Hematologic abnormalities such as autoimmune hemolytic anemia (AIHA) and immune thrombocytopenia (ITP) are the most common autoimmune manifestations of CVID. and/or non-necrotizing granulomas. We review the treatment strategies, including replacement of immunoglobulin and agents targeting B and T lymphocytes. Systematic characterization of GLILD cases and long term follow up studies are sorely needed to understand the natural history of GLILD. Keywords: Common variable immunodeficiency, CVID, granulomatous lymphocytic interstitial lung disease, GLILD, hypogammaglobulinemia Introduction Primary humoral immunodeficiencies are a group of immunodeficiency disorders with impaired antibody formation due to intrinsic B cell abnormalities resulting in decreased numbers or function of B lymphocytes. Common variable immunodeficiency (CVID) is one of the most common primary humoral immunodeficiency disorders with XL019 heterogenous manifestations that affects nearly 1 in 250,000 individuals (1). CVID is associated with polymorphisms in costimulatory molecules, (CD18, CD19, CD20, CD21) transmembrane activator and calcium modulator and cyclophilin ligand interactor (TACI), and B cell-activating factor of the tumor necrosis family (TNF) (2). Despite numerically normal B IQGAP1 cells, their function is impaired, which in part is related to defective peripheral maturation of B cells. The diagnosis of CVID requires reduced age-adjusted serum immunoglobulin G (IgG) levels along with abnormally low levels of at least one of the isotypes immunoglobulin M (IgM) or immunoglobulin A (IgA), or both IgA and IgM, and an inability to mount a specific antibody response to exogenous antigens such as vaccines or infections (3). Other causes of humoral immunodeficiency states such as malnutrition or medications, e.g., corticosteroids, anti-inflammatory drugs (hydroxychloroquine, sulfasalazine), immunosuppressive agents (cyclosporine, tacrolimus, mycophenolate mofetil), and biologic agents (Rituximab) must be excluded. CVID has a bimodal peak in presentation, usually in late teens/early adulthood and another peak XL019 in mid adult life. Patients commonly present with recurrent sinopulmonary tract and mucosal infections especially caused by encapsulated bacteria, similar to many other primary humoral immunodeficiency syndromes. However, in contrast to other humoral immunodeficiency disorders like Brutons agammaglobulinemia, a select subgroup of CVID patients may develop non-infectious complications (4). Non-infectious complications of CVID include autoimmunity as well as lymphoproliferative disorders mimicking malignancy, inflammatory and lymphoid malignancies. Mutations in TACI, reduction of isotype-switched memory B cells, increase in CD21low B cells and an interferon gene signature are associated with both autoimmunity and lymphoproliferation in CVID (5). Autoimmunity occurs in 25-30% of patients with CVID (1) and can be a XL019 presenting manifestation in up to 12% of patients (6). Autoimmune manifestation may pre-date recurrent infections in many patients. Severe cytopenia may be the first manifestation of autoimmunity (7). Hematologic abnormalities such as autoimmune hemolytic anemia (AIHA) and immune thrombocytopenia (ITP) are the most common autoimmune manifestations of CVID. Patients with hematologic autoimmune disorders may be less likely to have recurrent infections (8). Other autoimmune diseases that can occur in patients with CVID include inflammatory bowel disease, enteropathy, seronegative arthritis, pernicious anemia, Sjogren syndrome, uveitis, vasculitis, thyroiditis, alopecia, vitiligo, hepatitis, primary biliary cirrhosis, sicca syndrome, and systemic lupus erythematosus (9). Lymphocytic infiltration and granuloma formation in lymph nodes, spleen, liver, and lungs may occur. Up to 20% of patients with CVID have lymphoid hyperplasia (10). Cervical, mediastinal, and intestinal lymph nodes are commonly involved. The common biopsy findings are atypical lymphoid hyperplasia, reactive lymphoid hyperplasia, or granulomatous inflammation (3). Lymph nodes may lack plasma cells and have ill-defined germinal centers (11). Nodular lymphoid hyperplasia of the gastrointestinal tract is seen in the small intestine (12), and when present, is associated with an increased risk of intestinal and extraintestinal lymphoma (12). Splenomegaly may be present in 26% of patients with CVID (1). The histological changes seen in the spleen are granulomatous lesions, congestive red pulp, follicular hyperplasia, and atrophic germinal.