Ayper Somer

IL-12Rβ1 Deficiency in Two of Fifty Children with Severe Tuberculosis from Iran, Morocco, and Turkey

Background and Objectives In the last decade, autosomal recessive IL-12Rβ1 deficiency has been diagnosed in four children with severe tuberculosis from three unrelated families from Morocco, Spain, and Turkey, providing proof-of-principle that tuberculosis in otherwise healthy children may result from single-gene inborn errors of immunity. We aimed to estimate the fraction of children developing severe tuberculosis due to IL-12Rβ1 deficiency in areas endemic for tuberculosis and where parental consanguinity is common. Methods and Principal Findings We searched for IL12RB1 mutations in a series of 50 children from Iran, Morocco, and Turkey. All children had established severe pulmonary and/or disseminated tuberculosis requiring hospitalization and were otherwise normally resistant to weakly virulent BCG vaccines and environmental mycobacteria. In one child from Iran and another from Morocco, homozygosity for loss-of-function IL12RB1 alleles was documented, resulting in complete IL-12Rβ1 deficiency. Despite the small sample studied, our findings suggest that IL-12Rβ1 deficiency is not a very rare cause of pediatric tuberculosis in these countries, where it should be considered in selected children with severe disease. Significance This finding may have important medical implications, as recombinant IFN-γ is an effective treatment for mycobacterial infections in IL-12Rβ1-deficient patients. It also provides additional support for the view that severe tuberculosis in childhood may result from a collection of single-gene inborn errors of immunity.

Defects along the TH17 differentiation pathway underlie genetically distinct forms of the hyper IgE syndrome

BACKGROUND The hyper IgE syndrome (HIES) is characterized by abscesses, eczema, recurrent infections, skeletal and connective tissue abnormalities, elevated serum IgE, and diminished inflammatory responses. It exists as autosomal-dominant and autosomal-recessive forms that manifest common and distinguishing clinical features. A majority of those with autosomal-dominant HIES have heterozygous mutations in signal transducer and activator of transcription (STAT)-3 and impaired T(H)17 differentiation. OBJECTIVE To elucidate mechanisms underlying different forms of HIES. METHODS A cohort of 25 Turkish children diagnosed with HIES were examined for STAT3 mutations by DNA sequencing. Activation of STAT3 by IL-6 and IL-21 and STAT1 by IFN-alpha was assessed by intracellular staining with anti-phospho (p)STAT3 and -pSTAT1 antibodies. T(H)17 and T(H)1 cell differentiation was assessed by measuring the production of IL-17 and IFN-gamma, respectively. RESULTS Six subjects had STAT3 mutations affecting the DNA binding, Src homology 2, and transactivation domains, including 3 novel ones. Mutation-positive but not mutation-negative subjects with HIES exhibited reduced phosphorylation of STAT3 in response to cytokine stimulation, whereas pSTAT1 activation was unaffected. Both patient groups exhibited impaired T(H)17 responses, but whereas STAT3 mutations abrogated early steps in T(H)17 differentiation, the defects in patients with HIES with normal STAT3 affected more distal steps. CONCLUSION In this cohort of Turkish children with HIES, a majority had normal STAT3, implicating other targets in disease pathogenesis. Impaired T(H)17 responses were evident irrespective of the STAT3 mutation status, indicating that different genetic forms of HIES share a common functional outcome.

Inherited and acquired immunodeficiencies underlying tuberculosis in childhood.

Tuberculosis (TB), caused by Mycobacterium tuberculosis (M.tb) and a few related mycobacteria, is a devastating disease, killing more than a million individuals per year worldwide. However, its pathogenesis remains largely elusive, as only a small proportion of infected individuals develop clinical disease either during primary infection or during reactivation from latency or secondary infection. Subacute, hematogenous, and extrapulmonary disease tends to be more frequent in infants, children, and teenagers than in adults. Life‐threatening primary TB of childhood can result from known acquired or inherited immunodeficiencies, although the vast majority of cases remain unexplained. We review here the conditions conferring a predisposition to childhood clinical diseases caused by mycobacteria, including not only M.tb but also weakly virulent mycobacteria, such as BCG vaccines and environmental mycobacteria. Infections with weakly virulent mycobacteria are much rarer than TB, but the inherited and acquired immunodeficiencies underlying these infections are much better known. Their study has also provided genetic and immunological insights into childhood TB, as illustrated by the discovery of single‐gene inborn errors of IFN‐γ immunity underlying severe cases of TB. Novel findings are expected from ongoing and future human genetic studies of childhood TB in countries that combine a high proportion of consanguineous marriages, a high incidence of TB, and an excellent clinical care, such as Iran, Morocco, and Turkey.

Clinical Features of Candidiasis in Patients With Inherited Interleukin 12 Receptor β1 Deficiency

BACKGROUND Interleukin 12Rβ1 (IL-12Rβ1)-deficient patients are prone to clinical disease caused by mycobacteria, Salmonella, and other intramacrophagic pathogens, probably because of impaired interleukin 12-dependent interferon γ production. About 25% of patients also display mucocutaneous candidiasis, probably owing to impaired interleukin 23-dependent interleukin 17 immunity. The clinical features and outcome of candidiasis in these patients have not been described before, to our knowledge. We report here the clinical signs of candidiasis in 35 patients with IL-12Rβ1 deficiency. RESULTS Most (n = 71) of the 76 episodes of candidiasis were mucocutaneous. Isolated oropharyngeal candidiasis (OPC) was the most common presentation (59 episodes, 34 patients) and was recurrent or persistent in 26 patients. Esophageal candidiasis (n = 7) was associated with proven OPC in 2 episodes, and cutaneous candidiasis (n = 2) with OPC in 1 patient, whereas isolated vulvovaginal candidiasis (VVC; n = 3) was not. Five episodes of proven invasive candidiasis were documented in 4 patients; 1 of these episodes was community acquired in the absence of any other comorbid condition. The first episode of candidiasis occurred earlier in life (median age±standard deviation, 1.5 ± 7.87 years) than infections with environmental mycobacteria (4.29 ± 11.9 years), Mycobacterium tuberculosis (4 ± 3.12 years), or Salmonella species (4.58 ± 4.17 years) or other rare infections (3 ± 11.67 years). Candidiasis was the first documented infection in 19 of the 35 patients, despite the vaccination of 10 of these 19 patients with live bacille Calmette-Guérin. CONCLUSIONS Patients who are deficient in IL-12Rβ1 may have candidiasis, usually mucocutaneous, which is frequently recurrent or persistent. Candidiasis may be the first clinical manifestation in these patients.

Sonographic assessment of ceftriaxone-associated biliary pseudolithiasis in children

Ceftriaxone is a widely used third‐generation cephalosporin. In this prospective study, we used sonography to investigate the incidence and outcome of biliary complications in children receiving ceftriaxone therapy.

Invasive aspergillosis in hematopoietic stem cell and solid organ transplantation

Invasive aspergillosis (IA) is currently an important cause of morbidity and mortality in hematopoietic stem cell transplant and solid organ transplant recipients. A high index of suspicion and careful clinical and radiological examinations are the keys to identifying infected patients early. Chest computerized axial tomography is extremely useful in diagnosing pulmonary aspergillosis. Microbiologic or histologic identification of infection, however, remain essential. Successful management of invasive fungal infections depends on timely and appropriate treatment. There are multiple variables associated with survival in transplant patients with IA. Understanding these prognostic factors may assist in the development of treatment algorithms and clinical trials. In contrast to adult patients, large prospective comparitive studies have not been performed in pediatric patients with IA. Moreover, pediatric subgroups have not been analyzed in published studies that include a broader age range. Clinicians treating pediatric IA are largely left with the results of uncontrolled trials, observatory surveys, salvage therapy data and extrapolations from adult studies to guide their treatment choices. The aim of this article is to state the main characteristics of IA in both pediatric and adult populations.

Epidemiologic and microbiologic evaluation of nosocomial infections associated with Candida spp in children: A multicenter study from Istanbul, Turkey

BACKGROUND The purpose of this study was to establish species distribution of Candida isolates from pediatric patients in Istanbul, Turkey, and to determine risk factors associated with nosocomial Candida infections. METHODS This study was conducted between June 2013 and June 2014 by participation of 7 medical centers in Istanbul. Candida spp strains isolated from the clinical specimens of pediatric patients were included. Clinical features were recorded on a standardized data collection sheet. RESULTS A total of 134 systemic Candida infections were identified in 134 patients. The patients were admitted in pediatric and neonatal intensive care units (41.8% and 9.7%, respectively) and in pediatric wards (48.5%). Candida albicans was the most prevalent species (47%), followed by Candida parapsilosis (13.4%), Candida tropicalis (8.2%), Candida glabrata (4.5%), Candida lusitaniae (3.7%), Candida kefyr (2.2%), Candida guilliermondii (1.5%), Candida dubliniensis (0.7%), and Candida krusei (0.7%). Types of Candida infections were candidemia (50.7%), urinary tract infection (33.6%), surgical site infection (4.5%), central nervous system infection (3.7%), catheter infection (3.7%), and intra-abdominal infection (3.7%). In multivariate analysis, younger age (1-24 months) and detection of non-albicans Candida spp was found to be risk factors associated with candidemia (P = 0.040; odds ratio [OR], 4.1; 95% confidence interval [CI], 1.06-15.86; and P = 0.02; OR, 2.4; 95% CI, 1.10-5.53, respectively). CONCLUSIONS This study provides an update for the epidemiology of nosocomial Candida infections in Istanbul, which is important for the management of patients and implementation of appropriate infection control measures.

Atypical presentation of human bocavirus: Severe respiratory tract infection complicated with encephalopathy.

Human bocavirus (HBOV) has been reported as a worldwide distributed respiratory pathogen. It has also been associated with encephalitis recently by detection of the virus in cerebrospinal fluid (CSF) of patients presented with encephalitis. This retrospective study aimed to present clinical features of HBOV infections in children with respiratory symptoms and describe unexplained encephalopathy in a subgroup of these patients. Results of 1,143 pediatric nasal samples from mid‐December 2013 to July 2014 were reviewed for detection of HBOV. A multiplex real time polymerase chain reaction assay was used for viral detection. Medical records of the patients were retrospectively analyzed. HBOV was detected in 30 patients (2.6%). Median age was 14 months (5–80). Clinical diagnoses were upper respiratory tract infection (n = 10), bronchopneumonia (n = 9), acute bronchiolitis (n = 5), pneumonia (n = 4), acute bronchitis (n = 1), and asthma execarbation (n = 1). Hospitalization was required in 16 (53.3%) patients and 10 (62.5%) of them admitted to pediatric intensive care unit (PICU). Noninvasive mechanical ventilation modalities was applied to four patients and mechanical ventilation to four patients. Intractable seizures developed in four patients while mechanically ventilated on the 2nd–3rd days of PICU admission. No specific reason for encephalopathy was found after a thorough investigation. No mortality was observed, but two patients were discharged with neurological sequela. HBOV may lead to respiratory infections in a wide spectrum of severity. This report indicates its potential to cause severe respiratory infections requiring PICU admission and highlights possible clinical association of HBOV and encephalopathy, which developed during severe respiratory infection. J. Med. Virol. 87:1831–1838, 2015.

Low immunoglobulin G3 levels in wheezy children

This study aimed to investigate the prevalence of IgG subclass deficiency in wheezy children aged <3y. Serum levels of IgA, IgE and IgG subclasses were measured in 310 children with recurrent wheezing and in 100 healthy controls. IgG3 levels were below the normal lower limit in 123 (39.6%) patients. This finding may reflect delayed maturation of the immune system, predisposing young children <3 y of age to wheezing.

Clinical and Epidemiological Characteristics of Pandemic Influenza A/(H1N1) in Hospitalized Pediatric Patients at a University Hospital, Istanbul, Turkey

Abstract Background: The aim of this study was to describe the clinical and epidemiological characteristics of pandemic influenza in hospitalized children. Methods: A total of 114 patients with suspected H1N1 virus infection were hospitalized, and nasal swabs were sent to National Influenza Reference Laboratory for confirmation of pandemic influenza A (H1N1) virus infection by rRT–PCR assay. Results: Forty-six female and 68 male patients were included in the study. Age of the patients ranged from 40 days to 16 years. Clinical and/or radiological pneumonia were detected in 96% of all. Sixteen patients required mechanical ventilation due to hypoxemia. Previously healthy children required mechanical ventilation and oxygen therapy more than patients with chronic diseases. Elevated levels of CRP and LDH in patients with respiratory distress and patients who required mechanical ventilation were statistically significant. Conclusion: Our study showed that progress of pandemic influenza infection in previously healthy children is as severe as their counterparts with chronic underlying diseases.