Gonul Tanir

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.

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.

Presentation, complications, and treatment outcome of brucellosis in Turkish children

Background:  Brucellosis constitutes a public health problem in Turkey. In endemic Brucella melitensis areas such as Turkey, children represent 20–25% of cases.

A prospective study of etiology of childhood acute bacterial meningitis, Turkey.

Vaccines to prevent bacterial meningitis in this region must provide reliable protection against serogroup W-135.

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.

Pediatric cases of Crimean-Congo hemorrhagic fever in Turkey

Background:  The aim of the present study was to identify the epidemiological, clinical and laboratory features of Crimean‐Congo hemorrhagic fever (CCHF) virus infection in children.

Lactobacillus reuteri DSM 17938 shortens acute infectious diarrhea in a pediatric outpatient setting

OBJECTIVE Two randomized controlled clinical trials have shown that Lactobacillus (L) reuteri DSM 17938 reduces the duration of diarrhea in children hospitalized due to acute infectious diarrhea. This was the first trial evaluating the efficacy of L. reuteri DSM 17938 in outpatient children with acute infectious diarrhea. METHODS This was a multicenter, randomized, single-blinded, case control clinical trial in children with acute watery diarrhea. A total of 64 children who presented at outpatient clinics were enrolled. The probiotic group received 1×10(8)CFU L. reuteri DSM 17938 for five days in addition to oral rehydration solution (ORS) and the second group was treated with ORS only. The primary endpoint was the duration of diarrhea (in hours). The secondary endpoint was the number of children with diarrhea at each day of the five days of intervention. Adverse events were also recorded. RESULTS The mean duration of diarrhea was significantly reduced in the L. reuteri group compared to the control group (approximately 15h, 60.4±24.5h [95% CI: 51.0-69.7h] vs. 74.3±15.3h [95% CI: 68.7-79.9h], p<0.05). The percentage of children with diarrhea was lower in the L. reuteri group (13/29; 44.8%) after 48h than the control group (27/31; 87%; RR: 0.51; 95% CI: 0.34-0.79, p<0.01). From the 72nd hour of intervention onwards, there was no difference between the two groups in the percentage of children with diarrhea. No adverse effects related to L. reuteri were noted. CONCLUSION L. reuteri DSM 17938 is effective, safe, and well-tolerated in outpatient children with acute infectious diarrhea.

Pediatric visceral Leishmaniasis in Turkey

Background: Visceral Leishmaniasis (VL) type in Turkey is consistent with the Mediterranean type of VL, a fatal debilitating disease, which is mostly seen in infants.

Complete deficiency of the IL-12 receptor β1 chain: three unrelated Turkish children with unusual clinical features

Complete interleukin-12 receptor β1 deficiency is the most frequent known genetic etiology of the syndrome of Mendelian susceptibility to mycobacterial diseases (MSMD, OMIM 209950). Eleven disorders caused by different types of mutations in five different gene defects related to the IL-12 and IL-23/interferon (IFN)-γ axis have been described to date [2]. Refer to Fig. 1 for the pathways of IL-12/IL-23-dependent interferon IFN-gamma immunity. Patients with MSMD are vulnerable to the BacillusCalmette-Guerin (BCG) vaccine species Mycobacterium bovis, environmental mycobacteria and M. tuberculosis. Infectious diseases other than those caused by Salmonella species, the latter of which infect almost one-half of all patients, are rare [1, 3, 6]. We report here various and unusual clinical manifestations of three unrelated patients with complete IL-12Rβ1 deficiency due to three different mutations in the IL-12RB1 gene, of which two are novel (711insC, 628–644dup). The first patient was an 1-year-old infant girl who had BCG lymphadenitis at 6 months of age and disseminated mycobacterial infection complicated with spontaneous pneumomediastinum and subcutaneous emphysema at 12 months of age. She was treated with isoniazide, rifampin, ethambutol, amikacin, clarithromycin and clofazimine. Pre-tracheal fasciotomy was undertaken for subcutaneous emphysema. A complete IL-12 receptor β1 deficiency associated with the 711insC mutation in IL-12RB1 was detected (Fig. 2). The patient is still in remission. The second patient was an 19-month-old infant boy who presented with five episodes of infections attributable to Salmonella and two episodes of Salmonella enteritidis meningitis. There was no mycobacterial disease, including no adverse reaction to BCG immunization that was practiced at the age of 2 months. He was treated with meropenem, rIFN-γ and external ventricular drainage and then ventriculo-peritoneal shunting for hydrocephalus. Immunologic and molecular genetic examinations revealed complete IL-12Rβ1 deficiency and a IL-12RB1 783+ 1G>A mutation (Fig. 2) [3]. The third patient, a 4.5-year-old boy, had fistulized BCG lymphadenitis in early childhood followed by disseminated mycobacterial infection and splenic abscess with Salmonella bacteremia at 44 months of age. He was treated with meropenem and with isoniazide, rifampin, ethambutol, clarithromycin and amikacin. The patient improved; however, he was lost to follow-up and has been reported to have died. DNA sequencing revealed a 628–644dup mutation in IL-12RB1 (Fig. 2). A complete IL-12 receptor β1 deficiency is suspected. All three patients had persistent oral moniliasis. Among a total of 56 cases of IL-12 receptor β1 deficiency reported in the literature, the rate of infection with BCG M. bovis is 73% (27/37), environmental mycobacteria 21% (22/56), non-typhoidal Salmonella species 46% (26/56) and tuberculosis 7% (4/56) [4–6]. Paracoccidioides brasiliensis-disseminated disease has also recently been reported in an IL-12Rβ1-deficient patient. None of the 37 patients with BCG disease subsequently G. Tanir (*) . N. Tuygun . C. Aydemir . E. C. Boduroglu Dr. Sami Ulus Children Health and Diseases Training and Research Center, Hosdere Caddesi 166/3, Yukari Ayranci, 06550 Ankara, Turkey e-mail: gonultanir58@yahoo.com Fax: +90-312-3170353

Clinical and epidemiological features of Turkish children with 2009 pandemic influenza A (H1N1) infection: Experience from multiple tertiary paediatric centres in Turkey

Abstract Background: In April 2009 a novel strain of human influenza A, identified as H1N1 virus, rapidly spread worldwide, and in early June 2009 the World Health Organization raised the pandemic alert level to phase 6. Herein we present the largest series of children who were hospitalized due to pandemic H1N1 infection in Turkey. Methods: We conducted a retrospective multicentre analysis of case records involving children hospitalized with influenza-like illness, in whom 2009 H1N1 influenza was diagnosed by reverse-transcriptase polymerase chain reaction assay, at 17 different tertiary hospitals. Results: A total of 821 children with 2009 pandemic H1N1 were hospitalized. The majority of admitted children (56.9%) were younger than 5 y of age. Three hundred and seventy-six children (45.8%) had 1 or more pre-existing conditions. Respiratory complications including wheezing, pneumonia, pneumothorax, pneumomediastinum, and hypoxemia were seen in 272 (33.2%) children. Ninety of the patients (11.0%) were admitted or transferred to the paediatric intensive care units (PICU) and 52 (6.3%) received mechanical ventilation. Thirty-five children (4.3%) died. The mortality rate did not differ between age groups. Of the patients who died, 25.7% were healthy before the H1N1 virus infection. However, the death rate was significantly higher in patients with malignancy, chronic neurological disease, immunosuppressive therapy, at least 1 pre-existing condition, and respiratory complications. The most common causes of mortality were pneumonia and sepsis. Conclusions: In Turkey, 2009 H1N1 infection caused high mortality and PICU admission due to severe respiratory illness and complications, especially in children with an underlying condition.