Keeping up with recent developments in immunodeficiency.

Conflicts of Interests: EYW receives consulting and speaker fees from Pharming Healthcare, Inc. regarding their work on the medication leniolisib approved for activated PI3 kinase delta syndrome (APDS). The remaining authors AHS and MK declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.The number of inborn errors of immunity (IEI) is growing rapidly (1). They can be challenging to diagnose given the expanding and variable clinical phenotypes (2,3). Specifically, there is an increasing recognition that immune dysregulation can be an initial or predominant manifestation of a substantive portion of IEIs (4,5). Immune dysregulation can also have a large impact on disease treatment, monitoring, and outcomes. Significant progress has been made in the elucidation of molecular and cellular mechanisms underlying the immune dysregulation of IEIs. Tremendous improvement has also been made in the management of IEIs with availability of therapies expanding to include biologics and small molecular inhibitors. Despite progress, more understanding is needed to tailor the use of immunomodulatory therapy in IEIs. This Research Topic "Immune Dysregulation in Inborn Errors of Immunity" highlights recent advances in the understanding of the prevalence, mechanisms, spectrum of manifestations, and management of immune dysregulation in IEIs. Gagne et al. provide a concise review of how Mendelian type I interferonopathies can masquerade as non-Mendelian autoimmune disorders like systemic lupus erythematosus (SLE) and dermatomyositis, which are also associated with increased type I interferon (IFN) expression. Similarly, Hetrick et al. described how autoinflammatory bone disorders characterized by sterile osteomyelitis can be seen with both monogenic forms including Majeed syndrome and deficiency of the interleukin-1 antagonist (DIRA) and the more common sporadic form chronic nonbacterial osteomyelitis (CNO) or chronic recurrent multifocal osteomyelitis (CRMO). Other autoimmune manifestations of IEIs include, but are not limited to, autoimmune cytopenia, endocrinopathies, inflammatory bowel disease, neutrophilic dermatoses, arthritis, and vasculitis as illustrated by the case of activated phosphoinositide 3-kinase delta (PI3Kd) syndrome (APDS) from Sood et al.The highly variable clinical manifestations of IEIs can contribute to diagnostic delays, which in turn, can lead to poorer outcomes. Autoimmunity and autoinflammation can negatively impact morbidity and mortality and are an independent prognostic factor for death among individuals with IEIs (5). Immune dysregulation may also contribute to the increased risk of malignancy observed in IEIs as with the APDS case presented by Sood et al.Improving awareness and early recognition of IEIs is also critical because making a diagnosis can impact treatment and surveillance. There may be disease-specific treatments available like leniolisib, an oral selective PI3Kd inhibitor, for APDS as discussed by Sood et al. Because type 1 IFN work through the janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway, Gagne et al. also consider the increasing use of JAK inhibition in autoinflammatory IFN-mediated monogenic diseases. The study by Berrueco et al. showed mycophenolate mofetil may be an effective and safe treatment for pediatric patients with autoimmune cytopenia and IEI, even cases of autoimmune cytopenia refractory to first-line therapies like corticosteroids and intravenous immunoglobulin (IVIG).These articles also nicely illustrate the need for a multidisciplinary approach to the immune dysregulatory manifestations in IEIs as there are contributions from Rheumatology (inteferonopathies and pediatric autoinflammatory bone disorders), Hematology (autoimmune cytopenias), and Allergy/Immunology (APDS). The conditions covered in this topic represent only a fraction of disordered immune conditions in IEIs and should be considered in more detail in the future.The recognition of immune dysregulation in IEIs continues to increase as the number of patients impacted expands. There is a clear need for ongoing investigation into the epidemiology and pathophysiology for clinical manifestations and the risk factors for developing immune dysregulation as well as a collaborative multidisciplinary approach to improve diagnosis and management of this population. Our hope is that this topic has piqued the interest of researchers and clinicians in this area to provide better understanding, care, and outcomes to these patients.Lastly, we would like to thank the reviewers for their time and valuable assessments. This important collection of articles would not be possible without their contributions.

The aim of this study was to screen for inborn errors of immunity (IEIs) within a pediatric critical care population and further evaluate the mortality-related factors.This study included 1203 pediatric patients aged between 1 month and 18 years admitted to the pediatric intensive care unit (PICU) at Antalya Education and Research Hospital (in Turkey) between January 2020 and December 2022. Patients with chronic diseases, ongoing chronic medication regimens, other known comorbidities, traumas, postsurgical cases, poisonings, and preexisting IEI diagnoses were excluded.In this single-center prospective study, a total of 28 warning signs for IEI diagnosis were applied, including 10 per the Jeffery Modell Foundation (JMF) and 18 per literature review. Patients with severe illness requiring intensive care and at least 1 IEI warning sign were evaluated. These patients underwent standardized immunological screening, then those with abnormal findings had an extended immunologic assessment including functional analyses. Genetic analyses were conducted on those with abnormal findings concerning for IEI. Diagnoses of IEI were established using the European Society for Immunodeficiencies criteria and further categorized based on the International Union of Immunological Societies classification.Of the 1203 patients admitted to the PICU, 75 (6.2%) patients had at least 1 IEI warning sign and no exclusionary diagnoses. This study found a 4.3% confirmed IEI prevalence rate in the PICU during the 3-year study period. More than half (51.5%) of these patients presented with sepsis, 36.4% with acute respiratory failure, and 12.1% with neuroinflammatory disorders. The median age was 16 months, and there was a male predominance (60.6%). Consanguinity was present in 66.7% of the patients. History of severe viral infections was the most common IEI warning sign (61%), followed by life-threatening infections (51.7%), sibling/cousin death (25%), and a history of more than 2 episodes of pneumonia per year (22.5%). Only 31% of patients had 2 or more of the JMF warning signs. Regarding types of IEIs identified, nearly half (48.5%) were diagnosed with an immune dysregulation disorder, with the most prominent IEI diagnosis being hemophagocytic lymphohistiocytosis. Combined immunodeficiencies were also commonly identified (24.2%), followed by defects in innate immunity (15.2%) and predominant antibody deficiencies (6.1%). Genetic testing was performed on 78.8% (26/33) of patients with an IEI diagnosis. Among the 33 patients with confirmed IEI, the mortality rate was 58%.Patients with IEI can present critically ill without classic warning signs and have a high mortality rate. This highlights the need for systematic screening to reach early diagnosis and treatment, especially in critically ill children.This study highlights a significant yet underrecognized prevalence of IEI in PICUs. The identification of IEI in nearly 1 in 20 critically ill children and reported high mortality rate of 58% emphasizes the need for earlier screening and detection with targeted immunologic/genetic evaluation. The study also found that only 31% of patients exhibited 2 or more JMF warning signs, suggesting a need for wider criteria, especially in the PICU. Limitations of the study include a single-center study in a country with high consanguinity, thus limiting generalizability. There was a small sample size of only 33 patients with new IEI diagnosis, and data were limited to their hospitalization without long-term follow-up related to mortality. Despite these limitations, this study reinforces that IEIs are more common than traditionally thought and general pediatricians, as well as PICU specialists, have a critical role in early suspicion, diagnosis, and seeking immunology consultation to reduce mortality and long-term morbidity.

Introduction NFATC2 encodes the nuclear factor of activated T cells 2, a transcription factor essential for T cell activation, cytokine gene expression, and the maintenance of immune tolerance. Germline variants in NFATC2 have recently been implicated in a spectrum of inborn error of immunity (IEI) marked by combined immunodeficiency and immune dysregulation. Case Presentations We report two unrelated patients with recurrent and severe infections, atopy, and autoimmunity. Patient 1 A 21-year-old female presented with a history of viral meningitis, severe atopic dermatitis, asthma, and multiple recurrent infections. Immunological workup revealed markedly elevated serum IgE levels (5,780 IU/mL) and a reduced circulating Th17 cells. Genetic testing identified compound heterozygous variants in NFATC2 : c.677T>A (p.Leu226His) and c.1952G>A (p.Arg651His), affecting conserved regions involved in DNA binding and transcriptional activity. Patient 2 A 62-year-old woman with a history of recurrent otitis media and cutaneous abscesses since childhood, as well as bone marrow dysplasia and autoimmune hypothyroidism. Immunological evaluation revealed persistently elevated serum IgM levels, decreased naïve B cell counts, and the presence of antineutrophil cytoplasmic antibodies (ANCA). Genetic analysis revealed compound heterozygous variants c.1282G>C (p.Gly428Arg) and c.2462G>A (p.Arg821His), also located in functional domains of NFATC2. Discussion Both cases demonstrate overlapping features with immune dysregulation and susceptibility to infections, consistent with impaired NFATC2 function. The identified compound heterozygous variants in NFATC2 affect highly conserved residues located within functional domains involved in DNA binding and transcriptional activation, and are predicted to impair protein function. Although functional validation is pending, the consistency between the immunophenotypes and the known biology of NFATC2 strongly supports their pathogenicity. Conclusion Compound heterozygous NFATC2 variants may underlie a distinct IEI phenotype. Early recognition is essential to guide immunologic assessment, genetic counseling, and consideration of targeted therapies.

ABSTRACTHuman inborn errors of immunity (IEI) represent a diverse group of genetic disorders affecting the innate and/or adaptive immune system. Some IEI entities comprise defects in DNA repair factors, resulting in (severe) combined immunodeficiencies, bone marrow failure, predisposition to malignancies, and potentially result in radiosensitivity (RS). While other IEI subcategories such as common variable immunodeficiency (CVID) and immune dysregulation disorders also associate with lymphoproliferative and malignant complications, the occurrence of RS phenotypes in the broader IEI population is not well characterized. Nonetheless, identifying RS in IEI patients through functional testing is crucial to reconsider radiation-related therapeutic protocols and to improve overall patient management. This study aimed to investigate chromosomal RS in a diverse cohort of 107 IEI patients using the G0 cytokinesis-block micronucleus (MN) assay. Our findings indicate significant variability in RS across specific genetic and phenotypical subgroups. Severe RS was detected in all ataxia-telangiectasia (AT) patients, a FANCI deficient and ERCC6L2 deficient patient, but not in any other IEI patient included in this cohort. Age emerged as the single influencing factor for both spontaneous and radiation-induced MN yields, while the manifestation of additional clinical features, including infection susceptibility, immune dysregulation, or malignancies did not associate with increased MN levels. Our extensive analysis of RS in the IEI population underscores the clinical importance of RS assessment in AT patients and supports RS testing in all IEI patients suspected of having a DNA repair disorder associated with radiosensitivity.

Objective: Inborn errors of immunity (IEIs) comprise a genetically heterogeneous group of disorders predisposing individuals to recurrent and severe infections, autoimmunity, and immune dysregulation. Next-generation sequencing (NGS) has greatly improved diagnostic efficiency by allowing simultaneous analysis of multiple genes. This study aimed to evaluate the molecular diagnostic yield and characterize the variant spectrum in patients with suspected IEIs using a targeted NGS panel. Methods: A total of 101 pediatric patients clinically diagnosed with IEIs and referred to the Pediatric Genetics Department Ümraniye Training and Research Hospital between 2018 and 2021 were included in the study. Genetic analysis was performed using a targeted NGS panel encompassing 260 genes associated with IEIs. Variants were interpreted according to American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) and Clinical Genome (ClinGen) Sequence Variant Interpretation (SVI) guidelines. Single-nucleotide variants (SNVs) were confirmed by Sanger sequencing, and copy number variants (CNVs) were validated using array-based comparative genomic hybridization (array-CGH). Results: Pathogenic or likely pathogenic (P/LP) variants were identified in 25 of 101 patients (24.7%), yielding 26 distinct variants across 21 genes, including one patient with two variants in a compound heterozygous state. Among these, 18 were homozygous, 3 heterozygous, 3 hemizygous, and 1 compound heterozygous. The most frequently affected genes were RAG1, DCLRE1C, SPINK5, and STAT1. Three novel variants were identified, expanding the known mutational spectrum of IEIs. In addition, several variants initially identified in this cohort were later reported by our group, highlighting the contribution of our study to the expanding genetic spectrum of IEIs in Türkiye. Most variants exhibited autosomal recessive inheritance, consistent with the high consanguinity rate in the study population. Conclusion: In our IEI cohort, targeted NGS achieved a 24.7% molecular diagnostic yield and successfully identified both known and novel pathogenic variants across a broad spectrum of genes. These findings highlight the diagnostic value of targeted NGS in genetically and clinically heterogeneous conditions such as IEIs and underscore the importance of population-specific variant databases for improving variant interpretation and optimizing patient care.

Inborn errors of immunity (IEIs) are a heterogeneous group of disorders, genetically diverse but phenotypically overlapping. Over 500 IEI-related genes have been identified. Next generation sequencing (NGS) enables the simultaneous evaluation of a large number of genes in multiple patients in parallel. Since 2017, in our setting, custom IEI panels have been useful mainly for patients displaying clinical phenotypes of immune dysregulation and autoinflammatory disorders. Our aim is to evaluate the performance of targeted NGS panels based on International Union of Immunological Societies (IUIS) gene categories by examining how many patients achieved a conclusive diagnosis. A retrospective analysis was performed on 361 index cases submitted to four chronologically successive targeted NGS custom panels. The first panel included 124 IUIS genes, most of them related to autoimmune and immune dysregulation disease categories. The second panel contained 143 IUIS genes, including defects of innate immunity. The third and fourth, large panels covering 314 and 325 IUIS genes, respectively, included/comprised the majority of IUIS disease categories, with focus on autoinflammatory, immune dysregulation, and intrinsic immunity disease categories. From a total of 361 samples studied, 264 were referred due to clinical suspicion of immune dysregulation, autoinflammatory disease, or defects in innate immunity. Twenty-three percent of them (61/264) achieved a confirmed or highly probable genetic etiology. According to the main IEI IUIS disease categories included in targeted panels, immune dysregulation represented 26% (32/123) of these diagnoses, autoinflammatory disorders 21% (18/85), and defects in innate immunity 19% (11/56). In the remaining patients studied, 42% (41/97) of them achieved a conclusive diagnosis in others IEI IUIS disease categories. The NGS approach demonstrated the expected IEI diagnostic rate. The strategy of designing panels oriented toward IEI disease categories that present the greatest variability in clinical presentations with overlapping phenotypes proved to be effective regarding achievement of conclusive diagnoses in our cohort.

Mortality rate and causes of death in inborn errors of immunity: A systematic review and meta-analysis.

Inborn Errors of Immunity (IEIs) are rare genetic disorders that cause immunodeficiency. Diagnosis and classification of these disorders are challenging due to the heterogeneous clinical manifestations and genetic mutations. This is the first study to fully describe the spectrum of gene mutations and genetic diversity of IEIs in Vietnamese pediatric patients. A cross-sectional study was conducted on pediatric patients diagnosed with IEIs at Children’s Hospital 1, Vietnam, from 2014 to 2024. Ninety-two patients with identified mutations were enrolled. Genetic testing was performed using Sanger, fluorescence in situ hybridization, and whole exome sequencing to identify pathogenic variants. Clinical and epidemiological data were collected from medical records and mutations were classified according to the IUIS 2024 classification. The study identified 99 mutations in 33 different genes, with X-linked inheritance being predominant (53.2%). The antibody deficiency and immune dysregulation groups were the most common (22.8% for each mutation). Nineteen novel mutations were identified, all of which were predictively classified as pathogenic or likely pathogenic. The majority of mutations caused protein truncations, leading to loss of function, especially in the immunodeficiencies affecting cellular and humoral immunity and the phagocyte disorder groups. Clinical manifestations differed markedly between the different gene groups, highlighting the complexity of diagnosing IEIs. The number of cases with mutations causing X-linked inheritance was dominant, which was similar to studies from Asian countries, though different from studies from Africa due to the rates of consanguineous marriage. In addition, the variability between clinical phenotype and genotype in IEIs noted from our study has been a significant obstacle to the classification of diseases and their efficient treatment. This is the largest single center cohort to date in Vietnam to describe gene mutations in children with IEIs. The results of the study emphasize the importance of genetic testing in the diagnosis and treatment of IEIs, and open possible directions for further research for novel mutations.

Inborn errors of immunity (IEIs) are a heterogeneous group of germline disorders whose recognition is increasing but which remain underdiagnosed and associated with significant pediatric morbidity and mortality. This review aims to systematize the main neuroimaging manifestations of IEIs, addressing how neuroradiologists can identify characteristic patterns to support earlier diagnosis and guide clinical management. A narrative review of IEIs with neurological involvement was performed, focusing on reported primary and secondary neuroimaging features across major IEI categories. Imaging findings were correlated with underlying immune defects, typical clinical phenotypes, and their impact on diagnostic workup, risk assessment, and genetic counseling. IEIs demonstrate a broad neurological spectrum that extends beyond recurrent infections to encompass autoinflammatory, autoimmune, allergic, and malignant phenotypes with central nervous system involvement. Neuroimaging reveals both primary manifestations directly related to immune dysregulation and secondary features, allowing recognition of patterns in IEI subgroups that can provide crucial diagnostic clues in otherwise non-specific clinical scenarios. Neurological involvement in IEIs is not uncommon and may be radiologically detectable, making imaging an important ancillary tool in their evaluation. Systematic recognition of primary and secondary neuroimaging features by neuroradiologists can raise suspicion for an underlying IEI, prompting appropriate immunologic and genetic work-up. Earlier diagnosis is crucial to enable timely implementation of preventive or targeted therapies, with the potential to improve long-term outcomes.

ObjectiveIn this study, we analyzed a large cohort of Algerian patients with inborn errors of immunity (IEI) to delineate the burden, spectrum, and distribution of autoimmune and autoinflammatory manifestations.MethodsThis retrospective cohort study was based on recorded data from 825 Algerian patients with IEI. For each patient, autoimmune and autoinflammatory complications occurring before and/or after IEI diagnosis were systematically assessed and documented.ResultsAutoimmune and/or autoinflammatory manifestations were observed in 217 patients (26.3%) and, notably, represented the initial clinical presentation in nearly half. Autoimmune features were documented in 163 patients (19.8%), including 26 (3.2%) with concurrent autoinflammatory findings, whereas isolated autoinflammatory conditions were observed in 54 patients (6.5%). A broad spectrum was observed, with autoimmune cytopenias predominating (11.4%), followed by gastrointestinal (7.8%), rheumatologic (5.3%), and endocrine (3.4%) disorders. Immune dysregulation was a recurrent theme across all IEI categories, with a distinct, disease-specific, clustering of autoimmunity and autoinflammation. Autoimmune cytopenias predominated in T-cell defects, including hypomorphic RAG and CD3γ deficiencies; Inflammatory bowel disease (IBD) was enriched in ARPC1B, DOCK8, and CD55 deficiencies, as well as in chronic granulomatous disease (CGD); endocrine autoimmunity, while a cardinal feature of APECED and IPEX, also characterized STAT1 gain-of-function; inflammatory granulomatous lung disease was a consistent feature in LRBA deficiency; and granulomatous inflammation, whether confined to the lungs or extending to other organs, was prominent in common variable immunodeficiency.ConclusionRecognition of clustering patterns, particularly autoimmune cytopenias, IBD, and endocrine autoimmunity, has direct clinical implications. These manifestations should be regarded as red flags, guiding targeted evaluation and genetic testing. Mapping such associations not only refines our understanding of pathogenesis but also provides a practical framework for earlier diagnosis and tailored management.

New technologies in genetic diagnostics have revolutionized the understanding and management of rare diseases. This review highlights the significant advances and latest developments in genetic diagnostics in inborn errors of immunity (IEI), which encompass a diverse group of disorders characterized by defects in the immune system, leading to increased susceptibility to infections, autoimmunity, autoinflammatory diseases, allergies, and malignancies. Various diagnostic approaches, including targeted gene sequencing panels, whole exome sequencing, whole genome sequencing, RNA sequencing, or proteomics, have enabled the identification of causative genetic variants of rare diseases. These technologies not only facilitated the accurate diagnosis of IEI but also provided valuable insights into the underlying molecular mechanisms. Emerging technologies, currently mainly used in research, such as optical genome mapping, single cell sequencing or the application of artificial intelligence will allow even more insights in the aetiology of hereditary immune defects in the near future. The integration of genetic diagnostics into clinical practice significantly impacts patient care. Genetic testing enables early diagnosis, facilitating timely interventions and personalized treatment strategies. Additionally, establishing a genetic diagnosis is necessary for genetic counselling and prognostic assessments. Identifying specific genetic variants associated with inborn errors of immunity also paved the way for the development of targeted therapies and novel therapeutic approaches. This review emphasizes the challenges related with genetic diagnosis of rare diseases and provides future directions, specifically focusing on IEI. Despite the tremendous progress achieved over the last years, several obstacles remain or have become even more important due to the increasing amount of genetic data produced for each patient. This includes, first and foremost, the interpretation of variants of unknown significance (VUS) in known IEI genes and of variants in genes of unknown significance (GUS). Although genetic diagnostics have significantly contributed to the understanding and management of IEI and other rare diseases, further research, exchange between experts from different clinical disciplines, data integration and the establishment of comprehensive guidelines are crucial to tackle the remaining challenges and maximize the potential of genetic diagnostics in the field of rare diseases, such as IEI.

For over 20 years, haematopoietic stem cell (HSC) gene therapy (GT) has been developed for several inborn errors of immunity (IEI) and transformative results have been seen, particularly for severe combined immune deficiency (SCID) disorders. Gene therapy was developed as an alternative to haematopoietic stem cell transplant (HSCT), where outcomes are dependent on a well‐matched donor. The most common approach is gene addition, adding a functional copy of the defective gene into the patient's genome using lentiviral vectors. This autologous approach offers a potentially safer treatment than HSCT by reducing risks of alloreactivity, using less preparative chemotherapy and no requirement for immune suppression after transplant. Clinical trials have been undertaken and preclinical studies performed for an expanding range of IEIs including Wiskott‐Aldrich syndrome (WAS) and Leukocyte adhesion deficiency type I (LAD‐I). More recently, gene editing platforms such as CRISPR/Cas9‐based strategies are being explored but are yet to enter the clinic. Key Concepts Inborn errors of immunity are rare genetic disorders caused by gene mutations leading to abnormal development or function of the immune system or immune dysregulation. The first clinical trial to address an IEI, X‐SCID, used a gammaretroviral vector (ɣRV) which led to the development of leukaemia in several patients, termed insertional mutagenesis. Viral long terminal repeat (LTR) regions within γRVs were responsible for these adverse events and so self‐inactivating vectors were developed, which resulted in a safer and still effective approach. Self‐inactivating lentivirus vectors have proven to be a safer option for gene addition, reducing the risk of oncogenesis and being employed in numerous clinical trials for not only IEIs but also metabolic, haematological and oncological indications. More recently gene editing platforms have been applied to several IEIs to deliver precise gene correction in situ and likely we will see these therapies entering clinic in the coming years.

In this study, we retrospectively reviewed the use of flow cytometry (FCM) in the diagnosis of inborn errors of immunity (IEIs) at a single center in Algeria. Sharing insights into our practical experience, we present FCM based diagnostic approaches adapted to different clinical scenarios. Between May 2017 and February 2024, pediatric and adult patients presenting with clinical features suggestive of immunodeficiency were subjected to FCM evaluation, including lymphocyte subset analysis, detection of specific surface or intracellular proteins, and functional analysis of immune cells. Over a nearly seven-year period, our laboratory diagnosed a total of 670 patients (372 (55.5%) males and 298 (44.5%) females), distributed into 70 different IEIs belonging to 9 different categories of the International Union of Immunological Societies classification. FCM was used to diagnose and categorize IEI in 514 patients (76.7%). It provided direct diagnostic insights for IEIs such as severe combined immunodeficiency, Omenn syndrome, MHC class II deficiency, familial hemophagocytic lymphohistiocytosis, and CD55 deficiency. For certain IEIs, including hyper-IgE syndrome, STAT1-gain of function, autoimmune lymphoproliferative syndrome, and activated PI3K delta syndrome, FCM offered suggestive evidence, necessitating subsequent genetic testing for confirmation. Protein expression and functional assays played a crucial role in establishing definitive diagnoses for various disorders. To setup such diagnostic assays at high and reproducible quality, high level of expertise is required; in house reference values need to be determined and the parallel testing of healthy controls is highly recommended. Flow cytometry has emerged as a highly valuable and cost-effective tool for diagnosing and studying most IEIs, particularly in low-income countries where access to genetic testing can be limited. FCM analysis could provide direct diagnostic insights for most common IEIs, offer clues to the underlying genetic defects, and/or aid in narrowing the list of putative genes to be analyzed.

Inborn errors of immunity (IEIs) can exhibit variant clinical manifestations beyond the classic presentation of recurrent infections. Allergic diseases represent an important subset that can arise as the primary feature or coexist with IEIs. In this study, we aimed to investigate the burden of the most frequent allergic diseases among individuals with primary immune deficiency. Over 70 registered patients with a definite diagnosis of IEI were enrolled in our study. Patients and their records were evaluated, and data were collected via a questionnaire. Additionally, laboratory investigations, including spirometry, skin prick tests, and specific IgE, were used to confirm the diagnosis of allergic diseases. Statistical analysis was performed via SPSS software. The most frequent IEIs in our study comprise agammaglobulinemia, hyper-IgE syndrome, and common variable immune deficiency. The overall prevalence of allergic diseases among IEI patients was 77.8%. Allergic rhinitis, with a prevalence of 47.2%, atopic dermatitis 40.3% and asthma 37.5% were the most frequent allergic diseases among these patients. The highest prevalence of allergic rhinitis and asthma was detected among patients with agammaglobulinemia (23.5% and 33.5%). Also, Atopic dermatitis and food allergy had the highest prevalence in hyper IgE syndrome (27.6% and 75%). Agammaglobulinemia was accounted for as the most frequent IEI accompanying allergic disorders in our study. The interplay between atopy and IEIs is complex, highlighting the role of immune dysregulation in allergic diseases. Our study investigated the prevalence of allergic diseases among individuals with inborn errors of immunity. According to the coexistence of allergic diseases and IEIs, in patients with unusual, early onset, and severe allergic manifestations, underlying IEI may be suspected.

PurposeAllogeneic hematopoietic stem cell transplantation (HSCT) is an established therapy for many inborn errors of immunity (IEI). The indications for HSCT have expanded over the last decade. The study aimed to collect and analyze the data on HSCT activity in IEI in Russia.MethodsThe data were collected from the Russian Primary Immunodeficiency Registry and complemented with information from five Russian pediatric transplant centers. Patients diagnosed with IEI by the age of 18 years and who received allogeneic HSCT by the end of 2020 were included.ResultsFrom 1997 to 2020, 454 patients with IEI received 514 allogeneic HSCT. The median number of HSCTs per year has risen from 3 in 1997–2009 to 60 in 2015-2020. The most common groups of IEI were immunodeficiency affecting cellular and humoral immunity (26%), combined immunodeficiency with associated/syndromic features (28%), phagocyte defects (21%), and diseases of immune dysregulation (17%). The distribution of IEI diagnosis has changed: before 2012, the majority (65%) had severe combined immunodeficiency (SCID) and hemophagocytic lymphohistiocytosis (HLH), and after 2012, only 24% had SCID and HLH. Of 513 HSCTs, 48.5% were performed from matched-unrelated, 36.5% from mismatched-related (MMRD), and 15% from matched-related donors. In 349 transplants T-cell depletion was used: 325 TCRαβ/CD19+ depletion, 39 post-transplant cyclophosphamide, and 27 other. The proportion of MMRD has risen over the recent years.ConclusionThe practice of HSCT in IEI has been changing in Russia. Expanding indications to HSCT and SCID newborn screening implementation may necessitate additional transplant beds for IEI in Russia.Supplementary InformationThe online version contains supplementary material available at 10.1007/s10875-023-01476-w.