Vas Novelli

HIV evolution: CTL escape mutation and reversion after transmission

Within-patient HIV evolution reflects the strong selection pressure driving viral escape from cytotoxic T-lymphocyte (CTL) recognition. Whether this intrapatient accumulation of escape mutations translates into HIV evolution at the population level has not been evaluated. We studied over 300 patients drawn from the B- and C-clade epidemics, focusing on human leukocyte antigen (HLA) alleles HLA-B57 and HLA-B5801, which are associated with long-term HIV control and are therefore likely to exert strong selection pressure on the virus. The CTL response dominating acute infection in HLA-B57/5801-positive subjects drove positive selection of an escape mutation that reverted to wild-type after transmission to HLA-B57/5801-negative individuals. A second escape mutation within the epitope, by contrast, was maintained after transmission. These data show that the process of accumulation of escape mutations within HIV is not inevitable. Complex epitope- and residue-specific selection forces, including CTL-mediated positive selection pressure and virus-mediated purifying selection, operate in tandem to shape HIV evolution at the population level.

Diagnosis and treatment of tuberculosis in children

There has been a recent global resurgence of tuberculosis in both resource-limited and some resource-rich countries. Several factors have contributed to this resurgence, including HIV infection, overcrowding, and immigration. Childhood tuberculosis represents a sentinel event in the community suggesting recent transmission from an infectious adult. The diagnosis of tuberculosis in children is traditionally based on chest radiography, tuberculin skin testing, and mycobacterial staining/culture although these investigations may not always be positive in children with tuberculosis. Newer diagnostic methods, such as PCR and immune-based methods, are increasingly being used although they are not widely available and have a limited role in routine clinical practice. Diagnostic approaches have been developed for use in resource-limited settings; however, these diagnostic methods have not been standardised and few have been validated. Short-course, multidrug treatment has been adopted as standard therapy for adults and children with tuberculosis, with or without directly observed therapy. Compliance is a major determinant of the success of drug treatment. Although uncommon in children, multidrug-resistant tuberculosis is also increasing and treatment will often involve longer courses of therapy with second-line antituberculosis drugs. Treatment of latent infection and chemoprophylaxis of young household contacts is also recommended for tuberculosis prevention, although this may not always be carried out, particularly in high incidence areas.

Endothelial Dysfunction Late After Kawasaki Disease

BACKGROUND Kawasaki disease (KD) is a systemic vasculitis of childhood with widespread vascular endothelial damage in the acute stage. Long-term complications, such as myocardial infarction and death, are recognized, but the extent and nature of late vascular abnormalities that might predispose to these events have not been studied. METHODS AND RESULTS We used high-resolution ultrasound to study endothelial function in the brachial artery of 20 patients 5 to 17 years after acute KD (median, 11 years) and compared findings with those in 20 age- and sex-matched control subjects. Vascular responses to reactive hyperemia (with flow increase leading to endothelium-dependent dilation) and to sublingual glyceryl trinitrate (GTN; endothelium-independent dilation) were recorded. The relationship between endothelium-dependent vascular responses and features of the endothelium acute illness was examined. There was no difference in baseline vessel diameter, degree of reactive hyperemia, or response to GTN between patients and control subjects. In contrast, flow-mediated dilation was markedly reduced in KD patients compared with control subjects (3.1% versus 9.4%; P < .001). Late endothelium-dependent responses were not related to features of the acute illness. CONCLUSIONS Abnormalities of systemic endothelial function are present many years after resolution of acute KD, even in patients without detectable early coronary artery involvement. Because this may be an important factor in the genesis of late vascular complications, long-term follow-up of all patients with KD is indicated.

Decline in mortality, AIDS, and hospital admissions in perinatally HIV-1 infected children in the United Kingdom and Ireland

Abstract Objective To describe changes in demographic factors, disease progression, hospital admissions, and use of antiretroviral therapy in children with HIV. Design Active surveillance through the national study of HIV in pregnancy and childhood (NSHPC) and additional data from a subset of children in the collaborative HIV paediatric study (CHIPS). Setting United Kingdom and Ireland. Participants 944 children with perinatally acquired HIV-1 under clinical care. Main outcome measures Changes over time in progression to AIDS and death, hospital admission rates, and use of antiretroviral therapy. Results 944 children with perinatally acquired HIV were reported in the United Kingdom and Ireland by October 2002; 628 (67%) were black African, 205 (22%) were aged ≥ 10 years at last follow up, 193 (20%) are known to have died. The proportion of children presenting who were born abroad increased from 20% in 1994-5 to 60% during 2000-2. Mortality was stable before 1997 at 9.3 per 100 child years at risk but fell to 2.0 in 2001-2 (trend P < 0.001). Progression to AIDS also declined (P < 0.001). From 1997 onwards the proportion of children on three or four drug antiretroviral therapy increased. Hospital admission rates declined by 80%, but with more children in follow up the absolute number of admissions fell by only 26%. Conclusion In children with HIV infection, mortality, AIDS, and hospital admission rates have declined substantially since the introduction of three or four drug antiretroviral therapy in 1997. As infected children in the United Kingdom and Ireland are living longer, there is an increasing need to address their medical, social, and psychological needs as they enter adolescence and adult life.

Morbidity, Mortality, and Response to Treatment by Children in the United Kingdom and Ireland with Perinatally Acquired HIV Infection during 1996–2006: Planning for Teenage and Adult Care

BACKGROUND Recent evidence suggests that decreases in morbidity and mortality in cohorts of adults infected with human immunodeficiency virus (HIV) are showing signs of reversal. We describe changes over time in these characteristics and in the response to treatment among children in the United Kingdom and Ireland with perinatally acquired HIV infection, many of whom are now adolescents. METHODS We analyzed prospective cohort data reported to the National Study of HIV in Pregnancy and Childhood (NSHPC) and the Collaborative HIV Paediatric Study. RESULTS By mid 2006, 1441 HIV-infected children were reported to NSHPC; 40% were > or = 10 years old at their most recent follow-up visit, and 34% were receiving care outside London. The proportion of children born abroad increased from 24% during 1994-1996 to 64% during 2003-2006. The percentage of total child time during which children received highly active antiretroviral therapy (HAART) increased from 36% during 1997-1999 to 61% during 2000-2002 and 63% during 2003-2006. Of children who were naive to antiretroviral therapy at the start of HAART, the percentage with an HIV-1 RNA load of < 400 copies/mL after 12 months increased from 52% during 1997-1999 to 79% during 2003-2006. In multivariate analysis, only calendar time predicted virological response, whereas both younger age and lower CD4 cell percentage at HAART initiation predicted increases of > 10% in the CD4 cell percentage. A total of 31% of children aged 5-14 years and 38% aged > or = 15 years at their most recent follow-up visit had been exposed to drugs from each of the 3 main HAART classes. The rate of AIDS and mortality combined decreased from 13.3 cases per 100 person-years before 1997 to 3.1 and 2.5 cases per 100 person-years, respectively, during 2000-2002 and 2003-2006; rates of hospital admission also declined during this interval. Of 18 children known to have died since 2003, 9 died within 1 month after presentation. CONCLUSIONS Morbidity and mortality rates among HIV-infected children continue to decrease over time. Because these children are increasingly dispersed outside London, specialist care is now provided in national clinical networks. Transition pathways to adolescent and adult services and long-term observation to monitor the effects of prolonged exposure to both HIV and HAART are required.

The Likelihood of an Indeterminate Test Result from a Whole-Blood Interferon-γ Release Assay for the Diagnosis of Mycobacterium tuberculosis Infection in Children Correlates With Age and Immune Status

Background: Interferon-&ggr; release assays for the diagnosis of infection with Mycobacterium tuberculosis have been increasingly used in recent years and are endorsed by national guidelines, but experience regarding their use in children is still limited. Methods: We retrospectively evaluated the routine use of the QuantiFERON-TB Gold In-Tube assay (QFT-IT) in a pediatric tertiary care center with a high prevalence of immunocompromising conditions. The relationship between age, immune status, and likelihood of an indeterminate test result was analyzed using logistic regression analysis and fractional polynomials. Results: Two hundred thirty-seven tests from 237 children were included in the analysis. Fifty-nine children (25%) were immunocompromised by our definition. An indeterminate test result was obtained in 83 children (35%). The likelihood of an indeterminate test result was inversely correlated with age (P < 0.001) for children who were not known to be immunocompromised, and decreased by 13% per year of age. Impaired immunity (P < 0.001) was independently associated with a higher probability of an indeterminate QFT-IT. Among 161 children with a documented tuberculin skin test, 89% had a concordant QFT-IT (&kgr; = 0.71). Twelve of 16 patients with culture-proven TB had a positive QFT-IT. Conclusion: These data suggest that QFT-IT may not provide a determinate test result in a substantial proportion of children in a tertiary care setting due to the combination of young age and primary and acquired immune deficiencies.

The radiological spectrum of invasive aspergillosis in children: a 10-year review

BackgroundInvasive aspergillosis is an uncommon but life-threatening event in the immunocompromised child. Attempts at fungal isolation are often unrewarding and a high index of radiological suspicion is essential in the early diagnosis of infected children.ObjectiveTo document the radiological spectrum of disease in invasive aspergillosis in the paediatric population.Materials and methodsA retrospective review of the imaging performed in 27 consecutive patients (age 7 months to 18 years) with documented invasive Aspergillosis encountered over a 10-year period at a single institution.ResultsRadiographic findings of pulmonary disease (20 patients) included segmental and multilobar consolidation, perihilar infiltrates, multiple small nodules, peripheral nodular masses and pleural effusions. No cavitating lesions were seen on CXR. Small cavitating nodules were present on CT in two of eight children. Chest wall disease was particularly associated with underlying chronic granulomatous disease. Disseminated disease manifested as osteomyelitis (n=5), cerebral (n=3), oesophageal (n=1), hepatic (n=2), renal (n=2) and cutaneous (n=5) involvement. Imaging findings are discussed. Twelve patients (44%) subsequently died from Aspergillus-related complications.ConclusionsInvasive aspergillosis presents with a wide variety of radiographic findings involving multiple organ systems. Respiratory findings are varied but often non-specific, and a high index of suspicion is necessary in immunocompromised patients. In contrast to adult disease, the incidence of cavitation of pulmonary lesions appears low.

Differential selection pressure exerted on HIV by CTL targeting identical epitopes but restricted by distinct HLA alleles from the same HLA supertype

HLA diversity is seen as a major challenge to CTL vaccines against HIV. One current approach focuses on “promiscuous” epitopes, presented by multiple HLA alleles from within the same HLA supertype. However, the effectiveness of such supertype vaccines depends upon the functional equivalence of CTL targeting a particular epitope, irrespective of the restricting HLA. In this study, we describe the promiscuous HIV-specific CTL epitopes presented by alleles within the B7 supertype. Substantial differences were observed in the ability of CTL to select for escape mutation when targeting the same epitope but restricted by different HLA. This observation was common to all six promiscuous B7 epitopes identified. Moreover, with one exception, there were no significant differences in the frequency, magnitude, or immunodominance of the CTL responses restricted by different HLA alleles to explain these discrepancies. This suggests that the unique peptide/MHC complexes generated by even closely related HLA induce CTL responses that are qualitatively different. This hypothesis is supported by additional differences observed between CTL targeting identical epitopes but restricted by different HLA: first, the occurrence of distinct, HLA-specific escape mutation; second, the recruitment of distinct TCR repertoires by particular peptide/MHC complexes; and, third, significant differences in the functional avidity of CTL. Taken together, these data indicate that significant functional differences exist between CTL targeting identical epitopes but restricted by different, albeit closely related HLA. These findings are of relevance to vaccine approaches that seek to exploit HLA supertypes to overcome the problem of HLA diversity.

Probable Mother-to-Infant Transmission of Pneumocystis carinii f. sp. hominis Infection

ABSTRACT A mother and her 4.5-week-old infant had Pneumocystis carinii pneumonia contemporaneously. Genotyping of P. carinii f. sp. hominis DNA at three independent loci showed the same genotype in samples from mother and infant. These data suggest transmission of P. carinii organisms from the mother to her infant.

Outcomes for human immunodeficiency virus-1-infected infants in the United kingdom and Republic of Ireland in the era of effective antiretroviral therapy.

Background: There are few data about disease progression and response to antiretroviral therapy (ART) in vertically HIV-infected infants in the era of effective therapy. Design: Cohort study. Methods: We examined progression to acquired immunodeficiency syndrome (AIDS) and death over calendar time for infants reported to the National Study of HIV in Pregnancy and Childhood in the United Kingdom/Ireland. The use of ART and CD4 and HIV-1 RNA responses were assessed in a subset in the Collaborative HIV Pediatric Study. Results: Among 481 infants, mortality was lower in those born after 1997 (HR 0.30; P < 0.001), with no significant change in progression to AIDS. Of 174 infants born since 1997 in the Collaborative HIV Pediatric Study, 41 (24%) were followed from birth, 77 (44%) presented pre-AIDS and 56 (32%) presented with AIDS. Of 125 (72%) children on 3- or 4-drug ART by the age of 2 years, 59% had HIV-1 RNA <400 at 12 months; median CD4 percentage increased from 24% to 35%. Among 41 infants followed from birth, 12 progressed to AIDS (5 while ART naive) and 3 died; 1 of 10 infants initiating ART before 3 months of age progressed clinically. Conclusion: Mortality in HIV-infected infants is significantly lower in the era of effective ART, but symptomatic disease rates remain high. Infrequent clinic attendance and poor compliance with cotrimoxazole prophylaxis and/or ART in infants born to diagnosed HIV-infected women and late presentation of infants identified after birth appear to be major contributors. Poor virologic response to ART during infancy is of concern because of increased likelihood of early development of resistance.