Granulomatous disease in common variable immunodeficiency

Abstract

Granulomatous disease occurs in 8–22% of patients with common variable immunodeficiency (CVID). We examined the clinical and immunologic information of all 37 of 455 (8.1%) CVID subjects with this complication. The median age at diagnosis of CVID was 26 (2–59). 14 had granulomas 1–18 years before diagnosis of CVID. In 6 detection of granulomas coincided with this diagnosis; for 17, granulomas were documented later. 54% had lung granulomas, 43% in lymph nodes and 32% in liver. 54% of the group had had autoimmune diseases, mostly immune thrombocytopenia and hemolytic anemia. 24% had had a splenectomy. Nineteen (51.3%) required steroid treatment for granulomas; other immune suppressants were used in some. Over 25 years 28.5% died (median age 37.5), but not significantly more when compared to our CVID patients without granulomas (19.8%). Those with lung granulomas had similar mortality to those with granulomas in other tissues.

Introduction

Common variable immunodeficiency (CVID) is characterized by hypogammaglobulinemia, defective antibody responses and recurrent infections [1], [2], [3], [4], [5]. Recurrent pulmonary infections especially for patients with delayed diagnosis or inadequate immune globulin replacement [6], [7], [8], [9], [10], can lead to bronchiectasis, respiratory failure and cor pulmonale, some of the most significant causes of both morbidity and mortality in this immune defect [1], [2], [3], [6], [7]. While hallmark of CVID is that of a B cell defect, many patients also have variable T cell abnormalities including cytokine defects, poor lymphocyte proliferation [1], [11], [12] and dendritic cell defects [13], [14], [15]. Mutations in selected genes are known to lead to the CVID phenotype, including the inducible co stimulator (ICOS) [16], [17], [18], [19] and CD19 [17], [18]. The role of mutations in the TNFRSF13B gene encoding TACI (transmembrane activator and calcium modulator and cyclophilin ligand interactor) although demonstrated in a significantly increased number (8%) of patients [20], [21] is somewhat less clear as the same mutations can be found in healthy family members [22], [23]. In order to classify CVID subjects, a number of reports have used various immunological characteristics, particularly B cell functions in response to selected activators in vitro. Most recently, enumeration of peripheral blood switched memory B cells has been used as an indictor of immunologic capacity also showing significant clinical relevance [24], [25], [26], [27], [28].

The developments of granulomatous disease or autoimmunity in CVID are two of the most problematic of clinical conditions, as some form of immune suppression may be required for adequate treatment. The granulomatous changes, or what is reported to be “sarcoidosis” is not infrequently diagnosed years prior to the recognition of hypogammaglobulinemia and in these cases, greatly delays the recognition of the immune defect and the revision of the diagnosis to CVID with granuloma [29], [30], [31], [32], [33]. Alternatively, those with known CVID may be found to have granulomata when a tissue is biopsied at a later date. Although granulomas can be found in many organ systems, lungs are the most prominent location [31], [33]. In some patients an intense lymphoid infiltration accompanies the granulomata leading what has been termed “granulomatous lymphocytic interstitial lung disease” (GLILD) [33], [34] the presence of which may be associated with a poorer outcome [34]. For unclear reasons, granulomatous disease is often found in associated with autoimmunity, in particular, immune thrombocytopenic purpura (ITP) or autoimmune hemolytic anemia (AIHA) [31]. These episodes may occur years before the discovery of granulomas in any tissues. Here we outline the clinical and immunological data of 37 CVID patients in whom granulomas were documented in one or more organ systems and compare the mortality of these subjects to other CVID subjects.