A randomized controlled study of accelerated versus standard hepatitis B vaccination in HIV-positive patients.

BACKGROUND: In human immunodeficiency virus (HIV)-infected patients, the immunogenicity of hepatitis B vaccines is impaired. The primary and secondary aims of our study were to investigate the effectiveness and compliance of 2 different vaccination regimen in an HIV-infected population. METHODS: A noninferiority trial with a 10% response margin was designed. Included were patients ≥ 18 years old, with negative HBsAg/anti-HBc serology, and not previously vaccinated against hepatitis B. Patients were stratified according to CD4(+) cell count: <200, 200-500, >500. Participants received 10 µg HBvaxPRO intramuscularly according to a 0-1-3 week schedule or the standard 0-4-24 week schedule. Anti-HBs levels were measured at week 28, considered protective ≥ 10 IU/L. RESULTS: Modified intention to treat analysis in 761 patients was performed. Overall response difference was 50%(standard arm) versus 38.7% (accelerated arm) =11.3% (95% confidence interval [CI], [4.3, 18.3]), close to the 10% response margin. In CD4(+) cell count group 200-500 cells/mm(3,) the response difference was 20.8% (95% CI [10.9, 30.7]). However, the response difference in CD4(+)cell count group >500 cells/mm(3) was -1.8% (95% CI [-13.4,+9.7]). Compliance was significantly superior with the accelerated schedule, 91.8% versus 82.7% (P ≤ .001). CONCLUSION: In HIV-infected patients, compliance with an accelerated hepatitis B vaccination schedule is significantly better. The efficacy of an accelerated schedule proved to be non-inferior in CD4(+) cell count group >500 cells/mm(3). CLINICAL TRIALS REGISTRATION: CT00230061.

Recombination in hepatitis C virus genotype 1 evaluated by phylogenetic and population-genetic methods.

Although hepatitis C virus (HCV) is a major cause of viral hepatitis and hepatocellular carcinoma, many aspects of its evolution remain poorly understood. Relevant to its evolution and the development of antiviral drug resistance is the role of recombination in HCV, which has not been resolved using phylogenetic tests. In line with previous studies, we found no strong support for a role of recombination in the dominant subtypes 1A and 1B using phylogenetic approaches. In contrast, signatures of gene conversion were abundant if a population recombination model, which takes into account diversity within and between groups, was used (9676 gene conversion signatures between the genomes of subtypes 1A and 1B and 170 between the NS5A regions of subtypes 1A and 1B and the minor subtypes 1c-1g). The gene conversion signatures coincided with a striking lack of diagnostically informative sites between subtypes and a large number of shared mutations between complete subtype 1A and 1B genomes (0.76 and 62.2 % of nucleotide sites, respectively). Maximum-likelihood trees revealed significant topological incongruence among conserved PFAM domains and genome regions targeted by diagnostic assays, which underpins a major role for recombination. The same results were obtained with smaller numbers of genomes and with only synonymous sites. Topological concordance increased only marginally if larger genome regions were compared. The level of recombination in HCV subtype 1, which is probably significantly higher than can currently be measured, also illustrates the complexity of designing diagnostic assays based on the unusual patterns of genomic diversity of HCV.

Viral respiratory tract infections among patients with acute undifferentiated fever in Vietnam.

To investigate the proportion of viral respiratory tract infections among acute undifferentiated fevers (AUFs) at primary health facilities in southern Vietnam during 2001-2005, patients with AUF not caused by malaria were enrolled at twelve primary health facilities and a clinic for malaria control program. Serum was collected on first presentation (t0) and after 3 weeks (t3) for serology. After exclusion of acute dengue infection, acute and convalescent serum samples from 606 patients were using enzyme-linked immunoassays to detect IgA, as well as IgM and IgG antibodies against common respiratory viruses. Paired sera showed the following infections: human parainfluenza virus (HPIV, 4.7%), influenza B virus (FLUBV, 2.2%), influenza A virus (FLUAV, 1.9%) and human respiratory syncytial virus (HRSV, 0.6%). There was no association between type of infection and age, sex or seasonality; some inter-annual differences were observed for influenza. Antibody prevalence, indicative of previous infections, was relatively low: HPV, 56.8%, FLUBV, 12.1%; FLUAV, 5.9% and HRSV, 6.8%.

Response to imported case of Marburg hemorrhagic fever, the Netherland.

On July 10, 2008, Marburg hemorrhagic fever was confirmed in a Dutch patient who had vacationed recently in Uganda. Exposure most likely occurred in the Python Cave (Maramagambo Forest), which harbors bat species that elsewhere in Africa have been found positive for Marburg virus. A multidisciplinary response team was convened to perform a structured risk assessment, perform risk classification of contacts, issue guidelines for follow-up, provide information, and monitor the crisis response. In total, 130 contacts were identified (66 classified as high risk and 64 as low risk) and monitored for 21 days after their last possible exposure. The case raised questions specific to international travel, postexposure prophylaxis for Marburg virus, and laboratory testing of contacts with fever. We present lessons learned and results of the follow-up serosurvey of contacts and focus on factors that prevented overreaction during an event with a high public health impact.

An improved approach to identify epidemiological and phylogenetic transmission pairs of source and contact tracing of hepatitis B.

The transmission of infectious diseases can be traced using epidemiological and molecular information. In the current study, the congruence was assessed between sequence data of the hepatitis B virus (HBV) and epidemiological information resulting from source and contact tracing of patients seen at the Municipal Public Health Service in Rotterdam between 2002 and 2005. HBV genotypes A-G were present in 62 acute and 334 chronic HBV patients. At the sequence level, the identical sequences of members of epidemiological transmission pairs and the rarity of such pairs provided strong support for correctness of the hypothesized transmission routes. The molecular support for epidemiological transmission pairs derived from source and contact tracing was further assessed by using topological constraints in parsimony analyses in agreement with epidemiological information, and by taking the presence of polymorphic sites of HBV within patients into account. This, in principle, allows mutations in epidemiological clusters. Of 22 epidemiological clusters, six could be refuted, four clusters received support from the molecular analysis, and support for the remaining twelve clusters was ambiguous. Two of the four epidemiological pairs that received molecular support had diverged (by 3 and 15 mutations). These results show that levels of divergence cannot be used simply as an indicator of the likelihood that groups of sequences constitute transmission pairs. Instead, to confirm or refute transmission pairs, it is necessary to assess the likelihood of a common origin of HBV variants in epidemiologically defined transmission groups relative to the HBV diversity in the local community.

Incidence of primary dengue virus infections in Southern Vietnamese children and reactivity against other flaviviruses.

OBJECTIVE: To study the incidence of asymptomatic primary dengue infections among children and reactivity against other flaviviruses. METHODS: A total of 216 children, who had no dengue-specific IgG antibodies during a serosurvey in 2003 were re-examined 23 months later to determine if seroconversion had occurred. Dengue-specific IgG was demonstrated with enzyme-linked immunosorbent assay (ELISA) and reactivity patterns against other flaviviruses were assessed by using immunofluorescence assay (IFA). RESULTS: Sixty-six children had seroconverted for dengue virus-specific IgG; the true annual incidence of primary dengue was thus 17.3% (95% CI: 13.8-21.4). Japanese Encephalitis virus (JEV)-specific IgG antibodies were detected by IFA among three (4.6%) samples that showed seroconversion in the dengue ELISA, because of cross-reactivity. CONCLUSION: Our findings highlight the high incidence of dengue among Vietnamese children; JEV infections are rare. The true annual incidence of dengue can be estimated with a single cross-sectional seroprevalence survey.

Cytokine and viral load kinetics in human herpesvirus 8-associated multicentric Castleman's disease complicated by hemophagocytic lymphohistiocytosis.

Human herpes virus 8 (HHV-8)-associated secondary hemophagocytic lymphohistiocytosis is a rare but critical immuno-hematological entity in immunocompetent patients. Establishing a diagnosis is challenging as is the monitoring of disease activity and therapeutic effects. We report a case of a HHV-8-associated hemophagocytic lymphohistiocytosis in a HIV-negative adult patient with multicentric Castleman's disease. As a novel finding, we report the use of certain inflammatory parameters, primarily interleukin-10 combined with viral load monitoring of the causative infectious agent in this case HHV-8 to monitor the clinical course of the hemophagocytic lymphohistiocytosis in the setting of bacterial septic complications.

A cluster of acute hepatitis C virus infection among men who have sex with men--results from contact tracing and public health implications.

OBJECTIVE: An acute hepatitis C virus (HCV) infection in an HIV-positive man who had sex with men (MSM) was notified. In the period of his seroconversion he was also diagnosed with a rectal lymphogranuloma venereum (LGV) infection, and was part of a cluster of 15 LGV cases in 2003. Our aim was to investigate HCV transmission and to search for potential spread among sexual contacts and known LGV patients. METHODS: Our case series included the index, two recent contacts, and 14 LGV cases. They were interviewed about parenteral exposure for HCV, history of sexually transmitted diseases(STDs), sexual behaviour and drug use. Laboratory investigations included anti-HCV antibodies, HCV-polymerase chain reaction, and HCV genotyping. RESULTS: Seven out of 17 MSM recently seroconverted for HCV (41%). Three genotypes were found. Parenteral risk factors were excluded. Six out of seven had LGV proctitis coinciding with HCV seroconversion, six (86%) were HIV infected. Unprotected anal contact was practised by both HCV uninfected and infected cases. Unprotected active and passive fisting was reported by all seven HCV infected men, compared with two of nine uninfected men (P = 0.003). Non-intravenous drug use during sexual activities was common among all MSM. Numerous, often anonymous, sexual contacts in various European countries were reported. CONCLUSIONS: A cluster of acute HCV infection is reported among mostly HIV-positive MSM, with multiple partners throughout Europe. Sexual techniques potentially leading to mucosal damage (fisting), concomitant STDs such as LGV and drug use seem facilitating factors for spread. Extensive case finding and partner tracing is advocated as well as targeted prevention messages.

Newly discovered coronavirus as the primary cause of severe acute respiratory syndrome.

BACKGROUND: The worldwide outbreak of severe acute respiratory syndrome (SARS) is associated with a newly discovered coronavirus, SARS-associated coronavirus (SARS-CoV). We did clinical and experimental studies to assess the role of this virus in the cause of SARS. METHODS: We tested clinical and postmortem samples from 436 SARS patients in six countries for infection with SARS-CoV, human metapneumovirus, and other respiratory pathogens. We infected four cynomolgus macaques (Macaca fascicularis) with SARS-CoV in an attempt to replicate SARS and did necropsies on day 6 after infection. FINDINGS: SARS-CoV infection was diagnosed in 329 (75%) of 436 patients fitting the case definition of SARS; human metapneumovirus was diagnosed in 41 (12%) of 335, and other respiratory pathogens were diagnosed only sporadically. SARS-CoV was, therefore, the most likely causal agent of SARS. The four SARS-CoV-infected macaques excreted SARS-CoV from nose, mouth, and pharynx from 2 days after infection. Three of four macaques developed diffuse alveolar damage, similar to that in SARS patients, and characterised by epithelial necrosis, serosanguineous exudate, formation of hyaline membranes, type 2 pneumocyte hyperplasia, and the presence of syncytia. SARS-CoV was detected in pneumonic areas by virus isolation and RT-PCR, and was localised to alveolar epithelial cells and syncytia by immunohistochemistry and transmission electron microscopy. INTERPRETATION: Replication in SARS-CoV-infected macaques of pneumonia similar to that in human beings with SARS, combined with the high prevalence of SARS-CoV infection in SARS patients, fulfill the criteria required to prove that SARS-CoV is the primary cause of SARS.

Respiratory virus infections in febrile children presenting to a general practice out-of-hours service.

BACKGROUND: Fever is common in young children and is assumed to be frequently caused by viral infections. OBJECTIVES: To document respiratory viruses in children with fever presenting at a general practice out-of-hours service (OHS), evaluate presenting symptoms in febrile children with a virus infection, and examine the association between antibiotic prescription and the presence of a viral infection. METHODS: Nasopharyngeal swabs were obtained to detect respiratory viruses in non-hospitalized children aged ≥ three months to six years presenting with fever at an OHS. Symptoms were assessed using physical examinations and questionnaires. Logistic regression analysis was used to reveal associations between symptoms or diagnoses, and the presence of at least one virus RESULTS: In total 257 nasopharyngeal swabs were obtained in 306 eligible children; 53% of these children were infected by at least one virus. The most frequently detected viruses were adenovirus (10.9%), RSV type A (10.5%) and PIV type 1 (8.6%). Cough (OR 2.6; 95% CI: 1.4-4.6) and temperature ≥ 38.0°C (OR 2.1; 95% CI: 1.3-3.5) were independent predictors of the presence of a virus, but the discriminative ability was low (AUC 0.64; 95% CI: 0.58-0.71). Antibiotic prescription rate was 37.3%. In 57.4% of children with an antibiotic prescription, a virus was found. CONCLUSION: In over 50% of all febrile children presenting at an OHS, a virus was found. Antibiotic prescription rate was high and not associated to the outcome of viral testing.

An outbreak of diarrhea in a neonatal medium care unit caused by a novel strain of rotavirus: investigation using both epidemiologic and microbiological methods.

OBJECTIVE: In December 1999, an outbreak of diarrhea was reported in a general hospital neonatal medium care unit (NMCU) caused by a novel strain of rotavirus with genotype P[6], G9. An investigation was conducted to determine risk factors for illness among neonates. DESIGN: Rotavirus diagnosis was by latex agglutination and typing by reverse transcriptase polymerase chain reaction. A case-control study was performed using data collected from medical records on exposures in a 3-day period before illness (cases) or a random 3-day period (controls). Environmental swabs were tested for rotavirus. Antenatal blood samples from mothers and blood samples provided by hospital staff were analyzed for rotavirus antibodies. RESULTS: Fifty-six cases of rotaviral illness were confirmed by latex agglutination. Forty-seven of these were among 118 neonates exposed to the NMCU (attack rate, 40%). There was a 4-week period with no clinical cases in the course of the outbreak. Increased frequency (> or = 15 times in 3 days) of ungloved nasogastric feeding was a significant risk factor (adjusted odds ratio, 8.79), controlling for birth weight and gestational age. Environmental sampling showed persistence of the virus on ward surfaces despite cleaning. None of 24 NMCU staff members had high levels of antibodies against P[6], G9. Three (8%) of 38 mothers had high antibody levels; 2 had infants who became ill. The outbreak ended with a 7-day ward closure, disinfection, and introduction of gloved nasogastric feeding. CONCLUSIONS: Case-control studies can be successful in identiffying risk factors for nosocomial outbreaks of diarrhea. High levels of rotavirus antibodies in mothers may not protect infants. The environment may be the most important reservoir of rotavirus during outbreaks.

Etiology of suspected pneumonia in adults admitted to a high-dependency unit in Blantyre, Malawi.

The microbiologic etiology of severe pneumonia in hospitalized patients is rarely known in sub-Saharan Africa. Through a comprehensive diagnostic work-up, we aimed to identify the causative agent in severely ill patients with a clinical picture of pneumonia admitted to a high-dependency unit. A final diagnosis was made and categorized as confirmed or probable by using predefined criteria. Fifty-one patients were recruited (45% females), with a mean age of 35 years (range = 17-88 years), of whom 11(22%) died. Forty-eight (94%) of the patients were seropositive for human immunodeficiency virus; 14 (29%) of these patients were receiving antiretroviral treatment. Final diagnoses were bacterial pneumonia (29%), Pneumocystis jirovecii pneumonia (27%), pulmonary tuberculosis (22%), and pulmonary Kaposi's sarcoma (16%); 39 (77%) of these cases were confirmed cases. Fifteen (29%) patients had multiple isolates. At least 3 of 11 viral-positive polymerase chain reaction (PCR) results of bronchoalveolar lavage fluid were attributed clinical relevance. No atypical bacterial organisms were found.

Population genetic tests suggest that the epidemiologies of JCV and BKV are strikingly different.

The JCV and BKV viruses have been used as markers for the study of human evolution by assuming that these viruses coevolved with their host. However, it is currently unclear whether the details of the population expansion of these viruses and humans agree. To study this in more detail, large numbers of complete genomes were used for population genetic tests to detect evidence for population expansion. Relative to the neutral expectation of no selective forces and no demographic changes, the JCV data set contained a striking excess of synonymous and non-synonymous mutations that occur only once in the data set. The same was found for non-synonymous mutations of BKV, but not at all for synonymous mutations of BKV. The different frequency spectra of mutations in JCV and BKV do not result from the inclusion of patients with clinical symptoms associated with BKV and JCV, such as nephropathy or progressive multifocal leucoencefalopathy, nor from the different numbers of genomes available for JCV and BKV. Instead, the distribution of unique mutations and population genetic models that use older mutation classes indicate a striking difference of the historical demographies of JCV and BKV with only the former virus exhibiting the evidence of demographic expansion. Our analyses expand on recent population genetic analyses that document a global population expansion of JCV by taking into account the impact of deleterious mutations and by comparing both human viruses. The striking difference between the demographics of BKV and JCV suggests that important aspects of their epidemiology remain to be discovered.

Imported Mayaro virus infection in the Netherlands.

A Dutch couple, presenting with persisting arthralgias, temporary fever and rash after a stay in Surinam were diagnosed with Mayaro virus infection. Mayaro virus is a relatively unknown South American Alphavirus responsible for dengue-like clinical features and persisting arthralgias. An important, but probably underappreciated cross-reactivity with other Alphaviruses like Chikungunya virus is present, which may become of clinical importance in the event the various Alphaviruses will have overlapping geographical distributions and in seroprevalence studies.

Viral hepatitis in a multi-ethnic neighborhood in the Netherlands: results of a community-based study in a low prevalence country.

OBJECTIVES: The prevalence of viral hepatitis varies worldwide. Although the prevalence of hepatitis A virus (HAV) and hepatitis B virus (HBV) infection is generally low in Western countries, pockets of higher prevalence may exist in areas with large immigrant populations. The aim of this study was to obtain further information on the prevalence of viral hepatitis in a multi-ethnic area in the Netherlands. METHODS: We conducted a community-based study in a multi-ethnic neighborhood in the city of Rotterdam, the Netherlands, including both native Dutch and migrant participants, who were tested for serological markers of hepatitis A, hepatitis B, and hepatitis C infection. RESULTS: Markers for hepatitis A infection were present in 68% of participants. The prevalence of hepatitis B core antibodies (anti-HBc), a marker for previous or current infection, was 20% (58/284). Prevalence of hepatitis A and B varied by age group and ethnicity. Two respondents (0.7%) had chronic HBV infection. The prevalence of hepatitis C was 1.1% (3/271). High levels of isolated anti-HBc were found. CONCLUSIONS: We found a high prevalence of (previous) viral hepatitis infections. This confirms previous observations in ethnic subgroups from a national general population study and illustrates the high burden of viral hepatitis in areas with large immigrant populations.

[Acute myocarditis due to Coxsackie virus B3 in two infants]. / Acute myocarditis door coxsackie B3-virus bij twee zuigelingen.

In the spring and summer of 2008 two seriously ill male infants were admitted to a paediatric intensive care unit. Initially, both had a fever, were drinking less and were pale complexioned. Physical examination revealed tachycardia, slow capillary filling and liver enlargement. Within a few hours, both infants developed circulatory and respiratory failure. A chest radiograph showed that the heart was enlarged and echocardiography revealed that the pump function of both ventricles was severely diminished. Myocarditis caused by Coxsackie virus B3 was diagnosed when the virus was demonstrated in serum and faeces. At the last follow-up, one infant still had severe pump function disorders, and the other one died. Coxsackie virus B3 is a non-polio enterovirus that usually causes mild clinical syndromes but is also associated with myocarditis and overwhelming, systemic neonatal infections. In neonates with mild symptoms one should be alert to progression to circulatory insufficiency, especially if the mother experiences a flu-like illness in the perinatal period. Early recognition of heart failure and adequate diagnostic testing for cardiotropic viruses is important as morbidity and mortality is considerable.

Monitoring cytomegalovirus IE-1 and pp65-specific CD4+ and CD8+ T-cell responses after allogeneic stem cell transplantation may identify patients at risk for recurrent CMV reactivations.

We studied the recovery of CMV-specific CD4+ and CD8+ T-cell immunity in 52 recipients of allogeneic stem cell transplantation (SCT). The proportions of IFN-gamma-producing CD4+ and CD8+ T cells upon in vitro activation using peptide pools representing the CMV pp65 and IE-1 proteins were assessed at multiple time points post SCT, and correlated with the occurrence of CMV reactivation. In a retrospective analysis, recurrent CMV reactivations occurred in 9 patients and were associated with low pp65-specific CD4+ T-cell and low IE-1-specific CD8(+) T-cell reactivities, whereas patients without detectable CMV reactivation (n = 30) or a single reactivation (n = 13) showed a better recovery of these immune responses. CD4+ T-cell responses to IE-1 were infrequent in most patients, whereas CD8+ T-cell responses to pp65 occurred frequently, but did not correlate with protection against (recurrent) reactivation. Prospectively, CMV-specific T-cell responses could be studied prior to 14 reactivation episodes in 8 patients. CD4+ T-cell responses to IE-1 and pp65 were positive in only 1 and 2 episodes, respectively. CD8+ T-cell responses against IE-1 were positive in 4, but against pp65 in 12 episodes, again showing that CD8+ T-cell reactivity against pp65 did not prevent CMV reactivation. Thus, monitoring of particular CMV-specific CD4+ and CD8+ T-cell responses after allogeneic SCT may identify patients at risk for recurrent CMV reactivations.

A prospective open study of the efficacy of high-dose recombinant hepatitis B rechallenge vaccination in HIV-infected patients.

Double-dose hepatitis B virus revaccination of human immunodeficiency virus (HIV)-infected patients proved to be effective in 50.7% of 144 patients who had previously failed to respond to standard doses. In the multivariate analysis, female patients were found to have a significantly better response (P= .03). The effect of age on the response depended on the viral load at the time of revaccination. For patients with a detectable HIV RNA load, the effect of age was stronger (odds ratio [OR], 0.34 per 10 years older [95% confidence interval {CI}, 0.16-0.72]; P= .005) than for patients with an undetectable HIV RNA load (OR, 0.74 per 10 years older [95% CI, 0.50-1.09]; P= .12).

Sirolimus for Kaposi's sarcoma.

The risk of Kaposi's sarcoma (KS) is increased after organ transplantation. Management of KS in the cardiac transplant population may be difficult because reduction of immunosuppression is often not practical. This report describes a case of KS occurring in the early post-transplant period. Modification of immunosuppression with the use of sirolimus led to tumor regression for 24 months, but with subsequent localized progression of disease.