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.

CVID-Associated Intestinal Disorders in the USIDNET Registry: An Analysis of Disease Manifestations, Functional Status, Comorbidities, and Treatment.

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.

Respiratory Comorbidities Associated with Bronchiectasis in Patients with Common Variable Immunodeficiency in the USIDNET Registry.

BACKGROUND: Bronchiectasis is a major respiratory complication in patients with common variable immunodeficiency (CVID) and is associated with recurrent pulmonary infections. However, it is unclear whether other infections or non-infectious respiratory conditions are related to its development. OBJECTIVE: To identify respiratory comorbidities associated with bronchiectasis in patients with CVID. METHODS: A total of 1470 CVID patients enrolled in the USIDNET registry were included in a cross-sectional analysis. The primary outcome of our study was to determine the clinical characteristics and other respiratory conditions associated with respiratory comorbidities and physician-reported bronchiectasis. RESULTS: One hundred ninety-seven CVID patients were noted to have bronchiectasis (13.4%). Affected patients were significantly older than patients without bronchiectasis (median age 54 years vs. 49 years, p = 0.0004). These patients also had lower serum IgA (13 mg/dL IQR 60 mg/dL vs. 28.4 mg/dL IQR 66 mg/dL, p = 0.000). Notably, chronic rhinosinusitis (OR = 1.69 95%CI 1.05-2.75), sinusitis (OR = 2.06 95%CI 1.38-3.09), pneumonia (OR = 2.70 95%CI 1.88-3.88), COPD (OR = 2.66 95%CI 1.51-4.67), and interstitial lung disease (OR = 2.34 95%CI 1.41-3.91) were independently associated with the development of bronchiectasis in this population. CONCLUSION: These data suggest that lower and upper respiratory infections, chronic lower airway disease, and interstitial lung diseases are independently associated with bronchiectasis in CVID patients. Further study into predisposing conditions related to the development of bronchiectasis in CVID patients may allow prediction and early intervention strategies to prevent the development of this complication.

Decline of gastric cancer mortality in common variable immunodeficiency in the years 2018-2022.

Introduction: In patients with Common Variable Immunodeficiency, malignancy has been reported as the leading cause of death in adults, with a high risk of B-cell lymphomas and gastric cancer. Methods: We conducted a five-year prospective study aiming to update the incidence and mortality of gastric cancer and the incidence of gastric precancerous lesions in 512 CVID patients who underwent a total of 400 upper gastrointestinal endoscopies. Results: In the pre-pandemic period, 0.58 endoscopies were performed per patient/year and in the COVID-19 period, 0.39 endoscopies were performed per patient/year. Histology revealed areas with precancerous lesions in about a third of patients. Patients who had more than one gastroscopy during the study period were more likely to have precancerous lesions. Two patients received a diagnosis of gastric cancer in the absence of Helicobacter pylori infection. The overall prevalence of Helicobacter pylori infection in biopsy specimens was 19.8% and related only to active gastritis. Among patients who had repeated gastroscopies, about 20% progressed to precancerous lesions, mostly independent of Helicobacter pylori. Discussion: While gastric cancer accounted for one in five deaths from CVID in our previous survey, no gastric cancer deaths were recorded in the past five years, likely consistent with the decline in stomach cancer mortality observed in the general population. However, during the COVID-19 pandemic, cancer screening has been delayed. Whether such a delay or true decline could be the reason for the lack of gastric cancer detection seen in CVID may become clear in the coming years. Due to the high incidence of precancerous lesions, we cannot rely on observed and predicted trends in gastric cancer mortality and strongly recommend tailored surveillance programs.

Evaluating Drug Prescription Patterns in Undiagnosed Common Variable Immunodeficiency Patients.

OBJECTIVE: To compare the consumption of antibiotics (AB), systemic steroids, and inhaled bronchodilators/glucocorticoids in the 3 years preceding the diagnosis of common variable immunodeficiency (CVID) among CVID patients and matched controls and to estimate whether the level of consumption was associated with the risk of a subsequent CVID diagnosis. METHODS: We conducted a nested case-control study, identifying all individuals (n=130 cases) diagnosed with CVID in Denmark (1994-2014) and 45 age- and sex-matched population controls per case (n=5850 controls) from national registers. Drug consumption was estimated as defined daily doses per person-year. We used conditional logistic regression to compute odds ratios and 95% confidence intervals. RESULTS: In the 3 years preceding a CVID diagnosis, we observed more frequent and higher consumption of all three drug classes. The association between consumption and risk of subsequent CVID diagnosis was statistically significant for all drug classes. The association was stronger with higher consumption and shorter time to CVID diagnosis. The fraction of cases compared to the controls redeeming ≥1 prescription of the included drugs during the study period was higher for AB (97% vs 52%), systemic steroids (35% vs 7.4%), and inhaled bronchodilators/glucocorticoids (46% vs 11.7%) (p<0.001). CONCLUSION: CVID patients have significantly higher use of AB, systemic steroids, and inhaled bronchodilators/glucocorticoids in the 3 years preceding CVID diagnosis than controls. Prescribing these drugs in primary healthcare could be an opportunity to consider (proactive) screening for CVID. Further studies are needed to identify optimal prescription cutoffs that could endorse its inclusion in public health policies.

Missed Opportunities to Diagnose Common Variable Immunodeficiency: a Population-Based Case-Control Study Identifying Indicator Diseases for Common Variable Immunodeficiency.

PURPOSE: Delayed diagnosis of common variable immunodeficiency (CVID) remains a serious problem. We investigated whether some diseases diagnosed during out-patient visits or admission to hospitals could act as indicator conditions for CVID diagnosis. METHODS: In this nested case-control study, we identified 128 cases diagnosed with CVID in Denmark (1999-2013) and 640 age-, gender-, and region-matched controls. We obtained data on diseases diagnosed at hospitals in the five years before CVID diagnosis from The National Hospital Registry. We grouped hospital diagnoses in 33 major disease categories and 210 subcategories. We used conditional logistic regression to calculate the odds ratios (OR) and 95% confidence intervals (CI) to estimate associations between disease exposure and subsequent CVID. RESULTS: During the five years preceding a CVID diagnosis, cases had four times as many hospital contacts as the controls (p < 0.001). A diagnosis in 18 major disease categories showed a significant OR for subsequent diagnosis of CVID. The most substantial association with a subsequent CVID diagnosis was a diagnosis of lower respiratory tract infections (OR: 29.9; 95% CI: 14.2-63.2) and lung diseases (35.1; 15.0-82.5). We observed a similar association when we removed the last year before diagnosis from analysis and overall, in the years < 1, ≥ 1-3, and ≥ 3-5 before diagnosis, although the absolute number of exposures was small. Twenty-eight specific diseases displayed an at least 3-fold risk of subsequent CVID diagnosis. CONCLUSION: Targeted screening for antibody deficiency in patients diagnosed with specific diseases associated with CVID may lead to earlier CVID diagnosis and treatment and thereby potentially reduced morbidity and mortality.

Relationship between autoimmune diseases and serum basal immunoglobulin E levels in patients with common variable immunodeficiency.

Background: Autoimmune diseases can occur at any time in patients with common variable immunodeficiency (CVID). However, the relationship between low immunoglobulin E (IgE) levels and autoimmune diseases in patients with CVID remains poorly understood. Objective: We aimed to determine the relationship between autoimmunity and low IgE in patients with CVID. Methods: This retrospective cohort study was conducted by using data that had been collected from 62 adult patients with CVID between April 2012 and December 2021. Serum basal IgE levels were compared between patients with and patients without autoimmune disease. Results: Overall, 23 of the 62 patients with CVID (37.1%) had at least one autoimmune disease (CVID-O). Autoimmune cytopenias, mainly immune thrombocytopenic purpura, were observed in half of all the patients. Other autoimmune diseases present among the patients included rheumatological diseases, inflammatory bowel diseases, lymphoma, granulomatous lymphocytic interstitial lung disease, autoimmune hepatitis, alopecia, and multiple sclerosis. Serum IgE levels were measured at the time of diagnosis; IgE was undetectable (<2.5 IU/mL) in 82.6% of the patients with CVID-O (n = 19). The median (interquartile range) serum IgE value in the patients with CVID-O was 2 IU/mL (1-16 IU/mL), which was significantly lower than the median serum IgE value in patients with CVID and without autoimmune disease (p < 0.001). Low IgE levels in patients with CVID-O were an independent risk factor for the development of autoimmune disease in patients with CVID (odds ratio 3.081 [95% confidence interval, 1.222-7.771]; p = 0.017). Conclusion: Low serum IgE levels were associated with the development of autoimmune disease in patients with CVID. The monitoring of serum IgE levels in patients with CVID may be useful in the early diagnosis and treatment of autoimmune diseases.

Clinical features and predictors of osteoarticular manifestations in common variable immunodeficiency.

INTRODUCTION: This study aimed to assess osteoarticular manifestations in patients with common variable immunodeficiency (CIVD) and to identify the predictive factors. METHODS: This was a retrospective and prognostic study conducted in the pediatrics: immuno-hematology and stem cell transplantation department, including patients who fit the definition of CVID. A Cox model analysis was used to identify predictive factors. RESULTS: A total of 36 patients were enrolled. Osteoarticular involvement was noted in 15 patients (42%) with a cumulative incidence of 90% after a median follow-up of 25 years. Non-infectious manifestations were reported in 14 patients (39%). The cumulative risk of inflammatory or autoimmune osteoarticular etiology was 74%. Well-characterized rheumatic diseases were retained in six patients and unlabeled autoimmune or inflammatory mechanism in five cases. Bone mineral density revealed osteoporosis in six cases leading to a cumulative risk of degenerative complications of 72%. The cumulative incidence of infectious complications was 17%. In multivariate analysis, predictors of osteoarticular complications were low body weight (HR = 8.67, CI: 1.496-50.278, p = 0.01) and hepatomegaly at diagnosis (HR = 6.2, CI: 1.537-25.075, p = 0.01). Reduced CD4 cells rate < 600 cells/mm3 and hepatomegaly were predictors of autoimmune or inflammatory complications, while chronic diarrhea and iron deficiency were associated with degenerative manifestations. CONCLUSIONS: Osteoarticular manifestations have emerged as a real health problem for CVID patients. Risk increases with low body weight, hepatomegaly, chronic diarrhea, iron deficiency, and CD4 cells rate under 600 cell/mm3. Elucidating the mechanisms of these complications in CVID is important for developing preventive strategies. Key Points • This retrospective and prognostic study described the clinical characteristics of osteoarticular manifestations in 36 patients with CVID to ensure better recognition and understanding of this association by clinicians. • Identification of predictive factors of osteoarticular complications according to its etiology is crucial to establish appropriate, optimal and early management of patients at risk.

Allergic Diseases as a Clinical Phenotype Marker in Patients with Common Variable Immunodeficiency.

INTRODUCTION: Patients with common variable immunodeficiency (CVID) have been shown to be more predisposed to develop allergic diseases because of mucosal immune defects and immune dysregulation. The aim of this study was to determine the prevalence, and clinical and laboratory characteristics of various allergic diseases in patients with CVID. METHODS: The study included patients aged ≥18 years who were followed up for a diagnosis of CVID. Patients were separated into 5 groups according to the clinical phenotypic characteristics of lymphoproliferation, autoimmunity, gastrointestinal diseases, allergic diseases, and malignancy. Atopic dermatitis (AD), drug hypersensitivity reaction (DHR), allergic rhinitis (AR), and asthma were accepted as allergic diseases. RESULTS: The most commonly seen clinical phenotypes were lymphoproliferation in 41 (48.8%) patients and allergic diseases in 31 (37%). AD was determined in 2 (2.4%) patient, DHR in 5 (6%), AR in 7 (8.3%), and asthma in 21 (25%). The delay in diagnosis of patients with allergic disease was determined to be shorter compared to those without allergic disease (p = 0.042). Serum total immunoglobulin E level, CD19+ B cell, switched memory B cell, and natural killer cell counts were determined to be higher in the CVID patients with allergic disease compared to those without (p = 0.007, p = 0.022, p = 0.023, p = 0.017, respectively). CONCLUSION: Allergic diseases should be considered as a marker of clinical phenotype in CVID because of the clinical and immunological differences. Early diagnosis and treatment of allergic diseases in patients with CVID can improve quality of life.

Low and high serum IgG associates with respiratory infections in a young and working age population.

BACKGROUND: We investigated health consequences and genetic properties associated with serum IgG concentration in a young and working age general population. METHODS: Northern Finland Birth Cohort 1966 (NFBC1966, n = 12,231) health data have been collected from birth to 52 years of age. Relationships between life-long health events, medications, chronic conditions, lifestyle, and serum IgG concentration measured at age 46 years (n = 5430) were analysed. Regulatory mechanisms of serum IgG concentration were considered. FINDINGS: Smoking and genetic variation (FCGR2B and TNFRSF13B) were the most important determinants of serum IgG concentration. Laboratory findings suggestive of common variable immunodeficiency (CVID) were 10-fold higher compared to previous reports (73.7 per 100,000 vs 0.6-6.9 per 100,000). Low IgG was associated with antibiotic use (relative risk 1.285, 95% CI 1.001-1.648; p = 0.049) and sinus surgery (relative risk 2.257, 95% CI 1.163-4.379; p = 0.016). High serum IgG was associated with at least one pneumonia episode (relative risk 1.737, 95% CI 1.032-2.922; p = 0.038) and with total number of pneumonia episodes (relative risk 2.167, 95% CI 1.443-3.254; p < 0.001). INTERPRETATION: CVID-like laboratory findings are surprisingly common in our unselected study population. Any deviation of serum IgG from normal values can be harmful; both low and high serum IgG may indicate immunological insufficiency. Critical evaluation of clinical presentation must accompany immunological laboratory parameters. FUNDING: Oulu University Hospital VTR, CSL Behring, Foundation for Pediatric Research.

Assessment of the first presentations of common variable immunodeficiency in a large cohort of patients.

BACKGROUND: Common Variable Immunodeficiency (CVID) is a primary immunodeficiency syndrome resulting in recurrent infections, autoimmunity, and granulomatous manifestations. METHODS AND MATERIALS: This retrospective study was conducted on an Iranian national registry of immunodeficient patients from 2010 to 2021. The frequency of first presentations of CVID and its association with sex, age of onset, and family history of CVID was evaluated. RESULTS: A total of 383 patients entered the study, 164 of whom were female, and the rest were male. The mean age of the patients was 25.3 ± 14.5 years. The most frequent first presentations of CVID were pneumonia (36.8%) and diarrhea (19.1%). Patient sex, age of onset, and family history did not make significant differences in first presentations of this disease. CONCLUSION: pneumonia is the most common first presentation of CVID. Family history of CVID, the age of symptom onset, and sex made no differences in the first presentations of CVID.

When malignancy hits twice - synchronous gastric carcinoma and non-Hodgkin-B-cell lymphoma in a patient with common variable immunodeficiency.

Patients with common variable immunodeficiency (CVID) generally bear a higher risk of non Hodgkin B-cell lymphomas and solid tumors, in particular gastric adenocarcinoma.Here we report a case of a 58-year-old male CVID patient who developed both malignancies within a very short period, as documented by two subsequent esophagogastroduodenoscopies performed within 4 months. While the first upper gastrointestinal endoscopy for routine surveillance purposes was uneventful, the second one after developing unexplained weight loss revealed two new neoplastic lesions in the stomach. The histological evaluation revealed a poorly differentiated adenocarcinoma infiltrating the muscularis propria forcing gastrectomy as well as a high-grade B-non-Hodgkin-lymphoma with detection of a MYC- and BCL6-translocation, necessitating chemotherapy with R-CHOP.This case emphasizes the necessity of high awareness for gastric neoplasia in patients with CVID and highlights the need of a standardized yet not established endoscopic surveillance protocol for this vulnerable group.

Atopic Manifestations Are Underestimated Clinical Features in Various Primary Immunodeficiency Disease Phenotypes

Background: Atopic manifestations are described as a clinical feature of various primary immunodeficiency disease (PID) phenotypes and are frequently reported in combined immunodeficiencies. The prevalence of atopic manifestations in other PIDs remains largely unknown. Objective: To evaluate the prevalence of atopic manifestations in PIDs other than combined immunodeficiencies and to identify in which PIDs atopic manifestations are most common with the aim of improving patient care. Methods: A partner-controlled, questionnaire-based study was performed in pediatric and adult PID patients. Data from diagnostic tests to assess atopic manifestations (ie, diagnostic criteria for atopic dermatitis, spirometry, specific IgE against food and inhalant allergens) were collected from adult patients to confirm patient-reported atopic manifestations. Results: Forty-seven children and 206 adults with PIDs and 56 partner-controls completed the questionnaire. Thirty-five pediatric patients (74.5%) and 164 adult patients (79.6%) reported having experienced 1 or more atopic manifestations compared with 28 partner-controls (50.0%). In the comparison of adult patients with partner-controls, prevalence values were as follows: atopic dermatitis, 49.5% vs 27.3% (P=.003); food allergy, 10.7% vs 1.9% (P=.031); asthma, 55.7% vs 14.8% (P<.001); and allergic rhinitis, 49.8% vs 21.8% (P<.001). The frequency of current atopic manifestations reported by patients was higher than the prevalence based on diagnostic tests (atopic dermatitis, 11.2%; food allergy, 1.9%; asthma 16.4%; and allergic rhinitis, 11.5%). Conclusion: Atopic manifestations are prevalent clinical features across a broad spectrum of PIDs and, in our cohort, frequently present in patients with combined immunodeficiencies and predominant antibody deficiencies. Atopic manifestations should be evaluated in patients with PIDs (AU)

Antecedentes: En varios de los fenotipos asociados a las inmunodeficiencias primarias (PID), se describen, frecuentemente, diversas manifestaciones atópicas, en particular, en la inmunodeficiencia combinada. Sin embargo, la prevalencia de las manifestaciones atópicas en otras PID sigue siendo desconocida. Objetivo: Calcular la prevalencia de las manifestaciones atópicas en otras PID e identificar en cuáles de éstas son las más frecuentes con el fin de mejorar la atención a los pacientes. Métodos: Se realizó un estudio basado en un cuestionario validado, tanto en pacientes pediátricos como en adultos diagnosticados de PID. Posteriormente, se recopilaron los resultados de diferentes pruebas diagnósticas para enfermedades atópicas con el fin de corroborar los síntomas notificados por los pacientes adultos; es decir, criterios de diagnóstico para la dermatitis atópica, espirometría e IgE específica contra alérgenos alimentarios e inhalados. Resultados: El cuestionario se completó por 47 niños y 206 adultos con PID, y por 56 controles. Treinta y cinco pacientes pediátricos (74,5%) y 164 adultos (79,6%) informaron haber experimentado alguna vez una o más manifestaciones atópicas en comparación con 28 controles (50,0%). En los pacientes adultos, al comparar la prevalencia con sus controles, se observaron los siguientes resultados, respectivamente: dermatitis atópica 49,5% vs. 27,3% (p = 0,003); alergia alimentaria 10,7% vs. 1,9% (p = 0,031); asma 55,7% vs. 14,8% (p <0,001); y rinitis alérgica 49,8% frente a 21,8% (p <0,001). La frecuencia de manifestaciones atópicas objetivadas en los pacientes fue superior a la prevalencia basada en las pruebas diagnósticas (dermatitis atópica 11,2%, alergia alimentaria 1,9%, asma 16,4% y rinitis alérgica 11,5%) (AU)

Current clinical spectrum of common variable immunodeficiency in Spain: The multicentric nationwide GTEM-SEMI-CVID registry.

Common variable immunodeficiency (CVID) constitutes a heterogenic group of primary immunodeficiency disorders with a wide-ranging clinical spectrum. CVID-associated non-infectious morbidity constitutes a major challenge requiring a full understanding of its pathophysiology and its clinical importance and global variability, especially considering the broad clinical, genetic, and regional heterogeneity of CVID disorders. This work aimed to develop a nationwide, multicenter, retrospective study over a 3-year period describing epidemiological, clinical, laboratory, therapeutic, and prognostic features of 250 CVID patients in Spain. The mean diagnostic delay was around 10 years and most patients initially presented with infectious complications followed by non-infectious immune disorders. However, infectious diseases were not the main cause of morbimortality. Non-infectious lung disease was extraordinarily frequent in our registry affecting approximately 60% of the patients. More than one-third of the patients in our cohort showed lymphadenopathies and splenomegaly in their follow-up, and more than 33% presented immune cytopenias, especially Evans' syndrome. Gastrointestinal disease was observed in more than 40% of the patients. Among biopsied organs in our cohort, benign lymphoproliferation was the principal histopathological alteration. Reaching 15.26%, the global prevalence of cancer in our registry was one of the highest reported to date, with non-Hodgkin B lymphoma being the most frequent. These data emphasize the importance of basic and translational research delving into the pathophysiological pathways involved in immune dysregulation and diffuse lymphocytic infiltration. This would reveal new tailored strategies to reduce immune complications, and the associated healthcare burden, and ensure a better quality of life for CVID patients.

Outcome of SARS-CoV-2 infection among patients with common variable immunodeficiency and a matched control group: A Danish nationwide cohort study.

The risk of severe adult respiratory coronavirus-2 (SARS-CoV-2) infection and the course of the infection among individuals with common variable immunodeficiency (CVID) relative to the general population have been a matter of debate. We conducted a Danish nationwide study comparing the timing of SARS-CoV-2 vaccination, the risk of first confirmed SARS-CoV-2 infection, re-infection, and the outcome of infection among individuals with CVID relative to an age- and gender matched control group. Cox regression was used to calculate incidence rate ratios. The CVID patients received SARS-CoV-2 vaccinations earlier than those included in the population control group. Even so, the risks of both first infection and re-infection were increased among the individuals with CVID. The CVID group also had increased risk for hospital contacts due to SARS-CoV-2 infection relative to the general population. However, reassuringly, the risk of mechanical ventilation and death did not differ between the groups, but the numbers were low in both groups, making the estimates uncertain. Though this is the largest study to investigate the risk of SARS-CoV-2 infections and outcomes hereof among individuals with CVID relative to the general population, we cannot rule out minor differences in severity, which might only be detectable with an even larger sample size.

Common Variable Immune Deficiency: An Outpatient Experience.

OBJECTIVES: Common variable immunodeficiency (CVID) is one of the most common primary immunodeficiencies encountered by physicians, yet it is still poorly described and vastly underdiagnosed and underreported. It is characterized by low levels of immunoglobulins IgG, IgM, and IgA, recurrent infections, and an increased incidence of autoimmune conditions and malignancies. Diverse clinical presentation, poor understanding of its true prevalence, and the daunting, rarely ordered, diagnostic testing make this disease incredibly difficult to diagnose in a primary care setting. Our objectives in this study were to establish a simple marker that can be used in a primary care setting to raise suspicion of CVID and prompt further diagnostic testing and to demonstrate that the true prevalence of CVID is much higher than previously reported. METHODS: Data on 441 patients who underwent Ig electrophoresis testing during a 4-year period were analyzed retrospectively for the presence of hypogammaglobulinemia and number of clinic visits for infectious processes. RESULTS: The average number of clinic visits before testing in patients with no identified antibody deficiency was 1.89 and in patients with any deficiency 2.22. The odds ratio for each additional visit was 1.089, which was not statistically significant (P = 0.103). When the data were recoded to be capped at 6 clinic visits, the odds ratio for each visit up to 6 was 1.119, which was marginally significant (P = 0.058). CONCLUSIONS: Patients with Ig deficiencies tend to have a higher number of office visits related to infectious processes. This difference, however, was not statistically significant in our study, likely because of the small number of participants. Our study also demonstrated that the prevalence of CVID is likely much higher than currently reported, and it highlights the difficulties related to the convoluted diagnostic process of this disease.

Risk Factors of Pneumonia in Primary Antibody Deficiency Patients Receiving Immunoglobulin Therapy: Data from the US Immunodeficiency Network (USIDNET).

BACKGROUND: Despite immunoglobulin replacement (IgRT) therapy, some patients with primary antibody deficiency (PAD) continue to develop respiratory infections. Recurrent and severe respiratory infections, particularly pneumonia, can lead to significant morbidity and mortality. Therefore, we sought to determine the risk factors of developing pneumonia in PAD patients, already receiving IgRT. METHODS: We evaluated clinical and laboratory features of PAD patients enrolled in the US Immune Deficiency Network (USIDNET) registry by April 2017. Patients were included if they met the following criteria: (1) PAD diagnosis (common variable immunodeficiency (CVID), agammaglobulinemia, hypogammaglobinemia, and specific antibody deficiency (SAD) and (2) available data on infections before and after IgRT. Patients were excluded if they were not receiving IgRT, or if no pre/post infections data were available. Descriptive and multivariable logistic regression analyses were used to identify factors associated with pneumonia post-IgRT. RESULTS: A total of 1232 patients met the inclusion criteria. Following IgRT, 218 patients (17.7%) were reported to have at least one pneumonia episode. Using multivariate logistic regression analysis, we found a statistically significant increased risk of pneumonia in patients with asthma (OR: 2.55, 95% CI (1.69-3.85), p < 0.001) bronchiectasis (OR: 3.94, 95% CI (2.29-6.80), p < 0.001), interstitial lung disease (ILD) (OR: 3.28, 95%CI (1.43-7.56), p < 0.005), splenomegaly (OR: 2.02, 95%CI (1.08-3.76), p < 0.027), allergies (OR: 2.44, 95% CI [1.44-4.13], p = 0.001), and patients who were not on immunosuppressives (OR: 1.61; 95%CI [1.06-2.46]; p = 0.027). For every 50 unit increase in IgA, the odds of reporting pneumonia post IgRT decreased (OR: 0.86, 95% CI [0.73-1.02], p = 0.062). Infectious organisms were reported in 35 of 218 patients who reported pneumonia after IgRT. Haemophilus influenzae was the most frequently reported (n = 11, 31.43%), followed by Streptococcus pneumoniae (n = 7, 20.00%). CONCLUSION: Our findings suggest PAD patients with chronic and structural lung disease, splenomegaly, and allergies were associated with persistent pneumonia. However, our study is limited by the cross-sectional nature of the USIDNET database and limited longitudinal data. Further studies are warranted to identify susceptible causes and explore targeted solutions for prevention and associated morbidity and mortality. CLINICAL IMPLICATIONS: Patients with primary antibody deficiency with structural lung disease, allergies, and splenomegaly are associated with persistent pneumonia post-IgRT.

[Antibody deficiencies in adults. Forty years of follow up]. / Inmunodeficiencias humorales en pacientes adultos. Cuatro décadas de seguimiento.

Antibody deficiencies (AD) are characterized by low or absent immunoglobulin levels or the inability to develop a specific antibody response. They are classified in primary (PAD) when there is an intrinsic immune defect, or secondary (SAD) to other diseases or drugs. The aim of our study was to review the evolutio n of AD assisted at the Immunology Unit, Hospital Durand between 1982 and 2020, divided into two periods: Period I (1982-2009) and Period II (2010-2020); to evaluate their growth, epidemiologic features and treatment options. A total of 205 patients were identified, 176 (85.8%) with PAD and 29 (14.2%) with SAD. The most frequent PAD were common variable immunodeficiency in 104 (59%) patients, X linked agammaglobulinemia in 17 (9.6%) and selective IgA deficiency in 26 (14.8%). Genetic defects were found in 25 (14.2%) patients with PAD. SAD cases were associated with rituximab in 21 (72.4%) subjects, haematological disease in three (10.2%) and with antiepileptic drugs in other three; 161 (78.5%) patients were treated with immunoglobulins, 140 (87%) PAD y 21 (13%) SAD; 152 (94.4%) received intravenous immunoglobulins and nine (5.6%) subcutaneous immunoglobulins. Thirty (19.7%) patients treated at first with intravenous immunoglobulins changed to subcutaneous formulations. The increase in number of patients between both periods was greater than 250%, and more than 700% in patients added per year. SAD growth was greater than twice times comparing with PAD. By the end of the study 125 patients continued in follow up, 80% PAD y 20% SAD and 14 died.

Las inmunodeficiencias humorales (IDH) comprenden un grupo de enfermedades caracterizadas por una deficiente respuesta mediada por anticuerpos. Se clasifican en primarias (IDHP), causadas por defectos propios del sistema inmune, o secundarias (IDHS) a otras enfermedades o fármacos. Nuestro objetivo fue revisar la evolución de las IDH asistidas en la Unidad Inmunología del Hospital Durand entre 1982 y 2020, dividido en dos periodos, Periodo I (1982-2009) y Periodo II (2010-2020); para evaluar el crecimiento de éstas, sus características epidemiológicas y las formas de tratamiento. Se evaluaron 205 pacientes, 176 (85.8%) IDHP y 29 (14.2%) IDHS. Las IDHP más diagnosticadas fueron: inmunodeficiencia común variable en 104 (59%) pacientes, agammaglobulinemia ligada al cromosoma X en 17 (9.6%) y deficiencia selectiva de IgA en 26 (14.8%). En 25 (14.2%) IDHP se realizó un diagnóstico molecular. Las causas de IDHS fueron: secundaria a rituximab en 21 (72.4%) pacientes, enfermedades hematológicas en tres (10.2%) y fármacos antiepilépticos en tres. Un total de 161 (78.5%) pacientes recibieron gammaglobulina, 140 (87%) IDHP y 21 (13%) IDHS; 152 (94.4%) fueron tratados con gammaglobulina endovenosa y nueve (5.6%) con gammaglobulina subcutánea. De los tratados inicialmente con forma endovenosa, 30 (19.7%) cambiaron a subcutánea. El crecimiento en la cantidad de pacientes entre ambos periodos del estudio fue mayor al 250%, y al 700% en pacientes incorporados por año. El crecimiento de las IDHS con relación al de las IDHP fue más del doble. Al finalizar el estudio 125 pacientes continuaban en seguimiento, 80% IDHP y 20% IDHS, y 14 fallecieron.

Clinical and Phenotypic Characterization of Common Variable Immunodeficiency Diagnosed in Younger and Older Adults.

PURPOSE: Common variable immunodeficiency (CVID) is the most prevalent symptomatic immunodeficiency in adults. Little is known about the manifestations of CVID presenting in older adults. Herein, we performed a phenotypic characterization of patients diagnosed older than age 40. METHODS: A retrospective chart review of 79 patients seen at UF Health between 2006 and 2020 with a verified diagnosis of CVID per the ICON 2016 criteria was conducted. Patients were classified according to four phenotypes: no-disease-related complications, autoimmune cytopenias, polyclonal lymphoproliferation, and unexplained enteropathy. Patients diagnosed with CVID from age 2 to 40 (n = 41, "younger cohort") were compared to patients diagnosed with CVID age 41 and older (n = 38, "older cohort"). RESULTS: Among the younger cohort, pathologic genetic variants, positive family history for immunodeficiency, autoimmunity (49% vs 24%, p = 0.03), and splenomegaly (46% vs 16%, p = 0.004) were more common, as was the "autoimmune cytopenias" phenotype (24% vs 3%, p = 0.007). Among the older cohort, lymphoma (11% vs 0%, p = 0.049) and the "no disease-related complications" phenotype (79% vs 57%, p = 0.03) were more commonly seen. Comorbidities such as bronchiectasis (27% vs 21%, p = 0.61), GI involvement (34% vs 24%, p = 0.33), and GLILD (5% vs 8%, p = 0.67) were equally present among both the younger and older cohorts, respectively. CONCLUSION: The lower incidence of autoimmunity and splenomegaly, as well as overlapping clinical features with immunosenescence, may make diagnosing CVID in older patients more challenging; however, the disease is not more indolent as the risks for lymphoma, bronchiectasis, and GLILD are similar to those of younger patients.

The Impact of SARS-CoV-2 Infection in Patients with Inborn Errors of Immunity: the Experience of the Italian Primary Immunodeficiencies Network (IPINet).

COVID-19 manifestations range from asymptomatic to life-threatening infections. The outcome in different inborn errors of immunity (IEI) is still a matter of debate. In this retrospective study, we describe the experience of the of the Italian Primary Immunodeficiencies Network (IPINet). Sixteen reference centers for adult or pediatric IEI were involved. One hundred fourteen patients were enrolled including 35 pediatric and 79 adult patients. Median age was 32 years, and male-to-female ratio was 1.5:1. The most common IEI were 22q11.2 deletion syndrome in children (26%) and common variable immunodeficiency (CVID) in adults (65%). Ninety-one patients did not require hospital admission, and among these, 33 were asymptomatic. Hospitalization rate was 20.17%. Older age (p 0.004) and chronic lung disease (p 0.0008) represented risk factors for hospitalization. Hospitalized patients mainly included adults suffering from humoral immunodeficiencies requiring immunoglobulin replacement therapy and as expected had lower B cell counts compared to non-hospitalized patients. Infection fatality rate in the whole cohort was 3.5%. Seroconversion was observed is 86.6% of the patients evaluated and in 83.3% of CVID patients. 16.85% of the patients reported long-lasting COVID symptoms. All but one patient with prolonged symptoms were under IgRT. The fatality rate observed in IEI was slightly similar to the general population. The age of the patients who did not survive was lower compared to the general population, and the age stratified mortality in the 50-60 age range considerable exceeded the mortality from 50 to 60 age group of the Italian population (14.3 vs 0.6%; p < 0.0001). We hypothesize that this is due to the fact that comorbidities in IEI patients are very common and usually appear early in life.