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.

The common variable immunodeficiency IgM repertoire narrowly recognizes erythrocyte and platelet glycans.

BACKGROUND: Autoimmune cytopenias (AICs) regularly occur in profoundly IgG-deficient patients with common variable immunodeficiency (CVID). The isotypes, antigenic targets, and origin(s) of their disease-causing autoantibodies are unclear. OBJECTIVE: We sought to determine reactivity, clonality, and provenance of AIC-associated IgM autoantibodies in patients with CVID. METHODS: We used glycan arrays, patient erythrocytes, and platelets to determine targets of CVID IgM autoantibodies. Glycan-binding profiles were used to identify autoreactive clones across B-cell subsets, specifically circulating marginal zone (MZ) B cells, for sorting and IGH sequencing. The locations, transcriptomes, and responses of tonsillar MZ B cells to different TH- cell subsets were determined by confocal microscopy, RNA-sequencing, and cocultures, respectively. RESULTS: Autoreactive IgM coated erythrocytes and platelets from many CVID patients with AICs (CVID+AIC). On glycan arrays, CVID+AIC plasma IgM narrowly recognized erythrocytic i antigens and platelet i-related antigens and failed to bind hundreds of pathogen- and tumor-associated carbohydrates. Polyclonal i antigen-recognizing B-cell receptors were highly enriched among CVID+AIC circulating MZ B cells. Within tonsillar tissues, MZ B cells secreted copious IgM when activated by the combination of IL-10 and IL-21 or when cultured with IL-10/IL-21-secreting FOXP3-CD25hi T follicular helper (Tfh) cells. In lymph nodes from immunocompetent controls, MZ B cells, plentiful FOXP3+ regulatory T cells, and rare FOXP3-CD25+ cells that represented likely CD25hi Tfh cells all localized outside of germinal centers. In CVID+AIC lymph nodes, cellular positions were similar but CD25hi Tfh cells greatly outnumbered regulatory cells. CONCLUSIONS: Our findings indicate that glycan-reactive IgM autoantibodies produced outside of germinal centers may contribute to the autoimmune pathogenesis of CVID.

ICOS agonist vopratelimab modulates follicular helper T cells and improves B cell function in common variable immunodeficiency.

Common variable immunodeficiency (CVID) is an immune defect characterized by hypogammaglobulinemia and impaired development of B cells into plasma cells. As follicular helper T cells (TFH) play a central role in humoral immunity, we examined TFH cells in CVID, and investigated whether an inducible T cell co-stimulator (ICOS) agonist, vopratelimab, could modulate TFH, B cell interactions and enhance immunoglobulin production. CVID subjects had decreased TFH17 and increased TFH1 subsets; this was associated with increased transitional B cells and decreased IgG+ B and IgD-IgM-CD27+ memory B cells. ICOS expression on CVID CD4+ T cells was also decreased. However, ICOS activation of CD4+ T cells by vopratelimab significantly increased total CVID TFH, TFH2, cell numbers, as well as IL-4, IL-10 and IL-21 secretion in vitro. Vopratelimab treatment also increased plasma cells, IgG+ B cells, reduced naïve & transitional B cells and significantly increased IgG1 secretion by CVID B cells. Interestingly, vopratelimab treatment also restored IgA secretion in PBMCs from several CVID patients who had a complete lack of endogenous serum IgA. Our data demonstrate the potential of TFH modulation in restoring TFH and enhancing B cell maturation in CVID. The effects of an ICOS agonist in antibody defects warrants further investigation. This biologic may also be of therapeutic interest in other clinical settings of antibody deficiency.

Uniparental Disomy of Chromosome 4: A Case of Whole Chromosome UPD Presenting with LRBA Deficiency.

PURPOSE: Lipopolysaccharide-responsive beige-like anchor protein (LRBA) encodes a widely expressed cytosolic protein that participates in polarized vesicle trafficking. Homozygous loss-of-function LRBA mutations can lead to immune deficiency due to the lack of immune regulation, classified as a part of Tregopathies. We present a case of a 49-year-old female, with polyarthralgia in metacarpophalangeal and proximal interphalangeal joints bilaterally, and morning stiffness, leading to the diagnosis of rheumatoid arthritis treated with pulse steroid therapy. She had experienced sepsis and in-depth scrutiny revealed panhypogammaglobulinemia. After being referred to the immunology clinic, she was followed under the diagnosis of common variable immunodeficiency (CVID)-like inborn errors of immunity (IEI). METHODS AND RESULTS: Physical examination and diagnostic follow-up revealed massive splenomegaly accompanied by portal hypertension, and ulcerations in the colon. She also presented with periodic hematuria and dysuria. Cystoscopic biopsy revealed mast cell-derived interstitial cystitis which has not been previously reported in LRBA deficiency in the literature to our knowledge. A multi-gene next-generation sequencing panel performed for immune deficiencies (264 genes and 524 amplicons), resulted in the identification of an apparently homozygous LRBA mutation (p.Arg722His) in the Beige and Chediak-Higashi (BEACH) domain. The SNP array showed copy neutral absence of heterozygosity of the entire chromosome 4, which is consistent with uniparental isodisomy of chromosome 4. CONCLUSION: In conclusion, this case study underscores the critical role of LRBA in immune regulation and highlights the clinical heterogeneity associated with LRBA deficiency. The patient's presentation with severe immune dysregulation, including massive splenomegaly, portal hypertension, and the novel finding of mast cell-derived interstitial cystitis, expands the clinical spectrum of LRBA mutations. The identification of an apparently homozygous LRBA mutation via next-generation sequencing further emphasizes the importance of genetic analysis in diagnosing monogenic defects manifested as CVID-like phenotype. This is the first reported case of LRBA deficiency due to whole chromosome UPD to our knowledge. Future research should focus on elucidating the full range of clinical manifestations and developing targeted therapies for patients with LRBA deficiency.

Immune dysregulation.

The understanding of immune dysregulation in many different diseases continues to grow. There is increasing evidence that altered microbiome and gut barrier dysfunction contribute to systemic inflammation in patients with primary immunodeficiency and in patients with rheumatic disease. Recent research provides insight into the process of induction and maturation of pathogenic age-associated B cells and highlights the role of age-associated B cells in creating tissue inflammation. T follicular regulatory cells are shown to help maintain B-cell tolerance, and therapeutic approaches to increase or promote T follicular regulatory cells may help prevent or decrease immune dysregulation. Meanwhile, novel studies of systemic-onset juvenile idiopathic arthritis reveal a strong HLA association with interstitial lung disease and identify key aspects of the pathogenesis of macrophage activation syndrome. Studies of hyperinflammatory syndromes, including the recently described multisystem inflammatory syndrome of children, characterize similarities and differences in cytokine profiles and T-cell activation. This review focuses on recent advances in the understanding of immune dysregulation and describes potential key factors that may function as biomarkers for disease or targets for therapeutic interventions. Future trials are necessary to address the many remaining questions with regards to pathogenesis, diagnosis, and treatment of autoimmune, inflammatory, and immunodeficiency syndromes.

Predominant Antibody Deficiency and Risk of Microscopic Colitis: a Nationwide Case-Control Study in Sweden.

PURPOSE : Predominant antibody deficiency (PAD) disorders, including common variable immunodeficiency (CVID), have been linked to increased risk of gastrointestinal infections and inflammatory bowel diseases. However, there are limited data on the relationship between PAD, specifically CVID, and risk of microscopic colitis (MC). METHODS: We performed a nationwide case-control study of Swedish adults with MC diagnosed between 1997 and 2017 (n = 13,651). Data on biopsy-verified MC were retrieved from all of Sweden's pathology departments through the Epidemiology Strengthened by histoPathology Reports in Sweden (ESPRESSO) study. We defined predominant antibody deficiency using International Union of Immunologic Societies (IUIS) phenotypic classification. Individuals with MC were matched to population controls by age, sex, calendar year, and county. We used logistic regression to estimate adjusted odds ratios (aORs) and 95% confidence intervals (CIs). RESULTS: The prevalence of PAD in MC was 0.4% as compared to 0.05% in controls. After adjustment for potential confounders, this corresponded to an aOR of 7.29 (95%CI 4.64-11.63). The magnitude of the association was higher for CVID (aOR 21.01, 95% 5.48-137.44) compared to other antibody deficiencies (aOR 6.16, 95% CI 3.79-10.14). In exploratory analyses, the association between PAD and MC was particularly strong among males (aOR 31.73, 95% CI 10.82-135.04). CONCLUSION: In this population-based study, predominant antibody deficiency was associated with increased risk of MC, particularly among males. Clinicians who encounter these patients should consider a detailed infectious history and screening for antibody deficiency.

Perceived Sleep Quality in Individuals with Inborn Errors of Immunity.

PURPOSE: Chronic sleep issues can lead to poor quality of life and increased mortality and patients with chronic health conditions often report impaired sleep quality. Higher levels of fatigue have been identified in patients diagnosed with inborn errors of immunity (or primary immunodeficiency diseases). This research sought to better understand perceived sleep quality in individuals diagnosed with IEI. METHODS: A survey, which included the validated Sleep Quality Scale, was shared across multiple social media groups for individuals with a diagnosis of IEI. RESULTS: Most of the participants were White/Caucasian females, between the ages of 30 and 74 years. The results of the Sleep Quality Scale suggest that this sample of individuals has moderate impairment of their sleep quality (71.8%), with a mean score of 43.0 (SD = 13.1). When comparing the results of the SQS to other patient populations and healthy control groups, the participants in this study had a poorer sleep quality score. Associations were identified between sleep quality and age, hours of sleep per night, time awake at night, times awake to urinate, attempted daytime naps, chronic pain, and mental health diagnoses. CONCLUSION: This survey suggests that individuals with inborn errors of immunity have a moderate degree of perceived impairment in sleep quality. Healthcare providers are strongly encouraged to incorporate sleep quality screening in their routine assessments of patients with a diagnosis of Inborn Error of Immunity. Patients who are identified as having impaired sleep quality should be referred for further testing and interventions.

Common variable immune deficiency: Dissection of the variable.

Starting about 60 years ago, a number of reports appeared that outlined the severe clinical course of a few adult subjects with profound hypogammaglobinemia. Puzzled by the lack of family history and adult onset of symptoms in most, the name "acquired" hypogammaglobinemia was given, but later altered to the current name common variable immune deficiency. Pathology reports remarked on the loss of lymph node architecture and paucity of plasma cells in lymphoid tissues in these subjects. While characterized by reduced serum IgG and IgA and often IgM, and thus classified among the B-cell defects, an increasing number of cellular defects in these patients have been recognized over time. In the early years, severe respiratory tract infections commonly led to a shortened life span, but the wide spread availability of immune globulin concentrates for the last 25 years has improved survival. However, chronic non-infectious inflammatory and autoimmune conditions have now emerged as challenging clinical problems; these require further immunologic understanding and additional therapeutic measures. Recent study of this phenotypic syndrome have provided an increasingly fertile ground for the identification of autosomal recessive and now more commonly, autosomal dominant gene defects which lead to the loss of B-cell development in this syndrome.

Defining Clinical and Immunological Predictors of Poor Immune Responses to COVID-19 mRNA Vaccines in Patients with Primary Antibody Deficiency.

Immune responses to coronavirus disease 2019 (COVID-19) mRNA vaccines in primary antibody deficiencies (PADs) are largely unknown. We investigated antibody and CD4+ T-cell responses specific for SARS-CoV-2 spike protein (S) before and after vaccination and associations between vaccine response and patients' clinical and immunological characteristics in PADs. The PAD cohort consisted of common variable immune deficiency (CVID) and other PADs, not meeting the criteria for CVID diagnosis (oPADs). Anti-S IgG, IgA, and IgG subclasses 1 and 3 increased after vaccination and correlated with neutralization activity in HCs and patients with oPADs. However, 42% of CVID patients developed such responses after the 2nd dose. A similar pattern was also observed with S-specific CD4+ T-cells as determined by OX40 and 4-1BB expression. Patients with poor anti-S IgG response had significantly lower levels of baseline IgG, IgA, CD19+ B-cells, switched memory B-cells, naïve CD8+ T-cells, and a higher frequency of EM CD8+ T-cells and autoimmunity compared to patients with adequate anti-S IgG responses. Patients with oPADs can develop humoral and cellular immune responses to vaccines similar to HCs. However, a subset of CVID patients exhibit impairment in developing such responses, which can be predicted by the baseline immune profile and history of autoimmunity.

Allergic-like disorders and asthma in patients with common variable immunodeficiency: a multi-center experience.

OBJECTIVE: Common variable immune deficiency (CVID) encompasses a variety of diseases characterized by disturbed immunoglobulin (Ig) production and various immune dysregulations. Scarce data are available regarding relationships between CVID and allergic diseases. Here we examined possible associations between allergies and CVID. METHODS: For this multicenter study, we prospectively enrolled 79 adult CVID patients (≥18 years) who were diagnosed and treated between 2002-2017 at the Hadassah-Hebrew University and Shaare Zedek Medical Centers, Jerusalem, Israel. These patients were examined for allergic manifestations. Patient evaluation comprised medical history, physical examination, skin allergen testing, complete blood count, serum immunoglobulins, IgE levels, and pulmonary function tests. RESULTS: After implementing exclusion criteria, 29 patients were included in the final analysis. Allergic-like disorders were diagnosed in 65% of CVID patients with non-elevated serum IgE levels. Moreover, allergic CVID patients exhibited a higher prevalence of bronchiectasis on chest CT. Autoimmunity was diagnosed in 41.3% of CVID subjects. The type I allergy detected in our study was non-IgE mediated. CONCLUSIONS: Timely diagnosis and stratification of allergy in CVID patients is expected to improve their outcome and quality of life, as well as promote appropriate treatment and better management of pulmonary exacerbations.

Mild to moderate clinical course of COVID-19 infection in patients with common variable immune deficiency.

The association of immunocompromised patients and severity of COVID-19 infection is not well established. According to the Centers for Disease Control and Prevention (CDC), primary immune deficiencies (PIDs) are among the conditions that can predispose to a more severe course of COVID-19. We report the clinical course and immunological evaluation of five patients with common variable immune deficiency (CVID) who have experienced SARS-CoV-2 virus. Here we assess the severity of the infection, the immunophenotypic profile of the major lymphocyte subgroups, the nonspecific T-cell functional capacity and the SARS-CoV-2 specific effector T-cell immune response. Our results showed that the course of COVID-19 infection in CVID patients was mild to moderate and none of them developed a critical form of the disease. All patients developed a specific SARS-CoV-2 T cell immune response. Lymphopenia as well as impaired T-cell response prior to COVID-19 appeared to be related to a more severe course of the infection. Data on a good specific T cell response against SARS-CoV-2 in CVID patients will help to make the right vaccination decision and establish its efficacy. Clinical outcome even in these individual cases was in agreement with the therapeutic recommendations underlining that regular maintenance with subcutaneous immunoglobulins can be beneficial against immune system overreaction and a severe disease course and convalescent plasma is a treatment option in patients with CVID and COVID-19.

IKAROS-Associated Diseases in 2020: Genotypes, Phenotypes, and Outcomes in Primary Immune Deficiency/Inborn Errors of Immunity.

IKAROS, encoded by IKZF1, is a zinc finger transcription factor and a critical regulator of hematopoiesis. Mutations in IKZF1 have been implicated in immune deficiency, autoimmunity, and malignancy in humans. Somatic IKZF1 loss-of-function mutations and deletions have been shown to increase predisposition to the development of B cell acute lymphoblastic leukemia (B-ALL) and associated with poor prognosis. In the last 4 years, germline heterozygous IKZF1 mutations have been reported in primary immune deficiency/inborn errors of immunity. These allelic variants, acting by either haploinsufficiency or dominant negative mechanisms affecting particular functions of IKAROS, are associated with common variable immunodeficiency, combined immunodeficiency, or primarily hematologic phenotypes in affected patients. In this review, we provide an overview of genetic, clinical, and immunological manifestations in patients with IKZF1 mutations, and the molecular and cellular mechanisms that contribute to their disease as a consequence of IKAROS dysfunction.

Reconstitution of IgG Subclasses Following Immunoglobulin Administration in Adult Patients with Common Variable Immune Deficiency.

BACKGROUND: Immunoglobulin (Ig) therapy reduces the frequency and severity of infection among patients with antibody deficiency disorders. However, a subset of patients lacks adequate clinical response. OBJECTIVE: The purpose of this study was to determine in adult common variable immune deficiency (CVID) patients (A) if lack of clinical response to Ig therapy correlates with lack of reconstitution of IgG subclass (es), (B) correlation between Ig dosing and/or IgG trough levels and IgG subclass reconstitution, (C) and most common impaired Streptococcus pneumoniae (S. pneumoniae) serotype antibody response. METHODS: Single-institution, retrospective chart review for CVID patients at immunology clinics from 2015 to 2019. Patients were monitored every 3-6 months for IgG dosage, IgG trough levels, IgG subclass reconstitution, infectious episodes (chronic sinusitis, bronchitis, upper respiratory, and lower respiratory tract infections), urinary tract infections, and antibiotic use. Follow-up was calculated in patient years. RESULTS: Twenty-five of 41 patients achieved complete reconstitution of all IgG subclasses, and 16/41 demonstrated intermittent or lack of reconstitution. There were significantly less (p < 0.001) infections among fully reconstituted patients (0.66 ± 0.19 infections per patient year) as compared to those with intermittent or lack of reconstitution (1.26 ± 0.13 infections per patient year). There was a significant correlation between IgG trough levels and IgG subclass reconstitution. Most common impaired S. pneumoniae serotype included 3, 4, 9n, 10a, 11a, 12f, and 15b. CONCLUSIONS: Incomplete IgG subclass reconstitution was associated with increased frequency of infections. IgG trough levels correlate with IgG subclass reconstitution. A limited number of S. pneumoniae serotype antibodies are commonly impaired in CVID.

Lymphoid malignancy in common variable immunodeficiency in a single-center cohort.

One of the complications of common variable immunodeficiency (CVID) is the development of lymphoid malignancy. In this retrospective, single-center study of 647 CVID subjects followed over 4 decades, we present immunologic and clinical phenotypes, pathology, treatment, and outcomes of 45 patients (15 males and 30 females, 7%) who developed 49 lymphoid malignancies. The mean age at CVID diagnosis was 42.6 years) and at lymphoma diagnosis was 48.8 years. Of the 41 with known follow up, 29 (70%) have died, 27 of these due to this diagnosis. Twelve are alive, in remission or have achieved cure; four others were alive at last encounter. Some patients had a history of only recurrent infections (36.3%); others had autoimmunity (33%), enteropathy (20%), and/or granulomatous disease (11%). Six had previously been treated for another cancer. This report also includes 6 additional living CVID patients who had been diagnosed with NHL; 4 were given treatment for this. However, on pathology review, the initial diagnosis was reversed, as the findings were more consistent with a benign lymphoproliferative process. This study outlines the high incidence of lymphoma in this single CVID cohort, and some of the diagnostic challenges presented due to immune dysregulation characteristic of this immune defect.

Acute pericarditis: A peculiar manifestation of common variable immune deficiency.

Common variable immune deficiency (CVID) is known as the most prevalent symptomatic inborn error of immunity associated with autoimmune and inflammatory complications in addition to recurrent infections. In this study, we investigated the prevalence of acute pericarditis as a complication in the past medical history of 337 CVID patients. We found five patients (1.5%) that had experienced acute pericarditis, and described the medical history of three patients.

Vedolizumab therapy in common variable immune deficiency associated enteropathy: A case series.

A number of gastrointestinal complications occur in common variable immunodeficiency (CVID). Infections are one cause, but various forms of severe non-infectious enteropathy also lead to substantial morbidity. The presence of T cell lymphocytic infiltrates in the mucosa have suggested that vedolizumab, a humanized monoclonal antibody which binds to alpha4 beta7 integrin and inhibits the migration of effector T-lymphocytes into gastrointestinal tissues, would be an effective treatment. A previous report of 3 CVID cases suggested benefit in 2 subjects. In this study 7 CVID patients with severe enteropathy were treated with vedolizumab. Four of the 7 completed vedolizumab induction therapy but 3 subjects had acute decompensation during induction and treatment was stopped. While one subject showed improvement, 6 of the 7 patients were withdrawn from therapy. While vedolizumab may be of use in some CVID subjects, it was not ultimately found helpful in most of these patients.

Granulomatous and lymphocytic interstitial lung disease diagnosed by transbronchial lung cryobiopsy.

Granulomatous and lymphocytic interstitial lung disease is a pulmonary complication of common variable immune deficiency with significant morbidity and increased mortality. Diagnosis has historically been obtained by surgical lung biopsy as transbronchial biopsy typically yields insufficient tissue for definitive diagnosis from a disease process with a patchy distribution. However, the potential for significant morbidity and mortality with surgical lung biopsy exists, necessitating the development of alternative diagnostic approaches. We present a case of granulomatous and lymphocytic interstitial lung disease confirmed through minimally invasive transbronchial lung cryobiopsy and discuss the role of this modality in diagnosing interstitial lung disease.

Therapeutic plasma exchange for exogenous insulin antibody syndrome in combined variable immunodeficiency: a case report.

A 32-year-old male with type I diabetes presented with profound hypoglycemia due to exogenous insulin antibody syndrome in the setting of newly-diagnosed common variable immunodeficiency. Immunomodulatory therapy was not initially effective, but after the initiation of plasma exchange hypoglycemia resolved, and glucose lability improved.

Evaluation of the frequency and diagnostic delay of primary immunodeficiency disorders among suspected patients based on the 10 warning sign criteria: A cross-sectional study in Iran.

INTRODUCTION: The prevalence of undiagnosed primary immunodeficiency diseases is remarkably high and contributes to increasing the rate of morbidity and mortality among this group of patients. OBJECTIVE: To examine the 10 warning sign scoring system in patients suspected of primary immune deficiency and also estimate the diagnostic delay in patients with proven disease. METHODS: This descriptive cross-sectional study was carried out during the years 2015-2016 in Ali Asghar (AS) Clinic and Hospital. Two hundred patients with suspected primary immune deficiency disease were eligible for inclusion in the study. Multivariable logistic regression analysis was used to determine the relation between findings. RESULTS: In this study, the majority of suspected cases of immunodeficiency were males (57%) with a mean age of 3.33±2.89 years. Twenty-one (10.5%) patients were diagnosed with immunodeficiency disease. The mean diagnostic delay among primary immune deficient patients was 2.05±1.7 years. There was a significant relationship between having parental consanguinity (OR=2.68, 95% CI: 1.07-6.70), allergies (OR=5.03, 95% CI: 1.13-22.31), vaccine adverse effects (OR=9.31, 95% CI: 1.24-69.96) and primary immune deficiency diagnosis. No association was observed between age (OR=0.98, 95% CI: 0.84-1.14), gender (OR=0.99, 95% CI: 0.39-2.47), immune deficiency scoring (OR=0.68, 95% CI: 0.31-1.45) and primary immune deficiency diagnosis. CONCLUSION: Ten warning sign scoring system is of less value to consider a patient suspected of having primary immune deficiency. There is a meaningful delay in diagnosis of primary immune deficiencies especially in antibody deficiency defects which seeks further upgrading of knowledge in physicians.

Primary immunodeficiency-related bronchiectasis in adults: comparison with bronchiectasis of other etiologies in a French reference center.

BACKGROUND: Bronchiectasis is a heterogeneous disease depending on etiology. It represents the most frequent non-infectious pulmonary complication of primary immunodeficiencies (PID). We investigated whether bronchiectasis associated with PID had a distinct course in comparison to bronchiectasis of other causes. METHODS: Retrospective single-center study of adult patients diagnosed with non-cystic fibrosis bronchiectasis with more than 5 years of follow-up and at least 4 pulmonary functional tests available at one year apart. They were divided into three groups: PID- related bronchiectasis, idiopathic/post infectious-related bronchiectasis and other causes of bronchiectasis. Respiratory functional data and clinical outcomes were compared. RESULTS: Of 329 patients with bronchiectasis diagnosed in Foch Hospital (Suresnes, France), 98 patients fulfilled the selected criteria (20 PID-related cases, 39 idiopathic or post-infectious cases, and 39 cases with other causes). Median time of follow-up was 9.5 years. Groups were similar concerning initial characteristics (female 70.4%, never smokers 59.2%, mild severity bronchiectasis according to the FACED score and median FEV1 at diagnosis 73.5% predicted values [Q1-Q3: 53.75-90.5]), except PID patients who were younger (median age of 51.5 vs 62 years, p = 0.02). Eighty-five percent of PID patients received immunoglobulin substitution (median trough level was measured at 10.5 g/dl [10;10.92]). Global median FEV1 annual decline was 25.03 ml/year [8.16;43.9] and 19.82 ml/year [16.08;48.02] in the PID patients group. Forty-five percent of patients had bacterial colonization, pneumoniae occurred in 56% of patients and median exacerbation annual rate was 0.8 [0.3-1.4]. Hemoptysis occurred in 31.6% of patients. Global mortality rate was 11.2%. We did not record any significant difference for all clinical and functional outcomes between patients with PID and other etiologies. The median decline in FEV1 was similar in the three groups. CONCLUSIONS: The course of PID-related bronchiectasis was similar to bronchiectasis of other causes. Provided that patients receive immunoglobulin replacement, the course of PID-related bronchiectasis seems to be independent of the underlying immune disorder.