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Jayne Ash Address TB in Your Practice: Focus on Co-Morbidities Gisela Schecter, MD, MPH CA Dept of Public Health May 6, 2010 I have no conflicts of interest to declare Who was Jayne Ash? Executive Director of strategic planning for CTCA from 1998-2001 Graduate of the N.C. School of PH Jazz singer Great facilitator On task Great sense of humor Died tragically in 2001 60 years ago Now Highest incidence of TB is in > 65 y.o., many of whom have concurrent diseases A new disease has put people at increased risk of TB New therapies that modulate immunity put people at increased risk of TB Lifestyle choices put people at risk for TB Co-morbidity is the rule, not the exception TB is not your patient’s only problem Diabetes Mellitus Smoking Chronic Kidney Disease and Hemodialysis HIV infection (Immunosuppressive therapies) Tuberculosis and Diabetes Mellitus LTBI and Progression to Active TB The frequent association of DM and TB has been observed for over 2,000 years Systematic Review from Harvard, 2008 13 observational studies that reported an ageadjusted estimate of assoc. between TB and DM Almost 1.8 million participants 3 Cohort studies gave RR of 3.11 (CI 2.27-4.6) 10 Case/control studies Odds Ratios ranged from 1.16-7.83 Jeon CY, PLos Med. 2008 LTBI and Progression to Active TB Diabetic Contacts A Hong Kong study examined 4661 close contacts to TB cases Both early (within 3 months) and late (followed for 5 years) disease in contacts was strongly associated with diabetes in the contact (RR= 3.44) Lee MS, Int J Tuberc Lung Dis. 2008 LTBI and Progression to Active TB Why are patients with diabetes at increased risk of TB? Impaired cell-mediated immunity Renal failure Micronutrient deficiency Pulmonary microangiopathy Harries AD, Trans Royal S of Trop Med & Hyg. 2009 Presentation and Diagnosis Diabetes and Radiological Presentation of Pulmonary TB Cavitary lung lesions • Yes DM; 50.8% • No DM; 39% Lower lobe lung lesions • Yes DM; 23.5% lower lobe lesions only • No DM; 2.4% lower lobe lesions only Shaikh MA, Saudi Med J, 2003 Presentation and Diagnosis More advanced disease Patients with DM are more frequently smear + Cavitary findings Hemoptysis is more common Fever more common Is this a result of delay in diagnosis or more rapid disease progression? Wang CS, Epidemiol Infect, 2008 Response to Treatment Old Dogma: Despite increased risk of progression to active TB if infected, diabetic patients did just as well. 5 new studies Baltimore: delayed culture conversion, higher mortality Texas: delayed sputum culture conversion Taiwan: higher mortality Indonesia: slower smear and culture conversion Shanghai: significantly higher relapse rate Response to Treatment Data on drug resistance is less clear with some studies showing increased drug resistance in patients with DM, but others not Patients with DM may be at increased risk of acquired drug resistance Acquired MDR TB is infrequent in CA, but anecdotally, the 2 most recent cases were among persons with DM Rifampin and DM Comparison of 17 age and sex matched persons with and without DM. (All had TB) AUC 12.3 mg x h/L TB and DM AUC 25.9 mg x h/L TB only Peak levels also about half in Diabetics Low levels associated with higher body weight and poor glucose control Nijland HM, Clin Infect Dis, 2006 Case 1 64 yo Hmong woman diagnosed with extensive, smear + pan-sensitive tuberculosis in August, 2009 Longstanding, poorly controlled DM Began RIPE 8/31/09 Smears improved gradually and became negative in October, 2009 Cultures remained + Case 1 Late January 2010, smears again + Culture sent for molecular beacons and DST Molecular beacon showed no INH resistance mutations in katG or inhA, results for Rif were initially inconclusive, but repeat test showed rpoB Rif mutation Culture very slow growing, but DST report in late March showed INH and Rif resistant Case 1 What happened? Without informing DOT staff, patient had developed almost daily vomiting after taking TB meds Why? Poorly controlled diabetic patients frequently have gastroparesis Rifampin levels are lower even w/o vomiting Effect of TB treatment on DM Rifampin raises blood glucose levels even in non diabetics Rifampin activates the CYP450 enzyme system Sulfonorylureas and thiozolidinediones are metabolized by this same system. Blood levels of these drugs significantly lowered by Rifampin When treating TB in a patient with DM remember: Both PZA and EMB need adjustment for renal impairment; check serum Cr (renal dys-function common in DM) INH peripheral neuropathy is more common in diabetics: always supplement Vitamin B6 Follow patients closely and monitor for sputum conversion Consider extending treatment to 9 months if risk factors for relapse such as slow sputum conversion OR cavitary CXR are present When treating TB in a patient with DM remember: Just as we recommend screening TB patients for HIV, screen for DM when TB is diagnosed Repeat serum glucose after one month Monitor for polyuria/polydipsia during treatment Follow diabetes closely and adjust diabetic medications to bring blood sugar as close to normal as possible When treating TB in a patient with DM remember: At treatment end, be aware that diabetic medications may need to be adjusted downward Recommendations for TB screening and LTBI treatment Screen all diabetics at risk for TB infection for LTBI (and active TB), at diagnosis of DM and periodically, as local epi dictates Strongly encourage LTBI treatment if TST and/or IGRA is positive. Contacts with DM should be given high priority for evaluation and LTBI treatment TB and Diabetes Mellitus DM increases risk of LTBI progressing to disease Diabetic patients need LTBI screening and rx TB may present differently in diabetics Diabetics clear sputum more slowly and have higher mortality Consider prolonging treatment to 9 months if risk factors for relapse such as either delayed sputum conversion OR cavitary CXR are present Consider obtaining Rifampin blood levels Monitor diabetic control closely Use B6 if on INH Tobacco and Tuberculosis Is there a problem? Tobacco use is the leading preventable cause of death in the world Tobacco use is a risk factor for 6 of the 8 leading causes of death in the world Ischemic heart disease, cerebral vascular disease, COPD, lower respiratory infections, lung cancer AND Tuberculosis The tobacco epidemic is about to get much worse Tobacco currently kills about 5 million/year but this will increase to 10 million/year in a few decades Total deaths attributable to tobacco in the 21st century are estimated to be 1 billion Tobacco and Development Tobacco and Poverty: A vicious circle The poor are the ones who smoke the most Smoking worsens poverty due to: • Money spent of tobacco can’t be used for food or other essential items • Increased illness and health care costs Smoking accounts for much of the mortality gap between rich and poor High burden TB countries are those with high-burden tobacco use 40% of new and relapsed TB cases live in just 2 countries, India and China >40% of smokers live in those same two countries So what is the association between tobacco exposure and tuberculosis? A Qualitative Systematic Review Jointly Conducted by WHO and IUATLD Selection of articles: All English language journal articles on tobacco exposure and tuberculosis available in: • PubMed from 1954 through 2005 • The Union data base of TB articles since 1918 42 articles containing 50 studies were included in the review. Main Results of the Systematic Review The effects of tobacco use on TB outcomes are independent of the effects of alcohol use, SES, age, sex and other potential confounders Exposure to tobacco smoke is significantly related to TB infection: Eight studies investigated tuberculosis infection All of the studies of infection found significant effects of exposure to tobacco Odds ratios ranging from 1.03 to 3.20 Main Results of the Systematic Review Passive or active exposure to tobacco smoke is significantly associated with a new and/or recurrent tuberculosis disease: 24 studies explored the relationship between tobacco smoke exposure and new and/or recurrent tuberculosis disease: • Of 19 studies with significant results for active exposure, odds ratios ranged from 1.01 to 6.26 • Of 4 studies with significant effects for passive exposure, odds ratios ranged from 1.6 to 9.3 Main Results of the Systematic Review Active smoking is significantly associated with tuberculosis mortality: 5 studies investigated the role of exposure to tobacco smoke and tuberculosis mortality All of the mortality studies found significant relationships with tobacco use. Risk ratios ranging from 1.02 to 6.62 A Nationally Representative CaseControl Study of Smoking and Death in India Smoking will cause about 930,000 deaths in India in 2010 and smoking could also be a cause of many of the deaths from TB 38% of total numbers of deaths associated with smoking will be caused by TB Prabhat, NEJM 2008 Mechanisms underlying the Association between Tobacco and TB Smoking may attenuate mycobactericidal activities including oxidative stress in the lung tissues Mechanical disruption of cilia function and other clearance mechanisms in the tracheobronchial system Nicotine turns off the production of TNFalpha by macrophages in the lungs (decreasing local levels of TNF-alpha might reactivate LTBI) 1) Pai, Expert Rev Anti Infect Ther, 2007; 2) Davis, Trans Roy Soc Trop Med Hygiene, 2006 The New Stop TB Strategy WHO developed a new Stop TB strategy in 2006, recognizing that prevention of the most frequent risk factors is an important contributor to TB control Any reduction in the prevalence of tobacco smoking should benefit TB control We in the health care system must play an important role in reducing both of these epidemics What can we do? MPOWER: Six policies to Reverse the Tobacco Epidemic Monitor tobacco use and prevention policies Protect people from tobacco smoke Offer help to quit tobacco use Warm about the dangers of tobacco Enforce bans on tobacco advertising, promotion, and sponsorship Raise taxes on tobacco Treatment of tobacco dependence is effective Effectiveness data for smoking cessation interventions (abstinence for at least 6 months) Cochrane Reviews Interventions Comparator Odds Ratio Self-help No intervention 1.24 Physician advice No advice 1.74 Physician intensive advice Minimal advice 1.44 Group behavior rx No intervention 2.17 NRT Placebo or non-ART 1.58 Telephone counseling No telephone c. 1.41 Can we reduce both morbidity and mortality from TB by increasing our efforts to reduce smoking? DOTS + MPOWER = TB Raviglione, M. RR if factor present Prevalence of factor Population attributable risk Malnutrition 3.0 17% 25% D. M. 3.0 3.4% 6% Smoking 2.6 18% 23% HIV 8.3 1% 7% TB and Renal Disease Impaired CMI with cutaneous anergy rates of 30-80% in ESRD Risk of active TB 7-52 X higher than general population 2004 Kaiser Permanente study: Active TB in their dialysis patients 11.3 X rate in California population as a whole Renal Disease TB Treatment Principals For INH and RIF not affected and dose adjustments are not necessary (metabolized by the liver) EMB, PZA and levofloxacin: use usual daily dose, but decrease frequency to 3 X weekly Give all drugs immediately after dialysis Always use vitamin B6 with INH For CrCl < 30 ml/min: CrCl > 30, but <70 ml/min: Monitor closely for EMB optic neuropathy First Line Agents and Hemodialysis Drug Isoniazid Change frequency? NO Removed by hemodialysis + Rifampin NO NO Ethambutol YES + Pyrazinamide YES +++ TB and Renal Disease Resources: http://www.ctca.org/guidelines/New_Renal_Dialysis_Guid elines_02_22_08.pdf http://www.thoracic.org/sections/publications/statements/pa ges/mtpi/rr5211.html TB Treatment Doses and Intervals in ESRD TB and Renal Disease Prevention is the key! All patients with renal impairment should have baseline TST or IGRA to assess for LTBI, ideally before CrCL < 30 ml/min If LTBI present, must be very strongly encouraged to complete LTBI Rx • INH 300 mg daily or 900 mg twice or thrice weekly after dialysis for 9 months • Rifampin 600 mg daily or twice or thrice weekly for 4 months HIV related Tuberculosis WHO estimates that TB is cause of death for 13% of persons with AIDS Risk of progression to active TB if LTBI present is about 10% per annum Occurs even with relatively high CD4 counts Presentation influenced by degree of immunodeficiency CXR Pattern: Early vs. Advanced HIV Early HIV Advanced HIV (CD4 >200) (CD4 <200) “Typical” (Reactivation) “Atypical” (Primary) Infiltrate Upper lobes Lower lobes, multiple sites, or miliary Cavitation Common Uncommon Adenopathy Uncommon Common Effusion Uncommon More common Pattern Adenitis and Consolidation Courtesy M. Gotway, MD HIV related Tuberculosis When CD4 < 200, extra pulmonary TB (lymphadenitis, pleuritis, pericarditis, and meningitis) with or without pulmonary disease found > 50% of patients Can present with high fevers, rapid progression, sepsis syndrome HIV related Tuberculosis Screen all persons for LTBI at time of HIV diagnosis If initial CD4 < 200 and LTBI test negative, repeat screening after ART begun and CD4 > 200 Annual screening only if at risk for repeated or ongoing exposure to persons with active TB Screening Tests: TST; 5 mm or greater reaction is positive Interferon Gamma Release Assays (IGRAs) HIV related Tuberculosis Treat for LTBI if no evidence of active TB AND: Any positive diagnostic test for LTBI without prior treatment Close contact of infectious TB case, regardless of TST or IGRA result History of untreated or inadequately treated healed TB (old fibrotic lesions on CXR) Preferred 9 months regimen is INH 300 mg daily for HIV related Tuberculosis Initiation of ART in Patients with Active TB: Always start TB treatment immediately CD4 count Timing of ART Initiation <100 After 2 or more weeks of TB rx 100-200 After 2-8 weeks of TB rx 201-350 During maintenance phase of TB rx > 350 After completion of TB rx CDC: MMWR, Guidelines for Prev/Treat of Opp Inf in HIV- HIV related Tuberculosis Efavirenz based ART is preferred If pregnant or under 3 years of age, Nevirapine is the NNRTI of choice If patient is already on a protease inhibitor based regimen or a PI must be used, then Rifabutin may be used instead of Rifampin Case 2 A 40 year-old man presents with fever for 4 weeks, cough with bloody sputum, night sweats and weight loss of 7kg Chest X-ray shows right mid lung infiltrate Sputum AFB is positive His HIV test is positive and CD4 is180 cell/cu mm RIPE is begun Case 2 When seen after 8 weeks of treatment, his fevers, night sweats, and cough have stopped and he has gained 5kg His TB regimen is changed to isoniazid and rifampin Atripla is begun (efavirenz, tenofovir, emtricitabine) X-ray shows improvement Case 2 The patient returns 1 month after starting Atripla He says that his fever, cough and night sweats have “come back” “ He has taken the Atripla as prescribed but thinks they are making him more sick and would like to stop them Case 2 The patient has had excellent adherence and denies nausea, vomiting or diarrhea His oxygen saturation comes back at 96% on room air Heart rate, respiratory rate and other vital signs are normal Some axillary nodes are present Sputum smear is 1+ AFB NSAIDS given NEW CHEST X RAY Case 2 2 weeks later he is worse Sputum cultures have converted to negative Sputum smear is still 1+ AFB On physical exam is tachypneic Respiratory rate is elevated and oxygen saturations is 90% on room air Crackles heard in right lung field X-ray shows worsening Immune Reconstitution Inflammatory Syndrome (IRIS) Paradoxical worsening of symptoms after initiating ART (or sometimes TB rx itself) Remains a major problem, particularly if initial CD4 count low Usually occurs 1-3 months into ART Greatest risk if ART started in first 2 months of TB rx, and/or CD4 < 100 Immune Reconstitution Inflammatory Syndrome (IRIS) Signs/symptoms High fevers Worsening respiratory status, parenchymal infiltrates, pleural effusions Increase in lymphadenopathy Breakthrough meningitis or CNS lesions Evaluate thoroughly for other possible causes, especially TB treatment failure Immune Reconstitution Inflammatory Syndrome (IRIS) Treat with NSAIDS if mild to moderate Use steroids if severe (1mg/kg of prednisone daily with gradual taper) Try not to change anti-TB or ARV therapy In Summary Many, if not most of our TB patients now have significant co morbidities Our colleagues in the private sector will need to remember TB in order to promptly diagnose, or better yet, prevent TB Epidemics of DM and HIV, and ongoing tobacco use place large numbers of patients at risk for TB Co morbid conditions complicate the treatment of TB TB Prevention is key