1974-01-01

Rabbits were inoculated intravenously with “wild” rubella virus, RA 27/3 rubella vaccine virus, or rubella virus isolated from recipients of RA 27/3 vaccine. Rabbits receiving “wild” virus developed rubella hemagglutination inhibition antibody, and those receiving vaccine virus did not. One of the five reisolates tested produced a low transient antibody response in two of the five rabbits inoculated with this strain. The study indicates that the rabbit immunogenic marker after intravenous injection can be used to determine if a rubella virus isolated from a patient is of “wild” or vaccine origin. There was no significant change in the reduced immunogenicity characteristics of the RA 27/3 vaccine virus after human passage. PMID:4206028

Immunogenicity and immune tolerance coagulation Factors VIII and IX.

PubMed

Rup, B

2003-01-01

Some of the major issues related to the development and control of antibodies that occur during treatment of haemophilia with replacement factors (Factor VIII and Factor IX) are reviewed. Information on analytical issues, immunogenicity, and immune tolerance may be applicable to the study of other therapeutic proteins. Conversely, new information obtained from evaluation of other therapeutic protein products may address issues that remain unresolved for Factor VIII and FIX replacement therapy.

Enhancing the Immunogenicity of a Tetravalent Dengue DNA Vaccine

DTIC Science & Technology

2016-08-01

is safe and well tolerated, but does not elicit a sufficient immune response. The objectives of this project are to conduct studies in non -human...injection for enhancing TVDV in non -human primates. Specific Aim 2: Develop an improved dengue vaccine using a heterologous prime boost approach...not elicit a sufficient immune response. The objectives of this project are to conduct studies in non -human primates to enhance the immunogenicity of

Preclinical development of BCG.HIVA2auxo.int, harboring an integrative expression vector, for a HIV-TB Pediatric vaccine. Enhancement of stability and specific HIV-1 T-cell immunity.

PubMed

Mahant, Aakash; Saubi, Narcís; Eto, Yoshiki; Guitart, Núria; Gatell, Josep Ma; Hanke, Tomáš; Joseph, Joan

2017-08-03

One of the critical issues that should be addressed in the development of a BCG-based HIV vaccine is genetic plasmid stability. Therefore, to address this issue we have considered using integrative vectors and the auxotrophic mutant of BCG complemented with a plasmid carrying a wild-type complementing gene. In this study, we have constructed an integrative E. coli-mycobacterial shuttle plasmid, p2auxo.HIVA int , expressing the HIV-1 clade A immunogen HIVA. This shuttle vector uses an antibiotic resistance-free mechanism for plasmid selection and maintenance. It was first transformed into a glycine auxotrophic E. coli strain and subsequently transformed into a lysine auxotrophic Mycobacterium bovis BCG strain to generate the vaccine BCG.HIVA 2auxo.int . Presence of the HIVA gene sequence and protein expression was confirmed. We demonstrated that the in vitro stability of the integrative plasmid p2auxo.HIVA int was increased 4-fold, as compared with the BCG strain harboring the episomal plasmid, and was genetically and phenotypically characterized. The BCG.HIVA 2auxo.int vaccine in combination with modified vaccinia virus Ankara (MVA).HIVA was found to be safe and induced HIV-1 and Mycobacterium tuberculosis-specific interferon-γ-producing T-cell responses in adult BALB/c mice. We have engineered a more stable and immunogenic BCG-vectored vaccine using the prototype immunogen HIVA. Thus, the use of integrative expression vectors and the antibiotic-free plasmid selection system based on "double" auxotrophic complementation are likely to improve the mycobacterial vaccine stability in vivo and immunogenicity to develop not only recombinant BCG-based vaccines expressing second generation of HIV-1 immunogens but also other major pediatric pathogens to prime protective responses shortly following birth.

Analysis of the immunoproteome of Mycoplasma mycoides subsp. mycoides small colony type reveals immunogenic homologues to other known virulence traits in related Mycoplasma species.

PubMed

Jores, Joerg; Meens, Jochen; Buettner, Falk F R; Linz, Bodo; Naessens, Jan; Gerlach, Gerald F

2009-10-15

Contagious bovine pleuropneumonia (CBPP) caused by Mycoplasma mycoides subsp. mycoides small colony type (MmmSC) has been eradicated in the developed world, but it is still present in many countries of sub-Saharan Africa. After initially successful control measures in the 1960s it has been spreading due to a lack of money, fragmentation of veterinary services, uncontrolled cattle movement, insufficient vaccine efficacy and sensitivity of current diagnostic tests. In this study we used two-dimensional polyacrylamide gel electrophoresis followed by immunoblot with sera from MmmSC-infected animals and MALDI-ToF mass spectrometry to identify novel immunogenic proteins as candidate molecules for improved diagnostics and vaccines. We identified 24 immunogens recognized by pooled sera from experimentally infected cattle. Furthermore, a serum from an animal with acute clinical disease as well as severe pathomorphological lesions recognized 13 additional immunogens indicating variation in the antibody responses to CBPP amongst cattle. Most immunogens showed compelling similarity to protein/gene sequences in the two ruminant pathogens M. capricolum subsp. capricolum and M. mycoides subsp. mycoides large colony type both belonging to the mycoides cluster. Three of these proteins, namely glycerol-3-phosphate oxidase, adenylosuccinate synthase, and glyceraldehyde-3-phosphate dehydrogenase, had no compelling homologue in the other distantly related bovine pathogen M. agalactiae. In addition, translation elongation factor Tu, heat shock protein 70, pyruvate dehydrogenase, and FKBP-type peptidyl-prolyl isomerase, which have been found to mediate adhesion to host tissue in other mycoplasmas were shown to be expressed and recognized by sera. These proteins have potential for the development of improved diagnostic tests and possibly vaccines.

Virus-Like Particle, Liposome, and Polymeric Particle-Based Vaccines against HIV-1

PubMed Central

Gao, Yong; Wijewardhana, Chanuka; Mann, Jamie F. S.

2018-01-01

It is acknowledged that vaccines remain the best hope for eliminating the HIV-1 epidemic. However, the failure to produce effective vaccine immunogens and the inability of conventional delivery strategies to elicit the desired immune responses remains a central theme and has ultimately led to a significant roadblock in HIV vaccine development. Consequently, significant efforts have been applied to generate novel vaccine antigens and delivery agents, which mimic viral structures for optimal immune induction. Here, we review the latest developments that have occurred in the nanoparticle vaccine field, with special emphasis on strategies that are being utilized to attain highly immunogenic, systemic, and mucosal anti-HIV humoral and cellular immune responses. This includes the design of novel immunogens, the central role of antigen-presenting cells, delivery routes, and biodistribution of nanoparticles to lymph nodes. In particular, we will focus on virus-like-particle formulations and their preclinical uses within the HIV prophylactic vaccine setting. PMID:29541072

Therapeutic outcomes, assessments, risk factors and mitigation efforts of immunogenicity of therapeutic protein products.

PubMed

Yin, Liusong; Chen, Xiaoying; Vicini, Paolo; Rup, Bonita; Hickling, Timothy P

2015-06-01

Therapeutic protein products (TPPs) are of considerable value in the treatment of a variety of diseases, including cancer, hemophilia, and autoimmune diseases. The success of TPP mainly results from prolonged half-life, increased target specificity and decreased intrinsic toxicity compared with small molecule drugs. However, unwanted immune responses against TPP, such as generation of anti-drug antibody, can impact both drug efficacy and patient safety, which has led to requirements for increased monitoring in regulatory studies and clinical practice, termination of drug development, or even withdrawal of marketed products. We present an overview of current knowledge on immunogenicity of TPP and its impact on efficacy and safety. We also discuss methods for measurement and prediction of immunogenicity and review both product-related and patient-related risk factors that affect its development, and efforts that may be taken to mitigate it. Lastly, we discuss gaps in knowledge and technology and what is needed to fill these. Copyright © 2015 Elsevier Inc. All rights reserved.

Supramolecular peptide hydrogel adjuvanted subunit vaccine elicits protective antibody responses against West Nile virus.

PubMed

Friedrich, Brian M; Beasley, David W C; Rudra, Jai S

2016-11-04

A crucial issue in vaccine development is to balance safety with immunogenicity. The low immunogenicity of most subunit antigens warrants a search for adjuvants able to stimulate both cell-mediated and humoral immunity. In recent years, successful applications of nanotechnology and bioengineering in the field of vaccine development have enabled the production of novel adjuvant technologies. In this work, we investigated totally synthetic and supramolecular peptide hydrogels as novel vaccine adjuvants in conjunction with the immunoprotective envelope protein domain III (EIII) of West Nile virus as an immunogen in a mouse model. Our results indicate that, compared to the clinically approved adjuvant alum, peptide hydrogel adjuvanted antigen elicited stronger antibody responses and conferred significant protection against mortality after virus challenge. The high chemical definition and biocompatibility of self-assembling peptide hydrogels makes them attractive as immune adjuvants for the production of subunit vaccines against viral and bacterial infections where antibody-mediated protection is desirable. Copyright © 2016 Elsevier Ltd. All rights reserved.

Mathematical Modeling for Scrub Typhus and Its Implications for Disease Control.

PubMed

Min, Kyung Duk; Cho, Sung Il

2018-03-19

The incidence rate of scrub typhus has been increasing in the Republic of Korea. Previous studies have suggested that this trend may have resulted from the effects of climate change on the transmission dynamics among vectors and hosts, but a clear explanation of the process is still lacking. In this study, we applied mathematical models to explore the potential factors that influence the epidemiology of tsutsugamushi disease. We developed mathematical models of ordinary differential equations including human, rodent and mite groups. Two models, including simple and complex models, were developed, and all parameters employed in the models were adopted from previous articles that represent epidemiological situations in the Republic of Korea. The simulation results showed that the force of infection at the equilibrium state under the simple model was 0.236 (per 100,000 person-months), and that in the complex model was 26.796 (per 100,000 person-months). Sensitivity analyses indicated that the most influential parameters were rodent and mite populations and contact rate between them for the simple model, and trans-ovarian transmission for the complex model. In both models, contact rate between humans and mites is more influential than morality rate of rodent and mite group. The results indicate that the effect of controlling either rodents or mites could be limited, and reducing the contact rate between humans and mites is more practical and effective strategy. However, the current level of control would be insufficient relative to the growing mite population. © 2018 The Korean Academy of Medical Sciences.

Travelers' Health: Rickettsial (Spotted and Typhus Fevers) and Related Infections (Anaplasmosis and Ehrlichiosis)

MedlinePlus

... Climates Humanitarian Aid Workers Humanitarian Aid Workers in Ecuador Insurance International Adoption Jet Lag Last-Minute Travel Long-Term Travel Mass Gatherings Medical Tourism Mental Health Motion Sickness Natural Disasters Pregnant Travelers ...

Tests on ticks from wild birds collected in the eastern United States for rickettsiae and viruses

USGS Publications Warehouse

Clifford, C.M.; Sonenshine, D.E.; Atwood, E.L.; Robbins, C.S.; Hughes, L.E.

1969-01-01

Results of tests for rickettsiae and viruses on 4,266 ticks taken from more than 10,000 birds, comprising 150 species, in the eastern United States indicated the presence of two agents: Rickettsia rickettsii and an agent of the typhus group. Infection with R. rickettsii was indicated in 24 pools of Haemaphysalis leporispalustris, five pools of Ixodes dentatus, one pool of Ixodes brunneus, and two pools that contained both I. dentatus and H. leporispalustris. The pools positive for R. rickettsii were from a variety of locations in the eastern U. S. The typhus-group agent was demonstrated only once, in a single pool of H. leporispalustris taken at Kent Point, Maryland. A strain of R. rickettsii was isolated from a pool of 21 larval H. leporispalustris collected at Ocean City, Maryland. This agent possessed several characteristics of other strains of low virulence isolated previously in this region by various authors.

Laboratory tests of arthropod repellents against Leptotrombidium deliense--noninfected and infected with Rickettsia tsutsugamushi--and noninfected L. fletcheri (Acari: Trombiculidae).

PubMed

Frances, S P; Khlaimanee, N

1996-03-01

Laboratory tests were conducted to compare the response of noninfected Leptotrombidium deliense Sambon and Leptotrombidium fletcheri (Womersley & Heaslip) and L. deliense naturally infected with Rickettsia tsutsugamushi, the etiologic agent of scrub typhus, to 8 chemical repellents and toxicants. Low concentrations of permethrin, dimethylphthalate, diethyl methylbenzamide, benzyl benzoate, di-n-propyl 2,5-pyridine-dicarboxylate, 1-(3-Cyclohexen-1-yl-carbonyl)-2-methylpiperidine (AI3-37220), 2-hydroxymethyl-cyclohexyl acetic acid lactone, and a high concentration of dibutylphthalate (DBP) were toxic for noninfected larvae of both species tested. The median effective knockdown time for all chemicals, except 1% AI3-37220 and 5% permethrin, were longer against infected L. deliense than uninfected larvae of the same species. However, the results indicate that low concentrations of all chemicals, except DBP, should be effective against 2 important vectors of scrub typhus.

Randomized phase I trial HIV-CORE 003: Depletion of serum amyloid P component and immunogenicity of DNA vaccination against HIV-1.

PubMed

Borthwick, Nicola J; Lane, Thirusha; Moyo, Nathifa; Crook, Alison; Shim, Jung Min; Baines, Ian; Wee, Edmund G; Hawkins, Philip N; Gillmore, Julian D; Hanke, Tomáš; Pepys, Mark B

2018-01-01

The failure of DNA vaccination in humans, in contrast to its efficacy in some species, is unexplained. Observational and interventional experimental evidence suggests that DNA immunogenicity may be prevented by binding of human serum amyloid P component (SAP). SAP is the single normal DNA binding protein in human plasma. The drug (R)-1-[6-[(R)-2-carboxypyrrolidin-1-yl]-6-oxo-hexanoyl]pyrrolidine-2-carboxylic acid (CPHPC, miridesap), developed for treatment of systemic amyloidosis and Alzheimer's disease, depletes circulating SAP by 95-99%. The proof-of-concept HIV-CORE 003 clinical trial tested whether SAP depletion by CPHPC would enhance the immune response in human volunteers to DNA vaccination delivering the HIVconsv immunogen derived from conserved sub-protein regions of HIV-1. Human volunteers received 3 intramuscular immunizations with an experimental DNA vaccine (DDD) expressing HIV-1-derived immunogen HIVconsv, with or without prior depletion of SAP by CPHPC. All subjects were subsequently boosted by simian (chimpanzee) adenovirus (C)- and poxvirus MVA (M)-vectored vaccines delivering the same immunogen. After administration of each vaccine modality, the peak total magnitudes, kinetics, functionality and memory subsets of the T-cell responses to HIVconsv were thoroughly characterized. No differences were observed between the CPHPC treated and control groups in any of the multiple quantitative and qualitative parameters of the T-cell responses to HIVconsv, except that after SAP depletion, there was a statistically significantly greater breadth of T-cell specificities, that is the number of recognized epitopes, following the DDDC vaccination. The protocol used here for SAP depletion by CPHPC prior to DNA vaccination produced only a very modest suggestion of enhanced immunogenicity. Further studies will be required to determine whether SAP depletion might have a practical value in DNA vaccination for other plasmid backbones and/or immunogens. Clinicaltrials.gov NCT02425241.

Coupling of aggregation and immunogenicity in biotherapeutics: T- and B-cell immune epitopes may contain aggregation-prone regions.

PubMed

Kumar, Sandeep; Singh, Satish K; Wang, Xiaoling; Rup, Bonita; Gill, Davinder

2011-05-01

Biotherapeutics, including recombinant or plasma-derived human proteins and antibody-based molecules, have emerged as an important class of pharmaceuticals. Aggregation and immunogenicity are among the major bottlenecks during discovery and development of biotherapeutics. Computational tools that can predict aggregation prone regions as well as T- and B-cell immune epitopes from protein sequence and structure have become available recently. Here, we describe a potential coupling between aggregation and immunogenicity: T-cell and B-cell immune epitopes in therapeutic proteins may contain aggregation-prone regions. The details of biological mechanisms behind this observation remain to be understood. However, our observation opens up an exciting potential for rational design of de-immunized novel, as well as follow on biotherapeutics with reduced aggregation propensity.

Monocyte NOTCH2 expression predicts IFN-β immunogenicity in multiple sclerosis patients.

PubMed

Adriani, Marsilio; Nytrova, Petra; Mbogning, Cyprien; Hässler, Signe; Medek, Karel; Jensen, Poul Erik H; Creeke, Paul; Warnke, Clemens; Ingenhoven, Kathleen; Hemmer, Bernhard; Sievers, Claudia; Lindberg Gasser, Raija Lp; Fissolo, Nicolas; Deisenhammer, Florian; Bocskei, Zsolt; Mikol, Vincent; Fogdell-Hahn, Anna; Kubala Havrdova, Eva; Broët, Philippe; Dönnes, Pierre; Mauri, Claudia; Jury, Elizabeth C

2018-06-07

Multiple sclerosis (MS) is an autoimmune disease characterized by CNS inflammation leading to demyelination and axonal damage. IFN-β is an established treatment for MS; however, up to 30% of IFN-β-treated MS patients develop neutralizing antidrug antibodies (nADA), leading to reduced drug bioactivity and efficacy. Mechanisms driving antidrug immunogenicity remain uncertain, and reliable biomarkers to predict immunogenicity development are lacking. Using high-throughput flow cytometry, NOTCH2 expression on CD14+ monocytes and increased frequency of proinflammatory monocyte subsets were identified as baseline predictors of nADA development in MS patients treated with IFN-β. The association of this monocyte profile with nADA development was validated in 2 independent cross-sectional MS patient cohorts and a prospective cohort followed before and after IFN-β administration. Reduced monocyte NOTCH2 expression in nADA+ MS patients was associated with NOTCH2 activation measured by increased expression of Notch-responsive genes, polarization of monocytes toward a nonclassical phenotype, and increased proinflammatory IL-6 production. NOTCH2 activation was T cell dependent and was only triggered in the presence of serum from nADA+ patients. Thus, nADA development was driven by a proinflammatory environment that triggered activation of the NOTCH2 signaling pathway prior to first IFN-β administration.

Aggregated Recombinant Human Interferon Beta Induces Antibodies but No Memory in Immune-Tolerant Transgenic Mice

PubMed Central

Sauerborn, Melody; Gilli, Francesca; Brinks, Vera; Schellekens, Huub; Jiskoot, Wim

2010-01-01

ABSTRACT Purpose To study the influence of protein aggregation on the immunogenicity of recombinant human interferon beta (rhIFNβ) in wild-type mice and transgenic, immune-tolerant mice, and to evaluate the induction of immunological memory. Methods RhIFNβ-1b and three rhIFNβ-1a preparations with different aggregate levels were injected intraperitoneally in mice 15× during 3 weeks, and the mice were rechallenged with rhIFNβ-1a. The formation of binding (BABs) and neutralizing antibodies (NABs) was monitored. Results Bulk rhIFNβ-1a contained large, mainly non-covalent aggregates and stressed rhIFNβ-1a mainly covalent, homogeneous (ca. 100 nm) aggregates. Reformulated rhIFNβ-1a was essentially aggregate-free. All products induced BABs and NABs in wild-type mice. Immunogenicity in the transgenic mice was product dependent. RhIFNβ-1b showed the highest and reformulated rhIFNβ-1a the lowest immunogenicity. In contrast with wild-type mice, transgenic mice did not show NABs, nor did they respond to the rechallenge. Conclusions The immunogenicity of the products in transgenic mice, unlike in wild-type mice, varied. In the transgenic mice, neither NABs nor immunological memory developed. The immunogenicity of rhIFNβ in a model reflecting the human immune system depends on the presence and the characteristics of aggregates. PMID:20499141

Scrub typhus (Orientia tsutsugamushi), spotted fever (Rickettsia australis) and dengue fever as possible causes of mysterious deaths in the Strickland Gorge area of Southern Highlands and West Sepik Provinces of Papua New Guinea.

PubMed

Spicer, P E; Taufa, T; Benjamin, A L

2007-01-01

A medical investigation was carried out in April 2001 into an outbreak of a mysterious haemorrhagic disease and deaths in the remote picturesque Strickland River area of Papua New Guinea (PNG). The area is in part of the Southern Highlands and West Sepik Provinces and situated downstream from the Porgera Joint Venture gold mine. 9 villages were visited and 140 persons, consisting of immediate blood relatives of the deceased (cases) and others in the village picked at random (controls), were physically examined. Specimens of blood, urine and faeces were collected from each person for laboratory tests in PNG and Australia. Positive sera for dengue (15%) and Japanese encephalitis (JE) (6%) were identified. Surprisingly, a number of the sera were positive for scrub typhus (Orientia tsutsugamushi) (28%) and spotted fever (Rickettsia australis) (11%). The last reported cases of scrub typhus in PNG were during World War Two among the allied troops. This is the first time spotted fever (R. australis) has been reported in PNG. These conditions may have been the cause of the deaths described by the villagers. However, there were significantly more dengue-positive results among relatives of the deceased than non-relatives though no such difference was found with rickettsial infections: haemorrhagic dengue fever is thus the most likely cause of this recurring outbreak. Mining did not appear to be a direct causal factor for the deaths in the area.

Rickettsiae and rickettsial diseases

PubMed Central

Brezina, R.; Murray, E. S.; Tarizzo, M. L.; Bögel, K.

1973-01-01

This paper summarizes present knowledge on rickettsiae and rickettsial diseases, and on their epidemiological characteristics, control, and public health significance. There are many natural foci of rickettsial diseases, from where the disease may spread to other areas in the world under changing socioeconomic conditions. Because of rapid long-distance travel, sporadic cases of serious rickettsial diseases may today appear far from endemic areas where the infection occurred. Even in endemic areas the disease may be misdiagnosed and deaths may occur as a result of inadequate treatment. Rapid treatment of rickettsial infections (preferably with tetracyclines) is therefore most important. Epidemic louse-borne typhus, though no longer subject to the International Health Regulations, remains one of the diseases in the WHO epidemiological surveillance programme. This disease continues to be a major cause of morbidity and mortality in some parts of Africa and it is present also in parts of the Americas and of Asia. Scrub typhus remains a continuing and serious public health problem in areas of South-East Asia and in the Western Pacific. The annual number of reported cases of Rocky Mountain spotted fever in the USA showed an increase during the last two decades, which may be due to improved recognition as well as to increased outdoor activities and migration of people from the city centres to the suburbs. Related forms of tick-borne typhus occur in South America, the Mediterranean region, Africa, South-East Asia, the Far East, and the Western Pacific. Increasing in number, though still sporadic, are reports of serious illness from chronic Q fever infection in many parts of the world. PMID:4547297

Serologic evidence of human Rickettsia infection found in three locations in Panamá.

PubMed

Bermúdez, Sergio E; Lyons, Cirilo R; García, Gleydis G; Zaldíva, Yamitzel L; Gabster, Amanda; Arteaga, Griselda B

2013-09-01

Since the middle of last century, cases of rickettsiosis have been found in Panamá when outbreaks of murine typhus and spotted fever were reported. Since then, little information exists about its prevalence in this country, since it is most often is misdiagnosed as another disease. The aim of this paper is to demonstrate the presence of Rickettsia infections in humans in three locations in Panamá. These locations are agricultural areas, near forested areas or those who work in zoo. Three locations where chosen for this study: Tortí, El Valle de Antón and workers in the Summit Municipal Park in Panamá City. All volunteers signed an informed consent and answered a questionnaire. The samples were analyzed for the detection of rickettsial spotted fever and typhus group by the indirect immunofluorescence (using commercial kits) and antigens of Rickettsia rickettsii and R. amblyommii. Blood samples were taken from 97 volunteers in Tortí (25), El Valle de Anton (37) and Summit Municipal Park (35). Of these, a total of 38 (39%) samples reacted to one of the two methods: eight (32%) in Tortí, 18 (48%) in El valle and 12 (34%) in Summit Municipal Park. The results show a high prevalence of antibodies to Rickettsia belonging to the spotted fever group in each of the three study areas, in addition to presenting evidence of the typhus group Rickettsia in El Valle de Anton. These areas could be considered endemic for rickettsiosis as there are conditions for maintaining them.

The RAMC at Belsen 1945: typhus revisited.

PubMed

MacAuslan, Rowan

2016-02-01

The Royal Army Medical Corps (RAMC) has justly regarded its relief of the appalling conditions found in the liberated Nazi concentration camp at Bergen-Belsen in April 1945 as one of its more glorious achievements. This view has, in the last decade, come under attack from historians who have, inter alia, criticised the nature and speed of the medical measures employed by the British. This has focused particularly on the management of the typhus epidemic, erroneously claimed to be the major disease killer of the survivors, and which was the catalyst for the premature German surrender of the camp to the approaching Allies about 3 weeks before the end of the war. This review examines the veracity of this statement and the nature of the evidence on which it was based. Review of all the relevant extant primary source written evidence both published and archived in major collections in London, Washington and Belsen, in addition to the relevant subsequent secondary evidence. Disprove the ill-considered and scientifically flawed attempts to discredit the RAMC and demonstrate that the RAMC can be shown to have made the correct prioritising decisions in relieving starvation as well as in implementing the appropriate public health anti-typhus measures and to have acquitted itself honourably. Underlines the pitfalls of basing sweeping conclusions on an imperfectly understood inadequate selection of the available evidence. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/

Mite vectors (Acari: Trombiculidae) of scrub typhus in a new endemic area in northern Kyoto, Japan.

PubMed

Takahashi, Mamoru; Misumi, Hitoko; Urakami, Hiroshi; Nakajima, Satoko; Furui, Sataro; Yamamoto, Seigo; Furuya, Yumiko; Misumi, Motohiro; Matsumoto, Isao

2004-01-01

Between 1983 and 1999, 27 human cases of scrub typhus (two fatal) occurred in the Nodagawa River basin of northern Kyoto, Japan, an area where no cases had been previously reported. Antibody screening of infected patients' sera showed that nine of 15 patients had high titers against the Gilliam type of Orientia tsutsugamushi (Hayashi). To determine the vector mite transmitting the disease, we studied rodent and chigger populations in and near a rice field alongside the Nodagawa River between 1996 and 1999. The most common rodent species was Microtus montebelli (Milne-Edwards), representing 73.3% (33/45) of the population. The mite index (average number of mites per infested host) was highest (190.8) in Leptotrombidium pallidum Nagayo, Mitamura & Tamiya parasitizing on M. montebelli, followed by Leptotrombidium intermedium (Nagayo, Mitamura & Tamiya) (174.9) on the same host species. Orientia tsutsugamushi was isolated from 60.5% (23/38) of rodents and from 71.2% (37/52) of pools of engorged L. pallidum. The Gilliam type of O. tsutsugamushi was most prevalent in rodents, and in engorged L. pallidum and it was the only type recovered from 10 isolates inoculated into L 929 cells for indirect immunofluorescence examination. Orientia tsutsugamushi infected 14.3% (181/1263) and 14.8% (306/2066) of engorged and unfed L. pallidum larvae, respectively, and was also detected in 0.055% (2/3634) of unfed L. intermedium, although previous studies suggest that this mite rarely bites humans. These results show that L. pallidum is the primary vector species of scrub typhus in this new endemic area in Japan.

Tryptophan 375 stabilizes the outer-domain core of gp120 for HIV vaccine immunogen design.

PubMed

Hu, Duoyi; Bowder, Dane; Wei, Wenzhong; Thompson, Jesse; Wilson, Mark A; Xiang, Shi-Hua

2017-05-25

The outer-domain core of gp120 may serve as a better HIV vaccine immunogen than the full-length gp120 because of its greater stability and immunogenicity. In our previous report, we introduced two disulfide bonds to the outer-domain core of gp120 to fix its conformation into a CD4-bound state, which resulted in a significant increase in its immunogenicity when compared to the wild-type outer-domain core. In this report, to further improve the immunogenicity of the outer-domain core based immunogen, we have introduced a Tryptophan residue at gp120 amino acid sequence position 375 (375S/W). Our data from immunized guinea pigs indeed shows a striking increase in the immune response due to this stabilized core outer-domain. Therefore, we conclude that the addition of 375W to the outer-domain core of gp120 further stabilizes the structure of immunogen and increases the immunogenicity. Copyright © 2017 The Author(s). Published by Elsevier Ltd.. All rights reserved.

Foreignness as a matter of degree: the relative immunogenicity of peptide/MHC ligands.

PubMed

van den Berg, Hugo A; Rand, David A

2004-12-21

The ability of T lymphocytes (T cells) to recognize and attack foreign invaders while leaving healthy cells unharmed is often analysed as a discrete self/non-self dichotomy, with each peptide/MHC ligand classified as either self or non-self. We argue that the ligand immunogenicity is more naturally treated as a continuous quantity, and show how to define and quantitate relative ligand immunogenicity. In our theory, self-tolerance is acquired through reduction of the relative immunogenicity of autoantigens, whereas xenoantigens, typically not presented during induction of deletional tolerance, retain a high degree of relative immunogenicity. Autoantigens that are not prominently presented in deletional tolerance likewise retain a high relative immunogenicity and remain essentially foreign. According to our analysis, any given autoantigen can attain a high level of relative immunogenicity, provided it is presented at sufficiently high levels. Our theory provides a quantitative tool to analyse the immunogenicity of tumour-associated neoantigens and the aetiology of autoimmune disease.

MEFA (multiepitope fusion antigen)-Novel Technology for Structural Vaccinology, Proof from Computational and Empirical Immunogenicity Characterization of an Enterotoxigenic Escherichia coli (ETEC) Adhesin MEFA

PubMed Central

Duan, Qiangde; Lee, Kuo Hao; Nandre, Rahul M; Garcia, Carolina; Chen, Jianhan; Zhang, Weiping

2017-01-01

Vaccine development often encounters the challenge of virulence heterogeneity. Enterotoxigenic Escherichia coli (ETEC) bacteria producing immunologically heterogeneous virulence factors are a leading cause of children’s diarrhea and travelers’ diarrhea. Currently, we do not have licensed vaccines against ETEC bacteria. While conventional methods continue to make progress but encounter challenge, new computational and structure-based approaches are explored to accelerate ETEC vaccine development. In this study, we applied a structural vaccinology concept to construct a structure-based multiepitope fusion antigen (MEFA) to carry representing epitopes of the seven most important ETEC adhesins [CFA/I, CFA/II (CS1–CS3), CFA/IV (CS4–CS6)], simulated antigenic structure of the CFA/I/II/IV MEFA with computational atomistic modeling and simulation, characterized immunogenicity in mouse immunization, and examined the potential of structure-informed vaccine design for ETEC vaccine development. A tag-less recombinant MEFA protein (CFA/I/II/IV MEFA) was effectively expressed and extracted. Molecular dynamics simulations indicated that this MEFA immunogen maintained a stable secondary structure and presented epitopes on the protein surface. Empirical data showed that mice immunized with the tagless CFA/I/II/IV MEFA developed strong antigen-specific antibody responses, and mouse serum antibodies significantly inhibited in vitro adherence of bacteria expressing these seven adhesins. These results revealed congruence of antigen immunogenicity between computational simulation and empirical mouse immunization and indicated this tag-less CFA/I/II/IV MEFA potentially an antigen for a broadly protective ETEC vaccine, suggesting a potential application of MEFA-based structural vaccinology for vaccine design against ETEC and likely other pathogens. PMID:28944092

Empirical fitness models for hepatitis C virus immunogen design

NASA Astrophysics Data System (ADS)

Hart, Gregory R.; Ferguson, Andrew L.

2015-12-01

Hepatitis C virus (HCV) afflicts 170 million people worldwide, 2%-3% of the global population, and kills 350 000 each year. Prophylactic vaccination offers the most realistic and cost effective hope of controlling this epidemic in the developing world where expensive drug therapies are not available. Despite 20 years of research, the high mutability of the virus and lack of knowledge of what constitutes effective immune responses have impeded development of an effective vaccine. Coupling data mining of sequence databases with spin glass models from statistical physics, we have developed a computational approach to translate clinical sequence databases into empirical fitness landscapes quantifying the replicative capacity of the virus as a function of its amino acid sequence. These landscapes explicitly connect viral genotype to phenotypic fitness, and reveal vulnerable immunological targets within the viral proteome that can be exploited to rationally design vaccine immunogens. We have recovered the empirical fitness landscape for the HCV RNA-dependent RNA polymerase (protein NS5B) responsible for viral genome replication, and validated the predictions of our model by demonstrating excellent accord with experimental measurements and clinical observations. We have used our landscapes to perform exhaustive in silico screening of 16.8 million T-cell immunogen candidates to identify 86 optimal formulations. By reducing the search space of immunogen candidates by over five orders of magnitude, our approach can offer valuable savings in time, expense, and labor for experimental vaccine development and accelerate the search for a HCV vaccine. Abbreviations: HCV—hepatitis C virus, HLA—human leukocyte antigen, CTL—cytotoxic T lymphocyte, NS5B—nonstructural protein 5B, MSA—multiple sequence alignment, PEG-IFN—pegylated interferon.

Evaluation of the immunogenicity and protective effects of a trivalent chimeric norovirus P particle immunogen displaying influenza HA2 from subtypes H1, H3 and B.

PubMed

Gong, Xin; Yin, He; Shi, Yuhua; He, Xiaoqiu; Yu, Yongjiao; Guan, Shanshan; Kuai, Ziyu; Haji, Nasteha M; Haji, Nafisa M; Kong, Wei; Shan, Yaming

2016-05-25

The ectodomain of the influenza A virus (IAV) hemagglutinin (HA) stem is highly conserved across strains and has shown promise as a universal influenza vaccine in a mouse model. In this study, potential B-cell epitopes were found through sequence alignment and epitope prediction in a stem fragment, HA2:90-105, which is highly conserved among virus subtypes H1, H3 and B. A norovirus (NoV) P particle platform was used to express the HA2:90-105 sequences from subtypes H1, H3 and B in loops 1, 2 and 3 of the protrusion (P) domain, respectively. Through mouse immunization and microneutralization assays, the immunogenicity and protective efficacy of the chimeric NoV P particle (trivalent HA2-PP) were tested against infection with three subtypes (H1N1, H3N2 and B) of IAV in Madin-Darby canine kidney cells. The protective efficacy of the trivalent HA2-PP was also evaluated preliminarily in vivo by virus challenge in the mouse model. The trivalent HA2-PP immunogen induced significant IgG antibody responses, which could be enhanced by a virus booster vaccination. Moreover, the trivalent HA2-PP immunogen also demonstrated in vitro neutralization of the H3 and B viruses, and in vivo protection against the H3 virus. Our results support the notion that a broadly protective vaccine approach using an HA2-based NoV P particle platform can provide cross-protection against challenge viruses of different IAV subtypes. The efficacy of the immunogen should be further enhanced for practicality, and a better understanding of the protective immune mechanism will be critical for the development of HA2-based multivalent vaccines.

Ten tandem repeats of {beta}-hCG 109-118 enhance immunogenicity and anti-tumor effects of {beta}-hCG C-terminal peptide carried by mycobacterial heat-shock protein HSP65

DOE Office of Scientific and Technical Information (OSTI.GOV)

Zhang Yankai; Yan Rong; He Yi

2006-07-14

The {beta}-subunit of human chorionic gonadotropin ({beta}-hCG) is secreted by many kinds of tumors and it has been used as an ideal target antigen to develop vaccines against tumors. In view of the low immunogenicity of this self-peptide,we designed a method based on isocaudamer technique to repeat tandemly the 10-residue sequence X of {beta}-hCG (109-118), then 10 tandemly repeated copies of the 10-residue sequence combined with {beta}-hCG C-terminal 37 peptides were fused to mycobacterial heat-shock protein 65 to construct a fusion protein HSP65-X10-{beta}hCGCTP37 as an immunogen. In this study, we examined the effect of the tandem repeats of this 10-residuemore » sequence in eliciting an immune by comparing the immunogenicity and anti-tumor effects of the two immunogens, HSP65-X10-{beta}hCGCTP37 and HSP65-{beta}hCGCTP37 (without the 10 tandem repeats). Immunization of mice with the fusion protein HSP65-X10-{beta}hCGCTP37 elicited much higher levels of specific anti-{beta}-hCG antibodies and more effectively inhibited the growth of Lewis lung carcinoma (LLC) in vivo than with HSP65-{beta}hCGCTP37, which should suggest that HSP65-X10-{beta}hCGCTP37 may be an effective protein vaccine for the treatment of {beta}-hCG-dependent tumors and multiple tandem repeats of a certain epitope are an efficient method to overcome the low immunogenicity of self-peptide antigens.« less

Science in 60 - The Forecast Calls for Flu

DOE Office of Scientific and Technical Information (OSTI.GOV)

Del Valle, Sara

What if we could forecast infectious diseases the same way we forecast the weather, and predict how diseases like Dengue, Typhus, or Zika were going to spread? Using real-time data from Wikipedia and social media, Sara Del Valle and her team from Los Alamos National Laboratory have developed a global disease-forecasting system that will improve the way we respond to epidemics. Using this model, individuals and public health officials can monitor disease incidence and implement strategies — such as vaccination campaigns, communicating to the public and allocating resources — to stay one step ahead of infectious disease spread.

Nucleic acids encoding modified human immunodeficiency virus type 1 (HIV-1) group M consensus envelope glycoproteins

DOEpatents

Haynes, Barton F [Durham, NC; Gao, Feng [Durham, NC; Korber, Bette T [Los Alamos, NM; Hahn, Beatrice H [Birmingham, AL; Shaw, George M [Birmingham, AL; Kothe, Denise [Birmingham, AL; Li, Ying Ying [Hoover, AL; Decker, Julie [Alabaster, AL; Liao, Hua-Xin [Chapel Hill, NC

2011-12-06

The present invention relates, in general, to an immunogen and, in particular, to an immunogen for inducing antibodies that neutralizes a wide spectrum of HIV primary isolates and/or to an immunogen that induces a T cell immune response. The invention also relates to a method of inducing anti-HIV antibodies, and/or to a method of inducing a T cell immune response, using such an immunogen. The invention further relates to nucleic acid sequences encoding the present immunogens.

Unlocking Barriers to DNA Vaccine Immunogenicity: A Cross-Species Analysis of Cytosolic DNA Sensing in Skeletal Muscle Myocytes

DTIC Science & Technology

2016-10-01

AWARD NUMBER: W81XWH-15-1-0505 TITLE: Unlocking Barriers to DNA Vaccine Immunogenicity: A Cross-Species Analysis of Cytosolic DNA Sensing in...REPORT TYPE Annual 3. DATES COVERED 10 Sept 2015 – 9 Sept 2016 4. TITLE AND SUBTITLE 5a. CONTRACT NUMBER Unlocking Barriers to DNA Vaccine ...Annual Report submitted 04/10/2016. 14. ABSTRACT DNA vaccine technology holds great promise as a platform for developing vaccines against both

Accelerating clinical development of HIV vaccine strategies: methodological challenges and considerations in constructing an optimised multi-arm phase I/II trial design.

PubMed

Richert, Laura; Doussau, Adélaïde; Lelièvre, Jean-Daniel; Arnold, Vincent; Rieux, Véronique; Bouakane, Amel; Lévy, Yves; Chêne, Geneviève; Thiébaut, Rodolphe

2014-02-26

Many candidate vaccine strategies against human immunodeficiency virus (HIV) infection are under study, but their clinical development is lengthy and iterative. To accelerate HIV vaccine development optimised trial designs are needed. We propose a randomised multi-arm phase I/II design for early stage development of several vaccine strategies, aiming at rapidly discarding those that are unsafe or non-immunogenic. We explored early stage designs to evaluate both the safety and the immunogenicity of four heterologous prime-boost HIV vaccine strategies in parallel. One of the vaccines used as a prime and boost in the different strategies (vaccine 1) has yet to be tested in humans, thus requiring a phase I safety evaluation. However, its toxicity risk is considered minimal based on data from similar vaccines. We newly adapted a randomised phase II trial by integrating an early safety decision rule, emulating that of a phase I study. We evaluated the operating characteristics of the proposed design in simulation studies with either a fixed-sample frequentist or a continuous Bayesian safety decision rule and projected timelines for the trial. We propose a randomised four-arm phase I/II design with two independent binary endpoints for safety and immunogenicity. Immunogenicity evaluation at trial end is based on a single-stage Fleming design per arm, comparing the observed proportion of responders in an immunogenicity screening assay to an unacceptably low proportion, without direct comparisons between arms. Randomisation limits heterogeneity in volunteer characteristics between arms. To avoid exposure of additional participants to an unsafe vaccine during the vaccine boost phase, an early safety decision rule is imposed on the arm starting with vaccine 1 injections. In simulations of the design with either decision rule, the risks of erroneous conclusions were controlled <15%. Flexibility in trial conduct is greater with the continuous Bayesian rule. A 12-month gain in timelines is expected by this optimised design. Other existing designs such as bivariate or seamless phase I/II designs did not offer a clear-cut alternative. By combining phase I and phase II evaluations in a multi-arm trial, the proposed optimised design allows for accelerating early stage clinical development of HIV vaccine strategies.

COMMISSION ON EPIDEMIOLOGICAL SURVEY

DTIC Science & Technology

Ribonucleic Acid Metabolism during Infection; Mechanisms of Endotoxin Tolerance; Typhoid Fever: Pathogenesis and Prevention; Studies on Rocky Mountain Spotted Fever : Serologic...Response in Man to Vaccination with Combined Epidemic Typhus, Rocky Mountain Spotted Fever and Q Fever Vaccine; and Influence of Tularemia on Insulin Secretion.

Sir William Jenner (1815-1898) and Queen Victoria.

PubMed

Seddon, David; Queen Victoria

2004-08-01

This biographical note outlines the work of Sir William Jenner (1815-1898), court physician 1861-93 and President of the Royal College of Physicians 1881-8. He was the first to distinguish between typhoid and typhus both clinically and pathologically.

Food Processing: The Influence of the Maillard Reaction on Immunogenicity and Allergenicity of Food Proteins

PubMed Central

Teodorowicz, Malgorzata; van Neerven, Joost

2017-01-01

The majority of foods that are consumed in our developed society have been processed. Processing promotes a non-enzymatic reaction between proteins and sugars, the Maillard reaction (MR). Maillard reaction products (MRPs) contribute to the taste, smell and color of many food products, and thus influence consumers’ choices. However, in recent years, MRPs have been linked to the increasing prevalence of diet- and inflammation-related non-communicable diseases including food allergy. Although during the last years a better understanding of immunogenicity of MRPs has been achieved, still only little is known about the structural/chemical characteristics predisposing MRPs to interact with antigen presenting cells (APCs). This report provides a comprehensive review of recent studies on the influence of the Maillard reaction on the immunogenicity and allergenicity of food proteins. PMID:28777346

Immunogenic activity of the fish tapeworm Pterobothrium heteracanthum (Trypanorhyncha: Pterobothriidae) in BALB/c mice.

PubMed

Mattos, D P B G; Verícimo, M A; Lopes, L M S; São Clemente, S C

2015-03-01

The aim of this study was to verify the immunogenicity of Pterobothrium heteracanthum (Cestoda: Trypanorhyncha) crude protein extract (PH-CPE) in BALB/c mice. The parasites were obtained from Micropogonias furnieri (Osteichthyes: Sciaenidae). Groups of six mice were each immunized with 10, 50 or 100 μg of PH-CPE, on days 0 and 35. Both specific IgG and IgE responses were developed after immunization. The immunoblot assay revealed that specific IgG recognizes PH-CPE proteins with two molecular weight ranges, 60-75 and 30-40 kDa, and that IgE recognizes larger proteins over 120 kDa. This appears to be the first report on the immunogenicity of metacestodes within the Pterobothriidae and that PH-CPE is a potential inducer of a specific IgE response.

Food Processing: The Influence of the Maillard Reaction on Immunogenicity and Allergenicity of Food Proteins.

PubMed

Teodorowicz, Malgorzata; van Neerven, Joost; Savelkoul, Huub

2017-08-04

The majority of foods that are consumed in our developed society have been processed. Processing promotes a non-enzymatic reaction between proteins and sugars, the Maillard reaction (MR). Maillard reaction products (MRPs) contribute to the taste, smell and color of many food products, and thus influence consumers' choices. However, in recent years, MRPs have been linked to the increasing prevalence of diet- and inflammation-related non-communicable diseases including food allergy. Although during the last years a better understanding of immunogenicity of MRPs has been achieved, still only little is known about the structural/chemical characteristics predisposing MRPs to interact with antigen presenting cells (APCs). This report provides a comprehensive review of recent studies on the influence of the Maillard reaction on the immunogenicity and allergenicity of food proteins.

Comparison of Immunogenicity in Rhesus Macaques of Transmitted-Founder, HIV-1 Group M Consensus, and Trivalent Mosaic Envelope Vaccines Formulated as a DNA Prime, NYVAC, and Envelope Protein Boost

PubMed Central

Hulot, Sandrine L.; Korber, Bette; Giorgi, Elena E.; Vandergrift, Nathan; Saunders, Kevin O.; Balachandran, Harikrishnan; Mach, Linh V.; Lifton, Michelle A.; Pantaleo, Giuseppe; Tartaglia, Jim; Phogat, Sanjay; Jacobs, Bertram; Kibler, Karen; Perdiguero, Beatriz; Gomez, Carmen E.; Esteban, Mariano; Rosati, Margherita; Felber, Barbara K.; Pavlakis, George N.; Parks, Robert; Lloyd, Krissey; Sutherland, Laura; Scearce, Richard; Letvin, Norman L.; Seaman, Michael S.; Alam, S. Munir; Montefiori, David; Liao, Hua-Xin; Haynes, Barton F.

2015-01-01

ABSTRACT An effective human immunodeficiency virus type 1 (HIV-1) vaccine must induce protective antibody responses, as well as CD4+ and CD8+ T cell responses, that can be effective despite extraordinary diversity of HIV-1. The consensus and mosaic immunogens are complete but artificial proteins, computationally designed to elicit immune responses with improved cross-reactive breadth, to attempt to overcome the challenge of global HIV diversity. In this study, we have compared the immunogenicity of a transmitted-founder (T/F) B clade Env (B.1059), a global group M consensus Env (Con-S), and a global trivalent mosaic Env protein in rhesus macaques. These antigens were delivered using a DNA prime-recombinant NYVAC (rNYVAC) vector and Env protein boost vaccination strategy. While Con-S Env was a single sequence, mosaic immunogens were a set of three Envs optimized to include the most common forms of potential T cell epitopes. Both Con-S and mosaic sequences retained common amino acids encompassed by both antibody and T cell epitopes and were central to globally circulating strains. Mosaics and Con-S Envs expressed as full-length proteins bound well to a number of neutralizing antibodies with discontinuous epitopes. Also, both consensus and mosaic immunogens induced significantly higher gamma interferon (IFN-γ) enzyme-linked immunosorbent spot assay (ELISpot) responses than B.1059 immunogen. Immunization with these proteins, particularly Con-S, also induced significantly higher neutralizing antibodies to viruses than B.1059 Env, primarily to tier 1 viruses. Both Con-S and mosaics stimulated more potent CD8-T cell responses against heterologous Envs than did B.1059. Both antibody and cellular data from this study strengthen the concept of using in silico-designed centralized immunogens for global HIV-1 vaccine development strategies. IMPORTANCE There is an increasing appreciation for the importance of vaccine-induced anti-Env antibody responses for preventing HIV-1 acquisition. This nonhuman primate study demonstrates that in silico-designed global HIV-1 immunogens, designed for a human clinical trial, are capable of eliciting not only T lymphocyte responses but also potent anti-Env antibody responses. PMID:25855741

Challenges and opportunities in bioanalytical support for gene therapy medicinal product development.

PubMed

Ma, Mark; Balasubramanian, Nanda; Dodge, Robert; Zhang, Yan

2017-09-01

Gene and nucleic acid therapies have demonstrated patient benefits to address unmet medical needs. Beside considerations regarding the biological nature of the gene therapy, the quality of bioanalytical methods plays an important role in ensuring the success of these novel therapies. Inconsistent approaches among bioanalytical labs during preclinical and clinical phases have been observed. There are many underlying reasons for this inconsistency. Various platforms and reagents used in quantitative methods, lacking of detailed regulatory guidance on method validation and uncertainty of immunogenicity strategy in supporting gene therapy may all be influential. This review summarizes recent practices and considerations in bioanalytical support of pharmacokinetics/pharmacodynamics and immunogenicity evaluations in gene therapy development with insight into method design, development and validations.

A Novel Immunogenic Spore Coat-Associated Protein in Bacillus Anthracis: Characterization via Proteomics Approaches and a Vector-Based Vaccine System

PubMed Central

Liu, Yu-Tsueng; Lin, Shwu-Bin; Huang, Cheng-Po; Huang, Chun-Ming

2007-01-01

New generation anthrax vaccines have been actively explored with the aim of enhancing efficacies and decreasing undesirable side effects that could be caused by licensed vaccines. Targeting novel antigens and/or eliminating the requirements for multiple needle injections and adjuvants are major objectives in the development of new anthrax vaccines. Using proteomics approaches, we identified a spore coat-associated protein (SCAP) in Bacillus anthracis. An E. coli vector-based vaccine system was used to determine the immunogenicity of SCAP. Mice generated detectable SCAP antibodies three weeks after intranasal immunization with an intact particle of ultraviolet (UV)-irradiated E. coli vector overproducing SCAP. The production of SCAP antibodies was detected via western blotting and SCAP-spotted antigen-arrays. The adjuvant effect of a UV-irradiated E. coli vector eliminates the necessity of boosting and the use of other immunomodulators which will foster the screening and manufacturing of new generation anthrax vaccines. More importantly, the immunogenic SCAP may potentially be a new candidate for the development of anthrax vaccines. PMID:18029197

Development of a bivalent conjugate vaccine candidate against malaria transmission and typhoid fever.

PubMed

An, So Jung; Scaria, Puthupparampil V; Chen, Beth; Barnafo, Emma; Muratova, Olga; Anderson, Charles; Lambert, Lynn; Chae, Myung Hwa; Yang, Jae Seung; Duffy, Patrick E

2018-05-17

Immune responses to poorly immunogenic antigens, such as polysaccharides, can be enhanced by conjugation to carriers. Our previous studies indicate that conjugation to Vi polysaccharide of Salmonella Typhi may also enhance immunogenicity of some protein carriers. We therefore explored the possibility of generating a bivalent vaccine against Plasmodium falciparum malaria and typhoid fever, which are co-endemic in many parts of the world, by conjugating Vi polysaccharide, an approved antigen in typhoid vaccine, to Pfs25, a malaria transmission blocking vaccine antigen in clinical trials. Vi-Pfs25 conjugates induced strong immune responses against both Vi and Pfs25 in mice, whereas the unconjugated antigens are poorly immunogenic. Functional assays of immune sera revealed potent transmission blocking activity mediated by anti-Pfs25 antibody and serum bactericidal activity due to anti-Vi antibody. Pfs25 conjugation to Vi modified the IgG isotype distribution of antisera, inducing a Th2 polarized immune response against Vi antigen. This conjugate may be further developed as a bivalent vaccine to concurrently target malaria and typhoid fever. Copyright © 2018. Published by Elsevier Ltd.

Oxygen-boosted immunogenic photodynamic therapy with gold nanocages@manganese dioxide to inhibit tumor growth and metastases.

PubMed

Liang, Ruijing; Liu, Lanlan; He, Huamei; Chen, Zhikuan; Han, Zhiqun; Luo, Zhenyu; Wu, Zhihao; Zheng, Mingbin; Ma, Yifan; Cai, Lintao

2018-09-01

Metastatic triple-negative breast cancer (mTNBC) is an aggressive disease among women worldwide, characterized by high mortality and poor prognosis despite systemic therapy with radiation and chemotherapies. Photodynamic therapy (PDT) is an important strategy to eliminate the primary tumor, however its therapeutic efficacy against metastases and recurrence is still limited. Here, we employed a template method to develop the core-shell gold nanocage@manganese dioxide (AuNC@MnO 2 , AM) nanoparticles as tumor microenvironment responsive oxygen producers and near-infrared (NIR)-triggered reactive oxygen species (ROS) generators for oxygen-boosted immunogenic PDT against mTNBC. In this platform, MnO 2 shell degrades in acidic tumor microenvironment pH/H 2 O 2 conditions and generates massive oxygen to boost PDT effect of AM nanoparticles under laser irradiation. Fluorescence (FL)/photoacoustic (PA)/magnetic resonance (MR) multimodal imaging confirms the effective accumulation of AM nanoparticles with sufficient oxygenation in tumor site to ameliorate local hypoxia. Moreover, the oxygen-boosted PDT effect of AM not only destroys primary tumor effectively but also elicits immunogenic cell death (ICD) with damage-associated molecular patterns (DAMPs) release, which subsequently induces DC maturation and effector cells activation, thereby robustly evoking systematic antitumor immune responses against mTNBC. Hence, this oxygen-boosted immunogenic PDT nanosystem offers a promising approach to ablate primary tumor and simultaneously prevent tumor metastases via immunogenic abscopal effects. Copyright © 2018 Elsevier Ltd. All rights reserved.

The Immunogenicity and Safety of CYD-Tetravalent Dengue Vaccine (CYD-TDV) in Children and Adolescents: A Systematic Review.

PubMed

Agarwal, Raksheeth; Wahid, Mardiastuti H; Yausep, Oliver E; Angel, Sharon H; Lokeswara, Angga W

2017-01-01

to assess the immunogenicity and safety of CYD-tetravalent dengue vaccine (CYD-TDV) in children. comprehensive literature searches were conducted on various databases. Randomized-controlled trials on children with CYD-TDV as intervention were selected based on inclusion and exclusion criteria. Data extracted from selected trials included safety of vaccine and immunogenicity in terms of Geometric Mean Titres (GMT) of antibodies.   six clinical trials were selected based on preset criteria. GMT values were obtained using 50% Plaque Reduction Neutralization Test (PRNT) and safety was semi-quantitatively assessed based on adverse effects. Additional data processing was done to obtain a better understanding on the trends among the studies. The results showed that the groups vaccinated with CYD-TDV showed higher immunogenicity against dengue virus antigens than the control groups. Safety results were satisfactory in all trials, and most severe side effects were unrelated to the vaccine. CYD-TDV is both effective and safe for patients in endemic regions. This gives promise for further development and large-scale research on this vaccine to assess its efficacy in decreasing dengue prevalence, and its pervasive implementation in endemic countries, such as Indonesia.

COMMISSION ON EPIDEMIOLOGICAL SURVEY

DTIC Science & Technology

Ribonucleic Acid Metabolism during Infection; Mechanisms of Endotoxin Tolerance; Typhoid Fever: Pathogenesis and Prevention; Studies on Rocky Mountain Spotted Fever : Serologic...Response in Man to Vaccination with Combined Epidemic Typhus, Rocky Mountain Spotted Fever and Q Fever Vaccine; and Influence of Tularemia on Tularemia on Insulin Secretion.

Reproducing SIVΔnef vaccine correlates of protection: trimeric gp41 antibody concentrated at mucosal front lines

PubMed Central

Voss, James E.; Macauley, Matthew S.; Rogers, Kenneth A.; Villinger, Francois; Duan, Lijie; Shang, Liang; Fink, Elizabeth A.; Andrabi, Raiees; Colantonio, Arnaud D.; Robinson, James E.; Johnson, R. Paul; Burton, Dennis R.; Haase, Ashley T.

2016-01-01

Vaccination with SIVmac239Δnef provides robust protection against subsequent challenge with wild type SIV, but safety issues have precluded designing an HIV-1 vaccine based on a live attenuated virus concept. Safe immunogens and adjuvants that could reproduce identified immune correlates of SIVmac239Δnef protection therefore offer an alternative path for development of an HIV vaccine. Here we describe SIV envelope trimeric gp41 (gp41t) immunogens based on a protective correlate of antibodies to gp41t concentrated on the path of virus entry by the neonatal Fc receptor (FcRn) in cervical vaginal epithelium. We developed a gp41t immunogen-MPLA adjuvant liposomal nanoparticle for intra-muscular immunization and a gp41t-Fc immunogen for intranasal immunization for pilot studies in mice, rabbits, and rhesus macaques. Repeated immunizations to mimic persistent antigen exposure in infection elicited gp41t antibodies in rhesus macaques that were detectable in FcRn+ cervical vaginal epithelium, thus recapitulating one key feature of SIVmac239Δnef vaccinated and protected animals. While this strategy did not reproduce the system of local production of antibody in SIVmac239Δnef-vaccinated animals, passive immunization experiments supported the concept that sufficiently high levels of antibody can be concentrated by the FcRn at mucosal frontlines, thus setting the stage for assessing protection against vaginal challenge by gp41t immunization. PMID:27428745

Future HLA matching strategies in clinical transplantation.

PubMed

Claas, Frans H J; Roelen, Dave L; Oudshoorn, Machteld; Doxiadis, Ilias I N

2003-01-01

HLA matching has shown to be beneficial in clinical transplantation. Due to the enormous polymorphism of the HLA system, however, it is not feasible to select a completely HLA-matched donor for every potential recipient. Only for patients with frequently occurring HLA phenotypes is it realistic to expect a well-matched donor within a reasonable waiting time. The majority of patients will be transplanted with a partially mismatched donor. In order to select the optimal donor for this category of patients, it is important to take advantage of the differential immunogenicity and thus differential importance of mismatched HLA antigens. Based on retrospective analyses of graft survival data and in vitro tests measuring T-cell alloreactivity, the relative importance of different mismatches was evaluated. It has been possible to define acceptable or permissible mismatches with a low immunogenicity, which are associated with a good graft survival, versus taboo mismatches with a high immunogenicity and a poor graft survival. Further developing this new line of permissible versus taboo mismatches, a new strategy will emerge for future HLA matching, which will not only suit a rare number of patients with frequent haplotypes but a great percentage of all patients. This principle of different immunogenicity of different mismatches can not only be applied to T-cell alloreactivity as shown here, but also to B-cell alloreactivity, where a recently developed computer algorithm (HLA matchmaker) can be instrumental in selecting donors with HLA mismatches, which do not lead to alloantibody formation.

Allergenicity, immunogenicity and dose-relationship of three intact allergen vaccines and four allergoid vaccines for subcutaneous grass pollen immunotherapy.

PubMed

Henmar, H; Lund, G; Lund, L; Petersen, A; Würtzen, P A

2008-09-01

Different vaccines containing intact allergens or chemically modified allergoids as active ingredients are commercially available for specific immunotherapy. Allergoids are claimed to have decreased allergenicity without loss of immunogenicity and this is stated to allow administration of high allergoid doses. We compared the allergenicity and immunogenicity of four commercially available chemically modified grass pollen allergoid products with three commercially available intact grass pollen allergen vaccines. The allergenicity was investigated with immunoglobulin (Ig)E-inhibition and basophil activation assays. Human T cell proliferation and specific IgG-titres following mouse immunizations were used to address immunogenicity. Furthermore, intact allergen vaccines with different contents of active ingredients were selected to study the influence of the allergen dose. In general, a lower allergenicity for allergen vaccines was clearly linked to a reduced immunogenicity. Compared with the vaccine with the highest amount of intact allergen, the allergoids caused reduced basophil activation as well as diminished immunogenicity demonstrated by reduced T cell activation and/or reduced induction of murine grass-specific IgG antibodies. Interestingly, intact allergen vaccines with lower content of active ingredient exhibited similarly reduced allergenicity, while immunogenicity was still higher or equal to that of allergoids. The low allergenicity observed for some allergoids was inherently linked to a significantly lower immunogenic response questioning the rationale behind the chemical modification into allergoids. In addition, the linkage between allergenicity, immunogenicity and dose found for intact allergen vaccines and the immunogen as well as allergenic immune responses observed for allergoids suggest that the modified allergen vaccines do not contain high doses of immunologically active ingredients.

Scrub Typhus in a Tertiary Care Hospital in North India.

PubMed

Sharma, Navneet; Biswal, Manisha; Kumar, Abhay; Zaman, Kamran; Jain, Sanjay; Bhalla, Ashish

2016-08-03

Scrub typhus, a zoonotic disease caused by the bacterium Orientia tsutsugamushi, has become endemic in many parts of India. We studied the clinical profile of this infection in 228 patients that reported to this tertiary care center from July 2013 to December 2014. The median age of patients was 35 years (interquartile range = 24.5-48.5 years), and 111 were males and 117 females. A high-grade fever occurred in 85%, breathlessness in 42%, jaundice in 32%, abdominal pain in 28%, renal failure in 11%, diarrhea in 10%, rashes in 9%, and seizures in 7%. Common laboratory abnormalities at presentation were a deranged hepatic function in 61%, anemia in 54%, leukopenia in 15%, and thrombocytopenia in 90% of our patients. Acute kidney injury (32%), acute respiratory distress syndrome (ARDS) (25%), and disseminated intravascular coagulation (DIC) (16%) were the commonest complications. A hepatorenal syndrome was seen in 38% and multiple organ dysfunction syndrome (MODS) in 20% patients. The overall case fatality rate was 13.6%. In univariate analysis, ARDS requiring mechanical ventilation, acute kidney injury requiring hemodialysis, hypotension requiring inotropic support, central nervous system dysfunction at presentation, and MODS were inversely associated with survival. Survival was significantly higher in patients that presented with a duration of fever < 10 days compared with those that presented ≥ 12 days (P < 0.05) after onset. In conclusion, scrub typhus has become a leading infectious disease in north India and an important cause of infectious fever. An increasing awareness of this disease coupled with prompt management will go a long way in reducing both morbidity and mortality from this disease. © The American Society of Tropical Medicine and Hygiene.

Predictive diagnostic value of the tourniquet test for the diagnosis of dengue infection in adults

PubMed Central

Mayxay, Mayfong; Phetsouvanh, Rattanaphone; Moore, Catrin E; Chansamouth, Vilada; Vongsouvath, Manivanh; Sisouphone, Syho; Vongphachanh, Pankham; Thaojaikong, Thaksinaporn; Thongpaseuth, Soulignasack; Phongmany, Simmaly; Keolouangkhot, Valy; Strobel, Michel; Newton, Paul N

2011-01-01

Objective To examine the accuracy of the admission tourniquet test in the diagnosis of dengue infection among Lao adults. Methods Prospective assessment of the predictive diagnostic value of the tourniquet test for the diagnosis of dengue infection, as defined by IgM, IgG and NS1 ELISAs (Panbio Ltd, Australia), among Lao adult inpatients with clinically suspected dengue infection. Results Of 234 patients with clinically suspected dengue infection on admission, 73% were serologically confirmed to have dengue, while 64 patients with negative dengue serology were diagnosed as having scrub typhus (39%), murine typhus (11%), undetermined typhus (12%), Japanese encephalitis virus (5%), undetermined flavivirus (5%) and typhoid fever (3%); 25% had no identifiable aetiology. The tourniquet test was positive in 29.1% (95% CI = 23.2–34.9%) of all patients and in 34.1% (95% CI = 27.0–41.2%) of dengue-seropositive patients, in 32.7% (95% CI = 23.5–41.8) of those with dengue fever and in 36.4% (95% CI = 24.7–48.0) of those with dengue haemorrhagic fever. Interobserver agreement for the tourniquet test was 90.2% (95% CI = 86.4–94.0) (Kappa = 0.76). Using ELISAs as the diagnostic gold standard, the sensitivity of the tourniquet test was 33.5–34%; its specificity was 84–91%. The positive and negative predictive values were 85–90% and 32.5–34%, respectively. Conclusions The admission tourniquet test has low sensitivity and adds relatively little value to the diagnosis of dengue among Lao adult inpatients with suspected dengue. Although a positive tourniquet test suggests dengue and that treatment of alternative diagnoses may not be needed, a negative test result does not exclude dengue. PMID:20958892

Aetiology of acute encephalitis syndrome in Uttar Pradesh, India from 2014 to 2016.

PubMed

Jain, Parul; Prakash, Shantanu; Khan, Danish N; Garg, Ravindra Kumar; Kumar, Rashmi; Bhagat, Amit; Ramakrishna, V; Jain, Amita

2017-01-01

It is imperative to know the aetiology of acute encephalitis syndrome (AES) for patient management and policy making. The present study was carried out to determine the prevalence of common aetiological agents of AES in Uttar Pradesh (UP) state of India. Serum and/or CSF samples were collected from AES patients admitted at Gandhi Memorial and Associated Hospital, King George's Medical University, Lucknow, a tertiary care centre, UP during 2014-16. Cerebrospinal fluid (CSF) and serum samples from cases were tested for IgM antibodies against Japanese encephalitis virus (anti-JEV), and dengue virus (anti-DENV) by ELISA; and for enterovirus, herpes simplex virus (HSV) and varicella zoster virus (VZV) by real-time PCR. Serum samples of cases having sufficient CSF volume, were also tested for anti-scrub typhus IgM antibodies and for Neisseria meningitides, Streptococcus pneumoniae and Haemophilus influenzae. JEV and DENV (8% each) were the most common identified aetiology from the 4092 enrolled patients. Enterovirus, HSV and VZV, each were detected in <1% AES cases. Co-positivity occurred in 48 cases. Scrub typhus (31.8%) was the most common aetiology detected. Haemophilus influenzae and S. pneumoniae were detected in 0.97 and 0.94% cases, respectively, however, N. meningitides was not detected in any of the cases. About 40% of the JEV/DENV positive AES cases were adults. The gap between the total number of AES cases and those with JEV/ DENV infection increased during monsoon and post-monsoon seasons. Scrub typhus, JEV and DENV are the main aetiological agents of AES in UP. DENV and JEV can no longer be considered paediatric diseases. The prevalence of non-JEV/DENV aetiology of AES increases in the monsoon and post-monsoon seasons.

Properties of MHC Class I Presented Peptides That Enhance Immunogenicity

PubMed Central

Calis, Jorg J. A.; Maybeno, Matt; Greenbaum, Jason A.; Weiskopf, Daniela; De Silva, Aruna D.; Sette, Alessandro; Keşmir, Can; Peters, Bjoern

2013-01-01

T-cells have to recognize peptides presented on MHC molecules to be activated and elicit their effector functions. Several studies demonstrate that some peptides are more immunogenic than others and therefore more likely to be T-cell epitopes. We set out to determine which properties cause such differences in immunogenicity. To this end, we collected and analyzed a large set of data describing the immunogenicity of peptides presented on various MHC-I molecules. Two main conclusions could be drawn from this analysis: First, in line with previous observations, we showed that positions P4–6 of a presented peptide are more important for immunogenicity. Second, some amino acids, especially those with large and aromatic side chains, are associated with immunogenicity. This information was combined into a simple model that was used to demonstrate that immunogenicity is, to a certain extent, predictable. This model (made available at http://tools.iedb.org/immunogenicity/) was validated with data from two independent epitope discovery studies. Interestingly, with this model we could show that T-cells are equipped to better recognize viral than human (self) peptides. After the past successful elucidation of different steps in the MHC-I presentation pathway, the identification of variables that influence immunogenicity will be an important next step in the investigation of T-cell epitopes and our understanding of cellular immune responses. PMID:24204222

Polyvalent immunogen

DOEpatents

Haynes, Barton F [Durham, NC; Korber, Bette T [Los Alamos, NM; De Lorimier, Robert M [Durham, NC; Liao, Hua-Xin [Chapel Hill, NC

2007-02-06

The present invention relates, generally, to a polyvalent immunogen and, more particularly, to a method of inducing neutralizing antibodies against HIV and to a polyvalent immunogen suitable for use in such a method.

Polyvalent immunogen

DOEpatents

Haynes, Barton F [Durham, NC; Korber, Bette T [Los Alamos, NM; De Lorimier, Robert M [Durham, NC

2007-03-27

The present invention relates, generally, to a polyvalent immunogen and, more particularly, to a method of inducing neutralizing antibodies against HIV and to a polyvalent immunogen suitable for use in such a method.

Identification of Immunogenic Hot Spots within Plum Pox Potyvirus Capsid Protein for Efficient Antigen Presentation

PubMed Central

Fernández-Fernández, M. Rosario; Martínez-Torrecuadrada, Jorge L.; Roncal, Fernando; Domínguez, Elvira; García, Juan Antonio

2002-01-01

PEPSCAN analysis has been used to characterize the immunogenic regions of the capsid protein (CP) in virions of plum pox potyvirus (PPV). In addition to the well-known highly immunogenic N- and C-terminal domains of CP, regions within the core domain of the protein have also shown high immunogenicity. Moreover, the N terminus of CP is not homogeneously immunogenic, alternatively showing regions frequently recognized by antibodies and others that are not recognized at all. These results have helped us to design efficient antigen presentation vectors based on PPV. As predicted by PEPSCAN analysis, a small displacement of the insertion site in a previously constructed vector, PPV-γ, turned the derived chimeras into efficient immunogens. Vectors expressing foreign peptides at different positions within a highly immunogenic region (amino acids 43 to 52) in the N-terminal domain of CP were the most effective at inducing specific antibody responses against the foreign sequence. PMID:12438590

Maternal Milk T Cells Drive Development of Transgenerational Th1 Immunity in Offspring Thymus.

PubMed

Ghosh, Mrinal K; Nguyen, Virginia; Muller, H Konrad; Walker, Ameae M

2016-09-15

Using multiple murine foster-nursing protocols, thereby eliminating placental transfer and allowing a distinction between dam- and pup-derived cells, we show that foster nursing by an immunized dam results in development of CD8(+) T cells in nonimmunized foster pups that are specific for Ags against which the foster dam was immunized (Mycobacterium tuberculosis or Candida albicans). We have dubbed this process "maternal educational immunity" to distinguish it from passive cellular immunity. Of the variety of maternal immune cells present in milk, only T cells were detected in pup tissues. Maternal T cells, a substantial percentage of which were CD4(+)MHC class II(+), accumulated in the pup thymus and spleen during the nursing period. Further analysis of maternal cells in the pup thymus showed that a proportion was positive for maternal immunogen-specific MHC class II tetramers. To determine the outcome of Ag presentation in the thymus, the maternal or foster pup origin of immunogen-responding CD8(+) cells in foster pup spleens was assessed. Whereas ∼10% were maternally derived in the first few weeks after weaning, all immunogen-responding CD8(+) T cells were pup derived by 12 wk of age. Pup-derived immunogen-responsive CD8(+) cells persisted until at least 1 y of age. Passive cellular immunity is well accepted and has been demonstrated in the human population. In this study, we show an arguably more important role for transferred immune cells: the direction of offspring T cell development. Harnessing maternal educational immunity through prepregnancy immunization programs has potential for improvement of infant immunity. Copyright © 2016 by The American Association of Immunologists, Inc.

IMOJEV(®): a Yellow fever virus-based novel Japanese encephalitis vaccine.

PubMed

Appaiahgari, Mohan Babu; Vrati, Sudhanshu

2010-12-01

Japanese encephalitis (JE) is a disease of the CNS caused by Japanese encephalitis virus (JEV). The disease appears in the form of frequent outbreaks in most south- and southeast Asian countries and the virus has become endemic in several areas. There is no licensed therapy available and disease control by vaccination is considered to be most effective. Mouse brain-derived inactivated JE vaccines, although immunogenic, have several limitations in terms of safety, availability and requirement for multiple doses. Owing to these drawbacks, the WHO called for the development of novel, safe and more efficacious JE vaccines. Several candidate vaccines have been developed and at least three of them that demonstrated strong immunogenicity after one or two doses of the vaccine in animal models were subsequently tested in various clinical trials. One of these vaccines, IMOJEV(®) (JE-CV and previously known as ChimeriVax™-JE), is a novel recombinant chimeric virus vaccine, developed using the Yellow fever virus (YFV) vaccine vector YFV17D, by replacing the cDNA encoding the envelope proteins of YFV with that of an attenuated JEV strain SA14-14-2. IMOJEV was found to be safe, highly immunogenic and capable of inducing long-lasting immunity in both preclinical and clinical trials. Moreover, a single dose of IMOJEV was sufficient to induce protective immunity, which was similar to that induced in adults by three doses of JE-VAX(®), a mouse brain-derived inactivated JE vaccine. Recently, Phase III trials evaluating the immunogenicity and safety of the chimeric virus vaccine have been successfully completed in some JE-endemic countries and the vaccine manufacturers have filed an application for vaccine registration. IMOJEV may thus be licensed for use in humans as an improved alternative to the currently licensed JE vaccines.

Improved Prefusion Stability, Optimized Codon Usage, and Augmented Virion Packaging Enhance the Immunogenicity of Respiratory Syncytial Virus Fusion Protein in a Vectored-Vaccine Candidate

PubMed Central

Liang, Bo; Ngwuta, Joan O.; Surman, Sonja; Kabatova, Barbora; Liu, Xiang; Lingemann, Matthias; Liu, Xueqiao; Yang, Lijuan; Herbert, Richard; Swerczek, Joanna; Chen, Man; Moin, Syed M.; Kumar, Azad; McLellan, Jason S.; Kwong, Peter D.; Graham, Barney S.; Collins, Peter L.

2017-01-01

ABSTRACT Respiratory syncytial virus (RSV) is the most important viral agent of severe pediatric respiratory tract disease worldwide, but it lacks a licensed vaccine or suitable antiviral drug. A live attenuated chimeric bovine/human parainfluenza virus type 3 (rB/HPIV3) was developed previously as a vector expressing RSV fusion (F) protein to confer bivalent protection against RSV and HPIV3. In a previous clinical trial in virus-naive children, rB/HPIV3 was well tolerated but the immunogenicity of wild-type RSV F was unsatisfactory. We previously modified RSV F with a designed disulfide bond (DS) to increase stability in the prefusion (pre-F) conformation and to be efficiently packaged in the vector virion. Here, we further stabilized pre-F by adding both disulfide and cavity-filling mutations (DS-Cav1), and we also modified RSV F codon usage to have a lower CpG content and a higher level of expression. This RSV F open reading frame was evaluated in rB/HPIV3 in three forms: (i) pre-F without vector-packaging signal, (ii) pre-F with vector-packaging signal, and (iii) secreted pre-F ectodomain trimer. Despite being efficiently expressed, the secreted pre-F was poorly immunogenic. DS-Cav1 stabilized pre-F, with or without packaging, induced higher titers of pre-F specific antibodies in hamsters, and improved the quality of RSV-neutralizing serum antibodies. Codon-optimized RSV F containing fewer CpG dinucleotides had higher F expression, replicated more efficiently in vivo, and was more immunogenic. The combination of DS-Cav1 pre-F stabilization, optimized codon usage, reduced CpG content, and vector packaging significantly improved vector immunogenicity and protective efficacy against RSV. This provides an improved vectored RSV vaccine candidate suitable for pediatric clinical evaluation. IMPORTANCE RSV and HPIV3 are the first and second leading viral causes of severe pediatric respiratory disease worldwide. Licensed vaccines or suitable antiviral drugs are not available. We are developing a chimeric rB/HPIV3 vector expressing RSV F as a bivalent RSV/HPIV3 vaccine and have been evaluating means to increase RSV F immunogenicity. In this study, we evaluated the effects of improved stabilization of F in the pre-F conformation and of codon optimization resulting in reduced CpG content and greater pre-F expression. Reduced CpG content dampened the interferon response to infection, promoting higher replication and increased F expression. We demonstrate that improved pre-F stabilization and strategic manipulation of codon usage, together with efficient pre-F packaging into vector virions, significantly increased F immunogenicity in the bivalent RSV/HPIV3 vaccine. The improved immunogenicity included induction of increased titers of high-quality complement-independent antibodies with greater pre-F site Ø binding and greater protection against RSV challenge. PMID:28539444

Safety and immunogenicity of HIV-1 Tat toxoid in immunocompromised HIV-1-infected patients.

PubMed

Gringeri, A; Santagostino, E; Muça-Perja, M; Mannucci, P M; Zagury, J F; Bizzini, B; Lachgar, A; Carcagno, M; Rappaport, J; Criscuolo, M; Blattner, W; Burny, A; Gallo, R C; Zagury, D

1998-01-01

To antagonize the deleterious effects of the HIV-1 toxin extracellular Tat on uninfected immune cells, we developed a new strategy of anti-HIV-1 vaccine using an inactivated but immunogenic Tat (Tat toxoid). Tat toxoid has been assayed for safety and immunogenicity in seropositive patients. The phase I vaccine clinical trial testing Tat toxoid preparation in Seppic Isa 51 oil adjuvant was performed on 14 HIV-1-infected asymptomatic although biologically immunocompromised individuals (500-200 CD4+ cells/mm3). Following as many as 8 injections, no clinical defects were observed. All patients exhibited an antibody (Ab) response to Tat, and some had cell-mediated immunity (CMI) as evaluated by skin test in vivo and T-cell proliferation in vitro. These results provide initial evidence of safety and potency of Tat toxoid vaccination in HIV-1-infected individuals.

The future of human DNA vaccines

PubMed Central

Li, Lei; Saade, Fadi; Petrovsky, Nikolai

2012-01-01

DNA vaccines have evolved greatly over the last 20 years since their invention, but have yet to become a competitive alternative to conventional protein or carbohydrate based human vaccines. Whilst safety concerns were an initial barrier, the Achilles heel of DNA vaccines remains their poor immunogenicity when compared to protein vaccines. A wide variety of strategies have been developed to optimize DNA vaccine immunogenicity, including codon optimization, genetic adjuvants, electroporation and sophisticated prime-boost regimens, with each of these methods having its advantages and limitations. Whilst each of these methods has contributed to incremental improvements in DNA vaccine efficacy, more is still needed if human DNA vaccines are to succeed commercially. This review foresees a final breakthrough in human DNA vaccines will come from application of the latest cutting-edge technologies, including “epigenetics” and “omics” approaches, alongside traditional techniques to improve immunogenicity such as adjuvants and electroporation, thereby overcoming the current limitations of DNA vaccines in humans PMID:22981627

Immunogenicity is preferentially induced in sparse dendritic cell cultures.

PubMed

Nasi, Aikaterini; Bollampalli, Vishnu Priya; Sun, Meng; Chen, Yang; Amu, Sylvie; Nylén, Susanne; Eidsmo, Liv; Rothfuchs, Antonio Gigliotti; Réthi, Bence

2017-03-09

We have previously shown that human monocyte-derived dendritic cells (DCs) acquired different characteristics in dense or sparse cell cultures. Sparsity promoted the development of IL-12 producing migratory DCs, whereas dense cultures increased IL-10 production. Here we analysed whether the density-dependent endogenous breaks could modulate DC-based vaccines. Using murine bone marrow-derived DC models we show that sparse cultures were essential to achieve several key functions required for immunogenic DC vaccines, including mobility to draining lymph nodes, recruitment and massive proliferation of antigen-specific CD4+ T cells, in addition to their TH1 polarization. Transcription analyses confirmed higher commitment in sparse cultures towards T cell activation, whereas DCs obtained from dense cultures up-regulated immunosuppressive pathway components and genes suggesting higher differentiation plasticity towards osteoclasts. Interestingly, we detected a striking up-regulation of fatty acid and cholesterol biosynthesis pathways in sparse cultures, suggesting an important link between DC immunogenicity and lipid homeostasis regulation.

Immunological Properties of Hepatitis B Core Antigen Fusion Proteins

NASA Astrophysics Data System (ADS)

Francis, Michael J.; Hastings, Gillian Z.; Brown, Alan L.; Grace, Ken G.; Rowlands, David J.; Brown, Fred; Clarke, Berwyn E.

1990-04-01

The immunogenicity of a 19 amino acid peptide from foot-and-mouth disease virus has previously been shown to approach that of the inactivated virus from which it was derived after multimeric particulate presentation as an N-terminal fusion with hepatitis B core antigen. In this report we demonstrate that rhinovirus peptide-hepatitis B core antigen fusion proteins are 10-fold more immunogenic than peptide coupled to keyhole limpet hemocyanin and 100-fold more immunogenic than uncoupled peptide with an added helper T-cell epitope. The fusion proteins can be readily administered without adjuvant or with adjuvants acceptable for human and veterinary application and can elicit a response after nasal or oral dosing. The fusion proteins can also act as T-cell-independent antigens. These properties provide further support for their suitability as presentation systems for "foreign" epitopes in the development of vaccines.

Effect of Vaccine Administration Modality on Immunogenicity and Efficacy

PubMed Central

Zhang, Lu; Wang, Wei; Wang, Shixia

2016-01-01

Summary The many factors impacting the efficacy of a vaccine can be broadly divided into three categories: (1) features of the vaccine itself, including immunogen design, vaccine type, formulation, adjuvant, and dosing; (2) individual variations among vaccine recipients; and (3) vaccine administration-related parameters. While much literature exists related to vaccines, and recently systems biology has started to dissect the impact of individual subject variation on vaccine efficacy, few studies have focused on the role of vaccine administration-related parameters on vaccine efficacy. Parenteral and mucosal vaccinations are traditional approaches for licensed vaccines; novel vaccine delivery approaches, including needless injection and adjuvant formulations, are being developed to further improve vaccine safety and efficacy. This review provides a brief summary of vaccine administration-related factors, including vaccination approach, delivery route, and method of administration, to gain a better understanding of their potential impact on the safety and immunogenicity of candidate vaccines. PMID:26313239

Efficacy, immunogenicity, and safety of a 9-valent human papillomavirus vaccine in Latin American girls, boys, and young women.

PubMed

Ruiz-Sternberg, Ángela María; Moreira, Edson D; Restrepo, Jaime A; Lazcano-Ponce, Eduardo; Cabello, Robinson; Silva, Arnaldo; Andrade, Rosires; Revollo, Francisco; Uscanga, Santos; Victoria, Alejandro; Guevara, Ana María; Luna, Joaquín; Plata, Manuel; Dominguez, Claudia Nossa; Fedrizzi, Edison; Suarez, Eugenio; Reina, Julio C; Ellison, Misoo C; Moeller, Erin; Ritter, Michael; Shields, Christine; Cashat, Miguel; Perez, Gonzalo; Luxembourg, Alain

2018-06-01

A 9-valent human papillomavirus (HPV6/11/16/18/31/33/45/52/58; 9vHPV) vaccine was developed to expand coverage of the previously developed quadrivalent (HPV6/11/16/18; qHPV) vaccine. Efficacy, immunogenicity, and safety outcomes were assessed in Latin American participants enrolled in 2 international studies of the 9vHPV vaccine, including a randomized, double-blinded, controlled with qHPV vaccine, efficacy, immunogenicity, and safety study in young women aged 16-26 years, and an immunogenicity and safety study in girls and boys aged 9-15 years. Participants (N=5312) received vaccination at Day 1, Month 2, and Month 6. Gynecological swabs were collected regularly in young women for cytological and HPV DNA testing. Serum was analyzed for HPV antibodies in all participants. Adverse events (AEs) were also monitored in all participants. The 9vHPV vaccine prevented HPV 31-, 33-, 45-, 52-, and 58-related high-grade cervical, vulvar, and vaginal dysplasia with 92.3% efficacy (95% confidence interval 54.4, 99.6). Anti-HPV6, 11, 16, and 18 geometric mean titers at Month 7 were similar in the 9vHPV and qHPV vaccination groups. Anti-HPV antibody responses following vaccination were higher among girls and boys than in young women. Most (>99%) 9vHPV vaccine recipients seroconverted for all 9 HPV types at Month 7. Antibody responses to the 9 HPV types persisted over 5 years. The most common AEs were injection-site related, mostly of mild to moderate intensity. The 9vHPV vaccine is efficacious, immunogenic, and well tolerated in Latin American young women, girls, and boys. These data support 9vHPV vaccination programs in Latin America, a region with substantial cervical cancer burden. Copyright © 2018 Merck Sharp & Dohme Corp., and The Authors. Published by Elsevier B.V. All rights reserved.

Grand Bay-Banks Lake Stewardship Partnership - Phase 2

DTIC Science & Technology

2006-11-01

including smallpox, measles, typhus, tuberculosis, chicken pox and influenza, any of which could prove fatal. When the southeastern Indians were hit...Gulf of Mexico coastal plain within southeast Mississippi, Alabama, and southwest Georgia where they are called "Grady Ponds" because of the Grady

ACHIEVEMENTS IN THE STRUGGLE AGAINST INFECTIOUS DISEASES IN THE AZERBAIDZHAN SSR,

DTIC Science & Technology

Great achievements have been made in controlling such diseases as malaria, exanthemous, and recurrent typhus, dysentery, typhoid fever, whooping ... cough , and many childhood diseases such as diphtheria, scarlet fever, and measles. The success is attributed to a system of sanitary-epidemiological

Multispacer Typing of Rickettsia prowazekii Enabling Epidemiological Studies of Epidemic Typhus†

PubMed Central

Zhu, Yong; Fournier, Pierre-Edouard; Ogata, Hiroyuki; Raoult, Didier

2005-01-01

Currently, there is no tool for typing Rickettsia prowazekii, the causative agent of epidemic typhus, currently considered a potential bioterrorism agent, at the strain level. To test if the multispacer typing (MST) method could differentiate strains of R. prowazekii, we amplified and sequenced the 25 most variable intergenic spacers between the R. prowazekii and R. conorii genomes in five strains and 10 body louse amplicons of R. prowazekii from various geographic origins. Two intergenic spacers, i.e., rpmE/tRNAfMet and serS/virB4, were variable among tested R. prowazekii isolates and allowed identification of three and two genotypes, respectively. When the genotypes obtained from the two spacers were combined, we identified four different genotypes. MST demonstrated that several R. prowazekii strains circulated in human body lice during an outbreak of epidemic typhus in Burundi. This may help to discriminate between natural and intentional outbreaks. Our study supports the usefulness of MST as a versatile method for rickettsial strain genotyping. PMID:16145131

Seroepidemiololgy of rickettsioses in Sri Lanka: a patient based study

PubMed Central

2011-01-01

Background Rickettsioses are emerging infections in Sri Lanka as shown by the increase in the number of clinically diagnosed rickettsial patients being reported to the Epidemiology Unit, Sri Lanka. However, mapping the disease for the whole island with laboratory confirmed cases has not been previously carried out. Methods 615 samples received from 23 hospital representing 8 provinces were tested using ELISA or IFA methods and clinical data was collected using a validated questionnaire. Results Rash was found among more spotted fever seropositive patients than scrub typhus seropositive patients while the opposite was true for the presence of eschar. Spotted fever and scrub typhus was found in a geographically restricted manner. Consistent temporal patterns were seen for the presentation of patients with rickettsioses in Kandy and Kurunegala districts for 2009 and 2010. Conclusions This study expanded knowledge on the distribution of rickettsioses in Sri Lanka and their clinical profiles which in turn helps in the clinical diagnosis of these infections. PMID:22118601

Tick-borne infectious diseases in Australia.

PubMed

Graves, Stephen R; Stenos, John

2017-04-17

Tick bites in Australia can lead to a variety of illnesses in patients. These include infection, allergies, paralysis, autoimmune disease, post-infection fatigue and Australian multisystem disorder. Rickettsial (Rickettsia spp.) infections (Queensland tick typhus, Flinders Island spotted fever and Australian spotted fever) and Q fever (Coxiella burnetii) are the only systemic bacterial infections that are known to be transmitted by tick bites in Australia. Three species of local ticks transmit bacterial infection following a tick bite: the paralysis tick (Ixodes holocyclus) is endemic on the east coast of Australia and causes Queensland tick typhus due to R. australis and Q fever due to C. burnetii; the ornate kangaroo tick (Amblyomma triguttatum) occurs throughout much of northern, central and western Australia and causes Q fever; and the southern reptile tick (Bothriocroton hydrosauri) is found mainly in south-eastern Australia and causes Flinders Island spotted fever due to R. honei. Much about Australian ticks and the medical outcomes following tick bites remains unknown. Further research is required to increase understanding of these areas.

Comparison of a conventional and nested PCR for diagnostic confirmation and genotyping of Orientia tsutsugamushi.

PubMed

Janardhanan, Jeshina; Prakash, John Antony Jude; Abraham, Ooriapadickal C; Varghese, George M

2014-05-01

A nested polymerase chain reaction (PCR) targeting the 56-kDa antigen gene is currently the most commonly used molecular technique for confirmation of scrub typhus and genotyping of Orientia tsutsugamushi. In this study, we have compared the commonly used nested PCR (N-PCR) with a single-step conventional PCR (C-PCR) for amplification and genotyping. Eschar samples collected from 24 patients with scrub typhus confirmed by IgM enzyme-linked immunosorbent assay were used for DNA extraction following which amplifications were carried out using nested and C-PCR methods. The amplicons were sequenced and compared to other sequences in the database using BLAST. Conventional PCR showed a high positivity rate of 95.8% compared to the 75% observed using N-PCR. On sequence analysis, the N-PCR amplified region showed more variation among strains than the C-PCR amplified region. The C-PCR, which is more economical, provided faster and better results compared to N-PCR. Copyright © 2014 Elsevier Inc. All rights reserved.

Evidence of a louse-borne outbreak involving typhus in Douai, 1710-1712 during the war of Spanish succession.

PubMed

Nguyen-Hieu, Tung; Aboudharam, Gérard; Signoli, Michel; Rigeade, Catherine; Drancourt, Michel; Raoult, Didier

2010-10-27

The new field of paleomicrobiology allows past outbreaks to be identified by testing dental pulp of human remains with PCR. We identified a mass grave in Douai, France dating from the early XVIII(th) century. This city was besieged during the European war of Spanish succession. We tested dental pulp from 1192 teeth (including 40 from Douai) by quantitative PCR (qPCR) for R. prowazekii and B. quintana. We also used ultra-sensitive suicide PCR to detect R. prowazekii and genotyped positive samples. In the Douai remains, we identified one case of B. quintana infection (by qPCR) and R. prowazekii (by suicide PCR) in 6/21 individuals (29%). The R. prowazekii was genotype B, a genotype previously found in a Spanish isolate obtained in the first part of the XX(th) century. Louse-borne outbreaks were raging during the XVIII(th) century; our results support the hypothesis that typhus was imported into Europe by Spanish soldiers from America.

Evidence of a Louse-Borne Outbreak Involving Typhus in Douai, 1710-1712 during the War of Spanish Succession

PubMed Central

Nguyen-Hieu, Tung; Aboudharam, Gérard; Signoli, Michel; Rigeade, Catherine; Drancourt, Michel; Raoult, Didier

2010-01-01

Background The new field of paleomicrobiology allows past outbreaks to be identified by testing dental pulp of human remains with PCR. Methods We identified a mass grave in Douai, France dating from the early XVIIIth century. This city was besieged during the European war of Spanish succession. We tested dental pulp from 1192 teeth (including 40 from Douai) by quantitative PCR (qPCR) for R. prowazekii and B. quintana. We also used ultra-sensitive suicide PCR to detect R. prowazekii and genotyped positive samples. Results and Discussion In the Douai remains, we identified one case of B. quintana infection (by qPCR) and R. prowazekii (by suicide PCR) in 6/21 individuals (29%). The R. prowazekii was genotype B, a genotype previously found in a Spanish isolate obtained in the first part of the XXth century. Conclusion Louse-borne outbreaks were raging during the XVIIIth century; our results support the hypothesis that typhus was imported into Europe by Spanish soldiers from America. PMID:21060879

Progress in Developing Virus-like Particle Influenza Vaccines

PubMed Central

Quan, Fu-Shi; Lee, Young-Tae; Kim, Ki-Hye; Kim, Min-Chul; Kang, Sang-Moo

2016-01-01

Summary Recombinant vaccines based on virus-like particles (VLPs) or nanoparticles have been successful in their safety and efficacy in preclinical and clinical studies. The technology of expressing enveloped VLP vaccines has combined with molecular engineering of proteins in membrane-anchor and immunogenic forms mimicking the native conformation of surface proteins on the enveloped viruses. This review summarizes recent developments in influenza VLP vaccines against seasonal, pandemic, and avian influenza viruses from the perspective of use in humans. The immunogenicity and efficacies of influenza VLP vaccine in the homologous and cross-protection were reviewed. Discussions include limitations of current influenza vaccination strategies and future directions to confer broadly cross protective new influenza vaccines as well as vaccination. PMID:27058302

Dietary Immunogen® modulated digestive enzyme activity and immune gene expression in Litopenaeus vannamei post larvae.

PubMed

Miandare, Hamed Kolangi; Mirghaed, Ali Taheri; Hosseini, Marjan; Mazloumi, Nastaran; Zargar, Ashkan; Nazari, Sajad

2017-11-01

Pacific white shrimp Litopenaeus vannamei (Boone, 1931) is an important economical shrimp species worldwide, especially in the Middle East region, and farming activities of this species have been largely affected by diseases, mostly viral and bacterial diseases. Scientists have started to use prebiotics for bolstering the immune status of the animal. This study aimed to investigate the influence of Immunogen ® on growth, digestive enzyme activity and immune related gene expression of Litopenaeus vannamei post-larvae. All post-larvae were acclimated to the laboratory condition for 14 days. Upon acclimation, shrimps were fed on different levels of Immunogen ® (0, 0.5, 1 and 1.5 g kg -1 ) for 60 days. No significant differences were detected in weight gain, specific growth rate (SGR) and food conversion ratio (FCR) in shrimp post-larvae in which fed with different levels of Immunogen ® and control diet. The results showed that digestive enzymes activity including protease and lipase increased with different amounts of Immunogen ® in the shrimp diet. Protease activity increased with 1.5 g kg -1 Immunogen ® after 60 days and lipase activity increased with 1 and 1.5 g kg -1 Immunogen ® after 30 and 60 days of the trial respectively (P < 0.05), while amylase activity did not change in response to different levels of Immunogen ® (P > 0.05). The expression of immune related genes including, prophenoloxidase, crustin and g-type lysozyme increased with diet 1.5 g kg -1 Immunogen ® (P < 0.05) while expression of penaeidin gene increased only with experimental diet 1 g kg -1 of Immunogen ® . These results indicated that increase in digestive enzymes activity and expression of immune related genes could modulate the Immunogen ® in the innate immune system in L. vannamei in this study. Copyright © 2017. Published by Elsevier Ltd.

Zagreb Regimen, an Abbreviated Intramuscular Schedule for Rabies Vaccination

PubMed Central

Ren, Jiangping; Yao, Linong; Sun, Jimin

2014-01-01

The Zagreb regimen, an abbreviated intramuscular schedule for rabies vaccination, was developed by I. Vodopija and colleagues of the Zagreb Institute of Public Health in Croatia in the 1980s. It was recommended by WHO as one of the intramuscular (IM) schedules for rabies vaccination in 2010. We reviewed the literature on the immunogenicity, safety, economic burden, and compliance of the Zagreb 2-1-1 regimen. Compared to Essen, another IM schedule recommended by WHO, Zagreb has higher compliance, lower medical cost, and better immunogenicity at an early stage. PMID:25392012

Safety and immunogenicity of a recombinant parvovirus B19 vaccine formulated with MF59C.1.

PubMed

Ballou, W Ripley; Reed, Jennifer L; Noble, William; Young, Neal S; Koenig, Scott

2003-02-15

A recombinant human parvovirus B19 vaccine (MEDI-491; MedImmune) composed of the VP1 and VP2 capsid proteins and formulated with MF59C.1 adjuvant was evaluated in a randomized, double-blind, phase 1 trial. Parvovirus B19-seronegative adults (n=24) received either 2.5 or 25 microg MEDI-491 at 0, 1, and 6 months. MEDI-491 was safe and immunogenic. All volunteers developed neutralizing antibody titers that peaked after the third immunization and were sustained through study day 364.

Allergenicity, immunogenicity and dose-relationship of three intact allergen vaccines and four allergoid vaccines for subcutaneous grass pollen immunotherapy

PubMed Central

Henmar, H; Lund, G; Lund, L; Petersen, A; Würtzen, P A

2008-01-01

Different vaccines containing intact allergens or chemically modified allergoids as active ingredients are commercially available for specific immunotherapy. Allergoids are claimed to have decreased allergenicity without loss of immunogenicity and this is stated to allow administration of high allergoid doses. We compared the allergenicity and immunogenicity of four commercially available chemically modified grass pollen allergoid products with three commercially available intact grass pollen allergen vaccines. The allergenicity was investigated with immunoglobulin (Ig)E-inhibition and basophil activation assays. Human T cell proliferation and specific IgG-titres following mouse immunizations were used to address immunogenicity. Furthermore, intact allergen vaccines with different contents of active ingredients were selected to study the influence of the allergen dose. In general, a lower allergenicity for allergen vaccines was clearly linked to a reduced immunogenicity. Compared with the vaccine with the highest amount of intact allergen, the allergoids caused reduced basophil activation as well as diminished immunogenicity demonstrated by reduced T cell activation and/or reduced induction of murine grass-specific IgG antibodies. Interestingly, intact allergen vaccines with lower content of active ingredient exhibited similarly reduced allergenicity, while immunogenicity was still higher or equal to that of allergoids. The low allergenicity observed for some allergoids was inherently linked to a significantly lower immunogenic response questioning the rationale behind the chemical modification into allergoids. In addition, the linkage between allergenicity, immunogenicity and dose found for intact allergen vaccines and the immunogen as well as allergenic immune responses observed for allergoids suggest that the modified allergen vaccines do not contain high doses of immunologically active ingredients. PMID:18647321

Human Immunity and the Design of Multi-Component, Single Target Vaccines

PubMed Central

Saul, Allan; Fay, Michael P.

2007-01-01

Background Inclusion of multiple immunogens to target a single organism is a strategy being pursued for many experimental vaccines, especially where it is difficult to generate a strongly protective response from a single immunogen. Although there are many human vaccines that contain multiple defined immunogens, in almost every case each component targets a different pathogen. As a consequence, there is little practical experience for deciding where the increased complexity of vaccines with multiple defined immunogens vaccines targeting single pathogens will be justifiable. Methodology/Principal Findings A mathematical model, with immunogenicity parameters derived from a database of human responses to established vaccines, was used to predict the increase in the efficacy and the proportion of the population protected resulting from addition of further immunogens. The gains depended on the relative protection and the range of responses in the population to each immunogen and also to the correlation of the responses between immunogens. In most scenarios modeled, the gain in overall efficacy obtained by adding more immunogens was comparable to gains obtained from a single immunogen through the use of better formulations or adjuvants. Multi-component single target vaccines were more effective at decreasing the proportion of poor responders than increasing the overall efficacy of the vaccine in a population. Conclusions/Significance Inclusion of limited number of antigens in a vaccine aimed at targeting a single organism will increase efficacy, but the gains are relatively modest and for a practical vaccine there are constraints that are likely to limit multi-component single target vaccines to a small number of key antigens. The model predicts that this type of vaccine will be most useful where the critical issue is the reduction in proportion of poor responders. PMID:17786221

Science in 60 - The Forecast Calls for Flu

ScienceCinema

Del Valle, Sara

2018-05-21

What if we could forecast infectious diseases the same way we forecast the weather, and predict how diseases like Dengue, Typhus, or Zika were going to spread? Using real-time data from Wikipedia and social media, Sara Del Valle and her team from Los Alamos National Laboratory have developed a global disease-forecasting system that will improve the way we respond to epidemics. Using this model, individuals and public health officials can monitor disease incidence and implement strategies — such as vaccination campaigns, communicating to the public and allocating resources — to stay one step ahead of infectious disease spread.

What Happened to the Kalapuya? A Study of the Depletion of Their Economic Base

ERIC Educational Resources Information Center

Ratcliff, James L.

1973-01-01

The Kalapuyan economy of hunting, fishing, root digging, berry gathering, and intertribal trade was depleted in the first 30 years of white contact, causing the natives considerable hunger and starvation. Many died from infectious diseases--typhus, smallpox, and venereal diseases. (FF)

Perinatal exposure to the pesticide DDT impairs energy expenditure and metabolism in adult female mice

USDA-ARS?s Scientific Manuscript database

Dichlorodiphenyltrichloroethane (DDT) has been used extensively to control malaria, typhus, body lice and bubonic plague worldwide, until countries began restricting its use in the 1970s. Individuals exposed to elevated levels of DDT and its metabolite dichlorodiphenyldichloroethylene have an increa...

Desert Operations Tactics, Techniques, and Procedures. Southwest Asia Focus

DTIC Science & Technology

1990-11-01

6-5 CONTAM IN ATION TRAN SFER ...................................................................... 6-7 PRINCIPLES OF CONTAMINATION AVOIDANCE...6-14 Decontam ination Principles ....................................................................... 6-14 Aircraft Spraydown...moisture or food, lice, mites, and flies can be extremely unpleasant and carry diseases such as scrub typhus and dysentery. The stings of many

Evaluation of the immunogenicity and protective effects of a trivalent chimeric norovirus P particle immunogen displaying influenza HA2 from subtypes H1, H3 and B

PubMed Central

Gong, Xin; Yin, He; Shi, Yuhua; He, Xiaoqiu; Yu, Yongjiao; Guan, Shanshan; Kuai, Ziyu; Haji, Nasteha M; Haji, Nafisa M; Kong, Wei; Shan, Yaming

2016-01-01

The ectodomain of the influenza A virus (IAV) hemagglutinin (HA) stem is highly conserved across strains and has shown promise as a universal influenza vaccine in a mouse model. In this study, potential B-cell epitopes were found through sequence alignment and epitope prediction in a stem fragment, HA2:90-105, which is highly conserved among virus subtypes H1, H3 and B. A norovirus (NoV) P particle platform was used to express the HA2:90-105 sequences from subtypes H1, H3 and B in loops 1, 2 and 3 of the protrusion (P) domain, respectively. Through mouse immunization and microneutralization assays, the immunogenicity and protective efficacy of the chimeric NoV P particle (trivalent HA2-PP) were tested against infection with three subtypes (H1N1, H3N2 and B) of IAV in Madin–Darby canine kidney cells. The protective efficacy of the trivalent HA2-PP was also evaluated preliminarily in vivo by virus challenge in the mouse model. The trivalent HA2-PP immunogen induced significant IgG antibody responses, which could be enhanced by a virus booster vaccination. Moreover, the trivalent HA2-PP immunogen also demonstrated in vitro neutralization of the H3 and B viruses, and in vivo protection against the H3 virus. Our results support the notion that a broadly protective vaccine approach using an HA2-based NoV P particle platform can provide cross-protection against challenge viruses of different IAV subtypes. The efficacy of the immunogen should be further enhanced for practicality, and a better understanding of the protective immune mechanism will be critical for the development of HA2-based multivalent vaccines. PMID:27222326

Antigenicity and Immunogenicity of RV144 Vaccine AIDSVAX Clade E Envelope Immunogen Is Enhanced by a gp120 N-Terminal Deletion

PubMed Central

Liao, Hua-Xin; Tomaras, Georgia D.; Bonsignori, Mattia; Tsao, Chun-Yen; Hwang, Kwan-Ki; Chen, Haiyan; Lloyd, Krissey E.; Bowman, Cindy; Sutherland, Laura; Jeffries, Thomas L.; Kozink, Daniel M.; Stewart, Shelley; Anasti, Kara; Jaeger, Frederick H.; Parks, Robert; Yates, Nicole L.; Overman, R. Glenn; Sinangil, Faruk; Berman, Phillip W.; Pitisuttithum, Punnee; Kaewkungwal, Jaranit; Nitayaphan, Sorachai; Karasavva, Nicos; Rerks-Ngarm, Supachai; Kim, Jerome H.; Michael, Nelson L.; Zolla-Pazner, Susan; Santra, Sampa; Letvin, Norman L.; Harrison, Stephen C.

2013-01-01

An immune correlates analysis of the RV144 HIV-1 vaccine trial revealed that antibody responses to the gp120 V1/V2 region correlated inversely with infection risk. The RV144 protein immunogens (A244-rp120 and MN-rgp120) were modified by an N-terminal 11-amino-acid deletion (Δ11) and addition of a herpes simplex virus (HSV) gD protein-derived tag (gD). We investigated the effects of these modifications on gp120 expression, antigenicity, and immunogenicity by comparing unmodified A244 gp120 with both Δ11 deletion and gD tag and with Δ11 only. Analysis of A244 gp120, with or without Δ11 or gD, demonstrated that the Δ11 deletion, without the addition of gD, was sufficient for enhanced antigenicity to gp120 C1 region, conformational V2, and V1/V2 gp120 conformational epitopes. RV144 vaccinee serum IgGs bound more avidly to A244 gp120 Δ11 than to the unmodified gp120, and their binding was blocked by C1, V2, and V1/V2 antibodies. Rhesus macaques immunized with the three different forms of A244 gp120 proteins gave similar levels of gp120 antibody titers, although higher antibody titers developed earlier in A244 Δ11 gp120-immunized animals. Conformational V1/V2 monoclonal antibodies (MAbs) gave significantly higher levels of blocking of plasma IgG from A244 Δ11 gp120-immunized animals than IgG from animals immunized with unmodified A244 gp120, thus indicating a qualitative difference in the V1/V2 antibodies induced by A244 Δ11 gp120. These results demonstrate that deletion of N-terminal residues in the RV144 A244 gp120 immunogen improves both envelope antigenicity and immunogenicity. PMID:23175357

Diverse manifestations of tumorigenicity and immunogenicity displayed by the poorly immunogenic B16-BL6 melanoma transduced with cytokine genes.

PubMed

Arca, M J; Krauss, J C; Strome, S E; Cameron, M J; Chang, A E

1996-05-01

We evaluated the in vivo response to the poorly immunogenic B16-BL6 (BL6) murine melanoma genetically altered to secrete interleukin-2 (IL-2), IL-4, interferon gamma (IFN gamma) and granulocyte/macrophage-colony-stimulating factor (GM-CSF). Three parameters were evaluated: (1) tumorigenicity, (2) vaccination of naive animals, and (3) assessment of antitumor reactivity of T cells derived from tumor-draining lymph nodes (TDLN). Secretion of IL-2 abrogated the tumorigenicity of BL6, while IFN gamma and IL-4 partially reduced tumorigenicity, and GM-CSF had no effect. Protective immunity to wild-type tumor challenge could not be achieved by vaccination with irradiated cytokine-secreting tumors, although IL-2 and IL-4 secretion appeared to retard the growth of the challenge inoculum significantly. An alternative method to evaluate the immunogenicity of the cytokine-secreting tumors was to measure the ability of T cells obtained from TDLN to mediate regression of wild-type tumor in adoptive immunotherapy. Neither IL-2 nor IFN gamma secretion resulted in the induction of immune T cells. By contrast, GM-CSF and IL-4 secretion were found to induce immune T cells in the TDLN with GM-CSF being superior to IL-4. The combined secretion of GM-CSF and IL-4 did not lead to enhanced induction of immune T cells. GM-CSF secretion was found to upregulate B7-1 expression in TDLN, consistent with an increase in the population of antigen-presenting cells. These studies demonstrated that reduced tumorigenicity by cytokine secretion did not correlate with increased immunogenicity. With the cytokines examined, there was limited capability of developing protective immunity against the BL6 tumor. Nevertheless, GM-CSF and IL-4 secretion significantly enhanced T cell immune reactivity to the poorly immunogenic BL6 tumor.

Contribution of enhanced engagement of antigen presentation machinery to the clinical immunogenicity of a human interleukin (IL)-21 receptor-blocking therapeutic antibody.

PubMed

Xue, L; Hickling, T; Song, R; Nowak, J; Rup, B

2016-01-01

Reliable risk assessment for biotherapeutics requires accurate evaluation of risk factors associated with immunogenicity. Immunogenicity risk assessment tools were developed and applied to investigate the immunogenicity of a fully human therapeutic monoclonal antibody, ATR-107 [anti-interleukin (IL)-21 receptor] that elicited anti-drug antibodies (ADA) in 76% of healthy subjects in a Phase 1 study. Because the ATR-107 target is expressed on dendritic cells (DCs), the immunogenicity risk related to engagement with DC and antigen presentation pathways was studied. Despite the presence of IL-21R on DCs, ATR-107 did not bind to the DCs more extensively than the control therapeutic antibody (PF-1) that had elicited low clinical ADA incidence. However, ATR-107, but not the control therapeutic antibody, was translocated to the DC late endosomes, co-localized with intracellular antigen-D related (HLA-DR) molecules and presented a dominant T cell epitope overlapping the complementarity determining region 2 (CDR2) of the light chain. ATR-107 induced increased DC activation exemplified by up-regulation of DC surface expression of CD86, CD274 (PD-L1) and CD40, increased expansion of activated DC populations expressing CD86(hi), CD40(hi), CD83(hi), programmed death ligand 1 (PD-L1)(hi), HLA-DR(hi) or CCR7(hi), as well as elevated secretion of tumour necrosis factor (TNF)-α by DCs. DCs exposed to ATR-107 stimulated an autologous T cell proliferative response in human donor cells, in concert with the detection of immunoglobulin (Ig)G-type anti-ATR-107 antibody response in clinical samples. Collectively, the enhanced engagement of antigen presentation machinery by ATR-107 was suggested. The approaches and findings described in this study may be relevant to identifying lower immunogenicity risk targets and therapeutic molecules. © 2015 British Society for Immunology.

Quality, immunogenicity and stability of meningococcal serogroup ACWY-CRM197, DT and TT glycoconjugate vaccines.

PubMed

Beresford, Nicola J; Martino, Angela; Feavers, Ian M; Corbel, Michael J; Bai, Xilian; Borrow, Ray; Bolgiano, Barbara

2017-06-16

A physicochemical and immunological study of the stability of three different meningococcal (Men) ACWY conjugate vaccines was performed to evaluate any patterns of serogroup oligo- or polysaccharide-specific or carrier protein-specific stability that would affect immunogenicity. Critical quality and stability-indicating characteristics were measured, with the study supporting the suitability of both HPLC-SEC and HPAEC-PAD methods to detect changes following inappropriate vaccine storage. All three final products, ACWY-CRM 197 , -DT and -TT conjugate vaccines had expected quality indicator values and similar immunogenicity in a mouse model (anti-PS IgG and rSBA) when stored at +2-8°C. When stored at ≥+37°C, all conjugated carrier proteins and serogroup saccharides were affected. Direct correlations were observed between the depolymerization of the MenA saccharide as evidenced by a size-reduction in the MenA conjugates (CRM 197 , DT and TT) and their immunogenicity. MenA was the most labile serogroup, followed by MenC; then MenW and Y, which were similar. At high temperatures, the conjugated carrier proteins were prone to unfolding and/or aggregation. The anti-MenC IgG responses of the multivalent conjugate vaccines in mice were equivalent to those observed in monovalent MenC conjugate vaccines, and were independent of the carrier protein. For any newly developing MenACWY saccharide-protein conjugate vaccines, a key recommendation would be to consider the lyophilization of final product to prevent deleterious degradation that would affect immunogenicity. Crown Copyright © 2017. Published by Elsevier Ltd. All rights reserved.

Predicted MHC peptide binding promiscuity explains MHC class I 'hotspots' of antigen presentation defined by mass spectrometry eluted ligand data.

PubMed

Jappe, Emma Christine; Kringelum, Jens; Trolle, Thomas; Nielsen, Morten

2018-02-15

Peptides that bind to and are presented by MHC class I and class II molecules collectively make up the immunopeptidome. In the context of vaccine development, an understanding of the immunopeptidome is essential, and much effort has been dedicated to its accurate and cost-effective identification. Current state-of-the-art methods mainly comprise in silico tools for predicting MHC binding, which is strongly correlated with peptide immunogenicity. However, only a small proportion of the peptides that bind to MHC molecules are, in fact, immunogenic, and substantial work has been dedicated to uncovering additional determinants of peptide immunogenicity. In this context, and in light of recent advancements in mass spectrometry (MS), the existence of immunological hotspots has been given new life, inciting the hypothesis that hotspots are associated with MHC class I peptide immunogenicity. We here introduce a precise terminology for defining these hotspots and carry out a systematic analysis of MS and in silico predicted hotspots. We find that hotspots defined from MS data are largely captured by peptide binding predictions, enabling their replication in silico. This leads us to conclude that hotspots, to a great degree, are simply a result of promiscuous HLA binding, which disproves the hypothesis that the identification of hotspots provides novel information in the context of immunogenic peptide prediction. Furthermore, our analyses demonstrate that the signal of ligand processing, although present in the MS data, has very low predictive power to discriminate between MS and in silico defined hotspots. © 2018 John Wiley & Sons Ltd.

Randomized Controlled Field Trial to Assess the Immunogenicity and Safety of Rift Valley Fever Clone 13 Vaccine in Livestock

PubMed Central

Njenga, M. Kariuki; Njagi, Leonard; Thumbi, S. Mwangi; Kahariri, Samuel; Githinji, Jane; Omondi, Eunice; Baden, Amy; Murithi, Mbabu; Paweska, Janusz; Ithondeka, Peter M.; Ngeiywa, Kisa J.; Dungu, Baptiste; Donadeu, Meritxell; Munyua, Peninah M.

2015-01-01

Background Although livestock vaccination is effective in preventing Rift Valley fever (RVF) epidemics, there are concerns about safety and effectiveness of the only commercially available RVF Smithburn vaccine. We conducted a randomized controlled field trial to evaluate the immunogenicity and safety of the new RVF Clone 13 vaccine, recently registered in South Africa. Methods In a blinded randomized controlled field trial, 404 animals (85 cattle, 168 sheep, and 151 goats) in three farms in Kenya were divided into three groups. Group A included males and non-pregnant females that were randomized and assigned to two groups; one vaccinated with RVF Clone 13 and the other given placebo. Groups B included animals in 1st half of pregnancy, and group C animals in 2nd half of pregnancy, which were also randomized and either vaccinated and given placebo. Animals were monitored for one year and virus antibodies titers assessed on days 14, 28, 56, 183 and 365. Results In vaccinated goats (N = 72), 72% developed anti-RVF virus IgM antibodies and 97% neutralizing IgG antibodies. In vaccinated sheep (N = 77), 84% developed IgM and 91% neutralizing IgG antibodies. Vaccinated cattle (N = 42) did not develop IgM antibodies but 67% developed neutralizing IgG antibodies. At day 14 post-vaccination, the odds of being seropositive for IgG in the vaccine group was 3.6 (95% CI, 1.5 – 9.2) in cattle, 90.0 (95% CI, 25.1 – 579.2) in goats, and 40.0 (95% CI, 16.5 – 110.5) in sheep. Abortion was observed in one vaccinated goat but histopathologic analysis did not indicate RVF virus infection. There was no evidence of teratogenicity in vaccinated or placebo animals. Conclusions The results suggest RVF Clone 13 vaccine is safe to use and has high (>90%) immunogenicity in sheep and goats but moderate (> 65%) immunogenicity in cattle. PMID:25756501

A Streptococcus mutans immunogen that reacts equally with S. mutans antibody of all serotypes.

PubMed

Everhart, D L; Miglietta, L M; Maresca, V A; Kelly-Hatfield, P

1984-01-01

We have studied a possible immunogen from S. mutans that has the capability of producing antibody to S. mutans which reacts equally well with all serotypes. This immunogen, a ribosomal preparation, is immunogenic in mice, is antigenic with rabbit anti-S. mutans, and is antigenic with the human antibody that also reacts with S. mutans. The human antibody is of the IgG class and S-IgA class.

Safety and Immunogenicity Testing of a Pilot Polysaccharide Vaccine Preparation to Pseudomonas aeruginosa.

DTIC Science & Technology

1981-09-01

8217-NAL." BUR-._,AL)- ’..O,.-,.S.AN--DA. .-D-S.... . . . .A AD___________ Safety and Immunogenicity Testing of a Pilot Polysaccharide Vaccine Preparation...COVERED Safety and Immunogenicity Testing of a Pilot Annual Report Polysaccharide Vaccine Preparation to (16 Aug. 80 - 1 Aug. 81) Pseudomonas...immunogenic or biologically active component of the vaccine. The vaccine is a high molecu- lar weight polysaccharide (PS) material isolated from the outer

Immunogenicity of therapeutic proteins. Part 2: impact of container closures.

PubMed

Sharma, Basant

2007-01-01

Immunogenicity as a potential consequence of therapeutic protein administration is increasingly being scrutinized in the biopharmaceuticals industry, particularly with the imminent introduction of biosimilar products. Immunogenicity is an important safety aspect requiring rigorous investigation to fully appreciate its impact. Factors involved in product handling, such as storage temperature, light exposure, and shaking, have been implicated in immunogenicity, while container closure systems are no less important. Intended to provide a stable environment for the dosage form, container closures may also interact with a product, affecting performance and potentially enhancing immunogenicity. Glass surfaces, air-liquid interfaces, and lubricants can mediate protein denaturation, while phthalates in plastics and latex rubber are sources of extractables and leachates that may contaminate a product, causing allergic reactions and increasing immunogenicity. The manufacture of therapeutic proteins therefore requires rigorous safety evaluations not just in the context of the product, but also product containment.

A Therapeutic Uricase with Reduced Immunogenicity Risk and Improved Development Properties.

PubMed

Nyborg, Andrew C; Ward, Chris; Zacco, Anna; Chacko, Benoy; Grinberg, Luba; Geoghegan, James C; Bean, Ryan; Wendeler, Michaela; Bartnik, Frank; O'Connor, Ellen; Gruia, Flaviu; Iyer, Vidyashankara; Feng, Hui; Roy, Varnika; Berge, Mark; Miner, Jeffrey N; Wilson, David M; Zhou, Dongmei; Nicholson, Simone; Wilker, Clynn; Wu, Chi Y; Wilson, Susan; Jermutus, Lutz; Wu, Herren; Owen, David A; Osbourn, Jane; Coats, Steven; Baca, Manuel

2016-01-01

Humans and higher primates are unique in that they lack uricase, the enzyme capable of oxidizing uric acid. As a consequence of this enzyme deficiency, humans have high serum uric acid levels. In some people, uric acid levels rise above the solubility limit resulting in crystallization in joints, acute inflammation in response to those crystals causes severe pain; a condition known as gout. Treatment for severe gout includes injection of non-human uricase to reduce serum uric acid levels. Krystexxa® is a hyper-PEGylated pig-baboon chimeric uricase indicated for chronic refractory gout that induces an immunogenic response in 91% of treated patients, including infusion reactions (26%) and anaphylaxis (6.5%). These properties limit its use and effectiveness. An innovative approach has been used to develop a therapeutic uricase with improved properties such as: soluble expression, neutral pH solubility, high E. coli expression level, thermal stability, and excellent activity. More than 200 diverse uricase sequences were aligned to guide protein engineering and reduce putative sequence liabilities. A single uricase lead candidate was identified, which showed low potential for immunogenicity in >200 human donor samples selected to represent diverse HLA haplotypes. Cysteines were engineered into the lead sequence for site specific PEGylation and studies demonstrated >95% PEGylation efficiency. PEGylated uricase retains enzymatic activity in vitro at neutral pH, in human serum and in vivo (rats and canines) and has an extended half-life. In canines, an 85% reduction in serum uric acid levels was observed with a single subcutaneous injection. This PEGylated, non-immunogenic uricase has the potential to provide meaningful benefits to patients with gout.

Variable epitope libraries: new vaccine immunogens capable of inducing broad human immunodeficiency virus type 1-neutralizing antibody response.

PubMed

Charles-Niño, Claudia; Pedroza-Roldan, Cesar; Viveros, Monica; Gevorkian, Goar; Manoutcharian, Karen

2011-07-18

The extreme antigenic variability of human immunodeficiency virus (HIV) leads to immune escape of the virus, representing a major challenge in the design of effective vaccine. We have developed a novel concept for immunogen construction based on introduction of massive mutations within the epitopes targeting antigenically variable pathogens and diseases. Previously, we showed that these immunogens carrying large combinatorial libraries of mutated epitope variants, termed as variable epitope libraries (VELs), induce potent, broad and long lasting CD8+IFN-γ+ T-cell response. Moreover, we demonstrated that these T cells recognize more than 50% of heavily mutated variants (5 out of 10 amino acid positions were mutated in each epitope variant) of HIV-1 gp120 V3 loop-derived cytotoxic T lymphocyte epitope (RGPGRAFVTI) in mice. The constructed VELs had complexities of 10000 and 12500 individual members, generated as plasmid DNA or as M13 phage display combinatorial libraries, respectively, and with structural composition RGPGXAXXXX or XGXGXAXVXI, where X is any of 20 natural amino acids. Here, we demonstrated that sera from mice immunized with these VELs are capable of neutralizing 5 out of 10 viral isolates from Tier 2 reference panel of subtype B envelope clones, including HIV-1 isolates which are known to be resistant to neutralization by several potent monoclonal antibodies, described previously. These data indicate the feasibility of the application of immunogens based on VEL concept as an alternative approach for the development of molecular vaccines against antigenically variable pathogens. Copyright © 2011 Elsevier Ltd. All rights reserved.

The modulation of Dicer regulates tumor immunogenicity in melanoma

PubMed Central

Hoffend, Nicholas C.; Magner, William J.; Tomasi, Thomas B.

2016-01-01

MicroRNAs (miRs) are small non-coding RNAs that regulate most cellular protein networks by targeting mRNAs for translational inhibition or degradation. Dicer, a type III endoribonuclease, is a critical component in microRNA biogenesis and is required for mature microRNA production. Abnormal Dicer expression occurs in numerous cancer types and correlates with poor patient prognosis. For example, increased Dicer expression in melanoma is associated with more aggressive tumors (higher tumor mitotic index and depth of invasion) and poor patient prognosis. However, the role that Dicer plays in melanoma development and immune evasion remains unclear. Here, we report on a newly discovered relationship between Dicer expression and tumor immunogenicity. To investigate Dicer's role in regulating melanoma immunogenicity, Dicer knockdown studies were performed. We found that B16F0-Dicer deficient cells exhibited decreased tumor growth compared to control cells and were capable of inducing anti-tumor immunity. The decrease in tumor growth was abrogated in immunodeficient NSG mice and was shown to be dependent upon CD8+ T cells. Dicer knockdown also induced a more responsive immune gene profile in melanoma cells. Further studies demonstrated that CD8+ T cells preferentially killed Dicer knockdown tumor cells compared to control cells. Taken together, we present evidence which links Dicer expression to tumor immunogenicity in melanoma. PMID:27356752

The modulation of Dicer regulates tumor immunogenicity in melanoma.

PubMed

Hoffend, Nicholas C; Magner, William J; Tomasi, Thomas B

2016-07-26

MicroRNAs (miRs) are small non-coding RNAs that regulate most cellular protein networks by targeting mRNAs for translational inhibition or degradation. Dicer, a type III endoribonuclease, is a critical component in microRNA biogenesis and is required for mature microRNA production. Abnormal Dicer expression occurs in numerous cancer types and correlates with poor patient prognosis. For example, increased Dicer expression in melanoma is associated with more aggressive tumors (higher tumor mitotic index and depth of invasion) and poor patient prognosis. However, the role that Dicer plays in melanoma development and immune evasion remains unclear. Here, we report on a newly discovered relationship between Dicer expression and tumor immunogenicity. To investigate Dicer's role in regulating melanoma immunogenicity, Dicer knockdown studies were performed. We found that B16F0-Dicer deficient cells exhibited decreased tumor growth compared to control cells and were capable of inducing anti-tumor immunity. The decrease in tumor growth was abrogated in immunodeficient NSG mice and was shown to be dependent upon CD8+ T cells. Dicer knockdown also induced a more responsive immune gene profile in melanoma cells. Further studies demonstrated that CD8+ T cells preferentially killed Dicer knockdown tumor cells compared to control cells. Taken together, we present evidence which links Dicer expression to tumor immunogenicity in melanoma.

Formulation and Immunogenicity studies of Type III Secretion System needle antigens as Vaccine Candidates

PubMed Central

Barrett, Brooke S.; Markham, Aaron P.; Esfandiary, Reza; Picking, Wendy L.; Picking, William D.; Joshi, Sangeeta B.; Middaugh, C. Russell

2013-01-01

Bacterial infections caused by Shigella flexneri, Salmonella typhimurium and Burkholderia pseudomallei are currently difficult to prevent due to the lack of a licensed vaccine. Here we present formulation and immunogenicity studies for the three type III secretion system (TTSS) needle proteins MxiHΔ5, PrgIΔ5 and BsaLΔ5 (each truncated by five residues at its C terminus) as potential candidates for vaccine development. These antigens are found to be thermally stabilized by the presence of carbohydrates and polyols. Additionally, all adsorb readily to aluminum hydroxide apparently through a combination of hydrogen bonds and/or Van der Waals forces. The interaction of these proteins with the aluminum-based adjuvant changes with time to resulting in varying degrees of irreversible binding. Peptide maps of desorbed protein, however, suggest that chemical changes are not responsible for this irreversible association. The ability of MxiHΔ5 and PrgIΔ5 to elicit strong humoral immune responses was tested in a murine model. When administered intramuscularly as monomers, the needle components exhibited dose dependent immunogenic behavior. The polymerized version of MxiH was exceptionally immunogenic even at low doses. The responses of both monomeric and polymerized forms were boosted by adsorption to an aluminum salt adjuvant. PMID:20845448

Immunogenic peptides comprising a T-helper epitope and a B-cell neutralizing antibody epitope

DOEpatents

Haynes, Barton F [Durham, NC; Korber, Bette T [Los Alamos, NM; De Lorimier, Robert M [Durham, NC

2006-12-26

The present invention relates, generally, to a polyvalent immunogen and, more particularly, to a method of inducing neutralizing antibodies against HIV and to a polyvalent immunogen suitable for use in such a method.

Oral Administration of Electron-Beam Inactivated Rhodococcus equi Failed to Protect Foals against Intrabronchial Infection with Live, Virulent R. equi

PubMed Central

Rocha, Joana N.; Cohen, Noah D.; Bordin, Angela I.; Brake, Courtney N.; Giguère, Steeve; Coleman, Michelle C.; Alaniz, Robert C.; Lawhon, Sara D.; Mwangi, Waithaka; Pillai, Suresh D.

2016-01-01

There is currently no licensed vaccine that protects foals against Rhodococcus equi–induced pneumonia. Oral administration of live, virulent R. equi to neonatal foals has been demonstrated to protect against subsequent intrabronchial challenge with virulent R. equi. Electron beam (eBeam)-inactivated R. equi are structurally intact and have been demonstrated to be immunogenic when administered orally to neonatal foals. Thus, we investigated whether eBeam inactivated R. equi could protect foals against developing pneumonia after experimental infection with live, virulent R. equi. Foals (n = 8) were vaccinated by gavaging with eBeam-inactivated R. equi at ages 2, 7, and 14 days, or gavaged with equal volume of saline solution (n = 4), and subsequently infected intrabronchially with live, virulent R. equi at age 21 days. The proportion of vaccinated foals that developed pneumonia following challenge was similar among the vaccinated (7/8; 88%) and unvaccinated foals (3/4; 75%). This vaccination regimen did not appear to be strongly immunogenic in foals. Alternative dosing regimens or routes of administration need further investigation and may prove to be immunogenic and protective. PMID:26828865

Antigenic determinants of hepatitis E virus and vaccine-induced immunogenicity and efficacy.

PubMed

Zhao, Qinjian; Zhang, Jun; Wu, Ting; Li, Shao-Wei; Ng, Mun-Hon; Xia, Ning-Shao; Shih, James Wai-Kuo

2013-02-01

There is emerging evidence for an under-recognized hepatitis E virus (HEV) as a human pathogen. Among different reasons for this neglect are the unsatisfactory performance and under-utilization of commercial HEV diagnostic kits; for instance, the number of anti-HEV IgM kits marketed in China is about one-fifth of that of hepatitis A kits. Over the last two decades, substantial progress has been achieved in furthering our knowledge on the HEV-specific immune responses, antigenic features of HEV virions, and development of serological assays and more recently prophylactic vaccines. This review will focus on presenting the evidence of the importance of HEV infection for certain cohorts such as pregnant women, the key antigenic determinants of the virus, and immunogenicity and clinical efficacy conferred by a newly developed prophylactic vaccine. Robust immunogenicity, greater than 195-fold and approximately 50-fold increase of anti-HEV IgG level in seronegative and seropositive vaccinees, respectively, as well as impressive clinical efficacy of this vaccine was demonstrated. The protection rate against the hepatitis E disease and the virus infection was shown to be 100% (95% CI 75-100) and 78% (95% CI 66-86), respectively.

Engineering RENTA, a DNA prime-MVA boost HIV vaccine tailored for Eastern and Central Africa.

PubMed

Nkolola, J P; Wee, E G-T; Im, E-J; Jewell, C P; Chen, N; Xu, X-N; McMichael, A J; Hanke, T

2004-07-01

For the development of human immunodeficiency virus type 1 (HIV-1) vaccines, traditional approaches inducing virus-neutralizing antibodies have so far failed. Thus the effort is now focused on elicitation of cellular immunity. We are currently testing in clinical trials in the United Kingdom and East Africa a T-cell vaccine consisting of HIV-1 clade A Gag-derived immunogen HIVA delivered in a prime-boost regimen by a DNA plasmid and modified vaccinia virus Ankara (MVA). Here, we describe engineering and preclinical development of a second immunogen RENTA, which will be used in combination with the present vaccine in a four-component DNA/HIVA-RENTA prime-MVA/HIVA-RENTA boost formulation. RENTA is a fusion protein derived from consensus HIV clade A sequences of Tat, reverse transcriptase, Nef and gp41. We inactivated the natural biological activities of the HIV components and confirmed immunogenicities of the pTHr.RENTA and MVA.RENTA vaccines in mice. Furthermore, we demonstrated in mice and rhesus monkeys broadening of HIVA-elicited T-cell responses by a parallel induction of HIVA- and RENTA-specific responses recognizing multiple HIV epitopes.

[Effect of immune modulation on immunogenic and protective activity of a live plague vaccine].

PubMed

Karal'nik, B V; Ponomareva, T S; Deriabin, P N; Denisova, T G; Mel'nikova, N N; Tugambaev, T I; Atshabar, B B; Zakarian, S B

2014-01-01

Comparative evaluation of the effect of polyoxidonium and betaleukin on immunogenic and protective activity of a live plague vaccine in model animal experiments. Plague vaccine EV, polyoxidonium, betaleukin, erythrocytic antigenic diagnosticum for determination of F1 antibodies and immune reagents for detection of lymphocytes with F1 receptors (LFR) in adhesive test developed by the authors were used. The experiments were carried out in 12 rabbits and 169 guinea pigs. Immune modulation accelerated the appearance and disappearance of LFR (early phase) and ensured a more rapid and intensive antibody formation (effector phase). Activation by betaleukin is more pronounced than by polyoxidonium. The more rapid and intensive was the development of early phase, the more effective was antibody response to the vaccine. Immune modulation in the experiment with guinea pigs significantly increased protective activity of the vaccine. The use of immune modulators increased immunogenic (in both early and effector phases of antigen-specific response) and protective activity of the EV vaccine. A connection between the acceleration of the first phase of antigen-specific response and general intensity of effector phase of immune response to the EV vaccine was detected. ,