Gowen, Brian B.; Sefing, Eric J.; Westover, Jonna B.; Smee, Donald F.; Hagloch, Joseph; Furuta, Yousuke; Hall, Jeffery O.
Favipiravir (T-705) is a new anti-influenza drug approved for human use in Japan and progressing through Phase 3 clinical trials in the U.S. In addition to its potent inhibitory effects against influenza virus infection, the compound has been shown to be broadly active against RNA viruses from 9 different families, including the Arenaviridae. Several members of the Arenaviridae family of viruses are significant human pathogens that cause viral hemorrhagic fever, a severe systemic syndrome where vascular leak is a cardinal feature. Because arenaviral infections are unlikely to be diagnosed and treated until the illness has progressed to a more advanced state, it is important to understand the effects of the disease state on favipiravir pharmacokinetics (PK) and biodistribution to help guide therapeutic strategy. During acute arenavirus infection in hamsters, we found reduced plasma favipiravir concentrations and altered kinetics of absorption, elimination and time to maximum drug concentration. In addition, the amounts of the favipiravir M1 primary metabolite were higher in the infected animals, suggesting that favipiravir metabolism may favor the formation of this inactive metabolite during viral infection. We also discovered differences in favipiravir and M1 PK parameters associated with arenavirus infection in a number of hamster tissues. Finally, analysis at the individual animal level demonstrated a correlation between reduced plasma favipiravir concentration with increased disease burden as reflected by weight loss and viral load. Our study is the first to show the impact of active viral infection and disease on favipiravir PK and biodistribution, highlighting the need to consider alterations in these parameters when treating individuals with viral hemorrhagic fever of arenavirus or other etiology. PMID:26186980
Gowen, Brian B; Sefing, Eric J; Westover, Jonna B; Smee, Donald F; Hagloch, Joseph; Furuta, Yousuke; Hall, Jeffery O
Favipiravir (T-705) is a new anti-influenza drug approved for human use in Japan and progressing through Phase 3 clinical trials in the U.S. In addition to its potent inhibitory effects against influenza virus infection, the compound has been shown to be broadly active against RNA viruses from 9 different families, including the Arenaviridae. Several members of the Arenaviridae family of viruses are significant human pathogens that cause viral hemorrhagic fever, a severe systemic syndrome where vascular leak is a cardinal feature. Because arenaviral infections are unlikely to be diagnosed and treated until the illness has progressed to a more advanced state, it is important to understand the effects of the disease state on favipiravir pharmacokinetics (PK) and biodistribution to help guide therapeutic strategy. During acute arenavirus infection in hamsters, we found reduced plasma favipiravir concentrations and altered kinetics of absorption, elimination and time to maximum drug concentration. In addition, the amounts of the favipiravir M1 primary metabolite were higher in the infected animals, suggesting that favipiravir metabolism may favor the formation of this inactive metabolite during viral infection. We also discovered differences in favipiravir and M1 PK parameters associated with arenavirus infection in a number of hamster tissues. Finally, analysis at the individual animal level demonstrated a correlation between reduced plasma favipiravir concentration with increased disease burden as reflected by weight loss and viral load. Our study is the first to show the impact of active viral infection and disease on favipiravir PK and biodistribution, highlighting the need to consider alterations in these parameters when treating individuals with viral hemorrhagic fever of arenavirus or other etiology.
Mendenhall, Michelle; Russell, Andrew; Smee, Donald F.; Hall, Jeffery O.; Skirpstunas, Ramona; Furuta, Yousuke; Gowen, Brian B.
Background Lassa and Junín viruses are the most prominent members of the Arenaviridae family of viruses that cause viral hemorrhagic fever syndromes Lassa fever and Argentine hemorrhagic fever, respectively. At present, ribavirin is the only antiviral drug indicated for use in treatment of these diseases, but because of its limited efficacy in advanced cases of disease and its toxicity, safer and more effective antivirals are needed. Methodology/Principal Findings Here, we used a model of acute arenaviral infection in outbred guinea pigs based on challenge with an adapted strain of Pichindé virus (PICV) to further preclinical development of T-705 (Favipiravir), a promising broad-spectrum inhibitor of RNA virus infections. The guinea pig-adapted passage 19 PICV was uniformly lethal with an LD50 of ∼5 plaque-forming units and disease was associated with fever, weight loss, thrombocytopenia, coagulation defects, increases in serum aspartate aminotransferase (AST) concentrations, and pantropic viral infection. Favipiravir (300 mg/kg/day, twice daily orally for 14 days) was highly effective, as all animals recovered fully from PICV-induced disease even when therapy was initiated one week after virus challenge when animals were already significantly ill with marked fevers and thrombocytopenia. Antiviral activity and reduced disease severity was evidenced by dramatic reductions in peak serum virus titers and AST concentrations in favipiravir-treated animals. Moreover, a sharp decrease in body temperature was observed shortly after the start of treatment. Oral ribavirin was also evaluated, and although effective, the slower rate of recovery may be a sign of the drug's known toxicity. Conclusions/Significance Our findings support further development of favipiravir for the treatment of severe arenaviral infections. The optimization of the experimental favipiravir treatment regimen in the PICV guinea pig model will inform critical future studies in the same species based
Tani, Hideki; Fukuma, Aiko; Fukushi, Shuetsu; Taniguchi, Satoshi; Yoshikawa, Tomoki; Iwata-Yoshikawa, Naoko; Sato, Yuko; Suzuki, Tadaki; Nagata, Noriyo; Hasegawa, Hideki; Kawai, Yasuhiro; Uda, Akihiko; Morikawa, Shigeru; Shimojima, Masayuki; Watanabe, Haruo
ABSTRACT Severe fever with thrombocytopenia syndrome virus (SFTSV) is the causative agent of SFTS, an emerging hemorrhagic fever. This disease has a high case fatality rate and is endemic to China, South Korea, and Japan. Because there are currently no effective therapeutics for SFTS, potent and safe antivirals are needed for the treatment of SFTS. The inhibitory effect of T-705 (favipiravir) on the replication of SFTSV in Vero cells was evaluated. Mice lacking the type I interferon receptor (IFNAR−/−) were used as an in vivo lethal model for SFTSV infection. T-705, which has been licensed as an anti-influenza drug in Japan, inhibits SFTSV replication both in vitro and in vivo. T-705 inhibited replication of SFTSV in Vero cells by 5 log units, with a 50% inhibitory concentration (IC50) and IC90 of 6.0 µM and 22 µM, respectively. Intraperitoneal or oral administration of T-705 for 5 days to IFNAR−/− mice infected with lethal SFTSV significantly improved survival rates (100% survival) without causing body weight loss and reduced the viral load in the serum. Ribavirin also inhibited SFTSV replication. However, it was less effective than T-705 both in vitro and in vivo. A time-of-drug-addition study revealed that therapeutic T-705 treatment of SFTSV infection in IFNAR−/− mice was effective. These results suggest that T-705 is a promising candidate for the treatment of SFTS. IMPORTANCE Severe fever with thrombocytopenia syndrome (SFTS), caused by SFTS virus (SFTSV), is a recently identified emerging viral infectious disease. Despite the medical importance of this disease, there are currently neither vaccines nor effective therapeutics for SFTS. T-705, which is a pyrazine derivative, has shown broad antiviral activity against various RNA viruses. The present study demonstrated, for the first time to our knowledge, the efficacy of T-705 in treating SFTSV infection in a mouse lethal model. T-705 showed a high efficacy in the treatment of SFTSV infection in
Caroline, Amy L.; Powell, Diana S.; Bethel, Laura M.; Oury, Tim D.; Reed, Douglas S.; Hartman, Amy L.
Background Development of antiviral drugs that have broad-spectrum activity against a number of viral infections would be of significant benefit. Due to the evolution of resistance to currently licensed antiviral drugs, development of novel anti-influenza drugs is in progress, including Favipiravir (T-705), which is currently in human clinical trials. T-705 displays broad-spectrum in vitro activity against a number of viruses, including Rift Valley Fever virus (RVFV). RVF is an important neglected tropical disease that causes human, agricultural, and economic losses in endemic regions. RVF has the capacity to emerge in new locations and also presents a potential bioterrorism threat. In the current study, the in vivo efficacy of T-705 was evaluated in Wistar-Furth rats infected with the virulent ZH501 strain of RVFV by the aerosol route. Methodology/Principal Findings Wistar-Furth rats are highly susceptible to a rapidly lethal disease after parenteral or inhalational exposure to the pathogenic ZH501 strain of RVFV. In the current study, two experiments were performed: a dose-determination study and a delayed-treatment study. In both experiments, all untreated control rats succumbed to disease. Out of 72 total rats infected with RVFV and treated with T-705, only 6 succumbed to disease. The remaining 66 rats (92%) survived lethal infection with no significant weight loss or fever. The 6 treated rats that succumbed survived significantly longer before succumbing to encephalitic disease. Conclusions/Significance Currently, there are no licensed antiviral drugs for treating RVF. Here, T-705 showed remarkable efficacy in a highly lethal rat model of Rift Valley Fever, even when given up to 48 hours post-infection. This is the first study to show protection of rats infected with the pathogenic ZH501 strain of RVFV. Our data suggest that T-705 has potential to be a broad-spectrum antiviral drug. PMID:24722586
... by four families of viruses. These include the Ebola and Marburg, Lassa fever, and yellow fever viruses. ... Some VHFs cause mild disease, but some, like Ebola or Marburg, cause severe disease and death. VHFs ...
Mendenhall, Michelle; Russell, Andrew; Juelich, Terry; Messina, Emily L; Smee, Donald F; Freiberg, Alexander N; Holbrook, Michael R; Furuta, Yousuke; de la Torre, Juan-Carlos; Nunberg, Jack H; Gowen, Brian B
A number of New World arenaviruses (Junín [JUNV], Machupo [MACV], and Guanarito [GTOV] viruses) can cause human disease ranging from mild febrile illness to a severe and often fatal hemorrhagic fever syndrome. These highly pathogenic viruses and the Old World Lassa fever virus pose a significant threat to public health and national security. The only licensed antiviral agent with activity against these viruses, ribavirin, has had mixed success in treating severe arenaviral disease and is associated with significant toxicities. A novel pyrazine derivative currently in clinical trials for the treatment of influenza virus infections, T-705 (favipiravir), has demonstrated broad-spectrum activity against a number of RNA viruses, including arenaviruses. T-705 has also been shown to be effective against Pichinde arenavirus infection in a hamster model. Here, we demonstrate the robust antiviral activity of T-705 against authentic highly pathogenic arenaviruses in cell culture. We show that T-705 disrupts an early or intermediate stage in viral replication, distinct from absorption or release, and that its antiviral activity in cell culture is reversed by the addition of purine bases and nucleosides, but not with pyrimidines. Specific inhibition of viral replication/transcription by T-705 was demonstrated using a lymphocytic choriomeningitis arenavirus replicon system. Our findings indicate that T-705 acts to inhibit arenavirus replication/transcription and may directly target the viral RNA-dependent RNA polymerase.
Oestereich, Lisa; Lüdtke, Anja; Wurr, Stephanie; Rieger, Toni; Muñoz-Fontela, César; Günther, Stephan
Outbreaks of Ebola hemorrhagic fever in sub-Saharan Africa are associated with case fatality rates of up to 90%. Currently, neither a vaccine nor an effective antiviral treatment is available for use in humans. Here, we evaluated the efficacy of the pyrazinecarboxamide derivative T-705 (favipiravir) against Zaire Ebola virus (EBOV) in vitro and in vivo. T-705 suppressed replication of Zaire EBOV in cell culture by 4log units with an IC90 of 110μM. Mice lacking the type I interferon receptor (IFNAR(-)(/)(-)) were used as in vivo model for Zaire EBOV-induced disease. Initiation of T-705 administration at day 6 post infection induced rapid virus clearance, reduced biochemical parameters of disease severity, and prevented a lethal outcome in 100% of the animals. The findings suggest that T-705 is a candidate for treatment of Ebola hemorrhagic fever. Copyright © 2014 The Authors. Published by Elsevier B.V. All rights reserved.
Pigott, David C
This article reviews the epidemiology, pathophysiology, and clinical management of patients with suspected or confirmed viral hemorrhagic fever infection. The focus is on clinical management based on case series from naturally occuring outbreaks of viral hemorrhagic fever infection as well as imported cases of viral hemorrhagic fever encountered in industrialized nations. The potential risk of bioterrorism involving these agents is discussed as well as emergency department and critical care management of isolated cases or larger outbreaks. Important aspects of management, including recognition of infected patients, isolation and decontamination procedures, as well as available vaccines and therapies are emphasized.
This book chapter describes the taxonomic classification of Simian hemorrhagic fever virus (SHFV). Included are: host, genome, classification, morphology, physicochemical and physical properties, nucleic acid, proteins, lipids, carbohydrates, geographic range, phylogenetic properties, biological pro...
Burnett, Mark W
Ebola hemorrhagic fever is an often-fatal disease caused by a virus of the Filoviridae family, genus Ebolavirus. Initial signs and symptoms of the disease are nonspecific, often progressing on to a severe hemorrhagic illness. Special Operations Forces Medical Providers should be aware of this disease, which occurs in sporadic outbreaks throughout Africa. Treatment at the present time is mainly supportive. Special care should be taken to prevent contact with bodily fluids of those infected, which can transmit the virus to caregivers.
AD-A<m 761 KOREA UNIV SEOUL COLL OF MEDICINE KOREAN HEM0RRHA6IC FEVER.(U) MAR 80 H W LEE UNCLASSIFIED ICFI F/6 6/5 DAM017-79-6-9<*55 NL...I» > I,,iu. •Uli ••-. SUMMARY There were 364 hospitalized cases of Korean hemorrhagic fever (KHF) in 1979 in Korea . Lee et al...STANDARDS-1963-A ?H "LEVEtf® AD <o KOREAN HEMORRHAGIC F EVER A D A 09 47 Final Report HO WANG LEE, M. D. March 1980 i MIL. IIB«I . Mm k iw
RD-RI55 255 KOREAN HEMORRHAGIC FEVER (HEMORRHAGIC FEVER WITH RENAL 11 SYNDROME (HFRS))(U) KOREA UNIV SEOUL DEPT OF MICROBIOLOGY H U LEE RUG 83 DRMDi...the first time in Korea (4,13). WHO has recently adapted to call Korean hemorrhagic fever and clinically similar diseases with a different name, HFRS...AD_______ I •. KOREAN HEMORRHAGIC FEVER • (HEMORRHAGIC FEVER WITH RENAL SYNDROME (HFRS)) I Final Report 0 In HO WANG LEE, M.D. August 1983 Supported by U.S
Korean hemorrhagic fever (KHF) occurred for the first time in Korea , 1951, although it had previously been known to both the Japanese and Russians...After Korean war, the disease has been fixed in the areas of DMZ as an endemic one, and from 100 to 400 cases have been being reportee every year
Medicine Seoul, Korea * S 0 0 0 0 0 0 0 0 0 0 0 0 0 0 SUM ARY Urban rats captured in Seoul and four nearby Korean cities were found to have...rattus, urban Korean cities, 1980. . . . 15 Table 2. Isolation of Hantaan virus from antigen-positive wild house rats, Korea , 1980 .... ........... .. 16...Figures Figure 1. Map of Seoul City, South Korea and metropolitan area showing locations of urban Korean hemorrhagic fever cases, andRattu s positive
53 INTRODUCTION During the Korean War more than 3,200 United Nations troops in Korea devel6ped a rare hemorrhagic fever which attracted...patients in the Republic of Korea . Year Korean Korean US Total civilian soldiers soldiers 1951 ...... 627 827 1952 .... 833 833 1953 ... ... 455 455...0 RI m HEMORRHAGIC FEVER WITH RENAL SYNDROME ( KOREAN HEMORRHAGIC FEVER) ANNUAL SUMMARY REPORT HO WANG LEE, M.D. June 30, 1988 Door., Supported by U.S
Scharton, Dionna; Bailey, Kevin W; Vest, Zachary; Westover, Jonna B; Kumaki, Yohichi; Van Wettere, Arnaud; Furuta, Yousuke; Gowen, Brian B
Rift Valley fever is a zoonotic, arthropod-borne disease that affects livestock and humans. The etiologic agent, Rift Valley fever virus (RVFV; Bunyaviridae, Phlebovirus) is primarily transmitted through mosquito bites, but can also be transmitted by exposure to infectious aerosols. There are presently no licensed vaccines or therapeutics to prevent or treat severe RVFV infection in humans. We have previously reported on the activity of favipiravir (T-705) against the MP-12 vaccine strain of RVFV and other bunyaviruses in cell culture. In addition, efficacy has also been documented in mouse and hamster models of infection with the related Punta Toro virus. Here, hamsters challenged with the highly pathogenic ZH501 strain of RVFV were used to evaluate the activity of favipiravir against lethal infection. Subcutaneous RVFV challenge resulted in substantial serum and tissue viral loads and caused severe disease and mortality within 2-3 days of infection. Oral favipiravir (200 mg/kg/day) prevented mortality in 60% or greater of hamsters challenged with RVFV when administered within 1 or 6h post-exposure and reduced RVFV titers in serum and tissues relative to the time of treatment initiation. In contrast, although ribavirin (75 mg/kg/day) was effective at protecting animals from the peracute RVFV disease, most ultimately succumbed from a delayed-onset neurologic disease associated with high RVFV burden observed in the brain in moribund animals. When combined, T-705 and ribavirin treatment started 24 h post-infection significantly improved survival outcome and reduced serum and tissue virus titers compared to monotherapy. Our findings demonstrate significant post-RVFV exposure efficacy with favipiravir against both peracute disease and delayed-onset neuroinvasion, and suggest added benefit when combined with ribavirin.
Scharton, Dionna; Bailey, Kevin W.; Vest, Zachary; Westover, Jonna B.; Kumaki, Yohichi; Van Wettere, Arnaud; Furuta, Yousuke; Gowen, Brian B.
Rift Valley Fever is a zoonotic, arthropod-borne disease that affects livestock and humans. The etiologic agent, Rift Valley fever virus (RVFV; Bunyaviridae, Phlebovirus) is primarily transmitted through mosquito bites, but can also be transmitted by exposure to infectious aerosols. There are presently no licensed vaccines or therapeutics to prevent or treat severe RVFV infection in humans. We have previously reported on the activity of favipiravir (T-705) against the MP-12 vaccine strain of RVFV and other bunyaviruses in cell culture. In addition, efficacy has also been documented in mouse and hamster models of infection with the related Punta Toro virus. Here, we challenged hamsters with the highly pathogenic ZH501 strain of RVFV to evaluate the activity of favipiravir against lethal infection. Subcutaneous RVFV challenge resulted in substantial serum and tissue viral loads and caused severe disease and mortality within 2–3 days after infection. Oral favipiravir (200 mg/kg/day) prevented mortality in 60% or greater in hamsters challenged with RVFV when administered within 1 or 6 h post-exposure and reduced RVFV titers in serum and tissues relative to the time of treatment initiation. In contrast, although ribavirin (75 mg/kg/day) was effective at protecting animals from the peracute RVFV disease, most ultimately succumbed from a delayed-onset neurologic disease associated with high RVFV burden in the brain observed in moribund animals. When combined, T-705 and ribavirin treatment started 24 h post-infection significantly improved survival outcome and reduced serum and tissue virus titers compared to monotherapy. Our findings demonstrate significant post-RVFV exposure efficacy with favipiravir against both peracute disease and delayed-onset neuroinvasion, and suggest added benefit when combined with ribavirin. PMID:24486952
Korean hemorrhagic fever (KHF) occurred for the first time in Korea , 1951, although it had previously been known to both the Japanese and Russians...After Korean war, the disease has been fixed in the areas of DMZ as an endemic one, and from 100 to 300 cases have been reported every year. The aims...but in 1971 affected the middle districts and in 1972 invaded the southern parts of South Korea . The number of patients and the areas of KHF in 1972
Ambrosio, Ana; Saavedra, Maria; Mariani, Mauricio; Gamboa, Graciela; Maiza, Andrea
Argentine hemorrhagic fever (AHF), an acute disease caused by Junin virus (JUNV, Arenaviridae), has been an important issue to public health in Argentina since the early 1950s. The field rodent Calomys musculinus is JUNV natural reservoir and human disease is a consequence of contact with infected rodents. A steady extention of AHF endemic area is being observed since the first reports of the disease. Important achievements have been made in: (a) improvement of methods for the etiological diagnosis; (b) implementation and validation of therapeutical measures; (c) development of vaccines to protect against AHF. Reference is made to different research strategies used to obtain anti-AHF vaccines in the past and anti-arenaviral diseases in the present. Information is updated on features and field performance of Candid #1 vaccine, a live attenuted vaccine currently used to prevent AHF. This vaccine was developed through a joint international effort that envisioned it as an orphan drug. With transferred technology, Argentine government was committed to be Candid #1 manufacturer and to register this vaccine as a novel medical product under the Argentine regulatory authority. Candid #1 vaccine is the first one used to control an arenaviral hemorrhagic fever, the first live viral vaccine to be manufactured and registered in Argentina, reaching its target population through governmental effort.
Gubler, Duane J.
Dengue fever, a very old disease, has reemerged in the past 20 years with an expanded geographic distribution of both the viruses and the mosquito vectors, increased epidemic activity, the development of hyperendemicity (the cocirculation of multiple serotypes), and the emergence of dengue hemorrhagic fever in new geographic regions. In 1998 this mosquito-borne disease is the most important tropical infectious disease after malaria, with an estimated 100 million cases of dengue fever, 500,000 cases of dengue hemorrhagic fever, and 25,000 deaths annually. The reasons for this resurgence and emergence of dengue hemorrhagic fever in the waning years of the 20th century are complex and not fully understood, but demographic, societal, and public health infrastructure changes in the past 30 years have contributed greatly. This paper reviews the changing epidemiology of dengue and dengue hemorrhagic fever by geographic region, the natural history and transmission cycles, clinical diagnosis of both dengue fever and dengue hemorrhagic fever, serologic and virologic laboratory diagnoses, pathogenesis, surveillance, prevention, and control. A major challenge for public health officials in all tropical areas of the world is to devleop and implement sustainable prevention and control programs that will reverse the trend of emergent dengue hemorrhagic fever. PMID:9665979
AD-Ai55 228 KOREAN HEMORRHAGIC FEVER (HEMORRHAGIC FEVER WITH RENAL in. SYNDROME (HFRS))(U) KOREA UNIV SEOUL DEPT OF MICROBIOLOGY H W LEE JUL 84...INTRODUCTION During the Korean War, more than 2,400 United Nations troops stationed in the 38th Parallel in Korea developed a rare disease which had not... Korean hemorrhagic fever patients in urban areas of Seoul. Korean J. Virol. 10: 1-6, 1980. 8. Lee, H. W. New epidemiological findings of HFRS in Korea . J
Racsa, Lori D.; Kraft, Colleen S.; Olinger, Gene G.; Hensley, Lisa E.
There are 4 families of viruses that cause viral hemorrhagic fever (VHF), including Filoviridae. Ebola virus is one virus within the family Filoviridae and the cause of the current outbreak of VHF in West Africa. VHF-endemic areas are found throughout the world, yet traditional diagnosis of VHF has been performed in large reference laboratories centered in Europe and the United States. The large amount of capital needed, as well as highly trained and skilled personnel, has limited the availability of diagnostics in endemic areas except in conjunction with governmental and nongovernmental entities. However, rapid diagnosis of VHF is essential to efforts that will limit outbreaks. In addition, increased global travel suggests VHF diagnoses may be made outside of the endemic areas. Thus, understanding how to diagnose VHF is imperative for laboratories worldwide. This article reviews traditional and current diagnostic modalities for VHF. PMID:26354968
36 DISTRIBUTION LIST. .................... 40 INTRODUCTION During the Korean War more than 3,200 United Nations troops in Korea developed a rare...hemorrhagic fever, a situa- tion that attracted worldwide attention (1). Since then it has been known as Korean hemorrhagic fever (KHF) in Korea . This...Kyunggido and Kangwondo, northern parts of South Korea . All of the 97 HFRS patients among Korean soldiers occurred in Kyunggido, Kangwondo and Seoul
Kager, P A
Viral haemorrhagic fevers, such as Lassa fever and yellow fever, cause tens of thousands of deaths annually outside the Netherlands. The viruses are mostly transmitted by mosquitoes, ticks or via excreta of rodents. Important to travellers are yellow fever, dengue and Lassa and Ebola fever. For yellow fever there is an efficacious vaccine. Dengue is frequently observed in travellers; prevention consists in avoiding mosquito bites, the treatment is symptomatic. Lassa and Ebola fever are extremely rare among travellers; a management protocol can be obtained from the Netherlands Ministry of Health, Welfare and Sports. Diagnostics of a patient from the tropics with fever and haemorrhagic diathesis should be aimed at treatable disorders such as malaria, typhoid fever, rickettsiosis or bacterial sepsis, because the probability of such a disease is much higher than that of Lassa or Ebola fever.
... dialect) (简体中文) Expand Section Vaccine Information Statement (VIS) -- Yellow Fever Vaccine: What You Need to Know - English Vaccine Information Statement (VIS) -- Yellow Fever Vaccine: What You Need to Know - 简体中文 (Chinese, ...
13 Table 5. Monthly incidence of HFRS among Korean in the Republic of Korea , 1966-1985 . . . . . . . 14 A Table 6. Incidence of HFRS by...GRANT SUPPORT .. ........ 57.... 5 INTRODUCTION During the Korean War more than 3,000 United Nations .00 troops in Korea developed a rare hemorrhagic...8217;.-.* * S.’ . " 10 ... Table 1. Hospitalized cases of Hemorrhagic fever with renal syndrome patients in the Republic of Korea Year US Korean Korean
Moraz, Marie-Laurence; Kunz, Stefan
Viral hemorrhagic fevers (VHFs) caused by arenaviruses belong to the most devastating emerging human diseases and represent serious public health problems. Arenavirus VHFs in humans are acute diseases characterized by fever and, in severe cases, different degrees of hemorrhages associated with a shock syndrome in the terminal stage. Over the past years, much has been learned about the pathogenesis of arenaviruses at the cellular level, in particular their ability to subvert the host cell's innate antiviral defenses. Clinical studies and novel animal models have provided important new information about the interaction of hemorrhagic arenaviruses with the host's adaptive immune system, in particular virus-induced immunosuppression, and have provided the first hints towards an understanding of the terminal hemorrhagic shock syndrome. The scope of this article is to review our current knowledge on arenavirus VHF pathogenesis with an emphasis on recent developments.
... Congo Hemorrhagic Fever (CCHF) [PDF – 2 pages] Virus Ecology Viral Hemorrhagic Fever (VHF) Information for Specific Groups ... Diagnosis Treatment Prevention Outbreak Distribution Map Resources Virus Ecology File Formats Help: How do I view different ...
Hartman, Amy L; Towner, Jonathan S; Nichol, Stuart T
Ebola and Marburg viruses cause a severe viral hemorrhagic fever disease mainly in Sub-Saharan Africa. Although outbreaks are sporadic, there is the potential for filoviruses to spread to other continents unintentionally because of air travel or intentionally because of bioterrorism. This article discusses the natural history, epidemiology, and clinical presentation of patients infected with Ebola and Marburg viruses. Clinicians in the United States should be aware of the symptoms of these viral infections in humans and know the appropriate procedures for contacting local, state, and national reference laboratories in the event of a suspected case of filoviral hemorrhagic fever.
Viral hemorrhagic fever (VHF) is defined as virus infections that usually cause pyrexia and hemorrhagic symptoms with multiple organ failure. VHF includes following viral infections: Ebola hemorrhagic fever (EHF), Marburg hemorrhagic fever (MHF), Crimean-Congo hemorrhagic fever (CCHF) and Lassa fever. In particular, the causative agents of EHF, MHF, CCHF, and Lassa fever are Ebola, Marburg, CCHF, Lassa viruses, respectively, and regarded as biosafety level-4 pathogens because of their high virulence to humans. Recently, relatively large outbreaks of EHF and MHF have occurred in Africa, and areas of EHF- and MHF-outbreaks seem to be expanding. Although outbreaks of VHF have not been reported in Japan, there is a possibility that the deadly hemorrhagic fever viruses would be introduced to Japan in future. Therefore, preparedness for possible future outbreaks of VHF is necessary in areas without VHF outbreaks.
Shayan, Sara; Bokaean, Mohammad; Shahrivar, Mona Ranjvar; Chinikar, Sadegh
Crimean-Congo hemorrhagic fever virus (CCHFV) is a member of the Bunyaviridae family and Nairovirus genus. The viral genome consists of 3 RNA segments of 12 kb (L), 6.8 kb (M), and 3 kb (S). Crimean-Congo hemorrhagic fever (CCHF) is the most widespread tickborne viral infection worldwide: it has been reported in many regions of Africa, the Middle East, and Asia. The geographical distribution of CCHFV corresponds most closely with the distribution of members of the tick genera, and Hyalomma ticks are the principal source of human infection. In contrast to human infection, CCHFV infection is asymptomatic in all species. Treatment options for CCHF are limited; immunotherapy and ribavirin are effective in the treatment of CCHF; the efficacy of ribavirin in the treatment of CCHF has not yet been proven. This article reviews the history, epidemiology, clinical symptoms, pathogenesis, diagnosis, and treatment of CCHFV, as well as the development of a vaccine against it.
Burnett, Mark W
In mid-September 2009, a 22-year-old critically ill Soldier was medically evacuated from a treatment facility in southern Afghanistan to Landstuhl Regional Medical Center in Germany. Despite the efforts of the team at Landstuhl, this patient died and became the US military's first known victim of Crimean-Congo hemorrhagic fever (CCHF). CCHF is caused by a virus, which bears the same name. Because a vaccine is lacking, as well as an effective antiviral treatment, prevention is key.
tlll AD111 CONTRACT NO: DAMDI7-91-C-1006 TITLE: SIMIAN HEMORRHAGIC FEVER (SHF) VIRUS PRINCIPAL INVESTIGATOR: Margo A. Brinton, Ph.D. CONTRACTING...SUBTITLE S. FUNDING NUMBERS Simian Hemorrhagic Fever (SHF) Virus DAMD17-91-C-1006 6. AUTHOR(S) Margo A. Brinton, Ph.D. 7. PERFORMING ORGANIZATION...simian hemorrhagic fever (SHF) virus -specific hybridoma cultures, expand two clones from each clone as well as 50 ml of supernatant fluid from
Enria, Delia A; Briggiler, Ana M; Sánchez, Zaida
Argentine hemorrhagic fever (AHF) is a rodent-borne illness caused by the arenavirus Junin that is endemic to the humid pampas of Argentina. AHF has had significant morbidity since its emergence in the 1950s, with a case-fatality rate of the illness without treatment between 15% and 30%. The use of a live attenuated vaccine has markedly reduced the incidence of AHF. Present specific therapy involves the transfusion of immune plasma in defined doses of neutralizing antibodies during the prodromal phase of illness. However, alternative forms of treatment are called for due to current difficulties in early detection of AHF, related to its decrease in incidence, troubles in maintaining adequate stocks of immune plasma, and the absence of effective therapies for severely ill patients that progress to a neurologic-hemorrhagic phase. Ribavirin might be a substitute for immune plasma, provided that the supply is guaranteed. Immune immunoglobulin or monoclonal antibodies should also be considered. New therapeutic options such as those being developed for systemic inflammatory syndromes should also be valuated in severe forms of AHF.
Enria, D A; Maiztegui, J I
Argentine hemorrhagic fever is a systemic viral disease caused by Junin virus, with a mortality of 15-30% in untreated individuals. Current specific therapy is highly effective in reducing mortality, and consists of the early administration of immune plasma in defined doses of specific neutralizing antibodies per kg of body weight. However, several reasons suggest the need to investigate alternative therapies. Ribavirin, a broad spectrum antiviral agent, is effective in the treatment of other viral hemorrhagic fevers, and the studies done with Junin virus infections to date indicate that this drug may also have a beneficial effect in Argentine hemorrhagic fever.
Hafner, C; Koellner, K; Vogt, T; Landthaler, M; Szeimies, R-M
A 39-year-old patient developed a disseminated rash with scattered petechiae, fever, malaise and arthralgia after a trip to Malaysia. The patient displayed increasing dengue IgG titers and borderline dengue IgM titers. Dengue fever with a hemorrhagic course is a rare condition in adult patients. Patients who have previously had dengue fever and retained non-neutralizing heterotypic antibodies are more likely to develop this complication via the phenomenon of antibody-dependent enhancement.
Mehedi, Masfique; Groseth, Allison; Feldmann, Heinz; Ebihara, Hideki
Marburg virus belongs to the genus Marburgvirus in the family Filoviridae and causes a severe hemorrhagic fever, known as Marburg hemorrhagic fever (MHF), in both humans and nonhuman primates. Similar to the more widely known Ebola hemorrhagic fever, MHF is characterized by systemic viral replication, immunosuppression and abnormal inflammatory responses. These pathological features of the disease contribute to a number of systemic dysfunctions including hemorrhages, edema, coagulation abnormalities and, ultimately, multiorgan failure and shock, often resulting in death. A detailed understanding of the pathological processes that lead to this devastating disease remains elusive, a fact that contributes to the lack of licensed vaccines or effective therapeutics. This article will review the clinical aspects of MHF and discuss the pathogenesis and possible options for diagnosis, treatment and prevention. PMID:22046196
Papa, Anna; Sidira, Persefoni; Larichev, Victor; Gavrilova, Ludmila; Kuzmina, Ksenia; Mousavi-Jazi, Mehrdad; Mirazimi, Ali; Ströher, Ute; Nichol, Stuart
Seroprevalence of Crimean-Congo hemorrhagic fever virus (CCHFV) is high in some regions of Greece, but only 1 case of disease has been reported. We used 4 methods to test 118 serum samples that were positive for CCHFV IgG by commercial ELISA and confirmed the positive results. A nonpathogenic or low-pathogenicity strain may be circulating.
Sidira, Persefoni; Larichev, Victor; Gavrilova, Ludmila; Kuzmina, Ksenia; Mousavi-Jazi, Mehrdad; Mirazimi, Ali; Ströher, Ute; Nichol, Stuart
Seroprevalence of Crimean-Congo hemorrhagic fever virus (CCHFV) is high in some regions of Greece, but only 1 case of disease has been reported. We used 4 methods to test 118 serum samples that were positive for CCHFV IgG by commercial ELISA and confirmed the positive results. A nonpathogenic or low-pathogenicity strain may be circulating. PMID:24447877
Navarrete-Espinosa, Joel; Gómez-Dantés, Héctor
To know the arbovirus causing hemorrhagic fever in patients at the Mexican Institute of Social Security. A follow-up study was made in patients with probable diagnosis of hemorrhagic dengue. Blood samples were taken to look for dengue fever, yellow fever and San Luis, Tonate and Mayaro encephalitis viruses. Frequencies and proportions of the interest variables were analyzed. 35 patients were studied. Isolation and PCR results of the 13 samples were negative in 12 of them and positive to denguevirus-3 in one of them. The determination of IgM was positive for dengue fever in 25 cases; 2 were positive to Mayaro virus and 8 were negative to what was looked for. Hemorrhages and thrombocytopenia were more frequent in patients infected with dengue and Mayaro viruses; jaundice and encephalopathy were more frequent in the latter, and renal dysfunction, in patients with a negative result. Evolution was satisfactory in all cases, except for one (Mayaro), which presented hemorrhages, thrombocytopenia, jaundice and encephalopathy that lead to death. The results show the risk of appearance and dissemination of several vector-born diseases in Mexico. Thus, they require intensive epidemiological surveillance to identify them and to know their real occurrence and specific clinical profile.
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
patients in districts of Seoul city in 1989 ...... ............ .. 15 Table 6. Age and sex distribution of HFRS, murine typhus, scrub typhus, spotted...patients by sex in Korea, 1989 .... .................... 21 Table 11. Number of HFRS, scrub typhus, murine typhus and spotted fever diagnosed...C.H. Calisher, porn . comm., 1990) but it is too preliminary to determine the status of this virus. The monoclonal intibodies produced with Hantaen
Durrani, Abdul Baqi; Shaikh, Muzaffar; Khan, Zahir
To observe the pattern and mortality of Congo-Crimean Hemorrhagic Fever (CCHF) in Balochistan. Case series. Department of Medicine, Sandeman Provincial Hospital and Bolan Medical Complex Hospital, Quetta, from September, 1995 to August, 2005. Two hundred and twenty-six febrile patients with bleeding of sudden onset, with initial signs and symptoms including headache, high fever, back pain, joint pain, stomach pain, vomiting, red eyes, flushed face, red throat and petechiae on the palate of both sexes were screened for CCHF over a period of 10 years. Clinical criteria for initial diagnosis directed the subsequent diagnostic work-up. The ages of these patients ranged from 7 years to 74 years. Sixty-three percent of these patients were positive for CCHF. Males were 68% of the total patients. Over the years, CCHF showed a gradual increase ranging from 43% to 80%. Total mortality was 15%, all being secondary cases. Death was not observed in primary CCHF cases. In this study, suspicion of viral hemorrhagic fever was raised in 62% cases at the time of admission and the patients were immediately isolated, noninvasive procedures were instigated and barrier nursing was implemented. None of the family and hospital staff members who had close contact with the patient became ill, while those who were not suspected initially (38%) infected the health care workers and the family members. Although CCHF is rare, this study stresses the need for proper health facilities in Pakistan and to include VHF (viral hemorrhagic fevers) in the differential diagnosis of unexplained fever with hemorrhagic tendencies of sudden onset.
Raabea, Vanessa N; Borcherta, Matthias
Breaking the human-to-human transmission cycle remains the cornerstone of infection control during filoviral (Ebola and Marburg) hemorrhagic fever outbreaks. This requires effective identification and isolation of cases, timely contact tracing and monitoring, proper usage of barrier personal protection gear by health workers, and safely conducted burials. Solely implementing these measures is insufficient for infection control; control efforts must be culturally sensitive and conducted in a transparent manner to promote the necessary trust between the community and infection control team in order to succeed. This article provides a review of the literature on infection control during filoviral hemorrhagic fever outbreaks focusing on outbreaks in a developing setting and lessons learned from previous outbreaks. The primary search database used to review the literature was PUBMED, the National Library of Medicine website.
Vanessa, N Raabe; Matthias, Borchert
Breaking the human-to-human transmission cycle remains the cornerstone of infection control during filoviral (Ebola and Marburg) hemorrhagic fever outbreaks. This requires effective identification and isolation of cases, timely contact tracing and monitoring, proper usage of barrier personal protection gear by health workers, and safely conducted burials. Solely implementing these measures is insufficient for infection control; control efforts must be culturally sensitive and conducted in a transparent manner to promote the necessary trust between the community and infection control team in order to succeed. This article provides a review of the literature on infection control during filoviral hemorrhagic fever outbreaks focusing on outbreaks in a developing setting and lessons learned from previous outbreaks. The primary search database used to review the literature was PUBMED, the National Library of Medicine website. PMID:22529631
Messaoudi, Ilhem; Basler, Christopher F.
Several enveloped RNA viruses of the arenavirus, bunyavirus, filovirus and flavivirus families are associated with a syndrome known as viral hemorrhagic fever (VHF). VHF is characterized by fever, vascular leakage, coagulation defects and multi organ system failure. VHF is currently viewed as a disease precipitated by viral suppression of innate immunity, which promotes systemic virus replication and excessive proinflammatory cytokine responses that trigger the manifestations of severe disease. However, the mechanisms by which immune dysregulation contributes to disease remain poorly understood. Infection of nonhuman primates closely recapitulates human VHF, notably Ebola and yellow fever, thereby providing excellent models to better define the immunological basis for this syndrome. Here we review the current state of our knowledge and suggest future directions that will better define the immunological mechanisms underlying VHF. PMID:26163194
Viral hemorrhagic fevers are diseases caused by viruses which belong to different families, many of them causing severe diseases. These viruses may produce different symptomatology together with a severe multisystem syndrome, and the final result might be the production of hemorrhages in several sites of the body. The majority of them have no other treatment than supportive therapy, although some antiviral drugs can be used in some circumstances. Transmission of VHF has been demonstrated through contact with animal vectors or person-to-person through the contact with body fluids. No risk of transmission has been found during the incubation period, but when the viral load is high the risk of transmission is greatest. Both health care and clinical laboratory workers must safely handle patients and specimens by taking all required precautions during their management. PMID:27014378
Leblebicioglu, Hakan; Ozaras, Resat; Erciyas-Yavuz, Kiraz
Crimean-Congo hemorrhagic fever (CCHF) is a life-threatening tick-borne infection in Africa and Eurasia. Although knowledge of epidemiology is increasing, the global extent and risk of infection is not well described. A niche-modeling framework has been used to map the global distribution of risk for CCHF based on analysis of human CCHF reports. The new risk maps provide a valuable starting point for understanding the zoonotic niche of CCHF. Migratory birds travelling across continents may also introduce CCHF to new areas through attached ticks. There is an overlap between CCHF endemic areas and breeding and wintering grounds of migratory birds.
Klimentov, Alexander S.; Dzagurova, Tamara K.; Drexler, Jan Felix; Gmyl, Anatoly P.
Crimean Congo hemorrhagic fever virus (CCHFV) is one of the most severe viral zoonozes. It is prevalent throughout Africa, Asia and southern Europe. Limited availability of sequence data has hindered phylogeographic studies. The complete genomic sequence of all three segments of 14 Crimean Congo hemorrhagic fever virus strains isolated from 1958–2000 in Russia, Central Asia and Africa was identified. Each genomic segment was independently subjected to continuous Bayesian phylogeographic analysis. The origin of each genomic segment was traced to Africa about 1,000–5,000 years ago. The virus was first introduced to South and Central Asia in the Middle Ages, and then spread to China, India and Russia. Reverse transfers of genomic segments from Asia to Africa were also observed. The European CCHFV genotype V was introduced to Europe via the Astrakhan region in South Russia 280–400 years ago and subsequently gradually spread westward in Russia, to Turkey and the Balkans less than 150 years ago. Only a few recombination events could be suggested in S and L genomic segments, while segment reassortment was very common. The median height of a non-reassortant phylogenetic tree node was 68–156 years. There were reassortment events within the European CCHFV lineage, but not with viruses from other locations. Therefore, CCHFV in Europe is a recently emerged zoonosis that represents a spillover from the global gene pool. PMID:27880794
Navarrete-Espinosa, Joel; Gómez-Dantés, Héctor; Celis-Quintal, Juan Germán; Vázquez-Martínez, José Luis
Dengue hemorrhagic fever is a public health problem in Mexico since 1994. With four serotypes circulating the risk of epidemic dengue hemorrhagic fever is increasing. We describe the clinical features of confirmed cases in the social security health system (IMSS) from 1995 to 2003. Clinical picture and epidemiological features were compared and a multivariate model was fitted to evaluate associations. Cases were divided into two groups: 438 patients with dengue fever, including 109 cases with hemorrhagic manifestations without thrombocytopenia, and 977 cases with dengue hemorrhagic fever, including 79 deaths. The main risk factors associated with mortality were hematemesis (RR 2.6; CI 95% 1.4-4.6) and melena (RR 2.2; Cl 95% 1.2-3.7). Our results characterize the clinical profile of dengue hemorrhagic fever cases in Mexico and identify prognostic factors to alert clinician for the prevention of a fatal evolution.
Arenavirus Lassa fever virus Lassa fever High Junin virus Argentine hemorrhagic fever High Machupo virus Bolivian hemorrhagic fever High Bunyaviridae...assumes aerosol against respiratory syncytial virus was demon- its greatest importance in the case of Lassa fever (dis- strated in experimentally...hemorrhagic fevers and efficacy of various therapeutic approaches Arenavirus infections Bunyavirus infections Argentine
Identify by block number) Congo Crimean Homorrhagic Fever (CCHF), Hemorrhagic Fever with Renal Syndrom . * -(HFRS), CCHF virus , Hantaan virus , Gre2ce - 20...A.STRACT ("C.une do re, ri It nreuarv md Idewtf by block number) *> CCHF virus or a virus closely related to it exists in clreece, infects humans...Hantaan-li- ke virus occuring in the colntry is orobablv a;tiqenically closer to Hantaan-- J,. DO IN 14n EOiTIONor I NOV 6S IS OBSOLETE,. SECURITY
Tezer, Hasan; Polat, Meltem
Crimean-Congo hemorrhagic fever (CCHF) virus is the most extensive tick-borne virus, it causes a severe infection, which occurs widely in Africa, Eastern Europe and Asia. In recent years, the dramatic increase in the global distribution of CCHF, with the high mortality rates, highlights the importance of improving diagnostic capacity. Clinical and epidemiological data play a crucial role for early recognition of CCHF. However, CCHF is clinically difficult to diagnose and to distinguish, a rapid and reliable laboratory confirmation is necessary. Confirmation of infection in the acute phase of the disease can be made by detection of viral nucleic acid using reverse transcription-PCR, by demonstration of viral antigen or by virus isolation. In the convalescent phase of the disease, the diagnosis is confirmed by demonstration of an antibody response. The consideration of viral replication kinetics and antiviral humoral immune responses facilitates the selection of appropriate laboratory tests and accurate interpretation of laboratory findings.
Patterson, Michael; Grant, Ashley; Paessler, Slobodan
The etiologic agent of Bolivian hemorrhagic fever (BHF), Machupo virus (MACV) is reported to have a mortality rate of 25 to 35%. First identified in 1959, BHF was the cause of a localized outbreak in San Joaquin until rodent population controls were implemented in 1964. The rodent Calomys collosus was identified as the primary vector and reservoir for the virus. Multiple animal models were considered during the 1970’s with the most human-like disease identified in Rhesus macaques but minimal characterization of the pathogenesis has been published since. A reemergence of reported BHF cases has been reported in recent years, which necessitates the further study and development of a vaccine to prevent future outbreaks. PMID:24636947
Smith, Darci R; Holbrook, Michael R; Gowen, Brian B
The term "viral hemorrhagic fever" (VHF) designates a syndrome of acute febrile illness, increased vascular permeability and coagulation defects which often progresses to bleeding and shock and may be fatal in a significant percentage of cases. The causative agents are some 20 different RNA viruses in the families Arenaviridae, Bunyaviridae, Filoviridae and Flaviviridae, which are maintained in a variety of animal species and are transferred to humans through direct or indirect contact or by an arthropod vector. Except for dengue, which is transmitted among humans by mosquitoes, the geographic distribution of each type of VHF is determined by the range of its animal reservoir. Treatments are available for Argentine HF and Lassa fever, but no approved countermeasures have been developed against other types of VHF. The development of effective interventions is hindered by the sporadic nature of most infections and their occurrence in geographic regions with limited medical resources. Laboratory animal models that faithfully reproduce human disease are therefore essential for the evaluation of potential vaccines and therapeutics. The goal of this review is to highlight the current status of animal models that can be used to study the pathogenesis of VHF and test new countermeasures.
Polesky, Andrea; Bhatia, Gulshan
Viral hemorrhagic fevers are among a small group of infectious diseases considered potential candidates for use as agents of bioterrorism. Ebola hemorrhagic fever, the focus of this article, has the highest mortality rate of the viral hemorrhagic fevers and has no effective treatment. It is transmitted easily to family members and health care professionals not following universal precautions. The history of this infection, its clinical presentation, and epidemiology are discussed. Attention is paid to the immunopathogenesis of the disease with a focus on pulmonary involvement. Recommendations for infection control and Ebola virus' potential as a bioterrorism agent are addressed.
Ardalan, Mohammadreza; Chinikar, Sadegh; Mohajel Shoja, Mohammadali
Hemorrhagic fever with renal syndrome (HFRS) is a serious human disease of zoonotic viral origin. A group of different viruses that belong to the family of hemorrhagic fever could represent with HFRS. The basic pathophysiologic feature is virus-induced leaky microcirculation. There is no effective antiviral treatment against them. Because of rapid environmental changes, global warming, and increased global traveling, different hemorrhagic fever syndromes could be found anywhere in the world and beyond their old endemic borders. This review is a brief overview of HFRS in Iran during the early and mid-twentieth century.
cessation, values began to patients with Lassa fever in Sierra Leone. where mortality increase, progressively returning toward the base line. The reductions...similar to Bo- Virus isolation and serology. Virus was recovered from all livian hemorrhagic fever than to Lassa fever in humans (18). placebo-treated...clinical re- pti- d for use in Lassa fever patient%. Trisicol. Appi. Phama- spofl5c. J Infect. Dis. 152:218-221. cl 41519 16. McKee, K. T., Jr., IL. G
Carrion, Ricardo; Bredenbeek, Peter; Jiang, Xiaohong; Tretyakova, Irina; Pushko, Peter; Lukashevich, Igor S.
Arenaviruses are rodent-borne emerging human pathogens. Diseases caused by these viruses, e.g., Lassa fever (LF) in West Africa and South American hemorrhagic fevers (HFs), are serious public health problems in endemic areas. We have employed replication-competent and replication-deficient strategies to design vaccine candidates potentially targeting different groups “at risk”. Our leader LF vaccine candidate, the live reassortant vaccine ML29, is safe and efficacious in all tested animal models including non-human primates. In this study we showed that treatment of fatally infected animals with ML29 two days after Lassa virus (LASV) challenge protected 80% of the treated animals. In endemic areas, where most of the target population is poor and many live far from health care facilities, a single-dose vaccination with ML29 would be ideal solution. Once there is an outbreak, a fast-acting vaccine or post-exposure prophylaxis would be best. The 2nd vaccine technology is based on Yellow Fever (YF) 17D vaccine. We designed YF17D-based recombinant viruses expressing LASV glycoproteins (GP) and showed protective efficacy of these recombinants. In the current study we developed a novel technology to clone LASV nucleocapsid within YF17D C gene. Low immunogenicity and stability of foreign inserts must be addressed to design successful LASV/YFV bivalent vaccines to control LF and YF in overlapping endemic areas of West Africa. The 3rd platform is based on the new generation of alphavirus replicon virus-like-particle vectors (VLPV). Using this technology we designed VLPV expressing LASV GP with enhanced immunogenicity and bivalent VLPV expressing cross-reactive GP of Junin virus (JUNV) and Machupo virus (MACV), causative agents of Argentinian and Bolivian HF, respectively. A prime-boost regimen required for VLPV immunization might be practical for medical providers, military, lab personnel, and visitors in endemic areas. PMID:23420494
Carrion, Ricardo; Bredenbeek, Peter; Jiang, Xiaohong; Tretyakova, Irina; Pushko, Peter; Lukashevich, Igor S
Arenaviruses are rodent-borne emerging human pathogens. Diseases caused by these viruses, e.g., Lassa fever (LF) in West Africa and South American hemorrhagic fevers (HFs), are serious public health problems in endemic areas. We have employed replication-competent and replication-deficient strategies to design vaccine candidates potentially targeting different groups "at risk". Our leader LF vaccine candidate, the live reassortant vaccine ML29, is safe and efficacious in all tested animal models including non-human primates. In this study we showed that treatment of fatally infected animals with ML29 two days after Lassa virus (LASV) challenge protected 80% of the treated animals. In endemic areas, where most of the target population is poor and many live far from health care facilities, a single-dose vaccination with ML29 would be ideal solution. Once there is an outbreak, a fast-acting vaccine or post-exposure prophylaxis would be best. The 2(nd) vaccine technology is based on Yellow Fever (YF) 17D vaccine. We designed YF17D-based recombinant viruses expressing LASV glycoproteins (GP) and showed protective efficacy of these recombinants. In the current study we developed a novel technology to clone LASV nucleocapsid within YF17D C gene. Low immunogenicity and stability of foreign inserts must be addressed to design successful LASV/YFV bivalent vaccines to control LF and YF in overlapping endemic areas of West Africa. The 3(rd) platform is based on the new generation of alphavirus replicon virus-like-particle vectors (VLPV). Using this technology we designed VLPV expressing LASV GP with enhanced immunogenicity and bivalent VLPV expressing cross-reactive GP of Junin virus (JUNV) and Machupo virus (MACV), causative agents of Argentinian and Bolivian HF, respectively. A prime-boost regimen required for VLPV immunization might be practical for medical providers, military, lab personnel, and visitors in endemic areas.
Human have struggled against many infectious diseases such as cholera, plague, dysentery and yellow fever for a long time. And we have spent a lot of energy to control these infectious diseases and developed various tool for them. One of these efforts was Quarantine system that was established in 14th century in Europe. But during recent days, we are suffering from newly emerged diseases. These new infectious diseases are zoonosis and most of them are serious and highly infectious. Viral hemorrhagic fever such as Ebola hemorrhagic fever, Marburg hemorrhagic fever and Lassa fever are typical these emerging serious diseases, and these outbreak always have occurred in Africa and neighboring countries. Fortunately we have never experienced any case, but as these diseases are so serious, we are so nervous diseases entering in Japan. Against these serious diseases, in Japan, Quarantine Station are doing screening examination at airport and port by questionnaire and measuring body temperature, because these viral hemorrhagic fever patients show high fever. If people were suspected viral hemorrhagic fever at Quarantine Station at the border, they will be leaded to hospital for further examination and treatment as soon as possible.
64. SUPPIAMINTA01T1 NOTATION COWA’ COW1 S $IAjCT TERMS XConinWO *A ?*,*fit I nocessary #md Voriti, by biwit flume..,FIELD I GRoi .’f ;Irra:c ee...vomiting, and abdominal pain , while flushing of the face, conjunctival injection, pulmonary edema, shock and hemorrhagic manifestations were only common...signs in 20 HFRS Greek Patients. Symptoms and signs No. of Patients Fever 20 Rigors 20 Headache 20 Abdominal pain 20 Myalgia 18 Arthralgia 18
Gledovic, Z B; Jeknic, A S; Grgurevic, A D; Rakocevic, B B; Bozovic, B R; Mugosa, B V
The objective of the study was to analyze the epidemiological features of hemorrhagic fever with renal syndrome (HFRS) in Montenegro. The study included 169 cases of HFRS diagnosed in the period between 1995 and 2005 according to the clinical symptoms and serological confirmation. For the analysis of the demographic characteristics of the cases, as well as of the chronological and topographical features of the disease, a descriptive epidemiological method was employed. The average incidence rate in the observed period was 2.6 per 100,000. In the observed period, 8 people died; the average case fatality rate was 4.8% (range: 0.1-15%). Among the diseased persons, 116 were males and 53 were females; most of the cases were adults. The greatest number of HFRS cases occurred during the summer months. The highest incidence rates were registered in the northeastern, rural part of the country. The most frequent type of hantaviruses in Montenegro were Dobrava-Belgrade and Hantaan, carried by rodent species, i.e., the yellow-neck mouse and the striped-field mouse. It is likely that HFRS in Montenegro will become more common in the near future, unless public health control measures are taken.
Jae, Lucas T; Brummelkamp, Thijn R
Ebola virus and Lassa virus belong to different virus families that can cause viral hemorrhagic fever, a life-threatening disease in humans with limited treatment options. To infect a target cell, Ebola and Lassa viruses engage receptors at the cell surface and are subsequently shuttled into the endosomal compartment. Upon arrival in late endosomes/lysosomes, the viruses trigger membrane fusion to release their genome into the cytoplasm. Although contact sites at the cell surface were recognized for Ebola virus and Lassa virus, it was postulated that Ebola virus requires a critical receptor inside the cell. Recent screens for host factors identified such internal receptors for both viruses: Niemann-Pick disease type C1 protein (NPC1) for Ebola virus and lysosome-associated membrane protein 1 (LAMP1) for Lassa virus. A cellular trigger is needed to permit binding of the viral envelope protein to these intracellular receptors. This 'receptor switch' represents a previously unnoticed step in virus entry with implications for host-pathogen interactions and viral tropism.
Keshtkar-Jahromi, Maryam; Sajadi, Mohammad M.; Ansari, Hossein; Mardani, Masoud; Naieni, Kourosh Holakouie
The presence of Crimean-Congo hemorrhagic fever virus (CCHFV) in Iran was first identified in studies of livestock sera and ticks in the 1970s, but the first human infection was not diagnosed until 1999. Since that time, the number of cases of CCHF in Iran has markedly increased. Through January 2012, articles in the published literature have reported a total of 870 confirmed cases, with 126 deaths, for a case fatality rate (CFR) of 17.6%. The disease has been seen in 26 of the country’s 31 provinces, with the greatest number of cases in Sistan and Baluchestan, Isfahan, Fars, Tehran, Khorasan, and Khuzestan provinces. The increase in CCHF in Iran has paralleled that in neighboring Turkey, though the number of cases in Turkey has been much larger, with an overall CFR of around 5%. In this article, we review the features of CCHF in Iran, including its history, epidemiology, animal and tick reservoirs, current surveillance and control programs, diagnostic methods, clinical features and experience with ribavirin therapy, and consider possible explanations for the difference in the CFR of CCHF between Iran and Turkey. The emergence of CCHF in Iran calls for countermeasures at many levels to protect the population, but also provides opportunities for studying the epidemiology, diagnosis and management of the disease. PMID:23872313
Keshtkar-Jahromi, Maryam; Sajadi, Mohammad M; Ansari, Hossein; Mardani, Masoud; Holakouie-Naieni, Kourosh
The presence of Crimean-Congo hemorrhagic fever virus (CCHFV) in Iran was first identified in studies of livestock sera and ticks in the 1970s, but the first human infection was not diagnosed until 1999. Since that time, the number of cases of CCHF in Iran has markedly increased. Through January 2012, articles in the published literature have reported a total of 870 confirmed cases, with 126 deaths, for a case fatality rate (CFR) of 17.6%. The disease has been seen in 26 of the country's 31 provinces, with the greatest number of cases in Sistan and Baluchestan, Isfahan, Fars, Tehran, Khorasan, and Khuzestan provinces. The increase in CCHF in Iran has paralleled that in neighboring Turkey, though the number of cases in Turkey has been much larger, with an overall CFR of around 5%. In this article, we review the features of CCHF in Iran, including its history, epidemiology, animal and tick reservoirs, current surveillance and control programs, diagnostic methods, clinical features and experience with ribavirin therapy, and consider possible explanations for the difference in the CFR of CCHF between Iran and Turkey. The emergence of CCHF in Iran calls for countermeasures at many levels to protect the population, but also provides opportunities for studying the epidemiology, diagnosis and management of the disease.
Akıncı, Esragül; Bodur, Hürrem; Leblebicioglu, Hakan
Although Crimean-Congo hemorrhagic fever (CCHF) is a widespread tick-borne disease, little is known about its pathogenesis. The interaction of the virus with host cells is most likely responsible for the pathogenesis of CCHF. The main contributors are endothelial cells (ECs) and immune cells. There are 2 theories underlying the CCHF pathogenesis: One is that the virus interacts with the ECs directly and the other that it interacts indirectly via immune cells with subsequent release of soluble mediators. ECs are activated upon infection by the upregulation of soluble molecules and proinflammatory cytokines. Probably, in severe cases, deregulation and excessive release of the cytokines accompanied by endothelial activation have toxic effects, leading to increased vascular permeability, vasodilatation, and subsequently hypotension, multiple organ failure, shock, and death. Studies indicate that CCHF virus (CCHFV) also can impair the innate immune system and cause a delay in adaptive immune response, which is critical for the clearance of CCHFV. The virus has many different ways to block the immune response, leading to uncontrolled viral replication followed by systemic spread of the virus throughout the body. Partial activation of dendritic cells and macrophages, delayed induction of interferons, weak antibody response, apoptosis of lymphocytes, and hemophagocytosis are some of these tactics. However, there are many points waiting for clarification about the pathogenesis of CCHF. Although the high risk of contagiousness limits research, we need more studies to understand the CCHF pathogenesis better. Here we review the main characteristics of the pathogenesis of CCHF.
Karanth, Suman S; Gupta, Anurag; Prabhu, Mukhyaprana
Dengue hemorrhagic fever is a more serious form of disease characterised by plasma leakage syndrome, thrombocytopenia and disseminated intravascular coagulation. We present a 51 year old male who presented with fever, petechiae and acute onset of breathlessness. Emergency chest rhoentogram showed a massive right sided pleural effusion. On insertion of intercostal drain, there was a sudden gush of blood tinged fluid suggestive of hemothorax. There was no history of trauma or bleeding tendencies. Laboratory investigations revealed a raised hematocrit and severe thrombocytopenia. Dengue IgM was surprisingly positive. After aggressive supportive management the patient gradually improved and was discharged. While bilateral pleural effusion is a known occurrence in dengue hemorrhagic fever, massive hemothorax is unheard of. We report the first case in literature of dengue hemorrhagic fever presenting as unilateral massive hemothorax. A suspicion of dengue must also be borne in mind in cases of non-traumatic hemothorax especially in endemic areas.
Alvarez, F A; Biquard, C; Figini, H A; Gutiérrez Márquez, J M; Melcon, M O; Monteverde, D A; Somoza, M J
The Argentine hemorrhagic fever (AHF) is an infectious disease, endemo-epidemical, of viral etiology, produced by the Junin virus and limited to the Buenos Aires Province, South of Córdoba, East of La Pampa, and South of Santa Fe. It generally assails rural workers at harvest-time, especially during corn-harvest. The incubation period of the disease does not exceed 12 days. A feverish syndrome with asthenia, adynamia, myalgias, migraine, photophobia, epigastralgia etc., appear. The patient has a facial erythema, petechias on the skin, enantema on the palate, conjunctive micropolyadenopaty injection. The laboratory shows a low erytro, leukopenia with aneosinophilia, thrombopenia and a urine with albuminuria and virous cells. After the fourth day, hemorrhage and a neurological case appears. The laboratory tends to normalize and cast appears in the urine. The most striking neurological signs are the following: muscular hypotonia, proprioceptive hyporreflexia or arreflexia, marinesco reflex, shakings, difficulty to stand and walk, oscillations in consciousness level, and ocular disturbances. The cytochemical test of the C.L. Rachis in the usual ways of the AHF is within its normal characteristics; on the other hand there are modifications in the nervous cases: the total proteins are nearly always increased and the cells augmented with a great predominance of mononuclear cells. The electroencephalogrammes were always abnormal, varying from a brief disorganization up to a diffusive and permanent slowness. The half of which additionally presented paroxisms generalized by slow waves. The pathological anatomy over the central nervous system makes us think that the lesion would not primitively neuronal but that the action of the virus would be indirectly done through the capillar wall. This capillar lesion is produced by multiple focuses. The neuronal destruction with necrosis by microinfarcts is minimum. The symptoms and neurological signs are present in 10% of the
Marburg and Ebola hemorrhagic fevers are severe, systemic viral diseases affecting humans and non-human primates. They are characterized by multiple symptoms such as hemorrhages, fever, headache, muscle and abdominal pain, chills, sore throat, nausea, vomiting and diarrhea. Elevated liver-associated enzyme levels and coagulopathy are also associated with these diseases. Marburg and Ebola hemorrhagic fevers are caused by (Lake victoria) Marburg virus and different species of Ebola viruses, respectively. They are enveloped, single-stranded RNA viruses and belong to the family of filoviridae. Case fatality rates of filovirus disease outbreaks are among the highest reported for any human pathogen, ranging from 25 to 90% or more. Outbreaks of Marburg and Ebola hemorrhagic fever occur in certain regions of equatorial Africa at irregular intervals. Since 2000, the number of outbreaks has increased. In 2014, the biggest outbreak of a filovirus-induced hemorrhagic fever that has been documented so far occurred from March to July 2014 in Guinea, Sierra Leone, Liberia and Nigeria. The outbreak was caused by a new variant of Zaire Ebola-Virus, affected more than 2600 people (stated 20 August) and was associated with case-fatality rates of up to 67% (Guinea). Treatment of Marburg and Ebola hemorrhagic fevers is symptomatic and supportive, licensed antiviral agents are currently not available. Recently, BCX4430, a promising synthetic adenosine analogue with high in vitro and in vivo activity against filoviruses and other RNA viruses, has been described. BCX4430 inhibits viral RNA polymerase activity and protects cynomolgus macaques from Marburg virus infection when administered as late as 48 hours after infection. Nucleic acid-based products, recombinant vaccines and antibodies appear to be less suitable for the treatment of Marburg and Ebola hemorrhagic fevers.
Christova, Iva; Younan, Rasha; Taseva, Evgenia; Gladnishka, Teodora; Trifonova, Iva; Ivanova, Vladislava; Spik, Kristin; Schmaljohn, Connie; Mohareb, Emad
Hemorrhagic fever with renal syndrome (HFRS) and Crimean-Congo hemorrhagic fever (CCHF) are the 2 widespread viral hemorrhagic fevers occurring in Europe. HFRS is distributed throughout Europe, and CCHF has been reported mainly on the Balkan Peninsula and Russia. Both hemorrhagic fevers are endemic in Bulgaria. We investigated to what extent acute undifferentiated febrile illness in Bulgaria could be due to hantaviruses or to CCHF virus. Using enzyme-linked immunosorbent assays (ELISAs), we tested serum samples from 527 patients with acute febrile illness for antibodies against hantaviruses and CCHF virus. Immunoglobulin M (IgM) antibodies against hantaviruses were detected in 15 (2.8%) of the patients. Of the 15 hantavirus-positive patients, 8 (1.5%) were positive for Dobrava virus (DOBV), 5 (0.9%) were positive for Puumala virus (PUUV), and the remaining 2 were positive for both hantaviruses. A plaque reduction neutralization test (PRNT) confirmed 4 of the 10 DOBV-positive samples. PRNT was negative for all PUUV-positive samples. Serologic evidence of recent CCHF virus infection was found in 13 (2.5%) of the patients. Interestingly, HFRS and CCHF were not only detected in well-known endemic areas of Bulgaria but also in nonendemic regions. Our results suggested that in endemic countries, CCHF and/or HFRS might appear as a nonspecific febrile illness in a certain proportion of patients. Physicians must be aware of possible viral hemorrhagic fever cases, even if hemorrhages or renal impairment are not manifested.
Furuta, Yousuke; Gowen, Brian B.; Takahashi, Kazumi; Shiraki, Kimiyasu; Smee, Donald F.; Barnard, Dale L.
Favipiravir (T-705; 6-fluoro-3-hydroxy-2-pyrazinecarboxamide) is an antiviral drug that selectively inhibits the RNA-dependent RNA polymerase of influenza virus. It is phosphoribosylated by cellular enzymes to its active form, favipiravir-ribofuranosyl-5′-triphosphate (RTP). Its antiviral effect is attenuated by the addition of purine nucleic acids, indicating the viral RNA polymerase mistakenly recognizes favipiravir-RTP as a purine nucleotide. Favipiravir is active against a broad range of influenza viruses, including A(H1N1)pdm09, A(H5N1) and the recently emerged A(H7N9) avian virus. It also inhibits influenza strains resistant to current antiviral drugs, and shows a synergistic effect in combination with oseltamivir, thereby expanding influenza treatment options. A Phase III clinical evaluation of favipiravir for influenza therapy has been completed in Japan and two Phase II studies have been completed in the United States. In addition to its anti-influenza activity, favipiravir blocks the replication of many other RNA viruses, including arenaviruses (Junin, Machupo and Pichinde); phleboviruses (Rift Valley fever, sandfly fever and Punta Toro); hantaviruses (Maporal, Dobrava, and Prospect Hill); flaviviruses (yellow fever and West Nile); enteroviruses (polio- and rhinoviruses); an alphavirus, Western equine encephalitis virus; a paramyxovirus, respiratory syncytial virus; and noroviruses. With its unique mechanism of action and broad range of antiviral activity, favipiravir is a promising drug candidate for influenza and many other RNA viral diseases for which there are no approved therapies. PMID:24084488
Furuta, Yousuke; Gowen, Brian B; Takahashi, Kazumi; Shiraki, Kimiyasu; Smee, Donald F; Barnard, Dale L
Favipiravir (T-705; 6-fluoro-3-hydroxy-2-pyrazinecarboxamide) is an antiviral drug that selectively inhibits the RNA-dependent RNA polymerase of influenza virus. It is phosphoribosylated by cellular enzymes to its active form, favipiravir-ribofuranosyl-5'-triphosphate (RTP). Its antiviral effect is attenuated by the addition of purine nucleic acids, indicating the viral RNA polymerase mistakenly recognizes favipiravir-RTP as a purine nucleotide. Favipiravir is active against a broad range of influenza viruses, including A(H1N1)pdm09, A(H5N1) and the recently emerged A(H7N9) avian virus. It also inhibits influenza strains resistant to current antiviral drugs, and shows a synergistic effect in combination with oseltamivir, thereby expanding influenza treatment options. A Phase III clinical evaluation of favipiravir for influenza therapy has been completed in Japan and two Phase II studies have been completed in the United States. In addition to its anti-influenza activity, favipiravir blocks the replication of many other RNA viruses, including arenaviruses (Junin, Machupo and Pichinde); phleboviruses (Rift Valley fever, sandfly fever and Punta Toro); hantaviruses (Maporal, Dobrava, and Prospect Hill); flaviviruses (yellow fever and West Nile); enteroviruses (polio- and rhinoviruses); an alphavirus, Western equine encephalitis virus; a paramyxovirus, respiratory syncytial virus; and noroviruses. With its unique mechanism of action and broad range of antiviral activity, favipiravir is a promising drug candidate for influenza and many other RNA viral diseases for which there are no approved therapies.
Gowen, Brian B.; Wong, Min-Hui; Jung, Kie-Hoon; Smee, Donald F.; Morrey, John D.; Furuta, Yousuke
Several studies have reported favipiravir (T-705) to be effective in treating a number of viral diseases modeled in rodent systems. Notably, the related pyrazine derivative, T-1106, was found to be more effective than T-705 in treating yellow fever virus infection in hamsters. Based on these findings, we hypothesized that T-1106 may be more effective in treating hepatotropic Punta Toro virus (PTV, Phlebovirus) infection in rodents. In cell culture, the inhibitory concentrations of the compounds against various phleboviruses ranged from 3–55 µM for T-705 and 76–743 µM for T-1106. In PTV-challenged hamsters, a model that generally presents with high liver viral loads, T-1106 was more effective at reducing mortality. However, in mice infected with PTV, a model wherein systemic infection is more prominent, the greater efficacy exhibited by T-1106 in the hamster system was not apparent. In contrast, T-705 was superior in preventing mortality in hamsters challenged with Pichinde virus (PICV, Arenavirus), an infection characterized as diffuse and pantropic. Remarkably, T-1106 has proven more active in vivo than would have been expected from our cell culture results, and our in vivo findings suggest that it is more effective in infections characterized predominantly by high levels of hepatic viral burden. PMID:19874853
Rasmussen, Angela L; Okumura, Atsushi; Ferris, Martin T; Green, Richard; Feldmann, Friederike; Kelly, Sara M; Scott, Dana P; Safronetz, David; Haddock, Elaine; LaCasse, Rachel; Thomas, Matthew J; Sova, Pavel; Carter, Victoria S; Weiss, Jeffrey M; Miller, Darla R; Shaw, Ginger D; Korth, Marcus J; Heise, Mark T; Baric, Ralph S; de Villena, Fernando Pardo-Manuel; Feldmann, Heinz; Katze, Michael G
Existing mouse models of lethal Ebola virus infection do not reproduce hallmark symptoms of Ebola hemorrhagic fever, neither delayed blood coagulation and disseminated intravascular coagulation nor death from shock, thus restricting pathogenesis studies to nonhuman primates. Here we show that mice from the Collaborative Cross panel of recombinant inbred mice exhibit distinct disease phenotypes after mouse-adapted Ebola virus infection. Phenotypes range from complete resistance to lethal disease to severe hemorrhagic fever characterized by prolonged coagulation times and 100% mortality. Inflammatory signaling was associated with vascular permeability and endothelial activation, and resistance to lethal infection arose by induction of lymphocyte differentiation and cellular adhesion, probably mediated by the susceptibility allele Tek. These data indicate that genetic background determines susceptibility to Ebola hemorrhagic fever.
Abdelhakam, Haydar Awad Abdelrazig; Taha, Mohamed Ahmed
Crimean-Congo hemorrhagic fever (CCHF) is a disease that poses a great threat to public health owing to its high mortality rate (30-70%), mode of transmission and geographic distribution. Here, we report on a nine years-old Sudanese boy from Southern Kordofan State who presented with Jaundice, high-grade fever, severe headache, abdominal pain and a history of hematemesis. The diagnosis of CCHF was confirmed based on clinical and serological findings.
Jha, Ratan; Gude, Dilip; Chennamsetty, Sashidhar
Acute kidney injury occurs in 33-50% of patients with rhabdomyolysis and infections remain one of the major contributing factors. The incidence of rhabdomyolysis in non-hemorrhagic dengue virus infection is quite low and may go unnoticed, especially if the presentation is not florid. We report a case of a young male patient, sero-positive for dengue, with no hemorrhagic manifestations or hypotension, who developed rhabdomyolysis complicated by renal failure. The patient eventually needed dialysis support and later recovered fully. Clinicians need to be aware of the occurrence of rhabdomyolysis even in patients without the hemorrhagic manifestations of dengue viral infection and should employ early preventive strategies in such cases.
El-Bahnasawy, Mamdouh M; Megahed, Laila Abdel-Mawla; Abdalla Saleh, Hala Ahmed; Morsy, Tosson A
Viral hemorrhagic fevers (VHFs) typically manifest as rapidly progressing acute febrile syndromes with profound hemorrhagic manifestations and very high fatality rates. Lassa fever, an acute hemorrhagic fever characterized by fever, muscle aches, sore throat, nausea, vomiting, diarrhea and chest and abdominal pain. Rodents are important reservoirs of rodent-borne zoonosis worldwide. Transmission rodents to humans occur by aerosol spread, either from the genus Mastomys rodents' excreta (multimammate rat) or through the close contact with infected patients (nosocomial infection). Other rodents of the genera Rattus, Mus, Lemniscomys, and Praomys are incriminated rodents hosts. Now one may ask do the rodents' ectoparasites play a role in Lassa virus zoonotic transmission. This paper summarized the update knowledge on LHV; hopping it might be useful to the clinicians, nursing staff, laboratories' personals as well as those concerned zoonoses from rodents and rodent control.
Sewlall, Nivesh H.; Richards, Guy; Duse, Adriano; Swanepoel, Robert; Paweska, Janusz; Blumberg, Lucille; Dinh, Thu Ha; Bausch, Daniel
Background In 2008 a nosocomial outbreak of five cases of viral hemorrhagic fever due to a novel arenavirus, Lujo virus, occurred in Johannesburg, South Africa. Lujo virus is only the second pathogenic arenavirus, after Lassa virus, to be recognized in Africa and the first in over 40 years. Because of the remote, resource-poor, and often politically unstable regions where Lassa fever and other viral hemorrhagic fevers typically occur, there have been few opportunities to undertake in-depth study of their clinical manifestations, transmission dynamics, pathogenesis, or response to treatment options typically available in industrialized countries. Methods and Findings We describe the clinical features of five cases of Lujo hemorrhagic fever and summarize their clinical management, as well as providing additional epidemiologic detail regarding the 2008 outbreak. Illness typically began with the abrupt onset of fever, malaise, headache, and myalgias followed successively by sore throat, chest pain, gastrointestinal symptoms, rash, minor hemorrhage, subconjunctival injection, and neck and facial swelling over the first week of illness. No major hemorrhage was noted. Neurological signs were sometimes seen in the late stages. Shock and multi-organ system failure, often with evidence of disseminated intravascular coagulopathy, ensued in the second week, with death in four of the five cases. Distinctive treatment components of the one surviving patient included rapid commencement of the antiviral drug ribavirin and administration of HMG-CoA reductase inhibitors (statins), N-acetylcysteine, and recombinant factor VIIa. Conclusions Lujo virus causes a clinical syndrome remarkably similar to Lassa fever. Considering the high case-fatality and significant logistical impediments to controlled treatment efficacy trials for viral hemorrhagic fever, it is both logical and ethical to explore the use of the various compounds used in the treatment of the surviving case reported here
hantaviruses . The 130 individuals possessed hantaviral antibodies. A nationwide epidemic of hemorrhagic fever with renal syndrome (HFRS) occurred in...where four types of antibody patterns were found. Two of these antibody patterns suggested the existence of hantaviruses which are antigenically distinct...endemic areas in Yugoslavia tested for IF antibodies to Hantaan and Puumala viruses and hantaviruses antigens ...... ................. 28 10. Percentage
hemorrhagic fever. Donors were recruited from the rural area of San Joaquin, Bolivia, where a temporary plasmapheresis unit was established, using project...funds. The collected plasma was fractionated in the United States where one half was retained for prophylactic or therapeutic use following potential
Salem, Mohamed Lemine Ould; Baba, Sidi El Wafi Ould; Fall-Malick, Fatimetou Zahra; Boushab, Boushab Mohamed; Ghaber, Sidi Mohamed; Mokhtar, Abdelwedoud
Rift Valley fever (RVF) is an arbovirus caused by an RNA virus belonging to family Bunyaviridae (genus phlebovirus). It is a zoonosis that primarily affects animals but it also has the capacity to infect humans, either by handling meat, runts of sick animals or, indirectly, by the bite of infected mosquitoes (Aedes sp, Anopheles sp, Culex sp). In most cases, RVF infection in humans is asymptomatic, but it can also manifest as moderate febrile syndrome with a favorable outcome. However, some patients may develop hemorrhagic syndrome and/or neurological damages with a fatal evolution. We present a case study of the development of 5 patients with RVF associated with hemorrhagic fever syndrome admitted to the internal medicine department at National Hospital Center in Nouakchott (Mauritania), in October 2015. The outcome was favorable for two of the five patients. The other 3 died, two of hemorrhagic shock and one of septic shock.
El Sayed, Salah Mohamed; Abdelrahman, Ali A.; Ozbak, Hani Adnan; Hemeg, Hassan Abdullah; Kheyami, Ali Mohammed; Rezk, Nasser; El-Ghoul, Mohamed Baioumy; Nabo, Manal Mohamed Helmy; Fathy, Yasser Mohamed
Ebola hemorrhagic fever is a lethal viral disease transmitted by contact with infected people and animals. Ebola infection represents a worldwide health threat causing enormous mortality rates and fatal epidemics. Major concern is pilgrimage seasons with possible transmission to Middle East populations. In this review, we aim to shed light on Ebola hemorrhagic fever as regard: virology, transmission, biology, pathogenesis, clinical picture, and complications to get the best results for prevention and management. We also aim to guide future research to new therapeutic perspectives to precise targets. Our methodology was to review the literature extensively to make an overall view of the biology of Ebola virus infection, its serious health effects and possible therapeutic benefits using currently available remedies and future perspectives. Key findings in Ebola patients are fever, hepatic impairment, hepatocellular necrosis, lymphopenia (for T-lymphocyte and natural killer cells) with lymphocyte apoptosis, hemorrhagic manifestations, and complications. Pathogenesis in Ebola infection includes oxidative stress, immune suppression of both cell-mediated and humoral immunities, hepatic and adrenal impairment and failure, hemorrhagic fever, activation of deleterious inflammatory pathways, for example, tumor necrosis factor-related apoptosis-inducing ligand, and factor of apoptotic signal death receptor pathways causing lymphocyte depletion. Several inflammatory mediators and cytokines are involved in pathogenesis, for example, interleukin-2, 6, 8, and 10 and others. In conclusion, Ebola hemorrhagic fever is a serious fatal viral infection that can be prevented using strict health measures and can be treated to some extent using some currently available remedies. Newer treatment lines, for example, prophetic medicine remedies as nigella sativa may be promising. PMID:28163730
El Sayed, Salah Mohamed; Abdelrahman, Ali A; Ozbak, Hani Adnan; Hemeg, Hassan Abdullah; Kheyami, Ali Mohammed; Rezk, Nasser; El-Ghoul, Mohamed Baioumy; Nabo, Manal Mohamed Helmy; Fathy, Yasser Mohamed
Ebola hemorrhagic fever is a lethal viral disease transmitted by contact with infected people and animals. Ebola infection represents a worldwide health threat causing enormous mortality rates and fatal epidemics. Major concern is pilgrimage seasons with possible transmission to Middle East populations. In this review, we aim to shed light on Ebola hemorrhagic fever as regard: virology, transmission, biology, pathogenesis, clinical picture, and complications to get the best results for prevention and management. We also aim to guide future research to new therapeutic perspectives to precise targets. Our methodology was to review the literature extensively to make an overall view of the biology of Ebola virus infection, its serious health effects and possible therapeutic benefits using currently available remedies and future perspectives. Key findings in Ebola patients are fever, hepatic impairment, hepatocellular necrosis, lymphopenia (for T-lymphocyte and natural killer cells) with lymphocyte apoptosis, hemorrhagic manifestations, and complications. Pathogenesis in Ebola infection includes oxidative stress, immune suppression of both cell-mediated and humoral immunities, hepatic and adrenal impairment and failure, hemorrhagic fever, activation of deleterious inflammatory pathways, for example, tumor necrosis factor-related apoptosis-inducing ligand, and factor of apoptotic signal death receptor pathways causing lymphocyte depletion. Several inflammatory mediators and cytokines are involved in pathogenesis, for example, interleukin-2, 6, 8, and 10 and others. In conclusion, Ebola hemorrhagic fever is a serious fatal viral infection that can be prevented using strict health measures and can be treated to some extent using some currently available remedies. Newer treatment lines, for example, prophetic medicine remedies as nigella sativa may be promising.
Yamada, Kentaro; Noguchi, Kazuko; Komeno, Takashi; Furuta, Yousuke; Nishizono, Akira
Rabies is a fatal encephalitis caused by rabies virus (RABV), and no antiviral drugs for RABV are currently available. We report for the first time the efficacy of favipiravir (T-705) against RABV in vitro and in vivo. T-705 produced a significant, 3-4 log10 reduction in the multiplication of street and fixed RABV strains in mouse neuroblastoma Neuro-2a cells, with half-maximal inhibitory concentrations of 32.4 µM and 44.3 µM, respectively. T-705 significantly improved morbidity and mortality among RABV-infected mice when orally administered at a dose of 300 mg/kg/day for 7 days, beginning 1 hour after inoculation. T-705 significantly reduced the rate of virus positivity in the brain. Furthermore, the effectiveness of T-705 was comparable to that of equine rabies virus immunoglobulin for postexposure prophylaxis. Collectively, our results suggest that T-705 is active against RABV and may serve as a potential alternative to rabies immunoglobulin in rabies postexposure prophylaxis.
MacNeil, Adam; Rollin, Pierre E.
Ebola hemorrhagic fever (EHF) and Marburg hemorrhagic fever (MHF) are rare viral diseases, endemic to central Africa. The overall burden of EHF and MHF is small in comparison to the more common protozoan, helminth, and bacterial diseases typically referred to as neglected tropical diseases (NTDs). However, EHF and MHF outbreaks typically occur in resource-limited settings, and many aspects of these outbreaks are a direct consequence of impoverished conditions. We will discuss aspects of EHF and MHF disease, in comparison to the “classic” NTDs, and examine potential ways forward in the prevention and control of EHF and MHF in sub-Saharan Africa, as well as examine the potential for application of novel vaccines or antiviral drugs for prevention or control of EHF and MHF among populations at highest risk for disease. PMID:22761967
Tucker, Compton J.; Pinzon, Jorge E.
Ebola hemorrhagic fever, named after the Ebola River in Central Africa, first appeared in June 1976, during an outbreak in Nzara and Maridi, Sudan. In September 1976, a separate outbreak was recognized in Yambuku, Democratic Republic of the Congo (DRC). One fatal case was identified in Tandala, DRC, in June 1977, followed by another outbreak in Nzara, Sudan, in July 1979. Ebola hemorrhagic fever outbreaks results in a very high mortality of patients who contract the disease: from 50 to 80% of infected people perish from this highly virulent disease. Death is gruesome, with those afflicted bleeding to death from massive hemorrhaging of organs and capillaries. The disease was not identified again until the end of 1994, when three outbreaks occurred almost simultaneously in Africa. In October, an outbreak was identified in a chimpanzee community studied by primatologists in Tal, Cote d'lvoire, with one human infection. The following month, multiple cases were reported in northeast Gabon in the gold panning camps of Mekouka, Andock, and Minkebe. Later that same month, the putative index case of the 1995 Kikwit, DRC, outbreak was exposed through an unknown mechanism while working in a charcoal pit. In Gabon, two additional outbreaks were reported in February and JuIy,1996, respectively, in Mayibout II, a village 40 km south of the original outbreak in the gold panning camps, and a logging camp between Ovan and Koumameyong, near Booue. The largest Ebola hemorrhagic fever epidemic occurred in Gulu District, Uganda from August 2000 to January 2001. In December 2001, Ebola reappeared in the Ogooue-lvindo Province, Gabon with extension into Mbomo District, The Republic of the Congo lasting until July 2002. Since 2002 there have been several outbreaks of Ebola hemorrhagic fever in Gabon and adjacent areas of Congo. Of interest is the seasonal context and occasional temporal clustering of Ebola hemorrhagic fever outbreaks. Near simultaneous appearances of Ebola epidemics in
Zivcec, Marko; Scholte, Florine; Spiropoulou, Christina; Spengler, Jessica; Bergeron, Éric
Crimean-Congo hemorrhagic fever virus (CCHFV) is a tick-borne pathogen that causes high morbidity and mortality. Efficacy of vaccines and antivirals to treat human CCHFV infections remains limited and controversial. Research into pathology and underlying molecular mechanisms of CCHFV and other nairoviruses is limited. Significant progress has been made in our understanding of CCHFV replication and pathogenesis in the past decade. Here we review the most recent molecular advances in CCHFV-related research, and provide perspectives on future research.
Zhdanov, K V; Zakharenko, S M; Kovalenko, A N; Semenov, A V; Fisun, A Ya
The data on diagnostics, etiotropic and pathogenetic therapy, prevention of Ebola hemorrhagic fever are presented including diagnostic algorithms for different clinical situations. Fundamentals of pathogenetic therapy are described. Various groups of medications used for antiviral therapy of conditions caused by Ebola virus are characterized. Experimental drugs at different stages of clinical studies are considered along with candidate vaccines being developed for the prevention of the disease.
Jiang, Hong; Du, Hong; Wang, Li M; Wang, Ping Z; Bai, Xue F
Hantaan virus (HTNV) causes hemorrhagic fever with renal syndrome (HFRS), which is a zoonosis endemic in eastern Asia, especially in China. The reservoir host of HTNV is field mouse (Apodemus agraricus). The main manifestation of HFRS, including acute kidney injury, increases vascular permeability, and coagulation abnormalities. In this paper, we review the current knowledge of the pathogenesis of HFRS including virus factor, immunity factor and host genetic factors. Furthermore, the treatment and prevention will be discussed.
Zivcec, Marko; Scholte, Florine E M; Spiropoulou, Christina F; Spengler, Jessica R; Bergeron, Éric
Crimean-Congo hemorrhagic fever virus (CCHFV) is a tick-borne pathogen that causes high morbidity and mortality. Efficacy of vaccines and antivirals to treat human CCHFV infections remains limited and controversial. Research into pathology and underlying molecular mechanisms of CCHFV and other nairoviruses is limited. Significant progress has been made in our understanding of CCHFV replication and pathogenesis in the past decade. Here we review the most recent molecular advances in CCHFV-related research, and provide perspectives on future research.
Zivcec, Marko; Scholte, Florine; Spiropoulou, Christina; ...
Crimean-Congo hemorrhagic fever virus (CCHFV) is a tick-borne pathogen that causes high morbidity and mortality. Efficacy of vaccines and antivirals to treat human CCHFV infections remains limited and controversial. Research into pathology and underlying molecular mechanisms of CCHFV and other nairoviruses is limited. Significant progress has been made in our understanding of CCHFV replication and pathogenesis in the past decade. Here we review the most recent molecular advances in CCHFV-related research, and provide perspectives on future research.
Peters, C. J
Two Institute of Medicine reports since 1992 have emphasized the dangerous and continuing threat to the world from emerging infectious diseases. Working with viral hemorrhagic fevers provides a number of lessons related to the processes that control emergence, the pattern of disease after emergence, and how to cope with these incidents. This short paper uses two arenavirus hemorrhagic fevers to illustrate some of these principles. Argentine and Bolivian hemorrhagic fevers first came to medical attention in the 1950’s. The forces that underlie the emergence of disease in Argentina are not understood, but the Bolivian episode has a reasonably understandable train of events behind it. The Argentine disease had serious impact on the large agricultural economy, and the ecology of the rodent reservoir did not lend itself to control; a vaccine was developed by Argentina and the U.S. with the latter motivated largely by biodefense. The Bolivian disease was controlled in large part by eliminating rodents that invaded towns, and the impact was subsequently below the level needed to trigger drug or vaccine development. These two viruses were important in the recognition of a new family of viruses (Arenaviridae), and this finding of new taxons during the investigation of emerging infectious diseases continues. PMID:18528473
Johnson, Reed F; Dodd, Lori E; Yellayi, Srikanth; Gu, Wenjuan; Cann, Jennifer A; Jett, Catherine; Bernbaum, John G; Ragland, Dan R; St Claire, Marisa; Byrum, Russell; Paragas, Jason; Blaney, Joseph E; Jahrling, Peter B
Simian Hemorrhagic Fever Virus (SHFV) has caused sporadic outbreaks of hemorrhagic fevers in macaques at primate research facilities. SHFV is a BSL-2 pathogen that has not been linked to human disease; as such, investigation of SHFV pathogenesis in non-human primates (NHPs) could serve as a model for hemorrhagic fever viruses such as Ebola, Marburg, and Lassa viruses. Here we describe the pathogenesis of SHFV in rhesus macaques inoculated with doses ranging from 50 PFU to 500,000 PFU. Disease severity was independent of dose with an overall mortality rate of 64% with signs of hemorrhagic fever and multiple organ system involvement. Analyses comparing survivors and non-survivors were performed to identify factors associated with survival revealing differences in the kinetics of viremia, immunosuppression, and regulation of hemostasis. Notable similarities between the pathogenesis of SHFV in NHPs and hemorrhagic fever viruses in humans suggest that SHFV may serve as a suitable model of BSL-4 pathogens.
Terrell, Timothy G.; Stookey, James L.; Eddy, Gerald A.; Kastello, Michael D.
Gross and microscopic lesions associated with Bolivan hemorrhagic fever virus infection in the rhesus monkey were studied in 10 animals which died following inoculation. Gross lesions included skin rash, lymphadenopathy, splenomegaly, meningeal edema, hydropericardium and enlarged friable livers. Hemorrhagic manifestations of the infection were not consistently observed, but hemorrhages were present in the skin, heart, brain and nares in some monkeys. Histopathologic lesions were fairly consistent. Hepatic necrosis with the presence of acidophilic hyaline bodies, necrotizing enteritis, epithelial necrosis and adrenal cortical necrosis were present in all monkeys. Those monkeys which died after the seventeenth day of infection had nonsupurative meningoencephalitis; lymphoid necrosis was present in 3 monkeys that died after day 18. Other microscopic lesions included myocardial degeneration, lymphoid and reticuloendothelial cell hyperplasia and lymphoid depletion. Most of the histopathologic lesions described in human autopsy material were reproduced; however, the necrosis in the skin and oral mucosa, mucosa of the gastrointestinal tract and the adrenal cortex have not been described in man. Despite these apparent discrepancies the results of this investigation indicate that the rhesus monkey is a good experimental model for the study of Bolivian hemorrhagic fever infection. ImagesFig 12Fig 13Fig 1Fig 2Fig 3Fig 4Fig 5Fig 6Fig 7Fig 8Fig 9Fig 10Fig 11 PMID:4202335
Vatter, Heather A; Donaldson, Eric F; Huynh, Jeremy; Rawlings, Stephanie; Manoharan, Minsha; Legasse, Alfred; Planer, Shannon; Dickerson, Mary F; Lewis, Anne D; Colgin, Lois M A; Axthelm, Michael K; Pecotte, Jerilyn K; Baric, Ralph S; Wong, Scott W; Brinton, Margo A
Simian hemorrhagic fever virus is an arterivirus that naturally infects species of African nonhuman primates causing acute or persistent asymptomatic infections. Although it was previously estimated that 1% of baboons are SHFV-positive, more than 10% of wild-caught and captive-bred baboons tested were SHFV positive and the infections persisted for more than 10 years with detectable virus in the blood (100-1000 genomes/ml). The sequences of two baboon SHFV isolates that were amplified by a single passage in primary macaque macrophages had a high degree of identity to each other as well as to the genome of SHFV-LVR, a laboratory strain isolated in the 1960s. Infection of Japanese macaques with 100PFU of a baboon isolate consistently produced high level viremia, pro-inflammatory cytokines, elevated tissue factor levels and clinical signs indicating coagulation defects. The baboon virus isolate provides a reliable BSL2 model of viral hemorrhagic fever disease in macaques.
Rai, Mohammad A; Khanani, Mohammad R; Warraich, Haider J; Hayat, Abbas; Ali, Syed H
Crimean-Congo virus, the causative agent of Crimean-Congo Virus Fever (CCVF) is endemic in Pakistan. Cases are documented sporadically ever year, mostly at and around the time of Eid-ul-Adha, an Islamic festival, celebrated on day 10 through 13 of the 12th month of each lunar calendar year. At this time of the year in Pakistan, livestock are brought down to the urban areas from the rural parts of the country. Animals are housed in open spaces and private houses until they are slaughtered during the 3 days of Eid-ul-Adha. This allows the CCHF virus, which is carried by a tick that inhabits the animal hide, to be transmitted through unprotected contact with live animals as well as through contact with animal blood subsequent to its slaughter. In this report, a typical case of CCVF is described that was encountered in Rawalpindi, Pakistan. A number of issues pertaining to the management of recurrent outbreaks of CCVF in the country are discussed.
McElroy, Anita K.; Erickson, Bobbie R.; Flietstra, Timothy D.; Rollin, Pierre E.; Nichol, Stuart T.; Towner, Jonathan S.; Spiropoulou, Christina F.
Background. Ebola hemorrhagic fever (EHF) outbreaks occur sporadically in Africa and result in high rates of death. The 2000–2001 outbreak of Sudan virus–associated EHF in the Gulu district of Uganda led to 425 cases, of which 216 were laboratory confirmed, making it the largest EHF outbreak on record. Serum specimens from this outbreak had been preserved in liquid nitrogen from the time of collection and were available for analysis. Methods. Available samples were tested using a series of multiplex assays to measure the concentrations of 55 biomarkers. The data were analyzed to identify statistically significant associations between the tested biomarkers and hemorrhagic manifestations, viremia, and/or death. Results. Death, hemorrhage, and viremia were independently associated with elevated levels of several chemokines and cytokines. Death and hemorrhage were associated with elevated thrombomodulin and ferritin levels. Hemorrhage was also associated with elevated levels of soluble intracellular adhesion molecule. Viremia was independently associated with elevated levels of tissue factor and tissue plasminogen activator. Finally, samples from nonfatal cases had higher levels of sCD40L. Conclusions. These novel associations provide a better understanding of EHF pathophysiology and a starting point for researching new potential targets for therapeutic interventions. PMID:24526742
McElroy, Anita K; Erickson, Bobbie R; Flietstra, Timothy D; Rollin, Pierre E; Nichol, Stuart T; Towner, Jonathan S; Spiropoulou, Christina F
Ebola hemorrhagic fever (EHF) outbreaks occur sporadically in Africa and result in high rates of death. The 2000-2001 outbreak of Sudan virus-associated EHF in the Gulu district of Uganda led to 425 cases, of which 216 were laboratory confirmed, making it the largest EHF outbreak on record. Serum specimens from this outbreak had been preserved in liquid nitrogen from the time of collection and were available for analysis. Available samples were tested using a series of multiplex assays to measure the concentrations of 55 biomarkers. The data were analyzed to identify statistically significant associations between the tested biomarkers and hemorrhagic manifestations, viremia, and/or death. Death, hemorrhage, and viremia were independently associated with elevated levels of several chemokines and cytokines. Death and hemorrhage were associated with elevated thrombomodulin and ferritin levels. Hemorrhage was also associated with elevated levels of soluble intracellular adhesion molecule. Viremia was independently associated with elevated levels of tissue factor and tissue plasminogen activator. Finally, samples from nonfatal cases had higher levels of sCD40L. These novel associations provide a better understanding of EHF pathophysiology and a starting point for researching new potential targets for therapeutic interventions. Published by Oxford University Press on behalf of the Infectious Diseases Society of America 2014. This work is written by (a) US Government employee(s) and is in the public domain in the US.
Leroy, E; Baize, S; Gonzalez, J P
The Ebola and Marburg viruses are the sole members of the Filoviridae family of viruses. They are characterized by a long filamentous form that is unique in the viral world. Filoviruses are among the most virulent pathogens currently known to infect humans. They cause fulminating disease characterized by acute fever followed by generalized hemorrhagic syndrome that is associated with 90% mortality in the most severe forms. Epidemic outbreaks of Marburg and Ebola viruses have taken a heavy toll on human life in Central Africa and devastated large ape populations in Gabon and Republic of Congo. Since their discovery in 1967 (Marburg) and 1976 (Ebola), more than 2,300 cases and 1,670 deaths have been reported. These numbers pale in comparison with the burden caused by malnutrition or other infectious disease scourges in Africa such as malaria, cholera, AIDS, dengue or tuberculosis. However, due to their extremely high lethality, association with multifocal hemorrhaging and specificity to the African continent, these hemorrhagic fever viruses have given rise to great interest on the part not only of the international scientific community but also of the general public because of their perceived potential as biological weapons. Much research has been performed on these viruses and major progress has been made in knowledge of their ecology, epidemiology and physiopathology and in development of vaccine candidates and therapeutic schemes. The purpose of this review is to present the main developments in these particular fields in the last decade.
Bell, T M; Bunton, T E; Shaia, C I; Raymond, J W; Honnold, S P; Donnelly, G C; Shamblin, J D; Wilkinson, E R; Cashman, K A
Machupo virus, the cause of Bolivian hemorrhagic fever, is a highly lethal viral hemorrhagic fever with no Food and Drug Administration-approved vaccines or therapeutics. This study evaluated the guinea pig as a model using the Machupo virus-Chicava strain administered via aerosol challenge. Guinea pigs (Cavia porcellus) were serially sampled to evaluate the temporal progression of infection, gross and histologic lesions, and sequential changes in serum chemistry and hematology. The incubation period was 5 to 12 days, and complete blood counts revealed leukopenia with lymphopenia and thrombocytopenia. Gross pathologic findings included congestion and hemorrhage of the gastrointestinal mucosa and serosa, noncollapsing lungs with fluid exudation, enlarged lymph nodes, and progressive pallor and friability of the liver. Histologic lesions consisted of foci of degeneration and cell death in the haired skin, liver, pancreas, adrenal glands, lymph nodes, tongue, esophagus, salivary glands, renal pelvis, small intestine, and large intestine. Lymphohistiocytic interstitial pneumonia was also present. Inflammation within the central nervous system, interpreted as nonsuppurative encephalitis, was histologically apparent approximately 16 days postexposure and was generally progressive. Macrophages in the tracheobronchial lymph node, on day 5 postexposure, were the first cells to demonstrate visible viral antigen. Viral antigen was detected throughout the lymphoid system by day 9 postexposure, followed by prominent spread within epithelial tissues and then brain. This study provides insight into the course of Machupo virus infection and supports the utility of guinea pigs as an additional animal model for vaccine and therapeutic development.
Flusin, O; Iseni, F; Rodrigues, R; Paranhos-Baccalà, G; Crance, J M; Marianneau, P; Bouloy, M; Peyrefitte, C N
Crimean-Congo hemorrhagic fever (CCHF) is a tick-borne disease described in more than 30 countries in Europe, Asia and Africa. The causative agent is the Crimean-Congo hemorrhagic fever virus (CCHFV) that is a member of the genus Nairovirus of the family Bunyaviridae. CCHFV that is characterized by a high genetic variability is transmitted to humans by tick bites or contact with fluids from an infected individual or animal. The initial symptoms of CCHF are nonspecific and gradually progress to a hemorrhagic phase that can be lethal (case-fatality rate: 10 to 50%). Characteristic laboratory findings of CCHF are thrombocytopenia, elevated liver and muscle enzymes, and coagulation defects. The pathogenesis of CCHF remains unclear but might involve excessive pro-inflammatory cytokine production and dysfunction of the innate immune response. Diagnosis of CCHF is based mainly on isolation of the virus, identification of the viral genome by molecular techniques (RT-PCR), and serological detection of anti-CCHFV antibodies. There is currently no specific treatment for CCHFV infection and the efficacy of ribavirin is controversial. In absence of an effective vaccine, prevention is based mainly on vector control, protection measures, and information to increase the awareness of the population and of healthcare workers.
Crimean-Congo hemorrhagic fever (CCHF) is a fatal viral infection described in Asia, Africa and Europe. Humans become infected through the bites of ticks, by contact with a patient with CCHF during the acute phase of infection, or by contact with blood or tissues from viremic livestock. The occurrence of CCHF closely approximates the known world distribution of Hyalomma spp. ticks. The novel studies of phylogenetic analyses reveal the interesting relations between the strains from distant outbreaks. The clinical features show common dramatic progress characterized by hemorrhage, myalgia, and fever. Besides the direct infection of endothelium, indirect damage by viral or virus mediated host-derived soluble factors that cause endothelial activations and dysfunction occur. In diagnosis, enzyme linked immunoassay and real-time reverse transcription-polymerase chain reaction are used. Early diagnosis is critical for the patient and potential nosocomial infections. Supportive therapy is the essential part of the case management. Ribavirin was suggested as an effective drug in recent studies, and it was found to be beneficial. The health care workers are under serious risk of transmission of the infection, particularly during the follow-up of the patient, with hemorrhages from the nose, mouth, gums, vagina, and injection sites.
Papa, Anna; Mirazimi, Ali; Köksal, Iftihar; Estrada-Pena, Augustin; Feldmann, Heinz
Crimean-Congo hemorrhagic fever (CCHF) is an expanding tick-borne hemorrhagic disease with increasing human and animal health impact. Immense knowledge was gained over the past 10 years mainly due to advances in molecular biology, but also driven by an increased global interest in CCHFV as an emerging/re-emerging zoonotic pathogen. In the present article, we discuss the advances in research with focus on CCHF ecology, epidemiology, pathogenesis, diagnostics, prophylaxis and treatment. Despite tremendous achievements, future activities have to concentrate on the development of vaccines and antivirals/therapeutics to combat CCHF. Vector studies need to continue for better public and animal health preparedness and response. We conclude with a roadmap for future research priorities.
Papa, Anna; Mirazimi, Ali; Köksal, Iftihar; Estrada-Pena, Augustin; Feldmann, Heinz
Crimean-Congo hemorrhagic fever (CCHF) is an expanding tick-borne hemorrhagic disease with increasing human and animal health impact. Immense knowledge was gained over the past 10 years mainly due to advances in molecular biology, but also driven by an increased global interest in CCHFV as an emerging/re-emerging zoonotic pathogen. In the present article we discuss the advances in research with focus on CCHF ecology, epidemiology, pathogenesis, diagnostics, prophylaxis and treatment. Despite tremendous achievements, future activities have to concentrate on the development of vaccines and antivirals/therapeutics to combat CCHF. Vector studies need to continue for better public and animal health preparedness and response. We conclude with a roadmap for future research priorities. PMID:25453328
Falzarano, Darryl; Feldmann, Heinz
With a few exceptions, vaccines for viruses that cause hemorrhagic fever remain unavailable or lack well-documented efficacy. In the past decade this has not been due to a lack of the ability to develop vaccine platforms against highly pathogenic viruses, but rather the lack of will/interest to invest in platforms that have the potential to become successful vaccines. The two exceptions to this are vaccines against Dengue virus and Rift Valley Fever virus, which recently have seen significant progress in putting forward new and improved vaccines, respectively. Experimental vaccines for filoviruses and Lassa virus do exist but are hindered by a lack of financial interest and only partially or ill-defined correlates/mechanisms of protection that could be assessed in clinical trials. PMID:23773330
Timen, Aura; Koopmans, Marion P G; Vossen, Ann C T M; van Doornum, Gerard J J; Günther, Stephan; van den Berkmortel, Franchette; Verduin, Kees M; Dittrich, Sabine; Emmerich, Petra; Osterhaus, Albert D M E; van Dissel, Jaap T; Coutinho, Roel A
On July 10, 2008, Marburg hemorrhagic fever was confirmed in a Dutch patient who had vacationed recently in Uganda. Exposure most likely occurred in the Python Cave (Maramagambo Forest), which harbors bat species that elsewhere in Africa have been found positive for Marburg virus. A multidisciplinary response team was convened to perform a structured risk assessment, perform risk classification of contacts, issue guidelines for follow-up, provide information, and monitor the crisis response. In total, 130 contacts were identified (66 classified as high risk and 64 as low risk) and monitored for 21 days after their last possible exposure. The case raised questions specific to international travel, postexposure prophylaxis for Marburg virus, and laboratory testing of contacts with fever. We present lessons learned and results of the follow-up serosurvey of contacts and focus on factors that prevented overreaction during an event with a high public health impact.
Koopmans, Marion P.G.; Vossen, Ann C.T.M.; van Doornum, Gerard J.J.; Günther, Stephan; van den Berkmortel, Franchette; Verduin, Kees M.; Dittrich, Sabine; Emmerich, Petra; Osterhaus, Albert D.M.E.; van Dissel, Jaap T.; Coutinho, Roel A.
On July 10, 2008, Marburg hemorrhagic fever was confirmed in a Dutch patient who had vacationed recently in Uganda. Exposure most likely occurred in the Python Cave (Maramagambo Forest), which harbors bat species that elsewhere in Africa have been found positive for Marburg virus. A multidisciplinary response team was convened to perform a structured risk assessment, perform risk classification of contacts, issue guidelines for follow-up, provide information, and monitor the crisis response. In total, 130 contacts were identified (66 classified as high risk and 64 as low risk) and monitored for 21 days after their last possible exposure. The case raised questions specific to international travel, postexposure prophylaxis for Marburg virus, and laboratory testing of contacts with fever. We present lessons learned and results of the follow-up serosurvey of contacts and focus on factors that prevented overreaction during an event with a high public health impact. PMID:19751577
Pinzon, Jorge E.; Wilson, James M.; Tucker, Compton J.; Arthur, Ray; Jahrling, Peter B.; Formenty, Pierre
We use spatially continuous satellite data as a correlate of precipitation within tropical Africa and show that the majority of documented Ebola hemorrhagic fever outbreaks were closely associated with sharply drier conditions at the end of the rainy season. We propose that these trigger events may enhance transmission of Ebola virus from its cryptic reservoir to humans. These findings suggest specific directions to help understand the sylvatic cycle of the virus and may provide early warning tools to detect possible future outbreaks of this enigmatic disease.
Ebola virus, described in 1976 in Zaire, causes severe hemorrhagic fever with a high mortality rate in humans and nonhuman primates. Epidemics occurred since this time to nowadays in Sudan, Gabon, Congo and currently in Guinea, Liberia, Sierra-Leone, Nigeria and Senegal. Specific treatment and vaccine are not available. So, to prevent the virus transmission with live and dead patients, we must use strict individual and collective measures which are not always understood by local populations and make contact tracing; it is the only way to curb the epidemic.
Zivcec, Marko; Scholte, Florine E. M.; Spiropoulou, Christina F.; Spengler, Jessica R.; Bergeron, Éric
Crimean-Congo hemorrhagic fever virus (CCHFV) is a tick-borne pathogen that causes high morbidity and mortality. Efficacy of vaccines and antivirals to treat human CCHFV infections remains limited and controversial. Research into pathology and underlying molecular mechanisms of CCHFV and other nairoviruses is limited. Significant progress has been made in our understanding of CCHFV replication and pathogenesis in the past decade. Here we review the most recent molecular advances in CCHFV-related research, and provide perspectives on future research. PMID:27110812
Pinzon, Jorge E; Wilson, James M; Tucker, Compton J; Arthur, Ray; Jahrling, Peter B; Formenty, Pierre
We use spatially continuous satellite data as a correlate of precipitation within tropical Africa and show that the majority of documented Ebola hemorrhagic fever outbreaks were closely associated with sharply drier conditions at the end of the rainy season. We propose that these trigger events may enhance transmission of Ebola virus from its cryptic reservoir to humans. These findings suggest specific directions to help understand the sylvatic cycle of the virus and may provide early warning tools to detect possible future outbreaks of this enigmatic disease.
Dengue fever is a mosquito-transmitted disease caused by any of four closely related virus serotypes (DEN-1, DEN-2, DEN-3, and DEN-4) of the genus Flavivirus. Infection with one of these serotypes provides lifelong immunity to the infecting serotype only. Therefore, persons can acquire a second dengue infection from a different serotype, and second infections place them at greater risk for dengue hemorrhagic fever (DHF), the more severe form of the disease. DHF is characterized by bleeding manifestations, thrombocytopenia, and increased vascular permeability that can lead to life-threatening shock. In south Texas, near the border with Mexico, sporadic, locally acquired outbreaks of dengue fever have been reported previously; however, on the Texas side of the border, these outbreaks have not included recognized cases of locally acquired DHF in persons native to the area. In July 2005, a case of DHF was reported in a resident of Brownsville, Texas. In August 2005, health authorities in the neighboring state of Tamaulipas, Mexico, reported an ongoing dengue outbreak with 1,251 cases of dengue fever, including 223 cases (17.8%) of DHF. To characterize this dengue outbreak, the Texas Department of State Health Services (TDSHS), Mexican health authorities, and CDC conducted a clinical and epidemiologic investigation. This report summarizes the results of that investigation, which determined that the percentage of DHF cases associated with dengue fever outbreaks at the Texas-Tamaulipas border has increased. Health-care providers along the U.S. border with Mexico should be vigilant for DHF and familiar with its diagnosis and management to reduce the number of severe illnesses and deaths associated with outbreaks of dengue fever.
Marburg hemorrhagic fever (MHF) is a rare, viral hemorrhagic fever (VHF); the causative agent is an RNA virus in the family Filoviridae, and growing evidence demonstrates that fruit bats are the natural reservoir of Marburg virus (MARV). On January 9, 2008, an infectious disease physician notified the Colorado Department of Public Health and Environment (CDPHE) of a case of unexplained febrile illness requiring hospitalization in a woman who had returned from travel in Uganda. Testing of early convalescent serum demonstrated no evidence of infection with agents that cause tropical febrile illnesses, including VHF. Six months later, in July 2008, the patient requested repeat testing after she learned of the death from MHF of a Dutch tourist who had visited the same bat-roosting cave as the patient, the Python Cave in Queen Elizabeth National Park, Uganda. The convalescent serologic testing revealed evidence of prior infection with MARV, and MARV RNA was detected in the archived early convalescent serum. A public health investigation did not identify illness consistent with secondary MHF transmission among her contacts, and no serologic evidence of infection was detected among the six tested of her eight tour companions. The patient might have acquired MARV infection through exposure to bat secretions or excretions while visiting the Python Cave. Travelers should be aware of the risk for acquiring MHF in caves or mines inhabited by bats in endemic areas in sub-Saharan Africa. Health-care providers should consider VHF among travelers returning from endemic areas who experience unexplained febrile illness.
Papa, Anna; Tsergouli, Katerina; Çağlayık, Dilek Yağcı; Bino, Silvia; Como, Najada; Uyar, Yavuz; Korukluoglu, Gulay
Crimean-Congo hemorrhagic fever (CCHF) is a potentially severe disease caused by CCHF virus. As in other viral hemorrhagic fevers, it is considered that the course and outcome of the disease depend on the viral load and the balance among the immune response mediators, and that a fatal outcome is the result of a "cytokine storm." The level of 27 cytokines was measured in serum samples taken from 29 patients during the acute phase of the disease. Two cases were fatal. Among survivors, significant differences between severe and non-severe cases were observed in the levels of IP-10, and MCP-1, while the levels of IL-1b, IL-5, IL-6, IL-8, IL-9, IL-10, IL-15, IP-10, MCP-1, TNF-α, and RANTES differed significantly between fatal and non-fatal cases (P < 0.05). RANTES was negatively correlated with the outcome of the disease. A striking similarity with the cytokine patterns seen in Ebola virus disease was observed. A weak Th1 immune response was seen. The viral load was positively correlated with IL-10, IP-10, and MCP-1 levels, and negatively correlated with the ratio IL-12/IL-10. Especially IP-10 and MCP-1 were significantly associated with the viral load, the severity and outcome of the disease, and they could act as biomarkers and, probably, as potential targets for treatment strategies design.
Warfield, Kelly Lyn; Olinger, Gene Garrard
Infection with many emerging viruses, such as the hemorrhagic fever disease caused by the filoviruses, Marburg (MARV), and Ebola virus (EBOV), leaves the host with a short timeframe in which to mouse a protective immune response. In lethal cases, uncontrolled viral replication and virus-induced immune dysregulation are too severe to overcome, and mortality is generally associated with a lack of notable immune responses. Vaccination studies in animals have demonstrated an association of IgG and neutralizing antibody responses against the protective glycoprotein antigen with survival from lethal challenge. More recently, studies in animal models of filovirus hemorrhagic fever have established that induction of a strong filovirus-specific cytotoxic T lymphocyte (CTL) response can facilitate complete viral clearance. In this review, we describe assays used to discover CTL responses after vaccination or live filovirus infection in both animal models and human clinical trials. Unfortunately, little data regarding CTL responses have been collected from infected human survivors, primarily due to the low frequency of disease and the inability to perform these studies in the field. Advancements in assays and technologies may allow these studies to occur during future outbreaks. PMID:22253531
Lee, Andrew M; Rojek, Jillian M; Spiropoulou, Christina F; Gundersen, Anette T; Jin, Wei; Shaginian, Alex; York, Joanne; Nunberg, Jack H; Boger, Dale L; Oldstone, Michael B A; Kunz, Stefan
Viral hemorrhagic fevers caused by the arenaviruses Lassa virus in Africa and Machupo, Guanarito, Junin, and Sabia virus in South America are among the most devastating emerging human diseases with fatality rates of 15-35% and a limited antiviral therapeutic repertoire available. Here we used high throughput screening of synthetic combinatorial small molecule libraries to identify inhibitors of arenavirus infection using pseudotyped virion particles bearing the glycoproteins (GPs) of highly pathogenic arenaviruses. Our screening efforts resulted in the discovery of a series of novel small molecule inhibitors of viral entry that are highly active against both Old World and New World hemorrhagic arenaviruses. We observed potent inhibition of infection of human and primate cells with live hemorrhagic arenaviruses (IC(50)=500-800 nm). Investigations of the mechanism of action revealed that the candidate compounds efficiently block pH-dependent fusion by the arenavirus GPs (IC(50) of 200-350 nm). Although our lead compounds were potent against phylogenetically distant arenaviruses, they did not show activity against other enveloped viruses with class I viral fusion proteins, indicating specificity for arenavirus GP-mediated membrane fusion.
nasal bleeding, hematuria and gross gastrointestinal bleeding. K-- F -6- Up todate 41 HFRS cases have been serologically diagnosed in Greece. The...CCHF in Greece up until April 1987, was discussed and the conclusions drawn are reported. 4 pA. : -3- B. HORAGIC FEVER WITH RENAL SYNDROKE (HilS) B1...level. Two house rats (Rattus rattus) captured in a slaughter house in Thessaloniki were found to be seropositive (Table 2). _ _ I -9-. Todate
Ebihara, Hideki; Zivcec, Marko; Gardner, Donald; Falzarano, Darryl; LaCasse, Rachel; Rosenke, Rebecca; Long, Dan; Haddock, Elaine; Fischer, Elizabeth; Kawaoka, Yoshihiro; Feldmann, Heinz
Ebola hemorrhagic fever (EHF) is a severe viral infection for which no effective treatment or vaccine is currently available. While the nonhuman primate (NHP) model is used for final evaluation of experimental vaccines and therapeutic efficacy, rodent models have been widely used in ebolavirus research because of their convenience. However, the validity of rodent models has been questioned given their low predictive value for efficacy testing of vaccines and therapeutics, a result of the inconsistent manifestation of coagulopathy seen in EHF. Here, we describe a lethal Syrian hamster model of EHF using mouse-adapted Ebola virus. Infected hamsters displayed most clinical hallmarks of EHF, including severe coagulopathy and uncontrolled host immune responses. Thus, the hamster seems to be superior to the existing rodent models, offering a better tool for understanding the critical processes in pathogenesis and providing a new model for evaluating prophylactic and postexposure interventions prior to testing in NHPs.
Halide, Halmar; Ridd, Peter
A statistical model for predicting monthly Dengue Hemorrhagic Fever (DHF) cases from the city of Makassar is developed and tested. The model uses past and present DHF cases, climate and meteorological observations as inputs. These inputs are selected using a stepwise regression method to predict future DHF cases. The model is tested independently and its skill assessed using two skill measures. Using the selected variables as inputs, the model is capable of predicting a moderately-severe epidemic at lead times of up to six months. The most important input variable in the prediction is the present number of DHF cases followed by the relative humidity three to four months previously. A prediction 1-6 months in advance is sufficient to initiate various activities to combat DHF epidemic. The model is suitable for warning and easily becomes an operational tool due to its simplicity in data requirement and computational effort.
Ozsoy, Sait; Gokmen, Asude; Ozdemir, Mehtap; Akduman, Baris; Korkusuz, Irfan; Javan, Gulnaz T
Crimean-Congo Hemorrhagic Fever (CCHF) is an acute zoonotic infection caused by the CCHF virus. The viruses' activity peaks during April and May with a mortality rate of 3-30%. Transmission of the virus to human occurs through tick bites or exposure to infected animals' tissues or blood. The major at-risk group includes farmers living in endemic areas. Health-care workers are the second most affected group. Virus has shown up in a diverse geographic area which includes Middle East, Asia, Africa and Eastern Europe and is considered one of the most wide-spread tick borne infections. The most recent cases are from Iran and Turkey. This article represents autopsy results of four CCHF infected cases in 2011 and 2012, in Ankara, Turkey.
Kortepeter, Mark G; Bausch, Daniel G; Bray, Mike
The filoviruses Marburg and Ebola cause severe hemorrhagic fever (HF) in humans. Beginning with the 1967 Marburg outbreak, 30 epidemics, isolated cases, and accidental laboratory infections have been described in the medical literature. We reviewed those reports to determine the basic clinical and laboratory features of filoviral HF. The most detailed information was found in descriptions of patients treated in industrialized countries; except for the 2000 outbreak of Ebola Sudan HF in Uganda, reports of epidemics in central Africa provided little controlled or objective clinical data. Other than the case fatality rate, there were no clear differences in the features of the various filovirus infections. This compilation will be of value to medical workers responding to epidemics and to investigators attempting to develop animal models of filoviral HF. By identifying key unanswered questions and gaps in clinical data, it will help guide clinical research in future outbreaks.
Vallejos, D A; Ambrosio, A M; Feuillade, M R; Maiztegui, J I
Peripheral blood lymphocyte subpopulations were studied in 15 patients with Argentine Hemorrhagic Fever (AHF), during the acute period of the disease and in early convalescence. Anti-human Ig antibodies were used to identify B cells and monoclonal antibodies to assess T4 and T8 subsets. During the acute period of the disease, significant alterations were found in B, T4, and T8 lymphocytes (P less than .001), as well as in T4/T8 ratios (P less than .001). These abnormalities disappeared in early convalescence, around 30 days after the clinical onset. Diminished numbers of T4 lymphocytes are interpreted as relevant to the immunodepression that characterizes the acute phase of AHF.
Metin, Ozge; Teke, Turkan A; Gayretli Aydin, Zeynep G; Kaman, Ayse; Oz, Fatma N; Bayhan, Gulsum I; Tanir, Gonul
Brucellosis is a zoonotic disease caused by Brucella spp. that is transmitted to humans by the ingestion of unpasteurized milk and other dairy products from infected animals or through close contact with secretions. Crimean-Congo hemorrhagic fever (CCHF) is a tick-borne disease caused by a virus that is transmitted to humans by ixoid tick bites, contact with blood and tissue of infected animals or contact with infected humans. The symptoms of brucellosis are non-specific; it can mimic other diseases. In this paper, we present a case of brucellosis that was initially evaluated as CCHF. We emphasize that brucellosis should be considered in the differential diagnosis of CCHF, especially in endemic countries.
Yastrebov, V K; Yakimenko, V V
The main aspects of epidemiology and epizootology of the Omsk hemorrhagic fever (OHF) are analyzed. The discovery of the virus OHF in 1947, as well as the first outbreak of new diseases in the districts of the Omsk region, is described. Comprehensive work for decryption of the etiology of the OHF by specialists from the Omsk and Moscow Institutes is carried out. Long-term dynamics of activity of natural foci of OHF contains four periods of variable intensity of epidemic and epizootic processes. The main reservoir of the virus OHF in natural foci and the source of human infection is muskrat. Metaxenosis provides maintaining of the population of the virus, which is of some significance for hosts. Independent position of the virus OHF in the group of the Flaviviruses of mammals transmitted by ticks is established. There are two aenovariants of the virus OHF.
The Crimean-Congo hemorrhagic fever (CCHF) is a tick-borne viral disease that has been known for centuries. In the last years more frequent cases reflect the effects of climate change, globalization and the increasing encroachment of humans into previously unexploited areas. Humans acquire the infection by tick bites or through the slaughtering and processing of infected animals. The course of the disease can be severe and the average mortality reaches up to 30 %. It is transmissible from human to human and there is no causal treatment. Thus, CCHF meets the criteria for a highly contagious life-threatening disease. In the following current data on the virus, its vector, the distribution and transmission will be presented, as well as information on the diagnosis, the disease, the underlying pathophysiology and consequences in dealing with patients and deceased.
Mostafavi, Ehsan; Haghdoost, AliAkbar; Khakifirouz, Sahar; Chinikar, Sadegh
Crimean Congo hemorrhagic fever (CCHF) is a viral zoonotic disease. During 1999–2011, 871 human cases of CCHF were diagnosed in Iran. A history of serologic conversion for CCHF virus was seen in 58.7% of 2,447 sheep samples, 25.0% of 1,091 cattle samples and 24.8% of 987 goat samples from different parts of Iran. Spatial analysis showed that the main foci of this disease in humans during these years were in eastern Iran (P < 0.01) and the second most common foci were in northeastern and central Iran. Two livestock foci were detected in the northeastern northwestern Iran. On the basis of the results of this study, infection likely entered Iran from eastern and western neighboring countries. PMID:24166038
Negredo, Anabel; de la Calle-Prieto, Fernando; Palencia-Herrejón, Eduardo; Mora-Rillo, Marta; Astray-Mochales, Jenaro; Sánchez-Seco, María P; Bermejo Lopez, Esther; Menárguez, Javier; Fernández-Cruz, Ana; Sánchez-Artola, Beatriz; Keough-Delgado, Elena; Ramírez de Arellano, Eva; Lasala, Fátima; Milla, Jakob; Fraile, Jose L; Ordobás Gavín, Maria; Martinez de la Gándara, Amalia; López Perez, Lorenzo; Diaz-Diaz, Domingo; López-García, M Aurora; Delgado-Jimenez, Pilar; Martín-Quirós, Alejandro; Trigo, Elena; Figueira, Juan C; Manzanares, Jesús; Rodriguez-Baena, Elena; Garcia-Comas, Luis; Rodríguez-Fraga, Olaia; García-Arenzana, Nicolás; Fernández-Díaz, Maria V; Cornejo, Victor M; Emmerich, Petra; Schmidt-Chanasit, Jonas; Arribas, Jose R
Crimean-Congo hemorrhagic fever (CCHF) is a widely distributed, viral, tickborne disease. In Europe, cases have been reported only in the southeastern part of the continent. We report two autochthonous cases in Spain. The index patient acquired the disease through a tick bite in the province of Ávila - 300 km away from the province of Cáceres, where viral RNA from ticks was amplified in 2010. The second patient was a nurse who became infected while caring for the index patient. Both were infected with the African 3 lineage of this virus. (Funded by Red de Investigación Cooperativa en Enfermedades Tropicales [RICET] and Efficient Response to Highly Dangerous and Emerging Pathogens at EU [European Union] Level [EMERGE].).
Ebihara, Hideki; Zivcec, Marko; Gardner, Donald; Falzarano, Darryl; LaCasse, Rachel; Rosenke, Rebecca; Long, Dan; Haddock, Elaine; Fischer, Elizabeth; Kawaoka, Yoshihiro; Feldmann, Heinz
Ebola hemorrhagic fever (EHF) is a severe viral infection for which no effective treatment or vaccine is currently available. While the nonhuman primate (NHP) model is used for final evaluation of experimental vaccines and therapeutic efficacy, rodent models have been widely used in ebolavirus research because of their convenience. However, the validity of rodent models has been questioned given their low predictive value for efficacy testing of vaccines and therapeutics, a result of the inconsistent manifestation of coagulopathy seen in EHF. Here, we describe a lethal Syrian hamster model of EHF using mouse-adapted Ebola virus. Infected hamsters displayed most clinical hallmarks of EHF, including severe coagulopathy and uncontrolled host immune responses. Thus, the hamster seems to be superior to the existing rodent models, offering a better tool for understanding the critical processes in pathogenesis and providing a new model for evaluating prophylactic and postexposure interventions prior to testing in NHPs. PMID:23045629
Geisbert, Thomas W.; Hensley, Lisa E.; Larsen, Tom; Young, Howard A.; Reed, Douglas S.; Geisbert, Joan B.; Scott, Dana P.; Kagan, Elliott; Jahrling, Peter B.; Davis, Kelly J.
Ebola virus (EBOV) infection causes a severe and fatal hemorrhagic disease that in many ways appears to be similar in humans and nonhuman primates; however, little is known about the development of EBOV hemorrhagic fever. In the present study, 21 cynomolgus monkeys were experimentally infected with EBOV and examined sequentially over a 6-day period to investigate the pathological events of EBOV infection that lead to death. Importantly, dendritic cells in lymphoid tissues were identified as early and sustained targets of EBOV, implicating their important role in the immunosuppression characteristic of EBOV infections. Bystander lymphocyte apoptosis, previously described in end-stage tissues, occurred early in the disease-course in intravascular and extravascular locations. Of note, apoptosis and loss of NK cells was a prominent finding, suggesting the importance of innate immunity in determining the fate of the host. Analysis of peripheral blood mononuclear cell gene expression showed temporal increases in tumor necrosis factor-related apoptosis-inducing ligand and Fas transcripts, revealing a possible mechanism for the observed bystander apoptosis, while up-regulation of NAIP and cIAP2 mRNA suggest that EBOV has evolved additional mechanisms to resist host defenses by inducing protective transcripts in cells that it infects. The sequence of pathogenetic events identified in this study should provide new targets for rational prophylactic and chemotherapeutic interventions. PMID:14633608
Kaya, Selçuk; Yilmaz, Gurdal; Ertunç, Barış; Koksal, Iftihar
Crimean Congo Hemorrhagic Fever (CCHF) is a potentially fatal tick-borne viral disease, the course of which may accompanied by various clinical findings. We describe a picture of non-suppurative parotitis developing in association with CCHF virus. A 48-year-old patient presenting to our hospital with lethargy, hemorrhage and pain and swelling below the left ear was diagnosed with CCHF through IgM antibody and polymerase chain reaction positivity in serum investigated for CCHF virus. A picture of non-suppurative parotitis developed on the 3rd day of admission. Other causes of parotitis were excluded with the help of serological tests, and the case was regarded as one of CCHF-associated parotitis. The patient was put on adjuvant therapy, an improvement in clinical findings was observed and he was discharged in a healthy condition on the 8th day. Ours is the first case in the literature of parotitis seen during CCHF. CCHF should be considered in differential diagnosis in addition to other frequently encountered viral agents in patients from endemic regions presenting with a picture of non-suppurative parotitis. Copyright © 2011 Elsevier B.V. All rights reserved.
virus isolations we were able to show that five hazardous haemorrhagic fever viruses : Ebola, Marburg, Lassa , Congo-Crimean and Rift-Valley- Fever , were...JOHtJSON & WILLIAMS :unpublished observations 9-IVA’JOFF & al:Hemorragic fever in GABON.I.Incidence of Lassa ,Ebola and Marburg virus in Haut Ogout...AD ...... EPIDEMIOLOGY AND EPIZOOTIOLOGICAL INVESTIGATIONS OF HEMORRHAGIC FEVER VIRUSES IN THE CENTRAL AFRICAN REPUBLIC Final Report 000 N 0A. J
Mahmutovic, Selma; Clark, Lars; Levis, Silvana C; Briggiler, Ana M; Enria, Delia A; Harrison, Stephen C; Abraham, Jonathan
In the Western hemisphere, at least five mammarenaviruses cause human viral hemorrhagic fevers with high case fatality rates. Junín virus (JUNV) is the only hemorrhagic fever virus for which transfusion of survivor immune plasma that contains neutralizing antibodies ("passive immunity") is an established treatment. Here, we report the structure of the JUNV surface glycoprotein receptor-binding subunit (GP1) bound to a neutralizing monoclonal antibody. The antibody engages the GP1 site that binds transferrin receptor 1 (TfR1)-the host cell surface receptor for all New World hemorrhagic fever mammarenaviruses-and mimics an important receptor contact. We show that survivor immune plasma contains antibodies that bind the same epitope. We propose that viral receptor-binding site accessibility explains the success of passive immunity against JUNV and that this functionally conserved epitope is a potential target for therapeutics and vaccines to limit infection by all New World hemorrhagic fever mammarenaviruses.
Mahmutovic, Selma; Clark, Lars; Levis, Silvana C.; Briggiler, Ana M.; Enria, Delia A.; Harrison, Stephen C.; Abraham, Jonathan
SUMMARY In the Western hemisphere, at least five mammarenaviruses cause human viral hemorrhagic fevers with high case fatality rates. Junín virus (JUNV) is the only hemorrhagic fever virus for which transfusion of survivor immune plasma that contains neutralizing antibodies (‘passive immunity’) is an established treatment. Here, we report the structure of the JUNV surface glycoprotein receptor-binding subunit (GP1) bound to a neutralizing monoclonal antibody. The antibody engages the GP1 site that binds transferrin receptor 1 (TfR1) – the host cell surface receptor for all New World hemorrhagic fever mammarenaviruses - and mimics an important receptor contact. We show that survivor immune plasma contains antibodies that bind the same epitope. We propose that viral receptor-binding site accessibility explains the success of passive immunity against JUNV and that this functionally conserved epitope is a potential target for therapeutics and vaccines to limit infection by all New World hemorrhagic fever mammarenaviruses. PMID:26651946
Villamor, E; Villar, L A; Lozano, A; Herrera, V M; Herrán, O F
Vitamin D could modulate pathways leading to dengue hemorrhagic fever/dengue shock syndrome (DHF/DSS). We examined the associations of serum total 25-hydroxy vitamin D [25(OH)D] and vitamin D binding protein (VDBP) concentrations in patients with uncomplicated dengue fever (DF) with risk of progression to DHF/DSS. In a case-control study nested in a cohort of DF patients who were followed during the acute episode in Bucaramanga, Colombia, we compared 25(OH)D and VDBP at onset of fever between 110 cases who progressed to DHF/DSS and 235 DF controls who did not progress. 25(OH)D concentrations were also compared between the acute sample and a sample collected >1 year post-convalescence in a subgroup. Compared with 25(OH)D ⩾75 nmol/l, adjusted odds ratios (95% CI) for progression were 0·44 (0·22-0·88) and 0·13 (0·02-1·05) for 50 to 75 nmol/l (vitamin D insufficiency) and <50 nmol/l (vitamin D deficiency), respectively (P, trend = 0·003). Mean 25(OH)D concentrations were much lower post-convalescence compared with the acute episode, regardless of case status. Compared with controls, mean VDBP was non-significantly lower in cases. We conclude that low serum 25(OH)D concentrations in DF patients predict decreased odds of progression to DHF/DSS.
Lauck, Michael; Alkhovsky, Sergey V.; Bào, Yīmíng; Bailey, Adam L.; Shevtsova, Zinaida V.; Shchetinin, Alexey M.; Vishnevskaya, Tatyana V.; Lackemeyer, Matthew G.; Postnikova, Elena; Mazur, Steven; Wada, Jiro; Radoshitzky, Sheli R.; Friedrich, Thomas C.; Lapin, Boris A.; Deriabin, Petr G.; Jahrling, Peter B.; Goldberg, Tony L.; O'Connor, David H.
Simian hemorrhagic fever (SHF) is lethal for macaques. Based on clinical presentation and serological diagnosis, all reported SHF outbreaks were thought to be caused by different strains of the same virus, simian hemorrhagic fever virus (SHFV; Arteriviridae). Here we show that the SHF outbreaks in Sukhumi in 1964 and in Alamogordo in 1989 were caused not by SHFV but by two novel divergent arteriviruses. Our results indicate that multiple divergent simian arteriviruses can cause SHF. PMID:25972539
ecology of tick-borne Crimean-Congo hemorrhagic fever ( CCHF ) virus in the West African savannah was devoted to integration and analysis of results, and...continued surveillance at field sites. These observations of tick and virus activity in northern Senegal produced numerous new isolates of CCHF virus...epidemiology of Crimean-Congo hemorrhagic fever ( CCHF ) in West Africa, a widespread, life-threatening, tick-borne, viral zoonosis, remains poorly understood
of Specific Trangfer Factor Therapy on EUF 2130 Wu Zhen-ou Clinical Features of EHF in People’s Republic of China 3:00 Wang X.H The Complicatione of...Chinese Academy of Preventive Medicine, loo Ying Xing fie, Xuan Wu Qu, Beijing 100052 Hantaan (HFRS) virus, the etiologic agent of Hemorrhagic Fever...PATHOGENESIS OF EPIDEMIC HEMORRHAGIC FEVER Wang Wenyu, Ma Ying-ji, Tian Jing-Xian, Li Xian-zong Wu chang-you Dept Immunol., Institute of Basic Medical
Bitterman, Roni; Oren, Ilana; Geffen, Yuval; Sprecher, Hannah; Schwartz, Eli; Neuberger, Ami
We present a case of progressive disseminated histoplasmosis in an immunocompetent traveler. Histoplasmosis was acquired in South America; its manifestations included prolonged fever, splinter hemorrhages, erythema multiforme, arthritis, and mediastinal lymphadenopathy. To the best of our knowledge no splinter hemorrhages had previously been reported in a patient with histoplasmosis.
Gear, J H
In considering the diagnosis of a patient admitted to the Johannesburg Hospital, suffering from an illness characterized by high fever and complicated by a hemorrhagic state from which he died, a list of possible causes of his illness was drawn up. This list included the arthropodborne viral infections prevalent in southern Africa, namely, chikungunya fever, Sindbis fever, West Nile fever, yellow fever, and Rift Valley fever; viral infections associated with rodents, such as Lassa fever; the viral infection associated with monkeys, Marburg virus disease; the rickettsial infections; tick-bite fever (the variety of spotted fever of tick typhus occurring in southern Africa) and Q fever; the bacterial infections, especially the coccal infections, plague septicemia, and meningococcal, staphylococcal, and streptococcal septicemia; and the blood protozoal infections malaria and trypanosomiasis. In addition, rubella, Gasser's syndrome, Henoch-Schönlein purpura, and viperine snakebite were briefly described in this review. All of these conditions may be complicated by the development of a hemorrhagic state. The circulation of large numbers of infecting organisms, by they viruses, rickettsiae, bacteria, or protozoa, may initiate the coagulation cascade, the formation of fibrin and its deposition in the finer blood vessels, and the aggregation and entanglement of platelets resulting in marked thrombocytopenia and bleeding. This bleeding tendency is greatly aggravated when the infection specifically involves the parenchymal cells of the liver; such a condition results in defective formation of coagulation factors such as prothrombin. The proper care of patients in whom a hemorrhagic state has developed requires urgent and accurate diagnosis followed by immediate and appropriate treatment that will combat the infection and alleviate the hemorrhagic state and liver disorder. If the hemorrhagic state is due to one of the dangerous infectious fevers, adequate protection of the
Hong, Joo Eun; Hong, Kee-Jong; Choi, Woo Young; Lee, Won-Ja; Choi, Yeon Hwa; Jeong, Chung-Hyeon; Cho, Kwang-Il
Current Ebola virus outbreak in West Africa already reached the total number of 1,323 including 729 deaths by July 31st. the fatality is around 55% in the southeastern area of Guinea, Sierra Leone, Liberia, and Nigeria. The number of patients with Ebola Hemorrhagic Fever (EHF) was continuously increasing even though the any effective therapeutics or vaccines has not been developed yet. The Ebola virus in Guinea showed 98% homology with Zaire Ebola Virus. Study of the pathogenesis of Ebola virus infection and assess of the various candidates of vaccine have been tried for a long time, especially in United States and some European countries. Even though the attenuated live vaccine and DNA vaccine containing Ebola viral genes were tested and showed efficacy in chimpanzees, those candidates still need clinical tests requiring much longer time than the preclinical development to be approved for the practical treatment. It can be expected to eradicate Ebola virus by a safe and efficient vaccine development similar to the case of smallpox virus which was extinguished from the world by the variola vaccine.
Messina, Jane P.; Pigott, David M.; Golding, Nick; Duda, Kirsten A.; Brownstein, John S.; Weiss, Daniel J.; Gibson, Harry; Robinson, Timothy P.; Gilbert, Marius; William Wint, G. R.; Nuttall, Patricia A.; Gething, Peter W.; Myers, Monica F.; George, Dylan B.; Hay, Simon I.
Background Crimean-Congo hemorrhagic fever (CCHF) is a tick-borne infection caused by a virus (CCHFV) from the Bunyaviridae family. Domestic and wild vertebrates are asymptomatic reservoirs for the virus, putting animal handlers, slaughter-house workers and agricultural labourers at highest risk in endemic areas, with secondary transmission possible through contact with infected blood and other bodily fluids. Human infection is characterized by severe symptoms that often result in death. While it is known that CCHFV transmission is limited to Africa, Asia and Europe, definitive global extents and risk patterns within these limits have not been well described. Methods We used an exhaustive database of human CCHF occurrence records and a niche modeling framework to map the global distribution of risk for human CCHF occurrence. Results A greater proportion of shrub or grass land cover was the most important contributor to our model, which predicts highest levels of risk around the Black Sea, Turkey, and some parts of central Asia. Sub-Saharan Africa shows more focalized areas of risk throughout the Sahel and the Cape region. Conclusions These new risk maps provide a valuable starting point for understanding the zoonotic niche of CCHF, its extent and the risk it poses to humans. PMID:26142451
Aslani, Dalileh; Salehi-Vaziri, Mostafa; Baniasadi, Vahid; Jalali, Tahmineh; Azad-Manjiri, Sanam; Mohammadi, Tahereh; Khakifirouz, Sahar; Fazlalipour, Mehdi
Crimean-Congo hemorrhagic fever (CCHF) is a viral zoonotic disease which is endemic in Iran. The etiological agent of CCHF is an RNA virus belonging to the genus Nairovirus of the family Bunyaviridae. CCHF virus (CCHFV) can be transmitted to humans through bites from infected ticks and direct contact with infected blood or tissues. Although the disease has been observed in different age groups, the rate of disease is lower in children and elderly. This study was designed to characterize CCHFV-infected children in Iran. Between 2000 and 2016, a total of 908 CCHF suspected cases (in children less than 19 years old) were evaluated for CCHFV infection by CCHF IgM ELISA and RT-PCR. CCHFV infection was observed in 161 (17.73%) of subjects. Most CCHF positive children were male (70.8%) and >15 years of age (65.8%). Contact with livestock was the main risk factor (35.4%). Sistan and Baluchestan provinces had the highest frequency within the infected cohort (68.3%). The overall mortality rate was 11.8%. This study also revealed a significant reduction in CCHF-fatality rates in Iranian children when compared to earlier studies in Iran. Having contact with livestock was the major risk factor and CCHF was more common in male children of an older age.
Fang, Liqun; Yan, Lei; Liang, Song; de Vlas, Sake J; Feng, Dan; Han, Xiaona; Zhao, Wenjuan; Xu, Bing; Bian, Ling; Yang, Hong; Gong, Peng; Richardus, Jan Hendrik; Cao, Wuchun
Background Hemorrhagic fever with renal syndrome (HFRS) is endemic in many provinces with high incidence in mainland China, although integrated intervention measures including rodent control, environment management and vaccination have been implemented for over ten years. In this study, we conducted a geographic information system (GIS)-based spatial analysis on distribution of HFRS cases for the whole country with an objective to inform priority areas for public health planning and resource allocation. Methods Annualized average incidence at a county level was calculated using HFRS cases reported during 1994–1998 in mainland China. GIS-based spatial analyses were conducted to detect spatial autocorrelation and clusters of HFRS incidence at the county level throughout the country. Results Spatial distribution of HFRS cases in mainland China from 1994 to 1998 was mapped at county level in the aspects of crude incidence, excess hazard and spatial smoothed incidence. The spatial distribution of HFRS cases was nonrandom and clustered with a Moran's I = 0.5044 (p = 0.001). Spatial cluster analyses suggested that 26 and 39 areas were at increased risks of HFRS (p < 0.01) with maximum spatial cluster sizes of ≤ 20% and ≤ 10% of the total population, respectively. Conclusion The application of GIS, together with spatial statistical techniques, provide a means to quantify explicit HFRS risks and to further identify environmental factors responsible for the increasing disease risks. We demonstrate a new perspective of integrating such spatial analysis tools into the epidemiologic study and risk assessment of HFRS. PMID:16638156
Papa, Anna; Tsergouli, Katerina; Tsioka, Katerina; Mirazimi, Ali
Crimean-Congo hemorrhagic fever virus (CCHFV) is transmitted to humans by bite of infected ticks or by direct contact with blood or tissues of viremic patients or animals. It causes to humans a severe disease with fatality up to 30%. The current knowledge about the vector-host-CCHFV interactions is very limited due to the high-level containment required for CCHFV studies. Among ticks, Hyalomma spp. are considered the most competent virus vectors. CCHFV evades the tick immune response, and following its replication in the lining of the tick's midgut, it is disseminated by the hemolymph in the salivary glands and reproductive organs. The introduction of salivary gland secretions into the host cells is the major route via which CCHFV enters the host. Following an initial amplification at the site of inoculation, the virus is spread to the target organs. Apoptosis is induced via both intrinsic and extrinsic pathways. Genetic factors and immune status of the host may affect the release of cytokines which play a major role in disease progression and outcome. It is expected that the use of new technology of metabolomics, transcriptomics and proteomics will lead to improved understanding of CCHFV-host interactions and identify potential targets for blocking the CCHFV transmission.
Papa, Anna; Tsergouli, Katerina; Tsioka, Katerina; Mirazimi, Ali
Crimean-Congo hemorrhagic fever virus (CCHFV) is transmitted to humans by bite of infected ticks or by direct contact with blood or tissues of viremic patients or animals. It causes to humans a severe disease with fatality up to 30%. The current knowledge about the vector-host-CCHFV interactions is very limited due to the high-level containment required for CCHFV studies. Among ticks, Hyalomma spp. are considered the most competent virus vectors. CCHFV evades the tick immune response, and following its replication in the lining of the tick's midgut, it is disseminated by the hemolymph in the salivary glands and reproductive organs. The introduction of salivary gland secretions into the host cells is the major route via which CCHFV enters the host. Following an initial amplification at the site of inoculation, the virus is spread to the target organs. Apoptosis is induced via both intrinsic and extrinsic pathways. Genetic factors and immune status of the host may affect the release of cytokines which play a major role in disease progression and outcome. It is expected that the use of new technology of metabolomics, transcriptomics and proteomics will lead to improved understanding of CCHFV-host interactions and identify potential targets for blocking the CCHFV transmission. PMID:28603698
Ergönül, Önder; Şeref, Ceren; Eren, Şebnem; Çelikbaş, Aysel; Baykam, Nurcan; Dokuzoğuz, Başak; Gönen, Mehmet; Can, Füsun
We described the predictive role of cytokines in fatality of Crimean Congo Hemorrhagic Fever Virus (CCHFV) infection by using daily clinical sera samples. Consequent serum samples of the selected patients in different severity groups and healthy controls were examined by using human cytokine 17-plex assay. We included 12 (23%) mild, 30 (58%) moderate, 10 (19%) severe patients, and 10 healthy volunteers. The mean age of the patients was 52 (sd 15), 52% were female. Forty-six patients (88%) received ribavirin. During disease course, the median levels of IL-6, IL-8, IL-10, IL-10/12, IFN-γ, MCP-1, and MIP-1b were found to be significantly higher among CCHF patients than the healthy controls. Within the first 5 days after onset of disease, among the fatal cases, the median levels of IL-6 and IL-8 were found to be significantly higher than the survived ones (Fig. 3), and MCP-1 was elevated among fatal cases, but statistical significance was not detected. In receiver operating characteristic (ROC) analysis, IL-8 (92%), IL-6 (92%), MCP-1 (79%) were found to be the most significant cytokines in predicting the fatality rates in the early period of the disease (5 days). IL-6 and IL-8 can predict the poor outcome, within the first 5 days of disease course. Elevated IL-6 and IL-8 levels within first 5 days could be used as prognostic markers. © 2017 Wiley Periodicals, Inc.
explaining the progressive lym- phopenia observed over the course of illness (Geisbert et al., 2000; Reed et al., 2004). Blood samples from fatally infected ...30 December 2004; accepted 14 February 2005 Abstract Ebola hemorrhagic fever is a severe viral infection characterized by fever, shock and coagulation... Infected macrophages produce proinflammatory cytokines, chemokines and tissue factor, attracting additional target cells and inducing vasodilatation
Resman Rus, Katarina; Fajs, Luka; Korva, Miša; Avšič-Županc, Tatjana
Hemorrhagic fever with renal syndrome (HFRS) and Crimean-Congo hemorrhagic fever (CCHF) are common representatives of viral hemorrhagic fevers still often neglected in some parts of the world. Infection with Dobrava or Puumala virus (HFRS) and Crimean-Congo hemorrhagic fever virus (CCHFV) can result in a mild, nonspecific febrile illness or as a severe disease with hemorrhaging and high fatality rate. An important factor in optimizing survival rate in patients with VHF is instant recognition of the severe form of the disease for which significant biomarkers need to be elucidated. To determine the prognostic value of High Mobility Group Box 1 (HMGB1) as a biomarker for disease severity, we tested acute serum samples of patients with HFRS or CCHF. Our results showed that HMGB1 levels are increased in patients with CCHFV, DOBV or PUUV infection. Above that, concentration of HMGB1 is higher in patients with severe disease progression when compared to the mild clinical course of the disease. Our results indicate that HMGB1 could be a useful prognostic biomarker for disease severity in PUUV and CCHFV infection, where the difference between the mild and severe patients group was highly significant. Even in patients with severe DOBV infection concentrations of HMGB1 were 2.8–times higher than in the mild group, but the difference was not statistically significant. Our results indicated HMGB1 as a potential biomarker for severe hemorrhagic fevers. PMID:27348219
Guo, Xiling; Zhang, Li; Zhang, Wenshuai; Chi, Ying; Zeng, Xiaoyan; Li, Xian; Qi, Xian; Jin, Qiu; Zhang, Xiao; Huang, Mingming; Wang, Hua; Chen, Yin; Bao, Changjun; Hu, Jianli; Liang, Shuyi; Bao, Lin; Wu, Tao
Severe fever with thrombocytopenia syndrome virus (SFTSV), a newly discovered member of the Bunyaviridae family, is the causative agent of an emerging hemorrhagic fever, SFTS, in China. Currently, there are no vaccines or effective therapies against SFTS. In this study, a combinatorial human antibody library was constructed from the peripheral lymphocytes of 5 patients who had recovered from SFTS. The library was screened against purified virions for the production of single-chain variable-region fragments (ScFv). Of the 6 positive clones, one clone (monoclonal antibody [MAb] 4-5) showed neutralizing activity against SFTSV infection in Vero cells. MAb 4-5 was found to effectively neutralize all of the clinical isolates of SFTSV tested, which were isolated from patients in China from 2010 to 2012. MAb 4-5 was found to bind a linear epitope in the ectodomain of glycoprotein Gn. Its neutralizing activity is attributed to blockage of the interactions between the Gn protein and the cellular receptor, indicating that inhibition of virus-cell attachment is its main mechanism. These data suggest that MAb 4-5 can be used as a promising candidate molecule for immunotherapy against SFTSV infection. PMID:23863504
Tanaka, T; Kamiyama, T; Daikoku, T; Takahashi, K; Nomura, N; Kurokawa, M; Shiraki, K
Influenza virus infection induces the production of various cytokines, which play important roles in the pathogenesis of infection. Among the cytokines induced by influenza, tumor necrosis factor α (TNF-α) production has been correlated with the severity of lung lesions. We investigated the effects of T-705 (Favipiravir, 6-fluoro-3-hydroxy-2-pyrazinecarboxamide) on cytokine production due to influenza virus infection in vitro and in vivo, compared with oseltamivir or GS 4071, an active form of oseltamivir. TNF-α production in mouse macrophage-derived P388D1 cells infected with the influenza virus was lower following treatment with T-705 at concentrations of 0.3 to 100 µg/ml than treatment with GS 4071 at the same concentrations. The effect of treatment with T-705 on the cytokine production induced by the influenza virus infection was investigated in mouse influenza virus infection model. At 48 h post-infection (p.i.) T-705 significantly suppressed the viral load in the lungs and TNF-α production in the airways of infected mice even when viral loads were high. Furthermore, T-705 suppressed only TNF-α production from the early phase of infection. In this study, T-705 showed the antiviral activity of reducing pulmonary viral load compared with oseltamivir, thereby suppressing the TNF-α production. This feature of T-705 is benefit against severe influenza infection.
unlimited. Abstract 32 33 Crimean-Congo hemorrhagic fever virus (CCHFV) is a tick-borne virus capable of causing a 34 severe hemorrhagic fever...the 50 glycoprotein genes of CCHFV elicits protective immunity against CCHFV. 51 52 Author summary 53 Crimean-Congo Hemorrhagic Fever Virus ...CCHFV) is a tick-borne virus capable of causing 54 lethal human disease against which there are currently no approved vaccines. In this study, we 55 TR
Telmadarraiy, Zakkyeh; Chinikar, Sadegh; Vatandoost, Hassan; Faghihi, Faezeh; Hosseini-Chegeni, Asadollah
Background: Ticks are important vectors and reservoirs of Crimean Congo Hemorrhagic Fever (CCHF) virus. Human beings may be infected whenever the normal life cycle of the infected ticks on non-human vertebrate hosts is interrupted by the undesirable presence of humans in the cycle. A total of 26 species of Argasid and Ixodid ticks have been recorded in Iran; including nine Hyalomma, two Rhipicephalus, two Dermacentor, five Haemaphysalis, two Boophilus, one Ixodes and two Argas as well as three Ornithodoros species as blood sucking ectoparasites of livestock and poultries. The present paper reviews tick vectors of CCHF virus in Iran, focusing on the role of ticks in different provinces of Iran using reverse transcription polymerase chain reaction (RT-PCR) assay. Methods: During ten years study, 1054 tick specimens; including two species of Argasidae and 17 species of Ixodidae were examined for their infection to CCHF virus genome. The output of all studies as well as related publications were discussed in the current paper. Results: The results show that Rhipicephalus sanguineus, Hyalomma marginatum, H. anatolicum, H. asiaticum and H. dromedarii were known as the most frequent species which were positive for CCHF virus. Conclusion: The status of ticks which were positive for CCHF virus revealed that unlike the most common idea that Hyalomma species are the most important vectors of CCHF virus, other ticks including Rhipicephalus, Haemaphysalis and Dermacentor can be reservoir of this virus; thus, considering geographical distribution, type of host and environmental conditions, different tick control measurements should be carried out in areas with high incidence of CCHF disease. PMID:26623426
Demirpençe, Özlem; Doğan, Halef Okan; Erşan, Serpil; Şahin, Mehtap; Şahin, Hasan; Bakır, Mehmet
Levels of presepsin (a soluble cluster of differentiation subtype 14 [CD14]) are thought to increase in cases of bacterial infection. CD14 has also been found to play a role in the pathogenesis of various viral diseases. Crimean-Congo hemorrhagic fever (CCHF) is a zoonotic arboviral infection. Our study focuses on presepsin levels as a biomarker for CCHF. Serum presepsin levels in a CCHF group (n = 59) and control group (n = 28) were compared. Patients with CCHF were classified according to severity grading score as having mild, moderate, or severe infection and were allocated to corresponding subgroups (groups 1, 2, and 3, respectively). Presepsin levels were measured in serum samples by using a commercial enzyme-linked immunosorbent assay kit. The mean presepsin levels in the CCHF group as a whole and the healthy group were found to be significantly different (1,499.46 ± 411.96 pg/ml and 430.68 ± 61.21 pg/ml, respectively). The mean presepsin levels of the CCHF subgroups (1, 2 and 3) and the healthy group were also found to be significantly different (1,204.53 ± 371.18, 1,464.21 ± 338.37, 2,007.36 ± 82.18, and 430.68 ± 61.21 pg/ml, respectively) (p < 0.05). We also found that as the severity of the disease increased, the presepsin level also increased. We postulate that the presepsin levels could be used as a supportive biomarker for diagnosis and follow-up of the disease.
vertebrates and/or invertebrates as reservoirs of Haemorrhagic fever viruses particularly Marburg virus . The final results of this particular investigation...Research work done in Kenya has shown that three haemorrhagic fever viruses occur in the country. These are Rift Valley Fever Virus (RVF), Crimean...members for serology and or virus isolation. 2. Virus Isolation Attempts in VRC Haemorrhagic fever viruses are hazardous to culture and handle in
Ajelli, Marco; Merler, Stefano
Marburg hemorrhagic fever is rare yet among the most severe diseases affecting humans, with case fatality ratio even higher than 80%. By analyzing the largest documented Marburg hemorrhagic fever epidemic, which occurred in Angola in 2005 and caused 329 deaths, and data on viral load over time in non-human primates, we make an assessment of transmissibility and severity of the disease. We also give insight into the control of new Marburg hemorrhagic fever epidemics to inform appropriate health responses. We estimated the distribution of the generation time to have mean 9 days (95%CI: 8.2-10 days) and standard deviation 5.4 days (95%CI: 3.9-8.6 days), and the basic reproduction number to be R(0) = 1.59 (95%CI: 1.53-1.66). Model simulations suggest that a timely isolation of cases, starting no later than 2-3 days after symptoms onset, is sufficient to contain an outbreak. Our analysis reveals that Marburg hemorrhagic fever is characterized by a relatively small reproduction number and by a relatively long generation time. Such factors, along with the extremely high severity and fatality, support the rare occurrence of large epidemics in human populations. Our results also support the effectiveness of social distancing measures--case isolation in particular--to contain or at least to mitigate an emerging outbreak. This work represents an advance in the knowledge required to manage a potential Marburg hemorrhagic fever epidemic.
El-Bahnasawy, Mamdouh M; Megahed, Laila Abdel-Mawla; Saleh, Halla Ahmed Abdullah; Abdelfattah, Magda Abdelhamid; Morsy, Tosson Aly
Viral hemorrhagic fevers (VHFs) refer to a group of illnesses caused by several distinct families of viruses. In general, the term "viral hemorrhagic fever" is used to describe a severe multisystem syndrome (multisystem in that multiple organ systems in the bpdy are affected). Characteristically, the overall vascular system is damaged, and the body's ability to regulate itself is impaired. These symptoms are often accompanied by hemorrhage (bleeding); however, the bleeding is it rarely life-threatening. While some types of hemorrhagic fever viruses can cause relatively mild illnesses, many of these viruses cause severe, life-threatening disease. The selected disaster diseases for this study included: 1-Crimean-Congo hemorrhagic Fever, 2-Dengue Fever, 3-Ebola Fever, 4-Hem-orrhagic Fever with renal syndrome (HFRS), 5-Hantavirus Pulmonary Syndrome, 6-Lassa Fever, 7-Marburg Fever, 8-Rift Valley Fever and 9-Yellow Fever. The educational training program was given over ten sessions to a group of Staff Nurses. The results showed that the program succeeded in enhancing nurse' knowledge, awareness, responsibility, and obligations toward patients with the Viral Hemorrhagic Fevers The results showed a significant impact of training sessions illuminated in the follow-up test on the knowledge score of nurses in all types of diseases except for the Congo hemorrhagic fever, while, statistical significance varied in some diseases in the study when it comes to the comparison between pretest and post-test. All results confirmed on the positive impact of the training program in enhancing the knowledge of nurses toward VHFs patients and their relevant. There was a significant positive impact of the training sessions on changing the attitude of nurses toward patients with VHFs. This result was confirmed on the collective level since the total scores on tests revealed significant positive impact of the study on changing the attitude of nurses toward relevant patients. The relationship
Smirnova, S E; Mamaev, V I; Nepesova, N M; Filipenko, P I; Kalieva, V Ia
Final results of the virological and serological investigations of the circulation of the Crimean hemorrhagic fever virus in the Turkmenian SSR carried out in 1968-1976 are presented in this report. In the examination of 2294 blood serum samples of human beings complement binding antibodies against the Crimean hemorrhagic fever were revealed in 0.4% of cases. It was revealed that five species of ixodes ticks could he infected with this virus; for the first time its strains were also isolated from the Hyalomma dromedarii ticks. Isolation of the Crimean hemorrhagic fever virus from ticks and determination of the precipitating antibodies against this virus in agricultural animals--from 6.2 to 11.1%--in all the regions of the republic pointed out that the natural nidi zones were widespread at the territory of the Turkmenian SSR, and that it was necessary to carry out further study of the given focus.
Wamala, Joseph F; Lukwago, Luswa; Malimbo, Mugagga; Nguku, Patrick; Yoti, Zabulon; Musenero, Monica; Amone, Jackson; Mbabazi, William; Nanyunja, Miriam; Zaramba, Sam; Opio, Alex; Lutwama, Julius J; Talisuna, Ambrose O; Okware, Sam I
During August 2007-February 2008, the novel Bundibugyo ebolavirus species was identified during an outbreak of Ebola viral hemorrhagic fever in Bundibugyo district, western Uganda. To characterize the outbreak as a requisite for determining response, we instituted a case-series investigation. We identified 192 suspected cases, of which 42 (22%) were laboratory positive for the novel species; 74 (38%) were probable, and 77 (40%) were negative. Laboratory confirmation lagged behind outbreak verification by 3 months. Bundibugyo ebolavirus was less fatal (case-fatality rate 34%) than Ebola viruses that had caused previous outbreaks in the region, and most transmission was associated with handling of dead persons without appropriate protection (adjusted odds ratio 3.83, 95% confidence interval 1.78-8.23). Our study highlights the need for maintaining a high index of suspicion for viral hemorrhagic fevers among healthcare workers, building local capacity for laboratory confirmation of viral hemorrhagic fevers, and institutionalizing standard precautions.
Westover, Jonna B; Sefing, Eric J; Bailey, Kevin W; Van Wettere, Arnaud J; Jung, Kie-Hoon; Dagley, Ashley; Wandersee, Luci; Downs, Brittney; Smee, Donald F; Furuta, Yousuke; Bray, Mike; Gowen, Brian B
Favipiravir is approved in Japan to treat novel or re-emerging influenza viruses, and is active against a broad spectrum of RNA viruses, including Ebola. Ribavirin is the only other licensed drug with activity against multiple RNA viruses. Recent studies show that ribavirin and favipiravir act synergistically to inhibit bunyavirus infections in cultured cells and laboratory mice, likely due to their different mechanisms of action. Convalescent immune globulin is the only approved treatment for Argentine hemorrhagic fever caused by the rodent-borne Junin arenavirus. We previously reported that favipiravir is highly effective in a number of small animal models of Argentine hemorrhagic fever. We now report that addition of low dose of ribavirin synergistically potentiates the activity of favipiravir against Junin virus infection of guinea pigs and another arenavirus, Pichinde virus infection of hamsters. This suggests that the efficacy of favipiravir against hemorrhagic fever viruses can be further enhanced through the addition of low-dose ribavirin.
Westover, Jonna B.; Sefing, Eric J.; Bailey, Kevin W.; Van Wettere, Arnaud J.; Jung, Kie-Hoon; Dagley, Ashley; Wandersee, Luci; Downs, Brittney; Smee, Donald F.; Furuta, Yousuke; Bray, Mike; Gowen, Brian B.
Favipiravir is approved in Japan to treat novel or re-emerging influenza viruses, and is active against a broad spectrum of RNA viruses, including Ebola. Ribavirin is the only other licensed drug with activity against multiple RNA viruses. Recent studies show that ribavirin and favipiravir act synergistically to inhibit bunyavirus infections in cultured cells and laboratory mice, likely due to their different mechanisms of action. Convalescent immune globulin is the only approved treatment for Argentine hemorrhagic fever caused by the rodent-borne Junin arenavirus. We previously reported that favipiravir is highly effective in a number of small animal models of Argentine hemorrhagic fever. We now report that addition of low dose of ribavirin synergistically potentiates the activity of favipiravir against Junin virus infection of guinea pigs and another arenavirus, Pichinde virus infection of hamsters. This suggests that the efficacy of favipiravir against hemorrhagic fever viruses can be further enhanced through the addition of low-dose ribavirin. PMID:26711718
Puljiz, Ivan; Kuzman, Ilija; Turcinov, Drago; Makek, Nikola; Markotić, Alemka
To examine the frequency and distribution of hematologic and biochemical laboratory findings in 94 patients with hemorrhagic fever with renal syndrome (HFRS) in the epidemic year 2002. The following laboratory findings were retrospectively analyzed: erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), hemoglobin, hematocrit, leukocyte count and differential percentage (segmented neutrophils, band neutrophils, atypical lymphocytes), platelet count, coagulation tests, blood urea nitrogen (BUN), creatinine, urine, potassium, bilirubin (BIL), aspartate aminotransferase (AST), alanine aminotransferase (ALT), gamma-glutamyltransferase (GT), alkaline phosphatase (ALP), and serum protein electrophoresis. The study included 94 HFRS patients treated at the Dr Fran Mihaljević University Hospital for Infectious Diseases in Zagreb during 2002. ESR increase, mostly mild to moderate, was found in 86.2% of study patients. Increased CRP was recorded in 98.9% of study patients, however, one-fourth had CRP higher than 100 mg/L. Leukocytosis was recorded in 38.3% (10.1 +/- 4.2 x 10(9)/L), thrombocytopenia in 89.4% patients (68.2 +/- 48.3 x 10(9)/L), and severe thrombocytopenia (x 10(9)/L) in six patients. Three patients had abnormal coagulation tests. Increased values of BUN and creatinine were recorded in more than a half of patients, while only four patients had mild hyperkalemia. Only three patinets required hemodialysis. Mildly to moderately increased values of aminotransferases (AST, ALT, GT) were observed in more than 2/3; hypoalbuminaemia in nearly 1/3, and elevated alpha-2 fraction in more than 2/3 of patients. The majority of patients had pathologic urine findings. First laboratory abnormalities were usually found between day 5 and 7 of the disease (increased CRP level, thrombocytopenia, leukocytosis, and elevation of hemoglobin and hematocrit). Biochemical abnormalities(elevation of cratinine and urea, increased levels of aminotransferases) usually occurred at
Virus Research Centre (VRC) permitting the safe handling of specimens suspected to contain haemorrhagic fever viruses . Incidence and prevalence rates of...in Kenya Research work done in Kenya has shown that three naemorrnagic fever viruses occur in the country. These are Rift Valley Fever Virus , Crimean... viruses are nazardous to culture and handle in conventional type I and two oiohazard hoods. It wds therefore necessary to construct an absolute virus
Berber, Engin; Canakoglu, Nurettin; Yoruk, Mustafa D; Tonbak, Sukru; Aktas, Munir; Ertek, Mustafa; Bolat, Yusuf; Kalkan, Ahmet; Ozdarendeli, Aykut
A pseudo-plaque assay was developed for detection and quantitation of Crimean-Congo hemorrhagic fever virus Turkey-Kelkit06. Enzyme-catalyzed color development of infected cells probed with anti-Crimean-Congo hemorrhagic fever virus antibodies was used for determining the titer of Crimean-Congo hemorrhagic fever Turkey-Kelkit06 and for its detection in samples from persons infected with the Crimean-Congo hemorrhagic fever virus. The pseudo-plaque assay accuracy was confirmed by comparing pseudo-plaque assay titers with fluorescent immunofocus assay and focus formation assay titers using three stocks of virus. No significant difference in virus titers of Crimean-Congo hemorrhagic fever Turkey-Kelkit06 among the three methods was observed. The pseudo-plaque assay is more sensitive than the fluorescent immunofocus assay for detecting the virus in primary isolates of Crimean-Congo hemorrhagic fever virus collected from humans, but no difference in sensitivity between the two methods was observed in the cell-adapted strain of Crimean-Congo hemorrhagic fever Turkey-Kelkit06. The pseudo-plaque assay is suitable for titration of Crimean-Congo hemorrhagic fever Turkey-Kelkit06, which does not develop plaques, suggesting it may also be suitable for the detection of other viruses.
Iashina, L N; Malyshev, B S; Netesova, N A; Volynkina, A S; Vasilenko, N F
The genetic analysis of the Crimean-Congo hemorrhagic fever (CCHF) virus circulating in Stavropol region during 2011 year was suggested. A total of 14 RNA isolates from the Crimean hemorrhagic fever patients were genetically typed. The genetic analysis of the CCHF virus stains based on M-segment sequences (positions 2607-2932) supported the circulation of the genotype Europe 1 in the Stavropol region of Russia. In addition to previously known lineage STV-ROS, the second lineage VLG/ROS was observed in Stavropol region.
Ture, Zeynep; Ulu Kılıç, Ayşegül; Celik, Ilhami; Tok, Tugba; Yağcı-Çağlayık, Dilek
Crimean-Congo hemorrhagic fever (CCHF) is a fatal systemic viral infection which is an important health problem in Turkey. Many systemic symptoms have been reported including fever, hemorrhage, headache, fatigue, muscle ache, abdominal pain, nausea and vomiting. A 45-year-old male farmer with CCHF presented with massive peritoneal effusion and hyperbilirubinemia. To our knowledge, this is the first case of peritoneal effusion and hyperbilirubinemia in an adult patient with CCHF. His clinical symptoms successfully improved with supportive therapy. In patients who live in endemic areas with atypical presentation for the diagnosis of CCHF should be kept in mind.
Chinikar, Sadegh; Shah-Hosseini, Nariman; Bouzari, Saeid; Jalali, Tahmineh; Shokrgozar, Mohammad Ali; Mostafavi, Ehsan
Crimean-Congo hemorrhagic fever is a viral infection that is caused by Crimean-Congo hemorrhagic fever virus (CCHFV). On May 27, 2012, a woman became ill after accidentally splashing cow's blood into her eyes. Serological and molecular investigations were carried out on the serum of the patient. The test results for serological testing were negative, but RT-PCR was strongly positive for CCHFV. A phylogenetic study on the CCHFV genome sequence showed 50 % similarity to a 520-bp region of Russian strains. By combining historical phylogenetic data and current data, it can be surmised that there are potentially more than five circulating CCHFV genomic variants in Iran.
Mohr, Emma L; McMullan, Laura K; Lo, Michael K; Spengler, Jessica R; Bergeron, Éric; Albariño, César G; Shrivastava-Ranjan, Punya; Chiang, Cheng-Feng; Nichol, Stuart T; Spiropoulou, Christina F; Flint, Mike
Host cell kinases are important for the replication of a number of hemorrhagic fever viruses. We tested a panel of kinase inhibitors for their ability to block the replication of multiple hemorrhagic fever viruses. OSU-03012 inhibited the replication of Lassa, Ebola, Marburg and Nipah viruses, whereas BIBX 1382 dihydrochloride inhibited Lassa, Ebola and Marburg viruses. BIBX 1382 blocked both Lassa and Ebola virus glycoprotein-dependent cell entry. These compounds may be used as tools to understand conserved virus-host interactions, and implicate host cell kinases that may be targets for broad spectrum therapeutic intervention.
Limonta, D; Falcón, V; Torres, G; Capó, V; Menéndez, I; Rosario, D; Castellanos, Y; Alvarez, M; Rodríguez-Roche, R; de la Rosa, M C; Pavón, A; López, L; González, K; Guillén, G; Diaz, J; Guzmán, M G
Dengue virus is the most significant virus transmitted by arthropods worldwide and may cause a potentially fatal systemic disease named dengue hemorrhagic fever. In this work, dengue virus serotype 4 was detected in the tissues of one fatal dengue hemorrhagic fever case using electron immunomicroscopy and molecular methods. This is the first report of dengue virus polypeptides findings by electron immunomicroscopy in human samples. In addition, not-previously-documented virus-like particles visualized in spleen, hepatic, brain, and pulmonary tissues from a dengue case are discussed.
Petrov, A A; Plekhanova, T M; Sidorova, O N; Borisevich, S V; Makhlay, A A
The status of the various recombinant DNA and RNA-derived candidate vaccines, as well as the Venezuelan equine encephalomyelitis virus (VEEV) replicon vaccine system against extremely hazardous viral hemorrhagic fevers, were reviewed. The VEEV-based replication-incompetent vectors offer attractive features in terms of safety, high expression levels of the heterologous viral antigen, tropism to dendritic cells, robust immune responses, protection efficacy, low potential for pre-existing anti-vector immunity and possibility of engineering multivalent vaccines were tested. These features of the VEEV replicon system hold much promise for the development of new generation vaccine candidates against viral hemorrhagic fevers.
Izzah, L. N.; Majid, Z.; Ariff, M. A. M.; Fook, C. K.
Human modification of the natural environment continues to create habitats in which vectors of a wide variety of human and animal pathogens (such as Plasmodium, Aedes aegypti, Arenavirus etc.) thrive if unabated with an enormous potential to negatively affect public health. Typical examples of these modifications include impoundments, dams, irrigation systems, landfills and so on that provide enabled environment for the transmission of Hemorrhagic fever such as malaria, dengue, avian flu, Lassa fever etc. Furthermore, contemporary urban dwelling pattern appears to be associated with the prevalence of Hemorrhagic diseases in recent years. These observations are not peculiar to the developing world, as urban expansion also contributes significantly to mosquito and other vectors habitats. This habitats offer breeding ground to some vector virus populations. The key to disease control is developing an understanding of the contribution of human landscape modification to vector-borne pathogen transmission and how a balance may be achieved between human development, public health, and responsible urban land use. A comprehensive review of urban land use Pattern Analysis for Hemorrhagic fever risk has been conducted in this paper. The study found that most of the available literatures dwell more on the impact of urban land use on malaria and dengue fevers; however, studies are yet to be found discussing the implications of urban land use on the risk of Ebola, Lassa and other non-mosquito borne VHFs. A relational model for investigating the influence of urban land use change pattern on the risk of Hemorrhagic fever has been proposed in this study.
and Sabiá virus (Arenaviridae); Rift Valley fever virus (RVFV), Crimean-Congo hemorrhagic fever virus (CCHFV), and hantaviruses (Bunyaviridae); and...agents are encountered out of their natu- ral geographic context. Vaccines have been developed for YFV, RVFV, Junín virus, KFDV, and hantaviruses (3–7...239–61. 6. Hooper JW, Li D. Vaccines against hantaviruses . Curr Top Microbiol Immunol. 2001;256:171–91. 7. Dandawate CN, Desai GB, Achar TR, Banerjee K
Hussain, Qurban; Shaikh, Bilal Hussain; Bhutto, Ali Raza; Sohaib, Muneebah
Crimean Congo Hemorrhagic Fever (CCHF) is a tick-borne viral disease with a major reservoir in both domestic and wild animals. In Pakistan, it is endemic largely in rural areas and most cases occur in spring and autumn. Recently, cases are being reported throughout the year, including winter months, with some even from urban areas. Death from CCHF is most likely to occur during the hemorrhagic phase. We report a case presenting from an urban locality in December. Clinical presentation was characterized by a prolonged hemorrhagic phase and a delayed normalization of platelet counts.
characterization of highly pathogenic viruses : application during Crimean-Congo 313 haemorrhagic fever virus outbreaks in Eastern Europe and the Middle East...1 Sequence optimized real-time RT-PCR assay for detection of Crimean-Congo hemorrhagic fever 1 virus 2 3 JW Koehler1, KL Delp1, AT Hall1, SP...Institute of Infectious Diseases, 1425 Porter 9 Street, Fort Detrick, MD, 21702 USA 10 11 12 Abstract 13 14 Crimean-Congo hemorrhagic fever virus
Carletti, Fabrizio; Castilletti, Concetta; Di Caro, Antonino; Capobianchi, Maria R.; Nisii, Carla; Suter, Fredy; Rizzi, Marco; Tebaldi, Alessandra; Goglio, Antonio; Tosi, Cristiana Passerini
Two travelers returning to Italy from southern Egypt were hospitalized with a fever of unknown origin. Test results showed infection with Alkhurma virus. The geographic distribution of this virus could be broader than previously thought. PMID:21122237
Wang, Ling; Wang, Tao; Cui, Feng; Zhai, Shen-Yong; Zhang, Ling; Yang, Shu-Xia; Wang, Zhi-Qiang
Analysis of hemorrhagic fever with renal syndrome cases in Zibo City, China, during 2006–2014 showed that it occurred year-round. Peaks in spring and fall/winter were caused by Hantaan and Seoul viruses, respectively. Rodent hosts were the striped field mouse for Hantaan virus and the brown rat and house mouse for Seoul virus. PMID:26812444
Eroglu, Cafer; Erciyas-Yavuz, Kiraz; Hokelek, Murat; Acici, Mustafa; Yilmaz, Hava
We investigated migratory birds’ role in spreading Crimean-Congo hemorrhagic fever virus (CCHFV) through attached ticks. We detected CCHFV RNA in ticks on migratory birds in Turkey. Two isolates showed similarity with CCHFV genotype 4, suggesting a role for ticks in CCHFV epidemics in Turkey and spread of CCHFV by birds. PMID:25062428
Nabeth, Pierre; Tattevin, Pierre; Michelet, Christian; Zeller, Hervé
A patient with suspected malaria was hospitalized successively in 2 hospitals, first in Dakar, Senegal, then in Rennes, France, where tests diagnosed Crimean-Congo hemorrhagic fever. An international incident management group was set up in France and Senegal, which traced 181 contacts and analyzed 50 samples from 3 countries. No secondary cases were identified clinically. PMID:17073094
Papa, Anna; Bozovi, Bojana; Pavlidou, Vassiliki; Papadimitriou, Evangelia; Pelemis, Mijomir; Antoniadis, Aantonis
Crimean-Congo hemorrhagic fever virus (C-CHFV) strains were isolated from a fatal case and the attending physician in Kosovo, Yugoslavia. Early, rapid diagnosis of the disease was achieved by reverse transcription-polymerase chain reaction. The physician was successfully treated with oral ribavirin. These cases yielded the first genetically studied C-CHFV human isolates in the Balkans.
Leblebicioglu, Hakan; Eroglu, Cafer; Erciyas-Yavuz, Kiraz; Hokelek, Murat; Acici, Mustafa; Yilmaz, Hava
We investigated migratory birds' role in spreading Crimean-Congo hemorrhagic fever virus (CCHFV) through attached ticks. We detected CCHFV RNA in ticks on migratory birds in Turkey. Two isolates showed similarity with CCHFV genotype 4, suggesting a role for ticks in CCHFV epidemics in Turkey and spread of CCHFV by birds.
fever viruses and is manifested by hemorrhage into the skin as petechiae or ec- chymoses, oozing at puncture sites, epistaxis, gingival bleeding...through limiting virus dilution and plaque selection. All subsequent passages, in- Militaiy Medicine, Vol. 170, April Supplement 2005 82 U.S. Military
Song, Jin Won; Moon, Sung Sil; Gu, Se Hun; Song, Ki Joon; Baek, Luck Ju; Kim, Heung Chul; Kijek, Todd; O'Guinn, Monica L; Lee, John S; Turell, Michael J; Klein, Terry A
Four US soldiers acquired hemorrhagic fever with renal syndrome while training near the Demilitarized Zone, South Korea, in 2005. Hantaan virus sequences were amplified by reverse transcription-PCR from patient serum samples and from lung tissues of striped field mice (Apodemus agrarius) captured at training sites. Epidemiologic investigations specified the ecology of possible sites of patient infection.
hemorrhagic fever virus isolates in China. Virology 296, 159–164. Nichol, S.T., 2001. Bunyaviruses. In: Knipe, D.M., Howley, P.M. (Eds.), Fields ... Virology , vol. 1, 4th ed. Lippincott Williams and Wikins, Philadephlia, pp. 1603–1633. Papa, A., Bozovi, B., Pavlidou, V., Papadimitriou, E., Pelemis, M
Allaranga, Yokouide; Kone, Mamadou Lamine; Formenty, Pierre; Libama, Francois; Boumandouki, Paul; Woodfill, Celia J I; Sow, Idrissa; Duale, Sambe; Alemu, Wondimagegnehu; Yada, Adamou
To review epidemiological surveillance approaches used during Ebola and Marburg hemorrhagic fever epidemics in Africa in the past fifteen years. Overall, 26 hemorrhagic epidemic outbreaks have been registered in 12 countries; 18 caused by the Ebola virus and eight by the Marburg virus. About 2551 cases have been reported, among which 268 were health workers (9,3%). Based on articles and epidemic management reports, this review analyses surveillance approaches, route of introduction of the virus into the population (urban and rural), the collaboration between the human health sector and the wildlife sector and factors that have affected epidemic management. Several factors affecting the epidemiological surveillance during Ebola and Marburg viruses hemorrhagic epidemics have been observed. During epidemics in rural settings, outbreak investigations have shown multiple introductions of the virus into the human population through wildlife. In contrast, during epidemics in urban settings a single introduction of the virus in the community was responsible for the epidemic. Active surveillance is key to containing outbreaks of Ebola and Marburg viruses Collaboration with those in charge of the conservation of wildlife is essential for the early detection of viral hemorrhagic fever epidemics. Hemorrhagic fever epidemics caused by Ebola and Marburg viruses are occurring more and more frequently in Sub-Saharan Africa and only an adapted epidemiological surveillance system will allow for early detection and effective response.
Oliveira, Renato Antonio Dos Santos; Cordeiro, Marli Tenório; Moura, Patrícia Muniz Mendes Freire de; Baptista Filho, Paulo Neves Bapti; Braga-Neto, Ulisses de Mendonça; Marques, Ernesto Torres de Azevedo; Gil, Laura Helena Vega Gonzales
DENV infection can induce different clinical manifestations varying from mild forms to dengue fever (DF) or the severe hemorrhagic fever (DHF). Several factors are involved in the progression from DF to DHF. No marker is available to predict this progression. Such biomarker could allow a suitable medical care at the beginning of the infection, improving patient prognosis. The aim of this study was to compare the serum expression levels of acute phase proteins in a well-established cohort of dengue fever (DF) and dengue hemorrhagic fever (DHF) patients, in order to individuate a prognostic marker of diseases severity. The serum levels of 36 cytokines, chemokines and acute phase proteins were determined in DF and DHF patients and compared to healthy volunteers using a multiplex protein array and near-infrared (NIR) fluorescence detection. Serum levels of IL-1ra, IL-23, MIF, sCD40 ligand, IP-10 and GRO-α were also determined by ELISA. At the early stages of infection, GRO-α and IP-10 expression levels were different in DF compared to DHF patients. Besides, GRO-α was positively correlated with platelet counts and IP-10 was negatively correlated with total protein levels. These findings suggest that high levels of GRO-α during acute DENV infection may be associated with a good prognosis, while high levels of IP-10 may be a warning sign of infection severity. Copyright © 2017 Elsevier B.V. All rights reserved.
Zakham, Fathiah; Al-Habal, Mohammed; Taher, Rola; Alaoui, Altaf; El Mzibri, Mohammed
Viral hemorrhagic fever (VHF) refers to a group of diseases characterized by an acute febrile syndrome with hemorrhagic manifestations and high mortality rates caused by several families of viruses that affect humans and animals. These diseases are typically endemic in certain geographical regions and sometimes cause major outbreaks. The history of hemorrhagic fever in the Arabian Peninsula refers to the 19th century and most outbreaks were reported in the Tihamah region-the Red Sea coastal plain of the Arabian Peninsula in the west and southwest of Saudi Arabia and Yemen. Herein, we describe the agents that cause VHFs and their epidemiology in Tihamah, the history of the diseases, transmission, species affected, and clinical signs. Finally, we address challenges in the diagnosis and control of VHFs in this region.
Kuchuloria, Tinatin; Imnadze, Paata; Chokheli, Maiko; Tsertsvadze, Tengiz; Endeladze, Marina; Mshvidobadze, Ketevan; Clark, Danielle V; Bautista, Christian T; Abdel Fadeel, Moustafa; Pimentel, Guillermo; House, Brent; Hepburn, Matthew J; Wölfel, Silke; Wölfel, Roman; Rivard, Robert G
Minimal information is available on the incidence of Crimean-Congo hemorrhagic fever (CCHF) virus and hantavirus infections in Georgia. From 2008 to 2011, 537 patients with fever ≥ 38°C for ≥ 48 hours without a diagnosis were enrolled into a sentinel surveillance study to investigate the incidence of nine pathogens, including CCHF virus and hantavirus. Of 14 patients with a hemorrhagic fever syndrome, 3 patients tested positive for CCHF virus immunoglobulin M (IgM) antibodies. Two of the patients enrolled in the study had acute renal failure. These 2 of 537 enrolled patients were the only patients in the study positive for hantavirus IgM antibodies. These results suggest that CCHF virus and hantavirus are contributing causes of acute febrile syndromes of infectious origin in Georgia. These findings support introduction of critical diagnostic approaches and confirm the need for additional surveillance in Georgia.
Özer, Samet; Kazancı, Nafia Özlem; Sönmezgöz, Ergün; Karaaslan, Erhan; Yılmaz, Resul
Crimean-Congo hemorrhagic fever (CCHF) is a potentially fatal systemic disease in children caused by a tick- borne virus. Many different clinical and laboratory findings are seen in CCHF. We report here an atypical presentation of CCHF with hyponatremia. CCHF with electrolyte imbalance is not reported before. A 4-year-old girl presented with fever, fatigue and unconsciousness with hyponatremia. Based on the clinical and epidemiological findings, virus infection was suspected. Hyponatremia is has never been reported in Crimean-Congo hemorrhagic fever (CCHF), as was observed in this case. The diagnosis was confirmed by detection of IgM antibody to CCHF virus and positive Real-Time PCR. We report the first case of imported CCHF presenting as hyponatremia. This electrolyte imbalance has never been reported before in CCHF in children, and the clinician should consider this entity in complications to explain unconsciousness.
Bwaka, M A; Bonnet, M J; Calain, P; Colebunders, R; De Roo, A; Guimard, Y; Katwiki, K R; Kibadi, K; Kipasa, M A; Kuvula, K J; Mapanda, B B; Massamba, M; Mupapa, K D; Muyembe-Tamfum, J J; Ndaberey, E; Peters, C J; Rollin, P E; Van den Enden, E; Van den Enden, E
During the 1995 outbreak of Ebola hemorrhagic fever in the Democratic Republic of the Congo, a series of 103 cases (one-third of the total number of cases) had clinical symptoms and signs accurately recorded by medical workers, mainly in the setting of the urban hospital in Kikwit. Clinical diagnosis was confirmed retrospectively in cases for which serum samples were available (n = 63, 61% of the cases). The disease began unspecifically with fever, asthenia, diarrhea, headaches, myalgia, arthralgia, vomiting, and abdominal pain. Early inconsistent signs and symptoms included conjunctival injection, sore throat, and rash. Overall, bleeding signs were observed in <45% of the cases. Typically, terminally ill patients presented with obtundation, anuria, shock, tachypnea, and normothermia. Late manifestations, most frequently arthralgia and ocular diseases, occurred in convalescent patients. This series is the most extensive number of cases of Ebola hemorrhagic fever observed during an outbreak.
Mohamed AL Dabal, Laila; Rahimi Shahmirzadi, Mohmamed Reza; Baderldin, Samar; Abro, Ali; Zaki, Ali; Dessi, Zulfa; Al Eassa, Essa; Khan, Gulfaraz; Shuri, Hassan; Alwan, Abid Mustafa
Introduction Crimean-Congo hemorrhagic fever (CCHF) is a severe infectious disease that is not endemic in the United Arab Emirates (UAE). Case Presentation We report two cases of confirmed CCHF diagnosed in Dubai, UAE, during Hajj season 2010. Both patients presented with an acute history of high-grade fever, skin rash, and hematemesis. Conclusions In spite of maximal supportive measures and intravenous ribavirin therapy, both patients died within a few days from start of illness. More than 250 health care workers came into variable degrees of contact with the index cases, and none of them developed signs or symptoms suggestive of acquiring the illness. Health care workers from nonendemic regions should be aware of zoonotic hemorrhagic fevers imported via infected cattle and ticks and be able to diagnose and properly manage suspected cases in a timely manner. In addition, proper infection-control measures should be undertaken to prevent nosocomial spread of infection. PMID:27795839
Acuna-Soto, Rodofo; Stahle, David W; Therrell, Matthew D; Griffin, Richard D; Cleaveland, Malcolm K
During the 16th century, Mexico suffered a demographic catastrophe with few parallels in world's history. In 1519, the year of the arrival of the Spaniards, the population in Mexico was estimated to be between 15 and 30 million inhabitants. Eighty-one years later, in 1600, only two million remained. Epidemics (smallpox, measles, mumps), together with war, and famine have been considered to be the main causes of this enormous population loss. However, re-evaluation of historical data suggests that approximately 60-70% of the death toll was caused by a series of epidemics of hemorrhagic fevers of unknown origin. In order to estimate the impact of the 1576 epidemic of hemorrhagic fevers on the population we analyzed the historical record and data from the 1570 and 1580 censuses of 157 districts. The results identified several remarkable aspects of this epidemic: First, overall, the population loss for these 157 districts was 51.36%. Second, there was a clear ethnic preference of the disease, the Spanish population was minimally affected whereas native population had high mortality rate. Third, the outbreak originated in the valleys of central Mexico whence it evolved as an expansive wave. Fourth, a positive correlation between altitude and mortality in central Mexico was found. Fifth, a specific climatic sequence of events was associated with the initiation and dissemination of the hemorrhagic fevers. Although the last epidemic of hemorrhagic fevers in Mexico ended in 1815, many questions remain to be answered. Perhaps the most relevant ones are whether there is a possible reemergence of the hemorrhagic fevers and how vulnerable we are to the disease.
Yilmaz, Hülya; Yilmaz, Gürdal; Kostakoğlu, Uğur; Yaman, Hüseyin; Örem, Asım; Köksal, İftihar
Crimean-Congo Hemorrhagic Fever (CCHF) is a disease transmitted by the Crimean-Congo hemorrhagic fever virus (CCHFV), characterized by severe fever and hemorrhage and with a reported fatality level of 3-30%. Cerebral hemorrhage, gastrointestinal hemorrhage, severe anemia, shock, myocardial infarction, pulmonary edema, and pleural effusion may be seen as causes of death. Cardiac troponin T (cTn-T) is a biochemical marker with high sensitivity and specificity in myocardial injury. The purpose of this study was to determine the prognostic significance of serum troponin T levels in CCHF patients. Patients hospitalized with a diagnosis of CCHF and whose serum cTn-T was investigated were examined retrospectively. Patients were divided into two groups on the basis of presence or absence of hemorrhage. Data were subjected to statistical analysis. One hundred thirty-five CCHF patients and 72 control subjects were included. Hemorrhage was present in 48 (35.6%) patients. Mean serum cTn-T level was 17.3 ± 28.0 ng/L in the patients with hemorrhage, 9.98 ± 5.97 ng/L in the non-hemorrhage patients (P = 0.001) and 6.6P = 2.6 ng/L in the control samples (P < 0.001). At a cTn-T level cut-off point of 9 ng/L, area under the ROC curve was 0.797 (95%CI: 0.730-0.854), sensitivity 83.0%, specificity 87.5%, PPD 95.7%, and NPV 60.3%. At logistic regression analysis, a rise in cTn-T level above 14 ng/L increased the probability of hemorrhage in CCHF patients approximately threefold. An increased troponin T level may be a prognostic risk factor for hemorrhage in CCHF patients. This marker should therefore be borne in mind in determining treatment strategy in these patients. J. Med. Virol. 89:408-412, 2017. © 2015 Wiley Periodicals, Inc.
Todd, Michael M; Hindman, Bradley J; Clarke, William R; Torner, James C; Weeks, Julie B; Bayman, Emine O; Shi, Qian; Spofford, Christina M
We examined the incidence of perioperative fever and its relationship to outcome among patients enrolled in the Intraoperative Hypothermia for Aneurysm Surgery Trial. One thousand patients with initial World Federation of Neurological Surgeons grades of I to III undergoing clipping of intracranial aneurysms after subarachnoid hemorrhage were randomized to intraoperative normothermia (36 degrees C-37 degrees C) or hypothermia (32.5 degrees C-33.5 degrees C). Fever (> or =38.5 degrees C) and other complications (including infections) occurring between admission and discharge (or death) were recorded. Functional and neuropsychologic outcomes were assessed 3 months postoperatively. The primary outcome variable for the trial was dichotomized Glasgow Outcome Scale (good outcome versus all others). Fever was reported in 41% of patients. In 97% of these, fever occurred in the postoperative period. The median time from surgery to first fever was 3 days. All measures of outcome were worse in patients who developed fever, even in those without infections or who were World Federation of Neurological Surgeons grade I. Logistic regression analyses were performed to adjust for differences in preoperative factors (e.g., age, Fisher grade, initial neurological status). This demonstrated that fever continued to be significantly associated with most outcome measures, even when infection was added to the model. An alternative stepwise model selection process including all fever-related measures from the preoperative and intraoperative period (e.g., hydrocephalus, duration of surgery, intraoperative blood loss) resulted in the loss of significance for dichotomized Glasgow Outcome Scale, but significant associations between fever and several other outcome measures remained. After adding postoperative delayed ischemic neurological deficits to the model, only worsened National Institutes of Health Stroke Scale score, Barthel Activities of Daily Living index, and discharge destination
Here we outline serious diseases of food and fiber animals that cause damaging economic effects on producers all over the world. The only vector-borne DNA virus is included here (i.e., African swine fever virus), and the herpesviruses discussed have a complex epidemiology characterized by outbreaks ...
Here we outline serious diseases of food and fiber animals that cause damaging economic effect on products all over the world. The only vector-borne DNA virus is included here, such as African swine fever virus, and the herpes viruses discussed have a complex epidemiology characterized by outbreak...
Rudd, Penny A.; Wilson, Jane; Gardner, Joy; Larcher, Thibaut; Babarit, Candice; Le, Thuy T.; Anraku, Itaru; Kumagai, Yutaro; Loo, Yueh-Ming; Gale, Michael; Akira, Shizuo; Khromykh, Alexander A.
Chikungunya virus (CHIKV) infections can produce severe disease and mortality. Here we show that CHIKV infection of adult mice deficient in interferon response factors 3 and 7 (IRF3/7−/−) is lethal. Mortality was associated with undetectable levels of alpha/beta interferon (IFN-α/β) in serum, ∼50- and ∼10-fold increases in levels of IFN-γ and tumor necrosis factor (TNF), respectively, increased virus replication, edema, vasculitis, hemorrhage, fever followed by hypothermia, oliguria, thrombocytopenia, and raised hematocrits. These features are consistent with hemorrhagic shock and were also evident in infected IFN-α/β receptor-deficient mice. In situ hybridization suggested CHIKV infection of endothelium, fibroblasts, skeletal muscle, mononuclear cells, chondrocytes, and keratinocytes in IRF3/7−/− mice; all but the latter two stained positive in wild-type mice. Vaccination protected IRF3/7−/− mice, suggesting that defective antibody responses were not responsible for mortality. IPS-1- and TRIF-dependent pathways were primarily responsible for IFN-α/β induction, with IRF7 being upregulated >100-fold in infected wild-type mice. These studies suggest that inadequate IFN-α/β responses following virus infection can be sufficient to induce hemorrhagic fever and shock, a finding with implications for understanding severe CHIKV disease and dengue hemorrhagic fever/dengue shock syndrome. PMID:22761364
Baranovich, Tatiana; Wong, Sook-San; Armstrong, Jianling; Marjuki, Henju; Webby, Richard J; Webster, Robert G; Govorkova, Elena A
Several novel anti-influenza compounds are in various phases of clinical development. One of these, T-705 (favipiravir), has a mechanism of action that is not fully understood but is suggested to target influenza virus RNA-dependent RNA polymerase. We investigated the mechanism of T-705 activity against influenza A (H1N1) viruses by applying selective drug pressure over multiple sequential passages in MDCK cells. We found that T-705 treatment did not select specific mutations in potential target proteins, including PB1, PB2, PA, and NP. Phenotypic assays based on cell viability confirmed that no T-705-resistant variants were selected. In the presence of T-705, titers of infectious virus decreased significantly (P < 0.0001) during serial passage in MDCK cells inoculated with seasonal influenza A (H1N1) viruses at a low multiplicity of infection (MOI; 0.0001 PFU/cell) or with 2009 pandemic H1N1 viruses at a high MOI (10 PFU/cell). There was no corresponding decrease in the number of viral RNA copies; therefore, specific virus infectivity (the ratio of infectious virus yield to viral RNA copy number) was reduced. Sequence analysis showed enrichment of G→A and C→T transversion mutations, increased mutation frequency, and a shift of the nucleotide profiles of individual NP gene clones under drug selection pressure. Our results demonstrate that T-705 induces a high rate of mutation that generates a nonviable viral phenotype and that lethal mutagenesis is a key antiviral mechanism of T-705. Our findings also explain the broad spectrum of activity of T-705 against viruses of multiple families.
Baranovich, Tatiana; Wong, Sook-San; Armstrong, Jianling; Marjuki, Henju; Webby, Richard J.; Webster, Robert G.
Several novel anti-influenza compounds are in various phases of clinical development. One of these, T-705 (favipiravir), has a mechanism of action that is not fully understood but is suggested to target influenza virus RNA-dependent RNA polymerase. We investigated the mechanism of T-705 activity against influenza A (H1N1) viruses by applying selective drug pressure over multiple sequential passages in MDCK cells. We found that T-705 treatment did not select specific mutations in potential target proteins, including PB1, PB2, PA, and NP. Phenotypic assays based on cell viability confirmed that no T-705-resistant variants were selected. In the presence of T-705, titers of infectious virus decreased significantly (P < 0.0001) during serial passage in MDCK cells inoculated with seasonal influenza A (H1N1) viruses at a low multiplicity of infection (MOI; 0.0001 PFU/cell) or with 2009 pandemic H1N1 viruses at a high MOI (10 PFU/cell). There was no corresponding decrease in the number of viral RNA copies; therefore, specific virus infectivity (the ratio of infectious virus yield to viral RNA copy number) was reduced. Sequence analysis showed enrichment of G→A and C→T transversion mutations, increased mutation frequency, and a shift of the nucleotide profiles of individual NP gene clones under drug selection pressure. Our results demonstrate that T-705 induces a high rate of mutation that generates a nonviable viral phenotype and that lethal mutagenesis is a key antiviral mechanism of T-705. Our findings also explain the broad spectrum of activity of T-705 against viruses of multiple families. PMID:23325689
Interim Report on SNP analysis and forensic microarray probe design for South American hemorrhagic fever viruses, tick-borne encephalitis virus, henipaviruses, Old World Arenaviruses, filoviruses, Crimean-Congo hemorrhagic fever viruses, Rift Valley fever
Jaing, C; Gardner, S
The goal of this project is to develop forensic genotyping assays for select agent viruses, enhancing the current capabilities for the viral bioforensics and law enforcement community. We used a multipronged approach combining bioinformatics analysis, PCR-enriched samples, microarrays and TaqMan assays to develop high resolution and cost effective genotyping methods for strain level forensic discrimination of viruses. We have leveraged substantial experience and efficiency gained through year 1 on software development, SNP discovery, TaqMan signature design and phylogenetic signature mapping to scale up the development of forensics signatures in year 2. In this report, we have summarized the whole genome wide SNP analysis and microarray probe design for forensics characterization of South American hemorrhagic fever viruses, tick-borne encephalitis viruses and henipaviruses, Old World Arenaviruses, filoviruses, Crimean-Congo hemorrhagic fever virus, Rift Valley fever virus and Japanese encephalitis virus.
Schattner, Mirta; Rivadeneyra, Leonardo; Pozner, Roberto G.; Gómez, Ricardo M.
Viral hemorrhagic fevers (VHFs) caused by arenaviruses are acute diseases characterized by fever, headache, general malaise, impaired cellular immunity, eventual neurologic involvement, and hemostatic alterations that may ultimately lead to shock and death. The causes of the bleeding are still poorly understood. However, it is generally accepted that these causes are associated to some degree with impaired hemostasis, endothelial cell dysfunction and low platelet counts or function. In this article, we present the current knowledge about the hematological alterations present in VHF induced by arenaviruses, including new aspects on the underlying pathogenic mechanisms. PMID:23337384
Schattner, Mirta; Rivadeneyra, Leonardo; Pozner, Roberto G; Gómez, Ricardo M
Viral hemorrhagic fevers (VHFs) caused by arenaviruses are acute diseases characterized by fever, headache, general malaise, impaired cellular immunity, eventual neurologic involvement, and hemostatic alterations that may ultimately lead to shock and death. The causes of the bleeding are still poorly understood. However, it is generally accepted that these causes are associated to some degree with impaired hemostasis, endothelial cell dysfunction and low platelet counts or function. In this article, we present the current knowledge about the hematological alterations present in VHF induced by arenaviruses, including new aspects on the underlying pathogenic mechanisms.
Kortekaas, Jeroen; Ergönül, Onder; Moormann, Rob J M
ARBO-ZOONET is an international network financed by the European Commission's seventh framework program. The major goal of this initiative is capacity building for the control of emerging viral vector-borne zoonotic diseases, with a clear focus on West Nile virus, Rift Valley fever virus, and Crimean-Congo hemorrhagic fever virus. To evaluate the status quo of control measures against these viruses, an ARBO-ZOONET meeting was held in Istanbul, Turkey, from 19 to 20 November 2009. The symposium consisted of three themes: (1) vaccines: new and existing ones; (2) antivirals: existing and new developments; and (3) antivector vaccines. In addition, a satellite workshop was held on epidemiology and diagnosis. The meeting brought together foremost international experts on the subjects from both within and without the ARBO-ZOONET consortium. This report highlights selected results from these presentations and major conclusions that emanated from the discussions held.
Ardouin, C; Chevalier, J M; Algayres, J P
For each of these three fevers recently described, the authors report the history of their identification. The features of the three viruses, and the clinical aspects of the diseases they induce, are also indicated. The laboratory diagnosis is described. Practical indications are given for the transportation of the specimens to the only three high security laboratories in the world. The laboratory diagnosis is described. Some cautions are indicated handling and treating patients. It must be envisaged also to organize a four degrees quarantive cautions; compulsory for necropsies, burials, and occasionally for long distant transportations of patients are indicated.
Clamfication) Antibody-Dependent Enhancement of Dengue Virus Growth in Human Monocytes as a Risk Factor for Dengue Hemorrhagic Fever PERSONAL AjTHOR(S...FELD GROUP SUBGROUP Antibody-Dependent Enhancement of Dengue Virus Growth in Human Monocytes as a Risk Factor for Dengue Hemorrhagic Fever. 19...ABSTRAC7 (Continue on reverse if necessary and identify by block number) Serum specimens~collected during a prospective study of dengue infections among
Smith, Lauren M; Hensley, Lisa E; Geisbert, Thomas W; Johnson, Joshua; Stossel, Andrea; Honko, Anna; Yen, Judy Y; Geisbert, Joan; Paragas, Jason; Fritz, Elizabeth; Olinger, Gene; Young, Howard A; Rubins, Kathleen H; Karp, Christopher L
There is a clear need for novel, effective therapeutic approaches to hemorrhagic fever due to filoviruses. Ebola virus hemorrhagic fever is associated with robust interferon (IFN)-α production, with plasma concentrations of IFN-α that greatly (60- to 100-fold) exceed those seen in other viral infections, but little IFN-β production. While all of the type I IFNs signal through the same receptor complex, both quantitative and qualitative differences in biological activity are observed after stimulation of the receptor complex with different type I IFNs. Taken together, this suggested potential for IFN-β therapy in filovirus infection. Here we show that early postexposure treatment with IFN-β significantly increased survival time of rhesus macaques infected with a lethal dose of Ebola virus, although it failed to alter mortality. Early treatment with IFN-β also significantly increased survival time after Marburg virus infection. IFN-β may have promise as an adjunctive postexposure therapy in filovirus infection.
Safari, Saeed; Baratloo, Alireza; Rouhipour, Alaleh; Ghelichkhani, Parisa; Yousefifard, Mahmood
Ebola hemorrhagic fever (EHF) was first reported in 1976 with two concurrent outbreaks of acute viral hemorrhagic fever centered in Yambuku (near the Ebola river), Democratic Republic of Congo, and in Nzara, Sudan. The current outbreak of the Ebola virus was started by reporting the first case in March 2014 in the forest regions of southeastern Guinea. Due to infection rates raising over 13,000% within a 6-month period, Ebola is now considered as a global public health emergency and on August 8(th), 2014 the World Health Organization (WHO) declared the epidemic to be a Public Health Emergency of International Concern. With more than 5000 involved cases and nearly 3000 deaths, this event has turned into the largest and most dangerous Ebola virus outbreak in the world. Based on the above-mentioned, the present article aimed to review the virologic characteristics, transmission, clinical manifestation, diagnosis, treatment, and prevention of Ebola virus disease.
Martinez, Osvaldo; Leung, Lawrence W.; Basler, Christopher F.
The filoviruses, ebolavirus (EBOV) and marburgvirus (MARV), are highly lethal zoonotic agents of concern as emerging pathogens and potential bioweapons. Antigen-presenting cells (APCs), particularly macrophages and dendritic cells, are targets of filovirus infection in vivo. Infection of these cell types has been proposed to contribute to the inflammation, activation of coagulation cascades and ineffective immune responses characteristic of filovirus hemorrhagic fever. However, many aspects of filovirus-APC interactions remain to be clarified. Among the unanswered questions: What determines the ability of filoviruses to replicate in different APC subsets? What are the cellular signaling pathways that sense infection and lead to production of copious quantities of cytokines, chemokines and tissue factor? What are the mechanisms by which innate antiviral responses are disabled by these viruses, and how may these mechanisms contribute to inadequate adaptive immunity? A better understanding of these issues will clarify the pathogenesis of filoviral hemorrhagic fever and provide new avenues for development of therapeutics. PMID:22333482
Spiropoulou, Christina F; Srikiatkhachorn, Anon
The loss of the endothelium barrier and vascular leakage play a central role in the pathogenesis of hemorrhagic fever viruses. This can be caused either directly by the viral infection and damage of the vascular endothelium, or indirectly by a dysregulated immune response resulting in an excessive activation of the endothelium. This article briefly reviews our knowledge of the importance of the disruption of the vascular endothelial barrier in two severe disease syndromes, dengue hemorrhagic fever and hantavirus pulmonary syndrome. Both viruses cause changes in vascular permeability without damaging the endothelium. Here we focus on our understanding of the virus interaction with the endothelium, the role of the endothelium in the induced pathogenesis, and the possible mechanisms by which each virus causes vascular leakage. Understanding the dynamics between viral infection and the dysregulation of the endothelial cell barrier will help us to define potential therapeutic targets for reducing disease severity. PMID:23841977
Franco, Leticia; Palacios, Gustavo; Martinez, José Antonio; Vázquez, Ana; Savji, Nazir; De Ory, Fernando; Sanchez-Seco, María Paz; Martín, Dolores; Lipkin, W Ian; Tenorio, Antonio
Dengue virus (DENV) circulates in human and sylvatic cycles. Sylvatic strains are both ecologically and evolutionarily distinct from endemic viruses. Although sylvatic dengue cycles occur in West African countries and Malaysia, only a few cases of mild human disease caused by sylvatic strains and one single case of dengue hemorrhagic fever in Malaysia have been reported. Here we report a case of dengue hemorrhagic fever (DHF) with thrombocytopenia (13000/µl), a raised hematocrit (32% above baseline) and mucosal bleeding in a 27-year-old male returning to Spain in November 2009 after visiting his home country Guinea Bissau. Sylvatic DENV-2 West African lineage was isolated from blood and sera. This is the first case of DHF associated with sylvatic DENV-2 in Africa and the second case worldwide of DHF caused by a sylvatic strain.
Kumar, Santosh; Pushkarna, Arawat; Ganesamoni, Raguram; Nanjappa, Bhuvanesh
Post percutaneous nephrolithotomy (PNL) bleeding is an uncommon yet serious complication and is almost always related to a surgical cause. Nevertheless, medical cause of bleeding is rarely encountered as a cause of this dangerous complication. Dengue has been rarely reported as a cause of post operative bleeding. Bleeding diathesis in dengue occurs not only due to thrombocytopenia but also due to dysfunctional surviving platelets and increased fibrinolysis. We report a patient who developed bleeding after an uneventful PNL due to dengue hemorrhagic fever. Medical causes of bleeding such as locally endemic viral hemorrhagic fevers should also be kept in mind and evaluated especially when a surgical cause of the bleed is not found or suspected in bleeding after any surgery.
initiator of the extrinsic coagulation cascade, is upregulated in macrophages following infection of nonhuman primates with the filovirus Ebola virus...Jahrling PB, Larsen T, Geisbert JB, Paragas J, Young HA, Fredeking TM, Rote WE, Vlasuk GP. 2003. Treatment of Ebola virus infection with a recombinant...coagulation abnormalities in ebola hemorrhagic fever: overexpression of tissue factor in primate monocytes/macrophages is a key event. J Infect Dis 188:1618
Tanyel, Esra; Sunbul, Mustafa; Fletcher, Tom E; Leblebicioglu, Hakan
Crimean-Congo hemorrhagic fever (CCHF) is a potentially fatal tick-borne viral infection that is widely distributed worldwide. The diagnosis is frequently missed due to the non-specific initial symptoms and the differential diagnosis included many infectious and non-infectious causes. This retrospective study describes the clinical features and final diagnoses of 116 suspect CCHF cases that were admitted to a tertiary CCHF center in Turkey, and were CCHF IgM and PCR negative.
other viruses , most notably infection and the brain was harvested. Brains were homogenized to the Ebola virus glycoprotein (Simmons et al., 2002). 10% (w...at the United States Army Medical Research Institute of Infectious Diseases (USAMRIID), and is directed at working with the intact virus in high...characterization of Crimean-Congo hemorrhagic fever virus glycoproteins. Bioterrorism and Emerging Infectious Diseases : Antimicrobial, Therapeutics and
Horton, Katherine C; Fahmy, Nermeen T; Watany, Noha; Zayed, Alia; Mohamed, Abro; Ahmed, Ammar Abdo; Rollin, Pierre E; Dueger, Erica L
Crimean Congo hemorrhagic fever virus and Alkhumra virus, not previously reported in Djibouti, were detected among 141 (infection rate = 15.7 per 100, 95% CI: 13.4-18.1) tick pools from 81 (37%) cattle and 2 (infection rate = 0.2 per 100, 95% CI: 0.0-0.7) tick pools from 2 (1%) cattle, respectively, collected at an abattoir in 2010 and 2011.
bioterrorism pathogens that threaten troops. 1. INTRODUCTION Hantaviruses are RNA viruses belonging to the family Bunyaviridae, and are...the etiologic agents of hemorrhagic fever with renal syndrome (HFRS) in the Old World and hantavirus pulmonary syndrome in the New World. The...viruses are carried by persistently infected rodents and are found worldwide. There are no licensed vaccines for hantaviruses ; thus, they continue to
inflammatory pathways. Hantaviruses can cause two distinct types of human disease: hemorrhagic fever with renal syndrome (HFRS) and hantavirus pulmonary...or of CCHFV. To examine this for hantaviruses , lung epithelial cells (A549) were mock-infected or infected with the HPS-causing hantavirus , Andes... author (s) and should not be construed as an official Department of the Army position, policy or decision unless so designated by other documentation
of leptospirosis ; no diagnosis could be made for the other 14. virus-specific pooled mouse monoclonal antibodies or control fluids: Seropositive...day 7 of disease. Further, 1184 Concise Communications JID 1990:162 INovember) 100,00o - tion of a single case of leptospirosis , the etiology of the...prototype Hantaan tibodies to Rift Valley fever virus in ovine and bovine sera. Am JVet Res 1987:48:1138-1141virus as the causative agent of hemorrhagic
Sunbul, Mustafa; Fletcher, Tom E.
Crimean–Congo hemorrhagic fever (CCHF) is a potentially fatal tick-borne viral infection that is widely distributed worldwide. The diagnosis is frequently missed due to the non-specific initial symptoms and the differential diagnosis included many infectious and non-infectious causes. This retrospective study describes the clinical features and final diagnoses of 116 suspect CCHF cases that were admitted to a tertiary CCHF center in Turkey, and were CCHF IgM and PCR negative. PMID:27677379
Slikas, Elizabeth; Steffen, Imke; Muyembe, Jean-Jacques; Sittler, Taylor; Veeraraghavan, Narayanan; Ruby, J. Graham; Wang, Chunlin; Makuwa, Maria; Mulembakani, Prime; Tesh, Robert B.; Mazet, Jonna; Rimoin, Anne W.; Taylor, Travis; Schneider, Bradley S.; Simmons, Graham; Delwart, Eric; Wolfe, Nathan D.; Chiu, Charles Y.; Leroy, Eric M.
Deep sequencing was used to discover a novel rhabdovirus (Bas-Congo virus, or BASV) associated with a 2009 outbreak of 3 human cases of acute hemorrhagic fever in Mangala village, Democratic Republic of Congo (DRC), Africa. The cases, presenting over a 3-week period, were characterized by abrupt disease onset, high fever, mucosal hemorrhage, and, in two patients, death within 3 days. BASV was detected in an acute serum sample from the lone survivor at a concentration of 1.09×106 RNA copies/mL, and 98.2% of the genome was subsequently de novo assembled from ∼140 million sequence reads. Phylogenetic analysis revealed that BASV is highly divergent and shares less than 34% amino acid identity with any other rhabdovirus. High convalescent neutralizing antibody titers of >1∶1000 were detected in the survivor and an asymptomatic nurse directly caring for him, both of whom were health care workers, suggesting the potential for human-to-human transmission of BASV. The natural animal reservoir host or arthropod vector and precise mode of transmission for the virus remain unclear. BASV is an emerging human pathogen associated with acute hemorrhagic fever in Africa. PMID:23028323
Chang, Jinhong; Warren, Travis K.; Zhao, Xuesen; Gill, Tina; Guo, Fang; Wang, Lijuan; Comunale, Mary Ann; Du, Yanming; Alonzi, Dominic S.; Yu, Wenquan; Ye, Hong; Liu, Fei; Guo, Ju-Tao; Mehta, Anand; Cuconati, Andrea; Butters, Terry D.; Bavari, Sina; Xu, Xiaodong; Block, Timothy M.
Host cellular endoplasmic reticulum α-glucosidases I and II are essential for the maturation of viral glycosylated envelope proteins that use the calnexin mediated folding pathway. Inhibition of these glycan processing enzymes leads to the misfolding and degradation of these viral glycoproteins and subsequent reduction in virion secretion. We previously reported that, CM-10-18, an imino sugar α-glucosidase inhibitor, efficiently protected the lethality of dengue virus infection of mice. In the current study, through an extensive structure-activity relationship study, we have identified three CM-10-18 derivatives that demonstrated superior in vitro antiviral activity against representative viruses from four viral families causing hemorrhagic fever. Moreover, the three novel imino sugars significantly reduced the mortality of two of the most pathogenic hemorrhagic fever viruses, Marburg virus and Ebola virus, in mice. Our study thus proves the concept that imino sugars are promising drug candidates for the management of viral hemorrhagic fever caused by variety of viruses. PMID:23578725
Hastie, Kathryn M.; Bale, Shridhar; Kimberlin, Christopher R.; Saphire, Erica Ollmann
The innate immune system is one of the first lines of defense against invading pathogens. Pathogens have, in turn, evolved different strategies to counteract these responses. Recent studies have illuminated how the hemorrhagic fever viruses Ebola and Lassa fever prevent host sensing of double-stranded RNA (dsRNA), a key hallmark of viral infection. The ebolavirus protein VP35 adopts a unique bimodal configuration to mask key cellular recognition sites on dsRNA. Conversely, the Lassa fever virus nucleoprotein, NP, actually digests the dsRNA signature. Collectively, these structural and functional studies shed new light on the mechanisms of pathogenesis of these viruses and provide new targets for therapeutic intervention. PMID:22482712
Dengue is becoming recognized as one of the most important vector-borne human diseases. It is predominant in tropical and subtropical zones but its geographical distribution is progressively expanding, making it an escalating global health problem of today. Dengue presents with spectrum of clinical manifestations, ranging from asymptomatic, undifferentiated mild fever, dengue fever (DF), to dengue hemorrhagic fever (DHF) with or without shock (DSS), a life-threatening illness characterized by plasma leakage due to increased vascular permeability. Currently, there are no antiviral modalities or vaccines available to treat and prevent dengue. Supportive care with close monitoring is the standard clinical practice. The mechanisms leading to DHF/DSS remains poorly understood. Multiple factors have been attributed to the pathological mechanism, but only a couple of these hypotheses are popular in scientific circles. The current discussion focuses on underappreciated factors, temperature, natural IgM, and endotoxin, which may be critical components playing roles in dengue pathogenesis. PMID:24305068
Bhanot, Abhinav; Khanna, Arjun; Talwar, Deepak
We present the case of a 55-year-old female, who presented with 15 days of fever with rash, pancytopenia, and altered behavior. She was investigated for routine causes of fever with rash and multi organ dysfunction and treated for the same. As she tested negative for all routine causes of such an illness and did not show improvement to therapy, she was investigated for Crimean-Congo hemorrhagic fever and tested positive for the same. She was started on ribavirin, but eventually succumbed to her illness. This disease has rarely been reported from the Northern India and we need to have high clinical suspicion for this deadly disease so that appropriate therapy can be started in time for the patient and prophylaxis given to all inadvertently exposed. PMID:26430344
In: Chumakov, M.P (ed.) Crimean Hemorrhagi c Fever Mater. 3. Oblast. Nauch-Prakt. Konf. (Rostov-na-Donu , May, 1970) 1 41-44 Kuchin, VV, Yanovich, TD ...and L’vov, DK. 1972 Isolation o f Crimean haemorrhagic fever (CHF) virus from Hyalomma plumb eum ticks in Tadzhikistan. (In Russian)(In English... TD . 1970 Reports of the committee on coordinated study of prophylactic measures against Crimean hemorrhagic fever i n Rostov Oblast. (In russian)(In
Kiso, Maki; Takahashi, Kazumi; Sakai-Tagawa, Yuko; Shinya, Kyoko; Sakabe, Saori; Le, Quynh Mai; Ozawa, Makoto; Furuta, Yousuke; Kawaoka, Yoshihiro
The neuraminidase inhibitors oseltamivir and zanamivi are used to treat H5N1 influenza. However, oseltamivir-resistant H5N1 viruses have been isolated from oseltamivir-treated patients. Moreover, reassortment between H5N1 viruses and oseltamvir-resistant human H1N1 viruses currently circulating could create oseltamivir-resistant H5N1 viruses, rendering the oseltamivir stockpile obsolete. Therefore, there is a need for unique and effective antivirals to combat H5N1 influenza viruses. The investigational drug T-705 (favipiravir; 6-fluoro-3-hydroxy-2-pyrazinecarboxamide) has antiviral activity against seasonal influenza viruses and a mouse-adapted H5N1 influenza virus derived from a benign duck virus. However, its efficacy against highly pathogenic H5N1 viruses, which are substantially more virulent, remains unclear. Here, we demonstrate that T-705 effectively protects mice from lethal infection with oseltamivir-sensitive or -resistant highly pathogenic H5N1 viruses. Furthermore, our biochemical analysis suggests that T-705 ribofuranosyl triphosphate, an active form of T-705, acts like purines or purine nucleosides in human cells and does not inhibit human DNA synthesis. We conclude that T-705 shows promise as a therapeutic agent for the treatment of highly pathogenic H5N1 influenza patients.
Hervind, Widyaningsih, Y.
Concurrent infection with multiple infectious agents may occur in one patient, it appears frequently in dengue hemorrhagic fever (DHF) and typhoid fever. This paper depicted association between DHF and typhoid based on spatial point of view. Since paucity of data regarding dengue and typhoid co-infection, data that be used are the number of patients of those diseases in every district (kecamatan) in Jakarta in 2014 and 2015 obtained from Jakarta surveillance website. Poisson spatial scan statistics is used to detect DHF and typhoid hotspots area district in Jakarta separately. After obtain the hotspot, Fisher's exact test is applied to validate association between those two diseases' hotspot. The result exhibit hotspots of DHF and typhoid are located around central Jakarta. The further analysis used Poisson space-time scan statistics to reveal the hotspot in term of spatial and time. DHF and typhoid fever more likely occurr from January until May in the area which is relatively similar with pure spatial result. Preventive action could be done especially in the hotspot areas and it is required further study to observe the causes based on characteristics of the hotspot area.
In the 1960-70s, South Korea was still in the position of a science latecomer. Although the scientific research environment in South Korea at that time was insufficient, there was a scientist who achieved outcomes that could be recognized internationally while acting in South Korea. He was Ho Wang Lee(1928~ ) who found Hantann Virus that causes epidemic hemorrhagic fever for the first time in the world. It became a clue to identify causative viruses of hemorrhagic diseases that were scattered here and there throughout the world. In addition, these outcomes put Ho Wang Lee on the global center of research into epidemic hemorrhagic fever. This paper examines how a Korean scientist who was in the periphery of virology could go into the central area of virology. Also this article shows the process through which the virus found by Ho Wang Lee was registered with the international academia and he proceeded with follow-up research based on this progress to reach the level at which he generalized epidemic hemorrhagic fever related studies throughout the world. While he was conducting the studies, experimental methods that he had never experienced encountered him as new difficulties. He tried to solve the new difficulties faced in his changed status through devices of cooperation and connection. Ho Wang Lee's growth as a researcher can be seen as well as a view of a researcher that grew from a regional level to an international level and could advance from the area of non-mainstream into the mainstream. This analytic tool is meaningful in that it can be another method of examining the growth process of scientists in South Korea or developing countries.
Digoutte, J P
In the early 20th century, when it was discovered that the yellow fever virus was transmitted in its urban cycle by Aedes aegypti, measures of control were introduced leading to its disappearance. Progressive neglect of the disease, however, led to a new outbreak in 1927 during which the etiological agent was isolated; some years later a vaccine was discovered and yellow fever disappeared again. In the 1960s, rare cases of encephalitis were observed in young children after vaccination and the administration of the vaccine was forbidden for children under 10 years. Five years later, a new outbreak of yellow fever in Diourbel, Senegal, was linked to the presence of Aedes aegypti. In the late 1970s, the idea of a selvatic cycle for yellow fever arose. Thanks to new investigative techniques in Senegal and Côte d'Ivoire, the yellow fever virus was isolated from the reservoir of virus and vectors. The isolated virus was identified in monkeys and several vectors: Aedes furcifer, Aedes taylori, Aedes luteocephalus. Most importantly, the virus was isolated in male mosquitoes. Until recently, the only known cycle had been that of Haddow in East Africa. The virus circulate in the canopea between monkeys and Aedes africanus. These monkeys infect Aedes bromeliae when they come to eat in banana plantations. This cycle does not occur in West Africa. Vertical transmission is the main method of maintenance of the virus through the dry season. "Reservoirs of virus" are often mentioned in medical literature, monkeys having a short viremia whereas mosquitoes remain infected throughout their life cycle. In such a selvatic cycle, circulation can reach very high levels and no child would be able to escape an infecting bite and yet no clinical cases of yellow fever have been reported. The virulence--as it affects man--of the yellow fever virus in its wild cycle is very low. In areas where the virus can circulate in epidemic form, two types of circulation can be distinguished
Mourya, Devendra T; Yadav, Pragya D; Shete, Anita; Majumdar, Triparna D; Kanani, Amit; Kapadia, Dhirendra; Chandra, Vartika; Kachhiapatel, Anantdevesh J; Joshi, Pravinchandra T; Upadhyay, Kamalesh J; Dave, Paresh; Raval, Dinkar
Crimean-Congo hemorrhagic fever (CCHF) is a tick-borne viral disease that causes a fatal hemorrhagic illness in humans. This disease is asymptomatic in animals. CCHF was first confirmed in a nosocomial outbreak in 2011 in Gujarat State. Another notifiable outbreak occurred in July, 2013, in Karyana Village, Amreli district, Gujarat State. Anti-CCHF virus (CCHFV) immunoglobulin G (IgG) antibodies were detected in domestic animals from the adjoining villages of the affected area, indicating a considerable amount of positivity against domestic animals. The present serosurvey was carried out to determine the prevalence of CCHFV among bovine, sheep, and goat populations from 15 districts of Gujarat State, India. A total of 1226 serum samples from domestic animals were screened for IgG antibodies using a CCHF animal IgG enzyme-linked immunosorbent assay (ELISA) kit from the Centers for Disease Control and Prevention. Antibodies were detected in all the 15 districts surveyed; with positivity of 12.09%, 41.21%, and 33.62% in bovine, sheep, and goat respectively. This necessitates the surveillance of CCHFV IgG antibodies in animals and hemorrhagic fever cases in human.
Balaparameswara Rao, S. J.; Savardekar, Amey R.; Nandeesh, B. N.; Arivazhagan, A.
Background: Pituitary apoplexy occurs due to infarction or hemorrhage, within a pituitary adenoma or a nontumorous pituitary gland and can have catastrophic consequences. Dengue hemorrhagic fever (DHF) is a severe manifestation of the spectrum of dengue virus infection and is characterized by high-grade fever, thrombocytopenia, hemorrhagic tendencies, and increased vascular permeability. Cases of incidentalomas complicated by DHF and presenting with apoplexy are extremely rare. Case Description: We describe the case of a 45-year-old gentleman who suffered an attack of pituitary apoplexy while being treated for DHF. The issues pertaining to the management of hydrocephalus, timing of surgical intervention, and treatment of electrolyte imbalances encountered in the dual setting of DHF and pituitary apoplexy are discussed with reference to the outcome in our case. Conclusion: Although patients suffering from DHF harbor multiple factors, which may be precipitants of pituitary apoplexy, the association between these two conditions is rare and only few case reports document their coexistence. We review the pertinent literature and discuss the management dilemmas faced by us while dealing with these dual pathological states. PMID:28217383
Balaparameswara Rao, S J; Savardekar, Amey R; Nandeesh, B N; Arivazhagan, A
Pituitary apoplexy occurs due to infarction or hemorrhage, within a pituitary adenoma or a nontumorous pituitary gland and can have catastrophic consequences. Dengue hemorrhagic fever (DHF) is a severe manifestation of the spectrum of dengue virus infection and is characterized by high-grade fever, thrombocytopenia, hemorrhagic tendencies, and increased vascular permeability. Cases of incidentalomas complicated by DHF and presenting with apoplexy are extremely rare. We describe the case of a 45-year-old gentleman who suffered an attack of pituitary apoplexy while being treated for DHF. The issues pertaining to the management of hydrocephalus, timing of surgical intervention, and treatment of electrolyte imbalances encountered in the dual setting of DHF and pituitary apoplexy are discussed with reference to the outcome in our case. Although patients suffering from DHF harbor multiple factors, which may be precipitants of pituitary apoplexy, the association between these two conditions is rare and only few case reports document their coexistence. We review the pertinent literature and discuss the management dilemmas faced by us while dealing with these dual pathological states.
Karlberg, Helen; Sharifi-Mood, Batool; Mousavi-Jazi, Mehrdad; Dilcher, Meik; Lindegren, Gunnel; Mardani, Masoud; Bereskly, Sandor; Weidmann, Manfred; Mirazimi, Ali
Crimean-Congo hemorrhagic fever (CCHF) is an arthropod-borne disease of humans associated with a severe clinical picture, including hemorrhagic syndrome and a high mortality rate. CCHF virus is widely distributed throughout large areas of the world. To characterize the serological status in CCHF patients, paired clinical samples were collected from suspected CCHF patients and analyzed by microbiological and other laboratory analyses with the aim of: determining the presence of neutralizing antibodies against CCHF virus; investigating the cross-reactivity of these neutralizing antibodies against virus isolated from the same outbreak and against other available laboratory strain; and studying the relationship between the isolated virus with other virus by whole genome sequencing. Patients at Boo-Ali Hospital, Zahedan, Iran, with clinical symptoms ranging from mild to severe hemorrhagic fever were included in the study. Two serum samples were taken from each patient, the first as soon as the patient matched the criteria for CCHF notification and the second when the patient was discharged from hospital (2 weeks later). Commercial and in-house assays revealed a positive IgM signal in acute serum samples from six patients. A novel finding was that CCHF patients develop neutralizing antibodies soon after infection. Interestingly these antibodies were able to neutralize other CCHF virus strains too. The complete sequence of the Zahedan 2007 isolate, including the hitherto unknown first L-segment sequence, was identified using an original clinical sample from one patient with confirmed CCHF infection.
Spengler, Jessica R.; Bergeron, Eric; Rollin, Pierre E.; ...
Crimean-Congo hemorrhagic fever (CCHF) is a widely distributed, tick-borne viral disease. Humans are the only species known to develop illness after CCHF virus (CCHFV) infection, characterized by a nonspecific febrile illness that can progress to severe, often fatal, hemorrhagic disease. A variety of animals may serve as asymptomatic reservoirs of CCHFV in an endemic cycle of transmission. Seroepidemiological studies have been instrumental in elucidating CCHFV reservoirs and in determining endemic foci of viral transmission. Herein, we review over 50 years of CCHFV seroepidemiological studies in domestic and wild animals. Furthermore, this review highlights the role of livestock in the maintenancemore » and transmission of CCHFV, and provides a detailed summary of seroepidemiological studies of wild animal species, reflecting their relative roles in CCHFV ecology.« less
Spengler, Jessica R.; Bergeron, Éric; Rollin, Pierre E.
Crimean-Congo hemorrhagic fever (CCHF) is a widely distributed, tick-borne viral disease. Humans are the only species known to develop illness after CCHF virus (CCHFV) infection, characterized by a nonspecific febrile illness that can progress to severe, often fatal, hemorrhagic disease. A variety of animals may serve as asymptomatic reservoirs of CCHFV in an endemic cycle of transmission. Seroepidemiological studies have been instrumental in elucidating CCHFV reservoirs and in determining endemic foci of viral transmission. Herein, we review over 50 years of CCHFV seroepidemiological studies in domestic and wild animals. This review highlights the role of livestock in the maintenance and transmission of CCHFV, and provides a detailed summary of seroepidemiological studies of wild animal species, reflecting their relative roles in CCHFV ecology. PMID:26741652
Spengler, Jessica R; Bergeron, Éric; Rollin, Pierre E
Crimean-Congo hemorrhagic fever (CCHF) is a widely distributed, tick-borne viral disease. Humans are the only species known to develop illness after CCHF virus (CCHFV) infection, characterized by a nonspecific febrile illness that can progress to severe, often fatal, hemorrhagic disease. A variety of animals may serve as asymptomatic reservoirs of CCHFV in an endemic cycle of transmission. Seroepidemiological studies have been instrumental in elucidating CCHFV reservoirs and in determining endemic foci of viral transmission. Herein, we review over 50 years of CCHFV seroepidemiological studies in domestic and wild animals. This review highlights the role of livestock in the maintenance and transmission of CCHFV, and provides a detailed summary of seroepidemiological studies of wild animal species, reflecting their relative roles in CCHFV ecology.
Spengler, Jessica R.; Bergeron, Eric; Rollin, Pierre E.; Clements, Archie C. A.
Crimean-Congo hemorrhagic fever (CCHF) is a widely distributed, tick-borne viral disease. Humans are the only species known to develop illness after CCHF virus (CCHFV) infection, characterized by a nonspecific febrile illness that can progress to severe, often fatal, hemorrhagic disease. A variety of animals may serve as asymptomatic reservoirs of CCHFV in an endemic cycle of transmission. Seroepidemiological studies have been instrumental in elucidating CCHFV reservoirs and in determining endemic foci of viral transmission. Herein, we review over 50 years of CCHFV seroepidemiological studies in domestic and wild animals. Furthermore, this review highlights the role of livestock in the maintenance and transmission of CCHFV, and provides a detailed summary of seroepidemiological studies of wild animal species, reflecting their relative roles in CCHFV ecology.
Marzi, Andrea; Banadyga, Logan; Haddock, Elaine; Thomas, Tina; Shen, Kui; Horne, Eva J; Scott, Dana P; Feldmann, Heinz; Ebihara, Hideki
Marburg virus (MARV), a close relative of Ebola virus, is the causative agent of a severe human disease known as Marburg hemorrhagic fever (MHF). No licensed vaccine or therapeutic exists to treat MHF, and MARV is therefore classified as a Tier 1 select agent and a category A bioterrorism agent. In order to develop countermeasures against this severe disease, animal models that accurately recapitulate human disease are required. Here we describe the development of a novel, uniformly lethal Syrian golden hamster model of MHF using a hamster-adapted MARV variant Angola. Remarkably, this model displayed almost all of the clinical features of MHF seen in humans and non-human primates, including coagulation abnormalities, hemorrhagic manifestations, petechial rash, and a severely dysregulated immune response. This MHF hamster model represents a powerful tool for further dissecting MARV pathogenesis and accelerating the development of effective medical countermeasures against human MHF.
Bui-Mansfield, Liem T; Cressler, Dana K
Hemorrhagic fever with renal syndrome (HFRS) is a potentially fatal infectious disease with worldwide distribution. Its etiologic agents are viruses of the genus Hantavirus of the virus family Bunyaviridae. Hypothetical ease of production and distribution of these agents, with their propensity to incapacitate victims and overwhelm health care resources, lend themselves as significant potential biological agents of terrorism. HFRS has protean clinical manifestations, which may mimic upper respiratory tract infection, nephrolithiasis, and Hantavirus pulmonary syndrome and may delay proper treatment. Sequelae of HFRS, such as hemorrhage, acute renal failure, retroperitoneal edema, pancreatitis, pulmonary edema, and neurologic symptoms, can be detected by different imaging modalities. Medical providers caring for HFRS patients must be aware of its radiologic features, which may help to confirm its clinical diagnosis. In this article, the authors review the epidemiology, pathophysiology, clinical presentation, diagnosis, treatment, and complications of HFRS.
Xu, M.; Cao, C. X.; Guo, H. F.
Ebola hemorrhagic fever (EHF) is an acute hemorrhagic diseases caused by the Ebola virus, which is highly contagious. This paper aimed to explore the possible gathering area of EHF cases in West Africa in 2014, and identify endemic areas and their tendency by means of time-space analysis. We mapped distribution of EHF incidences and explored statistically significant space, time and space-time disease clusters. We utilized hotspot analysis to find the spatial clustering pattern on the basis of the actual outbreak cases. spatial-temporal cluster analysis is used to analyze the spatial or temporal distribution of agglomeration disease, examine whether its distribution is statistically significant. Local clusters were investigated using Kulldorff's scan statistic approach. The result reveals that the epidemic mainly gathered in the western part of Africa near north Atlantic with obvious regional distribution. For the current epidemic, we have found areas in high incidence of EVD by means of spatial cluster analysis.
Marzi, Andrea; Banadyga, Logan; Haddock, Elaine; Thomas, Tina; Shen, Kui; Horne, Eva J.; Scott, Dana P.; Feldmann, Heinz; Ebihara, Hideki
Marburg virus (MARV), a close relative of Ebola virus, is the causative agent of a severe human disease known as Marburg hemorrhagic fever (MHF). No licensed vaccine or therapeutic exists to treat MHF, and MARV is therefore classified as a Tier 1 select agent and a category A bioterrorism agent. In order to develop countermeasures against this severe disease, animal models that accurately recapitulate human disease are required. Here we describe the development of a novel, uniformly lethal Syrian golden hamster model of MHF using a hamster-adapted MARV variant Angola. Remarkably, this model displayed almost all of the clinical features of MHF seen in humans and non-human primates, including coagulation abnormalities, hemorrhagic manifestations, petechial rash, and a severely dysregulated immune response. This MHF hamster model represents a powerful tool for further dissecting MARV pathogenesis and accelerating the development of effective medical countermeasures against human MHF. PMID:27976688
Chen, Zhi-Hai; Qin, Xin-Cheng; Song, Rui; Shen, Yi; Chen, Xiao-Ping; Wang, Wen; Zhao, Yong-Xiang; Zhang, Jing-Shan; He, Jin-Rong; Li, Ming-Hui; Zhao, Xue-Hua; Liu, De-Wei; Fu, Xiao-Kang; Tian, Di; Li, Xing-Wang; Xu, Jianguo; Plyusnin, Alexander; Holmes, Edward C; Zhang, Yong-Zhen
Hemorrhagic fevers (HF) caused by viruses and bacteria are a major public health problem in China and characterized by variable clinical manifestations, such that it is often difficult to achieve accurate diagnosis and treatment. The causes of HF in 85 patients admitted to Dandong hospital, China, between 2011-2012 were determined by serological and PCR tests. Of these, 34 patients were diagnosed with Huaiyangshan hemorrhagic fever (HYSHF), 34 with Hemorrhagic Fever with Renal Syndrome (HFRS), one with murine typhus, and one with scrub typhus. Etiologic agents could not be determined in the 15 remaining patients. Phylogenetic analyses of recovered bacterial and viral sequences revealed that the causative infectious agents were closely related to those described in other geographical regions. As these diseases have no distinctive clinical features in their early stage, only 13 patients were initially accurately diagnosed. The distinctive clinical features of HFRS and HYSHF developed during disease progression. Enlarged lymph nodes, cough, sputum, and diarrhea were more common in HYSHF patients, while more HFRS cases presented with headache, sore throat, oliguria, percussion pain kidney area, and petechiae. Additionally, HYSHF patients displayed significantly lower levels of white blood cells (WBC), higher levels of creations kinase (CK) and alanine aminotransferase (ALT), while HFRS patients presented with an elevation of blood urea nitrogen (BUN) and creatinine (CREA). These clinical features will assist in the accurate diagnosis of both HYSHF and HFRS. Overall, our data reveal the complexity of pathogens causing HFs in a single Chinese hospital, and highlight the need for accurate early diagnosis and a better understanding of their distinctive clinical features.
Brown, Hannah; Kelly, Ann H
This article outlines a research program for an anthropology of viral hemorrhagic fevers (collectively known as VHFs). It begins by reviewing the social science literature on Ebola, Marburg, and Lassa fevers and charting areas for future ethnographic attention. We theoretically elaborate the hotspot as a way of integrating analysis of the two routes of VHF infection: from animal reservoirs to humans and between humans. Drawing together recent anthropological investigations of human–animal entanglements with an ethnographic interest in the social production of space, we seek to enrich conceptualizations of viral movement by elaborating the circumstances through which viruses, humans, objects, and animals come into contact. We suggest that attention to the material proximities—between animals, humans, and objects—that constitute the hotspot opens a frontier site for critical and methodological development in medical anthropology and for future collaborations in VHF management and control. PMID:24752909
Brown, Hannah; Kelly, Ann H
This article outlines a research program for an anthropology of viral hemorrhagic fevers (collectively known as VHFs). It begins by reviewing the social science literature on Ebola, Marburg, and Lassa fevers and charting areas for future ethnographic attention. We theoretically elaborate the hotspot as a way of integrating analysis of the two routes of VHF infection: from animal reservoirs to humans and between humans. Drawing together recent anthropological investigations of human-animal entanglements with an ethnographic interest in the social production of space, we seek to enrich conceptualizations of viral movement by elaborating the circumstances through which viruses, humans, objects, and animals come into contact. We suggest that attention to the material proximities-between animals, humans, and objects-that constitute the hotspot opens a frontier site for critical and methodological development in medical anthropology and for future collaborations in VHF management and control. © 2014 by the American Anthropological Association.
Bour, A; Reynes, J-M; Plaisancie, X; Dufour, J-F
Rodents are hantavirus hosts. In Europe, hantaviruses are responsible for human infections resulting in hemorrhagic fever with renal syndrome. Thousands of Puumala virus infections are reported annually in Europe, whereas human Seoul virus infections are rarely detected. We report the case of a 38-year-old patient who presented initially with flu-like symptoms and transitory blurred vision. He developed thrombocytopenia, acute renal failure, and elevated aminotransferases levels during the disease course, but the outcome was favorable with a full recovery. Afterwards, the hantavirus serology results were indicative of Seoul virus infection. This report serves to remind physicians to consider diagnosing hantavirus infection when observing the association of fever, acute renal failure and thrombocytopenia. Transitory blurred vision is a specific element to indicate this diagnosis. Copyright © 2015 Société Nationale Française de Médecine Interne (SNFMI). Published by Elsevier SAS. All rights reserved.
Geisbert, Thomas W; Daddario-DiCaprio, Kathleen M; Williams, Kinola J N; Geisbert, Joan B; Leung, Anders; Feldmann, Friederike; Hensley, Lisa E; Feldmann, Heinz; Jones, Steven M
Recombinant vesicular stomatitis virus (VSV) vectors expressing homologous filoviral glycoproteins can completely protect rhesus monkeys against Marburg virus when administered after exposure and can partially protect macaques after challenge with Zaire ebolavirus. Here, we administered a VSV vector expressing the Sudan ebolavirus (SEBOV) glycoprotein to four rhesus macaques shortly after exposure to SEBOV. All four animals survived SEBOV challenge, while a control animal that received a nonspecific vector developed fulminant SEBOV hemorrhagic fever and succumbed. This is the first demonstration of complete postexposure protection against an Ebola virus in nonhuman primates and provides further evidence that postexposure vaccination may have utility in treating exposures to filoviruses.
Atangana, Abdon; Goufo, Emile Franc Doungmo
For a given West African country, we constructed a model describing the spread of the deathly disease called Ebola hemorrhagic fever. The model was first constructed using the classical derivative and then converted to the generalized version using the beta-derivative. We studied in detail the endemic equilibrium points and provided the Eigen values associated using the Jacobian method. We furthered our investigation by solving the model numerically using an iteration method. The simulations were done in terms of time and beta. The study showed that, for small portion of infected individuals, the whole country could die out in a very short period of time in case there is not good prevention.
Yagci-Caglayik, Dilek; Korukluoglu, Gülay; Uyar, Yavuz
Turkey has been one of the most endemic regions since 2002, when Crimean-Congo hemorrhagic fever emerged worldwide. The aim of the present study was to estimate the seroprevelance of CCHF virus in humans who reside in rural and urban areas of known endemic and nonendemic selected provinces of Turkey by using commercial ELISA kit. CCHFV IgG antibodies were detected in 2.3% of the population. The most important risk factors for CCHF seropositivity, were older age, male gender, illiterate, farmer, animal husbandry, living in rural residence in adobe houses, and a previous tick bite history. © 2013 Wiley Periodicals, Inc.
Leblebicioglu, Hakan; Ozaras, Resat; Irmak, Hasan; Sencan, Irfan
Crimean-Congo hemorrhagic fever (CCHF) is a tick-borne viral disease of humans that affects a wide geographic area of Africa and Eurasia, including Turkey, Iran, Pakistan, Afghanistan and Russia. Since the first detection of CCHF cases in Turkey in 2002, more than 9700 patients have been reported, with an overall mortality rate just under 5%. This article assesses the present epidemiological situation of CCHF in Turkey, with an updated literature review, describes national practices and summarizes lessons learned in preparation for future outbreaks.
Enria, D A; Briggiler, A M; Levis, S; Vallejos, D; Maiztegui, J I; Canonico, P G
Tolerance and antiviral effect of ribavirin was studied in 6 patients with Argentine hemorrhagic fever (AHF) of more than 8 days of evolution. Administration of ribavirin resulted in a neutralization of viremia and a drop of endogenous interferon titers. The average time of death was delayed. A reversible anemia was the only adverse effect observed. From these results, we conclude that ribavirin has an antiviral effect in advanced cases of AHF, and that anemia, the only secondary reaction observed, can be easily managed. The possible beneficial effect of ribavirin during the initial days of AHF is discussed.
Enria, D A; Pinheiro, F
Hantaviruses and arenaviruses are naturally occurring viruses of rodents. Four South American hemorrhagic fevers caused by arenaviruses have emerged in the last 5 decades. All have similar clinical manifestations, with a case-fatality rate as high as 15% to 30%. Hantavirus infections have been increasingly recognized in South America since the description in 1993 of Hantavirus pulmonary syndrome. Given the diversity of rodent species in the region, it can be foreseen that many other viruses will be discovered, and some of them will be causing human illnesses of high public health impact.
Zapata, Juan C.; Cox, Dermot; Salvato, Maria S.
Viral hemorrhagic fevers (VHF) are acute zoonotic diseases that, early on, seem to cause platelet destruction or dysfunction. Here we present the four major ways viruses affect platelet development and function and new evidence of molecular factors that are preferentially induced by the more pathogenic members of the families Flaviviridae, Bunyaviridae, Arenaviridae, and Filoviridae. A systematic search was performed through the main medical electronic databases using as parameters all current findings concerning platelets in VHF. Additionally, the review contains information from conference proceedings. PMID:24921924
Kuznetsov, V I; Iushchuk, N D; Morrison, V V
The subjects of the study--patients with severe hemorrhagic fever with renal syndrome--were divided into two groups: those who were on hemodialysis, and those who were not. The study included evaluation of the phospholipid spectrum of erythrocyte membranes in the acute period and during recovery. The results revealed conformational shifts in the structure of the bilipid membrane layer, which were maximal during the acute phase of the disease, as well as less prominent and varied changes in the phospholipid spectrum during recovery. This allows determination of the terms of rehabilitation of the patients and substantiates administration of membrane stabilizers as a part of complex therapy of residual syndrome.
Clark, Danielle V; Mammen, Mammen P; Nisalak, Ananda; Puthimethee, Virat; Endy, Timothy P
Dengue fever and dengue hemorrhagic fever constitute a substantial health burden on the population in Thailand. In this study, the impact of symptomatic dengue virus infection on the families of patients hospitalized at the Kamphaeng Phet Provincial Hospital with laboratory-confirmed dengue in 2001 was assessed, and the disability-adjusted life years (DALYs) lost for fatal and non-fatal cases of dengue were calculated using population level data for Thailand. When we accounted for the direct cost of hospitalization, indirect costs due to loss of productivity, and the average number of persons infected per family, we observed a financial loss of approximately US$61 per family, which is more than the average monthly income in Thailand. The DALYs were calculated using select results from a family level survey, and resulted in an estimated 427 DALYs/million population in 2001. This figure is of the same order of magnitude as the impact of several diseases currently given priority in southeast Asia, such as the tropical cluster (trypanosomiasis, Chagas disease, schistosomiasis, leishmaniasis, lymphatic filariasis, and onchocerciasis), malaria, meningitis, and hepatitis. These results indicate that dengue prevention, control, and research should be considered equally important as that of diseases currently given priority.
Huang, J H; Wey, J J; Sun, Y C; Chin, C; Chien, L J; Wu, Y C
Two flaviviruses, dengue (DEN) virus and Japanese encephalitis (JE) virus, are important because of their global distribution and the frequency of epidemics in tropical and subtropical areas. To study the B-cell epitopes of nonstructural 1 (NS1) glycoprotein and anti-NS1 antibody response in DEN infection, a series of 15-mer synthetic peptides from the predicted B-cell linear epitopes of DEN-2 NS1 protein were prepared. Enzyme-linked immunosorbent assay (ELISA) was performed to analyze antibody responses to these peptides from sera of both DEN and JE patients. One peptide derived from DEN-2 NS1, D2 NS1-P1 (amino acids 1-15), was identified as the immunodominant epitope that reacted with sera from dengue fever (DF) patients but not JE patients. The isotype of D2 NS1-P1-specific antibodies was mainly immunoglobulin M (IgM) in all sera that tested positive. A specificity study demonstrated that sera from all four DEN types reacted with D2 NS1-P1. A dynamics study showed that specific antibodies to this peptide could be detected as early as 2 days after the onset of symptoms. We observed significant anti-D2 NS1-P1 antibody responses in 45% of patients with primary and secondary infections with DF or with dengue hemorrhagic fever. This is the first report demonstrating that significant anti-DEN NS1 antibodies can be induced in the sera of patients with primary DEN infection.
Lukashevich, Igor S.; Djavani, Mahmoud; Rodas, Juan D.; Zapata, Juan C.; Usborne, Amy; Emerson, Carol; Mitchen, Jacque; Jahrling, Peter B.; Salvato, Maria S.
Arenaviruses can cause hemorrhagic fever and death in primates and guinea pigs, but these viruses are not highly pathogenic for most rodent carriers. In the United States, arenaviruses precipitated outbreaks of hepatitis in captive monkeys, and they present an emerging health threat in the tropical areas of Africa and South America. We describe infection of rhesus macaques with the prototype arenavirus, lymphocytic choriome-ningitis virus (LCMV), using the WE strain that has been known to cause both encephalopathy and multifocal hemorrhage. Five macaques were inoculated: two by the intravenous (i.v.) and three by the intragastric (i.g.) route. Whereas the two i.v.-inoculated monkeys developed signs and lesions consistent with fatal hemorrhagic fever, the i.g.-inoculated monkeys had an attenuated infection with no disease. Pathological signs of the primate i.v. infection differ significantly from guinea pig arenavirus infections and make this a superior model for human viral hemorrhagic disease. PMID:11992578
Smither, Sophie J; Eastaugh, Lin S; Steward, Jackie A; Nelson, Michelle; Lenk, Robert P; Lever, Mark S
Filoviruses cause disease with high case fatality rates and are considered biological threat agents. Licensed post-exposure therapies that can be administered by the oral route are desired for safe and rapid distribution and uptake in the event of exposure or outbreaks. Favipiravir or T-705 has broad antiviral activity and has already undergone phase II and is undergoing phase III clinical trials for influenza. Here we report the first use of T-705 against Ebola virus. T-705 gave 100% protection against aerosol Ebola virus E718 infection; protection was shown in immune-deficient mice after 14 days of twice-daily dosing. T-705 was also shown to inhibit Ebola virus infection in cell culture. T-705 is likely to be licensed for use against influenza in the near future and could also be used with a new indication for filovirus infection.
Colebunders, Robert; Tshomba, Antoine; Van Kerkhove, Maria D; Bausch, Daniel G; Campbell, Pat; Libande, Modeste; Pirard, Patricia; Tshioko, Florimond; Mardel, Simon; Mulangu, Sabue; Sleurs, Hilde; Rollin, Pierre E; Muyembe-Tamfum, Jean-Jacques; Jeffs, Benjamin; Borchert, Matthias
The objective of the present study was to describe day of onset and duration of symptoms of Marburg hemorrhagic fever (MHF), to summarize the treatments applied, and to assess the quality of clinical documentation. Surveillance and clinical records of 77 patients with MHF cases were reviewed. Initial symptoms included fever, headache, general pain, nausea, vomiting, and anorexia (median day of onset, day 1-2), followed by hemorrhagic manifestations (day 5-8+), and terminal symptoms included confusion, agitation, coma, anuria, and shock. Treatment in isolation wards was acceptable, but the quality of clinical documentation was unsatisfactory. Improved clinical documentation is necessary for a basic evaluation of supportive treatment.
Marzi, Andrea; Yoshida, Reiko; Miyamoto, Hiroko; Ishijima, Mari; Suzuki, Yasuhiko; Higuchi, Megumi; Matsuyama, Yukie; Igarashi, Manabu; Nakayama, Eri; Kuroda, Makoto; Saijo, Masayuki; Feldmann, Friederike; Brining, Douglas; Feldmann, Heinz; Takada, Ayato
Ebola virus (EBOV) is the causative agent of severe hemorrhagic fever in primates, with human case fatality rates up to 90%. Today, there is neither a licensed vaccine nor a treatment available for Ebola hemorrhagic fever (EHF). Single monoclonal antibodies (MAbs) specific for Zaire ebolavirus (ZEBOV) have been successfully used in passive immunization experiments in rodent models, but have failed to protect nonhuman primates from lethal disease. In this study, we used two clones of human-mouse chimeric MAbs (ch133 and ch226) with strong neutralizing activity against ZEBOV and evaluated their protective potential in a rhesus macaque model of EHF. Reduced viral loads and partial protection were observed in animals given MAbs ch133 and ch226 combined intravenously at 24 hours before and 24 and 72 hours after challenge. MAbs circulated in the blood of a surviving animal until virus-induced IgG responses were detected. In contrast, serum MAb concentrations decreased to undetectable levels at terminal stages of disease in animals that succumbed to infection, indicating substantial consumption of these antibodies due to virus replication. Accordingly, the rapid decrease of serum MAbs was clearly associated with increased viremia in non-survivors. Our results indicate that EBOV neutralizing antibodies, particularly in combination with other therapeutic strategies, might be beneficial in reducing viral loads and prolonging disease progression during EHF.
Mohamed, Mohamed M G; Shwaib, Hussam M; Fahim, Monica M; Ahmed, Elhamy A; Omer, Mawadda K; Monier, Islam A; Balla, Siham A
Ebola hemorrhagic fever (EHF) is an emerging threat to public health. The last epidemic in West Africa had a great effect on the affected communities. Timely and effective interventions were necessary in addition to community participation to control the epidemic. The knowledge, attitude and practices of vulnerable communities remain unknown, particularly in Sudan. The aim of this study was to explore the knowledge, attitude and practices of rural residents in Sudan regarding Ebola hemorrhagic fever. We conducted a cross sectional, community-based large-scale study in Al Gaziera state in rural Sudan in eight localities. In total, 1500 random adult participants were selected. The participants were assessed by a predesigned pretested questionnaire regarding their knowledge, attitude and practices regarding Ebola. Their sources of information were determined, and we assessed demographic factors as predictors of knowledge. We found poor knowledge, a fair attitude and suboptimal practices among the participants. The main sources of information were the press and media. Education was the only predictor of knowledge regarding Ebola. A lack of knowledge and suboptimal preventive practices mandates orientation and education programs to raise public awareness. Health care providers are advised to engage more in educating the community.
Background Pakistan is considered as an endemic country for Crimean-Congo Hemorrhagic fever with numerous outbreaks and sporadic cases reported during the past two decades. Majority of cases are reported from Baluchistan province with subsequent transmissions to non-endemic regions mainly through infected animals directly or via infested ticks. We hereby describe the molecular investigations of CCHF cases reported during 2008 in Quetta city of Baluchistan province. Methods Serum Samples from 44 patients, with clinical signs of hemorrhagic fever attending a tertiary care hospital in Quetta city, were collected and tested for CCHF virus antigen and genomic RNA, using capture IgM EIA kit and standard RT-PCR assay, respectively. The partial S-gene fragments were directly sequenced to get information related to the prevailing CCHFV genotypes and their molecular epidemiology in Pakistan. Results Out of the total forty four, sixteen (36%) samples were found positive for CCHF IgM. Similarly, viral RNA was detected in six (16%) samples. Phylogenetic analysis revealed that all study viruses belong to genotype Asia-1 with closest similarity (99-100%) to the previously reported strains from Pakistan, Afghanistan and Iran. Conclusion We conclude that CCHF virus remains endemic within Baluchistan and its neighboring regions of Afghanistan warranting a need of incessant surveillance activities. PMID:23641865
Sas, Miriam A; Mertens, Marc; Isselmou, Ekaterina; Reimer, Nicole; El Mamy, Bezeid O; Doumbia, Baba; Groschup, Martin H
Crimean-Congo hemorrhagic fever virus (CCHFV) was detected for the first time in Mauritania in 1983 and several CCHFV outbreaks were reported in the following years. The last human case was diagnosed in 2015. However, no recent data exist about the prevalence of CCHFV in animals, although it is already described that prevalence studies in animals serve as good risk indicators. CCHFV can cause a severe hemorrhagic fever with a high case fatality rate in humans. Therefore, a precise risk assessment on the basis of updated data is very important. This article gives an overview about the current CCHFV prevalence in cattle in Mauritania. A seroprevalence study was carried out using 495 cattle sera from Mauritania, which were collected in the year 2013. The sera were analyzed by an inhouse CCHFV-IgG-ELISA. As second screening test, an adapted commercial CCHFV-IgG-ELISA was performed. Inconclusive sera were additionally tested by a modified commercial CCHFV-IgG-IFA. All assays showed high diagnostic sensitivity (>95%) and specificity (>98%). The overall prevalence of CCHFV-specific antibodies found in Mauritanian cattle was 67%, ranging from 56% to 90% in different provinces. This study shows a very high CCHFV-specific antibody prevalence in cattle in Mauritania. It is the highest seroprevalence detected in Mauritania so far. This strengthens the hypothesis that CCHFV is a serious and ongoing threat for public health in Mauritania.
Timen, Aura; Isken, Leslie D; Willemse, Patricia; van den Berkmortel, Franchette; Koopmans, Marion P G; van Oudheusden, Danielle E C; Bleeker-Rovers, Chantal P; Brouwer, Annemarie E; Grol, Richard P T M; Hulscher, Marlies E J L; van Dissel, Jaap T
After an imported case of Marburg hemorrhagic fever was reported in 2008 in the Netherlands, control measures to prevent transmission were implemented. To evaluate consequences of these measures, we administered a structured questionnaire to 130 contacts classified as either having high-risk or low-risk exposure to body fluids of the case-patient; 77 (59.2%) of 130 contacts responded. A total of 67 (87.0%) of 77 respondents agreed that temperature monitoring and reporting was necessary, significantly more often among high-risk than low-risk contacts (p<0.001). Strict compliance with daily temperature monitoring decreased from 80.5% (62/77) during week 1 to 66.2% (51/77) during week 3. Contacts expressed concern about development of Marburg hemorrhagic fever (58.4%, 45/77) and infecting a family member (40.2%, 31/77). High-risk contacts had significantly higher scores on psychological impact scales (p<0.001) during and after the monitoring period. Public health authorities should specifically address consequences of control measures on the daily life of contacts.
Mostafavi, Ehsan; Chinikar, Sadegh; Bokaei, Saeid; Haghdoost, Aliakbar
This study was conducted to determine the predicting factors of Crimean Congo hemorrhagic fever (CCHF) in Zabol and Zahedan, from where more than 60% of all national cases are reported, in order to improve CCHF disease surveillance and to target control efforts. Data were collected from the National Reference Laboratory on Arboviruses and Viral Hemorrhagic Fevers, the national meteorology organization, the veterinary organization, and the national statistics center of Iran. A Poisson regression analysis was applied for the temporal modeling of human samples between 2000 and 2006. The modeling fitness was checked with data from 2007. This modeling revealed that the disease occurrence followed a seasonal pattern. The maximum temperature and relative humidity in previous months was found to positively affect the occurrence of the disease. Variables such as the level of livestock imports and the number of slaughtered animals were also found to be influential in the occurrence of the disease. The pseudo R(2) was 0.51 in the final model. The model predicted the number of cases 1 month in advance with more or less acceptable accuracy. Therefore, it appears that the model might be useful as part of an early warning system. Copyright © 2013 International Society for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.
Papa, Anna; Weber, Friedemann; Hewson, Roger; Weidmann, Manfred; Koksal, Iftihar; Korukluoglu, Gulay; Mirazimi, Ali
Crimean-Congo hemorrhagic fever (CCHF) is the most widespread tick-borne disease of humans, occurring from western China to the Balkans in Eurasia and south throughout the length of Africa. Its incidence has increased over the past decade, particularly in Turkey and Iran, and the disease has also emerged in India. Research has been hindered by limited laboratory capacity in many regions where the disease is prevalent, indicating the need for collaboration between investigators in endemic countries and those with greater scientific resources. In an effort to increase such collaboration, the First International Conference on Crimean-Congo hemorrhagic fever was held in Thessaloniki, Greece, from February 13 to 14, 2015. This meeting followed the conclusion of an EU-supported Collaborative Project under the Health Cooperation Work Programme of the 7th Framework Programme (Grant agreement No. 260427). It is expected to be the first in a series of meetings that will bring together researchers from around the world to exchange knowledge and experience on various aspects of CCHF. This report summarizes major presentations by the invited speakers at the First International Conference on CCHF.
Jeeva, Subbiah; Pador, Sean; Voss, Brittany; Ganaie, Safder Saieed; Mir, Mohammad Ayoub
Crimean Congo hemorrhagic fever, a zoonotic viral disease, has high mortality rate in humans. There is currently no vaccine for Crimean Congo hemorrhagic fever virus (CCHFV) and chemical interventions are limited. The three negative sense genomic RNA segments of CCHFV are specifically encapsidated by the nucleocapsid protein into three ribonucleocapsids, which serve as templates for the viral RNA dependent RNA polymerase. Here we demonstrate that CCHFV nucleocapsid protein has two distinct binding modes for double and single strand RNA. In the double strand RNA binding mode, the nucleocapsid protein preferentially binds to the vRNA panhandle formed by the base pairing of complementary nucleotides at the 5' and 3' termini of viral genome. The CCHFV nucleocapsid protein does not have RNA helix unwinding activity and hence does not melt the duplex vRNA panhandle after binding. In the single strand RNA binding mode, the nucleocapsid protein does not discriminate between viral and non-viral RNA molecules. Binding of both vRNA panhandle and single strand RNA induce a conformational change in the nucleocapsid protein. Nucleocapsid protein remains in a unique conformational state due to simultaneously binding of structurally distinct vRNA panhandle and single strand RNA substrates. Although the role of dual RNA binding modes in the virus replication cycle is unknown, their involvement in the packaging of viral genome and regulation of CCHFV replication in conjunction with RdRp and host derived RNA regulators is highly likely.
Isken, Leslie D.; Willemse, Patricia; van den Berkmortel, Franchette; Koopmans, Marion P.G.; van Oudheusden, Danielle E.C.; Bleeker-Rovers, Chantal P.; Brouwer, Annemarie E.; Grol, Richard P.T.M.; Hulscher, Marlies E.J.L.; van Dissel, Jaap T.
After an imported case of Marburg hemorrhagic fever was reported in 2008 in the Netherlands, control measures to prevent transmission were implemented. To evaluate consequences of these measures, we administered a structured questionnaire to 130 contacts classified as either having high-risk or low-risk exposure to body fluids of the case-patient; 77 (59.2%) of 130 contacts responded. A total of 67 (87.0%) of 77 respondents agreed that temperature monitoring and reporting was necessary, significantly more often among high-risk than low-risk contacts (p<0.001). Strict compliance with daily temperature monitoring decreased from 80.5% (62/77) during week 1 to 66.2% (51/77) during week 3. Contacts expressed concern about development of Marburg hemorrhagic fever (58.4%, 45/77) and infecting a family member (40.2%, 31/77). High-risk contacts had significantly higher scores on psychological impact scales (p<0.001) during and after the monitoring period. Public health authorities should specifically address consequences of control measures on the daily life of contacts. PMID:22710186
Smith, Lauren M.; Hensley, Lisa E.; Geisbert, Thomas W.; Johnson, Joshua; Stossel, Andrea; Honko, Anna; Yen, Judy Y.; Geisbert, Joan; Paragas, Jason; Fritz, Elizabeth; Olinger, Gene; Young, Howard A.; Rubins, Kathleen H.; Karp, Christopher L.
There is a clear need for novel, effective therapeutic approaches to hemorrhagic fever due to filoviruses. Ebola virus hemorrhagic fever is associated with robust interferon (IFN)–α production, with plasma concentrations of IFN-α that greatly (60- to 100-fold) exceed those seen in other viral infections, but little IFN-β production. While all of the type I IFNs signal through the same receptor complex, both quantitative and qualitative differences in biological activity are observed after stimulation of the receptor complex with different type I IFNs. Taken together, this suggested potential for IFN-β therapy in filovirus infection. Here we show that early postexposure treatment with IFN-β significantly increased survival time of rhesus macaques infected with a lethal dose of Ebola virus, although it failed to alter mortality. Early treatment with IFN-β also significantly increased survival time after Marburg virus infection. IFN-β may have promise as an adjunctive postexposure therapy in filovirus infection. PMID:23255566
Delgado, Simon; Erickson, Bobbie R.; Agudo, Roberto; Blair, Patrick J.; Vallejo, Efrain; Albariño, César G.; Vargas, Jorge; Comer, James A.; Rollin, Pierre E.; Ksiazek, Thomas G.; Olson, James G.; Nichol, Stuart T.
A small focus of hemorrhagic fever (HF) cases occurred near Cochabamba, Bolivia, in December 2003 and January 2004. Specimens were available from only one fatal case, which had a clinical course that included fever, headache, arthralgia, myalgia, and vomiting with subsequent deterioration and multiple hemorrhagic signs. A non-cytopathic virus was isolated from two of the patient serum samples, and identified as an arenavirus by IFA staining with a rabbit polyvalent antiserum raised against South American arenaviruses known to be associated with HF (Guanarito, Machupo, and Sabiá). RT-PCR analysis and subsequent analysis of the complete virus S and L RNA segment sequences identified the virus as a member of the New World Clade B arenaviruses, which includes all the pathogenic South American arenaviruses. The virus was shown to be most closely related to Sabiá virus, but with 26% and 30% nucleotide difference in the S and L segments, and 26%, 28%, 15% and 22% amino acid differences for the L, Z, N, and GP proteins, respectively, indicating the virus represents a newly discovered arenavirus, for which we propose the name Chapare virus. In conclusion, two different arenaviruses, Machupo and Chapare, can be associated with severe HF cases in Bolivia. PMID:18421377
Müller, Marcel A.; Devignot, Stéphanie; Lattwein, Erik; Corman, Victor Max; Maganga, Gaël D.; Gloza-Rausch, Florian; Binger, Tabea; Vallo, Peter; Emmerich, Petra; Cottontail, Veronika M.; Tschapka, Marco; Oppong, Samuel; Drexler, Jan Felix; Weber, Friedemann; Leroy, Eric M.; Drosten, Christian
Crimean Congo hemorrhagic fever virus (CCHFV) is a highly virulent tick-borne pathogen that causes hemorrhagic fever in humans. The geographic range of human CCHF cases largely reflects the presence of ticks. However, highly similar CCHFV lineages occur in geographically distant regions. Tick-infested migratory birds have been suggested, but not confirmed, to contribute to the dispersal. Bats have recently been shown to carry nairoviruses distinct from CCHFV. In order to assess the presence of CCHFV in a wide range of bat species over a wide geographic range, we analyzed 1,135 sera from 16 different bat species collected in Congo, Gabon, Ghana, Germany, and Panama. Using a CCHFV glycoprotein-based indirect immunofluorescence test (IIFT), we identified reactive antibodies in 10.0% (114/1,135) of tested bats, pertaining to 12/16 tested species. Depending on the species, 3.6%–42.9% of cave-dwelling bats and 0.6%–7.1% of foliage-living bats were seropositive (two-tailed t-test, p = 0.0447 cave versus foliage). 11/30 IIFT-reactive sera from 10 different African bat species had neutralizing activity in a virus-like particle assay. Neutralization of full CCHFV was confirmed in 5 of 7 sera. Widespread infection of cave-dwelling bats may indicate a role for bats in the life cycle and geographic dispersal of CCHFV. PMID:27217069
Uckun, Fatih M; Petkevich, Alexander S; Vassilev, Alexei O; Tibbles, Heather E; Titov, Leonid
Background The potential use of microorganisms as agents of biological warfare (BW) is a growing concern. Lassa virus, a member of the Arenavirus class of Hemorrhagic fever (HF) viruses has emerged as a worldwide concern among public health officials. The purpose of the present study was to further elucidate the antiviral activity spectrum of stampidine, a novel nucleoside analog with potent anti-viral activity against the immunodeficiency viruses HIV-1, HIV-2, and FIV, by examining its effects on survival of mice challenged with Lassa virus. Methods We examined the therapeutic effect of Stampidine in CBA mice inoculated with intracerebral injections of the Josiah strain of Lassa virus. Mice were treated either with vehicle or nontoxic doses of stampidine administered intraperitoneally 24 hours prior to, 1 hour prior to, and 24 hours, 48 hours, 72 hours, and 96 hours after virus inoculation. Results The probability of survival following the Lassa challenge was significantly improved for stampidine treated mice (Kaplan Meier, Chi-squared = 11.7, df = 2, Log-Rank p-value = 0.003). Conclusion Therefore, stampidine shows clinical potential as a new agent for treatment of viral hemorrhagic fevers caused by Lassa virus. PMID:14720304
Almiş, Habip; Yakıncı, Cengiz
Brucellosis which is a zoonotic infection, is an important public health problem in Turkey and all over the world. The disease may involve many organs and systems. Since the symptoms of brucellosis are non-specific, difficulties in differential diagnosis and misdiagnosis are frequent. In this case report we present a case of brucellosis, misdiagnosed as Crimean-Congo hemorrhagic fever (CCHF). A 13-year-old boy was referred from another medical center with preliminary diagnosis of CCHF and admitted to our clinic with fever and a history of presence of a tick on his back. His physical observation only included splenomegaly. The laboratory results on admission were anemia, thrombocytopenia, elevation of acute phase reactants and liver transaminase levels. Abdominal ultrasonography revealed splenomegaly. Since the patient had anemia, epistaxis, fever and thrombocytopenia, he was initially diagnosed as CCHF. Meantime serum sample of the patient had been sent to Refik Saydam National Public Health Agency for CCHF PCR test. The fever of the patient could not be controlled. His detailed medical history revealed stockbreeding and consumption of raw milk products. Patient's signs and symptoms were also compatible with brucellosis and standard tube agglutination test for brucellosis was positive at 1/1280 titer in serum. The patient was diagnosed as brucellosis and the treatment was started with combination of rifampicin (1 x 600 mg/day) and doxycycline (2 x 100 mg/day). Blood cultures yielded negative result. The PCR tests for CCHF was found also negative. His fever and other complaints improved with treatment which was completed in six weeks and the follow-up was without complications. Turkey is endemic both for brucellosis and CCHF. This case was reported to emphasize that the cases of brucellosis could mimic other diseases and brucellosis should also be considered in the differential diagnosis of CCHF.
fever in Nonhuman Primate Models" Date d?JO )oi Date )&*7 Date Dissertation and Abstract Approved: Robert Friedm ,M.D. Department of Pathology Committee...in Nonhuman Primate Models" is appropriately acknowledged and, beyond brief excerpts, is with the permission of the copyright owner. ~~l!!~ Kathleen...stomatitis virus vectors against Marburg hemorrhagic fever in nonhuman primate models By Kathleen Daddario-DiCaprio Dissertation
Mayurasakorn, Saengdao; Suttipun, Nipar
This study compared the case fatality ratio (CFR) of dengue shock syndrome (DSS) patients admitted to Buri Ram Hospital, an area with CFR of 0.11, 0.43 and 0.23% in 2002, 2003 and 2004, respectively, to obtain a provincial model for dengue case management using the I. development of a special program for strengthening dengue hemorrhagic fever (DHF) case management (No deaths in DSS patients), II. a retrospective review of the medical records of dengue fever (DF), DHF and DSS patients referred to Buri Ram Hospital. We compared the data during the 3 periods of the implementation of this program. Data was statistically analyzed using chi2 or Fisher's exact test for categorical variables, one-way ANOVA for continuous data with normal distribution and Kruskal-Wallis test for nonparametric variables. The numbers of DF, DHF and DSS cases in Buri Ram were 1332, 1700 and 1630 person, respectively, during 2006-2008. The number of DSS patients increased after implementation of the program: 12.2, 51.2 and 47.22 for 2006, 2007 and 2008, respectively, but the complications of the disease decreased. The CFR during 2006, 2007 and 2008 were 0.15, 0 and 0.06% (p > 0.05). The program for strengthening DHF case management did improve clinical outcomes in dengue patients after the implementation. The CFR in 2008 was only 0.06%, lower than the goal of the Ministry of Public Health (<0.13%). This program is still running, sustaining low CFR in dengue patients. It may be used as a model for other provinces in Thailand that have high dengue deaths.
Moncla, Louise H.; Weiler, Andrea M.; Charlier, Olivia; Rojas, Oscar; Byrum, Russell; Ragland, Dan R.; Cohen, Melanie; Sanford, Hannah B.; Qin, Jing
ABSTRACT Simian hemorrhagic fever (SHF) is a highly lethal disease in captive macaques. Three distinct arteriviruses are known etiological agents of past SHF epizootics, but only one, simian hemorrhagic fever virus (SHFV), has been isolated in cell culture. The natural reservoir(s) of the three viruses have yet to be identified, but African nonhuman primates are suspected. Eleven additional divergent simian arteriviruses have been detected recently in diverse and apparently healthy African cercopithecid monkeys. Here, we report the successful isolation in MARC-145 cell culture of one of these viruses, Kibale red colobus virus 1 (KRCV-1), from serum of a naturally infected red colobus (Procolobus [Piliocolobus] rufomitratus tephrosceles) sampled in Kibale National Park, Uganda. Intramuscular (i.m.) injection of KRCV-1 into four cynomolgus macaques (Macaca fascicularis) resulted in a self-limiting nonlethal disease characterized by depressive behavioral changes, disturbance in coagulation parameters, and liver enzyme elevations. In contrast, i.m. injection of SHFV resulted in typical lethal SHF characterized by mild fever, lethargy, lymphoid depletion, lymphoid and hepatocellular necrosis, low platelet counts, increased liver enzyme concentrations, coagulation abnormalities, and increasing viral loads. As hypothesized based on the genetic and presumed antigenic distance between KRCV-1 and SHFV, all four macaques that had survived KRCV-1 injection died of SHF after subsequent SHFV injection, indicating a lack of protective heterotypic immunity. Our data indicate that SHF is a disease of macaques that in all likelihood can be caused by a number of distinct simian arteriviruses, although with different severity depending on the specific arterivirus involved. Consequently, we recommend that current screening procedures for SHFV in primate-holding facilities be modified to detect all known simian arteriviruses. PMID:26908578
Mostafavi, Ehsan; Pourhossein, Behzad; Chinikar, Sadegh
Crimean-Congo hemorrhagic fever (CCHF) is a zoonotic disease, which is usually transmitted to humans by tick bites or contact with blood or other infected tissues of livestock. Patients suffering from CCHF demonstrate an extensive spectrum of clinical symptoms. As it can take considerable time from suspecting the disease in hospital until reaching a definitive diagnosis in the laboratory, understanding the clinical symptoms and laboratory findings of CCHF patients is of paramount importance for clinicians. The data were collected from patients who were referred to the Laboratory of Arboviruses and Viral Hemorrhagic Fevers at the Pasteur institute of Iran with a primary diagnosis of CCHF between 1999 and 2012 and were assessed by molecular and serologic tests. Referred patients were divided into two groups: patients with a CCHF positive result and patients with a CCHF negative result. The laboratory and clinical findings of these two groups were then compared. Two-thousand five hundred thirty-six probable cases of CCHF were referred to the laboratory, of which 871 cases (34.3%) were confirmed to be CCHF. Contact with infected humans and animals increased the CCHF infection risk (P < 0.001). A tick bite was not a risk factor. Fever; bleeding, vomiting, leucopoenia, thrombocytopenia, and increases in alanine transaminase (ALT) and aspartate transaminase (AST) levels were also indicative of CCHF infection. Accurate and speedy diagnosis of CCHF and appropriate treatment play an important role in patient survival and the application of the findings of this study can prove helpful as a key for early diagnosis.
ASLAM, SAADIA; LATIF, MUHAMMAD SHAHZAD; DAUD, MUHAMMAD; RAHMAN, ZIA UR; TABASSUM, BUSHRA; RIAZ, MUHAMMAD SOHAIL; KHAN, ANWAR; TARIQ, MUHAMMAD; HUSNAIN, TAYYAB
Crimean-Congo hemorrhagic fever (CCHF) is a vector-borne viral disease, widely distributed in different regions of the world. The fever is caused by the CCHF virus (CCHFV), which belongs to the Nairovirus genus and Bunyaviridae family. The virus is clustered in seven genotypes, which are Africa-1, Africa-2, Africa-3, Europe-1, Europe-2, Asia-1 and Asia-2. The virus is highly pathogenic in nature, easily transmissible and has a high case fatality rate of 10–40%. The reservoir and vector of CCHFV are the ticks of the Hyalomma genus. Therefore, the circulation of this virus depends upon the distribution of the ticks. The virus can be transmitted from tick to animal, animal to human and human to human. The major symptoms include headache, high fever, abdominal pain, myalgia, hypotension and flushed face. As the disease progresses, severe symptoms start appearing, which include petechiae, ecchymosis, epistaxis, bleeding gums and emesis. Enzyme-linked immunosorbent assay, quantitative polymerase chain reaction, antigen detection, serum neutralization and isolation of the virus by cell culture are the diagnostic techniques used for this viral infection. There is no specific antiviral therapy available thus far. However, ribavirin has been approved by the World Health Organization for the treatment of CCHFV infection. Awareness campaigns regarding the risk factors and control measures can aid in reducing the spread of this disease to a greater extent, particularly in developing countries. PMID:26870327
Ibrahim, Sofi M; Aitichou, Mohamed; Hardick, Justin; Blow, Jamie; O'Guinn, Monica L; Schmaljohn, Connie
The development of sensitive and specific nucleic acid diagnostic assays for viral pathogens is essential for proper medical intervention. This chapter describes four fluorescence-based PCR assays to detect the Crimean-Congo Hemorrhagic Fever (CCHFV), Andes (ANDV), Hantaan (HANV), and Sandfly Fever Sicilian (SFSV) Viruses. These assays are based on species-specific hydrolysis probes targeting the nucleocapsid protein gene for CCHFV and SFSV and the glycoprotein gene for ANDV and HANV. All four assays were optimized for LightCycler 2.0 (Roche Diagnostics, Indianapolis, IN) or Ruggedized Advanced Pathogen Identification Device (R.A.P.I.D.; Idaho Technology Inc., Salt Lake City, UT). The assays were evaluated using the protocols described in the Subheading 3. The limits of detection were approximately 5, 2, 2, and 5 plaque-forming units (PFUs) for CCHFV, ANDV, HTNV, and SFSV assays, respectively. The sensitivity and specificity of the assays were evaluated with test panels that consisted of 20-60 known positive and 30-135 known negative samples, representing 7-34 genetically diverse bacterial and viral species. The CCHFV assay detected 59 out of the 60 positive samples and no false positives, resulting in 98.3% sensitivity at LOD of 5 PFU and 100% specificity. The ANDV and HTNV assays correctly identified all the positive samples with no false positive reactions; therefore, the sensitivity and specificity of these assays were determined to be 100% at LOD of 2 PFU. The SFSV assay missed three positive samples and cross-reacted with one of 48 negative samples, resulting in 95% sensitivity at LOD of 5 PFU and 98% specificity.
Mourya, Devendra T; Yadav, Pragya D; Shete, Anita M; Sathe, Padmakar S; Sarkale, Prasad C; Pattnaik, Bramhadev; Sharma, Gaurav; Upadhyay, Kamlesh J; Gosavi, Surekha; Patil, Deepak Y; Chaubal, Gouri Y; Majumdar, Triparna D; Katoch, Vishwa M
We conducted a cross-sectional serosurvey of Crimean-Congo hemorrhagic fever (CCHF) among livestock in 22 states and 1 union territory of India. A total of 5,636 samples from bovines, sheep, and goats were screened for CCHF virus IgG. IgG was detected in 354 samples, indicating that this virus is widespread in this country.
Yadav, Pragya D.; Shete, Anita M.; Sathe, Padmakar S.; Sarkale, Prasad C.; Pattnaik, Bramhadev; Sharma, Gaurav; Upadhyay, Kamlesh J.; Gosavi, Surekha; Patil, Deepak Y.; Chaubal, Gouri Y.; Majumdar, Triparna D.; Katoch, Vishwa M.
We conducted a cross-sectional serosurvey of Crimean-Congo hemorrhagic fever (CCHF) among livestock in 22 states and 1 union territory of India. A total of 5,636 samples from bovines, sheep, and goats were screened for CCHF virus IgG. IgG was detected in 354 samples, indicating that this virus is widespread in this country. PMID:26402332
Mamuchishvili, Nana; Salyer, Stephanie J; Stauffer, Kendra; Geleishvili, Marika; Zakhashvili, Khatuna; Morgan, Juliette
During January-September 2014, Georgia's National Centers for Disease Control and Public Health (NCDC) detected 22 cases of Crimean-Congo hemorrhagic fever (CCHF) in the country. CCHF is caused by infection with a tickborne virus of the Bunyaviridae family. Transmission occurs from the bite of an infected tick or from crushing an infected tick with bare skin. Secondary transmission can result from contact with blood or tissues of infected animals and humans. CCHF initially manifests as a nonspecific febrile illness that progresses to a hemorrhagic phase, marked by rapidly developing symptoms leading to multiorgan failure, shock, and death in severe cases. The clinical severity, transmissibility, and infectiousness of CCHF are responsible for its categorization as a viral hemorrhagic fever high-priority bioterrorism agent.
Haverkort, J J Mark; Minderhoud, A L C Ben; Wind, Jelte D D; Leenen, Luke P H; Hoepelman, Andy I M; Ellerbroek, Pauline M
The Major Incident Hospital of the University Medical Centre of Utrecht has a longstanding history of preparing for the management of highly pathogenic and infectious organisms. An assessment of the hospital's preparations for an outbreak of viral hemorrhagic fever and its experience during admission of a patient with Ebola virus disease showed that the use of the buddy system, frequent training, and information sessions for staff and their relatives greatly increased the sense of safety and motivation among staff. Differing procedures among ambulance services limited the number of services used for transporting patients. Waste management was the greatest concern, and destruction of waste had to be outsourced. The admission of an Ebola patient proceeded without incident but led to considerable demands on staff. The maximum time allowed for wearing personal protective equipment was 45 minutes to ensure safety, and an additional 20 minutes was needed for recovery.
Minderhoud, A.L.C. (Ben); Wind, Jelte D.D.; Leenen, Luke P.H.; Hoepelman, Andy I.M.; Ellerbroek, Pauline M.
The Major Incident Hospital of the University Medical Centre of Utrecht has a longstanding history of preparing for the management of highly pathogenic and infectious organisms. An assessment of the hospital’s preparations for an outbreak of viral hemorrhagic fever and its experience during admission of a patient with Ebola virus disease showed that the use of the buddy system, frequent training, and information sessions for staff and their relatives greatly increased the sense of safety and motivation among staff. Differing procedures among ambulance services limited the number of services used for transporting patients. Waste management was the greatest concern, and destruction of waste had to be outsourced. The admission of an Ebola patient proceeded without incident but led to considerable demands on staff. The maximum time allowed for wearing personal protective equipment was 45 minutes to ensure safety, and an additional 20 minutes was needed for recovery. PMID:26812146
Papa, Anna; Pappa, Styliani; Panayotova, Elitsa; Papadopoulou, Elpida; Christova, Iva
Crimean-Congo hemorrhagic fever (CCHF) is endemic in Bulgaria. During 2013-2014, 11 confirmed CCHF cases have been reported in the country (seven in 2013 and four in 2014). The present study provides the CCHF molecular epidemiology in Bulgaria based on all currently available S, M, and L RNA segment nucleotide sequences spanning the years 1978-2014. A relatively low genetic difference (0-6%, the maximum seen in the M RNA segment) was seen among the CCHFV sequences suggesting that a slow evolving CCHFV strain belonging to "Europe 1" clade is present in Bulgaria. Although the virus emerged in new foci during the recent years, it is more active in the established endemic foci which seem to offer the most suitable ecosystem and environment. Understanding the CCHF epidemiology and virus evolution is the basis for public health programs and vaccine design.
Gowen, Brian B; Hickerson, Brady T
A growing number of bunyaviruses are known to cause viral hemorrhagic fever (VHF), a severe febrile illness which can progress to hypovolemic shock and multi-organ failure and is characterized by hematologic abnormalities and vascular leak. At present, there are no approved vaccines or antiviral therapies to effectively prevent or treat VHF caused by pathogenic bunyaviruses. Advances in the modeling of bunyaviral infections have facilitated efforts towards the development of novel post-exposure prophylactic and therapeutic countermeasures, several of which may some day be approved for human use. Here, we review recent progress in animal models of severe bunyaviral infections essential to this mission, as well as promising antivirals and biologicals that are at various stages of the development process.
Fan, H.; Ge, L.; Song, L.; Zhao, Q.
Hemorrhagic fever with renal syndrome(HFRS) is a worldwide fulminant infectious disease. Since the first HFRS cases in Hubei Province were reported in 1957, the disease has spread across the province and Hubei has become one of seriously affected areas in China. However, the epidemic characteristics of HFRS are still not entirely clear. Therefore, a systematic investigation of spatial and temporal distribution pattern of HFRS system is needed. In order to facilitate better prevention and control of HFRS in Hubei Province, in this paper, a GIS spatiotemporal analysis and modeling tool was developed to analyze the spatiotemporal dynamics of the HFRS epidemic, as well as providinga comprehensive examination the dynamic pattern of HFRS in Hubei over the past 30 years (1980-2009), to determine spatiotemporal change trends and the causes of HFRS. This paper describes the experiments and their results.
Yashina, Lyudmila; Vyshemirskii, Oleg; Seregin, Sergei; Petrova, Irina; Samokhvalov, Evgeny; Lvov, Dmitry; Gutorov, Valery; Kuzina, Irina; Tyunnikov, Georgy; Tang, Yi-Wei; Netesov, Sergei; Petrov, Vladimir
Genetic analysis of wild-type Crimean-Congo hemorrhagic fever (CCHF) virus strains recovered in the European part of Russia was performed. Reverse transcriptase PCR followed by direct sequencing was used to recover partial sequences of the CCHF virus medium (M) genome segment (M segment) from four pools of Hyalomma marginatum ticks and six human patients. Phylogenetic analysis of the M-segment sequences from Russian strains revealed a close relatedness of the strains (nucleotide sequence diversity, ≤5.0%). The strains differed significantly from CCHF viruses from other regions of the world (nucleotide sequence diversity, 10.3 to 20.4%), suggesting that CCHF virus strains recovered in the European part of Russia form a distinct group. PMID:12574301
Yashina, Lyudmila; Vyshemirskii, Oleg; Seregin, Sergei; Petrova, Irina; Samokhvalov, Evgeny; Lvov, Dmitry; Gutorov, Valery; Kuzina, Irina; Tyunnikov, Georgy; Tang, Yi-Wei; Netesov, Sergei; Petrov, Vladimir
Genetic analysis of wild-type Crimean-Congo hemorrhagic fever (CCHF) virus strains recovered in the European part of Russia was performed. Reverse transcriptase PCR followed by direct sequencing was used to recover partial sequences of the CCHF virus medium (M) genome segment (M segment) from four pools of Hyalomma marginatum ticks and six human patients. Phylogenetic analysis of the M-segment sequences from Russian strains revealed a close relatedness of the strains (nucleotide sequence diversity,
Maiztegui, J I; McKee, K T; Barrera Oro, J G; Harrison, L H; Gibbs, P H; Feuillade, M R; Enria, D A; Briggiler, A M; Levis, S C; Ambrosio, A M; Halsey, N A; Peters, C J
Argentine hemorrhagic fever (AHF), caused by the arenavirus Junin, is a major public health problem among agricultural workers in Argentina. A prospective, randomized, double-blind, placebo-controlled, efficacy trial of Candid 1, a live attenuated Junin virus vaccine, was conducted over two consecutive epidemic seasons among 6500 male agricultural workers in the AHF-endemic region. Twenty-three men developed laboratory-confirmed AHF during the study; 22 received placebo and 1 received vaccine (vaccine efficacy 95%; 95% confidence interval [CI], 82%-99%). Three additional subjects in each group developed laboratory-confirmed Junin virus infection associated with mild illnesses that did not fulfill the clinical case definition for AHF, yielding a protective efficacy for prevention of any illness associated with Junin virus infection of 84% (95% CI, 60%-94%). No serious adverse events were attributed to vaccination. Candid 1, the first vaccine for the prevention of illness caused by an arenavirus, is safe and highly efficacious.
Kalongi, Y; Mwanza, K; Tshisuaka, M; Lusiama, N; Ntando, E; Kanzake, L; Shieh, W J; Zaki, S R; Lloyd, E S; Ksiazek, T G; Rollin, P E
A patient with undiagnosed Ebola (EBO) hemorrhagic fever (EHF) was transferred from Kikwit to a private clinic in Kinshasa, Democratic Republic of the Congo. A diagnosis of EHF was suspected on clinical grounds and was confirmed by detection of EBO virus-specific IgM and IgG in serum of the patient. During the course of the disease, although she had no known predisposing factors, the patient developed a periorbital mucormycosis abscess on eyelid tissue that was biopsied during surgical drainage; the abscess was histologically confirmed. Presence of EBO antigen was also detected by specific immunohistochemistry on the biopsied tissue. The patient survived the EBO infection but had severe sequelae associated with the mucormycosis. Standard barrier-nursing precautions were taken upon admission and upgraded when EHF was suspected; there was no secondary transmission of the disease.
Zhang, Y; Li, X; Zhu, J; Tang, J; Li, Y; Wu, G; Zhang, J; Jiang, K; Gan, Y; Zhou, Y; Tian, J
In order to observe further the proliferation and kinetic changes of hemorrhagic fever with renal syndrome virus (HFRSV) in Leptotrombidium (L.) Scutellare infected with HFRSV, the raised Leptotrombidium (L.) Scutellare which were at larve stage or at nymph stage were grinded and sterilized by filtration at interval of 20 days, each batch of the filtrate was inoculated separately to Vero-E6 cells and the titre (TCID50/ml) of HFRSV was measured. The results confirmed: HFRSV were isolated from each batch of larve besides the batch at the 60th days, and the titre of HFRSV was -10(-1)-10(-4); HFRSV were also isolated from two batches of nymph. The isolated HFRSV were amplified by PCR technique and the HFRSV RNA were positive. The above results give rise to evidence that Leptotrombidium (L.) Scutellare might be the transmission vector of HFRSV.
Li, Shujuan; Cao, Wei; Ren, Hongyan; Lu, Liang; Zhuang, Dafang; Liu, Qiyong
Exact prediction of Hemorrhagic fever with renal syndrome (HFRS) epidemics must improve to establish effective preventive measures in China. A Seasonal Autoregressive Integrated Moving Average (SARIMA) model was applied to establish a highly predictive model of HFRS. Meteorological factors were considered external variables through a cross correlation analysis. Then, these factors were included in the SARIMA model to determine if they could improve the predictive ability of HFRS epidemics in the region. The optimal univariate SARIMA model was identified as (0,0,2)(1,1,1)12. The R2 of the prediction of HFRS cases from January 2014 to December 2014 was 0.857, and the Root mean square error (RMSE) was 2.708. However, the inclusion of meteorological variables as external regressors did not significantly improve the SARIMA model. This result is likely because seasonal variations in meteorological variables were included in the seasonal characteristics of the HFRS itself. PMID:27706256
Godeny, E K; Zeng, L; Smith, S L; Brinton, M A
The 3' end of the simian hemorrhagic fever virus (SHFV) single-stranded RNA genome was cloned and sequenced. Adjacent to the 3' poly(A) tract, we identified a 76-nucleotide noncoding region preceded by two overlapping reading frames (ORFs). The ultimate 3' ORF of the viral genome encodes the capsid protein, and the penultimate ORF encodes the smallest SHFV envelope protein. These two ORFs overlap each other by 26 nucleotides. Northern (RNA) blot hybridization analyses of cytoplasmic RNA extracts from SHFV-infected MA-104 cells with gene-specific probes revealed the presence of full-length genomic RNA as well as six subgenomic SHFV-specific mRNA species. The subgenomic mRNAs are 3' coterminal. In its virion morphology and size, genome structure and length, and replication strategy, SHFV is most similar to lactate dehydrogenase-elevating virus, equine arteritis virus, and porcine reproductive and respiratory syndrome virus. PMID:7884922
Abbas, Tariq; Younus, Muhammad; Muhammad, Sayyad Aun
Crimean Congo hemorrhagic fever (CCHF) is a tick-borne viral zoonotic disease that has been reported in almost all geographic regions in Pakistan. The aim of this study was to identify spatial clusters of human cases of CCHF reported in country. Kulldorff's spatial scan statisitc, Anselin's Local Moran's I and Getis Ord Gi* tests were applied on data (i.e. number of laboratory confirmed cases reported from each district during year 2013). The analyses revealed a large multi-district cluster of high CCHF incidence in the uplands of Balochistan province near it border with Afghanistan. The cluster comprised the following districts: Qilla Abdullah; Qilla Saifullah; Loralai, Quetta, Sibi, Chagai, and Mastung. Another cluster was detected in Punjab and included Rawalpindi district and a part of Islamabad. We provide empirical evidence of spatial clustering of human CCHF cases in the country. The districts in the clusters should be given priority in surveillance, control programs, and further research.
Kohl, Alain; Bente, Dennis A.; Fazakerley, John K.
Abstract Continuous cell lines derived from many of the vectors of tick-borne arboviruses of medical and veterinary importance are now available. Their role as tools in arbovirus research to date is reviewed and their potential application in studies of tick cell responses to virus infection is explored, by comparison with recent progress in understanding mosquito immunity to arbovirus infection. A preliminary study of propagation of the human pathogen Crimean-Congo hemorrhagic fever virus (CCHFV) in tick cell lines is reported; CCHFV replicated in seven cell lines derived from the ticks Hyalomma anatolicum (a known vector), Amblyomma variegatum, Rhipicephalus (Boophilus) decoloratus, Rhipicephalus (Boophilus) microplus, and Ixodes ricinus, but not in three cell lines derived from Rhipicephalus appendiculatus and Ornithodoros moubata. This indicates that tick cell lines can be used to study growth of CCHFV in arthropod cells and that there may be species-specific restriction in permissive CCHFV infection at the cellular level. PMID:21955214
Ambrosio, Ana María; Mariani, Mauricio Andrés; Maiza, Andrea Soledad; Gamboa, Graciela Susana; Fossa, Sebastián Edgardo; Bottale, Alejando Javier
Argentinian hemorrhagic Fever (AHF) is a febrile, acute disease caused by Junín virus (JUNV), a member of the Arenaviridae. Different approaches to obtain an effective antigen to prevent AHF using complete live or inactivated virus, as well as molecular constructs, have reached diverse development stages. This chapter refers to JUNV live attenuated vaccine strain Candid #1, currently used in Argentina to prevent AHF. A general standardized protocol used at Instituto Nacional de Enfermedades Virales Humanas (Pergamino, Pcia. Buenos Aires, Argentina) to manufacture the tissue culture derived Candid #1 vaccine is described. Intermediate stages like viral seeds and cell culture bank management, bulk vaccine manufacture, and finished product processing are also separately presented in terms of Production and Quality Control/Quality Assurance requirements, under the Adminitracion Nacional de Medicamentos, Alimentos y Tecnología Medica (ANMAT), the Argentine national regulatory authority.
Németh, Viktória; Oldal, Miklós; Egyed, László; Gyuranecz, Miklós; Erdélyi, Károly; Kvell, Krisztián; Kalvatchev, Nikolay; Zeller, Herve; Bányai, Krisztián; Jakab, Ferenc
Crimean-Congo hemorrhagic fever virus (CCHFV) is a typical tick-borne pathogen that causes an increasing number of severe infections in many parts of Africa, Asia, the Middle East, and the Balkans, as well as in some other parts of Europe. The virus is transmitted primarily by Hyalomma spp., and the spectrum of natural hosts for CCHFV is broad, including wild and domestic animals. Although, the presence of CCHFV was hypothesized in Hungary, no significant research activity has been carried out in the past 30 years. In the present study, we provide serological evidence of CCHFV infection in Lepus europeus using newly developed antibody detection assays. Of 198 samples, 12 (6%) were positive for immunoglobulin G antibody against CCHFV, with 2 independent detection assays. This observation indicates a need for a large-scale surveillance to estimate the potential public health risk of CCHFV in Hungary.
Matua, Gerald Amandu; Van der Wal, Dirk Mostert; Locsin, Rozzano C
Ebola hemorrhagic fever, caused by the highly virulent RNA virus of the filoviridae family, has become one of the world's most feared pathogens. The virus induces acute fever and death, often associated with hemorrhagic symptoms in up to 90% of infected patients. The known sub-types of the virus are Zaire, Sudan, Taï Forest, Bundibugyo and Reston Ebola viruses. In the past, outbreaks were limited to the East and Central African tropical belt with the exception of Ebola Reston outbreaks that occurred in animal facilities in the Philippines, USA and Italy. The on-going outbreak in West Africa that is causing numerous deaths and severe socio-economic challenges has resulted in widespread anxiety globally. This panic may be attributed to the intense media interest, the rapid spread of the virus to other countries like United States and Spain, and moreover, to the absence of an approved treatment or vaccine. Informed by this widespread fear and anxiety, we analyzed the commonly used strategies to manage and control Ebola outbreaks and proposed new approaches that could improve epidemic management and control during future outbreaks. We based our recommendations on epidemic management practices employed during recent outbreaks in East, Central and West Africa, and synthesis of peer-reviewed publications as well as published "field" information from individuals and organizations recently involved in the management of Ebola epidemics. The current epidemic management approaches are largely "reactive", with containment efforts aimed at halting spread of existing outbreaks. We recommend that for better outcomes, in addition to "reactive" interventions, "pre-emptive" strategies also need to be instituted. We conclude that emphasizing both "reactive" and "pre-emptive" strategies is more likely to lead to better epidemic preparedness and response at individual, community, institutional, and government levels, resulting in timely containment of future Ebola outbreaks.
Ziraman, Ipek; Celikbas, Aysel; Ergonul, Onder; Degirmenci, Tulin; Uyanik, Sadik Ahmet; Koparal, Suha; Dokuzoguz, Basak
Crimean-Congo hemorrhagic fever (CCHF) is a fatal viral infection that involves multiple organs, and endothelium. We described abdominal sonographic findings of the patients infected with the Crimean-Congo hemorrhagic fever virus (CCHFV) in relation to the severity of the disease. This is a prospective study performed among hospitalized patients infected with CCHF between 2005 and 2011. A total of 210 hospitalized patients with confirmed CCHF infection were included in the study. The mean age was 47 and 49.5% of the patients were female. Patients were classified as mild, moderate, or severe disease according to their clinical and laboratory findings. The relationship between the clinical severity of CCHF and the abdominal sonographic findings was analyzed. Sonographic findings of abdomen included gallbladder wall thickening (GBWT) in 44 (21%), splenomegaly in 39 (19%), hepatomegaly in 52 (25%), decrease in echo of liver parenchyma in nine (4%), increase in echo liver parenchyma in 13 (6%), intra-abdominal fluid collection/ascites in 23 (11%), and enlarged periportal lymph nodes in seven (3%) cases. GBWT was detected in 3% of mild patients, 23% of moderate patients, and 61% of severe patients (p<0.001). In multivariate analysis to predict the severity, GBWT (odds ratio [OR] 5.4, confidence interval [CI] 1.76-16.49, p=0.003) and intra-abdominal fluid collection/ascites (OR 3.5, CI 1.07-12.61, p=0.049) were found to be significantly associated with disease severity. In conclusion, ultrasonography is a reliable, useful, and noninvasive diagnostic tool for evaluation of the abdominal findings of the patients with CCHFV infection. GBWT and intra-abdominal fluid collection/ascites were found to be predictors of severity.
Engin, Aynur; Arslan, Serdal; Kizildag, Sibel; Oztürk, Hasret; Elaldi, Nazif; Dökmetas, Ilyas; Bakir, Mehmet
Crimean-Congo hemorrhagic fever (CCHF) is an acute viral hemorrhagic fever. The clinical course and outcome of the CCHF infection are different in humans. Toll-like receptors (TLRs) are a family of pathogen recognition receptors. TLR8 and TLR9 contribute to the recognition of viruses. We investigated frequency of TLR8 Met1Val, TLR8 -129C/G, TLR9 -1486T/C and TLR9 2458G/A polymorphisms in CCHF patients and healthy controls. Our study was conducted between June 1 and August 31, 2007 in Cumhuriyet University Hospital, Turkey. TLR genotypes were detected using the PCR-RFLP assay in 85 CCHF patients and 171 healthy controls. We found that heterozygous plus homozygous mutant genotypes frequency for TLR8 Met1Val and for TLR9 -1486T/C were significantly higher in CCHF patients than controls (p = 0.038 and p = 0.009, respectively). The frequency of TLR8 -129G/G genotype in the fatal CCHF patients was significantly higher than that of the non-fatal patients (p = 0.026). The frequency of TLR9 -1486C/C genotype was significantly higher in fatal CCHF patients than in healthy controls (p = 0.009) and in patients with severe disease compared to non-severe disease (p = 0.044). Our findings suggest that TLR8 Met1Val, TLR8 -129C/G, and TLR9 -1486T/C polymorphisms are important on clinical course of CCHF disease.
Zehender, Gianguglielmo; Ebranati, Erika; Shkjezi, Renata; Papa, Anna; Luzzago, Camilla; Gabanelli, Elena; Lo Presti, Alessandra; Lai, Alessia; Rezza, Giovanni; Galli, Massimo; Bino, Silvia; Ciccozzi, Massimo
Crimean-Congo hemorrhagic fever (CCHF) is a zoonosis mainly transmitted by ticks that causes severe hemorrhagic fever and has a mortality rate of 5-60%. The first outbreak of CCHF occurred in the Crimean peninsula in 1944-45 and it has recently emerged in the Balkans and eastern Mediterranean. In order to reconstruct the origin and pathway of the worldwide dispersion of the virus at global and regional (eastern European) level, we investigated the phylogeography of the infection by analysing 121 publicly available CCHFV S gene sequences including two recently characterised Albanian isolates. The spatial and temporal phylogeny was reconstructed using a Bayesian Markov chain Monte Carlo approach, which estimated a mean evolutionary rate of 2.96 x 10-4 (95%HPD=1.6 and 4.7 x 10-4) substitutions/site/year for the analysed fragment. All of the isolates segregated into seven highly significant clades that correspond to the known geographical clades: in particular the two new isolates from northern Albania clustered significantly within the Europe 1 clade. Our phylogeographical reconstruction suggests that the global CCHFV clades originated about one thousand years ago from a common ancestor probably located in Africa. The virus then spread to Asia in the XV century and entered Europe on at least two occasions: the first in the early 1800s, when a still circulating but less or non-pathogenic virus emerged in Greece and Turkey, and the second in the early 1900s, when a pathogenic CCHFV strain began to spread in eastern Europe. The most probable location for the origin of this European clade 1 was Russia, but Turkey played a central role in spreading the virus throughout Europe. Given the close proximity of the infected areas, our data suggest that the movement of wild and domestic ungulates from endemic areas was probably the main cause of the dissemination of the virus in eastern Europe. PMID:24223988
Lu, Jianhong; Han, Ziying; Liu, Yuliang; Liu, Wenbo; Lee, Michael S.; Olson, Mark A.; Ruthel, Gordon; Freedman, Bruce D.
ABSTRACT There are currently no U.S. Food and Drug Administration (FDA)-approved vaccines or therapeutics to prevent or treat Argentine hemorrhagic fever (AHF). The causative agent of AHF is Junin virus (JUNV); a New World arenavirus classified as a National Institute of Allergy and Infectious Disease/Centers for Disease Control and Prevention category A priority pathogen. The PTAP late (L) domain motif within JUNV Z protein facilitates virion egress and transmission by recruiting host Tsg101 and other ESCRT complex proteins to promote scission of the virus particle from the plasma membrane. Here, we describe a novel compound (compound 0013) that blocks the JUNV Z-Tsg101 interaction and inhibits budding of virus-like particles (VLPs) driven by ectopic expression of the Z protein and live-attenuated JUNV Candid-1 strain in cell culture. Since inhibition of the PTAP-Tsg101 interaction inhibits JUNV egress, compound 0013 serves as a prototype therapeutic that could reduce virus dissemination and disease progression in infected individuals. Moreover, since PTAP l-domain-mediated Tsg101 recruitment is utilized by other RNA virus pathogens (e.g., Ebola virus and HIV-1), PTAP inhibitors such as compound 0013 have the potential to function as potent broad-spectrum, host-oriented antiviral drugs. IMPORTANCE There are currently no FDA-approved vaccines or therapeutics to prevent or treat Argentine hemorrhagic fever (AHF). The causative agent of AHF is Junin virus (JUNV); a New World arenavirus classified as an NIAID/CDC category A priority pathogen. Here, we describe a prototype therapeutic that blocks budding of JUNV and has the potential to function as a broad-spectrum antiviral drug. PMID:24522922
Lu, Jianhong; Han, Ziying; Liu, Yuliang; Liu, Wenbo; Lee, Michael S; Olson, Mark A; Ruthel, Gordon; Freedman, Bruce D; Harty, Ronald N
There are currently no U.S. Food and Drug Administration (FDA)-approved vaccines or therapeutics to prevent or treat Argentine hemorrhagic fever (AHF). The causative agent of AHF is Junin virus (JUNV); a New World arenavirus classified as a National Institute of Allergy and Infectious Disease/Centers for Disease Control and Prevention category A priority pathogen. The PTAP late (L) domain motif within JUNV Z protein facilitates virion egress and transmission by recruiting host Tsg101 and other ESCRT complex proteins to promote scission of the virus particle from the plasma membrane. Here, we describe a novel compound (compound 0013) that blocks the JUNV Z-Tsg101 interaction and inhibits budding of virus-like particles (VLPs) driven by ectopic expression of the Z protein and live-attenuated JUNV Candid-1 strain in cell culture. Since inhibition of the PTAP-Tsg101 interaction inhibits JUNV egress, compound 0013 serves as a prototype therapeutic that could reduce virus dissemination and disease progression in infected individuals. Moreover, since PTAP l-domain-mediated Tsg101 recruitment is utilized by other RNA virus pathogens (e.g., Ebola virus and HIV-1), PTAP inhibitors such as compound 0013 have the potential to function as potent broad-spectrum, host-oriented antiviral drugs. There are currently no FDA-approved vaccines or therapeutics to prevent or treat Argentine hemorrhagic fever (AHF). The causative agent of AHF is Junin virus (JUNV); a New World arenavirus classified as an NIAID/CDC category A priority pathogen. Here, we describe a prototype therapeutic that blocks budding of JUNV and has the potential to function as a broad-spectrum antiviral drug.
Wu, Wei; Zhang, Shuo; Qu, Jing; Zhang, Quanfu; Li, Chuan; Li, Jiandong; Jin, Cong; Liang, Mifang; Li, Dexin
Viral hemorrhagic fevers (VHFs) are worldwide diseases caused by several kinds of viruses. With the emergence of new viruses, advanced diagnostic methods are urgently needed for identification of VHFs. Based on Luminex xMAP technology, a rapid, sensitive, multi-pathogen and high-throughput method which could simultaneously detect hemorrhagic fever viruses (HFVs) specific IgG antibodies was developed. Recombinant antigens of nine HFVs including Hantaan virus (HTNV), Seoul virus (SEOV), Puumala virus (PUUV), Andes virus (ANDV), Sin Nombre virus (SNV), Crimean-Congo hemorrhagic fever virus (CCHFV), Rift Valley fever virus (RVFV), Severe fever with thrombocytopenia syndrome bunyavirus (SFTSV) and dengue virus (DENV) were produced and purified from a prokaryotic expression system and the influence of the coupling amount was investigated. Cross-reactions among antigens and their rabbit immune sera were evaluated. Serum samples collected from 51 laboratory confirmed hemorrhagic fever with renal syndrome (HFRS) patients, 43 confirmed SFTS patients and 88 healthy donors were analyzed. Results showed that recombinant nucleocapsid protein of the five viruses belonging to the genus Hantavirus, had serological cross-reactivity with their corresponding rabbit immune sera, but not apparent with immune sera of other four viruses. Evaluation of this new method with clinical serum samples showed 98.04% diagnostic sensitivity for HFRS, 90.70% for SFTS detection and the specificity was ranging from 66.67% to 100.00%. The multiplexed Luminex-based immunoassay has firstly been established in our study, which provides a potentially reliable diagnostic tool for IgG antibody detection of VHFs.
Yolcu, Sadiye; Kader, Cigdem; Kayipmaz, Afsin Emre; Ozbay, Sedat; Erbay, Ayse
Background In this study, we aimed to determine knowledge levels regarding Crimean-Congo hemorrhagic fever (CCHF) among emergency healthcare workers (HCWs) in an endemic region. Methods A questionnaire form consisting of questions about CCHF was applied to the participants. Results The mean age was 29.6 ± 6.5 years (range 19 - 45). Fifty-four (49.5%) participants were physicians, 39 (35.8%) were nurses and 16 (14.7%) were paramedics. All of the participants were aware of CCHF, and 48 (44%) of them had previously followed CCHF patients. Rates of the use of protective equipment (masks and gloves) during interventions for patients who were admitted to the emergency service with active hemorrhage were 100% among paramedics, 76.9% among nurses and 61.1% among physicians (P = 0.003). Among 86 (78.9%) HCWs who believed that their knowledge regarding CCHF was adequate, 62 (56.9%) declared that they would prefer not to care for patients with CCHF (P = 0.608). Conclusions The use of techniques to prevent transmission of this disease, including gloves, face masks, face visors and box coats, should be explained to emergency room HCWs, and encouragement should be provided for using these techniques. PMID:24734146
Fajs, Luka; Humolli, Isme; Saksida, Ana; Knap, Nataša; Jelovšek, Mateja; Korva, Miša; Dedushaj, Isuf; Avšič-Županc, Tatjana
Crimean-Congo hemorrhagic fever (CCHF) is an acute, tick borne disease often associated with hemorrhagic presentations and high case fatality rate. Kosovo is a highly endemic area for CCHF, with a significant case fatality rate. The aim of our study was to determine the prevalence of CCHF in Kosovo. We tested 1105 serum samples from healthy population in both endemic and non-endemic areas in the country. Our results revealed a seroprevalence of 4.0% (range 0-9.3%) which is comparable to the seroprevalence in other countries. We show that seroprevalence is correlated to the disease incidence in each studied municipality. We also tested 401 animal sera (353 cow, 30 sheep, 10 goat and 8 chicken) in four endemic municipalities in Kosovo. We detected specific antibodies in all animals except in chicken. Seroprevalence in cows is comparable to other endemic areas and correlates to the seroprevalence in humans. No CCHF RNA could be detected in 105 tick samples obtained in 2012 and 2013. Sequencing of CCHFV positive ticks from 2001 revealed that the virus is most closely related to viral strains that were detected in CCHF patients from Kosovo. Results suggest that mild CCHF cases are most probably underdiagnosed and consequently that the burden of disease is higher than reported. Our study provides key information for CCHF surveillance and raises awareness for possible imported cases in CCHF non-endemic countries.
Papa, Anna; Yagci Caglayık, Dilek; Christova, Iva; Tsergouli, Katerina; Korukluoglu, Gulay; Uyar, Yavuz
Crimean-Congo hemorrhagic fever (CCHF) is a human disease with high fatality rate. Although its pathogenesis is not elucidated yet, it is considered that cytokines play a significant role in the progression and outcome of the disease. Serum CXCL10 levels were estimated in 35 patients with acute CCHF and were correlated with the viral load, and various demographic and clinical parameters. The mean CXCL10 concentration in the patients' group was higher compared to the respective value in the control group (4421.74 pg/ml vs. 28.47 pg/ml, P < 0.05). A strong positive correlation between CXCL10 and viral load was seen (rs = 0.57, P < 0.001), while the outcome of the disease was related with the viral load (rs = 0.47, P = 0.004) and the presence of hemorrhagic manifestations (P < 0.001). The study provides an insight into the strong correlation between CXCL10 and viral load in acute CCHF cases suggesting that it plays an important role in CCHF pathogenesis.
Fraisier, Christophe; Rodrigues, Raquel; Vu Hai, Vinh; Belghazi, Maya; Bourdon, Stéphanie; Paranhos-Baccala, Glaucia; Camoin, Luc; Almeras, Lionel; Peyrefitte, Christophe Nicolas
Crimean-Congo hemorrhagic fever virus (CCHFV) is a tick-borne virus responsible for hemorrhagic manifestations and multiple organ failure, with a high mortality rate. In infected humans, damage to endothelial cells and vascular leakage may be a direct result of virus infection or an immune response-mediated indirect effect. The main target cells are mononuclear phagocytes, endothelial cells and hepatocytes; the liver being a key target for the virus, which was described as susceptible to interferon host response and to induce apoptosis. To better understand the early liver cell alterations due to virus infection, the protein profile of in vitro CCHFV-infected HepG2 cells was analyzed using two quantitative proteomic approaches, 2D-DIGE and iTRAQ. A set of 243 differentially expressed proteins was identified. Bioinformatics analysis (Ingenuity Pathways Analysis) revealed multiple host cell pathways and functions altered after CCHFV infection, with notably 106 proteins related to cell death, including 79 associated with apoptosis. Different protein networks emerged with associated pathways involved in inflammation, oxidative stress and apoptosis, ubiquitination/sumoylation, regulation of the nucleo-cytoplasmic transport, and virus entry. Collectively, this study revealed host liver protein abundances that were modified at the early stages of CCHFV infection, offering an unparalleled opportunity of the description of the potential pathogenesis processes and of possible targets for antiviral research.
Fajs, Luka; Humolli, Isme; Saksida, Ana; Knap, Nataša; Jelovšek, Mateja; Korva, Miša; Dedushaj, Isuf; Avšič-Županc, Tatjana
Crimean-Congo hemorrhagic fever (CCHF) is an acute, tick borne disease often associated with hemorrhagic presentations and high case fatality rate. Kosovo is a highly endemic area for CCHF, with a significant case fatality rate. The aim of our study was to determine the prevalence of CCHF in Kosovo. We tested 1105 serum samples from healthy population in both endemic and non-endemic areas in the country. Our results revealed a seroprevalence of 4.0% (range 0–9.3%) which is comparable to the seroprevalence in other countries. We show that seroprevalence is correlated to the disease incidence in each studied municipality. We also tested 401 animal sera (353 cow, 30 sheep, 10 goat and 8 chicken) in four endemic municipalities in Kosovo. We detected specific antibodies in all animals except in chicken. Seroprevalence in cows is comparable to other endemic areas and correlates to the seroprevalence in humans. No CCHF RNA could be detected in 105 tick samples obtained in 2012 and 2013. Sequencing of CCHFV positive ticks from 2001 revealed that the virus is most closely related to viral strains that were detected in CCHF patients from Kosovo. Results suggest that mild CCHF cases are most probably underdiagnosed and consequently that the burden of disease is higher than reported. Our study provides key information for CCHF surveillance and raises awareness for possible imported cases in CCHF non-endemic countries. PMID:25393542
Sharifinia, Narges; Rafinejad, Javad; Hanafi-Bojd, Ahmad Ali; Chinikar, Sadegh; Piazak, Norayer; Baniardalan, Mojgan; Biglarian, Akbar; Sharifinia, Farhad
Ticks are vectors of some important arthropod-borne diseases in both fields of veterinary and medicine, such as Lyme, tularemia, Rocky Mountain spotted fever, and some types of encephalitis as well as Crimean Congo hemorrhagic fever (CCHF). Iran is known as one of the main foci of CCHF in west of Asia. This study was conducted in DarrehShahr County because of the development of animal husbandry in this area to detect the fauna and viral infection of the hard ticks of livestock. A cross-sectional survey was conducted during 2011-2012 with random sampling in four villages. A sample of ticks was subjected to RT-PCR method for detection of viral infection. During the study period, 592 Ixodidae ticks were collected and identified as seven species of Hyalomma asiaticum, Hy. marginatum, Hy. anatolicum, Hy. dromedarii, Hy. detritum, Rhipicephalus bursa and Rh. sanguineus. More than 20% of these ticks were examined to detect the genome of CCHF virus while 6.6% were positive. All species of Hyalomma were found to be positive. A high rate of livestock was found to be infected with hard ticks, which can act as the vectors of the CCHF disease. Regarding infection of all five Hyalomma species captured in this area, this genus should be considered as the main vector of CCHF. Planning control program can be performed based on the obtained data on seasonal activity of Ixodidae to prevent animal infestation as well as to reduce the risk of CCHF transmission.
Estrada-Jiménez, Tania; Sedeño-Monge, Virginia; Moreno, Margarita; Manjarrez, María del Consuelo; González-Ochoa, Guadalupe; Millán-Pérez Peña, Lourdes
Background Cytokines play important roles in the physiopathology of dengue infection; therefore, the suppressors of cytokine signaling (socs) that control the type and timing of cytokine functions could be involved in the origin of immune alterations in dengue. Objective To explore the association of cytokine and socs levels with disease severity in dengue patients. Methods Blood samples of 48 patients with confirmed dengue infection were analyzed. Amounts of interleukins IL-2, IL-4, IL-6, and IL-10, interferon- (IFN-) γ, and tumor necrosis factor- (TNF-) α were quantified by flow cytometry, and the relative expression of socs1 and socs3 mRNA was quantified by real-time RT-PCR. Results Increased levels of IL-10 and socs3 and lower expression of socs1 were found in patients with dengue hemorrhagic fever (DHF) with respect to those with dengue fever (DF) (p < 0.05). Negative correlations were found between socs1 and both IL-10 and socs3 (p < 0.01). The cutoff values of socs3 (>199.8-fold), socs1 (<1.94-fold), and IL-10 (>134 pg/ml) have the highest sensitivity and specificity to discriminate between DF and DHF. Conclusion Simultaneous changes in IL-10 and socs1/socs3 could be used as prognostic biomarkers of dengue severity. PMID:28827898
Macleod, Jesica M. Levingston; Marmor, Hannah; Frias-Staheli, Natalia
Crimean–Congo hemorrhagic fever virus (CCHFV) is a member of the genus Nairovirus of the family Bunyaviridae, that can cause severe haemorrhagic fever in humans, with mortality rates above 30 %. CCHFV is the most widespread of the tick-borne human viruses and it is endemic in areas of central Asia, the Middle East, Africa and southern Europe. Its viral genome consists of three negative-sense RNA segments. The large segment (L) encodes a viral RNA-dependent RNA polymerase (L protein), the small segment (S) encodes the nucleocapsid protein (N protein) and the medium segment (M) encodes the envelope proteins. The N protein of bunyaviruses binds genomic RNA, forming the viral ribonucleoprotein (RNP) complex. The L protein interacts with these RNP structures, allowing the initiation of viral replication. The N protein also interacts with actin, although the regions and specific residues involved in these interactions have not yet been described. Here, by means of immunoprecipitation and immunofluorescence assays, we identified the regions within the CCHFV N protein implicated in homo-oligomerization and actin binding. We describe the interaction of the N protein with the CCHFV L protein, and identify the N- and C-terminal regions within the L protein that might be necessary for the formation of these N–L protein complexes. These results may guide the development of potent inhibitors of these complexes that could potentially block CCHFV replication. PMID:25389186
Flores-Mendoza, Lilian Karem; Estrada-Jiménez, Tania; Sedeño-Monge, Virginia; Moreno, Margarita; Manjarrez, María Del Consuelo; González-Ochoa, Guadalupe; Millán-Pérez Peña, Lourdes; Reyes-Leyva, Julio
Cytokines play important roles in the physiopathology of dengue infection; therefore, the suppressors of cytokine signaling (socs) that control the type and timing of cytokine functions could be involved in the origin of immune alterations in dengue. To explore the association of cytokine and socs levels with disease severity in dengue patients. Blood samples of 48 patients with confirmed dengue infection were analyzed. Amounts of interleukins IL-2, IL-4, IL-6, and IL-10, interferon- (IFN-) γ, and tumor necrosis factor- (TNF-) α were quantified by flow cytometry, and the relative expression of socs1 and socs3 mRNA was quantified by real-time RT-PCR. Increased levels of IL-10 and socs3 and lower expression of socs1 were found in patients with dengue hemorrhagic fever (DHF) with respect to those with dengue fever (DF) (p < 0.05). Negative correlations were found between socs1 and both IL-10 and socs3 (p < 0.01). The cutoff values of socs3 (>199.8-fold), socs1 (<1.94-fold), and IL-10 (>134 pg/ml) have the highest sensitivity and specificity to discriminate between DF and DHF. Simultaneous changes in IL-10 and socs1/socs3 could be used as prognostic biomarkers of dengue severity.
Guler, Nil; Eroglu, Cafer; Yilmaz, Hava; Karadag, Adil; Alacam, Hasan; Sunbul, Mustafa; Fletcher, Tom E; Leblebicioglu, Hakan
Crimean-Congo Hemorrhagic Fever (CCHF) is a life threatening acute viral infection characterized by fever, bleeding, leukopenia and thrombocytopenia. It is a major emerging infectious diseases threat, but its pathogenesis remains poorly understood and few data exist for the role of apoptosis in acute infection. We aimed to assess apoptotic gene expression in leukocytes in a cross-sectional cohort study of adults with CCHF. Twenty participants with CCHF and 10 healthy controls were recruited at a tertiary CCHF unit in Turkey; at admission baseline blood tests were collected and total RNA was isolated. The RealTime ready Human Apoptosis Panel was used for real-time PCR, detecting differences in gene expression. Participants had CCHF severity grading scores (SGS) with low risk score (10 out of 20) and intermediate or high risk scores (10 out of 20) for mortality. Five of 20 participants had a fatal outcome. Gene expression analysis showed modulation of pro-apoptotic and anti-apoptotic genes that facilitate apoptosis in the CCHF patient group. Dominant extrinsic pathway activation, mostly related with TNF family members was observed. Severe and fatal cases suggest additional intrinsic pathway activation. The clinical significance of relative gene expression is not clear, and larger longitudinal studies with simultaneous measurement of host and viral factors are recommended.
Guler, Nil; Eroglu, Cafer; Yilmaz, Hava; Karadag, Adil; Alacam, Hasan; Sunbul, Mustafa; Fletcher, Tom E.; Leblebicioglu, Hakan
Crimean-Congo Hemorrhagic Fever (CCHF) is a life threatening acute viral infection characterized by fever, bleeding, leukopenia and thrombocytopenia. It is a major emerging infectious diseases threat, but its pathogenesis remains poorly understood and few data exist for the role of apoptosis in acute infection. We aimed to assess apoptotic gene expression in leukocytes in a cross-sectional cohort study of adults with CCHF. Twenty participants with CCHF and 10 healthy controls were recruited at a tertiary CCHF unit in Turkey; at admission baseline blood tests were collected and total RNA was isolated. The RealTime ready Human Apoptosis Panel was used for real-time PCR, detecting differences in gene expression. Participants had CCHF severity grading scores (SGS) with low risk score (10 out of 20) and intermediate or high risk scores (10 out of 20) for mortality. Five of 20 participants had a fatal outcome. Gene expression analysis showed modulation of pro-apoptotic and anti-apoptotic genes that facilitate apoptosis in the CCHF patient group. Dominant extrinsic pathway activation, mostly related with TNF family members was observed. Severe and fatal cases suggest additional intrinsic pathway activation. The clinical significance of relative gene expression is not clear, and larger longitudinal studies with simultaneous measurement of host and viral factors are recommended. PMID:27304063
genus of the family Bunyaviridae and is one of four hantaviruses known to cause hemorrhagic fever with renal syndrome (HFRS). HFRS caused by HTNV...infection is found exclusively in Asia, with most cases occurring in China (reviewed in ). Hantaviruses are transmitted to humans by exposure to...before in our studies of antavirus DNA vaccines. We showed that although DNA accines for two hantaviruses , HTNV and Seoul virus, are ighly immunogenic
Hariyanto, Hori; Yahya, Corry Quando; Wibowo, Primartanto; Tampubolon, Oloan E
The incidence of dengue hemorrhagic fever is increasing among the adult population living in endemic areas. The disease carries a 0.73% fatality rate for the general population, but what happens when the disease strikes a special subpopulation group, the obstetrics? Perhaps the important question specific to this special subpopulation revolves around the right time and mode of delivery under severe coagulopathy and plasma leakage in conditions of imminent delivery. A 24-year-old primigravid Sundanese woman presented to our intensive care unit due to acute pulmonary edema secondary to massive plasma leakage caused by severe dengue. She tested positive for both immunoglobulin G and immunoglobulin M dengue serology indicating she had secondary dengue infection, which placed her at risk for an exaggerated cytokine response as was evident clinically. She had to undergo an emergency cesarean section which was later complicated by rebleeding and hemodynamic instability due to an atypical defervescence period. She was successfully managed by multiple blood transfusions and was discharged from our intensive care unit on day 8 without any negative sequel. Fever, thrombocytopenia, and hemoconcentration are the classical symptoms of dengue hemorrhagic fever observed in adult, pediatric, and obstetric populations. However, a clinician must be particularly watchful in treating a pregnant dengue-infected patient as physiologic hematology changes provide greater volume compensation and the advent of shock marks significant volume loss. In conclusion, an important principle in the management of dengue hemorrhagic fever in pregnancy is to prioritize maternal well-being prior to addressing fetal issues.
Background Investigations were conducted by the authors to explore an outbreak of viral hemorrhagic fever (VHF) reported in 2010 from Al-Mukalla city, the capital of Hadramout in Yemen. Methods From 15–17 June 2010, the outbreak investigation period, specimens were obtained within 7 days after onset of illness of 18 acutely ill patients hospitalized with VHF and 15 household asymptomatic contacts of 6 acute cases. Additionally, 189 stored sera taken from acutely ill patients with suspected VHF hospitalized in the preceding 12 months were obtained from the Ministry of Health of Yemen. Thus, a total of 222 human specimens were collected; 207 specimens from acute cases and 15 specimens from contacts. All samples were tested with RT-PCR for dengue (DENV), Alkhumra (ALKV), Rift Valley Fever (RVFV), Yellow Fever (YFV), and Chikungunya (CHIKV) viruses. Samples were also tested for DENV IgM, IgG, and NS1-antigen. Medical records of patients were reviewed and demographic, clinical, and laboratory data was collected. Results Of 207 patients tested, 181 (87.4%) patients were confirmed to have acute dengue with positive dengue NS1-antigen (97 patients, 46.9%) and/or IgM (163 patients, 78.7%). Of the 181 patients with confirmed dengue, 100 (55.2%) patients were IgG-positive. DENV RNA was detected in 2 (1%) patients with acute symptoms; both samples were molecularly typed as DENV type 3. No other VHF viruses were detected. For the 15 contacts tested, RT-PCR tests for the five viruses were negative, one contact was dengue IgM positive, and another one was dengue IgG positive. Of the 181 confirmed dengue patients, 120 (66.3%) patients were males and the median age was 24 years. The most common manifestations included fever (100%), headache (94.5%), backache (93.4%), malaise (88.4%), arthralgia (85.1%), myalgia (82.3%), bone pain (77.9%), and leukopenia (76.2%). Two (1.1%) patients died. Conclusions DENV-3 was confirmed to be the cause of an outbreak of VHF in Al
harvested , cellular debris was removed by centrifugation, and the supernatant was stored at −70°C. Total RNA was extracted from 18 CCHFV isolates using the...Year of disease Days from exposure to hospitalization Hospital duration day Blood sample collection day post -infection Death day post -infection...hemorrhagic fever caused by Crimean Hemorrhagic fever-Congo virus in Pakistan, January 1976. Am J Trop Med Hyg 29: 941–947. 8. Papa A, Bino S, Llagami
Gerrard, Sonja R.; Li, Li; Barrett, Alan D.; Nichol, Stuart T.
Two isolates of a virus of the genus Orthobunyavirus (family Bunyaviridae) were obtained from hemorrhagic fever cases during a large disease outbreak in East Africa in 1997 and 1998. Sequence analysis of regions of the three genomic RNA segments of the virus (provisionally referred to as Garissa virus) suggested that it was a genetic reassortant virus with S and L segments derived from Bunyamwera virus but an M segment from an unidentified virus of the genus Orthobunyavirus. While high genetic diversity (52%) was revealed by analysis of virus M segment nucleotide sequences obtained from 21 members of the genus Orthobunyavirus, the Garissa and Ngari virus M segments were almost identical. Surprisingly, the Ngari virus L and S segments showed high sequence identity with those of Bunyamwera virus, showing that Garissa virus is an isolate of Ngari virus, which in turn is a Bunyamwera virus reassortant. Ngari virus should be considered when investigating hemorrhagic fever outbreaks throughout sub-Saharan Africa. PMID:15280501
Mohammadian, Maria; Chinikar, Sadegh; Telmadarraiy, Zakkyeh; Vatandoost, Hassan; Oshaghi, Mohammad Ali; Hanafi-Bojd, Ahmad Ali; Sedaghat, Mohammad Mehdi; Noroozi, Mehdi; Faghihi, Faezeh; Jalali, Tahmineh; Khakifirouz, Sahar; Shahhosseini, Nariman; Farhadpour, Firoozeh
Background: Crimean-Congo Hemorrhagic Fever (CCHF) is a feverous and hemorrhagic disease endemic in some parts of Iran and caused by an arbovirus related to Bunyaviridae family and Nairovirusgenus. The main virus reservoir in the nature is ticks, however small vertebrates and a wide range of domestic and wild animals are regarded as reservoir hosts. This study was conducted to determine the infection rate of CCHF virus in hard ticks of Sarpole-Zahab County, Kermanshah province, west of Iran. Methods: From total number of 851 collected ticks from 8 villages, 131 ticks were selected randomlyand investigated for detection of CCHF virus using RT-PCR. Results: The virus was found in 3.8% of the tested ticks. Hyalommaanatolicum, H. asiaticum and Rhipicephalus sanguineus species were found to have viral infection, with the highest infection rate (11.11%) in Rh. sanguineus. Conclusion: These findings provide epidemiological evidence for planning control strategies of the disease in the study area. PMID:27308296
Ibrahim, Alaa M; Adam, Ibrahim A; Osman, Badreldin T; Aradaib, Imadeldin E
Crimean-Congo hemorrhagic fever (CCHF) is a tick-borne disease caused by CCHF virus (CCHFV) of the genus Nairovirus in the family Bunyaviridae. CCHFV causes subclinical infection in domestic livestock and an often fatal hemorrhagic illness in humans, with approximately 30% mortality rates. In the present study, a cross-sectional serosurvey was conducted in a total of 282 randomly selected cattle from five localities in East Darfur State, Sudan. The exposure status to CCHF was determined using enzyme-linked immunosorbent assay (ELISA) for detection of CCHFV-specific IgG antibodies in cattle serum samples. The CCHFV-specific IgG antibodies were detected in 54 out of 282 animals, accounting for a 19.14% prevalence rate. Older cattle (>2 years of age) were approximately five times more likely to be infected with the virus (OR=4.90, CI=1.28-18.98, p-value=0.02). Heavily tick-infested cattle (ticks all over the body) were at 11 times higher at risk compared to tick-free animals (OR=11.11, CI=2.86-43.25, p-value=0.01). Grazing system is another factor affecting CCHF, where cattle grazing on open system were 27 times more at risk compared to other grazing systems (OR=27.22, CI=7.46-99.24, p-value=0.001). There was an association between localities and CCHF cattle (OR=0.24, CI=0.07-0.83, p-value=0.02). This study confirms the exposure of cattle to CCHF in East Darfur and identifies potential risk factors associated with the disease. Further epidemiological studies and improved surveillance are urgently needed to prevent a possible outbreak of CCHF among humans in the Darfur region of Sudan.
Rigau-Pérez, J G; Vorndam, A V; Clark, G G
From June 1, 1994 to May 31, 1995 a total of 24,700 cases of dengue (7.01/1,000 population) were reported to the laboratory-based surveillance system in Puerto Rico (1991-1994, annual average: 2.55/1,000). Dengue virus 2 predominated. The earliest indicator of epidemic activity was the virus isolation rate in May 1994 (14.0% versus 5.7% average). The male-to-female ratio among cases was 1:1.1; 65.4% were younger than 30 years (the 10 to 19 year age group had the highest incidence, 11.8/1,000). At least 5,687 cases (23.0%) showed a hemorrhagic manifestation; 4,662 (18.9%) were hospitalized, and 40 died (0.2%; 10 laboratory-positive). Two cases documented by laboratory were transmitted by unusual routes--intrapartum and through a bone marrow transplant. Among 2,004 hospitalized cases reported by infection control nurses, 139 (6.9%) fulfilled the criteria for dengue hemorrhagic fever (DHF) and another 13 cases (0.6%) had dengue shock syndrome. This epidemic produced the largest number of hospitalizations, DHF cases, and deaths from any dengue epidemic in Puerto Rico. Severity did not change throughout the year. Surveillance capabilities were maintained by temporary, simplified reporting methods, none of which could be recommended as the single method of choice for surveillance; each must be used (on site, or as a service available from a reference laboratory) at the right time in the epidemic cycle. The utility of comparisons of current and previous data underscores the value of long-term surveillance. Our analysis was unable to document whether significantly increased transmission occurred more often in cities where the water supply was rationed or where the local landfill was closed.
Yilmaz, Gürdal; Mentese, Ahmet; Yilmaz, Hülya; Koksal, İftihar
Crimean-Congo Hemorrhagic Fever (CCHF) may present with a mild clinical course or else exhibit a severe profile with potentially fatal hemorrhaging. The pathogenesis of the disease has not yet been well described. Cytokines have recently been investigated in order to explain the pathogenesis. The latest reports show that adipokines are powerful inflammation modulators. This study investigated the effect of adipokines (resistin, leptin, and adiponectin) and ghrelin on disease severity in CCHF patients by testing their serum levels. This retrospective study was conducted with patients with CCHF hospitalized at the Karadeniz Technical University, Medical Faculty in Turkey. Patients were divided into severe and non-severe groups. Serum adipokine levels of patients with CCHF were measured using enzyme-linked immunosorbent assay (ELISA). Fifty-three patients with confirmed CCHF were investigated. Twenty-five (47.2%) of these patients constituted the severe group. Serum resistin levels in the severe and non-severe groups were 108.9 ± 24.7 ng/ml and 77.5 ± 27.7 ng/ml (P < 0.001), leptin levels 15.5 ± 9.8 and 11.2 ± 5.1 ng/ml (P = 0.074), adiponectin levels 26.8 ± 18.9 and 27.4 ± 16.3 ng/ml (P = 0.903) and ghrelin levels 57.1 ± 48.7 and 200.9 ± 182.7 ng/ml (P = 0.001), all respectively. This study confirms that significant changes in serum levels of resistin and ghrelin take place in severe CCHF.
Jeeva, Subbiah; Cheng, Erdong; Ganaie, Safder S; Mir, Mohammad A
Crimean-Congo hemorrhagic fever virus (CCHFV) is a tick-borne Nairovirus of the Bunyaviridae family, causing severe illness with high mortality rates in humans. Here, we demonstrate that CCHFV nucleocapsid protein (CCHFV-NP) augments mRNA translation. CCHFV-NP binds to the viral mRNA 5' untranslated region (UTR) with high affinity. It facilitates the translation of reporter mRNA both in vivo and in vitro with the assistance of the viral mRNA 5' UTR. CCHFV-NP equally favors the translation of both capped and uncapped mRNAs, demonstrating the independence of this translation strategy on the 5' cap. Unlike the canonical host translation machinery, inhibition of eIF4F complex, an amalgam of three initiation factors, eIF4A, eIF4G, and eIF4E, by the chemical inhibitor 4E1RCat did not impact the CCHFV-NP-mediated translation mechanism. However, the proteolytic degradation of eIF4G alone by the human rhinovirus 2A protease abrogated this translation strategy. Our results demonstrate that eIF4F complex formation is not required but eIF4G plays a critical role in this translation mechanism. Our results suggest that CCHFV has adopted a unique translation mechanism to facilitate the translation of viral mRNAs in the host cell cytoplasm where cellular transcripts are competing for the same translation apparatus.IMPORTANCE Crimean-Congo hemorrhagic fever, a highly contagious viral disease endemic to more than 30 countries, has limited treatment options. Our results demonstrate that NP favors the translation of a reporter mRNA harboring the viral mRNA 5' UTR. It is highly likely that CCHFV uses an NP-mediated translation strategy for the rapid synthesis of viral proteins during the course of infection. Shutdown of this translation mechanism might selectively impact viral protein synthesis, suggesting that an NP-mediated translation strategy is a target for therapeutic intervention against this viral disease. Copyright © 2017 American Society for Microbiology.
Bonney, Joseph Humphrey Kofi; Osei-Kwasi, Mubarak; Adiku, Theophilus Korku; Barnor, Jacob Samson; Amesiya, Robert; Kubio, Chrysantus; Ahadzie, Lawson; Ölschläger, Stephan; Lelke, Michaela; Becker-Ziaja, Beate; Pahlmann, Meike; Günther, Stephan
Background Viral hemorrhagic fevers (VHF) are acute diseases associated with bleeding, organ failure, and shock. VHF may hardly be distinguished clinically from other diseases in the African hospital, including viral hepatitis. This study was conducted to determine if VHF and viral hepatitis contribute to hospital morbidity in the Central and Northern parts of Ghana. Methodology/Principal Findings From 2009 to 2011, blood samples of 258 patients with VHF symptoms were collected at 18 hospitals in Ashanti, Brong-Ahafo, Northern, Upper West, and Upper East regions. Patients were tested by PCR for Lassa, Rift Valley, Crimean-Congo, Ebola/Marburg, and yellow fever viruses; hepatitis A (HAV), B (HBV), C (HCV), and E (HEV) viruses; and by ELISA for serological hepatitis markers. None of the patients tested positive for VHF. However, 21 (8.1%) showed anti-HBc IgM plus HBV DNA and/or HBsAg; 37 (14%) showed HBsAg and HBV DNA without anti-HBc IgM; 26 (10%) showed anti-HAV IgM and/or HAV RNA; and 20 (7.8%) were HCV RNA-positive. None was positive for HEV RNA or anti-HEV IgM plus IgG. Viral genotypes were determined as HAV-IB, HBV-A and E, and HCV-1, 2, and 4. Conclusions/Significance VHFs do not cause significant hospital morbidity in the study area. However, the incidence of acute hepatitis A and B, and hepatitis B and C with active virus replication is high. These infections may mimic VHF and need to be considered if VHF is suspected. The data may help decision makers to allocate resources and focus surveillance systems on the diseases of relevance in Ghana. PMID:24069490
Jochmans, D.; van Nieuwkoop, S.; Smits, S. L.; Neyts, J.; Fouchier, R. A. M.
The clinical impact of infections with respiratory viruses belonging to the family Paramyxoviridae argues for the development of antiviral therapies with broad-spectrum activity. Favipiravir (T-705) has demonstrated potent antiviral activity against multiple RNA virus families and is presently in clinical evaluation for the treatment of influenza. Here we demonstrate in vitro activity of T-705 against the paramyxoviruses human metapneumovirus (HMPV), respiratory syncytial virus, human parainfluenza virus, measles virus, Newcastle disease virus, and avian metapneumovirus. In addition, we demonstrate activity against HMPV in hamsters. T-705 treatment inhibited replication of all paramyxoviruses tested in vitro, with 90% effective concentration (EC90) values of 8 to 40 μM. Treatment of HMPV-challenged hamsters with T-705 at 200 mg/kg of body weight/day resulted in 100% protection from infection of the lungs. In all treated and challenged animals, viral RNA remained detectable in the respiratory tract. The observation that T-705 treatment had a significant effect on infectious viral titers, with a limited effect on viral genome titers, is in agreement with its proposed mode of action of viral mutagenesis. However, next-generation sequencing of viral genomes isolated from treated and challenged hamsters did not reveal (hyper)mutation. Polymerase activity assays revealed a specific effect of T-705 on the activity of the HMPV polymerase. With the reported antiviral activity of T-705 against a broad range of RNA virus families, this small molecule is a promising broad-range antiviral drug candidate for limiting the viral burden of paramyxoviruses and for evaluation for treatment of infections with (re)emerging viruses, such as the henipaviruses. PMID:27185803
Jochmans, D; van Nieuwkoop, S; Smits, S L; Neyts, J; Fouchier, R A M; van den Hoogen, B G
The clinical impact of infections with respiratory viruses belonging to the family Paramyxoviridae argues for the development of antiviral therapies with broad-spectrum activity. Favipiravir (T-705) has demonstrated potent antiviral activity against multiple RNA virus families and is presently in clinical evaluation for the treatment of influenza. Here we demonstrate in vitro activity of T-705 against the paramyxoviruses human metapneumovirus (HMPV), respiratory syncytial virus, human parainfluenza virus, measles virus, Newcastle disease virus, and avian metapneumovirus. In addition, we demonstrate activity against HMPV in hamsters. T-705 treatment inhibited replication of all paramyxoviruses tested in vitro, with 90% effective concentration (EC90) values of 8 to 40 μM. Treatment of HMPV-challenged hamsters with T-705 at 200 mg/kg of body weight/day resulted in 100% protection from infection of the lungs. In all treated and challenged animals, viral RNA remained detectable in the respiratory tract. The observation that T-705 treatment had a significant effect on infectious viral titers, with a limited effect on viral genome titers, is in agreement with its proposed mode of action of viral mutagenesis. However, next-generation sequencing of viral genomes isolated from treated and challenged hamsters did not reveal (hyper)mutation. Polymerase activity assays revealed a specific effect of T-705 on the activity of the HMPV polymerase. With the reported antiviral activity of T-705 against a broad range of RNA virus families, this small molecule is a promising broad-range antiviral drug candidate for limiting the viral burden of paramyxoviruses and for evaluation for treatment of infections with (re)emerging viruses, such as the henipaviruses.
Charrel, R N; de Lamballerie, X
To date tick-borne flaviviruses causing hemorrhagic fevers in humans have been isolated in Siberia (Omsk hemorrhagic fever virus), India (Kyasanur Forest disease virus), and Saudi Arabia (Akhurma virus). Because of their potential use as biological weapons for bioterrorism, these 3 viruses require level 4 biosafety handling facilities and have been listed as hypervirulent pathogens by the Center for Disease Control and Prevention. Alkhurma virus was isolated in 1995 from patients with hemorrhagic fever in Saudi Arabia. Current evidence suggests that transmission to humans can occur either transcutaneously either by contamination of a skin wound with the blood of an infected vertebrate or bites of an infected tick or orally by drinking unpasteurized contaminated milk. To date a total of 24 symptomatic human cases have been recorded with a mortality rate at 25% (6/24). Pauci-symptomatic or asymptomatic cases are likely but epidemiologic data are currently unavailable. The complete coding sequence of the prototype strain of Alkhurma virus was determined and published in 2001 based on international research project involving investigators from France, Great Britain, and Saudi Arabia. Phylogenetic studies demonstrate that closest known relative of Alkhurma virus is Kyasanur Forest disease virus and that both viruses share a common ancestor. Genetic analysis of several human strains sequentially isolated over a 5-year period showed a very low diversity. This finding has important potential implications for diagnosis and vaccination.
Kara, Soner S; Kara, Duygu; Fettah, Ali
Crimean-Congo hemorrhagic fever (CCHF) is a tick-borne disease with high mortality. Many disorders can mimic CCHF. It is important to recognize the condition and to perform differential diagnosis in endemic countries. Twenty-one children aged 18 years or less with a preliminary diagnosis of CCHF were retrospectively evaluated. Real-time PCR and a confirmatory indirect immunofluorescence assay for negative results were performed. The diagnoses determined that 9 patients had (42.9%) CCHF; 7 patients had (33.3%) viral upper respiratory tract infections (URTI); 2 patients had (9.5%) brucellosis; 1 patients had (4.7%) periodic fever, aphthous stomatitis, pharyngitis, and adenitis (PFAPA) syndrome episode; 1 patient had (4.7%) cerebral palsy, diabetes insipidus, acute gastroenteritis, and hypernatremic dehydration; and 1 patient had (4.7%) cellulitis after a tick bite. The mean age of patients with CCHF was greater than that of the other patients (116.1±53.6 vs. 94.1±52.1 months, p=0.02). Seventeen (81%) of the children included had a history of tick bites, 2 (9.5%) had a history of contact with a patient with CCHF, and 2 (9.5%) had no exposure, but were living in an endemic region. Three patients had an underlying disorder: cerebral palsy and diabetes insipidus, epilepsy, or PFAPA. All of the children experienced fever. Other frequent symptoms were malaise, diarrhea, vomiting, and abdominal pain, but none of these differed statistically between the patient groups. CCHF patients had a longer mean duration of symptoms (10.56±1.42 vs. 6.75±3.62 days, p=0.008) and a longer mean length of hospitalization (8.00±2.08 vs. 3.58±1.56 days, p<0.001) than the other patients. At laboratory examination, patients with CCHF had statistically significant lower leukocyte and platelet counts, more prolonged coagulation parameters, and greater AST, ALT, LDH, and CK levels than the other patients. No mortality or complications occurred in the study. Both infectious causes, such as
Saavedra, M C; Briggiler, A M; Enría, D; Riera, L; Ambrosio, A M
For Argentine Hemorrhagic Fever, a disease caused by Junin virus (JV), there is an effective treatment, consisting of the transfusion of immune plasma (IP). This plasma is obtained from individuals who have had the disease. Since Hepatitis C virus (HCV) is transmitted parenterally, this study was aimed to estimate the prevalence of anti-HCV in a population of IP donors. In this study, 376 donors (47 females and 329 males) were studied: 95 individuals (24 females and 71 males) who had had FHA but had not received treatment and 88 laboratory workers (57 females and 31 males) who were included as controls. Serum samples were tested by EIA (Abbott, Germany) for HCV, and later confirmed by LIATEK (Organon, Ireland). Antibodies to HCV were detected in 29/376 donors (7.7%), in only 1/95 (1.0%) untreated convalescents of AHF and in 1/ 88 (1.1%) of laboratory workers. Retrospective analysis of the seroconversion for HCV in these individuals demonstrated that in 16/24 donors (66.6%) the infection by HCV was probably associated with the IP transfusion. The data presented herein show how the infection with HCV was disseminated among donors of IP, stressing the risk associated to transfusional practices, and emphasizing the need of vaccination to prevent AHF and also the risk inherent to its treatment.
Onyango, Clayton O; Opoka, Martin L; Ksiazek, Thomas G; Formenty, Pierre; Ahmed, Abdullahi; Tukei, Peter M; Sang, Rosemary C; Ofula, Victor O; Konongoi, Samson L; Coldren, Rodney L; Grein, Thomas; Legros, Dominique; Bell, Mike; De Cock, Kevin M; Bellini, William J; Towner, Jonathan S; Nichol, Stuart T; Rollin, Pierre E
Between the months of April and June 2004, an Ebola hemorrhagic fever (EHF) outbreak was reported in Yambio county, southern Sudan. Blood samples were collected from a total of 36 patients with suspected EHF and were tested by enzyme-linked immunosorbent assay (ELISA) for immunoglobulin G and M antibodies, antigen ELISA, and reverse-transcription polymerase chain reaction (PCR) of a segment of the Ebolavirus (EBOV) polymerase gene. A total of 13 patients were confirmed to be infected with EBOV. In addition, 4 fatal cases were classified as probable cases, because no samples were collected. Another 12 patients were confirmed to have acute measles infection during the same period that EBOV was circulating. Genetic analysis of PCR-positive samples indicated that the virus was similar to but distinct from Sudan EBOV Maleo 1979. In response, case management, social mobilization, and follow-up of contacts were set up as means of surveillance. The outbreak was declared to be over on 7 August 2004.
Olszanecki, Rafał; Gawlik, Grzegorz
The 2014 outbreak clearly showed that Ebola viruses (EBOV) remain a substantial threat for public health. The mainstay of management of patients with Ebola disease is isolation of patients and use of strict barrier nursing procedures; the present treatment strategies are mainly symptomatic and supportive (fluid resuscitation, antypyretics, antidiarrheal drugs). Currently, there is no approved therapy for Ebola hemorrhagic fever (EHF), however several advanced treatment options were tested in animal models (on non-human primates or rodents). They include use of both symptomatic (e.g. use of tissue factor inhibitors - rhNAPc2, rhAPC - to abolish coagulopathy) and specific antiviral approaches: e.g. monoclonal anti EBOV antibodies (ZMapp, MB-003), phosphorodiamidate morpholino oligomers (PMOs), liposomes containing siRNA (LNP-siRNA:TKM-Ebola) and small molecule inhibitors (e.g. BCX4430, favipiravir). The scope of this article is to briefly review the most promising therapeutics for EHF, based on the data coming from rare clinical reports, studies on animals and results from in vitro models.
Zhang, Wen-Yi; Guo, Wei-Dong; Fang, Li-Qun; Li, Chang-Ping; Bi, Peng; Glass, Gregory E; Jiang, Jia-Fu; Sun, Shan-Hua; Qian, Quan; Liu, Wei; Yan, Lei; Yang, Hong; Tong, Shi-Lu; Cao, Wu-Chun
The transmission of hemorrhagic fever with renal syndrome (HFRS) is influenced by climatic variables. However, few studies have examined the quantitative relationship between climate variation and HFRS transmission. We examined the potential impact of climate variability on HFRS transmission and developed climate-based forecasting models for HFRS in northeastern China. We obtained data on monthly counts of reported HFRS cases in Elunchun and Molidawahaner counties for 1997-2007 from the Inner Mongolia Center for Disease Control and Prevention and climate data from the Chinese Bureau of Meteorology. Cross-correlations assessed crude associations between climate variables, including rainfall, land surface temperature (LST), relative humidity (RH), and the multivariate El Niño Southern Oscillation (ENSO) index (MEI) and monthly HFRS cases over a range of lags. We used time-series Poisson regression models to examine the independent contribution of climatic variables to HFRS transmission. Cross-correlation analyses showed that rainfall, LST, RH, and MEI were significantly associated with monthly HFRS cases with lags of 3-5 months in both study areas. The results of Poisson regression indicated that after controlling for the autocorrelation, seasonality, and long-term trend, rainfall, LST, RH, and MEI with lags of 3-5 months were associated with HFRS in both study areas. The final model had good accuracy in forecasting the occurrence of HFRS. Climate variability plays a significant role in HFRS transmission in northeastern China. The model developed in this study has implications for HFRS control and prevention.
Jiang, Fachun; Zhang, Zhentang; Dong, Liyan; Hao, Bi; Xue, Zaifeng; Ma, Dongqiang; Su, Hang; Wen, Hong-ling; Yu, Hao; Yu, Xue-jie
Hemorrhagic fever with renal syndrome (HFRS) was considered to be transmitted by Apodemus agrarius and Rattus norvegicus, the principal animal hosts of Hantaan virus and Seoul virus, respectively. The aim of this study is to determine the correlation of HFRS incidence with capture rate and hantavirus infection rate of rodent species in Qingdao City, China. We collected HFRS patients’ information and captured field and residential rodents in Qingdao City, China from 2010 to 2014. The correlations of HFRS incidence to rodent capture rate and hantavirus infection rate of rodents were analyzed statistically. The main findings of this study are that the high HFRS incidence (19.3/100,000) is correlated to the capture rate of field Mus musculus (p = 0.011, r = 0.037); but surprisingly it did not correlated to the capture rate of the principal rodent hosts Apodemus agrarius and Rattus norvegicus and the hantavirus infection rate of these rodent species in the field or residential area. These novel findings suggest that Mus musculus, a nontraditional animal host of hantavirus may play an important role in hantavirus transmission in Qingdao City. PMID:27786303
Terajima, Masanori; Ennis, Francis A.
We previously hypothesized that increased capillary permeability observed in both hantavirus cardiopulmonary syndrome (HCPS) and hemorrhagic fever with renal syndrome (HFRS) may be caused by hantavirus-specific cytotoxic T cells attacking endothelial cells presenting viral antigens on their surface based on clinical observations and in vitro experiments. In HCPS, hantavirus-specific T cell responses positively correlated with disease severity. In HFRS, in one report, contrary to HCPS, T cell responses negatively correlated with disease severity, but in another report the number of regulatory T cells, which are thought to suppress T cell responses, negatively correlated with disease severity. In rat experiments, in which hantavirus causes persistent infection, depletion of regulatory T cells helped infected rats clear virus without inducing immunopathology. These seemingly contradictory findings may suggest delicate balance in T cell responses between protection and immunopathogenesis. Both too strong and too weak T cell responses may lead to severe disease. It is important to clarify the role of T cells in these diseases for better treatment (whether to suppress T cell functions) and protection (vaccine design) which may need to take into account viral factors and the influence of HLA on T cell responses. PMID:21994770
Wasfi, Fares; Dowall, Stuart; Ghabbari, Tayssir; Bosworth, Andrew; Chakroun, Mohamed; Varghese, Anitha; Tiouiri, Hanene; Ben Jemaa, Mounir; Znazen, Abir; Hewson, Roger; Zhioua, Elyes; Letaief, Amel
Crimean-Congo hemorrhagic fever (CCHF) is a tick-borne disease associated with a high case fatality rate and transmitted mainly by Hyalomma marginatum. The geographical distribution of H. marginatum covers most of the Western Mediterranean basin. We aimed to investigate whether CCHF virus (CCHFv) is circulating in Tunisia. Samples from unexplained acute febrile patients (n = 181) and a high risk group of humans, mainly slaughter workers (n = 38), were collected in the summer of 2014 and analyzed for exposure to CCHFv using serological tests and real-time RT-PCR. Ticks were collected from Northern and Southern Tunisia during May-June 2014 and examined for the presence of CCHFv by real-time RT-PCR. Of the 181 febrile patients, 5 showed only high titers of IgM suggesting a recent exposure to CCHFv. Among 38 slaughter workers, 2 had IgG anti-CCHFv responses yielding a seroprevalence of 5.2%. No CCHFv was detected in ticks and sera. Our results provide evidence of human exposure to CCHFv in Tunisia.
Abraham, Jonathan; Corbett, Kevin D.; Farzan, Michael; Choe, Hyeryun; Harrison, Stephen C.
New World hemorrhagic fever arenaviruses are rodent-borne agents that cause severe human disease. The GP1 subunit of the surface glycoprotein mediates cell attachment through transferrin receptor 1 (TfR1). We report the structure of Machupo virus (MACV) GP1 bound with human TfR1. Atomic details of the GP1-TfR1 interface clarify the importance of TfR1 residues implicated in New World arenavirus host specificity. Analysis of sequence variation among New World arenavirus GP1s and their host-species receptors, in light of the molecular structure, indicates determinants of viral zoonotic transmission. Infectivities of pseudoviruses in cells expressing mutated TfR1 confirm that contacts at the tip of the TfR1 apical domain determine the capacity of human TfR1 to mediate infection by particular New World arenaviruses. We propose that New World arenaviruses that are pathogenic to humans fortuitously acquired affinity for human TfR1 during adaptation to TfR1 of their natural hosts.
Papa, Anna; Chaligiannis, Ilias; Kontana, Natasa; Sourba, Tatiana; Tsioka, Katerina; Tsatsaris, Andreas; Sotiraki, Smaragda
Ticks were collected from various regions of northern Greece and tested for the presence of Crimean-Congo hemorrhagic fever virus (CCHFV) RNA. Human and animal sera were collected in the regions where CCHFV-positive ticks were detected, and they were tested for the presence of IgG antibodies against the virus. A CCHFV strain was detected in Rhipicephalus bursa ticks collected from sheep in Kastoria regional unit, differing by 9.7% at the nucleotide level from the AP92 strain, which was isolated in 1975 in another region of Greece. Up to date, CCHF cases have not been reported in these regions. The human seroprevalence in the area was estimated at 6%, while IgG-positive sheep was detected in two of the four neighboring farms tested. The circulation of this specific CCHFV lineage in Greece, especially in a region where the seroprevalence is high, together with the lack of human CCHF cases, suggests a probable antigenic, but non- or low-pathogenic character of this lineage. Further studies on these strains will increase our knowledge about the role of AP92-like strains in the CCHF epidemiology, which might be useful for drug and vaccine design.
Eren, Sevki Hakan; Zengin, Suat; Büyüktuna, Seyit Ali; Gözel, Mustafa Gökhan
Crimean-Congo hemorrhagic fever (CCHF) is a life-threatening disease that develops as a result of infection by a member of the Nairovirus genus of the Bunyaviridae family, and its initial symptoms are not specific. In patients with severe clinical progression, in particular, the neutrophil rate is high, whereas lymphocyte and monocyte levels are low. A total of 149 patients, in whom the diagnosis was confirmed with reverse transcriptase PCR, were included in the study. In order to compare patient clinical progression severity, we divided the patients into two groups. For group 1, Çevik's severity score was used. The patients who had a platelet/lymphocyte ratio (PLR) <41 constituted group 2. Of 149 patients, 20 (13.4 %) were determined as group 1 (Çevik's classification) and 38 (25.5 %) were determined as group 2 (PLR <41). Of 11 deaths, 4 (36.4 %) patients were from group 1 and 7 (63.6 %) were from group 2. This is the first study to our knowledge to analyse the relationship between severity and PLR in patients with CCHF. PLR is a simple laboratory test that can aid in determining the prognosis of individuals with this disease.
Leblebicioglu, Hakan; Sunbul, Mustafa; Memish, Ziad A; Al-Tawfiq, Jaffar A; Bodur, Hurrem; Ozkul, Aykut; Gucukoglu, Ali; Chinikar, Sadegh; Hasan, Zahra
Crimean-Congo hemorrhagic fever (CCHF) is endemic in Eurasian countries such as, Turkey, Pakistan, Afghanistan and Iran. CCHF virus is spread by the Hyalomma tick, which is found mainly on cattle and sheep. Muslim countries, in which these animals are sacrificed during Eid-Al-Adha, are among the countries where CCHF is endemic, and it has been observed that CCHF is associated with practices surrounding the Eid-ad-Adha festival. The dates for Eid-Al-Adha drift 10 days earlier in each year according to Georgian calendar. In previous years Eid-al-Adha occurred in autumn-winter months however in the next 10-15 years it will be take place in the summer months when CCHF is more prevalent. This may lead to a rise in the number of cases due to increased dissemination of CCHF virus with uncontrolled animal movements in and between countries. This consensus report focuses on the variable practices regarding animal handling in different regions and possible preventative measures to reduce the incidence of CCHF. Environmental hygiene and personal protection are essential parts of prevention. There is a need for international collaborative preparedness and response plans for prevention and management of CCHF during Eid-Al-Adha in countries where the disease is prevalent.
Kuiken, Carla; Thurmond, Jim; Dimitrijevic, Mira; Yoon, Hyejin
Hemorrhagic fever viruses (HFVs) are a diverse set of over 80 viral species, found in 10 different genera comprising five different families: arena-, bunya-, flavi-, filo- and togaviridae. All these viruses are highly variable and evolve rapidly, making them elusive targets for the immune system and for vaccine and drug design. About 55 000 HFV sequences exist in the public domain today. A central website that provides annotated sequences and analysis tools will be helpful to HFV researchers worldwide. The HFV sequence database collects and stores sequence data and provides a user-friendly search interface and a large number of sequence analysis tools, following the model of the highly regarded and widely used Los Alamos HIV database [Kuiken, C., B. Korber, and R.W. Shafer, HIV sequence databases. AIDS Rev, 2003. 5: p. 52–61]. The database uses an algorithm that aligns each sequence to a species-wide reference sequence. The NCBI RefSeq database [Sayers et al. (2011) Database resources of the National Center for Biotechnology Information. Nucleic Acids Res., 39, D38–D51.] is used for this; if a reference sequence is not available, a Blast search finds the best candidate. Using this method, sequences in each genus can be retrieved pre-aligned. The HFV website can be accessed via http://hfv.lanl.gov. PMID:22064861
Kuiken, Carla; Thurmond, Jim; Dimitrijevic, Mira; Yoon, Hyejin
Hemorrhagic fever viruses (HFVs) are a diverse set of over 80 viral species, found in 10 different genera comprising five different families: arena-, bunya-, flavi-, filo- and togaviridae. All these viruses are highly variable and evolve rapidly, making them elusive targets for the immune system and for vaccine and drug design. About 55,000 HFV sequences exist in the public domain today. A central website that provides annotated sequences and analysis tools will be helpful to HFV researchers worldwide. The HFV sequence database collects and stores sequence data and provides a user-friendly search interface and a large number of sequence analysis tools, following the model of the highly regarded and widely used Los Alamos HIV database [Kuiken, C., B. Korber, and R.W. Shafer, HIV sequence databases. AIDS Rev, 2003. 5: p. 52-61]. The database uses an algorithm that aligns each sequence to a species-wide reference sequence. The NCBI RefSeq database [Sayers et al. (2011) Database resources of the National Center for Biotechnology Information. Nucleic Acids Res., 39, D38-D51.] is used for this; if a reference sequence is not available, a Blast search finds the best candidate. Using this method, sequences in each genus can be retrieved pre-aligned. The HFV website can be accessed via http://hfv.lanl.gov.
Fajs, Luka; Jakupi, Xhevat; Ahmeti, Salih; Humolli, Isme; Dedushaj, Isuf; Avšič-Županc, Tatjana
Crimean-Congo hemorrhagic fever virus (CCHFV) is a zoonotic agent that causes severe, life-threatening disease, with a case fatality rate of 10-50%. It is the most widespread tick-borne virus in the world, with cases reported in Africa, Asia and Eastern Europe. CCHFV is a genetically diverse virus. Its genetic diversity is often correlated to its geographical origin. Genetic variability of CCHFV was determined within few endemic areas, however limited data is available for Kosovo. Furthermore, there is little information about the spatiotemporal genetic changes of CCHFV in endemic areas. Kosovo is an important endemic area for CCHFV. Cases were reported each year and the case-fatality rate is significantly higher compared to nearby regions. In this study, we wanted to examine the genetic variability of CCHFV obtained directly from CCHF-confirmed patients, hospitalized in Kosovo from 1991 to 2013. We sequenced partial S segment CCHFV nucleotide sequences from 89 patients. Our results show that several viral variants are present in Kosovo and that the genetic diversity is high in relation to the studied area. We also show that variants are mostly uniformly distributed throughout Kosovo and that limited evolutionary changes have occurred in 22 years. Our results also suggest the presence of a new distinct lineage within the European CCHF phylogenetic clade. Our study provide the largest number of CCHFV nucleotide sequences from patients in 22 year span in one endemic area.
Ambrosio, Ana M; Riera, Laura M; Saavedra, María del Carmen; Sottosanti, María J
Candid #1 vaccine against Argentine Hemorrhagic Fever produced in USA versus lots of the same vaccine made in Argentina were compared in guinea pigs regarding safety, immunogenicity and protective efficacy against a challenge with pathogenic Junin virus. Lots No Exp 3, 7A and 8A of Argentine origin as well as lot TSI 5-1-92 from USA were inoculated in guinea pigs of 250-400 g in two consecutive assays. Ten animals inoculated with saline performed as normal controls in each experiment. Parameters studied were: a) temperature; b) body weight; c) neutralizing antibodies to Junin virus; d) response to viral challenge. Animals gained weight and remained normothermic up to the challenge. Guinea pigs that received Candid #1 from any manufacturer elicited neutralizing antibodies to Junin virus (titles from 40 to 81920) and survived to challenge whilst 8/10 animals died in each control group. Data presented demonstrated that Candid #1 vaccines from USA or Argentine manufacturers were equally safe, immunogenic and protective in guinea pigs.
Borchert, Matthias; Grein, Thomas; Roth, Cathy; Swanepoel, Robert; Libande, Modeste L.; Talarmin, Antoine; Bertherat, Eric; Muyembe-Tamfum, Jean-Jacques; Tugume, Ben; Colebunders, Robert; Kondé, Kader M.; Pirard, Patricia; Olinda, Loku L.; Rodier, Guénaël R.; Campbell, Patricia; Tomori, Oyewale; Ksiazek, Thomas G.; Rollin, Pierre E.
We conducted two antibody surveys to assess risk factors for Marburg hemorrhagic fever in an area of confirmed Marburg virus transmission in the Democratic Republic of the Congo. Questionnaires were administered and serum samples tested for Marburg-specific antibodies by enzyme-linked immunosorbent assay. Fifteen (2%) of 912 participants in a general village cross-sectional antibody survey were positive for Marburg immunoglobulin G antibody. Thirteen (87%) of these 15 were men who worked in the local gold mines. Working as a miner (odds ratio [OR] 13.9, 95% confidence interval [CI] 3.1 to 62.1) and receiving injections (OR 7.4, 95% CI 1.6 to 33.2) were associated with a positive antibody result. All 103 participants in a targeted antibody survey of healthcare workers were antibody negative. Primary transmission of Marburg virus to humans likely occurred via exposure to a still unidentified reservoir in the local mines. Secondary transmission appears to be less common with Marburg virus than with Ebola virus, the other known filovirus. PMID:14720391
Kiselev, O I; Vasin, A V; Shevyryova, M P; Deeva, E G; Sivak, K V; Egorov, V V; Tsvetkov, V B; Egorov, A Yu; Romanovskaya-Romanko, E A; Stepanova, L A; Komissarov, A B; Tsybalova, L M; Ignatjev, G M
Ebola hemorrhagic fever (EHF) epidemic currently ongoing in West Africa is not the first among numerous epidemics in the continent. Yet it seems to be the worst EHF epidemic outbreak caused by Ebola virus Zaire since 1976 as regards its extremely large scale and rapid spread in the population. Experiments to study the agent have continued for more than 20 years. The EHF virus has a relatively simple genome with seven genes and additional reading frame resulting from RNA editing. While being of a relatively low genetic capacity, the virus can be ranked as a standard for pathogenicity with the ability to evade the host immune response in uttermost perfection. The EHF virus has similarities with retroviruses, but belongs to (-)RNA viruses of a nonretroviral origin. Genetic elements of the virus, NIRV, were detected in animal and human genomes. EHF virus glycoprotein (GP) is a class I fusion protein and shows more similarities than distinctions in tertiary structure with SIV and HIV gp41 proteins and even influenza virus hemagglutinin. EHF is an unusual infectious disease, and studying the molecular basis of its pathogenesis may contribute to new findings in therapy of severe conditions leading to a fatal outcome.
Golden, Joseph W.; Hammerbeck, Christopher D.; Mucker, Eric M.; Brocato, Rebecca L.
Human pathogenic hantaviruses and arenaviruses are maintained in nature by persistent infection of rodent carrier populations. Several members of these virus groups can cause significant disease in humans that is generically termed viral hemorrhagic fever (HF) and is characterized as a febrile illness with an increased propensity to cause acute inflammation. Human interaction with rodent carrier populations leads to infection. Arenaviruses are also viewed as potential biological weapons threat agents. There is an increased interest in studying these viruses in animal models to gain a deeper understating not only of viral pathogenesis, but also for the evaluation of medical countermeasures (MCM) to mitigate disease threats. In this review, we examine current knowledge regarding animal models employed in the study of these viruses. We include analysis of infection models in natural reservoirs and also discuss the impact of strain heterogeneity on the susceptibility of animals to infection. This information should provide a comprehensive reference for those interested in the study of arenaviruses and hantaviruses not only for MCM development but also in the study of viral pathogenesis and the biology of these viruses in their natural reservoirs. PMID:26266264
Nitatpattana, Narong; Singhasivanon, Pratap; Kiyoshi, Honda; Andrianasolo, Haja; Yoksan, Sutee; Gonzalez, Jean-Paul; Barbazan, Philippe
A pilot study was designed to analyze a potential association between dengue hemorrhagic fever (DHF) incidence and, temperature computed by satellite. DHF is a mosquito transmitted disease, and water vapor and humidity are known to have a positive effect on mosquito life by increasing survival time and shortening the development cycle. Among other available satellite data, Land Surface Temperature (LST) was chosen as an indicator that combined radiated earth temperature and atmospheric water vapor concentration. Monthly DHF incidence was recorded by province during the 1998 epidemic and obtained as a weekly combined report available from the National Ministry of Public Health. Conversely, LST was calculated using remotely sensed data obtained from thermal infrared sensors of NOAA satellites and computed on a provincial scale. Out of nine selected study provinces, five (58.3%) exhibited an LST with a significant positive correlation with rainfall (p < 0.05). In four out of nineteen surveyed provinces (21.3%), LST showed a significant positive correlation with DHF incidence (p < 0.05). Positive association between LST and DHF incidence was significantly correlated in 75% of the cases during non-epidemic months, while no correlation was found during epidemic months. Non-climatic factors are supposed to be at the origin of this discrepancy between seasonality in climate (LST) and DHF incidence during epidemics.
Wasfi, Fares; Dowall, Stuart; Ghabbari, Tayssir; Bosworth, Andrew; Chakroun, Mohamed; Varghese, Anitha; Tiouiri, Hanene; Ben Jemaa, Mounir; Znazen, Abir; Hewson, Roger; Zhioua, Elyes; Letaief, Amel
Crimean-Congo hemorrhagic fever (CCHF) is a tick-borne disease associated with a high case fatality rate and transmitted mainly by Hyalomma marginatum. The geographical distribution of H. marginatum covers most of the Western Mediterranean basin. We aimed to investigate whether CCHF virus (CCHFv) is circulating in Tunisia. Samples from unexplained acute febrile patients (n = 181) and a high risk group of humans, mainly slaughter workers (n = 38), were collected in the summer of 2014 and analyzed for exposure to CCHFv using serological tests and real-time RT-PCR. Ticks were collected from Northern and Southern Tunisia during May–June 2014 and examined for the presence of CCHFv by real-time RT-PCR. Of the 181 febrile patients, 5 showed only high titers of IgM suggesting a recent exposure to CCHFv. Among 38 slaughter workers, 2 had IgG anti-CCHFv responses yielding a seroprevalence of 5.2%. No CCHFv was detected in ticks and sera. Our results provide evidence of human exposure to CCHFv in Tunisia. PMID:26956221
Golden, Joseph W; Hammerbeck, Christopher D; Mucker, Eric M; Brocato, Rebecca L
Human pathogenic hantaviruses and arenaviruses are maintained in nature by persistent infection of rodent carrier populations. Several members of these virus groups can cause significant disease in humans that is generically termed viral hemorrhagic fever (HF) and is characterized as a febrile illness with an increased propensity to cause acute inflammation. Human interaction with rodent carrier populations leads to infection. Arenaviruses are also viewed as potential biological weapons threat agents. There is an increased interest in studying these viruses in animal models to gain a deeper understating not only of viral pathogenesis, but also for the evaluation of medical countermeasures (MCM) to mitigate disease threats. In this review, we examine current knowledge regarding animal models employed in the study of these viruses. We include analysis of infection models in natural reservoirs and also discuss the impact of strain heterogeneity on the susceptibility of animals to infection. This information should provide a comprehensive reference for those interested in the study of arenaviruses and hantaviruses not only for MCM development but also in the study of viral pathogenesis and the biology of these viruses in their natural reservoirs.
Li, Shujuan; Ren, Hongyan; Hu, Wensheng; Lu, Liang; Xu, Xinliang; Zhuang, Dafang; Liu, Qiyong
Hemorrhagic fever with renal syndrome (HFRS) is an important public health problem in China. The identification of the spatiotemporal pattern of HFRS will provide a foundation for the effective control of the disease. Based on the incidence of HFRS, as well as environmental factors, and social-economic factors of China from 2005-2012, this paper identified the spatiotemporal characteristics of HFRS distribution and the factors that impact this distribution. The results indicate that the spatial distribution of HFRS had a significant, positive spatial correlation. The spatiotemporal heterogeneity was affected by the temperature, precipitation, humidity, NDVI of January, NDVI of August for the previous year, land use, and elevation in 2005-2009. However, these factors did not explain the spatiotemporal heterogeneity of HFRS incidences in 2010-2012. Spatiotemporal heterogeneity of provincial HFRS incidences and its relation to environmental factors would provide valuable information for hygiene authorities to design and implement effective measures for the prevention and control of HFRS in China.
Kayedi, Mohammad Hassan; Chinikar, Sadegh; Mostafavi, Ehsan; Khakifirouz, Sahar; Jalali, Tahmineh; Hosseini-Chegeni, Asadolah; Naghizadeh, Ali; Niedrig, Matthias; Fooks, Anthony R; Shahhosseini, Nariman
Crimean-Congo Hemorrhagic Fever virus (CCHFV) is transmitted through the bite of an infected tick, or by direct contact with CCHFV-infected patients' blood or the products of infected livestock. In 2012, ticks were collected in eight regions of Lorestan Province, Iran. In total, 434 ticks were collected. Reverse transcriptase polymerase chain reaction was used for the detection of CCHFV RNA. Of 434 ticks, 419 (96.6%) ticks were from the family Ixodidae (hard ticks) and 15 (3.5%) ticks were from the family Argasidae (soft ticks). The presence of CCHFV RNA was detected in 29 (6.7%) of 434 ticks. The infected tick species include Hyalomma asiaticum (n = 7, 7.4%), Hyalomma anatolicum (n = 12, 13.2%), Hyalomma marginatum (n = 1, 16.7%), and Rhipicephalus sanguineus (n = 9, 4.3%). These empirical data demonstrated that the majority of CCHFV-positive ticks belonged to the Ixodidae. None of the Argasidae and Haemaphysalis sulcata species was infected with CCHFV. The phylogenetic analyses of the tick-derived CCHFV strains revealed that all 29 viral strains fell in clade IV (Asia 1). The most abundant species of tick collected in this study was R. sanguineus followed by different species of Hyalomma. Given the infection rate among collected ticks, H. marginatum was the most abundant infected tick species (16.7%) followed by H. anatolicum (13.2%), H. asiaticum (7.4%), and R. sanguineus (4.3%).
Fajs, Luka; Jakupi, Xhevat; Ahmeti, Salih; Humolli, Isme; Dedushaj, Isuf; Avšič-Županc, Tatjana
Crimean-Congo hemorrhagic fever virus (CCHFV) is a zoonotic agent that causes severe, life-threatening disease, with a case fatality rate of 10–50%. It is the most widespread tick-borne virus in the world, with cases reported in Africa, Asia and Eastern Europe. CCHFV is a genetically diverse virus. Its genetic diversity is often correlated to its geographical origin. Genetic variability of CCHFV was determined within few endemic areas, however limited data is available for Kosovo. Furthermore, there is little information about the spatiotemporal genetic changes of CCHFV in endemic areas. Kosovo is an important endemic area for CCHFV. Cases were reported each year and the case-fatality rate is significantly higher compared to nearby regions. In this study, we wanted to examine the genetic variability of CCHFV obtained directly from CCHF-confirmed patients, hospitalized in Kosovo from 1991 to 2013. We sequenced partial S segment CCHFV nucleotide sequences from 89 patients. Our results show that several viral variants are present in Kosovo and that the genetic diversity is high in relation to the studied area. We also show that variants are mostly uniformly distributed throughout Kosovo and that limited evolutionary changes have occurred in 22 years. Our results also suggest the presence of a new distinct lineage within the European CCHF phylogenetic clade. Our study provide the largest number of CCHFV nucleotide sequences from patients in 22 year span in one endemic area. PMID:24416468
Towner, Jonathan S.; Sealy, Tara K.; Khristova, Marina L.; Albariño, César G.; Conlan, Sean; Reeder, Serena A.; Quan, Phenix-Lan; Lipkin, W. Ian; Downing, Robert; Tappero, Jordan W.; Okware, Samuel; Lutwama, Julius; Bakamutumaho, Barnabas; Kayiwa, John; Comer, James A.; Rollin, Pierre E.; Ksiazek, Thomas G.; Nichol, Stuart T.
Over the past 30 years, Zaire and Sudan ebolaviruses have been responsible for large hemorrhagic fever (HF) outbreaks with case fatalities ranging from 53% to 90%, while a third species, Côte d'Ivoire ebolavirus, caused a single non-fatal HF case. In November 2007, HF cases were reported in Bundibugyo District, Western Uganda. Laboratory investigation of the initial 29 suspect-case blood specimens by classic methods (antigen capture, IgM and IgG ELISA) and a recently developed random-primed pyrosequencing approach quickly identified this to be an Ebola HF outbreak associated with a newly discovered ebolavirus species (Bundibugyo ebolavirus) distantly related to the Côte d'Ivoire ebolavirus found in western Africa. Due to the sequence divergence of this new virus relative to all previously recognized ebolaviruses, these findings have important implications for design of future diagnostic assays to monitor Ebola HF disease in humans and animals, and ongoing efforts to develop effective antivirals and vaccines. PMID:19023410
Lagerqvist, Nina; Hagström, Åsa; Lundahl, Malin; Nilsson, Elin; Juremalm, Mikael; Larsson, Inger; Alm, Erik; Bucht, Göran; Ahlm, Clas
Rodent-borne hantaviruses cause two severe acute diseases: hemorrhagic fever with renal syndrome (HFRS) in Eurasia, and hantavirus pulmonary syndrome (HPS; also called hantavirus cardiopulmonary syndrome [HCPS]) in the Americas. Puumala virus (PUUV) is the most common causative agent of HFRS in Europe. Current routine diagnostic methods are based on serological analyses and can yield inconclusive results. Hantavirus-infected patients are viremic during the early phase of disease; therefore, detection of viral RNA genomes can be a valuable complement to existing serological methods. However, the high genomic sequence diversity of PUUV has hampered the development of molecular diagnostics, and currently no real-time reverse transcription-quantitative (RT)-PCR assay is available for routine diagnosis of HFRS. Here, we present a novel PUUV RT-PCR assay. The assay was validated for routine diagnosis of HFRS on samples collected in Sweden during the winter season from 2013 to 2014. The assay allowed detection of PUUV RNA in 98.7% of confirmed clinical HFRS samples collected within 8 days after symptomatic onset. In summary, this study shows that real-time RT-PCR can be a reliable alternative to serological tests during the early phase of HFRS. PMID:26962084
McLay, Lisa; Ansari, Aftab; Liang, Yuying; Ly, Hinh
A number of arenaviruses are pathogenic for humans, but they differ significantly in virulence. Lassa virus, found in West Africa, causes severe hemorrhagic fever (HF), while the other principal Old World arenavirus, lymphocytic choriomeningitis virus, causes mild illness in persons with normal immune function, and poses a threat only to immunocompromised individuals. The New World agents, including Junin, Machupo and Sabia virus, are highly pathogenic for humans. Arenaviral HF is characterized by high viremia and general immune suppression, the mechanism of which is unknown. Studies using viral reverse genetics, cell-based assays, animal models and human genome-wide association analysis have revealed potential mechanisms by which arenaviruses cause severe disease in humans. Each of the four viral gene products (GPC, L polymerase, NP, and Z matrix protein) and several host-cell factors (e.g., α-dystroglycan) are responsible for mediating viral entry, genome replication, and the inhibition of apoptosis, translation and interferon-beta (IFNβ) production. This review summarizes current knowledge of the role of each viral protein and host factor in the pathogenesis of arenaviral HF. Insights from recent studies are being exploited for the development of novel therapies.
Papa, Anna; Kontana, Anastasia; Tsioka, Katerina; Chaligiannis, Ilias; Sotiraki, Smaragda
Crimean-Congo hemorrhagic fever virus (CCHFV) is transmitted to humans mainly through the bite of infected ticks. In Greece, only one clinical case has been observed, in 2008, but the seroprevalence in humans is relatively high (4.2%). To have a first insight into the circulation of CCHFV in Greece, 2000 ticks collected from livestock during 2012-2014 were tested. CCHFV was detected in 36 of the 1290 (2.8%) tick pools (1-5 ticks per pool). Two genetic lineages were identified: Europe 1 and Europe 2. Most Europe 1 sequences were obtained from Rhipicephalus sanguineus sensu lato ticks, while most Europe 2 sequences were recovered from Rhipicephalus bursa ticks. The number of collected Hyalomma marginatum ticks (the principal vector of CCHFV) was low (0.5% of ticks) and all were CCHFV negative. Since it is not known how efficient ticks of the Rhipicephalus genus are as vectors of the virus, laboratory studies will be required to explore the role of Rhipicephalus spp. ticks in CCHFV maintenance and transmission.
Halstead, Scott B; Cohen, Sanford N
During the decade of the 1960s, the epidemiology of a new dengue disease, dengue hemorrhagic fever and dengue shock syndrome (DHF/DSS), was described by collaborative research performed by Thai scientists from many institutions and by workers at the U.S. Army's SEATO Medical Research Laboratory in Bangkok, Thailand. Careful clinical and physiological studies provided the initial description of DSS. DSS cases were caused by each of the four dengue viruses (DENV) and not chikungunya (CHIK) virus or DENV 5 and 6, were associated with a secondary-type dengue antibody response in children over the age of 1 year, were associated with a primary antibody response in infants less than 1 year old whose mothers had neutralizing antibodies to all four DENV, were associated more frequently with secondary DENV 2 infections than those due to DENV 1 and 3, and were more common in females than males over the age of 3 years. Robust laboratory methods for growth and recovery of DENV in tissue cultures were introduced. In addition, life-saving principles of fluid and plasma protein resuscitation of hypovolemia were described. Most epidemiological observations made during the decade of the 1960s have been confirmed in the succeeding 45 years. Much contemporary research on pathogenesis fails to address the two distinct immunological antecedents of DHF/DSS.
Cohen, Sanford N.
SUMMARY During the decade of the 1960s, the epidemiology of a new dengue disease, dengue hemorrhagic fever and dengue shock syndrome (DHF/DSS), was described by collaborative research performed by Thai scientists from many institutions and by workers at the U.S. Army's SEATO Medical Research Laboratory in Bangkok, Thailand. Careful clinical and physiological studies provided the initial description of DSS. DSS cases were caused by each of the four dengue viruses (DENV) and not chikungunya (CHIK) virus or DENV 5 and 6, were associated with a secondary-type dengue antibody response in children over the age of 1 year, were associated with a primary antibody response in infants less than 1 year old whose mothers had neutralizing antibodies to all four DENV, were associated more frequently with secondary DENV 2 infections than those due to DENV 1 and 3, and were more common in females than males over the age of 3 years. Robust laboratory methods for growth and recovery of DENV in tissue cultures were introduced. In addition, life-saving principles of fluid and plasma protein resuscitation of hypovolemia were described. Most epidemiological observations made during the decade of the 1960s have been confirmed in the succeeding 45 years. Much contemporary research on pathogenesis fails to address the two distinct immunological antecedents of DHF/DSS. PMID:26085471
Wu, Wei; An, Shuyi; Guo, Junqiao; Guan, Peng; Ren, Yangwu; Xia, Lingzi; Zhou, Baosen
To explore the prospect of nonlinear autoregressive neural network in fitting and predicting the incidence tendency of hemorrhagic fever with renal syndrome (HFRS) , in the mainland of China. Monthly reported case series of HFRS in China from 2004 to 2013 were used to build both ARIMA and NAR neural network models, in order to predict the monthly incidence of HFRS in China in 2014. Fitness and prediction on the effects of these two models were compared. For the Fitting dataset, MAE, RMSE and MAPE of the ARIMA model were 148.058, 272.077 and 12.678% respectively, while the MAE, RMSE and MAPE of NAR neural network appeared as 119.436, 186.671 and 11.778% respectively. For the Predicting dataset, MAE, RMSE and MAPE of the ARIMA model appeared as 189.088, 221.133 and 21.296%, while the MAE, RMSE and MAPE of the NAR neural network as 119.733, 151.329 and 11.431% respectively. The NAR neural network showed better effects in fitting and predicting the incidence tendency of HFRS than using the traditional ARIMA model, in China. NAR neural network seemed to have strong application value in the prevention and control of HFRS.
Guner, Rahmet; Hasanoglu, Imran; Tasyaran, Mehmet Akin; Yapar, Derya; Keske, Siran; Guven, Tumer; Yilmaz, Gul Ruhsar
Crimean-Congo hemorrhagic fever (CCHF) is a viral zoonotic disease that is transmitted primarily through contact with ticks. Nosocomial cases and outbreaks of CCHF have been reported from many countries. Health care workers (HCWs) are at risk of exposure to CCHF. In our study, we evaluated seven HCWs' exposure to confirmed CCHF patients' infected blood and body fluids and prophylactic efficacy of the ribavirin on nosocomial transmission of CCHF retrospectively. Between 2007 and 2013, 150 CCHF cases were admitted to our clinic. During the follow-up of these patients, four doctors and three nurses had contact with infected blood and body fluids through needle stick injury, contact of skin and mucosal surfaces, and probable aerosolization. All of the index cases' diagnoses of CCHF were confirmed during the contact. Ribavirin prophylaxis was administered within 0.5-1 h in six out of seven cases. All of these cases' CCHF virus PCR results were negative. One physician had no contact with infected blood or body fluid, so ribavirin prophylaxis was not administered. The physician developed CCHF and diagnosis was confirmed. Although efficacy of ribavirin for prophylaxis is not clear and very few data exist on prophylactic usage of ribavirin, lack of clinical manifestations in our cases that were given ribavirin compared with the developed clinical manifestations in the physician may be explained by the prophylactic efficacy of the ribavirin.
Gayretli Aydin, Zeynep Gokce; Tanir, Gonul; Metin, Ozge; Aydin Teke, Turkan; Bayhan, Gulsum Iclal; Oz, Fatma Nur; Caglayik, Dilek Yagci; Gençtürk, Zeynep
Crimean-Congo hemorrhagic fever (CCHF) is an acute tick-borne viral zoonotic disease which is endemic in Turkey. Bradycardia has been reported among pediatric and adult patients with CCHF. But, it remains unclear, whether bradycardia is associated with ribavirin treatment or the severity of CCHF. In this study 26 hospitalized CCHF patients were reviewed in terms of age, gender, history of tick bite, duration of hospitalization, presence of bradycardia, laboratory features, ribavirin treatment, and blood products requirement. The demographic, clinical, laboratory and treatment characteristics of CCHF patients with or without bradycardia were compared. The mean age of the patients was 126.42±48.21 months. There were 8 female and 18 male patients. Sinus bradycardia was noted in 15 patients (mean age was 120.20±50.59 months, 5 female). Ribavirin had been administered 18 (69.2%) patients and 11 of them had bradycardia. There was not statistically significant relationships between bradycardia and ribavirin treatment (p=0.683). Furthermore the occurrence of bradycardia was not associated with disease severity according to Swanepoel severity criteria (p=0.683). We concluded that independent of the disease severity and the ribavirin treatment, transient sinus bradycardia might occur during the clinical course of CCHF in pediatric patients. For this reason clinicians should be aware of this finding and all CCHF patients should be monitored closely.
Lwande, Olivia Wesula; Irura, Zephania; Tigoi, Caroline; Chepkorir, Edith; Orindi, Benedict; Musila, Lillian; Venter, Marietjie; Fischer, Anne; Sang, Rosemary
Crimean-Congo hemorrhagic fever (CCHF) is a tick-borne viral disease mainly affecting pastoralists who come in contact with animals infested with Hyalomma ticks, which are the key vectors of CCHF virus (CCHFV). CCHFV has been detected among these ticks in parts of North Eastern Kenya. This study aimed to identify acute cases of CCHF, and to determine the extent of previous exposure to CCHFV in an outpatient population attending Sangailu and Ijara health centers, Ijara District, North Eastern Kenya, presenting with acute febrile illnesses. A total of 517 human serum samples were collected from these patients. The samples were screened for the presence of IgM and IgG antibodies to CCHF using CCCHF-IgG and IgM ELISA test kits. A multivariable logistic regression model was used to investigate the risk factors associated with evidence of exposure to CCHFV. A single patient tested positive for anti-CCHF IgM, while 96 were positive for anti-CCHF IgG. The seroprevalence of CCHFV was 23% in Sangailu and 14% in Ijara. Most exposed persons were aged 40-49 years. The likelihood of exposure was highest among farmers (29%). Age, location, and contact with donkeys were significantly associated with exposure to CCHFV. Acute CCHFV infections could be occurring without being detected in this population. This study confirms human exposure to CCHF virus in Ijara District, Kenya, and identifies several significant risk factors associated with exposure to CCHFV.
Karadag-Oncel, Eda; Erel, Ozcan; Ozsurekci, Yasemin; Caglayik, Dilek Yagci; Kaya, Ali; Gozel, Mustafa Gokhan; Icagasioglu, Fusun Dilara; Engin, Aynur; Korukluoglu, Gulay; Uyar, Yavuz; Elaldi, Nazif; Ceyhan, Mehmet
In this study, we investigated the pro- and antioxidant status of patients with a pathogenesis of Crimean-Congo hemorrhagic fever (CCHF) in terms of their role in its pathogenesis. During the study period, 34 children and 41 adults were diagnosed with CCHF. The control group consisted of healthy age- and gender-matched children and adults. Serum levels of the total antioxidant capacity (TAC), total oxidant status (TOS), oxidative stress index (OSI), and plasma total thiol (TTL) were evaluated and compared between groups. The difference in mean TAC values between CCHF patients and healthy controls was not statistically significant (P > 0.05). Mean TOS, OSI, and TTL values were significantly lower in CCHF patients than in healthy controls (P < 0.001). Comparisons between the 2 groups revealed that mean TOS and OSI values were significantly lower in adults with CCHF than in their healthy counterparts (P < 0.001). Similarly, mean TTL levels were lower in both children and adults with CCHF when compared separately with healthy controls (P < 0.05). There was no significant difference in the mean serum TTL levels between children and adults with CCHF (P > 0.05). Our results suggest that TTL may play a more important role in CCHF pathogenesis than the other parameters investigated. The mean TOS and OSI values were higher in the control group than in CCHF patients.
Mostafavi, Ehsan; Chinikar, Sadegh; Moradi, Maryam; Bayat, Neda; Meshkat, Mohsen; Fard, Mohammad Khalili; Ghiasi, Seyyed Mojtaba
Crimean Congo hemorrhagic fever (CCHF) is a viral zoonosis, which is usually transmitted via tick bites or close contact with infected blood or tissue. This disease can cause a case fatality rate of up to 25%-30% in humans. CCHF Infection in birds is less documented. An ostrich can reproduce viruses and can also play the role of a mechanical vector, by transporting infected ticks without becoming ill. In March 2007, three butchers and one worker in an ostrich farm were infected with CCHF in central part of Iran. Considering the role ostriches play in transmitting the disease, serum samples from five ostriches of that farm were taken and sent to the laboratory for CCHF ELISA tests. The result of the IgG test was positive for one (20%) of the ostriches. At the same time, serum samples of eight sheep from the same farm were sent for IgG testing, two (25%) of which were positive. This was the first report of CCHF infection of an ostrich in Iran and tracing CCHF IgG against this ostrich and the afore-mentioned sheep may have revealed that the disease in the worker was the cause of transmission of this disease from these animals or their ticks.
Ahmadkhani, Mohsen; Alesheikh, Ali Asghar; Khakifirouz, Sahar; Salehi-Vaziri, Mostafa
Iran, as an endemic country of Crimean-Congo hemorrhagic fever (CCHF), has been suffering from severe health issues and substantial economic burdens imposed by the disease. We analyzed monthly and yearly spatial and temporal distributions of CCHF to better understand the epidemiology of the disease in Iran. A cross-sectional survey was performed on 1027 recorded cases between 2000 and 2014. Global Moran's I analysis was applied to statistically evaluate the spatial pattern of the disease. Additionally, spatial and space-time scan statistics were used to study the presence of possible spatial and space-time hotspots. Global Moran's I analysis proved that the incidence of the disease is strongly clustered in Iran (p<0.01). Purely spatial scan statistics identified that there were three clusters in the eastern, southern and western parts of the country. Through space-time analysis, we found that the highest incidence of CCHF occurred in the eastern parts of the country between 2006 and 2012. Monthly clusters, which include cities with lower (average) temperatures, had been occurring in relatively short periods. The distribution of CCHF incidence in this country is spatially and temporally clustered. The majority of the clusters emerged during the critical years of 2009 and 2013. Summer is the predominant period for the formation of CCHF clusters. Copyright © 2017 Elsevier GmbH. All rights reserved.
Shao, Junjie; Liang, Yuying; Ly, Hinh
Arenaviruses include multiple human pathogens ranging from the low-risk lymphocytic choriomeningitis virus (LCMV) to highly virulent hemorrhagic fever (HF) causing viruses such as Lassa (LASV), Junin (JUNV), Machupo (MACV), Lujo (LUJV), Sabia (SABV), Guanarito (GTOV), and Chapare (CHPV), for which there are limited preventative and therapeutic measures. Why some arenaviruses can cause virulent human infections while others cannot, even though they are isolated from the same rodent hosts, is an enigma. Recent studies have revealed several potential pathogenic mechanisms of arenaviruses, including factors that increase viral replication capacity and suppress host innate immunity, which leads to high viremia and generalized immune suppression as the hallmarks of severe and lethal arenaviral HF diseases. This review summarizes current knowledge of the roles of each of the four viral proteins and some known cellular factors in the pathogenesis of arenaviral HF as well as of some human primary cell-culture and animal models that lend themselves to studying arenavirus-induced HF disease pathogenesis. Knowledge gained from these studies can be applied towards the development of novel therapeutics and vaccines against these deadly human pathogens. PMID:26011826
McLay, Lisa; Ansari, Aftab; Liang, Yuying; Ly, Hinh
A number of arenaviruses are pathogenic for humans, but they differ significantly in virulence. Lassa virus, found in West Afri ca, causes severe hemorrhagic fever (HF), while the other principal Old World arenavirus, lymphocytic choriomeningitis virus, causes mild illness in persons with normal immune function, and poses a threat only to immunocompromised individuals. The New World agents, including Junin, Machupo and Sabia virus, are highly pathogenic for humans. Arenaviral HF is characterized by high viremia and general immune suppression, the mechanism of which is unknown. Studies using viral reverse genetics, cell-based assays, animal models and human genome-wide association analysis have revealed potential mechanisms by which arenaviruses cause severe disease in humans. Each of the four viral gene products (GPC, L polymerase, NP, and Z matrix protein) and several host-cell factors (e.g., α-dystroglycan) are responsible for mediating viral entry, genome replication, and the inhibition of apoptosis, translation and interferon-beta (IFNβ) production. This review summarizes current knowledge of the role of each viral protein and host factor in the pathogenesis of arenaviral HF. Insights from recent studies are being exploited for the development of novel therapies. PMID:23261843
Loeb, Mark; MacPherson, Douglas; Barton, Michele; Olde, Jan
To describe the implementation of the Canadian contingency plan for viral hemorrhagic fever (VHF) in response to a suspected case. A 300-bed, tertiary-care, university-affiliated hospital. A 32-year-old Congolese woman admitted to the hospital with suspected VHF in February 2001. Contact evaluation included hospital healthcare workers and laboratory staff. Enhanced isolation precautions were implemented in the patient care setting to prevent nosocomial transmission. Contact tracing and evaluation of close and high-risk contacts with symptoms was conducted. Laboratory precautions included barrier precautions and diversion of specimens. Communication occurred media. to both hospital employees and the media. Three high-risk contacts, 13 close contacts, and 60 casual contacts were identified. Two close contacts became symptomatic and required evaluation. Challenging process issues included tracing of laboratory specimens, decontamination of laboratory equipment, and internal and external communication. After 5 days, a transmissible VHF of public health consequence was ruled out in the index case. Contingency plans for VHF can be implemented in an efficient and feasible manner. Contact tracing, laboratory issues, internal communication, and media interest can be anticipated to be the key challenges.
Karakeçili, Faruk; Çıkman, Aytekin; Akın, Hicran; Gülhan, Barış; Özçiçek, Adalet
Brucellosis, a zoonotic disease which is especially seen in developing countries is still an important public health problem worldwide. Crimean-Congo hemorrhagic fever (CCHF) is another zoonotic disease that transmits to humans by infected tick bites as well as exposure to blood or tissue from infected animals. Both of the diseases are common among persons who live in rural areas and deal with animal husbandry. Since brucellosis usually presents with non-specific clinical symptoms and may easily be confused with many other diseases, the diagnosis of those infections could be delayed or misdiagnosed. In this report, a case of coinfection of brucellosis and CCHF has been presented to emphasize the possibility of association of these infections. A 70-year-old female patient with a history of dealing with animal husbandry in a rural area admitted to our hospital with the complaints of fever, malaise, generalized body and joint pains, and headache. Her complaints had progressed within the past two days. She also reported nausea, vomiting, abdominal pain and bloody diarrhea. She denied any history of tick bites. Her physical examination was significant for the presence of 38.8°C fever, increased bowel sounds and splenomegaly. Laboratory analysis revealed leukopenia, thrombocytopenia and high levels of liver enzymes. The patient was admitted to our service with the prediagnosis of CCHF. Serum sample was sent to the Department of Microbiology Reference Laboratory at Public Health Agency of Turkey for CCHF testing. During patient's hospitalization in service, more detailed history was confronted and it was learned that she had fatigue, loss of appetite, sweating, joint pain, and intermittent fever complaints were continuing within a month and received various antibiotic treatments. The tests for brucellosis were conducted and positive results for Brucella Rose Bengal test, tube agglutination (1/160 titers) and immune capture test with Coombs (1/320 titers) were determined
Teixeira, Maria Glória; Paixão, Enny S; Costa, Maria da Conceição N; Cunha, Rivaldo V; Pamplona, Luciano; Dias, Juarez P; Figueiredo, Camila A; Figueiredo, Maria Aparecida A; Blanton, Ronald; Morato, Vanessa; Barreto, Maurício L; Rodrigues, Laura C
Currently, knowledge does not allow early prediction of which cases of dengue fever (DF) will progress to dengue hemorrhagic fever (DHF), to allow early intervention to prevent progression or to limit severity. The objective of this study is to investigate the hypothesis that some specific comorbidities increase the likelihood of a DF case progressing to DHF. A concurrent case-control study, conducted during dengue epidemics, from 2009 to 2012. Cases were patients with dengue fever that progressed to DHF, and controls were patients of dengue fever who did not progress to DHF. Logistic regression was used to estimate the association between DHF and comorbidities. There were 490 cases of DHF and 1,316 controls. Among adults, progression to DHF was associated with self-reported hypertension (OR = 1.6; 95% CI 1.1-2.1) and skin allergy (OR = 1.8; 95% CI 1.1-3.2) with DHF after adjusting for ethnicity and socio-economic variables. There was no statistically significant association between any chronic disease and progression to DHF in those younger than 15 years. Physicians attending patients with dengue fever should keep those with hypertension or skin allergies in health units to monitor progression for early intervention. This would reduce mortality by dengue.
Teixeira, Maria Glória; Paixão, Enny S.; Costa, Maria da Conceição N.; Cunha, Rivaldo V.; Pamplona, Luciano; Dias, Juarez P.; Figueiredo, Camila A.; Figueiredo, Maria Aparecida A.; Blanton, Ronald; Morato, Vanessa; Barreto, Maurício L.; Rodrigues, Laura C.
Background Currently, knowledge does not allow early prediction of which cases of dengue fever (DF) will progress to dengue hemorrhagic fever (DHF), to allow early intervention to prevent progression or to limit severity. The objective of this study is to investigate the hypothesis that some specific comorbidities increase the likelihood of a DF case progressing to DHF. Methods A concurrent case-control study, conducted during dengue epidemics, from 2009 to 2012. Cases were patients with dengue fever that progressed to DHF, and controls were patients of dengue fever who did not progress to DHF. Logistic regression was used to estimate the association between DHF and comorbidities. Results There were 490 cases of DHF and 1,316 controls. Among adults, progression to DHF was associated with self-reported hypertension (OR = 1.6; 95% CI 1.1-2.1) and skin allergy (OR = 1.8; 95% CI 1.1-3.2) with DHF after adjusting for ethnicity and socio-economic variables. There was no statistically significant association between any chronic disease and progression to DHF in those younger than 15 years. Conclusions Physicians attending patients with dengue fever should keep those with hypertension or skin allergies in health units to monitor progression for early intervention. This would reduce mortality by dengue. PMID:25996882
Osman, Hana A M; Eltom, Kamal H; Musa, Nasreen O; Bilal, Nasreldin M; Elbashir, Mustafa I; Aradaib, Imadeldin E
Crimean-Congo hemorrhagic fever (CCHF) virus (CCHFV) activity has been detected in Kordufan region of the Sudan in 2008 with high case-fatality rates in villages and rural hospitals in the region. Therefore, in the present study, a reverse transcription (RT) loop-mediated isothermal amplification (RT-LAMP) assay was developed and compared to nested RT-PCR for rapid detection of CCHFV targeting the small (S) RNA segment. A set of RT-LAMP primers, designed from a highly conserved region of the S segment of the viral genome, was employed to identify all the Sudanese CCHFV strains. The sensitivity studies indicated that the RT-LAMP detected 10fg of CCHFV RNA as determined by naked eye turbidity read out, which is more likely the way it would be read in a resource-poor setting. This level of sensitivity is good enough to detect most acute cases. Using agarose gel electrophoresis, the RT-LAMP assay detected as little as 0.1fg of viral RNA (equivalent to 50 viral particle). There was 100% agreement between results of the RT-LAMP and the nested PCR when testing 10-fold serial dilution of CCHFV RNA. The specificity studies indicated that there was no cross-reactivity with other related hemorrhagic fever viruses circulating in Sudan including, Rift Valley fever virus (RVFV), Dengue fever virus, and yellow fever virus. The RT-LAMP was performed under isothermal conditions at 63°C and no special apparatus was needed, which rendered the assay more economical and practical than real-time PCR in such developing countries, like Sudan. In addition, the RT-LAMP provides a valuable tool for rapid detection and differentiation of CCHFV during an outbreak of the disease in remote areas and in rural hospitals with resource-poor settings.
Olson, Sarah H; Reed, Patricia; Cameron, Kenneth N; Ssebide, Benard J; Johnson, Christine K; Morse, Stephen S; Karesh, William B; Mazet, Jonna A K; Joly, Damien O
There are currently no widely accepted animal surveillance guidelines for human Ebola hemorrhagic fever (EHF) outbreak investigations to identify potential sources of Ebolavirus (EBOV) spillover into humans and other animals. Animal field surveillance during and following an outbreak has several purposes, from helping identify the specific animal source of a human case to guiding control activities by describing the spatial and temporal distribution of wild circulating EBOV, informing public health efforts, and contributing to broader EHF research questions. Since 1976, researchers have sampled over 10,000 individual vertebrates from areas associated with human EHF outbreaks and tested for EBOV or antibodies. Using field surveillance data associated with EHF outbreaks, this review provides guidance on animal sampling for resource-limited outbreak situations, target species, and in some cases which diagnostics should be prioritized to rapidly assess the presence of EBOV in animal reservoirs. In brief, EBOV detection was 32.7% (18/55) for carcasses (animals found dead) and 0.2% (13/5309) for live captured animals. Our review indicates that for the purposes of identifying potential sources of transmission from animals to humans and isolating suspected virus in an animal in outbreak situations, (1) surveillance of free-ranging non-human primate mortality and morbidity should be a priority, (2) any wildlife morbidity or mortality events should be investigated and may hold the most promise for locating virus or viral genome sequences, (3) surveillance of some bat species is worthwhile to isolate and detect evidence of exposure, and (4) morbidity, mortality, and serology studies of domestic animals should prioritize dogs and pigs and include testing for virus and previous exposure.
Olson, Sarah H.; Reed, Patricia; Cameron, Kenneth N.; Ssebide, Benard J.; Johnson, Christine K.; Morse, Stephen S.; Karesh, William B.; Mazet, Jonna A. K.; Joly, Damien O.
There are currently no widely accepted animal surveillance guidelines for human Ebola hemorrhagic fever (EHF) outbreak investigations to identify potential sources of Ebolavirus (EBOV) spillover into humans and other animals. Animal field surveillance during and following an outbreak has several purposes, from helping identify the specific animal source of a human case to guiding control activities by describing the spatial and temporal distribution of wild circulating EBOV, informing public health efforts, and contributing to broader EHF research questions. Since 1976, researchers have sampled over 10,000 individual vertebrates from areas associated with human EHF outbreaks and tested for EBOV or antibodies. Using field surveillance data associated with EHF outbreaks, this review provides guidance on animal sampling for resource-limited outbreak situations, target species, and in some cases which diagnostics should be prioritized to rapidly assess the presence of EBOV in animal reservoirs. In brief, EBOV detection was 32.7% (18/55) for carcasses (animals found dead) and 0.2% (13/5309) for live captured animals. Our review indicates that for the purposes of identifying potential sources of transmission from animals to humans and isolating suspected virus in an animal in outbreak situations, (1) surveillance of free-ranging non-human primate mortality and morbidity should be a priority, (2) any wildlife morbidity or mortality events should be investigated and may hold the most promise for locating virus or viral genome sequences, (3) surveillance of some bat species is worthwhile to isolate and detect evidence of exposure, and (4) morbidity, mortality, and serology studies of domestic animals should prioritize dogs and pigs and include testing for virus and previous exposure. PMID:22558004
Zambrano, L I; Sevilla, C; Reyes-García, S Z; Sierra, M; Kafati, R; Rodriguez-Morales, A J; Mattar, S
Climate change and variability are affecting human health and disease direct or indirectly through many mechanisms. Dengue is one of those diseases that is strongly influenced by climate variability; however its study in Central America has been poorly approached. In this study, we assessed potential associations between macroclimatic and microclimatic variation and dengue hemorrhagic fever (DHF) cases in the main hospital of Honduras during 2010. In this year, 3,353 cases of DHF were reported in the Hospital Escuela, Tegucigalpa. Climatic periods marked a difference of 158% in the mean incidence of cases, from El Niño weeks (-99% of cases below the mean incidence) to La Niña months (+59% of cases above it) (p<0.01). Linear regression showed significantly higher dengue incidence with lower values of Oceanic Niño Index (p=0.0097), higher rain probability (p=0.0149), accumulated rain (p=0.0443) and higher relative humidity (p=0.0292). At a multiple linear regression model using those variables, ONI values shown to be the most important and significant factor found to be associated with the monthly occurrence of DHF cases (r²=0.649; βstandardized=-0.836; p=0.01). As has been shown herein, climate variability is an important element influencing the dengue epidemiology in Honduras. However, it is necessary to extend these studies in this and other countries in the Central America region, because these models can be applied for surveillance as well as for prediction of dengue.
Zhang, Wen-Yi; Guo, Wei-Dong; Fang, Li-Qun; Li, Chang-Ping; Bi, Peng; Glass, Gregory E.; Jiang, Jia-Fu; Sun, Shan-Hua; Qian, Quan; Liu, Wei; Yan, Lei; Yang, Hong; Tong, Shi-Lu; Cao, Wu-Chun
Background The transmission of hemorrhagic fever with renal syndrome (HFRS) is influenced by climatic variables. However, few studies have examined the quantitative relationship between climate variation and HFRS transmission. Objective We examined the potential impact of climate variability on HFRS transmission and developed climate-based forecasting models for HFRS in northeastern China. Methods We obtained data on monthly counts of reported HFRS cases in Elunchun and Molidawahaner counties for 1997–2007 from the Inner Mongolia Center for Disease Control and Prevention and climate data from the Chinese Bureau of Meteorology. Cross-correlations assessed crude associations between climate variables, including rainfall, land surface temperature (LST), relative humidity (RH), and the multivariate El Niño Southern Oscillation (ENSO) index (MEI) and monthly HFRS cases over a range of lags. We used time-series Poisson regression models to examine the independent contribution of climatic variables to HFRS transmission. Results Cross-correlation analyses showed that rainfall, LST, RH, and MEI were significantly associated with monthly HFRS cases with lags of 3–5 months in both study areas. The results of Poisson regression indicated that after controlling for the autocorrelation, seasonality, and long-term trend, rainfall, LST, RH, and MEI with lags of 3–5 months were associated with HFRS in both study areas. The final model had good accuracy in forecasting the occurrence of HFRS. Conclusions Climate variability plays a significant role in HFRS transmission in northeastern China. The model developed in this study has implications for HFRS control and prevention. PMID:20142167
Background The effects of air pollution on the respiratory and cardiovascular systems, and the resulting impacts on public health, have been widely studied. However, little is known about the effect of air pollution on the occurrence of hemorrhagic fever with renal syndrome (HFRS), a rodent-borne infectious disease. In this study, we evaluated the correlation between air pollution and HFRS incidence from 2001 to 2010, and estimated the significance of the correlation under the effect of climate variables. Methods We obtained data regarding HFRS, particulate matter smaller than 10 μm (PM10) as an index of air pollution, and climate variables including temperature, humidity, and precipitation from the national database of South Korea. Poisson regression models were established to predict the number of HFRS cases using air pollution and climate variables with different time lags. We then compared the ability of the climate model and the combined climate and air pollution model to predict the occurrence of HFRS. Results The correlations between PM10 and HFRS were significant in univariate analyses, although the direction of the correlations changed according to the time lags. In multivariate analyses of adjusted climate variables, the effects of PM10 with time lags were different. However, PM10 without time lags was selected in the final model for predicting HFRS cases. The model that combined climate and PM10 data was a better predictor of HFRS cases than the model that used only climate data, for both the study period and the year 2011. Conclusions This is the first report to document an association between HFRS and PM10 level. PMID:23587219
Lozano, M E; Enría, D; Maiztegui, J I; Grau, O; Romanowski, V
Argentine hemorrhagic fever (AHF) is an endemo-epidemic disease caused by Junín virus. This report demonstrates that a reverse transcriptase (RT) PCR-based assay developed in our laboratory to detect Junín virus in whole blood samples is sensitive and specific. The experiments were conducted in a double-blinded manner using 94 clinical samples collected in the area in which AHF is endemic. The RT-PCR-based assay was compared with traditional methodologies, including enzyme-linked immunosorbent assay, plaque neutralization tests, and occasionally viral isolation. The calculated parameters for RT-PCR diagnosis, with seroconversion as the "gold standard," were 98% sensitivity and 76% specificity. It is noteworthy that 94% of the patients with putative false-positive results (RT-PCR positive and no seroconversion detected) exhibited febrile syndromes of undefined etiology. These results could be interpreted to mean that most of those patients with febrile syndromes were actually infected with Junín virus but did not develop a detectable immune response. Furthermore, 8 laboratory-fabricated samples and 25 blood samples of patients outside the area in which AHF is endemic tested in a similar way were disclosed correctly (100% match). The RT-PCR assay is the only laboratory test available currently for the early and rapid diagnosis of AHF. It is sensitive enough to detect the low viremia found during the period in which immune plasma therapy can be used effectively, reducing mortality rates from 30% to less than 1%. PMID:7542268
Bird, Brian H.; Dodd, Kimberly A.; Erickson, Bobbie R.; Albariño, César G.; Chakrabarti, Ayan K.; McMullan, Laura K.; Bergeron, Eric; Ströeher, Ute; Cannon, Deborah; Martin, Brock; Coleman-McCray, JoAnn D.; Nichol, Stuart T.; Spiropoulou, Christina F.
Lujo virus (LUJV) is a novel member of the Arenaviridae family that was first identified in 2008 after an outbreak of severe hemorrhagic fever (HF). In what was a small but rapidly progressing outbreak, this previously unknown virus was transmitted from the critically ill index patient to 4 attending healthcare workers. Four persons died during this outbreak, for a total case fatality of 80% (4/5). The suspected rodent source of the initial exposure to LUJV remains a mystery. Because of the ease of transmission, high case fatality, and novel nature of LUJV, we sought to establish an animal model of LUJV HF. Initial attempts in mice failed, but infection of inbred strain 13/N guinea pigs resulted in lethal disease. A total of 41 adult strain 13/N guinea pigs were infected with either wild-type LUJV or a full-length recombinant LUJV. Results demonstrated that strain 13/N guinea pigs provide an excellent model of severe and lethal LUJV HF that closely resembles what is known of the human disease. All infected animals experienced consistent weight loss (3–5% per day) and clinical illness characterized by ocular discharge, ruffled fur, hunched posture, and lethargy. Uniform lethality occurred by 11–16 days post-infection. All animals developed disseminated LUJV infection in various organs (liver, spleen, lung, and kidney), and leukopenia, lymphopenia, thrombocytopenia, coagulopathy, and elevated transaminase levels. Serial euthanasia studies revealed a temporal pattern of virus dissemination and increasing severity of disease, primarily targeting the liver, spleen, lungs, and lower gastrointestinal tract. Establishing an animal LUJV model is an important first step towards understanding the high pathogenicity of LUJV and developing vaccines and antiviral therapeutic drugs for this highly transmissible and lethal emerging pathogen. PMID:22953019
Background Hemorrhagic fever with renal syndrome (HFRS) is an important public health problem in mainland China. HFRS is particularly endemic in Changsha, the capital city of Hunan Province, with one of the highest incidences in China. The occurrence of HFRS is influenced by environmental factors. However, few studies have examined the relationship between environmental variation (such as land use changes and climate variations), rodents and HFRS occurrence. The purpose of this study is to predict the distribution of HFRS and identify the risk factors and relationship between HFRS occurrence and rodent hosts, combining ecological modeling with the Markov chain Monte Carlo approach. Methods Ecological niche models (ENMs) were used to evaluate potential geographic distributions of rodent species by reconstructing details of their ecological niches in ecological dimensions, and projecting the results onto geography. The Genetic Algorithm for Rule-set Production was used to produce ENMs. Data were collected on HFRS cases in Changsha from 2005 to 2009, as well as national land survey data, surveillance data of rodents, meteorological data and normalized difference vegetation index (NDVI). Results The highest occurrence of HFRS was in districts with strong temperature seasonality, where elevation is below 200 m, mean annual temperature is around 17.5°C, and annual precipitation is below 1600 mm. Cultivated and urban lands in particular are associated with HFRS occurrence. Monthly NDVI values of areas predicted present is lower than areas predicted absent, with high seasonal variation. The number of HFRS cases was correlated with rodent density, and the incidence of HFRS cases in urban and forest areas was mainly associated with the density of Rattus norvegicus and Apodemus agrarius, respectively. Conclusions Heterogeneity between different areas shows that HFRS occurrence is affected by the intensity of human activity, climate conditions, and landscape elements. Rodent
Carter, Stephen D.; Surtees, Rebecca; Walter, Cheryl T.; Ariza, Antonio; Bergeron, Éric; Nichol, Stuart T.; Hiscox, Julian A.
Crimean-Congo hemorrhagic fever virus (CCHFV) is an emerging tick-borne virus of the Bunyaviridae family that is responsible for a fatal human disease for which preventative or therapeutic measures do not exist. We solved the crystal structure of the CCHFV strain Baghdad-12 nucleocapsid protein (N), a potential therapeutic target, at a resolution of 2.1 Å. N comprises a large globular domain composed of both N- and C-terminal sequences, likely involved in RNA binding, and a protruding arm domain with a conserved DEVD caspase-3 cleavage site at its apex. Alignment of our structure with that of the recently reported N protein from strain YL04057 shows a close correspondence of all folds but significant transposition of the arm through a rotation of 180 degrees and a translation of 40 Å. These observations suggest a structural flexibility that may provide the basis for switching between alternative N protein conformations during important functions such as RNA binding and oligomerization. Our structure reveals surfaces likely involved in RNA binding and oligomerization, and functionally critical residues within these domains were identified using a minigenome system able to recapitulate CCHFV-specific RNA synthesis in cells. Caspase-3 cleaves the polypeptide chain at the exposed DEVD motif; however, the cleaved N protein remains an intact unit, likely due to the intimate association of N- and C-terminal fragments in the globular domain. Structural alignment with existing N proteins reveals that the closest CCHFV relative is not another bunyavirus but the arenavirus Lassa virus instead, suggesting that current segmented negative-strand RNA virus taxonomy may need revision. PMID:22875964
Rodrigues, Raquel; Paranhos-Baccalà, Gláucia; Vernet, Guy; Peyrefitte, Christophe N.
Crimean-Congo hemorrhagic fever virus (CCHFV) is a widely distributed tick-borne member of the Nairovirus genus (Bunyaviridae) with a high mortality rate in humans. CCHFV induces a severe disease in infected patients that includes, among other symptoms, massive liver necrosis and failure. The interaction between liver cells and CCHFV is therefore important for understanding the pathogenesis of this disease. Here, we described the in vitro CCHFV-infection and -replication in the hepatocyte cell line, Huh7, and the induced cellular and molecular response modulation. We found that CCHFV was able to infect and replicate to high titres and to induce a cytopathic effect (CPE). We also observed by flow cytometry and real time quantitative RT-PCR evidence of apoptosis, with the participation of the mitochondrial pathway. On the other hand, we showed that the replication of CCHFV in hepatocytes was able to interfere with the death receptor pathway of apoptosis. Furthermore, we found in CCHFV-infected cells the over-expression of PUMA, Noxa and CHOP suggesting the crosstalk between the ER-stress and mitochondrial apoptosis. By ELISA, we observed an increase of IL-8 in response to viral replication; however apoptosis was shown to be independent from IL-8 secretion. When we compared the induced cellular response between CCHFV and DUGV, a mild or non-pathogenic Nairovirus for humans, we found that the most striking difference was the absence of CPE and apoptosis. Despite the XBP1 splicing and PERK gene expression induced by DUGV, no ER-stress and apoptosis crosstalk was observed. Overall, these results suggest that CCHFV is able to induce ER-stress, activate inflammatory mediators and modulate both mitochondrial and death receptor pathways of apoptosis in hepatocyte cells, which may, in part, explain the role of the liver in the pathogenesis of CCHFV. PMID:22238639
Zhang, Yi-Hui; Ge, Liang; Liu, Li; Huo, Xi-Xiang; Xiong, Hai-Rong; Liu, Yuan-Yuan; Liu, Dong-Ying; Luo, Fan; Li, Jin-Lin; Ling, Jia-Xin; Chen, Wen; Liu, Jing; Hou, Wei; Zhang, Yun; Fan, Hong; Yang, Zhan-Qiu
Background Hemorrhagic fever with renal syndrome (HFRS) is caused by different hantaviruses within the Bunyaviridae family. HFRS is a fulminant, infectious disease that occurs worldwide and is endemic in all 31 provinces of China. Since the first HFRS case in Hubei Province was reported in 1957, the disease has spread across the province and Hubei has become one of the seriously affected areas in China with the greatest number of reported HFRS cases in the 1980's. However, the epidemic characteristics of HFRS in Hubei are still not entirely clear and long-term, systematic investigations of this epidemic area have been very limited. Methods The spatiotemporal distribution of HFRS was investigated using data spanning the years 1980 to 2009. The annual HFRS incidence, fatality rate and seasonal incidence between 1980 and 2009 were calculated and plotted. GIS-based spatial analyses were conducted to detect the spatial distribution and seasonal pattern of HFRS. A spatial statistical analysis, using Kulldorff's spatial scan statistic, was performed to identify clustering of HFRS. Results A total of 104,467 HFRS cases were reported in Hubei Province between 1980 and 2009. Incidence of and mortality due to HFRS declined after the outbreak in 1980s and HFRS cases have been sporadic in recent years. The locations and scale of disease clusters have changed during the three decades. The seasonal epidemic pattern of HFRS was characterized by the shift from the unimodal type (autumn/winter peak) to the bimodal type. Conclusions Socioeconomic development has great influence on the transmission of hantaviruses to humans and new epidemic characteristics have emerged in Hubei Province. It is necessary to reinforce preventative measures against HFRS according to the newly-presented seasonal variation and to intensify these efforts especially in the urban areas of Hubei Province. PMID:24658382
Fukushi, Shuetsu; Tani, Hideki; Yoshikawa, Tomoki; Saijo, Masayuki; Morikawa, Shigeru
The family Arenaviridae, genus Arenavirus, consists of two phylogenetically independent groups: Old World (OW) and New World (NW) complexes. The Lassa and Lujo viruses in the OW complex and the Guanarito, Junin, Machupo, Sabia, and Chapare viruses in the NW complex cause viral hemorrhagic fever (VHF) in humans, leading to serious public health concerns. These viruses are also considered potential bioterrorism agents. Therefore, it is of great importance to detect these pathogens rapidly and specifically in order to minimize the risk and scale of arenavirus outbreaks. However, these arenaviruses are classified as BSL-4 pathogens, thus making it difficult to develop diagnostic techniques for these virus infections in institutes without BSL-4 facilities. To overcome these difficulties, antibody detection systems in the form of an enzyme-linked immunosorbent assay (ELISA) and an indirect immunofluorescence assay were developed using recombinant nucleoproteins (rNPs) derived from these viruses. Furthermore, several antigen-detection assays were developed. For example, novel monoclonal antibodies (mAbs) to the rNPs of Lassa and Junin viruses were generated. Sandwich antigen-capture (Ag-capture) ELISAs using these mAbs as capture antibodies were developed and confirmed to be sensitive and specific for detecting the respective arenavirus NPs. These rNP-based assays were proposed to be useful not only for an etiological diagnosis of VHFs, but also for seroepidemiological studies on VHFs. We recently developed arenavirus neutralization assays using vesicular stomatitis virus (VSV)-based pseudotypes bearing arenavirus recombinant glycoproteins. The goal of this article is to review the recent advances in developing laboratory diagnostic assays based on recombinant viral proteins for the diagnosis of VHFs and epidemiological studies on the VHFs caused by arenaviruses.
Pagliari, Carla; Quaresma, Juarez Antonio Simões; Fernandes, Elaine Raniero; Stegun, Felipe Weisshaupt; Brasil, Roosecelis Araújo; de Andrade, Heitor Franco; Barros, Vera; Vasconcelos, Pedro Fernando C; Duarte, Maria Irma Seixas
Dengue infection is an important tropical disease worldwide. The host immune response has been studied in order to better understand lesion mechanisms. It was performed an immunohistochemical study in 14 specimens of liver from patients with dengue hemorrhagic fever (DHF) to characterize cytokines and some factors present in liver lesions and their possible role in the pathogenesis of hepatic injury. Portal tract and hepatic acinus presented high expression of TLR2, TLR3, IL6, and granzyme B. Hepatic acinus also presented iNOS, IL18, and TGF-beta. Cells expressing IL12, IL13, JAk1, STAT1, and NF-κB were rarely visualized. Treg cells foxp3+ were absent. TLR2 and TLR3 seem to participate in cellular activation and cytokine production. Cytotoxic response seems to play a role. Although TGF-beta promotes the activation of Foxp3+ regulatory T cells, IL6 can significantly suppresses their generation. The expression of Treg cells is diminished probably as a result of the high frequency of these cytokines. Both cytokines play a role in the increased vascular permeability and edema observed in dengue liver specimens, with consequent plasma leakage and severity of the disease. It was observed a regular expression of IL-18 in hepatocytes and lymphocytes of the inflammatory infiltrate in portal tract, which reflects the acute inflammatory response that occurs in the liver and contributes to hepatic injury. At least in part, the increased number of cells expressing IL-18 could play a role of "up" regulation of FasL and correlate to the phenomenon of apoptosis, a mechanism of destruction of hepatocytes in DHF.
Xiao, Hong; Lin, Xiaoling; Gao, Lidong; Huang, Cunrui; Tian, Huaiyu; Li, Na; Qin, Jianxin; Zhu, Peijuan; Chen, Biyun; Zhang, Xixing; Zhao, Jian
Hemorrhagic fever with renal syndrome (HFRS) is an important public health problem in mainland China. HFRS is particularly endemic in Changsha, the capital city of Hunan Province, with one of the highest incidences in China. The occurrence of HFRS is influenced by environmental factors. However, few studies have examined the relationship between environmental variation (such as land use changes and climate variations), rodents and HFRS occurrence. The purpose of this study is to predict the distribution of HFRS and identify the risk factors and relationship between HFRS occurrence and rodent hosts, combining ecological modeling with the Markov chain Monte Carlo approach. Ecological niche models (ENMs) were used to evaluate potential geographic distributions of rodent species by reconstructing details of their ecological niches in ecological dimensions, and projecting the results onto geography. The Genetic Algorithm for Rule-set Production was used to produce ENMs. Data were collected on HFRS cases in Changsha from 2005 to 2009, as well as national land survey data, surveillance data of rodents, meteorological data and normalized difference vegetation index (NDVI). The highest occurrence of HFRS was in districts with strong temperature seasonality, where elevation is below 200 m, mean annual temperature is around 17.5°C, and annual precipitation is below 1600 mm. Cultivated and urban lands in particular are associated with HFRS occurrence. Monthly NDVI values of areas predicted present is lower than areas predicted absent, with high seasonal variation. The number of HFRS cases was correlated with rodent density, and the incidence of HFRS cases in urban and forest areas was mainly associated with the density of Rattus norvegicus and Apodemus agrarius, respectively. Heterogeneity between different areas shows that HFRS occurrence is affected by the intensity of human activity, climate conditions, and landscape elements. Rodent density and species composition have
Han, Ziying; Madara, Jonathan J.; Herbert, Andrew; Prugar, Laura I.; Ruthel, Gordon; Lu, Jianhong; Liu, Yuliang; Liu, Wenbo; Liu, Xiaohong; Wrobel, Jay E.; Reitz, Allen B.; Dye, John M.; Harty, Ronald N.; Freedman, Bruce D.
Hemorrhagic fever viruses, including the filoviruses (Ebola and Marburg) and arenaviruses (Lassa and Junín viruses), are serious human pathogens for which there are currently no FDA approved therapeutics or vaccines. Importantly, transmission of these viruses, and specifically late steps of budding, critically depend upon host cell machinery. Consequently, strategies which target these mechanisms represent potential targets for broad spectrum host oriented therapeutics. An important cellular signal implicated previously in EBOV budding is calcium. Indeed, host cell calcium signals are increasingly being recognized to play a role in steps of entry, replication, and transmission for a range of viruses, but if and how filoviruses and arenaviruses mobilize calcium and the precise stage of virus transmission regulated by calcium have not been defined. Here we demonstrate that expression of matrix proteins from both filoviruses and arenaviruses triggers an increase in host cytoplasmic Ca2+ concentration by a mechanism that requires host Orai1 channels. Furthermore, we demonstrate that Orai1 regulates both VLP and infectious filovirus and arenavirus production and spread. Notably, suppression of the protein that triggers Orai activation (Stromal Interaction Molecule 1, STIM1) and genetic inactivation or pharmacological blockade of Orai1 channels inhibits VLP and infectious virus egress. These findings are highly significant as they expand our understanding of host mechanisms that may broadly control enveloped RNA virus budding, and they establish Orai and STIM1 as novel targets for broad-spectrum host-oriented therapeutics to combat these emerging BSL-4 pathogens and potentially other enveloped RNA viruses that bud via similar mechanisms. PMID:26513362
Chinikar, Sadegh; Bouzari, Saeid; Shokrgozar, Mohammad Ali; Mostafavi, Ehsan; Jalali, Tahmineh; Khakifirouz, Sahar; Nowotny, Norbert; Fooks, Anthony R.; Shah-Hosseini, Nariman
Background: Crimean Congo hemorrhagic fever virus (CCHFV) is a member of the Bunyaviridae family and Nairovirus genus. It has a negative-sense, single stranded RNA genome approximately 19.2 kb, containing the Small, Medium, and Large segments. CCHFVs are relatively divergent in their genome sequence and grouped in seven distinct clades based on S-segment sequence analysis and six clades based on M-segment sequences. Our aim was to obtain new insights into the molecular epidemiology of CCHFV in Iran. Methods: We analyzed partial and complete nucleotide sequences of the S and M segments derived from 50 Iranian patients. The extracted RNA was amplified using one-step RT-PCR and then sequenced. The sequences were analyzed using Mega5 software. Results: Phylogenetic analysis of partial S segment sequences demonstrated that clade IV-(Asia 1), clade IV-(Asia 2) and clade V-(Europe) accounted for 80 %, 4 % and 14 % of the circulating genomic variants of CCHFV in Iran respectively. However, one of the Iranian strains (Iran-Kerman/22) was associated with none of other sequences and formed a new clade (VII). The phylogenetic analysis of complete S-segment nucleotide sequences from selected Iranian CCHFV strains complemented with representative strains from GenBank revealed similar topology as partial sequences with eight major clusters. A partial M segment phylogeny positioned the Iranian strains in either association with clade III (Asia-Africa) or clade V (Europe). Conclusion: The phylogenetic analysis revealed subtle links between distant geographic locations, which we propose might originate either from international livestock trade or from long-distance carriage of CCHFV by infected ticks via bird migration. PMID:27308271
Han, Seung Seok; Kim, Sunhee; Choi, Yunhee; Kim, Suhnggwon; Kim, Yon Su
The effects of air pollution on the respiratory and cardiovascular systems, and the resulting impacts on public health, have been widely studied. However, little is known about the effect of air pollution on the occurrence of hemorrhagic fever with renal syndrome (HFRS), a rodent-borne infectious disease. In this study, we evaluated the correlation between air pollution and HFRS incidence from 2001 to 2010, and estimated the significance of the correlation under the effect of climate variables. We obtained data regarding HFRS, particulate matter smaller than 10 μm (PM₁₀) as an index of air pollution, and climate variables including temperature, humidity, and precipitation from the national database of South Korea. Poisson regression models were established to predict the number of HFRS cases using air pollution and climate variables with different time lags. We then compared the ability of the climate model and the combined climate and air pollution model to predict the occurrence of HFRS. The correlations between PM₁₀ and HFRS were significant in univariate analyses, although the direction of the correlations changed according to the time lags. In multivariate analyses of adjusted climate variables, the effects of PM₁₀ with time lags were different. However, PM₁₀ without time lags was selected in the final model for predicting HFRS cases. The model that combined climate and PM₁₀ data was a better predictor of HFRS cases than the model that used only climate data, for both the study period and the year 2011. This is the first report to document an association between HFRS and PM₁₀ level.
Madelain, Vincent; Guedj, Jérémie; Mentré, France; Nguyen, Thi Huyen Tram; Jacquot, Frédéric; Oestereich, Lisa; Kadota, Takumi; Yamada, Koichi; Taburet, Anne-Marie; de Lamballerie, Xavier; Raoul, Hervé
Favipiravir is an RNA polymerase inhibitor that showed strong antiviral efficacy in vitro and in small-animal models of several viruses responsible for hemorrhagic fever (HF), including Ebola virus. The aim of this work was to characterize the complex pharmacokinetics of favipiravir in nonhuman primates (NHPs) in order to guide future efficacy studies of favipiravir in large-animal models. Four different studies were conducted in 30 uninfected cynomolgus macaques of Chinese (n = 17) or Mauritian (n = 13) origin treated with intravenous favipiravir for 7 to 14 days with maintenance doses of 60 to 180 mg/kg of body weight twice a day (BID). A pharmacokinetic model was developed to predict the plasma concentrations obtained with different dosing regimens, and the model predictions were compared to the 50% effective concentration (EC50) of favipiravir against several viruses. Favipiravir pharmacokinetics were described by a model accounting for concentration-dependent aldehyde oxidase inhibition. The enzyme-dependent elimination rate increased over time and was higher in NHPs of Mauritian origin than in those of Chinese origin. Maintenance doses of 100 and 120 mg/kg BID in Chinese and Mauritian NHPs, respectively, are predicted to achieve median trough plasma free concentrations above the EC50 for Lassa and Marburg viruses until day 7. For Ebola virus, higher doses are required. After day 7, a 20% dose increase is needed to compensate for the increase in drug clearance over time. These results will help rationalize the choice of dosing regimens in future studies evaluating the antiviral effect of favipiravir in NHPs and support its development against a variety of HF viruses.
Papa, Anna; Velo, Enkeleda; Kadiaj, Perparim; Tsioka, Katerina; Kontana, Anastasia; Kota, Majlinda; Bino, Silvia
Albania is a Balkan country endemic for Crimean-Congo hemorrhagic fever (CCHF). It was shown previously that CCHF virus (CCHFV) sequences from Albanian patients cluster into Europe 1 clade. Aim of the present study was to test for CCHFV ticks collected in several regions of Albania, and to determine the genetic lineage(s) of the CCHFV strains in relation with their geographic distribution. A total of 726 ticks (366 Hyalomma marginatum, 349 Rhipicephalus bursa and 11 Rhipicephalus sanguineus) collected from livestock during 2007-2014 were included in the study. Thirty of 215 (13.9%) tick pools were positive for CCHFV. Lineage Europe 1 was detected in H. marginatum ticks collected in the endemic region of Albania, while lineage Europe 2 was detected mainly in R. bursa ticks in various regions of the country. Both genetic lineages were detected in the CCHF endemic area (northeastern Albania), while only Europe 2 lineage was detected in the south of the country. A higher genetic diversity was seen among Europe 2 than Europe 1 Albanian sequences (mean distance 3.7% versus 1%), suggesting a longer evolution of AP92-like strains (Europe 2) in their tick hosts. The present study shows that besides CCHFV lineage Europe 1, lineage Europe 2 is also present in Albania. Combined with results from recent studies, it is concluded that lineage Europe 2 is widely spread in the Balkans and Turkey, and is associated mainly with R. bursa ticks (at least in this region). Its pathogenicity and impact to the public health remain to be elucidated. Copyright © 2017. Published by Elsevier B.V.
Spengler, Jessica R.; Patel, Jenish R.; Chakrabarti, Ayan K.; Zivcec, Marko; García-Sastre, Adolfo; Spiropoulou, Christina F.
ABSTRACT In the cytoplasm, the retinoic acid-inducible gene I (RIG-I) senses the RNA genomes of several RNA viruses. RIG-I binds to viral RNA, eliciting an antiviral response via the cellular adaptor MAVS. Crimean-Congo hemorrhagic fever virus (CCHFV), a negative-sense RNA virus with a 5′-monophosphorylated genome, is a highly pathogenic zoonotic agent with significant public health implications. We found that, during CCHFV infection, RIG-I mediated a type I interferon (IFN) response via MAVS. Interfering with RIG-I signaling reduced IFN production and IFN-stimulated gene expression and increased viral replication. Immunostimulatory RNA was isolated from CCHFV-infected cells and from virion preparations, and RIG-I coimmunoprecipitation of infected cell lysates isolated immunostimulatory CCHFV RNA. This report serves as the first description of a pattern recognition receptor for CCHFV and highlights a critical signaling pathway in the antiviral response to CCHFV. IMPORTANCE CCHFV is a tick-borne virus with a significant public health impact. In order for cells to respond to virus infection, they must recognize the virus as foreign and initiate antiviral signaling. To date, the receptors involved in immune recognition of CCHFV are not known. Here, we investigate and identify RIG-I as a receptor involved in initiating an antiviral response to CCHFV. This receptor initially was not expected to play a role in CCHFV recognition because of characteristics of the viral genome. These findings are important in understanding the antiviral response to CCHFV and support continued investigation into the spectrum of potential viruses recognized by RIG-I. PMID:26223644
Ozer, Ali; Miraloglu, Meral; Ekerbicer, Hasan Cetin; Cevik, Firdevs; Aloglu, Nihal
The aim of this study was to determine the knowledge levels of students in the Midwifery and Nursing Departments of the School of Health Sciences in Kahramanmaras Sutcuimam University (KSU) about Crimean-Congo hemorrhagic fever (CCHF) and to examine the factors influencing those knowledge levels. The study was conducted between April-June 2009 in the School of Health Sciences, KSU, Turkey. All the midwifery and nursing students in the School of Health Sciences at that time, 296 individuals, were included in the study. Questionnaire forms, developed from literature data and comprised of 66 questions, were given to the students, and they were asked to fill them out. Twenty-four point seven percent of the students were not available, thus 223 students(75.3%) were included in the study. Seventy-five point three percent of students stated a viruse was the cause for CCHF, 78.9% stated CCHF is seen between April and September in Turkey, and 80.7% stated there was no vaccine avaiable against it. Ninety-three point three percent of the study group stated that CCHF was transmitted by tick bite, 75.8% and 53.4% stated CCHF can be transmitted by exposure to blood of an infected animal or direct contact with an acutely infected animal, respectively. Thirty-three point two percent of students stated CCHF had no specific treatment. The mean knowledge score of students regarding CCHF was 54.6 +/- 14.8. The CCHF scores of the nursing students were significantly higher than those of the midwifery students. The CCHF knowledge scores did not vary by age or college year.
Aker, Servet; Akıncı, Halil; Kılıçoğlu, Cem; Leblebicioglu, Hakan
The purpose of this study was to analyze the epidemiological characteristics of cases diagnosed with Crimean-Congo Hemorrhagic Fever (CCHF) with the help of Geographic Information Systems (GIS) and to establish an epidemiological risk map. Data for 434 cases diagnosed with CCHF between 01.01.2004 and 31.12.2013 were subjected to statistical analysis SPSS 13.0 software. A digital map of Kastamonu was transferred onto ArcGIS 10.0 software in order to establish a risk map for CCHF. The highest cumulative incidence of CCHF is 41.29/10,000, and in people living at altitudes of 1001-1200 meters. ROC analysis of altitudes above sea level of residences with CCHF cases revealed an area under the curve of 74.5% (95% CI: 0.72-0.76, p<0.05). At a cut-off point of 836.5 meters, sensitivity was 0.74 and specificity 0.76. Cumulative incidence of CCHF was significantly positively correlated with number of animals per head (r=0.76) and area of agricultural land per head (r=0.59) (p<0.05). No significant correlation was determined between cumulative incidence and forested area percentages. This study reveals that both men and women living at more than 836.5 meters above sea level and working in agriculture and animal husbandry are at risk of CCHF between May and July. Detailed examination of the ecology of vector ticks is now needed in order to fully determine the epidemiology of the disease. Copyright © 2015 Elsevier GmbH. All rights reserved.
Liu, Jianling; Pei, Tianli; Mu, Jiexin; Zheng, Chunli; Chen, Xuetong; Huang, Chao; Fu, Yingxue; Liang, Zongsuo; Wang, Yonghua
Background. Viral hemorrhagic fevers (VHF) are a group of systemic diseases characterized by fever and bleeding, which have posed a formidable potential threat to public health with high morbidity and mortality. Traditional Chinese Medicine (TCM) formulas have been acknowledged with striking effects in treatment of hemorrhagic fever syndromes in China's history. Nevertheless, their accurate mechanisms of action are still confusing. Objective. To systematically dissect the mechanisms of action of Chinese medicinal formula Xijiao Dihuang (XJDH) decoction as an effective treatment for VHF. Methods. In this study, a systems pharmacology method integrating absorption, distribution, metabolism, and excretion (ADME) screening, drug targeting, network, and pathway analysis was developed. Results. 23 active compounds of XJDH were obtained and 118 VHF-related targets were identified to have interactions with them. Moreover, systematic analysis of drug-target network and the integrated VHF pathway indicate that XJDH probably acts through multiple mechanisms to benefit VHF patients, which can be classified as boosting immune system, restraining inflammatory responses, repairing the vascular system, and blocking virus spread. Conclusions. The integrated systems pharmacology method provides precise probe to illuminate the molecular mechanisms of XJDH for VHF, which will also facilitate the application of traditional medicine in modern medicine. PMID:27239215
Dengue fever, or West Nile fever, is a mild viral illness transmitted by mosquitoes which causes fever, ... second exposure to the virus can result in Dengue hemorrhagic fever, a life-threatening illness.
Yadav, Pragya D; Gurav, Yogesh K; Mistry, Madhulika; Shete, Anita M; Sarkale, Prasad; Deoshatwar, Avinash R; Unadkat, Vishwa B; Kokate, Prasad; Patil, Deepak Y; Raval, Dinkar K; Mourya, Devendra T
Crimean-Congo hemorrhagic fever virus (CCHFV) etiology was detected in a family cluster (nine cases, including two deaths) in the village of Karyana, Amreli District, and also a fatal case in the village of Undra, Patan District, in Gujarat State, India. Anti-CCHFV IgG antibodies were detected in domestic animals from Karyana and adjoining villages. Hyalomma ticks from households were found to be positive for CCHF viral RNA. This confirms the emergence of CCHFV in new areas and the wide spread of this disease in Gujarat State.
Pshenichnaya, Natalia Yurievna; Nenadskaya, Svetlana Alexeevna
We report here a fatal case of laboratory confirmed Crimean-Congo hemorrhagic fever (CCHF), which caused nosocomial infection in eight health care workers (HCWs), who had provided medical care for the patient. All the HCWs survived. The report demonstrates that airborne transmission of CCHF is a real risk, at least when the CCHF patient is in a ventilator. During performance of any aerosol-generating medical procedures for any CCHF patient airborne precautions should always be added to standard precautions, in particular, airway protective N95 mask or equivalent standard, eye protection, single airborne precaution room, or a well-ventilated setting.
hemorrhagic fever ( CCHF ) virus (IbAr 10200 strain). The mean viral titer Wof mouse blood at the time of tick feeding was 1)0:12 plaque-forming units (PFU...per ml. N Samples of ticks were assayed on 12 occasions between days 0 and 31 after the viremic blood meal. Mean CCHF viral titers were 102 A PFU per...more days. Ticks were allowed to feed on sets of three naive suckling mice on days 0, 2, 5, 8, 11, 14, 21, and 28 after the viremic blood meal, but CCHF
Jin, Zhinan; Smith, Lucas K.; Rajwanshi, Vivek K.; Kim, Baek; Deval, Jerome
T-705 (Favipiravir) is a broad-spectrum antiviral molecule currently in late stage clinical development for the treatment of influenza virus infection. Although it is believed that T-705 potency is mediated by its ribofuranosyl triphosphate (T-705 RTP) metabolite that could be mutagenic, the exact molecular interaction with the polymerase of influenza A virus (IAVpol) has not been elucidated. Here, we developed a biochemical assay to measure the kinetics of nucleotide incorporation by IAVpol in the elongation mode. In this assay, T-705 RTP was recognized by IAVpol as an efficient substrate for incorporation to the RNA both as a guanosine and an adenosine analog. Compared to natural GTP and ATP, the discrimination of T-705 RTP was about 19- and 30-fold, respectively. Although the single incorporation of the ribonucleotide monophosphate form of T-705 did not efficiently block RNA synthesis, two consecutive incorporation events prevented further primer extension. In comparison, 3′-deoxy GTP caused immediate chain termination but was incorporated less efficiently by the enzyme, with a discrimination of 4,900-fold relative to natural GTP. Collectively, these results provide the first detailed biochemical characterization to evaluate the substrate efficiency and the inhibition potency of nucleotide analogs against influenza virus polymerase. The combination of ambiguous base-pairing with low discrimination of T-705 RTP provides a mechanistic basis for the in vitro mutagenic effect of T-705 towards influenza virus. PMID:23874596
Li, Yan-Li; Song, Shao-Xia; Zhang, Wen-Yi; Qian, Quan; Li, Ya-Pin; Wei, Lan; Wang, Zhi-Qiang; Yang, Hong; Cao, Wu-Chun
Background Hemorrhagic fever with renal syndrome (HFRS) is a rodent-borne disease caused by Hantaviruses. It is endemic in all 31 provinces, autonomous regions, and metropolitan areas in mainland China where human cases account for 90% of the total global cases. Shandong Province is among the most serious endemic areas. HFRS cases in Shandong Province were first reported in Yutai County in 1968. Since then, the disease has spread across the province, and as of 2005, all 111 counties were reported to have local human infections. However, causes underlying such rapid spread and wide distribution remain less well understood. Methods and Findings Here we report a spatiotemporal analysis of human HFRS cases in Shandong using data spanning 1973 to 2005. Seasonal incidence maps and velocity vector maps were produced to analyze the spread of HFRS over time in Shandong Province, and a panel data analysis was conducted to explore the association between HFRS incidence and climatic factors. Results show a rapid spread of HFRS from its epicenter in Rizhao, Linyi, Weifang Regions in southern Shandong to north, east, and west parts of the province. Based on seasonal shifts of epidemics, three epidemic phases were identified over the 33-year period. The first phase occurred between 1973 and 1982 during which the foci of HFRS was located in the south Shandong and the epidemic peak occurred in the fall and winter, presenting a seasonal characteristic of Hantaan virus (HTNV) transmission. The second phase between 1983 and 1985 was characterized by northward and westward spread of HFRS foci, and increases in incidence of HFRS in both fall-winter and spring seasons. The human infections in the spring reflected a characteristic pattern of Seoul virus (SEOV) transmission. The third phase between 1986 and 2005 was characterized by the northeast spread of the HFRS foci until it covered all counties, and the HFRS incidence in the fall-winter season decreased while it remained high in the
Nagpal, Sajan Jiv Singh; Karimianpour, Ahmadreza; Mukhija, Dhruvika; Mohan, Diwakar; Brateanu, Andrei
The content and quality of medical information available on video sharing websites such as YouTube is not known. We analyzed the source and quality of medical information about Ebola hemorrhagic fever (EHF) disseminated on YouTube and the video characteristics that influence viewer behavior. An inquiry for the search term 'Ebola' was made on YouTube. The first 100 results were arranged in decreasing order of "relevance" using the default YouTube algorithm. Videos 1-50 and 51-100 were allocated to a high relevance (HR), and a low relevance (LR) video group, respectively. Multivariable logistic regression models were used to assess the predictors of a video being included in the HR vs. LR groups. Fourteen videos were excluded because they were parodies, songs or stand-up comedies (n = 11), not in English (n = 2) or a remaining part of a previous video (n = 1). Two scales, the video information and quality and index and the medical information and content index (MICI) assessed the overall quality, and the medical content of the videos, respectively. There were no videos from hospitals or academic medical centers. Videos in the HR group had a higher median number of views (186,705 vs. 43,796, p < 0.001), more 'likes' (1119 vs. 224, p < 0.001), channel subscriptions (208 vs. 32, p < 0.001), and 'shares' (519 vs. 98, p < 0.001). Multivariable logistic regression showed that only the 'clinical symptoms' component of the MICI scale was associated with a higher likelihood of a video being included in the HR vs. LR group.(OR 1.86, 95 % CI 1.06-3.28, p = 0.03). YouTube videos presenting clinical symptoms of infectious diseases during epidemics are more likely to be included in the HR group and influence viewers behavior.
Bente, Dennis A; Forrester, Naomi L; Watts, Douglas M; McAuley, Alexander J; Whitehouse, Chris A; Bray, Mike
Crimean-Congo hemorrhagic fever (CCHF) is the most important tick-borne viral disease of humans, causing sporadic cases or outbreaks of severe illness across a huge geographic area, from western China to the Middle East and southeastern Europe and throughout most of Africa. CCHFV is maintained in vertical and horizontal transmission cycles involving ixodid ticks and a variety of wild and domestic vertebrates, which do not show signs of illness. The virus circulates in a number of tick genera, but Hyalomma ticks are the principal source of human infection, probably because both immature and adult forms actively seek hosts for the blood meals required at each stage of maturation. CCHF occurs most frequently among agricultural workers following the bite of an infected tick, and to a lesser extent among slaughterhouse workers exposed to the blood and tissues of infected livestock and medical personnel through contact with the body fluids of infected patients. CCHFV is the most genetically diverse of the arboviruses, with nucleotide sequence differences among isolates ranging from 20% for the viral S segment to 31% for the M segment. Viruses with diverse sequences can be found within the same geographic area, while closely related viruses have been isolated in far distant regions, suggesting that widespread dispersion of CCHFV has occurred at times in the past, possibly by ticks carried on migratory birds or through the international livestock trade. Reassortment among genome segments during co-infection of ticks or vertebrates appears to have played an important role in generating diversity, and represents a potential future source of novel viruses. In this article, we first review current knowledge of CCHFV, summarizing its molecular biology, maintenance and transmission, epidemiology and geographic range. We also include an extensive discussion of CCHFV genetic diversity, including maps of the range of the virus with superimposed phylogenetic trees. We then review
Sidwell, Robert W; Barnard, Dale L; Day, Craig W; Smee, Donald F; Bailey, Kevin W; Wong, Min-Hui; Morrey, John D; Furuta, Yousuke
T-705 (6-fluoro-3-hydroxy-2-pyrazinecarboxamide) was inhibitory to four strains of avian H5N1 influenza virus in MDCK cells, with the 90% effective concentrations ranging from 1.3 to 7.7 microM, as determined by a virus yield reduction assay. The efficacy was less than that exerted by oseltamivir carboxylate or zanamivir but was greater than that exerted by ribavirin. Experiments with mice lethally infected with influenza A/Duck/MN/1525/81 (H5N1) virus showed that T-705 administered per os once, twice, or four times daily for 5 days beginning 1 h after virus exposure was highly inhibitory to the infection. Dosages from 30 to 300 mg/kg of body weight/day were well tolerated; each prevented death, lessened the decline of arterial oxygen saturation (SaO(2)), and inhibited lung consolidation and lung virus titers. Dosages from 30 to 300 mg/kg/day administered once or twice daily also significantly prevented the death of the mice. Oseltamivir (20 mg/kg/day), administered per os twice daily for 5 days, was tested in parallel in two experiments; it was only weakly effective against the infection. The four-times-daily T-705 treatments at 300 mg/kg/day could be delayed until 96 h after virus exposure and still significantly inhibit the infection. Single T-705 treatments administered up to 60 h after virus exposure also prevented death and the decline of SaO(2). Characterization of the pathogenesis of the duck influenza H5N1 virus used in these studies was undertaken; although the virus was highly pathogenic to mice, it was less neurotropic than has been described for clinical isolates of the H5N1 virus. These data indicate that T-705 may be useful for the treatment of avian influenza virus infections.
Hvala, Anastazija; Ferluga, Dusan; Rott, Tomaz; Kobenter, Tatjana; Koselj-Kajtna, Mira; Trnacević, Seneid
The morphology of peritubular capillary has been mostly studied in relation to chronic transplant rejection, where an association has been found between transplant glomerulopathy and reduplication of peritubular capillary basement membranes (PCBM). This electron microscopy study of peritubular capillaries was done on kidney biopsies performed on patients with conditions involving primarily glomeruli (diabetic glomerulopathy (23), Alport syndrome (37)) or causing more or less isolated changes of nephron structures outside the glomeruli (Balkan endemic nephropathy (15) and hemorrhagic fever with renal syndrome (19)). The aim was to explore the ultrastructural features of the PCBM. In patients with diabetic glomerulopathy, the PCBM was homogeneous, with a width ranging from normal to evidently increased (55-355 nm). In patients with Alport syndrome, the PCBM was homogeneous, with no substantial splitting or prominent thickening. Mean thickness varied between 80 (85-100) nm in children and 120 (46-250) nm in adults. Mean PCBM thickness in patients with Balkan endemic nephropathy was 209 (90-1270) nm. The thickened PCBM was also often split. In patients with hemorrhagic fever with renal syndrome, peritubular capillaries and medular vasa recta were generally extremely congested and focally ruptured, and their basal lamina showed prevailing thinning and focal discontinuities.
de Castro, Reynaldo Angelo C; de Castro, Jo-Anne A; Barez, Marie Yvette C; Frias, Melchor V; Dixit, Jitendra; Genereux, Maurice
Severe thrombocytopenia and increased vascular permeability are two major characteristics of dengue hemorrhagic fever (DHF). An immune mechanism of thrombocytopenia due to increased platelet destruction appears to be operative in patients with DHF (see Saito et al., 2004, Clin Exp Immunol 138: 299-303; Mitrakul, 1979, Am J Trop Med Hyg 26: 975-984; and Boonpucknavig, 1979, Am J Trop Med Hyg 28: 881-884). The interim data of two randomized placebo controlled trials in patients (N = 47) meeting WHO criteria for dengue hemorrhagic fever (DHF) with severe thrombocytopenia (platelets < or = 50,000/mm(3)) reveal that the increase in platelet count with anti-D immune globulin (WinRho SDF), 50 microg/kg (250 IU/kg) intravenously is more brisk than the placebo group. The mean maximum platelet count of the anti-D-treated group at 48 hours was 91,500/mm(3) compared with 69,333/mm(3) in the placebo group. 75% of the anti-D-treated group demonstrated an increase of platelet counts > or = 20,000 compared with only 58% in the placebo group. These data suggest that treatment of severe thrombocytopenia accompanying DHF with anti-D may be a useful and safe therapeutic option.
Bailey, Adam L; Lauck, Michael; Weiler, Andrea; Sibley, Samuel D; Dinis, Jorge M; Bergman, Zachary; Nelson, Chase W; Correll, Michael; Gleicher, Michael; Hyeroba, David; Tumukunde, Alex; Weny, Geoffrey; Chapman, Colin; Kuhn, Jens H; Hughes, Austin L; Friedrich, Thomas C; Goldberg, Tony L; O'Connor, David H
Key biological properties such as high genetic diversity and high evolutionary rate enhance the potential of certain RNA viruses to adapt and emerge. Identifying viruses with these properties in their natural hosts could dramatically improve disease forecasting and surveillance. Recently, we discovered two novel members of the viral family Arteriviridae: simian hemorrhagic fever virus (SHFV)-krc1 and SHFV-krc2, infecting a single wild red colobus (Procolobus rufomitratus tephrosceles) in Kibale National Park, Uganda. Nearly nothing is known about the biological properties of SHFVs in nature, although the SHFV type strain, SHFV-LVR, has caused devastating outbreaks of viral hemorrhagic fever in captive macaques. Here we detected SHFV-krc1 and SHFV-krc2 in 40% and 47% of 60 wild red colobus tested, respectively. We found viral loads in excess of 10(6)-10(7) RNA copies per milliliter of blood plasma for each of these viruses. SHFV-krc1 and SHFV-krc2 also showed high genetic diversity at both the inter- and intra-host levels. Analyses of synonymous and non-synonymous nucleotide diversity across viral genomes revealed patterns suggestive of positive selection in SHFV open reading frames (ORF) 5 (SHFV-krc2 only) and 7 (SHFV-krc1 and SHFV-krc2). Thus, these viruses share several important properties with some of the most rapidly evolving, emergent RNA viruses.
Li, Xiu-Jun; Tong, Shi-Lu; Gao, Li-Dong; Qin, Jian-Xin; Lin, Xiao-Ling; Liu, Hai-Ning; Zhang, Xi-Xing
Background The transmission of hemorrhagic fever with renal syndrome (HFRS) is influenced by environmental determinants. This study aimed to explore the association between atmospheric moisture variability and the transmission of hemorrhagic fever with renal syndrome (HFRS) for the period of 1991–2010 in Changsha, China. Methods and Findings Wavelet analyses were performed by using monthly reported time series data of HFRS cases to detect and quantify the periodicity of HFRS. A generalized linear model with a Poisson distribution and a log link model were used to quantify the relationship between climate and HFRS cases, highlighting the importance of moisture conditions. There was a continuous annual oscillation mode and multi-annual cycle around 3–4 years from 1994 to 1999. There was a significant association of HFRS incidence with moisture conditions and the Multivariate El Niño–Southern Oscillation Index (MEI). Particularly, atmospheric moisture has a significant effect on the propagation of HFRS; annual incidence of HFRS was positively correlated with annual precipitation and annual mean absolute humidity. Conclusions The final model had good accuracy in forecasting the occurrence of HFRS and moisture condition can be used in disease surveillance and risk management to provide early warning of potential epidemics of this disease. PMID:23755316
Pushko, P; Bray, M; Ludwig, G V; Parker, M; Schmaljohn, A; Sanchez, A; Jahrling, P B; Smith, J F
RNA replicons derived from an attenuated strain of Venezuelan equine encephalitis virus (VEE), an alphavirus, were configured as candidate vaccines for Ebola hemorrhagic fever. The Ebola nucleoprotein (NP) or glycoprotein (GP) genes were introduced into the VEE RNA downstream from the VEE 26S promoter in place of the VEE structural protein genes. The resulting recombinant replicons, expressing the NP or GP genes, were packaged into VEE replicon particles (NP-VRP and GP-VRP, respectively) using a bipartite helper system that provided the VEE structural proteins in trans and prevented the regeneration of replication-competent VEE during packaging. The immunogenicity of NP-VRP and GP-VRP and their ability to protect against lethal Ebola infection were evaluated in BALB/c mice and in two strains of guinea pigs. The GP-VRP alone, or in combination with NP-VRP, protected both strains of guinea pigs and BALB/c mice, while immunization with NP-VRP alone protected BALB/c mice, but neither strain of guinea pig. Passive transfer of sera from VRP-immunized animals did not confer protection against lethal challenge. However, the complete protection achieved with active immunization with VRP, as well as the unique characteristics of the VEE replicon vector, warrant further testing of the safety and efficacy of NP-VRP and GP-VRP in primates as candidate vaccines against Ebola hemorrhagic fever.
Palomar, Ana M; Portillo, Aránzazu; Santibáñez, Sonia; García-Álvarez, Lara; Muñoz-Sanz, Agustín; Márquez, Francisco J; Romero, Lourdes; Eiros, José M; Oteo, José A
Crimean-Congo hemorrhagic fever (CCHF) is a viral disease, mainly transmitted through tick bite, of great importance in Public Health. In Spain, Crimean-Congo hemorrhagic fever virus (CCHFV) was detected for the first time in 2010 in Hyalomma lusitanicum ticks collected from deer in Cáceres. The aim of this study was to investigate the presence of CCHFV in ticks from Cáceres, and from other Spanish areas, and to evaluate the presence of antibodies against the virus in individuals exposed to tick bites. A total of 2053 ticks (1333 Hyalomma marginatum, 680 H. lusitanicum and 40 Rhipicephalus bursa) were analyzed using molecular biology techniques (PCR) for CCHFV detection. The determination of specific IgG antibodies against CCHFV in 228 serum samples from humans with regular contact with ticks (at risk of acquiring the infection) was performed by indirect immunofluorescence assay. The CCHFV was not amplified in ticks, nor were antibodies against the virus found in the serum samples analyzed. The absence of the CCHFV in the ticks studied and the lack of antibodies against the virus in individuals exposed to tick bites would seem to suggest a low risk of acquisition of human infection by CCHFV in Spain. Copyright © 2017 Elsevier España, S.L.U. and Sociedad Española de Enfermedades Infecciosas y Microbiología Clínica. All rights reserved.
Bente, Dennis A.; Alimonti, Judie B.; Shieh, Wun-Ju; Camus, Gaëlle; Ströher, Ute; Zaki, Sherif; Jones, Steven M.
Tick-borne Crimean-Congo hemorrhagic fever virus (CCHFV) causes a severe hemorrhagic syndrome in humans but not in its vertebrate animal hosts. The pathogenesis of the disease is largely not understood due to the lack of an animal model. Laboratory animals typically show no overt signs of disease. Here, we describe a new small-animal model to study CCHFV pathogenesis that manifests clinical disease, similar to that seen in humans, without adaptation of the virus to the host. Our studies revealed that mice deficient in the STAT-1 signaling molecule were highly susceptible to infection, succumbing within 3 to 5 days. After CCHFV challenge, mice exhibited fever, leukopenia, thrombocytopenia, and highly elevated liver enzymes. Rapid viremic dissemination and extensive replication in visceral organs, mainly in liver and spleen, were associated with prominent histopathologic changes in these organs. Dramatically elevated proinflammatory cytokine levels were detected in the blood of the animals, suggestive of a cytokine storm. Immunologic analysis revealed delayed immune cell activation and intensive lymphocyte depletion. Furthermore, this study also demonstrated that ribavirin, a suggested treatment in human cases, protects mice from lethal CCHFV challenge. In conclusion, our data demonstrate that the interferon response is crucial in controlling CCHFV replication in this model, and this is the first study that offers an in-depth in vivo analysis of CCHFV pathophysiology. This new mouse model exhibits key features of fatal human CCHF, proves useful for the testing of therapeutic strategies, and can be used to study virus attenuation. PMID:20739514
Weiler, Andrea; Sibley, Samuel D.; Dinis, Jorge M.; Bergman, Zachary; Nelson, Chase W.; Correll, Michael; Gleicher, Michael; Hyeroba, David; Tumukunde, Alex; Weny, Geoffrey; Chapman, Colin; Kuhn, Jens H.; Hughes, Austin L.; Friedrich, Thomas C.; Goldberg, Tony L.; O'Connor, David H.
Key biological properties such as high genetic diversity and high evolutionary rate enhance the potential of certain RNA viruses to adapt and emerge. Identifying viruses with these properties in their natural hosts could dramatically improve disease forecasting and surveillance. Recently, we discovered two novel members of the viral family Arteriviridae: simian hemorrhagic fever virus (SHFV)-krc1 and SHFV-krc2, infecting a single wild red colobus (Procolobus rufomitratus tephrosceles) in Kibale National Park, Uganda. Nearly nothing is known about the biological properties of SHFVs in nature, although the SHFV type strain, SHFV-LVR, has caused devastating outbreaks of viral hemorrhagic fever in captive macaques. Here we detected SHFV-krc1 and SHFV-krc2 in 40% and 47% of 60 wild red colobus tested, respectively. We found viral loads in excess of 106–107 RNA copies per milliliter of blood plasma for each of these viruses. SHFV-krc1 and SHFV-krc2 also showed high genetic diversity at both the inter- and intra-host levels. Analyses of synonymous and non-synonymous nucleotide diversity across viral genomes revealed patterns suggestive of positive selection in SHFV open reading frames (ORF) 5 (SHFV-krc2 only) and 7 (SHFV-krc1 and SHFV-krc2). Thus, these viruses share several important properties with some of the most rapidly evolving, emergent RNA viruses. PMID:24651479
Sharifi, Amirhossein; Amanlou, Arash; Moosavi-Movahedi, Faezeh; Golestanian, Sahand; Amanlou, Massoud
Crimean-Congo Hemorrhagic Fever Virus (CCHFV) is one of the deadliest human diseases with mortality rate near 50%. Special attention should be paid to this virus since there is no approved treatment for it. On the other hand, the recent outbreak of Ebola virus which is a member of hemorrhagic fever viruses shows this group of viruses can be extremely dangerous. Previous studies have indicated that nucleoprotein of CCHFV, a pivotal protein in virus replication, is an appropriate target for antiviral drug development. The aim of this study is finding inhibitor(s) of this protein. Herein, a virtual screening procedure employing docking followed by molecular dynamic was used to identify small molecule inhibitors of the nucleoprotein from FDA-approved drugs. Regarding CCHFV, using in-silico method is a safe way to achieve its inhibitor(s) since this virus is categorized as a World Health Organization (WHO) biosafety level 4 pathogen and therefore investigation in general laboratories is restricted. In conclusion, considering docking and molecular dynamic results alongside with bioavailability of FDA-approved drugs, doxycycline and minocycline are proposed as potential inhibitors of CCHFV nucleoprotein. There is hope, this study encourage other research groups for in-vitro and in-vivo studies about the efficacy of those two medicines in CCHFV treatment. Copyright © 2017 Elsevier Ltd. All rights reserved.
Lassa fever is a neglected tropical disease with a significant impact on the health care system of endemic West African nations. To date, case reports of Lassa fever have focused on laboratory characterisation of serological, biochemical and molecular aspects of the disease imported by infected individuals from Western Africa to the United States, Canada, Europe, Japan and Israel. Our report presents the first comprehensive real time diagnosis and characterization of a severe, hemorrhagic Lassa fever case in a Sierra Leonean individual admitted to the Kenema Government Hospital Lassa Fever Ward. Fever, malaise, unresponsiveness to anti-malarial and antibiotic drugs, followed by worsening symptoms and onset of haemorrhaging prompted medical officials to suspect Lassa fever. A recombinant Lassa virus protein based diagnostic was employed in diagnosing Lassa fever upon admission. This patient experienced a severe case of Lassa hemorrhagic fever with dysregulation of overall homeostasis, significant liver and renal system involvement, the interplay of pro- and anti-inflammatory cytokines during the course of hospitalization and an eventual successful outcome. These studies provide new insights into the pathophysiology and management of this viral illness and outline the improved infrastructure, research and real-time diagnostic capabilities within LASV endemic areas. PMID:21689444
Grove, Jessica N; Branco, Luis M; Boisen, Matt L; Muncy, Ivana J; Henderson, Lee A; Schieffellin, John S; Robinson, James E; Bangura, James J; Fonnie, Mbalu; Schoepp, Randal J; Hensley, Lisa E; Seisay, Alhassan; Fair, Joseph N; Garry, Robert F
Lassa fever is a neglected tropical disease with a significant impact on the health care system of endemic West African nations. To date, case reports of Lassa fever have focused on laboratory characterisation of serological, biochemical and molecular aspects of the disease imported by infected individuals from Western Africa to the United States, Canada, Europe, Japan and Israel. Our report presents the first comprehensive real time diagnosis and characterization of a severe, hemorrhagic Lassa fever case in a Sierra Leonean individual admitted to the Kenema Government Hospital Lassa Fever Ward. Fever, malaise, unresponsiveness to anti-malarial and antibiotic drugs, followed by worsening symptoms and onset of haemorrhaging prompted medical officials to suspect Lassa fever. A recombinant Lassa virus protein based diagnostic was employed in diagnosing Lassa fever upon admission. This patient experienced a severe case of Lassa hemorrhagic fever with dysregulation of overall homeostasis, significant liver and renal system involvement, the interplay of pro- and anti-inflammatory cytokines during the course of hospitalization and an eventual successful outcome. These studies provide new insights into the pathophysiology and management of this viral illness and outline the improved infrastructure, research and real-time diagnostic capabilities within LASV endemic areas.
Rapid detection and quantification of RNA of Ebola and Marburg viruses, Lassa virus, Crimean-Congo hemorrhagic fever virus, Rift Valley fever virus, dengue virus, and yellow fever virus by real-time reverse transcription-PCR.
Drosten, Christian; Göttig, Stephan; Schilling, Stefan; Asper, Marcel; Panning, Marcus; Schmitz, Herbert; Günther, Stephan
Viral hemorrhagic fevers (VHFs) are acute infections with high case fatality rates. Important VHF agents are Ebola and Marburg viruses (MBGV/EBOV), Lassa virus (LASV), Crimean-Congo hemorrhagic fever virus (CCHFV), Rift Valley fever virus (RVFV), dengue virus (DENV), and yellow fever virus (YFV). VHFs are clinically difficult to diagnose and to distinguish; a rapid and reliable laboratory diagnosis is required in suspected cases. We have established six one-step, real-time reverse transcription-PCR assays for these pathogens based on the Superscript reverse transcriptase-Platinum Taq polymerase enzyme mixture. Novel primers and/or 5'-nuclease detection probes were designed for RVFV, DENV, YFV, and CCHFV by using the latest DNA database entries. PCR products were detected in real time on a LightCycler instrument by using 5'-nuclease technology (RVFV, DENV, and YFV) or SybrGreen dye intercalation (MBGV/EBOV, LASV, and CCHFV). The inhibitory effect of SybrGreen on reverse transcription was overcome by initial immobilization of the dye in the reaction capillaries. Universal cycling conditions for SybrGreen and 5'-nuclease probe detection were established. Thus, up to three assays could be performed in parallel, facilitating rapid testing for several pathogens. All assays were thoroughly optimized and validated in terms of analytical sensitivity by using in vitro-transcribed RNA. The >or=95% detection limits as determined by probit regression analysis ranged from 1,545 to 2,835 viral genome equivalents/ml of serum (8.6 to 16 RNA copies per assay). The suitability of the assays was exemplified by detection and quantification of viral RNA in serum samples of VHF patients.
Akuffo, R; Brandful, J A M; Zayed, A; Adjei, A; Watany, N; Fahmy, N T; Hughes, R; Doman, B; Voegborlo, S V; Aziati, D; Pratt, D; Awuni, J A; Adams, N; Dueger, E
Crimean-Congo Haemorrhagic Fever Virus (CCHFV) is a zoonotic virus transmitted by Ixodid ticks and causes Crimean-Congo hemorrhagic fever (CCHF) disease in humans with up to 50 % mortality rate. Freshly slaughtered livestock at the Kumasi abattoir in the Ashanti Region of Ghana were examined for the presence of ticks once a month over a 6-month period from May to November 2011. The ticks were grouped into pools by species, sex, and animal source. CCHFV was detected in the ticks using reverse transcription PCR. Blood samples were collected from enrolled abattoir workers at initiation, and from those who reported fever in a preceding 30-day period during monthly visits 2-5 months after initiation. Six months after initiation, all participants who provided baseline samples were invited to provide blood samples. Serology was performed using enzyme linked immunosorbent assay (ELISA). Demographic and epidemiological data was also obtained from enrolled participants using a structured questionnaire. Of 428 freshly slaughtered animals comprising 130 sheep, 149 cattle, and 149 goats examined, 144 ticks belonging to the genera Ambylomma, Hyalomma and Boophilus were identified from 57 (13.3 %): 52 (34.9 %), 4 (3.1 %) and 1 (0.7 %) cattle, sheep and goat respectively. Of 97 tick pools tested, 5 pools comprising 1 pool of Hyalomma excavatum and 4 pools of Ambylomma variegatum, collected from cattle, were positive for CCHFV. Of 188 human serum samples collected from 108 abattoir workers, 7 (3.7 %) samples from 6 persons were anti-CCHF IgG positive with one of them also being CCHF IgM positive. The seroprevalence of CCHFV identified in this study was 5.7 %. This study detected human exposure to CCHF virus in slaughterhouse workers and also identified the CCHF virus in proven vectors (ticks) of Crimean Congo hemorrhagic fever in Ghana. The CCHFV was detected only in ticks collected from cattle, one of the livestock known to play a role in the amplification of the CCHF virus.
Zivcec, Marko; Safronetz, David; Scott, Dana; Robertson, Shelly; Ebihara, Hideki; Feldmann, Heinz
Crimean-Congo hemorrhagic fever (CCHF) is a widely distributed viral hemorrhagic fever characterized by rapid onset of flu-like symptoms often followed by hemorrhagic manifestations. CCHF virus (CCHFV), a bunyavirus in the Nairovirus genus, is capable of infecting a wide range of mammalian hosts in nature but so far only causes disease in humans. Recently, immunocompromised mice have been reported as CCHF disease models, but detailed characterization is lacking. Here, we closely followed infection and disease progression in CCHFV-infected interferon α/β receptor knockout (IFNAR(-/-)) mice and age-matched wild-type (WT) mice. WT mice quickly clear CCHFV without developing any disease signs. In contrast, CCHFV infected IFNAR(-/-) mice develop an acute fulminant disease with high viral loads leading to organ pathology (liver and lymphoid tissues), marked proinflammatory host responses, severe thrombocytopenia, coagulopathy, and death. Disease progression closely mimics hallmarks of human CCHF disease, making IFNAR(-/-) mice an excellent choice to assess medical countermeasures.
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Petrova, I D; Kononova, Iu V; Chausov, E V; Shestopalov, A M; Tishkova, F Kh
506 Hyalomma anatolicum ticks were collected and assayed in two Crimean-Congo hemorrhagic fever (CCHF) endemic regions of Tajikistan. Antigen and RNA of CCHF virus were detected in 3.4% of tick pools from Rudaki district using ELISA and RT-PCR tests. As of Tursunzade district, viral antigen was identified in 9.0% of samples and viral RNA was identified in 8.1% of samples. The multiple alignment of the obtained nucleotide sequences of CCHF virus genome S-segment 287-nt region (996-1282) and multiple alignment of deduced amino acid sequences of the samples, carried out to compare with CCHF virus strains from the GenBank database, as well as phylogenetic analysis, enabled us to conclude that Asia 1 and Asia 2 genotypes of CCHF virus are circulating in Tajikistan. It is important to note that the genotype Asia 1 virus was detected for the first time in Tajikistan.
Mahzounieh, Mohammadreza; Dincer, Ender; Faraji, Alireza; Akin, Humay; Akkutay, Ayse Zeynep; Ozkul, Aykut
Crimean-Congo hemorrhagic fever (CCHF) is an important zoonotic viral disease that is asymptomatic in infected livestock, but poses a serious threat to humans. The high fatality rate may be due to phylogenetic variations in the virus, transmission routes, and a lack of an efficient surveillance system for the disease. The geographical features of the eastern and southeastern borders of Turkey may facilitate transmission of viruses between countries of the region. Therefore in this study we focused on the genetic relationship between Turkish and Iranian CCHF viruses based on their S-segment sequences. The research was performed on a total of 104 blood samples from small ruminants reared in southwest Iran. The results of phylogenetic analysis showed that Iranian CCHF virus isolates were closely related to human-originating Turkish Group II viruses from a European lineage reported previously.
Scholte, Florine E M; Zivcec, Marko; Dzimianski, John V; Deaton, Michelle K; Spengler, Jessica R; Welch, Stephen R; Nichol, Stuart T; Pegan, Scott D; Spiropoulou, Christina F; Bergeron, Éric
Antiviral responses are regulated by conjugation of ubiquitin (Ub) and interferon-stimulated gene 15 (ISG15) to proteins. Certain classes of viruses encode Ub- or ISG15-specific proteases belonging to the ovarian tumor (OTU) superfamily. Their activity is thought to suppress cellular immune responses, but studies demonstrating the function of viral OTU proteases during infection are lacking. Crimean-Congo hemorrhagic fever virus (CCHFV, family Nairoviridae) is a highly pathogenic human virus that encodes an OTU with both deubiquitinase and deISGylase activity as part of the viral RNA polymerase. We investigated CCHFV OTU function by inactivating protease catalytic activity or by selectively disrupting its deubiquitinase and deISGylase activity using reverse genetics. CCHFV OTU inactivation blocked viral replication independently of its RNA polymerase activity, while deubiquitinase activity proved critical for suppressing the interferon responses. Our findings provide insights into viral OTU functions and support the development of therapeutics and vaccines. Published by Elsevier Inc.
Reiter, P; Turell, M; Coleman, R; Miller, B; Maupin, G; Liz, J; Kuehne, A; Barth, J; Geisbert, J; Dohm, D; Glick, J; Pecor, J; Robbins, R; Jahrling, P; Peters, C; Ksiazek, T
During the final weeks of a 6-month epidemic of Ebola hemorrhagic fever in Kikwit, Democratic Republic of the Congo, an extensive collection of arthropods was made in an attempt to learn more of the natural history of the disease. A reconstruction of the activities of the likely primary case, a 42-year-old man who lived in the city, indicated that he probably acquired his infection in a partly forested area 15 km from his home. Collections were made throughout this area, along the route he followed from the city, and at various sites in the city itself. No Ebola virus was isolated, but a description of the collections and the ecotopes involved is given for comparison with future studies of other outbreaks.
de la Torre, Juan C
Arenaviruses merit interest as experimental model systems to study virus-host interactions and as clinically important human pathogens. Several arenaviruses, chiefly Lassa virus (LASV), cause hemorrhagic fever (HF) in humans. In addition, evidence indicates that the worldwide-distributed prototypic arenavirus lymphocytic choriomeningitis virus (LCMV) is a neglected human pathogen. Moreover, arenaviruses pose a biodefense threat. No licensed arenavirus vaccines are available, and current therapy is limited to the use of ribavirin, which is only partially effective and associated with significant side effects. The development of arenavirus reverse genetics systems has made it possible to manipulate the arenavirus genome, which is contributing to significant progress in understanding arenavirus molecular and cell biology, as well as arenavirus-host interactions underlying arenavirus-induced HF disease in humans. This, in turn, should facilitate the development of novel both vaccines and antiviral drugs to combat the dual threats of naturally occurring and intentionally introduced arenavirus infections.
Li, Qi; Guo, Na-Na; Han, Zhan-Ying; Zhang, Yan-Bo; Qi, Shun-Xiang; Xu, Yong-Gang; Wei, Ya-Mei; Han, Xu; Liu, Ying-Ying
The Box-Jenkins approach was used to fit an autoregressive integrated moving average (ARIMA) model to the incidence of hemorrhagic fever with renal Syndrome (HFRS) in China during 1986–2009. The ARIMA (0, 1, 1) × (2, 1, 0)12 models fitted exactly with the number of cases during January 1986–December 2009. The fitted model was then used to predict HFRS incidence during 2010, and the number of cases during January–December 2010 fell within the model's confidence interval for the predicted number of cases in 2010. This finding suggests that the ARIMA model fits the fluctuations in HFRS frequency and it can be used for future forecasting when applied to HFRS prevention and control. PMID:22855772
Tarasov, M A; Sonin, K A; Tolokonnikova, S I; Iakovlev, S A; Bil'ko, E A; Popov, N V
The role of necrophagy in the epizootic manifestations of hemorrhagic fever with renal syndrome (HFRS) is first shown. By analyzing a great body of data obtained in the Saratov Region in 1982-2000, it has been established that the frequency of manifestations of necrophagy depends on many factors, the most important of which are a season, the size (density) of populations of small mammals, their species composition and the type of biotopes inhabited by these animals. Necrophagy is ascertained to be of great importance in HFRS foci as one of the alimentary routes of infection transmission in the parasitic systems. The presence or absence of necrophagy may serve as a preliminary test for the activity of HFRS foci.
Xiao, Hong; Huang, Ru; Gao, Li-Dong; Huang, Cun-Rui; Lin, Xiao-Ling; Li, Na; Liu, Hai-Ning; Tong, Shi-Lu; Tian, Huai-Yu
Infection rates of rodents have a significant influence on the transmission of hemorrhagic fever with renal syndrome (HFRS). In this study, four cities and two counties with high HFRS incidence in eastern Hunan Province in China were studied, and surveillance data of rodents, as well as HFRS cases and related environmental variables from 2007 to 2010, were collected. Results indicate that the distribution and infection rates of rodents are closely associated with environmental conditions. Hantavirus infections in rodents were positively correlated with temperature vegetation dryness index and negatively correlated with elevation. The predictive risk maps based on multivariate regression model revealed that the annual variation of infection risks is small, whereas monthly variation is large and corresponded well to the seasonal variation of human HFRS incidence. The identification of risk factors and risk prediction provides decision support for rodent surveillance and the prevention and control of HFRS. PMID:26711521
Chinikar, Sadegh; Shah-Hosseini, Nariman; Bouzari, Saeid; Shokrgozar, Mohammad Ali; Mostafavi, Ehsan; Jalali, Tahmineh; Khakifirouz, Sahar; Groschup, Martin H; Niedrig, Matthias
Background: Crimean-Congo Hemorrhagic Fever Virus (CCHFV) belongs to genus Nairovirus and family Bunyaviridae. The main aim of this study was to investigate the extent of recombination in S-segment genome of CCHFV in Iran. Methods: Samples were isolated from Iranian patients and those available in GenBank, and analyzed by phylogenetic and bootscan methods. Results: Through comparison of the phylogenetic trees based on full length sequences and partial fragments in the S-segment genome of CCHFV, genetic switch was evident, due to recombination event. Moreover, evidence of multiple recombination events was detected in query isolates when bootscan analysis was used by SimPlot software. Conclusion: Switch of different genomic regions between different strains by recombination could contribute to CCHFV diversification and evolution. The occurrence of recombination in CCHFV has a critical impact on epidemiological investigations and vaccine design. PMID:27047968
Gozel, Mustafa Gokhan; Bakir, Mehmet; Oztop, Atifet Yasemin; Engin, Aynur; Dokmetas, Ilyas; Elaldi, Nazif
We investigated the possibility of transmission of Crimean-Congo hemorrhagic fever (CCHF) virus through respiratory and physical contact. In this prospective study, we traced 116 close relatives of confirmed CCHF cases who were in close contact with the patients during the acute phase of the infection and evaluated the type of contact between patients and their relatives. These relatives were followed for clinical signs or symptoms indicative of CCHF disease, blood samples of those with and without clinical signs were analyzed for CCHF virus immunoglobulin M and G (IgM and IgG, respectively) by enzyme-linked immunosorbent assay. No close relatives developed any signs or symptoms of CCHF and were negative for CCHF virus IgM and IgG. The results suggest that CCHF virus is not easily transmitted from person to person through respiratory or physical contact.
Duh, Darja; Nichol, Stuart T; Khristova, Marina L; Saksida, Ana; Hafner-Bratkovič, Iva; Petrovec, Miroslav; Dedushaj, Iusuf; Ahmeti, Salih; Avšič-Županc, Tatjana
The Balkan region and Kosovo in particular, is a well-known Crimean-Congo hemorrhagic fever (CCHF) endemic region, with frequent epidemic outbreaks and sporadic cases occurring with a hospitalized case fatality of approximately 30%. Recent analysis of complete genome sequences of diverse CCHF virus strains showed that the genome plasticity of the virus is surprisingly high for an arthropod-borne virus. High levels of nucleotide and amino acid differences, frequent RNA segment reassortment and even RNA recombination have been recently described. This diversity illustrates the need to determine the complete genome sequence of CCHF virus representatives of all geographically distinct endemic areas, particularly in light of the high pathogenicity of the virus and its listing as a potential bioterrorism threat. Here we describe the first complete CCHF virus genome sequence of a virus (strain Kosova Hoti) isolated from a hemorrhagic fever case in the Balkans. This virus strain was isolated from a fatal CCHF case, and passaged only twice on Vero E6 cells prior to sequence analysis. The virus total genome was found to be 19.2 kb in length, consisting of a 1672 nucleotide (nt) S segment, a 5364 nt M segment and a 12150 nt L segment. Phylogenetic analysis of CCHF virus complete genomes placed the Kosova Hoti strain in the Europe/Turkey group, with highest similarity seen with Russian isolates. The virus M segments are the most diverse with up to 31 and 27% differences seen at the nt and amino acid levels, and even 1.9% amino acid difference found between the Kosova Hoti and another strain from Kosovo (9553-01). This suggests that distinct virus strains can coexist in highly endemic areas. PMID:18197964
Devignot, Stephanie; Bergeron, Eric; Nichol, Stuart; Mirazimi, Ali
ABSTRACT Crimean-Congo hemorrhagic fever virus (CCHFV; genus Nairovirus) is an extremely pathogenic member of the Bunyaviridae family. Since handling of the virus requires a biosafety level 4 (BSL-4) facility, little is known about pathomechanisms and host interactions. Here, we describe the establishment of a transcriptionally competent virus-like particle (tc-VLP) system for CCHFV. Recombinant polymerase (L), nucleocapsid protein (N) and a reporter minigenome expressed in human HuH-7 cells resulted in formation of transcriptionally active nucleocapsids that could be packaged by coexpressed CCHFV glycoproteins into tc-VLPs. The tc-VLPs resembled authentic virus particles in their protein composition and neutralization sensitivity to anti-CCHFV antibodies and could recapitulate all steps of the viral replication cycle. Particle attachment, entry, and primary transcription were modeled by infection of naive cells. The subsequent steps of genome replication, secondary transcription, and particle assembly and release can be obtained upon passaging the tc-VLPs on cells expressing CCHFV structural proteins. The utility of the VLP system was demonstrated by showing that the endonuclease domain of L is located around amino acid D693, as was predicted in silico by B. Morin et al. (PLoS Pathog 6:e1001038, 2010, http://dx.doi.org/10.1371/journal.ppat.1001038). The tc-VLP system will greatly facilitate studies and diagnostics of CCHFV under non-BSL-4 conditions. IMPORTANCE Crimean-Congo hemorrhagic fever virus (CCHFV) is an extremely virulent pathogen of humans. Since the virus can be handled only at the highest biosafety level, research is restricted to a few specialized laboratories. We developed a plasmid-based system to produce virus-like particles with the ability to infect cells and transcribe a reporter genome. Due to the absence of viral genes, the virus-like particles are unable to spread or cause disease, thus allowing study of aspects of CCHFV biology under relaxed
Bergeron, Éric; Zivcec, Marko; Chakrabarti, Ayan K.; Nichol, Stuart T.; Albariño, César G.; Spiropoulou, Christina F.
Crimean Congo hemorrhagic fever virus (CCHFV) is a negative-strand RNA virus of the family Bunyaviridae (genus: Nairovirus). In humans, CCHFV causes fever, hemorrhage, severe thrombocytopenia, and high fatality. A major impediment in precisely determining the basis of CCHFV’s high pathogenicity has been the lack of methodology to produce recombinant CCHFV. We developed a reverse genetics system based on transfecting plasmids into BSR-T7/5 and Huh7 cells. In our system, bacteriophage T7 RNA polymerase produced complementary RNA copies of the viral S, M, and L segments that were encapsidated with the support, in trans, of CCHFV nucleoprotein and L polymerase. The system was optimized to systematically recover high yields of infectious CCHFV. Additionally, we tested the ability of the system to produce specifically designed CCHFV mutants. The M segment encodes a polyprotein that is processed by host proprotein convertases (PCs), including the site-1 protease (S1P) and furin-like PCs. S1P and furin cleavages are necessary for producing the non-structural glycoprotein GP38, while S1P cleavage yields structural Gn. We studied the role of furin cleavage by rescuing a recombinant CCHFV encoding a virus glycoprotein precursor lacking a functional furin cleavage motif (RSKR mutated to ASKA). The ASKA mutation blocked glycoprotein precursor’s maturation to GP38, and Gn precursor’s maturation to Gn was slightly diminished. Furin cleavage was not essential for replication, as blocking furin cleavage resulted only in transient reduction of CCHFV titers, suggesting that either GP38 and/or decreased Gn maturation accounted for the reduced virion production. Our data demonstrate that nairoviruses can be produced by reverse genetics, and the utility of our system uncovered a function for furin cleavage. This viral rescue system could be further used to study the CCHFV replication cycle and facilitate the development of efficacious vaccines to counter this biological and public
Suda, Yuto; Fukushi, Shuetsu; Tani, Hideki; Murakami, Shin; Saijo, Masayuki; Horimoto, Taisuke; Shimojima, Masayuki
Crimean-Congo hemorrhagic fever (CCHF) is a tick-borne disease causing severe hemorrhagic symptoms with a nearly 30 % case-fatality rate in humans. The experimental use of CCHF virus (CCHFV), which causes CCHF, requires high-biosafety-level (BSL) containment. In contrast, pseudotyping of various viral glycoproteins (GPs) onto vesicular stomatitis virus (VSV) can be used in facilities with lower BSL containment, and this has facilitated studies on the viral entry mechanism and the measurement of neutralizing activity, especially for highly pathogenic viruses. In the present study, we generated high titers of pseudotyped VSV bearing the CCHFV envelope GP and analyzed the mechanisms involved in CCHFV infection. A partial deletion of the CCHFV GP cytoplasmic domain increased the titer of the pseudotyped VSV, the entry mechanism of which was dependent on the CCHFV envelope GP. Using the pseudotype virus, DC-SIGN (a calcium-dependent [C-type] lectin cell-surface molecule) was revealed to enhance viral infection and act as an entry factor for CCHFV.
Molinas, Andrea; Mirazimi, Ali; Holm, Angelika; Loitto, Vesa M; Magnusson, Karl-Eric; Vikström, Elena
Crimean-Congo hemorrhagic fever virus (CCHFV) is an arthropod-borne pathogen that causes infectious disease with severe hemorrhagic manifestations in vascular system in humans. The proper function of the cells in the vascular system is critically regulated by aquaporins (AQP), water channels that facilitate fluxes of water and small solutes across membranes. With Hazara virus as a model for CCHFV, we investigated the effects of viruses on AQP6 and the impact of AQP6 on virus infectivity in host cells, using transiently expressed GFP-AQP6 cells, immunofluorescent assay for virus detection, epifluorescent imaging of living cells and confocal microscopy. In GFP-AQP6 expressing cells, Hazara virus reduced both the cellular and perinuclear AQP6 distribution and changed the cell area. Infection of human cell with CCHFV strain IbAR 10200 downregulated AQP6 expression at mRNA level. Interestingly, the overexpression of AQP6 in host cells decreased the infectivity of Hazara virus, speaking for a protective role of AQP6. We suggest the possibility for AQP6 being a novel player in the virus-host interactions, which may lead to less severe outcomes of an infection. © FEMS 2016. All rights reserved. For permissions, please e-mail: firstname.lastname@example.org.
Hasan, Zahra; Mahmood, Faisal; Jamil, Bushra; Atkinson, Barry; Mohammed, Murtaza; Samreen, Azra; Altaf, Lamia; Moatter, Tariq; Hewson, Roger
Crimean-Congo hemorrhagic fever (CCHF) is endemic in the Baluchistan province, Pakistan. Sporadic outbreaks of CCHF occur throughout the year especially in individuals in contact with infected livestock. Nosocomial transmission remains a risk due to difficulties in the diagnosis of CCHF and limited availability of facilities for the isolation of suspected patients. Rapid diagnosis of CCHF virus infection is required for early management of the disease and to prevent transmission. This study describes the case of a 43-year-old surgeon who contracted CCHF during a surgical procedure in Quetta, Baluchistan and who was transferred to a tertiary care facility at the Aga Khan University Hospital, Karachi within 1 week of contracting the infection. Diagnosis of CCHF was made using a rapid real-time reverse transcription polymerase chain reaction (RT-PCR) assay for CCHF viral RNA. The patient had chronic hepatitis B and hepatitis D infection for which he had previously received a liver transplant. He proceeded to develop classic hemorrhagic manifestations and succumbed to the infection 14 days post-onset of disease. There was no further nosocomial transmission of the CCHF during the hospital treatment of the surgeon. Early diagnosis of CCHF enables rapid engagement of appropriate isolation, barrier nursing and infection control measures thus preventing nosocomial transmission of the virus.
Yilmaz, Gürdal; Yilmaz, Hülya; Arslan, Mustafa; Kostakoğlu, Uğur; Menteşe, Ahmet; Karahan, Süleyman Caner; Köksal, İftihar
Crimean-Congo Hemorrhagic Fever (CCHF) may exhibit a mild clinical course or a severe profile like mortal bleeding. The pathogenesis of the illness and reason of bleeding are unclear. However, endothelial injury is a key factor in the pathogenesis of the illness. Transforming growth factor beta (TGF-β) is one of the materials involved in repairing injured endothelium. This is a significant polypeptide released in pretty much all cells and important for the regulation of cellular events, epithelium formation, inflammation, blood coagulation, and collagen synthesis. This study aimed to determine the prognostic significance of serum TGF-β1 levels in CCHF patients. We examined 120 patients hospitalized with CCHF diagnosis and their serum TGF-β1 was investigated, retrospectively. Patients were put into two groups according to the existence of hemorrhage. Forty-four (36.7%) patients had hemorrhage. TGF-β1 levels in patients with bleeding were 5.2 ± 1.8, and 7.1 ± 2.2 for non-bleeding (P < 0.0001). When ROC analysis was performed in patients with CCHF alone in order to identify patients with bleeding, at a TGF-β1 cut-off point of 4.9, AUC was 0.762 (0.675-0.835), sensitivity 59.1%, specificity 85.5%, PPV 70.3%, and NPV 78.3%. We summarize that TGF-β1 level and endothelial dysfunction can be related. A decreased TGF-β1 level is a likely prognostic and diagnostic factor for bleeding in CCHF patients. Therefore, this marker should be considered in the treatment strategy for these patients. J. Med. Virol. 89:413-416, 2017. © 2016 Wiley Periodicals, Inc.
Ngwe Tun, Mya Myat; Thant, Kyaw Zin; Inoue, Shingo; Kurosawa, Yae; Lwin, Yee Yee; Lin, Sanda; Aye, Kay Thi; Thet Khin, Pe; Myint, Tin; Htwe, Khin; Mapua, Cynthia A; Natividad, Filipinas F; Hirayama, Kenji; Morita, Kouichi
In Myanmar, dengue fever (DF)/dengue hemorrhagic fever (DHF) is one of the leading causes of morbidity and mortality among children. From Pyinmana Hospital in 2004 and Mandalay Children Hospital in 2006, 160 patients diagnosed clinically to have DHF/dengue shock syndrome (DSS) were examined for immunoglobulin M (IgM) and IgG levels. A focus reduction neutralization test was also used to determine primary or secondary dengue virus (DENV) infection. By using IgM-capture ELISA, 139 cases were confirmed as DENV infections. Of these IgM-positives, 94 samples were collected 7-24 days from the onset of illness, to which 13 (14%) and 81 (86%) were determined to be primary and secondary DENV infections, respectively. The 13 primary DENV infection cases were spread among the various severity groups (DHF grade I-IV and DSS) and represented age groups ranging from <1 year of age to 9 years of age. The patients in these primary infection cases showed a remarkably high IgM with a low IgG titer response compared with the secondary infection cases. No significant differences were observed in IgG titers with clinical severity. The data obtained in this study suggest that primary DENV infection cases exist certainly among DHF/DSS cases in Myanmar, and that additional mechanism(s) aside from the antibody-dependent enhancement mechanism could have influenced the clinical severity in DHF/DSS cases.
Porter, Kevin R; Beckett, Charmagne G; Kosasih, Herman; Tan, Ratna Irsiana; Alisjahbana, Bachti; Rudiman, Pandji Irani Fianza; Widjaja, Susana; Listiyaningsih, Erlin; Ma'Roef, Chairin Nisa; McArdle, James L; Parwati, Ida; Sudjana, Primal; Jusuf, Hadi; Yuwono, Djoko; Wuryadi, Suharyono
A prospective study of dengue fever (DF) and dengue hemorrhagic fever (DHF) was conducted in a cohort of adult volunteers from two textile factories located in West Java, Indonesia. Volunteers in the cohort were bled every three months and were actively followed for the occurrence of dengue (DEN) disease. The first two years of the study showed an incidence of symptomatic DEN disease of 18 cases per 1,000 person-years and an estimated asymptomatic/ mild infection rate of 56 cases per 1,000 person-years in areas of high disease transmission. In areas where no symptomatic cases were detected, the incidence of asymptomatic or mild infection was 8 cases per 1,000 person-years. Dengue-2 virus was the predominant serotype identified, but all four serotypes were detected among the cohort. Four cases of DHF and one case of dengue shock syndrome (DSS) were identified. Three of the four DHF cases were due to DEN-3 virus. The one DSS case occurred in the setting of a prior DEN-2 virus infection, followed by a secondary infection with DEN-1 virus. To our knowledge, this is the first report of a longitudinal cohort study of naturally acquired DF and DHF in adults.
Rodas, Juan D; Lukashevich, Igor S; Zapata, Juan C; Cairo, Cristiana; Tikhonov, Ilia; Djavani, Mahmoud; Pauza, C David; Salvato, Maria S
Arenaviruses are transmitted from rodents to human beings by blood or mucosal exposure. The most devastating arenavirus in terms of human disease is Lassa fever virus, causing up to 300,000 annual infections in West Africa. We used a model for Lassa fever in which Rhesus macaques were infected with a related virus, lymphocytic choriomeningitis virus (LCMV). Our goals were to determine the outcome of infection after mucosal inoculation and later lethal challenge, to characterize protective immune responses, and to test cross-protection between a virulent (LCMV-WE) and an avirulent (LCMV-ARM) strain of virus. Although intravenous infections in the monkey model were uniformly lethal, intragastric infections recapitulated the spectrum of clinical outcomes seen in human exposure to Lassa fever virus: death, recovery from disease, and most often, subclinical infection. Plaque neutralization, ELISA, lymphocyte proliferation, and chromium-release assays were used to monitor humoral and cellular immune responses. Cross protection between the two strains was observed. The three out of seven monkeys that experienced protection were also the three with the strongest cell-mediated immunity.
Das, Sanchita; Rundell, Mark S; Mirza, Aashiq H; Pingle, Maneesh R; Shigyo, Kristi; Garrison, Aura R; Paragas, Jason; Smith, Scott K; Olson, Victoria A; Larone, Davise H; Spitzer, Eric D; Barany, Francis; Golightly, Linnie M
CDC designated category A infectious agents pose a major risk to national security and require special action for public health preparedness. They include viruses that cause viral hemorrhagic fever (VHF) syndrome as well as variola virus, the agent of smallpox. VHF is characterized by hemorrhage and fever with multi-organ failure leading to high morbidity and mortality. Smallpox, a prior scourge, has been eradicated for decades, making it a particularly serious threat if released nefariously in the essentially non-immune world population. Early detection of the causative agents, and the ability to distinguish them from other pathogens, is essential to contain outbreaks, implement proper control measures, and prevent morbidity and mortality. We have developed a multiplex detection assay that uses several species-specific PCR primers to generate amplicons from multiple pathogens; these are then targeted in a ligase detection reaction (LDR). The resultant fluorescently-labeled ligation products are detected on a universal array enabling simultaneous identification of the pathogens. The assay was evaluated on 32 different isolates associated with VHF (ebolavirus, marburgvirus, Crimean Congo hemorrhagic fever virus, Lassa fever virus, Rift Valley fever virus, Dengue virus, and Yellow fever virus) as well as variola virus and vaccinia virus (the agent of smallpox and its vaccine strain, respectively). The assay was able to detect all viruses tested, including 8 sequences representative of different variola virus strains from the CDC repository. It does not cross react with other emerging zoonoses such as monkeypox virus or cowpox virus, or six flaviviruses tested (St. Louis encephalitis virus, Murray Valley encephalitis virus, Powassan virus, Tick-borne encephalitis virus, West Nile virus and Japanese encephalitis virus).
Das, Sanchita; Rundell, Mark S.; Mirza, Aashiq H.; Pingle, Maneesh R.; Shigyo, Kristi; Garrison, Aura R.; Paragas, Jason; Smith, Scott K.; Olson, Victoria A.; Larone, Davise H.; Spitzer, Eric D.; Barany, Francis; Golightly, Linnie M.
CDC designated category A infectious agents pose a major risk to national security and require special action for public health preparedness. They include viruses that cause viral hemorrhagic fever (VHF) syndrome as well as variola virus, the agent of smallpox. VHF is characterized by hemorrhage and fever with multi-organ failure leading to high morbidity and mortality. Smallpox, a prior scourge, has been eradicated for decades, making it a particularly serious threat if released nefariously in the essentially non-immune world population. Early detection of the causative agents, and the ability to distinguish them from other pathogens, is essential to contain outbreaks, implement proper control measures, and prevent morbidity and mortality. We have developed a multiplex detection assay that uses several species-specific PCR primers to generate amplicons from multiple pathogens; these are then targeted in a ligase detection reaction (LDR). The resultant fluorescently-labeled ligation products are detected on a universal array enabling simultaneous identification of the pathogens. The assay was evaluated on 32 different isolates associated with VHF (ebolavirus, marburgvirus, Crimean Congo hemorrhagic fever virus, Lassa fever virus, Rift Valley fever virus, Dengue virus, and Yellow fever virus) as well as variola virus and vaccinia virus (the agent of smallpox and its vaccine strain, respectively). The assay was able to detect all viruses tested, including 8 sequences representative of different variola virus strains from the CDC repository. It does not cross react with other emerging zoonoses such as monkeypox virus or cowpox virus, or six flaviviruses tested (St. Louis encephalitis virus, Murray Valley encephalitis virus, Powassan virus, Tick-borne encephalitis virus, West Nile virus and Japanese encephalitis virus). PMID:26381398
Jayasinghe, Nayomi Shermila; Thalagala, Eranga; Wattegama, Milanka; Thirumavalavan, Kanapathipillai
Neurological manifestations in dengue fever occur in <1 % of the patients and known to be due to multisystem dysfunction secondary to vascular leakage. Occurrence of wide spread cerebral haemorrhages with subdural hematoma during the leakage phase without profound thrombocytopenia and occurrence of cranial diabetes insipidus are extremely rare and had not been reported in published literature earlier, thus we report the first case. A 24 year old previously healthy lady was admitted on third day of fever with thrombocytopenia. Critical phase started on fifth day with evidence of pleural effusion and moderate ascites. Thirty one hours into critical phase she developed headache, altered level of consciousness, limb rigidity and respiratory depression without definite seizures. Non-contrast CT brain done at tertiary care level revealed diffuse intracranial haemorrhages and sub arachnoid haemorrhages in right frontal, parietal, occipital lobes and brainstem, cerebral oedema with an acute subdural hematoma in right temporo- parietal region. Her platelet count was 40,000 at this time with signs of vascular leakage. She was intubated and ventilated with supportive care. Later on she developed features of cranial diabetes insipidus and it responded to intranasal desmopressin therapy. In spite of above measures signs of brainstem herniation developed and she succumbed to the illness on day 8. Dengue was confirmed serologically. Exact pathophysiological mechanism of diffuse cerebral haemorrhages without profound thrombocytopenia is not well understood. Increased awareness and high degree of clinical suspicion is needed among clinicians for timely diagnosis of this extremely rare complication of dengue fever. We postulate that immunological mechanisms may play a role in pathogenesis. However further comprehensive research and studies are needed to understand the pathophysiological mechanisms leading to this complication.
Diseases (USAMRIID) testing of these products. Each preparation has viral neutralizing activity and is a safe, stable, well tolerated solution...Army Medical Research Institute of Infectious Diseases (USAMRIID), there were five different human anti-Lassa fever (ALF) preparations, two monkey...include: 1) Human ALF IgG containing all four subclasses IgG1 , IgG2 , IgG3 , IgG4 ; 2) Human ALF IgG containing only the three subclasses IgG1
Kızılgun, Murat; Ozkaya-Parlakay, Aslınur; Tezer, Hasan; Gulhan, Belgin; Yuksek, Saliha Kanık; Celikel, Elif; Tunc, Bahattin
Crimean-Congo haemorrhagic fever (CCHF) is a fatal viral infection and an important public health issue in Turkey because of its high case fatality rate. Severity criteria of CCHF were defined previously in adults on the basis of epidemiological, clinical, and laboratory findings,. This study evaluated the course of CCHF in children. Between January, 2009, and November, 2012, 41 patients aged between 1 and 17 years (mean 9.78 ± 4.85) with a diagnosis of CCHF were included in the study. According to results of our study, Turkish pediatric patients had a milder course of CCHF.
Kerstiëns, B; Matthys, F
On 6 May 1995, the Médecins sans Frontières (MSF) coordinator in Kinshasa, Democratic Republic of the Congo (DRC), received a request for assistance for what was believed to be a concurrent outbreak of bacillary dysentery and viral hemorrhagic fever (suspected Ebola hemorrhagic fever [EHF]) in the town of Kikwit, DRC. On 11 May, the MSF intervention team assessed Kikwit General Hospital. This initial assessment revealed a nonfunctional isolation ward for suspected EHF cases; a lack of water and electricity; no waste disposal system; and no protective gear for medical staff. The priorities set by MSF were to establish a functional isolation ward to deal with EHF and to distribute protective supplies to individuals who were involved with patient care. Before the intervention, 67 health workers contracted EHF; after the initiation of control measures, just 3 cases were reported among health staff and none among Red Cross volunteers involved in body burial.
Kortekaas, Jeroen; Vloet, Rianka P M; McAuley, Alexander J; Shen, Xiaoli; Bosch, Berend Jan; de Vries, Laura; Moormann, Rob J M; Bente, Dennis A
Crimean-Congo hemorrhagic fever virus is a tick-borne bunyavirus of the Nairovirus genus that causes hemorrhagic fever in humans with high case fatality. Here, we report the development of subunit vaccines and their efficacy in signal transducer and activator of transcription 1 (STAT1) knockout mice. Ectodomains of the structural glycoproteins Gn and Gc were produced using a Drosophila insect cell-based expression system. A single vaccination of STAT129 mice with adjuvanted Gn or Gc ectodomains induced neutralizing antibody responses, which were boosted by a second vaccination. Despite these antibody responses, mice were not protected from a CCHFV challenge infection. These results suggest that neutralizing antibodies against CCHFV do not correlate with protection of STAT1 knockout mice.
Ferraris, O; Moroso, M; Pernet, O; Emonet, S; Ferrier Rembert, A; Paranhos-Baccalà, G; Peyrefitte, C N
Crimean-Congo hemorrhagic virus (CCHFV) causes hemorrhagic fever with high case mortality rates and is endemic in south-eastern Europe, Africa, and Asia. The limited catalog of specific treatment, highlight the necessity to look for additional therapeutic solutions. Previous experiments suggested that CCHFV enters the cells via a clathrin dependent pathway. Therefore, we have evaluated the potential anti-CCHFV activity of several molecules targeting this entry possibility. We identified two molecules chloroquine and chlorpromazine. Neutralization and virus yield reduction assays were tested in Vero E6 and Huh7 cells on two different CCHFV strains. Several combinations, including ribavirin, were assayed to test a potential synergistic effect. The two molecules inhibited CCHFV, and depending on the virus and the cell lines, the 50% inhibitory concentration (IC50) values for chloroquine and chlorpromazine ranged from 28 to 43 and 10.8-15.7 μM, respectively. Time-of-addition studies demonstrated that these molecules had a direct effect on CCHFV infectivity and spread. The antiviral activity of the two molecules was still effective even when added up to 6h post-infection and up to 24h. The selectivity index ranging from 3 to 35 lead us to evaluate combinations with ribavirin. Combinations of ribavirin and chloroquine or chlorpromazine were synergistic against CCHFV. Though the low chlorpromazine selectivity index suggests the need for a chemical improvement, our present study highlights chloroquine as the main drug having the potential for drug repurposing. Copyright © 2015 Elsevier B.V. All rights reserved.
Branco, Luis M; Boisen, Matt L; Andersen, Kristian G; Grove, Jessica N; Moses, Lina M; Muncy, Ivana J; Henderson, Lee A; Schieffellin, John S; Robinson, James E; Bangura, James J; Grant, Donald S; Raabe, Vanessa N; Fonnie, Mbalu; Zaitsev, Eleina M; Sabeti, Pardis C; Garry, Robert F
Lassa fever (LF) is a devastating viral disease prevalent in West Africa. Efforts to take on this public health crisis have been hindered by lack of infrastructure and rapid field deployable diagnosis in areas where the disease is prevalent. Recent capacity building at the Kenema Government Hospital Lassa Fever Ward (KGH LFW) in Sierra Leone has lead to a major turning point in the diagnosis, treatment and study of LF. Herein we present the first comprehensive rapid diagnosis and real time characterization of an acute hemorrhagic LF case at KGH LFW. This case report focuses on a third trimester pregnant Sierra Leonean woman from the historically non-endemic Northern district of Tonkolili who survived the illness despite fetal demise. Employed in this study were newly developed recombinant LASV Antigen Rapid Test cassettes and dipstick lateral flow immunoassays (LFI) that enabled the diagnosis of LF within twenty minutes of sample collection. Deregulation of overall homeostasis, significant hepatic and renal system involvement, and immunity profiles were extensively characterized during the course of hospitalization. Rapid diagnosis, prompt treatment with a full course of intravenous (IV) ribavirin, IV fluids management, and real time monitoring of clinical parameters resulted in a positive maternal outcome despite admission to the LFW seven days post onset of symptoms, fetal demise, and a natural still birth delivery. These studies solidify the growing rapid diagnostic, treatment, and surveillance capabilities at the KGH LF Laboratory, and the potential to significantly improve the current high mortality rate caused by LF. As a result of the growing capacity, we were also able to isolate Lassa virus (LASV) RNA from the patient and perform Sanger sequencing where we found significant genetic divergence from commonly circulating Sierra Leonean strains, showing potential for the discovery of a newly emerged LASV strain with expanded geographic distribution
Noh, Ji Yun; Cheong, Hee Jin; Song, Joon Young; Kim, Woo Joo; Song, Ki-Joon; Klein, Terry A; Lee, Sam H; Yanagihara, Richard; Song, Jin-Won
Laboratory diagnosis of hemorrhagic fever with renal syndrome (HFRS), an infectious disease caused by rodent-borne hantaviruses in Asia and Europe, depends primarily on serological methods. Since the advent of such serodiagnostic tests, few reports are available about the clinical and molecular epidemiological features of HFRS. To investigate the epidemioclinical features of HFRS patients treated at a tertiary-care teaching hospital in Seoul over a 10-year period. Medical records of HFRS patients, admitted to a tertiary-care teaching hospital during February 2002 to February 2012, were reviewed. Sera from patients were tested for Hantaan virus (HTNV) and Seoul virus (SEOV) RNA using RT-PCR. Among 35 HFRS patients (mean age was 44.2±14.7 years), 29 were male (82.9%). Acute renal failure developed in 27 patients (77.1%), and 12 patients (34.3%) were admitted to the intensive care unit (ICU). Conjunctival injection (OR 10.32, 95% CI 1.09-97.77, P=.04) and initial serum albumin less than 3g/dL (OR 22.83, 95% CI 1.45-359.93, P=.03) were risk factors for ICU admission. Of 35 acute-phase sera, 11 (31.4%) were positive for HTNV RNA. None were positive for SEOV RNA. HFRS was characterized by the clinical triad of fever, renal insufficiency and gastrointestinal symptoms. Conjunctival injection and serum albumin level were related to severity. A large-scale multi-center study is needed to enhance insights into epidemioclinical characteristics of HFRS in Korea. Copyright © 2013 Elsevier B.V. All rights reserved.
Background Dengue viral infections are prevalent in the tropical and sub-tropical regions of the world, resulting in substantial morbidity and mortality. Clinical manifestations range from a self-limited fever to a potential life-threatening plasma leakage syndrome (dengue hemorrhagic fever). The objective of this study was to assess the utility of near infrared spectroscopy (NIRS) measurements of muscle oxygen saturation (SmO2) as a possible continuous measure to detect plasma leakage in children with dengue. Methods Children ages 6 months to 15 years of age admitted with suspected dengue were enrolled from the dengue ward at Queen Sirikit National Institute for Child Health. Children were monitored daily until discharge. NIRS data were collected continuously using a prototype CareGuide Oximeter 1100 with sensors placed on the deltoid or thigh. Daily ultrasound of the chest and a right lateral decubitus chest x-ray the day after defervescence were performed to detect and quantitate plasma leakage in the pleural cavity. Results NIRS data were obtained from 19 children with laboratory-confirmed dengue. Average minimum SmO2 decreased for all subjects prior to defervescence. Average minimum SmO2 subsequently increased in children with no ultrasound evidence of pleural effusion but remained low in children with pleural effusion following defervescence. Average minimum SmO2 was inversely correlated with pleural space fluid volume. ROC analysis revealed a cut-off value for SmO2 which yielded high specificity and sensitivity. Conclusions SmO2 measured using NIRS may be a useful guide for real-time and non-invasive identification of plasma leakage in children with dengue. Further investigation of the utility of NIRS measurements for prediction and management of severe dengue syndromes is warranted. PMID:25033831
Lloyd, E S; Zaki, S R; Rollin, P E; Tshioko, K; Bwaka, M A; Ksiazek, T G; Calain, P; Shieh, W J; Kondé, M K; Verchueren, E; Perry, H N; Manguindula, L; Kabwau, J; Ndambi, R; Peters, C J
After the large-scale outbreak of Ebola hemorrhagic fever (EHF) in Bandundu region, Democratic Republic of the Congo, a program was developed to help detect and prevent future outbreaks of EHF in the region. The long-term surveillance and prevention strategy is based on early recognition by physicians, immediate initiation of enhanced barrier-nursing practices, and the use of an immunohistochemical diagnostic test performed on formalin-fixed skin specimens of patients who die of suspected viral hemorrhagic fever. The program was implemented in September 1995 during a 4-day workshop with 28 local physicians representing 17 of 22 health zones in the region. Specimen collection kits were distributed to clinics in participating health zones, and a follow-up evaluation was conducted after 6 months. The use of a formalin-fixed skin specimen for laboratory confirmation of EHF can provide an appropriate method for EHF surveillance when linked with physician training, use of viral hemorrhagic fever isolation precautions, and follow-up investigation.
Lan, Shuiyun; McLay Schelde, Lisa; Wang, Jialong; Kumar, Naveen; Ly, Hinh; Liang, Yuying
Several arenaviruses can cause hemorrhagic fever diseases (VHFs) in humans, the pathogenic mechanism of which is poorly understood due to their virulent nature and the lack of molecular clones. A safe, convenient, and economical small animal model of arenavirus hemorrhagic fever is based on guinea pigs infected by the arenavirus Pichinde (PICV). PICV does not cause disease in humans, but an adapted strain of PICV (P18) causes a disease in guinea pigs that mimics arenavirus hemorrhagic fever in humans in many aspects, while a low-passaged strain (P2) remains avirulent in infected animals. In order to identify the virulence determinants within the PICV genome, we developed the molecular clones for both the avirulent P2 and virulent P18 viruses. Recombinant viruses were generated by transfecting plasmids that contain the antigenomic L and S RNA segments of PICV under the control of the T7 promoter into BSRT7-5 cells, which constitutively express T7 RNA polymerase. By analyzing viral growth kinetics in vitro and virulence in vivo, we show that the recombinant viruses accurately recapitulate the replication and virulence natures of their respective parental viruses. Both parental and recombinant virulent viruses led to high levels of viremia and titers in different organs of the infected animals, whereas the avirulent viruses were effectively controlled and cleared by the hosts. These novel infectious clones for the PICV provide essential tools to identify the virulence factors that are responsible for the severe VHF-like disease in infected animals. PMID:19386714
Hoenen, Thomas; Groseth, Allison; de Kok-Mercado, Fabian; Kuhn, Jens H; Wahl-Jensen, Victoria
Reverse-genetics systems are powerful tools enabling researchers to study the replication cycle of RNA viruses, including filoviruses and other hemorrhagic fever viruses, as well as to discover new antivirals. They include full-length clone systems as well as a number of life cycle modeling systems. Full-length clone systems allow for the generation of infectious, recombinant viruses, and thus are an important tool for studying the virus replication cycle in its entirety. In contrast, life cycle modeling systems such as minigenome and transcription and replication competent virus-like particle systems can be used to simulate and dissect parts of the virus life cycle outside of containment facilities. Minigenome systems are used to model viral genome replication and transcription, whereas transcription and replication competent virus-like particle systems also model morphogenesis and budding as well as infection of target cells. As such, these modeling systems have tremendous potential to further the discovery and screening of new antivirals targeting hemorrhagic fever viruses. This review provides an overview of currently established reverse genetics systems for hemorrhagic fever-causing negative-sense RNA viruses, with a particular emphasis on filoviruses, and the potential application of these systems for antiviral research.
Mallhi, Tauqeer Hussain; Khan, Amer Hayat; Adnan, Azreen Syazril; Sarriff, Azmi; Khan, Yusra Habib; Jummaat, Fauziah
The incidence of dengue is rising steadily in Malaysia since the first major outbreak in 1973. Despite aggressive measures taken by the relevant authorities, Malaysia is still facing worsening dengue crisis over the past few years. There is an urgent need to evaluate dengue cases for better understanding of clinic-laboratory spectrum in order to combat this disease. A retrospective analysis of dengue patients admitted to a tertiary care teaching hospital during the period of six years (2008 - 2013) was performed. Patient's demographics, clinical and laboratory findings were recorded via structured data collection form. Patients were categorized into dengue fever (DF) and dengue hemorrhagic fever (DHF). Appropriate statistical methods were used to compare these two groups in order to determine difference in clinico-laboratory characteristics and to identify independent risk factors of DHF. A total 667 dengue patients (30.69 ± 16.13 years; Male: 56.7 %) were reviewed. Typical manifestations of dengue like fever, myalgia, arthralgia, headache, vomiting, abdominal pain and skin rash were observed in more than 40 % patients. DHF was observed in 79 (11.8 %) cases. Skin rash, dehydration, shortness of breath, pleural effusion and thick gall bladder were more significantly (P < 0.05) associated with DHF than DF. Multivariate regression analysis demonstrated presence of age > 40 years (OR: 4.1, P < 0.001), secondary infection (OR: 2.7, P = 0.042), diabetes mellitus (OR: 2.8, P = 0.041), lethargy (OR: 3.1, P = 0.005), thick gallbladder (OR: 1.7, P = 0.029) and delayed hospitalization (OR: 2.3, P = 0.037) as independent predictors of DHF. Overall mortality was 1.2 % in our study. Current study demonstrated that DF and DHF present significantly different clinico-laboratory profile. Older age, secondary infection, diabetes mellitus, lethargy, thick gallbladder and delayed hospitalization significantly predict DHF. Prior knowledge of expected
Weidmann, Manfred; Avsic-Zupanc, Tatjana; Bino, Silvia; Bouloy, Michelle; Burt, Felicity; Chinikar, Sadegh; Christova, Iva; Dedushaj, Isuf; El-Sanousi, Ahmed; Elaldi, Nazif; Hewson, Roger; Hufert, Frank T; Humolli, Isme; Jansen van Vuren, Petrus; Koçak Tufan, Zeliha; Korukluoglu, Gülay; Lyssen, Pieter; Mirazimi, Ali; Neyts, Johan; Niedrig, Matthias; Ozkul, Aykut; Papa, Anna; Paweska, Janusz; Sall, Amadou A; Schmaljohn, Connie S; Swanepoel, Robert; Uyar, Yavuz; Weber, Friedemann; Zeller, Herve
In countries from which Crimean-Congo haemorrhagic fever (CCHF) is absent, the causative virus, CCHF virus (CCHFV), is classified as a hazard group 4 agent and handled in containment level (CL)-4. In contrast, most endemic countries out of necessity have had to perform diagnostic tests under biosafety level (BSL)-2 or -3 conditions. In particular, Turkey and several of the Balkan countries have safely processed more than 100 000 samples over many years in BSL-2 laboratories. It is therefore advocated that biosafety requirements for CCHF diagnostic procedures should be revised, to allow the tests required to be performed under enhanced BSL-2 conditions with appropriate biosafety laboratory equipment and personal protective equipment used according to standardized protocols in the countries affected. Downgrading of CCHFV research work from CL-4, BSL-4 to CL-3, BSL-3 should also be considered.
... liver, and kidney. Bleeding disorders, seizures, coma, and delirium may also occur. Symptoms may include: Fever, headache, ... tongue Yellow skin and eyes (jaundice) Decreased urination Delirium Irregular heartbeats (arrhythmias) Bleeding (may progress to hemorrhage) ...
Ma, Chaofeng; Wang, Zengguo; Li, Shen; Xing, Yuan; Wu, Rui; Wei, Jing; Nawaz, Muhammad; Tian, Huaiyu; Xu, Bing; Wang, Jingjun; Yu, Pengbo
The aim of the present study was to analyze an outbreak of hemorrhagic fever with renal syndrome (HFRS), caused by a Hantavirus, in college students in the northern urban area of Xi’an in 2012. The outbreak affected six students and included two deaths. The epidemiological survey revealed that both of the deceased cases were misdiagnosed initially, and treatment was delayed. Furthermore, a higher rodent population density and lower HFRS vaccine coverage were observed in the affected area, which indicates a possible role in the outbreak. Rattus norvegicus (Rn) and Mus musculus (Mm) were the predominant host populations in the area. Genotyping revealed that all HVs from patients and rodents were Hantaan virus (HTNV). Sequence analysis of the S segments revealed that the HTNVs reported in this study had high similarity with strains reported in 2011 and 1985, but these viruses diverged from a strain isolated in 1984 and the HTNV prototype strain 76-118. Detection of anti-HV IgG and amplification of the S segment of HTNV from a non-natural HTNV reservoir indicates that further investigations by increased rodent trapping are necessary. PMID:24481251
Brasier, Allan R; Garcia, Josefina; Wiktorowicz, John E.; Spratt, Heidi M.; Comach, Guillermo; Ju, Hyunsu; Recinos, Adrian; Soman, Kizhake; Forshey, Brett M.; Halsey, Eric S.; Blair, Patrick J.; Rocha, Claudio; Bazan, Isabel; Victor, Sundar S; Wu, Zheng; Stafford, Susan; Watts, Douglas; Morrison, Amy C.; Scott, Thomas W.; Kochel, Tadeusz J.
Secondary Dengue viral infection can produce capillary leakage associated with increased mortality known as Dengue Hemorrhagic Fever (DHF). Because the mortality of DHF can be reduced by early detection and intensive support, improved methods for its detection are needed. We applied multidimensional protein profiling to predict outcomes in a prospective Dengue surveillance study in South America. Plasma samples taken from initial clinical presentation of acute Dengue infection were subjected to proteomics analyses using ELISA and a recently developed biofluid analysis platform. Demographics, clinical laboratory measurements, 9 cytokines and 419 plasma proteins collected at the time of initial presentation were compared between the DF and DHF outcomes. Here, the subject’s gender, clinical parameters, 2 cytokines and 42 proteins discriminated between the outcomes. These factors were reduced by multivariate adaptive regression splines (MARS) that a highly accurate classification model based on 8 discriminant features with an AUC of 0.999. Model analysis indicated that the feature-outcome relationship were non-linear. Although this DHF risk model will need validation in a larger cohort, we conclude that approaches to develop predictive biomarker models for disease outcome will need to incorporate nonparametric modeling approaches. PMID:22376251
Bausch, Daniel G; Sprecher, A G; Jeffs, Benjamin; Boumandouki, Paul
The filoviruses, Marburg and Ebola, have the dubious distinction of being associated with some of the highest case-fatality rates of any known infectious disease--approaching 90% in many outbreaks. In recent years, laboratory research on the filoviruses has produced treatments and vaccines that are effective in laboratory animals and that could potentially drastically reduce case-fatality rates and curtail outbreaks in humans. However, there are significant challenges in clinical testing of these products and eventual delivery to populations in need. Most cases of filovirus infection are recognized only in the setting of large outbreaks, often in the most remote and resource-poor areas of sub-Saharan Africa, with little infrastructure and few personnel experienced in clinical research. Significant political, legal, and socio-cultural barriers also exist. Here, we review the present research priorities and environment for field study of the filovirus hemorrhagic fevers and outline a strategy for future prospective clinical research on treatment and vaccine prevention.
Shimada, Satoshi; Aoki, Kotaro; Nabeshima, Takeshi; Fuxun, Yu; Kurosaki, Yohei; Shiogama, Kazuya; Onouchi, Takanori; Sakaguchi, Miako; Fuchigami, Takeshi; Ono, Hokuto; Nishi, Kodai; Posadas-Herrera, Guillermo; Uchida, Leo; Takamatsu, Yuki; Yasuda, Jiro; Tsutsumi, Yutaka; Fujita, Hiromi; Morita, Kouichi; Hayasaka, Daisuke
Ixodid ticks transmit several important viral pathogens. We isolated a new virus (Tofla virus: TFLV) from Heamaphysalis flava and Heamaphysalis formsensis in Japan. The full-genome sequences revealed that TFLV belonged to the genus Nairovirus, family Bunyaviridae. Phylogenetic analyses and neutralization tests suggested that TFLV is closely related to the Hazara virus and that it is classified into the Crimean-Congo hemorrhagic fever group. TFLV caused lethal infection in IFNAR KO mice. The TFLV-infected mice exhibited a gastrointestinal disorder, and positron emission tomography-computed tomography images showed a significant uptake of 18F-fluorodeoxyglucose in the intestinal tract. TFLV was able to infect and propagate in cultured cells of African green monkey-derived Vero E6 cells and human-derived SK-N-SH, T98-G and HEK-293 cells. Although TFLV infections in humans and animals are currently unknown, our findings may provide clues to understand the potential infectivity and to develop of pre-emptive countermeasures against this new tick-borne Nairovirus. PMID:26863911
Tang, Z; Xu, X J; He, X J; Liang, Z S; Liang, W B; Li, Y; Gao, K
This study analyzed the temporal-spatial distribution characteristics, epidemiological characteristics and gene sequences of hemorrhagic fever with renal syndrome (HFRS) in Guangxi, with the intention of providing a theoretical and technical support for the prevention of HFRS. A map of the incidence of HFRS of different cities in Guangxi was drawn up using the Geographic Information System (GIS) to investigate the epidemiological characteristics and infection source of HFRS between 2013 and 2016. Guangxi has a low incidence of HFRS, and autumn and winter are the main high-incidence seasons. Cases of HFRS were reported in all regions in Guangxi except Laibin city between 2013 and 2016. The distribution of cases in the four years suggested that Guilin, Nanning, Hechi and Wuzhou were the main infected regions, especially the local areas in the north of Guilin. The nucleotide and amino acid of S fragment and M fragment of Hantaviruses (HV) detected were highly homologous, and no obvious variation was found. Through analyzing the space-time characteristics, epidemiological characteristics and gene sequence of HFRS in Guangxi, it was found that areas rich in water, grass and moisture, such as paddy fields, are the main active areas for the host of HFRS.
Kinoshita, Hitomi; Mathenge, Edward Gitau Matumbi; Hung, Nguyen Thanh; Huong, Vu Thi Que; Kumatori, Atsushi; Yu, Fuxun; Parquet, Maria Carmen; Inoue, Shingo; Matias, Ronald Roll; Natividad, Filipinas Florendo; Morita, Kouichi; Hasebe, Futoshi
Dengue is the one of the most prevalent arthropod-borne viral diseases. Dengue virus circulates between humans and mosquitoes, and causes a wide range of disease in humans. To elucidate the link between the cell tropism of dengue virus and its pathogenesis, peripheral blood cells of infected patients were analyzed by flow cytometry. The dengue virus antigen was detected in peripheral CD19+ cells (B cells) in one dengue hemorrhagic fever patient. Two dengue type-2 virus isolates were recovered from this patient using mosquito cell line C6/36 and human hematopoietic cell line K562, and designated VNHCM18-C/02 and VNHCM18-K/02, respectively. VNHCM18-K/02 exhibited strong binding ability and high infectivity to a B-lymphocyte cell line (RPMI8226) but showed poor growth in C6/36 cells, while VNHCM18-C/02 more efficiently and dominantly grew in C6/36 cells but did not efficiently bind to nor infect the B-cell line. Three amino acid differences were detected; one in an envelope protein (E-62) and two in nonstructural proteins. The distinct cell-binding to RPMI8226 was attributed to the difference between the two isolates in envelope protein E-62. Thus, we isolated two dengue type-2 virus variants with different cell-tropisms from the same patient, suggesting possible co-circulation in the patient.
Eisenmesser, Elan Z.; Capodagli, Glenn; Armstrong, Geoffrey S.; Holliday, Michael; Isern, Nancy G.; Zhang, Fengli; Pegan, Scott D.
Crimean-Congo Hemorrhagic fever virus (CCHFV) is one of several lethal viruses that encodes for a viral ovarian tumor domain (vOTU), which serves to cleave and remove multiple proteins involved in cellular signaling such as ubiquitin (Ub) and interferon stimulated gene produce 15 (ISG15). Such manipulation of the host cell machinery serves to downregulate the host response and, therefore, complete characterization of these proteases is important. While several structures of the CCHFV vOTU protease have been solved, both free and bound to Ub and ISG15, few structural differences have been found and little insight has been gained as to the dynamic plasticity of this protease. Therefore, we have used NMR relaxation experiments to probe the dynamics of CCHV vOTU, both alone and in complex with Ub, thereby discovering a highly dynamic protease that exhibits conformational exchange within the same regions found to engage its Ub substrate. These experiments reveal a structural plasticity around the N-terminal regions of CCHV vOTU, which are unique to vOTUs, and provide a rationale for engaging multiple substrates with the same binding site.
Lin, Hualiang; Zhang, Zhentang; Lu, Liang; Li, Xiujun; Liu, Qiyong
This study examined the effect of meteorological factors on the occurrence of hemorrhagic fever with renal syndrome (HFRS) using a generalized additive model with penalized smoothing splines in Jiaonan, China, from 2006 to 2011. The dose-response relationship was first examined, and then the association between daily meteorological variables and HFRS occurrence was investigated according to the dose-response curves. There were two linear segments in the temperature-HFRS relationship curve. When daily temperature was lower than 17 °C, a positive association was found [with excessive risk (ER) for 1 °C increase on the current day being 2.56 %, 95 % confidence interval (CI): 0.36 % to 4.80 %]. An inverse association was found when daily temperature was higher than 17 °C [ER for 1 °C increase on the current day was -12.82 % (95 % CI: -17.51 % to -7.85 %)]. Inverse associations were observed for relative humidity [ER for 1 % increase on lag day 4 was -1.21 % (95 % CI: -1.63 % to -0.79 %)] and rainfall [ER for 1 mm increase on lag day 1 was -2.20 % (95 % CI: -3.56 % to -0.82 %)]. Meteorological factors might be important predictor of HFRS epidemics in Jiaonan County.
Wu, Wei; Guo, Junqiao; An, Shuyi; Guan, Peng; Ren, Yangwu; Xia, Linzi; Zhou, Baosen
Background Cases of hemorrhagic fever with renal syndrome (HFRS) are widely distributed in eastern Asia, especially in China, Russia, and Korea. It is proved to be a difficult task to eliminate HFRS completely because of the diverse animal reservoirs and effects of global warming. Reliable forecasting is useful for the prevention and control of HFRS. Methods Two hybrid models, one composed of nonlinear autoregressive neural network (NARNN) and autoregressive integrated moving average (ARIMA) the other composed of generalized regression neural network (GRNN) and ARIMA were constructed to predict the incidence of HFRS in the future one year. Performances of the two hybrid models were compared with ARIMA model. Results The ARIMA, ARIMA-NARNN ARIMA-GRNN model fitted and predicted the seasonal fluctuation well. Among the three models, the mean square error (MSE), mean absolute error (MAE) and mean absolute percentage error (MAPE) of ARIMA-NARNN hybrid model was the lowest both in modeling stage and forecasting stage. As for the ARIMA-GRNN hybrid model, the MSE, MAE and MAPE of modeling performance and the MSE and MAE of forecasting performance were less than the ARIMA model, but the MAPE of forecasting performance did not improve. Conclusion Developing and applying the ARIMA-NARNN hybrid model is an effective method to make us better understand the epidemic characteristics of HFRS and could be helpful to the prevention and control of HFRS. PMID:26270814
Wu, Wei; Guo, Junqiao; An, Shuyi; Guan, Peng; Ren, Yangwu; Xia, Linzi; Zhou, Baosen
Cases of hemorrhagic fever with renal syndrome (HFRS) are widely distributed in eastern Asia, especially in China, Russia, and Korea. It is proved to be a difficult task to eliminate HFRS completely because of the diverse animal reservoirs and effects of global warming. Reliable forecasting is useful for the prevention and control of HFRS. Two hybrid models, one composed of nonlinear autoregressive neural network (NARNN) and autoregressive integrated moving average (ARIMA) the other composed of generalized regression neural network (GRNN) and ARIMA were constructed to predict the incidence of HFRS in the future one year. Performances of the two hybrid models were compared with ARIMA model. The ARIMA, ARIMA-NARNN ARIMA-GRNN model fitted and predicted the seasonal fluctuation well. Among the three models, the mean square error (MSE), mean absolute error (MAE) and mean absolute percentage error (MAPE) of ARIMA-NARNN hybrid model was the lowest both in modeling stage and forecasting stage. As for the ARIMA-GRNN hybrid model, the MSE, MAE and MAPE of modeling performance and the MSE and MAE of forecasting performance were less than the ARIMA model, but the MAPE of forecasting performance did not improve. Developing and applying the ARIMA-NARNN hybrid model is an effective method to make us better understand the epidemic characteristics of HFRS and could be helpful to the prevention and control of HFRS.
Jezek, Z; Szczeniowski, M Y; Muyembe-Tamfum, J J; McCormick, J B; Heymann, D L
Surveillance for Ebola hemorrhagic fever was conducted in the Democratic Republic of the Congo from 1981 to 1985 to estimate the incidence of human infection. Persons who met the criteria of one of three different case definitions were clinically evaluated, and blood was obtained for antibody confirmation by IFA. Contacts of each case and 4 age- and sex-matched controls were also clinically examined and tested for immunofluorescent antibody. Twenty-one cases of Ebola infection (persons with an antibody titer of > or = 1:64, or lower if they fit the clinical case definition) were identified, with a maximum 1-year incidence of 9 and a case fatality rate of 43%. Cases occurred throughout the year, but most (48%) occurred early in the rainy season. Fifteen percent of contacts had antibody titers > or =1:64 to Ebola virus, compared with 1% of controls (P < .0001). Results suggest that Ebola virus periodically emerges from nature to infect humans, that person-to-person transmission is relatively limited, and that amplification to large epidemics is unusual.
Gergova, Ivanka; Kamarinchev, Bozhin
The Balkans is an endemic region for Crimean-Congo hemorrhagic fever (CCHF), caused by the CCHF virus (CCHFV). Several Bulgarian regions comprised of smaller locations are categorized either as endemic or non-endemic for CCHF. However, little is known about the dynamics that underlie the development of endemicity within the locations throughout the years. Seven locations categorized as endemic in one central Bulgarian region (Stara Zagora) were compared to seven non-endemic areas. During the period 2006-12, a total of 1775 blood samples from cattle, were tested for anti-CCHFV antibodies using an indirect immunofluorescence antibody assay. Also, the infestation of 617 mature ticks for CCHFV was studied using a combination of an immunofluorescence haemocytes assay and molecular-virological methods. Anti-CCHFV antibodies were established in 7.89% (140/1775) of the sera. The average CCHFV-infestation in the ticks was 1.46% (9/617). CCHFV was detected in three tick species: H.m. marginatum (3.73%, 6/161), being the main vector of the infection; R. sanguineus (1.63%, 2/123); and I. ricinus (1.96%, 1/51). The data for the endemic and non-endemic locations did not reveal significant differences for the prevalence of CCHFV. Mosaic dispersion of the virus was determined in the studied region and the results did not vary significantly throughout the investigated years.
Xia, Han; Beck, Andrew S.; Gargili, Aysen; Forrester, Naomi; Barrett, Alan D. T.; Bente, Dennis A.
The trade-off hypothesis, the current paradigm of arbovirus evolution, proposes that cycling between vertebrate and invertebrate hosts presents significant constraints on genetic change of arboviruses. Studying these constraints in mosquito-borne viruses has led to a new understanding of epizootics. The trade-off hypothesis is assumed to be applicable to tick-borne viruses too, although studies are lacking. Tick-borne Crimean-Congo hemorrhagic fever virus (CCHFV), a member of the family Bunyaviridae, is a major cause of severe human disease worldwide and shows an extraordinary amount of genetic diversity compared to other arboviruses, which has been linked to increased virulence and emergence in new environments. Using a transmission model for CCHFV, utilizing the main vector tick species and mice plus next generation sequencing, we detected a substantial number of consensus-level mutations in CCHFV recovered from ticks after only a single transstadial transmission, whereas none were detected in CCHFV obtained from the mammalian host. Furthermore, greater viral intra-host diversity was detected in the tick compared to the vertebrate host. Long-term association of CCHFV with its tick host for 1 year demonstrated mutations in the viral genome become fixed over time. These findings suggest that the trade-off hypothesis may not be accurate for all arboviruses. PMID:27775001
Ghiasi, S. M.; Salmanian, A. H.; Chinikar, S.; Zakeri, S.
While Crimean-Congo hemorrhagic fever (CCHF) has a high mortality rate in humans, the associated virus (CCHFV) does not induce clinical symptoms in animals, but animals play an important role in disease transmission to humans. Our aim in this study was to examine the immunogenicity of the CCHFV glycoprotein when expressed in the root and leaf of transgenic plants via hairy roots and stable transformation of tobacco plants, respectively. After confirmatory analyses of transgenic plant lines and quantification of the expressed glycoprotein, mice were either fed with the transgenic leaves or roots, fed the transgenic plant material and injected subcutaneously with the plant-made CCHFV glycoprotein (fed/boosted), vaccinated with an attenuated CCHF vaccine (positive control), or received no treatment (negative control). All immunized groups had a consistent rise in anti-glycoprotein IgG and IgA antibodies in their serum and feces, respectively. The mice in the fed/boosted group showed a significant rise in specific IgG antibodies after a single boost. Our results imply that oral immunization of animals with edible materials from transgenic plants is feasible, and further assessments are under way. In addition, while the study of CCHF is challenging, our protocol should be further used to study CCHFV infection in the knockout mouse model and virus neutralization assays in biosafety level 4 laboratories. PMID:22012978
Tahmasebi, F; Ghiasi, S M; Mostafavi, E; Moradi, M; Piazak, N; Mozafari, A; Haeri, A; Fooks, A R; Chinikar, S
Crimean-Congo hemorrhagic fever (CCHF) virus is a tick-borne member of the genus Nairovirus, family Bunyaviridae. CCHFV has been isolated from at least 31 different tick species. The virus is transmitted through the bite of an infected tick, or by direct contact with CCHFV-infected patients or the products of infected livestock. This study was undertaken to study the genetic relationship and distribution of CCHFV in the tick population of Hamadan province of Iran. In this study, RT-PCR has been used for detection of the CCHFV genome. This genome was detected in 19.2% of the ticks collected from livestock of different regions of the Hamadan province in western Iran. The infected species belonged to Hyalomma detritum, H. anatolicum, Rhipicephalus sanguineus and Argas reflexus. With one exception, genetic analysis of the virus genome isolates showed high sequence identity to each other. Even though they clustered in the same group with the strain circulating in Iran, they had a closer relationship to the Matin strain. Vector control programs should be applied for reducing population density of potential tick vectors in this province. Further surveys are indicated in this region to provide a better view of the distribution and epidemiology of the virus.
Panculescu-Gatej, Raluca Ioana; Sirbu, Anca; Dinu, Sorin; Waldstrom, Maria; Heyman, Paul; Murariu, Dimitru; Petrescu, Angela; Szmal, Camelia; Oprisan, Gabriela; Lundkvist, Ake; Ceianu, Cornelia S
Hemorrhagic fever with renal syndrome (HFRS) has been confirmed by serological methods during recent years in Romania. In the present study, focus-reduction neutralization tests (FRNT) confirmed Dobrava hantavirus (DOBV) as the causative agent in some HFRS cases, but could not distinguish between DOBV and Saaremaa virus (SAAV) infections in other cases. DOBV was detected by a DOBV-specific TaqMan assay in sera of nine patients out of 22 tested. Partial sequences of the M genomic segment of DOBV were obtained from sera of three patients and revealed the circulation of two DOBV lineages in Romania. Investigation of rodents trapped in Romania found three DOBV-positive Apodemus flavicollis out of 83 rodents tested. Two different DOBV lineages were also detected in A. flavicollis as determined from partial sequences of the M and S genomic segments. Sequences of DOBV in A. flavicollis were either identical or closely related to the sequences obtained from the HFRS patients. The DOBV strains circulating in Romania clustered in two monophyletic groups, together with strains from Slovenia and the north of Greece. This is the first evidence for the circulation of DOBV in wild rodents and for a DOBV etiology of HFRS in Romania.
Miasnikov, Iu A; Apekina, N S; Zuevskiĭ, A P; Khitrin, A V; Bernshteĭn, A D
Lungs of 3159 animals of the forest complex from 90 areas of 30 administrative districts of Tyumen Province were examined by enzyme immunoassays for antigen of hemorrhagic fever with renal syndrome (HFRS) during 5 years, 1985-1989. The antigen of HERS virus was detected in the lungs of mammals of 8 species: Clethrionomys glareolus and Cl. rutilus, Siberian and Arctic lemmings (first findings in the world), M. oeconomus, field mouse, common and pygmy shrews. Nearly all the findings refer to the subzone of southern taiga and adjacent areas of subtaiga subzone where Cl. glareolus is the main reservoir of infection and Cl. rutilus an additional one. In the tundra zone, Siberian lemming is the main reservoir of infection and Arctic lemming an additional one. No natural foci of HFRS were found in forest steppe and forest tundra zones. In the subzone of the northern and middle taiga, the antigen was found only on 4 occasions: 3 in common shrews and one in Cl. glareolus (near the town of Khanty-Mansisk). An irregular annual infection rate with HFRS virus was observed in Cl. glareolus as well as its decline from spring to autumn. It cannot be ruled out that lemmings are carriers of a distinct HFRS virus serotype.
Chen, Yunru; Yang, Xueliang; Ye, Feng; Chen, Tianyan; Liu, Zhengwen; Zhao, Yingren
This retrospective study is aimed to investigate the clinical features of the patients with history of incomplete vaccination against hemorrhagic fever with renal syndrome (HFRS). Data of 140 cases of hospitalized patients with HFRS were collected. The patients were divided into incomplete vaccinated group (n = 10) and unvaccinated group (n = 130) according to vaccination status. Demographic, clinical, and laboratory characteristics of the two groups' patients were compared through t test, Pearson χ(2) test, and Mann-Whitney test. In comparison with the unvaccinated group, the incidence rate of vomiting and hypotensive-shock, the white blood cell (WBC) and platelet count, the level of blood urea nitrogen and albumin, total number of dialysis and hospitalization cost of patients in the incomplete vaccinated group have statistically significant differences. HFRS disease may still occur in individuals with a history of HFRS incomplete vaccination although the symptoms may be mild. Effective vaccination against HFRS needs sufficient doses and booster shot of the vaccine. © 2015 Wiley Periodicals, Inc.
Ghiasi, S M; Salmanian, A H; Chinikar, S; Zakeri, S
While Crimean-Congo hemorrhagic fever (CCHF) has a high mortality rate in humans, the associated virus (CCHFV) does not induce clinical symptoms in animals, but animals play an important role in disease transmission to humans. Our aim in this study was to examine the immunogenicity of the CCHFV glycoprotein when expressed in the root and leaf of transgenic plants via hairy roots and stable transformation of tobacco plants, respectively. After confirmatory analyses of transgenic plant lines and quantification of the expressed glycoprotein, mice were either fed with the transgenic leaves or roots, fed the transgenic plant material and injected subcutaneously with the plant-made CCHFV glycoprotein (fed/boosted), vaccinated with an attenuated CCHF vaccine (positive control), or received no treatment (negative control). All immunized groups had a consistent rise in anti-glycoprotein IgG and IgA antibodies in their serum and feces, respectively. The mice in the fed/boosted group showed a significant rise in specific IgG antibodies after a single boost. Our results imply that oral immunization of animals with edible materials from transgenic plants is feasible, and further assessments are under way. In addition, while the study of CCHF is challenging, our protocol should be further used to study CCHFV infection in the knockout mouse model and virus neutralization assays in biosafety level 4 laboratories.
Kim, Won-Keun; Kim, Jeong-Ah; Song, Dong Hyun; Lee, Daesang; Kim, Yong Chul; Lee, Sook-Young; Lee, Seung-Ho; No, Jin Sun; Kim, Ji Hye; Kho, Jeong Hoon; Gu, Se Hun; Jeong, Seong Tae; Wiley, Michael; Kim, Heung-Chul; Klein, Terry A.; Palacios, Gustavo; Song, Jin-Won
Emerging and re-emerging infectious diseases caused by RNA viruses pose a critical public health threat. Next generation sequencing (NGS) is a powerful technology to define genomic sequences of the viruses. Of particular interest is the use of whole genome sequencing (WGS) to perform phylogeographic analysis, that allows the detection and tracking of the emergence of viral infections. Hantaviruses, Bunyaviridae, cause hemorrhagic fever with renal syndrome (HFRS) and hantavirus pulmonary syndrome (HPS) in humans. We propose to use WGS for the phylogeographic analysis of human hantavirus infections. A novel multiplex PCR-based NGS was developed to gather whole genome sequences of Hantaan virus (HTNV) from HFRS patients and rodent hosts in endemic areas. The obtained genomes were described for the spatial and temporal links between cases and their sources. Phylogenetic analyses demonstrated geographic clustering of HTNV strains from clinical specimens with the HTNV strains circulating in rodents, suggesting the most likely site and time of infection. Recombination analysis demonstrated a genome organization compatible with recombination of the HTNV S segment. The multiplex PCR-based NGS is useful and robust to acquire viral genomic sequences and may provide important ways to define the phylogeographical association and molecular evolution of hantaviruses. PMID:27221218
Bai, Yuntao; Xu, Zhiguang; Lu, Bo; Sun, Qinghua; Tang, Wenge; Liu, Xiaobo; Yang, Weizhong; Xu, Xinyi; Liu, Qiyong
China has the highest global incidence of hemorrhagic fever with renal syndrome (HFRS), constituting 90% of the cases in the world. Chongqing, located in the Three Gorges Reservoir Region, has been experiencing differences in the occurrence of HFRS from 1997 to 2008. The current study was designed to explore the effects of climate and rodent factors on the transmission of HFRS in Chongqing. Data on monthly HFRS cases, rodent strains, and climatic factors were collected from 1997 to 2008. Spatio-temporal analysis indicated that most HFRS cases were clustered in central Chongqing and that the incidence of HFRS decreased from 1997 to 2008. Poisson regression models showed that temperature (with lagged months of 0 and 5) and rainfall (with 2 lagged months) were key climatic factors contributing to the transmission of HFRS. A zero-inflated negative binomial model revealed that rodent density was also significantly associated with the occurrence of HFRS in the Changshou district. The monthly trend in HFRS incidence was positively associated with rodent density and rainfall and negatively associated with temperature. Possible mechanisms are proposed through which construction of the dam influenced the incidence of HFRS in Chongqing. The findings of this study may contribute to the development of early warning systems for the control and prevention of HFRS in the Three Gorges Reservoir Region.
Mills, J N; Calderón, G E; Ellis, B A; McKee, K T; Ksiazek, T G; Oro, J G; Peters, C J; Childs, J E; Maiztegui, J I
In conjunction with field trials for a vaccine against Argentine Hemorrhagic Fever (AHF), small mammals were trapped during a 28-month period (1 November 1987 to 13 March 1990) in 3 epidemiologically defined areas of the central Argentine pampas: northern and central Buenos Aires provinces were included in the AHF "historic" area, where the disease was common 15-20 years ago, but case rates are currently low; southern Santa Fe province is the current high-incidence area for AHF; the nonendemic area was represented by two localities 60-90 km beyond the northernmost extension of human disease. Animals were live-trapped for 3 days per month in permanent "mark-recapture" grids in each of the 3 areas. Samples of blood, sera, and oral swabs were taken from these animals before they were marked and released at the site of capture. In addition, "removal" traplines provided animals from 16 localities in these 3 areas which were sacrificed to obtain samples of organs in addition to the aforementioned samples. Samples were tested for the presence of Junin virus (JV) antigen by enzyme immunoassay (ELISA). In this assay, a pool of 13 mouse anti-JV glycoprotein and nucleocapsid monoclonal antibodies adsorbed to the surface of microtiter plates was used to capture JV antigen in sample suspensions. A polyclonal rabbit anti-JV antiserum was added as a detector antibody, and an anti-rabbit antibody conjugated to horseradish peroxidase applied with substrate to complete the sandwich.(ABSTRACT TRUNCATED AT 250 WORDS)
Mathes, Robert W; Page, William F; Crawford, Harriet M; McBean, A Marshall; Miller, Richard N
Health status was sought for approximately 1600 Korean War veterans who contracted hemorrhagic fever with renal syndrome (HFRS) during deployment to Korea between 1951 and 1953. To determine whether long-term sequelae were present for these individuals, mortality and morbidity data were collected from the Department of Veterans Affairs, the Centers for Medicare and Medicaid Services, the Social Security Administration, and the National Death Index records. Control subjects were selected from military units in Korea with no reported cases of HFRS. Those with HFRS had a slightly higher mortality rate (33.2%) than did noninfected individuals (32.0%), but this difference was not statistically significant. Non-Caucasian cases had significantly higher morbidity rates than did non-Caucasian controls only for transient ischemic attacks (4.8% versus 0%) and diabetes mellitus (19.3% versus 8.1%). In conclusion, HFRS did not increase mortality rates in this cohort but might have had an impact on selected morbidity outcomes.
Algaar, Fairoz; Eltzov, Evgeni; Vdovenko, Marina M; Sakharov, Ivan Yu; Fajs, Luka; Weidmann, Manfred; Mirazimi, Ali; Marks, Robert S
Crimean-Congo hemorrhagic fever (CCHF) is a severe viral disease with high fatality rate. CCHF virus is endemic in parts of Africa, Asia, the Middle East, and southeastern Europe. Rapid diagnostics of CCHF is vital for appropriate clinical management and prevention of secondary spread from human-to-human. Currently, diagnostics relies on real-time RT-PCR and antibody or antigen detection using ELISA. These methods require trained personnel and expensive equipment and are not appropriate for point-of-care (POC) diagnostics. Furthermore, there are no POC assays available for CCHF. We developed a fiber-optic biosensor for the detection of CCHF IgG antibodies. In order to improve sensitivity, we optimized both the bioreceptor immobilization protocol and the chemiluminescence substrate formulation. The resulting protocol showed a 100-fold greater sensitivity for detection of CCHF antibodies. Finally, we evaluated the fiber-optic biosensor with two CCHF patient sera. We showed that the fiber-optic biosensor is 10-times more sensitive than colorimetric ELISA and is able to detect both patients with high and low levels of IgG antibodies. We believe that the fiber-optic biosensor is a suitable alternative to ELISA as it is much more sensitive and makes it possible to detect a small amount of antibodies at an early stage of infection and can be integrated as a point-of-care diagnostic system of CCHF.
Zivcec, Marko; Metcalfe, Maureen G.; Albariño, César G.; Guerrero, Lisa W.; Pegan, Scott D.; Spiropoulou, Christina F.; Bergeron, Éric
Crimean-Congo hemorrhagic fever (CCHF) is an often lethal, acute inflammatory illness that affects a large geographic area. The disease is caused by infection with CCHF virus (CCHFV), a nairovirus from the Bunyaviridae family. Basic research on CCHFV has been severely hampered by biosafety requirements and lack of available strains and molecular tools. We report the development of a CCHF transcription- and entry-competent virus-like particle (tecVLP) system that can be used to study cell entry and viral transcription/replication over a broad dynamic range (~4 orders of magnitude). The tecVLPs are morphologically similar to authentic CCHFV. Incubation of immortalized and primary human cells with tecVLPs results in a strong reporter signal that is sensitive to treatment with neutralizing monoclonal antibodies and by small molecule inhibitors of CCHFV. We used glycoproteins and minigenomes from divergent CCHFV strains to generate tecVLPs, and in doing so, we identified a monoclonal antibody that can prevent cell entry of tecVLPs containing glycoproteins from 3 pathogenic CCHFV strains. In addition, our data suggest that different glycoprotein moieties confer different cellular entry efficiencies, and that glycoproteins from the commonly used strain IbAr10200 have up to 100-fold lower ability to enter primary human cells compared to glycoproteins from pathogenic CCHFV strains. PMID:26625182
Gurbuz, Yunus; Ozturk, Baris; Tutuncu, Emin Ediz; Sencan, Irfan; Cicek Senturk, Gonul; Altay, Fatma Aybala
Background: Crimean-Congo hemorrhagic fever (CCHF) is a widespread disease in Turkey, and was responsible for many deaths in endemic regions during the last decade. The pathogenesis of the disease is not fully understood yet. Objectives: In this study we aimed to determine the levels of tissue plasminogen activator (tPA) and Plasminogen activator inhibitor-1 (PAI-1) as predictors of prognosis in CCHF. Patients and Methods: Patients who were diagnosed by the polymerase chain reaction (PCR) and IgM positivity in the reference laboratory were included in this study. Tissue Plasminogen activator and PAI-1 levels were measured by the enzyme linked immunosorbent assay (ELISA) using a commercial kit (human t-PA ELISA and human PAL-1 ELISA; BioVendor research and diagnostic products, BioVendor-Laboratorni medicina a.s., Brno, Czech Republic). Results: A total of 46 patients participated in this study. The significant differences between recovering patients and the patients who died, regarding Aspartate aminotransferase (AST), Creatine Phosphokinase (CPK), Lactate Dehydrogenase (LDH), Prothrombin Time (PT), activated Partial Thromboplastin time (aPTT), and thrombocyte and fibrinogen levels, were consistent with many clinical studies in the literature. The fatal cases were found to have higher tPA and PAI-1 levels in contrast to the patients who completely recovered. Conclusions: We think that these findings may help the progress of understanding of CCHF pathogenesis. PMID:26587219
Pagliari, Carla; Simões Quaresma, Juarez Antônio; Kanashiro-Galo, Luciane; de Carvalho, Leda Viegas; Vitoria, Webster Oliveira; da Silva, Wellington Luiz Ferreira; Penny, Ricardo; Vasconcelos, Barbara Cristina Baldez; da Costa Vasconcelos, Pedro Fernando; Duarte, Maria Irma Seixas
Acute kidney injury is an unusual complication during dengue infection. The objective of this study was to better identify the characteristics of glomerular changes focusing on in situ immune cells and cytokines. An immunohistochemical assay was performed on 20 kidney specimens from fatal human cases of dengue hemorrhagic fever (DHF). It was observed a lymphomononuclear infiltrate, neutrophils and nuclear fragmentation in the glomeruli, hydropic degeneration, nuclear retraction, eosinophilic tubules and intense acute congestion. Sickle erythrocytes were frequent in glomeruli and inflammatory infiltrate. The glomeruli presented endothelial swelling and mesangial proliferation. Lymphocytes CD4+ predominated over CD8+ T cells, B cells and natural killer cells. There were also an expressive number of macrophagic CD68+ cells. S100, Foxp3 and CD123 cells were not identified. Cells expressing IL17 and IL18+ cytokines predominated in the renal tissues, while IL4, IL6, IL10, IL13, TNF-alpha and IFN-gamma were rarely visualized. The high number of cells expressing IL17 and IL18+ could reflect the acute inflammatory response and possibly contribute to the local lesion. CD8+ T cells could play a role in the cytotoxic response. DHF is a multifactorial disease of capillary leakage associated with a "Tsunami of cytokines expression". The large numbers of cells expressing IL17 seems to play a role favoring the increased permeability.
Izadi, Shahrokh; Salehi, Masoud; Holakouie-Naieni, Kourosh; Chinikar, Sadegh
To determine the infectivity of Crimean-Congo hemorrhagic fever (CCHF) virus via routine contacts between serologically confirmed cases and their close relatives from May 2005 up to March 2006, 79 serum samples of 57 close relatives of 12 newly diagnosed serologically confirmed CCHF cases in the Sistan-va-Baluchestan province of Iran were tested for IgG and IgM antibodies against CCHF virus using the enzyme-linked immunosorbent assay technique. Nine levels of contacts were considered: percutaneous contact with the patient's blood, cutaneous contact with the patient's blood, cutaneous contact with non-sanguineous body fluids, cutaneous contact with the patient's skin, sexual contact, eating at the same table, being a roommate of the patient, being a housemate of the patient, and living with the patient in the same building. Only one out of 57 relatives was positive for anti-CCHF IgG (1.8%, 95% confidence interval 0.0 to 9.8%). Thus, the infectivity of the virus via usual routine contacts with patients appears to be low.
Shepherd, A J; Leman, P A; Swanepoel, R
Eleven species of small African wild mammals, laboratory rabbits, guinea pigs, and Syrian hamsters were infected with Crimean-Congo hemorrhagic fever (CCHF) virus. Low-titered viremia followed by development of antibody was observed in scrub hares (Lepus saxatilis), Cape ground squirrels (Xerus inauris), red veld rats (Aethomys chrysophilus), white tailed rats (Mystromys albicaudatus), bushveld gerbils (Tatera leucogaster), striped mice (Rhabdomys pumilio), and guinea pigs. The maximum viremic titer in 4 scrub hares was 10(1.7-4.2) 50% mouse lethal doses/ml. Viremia was detected in 1/17 infected laboratory rabbits. Antibody response was only detected in South African hedgehogs (Atelerix frontalis), highveld gerbils (T. brantsii), Namaqua gerbils (Desmodillus auricularis), 2 species of multimammate mouse (Mastomys natalensis and M. coucha), and Syrian hamsters. The results of the study indicate that a proportion of infected scrub hares develop CCHF viremia of an intensity shown in the Soviet Union to be sufficient for infection of feeding immature ixodid ticks, but that South African hedgehogs and wild rodents are unlikely to be of importance as maintenance hosts of the virus in southern Africa.
Enria, Delia A; Ambrosio, Ana M; Briggiler, Ana M; Feuillade, María Rosa; Crivelli, Eleonora
A clinical study in 946 human volunteers was done to compare Candid #1 vaccine manufactured in Argentina with the vaccine produced in USA that had been previously used. The efficacy was evaluated using immunogenicity measured by the detection of neutralizing antibodies as a subrogate marker. Safety was evaluated comparing the rate of adverse events. Both vaccines showed a comparable rate of seroconversion, slightly higher than the efficacy estimated from previous studies (95.5%). There were no severe adverse events related to the vaccines. The general events considered related to the vaccines were not clinically relevant and disappeared either spontaneously or with symptomatic treatment. Similar rates of adverse events (29.9% for the Argentine vaccine and 35.0% for the USA vaccine) were found for both vaccines. These included: headache, weakness, myalgias, mild low blood cell (< 4,000/mm(3)) and platelet (< 150,000/mm(3)) counts, nausea and/or vomiting, fever, retroocular pain, dizziness, microhematuria, low backache and exantema. These results indicate that the vaccine Candid#1 manufactured in Argentina is equivalent to the manufactured in USA. These results allowed the National Institute of Human Viral Diseases (INEVH) to register the vaccine produced locally under the National Regulatory Authority (ANMAT).
Sam, Sing-Sin; Omar, Sharifah Faridah Syed; Teoh, Boon-Teong; Abd-Jamil, Juraina; AbuBakar, Sazaly
Background Dengue is a mosquito-borne viral disease endemic in many countries in the tropics and sub-tropics. The disease affects mainly children, but in recent years it is becoming more of an adult disease. Malaysia experienced a large dengue outbreak in 2006 to 2007, involving mostly adults, with a high number of deaths. Methodology/Principal Findings We undertook a retrospective study to examine dengue death cases in our hospital from June 2006 to October 2007 with a view to determine if there have been changes in the presentation of severe to fatal dengue. Nine of ten fatal cases involved adult females with a median age of 32 years. All had secondary dengue infection. The mean duration of illness prior to hospitalization was 4.7 days and deaths occurred at an average of 2.4 days post-admission. Gastrointestinal pain, vomiting, diarrhea, intravascular leakages and bleeding occurred in the majority of cases. DSS complicated with severe bleeding, multi-organ failure and coagulopathy were the primary causes of deaths. Seven patients presented with thrombocytopenia and hypoalbuminemia, five of which had hemoconcentration and increased ALT and AST indicative of liver damage. Co-morbidities particularly diabetes mellitus was common in our cohort. Prominent unusual presentations included acute renal failure, acute respiratory distress syndrome, myocarditis with pericarditis, and hemorrhages over the brain and heart. Conclusions In our cohort, dengue fatalities are seen primarily in adult females with secondary dengue infection. The majority of the patients presented with common clinical and laboratory warning signs of severe dengue. Underlying co-morbidities may contribute to the rapid clinical deterioration in severe dengue. The uncommon presentations of dengue are likely a reflection of the changing demographics where adults are now more likely to contract dengue in dengue endemic regions. PMID:23658849
Sam, Sing-Sin; Omar, Sharifah Faridah Syed; Teoh, Boon-Teong; Abd-Jamil, Juraina; AbuBakar, Sazaly
Dengue is a mosquito-borne viral disease endemic in many countries in the tropics and sub-tropics. The disease affects mainly children, but in recent years it is becoming more of an adult disease. Malaysia experienced a large dengue outbreak in 2006 to 2007, involving mostly adults, with a high number of deaths. We undertook a retrospective study to examine dengue death cases in our hospital from June 2006 to October 2007 with a view to determine if there have been changes in the presentation of severe to fatal dengue. Nine of ten fatal cases involved adult females with a median age of 32 years. All had secondary dengue infection. The mean duration of illness prior to hospitalization was 4.7 days and deaths occurred at an average of 2.4 days post-admission. Gastrointestinal pain, vomiting, diarrhea, intravascular leakages and bleeding occurred in the majority of cases. DSS complicated with severe bleeding, multi-organ failure and coagulopathy were the primary causes of deaths. Seven patients presented with thrombocytopenia and hypoalbuminemia, five of which had hemoconcentration and increased ALT and AST indicative of liver damage. Co-morbidities particularly diabetes mellitus was common in our cohort. Prominent unusual presentations included acute renal failure, acute respiratory distress syndrome, myocarditis with pericarditis, and hemorrhages over the brain and heart. In our cohort, dengue fatalities are seen primarily in adult females with secondary dengue infection. The majority of the patients presented with common clinical and laboratory warning signs of severe dengue. Underlying co-morbidities may contribute to the rapid clinical deterioration in severe dengue. The uncommon presentations of dengue are likely a reflection of the changing demographics where adults are now more likely to contract dengue in dengue endemic regions.
Branco, Luis M; Grove, Jessica N; Geske, Frederick J; Boisen, Matt L; Muncy, Ivana J; Magliato, Susan A; Henderson, Lee A; Schoepp, Randal J; Cashman, Kathleen A; Hensley, Lisa E; Garry, Robert F
demonstrated that LASV VLP appeared structurally similar to native virions, with pleiomorphic distribution in size and shape. LASV VLP that displayed GPC or GPC+NP were immunogenic in mice, and generated a significant IgG response to individual viral proteins over the course of three immunizations, in the absence of adjuvants. Furthermore, sera from convalescent Lassa fever patients recognized VLP in ELISA format, thus affirming the presence of native epitopes displayed by the recombinant pseudoparticles. These results established that modular LASV VLP can be generated displaying high levels of immunogenic viral proteins, and that small laboratory scale mammalian expression systems are capable of producing multi-milligram quantities of pseudoparticles. These VLP are structurally and morphologically similar to native LASV virions, but lack replicative functions, and thus can be safely generated in low biosafety level settings. LASV VLP were immunogenic in mice in the absence of adjuvants, with mature IgG responses developing within a few weeks after the first immunization. These studies highlight the relevance of a VLP platform for designing an optimal vaccine candidate against Lassa hemorrhagic fever, and warrant further investigation in lethal challenge animal models to establish their protective potential.
Muji, Skender; Robaj, Avni; Ahmeti, Salih; Jakupi, Xhevat; Emmerich, Petra; Krüger, Andreas
Despite being a small country, Kosovo represents one of the few foci of Crimean-Congo hemorrhagic fever (CCHF) in Europe. The distribution of Kosovar tick vectors and the evolution of CCHF virus in ticks are both as yet unknown. A better description of the extent and the genetic diversity of CCHFV in ticks from endemic settings is essential, in order to be controlled. We investigated the 2012 distribution of Kosovar ticks alongside the prevalence and the phylogeography of tick-derived CCHFV. Hyalomma marginatum dominated in the endemic municipalities with 90.2% versus 24.3% in the non-endemic regions. Of 1,102 tested ticks, 40 (3.6%) were CCHFV-positive, belonging to H. marginatum (29), Rhipicephalus bursa (10), and Ixodes ricinus (1). The virus strains clustered with clade V and VI related sequences. They fell into two lineages: Kosovo I and II. Kosovo I comprised strains recovered exclusively from R. bursa ticks and was closely related to AP92 prototype strain. Kosovo II clustered into Kosovo IIa, including human-derived strains, and IIb including only strains detected in H. marginatum and I. ricinus. Our phylogeographic reconstruction suggests two temporally distinct CCHFV introductions: the most probable location of the most recent common ancestor of Kosovo I lineage was in Greece (63 years ago) and that of lineages IIa-b in Turkey (35 years ago). After each CCHFV introduction into Kosovo, subsequent lineage expansions suggest periods of in situ evolution. The study provides the first insight into the genetic variability and the origin of CCHFV in ticks from Kosovo. Our findings indicate the spreading of CCHFV to non-endemic areas, which underlines the importance of further studies in order to monitor and predict future CCHF outbreaks in Kosovo. The AP92-like strains appear to be more widespread than previously thought and may provide a promising target for experimental studies due to their assumed low pathogenicity. PMID:25255381
Liu, Dongliang; Li, Yang; Zhao, Jing; Deng, Fei; Duan, Xiaomei; Kou, Chun; Wu, Ting; Li, Yijie; Wang, Yongxing; Ma, Ji; Yang, Jianhua; Hu, Zhihong; Zhang, Fuchun; Zhang, Yujiang; Sun, Surong
Crimean-Congo hemorrhagic fever (CCHF), a severe viral disease known to have occurred in over 30 countries and distinct regions, is caused by the tick-borne CCHF virus (CCHFV). Nucleocapsid protein (NP), which is encoded by the S gene, is the primary antigen detectable in infected cells. The goal of the present study was to map the minimal motifs of B-cell epitopes (BCEs) on NP. Five precise BCEs (E1, 247FDEAKK252; E2a, 254VEAL257; E2b, 258NGYLNKH264; E3, 267EVDKA271; and E4, 274DSMITN279) identified through the use of rabbit antiserum, and one BCE (E5, 258NGYL261) recognized using a mouse monoclonal antibody, were confirmed to be within the central region of NP and were partially represented among the predicted epitopes. Notably, the five BCEs identified using the rabbit sera were able to react with positive serum mixtures from five sheep which had been infected naturally with CCHFV. The multiple sequence alignment (MSA) revealed high conservation of the identified BCEs among ten CCHFV strains from different areas. Interestingly, the identified BCEs with only one residue variation can apparently be recognized by the positive sera of sheep naturally infected with CCHFV. Computer-generated three-dimensional structural models indicated that all the antigenic motifs are located on the surface of the NP stalk domain. This report represents the first identification and mapping of the minimal BCEs of CCHFV-NP along with an analysis of their primary and structural properties. Our identification of the minimal linear BCEs of CCHFV-NP may provide fundamental data for developing rapid diagnostic reagents and illuminating the pathogenic mechanism of CCHFV. PMID:25365026
Sherifi, Kurtesh; Cadar, Daniel; Muji, Skender; Robaj, Avni; Ahmeti, Salih; Jakupi, Xhevat; Emmerich, Petra; Krüger, Andreas
Despite being a small country, Kosovo represents one of the few foci of Crimean-Congo hemorrhagic fever (CCHF) in Europe. The distribution of Kosovar tick vectors and the evolution of CCHF virus in ticks are both as yet unknown. A better description of the extent and the genetic diversity of CCHFV in ticks from endemic settings is essential, in order to be controlled. We investigated the 2012 distribution of Kosovar ticks alongside the prevalence and the phylogeography of tick-derived CCHFV. Hyalomma marginatum dominated in the endemic municipalities with 90.2% versus 24.3% in the non-endemic regions. Of 1,102 tested ticks, 40 (3.6%) were CCHFV-positive, belonging to H. marginatum (29), Rhipicephalus bursa (10), and Ixodes ricinus (1). The virus strains clustered with clade V and VI related sequences. They fell into two lineages: Kosovo I and II. Kosovo I comprised strains recovered exclusively from R. bursa ticks and was closely related to AP92 prototype strain. Kosovo II clustered into Kosovo IIa, including human-derived strains, and IIb including only strains detected in H. marginatum and I. ricinus. Our phylogeographic reconstruction suggests two temporally distinct CCHFV introductions: the most probable location of the most recent common ancestor of Kosovo I lineage was in Greece (63 years ago) and that of lineages IIa-b in Turkey (35 years ago). After each CCHFV introduction into Kosovo, subsequent lineage expansions suggest periods of in situ evolution. The study provides the first insight into the genetic variability and the origin of CCHFV in ticks from Kosovo. Our findings indicate the spreading of CCHFV to non-endemic areas, which underlines the importance of further studies in order to monitor and predict future CCHF outbreaks in Kosovo. The AP92-like strains appear to be more widespread than previously thought and may provide a promising target for experimental studies due to their assumed low pathogenicity.
Bakir, Mehmet; Engin, Aynur; Kuskucu, Mert Ahmet; Bakir, Sevtap; Gündag, Omür; Midilli, Kenan
Crimean-Congo hemorrhagic fever (CCHF) is a viral infection. Circulating plasma cell-free DNA (pcf-DNA) is a novel marker indicating cellular damage. So far, the role of pcf-DNA did not investigate in CCHF patients. In the current study, pcf-DNA levels were investigated in CCHF patients with different clinical severity grades to explore the relationship between circulating pcf-DNA level, virus load, and disease severity. Seventy-two patients were categorized as mild, intermediate, and severe based on severity grading scores. The pcf-DNA level was obtained from all participants on admission and from the survivors on the day of the discharge. The controls consisted of 31 healthy. Although the pcf-DNA level at admission was higher in patients than in the controls, the difference was not statistically significant (P = 0.291). However, at admission and in the convalescent period, the difference between pcf-DNA levels in mild, intermediate, and severe patient groups was significant. The pcf-DNA level in severe patients was higher than in the others. Furthermore, compared to survivors, non-survivors had higher pcf-DNA levels at admission (P = 0.001). A direct relationship was found between the pcf-DNA level and the viral load on the day of discharge in surviving patients. ROC curve analysis identified a pcf-DNA level of 0.42 as the optimal cut-off for prediction of mortality. The positive predictive value, negative predictive value, specificity, and sensitivity for predicting mortality was 100%, 72%, 100%, and 79%, respectively. In summary, our findings revealed that pcf-DNA levels may be used as a biomarker in predicting CHHF prognosis.
Cikman, Aytekin; Aydin, Merve; Gulhan, Baris; Karakecili, Faruk; Kesik, Ozan Arif; Ozcicek, Adalet; Akin, Hicran; Kara, Murat
To determine the seroprevalence and risk factors associated with Crimean-Congo hemorrhagic fever virus (CCHFV) in residents of Erzincan, Turkey. Although CCHFV is endemic in Erzincan, this is the first study to evaluate its seroprevalence in this region. This study included a total of 372 subjects, 174 of whom had been exposed to or bitten by ticks, 145 of whom worked with livestock, and 53 of whom resided in the city and did not have exposure to livestock. Data on CCHFV IgG and IgM antibodies were extracted from serum samples collected from all subjects using an ELISA. All samples were tested for CCHFV IgG and CCHFV IgM. Only IgM-positive samples were processed for detection of viral RNA through RT-PCR. Using seropositive cases only, we performed spatial analyses to evaluate correlations between seroprevalence and geographic location (i.e., proximity to rivers, altitude, and slope angle of land). In this study, 14.0% (52/322) of the total subjects were positive for CCHFV IgG. Seven of the individuals were positive both for CCHFV IgG and CCHFV IgM. Of these seven, only one sample tested positive for CCHFV RNA. Individuals who worked with livestock in the rural areas and had a history of tick exposure were statistically more likely to test positive for CCHFV IgG than individuals from the city and not exposed to ticks (p < 0.05). Seroprevalence was affected by geographic characteristics, including distance to rivers, altitude, and slope angle of land. We observed a high seroprevalence of CCHFV in Erzincan, which is similar to that observed in other endemic regions of Turkey. CCHFV seroprevalence rates are found to be quite high in the people who live in the sloping fields at certain heights and where there are a lot of rivers and streams.
Champour, Mohsen; Chinikar, Sadegh; Mohammadi, Gholamreza; Razmi, Gholamreza; Mostafavi, Ehsan; Shah-Hosseini, Nariman; Khakifirouz, Sahar; Jalali, Tahmineh
Background: This comprehensive study was conducted on multi-purpose one-humped camel (Camelus dromedarius) sera and ticks to assess the epidemiological aspects of the Crimean-Congo hemorrhagic fever virus (CCHFV) in northeast Iran. Methods: From May 2012 to January 2013, eleven cities were randomly selected in the Khorasan Provinces of Iran as “clusters,” and at least 14 one-humped camels were sampled from each area. Reverse transcriptase polymerase chain reaction was used for the detection of the CCHFV genome in ticks. Sera were analyzed using specific enzyme-linked immunosorbent assay tests. Results: Four hundred and eighty ixodid ticks were collected, and the genome of the CCHFV was detected in 49 (10.2%) out of 480 ticks. The CCHFV genome was detected in two out of four tick species, and in tick samples from three cities in Khorassan-e-Jonoobi. All three provinces, and six out of eleven cities, were CCHFV-specific IgG-positive. In total, nine (5.3%) out of 170 one-humped camels were IgG-positive. The highest rate of IgG-positive samples was found in Nehbandan (16.67%). Conclusion: Continued surveillance and strictly enforced importation and quarantine practices should be implemented to prevent human exposure and the on-going dispersal of infected ticks and livestock in these regions. It is recommended that acaricides be used to prevent CCHF transmission to humans, and to reduce the tick population. In addition, care should be taken by abattoirs workers and people who work with one-humped camels. PMID:27308275