mendelian susceptibility to mycobacterial diseases

Mendelian susceptibility to mycobacterial diseases

(MSMD)

Kanlada wongworapat, MD.

9th September 2016

Topic review

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

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.

PATHOGENESIS

• Genetic defects in the IL-12/IFN- γ pathway


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


Macrophage Monocyte

Dendritic cell

T-cell NK-cell IFN-ɤ

IL-12

IL-12

IL-12/IFN- γ pathway

Macrophage Monocyte

Dendritic cell


IL-12

IL-12

IL-12/IFN- γ pathway defect

• 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)



Gulbu Uzel, et al. UTD. Aug 2016

Macrophage Monocyte

Dendritic cell


IL-12

IL-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)



• 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.

• (Rare)

– Intramacrophagic bacteria (listeriosis, nocar-diosis, klebsiellosis)

– Fungi (candidiasis, histoplasmosis, paracoccidioidomycosis, coccidioidomycosis)

– Parasites (leishmaniasis, toxoplasmosis)

Diseases cause by these organisms


Organisms

115 IFN- R1 deficiencies (C and P) 21 IFN- R2deficiencies (C and P) 17 partial STAT1 deficiency


Organisms


180 complete IL-12R 1 deficiency 50 completeIL-12p40 deficiency

• MSMD is misleading name due to other types of intracellular pathogens(eg, Nocardia and Paracoccidioidomyces

• “inborn defects of the IL-12/IFN-γ axis”

CLINICAL FEATURES

• Complete defects

• onset early childhood

• disseminated disease

• Partial defects or less severe defects

(IRF8 or IL12RB1 mutations )

• adolescence

• milder recurrent infections


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

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)


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


PID with BCG complications.

PID with BCG complications.

S.Norouzi, et al. Journal of Infection (2012) 64, 543e554

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


• 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

• Multiple erythematous papules on the left leg

• (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

DIAGNOSIS

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

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.

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.

Known genetic defect


406 MSMD patients


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

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.

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

• 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

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

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

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.


• 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



• Surgical excision (additional)

• HSCT: severe forms of MSMD (AR complete IFN-γR1 and IFN-γR2 deficiencies, AR complete STAT1 deficiency, and GATA2 deficiency)


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

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


THANK YOU

mendelian susceptibility to mycobacterial diseases

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