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Tuberculosis progression rates in U.S. Immigrants following screening with interferon-gamma release assays

Tuberculosis progression rates in U.S. Immigrants following screening with interferon-gamma... Background: Interferon-gamma release assays may be used as an alternative to the tuberculin skin test for detection of M. tuberculosis infection. However, the risk of active tuberculosis disease following screening using interferon-gamma release assays in immigrants is not well defined. To address these uncertainties, we determined the incidence rates of active tuberculosis disease in a cohort of high-risk immigrants with Class B TB screened with interferon-gamma release assays (IGRAs) upon arrival in the United States. Methods: Using a retrospective cohort design, we enrolled recent U.S. immigrants with Class B TB who were screened with an IGRA (QuantiFERON ® Gold or Gold In-Tube Assay) at the San Francisco Department of Public Health Tuberculosis Control Clinic from January 2005 through December 2010. We reviewed records from the Tuberculosis Control Patient Management Database and from the California Department of Public Health Tuberculosis Case Registry to determine incident cases of active tuberculosis disease through February 2015. Results: Of 1233 eligible immigrants with IGRA screening at baseline, 81 (6.6 %) were diagnosed with active tuberculosis disease as a result of their initial evaluation. Of the remaining 1152 participants without active tuberculosis disease at baseline, 513 tested IGRA-positive and 639 tested IGRA-negative. Seven participants developed incident active tuberculosis disease over 7730 person-years of follow-up, for an incidence rate of 91 per 100,000 person-years (95 % CI 43–190). Five IGRA-positive and two IGRA-negative participants developed active tuberculosis disease (incidence rates 139 per 100,000 person-years (95 % CI 58–335) and 48 per 100,000 person- years (95 % CI 12–193), respectively) for an unadjusted incidence rate ratio of 2.9 (95 % CI 0.5–30, p = 0.21). IGRA test results had a negative predictive value of 99.7 % but a positive predictive value of only 0.97 %. Conclusions: Among high-risk immigrants without active tuberculosis disease at the time of entry into the United States, risk of progression to active tuberculosis disease was higher in IGRA-positive participants compared with IGRA-negative participants. However, these findings did not reach statistical significance, and a positive IGRA at enrollment had a poor predictive value for progressing to active tuberculosis disease. Additional research is needed to identify biomarkers and develop clinical algorithms that can better predict progression to active tuberculosis disease among U.S. immigrants. (Continued on next page) * Correspondence: Robert.Blount@ucsf.edu; minhchi.tran@gmail.com Equal contributors Division of Pulmonary and Critical Care Medicine, San Francisco General Hospital, University of California San Francisco, San Francisco, CA, USA Department of Internal Medicine, University of California, Davis, Sacramento, CA, USA Full list of author information is available at the end of the article © 2016 The Author(s). Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Blount et al. BMC Public Health (2016) 16:875 Page 2 of 10 (Continued from previous page) Keywords: Interferon-gamma release assay (IGRA), Tuberculosis (TB), Latent tuberculosis infection (LTBI), Active tuberculosis disease, Foreign-born, Immigrant, Incidence rate, Chest x-ray (CXR), Preventive chemotherapy Abbreviations: ATS, American thoracic society; BCG, Bacillus Calmette-Guerin; BUL, Bilateral upper lobes; CDC, Centers for disease control; CXR, Chest x-ray; HIV, Human immunodeficiency virus; IDSA, Infectious diseases society of America; IGRA, Interferon-gamma release assay; IQR, Interquartile range; IRR, Incidence rate ratio; LLL, Left lower lobe; LTBI, Latent tuberculosis infection; LUL, Left upper lobe; RUL, Right upper lobe; SD, Standard deviation; SFDPH, San Francisco department of public health; TB, Tuberculosis; TST, Tuberculin skin test Background (ATS), CDC, and Infectious Diseases Society of America The number of active tuberculosis (TB) cases in the (IDSA) guidelines [21, 22]. Among these patients are im- United States (U.S.) has declined each year since 1993, migrants, refugees, and asylum-seekers. As part of the yet the proportion of cases in foreign-born persons is immigrant medical evaluation for TB, patients may have steadily rising [1]. In 2014, foreign-born persons had a TST or IGRA, a chest radiograph CXR, and/or accounted for 66.5 % of total cases in the U.S. and had a sputum collected for smear and/or culture. Recommen- 13.4 times higher incidence rate of active TB disease dations for immigration evaluation have changed during compared with U.S.-born persons [2]. Additionally, up the study period [9, 23–25]. Currently, visa applicants to 84 % of active TB in foreign-born persons can be at- outside the U.S. are screened with CXR followed by spu- tributed to reactivation of an infection acquired prior to tum examination if the CXR is suspicious, whereas for arrival in the U.S. [3–5]. Accurately identifying and those residing in the U.S. at the time of application or treating foreign-born persons with latent tuberculosis in- are <15 years old, screening involves a TST or IGRA and fection (LTBI) who are at high risk for progression to ac- if either is positive, a CXR is obtained. From this evalu- tive TB disease should improve overall TB control in the ation visa applicants are assigned a TB classification sta- U.S. [6–9]. tus by the U.S. Citizenship and Immigration Services Interferon-gamma release assays (IGRAs) measure (Table 1). All persons with Class B TB are then referred interferon-gamma secretion following stimulation of T- to their local jurisdiction TB control program upon U.S. lymphocytes with Mycobacterium tuberculosis antigens arrival for further clinical evaluation [25–27]. The Class [10], and may be used as an alternative to the tuberculin B TB classification scheme has been modified during the skin test (TST) [1, 10]. Several studies conducted in close study period and currently includes those with possible contacts of active TB index cases have reported a higher smear and culture negative pulmonary TB (B1-Pulmon- active TB incidence in IGRA-positive persons compared ary), those with a history of successfully treated pulmon- with IGRA-negative persons [11–17]. However, few stud- ary TB (B1-Pulmonary), those with extrapulmonary TB ies have addressed this question in the evaluation of high- (B1-Extrapulmonary), those with a positive TST or risk newly arriving immigrants [18, 19]. IGRA but no evidence of active TB (B2), and those in Since 2005, the San Francisco Department of Public close contact with a known case of smear or culture Health (SFDPH) TB Control Clinic has incorporated positive pulmonary TB but with a negative TST or IGRA IGRAs into routine clinical practice according to Cen- (B3). Prior to 2008, Class B immigrants also included ters for Disease Control and Prevention (CDC) guide- those who had radiographic evidence of old/healed TB. lines [20]. We analyzed data from the SFDPH TB All children and adults with B1-Pulmonary, B2, and B3 Control Patient Management Database and the Califor- TB were offered IGRA screening at the SFDPH TB Con- nia TB Case Registry to provide program-relevant guid- trol Clinic during the enrollment period of January 1, ance on the management of foreign-born patients 2005 through December 31, 2010, and those who re- screened with IGRAs. Our primary objective was to de- ceived IGRA testing were considered for inclusion in termine the risk of progression to active TB disease our study. The IGRA assays (QuantiFERON-TB Gold® among immigrants screened for LTBI with an IGRA from January 1, 2005 through December 31, 2007 and within 1 year of arrival into the United States. QuantiFERON®-TB Gold In-Tube from January 1, 2008 through December 31, 2010, Cellestis Limited, Carnegie, Methods Australia) were performed at the SFDPH laboratory ac- Study population cording to manufacturers’ instructions and interpreted The SFDPH TB Control Clinic evaluates and treats pa- using FDA approved criteria [20]. In addition to IGRA tients with suspected active TB, prior TB, and suspected testing, tuberculin skin tests (Tubersol, 5TU from Sanofi LTBI in accordance with American Thoracic Society Pasteur Limited, Toronto, Canada) were offered at the Blount et al. BMC Public Health (2016) 16:875 Page 3 of 10 Table 1 Current tuberculosis classification for U.S. immigration Department of Public Health TB Case Registry. All inci- applicants dent active TB cases were microbiologically or patho- TB classification Description logically confirmed. We performed a death registry Status match with the California Department of Public Health No TB No evidence of TB infection or disease Vital Statistics Office to determine mortality through classification December 2009. We did not update this match in 2015 A Smear or culture positive pulmonary TB. due to low yield, finding only four deaths in the initial Typically requires treatment prior to U.S. entry. assessment, none of which were known to be attribut- B1-Pulmonary 1. Suspected active pulmonary TB based on able to TB. We classified active TB cases by adapting an clinical findings but with negative sputum existing classification scheme [29]: 1) “likely LTBI reacti- smears and cultures vation” if the IGRA was positive at enrollment but the 2. History of pulmonary TB, treatment complete immigration chest X-ray (CXR) was normal; 2) “likely B1-Extrapulmonary Extrapulmonary TB reactivation of prior TB” if the immigration CXR was B2 TST ≥ 10 mm or positive IGRA but otherwise abnormal but the participant was not diagnosed with ac- negative TB evaluation (LTBI) tive TB disease as a result of the enrollment evaluation; B3 Recent close contact with a known active 3) “likely imported active TB” if the immigration CXR TB case and TST/IGRA negative was abnormal and the participant was diagnosed with Abbreviations: TB tuberculosis, LTBI latent tuberculosis infection, TST tuberculin active TB disease as a result of the enrollment evalu- skin test Cultures were gradually introduced into the overseas screening process ation; and 4) “likely TB infection and disease acquired from 2007–2014 after U.S. immigration” if the participant was IGRA- negative with a normal CXR at the time of enrollment. discretion of the attending physician, performed accord- CXRs were performed overseas near the time of immi- ing to manufacturer guidelines, and interpreted by clinic gration and were repeated upon arrival in the U.S. CXRs staff according to CDC guidelines [28]. Patients diag- were interpreted by physicians at the SFDPH TB Control nosed with LTBI at the time of enrollment were offered Clinic during the baseline evaluation. The CXR per- preventive chemotherapy if they had not yet received ad- formed in the U.S. closest to baseline evaluation was equate therapy overseas. Patients typically self- used as the CXR interpretation for the study. The IGRA administered their medication, coming in to the TB and TST results reported in this study were from the clinic for monthly refills. Adherence was monitored at post-arrival baseline evaluation. monthly clinic visits, and completion of therapy docu- mented once the required course of preventive chemo- Statistical analysis therapy had be taken per patient report. We excluded We used Pearson’s chi-squared test for comparisons of persons who were evaluated more than 1 year following proportions and Student’s T-test for comparisons of their immigration date or had persistently indeterminate means. We calculated unadjusted incidence and inci- IGRA results despite repeat testing. Patients who were dence rate ratios (IRR) with 95 % confidence intervals diagnosed with or treated for active TB disease for > per 100,000 person-years of follow-up, with statistical 30 days as a direct result of their initial evaluation at the significance defined as an IRR p value < 0.05. We esti- TB Control Clinic were counted as prevalent cases and mated the cumulative incidence of active TB disease excluded from the final analysis. Clinical, radiologic, and using Kaplan-Meier curves. We determined IGRA test laboratory data were written on standardized forms in performance by calculating sensitivity, specificity, posi- the medical record and then entered into the SFDPH TB tive and negative predictive value, and positive and nega- Control Patient Management Database. Study treatment tive likelihood ratios. We performed statistical analyses status was reflective of any documented TB treatment using Stata/SE 13.1 (College Station, Texas, USA). received either before or after U.S. entry and throughout the followup period up until a diagnosis of active TB or Results the end of the study, whichever came first. Baseline demographic and clinical characteristics During the enrollment period January 1, 2005 through Study outcome December 31, 2010 we screened 1,419 Class B TB immi- Follow-up time began on the day of IGRA testing at the grants for LTBI. We excluded 78 (5.5 %) who did not initial SFDPH TB Control Clinic visit and was censored have IGRA testing completed, 79 (5.6 %) who were eval- on the day of active TB diagnosis (event), death, or the uated > 1 year following immigration, 23 (1.6 %) who end of the study (February 2015). We identified active had indeterminate IGRA results despite repeat testing, TB cases during follow-up using the SFDPH TB Control and 6 (0.4 %) who had an unknown or incorrect immi- Patient Management Database and the California gration date (Fig. 1). From the remaining 1,233 eligible Blount et al. BMC Public Health (2016) 16:875 Page 4 of 10 Fig. 1 Enrollment flow chart participants, 81 (6.6 %) were found to have active TB Among IGRA-positive participants, 87 % had received disease during enrollment screening. All but one preva- either overseas treatment for TB infection or disease lent case, and all of the 42 microbiologically confirmed prior to immigration (n = 188) or LTBI treatment upon prevalent cases, had abnormal immigration CXRs at the immigration in the U.S. (n = 260). Tuberculin skin test- time of U.S. entry. IGRA was positive in 54 (67 %) of ing was performed in only 298 participants with a simi- total prevalent cases and in 34 (81 %) of microbiologic- lar percent positive TST in IGRA-negative participants ally confirmed prevalent cases. All prevalent cases were (76 %) as in IGRA-positive participants (79 %) (p = 0.5). then excluded, while the remaining 1,152 subjects were TST test results correlated poorly with IGRA test results included in the final analysis. The average time from im- (r = 0.037). CXR results were available for nearly all par- migration to IGRA testing was 32 days (SD 42). We ex- ticipants (n = 1150) and found to be abnormal in 881 amined baseline demographic and clinical characteristics (77 %). IGRA-positive participants were more likely to by IGRA test results: 639 (55 %) were IGRA-negative have an abnormal CXR compared with IGRA-negative and 513 (45 %) were IGRA-positive (Table 2). Median participants (90 vs 66 %, p < 0.0001). age was 54 (IQR 39–64) years and IGRA-positive partic- ipants were significantly older than those with IGRA- Incident active TB cases negative test results at enrollment (p < 0.0001). Of the Seven participants (0.6 %) developed incident active TB 973 participants over the age of 21, 494 (51 %) were disease over the 10 year follow-up period (Table 3). The IGRA-positive at enrollment, whereas of the 179 partici- majority of cases (57 %) were male, all were adults be- pants under the age of 21, only 19 (11 %) were IGRA- tween the ages of 39 and 60 (median 52) at the time of positive. The majority of participants were male (n = enrollment, and all but one case had emigrated from 645, 56 %), and 1066 (93 %) emigrated from one of three China. Five (71 %) were IGRA-positive while two were countries: China, the Philippines, or Vietnam. Baseline IGRA-negative at enrollment. Case #5 was likely LTBI TB risk factors were assessed: only 0.25 % of participants reactivation as the CXR performed 1 week after arrival had known HIV-infection, 5.4 % had diabetes, while in the U.S. was normal and the IGRA at that time was 30 % reported current or former tobacco smoking. positive. This participant was diagnosed with active TB IGRA-positive participants were more likely to be disease latest at 6.3 years after enrollment. The other six smokers than IGRA-negative participants (p < 0.0001). cases (86 %) were likely reactivation of prior TB, having Nearly half (49 %) of participants immigrated with a B1- immigration CXR findings in the upper lobes consistent Pulmonary classification (TB suspect or prior TB), while with prior TB. These participants were diagnosed with 51 % received an overseas classification of B2 (LTBI). active TB disease a median of 4.5 years after enrollment Blount et al. BMC Public Health (2016) 16:875 Page 5 of 10 Table 2 Baseline demographic and clinical characteristics by IGRA status Characteristic All subjects IGRA-negative IGRA-positive p value n (%) n (%) n (%) All 1152 (100) 639 (55) 513 (45) Median age, years (IQR) 54 (39–64) 52 (21–64) 55 (45–65) Mean age, years (SD) 49 (20) 45 (23) 53 (15) <0.0001 Age by category, years, n (%) n = 1152 n = 639 n = 513 <0.0001 0–4 18 (1.6) 17 (2.7) 1 (0.2) 5–12 87 (7.6) 81 (13) 6 (1.2) 13–20 74 (6.4) 62 (9.7) 12 (2.3) ≥ 21 973 (84) 479 (75) 494 (96) Gender n = 1152 n = 639 n = 513 0.141 Male 645 (56) 345 (54) 300 (58) Female 507 (44) 294 (46) 213 (42) Country of origin n = 1150 n = 638 n = 512 0.001 China 586 (51) 302 (47) 284 (55) Philippines 386 (34) 245 (38) 141 (28) Vietnam 94 (8.2) 42 (6.6) 52 (10) Burma 18 (1.6) 11 (1.7) 7 (1.4) Other 66 (5.7) 38 (6.0) 28 (5.4) HIV status n = 799 n = 404 n = 395 <0.0001 HIV- 797 (99.8) 402 (99.5) 395 (100) HIV+ 2 (0.25) 2 (0.5) 0 Diabetes n = 1152 n = 639 n = 513 0.09 No 1090 (95) 611 (96) 479 (93) Yes 62 (5.4) 28 (4.4) 34 (6.6) Smoking status n = 1152 n = 639 n = 513 <0.0001 Never 803 (70) 476 (74) 327 (64) Current or Former 349 (30) 163 (26) 186 (36) TB Classification at immigration n = 1152 n = 639 n = 513 0.0001 B1-Pulmonary (TB suspect or prior TB) 561 (49) 276 (43) 285 (56) B2 (LTBI) 588 (51) 361 (56) 227 (44) B3 (Contact) 3 (0.26) 2 (0.31) 1 (0.19) BCG n = 490 n = 309 n = 181 0.004 No evidence of BCG vaccination 114 (23) 59 (19) 55 (30) Evidence of BCG vaccination 376 (77) 250 (81) 126 (70) Treatment status n = 1152 n = 639 n = 513 <0.0001 Inadequate or no TB treatment 498 (43) 433 (68) 65 (13) Overseas TB treatment prior to immigration 324 (28) 136 (21) 188 (37) LTBI treatment in U.S. after immigration 330 (29) 70 (11) 260 (51) TST Result n = 298 n = 230 n = 68 0.5 Negative 70 (23) 56 (24) 14 (21) Positive 228 (77) 174 (76) 54 (79) Immigration CXR Result n = 1150 n = 637 n = 513 <0.0001 Normal 269 (23) 216 (34) 53 (10) Abnormal 881(77) 421 (66) 460 (90) Blount et al. BMC Public Health (2016) 16:875 Page 6 of 10 Table 2 Baseline demographic and clinical characteristics by IGRA status (Continued) Prevalent TB cases at enrollment Total 81/1233 (6.6) 27/666 (4.1) 54/567 (9.5) 0.0001 Microbiologically confirmed 42/1233 (3.4) 8/666 (1.2) 34/567 (6.0) <0.0001 Abbreviations: IGRA interferon-gamma release assay, IQR interquartile range, HIV human immunodeficiency virus, TST tuberculin skin test, TB tuberculosis, CXR chest x-ray Table numbers represent n (%) unless otherwise indicated Treatment status reflects any TB treatment received up until the time of diagnosis with active TB disease: either overseas treatment for TB infection or disease prior to U.S. entry, or LTBI treatment received in the U.S. after immigration (IQR 3.7–4.8). None of the cases had known HIV, dia- IRR of 1.9 (95 % CI 0.33–13, p = 0.41). These differences, betes, or tobacco smoking risk factors. Three of the five however, did not reach statistical significance. The risk cases that were IGRA-positive at enrollment completed for progression to active TB disease was highest among LTBI treatment after enrollment. Diagnosis was con- IGRA-positive participants who had received inadequate firmed with sputum culture for six cases and by lung bi- or no TB treatment before and after U.S. arrival (inci- opsy pathologic features (caseating granulomatous dence rate 443 per 100,000 person-years, 95 % CI 111– inflammation) for one case. 1775), while risk was lower in IGRA-positive partici- pants who received TB treatment (incidence rate 96 per Incidence rates for active TB disease during follow-up 100,000 person-years, 95 % CI 31–296), for an IRR of The seven incident active TB cases occurred over 7730 4.6 (95 % CI 0.39–41, p = 0.14). The risk was lowest person-years of cumulative follow-up, for a median among IGRA-negative participants who had received follow-up of 6.7 years (IQR 5.1–8.2) and an overall inci- prior treatment for TB (incidence rate of 0) and IGRA- dence rate of 91 per 100,000 person-years (95 % CI 43– negative participants who had a normal immigration 190) (Table 4). Incidence rates for active TB disease di- CXR (incidence rate of 0). For the entire cohort we agnosed during follow-up were higher in IGRA-positive found a 5 year cumulative incidence of 0.48 % and a participants (139 per 100,000 person-years, 95 % CI 58– 10 year cumulative incidence of 0.77 % (Fig. 2). 335) compared with those who were IGRA-negative at enrollment (48 per 100,000 person-years, 95 % CI 12– IGRA test characteristics 193), for an unadjusted incidence rate ratio (IRR) of 2.9 The IGRA test had a sensitivity of 71 % (95 % CI 29- (95 % CI 0.5–30, p = 0.21). Additionally, active TB inci- 96 %) for predicting progression to active TB disease, a dence rates were higher in those with inadequate or no specificity of 56 % (95 % CI 53–59 %), a positive predict- prior TB treatment (127 per 100,000 person-years, 95 % ive value of only 0.97 % (95 % CI 0.32–2.3 %), and a CI 48–339) compared to those with prior TB treatment negative predictive value of 99.7 % (95 % CI 98.9– (65 per 100,000 person-years 95 %, CI 21–203), for an 100 %). The positive likelihood ratio was 1.6 (95 % CI Table 3 Incident active TB cases Case IGRA Ag-Nil, Mitogen CXR findings HIV Diabetes Smoker TB Treatment status TB confirmation (IU/ml) Class 1 Neg 0.38–0.11, 20 Pleural thickening, RUL Neg No No B1 None Lung biopsy pathology 2 Pos 0.93–0.12, 2.0 Fibronodular changes, BUL Unk No No B2 None sputum culture & LLL 3 Neg 0.29–0.11, 25 Fibrotic changes, LUL Neg No No B2 Incomplete tx prior to sputum culture immigration 4 Pos 2.4–0.12, 25 Fibronodular changes, RUL Neg No No B1 LTBI tx at enrollment sputum culture 5 Pos 9.7–0.70, 24 Normal Neg No No B1 LTBI tx at enrollment sputum culture 6 Pos 3.1–0.12, 8.9 Nodular infiltrate, LUL Neg No No B1 LTBI tx at enrollment sputum culture 7 Pos 1.1–0.16, 6.9 Fibrotic changes, LUL; Neg No No B1 Incomplete LTBI tx at sputum culture Effusion, L enrollment Abbreviations: TB tuberculosis, IGRA interferon-gamma release assay, Ag-Nil interferon-gamma response with antigen minus response without antigen, Mitogen interferon-gamma response to mitogen, HIV human immunodeficiency virus, CXR chest x-ray, Pos positive, Neg negative, Unk unknown, RUL right upper lobe, BUL bilateral upper lobes, LLL left lower lobe, LUL left upper lobe, L left, LTBI latent tuberculosis infection, tx treatment Treatment status reflects any TB treatment received up until the time of diagnosis with active TB disease: either overseas treatment for TB infection or disease prior to U.S. entry, or LTBI treatment received in the U.S. after immigration Defaulted after 3 months of active TB treatment Received a 1 month prescription for isoniazid but was lost to follow-up. Unclear if patient took any of the medication Blount et al. BMC Public Health (2016) 16:875 Page 7 of 10 Table 4 Active TB incidence rates for treatment status, CXR findings, and overseas TB classification by IGRA result Treatment status, CXR, and TB class by IGRA result n (% of all participants) Incident active TB cases, Total follow-up Incidence rate per 100,000 n (% cases in sub-group) (person-years) person-years (95 % CI) All participants 1152 (100) 7 (0.60) 7730 91 (43–190) IGRA- 639 (55) 2 (0.31) 4139 48 (12–193) IGRA+ 513 (45) 5 (0.97) 3591 139 (58–335) Inadequate or no TB treatment 498 (43) 4 (0.80) 3148 127 (48–339) IGRA- 433 (38) 2 (0.46) 2698 74 (19–296) IGRA+ 65 (6.0) 2 (3.1) 451 443 (111–1775) Adequate TB treatment 654 (57) 3 (0.46) 4581 65 (21–203) IGRA- 206 (18) 0 1441 0 IGRA+ 448 (39) 3 (0.67) 3140 96 (31–296) Normal CXR 269 (23) 1 (0.37) 1553 64 (9.1–457) IGRA- 216 (19) 0 1206 0 IGRA+ 53 (4.6) 1 (1.9) 347 288 (41–2047) Abnormal CXR 881 (77) 6 (0.68) 6158 97 (44–217) IGRA- 421 (37) 2 (0.48) 2914 69 (17–274) IGRA+ 460 (40) 4 (0.87) 3244 123 (46–329) B1 TB, Pulmonary 561 (49) 5 (0.89) 3630 138 (57–331) IGRA- 276 (24) 1 (0.36) 1759 57 (8.0–404) IGRA+ 285 (25) 4 (1.4) 1870 214 (80–570) B2 (LTBI) 588 (51) 2 (0.34) 4084 49 (12–196) IGRA- 361 (31) 1 (0.28) 2370 42 (5.9–300) IGRA+ 227 (20) 1 (0.44) 1714 58 (8.2–414) B3 (Contacts) 3 (0.26) 0 16 0 Abbreviations: TB tuberculosis, IGRA interferon-gamma release assay Treatment status reflects any TB treatment received up until the time of diagnosis with active TB: either overseas treatment for TB infection or disease prior to U.S. entry, or LTBI treatment received in the U.S. after immigration n = 1150 (2 participants missing CXRs) Fig. 2 Cumulative incidence of active tuberculosis (TB) disease among high-risk U.S. immigrants, 2005–2015 Blount et al. BMC Public Health (2016) 16:875 Page 8 of 10 1.0–2.6) and the negative likelihood ratio was 0.51 (95 % absent [29]. Six of the seven immigrants who developed CI 0.16–1.7). Among IGRA-positive participants with nil active TB disease had upper lobe abnormalities on their values ≤ 0.7 IU/ml, there was not a statistically signifi- immigration CXR. None had overseas documentation of cant difference in TB response values at baseline among adequate prior TB therapy, two had negative IGRA re- those that developed active TB (median 2.3 IU/ml, IQR sults, and only two completed LTBI treatment in the 0.93–3.0) compared with those who did not develop ac- U.S. Conversely, no active TB developed among immi- tive TB (1.6, 0.71–4.0) (p = 0.6). grants who were both IGRA-negative and had a normal immigration CXR. These findings suggest that high-risk Discussion immigrants with abnormal CXRs consistent with prior We evaluated the rates of progression to active TB dis- TB should be considered for preventive chemotherapy ease among a cohort of high-risk immigrants screened regardless of IGRA result. for LTBI with IGRAs at the San Francisco Department As expected, active TB incidence was highest among of Public Health TB Control Clinic in a large study of 13 % of participants who were IGRA-positive at enroll- 1152 participants with 7730 person-years of follow-up ment but received inadequate or no prior TB treatment. time. We found a high prevalence of active TB disease at Our findings suggest that IGRA-positive immigrants are baseline evaluation and a high incidence of active TB at high risk for progression to active TB disease, espe- disease over the median follow-up time of 6.7 years. The cially if they have not received adequate preventive incidence rates of active TB disease were higher in chemotherapy, and efforts should be made to treat this IGRA-positive participants compared with those who group. The remaining 87 % of IGRA-positive partici- were IGRA-negative at enrollment. However, these find- pants did receive TB treatment and although the inci- ings were not statistically significant and a positive IGRA dence rate for progression to active TB was more than 4 at enrollment had a poor predictive value for progres- times lower than in those who had not received ad- sion to active TB disease. equate therapy, the rate in treated individuals remained Our findings are largely consistent with a prior meta- unacceptably high. It is unclear why preventive TB analysis and a recent prospective cohort study from Eur- chemotherapy had only a modest impact on progression ope, both of which found that IGRAs had poor predict- to active TB in our study. Preventive chemotherapy for ive value for active TB disease in one or more high-risk LTBI was not typically delivered as directly observed groups (case contacts, health care workers, immigrants, therapy, so adherence was not guaranteed. Also, since people living with HIV, and patients with silicosis) [11, treatment was not randomized, participants who were 12]. In our cohort, the risk of developing active TB dis- more likely to progress to active TB disease (such as ease was high regardless of IGRA results. The overall in- those with a positive IGRA and evidence of prior TB by cidence rate of 91 per 100,000 person-years and even CXR) may have preferentially received preventive the incidence rate for IGRA-negative participants (48 chemotherapy (confounding by indication). per 100,000 person years) were considerably higher than More than 6 % of our initial cohort were diagnosed with the incidence for U.S.-born persons, which decreased prevalent active TB as a result of the enrollment evalu- from 2.5 cases per 100,000 persons in 2005 to 1.1 cases ation. All but one of the prevalent cases had an abnormal per 100,000 persons in 2014 [2, 30]. immigration CXR consistent with imported active pul- In our cohort there was a heightened risk of develop- monary TB. This high prevalence is consistent with other ing active TB among Class B immigrants with CXR evi- studies of recent immigrants [13, 29, 32], and highlights dence of prior TB. This elevated risk was sustained over the importance of a thorough and timely TB evaluation of several years, with incident active TB disease occurring high-risk immigrants upon U.S. entry. In response to high from 2.8 to 6.3 years after enrollment and 10 year cumu- numbers of imported active TB among newly arrived im- lative incidence nearly double the 5 year cumulative inci- migrants, the CDC has recently modified its pre- dence. The sustained high incidence is consistent with immigration screening to include sputum cultures instead other studies of immigrants from TB-endemic countries of smears alone for TB suspects. This intensified overseas [1, 29, 31], suggesting that foreign-born persons from screening has resulted in a decrease in prevalent active TB TB-endemic countries should be screened for LTBI re- among recent immigrants [29, 33, 34]. gardless of how recently they immigrated to the U.S., Our study had several limitations. We identified only and that a high level of suspicion for active TB disease seven cases of incident active TB despite following a should be maintained in this group even when IGRA re- large cohort for more than 7,000 person-years. This sults are negative. small number of outcomes led to imprecise incidence Our findings confirm the importance of radiographic rate estimates and difficulty in determining the effects of evidence of prior TB as a key risk factor for developing multiple predictors such as IGRA status, LTBI treat- TB, particularly when overseas treatment is uncertain or ment, and CXR abnormalities on active TB incidence Blount et al. BMC Public Health (2016) 16:875 Page 9 of 10 rates. We were careful only to include true incident additional research is needed to identify biomarkers and cases, excluding prevalent cases diagnosed as a result of develop clinical algorithms that can better predict pro- enrollment screening and only including microbiologic- gression to active TB disease among U.S. immigrants. ally or pathologically confirmed cases of active TB dis- Acknowledgments ease in the final analysis. Inclusion of clinically We thank L. Masae Kawamura, M.D., former Director of the SFDPH TB Control diagnosed cases would have increased incidence rates, Clinic, who supported this research in that role. We would like to acknowledge the clinicians and staff of the SFDPH TB Control Clinic, who but would have also increased the likelihood of mis- work to prevent and treat TB in San Francisco, and without whom this classification of outcome. Case detection was limited by research would not have been possible. a passive follow-up and case finding approach. We iden- tified cases reported in California but may have missed Funding This work was supported by the National Institutes of Health: grants cases among those participants that moved out of state, K23ES025807 (RB), K23HL094141 (AC), and R01AI104589 (PN). Its contents are resulting in an underestimation of incidence rates. Add- solely the responsibility of the authors and do not necessarily represent the itionally, we were unable to censor follow-up time for official view of the NIH. participants that moved out of state or for all partici- Availability of data and materials pants that died during the follow-up period, which The data used in this study is stored and maintained by the San Francisco would result in an overestimation of person-years at risk. Department of Public Health and the California Department of Public Health, These limitations would have led to a conservative, non- and is available through an application process. informative bias whereby incidence rates in both IGRA- Authors’ contributions positive and IGRA-negative participants were equally RJB and MCT were involved in all aspects of the study, including study underestimated, assuming that moving and death were design, data acquisition, data analysis, and writing of the manuscript. AC, JH, not associated with IGRA status. Second, although our and PN were involved in study design and critical revision of the manuscript. CKE, JZM, CRM, JG, and DC were involved in data analysis and critical case registries were rich sources of demographic and revision of the manuscript. All authors have given final approval of the clinical data, reliance on registry data limited our ability version to be published and agree to be accountable for all aspects of the to comprehensively characterize patients. Additionally, work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. without TB genotypes for the active cases we were un- able to confirm M. tuberculosis origin. Finally, this is a Competing interests single center’s experience and reflects the largely Asian The authors declare that they have no competing interests. immigrant population of San Francisco. As such our Consent to publish findings might not be generalizable to other high TB Not applicable. burden areas in the U.S. such as southern California and Texas which experience a higher proportion of immi- Ethics approval and consent grants from Central and South America. The Committee on Human Research at the University of California, San Francisco and the Committee for the Protection of Human Subjects at the California Department of Health and Human Services approved the study Conclusions protocol. A consent to participate was not required for this retrospective Our study found a high prevalence of active TB disease review of public health data. among newly arrived immigrants and high incidence Author details rates of active TB disease throughout a median of 1 Division of Pulmonary and Critical Care Medicine, San Francisco General 6.7 years follow-up. Risk of progression to active TB dis- Hospital, University of California San Francisco, San Francisco, CA, USA. Division of Pediatric Pulmonary Medicine, University of California, San ease was higher in IGRA-positive participants compared Francisco, CA, USA. Department of Internal Medicine, University of California, with IGRA-negative participants, although these findings 4 Davis, Sacramento, CA, USA. Department of Medicine, University of did not reach statistical significance. Risk was highest California, San Francisco, CA, USA. San Francisco Department of Public Health, Population Health Division, Office of Equity and Quality among IGRA-positive participants who had received in- Improvement, San Francisco, CA, USA. San Francisco Department of Public adequate or no prior treatment for TB and lowest Health, Population Health Division, Disease Prevention and Control Branch, among IGRA-negative participants who had received San Francisco, CA, USA. prior treatment for TB or who had a normal CXR. Our Received: 19 August 2015 Accepted: 17 June 2016 findings support the role of timely and thorough TB screening of high-risk newly arrived immigrants from TB-endemic countries, preventive chemotherapy for References 1. LoBue PA, Enarson DA, Thoen TC. Tuberculosis in humans and its IGRA-positive foreign-born persons from TB-endemic epidemiology, diagnosis and treatment in the United States. 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American Thoracic Society/Centers for Disease Control and Prevention/Infectious Diseases Society of America: controlling tuberculosis � Thorough peer review in the United States. Am J Respir Crit Care Med. 2005;172(9):1169–227. � Inclusion in PubMed and all major indexing services doi:10.1164/rccm.2508001. � Maximum visibility for your research 23. Tuberculosis among foreign-born persons entering the United States. Recommendations of the Advisory Committee for Elimination of Submit your manuscript at Tuberculosis. MMWR Recomm Rep. 1990;39(Rr-18):1–21. www.biomedcentral.com/submit http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png BMC Public Health Springer Journals

Tuberculosis progression rates in U.S. Immigrants following screening with interferon-gamma release assays

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Springer Journals
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2016 The Author(s).
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1471-2458
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10.1186/s12889-016-3519-6
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Abstract

Background: Interferon-gamma release assays may be used as an alternative to the tuberculin skin test for detection of M. tuberculosis infection. However, the risk of active tuberculosis disease following screening using interferon-gamma release assays in immigrants is not well defined. To address these uncertainties, we determined the incidence rates of active tuberculosis disease in a cohort of high-risk immigrants with Class B TB screened with interferon-gamma release assays (IGRAs) upon arrival in the United States. Methods: Using a retrospective cohort design, we enrolled recent U.S. immigrants with Class B TB who were screened with an IGRA (QuantiFERON ® Gold or Gold In-Tube Assay) at the San Francisco Department of Public Health Tuberculosis Control Clinic from January 2005 through December 2010. We reviewed records from the Tuberculosis Control Patient Management Database and from the California Department of Public Health Tuberculosis Case Registry to determine incident cases of active tuberculosis disease through February 2015. Results: Of 1233 eligible immigrants with IGRA screening at baseline, 81 (6.6 %) were diagnosed with active tuberculosis disease as a result of their initial evaluation. Of the remaining 1152 participants without active tuberculosis disease at baseline, 513 tested IGRA-positive and 639 tested IGRA-negative. Seven participants developed incident active tuberculosis disease over 7730 person-years of follow-up, for an incidence rate of 91 per 100,000 person-years (95 % CI 43–190). Five IGRA-positive and two IGRA-negative participants developed active tuberculosis disease (incidence rates 139 per 100,000 person-years (95 % CI 58–335) and 48 per 100,000 person- years (95 % CI 12–193), respectively) for an unadjusted incidence rate ratio of 2.9 (95 % CI 0.5–30, p = 0.21). IGRA test results had a negative predictive value of 99.7 % but a positive predictive value of only 0.97 %. Conclusions: Among high-risk immigrants without active tuberculosis disease at the time of entry into the United States, risk of progression to active tuberculosis disease was higher in IGRA-positive participants compared with IGRA-negative participants. However, these findings did not reach statistical significance, and a positive IGRA at enrollment had a poor predictive value for progressing to active tuberculosis disease. Additional research is needed to identify biomarkers and develop clinical algorithms that can better predict progression to active tuberculosis disease among U.S. immigrants. (Continued on next page) * Correspondence: Robert.Blount@ucsf.edu; minhchi.tran@gmail.com Equal contributors Division of Pulmonary and Critical Care Medicine, San Francisco General Hospital, University of California San Francisco, San Francisco, CA, USA Department of Internal Medicine, University of California, Davis, Sacramento, CA, USA Full list of author information is available at the end of the article © 2016 The Author(s). Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Blount et al. BMC Public Health (2016) 16:875 Page 2 of 10 (Continued from previous page) Keywords: Interferon-gamma release assay (IGRA), Tuberculosis (TB), Latent tuberculosis infection (LTBI), Active tuberculosis disease, Foreign-born, Immigrant, Incidence rate, Chest x-ray (CXR), Preventive chemotherapy Abbreviations: ATS, American thoracic society; BCG, Bacillus Calmette-Guerin; BUL, Bilateral upper lobes; CDC, Centers for disease control; CXR, Chest x-ray; HIV, Human immunodeficiency virus; IDSA, Infectious diseases society of America; IGRA, Interferon-gamma release assay; IQR, Interquartile range; IRR, Incidence rate ratio; LLL, Left lower lobe; LTBI, Latent tuberculosis infection; LUL, Left upper lobe; RUL, Right upper lobe; SD, Standard deviation; SFDPH, San Francisco department of public health; TB, Tuberculosis; TST, Tuberculin skin test Background (ATS), CDC, and Infectious Diseases Society of America The number of active tuberculosis (TB) cases in the (IDSA) guidelines [21, 22]. Among these patients are im- United States (U.S.) has declined each year since 1993, migrants, refugees, and asylum-seekers. As part of the yet the proportion of cases in foreign-born persons is immigrant medical evaluation for TB, patients may have steadily rising [1]. In 2014, foreign-born persons had a TST or IGRA, a chest radiograph CXR, and/or accounted for 66.5 % of total cases in the U.S. and had a sputum collected for smear and/or culture. Recommen- 13.4 times higher incidence rate of active TB disease dations for immigration evaluation have changed during compared with U.S.-born persons [2]. Additionally, up the study period [9, 23–25]. Currently, visa applicants to 84 % of active TB in foreign-born persons can be at- outside the U.S. are screened with CXR followed by spu- tributed to reactivation of an infection acquired prior to tum examination if the CXR is suspicious, whereas for arrival in the U.S. [3–5]. Accurately identifying and those residing in the U.S. at the time of application or treating foreign-born persons with latent tuberculosis in- are <15 years old, screening involves a TST or IGRA and fection (LTBI) who are at high risk for progression to ac- if either is positive, a CXR is obtained. From this evalu- tive TB disease should improve overall TB control in the ation visa applicants are assigned a TB classification sta- U.S. [6–9]. tus by the U.S. Citizenship and Immigration Services Interferon-gamma release assays (IGRAs) measure (Table 1). All persons with Class B TB are then referred interferon-gamma secretion following stimulation of T- to their local jurisdiction TB control program upon U.S. lymphocytes with Mycobacterium tuberculosis antigens arrival for further clinical evaluation [25–27]. The Class [10], and may be used as an alternative to the tuberculin B TB classification scheme has been modified during the skin test (TST) [1, 10]. Several studies conducted in close study period and currently includes those with possible contacts of active TB index cases have reported a higher smear and culture negative pulmonary TB (B1-Pulmon- active TB incidence in IGRA-positive persons compared ary), those with a history of successfully treated pulmon- with IGRA-negative persons [11–17]. However, few stud- ary TB (B1-Pulmonary), those with extrapulmonary TB ies have addressed this question in the evaluation of high- (B1-Extrapulmonary), those with a positive TST or risk newly arriving immigrants [18, 19]. IGRA but no evidence of active TB (B2), and those in Since 2005, the San Francisco Department of Public close contact with a known case of smear or culture Health (SFDPH) TB Control Clinic has incorporated positive pulmonary TB but with a negative TST or IGRA IGRAs into routine clinical practice according to Cen- (B3). Prior to 2008, Class B immigrants also included ters for Disease Control and Prevention (CDC) guide- those who had radiographic evidence of old/healed TB. lines [20]. We analyzed data from the SFDPH TB All children and adults with B1-Pulmonary, B2, and B3 Control Patient Management Database and the Califor- TB were offered IGRA screening at the SFDPH TB Con- nia TB Case Registry to provide program-relevant guid- trol Clinic during the enrollment period of January 1, ance on the management of foreign-born patients 2005 through December 31, 2010, and those who re- screened with IGRAs. Our primary objective was to de- ceived IGRA testing were considered for inclusion in termine the risk of progression to active TB disease our study. The IGRA assays (QuantiFERON-TB Gold® among immigrants screened for LTBI with an IGRA from January 1, 2005 through December 31, 2007 and within 1 year of arrival into the United States. QuantiFERON®-TB Gold In-Tube from January 1, 2008 through December 31, 2010, Cellestis Limited, Carnegie, Methods Australia) were performed at the SFDPH laboratory ac- Study population cording to manufacturers’ instructions and interpreted The SFDPH TB Control Clinic evaluates and treats pa- using FDA approved criteria [20]. In addition to IGRA tients with suspected active TB, prior TB, and suspected testing, tuberculin skin tests (Tubersol, 5TU from Sanofi LTBI in accordance with American Thoracic Society Pasteur Limited, Toronto, Canada) were offered at the Blount et al. BMC Public Health (2016) 16:875 Page 3 of 10 Table 1 Current tuberculosis classification for U.S. immigration Department of Public Health TB Case Registry. All inci- applicants dent active TB cases were microbiologically or patho- TB classification Description logically confirmed. We performed a death registry Status match with the California Department of Public Health No TB No evidence of TB infection or disease Vital Statistics Office to determine mortality through classification December 2009. We did not update this match in 2015 A Smear or culture positive pulmonary TB. due to low yield, finding only four deaths in the initial Typically requires treatment prior to U.S. entry. assessment, none of which were known to be attribut- B1-Pulmonary 1. Suspected active pulmonary TB based on able to TB. We classified active TB cases by adapting an clinical findings but with negative sputum existing classification scheme [29]: 1) “likely LTBI reacti- smears and cultures vation” if the IGRA was positive at enrollment but the 2. History of pulmonary TB, treatment complete immigration chest X-ray (CXR) was normal; 2) “likely B1-Extrapulmonary Extrapulmonary TB reactivation of prior TB” if the immigration CXR was B2 TST ≥ 10 mm or positive IGRA but otherwise abnormal but the participant was not diagnosed with ac- negative TB evaluation (LTBI) tive TB disease as a result of the enrollment evaluation; B3 Recent close contact with a known active 3) “likely imported active TB” if the immigration CXR TB case and TST/IGRA negative was abnormal and the participant was diagnosed with Abbreviations: TB tuberculosis, LTBI latent tuberculosis infection, TST tuberculin active TB disease as a result of the enrollment evalu- skin test Cultures were gradually introduced into the overseas screening process ation; and 4) “likely TB infection and disease acquired from 2007–2014 after U.S. immigration” if the participant was IGRA- negative with a normal CXR at the time of enrollment. discretion of the attending physician, performed accord- CXRs were performed overseas near the time of immi- ing to manufacturer guidelines, and interpreted by clinic gration and were repeated upon arrival in the U.S. CXRs staff according to CDC guidelines [28]. Patients diag- were interpreted by physicians at the SFDPH TB Control nosed with LTBI at the time of enrollment were offered Clinic during the baseline evaluation. The CXR per- preventive chemotherapy if they had not yet received ad- formed in the U.S. closest to baseline evaluation was equate therapy overseas. Patients typically self- used as the CXR interpretation for the study. The IGRA administered their medication, coming in to the TB and TST results reported in this study were from the clinic for monthly refills. Adherence was monitored at post-arrival baseline evaluation. monthly clinic visits, and completion of therapy docu- mented once the required course of preventive chemo- Statistical analysis therapy had be taken per patient report. We excluded We used Pearson’s chi-squared test for comparisons of persons who were evaluated more than 1 year following proportions and Student’s T-test for comparisons of their immigration date or had persistently indeterminate means. We calculated unadjusted incidence and inci- IGRA results despite repeat testing. Patients who were dence rate ratios (IRR) with 95 % confidence intervals diagnosed with or treated for active TB disease for > per 100,000 person-years of follow-up, with statistical 30 days as a direct result of their initial evaluation at the significance defined as an IRR p value < 0.05. We esti- TB Control Clinic were counted as prevalent cases and mated the cumulative incidence of active TB disease excluded from the final analysis. Clinical, radiologic, and using Kaplan-Meier curves. We determined IGRA test laboratory data were written on standardized forms in performance by calculating sensitivity, specificity, posi- the medical record and then entered into the SFDPH TB tive and negative predictive value, and positive and nega- Control Patient Management Database. Study treatment tive likelihood ratios. We performed statistical analyses status was reflective of any documented TB treatment using Stata/SE 13.1 (College Station, Texas, USA). received either before or after U.S. entry and throughout the followup period up until a diagnosis of active TB or Results the end of the study, whichever came first. Baseline demographic and clinical characteristics During the enrollment period January 1, 2005 through Study outcome December 31, 2010 we screened 1,419 Class B TB immi- Follow-up time began on the day of IGRA testing at the grants for LTBI. We excluded 78 (5.5 %) who did not initial SFDPH TB Control Clinic visit and was censored have IGRA testing completed, 79 (5.6 %) who were eval- on the day of active TB diagnosis (event), death, or the uated > 1 year following immigration, 23 (1.6 %) who end of the study (February 2015). We identified active had indeterminate IGRA results despite repeat testing, TB cases during follow-up using the SFDPH TB Control and 6 (0.4 %) who had an unknown or incorrect immi- Patient Management Database and the California gration date (Fig. 1). From the remaining 1,233 eligible Blount et al. BMC Public Health (2016) 16:875 Page 4 of 10 Fig. 1 Enrollment flow chart participants, 81 (6.6 %) were found to have active TB Among IGRA-positive participants, 87 % had received disease during enrollment screening. All but one preva- either overseas treatment for TB infection or disease lent case, and all of the 42 microbiologically confirmed prior to immigration (n = 188) or LTBI treatment upon prevalent cases, had abnormal immigration CXRs at the immigration in the U.S. (n = 260). Tuberculin skin test- time of U.S. entry. IGRA was positive in 54 (67 %) of ing was performed in only 298 participants with a simi- total prevalent cases and in 34 (81 %) of microbiologic- lar percent positive TST in IGRA-negative participants ally confirmed prevalent cases. All prevalent cases were (76 %) as in IGRA-positive participants (79 %) (p = 0.5). then excluded, while the remaining 1,152 subjects were TST test results correlated poorly with IGRA test results included in the final analysis. The average time from im- (r = 0.037). CXR results were available for nearly all par- migration to IGRA testing was 32 days (SD 42). We ex- ticipants (n = 1150) and found to be abnormal in 881 amined baseline demographic and clinical characteristics (77 %). IGRA-positive participants were more likely to by IGRA test results: 639 (55 %) were IGRA-negative have an abnormal CXR compared with IGRA-negative and 513 (45 %) were IGRA-positive (Table 2). Median participants (90 vs 66 %, p < 0.0001). age was 54 (IQR 39–64) years and IGRA-positive partic- ipants were significantly older than those with IGRA- Incident active TB cases negative test results at enrollment (p < 0.0001). Of the Seven participants (0.6 %) developed incident active TB 973 participants over the age of 21, 494 (51 %) were disease over the 10 year follow-up period (Table 3). The IGRA-positive at enrollment, whereas of the 179 partici- majority of cases (57 %) were male, all were adults be- pants under the age of 21, only 19 (11 %) were IGRA- tween the ages of 39 and 60 (median 52) at the time of positive. The majority of participants were male (n = enrollment, and all but one case had emigrated from 645, 56 %), and 1066 (93 %) emigrated from one of three China. Five (71 %) were IGRA-positive while two were countries: China, the Philippines, or Vietnam. Baseline IGRA-negative at enrollment. Case #5 was likely LTBI TB risk factors were assessed: only 0.25 % of participants reactivation as the CXR performed 1 week after arrival had known HIV-infection, 5.4 % had diabetes, while in the U.S. was normal and the IGRA at that time was 30 % reported current or former tobacco smoking. positive. This participant was diagnosed with active TB IGRA-positive participants were more likely to be disease latest at 6.3 years after enrollment. The other six smokers than IGRA-negative participants (p < 0.0001). cases (86 %) were likely reactivation of prior TB, having Nearly half (49 %) of participants immigrated with a B1- immigration CXR findings in the upper lobes consistent Pulmonary classification (TB suspect or prior TB), while with prior TB. These participants were diagnosed with 51 % received an overseas classification of B2 (LTBI). active TB disease a median of 4.5 years after enrollment Blount et al. BMC Public Health (2016) 16:875 Page 5 of 10 Table 2 Baseline demographic and clinical characteristics by IGRA status Characteristic All subjects IGRA-negative IGRA-positive p value n (%) n (%) n (%) All 1152 (100) 639 (55) 513 (45) Median age, years (IQR) 54 (39–64) 52 (21–64) 55 (45–65) Mean age, years (SD) 49 (20) 45 (23) 53 (15) <0.0001 Age by category, years, n (%) n = 1152 n = 639 n = 513 <0.0001 0–4 18 (1.6) 17 (2.7) 1 (0.2) 5–12 87 (7.6) 81 (13) 6 (1.2) 13–20 74 (6.4) 62 (9.7) 12 (2.3) ≥ 21 973 (84) 479 (75) 494 (96) Gender n = 1152 n = 639 n = 513 0.141 Male 645 (56) 345 (54) 300 (58) Female 507 (44) 294 (46) 213 (42) Country of origin n = 1150 n = 638 n = 512 0.001 China 586 (51) 302 (47) 284 (55) Philippines 386 (34) 245 (38) 141 (28) Vietnam 94 (8.2) 42 (6.6) 52 (10) Burma 18 (1.6) 11 (1.7) 7 (1.4) Other 66 (5.7) 38 (6.0) 28 (5.4) HIV status n = 799 n = 404 n = 395 <0.0001 HIV- 797 (99.8) 402 (99.5) 395 (100) HIV+ 2 (0.25) 2 (0.5) 0 Diabetes n = 1152 n = 639 n = 513 0.09 No 1090 (95) 611 (96) 479 (93) Yes 62 (5.4) 28 (4.4) 34 (6.6) Smoking status n = 1152 n = 639 n = 513 <0.0001 Never 803 (70) 476 (74) 327 (64) Current or Former 349 (30) 163 (26) 186 (36) TB Classification at immigration n = 1152 n = 639 n = 513 0.0001 B1-Pulmonary (TB suspect or prior TB) 561 (49) 276 (43) 285 (56) B2 (LTBI) 588 (51) 361 (56) 227 (44) B3 (Contact) 3 (0.26) 2 (0.31) 1 (0.19) BCG n = 490 n = 309 n = 181 0.004 No evidence of BCG vaccination 114 (23) 59 (19) 55 (30) Evidence of BCG vaccination 376 (77) 250 (81) 126 (70) Treatment status n = 1152 n = 639 n = 513 <0.0001 Inadequate or no TB treatment 498 (43) 433 (68) 65 (13) Overseas TB treatment prior to immigration 324 (28) 136 (21) 188 (37) LTBI treatment in U.S. after immigration 330 (29) 70 (11) 260 (51) TST Result n = 298 n = 230 n = 68 0.5 Negative 70 (23) 56 (24) 14 (21) Positive 228 (77) 174 (76) 54 (79) Immigration CXR Result n = 1150 n = 637 n = 513 <0.0001 Normal 269 (23) 216 (34) 53 (10) Abnormal 881(77) 421 (66) 460 (90) Blount et al. BMC Public Health (2016) 16:875 Page 6 of 10 Table 2 Baseline demographic and clinical characteristics by IGRA status (Continued) Prevalent TB cases at enrollment Total 81/1233 (6.6) 27/666 (4.1) 54/567 (9.5) 0.0001 Microbiologically confirmed 42/1233 (3.4) 8/666 (1.2) 34/567 (6.0) <0.0001 Abbreviations: IGRA interferon-gamma release assay, IQR interquartile range, HIV human immunodeficiency virus, TST tuberculin skin test, TB tuberculosis, CXR chest x-ray Table numbers represent n (%) unless otherwise indicated Treatment status reflects any TB treatment received up until the time of diagnosis with active TB disease: either overseas treatment for TB infection or disease prior to U.S. entry, or LTBI treatment received in the U.S. after immigration (IQR 3.7–4.8). None of the cases had known HIV, dia- IRR of 1.9 (95 % CI 0.33–13, p = 0.41). These differences, betes, or tobacco smoking risk factors. Three of the five however, did not reach statistical significance. The risk cases that were IGRA-positive at enrollment completed for progression to active TB disease was highest among LTBI treatment after enrollment. Diagnosis was con- IGRA-positive participants who had received inadequate firmed with sputum culture for six cases and by lung bi- or no TB treatment before and after U.S. arrival (inci- opsy pathologic features (caseating granulomatous dence rate 443 per 100,000 person-years, 95 % CI 111– inflammation) for one case. 1775), while risk was lower in IGRA-positive partici- pants who received TB treatment (incidence rate 96 per Incidence rates for active TB disease during follow-up 100,000 person-years, 95 % CI 31–296), for an IRR of The seven incident active TB cases occurred over 7730 4.6 (95 % CI 0.39–41, p = 0.14). The risk was lowest person-years of cumulative follow-up, for a median among IGRA-negative participants who had received follow-up of 6.7 years (IQR 5.1–8.2) and an overall inci- prior treatment for TB (incidence rate of 0) and IGRA- dence rate of 91 per 100,000 person-years (95 % CI 43– negative participants who had a normal immigration 190) (Table 4). Incidence rates for active TB disease di- CXR (incidence rate of 0). For the entire cohort we agnosed during follow-up were higher in IGRA-positive found a 5 year cumulative incidence of 0.48 % and a participants (139 per 100,000 person-years, 95 % CI 58– 10 year cumulative incidence of 0.77 % (Fig. 2). 335) compared with those who were IGRA-negative at enrollment (48 per 100,000 person-years, 95 % CI 12– IGRA test characteristics 193), for an unadjusted incidence rate ratio (IRR) of 2.9 The IGRA test had a sensitivity of 71 % (95 % CI 29- (95 % CI 0.5–30, p = 0.21). Additionally, active TB inci- 96 %) for predicting progression to active TB disease, a dence rates were higher in those with inadequate or no specificity of 56 % (95 % CI 53–59 %), a positive predict- prior TB treatment (127 per 100,000 person-years, 95 % ive value of only 0.97 % (95 % CI 0.32–2.3 %), and a CI 48–339) compared to those with prior TB treatment negative predictive value of 99.7 % (95 % CI 98.9– (65 per 100,000 person-years 95 %, CI 21–203), for an 100 %). The positive likelihood ratio was 1.6 (95 % CI Table 3 Incident active TB cases Case IGRA Ag-Nil, Mitogen CXR findings HIV Diabetes Smoker TB Treatment status TB confirmation (IU/ml) Class 1 Neg 0.38–0.11, 20 Pleural thickening, RUL Neg No No B1 None Lung biopsy pathology 2 Pos 0.93–0.12, 2.0 Fibronodular changes, BUL Unk No No B2 None sputum culture & LLL 3 Neg 0.29–0.11, 25 Fibrotic changes, LUL Neg No No B2 Incomplete tx prior to sputum culture immigration 4 Pos 2.4–0.12, 25 Fibronodular changes, RUL Neg No No B1 LTBI tx at enrollment sputum culture 5 Pos 9.7–0.70, 24 Normal Neg No No B1 LTBI tx at enrollment sputum culture 6 Pos 3.1–0.12, 8.9 Nodular infiltrate, LUL Neg No No B1 LTBI tx at enrollment sputum culture 7 Pos 1.1–0.16, 6.9 Fibrotic changes, LUL; Neg No No B1 Incomplete LTBI tx at sputum culture Effusion, L enrollment Abbreviations: TB tuberculosis, IGRA interferon-gamma release assay, Ag-Nil interferon-gamma response with antigen minus response without antigen, Mitogen interferon-gamma response to mitogen, HIV human immunodeficiency virus, CXR chest x-ray, Pos positive, Neg negative, Unk unknown, RUL right upper lobe, BUL bilateral upper lobes, LLL left lower lobe, LUL left upper lobe, L left, LTBI latent tuberculosis infection, tx treatment Treatment status reflects any TB treatment received up until the time of diagnosis with active TB disease: either overseas treatment for TB infection or disease prior to U.S. entry, or LTBI treatment received in the U.S. after immigration Defaulted after 3 months of active TB treatment Received a 1 month prescription for isoniazid but was lost to follow-up. Unclear if patient took any of the medication Blount et al. BMC Public Health (2016) 16:875 Page 7 of 10 Table 4 Active TB incidence rates for treatment status, CXR findings, and overseas TB classification by IGRA result Treatment status, CXR, and TB class by IGRA result n (% of all participants) Incident active TB cases, Total follow-up Incidence rate per 100,000 n (% cases in sub-group) (person-years) person-years (95 % CI) All participants 1152 (100) 7 (0.60) 7730 91 (43–190) IGRA- 639 (55) 2 (0.31) 4139 48 (12–193) IGRA+ 513 (45) 5 (0.97) 3591 139 (58–335) Inadequate or no TB treatment 498 (43) 4 (0.80) 3148 127 (48–339) IGRA- 433 (38) 2 (0.46) 2698 74 (19–296) IGRA+ 65 (6.0) 2 (3.1) 451 443 (111–1775) Adequate TB treatment 654 (57) 3 (0.46) 4581 65 (21–203) IGRA- 206 (18) 0 1441 0 IGRA+ 448 (39) 3 (0.67) 3140 96 (31–296) Normal CXR 269 (23) 1 (0.37) 1553 64 (9.1–457) IGRA- 216 (19) 0 1206 0 IGRA+ 53 (4.6) 1 (1.9) 347 288 (41–2047) Abnormal CXR 881 (77) 6 (0.68) 6158 97 (44–217) IGRA- 421 (37) 2 (0.48) 2914 69 (17–274) IGRA+ 460 (40) 4 (0.87) 3244 123 (46–329) B1 TB, Pulmonary 561 (49) 5 (0.89) 3630 138 (57–331) IGRA- 276 (24) 1 (0.36) 1759 57 (8.0–404) IGRA+ 285 (25) 4 (1.4) 1870 214 (80–570) B2 (LTBI) 588 (51) 2 (0.34) 4084 49 (12–196) IGRA- 361 (31) 1 (0.28) 2370 42 (5.9–300) IGRA+ 227 (20) 1 (0.44) 1714 58 (8.2–414) B3 (Contacts) 3 (0.26) 0 16 0 Abbreviations: TB tuberculosis, IGRA interferon-gamma release assay Treatment status reflects any TB treatment received up until the time of diagnosis with active TB: either overseas treatment for TB infection or disease prior to U.S. entry, or LTBI treatment received in the U.S. after immigration n = 1150 (2 participants missing CXRs) Fig. 2 Cumulative incidence of active tuberculosis (TB) disease among high-risk U.S. immigrants, 2005–2015 Blount et al. BMC Public Health (2016) 16:875 Page 8 of 10 1.0–2.6) and the negative likelihood ratio was 0.51 (95 % absent [29]. Six of the seven immigrants who developed CI 0.16–1.7). Among IGRA-positive participants with nil active TB disease had upper lobe abnormalities on their values ≤ 0.7 IU/ml, there was not a statistically signifi- immigration CXR. None had overseas documentation of cant difference in TB response values at baseline among adequate prior TB therapy, two had negative IGRA re- those that developed active TB (median 2.3 IU/ml, IQR sults, and only two completed LTBI treatment in the 0.93–3.0) compared with those who did not develop ac- U.S. Conversely, no active TB developed among immi- tive TB (1.6, 0.71–4.0) (p = 0.6). grants who were both IGRA-negative and had a normal immigration CXR. These findings suggest that high-risk Discussion immigrants with abnormal CXRs consistent with prior We evaluated the rates of progression to active TB dis- TB should be considered for preventive chemotherapy ease among a cohort of high-risk immigrants screened regardless of IGRA result. for LTBI with IGRAs at the San Francisco Department As expected, active TB incidence was highest among of Public Health TB Control Clinic in a large study of 13 % of participants who were IGRA-positive at enroll- 1152 participants with 7730 person-years of follow-up ment but received inadequate or no prior TB treatment. time. We found a high prevalence of active TB disease at Our findings suggest that IGRA-positive immigrants are baseline evaluation and a high incidence of active TB at high risk for progression to active TB disease, espe- disease over the median follow-up time of 6.7 years. The cially if they have not received adequate preventive incidence rates of active TB disease were higher in chemotherapy, and efforts should be made to treat this IGRA-positive participants compared with those who group. The remaining 87 % of IGRA-positive partici- were IGRA-negative at enrollment. However, these find- pants did receive TB treatment and although the inci- ings were not statistically significant and a positive IGRA dence rate for progression to active TB was more than 4 at enrollment had a poor predictive value for progres- times lower than in those who had not received ad- sion to active TB disease. equate therapy, the rate in treated individuals remained Our findings are largely consistent with a prior meta- unacceptably high. It is unclear why preventive TB analysis and a recent prospective cohort study from Eur- chemotherapy had only a modest impact on progression ope, both of which found that IGRAs had poor predict- to active TB in our study. Preventive chemotherapy for ive value for active TB disease in one or more high-risk LTBI was not typically delivered as directly observed groups (case contacts, health care workers, immigrants, therapy, so adherence was not guaranteed. Also, since people living with HIV, and patients with silicosis) [11, treatment was not randomized, participants who were 12]. In our cohort, the risk of developing active TB dis- more likely to progress to active TB disease (such as ease was high regardless of IGRA results. The overall in- those with a positive IGRA and evidence of prior TB by cidence rate of 91 per 100,000 person-years and even CXR) may have preferentially received preventive the incidence rate for IGRA-negative participants (48 chemotherapy (confounding by indication). per 100,000 person years) were considerably higher than More than 6 % of our initial cohort were diagnosed with the incidence for U.S.-born persons, which decreased prevalent active TB as a result of the enrollment evalu- from 2.5 cases per 100,000 persons in 2005 to 1.1 cases ation. All but one of the prevalent cases had an abnormal per 100,000 persons in 2014 [2, 30]. immigration CXR consistent with imported active pul- In our cohort there was a heightened risk of develop- monary TB. This high prevalence is consistent with other ing active TB among Class B immigrants with CXR evi- studies of recent immigrants [13, 29, 32], and highlights dence of prior TB. This elevated risk was sustained over the importance of a thorough and timely TB evaluation of several years, with incident active TB disease occurring high-risk immigrants upon U.S. entry. In response to high from 2.8 to 6.3 years after enrollment and 10 year cumu- numbers of imported active TB among newly arrived im- lative incidence nearly double the 5 year cumulative inci- migrants, the CDC has recently modified its pre- dence. The sustained high incidence is consistent with immigration screening to include sputum cultures instead other studies of immigrants from TB-endemic countries of smears alone for TB suspects. This intensified overseas [1, 29, 31], suggesting that foreign-born persons from screening has resulted in a decrease in prevalent active TB TB-endemic countries should be screened for LTBI re- among recent immigrants [29, 33, 34]. gardless of how recently they immigrated to the U.S., Our study had several limitations. We identified only and that a high level of suspicion for active TB disease seven cases of incident active TB despite following a should be maintained in this group even when IGRA re- large cohort for more than 7,000 person-years. This sults are negative. small number of outcomes led to imprecise incidence Our findings confirm the importance of radiographic rate estimates and difficulty in determining the effects of evidence of prior TB as a key risk factor for developing multiple predictors such as IGRA status, LTBI treat- TB, particularly when overseas treatment is uncertain or ment, and CXR abnormalities on active TB incidence Blount et al. BMC Public Health (2016) 16:875 Page 9 of 10 rates. We were careful only to include true incident additional research is needed to identify biomarkers and cases, excluding prevalent cases diagnosed as a result of develop clinical algorithms that can better predict pro- enrollment screening and only including microbiologic- gression to active TB disease among U.S. immigrants. ally or pathologically confirmed cases of active TB dis- Acknowledgments ease in the final analysis. Inclusion of clinically We thank L. Masae Kawamura, M.D., former Director of the SFDPH TB Control diagnosed cases would have increased incidence rates, Clinic, who supported this research in that role. We would like to acknowledge the clinicians and staff of the SFDPH TB Control Clinic, who but would have also increased the likelihood of mis- work to prevent and treat TB in San Francisco, and without whom this classification of outcome. Case detection was limited by research would not have been possible. a passive follow-up and case finding approach. We iden- tified cases reported in California but may have missed Funding This work was supported by the National Institutes of Health: grants cases among those participants that moved out of state, K23ES025807 (RB), K23HL094141 (AC), and R01AI104589 (PN). Its contents are resulting in an underestimation of incidence rates. Add- solely the responsibility of the authors and do not necessarily represent the itionally, we were unable to censor follow-up time for official view of the NIH. participants that moved out of state or for all partici- Availability of data and materials pants that died during the follow-up period, which The data used in this study is stored and maintained by the San Francisco would result in an overestimation of person-years at risk. Department of Public Health and the California Department of Public Health, These limitations would have led to a conservative, non- and is available through an application process. informative bias whereby incidence rates in both IGRA- Authors’ contributions positive and IGRA-negative participants were equally RJB and MCT were involved in all aspects of the study, including study underestimated, assuming that moving and death were design, data acquisition, data analysis, and writing of the manuscript. AC, JH, not associated with IGRA status. Second, although our and PN were involved in study design and critical revision of the manuscript. CKE, JZM, CRM, JG, and DC were involved in data analysis and critical case registries were rich sources of demographic and revision of the manuscript. All authors have given final approval of the clinical data, reliance on registry data limited our ability version to be published and agree to be accountable for all aspects of the to comprehensively characterize patients. Additionally, work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. without TB genotypes for the active cases we were un- able to confirm M. tuberculosis origin. Finally, this is a Competing interests single center’s experience and reflects the largely Asian The authors declare that they have no competing interests. immigrant population of San Francisco. As such our Consent to publish findings might not be generalizable to other high TB Not applicable. burden areas in the U.S. such as southern California and Texas which experience a higher proportion of immi- Ethics approval and consent grants from Central and South America. The Committee on Human Research at the University of California, San Francisco and the Committee for the Protection of Human Subjects at the California Department of Health and Human Services approved the study Conclusions protocol. A consent to participate was not required for this retrospective Our study found a high prevalence of active TB disease review of public health data. among newly arrived immigrants and high incidence Author details rates of active TB disease throughout a median of 1 Division of Pulmonary and Critical Care Medicine, San Francisco General 6.7 years follow-up. Risk of progression to active TB dis- Hospital, University of California San Francisco, San Francisco, CA, USA. Division of Pediatric Pulmonary Medicine, University of California, San ease was higher in IGRA-positive participants compared Francisco, CA, USA. Department of Internal Medicine, University of California, with IGRA-negative participants, although these findings 4 Davis, Sacramento, CA, USA. Department of Medicine, University of did not reach statistical significance. Risk was highest California, San Francisco, CA, USA. San Francisco Department of Public Health, Population Health Division, Office of Equity and Quality among IGRA-positive participants who had received in- Improvement, San Francisco, CA, USA. San Francisco Department of Public adequate or no prior treatment for TB and lowest Health, Population Health Division, Disease Prevention and Control Branch, among IGRA-negative participants who had received San Francisco, CA, USA. prior treatment for TB or who had a normal CXR. Our Received: 19 August 2015 Accepted: 17 June 2016 findings support the role of timely and thorough TB screening of high-risk newly arrived immigrants from TB-endemic countries, preventive chemotherapy for References 1. LoBue PA, Enarson DA, Thoen TC. Tuberculosis in humans and its IGRA-positive foreign-born persons from TB-endemic epidemiology, diagnosis and treatment in the United States. 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BMC Public HealthSpringer Journals

Published: Dec 1, 2016

Keywords: public health; medicine/public health, general; epidemiology; environmental health; biostatistics; vaccine

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