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Background: Two major complications of Aspergillus sensitization in patients with asthma, including severe asthma with fungal sensitization (SAFS) and asthma associated with fungal sensitization (AAFS), have been recently described. Objectives: In the present study, we aimed to evaluate the prevalence of SAFS and AAFS in Iranian patients with asthma. Methods: Two hundred consecutive outpatients aged ≥ 18 years with moderate to severe allergic asthma, referred to a pulmonary subspecialty hospital (Tehran, Iran) for 25 months, were included in the study. Skin prick test (SPT), total IgE (tIgE), and specific IgE (sIgEAf) and IgG against Aspergillus fumigatus (sIgGAf) were determined for all subjects. Comprehensive criteria were applied for the diagnosis of SAFS and AAFS. Results: Of 200 included patients, 103 (51.5%) and 97 (48.5%) were with moderate and severe asthma, respectively. Of these patients, 111 (55.5%) were female. The mean (range) of age was 45.8 (18 - 78) years. Of 200 patients, 27 (13.5%), 22 (11.0%), 114 (57.0%), and 131 (65.5%) were positive for Aspergillus SPT, sIgEAf, sIgGAf, and tIgE, respectively. The overall prevalence of SAFS in patients with severe asthma and AASF in patients with moderate asthma were 7.2% (7/97) and 3.9% (4/103), respectively. Conclusions: According to the findings, the prevalence of SAFS and AAFS in Iranian patients with severe and moderate allergic asthma was lower than the previously published global data. This low-prevalence reported rate may be due to the fact that we applied strict criteria in the present study.

In chronic granulomatous disease (CGD) patients, reactive oxygen species (ROS) production by neutrophils is impaired. So, they are susceptible to infections. Studies showed that, mesenchymal stem cells (MSCs) have protective effects on the function of neutrophils and an approach that MSCs use to apply their effects, is secreting soluble factors and exosomes. So, we investigated the effects of MSC-exosomes and MSC-conditioned media (MSC-CM) on the function and apoptosis of neutrophils in CGD patients. In this study, neutrophils were isolated from healthy donors and CGD patients and then incubated with exosomes or CM that were prepared from MSCs. Then, neutrophil respiratory burst, apoptosis and phagocytosis capacity were evaluated by NBT assay, Annexin V-PI method and Giemsa staining. It was demonstrated that both MSC-exosomes and CM could improve the phagocytosis capacity and ROS production of neutrophils in CGD patients and healthy donors. In contrast to the healthy group, in CGD patients, exosomes significantly reduced the percentage of viable neutrophils. This report indicated that MSC exosomes and CM could increase the function of the neutrophils isolated from CGD patients. But decreasing the number of the living cells is one of the limitations of them. However, it is hoped that this intervention will be developed in future studies to minimize its limitations.

Background and aims Respiratory infections are expressed very soon in the life in humoral immunodeficiencies and often lead to chronic irreversible complications such as bronchiectasis and chronic airflow limitation. This study was conducted to evaluate the pulmonary complications of predominantly antibody immunodeficiencies to show the benefits of timely diagnosis and appropriate therapy. Patients and methods The information of 48 patients involved with a type of predominantly antibody immunodeficiencies, including sex, type of primary immunodeficiency, age at the onset of symptoms, age at diagnosis, recurrent infections, respiratory symptoms, and pulmonary radiological and functional abnormalities were recorded and analyzed. Results In 48 patients evaluated, the mean age at diagnosis was 25.63 years. The mean diagnostic delay was estimated to be 13.62 years. The most recurring clinical manifestations, sinusitis (69.6%), otitis (43.5%), and recurrent pneumonia were the cause of frequent admissions in 68.8% of these patients. Bronchiectasis was frequently found (58.3%) in these patients mostly involving the middle and lower lobes (48.8% and 41.5%, respectively). Conclusions Respiratory complications, infectious or non-infectious, determine the prognosis of the disease in patients with predominantly antibody immunodeficiencies. Timely diagnosis and appropriate management may improve life expectancy and the quality of life in these patients.

Background and Purpose: Aspergillus fumigatus as a ubiquitous fungus can be found in the respiratory tract of the asthmatic and healthy people. The inhalation of Aspergillus spores leads to an immune response in individuals with asthma and results in the aggravation of the clinical symptoms. The present study aimed to investigate the prevalence of specific immunoglobulin E and G (IgE and IgG) against A.fumigatus in asthmatic patients.Materials and Methods: This study was conducted on 200 consecutive patients with moderate to severe asthma referring to Masih Daneshvari hospital Tehran, Iran, from January 2016 to February 2018. Skin prick test (SPT) was performed in all subjects with Aspergillus allergens. Moreover, all patients underwent specific IgE testing for Aspergillus using Hycor method. Enzyme immune assay was applied to measure total IgE and Aspergillus-specific IgG.Results: According to the results, the mean age of the patients was 45.8 years (age range: 18-78 years). The mean levels of total IgE and Aspergillus specific IgE in asthmatic patients were obtained as 316.3 (range: 6-1300 IU/ml) and 1.5 (range: 0.1-61.3 IU/ml), respectively. Out of 200 patients, 27 (13.5%), 65 (32.5%), 22 (11.0%), and 86 (43.0%) cases had positive Aspergillus SPT, total IgE of > 417 IU/ml, Aspergillus-specific IgE, and IgG, respectively. The level of these variables in patients with severe asthma were 16 (16.5%), 36 (37.1%), 15 (15.5%), and 46 (47.4%), respectively.Conclusion: As the findings indicated, reactivity to Aspergillus is a remarkable phenomenon in asthmatic patients. It is also emphasised that the climatic condition may affect the positive rate of hypersensitivity to Aspergillus.

The number of inherited diseases and the spectrum of clinical manifestations of primary immunodeficiency disorders (PIDs) are ever-expanding. Molecular diagnosis using genomic approaches should be performed for all PID patients since it provides a resource to improve the management and to estimate the prognosis of patients with these rare immune disorders. The current update of Iranian PID registry (IPIDR) contains the clinical phenotype of newly registered patients during last 5 years (2013–2018) and the result of molecular diagnosis in patients enrolled for targeted and next-generation sequencing. Considering the newly diagnosed patients (n = 1395), the total number of registered PID patients reached 3056 (1852 male and 1204 female) from 31 medical centers. The predominantly antibody deficiency was the most common subcategory of PID (29.5%). The putative causative genetic defect was identified in 1014 patients (33.1%) and an autosomal recessive pattern was found in 79.3% of these patients. Among the genetically different categories of PID patients, the diagnostic rate was highest in defects in immune dysregulation and lowest in predominantly antibody deficiencies and mutations in the MEFV gene were the most frequent genetic disorder in our cohort. During a 20-year registration of Iranian PID patients, significant changes have been observed by increasing the awareness of the medical community, national PID network establishment, improving therapeutic facilities, and recently by inclusion of the molecular diagnosis. The current collective study of PID phenotypes and genotypes provides a major source for ethnic surveillance, newborn screening, and genetic consultation for prenatal and preimplantation genetic diagnosis.

Introduction Asthma exacerbations may occur due to a variety of triggers including respiratory viruses. The aim of this study was to determine the role of particular viral infections in asthma exacerbations in children. Materials and methods The study was performed at Dr. Daneshvari Hospital Pediatric Emergency Department, Shahid Beheshti University of Medical Sciences, Tehran, Iran between 2014 and 2015. A nasopharyngeal aspirate or swab was obtained from each patient during admission. All samples were maintained at 4 °C until submission to the virology laboratory and were tested for respiratory viruses by nucleic acid testing. Results A total of 60 patients with asthma exacerbations were recruited for this study. Of the 60 samples collected from the patients with acute asthma exacerbations, rhinovirus was detected in 12 patients (20%), respiratory syncytial virus in 5 (8%), adenovirus in 5 (8%), and influenza virus in 1 (1.6%). Respiratory pathogens were not detected in 37 (61%) samples. All the samples investigated showed single viral infection. Conclusions To conclude, the most common viruses detected were rhinovirus followed by respiratory syncytial virus (RSV) and adenovirus. RSV was more commonly associated with more severe attacks. Both the study design (e.g., time of sampling, age of the patients, etc.) and also the method used for viral detection influence the frequency of detection of the respiratory viruses.

Background Combined immunodeficiencies (CIDs) are diseases of defective adaptive immunity with diverse clinical phenotypes. Although CIDs are more prevalent in the Middle East than Western countries, the resources for genetic diagnosis are limited. Objectives This study aims to characterize the categories of patients with CIDs in Iran clinically and genetically. Methods Clinical and laboratory data were obtained from 696 patients with CIDs. Patients were subdivided into those with syndromic (344 patients) and nonsyndromic (352 patients) CIDs. Targeted DNA sequencing was performed on 243 (34.9%) patients. Results The overall diagnostic yield of the 243 sequenced patients was 77.8% (189 patients). The clinical diagnosis of hyper-IgE syndrome ( P P = .02), and absence of multiple affected family members ( P = .04) were significantly more frequent in the patients without a genetic diagnosis. An autosomal recessive disease was found in 62.9% of patients, reflecting the high rate of consanguinity in this cohort. Mutations impairing VDJ recombination and DNA repair were the most common underlying causes of CIDs. However, in patients with syndromic CIDs, autosomal recessive mutations in ataxia-telangiectasia mutated (ATM) , autosomal dominant mutations in signal transducer and activator of transcription 3 (STAT3) , and microdeletions in 22q11.21 were the most commonly affected genomic loci. Patients with syndromic CIDs had a significantly lower 5-year survival rate rather than those with nonsyndromic CIDs. Conclusions This study provides proof of principle for the application of targeted next-generation sequencing panels in countries with limited diagnostic resources. The effect of genetic diagnosis on clinical care requires continued improvements in therapeutic resources for these patients.

Asthma is a chronic disease of the airways, and approximately three million people around the world are suffering from this disease. It can become a serious problem for the public health if it is not controlled. Specialists consider vital upgrading self-managing plans to control this disease. The main component of these programs is to control asthma attacks. The attacks are affected by different variables including the environmental factors such as air pollutants and meteorological factors. In this article, we attempted to develop a tool to make the patients aware potentially dangerous areas and places in terms of asthma attacks and help them in better control of the disease by providing daily monitoring maps of asthma attacks based on environmental factors. On the other hand, development of the information technology tools and penetration of mobile health tools have changed fundamentally the design of asthma self-management interventions by removing the spatial and temporal restrictions. The tool that is available for the patient in any time and place can make the patient be aware of potential risks. The purpose of this article is to develop a Mobile GIS 2 -based tool containing maps of monitoring asthma attacks based on environmental and local factors that will be generated using predictive algorithms. In fact, by developing this tool with an innovative and interdisciplinary approach, continuous self-management of asthma can be implemented more efficiently.

Background Intravenous immunoglobulins (IVIg) are the major treatment in inborn errors of immunity (IEI) disorders; However, IVIg infusions show some adverse effects. We aimed to assess the adverse reactions of IVIg infusions. Methods Data of IVIg infusions in IEI patients were collected from 2011 to 2021. Totally, 363 IEI patients received IVIg regularly in Iran entered the study. The adverse reactions are classified regarding their severity and chronicity. Results 22,667 IVIg infusions were performed in the study. 157 patients (43.2%) and 1349 (5.9%) infusions were associated with at least one type of adverse reaction. The highest rates of adverse reactions were seen in severe combined immunodeficiency. Myalgia, chills, headache, fever, and hypotension were the most frequent adverse effects of IVIg. Conclusion The reactions affect almost half of the patients mainly in the first infusions which necessitate the close observation of IEI patients receiving IVIg.

BACKGROUND Severe combined immunodeficiency (SCID) is a life-threatening pediatric disease. We report on the clinical evaluation, immunological assessment, molecular analysis, and outcomes of SCID patients in a tertiary referral center in Iran. METHODS From January 2006 to December 2015, we performed a prospective cohort study in which initial screening and advanced immunological tests were carried out on patients suspected of having SCID. Genetic analysis was also performed to confirm the diagnosis. RESULTS A total of 63 patients were diagnosed with SCID (43 male [68.3%]). The median age at onset and diagnosis and diagnostic delay were 40 and 110 and 60 days respectively. A total of 49 patients (77.8%) had a history of BCG vaccination, and of these, one-third experienced BCG-associated complications. The most common clinical manifestations were pneumonia, recurrent oral candidiasis, chronic diarrhea, and failure to thrive. Of the thirteen patients who underwent hematopoietic stem cell transplantation, 8 survived and 5 died before they could receive the transplant. Most patients (34.9%) were classified as having T-B-NK+ SCID and had a mutation in the RAG2 or RAG1 gene. CONCLUSIONS Autosomal recessive SCID is the most common type in Iranian patients. Providing high-quality training to physicians and patients' families to reduce the diagnostic delay should be prioritized. It is also important to raise awareness of live vaccination and to expand stem cell donor registries to speed up the transplantation process.

Background LPS-responsive beige-like anchor protein (LRBA) deficiency is a combined immunodeficiency caused by mutation in LRBA gene. The patients have a variety of clinical symptoms including hypogammaglobulinemia, recurrent infections, autoimmunity and enteropathy. Methods A total of 17 LRBA-deficient patients were enrolled in this longitudinal study. For all patients, demographic information, clinical records, laboratory and molecular data were collected. Results Hypogammaglobulinemia were reported in 14 (82.4%), CD4+ T cell deficiency in five (29.4%), NK cell deficiency in three (21.4%) and CD19+ B cell deficiency in 11 (64.7%) patients. All patients had history of infectious complications; pneumonia was the most common (76.5%) occurring infection. A history of lymphoproliferative disorders was observed in 14 (82.3%), enteropathy in 13 (76.5%), allergic symptoms in six (35.5%), neurological problems in four (23.5) and autoimmunity (mostly autoimmune cytopenia) in 13 (76.5%) patients. Sirolimus treatment improved enteropathy of patients with remarkable success. The 20-year overall survival rate declined to 70.6%. Conclusion LRBA deficiency has a very broad and variable phenotype and should be considered, especially in children with early onset hypogammaglobulinemia, severe autoimmune manifestations, enteropathy, lymphoproliferation, and recurrent respiratory tract infections. This article is protected by copyright. All rights reserved.

Background: One of the most serious complications of BCG immunization is disseminated BCG infection, which is suggested to occur in immunized children with underlying primary immunodeficiencies. Objectives: This study aimed to assess the clinical manifestations and underlying primary immunodeficiencies associated with disseminated BCG infection. Methods: The study enrolled 47 patients suspected of disseminated BCG infection referring to Mofid Children Hospital and Masih Daneshvari Hospital for 12 years. The patients’ records were reviewed and patients were classified into three distinctive groups of definitive, probable, or possible disseminated BCG infection. Results: Twenty-five (53.2%) patients were male and twenty-two (46.8%) were female. The mean age at onset of clinical manifestations was 4.83 months. The first presentation of the disease occurred within one year of vaccination in 28 (60%) patients. Clinical manifestations included lymphadenopathies (61%), fever (38%), hepatosplenomegaly (36%), failure to thrive (23%), skin rash (14%), chronic cough (10%), ascites (6%), and clubbing (6%). The confirmed underlying primary immunodeficiency detected in these patients were Mendelian Susceptibility to Mycobacterial Disease (MSMD; 69.56%), Severe Combined Immunodeficiency (SCID; 26%) and Chronic Granulomatous Disease (CGD; 4.3%). Conclusions: Disseminated BCG infection may be a devastating complication and an important preliminary manifestation of underlying primary immunodeficiency. Because of the wide spectrum of mortality and morbidity, as well as the socioeconomic burden on the health system, it is worth to take a careful medical history before BCG immunization particularly in families with a history of consanguineous marriage and death due to unknown etiology.

Objective Aspergillus sections Terrei and Nidulantes are the less common causes of invasive aspergillosis and pulmonary aspergillosis (PA) in immunocompromised patients when compared to A. fumigatus and A. flavus. Identifying these fungi as the infectious agent is crucial because of the resistance to amphotericin B (AMB) and increased lethality. The aim of this study was to identify the molecular status, evaluate the genetic diversity and examine the antifungal susceptibility profile of the uncommon Aspergillus species. Forty-five uncommon Aspergillus species were identified based on the microscopic and macroscopic criteria. Then, the molecular identification was performed using the sequencing beta tubulin (benA) gene. In vitro antifungal susceptibility to amphotericin B (AMB), itraconazole (ITC), ravuconazole (RAV), voriconazole (VRC), caspofungin (CFG) isavuconazole (ISA) and posaconazole (POS) test was performed according to the CLSI M38-A2 guidelines. Results A. terreus was the most species detected, followed by A. nidulans, A. latus, A. ochraceus, and A. citrinoterreus, respectively. The analysis of the benA gene showed the presence of 12 distinct genotypes among the A. terreus isolates. The other species did not show any intraspecies variation. CFG exhibited the lowest MEC50/MIC50 (0.007 μg/mL), followed by POS (0.125 μg/mL), VRC, ITC, ISA (0.25 μg/mL), RAV (0.5 μg/mL), and AMB (8 μg/mL). Among all the isolates, only 15.5% (7/45) were susceptible to AMB. Conclusion Antifungal susceptibility pattern of the uncommon Aspergillus species is useful to improve patient management and increase knowledge concerning the local epidemiology. Moreover, this information is necessary when an outbreak dealing with drug-resistant infections occurs.

Autoimmune polyendocrinopathy candidiasis ectodermal dystrophy (APECED) syndrome is a rare monogenic autosomal recessive disorder caused by biallelic mutations in the AIRE (autoimmune regulator) gene. Patients with APECED present with heterogeneous endocrine and non-endocrine manifestations. In this study, we report an Iranian patient who presented with Addison disease, chronic mucocutaneous candidiasis, alopecia totalis, keratopathy and asplenia treated as an isolated endocrinopathy for 25 years. In the adulthood, the diagnosis of APECED was made by genetic analysis which demonstrated homozygous nonsense p.R257* (c.769C>T) mutation of AIRE. APECED has been shown to be frequent in some ethnicities including Iranian Jews. Therefore, we reviewed 39 Iranian APECED patients published in the literature. We found that most of the Iranian patients were of Jewish ethnic background and presented hypoparathyroidism, adrenal insufficiency, and candidiasis as the main clinical manifestation.

Background Severe combined immunodeficiency (SCID) is the most severe form of primary immunodeficiency disorders that is characterized by impaired early T lymphocyte differentiation and is variably associated with abnormal development of other lymphocyte lineages. SCID can be caused by mutations in more than 20 different genes. Molecular diagnosis in SCID patients contributes to genetic counseling, prenatal diagnosis, treatment modalities, and overall prognosis. In this cohort, the clinical, laboratory and genetic data related to Iranian SCID patients were comprehensively evaluated and efficiency of stepwise sequencing methods approach based on immunophenotype grouping was investigated Methods Clinical and laboratory data from 242 patients with SCID phenotype were evaluated. Molecular genetic analysis methods including Sanger sequencing, targeted gene panel and whole exome sequencing were performed on 62 patients. Results Mortality rate was 78.9% in the cohort with a median follow-up of four months. The majority of the patients had a phenotype of T-NK-B+ (34.3%) and the most severe clinical manifestation and highest mortality rate were observed in T-NK-B- SCID cases. Genetic mutations were confirmed in 50 patients (80.6%), of which defects in recombination-activating genes (RAG1 and RAG2) were found in 16 patients (32.0%). The lowest level of CD4+ and CD8+ cells were observed in patients with ADA deficiency (p = 0.026) and IL2RG deficiency (p = 0.019), respectively. Conclusion Current findings suggest that candidate gene approach based on patient's immunophenotype might accelerate molecular diagnosis of SCID patients. Candidate gene selection should be done according to the frequency of disease-causing genes in different populations. Targeted gene panel, WES and WGS methods can be used for the cases which are not diagnosed using this method.

One of the components of NADPH oxidase is p47-phox, encoded by NCF1 gene. This study aims to find new genetic changes and clinical features in 38 Iranian patients with autosomal recessive chronic granulomatous disease (AR-CGD) caused by NCF1 gene defect. Patients who had abnormal NBT and DHR-1,2,3 assay with loss of p47-phox in Western blotting were included in this study. After recording demographic and clinical data, PCR amplification was performed followed by direct sequencing for all exons and exon-intron boundaries. The most common form of CGD in Iran was AR-CGD due to consanguinity marriages. Among patients with AR-CGD, NCF1 deficiency was found to be more common than other forms. Cutaneous involvements (53%), pulmonary infections (50%) and lymphadenopathy (29%) were more prevalent than other clinical manifestations of CGD. Mutation analysis of NCF1 gene identified five different mutations. Homozygous delta GT deletion (c.75_76delGT) was the most frequent mutation and was detected in more than 63% of families. Six families had a nonsense mutation in exon 7 (c.579G > A). Two novel mutations were found in exon 4 in two families, including a missense mutation (c.328C > T) and a nine-nucleotide deletion (c.331_339delTGTCCCCAC). Genetic detection of these mutations may result in early diagnosis and prevention of possible complications of the disease. This could be useful for timely decision-making for haematopoietic stem cell transplantation and for carrier detection as well as prenatal diagnosis of next children in the affected families. Our findings might help to predict outcomes, raise awareness and help effective treatment in these patients.

Introduction and objectives Exposure to fungi in patients with asthma leads to the release of various fungal antigens, which can increase the severity of asthma. Regarding this, the present study was conducted to evaluate the relationship between the colonisation of Aspergillus species and spirometry results in allergic asthma. Materials and methods Two hundred sixteen patients with mild to severe asthma and 30 healthy controls were included. All participants underwent pulmonary function tests. Furthermore, sputum samples were collected from each subject. Each sputum sample was subjected to direct microscopic examination and fungal culture. All cultured Aspergillus colonies were identified at species level by molecular methods. Finally, all available data from sputum culture and spirometry test were analysed. Results Out of 216 sputum samples, 145 (67.1%) were positive for fungal growth. Furthermore, out of 264 grown fungal colonies, 137 (51.9%) were Aspergillus species. Among the Aspergillus isolates, A. flavus (29.2%) was the most prevalent species, followed by A. fumigatus (27.7%). The mean forced expiratory volume in one second (FEV1) in the mild, moderate and severe asthmatic patients with a positive sputum culture for fungi were obtained as 90.0 ± 11.1, 71.1 ± 15.9 and 54.9 ± 16.4, respectively. In general, Aspergillus species colonisation had no statistically significant effect on spirometry results of study patients. Conclusion Our results showed that there is no difference in the FEV1 and forced vital capacity between Aspergillus positive and negative patients in any asthma severity group.

Background: Hyper-immunoglobulin M (HIGM) syndrome is a rare heterogeneous group of primary immunodeficiency disorders characterized by low or absent serum levels of IgG and IgA along with normal or elevated serum levels of IgM. Methods: Clinical and immunological data were collected from the 75 patients’ medical records diagnosed in Children’s Medical Center affiliated to Tehran University Medical Sciences and other Universities of Medical Sciences in Iran. Among 75 selected patients, 48 patients (64%) were analyzed genetically using targeted and whole-exome sequencing. Results: The ratio of male to female was 2.9:1. The median age at the onset of the disease, time of diagnosis, and diagnostic delay were 10.5, 50, and 24 months, respectively. Pneumonia and lower respiratory tract infections (61.3%) were the most common complications. Responsible genes were identified in 35 patients (72.9%) out 48 genetically analyzed patients. Cluster of differentiation 40 ligand gene was the most mutated gene observed in 24 patients (68.5%) followed by activation-induced cytidine deaminase gene in 7 patients, lipopolysaccharide-responsive and beige-like anchor (1 patient), nuclear factor-kappa-B essential modulator (1 patient), phosphoinositide-3-kinase regulatory subunit 1 (1 patient), and nuclear factor kappa B subunit 1 (1 patient) genes. Nineteen (25.3%) patients died during the study period, and pneumonia was the major cause of death occurred in 6 (31.6%) patients. Conclusion: Physicians in our country should carefully pay attention to respiratory tract infections and pneumonia, particularly in patients with a positive family history. Further investigations are required for detection of new genes and pathways resulting in HIGM phenotype.

BackgroundBronchiectasis is defined by permanent and abnormal widening of the bronchi. Although this process occurs in the context of chronic airway infection and inflammation, since there is no accurate estimation of the etiology of the disease. This study aimed to determine the most important cause of bronchiectasis in Tehran, Iran.Materials and MethodsIn this retrospective cohort study we used the information of 91 patients admitted to two subspecialty lung hospitals in Tehran-Iran, where a wide range of bronchiectasis patients from around the country referred during 2013to 2014 period. Patients referring with the manifestation of chronic productive cough who had not responded to conventional treatment with the evidences of bronchiectasis on high resolution computed tomography were included. Data were analyzed using SPSS-16.0.ResultsThe etiology of bronchiectasis was diagnosed in 73 of 91 patients (80.2%), the most important of which included cystic fibrosis, post infectious, and primary ciliary dyskinesia (PCD). The most common causes of bronchiectasis in the children group (Age ≤ 18 years), were cystic fibrosis (57.1%), allergic bronchopulmonary aspergillusis (14.3%) and PCD (9.5%), respectively. In the adults group (Age >18 years), the most common causes were post infectious (22.6%), PCD (15.7%) and cystic fibrosis (14.3%), respectively.ConclusionMain causes of bronchiectasis in this study were not significantly different from other studies. Special attention should be paid to the probable causes of bronchiectasis in order to effectively execute on-time diagnosis, proper treatment and management of complications.

An association between a hypercoagulable state and Mendelian susceptibility to mycobacterial disease (MSMD) has been established in a few studies; resultant thrombosis is considered rare. In a case-control study, the prevalence of factor V Leiden, prothrombin G20210A and methylenetetrahydrofolate reductase (MTHFR) C677T, A1298C mutations were investigated in mycobacterium-infected patients. The study comprised 30 patients with mycobacterial infections (invasive, disseminated and/or recurrent infections with Bacille Calmette-Guerin or non-tuberculosis mycobacteria and Mycobacterium Tuberculosis with positive results for acid-fast bacilli and tuberculin skin tests) and 30 normal healthy controls. Forty female (66.7%) and 20 male subjects (33.3%) aged from 3 to 70 years were recruited into this study. Genotyping of targeted genes was performed by RT-PCR and cytokine TNF-α concentrations were quantified using a commercially available ELISA kit. Significant associations between mycobacterial infection and TNF-α production after stimulating peripheral blood mononuclear cells with LPS alone and with IFN-γ plus LPS were identified. Moreover, genotyping analysis in the studied population revealed a significant association between MTHFR c.677C>T (OR, 3.28; 95% CI, 1.35-7.92; P C (OR, 2.33; 95% CI, 1.10-4.93; P

Objectives: Impairment in early B-cell development can cause a predominantly antibody deficiency with severe depletion of peripheral B-cells. Mutations in the gene encoding for Bruton’s-tyrosine-kinase (BTK) and the components of the pre-B-cell receptor complex or downstream signaling molecules have been related to this defect in patients with agammaglobulinemia. Methods: Iranian patients with congenital agammaglobulinemia were included and the correlation between disease-causing mutations and parameters such as clinical and immunologic phenotypes were evaluated in available patients. Results: Out of 87 patients, a molecular investigation was performed on 51 patients leading to identification of 39 cases with BTK (1 novel mutation), 5 cases of µ-heavy chain (3 novel mutations) and 1 case of Igα-deficiencies. Conclusion: Although there is no comprehensive correlation between type of responsible BTK mutation and severity of clinical phenotype, our data suggest that BTK-deficient and autosomal recessive agammaglobulinemia patients differ significantly regarding clinical/immunologic characteristics.

Summary Objective.There are different diagnostic criteria for the diagnosis of Allergic bronchopulmonary aspergillosis (ABPA) in CF patients. In this present study we evaluated the prevalence of ABPA in Iranian CF patients by two more usual diagnostic criteria as ISHAM working criteria (A) and CF Foundation Consensus Conference criteria (B). Methods.Eighty-six CF patients were included in the study. All CF patients underwent for Aspergillus skin prick test (AST), Aspergillus-specific IgE (sIgEAf) and Aspergillus-specific IgG (sIgGAf), total IgE. The ABPA prevalence was estimated by two diagnostic criteria, (A) and (B) and compared. Results. The frequency of positive AST, total IgE, sIgEAf and sIgGAf were 47 (54.6%), 9 (10.5%), 42 (48.8%) and 67 (77.9%), respectively. The obtained rate of ABPA prevalence (10.5%) was identical in two diagnostic criteria A and B (kappa value of 1.000). Conclusions.The applied diagnostic criteria had no significant effect on the reported rate of ABPA prevalence.

In this present study, for the first time, we evaluated the cystic fibrosis (CF) patients for the Scedosporium species and their antifungal susceptibility against eight antifungal agents. During one-year period, 90 Sputum samples were collected from Iranian CF patients. All samples were evaluated by direct microscopic examination, culture onto four different media including Malt extract agar, Inhibitory mold agar, Brain Heart Infusion and Scedo-Select III. The mold isolated fungi were identified by PCR-Sequencing of ITS and β-tubulin genes. In-vitro antifungal susceptibility was performed according to the Clinical & Laboratory Standards Institute (CLSI) M38-A2 guidelines. Out of 90 CF patients, 47 (52.2%) were male. The age of the patients ranged from 1 to 34 years (median of 15.84 ± 7.41 years). Overall, 3 (3.3%) cases were positive for Scedosporium spp. of which two isolates were characterized as Scedosporium boydii and one isolate as S. ellipsoideum. Among Aspergillus genus, A. flavus (29.4%) was the most prevalent species followed by A. tubingensis (24.7%), A. niger (17.0%) and A. fumigatus (14.5%). The minimum effective concentration ranges of micafungin, anidulafungin, and caspofungin were 0.008–0.031 μg/mL, 0.0625–0.25 μg/mL, and 0.0625–0.25 μg/mL, respectively. All isolates of Scedosporium species showed high minimum inhibitory concentration to the triazoles tested, except voriconazole. Our results showed that A. flavus and Scedosporium species are the most prevalent molds isolated from CF patient populations in Iran. Our findings have also showed that Scedo-Select III can be used as a reliable culture media for isolation of Scedosporium spp. in clinical samples.

The phagocytic system is an indispensable part of the immune defense mechanism and innate immune system. Pulmonary manifestations could be either ambiguous or misleading. The most common involved organ in chronic granulomatous deficiency (CGD) is the lung, which manifests with infectious and non-infectious (granuloma and fibrosis) complications. Myeloperoxidase (MPO)-deficient individuals are mostly asymptomatic; however, invasive Candida (IC) may present as candidemia, disseminated infection, and pneumonia. Neutrophil-specific granule deficiency pulmonary manifestations are recurrent pneumonias and lung abscess mostly due to Staphylococcus aureus and Pseudomonas aeruginosa. In leukocyte adhesion deficiency (LAD), involvement of the skin and mucus membranes is a predominant clinical feature and then recurrent pulmonary infections. In RAC-2 deficiency, pulmonary involvement although uncommon includes recurrent sinopulmonary infections, pneumonia, and bronchiectasis. In congenital neutropenia (CN), the child might begin to have fevers associated with respiratory symptoms of pneumonia. ELANE (neutrophil elastase) mutations are the most frequent known cause of congenital neutropenia which is characterized by oropharyngeal inflammation. G6PC3 deficiency and its severe form called Dursun syndrome are characterized by a triad of familial primary pulmonary hypertension (PPH), leukopenia, and atrial septal defects. Cyclic neutropenia is characterized by oscillating numbers of blood neutrophils. Pulmonary manifestations are upper respiratory infections (sinusitis and otitis media), pneumonia, and bronchitis. In Shwachman-Diamond syndrome (SDS), pulmonary manifestations are recurrent bronchopulmonary bacterial, viral, and fungal opportunistic infections and recurrent otitis media. Cohen syndrome is associated with laryngeal dysfunction and laryngomalacia to stenosis and vocal cord paralysis. Poikiloderma often accompanies severe neutropenia and bronchiectasis, lung abscesses, and lung granulomas. In other phagocytic deficiencies, including b-actin, aggressive periodontitis, Papillon-Lefevre syndrome, Barth syndrome, and glycogen storage disease Ib, no pulmonary manifestations have been reported.

Approximately 300 million people are afflicted with asthma around the world, with the estimated death rate of 250,000 cases, indicating the significance of this disease. If not treated, it can turn into a serious public health problem. The best method to treat asthma is to control it. Physicians recommend continuous monitoring on asthma symptoms and offering treatment preventive plans based on the patient's control level. Therefore, successful detection of the disease control level plays a critical role in presenting treatment plans. In view of this objective, we collected the data of 96 asthma patients within a 9-month period from a specialized hospital for pulmonary diseases in Tehran. A new ensemble learning algorithm with combining physicians' knowledge in the form of a rule-based classifier and supervised learning algorithms is proposed to detect asthma control level in a multivariate dataset with multiclass response variable. The model outcome resulting from the balancing operations and feature selection on data yielded the accuracy of 91.66%. Our proposed model combines medical knowledge with machine learning algorithms to classify asthma control level more accurately. This model can be applied in electronic self-care systems to support the real-time decision and personalized warnings on possible deterioration of asthma control level. Such tools can centralize asthma treatment from the current reactive care models into a preventive approach in which the physician's therapeutic actions would be based on control level.

International audience; Hundreds of patients with autosomal recessive, complete IL-12p40 or IL-12Rβ1 deficiency have been diagnosed over the last 20 years. They typically suffer from invasive mycobacteriosis and, occasionally, from mucocutaneous candidiasis. Susceptibility to these infections is thought to be due to impairments of IL-12-dependent IFN-γ immunity and IL-23-dependent IL-17A/IL-17F immunity, respectively. We report here patients with autosomal recessive, complete IL-12Rβ2 or IL-23R deficiency, lacking responses to IL-12 or IL-23 only, all of whom, unexpectedly, display mycobacteriosis without candidiasis. We show that αβ T, γδ T, B, NK, ILC1, and ILC2 cells from healthy donors preferentially produce IFN-γ in response to IL-12, whereas NKT cells and MAIT cells preferentially produce IFN-γ in response to IL-23. We also show that the development of IFN-γ-producing CD4 + T cells, including, in particular , mycobacterium-specific TH1* cells (CD45RA− CCR6+), is dependent on both IL-12 and IL-23. Last, we show that IL12RB1, IL12RB2, and IL23R have similar frequencies of deleterious variants in the general population. The comparative rarity of symptomatic patients with IL-12Rβ2 or IL-23R deficiency, relative to IL-12Rβ1 deficiency , is, therefore, due to lower clinical penetrance. There are fewer symptomatic IL-23R-and IL-12Rβ2-deficient than IL-12Rβ1-deficient patients, not because these genetic disorders are rarer, but because the isolated absence of IL-12 or IL-23 is, in part, compensated by the other cytokine for the production of IFN-γ, thereby providing some protection against mycobacteria. These experiments of nature show that human IL-12 and IL-23 are both required for optimal IFN-γ dependent immunity to mycobacteria, both individually and much more so cooperatively.

Background: Recent surveys have showed that asthma control still remains suboptimal. Family members have an extensive impact on the level of asthma control in school-age children. Family empowerment has a positive impact on the quality of life of school-age children with asthma. This study aimed to determine the efficacy of family empowerment on asthma control in school-age children. Materials and Methods: Forty-five children with asthma (6–12 years) and their parents were enrolled in a pediatric asthma clinic during their follow-up visits. The family empowerment program consisted of self-directed educational material, lectures (a nurse-focused format), group interaction (a learner-focused format), group discussions, and demonstration of educational films. The primary outcome was change in asthma control measured by the C-ACT questionnaire. Results: In this study, 45 patients were enrolled and randomly divided into two groups: intervention (n=23) and control (n=22). Demographic variables including age and sex were not significantly different between the two groups. There were no significant differences in pre-test asthma control scores between the intervention and control groups at pre-test (p=0.82). However, there was a significant difference in asthma control scores between the intervention and control groups at post-test (p

BACKGROUND: Predominantly antibody deficiencies (PADs) are the most common primary immunodeficiencies, characterized by hypogammaglobulinemia and inability to generate effective antibody responses. OBJECTIVE: We intended to report most common monogenic PADs and to investigate how patients with PAD who were primarily diagnosed as suffering from agammaglobulinemia, hyper-IgM (HIgM) syndrome, and common variable immunodeficiency (CVID) have different clinical and immunological findings. METHODS: Stepwise next-generation sequencing and Sanger sequencing were performed for confirmation of the mutations in the patients clinically diagnosed as suffering from agammaglobulinemia, HIgM syndrome, and CVID. RESULTS: Among 550 registered patients, the predominant genetic defects associated with agammaglobulinemia (48 Bruton's tyrosine kinase BTK and 6 mu heavy chain deficiencies), HIgM syndrome (21 CD40 ligand and 7 activation-induced cytidine deaminase deficiencies), and CVID (17 lipopolysaccharides-responsive beige-like anchor deficiency and 12 atypical Immunodeficiency, Centromeric instability, and Facial dysmorphism syndromes) were identified. Clinical disease severity was significantly higher in patients with mu heavy chain and CD40 ligand mutations compared with patients with BTK (P = .003) and activation-induced cytidine deaminase (P = .009) mutations. Paralysis following live polio vaccination was considerably higher in patients with mu heavy chain deficiency compared with BTK deficiency (P < .001). We found a genotype-phenotype correlation among patients with BTK mutations regarding clinical manifestation of meningitis and chronic diarrhea. Surprisingly, we noticed that first presentations in most patients with Immunodeficiency, Centromeric instability, and Facial dysmorphism were respiratory complications (P = .008), whereas first presentations in patients with lipopolysaccharides-responsive beige-like anchor deficiency were nonrespiratory complications (P = .008). CONCLUSIONS: This study highlights similarities and differences in the clinical and genetic spectrum of the most common PAD-associated gene defects. This comprehensive comparison will facilitate clinical decision making, and improve prognosis and targeted treatment.

WOS: 000350167200008, PubMed ID: 25703555, 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- 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., European Research CouncilEuropean Research Council (ERC) [ERC-2010-AdG-268777]; French National Research Agency (ANR)French National Research Agency (ANR) [ANR-10-IAHU-01, ANR-08-MIEN-014-02]; Institut National de la Sante et de la Recherche Medicale, Universite Paris DescartesInstitut National de la Sante et de la Recherche Medicale (Inserm); St. Giles Foundation; Rockefeller University from the National Center for Research Resources [8ULTR000043]; National Center for Advancing Sciences (NCATS) of the National Institute of Health; Rockefeller University; National Institute of Allergy and Infectious DiseasesUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Institute of Allergy & Infectious Diseases (NIAID) [U01AI088685, R01AI089970, R37AI095983], We thank all clinicians from many countries around the world for their help and contribution in the investigation of TB patients. Special thanks to A. Strickler and J. F. Emile for providing the pictures. We also thank all members of the Necker and Rockefeller branches of the Laboratory of Human Genetics of Infectious Diseases. This work was supported by grants from the European Research Council (ERC-2010-AdG-268777), the French National Research Agency (ANR) under "the Investments for the Future" grant number ANR-10-IAHU-01, ANR-08-MIEN-014-02, Institut National de la Sante et de la Recherche Medicale, Universite Paris Descartes, the St. Giles Foundation, the Rockefeller University grant number 8ULTR000043 from the National Center for Research Resources and the National Center for Advancing Sciences (NCATS) of the National Institute of Health, the Rockefeller University, the National Institute of Allergy and Infectious Diseases grant number U01AI088685, R01AI089970, and R37AI095983. The authors have no financial or commercial conflict of interest to declare.

Aim: New approaches such as oral immunotherapy (OIT) may be useful in IgE-mediated anaphylaxis to wheat. Patients & methods: 12 patients underwent OIT protocol that comprised of two phases: the first with semolina flour and the second with spaghetti. Total and specific wheat IgE were assayed by ELISA before and after OIT and 18 months later. Skin prick tests were also performed. Results: Patients successfully tolerated 50 g of wheat. The median baseline total IgE was decreased after up-dosing phase and decreased after follow-up (p < 0.01). The median baseline wheat-specific IgE was increased after up-dosing and decreased after follow-up (p < 0.001). Conclusion: The efficiency and safety of our OIT protocol were shown on wheat allergic patients but further investigation is needed.

Background Common variable immunodeficiency (CVID) is one of the most prevalent symptomatic primary immunodeficiencies (PIDs), which manifests a wide clinical variability such as autoimmunity, as well as T cell and B cell abnormalities. Methods A total of 72 patients with CVID were enrolled in this study. Patients were evaluated for clinical manifestations and classified according to the presence or absence of autoimmune disease. We measured regulatory T cells (Tregs) and B-cell subsets using flow cytometry, as well as specific antibody response (SAR) to pneumococcal vaccine, autoantibodies and anti-IgA in patients. Results Twenty-nine patients (40.3%) have shown at least one autoimmune manifestation. Autoimmune cytopenias and autoimmune gastrointestinal diseases were the most common. A significant association was detected between autoimmunity and presence of hepatomegaly and splenomegaly. Among CVID patients, 38.5% and 79.3% presented a defect in Tregs and switched memory B-cells, respectively, whereas 69.0% presented CD21low B cell expansion. Among patients with a defect in Treg, switched memory and CD21low B cell, the frequency of autoimmunity was 80.0%, 52.2% and 55.0%, respectively. A negative correlation was observed between the frequency of Tregs and CD21low B cell population. 82.2% of patients had a defective SAR which was associated with the lack of autoantibodies. Conclusions Autoimmunity may be the first clinical manifestation of CVID, thus routine screening of immunoglobulins is suggested for patients with autoimmunity. Lack of SAR in CVID is associated with the lack of specific autoantibodies in patients with autoimmunity. It is suggested that physicians use alternative diagnostic procedures.

Background Primary antibody deficiencies (PADs) are a heterogeneous group of disorders, characterised by increased susceptibility to recurrent bacterial infections. Common variable immunodeficiency (CVID) is the most important PAD from the clinical point of view and selective IgA deficiency (IgAD) is the most common PAD. However, the underlying gene defect in both is still unknown. As a recent study in Europe showed an association between a single nucleotide polymorphism (SNP) of AICDA gene with PADs, this study was performed to evaluate such an association in Iranian patients. Methods Fifty-eight patients with PAD, including 39 CVID and 19 IgAD, as well as 34 healthy volunteers, were enrolled in this study. Genotyping was done in all groups for an intronic SNP in AICDA (rs2580874), using real-time PCR genotyping assay. Results The less frequent genotype of AICDA in IgAD patients was AA, seen in 10.5% of the patients, which was much lower than the 30.8% in CVID patients and 38.2% in the controls. However, these differences were not significant. Indeed the GG genotype in the patients with PADs was seen in 20.7%, compared to 8.8% in the controls without any significant difference. Conclusions There was no significant association between the previously reported genetic variant of AICDA gene and the development of CVID or IgAD, but further multi-center studies are also needed.

Background: The aim of this study is to describe the clinical similarities and differences between atopic and non-atopic asthmatics in children. Methods: In this cross-sectional study, 95 asthmatics (75 allergics and 20 nonallergics) children were included and the demographic, clinical, and familial characteristics were compared across the groups. Results: There was no significant difference between important factors like sex (p=1.00), age of onset (0.75) and severity (0.70), and family history among two groups (P > 0.05). Patients with allergic asthma were significantly older than those with non- allergic asthma (11.28 ± 3.19 and 9.75 ± 2.35 years respectively, p Conclusion: The controversy over the presence of non-atopic asthma as a completely distinct clinical entity in children lingers. Our study suggests that phenotypes of allergic and non-allergic asthma in children are not highly distinct, along with the immunological similarities recently published.

An association between a hypercoagulable state and Mendelian susceptibility to mycobacterial disease (MSMD) has been established in a few studies; resultant thrombosis is considered rare. In a case-control study, the prevalence of factor V Leiden, prothrombin G20210A and methylenetetrahydrofolate reductase (MTHFR) C677T, A1298C mutations were investigated in mycobacterium-infected patients. The study comprised 30 patients with mycobacterial infections (invasive, disseminated and/or recurrent infections with Bacille Calmette-Guerin or non-tuberculosis mycobacteria and Mycobacterium Tuberculosis with positive results for acid-fast bacilli and tuberculin skin tests) and 30 normal healthy controls. Forty female (66.7%) and 20 male subjects (33.3%) aged from 3 to 70 years were recruited into this study. Genotyping of targeted genes was performed by RT-PCR and cytokine TNF-α concentrations were quantified using a commercially available ELISA kit. Significant associations between mycobacterial infection and TNF-α production after stimulating peripheral blood mononuclear cells with LPS alone and with IFN-γ plus LPS were identified. Moreover, genotyping analysis in the studied population revealed a significant association between MTHFR c.677CT (OR, 3.28; 95% CI, 1.35-7.92; P 0.05), MTHFR c.1298AC (OR, 2.33; 95% CI, 1.10-4.93; P 0.05) and mycobacterial infection in affected patients, indicating susceptibility to venous thromboembolism according to previous studies. Additionally, mycobacterium-infected patients had a significantly greater prevalence of MTHFR C677T and A1298C mutations than controls.

The hyper-immunoglobulin M (HIGM) syndrome comprises a group of primary immunodeficiency disorders characterized by normal or elevated serum levels of IgM and low levels of other immunoglobulin classes. Patients with HIGM usually suffer from a variety of recurrent infections. Herein, we report two siblings of a Tajik family with a HIGM phenotype in which a novel missense mutation in the activation-induced cytidine deaminase (AICDA) gene was detected. Mutations in this gene are responsible for an autosomal recessive form of HIGM. We have also reviewed and summarized all published cases with HIGM due to defects in AICDA.

Chronic granulomatous disease (CGD) is a rare immunodeficiency due to a genetic defect in one of the NADPH-oxidase components. We studied CGD inheritance forms (autosomal recessive (AR) or X-linked (XL)) and AR-CGD subtypes in Iran.Clinical and functional investigations were conducted in 93 Iranian CGD patients from 75 families.Most of the patients were AR-CGD (87.1%). This was related to consanguineous marriages (p = 0.001). The age of onset of symptoms and diagnosis were lower in XL-CGD compared with AR-CGD (p Although XL-CGD is the most common type of the disease worldwide, only 12 patients (12.9%) were XL-CGD in our study. The relatively high frequency of AR-CGD is probable due to widely common consanguineous marriages in Iran.

Asthma is one of the most common respiratory diseases caused by acute and chronic inflammation of airways. Proinflammatory cytokines could contribute to this inflammatory process. This study was performed in order to analyze the genetic profile of proinflammatory cytokines in Iranian asthmatic patients.The allele and genotype frequencies of a number polymorphic genes coding for tumor necrosis factor (TNF)-alpha, interleukin (IL)-1 alpha, IL-1 beta, IL-1 receptor (IL-1R), IL-1RA, and IL-6 were investigated in 60 patients with asthma in comparison with 140 controls using polymerase chain reaction with sequence-specific primers.The most frequent genotypes in our patients were TNF-alpha GA at position -308 (P = 0.001), TNF-alpha AA at position -238 (P = 0.01), IL-1 alpha TC at position -889 (P = 0.0001), IL-1 beta TC at position -511 (P = 0.0001), and IL-1RA TC at position Mspa-I 11100 (P = 0.001). In contrast, the frequencies of the genotypes TNF-alpha GG at position -308 (P = 0.001), IL-1 alpha CC at position -889 (P = 0.005), IL-1 beta CC at position -511 (P = 0.0001), and IL-1RA TT at position Mspa-I 11100 (P = 0.0001) in the patient group were significantly lower than controls. The most frequent haplotypes for TNF-alpha (positions 308, -238) was A/A in the patient group in comparison with controls (P = 0.0001).While environmental factors are important in the development of asthma, genetic factors could have a critical role in the expression of the disease. Considering the high frequency of presence of TNF-alpha AG genotype (-308), it seems that the production of TNF-alpha in the asthmatic patients could be higher than normal subjects.

Asthma is a complex respiratory disease, characterized by airway inflammation and reversible airway obstruction. Both genetic and environmental factors are important in the development and expression of the disease. In order to analyze the genetic profile of Th1 and Th2 cytokines in Iranian asthmatic patients, this study was performed. The allele and genotype frequencies of a number of polymorphic genes coding for IL-10, TGF-beta, IL-2, IL-12, and IFN-gamma were investigated in 60 patients with asthma in comparison with 140 controls. The most frequent genotypes in our patients were IL-10 GA at position-1082 (p = 0.001), IL-10 CT at position -819 (p = 0.001), IL-10 CA at position -592 (p = 0.0001), IL-12 CA at position -1188 (p = 0.003), TGF-beta CG at codon 25 (p = 0.002), IL-2 GT at position -330 (p = 0.004). In contrast, the frequencies of the genotypes IL-10 AA at position -1082 (p = 0.0001) and GG at position -1082 (p = 0.01), IL-10 CC at position -819 (p = 0.001) and TT at position -819 (p = 0.01), TGF-beta TT at codon 10 (p = 0.001), TGF-beta GG at codon 25 (p = 0.005), IL-12 AA at position -1188 (p = 0.004), IL-2 TT at position -330 (p = 0.01) were significantly lower in the patient group. The most frequent haplotypes in the patients were IL-10 GCC (p = 0.008) and ATA (p = 0.0001) at position -1082, -819, -592, and TGF-beta CC (p = 0.036) at codon 10 and codon 25. In contrast, the frequencies of the IL-10 ACC (p = 0.001), TGF-beta TG (p = 0.024), and IL-2 TT (p = 0.001) and GT (p= 0.0001) in the patients were significantly lower than controls. Considering the high frequency of presence of IL-10 ATA haplotype and the IL-2 GT genotype, it seems that the production of IL-10 and IL-2 in the asthmatic patients could be lower than normal subjects.

The Greater Middle East (GME) has been a central hub of human migration and population admixture. The tradition of consanguinity, variably practiced in the Persian Gulf region, North Africa, and Central Asia, has resulted in an elevated burden of recessive disease. Here we generated a whole-exome GME variome from 1,111 unrelated subjects. We detected substantial diversity and admixture in continental and subregional populations, corresponding to several ancient founder populations with little evidence of bottlenecks. Measured consanguinity rates were an order of magnitude above those in other sampled populations, and the GME population exhibited an increased burden of runs of homozygosity (ROHs) but showed no evidence for reduced burden of deleterious variation due to classically theorized 'genetic purging'. Applying this database to unsolved recessive conditions in the GME population reduced the number of potential disease-causing variants by four- to sevenfold. These results show variegated genetic architecture in GME populations and support future human genetic discoveries in Mendelian and population genetics.

Normal human breathing exhibits complex variability in both respiratory rhythm and volume. Analyzing such nonlinear fluctuations may provide clinically relevant information in patients with complex illnesses such as asthma. We compared the cycle-by-cycle fluctuations of inter-breath interval (IBI) and lung volume (LV) among healthy volunteers and patients with various types of asthma. Continuous respiratory datasets were collected from forty age-matched men including 10 healthy volunteers, 10 patients with controlled atopic asthma, 10 patients with uncontrolled atopic asthma, and 10 patients with uncontrolled non-atopic asthma during 60 min spontaneous breathing. Complexity of breathing pattern was quantified by calculating detrended fluctuation analysis, largest Lyapunov exponents, sample entropy, and cross-sample entropy. The IBI as well as LV fluctuations showed decreased long-range correlation, increased regularity and reduced sensitivity to initial conditions in patients with asthma, particularly in uncontrolled state. Our results also showed a strong synchronization between the IBI and LV in patients with uncontrolled asthma. Receiver operating characteristic (ROC) curve analysis showed that nonlinear analysis of breathing pattern has a diagnostic value in asthma and can be used in differentiating uncontrolled from controlled and non-atopic from atopic asthma. We suggest that complexity analysis of breathing dynamics may represent a novel physiologic marker to facilitate diagnosis and management of patients with asthma. However, future studies are needed to increase the validity of the study and to improve these novel methods for better patient management.

Chronic granulomatous disease is a rare primary immunodeficiency disorder, which leads to increased susceptibility to recurrent infections and severe inflammatory manifestations. There have been reports regarding different aspects of genitourinary involvement in chronic granulomatous disease, some of which are hydronephrosis, granulomatous cystitis, and glomerulonephritis, but among these complications, amyloidosis is rather rare. We report a patient with chronic granulomatous disease that developed amyloidosis later in the course of the disease.

Background Follicular helper T (T FH ) cells underpin T cell–dependent humoral immunity and the success of most vaccines. T FH cells also contribute to human immune disorders, such as autoimmunity, immunodeficiency, and malignancy. Understanding the molecular requirements for the generation and function of T FH cells will provide strategies for targeting these cells to modulate their behavior in the setting of these immunologic abnormalities. Objective We sought to determine the signaling pathways and cellular interactions required for the development and function of T FH cells in human subjects. Methods Human primary immunodeficiencies (PIDs) resulting from monogenic mutations provide a unique opportunity to assess the requirement for particular molecules in regulating human lymphocyte function. Circulating follicular helper T (cT FH ) cell subsets, memory B cells, and serum immunoglobulin levels were quantified and functionally assessed in healthy control subjects, as well as in patients with PIDs resulting from mutations in STAT3 , STAT1 , TYK2 , IL21 , IL21R , IL10R , IFNGR1/2 , IL12RB1 , CD40LG , NEMO , ICOS , or BTK . Results Loss-of-function (LOF) mutations in STAT3 , IL10R , CD40LG , NEMO , ICOS , or BTK reduced cT FH cell frequencies. STAT3 and IL21/R LOF and STAT1 gain-of-function mutations skewed cT FH cell differentiation toward a phenotype characterized by overexpression of IFN-γ and programmed death 1. IFN-γ inhibited cT FH cell function in vitro and in vivo , as corroborated by hypergammaglobulinemia in patients with IFNGR1/2 , STAT1 , and IL12RB1 LOF mutations. Conclusion Specific mutations affect the quantity and quality of cT FH cells, highlighting the need to assess T FH cells in patients by using multiple criteria, including phenotype and function. Furthermore, IFN-γ functions in vivo to restrain T FH cell–induced B-cell differentiation. These findings shed new light on T FH cell biology and the integrated signaling pathways required for their generation, maintenance, and effector function and explain the compromised humoral immunity seen in patients with some PIDs.

International audience; Background. Exophiala species are mostly responsible for skin infections. Invasive Exophiala dermatitidis disease is a rare and frequently fatal infection, with 42 cases reported. About half of these cases had no known risk factors. Similarly, invasive Exophiala spinifera disease is extremely rare, with only 3 cases reported, all in patients with no known immunodeficiency. Autosomal recessive CARD9 deficiency has recently been reported in otherwise healthy patients with severe fungal diseases caused by Candida species, dermatophytes, or Phialophora verrucosa. Methods. We investigated an 8-year-old girl from a nonconsanguineous Angolan kindred, who was born in France and developed disseminated E. dermatitidis disease and a 26 year-old woman from an Iranian consaguineous kindred, who was living in Iran and developed disseminated E. spinifera disease. Both patients were otherwise healthy. Results. We sequenced CARD9 and found both patients to be homozygous for loss-of-function mutations (R18W and E323del). The first patient had segmental uniparental disomy of chromosome 9, carrying 2 copies of the maternal CARD9 mutated allele. Conclusions. These are the first 2 patients with inherited CARD9 deficiency and invasive Exophiala disease to be described. CARD9 deficiency should thus be considered in patients with unexplained invasive Exophiala species disease, even in the absence of other infections.

Intracellular ISG15 is an interferon (IFN)-alpha/beta-inducible ubiquitin-like modifier which can covalently bind other proteins in a process called ISGylation; it is an effector of IFN-alpha/beta-dependent antiviral immunity in mice(1-4). We previously published a study describing humans with inherited ISG15deficiency but without unusually severe viral diseases(5). We showed that these patients were prone to mycobacterial disease and that human ISG15 was non-redundant as an extracellular IFN-gamma-inducing molecule. We show here that ISG15-deficient patients also display unanticipated cellular, immunological and clinical signs of enhanced IFN-alpha/beta immunity, reminiscent of the Mendelian autoinflammatory interferonopathies Aicardi-Goutieres syndrome and spondyloenchondrodysplasia(6-9). We further show that an absence of intracellular ISG15 in the patients' cells prevents the accumulation of USP18(10,11), a potent negative regulator of IFN-alpha/beta signalling, resulting in the enhancement and amplification of IFN-alpha/beta responses. Human ISG15, therefore, is not only redundant for antiviral immunity, but is a key negative regulator of IFN-alpha/beta immunity. In humans, intracellular ISG15 is IFN-alpha/beta-inducible not to serve as a substrate for ISGylation-dependent antiviral immunity, but to ensure USP18-dependent regulation of IFN-alpha/beta and prevention of IFN-alpha/beta-dependent autoinflammation.

Background Asthma is the most common, chronic, childhood disease. Its chronic nature and long-term treatment decrease the quality of life of children and significantly affect the family function. This study was conducted to assess the impact of family empowerment on the quality of life of school-aged children with asthma. Materials and Methods This was a quasi-experimental study. Forty-five asthmatic children (7-11 years) and their parents referred to the Pediatric Asthma Clinic in Masih Daneshvari Hospital were selected using convenience sampling and were randomly divided into case (n = 14) and control (n = 16) groups. Data collection tools included a demographic information questionnaire and Pediatric Asthma Quality of Life Questionnaire with standardized activities (PAQLQ). The validity and reliability of the questionnaire were tested. The family empowerment program for the intervention group included lectures, group discussions and demonstration of educational films. The questionnaires were filled out pre- and post-test. Results There were no significant differences before the intervention between the test and control groups in terms of demographic characteristics and PAQLQ scores. While, independent t-test showed significant differences between the two groups in PAQLQ total score and the subscale scores before and after the intervention (P < 0.05). Paired t-test showed significant differences before and after the intervention in the case group in terms of PAQLQ total score and the subscale scores (P < 0.001). Conclusion Considering the positive impact of of family empowerment program on the quality of life of school-aged children with asthma, this program is recommended for proper control and management of disease and decreasing the complications in asthmatic patients of all age groups.

Background Chronic granulomatous disease is a phagocyte defect, characterised by recurrent infections in different organs due to a defect in NADPH oxidase complex. This study was performed to investigate pulmonary problems of CGD in a group of patients who underwent computed tomography (CT) scan. Methods Computed tomography scan was performed in 24 patients with CGD. The findings of the CT scan were documented in all of these patients. Results Areas of consolidation and scan formation were the most common findings, which were detected in 79% of the patients. Other abnormalities in order of frequencies were as follows: small pulmonary nodules (58%); mediastinal lymphadenopathy (38%); pleural thickening (25%); unilateral hilar lymphadenopathy (25%); axillary lymphadenopathy (21%); bronchiectasis (17%); abscess formation (17%); pulmonary large nodules or masses (8%); and free pleural effusion (8%). Conclusion The pulmonary CT scans of the patients with CGD demonstrated a variety of respiratory abnormalities in the majority of the patients. While recurrent respiratory infections and abscesses are considered as prominent features of CGD, early diagnosis and precise check-up of the respiratory systems are needed to prevent further pulmonary complications.

Chronic granulomatous disease (CGD) is an inherited disorder, characterized by defects in superoxide-generating NADPH oxidase of phagocytes. The genetic defects in CGD induce failure to activate the respiratory burst in the phagocytes, leading to severe recurrent infections and unexplained prolonged inflammatory reactions that may produce granulomatous lesions. A noble advance in curative therapy for CGD is hematopoietic stem cell transplantation. Since the most common site of involvement in CGD is the lung, the pulmonologists (pediatrics or adult) may be among the first to recognize the pattern of infection, inflammation and granuloma formation, leading to diagnosis of CGD. Pulmonologists need to be aware of different lung manifestations of CGD.