Aspergillus infection in lung transplant patients: incidence and prognosis.

PubMed

Iversen, M; Burton, C M; Vand, S; Skovfoged, L; Carlsen, J; Milman, N; Andersen, C B; Rasmussen, M; Tvede, M

2007-12-01

Lung transplant recipients experience a particularly high incidence of Aspergillus infection in comparison with other solid-organ transplantations. This study was conducted to determine the incidence of Aspergillus colonisation and invasive aspergillosis, and the impact on long-term survival associated with Aspergillus infection. A retrospective study of 362 consecutive lung transplant patients from a single national centre who were transplanted 1992-2003 were studied. Twenty-seven patients were excluded due to incomplete or missing files. A total of 105/335 (31%) patients had evidence of Aspergillus infection (colonisation or invasion), including 83 (25%) patients with colonisation and 22 (6%) patients with radiographic or histological evidence of invasive disease. Most of the infections occurred within the first 3 months after transplantation. Cystic fibrosis (CF) patients had higher incidences of colonisation and invasive disease [15 (42%) and 4 (11%) of 36 patients] than non-CF patients [68 (23%) and 18 (6%) of 299 patients] (P = 0.01). Invasive aspergillosis was associated with 58% mortality after 2 years, whereas colonisation was not associated with early increased mortality but was associated with increased mortality after 5 years compared to non-infected patients (P < 0.05). An analysis of demographic factors showed that donor age [OR 1.40 per decade (95% CI 1.10-1.80)], ischaemia time [OR 1.17 per hour increase (95% CI 1.01-1.39)], and use of daclizumab versus polyclonal induction [OR 2.05 (95% CI 1.14-3.75)] were independent risk factors for Aspergillus infection. Invasive aspergillosis was associated with early and high mortality in lung transplant patients. Colonisation with Aspergillus was also associated with a significant increase in mortality after 5 years. CF patients have a higher incidence of Aspergillus infection than non-CF patients.

Trauma of lung due to impact load.

PubMed

Yen, R T; Fung, Y C; Liu, S Q

1988-01-01

A quantitative evaluation of lung injury due to impact loading is of general interest. Hemorrhage and edema are the usual sequelae to traumatic pulmonary impact. To gain some quantitative understanding of the phenomena, we perfused excised rabbit lung with Macrodex at isogravimetric condition and monitored lung weight continuously after impact. It is shown that a factor of importance is the rigidity of the surface on which the lung rests. The rate of lung weight increase is smaller if the lung was 'freely' supported on a soft cloth, more if it was supported on a rigid plate. This suggests the influence of stress wave reflection. The critical condition correlates with the initial velocity of impact at the surface of the lung, or with the maximum deflection. For a freely supported lung, the rate of lung weight increase was 22% of the initial total lung weight per h after impact when the impact velocity was 11.5 ms-1, 30% when the velocity was 13.2 ms-1, several 100% at 13.5 ms-1, signaling massive lung injury. Since the velocity of sound in rabbit lung is 33.3 ms-1 when the inflation (transpulmonary) pressure is 10 cm H2O, the critical velocity of 13.5 ms-1 corresponds to a Mach number of 0.4. The maximum surface displacement of the lung is almost linearly proportional to the initial velocity of impact. The exact cause of edema and hemorrhage is unknown; we hypothesize that it is due to tensile stress in the alveolar wall caused by the impact.

Lung Microbiota Changes Associated with Chronic Pseudomonas aeruginosa Lung Infection and the Impact of Intravenous Colistimethate Sodium

PubMed Central

Collie, David; Glendinning, Laura; Govan, John; Wright, Steven; Thornton, Elisabeth; Tennant, Peter; Doherty, Catherine; McLachlan, Gerry

2015-01-01

Background Exacerbations associated with chronic lung infection with Pseudomonas aeruginosa are a major contributor to morbidity, mortality and premature death in cystic fibrosis. Such exacerbations are treated with antibiotics, which generally lead to an improvement in lung function and reduced sputum P. aeruginosa density. This potentially suggests a role for the latter in the pathogenesis of exacerbations. However, other data suggesting that changes in P. aeruginosa sputum culture status may not reliably predict an improvement in clinical status, and data indicating no significant changes in either total bacterial counts or in P. aeruginosa numbers in sputum samples collected prior to pulmonary exacerbation sheds doubt on this assumption. We used our recently developed lung segmental model of chronic Pseudomonas infection in sheep to investigate the lung microbiota changes associated with chronic P. aeruginosa lung infection and the impact of systemic therapy with colistimethate sodium (CMS). Methodology/Principal Findings We collected protected specimen brush (PSB) samples from sheep (n = 8) both prior to and 14 days after establishment of chronic local lung infection with P aeruginosa. Samples were taken from both directly infected lung segments (direct) and segments spatially remote to such sites (remote). Four sheep were treated with daily intravenous injections of CMS between days 7 and 14, and four were treated with a placebo. Necropsy examination at d14 confirmed the presence of chronic local lung infection and lung pathology in every direct lung segment. The predominant orders in lung microbiota communities before infection were Bacillales, Actinomycetales and Clostridiales. While lung microbiota samples were more likely to share similarities with other samples derived from the same lung, considerable within- and between-animal heterogeneity could be appreciated. Pseudomonadales joined the aforementioned list of predominant orders in lung microbiota

Epidemic of Lung Cancer in Patients With HIV Infection

PubMed Central

Winstone, Tiffany A.; Man, S. F. Paul; Hull, Mark; Montaner, Julio S.

2013-01-01

The survival of patients with HIV infection has improved dramatically over the past 20 years, largely owing to a significant reduction in opportunistic infections and AIDs-defining malignancies, such as lymphoma and Kaposi sarcoma. However, with improved survival, patients with HIV are experiencing morbidity and mortality from other (non-AIDs-defining) complications, such as solid organ malignancies. Of these, the leading cause of mortality in the HIV-infected population is lung cancer, accounting for nearly 30% of all cancer deaths and 10% of all non-HIV-related deaths. Importantly, the average age of onset of lung cancer in the HIV-infected population is 25 to 30 years earlier than that in the general population and at lower exposure to cigarette smoke. This article provides an overview of the epidemiology of lung cancer in the HIV-infected population and discusses some of the important risk factors and pathways that may enhance the risk of lung cancer in this population. PMID:23381313

Respiratory infections and acute lung injury in systemic illness.

PubMed

Skerrett, S J; Niederman, M S; Fein, A M

1989-12-01

We have discussed the relationship between systemic illness, infection, and lung disease. As we have seen, patients with a wide variety of disease states, including advanced age, diabetes mellitus, alcoholism, collagen vascular disease, cancer, heart failure, and organ transplantation are potentially at increased risk for pneumonia because of disease-related impairments in host defenses. In addition, two virtually ubiquitous conditions in hospitalized patients, malnutrition and therapeutic interventions (especially with common medications), frequently add to the risk of airway invasion by bacterial pathogens. Systemic illness not only makes lung infection more common, but may adversely affect outcome and resolution, as well as determine the clinical presentation of pneumonia. In one particular population, the intubated and mechanically ventilated patient, the risk of infection is particularly high, and nosocomial pneumonia is a major cause of mortality. To the extent that the host response itself leads to the symptoms and signs of infection, systemically ill individuals may have subtle clinical features when serious bacterial invasion is present. Many components of the host defense system can become abnormal with serious illness, but a common mechanism that ties many systemic diseases to pneumonia is an alteration in airway epithelial cell receptivity for bacteria, namely, bacterial adherence, a process that mediates airway colonization, the first pathogenetic step on the road to pneumonia. The impetus for understanding how serious illness promotes lung infection is that once these mechanisms are identified, potential preventative strategies to minimize infection risk in the individual with systemic disease may be developed. The relationship among systemic illness, the lung, and infection also exists in a different direction: infection of a systemic nature (the septic syndrome) can lead to disease in the lung (ARDS). We have described the features of the septic

HIV infection in the etiology of lung cancer: confounding, causality, and consequences.

PubMed

Kirk, Gregory D; Merlo, Christian A

2011-06-01

Persons infected with HIV have an elevated risk of lung cancer, but whether the increase simply reflects a higher smoking prevalence continues to be debated. This review summarizes existing data on the association of HIV infection and lung cancer, with particular attention to study design and adjustment for cigarette smoking. Potential mechanisms by which HIV infection may lead to lung cancer are discussed. Finally, irrespective of causality and mechanisms, lung cancer represents an important and growing problem confronting HIV-infected patients and their providers. Substantial efforts are needed to promote smoking cessation and to control lung cancer among HIV-infected populations.

Respiratory infections: pneumonia, lung abscess, and empyema.

PubMed

Puligandla, Pramod S; Laberge, Jean-Martin

2008-02-01

Pneumonia is an important clinical problem that affects children of all ages. Although effectively treated on an outpatient basis in the majority of cases, some children with respiratory infections still require hospitalization. This may be particularly true for patients with immunocompromise, for whom the lung represents the most common site of infection. Furthermore, respiratory infections represent a significant source of morbidity and mortality in this patient population. This article focuses on the clinical presentation, etiology, and treatment of childhood pneumonia, with special consideration given to the immunocompromised child. Two specific complications of pneumonia, lung abscess and empyema, are discussed.

Type II secretion system of Pseudomonas aeruginosa: in vivo evidence of a significant role in death due to lung infection.

PubMed

Jyot, Jeevan; Balloy, Viviane; Jouvion, Gregory; Verma, Amrisha; Touqui, Lhousseine; Huerre, Michel; Chignard, Michel; Ramphal, Reuben

2011-05-15

The role of toxins secreted by the type II secretion system (T2SS) of Pseudomonas aeruginosa during lung infection has been uncertain despite decades of research. Using a model of pneumonia in Toll-like receptor (TLR) 2,4(-/-) mice, we reexamined the role of the T2SS system. Flagellin-deficient mutants of P. aeruginosa, with mutations in the T2SS and/or T3SS, were used to infect mice. Mice were followed up for survival, with some killed at different intervals to study bacterial clearance, inflammatory responses, and lung pathology. Strains carrying either secretion system were lethal for mice. Double mutants were avirulent. The T3SS(+) strains killed mice within a day, and the T2SS(+) strains killed them later. Mice infected with a strain that had only the T2SS were unable to eradicate the organism from the lungs, whereas those infected with a T2SS-T3SS double deletion were able to clear this mutant. Death caused by the T2SS(+) strain was accompanied by a >50-fold increase in bacterial counts and higher numbers of viable intracellular bacteria. The T2SS of P. aeruginosa may play a role in death from pneumonia, but its action is delayed. These data suggest that antitoxin strategies against this organism will require measures against the toxins secreted by both T2SS and T3SS.

Fusarium Infection in Lung Transplant Patients

PubMed Central

Carneiro, Herman A.; Coleman, Jeffrey J.; Restrepo, Alejandro; Mylonakis, Eleftherios

2013-01-01

Fusarium is a fungal pathogen of immunosuppressed lung transplant patients associated with a high mortality in those with severe and persistent neutropenia. The principle portal of entry for Fusarium species is the airways, and lung involvement almost always occurs among lung transplant patients with disseminated infection. In these patients, the immunoprotective mechanisms of the transplanted lungs are impaired, and they are, therefore, more vulnerable to Fusarium infection. As a result, fusariosis occurs in up to 32% of lung transplant patients. We studied fusariosis in 6 patients following lung transplantation who were treated at Massachusetts General Hospital during an 8-year period and reviewed 3 published cases in the literature. Cases were identified by the microbiology laboratory and through discharge summaries. Patients presented with dyspnea, fever, nonproductive cough, hemoptysis, and headache. Blood tests showed elevated white blood cell counts with granulocytosis and elevated inflammatory markers. Cultures of Fusarium were isolated from bronchoalveolar lavage, blood, and sputum specimens. Treatments included amphotericin B, liposomal amphotericin B, caspofungin, voriconazole, and posaconazole, either alone or in combination. Lung involvement occurred in all patients with disseminated disease and it was associated with a poor outcome. The mortality rate in this group of patients was high (67%), and of those who survived, 1 patient was treated with a combination of amphotericin B and voriconazole, 1 patient with amphotericin B, and 1 patient with posaconazole. Recommended empirical treatment includes voriconazole, amphotericin B or liposomal amphotericin B first-line, and posaconazole for refractory disease. High-dose amphotericin B is recommended for treatment of most cases of fusariosis. The echinocandins (for example, caspofungin, micafungin, anidulafungin) are generally avoided because Fusarium species have intrinsic resistance to them. Treatment

The Effective Treatment of Lung Infection Due to Scedosporium prolificans with Voriconazole and Surgery

PubMed Central

Masukane, Seiya; Kitahara, Yoshihiro; Okumoto, Joe; Sasaki, Keisuke; Nakano, Kikuo

2017-01-01

Scedosporium prolificans is a fungus that has demonstrated resistance against most currently available antifungal agents and which causes a rapidly disseminating and potentially fatal infection. A 68-year-old woman presented with a fever and consolidation in the lung field. Her symptoms and inflammatory reaction did not improve despite treatment with tazobactam/piperacillin, meropenem, and micafungin. Scedosporium prolificans was detected from the patient's bronchial lavage fluid, and we initiated treatment with voriconazole. Voriconazole was effective in shrinking the consolidation and suppressing the inflammatory reaction. The residual lesion was surgically resected because of the risk of systemic dissemination. The patient is currently alive without relapse or dissemination. PMID:28420849

The Effective Treatment of Lung Infection Due to Scedosporium prolificans with Voriconazole and Surgery.

PubMed

Masukane, Seiya; Kitahara, Yoshihiro; Okumoto, Joe; Sasaki, Keisuke; Nakano, Kikuo

2017-01-01

Scedosporium prolificans is a fungus that has demonstrated resistance against most currently available antifungal agents and which causes a rapidly disseminating and potentially fatal infection. A 68-year-old woman presented with a fever and consolidation in the lung field. Her symptoms and inflammatory reaction did not improve despite treatment with tazobactam/piperacillin, meropenem, and micafungin. Scedosporium prolificans was detected from the patient's bronchial lavage fluid, and we initiated treatment with voriconazole. Voriconazole was effective in shrinking the consolidation and suppressing the inflammatory reaction. The residual lesion was surgically resected because of the risk of systemic dissemination. The patient is currently alive without relapse or dissemination.

Lung needle biopsy

MedlinePlus

... may be due to any of the following: Bacterial, viral, or fungal lung infection Cancerous cells ( lung cancer , mesothelioma) Pneumonia Risks Sometimes, a collapsed lung ( pneumothorax ) occurs after ...

How an Opportunistic Infection Can Mess with Your Brain and Take Your Breath Away: A Rare Case of Simultaneous Lung and Brain Abscess due to Streptococcus anginosus.

PubMed

Al-Saffar, Farah; Torres-Miranda, Daisy; Ibrahim, Saif; Shujaat, Adil

2015-01-01

Streptococcus anginosus (S. anginosus) is considered a friendly bug and is a one of many different bacteria that constitute the normal flora of the oral cavity. Nevertheless, it has been infrequently associated with more invasive infections, like lung abscess. It is extremely rare to have multisystemic involvement with S. anginosus group. We present a unique case of pulmonary and brain abscess due to S. anginosus in an immunocompetent patient.

Persistent activation of an innate immune axis translates respiratory viral infection into chronic lung disease

PubMed Central

Kim, Edy Y.; Battaile, John T.; Patel, Anand C.; You, Yingjian; Agapov, Eugene; Grayson, Mitchell H.; Benoit, Loralyn A.; Byers, Derek E.; Alevy, Yael; Tucker, Jennifer; Swanson, Suzanne; Tidwell, Rose; Tyner, Jeffrey W.; Morton, Jeffrey D.; Castro, Mario; Polineni, Deepika; Patterson, G. Alexander; Schwendener, Reto A.; Allard, John D.; Peltz, Gary; Holtzman, Michael J.

2008-01-01

To understand the pathogenesis of chronic inflammatory disease, we analyzed an experimental mouse model of a chronic lung disease that resembles asthma and chronic obstructive pulmonary disease (COPD) in humans. In this model, chronic lung disease develops after infection with a common type of respiratory virus is cleared to trace levels of noninfectious virus. Unexpectedly, the chronic inflammatory disease arises independently of an adaptive immune response and is driven by IL-13 produced by macrophages stimulated by CD1d-dependent TCR-invariant NKT cells. This innate immune axis is also activated in the lungs of humans with chronic airway disease due to asthma or COPD. These findings provide new insight into the pathogenesis of chronic inflammatory disease with the discovery that the transition from respiratory viral infection into chronic lung disease requires persistent activation of a novel NKT cell-macrophage innate immune axis. PMID:18488036

Successful recovery after disseminated infection due to mycobacterium abscessus in a lung transplant patient: subcutaneous nodule as first manifestation--a case report.

PubMed

Morales, P; Ros, J A; Blanes, M; Pérez-Enguix, D; Saiz, V; Santos, M

2007-09-01

Mycobacterium abscessus infection following lung transplantation (LT) has been described in a few cases. It is characterized by a variable initial location and subsequent course in this special risk group of patients, particularly those with cystic fibrosis (CF). Herein we have presented the case of a patient subjected to LT due to CF, who 1 year after transplantation developed a subcutaneous nodule produced by M abscessus, with subsequent hematogenous spread as well as bronchial and bone marrow involvement. Antecedents prior to LT included Staphylococcus aureus colonization and sputum positivity for Aspergillus fumigatus and Scedosporium apioespermum. Treatment with ciprofloxacin and linezolid was started on the basis of the antibiogram findings. The latter antibiotic was replaced by clarithromycin for 6 months. Two years later, the patient remains asymptomatic with respiratory function parameters in the normal range. The infected patient described herein was our only case with sepsis and multisystemic spread. The important mortality among such cases reported in the literature makes early diagnosis and treatment essential.

Effects and molecular mechanisms of intrauterine infection/inflammation on lung development.

PubMed

Pan, Jiarong; Zhan, Canyang; Yuan, Tianming; Wang, Weiyan; Shen, Ying; Sun, Yi; Wu, Tai; Gu, Weizhong; Chen, Lihua; Yu, Huimin

2018-05-10

Intrauterine infection/inflammation plays an important role in the development of lung injury and bronchopulmonary dysplasia (BPD) in preterm infants, While a multifactorial genesis is likely, mechanisms involved in BPD after intrauterine infection/inflammation are largely unknown. Recent studies have suggested microRNAs (miRNAs) are likely to play a role. Therefore, this study aimed to study the effects and mechanisms of intrauterine infection/inflammation on lung development, and to identify miRNAs related to lung injury and BPD. An animal model of intrauterine infection/inflammation was established with pregnant SD rats endocervically inoculated with E.coli. The fetal and neonatal rats were observed at embryonic day (E) 17, 19, 21 and postnatal day (P) 1, 3, 7, 14, respectively. Body weight, lung weight, the expression levels of NLRP3, TNF-α, IL-lβ, IL-6, VEGF, Collagen I, SP-A, SP-B and SP-C in the lung tissues of fetal and neonatal rats were measured. Expression profiles of 1218 kinds of miRNAs in the lungs of neonatal rats were detected by miRNA microarray technique. Target genes of the identified miRNAs were predicted through online software. Intrauterine infection/inflammation compromised not only weight development but also lung development of the fetal and neonatal rats. The results showed significantly increased expression of NLRP3, TNF-α, IL-1β, IL-6, Collagen I, and significantly decreased expression of VEGF, SP-A, SP-B and SP-C in the fetal and neonatal rat lung tissues in intrauterine infection group compared to the control group at different observation time point (P < 0.05). Forty-three miRNAs with significant differential expression were identified. Possible target genes regulated by the identified miRNAs are very rich. Intrauterine infection/inflammation results in lung histological changes which are very similar to those observed in BPD. Possible mechanisms may include NLRP3 inflammasome activation followed by inflammatory cytokines

Infection, inflammation, and lung function decline in infants with cystic fibrosis.

PubMed

Pillarisetti, Naveen; Williamson, Elizabeth; Linnane, Barry; Skoric, Billy; Robertson, Colin F; Robinson, Phil; Massie, John; Hall, Graham L; Sly, Peter; Stick, Stephen; Ranganathan, Sarath

2011-07-01

Better understanding of evolution of lung function in infants with cystic fibrosis (CF) and its association with pulmonary inflammation and infection is crucial in informing both early intervention studies aimed at limiting lung damage and the role of lung function as outcomes in such studies. To describe longitudinal change in lung function in infants with CF and its association with pulmonary infection and inflammation. Infants diagnosed after newborn screening or clinical presentation were recruited prospectively. FVC, forced expiratory volume in 0.5 seconds (FEV(0.5)), and forced expiratory flows at 75% of exhaled vital capacity (FEF(75)) were measured using the raised-volume technique, and z-scores were calculated from published reference equations. Pulmonary infection and inflammation were measured in bronchoalveolar lavage within 48 hours of lung function testing. Thirty-seven infants had at least two successful repeat lung function measurements. Mean (SD) z-scores for FVC were -0.8 (1.0), -0.9 (1.1), and -1.7 (1.2) when measured at the first visit, 1-year visit, or 2-year visit, respectively. Mean (SD) z-scores for FEV(0.5) were -1.4 (1.2), -2.4 (1.1), and -4.3 (1.6), respectively. In those infants in whom free neutrophil elastase was detected, FVC z-scores were 0.81 lower (P=0.003), and FEV(0.5) z-scores 0.96 lower (P=0.001), respectively. Significantly greater decline in FEV(0.5) z-scores occurred in those infected with Staphylococcus aureus (P=0.018) or Pseudomonas aeruginosa (P=0.021). In infants with CF, pulmonary inflammation is associated with lower lung function, whereas pulmonary infection is associated with a greater rate of decline in lung function. Strategies targeting pulmonary inflammation and infection are required to prevent early decline in lung function in infants with CF.

Natural Killer Cell Recruitment to the Lung During Influenza A Virus Infection Is Dependent on CXCR3, CCR5, and Virus Exposure Dose

PubMed Central

Carlin, Lindsey E.; Hemann, Emily A.; Zacharias, Zeb R.; Heusel, Jonathan W.; Legge, Kevin L.

2018-01-01

Natural killer (NK) cells are vital components of the antiviral immune response, but their contributions in defense against influenza A virus (IAV) are not well understood. To better understand NK cell responses during IAV infections, we examined the magnitude, kinetics, and contribution of NK cells to immunity and protection during high- and low-dose IAV infections. Herein, we demonstrate an increased accumulation of NK cells in the lung in high-dose vs. low-dose infections. In part, this increase is due to the local proliferation of pulmonary NK cells. However, the majority of NK cell accumulation within the lungs and airways during an IAV infection is due to recruitment that is partially dependent upon CXCR3 and CCR5, respectively. Therefore, altogether, our results demonstrate that NK cells are actively recruited to the lungs and airways during IAV infection and that the magnitude of the recruitment may relate to the inflammatory environment found within the tissues during high- and low-dose IAV infections. PMID:29719539

Disseminated Aspergillus fumigatus infection with consecutive mitral valve endocarditis in a lung transplant recipient.

PubMed

Scherer, Mirela; Fieguth, Hans-Gerd; Aybek, Tayfun; Ujvari, Zsolt; Moritz, Anton; Wimmer-Greinecker, Gerhard

2005-12-01

Aspergillus infection is a known complication of lung transplantation and remains associated with high mortality rates. The manifestation of the infection varies from simple colonization of the lung to disseminated complicated infections. Early Aspergillus infection has been rarely observed in a small number of lung transplant recipients; most cases occur during the late post-operative period. The pulmonary involvement has often been described as the first clinical localization of the disease. Although other various forms of Aspergillus infection are not uncommonly encountered after lung transplantation, Aspergillus mitral valve endocarditis is rare. We present a case of disseminated Aspergillus fumigatus infection with consecutive mitral valve endocarditis having developed 78 days after double-lung transplantation for cystic fibrosis.

A Biomathematical Model of Pneumococcal Lung Infection and Antibiotic Treatment in Mice.

PubMed

Schirm, Sibylle; Ahnert, Peter; Wienhold, Sandra; Mueller-Redetzky, Holger; Nouailles-Kursar, Geraldine; Loeffler, Markus; Witzenrath, Martin; Scholz, Markus

2016-01-01

Pneumonia is considered to be one of the leading causes of death worldwide. The outcome depends on both, proper antibiotic treatment and the effectivity of the immune response of the host. However, due to the complexity of the immunologic cascade initiated during infection, the latter cannot be predicted easily. We construct a biomathematical model of the murine immune response during infection with pneumococcus aiming at predicting the outcome of antibiotic treatment. The model consists of a number of non-linear ordinary differential equations describing dynamics of pneumococcal population, the inflammatory cytokine IL-6, neutrophils and macrophages fighting the infection and destruction of alveolar tissue due to pneumococcus. Equations were derived by translating known biological mechanisms and assuming certain response kinetics. Antibiotic therapy is modelled by a transient depletion of bacteria. Unknown model parameters were determined by fitting the predictions of the model to data sets derived from mice experiments of pneumococcal lung infection with and without antibiotic treatment. Time series of pneumococcal population, debris, neutrophils, activated epithelial cells, macrophages, monocytes and IL-6 serum concentrations were available for this purpose. The antibiotics Ampicillin and Moxifloxacin were considered. Parameter fittings resulted in a good agreement of model and data for all experimental scenarios. Identifiability of parameters is also estimated. The model can be used to predict the performance of alternative schedules of antibiotic treatment. We conclude that we established a biomathematical model of pneumococcal lung infection in mice allowing predictions regarding the outcome of different schedules of antibiotic treatment. We aim at translating the model to the human situation in the near future.

Outcome of influenza infection managed with oseltamivir in lung transplant recipients.

PubMed

Ison, Michael G; Sharma, Amita; Shepard, Jo-Anne O; Wain, John C; Ginns, Leo C

2008-03-01

Influenza causes significant morbidity and mortality in lung transplant recipients and likely predisposes to obliterative bronchiolitis. Neuraminidase inhibitors shorten the duration of symptoms and virus shedding and the number of antibiotic-requiring complications in ambulatory immunocompetent patients, although the efficacy of these agents in lung transplant recipients has not been assessed previously. In this study, 9 lung transplant patients who were treated with oseltamivir for influenza infections were identified and analyzed retrospectively. Oseltamivir was well tolerated. Infection resolved in all patients and there were no deaths. Two patients developed pneumonia shortly after their influenza infection and both responded to antibiotic therapy. None of the patients had persistent abnormalities noted on chest imaging and most did not show significant changes on pulmonary function testing. Two patients with the lowest pulmonary function test (PFT) values pre-infection had persistent defects after infection. Oseltamivir is well tolerated in lung transplant recipients and may reduce the risk of complications, although further studies are warranted.

A case of IgG4-related lung disease complicated by asymptomatic chronic Epstein-Barr virus infection.

PubMed

Kotetsu, Yasuaki; Ikegame, Satoshi; Takebe-Akazawa, Keiko; Koga, Takaomi; Okabayashi, Kan; Takata, Shohei

2017-11-01

IgG4-related disease is characterized by IgG4-positive plasmacyte infiltration into various organs, but its etiology is not unknown. To elucidate the etiology of IgG4-related disease. We experienced an interesting case of IgG4-related lung disease complicated by chronic EB virus infection. A 70-year-old male visited our hospital due to failure of pneumonia treatment. Chest computed tomography (CT) showed consolidation in the right middle field and slight mediastinal lymphadenopathy in the subcarinal region. Lung consolidation improved with antibiotics; subcarinal lymphadenopathy progressed after 4 months. Malignant lymphoma was suspected given elevated sIL2-R levels (1862 U/mL). Patchy ground glass opacities appeared in the bilateral lung field just before surgical biopsy. He was diagnosed with IgG4-related lung disease after inspection of a pathological specimen obtained from the right upper lung and right hilar lymph node. EB virus-infected cells were also detected in the lymph node. Blood examination revealed EB virus viremia, but the patient did not present with symptoms or organ involvement. This led to a diagnosis of asymptomatic chronic EB virus infection. Recent studies have suggested an association between EB virus infection and IgG4-related diseases in the pathological exploration of surgically resected lymph nodes. Our case is the first case of IgG4-related lung disease in which EB virus infection was both pathologically and clinically proved. The present case is of particular interest in view of this newly reported association, and may serve as a fundamental report for future studies connecting EB virus infection with IgG4-related diseases. © 2016 John Wiley & Sons Ltd.

Viral Infection of Human Lung Macrophages Increases PDL1 Expression via IFNβ

PubMed Central

Staples, Karl J.; Nicholas, Ben; McKendry, Richard T.; Spalluto, C. Mirella; Wallington, Joshua C.; Bragg, Craig W.; Robinson, Emily C.; Martin, Kirstin; Djukanović, Ratko; Wilkinson, Tom M. A.

2015-01-01

Lung macrophages are an important defence against respiratory viral infection and recent work has demonstrated that influenza-induced macrophage PDL1 expression in the murine lung leads to rapid modulation of CD8+ T cell responses via the PD1 receptor. This PD1/PDL1 pathway may downregulate acute inflammatory responses to prevent tissue damage. The aim of this study was to investigate the mechanisms of PDL1 regulation by human macrophages in response to viral infection. Ex-vivo viral infection models using influenza and RSV were established in human lung explants, isolated lung macrophages and monocyte-derived macrophages (MDM) and analysed by flow cytometry and RT-PCR. Incubation of lung explants, lung macrophages and MDM with X31 resulted in mean cellular infection rates of 18%, 18% and 29% respectively. Viral infection significantly increased cell surface expression of PDL1 on explant macrophages, lung macrophages and MDM but not explant epithelial cells. Infected MDM induced IFNγ release from autologous CD8+ T cells, an effect enhanced by PDL1 blockade. We observed increases in PDL1 mRNA and IFNβ mRNA and protein release by MDM in response to influenza infection. Knockdown of IFNβ by siRNA, resulted in a 37.5% reduction in IFNβ gene expression in response to infection, and a significant decrease in PDL1 mRNA. Furthermore, when MDM were incubated with IFNβ, this cytokine caused increased expression of PDL1 mRNA. These data indicate that human macrophage PDL1 expression modulates CD8+ cell IFNγ release in response to virus and that this expression is regulated by autologous IFNβ production. PMID:25775126

Viral infection of human lung macrophages increases PDL1 expression via IFNβ.

PubMed

Staples, Karl J; Nicholas, Ben; McKendry, Richard T; Spalluto, C Mirella; Wallington, Joshua C; Bragg, Craig W; Robinson, Emily C; Martin, Kirstin; Djukanović, Ratko; Wilkinson, Tom M A

2015-01-01

Lung macrophages are an important defence against respiratory viral infection and recent work has demonstrated that influenza-induced macrophage PDL1 expression in the murine lung leads to rapid modulation of CD8+ T cell responses via the PD1 receptor. This PD1/PDL1 pathway may downregulate acute inflammatory responses to prevent tissue damage. The aim of this study was to investigate the mechanisms of PDL1 regulation by human macrophages in response to viral infection. Ex-vivo viral infection models using influenza and RSV were established in human lung explants, isolated lung macrophages and monocyte-derived macrophages (MDM) and analysed by flow cytometry and RT-PCR. Incubation of lung explants, lung macrophages and MDM with X31 resulted in mean cellular infection rates of 18%, 18% and 29% respectively. Viral infection significantly increased cell surface expression of PDL1 on explant macrophages, lung macrophages and MDM but not explant epithelial cells. Infected MDM induced IFNγ release from autologous CD8+ T cells, an effect enhanced by PDL1 blockade. We observed increases in PDL1 mRNA and IFNβ mRNA and protein release by MDM in response to influenza infection. Knockdown of IFNβ by siRNA, resulted in a 37.5% reduction in IFNβ gene expression in response to infection, and a significant decrease in PDL1 mRNA. Furthermore, when MDM were incubated with IFNβ, this cytokine caused increased expression of PDL1 mRNA. These data indicate that human macrophage PDL1 expression modulates CD8+ cell IFNγ release in response to virus and that this expression is regulated by autologous IFNβ production.

Lung cancer in HIV infected patients: facts, questions and challenges

PubMed Central

Cadranel, J; Garfield, D; Lavolé, A; Wislez, M; Milleron, B; Mayaud, C

2006-01-01

AIDS related mortality has fallen sharply in industrialised countries since 1996 following the introduction of highly active antiretroviral therapy. This has been accompanied by an increase in the proportion of deaths attributable to non‐AIDS defining solid tumours, especially lung cancer. The risk of developing lung cancer seems to be higher in HIV infected subjects than in the general population of the same age, partly because the former tend more frequently to be smokers and, especially, intravenous drug users. The carcinogenic role of the antiretroviral nucleoside drugs and their interaction with smoking needs to be examined. Interestingly, there is no clear relationship between the degree of immunosuppression and the risk of lung cancer, so the reason for the increased risk is unknown. The mean age of HIV infected patients at the time of lung cancer diagnosis is 45 years and most are symptomatic. Lung cancer is diagnosed when locally advanced or metastatic (stage III–IV) in 75–90% of cases, similar to patients with unknown HIV status. Adenocarcinoma is the most frequent histological type. The prognosis is worse in HIV infected patients than in the general lung cancer population. Efficacy and toxicity data for chemotherapy and radiation therapy are few and imprecise. Surgery remains the treatment of choice for localised disease in patients with adequate pulmonary function and general good health, regardless of immune status. Prospective clinical trials are needed to define the optimal detection and treatment strategies for lung cancer in HIV infected patients. PMID:17071836

Sirolimus alters lung pathology and viral load following influenza A virus infection.

PubMed

Alsuwaidi, Ahmed R; George, Junu A; Almarzooqi, Saeeda; Hartwig, Stacey M; Varga, Steven M; Souid, Abdul-Kader

2017-07-11

Inhibitors of mTOR, such as sirolimus, have been shown to induce thymus involution and inflammatory lung disease in mice. The latter effect supports the role of this serine/threonine kinase in ameliorating lung inflammation. Other studies have shown sirolimus reduces/delays lung disease associated with various strains of influenza A virus (IAV). Thus, the effects of mTOR inhibitors on influenza infection deserve further studies. Here, we examined the changes in lung viral copies, pathology and pulmonary function associated with IAV (A/PR/8/34) infection in mice treated with sirolimus. Body weight loss peaked between days 6-11 post-infection and was more severe in IAV-infected mice that were administered sirolimus as compared to mice that received IAV alone (p = 0.030). Natural log viral gene copies, mean ± SD per mg lung tissue, in IAV-infected mice that were administered sirolimus were 17.31 ± 1.27 on day 4, 19.31 ± 7.46 on day 10, and 0 on day 25. The corresponding number of copies in mice that received IAV alone were 18.56 ± 0.95 on day 4 (p = 0.132), 1.52 ± 1.39 on day 10 (p = 0.008), and 0 on day 25. Lung pathology was evident on days 4, 10, and 25 post infection, with mean ± SD inflammatory score of 9.0 ± 4.5 in IAV-infected mice that were administered sirolimus, as compared to 11.5 ± 4.5 (p = 0.335) in mice received IAV alone (maximum score, 26.0). Impaired lung function was evident in IAV-infected mice on days 4 and 10, as demonstrated by increased airway resistance and decreased compliance. In this model, the effects of sirolimus on influenza infection included severe weight loss and modified viral replication, respiratory function and lung inflammation. The adverse events associated with sirolimus treatment are consistent with its potent immunosuppressive activity and, thus, preclude its use in IAV infection.

Lung abscess in a child secondary to Mycoplasma pneumoniae infection.

PubMed

Ruffini, E; De Petris, L; Candelotti, P; Tulli, M; Sabatini, M R; Luciani, L; Carlucci, A

2014-01-01

We present a case of a lung abscess in a child 6-year-old admitted with a history of right hemithorax pain lasting for 15 days and the onset of mild fever in the last two days. Etiological research showed positivity of IgM antibodies to Mycoplasma pneumoniae after seven days of admission. The child has been successfully treated with antibiotic therapy, without the use of macrolides, for a duration of 4 weeks. Our study suggests that the Mycoplasma pneumoniae infection may predispose to severe infections, such as lung abscess, caused by typical respiratory pathogens. The reported case of lung abscess is one of the few reported in the literature in the modern antibiotic era and is the first preceded by Mycoplasma pneumoniae infection.

A human lung xenograft mouse model of Nipah virus infection.

PubMed

Valbuena, Gustavo; Halliday, Hailey; Borisevich, Viktoriya; Goez, Yenny; Rockx, Barry

2014-04-01

Nipah virus (NiV) is a member of the genus Henipavirus (family Paramyxoviridae) that causes severe and often lethal respiratory illness and encephalitis in humans with high mortality rates (up to 92%). NiV can cause Acute Lung Injury (ALI) in humans, and human-to-human transmission has been observed in recent outbreaks of NiV. While the exact route of transmission to humans is not known, we have previously shown that NiV can efficiently infect human respiratory epithelial cells. The molecular mechanisms of NiV-associated ALI in the human respiratory tract are unknown. Thus, there is an urgent need for models of henipavirus infection of the human respiratory tract to study the pathogenesis and understand the host responses. Here, we describe a novel human lung xenograft model in mice to study the pathogenesis of NiV. Following transplantation, human fetal lung xenografts rapidly graft and develop mature structures of adult lungs including cartilage, vascular vessels, ciliated pseudostratified columnar epithelium, and primitive "air" spaces filled with mucus and lined by cuboidal to flat epithelium. Following infection, NiV grows to high titers (10(7) TCID50/gram lung tissue) as early as 3 days post infection (pi). NiV targets both the endothelium as well as respiratory epithelium in the human lung tissues, and results in syncytia formation. NiV infection in the human lung results in the production of several cytokines and chemokines including IL-6, IP-10, eotaxin, G-CSF and GM-CSF on days 5 and 7 pi. In conclusion, this study demonstrates that NiV can replicate to high titers in a novel in vivo model of the human respiratory tract, resulting in a robust inflammatory response, which is known to be associated with ALI. This model will facilitate progress in the fundamental understanding of henipavirus pathogenesis and virus-host interactions; it will also provide biologically relevant models for other respiratory viruses.

Case of a lung mass due to melioidosis in Mexico.

PubMed

Truong, Kimberly K; Moghaddam, Samer; Al Saghbini, Samer; Saatian, Bahman

2015-05-06

Melioidosis, an infection caused by the gram-negative bacterium Burkholderia pseudomallei, is an important cause of pneumonia, skin infection, sepsis, and death in Southeast Asia and Australia, but is exceedingly rare in North America. Pulmonary melioidosis typically presents as acute bacterial pneumonia or cavitary lung lesions resembling tuberculosis. We report melioidosis in a 70-year-old active smoker from Mexico with no history of travel to disease-endemic areas. The patient presented with a left supraclavicular abscess and a non-cavitary, left lung mass encasing a pulmonary vein. Incision and drainage of the patient's subcutaneous abscess isolated B. pseudomallei, and fine-needle aspiration of enlarged mediastinal lymph nodes revealed the presence of intracellular gram-negative bacilli with no evidence of malignancy. Biochemical tests determined that the strain the patient acquired from Mexico is identical to only 1 other isolate from Thailand. This report highlights the blurring epidemiological borders of this organism, its rare presentation mimicking lung malignancy, and an aggressive antimicrobial treatment that resulted in resolution of the patient's symptoms.

Lung cancer in persons with HIV.

PubMed

Sigel, Keith; Makinson, Alain; Thaler, Jonathan

2017-01-01

Lung cancer is emerging as a leading cause of death in HIV-infected persons. This review will discuss the latest scientific evidence regarding the mechanisms driving lung cancer risk in HIV infection, the clinical presentation of lung cancer in HIV-infected persons and recent data regarding the outcomes, treatment and prevention of lung cancer in this group. Increased risk of lung cancer in HIV-infected persons is primarily due to higher smoking rates, but emerging evidence also implicates immunosuppression and inflammatory processes. Lung cancer outcomes may be worse in HIV-infected persons in the antiretroviral era, but this may stem, in part, from treatment disparities. Early detection of lung cancer using chest computed tomography (CT) is being increasingly adopted for smokers in the general population, and recent studies suggest that it may be safe and efficacious in HIV-infected smokers. Lung cancer is an important complication associated with chronic HIV infection. It is associated with unique HIV-related causal mechanisms, and may be associated with worse outcomes in some HIV-infected persons. Smoking cessation and early cancer detection with chest CT are likely to benefit HIV-infected smokers.

Critical role of CXCL4 in the lung pathogenesis of influenza (H1N1) respiratory infection.

PubMed

Guo, L; Feng, K; Wang, Y C; Mei, J J; Ning, R T; Zheng, H W; Wang, J J; Worthen, G S; Wang, X; Song, J; Li, Q H; Liu, L D

2017-11-01

Annual epidemics and unexpected pandemics of influenza are threats to human health. Lung immune and inflammatory responses, such as those induced by respiratory infection influenza virus, determine the outcome of pulmonary pathogenesis. Platelet-derived chemokine (C-X-C motif) ligand 4 (CXCL4) has an immunoregulatory role in inflammatory diseases. Here we show that CXCL4 is associated with pulmonary influenza infection and has a critical role in protecting mice from fatal H1N1 virus respiratory infection. CXCL4 knockout resulted in diminished viral clearance from the lung and decreased lung inflammation during early infection but more severe lung pathology relative to wild-type mice during late infection. Additionally, CXCL4 deficiency decreased leukocyte accumulation in the infected lung with markedly decreased neutrophil infiltration into the lung during early infection and extensive leukocyte, especially lymphocyte accumulation at the late infection stage. Loss of CXCL4 did not affect the activation of adaptive immune T and B lymphocytes during the late stage of lung infection. Further study revealed that CXCL4 deficiency inhibited neutrophil recruitment to the infected mouse lung. Thus the above results identify CXCL4 as a vital immunoregulatory chemokine essential for protecting mice against influenza A virus infection, especially as it affects the development of lung injury and neutrophil mobilization to the inflamed lung.

HIV infection is associated with an increased risk for lung cancer, independent of smoking.

PubMed

Kirk, Gregory D; Merlo, Christian; O' Driscoll, Peter; Mehta, Shruti H; Galai, Noya; Vlahov, David; Samet, Jonathan; Engels, Eric A

2007-07-01

Human immunodeficiency virus (HIV)-infected persons have an elevated risk for lung cancer, but whether the increase reflects solely their heavy tobacco use remains an open question. The Acquired Immunodeficiency Syndrome (AIDS) Link to the Intravenous Experience Study has prospectively observed a cohort of injection drug users in Baltimore, Maryland, since 1988, using biannual collection of clinical, laboratory, and behavioral data. Lung cancer deaths were identified through linkage with the National Death Index. Cox proportional hazards regression was used to examine the effect of HIV infection on lung cancer risk, controlling for smoking status, drug use, and clinical variables. Among 2086 AIDS Link to the Intravenous Experience Study participants observed for 19,835 person-years, 27 lung cancer deaths were identified; 14 of the deaths were among HIV-infected persons. All but 1 (96%) of the patients with lung cancer were smokers, smoking a mean of 1.2 packs per day. Lung cancer mortality increased during the highly active antiretroviral therapy era, compared with the pre-highly active antiretroviral therapy period (mortality rate ratio, 4.7; 95% confidence interval, 1.7-16). After adjusting for age, sex, smoking status, and calendar period, HIV infection was associated with increased lung cancer risk (hazard ratio, 3.6; 95% confidence interval, 1.6-7.9). Preexisting lung disease, particularly noninfectious diseases and asthma, displayed trends for increased lung cancer risk. Illicit drug use was not associated with increased lung cancer risk. Among HIV-infected persons, smoking remained the major risk factor; CD4 cell count and HIV load were not strongly associated with increased lung cancer risk, and trends for increased risk with use of highly active antiretroviral therapy were not significant. HIV infection is associated with significantly increased risk for developing lung cancer, independent of smoking status.

Immunodeficiency, AIDS-related pneumonia, and risk of lung cancer among HIV-infected individuals.

PubMed

Marcus, Julia L; Leyden, Wendy A; Chao, Chun R; Horberg, Michael A; Klein, Daniel B; Quesenberry, Charles P; Towner, William J; Silverberg, Michael J

2017-04-24

The objective is to clarify the role of immunodeficiency and pneumonia in elevated lung cancer risk among HIV-infected individuals. Cohort study of HIV-infected and HIV-uninfected adults in a large integrated healthcare system in California during 1996-2011. We used Poisson models to obtain rate ratios for lung cancer associated with HIV infection, overall and stratified by recent CD4 cells/μl (HIV-uninfected as reference group), with χ tests for trends across CD4 strata. Fully adjusted models included demographics, cancer risk factors (smoking, drug/alcohol abuse, overweight/obesity), and prior pneumonia. Among 24 768 HIV-infected and 257 600 HIV-uninfected individuals, the lung cancer rate per 100 000 person-years was 66 (n = 80 events) for HIV-infected and 33 (n = 506 events) for HIV-uninfected individuals [rate ratio 2.0, 95% confidence interval (CI): 1.7-2.2]. Overall, HIV-infected individuals were at increased risk of lung cancer after adjustment for demographics and cancer risk factors (rate ratio 1.4, 95% CI: 1.1-1.7), but not after additional adjustment for pneumonia (rate ratio 1.2, 95% CI: 0.9-1.6). Lower CD4 cell counts were associated with higher risk of lung cancer in unadjusted and demographics-adjusted models (P < 0.001 for all), but this trend did not remain after adjustment for cancer risk factors and pneumonia. Compared with HIV-uninfected individuals, HIV-infected individuals with CD4 less than 200 cells/μl were not at increased risk of lung cancer in fully adjusted models. The increased lung cancer risk among HIV patients is attributable to differences in demographics, risk factors such as smoking, and history of pneumonia. Immunodeficiency does not appear to have an independent effect on lung cancer risk.

Disparities in the treatment and outcomes of lung cancer among HIV-infected individuals

PubMed Central

Suneja, Gita; Shiels, Meredith S.; Melville, Sharon K.; Williams, Melanie A.; Rengan, Ramesh; Engels, Eric A.

2013-01-01

Objectives HIV-infected people have elevated risk for lung cancer and higher mortality following cancer diagnosis than HIV-uninfected individuals. It is unclear whether HIV-infected individuals with lung cancer receive similar cancer treatment as HIV-uninfected individuals. Design/methods We studied adults more than 18 years of age with lung cancer reported to the Texas Cancer Registry (N = 156 930) from 1995 to 2009. HIV status was determined by linkage with the Texas enhanced HIV/AIDS Reporting System. For nonsmall cell lung cancer (NSCLC) cases, we identified predictors of cancer treatment using logistic regression. We used Cox regression to evaluate effects of HIV and cancer treatment on mortality. Results Compared with HIV-uninfected lung cancer patients (N = 156 593), HIV-infected lung cancer patients (N = 337) were more frequently young, black, men, and with non-Hispanic distant stage disease. HIV-infected NSCLC patients less frequently received cancer treatment than HIV-uninfected patients [60.3 vs. 77.5%; odds ratio 0.39, 95% confidence interval (CI) 0.30–0.52, after adjustment for diagnosis year, age, sex, race, stage, and histologic subtype]. HIV infection was associated with higher lung cancer-specific mortality (hazard ratio 1.34, 95% CI 1.15–1.56, adjusted for demographics and tumor characteristics). Inclusion of cancer treatment in adjusted models slightly attenuated the effect of HIV on lung cancer-specific mortality (hazard ratio 1.25; 95% CI 1.06–1.47). Also, there was a suggestion that HIV was more strongly associated with mortality among untreated than among treated patients (adjusted hazard ratio 1.32 vs. 1.16, P-interaction = 0.34). Conclusion HIV-infected NSCLC patients were less frequently treated for lung cancer than HIV-uninfected patients, which may have affected survival. PMID:23079809

Superficial herpes simplex virus wound infection following lung transplantation.

PubMed

Karolak, Wojtek; Wojarski, Jacek; Zegleń, Sławomir; Ochman, Marek; Urlik, Maciej; Hudzik, Bartosz; Wozniak-Grygiel, Elzbieta; Maruszewski, Marcin

2017-08-01

Surgical site infections (SSIs) are infections of tissues, organs, or spaces exposed by surgeons during performance of an invasive procedure. SSIs are classified into superficial, which are limited to skin and subcutaneous tissues, and deep. The incidence of deep SSIs in lung transplant (LTx) patients is estimated at 5%. No reports have been published as to the incidence of superficial SSIs specifically in LTx patients. Common sense would dictate that the majority of superficial SSIs would be bacterial. Uncommonly, fungal SSIs may occur, and we believe that no reports exist as to the incidence of viral wound infections in LTx patients, or in any solid organ transplant patients. We report a de novo superficial wound infection with herpes simplex virus following lung transplantation, its possible source, treatment, and resolution. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Protective mechanical ventilation does not exacerbate lung function impairment or lung inflammation following influenza A infection.

PubMed

Zosky, Graeme R; Cannizzaro, Vincenzo; Hantos, Zoltan; Sly, Peter D

2009-11-01

The degree to which mechanical ventilation induces ventilator-associated lung injury is dependent on the initial acute lung injury (ALI). Viral-induced ALI is poorly studied, and this study aimed to determine whether ALI induced by a clinically relevant infection is exacerbated by protective mechanical ventilation. Adult female BALB/c mice were inoculated with 10(4.5) plaque-forming units of influenza A/Mem/1/71 in 50 microl of medium or medium alone. This study used a protective ventilation strategy, whereby mice were anesthetized, tracheostomized, and mechanically ventilated for 2 h. Lung mechanics were measured periodically throughout the ventilation period using a modification of the forced oscillation technique to obtain measures of airway resistance and coefficients of tissue damping and tissue elastance. Thoracic gas volume was measured and used to obtain specific airway resistance, tissue damping, and tissue elastance. At the end of the ventilation period, a bronchoalveolar lavage sample was collected to measure inflammatory cells, macrophage inflammatory protein-2, IL-6, TNF-alpha, and protein leak. Influenza infection caused significant increases in inflammatory cells, protein leak, and deterioration in lung mechanics that were not exacerbated by mechanical ventilation, in contrast to previous studies using bacterial and mouse-specific viral infection. This study highlighted the importance of type and severity of lung injury in determining outcome following mechanical ventilation.

Lung cancer incidence and survival among HIV-infected and uninfected women and men.

PubMed

Hessol, Nancy A; Martínez-Maza, Otoniel; Levine, Alexandra M; Morris, Alison; Margolick, Joseph B; Cohen, Mardge H; Jacobson, Lisa P; Seaberg, Eric C

2015-06-19

To determine the lung cancer incidence and survival time among HIV-infected and uninfected women and men. Two longitudinal studies of HIV infection in the United States. Data from 2549 women in the Women's Interagency HIV Study (WIHS) and 4274 men in the Multicenter AIDS Cohort Study (MACS), all with a history of cigarette smoking, were analyzed. Lung cancer incidence rates and incidence rate ratios were calculated using Poisson regression analyses. Survival time was assessed using Kaplan-Meier and Cox proportional-hazard analyses. Thirty-seven women and 23 men developed lung cancer (46 HIV-infected and 14 HIV-uninfected) during study follow-up. In multivariable analyses, the factors that were found to be independently associated with a higher lung cancer incidence rate ratios were older age, less education, 10 or more pack-years of smoking, and a prior diagnosis of AIDS pneumonia (vs. HIV-uninfected women). In an adjusted Cox model that allowed different hazard functions for each cohort, a history of injection drug use was associated with shorter survival, and a lung cancer diagnosis after 2001 was associated with longer survival. In an adjusted Cox model restricted to HIV-infected participants, nadir CD4 lymphocyte cell count less than 200 was associated with shorter survival time. Our data suggest that pulmonary damage and inflammation associated with HIV infection may be causative for the increased risk of lung cancer. Encouraging and assisting younger HIV-infected smokers to quit and to sustain cessation of smoking is imperative to reduce the lung cancer burden in this population.

Retinitis due to opportunistic infections in Iranian HIV infected patients.

PubMed

Abdollahi, Ali; Mohraz, Minoo; Rasoulinejad, Mehrnaz; Shariati, Mona; Kheirandish, Parastou; Abdollahi, Maryam; Soori, Tahereh

2013-01-01

We tried to evaluate prevalence and characteristics of Iranian HIV infected patients with retinitis due to opportunistic infections. In this cross sectional study, we evaluated 106 HIV infected patients via indirect ophthalmoscopy and slit lamp examination by 90 lens to find retinitis cases. General information and results of ophthalmologic examination were analyzed. Prevalence of retinitis due to opportunistic infections was 6.6%: cytomegalovirus (CMV) retinitis 1.88%, toxoplasmosis retinochoroiditis 1.88% and tuberculosis chorioretinitis 2.83%. CD4 count was higher than 50 cell/µlit in both cases with CMV retinitis. Along with increasing survival in the HIV infected patients, the prevalence of complications such as ocular manifestation due to opportunistic infections are increasing and must be more considered.

The effect of latent adenovirus 5 infection on cigarette smoke-induced lung inflammation.

PubMed

Vitalis, T Z; Kern, I; Croome, A; Behzad, H; Hayashi, S; Hogg, J C

1998-03-01

The aim of this study was to test the hypothesis that latent adenovirus (Ad) 5 infection increases the lung inflammation that follows a single acute exposure to cigarette smoke. A recently developed model of latent adenoviral infection in guinea-pigs was used. Twelve animals were infected with Ad5 (10(8) plaque-forming units) and 12 animals were sham-infected. Thirty five days later six Ad5-infected and six sham-infected animals were exposed to the smoke from five cigarettes. The remaining animals were used as controls for both infection and smoking. As markers of inflammation, the volume fraction of macrophages, T-lymphocytes, neutrophils and eosinophils were measured by quantitative histology. We found that latent Ad5-infection alone, doubled the number of macrophages in the lung parenchyma and that smoking alone, doubled the volume fraction of neutrophils in the airway wall and the volume fraction of macrophages in the lung parenchyma. Neither viral infection nor smoking, alone, had an effect on T-lymphocytes or eosinophils. However, the combination of viral infection and smoking doubled the T-lymphocyte helper cells and quadrupled the volume fraction of macrophages in the lung parenchyma. We conclude that in guinea-pigs, latent adenovirus 5 infection increases the inflammation that follows a single acute exposure to cigarette smoke, by increasing the volume fraction of macrophages and T-lymphocyte helper cells.

Viral infection of the lungs through the eye.

PubMed

Bitko, Vira; Musiyenko, Alla; Barik, Sailen

2007-01-01

Respiratory syncytial virus (RSV) is the foremost respiratory pathogen in newborns and claims millions of lives annually. However, there has been no methodical study of the pathway(s) of entry of RSV or its interaction with nonrespiratory tissues. We and others have recently established a significant association between allergic conjunctivitis and the presence of RSV in the eye. Here we adopt a BALB/c mouse model and demonstrate that when instilled in the live murine eye, RSV not only replicated robustly in the eye but also migrated to the lung and produced a respiratory disease that is indistinguishable from the standard, nasally acquired RSV disease. Ocularly applied synthetic anti-RSV small interfering RNA prevented infection of the eye as well as the lung. RSV infection of the eye activated a plethora of ocular cytokines and chemokines with profound relevance to inflammation of the eye. Anticytokine treatments in the eye reduced ocular inflammation but had no effect on viral growth in both eye and lung, demonstrating a role of the cytokine response in ocular pathology. These results establish the eye as a major gateway of respiratory infection and a respiratory virus as a bona fide eye pathogen, thus offering novel intervention and treatment options.

Curcumin alone and in combination with augmentin protects against pulmonary inflammation and acute lung injury generated during Klebsiella pneumoniae B5055-induced lung infection in BALB/c mice.

PubMed

Bansal, Shruti; Chhibber, Sanjay

2010-04-01

Acute lung injuries due to acute lung infections remain a major cause of mortality. Thus a combination of an antibiotic and a compound with immunomodulatory and anti-inflammatory activities can help to overcome acute lung infection-induced injuries. Curcumin derived from the rhizome of turmeric has been used for decades and it exhibits anti-inflammatory, anti-carcinogenic, immunomodulatory properties by downregulation of various inflammatory mediators. Keeping these properties in mind, we investigated the anti-inflammatory properties of curcumin in a mouse model of acute inflammation by introducing Klebsiella pneumoniae B5055 into BALB/c mice via the intranasal route. Intranasal instillation of bacteria in this mouse model of acute pneumonia-induced inflammation resulted in a significant increase in neutrophil infiltration in the lungs along with increased production of various inflammatory mediators [i.e. malondialdehyde (MDA), myeloperoxidase (MPO), nitric oxide (NO), tumour necrosis factor (TNF)-alpha] in the lung tissue. The animals that received curcumin alone orally or in combination with augmentin, 15 days prior to bacterial instillation into the lungs via the intranasal route, showed a significant (P <0.05) decrease in neutrophil influx into the lungs and a significant (P <0.05) decrease in the production of MDA, NO, MPO activity and TNF-alpha levels. Augmentin treatment alone did not decrease the MDA, MPO, NO and TNF-alpha levels significantly (P >0.05) as compared to the control group. We therefore conclude that curcumin ameliorates lung inflammation induced by K. pneumoniae B5055 without significantly (P <0.05) decreasing the bacterial load in the lung tissue whereas augmentin takes care of bacterial proliferation. Hence, curcumin can be used as an adjunct therapy along with antibiotics as an anti-inflammatory or an immunomodulatory agent in the case of acute lung infection.

CXCR3 chemokine ligands during respiratory viral infections predict lung allograft dysfunction.

PubMed

Weigt, S S; Derhovanessian, A; Liao, E; Hu, S; Gregson, A L; Kubak, B M; Saggar, R; Saggar, R; Plachevskiy, V; Fishbein, M C; Lynch, J P; Ardehali, A; Ross, D J; Wang, H-J; Elashoff, R M; Belperio, J A

2012-02-01

Community-acquired respiratory viruses (CARV) can accelerate the development of lung allograft dysfunction, but the immunologic mechanisms are poorly understood. The chemokine receptor CXCR3 and its chemokine ligands, CXCL9, CXCL10 and CXCL11 have roles in the immune response to viruses and in the pathogenesis of bronchiolitis obliterans syndrome, the predominant manifestation of chronic lung allograft rejection. We explored the impact of CARV infection on CXCR3/ligand biology and explored the use of CXCR3 chemokines as biomarkers for subsequent lung allograft dysfunction. Seventeen lung transplant recipients with CARV infection had bronchoalveolar lavage fluid (BALF) available for analysis. For comparison, we included 34 BALF specimens (2 for each CARV case) that were negative for infection and collected at a duration posttransplant similar to a CARV case. The concentration of each CXCR3 chemokine was increased during CARV infection. Among CARV infected patients, a high BALF concentration of either CXCL10 or CXCL11 was predictive of a greater decline in forced expiratory volume in 1 s, 6 months later. CXCR3 chemokine concentrations provide prognostic information and this may have important implications for the development of novel treatment strategies to modify outcomes after CARV infection. © 2011 American Society of Transplantation and the American Society of Transplant Surgeons.

Infected colonic mass revealing a lung adenocarcinoma.

PubMed

Doussot, Alexandre; Chalumeau, Claire; Combier, Christophe; Cheynel, Nicolas; Facy, Olivier

2013-12-01

We report the case of lung adenocarcinoma revealed by infected colonic tumor in a 62-year-old man. An en bloc surgical resection was performed with uneventful recovery. The pathologic report concluded in a right mesocolic lymph node metastases from a mildly differentiated adenocarcinoma from pulmonary origin. GI metastases of lung cancer are described in the literature and are frequently asymptomatic in patient with a known primary cancer. In this patient, the complication of the metastases revealed the primary and immunochemistry permitted to adapt the systemic chemotherapy. Copyright © 2012. Published by Elsevier Masson SAS.

Modeling tuberculosis pathogenesis through ex vivo lung tissue infection.

PubMed

Carranza-Rosales, Pilar; Carranza-Torres, Irma Edith; Guzmán-Delgado, Nancy Elena; Lozano-Garza, Gerardo; Villarreal-Treviño, Licet; Molina-Torres, Carmen; Villarreal, Javier Vargas; Vera-Cabrera, Lucio; Castro-Garza, Jorge

2017-12-01

Tuberculosis (TB) is one of the top 10 causes of death worldwide. Several in vitro and in vivo experimental models have been used to study TB pathogenesis and induction of immune response during Mycobacterium tuberculosis infection. Precision cut lung tissue slices (PCLTS) is an experimental model, in which all the usual cell types of the organ are found, the tissue architecture and the interactions amongst the different cells are maintained. PCLTS in good physiological conditions, monitored by MTT assay and histology, were infected with either virulent Mycobacterium tuberculosis strain H37Rv or the TB vaccine strain Mycobacterium bovis BCG. Histological analysis showed that bacilli infecting lung tissue slices were observed in the alveolar septa, alveolar light spaces, near to type II pneumocytes, and inside macrophages. Mycobacterial infection of PCLTS induced TNF-α production, which is consistent with previous M. tuberculosis in vitro and in vivo studies. This is the first report of using PCLTS as a system to study M. tuberculosis infection. The PCLTS model provides a useful tool to evaluate the innate immune responses and other aspects during the early stages of mycobacterial infection. Copyright © 2017. Published by Elsevier Ltd.

ImmunoPET/MR imaging allows specific detection of Aspergillus fumigatus lung infection in vivo

PubMed Central

Rolle, Anna-Maria; Hasenberg, Mike; Thornton, Christopher R.; Solouk-Saran, Djamschid; Männ, Linda; Weski, Juliane; Maurer, Andreas; Fischer, Eliane; Spycher, Philipp R.; Schibli, Roger; Boschetti, Frederic; Stegemann-Koniszewski, Sabine; Bruder, Dunja; Severin, Gregory W.; Autenrieth, Stella E.; Krappmann, Sven; Davies, Genna; Pichler, Bernd J.; Gunzer, Matthias; Wiehr, Stefan

2016-01-01

Invasive pulmonary aspergillosis (IPA) is a life-threatening lung disease caused by the fungus Aspergillus fumigatus, and is a leading cause of invasive fungal infection-related mortality and morbidity in patients with hematological malignancies and bone marrow transplants. We developed and tested a novel probe for noninvasive detection of A. fumigatus lung infection based on antibody-guided positron emission tomography and magnetic resonance (immunoPET/MR) imaging. Administration of a [64Cu]DOTA-labeled A. fumigatus-specific monoclonal antibody (mAb), JF5, to neutrophil-depleted A. fumigatus-infected mice allowed specific localization of lung infection when combined with PET. Optical imaging with a fluorochrome-labeled version of the mAb showed colocalization with invasive hyphae. The mAb-based newly developed PET tracer [64Cu]DOTA-JF5 distinguished IPA from bacterial lung infections and, in contrast to [18F]FDG-PET, discriminated IPA from a general increase in metabolic activity associated with lung inflammation. To our knowledge, this is the first time that antibody-guided in vivo imaging has been used for noninvasive diagnosis of a fungal lung disease (IPA) of humans, an approach with enormous potential for diagnosis of infectious diseases and with potential for clinical translation. PMID:26787852

Long-term outcomes of lung transplant recipients with hepatitis C infection: a retrospective study of the U.S. transplant registry.

PubMed

Koenig, A; Stepanova, M; Saab, S; Ahmed, A; Wong, R; Younossi, Z M

2016-08-01

Chronic hepatitis C patients in need of a lung transplant are often considered ineligible due to their infection. To assess the association of hepatitis C virus (HCV) infection with long-term outcomes of lung transplants. From the Scientific Registry of Transplant Recipients (1995-2011), we selected all adults with and without HCV infection who underwent lung transplantation. A total of 17 762 lung transplant recipients were included (55.5% bilateral). Of those, 319 (1.83%) had positive HCV serology. The HCV-positive recipients were 1.6 years younger, less Caucasian and more African-American, and had a significantly higher rate of co-infection with hepatitis B virus (all P < 0.001). Post-transplant patients were discharged alive at similar rates regardless of HCV status: 88.4% in HCV+ vs. 90.3% in HCV- (P = 0.25). The mortality rates were also similar at 1 and 2 years after transplantation (20.7% in HCV+ vs. 19.2% in HCV- and 31.6% in HCV+ vs. 28.9% in HCV-, respectively; both P > 0.05), but at post-transplant year 3 year, mortality rate in HCV+ became significantly higher (42.5% vs. 36.4%, P = 0.04) and remained higher for the duration of the follow-up (mean 9.1 years, max 18.4 years). In multivariate survival analysis, after adjustment for confounders, being HCV+ was associated with higher mortality: adjusted hazard ratio 1.24 (1.04-1.46), P = 0.01. No association of HCV infection with time to graft loss was found (P = 0.92). Chronic HCV infection is associated with a moderate increase in post-lung transplant mortality. Treatment of HCV in lung transplant recipients may, therefore, result in improvement of post-transplant outcomes. © 2016 John Wiley & Sons Ltd.

Chronic Stenotrophomonas maltophilia infection and mortality or lung transplantation in cystic fibrosis patients.

PubMed

Waters, Valerie; Atenafu, Eshetu G; Lu, Annie; Yau, Yvonne; Tullis, Elizabeth; Ratjen, Felix

2013-09-01

Chronic Stenotrophomonas maltophilia infection is an independent risk factor for severe pulmonary exacerbations in cystic fibrosis (CF) patients. The goal of this study was to determine the effect of chronic S. maltophilia infection on mortality and the need for lung transplantation in a longitudinal study of children and adults with CF. This was a cohort study of CF patients from the Hospital for Sick Children and St Michael's Hospital (Toronto, Canada) from 1997 to 2008. A Cox Regression model was used to estimate the hazard ratio (HR) to time of death or lung transplantation adjusting for age, gender, genotype, pancreatic status, CF related diabetes (CFRD), forced expiratory volume in 1 s (FEV1), body mass index, number of pulmonary exacerbations, Pseudomonas aeruginosa, Burkholderia cepacia complex, Aspergillus and chronic S. maltophilia infection. A total of 687 patients were followed over the 12 year study period; 95 patients underwent a lung transplantation (of which 26 died) and an additional 49 patients died (total 144 events). In a Cox Regression model adjusting for baseline FEV1, baseline infection with B. cepacia complex (HR 1.72, 95% CI 1.09-2.71) and baseline chronic S. maltophilia infection (HR 2.80, 95% CI 1.65-4.76) were significantly associated with death or lung transplant. However, in a time-varying model, infection with B. cepacia complex and chronic S. maltophilia infection were no longer significant. Baseline chronic S. maltophilia infection is associated with an almost three-fold increased risk of death or lung transplant in CF patients. It is still unclear, however, whether chronic S. maltophilia infection is simply a marker of severity of disease and ultimate mortality or whether it is causally related to disease progression. Copyright © 2012 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.

Fatal disseminated Rasamsonia infection in cystic fibrosis post-lung transplantation.

PubMed

Hong, Gina; White, Marissa; Lechtzin, Noah; West, Natalie E; Avery, Robin; Miller, Heather; Lee, Richard; Lovari, Robert J; Massire, Christian; Blyn, Lawrence B; Liang, Xinglun; Sutton, Deanna A; Fu, Jianmin; Wickes, Brian L; Wiederhold, Nathan P; Zhang, Sean X

2017-03-01

Disseminated fungal infections are a known serious complication in individuals with cystic fibrosis (CF) following orthotopic lung transplantation. Aspergillus fumigatus and Scedosporium species are among the more common causes of invasive fungal infection in this population. However, it is also important for clinicians to be aware of other emerging fungal species which may require markedly different antifungal therapies. We describe the first laboratory-documented case of a fatal disseminated fungal infection caused by Rasamsonia aegroticola in a 21-year-old female CF patient status post-bilateral lung transplantation, which was only identified post-mortem. Molecular analysis revealed the presence of the identical Rasamsonia strains in the patient's respiratory cultures preceding transplantation. We propose that the patient's disseminated fungal disease and death occurred as a result of recrudescence of Rasamsonia infection from her native respiratory system in the setting of profound immunosuppression post-operatively. Since Rasamsonia species have been increasingly recovered from the respiratory tract of CF patients, we further review the literature on these fungi and discuss their association with invasive fungal infections in the CF lung transplant host. Our report suggests Rasamsonia species may be important fungal pathogens that may have fatal consequences in immunosuppressed CF patients after solid organ transplantation. Copyright © 2017 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.

Acute diesel exhaust particle exposure increases viral titre and inflammation associated with existing influenza infection, but does not exacerbate deficits in lung function

PubMed Central

Larcombe, Alexander N.; Foong, Rachel E.; Boylen, Catherine E.; Zosky, Graeme R.

2012-01-01

Please cite this paper as: Larcombe et al. (2012) Acute diesel exhaust particle exposure increases viral titre and inflammation associated with existing influenza infection, but does not exacerbate deficits in lung function. Influenza and Other Respiratory Viruses DOI:10.1111/irv.12012. Background  Exposure to diesel exhaust particles (DEP) is thought to exacerbate many pre‐existing respiratory diseases, including asthma, bronchitis and chronic obstructive pulmonary disease, however, there is a paucity of data on whether DEP exacerbates illness due to respiratory viral infection. Objectives  To assess the physiological consequences of an acute DEP exposure during the peak of influenza‐induced illness. Methods  We exposed adult female BALB/c mice to 100 μg DEP (or control) 3·75 days after infection with 104·5 plaque forming units of influenza A/Mem71 (or control). Six hours, 24 hours and 7 days after DEP exposure we measured thoracic gas volume and lung function at functional residual capacity. Bronchoalveolar lavage fluid was taken for analyses of cellular inflammation and cytokines, and whole lungs were taken for measurement of viral titre. Results  Influenza infection resulted in significantly increased inflammation, cytokine influx and impairment to lung function. DEP exposure alone resulted in less inflammation and cytokine influx, and no impairment to lung function. Mice infected with influenza and exposed to DEP had higher viral titres and neutrophilia compared with infected mice, yet they did not have more impaired lung mechanics than mice infected with influenza alone. Conclusions  A single dose of DEP is not sufficient to physiologically exacerbate pre‐existing respiratory disease caused by influenza infection in mice. PMID:22994877

Prone position for the prevention of lung infection.

PubMed

Beuret, P

2002-04-01

Pulmonary infection is frequent in brain injured patients. It has been identified as an independent predictor of unfavorable neurological outcome, calling for attempts of prevention. We recently evaluated intermittent prone positioning for the prevention of ventilator-associated pneumonia (VAP) in comatose brain injured patients, in a randomized study. 25 patients were included in the prone position (PP) group: they were positioned on prone four hours once daily until they could get up to sit in an armchair; 26 patients were included in the supine position (SP) group. The main characteristics of the patients from the two groups were similar at randomization. The primary end-point was the incidence of lung worsening, defined by an increase in the Lung Injury Score by at least one point since the time of randomization. The incidence of lung worsening was lower in the PP group (12%) than in the SP group (50%) (p=0.003). The incidence of VAP was 38.4% in the SP group and 20% in the PP group (p=0.14). There was no serious complication attributable to prone positioning. In conclusion, the beneficial effect of prone positioning for prevention of lung infection in brain injured patients is not well established. However, in those patients, prone positioning is able to avoid the worsening of pulmonary function, especially in oxygenation.

Interleukin-12 Therapy Reduces the Number of Immune Cells and Pathology in Lungs of Mice Infected with Mycobacterium tuberculosis

PubMed Central

Nolt, Dawn; Flynn, JoAnne L.

2004-01-01

Alternate modalities for the treatment of Mycobacterium tuberculosis are needed due to the rise in numbers of immunosuppressed individuals at risk for serious disease and the increasing prevalence of multidrug-resistant isolates. Interleukin-12 (IL-12) has been shown to improve immune responses against M. tuberculosis infection in both humans and mice. Previous studies using high-dose IL-12 in various disease models reported a paradoxical immunosuppression. We demonstrate here that exogenous administration of IL-12 for 8 weeks after an aerosolized low dose of M. tuberculosis results in increased survival and decreased pulmonary bacterial loads for CD4-T-cell-deficient mice, most likely due to an early increase in gamma interferon. IL-12 treatment did not impair or enhance the ability of the wild-type mice to control infection, as measured by bacterial numbers. Two novel findings are reported here regarding exogenous IL-12 therapy for M. tuberculosis infections: (i) IL-12 treatment resulted in decreased numbers of immune cells and reduced frequencies of lymphocytes (CD8+, CD4+, and NK cells) in the lungs of infected mice and (ii) IL-12 therapy reduced the pathology of M. tuberculosis-infected lungs, as granulomas were smaller and less numerous. These studies support an immunoregulatory role for IL-12 in tuberculosis. PMID:15102810

Human papillomavirus 16/18 infections in lung cancer patients in Mexico.

PubMed

Badillo-Almaraz, I; Zapata-Benavides, P; Saavedra-Alonso, S; Zamora-Avila, D; Reséndez-Pérez, D; Tamez-Guerra, R; Herrera-Esparza, R; Rodríguez-Padilla, C

2013-01-01

Human papillomavirus (HPV) is an epitheliotropic, double-stranded DNA virus, and its high-risk genotypes are associated with human cancer. HPV genome has been detected in lung carcinomas in certain places around the world, including Mexico; however, the prevalence of this is unclear. In this study, we examine the frequency of high-risk HPV 16/18 in lung cancer tissues from a Mexican population. 39 lung cancer specimens were analyzed by polymerase chain reaction (PCR) using HPV GP5+/GP6+ primers and then were genotyped using specific primers to HPV 16/18. Additionally, in situ hybridization (ISH) was performed using BIO-labeled oligonucleotide probes. Our results identified 15 positive cases (38.46%) for HPV 16 and 1 positive case (2.56%) for HPV 18 by PCR. ISH showed the presence of HPV DNA in 13 of 16 (81%) samples, in agreement with the PCR results. In this study, we detected HPV 16/18 gene sequences in lung cancer samples obtained from Mexican patients by PCR and ISH. We found the highest prevalence of HPV 16 infection in lung adenocarcinomas, suggesting that HPV infection may be associated with lung cancer. However, further studies are needed to elucidate the role of HPV in lung carcinogenesis. Copyright © 2013 S. Karger AG, Basel.

The Superiority of IFN-λ as a Therapeutic Candidate to Control Acute Influenza Viral Lung Infection.

PubMed

Kim, Sujin; Kim, Min-Ji; Kim, Chang-Hoon; Kang, Ju Wan; Shin, Ha Kyung; Kim, Dong-Young; Won, Tae-Bin; Han, Doo Hee; Rhee, Chae Seo; Yoon, Joo-Heon; Kim, Hyun Jik

2017-02-01

Here, we studied the IFN-regulated innate immune response against influenza A virus (IAV) infection in the mouse lung and the therapeutic effect of IFN-λ2/3 in acute IAV lung infection. For viral infections, IAV (WS/33, H1N1, PR8 H1N1, H5N1) were inoculated into wild-type mice by intranasal delivery, and IAV mRNA level and viral titer were measured. To compare the antiviral effect of IFNs in vivo in the lung, neutralizing antibodies and recombinant IFNs were used. After intranasal inoculation of IAV into mice, viral infection peaked at 7 days postinfection, and the IAV titer also reached its peak at this time. We found that IFN-β and IFN-λ2/3 were preferentially induced after IAV infection and the IFN-λ2/3-mediated innate immune response was specifically required for the induction of IFN-stimulated genes (ISGs) transcription in the mouse respiratory tract. Neutralization of secreted IFN-λ2/3 aggravated acute IAV lung infection in mice with intact IFN-β induction; consistent with this finding, the transcription of ISGs was significantly reduced. Intranasal administration of IFN-λ2/3 significantly suppressed various strains of IAV infection, including WS/33 (H1N1), PR (H1N1), and H5N1 in the mouse lung, and was accompanied by greater up-regulation of ISGs. Taken together, our data indicate that the IFN-λ2/3-mediated innate immune response is necessary to protect the lungs from IAV infection, and intranasally delivered IFN-λ2/3 has the potential to be a useful therapeutic strategy for treating acute IAV lung infection.

Respiratory infections in patients with cystic fibrosis undergoing lung transplantation.

PubMed

Lobo, Leonard J; Noone, Peadar G

2014-01-01

Cystic fibrosis is an inherited disease characterised by chronic respiratory infections associated with bronchiectasis. Lung transplantation has helped to extend the lives of patients with cystic fibrosis who have advanced lung disease. However, persistent, recurrent, and newly acquired infections can be problematic. Classic cystic fibrosis-associated organisms, such as Staphylococcus aureus and Pseudomonas aeruginosa, are generally manageable post-transplantation, and are associated with favourable outcomes. Burkholderia cenocepacia poses particular challenges, although other Burkholderia species are less problematic. Despite concerns about non-tuberculous mycobacteria, especially Mycobacterium abscessus, post-transplantation survival has not been definitively shown to be less than average in patients with these infections. Fungal species can be prevalent before and after transplantation and are associated with high morbidity, so should be treated aggressively. Appropriate viral screening and antiviral prophylaxis are necessary to prevent infection with and reactivation of Epstein-Barr virus and cytomegalovirus and their associated complications. Awareness of drug pharmacokinetics and interactions in cystic fibrosis is crucial to prevent toxic effects and subtherapeutic or supratherapeutic drug dosing. With the large range of potential infectious organisms in patients with cystic fibrosis, infection control in hospital and outpatient settings is important. Despite its complexity, lung transplantation in the cystic fibrosis population is safe, with good outcomes if the clinician is aware of all the potential pathogens and remains vigilant by means of surveillance and proactive treatment. Copyright © 2014 Elsevier Ltd. All rights reserved.

Choline catabolism to glycine betaine contributes to Pseudomonas aeruginosa survival during murine lung infection.

PubMed

Wargo, Matthew J

2013-01-01

Pseudomonas aeruginosa can acquire and metabolize a variety of molecules including choline, an abundant host-derived molecule. In P. aeruginosa, choline is oxidized to glycine betaine which can be used as an osmoprotectant, a sole source of carbon and nitrogen, and as an inducer of the virulence factor, hemolytic phospholipase C (PlcH) via the transcriptional regulator GbdR. The primary objective was to determine the contribution of choline conversion to glycine betaine to P. aeruginosa survival during mouse lung infection. A secondary objective was to gain insight into the relative contributions of the different roles of glycine betaine to P. aeruginosa survival during infection. Using a model of acute murine pneumonia, we determined that deletion of the choline oxidase system (encoded by betBA) decreased P. aeruginosa survival in the mouse lung. Deletion of the glycine betaine demethylase genes (gbcA-B), required for glycine betaine catabolism, did not impact P. aeruginosa survival in the lung. Thus, the defect of the betBA mutant was not due to a requirement for glycine betaine catabolism or dependence on a downstream metabolite. Deletion of betBA decreased the abundance of plcH transcript during infection, which suggested a role for PlcH in the betBA survival defect. To test the contribution of plcH to the betBA mutant phenotype a betBAplcHR double deletion mutant was generated. The betBA and betBAplcHR double mutant had a small but significant survival defect compared to the plcHR single mutant, suggesting that regulation of plcH expression is not the only role for glycine betaine during infection. The conclusion was that choline acquisition and its oxidation to glycine betaine contribute to P. aeruginosa survival in the mouse lung. While defective plcH induction can explain a portion of the betBA mutant phenotype, the exact mechanisms driving the betBA mutant survival defect remain unknown.

Choline Catabolism to Glycine Betaine Contributes to Pseudomonas aeruginosa Survival during Murine Lung Infection

PubMed Central

Wargo, Matthew J.

2013-01-01

Pseudomonas aeruginosa can acquire and metabolize a variety of molecules including choline, an abundant host-derived molecule. In P. aeruginosa, choline is oxidized to glycine betaine which can be used as an osmoprotectant, a sole source of carbon and nitrogen, and as an inducer of the virulence factor, hemolytic phospholipase C (PlcH) via the transcriptional regulator GbdR. The primary objective was to determine the contribution of choline conversion to glycine betaine to P. aeruginosa survival during mouse lung infection. A secondary objective was to gain insight into the relative contributions of the different roles of glycine betaine to P. aeruginosa survival during infection. Using a model of acute murine pneumonia, we determined that deletion of the choline oxidase system (encoded by betBA) decreased P. aeruginosa survival in the mouse lung. Deletion of the glycine betaine demethylase genes (gbcA-B), required for glycine betaine catabolism, did not impact P. aeruginosa survival in the lung. Thus, the defect of the betBA mutant was not due to a requirement for glycine betaine catabolism or dependence on a downstream metabolite. Deletion of betBA decreased the abundance of plcH transcript during infection, which suggested a role for PlcH in the betBA survival defect. To test the contribution of plcH to the betBA mutant phenotype a betBAplcHR double deletion mutant was generated. The betBA and betBAplcHR double mutant had a small but significant survival defect compared to the plcHR single mutant, suggesting that regulation of plcH expression is not the only role for glycine betaine during infection. The conclusion was that choline acquisition and its oxidation to glycine betaine contribute to P. aeruginosa survival in the mouse lung. While defective plcH induction can explain a portion of the betBA mutant phenotype, the exact mechanisms driving the betBA mutant survival defect remain unknown. PMID:23457628

[Lung transplantation].

PubMed

Santillán-Doherty, Patricio; Jasso-Victoria, Rogelio; Olmos-Zúñiga, Raúl; Sotres-Vega, Avelina; Argote-Greene, Luis Marcelo; Escalante-Tattersfield, Tomás; Villalba-Caloca, Jaime

2005-01-01

Lung transplantation (LT) has evolved to become an important alternative in the management of patients with end-stage pulmonary disease and chronic respiratory failure. The beginnings of this technique can be traced back to the experiments of Carrel and Guthrie over a hundred years ago. However, it was not until 1963 when the first clinical experience was performed by Hardy. Clinical success did not arrive until the 1980's thanks to the works of the Toronto Lung Transplant Group. Well established criteria have been described in order to consider a patient as a potential candidate to receive a lung. Several diseases are capable of causing terminal lung damage and in general they can be classified according to their origin as obstructive (COPD, emphysema), restrictive (fibrosis), chronic infectious (cystic fibrosis, bronquiectasis), and vascular (primary pulmonary hypertension). The most frequent diagnosis is COPD. Clinically relevant modes of LT include the implant of one lung (single LT), or both lungs (bilateral sequential LT). Transplantation of the cardiopulmonary block is reserved for special situations and lobar transplantation is still considered experimental. Donor condition is essential to the success of LT. The potential donor patient frequently suffers deterioration in lung function due to edema formation or infection and both complications restrict lung's using for transplantation. Lung preservation is also limited to a short period of time which rarely exceeds 6 hours in spite of specially-designed preservative solutions such as the low potassium dextran. Outcome after LT shows current one-year survival between 65-70% with reduction to 40-45% after five years. Mortality within the first year is usually related to primary graft failure and infection. Long-term survival depends on controlling infectious problems due to immunosuppression as well as the development of bronchilitis obliterans as a manifestation of chronic rejection. LT is a therapeutic

A20 Deficiency in Lung Epithelial Cells Protects against Influenza A Virus Infection

PubMed Central

Vereecke, Lars; Mc Guire, Conor; Sze, Mozes; Schuijs, Martijn J.; Willart, Monique; Itati Ibañez, Lorena; Hammad, Hamida; Lambrecht, Bart N.; Beyaert, Rudi; Saelens, Xavier; van Loo, Geert

2016-01-01

A20 negatively regulates multiple inflammatory signalling pathways. We here addressed the role of A20 in club cells (also known as Clara cells) of the bronchial epithelium in their response to influenza A virus infection. Club cells provide a niche for influenza virus replication, but little is known about the functions of these cells in antiviral immunity. Using airway epithelial cell-specific A20 knockout (A20AEC-KO) mice, we show that A20 in club cells critically controls innate immune responses upon TNF or double stranded RNA stimulation. Surprisingly, A20AEC-KO mice are better protected against influenza A virus challenge than their wild type littermates. This phenotype is not due to decreased viral replication. Instead host innate and adaptive immune responses and lung damage are reduced in A20AEC-KO mice. These attenuated responses correlate with a dampened cytotoxic T cell (CTL) response at later stages during infection, indicating that A20AEC-KO mice are better equipped to tolerate Influenza A virus infection. Expression of the chemokine CCL2 (also named MCP-1) is particularly suppressed in the lungs of A20AEC-KO mice during later stages of infection. When A20AEC-KO mice were treated with recombinant CCL2 the protective effect was abrogated demonstrating the crucial contribution of this chemokine to the protection of A20AEC-KO mice to Influenza A virus infection. Taken together, we propose a mechanism of action by which A20 expression in club cells controls inflammation and antiviral CTL responses in response to influenza virus infection. PMID:26815999

Evolution of granulomas in lungs of mice infected aerogenically with Mycobacterium tuberculosis.

PubMed

Cardona, P J; Llatjós, R; Gordillo, S; Díaz, J; Ojanguren, I; Ariza, A; Ausina, V

2000-08-01

Aerogenous infection of C57Bl/6 mice with a virulent strain of Mycobacterium tuberculosis (CL 511) leads to the formation of primary granulomas in the lung where neutrophils, macrophages and subsequently, lymphocytes accumulate progressively around an initial cluster of infected macrophages. The spread of infection through the lung parenchyma gives rise to secondary granulomas featuring numerous lymphocytes that surround a small number of infected macrophages. Afterwards, foamy macrophages add an outer layer to the granulomas, which characteristically respect the pulmonary interstitium and remain confined within the alveolar spaces. This feature, in conjunction with the constant presence of M. tuberculosis in the products of broncho-alveolar lavage, suggests that the upward bronchial migration of infected macrophages may contribute significantly to pulmonary dissemination of mycobacterial infection. The latter would be in agreement with the persistence of chronic pulmonary infection in spite of a concomitant strong T helper 1 cell response.

Multiplicity of Mathematical Modeling Strategies to Search for Molecular and Cellular Insights into Bacteria Lung Infection

PubMed Central

Cantone, Martina; Santos, Guido; Wentker, Pia; Lai, Xin; Vera, Julio

2017-01-01

Even today two bacterial lung infections, namely pneumonia and tuberculosis, are among the 10 most frequent causes of death worldwide. These infections still lack effective treatments in many developing countries and in immunocompromised populations like infants, elderly people and transplanted patients. The interaction between bacteria and the host is a complex system of interlinked intercellular and the intracellular processes, enriched in regulatory structures like positive and negative feedback loops. Severe pathological condition can emerge when the immune system of the host fails to neutralize the infection. This failure can result in systemic spreading of pathogens or overwhelming immune response followed by a systemic inflammatory response. Mathematical modeling is a promising tool to dissect the complexity underlying pathogenesis of bacterial lung infection at the molecular, cellular and tissue levels, and also at the interfaces among levels. In this article, we introduce mathematical and computational modeling frameworks that can be used for investigating molecular and cellular mechanisms underlying bacterial lung infection. Then, we compile and discuss published results on the modeling of regulatory pathways and cell populations relevant for lung infection and inflammation. Finally, we discuss how to make use of this multiplicity of modeling approaches to open new avenues in the search of the molecular and cellular mechanisms underlying bacterial infection in the lung. PMID:28912729

Multiplicity of Mathematical Modeling Strategies to Search for Molecular and Cellular Insights into Bacteria Lung Infection.

PubMed

Cantone, Martina; Santos, Guido; Wentker, Pia; Lai, Xin; Vera, Julio

2017-01-01

Even today two bacterial lung infections, namely pneumonia and tuberculosis, are among the 10 most frequent causes of death worldwide. These infections still lack effective treatments in many developing countries and in immunocompromised populations like infants, elderly people and transplanted patients. The interaction between bacteria and the host is a complex system of interlinked intercellular and the intracellular processes, enriched in regulatory structures like positive and negative feedback loops. Severe pathological condition can emerge when the immune system of the host fails to neutralize the infection. This failure can result in systemic spreading of pathogens or overwhelming immune response followed by a systemic inflammatory response. Mathematical modeling is a promising tool to dissect the complexity underlying pathogenesis of bacterial lung infection at the molecular, cellular and tissue levels, and also at the interfaces among levels. In this article, we introduce mathematical and computational modeling frameworks that can be used for investigating molecular and cellular mechanisms underlying bacterial lung infection. Then, we compile and discuss published results on the modeling of regulatory pathways and cell populations relevant for lung infection and inflammation. Finally, we discuss how to make use of this multiplicity of modeling approaches to open new avenues in the search of the molecular and cellular mechanisms underlying bacterial infection in the lung.

Feasibility, tolerability, and outcomes of nebulized liposomal amphotericin B for Aspergillus infection prevention in lung transplantation.

PubMed

Monforte, Víctor; Ussetti, Piedad; Gavaldà, Joan; Bravo, Carles; Laporta, Rosalia; Len, Oscar; García-Gallo, Cristina López; Tenorio, Lluís; Solé, Joan; Román, Antonio

2010-05-01

Nebulized amphotericin B deoxycholate (n-ABD) is used to prevent Aspergillus infection in lung transplantation. Nebulized liposomal amphotericin B (n-LAB) is another option; however, no clinical data are available on the results of n-LAB for this purpose. In an observational study performed in 2 centers to assess the feasibility, tolerability, and outcomes of n-LAB prophylaxis, 104 consecutive patients undergoing prophylaxis with n-LAB were compared with 49 historical controls who received n-ABD. Patient follow-up lasted 12 months. The n-LAB prophylaxis regimen was 25 mg thrice weekly starting on the first post-operative day and continuing to 60 days, 25 mg once weekly from 60 to 180 days, and the same dose once every 2 weeks thereafter. Aspergillus infection developed in 8 of 104 patients (7.7%) with n-LAB prophylaxis (5 colonization, 1 simple tracheobronchitis, 1 ulcerative tracheobronchitis, and 1 invasive pulmonary infection). Ulcerative tracheobronchitis and invasive pulmonary aspergillosis were regarded as invasive disease; hence, the rate of invasive disease was 1.9% (2 patients). The control group had similar rates of Aspergillus infection (10.2%; p = 0.6) and invasive disease (4.1%; p = 0.43). In 3 patients (2.9%), n-LAB was withdrawn due to bronchospasm in 2 and nausea in 1. In the control group, prophylaxis was stopped in 2 patients (4.1%) because of bronchospasm (p = 0.7). At the dose and frequency described, n-LAB seems effective, safe, and convenient for the prevention of Aspergillus infection in lung transplant patients. Copyright (c) 2010 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.

In vivo imaging of the pathophysiological changes and neutrophil dynamics in influenza virus-infected mouse lungs.

PubMed

Ueki, Hiroshi; Wang, I-Hsuan; Fukuyama, Satoshi; Katsura, Hiroaki; da Silva Lopes, Tiago Jose; Neumann, Gabriele; Kawaoka, Yoshihiro

2018-06-25

The pathophysiological changes that occur in lungs infected with influenza viruses are poorly understood. Here we established an in vivo imaging system that combines two-photon excitation microscopy and fluorescent influenza viruses of different pathogenicity. This approach allowed us to monitor and correlate several parameters and physiological changes including the spread of infection, pulmonary permeability, pulmonary perfusion speed, number of recruited neutrophils in infected lungs, and neutrophil motion in the lungs of live mice. Several physiological changes were larger and occurred earlier in mice infected with a highly pathogenic H5N1 influenza virus compared with those infected with a mouse-adapted human strain. These findings demonstrate the potential of our in vivo imaging system to provide novel information about the pathophysiological consequences of virus infections.

Prior human polyomavirus and papillomavirus infection and incident lung cancer: a nested case-control study.

PubMed

Colombara, Danny V; Manhart, Lisa E; Carter, Joseph J; Hawes, Stephen E; Weiss, Noel S; Hughes, James P; Barnett, Matt J; Goodman, Gary E; Smith, Jennifer S; Qiao, You-Lin; Galloway, Denise A

2015-12-01

To test whether infection with select human polyomaviruses (HPyV) and human papillomaviruses (HPV) is associated with incident lung cancer. We performed a nested case-control study, testing serum from the carotene and retinol efficacy trial, conducted 1985-2005, for antibodies to Merkel cell (MCV), KI (KIV), and WU (WUV) HPyVs as well as to six high-risk and two low-risk HPV types. Incident lung cancer cases (n = 200) were frequency-matched with controls (n = 200) on age, enrollment and blood draw dates, intervention arm assignment, and the number of serum freeze/thaw cycles. Sera were tested using multiplex liquid bead microarray antibody assays. We used logistic regression to assess the association between HPyV and HPV antibodies and lung cancer. There was no evidence of a positive association between levels of MCV, KIV, or WUV antibodies and incident lung cancer (p corrected >0.10 for all trend tests; odds ratio (OR) range 0.72-1.09, p corrected >0.10 for all). There was also no evidence for a positive association between HPV 16 or 18 infection and incident lung cancer (p corrected ≥0.10 for all trend tests; OR range 0.25-2.54, p > 0.05 for all OR > 1), but the number of persons with serologic evidence of these infections was small. Prior infection with any of several types of HPyV or HPV was not associated with subsequent diagnosis of lung cancer. Infection with these viruses likely does not influence a person's risk of lung cancer in Western smoking populations.

Interstitial Lung Disease due to Siderosis in a Lathe Machine Worker.

PubMed

Gothi, D; Satija, B; Kumar, S; Kaur, Omkar

2015-01-01

Since its first description in 1936, siderosis of lung has been considered a benign pneumoconiosis due to absence of significant clinical symptoms or respiratory impairment. Subsequently, authors have questioned the non-fibrogenic property of iron. However, siderosis causing interstitial lung disease with usual interstitial pneumonia (UIP) pattern has not been described in the past. We report a case of UIP on high resolution computed tomography, proven to be siderosis on transbronchial lung biopsy in a lathe machine worker.

Concomitant Mycobacterium tuberculosis infection promotes lung tumor growth through enhancing Treg development.

PubMed

Zhou, Yan; Hu, Zhangguo; Cao, Shuhui; Yan, Bo; Qian, Jialin; Zhong, Hua

2017-08-01

Lung cancer is the most common malignancy in humans. An increased population of CD4+Foxp3+ regulatory T cells (Tregs) in the tumor-associated microenvironment plays an important role in cancer immune evasion. The exact role and the involved mechanisms of concomitant H37Rv infection in non-small cell lung cancer (NSCLC) development are still not clear. Here, we showed that H37Rv infection promoted NSCLC cell growth with a higher percentage of Tregs found in draining lymph nodes. We also determined in vitro that H37Rv infection induced macrophage maturation and PD-L1 expression, which promoted Treg proportion, with enhanced proliferation suppression function. Mechanism analysis revealed that AKT-mTORC1 signal was important for PD-L1 expression induced by H37Rv infection. Suppressing of AKT-mTORC1 signal by rapamycin or raptor deficiency showed decreased PD-L1 levels which further reduced Treg proportion in a co-culture system. Finally, tumor-bearing mice injected with H37Rv plus rapamycin enhance the immune response of lung cancer compared with injected with H37Rv alone. This study demonstrated that concomitant H37Rv infection promote NSCLC tumor immune eacape through enhancing Treg proportion.

Primary Severe Acute Respiratory Syndrome Coronavirus Infection Limits Replication but Not Lung Inflammation upon Homologous Rechallenge

PubMed Central

Clay, Candice; Donart, Nathan; Fomukong, Ndingsa; Knight, Jennifer B.; Lei, Wanli; Price, Lance; Hahn, Fletcher; Van Westrienen, Jesse

2012-01-01

Our knowledge regarding immune-protective and immunopathogenic events in severe acute respiratory syndrome coronavirus (SARS-CoV) infection is limited, and little is known about the dynamics of the immune response at the primary site of disease. Here, an African green monkey (AGM) model was used to elucidate immune mechanisms that facilitate viral clearance but may also contribute to persistent lung inflammation following SARS-CoV infection. During primary infection, SARS-CoV replicated in the AGM lung for up to 10 days. Interestingly, lung inflammation was more prevalent following viral clearance, as leukocyte numbers peaked at 14 days postinfection (dpi) and remained elevated at 28 dpi compared to those of mock-infected controls. Lung macrophages but not dendritic cells were rapidly activated, and both cell types had high activation marker expression at late infection time points. Lung proinflammatory cytokines were induced at 1 to 14 dpi, but most returned to baseline by 28 dpi except interleukin 12 (IL-12) and gamma interferon. In SARS-CoV homologous rechallenge studies, 11 of the 12 animals were free of replicating virus at day 5 after rechallenge. However, incidence and severity of lung inflammation was not reduced despite the limited viral replication upon rechallenge. Evaluating the role of antibodies in immune protection or potentiation revealed a progressive increase in anti-SARS-CoV antibodies in lung and serum that did not correlate temporally or spatially with enhanced viral replication. This study represents one of the first comprehensive analyses of lung immunity, including changes in leukocyte populations, lung-specific cytokines, and antibody responses following SARS-CoV rechallenge in AGMs. PMID:22345460

Effect of exposure to diesel exhaust particles on the susceptibility of the lung to infection.

PubMed

Castranova, V; Ma, J Y; Yang, H M; Antonini, J M; Butterworth, L; Barger, M W; Roberts, J; Ma, J K

2001-08-01

There are at least three mechanisms by which alveolar macrophages play a critical role in protecting the lung from bacterial or viral infections: production of inflammatory cytokines that recruit and activate lung phagocytes, production of antimicrobial reactive oxidant species, and production of interferon (an antiviral agent). In this article we summarize data concerning the effect of exposure to diesel exhaust particles on these alveolar macrophage functions and the role of adsorbed organic chemicals compared to the carbonaceous core in the toxicity of diesel particles. In vitro exposure of rat alveolar macrophages to diesel exhaust particles decreased the ability of lipopolysaccharide (LPS), a bacterial product] to stimulate the production of inflammatory cytokines interleukin-1 (IL-1) and tumor necrosis factor-alpha (TNF-alpha). Methanol extract exhibited this potential but methanol-washed diesel particles did not. Exposure of rats to diesel exhaust particles by intratracheal instillation also decreased LPS-induced TNF-alpha and IL-1 production from alveolar macrophages. In contrast, carbon black did not exhibit this inhibitory effect. Exposure of rats to diesel exhaust particles by inhalation decreased the ability of alveolar macrophages to produce antimicrobial reactive oxidant species in response to zymosan (a fungal component). In contrast, exposure to coal dust increased zymosan-stimulated oxidant production. In vivo exposure to diesel exhaust particles but not to carbon black decreased the ability of the lungs to clear bacteria. Inhalation exposure of mice to diesel exhaust particles but not to coal dust depressed the ability of the lung to produce the antiviral agent interferon and increased viral multiplication in the lung. These results support the hypothesis that exposure to diesel exhaust particles increases the susceptibility of the lung to infection by depressing the antimicrobial potential of alveolar macrophages. This inhibitory effect appears

Effect of exposure to diesel exhaust particles on the susceptibility of the lung to infection.

PubMed Central

Castranova, V; Ma, J Y; Yang, H M; Antonini, J M; Butterworth, L; Barger, M W; Roberts, J; Ma, J K

2001-01-01

There are at least three mechanisms by which alveolar macrophages play a critical role in protecting the lung from bacterial or viral infections: production of inflammatory cytokines that recruit and activate lung phagocytes, production of antimicrobial reactive oxidant species, and production of interferon (an antiviral agent). In this article we summarize data concerning the effect of exposure to diesel exhaust particles on these alveolar macrophage functions and the role of adsorbed organic chemicals compared to the carbonaceous core in the toxicity of diesel particles. In vitro exposure of rat alveolar macrophages to diesel exhaust particles decreased the ability of lipopolysaccharide (LPS), a bacterial product] to stimulate the production of inflammatory cytokines interleukin-1 (IL-1) and tumor necrosis factor-alpha (TNF-alpha). Methanol extract exhibited this potential but methanol-washed diesel particles did not. Exposure of rats to diesel exhaust particles by intratracheal instillation also decreased LPS-induced TNF-alpha and IL-1 production from alveolar macrophages. In contrast, carbon black did not exhibit this inhibitory effect. Exposure of rats to diesel exhaust particles by inhalation decreased the ability of alveolar macrophages to produce antimicrobial reactive oxidant species in response to zymosan (a fungal component). In contrast, exposure to coal dust increased zymosan-stimulated oxidant production. In vivo exposure to diesel exhaust particles but not to carbon black decreased the ability of the lungs to clear bacteria. Inhalation exposure of mice to diesel exhaust particles but not to coal dust depressed the ability of the lung to produce the antiviral agent interferon and increased viral multiplication in the lung. These results support the hypothesis that exposure to diesel exhaust particles increases the susceptibility of the lung to infection by depressing the antimicrobial potential of alveolar macrophages. This inhibitory effect appears

Early life rhinovirus infection exacerbates house-dust-mite induced lung disease more severely in female mice.

PubMed

Phan, Jennifer A; Kicic, Anthony; Berry, Luke J; Sly, Peter D; Larcombe, Alexander N

2016-01-01

Recent studies have employed animal models to investigate links between rhinovirus infection and allergic airways disease, however, most do not involve early life infection, and none consider the effects of sex on responses. Here, we infected male and female mice with human rhinovirus 1B (or control) on day 7 of life. Mice were then subjected to 7 weeks of exposure to house-dust-mite prior to assessment of bronchoalveolar inflammation, serum antibodies, lung function, and responsiveness to methacholine. There were significant differences in responses between males and females in most outcomes. In males, chronic house-dust-mite exposure increased bronchoalveolar inflammation, house-dust-mite specific IgG1 and responsiveness of the lung parenchyma, however, there was no additional impact of rhinovirus infection. Conversely, in females, there were additive and synergistic effects of rhinovirus infection and house-dust-mite exposure on neutrophilia, airway resistance, and responsiveness of the lung parenchyma. We conclude that early life rhinovirus infection influences the development of house-dust-mite induced lung disease in female, but not male mice.

Suppression in lung defense responses after bacterial infection in rats pretreated with different welding fumes

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

Antonini, James M.; Taylor, Michael D.; Millecchia, Lyndell

2004-11-01

Epidemiology suggests that inhalation of welding fumes increases the susceptibility to lung infection. The effects of chemically distinct welding fumes on lung defense responses after bacterial infection were compared. Fume was collected during gas metal arc (GMA) or flux-covered manual metal arc (MMA) welding using two consumable electrodes: stainless steel (SS) or mild steel (MS). The fumes were separated into water-soluble and -insoluble fractions. The GMA-SS and GMA-MS fumes were found to be relatively insoluble, whereas the MMA-SS was highly water soluble, with the soluble fraction comprised of 87% Cr and 11% Mn. On day 0, male Sprague-Dawley rats weremore » intratracheally instilled with saline (vehicle control) or the different welding fumes (0.1 or 2 mg/rat). At day 3, the rats were intratracheally inoculated with 5 x 10{sup 3} Listeria monocytogenes. On days 6, 8, and 10, left lungs were removed, homogenized, cultured overnight, and colony-forming units were counted to assess pulmonary bacterial clearance. Bronchoalveolar lavage (BAL) was performed on right lungs to recover phagocytes and BAL fluid to measure the production of nitric oxide (NO) and immunomodulatory cytokines, including tumor necrosis factor-{alpha} (TNF-{alpha}), interleukin (IL)-2, IL-6, and IL-10. In contrast to the GMA-SS, GMA-MS, and saline groups, pretreatment with the highly water soluble MMA-SS fume caused significant body weight loss, extensive lung damage, and a dramatic reduction in pulmonary clearance of L. monocytogenes after infection. NO concentrations in BAL fluid and lung immunostaining of inducible NO synthase were dramatically increased in rats pretreated with MMA-SS before and after infection. MMA-SS treatment caused a significant decrease in IL-2 and significant increases in TNF-{alpha}, IL-6, and IL-10 after infection. In conclusion, pretreatment with MMA-SS increased production of NO and proinflammatory cytokines (TNF-{alpha} and IL-6) after infection, which are

Suppression in lung defense responses after bacterial infection in rats pretreated with different welding fumes.

PubMed

Antonini, James M; Taylor, Michael D; Millecchia, Lyndell; Bebout, Alicia R; Roberts, Jenny R

2004-11-01

Epidemiology suggests that inhalation of welding fumes increases the susceptibility to lung infection. The effects of chemically distinct welding fumes on lung defense responses after bacterial infection were compared. Fume was collected during gas metal arc (GMA) or flux-covered manual metal arc (MMA) welding using two consumable electrodes: stainless steel (SS) or mild steel (MS). The fumes were separated into water-soluble and -insoluble fractions. The GMA-SS and GMA-MS fumes were found to be relatively insoluble, whereas the MMA-SS was highly water soluble, with the soluble fraction comprised of 87% Cr and 11% Mn. On day 0, male Sprague-Dawley rats were intratracheally instilled with saline (vehicle control) or the different welding fumes (0.1 or 2 mg/rat). At day 3, the rats were intratracheally inoculated with 5 x 10(3) Listeria monocytogenes. On days 6, 8, and 10, left lungs were removed, homogenized, cultured overnight, and colony-forming units were counted to assess pulmonary bacterial clearance. Bronchoalveolar lavage (BAL) was performed on right lungs to recover phagocytes and BAL fluid to measure the production of nitric oxide (NO) and immunomodulatory cytokines, including tumor necrosis factor-alpha (TNF-alpha), interleukin (IL)-2, IL-6, and IL-10. In contrast to the GMA-SS, GMA-MS, and saline groups, pretreatment with the highly water soluble MMA-SS fume caused significant body weight loss, extensive lung damage, and a dramatic reduction in pulmonary clearance of L. monocytogenes after infection. NO concentrations in BAL fluid and lung immunostaining of inducible NO synthase were dramatically increased in rats pretreated with MMA-SS before and after infection. MMA-SS treatment caused a significant decrease in IL-2 and significant increases in TNF-alpha, IL-6, and IL-10 after infection. In conclusion, pretreatment with MMA-SS increased production of NO and proinflammatory cytokines (TNF-alpha and IL-6) after infection, which are likely responsible for

Lung granulomatous response induced by infection with the intestinal nematode Nippostrongylusbrasiliensis is suppressed in mast cell-deficient Ws/Ws rats

PubMed Central

ARIZONO, N; NISHIDA, M; UCHIKAWA, R; YAMADA, M; MATSUDA, S; TEGOSHI, T; KITAMURA, Y; SASABE, M

1996-01-01

Certain nematode infections induce eosinophil infiltration and granulomatous responses in the lungs. To examine the role of mast cells in the development of lung lesions, normal +/+ and genetically mast cell-deficient Ws/Ws rats were infected with the nematode Nippostrongylusbrasiliensis. In +/+ rats, numbers of eosinophils in bronchoalveolar lavage fluid (BALF) increased significantly 3–7 days after infection, and granulomatous responses composed of histiocytes/macrophages and multinucleate giant cells were triggered in the lungs 3–14 days after infection. Challenge infection, which was carried out on day 28 after primary infection, induced much higher levels of granulomatous response than after primary infection, suggesting that the response is mediated at least in part by an immunological mechanism. In Ws/Ws rats, both the eosinophil percentage in BALF and the size of the granulomas in the lungs were significantly smaller than in +/+ rats after primary as well as after challenge infection. The amount of rat mast cell protease (RMCP) II in +/+ rat BALF was increased 1 day after primary infection and more significantly after challenge infection, suggesting that lung mucosal mast cells were activated more markedly after the challenge infection. In Ws/Ws rats, RMCP II was undetectable throughout the observation period. The time course of nematode migration in the lungs did not differ in +/+ and Ws/Ws rats. These results suggest that mast cell activation might be relevant to eosinophil infiltration and granulomatous response in the lungs, although the responses do not affect lung migration of the nematode. PMID:8870698

Pulmonary infections and risk of lung cancer among persons with AIDS.

PubMed

Shebl, Fatma M; Engels, Eric A; Goedert, James J; Chaturvedi, Anil K

2010-11-01

Lung cancer risk is significantly increased among persons with AIDS (PWA), and increased smoking may not explain all of the elevated risk, suggesting a role for additional cofactors. We investigated whether AIDS-defining pulmonary infections (recurrent pneumonia, Pneumocystis jirovecii pneumonia, and pulmonary tuberculosis) affected the risk of subsequent lung cancer over 10 years after AIDS onset among 322,675 PWA, whose records were linked with cancer registries in 11 US regions. We assessed lung cancer hazard ratios (HRs) using Cox regression and indirectly adjusted HRs for confounding by smoking. Individuals with recurrent pneumonia (n = 5317) were at significantly higher lung cancer risk than those without [HR = 1.63, 95% confidence interval (CI) = 1.08 to 2.46, adjusted for age, race, sex, HIV acquisition mode, CD4 count, and AIDS diagnosis year]. This association was especially strong among young PWA (<50 years HR = 1.99 vs. ≥50 years HR = 1.10) and was significantly elevated during 5-10 years after recurrent pneumonia diagnosis (HR = 2.41; 95% CI = 1.07 to 5.47). Although attenuated, HRs for recurrent pneumonia remained nonsignificantly elevated after indirect adjustment for smoking. Lung cancer risk was unrelated to tuberculosis [(n = 13,878) HR = 1.12, 95% CI = 0.82 to 1.53] or Pneumocystis jirovecii pneumonia [(n = 69,771) HR = 0.97, 95% CI = 0.80 to 1.18]. The increased lung cancer risk associated with recurrent pneumonia supports the hypothesis that chronic pulmonary inflammation arising from infections contributes to lung carcinogenesis.

Chromium in stainless steel welding fume suppresses lung defense responses against bacterial infection in rats.

PubMed

Antonini, James M; Roberts, Jenny R

2007-04-01

Pulmonary infections have been reported to be increased in welders. Previous animal studies have indicated that manual metal arc, stainless steel welding fume (MMA-SS) increased susceptibility to lung infections. MMA-SS is composed of a complex of metals (e.g., iron, chromium, nickel). The objective was to determine which metal component of MMA-SS welding fume alters lung defense responses. At Day 0, rats were intratracheally instilled one time with saline or MMA-SS at a concentration of 2 mg/rat. Additional rats were treated with the metal constituents, Fe(2)O(3), NiO, or Cr(2)Na(2)O(7) alone or in combination, at concentrations that are present in the dose used for MMA-SS treatment. At Day 3, rats were intratracheally inoculated with 5 x 10(3) Listeria monocytogenes. At Days 6, 8 and 10, homogenized left lungs were cultured, and colony-forming units were counted after an overnight incubation to assess pulmonary bacterial clearance. At Day 3 (prior to infection) and at Days 6, 8 and 10, right lungs were lavaged to recover cells and fluid from the airspaces to measure lung injury, inflammation, and cytokine secretion. The production of reactive oxygen species by phagocytes recovered from the lungs was measured. Exposure to MMA-SS, soluble Cr, or the mixture of all three metals before infection significantly increased bacterial lung burden and tissue damage when compared to control. Animals treated with NiO or Fe(2)O(3) did not differ from control. Animals pre-treated with soluble Cr had alterations in inflammation and in the production of different cytokines (TNFalpha, IL-6, IL-2, and IL-12) involved in lung immune responses. This study indicates that soluble Cr present in MMA-SS is likely the primary component responsible for the suppression of lung defense responses associated with stainless steel welding fumes.

Cytomegalovirus infections in lung and hematopoietic cell transplant recipients in the Organ Transplant Infection Prevention and Detection Study: A multi-year, multicenter prospective cohort study.

PubMed

Avery, Robin K; Silveira, Fernanda P; Benedict, Kaitlin; Cleveland, Angela A; Kauffman, Carol A; Schuster, Mindy G; Dubberke, Erik R; Husain, Shahid; Paterson, David L; Chiller, Tom; Pappas, Peter

2018-03-07

Most studies of post-transplant CMV infection have focused on either solid organ or hematopoietic cell transplant (HCT) recipients. A large prospective cohort study involving both lung and HCT recipients provided an opportunity to compare the epidemiology and outcomes of CMV infections in these 2 groups. Patients were followed up for 30 months in a 6-center prospective cohort study. Data on demographics, CMV infections, tissue-invasive disease, recurrences, rejection, and immunosuppression were recorded. The overall incidence of CMV infection was 83/293 (28.3%) in the lung transplant group and 154/444 (34.7%) in the HCT group (P = .0706). Tissue-invasive CMV disease occurred in 8/83 (9.6%) of lung and 6/154 (3.9%) of HCT recipients with CMV infection, respectively (P = .087). Median time to CMV infection was longer in the lung transplant group (236 vs 40 days, P < .0001), likely reflecting the effects of prophylaxis vs preemptive therapy. Total IgG levels of < 350 mg/dL in lung recipients and graft vs host disease (GvHD) in HCT recipients were associated with increased CMV risk. HCT recipients had a higher mean number of CMV episodes (P = .008), although duration of viremia was not significantly different between the 2 groups. CMV infection was not associated with reduced overall survival in either group. Current CMV prevention strategies have resulted in a low incidence of tissue-invasive disease in both lung transplant and HCT, although CMV viremia is still relatively common. Differences between the lung and HCT groups in terms of time to CMV and recurrences of CMV viremia likely reflect differences in underlying host immunobiology and in CMV prevention strategies in the modern era. © 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Modeling of lung cancer risk due to radon exhalation of granite stone in dwelling houses.

PubMed

Abbasi, Akbar

2017-01-01

Due to increasing occurrences of lung cancer, radon exhalation rates, radon concentrations, and lung cancer risks in several types of commonly used granite stone, samples used for flooring in buildings, have been investigated. We measured the radon exhalation rates due to granite stones by means of an AlphaGUARD Model PQ2000 in a cube container with changeable floor by various granite stones. The lung cancer risk and percentage of lung cancer deaths (LCRn) due to those conditions were calculated using Darby's model. The radon exhalation rates ranged from 1.59 ± 0.41 to 9.43 ± 0.74 Bq/m 2/h. The radon concentrations in the standard room with poor and normal ventilation were calculated 20.10-71.09 Bq/m 3 and 16.12-47.01 Bq/m 3, respectively. The estimated numbers of lung cancer deaths attributable to indoor radon due to granite stones in 2013 were 145 (3.33%) and 103 (2.37%) for poor and normal ventilation systems, respectively. According to our estimations, the values of 3.33% and 2.37% of lung cancer deaths in 2013 are attributed to radon exhalation of granite stones with poor and normal ventilation systems, respectively.

A role for Toll-like receptor 4 in the host response to the lung infection of Yersinia pseudotuberculosis in mice.

PubMed

Choi, Jin-A; Jeong, Yu-Jin; Kim, Jae-Eun; Kang, Min-Jung; Kim, Jee-Cheon; Oh, Sang-Muk; Lee, Kyung-Bok; Kim, Dong-Hyun; Kim, Dong-Jae; Park, Jong-Hwan

2016-02-01

Although a Yersinia pseudotuberculosis (Yptb) lung infection model has been developed to study Y. pestis pathogenesis, it is still necessary to establish a new animal model to mimic the pathophysiological features induced by Y. pestis infection. Here, we provide a new lung infection model using the Yptb strain, IP2777, which displayed rapid spread of bacteria to the liver, spleen, and blood. In addition, we examined whether TLR4 is involved in Yptb-induced pathogenesis in the lung infection model of mice we generated. Following lung infection of WT and TLR4-deficient mice with the Yptb strain IP2777, the survival rate, bacterial colonization, histopathology, and level of cytokines and chemokines in the lung, spleen, liver, and blood were analyzed. TLR4-deficient mice had a lower survival rate than WT mice in response to Yptb lung infection. Although the bacterial colonization and pathology of the lung were comparable between WT and TLR4-deficient mice, those of the spleen and liver were more severe in TLR4-deficient mice. In addition, the levels of TNF-α and CXCL2 in the liver and IL-6 and CXCL2 in the blood were higher in TLR4-deficient mice than in WT mice. Our results demonstrate that TLR4 is necessary for optimal host protection against Yptb lung infection and TLR4-deficient mice may serve as a better genetic model of Yptb infection for mimicking Y. pestis infection. Copyright © 2016 Elsevier Ltd. All rights reserved.

Transcriptome profile of lung dendritic cells after in vitro porcine reproductive and respiratory syndrome virus (PRRSV) infection

PubMed Central

Pröll, Maren Julia; Neuhoff, Christiane; Schellander, Karl; Uddin, Muhammad Jasim; Cinar, Mehmet Ulas; Sahadevan, Sudeep; Qu, Xueqi; Islam, Md. Aminul; Poirier, Mikhael; Müller, Marcel A.; Drosten, Christian; Tesfaye, Dawit; Tholen, Ernst; Große-Brinkhaus, Christine

2017-01-01

The porcine reproductive and respiratory syndrome (PRRS) is an infectious disease that leads to high financial and production losses in the global swine industry. The pathogenesis of this disease is dependent on a multitude of factors, and its control remains problematic. The immune system generally defends against infectious diseases, especially dendritic cells (DCs), which play a crucial role in the activation of the immune response after viral infections. However, the understanding of the immune response and the genetic impact on the immune response to PRRS virus (PRRSV) remains incomplete. In light of this, we investigated the regulation of the host immune response to PRRSV in porcine lung DCs using RNA-sequencing (RNA-Seq). Lung DCs from two different pig breeds (Pietrain and Duroc) were collected before (0 hours) and during various periods of infection (3, 6, 9, 12, and 24 hours post infection (hpi)). RNA-Seq analysis revealed a total of 20,396 predicted porcine genes, which included breed-specific differentially expressed immune genes. Pietrain and Duroc infected lung DCs showed opposite gene expression courses during the first time points post infection. Duroc lung DCs reacted more strongly and distinctly than Pietrain lung DCs during these periods (3, 6, 9, 12 hpi). Additionally, cluster analysis revealed time-dependent co-expressed groups of genes that were involved in immune-relevant pathways. Key clusters and pathways were identified, which help to explain the biological and functional background of lung DCs post PRRSV infection and suggest IL-1β1 as an important candidate gene. RNA-Seq was also used to characterize the viral replication of PRRSV for each breed. PRRSV was able to infect and to replicate differently in lung DCs between the two mentioned breeds. These results could be useful in investigations on immunity traits in pig breeding and enhancing the health of pigs. PMID:29140992

Profile of cytokines in the lungs of BALB/c mice after intra-nasal infection with Histoplasma capsulatum mycelial propagules.

PubMed

Sahaza, Jorge Humberto; Suárez-Alvarez, Roberto; Estrada-Bárcenas, Daniel Alfonso; Pérez-Torres, Armando; Taylor, Maria Lucia

2015-08-01

The host pulmonary response to the fungus Histoplasma capsulatum was evaluated, through the profile of cytokines detected by the MagPix magnetic beads platform in lung homogenates and by lung-granulomas formation, from mice intra-nasally infected with mycelial propagules (M-phase) of two virulent H. capsulatum strains, EH-46 and G-217B. Results highlight that mice lung inflammatory response depends on the H. capsulatum strain used, during the first step of the fungal infection. IL-1β and TNF-α increased their concentrations in mice infected with both strains. The highest levels of IL-6, IL-17, and IL-23 were found in EH-46-infected mice, whereas levels of IL-22 were variable at all post-infection times for both strains. Significant increases of IL-12, IFN-γ, IL-4, and IL-10 were associated to EH-46-infected mice. Histological lung findings from EH-46-infected mice revealed incipient and numerous well-developed granulomas, distributed in lung-lobes at the 14th and the 21st days after infection, according to cytokine profiles. Copyright © 2015 Elsevier Ltd. All rights reserved.

Benefits and harms of lung cancer screening in HIV-infected individuals with CD4+ ≥ 500: a simulation study.

PubMed

Kong, Chung Yin; Sigel, Keith; Criss, Steven D; Sheehan, Deirdre F; Triplette, Matthew; Silverberg, Michael J; Henschke, Claudia I; Justice, Amy; Braithwaite, R Scott; Wisnivesky, Juan; Crothers, Kristina

2018-04-19

Lung cancer is the leading cause of non-AIDS-defining cancer deaths among HIV-infected individuals. Although lung cancer screening with low-dose computed tomography (LDCT) is endorsed by multiple national organizations, whether HIV-infected individuals would have similar benefit as uninfected individuals from lung cancer screening is unknown. Our objective was to determine the benefits and harms of lung cancer screening among HIV-infected individuals. We modified an existing simulation model, the Lung Cancer Policy Model, for HIV-infected patients. Veterans Aging Cohort Study, Kaiser Permanente Northern California HIV Cohort, and medical literature. Target population: HIV-infected current and former smokers. Lifetime. Population. Annual LDCT screening from ages 45, 50, or 55 until ages 72 or 77 years. Benefits assessed included lung cancer mortality reduction and life-years gained; harms assessed included numbers of LDCT examinations, false-positive results, and overdiagnosed cases. For HIV-infected patients with CD4 at least 500 and 100% antiretroviral therapy adherence, screening using the Centers for Medicare & Medicaid Services criteria (age 55-77, 30 pack-years of smoking, current smoker or quit within 15 years of screening) would reduce lung cancer mortality by 18.9%, similar to the mortality reduction of uninfected individuals. Alternative screening strategies utilizing lower screening age and/or pack-years criteria increase mortality reduction, but require more LDCT examinations. Strategies assumed 100% screening adherence. Lung cancer screening reduces mortality in HIV-infected patients with CD4 at least l500, with a number of efficient strategies for eligibility, including the current Centers for Medicare & Medicaid Services criteria.

Chronic Mycobacterium abscessus infection and lung function decline in cystic fibrosis.

PubMed

Esther, Charles R; Esserman, Denise A; Gilligan, Peter; Kerr, Alan; Noone, Peadar G

2010-03-01

Although nontuberculous mycobacteria (NTM) are recognized pathogens in cystic fibrosis (CF), associations with clinical outcomes remain unclear. Microbiological data was obtained from 1216 CF patients over 8years (481+/-55patients/year). Relationships to clinical outcomes were examined in the subset (n=271, 203+/-23 patients/year) with longitudinal data. Five hundred thirty-six of 4862 (11%) acid-fast bacilli (AFB) cultures grew NTM, with Mycobacterium abscessus (n=298, 55.6%) and Mycobacterium avium complex (n=190, 35.4%) most common. Associated bacterial cultures grew Stenotrophomonas or Aspergillus species more often when NTM were isolated (18.2% vs. 8.4% and 13.9% vs. 7.2%, respectively, p<0.01). After controlling for confounders, patients with chronic M. abscessus infection had greater rates of lung function decline than those with no NTM infection (-2.52 vs. -1.64% predicted FEV(1)/year, p<0.05). NTM infection is common in CF and associated with particular pathogens. Chronic M. abscessus infection is associated with increased lung function decline. Copyright (c) 2009 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.

Detecting bacterial lung infections: in vivo evaluation of in vitro volatile fingerprints.

PubMed

Zhu, Jiangjiang; Bean, Heather D; Wargo, Matthew J; Leclair, Laurie W; Hill, Jane E

2013-03-01

The identification of bacteria by their volatilomes is of interest to many scientists and clinicians as it holds the promise of diagnosing infections in situ, particularly lung infections via breath analysis. While there are many studies reporting various bacterial volatile biomarkers or fingerprints using in vitro experiments, it has proven difficult to translate these data to in vivo breath analyses. Therefore, we aimed to create secondary electrospray ionization-mass spectrometry (SESI-MS) pathogen fingerprints directly from the breath of mice with lung infections. In this study we demonstrated that SESI-MS is capable of differentiating infected versus uninfected mice, P. aeruginosa-infected versus S. aureus-infected mice, as well as distinguish between infections caused by P. aeruginosa strains PAO1 versus FRD1, with statistical significance (p < 0.05). In addition, we compared in vitro and in vivo volatiles and observed that only 25-34% of peaks are shared between the in vitro and in vivo SESI-MS fingerprints. To the best of our knowledge, these are the first breath volatiles measured for P. aeruginosa PAO1, FRD1, and S. aureus RN450, and the first comparison of in vivo and in vitro volatile profiles from the same strains using the murine infection model.

Concomitant pulmonary infection with Nocardia transvalensis and Aspergillus ustus in lung transplantation.

PubMed

Cabada, Miguel M; Nishi, Shawn P; Lea, Alfred S; Schnadig, Vicki; Lombard, Gisele A; Lick, Scott D; Valentine, Vincent G

2010-08-01

Lung infections with Nocardia and Aspergillus spp in lung transplant recipients (LTRs) create diagnostic and therapeutic challenges. The present case illustrates the difficulties in identifying these pathogens in LTRs. A high degree of clinical suspicion and aggressive early management are required to ensure good outcomes. Although prospective data on treating these conditions are scarce, the empiric use of combination broad-spectrum anti-microbials initially seems prudent. Copyright (c) 2010 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.

Dietary protein intake may reduce hospitalisation due to infection in Māori of advanced age: LiLACS NZ.

PubMed

Wham, Carol; Baggett, Fiona; Teh, Ruth; Moyes, Simon; Kēpa, Mere; Connolly, Martin; Jatrana, Santosh; Kerse, Ngaire

2015-08-01

To investigate factors related to hospital admission for infection, specifically examining nutrient intakes of Māori in advanced age (80+ years). Face-to-face interviews with 200 Māori (85 men) to obtain demographic, social and health information. Diagnoses were validated against medical records. Detailed nutritional assessment using the 24-hour multiple-pass recall method was collected on two separate days. FOODfiles was used to analyse nutrient intake. National Health Index (NHI) numbers were matched to hospitalisations over a two-year period (12 months prior and 12 months following dietary assessment). Selected International Classification of Disease (ICD) codes were used to identify admissions related to infection. A total of 18% of participants were hospitalised due to infection, most commonly lower respiratory tract infection. Controlling for age, gender, NZ deprivation index, diabetes, CVD and chronic lung disease, a lower energy-adjusted protein intake was independently associated with hospitalisation due to infection: OR (95%CI) 1.14 (1.00-1.29), p=0.046. Protein intake may have a protective effect on the nutrition-related morbidity of older Māori. Improving dietary protein intake is a simple strategy for dietary modification aiming to decrease the risk of infections that lead to hospitalisation and other morbidities. © 2015 Public Health Association of Australia.

Innate lymphoid cells: the role in respiratory infections and lung tissue damage.

PubMed

Głobińska, Anna; Kowalski, Marek L

2017-10-01

Innate lymphoid cells (ILCs) represent a diverse family of cells of the innate immune system, which play an important role in regulation of tissue homeostasis, immunity and inflammation. Emerging evidence has highlighted the importance of ILCs in both protective immunity to respiratory infections and their pathological roles in the lungs. Therefore, the aim of this review is to summarize the current knowledge, interpret and integrate it into broader perspective, enabling greater insight into the role of ILCs in respiratory diseases. Areas covered: In this review we highlighted the role of ILCs in the lungs, citing the most recent studies in this area. PubMed searches (2004- July 2017) were conducted using the term 'innate lymphoid cells respiratory viral infections' in combination with other relevant terms including various respiratory viruses. Expert commentary: Since studies of ILCs have opened new areas of investigation, understanding the role of ILCs in respiratory infections may help to clarify the mechanisms underlying viral-induced exacerbations of lung diseases, providing the basis for novel therapeutic strategies. Potential therapeutic targets have already been identified. So far, the most promising strategy is cytokine-targeting, although further clinical trials are needed to verify its effectiveness.

Low pretransplant IgA level is associated with early post-lung transplant seromucous infection.

PubMed

Murthy, Sudish C; Avery, Robin K; Budev, Marie; Gupta, Sandeep; Pettersson, Gösta B; Nowicki, Edward R; Mehta, Atul; Chapman, Jeffrey T; Rajeswaran, Jeevanantham; Blackstone, Eugene H

2018-04-13

Infection is an important cause of morbidity and mortality after lung transplantation. Immunoglobulins are part of both seromucous (IgA) and serum (IgG) infection defense mechanisms. We therefore hypothesized that lower pretransplant IgA levels would be associated with more early post-lung transplant seromucous infections and greater mortality independent of IgG. From January 2000 to July 2010, 538 patients undergoing primary lung transplantation had pretransplant IgA (n = 429) and IgG (n = 488) measured as a clinical routine. Median IgA was 200 mg·dL -1 (2% < 70 mg·dL -1 , lower limit of normal); median IgG was 970 mg·dL -1 (5% < 600 mg·dL -1 ). Intensive microbiology review was used to categorize infections and their causative organisms within the first posttransplant year. In total, 397 seromucous infections were observed in 247 patients, most bacterial. Although IgA and IgG were moderately correlated (r = 0.5, P < .0001), low pretransplant IgA was a strong risk factor (P = .01) for seromucous infections, but pretransplant IgG was not (P ≥ .6). As pretransplant IgA levels fell below 200 mg·dL -1 , the risk of these posttransplant infections rose nearly linearly. Lower pretransplant levels of IgA were associated with greater posttransplant mortality to end of follow-up (P = .004), but pretransplant IgG was not (P ≥ .3). Low levels of preoperative IgA, an important immunoglobulin involved in mucosal immunologic defense, but not IgG, are associated with seromucous infections in the year after lung transplantation and increased follow-up mortality. It would appear prudent to identify patients with relative IgA deficiency at listing and to increase vigilance of monitoring for, and prophylaxis against, seromucous infection in this high-risk population. Copyright © 2018. Published by Elsevier Inc.

Bacterial infection profiles in lung cancer patients with febrile neutropenia.

PubMed

Lanoix, Jean-Philippe; Pluquet, Emilie; Lescure, Francois Xavier; Bentayeb, Houcine; Lecuyer, Emmanuelle; Boutemy, Marie; Dumont, Patrick; Jounieaux, Vincent; Schmit, Jean Luc; Dayen, Charles; Douadi, Youcef

2011-06-27

The chemotherapy used to treat lung cancer causes febrile neutropenia in 10 to 40% of patients. Although most episodes are of undetermined origin, an infectious etiology can be suspected in 30% of cases. In view of the scarcity of data on lung cancer patients with febrile neutropenia, we performed a retrospective study of the microbiological characteristics of cases recorded in three medical centers in the Picardy region of northern France. We analyzed the medical records of lung cancer patients with neutropenia (neutrophil count < 500/mm(3)) and fever (temperature > 38.3°C). The study included 87 lung cancer patients with febrile neutropenia (mean age: 64.2). Two thirds of the patients had metastases and half had poor performance status. Thirty-three of the 87 cases were microbiologically documented. Gram-negative bacteria (mainly enterobacteriaceae from the urinary and digestive tracts) were identified in 59% of these cases. Staphylococcus species (mainly S. aureus) accounted for a high proportion of the identified Gram-positive bacteria. Bacteremia accounted for 60% of the microbiologically documented cases of fever. 23% of the blood cultures were positive. 14% of the infections were probably hospital-acquired and 14% were caused by multidrug-resistant strains. The overall mortality rate at day 30 was 33% and the infection-related mortality rate was 16.1%. Treatment with antibiotics was successful in 82.8% of cases. In a multivariate analysis, predictive factors for treatment failure were age >60 and thrombocytopenia < 20000/mm(3). Gram-negative species were the most frequently identified bacteria in lung cancer patients with febrile neutropenia. Despite the success of antibiotic treatment and a low-risk neutropenic patient group, mortality is high in this particular population.

Downregulation of Aquaporins (AQP1 and AQP5) and Na,K-ATPase in Porcine Reproductive and Respiratory Syndrome Virus-Infected Pig Lungs.

PubMed

Zhang, Jianping; Yan, Meiping; Gu, Wei; Chen, Ao; Liu, Jie; Li, Lexing; Zhang, Songlin; Liu, Guoquan

2018-06-01

Aquaporins (AQPs) and Na,K-ATPase control water transport across the air space-capillary barrier in the distal lung and play an important role in the formation and resolution of lung edema. Porcine reproductive and respiratory syndrome virus (PRRSV) infection usually causes pulmonary inflammation and edema in the infected pig lungs. To investigate the possibility that PRRSV infection may cause altered expression of AQPs and Na,K-ATPase messenger RNA (mRNA) levels and protein expression of AQP1, AQP5, and Na,K-ATPase in the PRRSV-infected pig lungs were detected. Quantitative real-time PCR (qRT-PCR) analysis showed markedly decreased mRNA levels of AQP1 and AQP5 and Na,K-ATPase in the PRRSV-infected pig lungs compared to those of uninfected pig lungs. Western blot studies also revealed significantly reduced levels of AQP1, AQP5, and Na,K-ATPase proteins in the PRRSV-infected pig lungs. In addition, immunohistochemical (IHC) analysis showed decreased protein expression of AQP1 and AQP5 in the endothelial cells of the capillaries and venules and secretory cells of terminal bronchiole and the alveolar type I cells, respectively. The expression of Na,K-ATPase in the basolateral membrane of alveolar type II cells presented great reduction in the PRRSV-infected pig lungs. To further understand the reduction of these proteins, the ubiquitination of AQP1 and Na,K-ATPase was examined in uninfected and PRRSV-infected pig lungs. The results showed that there is no difference of ubiquitination for these proteins. Thus, our results suggest that PRRSV infection may induce downregulation of these proteins and cause impairment of edema resolution by failed water clearance in the infected pig lungs.

The influence of Actinobacillus pleuropneumoniae infection on tulathromycin pharmacokinetics and lung tissue disposition in pigs.

PubMed

Gajda, A; Bladek, T; Jablonski, A; Posyniak, A

2016-04-01

A tulathromycin concentration and pharmacokinetic parameters in plasma and lung tissue from healthy pigs and Actinobacillus pleuropneumoniae (App)-infected pigs were compared. Tulathromycin was administered intramuscularly (i.m.) to all pigs at a single dose of 2.5 mg/kg. Blood and lung tissue samples were collected during 33 days postdrug application. Tulathromycin concentration in plasma and lung was determined by high-performance liquid chromatography with tandem mass spectrometry (LC-MS/MS) method. The mean maximum plasma concentration (Cmax ) in healthy pigs was 586 ± 71 ng/mL, reached by 0.5 h, while the mean value for Cmax of tulathromycin in infected pigs was 386 ± 97 ng/mL after 0.5 h. The mean maximum tulathromycin concentration in lung of healthy group was calculated as 3412 ± 748 ng/g, detected at 12 h, while in pigs with App, the highest concentration in lung was 3337 ± 937 ng/g, determined at 48 h postdosing. The higher plasma and lung concentrations in pigs with no pulmonary inflammation were observed at the first time points sampling after tulathromycin administration, but slower elimination with elimination half-life t1/2el  = 126 h in plasma and t1/2el  = 165 h in lung, as well as longer drug persistent in infected pigs, was found. © 2015 John Wiley & Sons Ltd.

Serial Histopathological Examination of the Lungs of Mice Infected with Influenza A Virus PR8 Strain

PubMed Central

Fukushi, Masaya; Ito, Tateki; Oka, Teruaki; Kitazawa, Toshio; Miyoshi-Akiyama, Tohru; Kirikae, Teruo; Yamashita, Makoto; Kudo, Koichiro

2011-01-01

Avian influenza H5N1 and pandemic (H1N1) 2009 viruses are known to induce viral pneumonia and subsequent acute respiratory distress syndrome (ARDS) with diffuse alveolar damage (DAD). The mortality rate of ARDS/DAD is extremely high, at approximately 60%, and no effective treatment for ARDS/DAD has been established. We examined serial pathological changes in the lungs of mice infected with influenza virus to determine the progress from viral pneumonia to ARDS/DAD. Mice were intranasally infected with influenza A/Puerto Rico/8/34 (PR8) virus, and their lungs were examined both macro- and micro-pathologically every 2 days. We also evaluated general condition, survival rate, body weight, viral loads in lung, and surfactant proteins in serum. As a result, all infected mice died within 9 days postinfection. At 2 days postinfection, inflammation in alveolar septa, i.e., interstitial pneumonia, was observed around bronchioles. From 4 to 6 days postinfection, interstitial pneumonia with alveolar collapse expanded throughout the lungs. From 6 to 9 days postinfection, DAD with severe alveolar collapse was observed in the lungs of all of dying and dead mice. In contrast, DAD was not observed in the live infected-mice from 2 to 6 days postinfection, despite their poor general condition. In addition, histopathological analysis was performed in mice infected with a dose of PR8 virus which was 50% of the lethal dose for mice in the 20-day observation period. DAD with alveolar collapse was observed in all dead mice. However, in the surviving mice, instead of DAD, glandular metaplasia was broadly observed in their lungs. The present study indicates that DAD with severe alveolar collapse is associated with death in this mouse infection model of influenza virus. Inhibition of the development of DAD with alveolar collapse may decrease the mortality rate in severe viral pneumonia caused by influenza virus infection. PMID:21701593

Statistical signal processing technique for identification of different infected sites of the diseased lungs.

PubMed

Abbas, Ali

2012-06-01

Accurate Diagnosis of lung disease depends on understanding the sounds emanating from lung and its location. Lung sounds are of significance as they supply precise and important information on the health of the respiratory system. In addition, correct interpretation of breath sounds depends on a systematic approach to auscultation; it also requires the ability to describe the location of abnormal finding in relation to bony structures and anatomic landmark lines. Lungs consist of number of lobes; each lung lobe is further subdivided into smaller segments. These segments are attached to each other. Knowledge of the position of the lung segments is useful and important during the auscultation and diagnosis of the lung diseases. Usually the medical doctors give the location of the infection a segmental position reference. Breath sounds are auscultated over the anterior chest wall surface, the lateral chest wall surfaces, and posterior chest wall surface. Adventitious sounds from different location can be detected. It is common to seek confirmation of the sound detection and its location using invasive and potentially harmful imaging diagnosis techniques like x-rays. To overcome this limitation and for fast, reliable, accurate, and inexpensive diagnose a technique is developed in this research for identifying the location of infection through a computerized auscultation system.

Animals devoid of pulmonary system as infection models in the study of lung bacterial pathogens

PubMed Central

López Hernández, Yamilé; Yero, Daniel; Pinos-Rodríguez, Juan M.; Gibert, Isidre

2015-01-01

Biological disease models can be difficult and costly to develop and use on a routine basis. Particularly, in vivo lung infection models performed to study lung pathologies use to be laborious, demand a great time and commonly are associated with ethical issues. When infections in experimental animals are used, they need to be refined, defined, and validated for their intended purpose. Therefore, alternative and easy to handle models of experimental infections are still needed to test the virulence of bacterial lung pathogens. Because non-mammalian models have less ethical and cost constraints as a subjects for experimentation, in some cases would be appropriated to include these models as valuable tools to explore host–pathogen interactions. Numerous scientific data have been argued to the more extensive use of several kinds of alternative models, such as, the vertebrate zebrafish (Danio rerio), and non-vertebrate insects and nematodes (e.g., Caenorhabditis elegans) in the study of diverse infectious agents that affect humans. Here, we review the use of these vertebrate and non-vertebrate models in the study of bacterial agents, which are considered the principal causes of lung injury. Curiously none of these animals have a respiratory system as in air-breathing vertebrates, where respiration takes place in lungs. Despite this fact, with the present review we sought to provide elements in favor of the use of these alternative animal models of infection to reveal the molecular signatures of host–pathogen interactions. PMID:25699030

Intranasal delivery of Duox2 DNA using cationic polymer can prevent acute influenza A viral infection in vivo lung.

PubMed

Kim, Bong Jik; Cho, Sung Woo; Jeon, Yung Jin; An, Sujin; Jo, Ara; Lim, Jae Hyun; Kim, Dong-Young; Won, Tae-Bin; Han, Doo Hee; Rhee, Chae-Seo; Kim, Hyun Jik

2018-01-01

We studied the contribution of Duox2 in mucosal host defense against influenza A virus (IAV) infection in in vivo lung. We found that Duox2 was required for the induction of type I and III interferon (IFN)s and transient Duox2 overexpression using cationic polymer polyethyleneimine (PEI) leads to suppression of IAV infection in in vivo lung. Twenty mice (C57BL/6J) were anesthetized and challenged by intranasal administration of 213 pfu/30 μl of IAV (WS/33/H1N1), and IAV-infected mice were euthanized at 1, 3, 5, 7, 10, 14 days post infection (dpi). Duox2 small hairpin RNA (shRNA) and pCMV-Duox2 formulated with PEI were inoculated to mice to assess the regulatory mechanism between Duox2 and IFN secretion. Following intranasal IAV inoculation, viral infection was significantly aggravated from 3 dpi in in vivo lung and viral titer was highest at 7 dpi. Consistent with this, Duox2 messenger RNA (mRNA) and protein expressions were significantly induced from 3 dpi in the lung tissue of IAV-infected mice. Viral titer was much higher in IAV-infected mice that were inoculated with Duox2 shRNA accompanied with lower survival rate and extensive lung pathologies. Interestingly, severe lung pathologies in IAV-infected mice were not observed and viral titer was significantly reduced in mice with pulmonary administration of pCMV-Duox2 formulated with PEI before IAV inoculation. Both mRNA and secreted protein levels of IFN-β and IFN-λ 2/3 were highly elevated in IAV-infected mice with pCMV-Duox2 formulated with PEI. Duox2 is necessary for the regulation of IFN secretion in in vivo lung, and pulmonary administration of Duox2 DNA using cationic polymer triggers the induction of type I and III IFNs resulting in more complete suppression of IAV infection.

Influenza Infects Lung Microvascular Endothelium Leading to Microvascular Leak: Role of Apoptosis and Claudin-5

PubMed Central

Armstrong, Susan M.; Wang, Changsen; Tigdi, Jayesh; Si, Xiaoe; Dumpit, Carlo; Charles, Steffany; Gamage, Asela; Moraes, Theo J.; Lee, Warren L.

2012-01-01

Severe influenza infections are complicated by acute lung injury, a syndrome of pulmonary microvascular leak. The pathogenesis of this complication is unclear. We hypothesized that human influenza could directly infect the lung microvascular endothelium, leading to loss of endothelial barrier function. We infected human lung microvascular endothelium with both clinical and laboratory strains of human influenza. Permeability of endothelial monolayers was assessed by spectrofluorimetry and by measurement of the transendothelial electrical resistance. We determined the molecular mechanisms of flu-induced endothelial permeability and developed a mouse model of severe influenza. We found that both clinical and laboratory strains of human influenza can infect and replicate in human pulmonary microvascular endothelium, leading to a marked increase in permeability. This was caused by apoptosis of the lung endothelium, since inhibition of caspases greatly attenuated influenza-induced endothelial leak. Remarkably, replication-deficient virus also caused a significant degree of endothelial permeability, despite displaying no cytotoxic effects to the endothelium. Instead, replication-deficient virus induced degradation of the tight junction protein claudin-5; the adherens junction protein VE-cadherin and the actin cytoskeleton were unaffected. Over-expression of claudin-5 was sufficient to prevent replication-deficient virus-induced permeability. The barrier-protective agent formoterol was able to markedly attenuate flu-induced leak in association with dose-dependent induction of claudin-5. Finally, mice infected with human influenza developed pulmonary edema that was abrogated by parenteral treatment with formoterol. Thus, we describe two distinct mechanisms by which human influenza can induce pulmonary microvascular leak. Our findings have implications for the pathogenesis and treatment of acute lung injury from severe influenza. PMID:23115643

Antibiotic management of lung infections in cystic fibrosis. II. Nontuberculous mycobacteria, anaerobic bacteria, and fungi.

PubMed

Chmiel, James F; Aksamit, Timothy R; Chotirmall, Sanjay H; Dasenbrook, Elliott C; Elborn, J Stuart; LiPuma, John J; Ranganathan, Sarath C; Waters, Valerie J; Ratjen, Felix A

2014-10-01

Airway infections are a key component of cystic fibrosis (CF) lung disease. Whereas the approach to common pathogens such as Pseudomonas aeruginosa is guided by a significant body of evidence, other infections often pose a considerable challenge to treating physicians. In Part I of this series on the antibiotic management of difficult lung infections, we discussed bacterial organisms including methicillin-resistant Staphylococcus aureus, gram-negative bacterial infections, and treatment of multiple bacterial pathogens. Here, we summarize the approach to infections with nontuberculous mycobacteria, anaerobic bacteria, and fungi. Nontuberculous mycobacteria can significantly impact the course of lung disease in patients with CF, but differentiation between colonization and infection is difficult clinically as coinfection with other micro-organisms is common. Treatment consists of different classes of antibiotics, varies in intensity, and is best guided by a team of specialized clinicians and microbiologists. The ability of anaerobic bacteria to contribute to CF lung disease is less clear, even though clinical relevance has been reported in individual patients. Anaerobes detected in CF sputum are often resistant to multiple drugs, and treatment has not yet been shown to positively affect patient outcome. Fungi have gained significant interest as potential CF pathogens. Although the role of Candida is largely unclear, there is mounting evidence that Scedosporium species and Aspergillus fumigatus, beyond the classical presentation of allergic bronchopulmonary aspergillosis, can be relevant in patients with CF and treatment should be considered. At present, however there remains limited information on how best to select patients who could benefit from antifungal therapy.

Antibiotic Management of Lung Infections in Cystic Fibrosis. II. Nontuberculous Mycobacteria, Anaerobic Bacteria, and Fungi

PubMed Central

Aksamit, Timothy R.; Chotirmall, Sanjay H.; Dasenbrook, Elliott C.; Elborn, J. Stuart; LiPuma, John J.; Ranganathan, Sarath C.; Waters, Valerie J.; Ratjen, Felix A.

2014-01-01

Airway infections are a key component of cystic fibrosis (CF) lung disease. Whereas the approach to common pathogens such as Pseudomonas aeruginosa is guided by a significant body of evidence, other infections often pose a considerable challenge to treating physicians. In Part I of this series on the antibiotic management of difficult lung infections, we discussed bacterial organisms including methicillin-resistant Staphylococcus aureus, gram-negative bacterial infections, and treatment of multiple bacterial pathogens. Here, we summarize the approach to infections with nontuberculous mycobacteria, anaerobic bacteria, and fungi. Nontuberculous mycobacteria can significantly impact the course of lung disease in patients with CF, but differentiation between colonization and infection is difficult clinically as coinfection with other micro-organisms is common. Treatment consists of different classes of antibiotics, varies in intensity, and is best guided by a team of specialized clinicians and microbiologists. The ability of anaerobic bacteria to contribute to CF lung disease is less clear, even though clinical relevance has been reported in individual patients. Anaerobes detected in CF sputum are often resistant to multiple drugs, and treatment has not yet been shown to positively affect patient outcome. Fungi have gained significant interest as potential CF pathogens. Although the role of Candida is largely unclear, there is mounting evidence that Scedosporium species and Aspergillus fumigatus, beyond the classical presentation of allergic bronchopulmonary aspergillosis, can be relevant in patients with CF and treatment should be considered. At present, however there remains limited information on how best to select patients who could benefit from antifungal therapy. PMID:25167882

Intranasal IFNγ extends passive IgA antibody protection of mice against Mycobacterium tuberculosis lung infection

PubMed Central

Reljic, R; Clark, S O; Williams, A; Falero-Diaz, G; Singh, M; Challacombe, S; Marsh, P D; Ivanyi, J

2006-01-01

Intranasal inoculation of mice with monoclonal IgA against the α-crystallin (acr1) antigen can diminish the tuberculous infection in the lungs. As this effect has been observed only over a short-term, we investigated if it could be extended by inoculation of IFNγ 3 days before infection, and further coinoculations with IgA, at 2 h before and 2 and 7 days after aerosol infection with Mycobacterium tuberculosis H37Rv. This treatment reduced the lung infection at 4 weeks more than either IgA or IFNγ alone (i.e. 17-fold, from 4·2 × 107 to 2·5 × 106 CFU, P = 0·006), accompanied also by lower granulomatous infiltration of the lungs. IFNγ added prior to infection of mouse peritoneal macrophages with IgA-opsonized bacilli resulted in a synergistic increase of nitric oxide and TNFα production and a 2–3 fold decrease in bacterial counts. Our improved results suggest, that combined treatment with IFNγ and IgA could be developed towards prophylactic treatment of AIDS patients, or as an adjunct to chemotherapy. PMID:16487246

Bacterial infection profiles in lung cancer patients with febrile neutropenia

PubMed Central

2011-01-01

Background The chemotherapy used to treat lung cancer causes febrile neutropenia in 10 to 40% of patients. Although most episodes are of undetermined origin, an infectious etiology can be suspected in 30% of cases. In view of the scarcity of data on lung cancer patients with febrile neutropenia, we performed a retrospective study of the microbiological characteristics of cases recorded in three medical centers in the Picardy region of northern France. Methods We analyzed the medical records of lung cancer patients with neutropenia (neutrophil count < 500/mm3) and fever (temperature > 38.3°C). Results The study included 87 lung cancer patients with febrile neutropenia (mean age: 64.2). Two thirds of the patients had metastases and half had poor performance status. Thirty-three of the 87 cases were microbiologically documented. Gram-negative bacteria (mainly enterobacteriaceae from the urinary and digestive tracts) were identified in 59% of these cases. Staphylococcus species (mainly S. aureus) accounted for a high proportion of the identified Gram-positive bacteria. Bacteremia accounted for 60% of the microbiologically documented cases of fever. 23% of the blood cultures were positive. 14% of the infections were probably hospital-acquired and 14% were caused by multidrug-resistant strains. The overall mortality rate at day 30 was 33% and the infection-related mortality rate was 16.1%. Treatment with antibiotics was successful in 82.8% of cases. In a multivariate analysis, predictive factors for treatment failure were age >60 and thrombocytopenia < 20000/mm3. Conclusion Gram-negative species were the most frequently identified bacteria in lung cancer patients with febrile neutropenia. Despite the success of antibiotic treatment and a low-risk neutropenic patient group, mortality is high in this particular population. PMID:21707992

Morphology and Morphometry of the Lung in Corn Snakes (Pantherophis guttatus) Infected with Three Different Strains of Ferlavirus.

PubMed

Starck, J M; Neul, A; Schmidt, V; Kolb, T; Franz-Guess, S; Balcecean, D; Pees, M

2017-05-01

Ophidian paramyxovirus (ferlavirus) is a global threat to reptilian sauropsids in herpetological collections, with occasional but fatal effects. This study characterizes the effects of three different genetic strains of ferlavirus on the dynamic changes of histology and morphometry of the lung of corn snakes (Pantherophis guttatus). Lungs from 42 corn snakes were either sham-infected or infected experimentally under standardized conditions. From 4 to 49 days after intratracheal inoculation, the lungs were examined qualitatively and quantitatively. Progressive microscopical changes were seen in the lung. Initially, increased numbers of heterophils were observed in the interstitium followed by proliferation and vacuolation of epithelial cells lining faveoli. Electron microscopy revealed loss of type-I pneumocytes, hyperplasia of type-II pneumocytes, and interstitial infiltrates of heterophils and mononuclear cells. With progression of disease the respiratory epithelium was initially overgrown by transformed type-II pneumocytes and later became multilayered. The results of the study suggest that the respiratory capacity of the lungs declines with disease development. The dynamics of disease development and histopathology differed in snakes infected with different ferlavirus genogroups. Animals infected with virus genogroup B developed histopathological changes and morphometric changes more rapidly and of greater intensity than snakes infected with viruses from genogroups A or C. Copyright © 2017 Elsevier Ltd. All rights reserved.

Clinical Outcomes of Paramyxovirus Infections in Lung Transplant Recipients Treated With Oral Ribavirin: A Two-Center Case Series.

PubMed

Garcia, Bryan; Sharma, Nirmal; Johnson, Kevin; Salgado, Juan; Wille, Keith

2017-10-31

Paramyxoviruses contribute to morbidity and mortality after lung transplant and are associated with bronchiolitis obliterans syndrome. Oral ribavirin has been used off-label for treatment of paramyxoviruses in immunosuppressed patients; however, data supporting its use for this purpose are lacking. We conducted a retrospective review to evaluate clinical outcomes of lung transplant recipients infected with paramyxoviruses and received treatment with oral ribavirin at 2 tertiary referral centers. Patients who were diagnosed with paramyxovirus infection by polymerase chain reaction testing between January 2011 and December 2014 and who received oral ribavirin were included. Clinical outcomes included pulmonary function testing, infection severity, and adverse events related to treatment. Twenty-six patients were diagnosed with a paramyxovirus and received oral ribavirin. The changes in mean forced expiratory volume 1 second from preinfection to infection onset and from infection onset to postinfection were significant (1.79 ± 0.13 to 1.61 ± 0.12 L and 1.61 ± 0.12L to 1.74 ± 0.12 L; P = .0001). Similar results were seen in subgroup analysis when respiratory syncytial virus and parainfluenza infections were evaluated independently. Use of oral ribavirin for treatment of paramyxovirus infections in lung transplant recipients was safe and associated with recovery of lung function.

The association between human papillomavirus infection and lung cancer: a system review and meta-analysis

PubMed Central

Xiong, Wei-Min; Xu, Qiu-Ping; Li, Xu; Xiao, Ren-Dong; Cai, Lin; He, Fei

2017-01-01

To estimate the global attributable fraction of human papillomavirus (HPV) in lung cancer, we provided updated information through a system review and meta-analysis. We did a literature search on PubMed, Ovid and Web of Science to identify case-control studies and cohort studies that detected HPV in lung carcinomas. We included studies that tested 30 or more cases and were published before Feb 28, 2017. We collected information about gender, smoking status, HPV detection methods, HPV types, materials and clinical features. If it was not possible to abstract the required information directly from the papers, we contacted the authors. A meta-analysis was performed to calculate the pooled effect sizes (OR/RR) with 95% confidence intervals (CI) including subgroup analysis and meta-regression to explore sources of heterogeneity, by Stata 13.0 software. 36 case-control studies, contributing data for 6,980 cases of lung cancer and 7,474 controls from 17 countries and one cohort study with 24,162 exposed and 1,026,986 unexposed from China were included. HPV infection was associated with cancer of lung, pooled OR was 3.64 (95% CI: 2.60–5.08), calculated with the random-effects model. Pooled OR for allogeneic case-control studies, self-matched case-control studies and nested case-control studies were 6.71 (95% CI: 4.07–11.07), 2.59 (95% CI: 1.43–4.69) and 0.92 (95% CI: 0.63–1.36), respectively. Pooled OR for HPV 16 and HPV 18 infection, were 3.14 (95% CI: 2.07–4.76) and 2.25 (95% CI: 1.49–3.40), respectively. We also found that HPV infection may be associated with squamous cell carcinoma, adenocarcinoma and small cell carcinoma. There is evidence that HPV infection, especially HPV 16 and HPV 18 infection, significantly increase the risk of lung cancer. Future research needs to focus attention toward whether an HPV vaccine can effectively reduce the incidence of lung cancer. PMID:29221217

Imaging in lung transplants: Checklist for the radiologist.

PubMed

Madan, Rachna; Chansakul, Thanissara; Goldberg, Hilary J

2014-10-01

Post lung transplant complications can have overlapping clinical and imaging features, and hence, the time point at which they occur is a key distinguisher. Complications of lung transplantation may occur along a continuum in the immediate or longer postoperative period, including surgical and mechanical problems due to size mismatch and vascular as well as airway anastomotic complication, injuries from ischemia and reperfusion, acute and chronic rejection, pulmonary infections, and post-transplantation lymphoproliferative disorder. Life expectancy after lung transplantation has been limited primarily by chronic rejection and infection. Multiple detector computed tomography (MDCT) is critical for evaluation and early diagnosis of complications to enable selection of effective therapy and decrease morbidity and mortality among lung transplant recipients.

Lower incidence of CMV infection and acute rejections with valganciclovir prophylaxis in lung transplant recipients

PubMed Central

2013-01-01

Background Cytomegalovirus (CMV) is the most common opportunistic infection following lung transplantation. CMV replication in the lung allograft is described as accelerating the development of bronchiolitis obliterans syndrome (BOS). Finding a strategy to prevent CMV infection is an important issue. Methods We performed a retrospective, single-centre study of 114 lung transplant recipients (LTRs) who underwent lung transplantation from January 2001 to December 2006. In a smaller cohort of 88 CMV seropositive (R+) LTRs, three months of valganciclovir prophylaxis (2004-2006) was compared to three months of oral ganciclovir (2001-2003) with respect to the incidence of CMV infection/disease, the severity of CMV disease, acute rejection, BOS-free 4 year survival and 4 year survival. In the whole group of 114 LTRs the impact of CMV infection on long-term survival (BOS free 4 year survival and 6 year survival) was assessed. Results For the cohort of 88 CMV seropositive LTRs, the incidence of CMV infection/disease at one year was lower in the valganciclovir group compared to the ganciclovir group (24% vs. 54%, p = 0.003). There was a tendency towards reduced CMV disease, from 33% to 20% and a significant lower incidence of asymptomatic CMV infection (22% vs. 4%, p = 0.005). A lower incidence of acute rejection was observed in the valganciclovir group. However, there was no significant difference between the two groups in BOS free 4 year survival and 4 year survival. For the entire group of 114 LTRs, BOS-free 4 year survival for recipients with CMV disease was (32%, p = 0.005) and among those with asymptomatic CMV infection (36%, p = 0.061) as compared with patients without CMV infection (69%). Six year survival was lower among patients with CMV disease, (64%, p = 0.042) and asymptomatic CMV infection (55%, p = 0.018) than patients without CMV infection (84%). Conclusions A lower incidence of CMV infection/disease and acute rejections was

Anaphylactoid reaction in a heartworm-infected dog undergoing lung lobectomy.

PubMed

Carter, Jennifer E; Chanoit, Guillaume; Kata, Cheryl

2011-05-15

A 7-year-old 23-kg (50.6-lb) spayed female Border Collie with a history of heartworm disease was evaluated for respiratory distress. Computed tomography of the thorax revealed possible pulmonary bullae or blebs, and on the basis of these findings, a tentative diagnosis of bullous emphysema was made. Exploratory median sternotomy revealed gross pathological lesions in the right caudal lung lobe; the most peripheral portion appeared discolored (pale pink), and a clear line of demarcation was observed. Upon excision of the affected lung lobe, a worm segment was noticed both on the remaining stump of the lung lobe in the dog and in the removed lobe. At this time, the dog had an anaphylactoid reaction. The reaction was successfully treated with fluid therapy, antihistamines, and corticosteroids. Lung lobectomy of the right caudal lobe resulted in clinical resolution of the bilateral pneumothorax. However, during the postoperative period, the dog developed a hemothorax and was returned to surgery. As no obvious cause for the hemothorax was seen at the second surgery, the dog was treated for a potential coagulopathy with fresh frozen plasma, which provided clinical resolution of the hemothorax. Parasitological examination of the worm segment confirmed a Dirofilaria immitis infection. The dog was discharged 5 days after surgery and treated with doxycycline for 30 days and monthly administration of heartworm preventative was prescribed. Heartworm infection should be a differential diagnosis in dogs with spontaneous pneumothorax. Anaphylactoid reactions associated with accidental dissection of adult heartworms should be managed with treatment aimed at cardiovascular stabilization.

Host-Pathogen Interactions and Chronic Lung Allograft Dysfunction.

PubMed

Belperio, John; Palmer, Scott M; Weigt, S Sam

2017-09-01

Lung transplantation is now considered to be a therapeutic option for patients with advanced-stage lung diseases. Unfortunately, due to post-transplant complications, both infectious and noninfectious, it is only a treatment and not a cure. Infections (e.g., bacterial, viral, and fungal) in the immunosuppressed lung transplant recipient are a common cause of mortality post transplant. Infections have more recently been explored as factors contributing to the risk of chronic lung allograft dysfunction (CLAD). Each major class of infection-(1) bacterial (Staphylococcus aureus and Pseudomonas aeruginosa); (2) viral (cytomegalovirus and community-acquired respiratory viruses); and (3) fungal (Aspergillus)-has been associated with the development of CLAD. Mechanistically, the microbe seems to be interacting with the allograft cells, stimulating the induction of chemokines, which recruit recipient leukocytes to the graft. The recipient leukocyte interactions with the microbe further up-regulate chemokines, amplifying the influx of allograft-infiltrating mononuclear cells. These events can promote recipient leukocytes to interact with the allograft, triggering an alloresponse and graft dysfunction. Overall, interactions between the microbe-allograft-host immune system alters chemokine production, which, in part, plays a role in the pathobiology of CLAD and mortality due to CLAD.

Simvastatin attenuates stroke-induced splenic atrophy and lung susceptibility to spontaneous bacterial infection in mice

PubMed Central

Jin, Rong; Zhu, Xiaolei; Liu, Lin; Nanda, Anil; Granger, D Neil; Li, Guohong

2013-01-01

Background and Purpose Statins are widely used in the primary and secondary prevention of ischemic stroke, but their effects on stroke-induced immunodeppression and post-stroke infections are elusive. We investigated effects of simvastatin treatment on stroke-induced splenic atrophy and lung susceptibility to bacterial infection in acute experimental stroke in mice. Methods Ischemic stroke was induced by transient occlusion of middle cerebral artery (MCAO) followed by reperfusion. In some experiments, splenectomies were performed 2 weeks prior to MCAO. Animals were randomly assigned to sham and MCAO groups treated subcutaneously with vehicle or simvastatin (20 mg/kg/day). Brain infarction, neurological function, brain interferon-γ expression, splenic atrophy and apoptosis, and lung infection were examined. Results Simvastatin reduced stroke-induced spleen atrophy and splenic apoptosis via increased mitochrondrial anti-apoptotic Bcl-2 expression and decreased pro-apoptotic Bax translocation from cytosol into mitochondria. Splenectomy reduced brain interferon-γ (3d) and infarct size (5d) after stroke and these effects were reversed by adoptive transfer of splenocytes. Simvastatin inhibited brain interferon-γ (3d) and reduced infarct volume and neurological deficits (5d) after stroke, and these protective effects were observed not only in naïve stroke mice but also in splenectomied stroke mice adoptively transferred with splenocytes. Simvastatin also decreased the stroke-associated lung susceptibility to spontaneous bacterial infection. Conclusions Results provide the first direct experimental evidence that simvastatin ameliorates stroke-induced peripheral immunodepression by attenuating spleen atrophy and lung bacterial infection. These findings contribute to a better understanding of beneficial effects of statins in the treatment of stroke. PMID:23391769

Lung adenocarcinoma originates from retrovirus infection of proliferating type 2 pneumocytes during pulmonary post-natal development or tissue repair.

PubMed

Murgia, Claudio; Caporale, Marco; Ceesay, Ousman; Di Francesco, Gabriella; Ferri, Nicola; Varasano, Vincenzo; de las Heras, Marcelo; Palmarini, Massimo

2011-03-01

Jaagsiekte sheep retrovirus (JSRV) is a unique oncogenic virus with distinctive biological properties. JSRV is the only virus causing a naturally occurring lung cancer (ovine pulmonary adenocarcinoma, OPA) and possessing a major structural protein that functions as a dominant oncoprotein. Lung cancer is the major cause of death among cancer patients. OPA can be an extremely useful animal model in order to identify the cells originating lung adenocarcinoma and to study the early events of pulmonary carcinogenesis. In this study, we demonstrated that lung adenocarcinoma in sheep originates from infection and transformation of proliferating type 2 pneumocytes (termed here lung alveolar proliferating cells, LAPCs). We excluded that OPA originates from a bronchioalveolar stem cell, or from mature post-mitotic type 2 pneumocytes or from either proliferating or non-proliferating Clara cells. We show that young animals possess abundant LAPCs and are highly susceptible to JSRV infection and transformation. On the contrary, healthy adult sheep, which are normally resistant to experimental OPA induction, exhibit a relatively low number of LAPCs and are resistant to JSRV infection of the respiratory epithelium. Importantly, induction of lung injury increased dramatically the number of LAPCs in adult sheep and rendered these animals fully susceptible to JSRV infection and transformation. Furthermore, we show that JSRV preferentially infects actively dividing cell in vitro. Overall, our study provides unique insights into pulmonary biology and carcinogenesis and suggests that JSRV and its host have reached an evolutionary equilibrium in which productive infection (and transformation) can occur only in cells that are scarce for most of the lifespan of the sheep. Our data also indicate that, at least in this model, inflammation can predispose to retroviral infection and cancer.

Interstitial lung disease due to fumes from heat-cutting polymer rope.

PubMed

Sharman, P; Wood-Baker, R

2013-09-01

Interstitial lung disease (ILD) due to inhalation of fume/smoke from heating or burning of synthetic polymers has not been reported previously. A fish farm worker developed ILD after cutting rope (polypropylene and nylon) for about 2 hours per day over an extended period using an electrically heated 'knife'. This process produced fume/smoke that entered the workers breathing zone. No other likely cause was identified. This case suggests that exposure to airborne contaminants generated by the heating or burning of synthetic polymers has the potential to cause serious lung disease.

NKG2D is Required for Regulation of Lung Pathology and Dendritic Cell Function Following RSV Infection.

PubMed

Liu, Huan; Osterburg, Andrew R; Flury, Jennifer; Huang, Shuo; McCormack, Francis X; Cormier, Stephania A; Borchers, Michael T

2018-03-15

Respiratory syncytial virus (RSV) is a common cause of respiratory tract infection in vulnerable populations. Natural killer (NK) cells and dendritic cells (DC) are important for the effector functions of both cell types following infection. Wild type and NKG2D deficient mice were infected with RSV. Lung pathology, was assessed by histology. DC function and phenotype was evaluated by ELISA and flow cytometry. The expression of NKG2D ligands on lung and lymph node DCs was measured by immunostaining and flow cytometry. Adoptive transfer experiments were performed to assess the importance of NKG2D dependent DC function in RSV infection. NKG2D deficient mice exhibited greater lung pathology, marked by the accumulation of DCs following RSV infection.  DCs isolated from NKG2D deficient mice had impaired responses towards TLR ligands. DCs expressed NKG2D ligands on their surface, which was further increased in NKG2D deficient mice and during RSV infection. Adoptive transfer of DCs isolated from WT mice into the airways of NKG2D deficient mice ameliorated the enhanced inflammation in NKG2D deficient mice after RSV infection. NKG2D-dependent interactions with DCs control the phenotype and function of DCs and play a critical role in pulmonary host defenses against RSV infection.

Contribution of Human Lung Parenchyma and Leukocyte Influx to Oxidative Stress and Immune System-Mediated Pathology following Nipah Virus Infection

PubMed Central

Escaffre, Olivier; Saito, Tais B.; Juelich, Terry L.; Ikegami, Tetsuro; Smith, Jennifer K.; Perez, David D.; Atkins, Colm; Levine, Corri B.; Huante, Matthew B.; Nusbaum, Rebecca J.; Endsley, Janice J.

2017-01-01

ABSTRACT Nipah virus (NiV) is a zoonotic emerging paramyxovirus that can cause fatal respiratory illness or encephalitis in humans. Despite many efforts, the molecular mechanisms of NiV-induced acute lung injury (ALI) remain unclear. We previously showed that NiV replicates to high titers in human lung grafts in NOD-SCID/γ mice, resulting in a robust inflammatory response. Interestingly, these mice can undergo human immune system reconstitution by the bone marrow, liver, and thymus (BLT) reconstitution method, in addition to lung tissue engraftment, giving altogether a realistic model to study human respiratory viral infections. Here, we characterized NiV Bangladesh strain (NiV-B) infection of human lung grafts from human immune system-reconstituted mice in order to identify the overall effect of immune cells on NiV pathogenesis of the lung. We show that NiV-B replicated to high titers in human lung grafts and caused similar cytopathic effects irrespective of the presence of human leukocytes in mice. However, the human immune system interfered with virus spread across lung grafts, responded to infection by leukocyte migration to small airways and alveoli of the lung grafts, and accelerated oxidative stress in lung grafts. In addition, the presence of human leukocytes increased the expression of cytokines and chemokines that regulate inflammatory influx to sites of infection and tissue damage. These results advance our understanding of how the immune system limits NiV dissemination and contributes to ALI and inform efforts to identify therapeutic targets. IMPORTANCE Nipah virus (NiV) is an emerging paramyxovirus that can cause a lethal respiratory and neurological disease in humans. Only limited data are available on NiV pathogenesis in the human lung, and the relative contribution of the innate immune response and NiV to acute lung injury (ALI) is still unknown. Using human lung grafts in a human immune system-reconstituted mouse model, we showed that the Ni

Lung Metastases from Bile Duct Adenocarcinoma Mimicking Chronic Airway Infection and Causing Diagnostic Difficulty.

PubMed

Sato, Mitsuo; Okachi, Shotaro; Fukihara, Jun; Shimoyama, Yoshie; Wakahara, Keiko; Sakakibara, Toshihiro; Hase, Tetsunari; Onishi, Yasuharu; Ogura, Yasuhiro; Maeda, Osamu; Hasegawa, Yoshinori

2018-05-15

We herein report a case of lung metastases with unusual radiological appearances that mimicked those of chronic airway infection, causing diagnostic difficulty. A 60-year-old woman who underwent liver transplantation from a living donor was incidentally diagnosed with bile duct adenocarcinoma after a histopathological analysis of her explanted liver. Six months later, chest computed tomography (CT) revealed bilateral bronchogenic dissemination that had gradually worsened, suggesting chronic airway infection. A biopsy with bronchoscopy from a mass lesion beyond a segmental bronchus revealed adenocarcinoma identical to that of her bile duct adenocarcinoma, leading to the diagnosis of multiple lung metastases from bile duct adenocarcinoma.

Human infections due to Staphylococcus pseudintermedius, an emerging zoonosis of canine origin: report of 24 cases.

PubMed

Somayaji, R; Priyantha, M A R; Rubin, J E; Church, D

2016-08-01

Staphylococcus pseudintermedius has been recently identified as a novel species within the genus Staphylococcus, and is commonly associated with infections in dogs. Currently, there are few reports of human infections due to this bacterium. To use a population-based approach to describe the characteristics of human S. pseudintermedius infections in a large Canadian healthcare region. All adult cases aged ≥18 years identified at a large regional laboratory from April 1, 2013 to April 1, 2015 who had at least one positive culture for S. pseudintermedius were retrospectively reviewed. A combination of phenotypic methods, mass spectrometry (i.e., MALDI-TOF), and cpn60 sequencing were used to identify S. pseudintermedius. Chart review was conducted, and cases were analysed descriptively. Twenty-seven isolates of S. pseudintermedius from 24 human cases were included for analysis. 58.3% were male with median age of 61 years (IQR 55-70.5). Most patients [22 (92.1%)] had confirmed contact with dogs at time of infection. S. pseudintermedius was isolated in 18 cases (75.0%) of skin and soft tissue infections (SSTI), and 2 invasive cases (8.3%) including a prosthetic joint and bloodstream infection. The other 4 patients were considered to be colonized (skin - 3; lung - 1). Methicillin resistance was identified in 3 cases with 6 total isolates (22.2%); multi-drug resistance was also demonstrated commonly. S. pseudintermedius is most commonly associated with SSTIs in humans. Transmission probably occurs from a pet dog. Species-level identification of S. pseudintermedius is important due to the high prevalence of antibiotic resistance, particularly to methicillin. Copyright © 2016 Elsevier Inc. All rights reserved.

Infected intraparenchymal bronchogenic cyst mimicking recurrent lung abscess in a young adult.

PubMed

Ramzisham, A R M; Johann, K F; Talal, A R; Joanna, O S M; Zamrin, D M

2007-12-01

A 23 year old female with a past history of a lung abscess diagnosed at the age of 13 years presented with recurrent episodes of productive cough. Chest radiograph and a high resolution CT scan of the thorax led to the diagnosis of a left lower lobe lung abscess. She underwent a successful thoracotomy and a left lower lobe lobectomy. Histopathological examination revealed the diagnosis of an infected congenital bronchogenic cyst. The recent literature on this is reviewed.

[Lung infection by Mycobacterium terrae].

PubMed

Díaz Ricomá, N; González Vargas, F; Casado Moreno, I; Galán Antoñanza, L; Rojas Sierra, M; Alado Arboleda, J C

2001-02-01

Mycobacterium terrae complex encompasses three species of microbacteria that are usually saprophytic and that may occasionally cause disease in humans, particularly in joints and synovial fluid. The literature includes slightly over a dozen cases of pulmonary infection, although none has been described in Spain. We report a case of infection by M. terrae in an immunodepressed patient with no other risk factor. Microbial identification by culture was unexpected and clinical management was difficult due to the absence of an established treatment protocol.

Antitumor effect of malaria parasite infection in a murine Lewis lung cancer model through induction of innate and adaptive immunity.

PubMed

Chen, Lili; He, Zhengxiang; Qin, Li; Li, Qinyan; Shi, Xibao; Zhao, Siting; Chen, Ling; Zhong, Nanshan; Chen, Xiaoping

2011-01-01

Lung cancer is the most common malignancy in humans and its high fatality means that no effective treatment is available. Developing new therapeutic strategies for lung cancer is urgently needed. Malaria has been reported to stimulate host immune responses, which are believed to be efficacious for combating some clinical cancers. This study is aimed to provide evidence that malaria parasite infection is therapeutic for lung cancer. Antitumor effect of malaria infection was examined in both subcutaneously and intravenously implanted murine Lewis lung cancer (LLC) model. The results showed that malaria infection inhibited LLC growth and metastasis and prolonged the survival of tumor-bearing mice. Histological analysis of tumors from mice infected with malaria revealed that angiogenesis was inhibited, which correlated with increased terminal deoxynucleotidyl transferase-mediated (TUNEL) staining and decreased Ki-67 expression in tumors. Through natural killer (NK) cell cytotoxicity activity, cytokine assays, enzyme-linked immunospot assay, lymphocyte proliferation, and flow cytometry, we demonstrated that malaria infection provided anti-tumor effects by inducing both a potent anti-tumor innate immune response, including the secretion of IFN-γ and TNF-α and the activation of NK cells as well as adaptive anti-tumor immunity with increasing tumor-specific T-cell proliferation and cytolytic activity of CD8(+) T cells. Notably, tumor-bearing mice infected with the parasite developed long-lasting and effective tumor-specific immunity. Consequently, we found that malaria parasite infection could enhance the immune response of lung cancer DNA vaccine pcDNA3.1-hMUC1 and the combination produced a synergistic antitumor effect. Malaria infection significantly suppresses LLC growth via induction of innate and adaptive antitumor responses in a mouse model. These data suggest that the malaria parasite may provide a novel strategy or therapeutic vaccine vector for anti-lung cancer

Effects of Chinese medicinal herbs on a rat model of chronic Pseudomonas aeruginosa lung infection.

PubMed

Song, Z; Johansen, H K; Moser, C; Høiby, N

1996-05-01

The aim of the study was to evaluate the effects of two kinds of Chinese medicinal herbs, Isatis tinctoria L (ITL) and Daphne giraldii Nitsche (DGN), on a rat model of chronic Pseudomonas aeruginosa lung infection mimicking cystic fibrosis (CF). Compared to the control group, both drugs were able to reduce the incidence of lung abscess (p < 0.05) and to decrease the severity of the macroscopic pathology in lungs (p < 0.05). In the great majority of the rats, the herbs altered the inflammatory response in the lungs from an acute type inflammation, dominated by polymorphonuclear leukocytes (PMN), to a chronic type inflammation, dominated by mononuclear leukocytes (MN). DGN also improved the clearance of P. aeruginosa from the lungs (p < 0.03) compared with the control group. There were no significant differences between the control group and the two herbal groups with regard to serum IgG and IgA anti-P. aeruginosa sonicate antibodies. However, the IgM concentration in the ITL group was significantly lower than in the control group (p < 0.03). These results suggest that the two medicinal herbs might be helpful to CF patients with chronic P. aeruginosa lung infection, DGN being the most favorable.

Exacerbation of lung radiation injury by viral infection: the role of Clara cells and Clara cell secretory protein.

PubMed

Manning, Casey M; Johnston, Carl J; Hernady, Eric; Miller, Jen-nie H; Reed, Christina K; Lawrence, B Paige; Williams, Jacqueline P; Finkelstein, Jacob N

2013-06-01

Viral infections have been associated with exacerbation of disease in human cases of idiopathic pulmonary fibrosis. Since pulmonary fibrosis is a common outcome after irradiation to the lung, we hypothesized that viral infection after radiation exposure would exacerbate radiation-induced lung injury. Epithelial injury, a frequent outcome after infection, has been hypothesized to contribute to the pathogenesis of pulmonary fibrosis and bronchiolar epithelial Clara cells participate in epithelial repair. Therefore, it was further hypothesized that altered responses after irradiation involve the bronchiolar epithelial Clara cells. C57BL/6J or CCSP(-/-) mice were irradiated with 0 (sham), 5, 10 or 15 Gy to the whole thorax. At ten weeks post-irradiation, animals were mock infected or infected with influenza A virus and body weight and survival were monitored. Pulmonary function was assessed by whole-body plethysmography. The Clara cell markers, CCSP and Cyp2f2, were measured in the lung by qRT-PCR, and protein expression was visualized in the lung by immunofluorescence. Following pulmonary function tests, mice were sacrificed and tissues were collected for pathological analysis. In 15 Gy irradiated animals infected with influenza A virus, accelerated respiratory rates, reduced pulmonary function, and exacerbated lung pathology occurred earlier post-irradiation than previously observed after irradiation alone, suggesting infection accelerates the development of radiation injury. After irradiation alone, CCSP and Cyp2f2 mRNA levels were reduced, correlating with reductions in the number of Clara cells lining the airways. When combined with infection, these markers further declined and an apparent delay in recovery of mRNA expression was observed, suggesting that radiation injury leads to a chronic reduction in the number of Clara cells that may potentiate the epithelial injury observed after influenza A virus infection. This novel finding may have considerable

Stereological analysis of bacterial load and lung lesions in nonhuman primates (rhesus macaques) experimentally infected with Mycobacterium tuberculosis.

PubMed

Luciw, Paul A; Oslund, Karen L; Yang, Xiao-Wei; Adamson, Lourdes; Ravindran, Resmi; Canfield, Don R; Tarara, Ross; Hirst, Linda; Christensen, Miles; Lerche, Nicholas W; Offenstein, Heather; Lewinsohn, David; Ventimiglia, Frank; Brignolo, Laurie; Wisner, Erik R; Hyde, Dallas M

2011-11-01

Infection with Mycobacterium tuberculosis primarily produces a multifocal distribution of pulmonary granulomas in which the pathogen resides. Accordingly, quantitative assessment of the bacterial load and pathology is a substantial challenge in tuberculosis. Such assessments are critical for studies of the pathogenesis and for the development of vaccines and drugs in animal models of experimental M. tuberculosis infection. Stereology enables unbiased quantitation of three-dimensional objects from two-dimensional sections and thus is suited to quantify histological lesions. We have developed a protocol for stereological analysis of the lung in rhesus macaques inoculated with a pathogenic clinical strain of M. tuberculosis (Erdman strain). These animals exhibit a pattern of infection and tuberculosis similar to that of naturally infected humans. Conditions were optimized for collecting lung samples in a nonbiased, random manner. Bacterial load in these samples was assessed by a standard plating assay, and granulomas were graded and enumerated microscopically. Stereological analysis provided quantitative data that supported a significant correlation between bacterial load and lung granulomas. Thus this stereological approach enables a quantitative, statistically valid analysis of the impact of M. tuberculosis infection in the lung and will serve as an essential tool for objectively comparing the efficacy of drugs and vaccines.

A computational framework to detect normal and tuberculosis infected lung from H and E-stained whole slide images

NASA Astrophysics Data System (ADS)

Niazi, M. Khalid Khan; Beamer, Gillian; Gurcan, Metin N.

2017-03-01

Accurate detection and quantification of normal lung tissue in the context of Mycobacterium tuberculosis infection is of interest from a biological perspective. The automatic detection and quantification of normal lung will allow the biologists to focus more intensely on regions of interest within normal and infected tissues. We present a computational framework to extract individual tissue sections from whole slide images having multiple tissue sections. It automatically detects the background, red blood cells and handwritten digits to bring efficiency as well as accuracy in quantification of tissue sections. For efficiency, we model our framework with logical and morphological operations as they can be performed in linear time. We further divide these individual tissue sections into normal and infected areas using deep neural network. The computational framework was trained on 60 whole slide images. The proposed computational framework resulted in an overall accuracy of 99.2% when extracting individual tissue sections from 120 whole slide images in the test dataset. The framework resulted in a relatively higher accuracy (99.7%) while classifying individual lung sections into normal and infected areas. Our preliminary findings suggest that the proposed framework has good agreement with biologists on how define normal and infected lung areas.

Influenza A Virus Infection in Pigs Attracts Multifunctional and Cross-Reactive T Cells to the Lung

PubMed Central

Talker, Stephanie C.; Stadler, Maria; Koinig, Hanna C.; Mair, Kerstin H.; Rodríguez-Gómez, Irene M.; Graage, Robert; Zell, Roland; Dürrwald, Ralf; Starick, Elke; Harder, Timm; Weissenböck, Herbert; Lamp, Benjamin; Hammer, Sabine E.; Ladinig, Andrea; Saalmüller, Armin

2016-01-01

ABSTRACT Pigs are natural hosts for influenza A viruses and play a critical role in influenza epidemiology. However, little is known about their influenza-evoked T-cell response. We performed a thorough analysis of both the local and systemic T-cell response in influenza virus-infected pigs, addressing kinetics and phenotype as well as multifunctionality (gamma interferon [IFN-γ], tumor necrosis factor alpha [TNF-α], and interleukin-2 [IL-2]) and cross-reactivity. A total of 31 pigs were intratracheally infected with an H1N2 swine influenza A virus (FLUAVsw) and consecutively euthanized. Lungs, tracheobronchial lymph nodes, and blood were sampled during the first 15 days postinfection (p.i.) and at 6 weeks p.i. Ex vivo flow cytometry of lung lymphocytes revealed an increase in proliferating (Ki-67+) CD8+ T cells with an early effector phenotype (perforin+ CD27+) at day 6 p.i. Low frequencies of influenza virus-specific IFN-γ-producing CD4+ and CD8+ T cells could be detected in the lung as early as 4 days p.i. On consecutive days, influenza virus-specific CD4+ and CD8+ T cells produced mainly IFN-γ and/or TNF-α, reaching peak frequencies around day 9 p.i., which were up to 30-fold higher in the lung than in tracheobronchial lymph nodes or blood. At 6 weeks p.i., CD4+ and CD8+ memory T cells had accumulated in lung tissue. These cells showed diverse cytokine profiles and in vitro reactivity against heterologous influenza virus strains, all of which supports their potential to combat heterologous influenza virus infections in pigs. IMPORTANCE Pigs not only are a suitable large-animal model for human influenza virus infection and vaccine development but also play a central role in the emergence of new pandemic strains. Although promising candidate universal vaccines are tested in pigs and local T cells are the major correlate of heterologous control, detailed and targeted analyses of T-cell responses at the site of infection are scarce. With the present study, we

Influenza A Virus Infection in Pigs Attracts Multifunctional and Cross-Reactive T Cells to the Lung.

PubMed

Talker, Stephanie C; Stadler, Maria; Koinig, Hanna C; Mair, Kerstin H; Rodríguez-Gómez, Irene M; Graage, Robert; Zell, Roland; Dürrwald, Ralf; Starick, Elke; Harder, Timm; Weissenböck, Herbert; Lamp, Benjamin; Hammer, Sabine E; Ladinig, Andrea; Saalmüller, Armin; Gerner, Wilhelm

2016-10-15

Pigs are natural hosts for influenza A viruses and play a critical role in influenza epidemiology. However, little is known about their influenza-evoked T-cell response. We performed a thorough analysis of both the local and systemic T-cell response in influenza virus-infected pigs, addressing kinetics and phenotype as well as multifunctionality (gamma interferon [IFN-γ], tumor necrosis factor alpha [TNF-α], and interleukin-2 [IL-2]) and cross-reactivity. A total of 31 pigs were intratracheally infected with an H1N2 swine influenza A virus (FLUAVsw) and consecutively euthanized. Lungs, tracheobronchial lymph nodes, and blood were sampled during the first 15 days postinfection (p.i.) and at 6 weeks p.i. Ex vivo flow cytometry of lung lymphocytes revealed an increase in proliferating (Ki-67(+)) CD8(+) T cells with an early effector phenotype (perforin(+) CD27(+)) at day 6 p.i. Low frequencies of influenza virus-specific IFN-γ-producing CD4(+) and CD8(+) T cells could be detected in the lung as early as 4 days p.i. On consecutive days, influenza virus-specific CD4(+) and CD8(+) T cells produced mainly IFN-γ and/or TNF-α, reaching peak frequencies around day 9 p.i., which were up to 30-fold higher in the lung than in tracheobronchial lymph nodes or blood. At 6 weeks p.i., CD4(+) and CD8(+) memory T cells had accumulated in lung tissue. These cells showed diverse cytokine profiles and in vitro reactivity against heterologous influenza virus strains, all of which supports their potential to combat heterologous influenza virus infections in pigs. Pigs not only are a suitable large-animal model for human influenza virus infection and vaccine development but also play a central role in the emergence of new pandemic strains. Although promising candidate universal vaccines are tested in pigs and local T cells are the major correlate of heterologous control, detailed and targeted analyses of T-cell responses at the site of infection are scarce. With the present study, we

Contribution of Human Lung Parenchyma and Leukocyte Influx to Oxidative Stress and Immune System-Mediated Pathology following Nipah Virus Infection.

PubMed

Escaffre, Olivier; Saito, Tais B; Juelich, Terry L; Ikegami, Tetsuro; Smith, Jennifer K; Perez, David D; Atkins, Colm; Levine, Corri B; Huante, Matthew B; Nusbaum, Rebecca J; Endsley, Janice J; Freiberg, Alexander N; Rockx, Barry

2017-08-01

Nipah virus (NiV) is a zoonotic emerging paramyxovirus that can cause fatal respiratory illness or encephalitis in humans. Despite many efforts, the molecular mechanisms of NiV-induced acute lung injury (ALI) remain unclear. We previously showed that NiV replicates to high titers in human lung grafts in NOD-SCID/γ mice, resulting in a robust inflammatory response. Interestingly, these mice can undergo human immune system reconstitution by the bone marrow, liver, and thymus (BLT) reconstitution method, in addition to lung tissue engraftment, giving altogether a realistic model to study human respiratory viral infections. Here, we characterized NiV Bangladesh strain (NiV-B) infection of human lung grafts from human immune system-reconstituted mice in order to identify the overall effect of immune cells on NiV pathogenesis of the lung. We show that NiV-B replicated to high titers in human lung grafts and caused similar cytopathic effects irrespective of the presence of human leukocytes in mice. However, the human immune system interfered with virus spread across lung grafts, responded to infection by leukocyte migration to small airways and alveoli of the lung grafts, and accelerated oxidative stress in lung grafts. In addition, the presence of human leukocytes increased the expression of cytokines and chemokines that regulate inflammatory influx to sites of infection and tissue damage. These results advance our understanding of how the immune system limits NiV dissemination and contributes to ALI and inform efforts to identify therapeutic targets. IMPORTANCE Nipah virus (NiV) is an emerging paramyxovirus that can cause a lethal respiratory and neurological disease in humans. Only limited data are available on NiV pathogenesis in the human lung, and the relative contribution of the innate immune response and NiV to acute lung injury (ALI) is still unknown. Using human lung grafts in a human immune system-reconstituted mouse model, we showed that the NiV Bangladesh

Lung Metastases from Bile Duct Adenocarcinoma Mimicking Chronic Airway Infection and Causing Diagnostic Difficulty

PubMed Central

Sato, Mitsuo; Okachi, Shotaro; Fukihara, Jun; Shimoyama, Yoshie; Wakahara, Keiko; Sakakibara, Toshihiro; Hase, Tetsunari; Onishi, Yasuharu; Ogura, Yasuhiro; Maeda, Osamu; Hasegawa, Yoshinori

2017-01-01

We herein report a case of lung metastases with unusual radiological appearances that mimicked those of chronic airway infection, causing diagnostic difficulty. A 60-year-old woman who underwent liver transplantation from a living donor was incidentally diagnosed with bile duct adenocarcinoma after a histopathological analysis of her explanted liver. Six months later, chest computed tomography (CT) revealed bilateral bronchogenic dissemination that had gradually worsened, suggesting chronic airway infection. A biopsy with bronchoscopy from a mass lesion beyond a segmental bronchus revealed adenocarcinoma identical to that of her bile duct adenocarcinoma, leading to the diagnosis of multiple lung metastases from bile duct adenocarcinoma. PMID:29279503

CD4 T Cell Epitope Specificity and Cytokine Potential Are Preserved as Cells Transition from the Lung Vasculature to Lung Tissue following Influenza Virus Infection.

PubMed

DiPiazza, Anthony; Laniewski, Nathan; Rattan, Ajitanuj; Topham, David J; Miller, Jim; Sant, Andrea J

2018-07-01

Pulmonary CD4 T cells are critical in respiratory virus control, both by delivering direct effector function and through coordinating responses of other immune cells. Recent studies have shown that following influenza virus infection, virus-specific CD4 T cells are partitioned between pulmonary vasculature and lung tissue. However, very little is known about the peptide specificity or functional differences of CD4 T cells within these two compartments. Using a mouse model of influenza virus infection in conjunction with intravascular labeling in vivo , the cell surface phenotype, epitope specificity, and functional potential of the endogenous polyclonal CD4 T cell response was examined by tracking nine independent CD4 T cell epitope specificities. These studies revealed that tissue-localized CD4 cells were globally distinct from vascular cells in expression of markers associated with transendothelial migration, residency, and micropositioning. Despite these differences, there was little evidence for remodeling of the viral epitope specificity or cytokine potential as cells transition from vasculature to the highly inflamed lung tissue. Our studies also distinguished cells in the pulmonary vasculature from peripheral circulating CD4 T cells, providing support for the concept that the pulmonary vasculature does not simply reflect circulating cells that are trapped within the narrow confines of capillary vessels but rather is enriched in transitional cells primed in the draining lymph node that have specialized potential to enter the lung tissue. IMPORTANCE CD4 T cells convey a multitude of functions in immunity to influenza, including those delivered in the lymph node and others conveyed by CD4 T cells that leave the lymph node, enter the blood, and extravasate into the lung tissue. Here, we show that the transition of recently primed CD4 cells detected in the lung vasculature undergo profound changes in expression of markers associated with tissue localization as

Expression and arrangement of extracellular matrix proteins in the lungs of mice infected with Paracoccidioides brasiliensis conidia

PubMed Central

González, Angel; Lenzi, Henrique Leonel; Motta, Ester Maria; Caputo, Luzia; Restrepo, Angela; Cano, Luz Elena

2008-01-01

Extracellular matrix (ECM) proteins are important modulators of migration, differentiation and proliferation for the various cell types present in the lungs; they influence the immune response as well as participate in the adherence of several fungi including Paracoccidioides brasiliensis. The expression, deposition and arrangement of ECM proteins such as laminin, fibronectin, fibrinogen, collagen and proteoglycans in the lungs of mice infected with P. brasiliensis conidia has been evaluated in this study, together with the elastic fibre system. Lungs of BALB/c mice infected with P. brasiliensis conidia were analysed for the different ECM proteins by histological and immunohistochemical procedures at different times of infection. In addition, laser scanning confocal microscopy and scanning electron microscopy were used. During the early periods, the lungs of infected animals showed an inflammatory infiltrate composed mainly of polymorphonuclear neutrophils (PMNs) and macrophages, while during the later periods, mice presented a chronic inflammatory response with granuloma formation. Re-arrangement and increased expression of all ECM proteins tested were observed throughout all studied periods, especially during the occurrence of inflammatory infiltration and formation of the granuloma. The elastic fibre system showed an elastolysis process in all experiments. In conclusion, this study provides new details of pulmonary ECM distribution during the course of paracoccidioidomycosis. PMID:18336528

[Lung transplant].

PubMed

Espinosa, M; Rodil, R; Goikoetxea, M J; Zulueta, J; Seijo, L M

2006-01-01

A lung transplant is usually the final therapeutic option for patients with respiratory insufficiency. In spite of the many advances in immunology and the management of complications, mortality and morbidity associated with this transplant are far higher than with others. Acute rejection is an almost universal problem in the first year, while obliterative bronchitis reduces long term survival. Respiratory infections also play a significant role in the complications associated with lung transplants due to the constant exposure of the graft to the outside. However, the success of this therapeutic option, which basically depends on a suitable selection of donor and recipient, are evident, above all with respect to quality of life.

Nano-antibiotics in chronic lung infection therapy against Pseudomonas aeruginosa.

PubMed

Hadinoto, Kunn; Cheow, Wean Sin

2014-04-01

Antibiotic encapsulation into nanoparticle carriers has emerged as a promising inhaled antibiotic formulation for treatment of chronic Pseudomonas aeruginosa lung infection prevalent in chronic obstructive pulmonary diseases. Attributed to their prolonged lung retention, sustained antibiotic release, and mucus penetrating ability, antibiotic nanoparticles, or nano-antibiotics in short, can address the principal weakness of inhaled antibiotic solution, i.e. low antibiotic exposure in the vicinity of P. aeruginosa biofilm colonies resulting in diminished anti-pseudomonal efficacy after repeated uses. This review details the current state of development and limitations of the two most widely studied forms of nano-antibiotics, i.e. liposomes and polymer nanoparticles. Factors in their formulation that influence the anti-pseudomonal efficacy in vitro and in vivo, such as liposome's membrane rigidity, surface charge, size, and polymer hydrophobicity, are discussed. This review reveals that the superior anti-pseudomonal efficacy of liposomal antibiotics to free antibiotics has been clearly established when they are correctly formulated, with several liposomal antibiotic formulations are currently undergoing clinical trials. Liposomal antibiotics, nevertheless, are not without limitation due to their weak physicochemical stability. In contrast, only mucus penetrating ability of the more stable polymeric nano-antibiotics has been established, while their anti-pseudomonal efficacy has only been examined in vitro from which their superiority to free antibiotics has not been ascertained. Lastly, future research needs to bring liposome and polymer-based nano-antibiotics closer to their clinical realization are identified. Copyright © 2014 Elsevier B.V. All rights reserved.

Immune function monitoring in lung transplantation using adenosine triphosphate production: time trends and relationship to postoperative infection.

PubMed

Takahashi, Mamoru; Ohsumi, Akihiro; Ohata, Keiji; Kondo, Takeshi; Motoyama, Hideki; Hijiya, Kyoko; Aoyama, Akihiro; Date, Hiroshi; Chen-Yoshikawa, Toyofumi F

2017-06-01

The ImmuKnow (IK) assay is a comprehensive immune function test that involves measuring adenosine triphosphate produced by the cluster of differentiation 4+ T lymphocytes in peripheral blood. The aim of this study was to analyze the time trends of IK values and assess the relationship between IK values and infections in lung transplants. We prospectively collected 178 blood samples from 22 deceased-donor lung transplant (DDLT) recipients and 17 living-donor lobar lung transplant (LDLLT) recipients. A surveillance IK assay was performed postoperatively, then after 1 week and 1, 3, 6, and 12 months. Time trends of IK values in stable recipients peaked 1 week after DDLT (477 ± 247 ATP ng/ml), and 1 month after LDLLT (433 ± 134 ng/ml), followed by a gradual decline over 1 year. The mean IK values in infections were significantly lower than those in the stable state (119 vs 312 ATP ng/ml, p = 0.0002). IK values increased sharply after lung transplantation and then decreased gradually over time in the first year, suggesting a natural history of immune function. IK values were also significantly reduced during infections. These results may provide new insights into the utility of immune monitoring after lung transplantation.

Aspergillus infection in lung transplant recipients with cystic fibrosis: risk factors and outcomes comparison to other types of transplant recipients.

PubMed

Helmi, Mohamed; Love, Robert B; Welter, Debbie; Cornwell, Richard D; Meyer, Keith C

2003-03-01

To characterize Aspergillus infections in lung transplant recipients with cystic fibrosis (CF). A retrospective analysis of 32 consecutive lung transplant recipients with CF who underwent bilateral lung transplant at the University of Wisconsin from 1994 to 2000 to determine the incidence, risk factors, and consequences of Aspergillus infection. The findings were compared to 101 non-CF recipients of lung transplants (93) and heart-lung transplants (8) for other transplant indications. A university hospital. Lung transplant recipients with CF or other indications for transplantation. None. Seventeen of 32 CF recipients (53%) had Aspergillus fumigatus isolated from their respiratory secretions prior to undergoing transplantation. Ten of these 17 (59%) recipients had A fumigatus persistently found in their respiratory secretions posttransplant vs 6 of 15 CF patients (40%) who had not been colonized pretransplant and 28 of 101 of the non-CF recipients (28%). Four of the preoperatively colonized CF recipients developed tracheobronchial aspergillosis (TBA) just distal to the bronchial anastomoses, and one recipient had dehiscence of the involved anastomosis. None of the CF recipients developed disseminated aspergillosis or pneumonia. Prophylactic antifungal therapy did not prevent TBA, and IV amphotericin B therapy was required to clear the infection in all four patients, with endobronchial debridement of necrotic tissue required in two of them. In contrast, 10 of the non-CF (10%) recipients developed Aspergillus infections posttransplant (TBA, 4 recipients; pneumonitis, 6 recipients), and only 3 patients had successful treatment and long-term survival (TBA, 2 patients; pneumonia, 1 patient). Donor lung ischemia time, cytomegalovirus infection or pneumonia, or pretransplant mechanical ventilation did not increase the risk of developing TBA in CF recipients. The risk of TBA for patients receiving lung transplants for CF warrants early surveillance bronchoscopy to detect

The Lung Microbiome After Lung Transplantation

PubMed Central

Becker, Julia B.; Poroyko, Valeriy

2014-01-01

Summary Lung transplantation survival remains significantly impacted by infections and the development of chronic rejection manifesting as bronchiolitis obliterans syndrome (BOS). Traditional microbiologic data has provided insight into the role of infections in BOS. Now, new non-culture-based techniques have been developed to characterize the entire population of microbes resident on the surfaces of the body, also known as the human microbiome. Early studies have identified that lung transplant patients have a different lung microbiome and have demonstrated the important finding that the transplant lung microbiome changes over time. Furthermore, both unique bacterial populations and longitudinal changes in the lung microbiome have now been suggested to play a role in the development of BOS. In the future, this technology will need to be combined with functional assays and assessment of the immune responses in the lung to help further explain the microbiome’s role in the failing lung allograft. PMID:24601662

Guillain-Barré Syndrome in a Boy With Lung Fluke Infection: Case Report and Literature Review.

PubMed

Yang, Cui-Wei; Gao, Feng; Xia, Zhe-Zhi

2015-08-01

Guillain-Barré syndrome is the most common acute peripheral neuropathy in children in most countries. The cause and pathogenesis of the disease have yet to be clarified. There have been only a few reports of Guillain-Barré syndrome resulting from parasite infections worldwide, no cases of Guillain-Barré syndrome after lung fluke infection have been reported. We report a case of an 8-year-old male patient with Guillain-Barré syndrome after lung fluke infection. The child had a history of consumption of undercooked crabs. He was diagnosed with paragonimiasis. The patient experienced paralysis of and pain in the lower limbs about 3 weeks after symptom onset. Neurologic and electrophysiologic examination findings supported the diagnosis of Guillain-Barré syndrome. Parasitic infections should also be considered when determining which antecedent infection is associated with Guillain-Barré syndrome. © The Author(s) 2014.

Tsukamurella tyrosinosolvens - An unusual case report of bacteremic pneumonia after lung transplantation

PubMed Central

2009-01-01

Background Lung transplant recipients have an increased risk for actinomycetales infection secondary to immunosuppressive regimen. Case presentation A case of pulmonary infection with bacteremia due to Tsukamurella tyrosinosolvens in a 54-year old man who underwent a double lung transplantation four years previously is presented. Conclusion The identification by conventional biochemical assays was unsuccessful and hsp gene sequencing was used to identify Tsukamurella tyrosinosolvens. PMID:19909497

Active CMV infection before lung transplantation: risk factors and clinical implications.

PubMed

Milstone, A P; Brumble, L M; Loyd, J E; Ely, E W; Roberts, J R; Pierson, R N; Dummer, J S

2000-08-01

Cytomegalovirus (CMV) infection is a major cause of morbidity following lung transplantation, but active CMV infection has not been described before transplantation. Since 1990, we have screened all lung-transplant recipients for CMV infection with viral urine cultures on the day of transplantation. We retrospectively reviewed the medical records of all 102 lung-allograft recipients transplanted between March 1990 and September 1998. Patients with positive urine cultures for CMV were compared to culture negative patients for age, gender, pretransplant diagnosis, time from diagnosis to transplantation, CMV serostatus, use of pretransplant immunosuppression, T-lymphocyte subsets, and presence of fever. Posttransplant outcomes assessed were duration of intubation and hospitalization, acute rejection, frequency of CMV disease, duration of Nashville rabbit antithymocyte serum or globulin (N-RATS/G) and ganciclovir, and survival. Five (5%) of 102 patients had positive urine cultures for CMV; none had symptoms of CMV infection. All 5 had idiopathic pulmonary fibrosis (IPF) (5/5 vs 27/97; p = 0.002). The age, gender, and CMV serostatus of these patients did not differ from the 97 patients in the culture negative group. Four (80%) of the 5 patients with positive cultures were receiving treatment with azathioprine or cyclophosphamide vs only 18 (19%) of the 97 patients with negative cultures (p = 0.007), and all 5 (100%) were receiving steroids compared to 50 (52%) of 97 patients with negative cultures (p = 0.06). Culture-positive IPF patients, when compared with the 27 culture-negative IPF patients, did not differ in any demographic variable or in the use of immunosuppression, but culture-positive patients were more likely to have a CD4/CD8 T-cell subset ratio <1.0 (p = 0.02). Following transplantation, 3 (60%) of 5 IPF patients with positive CMV cultures developed CMV disease compared to 3 (11%) of 27 IPF patients with negative cultures (p = 0.03). Patients with positive

Induction of proinflammatory cytokines in human lung epithelial cells during Rhodococcus equi infection.

PubMed

Remuzgo-Martínez, Sara; Pilares-Ortega, Lilian; Alvarez-Rodríguez, Lorena; Aranzamendi-Zaldunbide, Maitane; Padilla, Daniel; Icardo, Jose Manuel; Ramos-Vivas, Jose

2013-08-01

Rhodococcus equi is an opportunistic human pathogen associated with immunosuppressed people. While the interaction of R. equi with macrophages has been comprehensively studied, little is known about its interactions with non-phagocytic cells. Here, we characterized the entry process of this bacterium into human lung epithelial cells. The invasion is inhibited by nocodazole and wortmannin, suggesting that the phosphatidylinositol 3-kinase pathway and microtubule cytoskeleton are important for invasion. Pre-incubation of R. equi with a rabbit anti-R. equi polyclonal antiserum resulted in a dramatic reduction in invasion. Also, the invasion process as studied by immunofluorescence and scanning electron microscopy indicates that R. equi make initial contact with the microvilli of the A549 cells, and at the structural level, the entry process was observed to occur via a zipper-like mechanism. Infected lung epithelial cells upregulate the expression of cytokines IL-8 and IL-6 upon infection. The production of these pro-inflammatory cytokines was significantly enhanced in culture supernatants from cells infected with non-mucoid plasmid-less strains when compared with cells infected with mucoid strains. These results demonstrate that human airway epithelial cells produce pro-inflammatory mediators against R. equi isolates.

Interstitial lung disease associated with Equine Infectious Anemia Virus infection in horses

PubMed Central

2013-01-01

EIA (Equine Infectious Anemia) is a blood-borne disease primarily transmitted by haematophagous insects or needle punctures. Other routes of transmission have been poorly explored. We evaluated the potential of EIAV (Equine Infectious Anemia Virus) to induce pulmonary lesions in naturally infected equids. Lungs from 77 EIAV seropositive horses have been collected in Romania and France. Three types of lesions have been scored on paraffin-embedded lungs: lymphocyte infiltration, bronchiolar inflammation, and thickness of the alveolar septa. Expression of the p26 EIAV capsid (CA) protein has been evaluated by immunostaining. Compared to EIAV-negative horses, 52% of the EIAV-positive horses displayed a mild inflammation around the bronchioles, 22% had a moderate inflammation with inflammatory cells inside the wall and epithelial bronchiolar hyperplasia and 6.5% had a moderate to severe inflammation, with destruction of the bronchiolar epithelium and accumulation of smooth muscle cells within the pulmonary parenchyma. Changes in the thickness of the alveolar septa were also present. Expression of EIAV capsid has been evidenced in macrophages, endothelial as well as in alveolar and bronchiolar epithelial cells, as determined by their morphology and localization. To summarize, we found lesions of interstitial lung disease similar to that observed during other lentiviral infections such as FIV in cats, SRLV in sheep and goats or HIV in children. The presence of EIAV capsid in lung epithelial cells suggests that EIAV might be responsible for the broncho-interstitial damages observed. PMID:24289102

Interstitial lung disease associated with Equine Infectious Anemia Virus infection in horses.

PubMed

Bolfa, Pompei; Nolf, Marie; Cadoré, Jean-Luc; Catoi, Cornel; Archer, Fabienne; Dolmazon, Christine; Mornex, Jean-François; Leroux, Caroline

2013-12-01

EIA (Equine Infectious Anemia) is a blood-borne disease primarily transmitted by haematophagous insects or needle punctures. Other routes of transmission have been poorly explored. We evaluated the potential of EIAV (Equine Infectious Anemia Virus) to induce pulmonary lesions in naturally infected equids. Lungs from 77 EIAV seropositive horses have been collected in Romania and France. Three types of lesions have been scored on paraffin-embedded lungs: lymphocyte infiltration, bronchiolar inflammation, and thickness of the alveolar septa. Expression of the p26 EIAV capsid (CA) protein has been evaluated by immunostaining. Compared to EIAV-negative horses, 52% of the EIAV-positive horses displayed a mild inflammation around the bronchioles, 22% had a moderate inflammation with inflammatory cells inside the wall and epithelial bronchiolar hyperplasia and 6.5% had a moderate to severe inflammation, with destruction of the bronchiolar epithelium and accumulation of smooth muscle cells within the pulmonary parenchyma. Changes in the thickness of the alveolar septa were also present. Expression of EIAV capsid has been evidenced in macrophages, endothelial as well as in alveolar and bronchiolar epithelial cells, as determined by their morphology and localization. To summarize, we found lesions of interstitial lung disease similar to that observed during other lentiviral infections such as FIV in cats, SRLV in sheep and goats or HIV in children. The presence of EIAV capsid in lung epithelial cells suggests that EIAV might be responsible for the broncho-interstitial damages observed.

[Lung disorders due to metals].

PubMed

Rüegger, M

1995-03-11

Though metals represent the largest group of elements they rather rarely cause respiratory diseases. This article will therefore review the most important ones caused by inhaled dusts of metals and some of their inorganic compounds, but leaving aside silicosis and silicatosis as well as iatrogenically induced metal pneumopathies. Among toxic inflammatory diseases metal fume fever, an influenza-like condition caused by zinc oxide, ranks as the commonest. Activities such as oxi-acetylene cutting and welding of zinc covered metal pieces account for about 90% of all cases compensated in Switzerland. Due to the non-recurrent character of this type of work, the typical waning of symptoms while exposure is going on has become seldom. Toxic pneumonia caused by inhaled metal fumes occurs rather seldom. However, serious cases have been reported where soldiers were exposed to zinc chloride from smoke bombs. The existence and extent of chronic airflow limitation due to occupational exposure to metallic dusts have not been widely examined but are to be assumed when there is poor occupational hygiene. Concerning asthma, there are at least four metals and several of their compounds which have been proven to cause variable airway narrowing, namely chromium, nickel, platinum and cobalt (the latter as hardmetal). Platinum complex salts (chloro-compounds) are very potent sensitizers leading to a notable prevalence of asthma among exposed workforces. Nevertheless, there have been no such cases in Switzerland for more than ten years. Hard-metal not only causes asthma but also an alveolitis-like interstitial lung disease progressing to fibrosis.(ABSTRACT TRUNCATED AT 250 WORDS)

NonTuberculous Mycobacteria infection and lung transplantation in cystic fibrosis: a worldwide survey of clinical practice.

PubMed

Tissot, Adrien; Thomas, Matthew F; Corris, Paul A; Brodlie, Malcolm

2018-05-22

In people with cystic fibrosis infection with NonTuberculous Mycobacteria is of increasing prevalence. Mycobacterium abscessus complex is of particular concern and has been associated with adverse clinical outcomes. Optimal treatment usually requires multiple antibiotics for over 12 months. When considering lung transplantation for patients with NonTuberculous Mycobacteria potential benefits must be balanced against the risks of uncontrolled infection post-transplant and significant side-effects associated with treatment. In this survey we assessed current international practice with regard to assessing and listing patients for lung transplantation. We designed a questionnaire enquiring about local practice regarding screening for NonTuberculous Mycobacteria infection, specific contra-indications to transplantation, management and segregation of patients pre- and post-transplant. The survey was sent via e-mail to 37 paediatric and adult lung transplant centres across Europe, North America and Australia. We gathered complete questionnaires from 21 centres (57% response rate). Few centres (29%) have a clear written policy regarding NonTuberculous Mycobacteria. Sixteen (76%) centres require molecular identification of NonTuberculous Mycobacteria species. Only four centres would consider infection with M. abscessus complex in itself a contra-indication for listing, however 76% regard it as a relative contra-indication. Eighty-six percent require treatment pre-transplantation. Finally, only 61% of centres had a clear policy regarding segration of patients pre-transplant and 48% post-transplant. The issue of NonTuberculous Mycobacteria infection in people with cystic fibrosis requiring lung transplantation is well-recognized however current international recommendations are not detailed and there is variation in practice between centres. There is an urgent requirement for high quality clinical data to inform decision-making.

Mixed Infections and their Control

DTIC Science & Technology

1983-04-29

endocarditis , bactereF.,;a, and closed-space infections , such as brain or lung abscesses that cavnot be surgically drained. Combination therapy should not be...Systemic infection is a common complication of multiple injury despite the availability of potent and specific antibiotics. 2 Infections following...trauma are due to opportunistic pathogens that . originate from endogenous nr exogenous sources. These pathogens, often present as mixed infections

Inducible Lung Epithelial Resistance Requires Multisource Reactive Oxygen Species Generation To Protect against Viral Infections

PubMed Central

2018-01-01

ABSTRACT Viral pneumonias cause profound worldwide morbidity, necessitating novel strategies to prevent and treat these potentially lethal infections. Stimulation of intrinsic lung defenses via inhalation of synergistically acting Toll-like receptor (TLR) agonists protects mice broadly against pneumonia, including otherwise-lethal viral infections, providing a potential opportunity to mitigate infectious threats. As intact lung epithelial TLR signaling is required for the inducible resistance and as these cells are the principal targets of many respiratory viruses, the capacity of lung epithelial cells to be therapeutically manipulated to function as autonomous antiviral effectors was investigated. Our work revealed that mouse and human lung epithelial cells could be stimulated to generate robust antiviral responses that both reduce viral burden and enhance survival of isolated cells and intact animals. The antiviral protection required concurrent induction of epithelial reactive oxygen species (ROS) from both mitochondrial and dual oxidase sources, although neither type I interferon enrichment nor type I interferon signaling was required for the inducible protection. Taken together, these findings establish the sufficiency of lung epithelial cells to generate therapeutically inducible antiviral responses, reveal novel antiviral roles for ROS, provide mechanistic insights into inducible resistance, and may provide an opportunity to protect patients from viral pneumonia during periods of peak vulnerability. PMID:29764948

Infection rate and tissue localization of murine IL-12p40-producing monocyte-derived CD103(+) lung dendritic cells during pulmonary tuberculosis.

PubMed

Leepiyasakulchai, Chaniya; Taher, Chato; Chuquimia, Olga D; Mazurek, Jolanta; Söderberg-Naucler, Cecilia; Fernández, Carmen; Sköld, Markus

2013-01-01

Non-hematopoietic cells, including lung epithelial cells, influence host immune responses. By co-culturing primary alveolar epithelial cells and monocytes from naïve donor mice, we show that alveolar epithelial cells support monocyte survival and differentiation in vitro, suggesting a role for non-hematopoietic cells in monocyte differentiation during the steady state in vivo. CD103(+) dendritic cells (αE-DC) are present at mucosal surfaces. Using a murine primary monocyte adoptive transfer model, we demonstrate that αE-DC in the lungs and pulmonary lymph nodes are monocyte-derived during pulmonary tuberculosis. The tissue localization may influence the functional potential of αE-DC that accumulate in Mycobacterium tuberculosis-infected lungs. Here, we confirm the localization of αE-DC in uninfected mice beneath the bronchial epithelial cell layer and near the vascular wall, and show that αE-DC have a similar distribution in the lungs during pulmonary tuberculosis and are detected in the bronchoalveolar lavage fluid from infected mice. Lung DC can be targeted by M. tuberculosis in vivo and play a role in bacterial dissemination to the draining lymph node. In contrast to other DC subsets, only a fraction of lung αE-DC are infected with the bacterium. We also show that virulent M. tuberculosis does not significantly alter cell surface expression levels of MHC class II on infected cells in vivo and that αE-DC contain the highest frequency of IL-12p40(+) cells among the myeloid cell subsets in infected lungs. Our results support a model in which inflammatory monocytes are recruited into the M. tuberculosis-infected lung tissue and, depending on which non-hematopoietic cells they interact with, differentiate along different paths to give rise to multiple monocyte-derived cells, including DC with a distinctive αE-DC phenotype.

Infection Rate and Tissue Localization of Murine IL-12p40-Producing Monocyte-Derived CD103+ Lung Dendritic Cells during Pulmonary Tuberculosis

PubMed Central

Leepiyasakulchai, Chaniya; Taher, Chato; Chuquimia, Olga D.; Mazurek, Jolanta; Söderberg-Naucler, Cecilia; Fernández, Carmen; Sköld, Markus

2013-01-01

Non-hematopoietic cells, including lung epithelial cells, influence host immune responses. By co-culturing primary alveolar epithelial cells and monocytes from naïve donor mice, we show that alveolar epithelial cells support monocyte survival and differentiation in vitro, suggesting a role for non-hematopoietic cells in monocyte differentiation during the steady state in vivo. CD103+ dendritic cells (αE-DC) are present at mucosal surfaces. Using a murine primary monocyte adoptive transfer model, we demonstrate that αE-DC in the lungs and pulmonary lymph nodes are monocyte-derived during pulmonary tuberculosis. The tissue localization may influence the functional potential of αE-DC that accumulate in Mycobacterium tuberculosis-infected lungs. Here, we confirm the localization of αE-DC in uninfected mice beneath the bronchial epithelial cell layer and near the vascular wall, and show that αE-DC have a similar distribution in the lungs during pulmonary tuberculosis and are detected in the bronchoalveolar lavage fluid from infected mice. Lung DC can be targeted by M. tuberculosis in vivo and play a role in bacterial dissemination to the draining lymph node. In contrast to other DC subsets, only a fraction of lung αE-DC are infected with the bacterium. We also show that virulent M. tuberculosis does not significantly alter cell surface expression levels of MHC class II on infected cells in vivo and that αE-DC contain the highest frequency of IL-12p40+ cells among the myeloid cell subsets in infected lungs. Our results support a model in which inflammatory monocytes are recruited into the M. tuberculosis-infected lung tissue and, depending on which non-hematopoietic cells they interact with, differentiate along different paths to give rise to multiple monocyte-derived cells, including DC with a distinctive αE-DC phenotype. PMID:23861965

Histamine plays an essential regulatory role in lung inflammation and protective immunity in the acute phase of Mycobacterium tuberculosis infection.

PubMed

Carlos, D; Fremond, C; Samarina, A; Vasseur, V; Maillet, I; Ramos, S G; Erard, F; Quesniaux, V; Ohtsu, H; Silva, C L; Faccioli, L H; Ryffel, B

2009-12-01

The course and outcome of infection with mycobacteria are determined by a complex interplay between the immune system of the host and the survival mechanisms developed by the bacilli. Recent data suggest a regulatory role of histamine not only in the innate but also in the adaptive immune response. We used a model of pulmonary Mycobacterium tuberculosis infection in histamine-deficient mice lacking histidine decarboxylase (HDC(-/-)), the histamine-synthesizing enzyme. To confirm that mycobacterial infection induced histamine production, we exposed mice to M. tuberculosis and compared responses in C57BL/6 (wild-type) and HDC(-/-) mice. Histamine levels increased around fivefold above baseline in infected C57BL/6 mice at day 28 of infection, whereas only small amounts were detected in the lungs of infected HDC(-/-) mice. Blocking histamine production decreased both neutrophil influx into lung tissue and the release of proinflammatory mediators, such as interleukin 6 (IL-6) and tumor necrosis factor alpha (TNF-alpha), in the acute phase of infection. However, the accumulation and activation of CD4(+) T cells were augmented in the lungs of infected HDC(-/-) mice and correlated with a distinct granuloma formation that contained abundant lymphocytic infiltration and reduced numbers of mycobacteria 28 days after infection. Furthermore, the production of IL-12, gamma interferon, and nitric oxide, as well as CD11c(+) cell influx into the lungs of infected HDC(-/-) mice, was increased. These findings indicate that histamine produced after M. tuberculosis infection may play a regulatory role not only by enhancing the pulmonary neutrophilia and production of IL-6 and TNF-alpha but also by impairing the protective Th1 response, which ultimately restricts mycobacterial growth.

Lymphopenia associated with highly virulent H5N1 virus infection due to plasmacytoid dendritic cell mediated apoptosis of T cells

PubMed Central

Boonnak, Kobporn; Vogel, Leatrice; Feldmann, Friederike; Feldmann, Heinz; Legge, Kevin L.; Subbarao, Kanta

2014-01-01

Although lymphopenia is a hallmark of severe infection with highly pathogenic H5N1 and the newly emerged H7N9 influenza viruses in humans, the mechanism(s) by which lethal H5N1 viruses cause lymphopenia in mammalian hosts remains poorly understood. Because influenza-specific T cell responses are initiated in the lung draining lymph nodes, and lymphocytes subsequently traffic to the lungs or peripheral circulation, we compared the immune responses in the lung draining lymph nodes following infection with a lethal A/HK/483/97 or non-lethal A/HK/486/97 (H5N1) virus in a mouse model. We found that lethal H5N1, but not non-lethal H5N1 virus infection in mice enhances Fas ligand (FasL) expression on plasmacytoid dendritic cells (pDCs), resulting in apoptosis of influenza-specific CD8+ T cells via a Fas-FasL mediated pathway. We also found that pDCs, but not other DC subsets, preferentially accumulate in the lung draining lymph nodes of lethal H5N1 virus-infected mice and that the induction of FasL expression on pDCs correlates with high levels of IL-12p40 monomer/homodimer in the lung draining lymph nodes. Our data suggest that one of the mechanisms of lymphopenia associated with lethal H5N1 virus infection involves a deleterious role for pDCs. PMID:24829418

Toll-like receptor 4 knockout ameliorates neuroinflammation due to lung-brain interaction in mechanically ventilated mice.

PubMed

Chen, Ting; Chen, Chang; Zhang, Zongze; Zou, Yufeng; Peng, Mian; Wang, Yanlin

2016-08-01

Toll-like receptor 4 (TLR4) is a crucial receptor in the innate immune system, and increasing evidence supports its role in inflammation, stress, and tissue injury, including injury to the lung and brain. We aimed to investigate the effects of TLR4 on neuroinflammation due to the lung-brain interaction in mechanically ventilated mice. Male wild-type (WT) C57BL/6 and TLR4 knockout (TLR4 KO) mice were divided into three groups: (1) control group (C): spontaneous breathing; (2) anesthesia group (A): spontaneous breathing under anesthesia; and (3) mechanical ventilation group (MV): 6h of MV under anesthesia. The behavioral responses of mice were tested with fear conditioning tests. The histological changes in the lung and brain were assessed using hematoxylin-eosin (HE) staining. The level of TLR4 mRNA in tissue was measured using reverse transcription-polymerase chain reaction (RT-PCR). The levels of inflammatory cytokines were measured with an enzyme-linked immunosorbent assay (ELISA). Microgliosis, astrocytosis, and the TLR4 immunoreactivity in the hippocampus were measured by double immunofluorescence. MV mice exhibited impaired cognition, and this impairment was less severe in TLR4 KO mice than in WT mice. In WT mice, MV increased TLR4 mRNA expression in the lung and brain. MV induced mild lung injury, which was prevented in TLR4 KO mice. MV mice exhibited increased levels of inflammatory cytokines, increased microglia and astrocyte activation. Microgliosis was alleviated in TLR4 KO mice. MV mice exhibited increased TLR4 immunoreactivity, which was expressed in microglia and astrocytes. These results demonstrate that TLR4 is involved in neuroinflammation due to the lung-brain interaction and that TLR4 KO ameliorates neuroinflammation due to lung-brain interaction after prolonged MV. In addition, Administration of a TLR4 antagonist (100μg/mice) to WT mice also significantly attenuated neuroinflammation of lung-brain interaction due to prolonged MV. TLR4 antagonism

Monitoring of early humoral immunity to identify lung recipients at risk for development of serious infections: A multicenter prospective study.

PubMed

Sarmiento, Elizabeth; Cifrian, Jose; Calahorra, Leticia; Bravo, Carles; Lopez, Sonia; Laporta, Rosalia; Ussetti, Piedad; Sole, Amparo; Morales, Carmen; de Pablos, Alicia; Jaramillo, Maria; Ezzahouri, Ikram; García, Sandra; Navarro, Joaquin; Lopez-Hoyos, Marcos; Carbone, Javier

2018-04-06

Infection is still a leading cause of death during the first year after lung transplantation. We performed a multicenter study among teaching hospitals to assess monitoring of early humoral immunity as a means of identifying lung recipients at risk of serious infections. We prospectively analyzed 82 adult lung recipients at 5 centers in Spain. Data were collected before transplantation and at 7 and 30 days after transplantation. Biomarkers included IgG, IgM, IgA, complement factors C3 and C4, titers of antibodies to pneumococcal polysaccharide antigens (IgG, IgA, IgM) and antibodies to cytomegalovirus (IgG), and serum B-cell activating factor (BAFF) levels. The clinical follow-up period lasted 6 months. Clinical outcomes were bacterial infections requiring intravenous anti-microbial agents, cytomegalovirus (CMV) disease, and fungal infections requiring therapy. We found that 33 patients (40.2%) developed at least 1 serious bacterial infection, 8 patients (9.8%) had CMV disease, and 10 patients (12.2%) had fungal infections. Lower IgM antibody levels against pneumococcal polysaccharide antigens at Day 7 (defined as <5 mg/dl) were a risk factor for serious bacterial infection (adjusted odds ratio [OR] 3.96; 95% confidence interval [CI] 1.39 to 11.26; p = 0.0099). At Day 7 after transplantation, IgG hypogammaglobulinemia (defined as IgG <600 mg/dl) was associated with a higher risk of CMV disease (after adjustment for CMV mismatch: OR 8.15; 95% CI 1.27 to 52.55; p = 0.028) and fungal infection (adjusted OR 8.03, 95% CI 1.51 to 42.72; p = 0.015). Higher BAFF levels before transplantation were associated with a higher rate of development of serious bacterial infection and acute cellular rejection. Early monitoring of specific humoral immunity parameters proved useful for the identification of lung recipients who are at risk of serious infections. Copyright © 2018 International Society for the Heart and Lung Transplantation. Published by Elsevier Inc. All rights

IL-10 restrains IL-17 to limit lung pathology characteristics following pulmonary infection with Francisella tularensis live vaccine strain.

PubMed

Slight, Samantha R; Monin, Leticia; Gopal, Radha; Avery, Lyndsay; Davis, Marci; Cleveland, Hillary; Oury, Tim D; Rangel-Moreno, Javier; Khader, Shabaana A

2013-11-01

IL-10 production during intracellular bacterial infections is generally thought to be detrimental because of its role in suppressing protective T-helper cell 1 (Th1) responses. Francisella tularensis is a facultative intracellular bacterium that activates both Th1 and Th17 protective immune responses. Herein, we report that IL-10-deficient mice (Il10(-/-)), despite having increased Th1 and Th17 responses, exhibit increased mortality after pulmonary infection with F. tularensis live vaccine strain. We demonstrate that the increased mortality observed in Il10(-/-)-infected mice is due to exacerbated IL-17 production that causes increased neutrophil recruitment and associated lung pathology. Thus, although IL-17 is required for protective immunity against pulmonary infection with F. tularensis live vaccine strain, its production is tightly regulated by IL-10 to generate efficient induction of protective immunity without mediating pathology. These data suggest a critical role for IL-10 in maintaining the delicate balance between host immunity and pathology during pulmonary infection with F. tularensis live vaccine strain. Copyright © 2013 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

Lung Infections Associated with Cystic Fibrosis

PubMed Central

Lyczak, Jeffrey B.; Cannon, Carolyn L.; Pier, Gerald B.

2002-01-01

While originally characterized as a collection of related syndromes, cystic fibrosis (CF) is now recognized as a single disease whose diverse symptoms stem from the wide tissue distribution of the gene product that is defective in CF, the ion channel and regulator, cystic fibrosis transmembrane conductance regulator (CFTR). Defective CFTR protein impacts the function of the pancreas and alters the consistency of mucosal secretions. The latter of these effects probably plays an important role in the defective resistance of CF patients to many pathogens. As the modalities of CF research have changed over the decades from empirical histological studies to include biophysical measurements of CFTR function, the clinical management of this disease has similarly evolved to effectively address the ever-changing spectrum of CF-related infectious diseases. These factors have led to the successful management of many CF-related infections with the notable exception of chronic lung infection with the gram-negative bacterium Pseudomonas aeruginosa. The virulence of P. aeruginosa stems from multiple bacterial attributes, including antibiotic resistance, the ability to utilize quorum-sensing signals to form biofilms, the destructive potential of a multitude of its microbial toxins, and the ability to acquire a mucoid phenotype, which renders this microbe resistant to both the innate and acquired immunologic defenses of the host. PMID:11932230

Changing epidemiology of infections due to extended spectrum beta-lactamase producing bacteria

PubMed Central

2014-01-01

Background Community-associated infections caused by extended-spectrum beta-lactamase (ESBL) producing bacteria are a growing concern. Methods Retrospective cohort study of clinical infections due to ESBL-producing bacteria requiring admission from 2006-2011 at a tertiary care academic medical center in Providence, RI. Results A total of 321 infections due to ESBL-producing bacteria occurred during the study period. Fifty-eight cases (18%) were community-acquired, 170 (53%) were healthcare–associated, and 93 (29%) were hospital-acquired. The incidence of ESBL infections per 10,000 discharges increased during the study period for both healthcare-associated infections, 1.9 per year (95% CI 1-2.8), and for community-acquired infections, 0.85 per year (95% CI 0.3-1.4) but the rate remained unchanged for hospital-acquired infections. For ESBL-producing E. coli isolates, resistance to both ciprofloxacin and trimethoprim-sulfamethoxazole was 95% and 65%, respectively but 94% of isolates were susceptible to nitrofurantoin. Conclusions Community-acquired and healthcare-associated infections due to ESBL-producing bacteria are increasing in our community, particularly urinary tract infections due to ESBL-producing E. coli. Most isolates are resistant to oral antibiotics commonly used to treat urinary tract infections. Thus, our findings have important implications for outpatient management of such infections. PMID:24666610

A 3D Human Lung Tissue Model for Functional Studies on Mycobacterium tuberculosis Infection.

PubMed

Braian, Clara; Svensson, Mattias; Brighenti, Susanna; Lerm, Maria; Parasa, Venkata R

2015-10-05

Tuberculosis (TB) still holds a major threat to the health of people worldwide, and there is a need for cost-efficient but reliable models to help us understand the disease mechanisms and advance the discoveries of new treatment options. In vitro cell cultures of monolayers or co-cultures lack the three-dimensional (3D) environment and tissue responses. Herein, we describe an innovative in vitro model of a human lung tissue, which holds promise to be an effective tool for studying the complex events that occur during infection with Mycobacterium tuberculosis (M. tuberculosis). The 3D tissue model consists of tissue-specific epithelial cells and fibroblasts, which are cultured in a matrix of collagen on top of a porous membrane. Upon air exposure, the epithelial cells stratify and secrete mucus at the apical side. By introducing human primary macrophages infected with M. tuberculosis to the tissue model, we have shown that immune cells migrate into the infected-tissue and form early stages of TB granuloma. These structures recapitulate the distinct feature of human TB, the granuloma, which is fundamentally different or not commonly observed in widely used experimental animal models. This organotypic culture method enables the 3D visualization and robust quantitative analysis that provides pivotal information on spatial and temporal features of host cell-pathogen interactions. Taken together, the lung tissue model provides a physiologically relevant tissue micro-environment for studies on TB. Thus, the lung tissue model has potential implications for both basic mechanistic and applied studies. Importantly, the model allows addition or manipulation of individual cell types, which thereby widens its use for modelling a variety of infectious diseases that affect the lungs.

Nitric Oxide as a Mediator of Oxidant Lung Injury Due to Paraquat

NASA Astrophysics Data System (ADS)

Berisha, Hasan I.; Pakbaz, Hedayatollah; Absood, Afaf; Said, Sami I.

1994-08-01

At low concentrations, nitric oxide is a physiological transmitter, but in excessive concentrations it may cause cell and tissue injury. We report that in acute oxidant injury induced by the herbicide paraquat in isolated guinea pig lungs, nitric oxide synthesis was markedly stimulated, as evidenced by increased levels of cyclic GMP in lung perfusate and of nitrite and L-citrulline production in lung tissue. All signs of injury, including increased airway and perfusion pressures, pulmonary edema, and protein leakage into the airspaces, were dose-dependently attenuated or totally prevented by either N^G-nitro-L-arginine methyl ester or N^ω-nitro-L-arginine, selective and competitive inhibitors of nitric oxide synthase. Protection was reversed by excess L-arginine but not by its enantiomer D-arginine. When blood was added to the lung perfusate, the paraquat injury was moderated or delayed as it was when paraquat was given to anesthetized guinea pigs. The rapid onset of injury and its failure to occur in the absence of Ca2+ suggest that constitutive rather than inducible nitric oxide synthase was responsible for the stimulated nitric oxide synthesis. The findings indicate that nitric oxide plays a critical role in the production of lung tissue injury due to paraquat, and it may be a pathogenetic factor in other forms of oxidant tissue injury.

Early Whole Blood Transcriptional Signatures Are Associated with Severity of Lung Inflammation in Cynomolgus Macaques with Mycobacterium tuberculosis Infection.

PubMed

Gideon, Hannah P; Skinner, Jason A; Baldwin, Nicole; Flynn, JoAnne L; Lin, Philana Ling

2016-12-15

Whole blood transcriptional profiling offers great diagnostic and prognostic potential. Although studies identified signatures for pulmonary tuberculosis (TB) and transcripts that predict the risk for developing active TB in humans, the early transcriptional changes immediately following Mycobacterium tuberculosis infection have not been evaluated. We evaluated the gene expression changes in the cynomolgus macaque model of TB, which recapitulates all clinical aspects of human M. tuberculosis infection, using a human microarray and analytics platform. We performed genome-wide blood transcriptional analysis on 38 macaques at 11 postinfection time points during the first 6 mo of M. tuberculosis infection. Of 6371 differentially expressed transcripts between preinfection and postinfection, the greatest change in transcriptional activity occurred 20-56 d postinfection, during which fluctuation of innate and adaptive immune response-related transcripts was observed. Modest transcriptional differences between active TB and latent infection were observed over the time course with substantial overlap. The pattern of module activity previously published for human active TB was similar in macaques with active disease. Blood transcript activity was highly correlated with lung inflammation (lung [ 18 F]fluorodeoxyglucose [FDG] avidity) measured by positron emission tomography and computed tomography at early time points postinfection. The differential signatures between animals with high and low lung FDG were stronger than between clinical outcomes. Analysis of preinfection signatures of macaques revealed that IFN signatures could influence eventual clinical outcomes and lung FDG avidity, even before infection. Our data support that transcriptional changes in the macaque model are translatable to human M. tuberculosis infection and offer important insights into early events of M. tuberculosis infection. Copyright © 2016 by The American Association of Immunologists, Inc.

Frequency of Th17 cells correlates with the presence of lung lesions in pigs chronically infected with Actinobacillus pleuropneumoniae.

PubMed

Sassu, Elena L; Ladinig, Andrea; Talker, Stephanie C; Stadler, Maria; Knecht, Christian; Stein, Heiko; Frömbling, Janna; Richter, Barbara; Spergser, Joachim; Ehling-Schulz, Monika; Graage, Robert; Hennig-Pauka, Isabel; Gerner, Wilhelm

2017-02-06

Porcine contagious pleuropneumonia caused by Actinobacillus pleuropneumoniae (APP) remains one of the major causes of poor growth performance and respiratory disease in pig herds. While the role of antibodies against APP has been intensely studied, the porcine T cell response remains poorly characterized. To address this, pigs were intranasally infected with APP serotype 2 and euthanized during the acute phase [6-10 days post-infection (dpi)] or the chronic phase of APP infection (27-31 dpi). Lymphocytes isolated from blood, tonsils, lung tissue and tracheobronchial lymph nodes were analyzed by intracellular cytokine staining (ICS) for IL-17A, IL-10 and TNF-α production after in vitro stimulation with crude capsular extract (CCE) of the APP inoculation strain. This was combined with cell surface staining for the expression of CD4, CD8α and TCR-γδ. Clinical records, microbiological investigations and pathological findings confirmed the induction of a subclinical APP infection. ICS-assays revealed the presence of APP-CCE specific CD4 + CD8α dim IL-17A-producing T cells in blood and lung tissue in most infected animals during the acute and chronic phase of infection and a minor fraction of these cells co-produced TNF-α. APP-CCE specific IL-17A-producing γδ T cells could not be found and APP-CCE specific IL-10-producing CD4 + T cells were present in various organs but only in a few infected animals. The frequency of identified putative Th17 cells (CD4 + CD8α dim IL-17A + ) in lung and blood correlated positively with lung lesion scores and APP-specific antibody titers during the chronic phase. These results suggest a potential role of Th17 cells in the immune pathogenesis of APP infection.

Evidence for the involvement of lung-specific γδ T cell subsets in local responses to Streptococcus pneumoniae infection

PubMed Central

Kirby, Alun C; Newton, Darren J; Carding, Simon R; Kaye, Paul M

2007-01-01

Although γδ T cells are involved in the response to many pathogens, the dynamics and heterogeneity of the local γδ T cell response remains poorly defined. We recently identified γδ T cells as regulators of macrophages and dendritic cells during the resolution of Streptococcus pneumoniae-mediated lung inflammation. Here, using PCR, spectratype analysis and flow cytometry, we show that multiple γδ T cell subsets, including those bearing Vγ1, Vγ4 and Vγ6 TCR, increase in number in the lungs of infected mice, but not in associated lymphoid tissue. These γδ T cells displayed signs of activation, as defined by CD69 and CD25 expression. In vivo BrdU incorporation suggested that local expansion, rather than recruitment, was the principal mechanism underlying this increase in γδ T cells. This conclusion was supported by the finding that pulmonary γδ T cells, but not αβ T cells, isolated from mice that had resolved infection exhibited lung-homing capacity in both naive and infected recipients. Together, these data provide novel insights into the origins of the heterogeneous γδ T cell response that accompanies lung infection, and the first evidence that inflammation-associated γδ T cells may exhibit distinct tissue-homing potential. PMID:18022862

Restoring Cystic Fibrosis Transmembrane Conductance Regulator Function Reduces Airway Bacteria and Inflammation in People with Cystic Fibrosis and Chronic Lung Infections.

PubMed

Hisert, Katherine B; Heltshe, Sonya L; Pope, Christopher; Jorth, Peter; Wu, Xia; Edwards, Rachael M; Radey, Matthew; Accurso, Frank J; Wolter, Daniel J; Cooke, Gordon; Adam, Ryan J; Carter, Suzanne; Grogan, Brenda; Launspach, Janice L; Donnelly, Seamas C; Gallagher, Charles G; Bruce, James E; Stoltz, David A; Welsh, Michael J; Hoffman, Lucas R; McKone, Edward F; Singh, Pradeep K

2017-06-15

Previous work indicates that ivacaftor improves cystic fibrosis transmembrane conductance regulator (CFTR) activity and lung function in people with cystic fibrosis and G551D-CFTR mutations but does not reduce density of bacteria or markers of inflammation in the airway. These findings raise the possibility that infection and inflammation may progress independently of CFTR activity once cystic fibrosis lung disease is established. To better understand the relationship between CFTR activity, airway microbiology and inflammation, and lung function in subjects with cystic fibrosis and chronic airway infections. We studied 12 subjects with G551D-CFTR mutations and chronic airway infections before and after ivacaftor. We measured lung function, sputum bacterial content, and inflammation, and obtained chest computed tomography scans. Ivacaftor produced rapid decreases in sputum Pseudomonas aeruginosa density that began within 48 hours and continued in the first year of treatment. However, no subject eradicated their infecting P. aeruginosa strain, and after the first year P. aeruginosa densities rebounded. Sputum total bacterial concentrations also decreased, but less than P. aeruginosa. Sputum inflammatory measures decreased significantly in the first week of treatment and continued to decline over 2 years. Computed tomography scans obtained before and 1 year after ivacaftor treatment revealed that ivacaftor decreased airway mucous plugging. Ivacaftor caused marked reductions in sputum P. aeruginosa density and airway inflammation and produced modest improvements in radiographic lung disease in subjects with G551D-CFTR mutations. However, P. aeruginosa airway infection persisted. Thus, measures that control infection may be required to realize the full benefits of CFTR-targeting treatments.

Reduced generation of lung tissue–resident memory T cells during infancy

PubMed Central

Zens, Kyra D.; Chen, Jun Kui; Wu, Felix L.; Cvetkovski, Filip

2017-01-01

Infants suffer disproportionately from respiratory infections and generate reduced vaccine responses compared with adults, although the underlying mechanisms remain unclear. In adult mice, lung-localized, tissue-resident memory T cells (TRMs) mediate optimal protection to respiratory pathogens, and we hypothesized that reduced protection in infancy could be due to impaired establishment of lung TRM. Using an infant mouse model, we demonstrate generation of lung-homing, virus-specific T effectors after influenza infection or live-attenuated vaccination, similar to adults. However, infection during infancy generated markedly fewer lung TRMs, and heterosubtypic protection was reduced compared with adults. Impaired TRM establishment was infant–T cell intrinsic, and infant effectors displayed distinct transcriptional profiles enriched for T-bet–regulated genes. Notably, mouse and human infant T cells exhibited increased T-bet expression after activation, and reduction of T-bet levels in infant mice enhanced lung TRM establishment. Our findings reveal that infant T cells are intrinsically programmed for short-term responses, and targeting key regulators could promote long-term, tissue-targeted protection at this critical life stage. PMID:28855242

Lung cancer: is the increasing incidence due to radioactive polonium in cigarettes

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

Marmorstein, J.

This paper presents clinical, experimental, and epidemiologic evidence to help explain the rapidly increasing incidence of primary lung cancer, with recently observed reversal in leading cell type from squamous cell to adenocarcinoma. It postulates that this may be due to changes in modern cigarettes, with or without filters, which allow inhalation of increased amounts of radioactive lead and polonium and decreased amounts of benzopyrene. This hypothesis is based upon measurements of increased concentrations of radioactive polonium in the lungs of cigarette smokers, in modern tobaccos grown since 1950, and in high-phosphate fertilizers used for tobacco farming in industrialized countries. Criticalmore » support for this thesis is based upon experimental animal studies in which lung cancers that resemble adenocarcinomas are induced with as little as 15 rads of radioactive polonium, equal to one fifth the dosage inhaled by cigarette smokers who average two packs a day during a 25-year period.« less

Total hip arthroplasty revision due to infection: a cost analysis approach.

PubMed

Klouche, S; Sariali, E; Mamoudy, P

2010-04-01

The treatment of total hip arthroplasty (THA) infections is long and costly. However,the number of studies in the literature analysing the real cost of THA revision in relation to their etiology, including infection, is limited. The aim of this retrospective study was to determine the cost of revision of infected THA and to compare these costs to those of primary THA and revision of non-infected THA. We performed a retrospective cost analysis for the year 2006 using an identical analytic accounting system in each hospital department (according to internal criteria) based on allotment of direct costs and receipts for each department. From January to December 2006, 424 primary THA, 57 non-infected THA revisions and 40 THA revisions due to infection were performed. The different cost areas of the patient's treatment were identified.This included preoperative medical work-up, medicosurgical management during hospital stay,a second stay in an orthopedic rehabilitation hospital (ORH) and post-hospitalisation antibiotic therapy after revision due to infection, as well as home-based hospitalisation (HH) costs, if this was the selected alternative option. We used the national health insurance fee schedule found in the "Common classification of medical procedures" and the "General nomenclature of professional procedures" applicable in France since September 1, 2005. Hospital costs included direct costs (hospital overhead costs) and indirect costs, (medical, surgical, technical settings and net general service expenses). The calculation of HH costs and ORH costs were based on the average daily charge of these departments. The cost of primary THA was used as the reference.We then compared our surgical costs with those found for the corresponding comparable hospital stay groups (Groupes homogènes de séjour). The average hospital stay (AHS) was 7.5 +/- 1.8 days for primary THA, 8.9 +/- 2.2 days for non-infected revisions and 30.6 +/- 14.9 days for revisions due to infection

[Update on congenital and neonatal herpes infections: infection due to cytomegalovirus and herpes simplex].

PubMed

Baquero-Artigao, F

2017-05-17

Newborn infants are a population which is especially susceptible to viral infections that frequently affect the central nervous system. Herpes infections can be transmitted to the foetus and to the newborn infant, and give rise to severe clinical conditions with long-term sensory and cognitive deficits. Two thirds of newborn infants with encephalitis due to herpes simplex virus and half of the children with symptomatic congenital infection by cytomegalovirus develop sequelae, which results in high community health costs in the long term. Fortunately, the better knowledge about these infections gained in recent years together with the development of effective antiviral treatments have improved the patients' prognosis. Valganciclovir (32 mg/kg/day in two doses for six months) prevents the development of hypoacusis and improves the neurological prognosis in symptomatic congenital infection due to cytomegalovirus. Acyclovir (60 mg/kg/day in three doses for 2-3 weeks) prevents the development of severe forms in skin-eyes-mouth herpes disease, and lowers the rate of mortality and sequelae when the disease has disseminated and is located in the central nervous system.

CD4+ T Cell Help Guides Formation of CD103+ Lung-Resident Memory CD8+ T Cells during Influenza Viral Infection

PubMed Central

Laidlaw, Brian J.; Zhang, Nianzhi; Marshall, Heather D.; Staron, Mathew M.; Guan, Tianxia; Hu, Yinghong; Cauley, Linda S.; Craft, Joe; Kaech, Susan M.

2014-01-01

SUMMARY Tissue-resident memory T (Trm) cells provide enhanced protection against infection at mucosal sites. Here we found that CD4+ T cells are important for the formation of functional lung-resident CD8+ T cells after influenza virus infection. In the absence of CD4+ T cells, CD8+ T cells displayed reduced expression of CD103 (Itgae), were mislocalized away from airway epithelia, and demonstrated an impaired ability to recruit CD8+ T cells to the lung air-ways upon heterosubtypic challenge. CD4+ T cell-derived interferon-γ was necessary for generating lung-resident CD103+ CD8+ Trm CD8 T cells. Furthermore, expression of the transcription factor T-bet was increased in “unhelped” lung Trm cells, and a reduction in T-bet rescued CD103 expression in the absence of CD4+ T cell help. Thus, CD4+ T cell-dependent signals are important to limit expression of T-bet and allow for the development of CD103+ CD8+ Trm cells in the lung airways following respiratory infection. PMID:25308332

Genes Required for Free Phage Production are Essential for Pseudomonas aeruginosa Chronic Lung Infections.

PubMed

Lemieux, Andrée-Ann; Jeukens, Julie; Kukavica-Ibrulj, Irena; Fothergill, Joanne L; Boyle, Brian; Laroche, Jérôme; Tucker, Nicholas P; Winstanley, Craig; Levesque, Roger C

2016-02-01

The opportunistic pathogen Pseudomonas aeruginosa causes chronic lung infection in patients with cystic fibrosis. The Liverpool Epidemic Strain LESB58 is highly resistant to antibiotics, transmissible, and associated with increased morbidity and mortality. Its genome contains 6 prophages and 5 genomic islands. We constructed a polymerase chain reaction (PCR)-based signature-tagged mutagenesis library of 9216 LESB58 mutants and screened the mutants in a rat model of chronic lung infection. A total of 162 mutants were identified as defective for in vivo maintenance, with 11 signature-tagged mutagenesis mutants having insertions in prophage and genomic island genes. Many of these mutants showed both diminished virulence and reduced phage production. Transcription profiling by quantitative PCR and RNA-Seq suggested that disruption of these prophages had a widespread trans-acting effect on the transcriptome. This study demonstrates that temperate phages play a pivotal role in the establishment of infection through modulation of bacterial host gene expression. © The Author 2015. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail journals.permissions@oup.com.

ROLE OF GENETIC SUSCEPTIBILITY TO LATENT ADENOVIRAL INFECTION AND DECREASED LUNG FUNCTION

PubMed Central

Kasuga, Ikuma; Hogg, James C.; Paré, Peter D.; Hayashi, Shizu; Sedgwick, Edward G.; Ruan, Jian; Wallace, Alison M.; He, Jian-Qing; Zhang, Xiaozhu; Sandford, Andrew J.

2009-01-01

Background Latent adenoviral infection may amplify cigarette smoke-induced lung inflammation and therefore play an important role in the development of chronic obstructive pulmonary disease (COPD). Adenoviruses can evade the human immune response via their 19-kDa protein (19K) which delays the expression of class I human leukocyte antigen (HLA) proteins. The 19K protein shows higher affinity to HLA-B7 and A2 compared with HLA-A1 and A3. The receptor for adenovirus (CXADR) and integrin β5 (ITGB5) are host factors which might affect adenovirus infection. Therefore, we investigated the contribution of HLA, CXADR, and ITGB5 genetic variants to the presence of the E1A gene and to level of lung function. Methods Study subjects were assayed for HLA-B7, A1, A2 and A3 by PCR-based assays using allele-specific primers. Polymorphisms of the CXADR and ITGB5 genes were genotyped by PCR-based restriction fragment length polymorphism assays. Detection of adenoviral E1A gene was performed by a real-time PCR TaqMan assay. Results E1A positive individuals have a lower FEV1 compared with E1A negative individuals. However, there was no significant difference in E1A positivity rate between the high (HLA-B7 and A2) and low (HLA-A1 and A3) 19K affinity groups. There was also no significant difference in FEV1 level between each affinity group. There was no significant difference in E1A positivity rate or lung function among the CXADR and ITGB5 genotypes. Conclusions Genetic variants in HLA, CXADR and ITGB5 do not influence latent adenoviral infections and are not associated with COPD. PMID:19502044

[Isolated lung transplantation--evaluation of patients and initial results].

PubMed

Speich, R; Böhler, A; Zollinger, A; Stocker, R; Vogt, P; Carrel, T; Lang, T; Schmid, R; Stöhr, S; Vogt, P R

1995-04-22

Between November 1992 and May 1994 we performed 10 single and 5 double lung transplants in patients with end-stage lung diseases due to lymphangioleiomyomatosis (4), cystic fibrosis (3), pulmonary hypertension (3), pulmonary fibrosis (3) and chronic obstructive lung disease (2). In the 13 patients (87%) surviving for median 245 (19-567) days, FEV1 improved from median 640 ml to 1410 ml and the 12-minute walk distance from median 315 to 1100 meters. 10 patients (77%) enjoy a good or even excellent quality of life. 2 patients died 11 and 62 days postoperatively, due to multi-organ failure and invasive pulmonary aspergillosis respectively. The main postoperative problems are fungal and cytomegalovirus infections and chronic rejection in the form of bronchiolitis obliterans. In Switzerland as elsewhere, lung transplantation has become an established modality for the management of end-stage diseases of the lung and pulmonary circulation.

Cough Due to TB and Other Chronic Infections: CHEST Guideline and Expert Panel Report.

PubMed

Field, Stephen K; Escalante, Patricio; Fisher, Dina A; Ireland, Belinda; Irwin, Richard S

2018-02-01

clinical diagnosis. To our knowledge, no published comparative studies addressed whether the rate of cough resolution is a reliable determinant of the response to treatment or whether the rate of cough resolution was faster in the absence of cavitary lung disease. All studies on cough prevalence in Mycobacterium avium complex (MAC) lung disease, other nontuberculous mycobacterial infections, fungal lung disease, and paragonimiasis were of poor quality and were excluded from the evidence review. On the basis of relatively few studies of fair to good quality, we conclude that most individuals at high risk and household contacts with cough ≥ 2 weeks do not have pulmonary TB, but we suggest screening them regardless of cough duration. In PLWHIV, the addition of the other WHO-endorsed symptoms increases the diagnostic sensitivity of cough. Earlier screening of patients with cough will help diagnose pulmonary TB sooner but will increase the cost of screening. The addition of ACF to PCF will increase the number of pulmonary TB cases identified. Screening asymptomatic individuals is cost-effective only in groups with a very high TB prevalence. Data are insufficient to determine whether cough resolution is delayed in individuals with cavitary lung disease or in those for whom treatment fails because of drug resistance, poor adherence, and/or drug malabsorption compared with results in other individuals with pulmonary TB. Cough is common in patients with lung infections due to MAC, other nontuberculous mycobacteria, fungal diseases, and paragonimiasis. Copyright © 2017 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.

Lung fluke (Paragonimus africanus) infects Nigerian red-capped mangabeys and causes respiratory disease

PubMed Central

Friant, Sagan; Brown, Kelsey; Saari, Mason T.; Segel, Nicholas H.; Slezak, Julia; Goldberg, Tony L.

2015-01-01

Eggs of the lung fluke genus Paragonimus were detected in red-capped mangabeys (Cercocebus torquatus) in Nigeria. We assess the role of these primates as potential sylvatic hosts and the clinical effects of the parasite on monkeys. DNA sequenced from eggs in feces were 100% identical in the ITS2 region to Paragonimus africanus sequences from humans in Cameroon. Paragonimus-positive monkeys coughed more than uninfected monkeys. Experimental de-worming led to reduction in parasite intensity and a corresponding reduction of coughing to baseline levels in infected monkeys. This report provides the first evidence of Paragonimus sp. in C. torquatus, of P. africanus in Nigerian wildlife, and the first molecular evidence of the parasite in African wildlife. Coughing, sometimes interpreted as a communication behavior in primates, can actually indicate infection with lung parasites. Observations of coughing in primates may, in turn, provide a useful mechanism for surveillance of Paragonimus spp, which are re-emerging human pathogens, in wildlife reservoirs. PMID:26543803

Lung fluke (Paragonimus africanus) infects Nigerian red-capped mangabeys and causes respiratory disease.

PubMed

Friant, Sagan; Brown, Kelsey; Saari, Mason T; Segel, Nicholas H; Slezak, Julia; Goldberg, Tony L

2015-12-01

Eggs of the lung fluke genus Paragonimus were detected in red-capped mangabeys (Cercocebus torquatus) in Nigeria. We assess the role of these primates as potential sylvatic hosts and the clinical effects of the parasite on monkeys. DNA sequenced from eggs in feces were 100% identical in the ITS2 region to Paragonimus africanus sequences from humans in Cameroon. Paragonimus-positive monkeys coughed more than uninfected monkeys. Experimental de-worming led to reduction in parasite intensity and a corresponding reduction of coughing to baseline levels in infected monkeys. This report provides the first evidence of Paragonimus sp. in C. torquatus, of P. africanus in Nigerian wildlife, and the first molecular evidence of the parasite in African wildlife. Coughing, sometimes interpreted as a communication behavior in primates, can actually indicate infection with lung parasites. Observations of coughing in primates may, in turn, provide a useful mechanism for surveillance of Paragonimus spp, which are re-emerging human pathogens, in wildlife reservoirs.

Choriodecidual Group B Streptococcal Inoculation Induces Fetal Lung Injury without Intra-Amniotic Infection and Preterm Labor in Macaca nemestrina

PubMed Central

Adams Waldorf, Kristina M.; Gravett, Michael G.; McAdams, Ryan M.; Paolella, Louis J.; Gough, G. Michael; Carl, David J.; Bansal, Aasthaa; Liggitt, H. Denny; Kapur, Raj P.; Reitz, Frederick B.; Rubens, Craig E.

2011-01-01

Background Early events leading to intrauterine infection and fetal lung injury remain poorly defined, but may hold the key to preventing neonatal and adult chronic lung disease. Our objective was to establish a nonhuman primate model of an early stage of chorioamnionitis in order to determine the time course and mechanisms of fetal lung injury in utero. Methodology/Principal Findings Ten chronically catheterized pregnant monkeys (Macaca nemestrina) at 118–125 days gestation (term = 172 days) received one of two treatments: 1) choriodecidual and intra-amniotic saline (n = 5), or 2) choriodecidual inoculation of Group B Streptococcus (GBS) 1×106 colony forming units (n = 5). Cesarean section was performed regardless of labor 4 days after GBS or 7 days after saline infusion to collect fetal and placental tissues. Only two GBS animals developed early labor with no cervical change in the remaining animals. Despite uterine quiescence in most cases, blinded review found histopathological evidence of fetal lung injury in four GBS animals characterized by intra-alveolar neutrophils and interstitial thickening, which was absent in controls. Significant elevations of cytokines in amniotic fluid (TNF-α, IL-8, IL-1β, IL-6) and fetal plasma (IL-8) were detected in GBS animals and correlated with lung injury (p<0.05). Lung injury was not directly caused by GBS, because GBS was undetectable in amniotic fluid (∼10 samples tested/animal), maternal and fetal blood by culture and polymerase chain reaction. In only two cases was GBS cultured from the inoculation site in low numbers. Chorioamnionitis occurred in two GBS animals with lung injury, but two others with lung injury had normal placental histology. Conclusions/Significance A transient choriodecidual infection can induce cytokine production, which is associated with fetal lung injury without overt infection of amniotic fluid, chorioamnionitis or preterm labor. Fetal lung injury may, thus, occur silently

Nanodiscs as a therapeutic delivery agent: inhibition of respiratory syncytial virus infection in the lung

PubMed Central

Numata, Mari; Grinkova, Yelena V; Mitchell, James R; Chu, Hong Wei; Sligar, Stephen G; Voelker, Dennis R

2013-01-01

There is increasing interest in the application of nanotechnology to solve the difficult problem of therapeutic administration of pharmaceuticals. Nanodiscs, composed of a stable discoidal lipid bilayer encircled by an amphipathic membrane scaffold protein that is an engineered variant of the human Apo A-I constituent of high-density lipoproteins, have been a successful platform for providing a controlled lipid composition in particles that are especially useful for investigating membrane protein structure and function. In this communication, we demonstrate that nanodiscs are effective in suppressing respiratory syncytial viral (RSV) infection both in vitro and in vivo when self-assembled with the minor pulmonary surfactant phospholipid palmitoyloleoylphosphatidylglycerol (POPG). Preparations of nanodiscs containing POPG (nPOPG) antagonized interleukin-8 production from Beas2B epithelial cells challenged by RSV infection, with an IC50 of 19.3 μg/mL. In quantitative in vitro plaque assays, nPOPG reduced RSV infection by 93%. In vivo, nPOPG suppressed inflammatory cell infiltration into the lung, as well as IFN-γ production in response to RSV challenge. nPOPG also completely suppressed the histopathological changes in lung tissue elicited by RSV and reduced the amount of virus recovered from lung tissue by 96%. The turnover rate of nPOPG was estimated to have a halftime of 60–120 minutes (m), based upon quantification of the recovery of the human Apo A-I constituent. From these data, we conclude that nPOPG is a potent antagonist of RSV infection and its inflammatory sequelae both in vitro and in vivo. PMID:23717040

Role of Mutant CFTR in Hypersusceptibility of Cystic Fibrosis Patients to Lung Infections

NASA Astrophysics Data System (ADS)

Pier, Gerald B.; Grout, Martha; Zaidi, Tanweer S.; Olsen, John C.; Johnson, Larry G.; Yankaskas, James R.; Goldberg, Joanna B.

1996-01-01

Cystic fibrosis (CF) patients are hypersusceptible to chronic Pseudomonas aeruginosa lung infections. Cultured human airway epithelial cells expressing the ΔF508 allele of the cystic fibrosis transmembrane conductance regulator (CFTR) were defective in uptake of P. aeruginosa compared with cells expressing the wild-type allele. Pseudomonas aeruginosa lipopolysaccharide (LPS)-core oligosaccharide was identified as the bacterial ligand for epithelial cell ingestion; exogenous oligosaccharide inhibited bacterial ingestion in a neonatal mouse model, resulting in increased amounts of bacteria in the lungs. CFTR may contribute to a host-defense mechanism that is important for clearance of P. aeruginosa from the respiratory tract.

Involvement of the different lung compartments in the pathogenesis of pH1N1 influenza virus infection in ferrets.

PubMed

Vidaña, Beatriz; Martínez, Jorge; Martorell, Jaime; Montoya, María; Córdoba, Lorena; Pérez, Mónica; Majó, Natàlia

2016-11-08

Severe cases after pH1N1 infection are consequence of interstitial pneumonia triggered by alveolar viral replication and an exacerbated host immune response, characterized by the up-regulation of pro-inflammatory cytokines and the influx of inflammatory leukocytes to the lungs. Different lung cell populations have been suggested as culprits in the unregulated innate immune responses observed in these cases. This study aims to clarify this question by studying the different induction of innate immune molecules by the distinct lung anatomic compartments (vascular, alveolar and bronchiolar) of ferrets intratracheally infected with a human pH1N1 viral isolate, by means of laser microdissection techniques. The obtained results were then analysed in relation to viral quantification in the different anatomic areas and the histopathological lesions observed. More severe lung lesions were observed at 24 h post infection (hpi) correlating with viral antigen detection in bronchiolar and alveolar epithelial cells. However, high levels of viral RNA were detected in all anatomic compartments throughout infection. Bronchiolar areas were the first source of IFN-α and most pro-inflammatory cytokines, through the activation of RIG-I. In contrast, vascular areas contributed with the highest induction of CCL2 and other pro-inflammatory cytokines, through the activation of TLR3.

The Immune Interplay between the Host and the Pathogen in Aspergillus fumigatus Lung Infection

PubMed Central

Sales-Campos, Helioswilton; Tonani, Ludmilla; Cardoso, Cristina Ribeiro Barros; Kress, Márcia Regina Von Zeska

2013-01-01

The interplay between Aspergillus fumigatus and the host immune response in lung infection has been subject of studies over the last years due to its importance in immunocompromised patients. The multifactorial virulence factors of A. fumigatus are related to the fungus biological characteristics, for example, structure, ability to grow and adapt to high temperatures and stress conditions, besides capability of evading the immune system and causing damage to the host. In this context, the fungus recognition by the host innate immunity occurs when the pathogen disrupts the natural and chemical barriers followed by the activation of acquired immunity. It seems clear that a Th1 response has a protective role, whereas Th2 reactions are often associated with higher fungal burden, and Th17 response is still controversial. Furthermore, a fine regulation of the effector immunity is required to avoid excessive tissue damage associated with fungal clearance, and this role could be attributed to regulatory T cells. Finally, in this work we reviewed the aspects involved in the complex interplay between the host immune response and the pathogen virulence factors, highlighting the immunological issues and the importance of its better understanding to the development of novel therapeutic approaches for invasive lung aspergillosis. PMID:23984400

Correlation of the lung microbiota with metabolic profiles in bronchoalveolar lavage fluid in HIV infection.

PubMed

Cribbs, Sushma K; Uppal, Karan; Li, Shuzhao; Jones, Dean P; Huang, Laurence; Tipton, Laura; Fitch, Adam; Greenblatt, Ruth M; Kingsley, Lawrence; Guidot, David M; Ghedin, Elodie; Morris, Alison

2016-01-20

While 16S ribosomal RNA (rRNA) sequencing has been used to characterize the lung's bacterial microbiota in human immunodeficiency virus (HIV)-infected individuals, taxonomic studies provide limited information on bacterial function and impact on the host. Metabolic profiles can provide functional information on host-microbe interactions in the lungs. We investigated the relationship between the respiratory microbiota and metabolic profiles in the bronchoalveolar lavage fluid of HIV-infected and HIV-uninfected outpatients. Targeted sequencing of the 16S rRNA gene was used to analyze the bacterial community structure and liquid chromatography-high-resolution mass spectrometry was used to detect features in bronchoalveolar lavage fluid. Global integration of all metabolic features with microbial species was done using sparse partial least squares regression. Thirty-nine HIV-infected subjects and 20 HIV-uninfected controls without acute respiratory symptoms were enrolled. Twelve mass-to-charge ratio (m/z) features from C18 analysis were significantly different between HIV-infected individuals and controls (false discovery rate (FDR) = 0.2); another 79 features were identified by network analysis. Further metabolite analysis demonstrated that four features were significantly overrepresented in the bronchoalveolar lavage (BAL) fluid of HIV-infected individuals compared to HIV-uninfected, including cystine, two complex carbohydrates, and 3,5-dibromo-L-tyrosine. There were 231 m/z features significantly associated with peripheral blood CD4 cell counts identified using sparse partial least squares regression (sPLS) at a variable importance on projection (VIP) threshold of 2. Twenty-five percent of these 91 m/z features were associated with various microbial species. Bacteria from families Caulobacteraceae, Staphylococcaceae, Nocardioidaceae, and genus Streptococcus were associated with the greatest number of features. Glycerophospholipid and lineolate pathways correlated

Effects of Marijuana on the Lung and Its Defenses against Infection and Cancer.

ERIC Educational Resources Information Center

Tashkin, Donald P.

1999-01-01

Examines the many effects of marijuana use on the lungs. States that patients with pre-existing immune deficits are particularly vulnerable to marijuana-related pulmonary infections. However, warns that habitual use of marijuana may lead to respiratory cancer must await epidemiological studies, which are now possible since 30 years have passed…

Epidemic Pseudomonas aeruginosa infection in patients with cystic fibrosis is not a risk factor for poor clinical Outcomes following lung transplantation.

PubMed

Pritchard, Julia; Thakrar, Mitesh V; Somayaji, Ranjani; Surette, Michael G; Rabin, Harvey R; Helmersen, Doug; Lien, Dale; Purighalla, Swathi; Waddell, Barbara; Parkins, Michael D

2016-05-01

Epidemic strains of Pseudomonas aeruginosa (ePA) causing infection in cystic fibrosis (CF) have been commonly identified from clinics around the world. ePA disproportionally impacts CF patient pre-transplant outcomes manifesting in increased exacerbation frequency, worsened treatment burden and increased rate of lung function decline, and disproportionally leads to death and/or transplantation. As other CF factors such as pre-transplant infection with multi-resistant organisms, and isolation of P. aeruginosa in the post transplant graft, may impact post-transplant outcomes, we sought to determine if infection with ePA similarly adversely impact post-transplant outcomes. Between 1991-2014, 53 CF patients from our center received lung transplants. Bacterial strain typing was performed retrospectively on isolates collected prior to transplantation. Comprehensive chart reviews were performed to obtain baseline patient characteristics and post-transplant outcomes. Of the 53 transplanted patients, 57% of patients were infected with ePA prior to transplant; the other 43% of patients had unique strains of P. aeruginosa. Mean age at transplant was 29.0years for ePA and 33.3years for unique (p=0.04). There were no differences in overall survival (HR=0.75, 95% CI 0.31-1.79), bronchiolitis obliterans syndrome (BOS) free survival (HR 1.43, 95% CI 0.54-4.84) or all other assessed outcomes including exacerbation frequency, chronic renal failure, acute cellular rejections, Aspergillus infection, airway stenosis, and post-transplant lymphoproliferative disorder. Unlike pre-transplant outcomes, CF patients infected with ePA do not experience worse post-transplant outcomes than those infected with unique strains. Therefore, lung transplantation should be considered for all patients with P. aeruginosa infection and end stage lung disease, irrespective of infection with ePA. Copyright © 2015 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.

Population Pharmacokinetic Modeling as a Tool To Characterize the Decrease in Ciprofloxacin Free Interstitial Levels Caused by Pseudomonas aeruginosa Biofilm Lung Infection in Wistar Rats

PubMed Central

Torres, Bruna G. S.; Helfer, Victória E.; Bernardes, Priscila M.; Macedo, Alexandre José; Nielsen, Elisabet I.; Friberg, Lena E.

2017-01-01

ABSTRACT Biofilm formation plays an important role in the persistence of pulmonary infections, for example, in cystic fibrosis patients. So far, little is known about the antimicrobial lung disposition in biofilm-associated pneumonia. This study aimed to evaluate, by microdialysis, ciprofloxacin (CIP) penetration into the lungs of healthy and Pseudomonas aeruginosa biofilm-infected rats and to develop a comprehensive model to describe the CIP disposition under both conditions. P. aeruginosa was immobilized into alginate beads and intratracheally inoculated 14 days before CIP administration (20 mg/kg of body weight). Plasma and microdialysate were sampled from different animal groups, and the observations were evaluated by noncompartmental analysis (NCA) and population pharmacokinetic (popPK) analysis. The final model that successfully described all data consisted of an arterial and a venous central compartment and two peripheral distribution compartments, and the disposition in the lung was modeled as a two-compartment model structure linked to the venous compartment. Plasma clearance was approximately 32% lower in infected animals, leading to a significantly higher level of plasma CIP exposure (area under the concentration-time curve from time zero to infinity, 27.3 ± 12.1 μg · h/ml and 13.3 ± 3.5 μg · h/ml in infected and healthy rats, respectively). Despite the plasma exposure, infected animals showed a four times lower tissue concentration/plasma concentration ratio (lung penetration factor = 0.44 and 1.69 in infected and healthy rats, respectively), and lung clearance (CLlung) was added to the model for these animals (CLlung = 0.643 liters/h/kg) to explain the lower tissue concentrations. Our results indicate that P. aeruginosa biofilm infection reduces the CIP free interstitial lung concentrations and increases plasma exposure, suggesting that plasma concentrations alone are not a good surrogate of lung concentrations. PMID:28461311

Lung Abscess in a Patient With VAP: A Rare Case of Lung Infection Complicated by Two Pathogens

PubMed Central

Mystakelli, Christina; Gourgiotis, Stavros; Aravosita, Paraskevi; Seretis, Charalampos; Kanna, Efthymia; Aloizos, Stavros

2013-01-01

Ventilator-associated pneumonia (VAP) is defined as pneumonia occurring in a patient after intubation with an endotracheal tube or tracheostomy tube lasting for 48 hours or more. We describe a case of 75-year-old male who initially presented with pneumonia of the right basis with accompanying plevritis. The patient was intubated and his condition was complicated with a VAP infection while he developed a lung abscess. The antibiotic therapy was based on susceptibility bronchial secretions isolated acinetobacter baumannii and klebsiella pneumoniae; these pathogens were also isolated from the drained abscess. The patient was discharged in good health. The interest of this case is recommended in the existence of two responsible pathogens, the paucity of the development of lung abscess in a patient with VAP, and the successful treatment of the patient with the combination of controlled drainage of the abscess and appropriate antibiotic therapy. PMID:23390479

Marvelous but Morbid: Infective endocarditis due to Serratia marcescens.

PubMed

Phadke, Varun K; Jacob, Jesse T

2016-05-01

A 46-year-old man with HIV infection and active intravenous drug use presented with approximately two weeks of fevers and body aches. On physical examination he was somnolent, had a new systolic murmur, bilateral conjunctival hemorrhages, diffuse petechiae, and left-sided arm weakness. Echocardiography revealed a large mitral valve vegetation and brain imaging demonstrated numerous embolic infarctions. Blood cultures grew Serratia marcescens . Despite aggressive treatment with meropenem the patient died due to intracranial hemorrhage complicated by herniation. Serratia marcescens is an uncommon cause of infective endocarditis. While this disease has historically been associated with intravenous drug use, more recent reports suggest that it is now largely a consequence of opportunistic infections of the chronically ill. Our case highlights several characteristic features of this infection, including isolation of a non-pigmented strain of the organism, an antibiotic susceptibility profile suggestive of AmpC β-lactamase production, and rapid clinical deterioration with multiple embolic complications resulting in death. In this review we discuss the history, epidemiology, and management of endovascular infections due to Serratia spp., emphasizing the continued importance of considering this organism in the differential diagnosis of endocarditis among intravenous drug users and as a potential indication for surgical therapy.

Marvelous but Morbid: Infective endocarditis due to Serratia marcescens

PubMed Central

Phadke, Varun K.; Jacob, Jesse T.

2016-01-01

A 46-year-old man with HIV infection and active intravenous drug use presented with approximately two weeks of fevers and body aches. On physical examination he was somnolent, had a new systolic murmur, bilateral conjunctival hemorrhages, diffuse petechiae, and left-sided arm weakness. Echocardiography revealed a large mitral valve vegetation and brain imaging demonstrated numerous embolic infarctions. Blood cultures grew Serratia marcescens. Despite aggressive treatment with meropenem the patient died due to intracranial hemorrhage complicated by herniation. Serratia marcescens is an uncommon cause of infective endocarditis. While this disease has historically been associated with intravenous drug use, more recent reports suggest that it is now largely a consequence of opportunistic infections of the chronically ill. Our case highlights several characteristic features of this infection, including isolation of a non-pigmented strain of the organism, an antibiotic susceptibility profile suggestive of AmpC β-lactamase production, and rapid clinical deterioration with multiple embolic complications resulting in death. In this review we discuss the history, epidemiology, and management of endovascular infections due to Serratia spp., emphasizing the continued importance of considering this organism in the differential diagnosis of endocarditis among intravenous drug users and as a potential indication for surgical therapy. PMID:27346925

PilY1 Promotes Legionella pneumophila Infection of Human Lung Tissue Explants and Contributes to Bacterial Adhesion, Host Cell Invasion, and Twitching Motility.

PubMed

Hoppe, Julia; Ünal, Can M; Thiem, Stefanie; Grimpe, Louisa; Goldmann, Torsten; Gaßler, Nikolaus; Richter, Matthias; Shevchuk, Olga; Steinert, Michael

2017-01-01

Legionnaires' disease is an acute fibrinopurulent pneumonia. During infection Legionella pneumophila adheres to the alveolar lining and replicates intracellularly within recruited macrophages. Here we provide a sequence and domain composition analysis of the L. pneumophila PilY1 protein, which has a high homology to PilY1 of Pseudomonas aeruginosa . PilY1 proteins of both pathogens contain a von Willebrand factor A (vWFa) and a C-terminal PilY domain. Using cellular fractionation, we assigned the L. pneumophila PilY1 as an outer membrane protein that is only expressed during the transmissive stationary growth phase. PilY1 contributes to infection of human lung tissue explants (HLTEs). A detailed analysis using THP-1 macrophages and A549 lung epithelial cells revealed that this contribution is due to multiple effects depending on host cell type. Deletion of PilY1 resulted in a lower replication rate in THP-1 macrophages but not in A549 cells. Further on, adhesion to THP-1 macrophages and A549 epithelial cells was decreased. Additionally, the invasion into non-phagocytic A549 epithelial cells was drastically reduced when PilY1 was absent. Complementation variants of a PilY1-negative mutant revealed that the C-terminal PilY domain is essential for restoring the wild type phenotype in adhesion, while the putatively mechanosensitive vWFa domain facilitates invasion into non-phagocytic cells. Since PilY1 also promotes twitching motility of L. pneumophila , we discuss the putative contribution of this newly described virulence factor for bacterial dissemination within infected lung tissue.

Use of an Artificial Neural Network to Construct a Model of Predicting Deep Fungal Infection in Lung Cancer Patients.

PubMed

Chen, Jian; Chen, Jie; Ding, Hong-Yan; Pan, Qin-Shi; Hong, Wan-Dong; Xu, Gang; Yu, Fang-You; Wang, Yu-Min

2015-01-01

The statistical methods to analyze and predict the related dangerous factors of deep fungal infection in lung cancer patients were several, such as logic regression analysis, meta-analysis, multivariate Cox proportional hazards model analysis, retrospective analysis, and so on, but the results are inconsistent. A total of 696 patients with lung cancer were enrolled. The factors were compared employing Student's t-test or the Mann-Whitney test or the Chi-square test and variables that were significantly related to the presence of deep fungal infection selected as candidates for input into the final artificial neural network analysis (ANN) model. The receiver operating characteristic (ROC) and area under curve (AUC) were used to evaluate the performance of the artificial neural network (ANN) model and logistic regression (LR) model. The prevalence of deep fungal infection from lung cancer in this entire study population was 32.04%(223/696), deep fungal infections occur in sputum specimens 44.05% (200/454). The ratio of candida albicans was 86.99% (194/223) in the total fungi. It was demonstrated that older (≥65 years), use of antibiotics, low serum albumin concentrations (≤37.18 g /L), radiotherapy, surgery, low hemoglobin hyperlipidemia (≤93.67 g /L), long time of hospitalization (≥14 days) were apt to deep fungal infection and the ANN model consisted of the seven factors. The AUC of ANN model (0.829±0.019) was higher than that of LR model (0.756±0.021). The artificial neural network model with variables consisting of age, use of antibiotics, serum albumin concentrations, received radiotherapy, received surgery, hemoglobin, time of hospitalization should be useful for predicting the deep fungal infection in lung cancer.

Diverse Epitope Specificity, Immunodominance Hierarchy, and Functional Avidity of Effector CD4 T Cells Established During Priming Is Maintained in Lung After Influenza A Virus Infection.

PubMed

Richards, Katherine A; DiPiazza, Anthony T; Rattan, Ajitanuj; Knowlden, Zackery A G; Yang, Hongmei; Sant, Andrea J

2018-01-01

One of the major contributions to protective immunity to influenza viruses that is provided by virus-specific CD4 T cells is delivery of effector function to the infected lung. However, there is little known about the selection and breadth of viral epitope-specific CD4 T cells that home to the lung after their initial priming. In this study, using a mouse model of influenza A infection and an unbiased method of epitope identification, the viral epitope-specific CD4 T cells elicited after infection were identified and quantified. We found that a very diverse specificity of CD4 T cells is primed by infection, including epitopes from hemagglutinin, neuraminidase, matrix protein, nucleoprotein, and non-structural protein-1. Using peptide-specific cytokine EliSpots, the diversity and immunodominance hierarchies established in the lung-draining lymph node were compared with specificities of CD4 T cells that home to the lung. Our studies revealed that CD4 T cells of all epitope specificities identified in peripheral lymphoid tissue home back to the lung and that most of these lung-homing cells are localized within the tissue rather than the pulmonary vasculature. There is a striking shift of CD4 T cell functionality that enriches for IFN-γ production as cells are primed in the lymph node, enter the lung vasculature, and finally establish residency in the tissue, but with no apparent shifts in their functional avidity. We conclude that CD4 T cells of broad viral epitope specificity are recruited into the lung after influenza infection, where they then have the opportunity to encounter infected or antigen-bearing antigen-presenting cells.

Effects of ozone on the defense to a respiratory Listeria monocytogenes infection in the rat. Suppression of macrophage function and cellular immunity and aggravation of histopathology in lung and liver during infection

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

Van Loveren, H.; Rombout, P.J.; Wagenaar, S.S.

1988-07-01

We have investigated the effect of exposure to ozone on defense mechanisms to a respiratory infection with Listeria monocytogenes in the rat. For this purpose rats were continuously exposed to O/sub 3/ concentrations ranging from 0.25 to 2.0 mg/m3 for a period of 1 week. In this model defense to a respiratory infection with Listeria depends on acquired specific cellular immune responses, as well as on natural nonspecific defense mechanisms. The results confirm earlier findings that show that ozone exposure can suppress the capacity of macrophages to ingest and kill Listeria. Moreover, the results show that ozone can also havemore » a suppressive effect on the development of cellular immune responses to a respiratory Listeria infection, i.e., on T/B ratios in lung draining lymph nodes, delayed-type hypersensitivity responses to Listeria antigen, and lymphoproliferative responses in spleen and lung draining lymph nodes to Listeria antigen. The effects on the specific immune responses are especially overt if exposure to the oxidant gas occurs during an ongoing primary infection. The pathological lesions induced by a pulmonary Listeria monocytogenes infection were characterized by multifocal infiltrates of histiocytic and lymphoid cells. The foci sometimes had a granulomatous appearance. Moreover, the cellularity of the interstitial tissues was increased. In the lung many diffuse alveolar macrophages could be seen in the alveoli. Ozone exposure greatly increased the severity of the lung lesions and also of liver lesions resulting from the pulmonary infection. A prominent finding was the formation of granulomas in ozone-exposed and Listeria-infected rats.« less

Transcriptional profiling of host gene expression in chicken embryo lung cells infected with laryngotracheitis virus

PubMed Central

2010-01-01

Background Infection by infectious laryngotracheitis virus (ILTV; gallid herpesvirus 1) causes acute respiratory diseases in chickens often with high mortality. To better understand host-ILTV interactions at the host transcriptional level, a microarray analysis was performed using 4 × 44 K Agilent chicken custom oligo microarrays. Results Microarrays were hybridized using the two color hybridization method with total RNA extracted from ILTV infected chicken embryo lung cells at 0, 1, 3, 5, and 7 days post infection (dpi). Results showed that 789 genes were differentially expressed in response to ILTV infection that include genes involved in the immune system (cytokines, chemokines, MHC, and NF-κB), cell cycle regulation (cyclin B2, CDK1, and CKI3), matrix metalloproteinases (MMPs) and cellular metabolism. Differential expression for 20 out of 789 genes were confirmed by quantitative reverse transcription-PCR (qRT-PCR). A bioinformatics tool (Ingenuity Pathway Analysis) used to analyze biological functions and pathways on the group of 789 differentially expressed genes revealed that 21 possible gene networks with intermolecular connections among 275 functionally identified genes. These 275 genes were classified into a number of functional groups that included cancer, genetic disorder, cellular growth and proliferation, and cell death. Conclusion The results of this study provide comprehensive knowledge on global gene expression, and biological functionalities of differentially expressed genes in chicken embryo lung cells in response to ILTV infections. PMID:20663125

Regulation of Proinflammatory Cytokines in Human Lung Epithelial Cells Infected with Mycoplasma pneumoniae

PubMed Central

Yang, Jun; Hooper, W. Craig; Phillips, Donald J.; Talkington, Deborah F.

2002-01-01

Mycoplasma pneumoniae is a small bacterium without a cell wall that causes tracheobronchitis and atypical pneumonia in humans. It has also been associated with chronic conditions, such as arthritis, and extrapulmonary complications, such as encephalitis. Although the interaction of mycoplasmas with respiratory epithelial cells is a critical early phase of pathogenesis, little is known about the cascade of events initiated by infection of respiratory epithelial cells by mycoplasmas. Previous studies have shown that M. pneumoniae can induce proinflammatory cytokines in several different study systems including cultured murine and human monocytes. In this study, we demonstrate that M. pneumoniae infection also induces proinflammatory cytokine expression in A549 human lung carcinoma cells. Infection of A549 cells resulted in increased levels of interleukin-8 (IL-8) and tumor necrosis factor alpha mRNA, and both proteins were secreted into culture medium. IL-1β mRNA also increased after infection and IL-1β protein was synthesized, but it remained intracellular. In contrast, levels of IL-6 and gamma interferon mRNA and protein remained unchanged or undetectable. Using protease digestion and antibody blocking methods, we found that M. pneumoniae cytadherence is important for the induction of cytokines. On the other hand, while M. pneumoniae protein synthesis and DNA synthesis do not appear to be prerequisites for the induction of cytokine gene expression, A549 cellular de novo protein synthesis is responsible for the increased cytokine protein levels. These results suggest a novel role for lung epithelial cells in the pathogenesis of M. pneumoniae infection and provide a better understanding of M. pneumoniae pathology at the cellular level. PMID:12065506

Aspirin-triggered resolvin D1 reduces pneumococcal lung infection and inflammation in a viral and bacterial coinfection pneumonia model.

PubMed

Wang, Hao; Anthony, Desiree; Yatmaz, Selcuk; Wijburg, Odilia; Satzke, Catherine; Levy, Bruce; Vlahos, Ross; Bozinovski, Steven

2017-09-15

Formyl peptide receptor 2/lipoxin A 4 (LXA 4 ) receptor (Fpr2/ALX) co-ordinates the transition from inflammation to resolution during acute infection by binding to distinct ligands including serum amyloid A (SAA) and Resolvin D1 (RvD1). Here, we evaluated the proresolving actions of aspirin-triggered RvD1 (AT-RvD1) in an acute coinfection pneumonia model. Coinfection with Streptococcus pneumoniae and influenza A virus (IAV) markedly increased pneumococcal lung load and neutrophilic inflammation during the resolution phase. Fpr2/ALX transcript levels were increased in the lungs of coinfected mice, and immunohistochemistry identified prominent Fpr2/ALX immunoreactivity in bronchial epithelial cells and macrophages. Levels of circulating and lung SAA were also highly increased in coinfected mice. Therapeutic treatment with exogenous AT-RvD1 during the acute phase of infection (day 4-6 post-pneumococcal inoculation) significantly reduced the pneumococcal load. AT-RvD1 also significantly reduced neutrophil elastase (NE) activity and restored total antimicrobial activity in bronchoalveolar lavage (BAL) fluid (BALF) of coinfected mice. Pneumonia severity, as measured by quantitating parenchymal inflammation or alveolitis was significantly reduced with AT-RvD1 treatment, which also reduced the number of infiltrating lung neutrophils and monocytes/macrophages as assessed by flow cytometry. The reduction in distal lung inflammation in AT-RvD1-treated mice was not associated with a significant reduction in inflammatory and chemokine mediators. In summary, we demonstrate that in the coinfection setting, SAA levels were persistently increased and exogenous AT-RvD1 facilitated more rapid clearance of pneumococci in the lungs, while concurrently reducing the severity of pneumonia by limiting excessive leukocyte chemotaxis from the infected bronchioles to distal areas of the lungs. © 2017 The Author(s).

[Influence of serious infections due to Gram-negative bacteria on the hospital economy].

PubMed

Martínez, B; Gómez, J; Gómez Vargas, J; Guerra, B; Ruiz Gómez, J; Simarro, E; Baños, V; Canteras, M; Valdes, M

2000-12-01

Nosocomial infections due to Gram-negative bacteria are very important since they are associated with high morbidity and high hospital costs. A prospective study of 250 inpatients was carried out, 200 of whom had Gram-negative bacterial infections. Patients were divided into groups of 50 according to the localization of the infection (urinary, surgical wound, respiratory tract and bacteremia), with a control group of 50 patients with similar characteristics but no infection. We calculated the cost for the different groups by multiplying the average length of hospital stay in days by the daily cost of the stay. Significant differences were observed in the average length of stay per patient according to the type of infection and how it was acquired. In terms of cost, nosocomial infection due to Gram-negative bacteria was 1,049,139 pesetas more expensive than community-acquired infection. The cost of the stay for patients with postsurgical infection due to Gram-negative bacteria was 1,108, 252 pesetas more expensive than for the group of control patients. Nosocomial infection due to Gram-negative bacteria is associated with a prolongation in hospital stay of 9 to 28 days, which is the factor that most reflects the cost that can be attributed to nosocomial infection. Consensual and protocolized measures which allow for better clinical management need to be developed.

Lung Irradiation Increases Mortality After Influenza A Virus Challenge Occurring Late After Exposure

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

Manning, Casey M.; Johnston, Carl J.; Department of Pediatrics, University of Rochester Medical Center, Rochester, New York

2013-05-01

Purpose: To address whether irradiation-induced changes in the lung environment alter responses to a viral challenge delivered late after exposure but before the appearance of late lung radiation injury. Methods and Materials: C57BL/6J mice received either lung alone or combined lung and whole-body irradiation (0-15 Gy). At 10 weeks after irradiation, animals were infected with 120 HAU influenza virus strain A/HKx31. Innate and adaptive immune cell recruitment was determined using flow cytometry. Cytokine and chemokine production and protein leakage into the lung after infection were assessed. Results: Prior irradiation led to a dose-dependent failure to regain body weight after infectionmore » and exacerbated mortality, but it did not affect virus-specific immune responses or virus clearance. Surviving irradiated animals displayed a persistent increase in total protein in bronchoalveolar lavage fluid and edema. Conclusions: Lung irradiation increased susceptibility to death after infection with influenza virus and impaired the ability to complete recovery. This altered response does not seem to be due to a radiation effect on the immune response, but it may possibly be an effect on epithelial repair.« less

Cutting edge: control of Mycobacterium tuberculosis infection by a subset of lung parenchyma-homing CD4 T cells.

PubMed

Sakai, Shunsuke; Kauffman, Keith D; Schenkel, Jason M; McBerry, Cortez C; Mayer-Barber, Katrin D; Masopust, David; Barber, Daniel L

2014-04-01

Th1 cells are critical for containment of Mycobacterium tuberculosis infection, but little else is known about the properties of protective CD4 T cell responses. In this study, we show that the pulmonary Th1 response against M. tuberculosis is composed of two populations that are either CXCR3(hi) and localize to lung parenchyma or are CX3CR1(hi)KLRG1(hi) and are retained within lung blood vasculature. M. tuberculosis-specific parenchymal CD4 T cells migrate rapidly back into the lung parenchyma upon adoptive transfer, whereas the intravascular effectors produce the highest levels of IFN-γ in vivo. Importantly, parenchymal T cells displayed greater control of infection compared with the intravascular counterparts upon transfer into susceptible T cell-deficient hosts. Thus, we identified a subset of naturally generated M. tuberculosis-specific CD4 T cells with enhanced protective capacity and showed that control of M. tuberculosis correlates with the ability of CD4 T cells to efficiently enter the lung parenchyma rather than produce high levels of IFN-γ.

Environmental exposure and HPV infection may act synergistically to induce lung tumorigenesis in nonsmokers

PubMed Central

Cheng, Ya-Wen; Lin, Frank Cheau-Feng; Chen, Chih-Yi; Hsu, Nan-Yung

2016-01-01

Most studies of lung tumorigenesis have focused on smokers rather than nonsmokers. In this study, we used human papillomavirus (HPV)-positive and HPV-negative lung cancer cells to test the hypothesis that HPV infection synergistically increases DNA damage induced by exposure to the carcinogen benzo[a]pyrene (B[a]P), and contributes to lung tumorigenesis in nonsmokers. DNA adduct levels induced by B[a]P in HPV-positive cells were significantly higher than in HPV-negative cells. The DNA adduct formation was dependent on HPV E6 oncoprotein expression. Gene and protein expression of two DNA repair genes, XRCC3 and XRCC5, were lower in B[a]P-treated E6-positive cells than in E6-negative lung cancer cells. The reduced expression was also detected immunohistochemically and was caused by increased promoter hypermethylation. Moreover, mutations of p53 and epidermal growth factor receptor (EGFR) genes in lung cancer patients were associated with XRCC5 inactivation. In sum, our study indicates that HPV E6-induced promoter hypermethylation of the XRCC3 and XRCC5 DNA repair genes and the resultant decrease in their expression increases B[a]P-induced DNA adducts and contributes to lung tumorigenesis in nonsmokers. PMID:26918347

Selection of genes of Mycobacterium tuberculosis upregulated during residence in lungs of infected mice.

PubMed

Srivastava, Vikas; Jain, Anamika; Srivastava, Brahm S; Srivastava, Ranjana

2008-05-01

In sequel to previous report [Srivastava V, Rouanet C, Srivastava R, Ramalingam B, Locht C, Srivastava BS. Macrophage-specific Mycobacterium tuberculosis genes: identification by green fluorescent protein and kanamycin resistance selection. Microbiology 2007;153:659-66], the genes of Mycobacterium tuberculosis upregulated during residence in lungs of infected mice were identified in an in vivo expression system based on kanamycin resistance. A promoter library of M. tuberculosis was constructed in a promoter trap shuttle vector pLL192 containing an artificial bicistronic operon composed of promoterless green fluorescent protein gene followed by kanamycin resistance gene. The library was introduced in M. bovis BCG and then infected in mice by intravenous route. Mice were treated twice daily with 40 mg/kg dose of kanamycin by intramuscular route for 21 days. Recombinant BCG recovered from the lungs were reinfected in mice to enrich clones surviving kanamycin treatment in the lung but sensitive to killing by kanamycin in vitro. After nucleotide sequencing of inserts from these clones, 20 genes belonging to fatty acids metabolism, membrane transport, nitric oxide defence and PE_PGRS/PPE family were identified. Real-time PCR analysis using RNA isolated from M. tuberculosis grown in vitro and from the lungs, confirmed upregulation of genes from 2 to 20-fold in vivo compared to growth in vitro. Several of these select 20 genes were also found upregulated ex vivo in macrophage-like cell line J774A.1, thus, suggesting a correlation in mycobacterial gene expression between ex vivo and in vivo conditions.

Purification of Legiobactin and importance of this siderophore in lung infection by Legionella pneumophila.

PubMed

Allard, Kimberly A; Dao, Jenny; Sanjeevaiah, Prakash; McCoy-Simandle, Kessler; Chatfield, Christa H; Crumrine, David S; Castignetti, Domenic; Cianciotto, Nicholas P

2009-07-01

When cultured in a low-iron medium, Legionella pneumophila secretes a siderophore (legiobactin) that is both reactive in the chrome azurol S (CAS) assay and capable of stimulating the growth of iron-starved legionellae. Using anion-exchange high-pressure liquid chromatography (HPLC), we purified legiobactin from culture supernatants of a virulent strain of L. pneumophila. In the process, we detected the ferrated form of legiobactin as well as other CAS-reactive substances. Purified legiobactin had a yellow-gold color and absorbed primarily from 220 nm and below. In accordance, nuclear magnetic resonance spectroscopy revealed that legiobactin lacks aromatic carbons, and among the 13 aliphatics present, there were 3 carbonyls. When examined by HPLC, supernatants from L. pneumophila mutants inactivated for lbtA and lbtB completely lacked legiobactin, indicating that the LbtA and LbtB proteins are absolutely required for siderophore activity. Independently derived lbtA mutants, but not a complemented derivative, displayed a reduced ability to infect the lungs of A/J mice after intratracheal inoculation, indicating that legiobactin is required for optimal intrapulmonary survival by L. pneumophila. This defect, however, was not evident when the lbtA mutant and its parental strain were coinoculated into the lung, indicating that legiobactin secreted by the wild type can promote growth of the mutant in trans. Legiobactin mutants grew normally in murine lung macrophages and alveolar epithelial cells, suggesting that legiobactin promotes something other than intracellular infection of resident lung cells. Overall, these data represent the first documentation of a role for siderophore expression in the virulence of L. pneumophila.

The Metabolic Sensor GPR43 Receptor Plays a Role in the Control of Klebsiella pneumoniae Infection in the Lung

PubMed Central

Galvão, Izabela; Tavares, Luciana P.; Corrêa, Renan O.; Fachi, José Luís; Rocha, Vitor Melo; Rungue, Marcela; Garcia, Cristiana C.; Cassali, Geovanni; Ferreira, Caroline M.; Martins, Flaviano S.; Oliveira, Sergio C.; Mackay, Charles R.; Teixeira, Mauro M.; Vinolo, Marco Aurélio R.; Vieira, Angélica T.

2018-01-01

Pneumonia is one of the leading causes of death and mortality worldwide. The inflammatory responses that follow respiratory infections are protective leading to pathogen clearance but can also be deleterious if unregulated. The microbiota is known to be an important protective barrier against infections, mediating both direct inhibitory effects against the potential pathogen and also regulating the immune responses contributing to a proper clearance of the pathogen and return to homeostasis. GPR43 is one receptor for acetate, a microbiota metabolite shown to induce and to regulate important immune functions. Here, we addressed the role of GPR43 signaling during pulmonary bacterial infections. We have shown for the first time that the absence of GPR43 leads to increased susceptibility to Klebsiella pneumoniae infection, which was associated to both uncontrolled proliferation of bacteria and to increased inflammatory response. Mechanistically, we showed that GPR43 expression especially in neutrophils and alveolar macrophages is important for bacterial phagocytosis and killing. In addition, treatment with the GPR43 ligand, acetate, is protective during bacterial lung infection. This was associated to reduction in the number of bacteria in the airways and to the control of the inflammatory responses. Altogether, GPR43 plays an important role in the “gut–lung axis” as a sensor of the host gut microbiota activity through acetate binding promoting a proper immune response in the lungs. PMID:29515566

Lung abscess from Staphylococcus aureus after varicella infection in a 3-month-old infant.

PubMed

Aygun, Deniz; Aygun, Fatih; Kılınc, Ayse A; Cam, Halit; Cokugras, Haluk; Camcıoglu, Yıldız

Varicella is a common, highly contagious viral infection of childhood. Varicella is a usually benign and self-limited disease, but it can be complicated by severe bacterial infections, especially in immunocompromised hosts. In this study, we describe a previously healthy 3-months-old infant who was admitted with high fever, cough, and respiratory distress, who had a history of varicella infection three weeks before, with exposure from her adolescent, unvaccinated sister. A lung abscess caused by Staphylococcus aureus complicating the varicella infection was discovered. The patient was aggressively treated with drainage of the abscess and intravenous antibiotics and had a good recovery. Copyright © 2016 King Saud Bin Abdulaziz University for Health Sciences. Published by Elsevier Ltd. All rights reserved.

Postnatal Infections and Immunology Affecting Chronic Lung Disease of Prematurity.

PubMed

Pryhuber, Gloria S

2015-12-01

Premature infants suffer significant respiratory morbidity during infancy with long-term negative consequences on health, quality of life, and health care costs. Enhanced susceptibility to a variety of infections and inflammation play a large role in early and prolonged lung disease following premature birth, although the mechanisms of susceptibility and immune dysregulation are active areas of research. This article reviews aspects of host-pathogen interactions and immune responses that are altered by preterm birth and that impact chronic respiratory morbidity in these children. Copyright © 2015 Elsevier Inc. All rights reserved.

Bone marrow transplantation alters lung antigen presenting cells to promote TH17 response and the development of pneumonitis and fibrosis following gammaherpesvirus infection

PubMed Central

Zhou, Xiaofeng; Loomis-King, Hillary; Gurczynski, Stephen J.; Wilke, Carol A.; Konopka, Kristine E.; Ptaschinski, Catherine; Coomes, Stephanie M; Iwakura, Yoichiro; van Dyk, Linda F.; Lukacs, Nicholas W.; Moore, Bethany B.

2015-01-01

Hematopoietic stem cell transplantation (HSCT) efficacy is limited by numerous pulmonary complications. We developed a model of syngeneic bone marrow transplant (BMT) followed by infection with murine gamma herpesvirus (γHV-68) that results in pneumonitis and fibrosis and mimics human “non-infectious” HSCT complications. BMT mice experience increased early lytic replication, but establish viral latency by 21 days post infection (dpi). CD4 T cells in BMT mice are skewed towards IL-17A rather than IFN-γ production. Transplantation of bone marrow from Il-17a−/− donors or treatment with anti-IL-17A neutralization antibodies at late stages attenuates pneumonitis and fibrosis in infected BMT mice, suggesting that hematopoietic-derived IL-17A is essential for development of pathology. IL-17A directly influences activation and extracellular matrix production by lung mesenchymal cells. Lung CD11c+ cells of BMT mice secrete more TGF-β1, and pro-TH17 mRNAs for IL-23 and IL-6, and less TH1-promoting cytokine mRNA for IFN-γ but slightly more IL-12 mRNA in response to viral infection. Adoptive transfer of non-BMT lung CD11c-enriched cells restores robust TH1 response and suppresses aberrant TH17 response in BMT mice to improve lung pathology. Our data suggest “non-infectious” HSCT lung complications may reflect preceding viral infections and demonstrate that IL-17A neutralization may offer therapeutic advantage even after disease onset. PMID:26376362

[Dermatomycoses due to pets and farm animals : neglected infections?].

PubMed

Nenoff, P; Handrick, W; Krüger, C; Vissiennon, T; Wichmann, K; Gräser, Y; Tchernev, G

2012-11-01

Dermatomycoses due to contact with pets and livestock frequently affect children and young adults. Zoophilic dermatophytes are the main important causative agents. It has long been known that the often high inflammatory dermatophytoses of the skin and the scalp are caused mostly by Microsporum canis. Due to an absence of an obligation for reporting fungal infections of the skin to the Public Health Office in Germany, an unnoticed but significant change in responsible pathogens has occurred. Today an increasing number of infections due to zoophilic strains of Trichophyton interdigitale (formerly Trichophyton mentagrophytes) and Trichophyton species of Arthroderma benhamiae are found. The latter mentioned dermatophyte is the anamorph species of the teleomorph Arthroderma benhamiae, which originally was isolated in the Far East (Japan). Source of infection of these dermatophytes are small rodents, in particular guinea pigs. These animals are bought in pet shops by the parents of those children who later are affected by the fungal infection. The coincidental purchase of the relevant fungal pathogen is not obvious to the parents. As a consequence, highly contagious dermatophytoses occur, often tinea capitis sometimes with kerion formation. Further dermatophytes should be considered as cause of a zoophilic dermatomycosis. Both Trichophyton verrucosum, the cause of the ringworm in cattle, and Trichophyton erinacei following contact to hedgehogs are worthy of note. Yeasts cannot be ignored as cause of dermatomycosis, especially Malassezia pachydermatis, the only non-lipophilic species within the genus Malassezia, which can be transferred from dog to men. Cryptococcus neoformans also comes from animal sources. The mucous yeast occurs in bird's dropping, and it causes both pulmonary and central nervous system infections, but also primary and secondary cutaneous cryptococcosis in immunocompromised patients (HIV/AIDS) as possible consequence after contact to these animals.

Deaths in Canada from lung cancer due to involuntary smoking.

PubMed Central

Wigle, D T; Collishaw, N E; Kirkbride, J; Mao, Y

1987-01-01

Recently published evidence indicates that involuntary smoking causes an increased risk of lung cancer among nonsmokers. Information was compiled on the proportion of people who had never smoked among victims of lung cancer, the risk of lung cancer for nonsmokers married to smokers and the prevalence of such exposure. On the basis of these data we estimate that 50 to 60 of the deaths from lung cancer in Canada in 1985 among people who had never smoked were caused by spousal smoking; about 90% occurred in women. The total number of deaths from lung cancer attributable to exposure to tobacco smoke from spouses and other sources (mainly the workplace) was derived by applying estimated age- and sex-specific rates of death from lung cancer attributable to such exposure to the population of Canadians who have never smoked; about 330 deaths from lung cancer annually are attributable to such exposure. PMID:3567810

SARS-CoV-Encoded Small RNAs Contribute to Infection-Associated Lung Pathology.

PubMed

Morales, Lucía; Oliveros, Juan Carlos; Fernandez-Delgado, Raúl; tenOever, Benjamin Robert; Enjuanes, Luis; Sola, Isabel

2017-03-08

Severe acute respiratory syndrome coronavirus (SARS-CoV) causes lethal disease in humans, which is characterized by exacerbated inflammatory response and extensive lung pathology. To address the relevance of small non-coding RNAs in SARS-CoV pathology, we deep sequenced RNAs from the lungs of infected mice and discovered three 18-22 nt small viral RNAs (svRNAs). The three svRNAs were derived from the nsp3 (svRNA-nsp3.1 and -nsp3.2) and N (svRNA-N) genomic regions of SARS-CoV. Biogenesis of CoV svRNAs was RNase III, cell type, and host species independent, but it was dependent on the extent of viral replication. Antagomir-mediated inhibition of svRNA-N significantly reduced in vivo lung pathology and pro-inflammatory cytokine expression. Taken together, these data indicate that svRNAs contribute to SARS-CoV pathogenesis and highlight the potential of svRNA-N antagomirs as antivirals. Copyright © 2017 Elsevier Inc. All rights reserved.

Unusual infections due to Listeria monocytogenes in the Southern California Desert.

PubMed

Cone, Lawrence A; Somero, Michael S; Qureshi, Farsana J; Kerkar, Shuba; Byrd, Richard G; Hirschberg, Joel M; Gauto, Anibal R

2008-11-01

During the past 22 years, 14 patients have been hospitalized with infection due to Listeria monocytogenes at the Eisenhower Medical Center, a regional 300-bed hospital in the desert southwest of Southern California. A large number of patients are retired, elderly, and have underlying and often systemic disease. Blood agar and routine media were inoculated with liquid from a sterile site such as blood, cerebrospinal fluid, or joint fluid and observed daily for growth. Appropriate biochemical studies were used to speciate the organism. While bacteremia and meningitis constitute 75% of infections in most studies, they made up only 36% of patients in the current study. Listeriosis occurred mostly in patients with infected aortic aneurysms and brain abscesses, and in prosthetic joint infections. While mortality is generally stated to be around 45% in patients with listeriosis, it was 35% in this study. However, there were no deaths in five patients with bacteremia or meningitis inferring that organ involvement poses a greater hazard for survival. Listeriosis usually presents as a bacteremia or meningitis due to a food-borne invasive infection. In the desert of Southern California most cases are seen in older patients with underlying disease and present with infected aortic aneurysms, prosthetic joints, and brain abscesses. They represent a greater threat to survival due to organ involvement.

Outcomes of lung transplantation in patients with scleroderma.

PubMed

Massad, Malek G; Powell, Charles R; Kpodonu, Jacques; Tshibaka, Cimenga; Hanhan, Ziad; Snow, Norman J; Geha, Alexander S

2005-11-01

Patients with pulmonary insufficiency due to scleroderma have long been considered suboptimal candidates for lung transplantation. This has been supported by small single-center experiences that did not reflect the entire U.S. experience. We sought to evaluate the outcome of patients with scleroderma who underwent lung transplantation. We conducted a retrospective review of 47 patients with scleroderma who underwent lung transplantation at 23 U.S. centers between 1987 and 2004 and were reported to the United Network for Organ Sharing. Women constituted 57% of the patients. The mean age was 46 years. Twenty-seven patients received single lung transplants (57%), and the remaining received double lung transplants. The mean cold ischemia time was 4.1 hours. There were 7 early deaths (< or =30 days) and 17 late deaths (> 30 days). The causes of early death were primary graft failure and a cardiac event in two patients each and bacterial infection and stroke in one patient each. Late mortality was due to infection in seven patients, respiratory failure in three, malignancy in two, and multisystem organ failure, rejection, pulmonary hypertension, and a cardiac event in one patient each. The causes of early and late death were not recorded for two patients. One patient received a second transplant owing to graft failure of the first. Twenty-three patients (49%) were alive at a mean follow-up of 24 months. The Kaplan-Meier 1- and 3-year survival rates were 67.6% and 45.9% respectively, which are not significantly different from those of 10,070 patients given transplants for other lung conditions during the same period (75.5% and 58.8% respectively, P = 0.25). Donor gender, recipient's age, and type of transplant did not affect survival. In carefully selected patients with scleroderma who have end-stage lung disease, lung transplantation is a valid life-saving therapeutic option. Available data suggest acceptable short-term morbidity and mortality and a long-term survival

[Skin and Soft Tissue Infections Due to Corynebacterium ulcerans - Case Reports].

PubMed

Jenssen, Christian; Schwede, Ilona; Neumann, Volker; Pietsch, Cristine; Handrick, Werner

2017-10-01

History and clinical findings  We report on three patients suffering from skin and soft tissue infections of the legs due to toxigenic Corynebacterium ulcerans strains. In all three patients, there was a predisposition due to chronic diseases. Three patients had domestic animals (cat, dog) in their households. Investigations and diagnosis  A mixed bacterial flora including Corynebacterium ulcerans was found in wound swab samples. Diphtheric toxin was produced by the Corynebacterium ulcerans strains in all three cases. Treatment and course  In all three patients, successful handling of the skin and soft tissue infections was possible by combining local treatment with antibiotics. Diphtheria antitoxin was not administered in any case. Conclusion  Based on a review of the recent literature pathogenesis, clinical symptoms and signs, diagnostics and therapy of skin and soft tissue infections due to Corynebacterium ulcerans are discussed. Corynebacterium ulcerans should be considered as a potential cause of severe skin and soft tissue infections. Occupational or domestic animal contacts should be evaluated. © Georg Thieme Verlag KG Stuttgart · New York.

Correlation between sinus and lung cultures in lung transplant patients with cystic fibrosis.

PubMed

Choi, Kevin J; Cheng, Tracy Z; Honeybrook, Adam L; Gray, Alice L; Snyder, Laurie D; Palmer, Scott M; Abi Hachem, Ralph; Jang, David W

2018-03-01

Lung transplantation has revolutionized the treatment of end-stage pulmonary disease due to cystic fibrosis. However, infection of the transplanted lungs can lead to serious complications, including graft failure and death. Although many of these patients have concurrent sinusitis, it is unclear whether bacteria from the sinuses can infect the allograft. This is a single-institution retrospective study of all patients who underwent lung transplantation for cystic fibrosis from 2005 to 2015 at Duke University Hospital. Pre- and posttransplant nasal and pulmonary cultures obtained via nasal endoscopy and bronchoalveolar lavage (BAL), respectively, were analyzed. A total of 141 patients underwent 144 lung transplants. Sinus cultures were available for 76 patients (12 pretransplant, 42 posttransplant, 22 both pre- and posttransplant). Pretransplant BAL cultures were available for 139 patients, and posttransplant BAL cultures were available for all patients. Pseudomonas aeruginosa (PsA) and methicillin-resistant Staphylococcus aureus (MRSA) were the most common organisms cultured. There was a significant correlation between pretransplant sinus and posttransplant BAL cultures for PsA (p = 0.003), MRSA (p = 0.013), and Burkholderia cepacia (p = 0.001). There was a high correlation between pretransplant sinus cultures and posttransplant BAL cultures for PsA, MRSA, and Burkholderia sp. This suggests that the paranasal sinuses may act as a reservoir for allograft colonization in patients with cystic fibrosis. Further studies are needed to determine whether treatment of sinusitis affects allograft colonization and transplant outcomes. © 2017 ARS-AAOA, LLC.

IL-17RA in Non-Hematopoietic Cells Controls CXCL-1 and 5 Critical to Recruit Neutrophils to the Lung of Mycobacteria-Infected Mice during the Adaptive Immune Response

PubMed Central

Lombard, Robin; Epardaud, Mathieu; Le Vern, Yves; Buzoni-Gatel, Dominique; Winter, Nathalie

2016-01-01

During chronic infection with Mycobacterium tuberculosis (Mtb), bacilli multiplication is constrained within lung granulomas until excessive inflammation destroys the lung. Neutrophils are recruited early and participate in granuloma formation, but excessive neutrophilia exacerbates the tuberculosis disease. Neutrophils thus appear as potential targets for therapeutic interventions, especially in patients for whom no antibiotic treatment is possible. Signals that regulate neutrophil recruitment to the lung during mycobacterial infection need to be better understood. We demonstrated here, in the mouse model, that neutrophils were recruited to the lung in two waves after intranasal infection with virulent Mtb or the live attenuated vaccine strain Bacillus Calmette Guérin (BCG). A first wave of neutrophils was swiftly recruited, followed by a subsequent adaptive wave that reached the lung together with IFN-γ- and IL-17A-producing T cells. Interestingly, the second neutrophil wave did not participate to mycobacteria control in the lung and established contacts with T cells. The adaptive wave was critically dependent on the expression of IL-17RA, the receptor for IL-17A, expressed in non-hematopoietic cells. In absence of this receptor, curtailed CXCL-1 and 5 production in the lung restrained neutrophil recruitment. CXCL-1 and 5 instillation reconstituted lung neutrophil recruitment in BCG-infected IL17RA-/- mice. PMID:26871571

IL-17RA in Non-Hematopoietic Cells Controls CXCL-1 and 5 Critical to Recruit Neutrophils to the Lung of Mycobacteria-Infected Mice during the Adaptive Immune Response.

PubMed

Lombard, Robin; Doz, Emilie; Carreras, Florence; Epardaud, Mathieu; Le Vern, Yves; Buzoni-Gatel, Dominique; Winter, Nathalie

2016-01-01

During chronic infection with Mycobacterium tuberculosis (Mtb), bacilli multiplication is constrained within lung granulomas until excessive inflammation destroys the lung. Neutrophils are recruited early and participate in granuloma formation, but excessive neutrophilia exacerbates the tuberculosis disease. Neutrophils thus appear as potential targets for therapeutic interventions, especially in patients for whom no antibiotic treatment is possible. Signals that regulate neutrophil recruitment to the lung during mycobacterial infection need to be better understood. We demonstrated here, in the mouse model, that neutrophils were recruited to the lung in two waves after intranasal infection with virulent Mtb or the live attenuated vaccine strain Bacillus Calmette Guérin (BCG). A first wave of neutrophils was swiftly recruited, followed by a subsequent adaptive wave that reached the lung together with IFN-γ- and IL-17A-producing T cells. Interestingly, the second neutrophil wave did not participate to mycobacteria control in the lung and established contacts with T cells. The adaptive wave was critically dependent on the expression of IL-17RA, the receptor for IL-17A, expressed in non-hematopoietic cells. In absence of this receptor, curtailed CXCL-1 and 5 production in the lung restrained neutrophil recruitment. CXCL-1 and 5 instillation reconstituted lung neutrophil recruitment in BCG-infected IL17RA-/- mice.

The hbhA Gene of Mycobacterium tuberculosis Is Specifically Upregulated in the Lungs but Not in the Spleens of Aerogenically Infected Mice

PubMed Central

Delogu, Giovanni; Sanguinetti, Maurizio; Posteraro, Brunella; Rocca, Stefano; Zanetti, Stefania; Fadda, Giovanni

2006-01-01

We report that hbhA is differentially regulated during Mycobacterium tuberculosis infection. Upregulation was observed in epithelial cell infection but not in macrophage infection and in the lungs but not in the spleens of infected mice, and it was greater during the early steps of infection, when bacilli disseminate from the site of primary infection. PMID:16622240

Trichinella spiralis: killing of newborn larvae by lung cells.

PubMed

Falduto, Guido H; Vila, Cecilia C; Saracino, María P; Calcagno, Marcela A; Venturiello, Stella M

2015-02-01

The migratory stage of Trichinella spiralis, the newborn larva (NBL), travels along the pulmonary microvascular system on its way to the skeletal muscle cells. The present work studies the capability of lung cells to kill NBL. For this purpose, in vitro cytotoxicity assays were performed using NBL, lung cell suspensions from Wistar rats, rat anti-NBL surface sera, and fresh serum as complement source. The cytotoxic activity of lung cells from rats infected on day 6 p.i. was compared with that from noninfected rats. Two and 20 h-old NBL (NBL2 and NBL20) were used as they had shown to exhibit different surface antigens altering their biological activity. Sera antibodies were analyzed by indirect immunofluorescence assay, and cell populations used in each assay were characterized by histological staining. The role of IgE in the cytotoxic attack against NBL was analyzed using heated serum. The FcεRI expression on cell suspensions was examined by flow cytometry. Results showed that lung cells were capable of killing NBL by antibody-dependent cell-mediated cytotoxicity (ADCC). Lung cells from infected animals yielded the highest mortality percentages of NBL, with NBL20 being the most susceptible to such attack. IgE yielded a critical role in the cytotoxic attack. Regarding the analysis of cell suspensions, cells from infected rats showed an increase in the percentage of eosinophils, neutrophils, and the number of cells expressing the FcεRI receptor. We conclude that lung cells are capable of killing NBL in the presence of specific antibodies, supporting the idea that the lung is one of the sites where the NBL death occurs due to ADCC.

Current questions in HIV-associated lung cancer.

PubMed

Shcherba, Marina; Shuter, Jonathan; Haigentz, Missak

2013-09-01

In this review, we explore current questions regarding risk factors contributing to frequent and early onset of lung cancer among populations with HIV infection, treatment, and outcomes of lung cancer in HIV-infected patients as well as challenges in a newly evolving era of lung cancer screening. Lung cancer, seen in three-fold excess in HIV-infected populations, has become the most common non-AIDS defining malignancy in the highly active antiretroviral therapy era. HIV-associated lung cancer appears to be associated with young age at diagnosis, cigarette smoking, advanced stage at presentation, and a more aggressive clinical course. There is no unified explanation for these observations, and aside from traditional risk factors, HIV-related immunosuppression and biological differences might play a role. In addition to smoking cessation interventions, screening and early cancer detection in HIV-infected populations are of high clinical importance, although evidence supporting lung cancer screening in this particularly high-risk subset is currently lacking, as are prospective studies of lung cancer therapy. There is an urgent need for prospective clinical trials in HIV-associated lung cancer to improve understanding of lung cancer pathogenesis and to optimize patient care. Several clinical trials are in progress to address questions in cancer biology, screening, and treatment for this significant cause of mortality in persons with HIV infection.

Nociceptor sensory neurons suppress neutrophil and γδ T cell responses in bacterial lung infections and lethal pneumonia.

PubMed

Baral, Pankaj; Umans, Benjamin D; Li, Lu; Wallrapp, Antonia; Bist, Meghna; Kirschbaum, Talia; Wei, Yibing; Zhou, Yan; Kuchroo, Vijay K; Burkett, Patrick R; Yipp, Bryan G; Liberles, Stephen D; Chiu, Isaac M

2018-05-01

Lung-innervating nociceptor sensory neurons detect noxious or harmful stimuli and consequently protect organisms by mediating coughing, pain, and bronchoconstriction. However, the role of sensory neurons in pulmonary host defense is unclear. Here, we found that TRPV1 + nociceptors suppressed protective immunity against lethal Staphylococcus aureus pneumonia. Targeted TRPV1 + -neuron ablation increased survival, cytokine induction, and lung bacterial clearance. Nociceptors suppressed the recruitment and surveillance of neutrophils, and altered lung γδ T cell numbers, which are necessary for immunity. Vagal ganglia TRPV1 + afferents mediated immunosuppression through release of the neuropeptide calcitonin gene-related peptide (CGRP). Targeting neuroimmunological signaling may be an effective approach to treat lung infections and bacterial pneumonia.

[Nosocomial infection due to Trichosporon asahii in a critical burned patient].

PubMed

Tamayo Lomas, Luis; Domínguez-Gil González, Marta; Martín Luengo, Ana Isabel; Eiros Bouza, José María; Piqueras Pérez, José María

2015-01-01

Invasive fungal infection is an important cause of morbimortality in patients with severe burns. The advances in burn care therapy have considerably extended the survival of seriously burned patients, exposing them to infectious complications, notably fungal infections, with increased recognition of invasive infections caused by Candida species. However, some opportunistic fungi, like Trichosporon asahii, have emerged as important causes of nosocomial infection. A case of nosocomial infection due to T. asahii in a severely ill burned patient successfully treated with voriconazole is presented. The management of invasive fungal infections in burned patients, from diagnosis to selection of the therapeutic protocol, is often a challenge. Early diagnosis and treatment are associated with a better prognosis. In this case report, current treatment options are discussed, and a review of previously published cases is presented. Due to the difficulty in the diagnosis of invasive mycoses and their high associated mortality rates, it is advisable to keep a high degree of clinical suspicion of trichosporonosis in susceptible patients, including burned patients. The isolation of T. asahii in clinical specimens of this type of host must raise clinical alert, since it may precede an invasive infection. Copyright © 2014 Revista Iberoamericana de Micología. Published by Elsevier Espana. All rights reserved.

Trauma-associated lung injury differs clinically and biologically from acute lung injury due to other clinical disorders*

PubMed Central

Calfee, Carolyn S.; Eisner, Mark D.; Ware, Lorraine B.; Thompson, B. Taylor; Parsons, Polly E.; Wheeler, Arthur P.; Korpak, Anna; Matthay, Michael A.

2009-01-01

Objective Patients with trauma-associated acute lung injury have better outcomes than patients with other clinical risks for lung injury, but the mechanisms behind these improved outcomes are unclear. We sought to compare the clinical and biological features of patients with trauma-associated lung injury with those of patients with other risks for lung injury and to determine whether the improved outcomes of trauma patients reflect their baseline health status or less severe lung injury, or both. Design, Setting, and Patients Analysis of clinical and biological data from 1,451 patients enrolled in two large randomized, controlled trials of ventilator management in acute lung injury. Measurements and Main Results Compared with patients with other clinical risks for lung injury, trauma patients were younger and generally less acutely and chronically ill. Even after adjusting for these baseline differences, trauma patients had significantly lower plasma levels of intercellular adhesion molecule-1, von Willebrand factor antigen, surfactant protein-D, and soluble tumor necrosis factor receptor-1, which are biomarkers of lung epithelial and endothelial injury previously found to be prognostic in acute lung injury. In contrast, markers of acute inflammation, except for interleukin-6, and disordered coagulation were similar in trauma and nontrauma patients. Trauma-associated lung injury patients had a significantly lower odds of death at 90 days, even after adjusting for baseline clinical factors including age, gender, ethnicity, comorbidities, and severity of illness (odds ratio, 0.44; 95% confidence interval, 0.24 – 0.82; p = .01). Conclusions Patients with trauma-associated lung injury are less acutely and chronically ill than other lung injury patients; however, these baseline clinical differences do not adequately explain their improved outcomes. Instead, the better outcomes of the trauma population may be explained, in part, by less severe lung epithelial and

Adult bone marrow-derived stem cells for the lung: implications for pediatric lung diseases.

PubMed

van Haaften, Timothy; Thébaud, Bernard

2006-04-01

Bronchopulmonary dysplasia (BPD) and cystic fibrosis (CF) are two common serious chronic respiratory disorders without specific treatments affecting children. BPD is characterized by an arrest in alveolar growth in premature infants requiring respiratory support. CF is the most common fatal inherited genetic disorder characterized by abnormally thick mucus secretions, recurrent infection and ultimately lung destruction. One commonality between these two diseases is the promise of utilizing stem cells therapeutically. Indeed, the use of exogenous cells to supplement the natural repair mechanisms or the possibility of genetic manipulation in vitro before administration are appealing therapeutic options for these diseases. Increasing attention has been focused on the use of adult bone marrow-derived stem cells (BMSC) to regenerate damaged organs such as the heart, the brain, and the liver. However, due to the lung's complexity as well as the low rate of cellular turnover within the lung, progress has been slower in this area compared with the skin or liver. Initial work suggests that BMSC can engraft and differentiate into a variety of lung cells, but these findings have been challenged recently. This article critically reviews the current advances on the therapeutic use of stem cells for lung regeneration.

Eosinophilia, parasite burden and lung damage in Toxocara canis infection in C57Bl/6 mice genetically deficient in IL-5.

PubMed Central

Takamoto, M; Ovington, K S; Behm, C A; Sugane, K; Young, I G; Matthaei, K I

1997-01-01

C57Bl/6 mice genetically deficient in interleukin (IL)-5 (IL-5-/-) and mice with the normal IL-5 gene (IL-5+/+) were infected with embryonated eggs of Toxocara canis. IL-5+/+ mice developed a marked eosinophilia in their peripheral bloods and bone marrows after infection. In contrast, the number of eosinophils at these sites actually decreased during the acute phase of infection in IL-5-/- mice. A smaller number of eosinophils infiltrated the lung, liver, heart and skeletal muscle of infected IL-5-/- mice than those of infected IL-5+/+ mice. Eosinophils were not produced in cultures of bone marrow cells from either IL-5+/+ or IL-5-/- mice which were stimulated with excretory secretory antigen of T. canis larvae. The capacity of cells from the bone marrow to differentiate into eosinophils when stimulated in vitro with recombinant murine IL-5 was the same whether the cells were from IL-5+/+ or IL-5-/- mice. Taken together, these results show that an IL-5-like molecule is not produced by the T. canis larvae and that IL-5 produced by host cells is solely responsible for the eosinophilia in mice infected with this nematode. The number and location of T. canis larvae were not altered in the absence of IL-5. In contrast, lung damage in infected IL-5-/- mice was less extensive than that in infected IL-5+/+ mice, although structures resembling Charcot-Leyden crystals were seen in the lungs of both IL-5+/+ and IL-5-/- mice. These results suggest that eosinophils play a role in the pathology in mice infected with T. canis. Images Figure 3 PMID:9176103

Sudden death of an Indian peafowl (Pavo cristatus) at a zoo due to non-pigmented Serratia marcescens infection

PubMed Central

LEE, Seung-Hun; PARK, Sang-Joon; KWAK, Dongmi; KIM, Kyoo-Tae

2017-01-01

A 16-year-old female Indian peafowl (Pavo cristatus) died two days after recognition of conjunctivitis in the right eye, anorexia and depression. Gross necropsy revealed a thick pseudomembrane under the eyelid and hydropericardium. Histopathological examination revealed hepatocellular necrosis, sinusoidal and vascular congestion and infiltrated inflammatory cells. Infiltration by inflammatory cells was noted in the epicardium. The lungs had mild interstitial pneumonia with the extensive congestion within the capillaries of the air sacs. Tubular interstitial congestion and necrosis was noted in the kidneys. Bacterial culture and nucleotide sequencing of the inflammatory specimens identified the causative agent as Serratia marcescens, an uncommon bacterium in birds. In summary, this study describes the sudden death of an Indian peafowl due to S. marcescens infection, which is rarely seen in animals. PMID:29081475

Risk Factors Associated with Quantitative Evidence of Lung Emphysema and Fibrosis in an HIV-infected Cohort

PubMed Central

Leader, Joseph K.; Crothers, Kristina; Huang, Laurence; King, Mark A.; Morris, Alison; Thompson, Bruce W.; Flores, Sonia C.; Drummond, M. Bradley; Rom, William N.; Diaz, Philip T.

2015-01-01

Introduction The disease spectrum for HIV-infected individuals has shifted towards co-morbid non-AIDS conditions including chronic lung disease, but quantitative image analysis of lung disease has not been performed. Objectives To quantify the prevalence of structural changes of the lung indicating emphysema or fibrosis on radiographic examination. Methods A cross-sectional analysis of 510 HIV-infected participants in the multi-center Lung-HIV study was performed. Data collected included: demographics, biological markers of HIV, pulmonary function testing, and chest CT examinations. Emphysema and fibrosis-like changes were quantified on CT images based on threshold approaches. Results In our cohort: 69% was on antiretroviral therapy, 13% had a current CD4 cell count less than 200 cells/μL, 39% had an HIV viral load greater than 500 copies/mL, 25% had at least a trace level of emphysema (defined as >2.5% of voxels <-950HU). Trace emphysema was significantly correlated with age, smoking, and pulmonary function. Neither current CD4 cell count nor HIV viral load was significantly correlated with emphysema. Fibrosis-like changes were detected in 29% of the participants and were significantly correlated with HIV viral load (Pearson correlation coefficient = 0.210, p<0.05); current CD4 cell count was not associated with fibrosis. In multivariable analyses including age, race, and smoking status, HIV viral load remained significantly correlated with fibrosis-like changes (coefficient = 0.107, P = 0.03). Conclusion A higher HIV viral load was significantly associated with fibrosis-like changes possibly indicating early interstitial lung disease, but emphysematous changes were not related to current CD4 cell count or HIV viral load. PMID:26914911

Cytotoxic immune responses in the lungs correlate to disease severity in patients with hantavirus infection.

PubMed

Rasmuson, J; Pourazar, J; Mohamed, N; Lejon, K; Evander, M; Blomberg, A; Ahlm, C

2016-04-01

Hantavirus infections may cause severe and sometime life-threatening lung failure. The pathogenesis is not fully known and there is an urgent need for effective treatment. We aimed to investigate the association between pulmonary viral load and immune responses, and their relation to disease severity. Bronchoscopy with sampling of bronchoalveolar lavage (BAL) fluid was performed in 17 patients with acute Puumala hantavirus infection and 16 healthy volunteers acting as controls. Lymphocyte subsets, granzyme concentrations, and viral load were determined by flow cytometry, enzyme-linked immunosorbent assay (ELISA), and quantitative reverse transcription polymerase chain reaction (RT-PCR), respectively. Analyses of BAL fluid revealed significantly higher numbers of activated CD8(+) T cells and natural killer (NK) cells, as well as higher concentrations of the cytotoxins granzymes A and B in hantavirus-infected patients, compared to controls. In patients, Puumala hantavirus RNA was detected in 88 % of BAL cell samples and correlated inversely to the T cell response. The magnitude of the pulmonary cytotoxic lymphocyte response correlated to the severity of disease and systemic organ dysfunction, in terms of need for supplemental oxygen treatment, hypotension, and laboratory data indicating renal failure, cardiac dysfunction, vascular leakage, and cell damage. Regulatory T cell numbers were significantly lower in patients compared to controls, and may reflect inadequate immune regulation during hantavirus infection. Hantavirus infection elicits a pronounced cytotoxic lymphocyte response in the lungs. The magnitude of the immune response was associated with disease severity. These results give insights into the pathogenesis and possibilities for new treatments.

Detection of Quiescent Infections with Multiple Elephant Endotheliotropic Herpesviruses (EEHVs), Including EEHV2, EEHV3, EEHV6, and EEHV7, within Lymphoid Lung Nodules or Lung and Spleen Tissue Samples from Five Asymptomatic Adult African Elephants.

PubMed

Zong, Jian-Chao; Heaggans, Sarah Y; Long, Simon Y; Latimer, Erin M; Nofs, Sally A; Bronson, Ellen; Casares, Miguel; Fouraker, Michael D; Pearson, Virginia R; Richman, Laura K; Hayward, Gary S

2015-12-30

More than 80 cases of lethal hemorrhagic disease associated with elephant endotheliotropic herpesviruses (EEHVs) have been identified in young Asian elephants worldwide. Diagnostic PCR tests detected six types of EEHV in blood of elephants with acute disease, although EEHV1A is the predominant pathogenic type. Previously, the presence of herpesvirus virions within benign lung and skin nodules from healthy African elephants led to suggestions that African elephants may be the source of EEHV disease in Asian elephants. Here, we used direct PCR-based DNA sequencing to detect EEHV genomes in necropsy tissue from five healthy adult African elephants. Two large lung nodules collected from culled wild South African elephants contained high levels of either EEHV3 alone or both EEHV2 and EEHV3. Similarly, a euthanized U.S. elephant proved to harbor multiple EEHV types distributed nonuniformly across four small lung nodules, including high levels of EEHV6, lower levels of EEHV3 and EEHV2, and a new GC-rich branch type, EEHV7. Several of the same EEHV types were also detected in random lung and spleen samples from two other elephants. Sanger PCR DNA sequence data comprising 100 kb were obtained from a total of 15 different strains identified, with (except for a few hypervariable genes) the EEHV2, EEHV3, and EEHV6 strains all being closely related to known genotypes from cases of acute disease, whereas the seven loci (4.0 kb) obtained from EEHV7 averaged 18% divergence from their nearest relative, EEHV3. Overall, we conclude that these four EEHV species, but probably not EEHV1, occur commonly as quiescent infections in African elephants. Acute hemorrhagic disease characterized by high-level viremia due to infection by members of the Proboscivirus genus threatens the future breeding success of endangered Asian elephants worldwide. Although the genomes of six EEHV types from acute cases have been partially or fully characterized, lethal disease predominantly involves a variety

Detection of Quiescent Infections with Multiple Elephant Endotheliotropic Herpesviruses (EEHVs), Including EEHV2, EEHV3, EEHV6, and EEHV7, within Lymphoid Lung Nodules or Lung and Spleen Tissue Samples from Five Asymptomatic Adult African Elephants

PubMed Central

Zong, Jian-Chao; Heaggans, Sarah Y.; Long, Simon Y.; Latimer, Erin M.; Nofs, Sally A.; Bronson, Ellen; Casares, Miguel; Fouraker, Michael D.; Pearson, Virginia R.; Richman, Laura K.

2015-01-01

ABSTRACT More than 80 cases of lethal hemorrhagic disease associated with elephant endotheliotropic herpesviruses (EEHVs) have been identified in young Asian elephants worldwide. Diagnostic PCR tests detected six types of EEHV in blood of elephants with acute disease, although EEHV1A is the predominant pathogenic type. Previously, the presence of herpesvirus virions within benign lung and skin nodules from healthy African elephants led to suggestions that African elephants may be the source of EEHV disease in Asian elephants. Here, we used direct PCR-based DNA sequencing to detect EEHV genomes in necropsy tissue from five healthy adult African elephants. Two large lung nodules collected from culled wild South African elephants contained high levels of either EEHV3 alone or both EEHV2 and EEHV3. Similarly, a euthanized U.S. elephant proved to harbor multiple EEHV types distributed nonuniformly across four small lung nodules, including high levels of EEHV6, lower levels of EEHV3 and EEHV2, and a new GC-rich branch type, EEHV7. Several of the same EEHV types were also detected in random lung and spleen samples from two other elephants. Sanger PCR DNA sequence data comprising 100 kb were obtained from a total of 15 different strains identified, with (except for a few hypervariable genes) the EEHV2, EEHV3, and EEHV6 strains all being closely related to known genotypes from cases of acute disease, whereas the seven loci (4.0 kb) obtained from EEHV7 averaged 18% divergence from their nearest relative, EEHV3. Overall, we conclude that these four EEHV species, but probably not EEHV1, occur commonly as quiescent infections in African elephants. IMPORTANCE Acute hemorrhagic disease characterized by high-level viremia due to infection by members of the Proboscivirus genus threatens the future breeding success of endangered Asian elephants worldwide. Although the genomes of six EEHV types from acute cases have been partially or fully characterized, lethal disease predominantly

Baicalin from Scutellaria baicalensis blocks respiratory syncytial virus (RSV) infection and reduces inflammatory cell infiltration and lung injury in mice.

PubMed

Shi, Hengfei; Ren, Ke; Lv, Baojie; Zhang, Wei; Zhao, Ying; Tan, Ren Xiang; Li, Erguang

2016-10-21

The roots of Scutellaria baicalensis has been used as a remedy for inflammatory and infective diseases for thousands of years. We evaluated the antiviral activity against respiratory syncytial virus (RSV) infection, the leading cause of childhood infection and hospitalization. By fractionation and chromatographic analysis, we determined that baicalin was responsible for the antiviral activity of S. baicalensis against RSV infection. The concentration for 50% inhibition (IC 50 ) of RSV infection was determined at 19.9 ± 1.8 μM, while the 50% cytotoxic concentration (CC 50 ) was measured at 370 ± 10 μM. We then used a mouse model of RSV infection to further demonstrate baicalin antiviral effect. RSV infection caused significant lung injury and proinflammatory response, including CD4 and CD8 T lymphocyte infiltration. Baicalin treatment resulted in reduction of T lymphocyte infiltration and gene expression of proinflammatory factors, while the treatment moderately reduced RSV titers recovered from the lung tissues. T lymphocyte infiltration and cytotoxic T lymphocyte modulated tissue damage has been identified critical factors of RSV disease. The study therefore demonstrates that baicalin subjugates RSV disease through antiviral and anti-inflammatory effect.

Baicalin from Scutellaria baicalensis blocks respiratory syncytial virus (RSV) infection and reduces inflammatory cell infiltration and lung injury in mice

PubMed Central

Shi, Hengfei; Ren, Ke; Lv, Baojie; Zhang, Wei; Zhao, Ying; Tan, Ren Xiang; Li, Erguang

2016-01-01

The roots of Scutellaria baicalensis has been used as a remedy for inflammatory and infective diseases for thousands of years. We evaluated the antiviral activity against respiratory syncytial virus (RSV) infection, the leading cause of childhood infection and hospitalization. By fractionation and chromatographic analysis, we determined that baicalin was responsible for the antiviral activity of S. baicalensis against RSV infection. The concentration for 50% inhibition (IC50) of RSV infection was determined at 19.9 ± 1.8 μM, while the 50% cytotoxic concentration (CC50) was measured at 370 ± 10 μM. We then used a mouse model of RSV infection to further demonstrate baicalin antiviral effect. RSV infection caused significant lung injury and proinflammatory response, including CD4 and CD8 T lymphocyte infiltration. Baicalin treatment resulted in reduction of T lymphocyte infiltration and gene expression of proinflammatory factors, while the treatment moderately reduced RSV titers recovered from the lung tissues. T lymphocyte infiltration and cytotoxic T lymphocyte modulated tissue damage has been identified critical factors of RSV disease. The study therefore demonstrates that baicalin subjugates RSV disease through antiviral and anti-inflammatory effect. PMID:27767097

Human Lung Homotransplantation

PubMed Central

White, J. J.; Tanser, P. H.; Anthonisen, N. R.; Wynands, J. E.; Pare, J. A. P.; Becklake, M. R.; Munro, D. D.; MacLean, L. D.

1966-01-01

Left lung homotransplantation was performed in a 31-year-old man in terminal irreversible respiratory failure due to advanced silicosis. Within 10 minutes of completion of transplantation, arterial pO2 rose from 52 to 211 mm. Hg, pCO2 dropped from 90 to 43 mm. Hg, and pH rose from 7.15 to 7.42. On assisted ventilation, arterial O2 tension was maintained within normal limits for the first four days. Thereafter, arterio-alveolar difference for O2 increased to 300 mm. and that for CO2 to 25 mm. Xenon-133 ventilation perfusion ratios confirmed differences between the two lungs. Terminally, bronchopneumonia and hypoxemia were present. Surfactant content of the lung was within normal limits. Postmortem examination revealed bronchopneumonia, bronchial infarction, lymphatic engorgement and mild rejection. Future efforts should emphasize selection of non-infected donors, minimal reliance on steroids for immunosuppression, cardiopulmonary bypass during transplantation, and more definite criteria for rejection. ImagesFig. 2Fig. 3Fig. 4Fig. 8Fig. 9Fig. 11Fig. 12Fig. 13Fig. 14 PMID:5328358

Uncertainties in planned dose due to the limited voxel size of the planning CT when treating lung tumors with proton therapy

NASA Astrophysics Data System (ADS)

España, Samuel; Paganetti, Harald

2011-07-01

Dose calculation for lung tumors can be challenging due to the low density and the fine structure of the geometry. The latter is not fully considered in the CT image resolution used in treatment planning causing the prediction of a more homogeneous tissue distribution. In proton therapy, this could result in predicting an unrealistically sharp distal dose falloff, i.e. an underestimation of the distal dose falloff degradation. The goal of this work was the quantification of such effects. Two computational phantoms resembling a two-dimensional heterogeneous random lung geometry and a swine lung were considered applying a variety of voxel sizes for dose calculation. Monte Carlo simulations were used to compare the dose distributions predicted with the voxel size typically used for the treatment planning procedure with those expected to be delivered using the finest resolution. The results show, for example, distal falloff position differences of up to 4 mm between planned and expected dose at the 90% level for the heterogeneous random lung (assuming treatment plan on a 2 × 2 × 2.5 mm3 grid). For the swine lung, differences of up to 38 mm were seen when airways are present in the beam path when the treatment plan was done on a 0.8 × 0.8 × 2.4 mm3 grid. The two-dimensional heterogeneous random lung phantom apparently does not describe the impact of the geometry adequately because of the lack of heterogeneities in the axial direction. The differences observed in the swine lung between planned and expected dose are presumably due to the poor axial resolution of the CT images used in clinical routine. In conclusion, when assigning margins for treatment planning for lung cancer, proton range uncertainties due to the heterogeneous lung geometry and CT image resolution need to be considered.

An Epithelial Integrin Regulates the Amplitude of Protective Lung Interferon Responses against Multiple Respiratory Pathogens.

PubMed

Meliopoulos, Victoria A; Van de Velde, Lee-Ann; Van de Velde, Nicholas C; Karlsson, Erik A; Neale, Geoff; Vogel, Peter; Guy, Cliff; Sharma, Shalini; Duan, Susu; Surman, Sherri L; Jones, Bart G; Johnson, Michael D L; Bosio, Catharine; Jolly, Lisa; Jenkins, R Gisli; Hurwitz, Julia L; Rosch, Jason W; Sheppard, Dean; Thomas, Paul G; Murray, Peter J; Schultz-Cherry, Stacey

2016-08-01

The healthy lung maintains a steady state of immune readiness to rapidly respond to injury from invaders. Integrins are important for setting the parameters of this resting state, particularly the epithelial-restricted αVβ6 integrin, which is upregulated during injury. Once expressed, αVβ6 moderates acute lung injury (ALI) through as yet undefined molecular mechanisms. We show that the upregulation of β6 during influenza infection is involved in disease pathogenesis. β6-deficient mice (β6 KO) have increased survival during influenza infection likely due to the limited viral spread into the alveolar spaces leading to reduced ALI. Although the β6 KO have morphologically normal lungs, they harbor constitutively activated lung CD11b+ alveolar macrophages (AM) and elevated type I IFN signaling activity, which we traced to the loss of β6-activated transforming growth factor-β (TGF-β). Administration of exogenous TGF-β to β6 KO mice leads to reduced numbers of CD11b+ AMs, decreased type I IFN signaling activity and loss of the protective phenotype during influenza infection. Protection extended to other respiratory pathogens such as Sendai virus and bacterial pneumonia. Our studies demonstrate that the loss of one epithelial protein, αVβ6 integrin, can alter the lung microenvironment during both homeostasis and respiratory infection leading to reduced lung injury and improved survival.

Lung transplantation in patients with pulmonary emphysema.

PubMed

Paik, Hyo Chae; Hwang, Jung Joo; Lee, Doo Yun

2004-12-31

Lung transplantation is a viable option for patients with chronic obstructive pulmonary disease (COPD), and emphysema is the most common indication to undergo lung transplantation. A total of seven lung and one heart-lung transplantations were performed between July 1996 and June 2004 at the Yongdong Severance Hospital, and herein, three emphysema patients who underwent single lung transplantations are reviewed. There were 2 males and 1 female, with a mean age of 50 years (35, 57 and 58 years). They all underwent an operation, without cardiopulmonary bypass, and there was no operative mortality. The mean survival was 12 months (4 months, 15 months and 17 months) and all succumbed to death due to activation of pulmonary tuberculosis, post-transplantation lymphoproliferative disease and cytomegalovirus (CMV) gastritis associated with asphyxia. Infection was the most common postoperative complication, resulting in longer hospital stays, higher medical expenses and shorter survival rates, necessitating aggressive prophylactic management. The accumulation of experience, modifications to operative procedures and perioperative care may lead to improved early and long-term survival in patients with emphysema undergoing single or bilateral lung transplantations.

Chronic infection sustained by a Pseudomonas aeruginosa High-Risk clone producing the VIM-1 metallo-β-lactamase in a cystic fibrosis patient after lung transplantation.

PubMed

Pollini, Simona; Mugnaioli, Claudia; Dolce, Daniela; Campana, Silvia; Neri, Anna Silvia; Taccetti, Giovanni; Rossolini, Gian Maria

2018-02-12

The significance of chronic lung infection by multidrug-resistant (MDR) pathogens in Cystic Fibrosis (CF) transplanted patients remains controversial, and the available information is overall limited. Here we describe the case of a chronic infection, sustained by a metallo-β-lactamase (MBL)-producing P. aeruginosa strain, in a CF patient following lung transplantation. Twelve P. aeruginosa isolates collected from a CF patient over a 15-years follow-up period after lung transplantation were analysed for their antibiotic susceptibility profile, MBL production and clonal relatedness. Available clinical and microbiological records were reviewed. The transplanted CF patient was chronically infected by an MBL-producing P. aeruginosa strain which harboured a bla VIM-1 determinant inserted into a novel class 1 integron. The strain exhibited an MDR phenotype and belonged to the globally widespread ST235 epidemic clonal lineage, which however is not a typical CF-associated epidemic clone. Despite the chronic infection, the long-term outcome of this patient during the post-transplant period was characterized by the absence of acute exacerbations and by a mostly stable pulmonary function. This report provides one of the few descriptions of MBL-producing P. aeruginosa infections in CF patients, and the first description of such an infection after lung transplantation in these patients. Infection with the MBL-producing strain apparently did not significantly affect the patient pulmonary function. Copyright © 2018 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.

EFFECT OF THE LESION DUE TO INFLUENZA VIRUS ON THE RESISTANCE OF MICE TO INHALED PNEUMOCOCCI

PubMed Central

Harford, Carl G.; Leidler, Virginia; Hara, Mary

1949-01-01

1. The normal lung of the mouse possesses the power of reducing markedly its content of Type I pneumococci within 3 hours after inhalation of the organisms in the form of fine droplets. 2. Lungs with fully developed influenza viral pneumonia not only fail to reduce the pulmonary content of pneumococci administered in this manner but, on the contrary, support their growth. 3. After intrabronchial inoculation into mice, influenza virus multiplies rapidly in the lung within 24 hours. 4. Criteria have been established for distinction between true viral lesions of the lung and changes due to the inoculation of diluents as vehicles for the virus. 5. 24 hours after inoculation of virus, there are no macroscopic lesions in the lung and the microscopic changes are due to the diluent. 6. Presence and multiplication of the virus in the lung 24 hours after inoculation have no apparent effect on the power of the lung to reduce rapidly its content of inhaled pneumococci. 7. The effect of the virus in lowering resistance to secondary bacterial infection appears to be due to the presence of the lesion produced by the virus. PMID:18099165

Subunit vaccine H56/CAF01 induces a population of circulating CD4 T cells that traffic into the Mycobacterium tuberculosis-infected lung.

PubMed

Woodworth, J S; Cohen, S B; Moguche, A O; Plumlee, C R; Agger, E M; Urdahl, K B; Andersen, P

2017-03-01

The capacity of CD4 T cells to protect against Mycobacterium tuberculosis (Mtb) is governed by their ability to localize to the lung site of infection. Subunit vaccine H56/CAF01, a liposome-adjuvanted fusion protein of Mtb antigens Ag85B, ESAT-6, and Rv2660, conferred durable protection and elicited polyfunctional CD4 T cells that preferentially localized to the lung parenchyma. These lung-resident T cells had reduced KLRG1 and increased CXCR3 expression, an intermediate state of Th1 differentiation that has been associated with Mtb protection. Importantly, KLGR1 - CXCR3 + cells were also enriched in the lung vasculature and peripheral circulation of vaccinated animals, but not controls. Moreover, S1P1R blockade rapidly cleared this population from the blood and adoptive transfer of T cells recovered from the vasculature of vaccinated, but not control, mice efficiently trafficked into the Mtb-infected lung parenchyma. Thus, durable immunity elicited by H56/CAF01 vaccination is associated with the maintenance of circulating CD4 T cells that selectively home to the lung parenchyma.

A 3D human tissue-engineered lung model to study influenza A infection.

PubMed

Bhowmick, Rudra; Derakhshan, Mina; Liang, Yurong; Ritchey, Jerry; Liu, Lin; Gappa-Fahlenkamp, Heather

2018-05-05

Influenza A virus (IAV) claims approximately 250,000-500,000 lives annually worldwide. Currently, there are a few in vitro models available to study IAV immunopathology. Monolayer cultures of cell lines and primary lung cells (2D cell culture) is the most commonly used tool, however, this system does not have the in vivo-like structure of the lung and immune responses to IAV as it lacks the three-dimensional (3D) tissue structure. To recapitulate the lung physiology in vitro, a system that contains multiple cell types within a 3D environment that allows cell movement and interaction, would provide a critical tool. In this study, as a first step in designing a 3D-Human Tissue-Engineering Lung Model (3D-HTLM), we described the 3D culture of primary human small airway epithelial cells (HSAEpCs), and determined the immunophenotype of this system in response to IAV infections. We constructed a 3D chitosan-collagen scaffold and cultured HSAEpCs on these scaffolds at air-liquid interface (ALI). These 3D cultures were compared with 2D-cultured HSAEpCs for viability, morphology, marker protein expression, and cell differentiation. Results showed that the 3D-cultured HSAEpCs at ALI yielded maximum viable cells and morphologically resembled the in vivo lower airway epithelium. There were also significant increases in aquaporin-5 and cytokeratin-14 expression for HSAEpCs cultured in 3D compared to 2D. The 3D culture system was used to study the infection of HSAEpCs with two major IAV strains, H1N1 and H3N2.The HSAEpCs showed distinct changes in marker protein expression, both at mRNA and protein levels, and the release of proinflammatory cytokines. This study is the first step in the development of the 3D-HTLM, which will have wide applicability in studying pulmonary pathophysiology and therapeutics development.

Pneumonia due to Enterobacter cancerogenus infection.

PubMed

Demir, Tülin; Baran, Gamze; Buyukguclu, Tuncay; Sezgin, Fikriye Milletli; Kaymaz, Haci

2014-11-01

Enterobacter cancerogenus (formerly known as CDC Enteric Group 19; synonym with Enterobacter taylorae) has rarely been associated with human infections, and little is known regarding the epidemiology and clinical significance of this organism. We describe a community-acquired pneumonia case in a 44-year-old female due to E. cancerogenus. Identification and antimicrobial susceptibility of the microorganism was performed by the automatized VITEK 2 Compact system (bioMerieux, France). The clinical case suggests that E. cancerogenus is a potentially pathogenic microorganism in determined circumstances; underlying diseases such as bronchial asthma, empiric antibiotic treatment, wounds, diagnostic, or therapeutic instruments.

Detection of Mycoplasma bovis by in-situ hybridization and expression of inducible nitric oxide synthase, nitrotyrosine and manganese superoxide dismutase in the lungs of experimentally-infected calves.

PubMed

Hermeyer, K; Jacobsen, B; Spergser, J; Rosengarten, R; Hewicker-Trautwein, M

2011-01-01

Pneumonic lesions occurring in calves after respiratory infection with Mycoplasma bovis are characterized by subacute or chronic suppurative bronchopneumonia with multiple foci of necrosis and by persistence of M. bovis antigen, which is frequently associated with phagocytes at the periphery of the necrotic foci. The aims of this study were: (1) to investigate the expression of inducible nitric oxide synthase (iNOS), nitrotyrosine (NT) and manganese superoxide dismutase (Mn-SOD) in the lung lesions of calves infected experimentally with M. bovis, and (2) to analyse the distribution and localization of M. bovis DNA by in-situ hybridization and correlate these findings with the immunohistochemical detection of M. bovis antigen. Phagocytic cells infiltrating the lung tissue were characterized using the markers CD68, S100A8 and S100A9. Lung tissue from 18 infected calves and three non-infected controls were examined. All infected calves had an increased number of cells expressing iNOS, NT and Mn-SOD in the inflamed lung tissue. These molecules were most strongly expressed by macrophages demarcating necrotic areas, by altered bronchiolar epithelial cells and by macrophages within obliterated bronchioles. Co-localization of M. bovis DNA, M. bovis antigen and macrophages expressing iNOS, NT and Mn-SOD was observed. These findings suggest that the generation of reactive oxygen and nitrogen species is involved in the development of severe chronic lung damage in M. bovis infection. Copyright © 2010 Elsevier Ltd. All rights reserved.

[Epidural aspergillosis secondary to lung aspergilloma despite long-term itraconazole treatment].

PubMed

Jeanrot, C; Guigui, P; Groussard, O; Deburge, A

2001-10-01

A 58-year-old man developed spinal cord compression at the T2-T3 level due to an Aspergillus epidural abscess. This presumably immunocompetent patient had been treated for two years by oral itraconazole (200 mg/day) for a lung aspergilloma that occurred seven years after removal of a lung adenocarcinoma. Surgical debridement was performed via a wide posterior approach associated with high-dose amphotericin B. Five months later, the patient's neurological deficit had not improved and the patient died from respiratory failure. Despite a long-term treatment with itraconazole, the infection spread locally from a lung aspergilloma to the epidural space.

Antibacterial Loaded Spray Dried Chitosan Polyelectrolyte Complexes as Dry Powder Aerosol for the Treatment of Lung Infections

PubMed Central

Mishra, Brahmeshwar; Mishra, Madhusmita; Yadav, Sarita Kumari

2017-01-01

Inhalation delivery of aerosolized antibacterials is preferred over conventional methods of delivery for targeting lung infection. The present study is concerned with the development and characterization of a novel, spray dried, aerosolized, chitosan polyelectrolyte complex (PEC) based microparticles containing antibacterials for the treatment of lung infections. Chitosan polyelectrolyte complex microparticles were formulated by spray drying process. Prepared spray dried chitosan PEC microparticles were studied for surface morphology, drug encapsulation efficiency, moisture content, Carr’s index, solid state interaction by XRD, aerosolization behaviour and in-vitro drug release. In-vitro cytotoxicity studies of microparticles were carried out on H1299 alveolar cell lines. Antibacterial efficacy of microparticles was assessed on the basis of determination of pharmacokinetic parameters in bronchial alveolar lavage (BAL) of rats using PK/PD analysis. The PEC microparticles were mostly spherical and exhibited high drug encapsulation efficiency. Release profiles showed an initial burst phase followed by a secondary sustained release phase. Good aerosolization behaviour as dry powder inhaler was demonstrated by microparticles with high values of recovered dose, emitted dose, and fine particle fraction. No overt cytotoxicity of microparticles was detected against H1299 alveolar cell line. More than 8 to 9 folds higher Cmax values were obtained in BAL fluid with microparticles as compared to intravenously administered antibacterial solution. The findings of the study suggest that chitosan polyelectrolyte complex based microparticles as dry powder inhaler can be an efficient antibacterial delivery system for sustained and effective management of lung infection. PMID:28496463

Analysis of adventitious lung sounds originating from pulmonary tuberculosis.

PubMed

Becker, K W; Scheffer, C; Blanckenberg, M M; Diacon, A H

2013-01-01

Tuberculosis is a common and potentially deadly infectious disease, usually affecting the respiratory system and causing the sound properties of symptomatic infected lungs to differ from non-infected lungs. Auscultation is often ruled out as a reliable diagnostic technique for TB due to the random distribution of the infection and the varying severity of damage to the lungs. However, advancements in signal processing techniques for respiratory sounds can improve the potential of auscultation far beyond the capabilities of the conventional mechanical stethoscope. Though computer-based signal analysis of respiratory sounds has produced a significant body of research, there have not been any recent investigations into the computer-aided analysis of lung sounds associated with pulmonary Tuberculosis (TB), despite the severity of the disease in many countries. In this paper, respiratory sounds were recorded from 14 locations around the posterior and anterior chest walls of healthy volunteers and patients infected with pulmonary TB. The most significant signal features in both the time and frequency domains associated with the presence of TB, were identified by using the statistical overlap factor (SOF). These features were then employed to train a neural network to automatically classify the auscultation recordings into their respective healthy or TB-origin categories. The neural network yielded a diagnostic accuracy of 73%, but it is believed that automated filtering of the noise in the clinics, more training samples and perhaps other signal processing methods can improve the results of future studies. This work demonstrates the potential of computer-aided auscultation as an aid for the diagnosis and treatment of TB.

Mycobacterium tuberculosis Cell Wall Fragments Released upon Bacterial Contact with the Human Lung Mucosa Alter the Neutrophil Response to Infection

PubMed Central

Scordo, Julia M.; Arcos, Jesús; Kelley, Holden V.; Diangelo, Lauren; Sasindran, Smitha J.; Youngmin, Ellie; Wewers, Mark D.; Wang, Shu-Hua; Balada-Llasat, Joan-Miquel; Torrelles, Jordi B.

2017-01-01

In 2016, the World Health Organization reported that one person dies of tuberculosis (TB) every 21 s. A host environment that Mycobacterium tuberculosis (M.tb) finds during its route of infection is the lung mucosa bathing the alveolar space located in the deepest regions of the lungs. We published that human lung mucosa, or alveolar lining fluid (ALF), contains an array of hydrolytic enzymes that can significantly alter the M.tb surface during infection by cleaving off parts of its cell wall. This interaction results in two different outcomes: modifications on the M.tb cell wall surface and release of M.tb cell wall fragments into the environment. Typically, one of the first host immune cells at the site of M.tb infection is the neutrophil. Neutrophils can mount an extracellular and intracellular innate immune response to M.tb during infection. We hypothesized that exposure of neutrophils to ALF-induced M.tb released cell wall fragments would prime neutrophils to control M.tb infection better. Our results show that ALF fragments activate neutrophils leading to an increased production of inflammatory cytokines and oxidative radicals. However, neutrophil exposure to these fragments reduces production of chemoattractants (i.e., interleukin-8), and degranulation, with the subsequent reduction of myeloperoxidase release, and does not induce cytotoxicity. Unexpectedly, these ALF fragment-derived modulations in neutrophil activity do not further, either positively or negatively, contribute to the intracellular control of M.tb growth during infection. However, secreted products from neutrophils primed with ALF fragments are capable of regulating the activity of resting macrophages. These results indicate that ALF-induced M.tb fragments could further contribute to the control of M.tb growth and local killing by resident neutrophils by switching on the total oxidative response and limiting migration of neutrophils to the infection site. PMID:28373877

Mycobacterium tuberculosis Cell Wall Fragments Released upon Bacterial Contact with the Human Lung Mucosa Alter the Neutrophil Response to Infection.

PubMed

Scordo, Julia M; Arcos, Jesús; Kelley, Holden V; Diangelo, Lauren; Sasindran, Smitha J; Youngmin, Ellie; Wewers, Mark D; Wang, Shu-Hua; Balada-Llasat, Joan-Miquel; Torrelles, Jordi B

2017-01-01

In 2016, the World Health Organization reported that one person dies of tuberculosis (TB) every 21 s. A host environment that Mycobacterium tuberculosis ( M.tb ) finds during its route of infection is the lung mucosa bathing the alveolar space located in the deepest regions of the lungs. We published that human lung mucosa, or alveolar lining fluid (ALF), contains an array of hydrolytic enzymes that can significantly alter the M.tb surface during infection by cleaving off parts of its cell wall. This interaction results in two different outcomes: modifications on the M.tb cell wall surface and release of M.tb cell wall fragments into the environment. Typically, one of the first host immune cells at the site of M.tb infection is the neutrophil. Neutrophils can mount an extracellular and intracellular innate immune response to M.tb during infection. We hypothesized that exposure of neutrophils to ALF-induced M.tb released cell wall fragments would prime neutrophils to control M.tb infection better. Our results show that ALF fragments activate neutrophils leading to an increased production of inflammatory cytokines and oxidative radicals. However, neutrophil exposure to these fragments reduces production of chemoattractants (i.e., interleukin-8), and degranulation, with the subsequent reduction of myeloperoxidase release, and does not induce cytotoxicity. Unexpectedly, these ALF fragment-derived modulations in neutrophil activity do not further, either positively or negatively, contribute to the intracellular control of M.tb growth during infection. However, secreted products from neutrophils primed with ALF fragments are capable of regulating the activity of resting macrophages. These results indicate that ALF-induced M.tb fragments could further contribute to the control of M.tb growth and local killing by resident neutrophils by switching on the total oxidative response and limiting migration of neutrophils to the infection site.

Fatty Acid Metabolism is Associated With Disease Severity After H7N9 Infection.

PubMed

Sun, Xin; Song, Lijia; Feng, Shuang; Li, Li; Yu, Hongzhi; Wang, Qiaoxing; Wang, Xing; Hou, Zhili; Li, Xue; Li, Yu; Zhang, Qiuyang; Li, Kuan; Cui, Chao; Wu, Junping; Qin, Zhonghua; Wu, Qi; Chen, Huaiyong

2018-06-22

Human infections with the H7N9 virus could lead to lung damage and even multiple organ failure, which is closely associated with a high mortality rate. However, the metabolic basis of such systemic alterations remains unknown. This study included hospitalized patients (n = 4) with laboratory-confirmed H7N9 infection, healthy controls (n = 9), and two disease control groups comprising patients with pneumonia (n = 9) and patients with pneumonia who received steroid treatment (n = 10). One H7N9-infected patient underwent lung biopsy for histopathological analysis and expression analysis of genes associated with lung homeostasis. H7N9-induced systemic alterations were investigated using metabolomic analysis of sera collected from the four patients by using ultra-performance liquid chromatography-mass spectrometry. Chest digital radiography and laboratory tests were also conducted. Two of the four patients did not survive the clinical treatments with antiviral medication, steroids, and oxygen therapy. Biopsy revealed disrupted expression of genes associated with lung epithelial integrity. Histopathological analysis demonstrated severe lung inflammation after H7N9 infection. Metabolomic analysis indicated that fatty acid metabolism may be inhibited during H7N9 infection. Serum levels of palmitic acid, erucic acid, and phytal may negatively correlate with the extent of lung inflammation after H7N9 infection. The changes in fatty acid levels may not be due to steroid treatment or pneumonia. Altered structural and secretory properties of the lung epithelium may be associated with the severity of H7N9-infection-induced lung disease. Moreover, fatty acid metabolism level may predict a fatal outcome after H7N9 virus infection. Copyright © 2018. Published by Elsevier B.V.

Diagnostic value of sTREM-1 in bronchoalveolar lavage fluid in ICU patients with bacterial lung infections: a bivariate meta-analysis.

PubMed

Shi, Jia-Xin; Li, Jia-Shu; Hu, Rong; Li, Chun-Hua; Wen, Yan; Zheng, Hong; Zhang, Feng; Li, Qin

2013-01-01

The serum soluble triggering receptor expressed on myeloid cells-1 (sTREM-1) is a useful biomarker in differentiating bacterial infections from others. However, the diagnostic value of sTREM-1 in bronchoalveolar lavage fluid (BALF) in lung infections has not been well established. We performed a meta-analysis to assess the accuracy of sTREM-1 in BALF for diagnosis of bacterial lung infections in intensive care unit (ICU) patients. We searched PUBMED, EMBASE and Web of Knowledge (from January 1966 to October 2012) databases for relevant studies that reported diagnostic accuracy data of BALF sTREM-1 in the diagnosis of bacterial lung infections in ICU patients. Pooled sensitivity, specificity, and positive and negative likelihood ratios were calculated by a bivariate regression analysis. Measures of accuracy and Q point value (Q*) were calculated using summary receiver operating characteristic (SROC) curve. The potential between-studies heterogeneity was explored by subgroup analysis. Nine studies were included in the present meta-analysis. Overall, the prevalence was 50.6%; the sensitivity was 0.87 (95% confidence interval (CI), 0.72-0.95); the specificity was 0.79 (95% CI, 0.56-0.92); the positive likelihood ratio (PLR) was 4.18 (95% CI, 1.78-9.86); the negative likelihood ratio (NLR) was 0.16 (95% CI, 0.07-0.36), and the diagnostic odds ratio (DOR) was 25.60 (95% CI, 7.28-89.93). The area under the SROC curve was 0.91 (95% CI, 0.88-0.93), with a Q* of 0.83. Subgroup analysis showed that the assay method and cutoff value influenced the diagnostic accuracy of sTREM-1. BALF sTREM-1 is a useful biomarker of bacterial lung infections in ICU patients. Further studies are needed to confirm the optimized cutoff value.

Metabolic pathways of lung inflammation revealed by high-resolution metabolomics (HRM) of H1N1 influenza virus infection in mice

PubMed Central

Chandler, Joshua D.; Hu, Xin; Ko, Eun-Ju; Park, Soojin; Lee, Young-Tae; Orr, Michael; Fernandes, Jolyn; Uppal, Karan; Kang, Sang-Moo; Jones, Dean P.

2016-01-01

Influenza is a significant health concern worldwide. Viral infection induces local and systemic activation of the immune system causing attendant changes in metabolism. High-resolution metabolomics (HRM) uses advanced mass spectrometry and computational methods to measure thousands of metabolites inclusive of most metabolic pathways. We used HRM to identify metabolic pathways and clusters of association related to inflammatory cytokines in lungs of mice with H1N1 influenza virus infection. Infected mice showed progressive weight loss, decreased lung function, and severe lung inflammation with elevated cytokines [interleukin (IL)-1β, IL-6, IL-10, tumor necrosis factor (TNF)-α, and interferon (IFN)-γ] and increased oxidative stress via cysteine oxidation. HRM showed prominent effects of influenza virus infection on tryptophan and other amino acids, and widespread effects on pathways including purines, pyrimidines, fatty acids, and glycerophospholipids. A metabolome-wide association study (MWAS) of the aforementioned inflammatory cytokines was used to determine the relationship of metabolic responses to inflammation during infection. This cytokine-MWAS (cMWAS) showed that metabolic associations consisted of distinct and shared clusters of 396 metabolites highly correlated with inflammatory cytokines. Strong negative associations of selected glycosphingolipid, linoleate, and tryptophan metabolites with IFN-γ contrasted strong positive associations of glycosphingolipid and bile acid metabolites with IL-1β, TNF-α, and IL-10. Anti-inflammatory cytokine IL-10 had strong positive associations with vitamin D, purine, and vitamin E metabolism. The detailed metabolic interactions with cytokines indicate that targeted metabolic interventions may be useful during life-threatening crises related to severe acute infection and inflammation. PMID:27558316

Continuum-kinetic-microscopic model of lung clearance due to core-annular fluid entrainment

PubMed Central

Mitran, Sorin

2013-01-01

The human lung is protected against aspirated infectious and toxic agents by a thin liquid layer lining the interior of the airways. This airway surface liquid is a bilayer composed of a viscoelastic mucus layer supported by a fluid film known as the periciliary liquid. The viscoelastic behavior of the mucus layer is principally due to long-chain polymers known as mucins. The airway surface liquid is cleared from the lung by ciliary transport, surface tension gradients, and airflow shear forces. This work presents a multiscale model of the effect of airflow shear forces, as exerted by tidal breathing and cough, upon clearance. The composition of the mucus layer is complex and variable in time. To avoid the restrictions imposed by adopting a viscoelastic flow model of limited validity, a multiscale computational model is introduced in which the continuum-level properties of the airway surface liquid are determined by microscopic simulation of long-chain polymers. A bridge between microscopic and continuum levels is constructed through a kinetic-level probability density function describing polymer chain configurations. The overall multiscale framework is especially suited to biological problems due to the flexibility afforded in specifying microscopic constituents, and examining the effects of various constituents upon overall mucus transport at the continuum scale. PMID:23729842

Continuum-kinetic-microscopic model of lung clearance due to core-annular fluid entrainment

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

Mitran, Sorin, E-mail: mitran@unc.edu

2013-07-01

The human lung is protected against aspirated infectious and toxic agents by a thin liquid layer lining the interior of the airways. This airway surface liquid is a bilayer composed of a viscoelastic mucus layer supported by a fluid film known as the periciliary liquid. The viscoelastic behavior of the mucus layer is principally due to long-chain polymers known as mucins. The airway surface liquid is cleared from the lung by ciliary transport, surface tension gradients, and airflow shear forces. This work presents a multiscale model of the effect of airflow shear forces, as exerted by tidal breathing and cough,more » upon clearance. The composition of the mucus layer is complex and variable in time. To avoid the restrictions imposed by adopting a viscoelastic flow model of limited validity, a multiscale computational model is introduced in which the continuum-level properties of the airway surface liquid are determined by microscopic simulation of long-chain polymers. A bridge between microscopic and continuum levels is constructed through a kinetic-level probability density function describing polymer chain configurations. The overall multiscale framework is especially suited to biological problems due to the flexibility afforded in specifying microscopic constituents, and examining the effects of various constituents upon overall mucus transport at the continuum scale.« less

Continuum-kinetic-microscopic model of lung clearance due to core-annular fluid entrainment

NASA Astrophysics Data System (ADS)

Mitran, Sorin

2013-07-01

The human lung is protected against aspirated infectious and toxic agents by a thin liquid layer lining the interior of the airways. This airway surface liquid is a bilayer composed of a viscoelastic mucus layer supported by a fluid film known as the periciliary liquid. The viscoelastic behavior of the mucus layer is principally due to long-chain polymers known as mucins. The airway surface liquid is cleared from the lung by ciliary transport, surface tension gradients, and airflow shear forces. This work presents a multiscale model of the effect of airflow shear forces, as exerted by tidal breathing and cough, upon clearance. The composition of the mucus layer is complex and variable in time. To avoid the restrictions imposed by adopting a viscoelastic flow model of limited validity, a multiscale computational model is introduced in which the continuum-level properties of the airway surface liquid are determined by microscopic simulation of long-chain polymers. A bridge between microscopic and continuum levels is constructed through a kinetic-level probability density function describing polymer chain configurations. The overall multiscale framework is especially suited to biological problems due to the flexibility afforded in specifying microscopic constituents, and examining the effects of various constituents upon overall mucus transport at the continuum scale.

[Lung transplantation.].

PubMed

Guðmundsson, G

2000-09-01

Lung transplantation is an option in the treatment of end stage lung diseases, excluding lung cancer, that lead to short life expectancy and poor quality of life. Now they are mostly limited by shortage of donor organs and longterm complications. They are used for various lung diseases such as pulmonary vascular diseases, fibrosing diseases, chronic obstructive pulmonary diseases and diseases that cause chronic infections. Depending on the indication it is possible to perform heart and lung transplantation, single lung or double lung transplantation.Indications, contraindications, surgical methods, immunosuppression, complications and outcomes will be discussed. Survival is not as good as for other solid organ transplantation. Measurement of pulmonary function and quality of life improve with lung transplantation. Bronchiolitis obliterans is the most common complication and is the most limiting factor. A few Icelanders have undergone lung transplantation, most of them in Gothenburg, Sweden. The future of lung transplantation depends on limiting the incidence of bronchiolitis obliterans and finding more organ donors.

Low-Dose Intestinal Trichuris muris Infection Alters the Lung Immune Microenvironment and Can Suppress Allergic Airway Inflammation.

PubMed

Chenery, Alistair L; Antignano, Frann; Burrows, Kyle; Scheer, Sebastian; Perona-Wright, Georgia; Zaph, Colby

2016-02-01

Immunological cross talk between mucosal tissues such as the intestine and the lung is poorly defined during homeostasis and disease. Here, we show that a low-dose infection with the intestinally restricted helminth parasite Trichuris muris results in the production of Th1 cell-dependent gamma interferon (IFN-γ) and myeloid cell-derived interleukin-10 (IL-10) in the lung without causing overt airway pathology. This cross-mucosal immune response in the lung inhibits the development of papain-induced allergic airway inflammation, an innate cell-mediated type 2 airway inflammatory disease. Thus, we identify convergent and nonredundant roles of adaptive and innate immunity in mediating cross-mucosal suppression of type 2 airway inflammation during low-dose helminth-induced intestinal inflammation. These results provide further insight in identifying novel intersecting immune pathways elicited by gut-to-lung mucosal cross talk. Copyright © 2016 Chenery et al.

Andes Hantavirus-Infection of a 3D Human Lung Tissue Model Reveals a Late Peak in Progeny Virus Production Followed by Increased Levels of Proinflammatory Cytokines and VEGF-A

PubMed Central

Sundström, Karin B.; Nguyen Hoang, Anh Thu; Gupta, Shawon; Ahlm, Clas; Svensson, Mattias; Klingström, Jonas

2016-01-01

Andes virus (ANDV) causes hantavirus pulmonary syndrome (HPS), a severe acute disease with a 40% case fatality rate. Humans are infected via inhalation, and the lungs are severely affected during HPS, but little is known regarding the effects of ANDV-infection of the lung. Using a 3-dimensional air-exposed organotypic human lung tissue model, we analyzed progeny virus production and cytokine-responses after ANDV-infection. After a 7–10 day period of low progeny virus production, a sudden peak in progeny virus levels was observed during approximately one week. This peak in ANDV-production coincided in time with activation of innate immune responses, as shown by induction of type I and III interferons and ISG56. After the peak in ANDV production a low, but stable, level of ANDV progeny was observed until 39 days after infection. Compared to uninfected models, ANDV caused long-term elevated levels of eotaxin-1, IL-6, IL-8, IP-10, and VEGF-A that peaked 20–25 days after infection, i.e., after the observed peak in progeny virus production. Notably, eotaxin-1 was only detected in supernatants from infected models. In conclusion, these findings suggest that ANDV replication in lung tissue elicits a late proinflammatory immune response with possible long-term effects on the local lung cytokine milieu. The change from an innate to a proinflammatory response might be important for the transition from initial asymptomatic infection to severe clinical disease, HPS. PMID:26907493

Andes Hantavirus-Infection of a 3D Human Lung Tissue Model Reveals a Late Peak in Progeny Virus Production Followed by Increased Levels of Proinflammatory Cytokines and VEGF-A.

PubMed

Sundström, Karin B; Nguyen Hoang, Anh Thu; Gupta, Shawon; Ahlm, Clas; Svensson, Mattias; Klingström, Jonas

2016-01-01

Andes virus (ANDV) causes hantavirus pulmonary syndrome (HPS), a severe acute disease with a 40% case fatality rate. Humans are infected via inhalation, and the lungs are severely affected during HPS, but little is known regarding the effects of ANDV-infection of the lung. Using a 3-dimensional air-exposed organotypic human lung tissue model, we analyzed progeny virus production and cytokine-responses after ANDV-infection. After a 7-10 day period of low progeny virus production, a sudden peak in progeny virus levels was observed during approximately one week. This peak in ANDV-production coincided in time with activation of innate immune responses, as shown by induction of type I and III interferons and ISG56. After the peak in ANDV production a low, but stable, level of ANDV progeny was observed until 39 days after infection. Compared to uninfected models, ANDV caused long-term elevated levels of eotaxin-1, IL-6, IL-8, IP-10, and VEGF-A that peaked 20-25 days after infection, i.e., after the observed peak in progeny virus production. Notably, eotaxin-1 was only detected in supernatants from infected models. In conclusion, these findings suggest that ANDV replication in lung tissue elicits a late proinflammatory immune response with possible long-term effects on the local lung cytokine milieu. The change from an innate to a proinflammatory response might be important for the transition from initial asymptomatic infection to severe clinical disease, HPS.

Study of epidemiological risk of lung cancer in Mexico due indoor radon exposure

NASA Astrophysics Data System (ADS)

Ángeles, A.; Espinosa, G.

2014-07-01

In this work the lifetime relative risks (LRR) of lung cancer due to exposure to indoor 222Rn on the Mexican population is calculated. Cigarette smoking is the number one risk factor for lung cancer (LC), because that, to calculate the number of cases of LC due to exposure to 222Rn is necessary considers the number of cases of LC for smoking cigarette. The lung cancer mortality rates published by the "Secretaría de Salud" (SSA), the mexican population data published by the "Consejo Nacional de Población" (CONAPO), smoking data in the mexican population, published by the "Comisión Nacional Contra las Adicciones" (CONADIC), the "Organización Panamericana de la Salud" (OPS) and indoor 222Rn concentrations in Mexico published in several recent studies are used. To calculate the lifetime relative risks (LRR) for different segments of the Mexican population, firstly the Excess Relative Risk (ERR) is calculated using the method developed by the BEIR VI committee and subsequently modified by the USEPA and published in the report "EPA Assessment of Risks from Radon in Homes". The excess relative risks were then used to calculate the corresponding lifetime relative risks, again using the method developed by the BEIR VI committee. The lifetime relative risks for Mexican male and female eversmokers and Mexican male and female never-smokers were calculated for radon concentrations spanning the range found in recent studies of indoor radon concentrations in Mexico. The lifetime relative risks of lung cancer induced by lifetime exposure to the mexican average indoor radon concentration were estimated to be 1.44 and 1.40 for never-smokers mexican females and males respectively, and 1.19 and 1.17 for ever-smokers Mexican females and males respectively. The Mexican population LRR values obtained in relation to the USA and Canada LRR published values in ever-smokers for both gender are similar with differences less than 4%, in case of never-smokers in relation with Canada

Interference with Intraepithelial TNF-α Signaling Inhibits CD8+ T-Cell-Mediated Lung Injury in Influenza Infection

PubMed Central

Srikiatkhachorn, Anon; Chintapalli, Jyothi; Liu, Jun; Jamaluddin, Mohammad; Harrod, Kevin S.; Whitsett, Jeffrey A.; Enelow, Richard I.

2010-01-01

Abstract CD8+ T-cell-mediated pulmonary immunopathology in respiratory virus infection is mediated in large part by antigen-specific TNF-α expression by antiviral effector T cells, which results in epithelial chemokine expression and inflammatory infiltration of the lung. To further define the signaling events leading to lung epithelial chemokine production in response to CD8+ T-cell antigen recognition, we expressed the adenoviral 14.7K protein, a putative inhibitor of TNF-α signaling, in the distal lung epithelium, and analyzed the functional consequences. Distal airway epithelial expression of 14.7K resulted in a significant reduction in lung injury resulting from severe influenza pneumonia. In vitro analysis demonstrated a significant reduction in the expression of an important mediator of injury, CCL2, in response to CD8+ T-cell recognition, or to TNF-α. The inhibitory effect of 14.7K on CCL2 expression resulted from attenuation of NF-κB activity, which was independent of Iκ-Bα degradation or nuclear translocation of the p65 subunit. Furthermore, epithelial 14.7K expression inhibited serine phosphorylation of Akt, GSK-3β, and the p65 subunit of NF-κB, as well as recruitment of NF-κB for DNA binding in vivo. These results provide insight into the mechanism of 14.7K inhibition of NF-κB activity, as well as further elucidate the mechanisms involved in the induction of T-cell-mediated immunopathology in respiratory virus infection. PMID:21142450

Oral ribavirin for respiratory syncytial virus infection after lung transplantation: Efficacy and cost-efficiency.

PubMed

Burrows, Fay S; Carlos, Lilibeth M; Benzimra, Mark; Marriott, Deborah J E; Havryk, Adrian P; Plit, Marshall L; Malouf, Monique A; Glanville, Allan R

2015-07-01

Respiratory syncytial virus (RSV) causes serious respiratory tract infections in lung transplant (LTx) recipients, is associated with development of bronchiolitis obliterans syndrome, and has no proven effective therapy. We evaluated the efficacy, safety, and cost-effectiveness of oral ribavirin for the treatment of RSV infection after LTx. Between December 2011 and May 2014, 52 LTx recipients developed 56 episodes of symptomatic RSV infection, which was diagnosed by positive RSV polymerase chain reaction on nasopharyngeal swabs. An intravenous (IV) loading dose of ribavirin (33 mg/kg) was given in 52 of 56 episodes; an equivalent oral loading dose was given in 2 episodes. Oral ribavirin (20 mg/kg/day) was given by day 2 in 53 of 56 episodes. Median duration of therapy was 8 days (range 6-31 days). Mean forced expiratory volume in 1 sec decreased from 2.38 ± 0.78 liters to 2.07 ± 0.85 liters (p < 0.001) at presentation, recovered to 2.26 ± 0.82 liters at cessation of ribavirin, and was maintained at 2.31 ± 0.81 liters within 3 months. New-onset bronchiolitis obliterans syndrome developed in 1 of 38 patients (2.6%) at 3 months. Anemia worsened in 23 episodes, and de novo anemia developed in 5 episodes. Mean hemoglobin decreased from 118 ± 16 g/liter to 113 ± 21 g/liter (p = 0.015). There were 4 late deaths. Compared with IV therapy, mean drug cost saving was US $6,035 per episode, and mean inpatient bed days was reduced by 6.7 days (p < 0.001). To our knowledge, we report the largest series of LTx recipients treated with oral ribavirin for RSV. Oral ribavirin appears to be an effective, well-tolerated alternative to IV or inhaled ribavirin; provides considerable cost savings and reduces length of hospital stay. Potential long-term benefits in preventing development of chronic lung allograft dysfunction are yet to be determined. Copyright © 2015 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.

Ureaplasma Transmitted From Donor Lungs Is Pathogenic After Lung Transplantation.

PubMed

Fernandez, Ramiro; Ratliff, Amy; Crabb, Donna; Waites, Ken B; Bharat, Ankit

2017-02-01

Hyperammonemia is a highly fatal syndrome in lung recipients that is usually refractory to medical therapy. We recently reported that infection by a Mollicute, Ureaplasma, is causative for hyperammonemia and can be successfully treated with antimicrobial agents. However, it remains unknown whether the pathogenic strain of Ureaplasma is donor or recipient derived. Here we provide evidence that donor-derived Ureaplasma infection can be pathogenic. As such, we uncover a previously unknown lethal donor-derived opportunistic infection in lung recipients. Given the high mortality associated with hyperammonemia, strategies for routine donor screening or prophylaxis should be further evaluated in prospective studies. Copyright © 2017 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.

Caspase-1 Dependent IL-1β Secretion Is Critical for Host Defense in a Mouse Model of Chlamydia pneumoniae Lung Infection

PubMed Central

Shimada, Kenichi; Crother, Timothy R.; Karlin, Justin; Chen, Shuang; Chiba, Norika; Ramanujan, V. Krishnan; Vergnes, Laurent; Ojcius, David M.; Arditi, Moshe

2011-01-01

Chlamydia pneumoniae (CP) is an important human pathogen that causes atypical pneumonia and is associated with various chronic inflammatory disorders. Caspase-1 is a key component of the ‘inflammasome’, and is required to cleave pro-IL-1β to bioactive IL-1β. Here we demonstrate for the first time a critical requirement for IL-1β in response to CP infection. Caspase-1−/− mice exhibit delayed cytokine production, defective clearance of pulmonary bacteria and higher mortality in response to CP infection. Alveolar macrophages harbored increased bacterial numbers due to reduced iNOS levels in Caspase-1−/− mice. Pharmacological blockade of the IL-1 receptor in CP infected wild-type mice phenocopies Caspase-1-deficient mice, and administration of recombinant IL-1β rescues CP infected Caspase-1−/− mice from mortality, indicating that IL-1β secretion is crucial for host immune defense against CP lung infection. In vitro investigation reveals that CP-induced IL-1β secretion by macrophages requires TLR2/MyD88 and NLRP3/ASC/Caspase-1 signaling. Entry into the cell by CP and new protein synthesis by CP are required for inflammasome activation. Neither ROS nor cathepsin was required for CP infection induced inflammasome activation. Interestingly, Caspase-1 activation during CP infection occurs with mitochondrial dysfunction indicating a possible mechanism involving the mitochondria for CP-induced inflammasome activation. PMID:21731762

Microbiology and management of joint and bone infections due to anaerobic bacteria.

PubMed

Brook, Itzhak

2008-03-01

To describes the microbiology, diagnosis, and management of septic arthritis and osteomyelitis due to anaerobic bacteria. The predominant anaerobes in arthritis are anaerobic Gram-negative bacilli (AGNB) including the Bacteroides fragilis group, Fusobacterium spp., Peptostreptococcus spp., and Propionibacterium acnes. Infection with P. acnes is associated with a prosthetic joint, previous surgery, and trauma. B. fragilis group is associated with distant infection, Clostridium spp. with trauma, and Fusobacterium spp. with oropharyngeal infection. Most cases of anaerobic arthritis, in contrast to anaerobic osteomyelitis, involved a single isolate, and most cases are secondary to hematogenous spread. The predominant anaerobes in osteomyelitis are Bacteroides, Peptostreptococcus, Fusobacterium, and Clostridium spp. as well as P. acnes. Conditions predisposing to bone infections are vascular disease, bites, contiguous infection, peripheral neuropathy, hematogenous spread, and trauma. Pigmented Prevotella and Porphyromonas spp. are mostly isolated in skull and bite infections, members of the B. fragilis group in hand and feet infections, and Fusobacterium spp. in skull, bite, and hematogenous long bone infections. Many patients with osteomyelitis due to anaerobic bacteria have evidence of an anaerobic infection elsewhere in the body that is the source of the organisms involved in the osteomyelitis. Treatment of arthritis and osteomyelitis involving anaerobic bacteria includes symptomatic therapy, immobilization in some cases, adequate drainage of purulent material, and antibiotic therapy effective against these organisms. Anaerobic bacteria can cause septic arthritis and osteomyelitis. Correct diagnosis and appropriate therapy are important contributor to successful outcome.

Lung transplantation in adults and children: putting lung function into perspective.

PubMed

Thompson, Bruce Robert; Westall, Glen Philip; Paraskeva, Miranda; Snell, Gregory Ian

2014-11-01

The number of lung transplants performed globally continues to increase year after year. Despite this growing experience, long-term outcomes following lung transplantation continue to fall far short of that described in other solid-organ transplant settings. Chronic lung allograft dysfunction (CLAD) remains common and is the end result of exposure to a multitude of potentially injurious insults that include alloreactivity and infection among others. Central to any description of the clinical performance of the transplanted lung is an assessment of its physiology by pulmonary function testing. Spirometry and the evaluation of forced expiratory volume in 1 s and forced vital capacity, remain core indices that are measured as part of routine clinical follow-up. Spirometry, while reproducible in detecting lung allograft dysfunction, lacks specificity in differentiating the different complications of lung transplantation such as rejection, infection and bronchiolitis obliterans. However, interpretation of spirometry is central to defining the different 'chronic rejection' phenotypes. It is becoming apparent that the maximal lung function achieved following transplantation, as measured by spirometry, is influenced by a number of donor and recipient factors as well as the type of surgery performed (single vs double vs lobar lung transplant). In this review, we discuss the wide range of variables that need to be considered when interpreting lung function testing in lung transplant recipients. Finally, we review a number of novel measurements of pulmonary function that may in the future serve as better biomarkers to detect and diagnose the cause of the failing lung allograft. © 2014 Asian Pacific Society of Respirology.

Degradable polyphosphoester-based silver-loaded nanoparticles as therapeutics for bacterial lung infections

NASA Astrophysics Data System (ADS)

Zhang, Fuwu; Smolen, Justin A.; Zhang, Shiyi; Li, Richen; Shah, Parth N.; Cho, Sangho; Wang, Hai; Raymond, Jeffery E.; Cannon, Carolyn L.; Wooley, Karen L.

2015-01-01

In this study, a new type of degradable polyphosphoester-based polymeric nanoparticle, capable of carrying silver cations via interactions with alkyne groups, has been developed as a potentially effective and safe treatment for lung infections. It was found that up to 15% (w/w) silver loading into the nanoparticles could be achieved, consuming most of the pendant alkyne groups along the backbone, as revealed by Raman spectroscopy. The well-defined Ag-loaded nanoparticles released silver in a controlled and sustained manner over 5 days, and displayed enhanced in vitro antibacterial activities against cystic fibrosis-associated pathogens and decreased cytotoxicity to human bronchial epithelial cells, in comparison to silver acetate.In this study, a new type of degradable polyphosphoester-based polymeric nanoparticle, capable of carrying silver cations via interactions with alkyne groups, has been developed as a potentially effective and safe treatment for lung infections. It was found that up to 15% (w/w) silver loading into the nanoparticles could be achieved, consuming most of the pendant alkyne groups along the backbone, as revealed by Raman spectroscopy. The well-defined Ag-loaded nanoparticles released silver in a controlled and sustained manner over 5 days, and displayed enhanced in vitro antibacterial activities against cystic fibrosis-associated pathogens and decreased cytotoxicity to human bronchial epithelial cells, in comparison to silver acetate. Electronic supplementary information (ESI) available: Materials, experimental details, and characterization. See DOI: 10.1039/c4nr07103d

Exaggerated Acute Lung Injury and Impaired Antibacterial Defenses During Staphylococcus aureus Infection in Rats with the Metabolic Syndrome

PubMed Central

Feng, Xiaomei; Maze, Mervyn; Koch, Lauren G.; Britton, Steven L.; Hellman, Judith

2015-01-01

Rats with Metabolic Syndrome (MetaS) have a dysregulated immune response to the aseptic trauma of surgery. We hypothesized that rats with MetaS would have dysregulated inflammation, increased lung injury, and less effective antibacterial defenses during Staphylococcus (S.) aureus sepsis as compared to rats without MetaS. Low capacity runner (LCR; a model of MetaS) and high capacity runner (HCR) rats were challenged intravenously with S. aureus bacteria. After 48 h, inflammatory mediators and bacteria were quantified in the blood, bronchoalveolar lavage fluid (BALF), and lung homogenates. Lungs were analyzed histologically. BALF protein and lung wet-dry ratios were quantified to assess for vascular leak. Endpoints were compared in infected LCR vs HCR rats. LCR rats had higher blood and lung S. aureus counts, as well as higher levels of IL-6 in plasma, lungs and BALF, MIP-2 in plasma and lung, and IL-17A in lungs. Conversely, LCR rats had lower levels of IL-10 in plasma and lungs. Although lactate levels, and liver and renal function tests were similar between groups, LCR rats had higher BALF protein and lung wet-dry ratios, and more pronounced acute lung injury histologically. During S. aureus bacteremia, as compared with HCR rats, LCR (MetaS) rats have heightened pro-inflammatory responses, accompanied by increased acute lung injury and vascular leak. Notably, despite an augmented pro-inflammatory phenotype, LCR rats have higher bacterial levels in their blood and lungs. The MetaS state may exacerbate lung injury and vascular leak by attenuating the inflammation-resolving response, and by weakening antimicrobial defenses. PMID:25978669

Prevention of infection in war chest injuries.

PubMed Central

Romanoff, H

1975-01-01

Infection is a major complication of military chest injuries. In a series of 142 wounded, infectious complications occurred in 7 (4.9%). Factors influencing the incidence of infection are evaluated. In this group of injuries, 81 patients were admitted soon after wounding. The intrathoracic damage was severe, due to penetration of metallic fragment. The hemothorax was treated by immediate intercostal drainage. Immediate thoracotomy was performed in 10 patients and late thoractomy in 15. One patient developed a lung abscess and 5 patients had infection following thoracotomy (7.4%). Another 61 wounded patients had been first managed in a forward hospital, including three with thoractomy for massive bleeding. Two, not in a forward hospital, had a bullet removed from the lung. Upon admission to this hospital, intercostal drains were inserted when needed and four patients underwent thoracotomy. Larger wounds were debrided in 24 patients. Late thoracotomy was perfromed in seven. Chronic empyema developed in one patient after pneumonectomy performed at the field hospital, resulting in a resuscitation or infection rate of less than 2%. Factors contributing to a low infection rate were: early drainage of hemothoraces and wide debridement of larger wounds with delayed closure and avoidance of thoracotomy as primary treatment. Resection of lung tissue was avoided. Thoraco-abdominal injuries were treated separately. The clotted hemothorax was immediately evacuated. Prolonged antibiotic therapy was usually indicated. PMID:1211991

Pharmacokinetics and Pharmacodynamics of Tildipirosin Against Pasteurella multocida in a Murine Lung Infection Model

PubMed Central

Zeng, Dongping; Sun, Meizhen; Lin, Zhoumeng; Li, Miao; Gehring, Ronette; Zeng, Zhenling

2018-01-01

Tildipirosin, a 16-membered-ring macrolide antimicrobial, has recently been approved for the treatment of swine respiratory disease and bovine respiratory disease. This macrolide is extensively distributed to the site of respiratory infection followed by slow elimination. Clinical efficacy has been demonstrated in cattle and swine clinical field trials. However, the pharmacokinetic/pharmacodynamic (PK/PD) index that best correlates with the efficacy of tildipirosin remains undefined. The objective of this study was to develop a PK/PD model following subcutaneous injection of tildipirosin against Pasteurella multocida in a murine lung infection model. The PK studies of unbound (f) tildipirosin in plasma were determined following subcutaneous injection of single doses of 1, 2, 4, 6, and 8 mg/kg of body weight in neutropenic lung-infected mice. The PD studies were conducted over 24 h based on twenty intermittent dosing regimens, of which total daily dose ranged from 1 to 32 mg/kg and dosage intervals included 6, 8, 12, and 24 h. The minimum inhibitory concentration (MIC) of tildipirosin against P. multocida was determined in serum. The inhibitory effect Imax model was employed for PK/PD modeling. The area under the unbound concentration-time profile over 24 h to MIC (fAUC0-24 h/MIC) was the PK/PD index that best described the antibacterial activity in the murine infection model. The fAUC0-24 h/MIC targets required to achieve the bacteriostatic action, a 1-log10 kill and 2-log10 kill of bacterial counts were 19.93, 31.89, and 53.27 h, respectively. These results can facilitate efforts to define more rational designs of dosage regimens of tildipirosin using classical PK/PD concepts for the treatment of respiratory diseases in pigs and cattle. PMID:29867911

A Study of Plazomicin Compared With Colistin in Patients With Infection Due to Carbapenem-Resistant Enterobacteriaceae (CRE)

ClinicalTrials.gov

2016-10-03

Bloodstream Infections (BSI) Due to CRE; Hospital-Acquired Bacterial Pneumonia (HABP) Due to CRE; Ventilator-Associated Bacterial Pneumonia (VABP) Due to CRE; Complicated Urinary Tract Infection (cUTI) Due to CRE; Acute Pyelonephritis (AP) Due to CRE

Metabolic pathways of lung inflammation revealed by high-resolution metabolomics (HRM) of H1N1 influenza virus infection in mice.

PubMed

Chandler, Joshua D; Hu, Xin; Ko, Eun-Ju; Park, Soojin; Lee, Young-Tae; Orr, Michael; Fernandes, Jolyn; Uppal, Karan; Kang, Sang-Moo; Jones, Dean P; Go, Young-Mi

2016-11-01

Influenza is a significant health concern worldwide. Viral infection induces local and systemic activation of the immune system causing attendant changes in metabolism. High-resolution metabolomics (HRM) uses advanced mass spectrometry and computational methods to measure thousands of metabolites inclusive of most metabolic pathways. We used HRM to identify metabolic pathways and clusters of association related to inflammatory cytokines in lungs of mice with H1N1 influenza virus infection. Infected mice showed progressive weight loss, decreased lung function, and severe lung inflammation with elevated cytokines [interleukin (IL)-1β, IL-6, IL-10, tumor necrosis factor (TNF)-α, and interferon (IFN)-γ] and increased oxidative stress via cysteine oxidation. HRM showed prominent effects of influenza virus infection on tryptophan and other amino acids, and widespread effects on pathways including purines, pyrimidines, fatty acids, and glycerophospholipids. A metabolome-wide association study (MWAS) of the aforementioned inflammatory cytokines was used to determine the relationship of metabolic responses to inflammation during infection. This cytokine-MWAS (cMWAS) showed that metabolic associations consisted of distinct and shared clusters of 396 metabolites highly correlated with inflammatory cytokines. Strong negative associations of selected glycosphingolipid, linoleate, and tryptophan metabolites with IFN-γ contrasted strong positive associations of glycosphingolipid and bile acid metabolites with IL-1β, TNF-α, and IL-10. Anti-inflammatory cytokine IL-10 had strong positive associations with vitamin D, purine, and vitamin E metabolism. The detailed metabolic interactions with cytokines indicate that targeted metabolic interventions may be useful during life-threatening crises related to severe acute infection and inflammation. Copyright © 2016 the American Physiological Society.

PC61 (Anti-CD25) Treatment Inhibits Influenza A Virus-Expanded Regulatory T Cells and Severe Lung Pathology during a Subsequent Heterologous Lymphocytic Choriomeningitis Virus Infection

PubMed Central

Kraft, Anke R. M.; Wlodarczyk, Myriam F.; Kenney, Laurie L.

2013-01-01

Prior immunity to influenza A virus (IAV) in mice changes the outcome to a subsequent lymphocytic choriomeningitis virus (LCMV) infection and can result in severe lung pathology, similar to that observed in patients that died of the 1918 H1N1 pandemic. This pathology is induced by IAV-specific memory CD8+ T cells cross-reactive with LCMV. Here, we discovered that IAV-immune mice have enhanced CD4+ Foxp3+ T-regulatory (Treg) cells in their lungs, leading us to question whether a modulation in the normal balance of Treg and effector T-cell responses also contributes to enhancing lung pathology upon LCMV infection of IAV-immune mice. Treg cell and interleukin-10 (IL-10) levels remained elevated in the lungs and mediastinal lymph nodes (mLNs) throughout the acute LCMV response of IAV-immune mice. PC61 treatment, used to decrease Treg cell levels, did not change LCMV titers but resulted in a surprising decrease in lung pathology upon LCMV infection in IAV-immune but not in naive mice. Associated with this decrease in pathology was a retention of Treg in the mLN and an unexpected partial clonal exhaustion of LCMV-specific CD8+ T-cell responses only in IAV-immune mice. PC61 treatment did not affect cross-reactive memory CD8+ T-cell proliferation. These results suggest that in the absence of IAV-expanded Treg cells and in the presence of cross-reactive memory, the LCMV-specific response was overstimulated and became partially exhausted, resulting in a decreased effector response. These studies suggest that Treg cells generated during past infections can influence the characteristics of effector T-cell responses and immunopathology during subsequent heterologous infections. Thus, in humans with complex infection histories, PC61 treatment may lead to unexpected results. PMID:24049180

Infective endocarditis due to Capnocytophaga canimorsus.

PubMed

Frigiola, Alessandro; Badia, Toni; Lovato, Roberto; Cogo, Alberto; Fugazzaro, Maria Pia; Lovisetto, Roberto; Di Donato, Marisa

2003-10-01

We report the case of a 41-year-old woman with severe mitral regurgitation due to infective endocarditis caused by a rare zoonotic microorganism (Capnocytophaga canimorsus). She had had a rheumatic mitral endocarditis successfully treated with antibiotics when she was 13 years old. She arrived to our attention for a fever of unknown origin. She had been bitten by her dog and medicated the wound herself. About 2 weeks later she developed a fever with values up to 39.5 degrees C. Blood cultures were initially negative but in view of her particular history (dog bite), the samples were sent to a specialized center where a Capnocytophaga canimorsus (a commensal bacterium contained in the saliva of dogs and cats) infection sensitive to ceftriaxone was detected. The antibiotic therapy was consequently modified and the patient's fever resolved. At echocardiography a mild mitral stenosis with severe regurgitation (3-4+/4+) was detected. We planned surgical mitral repair but the operative findings clearly showed the need for mitral replacement and a 29 mm size bileaflet mechanical prosthesis was implanted. The postoperative course was regular and the patient was discharged on the fifth day. We highlight the importance of a careful history and correct work-up for the diagnosis and treatment of false negative blood culture endocarditis.

Pulmonary cholera due to infection with a non-O1 Vibrio cholerae strain.

PubMed

Shannon, Jack D; Kimbrough, Robert C

2006-09-01

We present 2 cases of primary pulmonary non-O1 Vibrio cholerae infection. We believe that these are the first documented cases of primary pulmonary infection due to this organism from a freshwater source.

Population Pharmacokinetics of Colistin Methanesulfonate in Rats: Achieving Sustained Lung Concentrations of Colistin for Targeting Respiratory Infections

PubMed Central

W. S. Yapa, Shalini; Li, Jian; Porter, Christopher J. H.; Nation, Roger L.

2013-01-01

Colistin methanesulfonate (CMS), the inactive prodrug of colistin, is administered by inhalation for the management of respiratory infections. However, limited pharmacokinetic data are available for CMS and colistin following pulmonary delivery. This study investigates the pharmacokinetics of CMS and colistin following intravenous (i.v.) and intratracheal (i.t.) administration in rats and determines the targeting advantage after direct delivery into the lungs. In addition to plasma, bronchoalveolar lavage (BAL) fluid was collected to quantify drug concentrations in lung epithelial lining fluid (ELF). The resulting data were analyzed using a population modeling approach in S-ADAPT. A three-compartment model described the disposition of both compounds in plasma following i.v. administration. The estimated mean clearance from the central compartment was 0.122 liters/h for CMS and 0.0657 liters/h for colistin. Conversion of CMS to colistin from all three compartments was required to fit the plasma data. The fraction of the i.v. dose converted to colistin in the systemic circulation was 0.0255. Two BAL fluid compartments were required to reflect drug kinetics in the ELF after i.t. dosing. A slow conversion of CMS (mean conversion time [MCTCMS] = 3.48 h) in the lungs contributed to high and sustained concentrations of colistin in ELF. The fraction of the CMS dose converted to colistin in ELF (fm,ELF = 0.226) was higher than the corresponding fractional conversion in plasma after i.v. administration. In conclusion, pulmonary administration of CMS achieves high and sustained exposures of colistin in lungs for targeting respiratory infections. PMID:23917323

Epidemiology and outcomes of Clostridium difficile infection in allogeneic hematopoietic cell and lung transplant recipients.

PubMed

Dubberke, E R; Reske, K A; Olsen, M A; Bommarito, K; Cleveland, A A; Silveira, F P; Schuster, M G; Kauffman, C A; Avery, R K; Pappas, P G; Chiller, T M

2018-04-01

Clostridium difficile infection (CDI) is a common complication of lung and allogeneic hematopoietic cell (HCT) transplant, but the epidemiology and outcomes of CDI after transplant are poorly described. We performed a prospective, multicenter study of CDI within 365 days post-allogeneic HCT or lung transplantation. Data were collected via patient interviews and medical chart review. Participants were followed weekly in the 12 weeks post-transplant and while hospitalized and contacted monthly up to 18 months post-transplantation. Six sites participated in the study with 614 total participants; 4 enrolled allogeneic HCT (385 participants) and 5 enrolled lung transplant recipients (229 participants). One hundred and fifty CDI cases occurred within 1 year of transplantation; the incidence among lung transplant recipients was 13.1% and among allogeneic HCTs was 31.2%. Median time to CDI was significantly shorter among allogeneic HCT than lung transplant recipients (27 days vs 90 days; P = .037). CDI was associated with significantly higher mortality from 31 to 180 days post-index date among the allogeneic HCT recipients (Hazard ratio [HR] = 1.80; P = .007). There was a trend towards increased mortality among lung transplant recipients from 120 to 180 days post-index date (HR = 4.7, P = .09). The epidemiology and outcomes of CDI vary by transplant population; surveillance for CDI should continue beyond the immediate post-transplant period. © 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

The effect of chronic infection with Aspergillus fumigatus on lung function and hospitalization in patients with cystic fibrosis.

PubMed

Amin, Reshma; Dupuis, Annie; Aaron, Shawn D; Ratjen, Felix

2010-01-01

The relevance of Aspergillus fumigatus in patients with cystic fibrosis (CF) not affected by allergic bronchopulmonary aspergillosis is unclear. Our aim was to determine the effect of persistent infection with A fumigatus on pulmonary exacerbations and lung function in children with CF. This was a retrospective cohort study of patients with CF followed at The Hospital for Sick Children from 1999 to 2006. Persistent A fumigatus infection was defined as the presence of two or more positive sputum or bronchoalveolar cultures for A fumigatus in a given year. The primary outcome measure was the annual number of hospitalizations for pulmonary exacerbations. Two hundred thirty patients with CF were included in the analysis. The FEV(1) of patients persistently infected with A fumigatus was 3.61% (P< or =.0001) lower during the study period compared with uninfected patients. There was a significant interaction between A fumigatus and Pseudomonas aeruginosa on lung function (P=.0006). Patients not infected with either organism had the highest pulmonary function. Persistent A fumigatus infection (relative risk [RR]=1.94, P=.0002) and CF-related diabetes (RR=1.64, P=.028) were associated with an increased risk of pulmonary exacerbations requiring hospitalization, whereas there was no increased risk of pulmonary exacerbations among patients with allergic bronchopulmonary aspergillosis (RR=1.02, P=.94). When adjusted for baseline pulmonary function, none of these variables were associated with a significantly increased risk of pulmonary exacerbations, with only chronic A fumigatus infection trending toward significance (RR=1.40, P=.065). Persistent A fumigatus infection is an independent risk factor for hospital admissions in patients with CF.

Extracorporeal life support in lung and heart-lung transplantation for pulmonary hypertension in adults.

PubMed

Kortchinsky, Talna; Mussot, Sacha; Rezaiguia, Saïda; Artiguenave, Margaux; Fadel, Elie; Stephan, François

2016-09-01

After bilateral lung and heart-lung transplantation in adults with pulmonary hypertension, hemodynamic and oxygenation deficiencies are life-threatening complications that are increasingly managed with extracorporeal life support (ECLS). The primary aim of this retrospective study was to assess 30-day and 1-year survival rates in patients managed with vs without post-operative venoarterial ECLS in 2008-2013. The secondary endpoints were the occurrence rates of nosocomial infection, bleeding, and acute renal failure. Of the 93 patients with pulmonary hypertension who received heart-lung (n=29) or bilateral lung (n=64) transplants, 28 (30%) required ECLS a median of 0 [0-6] hours after surgery completion and for a median of 3.0 [2.0-8.5] days. Compared to ECLS patients, controls had higher survival at 30 days (95.0% vs 78.5%; P=.02) and 1 year (83% vs 64%; P=.005), fewer nosocomial infections (48% vs 79%; P=.0006), and fewer bleeding events (17% vs 43%; P=.008). The need for renal replacement therapy was not different between groups (11% vs 17%; P=.54). Venoarterial ECLS is effective in treating pulmonary graft dysfunction with hemodynamic failure after heart-lung or bilateral lung. However, ECLS use was associated with higher rates of infection and bleeding. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Extra corporeal membrane oxygenation to facilitate lung protective ventilation and prevent ventilator-induced lung injury in severe Pneumocystis pneumonia with pneumomediastinum: a case report and short literature review.

PubMed

Ali, Husain Shabbir; Hassan, Ibrahim Fawzy; George, Saibu

2016-04-14

Pulmonary infections caused by Pneumocystis jirovecii in immunocompromised host can be associated with cysts, pneumatoceles and air leaks that can progress to pneumomediastinum and pneumothoraxes. In such cases, it can be challenging to maintain adequate gas exchange by conventional mechanical ventilation and at the same time prevent further ventilator-induced lung injury. We report a young HIV positive male with poorly compliant lungs and pneumomediastinum secondary to severe Pneumocystis infection, rescued with veno-venous extra corporeal membrane oxygenation (V-V ECMO). A 26 year old male with no significant past medical history was admitted with fever, cough and shortness of breath. He initially required non-invasive ventilation for respiratory failure. However, his respiratory function progressively deteriorated due to increasing pulmonary infiltrates and development of pneumomediastinum, eventually requiring endotracheal intubation and invasive ventilation. Despite attempts at optimizing gas exchange by ventilatory maneuvers, patients' pulmonary parameters worsened necessitating rescue ECMO therapy. The introduction of V-V ECMO facilitated the use of ultra-protective lung ventilation and prevented progression of pneumomediastinum, maintaining optimal gas exchange. It allowed time for the antibiotics to show effect and pulmonary parenchyma to heal. Further diagnostic workup revealed Pneumocystis jirovecii as the causative organism for pneumonia and serology confirmed Human Immunodeficiency Virus infection. Patient was successfully treated with appropriate antimicrobials and de-cannulated after six days of ECMO support. ECMO was an effective salvage therapy in HIV positive patient with an otherwise fatal respiratory failure due to Pneumocystis pneumonia and air leak syndrome.

An optimized two-photon method for in vivo lung imaging reveals intimate cell collaborations during infection

NASA Astrophysics Data System (ADS)

Fiole, Daniel; Deman, Pierre; Trescos, Yannick; Douady, Julien; Tournier, Jean-Nicolas

2013-02-01

Lung tissue motion arising from breathing and heart beating has been described as the largest annoyance of in vivo imaging. Consequently, infected lung tissue has never been imaged in vivo thus far, and little is known concerning the kinetics of the mucosal immune system at the cellular level. We have developed an optimized post-processing strategy to overcome tissue motion, based upon two-photon and second harmonic generation (SHG) microscopy. In contrast to previously published data, we have freed the lung parenchyma from any strain and depression in order to maintain the lungs under optimal physiological parameters. Excitation beams swept the sample throughout normal breathing and heart movements, allowing the collection of many images. Given that tissue motion is unpredictably, it was essential to sort images of interest. This step was enhanced by using SHG signal from collagen as a reference for sampling and realignment phases. A normalized cross-correlation criterion was used between a manually chosen reference image and rigid transformations of all others. Using CX3CR1+/gfp mice this process allowed the collection of high resolution images of pulmonary dendritic cells (DCs) interacting with Bacillus anthracis spores, a Gram-positive bacteria responsible for anthrax disease. We imaged lung tissue for up to one hour, without interrupting normal lung physiology. Interestingly, our data revealed unexpected interactions between DCs and macrophages, two specialized phagocytes. These contacts may participate in a better coordinate immune response. Our results not only demonstrate the phagocytizing task of lung DCs but also infer a cooperative role of alveolar macrophages and DCs.

Human Lung Fibroblasts Present Bacterial Antigens to Autologous Lung Th Cells.

PubMed

Hutton, Andrew J; Polak, Marta E; Spalluto, C Mirella; Wallington, Joshua C; Pickard, Chris; Staples, Karl J; Warner, Jane A; Wilkinson, Tom M A

2017-01-01

Lung fibroblasts are key structural cells that reside in the submucosa where they are in contact with large numbers of CD4 + Th cells. During severe viral infection and chronic inflammation, the submucosa is susceptible to bacterial invasion by lung microbiota such as nontypeable Haemophilus influenzae (NTHi). Given their proximity in tissue, we hypothesized that human lung fibroblasts play an important role in modulating Th cell responses to NTHi. We demonstrate that fibroblasts express the critical CD4 + T cell Ag-presentation molecule HLA-DR within the human lung, and that this expression can be recapitulated in vitro in response to IFN-γ. Furthermore, we observed that cultured lung fibroblasts could internalize live NTHi. Although unable to express CD80 and CD86 in response to stimulation, fibroblasts expressed the costimulatory molecules 4-1BBL, OX-40L, and CD70, all of which are related to memory T cell activation and maintenance. CD4 + T cells isolated from the lung were predominantly (mean 97.5%) CD45RO + memory cells. Finally, cultured fibroblasts activated IFN-γ and IL-17A cytokine production by autologous, NTHi-specific lung CD4 + T cells, and cytokine production was inhibited by a HLA-DR blocking Ab. These results indicate a novel role for human lung fibroblasts in contributing to responses against bacterial infection through activation of bacteria-specific CD4 + T cells. Copyright © 2016 by The American Association of Immunologists, Inc.

Cavitating lung disease due to concomitant drug resistant tuberculosis and invasive pulmonary Aspergillosis in a post-partum patient: A case report.

PubMed

Ray, Animesh; Suri, J C; Sen, M K; Chakrabarti, S; Gupta, Ayush; Capoor, Malini

2015-01-01

Many disorders can present as cavitating lesions in the lung. In this case report, a case of mixed infection with drug resistant tuberculosis and invasive pulmonary aspergillosis in a post-partum patient has been presented. Copyright © 2015 Tuberculosis Association of India. Published by Elsevier B.V. All rights reserved.

Retroperitoneal abscess shortly after chemotherapy for lung cancer: A case report.

PubMed

Ohara, Gen; Kondo, Tadashi; Kagohashi, Katsunori; Watanabe, Hiroko; Kawaguchi, Mio; Kurishima, Koichi; Satoh, Hiroaki; Hizawa, Nobuyuki

2014-03-01

To the best of our knowledge, the formation of a retroperitoneal abscess due to acute appendicitis shortly after administration of chemotherapy for lung cancer has not been previously reported. This is the case report of a 59-year-old male who was admitted to the Mito Medical Center (Mito, Japan) and diagnosed with lung adenocarcinoma with pleuritis carcinomatosis. Although no distant metastasis was identified, combination chemotherapy with cisplatin and pemetrexed was administered. Nine days after initiating chemotherapy, the patient developed right lower quadrant abdominal pain and high fever. Computed tomography (CT) of the abdomen and pelvis revealed the collection of gas and fluid in the retroperitoneum adjacent to the cecum. The abscess was locally drained; however, the infection continued to spread, with subsequent development of a scrotal abscess. Consequently, appendectomy was performed. The patient recovered well and the lung adenocarcinoma was treated with additional courses of chemotherapy following the remission of the local inflammation. Retroperitoneal abscess due to acute appendicitis is an unusual finding; however, this rare complication should be considered during or shortly after chemotherapy in patients with lung cancer.

10 years of prophylaxis with nebulized liposomal amphotericin B and the changing epidemiology of Aspergillus spp. infection in lung transplantation.

PubMed

Peghin, Maddalena; Monforte, Victor; Martin-Gomez, Maria-Teresa; Ruiz-Camps, Isabel; Berastegui, Cristina; Saez, Berta; Riera, Jordi; Ussetti, Piedad; Solé, Juan; Gavaldá, Joan; Roman, Antonio

2016-01-01

The aim of this study was to assess the outcome and tolerability of prophylactic nebulized liposomal amphotericin B (n-LAB) in lung transplant recipients (LTR) and the changing epidemiology of Aspergillus spp. infection and colonization. We performed an observational study including consecutive LTR recipients (2003-2013) undergoing n-LAB prophylaxis lifetime. A total of 412 patients were included (mean postoperative follow-up 2.56 years; IQR 1.01-4.65). Fifty-three (12.8%) patients developed 59 Aspergillus spp. infections, and 22 invasive aspergillosis (overall incidence 5.3%). Since 2009, person-time incidence rates of Aspergillus spp. colonization and infection decreased (2003-2008, 0.19; 2009-2014, 0.09; P = 0.0007), but species with reduced susceptibility or resistance to amphotericin significantly increased (2003-2008, 38.1% vs 2009-2014, 58.1%; P = 0.039). Chronic lung allograft dysfunction (CLAD) was associated with Aspergillus spp. colonization and infection (HR 24.4, 95% CI 14.28-41.97; P = 0.00). Only 2.9% of patients presented adverse effects, and 1.7% required discontinuation. Long-term administration of prophylaxis with n-LAB has proved to be tolerable and can be used for preventing Aspergillus spp. infection in LTR. Over the last years, the incidence of Aspergillus spp. colonization and infection has decreased, but species with reduced amphotericin susceptibility or resistance are emerging. CLAD is associated with Aspergillus spp. colonization and infection. © 2015 Steunstichting ESOT.

Rotavirus Viremia and Extraintestinal Viral Infection in the Neonatal Rat Model

PubMed Central

Crawford, Sue E.; Patel, Dinesh G.; Cheng, Elly; Berkova, Zuzana; Hyser, Joseph M.; Ciarlet, Max; Finegold, Milton J.; Conner, Margaret E.; Estes, Mary K.

2006-01-01

Rotaviruses infect mature, differentiated enterocytes of the small intestine and, by an unknown mechanism, escape the gastrointestinal tract and cause viremia. The neonatal rat model of rotavirus infection was used to determine the kinetics of viremia, spread, and pathology of rotavirus in extraintestinal organs. Five-day-old rat pups were inoculated intragastrically with an animal (RRV) or human (HAL1166) rotavirus or phosphate-buffered saline. Blood was collected from a subset of rat pups, and following perfusion to remove residual blood, organs were removed and homogenized to analyze rotavirus-specific antigen by enzyme-linked immunosorbent assay and infectious rotavirus by fluorescent focus assay or fixed in formalin for histology and immunohistochemistry. Viremia was detected following rotavirus infection with RRV and HAL1166. The RRV 50% antigenemia dose was 1.8 × 103 PFU, and the 50% diarrhea dose was 7.7 × 105 PFU, indicating that infection and viremia occurred in the absence of diarrhea and that detecting rotavirus antigen in the blood was a more sensitive measure of infection than diarrhea. Rotavirus antigens and infectious virus were detected in multiple organs (stomach, intestines, liver, lungs, spleen, kidneys, pancreas, thymus, and bladder). Histopathological changes due to rotavirus infection included acute inflammation of the portal tract and bile duct, microsteatosis, necrosis, and inflammatory cell infiltrates in the parenchymas of the liver and lungs. Colocalization of structural and nonstructural proteins with histopathology in the liver and lungs indicated that the histological changes observed were due to rotavirus infection and replication. Replicating rotavirus was also detected in macrophages in the lungs and blood vessels, indicating a possible mechanism of rotavirus dissemination. Extraintestinal infectious rotavirus, but not diarrhea, was observed in the presence of passively or actively acquired rotavirus-specific antibody. These

A case of orbital apex syndrome due to Pseudomonas aeruginosa infection

PubMed Central

Kusunoki, Takeshi; Kase, Kaori; Ikeda, Katsuhisa

2011-01-01

Orbital apex syndrome is commonly been thought to have a poor prognosis. Many cases of this syndrome have been reported to be caused by paranasal sinus mycosis. We encountered a very rare case (60-year-old woman) of sinusitis with orbital apex syndrome due to Pseudomonas aeruginosa infection. She had received insulin and dialysis for diabtes and diabetic nephropathy, moreover anticoagulants after heart by-pass surgery. She underwent endoscopic sinus operation and was treated with antibiotics, but her loss of left vision did not improve. Recently, sinusitis cases due to Pseudomonas aeruginosa were reported to be a increasing. Therefore, we should consider the possibility of Pseudomonas aeruginosa as well as mycosis as infections of the sinus, especially inpatients who are immunocompromised body. PMID:24765368

A case of orbital apex syndrome due to Pseudomonas aeruginosa infection.

PubMed

Kusunoki, Takeshi; Kase, Kaori; Ikeda, Katsuhisa

2011-09-28

Orbital apex syndrome is commonly been thought to have a poor prognosis. Many cases of this syndrome have been reported to be caused by paranasal sinus mycosis. We encountered a very rare case (60-year-old woman) of sinusitis with orbital apex syndrome due to Pseudomonas aeruginosa infection. She had received insulin and dialysis for diabtes and diabetic nephropathy, moreover anticoagulants after heart by-pass surgery. She underwent endoscopic sinus operation and was treated with antibiotics, but her loss of left vision did not improve. Recently, sinusitis cases due to Pseudomonas aeruginosa were reported to be a increasing. Therefore, we should consider the possibility of Pseudomonas aeruginosa as well as mycosis as infections of the sinus, especially inpatients who are immunocompromised body.

[Tropical and travel-related dermatomycoses : Part 2: cutaneous infections due to yeasts, moulds, and dimorphic fungi].

PubMed

Nenoff, P; Reinel, D; Krüger, C; Grob, H; Mugisha, P; Süß, A; Mayser, P

2015-07-01

Besides dermatophytoses, a broad range of cutaneous infections due to yeasts and moulds may occur in subtropical and tropical countries where they can affect travellers. Not to be forgotten are endemic occurring dimorphic or biphasic fungi in countries with hot climate, which cause systemic and secondary cutaneous infections in immunosuppressed and immunocompetent people. In the tropics, the prevalence of pityriasis versicolor, caused by the lipophilic yeast Malassezia spp., is about 30-40 %, in distinct areas even 50 %. Increased hyperhidrosis under tropical conditions and simultaneously humidity congestion have to be considered as significant disposing factors for pityriasis versicolor. In tropical countries, therefore, an exacerbation of a preexisting pityriasis versicolor in travellers is not rare. Today, mostly genital yeast infections due to the new species Candida africana can be found worldwide. Due to migration from Africa this yeast pathogen has reached Germany and Europe. Eumycetomas due to mould fungi are rarely diagnosed in Europe. These deep cutaneous mould infections are only found in immigrants from African countries. The therapy of eumycetoma is protracted and often not successful. Cutaneous cryptococcoses due to the yeast species Cryptococcus neoformans and Cryptococcus gattii occur worldwide; however, they are found more frequently in the tropics. Immunosuppressed patients, especially those with HIV/AIDS, are affected by cryptococcoses. Furthermore, Cryptococcus gattii also causes infections in immunocompetent hosts in Central Africa, Australia, California, and Central America.Rarely found are infections due to dimorphic fungi after travel to countries where these fungal pathogens are endemic. In individual cases, cutaneous or lymphogenic transferred sporotrichosis due to Sporothrix schenkii can occur. Furthermore, scarcely known is secondary cutaneous coccidioidomycosis due to Coccidioides immitis after travelling to desert-like endemic

Stenotrophomonas maltophilia Virulence and Specific Variations in Trace Elements during Acute Lung Infection: Implications in Cystic Fibrosis

PubMed Central

Crocetta, Valentina; Consalvo, Ada; Zappacosta, Roberta; Di Ilio, Carmine; Di Bonaventura, Giovanni

2014-01-01

Metal ions are necessary for the proper functioning of the immune system, and, therefore, they might have a significant influence on the interaction between bacteria and host. Ionic dyshomeostasis has been recently observed also in cystic fibrosis (CF) patients, whose respiratory tract is frequently colonized by Stenotrophomonas maltophilia. For the first time, here we used an inductively mass spectrometry method to perform a spatial and temporal analysis of the pattern of changes in a broad range of major trace elements in response to pulmonary infection by S. maltophilia. To this, DBA/2 mouse lungs were comparatively infected by a CF strain and by an environmental one. Our results showed that pulmonary ionomic profile was significantly affected during infection. Infected mice showed increased lung levels of Mg, P, S, K, Zn, Se, and Rb. To the contrary, Mn, Fe, Co, and Cu levels resulted significantly decreased. Changes of element concentrations were correlated with pulmonary bacterial load and markers of inflammation, and occurred mostly on day 3 post-exposure, when severity of infection culminated. Interestingly, CF strain – significantly more virulent than the environmental one in our murine model - provoked a more significant impact in perturbing pulmonary metal homeostasis. Particularly, exposure to CF strain exclusively increased P and K levels, while decreased Fe and Mn ones. Overall, our data clearly indicate that S. maltophilia modulates pulmonary metal balance in a concerted and virulence-dependent manner highlighting the potential role of the element dyshomeostasis during the progression of S. maltophilia infection, probably exacerbating the harmful effects of the loss of CF transmembrane conductance regulator function. Further investigations are required to understand the biological significance of these alterations and to confirm they are specifically caused by S. maltophilia. PMID:24586389

Febrile status epilepticus due to respiratory syncytial virus infection.

PubMed

Uda, Kazuhiro; Kitazawa, Katsuhiko

2017-08-01

Febrile status epilepticus can have neurological sequelae. The type of sequelae, however, depend on the etiology, including infection due to viral agents such as the influenza virus. Respiratory syncytial virus (RSV) infection in childhood may also contribute to this. The aim of this study was therefore to characterize febrile status epilepticus associated with RSV infection, and to determine whether this type of infection is a risk factor for neurological sequelae in febrile status epilepticus. We reviewed the medical records of children aged ≤3 years with febrile status epilepticus who were admitted to a tertiary hospital between January 2007 and December 2011. The differences between the RSV-positive and RSV-negative groups were evaluated according to the demographic and clinical data. A total of 99 patients with febrile status epilepticus who had been tested for RSV infection were identified. Three patients in the RSV-positive group (n = 19) and four in the RSV-negative group (n = 80) presented with bronchiolitis. The incidence of intubation and anti-seizure drug treatment in the RSV-positive group was significantly higher than in the -negative group. While all of the patients in the RSV-negative group recovered completely, six patients in the RSV-positive group developed encephalopathy and profound neurological sequelae. In five of the six patients, diffusion-weighted magnetic resonance imaging showed subcortical white matter lesions. RSV infection in the absence of bronchiolitis can initially present as febrile status epilepticus and subsequently develop into acute encephalopathy with profound neurological sequelae. © 2017 Japan Pediatric Society.

Adenovirus vector infection of non-small-cell lung cancer cells is a trigger for multi-drug resistance mediated by P-glycoprotein.

PubMed

Tomono, Takumi; Kajita, Masahiro; Yano, Kentaro; Ogihara, Takuo

2016-08-05

P-glycoprotein (P-gp) is an ATP-binding cassette protein involved in cancer multi-drug resistance (MDR). It has been reported that infection with some bacteria and viruses induces changes in the activities of various drug-metabolizing enzymes and transporters, including P-gp. Although human adenoviruses (Ad) cause the common cold, the effect of Ad infection on MDR in cancer has not been established. In this study, we investigated whether Ad infection is a cause of MDR in A549, H441 and HCC827 non-small-cell lung cancer (NSCLC) cell lines, using an Ad vector system. We found that Ad vector infection of NSCLC cell lines induced P-gp mRNA expression, and the extent of induction was dependent on the number of Ad vector virus particles and the infection time. Heat-treated Ad vector, which is not infectious, did not alter P-gp mRNA expression. Uptake experiments with doxorubicin (DOX), a P-gp substrate, revealed that DOX accumulation was significantly decreased in Ad vector-infected A549 cells. The decrease of DOX uptake was blocked by verapamil, a P-gp inhibitor. Our results indicated that Ad vector infection of NSCLC cells caused MDR mediated by P-gp overexpression. The Ad vector genome sequence is similar to that of human Ad, and therefore human Ad infection of lung cancer patients may lead to chemoresistance in the clinical environment. Copyright © 2016 Elsevier Inc. All rights reserved.

Respiratory syncytial virus increases lung cellular bioenergetics in neonatal C57BL/6 mice

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

Alsuwaidi, Ahmed R., E-mail: alsuwaidia@uaeu.ac.ae; Albawardi, Alia, E-mail: alia.albawardi@uaeu.ac.ae; Almarzooqi, Saeeda, E-mail: saeeda.almarzooqi@uaeu.ac.ae

2014-04-15

We have previously reported that lung cellular bioenergetics (cellular respiration and ATP) increased in 4–10 week-old BALB/c mice infected with respiratory syncytial virus (RSV). This study examined the kinetics and changes in cellular bioenergetics in ≤2-week-old C57BL/6 mice following RSV infection. Mice (5–14 days old) were inoculated intranasally with RSV and the lungs were examined on days 1–10 post-infection. Histopathology and electron microscopy revealed preserved pneumocyte architectures and organelles. Increased lung cellular bioenergetics was noted from days 1–10 post-infection. Cellular GSH remained unchanged. These results indicate that the increased lung cellular respiration (measured by mitochondrial O{sub 2} consumption) and ATPmore » following RSV infection is independent of either age or genetic background of the host. - Highlights: • RSV infection increases lung cellular respiration and ATP in neonatal C57BL/6 mice. • Increased lung cellular bioenergetics is a biomarker of RSV infection. • Lung cellular glutathione remains unchanged in RSV infection.« less

[Aorto-bifermoral grafs infection due to Candida parapsilosis. An unusual pathogen].

PubMed

Guevara-Noriega, Kerbi Alejandro; Velescu, Alina; Zaffalon-Espinal, Diana Teresa; Mateos-Torres, Eduardo; Roig-Santamaría, Luis; Clará-Velasco, Albert

Aorto-enteric fistula is a rare and potentially lethal entity. Its presentation may be as an enteric-paraprosthetic fistula, due to injury in the gut caused by direct contact with the vascular prosthesis. We report a case of enteric-paraprosthetic fistulae with the unusual finding of Candida parapsilosis as the only isolated pathogen. A 65-year-old male, smoker, with aortobifemoral revascularisation with dacron due to aortoiliac occlusive disease, and re-intervention for thrombosis of left arm at 6 months. Hospitalisation at 22 months was required due to a toxic syndrome, which was diagnosed as enteric-paraprosthetic fistulae after complementary studies. The graft was removed and an extra-anatomic revascularisation was performed. Microbiology specimens taken from the duodenal segment in contact with the prosthesis showed the prosthetic segment and peri-prosthetic fluid were positive to C. parapsilosis. The finding of C. parapsilosis in all cultures taken during surgery, along with negative blood cultures and no other known sources of infection, is of interest. It is an unusual pathogen with low virulence and limited as regards other Candida species. Our patient had no clinical data common to cases of infection with C. parapsilosis, and the mechanism of graft infection is unknown. Graft infection by C. parapsilosis may be anecdotal. However, its consequences can also be severe. Microbiological tests can be useful to adjust antimicrobial therapy in the post-operative period, but their usefulness for determining the aetiology is doubtful, as it may be just an incidental finding. Copyright © 2016 Academia Mexicana de Cirugía A.C. Publicado por Masson Doyma México S.A. All rights reserved.

Lung cancer risk due to residential radon exposures: estimation and prevention.

PubMed

Truta, L A; Hofmann, W; Cosma, C

2014-07-01

Epidemiological studies proved that cumulative exposure to radon is the second leading cause of lung cancer, the world's most common cancer. The objectives of the present study are (i) to analyse lung cancer risk for chronic, low radon exposures based on the transformation frequency-tissue response (TF-TR) model formulated in terms of alpha particle hits in cell nuclei; (ii) to assess the percentage of attributable lung cancers in six areas of Transylvania where the radon concentration was measured and (iii) to point out the most efficient remediation measures tested on a pilot house in Stei, Romania. Simulations performed with the TF-TR model exhibit a linear dose-effect relationship for chronic, residential radon exposures. The fraction of lung cancer cases attributed to radon ranged from 9 to 28% for the investigated areas. Model predictions may represent a useful tool to complement epidemiological studies on lung cancer risk and to establish reasonable radiation protection regulations for human safety. © The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Tilmicosin does not inhibit interleukin-8 gene expression in the bovine lung experimentally infected with Mannheimia (Pasteurella) haemolytica.

PubMed Central

Goubau, S; Morck, D W; Buret, A

2000-01-01

The expression of the interleukin-8 (IL-8) gene was examined by in situ hybridization in lung tissues from calves experimentally infected with Mannheimia (Pasteurella) haemolytica and treated with tilmicosin. Interleukin-8 mRNA expression was detected in alveolar areas, particularly along interlobular septa, in the lumen, and in the epithelial cells of some bronchioles. In lesional lung tissues from animals that had received tilmicosin, we found large areas with limited inflammation. There was no staining for IL-8 mRNA in these areas. In contrast, in strongly inflamed areas, the same patterns and intensities of staining for IL-8 mRNA were detected in tilmicosin- and sham-treated animals. We conclude that tilmicosin does not affect the expression of IL-8 mRNA in tissue showing microscopic signs of inflammation. Together with previous reports, this supports the view that the pro-apoptotic properties of tilmicosin on neutrophils do not compromise the host defense mechanisms required to control the infection. Images Figure 1. PMID:11041503

Mixed Lineage Kinase 3 deficiency delays viral clearance in the lung and is associated with diminished influenza-induced cytopathic effect in infected cells

PubMed Central

Desmet, Emily A.; Hollenbaugh, Joseph A.; Sime, Patricia J.; Wright, Terry W.; Topham, David J.; Sant, Andrea J.; Takimoto, Toru; Dewhurst, Stephen; Maggirwar, Sanjay B.

2010-01-01

Influenza virus leads to acute respiratory disease resulting in seasonal epidemics and periodic pandemics. Little is known about the signaling events that regulate host defense to influenza. One particular pathway, the c-Jun amino-terminal kinase (JNK) cascade is activated following influenza infection and blocking JNK leads to enhanced viral replication. We hypothesize that Mixed Lineage Kinase 3 (MLK3), an upstream regulator of JNK, is involved in the host response to influenza. To test this, wild-type and MLK3−/− mice were infected with pathogenic strain of influenza A virus, A/PR/8/34 (PR8). Although, cellular and humoral immune responses were similar between wild-type and MLK3−/− hosts, the viral load in the lungs was comparatively higher in MLK3−/− mice at day 8 post infection. Consistent with this, MLK3−/− murine lung fibrobalsts had prolonged survival and increased virion production following infection compared to wild-type. These findings support a role for MLK3 in viral production during influenza infection. PMID:20185156

Cough physiology in elderly women with nontuberculous mycobacterial lung infections.

PubMed

Tsai, Hsiu-Wen; Fennelly, Kevin; Wheeler-Hegland, Karen; Adams, Sherry; Condrey, Jillian; Hosford, Jennifer L; Davenport, Paul W

2017-05-01

Elderly white, thin, nonsmoking women appear to be more susceptible to lung infections with Mycobacterium avium complex and other nontuberculous mycobacteria (NTM). It has been postulated that such disease in women is related to suppression of their cough. We hypothesized that patients with pulmonary NTM (pNTM) infections may have altered cough physiology compared with unaffected control subjects. We used capsaicin-induced cough to assess the cough reflex in pNTM subjects. Eight elderly white women with stable chronic pNTM infections and six unaffected age-matched control subjects were recruited. There was no significant difference between groups in capsaicin-elicited cough motor response, airflow pattern, or cough frequency. The urge-to-cough (UTC) score at the lowest capsaicin concentration was significantly lower in pNTM than control subjects ( P < 0.05). There were no significant differences in the UTC score between pNTM and control subjects at >50 μM capsaicin. These results suggest lower UTC sensitivity to the lowest concentration of capsaicin in pNTM than control subjects. In other words, the pNTM subjects do not sense a UTC when the stimulus is relatively small. NEW & NOTEWORTHY This study investigates the cough motor response and cough sensitivity in patients with nontuberculous mycobacteria (NTM) infection. In elderly white female pulmonary NTM subjects, we demonstrated a capacity to produce coughs similar to that of age-matched control subjects but decreased cough sensitivity in response to a low dose of capsaicin compared with control subjects. These findings are important to understand the pathophysiological mechanisms resulting in NTM disease in elderly white women and/or the syndrome developing in elderly white female NTM patients. Copyright © 2017 the American Physiological Society.

M-CSF Mediates Host Defense during Bacterial Pneumonia by Promoting the Survival of Lung and Liver Mononuclear Phagocytes.

PubMed

Bettina, Alexandra; Zhang, Zhimin; Michels, Kathryn; Cagnina, R Elaine; Vincent, Isaah S; Burdick, Marie D; Kadl, Alexandra; Mehrad, Borna

2016-06-15

Gram-negative bacterial pneumonia is a common and dangerous infection with diminishing treatment options due to increasing antibiotic resistance among causal pathogens. The mononuclear phagocyte system is a heterogeneous group of leukocytes composed of tissue-resident macrophages, dendritic cells, and monocyte-derived cells that are critical in defense against pneumonia, but mechanisms that regulate their maintenance and function during infection are poorly defined. M-CSF has myriad effects on mononuclear phagocytes but its role in pneumonia is unknown. We therefore tested the hypothesis that M-CSF is required for mononuclear phagocyte-mediated host defenses during bacterial pneumonia in a murine model of infection. Genetic deletion or immunoneutralization of M-CSF resulted in reduced survival, increased bacterial burden, and greater lung injury. M-CSF was necessary for the expansion of lung mononuclear phagocytes during infection but did not affect the number of bone marrow or blood monocytes, proliferation of precursors, or recruitment of leukocytes to the lungs. In contrast, M-CSF was essential to survival and antimicrobial functions of both lung and liver mononuclear phagocytes during pneumonia, and its absence resulted in bacterial dissemination to the liver and hepatic necrosis. We conclude that M-CSF is critical to host defenses against bacterial pneumonia by mediating survival and antimicrobial functions of mononuclear phagocytes in the lungs and liver. Copyright © 2016 by The American Association of Immunologists, Inc.

M-CSF mediates host defense during bacterial pneumonia by promoting the survival of lung and liver mononuclear phagocytes

PubMed Central

Bettina, Alexandra; Zhang, Zhimin; Michels, Kathryn; Cagnina, R. Elaine; Vincent, Isaah S.; Burdick, Marie D.; Kadl, Alexandra; Mehrad, Borna

2016-01-01

Gram-negative bacterial pneumonia is a common and dangerous infection with diminishing treatment options due to increasing antibiotic resistance among causal pathogens. The mononuclear phagocyte system is a heterogeneous group of leukocytes composed of tissue-resident macrophages, dendritic cells and monocyte-derived cells that are critical in defense against pneumonia, but mechanisms that regulate their maintenance and function during infection are poorly defined. Macrophage-colony stimulating factor (M-CSF) has myriad effects on mononuclear phagocytes but its role in pneumonia is unknown. We therefore tested the hypothesis that M-CSF is required for mononuclear phagocyte-mediated host defenses during bacterial pneumonia in a murine model of infection. Genetic deletion or immunoneutralization of M-CSF resulted in reduced survival, increased bacterial burden and greater lung injury. M-CSF was necessary for the expansion of lung mononuclear phagocytes during infection but did not affect the number of bone marrow or blood monocytes, the proliferation of precursors or the recruitment of leukocytes to the lungs. In contrast, M-CSF was essential to survival and anti-microbial functions of both lung and liver mononuclear phagocytes during pneumonia and its absence resulted in bacterial dissemination to the liver and hepatic necrosis. We conclude that M-CSF is critical to host defenses against bacterial pneumonia by mediating survival and anti-microbial functions of mononuclear phagocytes in the lungs and liver. PMID:27183631

Baicalin inhibits TLR7/MYD88 signaling pathway activation to suppress lung inflammation in mice infected with influenza A virus

PubMed Central

WAN, QIAOFENG; WANG, HAO; HAN, XUEBO; LIN, YUAN; YANG, YANHUI; GU, LIGANG; ZHAO, JIAQING; WANG, LI; HUANG, LING; LI, YANBIN; YANG, YURONG

2014-01-01

The present study aimed to investigate the protective effects and underlying mechanisms of baicalin on imprinting control region mice infected with influenza A/FM/1/47 (H1N1) virus. Oral administration of baicalin into mice infected with H1N1 prevented death, increased the mean time to death and inhibited lung index and lung consolidation. Subsequently, fluorescence quantitative polymerase chain reaction was used to assess the mRNA expression of toll-like receptor 7 (TLR7) and myeloid differentiation primary response gene 88 (MYD88), and western blot analysis was used to determine the expression of phosphorylated nuclear factor κB (NF-κB)-P65 and c-jun/activator protein 1 (AP-1). An enzyme-linked immunosorbent assay was applied to test for the inflammatory cytokines, tumor necrosis factor (TNF)-α and interleukin (IL)-1β and IL-6, in the lung tissue. The findings indicated that baicalin downregulated the mRNA expression of TLR7 and MYD88, significantly downregulated the protein expression of NF-κB-P65 and AP-1 and also inhibited the secretion of TNF-α, IL-1β and IL-6. In conclusion, baicalin effectively reduced the pathological damage and inflammation of the lungs by downregulating the TLR7/MYD88-mediated signaling pathway. PMID:24748990

Parasitemia due to Sarcocystis neurona-like infection in a clinically ill domestic cat.

PubMed

Zitzer, Nina C; Marsh, Antoinette E; Burkhard, Mary Jo; Radin, M Judith; Wellman, Maxey L; Jugan, Maria; Parker, Valerie

2017-09-01

An 8-year-old, 6-kg, male neutered Domestic Shorthair cat was presented to The Ohio State University Veterinary Medical Center (OSU-VMC) for difficulty breathing. Physical examination and thoracic radiographs indicated pneumonia, a soft-tissue mass in the left caudal lung lobe, and diffuse pleural effusion. The effusion was classified as modified transudate. Rare extracellular elongated (~5-7 μm × 1-2 μm) zoites with a central round to oval-shaped purple to deep purple vesicular nucleus with coarsely stippled chromatin and light blue cytoplasm were seen on a peripheral blood smear. Serum IgG and IgM were positive for Sarcocystis sp. antibodies and negative for Toxoplasma gondii antibodies, suggesting that the infection was acute rather than a recrudescence of prior infection. This organism was most consistent with either Sarcocystis neurona or Sarcocystis dasypi based on DNA sequence analysis of PCR products using COC ssRNA, ITS-1, snSAG2, and JNB25/JD396 primer sets. This is the first report to visualize by light microscopy circulating Sarcocystis sp. merozoites in the peripheral blood of a domestic cat. Therefore, Sarcocystis should be considered as a differential diagnosis in cats with suspected systemic protozoal infection. © 2017 American Society for Veterinary Clinical Pathology.

The economic burden of lung cancer and mesothelioma due to occupational and para-occupational asbestos exposure

PubMed Central

Tompa, Emile; Kalcevich, Christina; McLeod, Chris; Lebeau, Martin; Song, Chaojie; McLeod, Kim; Kim, Joanne; Demers, Paul A

2017-01-01

Objectives To estimate the economic burden of lung cancer and mesothelioma due to occupational and para-occupational asbestos exposure in Canada. Methods We estimate the lifetime cost of newly diagnosed lung cancer and mesothelioma cases associated with occupational and para-occupational asbestos exposure for calendar year 2011 based on the societal perspective. The key cost components considered are healthcare costs, productivity and output costs, and quality of life costs. Results There were 427 cases of newly diagnosed mesothelioma cases and 1904 lung cancer cases attributable to asbestos exposure in 2011 for a total of 2331 cases. Our estimate of the economic burden is $C831 million in direct and indirect costs for newly identified cases of mesothelioma and lung cancer and $C1.5 billion in quality of life costs based on a value of $C100 000 per quality-adjusted life year. This amounts to $C356 429 and $C652 369 per case, respectively. Conclusions The economic burden of lung cancer and mesothelioma associated with occupational and para-occupational asbestos exposure is substantial. The estimate identified is for 2331 newly diagnosed, occupational and para-occupational exposure cases in 2011, so it is only a portion of the burden of existing cases in that year. Our findings provide important information for policy decision makers for priority setting, in particular the merits of banning the mining of asbestos and use of products containing asbestos in countries where they are still allowed and also the merits of asbestos removal in older buildings with asbestos insulation. PMID:28756416

An efficient method to predict and include Bragg curve degradation due to lung-equivalent materials in Monte Carlo codes by applying a density modulation

NASA Astrophysics Data System (ADS)

Baumann, Kilian-Simon; Witt, Matthias; Weber, Uli; Engenhart-Cabillic, Rita; Zink, Klemens

2017-05-01

Sub-millimetre-sized heterogeneities such as lung parenchyma cause Bragg peak degradation which can lead to an underdose of the tumor and an overdose of healthy tissue when not accounted for in treatment planning. Since commonly used treatment-planning CTs do not resolve the fine structure of lungs, this degradation can hardly be considered. We present a mathematical model capable of predicting and describing Bragg peak degradation due to a lung-equivalent geometry consisting of sub-millimetre voxels filled with either lung tissue or air. The material characteristic ‘modulation power’ is introduced to quantify the Bragg peak degradation. A strategy was developed to transfer the modulating effects of such fine structures to rougher structures such as 2 mm thick CT voxels, which is the resolution of typically used CTs. This is done by using the modulation power to derive a density distribution applicable to these voxels. By replacing the previously used sub-millimetre voxels by 2 mm thick voxels filled with lung tissue and modulating the lung tissue’s density in each voxel individually, we were able to reproduce the Bragg peak degradation. Hence a solution is found to include Bragg curve degradation due to lung-equivalent materials in Monte Carlo-based treatment-planning systems.

Urinary tract infections due to Trichosporon spp. in severely ill patients in an intensive care unit

PubMed Central

Mattede, Maria das Graças Silva; Piras, Cláudio; Mattede, Kelly Dematte Silva; Ferrari, Aline Trugilho; Baldotto, Lorena Simões; Assbu, Michel Silvestre Zouain

2015-01-01

Objective To evaluate the incidence of urinary tract infections due to Trichosporon spp. in an intensive care unit. Methods This descriptive observational study was conducted in an intensive care unit between 2007 and 2009. All consecutive patients admitted to the intensive care unit with a confirmed diagnosis were evaluated. Results Twenty patients presented with urinary tract infections due to Trichosporon spp. The prevalence was higher among men (65%) and among individuals > 70 years of age (55%). The mortality rate was 20%. The average intensive care unit stay was 19.8 days. The onset of infection was associated with prior use of antibiotics and was more frequent in the fall and winter. Conclusion Infection due to Trichosporon spp. was more common in men and among those > 70 years of age and was associated with the use of an indwelling urinary catheter for more than 20 days and with the use of broadspectrum antibiotics for more than 14 days. In addition, patients with urinary infection due to Trichosporon spp. were most often hospitalized in intensive care units in the fall and winter periods. PMID:26465246

Respiratory syncytial virus infection accelerates lung fibrosis through the unfolded protein response in a bleomycin-induced pulmonary fibrosis animal model.

PubMed

Wang, Lina; Cheng, Wei; Zhang, Zhimin

2017-07-01

Emerging evidence has demonstrated that endoplasmic reticulum stress (ER) is involved in the pathogenesis of idiopathic pulmonary fibrosis, however, the underlying mechanism remains unclear. Viral infection often triggers a hyperinflammatory response by an expansion of the ER. The present study was designed to observe the role of respiratory syncytial virus infection (RSV)‑induced ER stress on lung fibrosis. In order to determine the role of ER stress on the onset and progression of pulmonary fibrosis, mice received an intratracheal combined injection of RSV and bleomycin on day 0. At day 7, 14 and 21 following combined injection, RSV in the lung tissues was assayed by immunohistochemistry, cellular classification was assayed by direct microscopic observation after Wright staining and the secretion of cytokines in the broncho‑alveolar lavage fluid (BALF) was assayed by ELISA. The expression of collagen type I was assayed by immunofluorescence and western blot analysis. The expression of ER stress related proteins was analyzed by western blot. In addition, the correlations of ER‑stress related proteins with collagen type‑1 were examined. RSV administration resulted in increased inflammation, as demonstrated by increased levels of leukocytes and pro‑inflammatory cytokines in the BALF, and increased collagen type‑1 deposition in the lung tissues of bleomycin-induced pulmonary fibrosis animal model at 7, 14 and 21 days. RSV promoted the expression of phosphorylated protein kinase R‑like endoplasmic reticulum kinase (p‑PERK), 78 kDa glucose‑regulated protein (GRP78) and activating transcription factor 6α (ATF6α), which accelerated the severity and process of fibrosis in bleomycin‑induced animal models. The present study provides evidence that RSV infection accelerated the unfolded protein response and bleomycin‑induced lung fibrosis, which may improve our understanding of the pathogenesis of pulmonary fibrosis.

Epidemiology, risk factors, and outcome of Clostridium difficile infection in heart and heart-lung transplant recipients.

PubMed

Bruminhent, Jackrapong; Cawcutt, Kelly A; Thongprayoon, Charat; Petterson, Tanya M; Kremers, Walter K; Razonable, Raymund R

2017-06-01

Clostridium difficile is a major cause of diarrhea in thoracic organ transplant recipients. We investigated the epidemiology, risk factors, and outcome of Clostridium difficile infection (CDI) in heart and heart-lung transplant (HT) recipients. This is a retrospective study from 2004 to 2013. CDI was defined by diarrhea and a positive toxigenic C. difficile in stool measured by toxin enzyme immunoassay (2004-2006) or polymerase chain reaction (2007-2013). Cox proportional hazards regression was used to model the association of risk factors with time to CDI and survival with CDI following transplantation. There were 254 HT recipients, with a median age of 53 years (IQR, 45-60); 34% were female. During the median follow-up of 3.1 years (IQR, 1.3-6.1), 22 (8.7%) patients developed CDI. In multivariable analysis, risk factors for CDI were combined heart-lung transplant (HR 4.70; 95% CI, 1.30-17.01 [P=.02]) and retransplantation (HR 7.19; 95% CI, 1.61-32.12 [P=.01]). Acute cellular rejection was associated with a lower risk of CDI (HR 0.34; 95% CI, 0.11-0.94 [P=.04]). CDI was found to be an independent risk factor for mortality (HR 7.66; 95% CI, 3.41-17.21 [P<.0001]). Clostridium difficile infection after HT is more common among patients with combined heart-lung and those undergoing retransplantation. CDI was associated with a higher risk of mortality in HT recipients. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Hyperactive immune cells (T cells) may be responsible for acute lung injury in influenza virus infections: a need for early immune-modulators for severe cases.

PubMed

Lee, Kyung-Yil; Rhim, Jung-Woo; Kang, Jin-Han

2011-01-01

It has been believed that acute lung injury in influenza virus infections is caused by a virus-induced cytopathy; viruses that have multiplied in the upper respiratory tract spread to lung tissues along the lower respiratory tract. However, some experimental and clinical studies have suggested that the pathogenesis of acute lung injury in influenza virus infections is associated with excessive host response including a cell-mediated immune reaction. During the pandemic H1N1 2009 influenza A virus infections in Korea, we experienced a dramatic effect of immune-modulators (corticosteroids) on the patients with severe pneumonia who had significant respiratory distress at presentation and those who showed rapidly progressive pneumonia during oseltamivir treatment. We also found that the pneumonia patients treated with corticosteroids showed the lowest lymphocyte differential and that the severity of pneumonia was associated with the lymphocyte count at presentation. From our findings and previous experimental and clinical studies, we postulated that hyperactive immune cells (T cells) may be involved in the acute lung injury of influenza virus infections, using a hypothesis of 'protein homeostasis system'; the inducers of the cell-mediated immune response are initially produced at the primary immune sites by the innate immune system. These substances reach the lung cells, the main target organ, via the systemic circulation, and possibly the cells of other organs, including myocytes or central nerve system cells, leading to extrapulmonary symptoms (e.g., myalgia and rhabdomyolysis, and encephalopathy). To control these substances that may be possibly toxic to host cells, the adaptive immune reaction may be operated by immune cells, mainly lymphocytes. Hyperimmune reaction of immune cells produces higher levels of cytokines which may be associated with acute lung injury, and may be controlled by early use of immune-modulators. Early initiation and proper dosage of immune

Mixed Fungal Lung Infection with Aspergillus Fumigatus and Candida Albicans in a Immunocomprimised Patient: Case Report

PubMed Central

Vipparti, Haritha

2014-01-01

The frequency of invasive, opportunistic mycoses has increased significantly over the past 2 decades. In the immune-compromised host, many fungi, including species of fungi typically considered non-pathogenic, have the potential to cause serious morbidity and mortality. Here we report a rare case of mixed fungal infection of the lung with Candida albicans and Aspergillus fumigatus in a patient on prolonged steroid therapy. PMID:24959447

Mycobacterium tuberculosis Cell Wall released Fragments by the Action of the Human Lung Mucosa modulate Macrophages to Control Infection in a IL-10 Dependent Manner

PubMed Central

Arcos, Jesus; Sasindran, Smitha J.; Moliva, Juan I.; Scordo, Julia M.; Sidiki, Sabeen; Guo, Hui; Venigalla, Poornima; Kelley, Holden V.; Lin, Guoxin; Diangelo, Lauren; Silwani, Sayeed N.; Zhang, Jian; Turner, Joanne; Torrelles, Jordi B.

2016-01-01

Mycobacterium tuberculosis (M.tb) , the causative agent of tuberculosis, is a major public health challenge facing the world. During infection, M.tb is deposited in the lung alveolar space where it comes in contact with the lung mucosa, known as alveolar lining fluid (ALF), an environment that M.tb encounters at different stages of the infection and disease. ALF is abundant in homeostatic and antimicrobial hydrolytic enzymes, also known as hydrolases. Here we demonstrate that ALF hydrolases, at their physiological concentrations and upon contact with M.tb, release M.tb cell envelope fragments into the milieu. These released fragments are bioactive, but non-cytotoxic, regulate the function of macrophages, and thus are capable of modulating the immune response contributing to the control of M.tb infection by human macrophages. Specifically, macrophages exposed to fragments derived from the exposure of M.tb to ALF were able to control the infection primarily by increasing phagosome-lysosome fusion and acidification events. This enhanced control was found to be dependent on fragment induced IL-10 production but also involves the STAT3 signaling pathway in an IL-10 independent manner. Collectively our data indicate that M.tb fragments released upon contact with lung mucosa hydrolases participate in the host immune response to M.tb infection through innate immune modulation. PMID:28000679

Complicated catheter-associated urinary tract infections due to Escherichia coli and Proteus mirabilis.

PubMed

Jacobsen, S M; Stickler, D J; Mobley, H L T; Shirtliff, M E

2008-01-01

Catheter-associated urinary tract infections (CAUTIs) represent the most common type of nosocomial infection and are a major health concern due to the complications and frequent recurrence. These infections are often caused by Escherichia coli and Proteus mirabilis. Gram-negative bacterial species that cause CAUTIs express a number of virulence factors associated with adhesion, motility, biofilm formation, immunoavoidance, and nutrient acquisition as well as factors that cause damage to the host. These infections can be reduced by limiting catheter usage and ensuring that health care professionals correctly use closed-system Foley catheters. A number of novel approaches such as condom and suprapubic catheters, intermittent catheterization, new surfaces, catheters with antimicrobial agents, and probiotics have thus far met with limited success. While the diagnosis of symptomatic versus asymptomatic CAUTIs may be a contentious issue, it is generally agreed that once a catheterized patient is believed to have a symptomatic urinary tract infection, the catheter is removed if possible due to the high rate of relapse. Research focusing on the pathogenesis of CAUTIs will lead to a better understanding of the disease process and will subsequently lead to the development of new diagnosis, prevention, and treatment options.

Complicated Catheter-Associated Urinary Tract Infections Due to Escherichia coli and Proteus mirabilis

PubMed Central

Jacobsen, S. M.; Stickler, D. J.; Mobley, H. L. T.; Shirtliff, M. E.

2008-01-01

Catheter-associated urinary tract infections (CAUTIs) represent the most common type of nosocomial infection and are a major health concern due to the complications and frequent recurrence. These infections are often caused by Escherichia coli and Proteus mirabilis. Gram-negative bacterial species that cause CAUTIs express a number of virulence factors associated with adhesion, motility, biofilm formation, immunoavoidance, and nutrient acquisition as well as factors that cause damage to the host. These infections can be reduced by limiting catheter usage and ensuring that health care professionals correctly use closed-system Foley catheters. A number of novel approaches such as condom and suprapubic catheters, intermittent catheterization, new surfaces, catheters with antimicrobial agents, and probiotics have thus far met with limited success. While the diagnosis of symptomatic versus asymptomatic CAUTIs may be a contentious issue, it is generally agreed that once a catheterized patient is believed to have a symptomatic urinary tract infection, the catheter is removed if possible due to the high rate of relapse. Research focusing on the pathogenesis of CAUTIs will lead to a better understanding of the disease process and will subsequently lead to the development of new diagnosis, prevention, and treatment options. PMID:18202436

Long-term outcomes and management of lung transplant recipients.

PubMed

Costa, Joseph; Benvenuto, Luke J; Sonett, Joshua R

2017-06-01

Lung transplantation is an established treatment for patients with end-stage lung disease. Improvements in immunosuppression and therapeutic management of infections have resulted in improved long-term survival and a decline in allograft rejection. Allograft rejection continues to be a serious complication following lung transplantation, thereby leading to acute graft failure and, subsequently, chronic lung allograft dysfunction (CLAD). Bronchiolitis obliterans syndrome (BOS), the most common phenotype of CLAD, is the leading cause of late mortality and morbidity in lung recipients, with 50% having developed BOS within 5 years of lung transplantation. Infections in lung transplant recipients are also a significant complication and represent the most common cause of death within the first year. The success of lung transplantation depends on careful management of immunosuppressive regimens to reduce the rate of rejection, while monitoring recipients for infections and complications to help identify problems early. The long-term outcomes and management of lung transplant recipients are critically based on modulating natural immune response of the recipient to prevent acute and chronic rejection. Understanding the immune mechanisms and temporal correlation of acute and chronic rejection is thus critical in the long-term management of lung recipients. Copyright © 2017 Elsevier Ltd. All rights reserved.

A computer simulation model of the cost-effectiveness of routine Staphylococcus aureus screening and decolonization among lung and heart-lung transplant recipients.

PubMed

Clancy, C J; Bartsch, S M; Nguyen, M H; Stuckey, D R; Shields, R K; Lee, B Y

2014-06-01

Our objective was to model the cost-effectiveness and economic value of routine peri-operative Staphylococcus aureus screening and decolonization of lung and heart-lung transplant recipients from hospital and third-party payer perspectives. We used clinical data from 596 lung and heart-lung transplant recipients to develop a model in TreeAge Pro 2009 (Williamsport, MA, USA). Sensitivity analyses varied S. aureus colonization rate (5-15 %), probability of infection if colonized (10-30 %), and decolonization efficacy (25-90 %). Data were collected from the Cardiothoracic Transplant Program at the University of Pittsburgh Medical Center. Consecutive lung and heart-lung transplant recipients from January 2006 to December 2010 were enrolled retrospectively. Baseline rates of S. aureus colonization, infection and decolonization efficacy were 9.6 %, 36.7 %, and 31.9 %, respectively. Screening and decolonization was economically dominant for all scenarios tested, providing more cost savings and health benefits than no screening. Savings per case averted (2012 $US) ranged from $73,567 to $133,157 (hospital perspective) and $10,748 to $16,723 (third party payer perspective), varying with the probability of colonization, infection, and decolonization efficacy. Using our clinical data, screening and decolonization led to cost savings per case averted of $240,602 (hospital perspective) and averted 6.7 S. aureus infections (4.3 MRSA and 2.4 MSSA); 89 patients needed to be screened to prevent one S. aureus infection. Our data support routine S. aureus screening and decolonization of lung and heart-lung transplant patients. The economic value of screening and decolonization was greater than in previous models of other surgical populations.

CFTR and lung homeostasis

PubMed Central

Matalon, Sadis

2014-01-01

CFTR is a cAMP-activated chloride and bicarbonate channel that is critical for lung homeostasis. Decreases in CFTR expression have dire consequences in cystic fibrosis (CF) and have been suggested to be a component of the lung pathology in chronic obstructive pulmonary disease. Decreases or loss of channel function often lead to mucus stasis, chronic bacterial infections, and the accompanying chronic inflammatory responses that promote progressive lung destruction, and, eventually in CF, lung failure. Here we discuss CFTR's functional role airway surface liquid hydration and pH, in regulation of other channels such as the epithelial sodium channel, and in regulating inflammatory responses in the lung. PMID:25381027

An initially unidentified case of urinary tract infection due to Aerococcus urinae.

PubMed

Meletis, Georgios; Chatzidimitriou, Dimitrios; Tsingerlioti, Fani; Chatzopoulou, Fani; Tzimagiorgis, Georgios

2017-07-01

Aerococcus urinae is a microorganism responsible for urinary tract and blood stream infections which are rarely reported in clinical practice. However, it has been proposed that the infrequency of such reports may be partially due to difficulties related to pathogen identification. We present here a case of an elderly male patient with urinary tract infection where A. urinae was initially not identified by a private microbiology laboratory. Our report highlights the need to consider A. urinae as a causative agent of urinary tract infections because if not identified and properly treated it may lead to endocarditis or septicemia.

Lung abscess following bronchoscopy due to multidrug-resistant Capnocytophaga sputigena adjacent to lung cancer with high PD-L1 expression.

PubMed

Migiyama, Yohei; Anai, Moriyasu; Kashiwabara, Kosuke; Tomita, Yusuke; Saeki, Sho; Nakamura, Kazuyoshi; Okamoto, Shinichiro; Ichiyasu, Hidenori; Fujii, Kazuhiko; Kohrogi, Hirotsugu

2018-04-24

Lung abscess following flexible bronchoscopy is a rare and sometimes fatal iatrogenic complication. Here, we report the first case of a lung abscess caused by multidrug-resistant Capnocytophaga sputigena following bronchoscopy. A 67-year-old man underwent bronchoscopy to evaluate a lung mass. Seven days after transbronchial lung biopsy, he presented with an abscess formation in a lung mass. Empirical antibiotic therapy, including with garenoxacin, ampicillin/sulbactam, clindamycin and cefepime, was ineffective. Percutaneous needle aspiration of lung abscess yielded C. sputigena resistant to multiple antibiotics but remained susceptible to carbapenem. He was successfully treated by the combination therapy with surgery and with approximately 6 weeks of intravenous carbapenem. Finally he was diagnosed with a lung abscess with adenocarcinoma expressing high levels of programmed cell death ligand 1. The emergence of multidrug-resistant Capnocytophaga species is a serious concern for effective antimicrobial therapy. Clinicians should consider multidrug-resistant C. sputigena as a causative pathogen of lung abscess when it is refractory to antimicrobial treatment. Copyright © 2018 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.

Pediatric Lung Transplantation.

PubMed

Sweet, Stuart C

2017-06-01

Pediatric lung transplant is a viable option for treatment of end-stage lung disease in children, with > 100 pediatric lung transplants reported to the Registry of the International Society of Heart and Lung Transplantation each year. Long-term success is limited by availability of donor organs, debilitation as a result of chronic disease, impaired mucus clearance resulting from both surgical and pharmacologic interventions, increased risk for infection resulting from immunosuppression, and most importantly late complications, such as chronic lung allograft dysfunction. Opportunities for investigation and innovation remain in all of these domains: (1) Ex vivo lung perfusion is a promising technology with the potential for increasing the lung donor pool, (2) evolving extracorporeal support strategies coupled with effective rehabilitation will effectively bridge critically ill patients to transplant, and most importantly, (3) research efforts intended to increase our understanding of the underlying mechanisms of chronic lung allograft dysfunction will ultimately lead to the development of effective therapies to prevent or treat the variety of chronic lung allograft dysfunction presentations. Copyright © 2017 by Daedalus Enterprises.

A retrospective study of abattoir condemnation due to parasitic infections: economic importance in Ahwaz, southwestern Iran.

PubMed

Borji, Hassan; Azizzadeh, Mohammad; Kamelli, Mehrab

2012-10-01

A 5-yr retrospective study in livestock slaughtered in abattoirs was carried out in Khuzestan Province (southwestern Iran) to determine the prevalence of parasitic infections responsible for condemnation of slaughtered animals' carcasses and viscera. The economic importance of such infections in terms of lost meat and offal were also estimated. Between 20 March 2006 and 19 March 2011, 125,593 cattle, 1,191,871 sheep, 240,221 goats, and 25,010 buffalos were slaughtered in the study area; the livers of 58,753 (3.7%; 95% confidence interval [CI]: 3.7-3.8%), the lungs of 34,522 (2.2%; 95% CI: 2.1-2.2%), and the carcasses of 78 (0.0049% 95% CI: 0.0048-0.0049%) of these animals were condemned. Proportions of liver, lung, and carcass condemnations during the 5-yr study period in buffalos were significantly greater than the other species (P < 0.001). Frequency of liver condemnation during the 5-yr period for cattle was greater than sheep and goats (P < 0.001), but condemnation of lungs in goat was significantly greater than sheep and cattle (P < 0.001). The parasitic lesions observed in the condemned livers were attributed to Echinococcus granulosus, Fasciola hepatica, or Dicrocoelium dendriticum, or some combination of these species. All the parasitic lesions observed in the condemned lungs from cattle, sheep, goats, and buffalos are ascribed to E. granulosus. Sarcocystis spp. cysts were found in ovine and buffalo muscles, whereas Taenia sp. cysticerci were detected in bovine muscle. Muscles of goats were devoid of any parasitic lesions. Parasites were responsible for 54.1% of the condemned organs or carcasses, with a retail value (based on market prices in 2011) of $1,148,181 (U.S.) ($137,880 for cattle, $602,699 for sheep, $280,955 for goats, and $126,647 for buffalos). The parasites contributing most to the condemnation of otherwise marketable organs and flesh were E. granulosus (29.2%) and F. hepatica (18.6%). These parasites clearly remain the most common, causing

Bacterial infection and acute lung injury in hamsters.

PubMed

Seidenfeld, J J; Mullins, R C; Fowler, S R; Johanson, W G

1986-07-01

Bacterial pneumonia is a common complication of lung injury that can be an important determinant of outcome. We studied experimental lung injury produced in hamsters by injecting 20 mg/kg paraquat (PQ) intraperitoneally; control animals received saline vehicle. Three days later, Pseudomonas aeruginosa (PAO1), 10(8) organisms in 0.25 ml, or saline, 0.25 ml, was inoculated intratracheally. Lung and systemic antibacterial defenses were studied at death 24 h later. Paraquat alone produced focal interstitial pneumonitis and neutrophilic alveolitis, and resulted in a 12% (3 of 26) mortality. PAO1 alone caused focal pneumonias and no deaths. Animals receiving both agents (PAO1/PQ) had extensive diffuse alveolar damage characterized by alveolar hemorrhage, edema, influx of neutrophils, and vasculitis; 50% (16 of 32) died within 96 h of PQ injection. Mean lung counts of PAO1 at death were 7.6 X 10(4) colony forming units/g in PAO1 and 2.8 X 10(7) in PAO1/PQ animals (p less than 0.05). PAO1 colony counts in liver were increased nearly 100-fold in PAO1/PQ animals (p less than 0.05). Half-time of clearance of P. aeruginosa from the blood was prolonged in PAO1 and in PAO1/PQ animals (p less than 0.05) but not in PQ animals. Phagocytosis of Staphylococcus aureus by leukocytes lavaged from the lung was not impaired in any group compared with that in control animals, but intracellular killing was impaired in PAO1 and PAO1/PQ but not in PQ animals. Paraquat injury impairs lung antibacterial defenses by uncertain mechanisms. Superinfection of PQ-injured lungs by PAO1 appears responsible for defects in intrapulmonary and systemic antibacterial defenses.

Cigarette Smoke Exposure Exacerbates Lung Inflammation and Compromises Immunity to Bacterial Infection

PubMed Central

Lugade, Amit A.; Bogner, Paul N.; Thatcher, Thomas H.; Sime, Patricia J.; Phipps, Richard P.; Thanavala, Yasmin

2014-01-01

The detrimental impact of tobacco on human health is clearly recognized and despite aggressive efforts to prevent smoking, close to one billion individuals worldwide continue to smoke. People with chronic obstructive pulmonary disease (COPD) are susceptible to recurrent respiratory infections with pathogens, including non-typeable Haemophilus influenzae (NTHI), yet the reasons for this increased susceptibility are poorly understood. As mortality rapidly increases with multiple exacerbations, development of protective immunity is critical to improving patient survival. Acute NTHI infection has been studied in the context of cigarette smoke exposure, but this is the first study to investigate chronic infection and the generation of adaptive immune responses to NTHI following chronic smoke exposure. After chronic NTHI infection, mice that had previously been exposed to cigarette smoke developed increased lung inflammation and compromised adaptive immunity relative to air-exposed controls. Importantly, NTHI-specific T cells from mice exposed to cigarette smoke produced lower levels of IFN-γ and IL-4, and B cells produced reduced levels of antibodies against outer membrane lipoprotein P6, with impaired IgG1, IgG2a and IgA class-switching. However, production of IL-17, which is associated with neutrophilic inflammation, was enhanced. Interestingly, cigarette smoke exposed mice exhibited a similar defect in the generation of adaptive immunity following immunization with P6. Our study has conclusively demonstrated that cigarette smoke exposure has a profound suppressive effect on the generation of adaptive immune responses to NTHI and suggests the mechanism by which prior cigarette smoke exposure predisposes COPD patients to recurrent infections, leading to exacerbations and contributing to mortality. PMID:24752444

[Lung transplantation in cystic fibrosis].

PubMed

Borro Maté, J M; Calvo Medina, V; Morant Guillén, P; Morales Marín, P; Vicente Guillén, R; Tarrazona Hervas, V; Ramos Briones, F; Lozano Ruiz, C; Ferrer Calvete, F

1996-11-01

Since 1990 we have performed 40 lung transplants in the Hospital "La Fe" in Valencia. Nine of them have been performed in cystic fibrosis patients, which is the subject of this paper. The mean age of the patients was 19.8 years, with the youngest patient being 14 years of age. In regards to patient selection, it is important to mention that one had a previous lobectomy, another one a thoracic deformity due to long term atelectasis and one needed intubation for hemoptysis within the 7 days before the lung transplant. Prophylaxis with imipenem and cyprofloxicin, aerosolized colistin and amphotericin B, prompt weaning and intensive respiratory physiotherapy were important for controlling postoperative infection. With 15.3 months as the mean follow-up (range 36-3), 3 year survival was 87.5%. Pulmonary infection, which was the most frequent complication, had a good response to adequate antibiotic treatment. The main postoperative problem pertained to the bronchial suture with 2 partial dehiscences, 2 stenoses and one bronchopleural fistula by Aspergillus, all of which were resolved with conservative procedures without surgery. Middle and long term evolution in these patients shows an excellent quality of life with spirometric and ergometric tests within the normal range.

Squamous cell lung cancer in a male with pulmonary tuberculosis.

PubMed

Skowroński, Marcin; Iwanik, Katarzyna; Halicka, Anna; Barinow-Wojewódzki, Aleksander

2015-01-01

Lung cancer and pulmonary tuberculosis (TB) are highly prevalent and representing major public health issues. They share common risk factors and clinical manifestations. It is also suggested that TB predicts raised lung cancer risk likely related to chronic inflammation in the lungs. However, it does not seem to influence the clinical course of lung cancer provided that it is properly treated. We present a case report of a 57-year old male with concurrent TB and lung cancer. He was diagnosed with positive sputum smear for acid fast bacilli (AFB) and subsequent culture of Mycobacterium tuberculosis. Besides, his comorbid conditions were chronic hepatitis C virus (HCV) infection and peripheral artery disease (PAD). Later while on anti-tuberculous treatment (ATT) squamous cell lung cancer (SCC) was confirmed with computed tomography (CT) guided biopsy. Due to poor general condition the patient was not fit for either surgery or radical chemo- and radiotherapy. He was transferred to hospice for palliative therapy. We want to emphasize that both TB and lung cancer should be actively sought for in patients with either disorder. In addition, there is no doubt that these patients with lung cancer and with good response to TB treatment should be promptly considered for appropriate anticancer therapy.

Case Report: Successful Lung Transplantation from a Donor Seropositive for Trypanosoma cruzi Infection (Chagas Disease) to a Seronegative Recipient.

PubMed

Salvador, Fernando; Sánchez-Montalvá, Adrián; Sulleiro, Elena; Berastegui, Cristina; Jauregui, Alberto; Pont, Teresa; Los-Arcos, Ibai; Len, Óscar; Gavaldà, Joan; Molina, Israel

2017-10-01

The increasing shortage of organs for transplantation has prompted transplant programs to investigate the use of extended criteria donors, such as those with transmissible infectious diseases. Successful cases of organ transplantation (mostly kidney and liver) from Trypanosoma cruzi seropositive donors to seronegative recipients have been reported. We present a case of lung transplantation from a donor serologically positive for Chagas disease to a seronegative recipient, and provide a review of the literature. Left single lung transplantation was performed in a 44-year-old Spanish woman presenting with interstitial lung disease in February 2016. The deceased donor was a Colombian immigrant living in Spain who was serologically positive for Chagas disease. Oral administration of 5 mg/kg/day benznidazole divided in three doses for 60 days was given for specific Chagas disease prophylaxis after transplantation. Periodic follow-up with serological reverse transcription polymerase chain reaction to detect T. cruzi DNA were performed until 6 months after the end of treatment. All results were negative, indicating that transmission of T. cruzi had not occurred. In a review of the literature, two similar cases were identified in Argentina and the United States. In both cases T. cruzi infection was detected posttransplant in the recipients, after which they were treated with benznidazole. The course of the patient described herein confirms that lungs from donors with chronic T. cruzi infection can be used successfully as allografts, and that posttransplant prophylaxis with benznidazole may reduce the probability of transmission of T. cruzi to the recipient.

Adenovirus vector infection of non-small-cell lung cancer cells is a trigger for multi-drug resistance mediated by P-glycoprotein

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

Tomono, Takumi; Kajita, Masahiro; Yano, Kentaro

P-glycoprotein (P-gp) is an ATP-binding cassette protein involved in cancer multi-drug resistance (MDR). It has been reported that infection with some bacteria and viruses induces changes in the activities of various drug-metabolizing enzymes and transporters, including P-gp. Although human adenoviruses (Ad) cause the common cold, the effect of Ad infection on MDR in cancer has not been established. In this study, we investigated whether Ad infection is a cause of MDR in A549, H441 and HCC827 non-small-cell lung cancer (NSCLC) cell lines, using an Ad vector system. We found that Ad vector infection of NSCLC cell lines induced P-gp mRNAmore » expression, and the extent of induction was dependent on the number of Ad vector virus particles and the infection time. Heat-treated Ad vector, which is not infectious, did not alter P-gp mRNA expression. Uptake experiments with doxorubicin (DOX), a P-gp substrate, revealed that DOX accumulation was significantly decreased in Ad vector-infected A549 cells. The decrease of DOX uptake was blocked by verapamil, a P-gp inhibitor. Our results indicated that Ad vector infection of NSCLC cells caused MDR mediated by P-gp overexpression. The Ad vector genome sequence is similar to that of human Ad, and therefore human Ad infection of lung cancer patients may lead to chemoresistance in the clinical environment. -- Highlights: •Adenovirus vector infection induced P-gp mRNA expression in three NSCLC cell lines. •Adenovirus vector infection enhanced P-gp-mediated doxorubicin efflux from the cells. •The increase of P-gp was not mediated by nuclear receptors (PXR, CAR) or COX-2.« less

Comprehensive evaluation of lung allograft function in infants after lung and heart-lung transplantation.

PubMed

Hayes, Don; Naguib, Aymen; Kirkby, Stephen; Galantowicz, Mark; McConnell, Patrick I; Baker, Peter B; Kopp, Benjamin T; Lloyd, Eric A; Astor, Todd L

2014-05-01

Limited data exist on methods to evaluate allograft function in infant recipients of lung and heart-lung transplants. At our institution, we developed a procedural protocol in coordination with pediatric anesthesia where infants were sedated to perform infant pulmonary function testing, computed tomography imaging of the chest, and flexible fiberoptic bronchoscopy with transbronchial biopsies. A retrospective review was performed of children aged younger than 1 year who underwent lung or heart-lung transplantation at our institution to assess the effect of this procedural protocol in the evaluation of infant lung allografts. Since 2005, 5 infants have undergone thoracic transplantation (3 heart-lung, 2 lung). At time of transplant, the mean ± standard deviation age was 7.2 ± 2.8 months (range, 3-11 months). Of 24 procedural sessions performed to evaluate lung allografts, 83% (20 of 24) were considered surveillance where the patients were completely asymptomatic. Of the surveillance procedures, 80% were performed as an outpatient, whereas 20% were done as inpatients during the lung or heart-lung transplant post-operative period before discharge home. Sedation was performed with propofol alone (23 of 24) or in addition to ketamine (1 of 24) infusion; mean sedation time was 141 ± 39 minutes (range, 70-214) minutes. Of the 16 outpatient procedures, patients were discharged after 14 (88%) on the same day, and after 2 (12%) were admitted for observation, with 1 being due to transportation issues and the other due to fever during the observation period. A comprehensive procedural protocol to evaluate allograft function in infant lung and heart-lung transplant recipients was performed safely as an outpatient. Copyright © 2014 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.

Clostridium Difficile Infection Due to Pneumonia Treatment: Mortality Risk Models.

PubMed

Chmielewska, M; Zycinska, K; Lenartowicz, B; Hadzik-Błaszczyk, M; Cieplak, M; Kur, Z; Wardyn, K A

2017-01-01

One of the most common gastrointestinal infection after the antibiotic treatment of community or nosocomial pneumonia is caused by the anaerobic spore Clostridium difficile (C. difficile). The aim of this study was to retrospectively assess mortality due to C. difficile infection (CDI) in patients treated for pneumonia. We identified 94 cases of post-pneumonia CDI out of the 217 patients with CDI. The mortality issue was addressed by creating a mortality risk models using logistic regression and multivariate fractional polynomial analysis. The patients' demographics, clinical features, and laboratory results were taken into consideration. To estimate the influence of the preceding respiratory infection, a pneumonia severity scale was included in the analysis. The analysis showed two statistically significant and clinically relevant mortality models. The model with the highest prognostic strength entailed age, leukocyte count, serum creatinine and urea concentration, hematocrit, coexisting neoplasia or chronic obstructive pulmonary disease. In conclusion, we report on two prognostic models, based on clinically relevant factors, which can be of help in predicting mortality risk in C. difficile infection, secondary to the antibiotic treatment of pneumonia. These models could be useful in preventive tailoring of individual therapy.

Integrating Lung Physiology, Immunology, and Tuberculosis.

PubMed

Torrelles, Jordi B; Schlesinger, Larry S

2017-08-01

Lungs are directly exposed to the air, have enormous surface area, and enable gas exchange in air-breathing animals. They are constantly 'attacked' by microbes from both outside and inside and thus possess a unique, highly regulated local immune defense system which efficiently allows for microbial clearance while minimizing damaging inflammatory responses. As a prototypic host-adapted airborne pathogen, Mycobacterium tuberculosis traverses the lung and has several 'interaction points' (IPs) which it must overcome to cause infection. These interactions are critical, not only from a pathogenesis perspective but also in considering the effectiveness of therapies and vaccines in the lungs. Here we discuss emerging views on immunologic interactions occurring in the lungs for M. tuberculosis and their impact on infection and persistence. Copyright © 2017 Elsevier Ltd. All rights reserved.

Non-tuberculous Mycobacterial Infections in Thoracic Transplant Candidates and Recipients.

PubMed

Rao, Mana; Silveira, Fernanda P

2018-05-12

To review and discuss the epidemiology, risk factors, clinical presentation, diagnosis, and treatment of non-tuberculous mycobacteria (NTM) in thoracic transplantation. Non-tuberculous mycobacteria are ubiquitous but are an uncommon cause of disease after solid organ transplantation. The incidence of infection is higher in thoracic transplant recipients than in abdominal transplant recipients, with most cases seen after lung transplantation. It is associated with increased morbidity and, occasionally, mortality. Infection in the pre-transplant setting can occur in lung transplant candidates, often posing a dilemma regarding transplant listing. Disease manifestations are diverse, and pulmonary disease is the most common. Diagnosis requires a high index of suspicion. Treatment requires a multiple-drug combination and is limited by drug-drug interactions and tolerability. Mycobacterium abscessus is a challenge in lung transplant recipients, due to its intrinsic resistance and propensity to relapse even after prolonged therapy. Mycobacterium chimaera is an emerging pathogen associated with contamination of heater-cooler units and is described to cause disease months after cardiothoracic surgery. NTM infections in thoracic organ transplant recipients are uncommon but are associated with substantial morbidity and mortality. Data from larger multicenter studies is needed to better define the epidemiology of NTM in thoracic transplantation, best treatment options, and the management of infected transplant candidates.

Contribution of Regulatory T Cells in Nucleotide-Binding Oligomerization Domain 2 Response to Influenza Virus Infection.

PubMed

Egarnes, Benoit; Gosselin, Jean

2018-01-01

Influenza A virus (IAV) is recognized to cause severe pulmonary illnesses in humans, particularly in elderly and children. One of the features associated with IAV infection is an excessive lung inflammation due to an uncontrolled immune response. The nucleotide-binding oligomerization domain 2 (NOD2) receptor is known to recognize ssRNA viruses such as IAV, but its role in the inflammatory process during viral infections remains to be clarified. In a previous report, we have shown that activation of NOD2 with muramyl dipeptide (MDP) significantly reduces both viral loads and lung inflammation and also improves pulmonary function during IAV infection. These findings prompted us to further investigate whether NOD2 receptor may contribute to regulate inflammation during viral infection. In the present study, we show that administration of MDP to mice infected with IAV stimulates the migration of regulatory T (Treg) cells to the lungs. Such a presence of Treg cells was also accompanied with a reduction of neutrophils in the lungs during IAV infection, which correlated, with a significant decrease of Th17 cells. In our model, Treg cell recruitment is dependent of CXCL12 and CCL5 chemokines. Moreover, we show that the presence of Ly6C low patrolling monocytes is required for Treg cells mobilization to the lung of mice treated with MDP. In fact, following monocyte depletion by administration of clodronate liposome, mobilization of Treg cells to the lungs of treated mice was found to occur when circulating Ly6C low monocytes begin to reemerge. In addition, we also detected an increased production of TGF-β, a cytokine contributing to Treg activity when blood Ly6C low monocytes are restored. Together, our results demonstrate that MDP treatment can promote an anti-inflammatory environment through the mobilization of Treg cells to the lung, a mechanism that requires the presence of Ly6C low monocytes during IAV infection. Overall, our results suggest that activation of NOD2

Neutropenia associated with osteomyelitis due to Hepatozoon canis infection in a dog.

PubMed

Shimokawa Miyama, Takako; Umeki, Saori; Baba, Kenji; Sada, Kumiko; Hiraoka, Hiroko; Endo, Yasuyuki; Inokuma, Hisashi; Hisasue, Masaharu; Okuda, Masaru; Mizuno, Takuya

2011-10-01

A 4-year-old, intact male Shiba dog was referred to Yamaguchi University Animal Medical Center, Yamaguchi, Japan, for the following complaints: anorexia, lethargy, intermittent fever, gingival bleeding and abdominal purpura. The dog presented with persistent neutropenia. Histopathological examination of a bone marrow sample revealed round to oval structures that resembled Hepatozoon micromerozoites and formed a "wheel-spoke" pattern. Furthermore, mature neutrophils were observed around these structures. PCR and sequencing using bone marrow aspirate confirmed Hepatozoon canis (H. canis) infection. These findings suggest that the neutropenia observed in this case was associated with osteomyelitis due to H. canis infection. This is the first report of neutropenia associated with H. canis infection. H. canis infection can be included in the differential diagnosis in canine cases of neutropenia in areas where the disease is endemic.

Neutrophils are important in early control of lung infection by Yersinia pestis.

PubMed

Laws, Thomas R; Davey, Martin S; Titball, Richard W; Lukaszewski, Roman

2010-04-01

In this paper we evaluate the role of neutrophils in pneumonic plague. Splenic neutrophils from naïve BALB/c mice were found to reduce numbers of culturable Yersinia pestis strain GB in suspension. A murine, BALB/c, intranasal model of pneumonic plague was used in conjunction with in vivo neutrophil ablation, using the GR-1 antibody. This treatment reduced neutrophil numbers without affecting other leukocyte numbers. Neutrophil ablated mice exhibited increased bacterial colonisation of the lung 24h post infection. Furthermore, exposure of Y. pestis to human neutrophils resulted in a 5-fold reduction in the number of viable bacterial cells, whereas, PBMCs had no effect. Crown Copyright 2010. Published by Elsevier SAS. All rights reserved.

Intervertebral infection due to Candida albicans in an intravenous heroin abuser.

PubMed Central

Rowe, I F; Wright, E D; Higgens, C S; Burnie, J P

1988-01-01

A 25 year old woman who had received intravenous heroin over one year previously developed an intervertebral abscess due to infection with Candida albicans. Immunological investigation of this patient showed no evidence of a specific defect in the host response to candida. Images PMID:3382272

Influenza A virus infection and cigarette smoke impair bronchodilator responsiveness to β-adrenoceptor agonists in mouse lung.

PubMed

Donovan, Chantal; Seow, Huei Jiunn; Bourke, Jane E; Vlahos, Ross

2016-05-01

β2-adrenoceptor agonists are the mainstay therapy for patients with asthma but their effectiveness in cigarette smoke (CS)-induced lung disease such as chronic obstructive pulmonary disease (COPD) is limited. In addition, bronchodilator efficacy of β2-adrenoceptor agonists is decreased during acute exacerbations of COPD (AECOPD), caused by respiratory viruses including influenza A. Therefore, the aim of the present study was to assess the effects of the β2-adrenoceptor agonist salbutamol (SALB) on small airway reactivity using mouse precision cut lung slices (PCLS) prepared from CS-exposed mice and from CS-exposed mice treated with influenza A virus (Mem71, H3N1). CS exposure alone reduced SALB potency and efficacy associated with decreased β2-adrenoceptor mRNA expression, and increased tumour necrosis factor α (TNFα) and interleukin-1β (IL-1β) expression. This impaired relaxation was restored by day 12 in the absence of further CS exposure. In PCLS prepared after Mem71 infection alone, responses to SALB were transient and were not well maintained. CS exposure prior to Mem71 infection almost completely abolished relaxation, although β2-adrenoceptor and TNFα and IL-1β expression were unaltered. The present study has shown decreased sensitivity to SALB after CS or a combination of CS and Mem71 occurs by different mechanisms. In addition, the PCLS technique and our models of CS and influenza infection provide a novel setting for assessment of alternative bronchodilators. © 2016 The Author(s).

[Infections after bite wounds : For example rat bite fever due to Streptobacillus moniliformis].

PubMed

Hof, Herbert; Binder, Rudolf; Schäfer, Christian; Stuber, Madeleine; Licht, Andreas; Bozenhardt-Stavrakidis, Iris; Bode, Konrad

2018-04-11

Rat bite fever due to Streptobacillus moniliformis induces typical but not pathognomonic clinical signs, such as local purulent wound infection followed by maculopapular exanthema, myalgia as well as purulent joint infections. Severe complications, such as osteomyelitis and endocarditis are possible. it seems that this infection is rarely diagnosed but this infection could be much more common because the final diagnostic proof is difficult to achieve. Firstly, the culture of these bacteria is critical because the bacteria are fastidious and secondly the exact differentiation of the isolates is hardly possible by standard laboratory methods. Modern techniques such as mass spectroscopy (MALDI-TOF) and molecular biology allow a precise clarification. Surgical cleansing of infection sites in combination with a rational antibiotic therapy, for example with beta-lactam antibiotics, are generally able to cure the infection if treatment is started early enough. In addition, vaccinations, for example against tetanus and rabies have to be considered in this situation as for all other bite wound infections.

Mortality and pathology in birds due to Plasmodium (Giovannolaia) homocircumflexum infection, with emphasis on the exoerythrocytic development of avian malaria parasites.

PubMed

Ilgūnas, Mikas; Bukauskaitė, Dovilė; Palinauskas, Vaidas; Iezhova, Tatjana A; Dinhopl, Nora; Nedorost, Nora; Weissenbacher-Lang, Christiane; Weissenböck, Herbert; Valkiūnas, Gediminas

2016-05-04

Species of avian malaria parasites (Plasmodium) are widespread, but their virulence has been insufficiently investigated, particularly in wild birds. During avian malaria, several cycles of tissue merogony occur, and many Plasmodium spp. produce secondary exoerythrocytic meronts (phanerozoites), which are induced by merozoites developing in erythrocytic meronts. Phanerozoites markedly damage organs, but remain insufficiently investigated in the majority of described Plasmodium spp. Avian malaria parasite Plasmodium (Giovannolaia) homocircumflexum (lineage pCOLL4) is virulent and produces phanerozoites in domestic canaries Serinus canaria, but its pathogenicity in wild birds remains unknown. The aim of this study was to investigate the pathology caused by this infection in species of common European birds. One individual of Eurasian siskin Carduelis spinus, common crossbill Loxia curvirostra and common starling Sturnus vulgaris were exposed to P. homocircumflexum infection by intramuscular sub-inoculation of infected blood. The birds were maintained in captivity and parasitaemia was monitored until their death due to malaria. Brain, heart, lungs, liver, spleen, kidney, and a piece of breast muscle were examined using histology and chromogenic in situ hybridization (ISH) methods. All exposed birds developed malaria infection, survived the peak of parasitaemia, but suddenly died between 30 and 38 days post exposure when parasitaemia markedly decreased. Numerous phanerozoites were visible in histological sections of all organs and were particularly easily visualized after ISH processing. Blockage of brain capillaries with phanerozoites may have led to cerebral ischaemia, causing cerebral paralysis and is most likely the main reason of sudden death of all infected individuals. Inflammatory response was not visible around the brain, heart and muscle phanerozoites, and it was mild in parenchymal organs. The endothelial damage likely causes dysfunction and failure of

The economic burden of lung cancer and mesothelioma due to occupational and para-occupational asbestos exposure.

PubMed

Tompa, Emile; Kalcevich, Christina; McLeod, Chris; Lebeau, Martin; Song, Chaojie; McLeod, Kim; Kim, Joanne; Demers, Paul A

2017-11-01

To estimate the economic burden of lung cancer and mesothelioma due to occupational and para-occupational asbestos exposure in Canada. We estimate the lifetime cost of newly diagnosed lung cancer and mesothelioma cases associated with occupational and para-occupational asbestos exposure for calendar year 2011 based on the societal perspective. The key cost components considered are healthcare costs, productivity and output costs, and quality of life costs. There were 427 cases of newly diagnosed mesothelioma cases and 1904 lung cancer cases attributable to asbestos exposure in 2011 for a total of 2331 cases. Our estimate of the economic burden is $C831 million in direct and indirect costs for newly identified cases of mesothelioma and lung cancer and $C1.5 billion in quality of life costs based on a value of $C100 000 per quality-adjusted life year. This amounts to $C356 429 and $C652 369 per case, respectively. The economic burden of lung cancer and mesothelioma associated with occupational and para-occupational asbestos exposure is substantial. The estimate identified is for 2331 newly diagnosed, occupational and para-occupational exposure cases in 2011, so it is only a portion of the burden of existing cases in that year. Our findings provide important information for policy decision makers for priority setting, in particular the merits of banning the mining of asbestos and use of products containing asbestos in countries where they are still allowed and also the merits of asbestos removal in older buildings with asbestos insulation. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

[Hospital infection due to Serratia marcescens and its sensitivity to antibiotics].

PubMed

Filloy, L; Serrano, D; Borjas, E

1980-01-01

A total of 164 isolations of Serratia marcescens achieved during 1978-1979 at the Hospital Infantil de México in children with various pathology due to this bacteria were studied. Most of the cases were debilitated patients from the newborns and prematures wards and contagious and surgery departments. The most frequent isolations were from wounds and abscesses (76 cases), the same as from meningitis (22 cases) and sepsis (12 patients). Serratia marcescens showed a high degree of resistance (87-100%) to the following antibiotics: carbenicillin, colimycin, chloramphenicol, phosphomicin, ampicillin and cephalothin. To gestamicin and kanamycin, 42% of strains were sensitive. Amikacin was the most effective drug with 92% of strains susceptible to it. The history of this bacteria, its mode of transmission, frequency of infections and resistance to antibiotics found in foreign institutions are commented. Likewise, the difficulty for the precision bacteriologic diagnosis is emphasized as the possible main cause for the ignorance in Mexico of infections due to this bacteria.

Assessment of morbidity due to Schistosoma japonicum infection in China

PubMed Central

2014-01-01

This paper presents a historical assessment of morbidity due to the Schistosoma japonicum infection in China. Due to the socio-economic situation, which did not allow for a control program to be implemented until the early 1950s, morbidity was serious and mortality was high before this. Based on a few investigations and published papers, it can be said that the disease caused millions of deaths, and destroyed numerous families and villages. Since the 1950s, there has been a national control program, intensive control and prevention work has been carried out, and consequently the disease is being controlled. At present, both the prevalence and the morbidity of the disease have been decreasing substantially. The morbidity of the three phases of the disease is outlined in this paper. Comparatively higher morbidity is seen in the acute and advanced phases of the disease. The four major forms of advanced schistosomiasis i.e., ascites, megalosplenia, dwarfism, and colonic tumoroid proliferation, are outlined with their characteristic clinical presentations; their proportions are different during various periods of the national control program. Ectopic schistosomiasis and the relationship between the S. japonicum infection and colorectal cancer are also discussed. Post-transmission schistosomiasis is briefly discussed (which can happen even if the disease reaches the criteria of elimination, and the infection and transmission have stopped, but yet it still develops). The problem of mammalian reservoir hosts of S. japonicum makes the epidemiology and control of schistosomiasis in China even more complicated and arduous, and the control progress in animal reservoirs is briefly presented. PMID:24529186

Integrated Lung and Tracheal mRNA-Seq and miRNA-Seq Analysis of Dogs with an Avian-Like H5N1 Canine Influenza Virus Infection

PubMed Central

Fu, Cheng; Luo, Jie; Ye, Shaotang; Yuan, Ziguo; Li, Shoujun

2018-01-01

Avian-like H5N1 canine influenza virus (CIV) causes severe respiratory infections in dogs. However, the mechanism underlying H5N1 CIV infection in dogs is unknown. The present study aimed to identify differentially expressed miRNAs and mRNAs in the lungs and trachea in H5N1 CIV-infected dogs through a next-generation sequencing-based method. Eighteen 40-day-old beagles were inoculated intranasally with CIV, A/canine/01/Guangdong/2013 (H5N1) at a tissue culture infectious dose 50 (TCID50) of 106, and lung and tracheal tissues were harvested at 3 and 7 d post-inoculation. The tissues were processed for miRNA and mRNA analysis. By means of miRNA-gene expression integrative negative analysis, we found miRNA–mRNA pairs. Lung and trachea tissues showed 138 and 135 negative miRNA–mRNA pairs, respectively. One hundred and twenty negative miRNA–mRNA pairs were found between the different tissues. In particular, pathways including the influenza A pathway, chemokine signaling pathways, and the PI3K-Akt signaling pathway were significantly enriched in all groups in responses to virus infection. Furthermore, dysregulation of miRNA and mRNA expression was observed in the respiratory tract of H5N1 CIV-infected dogs and notably, TLR4 (miR-146), NF-κB (miR-34c) and CCL5 (miR-335), CCL10 (miR-8908-5p), and GNGT2 (miR-122) were found to play important roles in regulating pathways that resist virus infection. To our knowledge, the present study is the first to analyze miRNA and mRNA expression in H5N1 CIV-infected dogs; furthermore, the present findings provide insights into the molecular mechanisms underlying influenza virus infection. PMID:29556219

Asymptomatic bacteriuria, bacteremia, and other infections due to NSU corynebacteria.

PubMed

Furness, G; Kaminski, Z

1975-11-01

By means of the new medium, nonspecific urethritis (NSU) chocolate agar, NSU corymebacteria were isolated from patients with asymptomatic bacteriuria, bacteremia, cervicitis, conjuctivitis, and pericarditis, and also with bone marrow, wound, and cul-de-sac infections. The NSU corynebacteria were considered the etiologic agents. On the basis of biochemical reactions, antibiotic sensitivity, and complement fixation tests some isolates were the same microorganisms. Both patients with conjunctivitis were infected with the same NSU corynebacteria. A second isolate was cultured from patients with osteomyelitis and cervicitis, while a third was recovered from an infected leg wound and from a patient with pericarditis. Seven of the isolates, when injected into rabbits hypersensitive to four NSU corynebacteria isolated from the inflamed epididymis of patients with epididymitis, elicited delayed hypersensitivity reactions, which indicated that they also were related antigenically. It is suggested that nonspecific urethritis and eididymitis may represent an infection with NSU corynebacteria, or may be an extension of bacteriuria due to these microorganisms, with a delayed hypersensitivity reaction as a possible additional complication. Colony counts on NSU chocolate agar of the bacteria in urines from male and female patients were higher than those obtained on conventional agar media. NSU chocolate agar is superior to other agar media for the isolation of pathogenic and saprophytic bacteria not only from the urogenital tract but also from other foci of infection. It is easily prepared from commercial blood agar plates and its use should be considered when a selective medium is not required.

In Vivo Pharmacodynamic Target Assessment of Delafloxacin against Staphylococcus aureus, Streptococcus pneumoniae, and Klebsiella pneumoniae in a Murine Lung Infection Model

PubMed Central

Lepak, Alexander J.

2016-01-01

Delafloxacin is a broad-spectrum anionic fluoroquinolone under development for the treatment of bacterial pneumonia. The goal of the study was to determine the pharmacokinetic/pharmacodynamic (PK/PD) targets in the murine lung infection model for Staphylococcus aureus, Streptococcus pneumoniae, and Klebsiella pneumoniae. Four isolates of each species were utilized for in vivo studies: for S. aureus, one methicillin-susceptible and three methicillin-resistant isolates; S. pneumoniae, two penicillin-susceptible and two penicillin-resistant isolates; K. pneumoniae, one wild-type and three extended-spectrum beta-lactamase-producing isolates. MICs were determined using CLSI methods. A neutropenic murine lung infection model was utilized for all treatment studies, and drug dosing was by the subcutaneous route. Single-dose plasma pharmacokinetics was determined in the mouse model after administration of 2.5, 10, 40, and 160 mg/kg. For in vivo studies, 4-fold-increasing doses of delafloxacin (range, 0.03 to 160 mg/kg) were administered every 6 h (q6h) to infected mice. Treatment outcome was measured by determining organism burden in the lung (CFU counts) at the end of each experiment (24 h). The Hill equation for maximum effect (Emax) was used to model the dose-response data. The magnitude of the PK/PD index, the area under the concentration-time curve over 24 h in the steady state divided by the MIC (AUC/MIC), associated with net stasis and 1-log kill endpoints was determined in the lung model for all isolates. MICs ranged from 0.004 to 1 mg/liter. Single-dose PK parameter ranges include the following: for maximum concentration of drug in serum (Cmax), 2 to 70.7 mg/liter; AUC from 0 h to infinity (AUC0–∞), 2.8 to 152 mg · h/liter; half-life (t1/2), 0.7 to 1 h. At the start of therapy mice had 6.3 ± 0.09 log10 CFU/lung. In control mice the organism burden increased 2.1 ± 0.44 log10 CFU/lung over the study period. There was a relatively steep dose

Co-infection of Influenza B and Streptococci causing severe pneumonia and septic shock in healthy women

PubMed Central

2010-01-01

Background Since the Influenza A pandemic in 1819, the association between the influenza virus and Streptococcus pneumoniae has been well described in literature. While a leading role has been so far attributed solely to Influenza A as the primary infective pathogen, Influenza B is generally considered to be less pathogenic with little impact on morbidity and mortality of otherwise healthy adults. This report documents the severe synergistic pathogenesis of Influenza B infection and bacterial pneumonia in previously healthy persons not belonging to a special risk population and outlines therapeutic options in this clinical setting. Case Presentation During the seasonal influenza epidemic 2007/2008, three previously healthy women presented to our hospital with influenza-like symptoms and rapid clinical deterioration. Subsequent septic shock due to severe bilateral pneumonia necessitated intensive resuscitative measures including the use of an interventional lung assist device. Microbiological analysis identified severe dual infections of Influenza B with Streptococcus pyogenes in two cases and Streptococcus pneumoniae in one case. The patients presented with no evidence of underlying disease or other known risk factors for dual infection such as age (< one year, > 65 years), pregnancy or comorbidity. Conclusions Influenza B infection can pose a risk for severe secondary infection in previously healthy persons. As patients admitted to hospital due to severe pneumonia are rarely tested for Influenza B, the incidence of admission due to this virus might be greatly underestimated, therefore, a more aggressive search for influenza virus and empirical treatment might be warranted. While the use of an interventional lung assist device offers a potential treatment strategy for refractory respiratory acidosis in addition to protective lung ventilation, the combined empiric use of a neuraminidase-inhibitor and antibiotics in septic patients with pulmonary manifestations

The Lung Immune Response to Nontypeable Haemophilus influenzae (Lung Immunity to NTHi)

PubMed Central

King, Paul T.; Sharma, Roleen

2015-01-01

Haemophilus influenzae is divided into typeable or nontypeable strains based on the presence or absence of a polysaccharide capsule. The typeable strains (such as type b) are an important cause of systemic infection, whilst the nontypeable strains (designated as NTHi) are predominantly respiratory mucosal pathogens. NTHi is present as part of the normal microbiome in the nasopharynx, from where it may spread down to the lower respiratory tract. In this context it is no longer a commensal and becomes an important respiratory pathogen associated with a range of common conditions including bronchitis, bronchiectasis, pneumonia, and particularly chronic obstructive pulmonary disease. NTHi induces a strong inflammatory response in the respiratory tract with activation of immune responses, which often fail to clear the bacteria from the lung. This results in recurrent/persistent infection and chronic inflammation with consequent lung pathology. This review will summarise the current literature about the lung immune response to nontypeable Haemophilus influenzae, a topic that has important implications for patient management. PMID:26114124

Differential Expression of Alpha 4 Integrins on Effector Memory T Helper Cells during Bordetella Infections. Delayed Responses in Bordetella pertussis

PubMed Central

Ferguson, Ryan; Tarlton, Nicole; Wu, Victoria; Sequeira, Christopher S.; Bremer, Martina; Abramson, Tzvia

2012-01-01

Bordetella pertussis (B. pertussis) is the causative agent of whooping cough, a respiratory disease that is reemerging worldwide. Mechanisms of selective lymphocyte trafficking to the airways are likely to be critical in the immune response to this pathogen. We compared murine infection by B. pertussis, B. parapertussis, and a pertussis toxin-deleted B. pertussis mutant (BpΔPTX) to test the hypothesis that effector memory T-helper cells (emTh) display an altered pattern of trafficking receptor expression in B. pertussis infection due to a defect in imprinting. Increased cell recruitment to the lungs at 5 days post infection (p.i.) with B. parapertussis, and to a lesser extent with BpΔPTX, coincided with an increased frequency of circulating emTh cells expressing the mucosal-associated trafficking receptors α4β7 and α4β1 while a reduced population of these cells was observed in B. pertussis infection. These cells were highly evident in the blood and lungs in B. pertussis infection only at 25 days p.i. when B. parapertussis and BpΔPTX infections were resolved. Although at 5 days p.i., an equally high percentage of lung dendritic cells (DCs) from all infections expressed maturation markers, this expression persisted only in B. pertussis infection at 25 days p.i. Furthermore, at 5 days p.i with B. pertussis, lung DCs migration to draining lymph nodes may be compromised as evidenced by decreased frequency of CCR7+ DCs, inhibited CCR7-mediated in vitro migration, and fewer DCs in lung draining lymph nodes. Lastly, a reduced frequency of allogeneic CD4+ cells expressing α4β1 was detected following co-culture with lung DCs from B. pertussis-infected mice, suggesting a defect in DC imprinting in comparison to the other infection groups. The findings in this study suggest that B. pertussis may interfere with imprinting of lung-associated trafficking receptors on T lymphocytes leading to extended survival in the host and a prolonged course of disease. PMID:23300813

Signal Transducer and Activator of Transcription Factor 6 Signaling Contributes to Control Host Lung Pathology but Favors Susceptibility against Toxocara canis Infection

PubMed Central

Faz-López, Berenice; Ledesma-Soto, Yadira; Romero-Sánchez, Yolanda; Calleja, Elsa; Martínez-Labat, Pablo; Terrazas, Luis I.

2013-01-01

Using STAT6−/− BALB/c mice, we have analyzed the role of STAT6-induced Th2 response in determining the outcome of experimental toxocariasis caused by embryonated eggs of the helminth parasite Toxocara canis. Following T. canis infection wild-type BALB/c mice developed a strong Th2-like response, produced high levels of IgG1, IgE, and IL-4, recruited alternatively activated macrophages, and displayed a moderate pathology in the lungs; however, they harbored heavy parasite loads in different tissues. In contrast, similarly infected STAT6−/− BALB/c mice mounted a weak Th2-like response, did not recruit alternatively activated macrophages, displayed a severe pathology in the lungs, but efficiently controlled T. canis infection. These findings demonstrate that Th2-like response induced via STAT6-mediated signaling pathway mediates susceptibility to larval stage of T. canis. Furthermore, they also indicate that unlike most gastrointestinal helminths, immunity against larvae of T. canis is not mediated by a Th2-dominant response. PMID:23509764

Toxoplasmosis complicating lung cancer: a case report.

PubMed

Lu, Nianhong; Liu, Caihong; Wang, Jiangyuan; Ding, Ying; Ai, Qing

2015-01-01

Toxoplasmosis complicating lung cancer has been described only rarely. Here, we report a case of acute Toxoplasma gondii infection in a patient with squamous lung cancer. A 64-year-old woman was admitted to our hospital with a history of cough of 6 months' duration and chest pain of 1 week's duration. Further examination revealed multiple swollen lymph nodes, palpable on the top of the right collarbone and without tenderness. The chest X-ray, bronchoscopy, and computed tomography scan confirmed squamous carcinoma of the right lung. The Wright-stained bronchoalveolar-lavage fluid cytology diagnosis was positive for T. gondii and tachyzoites were detected. All of them were of free type (ectocytic), without intracellular parasites. Serological examination revealed that the anti-T. gondii immunoglobulin (Ig) M and IgG antibodies were positive. Unfortunately the patient did not continue treatment and was lost to follow-up. Toxoplasmosis is a life-threatening opportunistic infection in patients with lung cancer. Prompt recognition of T. gondii infection among cancer patients with subsequent targeted treatment of toxoplasmosis could help alleviate symptoms and improve survival.

Recombinant Human Respiratory Syncytial Virus (RSV) Monoclonal Antibody Fab is Effective Therapeutically when Introduced Directly into the Lungs of RSV-Infected Mice

NASA Astrophysics Data System (ADS)

Crowe, James E., Jr.; Murphy, Brian R.; Chanock, Robert M.; Williamson, R. Anthony; Barbas, Carlos F., III; Burton, Dennis R.

1994-02-01

Previously, recombinant human respiratory syncytial virus (RSV) monoclonal antibody Fabs were generated by antigen selection from random combinatorial libraries displayed at the tip of filamentous phage. Two such Fabs, which exhibited high binding affinity for RSV F glycoprotein (a major protective antigen), were evaluated for therapeutic efficacy in infected mice just before or at the time of peak virus replication in the lungs. Fab 19, which neutralized RSV infectivity with high efficiency in tissue culture, was effective therapeutically when delivered directly into the lungs by intranasal instillation under anesthesia. In contrast, RSV Fab 126, which failed to neutralize virus in cell culture, did not exhibit a therapeutic effect under these conditions. The amount of Fab 19 required to effect a 5000- to 12,000-fold reduction in titer of RSV in the lungs within 24 hr was rather small. In four separate experiments, a single instillation of 12.9-50 μg of RSV Fab 19 was sufficient to achieve such a reduction in pulmonary virus in a 25g mouse. The use of Fabs instead of the whole immunoglobulin molecules from which they are derived reduced the protein content of a therapeutic dose. This is important because the protein load that can be delivered effectively into the lungs is limited. The therapeutic effect of a single treatment with Fab 19 was not sustained, so that a rebound in pulmonary virus titer occurred on the 2nd day after treatment. This rebound in pulmonary RSV titer could be prevented by treating infected mice with a single dose of Fab 19 daily for 3 days. These observations suggest that human monoclonal Fabs grown in Escherichia coli may prove useful in the treatment of serious RSV disease as well as diseases caused by other viruses where replication in vivo is limited primarily to the lumenal lining of the respiratory tract.

The characteristics and impact of source of infection on sepsis-related ICU outcomes.

PubMed

Jeganathan, Niranjan; Yau, Stephen; Ahuja, Neha; Otu, Dara; Stein, Brian; Fogg, Louis; Balk, Robert

2017-10-01

Source of infection is an independent predictor of sepsis-related mortality. To date, studies have failed to evaluate differences in septic patients based on the source of infection. Retrospective study of all patients with sepsis admitted to the ICU of a university hospital within a 12month time period. Sepsis due to intravascular device and multiple sources had the highest number of positive blood cultures and microbiology whereas lung and abdominal sepsis had the least. The observed hospital mortality was highest for sepsis due to multiple sources and unknown cause, and was lowest when due to abdominal, genitourinary (GU) or skin/soft tissue. Patients with sepsis due to lungs, unknown and multiple sources had the highest rates of multi-organ failure, whereas those with sepsis due to GU and skin/soft tissue had the lowest rates. Those with multisource sepsis had a significantly higher median ICU length of stay and hospital cost. There are significant differences in patient characteristics, microbiology positivity, organs affected, mortality, length of stay and cost based on the source of sepsis. These differences should be considered in future studies to be able to deliver personalized care. Copyright © 2017 Elsevier Inc. All rights reserved.

Budesonide Inhibits Intracellular Infection with Non-Typeable Haemophilus influenzae Despite Its Anti-Inflammatory Effects in Respiratory Cells and Human Lung Tissue: A Role for p38 MAP Kinase.

PubMed

Wagner, Christopher; Goldmann, Torsten; Rohmann, Kristina; Rupp, Jan; Marwitz, Sebastian; Rotta Detto Loria, Johannes; Limmer, Stefan; Zabel, Peter; Dalhoff, Klaus; Drömann, Daniel

2015-01-01

Inhaled corticosteroids (ICS) are widely used in the treatment of obstructive lung diseases. Recent data suggest a higher pneumonia risk in chronic obstructive pulmonary disease (COPD) patients treated with ICS. Since non-typeable Haemophilus influenzae (NTHi) is the most common pathogen associated with acute exacerbations of COPD, we investigated the effects of budesonide (BUD) on NTHi-induced inflammation and invasive infection. The alveolar epithelial cell line A549 and specimens of human lung tissue (HLT) were used in our experiments. Intracellular infection was determined by a lysis/culture assay of infected cells. Activated p38 mitogen-associated protein kinase (MAPK) was assessed using Western blotting and immunohistochemistry, expression of toll-like receptor 2 (TLR2) was determined by PCR, and CXCL-8 levels were measured using ELISA. Immunohistochemistry was used for detection of CXCL-8, platelet-activating factor receptor (PAF-R) and NTHi. BUD significantly reduced CXCL-8 secretion in A549 cells and lung tissue infected with NTHi. Furthermore, BUD decreased the expression of PAF-R in HLT and A549 cells. In A549 cells and HLT, BUD inhibited intracellular infection and - synergistically with NTHi - increased the expression of TLR2 (in A549 cells). TLR2 stimulation did not influence the intracellular infection of A549 cells, but p38 MAPK inhibition resulted in a significant reduction of infection. The present study adds new insights into the effects of glucocorticoids on pulmonary host defence after NTHi infection. Although the inflammatory response to infection is suppressed by BUD, interestingly, the intracellular infection is also inhibited. This effect seems to depend on the inhibition of p38 MAPK - a key enzyme in many pro-inflammatory pathways - as well as of PAF-R expression. © 2015 S. Karger AG, Basel.

Infectious pulmonary complications in lung transplant recipients.

PubMed

Chan, Kevin M; Allen, Samuel A

2002-12-01

Pulmonary infections are the most common cause of morbidity in the lung transplant population. Prompt recognition and treatment is necessary to prevent poor outcomes. An understanding of the temporal relationship between immunosuppression and the risk for developing infection can assist the clinician with appropriate treatment. Bacterial pneumonia is common within the first 4 months after transplantation whereas cytomegalovirus (CMV) infection or disease becomes prevalent after the discontinuation of prophylaxis in at-risk patients. Fungal infections, especially aspergillosis, can be fatal if not treated early and the risk for infection is present throughout the transplant period. Community-acquired viral infections present with upper-respiratory symptoms and wheezing that may lead to a chronic decline in lung function. Suspicion of a pulmonary infection in these immunosuppressed individuals should lead to an urgent diagnostic bronchoscopy and empiric antimicrobial therapy. Copyright 2002, Elsevier Science (USA). All rights reserved.

Lung transplantation

PubMed Central

Afonso, José Eduardo; Werebe, Eduardo de Campos; Carraro, Rafael Medeiros; Teixeira, Ricardo Henrique de Oliveira Braga; Fernandes, Lucas Matos; Abdalla, Luis Gustavo; Samano, Marcos Naoyuki; Pêgo-Fernandes, Paulo Manuel

2015-01-01

ABSTRACT Lung transplantation is a globally accepted treatment for some advanced lung diseases, giving the recipients longer survival and better quality of life. Since the first transplant successfully performed in 1983, more than 40 thousand transplants have been performed worldwide. Of these, about seven hundred were in Brazil. However, survival of the transplant is less than desired, with a high mortality rate related to primary graft dysfunction, infection, and chronic graft dysfunction, particularly in the form of bronchiolitis obliterans syndrome. New technologies have been developed to improve the various stages of lung transplant. To increase the supply of lungs, ex vivo lung reconditioning has been used in some countries, including Brazil. For advanced life support in the perioperative period, extracorporeal membrane oxygenation and hemodynamic support equipment have been used as a bridge to transplant in critically ill patients on the waiting list, and to keep patients alive until resolution of the primary dysfunction after graft transplant. There are patients requiring lung transplant in Brazil who do not even come to the point of being referred to a transplant center because there are only seven such centers active in the country. It is urgent to create new centers capable of performing lung transplantation to provide patients with some advanced forms of lung disease a chance to live longer and with better quality of life. PMID:26154550

Effect of Advanced HIV Infection on the Respiratory Microbiome.

PubMed

Twigg, Homer L; Knox, Kenneth S; Zhou, Jin; Crothers, Kristina A; Nelson, David E; Toh, Evelyn; Day, Richard B; Lin, Huaiying; Gao, Xiang; Dong, Qunfeng; Mi, Deming; Katz, Barry P; Sodergren, Erica; Weinstock, George M

2016-07-15

Previous work found the lung microbiome in healthy subjects infected with HIV was similar to that in uninfected subjects. We hypothesized the lung microbiome from subjects infected with HIV with more advanced disease would differ from that of an uninfected control population. To measure the lung microbiome in an HIV-infected population with advanced disease. 16s RNA gene sequencing was performed on acellular bronchoalveolar lavage (BAL) fluid from 30 subjects infected with HIV with advanced disease (baseline mean CD4 count, 262 cells/mm(3)) before and up to 3 years after starting highly active antiretroviral therapy (HAART) and compared with 22 uninfected control subjects. The lung microbiome in subjects infected with HIV with advanced disease demonstrated decreased alpha diversity (richness and diversity) and greater beta diversity compared with uninfected BAL. Differences improved with HAART, but still persisted up to 3 years after starting therapy. Population dispersion in the group infected with HIV was significantly greater than in the uninfected cohort and declined after treatment. There were differences in the relative abundance of some bacteria between the two groups at baseline and after 1 year of therapy. After 1 year on HAART, HIV BAL contained an increased abundance of Prevotella and Veillonella, bacteria previously associated with lung inflammation. The lung microbiome in subjects infected with HIV with advanced disease is altered compared with an uninfected population both in diversity and bacterial composition. Differences remain up to 3 years after starting HAART. We speculate an altered lung microbiome in HIV infection may contribute to chronic inflammation and lung complications seen in the HAART era.

Inhibiting Bruton's Tyrosine Kinase Rescues Mice from Lethal Influenza Induced Acute Lung Injury.

PubMed

Florence, Jon M; Krupa, Agnieszka; Booshehri, Laela M; Davis, Sandra A; Matthay, Michael A; Kurdowska, Anna K

2018-03-08

Infection with seasonal influenza A virus (IAV) leads to lung inflammation and respiratory failure, a main cause of death in influenza infected patients. Previous experiments in our laboratory indicated that Bruton's tyrosine kinase (Btk) plays a substantial role in regulating inflammation in the respiratory region during acute lung injury (ALI) in mice, therefore we sought to determine if blocking Btk activity had a protective effect in the lung during influenza induced inflammation. A Btk inhibitor (Btk Inh.) Ibrutinib (also known as PCI-32765) was administered intranasally to mice starting 72h after lethal infection with IAV. Our data indicates that treatment with the Btk inhibitor not only reduced weight loss and led to survival, but had a dramatic effect on morphological changes to the lungs of IAV infected mice. Attenuation of lung inflammation indicative of ALI such as alveolar hemorrhage, interstitial thickening, and the presence of alveolar exudate, together with reduced levels of inflammatory mediators TNFα, IL-1β, IL-6, KC, and MCP-1 strongly suggest amelioration of the pathological immune response in the lungs to promote resolution of the infection. Finally, we observed that blocking Btk specifically in the alveolar compartment led to significant attenuation of neutrophil extracellular traps (NET)s released into the lung in vivo, and NET formation in vitro. Our innovative findings suggest that Btk may be a new drug target for influenza induced lung injury, and in general immunomodulatory treatment may be key in treating lung dysfunction driven by excessive inflammation.

Cavitary mass lesion and recurrent pneumothoraces due to Paragonimus kellicotti infection: North American paragonimiasis.

PubMed

Castilla, Elias A; Jessen, Robert; Sheck, David N; Procop, Gary W

2003-08-01

North American paragonimiasis is well described in omnivorous and carnivorous animals on this continent. Humans are rarely infected, largely because of dietary customs, but are at risk for infection if raw or undercooked crayfish are consumed. We describe a patient with a pleuropulmonary infection due to Paragonimus kellicotti that presented as recurrent pneumothoraces and a cavitary lesion. This is the first case of North American paragonimiasis in which the diagnosis was based on the morphology of the eggs present in histologic sections.

Emergence of Persistent Infection due to Heterogeneity

NASA Astrophysics Data System (ADS)

Agrawal, Vidit; Moitra, Promit; Sinha, Sudeshna

2017-02-01

We explore the emergence of persistent infection in a closed region where the disease progression of the individuals is given by the SIRS model, with an individual becoming infected on contact with another infected individual. We investigate the persistence of contagion qualitatively and quantitatively, under increasing heterogeneity in the partitioning of the population into different disease compartments, as well as increasing heterogeneity in the phases of the disease among individuals within a compartment. We observe that when the initial population is uniform, consisting of individuals at the same stage of disease progression, infection arising from a contagious seed does not persist. However when the initial population consists of randomly distributed refractory and susceptible individuals, a single source of infection can lead to sustained infection in the population, as heterogeneity facilitates the de-synchronization of the phases in the disease cycle of the individuals. We also show how the average size of the window of persistence of infection depends on the degree of heterogeneity in the initial composition of the population. In particular, we show that the infection eventually dies out when the entire initial population is susceptible, while even a few susceptibles among an heterogeneous refractory population gives rise to a large persistent infected set.

Knee arthrodesis with modular nail after failed TKA due to infection.

PubMed

Gallusser, Nicolas; Goetti, Patrick; Luyet, Anais; Borens, Olivier

2015-12-01

Knee arthrodesis is an established procedure for limb salvage after failed total knee arthroplasty (TKA) in cases of recurrent infection, soft tissue damage, reduced bone stock or with a deficient extensor mechanism. Walking with an arthrodesis is more efficient and less costly in terms of energy expenditure than above-knee amputation. Surgical options include an arthrodesis nail, external fixator or compression plate. We present our results of knee arthrodesis using the modular Wichita Fusion Nail(®) in patients after infected TKA. Fifteen patients with irretrievably failed TKA, due to infection, who underwent arthrodesis with the Wichita Fusion Nail(®) from 2004 to 2012 were retrospectively reviewed to assess fusion rate, time to fusion, complication rate, including new infections, and ambulatory status. Three patients were lost to follow-up. Mean follow-up was 33 months (6-132 months). At their most recent follow-up, all patients were walking with full weight bearing on a fused arthrodesis. Mean time to union was 9 months (3-29 months). Three patients necessitated a revision arthrodesis to achieve union after a mean of 5 months after the last procedure. Arthrodesis with the Wichita Fusion Nail(®) provides satisfactory results in patients with failure after infected TKA, with 75 % primary union rate and no new or persistent infection at last follow-up visit. Although burdened with a high complication rate, it represents an acceptable option for limb salvage in this particular pathology.

Towards Translational ImmunoPET/MR Imaging of Invasive Pulmonary Aspergillosis: The Humanised Monoclonal Antibody JF5 Detects Aspergillus Lung Infections In Vivo

PubMed Central

Davies, Genna; Rolle, Anna-Maria; Maurer, Andreas; Spycher, Philipp R.; Schillinger, Claudia; Solouk-Saran, Djamschid; Hasenberg, Mike; Weski, Juliane; Fonslet, Jesper; Dubois, Adrien; Boschetti, Frederic; Denat, Franck; Gunzer, Matthias; Eichner, Martin; Ryder, Lauren S; Jensen, Mikael; Schibli, Roger; Pichler, Bernd J.; Wiehr, Stefan; Thornton, Christopher R.

2017-01-01

Invasive pulmonary aspergillosis (IPA) is a life-threatening lung disease of hematological malignancy or bone marrow transplant patients caused by the ubiquitous environmental fungus Aspergillus fumigatus. Current diagnostic tests for the disease lack sensitivity as well as specificity, and culture of the fungus from invasive lung biopsy, considered the gold standard for IPA detection, is slow and often not possible in critically ill patients. In a previous study, we reported the development of a novel non-invasive procedure for IPA diagnosis based on antibody-guided positron emission tomography and magnetic resonance imaging (immunoPET/MRI) using a [64Cu]DOTA-labeled mouse monoclonal antibody (mAb), mJF5, specific to Aspergillus. To enable translation of the tracer to the clinical setting, we report here the development of a humanised version of the antibody (hJF5), and pre-clinical imaging of lung infection using a [64Cu]NODAGA-hJF5 tracer. The humanised antibody tracer shows a significant increase in in vivo biodistribution in A. fumigatus infected lungs compared to its radiolabeled murine counterpart [64Cu]NODAGA-mJF5. Using reverse genetics of the pathogen, we show that the antibody binds to the antigenic determinant β1,5-galactofuranose (Galf) present in a diagnostic mannoprotein antigen released by the pathogen during invasive growth in the lung. The absence of the epitope Galf in mammalian carbohydrates, coupled with the enhanced imaging capabilities of the hJF5 antibody, means that the [64Cu]NODAGA-hJF5 tracer developed here represents an ideal candidate for the diagnosis of IPA and translation to the clinical setting. PMID:28912884

[Lung and heart-lung transplantation in respiratory tract diseases. Evaluation and development of the indications based on our first 15 cases].