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Metformin is a commonly used medication in diabetic patients. It can cause different complications including cutaneous adverse reactions. Metformin-induced fixed-drug eruption (FDE) has been reported in limited cases. Due to the popularity of metformin, clinicians need to be aware of uncommon drug reactions for proper diagnosis and treatment. Herein, we report a 43-year-old man with generalized bullous lesions with a positive dechallenge-rechallenge test diagnosed as metformin-induced generalized bullous fixed-drug eruption. Metformin dosage was stopped and lesions were treated with topical clobetasol propionate and oral prednisolone and cyclosporine-A. After a 6-month follow-up, he was well without any relapsing episodes. [ABSTRACT FROM AUTHOR]

Patients with very early-onset inflammatory bowel disease (VEO-IBD) may present because of underlying monogenic inborn errors of immunity (IEI). Strong differences have been observed in the causes of monogenic IBD among ethnic populations. This multicenter study was carried out on 16 Iranian patients with VEO-IBD. We reviewed clinical and basic immunologic evaluation including flow cytometry and immunoglobulin levels. All patients underwent clinical whole exome sequencing (WES). Sixteen patients (8 females and 8 males) with a median age of 43.5 months were enrolled. The median age at the onset of symptoms was 4 months. Most patients (12, 75%) had consanguineous parents. Chronic non-bloody diarrhea (13, 81.3%) and perianal diseases including perianal abscess (6, 37.5%), anal fissure (6, 37.5%), or anal fistula (2, 12.5%) were the most common manifestations. WES identified a spectrum of genetic variants in 13 patients (81.3%): IL10RB (6, 37.5%), MVK (3, 18.8%), and CASP8, SLC35C1, G6PC3, and IKBKB in 1 patient, respectively. In 3 patients (18.7%), no variant was identified. Flow cytometry identified a spectrum of abnormalities that helped to assess the evidence of genetic diagnosis. At the end of the survey, 3 (18.8%) patients were deceased. This high rate of monogenic defects with a broad spectrum of genes reiterates the importance of investigating IEI in patients with infantile-onset IBD. Patients with very early-onset inflammatory bowel disease (VEO-IBD) may present because of underlying monogenic inborn errors of immunity (IEI). Strong differences have been observed in the causes of monogenic IBD among ethnic populations. The high rate of monogenic defects with a broad spectrum of genes reiterates the importance of investigating IEI in patients with infantile-onset IBD. Graphical Abstract [ABSTRACT FROM AUTHOR]

Background: The prevalence of allergic diseases is increasing worldwide. The effective role of omega-3 fatty acids in the maturation of immune system and protection against atopic diseases has been well discussed. However, previous studies revealed conflicting results. This study was conducted to investigate the effect of fish oil consumption by nursing atopic mothers on the level of interferon gamma (IFN-γ) in their breast milk and incidence of allergic disease in their infants. Methods: This randomized clinical trial was conducted on 94 atopic mothers, who were assigned to two equal groups receiving either 1000 mg fish oil capsules or placebo for 60 days after delivery. The breast milk was collected 120 days after delivery, and IFN-γ level was measured. The history of the symptoms of atopic disease in infants was collected from their mothers through ISAAC questionnaire; in addition, the infants' growth was evaluated. Results: Sixty mother-infant pairs completed the trial. The mean values of IFN-γ in breast milk was higher in the fish oil group (1.11±1.15 Pg/ml) than in the placebo group (0.81±0.86 Pg/ml), but the difference was not significant (P=0.288). In addition, the incidence of allergic symptoms of infants was not significantly different between the two groups (P=0.84). Conclusion: In this trial, the consumption of fish oil by lactating mothers did not have a significant effect on IFN-γ level in their breast milk and the incidence of allergic symptoms in their infants. Future studies with longer follow-ups are necessary in this regard. [ABSTRACT FROM AUTHOR]

Eosinophilic esophagitis (EoE) is a chronic immune-mediated disease isolated to the esophagus Food allergy is thought to play an important role in the pathophysiology of EOE. The aim of this study is to evaluate demographic features and sensitivity of patients with reference to common food allergens. Children with documented EoE were enlisted for this study. Skin prick test and patch test were done for all participants. Each test contained common food allergens. Other tests, such as evaluation of total IgE and eosinophil count, were also done. A total of 30 patients (the mean age of participants was 3±6 years) with 6 months to 15 years documented EoE participated in this study. The mean duration of symptoms was 2 years. Association with other allergic disorders was seen in 16 (32%) patients [Asthma in 8 (26.7%), allergic rhinitis in 5 (16.7%) and eczema in 3 (10%)]. The mean level of total IgE was 413.5±505.5 (IU/ML): total IgE level was above normal range for age in 17 children. The mean level of eosinophil was 372.2±305.2, and eosinophilia was seen in 11 patients (36.7%). The skin prick test and patch test findings showed that 28 patients (93%) and 17 of 30 patients (56.6%) tested positive to foods respectively. The most common positive skin prick test was for sesame and walnut. Patch test showed that the most common positive test was for fish. Evaluating the symptoms indicated that vomiting (70%) is the most prevalent symptom in patients; the less prevalent symptom was dysphagia (3.3%). Other prevalent symptoms were subsequent abdominal pain (33.3%), gaining weight failure (33.3%), heartburn (16.6%), cough (10%), fecal impaction (10%), and constipation (6.66%). Our series confirms the high degree of atopy in Iranian children with EoE. These patients seem to be polysensitized to several food allergens Because of different eating cultures in different countries, considering special food in selecting allergens for allergic tests is needed. [ABSTRACT FROM AUTHOR]

Background: The relation between interleukin-33 (IL-33) and asthma is not precisely known yet. The present study set to compare the serum level of IL-33 in patients with asthma and controls and study the relation with the severity of disease. Methods: The serum level of IL-33 and total IgE in 89 asthmatic patients and 57 controls were analyzed. The association of levels of IL-33 with the severity of disease, levels of total IgE, measures of spirometry (forced expiratory volume in 1 s [FEV1]), age, sex, presence or absence of other allergic diseases, and the disease duration was evaluated. Results: Higher levels of IL-33 and total IgE were detected in asthmatic patients compared with controls (P = 0.0001 and P = 0.008, respectively). In the asthmatic group, a significant direct association of IL-33 with age (P = 0.02, R = 0.23) and with total IgE level (P = 0.003, R = 0.31) were observed, but there was no relationship between other variables. Comparison of mean level of IL-33 in different asthma groups concerning the disease severity showed the statistically significant difference between them and a significant increased serum level of total IgE was observed in more severe disease. The results showed a significant negative correlation between FEV1 and total IgE (P = 0.028, R = -0.23) and IL-33 level (P = 0.0001, R = -0.83). Conclusions: IL-33 is suggested as a new inflammatory marker of severe and refractory asthma. Therefore, it may be a unique therapeutic target in these patients. [ABSTRACT FROM AUTHOR]

Bullous systemic lupus erythematosus (BSLE) is an autoimmune blistering disease occurring in patients with systemic lupus erythematosus (SLE). It is a rare disease, especially in children. A 14-year-old girl initially presented with fatigue, generalized vesiculobullous skin lesions, and ulcers over the hard palate and oral mucosa. Clinical investigations revealed hematuria and proteinuria, a high erythrocyte sedimentation rate and titer of antinuclear antibody, and anti-double-stranded DNA. Skin biopsy findings were suggestive of BSLE. A renal biopsy confirmed the features of class V lupus nephritis. Based on the clinical features and investigations, a diagnosis of BSLE with nephritis was made. She received methylprednisolone pulse therapy and hydroxychloro quine ; however, it did not alleviate the vesiculobullous eruption, so treatment with dapsone started and resulted in the dramatic disappearance of the lesions. Interruption of dapsone due to hemolysis did not aggravate the bullous disease. During follow-up, she had multiple flare-ups of disease and nephritis without rebound of bullous lesions. BSLE is a rare presentation of SLE in children. Differentiating it from other skin bullous diseases and SLE with blister is important for the correct management. The unusual presentation of this disease may delay the diagnosis and therefore requires a high index of clinical suspicion. [ABSTRACT FROM AUTHOR]

Background: Kawasaki disease is an acute vasculitis that occurs mainly in children. Cervical lymphadenopathy is one of the major presenting manifestations of Kawasaki disease. We report a case of Kawasaki disease with para aortic lymphadenopathy, as an unusual feature in this disease. Case Presentation: This 2.5 year old girl presented with persistent high grade fever, erythematous rash, bilateral non purulent conjunctivitis, red lips, and edema of extremities. Laboratory results included an elevated erythrocyte sedimentation rate, leukocytosis, anemia, and positive C-reactive protein. On second day after admission she developed abdominal pain. Ultrasonography of abdomen revealed multiple lymph nodes around para aortic area, the largest measuring 12mm×6mm. Treatment consisted of aspirin and high dose intravenous γ-globulin. Ultrasonography and CT scan of abdomen performed one week later showed disappearance of the lymph nodes. Conclusion: There are few previous reports of lymphadenopathy in unusual sites such as mediastinum in Kawasaki disease. Para aortic lymph nodes enlargement might be an associated finding with acute phase of Kawasaki disease. In these patients a close observation and ultrasonographic follow up will prevent unnecessary further investigation. [ABSTRACT FROM AUTHOR]

Background. Eosinophilic esophagitis (EoE) is an allergic inflammatory disorder of the esophagus. Today, probiotics are included as adjuvant therapy in the treatment of allergic diseases. The aim of this study was to assess the effect of synbiotic on clinical symptom improvement in EoE patients. Methods. This study is designed by a double-blind, placebo-controlled clinical trial with two parallel groups, which was performed on 30 children with eosinophilic esophagitis. All participants were children aged 6 months to 15 years. Both groups received the same treatment (elimination diet, topical steroid, and proton pump inhibitor). A synbiotic (KidiLact) was added to the medication regimen of 15 patients (case), while the next 15 patients received a placebo (control). Severity and frequency of symptoms were assessed with a checklist derived from a validated scoring tool in both groups before and after 8 weeks of treatment. Results. There was a significant reduction in the severity score of chest pain and poor appetite (P value < 0.05) in the case group taking probiotics, while nausea and poor appetite were the only symptoms with a significant reduction in the frequency score after intervention in this group. Conclusion. Probiotics can be used as adjuvant treatment for patients with EoE. Improvement in the severity of chest pain and poor appetite and reduction in the frequency of nausea and poor appetite in these patients can be seen. [ABSTRACT FROM AUTHOR]

There are limited data on severe cutaneous adverse reactions (SCARs) associated with antiepileptic medications. The current study aims to investigate the clinical and epidemiological characteristics of antiepileptic medication-induced SCARs in hospitalized children. This five-year retrospective study was conducted at Isfahan University of Medical Sciences, Iran. The study included all children with a diagnosis of SCARs secondary to antiepileptic medications as defined by the World Health Organization (WHO). In our study SCARs were categorized into three groups: drug reaction with eosinophilia and systemic symptoms (DRESS), Stevens-Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN), and a group with symptoms overlapping between maculopapular eruptions (MPE) and DRESS. Among 259 children with SCARs induced by antiepileptic medications, 199 (76.83%), 42 (16.22%), and 18 (6.95%) had overlapping MPE/DRESS, DRESS, and SJS/TEN, respectively. Phenobarbital was the most common offending drug among SCARs. The multinomial logistic regression model revealed that lymphadenopathy increased DRESS occurrence by 35 times compared to overlapping MPE/DRESS. Girls were at risk of SJS/TEN approximately 6 times more than boys. Age, weight, and mucosal involvement affected hospitalization duration in children with SCARs related to antiepileptic medication. There are some similarities and differences in the clinical and epidemiological features of Iranian children suffering from antiepileptic medication-induced SCARs. [ABSTRACT FROM AUTHOR]

Purpose: Major histocompatibility complex class II (MHC-II) deficiency is a rare inborn error of immunity (IEI). Impaired antigen presentation to CD4 + T cells results in combined immunodeficiency (CID). Patients typically present with severe respiratory and gastrointestinal tract infections at early ages. Hematopoietic stem cell transplantation (HSCT) is the only curative therapy. Methods: We describe the clinical, immunologic, and genetic features of eighteen unrelated Iranian patients with MHC-II deficiency. Results: Consanguinity was present in all affected families. The median age at the initial presentation was 5.5 months (range 7 days to 18 years). The main symptoms included failure to thrive, persistent diarrhea, and pneumonia. Autoimmune and neurologic features were also documented in about one-third of the patients, respectively. Thirteen patients carried RFXANK gene mutations, two carried RFX5 gene mutations, and three carried a RFXAP gene mutation. Six patients shared the same RFXANK founder mutation (c.162delG); limited to the Iranian population and dated to approximately 1296 years ago. Four of the patients underwent HSCT; three of them are alive. On the other hand, nine of the fourteen patients who did not undergo HSCT had a poor prognosis and died. Conclusion: MHC-II deficiency is not rare in Iran, with a high rate of consanguinity. It should be considered in the differential diagnosis of CID at any age. With the limited access to HSCT and its variable results in MHC-II deficiency, implementing genetic counseling and family planning for the affected families are mandatory. We are better determined to study the c.162delG RFXANK heterozygous mutation frequency in the Iranian population. [ABSTRACT FROM AUTHOR]

Simple Summary: Cutaneous manifestations were observed in ~44% of Iranian patients with monogenic IEI. A considerable number of these patients developed cutaneous disorders as their first manifestation of the disease. Skin disorders in IEI patients might delay the immunodeficiency diagnosis but may improve their prognosis. Cutaneous manifestations are one of the most common presentations among patients with inborn errors of immunity (IEI). These skin manifestations are often among the first presenting features in the majority of patients preceding the IEI diagnosis. We studied 521 available monogenic patients with IEI listed in the Iranian IEI registry up to November 2022. We extracted each patient's demographic information, detailed clinical history of cutaneous manifestations, and immunologic evaluations. The patients were then categorized and compared based on their phenotypical classifications provided by the International Union of Immunological Societies. Most patients were categorized into syndromic combined immunodeficiency (25.1%), non-syndromic combined immunodeficiency (24.4%), predominantly antibody deficiency (20.7%), and diseases of immune dysregulation (20.5%). In total, 227 patients developed skin manifestations at a median (IQR) age of 2.0 (0.5–5.2) years; a total of 66 (40.7%) of these patients initially presented with these manifestations. Patients with cutaneous involvement were generally older at the time of diagnosis [5.0 (1.6–8.0) vs. 3.0 (1.0–7.0) years; p = 0.022]. Consanguinity was more common among patients who developed skin disorders (81.4% vs. 65.2%, p < 0.001). The overall skin infection rate and the type of dominant pathogens were significantly different among the IEI patients in different phenotypical classifications (p < 0.001). Atopic presentation, including urticaria, was highly prevalent among patients with congenital defects of phagocytes (p = 0.020). The frequency of eczema was also significantly higher among cases with both syndromic and non-syndromic combined immunodeficiency (p = 0.009). In contrast, autoimmune cutaneous manifestations, including alopecia and psoriasis, were most common in patients with immune dysregulation (p = 0.001) and defects in intrinsic or innate immunity (p = 0.031), respectively. The presence of autoimmune cutaneous complications significantly improved the survival rate of IEI patients (p = 0.21). In conclusion, cutaneous manifestations were observed in nearly 44% of Iranian patients with monogenic IEI. A considerable number of patients with cutaneous involvements developed these disorders as their first manifestation of the disease, which was particularly noticeable in patients with non-syndromic combined immunodeficiency and phagocytic defects. The neglected skin disorders in IEI patients might delay diagnosis, which is generally established within a 3-year interval from the development of skin-related problems. Cutaneous disorders, especially autoimmune features, might indicate a mild prognosis in IEI patients. [ABSTRACT FROM AUTHOR]

Purpose: MALT1 deficiency is a combined immune deficiency characterized by recurrent infections, eczema, chronic diarrhea, and failure to thrive. Clinical and immunological characterizations of the disease have not been previously reported in large cohorts. We sought to determine the clinical, immunological, genetic features, and the natural history of MALT-1 deficiency. Methods: The clinical findings and treatment outcomes were evaluated in nine new MALT1-deficient patients. Peripheral lymphocyte subset analyses, cytokine secretion, and proliferation assays were performed. We also analyzed ten previously reported patients to comprehensively evaluate genotype/phenotype correlation. Results: The mean age of patients and disease onset were 33 ± 17 and 1.6 ± 0.7 months, respectively. The main clinical findings of the disease were recurrent infections (100%), skin involvement (100%), failure to thrive (100%), oral lesions (67%), chronic diarrhea (56%), and autoimmunity (44%). Eosinophilia and high IgE were observed in six (67%) and two (22%) patients, respectively. The majority of patients had normal T and NK cells, while eight (89%) exhibited reduced B cells. Immunoglobulin replacement and antibiotics prophylaxis were mostly ineffective in reducing the frequency of infections and other complications. One patient received hematopoietic stem cell transplantation (HSCT) and five patients died as a complication of life-threatening infections. Analyzing this cohort with reported patients revealed overall survival in 58% (11/19), which was higher in patients who underwent HSCT (P = 0.03). Conclusion: This cohort provides the largest analysis for clinical and immunological features of MALT1 deficiency. HSCT should be offered as a curative therapeutic option for all patients at the early stage of life. [ABSTRACT FROM AUTHOR]

We report a 9-year old girl with an unusual presentation of granulomatosis with polyangiitis in association with Marfan phenotype. The patient presented with recurrent sinusitis, epistaxis, hearing loss and hyperplastic gingivitis, without any signs or symptoms of major organ involvement. [ABSTRACT FROM AUTHOR]

The article presents a case study of a 7-year old boy with clinical presentation of fever and nonproductive cough and also had hepatomegaly and digital clubbing. It mentions that the patient was later on diagnosed with Lymphocytic Interstitial Pneumonitis. It describes the presentation of the rare primary immunodeficiency disease of XHIGM syndrome presented with refractory pneumonia.

Background. Different epidemiologic aspects of drug-induced Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) in children are scarce. Aim. To compare the clinical and epidemiological features of patients with drug-induced SJS and TEN in children and adults. Method. This retrospective study was conducted at two academic referral centers (Isfahan, Iran) over 5 years. SJS and TEN were clinically diagnosed and confirmed by skin biopsy as needed. Results. One hundred one patients (31 children and 70 adults) with a female to male ratio of 1.1 : 1 was identified in the present study. SJS was more commonly diagnosed in both pediatric and adult patients. The most frequent reason for drug administration identified was the infection (45.2%) and seizure (45.2%) in children and infection (34.3%) and psychiatry disorder (27.1%) in adults (P = 0.001). The most common culprit drugs in the pediatric were phenobarbital (9/31), cotrimoxazole (4/31), and amoxicillin (4/31); however, in the adult group, the most common drugs were carbamazepine (11/70) and lamotrigine (9/70). Fever was significantly more common in adults (44.3%) compared to pediatric patients (22.6%) (P = 0.03). Multiple logistic regression models showed that pediatric patients had significantly lower odds of hospitalization (OR [odds ratio]: 0.14; 95% CI 0.02, 0.67). In addition, patients with SCORTEN 1 had significantly higher odds of hospitalization (OR: 6.3; 95% CI: 1.68, 23.79) compared to patients with SCORTEN 0. Conclusions. The present study showed several differences between the pediatric and adult patients with SJS and TEN, including the reason for drug administration, culprit drugs, length of hospital stay, presence of fever, and final diagnosis of disease. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Although it is estimated that COVID-19 life-threatening conditions may be diagnosed in less than 1:1000 infected individuals below the age of 50, but the real impact of this pandemic on pediatric patients with different types of primary immunodeficiency (PID) is not elucidated. The current prospective study on a national registry of PID patients showed that with only 1.23 folds higher incidence of infections, these patients present a 10-folds higher mortality rate compared to population mainly in patients with combined immunodeficiency and immune dysregulation. Therefore, further management modalities against COVID-19 should be considered to improve the survival rate in these two PID entities using hematopoietic stem cell transplantation and immunomodulatory agents. [ABSTRACT FROM AUTHOR]

Background: Common variable immunodeficiency (CVID) is the most frequent primary immunodeficiency disorder mainly characterized by recurrent bacterial infections besides other immunological defects including loss of or dysfunction of B cells and decreased immunoglobulin levels. In this study, our aim is to evaluate clinical, immunological, and molecular data of patients with a primary clinical diagnosis of CVID and autoimmune phenotype with a confirmed genetic diagnosis. Methods: Among 297 patients with CVID, who were registered in the Iranian Primary Immunodeficiency Registry at Children's Medical Center Hospital in Iran, 83 patients have been genetically examined and 27 patients with autoimmunity and confirmed genetic mutations were selected for analysis. Whole-exome sequencing and confirmatory Sanger sequencing methods were used for the study population. A questionnaire was retrospectively filled for all patients to evaluate demographic, laboratory, clinical, and genetic data. Results: In the 27 studied patients, 11 different genetic defects were identified, and the most common mutated gene was LRBA, reported in 17 (63.0%) patients. Two patients (7.7%) showed autoimmune complications as the first presentation of immunodeficiency. Eleven patients (40.7%) developed one type of autoimmunity, and 16 patients (59.3%) progressed to poly-autoimmunity. Most of the patients with mono-autoimmunity (n = 9, 90.0%) primarily developed infectious complications, while in patients with poly-autoimmunity, the most common first presentation was enteropathy (n = 6, 37.6%). In 13 patients (61.9%), the diagnosis of autoimmune disorders preceded the diagnosis of primary immunodeficiency. The most frequent autoimmune manifestations were hematologic (40.7%), gastrointestinal (48.1%), rheumatologic (25.9%), and dermatologic (22.2%) disorders. Patients with poly-autoimmunity had lower regulatory T cells than patients with mono-autoimmunity. Conclusion: In our cohort, the diagnosis of autoimmune disorders preceded the diagnosis of primary immunodeficiency in most patients. This association highlights the fact that patients referring with autoimmune manifestations should be evaluated for humoral immunity. [ABSTRACT FROM AUTHOR]

Obesity is commonly associated with immunometabolic dysfunctions. Activation of inflammatory macrophages through TLR4 (toll-like receptor 4) and the anti-inflammatory impact of exercise have been and are the new concerns among researchers. A new short-term combined high-intensity interval training was proposed in young sedentary overweight/obese females. All participants were allocated to one of two groups: the exercise group (EG) and the control group (CG), where the EG participated in a 2-week combined training and the CG continued its routine lifestyle. Gene expression levels of TLR4, NF-κB(nuclear factor κB), and IRF3 (interferon regulatory factor 3) were assessed by real-time PCR. Physiological, anthropometric, and biomedical metabolic factors were assessed. The between-group comparisons indicated a tendency to a decrease in NF-κB gene expression in the EG. The IRF3 levels were not significantly changed compared to CG and the levels before training. Fasting glucose levels and β-cell function revealed a significant improvement in EG. These findings indicated that this protocol decreased meta-inflammation levels and improved insulin resistance independent of body composition changes. Consequently, combined training may be recommended as a therapeutic approach in metabolic diseases. [ABSTRACT FROM AUTHOR]

• Detecting genetic defects in a large number of SCID patients. • Molecular diagnosis is a critical step for genetic counseling, carrier detection, and prenatal diagnosis in SCID patients. • Applying rational ways based on immunological and clinical findings can be very effective in managing the disease and reducing costs. 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 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. 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. 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. [ABSTRACT FROM AUTHOR]

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. 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. 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. 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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background and objective: Asthma is a growing problem worldwide. Acute exacerbations impose considerable morbidity, mortality, and increased cost. Viral respiratory infections are the most common cause (80-85%) of pediatric asthma exacerbations and admissions to the hospital. The aim of this study was to determine the effect of a new synbiotic Lactocare® on viral respiratory infections and asthma exacerbations in asthmatic children. Methods: In this double blind, placebo-controlled, randomized clinical trial, 72 children with mild persistent asthma, aged between 6 and 12 years, were randomized to receive either Lactocare®, a Synbiotic containing 1 billion CFU/Capsule of Lactobacillus casei, Lactobacillus rhamnosus, Streptococcus thermophilus, Bifidobacterium breve, Lactobacillus acidophilus, Bifidobacterium infantis, Lactobacillus bulgaricus, and Fructooligosacharide (Zist Takhmir, Tehran, Iran) or placebo daily for 60 days. The primary outcome was the number of viral respiratory infections, and secondary outcomes were school absence, salbutamol and prednisolone usage, outpatient visits, and hospital admission for asthma. The outcomes were compared among study groups using the SPSS 11.5 program and the Mann Whitney and Fisher exact tests. Results: Of the 72 children who were enrolled with mild persistent asthma, 36 were assigned randomly to be treated with synbiotic and 36 with placebo. The number of viral respiratory infections was significantly higher in placebo group than the synbiotic group during the first month of intervention (0.74 ± 0.12 vs. 0.44 ± 0.1, p < 0.007) but not during the second month (0.5 ± 0.8 vs. 0.5 ± 0.8, p < 0.641). Considering the total duration of the study (two months), infection episodes also were significantly lower in the synbiotic group (0.92 ± 0.15 vs. 0.69 ± 0.11, p < 0.046). Salbutamol consumption was significantly lower in the synbiotic group, but there were no significant differences in school absenteeism, oral prednisolone use, outpatient visits, or hospital admissions. Conclusion: This new synbiotic (a mixture of seven probiotic strains plus fructooligosacharide may reduce episodes of viral infection in asthmatic children. [ABSTRACT FROM AUTHOR]

Monogenic immune dysregulation diseases (MIDD) are caused by defective immunotolerance. This study was designed to increase knowledge on the prevalence and spectrum of MIDDs, genetic patterns, and outcomes in Middle East and North Africa (MENA). MIDD patients from 11 MENA countries (Iran, Turkey, Kuwait, Oman, Algeria, Egypt, United Arab Emirates, Tunisia, Jordan, Qatar, and Azerbaijan) were retrospectively evaluated. 343 MIDD patients (58% males and 42% female) at a median (IQR) age of 101 (42–192) months were enrolled. The most common defective genes were LRBA (23.9%), LYST (8.2%), and RAB27A (7.9%). The most prevalent initial and overall manifestations were infections (32.2% and 75.1%), autoimmunity (18.6% and 41%), and organomegaly (13.3% and 53.8%), respectively. Treatments included immunoglobulin replacement therapy (53%), hematopoietic stem cell transplantation (HSCT) (14.3%), immunosuppressives (36.7%), and surgery (3.5%). Twenty-nine (59.2%) patients survived HSCT. Along with infectious complications, autoimmunity and organomegaly may be the initial or predominant manifestations of MIDD. • MIDD prevalence is considered higher in MENA region due to consanguineous marriages. • The most prevalent defective genes were LRBA (23.9%), LYST (8.2%), and RAB27A (7.9%). • The infections, autoimmunity and organomegaly were common initial & overall symptoms. [ABSTRACT FROM AUTHOR]

Background: We aimed to investigate the prevalence of nephrocalcinosis (NC) among children with diagnosed congenital adrenal hyperplasia (CAH). Our findings would be helpful for earlier diagnosis, management, and prevention of NC-related complications. Materials and Methods: In this cross-sectional study, children with CAH, aged <18 years old who were regularly referred for follow-up, were included. The information of the patients was extracted from their medical files, and they underwent renal ultrasonography for evaluation of the presence of NC. Results: From 120 studied patients with CAH, four patients (3.3%) had NC. The prevalence of NC was higher in males than females (P = 0.05). Mean age and age of CAH diagnosis had a trend to be lower in CAH patients with NC than those without. Regression analysis indicated significant association between NC and sex (P = 0.027, r = 2.24). Conclusion: The results of this study indicated a 3.3% prevalence rate of NC for children with CAH. NC had a trend to be more prevalent in male children with CAH. Though it was not significantly different but given that the mean age and age at diagnosis of CAH in children with CAH and NC was lower that CAH patients without NC, it is suggested that in patients with CAH and NC other factors such as genetic background or unknown disease related factors are associated with hypercalcemia and NC. [ABSTRACT FROM AUTHOR]

Objective: Acute exacerbations impose considerable morbidity, mortality, and increased cost. Viral respiratory infections are the most common cause (80-85%) of pediatric asthma exacerbations and admissions to the hospital. The aim of this study was to determine the effect of a new synbiotic Lactocare® on viral respiratory infections and asthma exacerbations in asthmatic children. Material and Methods: In this double blind controlled clinical trial, 72 children with mild persistent asthma, aged between 6 and 12 years, were randomized to receive either Lactocare®, a Synbiotic containing 1 billion CFU/Capsule of Lactobacillus casei, Lactobacillus rhamnosus, Streptococcus thermophilus, Bifidobacterium breve, Lactobacillus acidophilus, Bifidobacterium infantis, Lactobacillus bulgaricus, and Fructooligosacharide (Zist Takhmir, Tehran, Iran) or placebo daily for 60 days. The primary outcome was the number of viral respiratory infections, and secondary outcomes were school absence, salbutamol and prednisolone usage, outpatient visits, and hospital admission for asthma. The outcomes were compared among study groups using the SPSS 11.5 program and the Mann Whitney and Fisher exact tests. Results: Of the 72 children who were enrolled with mild persistent asthma, 36 were assigned randomly to be treated with synbiotic and 36 with placebo. The number of viral respiratory infections was significantly higher in placebo group than the synbiotic group during the first month of intervention (0.74 ± 0.12 vs. 0.44 ± 0.1, p < 0.007) but not during the second month (0.5 ± 0.8 vs. 0.5 ± 0.8, p < 0.641). Considering the total duration of the study (two months), infection episodes also were significantly lower in the synbiotic group (0.92 ± 0.15 vs. 0.69 ± 0.11, p < 0.046). Salbutamol consumption was significantly lower in the synbiotic group, but there were no significant differences in school absenteeism, oral prednisolone use, outpatient visits, or hospital admissions. Conclusion: This new symbiotic, a mixture of seven probiotic strains plus fructooligosacharide may reduce episodes of viral infection in asthmatic children. [ABSTRACT FROM AUTHOR]