The Impact of Immune Dysregulation on Clinical Outcomes in Common Variable Immunodeficiency: A Systematic Literature Review

Introduction Common variable immunodeficiency (CVID) is the most common symptomatic inborn error of immunity. Complications of immune dysregulation in CVID are reported in cohort and consortia studies but have not been formally summarized. We performed a systematic literature review to generate a comprehensive reference focused on collating clinical manifestations of immune dysregulation and relevant outcomes. Methods Studies of humans with CVID were identified using predefined search terms to mine Embase, MEDLINE, and CENTRAL databases. The initial search resulted in 2,361 English-language articles. Filtering details are summarized in Figure 1. Studies that reported <10 patients, focused on immunoglobulin replacement, COVID-19, or lacked relevant data were excluded. Data were extracted from 92 articles. Figure 1. Results Out of patients with CVID who underwent genetic testing across 8 studies, the most frequently reported gene variants were LRBA (median, 10.1%), CTLA4 (median, 7.4%), and TACI (median, 6.5%). Manifestations of immune dysregulation were common and included gastrointestinal, lung, liver, rheumatologic, dermatologic, and others. Splenomegaly was reported in a median of 34.8% of patients (54 studies). Autoimmune cytopenias were reported in a median of 19.1% of patients (19 studies). Interstitial lung disease was reported in a median of 9.7% of patients (29 studies). Hepatomegaly and nodular regenerative hyperplasia were present in a median of 21.9% (17 studies) and 11.0% (13 studies) of patients, respectively. Frequent gastrointestinal manifestations reported in up to 38 publications included CVID enteropathy (median, 35.5%; 1 study), diarrhea (median, 26.9%; 21 studies), autoimmune enteropathy or villous atrophy (median, 8.5%; 17 studies), malabsorption (median, 6.4%; 10 studies), and inflammatory bowel disease (median, 5.3%; 23 studies). Treatment information and outcomes data were limited. Steroids and rituximab were used most frequently in a median of 35.4% and 14.0% of patients, respectively. A lack of robust or consistent complete responses was observed. Risk of death was adversely affected by lung, liver, and gastrointestinal disease, as indicated by median hazard ratios of 2.1-2.5. Conclusion These comprehensive summary data illustrate the pervasiveness and negative end-organ impact of unchecked immune dysregulation in CVID. Development of effective treatments to improve the morbidity and mortality associated with immune dysregulation in CVID is needed.