1. TB (Infection) or not TB? Who should we screen and treat? Primary Care Conference August 31, 2005 K. Mae Hla, M.D., M.H.S.

3. Learning Objectives Review guidelines for testing and treatment of LTBI using case examples Evaluate the rationale for targeted TST Discuss factors influencing TST results and interpretations Assess the evidence of current treatment recommendations for LTBI Updates on new tests and treatment recommendations

5. Case #1 43 year old female physician who underwent routine annual testing at UWHC: PPD was 10 mm. Previous year’s PPD was 0 mm. No known history of exposure but works with high risk patients No history of BCG No history of cough, low grade fever, night sweats or weight loss

6. What would you do with this patient?  Consider the test positive  Consider the test negative  Consider a Chest X-ray  Disregard test results if chest x-ray is negative since she’s older than 35 years

8. Case #2 32 year old man arrived from India 2 years ago TB tested during pre-employment exam 23 mm induration H/o BCG in childhood No symptoms of active TB

9. What would you do with this patient?  Positive TST is due to BCG  Old positive PPD  No need to consider for INH treatment since due to either of the above  Disregard BCG and recommend INH

11. What would you do now?  Positive TB test is due to BCG  Old positive PPD  No need to consider for INH treatment since due to either of the above  Disregard BCG and recommend INH – end of story  Test further

12. Case # 3 28 y.o. woman with SLE, ESRD, S/P kidney transplant on immunosuppressive therapy PPD placed during hospitalization with acute lung infiltrate was 6 mm Is this PPD positive or negative?

13. Case # 4 36 y.o. diabetic male, PPD 13 mm, recently in prison, known exposure to INH resistant TB, no known prior PPDs, no acute symptoms, CXR- negative.  Is this person at risk of developing TB?  What are his risk factors?  What would you recommend he be treated with?

14. Case # 5 30 y.o. male seen in clinic for naturalization physical Country of origin: England Hx of BCG at age 13 PPD: 11 mm induration, never been tested in past CXR normal

15. Case # 5  Consider his PPD positive  Consider his PPD negative  Consider his pos PPD to be due to BCG and not recommend INH  Disregard BCG and consider 9 months of INH

16. Case # 6 35 y.o. HIV positive male, PPD negative for past 2 yrs, tested 6 mm now; no known exposure history, no acute symptoms, CXR negative for active or old TB.  Is his PPD negative or positive?  How likely is he to develop active TB?

17. General Principles in Screening The disease is common (prior probability) The test is both accurate and reliable Treating the disease at an early phase will lead to improved outcome compared to that of treating it only when it manifests itself as active disease Treatment is feasible and not harmful

19. Reported TB Cases United States, 1953 - 1998 Year 10,000 20,000 * * 30,000 50,000 70,000 100,000 Cases (Log Scale) *Change in case definition 536070809098

20. Reported Cases of TB by Country of Birth - United States, 1986-1998 86 8788899091929394959697 98 0 5 10 15 20 25 30 35 40 U.S.-born All Cases Foreign-born Recent Cases per 100,000 population Year

21. Areas of Concern TB cases continue to be reported in every state Drug-resistant cases reported in almost every state Estimated 10-15 million persons in U.S. infected with M. tuberculosis –Without intervention, about 10% will develop TB disease at some point in life

22. Targeted TB Testing Identify persons with LTBI who would benefit by treatment of LTBI Find persons with TB disease who would benefit from treatment Groups that are not high risk for TB should not be tested routinely All testing activities should be accompanied by plan for follow-up care

23. Who should we screen? High Risk Groups for LTBI Groups that should be tested for LTBI regardless of age: Persons at higher risk for exposure to or infection with TB Persons at higher risk for TB once infected

24. Persons at Higher Risk for Exposure to or Infection with TB Close contacts of person known or suspected to have TB Foreign-born persons from areas where TB is common Residents and employees of high-risk congregate settings Health care workers (HCWs) who serve high-risk clients

25. Persons at Higher Risk for Exposure to or Infection with TB (cont.) Medically underserved, low-income populations High-risk racial or ethnic minority populations Children exposed to adults in high-risk categories Persons who inject illicit drugs

26. World Region of Origin TB Case Rates Rates US Residence <5 yr Rates US Residence >5 yr United States8.1-- Established market economies 4.76.04.7 Former socialist economies of Europe 11.214.913.7 India55.6108.235.8 Latin America33.768.430.8 Mainland China40.689.730.7 Middle East22.147.315.2 Other Asian countries81.8207.541.1 Sub-Saharan Africa58.4108.926.4 Total foreign-born30.666.321.7 TB Case Rates* according to the length of Residence in the U.S. for Foreign-Born Persons, 1986-1993 * Rates are per 100,000 person-years, adjusted for age.

28. Persons at Higher Risk of Developing TB Disease once Infected HIV infected Recently infected (converted within 2 yr) Persons with certain medical conditions Persons who inject illicit drugs History of inadequately treated TB

29. Incidence of active TB in persons with a positive PPD by selected risk factors Risk FactorTB Cases/1,000 person-years Recent TB infection Infection <1 yr past12.9 Infection 1-7 yr past 1.6 Human immunodeficiency virus (HIV) infection35.0-162 Injection drug use HIV seropositive76.0 HIV seronegative or unknown10.0

30. Relative risk* for developing active TB by selected clinical conditions Clinical ConditionRelative Risk Silicosis30 Diabetes mellitus 2.0-4.1 Chronic renal failure/hemodialysis10.0-25.3 *Relative to control population; independent of TB test status

31. Relative risk* for developing active TB by selected clinical conditions Clinical ConditionRelative Risk Gastrectomy 2-5 Jejunoileal bypass27-63 Solid organ transplantation Renal37 Cardiac20-74 Carcinoma of head or neck16 *Relative to control population; independent of TB test status

32. Are HCWs at high risk of LTBI? Prevalence of TB in the community, facility, institution Contact with high risk patients (HIV positive pts., injection drug users, homeless pts.) Increased risk in certain occupational groups (respiratory therapists) Individual risk factors (diverse workforce)

33. Test accuracy and reliability Prior probability of disease Method of administration Timing of reading Interpretation

34. Administering the Tuberculin Skin Test Inject intradermally 0.1 ml of 5 TU PPD tuberculin Produce wheal 6 mm to 10 mm in diameter Do not recap, bend, or break needles, or remove needles from syringes Follow universal precautions for infection control

35. Reading the Tuberculin Skin Test Read reaction 48-72 hours after injection Measure only induration Record reaction in millimeters

37. Classifying the Tuberculin Reaction >5 mm is classified as positive in HIV-positive persons Recent contacts of TB case Persons with fibrotic changes on chest radiograph consistent with old healed TB Patients with organ transplants and other immunosuppressed patients

38. >10 mm is classified as positive in Recent arrivals from high-prevalence countries Injection drug users Residents and employees of high-risk congregate settings (hospitals, prison, NH) Mycobacteriology laboratory personnel Persons with clinical conditions that place them at high risk Children <4 years of age, or children and adolescents exposed to high-risk adults

39. Classifying the Tuberculin Reaction (cont.) >15 mm is classified as positive in Persons with no known risk factors for TB HCWs otherwise at low risk for TB disease and who received baseline testing at start of employment

40. Factors that May Affect the Skin Test Reaction Type of ReactionPossible Cause False-positiveNontuberculous mycobacteria BCG vaccination False-negativeAnergy Recent TB infection Very young age (<6 months old) Live-virus vaccination Overwhelming TB disease Errors in application & interpretation

41. Boosting Some people with LTBI may have negative skin test reaction when tested years after infection Initial skin test may stimulate (boost) ability to react to tuberculin Positive reactions to subsequent tests may be misinterpreted as a new infection

42. Two-Step Testing If first test positive, consider the person infected If first test negative, give second test 1-3 weeks later If second test positive, consider person infected If second test negative, consider person uninfected Use two-step testing for initial skin testing of adults who will be retested periodically

43. BCG Vaccination and TST Tuberculin skin testing is not contraindicated in BCG-vaccinated persons Treatment for LTBI should be considered for any BCG- vaccinated person whose skin test reaction is >10 mm, if any of these circumstances are present: -Was contact of person with infectious TB -Was born or has resided in a country with high TB prevalence -Is continually exposed to populations where TB prevalence is high

44. BCG Effect vs. LTBI Case # 2 –Likely LTBI given country of origin and recent arrival Case # 5 –Likely BCG effect

45. New Test for Detecting LTBI QuantiFERON (QFT)– FDA approved in 2001 –in vitro cytokine assay –quantification of interferon-gamma released from sensitized lymphocytes in whole blood incubated overnight with PPD from M.TB –will not detect M. Bovis strains used in BCG –QFT results: % Tuberculin response: cut point of 15% for people with identified risk, 30% for people with no identified risk for infection

46. QuantiFERON-TB Test Advantages –Less subjective than interpretation of the TST –Requires single patient visit –Helps in detecting LTBI in patients who have had BCG –Does not boost anamnestic immune responses –Maybe more efficient and cost effective than TSTs in screening HCWs for infection with M.TB

47. QuantiFERON-TB Test (QFT) Disadvantages –limited laboratory and clinical experience –process within 12 hours after blood collection –ability of QFT in predicting progression to TB disease not evaluated –confirmation of a positive QFT with TST recommended especially if probability of LTBI low –active TB still needs to be ruled out

49. Who Should We Treat? Persons who are at very high risk of developing TB once infected should be given treatment regardless of age

50. Patients who should be treated if their TST result is >5, regardless of age HIV-positive persons Recent contacts of TB case Persons with fibrotic changes on chest radiograph consistent with old healed TB Patients with organ transplants and other immunosuppressed patients

51. Consider treatment if TST >10 mm Recent immigrants from high-prevalence countries Injection drug users Residents and employees of high-risk congregate settings Mycobacteriology laboratory personnel Persons with clinical conditions that place them at high risk Persons living in areas with high incidence of TB Children <5 years of age, or children and adolescents exposed to high-risk adults

52. Efficacy of INH in treating LTBI Many RCTs of isoniazid in 1950-1960 Industrialized and developing countries involving >100,000 participants at risk for TB –Children with primary TB, contacts of TB cases, positive PPDs, institutionalized pts,and persons with inactive TB

53. Efficacy of Treatment with 12 months of INH Decrease in TB among all participants varied from 25 to 92% In analysis restricted to compliant persons, protective efficacy was approximately 90%

54. Efficacy of various durations of isoniazid preventive therapy for persons with fibrotic lesions, by length of treatment (IUAT Trial, 1969-77) 5 yr TB incidence* (% reduction) GroupPlacebo12 wk24 wk52 wk All participants (n = 27,830)14.311.3 (21)5.0 (65)3.6 (75) Adherent participants (n = 21,635)15 9.4 (31)4.7 (69)1.1 (93) Fibrotic lesions <2cm 2 (n = 18,663)11.6 9.2 (20)4.0 (66)4.2 (64) Fibrotic lesions >2cm 2 (n = 8,428)21.316.2 (24)7.0 (67)2.4 (89)

56. Rating (A-E) A. Preferred; should generally be offered B. Alternative; acceptable to offer C. Offer when preferred or alternative regimens cannot be given D. Should generally not be offered E. Should never be offered Strength of Treatment Recommendations

57. Evidence (I-III) I.At least one randomized trial with clinical endpoints II.Clinical trials that either are not randomized or were conducted in other populations III. Expert opinion Quality of Evidence Supporting Recommendation

58. Rating and Evidence Duration Drugs (mo)Interval HIV - HIV + Isoniazid9DailyA (II)A (II) Twice weeklyB (II)B (II) Isoniazid6DailyB (I)C (I) Twice weeklyB (II)C (I) Rifampin4DailyB (II)B (III) Rifampin- pyrazinamide Generally should not be offered for treating LTBI in both HIV positive and negative (D/II)* * As revised in the ATS/CDC update, MMWR 2003 & JAMA 2005

59. Treatment of LTBI with Isoniazid (INH) 9-month regimen considered optimal Children, HIV infected persons and those with CXR evidence of prior TB (fibrotic lesions) should receive 9 months of therapy Can be given twice-weekly only if directly observed 6-month regimen is an acceptable alternative

60. Treatment of LTBI with Rifampin 4-month regimen considered acceptable as alternative Can be given twice-weekly only if directly observed Persons with HIV infection, and with CD4 cell counts <100 should not be treated with intermittent regimens, and should receive DOT, if feasible

61. Treatment of LTBI with Rifampin and Pyrazinamide (RZ) Reports of severe liver injury and death CDC & ATS have revised previous recommendations RZ should generally not be offered for treatment of LTBI for both HIV positive and negative Use only after consultation with infectious disease, if potential benefits outweigh risk and patient has no contraindications

62. Contacts of INH-Resistant TB Treatment with Rifampin, 4 month continuous regimen HIV infected: should not administer protease inhibitors or delavirdine concurrently with rifampin. Rifabutin could be used instead with appropriate dose adjustments

63. MDR TB Cases, 1993 - 1998 None > 1 case

64. Contacts of Multidrug-Resistant TB Use 2 drugs to which the infecting organism has demonstrated susceptibility Treat for 6 months or observe without treatment (HIV-negative) Treat HIV-positive persons for 12 months Follow for 2 years regardless of treatment

65. Pregnancy and Breast-feeding INH daily or twice weekly Pyridoxine supplementation Breast-feeding not contraindicated

66. Adverse Effects INH –rash, elevated LFTs, hepatitis, peripheral neuropathy, mild CNS effects, drug interactions Rifampin –rash, hepatitis, fever, thrombocytopenia, drug interactions with PIs or NNRTIs Pyrazinamide –GI upset, hepatitis, rash, arthralgias, gout (rare)

67. Monitoring Patients Before treatment for LTBI is started, clinicians should R/O possibility of TB disease with CXR Determine history of Rx for LTBI or disease Determine contraindications to treatment: medications and medical history Recommend HIV testing if risk factors are present Use State and Local Health Departments

68. Monitoring Patients (cont.) Baseline laboratory testing not routinely indicated Baseline hepatic measurements indicated for Patients whose initial evaluation suggests a liver disorder or regular use of alcohol Patients with HIV infection Pregnant women and those in immediate postpartum period Patients with history of chronic liver disorder

69. Monitoring Patients (cont.) At least monthly (public health nurse), evaluate for Adherence to prescribed regimen is major determinant of outcome of treatment Signs and symptoms of active TB disease Signs and symptoms of hepatitis Prompt evaluation of side effects and changes in treatment crucial

70. Guidelines!!! Sigourney Weaver: “I am Zule. Do you want this body?” Bill Murray: “Is this a trick question?” Sigourney Weaver: “Take me now!” Bill Murray: “I make it a rule never to get involved with possessed people” [Sigourney Weaver kisses Bill Murray fiercely] Bill Murray: “Actually, it’s more of a guideline than a rule”

71. References Am J Respir Crit Care Med 2000;161:S221-247 Targeted Tuberculin Testing and Treatment of Latent TB Infection. MMWR Weekly Report. DHHS. CDC. 2000;49:1- 51 Guidelines for Using the QuantiFERON TB test for diagnosing Latent TB infection. MMWR 2003;52;15-18 Update: Adverse Event Data and Revised ATS/CDC Recommendations against use of Rifampin and Pyrazinamide for Treatment of Latent TB Infection-United States, 2003 MMWR 2003:52(31) 735-739 Update on the Treatment of Tuberculosis and Latent Tuberculosis infection. Blumberg H. et al JAMA 2005;293 (22) 2776-2784