Mendelian susceptibility to mycobacterial diseases Presented by Kanlada Wongworapat, MD. September9, 2016

1. Mendelian susceptibility to
mycobacterial diseases
(MSMD)
Kanlada wongworapat, MD.
9th September 2016
Topic review

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. 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. PATHOGENESIS
• Genetic defects in the IL-12/IFN- γ pathway
Saleh Al-Muhsen, et al. J ALLERGY CLIN IMMUNOL. Dec 2008; 1043-51.

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. Macrophage
Monocyte
Dendritic cell
T-cell
NK-cellIFN-ɤ
IL-12
IL-12
IL-12/IFN- γ pathway

7. Macrophage
Monocyte
Dendritic cell
T-cell
NK-cellIFN-ɤ
IL-12
IL-12
IL-12/IFN- γ pathway defect

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. Gulbu Uzel, et al. UTD. Aug 2016

10. Gulbu Uzel, et al. UTD. Aug 2016

11. Macrophage
Monocyte
Dendritic cell
T-cell
NK-cellIFN-ɤ
IL-12
IL-12
IL-12/IFN- γ pathway defect

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. • 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. • (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. 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. Organisms
J. Bustamante et al. Seminars in Immunology 26. 2014; 454–470
180 complete IL-12R 1 deficiency
50 completeIL-12p40 deficiency

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. 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. M.H. Haverkamp et al. Journal of Infection (2014) 68, 134-150

20. M.H. Haverkamp et al. Journal of Infection (2014) 68, 134-150

21. M.H. Haverkamp et al. Journal of Infection (2014) 68, 134-150

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. 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.

25. PID with BCG complications.

26. PID with BCG complications.
S.Norouzi, et al. Journal of Infection (2012) 64, 543e554

27. 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.

28. • 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

29. • Multiple erythematous papules on the left leg

30. • (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

31. DIAGNOSIS
Un-In Wu, Steven M Holland. Lancet Infect Dis 2015;15: 968–80

32. 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.

33. 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.

34. Known genetic defect
J. Bustamante et al. Seminars in Immunology 26. 2014; 454–470

35. Known genetic defect
J. Bustamante et al. Seminars in Immunology 26. 2014; 454–470

36. 406 MSMD patients
J. Bustamante et al. Seminars in Immunology 26. 2014; 454–470

37. J. Bustamante et al. Seminars in Immunology 26. 2014; 454–470

38. 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

39. 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.

40. Browne SK, et al. N Engl J Med. August, 2012; 367:725-734

41. Browne SK, et al. N Engl J Med. August, 2012; 367:725-734

42. • 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

43. Browne SK, et al. N Engl J Med. August, 2012; 367:725-734

44. Browne SK, et al. N Engl J Med. August, 2012; 367:725-734

45. Lee WI, et al. Immunobiology 2013; 218:762.

46. Lee WI, et al. Immunobiology 2013; 218:762.

47. 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.

48. 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.

49. 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.

50. Un-In Wu, Steven M Holland. Lancet Infect Dis 2015; 15: 968–80

51. 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.

52. THANK YOU