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16.11.2022 | Original Article

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

verfasst von: Saul O. Lugo Reyes, Alejandro González Garay, Norma Yvett González Bobadilla, Diana Alejandra Rivera Lizárraga, Araceli Catalina Madrigal Paz, Edgar Alejandro Medina-Torres, Aristóteles Álvarez Cardona, José Luis Galindo Ortega, Cecilia Solís Galicia, Sara Elva Espinosa-Padilla, Chiharu Murata

Erschienen in: Journal of Clinical Immunology

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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.
Literatur
1.
Zurück zum Zitat Assari T. Chronic granulomatous disease; fundamental stages in our understanding of CGD. Med Immunol. 2006;5:1–8. CrossRef Assari T. Chronic granulomatous disease; fundamental stages in our understanding of CGD. Med Immunol. 2006;5:1–8. CrossRef
2.
Zurück zum Zitat Seger R. Chronic granulomatous disease: recent advances in pathophysiology and treatment. J Med. 2010;68(11):334–40. Seger R. Chronic granulomatous disease: recent advances in pathophysiology and treatment. J Med. 2010;68(11):334–40.
3.
Zurück zum Zitat 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. CrossRefPubMed 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. CrossRefPubMed
4.
Zurück zum Zitat Seger R. Modern Management of chronic granulomatous disease. Br J Haematol. 2008;140:255–66. CrossRefPubMed Seger R. Modern Management of chronic granulomatous disease. Br J Haematol. 2008;140:255–66. CrossRefPubMed
5.
Zurück zum Zitat 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. CrossRefPubMed 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. CrossRefPubMed
6.
Zurück zum Zitat 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. CrossRefPubMed 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. CrossRefPubMed
7.
Zurück zum Zitat 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. CrossRefPubMedPubMedCentral 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. CrossRefPubMedPubMedCentral
8.
Zurück zum Zitat 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. CrossRefPubMed 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. CrossRefPubMed
9.
Zurück zum Zitat 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. PubMed 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. PubMed
10.
Zurück zum Zitat 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. CrossRefPubMed 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. CrossRefPubMed
11.
Zurück zum Zitat 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. 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.
12.
Zurück zum Zitat 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. CrossRefPubMedPubMedCentral 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. CrossRefPubMedPubMedCentral
13.
Zurück zum Zitat 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. CrossRefPubMedPubMedCentral 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. CrossRefPubMedPubMedCentral
14.
Zurück zum Zitat 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. CrossRefPubMed 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. CrossRefPubMed
15.
Zurück zum Zitat 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. PubMed 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. PubMed
16.
Zurück zum Zitat 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. CrossRefPubMed 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. CrossRefPubMed
17.
Zurück zum Zitat 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. CrossRefPubMed 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. CrossRefPubMed
19.
Zurück zum Zitat 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. 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.
20.
Zurück zum Zitat 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. CrossRefPubMedPubMedCentral 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. CrossRefPubMedPubMedCentral
21.
Zurück zum Zitat 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. CrossRefPubMed 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. CrossRefPubMed
22.
Zurück zum Zitat 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. 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.
23.
Zurück zum Zitat 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. CrossRefPubMed 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. CrossRefPubMed
24.
Zurück zum Zitat 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. CrossRef 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. CrossRef
25.
26.
Zurück zum Zitat 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. CrossRefPubMed 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. CrossRefPubMed
27.
Zurück zum Zitat 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. CrossRefPubMed 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. CrossRefPubMed
28.
Zurück zum Zitat 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. PubMed 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. PubMed
29.
Zurück zum Zitat 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. CrossRefPubMedPubMedCentral 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. CrossRefPubMedPubMedCentral
30.
Zurück zum Zitat 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. CrossRef 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. CrossRef
31.
Zurück zum Zitat 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. CrossRefPubMed 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. CrossRefPubMed
32.
Zurück zum Zitat 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. CrossRefPubMed 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. CrossRefPubMed
33.
Zurück zum Zitat 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. CrossRefPubMedPubMedCentral 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. CrossRefPubMedPubMedCentral
35.
Zurück zum Zitat 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. CrossRefPubMed 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. CrossRefPubMed
36.
Zurück zum Zitat 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. CrossRefPubMed 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. CrossRefPubMed
37.
Zurück zum Zitat 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. PubMed 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. PubMed
38.
Zurück zum Zitat 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. CrossRefPubMed 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. CrossRefPubMed
39.
Zurück zum Zitat 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. 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.
40.
Zurück zum Zitat 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. CrossRefPubMed 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. CrossRefPubMed
Metadaten
Titel
Efficacy and Safety of Interferon-Gamma in Chronic Granulomatous Disease: a Systematic Review and Meta-analysis
verfasst von
Saul O. Lugo Reyes
Alejandro González Garay
Norma Yvett González Bobadilla
Diana Alejandra Rivera Lizárraga
Araceli Catalina Madrigal Paz
Edgar Alejandro Medina-Torres
Aristóteles Álvarez Cardona
José Luis Galindo Ortega
Cecilia Solís Galicia
Sara Elva Espinosa-Padilla
Chiharu Murata
Publikationsdatum
16.11.2022
Verlag
Springer US
Erschienen in
Journal of Clinical Immunology
Print ISSN: 0271-9142
Elektronische ISSN: 1573-2592
DOI
https://doi.org/10.1007/s10875-022-01391-6

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