Delane Shingadia

Adenovirus: an increasingly important pathogen in paediatric bone marrow transplant patients

Adenovirus is increasingly being recognised as a significant pathogen in children following bone marrow transplantation. The virus is endemic in the general paediatric population, and frequently causes severe disease in immunocompromised patients, especially children. Immune responses to adenovirus infection are not fully understood but T-cell responses appear to be important for recovery. Infections can affect a variety of organs with gastrointestinal and urinary tract diseases being the most common. When disseminated infection occurs, reported mortality rates are as high as 60%. The responses to treatment in immunocompromised patients have generally been disappointing. New molecular diagnostic techniques have meant that adenoviral infections can now be detected early, often before symptoms have developed. Clinicians now screen for adenovirus infection to allow early initiation of treatment. It is hoped that this approach, together with effective antiviral therapy, will reduce the deaths from this common virus in high-risk children.

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.

Global epidemiology of paediatric tuberculosis

Tuberculosis is one of the major infections affecting children worldwide. It causes significant morbidity and mortality, especially in infants and young children. Factors such as overcrowding, poverty and the HIV epidemic have all contributed to the resurgence of tuberculosis globally. The highest rates of tuberculosis occur in resource-poor countries and over the last decade case notifications in children have been increasing steadily, particularly in Sub-Saharan Africa. Mycobacterium tuberculosis infects millions of children worldwide every year, yet accurate information on the extent and distribution of disease in children is not available for most of the world. We describe some of the unique aspects of tuberculosis infection in children and review the epidemiology of disease in children worldwide.

Adenovirus infection after pediatric bone marrow transplantation: Is treatment always necessary?

BACKGROUND Adenovirus infections are associated with significant rates of morbidity and mortality among children after bone marrow transplantation (BMT). Many transplantation units use molecular virological methods, such as polymerase chain reaction (PCR), for surveillance for adenovirus infection and give preemptive antiviral therapy to children with evidence of disseminated adenovirus infection. This treatment strategy has never been evaluated in clinical trials. METHODS We retrospectively tested blood samples obtained from a cohort of children who had undergone BMT before the introduction of regular weekly surveillance for adenovirus infection. A total of 273 samples collected from 26 patients between May 1998 and June 2002 were tested for adenovirus infection by quantitative PCR. Virus load was quantified for each sample yielding positive test results, and the clinical notes and virological records of each child were reviewed. RESULTS Evidence of adenovirus infection was found in 11 children (42%), 7 of whom had not previously had positive test results. Receipt of T cell-depleted transplants was associated with a significantly higher incidence of adenovirus infection during the posttransplantation period. The 2 children who died from adenovirus disease developed infection within 2 weeks after transplantation, and both had very low absolute lymphocyte counts at the time of diagnosis. Seven of 11 children with blood samples that were found to be positive for adenovirus by PCR cleared the virus without antiviral therapy. CONCLUSIONS Surveillance for adenovirus by PCR is better than symptomatic testing for detecting adenovirus infection. Antiviral therapy may not be necessary for all children who develop adenovirus viremia after BMT.

Childhood malaria in East London.

Objectives. To describe the epidemiologic, clinical and laboratory features of children younger than 16 years with malaria in East London. Methods. Retrospective case review of all children admitted to two East London hospitals with malaria identified between 1996 and 2001 with the use of notifications and hospital discharge data. Results. A total of 211 children with a median age of 9 years (range, 11 to 179 months) were identified. Children living in the UK who acquired malaria while visiting a malaria-endemic country on holiday accounted for 82% of cases, whereas the rest were children visiting the UK from endemic areas. Three-fourths of children who had traveled to a malaria-endemic area were born in the UK, and 93% were of Black African ethnicity. The peak seasonal incidence was late summer/early autumn. Plasmodium falciparum acquired in Africa accounted for 91% of cases. Although 42% of children took antimalarial prophylaxis, only 15% of medications were taken according to recommended guidelines. Another family member, most often a sibling, was found to have concurrent malaria in 23% (49 of 211) of cases. On the basis of the WHO criteria, 15 children (7.1%) 15 months to 15 years of age had severe malaria, including convulsions (n = 4), acute renal failure (n = 3), jaundice (n = 4), severe anemia (n = 3) and >2% parasitemia (n = 6). Conclusions. The majority of children with malaria in this study were UK-born, school age, of Black African ethnicity and were visiting family in Africa, often with other family members. Most children had low level parasitemia and uncomplicated malaria, and they responded rapidly to antimalarial treatment.

The epidemiology of tuberculosis in Europe

Tuberculosis (TB) continues to be one of the most devastating and widespread infections in the world. It is estimated that in 2004 there were 8.9 million new cases of TB globally.1 In general, children make up only a small proportion of cases, but in some high-incidence countries up to 15% of all TB cases occur in children.2 In June 2005 the World Health Organization (WHO) approved a new Stop TB Strategy with the aim of dramatically reducing the global burden of TB by 2015.3 Their intention is to cure at least 85% of sputum smear-positive cases and reduce the prevalence of and deaths due to TB by 50% relative to the rates in 1990. The WHO Global tuberculosis control report shows that the greatest burden of TB is in sub-Saharan Africa and Asia, with TB case notifications in the WHO European Region constituting less than 10% of worldwide notifications.1 While notifications are an excellent source of information on adult disease, an accurate description of the burden of TB in children is very difficult to obtain. The WHO notification criteria include only cases that are sputum smear positive. Fewer than 15% of children with culture-proven TB will be sputum smear positive, with the result that only a small percentage of children with TB will be represented in the data. The quality of information provided to the WHO can also vary and in many countries surveillance data are often unreliable due to poor diagnostic facilities and reporting systems. Because of these issues the International Union Against Tuberculosis and Lung Disease has stated that reliable information on the incidence of TB in childhood can only be obtained in developed countries, which have better diagnostic and reporting systems.4 In Europe there is a huge disparity in the rates of …

Effect of tenofovir disoproxil fumarate on risk of renal abnormality in HIV-1-infected children on antiretroviral therapy: a nested case-control study.

Objective:To investigate the association between tenofovir disoproxil fumarate (TDF) use and renal abnormality in a large cohort of HIV-1-infected children on antiretroviral therapy (ART). Design:Nested case–control study. Methods:Patients were from the Collaborative HIV Paediatric Study, a cohort of approximately 95% of HIV-1-infected children in the UK/Ireland. Serum (but not urine) biochemistry results for 2002–2008 were obtained for 456 ART-exposed children (2–18 years) seen at seven hospitals. Cases had either confirmed hypophosphataemia DAIDS grade at least 2 or estimated glomerular filtration rate (eGFR) less than 60 ml/min per 1.73 m2; three controls per case were matched by hospital. Conditional logistic regression identified risk factors for renal abnormality. Results:Twenty of 456 (4.4%) had hypophosphataemia, and one had eGFR less than 60 ml/min per 1.73 m2. Ten of 20 (50%) cases versus 11 of 60 (18%) controls had taken TDF-containing ART for a median [interquartile range (IQR)] of 18 [17–20] months, as part of second-line or salvage therapy. The hypophosphataemia incidence rate was 4.3/100 person-years in the TDF group versus 0.9/100 person-years in those not exposed to TDF. In multivariable analysis, only TDF exposure in the previous 6 months was associated with hypophosphataemia [odds ratio (OR) = 4.81, 95% confidence interval (CI) 1.45–16.0, P = 0.01]. In six of 10 children with hypophosphataemia and at least four subsequent phosphate measurements, phosphate values returned to normal when TDF was stopped; in four with three measures or less, values rose but remained subnormal. Conclusions:Hypophosphataemia was uncommon (4%), but was associated with prolonged TDF use, and was generally reversible following TDF withdrawal. Findings highlight the importance of continuing to monitor longer-term renal function, in particular tubular function, especially in those taking TDF. Further studies assessing urine biochemistry measures which more accurately indicate renal tubular damage are required.

Prospective, National Clinical and Epidemiologic Study on Imported Childhood Malaria in the United Kingdom and the Republic of Ireland.

Background: Current knowledge of clinical features of imported childhood malaria is largely limited to small, retrospective, and/or single-center case series. This prospective, population-based study describes the epidemiology and clinical features of imported childhood malaria in children <16 years in the United Kingdom and Republic of Ireland. Methods: Active prospective national surveillance with clinical data collection was performed between January 1, 2006 and January 31, 2007 through the British Pediatric Surveillance Unit and capture-recapture analysis using cases reported independently to respective national surveillance centers. Results: There were 290 cases, including 186 reported through the British Pediatric Surveillance Unit with clinical details. Capture-recapture analysis estimated the burden of imported childhood malaria to be 2.8/100,000 per year for the United Kingdom and 4.6/100,000 per year for Ireland. Black-African children born in the United Kingdom and Ireland and traveling to West Africa during school holidays without antimalarial prophylaxis accounted for the majority of cases. Thirty of 117 children (26%) who had traveled to a malaria-endemic country had previously been diagnosed with malaria, reflecting missed opportunities to educate families on malaria prevention. A third of children (46/148) with Plasmodium falciparum malaria fulfilled World Health Organization criteria for severe or potentially complicated malaria, although only 11/46 (24%) required intensive care. The choice of antimalarials varied considerably among hospitals and within the same hospital. However, recrudescence occurred in only 1 child and none died. Conclusions: Interventions to prevent imported childhood malaria should focus on Black-African families traveling to West Africa, while pediatricians should be offered clearer guidance on the treatment of childhood malaria.

Epidemiology and treatment outcome of childhood tuberculosis in England and Wales: 1999–2006

Objective: To describe the recent trends in demographic, clinical and microbiological characteristics and outcome of treatment in paediatric cases of tuberculosis. Design: National surveillance study. Setting: England and Wales. Patients: All children under the age of 16 years reported with tuberculosis to the national enhanced surveillance system between 1999 and 2006 were included. Main outcome measures: Proportions, and rates of disease, by demographic characteristics, site of disease, diagnostic delay, culture confirmation, species, drug susceptibility and treatment outcome. Results: 3563 cases of tuberculosis in children were reported between 1999 and 2006. The incidence rate remained stable at around 4.3 per 100 000 (95% CI 4.1 to 4.4). Patients born outside the UK had a tuberculosis rate higher than children born in the UK (37 per 100 000 vs 2.5 per 100 000) and this rate increased over the period. Rates in the black African ethnic group were highest at 88 per 100 000. 60% of children had pulmonary disease, the commonest presentation, but only 948 (27%) had culture confirmed tuberculosis. The median time to diagnosis from onset of symptoms was 37 days (interquartile range 12–89). The proportions of cases with rifampicin, isoniazid and multi-drug resistant isolates were 2.4%, 9.3% and 2.3%, respectively. 88% of children completed treatment and less than 1% died. Conclusions: Overall rates of tuberculosis in children have remained stable, with the majority completing treatment. Rates are, however, highest in children not born in the UK, particularly among certain ethnic minority groups. Levels of drug resistance are also high.

Nonprogressing HIV-infected children share fundamental immunological features of nonpathogenic SIV infection

Pediatric HIV patients who do not rapidly develop AIDS are shown to have immunological features similar to nonhuman primates that experience nonpathogenic SIV infection. HIV progression at a standstill Although most people that get infected with HIV develop AIDS, rare individuals maintain immune function in the presence of virus, a phenomenon also seen in natural hosts of the closely related SIV. Muenchhoff et al. describe a cohort of pediatric HIV patients who have normal CD4 T cell counts, despite high viremia and lack of antiviral treatment. These children have low immune activation, including less chemokine receptor CCR5 expression on central memory CD4 T cells, similar to sooty mangabeys infected with SIV. The immune mechanisms described in these patients shed light on HIV pathogenesis, which may help develop future treatments. Disease-free infection in HIV-infected adults is associated with human leukocyte antigen–mediated suppression of viremia, whereas in the sooty mangabey and other healthy natural hosts of simian immunodeficiency virus (SIV), viral replication continues unabated. To better understand factors preventing HIV disease, we investigated pediatric infection, where AIDS typically develops more rapidly than in adults. Among 170 nonprogressing antiretroviral therapy–naïve children aged >5 years maintaining normal-for-age CD4 T cell counts, immune activation levels were low despite high viremia (median, 26,000 copies/ml). Potent, broadly neutralizing antibody responses in most of the subjects and strong virus-specific T cell activity were present but did not drive pediatric nonprogression. However, reduced CCR5 expression and low HIV infection in long-lived central memory CD4 T cells were observed in pediatric nonprogressors. These children therefore express two cardinal immunological features of nonpathogenic SIV infection in sooty mangabeys—low immune activation despite high viremia and low CCR5 expression on long-lived central memory CD4 T cells—suggesting closer similarities with nonpathogenetic mechanisms evolved over thousands of years in natural SIV hosts than those operating in HIV-infected adults.