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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, immunological, 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), 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 (due to phenocopies of IEI genes) to discover responsible genes for the immune dysregulation at an early stage of the disease.

Background: Congenital agammaglobulinemia is an inborn error of immunity, resulting in the impairment of effective antibody production. Agammaglobulinemia may be due to X-linked or autosomal genetic abnormalities. The primary defect in X-Linked agammaglobulinemia (XLA) and autosomal recessive agammaglobulinemia (ARAG) is the B cell precursors’ failure to mature B-lymphocytes and, ultimately, plasma cells. This study aims to evaluate the differences in clinical and paraclinical characteristics of XLA and ARAG patients. Method: A total of 58 patients were enrolled in this retrospective study. The data were extracted from the Iranian primary immunodeficiency registry (IPIDR). Forty-eight of the patients were diagnosed with XLA, while the other ten were diagnosed with ARAG. Measures including demographic data, clinical manifestations, and laboratory data of the patients were compared between the groups. Results: Patients with ARAG, presented manifestations at an earlier age and had a lower diagnosis delay compared to XLA patients. However, the mortality rate was not significantly affected. The pattern of organ involvement also differed between the two groups, as patients with ARAG showed manifestations that are more chronic in nature (e.g., autoimmunity, lymphoproliferation, and allergy). In contrast, XLA patients were more prone to infections and other associated complications (e.g., meningitis, sinusitis, diarrhea, and bronchiectasis). Meningitis was exclusively observed in the XLA group. The number of CD19+ B cells was significantly higher in the ARAG group (P=0.002), While the level of IgM was significantly higher in the XLA group (P=0.045). Conclusion: Identifying the clinical presentations of XLA and ARAG, may assist clinicians in early diagnosis in the setting of limited available genetic studies.

By unifying the diagnostic approach in different medical authority levels, the next step will be the improvement of the clinical therapy and follow-up visit schedules in all patients with different types of primary immunodeficiency disorders. Although for some rare genetic diseases, it is more difficult to find a consensus guideline on the precise modalities because many of them need further patients’ cohort with long-term prognostic analysis. However, regarding frequent clinically diagnosed PIDs, including antibody deficiencies and combined immunodeficiencies, the standard therapeutic protocols should be determined and provided accessibility universally. In this chapter we have provided a general insight about main management and therapeutic modalities for immunodeficient patients.

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.

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

Background Advances in the perinatal and neonatal cares have brought about considerable reductions in the neonatal mortality. The present study aimedto determine the disease patterns, outcomes and factors influencing the neonatal mortality in single neonatal intensive care unit. Materials and Methods This descriptive research was retrospective and cross-sectional in type. The study population enrolled all neonates who had been hospitalized in the neonatal intensive care unit (NICU) of the Besat hospital, Hamadan city, Iran, for a period of one year from October 1, 2015 to September 31, 2016 and the mothers and infants information (such as maternal diseases, delivery mode, neonatal age, birth weight, the causes and duration of hospitalization) were extracted from the Medical records and analyzed using SPSS software version 16.0 Results The study population included 600 infants and 13% (78) of whom were died. The results of the multivariate logistic regression analysis for the risk factors associated to the neonatal deaths indicated that there was a significant relationship between neonatal deaths and the use of mechanical ventilation, gastrointestinal bleeding, birth weight less than 2500 grams, positive urine cultures, need for surgery, administration of dopamine, anticonvulsant drugs, and surfactant (P

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

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

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

Introduction: The increased risk for childhood asthma in children suffering from hyperbilirubinemia, and those who underwent phototherapy has attracted enormous interest. Objectives: In this study, we attempted to explain the relationship between childhood asthma and phototherapy. Patients and Methods: This case-control study was performed on children aged between 2 and 14 years old with a definitive diagnosis of childhood asthma. A sex and age-matched group of children without any pieces of evidence, of asthma or other respiratory problems were also selected as the control group. The hospital’s recorded files were the primary sources for the information about demographics, history of asthma in neonates or his/her parents, history and time of phototherapy as well as the data on neonatal hyperbilirubinemia. Results: In total, 69 children who have asthma and 71 non-asthmatic children as the controls were included in this study. Moreover, these two groups were matched for baseline variables. Comparing the history of phototherapy between the asthmatic and non-asthmatic groups showed a higher rate of phototherapy in the former group (37.7% versus 11.3%; P < 0.001). Accordingly, the risk of asthma could be increased according to the history of phototherapy, up to four times (OR = 4.76, 95%CI: 1.97–11.51, P < 0.001). Conclusion: The risk of childhood asthma can increase if a child had the previous phototherapy. This causal effect is independent of the degree or the age of occurring hyperbilirubinemia, which is the main indication for phototherapy.

Background: The prevalence of diabetes mellitus (DM) is increasing worldwide. Thereby, an increasing rate of patients with DM are subjecting to spine surgery. Reviewing the literature, a higher rate of surgery-related complications is reported in DM patients. There is no prospective study comparing the outcomes of lumbar fusion surgery in patients with and without DM. We aimed to investigate whether DM is associated with worse patient-reported outcomes, lower fusion rate, and higher complication rate in subjects undergoing spinal lumbar fusion surgery. Methods: Forty-eight subjects with DM (DM group) and 48 controls (control group) were recruited. Data regarding age, duration of diabetes, comorbidities, fasting blood sugar, HbA1c, insulin dependence, duration of operation and the volume of bleeding, and the number of infused packed cell were recorded for all patients. Pain and functional status of the patients using the visual analogue scale (VAS) and Oswestry Disability Index (ODI) were measured before operation and 2 weeks, 6 months, and 1 year after lumbar spinal fusion surgery. Using lumbar computed tomography scan and anteroposterior and lateral x-ray 1 year after the surgery, fusion was assessed. Results: Fusion rate after 1 year was 78% in the control group and 53% in the DM group (P = .02). Patients with DM had higher VAS scores comparing to controls 1 year after the operation, but the difference was not significant (P = .07). However, comparing the functional status of the subjects, significantly higher ODI scores were found among DM patients comparing to controls (P = .002). Conclusion: Rate of fusion among diabetic patients who undergo lumbar spinal fusion surgery is lower than healthy controls. Spine surgeons should consider this to provide the best possible facilities during the surgery to increase the fusion rate in these patients.

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

Background: The majority of infants and children with cow’s milk allergy will grow out of their allergy after a few years. The aim of this study was to identify the natural course of cow’s milk allergy in infants and children during a follow-up of 18 months and also the predictive factors for its outgrowing. Methods: This prospective cross-sectional study included infants and children with IgE-mediated cow’s milk allergy. Demographic data, clinical manifestations and probable predictive factors were recorded. Skin prick tests were done with commercial extracts of cow’s milk, egg, fish, nuts and wheat on arrival. These infants and children were followed for 18 months and resolution was established by successful ingestion of cow’s milk. The collected data were analyzed using SPSS version 22.0. Descriptive statistics, student’s t-test or Mann-Whitney U-test and Chi-square test were used; a P < 0.05 was considered statistically significant. Results: Forty-nine infants and children (33 boys and 16 girls) with IgE-mediated cow’s milk allergy presentation ranged in age from 3.5 to 48 months with a mean of 17.5 ± 11.7 months enrolled in this study. Skin was the most common site of involvement, followed by gastrointestinal system and respiratory tract. Twenty-three (46) infants and children developed tolerance to cow’s milk during a follow-up of 18 months. There was a significant relationship between parental allergy and atopic dermatitis with the chance of tolerance of cow’s milk. Conclusions: Our findings showed that about one half of the infants and children with IgE-mediated cow’s milk allergy grew out of it over 18 months of follow-up (mean age 2 years). The follow-up of patients with cow’s milk allergy is important in appropriate timing of re-introduction of cow’s milk to the diet; atopic dermatitis and parental allergy can predict this outcome. © 2018, Iranian Journal of Pediatrics.

Polio might not be eradicated unless long-term vaccination with inactivated poliovirus vaccine is implemented., Widespread use of oral poliovirus vaccine has led to an ≈99.9% decrease in global incidence of poliomyelitis (from ≈350,000 cases in 1988 to 74 cases in 2015) and eradication of wild-type poliovirus serotypes 2 and 3. However, patients with primary immunodeficiency might shed vaccine-derived polioviruses (VDPVs) for an extended period, which could pose a major threat to polio eradication programs. Since 1995, sixteen VDPV populations have been isolated from 14 patients with immunodeficiency in Iran. For these patients, vaccine-associated paralysis, mostly in >1 extremity, was the first manifestation of primary immunodeficiency. Seven patients with humoral immunodeficiency cleared VDPV infection more frequently than did 6 patients with combined immunodeficiencies. Our results raise questions about manifestations of VDPVs in immunodeficient patients and the role of cellular immunity against enterovirus infections. On the basis of an association between VDPVs and immunodeficiency, we advocate screening of patients with primary immunodeficiency for shedding of polioviruses.

Small dense low-density lipoprotein (sd-LDL) has been demonstrated to be associated with cardiovascular diseases (CVD). The proposed atherogenic properties of hypoadiponectinemia might be mediated through increased sd-LDL. In this study, the associations of sd-LDL with cardiovascular and other complications of diabetes, and also with plasma levels of adiponectin, were investigated in diabetic patients.173 patients, with documented type 2 diabetes mellitus, were enrolled in this cross-sectional study. Laboratory, anthropometric, and clinical characteristics were all determined. The presence of CVD, hypertention, and microalbuminuria were also evaluated. Homeostasis model assessment of insulin resistance was calculated.Sd-LDL concentrations were significantly lower in patients with CVD than those without CVD (p = 0.020); and also lower in hypertensive patients relative to non-hypertensive ones (p = 0.008). Serum levels of adiponectin were significantly lower in patients with CVD (p0.001), and hypertension (p = 0.002), compared with those without each of these complications. Sd-LDL and adiponectin concentrations were positively correlated (r = 0.36, p0.001). Sd-LDL was also significantly associated with HbA1c (r = 0.24, p = 0.002).Our data suggest that decreased levels of adiponectin might be associated with developing complications of diabetes. This study did not provide any supportive results for the association of increased sd-LDL concentrations with CVD; neither for its association with other complications of diabetes.