Diabetic Immunopathy and TB

Transcription

1 Diabetic Immunopathy and TB 22 nd Conference of the North American Union Hardy Kornfeld Department of Medicine Division of Pulmonary, Allergy and Critical Care UMass Medical School Worcester, MA, USA Sadly, no conflicts of interest

2 Diabetes 101 Type 1 DM: insulin deficiency, hyperglycemia Type 2 DM: insulin resistance, hyperglycemia & dyslipidemia (Adipose tissue inflammation Insulin resistance Pre-DM T2DM) Atherosclerosis Retinopathy Nephropathy Neuropathy Immunopathy Glucotoxicity polyol, hexosamine, PKC & AGE pathways Oxidative stress, protein glycation, PKC & RAGE signals, epigenetics

3 Concurrent epidemics of TB and DM TB DM: 415M now 642M by % of people with DM live in LMIC DM incidence rising fastest in high TB burden countries DM

4 Geographic heterogeneity: TBDM hotspots South India, Pacific Islands, Mexico DM 54.0% NGT 24.9% IGT 21.1% Vijay Viswanathan MVDRC, Chennai N=209 Kornfeld, Chest 2016

5 STZ Control Late delivery of Mtb to lymph Delayed innate response Mechanisms to Mtb of susceptibility node delays T cell priming More cytokines & immune pathology Late control of Mtb replication, higher lung bacterial load?

6 Mouse data so far Delayed immune response to inhaled Mtb Excessive inflammation once underway Reduced MARCO & CD14 expression in AMΦ Pre-activated naïve T cells in DM Linked to DM complication pathway (RAGE) Defects persist in non-diabetic environment Martens, AJRCMB 2006 Martens, Infect Immun 2006 Martens, J Leukoc Biol 2008 Vallerskog, J Immunol 2010 Cheekatla, PLoS Pathog 2016 Martinez, J Immunol 2014 Martinez, J Infect Dis 2016 Martinez, submitted

7 Bench to bedside: predictions for human TBDM Higher risk for TBI (more productive hits) Risk for pulmonary > extrapulmonary TB More primary TB More bugs, cytokines & immune pathology Correlation with DM severity Outcomes determined by early events?

8 Predictions fulfilled: human TBDM Elevated risk for PTB >> EPTB More lower lung zone & cavitary TB More positive smear & culture Delayed sputum conversion Higher mortality More treatment failure & recurrence Risks correlate with HbA1c

9 Glycemic heterogeneity in TBDM Enrollment Were NDMs pre-dm before TB? TB severity in NDM (ENDOTS)? Is Pre-DM a TB risk factor? Does TB promote dysglycemia? Month-3 DOTS NDM 6.8% 5.8%, P=0.002 KDM 10.4% 9.8%, P=0.051 NGT 5.7% 5.3%, P=0.020 Kornfeld, CHEST 2016

10 More inflammation, less resolution Persistent infection vs sterile inflammation? Explanation for risk of recurrent TB? Risk for PIAT? IFNg, TNFa, IL-1b, IL-10, IL-17A, IL-17F in QFT supe Kumar, unpublished Prada Medina, Fukutani, Kumar Sci Rep 2017

11 Multiple comorbid risk factors (mean ± SD or percent) Additive or synergistic interactions? (median [IQR]) Composite risk, a low-cost biomarker? Kornfeld, Chest 2016

12 Top ten Ingenuity pathways TB unique TB shared TB drives DM complication pathways ssgsea of genes ranked by MDP TB-DM syndemic Factor in higher TB mortality? Prada Medina, Fukutani, Kumar, Sci Rep 2017

13 Metformin Degner NR, Wang J-Y, Golub JE, Karakousis PC. Metformin use reverses the increased mortality associated with diabetes mellitus during tuberculosis treatment. Clin Infect Dis 2018;66(2): Retrospective cohort study, NTUH N=2416 adult PTB, 28.9% DM Increased mortality in DM (aor=1.91) Decreased mortality with MET (HR=0.53) No association with glycemic control

14 Metformin Pan S-W, Yen Y-F, Kuo YR, Chuang P-H, Su V Y-F, Chan Y-J, Su W-J. The risk of TB in patients with type 2 diabetes initiating metformin vs sulfonylurea treatment. CHEST (in press; DOI: Retrospective cohort study; Taiwan NHIRD N=40,179 Protection with unrelated T2DM, to of glycemic whom 263 control acquired TB Candidate over mean HDT follow-up agent 6.1 years Fewer TB progressors with MET than sulfonylurea (ahr=0.477) Dose-dependent association Not association with adsci

15 Caveats Most published clinical data retrospective Mice and cavies aren t people Geographic differences in host & Mtb genetics, host environment & behaviors

16 Global sweetening Rising prevalence of DM in high TB burden countries Challenges to DM prevention & treatment in LMIC Fertile population for drug-resistant TB

17 FAQs 1. Tight glycemic control during TB treatment? Unlikely to help, might hurt 2. Extend duration of ATT in DM? Limited Trials evidence needed; base target for clinical highest and risk public people? health policy 3. Treat TBI in DM? Trials needed; benefit hinges on reinfection rate 4. Metformin for HDT? Yes, in Taiwan; trials needed, including non-dm

18 Known knowns Take home Higher TB disease risk with DM More adverse TB outcomes with DM TB risk correlates with DM severity Known unknowns Is diabetic immunopathy reversible? Does inflammation drive TB persistence? PIAT in TBDM? Does TB drive DM progression & complications? Is pre-dm an independent TB risk factor?

19 Thanks Kornfeld lab Nuria Martinez Kim West UMass Medical School Wenjun Li Chris Sassetti Sam Behar Prof. MV Diabetes Research Centre Vijay Viswanathan Shruthi BS Carl Lewis Satyavani Kumpatla EDOTS field team Support NIH, HL NIH, USB1-311-XX-13 RePORT India Consortium NIRT/ICER, Chennai Subash Babu Pavan Kumar NIRT, Chennai Siva Kumar Shanmugam Chennai RNTCP Lavanya J Senthil Kumar Singapore Immunology Network Amit Singhal Fundação Oswaldo Cruz, Salvador Bruno Andrade University of São Paulo Helder Nakaya

20 That s why they call it re-search - DM Center