Latent and Subclinical Tuberculosis: State of the Art Latent Tuberculosis (LTBI) and Subclinical Tuberculosis everything you always wanted to know

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1 Latent and Subclinical Tuberculosis: State of the Art Latent Tuberculosis (LTBI) and Subclinical Tuberculosis everything you always wanted to know E. Ann but Misch, were afraid MD to ask Assistant Professor (CHS) Division of Infectious Diseases no disclosures unaccountable interest in mycobacteria maternal grandmother treated for tuberculosis at Saranac Lake 1

2 SARANAC LAKE CURE COTTAGES OBJECTIVES 1. Epidemiology and Risk understand epidemiology of TB identify high risk groups in U.S. and Wisconsin new reporting mandate for LTBI in Wisconsin 2. Diagnosis of LTBI new U.S. guidelines in 2016 who should be tested? which test is better: PPD or IGRA? 2

3 OBJECTIVES, cont d 3. LTBI and difficulties with IGRA interpretation real life cases a. indeterminate results b. high responses c. low-level positive results d. conversions and reversions 4. Subclinical Tuberculosis TB epidemiology 3

4 Case 1 52-year-old Hmong female undergoing pre-liver transplant evaluation for chronic Hepatitis B and hepatocellular carcinoma. HIV negative born in 1965 in the highlands of Laos. In , hid in the jungle. Between 1980 and 1991, she was in a refugee camp on the Thai-Laos border near Chiang Mai. At the camp, everyone got a CXR and hers was possibly abnormal. After the CXR she got 7-8 skin tests, all negative she says. She immigrated in 1991 to northern Wisconsin Her chest CT shows a calcified plaque with scar, present since at least as part of her transplant workup, IGRA testing was performed to assess for latent tuberculosis infection Case 1 Q1: what is the estimated rate of latent tuberculosis among foreign-borne individuals in the United States? 4

5 TUBERCULOSIS WORLDWIDE 2016 data 1.7 billion latent TB (1/4 of world) 10.4 million active TB 1.7 million deaths (> HIV deaths!) 600,000 with rifampin-resistance 490,000 with multidrug resistance (MDR) MDR TB deaths: 210, (/195) countries with XDR TB Tuberculosis: WHO Fact Sheet no updated 16 Feb Houben RM (2016). PLoS Med. 13 (10):e Source: WHO Global Tuberculosis Report

6 Cases per 100,000 population 9/13/2018 Tuberculosis: Top Ten Countries Country Tb cases /100,000 population India 2,200 Indonesia 1,000 China 930 Nigeria 570 Pakistan 500 South Africa 450 Bangladesh 360 Phillipines 290 DR Congo 240 Ethiopia 200 WHO Global Tuberculosis Report. TB endemic : incidence > 50 cases/100,000 persons TB case rates among U.S born vs. non U.S born persons, * U.S. overall U.S.-born Non-U.S. born Asians: 18.0 Hawaiians/Pac Islands: 13.9 African Americans: 4.9 Native Americans: 4.7 Hispanics: 4.5 Whites 0.6 OVERALL: 2.9 (per 100,000) Year *As of June 21,

7 TB Case Rates,* United States, 2016 AK 7.7 MN 3.0 CA 5.3 NJ 3.3 MD 3.7 NYC 6.6 DC 3.7 AR 3.0 HI 8.3 FL 3.1 TX (2016 national average) >2.9 *Cases per 100,000; as of June 21, DC, District of Columbia; NYC, New York City TB in Wisconsin in rate: cases 7

8 Trempealeau Washington Calumet Ozauk ee Milwaukee Kewaunee 9/13/2018 TB rates* by county, Wisconsin: *10-year average rate, per 100,000 population >2.0 Burnett Polk St. Croix Pierce Douglas Washburn Dunn Barron Bayfield Saywer Rusk Chippewa Eau Claire Pepin Buffalo Ashland Taylor Clark Jackson Monroe La Crosse Vernon source: WI State TB program Iron Price Crawford Richland Grant Wood Juneau Iowa Vilas Lincoln Oneida Marathon Adams Sauk Portage Waushara Marquette Green Lake Columbia Dane Langlade LaFayette Green Rock Forest Menominee Shawano Waupaca Outagamie Brown Winnebago Fond du Lac Dodge Florence Oconto Jefferson Waukesha Walwort h Marinette Manitowoc Racine Kenosha Door Sheboygan 15 active TB rates in selected Wisconsin populations, group rate* country/location Number country rate New Refugees Mexico 94 Myanmar (Burma) 63.1 African-born 34.9 Hmong (Lao or Thai) 71 Somalia 43.7 Other refugees 32.1 India 55 India 38.9 Asian-born 26.0 Philippines 21 Philippines 34.0 Homeless 23.7 China 18 W. Africa 30.0 Long-Term Care 18.7 Myanmar 14 Hmong (Lao/Thai) 21.5 Corrections 13.1 Homeless 14 Mexico 13.4 Latin American 10.6 Corrections 11 China 13.0 All U.S Nepal 11 U.S. (African American) 2.2 U.S., caucasian 0.15 Long-Term Care 9 U.S. (Native American) 0.94 * Rate= persons with tuberculosis per 100,000 population + New refugee: diagnosed with TB within five years of arrival into the U.S slide credit: Julie Tans-Kersten, Director, WI State TB program 8

9 latent TB rates in the United States, 2011 NHANES : 7,821 individuals prevalence TST + US-born foreign-born US-born 1999: 1.9% 2011: 1.5% civilian, non-institutionalized aged 6 or older Foreign-born 1999: 18.1% 2011: 20.5% Miramontes R (2015). PLoS ONE 10(11): e

10 Case 1 Q1: what is the estimated rate of latent tuberculosis among foreignborne individuals in the United States? 1. 4% 2. 10% 3. 20% 4. 40% 5. 60% Strategy to eliminate TB in the U.S. 80% of tuberculosis in U.S. represents reactivation disease LTBI: ~4.7% of U.S. population or ~ 11 million people expand testing and treatment of LTBI 300,000 to 400,000 treated each year for LTBI in USA need to increase 4x involve primary care providers find more effective LTBI treatment regimens decrease testing of low-risk groups increase surveillance/reporting LTBI LoBue Lancet ID 2017 Miramontes. PLoS One Nov 4;10(11):e slide adapted from David Horne, MD, MPH 10

11 latent tuberculosis is now a reportable disease in Wisconsin (as of summer 2018) Diagnosis of latent tuberculosis infection 11

12 Definition LTBI 1. Evidence of prior exposure to TB in the form of cell mediated immunity to TB antigens (TST or IGRA) 2. No evidence of active disease clinical radiographic (chest, other sites) microbiologic Case 2 25 year old obese Caucasian female no apparent TB risk factors she presents for TB skin testing prior to employment as an occupational therapist at a local hospital meds: Ortho-cyclen, occ ASA Q1: what is the most appropriate test for this patient? 12

13 Diagnosis of latent tuberculosis infection: PPD vs IGRA TST (= PPD) cell-free purified protein fraction (derivative) obtained from a human strain of M. tuberculosis (Connaught Tuberculin (CT68) ) is Injected intradermally. Grown in protein-free media, inactivated, then solubilized in phenol and PBS. antigens shared among MTb complex, BCG, and environmental mycobacteria 13

14 what is measured INDURATION 10 mm measure induration, not redness redness 30 mm TST (= PPD) 14

15 CRITERIA FOR + PPD 5 mm 10 mm 15 mm HIV+ recent immigrants (< 5 yrs) from high Tb-burden countries ( countries/tbdata.asp) recent contact of TB+ IVDUs fibrotic s on CXR high risk congregate settings ** organ transplant TB lab workers 15 mg daily pred for >1 month children < 4 yrs TNF- inhibitor or other IS infants, children, adolescents exposed to high risk adults anyone low risk HCWs **prisons/jails, nursing homes and other long-term facilities for elderly or institutionalized (for mental health, other), homeless shelters. HCWs at moderate risk institutions. IGRA= Interferon gamma release assay test component Reference patient data Quantiferon mitogen minus NIL (pos control) 0.5 >10.00 Quantiferon NIL (neg control) Quantiferon TB minus NIL < (high) test interpretation Negative Positive CFP-10 ESAT-6 TB 7.7 Ermann (2015.) Nature Reviews Rheumatology 11: doi: /nrrheum Updated Guidelines for Using interferon Gamma Release Assays to Detect Mycobacterium tuberculosis Infection --- United States, 2010 ( 15

16 T-SPOT.TB Interpretation The T-SPOT.TB test requires four wells to be used for each patient sample T-SPOT.TB: example of actual result slide credit: Phil Wegner, TB RN consultant, DPH, WI 32 16

17 diagnosis of LTBI: who should be tested? USPTF recommendation on LTBI screening JAMA. 2016;316(9): doi: /jama

18 Who should be tested for latent tuberculosis infection? Lewinsohn DM (2017). Clin Infect Dis. 64: doi: /cid/ciw778. Lewinsohn DM (2017). Clin Infect Dis. 64: doi: /cid/ciw

19 WHO SHOULD BE TESTED FOR LATENT TB INFECTION? Lewinsohn DM (2017). Clin Infect Dis 64: ANSWER: persons likely to have been exposed WHO SHOULD BE TESTED FOR LATENT TB INFECTION? Lewinsohn DM et al (2017). Clin Infect Dis 64(2):

20 Risk Factors for TB Progression, 1 RISK FACTOR RR close contact with person with active TB 6.1 old, healed TB on imaging, not treated mg prednisone per day 2.8 underweight (>10%) 1.6 smoking 1.5 PPD 15 mm (relative to PPD <10 mm)* Horsburgh (2011). N Engl J Med 364: *depends on age of person Size matters Horsburg (2004). N Engl J Med 350:

21 PPD size, age, and conversion all matter Horsburg (2004). N Engl J Med 350: Risk Factors for TB Progression, 2 Risk Factor Head and Neck Cancer Silicosis Jejunoileal bypass pregnancy Kidney Transplant TNF- blockade Heart Transplant Chronic Renal Failure Cirrhosis HIV Gastrectomy Diabetes Mellitus Relative Risk* (RR) [SIR] [HR] Am Rev Respir Dis Mar;143(3):501-4 (RR=26, pregnant females): Int J Epidemiol Dec;22(6): (RR=8.3); Barber et al. Medicine (Baltimore) Nov;69(6): (9 patients and lit review: can present with mycobacteremia); Tuber Lung Dis Jun;75(3): (RR=3.1); Tuber Lung Dis Feb;76(1):11-6. (RR=11.5) Cote d Ivoire; AIDS Mar;10(3): (RR=7.1; age and sex adjusted); Trans R Soc Trop Med Hyg Sep-Oct;94(5):500-3 (RR= 7.1); Int J Epidemiol Apr;27(2): (RR=9.1 for CD4 count <200 vs. 500) patients with HIV; Med Pregl. 2004;57 Suppl 1:53-8. most estimates in slide (nonhiv) come from this abstract; cirrhosis risk: Lin YT Am J Epidemiol Jul 1;180(1): [hazard ratio reported] 21

22 Case 2 25 year old obese Caucasian female no apparent TB risk factors she presents for TB skin testing prior to employment as an occupational therapist at a local hospital meds: Ortho-cyclen, occ ASA Q1: what is the most appropriate test for this patient? 1. no testing 2. Interferon gamma release assay 3. Interferon gamma release assay and baseline CXR 4. one-time TST (PPD) 5. TST (PPD) with boosting Case 2 22

23 Case 2, cont d more information: PPD + (15 mm) no symptoms CXR negative *Must change birth control method if using rifampin Q2: given this result, what do you now recommend for LTBI testing and treatment? 1. Nothing 2. Treat with isoniazid for 9 months 3. Treat with isoniazid for 6 months 4. check IGRA and treat with isoniazid for 9 months if positive; do nothing if IGRA negative 5. check IGRA and treat with rifampin for 4 months if positive; do nothing if IGRA negative LTBI Treatment in the United States Isoniazid (9H) Daily or twice-weekly (preferred for preg females) Rifampin (4R) Isoniazid + Rifapentine (3HR) Isoniazid + Rifapentine (HIV+) (1HR) Daily weekly (HIV-) daily 90% 90% 90% *at least 63% probably >> months %* Getahun (2015) NEJM 372: MMWR 2003; 52 (31). Sterling (2011) NEJM 365: MMWR (60): MMWR (No. RR-6). Estimate of 9-INH efficacy from Comstock GW (1999). Int JL Tuber Lung Dis 3(10): **OBSERVED OR EXTRAPOLATED EFFICACY 23

24 Case 2 Case 2: IGRA test results not treated 24

25 IGRA or TST?: summary both measure T cell memory of prior TB exposure most adults use IGRA. TST also okay. HIV positive: either test. IGRA testing can reveal anergy if CD4<200. prior BCG vaccination use IGRA not likely to return for skin test reading use IGRA children < 2 use TST testing NOT recommended if infection is not likely IGRA test has an internal negative control. PPD does not. PPD cross reacts with environmental mycobacteria and BCG IGRA does not cross react with BCG or with most environmental mycobacteria (exceptions: M. marinum, M. szulgai, M. kansasi) LTBI and IGRAs in real life 25

26 Case 1 (again) 52-year-old Hmong female undergoing pre-liver transplant evaluation for chronic Hep B and hepatocellular carcinoma. HIV negative as part of transplant workup, had IGRA testing, which was indeterminate Case 1, cont d Q1: what does an indeterminate mean? 1. she has an intermediate (vs high) risk of having tuberculosis 2. T cells did not respond to the tuberculosis antigen, but did respond to the positive control 3. T cells did not respond to the tuberulosis antigen or to the positive control 4. there are not enough T cells to perform the assay 5. T cells response to the nil control was greater than 8 IU/ml. 26

27 The Indeterminate IGRA test Scenario #1: test is indeterminate because T cells are hyporesponsive (don t even react to generic (mitogen) stimulation) Test cannot rule in or rule out prior TB infection 27

28 Scenario #2: test is indeterminate because although T cells recognize TB antigen, they also react much more (4X) to no stimulation (nil) Test cannot rule in or rule out prior TB infection Scenario #3: test is indeterminate because T cells are reactive even when given no stimulation (nil) Test cannot rule in or rule out prior TB infection 28

29 Causes of an Indeterminate IGRA test depressed immune status >16 hours from blood draw to incubation at 37 C storage of blood outside recommended temperature range (22 C ± 5 C) insufficient mixing of blood collection tubes incomplete washing of the ELISA plate Case 3 55-year-old woman recently diagnosed with Crohn s Recently had a cold. Reports fatigue and diarrhea. No other symptoms. born and raised in the United States, no international travel, no known TB contacts works on the dock in distribution for Wal-Mart where she encounters people from many different countries. GI doctor obtains an interferon-gamma release assay before starting a biologic 29

30 Case 3, cont d 2/2/2018 quantiferon gold results Nil: 0.06 Tb minus nil: 0.48 Mitogen: > interpretation: positive 3/16/2018 repeat quantiferon gold Nil: 0.01 Tb minus nil: 0.17 Mitogen: > interpretation: negative low-level positive ( ) technically, a reversion Q1: which test result should be believed? 1. first, positive test 2. second, negative test 3. don t know. Do a third test to break the tie IGRA reversions and conversions Dorman (2014). Am J Respir Crit Care Med 189: ,563 U.S. HCWs Baseline and q6 month tests TST/QFT/ TSPOT 30

31 Poor reproducibility of low-level positive IGRAs, 1 Use of a single cutoff point criterion for IGRA may lead to overdiagnosis of new TB infections; clinical assessment and evaluation may help to prevent unnecessary therapy in these cases. Fong, KS et al, CHEST 142, July 2012 Clinicians should retest low-risk individuals with initial QFT results <1.11 IU/mL. Thanassi, W et al, Pulmonary Medicine, 2012 slide credit: Phil Wegner, TB RN consultant, DPH, WI 62 31

32 Poor reproducibility of low-level positive IGRAs, 2 Manufacturer s definition of QFT conversion results in an inflated conversion rate that is incompatible with our low-risk setting. A significantly higher QFT cutoff value is needed to match historical TBT conversion rate. Slater ML et al, AJRCCM (8) Most conversions among HCWs in low TB incidence settings appear to be false positives. Repeat testing is warranted. Dorman SE et al, AJRCCM (1) slide credit: Phil Wegner, TB RN consultant, DPH, WI 63 Case 4 36 year old woman from Honduras seen in clinic in May 2017 immigrated in 2014 on routine screening, PPD 13 mm denies cough, sputum production, weight loss, fevers, night sweats. quantiferon gold test is positive: QUANTIFERON MITOGEN MINUS NIL >10.00 QUANTIFERON NIL 0.04 QUANTIFERON TB MINUS NIL 5.10 (ref: ) 32

33 OPTIONS: CXR: left upper lobe fibronodular scar consistent with TB of indeterminate activity. 1. get sputum x 3. If neg on AFB cx/stain, wait 2-3 months and reimage. if no increase in nodule size, consider it old TB 2. get sputum x 3. If neg on AFB cx/stain, start 4 drug therapy for possible active TB and repeat CXR in 2 months. If scar smaller, continue TB therapy with two drugs (HR) for 2 more months (if initial cx neg) or 4 months (if initial cx positive). If nodules are unchanged, stop therapy at two months (will have completed LTBI). Subclinical Tuberculosis 33

34 Definition Subclinical Tuberculosis 1. Evidence of prior exposure to TB in the form of cell mediated immunity to TB antigens (TST or IGRA) 2. minimal or no clinical signs or symptoms of disease 1. radiographic or microbiologic evidence of disease 34

35 other examples subclinical tuberculosis: persistent asymptomatic pyuria GU Tb female infertility GU Tb single enlarged lymph node TB lymphadenitis pleural effusion pleural TB mass at head of the pancreas mimicking pancreatic CA pancreatic TB Summary latent TB may be present in up to 20% of the U.S. foreign population latent TB should be diagnosed and treated, but it is not an emergency (you have time to do repeat testing or further workup) In general, IGRA testing is appropriate for most patients (children < 2, TST still preferred) in situations where TB is unlikely, use an alternate test (PPD if igra used first). In high or intermediate risk patients, a negative or indeterminate IGRA DOES NOT rule out latent or active TB. Use clinical judgment and pre-test probability before starting treatment for LTBI, make sure to rule out ACTIVE TB, esp subclinical active TB. stay tuned for a one-month treatment regimen for LTBI (daily INH and rifapentine x one month) 35

36 The End 36