Identification of Risk Factors for Extrapulmonary Tuberculosis

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1 MAJOR ARTICLE Identification of Risk Factors for Extrapulmonary Tuberculosis Zhenhua Yang, 1 Ying Kong, 1 Frank Wilson, 2 Betsy Foxman, 1 Annadell H. Fowler, 2 Carl F. Marrs, 1 M. Donald Cave, 3 and Joseph H. Bates 2, 4 1 Department of Epidemiology, School of Public Health, University of Michigan, Ann Arbor; and 2 Arkansas Department of Health and 3 Department of Anatomy, College of Medicine, and 4 Department of Epidemiology, College of Public Health, University of Arkansas for Medical Sciences, Little Rock The proportion of extrapulmonary tuberculosis cases in the United States has increased from 16% of tuberculosis cases, in 1991, to 20%, in To determine associations between the demographic, clinical, and life style characteristics of patients with tuberculosis and the occurrence of extrapulmonary tuberculosis, a retrospective case-control study was conducted. This study included 705 patients with tuberculosis, representing 98% of the culture-proven cases of tuberculosis in Arkansas from 1 January 1996 through 31 December A comparison between 85 patients with extrapulmonary tuberculosis (case patients) and 620 patients with pulmonary tuberculosis (control patients) showed women (OR, 1.98; 95% CI, ), non-hispanic blacks (OR, 2.38; 95% CI, ), and HIV-positive persons (OR, 4.93; 95% CI, ) to have a significantly higher risk for extrapulmonary tuberculosis than men, non-hispanic whites, and HIV-negative persons. This study expands the knowledge base regarding the epidemiology of extrapulmonary tuberculosis and enhances our understanding of the relative contribution of host-related factors to the pathogenesis of tuberculosis. Tuberculosis remains an enormous global health problem, causing morbidity and mortality worldwide [1, 2]. One-third of the world s population is estimated to be latently infected with Mycobacterium tuberculosis [3]. The deadly synergy of HIV and tuberculosis, and the emergence of multidrug-resistant M. tuberculosis (MDRTB), have further complicated tuberculosis control [2, 4]. In the United States, although the nationwide incidence has decreased by 50% since its last peak, in 1992, the ratio of the rate of tuberculosis among foreign-born persons to the rate of tuberculosis among persons born in the US has doubled, from 4.2, in 1992, to 8.4, in 2002, and the proportion of MDRTB gen- Received 9 July 2003; accepted 27 August 2003; electronically published 19 December Financial support: National Institutes of Health (grant NIH-R01-AI151975). Reprints or correspondence: Dr. Zhenhua Yang, Epidemiology Dept., School of Public Health, University of Michigan, 109 S. Observatory St., Ann Arbor, MI (zhenhua@umich.edu). Clinical Infectious Diseases 2004; 38: by the Infectious Diseases Society of America. All rights reserved /2004/ $15.00 erated from foreign-born patients with tuberculosis increased from 31%, in 1993, to 73%, in 2001 [5 6]. The clinical manifestations of tuberculosis are variable and dependent on a number of characteristics of the host and the microbe, as well as on the interaction between the host and the microbe [7]. Before the beginning of the HIV epidemic, 85% of reported tuberculosis cases were limited to the lungs [8]. This proportional distribution is substantially different among persons with HIV infection [9], because extrapulmonary tuberculosis involvement tends to increase in frequency if immune function is compromised [10]. In the United States, the proportion of cases with extrapulmonary involvement among all cases of tuberculosis has progressively increased, from 16%, in 1991, to 20%, in 2001 [5]. The relatively slower decrease, in recent years, in the number of extrapulmonary tuberculosis cases, as compared with the number of pulmonary cases alone, remains largely unexplained, although increases in HIV-infection rates and the aging of the population have been suggested as possible explanations [11]. During the last 2 decades, there have Extrapulmonary Tuberculosis Risk Factors CID 2004:38 (15 January) 199

2 been only a limited number of published studies of extrapulmonary tuberculosis, and most of these studies were case reports [12 17], were limited to HIV-infected individuals [18 21], or presented analyses that did not control for potential confounders [22 24]. Here we present a retrospective, population-based, case-control study to explore the importance of demographics, life style variables, and clinical characteristics in the occurrence of extrapulmonary tuberculosis. extrapulmonary tuberculosis, we repeated the analyses and stratified by sex. To control for potential confounders, we examined the effect of multiple concurrent variables on the rate of extrapulmonary tuberculosis by logistic regression, using a base model that included 3 essential variables (i.e., sex, age, and race/ethnicity) and adding other variables into the model individually. All the statistical analyses were done using SAS version 8.0 (SAS). METHODS Patient population. This study included a total of 705 patients with tuberculosis, who represent 98% of the cultureproven tuberculosis cases diagnosed in Arkansas from 1 January 1996 through 31 December Of the 705 subjects, 451 (63%) were male and 254 (36%) were female. There were 392 non-hispanic whites (55.6% of subjects), 245 non-hispanic blacks (34.8%), 40 Asians/Pacific Islanders (5.7%), 25 Hispanics (3.5%), and 3 American Indians (0.4%). The majority (648 [92%]) of the study patients were born in the United States. Slightly less than one-half (351 patients; 46%) of the study patients were 65 years old. Case and control definitions. Patients in whom the sites of disease were exclusively intrathoracic, (i.e., confined to lungs, pleura, and intrathoracic lymph nodes) were considered to have cases of pulmonary tuberculosis and were classified as control patients ( n p 620). Patients whose disease extended to organs or tissues outside the thorax, including those patients who also had pulmonary involvement, were considered to have cases of extrapulmonary tuberculosis and were classified as case patients ( n p 85). Data collection. Patient information was obtained from the Arkansas Department of Health (ADH) surveillance records and molecular epidemiological database, which was established as part of the National Tuberculosis Genotyping and Sentinel Surveillance Program. Most data were previously collected using the Centers for Disease Control and Prevention standardized national tuberculosis case registry form [25]. Additional epidemiological and clinical information was obtained from detailed epidemiological interviews conducted by investigators at the ADH using a standardized questionnaire. Data collected included demographic information, life style variables, and clinical characteristics of the study subjects. Original clinical records were reviewed as needed. Statistical analysis. To test the difference between the case patients and the control patients, we used the x 2, Mantel-Haenszel, or Fisher exact tests, as appropriate, for categorical variables, and Student s t test, for continuous variables. To determine the association between extrapulmonary tuberculosis and demographic, life style, and clinical characteristics, we calculated ORs and 95% CIs. As sex was strongly associated with RESULTS Sites of extrapulmonary tuberculosis. The most common type of extrapulmonary tuberculosis among the 85 case patients was bone and/or joint tuberculosis (27.1% of case patients), followed by cervical lymphatic tuberculosis (17.7%) (figure 1). In addition, miliary, genitourinary, peritoneal, other lymphatic, and meningeal tuberculosis each accounted for 5.9% 10.6% of the total number of cases of extrapulmonary tuberculosis. Of the 85 case patients, 15% had tuberculosis in other sites, including disseminated (in 3 patients), pericardial (3), softtissue (2), breast (1), pancreas (1), colon (2), and laryngeal (1) tuberculosis. As illustrated by figure 1, the proportional distribution of different sites of the extrapulmonary involvement between females and males was statistically significantly different ( P!.0001). Proportions of patients with extrapulmonary tuberculosis. The proportion of patients with extrapulmonary tuberculosis found was 12.1% (85 of 705 patients), but the proportional distribution varied substantially with age, sex, and race/ethnicity. Of the 254 female patients, 43 (16.9%) had extrapulmonary disease, whereas only 42 (9.3%) of 451 male patients did. Among the various racial and ethnic groups, American Indians had the highest proportion of extrapulmonary tuberculosis (1 [33%] of 3), followed by Asian/Pacific Islanders (8 [20%] of 40), non-hispanic blacks (43 [17.6%] of 245), non-hispanic whites (32 [8.2%] of 392), and Hispanics (1 [4%] of 25). Among the 5 age groups studied, the youngest age group (0 24 years old) had the highest proportion of extrapulmonary tuberculosis (21.4%), and the lowest proportion (9.3%) was observed in the oldest age group (i.e., 185 years old). Comparison of the proportion of patients with extrapulmonary tuberculosis between HIV-positive and HIV-negative patients was limited to the 354 patients whose HIV status was known. Of the 25 HIV-positive patients, 9 (36.0%) had extrapulmonary tuberculosis, whereas only 39 (11.9%) of 329 HIV-negative patients had extrapulmonary disease. Characteristics of extrapulmonary tuberculosis. Significant differences in sex, race/ethnicity, homelessness, residence in a long-term care facility, noninjection drug use, excessive alcohol use, and HIV status were found between the case patients and control patients (table 1). Females, several races and/ 200 CID 2004:38 (15 January) Yang et al.

3 Figure 1. Sex-specific and overall proportional distributions of sites of extrapulmonary tuberculosis (TB). The proportional distributions of different sites of extrapulmonary involvement were statistically significantly different by sex ( P!.0001, as determined by x 2 test). or ethnicities, and HIV-positive individuals were overrepresented in the extrapulmonary tuberculosis group. By contrast, males, non-hispanic whites, and excessive alcohol users were significantly underrepresented in the extrapulmonary group. Age and sex influence. The average age was lower among the case patients than among the control patients (57.2 years vs years; P p.048). However, after stratifying by sex, no significant age difference was found between the 2 comparative groups in males ( P p.968), but, for females, the mean age of extrapulmonary case patients was significantly lower than that of patients with pulmonary involvement (53.4 vs years; P p.001). To examine the sex-specific association of age with extrapulmonary tuberculosis further, a comparison of age distribution between the pulmonary and extrapulmonary groups was done by trend analysis, stratifying by sex. Consistent with the sex-stratified t test, the sex-stratified trend test showed a significant difference in the age distribution between the extrapulmonary tuberculosis group and the pulmonary tuberculosis group, for females only ( P p.011; figure 2). In addition, the trend test showed that the proportional distribution of both extrapulmonary and pulmonary case patients by age was bimodal for both sexes. After stratification by sex, both race/ ethnicity and HIV status remained significantly associated with extrapulmonary tuberculosis, with an adjusted P value of.002, for race/ethnicity, and!.0001, for HIV status. Excessive alcohol use appeared to have a negative association with extrapulmonary tuberculosis for both sexes. Risk factors for extrapulmonary tuberculosis. To control for potential confounders, we used a series of logistic regression models. All models included sex, age, and race/ethnicity; other variables were added individually. After adjustment, sex, race/ ethnicity, and HIV status remained strongly associated with extrapulmonary tuberculosis (table 2). Patients with extrapulmonary tuberculosis were more likely to be female, non-hispanic black, and HIV-positive, whereas excessive alcohol use appeared to be negatively associated with extrapulmonary tuberculosis. Although other variables, such as homelessness, residence in a long-term care facility, and noninjection drug use, appeared to have a significant association with extrapulmonary disease using univariate analysis, these factors did not show a statistically significant association with extrapulmonary disease after controlling for potential confounders using multivariate logistic regression analysis. Because of the small size of the subpopulation of patients identified as American Indians and Asian/Pacific Islanders, these 2 groups were combined into a single group, designated as other, for analysis; this group showed an increased risk for extrapulmonary tuberculosis, compared with non-hispanic whites. DISCUSSION To our knowledge, this is the first population-based case-control study characterizing extrapulmonary tuberculosis. The study includes an approximately complete sampling of all active cases of extrapulmonary and pulmonary tuberculosis from the study population over a 5-year study period. Thus, we minimized the possible sample selection bias that might confound the association between variables of interest and extrapulmonary tuberculosis. We identified 3 independent risk factors for extrapulmonary tuberculosis: being female, being non-hispanic black, and being HIV-positive. Of all the study findings, the most striking is that Extrapulmonary Tuberculosis Risk Factors CID 2004:38 (15 January) 201

4 Table 1. Distribution of selected demographic characteristics among 85 patients with extrapulmonary tuberculosis (EPTB) and 620 patients with pulmonary tuberculosis (PB). No. (%) of patients Characteristic With EPTB With PTB Age, years (7.06) 22 (3.55) (29.41) 128 (20.65) (18.82) 157 (25.32) (24.71) 147 (23.71) (20.00) 166 (26.77) Sex.003 Male 42 (49.41) 409 (65.97) Female 43 (50.59) 211 (34.03) Race/ethnicity!.0001 Non-Hispanic white 32 (37.65) 360 (58.06) Non-Hispanic black 43 (50.59) 202 (32.58) Hispanic 1 (1.18) 24 (3.87) American Indian 1 (1.18) 2 (0.32) Asian/Pacific Islander 8 (9.41) 32 (5.16) Homelessness.048 Yes 2 (2.35) 21 (3.39) No 81 (95.29) 593 (95.65) Unknown 2 (2.35) 6 (0.97) Residence in a long-term care facility.018 Yes 5 (5.88) 67 (10.81) No 79 (92.94) 551 (88.87) Unknown 1 (1.18) 2 (0.32) Noninjection drug use.018 Yes 1 (1.18) 14 (2.26) No 76 (89.41) 574 (92.58) Unknown 8 (9.41) 32 (5.16) Excess alcohol use.023 Yes 4 (4.71) 91 (14.68) No 74 (87.06) 499 (80.48) Unknown 7 (8.24) 30 (4.84) HIV status.0008 Positive 9 (10.59) 16 (2.58) Negative 39 (45.88) 290 (46.77) Unknown 37 (43.53) 314 (50.65) a P value determined by x 2 test or Fisher exact test, as appropriate. P a being female is an independent risk factor for having extrapulmonary tuberculosis, an observation that seems contradictory to the traditional understanding that females are more resistant to tuberculosis than males. The notion that females possess an elevated resistance to tuberculosis was mainly based on animal studies [26] and the reported global sex-difference in tuberculosis case rates (i.e., in general, a higher proportion of tuberculosis case notifications worldwide are for male than are for female patients [1]). However, a lower notification rate for females does not necessarily mean that females are more resistant to tuberculosis than are males. The lower case notification rates for females might be due to underdiagnosis or underreporting of tuberculosis in females as a result of various social and/or cultural factors, including the stigmatization of females with tuberculosis and their consequent impaired access to health care, a situation which is often seen in developing 202 CID 2004:38 (15 January) Yang et al.

5 Figure 2. Proportional distribution of pulmonary and extrapulmonary tuberculosis (TB) among 705 patients with tuberculosis, by age and sex. A, trend test for male patients ( P p.839); B, trend test for female patients ( P p.011). countries [1, 27]. It might also be due to real differences in rates of infection with M. tuberculosis, reflecting social, cultural, and biological factors that influence opportunities for exposure to M. tuberculosis [28]. Despite the well-known global sex-difference in tuberculosis incidence rates, few studies in the past have specifically focused on a comparison of extrapulmonary tuberculosis among males with extrapulmonary tuberculosis among females. An exception is a recent cross-sectional study of 5747 patients with tuberculosis, conducted in Hong Kong, that found that extrapulmonary tuberculosis occurred more commonly among women than among men, whereas pulmonary tuberculosis occurred more commonly among men than among women [24]. Although large, the analysis was limited and did not include multivariate analysis. As we did not observe a biased distribution of any particular type of extrapulmonary tuberculosis that affects only women, the biological credibility of our finding that being female is strongly associated with extrapulmonary tuberculosis remains to be determined through further investigations. An association between non-hispanic black race and extrapulmonary tuberculosis has been reported in earlier studies of HIV-infected subjects [20, 21]. However, the applicability of these results to other populations is uncertain. This is the first report of an association between Asian/Pacific Islander race/ ethnicity and extrapulmonary tuberculosis; this association needs confirmation. HIV infection decreases an individual s immunity, and patients with HIV infection reportedly experience extrapulmonary tuberculosis as commonly as they experience pulmonary tuberculosis [11]. Because our study included both HIV-positive and -negative patients with tuberculosis, unlike a previous Extrapulmonary Tuberculosis Risk Factors CID 2004:38 (15 January) 203

6 Table 2. Logistic regression model determining independent risk factors for having extrapulmonary tuberculosis among 705 patients with tuberculosis. Variable P OR 95% CI Base model variables Age, years Referent Sex.004 Male 1.0 Referent Female Race/ethnicity.004 Non-Hispanic white 1.0 Referent Non-Hispanic black Other Additional variables a Alcohol excessive use.035 Yes Unknown HIV status.003 Negative 1.0 Referent Positive Negative Unknown Homelessness.440 Yes Unknown Residence in a long-term care facility.406 Yes Unknown Noninjection drug use.326 Yes Unknown a These variables were added one at a time to the base model. bias in the collection of data on alcohol consumption is a possible explanation for this finding. The true impact of excessive alcohol use on the occurrence of extrapulmonary tuberculosis remains unknown, and better data is required for this variable to be evaluated. The most important study finding regarding age is that the proportion of patients with extrapulmonary tuberculosis who are in a younger age group (i.e., years old) is larger among females than among males. This finding suggests that the increase in the elderly population in the US is not the only explanation for the proportional increase in extrapulmonary tuberculosis in recent years. In the Hong Kong study [23], almost one-third of the cases of extrapulmonary tuberculosis were genitourinary; however, we found bones and/or joints to be the most common site of extrapulmonary tuberculosis. The second most common site of extrapulmonary tuberculosis in the Hong Kong study [23] (found in 17.0% of patients with extrapulmonary tuberculosis) was skin, an organ not reported as a site of tuberculosis in our study at all. In addition, the proportion of patients with meningeal tuberculosis reported in the Hong Kong study [23] (17.2% of patients with tuberculosis) is much higher than that reported in the current study (5.9%). These differences suggest that the dynamics of extrapulmonary tuberculosis epidemiology may be specific to geographic location and population; more population-based studies in different geographic regions are needed. In conclusion, our study expands the knowledge base regarding the epidemiology of extrapulmonary tuberculosis and enhances understanding of the relative contribution of hostrelated factors to the pathogenesis of tuberculosis. To achieve a more complete understanding of the pathogenesis of tuberculosis, the role of microbial factors must be identified in future studies. In laboratory studies searching for M. tuberculosis virulence factors, the potential confounding effects of the hostrelated risk factors for extrapulmonary tuberculosis that we have identified should be considered and controlled for in sample selection and data analyses. study [19] that was limited to HIV-infected patients, we could demonstrate that being HIV-positive is an independent risk factor for extrapulmonary tuberculosis. The association of excessive alcohol use with pulmonary tuberculosis rather than with extrapulmonary tuberculosis was unexpected. In general, one would expect that excessive alcohol consumption would negatively affect immune function and, consequently, increase susceptibility to extrapulmonary infection. We do not have a good explanation for this finding. There was no explicit definition for excessive alcohol consumption; thus, the determination that a patient s alcoholic consumption was excessive was undoubtedly highly subjective. Therefore, Acknowledgment We acknowledge Dr. Kashef Ijaz s contribution to the establishment of the Arkansas Department of Health surveillance database that was used for the study. References 1. Holmes CB, Hausler H, Nunn P. A review of sex differences in the epidemiology of tuberculosis. Int J Tuberc Lung Dis 1998; 2: World Health Organization (WHO). Global tuberculosis control, WHO report Available at: Accessed 6 June Sudre P, Tendam G, Kochi A. Tuberculosis a global overview of the 204 CID 2004:38 (15 January) Yang et al.

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