Electronic health record signatures identify undiagnosed patients with common variable immunodeficiency disease.

Human inborn errors of immunity include rare disorders entailing functional and quantitative antibody deficiencies due to impaired B cells called the common variable immunodeficiency (CVID) phenotype. Patients with CVID face delayed diagnoses and treatments for 5 to 15 years after symptom onset because the disorders are rare (prevalence of ~1/25,000), and there is extensive heterogeneity in CVID phenotypes, ranging from infections to autoimmunity to inflammatory conditions, overlapping with other more common disorders. The prolonged diagnostic odyssey drives excessive system-wide costs before diagnosis. Because there is no single causal mechanism, there are no genetic tests to definitively diagnose CVID. Here, we present PheNet, a machine learning algorithm that identifies patients with CVID from their electronic health records (EHRs). PheNet learns phenotypic patterns from verified CVID cases and uses this knowledge to rank patients by likelihood of having CVID. PheNet could have diagnosed more than half of our patients with CVID 1 or more years earlier than they had been diagnosed. When applied to a large EHR dataset, followed by blinded chart review of the top 100 patients ranked by PheNet, we found that 74% were highly probable to have CVID. We externally validated PheNet using >6 million records from disparate medical systems in California and Tennessee. As artificial intelligence and machine learning make their way into health care, we show that algorithms such as PheNet can offer clinical benefits by expediting the diagnosis of rare diseases.

Assessment of Sleep Disorders in Patients with CVID.

Inborn errors of immunity have been associated with reduced health-related quality of life and increased fatigue. Sleep disorders, which have been shown to contribute to fatigue and other health concerns, are prevalent in the general population, but there are limited studies evaluating these conditions in patients with common variable immunodeficiency (CVID). Our aim was to evaluate the prevalence of fatigue, sleep disturbances, and sleep-disordered breathing in adults with CVID. Patients completed 4 validated, self-administered questionnaires and a 1-night disposable home sleep apnea test. Our results demonstrated increased median Patient-Reported Outcomes Measurement Information System fatigue scores of 58.7 in patients with CVID in addition to clinically significant fatigue as measured by Fatigue Severity Scale score (median, 5.2) and overall poor sleep quality based on global Pittsburgh Sleep Quality Index score (median, 9.0). For CVID patients who completed the home sleep apnea test, 76.9% met criteria for sleep-disordered breathing with an Apnea-Hypopnea Index score of 5 or greater. The results of our study indicate that patients with CVID may have increased rates of undiagnosed sleep disorders that may contribute to increased fatigue and reduced health-related quality of life.

Dysfunctional mitochondria, disrupted levels of reactive oxygen species, and autophagy in B cells from common variable immunodeficiency patients.

Introduction: Common Variable Immunodeficiency (CVID) patients are characterized by hypogammaglobulinemia and poor response to vaccination due to deficient generation of memory and antibody-secreting B cells. B lymphocytes are essential for the development of humoral immune responses, and mitochondrial function, hreactive oxygen species (ROS) production and autophagy are crucial for determining B-cell fate. However, the role of those basic cell functions in the differentiation of human B cells remains poorly investigated. Methods: We used flow cytometry to evaluate mitochondrial function, ROS production and autophagy processes in human naïve and memory B-cell subpopulations in unstimulated and stimulated PBMCs cultures. We aimed to determine whether any alterations in these processes could impact B-cell fate and contribute to the lack of B-cell differentiation observed in CVID patients. Results: We described that naïve CD19+CD27- and memory CD19+CD27+ B cells subpopulations from healthy controls differ in terms of their dependence on these processes for their homeostasis, and demonstrated that different stimuli exert a preferential cell type dependent effect. The evaluation of mitochondrial function, ROS production and autophagy in naïve and memory B cells from CVID patients disclosed subpopulation specific alterations. Dysfunctional mitochondria and autophagy were more prominent in unstimulated CVID CD19+CD27- and CD19+CD27+ B cells than in their healthy counterparts. Although naïve CD19+CD27- B cells from CVID patients had higher basal ROS levels than controls, their ROS increase after stimulation was lower, suggesting a disruption in ROS homeostasis. On the other hand, memory CD19+CD27+ B cells from CVID patients had both lower ROS basal levels and a diminished ROS production after stimulation with anti-B cell receptor (BCR) and IL-21. Conclusion: The failure in ROS cell signalling could impair CVID naïve B cell activation and differentiation to memory B cells. Decreased levels of ROS in CVID memory CD19+CD27+ B cells, which negatively correlate with their in vitro cell death and autophagy, could be detrimental and lead to their previously demonstrated premature death. The final consequence would be the failure to generate a functional B cell compartment in CVID patients.

Gene Signature of Regulatory T Cells Isolated from Children with Selective IgA Deficiency and Common Variable Immunodeficiency.

Selective IgA deficiency (SIgAD) is the most common form and common variable immunodeficiency (CVID) is the most symptomatic form of predominant antibody deficiency. Despite differences in the clinical picture, a similar genetic background is suggested. A common feature of both disorders is the occurrence of autoimmune conditions. Regulatory T cells (Tregs) are the major immune cell type that maintains autoimmune tolerance. As the different types of abnormalities of Treg cells have been associated with autoimmune disorders in primary immunodeficiency (PID) patients, in our study we aimed to analyze the gene expression profiles of Treg cells in CVID and SIgAD patients compared to age-matched healthy controls. The transcriptome-wide gene profiling was performed by microarray technology. As a result, we analyzed and visualized gene expression patterns of isolated population of Treg cells. We showed the differences at the gene level between patients with and without autoimmunizations. Our findings suggest that the gene signatures of Treg cells isolated from SIgAD and CVID patients differ from age-matched healthy controls and from each other, presenting transcriptional profiles enriched in innate immune or Th response, respectively. The occurrence of autoimmunity in both types of PID is associated with down-regulation of class I IFNs signaling pathways. In summary, our findings improve our understanding of Treg dysfunctions in patients with common PIDs and associated autoimmunity.

The autoimmune rheumatological presentation of Common Variable Immunodeficiency Disorders with an overview of genetic testing.

Primary immunodeficiency Disorders (PIDS) are rare, mostly monogenetic conditions which can present to a number of specialties. Although infections predominate in most PIDs, some individuals can manifest autoimmune or inflammatory sequelae as their initial clinical presentation. Identifying patients with PIDs can be challenging, as some can present later in life. This is often seen in patients with Common Variable Immunodeficiency Disorders (CVID), where symptoms can begin in the sixth or even seventh decades of life. Some patients with PIDs including CVID can initially present to rheumatologists with autoimmune musculoskeletal manifestations. It is imperative for these patients to be identified promptly as immunosuppression could lead to life-threatening opportunistic infections in these immunocompromised individuals. These risks could be mitigated by prior treatment with subcutaneous or intravenous (SCIG/IVIG) immunoglobulin replacement or prophylactic antibiotics. Importantly, many of these disorders have an underlying genetic defect. Individualized treatments may be available for the specific mutation, which may obviate or mitigate the need for hazardous broad-spectrum immunosuppression. Identification of the genetic defect has profound implications not only for the patient but also for affected family members, who may be at risk of symptomatic disease following an environmental trigger such as a viral infection. Finally, there may be clinical clues to the underlying PID, such as recurrent infections, the early presentation of severe or multiple autoimmune disorders, as well as a relevant family history. Early referral to a clinical immunologist will facilitate appropriate diagnostic evaluation and institution of treatment such as SCIG/IVIG immunoglobulin replacement. This review comprises three sections; an overview of PIDs, focusing on CVID, secondly genetic testing of PIDs and finally the clinical presentation of these disorders to rheumatologists.

A large deletion in a non-coding regulatory region leads to NFKB1 haploinsufficiency in two adult siblings.

Mutations in NFkB pathway genes can cause inborn errors of immunity (IEI), with NFKB1 haploinsufficiency being a significant etiology for common variable immunodeficiency (CVID). Indeed, mutations in NFKB1 are found in 4 to 5% of in European and United States CVID cohorts, respectively; CVID representing almost » of IEI patients in European countries registries. This case study presents a 49-year-old patient with respiratory infections, chronic diarrhea, immune thrombocytopenia, hypogammaglobulinemia, and secondary lymphoma. Comprehensive genetic analysis, including high-throughput sequencing of 300 IEI-related genes and copy number variation analysis, identified a critical 2.6-kb deletion spanning the first untranslated exon and its upstream region. The region's importance was confirmed through genetic markers indicative of enhancers and promoters. The deletion was also found in the patient's brother, who displayed similar but milder symptoms. Functional analysis supported haploinsufficiency with reduced mRNA and protein expression in both patients. This case underscores the significance of copy number variation (CNV) analysis and targeting noncoding exons within custom gene panels, emphasizing the broader genomic approaches needed in medical genetics.

Diagnostic evaluation of paediatric autoimmune lymphoproliferative immunodeficiencies (ALPID): a prospective cohort study.

BACKGROUND: Lymphoproliferation and autoimmune cytopenias characterise autoimmune lymphoproliferative syndrome. Other conditions sharing these manifestations have been termed autoimmune lymphoproliferative syndrome-like diseases, although they are frequently more severe. The aim of this study was to define the genetic, clinical, and immunological features of these disorders to improve their diagnostic classification. METHODS: In this prospective cohort study, patients were referred to the Center for Chronic Immunodeficiency in Freiburg, Germany, between Jan 1, 2008 and March 5, 2022. We enrolled patients younger than 18 years with lymphoproliferation and autoimmune cytopenia, lymphoproliferation and at least one additional sign of an inborn error of immunity (SoIEI), bilineage autoimmune cytopenia, or autoimmune cytopenia and at least one additional SoIEI. Autoimmune lymphoproliferative syndrome biomarkers were determined in all patients. Sanger sequencing followed by in-depth genetic studies were recommended for patients with biomarkers indicative of autoimmune lymphoproliferative syndrome, while IEI panels, exome sequencing, or genome sequencing were recommended for patients without such biomarkers. Genetic analyses were done as decided by the treating physician. The study was registered on the German Clinical Trials Register, DRKS00011383, and is ongoing. FINDINGS: We recruited 431 children referred for autoimmune lymphoproliferative syndrome evaluation, of whom 236 (55%) were included on the basis of lymphoproliferation and autoimmune cytopenia, 148 (34%) on the basis of lymphoproliferation and another SoIEI, 33 (8%) on the basis of autoimmune bicytopenia, and 14 (3%) on the basis of autoimmune cytopenia and another SoIEI. Median age at diagnostic evaluation was 9·8 years (IQR 5·5-13·8), and the cohort comprised 279 (65%) boys and 152 (35%) girls. After biomarker and genetic assessments, autoimmune lymphoproliferative syndrome was diagnosed in 71 (16%) patients. Among the remaining 360 patients, 54 (15%) had mostly autosomal-dominant autoimmune lymphoproliferative immunodeficiencies (AD-ALPID), most commonly affecting JAK-STAT (26 patients), CTLA4-LRBA (14), PI3K (six), RAS (five), or NFκB (three) signalling. 19 (5%) patients had other IEIs, 17 (5%) had non-IEI diagnoses, 79 (22%) were unresolved despite extended genetics (ALPID-U), and 191 (53%) had insufficient genetic workup for diagnosis. 16 (10%) of 161 patients with a final diagnosis had somatic mutations. Alternative classification of patients fulfilling common variable immunodeficiency or Evans syndrome criteria did not increase the proportion of genetic diagnoses. INTERPRETATION: The ALPID phenotype defined in this study is enriched for patients with genetic diseases treatable with targeted therapies. The term ALPID might be useful to focus diagnostic and therapeutic efforts by triggering extended genetic analysis and consideration of targeted therapies, including in some children currently classified as having common variable immunodeficiency or Evans syndrome. FUNDING: Deutsche Forschungsgemeinschaft under Germany's Excellence Strategy. TRANSLATION: For the German translation of the abstract see Supplementary Materials section.

High Prevalence of Long COVID in Common Variable Immunodeficiency: An Italian Multicentric Study.

The long-term effects of SARS-CoV-2 infection represent a relevant global health problem. Long COVID (LC) is defined as a complex of signs and symptoms developed during or after SARS-CoV-2 infection and lasting > 12 weeks. In common variable immunodeficiency (CVID) patients, we previously reported higher risk of hospitalization and death during SARS-CoV-2 infection, as well as prolonged swab positivity and frequent reinfections. The aim of the present study was to assess the risk of LC in an Italian cohort of CVID patients. We used a translated version of the survey proposed by Centers for Disease Control and Prevention (CDC) to collect data on LC. In the enrolled cohort of 175 CVID patients, we found a high prevalence of LC (65.7%). The most frequent LC symptoms were fatigue (75.7%), arthralgia/myalgia (48.7%), and dyspnea (41.7%). The majority of patients (60%) experienced prolonged symptoms, for at least 6 months after infection. In a multivariate analysis, the presence of complicated phenotype (OR 2.44, 95% CI 1.88-5.03; p = 0.015), obesity (OR 11.17, 95% CI 1.37-90.95; p = 0.024), and female sex (OR 2.06, 95% CI 1.09-3.89; p = 0.024) significantly correlated with the development of LC. In conclusion, in this multicenter observational cohort study, we demonstrated that CVID patients present an increased prevalence of LC when compared to the general population. Improved awareness on the risk of LC in CVID patients could optimize management of this new and alarming complication of SARS-CoV-2 infection.

Evaluation of the Effectiveness of the 6 Warning Signs of the European Society for Immunodeficiencies for Primary Immunodeficiencies in Older Adults.

INTRODUCTION: Diagnostic delay in cases of primary immunodeficiency (PID) is a significant problem for clinicians, and most do not have sufficient awareness of this uncommon disorder. The European Society for Immunodeficiencies (ESID) has developed 6 warning signs to increase awareness of adult PIDs. The aim of this study was to determine the prevalence of PID in older adults regardless of the reason for presentation and to evaluate the effectiveness of the 6 warning signs of ESID in the diagnosis of PIDs. METHODS: The study included 1,331 patients aged ≥65 years who presented at our clinic for any reason and were questioned about the ESID 6 warning signs for PIDs. After the exclusion of reasons for secondary immunodeficiency (SID), all the patients underwent immunological evaluation for the diagnosis of potential underlying PIDs. RESULTS: After excluding 6 patients diagnosed with SID, PID was diagnosed in 16 (1.2%) of 1,325 older adults using ESID warning signs. The most common reasons for presentation were infection (69%) in the PID group and urticaria and/or angioedema (41.5%) in the non-PID group. The most common PID subgroup was common variable immunodeficiency (50%). In 12 of the patients diagnosed with PID, there was at least 1 positive ESID warning sign. In 4 patients, PID was determined despite negative ESID warning signs. The patients diagnosed with PID showed a significant, minimal level of agreement with questions 1 and 4 of the ESID warning signs (p < 0.001, ĸ = 0.204, p = 0.005, ĸ = 0.208, respectively). CONCLUSION: The ESID warning signs do not encompass all the symptoms and findings of PIDs. There is a need for more infection-centered questions to determine PIDs in older adults. Therefore, the ESID warning signs should be further developed.

Allogeneic Hematopoietic Cell Transplantation Ameliorated Asymptomatic Granulomatous and Lymphocytic Interstitial Lung Disease in a Patient With XIAP Deficiency.

X-linked inhibitor of apoptosis protein (XIAP) deficiency is an inborn error of immunity (IEI). Allogeneic hematopoietic cell transplantation (HCT) is currently the only curative therapy available for XIAP deficiency. Granulomatous and lymphocytic interstitial lung disease (GLILD) is a common immune-related lung complication of IEIs. We present a 6-year-old boy with XIAP deficiency and GLILD. Computed tomography showed lung nodes but no symptoms. Before HCT, GLILD was not managed with immunosuppressive therapy, because he was asymptomatic. The HCT procedure was subsequently performed. The post-HCT course was uneventful; follow-up computed tomography on day 46 showed nodules had disappeared. HCT could potentially ameliorate GLILD like other inflammatory processes associated with the underlying IEIs.

Neurological involvement in patients with primary immunodeficiency.

INTRODUCTION: Primary immunodeficiency diseases (PID) are defined by recurrent infections, allergies, autoimmunity, and malignancies. Neurologic symptoms are one of the major components of some immunodeficiency syndromes, such as Ataxia-Telangiectasia (AT), Nijmegen breakage syndrome (NBS), and Purine Nucleoside Phosphorylase (PNP) deficiency, which are considered as the primary involvement. Various pathological mechanisms, DNA repair disorders, metabolic abnormalities, and autoimmune phenomena have also been linked with neurological conditions. MATERIALS AND METHOD: We retrospectively assessed the neurological involvement in 108 patients out of 6000 with PID in this study. RESULTS: The female/male ratio of the cases was 49/59, and the median age was 13 years (min = 1; max = 60). Neurological problems were detected at a median age of 7 years (min = 0.5; max = 30). Di George Syndrome (DGS) and CVID (common variable immunodeficiency) were the most common diseases in our cohort (n = 31, 30% and n = 30, 27%, respectively). The most frequent outcomes were cognitive delay (n = 63, 58%), epilepsy (n = 25, 23%), and ataxia (n = 20, 18%). Central nervous system involvement was found in 99% of the patients (n = 107), and peripheral nervous system complication was found in only one patient with CVID and chronic inflammatory demyelinating polyneuropathy (CDIP). Cranial MRI was found to be abnormal in 74% (n = 80) of the patients. MRI findings included cerebellar atrophy (n = 33, 34%), white matter lesion (n = 27, 28.4%), cerebral atrophy (n = 21, 22.3%), gray matter lesion (n = 6, 6.3%), hydrocephalus (n = 5, 5,3%), and pituitary gland lesion (n = 3, 3.2%), intracranial hemorrhage (n = 3, 3%), intracranial vasculitis (n = 3, 2.7%), and arterio-venous malformation (n = 1, 0,9%). Primary involvement (a component of the disease) was 60% (n = 65), and secondary (infection or autoimmunity) and tertiary involvements (structural or incidental lesions) contributed 20% (n = 20) each in the patients. CONCLUSION: In this study, we describe the various neurologic findings of patients with PID. The neurologic presentation may represent the initial manifestation of certain types of PID. Early diagnosis and treatment are essential to prevent or reduce further neurologic damages.

Influence of Splenomegaly and Splenectomy on the Immune Cell Profile of Patients with Common Variable Immunodeficiency Disease.

PURPOSE: About 25% of patients with common variable immunodeficiency disease (CVID) have splenomegaly, necessitating sometimes splenectomy whom consequences on the immunological profile of CVID patients have never been studied. We analyzed 11 CVID patients' comprehensive blood immune cell phenotypes pre- and post-splenectomy. METHODS: Flow cytometry analyses of immune cell populations. RESULTS: Among 89 CVID cohort patients, 41 with splenomegaly, splenomegaly was strongly associated with granulomatous disease, autoimmune disorders, lymphoid hyperplasia, and/or portal hypertension. CVID patients with splenomegaly have significant peripheral lymphopenia (p = 0.001), and significantly fewer peripheral class-switched memory B cells (smBs) (p = 0.001), CD4+ T lymphocytes (p = 0.001), NK (p = 0.0001) and dendritic cells (p ≤ 0.01), and significantly more circulating CD4+ and CD8+ (p = 0.00001) T cell subset activation (p = 0.00005), than CVID patients without splenomegaly. Examination of splenectomy impact on circulating lymphocyte subset distributions demonstrated the drastically enhanced total circulating lymphocyte count post-splenectomy, predominantly B lymphocytes and CD8+ T cells. However, splenectomy did not change B cell distribution, with smBs remaining persistently low, in contrast to complete inversion of the circulating T cell composition, with reversal of the CD4+/CD8+ ratio suggesting that amplification of the CD8+ T cell compartment is a CVID characteristic in patients with splenomegaly. Our results highlight this CD8+ amplification in CVID-splenomegaly patients that might be explained by a homing effect to the spleen and/or possible chronic virus replication, which in turn could induce T cell expansions. CONCLUSION: Splenectomizing CVID patients with splenomegaly restores the absolute circulating lymphocyte count, suggesting that the decreased T cell count in the presence of splenomegaly cannot be used as an exclusive criterion for combined immunodeficiency.

Role of Skewed X-Chromosome Inactivation in Common Variable Immunodeficiency.

The term common variable immunodeficiency (CVID) encompasses a clinically diverse group of disorders, mainly characterized by hypogammaglobulinemia, insufficient specific antibody production, and recurrent infections. The genetics of CVID is complex, and monogenic defects account for only a portion of cases, typically <30%. Other proposed mechanisms include digenic, oligogenic, or polygenic inheritance and epigenetic dysregulation. In this study, we aimed to assess the role of skewed X-chromosome inactivation (XCI) in CVID. Within our cohort of 131 genetically analyzed CVID patients, we selected female patients with rare variants in CVID-associated genes located on the X-chromosome. Four patients harboring heterozygous variants in BTK (n = 2), CD40LG (n = 1), and IKBKG (n = 1) were included in the study. We assessed XCI status using the HUMARA assay and an NGS-based method to quantify the expression of the 2 alleles in mRNA. Three of the 4 patients (75%) exhibited skewed XCI, and the mutated allele was predominantly expressed in all cases. Patient 1 harbored a hypomorphic variant in BTK (p.Tyr418His), patient 3 had a pathogenic variant in CD40LG (c.288+1G>A), and patient 4 had a hypomorphic variant in IKBKG (p.Glu57Lys) and a heterozygous splice variant in TNFRSF13B (TACI) (c.61+2T>A). Overall, the analysis of our cohort suggests that CVID in a small proportion of females (1.6% in our cohort) is caused by skewed XCI and highly penetrant gene variants on the X-chromosome. Additionally, skewed XCI may contribute to polygenic effects (3.3% in our cohort). These results indicate that skewed XCI may represent another piece in the complex puzzle of CVID genetics.

Bone Mineral Density is Related to CD4+ T Cell Counts and Muscle Mass is Associated with B Cells in Common Variable Immunodeficiency Patients.

BACKGROUND: Common variable immunodeficiency (CVID) is a primary immunodeficiency characterized by chronic/recurrent respiratory infections, bronchiectasis, autoimmunity, inflammatory, gastrointestinal diseases and malignancies associated with a chronic inflammatory state and increased risk of osteoporosis and muscle loss. AIM: The aim of this study was to evaluate bone mineral density (BMD), body composition and their relationship with lymphocyte subpopulations in CVID patients. METHODS: Dual-energy X-ray absorptiometry was performed to assess BMD, lean mass, and fat mass in CVID patients. Peripheral blood CD4+, CD8+, and CD19+ cells were measured using flow cytometry. RESULTS: Thirty-three patients (37.3 ± 10.8 years old) were examined. Although only 11.8% of the individuals were malnourished (BMI <18.5 kg/m2), 27.7% of them had low skeletal muscle mass index (SMI), and 57.6% of them had low BMD. Patients with osteopenia/osteoporosis presented lower weight (p = 0.007), lean mass (p = 0.011), appendicular lean mass (p = 0.011), SMI (p = 0.017), and CD4+ count (p = 0.030). Regression models showed a positive association between CD4+ count and bone/muscle parameters, whereas CD19+ B cell count was only associated with muscle variables. Analysis of ROC curves indicated a cutoff value of CD4+ count (657 cells/mm3; AUC: 0.71, 95% CI 0.52-0.90) which was related to low BMD. Weight (p = 0.004), lean mass (p = 0.027), appendicular lean mass (p = 0.022), SMI (p = 0.029), total bone mineral content (p = 0.005), lumbar (p = 0.005), femoral neck (p = 0.035), and total hip BMD (p<0.001) were found to be lower in patients with CD4+ count below the cutoff. CONCLUSION: CVID patients presented with low BMD, which was associated with CD4+ count. Moreover, low muscle parameters were correlated with B cell count.

Phenotype and oxidative burst of low-density neutrophil subpopulations are altered in common variable immunodeficiency patients.

Common variable immunodeficiency disorder (CVID) is the most common form of primary antibody immunodeficiency. Due to low antibody levels, CVID patients receive intravenous or subcutaneous immunoglobulin replacement therapy as treatment. CVID is associated with the chronic activation of granulocytes, including an increased percentage of low-density neutrophils (LDNs). In this study, we examined changes in the percentage of LDNs and the expression of their surface markers in 25 patients with CVID and 27 healthy donors (HD) after in vitro stimulation of whole blood using IVIg. An oxidative burst assay was used to assess the functionality of LDNs. CVID patients had increased both relative and absolute LDN counts with a higher proportion of mLDNs compared to iLDNs, distinguished based on the expression of CD10 and CD16. Immature LDNs in the CVID and HD groups had significantly reduced oxidative burst capacity compared to mature LDNs. Interestingly we observed reduced oxidative burst capacity, reduced expression of CD10 after stimulation of WB, and higher expression of PD-L1 in mature LDNs in CVID patients compared to HD cells. Our data indicate that that the functional characteristics of LDNs are closely linked to their developmental stage. The observed reduction in oxidative burst capacity in mLDNs in CVID patients could contribute to an increased susceptibility to recurrent bacterial infections among CVID patients.

A patient with Pitt-Hopkins syndrome with concomitant common variable immunodeficiency.

In patients with 18q deletion syndrome (18q-), immunodeficiency, autoimmunity, and allergies have been described in a subset. Pitt-Hopkins syndrome represents a specific subset of patients with 18q- who have a proximal deletion involving the TCF4 gene or a TCF4 variant. Immunodeficiency has been reported in the overall 18q- population; however, immunodeficiency with Pitt-Hopkins syndrome has not been highlighted. This case report details the immunologic evaluations and the associated infections seen in a young adult with Pitt-Hopkins syndrome to underscore the challenges of managing adults with a complex phenotype who develop frequent infections. This patient with Pitt-Hopkins syndrome ultimately fulfilled the diagnostic criteria for common variable immunodeficiency. Immunoglobulin replacement has led to a somewhat improved infection pattern, although she continues to have aspiration events leading to pneumonia. This case highlights the clinical evolution of Pitt-Hopkins syndrome and serves as a reminder that immunodeficiency can occur in this syndrome.

Challenges for gene editing in common variable immunodeficiency disorders: Current and future prospects.

The original CRISPR Cas9 gene editing system and subsequent innovations offers unprecedented opportunities to correct severe genetic defects including those causing Primary Immunodeficiencies (PIDs). Common Variable Immunodeficiency Disorders (CVID) are the most frequent symptomatic PID in adults and children. Unlike many other PIDs, patients meeting CVID criteria do not have a definable genetic defect and cannot be considered to have an inborn error of immunity (IEI). Patients with a CVID phenotype carrying a causative mutation are deemed to have a CVID-like disorder consequent to an IEI. Patients from consanguineous families often have highly penetrant early-onset autosomal recessive forms of CVID-like disorders. Individuals from non-consanguineous families may have autosomal dominant CVID-like disorders with variable penetrance and expressivity. This essay explores the potential clinical utility as well as the current limitations and risks of gene editing including collateral genotoxicity. In the immediate future the main application of this technology is likely to be the in vitro investigation of epigenetic and polygenic mechanisms, which are likely to underlie many cases of CVID and CVID-like disorders. In the longer-term, the CRISPR Cas9 system and other gene-based therapies could be utilized to treat CVID-like disorders, where the underlying IEI is known.

Common variable immunodeficiency, cross currents, and prevailing winds.

Common variable immunodeficiency (CVID) is a heterogenous disease category created to distinguish late-onset antibody deficiencies from early-onset diseases like agammaglobulinemia or more expansively dysfunctional combined immunodeficiencies. Opinions vary on which affected patients should receive a CVID diagnosis which confuses clinicians and erects reproducibility barriers for researchers. Most experts agree that CVID's most indeliable feature is defective germinal center (GC) production of isotype-switched, affinity-maturated antibodies. Here, we review the biological factors contributing to CVID-associated GC dysfunction including genetic, epigenetic, tolerogenic, microbiome, and regulatory abnormalities. We also discuss the consequences of these biological phenomena to the development of non-infectious disease complications. Finally, we opine on topics and lines of investigation we think hold promise for expanding our mechanistic understanding of this protean condition and for improving the lives of affected patients.

Secondary hypogammaglobulinemia in adults-A large retrospective cohort study.

BACKGROUND AND OBJECTIVE: IgG replacement therapy (IgG-RT) has radically changed the clinical evolution of primary immunodeficiencies, yet the information regarding secondary hypogammaglobulinemia (SHG) is insufficient or conflicting. We aim to describe clinical features, evolution and treatment of SHG patients in our center. METHODS: Dynamic retrospective cohort between January 2001 and July 2021 of adults with gamma globulin fraction <0.6g/dL in a serum protein electrophoresis and a coincident decrease of IgG levels - with a disease-related SHG or treatment that reduces serum immunoglobulins. RESULTS: We included 1012 patients with SHG with a median follow-up of 5 years (IQR 2-8). Hematological diseases were identified in 95% of the patients and 61% received drugs related to SHG. Sixty five percent had more than one etiological factor associated with SHG. Infectious diseases were present in 69% of the patients, 48% had respiratory infections and 17% had severe infections. There was statistical association between respiratory and severe infections with multiple myeloma (MM), lymphoma and rituximab. MGUS had less infections and death compared with other etiologies. IgG-RT was indicated in 18.7% of the patients and 4.6% received it for more than 6 months with variable intervals. Among the latter group, there was a significant reduction of all-type infections and respiratory infections with IgG-RT (p<0.001), and it was consistent with similar findings in lymphoma, MM and all IgG levels subgroups. CONCLUSION: SHG was associated with more than one etiological factor and a high frequency of infections. IgG-RT indication was irregular yet still effective. It is relevant to consider IgG levels screening, monitoring and accurate indication of IgG-RT.

Autoimmune lymphoproliferative immunodeficiencies (ALPIDs): A proposed approach to redefining ALPS and other lymphoproliferative immune disorders.

Chronic nonmalignant lymphoproliferation and autoimmune cytopenia are relevant manifestations of immunohematologic diseases of childhood. Their diagnostic classification is challenging but important for therapy. Autoimmune lymphoproliferative syndrome (ALPS) is a genetically defined inborn error of immunity combining these manifestations, but it can explain only a small proportion of cases. Diagnostic categories such as ALPS-like disease, common variable immunodeficiency, or Evans syndrome have therefore been used. Advances in genetics and increasing availablity of targeted therapies call for more therapy-oriented disease classification. Moreover, recent discoveries in the (re)analysis of genetic conditions affecting FAS signaling ask for a more precise definition of ALPS. In this review, we propose the term autoimmune lymphoproliferative immunodeficiencies for a disease phenotype that is enriched for patients with genetic diseases for which targeted therapies are available. For patients without a current molecular diagnosis, this term defines a subgroup of immune dysregulatory disorders for further studies. Within the concept of autoimmune lymphoproliferative immunodeficiencies, we propose a revision of the ALPS classification, restricting use of this term to conditions with clear evidence of perturbation of FAS signaling and resulting specific biologic and clinical consequences. This proposed approach to redefining ALPS and other lymphoproliferative conditions provides a framework for disease classification and diagnosis that is relevant for the many specialists confronted with these diseases.