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.

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.

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.

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.

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.

[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.

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.

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.

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).

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.

Importance of herpes simplex virus type-1 (HSV-1) in primary genital herpes.

Herpes simplex virus type 1 (HSV-1) is increasingly reported in primary genital herpes. Its incidence was assessed among Rotterdam sexually transmitted diseases clinic attendees between 1996 and 2001, and demographic and sexual behaviour factors were evaluated. A retrospective record analysis was performed. All herpes diagnoses were based on cell culture techniques. A clinical scoring system was used to select "primary" cases. Demographic and sexual behaviour characteristics were analysed using logistic regression. The clinical scoring system showed 115 cases of primary genital herpes. HSV-1 (n = 60) was found in 52% and HSV-2 (n = 55) in 48% of cases. The multiple logistic regression model showed that HSV-1 was associated with "oro-genital contact" (p < 0.001) and "having a single partner in the last 2 months" (p = 0.054) and that HSV-2 was associated with "a higher number of sexual partners in the last 6 months" (p = 0.085). Our data confirm the growing importance of HSV-1 in primary genital herpes; oro-genital sex is the main risk factor.

Acquisition and clearance of perianal human papillomavirus infection in relation to HIV-positivity in men who have sex with men in the Netherlands.

This study was performed to establish the prevalence of perianal human papillomavirus (HPV) infection in relation to HIV-positivity in a group of men who have sex with men (MSM), and to correlate follow-up data with regard to acquisition and clearance of HPV infection. Data with regard to HPV prevalence and HIV serostatus during two visits were compared. At both visits participants underwent a routine venereological examination and swabs were taken from the perianal region for HPV DNA testing. During both visits HPV types 16, 18, 31, 33 and 52 were significantly more often detected in HIV-positive individuals. Persistence of HPV type 31 at the perianal region was significantly more often seen in HIV-positive MSM (p=0.036) while the incidence of type 16 may be associated with HIV positivity (p=0.059). In HIV-positive MSM significantly more high-risk HPV types were detected at the perianal region.

Human metapneumovirus infection in hospital referred South African children.

Human metapneumovirus (hMPV) was first described in Dutch children with acute respiratory symptoms. A prospective analysis of the epidemiology, clinical manifestation, and seroprevalence of hMPV and other respiratory viruses in South African children referred to hospital for upper or lower respiratory tract infection were carried out during a single winter season, by using RT-PCR, viral culture, and enzyme-linked immunosorbent assays. In nasopharyngeal aspirates from 137 children, hMPV was detected by RT-PCR in 8 (5.8%) children (2-43 months of age) as a sole viral pathogen, respiratory syncytial virus (RSV) in 21 (15%), influenza A virus in 18 (13%) and influenza B virus in 20 (15%). Pneumonia was diagnosed in seven children and upper respiratory tract infection in one of the hMPV-infected children. One hMPV-infected child was admitted to the intensive care unit in need of mechanical ventilation and one child was infected with human immunodeficiency virus (HIV). No statistically significant differences were found between hMPV, RSV, and influenza virus infected groups with regard to clinical signs and symptoms and chest radiograph findings. The seropositive rate of hMPV specific IgG antibodies was 92% in children aged 24-36 months, the oldest seronegative child in our study was 7 years and 6 months of age. In conclusion, hMPV contributes to upper and lower respiratory tract morbidity in South African children.

Avian influenza A virus (H7N7) associated with human conjunctivitis and a fatal case of acute respiratory distress syndrome.

Highly pathogenic avian influenza A viruses of subtypes H5 and H7 are the causative agents of fowl plague in poultry. Influenza A viruses of subtype H5N1 also caused severe respiratory disease in humans in Hong Kong in 1997 and 2003, including at least seven fatal cases, posing a serious human pandemic threat. Between the end of February and the end of May 2003, a fowl plague outbreak occurred in The Netherlands. A highly pathogenic avian influenza A virus of subtype H7N7, closely related to low pathogenic virus isolates obtained from wild ducks, was isolated from chickens. The same virus was detected subsequently in 86 humans who handled affected poultry and in three of their family members. Of these 89 patients, 78 presented with conjunctivitis, 5 presented with conjunctivitis and influenza-like illness, 2 presented with influenza-like illness, and 4 did not fit the case definitions. Influenza-like illnesses were generally mild, but a fatal case of pneumonia in combination with acute respiratory distress syndrome occurred also. Most virus isolates obtained from humans, including probable secondary cases, had not accumulated significant mutations. However, the virus isolated from the fatal case displayed 14 amino acid substitutions, some of which may be associated with enhanced disease in this case. Because H7N7 viruses have caused disease in mammals, including horses, seals, and humans, on several occasions in the past, they may be unusual in their zoonotic potential and, thus, form a pandemic threat to humans.

Prevalence and clinical symptoms of human metapneumovirus infection in hospitalized patients.

During a 17-month period, we performed retrospective analyses of the prevalence of and clinical symptoms associated with human metapneumovirus (hMPV) infection, among patients in a university hospital in The Netherlands. All available nasal-aspirate, throat-swab, sputum, and bronchoalveolar-lavage samples (N=1515) were tested for hMPV RNA by reverse-transcriptase polymerase chain reaction. hMPV RNA was detected in 7% of samples from patients with respiratory tract illnesses (RTIs) and was the second-most-detected viral pathogen in these patients during the last 2 winter seasons. hMPV was detected primarily in very young children and in immunocompromised individuals. In young children, clinical symptoms associated with hMPV infection were similar to those associated with human respiratory syncytial virus (hRSV) infection, but dyspnea, feeding difficulties, and hypoxemia were reported more frequently in hRSV-infected children. Treatment with antibiotics and corticosteroids was reported more frequently in hMPV-infected children. From these data, we conclude that hMPV is an important pathogen associated with RTI.