Publications by authors named "Yildiz Camcioglu"

71 Publications

Global Emergencies in Child Health: Challenges and Solutions-Viewpoint and Recommendations from the European Paediatric Association and the International Pediatric Association.

J Pediatr 2021 Oct 29. Epub 2021 Oct 29.

International Pediatric Association, Marengo, IL; European Paediatric Association, Union of National European Paediatric Societies and Associations, Berlin, Germany; Association for Scientific Activity and Research, Nouchatel, Switzerland; Italian Academy of Pediatrics, Milan, Italy. Electronic address:

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http://dx.doi.org/10.1016/j.jpeds.2021.10.052DOI Listing
October 2021

Primary antibody deficiencies in Turkey: molecular and clinical aspects.

Immunol Res 2021 Oct 7. Epub 2021 Oct 7.

Istanbul University Graduate School of Health Sciences, Istanbul, Turkey.

Primary antibody deficiencies (PAD) are the most common subtype of primary immunodeficiencies, characterized by increased susceptibility to infections and autoimmunity, allergy, or malignancy predisposition. PAD syndromes comprise of immune system genes highlighted the key role of B cell activation, proliferation, migration, somatic hypermutation, or isotype switching have a wide spectrum from agammaglobulinemia to selective Ig deficiency. In this study, we describe the molecular and the clinical aspects of fifty-two PAD patients. The most common symptoms of our cohort were upper and lower respiratory infections, bronchiectasis, diarrhea, and recurrent fever. Almost all patients (98%) had at least one of the symptoms like autoimmunity, lymphoproliferation, allergy, or gastrointestinal disease. A custom-made next-generation sequencing (NGS) panel, which contains 24 genes, was designed to identify well-known disease-causing variants in our cohort. We identified eight variants (15.4%) among 52 PAD patients. The variants mapped to BTK (n = 4), CD40L (n = 1), ICOS (n = 1), IGHM (n = 1), and TCF3 (n = 1) genes. Three novel variants were described in the BTK (p.G414W), ICOS (p.G60*), and IGHM (p.S19*) genes. We performed Sanger sequencing to validate pathogenic variants and check for allelic segregation in the family. Targeted NGS panel sequencing can be beneficial as a suitable diagnostic modality for diagnosing well-known monogenic PAD diseases (only 2-10% of PADs); however, screening only the coding regions of the genome may not be adequately powered to solve the pathogenesis of PAD in all cases. Deciphering the regulatory regions of the genome and better understanding the epigenetic modifications will elucidate the molecular basis of complex PADs.
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http://dx.doi.org/10.1007/s12026-021-09242-zDOI Listing
October 2021

Evolution and long-term outcomes of combined immunodeficiency due to CARMIL2 deficiency.

Allergy 2021 Jul 20. Epub 2021 Jul 20.

Ludwig Boltzmann Institute for Rare and Undiagnosed Diseases, Vienna, Austria.

Background: Biallelic loss-of-function mutations in CARMIL2 cause combined immunodeficiency associated with dermatitis, inflammatory bowel disease (IBD), and EBV-related smooth muscle tumors. Clinical and immunological characterizations of the disease with long-term follow-up and treatment options have not been previously reported in large cohorts. We sought to determine the clinical and immunological features of CARMIL2 deficiency and long-term efficacy of treatment in controlling different disease manifestations.

Methods: The presenting phenotypes, long-term outcomes, and treatment responses were evaluated prospectively in 15 CARMIL2-deficient patients, including 13 novel cases. Lymphocyte subpopulations, protein expression, regulatory T (Treg), and circulating T follicular helper (cT ) cells were analyzed. Three-dimensional (3D) migration assay was performed to determine T-cell shape.

Results: Mean age at disease onset was 38 ± 23 months. Main clinical features were skin manifestations (n = 14, 93%), failure to thrive (n = 10, 67%), recurrent infections (n = 10, 67%), allergic symptoms (n = 8, 53%), chronic diarrhea (n = 4, 27%), and EBV-related leiomyoma (n = 2, 13%). Skin manifestations ranged from atopic and seborrheic dermatitis to psoriasiform rash. Patients had reduced proportions of memory CD4 T cells, Treg, and cT cells. Memory B and NK cells were also decreased. CARMIL2-deficient T cells exhibited reduced T-cell proliferation and cytokine production following CD28 co-stimulation and normal morphology when migrating in a high-density 3D collagen gel matrix. IBD was the most severe clinical manifestation, leading to growth retardation, requiring multiple interventional treatments. All patients were alive with a median follow-up of 10.8 years (range: 3-17 years).

Conclusion: This cohort provides clinical and immunological features and long-term follow-up of different manifestations of CARMIL2 deficiency.
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http://dx.doi.org/10.1111/all.15010DOI Listing
July 2021

Diagnostic Modalities Based on Flow Cytometry for Chronic Granulomatous Disease: A Multicenter Study in a Well-Defined Cohort.

J Allergy Clin Immunol Pract 2020 Nov - Dec;8(10):3525-3534.e1. Epub 2020 Jul 28.

Faculty of Medicine, Pediatric Allergy-Immunology, Marmara University, Istanbul, Turkey; Istanbul Jeffrey Modell Diagnostic and Research Center for Primary Immunodeficiencies, Istanbul, Turkey. Electronic address:

Background: Chronic granulomatous disease (CGD) is characterized by defective microbial killing due to mutations affecting subunits of the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase complex. Definitive genetic identification of disease subtypes may be delayed or not readily available.

Objective: Sought to investigate the role of intracellular staining of NADPH oxidase enzyme subunits in predicting the respective genetic defects in patients with CGD and carriers.

Methods: Thirty-four patients with genetically inherited CGD, including 12 patients with X-linked CGD (gp91 deficiency due to cytochrome b-245, beta polypeptide [CYBB] mutations) and 22 patients with autosomal-recessive CGD (p22, p47, and p67 deficiency due to cytochrome b-245, alpha polypeptide [CYBA], neutrophil cytosolic factor 1 [NCF1] and NCF2 mutations, respectively) were recruited from different immunology centers and followed up prospectively. Dihydrorhodamine testing and NADPH oxidase subunit expression in white blood cells were determined by flow cytometry.

Results: gp91 and p22 defects, which result in simultaneous loss of both proteins due to their complex formation, were differentiated only by comparative analysis of patients' and mothers' intracellular staining. p47 and p67 protein expression was almost undetectable in patients compared with carrier mothers and healthy controls. The expression values of the respective subunits were found to be significantly higher in all controls as compared with carrier mothers, which in turn were higher than those of patients.

Conclusions: Analysis of NADPH oxidase enzyme subunits by flow cytometry in patients and carriers is useful in the rapid prediction of the genetic defect of patients with CGD, thus guiding targeted sequencing and aiding in their early diagnosis.
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http://dx.doi.org/10.1016/j.jaip.2020.07.030DOI Listing
May 2021

The epidemiologic and clinical features of viral agents among hospitalized children with lower respiratory tract infections.

Turk Pediatri Ars 2020 19;55(2):166-173. Epub 2020 Jun 19.

Department of Pediatric Infectious Disease, İstanbul University-Cerrahpaşa, Cerrahpaşa Faculty of Medicine, İstanbul, Turkey.

Aim: Acute respiratory tract infections are among the most common infectious diseases worldwide. Respiratory viruses are the leading cause of respiratory infections in children. Herein, we aimed to determine the epidemiologic and clinical feautures of viral agents among hospitalized children with lower respiratory tract infections.

Material And Methods: Nasopharyngeal swab specimens were obtained from the 422 patients hospitalized with a diagnosis of lower respiratory tract infections between December 2012 and December 2016. Multiplex reverse-transcription polymerase chain reaction was performed for the detection of viruses.

Results: Viral respiratory pathogens were detected in 311 patients (73.7%). In regard to respiratory virus subtypes, 103 patients (33.1%) had respiratory syncytial virus, 102 (32.7%) had human rhinovirus, 49 (15.7%) had multiple viruses, 15 (4.8%) had parainfluenzavirus, 13 (4.1%) had adenovirus, nine (2.8%) had human metapneumovirus, eight (2.5%) had human coronaviruses, six (1.9%) had bocavirus, five (1.6%) had influenza virus, and one patient (0.3%) had enterovirus. The median age was lower in patients with multiple viruses (p<0.001). The respiratory syncytial virus was more commonly detected in patients with a history of prematurity (p<0.001). Stridor was more common in other viruses including parainfluenza viruses (p<0.001).

Conclusion: Respiratory viruses are the main causative agents of respiratory tract infections in children. Timely and accurate detection of viruses is necessary in terms of public health. The detection of respiratory viruses also contributes to epidemiologic results and vaccine studies.
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http://dx.doi.org/10.14744/TurkPediatriArs.2020.39114DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7344125PMC
June 2020

Epstein-Barr virus, cytomegalovirus and BK polyomavirus burden in juvenile systemic lupus erythematosus: correlation with clinical and laboratory indices of disease activity.

Lupus 2020 Sep 9;29(10):1263-1269. Epub 2020 Jul 9.

Department of Pediatric Rheumatology, Istanbul University-Cerrahpasa, Cerrahpasa Medical School, Istanbul, Turkey.

Objectives: Clinical and laboratory investigations have revealed that Epstein-Barr virus (EBV) is involved in altered immunological response of systemic lupus erythematosus (SLE). Higher seroprevalence rates of anti-EBV antibodies and increased viral load are demonstrated in adult SLE patients. The prevalence of BK polyomavirus (BKV) reactivation is also suggested to be higher in SLE. Herein, we aimed to evaluate the immune response of children with SLE to EBV antigens in addition to EBV and BKV DNA. We also tried to evaluate whether these serological results differ from another connective tissue disease - juvenile systemic sclerosis (jSS) - and healthy individuals.

Methods: Serum levels of EBV early antigen diffuse (EA-D) IgG, EBV nuclear antigen-1 IgG, EBV viral capsid antigen (VCA), cytomegalovirus (CMV) IgG, EBV DNA, CMV DNA and urinary BKV DNA were evaluated in healthy controls and in patients with a diagnosis of juvenile SLE (jSLE) and jSS.

Results: A total of 70 jSLE patients, 14 jSS patients and 44 sex-matched healthy individuals were involved in the study. EBV VCA was positive in 84.2% of jSLE patients, 85.7% of jSS patients and 36.3% of healthy controls. EBV EA-D IgG positivity was significantly higher in jSLE patients compared to jSS patients and healthy controls (20% vs. 7.1% and 0%,  = 0.005). EBV VCA positivity was associated with malar rash and immunological disorder, but there was no statistical significance in other antibody positivity in terms of clinical and haemogram findings and autoantibody positivity. CMV DNA positivity was present in only 2.8% of jSLE patients. None of the jSS patients or the healthy controls had CMV DNA positivity. EBV DNA and BKV DNA were also negative in all three groups.

Conclusion: The results of our study assume a relationship between SLE and EBV, but we could not demonstrate an association between CMV and BKV. The negative DNA results in contrast to serological positivity can be interpreted as an altered and impaired immune system and increased viral susceptibility. These results suggest that EBV contributes to disease continuity, even if it does not directly cause development.
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http://dx.doi.org/10.1177/0961203320940029DOI Listing
September 2020

Serotype distribution of in children with invasive disease in Turkey: 2015-2018.

Hum Vaccin Immunother 2020 11 12;16(11):2773-2778. Epub 2020 Jun 12.

Department of Microbiology, University of Health Sciences, Tepecik Training and Research Hospital , İzmir, Turkey.

: To determine the serotype distribution of pneumococcus causing invasive pneumococcal disease (meningitidis, bacteremia and empyema) in children in Turkey, and to observe potential changes in this distribution in time to guide effective vaccine strategies. : We surveyed with conventional bacteriological techniques and with real-time polymerase chain reaction (RT-PCR) in samples of cerebrospinal fluid (CSF), blood and pleural fluid. strains were isolated from 33 different hospitals in Turkey, which are giving health services to approximately 60% of the Turkish population. : A total of 167 cases were diagnosed with invasive pneumococcal disease between 2015 and 2018. We diagnosed 52 (31.1%) patients with meningitis, 104 (62.2%) patients with bacteremia, and 11 (6.6%) patients with empyema. Thirty-three percent of them were less than 2 years old and 56% less than 5 years old. Overall PCV13 serotypes accounted for 56.2% (94/167). The most common serotypes were 19 F (11.9%), 1 (10.7%) and 3 (10.1%). : Besides the increasing frequency of non-vaccine serotypes, vaccine serotypes continue to be a problem for Turkey despite routine and high-rate vaccination with PCV13 and significant reduction reported for the incidence of IPD in young children. Since new candidate pneumococcal conjugate vaccines with more serotype antigens are being developed, continuing IPD surveillance is a significant source of information for decision-making processes on pneumococcal vaccination.
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http://dx.doi.org/10.1080/21645515.2020.1747931DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7734139PMC
November 2020

Genetic Characteristics, Infectious, and Noninfectious Manifestations of 32 Patients with Chronic Granulomatous Disease.

Int Arch Allergy Immunol 2020 8;181(7):540-550. Epub 2020 Jun 8.

Department of Pediatric Infectious Disease, Istanbul University-Cerrahpasa, Cerrahpasa Medical School, Istanbul, Turkey.

Background: Chronic granulomatous disease (CGD) is a rare genetic disorder characterized by failure of phagocytic leukocytes to destroy certain microbes. We present a study on CGD patients enrolled at a single medical center concerning the infectious and noninfectious complications and genetic properties of the disease.

Methods: Icotinamide adenine dinucleotide phosphate oxidase activity and the expression of flavocytochrome b558 were measured by flow cytometry, and clinical outcomes of the patients were listed in relation to the genetic results.

Results: The clinical and genetic findings of 32 pediatric cases with CGD from 23 families were enrolled. Pneumonia and anemia were the most common infectious and noninfectious symptoms. Genetic analysis showed that 10 families (43.5%) carried CYBB variants and 13 families (56.5%) have autosomal recessive (AR) CGD, in which 6 families (26%) carried NCF1 variants, 4 (17.4%) carried CYBA variants, and 3 (13%) carried NCF2 variants. The median age of clinical onset was 3.3 and 48 months for patients with X-linked CGD (X-CGD) and AR-CGD, respectively. The onset of symptoms before age 1 year was 94% in X-CGD, 28.5% in AR-CGD, and 12.5% in patients with oxidase residual activity. Moreover, a de novo germline mutation at c.1415delG in CYBB (OMIM#300481) and a novel c.251_263del13bp in CYBA (OMIM#608508) were also investigated.

Conclusions: Ihydrorhodamine-1,2,3 assay could not detect carrier mother in de novo case with CYBB variant. Most X-CGD patients have the onset of symptoms before age 1 year. Additionally, residual oxidase activity in AR-CGD causes a delay in onset, diagnosis, and prophylaxis. The protective role of residual activity is limited while the infection is ongoing and becoming serious.
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http://dx.doi.org/10.1159/000507366DOI Listing
November 2020

Mutational landscape of severe combined immunodeficiency patients from Turkey.

Int J Immunogenet 2020 Dec 22;47(6):529-538. Epub 2020 May 22.

Department of Genetics, Aziz Sancar Institute of Experimental Medicine, Istanbul University, Istanbul, Turkey.

Severe combined immunodeficiency (SCID) has a diverse genetic aetiology, where a clinical phenotype, caused by single and/or multiple gene variants, can give rise to multiple presentations. The advent of next-generation sequencing (NGS) has recently enabled rapid identification of the molecular aetiology of SCID, which is crucial for prognosis and treatment strategies. We sought to identify the genetic aetiology of various phenotypes of SCIDs and assessed both clinical and immunologic characteristics associated with gene variants. An amplicon-based targeted NGS panel, which contained 18 most common SCID-related genes, was contumely made to screen the patients (n = 38) with typical SCID, atypical SCID or OMENN syndrome. Allelic segregations were confirmed for the detected gene variants within the families. In total, 24 disease-causing variants (17 known and 7 novel) were identified in 23 patients in 9 different SCID genes: RAG1 (n = 5), RAG2 (n = 2), ADA (n = 3), DCLRE1C (n = 2), NHEJ1 (n = 2), CD3E (n = 2), IL2RG (n = 3), JAK3 (n = 4) and IL7R (n = 1). The overall success rate of our custom-made NGS panel was 60% (39.3% for NK+ SCID and 100% for NK- SCID). Incidence of autosomal-recessive inherited genes is more frequently found in our cohort than the previously reported populations probably due to the high consanguineous marriages in Turkey. In conclusion, the custom-made sequencing panel was able to identify and confirm the previously known and novel disease-causing variants with high accuracy.
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http://dx.doi.org/10.1111/iji.12496DOI Listing
December 2020

Thyroid abscess due to Eikenella corrodens in a pediatric patient.

J Infect Dev Ctries 2019 10 31;13(10):945-947. Epub 2019 Oct 31.

Department of Pediatric Infectious Disease, Cerrahpasa Medical Faculty, Istanbul University, Istanbul, Turkey.

Eikenella corrodens is one of the HACEK bacteria that is commensal microorganism of the oropharngeal flora. E. corrodens has been increasingly reported to cause pyogenic abscesses, especially in diabetic or immunocompromised adults. It is less frequently reported in immunocompotent children. Here, we report a deep neck infection, including the thyroid gland, in a previously healthy girl. E. corrodens was the only microorganism isolated in two different cultures. Antibiotic susceptibility is variable, in contrast to other oropharyngeal pathogens. Thus, to avoid delayed treatment, E. corrodens should always be considered in infections of the head and neck area.
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http://dx.doi.org/10.3855/jidc.11057DOI Listing
October 2019

Evaluation of Clinical and Laboratory Characteristics of Children with Pulmonary and Extrapulmonary Tuberculosis.

Medicina (Kaunas) 2019 Aug 1;55(8). Epub 2019 Aug 1.

Department of Pediatric Infectious Disease, Cerrahpasa Medical School, Istanbul University-Cerrahpasa, 34303 Istanbul, Turkey.

: Tuberculosis (TB) is an important public health problem in both developing and developed countries. Childhood TB is also an important epidemiological indicator in terms of forming the future TB pool. The diagnosis of TB is difficult in children due to the lack of a standard clinical and radiological description. We aimed to evaluate and compare the clinical, laboratory, and radiologic findings of childhood pulmonary and extrapulmonary TB. The medical records of patients hospitalized with the diagnosis of pulmonary tuberculosis (PTB) and extrapulmonary tuberculosis (EPTB) between December 2007 and December 2017 were evaluated retrospectively. : There were 163 patients diagnosed with TB with 94 females (57.7%) and 69 males (42.3%). Seventy-three patients (44.8%) had PTB, 71 (43.6%) patients had EPTB, and 19 patients (11.7%) had both PTB and EPTB, called as disseminated TB. Ninety-six (58.9%) patients had tuberculin skin test (TST) positivity and 64 patients (39.3%) had interferon-gamma release assay (IGRA) positivity. Acid-resistant bacteria were observed in 34 (20.9%) body fluid samples and culture positivity was observed in 33 (20.2%) samples. Comparison of PTB, EPTB, and disseminated TB revealed that low socioeconomic status, TB contact, and low body weight were more common in disseminated TB, and TST positivity was more common in PTB. : Malnutrition, low socioeconomic status, and TB contact were important diagnostic variables in our study and all three parameters were more common in disseminated TB. Tuberculosis should be considered in patients admitted with different complaints and signs in populations with high TB incidence and low socioeconomic status.
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http://dx.doi.org/10.3390/medicina55080428DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6722557PMC
August 2019

Evaluation of Continuous Renal Replacement Therapy and Therapeutic Plasma Exchange, in Severe Sepsis or Septic Shock in Critically Ill Children.

Medicina (Kaunas) 2019 Jul 7;55(7). Epub 2019 Jul 7.

Department of Pediatric Intensive Care Unit, Istanbul University Cerrahpasa Medical Faculty, Fatih, Istanbul 34098, Turkey.

Severe sepsis and septic shock are life-threatening organ dysfunctions and causes of death in critically ill patients. The therapeutic goal of the management of sepsis is restoring balance to the immune system and fluid balance. Continuous renal replacement therapy (CRRT) is recommended in septic patients, and it may improve outcomes in patients with severe sepsis or septic shock. Therapeutic plasma exchange (TPE) is another extracorporeal procedure that can improve organ function by decreasing inflammatory and anti-fibrinolytic mediators and correcting haemostasis by replenishing anticoagulant proteins. However, research about sepsis and CRRT and TPE in children has been insufficient and incomplete. Therefore, we investigated the reliability and efficacy of extracorporeal therapies in paediatric patients with severe sepsis or septic shock. We performed a multicentre retrospective study using data from all patients aged <18 years who were admitted to two paediatric intensive care units. Demographic data and reason for hospitalization were recorded. In addition, vital signs, haemogram parameters, and biochemistry results were recorded at 0 h and after 24 h of CRRT. Patients were compared according to whether they underwent CRRT or TPE; mortality between the two treatment groups was also compared. Between January 2014 and April 2019, 168 septic patients were enrolled in the present study. Of them, 47 (27.9%) patients underwent CRRT and 24 underwent TPE. In patients with severe sepsis, the requirement for CRRT was statistically associated with mortality ( < 0.001). In contrast, the requirement for TPE was not associated with mortality ( = 0.124). Our findings revealed that the requirement for CRRT in patients with severe sepsis is predictive of increased mortality. CRRT and TPE can be useful techniques in critically ill children with severe sepsis. However, our results did not show a decrease of mortality with CRRT and TPE.
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http://dx.doi.org/10.3390/medicina55070350DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6680968PMC
July 2019

Clinical and immunophenotypic characteristics of patients with chromosome 22q11.2 deletion syndrome: a single institution's experience.

Turk Pediatri Ars 2019 1;54(1):28-34. Epub 2019 Mar 1.

Division of Pediatric Allergy, Department of Pediatrics, Immunology and Infectious Diseases, İstanbul University Cerrahpaşa Faculty of Medicine, İstanbul, Turkey.

Aim: The aim of this study was to identify the clinical and immunologic features of patients with 22q11.2 deletion syndrome who were followed up in our clinic. Thus, it is aimed to identify the syndrome early, choose the right treatment options according to humoral and cellular immunologic analysis, and enlighten how to follow up these kinds of patients with immunodeficiencies.

Material And Methods: We retrospectively collected data by reviewing the files of 11 patients with 22q11.2 deletion syndrome who were followed up in our clinic between January 2003 and January 2015. The diagnoses were based on the patients' clinical, genetic, and immunologic features. Demographic features, family history, initial symptoms on admission, physical findings, and results of immunologic studies of the patients. Age of diagnosis, treatment options, and clinical follow-up were evaluated.

Results: The patients' diagnosis age ranged from 1-11 months and the most common symptoms of admission were cardiac murmur and atypical facial appearance, which were detected during a routine physical examination. All patients had cardiac anomalies, and four patients had a history of cardiovascular surgery. Eight patients (72.7%) had a history of severe infection; recurrent lower respiratory tract infections were reported in six patients (54.5%), pulmonary tuberculosis in one patient (9.1%), and moniliasis resistant to treatment was detected in one patient. None of the patients required intravenous immunoglobulin replacement therapy, and antibiotic prophylaxis was administered to two patients with lymphopenia.

Conclusion: 22q11.2 deletion syndrome is a multi-systemic disorder that should be evaluated by a multidisciplinary team. It should be kept in mind for patients with neonatal hypocalcemic tetany or recurrent infections or atypical facial appearance with cardiac anomalies. Early diagnosis should lead to immunologic analysis and enable the choice of treatment. Preventive measures against infection is recommended for the patients with incomplete immunodeficiency, and thymus transplantation is recommended for patients with complete immunodeficiency.
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http://dx.doi.org/10.14744/TurkPediatriArs.2019.95815DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6559977PMC
March 2019

Infections with Carbapenem-Resistant Gram-Negative Bacteria are a Serious Problem Among Critically Ill Children: A Single-Centre Retrospective Study.

Pathogens 2019 May 21;8(2). Epub 2019 May 21.

Department of Pediatric Intensive Care Unit, Istanbul University Cerrahpasa Medical Faculty, Fatih, Istanbul 34098, Turkey.

Children in paediatric intensive care units (PICUs) are vulnerable to infections because invasive devices are frequently used during their admission. We aimed to determine the prevalence, associated factors, and prognosis of infections in our PICU. This retrospective study evaluated culture results from 477 paediatric patients who were treated in the PICU between January 2014 and March 2019. Ninety patients (18.9%) had bacterial infections, with gram-negative bacteria being the predominant infectious agents. Culture-positive patients were younger than culture-negative patients, and age was related to mortality and various clinical factors. Culture-positive bacterial infections in the PICU were associated with increased use of invasive mechanical ventilation (odds ratio(OR); 2.254), red blood cell (RBC) transfusions (OR:2.624), and inotropic drugs (OR:2.262). Carbapenem resistance was found in approximately one-third of gram-negative bacteria, and was most common in tracheal aspirate specimens and cases involving spp. Total parenteral nutrition was a significant risk factor (OR:5.870). Positive blood culture results were associated with poorer patient survival than other culture results. These findings indicate that infections, especially those involving carbapenem-resistant bacteria, are an important issue when treating critically ill children.
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http://dx.doi.org/10.3390/pathogens8020069DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6630812PMC
May 2019

Genotypic characterization of isolates from Turkish children with cystic fibrosis.

Infect Drug Resist 2019 27;12:675-685. Epub 2019 Mar 27.

Istanbul University, Institute for Medical Experimental Research (DETAE), 34390 Capa, Istanbul, Turkey.

To identify epidemic and other transmissible strains, genotypic analyses are required. The aim of this study was to assess the distribution of strains within the Turkish pediatric cystic fibrosis (CF) clinic population. Eighteen patients attending the pediatric CF clinic of Cerrahpasa Medical Faculty were investigated in the study. Throat swab and/or sputum samples were taken from each patient at 3-month intervals. The isolates of patients were analyzed by pulsed-field gel electrophoresis (PFGE). The intra- and interpatient genotypic heterogeneity of isolates was examined to determine the clonal isolates of within the cohort. A total of 108 clinical isolates of were obtained from 18 patients between May 2013 and May 2014. The pulsotypes of the first patient's isolates could not be obtained by PFGE. From the remaining 17 patients and 101 isolates, 55 distinct pulsotypes were detected. The number of pulsotypes observed in more than one patient (minor clonal strains, cluster strains) was 8 (14.5%), and one of them colonized three patients. However, none of them was detected in more than three patients. These pulsotypes were composed of 20 isolates. In addition, with the PFGE analysis of 81 isolates, we detected 47 (85.6%) pulsotypes, which belonged to only one patient. Over different periods of this study, only 2 (11.8%) patients were colonized with the same pulsotype. Our study indicates that there was considerable genomic diversity among the isolates in our clinic. The presence of shared pulsotypes supports cross-transmission between patients.
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http://dx.doi.org/10.2147/IDR.S183151DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6497484PMC
March 2019

Can Nebulised Colistin Therapy Improve Outcomes in Critically Ill Children with Multi-Drug Resistant Gram-Negative Bacterial Pneumonia?

Antibiotics (Basel) 2019 Apr 11;8(2). Epub 2019 Apr 11.

Department of Pediatric Intensive Care Unit, Istanbul University Cerrahpasa Medical Faculty, 34098 Fatih, Istanbul, Turkey.

In the past decade, multidrug-resistant (MDR) gram-negative bacteria have become a major problem, especially for patients in intensive care units. Recently, colistin became the last resort therapy for MDR gram-negative bacteria infections. However, nebulised colistin use was limited to adult patients. Thus, we investigated the efficacy and safety of nebulised colistin treatment against MDR microorganisms in the paediatric intensive care unit (PICU). Data of all patients admitted for various critical illnesses (January 2016 to January 2019) were reviewed. Differences between groups (with and without a history of nebulised colistin) were compared. Of 330 patients, 23 (6.97%) used nebulised colistin. Significant relationships were found between nebulised colistin usage and several prognostic factors (inotropic drug use ( = 0.009), non-invasive mechanical ventilation ( ≤ 0.001), duration in PICU ( ≤ 0.001), and C-reactive protein level ( = 0.003)). The most common microorganism in tracheal aspirate and sputum cultures was (13 patients). The most common underlying diagnosis was cystic fibrosis, noted in 6 patients. No serious nephrotoxicity and neurotoxicity occurred. This study showed that colistin can be safely used directly in the airway of critically ill children. However, nebulised colistin use did not have a positive effect on mortality and prognosis.
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http://dx.doi.org/10.3390/antibiotics8020040DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6627821PMC
April 2019

Tuberculin skin test response in patients with juvenile idiopathic arthritis on anti-TNF therapy

Turk J Med Sci 2018 Dec 12;48(6):1109-1114. Epub 2018 Dec 12.

Background/aim: The aim of this study is to evaluate the effect of biologic drugs on the tuberculin skin test in patients with juvenile idiopathic arthritis.

Materials And Methods: A total of 234 biologic drug-using juvenile idiopathic arthritis patients and 45 healthy controls were enrolled in the study. The tuberculin skin test results of the patients, which had been routinely provided during follow-up, were obtained from the patient files. Tuberculin skin test values of ≥5 mm were considered to be positive.

Results: The mean diameter of tuberculin skin test induration was 4.99 ± 6.84 mm (IQR: 0–10 mm) and 7.83 ± 3.47 mm (IQR: 0–16 mm) in patients and controls, respectively (P < 0.05). Tuberculin skin test positivity (≥5 mm) was found in 96 (41%) and 38 (84.4%) of patients and controls, respectively (P < 0.001). There was no induration in 125 (53.4%) patients and 3 (6.6%) healthy controls, respectively (P < 0.001).

Conclusion: In the patients with juvenile idiopathic arthritis who were using biologic drugs, tuberculin skin test induration was significantly lower compared to the control group. Tuberculin skin tests alone seem inadequate for recognition of latent tuberculosis in juvenile idiopathic arthritis patients on anti-TNF therapy.
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http://dx.doi.org/10.3906/sag-1710-190DOI Listing
December 2018

The frequency of infections in patients with juvenile idiopathic arthritis on biologic agents: 1-year prospective study.

Clin Rheumatol 2019 Apr 17;38(4):1025-1030. Epub 2018 Nov 17.

Department of Pediatric Rheumatology, Cerrahpasa Medical School, Istanbul University, Istanbul, Turkey.

Introduction: The most effective and concurrently the safest treatment regimen selection is important to provide early control of juvenile idiopathic arthritis (JIA) and to have an acceptable quality of life. The effectivity of biologic agents as well as standard disease-modifying drugs is well documented in treatment of JIA. In spite of their high benefit, these drugs have the risk of serious infections. Herein, we conducted a prospective study to investigate the infectious complications of biologic agents in patients diagnosed with JIA.

Methods: Patients on biologic treatment regimen were examined by the pediatric infectious disease specialist in every 2 months during 1-year long.

Results: Throughout the study period, 57% (n:175) of the patients developed infection and 43% (n:132) of them completed this period without any infection. Upper respiratory tract infections which were treated in outpatient clinic were the most common infection. Only three serious infections (two pneumonia, one pleural effusion), which required hospitalization, developed. The infection rate was highest in systemic JIA and lowest in enthesitis-related arthritis (p < 0.001). The total rate of infection development after 1-year period was lowest for etanercept; it was highest for the patients on infliximab treatment (p < 0.001).

Conclusion: We comment that the altered immune system of JIA can be responsible from the serious infections irrespective of immunosuppressive therapy. Biologic agents can be safely used in JIA evaluating the loss and benefit statement.
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http://dx.doi.org/10.1007/s10067-018-4367-9DOI Listing
April 2019

Antifungal consumption, indications and selection of antifungal drugs in paediatric tertiary hospitals in Turkey: Results from the first national point prevalence survey.

J Glob Antimicrob Resist 2018 12 16;15:232-238. Epub 2018 Aug 16.

Çukurova University, Faculty of Medicine, Department of Pediatric Infectious Diseases, Adana, Turkey.

Objectives: The aim of this point prevalence survey was to evaluate the consumption, indications and strategies of antifungal therapy in the paediatric population in Turkey.

Methods: A point prevalence study was performed at 25 hospitals. In addition to general data on paediatric units of the institutes, the generic name and indication of antifungal drugs, the presence of fungal isolation and susceptibility patterns, and the presence of galactomannan test and high-resolution computed tomography (HRCT) results were reviewed.

Results: A total of 3338 hospitalised patients were evaluated. The number of antifungal drugs prescribed was 314 in 301 patients (9.0%). Antifungal drugs were mostly prescribed in paediatric haematology and oncology (PHO) units (35.2%), followed by neonatal ICUs (NICUs) (19.6%), paediatric services (18.3%), paediatric ICUs (PICUs) (14.6%) and haematopoietic stem cell transplantation (HSCT) units (7.3%). Antifungals were used for prophylaxis in 147 patients (48.8%) and for treatment in 154 patients (50.0%). The antifungal treatment strategy in 154 patients was empirical in 77 (50.0%), diagnostic-driven in 29 (18.8%) and targeted in 48 (31.2%). At the point of decision-making for diagnostic-driven antifungal therapy in 29 patients, HRCT had not been performed in 1 patient (3.4%) and galactomannan test results were not available in 12 patients (41.4%). Thirteen patients (8.4%) were receiving eight different antifungal combination therapies.

Conclusion: The majority of antifungal drugs for treatment and prophylaxis were prescribed in PHO and HSCT units (42.5%), followed by ICUs. Thus, antifungal stewardship programmes should mainly focus on these patients within the availability of diagnostic tests of each hospital.
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http://dx.doi.org/10.1016/j.jgar.2018.08.007DOI Listing
December 2018

Evaluation of patients with orbital infections.

Turk Pediatri Ars 2017 Dec 1;52(4):221-225. Epub 2017 Dec 1.

Istanbul University, Cerrahpaşa Medical Faculty, Department of Pediatrics, Division of Immunology-Allergy and Infectious Diseases, Istanbul, Turkey.

Aim: Orbital tissue infections are common infections of childhood that can lead to severe complications. Herein, we aimed to evaluate the etiologic factors, diagnosis, follow-up, and treatment procedures in pediatric patients with orbital infections.

Material And Methods: This study was performed retrospectively between January 2014 and December 2015 in Cerrahpasa Medical Faculty Pediatric Infectious Disease Unit. Patients were studied for age, ophthalmologic examination features, laboratory and radiology results, treatment modalities, and the response to these treatments.

Results: Thirty-six patients (21 males, 15 females) with an average age of 71.43±42.24 months (5-168 months) participated in the study in the two-year period. Thirty-two patients (88.9%) had preseptal cellulitis, and four (11.9%) had orbital cellulitis. All patients had eyelid hyperemia, edema, and ocular pain, with chemosis in seven and proptosis in four cases. Twenty-five patients were admitted with fever. All cases were unilateral and 44.4% occurred secondary to paranasal sinusitis. All cases were treated with intravenous cefazolin-amikacin. The mean of duration of hospitalization was 12.02±8.75 days (range, 3-28 days) and the duration of parental antibiotics was 12.83±8.18 days (range, 7-21 days). All patients recovered without any vision loss, only one patient experienced subdural empyema complicating preseptal cellulitis.

Conclusions: Most orbital tissue infections occur secondary to paranasal sinusitis in childhood. Orbital tissue infections can be complicated by brain abscess, cavernous sinus thrombophlebitis, and vision loss. Early diagnosis and proper antibiotic treatment are essential to prevent these life-threatening complications.
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http://dx.doi.org/10.5152/TurkPediatriArs.2017.5511DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5819860PMC
December 2017

A case of severe combined immunodeficiency caused by adenosine deaminase deficiency with a new mutation.

Pediatr Neonatol 2018 02 11;59(1):97-99. Epub 2017 Jul 11.

Department of Pediatric Infectious Diseases, Clinical Immunology and Allergy, Istanbul University, Cerrahpasa Medical Faculty, Istanbul, Turkey. Electronic address:

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http://dx.doi.org/10.1016/j.pedneo.2016.10.008DOI Listing
February 2018

A novel pathogenic frameshift variant of CD3E gene in two T-B+ NK+ SCID patients from Turkey.

Immunogenetics 2017 10 9;69(10):653-659. Epub 2017 Jun 9.

Department of Genetics, Aziz Sancar Institute of Experimental Medicine, Istanbul University, Istanbul, Turkey.

Severe combined immunodeficiency (SCID) is the most severe form of primary immunodeficiency, which is characterized by the dysfunction and/or absence of T lymphocytes. Early diagnosis of SCID is crucial for overall survival, and if it remains untreated, SCID is often fatal. Next-generation sequencing (NGS) has become a rapid, high-throughput technology, and has already been proven to be beneficial in medical diagnostics. In this study, a targeted NGS panel was developed to identify the genetic variations of SCID by using SmartChip-TE technology, and a novel pathogenic frameshift variant was found in the CD3E gene. Sanger sequencing has confirmed the segregation of the variant among patients. We found a novel deletion in the CD3E gene (NM000733.3:p.L58Hfs*9) in two T-B+ NK+ patients. The variant was not found in the databases of dbSNP, ExAC, and 1000G. One sibling in family I was homozygous and the rest of the family members were heterozygous for this variant. T cell receptor excision circle (TREC) and kappa-deleting recombination excision circle (KREC) analyses were performed for T and B cell maturation. TRECs were not detected in both patients and the KREC copy numbers were similar to the other family members. In addition, heterozygous family members showed decreased TREC levels when compared with the wild-type sibling, indicating that carrying this variant in one allele does not cause immunodeficiency, but does effect T cell proliferation. Here, we report a novel pathogenic frameshift variant in CD3E gene by using targeted NGS panel.
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http://dx.doi.org/10.1007/s00251-017-1005-7DOI Listing
October 2017

Leukocyte Adhesion Deficiency III: Report of Two Siblings.

Pediatr Neonatol 2017 02 22;58(1):99-100. Epub 2016 Nov 22.

Istanbul University, Cerrahpasa Medical Faculty Department of Pediatric Infectious Diseases, Clinical Immunology and Allergy, Istanbul University, Istanbul, Turkey.

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http://dx.doi.org/10.1016/j.pedneo.2016.07.006DOI Listing
February 2017

Different clinical spectrum of leptospirosis.

Turk J Pediatr 2016 ;58(2):212-215

Division of Pediatric Infectious Diseases, Istanbul University Cerrahpasa Faculty of Medicine, Istanbul, Turkey.

Leptospirosis is a prevalent zoonotic disease. Human infection usually occurs through exposure to environmental sources. Clinical course of leptospirosis is variable. We presented five patients, aged between 4-14 years, having a history of contact with rodents and symptoms 7-10 days after contact. The first three cases were relatives and had contact with dead rats after applying insecticides to bakery across from their house. The first case diagnosed as isolated meningitis, others as flu-like illness. The fourth case had a contact history with a rat inundate in the canalization and diagnosed as acute hepatitis. The last case, living in a village with poor sanitation, developed secondary hemophagocytic syndrome. ELISA was performed for diagnosis. High dose penicillin and additional immunosuppressive drugs for the last case were used. All cases showed recovery within 10 days. Leptospirosis should be considered in any patient presenting with an abrupt onset or prolonged fever, myalgia, headache and jaundice.
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http://dx.doi.org/10.24953/turkjped.2016.02.015DOI Listing
May 2017

Genetic, immunological, and clinical features of patients with bacterial and fungal infections due to inherited IL-17RA deficiency.

Proc Natl Acad Sci U S A 2016 12 7;113(51):E8277-E8285. Epub 2016 Dec 7.

Department of Pediatric Immunology, Dr. Sami Ulus Maternity and Children's Health and Diseases Training and Research Hospital, 06080 Ankara, Turkey.

Chronic mucocutaneous candidiasis (CMC) is defined as recurrent or persistent infection of the skin, nails, and/or mucosae with commensal Candida species. The first genetic etiology of isolated CMC-autosomal recessive (AR) IL-17 receptor A (IL-17RA) deficiency-was reported in 2011, in a single patient. We report here 21 patients with complete AR IL-17RA deficiency, including this first patient. Each patient is homozygous for 1 of 12 different IL-17RA alleles, 8 of which create a premature stop codon upstream from the transmembrane domain and have been predicted and/or shown to prevent expression of the receptor on the surface of circulating leukocytes and dermal fibroblasts. Three other mutant alleles create a premature stop codon downstream from the transmembrane domain, one of which encodes a surface-expressed receptor. Finally, the only known missense allele (p.D387N) also encodes a surface-expressed receptor. All of the alleles tested abolish cellular responses to IL-17A and -17F homodimers and heterodimers in fibroblasts and to IL-17E/IL-25 in leukocytes. The patients are currently aged from 2 to 35 y and originate from 12 unrelated kindreds. All had their first CMC episode by 6 mo of age. Fourteen patients presented various forms of staphylococcal skin disease. Eight were also prone to various bacterial infections of the respiratory tract. Human IL-17RA is, thus, essential for mucocutaneous immunity to Candida and Staphylococcus, but otherwise largely redundant. A diagnosis of AR IL-17RA deficiency should be considered in children or adults with CMC, cutaneous staphylococcal disease, or both, even if IL-17RA is detected on the cell surface.
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http://dx.doi.org/10.1073/pnas.1618300114DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5187691PMC
December 2016

House Dust Mites Confer a Distinct Immunological Feature among Dermatitis.

Iran J Allergy Asthma Immunol 2016 Aug;15(4):264-274

Division of Pediatric Allergy and Immunology, Pendik Research and Training Hospital, Marmara University, Istanbul, Turkey.

Atopic dermatitis (AD) is a heterogeneous disease with regard to clinical phenotype and natural history. We investigated T cell subtypes and cytokine responses in peripheral blood and skin lesions of AD patients with various sensitivities. Immunological studies were performed in 27 subjects: 9 house dust mite (HDM)-sensitized; 6 subjects with sensitizations other than HDM; 7 non-allergic AD patients and 5 healthy controls. Among those, skin biopsy samples of 13 subjects were evaluated for immunohistochemical analyses, as well. The mean age was 8.93±5.17 years. HDM-allergic AD emerged as a distinct immunologic phenotype, with higher production of interleukin (IL)-4, -5, -2 both at rest and when stimulated by Der p1 or SEB along with higher Th17. As for TH17 cell percentage, it was increased in all AD groups compared to healthy controls, while HDM-allergic group was distinguished with a significantly lower production of IL-17. Patients with sensitizations other than HDM were mostly similar to non-allergic AD, with increased Th17 and CD4+CD69+interferon-gamma (IFN-γ)+ T cells percentage. The biopsy of lesional skin showed that HDM-allergic AD had lower IFN-γ and IFN-γ co-expressing CD8+ T cells compared to patients with other sensitizations (p=0.03 and p=0.04, respectively). Among the HDM allergic patients, pairwise comparison of lesional versus non-lesional skin revealed higher CD4+ T cells numbers, expression of forkhead box P3 (Foxp3) and T-cell-specific transcription factor (T-bet) (p=0.018, p=0.018, p=0.018, respectively). HDM-allergic AD is a distinct subtype with a predominant skewing in Th2 and higher Th17 cell percentage along with a blunted Th1 response in the skin, all of which may have therapeutic implications.
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August 2016

Dual T cell- and B cell-intrinsic deficiency in humans with biallelic RLTPR mutations.

J Exp Med 2016 10 19;213(11):2413-2435. Epub 2016 Sep 19.

Laboratory of Human Genetics of Infectious Diseases, Necker Branch, Institut National de la Santé et de la Recherche Médicale U1163, 75015 Paris, France.

Combined immunodeficiency (CID) refers to inborn errors of human T cells that also affect B cells because of the T cell deficit or an additional B cell-intrinsic deficit. In this study, we report six patients from three unrelated families with biallelic loss-of-function mutations in RLTPR, the mouse orthologue of which is essential for CD28 signaling. The patients have cutaneous and pulmonary allergy, as well as a variety of bacterial and fungal infectious diseases, including invasive tuberculosis and mucocutaneous candidiasis. Proportions of circulating regulatory T cells and memory CD4 T cells are reduced. Their CD4 T cells do not respond to CD28 stimulation. Their CD4 T cells exhibit a "Th2" cell bias ex vivo and when cultured in vitro, contrasting with the paucity of "Th1," "Th17," and T follicular helper cells. The patients also display few memory B cells and poor antibody responses. This B cell phenotype does not result solely from the T cell deficiency, as the patients' B cells fail to activate NF-κB upon B cell receptor (BCR) stimulation. Human RLTPR deficiency is a CID affecting at least the CD28-responsive pathway in T cells and the BCR-responsive pathway in B cells.
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http://dx.doi.org/10.1084/jem.20160576DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5068239PMC
October 2016

Multiple pericardial abscesses in a child with known chronic granulomatous disease.

Ann Pediatr Cardiol 2016 Sep-Dec;9(3):272-3

Department of Radiology, Cerrahpasa Medical Faculty, Istanbul University, Istanbul, Turkey. E-mail:

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http://dx.doi.org/10.4103/0974-2069.189120DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5007943PMC
September 2016

Bacterial agents causing meningitis during 2013-2014 in Turkey: A multi-center hospital-based prospective surveillance study.

Hum Vaccin Immunother 2016 11 25;12(11):2940-2945. Epub 2016 Jul 25.

w Department of Pediatrics , Suleyman Demirel University Faculty of Medicine , Isparta , Turkey.

This is an observational epidemiological study to describe causes of bacterial meningitis among persons between 1 month and 18 y of age who are hospitalized with suspected bacterial meningitis in 7 Turkish regions. covering 32% of the entire population of Turkey. We present here the results from 2013 and 2014. A clinical case with meningitis was defined according to followings: any sign of meningitis including fever, vomiting, headache, and meningeal irritation in children above one year of age and fever without any documented source, impaired consciousness, prostration and seizures in those < 1 y of age. Single tube multiplex PCR assay was performed for the simultaneous identification of bacterial agents. The specific gene targets were ctrA, bex, and ply for N. meningitidis, Hib, and S. pneumoniae, respectively. PCR positive samples were recorded as laboratory-confirmed acute bacterial meningitis. A total of 665 children were hospitalized for suspected acute meningitis. The annual incidences of acute laboratory-confirmed bacterial meningitis were 0.3 cases / 100,000 population in 2013 and 0.9 cases/100,000 in 2014. Of the 94 diagnosed cases of bacterial meningitis by PCR, 85 (90.4%) were meningococcal and 9 (9.6%) were pneumococcal. Hib was not detected in any of the patients. Among meningococcal meningitis, cases of serogroup Y, A, B and W-135 were 2.4% (n = 2), 3.5% (n = 3), 32.9% (n = 28), and 42.4% (n = 36). No serogroup C was detected among meningococcal cases. Successful vaccination policies for protection from bacterial meningitis are dependent on accurate determination of the etiology of bacterial meningitis. Additionally, the epidemiology of meningococcal disease is dynamic and close monitoring of serogroup distribution is comprehensively needed to assess the benefit of adding meningococcal vaccines to the routine immunization program.
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http://dx.doi.org/10.1080/21645515.2016.1209278DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5137527PMC
November 2016
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