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Abstract Introduction Interstitial lung disease (ILD) is a prevalent complication in patients with common variable immunodeficiency (CVID) and is often related to other characteristics such as bronchiectasis and autoimmunity. Because the term ILD encompasses a variety of acute and chronic pulmonary conditions, diagnosis is usually based on imaging features. Histopathology is less available. This study was conducted with the aim of investigating the ILD in patients with CVID. Materials and methods In this retrospective cross-sectional study, sixty CVID patients who referred to the pulmonology and immunodeficiency clinics of Mofid Children’s Hospital between 2013 and 2022 were included. The diagnosis of ILD were based on transbronchial lung biopsy (TBB) or clinical and radiological symptoms. The prevalence of ILD in CVID patients was determined. Also, the CVID patients with and without ILD were compared in terms of demographic characteristics, clinical, laboratory and radiologic findings. Results Among all patients, ten patients had ILD (16.6%). In terms of laboratory parameters, there was a significant difference between platelets in the two groups of CVID patients with and without ILD, and the level of platelets was higher in the group of patients with ILD. Moreover, in terms of clinical symptoms, pneumonia, diarrhea and hepatomegaly were significantly different between the two groups and were statistically higher in the group of patients with ILD (P

Background. Adenosine deaminase deficiency 2 (DADA2) is an autoinflammatory disorder, caused by the CECR1 gene mutation. The major clinical manifestations include recurrent vasculitis, neurological disorders such as stroke, hematologic abnormalities, and immunodeficiency. As reported in previous studies, DADA2 may be manifested by ischemic or hemorrhagic strokes. This disorder also includes various hematological manifestations (pure red cell aplasia, pancytopenia, hemolytic anemia, and pancytopenia with bone marrow involvement). Case Presentation. In this case report, we present the clinical and immunological findings of two unrelated patients with DADA2. The first patient was a 7-year-old female who experienced recurrent neurological symptoms such as vertigo, tinnitus, hearing loss, and right-sided hemiparesis. Her brain magnetic resonance imaging (MRI) revealed a left-sided stroke, and she responded well to antitumor necrosis factor alpha agents and plasmapheresis. The second patient was a 6-year-old female who had recurrent fever and bicytopenia, aphthous lesions, cervical lymphadenopathy, and elevated liver enzymes. We also discussed the strategies used to manage the clinical manifestations in these two DADA2 patients. Conclusion. In this case report, we discussed two cases with DADA2 deficiency and their respective manifestations. The first case showed neurological symptoms while the second case had hematological symptoms. Although there is no established treatment for DADA2 due to its rarity, steroids are commonly used to treat this disorder. Antitumor necrosis factor is also effective in controlling the symptoms, especially the neurological ones. In cases where there is no appropriate response to these treatments, hematopoietic stem cell transplantation can be beneficial.

Abstract Background STAT3 hyperimmunoglobulin E syndrome (STAT3-HIES) also referred to as autosomal dominant HIES (AD-HIES) is an inborn error of immunity characterized by the classic triad of eczema, frequent opportunistic infections, and elevated serum IgE levels. As a consequence of lung sequels due to repeated infections and impaired tissue healing, patients may require interventional pulmonary procedures. Method Four patients with dominant-negative STAT3 mutations who had received interventional pulmonary procedures were enrolled. The demographic, clinical, and molecular characteristics were gathered through a medical record search. All reported STAT3-HIES patients in the literature requiring pulmonary procedures as part of their treatment were reviewed. Result Recurrent episodes of pneumonia and lung abscess were the most prevalent symptoms. The most common non-immunological features were scoliosis, failure to thrive, and dental problems such as primary teeth retention and disseminated decays. Bronchiectasis, lung abscess, pneumatocele, and cavitary lesion were the most prevalent finding on high-resolution computed tomography at the earliest recording. All patients underwent pulmonary surgery and two of them experienced complications. Conclusion Patients with STAT3-HIES have marked pulmonary infection susceptibility which may necessitate thoracic surgeries. Since surgical procedures involve a high risk of complication, surgical options are recommended to be utilized only in cases of drug resistance or emergencies.

Abstract Background Primary immunodeficiencies are immunological disorders caused by gene mutations involved in immune system development and activation. Recently, activated phosphoinositide 3-kinase delta syndrome (APDS) due to mutations in the phosphoinositide 3-kinase (PI3K), phosphatidylinositol-4, 5-bisphosphate 3-kinase, catalytic subunit delta gene (PIK3CD), and phosphoinositide 3-kinase regulatory subunit 1 (PIK3R1) genes have been reported to induce a combined immunodeficiency syndrome leading to senescent T cells, lymphadenopathy, and immunodeficiency. The exact diagnosis of these deficiencies is essential for treatment and prognosis. In recent years, targeted treatment with selective PI3Kd inhibitors has had a significant effect on controlling the symptoms of these patients. Case presentation In this case report, we represent a 27-month-old girl with recurrent fever, an increased level of inflammatory markers, and erythema nodosum, who was referred to the rheumatology clinic. In the course of evaluations, because of the lack of clinical improvement with usual treatments, and a history of frequent respiratory infections, combined immunodeficiency was diagnosed in the immunological investigations. Moreover, whole-exome sequencing was performed for her. Conclusion The genetic analysis found a novel variant of PIK3CD (c.1429 G > A) in the patient. Following daily antibiotic prophylaxis and monthly IV therapy, the patient’s frequent infections and fevers were controlled.

Abstract Objectives Inborn errors of immunity (IEIs) are monogenic diseases of the immune system. Despite the increasing genetic advancements, the diagnosis of IEIs still lean on clinical diagnosis. Dermatological manifestations are observed in a large number of IEI patients and can lead to proper approach and prompt intervention. Methods This cross‐sectional study was carried out between 2018 and 2020 on IEIs at a Children's tertiary care center in Tehran, Iran. Demographic details and age at onset of symptoms of IEI were recorded. Results Overall, 212 patients were included. Cutaneous findings were reported in 95 (44.8%) patients, and 61 of 95 (64.2%) reported skin lesions as the first clinical presentation. Skin infection (69, 72.6%) was the most frequent cutaneous manifestation, followed by eczematous rash (24, 25%). Conclusions Skin manifestations are a common feature in IEI patients and are readily recognizable by healthcare providers. This study tried to provide information on prognostic consequences.

Abstract Background Interferon-gamma receptor deficiency is a heterogeneous spectrum of disease which involves mutations in IFNGR1, IFNGR2 genes, and the downstream signaling proteins such as STAT1. These mutations are associated with immunodeficiency 27 A and 27B, making the patient prone to mycobacterial infections. Patients with this condition are also at increased risk for affliction with viral and bacterial infections, such as with the Herpesviridae family, Listeria, and Salmonella. Moreover, SH2B3 mutation is associated with autoimmune and lymphoproliferative conditions. Case presentation the patient was a 19-month-old infant girl who presented with a two-week history of fever. She had near-normal flowcytometry with high IgM and IgE. She had pneumonic infiltration in her chest and right hilar and para-aortic lymphadenopathy. PCR of whole blood for Aspergillus fumigatus came back positive. In her Whole Exome Sequencing she had IFNGR1 and SH2B3 mutations. Conclusion systemic fungal infections such as Aspergillosis can occur in patients with interferon-gamma receptor one deficiency. This type of immunodeficiency should be considered in treating patients with systemic Aspergillosis.

Abstract Jagunal homolog 1 (JAGN1) has been recognized as an essential protein in neutrophil function. The mutated JAGN1 is responsible for immunodeficiency related to innate and humoral defense mechanisms. This deficiency impairs neutrophil development and function, leading to recurrent infections and facial dysmorphism as phenotypic consequences of severe congenital neutropenia (SCN). We report two siblings having the reported JAGN1 mutation with different clinical manifestations. Recurrent abscess formation unresponsive to antibiotic therapy, a history of delayed umbilical separation, frequent bacterial or fungal infection, dysmorphic face, failure to thrive, and other coexisting organ abnormalities should prompt physicians to syndromic immunodeficiencies involving neutrophils. Genetic investigations to elucidate the responsible mutation is critical as clinical management varies. Once the diagnosis is confirmed, a multi-disciplinary team should perform further workups to investigate other coexisting malformations and neurodevelopmental evaluation.

Abstract Background DCLRE1C gene mutation leads to Artemis deficiency, a severe form of combined immunodeficiency (SCID). Impaired DNA repair and block in early adaptive immunity maturation results in T-B-NK+ immunodeficiency associated with radiosensitivity. Recurrent infections early in life are the main characteristic of Artemis patients. Method Among 5373 registered patients, 9 Iranian patients (33.3% female) with confirmed DCLRE1C mutation were identified since 1999–2022. The demographic, clinical, immunological and genetic features were collected through retrospective investigation of medical records and using next generation sequencing. Results Seven patients were born in a consanguineous family (77.8%). The median age of onset was 6.0 (5.0–17.0) months. Severe combined immunodeficiency (SCID) was clinically detected at a median (IQR) age of 7.0 (6.0–20.5) months, following a median diagnostic delay of 2.0 (1.0–3.5) months The most typical first presentation was pneumonia (44.4%) and otitis media (3.33%), followed by BCG lymphadenitis (22.2%) and gastroenteritis (11.1%). The most prevalent manifestations were respiratory tract infections (including otitis media) (66.6%) and chronic diarrhea (66.6%). In addition, juvenile idiopathic arthritis (P5) and celiac disease and idiopathic thrombocytopenic purpura (P9) as autoimmune disorders were reported in 2 patients. All patients had reduced B CD19+ and CD4+ cell counts. IgA deficiency occurred in 77.8% of individuals. Conclusion Recurrent infections particulary respiratory tract infection and chronic diarrhea during the first months of life in patients born to consanguineous parents should raise the suspicion for inborn errors of immunity, even in the presence of normal growth and development.

Primary immunodeficiencies are a diverse group of rare genetic disorders, among which phagocytic dysfunction impairs neutrophil function in a wide range of inherited disorders. Due to the heterogeneity of the disorders a multidisciplinary approach is often required for early diagnosis and initiation of appropriate treatments. The aim of this study was to evaluate the imaging findings in children admitted with phagocytic primary immunodeficiencies. Thirty-five children who fulfilled the inclusion criteria for phagocytic dysfunction were enrolled in this study. The patients were under close observation and monitoring from January 2011 until data locking in December 2017. The diagnosis of phagocytic immunodeficiency was confirmed by the patient’s clinical course, presentation features, and laboratory data. Among the 35 patients studied, the most frequent condition was chronic granulomatous disease (CGD) (23 patients), followed by different types of neutropenia (8 patients) and Job’s syndrome (4 patients). Mediastinal and hilar lymphadenopathies and consolidation were the most frequent presentations. There was a significant relationship between mediastinal/hilar lymphadenopathies and fungal infections. A meaningful relationship was also found between pulmonary nodules without halo signs in patients with concomitant tuberculosis and fungal infections. A significant correlation was found between CGD, pulmonary fibrotic changes, and mediastinal lymphadenopathies. The most frequent radiological manifestations in children included mediastinal and hilar consolidations. Physicians’ awareness of the radiological and clinical manifestations of these inherited diseases may be helpful in the early diagnosis and timely initiation of specific prophylaxis measures to prevent infections and also to initiate hematopoietic stem cell transplantation as the curative management modality.

Abstract Background Bullous pemphigoid is the most common autoimmune subepidermal blistering disorder with a low incidence in childhood. Combined immunodeficiencies (CIDs) are a group of monogenic inborn errors of immunity (IEIs) characterized by T- and B-cell dysfunction leading to recurrent infections, lymphoproliferation, predisposition to malignancy, and autoimmunity. Here, we report two Afghan siblings with a diagnosis of CID and extremely rare manifestation of diffuse bullous pemphigoid skin lesions. Case presentation The older sibling (patient 1) was a 32-month-old male with facial dysmorphism, protracted diarrhea, failure to thrive, recurrent oral candidiasis, recurrent otitis media with tympanic membrane perforation, who had been previously diagnosed with CID. While he was under treatment with intravenous immunoglobulin (IVIg), he developed extensive blistering lesions, which were diagnosed as childhood bullous pemphigoid. Methylprednisolone and azathioprine were added to the regimen, which resulted in a remarkable improvement of the skin lesions and also the feeding condition. However,2 weeks later, he was re-admitted to the intensive care unit (ICU) and eventually died due to fulminant sepsis. Later, his 12-month-old sister (patient 2) with similar facial dysmorphism and a history of developmental delay, food allergy, recurrent oral candidiasis, and respiratory tract infections also developed blistering skin lesions. She was under treatment for occasional eczematous lesions, and had been receiving IVIg for 3 months due to low levels of immunoglobulins. Further immunologic workup showed an underlying CID and thus treatment with IVIg continued, gradually improving her clinical condition. The genetic study of both siblings revealed a novel homozygous mutation in exon 7 of the PGM3 gene, c.845 T > C (p.Val282Ala). Conclusions Dermatologic disorders may be the presenting sign in patients with CID and mutated PGM3. This case report further extends the spectrum of skin manifestations that could be observed in PGM3 deficiency and emphasizes the importance of considering CIDs during the assessment of skin disorders, particularly if they are extensive, recurrent, refractory to treatment, and/or associated with other signs of IEIs.

Abstract Genetic defects in the development, maturation, and/or function of the immune cells can lead to Inborn errors of immunity (IEI) which may predispose patients to malignancies. The overall risk for cancer in children with IEI ranges from 4 to 25% and the type of malignancy is highly dependent on the specific mutant gene underlying IEI. We investigated 3056 IEI patients registered in the Iranian national registry between the years 1999 and 2020 in this retrospective cohort study. The frequency of malignancy and its association with the type of IEI in these patients were evaluated. A total of 82 IEI patients with malignancy were enrolled in this study. Among them, predominantly lymphoma was the most common type of malignancy (67.1%), followed by leukemia (11%), and cancers of the head and neck (7.3%). Among identified lymphoma cancers, non-Hodgkin’s lymphomas were the most frequent type (43.9%) followed by different subtypes of Hodgkin’s lymphoma (23.2%). Solid tumors (18.3%) appeared to be very heterogeneous by type and localization. The correlation between the type of malignancy and survival status and the association between the type of malignancy and IEI entities were unremarkable. The awareness of the association between the presence of IEI and cancer highlights the importance of a synergistic effort by oncologists and immunologists in the early diagnosis of malignancy and personalized therapeutic strategies in IEI patients.

Emerging SARS-CoV-2 variants of concern (VOCs) raises concerns regarding vaccine efficacy. Here, the authors evaluate the neutralizing antibody, and cellular response elicited following inactivated vaccine immunization, and mRNA booster, against the Omicron variant.

CD27 is a costimulatory receptor involved in the maturation of the innate and adaptive immunity. CD27, through interaction with CD70, plays a role in the control of Epstein-Barr virus (EBV) infection. CD27 deficiency leads to an immune dysregulation disease characterized by EBV susceptibility. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) might put patients with primary immunodeficiency at risk for adverse outcomes. Chromogenic in situ hybridization (CISH) study was performed to detect EBV in the lymphoma tissue. Genetic analysis of the patient was done with Whole Exome Sequencing and detected variant was confirmed with PCR-Sanger sequencing. Here we report a 20-month-old boy with CD27 deficiency who developed lymphoma and coronary artery ectasia and had been infected with SARS-CoV-2. Clinical and laboratory findings were incompatible with atypical Kawasaki syndrome or multisystem inflammatory syndrome in children (MIS-C). As CD27 deficiency is a rare immune defect, publishing clinical data about the identified patient(s) can shed light on our knowledge about the related phenotype and the spectrum of clinical manifestations associated with CD27 deficiency. Thus, our findings expanded the spectrum of manifestations beyond EBV infection, highlighting this unusual cardiac sequela that could be related to EBV infection, lymphoma, or an underlying disease.

BackgroundCombined immune deficiencies (CIDs) with associated or syndromic features are a highly heterogeneous subgroup of inherited immune disorders. These patients represent specific clinical complications with an increased risk of autoimmune conditions.MethodsWe analyzed data of monogenic patients with syndromic CIDs adopted from the Iranian inborn errors of immunity registry up to January 2022. A comprehensive comparison in terms of demographic, clinical, and immunological features was performed between patients with and without autoimmunity and also among four mutation groups with the most registered cases including ATM, STAT3 (AD-LOF), DNMT3B/ZBTB24, and WAS mutations.ResultsA total of 137 patients with monogenic syndromic CIDs were included. Most commonly mutated genes were the ATM [80 (58.4%)] and STAT3 (AD-LOF) [19 (13.9%)], followed by DNMT3B [11 (8%)], and WAS [11 (8%)]. More than 18% of all patients with syndromic CIDs, including most DNMT3B/ZBTB24 mutations patients, were clinically diagnosed with antibody deficiencies before genetic evaluation. Patients with ATM and WAS mutations had the latest age of onset and the lowest age of diagnosis, respectively. Autoimmune disorders were diagnosed in 24 patients at a median age of 3.5 (2.6-6.0) years, 70.6% of which were diagnosed prior to the diagnosis of immunodeficiency. Lymphoproliferation, particularly hepatosplenomegaly, was significantly higher in patients with autoimmunity (p=0.004). Syndromic CID patients with autoimmunity had significantly lower IgG levels. Hematologic autoimmunity mainly immune thrombocytopenic purpura was the most frequent autoimmunity among major groups of ATM, STAT3 (AD-LOF), DNMT3B/ZBTB24, and WAS mutations, however ATM-mutated patients present more diversified involved organs including rheumatologic, gastrointestinal and dermatologic autoimmunity.ConclusionAbout 18% of patients with monogenic syndromic CIDs developed autoimmunity, mainly in the form of hematological immune diseases. Autoimmunity could be an early-onset involvement with a potential diagnostic impact on suspicious cases of syndromic CIDs.

Abstract Background Defective Cernunnos gene in nonhomologous end‐joining (NHEJ) pathway of the DNA repair is responsible for radiosensitive severe combined immunodeficiency (SCID). Herein, presented a new patient with Cernunnos deficiency and summarized the clinical, immunological, and molecular features of reported patients in the literature. Case The patient was a 6‐month‐old female born to consanguineous parents. She presented with long‐lasting fever, diarrhea, poor feeding, and restlessness. She had suffered from recurrent fever of unknown origin and multiple episodes of oral candidiasis. In the physical examination, microcephaly, failure to thrive, oral candidiasis, pustular rash on fingers, and perianal ulcers, but no dysmorphic feature were observed. The immunologic workup revealed lymphopenia, neutropenia, normocytic anemia, low T‐ but normal B‐ and natural killer (NK)‐ cells, low immunoglobulin (Ig)G, and normal IgA, IgM, and IgE. The T‐cell receptor excision circle (TREC) was low and the lymphocyte transformation test (LTT) was abnormal to mitogens and antigens. She was diagnosed with T− B+ NK+ SCID and improved by intravenous immunoglobulin along with antimicrobials. A homozygous splice site variant, c.390 + 1G > T, at the intron 3 of the NHEJ1, was identified and the diagnosis of Cernunnos deficiency was established. However, while a candidate for hematopoietic stem cell transplantation, she developed sepsis and died at 11 months of age. Conclusions Cernunnos deficiency should be considered as a differential diagnosis in patients with microcephaly, growth retardation, recurrent infections, T‐cell defects, and hypogammaglobulinemia. The normal B‐cell level in the index patient is an unexpected finding in Cernunnos deficiency which requires further evaluation.

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.

Respiratory diseases are considered as significant causes of morbidity and mortality in primary immunodeficiencies. This study aimed to reveal the radiologic patterns of thoracic involvement in these disorders. A total of 58 patients, including 38 cases with combined cellular-humoral and 20 cases with humoral immunodeficiencies, were enrolled in this study. The “combined” group consisted of 12 cases with severe combined immunodeficiency (SCID) and 26 cases with combined immunodeficiency. The “humoral” group included seven patients with Hyper IgM syndrome (HIGMs), seven cases with common variable immunodeficiency (CVID), three patients with X-linked agammaglobulinemia, and three patients with other types of humoral primary immunodeficiencies (PIDs). The mean age of patients at the time of evaluation was 3.3±3.8 and 5.3±3.9 years in combined and humoral groups, respectively. The findings of chest X-rays and CT scans were interpreted and compared. There was a significant difference for alveolar opacification between combined and humoral immunodeficiencies (58% vs. 30%). The bronchopneumonia-like pattern was detected as a significant finding in patients with SCID (42%) and HIGMs (43%). Atrophy of the thymus was detected significantly often in cases of SCID (67%). Two patients with CVID and lipopolysaccharide-responsive and beige-like anchor protein deficiency showed parenchymal changes of granulomatous lymphocytic interstitial lung disease. No significant difference was detected for bronchiectasis, bronchitis/bronchiolitis patterns, pleural effusion, and thoracic lymphadenopathy. Distinct subtypes of primary immunodeficiency may provoke differing and comparable radiological patterns of thoracic involvement; which can clue the clinician and radiologist to the diagnosis of the disease.

Combined Immunodeficiency (CID) is a group of inborn error of Immunity (IEI) that may present with both infectious and non-infectious complications. Autoimmunity is an unusual presentation of CID and can be presented as cytopenia. The initial management of cytopenia is corticosteroids and IVIG. The role of other cytotoxic and immunosuppressive drugs in management of cytopenia is not fully understood. The objective of this clinical case report is to highlight the possibly beneficial role of cyclosporine in controlling cytopenia in CID patients. A 26-month-old child with generalized ecchymosis was referred to Mofid Children's Hospital in Tehran, Iran. Physical examination revealed no substantial findings other than ecchymosis, and complete blood count (CBC) revealed thrombocytopenia. Diagnosis of CID and cytopenia followed. The patient was treated by 5 times prednisolone and 4 times Rituximab. Finally, his ecchymosis was controlled by Cellcept, which was then tempered and substituted by cyclosporine. [ABSTRACT FROM AUTHOR]