Tuberculosis Case Management for Public Health Nurses Bloomington, Minnesota April 26-28, 2006 Diagnosis and Management of Latent TB Infection Barbara J. Seaworth, MD April 26, 2006 DIAGNOSIS AND MANAGEMENT
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Tuberculosis Case Management for Public Health Nurses Bloomington, Minnesota April 26-28, 2006 Diagnosis and Management of Latent TB Infection Barbara J. Seaworth, MD April 26, 2006 DIAGNOSIS AND MANAGEMENT OF LATENT TB INFECTION Barbara J Seaworth MD Medical Director Heartland National TB Center Professor of Medicine University of Texas Health Center Tyler 1 Evaluation of a B1 Refugee Young woman from Uzbekistan Abnormal CXR prior to immigration Negative sputum smear prior to immigration Referral to local health department in US Denies prior treatment for tuberculosis How should she be evaluated and managed? March 8, 2005: 30 yr old refugee from Uzbekistan How Good is Our Management of Refugees? 2 Evaluation and Management of a B1 Refugee CXR in US: abnormal right apex age and significance undetermined Medical evaluation: unremarkable Denies symptoms of tuberculosis No adenopathy TST positive Husband and 2 young children also TST + Sputum smear and culture: negative INH treatment for LTBI ordered for 9 months Guidelines on Diagnosis and Treatment of LTBI ATS/CDC. Treatment of Latent TB April 2000 American Academy of Pediatrics. Targeted Tuberculin Skin Testing and Treatment of LTBI in Children & Adolescents. Pediatrics 2004; 114:No4 October 2004 ATS/CDC/IDSA. Controlling Tuberculosis in the U.S. November 2005 NTCA/CDC. Guidelines for the Investigation of Contacts of Persons with Infectious Tuberculosis. December 2005 CDC. Guidelines for Using the QuantiFERON-TB Gold Test for Detecting Mycobacterium tuberculosis Infection, United States. December Latent Tuberculosis Infection (LTBI) Infection without disease. Tuberculosis elimination in the U.S. depends on accurate diagnosis of LTBI. Diagnosis of LTBI currently depends on Tuberculin Skin Testing. Tuberculin Skin Testing One of (very) few diagnostic tests currently employed that was developed in the last century. Purified Protein Derivative : Extraction of protein from autoclaved MTB. PPD-S: All current material bioequivalent to standard lot. 4 Tuberculin Skin Testing Injection of PPD. Infiltration of previously sensitized lymphocytes circulating in blood. Accumulation CD 4 +, CD 8 + T lymphocytes. Release of inflammatory mediators: Erythema, Edema. Tuberculin Skin Testing False Negative Results TECHNICAL Material: Inadequate dose, improper storage. Administration: Material not injected. Reading: Inexperience, too early or late BIOLOGICAL Viral Infection HIV Malignancy: Lymphoma, Leukemia Therapy: Steroids, Chemotherapy Age: Newborn, Elderly Other: Malnutrition, Renal failure, Sarcoid 5 Tuberculin Skin Testing False Positive Results Mycobacterial exposure other than Tuberculosis. BCG (M. bovis Bacille Calmette Guerin) Vaccination Nontuberculous Mycobacterial (NTM) Infection / Disease. Tuberculin Skin Testing Cross Reactivity Mycobacteria contain many similar proteins (Antigens) Exposure to BCG or NTM, sensitizes lymphocytes and primes response to PPD, which contains many antigens found in all mycobacteria. 6 Tuberculin Skin Testing INTRA Observer variability (Same Reader) 1-2mm INTER Observer variability (Different Readers) 2-4mm Tuberculin Skin Testing Cross reactivity with BCG and NTM. Requires two visits. Experienced personnel needed for placement and interpretation. Different cut-offs for positive test. 7 Induration of 5mm Considered a Positive TST HIV positive persons Recent contacts of TB cases Fibrotic Changes on CXR c/w old (not treated) TB Patients with organ transplants or other immunosuppression Prednisone therapy 15 mg/day 1 month Induration of 10mm Considered a Positive TST Recent arrivals ( 5 yrs) high prevalence countries IVDU Residents/employees - high-risk congregate facilities (health care, prisons, shelters, etc.) TB lab personnel Persons with high-risk medical conditions Children 4 yrs or exposed to adults at risk 8 Induration of 15mm Considered a Positive TST Persons with no risk factors Usually shouldn t be tested unless as part of baseline assessment for those at risk due to jobs in high risk settings QuantiFERON-TB Gold FDA approval May 2, 2005 CDC July 2005 expert panel recommends: QFT-G may be used in all circumstances in which the TST is currently used, including contact investigations, evaluation of recent immigrants, and sequential-testing surveillance programs for infection control» MMWR December 16, QuantiFERON-TB Gold Test PROS Requires only one visit. Simple format. More objective than PPD skin testing. More specific for M tuberculosis CONS Clinical experience limited. Targeted Tuberculosis Antigens Early secreted antigenic target 6KD protein (ESAT-6). Culture filtrate protein 10 (CFP-10). Absent from BCG. Absent from most NTM (M. kansasii, M. marinum, M. szulgai). 10 Quantiferon Blood Test For LTBI Blood is incubated with synthetic peptides simulating 2 proteins present in M tuberculosis: ESAT-6 and CFP-10, a positive control (Mitogen) and a negative control (Placebo). Persons with LTBI: ESAT-6 and/or CFP-10 stimulate primed lymphocytes to produce Interferon Gamma IFNγ. The Quantiferon test uses an ELISA test to measure the amount of IFNγ after exposure to antigens compared to that of cells stimulated with, Mitogen and Placebo (nil). When To Use The QuantiFERON- Gold Test Anytime a TST can be used Some experts disagree with use in special circumstances until more knowledge is available, i.e. children, HIV + If Quantiferon is positive, confirmatory TST is not needed. Chest x-ray and evaluation for active tuberculosis. If no tuberculosis, treat for LTBI. 11 Interpretation of QFT-G Results MMWR December 16, 2005 QuantiFERON-TB Gold Test More specific than previous Quantiferon test and PPD skin test. Equal or greater sensitivity than PPD skin test in most populations tested. 12 QuantiFERON-TB Gold Cautions and Limitations Contacts to infectious TB should have a negative QFT-G repeated 8-10 weeks after end of exposure Window period prophylaxis should be given as with a negative TST Because of the greater specificity, QFT-G is expected to indicate a smaller proportion of contacts as infected than a TST QuantiFERON-TB Gold Cautions and Limitations A greater rate of positive results has been reported with TST than with QFT-G in persons with and without recognized risks for M TB infection, except for patients who have culture proven TB disease May be explained by: Greater specificity of QFT-G Greater sensitivity with TST Both greater specificity of QFT-G and greater sensitivity of the TST 13 QuantiFERON-TB Gold Cautions and Limitations The reproducibility of the QFT-G is less when the measured amount of IFN-gamma is near the test s cut-off point Detection of substantial amounts of released IFN-gamma in the nil sample disallows arriving at a negative test result An indeterminate test can be due to: a low mitogen response with low response to antigens (similar to anergy with TST) increased response to control (nil). QuantiFERON-TB Gold Cautions and Limitations An indeterminate QFT-G result does not provide useful information regarding the likelihood of M TB infection. The optimal follow-up of persons with indeterminate QFT-G results has not been determined For persons with an increased likelihood of M TB infection administration of a 2 nd test, either a TST or QFT-G might be prudent Labs should report reason for the indeterminate result 14 QuantiFERON-TB Gold Cautions and Limitations As with the TST, if TB disease is suspected, additional diagnostic evaluation should be done before or at the same time as the QFT-G and should not be delayed while awaiting QFT-G results QuantiFERON-TB Gold Future Research Needs Performance of QFT-G in children 5, those with impaired immune function, & in groups undergoing periodic screening. Determination of the subsequent incidence of TB disease after LTBI is diagnosed or excluded with QFT-G. Length of time between exposure, establishment of infection, and emergence of a positive QFT-G test. Ability of QFT-G to detect reinfection after treatment for LTBI and disease. Changes in QFT-G results during therapy for LTBI and disease. Performance of QFT-G in targeted testing programs. 15 Elispot Test Also based on ESAT-6 and CFP-10 stimulation of primed lymphocytes. Does not quantitate INFγ in supernatants of cells. Assay quantitates the number of INFγ producing cells. Currently requires separation of cells from blood (Automated system developed). Not FDA approved in US, used in Europe Why Is Testing for TB Now Recommended Only For Select Populations or Groups? Declining TB resources led to need to focus on those activities that are most likely to be effective and lead to a decrease in the incidence of tuberculosis Identification of those with LTBI most at risk of progression to disease limits treatment to those most likely to benefit Treatment of those whose risk of disease is greater than the risk of toxicity from medication 16 Who Should be Tested for TB Infection? Contacts of persons with active TB Persons with medical risk factors that increase risk of progression to disease Targeted testing of high risk individuals and groups to identify those at risk of recent infection Foreign born who entered US in last 5 years High risk populations where transmission of TB likely to have occurred Underlying Medical Conditions Which Increase Risk for Progression to Active TB Disease. HIV infection Chronic renal failure Transplant recipients Diabetes mellitus Malignancy TNF Alpha blocker therapy Immunosuppressive Rx 15 mg Prednisone/day Silicosis 17 Percentage of Foreign Born TB by Years in U.S., TX Percent Years in the U.S. 37.8% in U.S. 5yrs, 45.7% in U.S. 10 yrs or more Identification of Priority Subpopulations Jurisdictional TB-control agency identifies pockets of high TB risk through epidemiologic analysis and profiling Populations at risk separated into 3 tiers: Incidence of TB Prevalence of TB Risk for acquiring TB disease if infected Likelihood of accepting & adhering to LTBI treatment Ease of access to the population In a congregate setting, consequence of transmission 18 Priorities for Targeted Testing and Treatment of LTBI Tier 1 Persons working in or served by clinics or CHOs providing care to HIV-infected persons Prisoners Legal immigrants and refugees with Class B1 & B2 TB notification status Recently arrived refugees Well defined groups in congregate living facilities Persons enrolled in substance abuse treatment programs Priorities for Targeted Testing and Treatment of LTBI Tier 2 Jail detainees Persons working or living in homeless shelters Immigrants reporting for adjustment of status 19 Priorities for Targeted Testing and Treatment of LTBI Tier 3 Other foreign-born persons at high risk (i.e. those that immigrated 5 years from countries with a high incidence of TB Contacts of Active TB Case Among close contacts approximately 30% have LTBI and 1-3% have active TB disease Without treatment, approximately 5% of contacts with newly acquired LTBI progress to TB disease within 2 years Examination of contacts is one of the most important activities for identifying persons with disease and with LTBI 20 Who Should Be Treated for LTBI? Treatment of those most at risk of progression to active TB breaks the chain of transmission INFECTION -LTBI: Class Two Those at risk of TB who are: TST Positive, CXR normal, asymptomatic Sputum, if done, negative TREATMENT RECOMMENDED for: Positive at 5 and 10 mm cut-points unless contraindication Close Contacts of active case TST Converter (10 mm increase) New guidelines - no mention of age as a factor 21 Identifying Those at Highest Risk for Activation of LTBI Underlying medical conditions which increase risk for progression to active disease. HIV infection Chronic renal failure Immunosuppressive Rx Diabetes mellitus Malignancy Silicosis TNF Alpha Blockers Transplant recipients 15 mg Prednisone/day Recent infection Contacts of active infectious cases of TB High risk populations Recent immigrants from high prevalence areas National Performance Measures and Objectives for TB Control Increase the percentage of contacts of persons with infectious (AFB sputum +) TB who are placed on treatment for LTBI and complete a treatment regimen Objective (2005): 61% Performance (2000): 57% National data CDC, How Should Immunosuppressed Persons at Risk of TB Be Managed? Neither TST or QuantiFERON-Gold is able to detect many persons with infection or disease High incidence of suspicion Consider empiric therapy TNF alpha Antagonists Block TNF alpha activity which is required for granuloma formation and control of M TB infection Used for rheumatoid arthritis, Chron s disease, psoriasis and a variety of other immune mediated diseases Remicaid (inflixamab) Embril (entanercept) Humira (adalimubab) 23 Warning: Risk Of Infections Infliximab Tuberculosis (frequently disseminated or extrapulmonary at clinical presentation), and other opportunistic infections have been observed in patients receiving Remicade some of these infections have been fatal. Patients should be evaluated for LTBI with a TST. Treatment of LTBI should be initiated prior to therapy with Remicade. SEE WARNINGS» PDR 2004 Warnings Remicade should not be given in patients with a clinically important active infection. Caution when considering the use of Remicade in patients with a chronic infection or a history of recurrent infections. Patients should be monitored for signs and symptoms of infection while on or after treatment with Remicade. If a patient develops a serious infection Remicade should be discontinued.» PDR TB in Patients treated with TNF-á Monoclonal Antibodies 70 cases of active TB reported in patients treated with infliximab (up to 5/29/01) TB developed after median of 12 weeks 48 developed disease after 3 or less infusions 48/70 (69%) had extra pulmonary disease 17 disseminated 11 lymphatic, 4 peritoneal, 2 pleural 1 each meningeal, enteric, paravertebral, bone, genital and bladder Confirmed by biopsy in 33 patients 12 patients died despite stopping TNF-á antagonist» Keane N Engl J Med 2001; 345: TB in Patients treated with TNF-á Antagonists 47 additional cases reported to FDA for a total of 117 cases through Nov 30, Relative risk estimated increased 2 to 4 times» Letter to editor N Engl J Med 2002;346: cases reported in California 1/02-8/03» MMWR August reports to FDA by March 2003 Lifetime risk estimate 15-20% if 35yr & TST 15» Horsburgh. N Eng J Med TB in Rheumatoid Arthritis and Effect of TNF-á Antagonists TB incidence in 6,460 infliximab treated patients followed prospectively in Spanish data base 61.9/100,000 No cases with other agents TB incidence in 10,782 patients prior to widespread use of infliximab 6.2/100,000 Marked decrease in TB with use of screening No cases in patients who had had TST or prophylaxis» Gomez-Reino Arthritis Rheum 2003; 48: Unknown Beyond the Guidelines Does treatment of LTBI need to be completed prior to use of TNF- antagonist? Unknown Does a person at risk of TB who is TST negative need to be treated? Consider treatment of high risk TST negative patients No need to continue INH after completion of treatment for LTBI 26 Targeted Testing and Treatment of LTBI Effectiveness as a public health measure in US is limited by: Concern of drug toxicity Poor acceptance by medical professionals Poor adherence by patients Two approaches to increase: Clinic-based testing of persons with medical risk factors who are under physician s care Establish specific programs that target subpopulations Good Treatment of Patient at Risk for TB Depends on: Correct diagnosis Information must be complete and correct Exclusion of active TB before treating LTBI 27 Exclusion of Active Tuberculosis Absence of symptoms Negative CXR Negative medical evaluation Order and wait for sputum culture if any question Duration of therapy What is the duration of therapy that provides the maximum degree of protection against developing TB? 28 INH Therapy for LTBI Two studies suggest efficacy for therapy between 6 and 9 months USPHS study of household contacts TST+ after 9 years the reduction in active TB was 68% for those that took 80% of meds for 10 months 16% for those that took 80% for less time There was an indication that the total length of time that meds were taken was more important than the intensity of the pill taking Duration of INH Therapy of LTBI IUAT study of 3, 6 and 12 months Placebo controlled study in patients with fibrotic pulmonary lesions c/w inactive TB Expressed benefits in two ways intention to treat which assesses both efficacy of drug and ability to get patients to take it efficacy in treatment completers-compliers 29 Duration of INH Therapy for LTBI IUAT study of INH 3, 6 or 9 months Reduction in culture positive TB at 5 years all participants 6 months therapy 65% 12 months therapy 75% Bulletin WHO, 1982 Duration of INH Therapy for LTBI IUAT study of INH 3, 6 or 9 months Reduction in culture positive TB at 5 years in the group of completer-compliers 6 months therapy 69% 12 months therapy 93% Bulletin WHO, How Much Isoniazid Is Needed for the Prevention of Tuberculosis? Case rate % Longer durations of therapy corresponded to lower TB rates among those who took 0-9 mo No extra increase in protection among those who took 9 months Months of therapy Community based study, Bethel Alaska Comstock GW, Int J Tuberc. Lung Dis 3: Data on INH Therapy for LTBI IUAT study of INH from cost-effectiveness 6 months nearly as good as 12 months Snider, JAMA, Treatment of LTBI Treatment regimens: INH x 9 months Alternative: Rifampin 600mg daily x 4 months for adults, 6 months for children and HIV+ Possible: INH & Rifampin x 3 to 4 months INH, Rifampin, EMB & PZA x 2 months Has been: Rifampin/PZA x 2 months New? Rifapentine & INH weekly x 12 mo Rifampin/PZA Generally Should NOT BE USED! Extensively tested only on HIV + 50 patients with serious hepatotoxicity 12/50 (24%) died Routine LFT s did not prevent Rifampin and PZA should continue to be given as part of multi-drug RX regimens DTBE has a national surveillance system or 32 Rifampin/PZA for LTBI Baseline AST and bilirubin and at 2, 4 and 6 weeks Assessment by a health care provider at 2, 4, 6 and 8 weeks Education by a provider conversant in the patient s language at each visit to STOP medication and seek consultation for any abdominal pain, nausea, emesis, jaundice, unusual fatigue or loss of appetite RIFAMPIN/PZA for LTBI Provider continuity is recommended Assessment in person Only 2 week medication supply PZA dose of less than or equal to 20 mg per kg or no more than 2 grams 33 SCRIPT STUDY Hepatitis Rates in 589 HIV neg. Patients RIF/PZA (N=307) INH (N=282) P Hepatitis Mild ( 50 AST 250) 38 (12%) 30 (11%) Moderate (any AST 250) 14 (5%) 0 (0%) Severe (symptoms + AST) 2 (1%) 2 (1%) TOTAL 54 (18%) 32 (11%) 0.03 Discontinuation of meds due to hepatitis Jasmer et al. Ann Intern Med 2002; 137:640. SCRIPT STUDY Lost to follow-up Less than 50% of prescribed treatment More than 50% of prescribed treatment Completed treatment % of Patients Rifampin/Pyrazinamide Isoniazid Jasmer et al. Ann Intern Med 2002;137: Discontinue Rif-PZA Immediately & Do Not Restart ALT 5 x normal in asymptomatic patient ALT normal with symptoms of hepatitis Serum bilirubin normal with or without symptoms What About A Positive TST and No History of Exposure? 35 What Drug Should I Use in Patients From Areas with a High Incidence of Drug Resistance? Management of Contacts Who Have an Initial Negative TST Close Contacts Asymptomatic with a negative CXR Treatment with INH should be started for: HIV Infected Children 5 Significant Immunosuppressant Repeat TST in 3 months for all others Symptomatic Evaluate for Active TB CXR, smears and culture If a TB suspect, treat for TB disease 36 LTBI with abnormal CXR CLASS 4 - TB Not Clinically Active Exclude active disease Abnormal but stable CXR findings ( 2-3 mo) NODULES/ FIBROTIC LESIONS OF OLD TB PLEURAL THICKENING CALCIFIED GRANULOMA BRONCHIECTASI
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