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Mendelian susceptibility to mycobacterial diseases

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Mendelian susceptibility to mycobacterial diseases

Presented by Kanlada Wongworapat, MD.

September9, 2016

Published in: Health & Medicine
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Mendelian susceptibility to mycobacterial diseases

  1. 1. Mendelian susceptibility to mycobacterial diseases (MSMD) Kanlada wongworapat, MD. 9th September 2016 Topic review
  2. 2. INTRODUCTION • first reported in 1964 in families with disseminated NTM • rare congenital syndrome • named Mendelian susceptibility to mycobacterial diseases (MSMD, Picard and others 2006) • disease caused by weakly virulent mycobacteria such as BCG vaccines (disseminated BCG infection), non-tuberculous environmental mycobacteria (NTM infection) and recurrent or disseminated TB infection • in otherwise healthy individuals with no overt abnormalities in routine hematological and immunological tests J. Bustamante et al. Seminars in Immunology 26. 2014; 454–470
  3. 3. Geographical distribution • 44 countries • Asia (China, India, Indonesia, Japan, Malaysia, Taiwan, Lebanon, Iran, Israel, Pakistan, Qatar, Saudi Arabia, Sri Lanka, Turkey) Saleh Al-Muhsen, et al. J ALLERGY CLIN IMMUNOL. Dec 2008; 1043-51.
  4. 4. PATHOGENESIS • Genetic defects in the IL-12/IFN- γ pathway Saleh Al-Muhsen, et al. J ALLERGY CLIN IMMUNOL. Dec 2008; 1043-51.
  5. 5. IL-12/IFN- γ pathway • connecting myeloid cells (monocytes, macrophages, and dendritic cells) to lymphoid cells (T cells and natural killer cells) • Host defense against – M. tuberculosis (TB) – Nontuberculous mycobacteria (NTM) • (M. fortuitum, M. chelonae, M. abscessus, M. avium complex, M. kansasii, M. simiae, and M. marinum) – Salmonellae Saleh Al-Muhsen, et al. J ALLERGY CLIN IMMUNOL. Dec 2008; 1043-51.
  6. 6. Macrophage Monocyte Dendritic cell T-cell NK-cellIFN-ɤ IL-12 IL-12 IL-12/IFN- γ pathway
  7. 7. Macrophage Monocyte Dendritic cell T-cell NK-cellIFN-ɤ IL-12 IL-12 IL-12/IFN- γ pathway defect
  8. 8. • AR • IFN- γR1 • IFN- γR2 • IL-12R-β1 • IL-12 p40 (IL12B) • STAT1 • interferon regulatory factor 8 (IRF8) • interferon-stimulated gene 15 (ISG15) • tyrosine kinase 2 (TYK2) • the zinc-finger transcription factor GATA2 (GATA2) • XR • IKBKG (encodes nuclear factor kappa B essential modulator [NEMO]) • CYBB (encodes gp91phox) IL-12/IFN- γ pathway defect J. Bustamante et al. Seminars in Immunology 26. 2014; 454–470
  9. 9. Gulbu Uzel, et al. UTD. Aug 2016
  10. 10. Gulbu Uzel, et al. UTD. Aug 2016
  11. 11. Macrophage Monocyte Dendritic cell T-cell NK-cellIFN-ɤ IL-12 IL-12 IL-12/IFN- γ pathway defect
  12. 12. • Autosomal • IFN- γR1 • IFN- γR2 • IL-12R-β1 • IL-12 p40 (IL12B) • STAT1 • interferon regulatory factor 8 (IRF8) • interferon-stimulated gene 15 (ISG15) • tyrosine kinase 2 (TYK2) • the zinc-finger transcription factor GATA2 (GATA2) • XR • IKBKG (encodes nuclear factor kappa B essential modulator [NEMO]) • CYBB (encodes gp91phox) IL-12/IFN- γ pathway defect J. Bustamante et al. Seminars in Immunology 26. 2014; 454–470
  13. 13. • Weakly pathogenic mycobacteria – Environmental non-tuberculous mycobacteria (NTM) – Bacillus Calmette-Guérin (BCG vaccine: M. bovis) • disseminated BCG infection • Invasive salmonellosis/ Extraintestinal infection with nontyphoid Salmonella • Mycobacterium tuberculosis • Severe viral infection (CMV, HHV8, PRV-3, RSV and VZV) Diseases cause by these organisms Dorman SE, et al. Lancet 2004; 364:2113.
  14. 14. • (Rare) – Intramacrophagic bacteria (listeriosis, nocar- diosis, klebsiellosis) – Fungi (candidiasis, histoplasmosis, paracoccidioidomycosis, coccidioidomycosis) – Parasites (leishmaniasis, toxoplasmosis) Diseases cause by these organisms Dorman SE, et al. Lancet 2004; 364:2113.
  15. 15. Organisms 115 IFN- R1 deficiencies (C and P) 21 IFN- R2deficiencies (C and P) 17 partial STAT1 deficiency J. Bustamante et al. Seminars in Immunology 26. 2014; 454–470
  16. 16. Organisms J. Bustamante et al. Seminars in Immunology 26. 2014; 454–470 180 complete IL-12R 1 deficiency 50 completeIL-12p40 deficiency
  17. 17. • MSMD is misleading name due to other types of intracellular pathogens(eg, Nocardia and Paracoccidioidomyces • “inborn defects of the IL-12/IFN-γ axis”
  18. 18. CLINICAL FEATURES • Complete defects • onset early childhood • disseminated disease • Partial defects or less severe defects (IRF8 or IL12RB1 mutations ) • adolescence • milder recurrent infections Dorman SE, et al. Lancet 2004; 364:2113.
  19. 19. M.H. Haverkamp et al. Journal of Infection (2014) 68, 134-150
  20. 20. M.H. Haverkamp et al. Journal of Infection (2014) 68, 134-150
  21. 21. M.H. Haverkamp et al. Journal of Infection (2014) 68, 134-150
  22. 22. CLINICAL FEATURES • Infected strain depend on location • Routine BCG vaccine: infection with vaccine strain • Not routine BCG vaccine: infection with M. avium, M. fortuitum, M. chelonae, or M. smegmatis ensues (via environmental exposure) Dorman SE, et al. Lancet 2004; 364:2113.
  23. 23. Disseminated BCG infection • within weeks to months of immunization • similar to environmental NTM infection • few exceptions • Draining lymph nodes: enlarge and fistulize to skin and surrounding tissues, causing skin and soft tissue infection with direct spread or hematogenous spread to distant sites. Meningitis and osteomyelitis • Multifocal osteomyelitis: not isolated (difference from environmental atypical mycobacteria Dorman SE, et al. Lancet 2004; 364:2113.
  24. 24. PID with BCG complications.
  25. 25. PID with BCG complications. S.Norouzi, et al. Journal of Infection (2012) 64, 543e554
  26. 26. Disseminated NTM infection • nonspecific (fever, weight loss, sweating, diarrhea, generalized lymphadenopathy, generalized cutaneous lesions, diffuse abdominal tenderness, and hepatosplenomegaly) • Depend on major sites of involvement (eg, bone marrow, lymphoreticular system, gastrointestinal tract, lungs) • Skin lesions Dorman SE, et al. Lancet 2004; 364:2113.
  27. 27. • Diffuse nodular skin lesions caused by Mycobacterium avium intracellulare complex in a 39-year-old white man with GATA2 deficiency Un-In Wu, Steven M Holland. Lancet Infect Dis 2015;15: 968–80
  28. 28. • Multiple erythematous papules on the left leg
  29. 29. • (C) An unhealed BCG vaccination wound on the left arm • (D) Diffuse bilateral pulmonary nodular • infiltrates • (E) Improvement in CXR findings after 2 months of anti-BCG treatment • (F) Multiple vertebral osteomyelitis over L1e2 and L5 (shown by arrows) in MRI (G) A large and difficult-to-heal wound on the right knee • • (H) The wound improved after 2 months of antibiotic treatment against Mycobacterial abscessus. Li-Hui Wang. Journal of Microbiology, Immunology and Infection (2012) 45, 411e417
  30. 30. DIAGNOSIS Un-In Wu, Steven M Holland. Lancet Infect Dis 2015;15: 968–80
  31. 31. DIAGNOSIS 1st step • testing for presence or absence of proteins involved in IFN- γ pathway • cytokine secretion after leukocyte stimulation • cell-surface receptor on monocytes and lymphocytes analysis by flow cytometry • examination of signaling by intracellular staining (eg, lack of STAT1 phosphorylation in response to IFN-gamma or STAT4 phosphorylation in response to IL-12) or western blot Wang LH, et al. J Microbiol Immunol Infect 2012; 45:411.
  32. 32. DIAGNOSIS 2nd step • Identification of the genetic defect • cDNA sequencing of the gene • next-generation sequencing techniques (in cases which cannot identify specific defect) • 50% patients with disseminated non-tuberculous mycobacterial diseases: no identified defects in the interleukin 12–interferon γ axis Wang LH, et al. J Microbiol Immunol Infect 2012; 45:411.
  33. 33. Known genetic defect J. Bustamante et al. Seminars in Immunology 26. 2014; 454–470
  34. 34. Known genetic defect J. Bustamante et al. Seminars in Immunology 26. 2014; 454–470
  35. 35. 406 MSMD patients J. Bustamante et al. Seminars in Immunology 26. 2014; 454–470
  36. 36. J. Bustamante et al. Seminars in Immunology 26. 2014; 454–470
  37. 37. DIFFERENTIAL DIAGNOSIS • HIV • Other T cell immunodeficiencies • SCID • ectodermal dysplasia with immunodeficiency (EDID) due to mutations in NF-kappa B • essential modifier (NEMO) • CGD • Hairy cell leukaemia
  38. 38. DIFFERENTIAL DIAGNOSIS • autoantibodies to IFN-γ • adult-onset disseminated mycobacterial infection • Asian, no familial clustering • INV: high titers of anti-IFN-gamma antibodies with neutralizing activity • Additional treatment: IVIG, plasmapheresis, or anti-B cell targeted therapy Browne SK,et al. N Engl J Med 2012; 367:725.
  39. 39. Browne SK, et al. N Engl J Med. August, 2012; 367:725-734
  40. 40. Browne SK, et al. N Engl J Med. August, 2012; 367:725-734
  41. 41. • group 1: disseminated NTM • group 2: other opportunistic infections w or w/o NTM • group 3: disseminated tuberculosis • group 4: pulmonary tuberculosis • Group 5: healthy controls Browne SK, et al. N Engl J Med. August, 2012; 367:725-734
  42. 42. Browne SK, et al. N Engl J Med. August, 2012; 367:725-734
  43. 43. Browne SK, et al. N Engl J Med. August, 2012; 367:725-734
  44. 44. Lee WI, et al. Immunobiology 2013; 218:762.
  45. 45. Lee WI, et al. Immunobiology 2013; 218:762.
  46. 46. GENERAL APPROACH TO TREATMENT • Aggressive antibiotics (main) • same antibiotic as patients without MSMD • prolong duration of treatment: based on response to treatment (judged by clinical recovery, radiologic improvement, and microbiologic evidence of negative cultures Brown-Elliott BA, et al. Clin Microbiol Rev 2012; 25:545.
  47. 47. GENERAL APPROACH TO TREATMENT • Cytokine replacement therapy with interferon (IFN)-gamma (additional) • limited efficacy in – (AR) complete IFN-γR1 and IFN- γR2 deficiency (lack of receptors) – (AR) complete STAT1 defects • not require in – IL12RB1 defects • started on the same doses as CGD • higher dose for more severe defects. • Dosing adjustment based on tolerance and response to therapy Brown-Elliott BA, et al. Clin Microbiol Rev 2012; 25:545.
  48. 48. GENERAL APPROACH TO TREATMENT • Surgical excision (additional) • HSCT: severe forms of MSMD (AR complete IFN-γR1 and IFN-γR2 deficiencies, AR complete STAT1 deficiency, and GATA2 deficiency) Brown-Elliott BA, et al. Clin Microbiol Rev 2012; 25:545.
  49. 49. Un-In Wu, Steven M Holland. Lancet Infect Dis 2015; 15: 968–80
  50. 50. PROGNOSIS • NTM infections: most respond to prolonged courses of antimycobacterial therapy (with or without cytokine therapy) • Mycobacterial infections: more difficult to control • Increased susceptibility to certain viral infections: AR complete IFN-γR1 and IFN-γR2 deficiencies, AR complete STAT1 deficiency, and GATA2 deficiency • Poor survival in complete deficiencies of MSMD: need HSCT Brown-Elliott BA, et al. Clin Microbiol Rev 2012; 25:545.
  51. 51. THANK YOU

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