Targeted Testing and Treatment of Latent TB Infection L. Masae Kawamura, MD Director, TB Control Section, San Francisco Department of Public Health Francis J. Curry National Tuberculosis Center University of California, San Francisco Introduction L. Masae Kawamura, MD 2 Diagnosing TB infection and disease is a primary care issue….. 3 ↛ Preventing TB is a primary care issue… Know the TB status of your at risk patients Ensure evaluation and treatment 4 Meeting the challenge of LTBI • Latent TB Infection should be treated as a condition in itself which is a precursor to a serious and potentially fatal disease • Much the same way we treat hypertension as a condition in itself because it significantly heightens risk of heart disease, renal failure, and stroke or place infants in car seats because of the significant risk of injury without them, so should we approach latent TB infection • While the condition in itself is asymptomatic, the risks assumed by ignoring it are substantial Source: Carey Jackson, MD. Internal Medicine. International Clinic, Harborview Medical Center, Seattle, Washington. 5 TB is global 6 TB is local: “Hot spots” in San Francisco Tenderloin/SoMarket: Homeless hotspot Chinatown: old and new immigrant hot spot Click the diagram to expand 7 U.S.A. “Tuberculosis is a social disease with medical implications” –Sir William Osler § § § § ~11 million infected individuals * Pool of infected individuals grows by 400,000 per year due to legal immigration Over 50% of total cases are foreign-born Over 80% of US-born cases occur among racial and ethnic minorities *Bennett et al. Am J Respir Crit Care Med 2008; 177:348-355 8 Making the connection: Risk of infection and disease progression § Risk of infection -prior exposure to TB -current/recent exposure to TB -ongoing/chronic exposure § Risk of disease progression -medical risk factors 9 Targeted testing = Strategic screening of those at highest risk of TB infection and TB disease Intersection of risks: TB infection, medical, and population risks TB RISK OF EXPOSURE Foreign-born Homeless, urban poor Elderly US-born MEDICAL RISKS AIDS, diabetes, renal dialysis, cancer, Immunosuppressive drugs, organ transplant, prior TB Adapted slide: originally created by Jenny Flood, MD and staff, California Dept. of Public Health 10 Failing to meet the challenge: Case #1 Primary 33-year-old yr old son: son:+PPD +PPD asymptomatic asymptomatic Reactivation 28-year-old mom from Central American, coughing for 3 months. Failed to follow up for LTBI treatment refill 2.5 years before 11 Groups at high risk for TB infection Groups • Close contacts of active TB cases - Risk associated with disease burden and presence of cough of the source case • Residents & employees of congregate settings - Correctional facilities (inmates and staff), nursing homes, longterm care facilities, renal dialysis units • Healthcare workers • Medically underserved/low-income groups - Homeless or marginally housed Migrant workers Street drug users Children with parents who have risk factors 12 Testing by risk of infection Who is considered at risk? •Foreign-born patients from TB endemic countries, where prior TB exposure is almost certain • Frequent or prolonged travel to these areas What countries are considered TB endemic? • All of Asia except Japan • All of Central and South America • All of Africa • All of Eastern Europe (Yes, that is practically the whole world) 13 Refugee and immigrant screening The immigration process does not take care of Latent TB Infection (LTBI) for you! In Country of Origin • Adults evaluated for active TB ONLY • NEW: Children <15 yrs and contacts screened with TST in some countries but no LTBI treatment In the US • Those entering the US as suspects are expected to follow up with the local health dept but NOT mandated • Those applying for an adjustment of status are evaluated for LTBI but treatment is NOT mandated Not evaluated • Visitors, students, temporary workers, undocumented 14 LTBI: Medical conditions that increase risk of progression Medical Conditions • HIV + • Prior TB (lung fibrosis consistent with old TB) 15 LTBI: Medical conditions that increase risk of progression (2) Medical Conditions • Children under 5 • Recent infection (contacts and converters) 16 LTBI: Medical conditions that increase risk of progression (3) Medical Conditions • • • • • • • • • • Diabetes mellitus Cancer of the head and neck Hematologic and reticuloendothelial diseases Intestinal bypass or gastrectomy Chronic malabsorption syndromes Low body weight – malnutrition Renal dialysis Silicosis Alcoholism NEW - Tobacco users* *Lin HH, Ezzati M, Murray M. PLoS Med. 2007;4(1):e20 Slama K, Chiang CY, Enarson DA, Hassmiller K, Fanning A, Gupta P, Ray C. Int J Tuberc Lung Dis. 2007;11(10):1049-61 Bates MN, Khalakdina A, Pai M, Chang L, Lessa F, Smith KR. Arch Intern Med. 2007;167(4):335-42 17 Quantification of TB risks Risk factor Estimated increased risk (Compared control population with +TST) Advanced HIV infection* Anti-TNF agents** Old, healed TB* Diabetes mellitus*** Tobacco (ever smokers)**** Chronic renal failure* Silicosis* Gastrectomy * Underweight* * Horsburgh CR, N Eng J Med. 2004; 350(20) :2060-2067 **Gossec L, et al. Ann Rheum Dis. 2009; 68:1680-1685 ***Jeon CY, Murray MB. PLoS Med. 2008; 5(7): e152. Review ****Lin HH, Ezzati M, Murray MB. PLoS Med. 2007;4(1):e20 9.9 7.9 5.2 3.1 2.69 2.4 1.7 1.4 1.6 18 LTBI: Immunosupressive agents that increase risk of progression Immunosuppressive agents • • • • Steroids (not inhaled) (eg. >15 mg prednisone QD >3 wks) Cancer chemotherapy Cyclosporine and others drugs used in organ transplant Anti-Rheumatics* •Etanercept (Enbrel) •Infliximab (Remicade) •Adalimumab (Humira TM) •Anakinra (Kineret) *Brassard P, Kezouh A, Suissa S. Antirheumatic drugs and the risk of tuberculosis. Clin Infect Dis. 2006 ;43(6):717-22. 19 How often do I screen my patient for TB? § Retesting: dependent on ongoing risk of TB exposure § Frequency: dependent on degree of chronic TB exposure (use local epidemiology) – Annual testing*: HCWs, long-term care residents, shelter or homeless CBO or substance recovery program staff – Q 6 month testing*: TB clinic frontline staff, ER workers, pulmonologists performing bronchoscopy – Periodic testing*: extended travel to high risk area *Need to correlate with local epidemiologic data 20 Flowchart: Evaluation to treatment of LTBI Assess TB risks no yes STOP Tuberculin test + symptom review Negative Positive Chest x-ray Normal Treatment not indicated Candidate for Rx of latent TB Abnormal Evaluate for active TB 21 Diagnostic tools for tuberculosis infection TB Skin Test (TST) Interferon Gamma Release Assays (IGRAs) 22 In vivo and in vitro diagnostic tests TST – in vivo Presentation of mycobacterial antigens IFN-g TNF-a IL-8, etc. IGRA – in vitro IFN-g Antigen presenting cell Memory T-cell TNF-a Andersen P, et al. Lancet. 2000;356:1099-104 IL-8, etc. 23 Mantoux tuberculin skin test – Key points • TST should not be performed on someone with documented history of a positive test • TST should be read and interpreted by a trained healthcare professional • TB disease must be ruled out before initiating treatment for LTBI 24 Reading the TST • Measure reaction in 48 to 72 hours • Measure induration, not erythema (redness) • Record reaction in millimeters, not “negative” or “positive” • Positive reactions can be read for up to 7 days • Negative reactions can be read accurately for only 72 hours 25 Interpreting tuberculin skin test reactions 5 mm or greater • HIV positive persons • Recent contacts of persons with active tuberculosis • Fibrotic changes on chest radiograph, consistent with tuberculosis • Patients with organ transplants and other immunosuppressed patients 10 mm or greater • Immigrants from highprevalence areas • Injection drug users • Residents and employees of high-risk congregate settings • Personnel in mycobacteriology laboratories • Persons with clinical conditions that place them at high risk • Children: <4 years of age; all exposed to adults at high-risk 15 mm or greater No known risk factors Why did you test this person? Note: the CDC discourages testing of people at low risk for infection. 26 Tuberculin skin test interpretation: Tuberculin skin test conversion § Signifies new infection § CDC definition: >10 mm increase within 2-year period § Problems with interpretation: conversions may actually represent boosted reactions in some individuals 27 TB IGRAs Interferon Gamma Release Assays • Indirect test for M. tuberculosis infection using whole blood • Test for cell-mediated immune response (not antibody response) • Highly specific: Not affected by prior BCG vaccination and most environmental mycobacteria BCG X 2 in Chinese orphanage TST positive , QFT-G negative LTBI treatment avoided 28 3 FDA-approved highly specific IGRAs QuantiFERON®-TB Gold (Cellestis Ltd., Carnegie, Australia) • FDA cleared late 2004 • Uses ESAT-6 and CFP-10 as antigens QuantiFERON®-TB In-Tube • FDA approved in Dec. 2007 • Uses 3 antigens affixed to inside of tube - Adds TB7.7 (RD4) antigen to ESAT-6 and CFP-10 T-SpotTBÔ (Oxford Immunotec, Oxford, UK) • FDA conditionally approved in Aug. 2008 • Use 2 antigens: ESAT-6 and CFP-10 29 IGRAs: Species specificity of ESAT-6 and CFP-10 Tuberculosis complex M tuberculosis M africanum M bovis BCG substrain gothenburg moreau tice tokyo danish glaxo montreal pasteur Antigens ESAT CFP + + + + + + - - Environmental strains M abcessus M avium M branderi M celatum M chelonae M fortuitum M gordonii M intracellulare M kansasii M malmoense M marinum M oenavense M scrofulaceum M smegmatis M szulgai M terrae M vaccae M xenopi Antigens ESAT CFP + + + - + + + - 30 Interferon Gamma Release Assays vs. tuberculin skin test IGRA • • • • • • • In vitro Single antigens No boosting Not affected by BCG Result with one patient visit Minimal inter-reader variability Results: one standard for all TST • • • • • • • In vivo Multiple antigens Boosting BCG may affect results Two patient visits required for result Significant inter-reader variability Results: different cut points based on risk 31 Current IGRAs QuantiFERON® (QFT): Whole blood incubated with MTB specific antigens -> free IFN-γ release is measured (ELISA) 0.35 IU/ ml POS NEG QFT-TB Gold In-Tube TB Antigens CONTROL + CONTROL - T-Spot®.TB: T-cells incubated with MTB specific antigens; IFN-γ releasing cells are counted (ELISPOT-based technology) 32 IGRAs: Interpreting results Positive QuantiFERON® -TB Gold QuantiFERON® -TB In-Tube ≥0.35* T Spot TB Ô ≥8 Negative <0.35 * Gray Zone None Indeterminate Controls fail: High Nil Poor Mitogen response spots* <8 5-7 spots* same as above spots* * (TB Ag - Nil) and assumes appropriate control responses 33 2009 IGRA CDC Guidelines § IGRAs can be used in all situations where the skin test is currently being used § IGRAs preferred: § BCG vaccinated persons § Persons unlikely to return for a TST reading § Low risk individuals § Like the TST, clinical judgment required when interpreting Θ IGRA results in children <5yrs, immunocompromised persons, and TB suspects § TST preferred in children <5yrs § When maximum sensitivity needed → acceptable to use both TST and IGRA § Lab should report quantitative results 34 IGRAs: Managing & interpreting results Contact investigation:* Repeat test as you would the TST if initial QFT-G is negative, at 8-10 weeks Managing indeterminate results:* Repeat QFT-G or place TST or do nothing Definition of a QFT conversion:* Defined as change from negative to positive result *Guidelines for using the QuantiFERON-TB Gold test for detecting Mycobacterium tuberculosis infection, United States. MMWR. 2005 Dec 16;54(RR-15):49-55 Areas of ongoing research: • • Quantitative definition for “IGRA converter” Quantitative response to treatment (promising but not yet clinically relevant) 35 IGRA performance compared to TST Performance characteristics TST IFN-gamma assays Est. sensitivity 75-91% 80-95% Est. specificity 80-90% 95-100% Correlates with exposure Often no Yes Results change with Rx Usually yes ?? 36 Comparing different IGRAs QFT-GIT Tspots (≥ 6 spots) Characteristics QFT-G Est. sensitivity (%) 74-79 * 81 93 Est. specificity (%) 99 99 88 Correlates with exposure yes yes yes and risk factors Immunocompromised >indet > indet <indet *Pai M, Zwerling A, Menzies D. Ann Intern Med. 2008;149(3):177-84 If not designated, data from compiled research up to 8/08 37 Can IGRAs replace the TB skin test? Current data indicate…. • Contacts: yes • Screening BCG vaccinated individuals: yes, preferred! • Screening low risk individuals: yes • Screening the homeless and other poorly adherent populations: yes, preferred! • Serial testing: yes, with caveat 38 What to expect when you switch to IGRAs • Significant decrease in the positive rate and further work-up • Unnecessary testing and retesting! • Serial testing (excluding contact investigation and active cases) Ø Unexpected positives that require further investigation (e.g. repeat testing, review of quantitative results) Ø Beware of “wobblers”, results that hover around the baseline 39 TST and IGRA test interpretation: False-negative or indeterminate results Host factors affecting TST and likely IGRAs § HIV- low CD4, no ARVs § Recent TB infection (<10 weeks) § Infections (viral, fungal, bacterial) § Other illness affecting lymphoid organs § Live virus vaccination § Immunosuppressive drugs § Overwhelming TB § Age (newborn, elderly) 40 TST and IGRA test interpretation: False-negative or indeterminate results (2) TST technical factors § The tuberculin used (i.e., improper storage, contamination) § Improper method of administration, reading and/or recording of results IGRA technical factors § § § § Insufficient blood volume Insufficient mixing Endotoxin in lab tubes Lab errors 41 TST: False-positive results § Cross-reactions and boosted reactions from atypical mycobacterial infections and BCG § History of BCG vaccination, especially if recent (<1 yr) or multiple § Misinterpretation of immediate hypersensitivity to tuberculin § Switching tuberculin products (tubersol with applisol) IGRA: False-positive results § Cross-reactions from M. kansasii, M. szulgai, and M. marinum § Product failure: Endotoxin traces in tubes § Lab errors 42 TST and IGRAs are tools, not panaceas Screening individuals who are likely to have false-negative TB test results (young infants, HIV+s, immunosuppressed) § Chest x-ray – look for evidence of TB infection (e.g., hilar calcification, upper lobe fibrosis, calcified granuloma) § Symptom review § Assess TB risk factors § Decision to provide LTBI treatment in the absence of a positive TB test should be based on risk of true infection, chest x-ray findings, individual and public health implications 43 Does this remicade candidate have LTBI? TST = negative QFT = negative asymptomatic 44 Treatment for Latent Tuberculosis Infection (LTBI) Current guidelines for TB prevention § DECISION TO TEST IS DECISION TO TREAT! § No 35-year-old cut-off § 9 months of INH preferred over 6 months § Baseline laboratory monitoring not routinely indicated 46 Failing to meet the LTBI challenge Case #2 • 66 yo Vietnamese female with latent TB (untreated), diabetes, inflammatory arthritis, and depression/ PTSD • Developed idiopathic thrombocytopenic purpura and began to have bleeding • Treated with systemic high-dose steroids in the hospital and developed miliary TB • Died of complications Source: Carey Jackson, MD. Internal Medicine. International Clinic, Harborview Medical Center, Seattle, Washington 47 Who should be treated for Latent TB Infection (LTBI)? Note: Careful assessment to rule out the possibility of active TB disease is always necessary before treatment for LTBI is started. • Willing and able to complete a full course of therapy • Available to be monitored during the full course of treatment • No medical contraindications such as active liver disease 48 Clinical trials of isoniazid treatment of LTBI Efficacy of INH based on duration of treatment and compliance Duration of INH 5-year risk reduction Compliance Reduction if compliant 3 mos 21% 87% 31% 6 mos 65% 78% 69% 12 mos 75% 68% 93% Bull World Health Organ. 1982;60(4):555-64 49 INH for LTBI How long is enough? Calculated curve Calculated values Observed values 5 4 Cases per 100 • Lower TB rates among those who took 0-9 mo 3 • No extra increase among those who took >9 mo 2 1 0 0 6 12 18 24 Months of Treatment Comstock GW. Int J Tuberc Lung Dis. 1999 Oct;3(10):847-50 50 Current treatment for LTBI Drug Isoniazid (INH) Dose Max: 300 mg Children/ adolescents 10-15mg/kg 300 mg if over 20 kg Frequency Daily Duration 9 months Preferred for everyone 6 months is “acceptable” for: • Immunocompetent adults without scarring on chest radiograph • Programs unable to deliver 9 months A minimum of 270 doses must be administered within 12 months 51 Alternative regimens for LTBI Drug Dose Frequency Duration Requirements Isoniazid 900 mg Adults-15 mg/kg Children 20-40mg/kg Twice weekly 9 months DOT Isoniazid 900 mg Twice weekly 6 months DOT Rifampin with or without INH* 600 mg Adults-10 mg/kg Children 10-20 mg/kg Daily 4 months Immunocompetent Rifampin 600 mg Daily 6 months Children or immunocompromised *Combined use with rifampin/INH x 4 months is the preferred regimen by some TB programs for patients with abnormal CXRs consistent with old TB 52 Severe liver injury: 2-month Rifampin-Pyrazinamide LTBI regimen 53 Hepatic adverse drug effects of isoniazid (INH) • Frequent (10-20%): Asymptomatic liver enzyme elevations - Levels usually return to normal after completion of treatment MMWR June 9, 2000; 49(No. RR-6): 39 • Infrequent (~0.1%): Hepatitis Large-scale study: • 11,141 treated with INH from 1989-1995 • 11 had hepatitis, no deaths • Overall rate was 1 per 1000 0.1%! Nolan CM, Goldberg SV, Buskin SE. JAMA. 1999;281(11):1014-8. 54 Monitoring of patients on LTBI treatment Baseline and monthly laboratory testing not needed except for patients with: • • • • • HIV infection Pregnancy or postpartum (1st 3 months after delivery) History of liver disease/heavy alcohol use Chemotherapy Taking other medication that is potentially liver toxic Monthly monitoring: • Adherence with therapy • Symptoms of adverse drug reactions: “Nausea, anorexia, fatigue, yellow skin or eyes, dark urine? Allergic reactions?” • Plans to continue treatment 55 INH and peripheral neuropathy: Who needs Vitamin B6 (pyridoxine) • Adults: • • • • • • Diabetes Uremia Alcoholism HIV Malnutrition Pregnant or breastfeeding • Seizure disorder • Children: • Exclusively breastfed • Milk and meat deficient diet • Symptomatic HIV • Anyone with symptoms of peripheral neuropathy 56 What about drug resistant LTBI, refusal of treatment, or intolerance? Contacts of INH-resistant TB: 4-6 months of rifampin (longer for children and immunocompromised) Contacts of MDR-TB: Consult an expert! Regimen based on index cases susceptibility results If treatment is not available, refused or not tolerated Thoroughly educate patient: • TB signs and symptoms and how, when, and where to go if they develop • Current and future risk of TB if medical risks develop • Close clinical monitoring for 2 years is recommended for contacts and converters 57 Treatment of LTBI in special situations • Use rifabutin when rifampin is contraindicated or compromises patient care because of drugdrug interactions (eg. HIV on protease inhibitors, methadone users, transplant patients on cyclosporin, etc) • For persons intolerant of INH, use 4 months of rifampin (6 months for children and immunocompromised) • Pregnancy is not a contraindication to LTBI treatment with INH or rifampin 58 TB window prophylaxis Window: time between TB infection and fully developed cellular immunity (TB test is falsely negative) Who needs window prophylaxis? • High-risk TB contacts (young children and immunocompromised/HIV+) with initial ΘTB test and significant TB exposure When can window treatment be discontinued? • HIV-negative children: 8-10 weeks after contact broken to untreated case and repeat TB test negative • Immunocompromised/HIV: Unclear; repeat testing may not be helpful because of false negative results 59 Retreatment of Latent TB Infection • Re-infection can occur • Serious issue for immunocompromised individuals • Definitely recommended for persons with chronic immune suppression (e.g. HIV infection, drug induced, etc.) • Retreatment should be based on the severity of exposure, health status, and age of patient 60 Counseling a patient with LTBI Don’t say: • “You’ve been ‘exposed’ to TB so you need to be treated.” Say instead: • “You have been exposed and infected with the TB bacteria. But don’t worry…” 61 Counseling a patient with LTBI (2) Good news: • “You do not have the disease and you are not contagious to anyone.” Bad news: • “However, it is sleeping in your body and if you don’t treat it now, it can wake up later and make you very ill and contagious to others.” 62 Counseling a Patient with LTBI (3) Why get treated? • “Treatment will prevent future disease and protect you and those close to you.” Warning • “Taking medication for 9 months is a long time, but it takes that long to kill all the TB germs.” • “ TB germs are ‘TOUGH bugs’ … so take your medicine correctly and completely.” 63 Counseling a patient with LTBI (4) “INH treatment is safe but all medications, even over-the-counter drugs, can have side effects” “Be safe “ § “Avoid alcohol and acetominophen-containing products” § “Stop treatment and seek care immediately if anorexia, nausea or a diffuse rash develops (symptoms are reversible!)” Prior to leaving the office: Ensure that your patient understands what to monitor for and what to do if side effects occur 64 Meeting the challenge of LTBI For every patient… § Assess TB risk factors § If risk is present, perform a TB test § If TB test is positive, rule out active TB disease § If active TB disease is ruled out, evaluate as candidate for LTBI treatment § If good candidate, initiate treatment for LTBI § If treatment is initiated, ensure monthly monitoring and completion 65 Summary § TB will remain a primary care issue until better § control is established outside of the U.S. Targeted testing and treatment of LTBI is a key strategy to eliminate TB in the U.S. § The specificity of the new blood test for TB offers a significant advance in our ability to accurately diagnose LTBI § Final pearl: Absence of TST reaction or negative IGRA does not exclude disease 66 Resources for TB medical consultation § Local TB program § Your Regional Training and Medical Consultation Center § For the Western Region: Francis J. Curry National TB Center TB Warmline (415) 502-4700 or (877) 390-6682 67