Primary ciliary dyskinesia in six patients with bronchiectasis.

INTRODUCTION: Primary ciliary dyskinesia [PCD] is generally considered as a rare autosomal recessive disorder. Previous studies reported various prevalence of PCD among patients with bronchiectasis. MATERIAL AND METHODS: Six PCD patients who were diagnosed during the investigation of 40 patients with bronchiectasis were enrolled in this study. Ultra structural studies for both epithelium and cilia were performed, and the deformities in detailed electron microscopic images confirmed the diagnosis of PCD. RESULTS: Four patients experienced the first symptoms shortly after the birth, 1 by the age of 1 and 1 by the age of 4 years. Except of 1 case that was diagnosed 2 months after the onset of disease, diagnosis delay was longer than 5 years in all patients. Consanguineous marriage was observed in the parents of all patients. Upper respiratory tract infections were documented for all patients. CONCLUSIONS: PCD should be considered as a probable underlying disorder in patients with bronchiectasis. Past medical history of otitis media and history of similar clinical findings in family members should raise suspicion toward PCD.

Class switch recombination process in ataxia telangiectasia patients with elevated serum levels of IgM.

Ataxia telangiectasia (AT) is a rare primary immunodeficiency disorder with various clinical manifestations. Increased serum levels of IgM and recurrent infections, mainly sinopulmonary infections, can be the presenting feature in a number of AT patients and may be initially misdiagnosed as hyper-IgM (HIgM) syndrome. This study was designed to investigate class switch recombination (CSR) as a critical mechanism in B lymphocytes' maturation to produce different isotypes of antibody in response to antigen stimulation in AT cases with HIgM presentation. Quantitative IgE production after stimulation by IL-4 and CD40L was considered as an indicator for CSR function. We also compared their results with sex and age matched AT patients without HIgM presentation. We report four AT patients with recurrent infections during infancy and high serum levels of IgM. Laboratory evaluations revealed defective CSR while none of the three AT patients without HIgM presentation had a defect in the CSR process. The characterized defect in AT is a mutation in the ataxia telangiectasia mutated (ATM) gene. This gene may result in CSR defects due to impaired DNA break repair. A special association between AT and HIgM may indicate a new subgroup of AT patients according to their clinical phenotype and CSR condition.

Evaluation of CD4+CD25+FOXP3+ regulatory T cells function in patients with common variable immunodeficiency.

Common variable immunodeficiency (CVID) is one of the predominant antibody disorders where abnormalities in regulatory T cells (Tregs) may result in autoimmunity and chronic inflammation. To evaluate Tegs frequency and function, 13 CVID patients and 10 age- and sex-matched healthy volunteer were enrolled. The percentages of Tregs were calculated using flow cytomety method. For assessment of Treg function, Tregs were isolated and their suppressive functions were determined using Tregs suppression assay. The levels of immunoregulatory cytokines IL-10 and TGF-ß produced by Tregs were also measured. Our results revealed that Tregs frequency (P<0.001) and their suppressive functions (P<0.001) were impaired in CVID patients. The level of TGF-ß did not differ between CVID patients and controls (p=0.09); while the amount of IL-10 was remarkably decreased in CVID patients (P=0.007). Our findings suggest that disturbed Tregs frequency and their functional characteristics might account for aberrant immune responses observed in CVID patients.

Impact of IgE-mediated Food Allergy on Parental Quality of Life in Iranian Patients.

Food allergy is a common disorder especially in the first years of life. Strict avoidance of the responsible food is the most effective therapeutic measure so far. But this continuous vigilance could be stressful for the patient and family and decreases their quality of life (QOL). This survey was designed to evaluate the impact of IgE-mediated food allergy on parental QOL in Iranian patients and to develop a valid Persian version of "Food Allergy Quality Of Life- Parental Burden (FAQL-PB) questionnaire". 90 patients (28 females, 62 males) and their parents who were referred to the clinic of Allergy in Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran were enrolled. The questionnaire was translated with scientific method and its reliability was approved in a pilot study (ICC=0.75, cronbach-α=0.90). Among all patients the most common allergens were wheat (60%) and cow's milk (42%). The patient's age (p=0.02), parent's gender (p=0.004), mother's age (p=0.02), duration of the disease (p=0.048), and allergen multiplicity (p=0.004) were found to have the most significant correlation with family and social activity (FSA) domain. The most meaningful associations were achieved between parent's gender (p<0.001) and emotional issues (EM); as well as meal preparation (MP) with patient's age (p=0.02), parent's gender (p<0.0001) and also allergen multiplicity (p= 0.003); likewise nutrition and health concern (NH) domain with parent's gender (p<0.001). Anaphylaxis's history did not place any burden on each domain. It was concluded that presence of food allergic patients in families could considerably affect all domains of QOL.

Economic burden of common variable immunodeficiency: annual cost of disease.

OBJECTIVES: In the context of the unknown economic burden imposed by primary immunodeficiency diseases, in this study, we sought to calculate the costs associated with the most prevalent symptomatic disease, common variable immunodeficiency (CVID). METHODS: Direct, indirect and intangible costs were recorded for diagnosed CVID patients. Hidden Markov model was used to evaluate different disease-related factors and Monte Carlo method for estimation of uncertainty intervals. RESULTS: The total estimated cost of diagnosed CVID is US$274,200/patient annually and early diagnosis of the disease can save US$6500. Hospital admission cost (US$25,000/patient) accounts for the most important expenditure parameter before diagnosis, but medication cost (US$40,600/patients) was the main factor after diagnosis primarily due to monthly administration of immunoglobulin. CONCLUSION: The greatest cost-determining factor in our study was the cost of treatment, spent mostly on immunoglobulin replacement therapy of the patients. It was also observed that CVID patients' costs are reduced after diagnosis due to appropriate management.

Frequency of Genotype With ΔF508 Mutation in CFTR Gene Among Iranian Cystic Fibrosis Patients With Pancreatic Insufficiency.

BACKGROUND: Cystic fibrosis (CF) is the most prevalent lethal autosomal recessive disease with a broad spectrum of phenotypes. Mutation of ΔF508 in the CFTR gene is the most important and lethal mutation in CF, which contains 70% of all predisposing mutations for CF worldwide. OBJECTIVES: Determining frequency of genotypes with ΔF508 mutation in CFTR gene, and evaluation of correlation between genotype and phenotype of Iranian patients with CF. PATIENTS AND METHODS: Thirty six patients were included in this cross sectional study. ΔF508 mutations in both alleles of the CFTR gene were checked. RESULTS: Among 36 pediatric patients, ΔF508 mutation was detected in 9 (25%) patients; 2 patients were heterozygous, and 7 patients homozygous for this mutation. From overall 72 tracked alleles, 11 (15.2%) were found to have ΔF508 mutations. Differences in prevalence of dyspnea and bronchiectasis were significant in homozygote group, compared with non-mutated group for ΔF508. CONCLUSIONS: It seems that more ΔF508 mutated alleles lead to more severe symptoms of CF.

Antibiotic resistance in patients with primary immunodeficiency disorders versus immunocompetent patients.

OBJECTIVES: We aimed to investigate the antimicrobial susceptibility among bacterial isolates of patients with primary immunodeficiency disorders (PID) in comparison with immunocompetent patients. METHODS: Patients' antibiotic sensitivity profiles were extracted from their medical records. In order to compare the antibiotic sensitivity profiles of PID patients with immunocompetent patients, the results of antibiograms of patients who did not have a known or suspected immunodeficiency and were hospitalized during the same period were obtained and used as control subjects. RESULTS: A total number of 257 isolates were obtained from 86 PID patients. Antimicrobial susceptibilities of several organisms isolated from PID patients were significantly lower compared to that of immunocompetent patients. CONCLUSION: Antibiotic resistance seems to be higher among PID patients compared to immunocompetent patients. This indicates a need for further investigations for the possible factors responsible for antibiotic resistance in PID patients.

Alteration in frequency and function of CD4⁺CD25⁺FOXP3⁺ regulatory T cells in patients with immune thrombocytopenic purpura.

Immune thrombocytopenic purpura (ITP) is an autoimmune bleeding disorder characterized by production of auto-antibodies against platelet antigens. It is obvious that regulatory T cells (Tregs) have a major role in controlling immune homeostasis and preventing autoimmunity.To investigate the frequency and functions of Tregs, twenty ITP patients and twenty age- and sex-matched healthy controls were recruited. The peripheral blood mononuclear cells were isolated and the proportion of Tregs was defined by flow cytometry method. The expression of immune-regulatory markers, cytotoxic T-lymphocyte associated antigen-4 (CTLA-4) and glucocorticoid induced tumor necrosis factor receptor (GITR) were also assessed by quantitative Real-time PCR TaqMan method. For evaluation of Treg function, Tregs were enriched and their ability to inhibit proliferation of T cells was measured and levels of immune-regulatory cytokines IL-10 and TGF-ß were also measured.Results showed that the frequency of Tregs and the mean fluorescence intensity of FOXP3 protein significantly decreased in ITP patients compared to those in healthy controls. In addition, there was a significant reduction in relative expression of both CTLA-4 and GITR mRNA in ITP patients (P=0.02 and P=0.006, respectively). The suppressive function of Tregs also diminished in ITP patients compared to that in controls. Both IL-10 and TGF-ß cytokines were produced in lower amounts in ITP patients than controls.It could be concluded that alteration in Treg frequency and functional characteristics might be responsible for loss of self-tolerance and subsequently destructive immune responses observed in ITP patients.

Distribution of primary immunodeficiency disorders diagnosed in a tertiary referral center,Tehran, Iran (2006-2013).

BACKGROUND: Primary immunodeficiency disorders (PID) are a group of hereditary disorders characterized by an increased susceptibility to severe and recurrent infections, autoimmunity, lymphoproliferative disorders, and malignancy. OBJECTIVE: To evaluate the demographic and clinical data of PID patients diagnosed in a referral pediatric hospital. METHOD: All PID cases with a confirmed diagnosis, according to the criteria of International Union of Immunological Societies, who were referred to the Children's Medical Center in Tehran, Iran, between March 2006 and March 2013 were enrolled in this retrospective cohort study. RESULTS: Three-hundred and seven PID patients were investigated. Predominantly antibody deficiencies were the most common group of PID observed in 118 cases (38.4%), followed by the well-defined syndromes with immunodeficiency in 52 (16.9%), congenital defects of phagocyte in 45 (14.7%), combined immunodeficiencies in 36 (11.7%), autoinflammatory disorders in 34 (11.4%), immune dysregulation in 11 (3.6%), complement deficiencies in 7 (2.3%), and defects in innate immunity in 3 (1%). Selective IgA deficiency was the most prevalent disorder which affected 46 individuals (14.9%). The median diagnostic delay was 15 months. CONCLUSION: Increased awareness and availability of diagnostic tests could result in the better recognition of more undiagnosed PID cases and a decrease in diagnostic delay.

Family study of pediatric patients with primary antibody deficiencies.

Common variable immunodeficiency (CVID) and selective IgA deficiency (SIGAD) are the most common primary antibody deficiencies. These two diseases may have coincidence in one family and SIGAD can progress to CVID which suggest common underlying genetic defects between SIGAD and CVID. This study was designed to find the prevalence of multiple cases in families of Iranian patients with CVID or SIGAD.Serum samples were collected from all available first-degree relatives of 37 patients (23 patients with CVID and 14 with SIGAD) to check the levels of immunoglobulin and their subclasses and detect antibody deficiencies.First degree family members of 37 patients (106 individuals) were enrolled in this study. Thirty two percent of patients had multiple cases in their families. The frequency of primary antibody deficiency in the first relatives of the patients was estimated to be one per 9 family members. Most of the patients found among family members were siblings of the primary patients. Analysis in SIGAD family members showed that IgG and IgA levels in families with multiple cases were significantly lower than family members without multiple cases (p values of 0.048 and 0.021, respectively).Rate of families with multiple cases in Iran is more than the previous studies in other countries. This rate was not affected by the consanguinity of parents (p=0.081) or immunoglobulin level of the patients. Because of higher risk for the prevalence of these disorders in those with a positive family history of immunodeficiency, family screening programs in the patients with CVID and SIGAD can be suggested to be prioritized..

Expression of activation-induced cytidine deaminase gene in B lymphocytes of patients with common variable immunodeficiency.

OBJECTIVE: Common variable immunodeficiency (CVID) is a heterogeneous disorder characterized by reduced serum level of IgG, IgA or IgM and recurrent bacterial infections. Class switch recombination (CSR) as a critical process in immunoglobulin production is defective in a group of CVID patients. Activation-induced cytidine deaminase (AID) protein is an important molecule involving CSR process. The aim of this study was to investigate the AID gene mRNA production in a group of CVID patients indicating possible role of this molecule in this disorder. METHODS: Peripheral blood mononuclear cells (PBMC) of 29 CVID patients and 21 healthy controls were isolated and stimulated by CD40L and IL-4 to induce AID gene expression. After 5 days AID gene mRNA production was investigated by real time polymerase chain reaction. FINDINGS: AID gene was expressed in all of the studied patients. However the mean density of extracted AID mRNA showed higher level in CVID patients (230.95±103.04 ng/ml) rather than controls (210.00±44.72 ng/ml; P=0.5). CVID cases with lower level of AID had decreased total level of IgE (P=0.04) and stimulated IgE production (P=0.02); while cases with increased level of AID presented higher level of IgA (P=0.04) and numbers of B cells (P=0.02) and autoimmune disease (P=0.02). CONCLUSION: Different levels of AID gene expression may have important roles in dysregulation of immune system and final clinical presentation in CVID patients. Therefore investigating the expression of AID gene can help in classifying CVID patients.

Evaluation of humoral immune function in patients with chronic idiopathic thrombocytopenic purpura.

Coincidence of autoimmune diseases such as immune thrombocytopenic purpura (ITP) with immunodeficiencies has been reported previously in patients who suffered from primary antibody deficiency (PAD). But there is no original study on immunological profiles of ITP patients to find out their probable immune deficiency. In this case-control study, ITP patients' humoral immunity was investigated for diagnosis of PAD in comparison with normal population. To evaluate the humoral immune system against polysaccharide antigens, patients' serum immunoglobulin levels were measured and a 23-valent pneumococcal capsular polysaccharide vaccine (PPV23) was administrated to evaluate the antibody response to vaccination. In this study, 14 out of 36 patients (39%) were diagnosed with antibody mediated immune deficiency including 2 patients (5.5%) with immunoglobulin class deficiency and 4 (11%) with IgG subclass deficiency. The remaining patients suffered from specific antibody deficiency. The most frequent deficiency in ITP patients was specific antibody deficiency.Therefore, immunological survey on ITP patients may be important especially for those who have undergone splenectomy.