Risk factors for extrapulmonary dissemination of tuberculosis and associated mortality during treatment for extrapulmonary tuberculosis

Risk factors for extrapulmonary dissemination of tuberculosis and associated mortality during... Many environmental, host, and microbial characteristics have been recognized as risk factors for dissemination of extrapulmonary tuberculosis (EPTB). However, there are few population-based studies investigating the association between the primary sites of tuberculosis (TB) infection and mortality during TB treatment. De-identified population- based surveillance data of confirmed TB patients reported from 2009 to 2015 in Texas, USA, were analyzed. Regression analyses were used to determine the risk factors for EPTB, as well as its subsite distribution and mortality. We analyzed 7007 patients with exclusively pulmonary TB, 1259 patients with exclusively EPTB, and 894 EPTB patients with reported concomitant pulmonary involvement. Age ≥45 years, female gender, human immunodeficiency virus (HIV)-positive status, and end-stage renal disease (ESRD) were associated with EPTB. ESRD was associated with the most clinical presentations of EPTB other than meningeal and genitourinary TB. Patients age ≥45 years had a disproportionately high rate of bone TB, while foreign-born patients had increased pleural TB and HIV+ patients had increased meningeal TB. Age ≥45 years, HIV+ status, excessive alcohol use within the past 12 months, ESRD, and abnormal chest radiographs were independent risk factors for EPTB mortality during TB treatment. The epidemiologic risk factors identified by multivariate analyses provide new information that may be useful to health professionals in managing patients with EPTB. Introduction (19.3–39.3%) present with either primary extrapulmonary Tuberculosis (TB), especially with human immunode- tuberculosis (EPTB) or EPTB concurrent with pulmonary ficiency virus (HIV) co-infection, is a leading cause of involvement, while the majority of patients develop pul- 1 3, 4 death worldwide . Individuals infected with Mycobacter- monary TB (PTB) . Some studies have suggested that ium tuberculosis (Mtb) may either be asymptomatic the proportion of EPTB among all TB cases has been (latent TB infection, LTBI) or develop active TB disease . increasing in the United States (USA) (21% in 2013 For active TB disease, a small subset of patients compared to 16% in 1993) mainly because of the 5, 6 increasing prevalence of HIV infection . Typically, Mtb infection leads to spatial and temporal Correspondence: Edward A. Graviss (eagraviss@houstonmethodist.org) lesion dynamics not only within a single individual but also Key Laboratory of Laboratory Medicine, Ministry of Education, Zhejiang 7, 8 between individuals . The most common extra- Provincial Key Laboratory of Medical Genetics, Wenzhou Medical University, pulmonary sites of TB infection are the lymph nodes, the Wenzhou, P. R. China Center for Precision Biomedicine, Institute of Molecular Medicine, McGovern pleura, the genitourinary system, the gastrointestinal tract, Medical School, The University of Texas Health Science Center at Houston, the bones, and the central nervous system. To date, the Houston, TX, USA mechanisms for extrapulmonary dissemination remain Full list of author information is available at the end of the article. These authors contributed equally: Xu Qian, Duc T. Nguyen © The Author(s) 2018 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to theCreativeCommons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. 1234567890():,; 1234567890():,; Qian et al. Emerging Microbes & Infections (2018) 7:102 Page 2 of 14 largely unknown . It has been found that host–pathogen factors for EPTB and mortality at 6 months after TB interactions such as pathogen-associated molecular pattern diagnosis from 1995 through 1999 in Harris Country, signaling, antigen presentation, and immune recognition Texas, but this study analyzed data at the county level and may be used by Mtb to mediate latency induction and not at the state or country level . The third example is pathogen reactivation . These factors are believed to be the association of Mtb lineage with the site of TB disease important in establishing the site of disease presentation in a study that analyzed US data from 2004 through 2008; and dissemination. One recent study, which assessed the study reported that the Euro-American, Indo-Ocea- within-host bacterial population dynamics in a macaque nic, and East African-Indian bacterial lineages were found TB model by using a genome barcoding system coupled exclusively in EPTB . Given the variety of organ-specific with serial F-fluorodeoxyglucose radiotracers and posi- clinical scenarios and the nonspecific systemic symptoms tron emission tomography co-registered with computed of EPTB, a more profound understanding of the site tomography (PET/CT), suggested that in the first 6 weeks distribution of EPTB, as well as the risk factors associated after infection, granuloma size but not bacterial burden is with extrapulmonary dissemination and mortality, is correlated with risk of local dissemination (<10 mm away) important for developing suitable protocols to manage in the lungs . Furthermore, genomic analyses of samples EPTB patients. Accordingly, this analysis aimed to from lung and extrapulmonary biopsies of HIV-co-infected determine the characteristics associated with EPTB dis- patients have demonstrated that the dissemination of Mtb semination and mortality during TB treatment by using from the lungs to extrapulmonary sites may occur as fre- recent epidemiological data from Texas. quently as between lung sites . Importantly, Mtb sub- lineages were differentially distributed throughout the Materials and methods lungs of these immunocompromised patients. Therefore, De-identified surveillance data of all confirmed TB data from Lieberman and co-workers suggest that biop- patients reported to the Centers for Disease Control and sies from the upper airway represent only a small fraction Prevention’s TB Genotyping Information Management of the population diversity. These data are also consistent System (TBGMIS) between January 2009 and December with a nonhuman-primate-model study which showed 2015 from the state of Texas, USA, were analyzed. TB barcodes recovered from gastric and bronchoalveolar disease was classified as exclusively PTB, exclusively EPTB lavage samples represented only a fraction (3.75%) of all or EPTB with concurrent PTB involvement. Sites of EPTB bacterial barcodes . Additionally, there has been a study include pleural, lymphatic, bone, genitourinary, perito- neal, and meningeal locations, among others. All patients evaluating the immune response profile of inflammatory cytokinessuchasinterferon-γ, interleukin (IL)-1β,and received anti-TB treatment, and their outcomes were tumor necrosis factor (TNF)-β in HIV-negative children recorded as “completed”, “died”,or “unknown”. with TB disease . At the time of TB diagnosis, the immune Cases were categorized by site of disease. Differences response in all pediatric TB patients (suppressed pro- across groups (exclusively PTB, exclusively EPTB and inflammatory cytokines and increased regulatory T cell EPTB with concurrent PTB involvement) were deter- frequency) was not significantly different between PTB and mined by the chi-squared test or Fisher’s exact test as EPTB patients. However, the recovery of the immune appropriate. Logistic regression was used to determine the response was observed in children with PTB but not in characteristics that were associated with patients having children with EPTB after 6 months of TB treatment . exclusively PTB compared to individuals identified to These findings suggest that the host immune response have (1) exclusively EPTB, (2) EPTB with concurrent PTB following treatment is specific to the disease (PTB vs. involvement, or (3) any EPTB (patients with exclusively EPTB) rather than due to the within-host defense and EPTB and EPTB with concurrent PTB involvement). cannot explain why one individual develops PTB while Odds ratios (OR), adjusted odds ratios ( OR), and 95% another develops EPTB. confidence intervals (CI) were reported. Multiple logistic Clinically, EPTB is still underrecognized, and diagnoses regression modeling was also used to determine the risk are often delayed due to its paucibacillary nature and of patient mortality during treatment in patients with atypical presentations. In fact, many characteristics such exclusively EPTB. Analyses were performed with SPSS as HIV and female gender have been recognized as risk 16.0 (SPSS, Inc., Chicago, Illinois, USA) and Stata MP14.2 12–14 factors for EPTB dissemination . However, there are (StataCorp LP, College Station, TX, USA). A p-value of few population-based studies in the USA investigating the <0.05 was considered statistically significant. association between primary sites of Mtb infection and mortality during TB treatment. For instance, one study Results analyzed the epidemiology and risk factors of EPTB from Study population and characteristics 1993 through 2006 but did not analyze risk factors for From 2009 to 2015, there were 9246 confirmed TB patient mortality . Another study demonstrated risk patients in Texas recorded in the TBGIMS database. After Qian et al. Emerging Microbes & Infections (2018) 7:102 Page 3 of 14 Fig. 1 Flowchart of the study population. TBGIMS Genotyping Information Management System, PTB pulmonary TB, EPTB extrapulmonary TB excluding 86 patients because their EPTB site was (Table 2). Patients with a history of contact with a known unknown, we included 9160 TB patients in the analysis TB index case within 2 years ( OR 0.44, 95% CI 0.35–0.55) (Fig. 1). The patients’ demographic and clinical char- and those with diabetes ( OR 0.61, 95% CI 0.52–0.71) acteristics are presented in Table 1. The majority of were less likely to have EPTB than PTB (Table 2). exclusively EPTB patients were male (55.4%) and foreign ESRD was associated with most subtypes of EPTB, born (59.1%). The proportions of patients age 25–44 years excluding meningeal and genitourinary TB (Table 3). (39.6%) and Hispanic patients (46.6%) with exclusively Patients age ≥45 years had a disproportionately high rate EPTB were higher than the proportions of other age or of bone TB ( OR 1.47, 95% CI 1.04–2.08), while foreign- ethnic groups with exclusively EPTB. The percentage of born patients had more pleural TB ( OR 1.77, 95% CI TB contact history was higher in patients with exclusively 1.31–2.41) and HIV+ patients had more meningeal TB EPTB (3.7%) than in patients with PTB (9.0%) or EPTB ( OR 5.73, 95% CI 3.43–9.56) (Table 3). with concurrent PTB (6.9%). In patients with exclusively EPTB, 448/1259 (35.6%) had abnormal chest radiographs Risk factors for mortality during treatment in patients with and 17/1259 (1.4%) had culture-positive specimens. exclusively EPTB Multidrug-resistant TB (MDR-TB) was identified in 0.4% Among the 1111 patients with exclusively EPTB who of exclusively EPTB cases, 0.1% of EPTB cases with con- had mortality-related data available, 50 (4.5%) died during current PTB, and 0.8% of exclusive PTB cases. Two anti-TB treatment. Mortality was highest among those extensively drug-resistant cases were identified in PTB patients presenting with meningeal (9.6%) or peritoneal patients. The most prevalent Mtb lineages of exclusively TB (8.5%) and lower among those individuals with lym- EPTB were Euro-American L4, East Asian L2, and Indo- phatic TB (0.7%) (Fig. 2b). During treatment, no mortality Oceanic L1. was reported among patients having either laryngeal or multisite TB. Age ≥45 ( OR 3.75, 95% CI 1.71–8.22), HIV Sites of EPTB + status ( OR 4.70, 95% CI 1.54–14.32), excessive alcohol The distribution of EPTB sites is shown in Fig. 2a. Of use within the past 12 months ( OR 3.34, 95% CI the patients with exclusively EPTB, the most common 1.45–7.67), ESRD ( OR 4.45, 95% CI 1.38–14.33), and sites of TB disease included pleural (15.7%), lymphatic abnormal chest radiographs ( OR 2.18, 95% CI 1.09–4.35) (32.3%), bone (12.2%), and meningeal (7.5%) sites. The were risk factors for TB mortality with adjusted odds ratio most common sites of TB disease in patients having EPTB (Table 4). with concomitant PTB were also pleural (38.1%), lym- phatic (20.8%), bone (7.9%), and meningeal (6.7%) areas. Discussion Although risk factors for the development of exclusively Risk factors for EPTB and its specific sites EPTB compared to PTB have been described in several 5, 12, 16, 17 Multivariable analyses were performed in order to studies , there are still inconsistent findings identify associations between sociodemographic, micro- among studies from different regions, including sub- biologic, and clinical characteristics of EPTB patients and stantial state-level heterogeneity in the reported epide- a 18 sites of EPTB. Female patients ( OR 1.32, 95% CI miological data . We performed an analysis of EPTB 1.19–1.46), as well as patients with HIV+ status ( OR patients in the state of Texas. We found that patients who 1.77, 95% CI 1.47–2.13), immunosuppression ( OR 1.31, were age ≥45 years, female, HIV+, and suffering from 95% CI 1.00–1.77), and ESRD ( OR 3.42, 95% CI ESRD were at a significantly elevated risk of EPTB. In 2.39–4.88) were at a significantly elevated risk of EPTB particular, age ≥45 years, HIV+, excessive alcohol use Qian et al. Emerging Microbes & Infections (2018) 7:102 Page 4 of 14 Table 1 Characteristics of tuberculosis patients with pulmonary and extrapulmonary locations in Texas, USA, 2009–2015 Variable Total Exclusively PTB Exclusively EPTB EPTB with PTB p-Value N 9160 7007 1259 894 Age (years) <0.01 0–4 395 (4.3) 297 (4.2) 63 (5.0) 35 (3.9) 5–14 213 (2.3) 146 (2.1) 43 (3.4) 24 (2.7) 15–24 1048 (11.4) 808 (11.5) 129 (10.2) 111 (12.4) 25–44 3054 (33.3) 2245 (32.1) 498 (39.6) 311 (34.8) 45–64 3015 (33.0) 2403 (34.3) 361 (28.7) 251 (28.1) ≥65 1435 (15.7) 1108 (15.8) 165 (13.1) 162 (18.1) Gender <0.01 Male 5954 (65.0) 4684 (66.8) 697 (55.4) 573 (64.1) Female 3206 (35.0) 2323 (33.2) 562 (45.6) 321 (35.9) Ethnicity <0.01 White 1103 (12.0) 911 (13.0) 108 (8.6) 84 (9.4) Black 1717 (18.7) 1254 (17.9) 262 (20.8) 201 (22.5) Asian 1517 (16.6) 1052 (15.0) 297 (23.6) 168 (18.8) Hispanic 4771 (52.1) 3752 (53.6) 587 (46.6) 432 (48.3) Other 52 (0.6) 38 (0.5) 5 (0.4) 9 (1.0) HIV status <0.01 Negative 7128 (77.8) 5518 (78.7) 959 (76.2) 651 (72.9) Positive 608 (6.7) 409 (5.9) 77 (6.1) 122 (13.6) Not offered 1424 (15.5) 1080 (15.4) 223 (17.7) 121 (13.5) Homeless <0.01 No 8682 (94.8) 6600 (94.2) 1229 (97.6) 853 (95.4) Yes 478 (5.2) 407 (5.8) 30 (2.4) 41 (4.6) History of TB contact <0.01 No 8417 (91.9) 6373 (91.0) 1212 (96.3) 832 (93.1) Yes 743 (8.1) 634 (9.0) 47 (3.7) 62 (6.9) Excessive alcohol <0.01 No 7494 (81.8) 5633 (80.4) 1138 (90.4) 723 (80.9) Yes 1666 (18.2) 1374 (19.6) 121 (9.6) 171 (19.1) Injecting drug use 0.03 No 8930 (97.5) 6819 (97.3) 1241 (98.6) 870 (97.3) Yes 230 (2.5) 188 (2.7) 18 (1.4) 24 (2.7) Non-injecting drug use No 8263 (90.2) 6257 (89.3) 1202 (95.5) 804 (89.9) <0.01 Yes 897 (9.8) 750 (10.7) 57 (4.5) 90 (10.1) Origin 0.01 US born 4108 (44.8) 3188 (45.5) 515 (40.9) 405 (45.3) Foreign born 5052 (55.2) 3819 (54.5) 744 (59.1) 489 (54.7) Qian et al. Emerging Microbes & Infections (2018) 7:102 Page 5 of 14 Table 1 continued Variable Total Exclusively PTB Exclusively EPTB EPTB with PTB p-Value Diabetes <0.01 No 7800 (85.2) 5883 (84.0) 1122 (89.1) 795 (88.9) Yes 1360 (14.8) 1124 (16.0) 137 (10.9) 99 (11.1) End-stage renal disease <0.01 No 9024 (98.5) 6935 (99.0) 1230 (97.7) 859 (96.1) Yes 136 (1.5) 72 (1.0) 29 (2.3) 35 (3.9) Immunosuppression 0.01 No 8936 (97.6) 6854 (97.8) 1217 (96.7) 865 (96.8) Yes 224 (2.4) 153 (2.2) 42 (3.3) 29 (3.2) Previous TB 0.08 No 8819 (96.3) 6733 (96.1) 1226 (97.4) 860 (96.2) Yes 341 (3.7) 274 (3.9) 33 (2.6) 34 (3.8) Inmate of a correctional facility <0.01 No 8210 (89.6) 6161 (87.9) 1192 (94.7) 857 (95.9) Yes 950 (10.4) 846 (2.1) 67 (5.3) 37 (4.1) Resident of long-term care facility 0.56 No 9046 (98.8) 6921 (98.8) 1240 (98.5) 885 (99.0) Yes 114 (1.2) 86 (1.2) 19 (1.5) 9 (1.0) Specimen smear <0.01 Negative 4097 (44.7) 2832 (40.4) 707 (56.2) 558 (62.4) Positive 3585 (39.1) 3423 (48.9) 5 (0.4) 157 (17.6) Not done/Unknown 1478 (16.1) 752 (10.7) 547 (43.4) 179 (20.0) Specimen culture <0.01 Negative 2449 (26.7) 1462 (20.9) 669 (53.1) 318 (35.6) Positive 5185 (56.6) 4782 (68.2) 17 (1.4) 386 (43.2) Not done/Unknown 1526 (16.7) 763 (10.9) 573 (45.5) 190 (21.3) Chest radiography <0.01 Abnormal 7694 (84.0) 6485 (92.6) 448 (35.6) 761 (85.1) Normal 1024 (11.2) 233 (3.3) 700 (55.6) 91 (10.2) Not done/Unknown 442 (4.8) 289 (4.1) 111 (8.8) 42 (4.7) Radiographic cavity <0.01 No 5140 (56.1) 4031 (57.5) 437 (34.7) 672 (75.2) Yes 2540 (27.7) 2441 (34.8) 11 (0.9) 88 (9.8) Unknown 1480 (16.2) 535 (7.7) 811 (64.4) 134 (15.0) DST profile 0.11 None to RIF/INH 6183 (67.5) 4902 (70.0) 684 (54.3) 597 (66.8) RIF or INH 512 (5.6) 420 (6.0) 44 (3.5) 48 (5.4) MDR 69 (0.7) 63 (0.8) 5 (0.4) 1 (0.1) XDR 2 (0.1) 2 (0.1) 0 (0.0) 0 (0.0) Qian et al. Emerging Microbes & Infections (2018) 7:102 Page 6 of 14 Table 1 continued Variable Total Exclusively PTB Exclusively EPTB EPTB with PTB p-Value Unavailable 2394 (26.1) 1620 (23.1) 526 (41.8) 248 (27.7) Global Mtb Lineage <0.01 Indo-Oceanic L1 634 (6.9) 483 (6.9) 93 (7.4) 58 (6.5) East Asian L2 1121 (12.2) 918 (13.1) 98 (7.8) 105 (11.7) East African-Indian L3 174 (1.9) 115 (1.6) 37 (2.9) 22 (2.5) Euro-American L4 4344 (47.4) 3569 (50.9) 376 (29.9) 399 (44.6) M. bovis 105 (1.1) 52 (0.8) 36 (2.9) 17 (1.9) Other 28 (0.3) 12 (0.2) 8 (0.6) 8 (0.9) Unknown 2754 (30.2) 1858 (26.5) 611 (48.5) 285 (31.9) Death at time of diagnosis 0.04 No 8964 (97.9) 6870 (98.0) 1220 (96.9) 874 (97.8) Yes 196 (2.1) 137 (2.0) 39 (3.1) 20 (2.2) Death during TB treatment <0.01 No 8610 (94.0) 6592 (94.1) 1209 (96.0) 809 (90.5) Yes 551 (6.0) 416 (5.9) 50 (4.0) 85 (9.5) PTB pulmonary tuberculosis, EPTB extrapulmonary tuberculosis, HIV human immunodeficiency virus, RIF rifampin, INH isoniazid, MDR multidrug resistant, XDR extensively drug resistant. Differences across groups were compared using the chi-square test or Fisher’s exact test, as appropriate Patients with a history of contact with a known TB index case within 2 years Excessive alcohol use within the past 12 months Fig. 2 Distribution of extrapulmonary tuberculosis by site and associated mortality. a Distribution of extrapulmonary sites in patients with concurrent pulmonary tuberculosis (PTB) or exclusively extrapulmonary tuberculosis (EPTB). b Mortality distribution by extrapulmonary sites in patients with exclusively EPTB within the past 12 months, ESRD, and abnormal chest further noted that ethnicity was not associated with any radiographs were risk factors for EPTB mortality during specific site of EPTB and that female gender was asso- treatment. ciated with lymphatic and peritoneal TB. The observed demographics of female gender and The risk of TB development in the foreign-born foreign-born origin in the USA have been previously population was substantially elevated even more than 5 5, 12, 17, 19, 20 20 reported as risk factors for EPTB . Similarly, years after entering the USA . In our study population, we found that female gender and Hispanic ethnicity were more than half (55.2%) of the patients were born outside associated with patients who presented with exclusively the USA. The cervical lymphatic site was found to be a EPTB after adjusting for other confounding factors. We more common disease site among foreign-born EPTB Qian et al. Emerging Microbes & Infections (2018) 7:102 Page 7 of 14 Table 2 Multivariable analyses of patients’ characteristics with extrapulmonary tuberculosis in Texas, USA, 2009–2015 Characteristics Exclusively EPTB vs. exclusively PTB EPTB with PTB vs. exclusively PTB Any EPTB vs. exclusively PTB a a a OR (95% CI) OR (95% CI) OR (95% CI) OR (95% CI) OR (95% CI) OR (95% CI) Age (years) 0–4 (reference) (reference) (reference) (reference) (reference) (reference) 5–14 1.42 (1.04–1.96) 1.19 (0.85–1.68) 0.81 (0.55–1.19) 0.96 (0.62–1.49) 1.12 (0.86–1.50) 0.97 (0.74–1.28) 15–24 1.98 (1.356–2.88) 2.33 (1.56–3.46) 1.12 (0.71–1.79) 1.23 (0.76–1.99) 1.56 (1.14–2.13) 1.33 (0.96–1.84) 25–44 1.07 (0.837–1.37) 1.10 (0.85–1.42) 0.90 (0.73–1.22) 0.93 (0.71–1.21) 1.01 (0.83–1.22) 0.97 (0.80–1.18) 45–64 1.49 (1.232–1.80) 1.57 (1.29–1.91) 0.95 (0.77–1.16) 0.80 (0.67–1.03) 1.22 (1.05–1.42) 1.13 (0.72–1.32) ≥65 1.01 (0.828–1.23) 1.22 (0.99–1.49) 0.71 (0.58–0.88) 0.67 (0.54–0.83) 0.86 (0.74–1.01) 1.06 (0.91–1.24) Gender (female) 1.36 (1.20–1.54) 1.42 (1.26–1.62) 1.12 (0.96–1.30) 1.16 (1.00–1.36) 1.41 (1.27–1.55) 1.32 (1.19–1.46) Ethnicity White (reference) (reference) (reference) (reference) (reference) (reference) Black 0.84 (0.33–2.15) 0.92 (0.35–2.38) 0.39 (0.18–0.83) 0.37 (0.17–0.80) 0.57 (0.30–1.08) 0.53 (0.28–1.01) Asian 0.76 (0.61–0.94) 0.80 (0.63–1.02) 0.68 (0.32–1.42) 0.57 (0.17–1.20) 1.00 (0.54–1.87) 0.87 (0.46–1.63) Hispanic 1.34 (1.14–1.57) 1.34 (1.12–1.60) 0.67 (0.32–1.42) 0.67 (0.31–1.45) 1.20 (0.64–2.24) 1.03 (0.54–1.95) Other 1.81 (1.55–2.11) 1.57 (1.34–1.85) 0.49 (0.23–1.01) 0.48 (0.23–1.02) 0.74 (0.40–1.37) 0.68 (0.37–1.28) Homeless 0.56 (0.38–0.83) 0.57 (0.40–0.84) 0.78 (0.56–1.08) 0.70 (0.50–1.00) 0.55 (0.43–0.72) 0.65 (0.49–0.85) History of TB contact 0.39 (0.29–0.53) 0.28 (0.21–0.39) 0.75 (0.57–0.98) 0.71 (0.53–0.96) 0.54 (0.44–0.66) 0.44 (0.35–0.55) Excessive alcohol 0.61 (0.49–0.75) 0.60 (0.48–0.74) 1.12 (0.91–1.38) 1.03 (0.84–1.26) 0.64 (0.56–0.74) 0.78 (0.67–0.91) Injecting drug use 1.08 (0.64–1.82) 1.04 (0.62–1.76) 1.00 (0.63–1.60) 0.96 (0.60–1.53) 0.72 (0.52–1.01) 1.01 (0.70–1.46) Non-injecting drug use 0.53 (0.39–0.72) 0.52 (0.40–0.71) 0.87 (0.67–1.14) 0.85 (0.65–1.11) 0.61 (0.51–0.74) 0.68 (0.55–0.84) Diabetes 0.63 (0.51–0.77) 0.61 (0.50–0.74) 0.65 (0.51–0.82) 0.61 (0.49–0.77) 0.64 (0.56–0.75) 0.61 (0.52–0.71) HIV 1.14 (0.87–1.49) 1.20 (0.92–1.55) 2.65 (2.10–3.35) 2.57 (2.05–3.21) 1.64 (1.38–1.96) 1.77 (1.47–2.13) Immunosuppression 1.44 (0.10–2.07) 1.36 (0.95–1.95) 1.20 (0.78–1.83) 1.15 (0.75–1.76) 1.53 (1.15–2.03) 1.31 (1.00–1.77) ESRD 2.51 (1.58–3.99) 2.59 (1.63–4.17) 4.30 (2.78–6.64) 4.45 (2.88–6.86) 3.32 (2.33–4.75) 3.42 (2.39–4.88) Foreign born 1.04 (0.89–1.22) 0.92 (0.80–1.06) 1.06 (0.89–1.28) 0.99 (0.85–1.17) 1.05 (0.93–1.20) 0.95 (0.85–1.06) Previous TB 0.68 (0.47–1.00) 0.69 (0.47–1.01) 0.99 (0.68–1.43) 0.95 (0.66–1.38) 0.81 (0.61–1.07) 0.80 (0.61–1.06) EPTB extrapulmonary tuberculosis, PTB pulmonary tuberculosis, OR odds ratio, OR adjusted odds ratio, CI confidence interval, HIV human immunodeficiency virus, ESRD end-stage renal disease, TB, tuberculosis Patients with a history of contact with a known TB index case within 2 years Excessive alcohol use within the past 12 months HIV unknown categorized as negative Significant odds ratios (p<0.005) are in bold patients than among US-born patients in North Car- also possible that the association between foreign birth olina . However, a study at a single urban US public and pleural TB is due to the effect of BCG vaccination on hospital did not show any risk between foreign birth with foreign-born individuals. Studies have shown that sites of EPTB . From our results, foreign birth was pleuritis is induced by Mycobacterium bovis BCG, and associated with increased risk of pleural TB. Pleural TB the underlying mechanisms have been elucidated . is the second most common type of EPTB but the However, non-association of BCG status among patients 22, 23 leading manifestation in settings with high TB . with PTB, pleural TB, and other types of EPTB was seen Given that TB disease among foreign-born populations in a study with a majority of BCG-vaccinated patients . is normally considered to result from the reactivation of From the findings described herein, studies can be LTBI , one explanation might be that pleural TB was initiated to further evaluate the BCG status of foreign- the primary manifestation of LTBI reactivation .Itis born patients in relation to pleural TB. Qian et al. Emerging Microbes & Infections (2018) 7:102 Page 8 of 14 Drug users and the elderly remain the groups at high risk of developing LTBI and TB disease .The pre- valence of illicit drug use has been previously shown to be higher in patients with PTB than in patients with 15, 17 EPTB . Similarly, the prevalence of injecting drug use and non-injecting drug use was also higher in patients with PTB than patients with exclusively EPTB in our study. We further observed that injecting drug use was associated with patients with genitourinary TB. In addition, non-injecting drug use as a non-risk factor for EPTB compared to PTB has been reported .Fromour results, non-injecting drug use was also negatively associated with patients having exclusively EPTB or any EPTB comparedtoPTB.Wedemonstratedthatthe age groups 15–24 and 45–64 were associated with exclu- sively EPTB. Meanwhile, Click et al. indicated that age 0–4 was associated with exclusively EPTB. TB in elderly patients can involve almost any organ in the body .We found that patients age >45 years were at an increased risk of bone TB but not with other extrapulmonary sites. This finding is consistent with a large-population-based study in Europe . Additionally, ages <15 and >65 years were likely to be associated with the most comment types of EPTB . According to a 2016 CDC report, high rates of TB cases overall and TB cases attributable to extensive recent transmission were identified frequently among people experiencing homelessness within the past year and resi- dents of a correctional facility at the time of diagnosis However, EPTB was more common in non-homeless 5, 17 patients than in the homeless, as previously reported . The number of homeless cases was significantly higher in PTB (5.8%) than in exclusively EPTB (2.4%) in our population. Furthermore, we showed that being homeless was negatively associated with EPTB and especially lym- phatic TB. Neither the Magee study nor our study showed any significant differences in the proportion of residents of correctional facility patients with exclusively EPTB vs. PTB . These findings suggest that Mtb infection is not site-specific in correctional facility patients. It is well known that patients with HIV have an increased 13, 14 12 risk of EPTB . Click et al. foundthatHIV wasasso- ciated with both exclusively EPTB and any EPTB. More- over, the same study demonstrated that the association between individuals with HIV infection and extra- pulmonary disease was greater for EPTB with concurrent pulmonary involvement than for exclusively EPTB alone. In our population, HIV was associated with EPTB with concurrent pulmonary involvement and any EPTB but not with exclusively EPTB. We further identified that HIV was associated with meningeal TB at more than five times the odds, while other sites were not found to be related. In addition, low CD4 lymphocyte counts in hospitalized patients with HIV-co-infected EPTB were found to be Table 3 Risk factors associated with subsites of exclusively extrapulmonary tuberculosis compared to pulmonary tuberculosis in Texas, USA, 2009–2015 Characteristics Pleural (n = 198) Lymphatic (n = 407) Bone (n = 154) Genitourinary (n = 65) Peritoneal (n = 71) Meningeal (n = 94) Others (n = 212) a a a a a a a OR (95% CI) OR (95% CI) OR (95% CI) OR (95% CI) OR (95% CI) OR (95% CI) OR (95% CI) Age (≥45 years) 1.04 (0.76–1.40) 0.56 (0.44–0.71) 1.47 (1.04–2.08) 1.00 (0.60–1.68) 1.06 (0.64–1.74) 0.75 (0.48–1.17) 1.06 (0.79–1.42) Gender (female) 0.91 (0.67–1.25) 2.04 (1.66–2.51) 0.69 (0.48–0.99) 1.44 (0.87–2.40) 1.96 (1.20–3.21) 1.22 (0.79–1.88) 1.39 (1.05–1.86) Ethnicity (White) 0.73 (0.46–1.14) 0.47 (0.29–0.77) 1.14 (0.69–1.88) 1.26 (0.50–3.22) 0.62 (0.23–1.63) 0.82 (0.39–1.72) 0.77 (0.45–1.30) Homeless 0.90 (0.48–1.68) 0.29 (0.09–0.92) 0.54 (0.19–1.50) 0.47 (0.06–3.57) 0.69 (0.16–2.95) 0.38 (0.09–1.63) 0.72 (0.29–1.82) Excessive alcohol 1.17 (0.80–1.71) 0.38 (0.23–0.63) 0.42 (0.23–0.75) 0.82 (0.35–1.90) 1.50 (0.77–2.95) 0.54 (0.26–1.14) 0.30 (0.16–0.57) Injecting drug use 0.91 (0.35–2.34) 0.63 (0.15–2.68) 0.87 (0.20–3.79) 5.26 (1.10–25.36) 0.80 (0.10–6.36) 2.20 (0.60–8.05) 0.84 (0.20–3.62) Non-injecting drug use 0.82 (0.49–1.38) 0.37 (0.18–0.74) 0.70 (0.33–1.53) 0.12 (0.02–1.05) 0.58 (0.19–1.76) 0.39 (0.14–1.07) 0.58 (0.27–1.24) Diabetes 0.68 (0.43–1.07) 0.35 (0.23–0.54) 0.92 (0.60–1.42) 0.54 (0.24–1.22) 0.71 (0.35–1.44) 0.51 (0.23–1.13) 0.84 (0.56–1.26) HIV 0.62 (0.30–1.28) 1.20 (0.74–1.95) 0.54 (0.19–1.50) 0.64 (0.15–2.66) 1.13 (0.40–3.17) 5.73 (3.43–9.56) 1.52 (0.86–2.68) Immunosuppression 0.80 (0.28–2.23) 0.88 (0.41–1.90) 2.54 (1.30–4.97) 1.57 (0.36–6.78) 2.29 (0.77–6.85) 1.79 (0.62–5.12) 0.95 (0.38–2.38) ESRD 2.74 (1.06–7.10) 2.96 (1.28–6.87) 4.05 (1.82–8.98) 1.72 (0.22–13.32) 3.56 (1.01–12.56) – 1.40 (0.43–4.61) Foreign born 1.77 (1.31–2.41) 0.88 (0.71–1.10) 0.98 (0.68–1.40) 0.37 (0.19–0.70) 0.70 (0.41–1.18) 0.97 (0.62–1.51) 0.84 (0.62–1.14) Previous TB 0.27 (0.07–1.10) 0.80 (0.43–1.49) 1.37 (0.63–2.98) 1.20 (0.37–3.89) 0.37 (0.05–2.70) 0.76 (0.24–2.43) 0.52 (0.20–1.43) OR adjusted odds ratio, CI confidence interval, HIV human immunodeficiency virus, ESRD end-stage renal disease Analysis excluded subjects with multiple subsite involvement (n = 57) and laryngeal sites (n = 3) Excessive alcohol use within the past 12 months HIV unknown categorized as negative Significant odds ratios (p<0.005) are in bold Qian et al. Emerging Microbes & Infections (2018) 7:102 Page 9 of 14 Table 4 Risk factors for mortality during anti-tuberculosis treatment in patients with extrapulmonary tuberculosis in Texas, USA, 2009–2015 Variable Treatment completed Died during Mortality risk Crude OR (95% Adjusted OR Adjusted p- (n = 1061) treatment (n = 50) (%) CI) (95% CI) Value Age (years) 0–14 105 (9.9%) 0 (0.0%) 0.0% – 15–24 116 (10.9%) 2 (4.0%) 1.7% (reference) 25–44 438 (41.3%) 9 (18.0%) 2.0% 1.19 (0.25, 5.59) 45–64 292 (27.5%) 17 (34.0%) 5.5% 3.38 (0.77, 14.85) ≥65 110 (10.4%) 22 (44.0%) 16.7% 11.60 (2.66, 50.49) Age (years) <45 659 (62.1%) 11 (22.0%) 1.6% (reference) (reference) ≥45 402 (37.9%) 39 (78.0%) 8.8% 5.81 (2.94, 11.48) 3.75 (1.71, 8.22) 0.001 Gender Female 491 (46.3%) 20 (40.0%) 3.9% (reference) Male 570 (53.7%) 30 (60.0%) 5.0% 1.29 (0.72, 2.30) Race White 84 (7.9%) 9 (18.0%) 9.7% (reference) Black 209 (19.7%) 11 (22.0%) 5.0% 0.49 (0.20, 1.23) Hispanic 501 (47.2%) 24 (48.0%) 4.6% 0.45 (0.20, 1.00) Asian 262 (24.7%) 6 (12.0%) 2.2% 0.21 (0.07, 0.62) Other 5 (0.5%) 0 (0.0%) 0.0% 1.00 (0.00, 0.00) Race Non-White 977 (92.1%) 41 (82.0%) 4.0% (reference) White 84 (7.9%) 9 (18.0%) 9.7% 2.55 (1.20, 5.43) HIV status Negative 847 (79.8%) 21 (42.0%) 2.4% (reference) (reference) Positive 53 (5.0%) 6 (12.0%) 10.2% 4.57 (1.77, 11.79) 4.70 (1.54, 14.32) 0.01 Unknown 161 (15.2%) 23 (46.0%) 12.5% 5.76 (3.11, 10.66) 6.55 (3.19, 13.44) <0.001 Homeless No 1040 (98.0%) 46 (92.0%) 4.2% (reference) (reference) Yes 21 (2.0%) 4 (8.0%) 16.0% 4.31 (1.42, 13.06) 1.57 (0.40, 6.17) 0.52 Excessive alcohol use No 973 (91.7%) 37 (74.0%) 3.7% (reference) (reference) Yes 88 (8.3%) 13 (26.0%) 12.9% 3.88 (1.99, 7.58) 3.34 (1.45, 7.67) 0.01 Injecting drug use No 1050 (99.0%) 48 (96.0%) 4.4% (reference) Yes 11 (1.0%) 2 (4.0%) 15.4% 3.98 (0.86, 18.44) Foreign born No 415 (39.1%) 29 (58.0%) 6.5% (reference) Yes 646 (60.9%) 21 (42.0%) 3.1% 0.47 (0.26, 0.83) Diabetes Qian et al. Emerging Microbes & Infections (2018) 7:102 Page 10 of 14 Table 4 continued Variable Treatment completed Died during Mortality risk Crude OR (95% Adjusted OR Adjusted p- (n = 1061) treatment (n = 50) (%) CI) (95% CI) Value No 948 (89.3%) 40 (80.0%) 4.0% (reference) (reference) Yes 113 (10.7%) 10 (20.0%) 8.1% 2.10 (1.02, 4.31) 1.55 (0.65, 3.69) 0.32 End-stage renal disease No 1043 (98.3%) 44 (88.0%) 4.0% (reference) (reference) Yes 18 (1.7%) 6 (12.0%) 25.0% 7.90 (2.99, 20.88) 4.45 (1.38, 14.33) 0.01 Immunosuppression (medical condition or medication) No 1027 (96.8%) 44 (88.0%) 4.1% Yes 34 (3.2%) 6 (12.0%) 15.0% 4.12 (1.64, 10.32) Previous TB No 1033 (97.4%) 50 (100.0%) 4.6% – Yes 28 (2.6%) 0 (0.0%) 0.0% Inmate of a correctional facility No 967 (94.8%) 48 (98.0%) 4.7% (reference) Yes 53 (5.2%) 1 (2.0%) 1.9% 0.38 (0.05, 2.81) Resident of long-term care facility No 1048 (98.8%) 47 (94.0%) 4.3% (reference) (reference) Yes 13 (1.2%) 3 (6.0%) 18.8% 5.15 (1.42, 18.67) 2.15 (0.50, 9.26) 0.31 AFB smear Negative 627 (99.4%) 17 (94.4%) 2.6% (reference) Positive 4 (0.6%) 1 (5.6%) 20.0% 9.22 (0.98, 86.93) Culture Negative 602 (97.6%) 12 (92.3%) 2.0% (reference) Positive 15 (2.4%) 1 (7.7%) 6.3% 3.34 (0.41, 27.40) TB-CXR No 611 (62.8%) 15 (33.3%) 2.4% (reference) (reference) Yes 362 (37.2%) 30 (66.7%) 7.7% 3.38 (1.79, 6.36) 2.18 (1.09, 4.35) 0.03 Cavitation on CXR No 354 (97.8%) 30 (100.0%) 7.8% – Yes 8 (2.2%) 0 (0.0%) 0.0% DST profile Sensitive to RIF 560 (52.8%) 40 (80.0%) 6.7% and INH Resistant to RIF or 39 (3.7%) 0 (0.0%) 0.0% INH MDR-TB 3 (0.3%) 0 (0.0%) 0.0% (reference) Unavailable 459 (43.3%) 10 (20.0%) 2.1% 0.31 (0.15, 0.62) Genotyping lineage Indo-Oceanic (L1) 80 (7.5%) 4 (8.0%) 4.8% 0.79 (0.20, 3.05) East Asian (L2) 79 (7.4%) 5 (10.0%) 6.0% (reference) Qian et al. Emerging Microbes & Infections (2018) 7:102 Page 11 of 14 Table 4 continued Variable Treatment completed Died during Mortality risk Crude OR (95% Adjusted OR Adjusted p- (n = 1061) treatment (n = 50) (%) CI) (95% CI) Value East African- 35 (3.3%) 1 (2.0%) 2.8% 0.45 (0.05, 4.01) Indian (L3) Euro-American 300 (28.3%) 27 (54.0%) 8.3% 1.42 (0.53, 3.81) (L4) M. bovis 27 (2.5%) 3 (6.0%) 10.0% 1.76 (0.39, 7.84) Other 8 (0.8%) 0 (0.0%) 0.0% 1.00 (0.00, 0.00) Unknown 532 (50.1%) 10 (20.0%) 1.8% 0.30 (0.10, 0.89) Genotyping lineage Not East Asian 354 (97.8%) 30 (100.0%) 7.8% (reference) (reference) East Asian (L2) 8 (2.2%) 0 (0.0%) 0.0% 1.38 (0.53, 3.58) 1.58 (0.53, 4.74) 0.42 TB tuberculosis, HIV human immunodeficiency virus, TB-CXR tuberculosis chest X-ray, DST drug susceptibility test, RIF rifampin, INH isoniazid, MDR-TB multidrug- resistant tuberculosis, OR odds ratios Analysis was performed on 1111 patients with extrapulmonary tuberculosis only and having treatment outcome information available associated with meningeal TB and disseminated TB in a improve the prevention, detection, and treatment of EPTB single hospital study in the USA . with ESRD. The prevalence of end-stage renal disease (ESRD) con- Consistent with the current literature, our analyses tinues to rise by approximately 20,000 cases per year in showed that age ≥45 years, ESRD, HIV+ status, excessive the USA . Consistent epidemiologic evidence has shown alcohol use within the past 12 months, and abnormal that this population is at risk for developing active TB . chest radiography were significantly associated with ESRD as a risk factor for EPTB has also been reported in mortality during anti-TB treatment in patients with 17, 31 17, 38 studies in Taiwan and the US state of Georgia exclusively EPTB . . In the USA, excess alcohol use may Accordingly, ESRD was associated with exclusively EPTB, represent a large portion of TB burden . The relationship EPTB with concurrent pulmonary involvement, and all between excessive alcohol use and the development of TB cases of EPTB compared to PTB in our population-based disease as well as TB-associated morbidity and mortality analysis. We also found that ESRD was specifically asso- has been presumed to be due to impaired immune ciated with pleural, lymphatic, bone and peritoneal TB. function . Other confounding factors such as older age, Thus, patients with ESRD are at a high risk of progressing diabetes, ESRD, and HIV are all related to decreased to EPTB. One possibility regarding the underlying immune function. HIV was highly associated with mor- mechanisms is that the persistence of impaired cell- tality during treatment in our analysis, which is consistent mediated immunity in ESRD may leave these patients with other epidemiologic and observational studies with susceptible to Mtb infection or activation of latent infec- mortality ranging from 6% to 32% . Another important tion . This phenomenon has also been observed in organ finding of our study was that ESRD was associated with transplantation receipts who receive post-transplant more than quadruple the odds of mortality during anti-TB immunosuppressive medications that specifically target treatment in patients having exclusively EPTB. Given 33, 34 T cell-mediated immunity . In regard to the screening these findings, we suggest that patients with decreased strategy among patients with chronic renal disease (CRD), immune function or immunosuppression are at an both the American Thoracic Society and American increased risk of mortality during treatment and that host Transplant Society guidelines recommend that all immune response may determine the difference in sur- immunocompromised subjects and transplant candidates vival. Approaches to meet the objective of optimizing be screened for TB with a tuberculin skin test (TST) or efficacy and safety of treatment, especially for TB-HIV co- IFN-γ releasing assay (IGRA). The WHO provides more infection as well as ESRD, to reduce mortality both in specific guidance on screening all dialysis patients with adults and children are urgently required. As shown in a TST or IGRAs . Beyond the screening strategy, diagnosis prospective cohort study that enrolled hospitalized HIV of EPTB remains difficult because of the paucibacillary co-infected patients with microbiologically confirmed nature. Thus, it is necessary to advance knowledge about drug-susceptible TB in South Africa, mortality within the association of CRD/ESRD and EPTB and strategies to 12 weeks was positively associated with elevated Qian et al. Emerging Microbes & Infections (2018) 7:102 Page 12 of 14 concentrations of procalcitonin, activation of the innate EPTB with pulmonary involvement. Geographically, immune system, and anti-inflammatory markers . Pro- patients with M. bovis TB residing along the US–Mexico calcitonin, a product induced by TNF-α and IL-2 during a border had a disproportionately high incidence of M. bacterial infection, has already shown its value in distin- bovis . This may also be reflected in our results, as Texas guishing TB from bacterial pneumonia and TB meningitis is a US state bordering Mexico. The tradition of raw milk 42, 43 from bacterial meningitis . A higher level of serum and cheese consumption, especially in Hispanic commu- procalcitonin was associated with a poorer prognosis in nities, may be another common reason for M. bovis 43 52 TB meningitis . Moreover, serum procalcitonin has been infection . Additionally, we found that positive smear reported as an appropriate indicator of infection in ESRD and culture, direct susceptibility test profile and geno- patients . Therefore, identifying a correlation between typing lineage were not risk factors for mortality from the host’s immunologic phenotypes and the severity of exclusively EPTB during TB treatment. These results may disease or comorbidities, as well as treatment response, be limited due to many individuals with unknown Mtb would enable the direct selection of host-directed ther- status, either because the test was not performed or apeutics and a potentially beneficial and improved TB because the results were not recorded. Instead of bacterial outcome. factors, host risk factors such as HIV, age ≥45, excessive Another important consideration for the risk of EPTB is alcohol use, and abnormal chest X-ray findings were diabetes status, as several studies have identified diabetes associated with mortality during treatment of EPTB in our as a risk factor for developing active TB and poor treat- study. ment outcomes . For instance, a study in the UK has One important limitation of our study is the unavail- reported that patients with diabetes had an increased risk ability of data in some categories. Therefore, the reported of developing TB compared to a control group . Among crude and adjusted odds ratios could be biased due to patients undergoing TB treatment, patients with diabetes unmeasured covariates or unknown confounders. State had an increased mortality risk compared to those with- TB surveillance reporting does not include the depth of out diabetes . However, compared to the control group, clinical information necessary to further investigate TB patients with diabetes had an increased probability of recognized risk factors in the epidemiology of EPTB (e.g., having PTB as opposed to EPTB . Furthermore, both our CD4 lymphocyte counts for HIV patients and smoking study and a cohort study in the US state of Georgia found status). An observational design in a large cohort will be TB patients with diabetes to have an increased probability necessary to assess the true effect of these factors. Given of EPTB as opposed to PTB, and diabetes was not asso- that Texas has one of the highest TB prevalence rates of ciated with EPTB mortality during TB treatment .Inan any US state and has a more diverse population than additional study, diabetes did not contribute to TB-related many other states, findings from our analysis may not death in adult patients in the USA . Thus, the incon- apply to settings elsewhere in the country. sistent findings encourage further investigations on the impact of diabetes in PTB and EPTB patients. It is worth Conclusion emphasizing that the incidence of ESRD is higher in the The present study characterized the important differ- diabetic population than in the non-diabetic population . ences in the population-level dynamics of EPTB, as well as Since ESRD is an independent risk factor for EPTB as its specific sites, which included demographic factors and shown in our study, it may be necessary to account for the clinical characteristics in addition to the heterogeneities association between diabetes and ESRD as a co-epidemic, within sites of EPTB during the 7-year study period. Age which would potentially account for the risk of EPTB as ≥45 years, HIV+ status, and ESRD were identified as risk well as treatment outcomes. factors for both EPTB establishment and resulting mor- Among available data for patients with exclusively tality during treatment. Although the scientific question EPTB, the most prevalent Mtb lineages were Euro- of the extrapulmonary dissemination remains to be American L4, followed by East Asian L2 and Indo- answered, the study’s findings could allow us to design Oceanic L1. This finding was consistent with a previous supportive treatments for specific subgroups of patients 12 12 nationwide study in the USA . Click et al. suggested with increased mortality, such as those with a HIV+ that the percentage of cases with exclusively EPTB differs status and those with compromised renal function, in for the four lineages—East Asian, 13.0%; Euro-American, order to improve their outcomes and ultimately minimize 13.8%; Indo-Oceanic, 22.6%; and East African-Indian, the transmission of TB. 34.3%—while EPTB with pulmonary involvement did not. However, Click’s study did not show data for M. bovis. Acknowledgements 50, 51 This work was partially supported by the Opening Project of Zhejiang Consistent with the results of previous studies ,we Provincial Top Key Discipline of Clinical Medicine (LKFJ008 to X.Q.), the Key found a higher proportion of M. bovis in patients with Science and Technology Innovation Team of Zhejiang (2010R50048 to J.L.), exclusively EPTB than in patients with exclusively PTB or and Zhejiang Provincial Program for the Cultivation of High-level Innovative Qian et al. Emerging Microbes & Infections (2018) 7:102 Page 13 of 14 Health Talents and Key Laboratory of Laboratory Medicine, Ministry of 14. Sterling, T. R. et al. Human immunodeficiency virus-seronegative adults with Education, China. extrapulmonary tuberculosis have abnormal innate immune responses. Clin. Infect. Dis. 33,976–982 (2001). 15. Gonzalez, O. Y. et al. Extra-pulmonary manifestations in a large metropolitan Author contributions: area with a low incidence of tuberculosis. Int. J. Tuberc. Lung Dis. 7,1178–1185 X.Q. and E.A.G designed the study. D.T.N collected the data. X.Q. and D.T.N. (2003). analyzed the data. X.Q., D.T.G., J.L., A.E.A., X.B., and E.A.G. wrote the manuscript. 16. Sotgiu, G. et al. Determinants of site of tuberculosis disease: an analysis of All authors interpreted the data, critically reviewed the manuscript, and European surveillance data from 2003 to 2014. PLoS ONE 12, e0186499 (2017). approved the final version. 17. Magee,M. J., Foote, M., Ray, S.M., Gandhi,N.R. & Kempker, R. R. Diabetes mellitus and extrapulmonary tuberculosis: site distribution and risk of mortality. Epidemiol. Infect. 144, 2209–2216 (2016). Author details 18. Shrestha, S., Hill, A. N., Marks, S. M. & Dowdy, D. W. Comparing drivers and Key Laboratory of Laboratory Medicine, Ministry of Education, Zhejiang dynamics of tuberculosis in California, Florida, New York, and Texas. Am. J. Provincial Key Laboratory of Medical Genetics, Wenzhou Medical University, Respir. Crit. Care. Med. 196, 1050–1059 (2017). Wenzhou, P. R. China. Center for Precision Biomedicine, Institute of Molecular 19. Deiss, R. G., Rodwell, T. C. & Garfein, R. S. Tuberculosis and illicit drug use: Medicine, McGovern Medical School, The University of Texas Health Science review and update. Clin. Infect. Dis. 48,72–82 (2009). Center at Houston, Houston, TX, USA. People’s Hospital of Hangzhou Medical 20. Cain, K. P. et al. Tuberculosis among foreign-born persons in the United States: College, Hangzhou, P. R. China. Houston Methodist Research Institute, achieving tuberculosis elimination. Am.J.Respir. Crit.Care. Med. 175,75–79 Houston, TX, USA. Department of Otorhinolaryngology, Head and Neck (2007). Surgery, Berlin Institute of Health, Charité – Universitätsmedizin Berlin, 21. Kipp, A. M.,Stout,J.E., Hamilton,C. D.&VanRie,A. Extrapulmonarytuber- Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, culosis, human immunodeficiency virus, and foreign birth in North Carolina, Campus Benjamin Franklin, Berlin, Germany 1993-2006. BMC Public Health 8, 107 (2008). 22. Jeon, D. Tuberculous pleurisy: an update. Tuberc. Respir. Dis. (Seoul) 76, Conflict of interest 153–159 (2014). The authors declare that they have no conflict of interest. 23. RasolofoRazanamparany,V., Menard, D., Auregan, G.,Gicquel, B.&Chanteau,S. Extrapulmonary and pulmonary tuberculosis in Antananarivo (Madagascar): high clustering rate in female patients. J. Clin. Microbiol. 40,3964–3969 (2002). Publisher’s note 24. Tsang,C.A., Langer,A.J., Navin, T. R. & Armstrong,L.R.Tuberculosis among Springer Nature remains neutral with regard to jurisdictional claims in foreign-born persons diagnosed /=10 years after arrival in the United States, published maps and institutional affiliations. 2010-2015. Am. J. Transplant. 17,1414–1417 (2017). 25. Chavez-Galan, L. et al. Transmembrane tumor necrosis factor controls myeloid- derived suppressor cell activity via TNF receptor 2 and protects from excessive Received: 26 January 2018 Revised: 15 April 2018 Accepted: 29 April 2018 inflammation during BCG-induced pleurisy. Front. Immunol. 8, 999 (2017). 26. Yang, Z. et al. Identification of risk factors for extrapulmonary tuberculosis. Clin. Infect. Dis. 38,199–205 (2004). 27. Rajagopalan, S. Tuberculosis in older adults. Clin. Geriatr. Med. 32,479–491 (2016). References 28. Centers for Disease Control and Prevention. Reported Tuberculosis in the 1. World Health Organization. Global Tuberculosis Report (2016). http://www.who. United States 2016. http://www.cdc.gov/features/dstuberculosis. int/tb/publications/global_report/en/ 29. United States Renal Data System. USRDS 2017 Annual Data Report: Atlas of 2. Pai, M. et al. Tuberculosis. Nat. Rev. Dis. Primers 2, 16076 (2016). Chronic Kidney Disease and End-Stage Renal Disease in the United States 3. Sandgren,A., Hollo,V.&vander Werf, M. J. Extrapulmonary tuberculosis in the (National Institutes of Health, National Institute of Diabetes and Digestive and European Union and European Economic Area, 2002 to 2011. Eur. Surveill. 18, Kidney Diseases, Bethesda, MD). https://www.usrds.org/2017/view/v2_01.aspx. 20431 (2013). 30. Al-Efraij, K. et al. Risk of active tuberculosis in chronic kidney disease: a sys- 4. Sama, J. N. et al. High proportion of extrapulmonary tuberculosis in a low tematic review and meta-analysis. Int. J. Tuberc. Lung Dis. 19,1493–1499 (2015). prevalence setting: a retrospective cohort study. Public Health 138,101–107 31. Lin, J.N.etal. Risk factorsfor extra-pulmonary tuberculosis compared to (2016). pulmonary tuberculosis. Int. J. Tuberc. Lung Dis. 13,620–625 (2009). 5. Peto,H. M., Pratt, R. H.,Harrington, T. A.,LoBue, P.A.&Armstrong, L. R. 32. Kato, S. et al. Aspects of immune dysfunction in end-stage renal disease. Clin. J. Epidemiology of extrapulmonary tuberculosis in the United States, 1993-2006. Am.Soc.Nephrol. 3,1526–1533 (2008). Clin. Infect. Dis. 49, 1350–1357 (2009). 33. Mysore, K. R. et al. Longitudinal assessment of T cell inhibitory receptors in liver 6. Centers for Disease Control and Prevention. Reported Tuberculosis in the transplant recipients and their association with posttransplant infections. Am. J. United States 2013. http://www.cdc.gov/features/dstuberculosis Transplant 18,351–363 (2017). 7. Lin, P. L. et al. Sterilization of granulomas is common in active and latent 34. Liyanage, T. et al. Worldwide access to treatment for end-stage kidney disease: tuberculosis despite within-host variability in bacterial killing. Nat. Med. 20, a systematic review. Lancet 385,1975–1982 (2015). 75–79 (2014). 35. Lewinsohn,D.M.etal. Official American Thoracic Society/Infectious Diseases 8. Via, L. E. et al. Host-mediated bioactivation of pyrazinamide: implications for Society of America/Centers for Disease Control and Prevention Clinical Prac- efficacy, resistance, and therapeutic alternatives. ACS Infect. Dis. 1,203–214 tice Guidelines: diagnosis of tuberculosis in adults and children. Clin. Infect. Dis. (2015). 64,111–115 (2017). 9. Martin, C. J. et al. Digitally barcoding Mycobacterium tuberculosis reveals 36. Morris, M. I. et al. Diagnosis and management of tuberculosis in transplant in vivo infection dynamics in the Macaque model of tuberculosis. mBio 8, donors: a donor-derived infections consensus conference report. Am. J. e00312–e00317 (2017). Transplant 12, 2288–2300 (2012). 10. Lieberman, T. D. et al. Genomic diversity in autopsy samples reveals within- 37. WHO. Guidelines on the Management of Latent Tuberculosis Infection (World host dissemination of HIV-associated Mycobacterium tuberculosis. Nat. Med. Health Organization, Geneva, Switzerland, 2015). 22,1470–1474 (2016). 38. Volkmann, T., Moonan, P. K., Miramontes, R. & Oeltmann, J. E. Tuberculosis and 11. Whittaker, E., Nicol, M., Zar, H. J. & Kampmann, B. Regulatory T cells and pro- excess alcohol use in the United States, 1997-2012. Int. J. Tuberc. Lung Dis. 19, inflammatory responses predominate in children with tuberculosis. Front. 111–119 (2015). Immunol. 8, 448 (2017). 39. Happel, K. I. & Nelson, S. Alcohol, immunosuppression, and the lung. Proc. Am. 12. Click, E. S., Moonan, P. K., Winston, C. A., Cowan, L. S. & Oeltmann, J. E. Thorac. Soc. 2,428–432 (2005). Relationship between Mycobacterium tuberculosis phylogenetic lineage and 40. Odone, A. et al. The impact of antiretroviral therapy on mortality in HIV clinical site of tuberculosis. Clin. Infect. Dis. 54,211–219 (2012). positive people during tuberculosis treatment: a systematic review and meta- 13. Leeds, I. L. et al. Site of extrapulmonary tuberculosis is associated with HIV analysis. PLoS ONE 9, e112017 (2014). infection. Clin. Infect. Dis. 55,75–81 (2012). Qian et al. Emerging Microbes & Infections (2018) 7:102 Page 14 of 14 41. Janssen, S. et al. Mortality in severe human immunodeficiency virus- 47. Degner, N. R.,Wang, J. Y., Golub,J.E. & Karakousis,P.C.Metformin use reverses tuberculosis associates with innate immune activation and dysfunction of the increased mortality associated with diabetes mellitus during tuberculosis monocytes. Clin. Infect. Dis. 65,73–82 (2017). treatment. Clin. Infect. Dis. 66,198–205 (2018). 42. Huang, S. L. et al. Value of procalcitonin in differentiating pulmonary tuber- 48. Beavers, S. F., et al. Tuberculosis mortality in the United States: epidemiology culosis from other pulmonary infections: a meta-analysis. Int. J. Tuberc. Lung and prevention opportunities. Ann. Am. Thorac. Soc. (2018) [Epub ahead of Dis. 18,470–477 (2014). print]. 43. Kim, J. et al. Procalcitonin as a diagnostic and prognostic factor for tuberculosis 49. Narres, M. et al. The incidence of end-stage renal disease in the diabetic meningitis. J. Clin. Neurol. 12,332–339 (2016). (compared to the non-diabetic) population: a systematic review. PLoS ONE 11, 44. Lee, W. S. et al. Cutoff value of serum procalcitonin as a diagnostic biomarker e0147329 (2016). of infection in end-stage renal disease patients. Korean J. Intern. Med. 30, 50. Scott, C. et al. Human tuberculosis caused by Mycobacterium bovis in the 198–204 (2015). United States, 2006-2013. Clin. Infect. Dis. 63,594–601 (2016). 45. Critchley,J.A.etal. Defining a research agenda to address the converging 51. Majoor, C. J., Magis-Escurra, C., van Ingen, J., Boeree, M. J. & van Soolingen, D. epidemics of tuberculosis and diabetes: Part 1: Epidemiology and clinical Epidemiology of Mycobacterium bovis disease in humans, The Netherlands, management. Chest 152, 165–173 (2017). 1993-2007. Emerg. Infect. Dis. 17,457–463 (2011). 46. Young,F., Wotton,C. J., Critchley, J. A.,Unwin,N.C. & Goldacre,M.J.Increased 52. Hlavsa, M. C. et al. Human tuberculosis due to Mycobacterium bovis in the risk of tuberculosis disease in people with diabetes mellitus: record-linkage United States, 1995-2005. Clin. Infect. Dis. 47,168–175 (2008). study in a UK population. J. Epidemiol. Community Health 66,519–523 (2012). http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Emerging Microbes & Infections Springer Journals

Risk factors for extrapulmonary dissemination of tuberculosis and associated mortality during treatment for extrapulmonary tuberculosis

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Biomedicine; Biomedicine, general; Immunology; Medical Microbiology; Microbiology; Antibodies; Vaccine
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Abstract

Many environmental, host, and microbial characteristics have been recognized as risk factors for dissemination of extrapulmonary tuberculosis (EPTB). However, there are few population-based studies investigating the association between the primary sites of tuberculosis (TB) infection and mortality during TB treatment. De-identified population- based surveillance data of confirmed TB patients reported from 2009 to 2015 in Texas, USA, were analyzed. Regression analyses were used to determine the risk factors for EPTB, as well as its subsite distribution and mortality. We analyzed 7007 patients with exclusively pulmonary TB, 1259 patients with exclusively EPTB, and 894 EPTB patients with reported concomitant pulmonary involvement. Age ≥45 years, female gender, human immunodeficiency virus (HIV)-positive status, and end-stage renal disease (ESRD) were associated with EPTB. ESRD was associated with the most clinical presentations of EPTB other than meningeal and genitourinary TB. Patients age ≥45 years had a disproportionately high rate of bone TB, while foreign-born patients had increased pleural TB and HIV+ patients had increased meningeal TB. Age ≥45 years, HIV+ status, excessive alcohol use within the past 12 months, ESRD, and abnormal chest radiographs were independent risk factors for EPTB mortality during TB treatment. The epidemiologic risk factors identified by multivariate analyses provide new information that may be useful to health professionals in managing patients with EPTB. Introduction (19.3–39.3%) present with either primary extrapulmonary Tuberculosis (TB), especially with human immunode- tuberculosis (EPTB) or EPTB concurrent with pulmonary ficiency virus (HIV) co-infection, is a leading cause of involvement, while the majority of patients develop pul- 1 3, 4 death worldwide . Individuals infected with Mycobacter- monary TB (PTB) . Some studies have suggested that ium tuberculosis (Mtb) may either be asymptomatic the proportion of EPTB among all TB cases has been (latent TB infection, LTBI) or develop active TB disease . increasing in the United States (USA) (21% in 2013 For active TB disease, a small subset of patients compared to 16% in 1993) mainly because of the 5, 6 increasing prevalence of HIV infection . Typically, Mtb infection leads to spatial and temporal Correspondence: Edward A. Graviss (eagraviss@houstonmethodist.org) lesion dynamics not only within a single individual but also Key Laboratory of Laboratory Medicine, Ministry of Education, Zhejiang 7, 8 between individuals . The most common extra- Provincial Key Laboratory of Medical Genetics, Wenzhou Medical University, pulmonary sites of TB infection are the lymph nodes, the Wenzhou, P. R. China Center for Precision Biomedicine, Institute of Molecular Medicine, McGovern pleura, the genitourinary system, the gastrointestinal tract, Medical School, The University of Texas Health Science Center at Houston, the bones, and the central nervous system. To date, the Houston, TX, USA mechanisms for extrapulmonary dissemination remain Full list of author information is available at the end of the article. These authors contributed equally: Xu Qian, Duc T. Nguyen © The Author(s) 2018 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to theCreativeCommons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. 1234567890():,; 1234567890():,; Qian et al. Emerging Microbes & Infections (2018) 7:102 Page 2 of 14 largely unknown . It has been found that host–pathogen factors for EPTB and mortality at 6 months after TB interactions such as pathogen-associated molecular pattern diagnosis from 1995 through 1999 in Harris Country, signaling, antigen presentation, and immune recognition Texas, but this study analyzed data at the county level and may be used by Mtb to mediate latency induction and not at the state or country level . The third example is pathogen reactivation . These factors are believed to be the association of Mtb lineage with the site of TB disease important in establishing the site of disease presentation in a study that analyzed US data from 2004 through 2008; and dissemination. One recent study, which assessed the study reported that the Euro-American, Indo-Ocea- within-host bacterial population dynamics in a macaque nic, and East African-Indian bacterial lineages were found TB model by using a genome barcoding system coupled exclusively in EPTB . Given the variety of organ-specific with serial F-fluorodeoxyglucose radiotracers and posi- clinical scenarios and the nonspecific systemic symptoms tron emission tomography co-registered with computed of EPTB, a more profound understanding of the site tomography (PET/CT), suggested that in the first 6 weeks distribution of EPTB, as well as the risk factors associated after infection, granuloma size but not bacterial burden is with extrapulmonary dissemination and mortality, is correlated with risk of local dissemination (<10 mm away) important for developing suitable protocols to manage in the lungs . Furthermore, genomic analyses of samples EPTB patients. Accordingly, this analysis aimed to from lung and extrapulmonary biopsies of HIV-co-infected determine the characteristics associated with EPTB dis- patients have demonstrated that the dissemination of Mtb semination and mortality during TB treatment by using from the lungs to extrapulmonary sites may occur as fre- recent epidemiological data from Texas. quently as between lung sites . Importantly, Mtb sub- lineages were differentially distributed throughout the Materials and methods lungs of these immunocompromised patients. Therefore, De-identified surveillance data of all confirmed TB data from Lieberman and co-workers suggest that biop- patients reported to the Centers for Disease Control and sies from the upper airway represent only a small fraction Prevention’s TB Genotyping Information Management of the population diversity. These data are also consistent System (TBGMIS) between January 2009 and December with a nonhuman-primate-model study which showed 2015 from the state of Texas, USA, were analyzed. TB barcodes recovered from gastric and bronchoalveolar disease was classified as exclusively PTB, exclusively EPTB lavage samples represented only a fraction (3.75%) of all or EPTB with concurrent PTB involvement. Sites of EPTB bacterial barcodes . Additionally, there has been a study include pleural, lymphatic, bone, genitourinary, perito- neal, and meningeal locations, among others. All patients evaluating the immune response profile of inflammatory cytokinessuchasinterferon-γ, interleukin (IL)-1β,and received anti-TB treatment, and their outcomes were tumor necrosis factor (TNF)-β in HIV-negative children recorded as “completed”, “died”,or “unknown”. with TB disease . At the time of TB diagnosis, the immune Cases were categorized by site of disease. Differences response in all pediatric TB patients (suppressed pro- across groups (exclusively PTB, exclusively EPTB and inflammatory cytokines and increased regulatory T cell EPTB with concurrent PTB involvement) were deter- frequency) was not significantly different between PTB and mined by the chi-squared test or Fisher’s exact test as EPTB patients. However, the recovery of the immune appropriate. Logistic regression was used to determine the response was observed in children with PTB but not in characteristics that were associated with patients having children with EPTB after 6 months of TB treatment . exclusively PTB compared to individuals identified to These findings suggest that the host immune response have (1) exclusively EPTB, (2) EPTB with concurrent PTB following treatment is specific to the disease (PTB vs. involvement, or (3) any EPTB (patients with exclusively EPTB) rather than due to the within-host defense and EPTB and EPTB with concurrent PTB involvement). cannot explain why one individual develops PTB while Odds ratios (OR), adjusted odds ratios ( OR), and 95% another develops EPTB. confidence intervals (CI) were reported. Multiple logistic Clinically, EPTB is still underrecognized, and diagnoses regression modeling was also used to determine the risk are often delayed due to its paucibacillary nature and of patient mortality during treatment in patients with atypical presentations. In fact, many characteristics such exclusively EPTB. Analyses were performed with SPSS as HIV and female gender have been recognized as risk 16.0 (SPSS, Inc., Chicago, Illinois, USA) and Stata MP14.2 12–14 factors for EPTB dissemination . However, there are (StataCorp LP, College Station, TX, USA). A p-value of few population-based studies in the USA investigating the <0.05 was considered statistically significant. association between primary sites of Mtb infection and mortality during TB treatment. For instance, one study Results analyzed the epidemiology and risk factors of EPTB from Study population and characteristics 1993 through 2006 but did not analyze risk factors for From 2009 to 2015, there were 9246 confirmed TB patient mortality . Another study demonstrated risk patients in Texas recorded in the TBGIMS database. After Qian et al. Emerging Microbes & Infections (2018) 7:102 Page 3 of 14 Fig. 1 Flowchart of the study population. TBGIMS Genotyping Information Management System, PTB pulmonary TB, EPTB extrapulmonary TB excluding 86 patients because their EPTB site was (Table 2). Patients with a history of contact with a known unknown, we included 9160 TB patients in the analysis TB index case within 2 years ( OR 0.44, 95% CI 0.35–0.55) (Fig. 1). The patients’ demographic and clinical char- and those with diabetes ( OR 0.61, 95% CI 0.52–0.71) acteristics are presented in Table 1. The majority of were less likely to have EPTB than PTB (Table 2). exclusively EPTB patients were male (55.4%) and foreign ESRD was associated with most subtypes of EPTB, born (59.1%). The proportions of patients age 25–44 years excluding meningeal and genitourinary TB (Table 3). (39.6%) and Hispanic patients (46.6%) with exclusively Patients age ≥45 years had a disproportionately high rate EPTB were higher than the proportions of other age or of bone TB ( OR 1.47, 95% CI 1.04–2.08), while foreign- ethnic groups with exclusively EPTB. The percentage of born patients had more pleural TB ( OR 1.77, 95% CI TB contact history was higher in patients with exclusively 1.31–2.41) and HIV+ patients had more meningeal TB EPTB (3.7%) than in patients with PTB (9.0%) or EPTB ( OR 5.73, 95% CI 3.43–9.56) (Table 3). with concurrent PTB (6.9%). In patients with exclusively EPTB, 448/1259 (35.6%) had abnormal chest radiographs Risk factors for mortality during treatment in patients with and 17/1259 (1.4%) had culture-positive specimens. exclusively EPTB Multidrug-resistant TB (MDR-TB) was identified in 0.4% Among the 1111 patients with exclusively EPTB who of exclusively EPTB cases, 0.1% of EPTB cases with con- had mortality-related data available, 50 (4.5%) died during current PTB, and 0.8% of exclusive PTB cases. Two anti-TB treatment. Mortality was highest among those extensively drug-resistant cases were identified in PTB patients presenting with meningeal (9.6%) or peritoneal patients. The most prevalent Mtb lineages of exclusively TB (8.5%) and lower among those individuals with lym- EPTB were Euro-American L4, East Asian L2, and Indo- phatic TB (0.7%) (Fig. 2b). During treatment, no mortality Oceanic L1. was reported among patients having either laryngeal or multisite TB. Age ≥45 ( OR 3.75, 95% CI 1.71–8.22), HIV Sites of EPTB + status ( OR 4.70, 95% CI 1.54–14.32), excessive alcohol The distribution of EPTB sites is shown in Fig. 2a. Of use within the past 12 months ( OR 3.34, 95% CI the patients with exclusively EPTB, the most common 1.45–7.67), ESRD ( OR 4.45, 95% CI 1.38–14.33), and sites of TB disease included pleural (15.7%), lymphatic abnormal chest radiographs ( OR 2.18, 95% CI 1.09–4.35) (32.3%), bone (12.2%), and meningeal (7.5%) sites. The were risk factors for TB mortality with adjusted odds ratio most common sites of TB disease in patients having EPTB (Table 4). with concomitant PTB were also pleural (38.1%), lym- phatic (20.8%), bone (7.9%), and meningeal (6.7%) areas. Discussion Although risk factors for the development of exclusively Risk factors for EPTB and its specific sites EPTB compared to PTB have been described in several 5, 12, 16, 17 Multivariable analyses were performed in order to studies , there are still inconsistent findings identify associations between sociodemographic, micro- among studies from different regions, including sub- biologic, and clinical characteristics of EPTB patients and stantial state-level heterogeneity in the reported epide- a 18 sites of EPTB. Female patients ( OR 1.32, 95% CI miological data . We performed an analysis of EPTB 1.19–1.46), as well as patients with HIV+ status ( OR patients in the state of Texas. We found that patients who 1.77, 95% CI 1.47–2.13), immunosuppression ( OR 1.31, were age ≥45 years, female, HIV+, and suffering from 95% CI 1.00–1.77), and ESRD ( OR 3.42, 95% CI ESRD were at a significantly elevated risk of EPTB. In 2.39–4.88) were at a significantly elevated risk of EPTB particular, age ≥45 years, HIV+, excessive alcohol use Qian et al. Emerging Microbes & Infections (2018) 7:102 Page 4 of 14 Table 1 Characteristics of tuberculosis patients with pulmonary and extrapulmonary locations in Texas, USA, 2009–2015 Variable Total Exclusively PTB Exclusively EPTB EPTB with PTB p-Value N 9160 7007 1259 894 Age (years) <0.01 0–4 395 (4.3) 297 (4.2) 63 (5.0) 35 (3.9) 5–14 213 (2.3) 146 (2.1) 43 (3.4) 24 (2.7) 15–24 1048 (11.4) 808 (11.5) 129 (10.2) 111 (12.4) 25–44 3054 (33.3) 2245 (32.1) 498 (39.6) 311 (34.8) 45–64 3015 (33.0) 2403 (34.3) 361 (28.7) 251 (28.1) ≥65 1435 (15.7) 1108 (15.8) 165 (13.1) 162 (18.1) Gender <0.01 Male 5954 (65.0) 4684 (66.8) 697 (55.4) 573 (64.1) Female 3206 (35.0) 2323 (33.2) 562 (45.6) 321 (35.9) Ethnicity <0.01 White 1103 (12.0) 911 (13.0) 108 (8.6) 84 (9.4) Black 1717 (18.7) 1254 (17.9) 262 (20.8) 201 (22.5) Asian 1517 (16.6) 1052 (15.0) 297 (23.6) 168 (18.8) Hispanic 4771 (52.1) 3752 (53.6) 587 (46.6) 432 (48.3) Other 52 (0.6) 38 (0.5) 5 (0.4) 9 (1.0) HIV status <0.01 Negative 7128 (77.8) 5518 (78.7) 959 (76.2) 651 (72.9) Positive 608 (6.7) 409 (5.9) 77 (6.1) 122 (13.6) Not offered 1424 (15.5) 1080 (15.4) 223 (17.7) 121 (13.5) Homeless <0.01 No 8682 (94.8) 6600 (94.2) 1229 (97.6) 853 (95.4) Yes 478 (5.2) 407 (5.8) 30 (2.4) 41 (4.6) History of TB contact <0.01 No 8417 (91.9) 6373 (91.0) 1212 (96.3) 832 (93.1) Yes 743 (8.1) 634 (9.0) 47 (3.7) 62 (6.9) Excessive alcohol <0.01 No 7494 (81.8) 5633 (80.4) 1138 (90.4) 723 (80.9) Yes 1666 (18.2) 1374 (19.6) 121 (9.6) 171 (19.1) Injecting drug use 0.03 No 8930 (97.5) 6819 (97.3) 1241 (98.6) 870 (97.3) Yes 230 (2.5) 188 (2.7) 18 (1.4) 24 (2.7) Non-injecting drug use No 8263 (90.2) 6257 (89.3) 1202 (95.5) 804 (89.9) <0.01 Yes 897 (9.8) 750 (10.7) 57 (4.5) 90 (10.1) Origin 0.01 US born 4108 (44.8) 3188 (45.5) 515 (40.9) 405 (45.3) Foreign born 5052 (55.2) 3819 (54.5) 744 (59.1) 489 (54.7) Qian et al. Emerging Microbes & Infections (2018) 7:102 Page 5 of 14 Table 1 continued Variable Total Exclusively PTB Exclusively EPTB EPTB with PTB p-Value Diabetes <0.01 No 7800 (85.2) 5883 (84.0) 1122 (89.1) 795 (88.9) Yes 1360 (14.8) 1124 (16.0) 137 (10.9) 99 (11.1) End-stage renal disease <0.01 No 9024 (98.5) 6935 (99.0) 1230 (97.7) 859 (96.1) Yes 136 (1.5) 72 (1.0) 29 (2.3) 35 (3.9) Immunosuppression 0.01 No 8936 (97.6) 6854 (97.8) 1217 (96.7) 865 (96.8) Yes 224 (2.4) 153 (2.2) 42 (3.3) 29 (3.2) Previous TB 0.08 No 8819 (96.3) 6733 (96.1) 1226 (97.4) 860 (96.2) Yes 341 (3.7) 274 (3.9) 33 (2.6) 34 (3.8) Inmate of a correctional facility <0.01 No 8210 (89.6) 6161 (87.9) 1192 (94.7) 857 (95.9) Yes 950 (10.4) 846 (2.1) 67 (5.3) 37 (4.1) Resident of long-term care facility 0.56 No 9046 (98.8) 6921 (98.8) 1240 (98.5) 885 (99.0) Yes 114 (1.2) 86 (1.2) 19 (1.5) 9 (1.0) Specimen smear <0.01 Negative 4097 (44.7) 2832 (40.4) 707 (56.2) 558 (62.4) Positive 3585 (39.1) 3423 (48.9) 5 (0.4) 157 (17.6) Not done/Unknown 1478 (16.1) 752 (10.7) 547 (43.4) 179 (20.0) Specimen culture <0.01 Negative 2449 (26.7) 1462 (20.9) 669 (53.1) 318 (35.6) Positive 5185 (56.6) 4782 (68.2) 17 (1.4) 386 (43.2) Not done/Unknown 1526 (16.7) 763 (10.9) 573 (45.5) 190 (21.3) Chest radiography <0.01 Abnormal 7694 (84.0) 6485 (92.6) 448 (35.6) 761 (85.1) Normal 1024 (11.2) 233 (3.3) 700 (55.6) 91 (10.2) Not done/Unknown 442 (4.8) 289 (4.1) 111 (8.8) 42 (4.7) Radiographic cavity <0.01 No 5140 (56.1) 4031 (57.5) 437 (34.7) 672 (75.2) Yes 2540 (27.7) 2441 (34.8) 11 (0.9) 88 (9.8) Unknown 1480 (16.2) 535 (7.7) 811 (64.4) 134 (15.0) DST profile 0.11 None to RIF/INH 6183 (67.5) 4902 (70.0) 684 (54.3) 597 (66.8) RIF or INH 512 (5.6) 420 (6.0) 44 (3.5) 48 (5.4) MDR 69 (0.7) 63 (0.8) 5 (0.4) 1 (0.1) XDR 2 (0.1) 2 (0.1) 0 (0.0) 0 (0.0) Qian et al. Emerging Microbes & Infections (2018) 7:102 Page 6 of 14 Table 1 continued Variable Total Exclusively PTB Exclusively EPTB EPTB with PTB p-Value Unavailable 2394 (26.1) 1620 (23.1) 526 (41.8) 248 (27.7) Global Mtb Lineage <0.01 Indo-Oceanic L1 634 (6.9) 483 (6.9) 93 (7.4) 58 (6.5) East Asian L2 1121 (12.2) 918 (13.1) 98 (7.8) 105 (11.7) East African-Indian L3 174 (1.9) 115 (1.6) 37 (2.9) 22 (2.5) Euro-American L4 4344 (47.4) 3569 (50.9) 376 (29.9) 399 (44.6) M. bovis 105 (1.1) 52 (0.8) 36 (2.9) 17 (1.9) Other 28 (0.3) 12 (0.2) 8 (0.6) 8 (0.9) Unknown 2754 (30.2) 1858 (26.5) 611 (48.5) 285 (31.9) Death at time of diagnosis 0.04 No 8964 (97.9) 6870 (98.0) 1220 (96.9) 874 (97.8) Yes 196 (2.1) 137 (2.0) 39 (3.1) 20 (2.2) Death during TB treatment <0.01 No 8610 (94.0) 6592 (94.1) 1209 (96.0) 809 (90.5) Yes 551 (6.0) 416 (5.9) 50 (4.0) 85 (9.5) PTB pulmonary tuberculosis, EPTB extrapulmonary tuberculosis, HIV human immunodeficiency virus, RIF rifampin, INH isoniazid, MDR multidrug resistant, XDR extensively drug resistant. Differences across groups were compared using the chi-square test or Fisher’s exact test, as appropriate Patients with a history of contact with a known TB index case within 2 years Excessive alcohol use within the past 12 months Fig. 2 Distribution of extrapulmonary tuberculosis by site and associated mortality. a Distribution of extrapulmonary sites in patients with concurrent pulmonary tuberculosis (PTB) or exclusively extrapulmonary tuberculosis (EPTB). b Mortality distribution by extrapulmonary sites in patients with exclusively EPTB within the past 12 months, ESRD, and abnormal chest further noted that ethnicity was not associated with any radiographs were risk factors for EPTB mortality during specific site of EPTB and that female gender was asso- treatment. ciated with lymphatic and peritoneal TB. The observed demographics of female gender and The risk of TB development in the foreign-born foreign-born origin in the USA have been previously population was substantially elevated even more than 5 5, 12, 17, 19, 20 20 reported as risk factors for EPTB . Similarly, years after entering the USA . In our study population, we found that female gender and Hispanic ethnicity were more than half (55.2%) of the patients were born outside associated with patients who presented with exclusively the USA. The cervical lymphatic site was found to be a EPTB after adjusting for other confounding factors. We more common disease site among foreign-born EPTB Qian et al. Emerging Microbes & Infections (2018) 7:102 Page 7 of 14 Table 2 Multivariable analyses of patients’ characteristics with extrapulmonary tuberculosis in Texas, USA, 2009–2015 Characteristics Exclusively EPTB vs. exclusively PTB EPTB with PTB vs. exclusively PTB Any EPTB vs. exclusively PTB a a a OR (95% CI) OR (95% CI) OR (95% CI) OR (95% CI) OR (95% CI) OR (95% CI) Age (years) 0–4 (reference) (reference) (reference) (reference) (reference) (reference) 5–14 1.42 (1.04–1.96) 1.19 (0.85–1.68) 0.81 (0.55–1.19) 0.96 (0.62–1.49) 1.12 (0.86–1.50) 0.97 (0.74–1.28) 15–24 1.98 (1.356–2.88) 2.33 (1.56–3.46) 1.12 (0.71–1.79) 1.23 (0.76–1.99) 1.56 (1.14–2.13) 1.33 (0.96–1.84) 25–44 1.07 (0.837–1.37) 1.10 (0.85–1.42) 0.90 (0.73–1.22) 0.93 (0.71–1.21) 1.01 (0.83–1.22) 0.97 (0.80–1.18) 45–64 1.49 (1.232–1.80) 1.57 (1.29–1.91) 0.95 (0.77–1.16) 0.80 (0.67–1.03) 1.22 (1.05–1.42) 1.13 (0.72–1.32) ≥65 1.01 (0.828–1.23) 1.22 (0.99–1.49) 0.71 (0.58–0.88) 0.67 (0.54–0.83) 0.86 (0.74–1.01) 1.06 (0.91–1.24) Gender (female) 1.36 (1.20–1.54) 1.42 (1.26–1.62) 1.12 (0.96–1.30) 1.16 (1.00–1.36) 1.41 (1.27–1.55) 1.32 (1.19–1.46) Ethnicity White (reference) (reference) (reference) (reference) (reference) (reference) Black 0.84 (0.33–2.15) 0.92 (0.35–2.38) 0.39 (0.18–0.83) 0.37 (0.17–0.80) 0.57 (0.30–1.08) 0.53 (0.28–1.01) Asian 0.76 (0.61–0.94) 0.80 (0.63–1.02) 0.68 (0.32–1.42) 0.57 (0.17–1.20) 1.00 (0.54–1.87) 0.87 (0.46–1.63) Hispanic 1.34 (1.14–1.57) 1.34 (1.12–1.60) 0.67 (0.32–1.42) 0.67 (0.31–1.45) 1.20 (0.64–2.24) 1.03 (0.54–1.95) Other 1.81 (1.55–2.11) 1.57 (1.34–1.85) 0.49 (0.23–1.01) 0.48 (0.23–1.02) 0.74 (0.40–1.37) 0.68 (0.37–1.28) Homeless 0.56 (0.38–0.83) 0.57 (0.40–0.84) 0.78 (0.56–1.08) 0.70 (0.50–1.00) 0.55 (0.43–0.72) 0.65 (0.49–0.85) History of TB contact 0.39 (0.29–0.53) 0.28 (0.21–0.39) 0.75 (0.57–0.98) 0.71 (0.53–0.96) 0.54 (0.44–0.66) 0.44 (0.35–0.55) Excessive alcohol 0.61 (0.49–0.75) 0.60 (0.48–0.74) 1.12 (0.91–1.38) 1.03 (0.84–1.26) 0.64 (0.56–0.74) 0.78 (0.67–0.91) Injecting drug use 1.08 (0.64–1.82) 1.04 (0.62–1.76) 1.00 (0.63–1.60) 0.96 (0.60–1.53) 0.72 (0.52–1.01) 1.01 (0.70–1.46) Non-injecting drug use 0.53 (0.39–0.72) 0.52 (0.40–0.71) 0.87 (0.67–1.14) 0.85 (0.65–1.11) 0.61 (0.51–0.74) 0.68 (0.55–0.84) Diabetes 0.63 (0.51–0.77) 0.61 (0.50–0.74) 0.65 (0.51–0.82) 0.61 (0.49–0.77) 0.64 (0.56–0.75) 0.61 (0.52–0.71) HIV 1.14 (0.87–1.49) 1.20 (0.92–1.55) 2.65 (2.10–3.35) 2.57 (2.05–3.21) 1.64 (1.38–1.96) 1.77 (1.47–2.13) Immunosuppression 1.44 (0.10–2.07) 1.36 (0.95–1.95) 1.20 (0.78–1.83) 1.15 (0.75–1.76) 1.53 (1.15–2.03) 1.31 (1.00–1.77) ESRD 2.51 (1.58–3.99) 2.59 (1.63–4.17) 4.30 (2.78–6.64) 4.45 (2.88–6.86) 3.32 (2.33–4.75) 3.42 (2.39–4.88) Foreign born 1.04 (0.89–1.22) 0.92 (0.80–1.06) 1.06 (0.89–1.28) 0.99 (0.85–1.17) 1.05 (0.93–1.20) 0.95 (0.85–1.06) Previous TB 0.68 (0.47–1.00) 0.69 (0.47–1.01) 0.99 (0.68–1.43) 0.95 (0.66–1.38) 0.81 (0.61–1.07) 0.80 (0.61–1.06) EPTB extrapulmonary tuberculosis, PTB pulmonary tuberculosis, OR odds ratio, OR adjusted odds ratio, CI confidence interval, HIV human immunodeficiency virus, ESRD end-stage renal disease, TB, tuberculosis Patients with a history of contact with a known TB index case within 2 years Excessive alcohol use within the past 12 months HIV unknown categorized as negative Significant odds ratios (p<0.005) are in bold patients than among US-born patients in North Car- also possible that the association between foreign birth olina . However, a study at a single urban US public and pleural TB is due to the effect of BCG vaccination on hospital did not show any risk between foreign birth with foreign-born individuals. Studies have shown that sites of EPTB . From our results, foreign birth was pleuritis is induced by Mycobacterium bovis BCG, and associated with increased risk of pleural TB. Pleural TB the underlying mechanisms have been elucidated . is the second most common type of EPTB but the However, non-association of BCG status among patients 22, 23 leading manifestation in settings with high TB . with PTB, pleural TB, and other types of EPTB was seen Given that TB disease among foreign-born populations in a study with a majority of BCG-vaccinated patients . is normally considered to result from the reactivation of From the findings described herein, studies can be LTBI , one explanation might be that pleural TB was initiated to further evaluate the BCG status of foreign- the primary manifestation of LTBI reactivation .Itis born patients in relation to pleural TB. Qian et al. Emerging Microbes & Infections (2018) 7:102 Page 8 of 14 Drug users and the elderly remain the groups at high risk of developing LTBI and TB disease .The pre- valence of illicit drug use has been previously shown to be higher in patients with PTB than in patients with 15, 17 EPTB . Similarly, the prevalence of injecting drug use and non-injecting drug use was also higher in patients with PTB than patients with exclusively EPTB in our study. We further observed that injecting drug use was associated with patients with genitourinary TB. In addition, non-injecting drug use as a non-risk factor for EPTB compared to PTB has been reported .Fromour results, non-injecting drug use was also negatively associated with patients having exclusively EPTB or any EPTB comparedtoPTB.Wedemonstratedthatthe age groups 15–24 and 45–64 were associated with exclu- sively EPTB. Meanwhile, Click et al. indicated that age 0–4 was associated with exclusively EPTB. TB in elderly patients can involve almost any organ in the body .We found that patients age >45 years were at an increased risk of bone TB but not with other extrapulmonary sites. This finding is consistent with a large-population-based study in Europe . Additionally, ages <15 and >65 years were likely to be associated with the most comment types of EPTB . According to a 2016 CDC report, high rates of TB cases overall and TB cases attributable to extensive recent transmission were identified frequently among people experiencing homelessness within the past year and resi- dents of a correctional facility at the time of diagnosis However, EPTB was more common in non-homeless 5, 17 patients than in the homeless, as previously reported . The number of homeless cases was significantly higher in PTB (5.8%) than in exclusively EPTB (2.4%) in our population. Furthermore, we showed that being homeless was negatively associated with EPTB and especially lym- phatic TB. Neither the Magee study nor our study showed any significant differences in the proportion of residents of correctional facility patients with exclusively EPTB vs. PTB . These findings suggest that Mtb infection is not site-specific in correctional facility patients. It is well known that patients with HIV have an increased 13, 14 12 risk of EPTB . Click et al. foundthatHIV wasasso- ciated with both exclusively EPTB and any EPTB. More- over, the same study demonstrated that the association between individuals with HIV infection and extra- pulmonary disease was greater for EPTB with concurrent pulmonary involvement than for exclusively EPTB alone. In our population, HIV was associated with EPTB with concurrent pulmonary involvement and any EPTB but not with exclusively EPTB. We further identified that HIV was associated with meningeal TB at more than five times the odds, while other sites were not found to be related. In addition, low CD4 lymphocyte counts in hospitalized patients with HIV-co-infected EPTB were found to be Table 3 Risk factors associated with subsites of exclusively extrapulmonary tuberculosis compared to pulmonary tuberculosis in Texas, USA, 2009–2015 Characteristics Pleural (n = 198) Lymphatic (n = 407) Bone (n = 154) Genitourinary (n = 65) Peritoneal (n = 71) Meningeal (n = 94) Others (n = 212) a a a a a a a OR (95% CI) OR (95% CI) OR (95% CI) OR (95% CI) OR (95% CI) OR (95% CI) OR (95% CI) Age (≥45 years) 1.04 (0.76–1.40) 0.56 (0.44–0.71) 1.47 (1.04–2.08) 1.00 (0.60–1.68) 1.06 (0.64–1.74) 0.75 (0.48–1.17) 1.06 (0.79–1.42) Gender (female) 0.91 (0.67–1.25) 2.04 (1.66–2.51) 0.69 (0.48–0.99) 1.44 (0.87–2.40) 1.96 (1.20–3.21) 1.22 (0.79–1.88) 1.39 (1.05–1.86) Ethnicity (White) 0.73 (0.46–1.14) 0.47 (0.29–0.77) 1.14 (0.69–1.88) 1.26 (0.50–3.22) 0.62 (0.23–1.63) 0.82 (0.39–1.72) 0.77 (0.45–1.30) Homeless 0.90 (0.48–1.68) 0.29 (0.09–0.92) 0.54 (0.19–1.50) 0.47 (0.06–3.57) 0.69 (0.16–2.95) 0.38 (0.09–1.63) 0.72 (0.29–1.82) Excessive alcohol 1.17 (0.80–1.71) 0.38 (0.23–0.63) 0.42 (0.23–0.75) 0.82 (0.35–1.90) 1.50 (0.77–2.95) 0.54 (0.26–1.14) 0.30 (0.16–0.57) Injecting drug use 0.91 (0.35–2.34) 0.63 (0.15–2.68) 0.87 (0.20–3.79) 5.26 (1.10–25.36) 0.80 (0.10–6.36) 2.20 (0.60–8.05) 0.84 (0.20–3.62) Non-injecting drug use 0.82 (0.49–1.38) 0.37 (0.18–0.74) 0.70 (0.33–1.53) 0.12 (0.02–1.05) 0.58 (0.19–1.76) 0.39 (0.14–1.07) 0.58 (0.27–1.24) Diabetes 0.68 (0.43–1.07) 0.35 (0.23–0.54) 0.92 (0.60–1.42) 0.54 (0.24–1.22) 0.71 (0.35–1.44) 0.51 (0.23–1.13) 0.84 (0.56–1.26) HIV 0.62 (0.30–1.28) 1.20 (0.74–1.95) 0.54 (0.19–1.50) 0.64 (0.15–2.66) 1.13 (0.40–3.17) 5.73 (3.43–9.56) 1.52 (0.86–2.68) Immunosuppression 0.80 (0.28–2.23) 0.88 (0.41–1.90) 2.54 (1.30–4.97) 1.57 (0.36–6.78) 2.29 (0.77–6.85) 1.79 (0.62–5.12) 0.95 (0.38–2.38) ESRD 2.74 (1.06–7.10) 2.96 (1.28–6.87) 4.05 (1.82–8.98) 1.72 (0.22–13.32) 3.56 (1.01–12.56) – 1.40 (0.43–4.61) Foreign born 1.77 (1.31–2.41) 0.88 (0.71–1.10) 0.98 (0.68–1.40) 0.37 (0.19–0.70) 0.70 (0.41–1.18) 0.97 (0.62–1.51) 0.84 (0.62–1.14) Previous TB 0.27 (0.07–1.10) 0.80 (0.43–1.49) 1.37 (0.63–2.98) 1.20 (0.37–3.89) 0.37 (0.05–2.70) 0.76 (0.24–2.43) 0.52 (0.20–1.43) OR adjusted odds ratio, CI confidence interval, HIV human immunodeficiency virus, ESRD end-stage renal disease Analysis excluded subjects with multiple subsite involvement (n = 57) and laryngeal sites (n = 3) Excessive alcohol use within the past 12 months HIV unknown categorized as negative Significant odds ratios (p<0.005) are in bold Qian et al. Emerging Microbes & Infections (2018) 7:102 Page 9 of 14 Table 4 Risk factors for mortality during anti-tuberculosis treatment in patients with extrapulmonary tuberculosis in Texas, USA, 2009–2015 Variable Treatment completed Died during Mortality risk Crude OR (95% Adjusted OR Adjusted p- (n = 1061) treatment (n = 50) (%) CI) (95% CI) Value Age (years) 0–14 105 (9.9%) 0 (0.0%) 0.0% – 15–24 116 (10.9%) 2 (4.0%) 1.7% (reference) 25–44 438 (41.3%) 9 (18.0%) 2.0% 1.19 (0.25, 5.59) 45–64 292 (27.5%) 17 (34.0%) 5.5% 3.38 (0.77, 14.85) ≥65 110 (10.4%) 22 (44.0%) 16.7% 11.60 (2.66, 50.49) Age (years) <45 659 (62.1%) 11 (22.0%) 1.6% (reference) (reference) ≥45 402 (37.9%) 39 (78.0%) 8.8% 5.81 (2.94, 11.48) 3.75 (1.71, 8.22) 0.001 Gender Female 491 (46.3%) 20 (40.0%) 3.9% (reference) Male 570 (53.7%) 30 (60.0%) 5.0% 1.29 (0.72, 2.30) Race White 84 (7.9%) 9 (18.0%) 9.7% (reference) Black 209 (19.7%) 11 (22.0%) 5.0% 0.49 (0.20, 1.23) Hispanic 501 (47.2%) 24 (48.0%) 4.6% 0.45 (0.20, 1.00) Asian 262 (24.7%) 6 (12.0%) 2.2% 0.21 (0.07, 0.62) Other 5 (0.5%) 0 (0.0%) 0.0% 1.00 (0.00, 0.00) Race Non-White 977 (92.1%) 41 (82.0%) 4.0% (reference) White 84 (7.9%) 9 (18.0%) 9.7% 2.55 (1.20, 5.43) HIV status Negative 847 (79.8%) 21 (42.0%) 2.4% (reference) (reference) Positive 53 (5.0%) 6 (12.0%) 10.2% 4.57 (1.77, 11.79) 4.70 (1.54, 14.32) 0.01 Unknown 161 (15.2%) 23 (46.0%) 12.5% 5.76 (3.11, 10.66) 6.55 (3.19, 13.44) <0.001 Homeless No 1040 (98.0%) 46 (92.0%) 4.2% (reference) (reference) Yes 21 (2.0%) 4 (8.0%) 16.0% 4.31 (1.42, 13.06) 1.57 (0.40, 6.17) 0.52 Excessive alcohol use No 973 (91.7%) 37 (74.0%) 3.7% (reference) (reference) Yes 88 (8.3%) 13 (26.0%) 12.9% 3.88 (1.99, 7.58) 3.34 (1.45, 7.67) 0.01 Injecting drug use No 1050 (99.0%) 48 (96.0%) 4.4% (reference) Yes 11 (1.0%) 2 (4.0%) 15.4% 3.98 (0.86, 18.44) Foreign born No 415 (39.1%) 29 (58.0%) 6.5% (reference) Yes 646 (60.9%) 21 (42.0%) 3.1% 0.47 (0.26, 0.83) Diabetes Qian et al. Emerging Microbes & Infections (2018) 7:102 Page 10 of 14 Table 4 continued Variable Treatment completed Died during Mortality risk Crude OR (95% Adjusted OR Adjusted p- (n = 1061) treatment (n = 50) (%) CI) (95% CI) Value No 948 (89.3%) 40 (80.0%) 4.0% (reference) (reference) Yes 113 (10.7%) 10 (20.0%) 8.1% 2.10 (1.02, 4.31) 1.55 (0.65, 3.69) 0.32 End-stage renal disease No 1043 (98.3%) 44 (88.0%) 4.0% (reference) (reference) Yes 18 (1.7%) 6 (12.0%) 25.0% 7.90 (2.99, 20.88) 4.45 (1.38, 14.33) 0.01 Immunosuppression (medical condition or medication) No 1027 (96.8%) 44 (88.0%) 4.1% Yes 34 (3.2%) 6 (12.0%) 15.0% 4.12 (1.64, 10.32) Previous TB No 1033 (97.4%) 50 (100.0%) 4.6% – Yes 28 (2.6%) 0 (0.0%) 0.0% Inmate of a correctional facility No 967 (94.8%) 48 (98.0%) 4.7% (reference) Yes 53 (5.2%) 1 (2.0%) 1.9% 0.38 (0.05, 2.81) Resident of long-term care facility No 1048 (98.8%) 47 (94.0%) 4.3% (reference) (reference) Yes 13 (1.2%) 3 (6.0%) 18.8% 5.15 (1.42, 18.67) 2.15 (0.50, 9.26) 0.31 AFB smear Negative 627 (99.4%) 17 (94.4%) 2.6% (reference) Positive 4 (0.6%) 1 (5.6%) 20.0% 9.22 (0.98, 86.93) Culture Negative 602 (97.6%) 12 (92.3%) 2.0% (reference) Positive 15 (2.4%) 1 (7.7%) 6.3% 3.34 (0.41, 27.40) TB-CXR No 611 (62.8%) 15 (33.3%) 2.4% (reference) (reference) Yes 362 (37.2%) 30 (66.7%) 7.7% 3.38 (1.79, 6.36) 2.18 (1.09, 4.35) 0.03 Cavitation on CXR No 354 (97.8%) 30 (100.0%) 7.8% – Yes 8 (2.2%) 0 (0.0%) 0.0% DST profile Sensitive to RIF 560 (52.8%) 40 (80.0%) 6.7% and INH Resistant to RIF or 39 (3.7%) 0 (0.0%) 0.0% INH MDR-TB 3 (0.3%) 0 (0.0%) 0.0% (reference) Unavailable 459 (43.3%) 10 (20.0%) 2.1% 0.31 (0.15, 0.62) Genotyping lineage Indo-Oceanic (L1) 80 (7.5%) 4 (8.0%) 4.8% 0.79 (0.20, 3.05) East Asian (L2) 79 (7.4%) 5 (10.0%) 6.0% (reference) Qian et al. Emerging Microbes & Infections (2018) 7:102 Page 11 of 14 Table 4 continued Variable Treatment completed Died during Mortality risk Crude OR (95% Adjusted OR Adjusted p- (n = 1061) treatment (n = 50) (%) CI) (95% CI) Value East African- 35 (3.3%) 1 (2.0%) 2.8% 0.45 (0.05, 4.01) Indian (L3) Euro-American 300 (28.3%) 27 (54.0%) 8.3% 1.42 (0.53, 3.81) (L4) M. bovis 27 (2.5%) 3 (6.0%) 10.0% 1.76 (0.39, 7.84) Other 8 (0.8%) 0 (0.0%) 0.0% 1.00 (0.00, 0.00) Unknown 532 (50.1%) 10 (20.0%) 1.8% 0.30 (0.10, 0.89) Genotyping lineage Not East Asian 354 (97.8%) 30 (100.0%) 7.8% (reference) (reference) East Asian (L2) 8 (2.2%) 0 (0.0%) 0.0% 1.38 (0.53, 3.58) 1.58 (0.53, 4.74) 0.42 TB tuberculosis, HIV human immunodeficiency virus, TB-CXR tuberculosis chest X-ray, DST drug susceptibility test, RIF rifampin, INH isoniazid, MDR-TB multidrug- resistant tuberculosis, OR odds ratios Analysis was performed on 1111 patients with extrapulmonary tuberculosis only and having treatment outcome information available associated with meningeal TB and disseminated TB in a improve the prevention, detection, and treatment of EPTB single hospital study in the USA . with ESRD. The prevalence of end-stage renal disease (ESRD) con- Consistent with the current literature, our analyses tinues to rise by approximately 20,000 cases per year in showed that age ≥45 years, ESRD, HIV+ status, excessive the USA . Consistent epidemiologic evidence has shown alcohol use within the past 12 months, and abnormal that this population is at risk for developing active TB . chest radiography were significantly associated with ESRD as a risk factor for EPTB has also been reported in mortality during anti-TB treatment in patients with 17, 31 17, 38 studies in Taiwan and the US state of Georgia exclusively EPTB . . In the USA, excess alcohol use may Accordingly, ESRD was associated with exclusively EPTB, represent a large portion of TB burden . The relationship EPTB with concurrent pulmonary involvement, and all between excessive alcohol use and the development of TB cases of EPTB compared to PTB in our population-based disease as well as TB-associated morbidity and mortality analysis. We also found that ESRD was specifically asso- has been presumed to be due to impaired immune ciated with pleural, lymphatic, bone and peritoneal TB. function . Other confounding factors such as older age, Thus, patients with ESRD are at a high risk of progressing diabetes, ESRD, and HIV are all related to decreased to EPTB. One possibility regarding the underlying immune function. HIV was highly associated with mor- mechanisms is that the persistence of impaired cell- tality during treatment in our analysis, which is consistent mediated immunity in ESRD may leave these patients with other epidemiologic and observational studies with susceptible to Mtb infection or activation of latent infec- mortality ranging from 6% to 32% . Another important tion . This phenomenon has also been observed in organ finding of our study was that ESRD was associated with transplantation receipts who receive post-transplant more than quadruple the odds of mortality during anti-TB immunosuppressive medications that specifically target treatment in patients having exclusively EPTB. Given 33, 34 T cell-mediated immunity . In regard to the screening these findings, we suggest that patients with decreased strategy among patients with chronic renal disease (CRD), immune function or immunosuppression are at an both the American Thoracic Society and American increased risk of mortality during treatment and that host Transplant Society guidelines recommend that all immune response may determine the difference in sur- immunocompromised subjects and transplant candidates vival. Approaches to meet the objective of optimizing be screened for TB with a tuberculin skin test (TST) or efficacy and safety of treatment, especially for TB-HIV co- IFN-γ releasing assay (IGRA). The WHO provides more infection as well as ESRD, to reduce mortality both in specific guidance on screening all dialysis patients with adults and children are urgently required. As shown in a TST or IGRAs . Beyond the screening strategy, diagnosis prospective cohort study that enrolled hospitalized HIV of EPTB remains difficult because of the paucibacillary co-infected patients with microbiologically confirmed nature. Thus, it is necessary to advance knowledge about drug-susceptible TB in South Africa, mortality within the association of CRD/ESRD and EPTB and strategies to 12 weeks was positively associated with elevated Qian et al. Emerging Microbes & Infections (2018) 7:102 Page 12 of 14 concentrations of procalcitonin, activation of the innate EPTB with pulmonary involvement. Geographically, immune system, and anti-inflammatory markers . Pro- patients with M. bovis TB residing along the US–Mexico calcitonin, a product induced by TNF-α and IL-2 during a border had a disproportionately high incidence of M. bacterial infection, has already shown its value in distin- bovis . This may also be reflected in our results, as Texas guishing TB from bacterial pneumonia and TB meningitis is a US state bordering Mexico. The tradition of raw milk 42, 43 from bacterial meningitis . A higher level of serum and cheese consumption, especially in Hispanic commu- procalcitonin was associated with a poorer prognosis in nities, may be another common reason for M. bovis 43 52 TB meningitis . Moreover, serum procalcitonin has been infection . Additionally, we found that positive smear reported as an appropriate indicator of infection in ESRD and culture, direct susceptibility test profile and geno- patients . Therefore, identifying a correlation between typing lineage were not risk factors for mortality from the host’s immunologic phenotypes and the severity of exclusively EPTB during TB treatment. These results may disease or comorbidities, as well as treatment response, be limited due to many individuals with unknown Mtb would enable the direct selection of host-directed ther- status, either because the test was not performed or apeutics and a potentially beneficial and improved TB because the results were not recorded. Instead of bacterial outcome. factors, host risk factors such as HIV, age ≥45, excessive Another important consideration for the risk of EPTB is alcohol use, and abnormal chest X-ray findings were diabetes status, as several studies have identified diabetes associated with mortality during treatment of EPTB in our as a risk factor for developing active TB and poor treat- study. ment outcomes . For instance, a study in the UK has One important limitation of our study is the unavail- reported that patients with diabetes had an increased risk ability of data in some categories. Therefore, the reported of developing TB compared to a control group . Among crude and adjusted odds ratios could be biased due to patients undergoing TB treatment, patients with diabetes unmeasured covariates or unknown confounders. State had an increased mortality risk compared to those with- TB surveillance reporting does not include the depth of out diabetes . However, compared to the control group, clinical information necessary to further investigate TB patients with diabetes had an increased probability of recognized risk factors in the epidemiology of EPTB (e.g., having PTB as opposed to EPTB . Furthermore, both our CD4 lymphocyte counts for HIV patients and smoking study and a cohort study in the US state of Georgia found status). An observational design in a large cohort will be TB patients with diabetes to have an increased probability necessary to assess the true effect of these factors. Given of EPTB as opposed to PTB, and diabetes was not asso- that Texas has one of the highest TB prevalence rates of ciated with EPTB mortality during TB treatment .Inan any US state and has a more diverse population than additional study, diabetes did not contribute to TB-related many other states, findings from our analysis may not death in adult patients in the USA . Thus, the incon- apply to settings elsewhere in the country. sistent findings encourage further investigations on the impact of diabetes in PTB and EPTB patients. It is worth Conclusion emphasizing that the incidence of ESRD is higher in the The present study characterized the important differ- diabetic population than in the non-diabetic population . ences in the population-level dynamics of EPTB, as well as Since ESRD is an independent risk factor for EPTB as its specific sites, which included demographic factors and shown in our study, it may be necessary to account for the clinical characteristics in addition to the heterogeneities association between diabetes and ESRD as a co-epidemic, within sites of EPTB during the 7-year study period. Age which would potentially account for the risk of EPTB as ≥45 years, HIV+ status, and ESRD were identified as risk well as treatment outcomes. factors for both EPTB establishment and resulting mor- Among available data for patients with exclusively tality during treatment. Although the scientific question EPTB, the most prevalent Mtb lineages were Euro- of the extrapulmonary dissemination remains to be American L4, followed by East Asian L2 and Indo- answered, the study’s findings could allow us to design Oceanic L1. This finding was consistent with a previous supportive treatments for specific subgroups of patients 12 12 nationwide study in the USA . Click et al. suggested with increased mortality, such as those with a HIV+ that the percentage of cases with exclusively EPTB differs status and those with compromised renal function, in for the four lineages—East Asian, 13.0%; Euro-American, order to improve their outcomes and ultimately minimize 13.8%; Indo-Oceanic, 22.6%; and East African-Indian, the transmission of TB. 34.3%—while EPTB with pulmonary involvement did not. However, Click’s study did not show data for M. bovis. Acknowledgements 50, 51 This work was partially supported by the Opening Project of Zhejiang Consistent with the results of previous studies ,we Provincial Top Key Discipline of Clinical Medicine (LKFJ008 to X.Q.), the Key found a higher proportion of M. bovis in patients with Science and Technology Innovation Team of Zhejiang (2010R50048 to J.L.), exclusively EPTB than in patients with exclusively PTB or and Zhejiang Provincial Program for the Cultivation of High-level Innovative Qian et al. Emerging Microbes & Infections (2018) 7:102 Page 13 of 14 Health Talents and Key Laboratory of Laboratory Medicine, Ministry of 14. Sterling, T. R. et al. Human immunodeficiency virus-seronegative adults with Education, China. extrapulmonary tuberculosis have abnormal innate immune responses. Clin. Infect. Dis. 33,976–982 (2001). 15. Gonzalez, O. Y. et al. Extra-pulmonary manifestations in a large metropolitan Author contributions: area with a low incidence of tuberculosis. Int. J. Tuberc. Lung Dis. 7,1178–1185 X.Q. and E.A.G designed the study. D.T.N collected the data. X.Q. and D.T.N. (2003). analyzed the data. X.Q., D.T.G., J.L., A.E.A., X.B., and E.A.G. wrote the manuscript. 16. Sotgiu, G. et al. Determinants of site of tuberculosis disease: an analysis of All authors interpreted the data, critically reviewed the manuscript, and European surveillance data from 2003 to 2014. PLoS ONE 12, e0186499 (2017). approved the final version. 17. Magee,M. J., Foote, M., Ray, S.M., Gandhi,N.R. & Kempker, R. R. Diabetes mellitus and extrapulmonary tuberculosis: site distribution and risk of mortality. Epidemiol. Infect. 144, 2209–2216 (2016). Author details 18. Shrestha, S., Hill, A. N., Marks, S. M. & Dowdy, D. W. Comparing drivers and Key Laboratory of Laboratory Medicine, Ministry of Education, Zhejiang dynamics of tuberculosis in California, Florida, New York, and Texas. Am. J. Provincial Key Laboratory of Medical Genetics, Wenzhou Medical University, Respir. Crit. Care. Med. 196, 1050–1059 (2017). Wenzhou, P. R. China. Center for Precision Biomedicine, Institute of Molecular 19. Deiss, R. G., Rodwell, T. C. & Garfein, R. S. Tuberculosis and illicit drug use: Medicine, McGovern Medical School, The University of Texas Health Science review and update. Clin. Infect. Dis. 48,72–82 (2009). Center at Houston, Houston, TX, USA. People’s Hospital of Hangzhou Medical 20. Cain, K. P. et al. Tuberculosis among foreign-born persons in the United States: College, Hangzhou, P. R. China. Houston Methodist Research Institute, achieving tuberculosis elimination. Am.J.Respir. Crit.Care. Med. 175,75–79 Houston, TX, USA. Department of Otorhinolaryngology, Head and Neck (2007). Surgery, Berlin Institute of Health, Charité – Universitätsmedizin Berlin, 21. Kipp, A. M.,Stout,J.E., Hamilton,C. D.&VanRie,A. Extrapulmonarytuber- Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, culosis, human immunodeficiency virus, and foreign birth in North Carolina, Campus Benjamin Franklin, Berlin, Germany 1993-2006. BMC Public Health 8, 107 (2008). 22. Jeon, D. Tuberculous pleurisy: an update. Tuberc. Respir. Dis. (Seoul) 76, Conflict of interest 153–159 (2014). The authors declare that they have no conflict of interest. 23. RasolofoRazanamparany,V., Menard, D., Auregan, G.,Gicquel, B.&Chanteau,S. Extrapulmonary and pulmonary tuberculosis in Antananarivo (Madagascar): high clustering rate in female patients. J. Clin. Microbiol. 40,3964–3969 (2002). Publisher’s note 24. Tsang,C.A., Langer,A.J., Navin, T. R. & Armstrong,L.R.Tuberculosis among Springer Nature remains neutral with regard to jurisdictional claims in foreign-born persons diagnosed /=10 years after arrival in the United States, published maps and institutional affiliations. 2010-2015. Am. J. Transplant. 17,1414–1417 (2017). 25. Chavez-Galan, L. et al. Transmembrane tumor necrosis factor controls myeloid- derived suppressor cell activity via TNF receptor 2 and protects from excessive Received: 26 January 2018 Revised: 15 April 2018 Accepted: 29 April 2018 inflammation during BCG-induced pleurisy. Front. Immunol. 8, 999 (2017). 26. Yang, Z. et al. Identification of risk factors for extrapulmonary tuberculosis. Clin. Infect. Dis. 38,199–205 (2004). 27. Rajagopalan, S. Tuberculosis in older adults. Clin. Geriatr. Med. 32,479–491 (2016). References 28. Centers for Disease Control and Prevention. Reported Tuberculosis in the 1. World Health Organization. Global Tuberculosis Report (2016). http://www.who. United States 2016. http://www.cdc.gov/features/dstuberculosis. int/tb/publications/global_report/en/ 29. United States Renal Data System. USRDS 2017 Annual Data Report: Atlas of 2. Pai, M. et al. Tuberculosis. Nat. Rev. Dis. Primers 2, 16076 (2016). Chronic Kidney Disease and End-Stage Renal Disease in the United States 3. Sandgren,A., Hollo,V.&vander Werf, M. J. Extrapulmonary tuberculosis in the (National Institutes of Health, National Institute of Diabetes and Digestive and European Union and European Economic Area, 2002 to 2011. Eur. Surveill. 18, Kidney Diseases, Bethesda, MD). https://www.usrds.org/2017/view/v2_01.aspx. 20431 (2013). 30. Al-Efraij, K. et al. Risk of active tuberculosis in chronic kidney disease: a sys- 4. Sama, J. N. et al. High proportion of extrapulmonary tuberculosis in a low tematic review and meta-analysis. Int. J. Tuberc. Lung Dis. 19,1493–1499 (2015). prevalence setting: a retrospective cohort study. Public Health 138,101–107 31. Lin, J.N.etal. Risk factorsfor extra-pulmonary tuberculosis compared to (2016). pulmonary tuberculosis. Int. J. Tuberc. Lung Dis. 13,620–625 (2009). 5. Peto,H. M., Pratt, R. H.,Harrington, T. A.,LoBue, P.A.&Armstrong, L. R. 32. Kato, S. et al. Aspects of immune dysfunction in end-stage renal disease. Clin. J. Epidemiology of extrapulmonary tuberculosis in the United States, 1993-2006. Am.Soc.Nephrol. 3,1526–1533 (2008). Clin. Infect. Dis. 49, 1350–1357 (2009). 33. Mysore, K. R. et al. Longitudinal assessment of T cell inhibitory receptors in liver 6. Centers for Disease Control and Prevention. Reported Tuberculosis in the transplant recipients and their association with posttransplant infections. Am. J. United States 2013. http://www.cdc.gov/features/dstuberculosis Transplant 18,351–363 (2017). 7. Lin, P. L. et al. Sterilization of granulomas is common in active and latent 34. Liyanage, T. et al. Worldwide access to treatment for end-stage kidney disease: tuberculosis despite within-host variability in bacterial killing. Nat. Med. 20, a systematic review. Lancet 385,1975–1982 (2015). 75–79 (2014). 35. Lewinsohn,D.M.etal. Official American Thoracic Society/Infectious Diseases 8. Via, L. E. et al. Host-mediated bioactivation of pyrazinamide: implications for Society of America/Centers for Disease Control and Prevention Clinical Prac- efficacy, resistance, and therapeutic alternatives. ACS Infect. Dis. 1,203–214 tice Guidelines: diagnosis of tuberculosis in adults and children. Clin. Infect. Dis. (2015). 64,111–115 (2017). 9. Martin, C. J. et al. Digitally barcoding Mycobacterium tuberculosis reveals 36. Morris, M. I. et al. Diagnosis and management of tuberculosis in transplant in vivo infection dynamics in the Macaque model of tuberculosis. mBio 8, donors: a donor-derived infections consensus conference report. Am. J. e00312–e00317 (2017). Transplant 12, 2288–2300 (2012). 10. Lieberman, T. D. et al. Genomic diversity in autopsy samples reveals within- 37. WHO. Guidelines on the Management of Latent Tuberculosis Infection (World host dissemination of HIV-associated Mycobacterium tuberculosis. Nat. Med. Health Organization, Geneva, Switzerland, 2015). 22,1470–1474 (2016). 38. Volkmann, T., Moonan, P. K., Miramontes, R. & Oeltmann, J. E. Tuberculosis and 11. Whittaker, E., Nicol, M., Zar, H. J. & Kampmann, B. Regulatory T cells and pro- excess alcohol use in the United States, 1997-2012. Int. J. Tuberc. Lung Dis. 19, inflammatory responses predominate in children with tuberculosis. Front. 111–119 (2015). Immunol. 8, 448 (2017). 39. Happel, K. I. & Nelson, S. Alcohol, immunosuppression, and the lung. Proc. Am. 12. Click, E. S., Moonan, P. K., Winston, C. A., Cowan, L. S. & Oeltmann, J. E. Thorac. Soc. 2,428–432 (2005). Relationship between Mycobacterium tuberculosis phylogenetic lineage and 40. Odone, A. et al. The impact of antiretroviral therapy on mortality in HIV clinical site of tuberculosis. Clin. Infect. Dis. 54,211–219 (2012). positive people during tuberculosis treatment: a systematic review and meta- 13. Leeds, I. L. et al. Site of extrapulmonary tuberculosis is associated with HIV analysis. PLoS ONE 9, e112017 (2014). infection. Clin. Infect. Dis. 55,75–81 (2012). Qian et al. Emerging Microbes & Infections (2018) 7:102 Page 14 of 14 41. Janssen, S. et al. Mortality in severe human immunodeficiency virus- 47. Degner, N. R.,Wang, J. Y., Golub,J.E. & Karakousis,P.C.Metformin use reverses tuberculosis associates with innate immune activation and dysfunction of the increased mortality associated with diabetes mellitus during tuberculosis monocytes. Clin. Infect. Dis. 65,73–82 (2017). treatment. Clin. Infect. Dis. 66,198–205 (2018). 42. Huang, S. L. et al. Value of procalcitonin in differentiating pulmonary tuber- 48. Beavers, S. F., et al. Tuberculosis mortality in the United States: epidemiology culosis from other pulmonary infections: a meta-analysis. Int. J. Tuberc. Lung and prevention opportunities. Ann. Am. Thorac. Soc. (2018) [Epub ahead of Dis. 18,470–477 (2014). print]. 43. Kim, J. et al. Procalcitonin as a diagnostic and prognostic factor for tuberculosis 49. Narres, M. et al. The incidence of end-stage renal disease in the diabetic meningitis. J. Clin. Neurol. 12,332–339 (2016). (compared to the non-diabetic) population: a systematic review. PLoS ONE 11, 44. Lee, W. S. et al. Cutoff value of serum procalcitonin as a diagnostic biomarker e0147329 (2016). of infection in end-stage renal disease patients. Korean J. Intern. Med. 30, 50. Scott, C. et al. Human tuberculosis caused by Mycobacterium bovis in the 198–204 (2015). United States, 2006-2013. Clin. Infect. Dis. 63,594–601 (2016). 45. Critchley,J.A.etal. Defining a research agenda to address the converging 51. Majoor, C. J., Magis-Escurra, C., van Ingen, J., Boeree, M. J. & van Soolingen, D. epidemics of tuberculosis and diabetes: Part 1: Epidemiology and clinical Epidemiology of Mycobacterium bovis disease in humans, The Netherlands, management. Chest 152, 165–173 (2017). 1993-2007. Emerg. Infect. Dis. 17,457–463 (2011). 46. Young,F., Wotton,C. J., Critchley, J. A.,Unwin,N.C. & Goldacre,M.J.Increased 52. Hlavsa, M. C. et al. Human tuberculosis due to Mycobacterium bovis in the risk of tuberculosis disease in people with diabetes mellitus: record-linkage United States, 1995-2005. Clin. Infect. Dis. 47,168–175 (2008). study in a UK population. J. Epidemiol. Community Health 66,519–523 (2012).

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