Chronic granulomatous disease

1. Chronic Granulomatous Disease Yoavanit Srivaro M.D.

2. Outlines • Introduction • History • Epidemiology • Pathogenesis and Etiology • Clinical features • Evaluation and Diagnosis • Treatment

3. Introduction

4. Phagocytic cells • Neutrophil • Macrophage • Monocyte Abbas AK, Lichtman AH, Pillai Shiv. Cellular and molecular immunology. 8th ed.Philadelphia, W.B. Saunders Company.2015.

5. Neutrophil • Circulate as spherical cells about 12-15 μm in diameter • Nucleus of a neutrophil is segmented Abbas AK, Lichtman AH, Pillai Shiv. Cellular and molecular immunology. 8th ed.Philadelphia, W.B. Saunders Company.2015.

6. Neutrophil • Granule ( large lysosome): 1. Azurophilic granule (1°) :Defensins (>50% of contents) :Cathelicidins :MPO (myelopeoxidase) 2. Specific granule (2°)- only in neutrophil: :Lactoferrin :Lysozyme MPO – green color in pus Abbas AK, Lichtman AH, Pillai Shiv. Cellular and molecular immunology. 8th ed.Philadelphia, W.B. Saunders Company.2015.

7. Lekstrom-Himes JA, Gallin JI. Immunodeficiency diseases caused by defects in phagocytes. N Engl J Med 2000;343:1703-14.

15. History

16. Janeway & colleagues 1st reported 5 children with serum gamma globulin levels with recurrent infections 1954 Assari T. Chronic Granulomatous Disease; fundamental stages in our understanding of CGD. Med Immunol 2006;5:4.

17. Janeway & colleagues 1st reported 5 children with serum gamma globulin levels with recurrent infections 1954 1957 Bridges et al. described 4 boys with hypergammaglobulinemia, suffering recurrent infections of the lungs, lymph nodes, and skin, with granulomatous lesions " fatal granulomatous disease of childhood" was first described Assari T. Chronic Granulomatous Disease; fundamental stages in our understanding of CGD. Med Immunol 2006;5:4.

18. Janeway & colleagues 1st reported 5 children with serum gamma globulin levels with recurrent infections 1954 1957 Bridges et al. described 4 boys with hypergammaglobulinemia, suffering recurrent infections of the lungs, lymph nodes, and skin, with granulomatous lesions " fatal granulomatous disease of childhood" was first described 1960 Studies on patient blood confirmed CGD to be a disease of impaired phagocytes Assari T. Chronic Granulomatous Disease; fundamental stages in our understanding of CGD. Med Immunol 2006;5:4.

19. Janeway & colleagues 1st reported 5 children with serum gamma globulin levels with recurrent infections 1954 1957 Bridges et al. described 4 boys with hypergammaglobulinemia, suffering recurrent infections of the lungs, lymph nodes, and skin, with granulomatous lesions " fatal granulomatous disease of childhood" was first described 1960 Studies on patient blood confirmed CGD to be a disease of impaired phagocytes 1967 Tx using erythromycin & novobiocin antibiotics& regular sx drainage, survival rate 4yrs to 12yrs Chronic granulomatous disease

20. Speculation that a b-type cytochrome may also be involved in this O2-. generating activity 1979 Assari T. Chronic Granulomatous Disease; fundamental stages in our understanding of CGD. Med Immunol 2006;5:4.

21. Speculation that a b-type cytochrome may also be involved in this O2-. generating activity 1979 1980 Saw the formation of a disease- gene relationship. Assari T. Chronic Granulomatous Disease; fundamental stages in our understanding of CGD. Med Immunol 2006;5:4.

22. Speculation that a b-type cytochrome may also be involved in this O2-. generating activity 1979 1980 Saw the formation of a disease- gene relationship. 1986 The gp91phox subunit was first cloned , encoded from the CYBB gene Assari T. Chronic Granulomatous Disease; fundamental stages in our understanding of CGD. Med Immunol 2006;5:4.

23. Epidemiology

24. Epidemiology • Based on 2 large retrospective studies in the United States and Europe -> incidence= 1:200,000 Winkelstein JA, Marino MC, Johnston RB, Jr., Boyle J, Curnutte J, Gallin JI, et al. Chronic granulomatous disease. Report on a national registry of 368 patients. Medicine (Baltimore) 2000;79:155-69. van den Berg JM, van Koppen E, Ahlin A, Belohradsky BH, Bernatowska E, Corbeel L, et al. Chronic granulomatous disease: the European experience. PLoS One 2009;4:e5234.

25. Epidemiology • Sweden -> 1 :450,000 • Japan -> 1 :300,000 • Israeli Arabs -> 1 :111,000 Ahlin A, De Boer M, Roos D, Leusen J, Smith CI, Sundin U, et al. Prevalence, genetics and clinical presentation of chronic granulomatous disease in Sweden. Acta Paediatr 1995;84:1386-94. Hasui M, Japa SGPD. Chronic granulomatous disease in Japan: Incidence and natural history. Pediatrics International 1999;41:589-93. Wolach B, Gavrieli R, de Boer M, Gottesman G, Ben-Ari J, Rottem M, et al. Chronic granulomatous disease in Israel: clinical, functional and molecular studies of 38 patients. Clin Immunol 2008;129:103-14.

26. H Winkelstein JA, Marino MC, Johnston RB, Jr., Boyle J, Curnutte J, Gallin JI, et al. Chronic granulomatous disease. Report on a national registry of 368 patients. Medicine (Baltimore) 2000;79:155-69.

27. Winkelstein JA, Marino MC, Johnston RB, Jr., Boyle J, Curnutte J, Gallin JI, et al. Chronic granulomatous disease. Report on a national registry of 368 patients. Medicine (Baltimore) 2000;79:155-69.

32. van den Berg JM, van Koppen E, Ahlin A, Belohradsky BH, Bernatowska E, Corbeel L, et al. Chronic granulomatous disease: the European experience. PLoS One 2009;4:e5234.

36. Pathogenesis and Etiology

37. Abbas AK, Lichtman AH, Pillai Shiv. Cellular and molecular immunology. 8th ed.Philadelphia, W.B. Saunders Company.2015.

41. NADPH Oxygen complex Harris JB, Michelow IC, Westra SJ, Kradin RL. Case records of the Massachusetts General Hospital. Case 21-2008. An 11- month-old boy with fever and pulmonary infiltrates. N Engl J Med 2008;359:178-87.

42. https://www.roswellpark.edu/oico

48. NADPH Oxygen derive reductant Segal BH, Leto TL, Gallin JI, Malech HL, Holland SM. Genetic, biochemical, and clinical features of chronic granulomatous disease. Medicine (Baltimore) 2000;79:170-200.

56. Boxer LA .Neutrophil abnormalities Pediatr Rev. 2003 Feb;24(2):52-62.

59. Catalase positive Bacteria S-Staph aureus Serratia marcesens P-Pseudomonas A-Aspergillus C-Candida Cryptococcus Corynebacterium E-E.coli Enterobacter L-Listeria M-Mycobacterium N-Norcardia "LMN SPACE"

60. Song E, Jaishankar GB, Saleh H, Jithpratuck W, Sahni R, Krishnaswamy G. Chronic granulomatous disease: a review of the infectious and inflammatory complications. Clin Mol Allergy 2011;9:10.

64. Segal BH, Leto TL, Gallin JI, Malech HL, Holland SM. Genetic, biochemical, and clinical features of chronic granulomatous disease. Medicine (Baltimore) 2000;79:170-200.

65. Relation among the Components of NADPH Oxidase That Are Affected in Patients with Chronic Granulomatous Disease. Lekstrom-Himes JA, Gallin JI. Immunodeficiency diseases caused by defects in phagocytes. N Engl J Med 2000;343:1703-14.

66. X-linked CGD Song E, Jaishankar GB, Saleh H, Jithpratuck W, Sahni R, Krishnaswamy G. Chronic granulomatous disease: a review of the infectious and inflammatory complications. Clin Mol Allergy 2011;9:10.

67. X-linked CGD www.cgd.org.uk

72. X-linked CGD In affected women, lyonization (ie, the inactivation of one or the other X chromosome in every cell) leads to two populations of phagocytes: one with normal respiratory burst function and the other with impaired respiratory burst activity . Repine JE, Clawson CC, White JG, Holmes B. Spectrum of function of neutrophils from carriers of sex-linked chronic granulomatous disease. J Pediatr 1975;87:901-7.

73. X-linked CGD Carriers with less than 20 percent of normal oxidase activity due to skewed X-chromosome lyonization may present with the phenotype of mild to severe CGD. Anderson-Cohen M, Holland SM, Kuhns DB, Fleisher TA, Ding L, Brenner S, et al. Severe phenotype of chronic granulomatous disease presenting in a female with a de novo mutation in gp91-phox and a non familial, extremely skewed X chromosome inactivation. Clin Immunol 2003;109:308-17.

74. AR-CGD Song E, Jaishankar GB, Saleh H, Jithpratuck W, Sahni R, Krishnaswamy G. Chronic granulomatous disease: a review of the infectious and inflammatory complications. Clin Mol Allergy 2011;9:10.

75. Clinical features

76. Clinical features • Infection • Inflammation • Autoimmune disease

77. Inflammation • Enhanced & persistent inflammatory response • Reflected by hypergammaglobulinaemia & anaemia • Granuloma formation -> Occlusion of hollow viscera • Inflammatory cystitis • Granulomatous colitis mimicking Crohn’s disease Seger RA. Modern management of chronic granulomatous disease. Br J Haematol 2008;140:255-66.

78. Inflammation • Persistent inflammation can occur independently of infection • Inflammatory sites are frequently sterile. • One possible explanation for failure to resolve inflammation ->Inability of CGD phagocytes to degrade chemotactic factors Seger RA. Modern management of chronic granulomatous disease. Br J Haematol 2008;140:255-66.

79. Autoimmune disease • CYBB &other CGD-related genes could be lupus-susceptibility genes • Abnormal apoptosis coupled to abnormal clearance of apoptotic cells • Complement deficiencies Carneiro-Sampaio M, Liphaus BL, Jesus AA, Silva CA, Oliveira JB, Kiss MH. Understanding systemic lupus erythematosus physiopathology in the light of primary immunodeficiencies. J Clin Immunol 2008;28 Suppl 1:S34-41.

80. Battersby AC, Cale AM, Goldblatt D, Gennery AR. Clinical manifestations of disease in X-linked carriers of chronic granulomatous disease. J Clin Immunol 2013;33:1276-84.

81. Common site of infection www.cgd.org.uk

84. Harris JB, Michelow IC, Westra SJ, Kradin RL. Case records of the Massachusetts General Hospital. Case 21-2008. An 11- month-old boy with fever and pulmonary infiltrates. N Engl J Med 2008;359:178-87.

96. Marciano BE, Spalding C, Fitzgerald A, Mann D, Brown T, Osgood S, et al. Common severe infections in chronic granulomatous disease. Clin Infect Dis 2015;60:1176-83.

97. Marciano BE, Spalding C, Fitzgerald A, Mann D, Brown T, Osgood S, et al. Common severe infections in chronic granulomatous disease. Clin Infect Dis 2015;60:1176-83. 2.6 cases per 100 patient-years

102. Marciano BE, Spalding C, Fitzgerald A, Mann D, Brown T, Osgood S, et al. Common severe infections in chronic granulomatous disease. Clin Infect Dis 2015;60:1176-83. Total 268

103. Marciano BE, Spalding C, Fitzgerald A, Mann D, Brown T, Osgood S, et al. Common severe infections in chronic granulomatous disease. Clin Infect Dis 2015;60:1176-83. Total 268

109. Panel A shows painful inflammation of the nares. Lekstrom-Himes JA, Gallin JI. Immunodeficiency diseases caused by defects in phagocytes. N Engl J Med 2000;343:1703-14.

110. Fig. 1 Left fundus demonstrating typical punched out chorioretinal lesion with retinal vessel bowing in the base and pigmented margins. David Goldblatt , Jeremy Butcher , Adrian J. Thrasher , Isabelle Russell-Eggitt Chorioretinal lesions in patients and carriers of chronic granulomatous disease The Journal of Pediatrics, Volume 134, Issue 6, 1999, 780 - 783 http://dx.doi.org/10.1016/S0022-3476(99)70299-4

111. Panel B shows a large granuloma in the neck (arrow) Lekstrom-Himes JA, Gallin JI. Immunodeficiency diseases caused by defects in phagocytes. N Engl J Med 2000;343:1703-14.

112. Panel C shows severe gingivitis (arrow). Lekstrom-Himes JA, Gallin JI. Immunodeficiency diseases caused by defects in phagocytes. N Engl J Med 2000;343:1703-14.

113. Massive lymphadenopathy in the cervical, axillary, and preauricular areas Esfandbod M, Kabootari M. Images in clinical medicine. Chronic granulomatous disease. N Engl J Med 2012;367:753.

114. Massive lymphadenopathy in the inguinal areas Esfandbod M, Kabootari M. Images in clinical medicine. Chronic granulomatous disease. N Engl J Med 2012;367:753.

115. Chest radiographr evealed multiple bilateral abscesses in both lungs Esfandbod M, Kabootari M. Images in clinical medicine. Chronic granulomatous disease. N Engl J Med 2012;367:753.

116. Lublin M, Bartlett DL, Danforth DN, et al. Hepatic abscess in patients with chronic granulomatous disease. Ann Surg 2002;235:383-91.

117. Marciano BE, Rosenzweig SD, Kleiner DE, Anderson VL, Darnell DN, Anaya-O'Brien S, et al. Gastrointestinal involvement in

118. Panel D, a barium swallow shows an esophageal stricture (arrow) caused by a granuloma. Lekstrom-Himes JA, Gallin JI. Immunodeficiency diseases caused by defects in phagocytes. N Engl J Med 2000;343:1703-14.

121. Evaluation and Diagnosis

124. Diagnostic method of CGD • Nitroblue tetrazolium (NBT) dye test • Ferricytochrome C reduction • Chemiluminescence • Dihydrorhodamine and other fluorescene assay • H2O2 reduction(scopoletin oxidation) Segal BH, Leto TL, Gallin JI, Malech HL, Holland SM. Genetic, biochemical, and clinical features of chronic granulomatous disease. Medicine (Baltimore) 2000;79:170-200.

127. Nitroblue tetrazolium (NBT) dye test • Measures the ability of phagocytic cells to ingest • Reduce a soluble yellow dye to an intracellular blue crystal • Screening to rule out CGD Boxer LA .Neutrophil abnormalities Pediatr Rev. 2003 Feb;24(2):52-62.

128. Nitroblue tetrazolium (NBT) dye test Negative NBT Positive NBT

129. Dihydrorhodamine reduction test • DHR :Uncharged & nonfluorescent reactive oxygen species • Activation of granulocyte loaded with DHR ->generates reactive oxygen intermediate that react with DHR • Results in increase green fluorescence Jirapongsananuruk O, Malech HL, Kuhns DB, Niemela JE, Brown MR, Anderson-Cohen M, et al. Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease, based on the dihydrorhodamine 123 assay. J Allergy Clin Immunol 2003;111:374-9.

130. Dihydrorhodamine reduction test Leukocytes were loaded with DHR At 37°C for 5 minutes in the presence of catalase Cells were stimulated with phorbol myristate acetate (PMA) for 14 minutes Immediately analyzed by flow cytometry Jirapongsananuruk O, Malech HL, Kuhns DB, Niemela JE, Brown MR, Anderson-Cohen M, et al. Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease, based on the dihydrorhodamine 123 assay. J Allergy Clin Immunol 2003;111:374-9.

131. Jirapongsananuruk O, Malech HL, Kuhns DB, Niemela JE, Brown MR, Anderson-Cohen M, et al. Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease, based on the dihydrorhodamine 123 assay. J Allergy Clin Immunol 2003;111:374-9. Number of cell react with DHR Fluorescence intensity

132. Harris JB, Michelow IC, Westra SJ, Kradin RL. Case records of the Massachusetts General Hospital. Case 21-2008. An 11- month-old boy with fever and pulmonary infiltrates. N Engl J Med 2008;359:178-87. Figure 3. Dihydrorhodamine-123 Fluorescence Assay of Peripheral- Blood Neutrophils Unrelated Healthy Control.

133. Harris JB, Michelow IC, Westra SJ, Kradin RL. Case records of the Massachusetts General Hospital. Case 21-2008. An 11- month-old boy with fever and pulmonary infiltrates. N Engl J Med 2008;359:178-87. Figure 3. Dihydrorhodamine-123 Fluorescence Assay of Peripheral- Blood Neutrophils Unrelated Healthy Control.

134. Jirapongsananuruk O, Malech HL, Kuhns DB, Niemela JE, Brown MR, Anderson-Cohen M, et al. Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease, based on the dihydrorhodamine 123 assay. J Allergy Clin Immunol 2003;111:374-9.

138. Dihydrorhodamine reduction test Stimulation index= mean channel fluorescence of stimulated neutrophils mean channel fluorescence of unstimulated neutrophils Vowells SJ, Fleisher TA, Sekhsaria S, Alling DW, Maguire TE, Malech HL. Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in patients with chronic granulomatous disease. J Pediatr 1996;128:104-7.

139. Dihydrorhodamine reduction test Subjects Stimulation index Normal subjects 127.9 (85.2-264.6) gp91-phox-deficient 1.32 (0.9 -2.2) p47-phox-deficient 13.2 (3.5-52.1) Vowells SJ, Fleisher TA, Sekhsaria S, Alling DW, Maguire TE, Malech HL. Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in patients with chronic granulomatous disease. J Pediatr 1996;128:104-7.

140. Dihydrorhodamine reduction test CV of each fluorescent histogram = Standard deviation Mean Vowells SJ, Fleisher TA, Sekhsaria S, Alling DW, Maguire TE, Malech HL. Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in patients with chronic granulomatous disease. J Pediatr 1996;128:104-7. x 100

141. Dihydrorhodamine reduction test Subjects Coefficient of variation of histogram Normal subjects 18.9 (11.4- 41.1) gp91-phox-deficient 24.6 (18.1-48.8) p47-phox-deficient 75.5 (49.3 - 100) Vowells SJ, Fleisher TA, Sekhsaria S, Alling DW, Maguire TE, Malech HL. Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in patients with chronic granulomatous disease. J Pediatr 1996;128:104-7.

144. Western immunoblot analysis Jirapongsananuruk O, Malech HL, Kuhns DB, Niemela JE, Brown MR, Anderson-Cohen M, et al. Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease, based on the dihydrorhodamine 123 assay. J Allergy Clin Immunol 2003;111:374-9.

145. CYBB mutation analysis Jirapongsananuruk O, Malech HL, Kuhns DB, Niemela JE, Brown MR, Anderson-Cohen M, et al. Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease, based on the dihydrorhodamine 123 assay. J Allergy Clin Immunol 2003;111:374-9.

148. Treatment

149. Treatment • General health care • Antibiotic prophylaxis • Antimycotic prophylaxis • Interferon gamma prophylaxis • Treatment of acute infection • Treatment of inflammatory complications • Haematopoietic stem cell transplantation • Stem cell gene therapy

150. General health care www.cgd.org.uk

154. General health care • CGD pts should receive all routine immunizations(avoidance of BCG vaccination) • Dental hygiene is very important • Avoiding sources of Aspergillus spores • Risk of perirectal abscesses can be diminished by avoiding constipation Seger RA. Modern management of chronic granulomatous disease. Br J Haematol 2008;140:255-66.

155. Seger RA. Modern management of chronic granulomatous disease. Br J Haematol 2008;140:255-66. Antibiotic prophylaxis

156. Antibiotic prophylaxis www.primaryimmune.org

157. Seger RA. Modern management of chronic granulomatous disease. Br J Haematol 2008;140:255-66. Antimycotic prophylaxis

158. Antimycotic prophylaxis www.primaryimmune.org

159. Seger RA. Modern management of chronic granulomatous disease. Br J Haematol 2008;140:255-66. Interferon-gamma prophylaxis

160. Interferon gamma prophylaxis www.primaryimmune.org

161. 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;324:509-16.

164. Treatment of acute infection • Antibiotic therapy • Antifungal therapy • Surgical intervention • White cell transfusion Seger RA. Modern management of chronic granulomatous disease. Br J Haematol 2008;140:255-66.

165. Antibiotic therapy Seger RA. Modern management of chronic granulomatous disease. Br J Haematol 2008;140:255-66. Burkholderia spp., S. aureus and Nocardia spp

166. Antifungal therapy Seger RA. Modern management of chronic granulomatous disease. Br J Haematol 2008;140:255-66.

167. Surgical intervention • Drainage of abscesses • Relief of obstruction • Excision of consolidated suppurative & granulomatous lesions Seger RA. Modern management of chronic granulomatous disease. Br J Haematol 2008;140:255-66.

168. White cell transfusion • Complication 1. Leucoagglutinin 2. Rapid decrease of neutrophil 3. Leukastasis 4.Alloimmunization to HLA Ag Seger RA. Modern management of chronic granulomatous disease. Br J Haematol 2008;140:255-66.

169. Treatment of inflammatory complications Seger RA. Modern management of chronic granulomatous disease. Br J Haematol 2008;140:255-66.

170. Seger RA. Modern management of chronic granulomatous disease. Br J Haematol 2008;140:255-66.

173. Haematopoietic stem cell transplantation Seger RA. Modern management of chronic granulomatous disease. Br J Haematol 2008;140:255-66.

174. Haematopoietic stem cell transplantation Seger RA. Modern management of chronic granulomatous disease. Br J Haematol 2008;140:255-66.

175. Myeloablative bone marrow conditioning with busulfan based regimen Human leukocyte antigen (HLA)–identical sibling donors bone marrow transplantation N = 27 > Survival rate 85% , Cure rate 81% Seger RA, Gungor T, Belohradsky BH, Blanche S, Bordigoni P, Di Bartolomeo P, 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;100:4344-50.

176. Seger RA, Gungor T, Belohradsky BH, Blanche S, Bordigoni P, Di Bartolomeo P, 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;100:4344-50.

179. Stem cell gene therapy www.cgd.org.uk

180. Ott MG, Schmidt M, Schwarzwaelder K, Stein S, Siler U, Koehl U, 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;12:401-9.

186. Take Home Message • CGD is a genetically heterogeneous condition characterized by :Recurrent life-threatening bacterial & fungal infections :Granuloma formation • Most patients are diagnosed before the age of five years

187. Take Home Message • CGD is caused by defects in phagocyte NADPH oxidase. :Respiratory burst • Mutations in all four genes (gp91phox,p47phox, p22phox & p67phox) :Most common mutations are X linked gp91phox

188. Take Home Message • A neutrophil function test is the initial diagnostic test performed. :NBT :DHR • Current prophylaxis with :trimethoprim- sulfamethoxazole, itraconazole & in selected cases additional interferon gamma is efficient

189. Thank You

Chronic granulomatous disease

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