Clinical heterogeneity in families with multiple cases of inborn errors of immunity.

BACKGROUND: Inborn errors of immunity (IEI) are a diverse range of genetic immune system illnesses affecting the innate and/or adaptive immune systems. Variable expressivity and incomplete penetrance have been reported in IEI patients with similar clinical diagnoses or even the same genetic mutation. METHODS: Among all recorded patients in the national IEI registry, 193 families with multiple cases have been recognized. Clinical, laboratory and genetic variability were compared between 451 patients with different IEI entities. RESULTS: The diagnosis of the first children led to the earlier diagnosis, lower diagnostic delay, timely treatment and improved survival in the second children in the majority of IEI. The highest discordance in familial lymphoproliferation, autoimmunity and malignancy were respectively observed in STK4 deficiency, DNMT3B deficiency and ATM deficiency. Regarding immunological heterogeneity within a unique family with multiple cases of IEI, the highest discordance in CD3+, CD4+, CD19+, IgM and IgA levels was observed in syndromic combined immunodeficiencies (CID), while non-syndromic CID particularly severe combined immunodeficiency (SCID) manifested the highest discordance in IgG levels. Identification of the first ATM-deficient patient can lead to improved care and better survival in the next IEI children from the same family. CONCLUSION: Intrafamilial heterogeneity in immunological and/or clinical features could be observed in families with multiple cases of IEI indicating the indisputable role of appropriate treatment and preventive environmental factors besides specific gene mutations in the variable observed penetrance or expressivity of the disease. This also emphasizes the importance of implementing genetic evaluation in all members of a family with a history of IEI even if there is no suspicion of an underlying IEI as other factors besides the underlying genetic defects might cause a milder phenotype or delay in presentation of clinical features. Thus, affected patients could be timely diagnosed and treated, and their quality of life and survival would improve.

The Autoimmune Manifestations in Patients with Genetic Defects in the B Cell Development and Differentiation Stages.

PURPOSE: Primary B cell defects manifesting as predominantly antibody deficiencies result from variable inborn errors of the B cell lineage and their development, including impairments in early bone marrow development, class switch recombination (CSR), or terminal B cell differentiation. In this study, we aimed to investigate autoimmunity in monogenic patients with B cell development and differentiation defects. METHODS: Patients with known genetic defects in the B cell development and differentiation were recruited from the Iranian inborn errors of immunity registry. RESULTS: A total of 393 patients with a known genetic defect in the B cell development and differentiation (257 males; 65.4%) with a median age of 12 (6-20) years were enrolled in this study. After categorizing patients, 109 patients had intrinsic B cell defects. More than half of the patients had defects in one of the ATM (85 patients), BTK (76 patients), LRBA (34 patients), and DOCK8 (33 patients) genes. Fifteen patients (3.8%) showed autoimmune complications as their first manifestation. During the course of the disease, autoimmunity was reported in 81 (20.6%) patients at a median age of 4 (2-7) years, among which 65 patients had mixed intrinsic and extrinsic and 16 had intrinsic B cell defects. The comparison between patients with the mentioned four main gene defects showed that the patient group with LRBA defect had a significantly higher frequency of autoimmunity compared to those with other gene defects. Based on the B cell defect stage, 13% of patients with early B cell defect, 17% of patients with CSR defect, and 40% of patients who had terminal B cell defect presented at least one type of autoimmunity. CONCLUSION: Our results demonstrated that gene mutations involved in human B cell terminal stage development mainly LRBA gene defect have the highest association with autoimmunity.

Evaluation of the frequency of attention deficit hyperactivity disorder in patients with asthma.

BACKGROUND: Asthma is the most prevalent respiratory disease caused by chronic airway inflammation. Attention Deficit Hyperactivity Disorder (ADHD) is children's most common psychological and neurodevelopmental disorder. Increased risk for ADHD in patients with inflammatory and autoimmune diseases supports the role of inflammatory mechanisms in the occurrence of ADHD. However, the association between asthma and ADHD remains unclear. OBJECTIVE: This study was designed to evaluate the prevalence of ADHD in patients with asthma who were referred to the clinic of allergy and clinical immunology. METHODS: This cross-sectional study was conducted on children aged 6 to 18 with asthma at Imam Ali hospital, Karaj, Iran. The patient's demographic data, history of childbirth delivery type, premature birth, hospital admission, family income, birth rate, and family history information related to the patient's asthma and medicines were recorded. ADHD diagnosis was made using the Persian version of Conners Parent Behavioral Problems Rating Scale (CPRS-26). RESULTS: In this study, 677 asthmatic patients were enrolled; 46 patients (6.8%) had ADHD. The probability of ADHD in asthmatic patients inhabited in a rural area, males, and patients with a history of food allergy, allergic rhinitis, urticaria, and eczema was significantly higher (p < 0.05). In addition, our result demonstrated that the likelihood of ADHD in patients with asthma and a history of PICU admission was significantly higher (p < 0.05). CONCLUSIONS: The present study showed that severe asthma, was the risk factor for ADHD in patients with asthma. Physicians should be aware of this co-morbidity to refer asthmatic patients who have the symptoms of ADHD to a psychologist.

Pigeon mite: An underdiagnosed cause of papular urticaria.

BACKGROUND: Dermanyssus gallinae, known as bird mite, generally lives on nestlings' featherless skin. Humans are accidentally infected, and itchy dermatitis is induced when the mites are unable to use birds' blood. The diagnosis is difficult due to the very small size and rapid movement of the mites, which make them hard to spot. CASE PRESENTATION: A 14-year-old male and his mother were referred to the allergy clinic complaining of a 2-week generalized itchy cutaneous papular lesion, unresponsive to antihista-mines, with the feeling of an insect moving on the surface of the skin. Due to the history of recently hatched pigeons nesting on their balcony and finding very small bugs, diagnosed as D. gallinae, they were instructed to clean the pigeon's nest as the source of these parasites, which successfully solved the problem. CONCLUSION: Bird mite infestation should be considered in the differential diagnosis of recurrent pruritus and urticaria, refractory to conventional treatments. Physicians should be aware of this mite infestation in approach to any patient with papular urticaria.

A case of Familial Mediterranean Fever presented with recurrent infection.

INTRODUCTION: The periodic fever syndrome Familial Mediterranean Fever (FMF) is caused by mutations in MEFV, which promote inflammation and present with uncontrolled systemic and organ-specific inflammation that can resemble infectious conditions. It is diagnosed based on clinical criteria, including frequent symptoms such as abdominal and thoracic pain, family history, and response to treatment with colchicine, which is confirmed by genetic assessment. Herein, we present a case of FMF with a relatively uncommon presentation. CASE PRESENTATION: A 22-month-old female was referred to the allergy and clinical immunology clinic with eczematoid skin rashes. She was admitted to the hospital several times since the 2nd day of life with different complaints like fever, seizure, and restlessness, and treated with the diagnosis of septicemia. Endoscopy and colonoscopy were done at the age of 6 months due to poor weight gain and bloody diarrhea, which revealed active crypt-destructive colitis with foci of erosion in favor of infectious or allergic colitis. The colon biopsy was negative for Cytomegalovirus (CMV). Regarding family history, she was the second child of the first cousins parents and had a healthy 12-year-old sister. There was a history of death for unknown reasons of her cousin, whose parents were related. The immunologic evaluation was done, which showed a relatively normal immunoglobulin level, antibody response, flow cytometry, and lymphocyte transformation test. Nonetheless, a genetic study was done, which showed a homozygote mutation in exon 10 of the MEFV gene in the patient and a heterozygote mutation in both her parents. CONCLUSION: The periodic fever syndrome Familial Mediterranean Fever (FMF) is caused by mutations in MEFV, which promote inflammation and present with uncontrolled systemic and organ-specific inflammation that can resemble infectious conditions. The patient was diagnosed with FMF, and treatment was started using colchicine, which successfully controlled the patient's symptoms and prevented the recurrence of fever and other inflammatory manifestations.

Infection with SARS-CoV-2 among children with asthma: evidence from Global Asthma Network.

BACKGROUND: Clinical presentations of coronavirus disease 2019 (COVID-19) among children with asthma have rarely been investigated. This study aimed to assess clinical manifestations and outcome of COVID-19 among children with asthma, and whether the use of asthma medications was associated with outcomes of interest. METHODS: The Global Asthma Network (GAN) conducted a global survey among GAN centers. Data collection was between November 2020 and April 2021. RESULTS: Fourteen GAN centers from 10 countries provided data on 169 children with asthma infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). COVID-19 was asymptomatic in 58 (34.3%), mild in 93 (55.0%), moderate in 14 (8.3%), and severe/critical in 4 (2.4%). Thirty-eight (22.5%) patients had exacerbation of asthma and 21 (12.4%) were hospitalized for a median of 7 days (interquartile range 3-16). Those who had moderate or more severe COVID-19 were significantly more likely to have exacerbation of asthma as compared to those who were asymptomatic or had mild COVID-19 (adjusted odds ratio (adjOR) 3.97, 95% CI 1.23-12.84). Those who used inhaled bronchodilators were significantly more likely to have a change of asthma medications (adjOR 2.39, 95% CI 1.02-5.63) compared to those who did not. Children who used inhaled corticosteroids (ICS) did not differ from those who did not use ICS with regard to being symptomatic, severity of COVID-19, asthma exacerbation, and hospitalization. CONCLUSIONS: Over dependence on inhaled bronchodilator may be inappropriate. Use of ICS may be safe and should be continued in children with asthma during the pandemic of COVID-19.

Adverse reactions in a large cohort of patients with inborn errors of immunity receiving intravenous immunoglobulin.

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.

Autoimmune manifestations among 461 patients with monogenic inborn errors of immunity.

BACKGROUND: The inborn errors of immunity (IEIs) are a group of heterogeneous disorders mainly characterized by severe and recurrent infections besides other complications including autoimmune and inflammatory diseases. In this study, we aim to evaluate clinical, immunologic, and molecular data of monogenic IEI patients with and without autoimmune manifestations. METHODS: We have retrospectively screened cases of monogenic IEI in the Iranian PID registry for the occurrence of autoimmunity and immune dysregulation. A questionnaire was filled for all qualified patients with monogenic defects to evaluate demographic, laboratory, clinical, and molecular data. RESULTS: A total of 461 monogenic IEI patients (290 male and 171 female) with a median (IQR) age of 11.0 (6.0-20.0) years were enrolled in this study. Overall, 331 patients (72.1%) were born to consanguineous parents. At the time of the study, 330 individuals (75.7%) were alive and 106 (24.3%) were deceased. Autoimmunity was reported in 92 (20.0%) patients with a median (IQR) age at autoimmune diagnosis of 4.0 (2.0-7.0) years. Sixteen patients (3.5%) showed autoimmune complications (mostly autoimmune cytopenia) as the first presentation of the disease. Most of the patients with autoimmunity were diagnosed clinically with common variable immunodeficiency (42.4%). The frequency of sinusitis and splenomegaly was significantly higher in patients with autoimmunity than patients without autoimmunity. In patients with autoimmunity, the most common pathogenic variants were identified in LRBA (in 21 patients, 23.0%), ATM (in 13 patients, 14.0%), and BTK (in 9 patients, 10.0%) genes. In the evaluation of autoimmunity by different genes, 4 of 4 IL10RB (100%), 3 of 3 AIRE (100%), and 21 of 30 LRBA (70.0%) mutated genes had the highest prevalence of autoimmunity. CONCLUSIONS: Autoimmune phenomena are common features among patients with monogenic IEI and are associated with a more complicated course of the disease. Therefore, when encountering autoimmune disorders, especially in the setting of dysgammaglobulinemia, it would be appropriate to conduct next-generation sequencing to discover responsible genes for the immune dysregulation at an early stage of the disease.

Clinical and Mutation Description of the First Iranian Cohort of Infantile Inflammatory Bowel Disease: The Iranian Primary Immunodeficiency Registry (IPIDR).

We describe a cohort of 25 Iranian patients with infantile inflammatory bowel disease (IBD), 14 (56%) of whom had monogenic defects. After proper screening, patients were referred for whole exome sequencing (WES). Four patients had missense mutations in the IL10 RA, and one had a large deletion in the IL10 RB. Four patients had mutations in genes implicated in host:microbiome homeostasis, including TTC7A deficiency, and two patients with novel mutations in the TTC37 and NOX1. We found a novel homozygous mutation in the SRP54 in a deceased patient and the heterozygous variant in his sibling with a milder phenotype. Three patients had combined immunodeficiency: one with ZAP-70 deficiency (T+B+NK-), and two with atypical SCID due to mutations in RAG1 and LIG4. One patient had a G6PC3 mutation without neutropenia. Eleven of the 14 patients with monogenic defects were results of consanguinity and only 4 of them were alive to this date.

Clinical, immunologic, and genetic spectrum of 696 patients with combined immunodeficiency.

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 < .001), onset of disease at greater than 5 years (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.

Fourth Update on the Iranian National Registry of Primary Immunodeficiencies: Integration of Molecular Diagnosis.

BACKGROUND: 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. METHOD: 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. RESULTS: 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. CONCLUSIONS: 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.

Abnormality of regulatory T cells in common variable immunodeficiency.

Common variable immunodeficiency (CVID) is a heterogeneous group of primary antibody deficiencies (PAD) which is defined by recurrent infections, hypogammaglobulinemia and defects in B-cell differentiation into plasma cells and memory B cells. T cell abnormalities have also been described in CVID patients. Several studies reported that Treg frequencies and their functional characteristics are disturbed and might account for the aberrant immune responses observed in CVID patients. The aim of this review is to describe phenotypic and functional characteristics of Treg cells, and to review the literature with respect to the reported Treg defects and its association with the clinical manifestation in CVID.

Measurement of Health-Related Quality of Life in Primary Antibody-Deficient Patients.

BACKGROUND: Primary immunodeficiency diseases are a group of disorders that result from a variety of defects of the immune system. Primary antibody deficiencies (PADs) are the most common forms of these disorders. Occurrence of recurrent infections, autoimmune diseases, cancers, and lymphoproliferative disorders is higher in PAD patients. Chronicity of these diseases, delayed diagnosis, inadequate treatment, and treatment side effects may affect the quality of life (QoL) of PAD patients. Evaluating QoL is important for patient care, understanding the burden of these diseases, and finding the patients' major health problems. We investigated the QoL in a group of PAD patients undergoing regular follow-up and treatment at the Children's Medical Center Hospital in Tehran, Iran. METHODS: Seventy patients with a diagnosis of PAD in two age groups (younger and older than 18 years) were included. QoL was measured using PedsQL and SF-36 questionnaires. Correlation of demographic, clinical, and immunological parameters with QoL scores was assessed and patients' scores were compared with the normal population, using nonparametric tests of SPSS software. RESULTS: Patients expressed significantly reduced scores in some mental and physical components. Patients with longer follow-up periods had higher scores in mental components but physical component scores were still low. There was no significant correlation between sex, age, and disease types with scores. CONCLUSIONS: PAD patients had significantly lower scores in mental and physical components compared to normal population. By early diagnosis and long-term follow-up periods, we may be able to prevent complications and help patients to have a better QoL.

Physician practice in food allergy prevention in the Middle East and North Africa.

BACKGROUND: A number of scientific organisations have developed guidelines for the primary prevention of allergic disease through nutritional interventions. However, even if the best evidence-based guidelines are available, these guidelines do not necessarily lead to adherence and improved health outcomes. METHOD: To determine how closely the practice of physicians in select Middle Eastern and North African countries compares with the current recommendations on the primary prevention of allergy a survey study was performed using a structured questionnaire and convenience sampling. RESULTS: A total of 1481 physicians responded, of which 66.1% were pediatricians. A total of 76.6% of responding physicians routinely identify infants who are at risk for developing allergy. In infants at risk for developing allergy, 89.1% recommend exclusive breastfeeding for at least 4 months. In contrast to current recommendations, 51.6% routinely recommend avoidance of any allergenic food in the lactating mother. In infants at risk of developing allergy who are completely formula fed, standard infant formula was recommended by 22.5% of responders. Of the responding physicians, 50.6% would recommend delaying the introduction of complementary food in infants at risk of allergy compared to those not at risk, whereas 62.5% would recommend postponing the introduction of potentially allergenic foods. Only 6.6% stated they follow all current recommendations on food allergy prevention. CONCLUSION: The results of this survey suggest that a substantial part of responding physicians from select Middle Eastern and North African (MENA) countries do not follow current recommendations on primary prevention of allergic disease through nutritional interventions.

Evaluation of infectious and non-infectious complications in patients with primary immunodeficiency.

INTRODUCTION: Primary immunodeficiency diseases (PIDs) are a heterogeneous group of genetic immune disorders. PID patients suffer from a variety of complications. The aim of this study was to determine the infectious and non-infectious complications among PID patients. MATERIAL AND METHODS: This retrospective cohort study was performed on recorded data of 202 PID patients who were diagnosed with eight major categories: common variable immunodeficiency (CVID), X-linked agammaglobulinemia, hyper-IgM syndrome, hyper IgE syndrome, chronic granulomatous disease (CGD), ataxia telangiectasia, hereditary angioedema and leukocyte adhesion deficiency. For all patients, infectious and non-infectious manifestations and laboratory data were collected in a comprehensive questionnaire. RESULTS: Infectious complications were more frequent than non-infectious complications. Pneumonia and otitis media were the main infectious problems in PID patients, especially in patients with antibody deficiencies. Among the non-infectious complications, splenomegaly and hepatomegaly were the most common complications in PID patients, and were more commonly seen in CGD patients than others. Splenomegaly, hepatomegaly and autoimmunity were the most common findings in CVID patients. A significant correlation was observed between diagnostic delay and bronchiectasis in CVID patients (p = 0.042). CONCLUSIONS: PID patients are at risk of multiple infectious and non-infectious problems. Timely diagnosis of PIDs not only improves their outcome and quality of life, but also helps prevent these troubling complications.

A Quality-of-life Study in Patients with Anaphylaxis to Hymenoptera Venom in Iran.

Little is known about the quality of life of patients with anaphylaxis to Hymenoptera venom. The Vespid Allergy Quality of Life Questionnaire (VQLQ) is commonly used to assess the psychological burden of this condition. This study aimed to evaluate the validity and reliability of the Persian version of VQLQ. In this cross-sectional study, VQLQ was translated into Persian according to expert recommendations.  The final translated version of VQLQ was then administered to 115 patients with Hymenoptera venom allergy at an asthma and allergy clinic in Iran. More than half of the participants were between 20 and 40 years of age, and 60% were male. Fear, anxiety, and outdoor activities had the most significant impact on the quality of life of patients with Hymenoptera venom allergy. Additionally, quality of life was more affected in women than in men, while no correlation was found with age. Furthermore, the quality of life was affected by a history of acute anaphylactic shock due to Hymenoptera venom. The Persian version of VQLQ enables the measurement of quality of life in patients with Hymenoptera venom allergy in the Iranian population. The inclusion of VQLQ in the initial evaluation of these patients may potentially guide allergist in providing support for venom-specific immunotherapy.

Safety and efficacy of levetiracetam and carbamazepine monotherapy in the management of pediatric focal epilepsy: a randomized clinical trial.

Due to the limited number of studies in children with focal epilepsy and the importance of choosing the most suitable drug to control seizures in children, the administration of the most effective medication with the most negligible adverse events is vital. This study aimed to evaluate the effectiveness and adverse events of carbamazepine vs. levetiracetam monotherapy in children with focal seizures. A monocentric, randomized, controlled, double-blind, parallel-group clinical trial was designed. This study was approved by the Iranian Registry of Clinical Trials (registration number: IRCT20170216032603N2) on June 19, 2020, and conducted at the neurology department of Imam Ali Hospital, Karaj, Iran, from February 2020 to March 2021. This study assessed 120 patients with recently diagnosed focal seizures aged 2 to 14. Patients were randomly divided into two groups, who received carbamazepine (CBZ) 15 to 20 mg/kg and levetiracetam (LEV) 20 to 40 mg/kg daily, respectively. Patients were evaluated for improvement and complications at weeks 4, 12, and 24. Out of 120 patients included in the study, six patients were excluded due to various complications of CBZ. The mean number of seizures at the end of the fourth, twelfth, and twenty-fourth weeks were 1.09 ± 0.75, 0.62 ± 0.27, and 0.39 ± 0.12 in the carbamazepine group and 1.11 ± 0.63, 0.52 ± 0.21, and 0.37 ± 0.11 in the LEV group, respectively (P > 0.05). Similarly, the number of seizure-free patients was 34, 44, and 48 in the CBZ group compared to 41, 50, and 54 in the LEV group, respectively (P > 0.05). On the other hand, the frequency of somnolence, dermatologic complications, and agitation was considerably higher in the CBZ group (P < 0.05). Although both medicines were equally effective in seizure control, CBZ was associated with considerably more adverse events and less patient compliance. Physicians should be aware of this difference to prevent unwanted consequences.

Gene polymorphisms of Interleukin-4 in allergic rhinitis and its association with clinical phenotypes.

BACKGROUND: Allergic rhinitis (AR) is an inflammatory disorder of the upper airway. T-helper (Th)2 cytokines seems to have major roles behind the scene of unpleasant symptoms resulted from AR. Expression of interleukin (IL)-4 and its receptor could be affected by single nucleotide polymorphisms (SNPs). This study assessed the effect of 4 genetic variants within genes of IL-4 and IL-4R in AR. METHODS: Allele frequencies of one IL-4R variant (rs1801275) and three SNPs of IL-4 (rs2243248, rs2243250, and rs2070874) were investigated in 98 patients with AR, compared to a group of controls, using PCR sequence-specific-primers (PCR-SSP) method. RESULTS: Homozygosity for the C allele of rs2243250 in IL-4 was significantly overrepresented in the patient group. CC genotype in rs2070874 significantly was correlated with AR. GG/CC/CC and TT/TT/TT (rs2243248, rs2243250, and rs2070874) haplotypes in the IL-4 gene had a significant negative correlation with AR. CONCLUSION: SNPs in IL-4 are associated with AR and could change the clinical picture of the disease in patients.

A systematic review regarding the prevalence of malignancy in patients with the hyper-IgE syndrome.

The hyper-immunoglobulin E syndrome (HIES) is a primary immunodeficiency disease originally described as Job syndrome. The fundamental causative variant of the HIES is an autosomal dominant mutation in the signal transducer and activator of transcription 3 (STAT3) gene. It is characterized by recurrent staphylococcal cold skin abscess, sinopulmonary infection, eczema, head and face anomalies, frequent bone fractures, eosinophilia and extremely high serum IgE levels (IgE ≥ 2000 IU/mL). However, multiple other genetic defects are also known as HIES-like disorders. Apart from infectious manifestations, STAT3, DOCK8 and TYK2 gene mutations are associated with various malignancies. The most common malignancies reported in these patients are lymphomas, including Hodgkin's and non-Hodgkin's lymphomas (NHL) of B and T cells. This systematic review aimed to investigate the prevalence of malignancies in HIES and the factors associated with malignancy in these patients. In this survey, all articles published until April 1st, 2023, in Scopus, PubMed and Web of Science databases based on three groups of keywords related to HIES syndrome and malignancy were reviewed by three different researchers. Finally, 26 articles were evaluated from which 24 papers were meta-analyzed. In the current study, the demographic information of 1133 patients with HIES, which was mentioned in 24 articles enrolled in the project, was collected, and the information related to patients who had malignancy was analyzed and meta-analyzed. A total of 96 patients out of 1133 studied patients had at least one type of malignancy, the overall prevalence of malignancies reported in the articles was 6.5% (95% confidence interval 4.1-9%), and the total prevalence of malignancy in patients with NHL type and patients with squamous cell carcinoma (SCC) was 2.9% (95% confidence interval 1.7-4.4%) and 2.2% (95% confidence interval 0.3-4.1%), respectively. The results of this study indicated that in 6.5% of cases, HIES was complicated with malignancy, and considering the higher rate of these malignancies in women as well as in DOCK8 mutation sufferers, it is necessary for physicians to be aware of this association and includes malignancy screening in follow-up and periodic examinations of these patients. Indeed, more studies in this field will help to clarify the precise figures and predisposing factors of the relationship between HIES and malignancy.

Immunological Evaluation of Pediatric Patients with Polyautoimmunity.

BACKGROUND: Autoimmunity can be the first or predominant manifestation in patients with primary immunodeficiency disorder, also referred to as inborn errors of immunity (IEI). This study aims to evaluate the immune status of pediatric patients with polyautoimmunity to identify those with underlying immune defects. METHODS: In this cross-sectional study, pediatric patients with polyautoimmunity including at least one confirmed autoimmune endocrine disease were enrolled. Demographic and clinical data were collected using a questionnaire based on medical records and direct family interviews. For each patient, a basic immunologic evaluation was performed. The clinical diagnosis was established according to the criteria of the European Society for Immunodeficiencies (ESID). Based on the presence or absence of a history of severe and/or recurrent infections, patients were divided into two groups for comparison. RESULTS: Thirty-nine patients, 18 males (46.2%) and 21 females (53.8%), were included. Fourteen patients (35.9%) had consanguineous parents. Fifteen patients (38.5%) had a history of severe and/or recurrent infections. The median (interquartile range: IQR) age of our patients at the time of evaluation was 11.1 (9-16) years. The median (IQR) age at the onset of infections and autoimmunities were 3 (1-10.8) and 5 (2.6-8) years, respectively. The most common infectious complications reported were pneumonia and candidiasis, each in 12.8% of the patients. The most prevalent autoimmune disorders were type 1 diabetes (74.3%) and autoimmune thyroiditis (58.9%). IEI was diagnosed in six patients (15.38%), five of which were from the group with severe or recurrent infections: three with selective IgA deficiency, two with common variable immunodeficiency (CVID), and one with immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX), but without a history of infections. CONCLUSION: The occurrence of early onset polyautoimmunity in association with severe and/or recurrent infections or in patients with a positive family history should be a warning sign for physicians to initiate an evaluation for possible immunodeficiency disorders to prevent complications through early treatment.