Screening, Diagnosis, and Treatment of TB in Persons with Diabetes Dean Schillinger, M.D. University of California San Francisco CA Diabetes Program Gisela Schecter, M.D., M.P.H. TB Control Branch CA Department of Public Health Session Overview Discuss the importance of tuberculosis (TB) prevention in people with diabetes mellitus (DM) Translate the understanding that TB and DM frequently coexist into recommendations re TB screening practices among people with DM Provide rationale and recommendations for the treatment of latent TB among people with DM and positive TST or IGRA Session Overview (2) Discuss why persons with DM are at increased risk of active TB Identify the unique aspects of the presentation of active TB disease in patients with diabetes Discuss the response to treatment of active TB disease in persons with diabetes Share some concerns re reciprocal interactions between treatment of TB and blood sugar control Dean Schillinger, M.D. and Gisela Schecter, M.D., M.P.H. 1 of 18
Case 1 58 yo Latina from Guatemala with DM2 receives primary care in a community clinic Has HbA1c 9.3%, blood pressure 155/88, LDL 131, AST 96, ALT 102 On 8 chronic medications Primary and secondary prevention: Requires annual flu vaccine, retinal exam, foot monofilament exam, microalbuminuria test, blood tests, mammogram, colon/cervical CA screening, dental screening, etc How important is a TST/screening for latent TB? Rationale for LTBI Screening in DM Why treat latent TB in people with diabetes? People with DM have 3-fold greater risk of reactivation of latent TB Attributable risk is significant given growing prevalence of DM globally Derive significant public health benefit (prevention of spread in population) Promote individual well-being (prevention of disease in patient) Novel methods: QuantiFERON testing may make even more feasible IGRAs Interferon Gamma Releasing Assays Whole blood assays for M. tuberculosis infection Recently FDA approved QuantiFERON-TB Gold (2004) QuantiFERON-Gold In-tube (2007) Soon to be only QuantiFERON test available T-Spot TB from Immunotec (UK) (2009) Uses Elispot technology Dean Schillinger, M.D. and Gisela Schecter, M.D., M.P.H. 2 of 18
Who is at Higher Risk of Latent TB Infection? [and deserves to be screened] Foreign-born Homeless/marginally housed Injection drug use Racial/ethnic minority populations Recent contact to TB case Who is at Particular Risk of TB Reactivation? Recent contact to TB case Diabetes Other medical conditions: Renal failure/dialysis Tobacco use S/p Gastrectomy/jejuno-ileal bypass Transplant HIV Other immunosuppressed states, esp. anti-tnf alpha agents, steroids Case 1(a) Patient is screened and found to have a PPD @ 11 mm. Chest x-ray (CXR) is WNL Should she be treated? If so, for how long, and what concerns might arise re her co-existing diabetes? Dean Schillinger, M.D. and Gisela Schecter, M.D., M.P.H. 3 of 18
Treatment of Latent TB with NL CXR in Immigrant Patient with DM2 Length of treatment: Isoniazid (INH) x 9 months (>90% success) Or Rifampin (RIF) for 4 mos if INH not tolerated or contact to INH-resistant case Importance of vitamin i B6 (25-50 50 mg) for neuropathy prevention What about abnormal LFTS? Non-alcoholic hepatic steatosis (NASH) very common in DM Many DM meds cause LFT elevations Not a contraindication to INH prophylaxis Monitor monthly LFTs. Stop INH if 3x increase from baseline Case 1(b) Patient is screened and found to have +PPD @ 11mm CXR is abnormal ( old fibrotic changes ) Audience Response Question #1 Should anything be done differently from Case 1(a)? Yes No Dean Schillinger, M.D. and Gisela Schecter, M.D., M.P.H. 4 of 18
Rule out Active TB Disease before Initiating Treatment for Latent TB Obtain sputum samples x 3 for patients with abnormal CXRs, even if asymptomatic Await sputum cultures prior to LTBI treatment Then INH x 9 mos, or INH/Rifampin x 4 mos because fibrotic changes Case 2 66 y.o.. Native American male with history of diabetes mellitus (on Glipizide and Rosiglitazone) and peripheral neuropathy; HbA1c 8.9% Presented to emergency department (ED) with complaints of cough for 2-3 weeks, some weight loss and fatigue CXR: RLL infiltrate Given Levofloxacin for 10 days and sent home to follow up with primary care physician (PCP) Dean Schillinger, M.D. and Gisela Schecter, M.D., M.P.H. 5 of 18
Case 2 (2) Felt somewhat better and did not follow up 2 months later, returned to ED now c/o 20 pound weight loss, now with hemoptysis, fever, and night sweats Chest radiograph now showed extensive RLL infiltrate and extension of disease into L perihilar region Despite technical advances, clinical acumen with a high index of suspicion remains vital to the diagnosis of TB. Dean Schillinger, M.D. and Gisela Schecter, M.D., M.P.H. 6 of 18
Case 2 (3) The patient was admitted and placed in isolation Weight = 166 lbs TST = 0 mm Sputum smear 3+ AFB NAAT test not available in this rural area Audience Response Question #2 Is this likely to be TB? Yes No Dean Schillinger, M.D. and Gisela Schecter, M.D., M.P.H. 7 of 18
Case 2 (4) Cr, electrolytes, glucose, and LFTs were obtained Cr = 1.0, plasma glucose = 206, LFTs and electrolytes normal Case 2 (5) The patient was begun on: INH 300 mg daily Rifampin 600 mg daily Pyrazinamide 1,750 mg daily Ethambutol 1,200 mg daily Vitamin B6 50 mg daily Case 2 (6) Lives alone in a trailer Difficult patient Several times refused directly observed therapy (DOT) for a variety of reasons Blood sugar control worsened after beginning TB treatment, with random blood sugars in the 300 and 400 s Dean Schillinger, M.D. and Gisela Schecter, M.D., M.P.H. 8 of 18
Audience Response Question #3 Why is glucose control worsening? The patient has drug-resistant resistant disease and his TB is worsening He is not taking his diabetes medications His TB treatment negatively affects his glycemic control He is feeling much better and eating more Case 2 (7) Glipizide and Rosiglitazone were both already at maximum dosage, so Metformin at 500 mg 3 x daily was begun, with improvement in glucose control Case 2 (8) Drug susceptibility test (DST) shows pan- susceptible TB Sputum smears positive at 4 weeks but converted to negative after 8 weeks of treatment Sputum cultures still positive after 8 weeks, negative at 12 weeks Patient coughing less, regaining weight Dean Schillinger, M.D. and Gisela Schecter, M.D., M.P.H. 9 of 18
Audience Response Question #4 What is your recommendation for the continuation phase of treatment? INH and RIF for additional 4 months INH and RIF for additional 7 months Treatment of TB Standard Regimen for INH-Susceptible TB Initial Phase Continuation Phase Extended Continuation Phase Isoniazid Rifampin Pyrazinamide Ethambutol 5 mg/kg up to 300 mg 10 mg/kg up to 600 mg 20-25 mg/kg 15-25 mg/kg 0 1 2* 3 4 5 6 7 8 9 Months *ATS/CDC/IDSA Treatment Guidelines: If culture + after 2 months rx and cavitary CXR, prolong continuation phase to 7 months, for a total duration of 9 months. Treatment of TB Increased Risk of Relapse 2-month culture status and presence of cavitation correlates with the likelihood of relapse: Continuation INH/RIF biw Cavity Culture + @ 2 mos Yes No Yes 20.8% 4.7% No 5.9% 1.7% TBTC. Lancet 2002; 360:528 Dean Schillinger, M.D. and Gisela Schecter, M.D., M.P.H. 10 of 18
Case 2 (9) Over the last 7 months of treatment the patient missed 23 DOT doses. You are planning a 9-month regimen When should he finish treatment? Case 2 (10) The patient completed 9 months plus 23 doses and did very well He established a good relationship with his care providers and has made good lifestyle changes so that his diabetes is in much better control LTBI and Progression to Active TB Disease Greater in DM Systematic Review, 2008 13 observational studies that reported an ageadjusted estimate of association 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 Effect was higher in non-north American studies Jeon CY, PLos Med. 2008 Dean Schillinger, M.D. and Gisela Schecter, M.D., M.P.H. 11 of 18
LTBI and Progression to Active TB Disease Greater in DM (2) Contacts with Diabetes A Hong Kong study examined 4,661 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 Attributable Risk is a Function of Relative Risk and Underlying Prevalence RR if factor present Prevalence of factor HIV 8.3 1% 7% D.M. 3.0 3.4% 6% Population attributable risk 3.0 10% 17% 3.0 20% 29% Raviglione, WHO Population Attributable Risk Epidemiologic model from India, calculated that diabetes accounted for 14.8% of pulmonary tuberculosis, and 20.2% of smear + tuberculosis Stevenson CR, BMC Public Health, 2007 Dean Schillinger, M.D. and Gisela Schecter, M.D., M.P.H. 12 of 18
LTBI and Progression to Active TB Disease Why are patients with diabetes at increased risk for progressing to active TB disease? Impaired cell-mediated immunity Renal failure Micronutrient deficiency Pulmonary microangiopathy Harries AD, Trans Royal S of Trop Med & Hyg. 2009 Unique Patterns regarding TB Presentation and Diagnosis in DM 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 Dean Schillinger, M.D. and Gisela Schecter, M.D., M.P.H. 13 of 18
Presentation and Diagnosis of TB in Patients with Diabetes More advanced disease Patients with diabetes are more frequently smear + Cavitary findings Hemoptysis more common Fever more common Unclear if this a result of delay in diagnosis or more rapid disease progression? Wang CS, Epidemiol Infect, 2008 California Experience 280 patients with active pulmonary TB disease Self-reported DM = 20% Sputum smear + Yes DM = 66% No DM = 45% Cavitary CXR findings Yes DM = 31% No DM = 14% Suboptimal Response to TB Treatment in DM Old dogma: despite increased risk of progression to active TB disease, these patients did just as well 4 new studies Baltimore: delayed culture conversion, higher mortality Texas: delayed sputum culture conversion Taiwan: higher mortality Indonesia: slower smear and culture conversion Dooley, Tang, Am J Trop Med Hyg. 2009 ; Restrepo, Fisher-Hoch, Am J Trop Med Hyg. 2008; Wang, Yang, Chen, Epidemiol Infect. 2008; Alisjahbana, Sahiratmadja, Clin Infect Dis. 2007. Dean Schillinger, M.D. and Gisela Schecter, M.D., M.P.H. 14 of 18
California Experience (2) Patients with active pulmonary TB disease Culture conversion within 90 days Yes DM = 85.7% No DM = 92.0% Response to Treatment Data on drug resistance is less clear, with some studies showing increased drug resistance in patients with diabetes, but others not Relapse may be more frequent, recently shown again in a Shanghai study Patients with DM, 20% relapse with 6 month rx Patients w/o DM, 5.3% relapse with 6 month rx Zhang Q, et.al. Jpn. J Infect Dis, 2009 Rifampin Concentrations May be Lower in DM Comparison of 17 age and sex matched persons with and 17 without DM (all had TB) AUC 12.3 - TB and DM AUC 25.9 - TB only Peak levels also about half in persons with DM Low levels associated with higher body weight and poor glucose control Consider rifampin levels for slow conversion of sputum Nijland HM, Clin Infect Dis, 2006 Dean Schillinger, M.D. and Gisela Schecter, M.D., M.P.H. 15 of 18
TB and DM Treatment Caveats Pyrazinamide (PZA) and Ethambutol (EMB) need adjustment for renal impairment; check serum Cr INH-related peripheral neuropathy is more common in diabetes: should give Vitamin B6 Follow closely and monitor for sputum conversion Extend treatment to 9 months if slow sputum conversion OR cavitary CXR, consider rifampin levels TB and DM Treatment Caveats (2) Rifampin raises blood glucose levels even in non-diabetic Rifampin activates the CYP450 enzyme system Sulfonylureas and thiazolidinediones are metabolized by this same system Blood levels of these drugs significantly lowered by rifampin As a result, blood glucose control in people with diabetes may worsen when treating TB Monitoring for Hepatotoxicity Many patients with diabetes are on statins, as well as the thiazolidinediones, which carry risk of hepatotoxicity Now we add 3 anti-tb drugs with potential for liver toxicity: INH, PZA, and RIF These patients should have careful, monthly LFT follow-up, and if 5 x normal values, treatment should be adjusted Dean Schillinger, M.D. and Gisela Schecter, M.D., M.P.H. 16 of 18
Treatment Success Requires Communication Typically, the TB provider (often the health department) will not also treat the diabetes and vice versa Because of the effect of TB treatment on glycemic control, critical importance of 2-way communication between TB and DM providers, at onset, during, and at end of treatment Treatment Success Requires Communication (2) Equally important is patient/provider communication Communication barriers are very common among low-income, diverse patients with DM Limited literacy/numeracy (>50%) Limited English proficiency Sensory deficits are common: vision and hearing loss Subtle cognitive impairment common among those with longstanding DM Use the teach-back method Schillinger. JAMA 2002 Recommendations Just as we recommend screening TB patients for HIV, screen for DM when TB is diagnosed (FBS >125=DM) Repeat serum glucose after one month Monitor for polyuria/polydipsia during treatment If diabetes is present, treat, don t wait Follow diabetes closely and bring blood sugar as close to normal as possible Dean Schillinger, M.D. and Gisela Schecter, M.D., M.P.H. 17 of 18
Conclusions DM increases risk of LTBI progressing to disease Patients with diabetes and risk factors need LTBI screening and rx Active TB disease may present differently in people with diabetes Patients with diabetes may clear sputum more slowly and have higher mortality Consider prolonging treatment if risk factors for relapse are present Monitor diabetes control closely at onset and at end of rx; attempt to achieve optimal glycemic control, including use of insulin if necessary Always use vitamin B6 if on INH Dean Schillinger, M.D. and Gisela Schecter, M.D., M.P.H. 18 of 18