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1 Tuberculosis prevention in immunodepressed patients M. Carmen Fariñas Álvarez Infectious Diseases.H.U.Marqués de Valdecilla University of Cantabria, Spain

2 DISCLOSURES I have no potential conflicts with this presentation.

3 At the end of this presentation you WILL BE ABLE: TO remember the epidemiology, diagnosis and treatment of immunodepressed patients with Tuberculosis (TB), particularly in solid organ transplants recipients. TO learn the differences between TB infection and disease. TO understand how to prevent TB in immunodepressed patients. Learning objectives

4 Index 1. Introduction 2. Immunodepressed patients at risk of TB 3. How to Prevent TB in Immunosuppressed patients? A. Rule out active TB B. Diagnosis of TB infection/latent TB infection (LTBI) C. Identify people at risk D. Treatment of LTBI E. Vaccines

5 (TB) Transmitted from person to person via droplets from the throat and lungs of people with the active respiratory disease!!!. Infectious bacterial disease caused by Mycobacterium tuberculosis that most commonly affects the lungs.

6 Mycobacterium tuberculosis First discovered in 1882 by Robert Koch -Zhiel-Neelsen stain or acid-fast stain

7 Estimated TB incidence rates 2014

8 WHO we find ourselves at a crossroad in the fight against tuberculosis. Data reported by over 200 countries that account for more than 99% of the world s TB cases TB still remains one of the major world health challenges.

9 2. Who are we thinking about when we speak of immunosuppressed patients at risk for TB? General aspects of TB

10 HIV patients Patients with immunosuppressive therapy : biological therapy.. Patients with end-stage kidney disease Solid Organ Transplants recipients Stem Cell Transplants recipients Other types of patients: Diabetes, Tobacco??.

11 HIV Patients Condition Immunosuppressive therapy (biological therapy) End-stage kidney disease Solid organ transplant Stem cell Transplant Risk of Tuberculosis in immunosuppressed patients TB risk times greater than among those without HIV 25 times more than immunocompetent 6-25 times more than immunocompetent times more than immunocompetent 2 times more than immunocompetent

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13 Patients treated with anti-tnfα agents such infliximab, etanercept, adalimumab, certolizumab pegol and golimumab, have 1.6 to 25.1 times higher risk of tuberculosis. Within the anti-tnf agents the lowest risk of tuberculosis is associated with etanercept. Infliximab has 3 times higher risk of developing tuberculosis than etanercept.

14 Dialysis patients had a 3.62-fold increase in TB rate 12 eligible studies were identified with end-stage renal disease patients and 560 TB cases.

15 Tuberculosis in SOT recipients 1. Lopez de Castilla and Schluger, Transplant Infect Dis 2010; 12: Canet et al. Nephrol Dial Transplant Garcia-Goez et al. Transplantation Proc 2009; 41: Torre-Cisneros et al. Clin Infect Dis 2009; 48:

16 CID 2009:48 (15 June) Incidence of TB in SOT (RESITRA Cohort)

17 Timing of tuberculosis following SOT López de Castilla and Schluger, Transplant Infect Dis 2010; 12:

18 20 confirmed cases were found among 8013 patients (8 in 5147 autologous and 12 in 2866 allogeneic SCT). Compared with the general population, TB was more frequent after allogeneic (RR 2.95) but not after autologous SCT. Transplant type Incidence (95% CI) Autologous 71 (22-120) Allogeneic 136 (59-212) All 101 (57-145) RR (95% CI) 1.72 ( ) 2.95 ( ) 2.21 ( )

19 TB after SCT is a late infection (median 324 days post transplant), predominately affects the lungs (80% of the cases), appears to respond well to treatment but has a high mortality (25%) in allogeneic recipients Int J Tuberc Lung Dis 2015; 19 (1):58-64

20 3. How to Prevent TB in Immunodepressed patients?

21 A. Rule out active TB disease Evaluation for TB 1. Medical history : Past TB, Background TB endemicity, Current TB contact, Clinical Symptoms (Productive prolonged cough, Hemoptysis, Fever and chills, Night sweats, Fatigue, Loss of appetite, Weight loss ) 2. Physical examination 3. Chest x-ray: by itself, cannot confirm the diagnosis of TB but can be used in conjunction with other diagnostic indicators 4. Bacteriologic exam: Sputum smear and culture 5. Diagnosis of TB infection: Tuberculin skin test (TST) Interferon-gamma release assays (IGRAs)

22 B. Diagnosis of TB infection Tuberculin Skin Test (TST) Intradermal injection of PPD-S (Seibert s purified protein derivative), or the PPD-RT23. Interferon-Gamma Release Assays (IGRAs) IGRAs: detect interferon-gamma (IFN-) release by sensitized T cells after stimulation with specific M. tuberculosis antigens (earlysecreted antigenic target protein (ESAT-6); filtrate protein (CFP-10). QuantiFERON-TB Gold assay (QFT-G) and the T-SPOT QFT-G in-tube version (QFT-GIT) includes a third antigen, TB7.7

23 In infected individuals, both TST and IGRAs detect the presence of Mtb specific T-cell responses. Intradermal injection of PPD Ag presenting cell Ag MTC Central memory T cells Effector memory T cells TNFα IFNγ IL8 Neither of them can distinguish active disease from latent infection (LTBI) Induration Detection of in vitro IFNγ

24 TST IGRAs C. Diagnosis of Latent TB infection (LTBI) LTBI: presence of immune responses to previously acquired Mtb infection, without clinical evidence of active TB. A gold standard for the diagnosis of the LTBI is lacking. Low specificity : Contains a mixture of more than 200 antigens that are shared by mycobacteria other than Mtb, and includes the vaccine strain of M. bovis bacillus Calmette-Guerin (BCG). Higher specificity in low-tb-prevalence areas and less crossactivity with the BCG vaccine in non-hiv-infected persons

25 Remember LTBI LTBI vs. TB Disease Tubercle bacilli in the body TB Disease TST or IGRAs result usually positive Chest x-ray usually normal Sputum smears and cultures negative No symptoms Not infectious Not a case of TB Chest x-ray usually abnormal Smears and cultures positive Symptoms such as cough, fever, weight loss Often infectious before treatment A case of TB 25

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27 HIV patients Biological RX

28 SOT and SCT patients

29 Summary of the recommendations for different clinical settings

30 AIM. To compare the performance of TST and IGRAs and evaluated their ability to identify those at risk for development of TB. TUBERCULOSIS median follow-up 1.8 y. IComp (n = 211) HIV (n = 768) CRF (n = 270) June 1, 2008 to May 31, centers/11 European Countries 1537 immunocompromised patients 211 immunocompetent control subjects RA (n = 199) SOT (n = 197) 10 1 Negative tests 5 1 Am J Respir Crit Care Med, 2014 SCT (n = 103) Progression toward TB was highest in HIV infected individuals and was poorly predicted by TST or IGRAs..

31 Cross-Sectional Study: Between-Test Agreement and Association with Exposure to Mtb: -HIV: Moderate associations of + IGRA. -SOT: a positive ELISA was significantly associated. -RA: A significant association of each of the three tests. -CRF: the percentage of positive test results to RA, not association. It is unclear which test should be preferred for immunodiagnostic testing Am J Respir Crit Care Med, 2014

32 Implications of Latent Tuberculosis Infection (LTBI) Testing for progression towards TB 1-2 y 1-2 y When using a management strategy relying on universal screening, preventive chemotherapy is more effective when combined with assessment of additional TB-related risk factors. Sester M, Bumbacea D, Duarte R, Lange C. Tuberculosis in the immunocompromised host. Eur Respir Monogr 2012;58:

33 TB Risk Relative risk of TB compared to the general population WHO s recommendation for screening and treatment for LTBI Country A: countries with an estimated TB incidence less than 100/100,000 Population Country B: For resource-limited countries that do not belong to country A. Emerg Microb Infecti (2016) 5, e10; doi: /emi

34 Screening and treat LTBI before transplant?

35 Which should be done in practice? Is screening for LTBI recommended for all transplants patients? High incidence of TB (>100/ ) (South Africa): Treat without screening. Medium incidence: Screen and treat positives. Low incidence (<20/ ): Screen if one or more risk factors are present and treat positives. Eur Respir J 2012; 40:

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37 Will be in this paper the feature of LTBI diagnosis? -Blood from adolescents in South Africa every 6 months for 2 years and monitored the adolescents for progression of TB disease. - A prospective signature of risk was derived from whole blood RNA sequencing data by comparing participants who developed active TB disease (progressors) with those who remained healthy (matched controls). The whole blood TB risk signature prospectively identified people at risk of developing active TB, opening the possibility for targeted intervention to prevent the disease

38 D. Treatment of LTBI Well now we know how to identify patients for preventive therapy (that is not the same as patients with an actual risk of progression!!). Daily Isoniazid (INH) therapy for months are still considered the standard of care for preventive therapy? Alternative therapies?

39 World Health Organization. Guidelines on the management of latent tuberculosis infection. Geneva: WHO, Available at daily daily daily daily weekly WHO-recommended preventive regimens for LTBI

40 Treatment of latent TB infection (LTBI) is increasingly advocated in persons with HIV co-infection Daily self-administered INH 300 mg for 9 months (9H) or daily rifampin 600 mg for 4 months (4R).Isoniazid is the clear preference for treating LTBI in a patient on drugs that have unfavorable interactions with rifamycins. Rifabutin should be used for LTBI only if there is a compelling need for short-course treatment of LTBI, and/or if neither 9H nor 4R can be used. Recently a new regimen of 12 once-weekly doses of isoniazid 900 mg plus rifapentine 900 mg administered as directly observed therapy (DOT) has been recommended for use in persons who are HIV-uninfected or in persons with HIV who are otherwise healthy and not receiving ART.

41 INH administration at the dose of 5 mg/kg, along with pyridoxine for 6-9 months. Only once. Monitor liver function tests in monthly intervals. In exceptional cases RMP at the dose of 10 mg/kg for 4 months (neurotoxicity of INH, INH-resistant strain) or a combination of RMP + INH daily for 3 months.

42 daily European survey on the management of TB in SOT recipients and candidates (ESCMID Study Group of Infection in Compromised Hosts (ESGICH) Most centers (73%) initiated treatment of LTBI prior to transplantation in non-liver transplant candidates, but only 38% of centers did so in liver transplant patients. Transplant International Volume 26, Issue 8, pages e69-e70, 15 APR 2013 DOI: /tri

43 CID 2015;60(11):1642 9

44 Transplantation Jan 27;97(2): patients INH/RPT x 12 weeks No discontinuation due to hepatotoxicity Tx F-up HPTx Discontinuation Liver (n= 7) Kidney (n= 8) Heart (n= 2) m None 1 (Change hospice care) m None 3 (HT crisis, nausea/vomiting, lost insurance coverage) 6.6 & 7.2 m None None

45 TB Vaccines Until a new vaccine is proven more effective and safe than BCG, BCG should remain part of the immunization schedules for neonates and children at risk for TB as a fundamental prophylactic measure.

46 Messages TB is a major complication in immunosuppressed patients. Patients with high-risk factors for TB reactivation should undergo screening and treatment for LTBI. IGRAs and the TST are both used to screen for LTBI, and although some studies in low-tb-prevalence areas reported a higher specificity with IGRAs than with the TST, neither method had a satisfying predictive value for active TB.

47 Messages At present, the WHO recommends five prophylactic regimens 6INH, 9INH, 3-4RIF, 3-4RIF+ INH and 3RPT + INH none of which has shown superiority over the conventional 6INH or 9INH therapies. The 3-4RIF and 3RPT +INH regimens have been reported to have fewer hepatotoxicity events, but the quality of evidence is low. For high-risk groups, INH monotherapy could reduce the TB risk in HIV-infected patients and transplant recipients, but for others, little evidence is available to draw a conclusion at this time.

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