Confirmation and improvement of criteria for clinical phenotyping in common variable immunodeficiency disorders in replicate cohorts

  • Chapel H
  • Lucas M
  • Patel S
 et al. 
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Confirmation and improvement of criteria for clinical phenotyping in common variable im-munodeficiency disorders in replicate cohorts To the Editor: The clinical diversity of common variable immunodeficiency disorders (CVIDs) required division of these patients into distinct clinical phenotypes to provide more homogeneous groups for immunopathologic studies as well as individual patient prognosis. By using data on clinical complications and disease progression from 334 patients with CVID from 7 European centers including Oxford (''Northern European cohort''), distinct clinical pheno-types were defined with relatively little overlap: 83% of the patients had only 1 clinical phenotype. 1 The prognostic signifi-cance of the defined phenotypes was confirmed by significant cor-relation with survival. 1,2 Comparison of data in 2 independent databases (DEFI and Mount Sinai) (see this article's Online Repository at www. showed that it was feasible to confirm clinical phe-notyping criteria in replicate cohorts, using identical definitions for each clinical complication and laboratory finding. In addition, further associations were sought to improve the criteria for clini-cal phenotyping and survival. Predictors of clinical phenotypes were previously limited to IgM serum levels for the lymphoproli-ferative (LP) phenotype and malignancy as well as low peripheral CD8 counts for autoimmunity. Further searches for predictive lab-oratory measurements were undertaken on the combined cohorts. Since the dates of diagnosis for complications in patients in 2 cohorts (Oxford and the DEFI study) were known, the interval from the diagnoses of CVID and the first disease-related compli-cation was calculated to search for the earliest date for reliable prognosis. Initially, it was important to confirm the concept of clinical phenotyping in CVIDs. The proportions of patients in the independent replicate cohorts with features of only 1 clinical phenotype were similar between cohorts when the original criteria were used (see Fig E1 in this article's Online Repository at By using the discovery (Northern Euro-pean; n 5 334) cohort, further associations between complica-tions were found to improve the phenotyping criteria. Considering the LP phenotype, no significant correlation was found between granuloma or lymphoid interstitial pneumonitis (LIP) and hepatomegaly, and so hepatomegaly was discarded. Lymphadenopathy remained as a criterion for LP, since although only 1 patient of 11 in the extended Oxford cohort did not also have granuloma or LIP, there were 29 patients with persistent lymphadenopathy in the Mount Sinai cohort of whom 10 had no obvious symptoms of granuloma and/or LIP. When autoimmu-nity was split into 2 categories, autoimmune cytopenias and organ-specific autoimmune diseases, only cytopenias showed de-creased survival (P 5 .0001); organ-specific autoimmunity was not associated with cytopenias or the other clinical phenotypes. Lymphoid malignancies were excluded in the revised phenotyp-ing criteria since CVID may not be the primary event. 2

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