The EUROclass trial: defining subgroups in common variable immunodeficiency.
Wehr C., Kivioja T., Schmitt C., Ferry B., Witte T., Eren E., Vlkova M., Hernandez M., Detkova D., Bos PR., Poerksen G., von Bernuth H., Baumann U., Goldacker S., Gutenberger S., Schlesier M., Bergeron-van der Cruyssen F., Le Garff M., Debré P., Jacobs R., Jones J., Bateman E., Litzman J., van Hagen PM., Plebani A., Schmidt RE., Thon V., Quinti I., Espanol T., Webster AD., Chapel H., Vihinen M., Oksenhendler E., Peter HH., Warnatz K.
The heterogeneity of common variable immunodeficiency (CVID) calls for a classification addressing pathogenic mechanisms as well as clinical relevance. This European multicenter trial was initiated to develop a consensus of 2 existing classification schemes based on flowcytometric B-cell phenotyping and the clinical course. The clinical evaluation of 303 patients with the established diagnosis of CVID demonstrated a significant coincidence of granulomatous disease, autoimmune cytopenia, and splenomegaly. Phenotyping of B-cell subpopulations confirmed a severe reduction of switched memory B cells in most of the patients that was associated with a higher risk for splenomegaly and granulomatous disease. An expansion of CD21(low) B cells marked patients with splenomegaly. Lymphadenopathy was significantly linked with transitional B-cell expansion. Based on these findings and pathogenic consideration of B-cell differentiation, we suggest an improved classification for CVID (EUROclass), separating patients with nearly absent B cells (less than 1%), severely reduced switched memory B cells (less than 2%), and expansion of transitional (more than 9%) or CD21(low) B cells (more than 10%). Whereas the first group contains all patients with severe defects of early B-cell differentiation, severely reduced switched memory B cells indicate a defective germinal center development as found in inducible constimulator (ICOS) or CD40L deficiency. The underlying defects of expanded transitional or CD21(low) B cells remain to be elucidated. This trial is re-gistered at http://www.uniklinik-freiburg.de/zks/live/uklregister/Oeffentlich.html as UKF000308.