Chronic granulomatous disease: Treatment and prognosis
- Sergio D Rosenzweig, MD
Sergio D Rosenzweig, MD
- Department of Laboratory Medicine
- Steven M Holland, MD
Steven M Holland, MD
- Laboratory of Clinical Infectious Diseases
- National Institutes of Health, Bethesda, MD
Chronic granulomatous disease (CGD) is a genetically heterogeneous condition characterized by recurrent, life-threatening bacterial and fungal infections and granuloma formation. CGD is caused by defects in phagocyte nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (phox). The cornerstones of CGD management are antimicrobial and immunomodulatory prophylaxis, early diagnosis of infections, and aggressive management of infectious complications.
CGD was initially termed "fatal granulomatous disease of childhood" because patients rarely survived past their first decade in the time before routine use of prophylactic antimicrobial agents. The average patient now survives at least 40 years. Overall, survival rates are better for females than males, reflecting the greater severity of X-linked CGD.
The treatment and prognosis of CGD are reviewed here. The pathogenesis, clinical manifestations, and diagnosis of CGD, as well as an overview of primary disorders of phagocytic function, are discussed separately. (See "Chronic granulomatous disease: Pathogenesis, clinical manifestations, and diagnosis" and "Primary disorders of phagocytic function: An overview".)
The management of chronic granulomatous disease (CGD) focuses on aggressive diagnosis and treatment of infections. The reduction in mortality and morbidity seen over the past few decades is largely attributable to antimicrobial prophylaxis and rapid recognition and treatment of infections in these patients [1-4].
The cornerstones of CGD management are :
- Margolis DM, Melnick DA, Alling DW, Gallin JI. Trimethoprim-sulfamethoxazole prophylaxis in the management of chronic granulomatous disease. J Infect Dis 1990; 162:723.
- Gallin JI, Alling DW, Malech HL, et al. Itraconazole to prevent fungal infections in chronic granulomatous disease. N Engl J Med 2003; 348:2416.
- 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; 324:509.
- Sierre S, Lipsich J, Santos P, et al. Pulmonary fungal infection diagnosis in chronic granulomatous disease patients. Pediatr Pulmonol 2007; 42:851.
- Seger RA. Modern management of chronic granulomatous disease. Br J Haematol 2008; 140:255.
- Marciano BE, Wesley R, De Carlo ES, et al. Long-term interferon-gamma therapy for patients with chronic granulomatous disease. Clin Infect Dis 2004; 39:692.
- Kobayashi Y, Amano D, Ueda K, et al. Treatment of seven cases of chronic granulomatous disease with sulfamethoxazole-trimethoprim (SMX-TMP). Eur J Pediatr 1978; 127:247.
- Weening RS, Kabel P, Pijman P, Roos D. Continuous therapy with sulfamethoxazole-trimethoprim in patients with chronic granulomatous disease. J Pediatr 1983; 103:127.
- Mouy R, Fischer A, Vilmer E, et al. Incidence, severity, and prevention of infections in chronic granulomatous disease. J Pediatr 1989; 114:555.
- Petropoulou T, Liese J, Tintelnot K, et al. [Long-term treatment of patients with itraconazole for the prevention of Aspergillus infections in patients with chronic granulomatous disease (CGD)]. Mycoses 1994; 37 Suppl 2:64.
- Mouy R, Veber F, Blanche S, et al. Long-term itraconazole prophylaxis against Aspergillus infections in thirty-two patients with chronic granulomatous disease. J Pediatr 1994; 125:998.
- Cale CM, Jones AM, Goldblatt D. Follow up of patients with chronic granulomatous disease diagnosed since 1990. Clin Exp Immunol 2000; 120:351.
- Beauté J, Obenga G, Le Mignot L, et al. Epidemiology and outcome of invasive fungal diseases in patients with chronic granulomatous disease: a multicenter study in France. Pediatr Infect Dis J 2011; 30:57.
- Salvator H, Mahlaoui N, Catherinot E, et al. Pulmonary manifestations in adult patients with chronic granulomatous disease. Eur Respir J 2015; 45:1613.
- Alsultan A, Williams MS, Lubner S, Goldman FD. Chronic granulomatous disease presenting with disseminated intracranial aspergillosis. Pediatr Blood Cancer 2006; 47:107.
- Segal BH, Barnhart LA, Anderson VL, et al. Posaconazole as salvage therapy in patients with chronic granulomatous disease and invasive filamentous fungal infection. Clin Infect Dis 2005; 40:1684.
- Liese J, Kloos S, Jendrossek V, et al. Long-term follow-up and outcome of 39 patients with chronic granulomatous disease. J Pediatr 2000; 137:687.
- Weening RS, Leitz GJ, Seger RA. Recombinant human interferon-gamma in patients with chronic granulomatous disease--European follow up study. Eur J Pediatr 1995; 154:295.
- 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; 21:239.
- 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.
- Condino-Neto A, Newburger PE. 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; 95:3548.
- Ishibashi F, Mizukami T, Kanegasaki S, 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; 98:436.
- Jackson SH, Miller GF, Segal BH, et al. IFN-gamma is effective in reducing infections in the mouse model of chronic granulomatous disease (CGD). J Interferon Cytokine Res 2001; 21:567.
- Jones LB, McGrogan P, Flood TJ, et al. Special article: chronic granulomatous disease in the United Kingdom and Ireland: a comprehensive national patient-based registry. Clin Exp Immunol 2008; 152:211.
- Guide SV, Stock F, Gill VJ, et al. Reinfection, rather than persistent infection, in patients with chronic granulomatous disease. J Infect Dis 2003; 187:845.
- Lublin M, Bartlett DL, Danforth DN, et al. Hepatic abscess in patients with chronic granulomatous disease. Ann Surg 2002; 235:383.
- Leiding JW, Freeman AF, Marciano BE, et al. Corticosteroid therapy for liver abscess in chronic granulomatous disease. Clin Infect Dis 2012; 54:694.
- Yamazaki-Nakashimada MA, Stiehm ER, Pietropaolo-Cienfuegos D, et al. Corticosteroid therapy for refractory infections in chronic granulomatous disease: case reports and review of the literature. Ann Allergy Asthma Immunol 2006; 97:257.
- Greenberg DE, Ding L, Zelazny AM, et al. A novel bacterium associated with lymphadenitis in a patient with chronic granulomatous disease. PLoS Pathog 2006; 2:e28.
- Greenberg DE, Shoffner AR, Zelazny AM, et al. Recurrent Granulibacter bethesdensis infections and chronic granulomatous disease. Emerg Infect Dis 2010; 16:1341.
- Sirinavin S, Techasaensiri C, Benjaponpitak S, et al. Invasive Chromobacterium violaceum infection in children: case report and review. Pediatr Infect Dis J 2005; 24:559.
- Dorman SE, Guide SV, Conville PS, et al. Nocardia infection in chronic granulomatous disease. Clin Infect Dis 2002; 35:390.
- Freeman AF, Marciano BE, Anderson VL, et al. Corticosteroids in the treatment of severe nocardia pneumonia in chronic granulomatous disease. Pediatr Infect Dis J 2011; 30:806.
- Siddiqui S, Anderson VL, Hilligoss DM, et al. Fulminant mulch pneumonitis: an emergency presentation of chronic granulomatous disease. Clin Infect Dis 2007; 45:673.
- Segal BH, DeCarlo ES, Kwon-Chung KJ, et al. Aspergillus nidulans infection in chronic granulomatous disease. Medicine (Baltimore) 1998; 77:345.
- Yomtovian R, Abramson J, Quie P, McCullough J. Granulocyte transfusion therapy in chronic granulomatous disease. Report of a patient and review of the literature. Transfusion 1981; 21:739.
- von Planta M, Ozsahin H, Schroten H, et al. Greater omentum flaps and granulocyte transfusions as combined therapy of liver abscess in chronic granulomatous disease. Eur J Pediatr Surg 1997; 7:234.
- Ozsahin H, von Planta M, Müller I, et al. Successful treatment of invasive aspergillosis in chronic granulomatous disease by bone marrow transplantation, granulocyte colony-stimulating factor-mobilized granulocytes, and liposomal amphotericin-B. Blood 1998; 92:2719.
- Ikincioğullari A, Dogu F, Solaz N, et al. Granulocyte transfusions in children with chronic granulomatous disease and invasive aspergillosis. Ther Apher Dial 2005; 9:137.
- 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.
- Soncini E, Slatter MA, Jones LB, et al. Unrelated donor and HLA-identical sibling haematopoietic stem cell transplantation cure chronic granulomatous disease with good long-term outcome and growth. Br J Haematol 2009; 145:73.
- Chin TW, Stiehm ER, Falloon J, Gallin JI. Corticosteroids in treatment of obstructive lesions of chronic granulomatous disease. J Pediatr 1987; 111:349.
- Quie PG, Belani KK. Corticosteroids for chronic granulomatous disease. J Pediatr 1987; 111:393.
- Southwick FS, van der Meer JW. Recurrent cystitis and bladder mass in two adults with chronic granulomatous disease. Ann Intern Med 1988; 109:118.
- Marciano BE, Rosenzweig SD, Kleiner DE, et al. Gastrointestinal involvement in chronic granulomatous disease. Pediatrics 2004; 114:462.
- Zanditenas D, Hagège H, Rosa I, et al. [Inflammatory colitis and chronic granulomatous disease, a steroid-dependent case report]. Gastroenterol Clin Biol 2004; 28:398.
- Uzel G, Orange JS, Poliak N, et al. Complications of tumor necrosis factor-α blockade in chronic granulomatous disease-related colitis. Clin Infect Dis 2010; 51:1429.
- Myrup B, Valerius NH, Mortensen PB. Treatment of enteritis in chronic granulomatous disease with granulocyte colony stimulating factor. Gut 1998; 42:127.
- Wang J, Mayer L, Cunningham-Rundles C. Use of GM-CSF in the treatment of colitis associated with chronic granulomatous disease. J Allergy Clin Immunol 2005; 115:1092.
- 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 2013; 132:997.
- Seger RA. Hematopoietic stem cell transplantation for chronic granulomatous disease. Immunol Allergy Clin North Am 2010; 30:195.
- Kang EM, Marciano BE, DeRavin S, et al. Chronic granulomatous disease: overview and hematopoietic stem cell transplantation. J Allergy Clin Immunol 2011; 127:1319.
- Bielorai B, Toren A, Wolach B, et al. Successful treatment of invasive aspergillosis in chronic granulomatous disease by granulocyte transfusions followed by peripheral blood stem cell transplantation. Bone Marrow Transplant 2000; 26:1025.
- Seger RA, Gungor T, Belohradsky BH, et al. Treatment of chronic granulomatous disease with myeloablative conditioning and an unmodified hemopoietic allograft: a survey of the European experience, 1985-2000. Blood 2002; 100:4344.
- Schuetz C, Hoenig M, Gatz S, et al. Hematopoietic stem cell transplantation from matched unrelated donors in chronic granulomatous disease. Immunol Res 2009; 44:35.
- Martinez CA, Shah S, Shearer WT, et al. Excellent survival after sibling or unrelated donor stem cell transplantation for chronic granulomatous disease. J Allergy Clin Immunol 2012; 129:176.
- Güngör T, Halter J, Klink A, et al. Successful low toxicity hematopoietic stem cell transplantation for high-risk adult chronic granulomatous disease patients. Transplantation 2005; 79:1596.
- Horwitz ME, Barrett AJ, Brown MR, et al. Treatment of chronic granulomatous disease with nonmyeloablative conditioning and a T-cell-depleted hematopoietic allograft. N Engl J Med 2001; 344:881.
- Morio T, Atsuta Y, Tomizawa D, et al. Outcome of unrelated umbilical cord blood transplantation in 88 patients with primary immunodeficiency in Japan. Br J Haematol 2011; 154:363.
- Hoenig M, Niehues T, Siepermann K, et al. Successful HLA haploidentical hematopoietic SCT in chronic granulomatous disease. Bone Marrow Transplant 2014; 49:1337.
- Malech HL, Maples PB, Whiting-Theobald N, et al. Prolonged production of NADPH oxidase-corrected granulocytes after gene therapy of chronic granulomatous disease. Proc Natl Acad Sci U S A 1997; 94:12133.
- Weil WM, Linton GF, Whiting-Theobald N, et al. Genetic correction of p67phox deficient chronic granulomatous disease using peripheral blood progenitor cells as a target for retrovirus mediated gene transfer. Blood 1997; 89:1754.
- Dinauer MC, Li LL, Björgvinsdóttir H, et al. Long-term correction of phagocyte NADPH oxidase activity by retroviral-mediated gene transfer in murine X-linked chronic granulomatous disease. Blood 1999; 94:914.
- Kang EM, Choi U, Theobald N, et al. Retrovirus gene therapy for X-linked chronic granulomatous disease can achieve stable long-term correction of oxidase activity in peripheral blood neutrophils. Blood 2010; 115:783.
- Ott MG, Seger R, Stein S, et al. Advances in the treatment of Chronic Granulomatous Disease by gene therapy. Curr Gene Ther 2007; 7:155.
- Sokolic R, Kesserwan C, Candotti F. Recent advances in gene therapy for severe congenital immunodeficiency diseases. Curr Opin Hematol 2008; 15:375.
- Ott MG, 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; 12:401.
- 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.
- Santilli G, Almarza E, Brendel C, et al. Biochemical correction of X-CGD by a novel chimeric promoter regulating high levels of transgene expression in myeloid cells. Mol Ther 2011; 19:122.
- Panch SR, Yau YY, Kang EM, et al. Mobilization characteristics and strategies to improve hematopoietic progenitor cell mobilization and collection in patients with chronic granulomatous disease and severe combined immunodeficiency. Transfusion 2015; 55:265.
- Winkelstein JA, Marino MC, Johnston RB Jr, et al. Chronic granulomatous disease. Report on a national registry of 368 patients. Medicine (Baltimore) 2000; 79:155.
- Kobayashi S, Murayama S, Takanashi S, et al. Clinical features and prognoses of 23 patients with chronic granulomatous disease followed for 21 years by a single hospital in Japan. Eur J Pediatr 2008; 167:1389.
- Wolach B, Gavrieli R, de Boer M, et al. Chronic granulomatous disease in Israel: clinical, functional and molecular studies of 38 patients. Clin Immunol 2008; 129:103.
- Marciano BE, Spalding C, Fitzgerald A, et al. Common severe infections in chronic granulomatous disease. Clin Infect Dis 2015; 60:1176.
- Kuhns DB, Alvord WG, Heller T, et al. Residual NADPH oxidase and survival in chronic granulomatous disease. N Engl J Med 2010; 363:2600.
- van den Berg JM, van Koppen E, Ahlin A, et al. Chronic granulomatous disease: the European experience. PLoS One 2009; 4:e5234.
- Antimicrobial prophylaxis
- - Antibacterial prophylaxis
- - Antifungal prophylaxis
- - Immunomodulatory therapy with interferon-gamma
- Acute infections
- - Monitoring and diagnosis
- - Treatment
- Therapy for inflammatory manifestations
- Curative therapies
- - Hematopoietic cell transplantation
- - Gene therapy
- INFORMATION FOR PATIENTS
- SUMMARY AND RECOMMENDATIONS