Discordant Impact of HLA on Viral Replicative Capacity and Disease Progression in Pediatric and Adult HIV Infection.

HLA class I polymorphism has a major influence on adult HIV disease progression. An important mechanism mediating this effect is the impact on viral replicative capacity (VRC) of the escape mutations selected in response to HLA-restricted CD8+ T-cell responses. Factors that contribute to slow progression in pediatric HIV infection are less well understood. We here investigate the relationship between VRC and disease progression in pediatric infection, and the effect of HLA on VRC and on disease outcome in adult and pediatric infection. Studying a South African cohort of >350 ART-naïve, HIV-infected children and their mothers, we first observed that pediatric disease progression is significantly correlated with VRC. As expected, VRCs in mother-child pairs were strongly correlated (p = 0.004). The impact of the protective HLA alleles, HLA-B*57, HLA-B*58:01 and HLA-B*81:01, resulted in significantly lower VRCs in adults (p<0.0001), but not in children. Similarly, in adults, but not in children, VRCs were significantly higher in subjects expressing the disease-susceptible alleles HLA-B*18:01/45:01/58:02 (p = 0.007). Irrespective of the subject, VRCs were strongly correlated with the number of Gag CD8+ T-cell escape mutants driven by HLA-B*57/58:01/81:01 present in each virus (p = 0.0002). In contrast to the impact of VRC common to progression in adults and children, the HLA effects on disease outcome, that are substantial in adults, are small and statistically insignificant in infected children. These data further highlight the important role that VRC plays both in adult and pediatric progression, and demonstrate that HLA-independent factors, yet to be fully defined, are predominantly responsible for pediatric non-progression.

Vitamin D and tuberculosis: a multicenter study in children.

BACKGROUND: The aim of this study is to evaluate vitamin D levels in children with latent and active TB compared to healthy controls of the same age and ethnical background. METHODS: A multicenter observational study has been conducted in three tertiary care paediatric centres: Anna Meyer Children's University Hospital, Florence, Italy; Evelina London Children's Hospital, London, United Kingdom and Great Ormond Street Hospital, London, United Kingdom. Vitamin D was considered deficient if the serum level was <25 nmol/L, insufficient between 25 and 50 nmol/L and sufficient for a level >50 nmol/L. RESULTS: The study population included 996 children screened for TB, which have been tested for vitamin D. Forty-four children (4.4%) had active TB, 138 (13.9%) latent TB and 814 (81.7%) were controls. Our study confirmed a high prevalence of hypovitaminosis D in the study population. A multivariate analysis confirmed an increased risk of hypovitaminosis D in children with latent and active TB compared to controls [(P = 0.018; RR = 1.61; 95% CI: 1.086-2.388), (P < 0.0001; RR = 4.587; 95% CI:1.190-9.608)]. CONCLUSIONS: Hypovitaminosis D was significantly associated with TB infection in our study. Further studies are needed to evaluate a possible role of vitamin D in the treatment and prevention of tuberculosis in children.

Diagnostic features of community-acquired pneumonia in children: what's new?

AIM: To critically summarise the available data on diagnosis of CAP in children, focusing on the newest findings and on the need for new studies. METHODS: Eighty studies on the diagnosis of paediatric community-acquired pneumonia were scrutinised. RESULTS: We found no significant associations between the signs or symptoms and aetiology of pneumonia and concluded that chest radiographs remain controversial and real-time polymerase chain reaction appears more sensitive than blood cultures. CONCLUSION: Antibiotic overuse could make it difficult to differentiate viral and bacterial causes. Molecular methods provide promising tools for diagnosing infection by atypical bacteria, but are expensive and should be used selectively.

Skull base osteomyelitis and potential cerebrovascular complications in children.

Skull base osteomyelitis is an aggressive, life-threatening infection that can be challenging to diagnose and treat. It occurs predominantly in elderly immunocompromised patients, but it has also been reported in children with normal immunological status. Typical skul base osteomyelitis arises as a complication to ear infection mainly involving the temporal bone and is usually caused by Pseudomonas aeruginosa. Atypical or central skul base osteomyelitis originates from paranasal infections, is primarily centred on the clivus and is usually caused by Aspergillus, Pseudomonas, Salmonella or Staphylococcus species. Potential complications include retropharyngeal abscesses, cranial neuropathies, meningitis, intracranial abscesses, sinovenous thrombosis, and carotid artery involvement with or without ischemic infarcts. The purpose of this pictorial essay is to illustrate the spectrum of imaging findings and potential complications of skul base osteomyelitis.

Low penetrance, broad resistance, and favorable outcome of interleukin 12 receptor beta1 deficiency: medical and immunological implications.

The clinical phenotype of interleukin 12 receptor beta1 chain (IL-12Rbeta1) deficiency and the function of human IL-12 in host defense remain largely unknown, due to the small number of patients reported. We now report 41 patients with complete IL-12Rbeta1 deficiency from 17 countries. The only opportunistic infections observed, in 34 patients, were of childhood onset and caused by weakly virulent Salmonella or Mycobacteria (Bacille Calmette-Guérin -BCG- and environmental Mycobacteria). Three patients had clinical tuberculosis, one of whom also had salmonellosis. Unlike salmonellosis, mycobacterial infections did not recur. BCG inoculation and BCG disease were both effective against subsequent environmental mycobacteriosis, but not against salmonellosis. Excluding the probands, seven of the 12 affected siblings have remained free of case-definition opportunistic infection. Finally, only five deaths occurred in childhood, and the remaining 36 patients are alive and well. Thus, a diagnosis of IL-12Rbeta1 deficiency should be considered in children with opportunistic mycobacteriosis or salmonellosis; healthy siblings of probands and selected cases of tuberculosis should also be investigated. The overall prognosis is good due to broad resistance to infection and the low penetrance and favorable outcome of infections. Unexpectedly, human IL-12 is redundant in protective immunity against most microorganisms other than Mycobacteria and Salmonella. Moreover, IL-12 is redundant for primary immunity to Mycobacteria and Salmonella in many individuals and for secondary immunity to Mycobacteria but not to Salmonella in most.

Kikuchi-Fujimoto disease causing fever of unknown origin in a nine-year-old boy.

We describe a case of fever of unknown origin (FUO) in a 9-y-old boy finally diagnosed with Kikuchi-Fujimoto disease (KFD) and discuss the implications for the management of FUO in children. KFD should be considered in the differential diagnosis of patients presenting with FUO to prevent misdiagnosis and inappropriate treatment.

The likelihood of an indeterminate test result from a whole-blood interferon-gamma release assay for the diagnosis of Mycobacterium tuberculosis infection in children correlates with age and immune status.

BACKGROUND: Interferon-gamma 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 (kappa = 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 conundrum of prior bacille calmette-guerin vaccination in children of temporary residents in the United States.

Bacille Calmette-Guerin (BCG) is one of the most widely used vaccines throughout the world. Children of temporary residents in the United States frequently undergo tuberculin skin testing as part of their health maintenance visits. Management of those children with a positive skin test can lead to doctor-parent disagreements, because of differences in tuberculosis (TB) policies between the United States and other countries that routinely administer BCG vaccine. Two British specialists compare their approach with that of the United States. They also discuss the potential for specific diagnosis of latent TB infection with interferon-based TB diagnostic blood testing, to distinguish positive skin tests caused solely by BCG vaccination.

Hemophagocytic lymphohistiocytosis associated with Epstein Barr virus and Leishmania donovani coinfection in a child from Cyprus.

We present a case of a 9-month-old girl from Cyprus with hemophagocytic lymphohistiocytosis associated with Epstein Barr virus and Leishmania donovani coinfection. Treatment with liposomal amphotericin B resulted in a dramatic resolution of clinical and laboratory abnormalities. To our knowledge, this is the first reported case of a coinfection-associated hemophagocytic lymphohistiocytosis and the first clinical report of visceral leishmaniasis infection in Europe by L. donovani.

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.

Mannose-binding lectin in susceptibility and progression of HIV-1 infection in children.

BACKGROUND: Mannose-binding lectin (MBL; encoded by MBL-2) is a circulating pattern-recognition molecule that recognizes microbial carbohydrate motifs, leading to complement activation and cell lysis. Mutations in the MBL-2 promoter and of the MBL-2 gene exon 1 result in reduced protein levels and increased susceptibility to infection. We have investigated the effect of MBL-2 polymorphisms on susceptibility and progression of HIV-1 infection in children. PATIENTS AND METHODS: One-hundred and twenty-eight children, aged 2-16 years were recruited. MBL-2 genotypes were determined by PCR and heteroduplex analyses. Serum MBL levels were measured by ELISA. Comparison of genotypes (A=wild type, O=variant alleles) and protein levels between groups was performed using chi-squared, Mann-Whitney U or Kruskal-Wallis tests. RESULTS: Children were classified according to the Centers for Disease Control and Prevention clinical classification: A, B or C (mildly symptomatic [n=39], moderately symptomatic [n=58] or severely symptomatic AIDS [n=31]) or immune category 1 (n=77), 2 (n=46) or 3 (n=5). Analysis of MBL-2 genotypes with respect to clinical classification yielded minimal differences. However, patients in immunological categories 2 and 3 (<25% CD4+ T cells) were more likely to have MBL-2 variant alleles (P=0.01). We further explored MBL status with respect to disease progression. Only 1/10 long-term non-progressors (LTNPs) had an MBL-2 mutation (A/D) with a corresponding protein level of 611 ng/ml. CONCLUSIONS: MBL deficiency was more frequent in patients with severe disease as assessed by CD4+ T-cell status. MBL-2 variants may be less frequent in children classified as LTNPs. MBL analysis could be useful in identifying children with slow disease progression and, consequently, may not require immediate antiretroviral treatement.

Severe gynecomastia in an African boy with perinatally acquired human immunodeficiency virus infection receiving highly active antiretroviral therapy.

Highly active antiretroviral therapy (HAART) slows the progression of human immunodeficiency virus (HIV) disease and lowers mortality and morbidity in children. Coincident with these advances, an increasing number of side effects are being reported. We describe an adolescent boy with perinatally acquired HIV infection who developed significant bilateral breast enlargement as a result of HAART. He required bilateral mastectomies. Pediatricians need to be aware of less common side effects of HAART.

Adherence and acceptability of once daily Lamivudine and abacavir in human immunodeficiency virus type-1 infected children.

BACKGROUND: Data on adherence to and acceptability of once daily lamivudine and abacavir are few. METHODS: Twenty-four U.K. human immunodeficiency virus type-1 infected children 2-13 years of age participated in the Pediatric European Network for the Treatment of AIDS (PENTA) 13 single arm, open label pharmacokinetic study of twice (every 12 hours) versus once (every 24 hours) daily lamivudine and abacavir. Caregivers were asked to complete an adherence questionnaire at screening, week 0 (switch once daily to twice daily) and weeks 4, 12 and 24. Acceptability was also assessed at screening and week 24. RESULTS: Fifteen children were taking lamivudine and abacavir as part of their regimens, 8 lamivudine only and 1 abacavir only. After switching to lamivudine/abacavir every 24 hours, 7 (29%) received once daily regimens for all drugs. Twenty-three (96%) caregivers thought that switching to once daily lamivudine/abacavir would make things a lot/a little easier for their child: 17 (71%) thought it was actually easier after switching. Six mothers with children taking a mixture of twice/once daily drugs changed their mind, whereas all mothers of children on once daily regimens agreed that it was a lot easier. Nonadherence (missing doses in the last 3 days) was reported for 8 of 118 (7%) completed questionnaires; missed doses were reported for every drug in the regimen with reasons such as "not at home," "forgot" or "routine different from normal." However, viral loads in all these children remained <100 copies/mL. CONCLUSION: Adherence to once daily abacavir/lamivudine was good with no evidence of an association between nonadherence and virologic rebound. Acceptability of once daily drugs was best when the whole regimen was dosed once daily.

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.

Plasma pharmacokinetics of once- versus twice-daily lamivudine and abacavir: simplification of combination treatment in HIV-1-infected children (PENTA-13).

BACKGROUND: There are few data on plasma and intracellular pharmacokinetics (PK) of once-daily (q24h) nucleoside analogues in HIV-infected children. METHODS: Children aged 2-13 years receiving combination treatment containing lamivudine (3TC) (4 mg/kg) and/or abacavir (ABC) (8 mg/kg) twice daily (q12h) were included in this single-arm, open-label, crossover study. Intensive plasma PK sampling was performed at steady state, after which children switched to q24h dosing and PK sampling was repeated 4 weeks later. Daily area under the curve (AUC0-24) and peak level (Cmax) of q24h and q12h regimens were compared by geometric mean ratios (GMRs) with 90% confidence intervals (CIs). Children were followed for 24 weeks to evaluate safety and virological response. RESULTS: 24 children were enrolled, of whom 20 [median age (range) 5.6 (2.1-12.8) years] had evaluable PK data for 3TC (n=19) and/or ABC (n=14). GMRs of 3TC and ABC AUC0-24 and Cmax q24h versus q12h significantly exceeded 1.0. GMRs were not significantly different between children aged 2-6 versus 6-13 years old (P>0.08). Of note, 3TC Cmax values for both q12h and q24h were significantly lower in children aged 2-6 versus 6-13 years old. No child discontinued due to adverse events. At baseline, 16 out of 20 children had a viral load <100 copies/ml compared with 17 out of 19 at week 24. CONCLUSION: AUC0-24 and Cmax of both 3TC and ABC q24h were not inferior to q12h dosing in children. Insufficient results were obtained concerning intracellular levels of the active triphosphate moieties of both agents. Virological data did not indicate a marked difference in antiviral activity between q12h and q24h regimens.

Nevirapine use in HIV-1-infected children.

OBJECTIVES: To evaluate the safety, efficacy, and clinical, virological, and immunological responses in HIV-1-infected children receiving nevirapine as part of combination antiretroviral therapy (ART). METHODS: A review of case notes of all HIV-1-infected children 96 weeks after starting nevirapine, under a national compassionate access scheme between August 1997 and March 1999 in the UK. Nevirapine was dosed according to the manufacturer's guidelines. RESULTS: Seventy-four children (36 boys, 28 naive to ART) were enrolled, with a median age of 5.2 years, viral load of 5.1 log copies/ml and CD4 lymphocyte count of 13.5%. The liquid formulation and tablets of nevirapine were well tolerated. The proportions of patients achieving undetectable viral load levels at weeks 12, 24, 48 and 96 were 30, 40, 36 and 33%, respectively (intention-to-treat analysis). Of children not on a protease inhibitor who received more than 300 mg/m2/day of nevirapine, 60% had undetectable viral loads at week 96, compared with 17% on recommended doses. Outcomes were similar for patients receiving nevirapine once or twice daily. CD4 cell count percentages increased significantly, with median values sustained above 25% by week 48 onwards. Z-scores for weight and height increased significantly during 96 weeks of treatment. Rash occurred in 20%, of which four (5%) were severe. There were no cases of Stevens-Johnson syndrome. CONCLUSION: Nevirapine was mostly well tolerated, and was associated with encouraging clinical and immunological responses. Virological responses in this cohort support the use of nevirapine doses greater than 300 mg/m2/day, which is higher than currently recommended by the manufacturers.

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.

Could neonatal disseminated herpes simplex virus infections be treated earlier?

INTRODUCTION: Neonatal disseminated herpes simplex virus (HSV) infection can cause rapidly progressive multiple organ failure with an 85% mortality if untreated. Early recognition and treatment may improve outcome [N Engl J Med 324(1991)450]. OBJECTIVES: (i) To determine the number and presentation of neonates with disseminated HSV admitted to an intensive care unit. (ii) To determine paediatric Specialist Registrar (SpR) awareness of the diagnosis and management of a typical potential case of neonatal disseminated HSV. METHODS: (i) A 10-year review of case notes of neonates admitted to the intensive care unit (ICU) at Great Ormond Street Hospital. (ii) A telephone questionnaire of 'on-call' Paediatric SpR's in the London area. RESULTS: Eight cases of confirmed disseminated HSV infection were identified. All died. Each case followed a similar clinical course with presentation between days 5-9 of life (median day 7). A short prodrome preceded the rapid development of disseminated intravascular coagulopathy (DIC), hepatitis and multiple organ failure. Only three cases received antiviral treatment in the first 24 h after hospital admission. None of the 30 registrars who were interviewed initially considered disseminated HSV in the differential diagnosis of a 7-day-old baby presenting with non-specific signs of sepsis. Only 4/30 referring unit protocols included disseminated HSV in the differential diagnosis of neonatal sepsis. CONCLUSIONS: HSV infection should be considered in the differential diagnosis of the acutely unwell neonate. This condition is rare but well documented in the literature. Effective antiviral therapies exist but are often not started early in the clinical course. Awareness of this condition needs to be increased.

Polyarticular septic arthritis in an 11-year-old child.

A child with polyarthritis is always a diagnostic challenge for the treating physician. Polyarthritis can be a clinical manifestation of diverse disease processes, and the differential diagnosis is understandably very broad. We present a case of polyarticular septic arthritis, which is osteomyelitis complicated, caused by Streptococcus pyogenes identified by 16S polymerase chain reaction (PCR) in a healthy child, with previous synovial fluid cultures negative. This case underlines the importance of early aggressive therapy and the role of PCR/16S ribosomal bacterial DNA amplification to detect the causative microorganisms in septic arthritis when cultures remain negative.

Successful outcome of renal transplantation in a child with HIV-associated nephropathy.

Classical HIV-associated nephropathy (HIVAN) was first described before the advent of highly active antiretroviral therapy in late stages of HIV disease with high viral load and low CD4 cell count. Renal transplantation has been successful in a large series of carefully selected HIV-infected adults, with patient and renal allograft survival approaching those of non-HIV-infected patients. We report the successful outcome of living related renal transplantation in a vertically transmitted HIV-infected 8-year-old girl with end-stage kidney disease on haemodialysis due to HIVAN. The pretransplant preparations and post-transplant care, with particular emphasis on immunosuppression and avoidance of opportunistic infections, are discussed.