Efficacy and Safety of Interferon-Gamma in Chronic Granulomatous Disease: a Systematic Review and Meta-analysis.

ABSTRACT

BACKGROUND: Chronic granulomatous disease (CGD) is a primary immunodeficiency with increased susceptibility to several bacteria, fungi, and mycobacteria, caused by defective or null superoxide production by the NADPH oxidase enzymatic complex. Accepted treatment consists mainly of antimicrobial prophylaxis. The role of human recombinant subcutaneous interferon-gamma (IFNγ) is less clear since the available evidence on its efficacy derives mainly from a single clinical trial that has been challenged. OBJECTIVE: We aimed to assess the efficacy and safety of IFNγ as an added treatment for CGD when compared to antimicrobial prophylaxis alone. METHODS: A literature search was conducted using MeSH terms "Chronic granulomatous disease" AND ("interferon gamma" OR "interferon-gamma"), as well as antibiotics, placebo, no therapy, clinical trial, and trial, on MEDLINE, EMBASE, LILACS, WHOs, CENTRAL, KOREAMED, The Cochrane Library, clinicaltrials.gov, and abstracts from meetings, from 1976 to July 2022. We included clinical trials (CT) and prospective follow-up studies and registered the number of serious infections (requiring hospitalization and IV antibiotics) and deaths, adverse events, and autoimmune complications, in patients treated for CGD with antimicrobial prophylaxis plus IFN-γ, versus antimicrobial prophylaxis alone. We assessed the quality of the studies using risk of bias and STROBE. We performed a meta-analysis by calculating both Peto's odds ratio (OR) and risk reduction (RR) through the Mantel-Haenszel method with a fixed-effect model, using Review Manager 5.4, and we reported the number needed to treat (NNT). RESULTS: We identified 54 matches from databases and 4 from other sources. We excluded 12 duplicates, 7 titles, and 9 abstracts for relevance, after which we had 30 eligible studies. Twenty-four were then excluded after reading the full text. Six papers were included one randomized CT and 5 follow-up studies. In total, 324 patients with Chronic granulomatous disease were followed for 319 months under treatment with antibiotic prophylaxis plus interferon-gamma or placebo (or antibiotic prophylaxis alone), reported between the years 1991 and 2016. Three of the studies included a control group, allowing for the aggregate analysis of efficacy (prevention of serious infections). The aggregate OR was 0.49, with a 95% confidence interval of 0.19 to 1.23. The risk ratio for serious infection was 0.56 (95%CI 0.35-0.90) under IFN-γ. The meta-analysis thus favors interferon-gamma for a risk reduction of serious infection. DISCUSSION: The results from this meta-analysis support the use of IFN-γ in the treatment of patients with CGD. However, we found insufficient clinical evidence and believe more clinical trials are needed to better assess the efficacy and long-term safety of IFN-γ.