Gilbert T Chua1 †, MB, BS, FHKAM (Paediatrics), Joshua SC Wong2 †, MB, BS, FHKAM (Paediatrics), Jaime Chung2, MB, BS, Ivan Lam2, FHKCP, FHKAM (Paediatrics), Joyce Kwong3, FHKAM (Pathology), Kate Leung3, FRCPA, FHKAM (Pathology), CY Law4, PhD, FHKAM (Pathology), CW Lam5, PhD, FRCP, Janette Kwok6, PhD, FRCPA, Patrick WK Chu6, MPhil, Elaine YL Au7, FRCPA, FHKCPath, Crystal K Lam7, MB, BS, Daniel Mak2, MRCPCH, FHKAM (Paediatrics), NC Fong2, FRCPCH, Daniel Leung1, PhD (Candidate), Wilfred HS Wong1, PhD, Marco HK Ho1, MDM, FRCP, Sabrina SL Tsao1, MB, BS, FACC, Christina S Wong8, MRCP, FHKAM (Medicine), Jason C Yam9, MB, BS, FCOphthHK, Winnie WY Tso1, FHKAM (Paediatrics), Kelvin KW To10, MD, FRCPath, Paul KH Tam11,12, FRCS, FRCPCH, Godfrey CF Chan1, MD, FRCPCH, WH Leung1, MB, BS, PhD, KY Yuen10, MD, FRCPath, Vas Novelli13,14, FRCP, FRCPCH, Nigel Klein13,14, PhD, Michael Levin15, PhD, FRCPCH, Elizabeth Whitaker16, MRCPCH, PhD, YL Lau1, MD (Hon), FRCPCH, Patrick Ip1, MPH, FHKAM (Paediatrics), Mike YW Kwan2 *, MRCPCH, MSc (Applied Epidemiology CUHK)

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.

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.

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.

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.

To critically summarise the available data on diagnosis of CAP in children, focusing on the newest findings and on the need for new studies. Eighty studies on the diagnosis of paediatric community-acquired pneumonia were scrutinised. 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. 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.

Objectives: Antiretroviral therapy (ART) has been associated with lipodystrophy in children. We evaluated changes in various anthropometric measurements for the assessment of lipodystrophy and assessed whether there was an association with use of protease inhibitors (PI), non-PI containing ART and/or stavudine (d4T). Methods: Eighty-five HIV-infected children attending the HIV clinic at Great Ormond Street Hospital (GOSH) were included. The average follow-up was 8.4 months (range 3 - 12 months). Body fat redistribution was assessed by anthropometric measurements including skinfold thickness and circumferences of upper and lower limbs. Measurements were converted to age- and sex-adjusted z-scores through development stages including puberty. Results: Sixty children had taken ART; 37 received PI-containing; 38 received d4T; 25 had never been treated. In the studied population, clinically important changes with decreases in biceps (BSF), subscapular skinfolds and total body fat (4SFT) over period of 12 months were observed. Some increase was noticed in triceps skinfolds (TSF). Limbs circumferences remained at the same level. Further we looked at 4 months basis changes in anthropometric measurements stratified by baseline ART. Generally z-scores of anthropometric measurements were lower in therapy naive children when compared to ART groups. PI-based ART regimens resulted in significant increases in BSF with a trend towards increases in TSF, suprailiac and 4SFT. Mid-arm and thigh circumferences were higher in PI compared to naive group. Similarly, significant changes in BSF z-scores were associated with d4T use. Increases were seen in TSF and mid-arm circumference and decreases were observed in subscapular skinfolds and calf circumference z-scores. Conclusions: Body fat redistribution in HIV-infected children with sub-clinical lipodystrophy could be detected by anthropometric measurements, particularly when PI or d4T is included in ART. Over time, changes with increase in arm and trunk fat, and no change or decrease in leg fat were more pronounced among ART-receiving children.

Objectives To review our experience of spinal tuberculosis (TB) at a major UK paediatric tertiary referral centre. Methods The authors performed a retrospective case survey of 21 patients admitted to Great Ormond Street Hospital over a 15-year period (1995–2010) with confirmed or presumed spinal TB. Data were collected concerning demographics, clinical, laboratory and radiological characteristics, treatment and clinical outcome. Results Only one patient was of Caucasian origin. Four (19%) had a previous diagnosis of TB, 11 (52%) a known contact, 10 (48%) had received BCG vaccine and none were HIV-positive. Clinical presentations included systemic symptoms (18 patients), back pain (16 patients), deformity (five patients) and neurological deficits (12 patients). Mycobacterium tuberculosis was isolated from 14 patients (67%) including one multi-drug resistant strain. Spinal cord compression or critical stenosis was demonstrated in eight patients (38%). All received TB treatment for at least 12 months; six patients received treatment for a longer period. Seven (33%) underwent surgical intervention. Seventy-five per cent showed clinical and radiological resolution after treatment. No patients died or suffered long-term neurological deficit. Conclusions Spinal TB in children needs a high index of suspicion for diagnosis. Early referral to an expert centre allows a multidisciplinary approach to management. The authors recommend that treatment should be individually tailored and may need to exceed 12 months in cases of poor adherence, extensive disease or drug resistance.

Varicella is usually a benign and self-limited disease of infancy and childhood although it has been recognized that it sometimes has severe and life-threatening complications. We report a case of postinfectious purpura fulminans with acquired protein S deficiency following varicella in a 6-year-old child and discuss the underlying mechanism of postinfectious purpura fulminans.

Interleukin-12 receptor β1 (IL-12Rβ1) deficiency is the most common form of Mendelian susceptibility to mycobacterial disease (MSMD). We undertook an international survey of 141 patients from 102 kindreds in 30 countries. Among 102 probands, the first infection occurred at a mean age of 2.4 years. In 78 patients, this infection was caused by Bacille Calmette-Guérin (BCG; n = 65), environmental mycobacteria (EM; also known as atypical or nontuberculous mycobacteria) (n = 9) or Mycobacterium tuberculosis (n = 4). Twenty-two of the remaining 24 probands initially presented with nontyphoidal, extraintestinal salmonellosis. Twenty of the 29 genetically affected sibs displayed clinical signs (69%); however 8 remained asymptomatic (27%). Nine nongenotyped sibs with symptoms died. Recurrent BCG infection was diagnosed in 15 cases, recurrent EM in 3 cases, recurrent salmonellosis in 22 patients. Ninety of the 132 symptomatic patients had infections with a single microorganism. Multiple infections were diagnosed in 40 cases, with combined mycobacteriosis and salmonellosis in 36 individuals. BCG disease strongly protected against subsequent EM disease (p = 0.00008). Various other infectious diseases occurred, albeit each rarely, yet candidiasis was reported in 33 of the patients (23%). Ninety-nine patients (70%) survived, with a mean age at last follow-up visit of 12.7 years ± 9.8 years (range, 0.5-46.4 yr). IL-12Rβ1 deficiency is characterized by childhood-onset mycobacteriosis and salmonellosis, rare recurrences of mycobacterial disease, and more frequent recurrence of salmonellosis. The condition has higher clinical penetrance, broader susceptibility to infections, and less favorable outcome than previously thought. Abbreviations: BCG = Bacille Calmette-Guérin, CI = confidence interval, EBV-B cell lines = Epstein-Barr virus-transformed lymphoblastoid cell lines, ELISA = enzyme-linked immunosorbent assay, EM= environmental mycobacteria (nontuberculous mycobacteria), FBS = fetal bovine serum, FD = fibronectin domain, IFNGR = interferon-γ receptor, IL12B = interleukin-12B, IL-12Rβ1 = interleukin-12 receptor beta 1 chain, MSMD = Mendelian susceptibility tomycobacterial disease, NEMO = nuclear factor-κB essential modulator, PBS = phosphate-buffered saline, PCR = polymerase chain reaction, PHA = phytohemagglutinin, PR = present report, STAT1 = Signal transducer and activator of transcription 1.

Interleukin-12 receptor β1 (IL-12Rβ1) deficiency is the most common form of Mendelian susceptibility to mycobacterial disease (MSMD). We undertook an international survey of 141 patients from 102 kindreds in 30 countries. Among 102 probands, the first infection occurred at a mean age of 2.4 years. In 78 patients, this infection was caused by Bacille Calmette-Guérin (BCG; n = 65), environmental mycobacteria (EM; also known as atypical or nontuberculous mycobacteria) (n = 9) or Mycobacterium tuberculosis (n = 4). Twenty-two of the remaining 24 probands initially presented with nontyphoidal, extraintestinal salmonellosis. Twenty of the 29 genetically affected sibs displayed clinical signs (69%); however 8 remained asymptomatic (27%). Nine nongenotyped sibs with symptoms died. Recurrent BCG infection was diagnosed in 15 cases, recurrent EM in 3 cases, recurrent salmonellosis in 22 patients. Ninety of the 132 symptomatic patients had infections with a single microorganism. Multiple infections were diagnosed in 40 cases, with combined mycobacteriosis and salmonellosis in 36 individuals. BCG disease strongly protected against subsequent EM disease (p = 0.00008). Various other infectious diseases occurred, albeit each rarely, yet candidiasis was reported in 33 of the patients (23%). Ninety-nine patients (70%) survived, with a mean age at last follow-up visit of 12.7 years ± 9.8 years (range, 0.5-46.4 yr). IL-12Rβ1 deficiency is characterized by childhood-onset mycobacteriosis and salmonellosis, rare recurrences of mycobacterial disease, and more frequent recurrence of salmonellosis. The condition has higher clinical penetrance, broader susceptibility to infections, and less favorable outcome than previously thought.

Interleukin-12 receptor beta 1 (IL-12R beta 1) deficiency is the most common form of Mendelian susceptibility to mycobacterial disease (MSMD). We undertook an international survey of 141 patients from 102 kindreds in 30 countries. Among 102 probands, the first infection occurred at a mean age of 2.4 years. In 78 patients, this infection was caused by Bacille Calmette-Guerin (BCG; n = 65), environmental mycobacteria (EM; also known as atypical or nontuberculous mycobacteria) (n = 9) or Mycobacterium tuberculosis (n = 4). Twenty-two of the remaining 24 probands initially presented with nontyphoidal, extraintestinal salmonellosis. Twenty of the 29 genetically affected sibs displayed clinical signs (69%); however 8 remained asymptomatic (27%). Nine nongenotyped sibs with symptoms died. Recurrent BCG infection was diagnosed in 15 cases, recurrent EM in 3 cases, recurrent salmonellosis in 22 patients. Ninety of the 132 symptomatic patients had infections with a single microorganism. Multiple infections were diagnosed in 40 cases, with combined mycobacteriosis and salmonellosis in 36 individuals. BCG disease strongly protected against subsequent EM disease (p = 0.00008). Various other infectious diseases occurred, albeit each rarely, yet candidiasis was reported in 33 of the patients (23%). Ninety-nine patients (70%) survived, with a mean age at last follow-up visit of 12.7 years +/- 9.8 years (range, 0.5-46.4 yr). IL-12R beta 1 deficiency is characterized by childhood-onset mycobacteriosis and salmonellosis, rare recurrences of mycobacterial disease, and more frequent recurrence of salmonellosis. The condition has higher clinical penetrance, broader susceptibility to infections, and less favorable outcome than previously thought.

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.

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 Quanti-FERON-TB Gold In-Tube assay (QFF-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 QFF-IT. Among 161 children With a documented tuberculin kill 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.

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.

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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.