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.
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Data Availability
All data is available upon request.
Abbreviations
- CGD:
-
Chronic granulomatous disease
- DNA:
-
Deoxyribonucleic acid
- EBV-B:
-
Epstein-Barr virus–immortalized B cells
- IFNG:
-
Interferon-gamma
- NADPH:
-
Nicotinamide adenine dinucleotide phosphate
- NIH:
-
National Institutes of Health
- USA:
-
United States of America
- WHO:
-
World Health Organization
References
Assari T. Chronic granulomatous disease; fundamental stages in our understanding of CGD. Med Immunol. 2006;5:1–8.
Seger R. Chronic granulomatous disease: recent advances in pathophysiology and treatment. J Med. 2010;68(11):334–40.
Magnani A, Brosselin P, Beauté J, de Vergnes N, Mouy R, Debré M, et al. Inflammatory manifestations in a single-center cohort of patients with chronic granulomatous disease. J Allergy Clin Immunol. 2014;134(3):655-662.e8.
Seger R. Modern Management of chronic granulomatous disease. Br J Haematol. 2008;140:255–66.
Margolis DM, Melnick DA, Alling DW, Gallin JI. Trimethoprim-sulfamethoxazole prophylaxis in the management of chronic granulomatous disease. J Infect Dis. 1990;162(3):723–6.
Ott M, Schmidt M, Schwarzwaelder K, et al. Correction of X-linked chronic granulomatous disease by gene therapy, augmented by insertional activation of MDS1-EVI1, PRDM16 or SETBP1. Nat Med. 2006;12(4):401–9.
Bianchi M, Hakkim A, Brinkmann V, et al. Restoration of NET formation by gene therapy in CGD controls aspergillosis. Blood. 2009;114(13):2619–22.
Chiesa R, Wang J, Blok HJ, Hazelaar S, Neven B, Moshous D, et al. Hematopoietic cell transplantation in chronic granulomatous disease: a study of 712 children and adults. Blood. 2020;136(10):1201–11.
Goddard E, Hughes E, Duys P, Hoffman E, Beatty D. Treatment of chronic granulomatous disease with recombinant gamma interferon. S Afr Med J. 1992;81(2):81–3.
Ishibashi F, Mizukami T, Kanegasaki S, Motoda L, Kakinuma R, Endo F, et al. Improved superoxide-generating ability by interferon gamma due to splicing pattern change of transcripts in neutrophils from patients with a splice site mutation in CYBB gene. Blood. 2001;98(2):436–41.
Kang HS, Hwang G, Shin K. Long-term outcome of patients with p22 phox - deficient chronic granulomatous disease on Jeju Island. Korea. 2015;58(4):129–35.
Mühlebach TJ, Gabay J, Nathan CF, Erny C, Dopfer G, Schroten H, et al. Treatment of patients with chronic granulomatous disease with recombinant human interferon-gamma does not improve neutrophil oxidative metabolism, cytochrome b558 content or levels of four anti-microbial proteins. Clin Exp Immunol. 1992;88(2):203–6.
Sechler J, Malech H, White C, Gallin J. Recombinant human interferon-gamma reconstitutes defective phagocyte function in patients with chronic granulomatous disease of childhood. Proc Natl Acad Sci U S A. 1988;85:4874–8.
Newburger P, Ezekowitz R. Cellular and molecular effects of recombinant interferon gamma in chronic granulomatous disease. Hematol Oncol Clin North Am. 1988;2(2):267–76.
Kourtis AP, Abramowsky C, Ibegbu C, Kobrynski L. Enlargement of the thymus in a child with chronic granulomatous disease receiving interferon gamma therapy. Arch Pathol Lab Med. 1998;122(6):562–5.
Condino-Neto A, Newburger P. Interferon-gamma improves splicing efficiency of CYBB gene transcripts in an interferon-responsive variant of chronic granulomatous disease due to a splice site consensus region mutation. Blood. 2000;95(11):3548–54.
Frazão JB, Colombo M, Simillion C, Bilican A, Keller I, Wüthrich D, et al. Gene expression in chronic granulomatous disease and interferon-γ receptor-deficient cells treated in vitro with interferon-γ. J Cell Biochem. 2019;120(3):4321–32.
Ambruso DR, Briones NJ, Baroffio AF, Murphy JR, Tran AD, Gowan K, et al. In vivo interferon-gamma induced changes in gene expression dramatically alter neutrophil phenotype. PLoS One. 2022;17(2):e0263370. https://doi.org/10.1371/journal.pone.0263370 [cited 2022 Oct 18].
MedaSpaccamela V, Valencia RG, Pastukhov O, Duppenthaler A, Dettmer MS, Erb J, et al. High levels of IL-18 and IFN-γ in chronically inflamed tissue in chronic granulomatous disease. Front Immunol. 2019;10(October):1–11.
Segal BH, Doherty TM, Wynn TA, Cheever AW, Sher A, Holland SM. The p47(phox-/-) mouse model of chronic granulomatous disease has normal granuloma formation and cytokine responses to Mycobacterium avium and Schistosoma mansoni eggs. Infect Immun. 1999;67(4):1659–65.
Weisser M, Demel UM, Stein S, Chen-Wichmann L, Touzot F, Santilli G, et al. Hyperinflammation in patients with chronic granulomatous disease leads to impairment of hematopoietic stem cell functions. J Allergy Clin Immunol. 2016;138(1):219-228.e9.
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease. The International Chronic Granulomatous Disease Cooperative Study Group. New Engl J Med. 1991;324(8):509–16.
Mouy R, Seger R, Bourquin JP, Veber F, Blanche S, Griscelli C, et al. Interferon gamma for chronic granulomatous disease. N Engl J Med. 1991;325(21):1516–7.
Condino-neto A, Muscara M, Bellinati-Pires R, Carneiro-Sampaio M, Brandao A, Grumach A. Effect of therapy with recombinant human interferon-gamma on the release of nitric oxide by neutrophils and mononuclear cells from patients with chronic granulomatous disease. J Interf Cytokine Res. 1996;16(5):357–64.
Spencer D, Darbyshire P. Resolution of hepatic abscess after interferon gamma in chronic granulomatous disease. Arch Dis Child. 1994;70:356.
Malmvall B, Follin P. Successful interferon-gamma therapy in a chronic granulomatous disease (CGD) patient suffering from Staphylococcus aureus hepatic abscess and invasive Candida albicans infection. Scand J Infect Dis. 1993;25:61–6.
Pasic S, Abinun M, Pistignjat B. Aspergillus osteomyelitis in chronic granulomatous disease: treatment with recombinant gamma-interferon and itraconazole. Pediatr Infect Dis J. 1996;15:833–4.
Touza Rey F, Martinez Vazquez C, Alonso Alonso J, Mendez Pineiro M, Rubianes Gonzalez M, Crespo CM. The clinical response to interferon-gamma in a patient with chronic granulomatous disease and brain abscesses due to Aspergillus fumigatus. An Med Interna. 2000;17:86–7.
Van den Berg J, Van Koppen E, Ahlin A, Belohradsky B, Bernatowska E, Corbeel L. Chronic granulomatous disease: the European experience. PLoS ONE. 2009;4(4): e5234.
Winkelstein JA, Marino MC, Johnston RB, Boyle J, Curnutte J, Gallin JI, et al. Chronic granulomatous disease. Report on a national registry of 368 patients. Medicine (Baltimore). 2000;79(3):155–69.
Agudelo-Flórez P, Prando-Andrade CC, López JA, Costa-Carvalho BT, Quezada A, Espinosa FJ, et al. Chronic granulomatous disease in Latin American patients: clinical spectrum and molecular genetics. Pediatr Blood Cancer. 2006;46(2):243–52.
Lugo Reyes SO, Ramirez-Vazquez G, Cruz Hernández A, Medina-Torres EA, Ramirez-Lopez AB, España-Cabrera C, et al. Clinical features, non-infectious manifestations and survival analysis of 161 children with primary immunodeficiency in Mexico: a single center experience over two decades. J Clin Immunol. 2016;36(1):56–65.
De Ravin SS, Naumann N, Cowen EW, Friend J, Hilligoss D, Marquesen M, et al. Chronic granulomatous disease as a risk factor for autoimmune disease. J Allergy Clin Immunol. 2008;122(6):1097–103.
Greenland S, Salvan A. Bias in the one-step method for pooling study results. Stat Med. 1990;9(3):247–52. https://doi.org/10.1002/sim.4780090307 [cited 2022 Aug 29].
Martire B, Rondelli R, Soresina A, Pignata C, Broccoletti T, Finocchi A. Clinical features, long-term follow-up and outcome of a large cohort of patients with chronic granulomatous disease: an Italian multicenter study. Clin Immunol. 2008;126:155–64.
Bemiller LS, Roberts DH, Starko KM, Curnutte JT. Safety and effectiveness of long-term interferon gamma therapy in patients with chronic granulomatous disease. Blood Cells Mol Dis. 1995;21(3):239–47.
Weening R, Leitz G, Seger R. Recombinant human interferon-gamma in patients with chronic granulomatous disease–European follow up study. Eur J Pediatr. 1995;154:295–8.
Marciano BE, Wesley R, De Carlo ES, Anderson VL, Barnhart LA, Darnell D, et al. Long-term interferon-gamma therapy for patients with chronic granulomatous disease. Clin Infect Dis. 2004;39(5):692–9.
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease. The International Chronic Granulomatous Disease Cooperative Study Group. N Engl J Med. 1991 Feb 21;324(8):509–16.
Loffredo L, Perri L, Zicari A, Del Ben M, Angelico F, Violi F. Chronic granulomatous disease as an SOS call for multicenter cooperative effort to prevent infections. Ann Allergy Asthma Immunol. 2016;117(3):285–9.
Acknowledgements
The authors wish to thank Dr. Francisco J. Espinosa Rosales for useful discussions and support during the early stages of this study.
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The authors confirm their contribution to the paper as follows: study conception and design, SOLR and AGGG; systematic literature research and paper acquisition, JLGO and CSG; data collection, NYGB, DARL, and ACMP; critical appraisal of literature and article selection, EAMT, AAC, and SEEP; analysis and interpretation of results, AGGG and CM; and draft manuscript preparation, SOLR. All authors reviewed the results and approved the final version of the manuscript.
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Lugo Reyes, S.O., González Garay, A., González Bobadilla, N.Y. et al. Efficacy and Safety of Interferon-Gamma in Chronic Granulomatous Disease: a Systematic Review and Meta-analysis. J Clin Immunol 43, 578–584 (2023). https://doi.org/10.1007/s10875-022-01391-6
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DOI: https://doi.org/10.1007/s10875-022-01391-6