Search

Purpose of Review: The pathogenesis of granulomatous disease in common variable immunodeficiency (CVID) is still largely unknown, which hampers effective treatment. This review describes the current knowledge on the pathogenesis of granuloma formation in CVID and the biological basis of the current treatment options., Recent Findings: Histological analysis shows that T and B cells are abundantly present in the granulomas that are less well organized and are frequently associated with lymphoid hyperplasia. Increased presence of activation markers such as soluble IL-2 receptor (sIL-2R) and IFN-ɣ, suggest increased Th1-cell activity. Moreover, B-cell abnormalities are prominent in CVID, with elevated IgM, BAFF, and CD21low B cells correlating with granulomatous disease progression. Innate immune alterations, as M2 macrophages and neutrophil dysregulation, indicate chronic inflammation. Therapeutic regimens include glucocorticoids, DMARDs, and biologicals like rituximab., Summary: Our review links the biological context of CVID with granulomatous disease or GLILD to currently prescribed therapies and potential targeted treatments., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc.)

Common variable immunodeficiency (CVID) is a disorder characterized by hypogammaglobulinemia resulting in recurrent infections. While autoimmune disorders are common in patients with CVID, no association has been reported between CVID and immune thrombotic thrombocytopenic purpura (iTTP), a disorder most often caused by autoantibodies that compromise the activity of the enzyme ADAMTS13. Reduced ADAMTS13 activity results in the accumulation of large von Willebrand factor multimers that can consume platelets and cause microvascular thrombosis and organ injury, ultimately resulting in mortality in most cases of untreated iTTP. Here, we report a 12-year-old male with CVID who developed iTTP, underwent therapeutic plasma exchange (TPE), and subsequently recovered. We conducted a systematic review for other cases of CVID co-occurring with iTTP and present additional cases of this rare presentation. We highlight the importance of prompt recognition of iTTP in a patient with CVID and timely initiation of TPE., (© 2024 The Author(s). Journal of Clinical Apheresis published by Wiley Periodicals LLC.)

Purpose of Review: Liver disease has emerged as a major risk factor for increased mortality in patients with common variable immunodeficiency (CVID). This is mostly due to presinusoidal portal hypertension (PHTN) frequently secondary to nodular regenerative hyperplasia (NRH). Its pathogenesis is still poorly understood and treatment strategies for its various stages are often guided by trial and error. This review summarizes the most recent findings in the light of previous literature., Recent Findings: In the last 2 years, different groups have addressed pathology, diagnostics, treatment, and liver transplantation. Histological examinations seem to support the pathogenetic sequence of T-cell mediated infiltration and damage of the sinusoidal space with secondary development of NRH, pericellular fibrosis, and the manifestation of PHTN. While markers of the early phase - beyond slight elevation of cholestatic enzymes - are still missing, elevated liver stiffness and splenomegaly above 16 cm longitudinal diameter have been suggested as warning signs for PHTN in CVID patients. Data on immunosuppressive treatment of this manifestation is still very heterogeneous, but a recent report on liver transplantation was encouraging for end stage liver disease., Summary: Liver disease deserves higher attention in the management of CVID. More studies are needed to understand its pathogenesis and optimal treatment., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

The gut microbiota serves a crucial role in the development of host immunity. Immunocompromised patients are particularly vulnerable to dysbiosis not only by virtue of a defect in the immune system but also due to increased susceptibility to infection and multiple courses of antibiotic therapy. Fecal microbiota transplantation is by far the most effective option for restoring gastrointestinal homeostasis. However, it is contraindicated in patients with significant primary and secondary immunodeficiencies. This article presents the case of a 59-year-old patient with common variable immunodeficiency, after splenectomy at age 39 for primary immune thrombocytopenia, who manifested diarrhea of up to 10 stools per day accompanied by secondary malnutrition and cachexia. The patient was admitted to the hospital on multiple occasions due to this condition, with stool PCR tests confirming a HHV-5 ( Cytomegalovirus , CMV) infection. Following the administration of valganciclovir, the patient's complaints diminished, although, upon cessation of the drug, the symptoms recurred. In addition, the patient had an intestinal infection with C. difficile etiology. Given that the patient's therapeutic options had been exhausted, after obtaining informed consent from the patient and approval from the bioethics committee to conduct a medical experiment, treatment of diarrhea was undertaken by fecal microbiota transplantation with the certified preparation Mbiotix HBI from the Human Biome Institute. The patient underwent two transplants, with a one-week interval between them. The initial procedure was performed using the endoscopic method, while the subsequent was conducted using the capsule method. Following the administration of the applied treatment, the patient's symptoms were successfully alleviated, and no adverse effects were observed. A microbiological analysis of the intestinal microbiota was conducted prior to and following transplantation via next-generation sequencing (NGS). No recurrence of symptoms was observed during the two-year follow-up period. To the best of our knowledge, this is the first fecal microbiota transplantation in an adult patient with primary and secondary immunodeficiency., Competing Interests: The authors declare the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Napiórkowska-Baran, Biliński, Pujanek, Hałakuc, Pietryga, Szymczak, Deptuła, Rosada and Bartuzi.)

Natural antibodies (NAbs) occurring in individuals without prior exposure to specific antigens, provide direct first barrier protection against pathogens, and exert immunoregulation thus actively contributing to the maintenance of immune homeostasis, controlling inflammatory processes and preventing autoimmunity. Common variable immunodeficiency (CVID) is a heterogeneous group of disorders characterized by a compromised immune function that brings into focus the role of NAbs. Our aim was to explore whether NAb levels could serve as potential key indicators in CVID for monitoring disease progression and predicting outcomes. In this study, we analyzed a Hellenic cohort of 56 patients with CVID (31 newly diagnosed and 25 under immunoglobulin replacement therapy-IgRT) and 33 healthy controls, for total Ig levels and serum IgM and IgG NAb levels against five informative target-antigens of NAbs, namely, actin, DNA, carbonic anhydrase, F(ab΄) 2 fragments of human IgG and TriNitroPhenyl. In addition, follow-up pre- and post- IgRT samples were analyzed in ten (10) patients of our cohort. Results showed that Ig-treated patients exhibited significantly lower IgM NAb levels than untreated patients and healthy controls against all panel antigens. In the follow-up samples, pre-treatment IgM NAb levels negatively correlated with total serum IgM. This imbalance was only partially restored after IgRT, with a significant decrease in IgM NAb levels observed in nine out of ten patients. Moreover, post-treatment patients with recurrent infections presented significantly lower IgM NAb levels, a reduction also observed in patients with bronchiectasis independently of treatment status. On the contrary, post-treatment patients with enteropathy had significantly higher IgM NAb levels against all panel antigens, an increase also noted in patients with autoimmune diseases. Regarding IgG NAbs, replacement therapy restored levels to those of healthy controls. In conclusion, impaired NAb levels are found in CVID patients, particularly related to certain phenotypes. Moreover, the significant decrease in IgM NAb levels after IgRT suggests a potential association with disease course and complications. The results suggest that administration of human IgM NAbs may be an effective combinatorial treatment in selected patients. Further research is needed to understand the functional roles of NAbs in CVID and its complex clinical phenotypes., (© 2024. The Author(s).)

Background: The main treatment of common variable immunodeficiency (CVID) is to maintain immunoglobulin G (IgG) levels within the target range. However, trough IgG levels differ among patients with similar body mass index (BMI) and those receiving the same dose of immunoglobulin replacement therapy (IGRT). A crucial factor that underlies these differences is the presence of extensive bronchiectasis, which is associated with the immunoglobulin salvage pathway. Objective: We compared trough IgG levels in patients with CVID and with and in those without bronchiectasis who had received the same dose of IGRT for 2 years to determine the association of IgG level with infection frequency. Method: This retrospective cohort study included 61 patients with CVID, of whom 21 had bronchiectasis. We reviewed the electronic records for demographic variables, baseline immunoglobulin levels, mean trough IgG levels over 2 years, efficacy levels (trough IgG level - baseline IgG level), the time interval from treatment initiation to achieving the target trough IgG level (700 mg/dL), and the number of infections. Results: The median age of the patients was 39 years (IQR, 27-51), and 29 were women (47.5%). There were no significant differences between the groups in terms of age, age at diagnosis, delay in diagnosis, sex, BMI, IGRT type (subcutaneous or intravenous), and baseline immunoglobulin levels. Trough IgG and efficacy levels were lower (P < 0.001 and P = 0.016, respectively), the time required to achieve the target IgG level was longer in patients with bronchiectasis than in those without bronchiectasis, and this time interval was significantly associated with the infection frequency. Trough IgG and albumin levels were correlated (p = 0.007), with minor differences between the groups (p = 0.04). Conclusion: Bronchiectasis was significantly associated with a longer time to achieve the target IgG levels. These long-term differences between the patients with and those without bronchiectasis have significant clinical implications.

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., Competing Interests: Declaration of Competing Interest Ethics approval was not required for this paper, as it is a perspective of current literature. HL is an investigator for Intellia. Others authors do not have a conflict of interest or competing interests. This article was not funded. RA conceived the idea and wrote the first draft. All authors have contributed to the content in this manuscript., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Common variable immunodeficiency (CVID) is the most common primary immune deficiency characterized by impaired production of specific immunoglobulin. The clinical manifestations are heterogeneous including acquisition of recurrent bacterial infections after a period of wellness, lymphoproliferation, autoimmunity, pulmonary disease, liver disease, enteropathy, granulomas, and an increased risk of malignancy. The etiology of CVID is largely unknown, with a considerable number of patients having an underlying genetic defect causing immune dysregulation. The antibody deficiency found in CVID is treated with lifelong immunoglobulin therapy, which is preventative of the majority of infections when given regularly., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Common variable immunodeficiency (CVID) has been subdivided into five phenotypes, including one marked by non-infectious enteropathies that lead to significant morbidity and mortality. We examined a large national registry of patients with CVID to better characterize this population and understand how the presence of enteropathy influences nutritional status, patient function, and the risk of additional non-infectious disorders in CVID patients. We also sought to illustrate the range of treatment strategies for CVID-associated enteropathies. We extracted patient data from the United States Immunodeficiency Network (USIDNET) database, which included 1415 patients with CVID, and compared those with and without intestinal disorders. Demographic and genetic profiles, functional status, and treatments targeting intestinal disorders are reported. Intestinal disorders were present in 20% of patients with CVID, including chronic diarrhea, inflammatory bowel disease, malabsorption, and others. Compared to those without enteropathies, this patient subset exhibited significantly lower Karnofsky-Lansky functional scores, greater reliance on nutritional support, higher rates of vitamin deficiencies, and increased prevalence of hematologic disorders, liver disease, pulmonary disease, granulomatous disease, and lymphoma. Genetic data were reported for only 5% of the cohort. No mutations segregated significantly to patients with or without intestinal disease. Corticosteroids were most frequently used for treatment. Patients with CVID-associated intestinal disorders exhibit higher rates of autoimmune and inflammatory comorbidities, lymphoma, malnutrition, and debility. We review recent studies implicating specific pathways underlying this immune dysregulation. Further studies are needed to evaluate the role of targeted immunomodulatory therapies for CVID-associated intestinal disorders., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Purpose of Review: Common variable immunodeficiency (CVID) is the most common symptomatic inborn error of immunity. The disorder is characterized by variable clinical and immunological manifestations, and, in a small minority of patients, a monogenic cause may be identified. In this review, we focalized on three different monogenic forms of CVID-like disease., Recent Findings: Activated phosphoinositide 3-kinase delta syndrome (APDS) is a rare disorder characterized by hyperactivated class I phosphatidylinositol-3 kinase (PI3K) pathway. Affected patients present with respiratory infectious episodes, impaired viral clearance and lymphoproliferation. Recently, a direct PI3K inhibitor has been approved and it showed encouraging results both in controlling clinical and immunological manifestations of the disease. On the other hand, patients with defects in CTLA-4 or LRBA gene present with life-threatening immune dysregulation, autoimmunity and lymphocytic infiltration of multiple organs. Abatacept, a soluble cytotoxic T lymphocyte antigen 4 (CTLA-4) fusion protein that acts as a costimulation modulator, has been widely implemented for affected patients with good results as bridge treatment., Summary: Understanding the biological basis of CVID is important not only for enriching our knowledge of the human immune system, but also for setting the basis for potential targeted treatments in this disorder., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc.)

Background: Common variable immunodeficiency disorder (CVID) is a condition associated with recurrent infections and non-infectious outcomes, including lung disease like bronchiectasis and granulomatous and lymphocytic interstitial lung diseases (GLILD), autoimmune disease, enteropathy, and lymphoma. Treatment involves initiation of replacement immunoglobulin (Ig), which is a lifelong commitment. Prior to Ig replacement, life expectancy for patients with CVID was less than 15 years. With replacement Ig, it has improved to over 50 years. In most cases, patients present to a clinician with a history of recurrent infections, and treatment is indicated. However, in patients with asymptomatic disease, the best timing to start treatment can be difficult to determine. Case: We present a case of an otherwise healthy male who had an incidental diagnosis of CVID. Results: Workup revealed hypogammaglobulinemia for over 30 year. Discussion: Though successful in reducing infections, Ig replacement can come with many side effects, as well as a heavy medical burden to the patient and the healthcare system. It is also a big life adjustment, and can greatly affect a patient's quality of life. In the military, a diagnosis of an immunodeficiency, and the need for monthly intravenous immunoglobulin (IVIG) can be detrimental to deployment readiness, and a patient's military career. Risks and benefits need to be weighed prior to initiating Ig therapy.

Introduction: Primary antibody deficiencies (PAD) are inborn defects of the immune system that result in increased susceptibility to infections. Despite the reduced response to vaccination, PAD patients still benefit from it by reducing the risk of severe infections and complications. SARS-CoV-2 vaccines are recommended in PAD patients, but their immune effects are poorly studied. Here, we analyze virus-specific T-cell responses in PAD patients after booster vaccination against SARS-CoV-2., Patients and Methods: The study included 57 adult PAD patients on long-term immunoglobulin replacement therapy (IgRT) diagnosed with X-linked agammaglobulinemia (XLA; n = 4), common variable immunodeficiency (CVID; n = 33), isotype defects or IgG subclass deficiency (n = 6), and unclassified IgG deficiency (n = 14). Of those, 49 patients (86%) received vaccination against SARS-CoV-2 using mRNA vaccine (Pfizer-BioNTech). T-cell responses were assessed at a median of 21 (13 - 30) weeks after the booster dose (mainly the third dose) using commercially available interferon-gamma release assay (IGRA) with recombinant SARS-CoV-2 spike S1 protein., Results: Vaccinated PAD patients showed an increased (3.8-fold, p = 0.004) release of IFN-γ upon S1 stimulation. In this group, we also documented higher serum levels of anti-SARS-CoV-2 IgG (4.1-fold, p = 0.01), although they were not associated with IGRA results. Further subgroup analysis revealed very similar IGRA responses in CVID and unclassified IgG deficiencies that were 2.4-fold increased compared to XLA and 5.4-fold increased compared to patients with isotype defects or IgG subclass deficiencies (e.g., vs. CVID: p = 0.016). As expected, CVID and XLA patients showed decreased serum titers of anti-SARS-CoV-2 antibodies compared to other studied groups (e.g., CVID vs. unclassified IgG deficiency: 4.4-fold, p = 0.006). The results did not depend directly on IgRT mode or dose, number of vaccine doses and time from the last booster dose, and clinical manifestations of PAD. Interestingly, anti-SARS-CoV-2 titers were positively correlated with serum immunoglobulin levels before IgRT (e.g., for IgA: r = 0.45, p<0.001; for IgG: r = 0.34, p = 0.009) and the percentage of peripheral blood NK cells (r = 0.48, p<0.001)., Conclusions: Our results documented satisfactory in vitro cellular immune response in PAD patients after booster SARS-CoV-2 vaccination. Therefore, even patients with agammaglobulinemia should benefit from vaccination due to the apparent induction of cell-mediated immunity, which, together with IgRT, grants comprehensive protection against the pathogen., Competing Interests: The authors 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., (Copyright © 2023 Mizera, Dziedzic, Drynda, Gradzikiewicz, Jakieła, Celińska-Löwenhoff, Padjas, Matyja-Bednarczyk, Zaręba and Bazan-Socha.)

Common variable immunodeficiency (CVID) is a primary immunodeficiency characterized by low levels of serum immunoglobulins and increased susceptibility to infections, autoimmune disorders and cancer. CVID embraces a plethora of heterogeneous manifestations linked to complex immune dysregulation. While CVID is thought to be due to genetic defects, the exact cause of this immune disorder is unknown in the large majority of cases. Compelling evidences support a linkage between the gut microbiome and the CVID pathogenesis, therefore a potential for microbiome-based treatments to be a therapeutic pathway for this disorder. Here we discuss the potential of treating CVID patients by developing a gut microbiome-based personalized approach, including diet, prebiotics, probiotics, postbiotics and fecal microbiota transplantation. We also highlight the need for a better understanding of microbiota-host interactions in CVID patients to prime the development of improved preventive strategies and specific therapeutic targets., (© 2023. The Author(s).)

Purpose: Humoral and cellular immune responses were described after COVID-19 vaccination in patients with common variable immunodeficiency disorder (CVID). This study aimed to investigate SARS-CoV-2-specific antibody quality and memory function of B cell immunity as well as T cell responses after COVID-19 vaccination in seroresponding and non-responding CVID patients., Methods: We evaluated antibody avidity and applied a memory B cell ELSPOT assay for functional B cell recall memory response to SARS-CoV-2 after COVID-19 vaccination in CVID seroresponders. We comparatively analyzed SARS-CoV-2 spike reactive polyfunctional T cell response and reactive peripheral follicular T helper cells (pT FH ) by flow cytometry in seroresponding and non-seroresponding CVID patients. All CVID patients had previously failed to mount a humoral response to pneumococcal conjugate vaccine., Results: SARS-CoV-2 spike antibody avidity of seroresponding CVID patients was significantly lower than in healthy controls. Only 30% of seroresponding CVID patients showed a minimal memory B cell recall response in ELISPOT assay. One hundred percent of CVID seroresponders and 83% of non-seroresponders had a detectable polyfunctional T cell response. Induction of antigen-specific CD4 + CD154 + CD137 + CXCR5 + pT FH cells by the COVID-19 vaccine was higher in CVID seroresponder than in non-seroresponder. Levels of pT FH did not correlate with antibody response or avidity., Conclusion: Reduced avidity and significantly impaired recall memory formation after COVID-19 vaccination in seroresponding CVID patients stress the importance of a more differentiated analysis of humoral immune response in CVID patients. Our observations challenge the clinical implications that follow the binary categorization into seroresponder and non-seroresponder., (© 2023. The Author(s).)

Purpose: The clinical spectrum of common variable immunodeficiency (CVID) includes predisposition to infections, autoimmune/inflammatory complications and malignancy. Liver disease is developed by a proportion of patients with CVID, but limited evidence is available about its prevalence, pathogenesis and prognostic outcome. This lack of evidence leads to the absence of guidelines in clinical practice. In this study, we aimed at defining the characteristics, course and management of this CVID complication in Spain., Methods: Spanish reference centers were invited to complete a cross-sectional survey. Thirty-eight patients with CVID-related liver disease from different hospitals were evaluated by a retrospective clinical course review., Results: In this cohort, abnormal liver function and thrombocytopenia were found in most of the patients (95% and 79% respectively), in keeping with the higher incidence of abnormal liver imaging and splenomegaly. The most common histological findings included nodular regenerative hyperplasia (NRH) and lymphocytic infiltration, which have been associated with portal hypertension (PHTN) leading to a poorer prognosis. Autoimmune/inflammatory complications occurred in 82% of the CVID patients that developed liver disease and 52% of the patients treated with immunomodulators showed a reduction in the liver function tests' abnormalities during treatment. Among the experts that conducted the survey, there was 80% or more consensus that the workup of CVID-related liver disease requires liver profile, abdominal ultrasound and transient elastography. The majority agreed that liver biopsy should be essential for diagnosis. There was 94% consensus that endoscopic studies should be performed in the presence of PHTN. However, there was 89% consensus that there is insufficient evidence on the management of these patients., Conclusion: Liver disease varies in severity and may contribute substantially to morbidity and mortality in patients with CVID. Hence the importance of close follow-up and screening of this CVID complication to prompt early targeted intervention. Further research is needed to evaluate the pathophysiology of liver disease in patients with CVID to identify personalized treatment options. This study emphasizes the urgent need to develop international guidelines for the diagnosis and management of this CVID complication., Competing Interests: The authors 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., (Copyright © 2023 Daza-Cajigal, Segura-Guerrero, López-Cueto, Robles-Marhuenda, Camara, Gerra-Galán, Gómez-de-la-Torre, Avendaño-Monje, Sánchez-Ramón, Bosque-Lopez, Quintero-Duarte, Bonet-Vidal and Pons.)

Abstract: Common variable immunodeficiency (CVID) is a primary immunodeficiency disorder that results in decreased immunity and increased infection risk. This multisystem disorder often presents as recurrent, prolonged respiratory tract infections. Other manifestations include chronic lung disease, systemic granulomatous disease, malignancies, enteropathy, splenomegaly, and autoimmune disease including cytopenias. Diagnosis often is delayed, affecting patient quality of life, morbidity, and mortality. This article reviews the presentation, diagnosis, and management of patients with CVID., (Copyright © 2023 American Academy of Physician Associates.)

Background and Objectives: Common variable immunodeficiency is a systemic disease and not solely a disease of humoral immunity. Neurologic symptoms associated with common variable immunodeficiency are underrecognized and warrant further study. This work aimed to characterize the neurologic symptoms reported by people living with common variable immunodeficiency., Methods: We conducted a single academic medical center study of neurologic symptoms reported by adults previously diagnosed with common variable immunodeficiency. We used a survey of common neurologic symptoms to determine the prevalence of these symptoms in a population with common variable immunodeficiency and further assessed these patient-reported symptoms with validated questionnaires and compared symptom burden with other neurologic conditions., Results: A volunteer sample of adults (aged 18 years or older) previously diagnosed with common variable immunodeficiency at the University of Utah Clinical Immunology/Immune Deficiency Clinic who were able to read and comprehend English and willing and able to answer survey-based questions were recruited. Of 148 eligible participants identified, 80 responded and 78 completed the surveys. The mean age of respondents was 51.3 years (range 20-78 years); 73.1% female and 94.8% White. Patients with common variable immunodeficiency reported many common neurologic symptoms (mean 14.6, SD 5.9, range 1-25), with sleep issues, fatigue, and headache reported by more than 85%. Validated questionnaires addressing specific neurologic symptoms supported these results. T-scores on Neuro QoL questionnaires for sleep (mean 56.4, SD 10.4) and fatigue (mean 54.1, SD 11) were higher, indicating more dysfunction, than in the reference clinical population ( p < 0.005). The Neuro QoL questionnaire for cognitive function showed a lower T-score (mean 44.8, SD 11.1) than that in the reference general population ( p < 0.005), indicating worse function in this domain., Discussion: Among survey respondents, there is a marked burden of neurologic symptoms. Given the impact of neurologic symptoms on health-related quality-of-life measures, clinicians should screen patients with common variable immunodeficiency for the presence of these symptoms and offer referral to neurologists and/or symptomatic treatment when indicated. Frequently prescribed neurologic medications may also affect the immune system, and neurologists should consider screening patients for immune deficiency before prescribing them., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Introduction: Common variable immunodeficiency (CVID) is the most common symptomatic primary immunodeficiency. Due to the wide spectrum of the CVID manifestations, the differential diagnosis becomes complicated, ends in a diagnostic delay and increased morbidity and mortality rates. Autoimmunity is one of the important complications associated with CVID. While immunoglobulin replacement therapy has considerably decreased the mortality rate in CVID patients, mainly infection-related mortality, other complications such as autoimmunity appeared prevalent and, in some cases, life threatening., Areas Covered: In this article, genetics, responsible immune defects, autoimmune manifestations in different organs, and the diagnosis and treatment processes in CVID patients are reviewed, after searching the literature about these topics., Expert Opinion: Considering the many phenotypes of CVID and the fact that it remained undiagnosed until older ages, it is important to include various manifestations of CVID in the differential diagnosis. Due to the different manifestations of CVID, including autoimmune diseases, interdisciplinary collaboration of physicians from different fields is highly recommended, as discussed in the manuscript. Meanwhile, it is important to determine which patients could benefit from genetic diagnostic studies since such studies are not necessary for establishing the diagnosis of CVID.

Common variable immunodeficiency (CVID) is the most common symptomatic primary immunodeficiency. It is characterized by impaired B-cell differentiation. Although patients can be diagnosed with CVID anytime during their lifetime, most patients have symptoms for 5-9 years before their diagnosis. The diagnosis of CVID starts with a detailed history focusing on the infectious and noninfectious manifestations of the disease. In patients who are suspected to experience CVID, quantitative immunoglobulins (Ig) should be checked to confirm the diagnosis. IgG should be at least 2 times less than the age-specific SD along with either a low IgA or IgM and with evidence of impaired vaccine response. CVID is usually associated with infectious and/or noninfectious conditions, the latter of which can be inflammatory, autoimmune, lymphoproliferative, or malignant, among other manifestations. Ig therapy has positively affected the disease course of patients with infectious complications but has limited effect on the noninfectious manifestations because the noninfectious complications are related to immune dysregulation involving B cells and T cells rather than primarily due to antibody deficiency. When the gastrointestinal (GI) system is involved, patients with CVID may display signs and symptoms that mimic several GI conditions such as celiac disease, pernicious anemia, or inflammatory bowel diseases. The inflammatory bowel disease-like condition is usually treated with steroids, 5-aminosalicylates, thiopurines, or biologic agents to control the inflammation. In this review, the clinical presentations, diagnostic considerations, and therapeutic options for GI manifestations of CVID will be discussed to facilitate the individualized management of these often-complex patients., (Copyright © 2022 by The American College of Gastroenterology.)

Hydroa vacciniforme-like lymphoproliferative disorder (HV-LPD) is a cutaneous form of chronic active Epstein-Barrvirus (EBV) infection, which can develop into the extremely rare systemic lymphoma. Patients with Inborn errors of immunity (IEI), such as common variable immunodeficiency (CVID), are at higher risk of developing a severe course of infections especially viral and malignancies than the general population. The aim of the study was to present complex diagnostic and therapeutic management of HV-LPD. The clinical diagnosis was confirmed at the histological and molecular level with next generation sequencing. HV-LPD was diagnosed in a patient with CVID and chronic active Epstein-Barr virus (CAEBV) infection. The patient was refractory to CHOP chemotherapy and immunosuppressive treatment in combination with antiviral drugs (prednisone, bortezomib, gancyclovir). The third-party donor EBV-specific cytotoxic T cells (EBV-CTL, tabelecleucel) were used, which stabilised the disease course. Finally, matched unrelated donor hematopoietic cell transplantation (MUD-HCT) was performed followed by another cycle of EBV-CTL., Competing Interests: The authors 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., (Copyright © 2022 Grześk, Kołtan, Dąbrowska, Urbańczyk, Małdyk, Małkowski, Bogiel, Dębski, Czyżewski, Wysocki and Styczyński.)

Antibodydeficiencies Epidemiology, Clinical manifestation, Diagnostics and Therapy Abstract. Primary Immune Deficiencies (PID) are caused by a genetically induced malformation/dysfunction of the immune system. Leading symptoms include susceptibility to infection, autoimmune diseases, lymphoproliferative, allergic as well as malignant diseases. They can be divided into ten main groups, including the primary antibody deficiency syndromes (PAD) in adults. The most well-known PADs include the variable immunodeficiency syndrome (CVID), Bruton's agammaglobulinaemia, IgG subclass deficiencies, immunoglobulin A deficiency, Antibody deficiency and transient childhood hypogammaglobulinaemia. Secondary hypogammaglobulinaemia by medicinal products, haematological diseases, malignancies and infections should be excluded. Delayed diagnosis of CVID is associated with a significant increase in morbidity and an increase in mortality. In addition to vaccinations, immunoglobulin replacement therapy is used therapeutically.

Background: The antibody response after vaccination is impaired in common variable immunodeficiency (CVID)., Objective: We aimed to study the spike receptor-binding domain IgG antibody (anti-S-RBD) levels during a four-dose SARS-CoV-2 vaccination strategy and after monoclonal antibody (mAB) treatment in CVID. Moreover, we assessed the anti-S-RBD levels in immunoglobulin replacement therapy (IgRT) products., Methods: In an observational study, we examined anti-S-RBD levels after the second, third, and fourth dose of mRNA SARS-CoV-2 vaccines. Moreover, we measured anti-S-RBD after treatment with mAB. Finally, anti-S-RBD was assessed in common IgRT products. Antibody non-responders (anti-S-RBD < 7.1) were compared by McNemar's test and anti-S-RBD levels were compared with paired and non-paired Wilcoxon signed rank tests as well as Kruskal-Wallis tests., Results: Among 33 individuals with CVID, anti-S-RBD levels increased after the third vaccine dose (165 BAU/ml [95% confidence interval: 85; 2280 BAU/ml], p = 0.006) and tended to increase after the fourth dose (193 BAU/ml, [-22; 569 BAU/ml], p = 0.080) compared to the previous dose. With increasing number of vaccinations, the proportion of patients who seroconverted (anti-S-RBD ≥ 7.1) increased non-significantly. mAB treatment resulted in a large increase in anti-S-RBD and a higher median level than gained after the fourth dose of vaccine ( p = 0.009). IgRT products had varying concentrations of anti-S-RBD ( p < 0.001), but none of the products seemed to affect the overall antibody levels ( p = 0.460)., Conclusion: Multiple SARS-CoV-2 vaccine doses in CVID seem to provide additional protection, as antibody levels increased after the third and fourth vaccine dose. However, anti-S-RBD levels from mAB outperform the levels mounted after vaccination., Clinical Implications: Boosting with SARS-CoV-2 vaccines seems to improve the antibody response in CVID patients., Capsule Summary: The third and possibly also the fourth dose of mRNA SARS-CoV-2 vaccine in CVID improve the antibody response as well as stimulate seroconversion in most non-responders., Competing Interests: LR has after submission of the paper received support concerning conference fee and travelling by Takeda for the coming ESID conference. CD has unrelated to the current study received research grants from Takeda. MB has received consulting honorariums from Janssen and Kite/Gilead, in areas unrelated to this research. The remaining authors 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., (Copyright © 2022 Nielsen, Drabe, Barnkob, Johansen, Hansen, Nilsson and Rasmussen.)

Common variable immunodeficiency (CVID) is the most common symptomatic primary immunodeficiency (PID). CVID is a heterogenous condition and clinical manifestations may vary from increased susceptibility to infections to autoimmune manifestations, granulomatous disease, polyclonal lymphoproliferation, and increased risk of malignancy. Autoimmune manifestations may, at times, be the first and only clinical presentation of CVID, resulting in diagnostic dilemma for the treating physician. Autoimmune cytopenias (autoimmune haemolytic anaemia and/or thrombocytopenia) are the most common autoimmune complications seen in patients with CVID. Laboratory investigations such as antinuclear antibodies, direct Coomb's test and anti-platelet antibodies may not be useful in patients with CVID because of lack of specific antibody response. Moreover, presence of autoimmune cytopenias may pose a significant therapeutic challenge as use of immunosuppressive agents can be contentious in these circumstances. It has been suggested that serum immunoglobulins must be checked in all patients presenting with autoimmune cytopenia such as immune thrombocytopenia or autoimmune haemolytic anaemia. It has been observed that patients with CVID and autoimmune cytopenias have a different clinical and immunological profile as compared to patients with CVID who do not have an autoimmune footprint. Monogenic defects have been identified in 10-50% of all patients with CVID depending upon the population studied. Monogenic defects are more likely to be identified in patients with CVID with autoimmune complications. Common genetic defects that may lead to CVID with an autoimmune phenotype include nuclear factor kappa B subunit 1 (NF-kB1), Lipopolysaccharide (LPS)-responsive beige-like anchor protein (LRBA), cytotoxic T lymphocyte antigen 4 (CTLA4), Phosphoinositide 3-kinase (PI3K), inducible T-cell costimulatory (ICOS), IKAROS and interferon regulatory factor-2 binding protein 2 (IRF2BP2). In this review, we update on recent advances in pathophysiology and management of CVID with autoimmune cytopenias., Competing Interests: The authors 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., (Copyright © 2022 Chawla, Barman, Tyagi, Jindal, Sharma, Rawat and Singh.)

Common variable immunodeficiency is characterized by impaired B-cell differentiation and defective immunoglobulin production manifesting as recurrent respiratory tract infections. While the condition can masquerade as asthma, late diagnosis of CVID in known asthmatic is rarely reported., We present the case of a 43-year-old lady with recurrent episodes of wheeze, cough, sinusitis and multiple lower respiratory tract infections. Transiently responsive to antibiotics and steroids. These episodes had been occurring for many years and she had a longstanding clinical diagnosis of asthma., As part of her work up for recurrent respiratory tract infections a CT thorax was performed and demonstrated bronchiectasis. Further tests including Immunoglobulin levels revealed critically low IgG, IgM, and IgA levels. Immunoglobulin replacement therapy was commenced with a reduction in exacerbation frequency and severity, and objective improvement of asthma control. Subsequent lung function tests demonstrated reversible airflow limitation (obstructive lung function with 13% reversibility in FEV 1 post-bronchodilator) consistent with asthma., Our case illustrates the importance of searching for alternate and co-existent diagnoses in patients diagnosed with asthma who are unresponsive to conventional therapy. We believe that serum immunoglobulin measurement should form a component of such a workup.

Introduction: SARS-CoV-2 vaccines' effectiveness is not yet clearly known in immunocompromised patients. This study aims to assess the humoral and cellular specific immune response to SARS-CoV-2 vaccines and the predictors of poor response in patients with common variable immunodeficiency (CVID) phenotype and in patients treated with B-cell depletion therapies (BCDT), as well as the safety of these vaccines., Methods: From March to September 2021, we performed a prospective study of all adult patients who would receive the SARS-CoV-2 vaccination and were previously diagnosed with (i) a CVID syndrome (CVID phenotype group; n=28) or (ii) multiple sclerosis (MS) treated with B-cell depleting therapies three to six months before vaccination (BCD group; n=24). Participants with prior SARS-CoV-2 infection; or prior SARS-CoV-2 vaccine administration; or use of any immunosuppressant (except BCDT in MS group) were excluded. A group of subjects without any medical condition that confers immunosuppression and who met all study criteria was also assessed (control group; n=14). A chemiluminescence immunoassay was used to determine pre- and post-SARS-CoV-2 vaccine anti-S IgG antibodies. T-cell specific response was assessed by analysis of pre- and post-SARS-CoV-2 vaccination blood samples with an interferon-gamma release assay. The baseline blood sample also included several biochemical, haematological and immunological analyses., Results: SARS-CoV-2 vaccines are safe in immunocompromised patients, although their effectiveness was lower than in healthy individuals. CVID phenotype patients showed impaired humoral (29%) and cellular (29%) response, while BCD patients fundamentally presented humoral failure (54%). Low IgA values, low CD19+ peripheral B cells, low switched memory B cells, and a low CD4+/CD8+ ratio were predictors of inadequate specific antibody response in CVID phenotype patients. No factor was found to predict poor cellular response in CVID phenotype patients, nor a defective humoral or cellular response in BCD patients., Conclusion: The effectiveness of SARS-CoV-2 vaccines in CVID phenotype and BCD patients is lower than in healthy individuals. Knowledge of predictive factors of humoral and cellular response failure in immunocompromised patients could be very useful in clinical practice, and thus, studies in this regard are clearly needed., Competing Interests: The authors 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., (Copyright © 2022 Antolí, Rocamora-Blanch, Framil, Mas-Bosch, Navarro, Bermudez, Martinez-Yelamos, Dopico, Calatayud, Garcia-Muñoz, Hernández-Benítez, Riera-Mestre, Bas, Masuet-Aumatell, Rigo-Bonnin, Morandeira and Solanich.)

Common variable immunodeficiency (CVID) is the most prevalent antibody deficiency, characterized by remarkable genetic, immunological, and clinical heterogeneity. The diagnosis of pediatric CVID is challenging due to the immaturity of the immune response and sustained actively developing antibody affinity to antigens and immunological memory that may overlap with the inborn error of immunity. Significant progress has been recently done in the field of immunogenetics, yet a paucity of experimental and clinical studies on different systemic manifestations and immunological features of CVID in children may contribute to a delayed diagnosis and therapy. In this review, we aimed at defining the variable epidemiological, etiological, and clinical aspects of pediatric CVID with special emphasis on predominating infectious and non-infectious phenotypes in affected children., Conclusion: While pediatric CVID is a multifaceted and notorious disease, increasing the pediatricians' awareness of this disease entity and preventing the diagnostic and therapeutic delay are needed, thereby improving the prognosis and survival of pediatric CVID patients., What Is Known: • CVID is an umbrella diagnosis characterized by complex pathophysiology with an antibody deficiency as a common denominator. • It is a multifaceted disease characterized by marked genetic, immunological, and clinical heterogeneity.., What Is New: • The diagnosis of pediatric CVID is challenging due to the immaturity of innate and adaptive immune response. • Increasing the pediatricians' awareness of CVID for the early disease recognition, timely therapeutic intervention, and improving the prognosis is needed., (© 2021. The Author(s).)

Accurate and timely diagnosis of primary immunodeficiencies (PID) is an ongoing effort. Individuals with PID can be severely impacted by their disease and many experience chronic complications, treatment burden, and reduced quality of life (QoL). This review focuses on the impact of delayed diagnosis and treatment burden on patient QoL and outcomes. Adults tend to experience longer delays in diagnosis than pediatric populations. The median diagnostic delay has reduced over recent decades, but remains high for some antibody deficiency variants, such as common variable immunodeficiency. The largest burden impacting QoL tends to be poorly controlled disease and persistent chronic conditions rather than treatment burden. Hospitalization, physician/emergency room visits, and bronchiectasis were the most expensive PID complications prior to diagnosis and cost analyses estimate cost reductions once appropriate treatment is initiated. A combination of poor awareness, lack of infrastructure, and resources supporting national registries play a major role in delayed diagnosis., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Coronavirus disease 2019 (COVID-19) is an emerging infectious disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The usual presentation of the disease is a common cold-like illness but it can present with more severe and sometimes fatal manifestations. Immunocompromised patients such as those with common variable immunodeficiency (CVID) also are among the infected population. A limited number of reports have been published concerning CVID patients with COVID-19. The main reported symptoms were fever, cough, dyspnea and fatigue while the median duration of illness was 19 (interquartile range 14-26.5) days. Total recovery rate was 88.4%. It is still unknown whether primary immunodeficiency interacts as a predisposing or protective factor against the severe forms of COVID-19. Substitute immunoglobulin (IG) therapy is the only treatment option for CVID. Some reports suggest that early administration of intravenous IGs or convalescent plasma infusion may positively influence the outcome of COVID-19 in these patients.