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Mendelian susceptibility to mycobacterial diseases

Mendelian susceptibility to mycobacterial diseases

Presented by Nattasasi Suchamalawong, MD.

March12, 2021

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Mendelian susceptibility to mycobacterial diseases

  1. 1. Mendelian susceptibility to mycobacterial diseases : MSMD 12th March 2021 Nattasasi Suchamalawong, MD. Pediatric Allergy and Immunology Unit King Chulalongkorn Memorial Hospital
  2. 2. • Case study • Definition • Pathogenesis: Interferon gamma – IL 12 signaling pathways • Genetic etiologies of MSMD • Clinical features • Diagnosis • Differential diagnosis • Investigation • Treatment • Prognosis Outline
  3. 3. A 20-years-old, Thai man previous healthy , unknown underlying disease CC: chronic abdominal pain with abdominal distension with weight loss for 6 months PI: 1 day PTA abdominal distension with diarrhea PE: vital sign: BT 38.0 c, PR 100/min, RR 24/min, BP 124/82 mmHg HEENT: markedly pale conjunctivae ,no oral ulcer seen tonsil size 2+ Heart: normal S1S2, no murmur Lungs: clear , equally breath sound Abdomen: moderate distension, moderate tender at Rt sides abdomen and epigastrium, liver and spleen can’t be palpated FH: No family history of PID or unusual death Investigation >> film acute abdomen : suspected gut obstruction. Consult Sx : suspected gut obstruction plan set OR for explore laparotomy Case 1
  4. 4. Case 1: physical examination PE: BW 71 kg (78 →71 kg in 3 months), HT 160 cm • No dysmorphic feature , prognathism • Vital sign: BT 38.0 c, PR 100/min, RR 24/min, BP 124/82 mmHg • HEENT: markedly pale conjunctivae ,seen tonsil size 2+ • Heart: normal S1S2, no murmur • Lungs: clear , equally breath sound , • Abdomen: moderate distension, moderate tender at Rt sides abdomen and epigastrium, liver and spleen can’t be palpated • Skin : multiple discrete hyperpigmented papule symmetrical at both leg • Lymph node : no superficial lymphadenopathy
  5. 5. Case1: Lab investigation CT Whole abdomen 17/7/63 - Mildly thickened wall of small and large bowel complex rim-enhancing fluid collection in pelvic cavity DDx is tuberculosis. - Multiple enlarged necrotic nodes involving at paraaortic, aortocaval and mesenteric region - Multiple groups of centrilobular and ground-glass nodules, some with t ree-in bud, at superior segment of LLL, probably aspiration or infection/inflammation process. - Several small nodules in RLL with moderate right pleural effusion. CXR 17/7/63: RLL infiltration , no widening mediastinum
  6. 6. Chemistry 17/3/63 BUN 11 mg/dL Creatinine 0.6 mg/dL Na 131 mmol/L K 3.1 mmol/L Cl 106 mmol/L HCO3 22 mmol/L Calcium 7.8/8.8 mg/dL Magnesium 0.8 mg/dL Phosphate 2.4 mg/dL LFT 17/3/63 AST 14 U/L ALT 6 U/L ALP 113 U/L TB 2.6 mg/dL DB 1.23 mg/dL Albumin 2.7 g/dL Globulin 3.5 g/dL Culture Tracheal suction G/S No organism Tracheal suction C/S No growth Tracheal suction AFB Positive 1+ Sputum PCR for MTBC Detected C/S for TB Mycobacterium tuberculosis LPA MTBC+, sense I, R AFB negative AFB negative Sputum PCR for MTBC Detected Blood C/S for TB Negative CBC 16/3/63 Hb 6.6 g/dL Hct 22.9 % MCV 88.8 Fl RDW 12.8 % WBC 11,870 /ul Neutrophil 86 % Lymphocyte 13 % Monocyte 0.2 % Eosinophil 0 % Basophil 0.8 % Platelets 454,000 /ul ANC 10,208 ALC 1,543 Case1: Lab investigation Ascites Tissue (necrotic node) ,Pus wound , Stool H/C (20/7/63): no growth Anti-HIV : negative
  7. 7. CBC 16/7/63 17/7/63 18/7/63 19/7/63 20/7/63 Hb 6.6 8 9.2 9.3 8.2 g/dL Hct 22.2 25.4 28.4 29.2 25.2 % MCV 88.8 86.7 85.8 85.1 85.7 Fl RDW 21.8 19.9 17.5 17.34 17.1 % WBC 11,870 12,820 10,720 8,630 6,520 /ul Neutrophil 86 88.2 86.9 88 81.2 % Lymphocyte 13 5.2 4.3 3.6 6.3 % Monocyte 1 5.2 7.3 5.9 9.5 % Eosinophil 0 0.5 0.9 1.6 2.1 % Basophil 0 0.9 0.6 0.9 0.9 % Platelets 454,000 447,000 335,000 323,000 261,000 /ul ANC 10,208 11,300 9,320 7,590 6,300 ALC 1,543 670 460 310 410 Case1: Lab investigation Strat IRZE
  8. 8. Case 1: Problem list 1. Disseminated TB (Sputum AFB positive , small bowel caseous granuloma , LN AFB negative (necrotizing granulomatous lymphadenitis)) 2. Lymphopenia with anemia 3. hyperpigmented papule symmetrical at both leg 4. History of chronic rhinitis , seafood allergy Management : - Ceftriaxone 2 g IV OD (17/7/63-20/7/63)-> Sx start for empirical intraabdominal infection - anti TB drug : IRZE (19/7/63) * 2 months then IR until 9 months - supplement : Vit B6 (50 ) ½*1 hs ,Vit D2 (20,000) 3 cap po weekly Suspected primary immunodeficiency ??
  9. 9. DDx cause of disseminated TB in adolescent 1.Acquired : Infection: HIV Immunosuppressive drugs Autoimmune diseases Proliferative disorders : Lymphoma : no clues: (LDH 160+), no evidence thymoma Anti-Interferon gamma autoantibody (anti-IFN-γ autoantibody) 2. Congenital (PID) : hyper IgE syndrome, MSMD, CVID Disseminated TB in adolescent male Suggestion 1. Work up : CD3/CD4/CD8/CD19/CD56 level, IgG/M/A/E level 2. Check HbA1c, ANA, LDH, anti-IFN-gamma
  10. 10. 20/7/63 20 yr 8 mo IgG (mg/dl) 1091.4 (548-1194) IgM (mg/dl) 25  (45-153) IgA (mg/dl) 234 (78-322) IgE (IU/mL) 679  (<100) 20/7/63 20 yr 8 mo ALC (/ul) 335  (1,600-2,400) CD3 (/ul) 158  (960-2,600) CD4 (/ul) 104  (540-1660) CD8 (/ul) 47  (270-930) CD19 (/ul) 114  (122-632) CD56 (%) 47 (27-693) Flow cytometry report Immunoglobulins Immunologic work up Anti-Gamma interferon 20/7/63 : 5.943 (Positive)
  11. 11. CBC 16/7/63 17/7/63 18/7/63 19/7/63 20/7/63 11/8/63 28/9/63 Hb 6.6 8 9.2 9.3 8.2 10.4 15.5 g/dL Hct 22.2 25.4 28.4 29.2 25.2 33.1 46.5 % MCV 88.8 86.7 85.8 85.1 85.7 90.4 94.5 Fl RDW 21.8 19.9 17.5 17.34 17.1 22.2 14.1 % WBC 11,870 12,820 10,720 8,630 6,520 5700 4980 /ul Neutrophil 86 88.2 86.9 88 81.2 69 61.5 % Lymphocyte 13 5.2 4.3 3.6 6.3 16.5 25.1 % Monocyte 1 5.2 7.3 5.9 9.5 8.9 6.4 % Eosinophil 0 0.5 0.9 1.6 2.1 4.4 3.7 % Basophil 0 0.9 0.6 0.9 0.9 1.2 1.6 % Platelets 454,000 447,000 335,000 323,000 261,000 453,000 263,000 /ul ANC 10,208 11,300 9,320 7,590 6,300 3930 3,060 ALC 1,543 670 460 310 410 940 1,250 Case1: Progress note Strat IRZE 1st admission 2nd admission
  12. 12. Case 2 A 14-years-old, Thai girl previous healthy ,unknown underlying • CC: prolong fever 3 weeks PTA • PI: 3 weeks PTA Prolong fever with Bilateral cervical lymphadenopathy 2 weeks PTA Rt hemiparesis with ataxia • PH: – Hx of Injected and enlarged tonsils whitish oral patch suspected infectious mononucleosis – Chronic productive cough for 6 months • FH: – No family history of PID or unusual death – No history of consanguinity
  13. 13. Present illness 1 month PTA (10/12/2563) 3 weeks PTA (28/12/2563) 1 week PTA (10/01/2564) ไข้ต่่ำเป็นๆหำยๆเป็นช่วงกลำงคืน เหงื่อออก ไม่มีเบื่ออำหำร,น่ำหนักลด (BW 38 kg) ไอเล็กน้อย เจ็บคอ ไม่มีกลืนล่ำบำก ไม่มีนอนกรน ไม่มีคลื่นไส้อำเจียน ไปตรวจที่รพชวินิจฉัยว่ำเป็นคออักเสบ ได้ยำ Augmentin, Amoxycillin อำกำรยังไม่ดีขึน เริ่มรู้สึกอ่อนแรง ใช้ชีวิตประจ่ำวันได้ มำรดำสังเกตว่ำเริ่มเดินเซแต่ยังเดินเองได้ ไม่มีรองเท้ำหลุด จับปำกกำ ช้อนส้อมได้ ปกติ ยังมีไข้ต่่ำๆอยู่ตลอด เจ็บคอและไอ ไข้สูงมำกขึน ไอ เจ็บคอและอ่อนแรงพอๆเดิม ไม่มีผื่นตำมตัว ไปรักษำที่รพ.เอกชน admit 10-14/1/64
  14. 14. Case 2: physical examination • Vital sign: BT 36.5 C PR 80 bpm RR 12 /min BP 97/59 mmHg • Body weight 35 kg (P3) Height 152 cm (P25-50) BMI 15.15 kg/m2 • Skin: no rash, no petechiae, not seen BCG scar • HEENT: mild pale, anicteric sclerae, leukoplakia at tongue, no oral candidiasis • Lung: clear, equal breath sound both lungs, no adventitious sound • Heart: normal S1S2, no murmurs • Abdomen: no distension, normoactive BS, soft, liver &spleen cannot be palpated • Musculoskeletal: no deformities, no edema • Lymph node: multiple left cervical LN 2x2 cm, well-defined, rubbery consistency, movable, no soft tissue swelling,
  15. 15. Case 2: physical examination • Neuro: alert, not well co-operate, E4VTM6 • CN II: pupil right 4 mm, left 3 mm RTLBE, • CN III, IV, VI: eye deviate to right, not full EOM, limit saccadic gaze to left • CN V: corneal reflex positive both eyes • CN VII: left orbicularis oculi muscle weakness, cannot evaluate facial pals • DTR: 3+ all • Clonus: sustained clonus at right side • Babinski: no response at right side, plantar flexion left side • Sensation & Cerebellar signs: : cannot be evaluated • Motor power : Rt arm grade 2 Rt leg grade 0 , Lt arm and leg 3+
  16. 16. CXR - multiple small pulmonary nodules (miliary pattern) diffuse in both lungs with small patchy opacities at left apical lung Bilateral cervical lymphadenopathy (central necrotic nodes) Pulmonary nodules diffuse both lung Patchy opacities at superior segment LUL
  17. 17. - Multiple Rim enhancing hypodense lesion involve cortex and white matter of left frontal, parieto-temporal lobe, both side of pons, left cerebellum with marked vasogenic edema, probably tuberculous abscess or tuberculoma - Left uncal herniation , 0.6-cm midline shifting to the right
  18. 18. Case 2: Problem lists Impression : • 1. Miliary TB • 2. Cervical lymphadenopathy suspected TB LN • 3. Multiple brain abscess DDx TB • Mx - Ceftriaxone 2 gm IV q12hr - start IRZE (17/1/64) : INH 8.5 Mkday, Rifampicin 17 Mkday Pyrazinamide 35 Mkday, Ethambutol → Ethionamide(250) 1.5 tab po bid (21 mg/kg/day) 22 MKday - Dexamethasone 4 mg IV q6hr - Dilantin 70 mg IV q8hr (6 mg/kg/day) prophylaxis post op Suspected primary immunodeficiency ??
  19. 19. Case 2: Investigation Chemistry BUN 11 mg/dL Creatinine 0.34 mg/dL Na 132 mmol/L K 3.3 mmol/L Cl 103 mmol/L HCO3 18 mmol/L Calcium 8.3/9.5 mg/dL Magnesium 0.8 mg/dL Phosphate 3.3 mg/dL LFT AST 48 U/L ALT 90 U/L ALP 147 U/L TB 3.55 mg/dL DB 2.58 mg/dL Albumin 2.5 g/dL Globulin 3.7 g/dL Culture 18/1/64 Tracheal suction G/S No organism Tracheal suction C/S No growth Tracheal suction AFB Positive 1+ PCR for MTBC Detected C/S for TB Mycobacteriu m tuberculos is LPA MTBC+, sense I, R CBC 18/1/64 Hb 10.6 g/dL Hct 31.9 % MCV 69.3 Fl RDW 20.8 % WBC 34,730 /ul Neutrophil 93.8 % Lymphocyte 2.8 % Monocyte 0.2 % Eosinophil 0 % Basophil 3.2 % Atyp Lymph - % Platelets 538,000 /ul ANC 32,577 ALC 972
  20. 20. CBC 18/1/64 20/1/64 25/1/64 8/2/64 17/2/64 5/3/64 Hb 10.6 9.8 10.6 11.2 13.8 12.3 g/dL Hct 31.9 29.2 32.6 34.7 44.6 37.5 % MCV 69.3 68.7 71.2 80.9 84.3 82.6 Fl RDW 20.8 21.4 21.8 24.2 19.6 21.4 % WBC 34,730 10,110 17,360 11,840 12,560 17,980 /ul Neutrophil 93.8 80.9 82 76 67.6 83 % Lymphocyte 2.8 8.7 4 9 20 9 % Monocyte 0.2 9.9 3 6 7.8 1.1 % Eosinophil 0 0.1 0 3 3.1 0.2 % Basophil 3.2 0.4 0 2 1.5 0.16 % Platelets 538,000 493,000 572,000 323,000 372,000 375,000 /ul ANC 32,580 8180 8200 8990 8490 14,920 ALC 970 880 690 1060 2510 1620 Case1: Lab investigation Strat IRZE
  21. 21. Disseminated tuberculosis • Affected organs ; pulmonary, lymph node, CNS Plan for treatment 1) Anti-TB drugs -Isoniazid (100) 3 tabs po hs (8.5 mg/kg/day) -Rifampicin (300) 2 tabs po hs (17mg/kg/day) -Pyrazinamide(500) 2.5 tabs po hs (35 mg/kg/day) -Ethambutol → Ethionamide(250) 1.5 tab po bid (21 mg/kg/day) -Vitamin B6 (50) 1 tab po OD 2) Corticosteroid is indicated -Dexamethasone 4 mg IV q 6 hours (16mg/day max adult dose) 3) Side effects Monitoring -Liver function test before initiation of treatment -Observe rash and signs of hepatitis
  22. 22. Disseminated TB in adolescent female • Normal adolescent female host – Estrogen drives pro-inflammatory TH1-mediated immune response while testosterone has been found to inhibit the response • Acquired immune deficiency – HIV infection (50% of TB patient has HIV as underlying disease) – Anti IFN-γ autoantibody • Primary Immune deficiency – Mendelian susceptibility mycobacterium disease – Combined immunodeficiency – Chronic granulomatous disease Investigations -Flow cytometry -IgG, IgA, IgM, IgE -DHR -Anti-IFN-gamma antibodies DDx cause of disseminated TB in adolescent
  23. 23. 25/1/64 14 yr 1 mo 8/2/64 14 yr 8 mo IgG (mg/dl) 1318  (698-1194) 907.3 ↔ (698-1194) IgM (mg/dl) 169  (59-99) 102  (59-99) IgA (mg/dl) 569  (22-274) 361  (22-274) IgE (IU/mL) 1947  (<200) 985  (<200) 25/1/64 14 yr 1 mo 8/2/64 14 yr 8 mo ALC (/ul) 1,396  (2,000-2,700) 1,497  (2,000-2,700) CD3 (/ul) 796  (1,400-2,000) 988  (1,400-2,000) CD4 (/ul) 461  (700-1,100) 569  (700-1,100) CD8 (/ul) 279  (270-930) 419  (270-930) CD19 (/ul) 461 ↔ (300-500) 370 ↔ (300-500) CD56 (%) 126 ↔ (59-1178) 240 ↔ (59-1178) Flow cytometry report Immunoglobulins Case 2: immunologic work up Anti-Gamma interferon 25/1/64 : 1.79 (Negative) DHR 17/2/64 : normal Genetic work up : pending
  24. 24. Case 1 20-year-old boy Disseminated TB (Sputum AFB positive , small bowel and LN caseous granuloma ) No family history Lymphopenia Low number of T cell, B cell High Ig E Normal Ig G, Ig A Low Ig M Anti-gamma interferon : 5.838 (Positive) Case 2 14-year-old girl Disseminated tuberculosis (lung, brain, lymph node) with tuberculoma with meningitis No family history No neutropenia ,Lymphopenia Low number of T cell, B cell High IgG , IgM ,Ig A and Ig E Anti-gamma interferon : 1.79 (Negative) Anti-interferon-γ autoantibodies
  25. 25. Mendelian susceptibility to mycobacterial disease MSMD
  26. 26. J. Bustamante et al. Seminars in Immunology 2014; 26: 454-470. A.K. Abbas et al.cellular and molecular immunology.9th ed.Chapter 21. Mendelian susceptibility to mycobacterial disease: MSMD • Rare inherited condition • MSMD : patients are predisposed to severe disease caused by weakly virulent mycobacteria or other intracellular pathogens including various bacterial, fungal, and viral species. • Selective predisposition to clinical disease cause by weakly virulent mycobacteria • Bacillus Calmette-Guerin: BCG • non-tuberculous environmental mycobacteria : Mycobacterium avium, Mycobacterium kansasii, and Mycobacterium fortuitum. • Mycobacterial disease generally begins in childhood
  27. 27. • Vulnerable to more virulent Mycobacterium tuberculosis • MSMD is strictly speaking a misnomer. • The clinical phenotype extends beyond mycobacterial diseases. • Salmonella: Typhoidal and non-typhoidal • Intramacrophagic bacteria: listeriosis, nocardiosis, klebsiellosis • Fungi: candidiasis, histoplasmosis, paracoccidiomycosis, coccidiomycosis • Parasites: leishmaniasis, toxoplasmosis • Viruses: CMV, HHV8, PRV-3, RSV, VZV J. Bustamante et al. Seminars in Immunology 2014; 26: 454-470. A.K. Abbas et al.cellular and molecular immunology.9th ed.Chapter 21. Mendelian susceptibility to mycobacterial disease: MSMD
  28. 28. Interferon gamma– IL12 signaling pathway Macrophage/phagocyte/Dendritic cell T cell /NK cell 1 Depending on the specific mutation, inheritance of a disorder caused by mutation in one of these genes can be AD,AR or X-linked. Autoantibodies to interferon-γ itself can mimic these genetic lesions, since they can potently neutralize interferon-γ. 2 3 4 5 Holland SM et al. N Engl J Med 2017; 377: 1077-1091
  29. 29. Interferon gamma– IL12 signaling pathway IL-12 signaling - IL-12 - IL-12 receptor : (IL-12RB1 , IL-12RB2) - TYK2 ,JAK2 - STAT4 Interferon-gamma signaling - IFN-γ R1,R2 - JAK - STAT 1 - NEMO - GAF (interferon gamma activation factor) NF-kB/NEMO signaling - NEMO - IKKa , IKKb - NF-kB Holland SM et al. N Engl J Med 2017; 377: 1077-1091
  30. 30. Genetic etiologies of MSMD and Clinical feature
  31. 31. Genetic etiologies of MSMD • The first genetic etiology of MSMD was discovered in 1996. → IFNGR1 deficiency • 13 MSMD-causing genes including • 13 Autosomal mutations: IFNGR1, IFNGR2, STAT1(LOF), IL12B, IL12RB1, ISG15, IRF8, TYK2, RORC, JAK1 (LOF), SPPL2a, IL-12RB2, and IL-23R genes • 2 X-linked mutations: NEMO, CYBB - Mutations in JAK1 and RORC have been described as responsible for syndromic MSMD. • The high level of allelic heterogeneity has already led to the definition of 18 different disorders. • These defects account for only about half the known MSMD cases. J. Bustamante et al. Seminars in Immunology 2014; 26: 454–470 Ying W et al. Journal of Clinical Immunology (2019) 39:600–610
  32. 32. • The 13 gene products are physiologically related, as are involved in IFN-gamma-dependent immunity. • Impaired production of IFN-gamma: IL12B, IL12BR1, ISG15, IRF8, NEMO ,TYK2, RORC, JAK1 (LOF), SPPL2a • Impaired response of IFN-gamma: IFNGR1, IFNGR2, STAT1, IRF8, CYBB • Disseminated mycobacterial infections have also been associated with • GATA2 deficiency: MonoMAC syndrome • Autoantibodies to IFN-gamma: acquired disease • The identification of these genetic diseases has had clinical important. • Rational treatment, preventive care, family screening, transplantation Genetic etiologies of MSMD Ying W et al. Journal of Clinical Immunology (2019) 39:600–610 J. Bustamante et al. Seminars in Immunology 2014; 26: 454–470
  33. 33. Boisson-Dupuis et al. Immunol Rev 2015; 264(1): 103-120 Schematic diagram of the cooperation between phagocytes/dendritic cells and T lymphocytes/ NK cells during mycobacterial infection.
  34. 34. Genetic etiologies of MSMD J. Bustamante et al. Seminars in Immunology 2014; 26: 454–470 Genetic etiologies of MSMD. The functional defects : complete (C) or partial (P). The mutant proteins : may be (E+) , not expressed (E−), not phosphorylated (P−) unable to bind DNA (B−) on IFNs stimulation, lost both these functions (P−B−).
  35. 35. J. Bustamante et al. Seminars in Immunology 2014; 26: 454–470 Distribution of genetic disorders in MSMD patients with known etiologies Most common : IL12RB1 deficiency
  36. 36. Bousfiha A et al .2019 update of the IUIS phenotypical classification .J Clin Immunol (2020) 40:66–81
  37. 37. Clinical features • Patients with mendelian susceptibility to mycobacterial disease often have onset of infections in childhood, and BCG infection is common. • Recessive complete deficiencies tend to present early in life. • Recessive partial and dominant defects tend to present later in childhood or adulthood. • X-linked recessive disorders (NEMO and CYBB mutations) : suspected in the setting of multiple maternally related males with non-tuberculous mycobacterial infection. • GATA2 deficiency and anti-interferon γ autoantibodies : disseminated NTM infection. In adult onset Wu UI, Holland SM. Lancet Infect Dis 2015; 15: 968- 980 J. Bustamante et al. Seminars in Immunology 2014; 26: 454–470
  38. 38. Clinical features Ying W et al. Journal of Clinical Immunology (2019) 39:600–610 Clinical manifestations of MSMD. A. An enlarged left axillary lymph node with redness and tenderness on the skin surface. B. Groin abscess. C. Lung infection on chest CT. D. Bone destruction of the mandible
  39. 39. IFNGR deficiency Wu UI, Holland SM. Lancet Infect Dis 2015; 15: 968- 980 J. Bustamante et al. Seminars in Immunology 2014; 26: 454–470 • Mutation gene: IFNGR1, IFNGR2 • IFNGR1 > IFNGR2 • Infection: BCG, Mycobacterial, Salmonella, listeriosis, viral infections • Lab test: surface IFNGR, IFNGR function, 1st genetic etiology increase serum interferon gamma autosomal recessive complete IFNGR1/R2 deficiency Early-onset, disseminated, life-threatening with BCG or EM infections. -severe form, 50% of these patients die before 10 years of age Treatment : HSCT , anti-microbial autosomal recessive partial IFNGR1/R2 deficiency -less severe -mycobacterial infections caused by BCG or EM (M. avium, M. avium complex, M. abcessus, M. szulgai). anti-microbial, IFN-γ therapy autosomal dominant partial IFNGR1/R2 deficiency - Less severe ,milder disease, good treatment response • BCG or EM ; 80% of patients have mycobacterial osteomyelitis anti-microbial and/or IFN-γ therapy 1st genetic etiology Common form
  40. 40. Wu UI, Holland SM. Lancet Infect Dis 2015; 15: 968- 980 J. Bustamante et al. Seminars in Immunology 2014; 26: 454–470 STAT1 deficiency • Inheritance for MSMD: - AR complete STAT1 deficiency : life-threatening susceptibility to both mycobacteria and viruses - AR partial STAT 1 deficiency : intracellular bacteria (BCG, M. avium, M. szulgai, Salmonella) and virus (EBV, CMV and VZV) ; Partial impaired only IFN-gamma but not IFN-alpha/beta responses - AD partial STAT1 deficiency: hypomorphic , loss of function Infection: BCG, NTM, osteomyelitis, no unusual susceptibility to severe viral infections • Treatment : Anti-microbial and IFN-γ therapy (good prognosis).
  41. 41. Infections in patients with deficiencies of IFN-γR and STAT1 Infections in patients with deficiencies of IFN-γR and STAT1 Infections in 115 patients with IFN-γR1 deficiencies (complete and partial) 21 patients with IFN-γR2 deficiencies (complete and partial) 17 reported patients with partial dominant STAT1 deficiency. Some patients had multiple episodes of infectious diseases. J. Bustamante et al. Seminars in Immunology 2014; 26: 454–470 BCG, NTM
  42. 42. • Mutation gene: • IL12RB1: B chain of IL12, IL23 receptor ; IL12B: p40 subunit of IL12, IL23 • Clinical phenocopies: IL12RB1 vs IL12B • The most common genetic cause MSMD: IL12RB1 (AR complete IL12RB1 deficiency) • Clinical very heterogenous (early death to asymptomatic) • Infection: BCG, Mycobacterial infection, Salmonella (43%) • Lab test: • Reduce IFN gamma production, corrected by the additional of recombinant IL12 • IL12RB1: not express receptor on the surface, diminish pSTAT4 after IL12 stimulation • IL12B: undetectable IL12 p40 subunit • Treatment : prolonged & aggressive anti-microbial and subcutaneous IFN-γ therapy IL12RB1 - IL12B deficiency Wu UI, Holland SM. Lancet Infect Dis 2015; 15: 968- 980 J. Bustamante et al. Seminars in Immunology 2014; 26: 454–470
  43. 43. IL12RB1 - IL12B deficiency Wu UI, Holland SM. Lancet Infect Dis 2015; 15: 968- 980 J. Bustamante et al. Seminars in Immunology 2014; 26: 454–470 autosomal recessive complete IL-12Rβ1 deficiency Mycobacterial infections (TB ,NTM) , severe TB disease recurrent BCG disease rare invasive salmonellosis (40%) anti-microbial, IFN-γ therapy autosomal recessive complete IL-12p40 deficiency BCG disease , TB , NTM - Multiple mycobacterial infection –rare - Salmonella and Klebsiella infection (25%) ,candida anti-microbial, IFN-γ therapy
  44. 44. Infections in patients with IL12RB1 and IL12p40 deficiency J. Bustamante et al. Seminars in Immunology 2014; 26: 454–470 Infections in patients with IL-12Rβ1 and IL-12p40 deficiencies Infections 180 patients with complete IL-12Rβ1 deficiency 50 reported patients with complete IL-12p40 deficiency.
  45. 45. Wu UI, Holland SM. Lancet Infect Dis 2015; 15: 968-980 Clinical manifestation
  46. 46. IRF-8 deficiency Wu UI, Holland SM. Lancet Infect Dis 2015; 15: 968- 980 J. Bustamante et al. Seminars in Immunology 2014; 26: 454–470 • IRF8: Interferon regulatory factor 8 • Macrophages and dendritic cells need IRF8 for their ontogeny, maturation • Transcription factor for IL-12 production in response to interferon-gamma • AD IRF8 deficiency: • Absence of monocyte and dendritic cells (CD11+, CD1c+ circulating dendritic cell) • Impaired IL12 and IFN-gamma production • Lab test: PBMC+BCG → impaired IL12, IFN-gamma production, restored by the addition of IL12. autosomal recessive complete IRF8 deficiency Multiple disseminated BCG disease , oral candidiasis, severe respiratory infections HSCT (curative treatment) anti-microbial, antifungal autosomal dominant partial IRF8 deficiency Mild recurrent episodes of disseminated BCG disease without other infectious diseases anti-microbial
  47. 47. • AR complete ISG15 deficiency (ISG15: Interferon-stimulated gene 15) • Intracellular ubiquitin-like protein ,antiviral defense through ISGylation of various proteins • Extracellular cytokine secrete by granulocytes, monocytes and lymphocytes to induce interferon-gamma production by T cells and NK cells • Infection: BCG, mycobacterial infection epileptic seizure , intracranial calcification • Lab test: PBMC+BCG+IL-12 → impaired IFN-r production, restored by the addition of recombinant ISG15. • Treatment : anti-microbial and subcutaneous IFN-γ therapy ISG15 deficiency Wu UI, Holland SM. Lancet Infect Dis 2015; 15: 968- 980 J. Bustamante et al. Seminars in Immunology 2014; 26: 454–470
  48. 48. • Mutation gene: X-linked IKK-γ gene (IKBKG) • Inheritance for MSMD: X-linked recessive • somatic feature : anhidrotic ectodermal dysplasia (impair regulate development of skin, hair and teeth): hypodontia, sparse hair, abnormal hair whorls • Infection: Non-tuberculous mycobacterial infection, M. avium ,encapsulated bacteria ,herpes viruses, Pneumocystis jirovecii. Most common : invasive pneumococcal disease, Invasive Hib infection • Lab test: increase IgM, low IgA or IgG • Treatment : anti-microbial and subcutaneous IFN-γ therapy NEMO deficiency Wu UI, Holland SM. Lancet Infect Dis 2015; 15: 968- 980 J. Bustamante et al. Seminars in Immunology 2014; 26: 454–470
  49. 49. • Mutation gene: CYBB (gp91phox), Q231P, T178P • Inheritance for MSMD: X-linked recessive • Selective functional impairment of superoxide production limited to monocyte-derived macrophages and B cells • Normal production of IL12, Interferon-gamma • Infection: Staphylococcus, Aspergillus limited BCG susceptibility phenotype • Lab test: DHR to measure intracellular respiratory burst in macrophages and B cells CYBB deficiency Wu UI, Holland SM. Lancet Infect Dis 2015; 15: 968- 980 J. Bustamante et al. Seminars in Immunology 2014; 26: 454–470
  50. 50. Wu UI, Holland SM. Lancet Infect Dis 2015; 15: 968-980 Clinical manifestation X-linked recessive
  51. 51. • GATA2: transcription factor for early hemopoietic, lymphatic and vascular development • Monocytopenia with M. avium complex syndrome: MonoMAC • Decrease or absent circulating monocytes, dendritic cells, NK cells, B cells → impaired cytokine production • Onset: childhood to adulthood (3-80 years) • Infection: HPV(70%), disseminated non-tuberculous mycobacterial infection, disseminated histoplasmosis, cryptococcal meningitis, invasive aspergillosis, severe clostridium difficile infection. GATA2 deficiency Wu UI, Holland SM. Lancet Infect Dis 2015; 15: 968- 980
  52. 52. Clinical manifestation Wu UI, Holland SM. Lancet Infect Dis 2015; 15: 968-980 Late onset
  53. 53. Clinical manifestation Wu UI, Holland SM. Lancet Infect Dis 2015; 15: 968-980
  54. 54. • Functional studies of IL12/Interferon-gamma axis • Genotyping is the gold standard for the diagnosis of genetic defects. • Molecular assays are not available in all clinical settings. • Diagnostic clues: • Age at onset • Sex • Pattern of inheritance • Pathological features • Concomitant infections • complications Wu UI, Holland SM. Lancet Infect Dis 2015; 15: 968- 980 Diagnosis
  55. 55. Boisson-Dupuis et al. Immunol Rev 2015; 264(1): 103-120 Inherited and acquired immunodeficiencies underlying tuberculosis in childhood
  56. 56. Boisson-Dupuis et al. Immunol Rev 2015; 264(1): 103-120 Intramacrophage pathogen : salmonella Acquired and inherited conditions with mycobacterial susceptibility to BCG, NTM, or Mycobacterium tuberculosis (TB)
  57. 57. Differential diagnosis Boisson-Dupuis et al. Immunol Rev 2015; 264(1): 103-120 Mycobacterial susceptibility infection PID Inherited ID Acquired ID MSMD • HIV infection, hairy cell leukemia, individuals taking specific immunosuppressive therapies. • medication : TNF α blockers predispose individuals to reactivation of tuberculosis, and NTM infections. Anti-cytokine antibodies conferring a predisposition to mycobacterial diseases : adult onset 1.Anti IFN-γ autoantibodies : acquired phenocopy of inborn errors of IFN-γ. Mostly in NTM infection , Salmonella, Cryptococcus neoformans, Histoplasma capsulatum, Penicillium marneffei, and varicella zoster virus. Associated HLA-DRB1* 16:02 , HLA-DQB1*05:02 2.Anti TNFα- autoantibodies : Therapeutic TNFα-blocking antibodies : favor mycobacterial disease in JIA and pediatric inflammatory bowel disease
  58. 58. Rosenthal et al. Cureus 11(6). 2019 : e4967 case which disseminated TB was found in healthy adolescent, female patient, and to explore the effects of pubertal hormonal changes on the immune system. hormonal changes of estrogen and testosterone associated with puberty may influence the pathogenes is of active TB. Pathogenesis of disseminated TB : unknown A 16-year-old girl with previous healthy CC : dry cough with weight loss 9 kg the past 3 months PI : She also endorsed a three-month history of amenorrhea. patient denied hemoptysis, fevers, night sweats, sick contacts. PE: febrile (102.8F) and RR 56 pbm with normal SpO2 on RA BW 24 kg Ht 130 cm. lung : decreased breath sounds bilaterally and rhonchi BL Chest X-ray: extensive bilateral nodular opacities with a cavitary lesion in the upper right lung. Chest CT : extensive nodules and consolidations throughout bilateral lungs with large bilateral upper lobe cavitations. Labs : Hb 8.2 MCV 76 WBC 21,800/mcL (Neu 81%), CRP : 23.8 mg/dl. Sputum AFB : positive. Impression : Pulmonary tuberculosis
  59. 59. Rosenthal et al. Cureus 11(6). 2019 : e4967 Treatment : Start : high dose isoniazid (INH), ethambutol, rifampin, levofloxacin, steroids, Due to amenorrhea and the patient’s failure to thrive, Abdominal and pelvic CT : calcified granulomas in the spleen and liver, a cystic mass in the right adnexa, and thickening of t he ileum; findings indicative of disseminated TB. Progression On hospital D4 : Patient exhibited sluggish pupillary responses. MRI (brain) : mild ventriculomegaly, thickening of the meninges, and focal areas of demyelination in the left parietal and frontal lobes, consistent with central nervous system (CNS) TB. Sputum cultures : high resistance to INH (>2) and low resistance to streptomycin (>32). Mx : INH was continued due to its ability to penetrate the blood-brain barrier to target the CNS involvement. With continued treatment, her AFB smears&cultures were found to be negative in blood, urine, CSF and BM.
  60. 60. Proposed : Estrogen has been shown in vitro to drive the pro-inflammatory TH1-mediated immune responses while testosterone has been found to inhibit these responses. Androgens, alterations in the cortisol to DHEA ratio are associated with disturbances in concentrations of interferon-gamma, a key cytokine involved in TB containment. Chronic malnutrition : Decrease dendritic cell activity in mice , Decreased T helper type 1 (Th1) activation, there is insufficient IL-12 and IFN-gamma to stimulate macrophages. Failure of the host immune system to adequately contain the TB. Rosenthal et al. Cureus 11(6). 2019 : e4967
  61. 61. • Adult onset, Female (outside Asia) • Infection: Acquired susceptibility to NTM infections and other opportunistic infections (Salmonella , Penicillium marneffei, Histoplasma, Cryptococcus, Burkholderia pseudomallei cytomegalovirus, and varicella-zoster reactivation) • Lab test: high titer, neutralizing anti-interferon antibodies, normal CD4+T cell, monocyte numbers, IFNGR and IL12R • HLA-DRB1*16:02 and DQB1*05:02 – were associated with disease • When to test Anti- IFN-r autoantibody : NTM infection with reactive dermatosis (sweet syndrome , AGEP, erythema nodosum) Anti-interferon gamma autoantibodies Wu UI, Holland SM. Lancet Infect Dis 2015; 15: 968- 980 Kent Mun Loh et al.CORRESPONDENCE .cid 2020:71 (1 October)
  62. 62. Phoompoung P. et al. PLos one 2017; 24: 12(4):e0176342 Case control study Patients with NTM diseases who were diagnosed and treated at Siriraj Hospital, Bangkok, Thailand. Anti-IFN autoantibody was detected by enzyme-linked immunosorbent assay (ELISA) method. Cases : 70 patients with NTM diseases and detectable anti IFN- γ autoantibody. Controls : 70 patient randomly selected from those with undetectable anti IFN- γ autoantibody. Objective : Univariate & multivariate analyses were performed to identify independent risk factors for this syndrome.
  63. 63. Phoompoung P. et al. PLos one 2017; 24: 12(4):e0176342 Result Mycobacterial abscessus was the most common NTM pathogen found in both groups (72.9% in cases VS 41.4% in control). Disseminated NTM disease was significantly more common in cases (92.9%) than controls (14.3%, p<0.001). Binary logistic regression analysis showed that Previous OIs (adjusted OR14.87), birthplace outside Central region (adjusted OR 19.19), Lack of comorbidities lead to immunosuppression (HIV infection or DM)(adjusted OR 23.68), and presence of HLA DRB1*15/16 (adjusted OR 153.28) were independent factors associated syndrome. Conclusion Patients with NTM disease associated with anti IFN- γ autoantibody are previously healthy and HIV negative. Most of these patients presented with disseminated NTM disease with generalized lymphadenitis and reactive skin lesions. Factors associated with detectable anti IFN- γ autoantibody : HLA-DRB1 and DQB1 alleles, and history of previous OIs in patients without comorbidity that leads to immunosuppression.
  64. 64. Hong GH et al. anti-interferon-γ autoantibody-associated immunodeficiency syndrome in Thailand and the US. Clin Infect Dis 2020:71. Isolated organisms at presentation in Thailand and the United States M.abscessus M.avium complex 91% of US patients were of Southeast Asian; female predominance (91%) in US than Thai (64%) pts. Mycobacterium abscessus (34%) : most common NTM infection in Thailand Mycobacterium avium complex (83%) : most common NTM infection in US
  65. 65. Hong GH et al. anti-interferon-γ autoantibody-associated immunodeficiency syndrome in Thailand and the US. Clin Infect Dis 2020:71. Sites of infections at presentation in Thailand and the United States Site of infections in anti-IFN-r autoantibodies - Thailand : Skin infection - US : bone , lung CNS system Most common cause of death in Thailand - infection Treatment - Cyclophosphamide - Rituximab therapy Rituximab and cyclophosphamide significantly lowered autoantibody titers. effectively reduce autoantibody titers and improve IFN-r signaling.
  66. 66. Koizumi Y et al. anti-interferon-γ autoantibody-disseminated NTM infection. Clin Infect Dis 2020:1-3. • Specific treatment for IFN-γ autoantibodies–associated NTM infection is not codified and required prolonged, multiple-drug regimens. • The median treatment duration: 31 (IQR 22.8–60.0) months. • The use of azithromycin suppressive therapy, assuming the risk/ benefit balance including the possibility of NTM or macrolide resistant strain selection. • should be considered for persisting high levels of neutralizing antibodies • Use of immunomodulation strategies is still debated
  67. 67. Koizumi Y et al. anti-interferon-γ autoantibody-disseminated NTM infection. Clin Infect Dis 2020:1-3. • IFN-γ administration was invalidated by the autoimmune-driven inhibitory. • Rituximab has been recently associated with clinical response and decrease in IFN-γ autoantibody levels as well as neutralizing ability. • Treatment strategy 1.Recovery of cellular immunity 2.Elimination of anti-cytokine autoantibodies 3.Suppression of wasting inflammatory reaction Corticosteroid Decrease titers of neutralizing autoantibodies Cyclophosphamide adjunctive therapy regimen for refractory to conventional antimycobacterial therapies Rituximab Refractory disseminated NTM infection Daratumumab Disseminated NTM infection refractory to other agents
  68. 68. Differential diagnosis Boisson-Dupuis et al. Immunol Rev 2015; 264(1): 103-120 Mycobacterial susceptibility infection PID Inherited ID Acquired ID MSMD • Healthy individuals ( Especially for the airways : Isolated pulmonary NTM infection) : adult onset - Pts with structural lung abnormalities : COPD, bronchiectasis, emphysema, previous TB, pulmonary alveolar proteinosis, alpha-1-antitrypsin deficiency - Cystic fibrosis - Primary ciliary dyskinesia - Lady Windermere syndrome • Immunocompetent : children onset - Present as isolated cervical lymphadenitis or isolated pulmonary disease - To date, neither CFTR mutations nor other primary immune defects have been often noted in these patients.
  69. 69. Differential diagnosis Boisson-Dupuis et al. Immunol Rev 2015; 264(1): 103-120 Mycobacterial susceptibility infection PID Inherited ID Acquired ID MSMD PID with T-cell deficiency Severe combined immunodeficiency diseases (SCID) various infectious diseases (viral, bacterial, fungal, or parasitic) in the first few months of life. Disseminated BCG infection Combined immunodeficiency (CID), NTM infection ZAP-70 deficiency BCG-itis , NTM infection Autosomal dominant GATA2 deficiency immunodeficiency with marked susceptibility to HPVs mycobacteria (non-tuberculous and tuberculous) defect dendritic cell, monocyte, B cell, and NK cell Chronic granulomatous disease (CGD) pyogenic bacterial & fungal infections, (S.aureus , Aspergillus , mycobacterial infections). Anhidrotic ectodermal dysplasia with immunodeficiency (EDA-ID) ectodermal dysplasia , invasive pyogenic bacteria, NTM, TB, parasites, viruses, and fungi .
  70. 70. Differential diagnosis Boisson-Dupuis et al. Immunol Rev 2015; 264(1): 103-120 Mycobacterial susceptibility infection PID Inherited ID Acquired ID MSMD X-linked recessive CD40L deficiency (X-HIGM) recurrent bacterial infections, OI with PCP & Cryptosporidium species, localized and disseminated BCG ,NTM ,TB infection Autosomal recessive STAT1 deficiency Milder to severe, life threatening of mycobacterial and viral infection Autosomal recessive IRF8 deficiency Life-threatening disorder combine fungal and mycobacterial infections , myeloproliferation and an absence of monocytes and dendritic cells. BCG-osis, oral candidiasis. Autosomal recessive TYK2 deficiency disseminated mycobacterial and viral diseases. BCG-osis, severe abdominal TB, and miliary TB
  71. 71. Differential diagnosis Boisson-Dupuis et al. Immunol Rev 2015; 264(1): 103-120 Mycobacterial susceptibility infection PID Inherited ID Acquired ID MSMD IFN-γR deficiencies Very severe ,BCG and NTM or TB infection Autosomal dominant STAT1 deficiency BCGosis ,NTM, TB infection X-linked recessive gp91phox deficiency mycobacterial diseases due to impairment of respiratory burst in macrophage. Autosomal dominant IRF8 deficiency recurrent episodes of mycobacterial disease caused by BCG defect dendritic cell, monocyte, granulocyte X-linked recessive NEMO deficiency mycobacterial diseases (BCG and NTM), Invasive Hemophilus influenza typeB infection Autosomal recessive IL-12p40 and IL-12Rβ1 deficiencies Various clinical , BCG ,NTM,TB infection ,salmonellosis (30-40%) , candidiasis Autosomal recessive ISG15 deficiency BCG disease , intracranial calcification
  72. 72. Clinical diseases allelic with MSMD at the NEMO, CYBB, STAT1 and IRF8 loci J. Bustamante et al. Seminars in Immunology 2014; 26: 454–470
  73. 73. Investigation
  74. 74. Investigation Ying W et al. Journal of Clinical Immunology (2019) 39:600–610 • Exclude HIV infection • Routine Evaluation of Immunological Function : lymphocyte subsets, Immunoglobulins G, A, M, and NADPH oxidase activity in neutrophils (DHR) • Functional Evaluation of the IL-12/IFN-γ Pathway - Flow cytometry detection of CD119 and CD212 (Production of IFN-γ in whole blood after stimulation with medium alone, LPS, or LPS plus IL-12) The first row shows histograms of IL12Rβ1 expression in a healthy individual (left) and a patient (right). The second row shows expression of IFN-γR1 protein in a healthy individual (left), patient with decreased expression (middle), patient with no expression (right) CD 212 : IL12Rβ1 expression CD 119 : IFN-γR1 protein Flow cytometric detection of IL12RB1 and IFNGR1 : rapid diagnosis
  75. 75. Investigation Ying W et al. Journal of Clinical Immunology (2019) 39:600–610 • Gene Sequencing and Analysis : Next-generation sequencing (NGS) • Phosphorylated STAT1 Protein Detection by Western Blotting Reduced IFN-γ induced phosphorylation of STAT1. PBMCs were not stimulated (PBS) or were stimulated with IFN-γ IL12RB1 gene IFN-γR1 gene IFN-γR2 gene STAT1 genes
  76. 76. Wu UI, Holland SM. Lancet Infect Dis 2015; 15: 968- 980 Stepwise approach to diagnosis of patients with disseminated non-tuberculous mycobacterial (DNTM) infection X-linked Adult onset
  77. 77. Treatment & Prognosis
  78. 78. Treatment Early onset late onset GATA 2 deficiency : HSCT, Anti-microbial , IFN-gamma -Anti-IFN-gamma autoantibodies : Anti-microbial if severe/refractory : immunomodulation agent - Corticosteroid - Cyclophosphamide - Rituximab HSCT : IFN-gamma R1 , IFN-gamma R2 (complete deficiency) Anti-microbial : IFN-gamma R1 , IFN-gamma R2 (complete deficiency) IFN-gamma (rhIFN-γ therapy ) : IFN-gamma R1 (partial deficiency) IL-12 and IL-12R deficiency STAT1 LOF rhIFN-γ therapy is effective and improves prognosis, particularly in patients with IL12RB1 deficiency Wu UI, Holland SM. Lancet Infect Dis 2015; 15: 968-980
  79. 79. Prognosis a. Kaplan-Meier estimate of survival for patients with MSMD treated with (solid line) or without (dashed line) IFN-γ (log-rank χ20.998; P = 0.31). b. Kaplan-Meier estimate of survival for patients with IL12RB1 treated with (solid line) or without (dashed line) IFN-γ (log rank χ2 5.247; P = 0.022) Ying W et al. Journal of Clinical Immunology (2019) 39:600–610 The median survival time was 26 months (range, 5 to 173 months). MSMD IL12RB1 deficiency

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