Extra-pulmonary manifestations in a large ... - IngentaConnect

INT J TUBERC LUNG DIS 7(12):1178–1185 © 2003 IUATLD

Extra-pulmonary manifestations in a large metropolitan area with a low incidence of tuberculosis O. Y. Gonzalez,* G. Adams,† L. D. Teeter,† T. T. Bui,† J. M. Musser,†‡ E. A. Graviss*† Departments of * Internal Medicine, Division of Infectious Diseases, and † Pathology, Baylor College of Medicine, Houston, Texas, ‡ Rocky Mountain Laboratories, National Institute of Allergy and Infectious Disease, National Institutes for Health, Hamilton, Montana, USA SUMMARY BACKGROUND:

The increases in extra-pulmonary tuberculosis (EPTB) have been largely due to human immunodeficiency virus co-infection. The rates of EPTB have remained constant despite the decline in pulmonary tuberculosis (PTB) cases. O B J E C T I V E : To evaluate covariates associated with EPTB. M E T H O D S : A 4-year cohort of EPTB patients was compared with PTB cases. Enrollees were assessed for TB risk, medical records were reviewed, and Mycobacterium tuberculosis isolates were fingerprinted. R E S U L T S : We identified 538 EPTB cases (28.6%) in a total of 1878 enrollees. The most common sites of infection were lymph nodes (43%) and pleura (23%). EPTB cases included 320 (59%) males, 382 (71%) patients were culture-positive, and 332 (86.9%) patient isolates were fingerprinted. Fewer EPTB than PTB patients

belonged to clustered M. tuberculosis strains (58% vs. 65%; P  0.02). A multivariate model identified an increased risk for EPTB among African Americans (OR  1.9, P  0.01), HIV-seropositive (OR  3.1, P  0.01), liver cirrhosis (OR  2.3, P  0.02), and age 18 years (OR  2.0, P  0.04). Patients with concomitant pulmonary and extra-pulmonary infections were more likely to die within 6 months of TB diagnosis (OR  2.3, P  0.01). C O N C L U S I O N S : African American ethnicity is an independent risk factor for EPTB. Mortality at 6 months is partly due to the dissemination of M. tuberculosis and the severity of the underlying co-morbidity. K E Y W O R D S : Mycobacterium tuberculosis; tuberculosis; extra-pulmonary tuberculosis

AFTER AN AVERAGE decline of tuberculosis (TB) in the United States of 5.6% cases per year from 1953 to 1985,1,2 TB cases rose to a peak of 10.5 cases per 100 000 population in 1992. A second decline subsequently occurred, with rates dropping to their lowest level ever, from 26 673 cases in 1992 to 15 989 cases in 2001 (5.6/100 000).3 The striking increase in tuberculosis in the early 1990s has generally been attributed to the human immunodeficiency virus (HIV) epidemic, an increase in the number of foreign-born patients, and the deterioration of tuberculosis control programs.2,4–10 Extra-pulmonary tuberculosis (EPTB) has not decreased at the same rate as pulmonary tuberculosis (PTB) (25% vs. 41% between 1992 and 2000).11 This phenomenon has occurred in part due to immunosuppression caused by HIV infection, whereby more than 70% of HIV-positive patients with tuberculosis have had extra-pulmonary manifestations compared to 15–30% in negative patients.2,12,13 In addition, epi-

demiologic studies conducted in the pre-HIV era demonstrated that the annual number of EPTB cases remained almost constant.14–20 EPTB has a broad spectrum of clinical manifestations, and even in countries where PTB is still a prevalent health problem, it often presents a diagnostic challenge, implying delays in diagnosis.16,21–23 Moreover, EPTB involves relatively inaccessible sites, and due to the nature of the sites involved, fewer bacilli can cause greater damage. The combination of the above makes bacteriologic confirmation of EPTB cases more difficult, and invasive procedures are frequently required to establish a diagnosis.23 Most of the literature related to EPTB was published during the pre-HIV era, and limited populationbased studies have been performed examining EPTB. A retrospective study from Hong Kong, with a different population group and statistical design, was published recently.24 Due to the increasing proportion of reported TB cases due to EPTB and the more

Correspondence to: Edward Graviss, PhD, MPH, Department of Pathology, Infectious Disease Section, Baylor College of Medicine (209E) Houston, TX 77030, USA. Tel: (1) 713-798-8097/8919. Fax: (1) 713-798-8895. e-mail: egraviss@ bcm.tmc.edu Article submitted 6 March 2003. Final version accepted 22 May 2003.

Extra-pulmonary tuberculosis

frequent utilization of molecular characterization techniques to define TB dissemination, we performed a 4-year prospective molecular epidemiologic analysis of EPTB in Harris County, Texas (here referred to collectively as Houston).

PATIENTS AND METHODS Study population The Houston Tuberculosis Initiative is an ongoing, population-based surveillance and molecular epidemiology study of tuberculosis cases reported to the City of Houston Tuberculosis Control Division. Since 1995, 85% of all reported tuberculosis patients and over 85% of all culture-positive tuberculosis patients in Houston have been enrolled in the project. The present study was based on 1878 TB patients enrolled from October 1995 to September 1999. Enrollees were interviewed by a contact investigator for TB risk assessment and patients’ medical records were reviewed. Mycobacterium tuberculosis isolates from all available culture-positive patients underwent molecular characterization. After extensive medical record review and subject interview, HIV serology testing and results were available in 65% (349/538) of the EPTB and 69% (927/1340) of the PTB cases. Patients with no available test results were considered HIV-negative. Patients were excluded from the analysis if they were considered non-enrollees, i.e., a prevalent case (defined as a non-Harris County resident or living for fewer than 3 months in the county jurisdiction), isolates considered to be laboratory contaminants, patients whose TB diagnosis was later rescinded as non-TB, those who could not be located, and those who refused to participate in the study. Molecular characterization of M. tuberculosis isolates M. tuberculosis isolates were analyzed using three molecular typing methods. The isolates were assigned to one of three principal genetic groups of M. tuberculosis on the basis of nucleotide polymorphisms located at codon 463, the katG gene encoding catalaseperoxidase and codon 95 of the gyrA gene encoding the A subunit of DNA gyrase.25 Isolates were also characterized using an internationally standardized method of IS6110 restriction fragment length polymorphism (RFLP).26 The IS6110 profiles were analyzed using BioImage Whole Band analysis program version 3.2 (Ann Arbor, MI). For strains with less than five IS6110 copies, spacer oligonucleotide typing (spoligotyping) was performed to enhance the discriminatory power between M. tuberculosis clones.27 Data analysis Data from the questionnaires were entered into a longitudinal database. Statistical analysis was performed using SAS version 6.12 (Cary, NC). Initial compari-

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sons of socio-demographic, clinical, epidemiologic, and molecular characterization variables of EPTB and PTB were conducted with descriptive analysis including t-test, 2 testing or Fisher’s exact test. Variables associated with TB by descriptive analyses were selected for univariate analysis; thereafter, selected covariates that showed statistical difference (P  0.20) were included in the multivariate logistic regression model. Variables that had the potential to significantly decrease the number of subjects for modeling were excluded. A predetermined P value  0.05 was considered statistically significant for all analyses. Mortality at 6 months post TB diagnosis was analyzed in a logistic regression model comparing pulmonary cases, exclusively extrapulmonary cases and concomitant sites of infection (pulmonary and extra-pulmonary). Definitions EPTB cases were defined as per American Thoracic Society (ATS)/Centers for Disease Control and Prevention (CDC) guidelines.23 Cases of concomitant infections in pulmonary and extra-pulmonary sites were included only in the EPTB cohort. M. tuberculosis isolates belonging to the same molecularly characterized group were considered to be clonally related. Significant alcohol consumption was defined as drinking alcohol at least three times per week.

RESULTS From October 1995 to September 1999, the City of Houston reported 2240 tuberculosis patients, 23 of whom were later considered as non-TB cases either due to laboratory contamination or because their TB diagnosis was rescinded by the health department. A total of 1878 (85%) patients were enrolled during the 48-month study period. Of these, 538 (28.6%) patients were EPTB, and 1340 (71.4%) were PTB (Figure). All enrollees were included in the analysis.

Figure Texas.

Flow chart of enrollment of patients in Harris County,

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Table 1 Comparison of EPTB and PTB in enrollees and non-enrollees among African Americans, Asians, and foreign-born cases

African American Enrolled Not enrolled Asian Enrolled Not enrolled Foreign-born Enrolled Not enrolled

EPTB

PTB

OR

P*

242 28

524 77

1.00

0.99

64 20

147 46

0.79

0.30

169 43

409 107

0.97

0.89

* 2 analysis. EPTB  extra-pulmonary tuberculosis; PTB  pulmonary tuberculosis; OR  odds ratio.

Comparison of basic demographic characteristics of enrolled and non-enrolled cases Enrollees and non-enrollees did not differ significantly in age or sex. A higher proportion of African Americans was found among enrollees than in nonenrollees (766 [40.7%] vs. 105 [31%]; P  0.01), and Asians were less likely to be enrolled (211 [11.2%] vs. 66 [19.5%]; P  0.01); the other ethnic groups showed no difference by enrollment. A significantly higher proportion of foreign-born cases was found in the non-enrollee group (578 [30.8%] vs. 150 [44.2%]; P  0.01). In a sub-analysis comparing EPTB and PTB in enrollees and non-enrollees among African Americans, Asians and foreign-born cases, no significant differences were found (Table 1).

Table 2 Site of microbiologic isolation of M. tuberculosis in 382 EPTB cases Sites

n  581 n (%)*

Pulmonary Sputum Gastric Lung biopsy Peripheral lymph node Pleura Effusion Biopsy Blood and bone marrow Nervous system Cerebral spinal fluid Brain tissue Gastrointestinal Stool Liver Colon Peritoneal fluid Genitourinary Urine Kidney Other

219 (38) 200 12 7 104 (18) 88 (15) 84 4 33 (6) 23 (4) 22 1 15 (3) 10 1 1 2 11 (2) 10 1 92 (16)

* Proportion of culture positive by site/all reported positive culture. EPTB  extra-pulmonary tuberculosis.

Sites of infection in EPTB patients Among the study cohort (n  538), the most common extra-pulmonary sites affected were lymph nodes (43%), pleura (23%), central nervous system (8%), musculo-skeletal system (7%), genitourinary tract (5%), gastrointestinal tract (2%), and others (12%). Interestingly, concomitant infection of pulmonary and extra-pulmonary sites occurred in 171 enrollees. Among the 382 EPTB patients with bacteriologically proven M. tuberculosis, 581 positive cultures were identified (Table 2); the most common sources were pulmonary (38%), peripheral lymph nodes (18%), and pleura (15%). Fifty-two patients had multiple extra-pulmonary sites of infection. General characteristics of patients with EPTB and PTB As shown in Table 3, the mean age was 36  21.2 years vs. 44  17.3 years in the EPTB and PTB, respectively (P  0.01). Significant differences were

Table 3 Univariate analysis comparing socio-demographic variables among EPTB with PTB

Variables Age, years  SD 18 18 Sex Male Female Ethnicity Black White Hispanic Asian Other Foreign-born HIV-positive Diabetes mellitus Liver cirrhosis† PPD positive (self report) High school diploma Employed Income $10 000/year Homelessness Incarceration Cigarette smoker Alcohol use (3–4 times/week) Illicit drugs Contact with known TB patient History of TB M. tuberculosis culture-positive DNA fingerprint Cluster Mortality At 6 months

EPTB (n  538) n (%)

PTB (n  1340) n (%)

36  21.2 112 (21) 426 (79)

44  17.3 57 (4) 1060 (96)

P* 0.01 0.01 0.01

320 (59) 218 (41)

944 (70) 396 (30)

242 (45) 59 (11) 170 (32) 64 (12) 3 (0.01) 169 (31) 131 (24) 56 (10) 25 (4.6) 369 (69) 221 (41) 178 (33) 202 (44) 55 (10) 187 (35) 236 (44)

524 (39) 280 (21) 383 (29) 147 (11) 6 (0.01) 409 (31) 211 (16) 189 (14) 43 (3.2) 936 (78) 637 (48) 546 (41) 517 (48) 271 (20) 709 (53) 909 (68)

0.71 0.01 0.03 0.13 0.59 0.01 0.01 0.03 0.01 0.01 0.01

146 (27) 145 (27)

584 (44) 527 (40)

0.01 0.01

172 (32) 15 (3)

471 (35) 103 (8)

0.19 0.01

382 (71) 332 (62) 191 (58) 87 (16) 59 (11)

1222 (91) 1136 (85) 734 (65) 178 (13) 124 (9)

0.01

0.02 0.01 0.19 0.57

0.02 0.11 0.25

* 2 analysis. † Non-hepatitis C virus positive. EPTB  extra-pulmonary tuberculosis; PTB  pulmonary tuberculosis; SD  standard deviation; HIV  human immunodeficiency virus; PPD  pure protein derivative; TB  tuberculosis.

Extra-pulmonary tuberculosis

found in sex, ethnicity, and HIV status, exhibiting higher rates for EPTB in females (218 [41%] vs. 396 [30%]; P  0.01), African Americans (242 [45%] vs. 524 [39%]; P  0.02), and HIV-positive individuals (131 [34%] vs. 211 [16%]; P  0.01). Significant factors predictive of PTB included diabetes mellitus, 12 years of education, employment, income $10 000 per year, history of homelessness or incarceration, cigarette smoking, significant alcohol use, illicit drug use, past history of TB, and infection with clustered M. tuberculosis strains (clonally related to at least one other M. tuberculosis isolate from a patient in this data set). The EPTB and PTB groups did not differ significantly by foreign birth, pure protein derivative (PPD) status, history of contact with a known TB index case, or 6-month mortality. Comparison of symptoms in EPTB and PTB patients Significantly higher rates of diarrhea, abdominal pain, and adenopathy were found in EPTB cases (Table 4). Patients with EPTB were less likely to present with night sweats, weight loss, cough, anorexia, fatigue, dyspnea, and hemoptysis. The proportion of patients reporting fever and chills was not different between these groups. Microbiologic characteristics Isolation of M. tuberculosis was less likely among EPTB cases (382 [71%] vs. 1222 [91%]; P  0.01). Among retrieved isolates, 1468 (92%) were genotyped, and 191 (58%) in the EPTB belonged to a strain cluster compared with 731 (65%) in the PTB group (P  0.02). No differences in the distribution of the major genotype groups were found in this cohort (data not shown). Variables associated with EPTB on the basis of multivariate logistic regression analysis A total of 1359 patients with the following variables were analyzed by logistic regression modeling (Table Table 4

Comparison of symptoms between EPTB with PTB

Symptoms

EPTB (n  538) n (%)

PTB (n  1340) n (%)†

P*

Fever Chills Sweats Weight loss Cough Anorexia Fatigue Dyspnea Hemoptysis Abdominal pain Diarrhea Adenopathy Documented PPD positive

301 (56) 107 (74) 210 (39) 238 (44) 266 (49) 32 (44) 154 (29) 130 (24) 24 (4) 48 (9) 56 (10) 150 (28) 290 (58)

764 (57) 330 (84) 682 (51) 789 (59) 1091 (82) 117 (61) 496 (37) 400 (30) 269 (20) 76 (6) 104 (8) 33 (2) 747 (61)

0.35 0.13 0.01 0.01 0.01 0.05 0.01 0.01 0.01 0.02 0.05 0.01 0.35

* 2 analysis. † Calculated based on patients’ symptoms/patients for whom data were available in the tuberculosis questionnaire assessment. EPTB  extra-pulmonary tuberculosis; PTB  pulmonary tuberculosis.

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Table 5 Variables associated with EPTB on the basis of multivariate logistic regression analysis (n  1359) Variable Race/ethnicity Black (n  550) Asian (n  163) Hispanic (n  381) Age 18 years Sex Foreign-born Income $10 000/year Homelessness Alcohol consumption (3–4 times/week) Cigarette smoker Incarceration TB contact History of TB HIV-positive Clustering Diabetes mellitus Liver cirrhosis*

OR (95%CI)

P

1.86 (1.19–2.90) 1.64 (0.82–3.27) 1.91 (0.85–2.57) 0.48 (0.24–0.96) 0.93 (0.67–1.29) 0.59 (0.36–0.97) 0.69 (0.51–0.94) 0.71 (0.45–1.12)

0.01 0.16 0.17 0.04 0.66 0.04 0.02 0.14

0.82 (0.57–1.14) 0.54 (0.38–0.76) 0.62 (0.43–0.90) 0.67 (0.49–0.91) 0.29 (0.08–0.98) 3.11 (2.04–4.76) 0.70 (0.51–0.97) 0.80 (0.52–1.23) 2.33 (1.18–4.61)

0.21 0.01 0.01 0.01 0.05 0.01 0.03 0.30 0.02

* Non-hepatitis C virus positive. EPTB  extra-pulmonary tuberculosis; OR  odds ratio; CI  confidence interval; HIV  human immunodeficiency virus.

5): age, sex, M. tuberculosis clustering, black ethnicity, Hispanic ethnicity, Asian ethnicity, 12 years of education, income $10 000 per year, incarceration, homelessness, significant alcohol use, tobacco use, diabetes mellitus, HIV infection, liver cirrhosis, employment status, verified positive tuberculin skin test, travel outside US, foreign birth, and history of contact with a TB case. The variables most predictive for EPTB were HIV infection (odds ratio [OR] 3.11, 95% confidence interval [CI] 2.04–4.76; P  0.01) followed by liver cirrhosis (OR 2.33, 95%CI 1.18–4.61; P  0.02) and black ethnicity (OR 1.86, 95%CI 1.19–2.90; P  0.01). Significant factors for PTB included: age 18 years, foreign birth, income $10 000 per year, cigarette smoking, incarceration, contact with a known TB case, history of prior TB disease, and M. tuberculosis clustering. Gender, homelessness, significant alcohol use, and diabetes were found not to be significant. HIV positivity in the study population A total of 342 patients (18.2%) were identified as coinfected with HIV and tuberculosis, reflecting a rate of co-infection of 24% vs. 16% in EPTB and PTB cases, respectively (P  0.01). We found greater differences in patients exhibiting higher rates for EPTB when the CD4 count was 50 cells/mm3, and the HIV viral load was 100 000 copies/ml (data not shown). Concomitant pulmonary and extra-pulmonary sites of infections were observed more frequently in HIVpositive than -negative patients (61% vs. 22%, OR 5.49, 95%CI 3.52–8.57; P  0.01). On further analysis of the EPTB cases (n  538), comparing them by HIV status, the logistic regression model (n  533) revealed a strong association with HIV infection for the following variables: 18–35 years (OR 2.7, 95%CI 1.5–

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4.6; P  0.01), incarceration (OR 2.6, 95%CI 1.4–4.7; P  0.01), and homelessness (OR 2.7, 95%CI 1.3–5.5; P  0.01). Predictive factors for PTB in this sub-analysis were confined to the Hispanic and Asian ethnic groups, alcohol consumption and positive tuberculin skin test. Black ethnicity, age 18 years, sex, foreign birth, unemployment and lower income ($10 000/year) were not predictors of HIV infection in EPTB cases. Genetic group and drug susceptibility of the isolates in the univariate analysis were not different in HIVpositive and -negative patients. Mortality at 6 months Using a logistic regression model (n  1828), controlling for HIV status and age, no statistical difference was found when mortality at 6 months was compared in PTB and EPTB. However, in a sub-analysis, when EPTB patients were divided in two sub-groups, exclusively extra-pulmonary tuberculosis and concomitant pulmonary/extra-pulmonary infections, and these variables were analyzed individually with PTB, a significant association was found between mortality at 6 months and concomitant infection (OR 2.27, 95%CI 1.46–3.53; P  0.01).

DISCUSSION Similar to observations in the pre-HIV/AIDS era,14,15,18–20 a disproportionate decline among cases of EPTB compared with PTB has occurred in the last decade. Reported EPTB cases in the US between 1992 and 2000 dropped from 4288 to 3220 (25%), while PTB cases dropped from 22 371 to 13 142 (41%).11 These statistics indicate a relative increase in the percentage of extra-pulmonary cases from 16% in 1992 to 20% in 2000. In our 4-year study from Houston, Texas, the proportion of EPTB cases remained fairly constant (2 for linear trend 0.4, P  0.53). Farer et al. reported that states in the US with a high incidence of tuberculosis have a lower percentage of EPTB, and that those with a low incidence of tuberculosis have a higher percentage of EPTB.15 In 2000, 20.6% of the cases reported in Houston were EPTB, but in our 4-year analysis nearly one third of all the cases met the criteria for EPTB.23 It has also been suggested that during the past decade the increase in the proportion of cases with EPTB has been largely due to the HIV/ AIDS epidemic; however, this relationship with the decline in PTB cases is not completely understood. In this population-based study, we corroborate and expand findings from previous studies related to factors associated with EPTB and PTB. Similar to the findings of Snider14 and Farer et al.,15 our univariate analysis demonstrated that age 18 years, female sex and black ethnicity were risk factors associated with EPTB. We also found a strong association between HIV-positive status and EPTB, findings that were noted in several publications during the HIV era.2,4,5,12,13,28–30

In our multivariate model we excluded 537 cases where no genotypic analysis was done, because either the case was not culture-positive or isolates were not available. The most affected age group excluded was pediatric cases, where bacteriologic diagnosis was not achieved. To address the possible introduction of bias, we reanalyzed our model without the variable ‘clustering’ (data not shown), and obtained similar results. The association between EPTB and black ethnicity has been demonstrated in prior studies; this ethnic group may have increased susceptibility to tuberculosis,31–33 indicating an interaction between genetics, immunity, and environment in the pathogenesis of TB. Bellamy et al., in a cohort of patients from western Africa, found a significant increase in the frequency of natural resistance-associated macrophage protein 1 (Nramp 1) polymorphism among patients with TB.32 A recent US study suggests that there could be a possible association between Nramp1 polymorphism and EPTB,34 but this relationship between clinical presentation and TB susceptibility has not yet been elucidated. In the past decade it has become apparent that the spread of HIV infection and the immigration of persons from areas of high incidence have resulted in increased numbers of tuberculosis cases,23,35 even though rates among the foreign-born have remained relatively constant.11,36 In this study, contrary to what has been published previously,14,16–18,37 foreign-born individuals were significantly less likely to be associated with EPTB (OR 0.6, 95%CI 0.36–0.97; P  0.04). These findings may be due to a lower incidence of HIV infection among foreign-born cases in our population, under-recognized cases, or differences in genetic background compared to previous studies. In our study, among EPTB patients, HIV accounted for 24% of TB cases; this proportion is not surprising given other reported study populations such as Hong Kong, 1%24 and New York, 41%.38 An analysis of the cohort of EPTB cases in a multivariate model corroborated the findings published by Shafer et al. that young adults (18–35 years old), incarceration, and homelessness were predictors of HIV infection.38 On the other hand, we also found that black ethnicity, age 18 years, male sex, foreign birth, employment status, and lower income were not associated with HIV infection. The clinical presentation of EPTB is non-specific: EPTB is a protean disease that can involve virtually all organs,15 including relatively inaccessible sites.23 EPTB usually presents a diagnostic dilemma even for physicians with a great deal of experience with this disease. Our data do not differ from prior reports related to the site of involvement;15,20,22 however, as it is not uncommon to find concomitant pulmonary and extra-pulmonary infections, the most common source of isolation of M. tuberculosis is the pulmonary site, reaching up to 38% of all TB cases with EPTB-positive

Extra-pulmonary tuberculosis

cultures. EPTB can occur as a result of primary infection or as reactivation of a latent infection.22,23 EPTB is often found in immunocompromised persons22,39 such as those with HIV/AIDS, where other infections can co-exist, making its clinical presentation even more obscure for the clinician.35 The association between HIV-positive status and EPTB becomes stronger when comparisons are made with patients with concomitant infection (pulmonary and extra-pulmonary). Due to EPTB involvement in relatively inaccessible sites, and usually with small numbers of bacilli, bacteriologic confirmation is more difficult and invasive procedures are often required to establish TB diagnosis.23 Similar to the report by Weir et al.,17 in our study M. tuberculosis was cultured in 71% of the EPTB cases, and was even more common in adult cases (83%). As noted in prior studies, the source of the isolates in our study differed from Alvarez et al.,40 where a considerable proportion of isolates came from urine and respiratory specimens, reflecting a higher incidence of genitourinary tuberculosis during 1972–1977. In comparison, the isolates in our study were mainly obtained from respiratory, pleural and lymph node sources. The susceptibility of these isolates were not different from the PTB cases (data not shown). Even though the EPTB strains were less likely to be clonally related than the PTB strains, we found higher proportions of clustered cases than in the report published by Alland et al.41 and HernandezGarduno et al.42 (58% vs. 31% vs. 36%, respectively). These findings might be partly explained by differences in the definition of clustering, molecular genotyping techniques, geographic areas with differences in demographics, dynamic transmission in the city of Houston, TB/HIV co-infection incidence, and perhaps genetic variability among the TB strains with different tropisms. For example, in our cohort, Beijing family strains accounted for 20% of all the strains characterized and the top six of our largest 10 cluster groups. Although it may be true that there were no differences in the distribution of the major genetic groups among our cohort, further analysis needs to be done using the more sophisticated genetic marker systems currently available. The high mortality observed among EPTB cases was mainly due to concomitant pulmonary and extrapulmonary infections, as demonstrated by a logistic regression model controlling for age and HIV. These deaths could be explained by the severity of a disseminated disease. The diagnosis of EPTB depends in many instances on a high index of suspicion; however, it is definitive when mycobacteria are isolated from fluids and biopsy specimens. In cases where clinical, laboratory, and diagnostic tools are not useful, a more sensitive and specific diagnostic test is needed in addition to identifying risk factors associated to EPTB. Limitations of this study were the definition of clustering, which was based on molecular character-

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ization rather than traditional epidemiology; this could overestimate the number of clusters. The assumption of an unknown case of HIV as a negative case, which would underestimate the true prevalence, and the unavailability of some mycobacteria samples for molecular characterization, either due to non-enrollment or culture negative; could have introduced some bias. Extra-pulmonary tuberculosis is considered a less significant public health problem than PTB due to its lower levels of infectivity and prevalence. However, in Houston, this number represents almost a third of total tuberculosis cases. The fact that EPTB cases have not shown a decline proportional to that of PTB cases, along with the higher mortality among patients with concomitant infections in the EPTB group, impacts health resource utilization and thus requires greater attention. Moreover, with the increasing rates of patients with HIV/AIDS in Texas, especially among African Americans and other minority groups,43 these patients, who have a higher risk for tuberculosis and developing extra-pulmonary manifestations (specially concomitant infections) need greater recognition. Awareness of the changing epidemiology and clinical picture of tuberculosis will help health care providers to maintain a high index of suspicion, combined with rational investigation, to diagnose and treat EPTB in an appropriate and timely manner. Acknowledgements Written informed consent was obtained from all subjects. Guidelines of the US Department of Health and Human Services and of the Institutional Review Board of Baylor College of Medicine and Affiliated Hospitals were followed in the conduct of the study. The project was funded in part with federal funds from The National Institute of Allergy and Infectious Diseases, National Institutes of Health, under contract N01-AO-02738, and DA09238 from the National Institute of Drug Abuse. Presented at the 40th Annual Meeting, Infectious Disease Society of America, October 2002, Chicago, IL, #670.

References 1 Jereb J A, Kelly G D, Dooley S W Jr, Cauthen G M, Snider D E Jr. Tuberculosis morbidity in the United States: final data, 1990. Mor Mortal Wkly Rep CDC Surveill Summ 1991; 40: 23–27. 2 Slutsker L, Castro K G, Ward J W, Dooley S W Jr. Epidemiology of extrapulmonary tuberculosis among persons with AIDS in the United States. Clin Infect Dis 1993; 16: 513–518. 3 Centers for Disease Control and Prevention Surveillance Report. Reported Tuberculosis in the United States, 2001. Atlanta, GA: CDC, 2001. 4 Tuberculosis—United States, 1985—and the possible impact of human T-lymphotropic virus type III/lymphadenopathyassociated virus infection. Morb Mortal Wkly Rep 1986; 35: 74–76. 5 Centers for Disease Control and Prevention. Tuberculosis and acquired immunodeficiency syndrome—New York City. Morb Mortal Wkly Rep 1987; 36: 785–790, 795. 6 Centers for Disease Control and Prevention. Tuberculosis morbidity—United States, 1992. Morb Mortal Wkly Rep 1993; 42: 696–697, 703–704. 7 Brudney K, Dobkin J. Resurgent tuberculosis in New York City. Human immunodeficiency virus, homelessness, and the

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decline of tuberculosis control programs. Am Rev Respir Dis 1991; 144: 745–749. Cantwell M F, Snider D E Jr, Cauthen G M, Onorato I M. Epidemiology of tuberculosis in the United States, 1985 through 1992. JAMA 1994; 272: 535–539. El Sahly H M, Adams G J, Soini H, Teeter L, Musser J M, Graviss E A. Epidemiologic differences between United Statesand foreign-born tuberculosis patients in Houston, Texas. J Infect Dis 2001; 183: 461–468. Geng E, Kreiswirth B, Driver C, et al. Changes in the transmission of tuberculosis in New York City from 1990 to 1999. N Engl J Med 2002; 346: 1453–1458. Centers for Disease Control and Prevention. Surveillance Report. Reported Tuberculosis in the United States, 2000. Atlanta, GA: CDC, 2000. Barnes P F, Bloch A B, Davidson P T, Snider D E Jr. Tuberculosis in patients with human immunodeficiency virus infection. N Engl J Med 1991; 324: 1644–1650. Chaisson R E, Schecter G F, Theuer C P, Rutherford G W, Echenberg D F, Hopewell P C. Tuberculosis in patients with the acquired immunodeficiency syndrome. Clinical features, response to therapy, and survival. Am Rev Respir Dis 1987; 136: 570–574. Snider D E Jr. Extrapulmonary tuberculosis in Oklahoma, 1965 to 1973. Am Rev Respir Dis 1975; 111: 641–646. Farer L S, Lowell A M, Meador M P. Extrapulmonary tuberculosis in the United States. Am J Epidemiol 1979; 109: 205–217. Weir M R. The enigma of extrapulmonary tuberculosis. N Y State J Med 1989; 89: 251–252. Weir M R, Thornton G F. Extrapulmonary tuberculosis. Experience of a community hospital and review of the literature. Am J Med 1985; 79: 467–478. Rieder H L, Snider D E Jr, Cauthen G M. Extrapulmonary tuberculosis in the United States. Am Rev Respir Dis 1990; 141: 347–351. Mehta J B, Dutt A, Harvill L, Mathews K M. Epidemiology of extrapulmonary tuberculosis. A comparative analysis with pre-AIDS era. Chest 1991; 99: 1134–1138. Mehta J B, Kasprzyk D, Harvill L M, Anderson H R. Extrapulmonary tuberculosis in Tennessee from 1977–1981. A review of statistical analysis. J Tenn Med Assoc 1985; 78: 271–275. Al-Freihi H M, Al-Mohaya S A, Ibrahim E M, Al-Idrissi H Y, Baris I. Extrapulmonary tuberculosis: diverse manifestations and diagnosis challenge. East Afr Med J 1987; 64: 295–301. Elder N C. Extrapulmonary tuberculosis. A review. Arch Fam Med 1992; 1: 91–98. Diagnostic Standards and Classification of Tuberculosis in Adults and Children. This official statement of the American Thoracic Society and the Centers for Disease Control and Prevention was adopted by the ATS Board of Directors, July 1999. This statement was endorsed by the Council of the Infectious Disease Society of America, September 1999. Am J Respir Crit Care Med 2000; 161 (4 Pt 1): 1376–1395. Noertjojo K, Tam C M, Chan S L, Chan-Yeung M M. Extrapulmonary and pulmonary tuberculosis in Hong Kong. Int J Tuberc Lung Dis 2002; 6: 879–886. Sreevatsan S, Pan X, Stockbauer K E, et al. Restricted structural gene polymorphism in the Mycobacterium tuberculosis

26

27

28

29

30

31

32

33

34

35 36 37 38

39

40

41

42

43

complex indicates evolutionarily recent global dissemination. Proc Natl Acad Sci USA 1997; 94: 9869–9874. van Embden J D, Cave M D, Crawford J T, et al. Strain identification of Mycobacterium tuberculosis by DNA fingerprinting: recommendations for a standardized methodology. J Clin Microbiol 1993; 31: 406–409. Goyal M, Saunders N A, van Embden J D, Young D B, Shaw R J. Differentiation of Mycobacterium tuberculosis isolates by spoligotyping and IS6110 restriction fragment length polymorphism. J Clin Microbiol 1997; 35: 647–651. Antony S J, Harrell V, Christie J D, Adams H G, Rumley R L. Clinical differences between pulmonary and extrapulmonary tuberculosis: a 5-year retrospective study. J Natl Med Assoc 1995; 87: 187–192. Braun M M, Byers R H, Heyward W L, et al. Acquired immunodeficiency syndrome and extrapulmonary tuberculosis in the United States. Arch Intern Med 1990; 150: 1913–1916. Centers for Disease Control and Prevention. Tuberculosis and acquired immunodeficiency syndrome—Florida. Morb Mortal Wkly Rep 1986; 35: 587–590. Stead W W. Genetics and resistance to tuberculosis. Could resistance be enhanced by genetic engineering? Ann Intern Med 1992; 116: 937–941. Bellamy R, Ruwende C, Corrah T, McAdam K P, Whittle H C, Hill A V. Variations in the NRAMP1 gene and susceptibility to tuberculosis in West Africans. N Engl J Med 1998; 338: 640–644. Gao P S, Fujishima S, Mao X Q, et al. Genetic variants of NRAMP1 and active tuberculosis in Japanese populations. International Tuberculosis Genetics Team. Clin Genet 2000; 58: 74–76. Ma X D S, Wright J A, Reich RA, et al. 5 dinucleotide repeat polymorphism of NRAMP1 and susceptibility to tuberculosis among Caucasian patients in Houston, Texas. Int J Tuberc Lung Dis 2002; 6: 818–823. Huebner R E, Castro K G. The changing face of tuberculosis. Annu Rev Med 1995; 46: 47–55. Bloom B R. Tuberculosis—the global view. N Engl J Med 2002; 346: 1434–1435. Baydur A. The spectrum of extrapulmonary tuberculosis. West J Med 1977; 126: 253–262. Shafer R W, Kim D S, Weiss J P, Quale J M. Extrapulmonary tuberculosis in patients with human immunodeficiency virus infection. Medicine (Baltimore) 1991; 70: 384–397. Hass D W. Mycobacterial diseases. In: Mandell G L, Bennett J E, Dolin R, eds. Principles and Practice of Infectious Diseases. 5th ed. Philadelphia: Churchill Livingstone, 2000: pp 2597–2604. Alvarez S, McCabe W R. Extrapulmonary tuberculosis revisited: a review of experience at Boston City and other hospitals. Medicine (Baltimore) 1984; 63: 25–55. Alland D, Kalkut G E, Moss A R, et al. Transmission of tuberculosis in New York City. An analysis by DNA fingerprinting and conventional epidemiologic methods. N Engl J Med 1994; 330: 1710–1716. Hernandez-Garduno E, Kunimoto D, Wang L, et al. Predictors of clustering of tuberculosis in Greater Vancouver: a molecular epidemiologic study. CMAJ 2002; 167: 349–352. Centers for Disease Control and Prevention Surveillance reports: HIV prevalence trends in selected populations in the United States. Atlanta, GA: CDC, 2001.

RÉSUMÉ

L’augmentation des cas de tuberculose extrapulmonaires (EPTB) a été largement attribuée à la coinfection par le virus de l’immunodéficience humaine (VIH). Les taux d’EPTB sont restés constants malgré la décroissance des cas de tuberculose pulmonaire (PTB).

CONTEXTE :

Evaluer les covariantes associées à l’EPTB. Une cohorte de 4 ans de patients atteints de EPTB a été comparée à des cas de PTB. Les sujets enrôlés ont été évalués concernant les risques de TB. Les dossiers médicaux ont été revus et les empreintes

OBJECTIF :

MÉTHODES :

Extra-pulmonary tuberculosis

génomiques des isolats de Mycobacterium tuberculosis ont été caractérisés. R É S U L T A T S : Nous avons identifié 538 cas d’EPTB (28,6%) sur un total de 1.878 sujets enrôlés. Les sites les plus courants d’infection ont été les ganglions lymphatiques (43%) et la plèvre (23%). Les cas d’EPTB comportaient 320 hommes (59%), 382 patients (71%) à culture positive et 332 isolats (86,9%) de patients qui ont pu être caractérisés. Moins de patients EPTB que PTB se retrouvaient dans les souches en grappes de M. tuberculosis (58% vs 65% ; P  0.02). Un modèle multivarié a pu identifier un accroissement du risque d’EPTB parmi les sujets d’ethnie afro-américaine (OR 1,9 ; P  0,01),

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les séropositifs pour le VIH (OR 3,1 ; P  0.01), ceux atteints de cirrhose hépatique (OR 2,3 ; P  0,02) et ceux âgés de moins de 18 ans (OR 2,0 ; P  0,04). Les patients ayant une atteinte concomitante pulmonaire et extrapulmonaire avaient un risque plus élevé de décéder dans les 6 mois après le diagnostic de TB (OR 2,3 ; P  0,01). C O N C L U S I O N S : L’ethnicité afro-américaine est un facteur de risque indépendant d’EPTB. La mortalité à 6 mois observée est peut-être expliqué en partie par la dissémination de M. tuberculosis et la gravité de la comorbidité sousjacente.

RESUMEN C O N T E X T O : El aumento de la tuberculosis extrapulmonar (EPTB) es debido a un gran parte a la coinfección con el virus de la inmunodeficiencia humana (VIH). Las tasas de EPTB han permanecido constantes a pesar de la disminución de los casos de tuberculosis pulmonar (PTB). O B J E T I V O : Evaluar las covariables asociadas a la EPTB. M É T O D O : Una cohorte de 4 años de pacientes EPTB fue comparada con casos de PTB. Los sujetos enrolados fueron entrevistados y evaluados en lo que respecta a los riesgos de TB, se revisaron las fichas médicas de los pacientes y se procedió a una caracterización molecular de los aislados de Mycobacterium tuberculosis. R E S U L T A D O S : En un total de 1.878 enrolados se identificaron 538 casos de EPTB (28,6%). Las localizaciones más comunes de la infección eran los ganglios linfáticos (43%) y la pleura (23%). Los casos de EPTB incluían 320 pacientes de sexo masculino (59%), 382 con cultivo positivo (71%) y 332 (86,9%) cuyos aislados fueron

molecularmente caracterizados. Menos pacientes EPTB que de pacientes PTB se encontraban en las cepas de M. tuberculosis agrupadas en conglomerados (58% vs 65% ; P  0,02). Un modelo multivariado identificó un riesgo aumentado para la EPTB en los sujetos enrolados pertenecientes a la etnia afro-americana (OR 1,9 ; P  0,01), en los sujetos seropositivos para el VIH (OR 3,1 ; P  0,01), con cirrosis hepática (OR 2,3 ; P  0,02) y en los menores de 18 años de edad (OR 2,0 ; P  0,04). Los pacientes que presentaban concomitantemente una TB pulmonar y extrapulmonr tenían más probabilidades de morir dentro de los 6 meses después del diagnóstico (OR 2,3 ; P  0,01). C O N C L U S I Ó N : Se demostró que la etnia afro-americana es un factor de riesgo independiente para EPTB. La muerte observado a los 6 meses se explica parcialmente por la diseminación de M. tuberculosis y la gravedad de la comorbilidad subyacente.