Manifestations Of Common Variable Immunodeficiency Research Articles

Autoimmunity and Freiburg classification in common variable immunodeficiency

Up to 25% of patients with common variable immunodeficiency (CVID) debut with autoimmunity, which is related to the Freiburg classification, which is based on flow cytometry. to determine the frequency and type of autoimmune diseases and their association with the Freiburg classification in adults with CVID. A cross-sectional, analytical and observational study was carried out with 33 patients belonging to the Primary Immunodeficiency Clinic of a third level hospital, with a diagnosis of CVID. They were divided into 3 phenotypes according to the Freiburg classification. Of the 33 patients studied, 66.6% presented autoimmune diseases, 19 of them (86.3%) had cytopenia; 42.1% belonged to Freiburg group Ia, 36.8% to Ib and 21% to phenotype II. In 36.6% of the patients, autoimmune cytopenia were the first manifestation of CVID; and up to 70% of them belong to the Freiburg phenotype Ia (p = 0.086). Patients with autoimmune cytopenia had a lower percentage of isotype-switched memory B cells (p = 0.018), no higher percentage of CD21low B cells (p = 0.226). Classification by CVID phenotypes allows the identification of the patient's profile according to the percentage of memory B cells with isotype change, which is useful to intentionally search for non-infectious complications of the disease.

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

This study aimed to assess osteoarticular manifestations in patients with common variable immunodeficiency (CIVD) and to identify the predictive factors. 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. 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. 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.

Prevalence of Gastrointestinal (GI), Hepatic, and Infectious Manifestations in Patients with Common Variable Immunodeficiency (CVID)

RationaleCommon variable immunodeficiency (CVID) is the most common, symptomatic, primary immunodeficiency in adults. Gastrointestinal (GI) and hepatic manifestations in CVID remain poorly delineated. We assessed the prevalence of GI, hepatic, and infectious manifestations among patients with CVID and correlated the findings with immunophenotype. MethodsWe conducted a retrospective cohort study of CVID patients at our large, academic center. We evaluated baseline patient characteristics, GI, hepatic, and infectious manifestations of 319 CVID patients. Laboratory studies and immunologic profiles of the patients were evaluated. Results: 291/319 CVID patients (91%) had documented GI or hepatic manifestations. The most common GI symptoms were diarrhea (n = 153), vomiting/dysphagia (n = 146), abdominal pain (n = 117), and weight loss/malabsorption/protein wasting (n = 43). Autoimmune/inflammatory GI disease was reported in 72/319 (23%) of patients. 135/238 (57%) of patients had abnormal liver biochemistries at some point [ALT: 63/135 (47%), AST: 78/135 (58%), Alkaline phosphatase: 76/135 (56%)]. Chronic inflammatory hepatitis was identified in 43/319 (13%); including autoimmune hepatitis (n = 32), transaminitis hepatitis (n = 6), infectious hepatitis (n = 6). Other hepatic conditions were portal hypertension (n = 30), liver cirrhosis (n = 18), and nonalcoholic fatty liver disease (n = 15). 23/319 (7%) had undergone transient elastography, 42/319 (13%) had undergone liver biopsy, of which 22/42 (52%) had a diagnosis of nodular regenerative hyperplasia. The most common GI infections were H. pylori (n = 22), C. difficile (n = 18), Giardia (n = 8). Low absolute CD3+ cells were associated with autoimmune hepatitis [OR 2.91; 95%CI (1.07–7.87); P = 0.03], portal hypertension [OR 5.14; 95%CI (1.86–14.17); P = 0.002], autoimmune/inflammatory GI disease [OR 2.69; 95%CI (1.13–6.41); P = 0.02], and IBD [OR 5.09; 95%CI (1.07–24.20); P = 0.04]. Low absolute CD4+ cells were associated with portal hypertension [OR 5.11; 95%CI (1.87–13.93); P = 0.001], autoimmune/inflammatory GI disease [OR 3.47; 95%CI (1.49–8.12); P = 0.004], and autoimmune gastroenteropathy [OR 3.78; 95%CI (1.44–9.92); P = 0.007]. Low absolute CD19+ cells were associated with autoimmune gastroenteropathy [OR 3.66; 95%CI (1.16–11.6); P = 0.02]. Low switched memory B-cells (IgM-IgD-CD27+CD19+) were associated with autoimmune gastroenteropathy [OR 5.07; 95%CI (1.35–19.04); P = 0.01], and portal hypertension [OR 5.89; 95%CI (1.13–28.16); P = 0.02]. Conclusions: CVID patients had a high prevalence of GI, hepatic, and infectious manifestations, which was associated with more severe immunophenotypes.

Neurologic Manifestations of Common Variable Immunodeficiency: Impact on Quality of Life.

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. 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. 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. 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.

Autoimmune disorders associated with common variable immunodeficiency: prediction, diagnosis, and treatment

ABSTRACT 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.

S3415 Gastroenterological Manifestations in a Patient With Common Variable Immunodeficiency

Introduction: Gastrointestinal manifestation of common variable immunodeficiency (CVID) can present with protein-losing enteropathy (PLE). A wide spectrum of liver injuries can occur with CVID, including nodular regenerative hyperplasia (NRH). Case Description/Methods: 41 y.o. female with PMH of CVID on IgG, chronically elevated LFTs, and nutritional deficiencies. Patient presented with 8-year history of diarrhea, bloating, weight loss, abdominal pain, hepatic encephalopathy (HE), new ascites, and shock. Previously was diagnosed with celiac disease and has strictly followed a gluten-free diet with no improvement. EGD on the current presentation showed visible changes in duodenal mucosa including villous flattening. Biopsies this time revealed villous flattening and absence of plasma cells consistent with CVID enteropathy. Liver biopsy 5 years prior to admission showed no liver disease. Serologic workups, including anti-gp210 and anti-sp100, were negative. Biopsy showed nodular regenerative hyperplasia and non-cirrhotic portal hypertension, which was confirmed by reticulin stain. Patient was started on budesonide 9 mg daily for treatment of PLE, and marked improvement of diarrhea was noted. Non-cirrhotic portal hypertension was managed with furosemide and spironolactone. HE was managed with oral lactulose. The patient was started on enteral and parenteral supplements. Discussion: Duodenal villous atrophy which is a diagnostic criterion for celiac disease can be seen in multiple other conditions including immune disorders such as CVID. In CVID patients with gastrointestinal symptoms, up to 80% of biopsies from different sites in the GI tract will show histological abnormalities. Given their common presentation, celiac disease can be initially diagnosed. The absence of plasma cells and apoptosis presence in duodenal biopsy can suggest PLE diagnosis. Serological studies are not reliable for celiac disease diagnosis due to deficiency of immunoglobulin production in CVID. Steroids can be used for the treatment of PLE in CVID. Hepatic manifestations in CVID are extremely varied and often misdiagnosed given they can mimic other diseases. NRH is a potentially fatal complication of CVID. Recognition of this complication allowed for symptom resolution within two days of starting lactulose therapy. NRH in CVID represents an autoimmune-like liver disease that might be driven by a local vasculopathy, and thus severe cases can warrant a trial of immunosuppression.

Autoimmune Hepatitis as a Hepatic Manifestation of Common Variable Immunodeficiency: A Case Report

Common variable immunodeficiency (CVID) is one of the most prevalent primary immunodeficiency disorders, characterized by an alteration in the maturation of B lymphocytes. Patients with this condition are redisposed to a higher risk of infections. Despite being an immune deficiency disorder, the prevalence of autoimmune disorders is reported in more than 20% of patients. The likelihood of patients’ gastrointestinal tract being affected is relatively low, close to 6%. We present the case of a 22-year-old man with a history of CVID without medical treatment, who presented with upper gastrointestinal bleeding secondary to esophageal varices due to cirrhotic portal hypertension. Infectious and toxic causes of cirrhosis were ruled out. Histological changes compatible with autoimmune hepatitis (AIH) were documented by liver biopsy. The diagnosis of autoimmune diseases is a challenge in the presence of IDCV, we highlight the importance of establishing a timely diagnosis and an intentional search for these conditions to offer timely treatment and avoid late complications.

Dysregulatory processes of the cellular link of the immune system in the dynamics of common variable immunodeficiency.

Common variable immunodeficiency (CVID) is a variant of primary immunodeficiency in which inhibition of antibody production is formed due to disorders of intercellular interaction affecting cellular elements of both innate and adaptive immune responses. A feature of CVID is the late start and variability of clinical minifestation. These arguments determine the purpose of the study: to identify the dynamics of changes in the cellular parameters of the adaptive and innate immune response depending on the duration and severity of the infectious manifestation of CVID. In this regard, a retrospective analysis of medical histories and dynamic observation of fifteen patients with CVID were carried out. Selection of specific parameters of cellular indices of factors of innate resistance and adaptive immunity was carried out on the basis of systemic-functional approach of immunodiagnostics. It is shown that in patients with CVID -mediated hypogammaglobulinemia and infectious phenotype of clinical manifestation, enhancement of quantitative and functional potentials of T-link effector cells of adaptive immunity is recorded against the background of reduction of number of regulatory T-helpers. With a more severe clinical course of the disease, the number of CD3+HLA DR + limphocytes is lower than with a more favorable version, there is a tendency to decrease the number of these cells, as well as the number of peripheral Treg with an increase in the length of the disease. Cellular components of innate immunity are characterized by a decrease in neutrophil activity, inhibition of antigen-presenting monocyte activity, the number and cytotoxicity of natural killers. At the same time, the tendency to decrease the cytolytic potential of NK with an increase in the length of illness and statistically significant differences depending on the severity of the manifestation of the infectious phenotype of CVID was recorded. The obtained results determine the importance of evaluating the cellular link of the immune system in patients with CVID, including as a prognostic criterion for the severity of the course.

COMMON VARIABLE IMMUNODEFICIENCY-ASSOCIATED GRANULOMATOUS-LYMPHOCYTIC INTERSTITIAL LUNG DISEASE DIAGNOSED ON TRANSBRONCHIAL LUNG CRYOBIOPSY

SESSION TITLE: Medical Student/Resident Pulmonary Manifestations of Systemic Disease Posters SESSION TYPE: Med Student/Res Case Rep Postr PRESENTED ON: October 18-21, 2020 INTRODUCTION: Granulomatous-Lymphocytic Interstitial Lung Disease (GLILD) is a rare entity involving granulomatous and lymphoproliferative inflammation of the small airways and pulmonary interstitium. Imaging reveals lower lung predominant ground glass and/or consolidative opacities and nodules. Histopathology may have features of lymphocytic interstitial pneumonia, follicular bronchiolitis and/or organizing pneumonia. GLILD is often seen as a manifestation of common variable immunodeficiency (CVID). Diagnosis requires lung biopsy as imaging findings are nonspecific. Surgical lung biopsy (SLB) is the gold standard in diagnosing interstitial lung disease. However, the relatively new, less invasive approach of transbronchial lung cryobiopsy (TBLC) has been increasingly considered for diagnostic purposes for diffuse parenchymal lung disease (DPLD). CASE PRESENTATION: A 58 year old male with a history of idiopathic thrombocytopenic purpura status-post splenectomy and rituximab presented with dyspnea on exertion, chest pressure and a chronic cough. CT chest revealed areas of consolidation and ground glass opacities in a lower lung distribution on a background of pulmonary fibrosis. Pulmonary function tests showed mild restriction and low diffusing capacity. He underwent outpatient TBLC with histopathologic findings of organizing pneumonia, patchy chronic inflammation, fibrosis and peribronchial lymphoid hyperplasia. Labs revealed low IgG and IgA, absence of member B cells, and deficiency of T cells. The patient was diagnosed with GLILD in setting of CVID. He was started on prednisone and IVIG with improvement in imaging findings and symptoms. DISCUSSION: GLILD is a granulomatous and lymphoproliferative disorder that occurs in 8-25% of patients with CVID. Patients may have shortness of breath and cough, as well as splenomegaly, cytopenia, and adenopathy. The constellation of signs and imaging findings are suggestive but not specific. Biopsy is needed for diagnosis. SLB is associated with relatively higher morbidity and mortality compared to TBLC, and necessitates hospitalization. TBLC has been proposed as a less invasive alternative to SLB. Advantages include lower mortality and complication rate, and no requirement for hospitalization. In this case, we demonstrate the utility of TBLC done as an outpatient in obtaining a diagnostic tissue sample, with clinical improvement on steroids and IVIG. There is no standard treatment for GLILD, but corticosteroids are recommended as first line therapy. Success has also been shown with azathioprine, ritxumab and IVIG. CONCLUSIONS: Transbronchial lung cryobiopsy is emerging as a less invasive alternative modality for obtaining tissue with less morbidity, less mortality and the advantage of being performed in the outpatient setting. Further studies regarding safety, diagnostic accuracy and yield in SLB versus TBLC are required to establish TBLC as common practice. Reference #1: Granulomatous-lymphocytic interstitial lung disease (GLILD) in common variable immunodeficiency (CIVD). Park JH, Levinson AI. Clin Immunol. 2010; 134(2):97. Reference #2: Transbronchial Lung Cryobiopsy in Idiopathic Pulmonary Fibrosis: A State of the Art Review. Adv Ther (2019) 36:2193-2204. Reference #3: British Lung Foundation/United Kingdom Primary Immunodeficiency Network Consensus Statement on the Definition, Diagnosis, and Management of Granulomatous-Lymphocytic Interstitial Lung Disease in Common Variable Immunodeficiency Disorders. Hurst JR, Verma N. Lowe D, Daxendale HE, Jolles S, Kelleher P, Longhurst HJ, Patel Sy, Renzoni EA, Sander CR, Avery GR, Babar JL, Buckland MS, Burns S, Egner W, Gompels MM, Gordins P, Haddock JA, Hart SP, Hayman GR, Herriot R, Hoyles RK, Huissoon AP, Jacob J, Nicholson AG, Rassl DM, Sargur RB, Savic S, Seneviratne SL, Sheaff M, Vaailta PM, Walters GI, Whitehouse JL, Wright PA, Condliffe AM. J Allergy Clin Immunol Pract. 2017;5(4):938. Epub 2017 Mar 25. DISCLOSURES: No relevant relationships by Lawrence Benjamin, source=Web Response Speaker/Speaker's Bureau relationship with Boehringer-Ingelheim Pharmaceuticals Please note: $5001 - $20000 Added 04/07/2020 by Jaime Betancourt, source=Web Response, value=Honoraria Speaker/Speaker's Bureau relationship with Vapotherm, Inc Please note: $5001 - $20000 Added 04/07/2020 by Jaime Betancourt, source=Web Response, value=Honoraria No relevant relationships by Houda Boucekkine, source=Web Response No relevant relationships by Scott Oh, source=Web Response

Renal Manifestations of Common Variable Immunodeficiency.

Common variable immunodeficiency (CVID) is one of the most common primary immunodeficiency syndromes, affecting one in 25,000-50,000 people. Renal insufficiency occurs in approximately 2% of patients with CVID. To date, there are no case series of renal biopsies from patients with CVID, making it difficult to determine whether individual cases of renal disease in CVID represent sporadic events or are related to the underlying pathophysiology. We performed a retrospective analysis of renal biopsy specimens in our database from patients with a clinical history of CVID (n=22 patients, 27 biopsies). Light, immunofluorescence, and electron microscopy were reviewed. IgG subclasses, PLA2R immunohistochemistry, and THSD7A, EXT1, and NELL1 immunofluorescence were performed on all membranous glomerulopathy cases. CD3, CD4, CD8, and CD20 immunohistochemistry was performed on cases of tubulointerstitial nephritis. AKI and proteinuria were the leading indications for renal biopsy in patients with CVID. Immune-complex glomerulopathy was present in 12 of 22 (54.5%) cases, including nine cases with membranous glomerulopathy, one case with a C3 glomerulopathy, and one case with membranoproliferative GN with IgG3κ deposits. All membranous glomerulopathy cases were PLA2R, THSD7A, EXT1, and NELL1 negative. The second most common renal biopsy diagnosis was chronic tubulointerstitial nephritis, affecting 33% of patients. All tubulointerstitial nephritis cases showed tubulitis and a lymphocytic infiltrate with >90% CD3+ T cells. Other renal biopsy diagnoses within our cohort included acute tubular injury (n=1), amyloid light-chain amyloidosis (n=1), diabetic glomerulosclerosis (n=1), thin basement membranes (n=1), pauci-immune GN (n=1), and arterionephrosclerosis (n=1). Membranous glomerulopathy and tubulointerstitial nephritis were the predominant pathologic findings in patients with CVID. Membranous glomerulopathy cases in patients with CVID were IgG1 subclass dominant and showed mesangial immune deposits. Four of the membranous glomerulopathy cases had associated proliferation, with mesangial and/or endocapillary hypercellularity, with or without crescent formation. CVID should be considered as a potential cause when membranous glomerulopathy or chronic tubulointerstitial nephritis is seen in a young patient with a history of recurrent infections.

Spectrum of Hepatic Manifestations of Common Variable Immunodeficiency.

Common variable immunodeficiency (CVID) has a heterogenous clinical presentation and can be challenging to diagnose. Distinct histologic changes have been linked with CVID in several organ systems, which can help identify the correct diagnosis. In this study we review a cohort of hepatic CVID biopsies, to better define the spectrum of histologic and biochemical alterations. We reviewed 26 liver biopsies from 24 patients with CVID, obtained at 4 institutions between 2010 and 2019. Histologic slides were examined, and pathologic, biochemical, and clinical features were recorded. A control cohort of 21 patients with nodular regenerative hyperplasia (NRH) but lacking CVID was also examined. Liver function tests were frequently abnormal, especially alkaline phosphatase (median: 193 IU/L) and aspartate transaminase (median: 56 U/L), elevated in 23 and 17 of 25 biopsies, respectively. Fifteen patients had CVID involvement of other organs. Histologic features of primary biliary cholangitis were present in 2 patients, with florid duct lesions and prominent bile duct injury, in association with positive antimitochondrial antibodies. Among the other 24 biopsies, mild to moderate portal and lobular inflammation were present in 18 and 17 of 24 biopsies, respectively. Overall, 22 of 24 biopsies showed NRH-like changes. Plasma cell were absent. A distinct pattern of pericellular fibrosis was present in 23 of 26 biopsies overall. Involvement ranged from focal centrizonal fibrosis to bridging fibrosis and was accompanied by increased intrasinusoidal lymphocytes in 13 of 24 biopsies. Pericellular fibrosis was identified in 1 of 21 biopsies in the control cohort. Additional findings included granulomatous inflammation or nonhepatocellular foreign body-type multinucleate giant cells, identified in 4 biopsies. Three of 6 examined biopsies also demonstrated focal hepatocellular copper deposition. Hepatic disease in CVID is often associated with elevated alkaline phosphatase and aspartate transaminase and is characterized histologically by the mild nonspecific portal and lobular hepatitis, absence of plasma cells, NRH-like changes, and less commonly, typical histologic features of primary biliary cholangitis. We have also identified a distinctive pattern of delicate pericellular fibrosis that is a helpful clue to the diagnosis of hepatic disease in CVID, especially when accompanied by NRH-like changes.

Gastrointestinal manifestations in common variable immunodeficiency (CVID) are associated with an altered immunophenotype including B- and T-cell dysregulation

Gastrointestinal manifestations in common variable immunodeficiency (CVID) are associated with an altered immunophenotype including B- and T-cell dysregulation

A High Prevalence of Gastrointestinal Manifestations in Common Variable Immunodeficiency.

OBJECTIVES:Common variable immunodeficiency (CVID) is associated with a spectrum of autoimmune complications. We studied the prevalence of gastrointestinal (GI) manifestations and infections in patients with CVID.METHODS:Complete clinical data of 132 Finnish patients with CVID (106 probable and 26 possible CVID) followed up between 2007 and 2016 were collected to a structured database. Data on endoscopies, histology, and laboratory studies were retrieved from patient files.RESULTS:Most common referral indications were diarrhea and/or weight loss (47%–67%). Patients with probable CVID had higher fecal calprotectin and α1-antitrypsin and lower blood vitamin B12 than patients with possible CVID. Gastroscopy and colonoscopy were done to 71 (67%) and 63 (59%) patients with probable CVID, respectively. Endoscopies showed that 15% of them had chronic active gastritis and 17% atrophic gastritis and 3% had gastric adenocarcinoma. A celiac sprue-like condition was found in 7 patients (10%), of whom 3 responded to a gluten-free diet. Colonoscopies demonstrated unspecific colitis (14%), ulcerative colitis (8%), microscopic colitis (10%), and Crohn's disease (2%). Colonic polyps were noted in 30% of patients, and 3% had lower GI malignancies. Thirty-five patients with CVID had bacterial or parasitic gastroenteritis; chronic norovirus was detected in 4 patients with probable CVID. Patients with GI inflammation had higher levels of fecal calprotectin and blood CD8+ T lymphocytes but lower counts of CD19+CD27+ memory B cells and/or CD19+ B cells. Immunophenotype with low B-cell counts was associated with higher fecal calprotectin levels.DISCUSSION:Patients with CVID had a high prevalence of GI manifestations and infections of the GI tract. GI inflammation was associated with a distinct immunophenotype and elevated fecal calprotectin.

Pulmonary Manifestations of Common Variable Immunodeficiency.

Common variable immunodeficiency (CVID) is associated with significant chronic lung disease. The purpose of this paper was to describe the clinical, radiologic, and pathologic findings of CVID-associated lung diseases. These include airways' disease, interstitial lung disease, lymphoma, and mucosa-associated lymphoid tissue lymphoma. In addition, a genetic syndrome termed Kabuki syndrome results in CVID-like immune abnormalities. These patients may also present with CVID-associated lung disease. Awareness and precise identification of CVID-associated lung disease may allow for better assessment of prognosis and direction of therapy.

CASE OF A GRANULOMATOUS-LYMPHOCYTIC INTERSTITIAL LUNG DISEASE IN A PATIENT WITH COMMON VARIABLE IMMUNODEFICIENCY DISORDER

SESSION TITLE: Pulmonary Manifestations of Systemic Disease 1 SESSION TYPE: Med Student/Res Case Report PRESENTED ON: 10/09/2018 03:45 PM - 04:45 PM INTRODUCTION: Common variable Immunodeficiency Disorder (CVID), is the most common primary immunodeficiency disorder. Approximately 30% of patients with CVID develop autoimmune and granulomatous disease. Interstitial lung disease (ILD) manifests in 5-15% of CVID patients and represents a diagnostic challenge. It may present with sarcoid like granulomas, organizing pneumonia, lymphocytic interstitial pneumonia and nonspecific interstitial pneumonia. We present one such case of granulomatous-lymphocytic interstitial lung disease (GL-ILD). CASE PRESENTATION: 60 year old African American non-smoking female with no significant underlying medical history presented with cough in March 2006. Family history consisted of mother with stomach cancer, aunt with bone cancer, and grandmother with liver cancer. On physical exam, she had palpable axillary and inguinal lymph nodes. She had an abnormal CT chest showing bilateral lung nodules along with mediastinal lymphadenopathy. CT abdomen/pelvis showed retroperitoneal and pelvic adenopathy. PET scan showed uptake in multiple regions in neck, chest, abdomen and pelvis. PPD and HIV tests were negative.Workup for connective tissue disease came back negative except for low IgA, low normal IgG, and reduced IgM levels. She had minimally elevated ACE level. Inguinal and left axillary lymph node biopsies were non-diagnostic, showing benign lymph nodes with reactive follicular hyperplasia. Flow cytometry was negative. Video-assisted thoracoscopic left lung biopsies showed nodular airway-centered lymphoid hyperplasia with associated scattered small non-necrotizing granulomas. Follicular bronchiolitis was present. Biopsies did not suggest sarcoidosis. Mycobacterial and fungal cultures were negative. She had serial CT chest, abdomen and pelvis for the next two years showing no progression of her disease. After 2008, she had slow progression of lymphadenopathy and was evaluated at a tertiary care center in 2012. Definitive diagnosis of GL-ILD was given at that point. She was placed on steroids for about a year with stabilization of her disease. Subsequently, she had worsening of her lymphadenopathy off steroids and has been maintained on IgG infusions. DISCUSSION: CVID is present in a considerable number of patients with a small subset presenting with cryptic ILD. Exhaustive diagnostic workup is usually needed including open lung biopsy. Patients with GL-ILD may remain stable over years after optimization of their immunoglobulin levels. Following this, steroids remain first line treatment and response may be variable. In progressive disease, immunosuppressive treatment is recommended. CONCLUSIONS: This case illustrates an example of a form of interstitial lung disease associated with CVID. When lung biopsies demonstrate lymphocytic infiltrate and/or granuloma in the lung, CVID should be considered in the differential. Reference #1: British Lung Foundation/United Kingdom PrimaryImmunodeficiency Network Consensus Statement. J Allergy Clin Immunol Pract. 2017 Jul - Aug;5(4):938-945. https://doi.org/10.1016/j.jaip.2017.01.021. Epub 2017 Mar 25. Reference #2: Granulomatous-lymphocytic interstitial lung disease as the first manifestation of common variable immunodeficiency. Clin Respir J. 2018 Jan;12(1):337-343. https://doi.org/10.1111/crj.12511. Epub 2016 Jun 22. DISCLOSURES: No relevant relationships by Riju Dasgupta, source=Web Response No relevant relationships by Asok Dasgupta, source=Web Response No relevant relationships by Chelsea Leipold, source=Web Response No relevant relationships by David Taylor, source=Web Response No relevant relationships by Paresh Timbadia, source=Web Response

Phenotypic characterization of patients with rheumatologic manifestations of common variable immunodeficiency.

We conducted a retrospective analysis of 870 pediatric and adult patients with CVID included in the United States Immunodeficiency Network (USIDNET) registry. Outcomes included clinical characteristics (age, gender, ethnicity, rheumatologic diagnosis, and comorbidities), infectious history and basic immunophenotype (serum immunoglobulin levels, CD19+ B cells, and CD4/CD8 ratio) in patients with CVID and rheumatologic disorders compared to those with non-inflammatory CVID. Demographic and clinical data were compared using chi-square, Fisher's exact or Wilcoxon-Mann-Whitney tests. Non-parametric tests, single and multiple logistic regression models were used to evaluate the relationship between CVID-associated rheumatologic disorders and basic immunophenotypic parameters (IgA, IgM, CD19+ B-cell counts, and CD4/CD8 ratios). Physician-reported rheumatic diseases were present in 5.9% of patients with CVID (n = 51) included in the registry. Although CVID affects both sexes equally, and patients are of predominantly White-Caucasian ethnicity, there were more females (3.3:1 female to male ratio) and increased proportion of non-white patients in the rheumatologic disease group (p < 0.05). Specific disorders included: inflammatory arthritis (n = 18), Sjogren's syndrome (n = 11), SLE (n = 8), Raynaud's syndrome (n = 8), vasculitis (n = 9), MCTD (n = 3), and other (n = 5). In about one-third of patients, a rheumatologic condition was associated with an additional inflammatory complication or malignancy. In regards to the immunophenotype parameters compared (CD19+ B-cell counts, CD4/CD8 ratio, IgA, and IgM), no significant differences were demonstrated between the two groups. Our findings highlight the coexistence of primary antibody immunodeficiencies and systemic rheumatologic disorders, describe the spectrum of rheumatologic manifestations, and contrast differences in relevant demographic, clinical and immunophenotype parameters in the largest registry of CVID patients in the U.S. In spite of its limitations, our study details the intersection of systemic autoimmunity and CVID and provides valuable insights into these two groups of disorders. Further delineating the link between systemic autoimmunity and humoral immunodeficiencies can provide novel insights into the immune abnormalities underlying these related conditions.

Gastrointestinal (GI) Manifestations in Common Variable Immunodeficiency (CVID)

Gastrointestinal (GI) Manifestations in Common Variable Immunodeficiency (CVID)

Salivary Immunoglobulins in Individuals with Common Variable Immunodeficiency.

Oral manifestations of common variable immunodeficiency (CVID) are rare, have rarely been studied and have given controversial results. There are few data about IgA, IgG, and IgM antibody salivary levels in the literature, and there are few papers about the clinical impact of antibody deficiencies and CVID on the oral health of such patients. The aim of this study was to measure serum and salivary IgA, IgG, and IgM levels in CVID participants and controls, and to associate immunoglobulin levels with caries and periodontal disease. This was a case-control study involving 51 CVID individuals and 50 healthy controls. All participants underwent examination for dental caries and periodontal disease. Blood and whole saliva samples were collected on the same day of the oral examination. Serum IgA, IgM, and IgG levels were measured by turbidimetry and salivary IgA, IgM, and IgG titers were assessed by enzyme-linked immunosorbent assay. Incidences of caries and gingivitis were significantly higher in the CVID group than in the control group (p<0.05). Salivary and blood IgA and IgM titers were significantly reduced in the CVID group, but there was no association of salivary immunoglobulin levels with periodontal disease or with caries incidence (p>0.05 for both). Although CVID was associated with increased susceptibility to caries and gingivitis, it was not associated with low salivary levels of IgA and IgM.

Chronic Diarrhea in Hypogammaglobulinemia: A Case Report of Immunodeficiency

Introduction: Common variable immunodeficiency (CVID) or acquired hypogammaglobulinemia is the most common primary antibody deficiency which leads to lymphocytic dysfunction. CVID is not related to gender and can affect the person at any age, but the peaks of onset are the first and the third decades of life. CVID presents with various manifestations, which can obscure the proper diagnosis of the disease based on broad non-specific presentations. In this report, we describe a case of refractory chronic diarrhea secondary to underlying CVID disease without recurring bacterial infections. Case Presentation: A 31 year old woman with a chief complaint of persistent diarrhea and weight loss for five years. She did not complain of anysymptoms until the age of 26 when she started having several episodes of semi-solid diarrhea per day. Despite dietary and additional interventions, symptoms were persistent during a 5 year course of the disease and worsened in the last 2 months, with significantincrease in volume and frequency of diarrhea and associated weight loss of 10 kilograms. Several work-ups were inconclusive and she was referred to us for evaluation of CVID enteropathy. Discussion: Chronic diarrhea is considered one of the most common clinical manifestations of CVID. More than half of patients present with diarrhea and 10% develop idiopathic malabsorption associated with weight loss. This case report presents gastrointestinal manifestation of CVID as the only presentation during 5 years, which led to exhaustive diagnostic studies without definitive diagnosis or effective management. This report signifies the importance of early diagnosis of CVID, and the need to improve physicians’ general awareness of manifestations of the disease.

Genetic Diagnosis Using Whole Exome Sequencing in Common Variable Immunodeficiency.

Whole exome sequencing (WES) has proven an effective tool for the discovery of genetic defects in patients with primary immunodeficiencies (PIDs). However, success in dissecting the genetic etiology of common variable immunodeficiency (CVID) has been limited. We outline a practical framework for using WES to identify causative genetic defects in these subjects. WES was performed on 50 subjects diagnosed with CVID who had at least one of the following criteria: early onset, autoimmune/inflammatory manifestations, low B lymphocytes, and/or familial history of hypogammaglobulinemia. Following alignment and variant calling, exomes were screened for mutations in 269 PID-causing genes. Variants were filtered based on the mode of inheritance and reported frequency in the general population. Each variant was assessed by study of familial segregation and computational predictions of deleteriousness. Out of 433 variations in PID-associated genes, we identified 17 probable disease-causing mutations in 15 patients (30%). These variations were rare or private and included monoallelic mutations in NFKB1, STAT3, CTLA4, PIK3CD, and IKZF1, and biallelic mutations in LRBA and STXBP2. Forty-two other damaging variants were found but were not considered likely disease-causing based on the mode of inheritance and/or patient phenotype. WES combined with analysis of PID-associated genes is a cost-effective approach to identify disease-causing mutations in CVID patients with severe phenotypes and was successful in 30% of our cohort. As targeted therapeutics are becoming the mainstay of treatment for non-infectious manifestations in CVID, this approach will improve management of patients with more severe phenotypes.