Persistence of HIV reservoir following successful haematopoietic stem cell transplant for juvenile myelomonocytic leukaemia in a child with perinatally acquired HIV.

This report describes a case of juvenile myelomonocytic leukaemia (JMML) on a background of both perinatally acquired HIV infection and congenital cytomegalovirus, and management of antiretroviral therapy during haematopoietic stem cell transplant. Peripheral blood HIV viral load remained below the lower limit of detection throughout and following transplant and is currently <20 RNA copies/mL. The child is currently in remission from JMML, but HIV DNA remains detectable despite myeloablative conditioning and sustained plasma HIV viral suppression.

Management of paediatric tuberculosis in leading UK centres: unveiling consensus and discrepancies.

SETTING: Large specialist paediatric TB clinics in the UK. OBJECTIVE: To evaluate clinical practice and compare with national and international guidelines. DESIGN: A survey based on an electronic questionnaire on the management of latent tuberculous infection (LTBI) and tuberculosis (TB) disease was conducted in 13 specialist paediatric TB clinics. The consensus and discrepancies were evaluated by descriptive analysis. RESULTS: Practice was reportedly different when choosing age limits for preventive treatment for TB contacts with initially negative tuberculin skin tests (TSTs), interpretation of TST results and use of interferon-gamma release assays (IGRAs) in the context of LTBI. In relation to management of children with TB disease, practices varied for duration of treatment of osteoarticular TB, monitoring for ethambutol ocular toxicity and use of pyridoxine. There was limited experience with multidrug-resistant TB (MDR-TB), and over half of the clinics monitored MDR-TB contacts without giving preventive treatment. CONCLUSIONS: The survey showed heterogeneity in several aspects of clinical care for children with TB. Available paediatric TB guidelines differ substantially, explaining the wide variations in management of childhood TB. Prospective paediatric studies are urgently required to inform and standardise clinical practice, especially in the context of evolving drug resistance.

Fever in the returning child traveller: approach to diagnosis and management.

During the last half century there has been an exponential increase in international travel including to more exotic and long-haul destinations. The assessment of febrile returning child travellers presents diagnostic challenges and is often performed poorly. A detailed travel and medical history, clinical examination and appropriate first-line investigations are essential. While the majority of children will have a common self-limiting or easily treatable infection, it is important to consider other causes, including imported infections, which may be life-threatening or highly contagious. In this article, we provide guidance on the initial assessment and management of such children with a focus on some of the more important imported infections, including malaria, dengue, typhoid fever, travellers' diarrhoea, respiratory infections, tuberculosis, schistosomiasis and rickettsial diseases.

Management of Kawasaki disease.

Kawasaki disease (KD) is an acute self-limiting inflammatory disorder, associated with vasculitis, affecting predominantly medium-sized arteries, particularly the coronary arteries. In developed countries KD is the commonest cause of acquired heart disease in childhood. The aetiology of KD remains unknown, and it is currently believed that one or more as yet unidentified infectious agents induce an intense inflammatory host response in genetically susceptible individuals. Genetic studies have identified several susceptibility genes for KD and its sequelae in different ethnic populations, including FCGR2A, CD40, ITPKC, FAM167A-BLK and CASP3, as well as genes influencing response to intravenous immunoglobulin (IVIG) and aneurysm formation such as FCGR3B, and transforming growth factor (TGF) ß pathway genes. IVIG and aspirin are effective therapeutically, but recent clinical trials and meta-analyses have demonstrated that the addition of corticosteroids to IVIG is beneficial for the prevention of coronary artery aneurysms (CAA) in severe cases with highest risk of IVIG resistance. Outside of Japan, however, clinical scores to predict IVIG resistance perform suboptimally. Furthermore, the evidence base does not provide clear guidance on which corticosteroid regimen is most effective. Other therapies, including anti-TNFα, could also have a role for IVIG-resistant KD. Irrespective of these caveats, it is clear that therapy that reduces inflammation in acute KD, improves outcome. This paper summarises recent advances in the understanding of KD pathogenesis and therapeutics, and provides an approach for managing KD patients in the UK in the light of these advances.

Epidemiology of tuberculosis in children in London, 2009-2011: are opportunities for prevention being missed?

SETTING: London, United Kingdom. OBJECTIVE: To explore missed opportunities (MO) for the prevention of tuberculosis (TB) in children aged 0-15 years. DESIGN: Parents/guardians of children aged <15 years diagnosed with TB and reported through surveillance were interviewed about bacille Calmette-Guérin vaccination (MO-V) or contact tracing and screening for TB (MO-C) via an algorithm reflecting eligibility. RESULTS: Annual TB incidence was 12 per 100,000 (65/100,000 in Black Africans, 20/100,000 in Indian or Pakistani children). The response rate was 36% (145/405). About 20% of UK-born children had not been vaccinated. MO-V was not associated with any particular factor. Contact with a known TB case before illness had occurred in 71 children (49%; 71% in those aged 0-1 years vs. 30% in those aged 11-15 years), of whom 64 (91%) were diagnosed through contact tracing. MO-C had been conducted in six (4% overall). Children with MO-C were all of Black ethnic origin. Their index cases were family members (within their household) or relatives or family friends from abroad (outside their household). MO-C was not associated with any other factor. CONCLUSION: Although overall few missed opportunities for prevention had occurred, we recommend increased rigour when performing contact tracing in any case where a child may have been exposed.

Recent trends in tuberculosis in children in London.

BACKGROUND: Childhood tuberculosis (TB) represents a sentinel event of recent transmission and is an indication of the effectiveness of prevention and control interventions. We analysed the trends in the epidemiology of TB in children in London aged 0-14 years between 1999 and 2006. METHODS: Data were extracted from the Enhanced TB Surveillance System. RESULTS: Between 1999 and 2006, there were 1370 cases of TB in children. Incidence was higher in older children and in girls. The incidence rates in London Boroughs varied from 0.4/100,000 to 32.7/100,000. Between 1999 and 2006, Black-Africans comprised 49.2% of all TB cases in children, children from the Indian Subcontinent 21.8% and Whites 8.5%. The proportion of cases born in the UK averaged 52.4% during this period. Of non-UK-born children 79.3% were diagnosed with TB within 5 years of entry. CONCLUSIONS: Ethnicity, country of birth and age are important risk factors for development of. With an overall TB incidence in London exceeding 40/100,000, universal BCG immunization of all neonates should be considered across all London boroughs.

An evaluation of the completeness of reporting of childhood tuberculosis.

The sensitivity of the Enhanced Tuberculosis Surveillance (ETS) scheme for monitoring tuberculosis in children is unknown. We used the British Paediatric Surveillance Unit (BPSU) reporting scheme to conduct a prospective observational study of tuberculosis in children aged <16 yrs in the UK. Reported cases were then matched with records from the ETS database. A total of 320 cases were reported to the BPSU between January and December 2004. We estimated that there were 557 paediatric cases in England, Wales and Northern Ireland in 2004: 222 (40%) cases reported to both BPSU and ETS, 98 (18%) reported to BPSU but not ETS and 237 (42%) reported to ETS but not BPSU. Children aged <5 yrs were significantly less likely to be reported to ETS compared with older children (p<0.01). There is substantial under-reporting of childhood tuberculosis, especially of children aged <5 yrs. ETS provides a representative picture of the demographics but may miss approximately 20% of cases. This should be taken into account when planning training and resource requirements for tuberculosis. Increased efforts are needed to ensure that all paediatric cases are reported to ETS.

Tuberculosis in the United Kingdom and Republic of Ireland.

AIMS: To describe the clinical features, diagnosis and management of children with tuberculosis in the United Kingdom and Republic of Ireland. METHODS: Cases of culture-confirmed and clinically diagnosed tuberculosis were reported to the British Paediatric Surveillance Unit from December 2003 to January 2005. RESULTS: 385 eligible cases were reported. Pulmonary disease was present in 154 (40%) children. Just over half (197, 51%) of children presented clinically and most of the remainder (166, 43%) at contact tracing. A probable source case was identified for 73/197 (36%) of the children presenting clinically. The majority (253, 66%) of children had a microbiological and/or histological investigation, and culture results were available for 240 (62%), of whom 102 (26%) were culture positive. Drug resistance was reported in 15 (0.4%) cases. 44% (128/292) of non-white children did not receive the recommended quadruple drug therapy. Seven children died. Only 57% (217) of children were managed by a paediatric subspecialist in respiratory or infectious diseases or a general paediatrician with a special interest in one of these areas. Fewer than five cases were reported from 119/143 (83%) respondents and 72 of 96 (75%) centres. CONCLUSIONS: Many paediatricians and centres see few children with tuberculosis. This may affect adherence to national guidelines. Managed clinical networks for children with tuberculosis may improve management and should be the standard of care.

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.

Trends in imported childhood malaria in the UK: 1999-2003.

OBJECTIVE: To describe the epidemiology of imported malaria in children in the UK. METHODS: Surveillance data on children with imported malaria, collected through an enhanced surveillance network set up by the Malaria Reference Laboratory (London, UK), diagnosed between January 1999 and December 2003 were analysed. RESULTS: Over the 5-year study period, 9238 cases were reported to the Malaria Reference Laboratory, and children accounted for 1456 (14.8%) cases. The number of imported paediatric malaria cases fell from 326 in 1999 to 241 in 2003. Malarial infection occurred in children of all ages and the number of patients increased gradually with age. Visiting family and relatives was the most common reason for travel (59.5%), with only 7.2% travelling to an area endemic to malaria on holiday. Most infections (88.4%) were acquired in Africa, and mainly in Nigeria (49.7%). Plasmodium falciparum was responsible for 81.7% of all cases, followed by P. vivax (11.1%). The number of both P. falciparum and P. vivax cases fell gradually from 262 and 45 cases in 1999 to 196 and 20 cases in 2003, respectively. Malaria prophylaxis was taken by 39% of 500 children with malaria who had travelled to a country endemic to malaria. The proportion of children with malaria who had taken malaria prophylaxis decreased steadily from 53% in 1999 to 29% in 2003. Two (0.14%) children died compared with 62 (0.76%) adults over the 5-year study period (p = 0.007). CONCLUSIONS: Although the incidence of malaria has started to decline, a considerable number of children are still diagnosed with malaria in the UK. In addition, the proportion of children with malaria who had taken malaria prophylaxis is falling. Although it is reassuring to note the low mortality, there is an urgent need to improve preventive measures among families travelling to high-risk countries.

Does BCG have a role in tuberculosis control and prevention in the United Kingdom?

The United Kingdom has recently changed its BCG vaccination policy in response to the changing epidemiology of tuberculosis (TB) in children. One of the changes has been the abandonment of the long standing school's BCG programme because of the low risk of TB in that population. The other change has been the targeting of those infants and children at increased risk of TB, particularly in populations with increased rates of TB. However, there remain questions as to what role BCG plays in TB control and prevention in the UK.

Could a herpesvirus be the cause of Kawasaki disease?

Kawasaki disease (KD) is an acute vasculitis of early childhood, the cause of which remains unknown. Many lines of evidence suggest an infectious aetiology, which may-in association with host genetic factors-lead to the characteristic clinical presentation of this disease. Accumulating data including animal models and epidemiological and immunological studies, suggest that viruses have an important role in human vasculitic disease. Whereas many infectious agents including viruses have been postulated as possible causes of KD, no single agent has been shown definitely to be associated with this disease and the causative agent remains elusive. We hypothesise that a ubiquitous virus of the gamma herpesvirus family is the likely aetiological agent for KD in genetically susceptible individuals.

Kawasaki disease: an evidence based approach to diagnosis, treatment, and proposals for future research.

This article proposes a clinical guideline for the diagnosis and treatment of Kawasaki disease in the UK based on the best available evidence to date, and highlights areas of practice where evidence is anecdotal or based on retrospective data. Future research as proposed by the London Kawasaki Disease Research Group is outlined, and clinicians are invited to prospectively enroll their suspected cases into this collaborative research project.

Surface and cytoplasmic immunoglobulin expression in circulating B-lymphocytes in acute Kawasaki disease.

Kawasaki disease (KD) is an acute vasculitis of young childhood predominantly affecting the coronary arteries. IgA plasma cells have been found to infiltrate vascular and nonvascular tissues in fatal acute KD. To determine whether IgA B-lymphocytes were increased in the peripheral blood of patients with KD, we performed three-color flow cytometry to detect surface and cytoplasmic immunoglobulin expression (IgA, IgM, IgD, and IgG) of peripheral B-lymphocytes in KD patients during the acute, subacute, and convalescent stages of illness and in age-matched febrile and afebrile pediatric controls. Surprisingly, absolute numbers of B-lymphocytes expressing IgA were found to be significantly lower in peripheral blood of acute KD patients compared with febrile and afebrile pediatric controls. These findings indicate that IgA plasma cells are not present in KD tissue as a result of excess numbers of these IgA B-lymphocytes in peripheral blood. We speculate that IgA B-lymphocytes are selectively withdrawn from the peripheral circulation into KD target tissues as part of a specific IgA immune response.

Gastrostomy tube insertion for improvement of adherence to highly active antiretroviral therapy in pediatric patients with human immunodeficiency virus.

OBJECTIVES: Newer combination antiretroviral therapies used to treat human immunodeficiency virus (HIV)-infected individuals have resulted in dramatic delays in HIV progression, with reduction in mortality and morbidity. However, adherence to highly active antiretroviral therapy (HAART) may be problematic, particularly in HIV-infected children. Reasons for nonadherence include refusal, drug tolerability, and adverse reactions. We assess: 1) the potential benefits of gastrostomy tube (GT) for the improvement of adherence to HAART in HIV-infected children, and 2) the factors that may result in improved viral suppression after GT placement. METHODS: The medical records of 17 pediatric HIV-infected patients, in whom GT was used to improve HAART adherence, were retrospectively reviewed for clinical and laboratory parameters. Each record was reviewed for the period of 1 year before and after GT insertion. The main outcome parameters were virologic (plasma HIV RNA polymerase chain reaction quantification) and immunologic (CD4 cell counts). Documentation of adherence to medications in medical records was also assessed during the study. Parental questionnaires were used to determine GT satisfaction and medication administration times. The Wilcoxon rank sum test was used to assess change in viral load (VL) and CD4 cell percentages. RESULTS: GT was well-tolerated with minor complications, such as local site tenderness, reported by 4 patients (23%). Before GT insertion, only 6 patients (35%) were documented as being adherent, compared with all patients after GT insertion. Ten patients (58%) had >/=2 log(10) VL decline after GT insertion (median: 3.2 log(10)), compared with 7 patients (42%) who had /=2 log(10) VL decline, therapy was changed at the time of or soon after GT insertion (median:.8 months; range: 0-6 months), compared with 7 patients with <2 log(10) VL decline who had therapy changed before GT insertion (median: 3.2 months; range: 1-8 months). Parental questionnaires reported significantly shorter medication administration times after GT insertion, with 70% of patients taking >5 minutes before GT, compared with 0% after GT. Questionnaires indicated satisfaction with GT, with perceived benefits being reduced medication administration time and improved behavior surrounding taking medications. CONCLUSIONS: GT is well-tolerated in pediatric HIV-infected patients and should be considered for selected patients to overcome difficulties with medication administration and to improve adherence. For maximal virologic response, combination therapy should be changed at the time of GT insertion.

New perspectives in the drug treatment of Kawasaki disease.

Kawasaki disease (KD) has become the leading cause of acquired heart disease in developed countries. Conventional therapy for KD includes intravenous gammaglobulin (2 g/kg as a single dose over 12 hours) and aspirin (acetylsalicylic acid; high dose until the fourteenth day of illness then low dose). Therapy administered within the first 10 days of the onset of the illness has been shown to reduce arterial wall inflammation and thereby prevent the development of coronary artery aneurysm formation. The majority of patients with KD will respond to conventional therapy. However, the management of nonresponders and patients with complications (such as acute thrombosis and chronic coronary artery changes) remains controversial. In this review article, we address some of these controversies and also describe newer treatment modalities that have been used in the management of patients with KD, both in the acute and convalescent stages of the disease.