Tuberculosis Overview

Transcription

1 1/18/2011 Handling TB and HIV Co-Infection Fargo, North Dakota September 15-16, 2010 Tuberculosis Overview Dean Tsukayama, MD September 15,

2 Questions to answer in evaluation of tuberculosis 1. TB or not TB? 2. Infection or disease? 3. What treatment is needed? 4. Risk of transmission to others?

3 Natural History of Tuberculosis Death Susceptible Active disease Infected Latent infection Transmission of infection

4 Evaluating a Test TP- True Positive TN- True negative FP- False positive FN- False negative Test Performance Infection Yes No Positive TP FP Test Negative FN TN Positive predictive value = TP/(TP+FP) Negative predictive value = TN/(TN+FN) Sensitivity = TP/(TP+FN) Specificity = TN/(TN+FP)

5 Importance of Prevalence in the Population Population = 1000 Yes Infection No Sensitivity -90% Specificity- 90% Sensitivity -90% Specificity- 90% Yes Infection No Test Positive Negative Test Positive Negative Prevalence - 30% Infection- 300 PPV - 79% NPV - 95% Prevalence - 5% Infection - 50 PPV - 32% NPV - 99%

6 Likelihood Ratio and Post-test Probability Population = 1000 Prevalence 30% 5% Infection Positive LR 9 9 Negative LR 1/9 1/9 Assume: sensitivity = 0.90 specificity = LR = sensitivity/(1-specificity) -LR = 1-sensitivity/specificity Post-test odds of infection with a positive test Post-test odds = LR x pre-test odds Post-test probability of infection with a positive test 73% 31% Post-test odds of infection with a negative test Post-test probability of infection with a negative test 0.3/9 0.05/9 3.2% 0.6%

7 TB or not TB? Risks for infection How likely is TB in your patient? MMWR 59 (RR-5), 2010

8 TB incidence Top 30 Countries Global - 136/100,000 Swaziland South Africa Djibouti Zimbabwe Namibia Lesotho Sierra Leone Country Incidience Other countries of interest China 100 El Salvador 51 India 168 Zambia Botswana Iraq 168 Cambodia Mozambique Laos 155 Togo Cote d Ivoire Liberia 301 Gabon Congo Korea 96 Rwanda Democratic Republic of Congo Ethiopia Burundi Kirbati Kenya Malawi Central African Republic North Korea Mexico 23 Pakistan 181 Philippines 291 Russia 119 Thailand 142 Uganda Timor-Leste Somalia 224 Mali Mauritania USA 5 Nigeria Haiti Vietnam 175

9 Britain beat TB in the 19th and 20th centuries? Much of the (slow) decline preceded drugs C Bronte 1855 TB deaths/100,000/yr Keats 1821 E Bronte 1848 Lawrence 1930 Mansfield 1923 Orwell 1953 Leigh From Christopher Dye: Global Epidemiology of Tuberculosis

10 Reported TB Cases* United States, ,000 No. of Cases 23,500 19,000 14,500 10, Year *Updated as of April 23, 2008.

11 Reported TB Cases by Origin and Race/ Ethnicity,* United States, 2007 U.S.-born American Indian or Alaska Native (3%) Asian (2%) Foreign-born** White (5%) White (33%) Hispanic or Latino (38%) Asian (43%) Native Hawaiian/Other Pacific Islander (<1%) Hispanic or Latino (17%) Black or African American (45%) Black or African American (13%) *All races are non-hispanic. Persons reporting two or more races accounted for less than 1% of all cases. **American Indian or Alaska Native and Native Hawaiian or Other Pacific Islander accounted for less than 1% of foreign-born cases and are not shown.

12 Tuberculin Skin Test (TST) Standard test for diagnosing TB infection May not react for 8-10 weeks Cannot distinguish latent from active Negative test does not rule out active disease Booster effect from old TB infection or BCG

13 TST Interpretation

14 Tuberculin Skin Test False-positive Non-tuberculous mycobacteria BCG Improper reading False-negative Active tuberculosis Cell-mediated immunosuppression by disease medication extremes of age Some chronic diseases (A) Severe or febrile illness (B) <1 month after live virus vaccine (C) some illnesses (D) Improper placement or reading A. Chronic renal failure, cirrhosis, malnutrition, sarcoidosis B. Includes tuberculosis C. MMR, Polio, Yellow Fever D. Measles, mumps, rubella, varicella, mononcleosis, typhoid, brucellosis, influenza

15 Interferon gamma release assays Measures release of interferon gamma by lymphocytes to stimulation by specific MTB antigens- ESAT-6, CFP-10, TB7.7(QFT only) Test has positive and negative controls No cross-reactivity with BCG or Mycobacterium avium-intracellulare Cross-reactive with M. bovis, M. kansasii, M. marinum, M. szulgai Blood test, requires only one visit Two approved tests- Quantiferon and T-Spot

16 Latent Tuberculosis NO GOLD STANDARD FOR DIAGNOSIS

17 Test Sensitivity (%) Active TB Disease TST QFT T-Spot 70 81* 84* 88* 89* *in developed countries Diel et al. Chest 137:952, 2010 Metaanalysis of commercial IGRAs Sensitivity based on detection of active disease

18 Test Specificity (%) TST QFT T-Spot Korea Germany Japan (81) - Diel et al. Chest 137:952, 2010 From primary references in article

19 Test Specificity (%) TST QFT T-Spot Diel et al. Chest 137:952, 2010

20 CDC Guidelines for IGRA Use 2010 QFT-G may be used in place of (but not in addition to) a TST in all situations in which CDC recommends TST as an aid in diagnosing MTB infections... Performance of IGRA may be decreased in immunocompromised patients, including children less than 5 years old MMWR 59 (RR-5), 2010

21 2010 CDC Recommendations for IGRA MMWR 59 (RR-5), 2010 IGRA preferred likelihood that TST will not completed Patient has received BCG vaccine TST preferred Children less than 5 years old No preference Contact investigation Regular screening Both TST and IGRA can be considered High risk for TB infection or disease After positive TST in patient with BCG vaccination Indeterminate or borderline IGRA

22 Possible Scenarios 2 year old child from Somalia, had BCG vaccine, TST-10 mm 36 yo man with AIDS, close contact with recently diagnosed case of pulmonary tuberculosis, TST- 0 mm. 25 yo woman, born in US, no risk factors for exposure to TB, has screening TST of 13 mm.

23 Questions to answer in evaluation of tuberculosis 1. TB or not TB? 2. Infection or disease? 3. What treatment is needed? 4. Risk of transmission to others?

24 Infection or Disease? LI ID AD TD Latent infection Inactive disease Active disease Treated disease KEEP IN MIND: Cannot give one drug to a person with active disease Tuberculosis is not always pulmonary Do not need to make an immediate decision Others may be at risk Active tuberculosis is a reportable disease

25 Infection or Disease? Gathering information History Symptom review Physical findings CXR AFB Culture Histology Other imaging Response to treatment MMWR 59 (RR-5), 2010

26 Relative Risk of Reactivation CR Horsburgh. NEJM 350:

27 Infection or Disease? History Risk for infection Contact of recent case Family history of TB Liver and kidney function Medications Symptom Review Fever, fatigue, night sweats, weight loss Cough, chest pain, hemoptysis Other sites Physical Exam Eyes Lymph nodes Chest Liver Neurological AFB smear and culture Negative smear may still be culture-positive Positive smear may be NTM Culture needed for complete susceptibility testing Other Tests CT scan Bronchoscopy Fine needle aspiration/biopsy Gastric aspirate Thoracoscopy Endoscopic ultrasound Nucleic acid amplification Molecular tests for INH and RIF susceptibility

28 Evaluation of Tuberculosis Management Options Obtain or repeat diagnostic studies Wait for final culture results Work up for extrapulmonary tuberculosis No further testing or treatment Treat latent tuberculosis Treat active tuberculosis - Assess need for respiratory isolation - Assess need for evaluation of vulnerable contacts

29 Questions to answer in evaluation of tuberculosis 1. TB or not TB? 2. Infection or disease? 3. What treatment is needed? 4. Risk of transmission to others?

30 What treatment is needed? History Symptom review Physical examination AFB culture results Drug susceptibility results Molecular tests for INH and RIF resistance Patient input Latent TB Active Disease Site of infection Risk of drug-resistant TB Hepatic and renal function Risk of adverse drug effects Possible drug interactions

31 Pathogenesis of TB Sequence of events Host Defense Initial encounter in lung, may be controlled by alveolar macrophages Innate immunity If infection established, intracellular AFB carried to hilar lymph nodes AFB multiply in lymph nodes and spread hematogenously throughout the body Immunity is activated, killing and confining AFB in granulomas (latent infection) Cell-mediated immunity TNF alpha Granuloma breakdown results in reactivation disease

32 Latent TB in the US Total US Population (190M) Latent TB Active TB + 50,000 new cases of active TB per year Model developed in Percent LTBI in population- 13% (25000K) 2. Annual reactivation TB from LTBI- 0.16% (40K) 3. New infection from each new active cases- 3 (120K) 4. New active disease from new infections- 8% (10K)

33 Latent Tuberculosis Treatment

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35 Treatment of Tuberculosis. MMWR 52/RR-11

36 Treatment of Tuberculosis. MMWR 52/RR-11

37 Extrapulmonary Tuberculosis

38 Treatment Regimens Length of Treatment 4 mo Culture-negative 6 mo Must include RIF and PZA 9 mo CNS TB Bone TB Failure to clear sputum culture in 2 months PZA for less than 2 months HIV patient (?) 12 mo Cannot use RIF mo MDR TB Treatment completion determined by number of doses of therapy

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40 Special Situations Pediatric Pregnancy More likely to have primary disease More likely to have disseminated disease Less likely to transmit infection Often do not have culture results Aminoglycoside not recommended for use PZA not recommended for use (US) Risk for congential transmission (small) Kidney disease Liver disease Refusing treatment Usual doses of INH and RIF Increase dosing interval for PZA, ETB, aminoglycosides Risk for catastrophic hepatitis INH, RIF, PZA all have potential liver toxicity Need MDR regimen to avoid all hepatotoxic agents Be creative, work with patient in choosing treatment alternatives Consider the possibility of mental impairment in your patient Know the state law that pertains to TB treatment

41 KwaZulu Natal Gandhi et al. Lancet 368:1575, cases of extensively drug-resistant tuberculosis reported from a hospital in South Africa Represented 6% of all patients with culture-confirmed tuberculosis All 44 patients tested for HIV were positive 52 patients died The mean time to death was 16 days from the time of diagnosis 55% had no prior TB treatment 67% had a recent hospital admission

42 Drug Resistance Treatment failure (%) Pansensitive 0.9 Single drug resistance 8 Polydrug resistance 21 Multidrug resistance Extensive drug resistance Lew. Ann Intern Med 149:123, Orenstein. Lancet Infect Dis 9:153, Jacobson. Clin Infect Dis 51:6, 2010

43 TB Drugs isoniazid rifampin pyrazinamide ethambutol injectable agent* quinolone** ethionamide cycloserine PAS streptomycin * amikacin, kanamycin, capreomycin ** levofloxacin, moxifloxacin

44 MDR-TB Multi-Drug Resistant isoniazid rifampin pyrazinamide ethambutol injectable agent* quinolone** ethionamide cycloserine PAS streptomycin * amikacin, kanamycin, capreomycin ** levofloxacin, moxifloxacin

45 XDR-TB Extensively Drug-Resistant isoniazid rifampin pyrazinamide ethambutol injectable agent* quinolone** ethionamide cycloserine PAS streptomycin * amikacin, kanamycin, capreomycin ** levofloxacin, moxifloxacin

46 Questions to answer in evaluation of tuberculosis 1. TB or not TB? 2. Infection or disease? 3. What treatment is needed? 4. Risk of transmission to others?

47 Natural History of Tuberculosis Death Susceptible Active disease Infected Latent infection Transmission of infection

48 concentration of infectious particles duration of infectious period Environment volume of space ventilation vulnerability to acquiring infection Infectiousness of pathogen Environment Case smear positive cavitary disease duration of symptoms before diagnosis Contact duration of exposure closeness of contact vulnerability to acquiring infection High risk contact HIV infection children <5 yo

49 Contact Investigation Contact Investigations average of 10 contacts per case 20-30% of all contacts have LTBI 1% have TB disease Determine infectious period- 3 months before onset of symptoms Prioritize contacts by duration and closeness of exposure, risk factors of contacts May take 8-10 weeks after exposure for TST to turn positive Window prophylaxis for children less than 5 years old, other immunocompromised patients Full prophylaxis for HIV-infected patients regardless of TST/IGRA 1 2 Beginning of infectious period End of infectious period End of exposure period 8-10 weeks TST administered 2 Needs second TST 8-10 weeks after last exposure

50 Pathogen virulence: Beijing strain In South African study, absent before 1965, rare until 1996, caused 13% of pediatric infections in 2000, 33% in 2003 Caused outbreak of MDR-TB in New York prisons and hospitals in 1990s Accounts for 50% of the TB strains in Asia and 13% worldwide Highly conserved genotype Parwati et al. Lancet Infectious Diseases 10:103; 2010

51 Outbreak of TB in 2008 Ramsey County Workhouse Exposure between April 17 and June inmates tested latent tuberculosis- 93 (35%) active disease- 7 (2.7%) Star Tribune August 17,2010

52 Natural History Epidemiology Drug resistance Questions to answer in evaluation of tuberculosis 1. TB or not TB? 2. Infection or disease? 3. What treatment is needed? 4. Risk of transmission to others? Diagnosis Treatment Transmission Patients at risk

53 CDC Guidelines MMWR Recomm Rep May 21;42(RR-7):1-8. MMWR Recomm Rep Apr 26;45 (RR-4):1-18. MMWR Recomm Rep Oct 30;47 (RR-20):1-58. MMWR Recomm Rep Jun 6;52 (RR-10):1-42. MMWR Recomm Rep Nov 4;54 (RR-12):1-81. Initial therapy for tuberculosis in the era of multidrug resistance. Recommendations of the Advisory Council for the Elimination of Tuberculosis. The role of BCG vaccine in the prevention and control of tuberculosis in the United States. A joint statement by the Advisory Council for the Elimination of Tuberculosis and the Advisory Committee on Immunization Practices. Prevention and treatment of tuberculosis among patients infected with human immunodeficiency virus: principles of therapy and revised recommendations. Centers for Disease Control and Prevention. Guidelines for environmental infection control in health-care facilities. Recommendations of CDC and the Healthcare Infection Control Practices Advisory Committee (HICPAC). Controlling tuberculosis in the United States. Recommendations from the American Thoracic Society, CDC, and the Infectious Diseases Society of America. MMWR Recomm Rep Dec 16;54 (RR-15):1-47. Guidelines for the investigation of contacts of persons with infectious tuberculosis. Recommendations from the National Tuberculosis Controllers Association and CDC. MMWR Recomm Rep Dec 30;54 (RR-17): Guidelines for preventing the transmission of Mycobacterium tuberculosis in health-care settings, 2005.

54 CDC Guidelines MMWR Recomm Rep Jul 7;55 (RR-9):1-44. Prevention and control of tuberculosis in correctional and detention facilities: recommendations from CDC. Endorsed by the Advisory Council for the Elimination of Tuberculosis, the National Commission on Correctional Health Care, and the American Correctional Association. MMWR Morb Mortal Wkly Rep Jan 16;58(1):7-10. Updated guidelines for the use of nucleic acid amplification tests in the diagnosis of tuberculosis. MMWR Recomm Rep Feb 13;58 (RR-3):1-43. Plan to combat extensively drug-resistant tuberculosis: recommendations of the Federal Tuberculosis Task Force. MMWR Recomm Rep Apr 10;58 (RR-4):1-207 Guidelines for prevention and treatment of opportunistic infections in HIV-infected adults and adolescents: recommendations from CDC, the National Institutes of Health, and the HIV Medicine Association of the Infectious Diseases Society of America. MMWR Recomm Rep Jun 25;59 (RR-5):1-25. Updated guidelines for using Interferon Gamma Release Assays to detect Mycobacterium tuberculosis infection - United States, 2010.