HEV superinfection accelerates disease progression in patients with chronic HBV infection and increases mortality in those with cirrhosis.

BACKGROUND & AIMS: Acute HEV infection causes varying degrees of liver damage. Although liver-related death due to HEV infection alone is rare in healthy individuals, it is unclear whether HEV superinfection is associated with worse outcomes in patients with chronic HBV infection. Thus, we explored whether HEV superinfection was associated with increased incidence of liver-related death, cirrhosis, and hepatocellular carcinoma (HCC). METHODS: Serum and data were collected from 2 independent retrospective cohorts of patients with chronic HBV infection, comprising 2,123 patients without cirrhosis and 414 with cirrhosis at baseline, respectively. All the patients were negative for HEV-IgG at enrolment and HEV superinfection was defined by the presence of HEV-IgG seroconversion. RESULTS: In the non-cirrhotic cohort, 46 of 2,123 patients developed HEV superinfection. Though HEV superinfection was only associated with increased incidence of liver-related death in the overall cohort, it was a risk factor for all 3 endpoints (liver-related death, cirrhosis, and HCC) in a subgroup of 723 HBeAg-negative patients with chronic HBV infection. In addition, the 1-year mortality rate after HEV superinfection was higher in 4 patients who developed cirrhosis during the follow-up than in those who did not (50% vs. 2.4%, p = 0.001). To elucidate the perceived relationship between HEV superinfection and risk of mortality, an independent cohort of cirrhotic patients (n = 414) was further analyzed to control for the inherent increase in mortality risk due to cirrhosis. The 10 cirrhotic patients with HEV superinfection had a higher 1-year mortality rate than those without (30% vs. 0%, p <0.001). CONCLUSIONS: In both cohorts of patients with chronic HBV infection, acute HEV superinfection increases the risk of liver-related death, especially in those with cirrhosis. LAY SUMMARY: The mortality caused by acute hepatitis E virus infection is usually low in the healthy population, but it is unclear how it affects patients with chronic hepatitis B virus infection, as they already have compromised liver function. Our data show that the 1-year mortality rate is 35.7% in patients with hepatitis B-related cirrhosis who contract hepatitis E virus. Hepatitis E may accelerate disease progression in patients with chronic hepatitis B.

Survival during influenza-associated bacterial superinfection improves following viral- and bacterial-specific monoclonal antibody treatment.

Postinfluenza bacterial superinfections cause increased morbidity and mortality compared with singular infection with influenza during both pandemics and seasonal epidemics. Vaccines and current treatments provide limited benefit, a rationale to conduct studies utilizing alternative therapies. FY1 and an optimized version, MEDI8852, anti-influenza HA mAbs, have been shown to neutralize influenza virus during singular influenza infection. MEDI4893*, an anti-Staphylococcus aureus α-toxin mAb, has been shown to improve survival when administered prophylactically prior to S. aureus pneumonia. Our objective was to determine if mAbs can improve survival during postinfluenza bacterial pneumonia. We administered FY1 in a murine model of postinfluenza methicillin-resistant S. aureus (MRSA) pneumonia and observed improved survival rates when given early during the course of influenza infection. Our findings indicate decreased lung injury and increased uptake and binding of bacteria by macrophages in the mice that received FY1 earlier in the course of influenza infection, corresponding to decreased bacterial burden. We also observed improved survival when mice were treated with a combination of FY1 and MEDI4893* late during the course of postinfluenza MRSA pneumonia. In conclusion, both FY1 and MEDI4893* prolong survival when used in a murine model of postinfluenza MRSA pneumonia, suggesting pathogen-specific mAbs as a possible therapeutic in the context of bacterial superinfection.

STAT2 Signaling Regulates Macrophage Phenotype During Influenza and Bacterial Super-Infection.

Influenza is a common respiratory virus that infects between 5 and 20% of the US population and results in 30,000 deaths annually. A primary cause of influenza-associated death is secondary bacterial pneumonia. We have previously shown that influenza induces type I interferon (IFN)-mediated inhibition of Type 17 immune responses, resulting in exacerbation of bacterial burden during influenza and Staphylococcus aureus super-infection. In this study, we investigated the role of STAT2 signaling during influenza and influenza-bacterial super-infection in mice. Influenza-infected STAT2-/- mice had increased morbidity, viral burden, and inflammation when compared to wild-type mice. Despite an exaggerated inflammatory response to influenza infection, we found increased bacterial control and survival in STAT2 deficient mice during influenza-MRSA super-infection compared to controls. Further, we found that increased bacterial clearance during influenza-MRSA super-infection is not due to rescue of Type 17 immunity. Absence of STAT2 was associated with increased accumulation of M1, M2 and M1/M2 co-expressing macrophages during influenza-bacterial super-infection. Neutralization of IFNγ (M1) and/or Arginase 1 (M2) impaired bacterial clearance in Stat2-/- mice during super-infection, demonstrating that pulmonary macrophages expressing a mixed M1/M2 phenotype promote bacterial control during influenza-bacterial super-infection. Together, these results suggest that the STAT2 signaling is involved in suppressing macrophage activation and bacterial control during influenza-bacterial super-infection. Further, these studies reveal novel mechanistic insight into the roles of macrophage subpopulations in pulmonary host defense.

Infección por Strongyloides stercoralis: estudio epidemiológico, clínico, diagnóstico y terapéutico en 30 pacientes / Infection due to Strongyloides stercoralis: epidemiological, clinical, diagnosis findings and outcome in 30 patients

Background: Strongyloides stercoralis is a nematode parasite, which is endemic in tropical and subtropical regions. Infection usually remains asymptomatic, but in immunocompromised hosts severe and life-threatening manifestations such as hyperinfection syndrome and disseminated disease might occur. Methods: We retrospectively analyzed the epidemiological and clinical characteristics, including HIV co-infection, microbiological findings, and outcome in 30 patients with strongyloidiasis, who attended in the Infectious Diseases F. J. Muñiz Hospital in Buenos Aires from January 2004 to December 2008. Results: The study included 20 men and 10 women with an average age of 33 years. HIV co-infection was present in 21 patients (70 percent) with a median CD4 T cell count of 50 cells/mm³ (range 7-355) (average 56 cells/mm³). Among HIV negative patients the following comorbidities were detected: tuberculosis (n = 3) and chronic alcoholism, leprosy treated with corticosteroids, immunosuppressive treatment for psoriasis, and diabetes mellitus (each in one patient). Two patients did not have any predisposing diseases or immunosuppressive treatments. Seventeen patients presented with diarrhea and were classified as chronic intestinal strongyloidiasis (57 percent), asymptomatic infection with peripheral eosinophilia was diagnosed in 7 (23 percent), and 6 patients (20 percent) developed hyperinfection syndrome. Seventeen patients (57 percent) presented peripheral eosinophilia. Diagnosis was achieved by direct visualization of larvae in feces by Baermann technique (n = 20), by multiple stool smears examinations (n = 2), by combination of both (n = 1), by visualization of the filariform larvae in duodenal fluid and stool (n = 1), and in fecal and bronchoalveolar lavage specimens (n = 6). Overall mortality in this series was 20 percent (6/30). There was no significant correlation between age and mortality. A significant inverse correlation between the survival rate and CD4 T-cell count as well as eosinophilia was observed. There was also a significant correlation between HIV co-infection and mortality. Twenty-two patients responded favorably to treatment with ivermectin.

Antecedentes: Strongyloides stercoralis, parásito endémico de áreas tropicales y subtropicales del planeta, en sujetos inmunodeprimidos puede cursar con formas graves y aun mortales como el síndrome de hiperinfestación y la enfermedad diseminada. Métodos: Análisis retrospectivo de las características epidemiológicas, manifestaciones clínicas, co-infección por virus de inmunodeficiencia humana (VIH), hallazgos microbiológicos y evolución de 30 pacientes con estrongiloidiasis, atendidos en el Hospital de Enfermedades Infecciosas F. J. Muñiz de Buenos Aires, entre enero 2004 y diciembre 2008. Resultados: Se incluyeron en la evaluación 20 hombres y 10 mujeres con una mediana de edad de 33 años. Co-infección por VIH hubo en 21 pacientes (70 por ciento); la mediana de linfocitos T CD4+ en ellos al momento del diagnóstico de la parasitosis fue de 50 céls/mm³ (rango 7 a 355), (media de 56 céls/mm³). En los pacientes seronegativos para VIH, se comprobaron las siguientes co-morbilidades: tuberculosis (n: 3) y un caso de cada una de las siguientes afecciones: alcoholismo crónico, diabetes mellitus, reacción lepromatosa bajo corticotera-pia, y psoriasis en tratamiento inmunosupresor. Hubo dos pacientes sin aparentes enfermedades de base. Diecisiete pacientes presentaron enfermedad intestinal crónica con diarrea (57 por ciento), era asintomática y fue sospechada por la eosinofilia periférica (n: 7, 23 por ciento) y se clasificó como síndrome de hiperinfestación (n: 6, 20 por ciento) diagnosticado por la identificación de larvas en la materia fecal y secreciones broncopulmonares. Diecisiete pacientes (57 por ciento) presentaron eosinofilia periférica. El diagnóstico se efectuó por la visualización directa de las larvas en muestras de heces en fresco mediante la técnica de concentración de Baer-man (n: 20); por el examen copro-parasitológico seriado (n: 2) y por ambos métodos (n: 1); en líquido duodenal y materia fecal (n: 1) y por la identificación de larvas en materia fecal y secreciones respiratorias (n: 6). Letalidad global: 20 por ciento (6/30). Los pacientes con eosinofilia tuvieron una menor letalidad que aquellos sin esta respuesta (p < 0,001). No hubo correlación estadística entre la edad y la supervivencia. Sí fue significativa la correlación entre el recuento de CD4 y la letalidad, incluyendo 18 de los 21 pacientes seropositivos para VIH (p: 0,03). Finalmente, la correlación seropositividad para VIH y letalidad también fue significativa. Veintidós pacientes respondieron a la terapia antiparasitaria con ivermectina y evolucionaron favorablemente.

Clinical characteristics and therapeutic outcomes of nosocomial super-infection in adult bacterial meningitis.

BACKGROUND: Super-infection in adult bacterial meningitis (ABM) is a condition wherein the cerebrospinal fluid (CSF) grows new pathogen(s) during the therapeutic course of meningitis. It is an uncommon but clinically important condition rarely examined in literature. METHODS: Twenty-seven episodes of super-infection states in 21 ABM patients collected in a 9.5-year study period (January 2001 to June 2010) were evaluated. The clinical characteristics, implicated pathogens, results of antimicrobial susceptibility tests, and therapeutic outcomes were analyzed. RESULTS: Twenty-one patients (13 men, 8 women) aged 25-73 years (median, 45 years) had post-neurosurgical state as the preceding event and nosocomial infection. The post-neurosurgical states included spontaneous intracranial hemorrhage (ICH) with craniectomy or craniotomy with extra-ventricular drainage (EVD) or ventriculo-peritoneal shunt (VPS) in 10 patients, traumatic ICH with craniectomy or craniotomy with EVD or VPS in 6 patients, hydrocephalus s/p VPS in 2 patients, and one patient each with cerebral infarct s/p craniectomy with EVD, meningeal metastasis s/p Omaya implant, and head injury. All 21 patients had EVD and/or VP shunt and/or Omaya implant during the whole course of ABM. Recurrent fever was the most common presentation and the implicated bacterial pathogens were protean, many of which were antibiotic resistant. Most patients required adjustment of antibiotics after the pathogens were identified but even with antimicrobial therapy, 33.3% (7/21) died. Morbidity was also high among survivors. CONCLUSIONS: Super-infection in ABM is usually seen in patients with preceding neurosurgical event, especially insertion of an external drainage device. Repeat CSF culture is mandatory for diagnostic confirmation because most of the implicated bacterial strains are non-susceptible to common antibiotics used. Unusual pathogens like anaerobic bacteria and fungi may also appear. Despite antimicrobial therapy, prognosis remains poor.

A mouse model of lethal synergism between influenza virus and Haemophilus influenzae.

Secondary bacterial infections that follow infection with influenza virus result in considerable morbidity and mortality in young children, the elderly, and immunocompromised individuals and may also significantly increase mortality in normal healthy adults during influenza pandemics. We herein describe a mouse model for investigating the interaction between influenza virus and the bacterium Haemophilus influenzae. Sequential infection with sublethal doses of influenza and H. influenzae resulted in synergy between the two pathogens and caused mortality in immunocompetent adult wild-type mice. Lethality was dependent on the interval between administration of the bacteria and virus, and bacterial growth was prolonged in the lungs of dual-infected mice, although influenza virus titers were unaffected. Dual infection induced severe damage to the airway epithelium and confluent pneumonia, similar to that observed in victims of the 1918 global influenza pandemic. Increased bronchial epithelial cell death was observed as early as 1 day after bacterial inoculation in the dual-infected mice. Studies using knockout mice indicated that lethality occurs via a mechanism that is not dependent on Fas, CCR2, CXCR3, interleukin-6, tumor necrosis factor, or Toll-like receptor-4 and does not require T or B cells. This model suggests that infection with virulent strains of influenza may predispose even immunocompetent individuals to severe illness on secondary infection with H. influenzae by a mechanism that involves innate immunity, but does not require tumor necrosis factor, interleukin-6, or signaling via Toll-like receptor-4.

Similar geographic variations of mortality and hospitalization associated with IBD and Clostridium difficile colitis.

BACKGROUND: Superinfection with Clostridium difficile can aggravate the symptoms of preexisting inflammatory bowel disease (IBD). The study served to assess whether the geographic variation of IBD within the United States might be influenced by C. difficile infection. METHODS: Hospitalization data of the Healthcare Cost and Utilization Project (HCUP) from 2001-2006 and mortality data from 1979-2005 of the US were analyzed by individual states. Hospitalization and mortality associated with Crohn's disease (CD), ulcerative colitis (UC), and C. difficile colitis were correlated with each other, using weighted least square linear regression with the population size of individual states as weight. RESULTS: Among the hospitalization rates, there were strong correlations between both types of IBD, as well as each type of IBD with C. difficile colitis. Similarly, among the mortality rates there were strong correlations between both types of IBD, as well as each type of IBD with C. difficile colitis. Lastly, each type of hospitalization rate was also strongly correlated with each type of mortality rate. In general, hospitalization and mortality associated with IBD tended to be frequent in many of the northern states and infrequent in the Southwest and several southern states. CONCLUSIONS: The similarity in the geographic distribution of the 3 diseases could indicate the influence of C. difficile colitis in shaping the geographic patterns of IBD. It could also indicate that shared environmental risk factors influence the occurrence of IBD, as well as C. difficile colitis.

Basic measures and systemic medical treatment of patients with toxic epidermal necrolysis.

BACKGROUND: With an incidence of 1.5-1.8/1 million inhabitants per year, toxic epidermal necrolysis is a rare but life threatening disease. It is almost always drug-induced and its lethality is pronounced with up to 50 %. Several therapeutic options are described in literature; however, there is still lack of a universally accepted and specific therapy of toxic epidermal necrolysis. METHODS: This survey considers 8 cases of toxic epidermal necrolysis diagnosed and treated in our clinic from 2003 to 2007. The epidermal sloughing was > 30 % of the body surface in each case. RESULTS: After immediately discontinuing the drug suspected of being responsible for toxic epidermal necrolysis, we treated with systemic corticosteroids in an initial dose of up to 1.5 mg/kg. Moreover, special emphasis was put on basic measures such as control of vital parameters. With this treatment we reached good results; none of the patients died. conclusions: Immediate beginning of therapy is essential for a successful treatment of toxic epidermal necrolysis. Besides systemic therapy with corticosteroids, certain basic measures such as isolation of patients at adequate room temperature to prevent hypothermia, strict control of circulation, temperature and laboratory parameters, daily smears of skin and mucous membranes and a diet rich in calories due to the catabolic metabolic status are very important for successful outcome.

Discerning the complexity of community interactions using a Drosophila model of polymicrobial infections.

A number of human infections are characterized by the presence of more than one bacterial species and are defined as polymicrobial diseases. Methods for the analysis of the complex biological interactions in mixed infections with a large number of microorganisms are limited and do not effectively determine the contribution of each bacterial species to the pathogenesis of the polymicrobial community. We have developed a novel Drosophila melanogaster infection model to study microbe-microbe interactions and polymicrobe-host interactions. Using this infection model, we examined the interaction of 40 oropharyngeal isolates with Pseudomonas aeruginosa. We observe three classes of microorganisms, one of which acts synergistically with the principal pathogen, while being avirulent or even beneficial on its own. This synergy involves microbe-microbe interactions that result in the modulation of P. aeruginosa virulence factor gene expression within infected Drosophila. The host innate immune response to these natural-route polymicrobial infections is complex and characterized by additive, suppressive, and synergistic transcriptional activation of antimicrobial peptide genes. The polymicrobial infection model was used to differentiate the bacterial flora in cystic fibrosis (CF) sputum, revealing that a large proportion of the organisms in CF airways has the ability to influence the outcome of an infection when in combination with the principal CF pathogen P. aeruginosa.

Impact of acute hepatitis C virus superinfection in patients with chronic hepatitis B virus infection.

BACKGROUND & AIMS: Superinfection in patients with chronic hepatitis B virus (HBV) infection is not uncommon. Acute hepatitis delta virus (HDV) superinfection is associated with severe and/or progressive liver disease. The natural course following acute hepatitis C virus (HCV) superinfection has not been well studied. The aim of this study was to investigate the impact of acute HCV superinfection. METHODS: The clinical features during acute phase and long-term outcomes of acute HCV superinfection were studied and compared with a cohort of acute HDV superinfection and a matched control group of active chronic hepatitis B. RESULTS: Acute HCV superinfection typically occurs as acute icteric hepatitis. The severity is similar to acute HDV superinfection in that hepatic decompensation developed in 34% of patients, hepatitis failure occurred in 11%, and 10% died. During a follow-up period of 1-21 years, patients with acute HCV superinfection had a significantly higher cumulated incidence of cirrhosis (48% at 10 years) and hepatocellular carcinoma (14% at 10 years, 21% at 15 years, and 32% at 20 years) than acute HDV superinfection or active chronic hepatitis B. Hepatitis B surface antigen (HBsAg) seroclearance occurred earlier in HCV superinfected patients. Continuing hepatitis after HBsAg seroclearance was observed only in HCV superinfected patients. CONCLUSIONS: Acute HCV superinfection in patients with chronic HBV infection is clinically severe during its acute phase. The long-term prognosis following acute HCV superinfection is much worse than that following HDV superinfection or active hepatitis B in terms of continuing hepatitis activity after HBsAg loss and the development of cirrhosis or hepatocellular carcinoma.

[Clinical evaluation of the cause of death in patients with active pulmonary tuberculosis].

We made a clinical analysis of the cause of death of forty deceased patients with active pulmonary tuberculosis who were admitted to Kawasaki Medical School Hospital, Kawasaki Medical School Kawasaki Hospital, and Asahigaoka Hospital during the period from January 1996 to December 2001. The age of 40 deceased patients (29 males/11 females) ranged from 55 to 93 years old, and were mostly bedridden. Underlying diseases existed in all except one case, and they were respiratory diseases in 9 patients and non-respiratory diseases in 34 patients. Laboratory findings revealed poor nutritional conditions. The diagnosis of pulmonary tuberculosis was established within one month from the appearance of symptoms in over half of these patients because most of them were smear positive for Mycobacterium tuberculosis. None of the strains of Mycobacterium tuberculosis isolated from these patients were multidrug resistant for antituberculous drugs and only one strain was completely resistant for Rifampicin. Radiological findings of the tuberculosis were bilateral in 30 patients. Consolidation shadows without cavity were noted in 22 patients, and extension within the unilateral lung field was observed in 24 patients. Regarding the cause of death, advanced pulmonary tuberculosis was the cause in 17 patients and non-tuberculous diseases were the cause in 23 patients. There were 15 patients with bacterial superinfections such as bacterial pneumonia, 4 with malignancy, and 4 with other disease. The number of pulmonary tuberculosis patients in poor general and nutritional condition has been increasing with the aging of the Japanese population. Treatment for pulmonary tuberculosis has been successful in most cases, however, the number of the deaths unrelated to tuberculosis including those due to bacterial superinfection has been increasing. Therefore, treatment should be considered against resistant microoganisms such as MRSA.

Considerations for therapy of mixed infections: focus on intraabdominal infection.

Intraabdominal infections are a wide range of diseases that include penetrating abdominal trauma, appendicitis, peritonitis, and abscess. Most are polymicrobic, involving aerobic and anaerobic bacteria. The primary treatment is surgery, but important issues regarding administration of antimicrobials may affect patient outcome. Evaluation of an antimicrobial regimen must include consideration of outcomes--survival, organ failure, adverse drug effects, and superinfection. Single-agent regimens have demonstrated benefit in patients with acute intraabdominal contamination and established infections. Guidelines for selecting antimicrobial agents are available from the Surgical Infection Society. Regimens are effective when active against most bacteria isolated from the focus of abdominal infection. The patient's clinical response, not culture results independent of clinical findings, is the primary guide for directing changes in therapy.

[Is penicillin G the drug of choice in gas gangrene? Results of a prospective documentation of clinical, microbiological and animal experiment data]. / Ist Penicillin-G das Mittel der Wahl beim Gasödem? Ergebnisse aus prospektiver Dokumentation klinischer, mikrobiologischer und tierexperimenteller Daten.

Between 1978 and 1990 98 patients with gas gangrene were treated in the departments of general surgery and traumatology of the University of Kiel. The microbiological results of tissue samples and results of animal infectious experiments were correlated to the clinical outcome. It could be shown, that gas gangrene due to C.perfringens alone had a higher mortality than gas gangrene due to polymicrobial infection. In trauma patients, however, the rate of amputations was lower in cases of clostridial monoinfections (25%), than in patients with mixed infections (48%). The results of animal experiments with guinea pigs which were infected by patients' infectious material showed a correlation to the clinical outcome. This correlation could not bee shown using isolated and cultured clostridia. Therefore and because of the quantity of mixed infections it is necessary to use broad spectrum antibiotics for treatment in cases of gas gangrene and for perioperative antibiotic prophylaxis. Penicillin-G alone can not more be recommended for this purpose.

Use of ofloxacin in prevention and treatment of secondary infections in hematological malignancies.

We evaluated the effectiveness of ofloxacin (OFX) administered for prophylactic purposes during 77 episodes of neutropenia (less than 500/mm3) in 54 patients with hematological malignancies and to combat infection in 17 patients with both hematological malignancies and secondary infections. The prophylactic effect of OFX was demonstrated by the absence of febrile episodes in 73.3% of patients during the neutropenic phase. Of 16 patients who developed secondary infections, 13 showed good responses with other antibiotics. The overall efficacy rate of OFX in secondary infections was 64.7%. Although 4 patients developed elevated SGOT and SGPT levels and 1 showed an elevated BUN level, OFX was generally well tolerated.

[The incidence of lung infection in patients with mucoviscidosis and the disease course with various pathogen spectra]. / Zur Häufigkeit der Lungeninfektion bei Patienten mit Mukoviszidose und zum Krankheitsverlauf bei unterschiedlichem Erregerspektrum.

A retrospective review on the frequency of lung infections by the most important organisms Staphylococcus aureus and Pseudomonas aeruginosa in patients with cystic fibrosis in the GDR during the period from 1981 to 1985 revealed an average infectious rate of 58.6 per cent by Staphylococcus and of 26.9 per cent by Pseudomonas respectively. A distinct increase of the infections by Pseudomonas could only be documented from 1981 to 1982, later on the infectious rate remained nearly equal and showed only a peak value of 35.6 per cent in 1983. Thus the frequency of infections by Pseudomonas is significantly lower in the GDR than in most other countries. The comparison of the course of the disease in patients with permanent lung infection during 4 or 5 years established a mortality rate of a double amount in the group of patients with Pseudomonas colonisation versus the group with Staphylococcus colonisation. Otherwise no significant difference could be stated in the mean age of the beginning of lung infection (Staphylococcus = 9.7 years of age - Pseudomonas = 10.1 years of age). Analysing the pulmonary x-ray findings we found a significantly more rapid deterioriation during the follow-up period in patients with permanent Pseudomonas infection than in patients with permanent Staphylococcus infection, whereas the evolution of body height and weight did not take different course.