Chronic Granulomatous Disease (CGD: An Update on Pathogenesis and Management for Internists

Reinhard A. Seger


Inborn errors of immunity are emerging in the medical

practice of adult physicians. The median life expectancy of once fatal pediatric primary immunodeficiencies (PIDs) was extended into adulthood by increasing awareness , shortening diagnostic delays and developing modern treatment regimens, incl. hemopoietic stem cell transplantation (HSCT). A prime example of the impressive progress is chronic granulomatous disease (CGD), an inherited deficiency of the innate immune system, with a median patient survival of 40 years and more.

The last few years have witnessed four major advances in our knowledge of CGD:

  1. Realization of an increased burden of inflammatory complications in adult life requiring specialist medical care.
  2. Better understanding of the physiologic anti-inflammatory function of the defective NADPH system opening new avenues for targeted drug interventions
  3. Advances in reduced intensity conditioning (RIC) for allogeneic HSCT making it a safe procedure even for patients with severe infection or hyperinflammation.
  4. Encouraging early data of an ongoing trial of gene-replacement therapy using a self-inactivated lentiviral vector.

Combining targeted antiinfectious/antiinflammatory measures and considering  extended indications for curative HSCT are key to improving patient outcome further. Long-term assessment of gene therapy is not yet possible.

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Kuhns DB, Alvord WG, Heller T et al. Residual NADPH oxidase and survival in chronic granulomatous disease. N Engl J Med 2010; 363: 2600-10

Reeves EP, Lu H, Jacobs HL et al. Killing activity of neutrophils is mediated through activation of proteases by K+ flux. Nature 2002; 416: 291-97

Brinkmann V, Zychlinsky A. Neutrophil extracellular traps: Is immunity the second function of chromatin? J Cell Biol 2012; 198: 773-83

Bianchi M, Niemiec MJ, Siler U et al. Restoration of anti-Aspergillus defense by neutrophil extracellular traps in chronic granulomatous disease after gene therapy is calprotectin dependent. J Allergy Clin Immunol 2011; 127: 1243-52

Fuchs TA, Abed U, Goosmann C et al. Novel cell death program leads to neutrophil extracellular traps. J Cell Biol 2007; 176: 231-41

Matsura T. Oxidized phosphatidylserine: Production and bioactivities.Yonago Acta Medica 2014; 57: 119-27

Heckmann BL, Boada-Romero E, Cunha LD et al. LC3-associated phagocytosis and inflammation. J Mol Biol 2017; 429: 3561-76

Sanford AN, Suriano AR, Herche D et al. Abnormal apoptosis in chronic granulomatous disease and autoantibody production characteristic of lupus. Rheumatology 2006; 45: 178-81

Bagaitkar J, Huang J, Zeng MY et al. NADPH oxidase activation regulates apoptotic neutrophil clearance by murine macrophages. Blood 2018; 131: 2367-78

Fernandez-Boyanapalli RF, Falcone EL, Zerbe CS et al. Impaired efferocytosis in human CGD is reversed by Pioglitazone treatment. J Allergy Clin Immunol 2015; 136: 1399-401

Fernandez-Boyanapalli RF, Frasch SC, Thomas SM et al. Pioglitazone restores phagocyte mitochondrial oxidants and bactericidal capacity in CGD. J Allergy Clin Immunol 2015; 135: 517-27

Migliavacca M, Assanelli A, Ferrua F et al. Pioglitazone as a novel therapeutic approach in CGD. J Allergy Clin Immunol 2016; 137: 1913-15

Dunogué B, Pilmis B, Mahlaoui N et al.Chronic granulomatous disease in patients reaching adulthood: A nationwide study in France. Clin Infect Dis 2017; 64: 767-75

Winkelstein JA, Marino MC, Johnston RB et al. Chronic granulomatous disease. Report on a national registry of 368 patients.Medecine 2000 79: 155-69

Van den Berg JM, van Koppen E, Ahlin A et al. Chronic granulomatous disease: The European experience. PLoS One 2009; 4: e5234

Lee PP, Chan KW, Jiang L et al. Susceptibility to mycobacterial infections in children with X-linked CGD Pediatr Infect Dis J 2008; 27: 224-30

Conti F, Lugo-Reyes SO, Blancas Galicia L et al. Mycobacterial disease in chronic granulomatous disease: A retrospective analsis of 71 cases. J Allergy Clin Immunol 2016; 138: 241-48

Lee PP, Lau YL. Endemic infections in Southeast Asia provide new insights to the pheno-typic spectrum of primary immunodeficiency disorders. Asian Pac J Allergy Immunol 2013; 31: 217-26

Martin A, Marques L, Soler-Palacin P et al. Visceral leishmaniasis associated hemophagocytic syndrome in patients with chronic granulomatous disease. Pediatr Infect Dis 2009; 28: 753-54

Henriet SS, Verweij PE, Warris A. Aspergillus nidulans and chronic granulomatous disease:A unique host-pathogen interaction. J Infect Dis 2012; 206: 1128-37

Siddiqui S, Anderson VL, Hilligoss DM et al. Fulminant mulch pneumonitis: An emergency presentation of chronic granulomatous disease. Clin Infect Dis 2007; 45:673-81

Hussain N, Feld J, Kleiner DE et al. Hepatic abnormalities in patients with chronic granulomatous disease. Hepatology 2007; 45: 675-83

Straughan DM, McLoughlin KC, Mullinax JE et al. The changing paradigm of management of liver abscesses in chronic granulomatous disease. J Allergy Clin Immunol Pract 2016; 4: 1082-88

Marciano BE, Rosenzweig SD, Kleiner DE et al. Gastrointestinal involvement in chronic granulomatous disease. Pediatrics 2004; 114: 462-68

Thomsen IP, Smith MA, Holland SM et al. A comprehensive approach to the management of children and adults with chronic granulomatous disease. J Allergy Clin Immunol Pract 2016; 4: 1082-88

Leiding JW, Holland SM. Chronic granulomatous disease. Gene Reviews (internet) Seattle, University of Washington, 2016 (free full text)

Seger RA, Roos D, Segal BH, Kuijpers TW eds. Chronic granulomatous disease: Genetics, biology, clinical management (internet). New York, Nova Publishers, 2017 (free download

Margolis DM, Melnick DA, Alling DW et al. Trimethoprim-sulfamethoxazole prophylaxis in the management of chronic granulomatous disease. J Infect Dis 1990; 162: 723-26

Gallin JL, Alling DW, Malech HL et al. Itraconazole to prevent fungal infections in chronic granulomatous disease. N Engl J Med 2003; 348: 2416-22

International chronic granulomatous disease cooperative study group. A controlled trial of interferon gamma to prevent infection in CGD. N Engl J Med 1991; 324: 509-16

Martire B, Rondelli R, Soresina A et al. 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

Magnani A, Mahlaoui N. Managing inflammatory manifestations in patients with chronic granulomatous disease. Pediatr Drugs 2016; 18: 335-45

Maltesen HR, Nielsen CH, Dalboge CS et al.Methylprednisolone prevents tumour necrosis factor alpha-dependent multinucleated giant cell formation. Rheumatology 2010; 49: 2037-42

Noel N, Mahlaoui N, Blanche S et al. Efficacy and safety of thalidomide in patients with inflammatory manifestations of chronic granulomatous disease: A retrospective case series. J Allergy Clin Immunol 20132013; 132: 997-1000

Uzel G, Orange JS, Poliak N et al. Complications of tumor necrosis factor alpha blockade in chronic granulomatous disease-related colitis. Clin Infect Dis 2010; 51: 1429-34

Hahn KJ, Ho N, Yockey L et al. Treatment with anakinra, a recombinant IL1-receptor antagonist, unlikely to induce lasting remission in patients with chronic granulomatous disease Am J Gastroenterol 2015; 110: 938-39

Seger RA. Hematopoietic stem cell transplantation for chronic granulomatous disease. Immunol Allergy Clin North Am 2010; 30: 195-208

Güngör T, Teira P, Slatter M et al. Reduced-intensity conditioning and HLA-matched haemopoietic stem-cell transplantation in patients with chronic granulomatous disease: A prospective multicentre study.Lancet 2014: 383, 436-48

Morillo-Gutierrez B, Beier R, Rao K et al. Treosulfan-based conditioning for allogeneic HSCT in children with chronic granulomatous disease: A multicenter experience. Blood, 2016; 128: 440-48

Ahlin A, Fugeläng J, de Boer M. Chronic granulomatous disease: Haematopoietic stem cell transplantation versus conventional treatment. Acta Paediatr 2013; 24: 1087-94

Cole T, Pearce MS, Cant A et al. Clinical outcome in children with chronic granulomatous disease managed conservatively or with hematopoietic stem cell transplantation. J Allergy Clin Immunol 2013; 132: 1150-55

Luznik L, Jones RJ, Fuchs EJ. High dose cyclophosphamide for GvHD prevention. Curr Opin Hematol 2010; 17: 493-99

Parta M, Hilligoss D, Kelly C et al. Haploidentical hematopoietic cell transplantation with post-transplant cyclo-phosphamide in a patient with chronic granulomatous disease: A first report.J Clin Immunol 2015; 35: 675-80

Regueiro-Garcia A, Farina-Nogueira S, Porto-Arceo JA et al. Haploidentical stem cell transplantation in a boy with chronic granulomatous disease. Allergologia et Immunopathologia 2018; 46: 385-88

Stein S, Ott MG, Schultze-Strasser S et al. Genomic instability and myelodysplasia with monosomy 7 consequent to EVI1 activation after gene therapy for chronic granulomatous disease. Nat Med 2010; 16: 198-204

Santilli G, Almarza E, Brendel C et al. Biochemical correction of X-CGD by a novel chimeric promotor regulating high levels of transgene expression in myeloid cells. Mol Ther 2011; 19: 122-132

Thrasher A. Personal communication, August 2017



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