Pamela J. Vallely

Association of human parvovirus B19 infection with acute meningoencephalitis

To find out the incidence and clinical presentation of parvovirus B19 meningoencephalitis, we tested samples of cerebrospinal fluid from 162 patients (one from each patient) with undiagnosed meningoencephalitis, who presented between March, 1997, and March, 1998 (an outbreak period) using nested PCR for B19 genes. Seven patients were positive; an incidence of 4.3%. Five additional cases of meningoencephalitis were detected from other years. Three patients with underlying disorders (haemophagocytic lymphohistiocytosis, Cockaynes syndrome, and Turners syndrome) died. Neurological sequelae were observed in three surviving patients, all of whom had had striking abnormalities detected on brain scans done during the acute phase.

Detection of BK virus and JC virus DNA in urine samples from immunocompromised (HIV-infected) and immunocompetent (HIV-non-infected) patients using polymerase chain reaction and microplate hybridisation

BACKGROUND The majority of the human population is infected with two human polyomaviruses BK virus (BKV) and JC virus (JCV) during childhood. After initial infection both viruses persist within renal system. Reactivation of both viruses may be linked with immunodeficiency or immunosuppressive therapy. OBJECTIVE To evaluate the relationship between immunodeficiency and viruria, prevalence of BK and JC viruria over time was investigated in a cohort of HIV seropositive individuals at different stages of disease. The excretion in this group was compared with virus excretion in their HIV seronegative partners and in an unselected cohort of patients attending a Genito-Urinary Medicine (GUM) clinic. STUDY DESIGN The excretion of BKV and JCV DNA in multiple urine samples from HIV-infected patients at different stages of disease and their HIV-negative partners, and in single samples from a cohort of patients at a GUM clinic was investigated. A microplate hybridisation method was developed to increase both the sensitivity and specificity of detection of the PCR product. The method was also applied to estimate the DNA copy numbers of BKV and JCV in urine samples. RESULTS Within the HIV group, the level of immunosuppression (CD4+ category) was not associated with JCV viruria. By contrast, there was a modest correlation between immunodeficiency as indicated by a decline in CD4+ count and BKV viruria. Shedding of both BKV and JCV DNA together in urine samples of HIV-infected patients was much higher than in control groups (P = 0.02), indicating that HIV infection may associate with polyomavirus reactivation. The incidence of flu-like syndrome was much higher in HIV-infected asymptomatic individuals than acquired immunodeficiency syndrome (AIDS)-related complex (ARC)/AIDS patients. In general, the concentration of BKV DNA viruria (DNA copy number) was dependent to CD4+ counts (P = 0.008) while concentration of JCV DNA was independent to CD4+ cell count (P = 0.54). The prevalence of BKV and JCV DNA in patients who were infected with C. trachomatis was 9/50 (18%) and 11/50 (22%), respectively. BKV and JCV DNA was detected in 3/19 (15%) and 2/19 (10%) of patients who were infected with N. gonorrhoea. Results suggested that persons infected with C. trachomatis were more likely to show BKV and JCV viruria. CONCLUSION These results confirm that shedding of BK and JC viruses in urine is not exclusively found in immunosupression, it may also occur in healthy individuals. The frequency of virus excretion is however, apparently increased in HIV-infected patients, although no firm statistical difference could be established. One of the interesting aspects of these findings was the relatively high incidence of BKV and JCV viruria in both control groups, i.e. HIV-negative partners of HIV-infected patients and patients attending a GUM clinic.

Characterization of fHbp, nhba (gna2132), nadA, porA, and sequence type in group B meningococcal case isolates collected in England and Wales during January 2008 and potential coverage of an investigational group B meningococcal vaccine.

ABSTRACT Invasive disease caused by meningococcal capsular groups A, C, W-135, and Y is now preventable by means of glycoconjugate vaccines that target their respective polysaccharide capsules. The capsule of group B meningococci (MenB) is poorly immunogenic and may induce autoimmunity. Vaccines based on the major immunodominant surface porin, PorA, are effective against clonal epidemics but, thus far, have a limited scope of coverage against the wider MenB population at large. In an alternative approach, the first-generation, investigational, recombinant MenB (rMenB) plus outer membrane vesicle (OMV) (rMenB-OMV) vaccine contains a number of relatively conserved surface proteins, fHBP, NHBA (previously GNA2132), and NadA, alongside PorA P1.4-containing OMVs from the New Zealand MeNZB vaccine. MenB currently accounts for approximately 90% of cases of meningococcal disease in England and Wales. To assess potential rMenB-OMV vaccine coverage of pathogenic MenB isolates within this region, all English and Welsh MenB case isolates from January 2008 (n = 87) were genetically characterized with respect to fHBP, NHBA, NadA, and PorA. Alleles for fHbp, nhba, and porA were identified in all of the isolates, of which 22% were also found to harbor nadA alleles. On the basis of genotypic data and predicted immunological cross-reactivity, the potential level of rMenB-OMV vaccine coverage in England and Wales ranges from 66% to 100%.

Characterization of fHbp, nhba (gna2132), nadA, porA, sequence type (ST), and genomic presence of IS1301 in group B meningococcal ST269 clonal complex isolates from England and Wales.

ABSTRACT Highly effective glycoconjugate vaccines exist against four of the five major pathogenic groups of meningococci: A, C, W-135, and Y. An equivalent vaccine against group B meningococci (menB) has remained elusive due to the poorly immunogenic capsular polysaccharide. A promising alternative, the investigational recombinant menB (rMenB)- outer membrane vesicle (OMV) vaccine, contains fHBP, NHBA (previously GNA2132), NadA, and outer membrane vesicles (OMVs) from the New Zealand MeNZB vaccine. MenB currently accounts for 90% of meningococcal disease in England and Wales, where the multilocus sequence type (ST) 269 (ST269) clonal complex (cc269) has recently expanded to account for a third of menB cases. To assess the potential cc269 coverage of the rMenB-OMV vaccine, English and Welsh cc269 isolates from the past decade were genetically characterized with respect to fHBP, NHBA, and NadA. All of the isolates harbored fHbp and nhba alleles, while 98% of the cc269 isolates were devoid of nadA. Subvariant profiling of fHbp, nhba, and porA against STs revealed the presence of two broadly distinct and well-defined clusters of isolates, centered around ST269 and ST275, respectively. An additional molecular marker, insertion sequence IS1301, was found to be present in 100% and <2% of isolates of the respective clusters. On the basis of the genetic data, the potential rMenB-OMV coverage of cc269 in England and Wales is high (up to 100%) within both clusters. Expression studies and serum bactericidal antibody assays will serve to enhance predictions of coverage and will augment ongoing studies regarding the significance of IS1301 within the ST269 cluster.

Age-related pattern of KI and WU polyomavirus infection

Abstract Background The role of two recently identified polyomaviruses, KI and WU, in the causation of respiratory disease has not been established. Objectives To determine the prevalence of KI and WU viruses (KIV and WUV) in 371 respiratory samples and evaluate their contribution to respiratory disease. Study Design Specimens were screened for KIV and WUV using single, multiplex or real time PCR; co-infection with other respiratory viruses was evaluated. Results Of the 371 samples analysed, 10 (2.70%) were positive for KIV and 4 (1.08%) were positive for WUV yielding an overall case prevalence of KIV and WUV infection of 3.77%. KIV and WUV were identified in patients aged <15 years (11 patients) with upper or lower respiratory tract infection and >45 years (3 patients) with upper respiratory tract infection. Co-infections were found in 5 (50%) and 3 (75%) of the KIV and WUV positive samples, respectively. Conclusions This study supports previous conclusions that KIV and WUV detection in the respiratory tract may be coincidental and reflect reactivation of latent or persistent infection with these viruses. The age distribution of KIV and WUV infection in this study mirrors that found for the other human polyomaviruses, BK and JC.

Tumour necrosis factor c2 microsatellite allele is associated with the rate of HIV disease progression

Background:The rate of immunological deterioration and progression to AIDS differs markedly between HIV-positive individuals, and may be influenced by cofactors, HIV phenotype and host T-cell response. Tumour necrosis factor (TNF)-α and lymphotoxin stimulate HIV replication and may induce apoptosis of HIV-infected and uninfected lymphocytes in vitro, thus accelerating disease progression and CD4 depletion. Variability in TNF production between individuals is to a degree genetically determined and may be predicted from polymorphisms of microsatellite regions surrounding the human TNF gene locus. Methods:We examined TNF microsatellite polymorphisms in 24 HIV-positive patients with slower disease progression (CD4 count > 400 × 106/l at ≥ 6 years), 20 HIV-positive patients with faster progression (CD4 count < 200 × 106/l within 5 years) and 109 healthy controls resident in north-west England. Typing was performed by polymerase chain reaction amplification of TNF a, b, c and d microsatellites and alleles were defined using fluorescence-based semi-automated microsatellite mapping techniques. Results:No significant differences in TNF a, b and d allele frequencies were observed between faster and slower progressors, or with healthy controls. The frequency of the TNF c2 allele was significantly different between HIV-positive slower (60.9%) and faster (15%) progressors (P = 0.002) with an odds ratio of 0.1 (95% confidence interval, 0–0.6). TNF c2 was also less frequent in faster progressors than in healthy controls (45.9%, P = 0.006) with an odds ratio of 0.2 (95% confidence interval 0–0.8). Conclusions:This is the first report demonstrating a strong association between the TNF c2 allele and the rate of HIV progression. Although it is possible that this finding may have arisen as a result of linkage disequilibrium with other alleles within the major histocompatibility complex that exert a more powerful effect upon progression, evidence is mounting to suggest that both TNF-α and lymphotoxin are closely involved in HIV disease progression and CD4 depletion. Our results serve to highlight the potential importance of genetic polymorphism, particularly of the TNF locus, in influencing the progression of HIV infection.

Detection of BK virus in urine by polymerase chain reaction: a comparison of DNA extraction methods.

Using specimens spiked with BK virus, several DNA extraction methods were evaluated for their ability to remove polymerase chain reaction (PCR) inhibitors from urine samples. It was found that PCR inhibition could be completely overcome by extracting samples with 30% polyethylene glycol (PEG) in 3 M sodium chloride, and partially overcome by extracting samples with guanidine thiocyanate in the presence of high salt concentrations. The nature of the sample inhibition was investigated, leading to the conclusion that both urea and unidentified non-proteinaceous DNA associated substances inhibit BKV DNA amplification from urine.

Association of acute parvovirus B19 infection with new onset of acute lymphoblastic and myeloblastic leukaemia

Aims: To investigate the association of acute parvovirus B19 infection with new onset of acute lymphoblastic and myeloblastic leukaemia. Methods: Cerebrospinal fluid (CSF) samples from patients with acute myelogenous leukaemia (AML) at diagnosis (n = 2) and acute lymphoblastic leukaemia (ALL) at diagnosis (n = 14) were analysed for parvovirus B19 DNA by means of nested polymerase chain reaction. In addition, samples from patients with benign intracranial hypertension (BIH) (n = 10) and hydrocephalus (n = 13) were tested as controls. Results: Four leukaemia cases were positive—common ALL (n = 2), null cell ALL (n =1), and M7 AML (n = 1)—whereas all controls were negative (Yates corrected χ2 value, 3.97; p = 0.046; odds ratio, 16.92; confidence interval, 1.03 to 77.18). All four patients were significantly anaemic, but none was encephalitic or had evidence of central nervous system leukaemia. In three of these patients, serum tumour necrosis α, interferon γ, interleukin 6, granulocyte–macrophage colony stimulating factor (range, 34.93–3800.06pg/ml), and macrophage chemoattractant protein 1 were detectable. All of these four patients carried at least one of the HLA-DRB1 alleles, which have been associated with symptomatic parvovirus B19 infection. Conclusion: Erythroid suppression and immune cell proliferation are both associated with B19 infection and may also be important in the pathogenesis of acute leukaemia.

Epidemiology of posttransplantation lymphoproliferative disorder in adult renal transplant recipients.

Background There is little information in the literature describing the relationship between posttransplantation lymphoproliferative disorder (PTLD) incidence and presentation with both recipient Epstein-Barr virus (EBV) serostatus and EBV status of PTLD histology, particularly in the late posttransplantation period. Methods This study reports the largest UK single-center, single-organ analysis of PTLD to date in a retrospective cohort study of 80 cases occurring in 4189 adult renal transplant recipients. Results The incidence rate was 2.6 cases per 1000 patient-years (95% confidence interval [95% CI], 2.1–3.2) for PTLD, 1.8 (95% CI, 1.4–2.4) for non-Hodgkin’s lymphoma, and 0.2 (95% CI, 0.07–4.2) for Hodgkin’s lymphoma. Non-Hodgkin’s lymphoma occurred at a rate 7.6 times that of the adult general population in England, whereas the rate for Hodgkin’s lymphoma was 5.9 times. The incidence of PTLD was highest during the 10th to 14th posttransplantation years. Early-onset disease was associated with EBV-seronegative recipient status, EBV-positive histology, and the involvement of extranodal sites. PTLD occurring in EBV-seronegative recipients was associated with EBV nuclear antigen antibody deficiency, polymorphic disease, and the involvement of extranodal sites. EBV-negative histology occurred in 32% of cases at a median time to presentation of 109 months. PTLD involving the allograft, central nervous system, and skin was uncommon and occurred late. Conclusion The incidence of PTLD is highest in the late posttransplantation period. Close clinical surveillance and education for transplant recipients is required for the duration of time while immunosuppressed. Failure to detect EBV DNA in blood should not reassure, particularly in patients with symptoms such as abdominal pain, oropharyngeal complaints, neck lumps, and B-symptoms.

Influenza A viruses dual and multiple infections with other respiratory viruses and risk of hospitalisation and mortality

Please cite this paper as: Goka et al. (2013) Influenza A viruses dual and multiple infections with other respiratory viruses and risk of hospitalisation and mortality. Influenza and Other Respiratory Viruses 7(6), 1079–1087.