Recurrent Sinopulmonary Infections Research Articles

Inflammatory Bowel Disease in Activated PI3Kδ Syndrome: An Uncommon Complication of a Rare Condition

Background/Objectives: Monogenic primary immunodeficiencies represent a group of disorders with varying levels of severity, many of which remain poorly understood. Activated phosphoinositide-3 kinase delta syndrome (APDS) is a rare genetic condition resulting from dominant point mutations in the phosphoinositide-3 kinase delta (PI3Kδ) gene, which leads to hyperactivation of the PI3Kδ enzyme, primarily expressed in T and B lymphocytes. Children with this mutation often have recurrent sinopulmonary infections and immunodeficiency. Additional complications may include increased susceptibility to herpes virus infections, lymphoid hyperplasia, and autoimmune conditions. In this case, report, we describe the clinical course of a young boy diagnosed with APDS who developed unclassified inflammatory bowel disease (U-IBD) and explore a personalized treatment approach. Methods: We detail the clinical course of a 12-year-old boy with APDS who presented with fever, diarrhea, anemia, and significant weight loss. Diagnostic evaluations, including endoscopy and histological analysis, led to a diagnosis of U-IBD. Genetic testing confirmed a heterozygous PIK3CD mutation (c.G3061A, p.E1021K). Results: Although APDS is characterized by a broad spectrum of immune dysregulation, the occurrence of IBD in this context is rare. We managed the patient’s IBD with exclusively enteral nutrition to induce remission, followed by a maintenance regimen combining the Crohn’s Disease Exclusion Diet (CDED) and mesalamine, achieving sustained long-term clinical remission. Conclusions: This case underscores the importance of personalized treatment approaches in managing the complex manifestations of APDS.

Novel CYCLIN-O pathogenic variants in a patient presenting with bronchiectasis secondary to reduced generation of multiple motile cilia.

Reduced generation of multiple motile cilia (RGMC) represents a rare variant of Primary Ciliary Dyskinesia (PCD), associated with CYCLIN-O (CCNO) mutations. We report a novel compound mutation in the CCNO gene in an adult Chinese Singaporean exhibiting chronic productive cough since childhood and recurrent sino-pulmonary infections. Low nasal nitric oxide and bronchiectasis suggests PCD. Bronchoscopy for epithelial and nasal brushings for ciliary studies were repeated after adequate treatment of lower respiratory tract infections. Demonstration of oligo-cilia via transmission electron microscopy, and detection of CCNO mutation through genetic analysis were utilized to diagnose RGMC. Repeated courses of antibiotics including nebulised antibiotics were used to treat recurrent infections and exacerbations. Airway clearance techniques, immunizations and collaboration with otorhinolaryngologist form part of the long-term management. Heightened clinical suspicion and adherence to established diagnostic algorithms are essential for timely recognition of this entity.

Primary Immunodeficiency: Specific antibody deficiency with normal IgG.

Specific antibody deficiency (SAD) is a common primary immunodeficiency disorder that should be considered in older children and adults with recurrent and/or severe sinopulmonary infections. The diagnosis is characterized by inadequate antibody response to polysaccharide vaccine, specifically, pneumococcal, with normal responses to protein antigens and normal levels of serum immunoglobulins as well as immunoglobulin G (IgG) subclasses. The underlying mechanism for SAD is not completely elucidated. It is understood that young children have limited polysaccharide responsiveness, which develops with increased age. Due to this phenomenon, the consensus is that there is adequate immune maturity after age 2 years, which is the earliest for the SAD diagnosis to be established. There remains a lack of consensus on thresholds for polysaccharide nonresponse, and there are several commercial laboratories that measure a range of serotypes, with the recommendation for patients to have their diagnostic evaluation with serotype testing both before vaccination and after vaccination to be conducted by the same laboratory. Once a diagnosis has been made, the management of SAD is based on the clinical severity. Clinicians may consider prophylactic antibiotics as well as immunoglobulin replacement. These patients should be closely followed up, with the possibility of discontinuation of IgG replacement after 12 to 24 months. Children are more likely to demonstrate resolution of SAD than are adolescents and adults. Patients with SAD may also progress to a more severe immunodeficiency; therefore, continued monitoring remains a crucial principle of practice in the care of patients with SAD.

Primary antibody deficiencies.

Primary antibody deficiencies are characterized by the inability to effectively produce antibodies and may involve defects in B-cell development or maturation. Primary antibody deficiencies can occur at any age, depending on the disease pathology. Certain primary antibody deficiencies affect males and females equally, whereas others affect males more often. Patients typically present with recurrent sinopulmonary and gastrointestinal infections, and some patients can experience an increased risk of opportunistic infections. Multidisciplinary collaboration is important in the management of patients with primary antibody deficiencies because these patients require heightened monitoring for atopic, autoimmune, and malignant comorbidities and complications. The underlying genetic defects associated with many primary antibody deficiencies have been discovered, but, in some diseases, the underlying genetic defect and inheritance are still unknown. The diagnosis of primary antibody deficiencies is often made through the evaluation of immunoglobulin levels, lymphocyte levels, and antibody responses. A definitive diagnosis is obtained through genetic testing, which offers specific management options and may inform future family planning. Treatment varies but generally includes antibiotic prophylaxis, vaccination, and immunoglobulin replacement. Hematopoietic stem cell transplantation is also an option for certain primary antibody deficiencies.

A novel MALT1 variant in an Egyptian patient presenting with exfoliative dermatitis: a case-based review.

Inborn errors of the CARD11-BCL10-MALT1 (CBM) signalosome have recently been shown to underlie severe combined immunodeficiency (SCID) and combined immunodeficiency (CID) with variable immunological and clinical phenotypes, and patients usually present with recurrent bacterial, viral, and fungal infections, periodontal disease, enteropathy, dermatitis, and failure to thrive. In the present study, we describe the clinical and immunological characteristics of an Egyptian patient with a mutation in the MALT1 gene. The patient suffered from an itchy exfoliative skin rash and eczematous lesions over his face and flexural surface of the limbs. He also had dental enamel erosion, repeated attacks of diarrhea, and pneumonia. He had elevated serum IgE and normal B- and T-lymphocyte subset counts, but there was an arrest in the B-cell maturation. DOCK8 expression on the lymphocytes by flow cytometry was normal. Next-generation sequencing revealed a novel homozygous variant in the MALT1 gene (c.762dup in exon 5 of 17; p.Ile255TyrfsTer10); this variant is likely pathogenic, thus supporting the genetic diagnosis of immunodeficiency-12 (IMD12). Although the presence of eczema, recurrent sinopulmonary, and staphylococcal infections are suggestive of DOCK8 deficiency, they are also a finding in CARD11 and MALT1 deficiency. Thus, whenever DOCK 8 has been excluded, the molecular diagnosis is mandatory as this could lead to discovering more patients hence better understanding and reporting of the phenotype and natural history of the disease especially since there are very few documented cases. Early diagnosis will also enable the proper patient management by hematopoietic stem cell transplantation (HSCT) prior to the establishment of infections and pulmonary damage leading to a better outcome.

Artemis deficiency: A large cohort including a novel variant with increased radiosensitivity.

Artemis deficiency is an autosomal recessive disorder characterized by a combined immunodeficiency with increased cellular radiosensitivity. In this review, the clinical and genetic characteristics of 15 patients with DCLRE1C variants are presented. The demographic, clinical, immunologic, and genetic characteristics of patients with confirmed DCLRE1C variants diagnosed between 2013 and 2023 were collected retrospectively. Three patients were evaluated for radiosensitivity by the Comet assay, compared with age- and sex-matched healthy control. Seven patients who had severe infections in the first 6 months of life were diagnosed with T-B-NK+ SCID (severe combined immunodeficiency). Among them, four individuals underwent transplantation, and one of those died due to post-transplant complications in early life. Eight patients had hypomorphic variants. Half of them were awaiting a suitable donor, while the other half had already undergone transplantation. The majority of patients were born into a consanguineous family (93.3%). Most patients had recurrent sinopulmonary infections (73.3%), and one patient had no other infection than an acute respiratory infection before diagnosis. Two patients (13.3%) had autoimmunity in the form of autoimmune hemolytic anemia. Growth retardation was observed in only one patient (6.6%), and no malignancy was detected in the surviving 11 patients during the median (IQR) of 21.5 (12-45) months of follow-up. Three patients who had novel variants exhibited increased radiosensitivity and compromised DNA repair, providing a potential vulnerability to malignant transformation. Early diagnosis, radiation avoidance, and careful preparation for transplantation contribute to minimizing complications, enhancing life expectancy, and improving the patient's quality of life.

Infections in Disorders of Immune Regulation.

Primary immune regulatory disorders (PIRDs) constitute a spectrum of inborn errors of immunity (IEIs) that are primarily characterized by autoimmunity, lymphoproliferation, atopy, and malignancy. In PIRDs, infections are infrequent compared to other IEIs. While susceptibility to infection primarily stems from antibody deficiency, it is sometimes associated with additional innate immune and T or NK cell defects. The use of immunotherapy and chemotherapy further complicates the immune landscape, increasing the risk of diverse infections. Recurrent sinopulmonary infections, particularly bacterial infections such as those associated with staphylococcal and streptococcal organisms, are the most reported infectious manifestations. Predisposition to viral infections, especially Epstein-Barr virus (EBV)-inducing lymphoproliferation and malignancy, is also seen. Notably, mycobacterial and invasive fungal infections are rarely documented in these disorders. Knowledge about the spectrum of infections in these disorders would prevent diagnostic delays and prevent organ damage. This review delves into the infection profile specific to autoimmune lymphoproliferative syndrome (ALPS), Tregopathies, and syndromes with autoimmunity within the broader context of PIRD. Despite the critical importance of understanding the infectious aspects of these disorders, there remains a scarcity of comprehensive reports on this subject.

Heterogeneity in RAG1 and RAG2 deficiency: 35 cases from a single-centre.

Recombination activating genes (RAG)1 and RAG2 deficiency leads to combined T/B-cell deficiency with varying clinical presentations. This study aimed to define the clinical/laboratory spectrum of RAG1 and RAG2 deficiency. We retrospectively reviewed the clinical/laboratory data of 35 patients, grouped them as severe combined immunodeficiency (SCID), Omenn syndrome (OS), and delayed-onset combined immunodeficiency (CID) and reported nine novel mutations. The male/female ratio was 23/12. Median age of clinical manifestations was 1 months (mo) (0.5-2), 2 mo (1.25-5), and 14 mo (3.63-27), age at diagnosis was 4 mo (3-6), 4.5 mo (2.5-9.75), and 27 mo (14.5-70) in SCID (n = 25; 71.4%), OS (n = 5; 14.3%), and CID (n = 5; 14.3%) patients, respectively. Common clinical manifestations were recurrent sinopulmonary infections 82.9%, oral moniliasis 62.9%, diarrhea 51.4%, and eczema/dermatitis 42.9%. Autoimmune features were present in 31.4% of the patients; 80% were in CID patients. Lymphopenia was present in 92% of SCID, 80% of OS, and 80% of CID patients. All SCID and CID patients had low T (CD3, CD4, and CD8), low B, and increased NK cell numbers. Twenty-eight patients underwent hematopoietic stem cell transplantation (HSCT), whereas seven patients died before HSCT. Median age at HSCT was 7 mo (4-13.5). Survival differed in groups; maximum in SCID patients who had an HLA-matched family donor, minimum in OS. Totally 19 (54.3%) patients survived. Early molecular genetic studies will give both individualized therapy options, and a survival advantage because of timely diagnosis and treatment. Further improvement in therapeutic outcomes will be possible if clinicians gain time for HSCT.

Clinical, immunological, and genetic description of a Mexican cohort of patients with DOCK8 deficiency.

We aimed to describe the clinical, immunological, and genetic features of patients with DOCK8 deficiency (DOCK8-Def) in a tertiary care center for children. Retrospective chart review of patients' clinical, immunological, and genetic characteristics with DOCK8-Def. Genetic analysis was performed with targeted- or whole-exome sequencing; we also assessed DOCK8 protein expression and a lymphoproliferation assay and analyzed survival by the Kaplan-Meier method. We described 11 patients from 8 unrelated kindreds. The median age at symptoms' onset was 10 months (range 1-54 months). The median follow-up time was 53.4 months (4.8-118.8). All patients presented eczema and recurrent sinopulmonary and cutaneous infections. Besides those symptoms, the most frequent manifestations were bronchiectases (8/11), food allergies (6/11), and severe infections (6/11). Infrequent characteristics were detection of CMV in bronchial lavage, C. parvum-driven sclerosing cholangitis, Takayasu vasculitis, neurological syndromes, pulmonary tuberculosis, and lymphomatoid granulomatosis. DOCK8-Def has a broad spectrum of manifestations, including allergy, autoimmunity, inflammation, infection, and cancer. The hallmark of this inborn error of immunity is IEI-associated eczema with eosinophilia and increased IgE. Here, we report six new mutations causing human DOCK8 deficiency and symptoms previously unrecognized to occur in DOCK8-Def. Therefore, an early diagnosis of DOCK8-Def is essential to facilitate an adequate treatment such as HSCT.

Unraveling the Natural History of Good’s Syndrome: A Progressive Adult Combined Immunodeficiency

Good's syndrome (GS) is a rare immune deficiency described almost 6 decades ago. Despite numerous published individual case reports and data collected in cross-sectional studies of small cohorts, the natural history and long-term outcomes of this disease remain unknown. We aimed to determine the clinical and laboratory evolution of 8 adults diagnosed with GS and consecutively evaluated between 1983 and2023. In this prospective, longitudinal cohort study, newly diagnosed patients with GS were followed through repeated measures of clinical, immune, and hematologic changes, as well as targeted genetic screening. All patients reported a healthy childhood and adolescence with symptom onset during the third or fourth decade of life. All presented to our center with recurrent bacterial sinopulmonary infections, thymoma, hypogammaglobulinemia, and absence of B cells. The median age of GS diagnosis was 57 years. During follow-up, immunoglobin replacement therapy effectively minimized sinopulmonary infections. However, the majority experienced severe and systemic viral or fungal infections, 3 developed basal cell carcinomas, and 5 had progressive bronchiectasis and persistent splenomegaly. The most notable clinical feature was opportunistic infections and invitro evidence of cellular immune deficiency, which resulted in the death of 2 individuals. We also report a statistically significant, multidecade progressive decline in lymphocytes, platelets, hemoglobin, and red blood cells in our cohort, suggesting gradual bone marrow failure. Knowledge of the unique phenotype and temporal evolution of GS has allowed us to develop a more comprehensive diagnostic framework. It can be investigated as part of broader research into disease pathophysiology.

Clinical and Genetic Characterization of Patients with Primary Ciliary Dyskinesia in Southwest Saudi Arabia: A Cross Sectional Study.

Primary ciliary dyskinesia (PCD, MIM 244400) is an inherited ciliopathy disorder characterized by recurrent sinopulmonary infections, subfertility, and laterality defects. The true incidence of PCD in Saudi Arabia is not known, but it is likely underdiagnosed due to the high prevalence of consanguineous marriages. In this study, we aim to study the clinical and genetic characteristics of PCD patients in the southwestern region of Saudi Arabia to provide guidance to clinicians and researchers studying PCD. This was a cross-sectional study conducted between 2019 and 2023 in Abha Maternity and Children's Hospital. Twenty-eight patients with clinically diagnosed PCD were recruited. The diagnosis of PCD was confirmed via whole-exome sequencing. A total of 28 patients from 20 families were identified and recruited for this study. The median age of patients was 7.5 years (IQR = 3, 13 years). The people of different sexes were evenly distributed, and 18 patients (64%) had neonatal respiratory distress (NRD). The median age of diagnosis was 5.5 years (IQR = 2, 11 years), while the age when the first symptoms appeared was 3 months old (IQR = 1, 6 months). The prevalence of a chronic wet cough, chronic rhinosinusitis, ear infections were 100% (n = 28), 78.6% (n = 22), and 67.9% (19), respectively. The most common gene in our study was DNAH5, which represented 17.9% (five out of twenty-eight) of the cases. Furthermore, the remaining pathogenic variants included: 14.3% with RSPH9 in four individuals (three families), 14.3% with DNAI2 in four individuals (two families), and 10.7% with LRRC56 in three individuals (one family). The most common findings on the chest CT scans were consolidation (seen in all patients), mucus plugging (seen in 95%), and bronchiectasis (seen in 77%). In the patients with bronchiectasis, the most commonly affected lobes were the right lower lobe (88%) and left lower lobe (76%). The patients with PCD and situs inversus were more likely to experience NRD than the patients with PCD and situs solitus. The median PICADAR score in the patients with PCD and situs inversus (median: 11.5; Q1: 10-Q3: 12.5) was significantly higher compared to those with PCD and situs solitus (median: 7.5; Q1: 5.8-Q3: 8) (U = 10.5; p < 0.001). This study provides preliminary data on the clinical and genetic characteristics of PCD patients in the southwestern region of Saudi Arabia. We found that DNAH5 and RSPH9 genes were the most common genes among the studied population. Furthermore, PCD should be considered for each child with early NRD and laterality defects, and further confirmatory tests are recommended. These findings also highlight the need for greater awareness of the disease in daily clinical practice to facilitate early diagnosis and avoid irreversible lung damage.

Clinical, immunological and molecular profiles of DOCK8 deficiency in six patients from a tertiary care centre in North India.

Dedicator of cytokinesis protein 8 (DOCK8) deficiency is an autosomal recessive form of combined immunodeficiency. This rare disorder is characterized by an increased predisposition to allergy, autoimmunity and malignancies. To analyse clinical, immunological and molecular profiles of patients with DOCK8 deficiency. Clinic records of all patients attending the primary immunodeficiency clinic from 2018 to 2021 were reviewed. Six patients from five families were found to have DOCK8 deficiency. Median age at diagnosis was 7.5 years (range 2-13), with a male/female ratio of 5 : 1. Among the six patients, recurrent eczematous skin lesions were the predominant cutaneous manifestation, present in five patients (83%). Warts and molluscum contagiosum were evident in two patients (33%) and one patient (16%), respectively. Two patients had recalcitrant prurigo nodularis lesions and two had epidermodysplasia verruciformis-like lesions. Food allergies and asthma were reported by one patient each. Of the six patients, recurrent sinopulmonary infections were detected in five (83%). Epstein-Barr virus-driven non-Hodgkin lymphoma with liver metastases was the only case of malignancy, in a 4-year-old boy. IgE was elevated in all patients. Lymphopenia and eosinophilia were observed in three patients (50%) and five patients (83.3%), respectively. Genetic analysis showed DOCK8 pathogenic variants in all patients: homozygous deletion mutations in two patients, compound heterozygous deletion mutations in one, and homozygous nonsense mutations in two. A novel pathogenic homozygous missense variant in the DOCK8 gene was identified in one patient. DOCK8 deficiency should be considered as a possibility in any patient with early onset eczema, cutaneous viral infections and increased predisposition to allergy, autoimmunity and malignancy.

Interim analysis: Open-label extension study of leniolisib for patients with APDS

Activated phosphoinositide 3-kinase delta (PI3Kδ) syndrome (APDS; or p110δ-activating mutations causing senescent T cells, lymphadenopathy, and immunodeficiency) is an inborn error of immunity caused by PI3Kδ hyperactivity. Resultant immune deficiency and dysregulation lead to recurrent sinopulmonary infections, herpes viremia, autoimmunity, and lymphoproliferation. Leniolisib, a selective PI3Kδ inhibitor, demonstrated favorable impact on immune cell subsets and lymphoproliferation over placebo in patients with APDS over 12weeks. Here, we report results from an interim analysis of an ongoing open-label, single-arm extension study. Patients with APDS aged 12 years or older who completed NCT02435173 or had previous exposure to PI3Kδ inhibitors were eligible. The primary end point was safety, assessed via investigator-reported adverse events (AEs) and clinical/laboratory evaluations. Secondary and exploratory end points included health-related quality of life, inflammatory markers, frequency of infections, and lymphoproliferation. Between September 2016 and August 2021, 37 patients (median age, 20 years; 42.3% female) were enrolled. Of these 37 patients, 26, 9, and 2 patients had previously received leniolisib, placebo, or other PI3Kδ inhibitors, respectively. At the data cutoff date (December 13, 2021), median leniolisib exposure was 102 weeks. Overall, 32 patients (87%) experienced an AE. Most AEs were grades 1 to 3; none were grade 4. One patient with severe baseline comorbidities experienced a grade 5 AE, determined as unrelated to leniolisib treatment. While on leniolisib, patients had reduced annualized infection rates (P= .004), and reductions in immunoglobulin replacement therapy occurred in 10 of 27 patients. Other observations include reduced lymphadenopathy and splenomegaly, improved cytopenias, and normalized lymphocyte subsets. Leniolisib was well tolerated and maintained durable outcomes with up to 5 years of exposure in 37 patients with APDS. gov identifier: NCT02859727.

A child with polyarthritis and chronic lung disease: a case report of ataxia-telangiectasia

BackgroundAtaxia-telangiectasia (A-T) is a rare autosomal recessive DNA repair disorder, characterized by progressive cerebellar degeneration, telangiectasia, immunodeficiency, recurrent sinopulmonary infections, radiation sensitivity, premature aging and predisposition to cancer. Although the association with autoimmune and chronic inflammatory conditions such as vitiligo, thrombocytopenia and arthritis has occasionally been reported, an onset with articular involvement at presentation is rare.Case presentationWe herein report the case of a 7-year-old Caucasian girl who was admitted to the Rheumatology Department with a history of febrile chough and polyarthritis which led initially to the suspicion of an autoinflammatory disease. She had overt polyarthritis with knees deformities and presented with severe pneumonia. A chest Computed Tomography (CT) scan showed bilateral bronchiectasis, parenchymal consolidation and interstitial lung disease; rheumatoid factor and type I interferon signature resulted negative, therefore excluding COatomer Protein subunit Alpha (COPA) syndrome. A diagnosis of sarcoidosis had been suspected based on histological evidence of granulomatous liver inflammation, but ruled out after detecting normal angiotensin converting enzyme and chitotriosidase blood levels. Based on her past medical history characterized by at least six episodes of pneumonia in the previous 4 years, immunological phenotyping was performed. This showed complete IgA and IgE deficiency with defective antigen-specific antibodies to Pneumococcal, Tetanus toxin and Hemophilus Influenzae B vaccines. Additionally, low numbers of B cells and recent thymic emigrants (RTE) were found (CD4Ra 1.4%), along with a low CD4+/CD8 + T cells ratio (< 1). Finally, based on gait disturbances (wobbly wide-based walking), serum alfa-fetoprotein was dosed, which resulted increased at 276 ng/ml (normal value < 7 ng/ml). A diagnosis of Ataxia-Telangiectasia was made, strengthened by the presence of bulbar telangiectasia, and then confirmed by Whole Exome Sequencing (WES).ConclusionsAlthough rare, A-T should always be ruled out in case of pulmonary bronchiectasis and gait disturbances even in the absence of bulbar or skin telangiectasia. Autoimmune and granulomatous disorders must to be considered as differential diagnosis.

Neurodevelopmental disorder and immunodeficiency

Background: Neurodevelopment is closely entwined with immune maturation and function during embryogenesis. While haematopoietic-derived microglia have recognized roles in a number of neurodevelopmental processes, the contribution of molecules classically involved in the immune system (including complement, toll-like receptors, and cytokines) are also emerging. To date, approximately 11% of genes known to cause primary immunodeficiency also confer varying degrees of neurological abnormalities. These can range from intellectual disability, cognitive and behavioural disorders, through to seizures, spasticity, and motor development delay. However, very rarely are sensory processing defects associated with aberrations of the immune system. Aims: To define the clinical presentation and immune phenotype of a novel syndrome encompassing immunodeficiency, neurodevelopmental abnormalities, and altered pain sensitivity in two siblings. Methods: Comprehensive retrospective review of the patient’s charts were performed, in accordance with local research ethics board approval. Results: We describe two teenage sisters who presented with recurrent sinopulmonary infections, lymphopenia affecting both B and T cells, developmental delay, learning and processing disorder, seizures, and reduced sensitivity to pain. Other features include bronchogenic cyst, microscopic hematuria, oral ulcers, papular urticaria, and keratosis pilaris. Conclusion: An underlying defect in genes known to cause primary immunodeficiency was not identified, suggesting the role of an as-yet undefined molecule at the crossroads of immunity, neurodevelopment, and sensory processing. Statement of novelty: We report on two patients, siblings, with a novel phenotype of combined immunodeficiency, neurodevelopmental delay, and reduced sensitivity to painful stimuli.

Autosomal dominant NFKB1 haploinsufficiency and family planning

BackgroundThe nuclear factor kappa B subunit 1 (NFKB1) gene encodes a pleiotropic transcription factor involved in a vast array of biological processes including inflammation, immunity, differentiation, and tumorigenesis. Deleterious variants in NFKB1 have highly variable penetrance, but heterozygosity can lead to autosomal dominant (AD) haploinsufficiency resulting in intrinsic B cell disorders and late-onset antibody deficiencies.Case Description: A 33-year-old woman presented for an initial evaluation of recurrent autoimmune cytopenias and sinopulmonary infections. Her medical history was remarkable for pneumococcal sepsis, recurrent sinopulmonary infections, Evan’s syndrome, neutropenia, splenomegaly, recurrent oral and genital ulcers, and autoimmune alopecia. She required multiple and prolonged courses of systemic corticosteroids for the management of refractory autoimmune cytopenias. Imaging studies were significant for splenomegaly (28 cm). Laboratory workup prior to starting Ig replacement therapy showed normal total IgG with low IgG2, undetectable IgA, and high IgM. She had an impaired response to polysaccharide antigens and did not make IgG antibodies against the SARS-COV2 spike protein after COVID-19 immunization. She had leukopenia, neutropenia, normocytic anemia, and thrombocytopenia despite treatment with Ig replacement therapy and systemic corticosteroids. Lymphocyte immunophenotyping in peripheral blood revealed decreased CD19+ B cell counts (5/uL). Targeted genetic testing for inborn errors of immunity revealed that she is heterozygous for a pathogenic variant in NFKB1 (c.896del, p.Gly299Glufs*133). She expressed interest in having a child but her autoimmune cytopenias were not well controlled. Therapeutic options were discussed with the patient and an interdisciplinary team. Sirolimus, which is contraindicated in pregnancy, was recommended for the management of refractory autoimmune cytopenias as well as in vitro fertilization with pre-implantation genetic testing and surrogacy. Conclusiongenetic testing for inborn errors of immunity in patients with antibody deficiency and autoimmunity can be a valuable tool in family planning.

Analysis of novel RAC2 variants associated with neutrophil dysfunction, lymphopenia, and primary immunodeficiency

Abstract RAC2 is a member of Rho-family GTPases, abundant in neutrophils serving roles in NADPH oxidase activation and cytoskeleton dynamics. Patients with dominant, activating mutations in RAC2 (E62K, N92T, Q61R) are associated with neutrophil dysfunction, lymphopenia and immunodeficiency. We now characterize additional disease-related RAC2 variants with in-vitro analysis of RAC2 effector functions including NOX2-based superoxide production, regulation of PAK1-PDB binding, activation of AKT, protein stability, subcellular localization, and F-actin formation. We identified both active and inactive variants associated with lymphopenia and immunodeficiency. Patients with dominant, active RAC2 variants with high protein stability (Q61R, Q61K) presented in the first days of life with severe combined immunodeficiency and absent lymphocytes. Activating variants with lower protein stability (I21S, E62K, N92K, N92S) presented as combined variable immunodeficiency with lymphopenia, detectable by newborn screening but clinically presenting later with recurrent sinopulmonary infections, reduced B-cells and hypogammaglobulinemia. A third class of mutations with unstable transcript or protein were phenotypic only in homozygosity (W56*, R68W). Severity of phenotype and initial clinical presentation was correlated with protein stability, with increased stability leading to neonatal presentation and decreased stability of dominant mutations having later clinical onset. Thus, heterologous expression and analysis of RAC2 variants is useful for deciphering the genetic and molecular mechanistic basis for the common underlying clinical phenotype related to lymphopenia and immunodeficiency.

Retrospective Study on Vaccine Responses and Natural Course of COVID-19 Infections in Primary Immunodeficiency

We conducted a retrospective study in the adult primary immunodeficiency clinic at UAB examining COVID-19 infection and COVID-19 antibody response from vaccination, natural infection, and immunoglobulin replacement from February 2021 to November 2022. Our goal was to determine if nucleocapsid and spike antibodies could be found in our PID patients and if these antibodies could be derived from natural infection, vaccination, or antibody replacement exclusively or combinatory. We hypothesized that increasing antibodies would be detected in our population as the COVID period extended.Two hundred and forty-five subjects were tracked over 336 clinic visits during this period. Our PID population included subjects with CVID, XLA, thymoma, hypogammaglobulinemia, IgA deficiency, IgG subclass deficiency, specific antibody deficiency, Down syndrome, IgM deficiency, and patients with recurrent sinopulmonary infections. We had 196 females and 45 males in our study.In our patient population, 47% of our patient had known COVID-19 infection. Of those 47%, 21% of those infected patients had COVID-19 at least twice. Of those infected, three did not have COVID-19 spike antibodies and chose not to get vaccinated either. Two of those patients were not on IVIG and one was on Pangyza. Of those infected, 70% (n = 80) were on IgG infusions compared to those uninfected, 77% (n = 96) were on IgG infusions. Of interest, we had three XLA patients and all three had COVID-19 infection in the summer 2021. Two of them tested positive for nucleocapsid and spike antibodies in high titers and they were receiving Gammagard or Gamunex infusions, suggesting that these immunoglobulin preparations contain COVID-19 antibodies.We are still in the process of analyzing our data to see if diagnosis, IgG preparations, date of testing, B cell numbers, and drugs play a role in producing nucleocapsid antibodies and high spike antibody titers.

A step closer to understanding the predisposition to autoimmunity as well humoral defects in aging patients with 22q11.2 deletion syndrome

IntroductionOur previous work has shown that despite having a small thymus with a limited T cell repertoire, the majority of patients with 22q11.2 deletion syndrome have a normal T cell proliferation at young age. As these patients age, their T cell numbers normalize yet about 25% have recurrent sinopulmonary infections and autoimmune disease, suggesting that their Tcell compartment exhibits some dysregulation. Follicular helper T cells (Tfh) are crucial for humoral immunity (germinal center formation, affinity maturation, memory B cell formation), yet there has been emerging evidence showing that Tfh cells contribute to the pathogenesis of autoimmune disease such as SLE where Tfh correlate with titers of autoantibodies and the severity of end-organ involvement. Similarly, Tfh cells play a role in the of autoimmunity in diseases of immune dysregulation such as CTLA-4 deficiency and IPEX syndrome where abundant Tfh cells may facilitate breakdown of the peripheral tolerance of autoreactive B cells. Given the crucial role Tfh cells play humoral immunity and occasionally autoimmunity we sought to look at the percentage of Tfh cells in older patients with 22q11.2 deletion syndrome. MethodsWe compared the percentage of peripheral blood Tfh cells in 16 patients with 22q11.2 (age range 9–38 years) to age-matched healthy controls. T-tests were used to define significance. ResultsTfh cells in patients with 22q11.2 deletion syndrome were statistically significantly higher when compared to healthy controls, 19% and 8% respectively, Figure 1. DiscussionWe hypothesize that the observed increase in Tfh cells population in older 22q11.2 deletion patients is contributing to their autoimmune propensity. Our finding aligns with others who reported Tfh cells to play a role in the pathogenesis of autoimmunity seen in immune dysregulation syndromes. Further understanding the intrinsic characteristics of Tfh cells in these patients could be helpful in identifying the subset of patients at risk of antibody deficiency as well autoimmunity. [Display omitted]

Case of a 38-year-old man with NEMO deficiency syndrome complicated by marginal zone lymphoma

Here, we present a unique case of a 38-year-old man with history of Nuclear Factor-Kappa B Essential Modulator (NEMO) deficiency syndrome, whose course was complicated by marginal zone lymphoma. At 7 years of age, he was found to have MAI infection and throughout his life, developed further complications of MAI including osteomyelitis, intracranial lesions, adrenal abscesses, and cavitary pulmonary disease. Genetic testing revealed 1207 C-to-T mutation in NEMO, leading to R-for-C substitution at position 417 in the zinc finger domain. He has had a long history of recurrent viral and bacterial sinopulmonary infections since infancy continuing into adulthood, with over thirty lifetime episodes of serious pneumonia requiring hospitalizations, which has led to bronchiectasis.At 36 years of age, he presented to the hospital for five months of progressively worsening dyspnea and wheezing, hypoxemic respiratory failure, and a 15-pound weight loss. CT imaging demonstrated increased consolidation and nodularity, and sputum culture revealed methicillinsusceptible Staphylococcus aureus and Corynebacterium pneumonia treated with vancomycin. He was incidentally found to have a new 7.5 cm left periaortic lymph node conglomerate on CT abdomen/pelvis. Lymph node biopsy showed B-cell lymphoma with plasmacytic differentiation and with increased large cells, most concerning for marginal zone lymphoma. He received eight doses of rituximab as well as radiation therapy, with subsequent improvement on imaging. Following this diagnosis, lung biopsy was obtained, demonstrating nodular fibrosis in a primarily airwaycentered distribution with patchy, focal organizing pneumonia, most consistent with fibrosing chronic organizing pneumonia, treated with high dose prednisone. However, his course had since been complicated by increasingly frequent hospitalizations for acute on chronic hypoxemic respiratory failure corresponding with superimposed respiratory infectious as well as exacerbations of his organizing pneumonia.Hematopoietic stem cell transplantation was strongly considered as this would be a definitive treatment for his NEMO syndrome, as he has multiple severe complications of his NEMO deficiency syndrome. Unfortunately, after multidisciplinary discussions, he was ultimately considered to not be a candidate given his very poor pulmonary status. The patient was started on rituximab for his organizing pneumonia and continued on antibiotic prophylaxis with immunoglobulin replacement.