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.

How to Identify Common Variable Immunodeficiency Patients Earlier: General Practice Patterns.

PURPOSE: Diagnostic delay is a major problem concerning common variable immunodeficiency (CVID). We aimed to determine the pattern of general practitioner (GP) consultations in individuals diagnosed with CVID within 3 years before the diagnosis and whether the risk of diagnosis was associated with the frequency of consultations or character of examinations. METHODS: We conducted a nested case-control study, identifying 132 adult CVID patients and 5940 age- and gender-matched controls from national registers during 1997-2013. We used conditional logistic regression to calculate the odds ratios (OR) and 95% confidence intervals (95%CI). RESULTS: The median number of consultations among individuals with CVID was more than twice that of the controls in all 3 years (3rd, 10; 2nd, 11.5; and 1st, 15.4 vs. 4). We found a statistically significant association between the number of consultations and the risk of a subsequent CVID diagnosis, independent of age and gender, but strongest in the individuals < 40 years. In the 3rd year before diagnosis, having 9-15 consultations compared with 1-4 was associated with an OR (95%CI) of 5.0 (2.3-10.9), 2.4 (1.1-5.4), and 1.3 (0.3-5.3) for those aged 18-40, 41-60, and > 60, respectively. Several examinations (i.e., blood tests for inflammation/infection and pulmonary function test) were associated with increased odds of a subsequent CVID diagnosis. CONCLUSION: The risk of a CVID diagnosis was highly related to both the number of consultations and the character of examinations performed by the GP. CVID should be a differential diagnosis among patients with multiple consultations, especially in patients < 40 years old.

Altered fraction of regulatory B and T cells is correlated with autoimmune phenomena and splenomegaly in patients with CVID.

Common variable immunodeficiency (CVID) is a heterogeneous primary immunodeficiency disease, leading to recurrent bacterial airway infections and often also autoimmune complications. To shed light on the regulatory lymphocytes from these patients, we analyzed the levels of regulatory B (pro-B10) cell and regulatory T (Treg) cell subpopulations in PBMCs from twenty-six patients diagnosed with CVID using multi-color flowcytometry. Pro-B10 cells were induced by 48h in vitro stimulation prior to analysis. Suppressor function was measured on a subset of patients with splenomegaly and autoimmune complications. The levels of regulatory B and T cells were correlated to clinical manifestations, including autoimmunity, splenomegaly and CVID EUROclass subgroups. We demonstrate a significant association between elevated levels of pro-B10 cells, decreased levels of Tregs and autoimmune phenomena in CVID patients. The finding of marked abnormalities in regulatory lymphocyte populations contribute to our understanding of the pathogenesis of CVID and potentially be valuable in the clinical management and treatment of patients.

Rotavirus is frequent among adults hospitalised for acute gastroenteritis.

INTRODUCTION: Rotavirus infection is the most common aetiology of acute gastroenteritis (AGE) among young children. In adults, diagnostics focus mainly on bacterial causes, though recent studies suggest that rotavirus is a frequent agent. The aim of this study was to examine the proportion of rotavirus in adults hospitalised with AGE and to identify possible predictors. METHODS: During a 24-month period from 1 May 2010 adults (> 15 years) with AGE admitted to one of four hospitals in the Central Denmark Region were examined for rotavirus with VIKIA Rota-Adeno rapid test in addition to routine culture for bacterial pathogens. RESULTS: A total of 265 adult patients were included. 9.4% tested positive for rotavirus. Enteropathogenic bacteria were found in 24.5% of the cases. In the majority of cases (62.3%), no pathogen was found. Overall, rotavirus was the second-most frequent pathogen, exceeded only by Campylobacter spp. Immunosuppression and a C-reactive protein (CRP) below 50 mg/l (0-8 mg/l) were associated with rotavirus. The seasonality of rotavirus differed markedly from that of bacterial gastroenteritis. CONCLUSION: Rotavirus is the second-most frequently identified pathogen in adults hospitalised with AGE. Close contact to children or travel activity does not predict rotavirus gastroenteritis, but immunosuppression and a CRP below 50 mg/l do. The seasonality of rotavirus differs from that of bacterial gastroenteritis, making rotavirus the most frequently identified cause of AGE in adults admitted to hospital in the colder months. FUNDING: The trial was funded by an unrestricted grant from Sanofi Pasteur MSD. TRIAL REGISTRATION: not relevant.