Tuberculosis Now! Jon S Friedland MA, FRCPE, FMedSci. Infectious Diseases & Immunity

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2 Tuberculosis Now! Jon S Friedland MA, FRCPE, FMedSci Infectious Diseases & Immunity

3 What is TB Now? Epidemiology including international migration Biomarkers New treatments

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5 TB notification rate per 1 population by country, EU/EEA, 213 (ECDC data) Not included or not In 213, TB cases were reported in the EU/EEA.The notification rate was 12.7 per 1 population (range ). < 5 per 1 5 to 9 per 1 1 to 19 per 1 2 to 49 per 1 5 per 1

6 Extrapulmonary TB cases Proportion total 22.3% (range %). < 1% 1 to 19.9% 2 to 29.9% 3 to 39.9% 4% Not included or not reporting

7 Tuberculosis in Scotland 35 cases of TB in 214: 4 th consecutive yearly drop 6.5 cases / 1, population 49.4% born outside UK Case fatality ratio 9.4% 82.8% successfully treated

8 Primary migration routes into Europe

9 ( cases) as unknown 29 (Figure 4.2). Figure 4.2 Percentage of TB cases reported in the EU/EEA Member States by migration status, 21 % Active cases in the EU/EEA by migrant status Belgium Hungary Poland Bulgaria Romania Slovakia Lithuania Latvia Portugal Czech Republic Estonia Slovenia TOTAL Spain Finland Ireland Germany Austria Greece France Italy Luxemburg Denmark United Kingdom Iceland Netherlands Malta Cyprus Norway Sweden % 1% 2% 3% 4% 5% 6% 7% 8% 9% 1% Migration to low-incidence countries in Europe has changed epidemiology Great disparities between countries/regions Overall 25.8% of TB is in foreign-born in Europe Sweden (89.4% of TB cases in migrants); UK (7.1%) Source: ECDC/WHO, 214

10 Number of cases Presentation of TB after migration % migrants with active TB present within 5 years Rates of TB remain high for many years after entry TB burden is high in migrants: > Active TB on arrival (country of origin/?transit?) > Previously acquired latent TB infection that reactivates after arrival > Local transmission in host communities Years since entry to diagnosis

11 Outcome/ latent TB Start screening but drop out before a diagnosis is made Of migrants diagnosed + ve, how many start Rx? Systematic review of effectiveness of migrant screening in the EU Mean N per observation (SD) (514.87) Median % (range) ( ) 2.5 (15.89) ( ) 46 studies for multiple infections Uptake high (8%) but migrants drop out at every stage Latent TB has worst outcomes Meta-analyses post-arrival screening (US/Canada/Australia): Just 31% complete programme Only 26% migrants who could have benefited from LTBI Rx actually did

12 In 213, the percentage of new pulmonary TB cases with multidrugresistance in the EU/EEA was 2.6% (range 17.3%). Figure 11: Percentage of new pulmonary TB cases with MDR TB by country, EU/EEA, 213 < 1% 1 to 1.9% 2 to 4.9% 5% Not reporting

13 24-month treatment success rate in multidrug-resistant TB cases notified in 211, by country, EU/EEA, 213 [The mean was 37.8% (range 75.%).] Norway Belgium Sweden Austria Netherlands Bulgaria Latvia Germany Portugal Estonia United Kingdom Hungary Lithuania Poland Slovakia Ireland Czech Republic Romania Denmark EU/EEA Treatment success (%) * Malta and Slovenia reported zero MDR TB cases in 211, 9 Member States did not report treatment outcome data for MDR TB cases 13

14 Biomarkers for TB A measured characteristic(s) which indicate normal or pathologic biological responses or a response to a treatment or other intervention Not necessarily related by structure or function May not be of primary functional importance

15 What are biomarkers required for in TB? Diagnosis including in children Prognosis Relapse Drug resistance rising tide MDR / XDR Treatment Responses new drug trials Immunotherapeutics IRIS in HIV / TB Vaccine responses

16 What are Biomarkers? Clinical including symptoms, tuberculin test, time to culture negativity Single immune biomarkers CRP, Adenosine deaminase, TNFa, IP-1 and many others Organism antigens or metabolites in urine or sputum Complex biomarkers omics approaches

17 Training set Principles of -omics Testing set Training Testing Trained classifier Support vector machines, Neural Networks Decision tree classifiers

18 Some of the issues around omic approaches Large number of variables in relation to numbers of samples Sample collection may be key Influenced by tissue specificity & leukocyte migration Data crunching & Overfitting; key genes expressed transiently Requires verification in multiple settings Diabetes, older ages, pregnancy co-infection with helminths, HIV

19 Gene and protein signatures in TB Interferon-inducible neutrophil-driven blood signature using UK and South African testing sets; 393 transcripts. (Nature 21;466(739):973-7) Gene extraction can be turned into a kit form Diagnostic performance of a 7-marker serum protein biosignature for the diagnosis of active TB disease (Thorax 216;71: ) Diagnostic Potential of Salivary Host Biomarkers for Diagnosis of Tuberculosis Disease and Monitoring of Treatment Response. (PLoS One 216 Aug 3;11(8):e16546) Maybe breath tests urine less likely.

20 Old and New Drugs for TB For 4 years no new drugs Meropenem and clavulonic acid in MDR/XDR (Eur Respir. J. 216 Apr;47(4): ) - Better than imipenem (Eur Respir J. 216 Jun;47(6): ) Quinolones - principally moxifloxacin Bedaquiline & delamanid Immunotherapy

21 Moxifloxacin In use Renal and MDR/XDR patients But for general use disappointing:

22 Bedaquiline & Delamanid Bedaquiline inhibits mycobacterial ATP synthase i. Approved by FDA on 2 phase 2b studies on basis of ii. iii. early sputum culture conversion Does not penetrate CNS Was associated with initial increase in mortality Delamanid i. is a dihydro-nitroimidazooxazole derivative which inhibits ii. iii. synthesis of mycobacterial cell wall components Pro-drug Resistance is emerging

23 Immunotherapy: Pathology in TB driven by innate immunity Enzymes are the only effectors which destroy tissues Matrix metalloproteinases destroy all components of matrix including collagen MMP-1/8 increased in patients, is active and turns murine TB fibrosis to human-like cavities MMP-1 in TB Doxycycline is licenced in US for periodontal work as MMP inhibitor; MMP inhibitors used in Rx cancer. Prostaglandin/prostacyclin path also a potential target. - is PAS an immunomodulator?

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26 Treatment success rate of TB cases notified in 212, by country (ECDC) This has remained stable over the past five years. Slovakia Bulgaria Netherlands Iceland Slovenia Sweden Romania United Kingdom Norway Latvia Portugal Belgium Czech Republic Germany Spain Hungary Lithuania Austria Denmark Poland Ireland Estonia Finland Cyprus Malta Croatia EU/EEA Treatment success (%)

27 Do we already use immuno-modulation? PAS Introduced as treatment for Tb in 1947 Mechanism of action uncertain Increasingly important with the emergence of MDR-Tb PAS No effect on TB killing PAS decreases PGE 2 & MMP-1 secretion MMPs drive tissue destruction in TB