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Latent TB Infection Treatment Acceptance and Completion in the United States and Canada
CHEST
Original Research LUNG INFECTION
Latent TB Infection Treatment Acceptance and Completion in the United States and Canada C. Robert Horsburgh Jr, MD; Stefan Goldberg, MD; James Bethel, PhD; Shande Chen, PhD; Paul W. Colson, PhD; Yael Hirsch-Moverman, MPH; Stephen Hughes, PhD; Robin Shrestha-Kuwahara, MPH; Timothy R. Sterling, MD; Kirsten Wall, MHS; Paul Weinfurter, BA; and the Tuberculosis Epidemiologic Studies Consortium
Background: Treatment of latent TB infection (LTBI) is essential for preventing TB in North America, but acceptance and completion of this treatment have not been systematically assessed. Methods: We performed a retrospective, randomized two-stage cross-sectional survey of treatment and completion of LTBI at public and private clinics in 19 regions of the United States and Canada in 2002. Results: At 32 clinics that both performed tuberculin skin testing and offered treatment, 123 (17.1%; 95% CI, 14.5%-20.0%) of 720 subjects tested and offered treatment declined. Employees at healthcare facilities were more likely to decline (odds ratio [OR], 4.74; 95% CI, 1.75-12.9; P 5 .003), whereas those in contact with a patient with TB were less likely to decline (OR, 0.19; 95% CI, 0.070.50; P 5 .001). At 68 clinics starting treatment regardless of where skin testing was performed, 1,045 (52.7%; 95% CI, 48.5%-56.8%) of 1,994 people starting treatment failed to complete the recommended course. Risk factors for failure to complete included starting the 9-month isoniazid regimen (OR, 2.08; 95% CI, 1.23-3.57), residence in a congregate setting (nursing home, shelter, or jail; OR, 2.94; 95% CI, 1.58-5.56), injection drug use (OR, 2.13; 95% CI, 1.04-4.35), age ⱖ 15 years (OR, 1.49; 95% CI, 1.14-1.94), and employment at a health-care facility (1.37; 95% CI, 1.00-1.85). Conclusions: Fewer than half of the people starting treatment of LTBI completed therapy. Shorter regimens and interventions targeting residents of congregate settings, injection drug users, and employees of health-care facilities are needed to increase completion. CHEST 2010; 137(2):401–409 Abbreviations: BCG 5 bacillus Calmette-Guérin; CDC 5 Centers for Disease Control and Prevention; INH 5 isoniazid; LTBI 5 latent tuberculosis infection; TBESC 5 Tuberculosis Epidemiologic Studies Consortium
of latent TB infection (LTBI) has been Treatment identified by the Centers for Disease Control
and Prevention (CDC), the Advisory Council for the Elimination of Tuberculosis, the American Thoracic Society, and the Institute of Medicine of the National Academy of Sciences as the major strategy for elimination of TB in the United States.1-3 It is estimated that 10 to 15 million people in the United States have LTBI, and roughly 300,000 Americans are treated for LTBI each year.4,5 In both the United States and Canada, LTBI treatment is a cornerstone of national programs to reduce the burden of TB. Factors that limit the effectiveness of this strategy are failure of persons with LTBI to accept or com-
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plete treatment. Although there are anecdotal reports that most persons offered treatment accept it, there have been no systematic studies of treatment acceptance. Individual clinics have reported completion by 5% to 60% of persons receiving the 6-month regimen of isoniazid (INH),6-17 and 19% to 76% of persons receiving the 9-month INH regimen.18-21 However, the data for the 9-month regimen were from subjects enrolled in research studies and may not reflect completion achieved under program conditions. A more precise estimate of the proportion of persons declining and failing to complete treatment and identification of predictors of these outcomes would facilitate the development of interventions to CHEST / 137 / 2 / FEBRUARY, 2010
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improve acceptance and completion. In a previous study, we asked clinics to estimate the number of subjects treated for LTBI, but we were not able to determine acceptance or completion of such treatment. Therefore, in this study, we performed a randomized retrospective evaluation of the frequency of and risk factors for declining and failing to complete therapy for LTBI in the United States and Canada.
Methods
of the CDC determined that the study involved minimal risk to participants and approved waivers of Privacy Rule authorization and informed consent according to federal regulations. Definitions Completion of LTBI treatment was based on a specified number of doses to be completed within a specified period of time for each regimen, as previously defined.1 For the 9-month daily isoniazid regimen, completion was defined as 270 doses within 12 months; for 6 months of daily isoniazid completion was 180 doses within 9 months; for 4 months of daily rifampin, completion was 120 doses within 6 months; and for 2 months of daily rifampin/ pyrazinamide, completion was 60 doses within 3 months.
Study Sites
Data Analysis
The study was conducted at the 19 sites of the Tuberculosis Epidemiologic Studies Consortium (TBESC), each of which represents a partnership between an academic institution and a state or local TB control program.4 Each TBESC site was asked to examine practice sites in their catchment area that provided LTBI treatment to at least 10 persons in 2002 and could provide access to records of patients.
The analysis considered two end points: acceptance and completion of LTBI treatment. We analyzed risk factors for failure to accept (ie, declining) treatment only in clinics where we were able to identify and sample subjects who had been offered treatment. The analysis of the second end point, treatment completion, was based on all patients started on treatment at any clinic. Frequencies and descriptive statistics used x2 tests and confidence intervals to assess statistical significance; logistic regression was used to identify and evaluate risks associated with declining and failing to complete treatment. Data analyses were weighted to adjust for nonresponse and unequal selection probabilities due to the two-stage sample design. The sampling weights were adjusted for nonparticipation of sampled clinics and for charts that were sampled within clinics but could not be located for abstraction. Weighted frequencies, proportions, other descriptive statistics, and logistic regression analyses were performed using WesVar (Westat; Rockville, MD).22 Multivariate models for declining and failing to complete treatment were constructed by including all variables associated with the outcome of interest that had a P value of .15 or less, and then removing variables by stepwise elimination to arrive at the most parsimonious model; a significant P value was defined as , .05.
Study Design The study design was a random stratified two-stage cluster sample survey with 1-year follow-up; all persons who were offered and/or started treatment of LTBI during 2002 at a participating clinic were eligible. This design permits adjustment for nonresponse and unequal selection probabilities in clinics of differing size. Outcomes were evaluated during 1 year of follow-up from the date of starting treatment. Patient charts were sampled using a random, stratified two-stage cluster sample survey. In the first stage, clinics were sampled across the sites, stratified by clinic type; in the second stage, charts were selected at random from within the clinics using predesignated sampling intervals. In addition to abstraction of individual patient charts, a clinic characteristic survey was performed by interviewing the clinic director or staff designated by the clinic director. The Institutional Review Board
Results Study Clinics and Study Subjects
Manuscript received June 9, 2009; revision accepted August 4, 2009. Affiliations: From the Department of Epidemiology (Dr Horsburgh), Boston University School of Public Health, Boston, MA; Centers for Disease Control and Prevention (Dr Goldberg, Ms Shrestha-Kuwahara, Mr Weinfurter), Atlanta, GA; Westat (Dr Bethel), Rockville MD; Department of Biostatistics (Dr Chen), University of North Texas Health Science Center, Fort Worth, TX; Columbia University (Dr Colson, Ms HirschMoverman), New York, NY; New York State Department of Health (Dr Hughes), Albany, NY; Division of Infectious Diseases (Dr Sterling), Vanderbilt University School of Medicine, Nashville, TN; and the Denver Health and Hospital Authority (Ms Wall), Denver CO. Funding/Support: This study was supported by the Centers for Disease Control and Prevention, Contract Number 200-200100082. Correspondence to: C. Robert Horsburgh Jr, MD, Department of Epidemiology, Boston University School of Public Health, 715 Albany Street, T3E, Boston, MA 02118; e-mail: rhorsbu@ bu.edu © 2010 American College of Chest Physicians. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (www.chestjournal.org/ site/misc/reprints.xhtml). DOI: 10.1378/chest.09-0394
Sixty-eight (68%) of the 100 clinics randomly selected for chart abstraction within the 19 catchment areas participated in the study. There were some differences between responding and nonresponding clinics. The response rate was substantially higher among public health clinics (82%) than among other types of clinics (26%); the latter group included private clinics, HIV clinics, and clinics serving homeless persons, immigrants, and refugees. There were also differences by size of clinic, with response rates of 50%, 75%, and 81%, respectively, among clinics reporting 100 or fewer, 100 to 249, and 250 or more LTBI patients. Finally, there were differences by region, with response rates of 76%, 59%, and 52% in the South, Northeast, and Midwest/West (combined). In summary, our sample somewhat overrepresents larger clinics, public health clinics, and clinics in the South. Because of the small sample size overall, we were unable to adjust for all these factors in weighting, Original Research
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Table 1—Risk Factors for Declining LTBI Treatment Variable
Categories
Patient Characteristics Age, y
Sex Race/ethnicity
Recent contact with an active TB patient TST converter Ever homeless Ever incarcerated (jail or prison) Resident in a congregate setting (nursing home/ shelter/jail/prison) Foreign born Employee at health-care facility (hospital/nursing home) Years of residence in United States/Canadae HIV seropositive Immunosuppressive therapy Fibrotic lesions (class 4) Diabetes mellitus (type 1 or type 2) Injection drug user Received the BCG vaccinee Clinic Characteristics Written educational materials about LTBI are provided Clinician reviews chest radiograph film directly with the patient Blood specimens required
Number of d/wk open Walk-ins available
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,5 5-9 10-14 15-24 25-44 45-64 65 or older Male Female Hispanic White, nonHispanic Black, nonHispanic Asian Other/unknown Yes No/unknown Yes No/unknown Yes No/unknown Yes No/unknown Yes (ever) Never/unknown Yes No/unknown Yes No/unknown .5 y ⱕ5 y Yes No/unknown Yes No/unknown Yes No/unknown Yes No/unknown Yes No/unknown Yes No/unknown At least most of the time Half the time or less All the time Most, seldom, or no All patients Selected patients or no Less than 5 d 5 d or more Yes No or sometimes yes
Treatment Declined/Total
Weighteda % Declined
P Value
Odds Ratio
Lower Limit
Upper Limit
1/22 3/44 1/50 24/137 64/286 25/157 5/24 67/382 56/338 44/332 18/84
3.9 16.0 4.5 22.7 24.8 20.3 23.6 20.5 21.4 15.2 36.0
.1882 … … … … … … .8811 … .3895 …c
0.308b … … … … … … 0.945 … … 0.525
0.050 … … … … … … 0.311 … … 0.173
1.915 … … … … … … 2.870 … … 1.596
22/153
22.0
…d
2.440
0.752
7.916
11/101 28/50 10/212 113/508 15/107 108/613 15/51 108/669 16/58 107/662 16/58 107/662 78/440 45/280 22/53 101/667 37/242 25/158 0/18 123/702 0/6 123/714 1/15 122/705 0/24 123/696 0/8 123/712 41/230 37/210
11.9 50.8 6.3 25.5 22.7 20.6 37.0 20.0 42.3 18.7 34.5 20.1 23.4 17.7 51.7 18.5 21.2 19.9 0.0 21.4 0.0 21.0 9.1 21.1 0.0 21.5 0.0 21.1 18.3 27.6
… … .0140 … .7611 … .3285 … .2728 … .4878 … .5279 … .0381 … .9615 … .2075 … .0363 … .3043 … .0185 … .0357 … .1325 …
… … 0.197 … 1.135 … 2.354 … 3.181 … 2.097 … 1.418 … 4.722 … 1.079 … NC … NC … 0.375 … NC … NC … 0.588 …
… … 0.050 … 0.378 … 0.614 … 0.955 … 0.401 … 0.409 … 1.945 … 0.269 … NC … NC … 0.025 … NC … NC … 0.156 …
… … 0.799 … 3.410 … 9.024 … 10.589 … 10.959 … 4.924 … 11.464 … 4.072 … NC … NC … 5.718 … NC … NC … 3.601 …
119/668
21.5
.2927
4.212
0.673
26.377
4/52
6.2
…
…
…
…
26/343 96/376
11.0 27.1
.2772 …
0.332 …
0.057 …
1.948 …
13/45 110/675
25.3 20.3
.8067 …
1.306 …
0.185 …
9.210 …
18/108 105/612 110/495 13/225
24.0 20.0 25.8 6.8
.8090 … .2208 …
1.237 … 4.638 …
0.270 … 0.416 …
5.668 … 51.693 …
(Continued)
CHEST / 137 / 2 / FEBRUARY, 2010
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Table 1—(Continued) Variable
Categories
Time to schedule an initial appointment Time to complete evaluation Reschedule if arriving late Required to return for follow-up Reminders for upcoming follow-up Clinic is easily accessible for patients
Interpretation for first most common language Other primary care services, on site, most often
Less than a wk, same d A wk or longer ,4 h ⱖ4 h Yes No Yes, all Some, or none Yes No, or sometimes Car and public transport Neither, or one , 15 min . 15 min, rarely/ never On site, most often Not on site, most often
Treatment Declined/Total
Weighteda % Declined
P Value
Odds Ratio
Lower Limit
Upper Limit
30/295
9.0
.0366
0.233
0.059
0.913
93/425 51/222 72/498 73/342 50/378 121/639 2/81 73/348 50/371 107/630
29.7 17.3 22.1 23.1 18.9 22.1 2.3 21.3 20.7 19.9
… .7979 … .8085 … .0002 … .9715 … .7861
… 0.717 … 1.348 … 12.309 … 1.051 … 0.779
… 0.074 … 0.257 … 3.263 … 0.180 … 0.147
… 6.940 … 7.075 … 46.436 … 6.132 … 4.133
16/90 112/688 11/32
24.6 19.9 39.2
… .5336 …
… 0.391 …
… 0.076 …
… 5.987 …
55/286
23.8
.7031
1.434
0.282
7.296
68/434
17.5
…
…
…
…
Univariate analysis of patient-level variables and clinic characteristics among 720 patients seen at clinics that performed tuberculin skin testing and offered LTBI treatment. BCG 5 bacillus Calmette-Guérin; LTBI 5 latent tuberculosis infection; NC 5 not calculable; TST 5 tuberculin skin test. aThe sampling weights were adjusted for nonparticipation of sampled clinics and for charts that were sampled within clinics but could not be located for abstraction. bComparing aged 14 y and younger with aged 15 y and older. cWhite, non-Hispanic vs other. dBlack, non-Hispanic vs other. eAmong foreign-born only; 40 persons did not provide information about time of residence.
but we did adjust for type of clinic, which had the greatest disparity in response rates. Reasons for failure to participate included inability to identify records of persons tested or treated for LTBI (5), administrative refusal to participate (8), failure to obtain local institutional review board approval (11), and other reasons (8). Of the clinics, 61/68 (90%) were general public health clinics, 2/68 (3%) were immigrant/ refugee clinics, 2/68 (2%) were correctional clinics, one was an HIV clinic, one was a homeless clinic, and one was defined as other. At the 68 clinics, 3,540 charts were selected for review, of which 2,395 (67.7%) were located and abstracted, 797 (22.5%) were ineligible, and 348 (9.8%) could not be located or were not abstracted for some other reason. Of the 68 clinics, only 32 both performed skin testing and offered treatment. Thus, only patients sampled at these 32 clinics who had testing done on site were included in the analysis of declining treatment. Declining LTBI Treatment Of 720 patients at the 32 clinics, 123 (17.1%; 95% CI, 5.8%-36%) declined initiation of treatment (Table 1). Of the 440 foreign-born persons, 232 (52.7%) were from Mexico, 46 (10.5%) were from the Philippines, 20
(4.5%) were from Vietnam, and 142 (32.3%) were from other countries. In multivariate analysis (Table 2), employees at a health-care facility were more likely to decline treatment, whereas contacts of a case of TB were less likely to decline. The proportion of persons declining treatment was not different between US/Canada-born and foreign-born persons, nor was it different between foreign-born persons in the United States/Canada for 5 years or less compared with those in the United States/ Canada for more than 5 years. The proportion declining treatment was less among foreign-born persons in the United States/Canada 1 year or less (11.4%) compared with all others (25.7%), but this was not statistically significant (odds ratio, 0.373; 95% CI, 0.113-2.471; P 5 .464). Failure to Complete LTBI Treatment At the 68 clinics that provided treatment to those tested on site or elsewhere, 1,994 persons started treatment (Table 3). Of the 1,177 foreign-born persons, 482 (41.0%) were from Mexico, 146 (12.4%) were from the Philippines, 55 (4.7%) were from Vietnam, and 495 (42.0%) were from other countries, each of which represented less than 3% of the total. A regimen of 9 months of INH was prescribed for 1,674 (84.0%) of them, 6 months of INH for 181 Original Research
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Table 2—Multivariate Analysis of Risk Factors for Declining and Failing to Complete Treatment of LTBI Group Risk factors for declining treatment Risk factors for failing to complete treatment
Odds Ratio
Employee of a health-care facilitya Contact with a person with TB Resident in a congregate settingb 9-mo INH regimen Injection drug use Employee of a health-care facilitya Age ⱖ 15
4.74 0.19 2.94 2.08 2.13 1.37 1.49
95% CI
P Value
1.75-12.9 0.07-0.50 1.58-5.56 1.23-3.57 1.04-4.35 1.00-1.85 1.14-1.94
.003 .001 .001 .008 .038 .049 .004
INH 5 isoniazid. aHospital or nursing home. bNursing home, homeless shelter, jail, or prison.
(9.1%), 4 months of rifampin for 91 (4.6%), and 2 months of rifampin and pyrazinamide for 13 (0.7%). Overall, 1,054 (52.5%; 95% CI, 45.8%-59.2%) of the 1,994 patients did not complete treatment. Univariate analysis of characteristics associated with failure to complete treatment is shown in Table 3 and Figure 1. Of patients who were prescribed 9 months of INH but failed to complete the 9-month course, 21.9% failed to complete 6 months, whereas 78.1% completed 6 months but failed to complete the final 3 months. Thus, for the 9-month regimen, if failure had been defined as not taking at least 6 months of INH, the overall noncompletion rate would have been 42.9%. In multivariate analysis, failure to complete therapy was associated with being a resident in a congregate setting, initiating the 9-month INH regimen compared with all others, being an injection drug user, age ⱖ 15, and being an employee of a congregate setting (Table 2). As shown in Figure 2, more than 20% of persons initiating one of the three main LTBI treatment regimens stopped taking it in the first month. This was a significantly greater percentage than in all other months (P , .001). Failure to complete treatment was not different between US/Canada-born and foreign-born persons, nor was it different between foreign-born persons in the United States/Canada for 5 years or less compared with those in the United States/Canada for greater than 5 years. However, failure to complete treatment was significantly less among foreign-born persons in the United States/Canada 1 year or less (48.0%), compared with all others (55.3%; relative risk, 0.824; 95% CI, 0.671-0.975; P 5 .0262). Discussion This study shows that although acceptance of LTBI treatment is relatively high (83%), the proportion completing is low (47%). When the product of these two proportions is calculated, we see that completion was achieved by only 39% of persons who were offered LTBI treatment. The major risk factor for noncompletion was being prescribed the 9-month www.chestjournal.org
INH regimen. As shown in Figure 1, when the proportions completing the three most commonly prescribed regimens are compared, it can be seen that there is an inverse relationship between length of the regimen prescribed and the proportion completing treatment. The increased completion that we observed with the 4-month rifampin regimen is consistent with previous reports.18-20 It is of interest to note that if completion of the 9-month regimen were defined as completion of at least 6 months of INH, the noncompletion rate of the 9-month regimen, 42.9%, would have been almost identical to that of the 6- month regimen, 44.8%. Thus, prescribing the longer course seems neither to greatly encourage nor discourage patients from completing 6 months of INH. In addition to using regimens of shorter duration, another strategy for increasing completion suggested by the results of this study is targeting of populations at higher risk of failing to complete treatment. Such populations include residents in congregate settings (nursing homes, homeless shelters, jails, and prisons), injection drug users, and employees of hospitals and nursing homes. Some of these populations are recognized to include many difficult-to-reach subjects,1 but health-care workers could be targeted by adherence programs in the workplace. Unfortunately, only 336/1994 (16.9%) of the patients receiving LTBI treatment in this study were members of these groups, so improvement in completion among these populations might not translate to a substantial overall improvement. On the other hand, if strategies to improve completion in populations with low rates of completion cannot be implemented, focusing screening efforts on populations with better rates of completion might more efficiently use program resources. Such populations include those in contact with patients with infectious TB, persons younger than 15 years of age, and foreignborn persons during their first year in the United States/Canada. Such a strategy would have the additional advantage of targeting the group with the highest rates of TB disease of all foreign-born persons in the United States.23-26 Moreover, specialized programs CHEST / 137 / 2 / FEBRUARY, 2010
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Table 3—Risk Factors for Failure to Complete LTBI Treatment
Variable
Category
Patient Characteristics Age, y
Sexc Race/ethnicity
Recent contact with an active TB patient TST converter Ever homeless Ever incarcerated (jail or prison) Resident in congregate setting (nursing home/shelter/jail/prison) Foreign born . 2 wk in a TB-endemic area in previous year Employee at health-care facility, (hospital/nursing home) Years of residence in United States/ Canadaf HIV-infected Immunosuppressive therapy Fibrotic lesions (class 4) Diabetes mellitus (type 1 or type 2) Chronic renal failure Injection drug user Received the BCG vaccine Regimen
Clinic Characteristics Written educational materials about LTBI are provided Clinician reviews chest radiograph film directly with the patient
,5 5-9 10-14 15-24 25-44 45-64 65 or older Male Female Hispanic White, non-Hispanic Black, non-Hispanic Asian, non-Hispanic Other/unknown Yes No/unknown Yes No/unknown Yes No/unknown Yes No/unknown Yes (ever) No/unknown Yes United States/unknown Yes No/unknown Yes No/unknown .5 y ⱕ5 y Yes No/unknown Yes No/unknown Yes No/unknown Yes No/unknown Yes No/unknown Yes No/unknown Yes No/unknown 9 mo of INH 6 mo of INH 2 mo Rifampin/ pyrazinamide 4 mo Rifampin Other/unknown At least most of the time Half the time or less All the time Most, seldom, or no
Treatment Not Completed/Total
Weighteda % Not Completed
P Value
Lower Limit
Upper Limit
0.755 … … … … … … 0.879 … … 0.832 0.830 … … 0.820 … 0.903 … 0.916 … 0.909 … 1.013 … 0.847 … 0.753 … 0.929 … 0.800 … 0.632 … 0.544 … 0.441 … 0.701 … 0.271 … 0.986 … 0.809 … 0.849 … …
1.073 … … … … … … 1.145 … … 1.115 1.148 … … 1.171 … 1.182 … 1.445 … 1.404 … 1.392 … 1.174 … 1.319 … 1.243 … 1.207 … 1.575 … 1.906 … 1.688 … 1.211 … 3.944 … 1.360 … 1.218 … 1.612 … …
34/71 51/120 60/156 238/430 454/807 178/351 30/59 522/1,007 523/985 375/753 162/313 229/408 226/433 53/87 208/401 837/1,593 175/314 870/1,680 44/59 1,001/1,935 67/99 978/1,895 78/102 967/1,892 606/1,177 439/817 93/178 951/1,816 125/209 920/1,785 241/460 330/661 14/29 1,031/1,965 8/16 1,037/1,978 10/27 1,035/1,967 31/75 1,014/1,919 8/14 1,037/1,980 19/25 1,026/1,969 312/618 294/559 915/1,674 84/181 5/13
48.3 40.8 42.4 56.0 55.9 51.2 52.1 52.9 52.5 49.6 50.2 55.3 54.1 62.4 50.7 53.1 56.1 52.0 72.0 52.2 68.8 51.9 76.7 51.6 52.5 52.9 52.2 52.7 60.9 51.6 53.2 52.1 52.4 52.7 54.9 52.6 37.7 52.9 43.9 53.0 56.8 52.6 73.2 52.2 52.0 52.9 54.8 44.8 41.8
… … .5739 … .2481 … .0549 … .0697 … .0035 … .9327 … .9445 … .0087 … .3717 … .9807 … .8817 … .2719 … .1134 … .8360 … .0751 … .8072 … .0122g … …
0.785b … … … … … … 1.007 … … 0.917 0.945 … … 0.954 … 1.078 … 1.380 … 1.324 … 1.486 … 0.993 … 0.991 … 1.181 … 0.960 … 0.995 … 1.043 … 0.712 … 0.828 … 1.080 … 1.401 … 0.983 … 1.435 … …
32/91 9/35
31.2 23.9
… …
… …
… …
… …
52.8 53.8 51.9 54.0
.7924 … .6425 …
0.982 … 0.960 …
0.860 … 0.822 …
1.145 … 1.175 …
948/1,820 97/174 435/872 590/1,087
.1738 … … … … … … .8850 … .2788
Relative Risk
d e
(Continued)
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Table 3—(Continued)
Variable
Category
Blood specimens required How many d/wk open Walk-ins available Time to schedule an initial appointment Time to complete evaluation Reschedule if arriving late Required to return for follow-up Reminders for upcoming follow-up Clinic is easily accessible for patients Interpretation for first most common language Other primary care services, on site, most often
Treatment Not Completed/Total
All patients Selected patients or no Less than 5 d 5 d or more Yes No or sometimes yes Less than 1 wk, same d 1 wk or longer ,4 h ⱖ4 h Yes No Yes, all Some, or none Yes No, or sometimes Car and public transport Neither, or one , 15 min . 15 min, rarely/never On site, most often Not on site, most often
119/217 926/1,777 172/342 873/1,652 423/823 222/443 494/932 551/1,062 377/679 668/1,315 356/687 689/1,307 952/1,810 93/184 579/1,122 466/872 917/1,758 128/236 937/1,793 101/190 431/833 614/1,161
Weighteda % Not Completed 57.2 52.3 49.8 53.5 53.1 52.5 52.8 53.1 54.4 52.0 51.4 53.5 53.1 50.2 51.5 54.7 52.6 56.1 52.6 55.7 52.2 53.5
P Value
Relative Risk
Lower Limit
Upper Limit
.4883 … .4569 … .9169 … .9537 … .5951 … .7033 … .5396 … .4833 … .5776 … .6524 … .7794 …
1.094 … 0.931 … 1.010 … 0.995 … 1.047 … 0.960 … 1.058 … 0.941 … 0.937 … 0.943 … 0.977 …
0.819 … 0.780 … 0.819 … 0.845 … 0.862 … 0.784 … 0.830 … 0.822 … 0.772 … 0.747 … 0.840 …
1.320 … 1.205 … 1.232 … 1.178 … 1.207 … 1.231 … 1.265 … 1.155 … 1.224 … 1.272 … 1.166 …
Univariate analysis of patient-level variables and clinic characteristics among 1,994 patients seen at clinics that offered LTBI treatment. See Table 1 for expansion of abbreviations. aThe sampling weights were adjusted for nonparticipation of sampled clinics and for charts that were sampled within clinics but could not be located for abstraction. bComparing aged 14 y and younger to aged 15 y and older. cTwo persons had unknown gender. dWhite, non-Hispanic vs other. eBlack, non-Hispanic vs other. fAmong foreign-born only; 56 persons had unknown duration of residence. gNine-month regimen vs other regimens.
that are designed to be culturally sensitive have been shown to be successful in reaching such populations.27 We did not find significant differences in completion of LTBI treatment by race, sex or birth outside the United States, or between those who had received bacillus Calmette-Guérin (BCG) vaccination and those who had not, as has been reported by others.12,14,16,17 Moreover, characteristics of the treating clinic and the patient experience at the clinic were not associated with completion. Thus, factors that have been reported to be associated with completion in single-clinic studies may not be generalizable to the United States as a whole. More than 20% of those initiating treatment stopped it within 1 month of starting; this amounts to one-third of all those who failed to complete treatment. It is possible that some of those failing to complete in the first month may have been individuals who were unwilling to refuse the offer of treatment, but who never intended to initiate it. Thus, acceptance rates may not be as encouraging as they appear. In addition, because more than one-half of those who did not complete stopped within 2 months after www.chestjournal.org
starting, close follow-up of patients during the first 2 months with prompt intervention to encourage completion among those stopping treatment might pay substantial dividends. Our study has several limitations. First, not all clinics that were selected for the study agreed to participate, and clinics that did not participate differed from those that did participate. Although we were able to adjust for some of these differences in the analysis, our results may still reflect unmeasured or uncorrected bias. Second, clinics that treated fewer than 10 persons per year for LTBI were excluded. Thus, it is possible that large numbers of small clinics and practices, each treating a small number of persons each year, could represent a substantial number of LTBI diagnoses and courses of treatment that were missed by our survey. Based on our informal understanding of the relative importance assigned to LTBI treatment by primary care physicians and infectious diseases specialists, we doubt that this is the case. Third, some charts were ineligible or could not be located. Such charts might be expected to have been more likely to represent patients who declined or did CHEST / 137 / 2 / FEBRUARY, 2010
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rifampin has only been conclusively demonstrated to be effective in HIV-infected persons,28 and is not recommended for use in the United States. Another 3-month regimen, once weekly rifapentine plus INH, has been shown to be well tolerated and lead to improved completion.29 The efficacy of this regimen compared with the 9-month INH regimen is currently being studied by the Tuberculosis Trials Consortium.30 If this regimen is as effective as the 9-month INH regimen, its widespread adoption might lead to substantially improved treatment completion rates and result in prevention of more cases of TB. Figure 1. Percent LTBI treatment completion by duration of treatment. Shorter treatment duration was associated with increased completion (P , .001). Vertical lines indicate standard errors. 4R 5 4 months of rifampin; 6H 5 6 months of INH; 9H 5 9 months of INH; INH 5 isoniazid; LTBI 5 latent tuberculosis infection.
not complete treatment. To the extent that this occurred, our proportions of acceptance and completion may be overestimates. We conclude that the most important advance that could improve the effectiveness of LTBI treatment would be a regimen of shorter duration. The 4-month rifampin regimen and the 3-month regimen of daily INH plus rifampin are both shorter regimens with better completion rates, but the 4-month rifampin regimen has not had efficacy evaluated in a large prospective trial, whereas the 3-month regimen of INH plus
Figure 2. Failure to complete LTBI treatment, by month in which last dose was taken, as a percent of all persons taking treatment at the beginning of that month (among those taking the 9-month INH regimen, the 6-month isoniazid regimen, or the 4-month rifampin regimen only). See Figure 1 legend for expansion of abbreviations.
Acknowledgments Author contributions: Dr Horsburgh Jr: contributed to the design of the study, abstraction of study data, and analysis of the data, and wrote the first draft of the manuscript. Dr Goldberg: contributed to the design of the study, analysis of the data, and preparation of the manuscript. Dr Bethel: contributed to the design of the study, analysis of the data, and preparation of the manuscript. He had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Dr Chen: contributed to the creation of the study database, analysis of the data, and preparation of the manuscript. Dr Colson: contributed to the design of the study, abstraction of study data, analysis of the data, and preparation of the manuscript. Ms Hirsch-Moverman: contributed to the design of the study, abstraction of study data, analysis of the data, and preparation of the manuscript. Dr Hughes: contributed to the design of the study, abstraction of study data, analysis of the data, and preparation of the manuscript. Ms Shrestha-Kuwahara: contributed to the design of the study, analysis of the data, and preparation of the manuscript. Dr Sterling: contributed to the design of the study, abstraction of study data, analysis of the data, and preparation of the manuscript. Ms Wall: contributed to the design of the study, abstraction of study data, analysis of the data, and preparation of the manuscript. Mr Weinfurter: contributed to the design of the study, analysis of the data, and preparation of the manuscript. Financial/nonfinancial disclosures: The authors have reported to CHEST the following conflicts of interest: Dr Sterling has received grant money from Pfizer and Oxford/Immunotec. Mr Weinfurter has a sibling who works for and owns stock in Amgen. Drs Horsburgh, Goldberg, Bethel, Chen, Colson, and Hughes, and Mss Hirsch-Moverman, Shrestha-Kuwahara, and Wall have reported that no potential conflicts exist with any companies/ organizations whose products or services may be discussed in this article. Role of sponsor: The findings and conclusions in this report are those of the authors and do not necessarily represent the official position of the Centers for Disease Control and Prevention. Other contributions: We thank the investigators and staff at all the participating TBESC sites: James McAuley, MD, MPH, Judith Beison, Chicago, IL; Frank Wilson, MD, Cheryl LeDoux, MT, MPH, Little Rock, AR; Jennifer Flood, MD, MPH, Sumi Sun, MPH, Berkeley, CA; Hugo Ortega, New York, NY; Randall Reves, MD, MSc, Denver, CO; Henry M. Blumberg, MD, Jane Tapia, BSN, Atlanta, GA; Jessie Wing, MD, Sara Jacobson, MPH, Honolulu HI; Cara Endyke-Doran, RN, BSN, MPH, Baltimore MD; Sue Etkind, RN, MPH, Sharon Sharnprapai, MPH, Boston MA; Wendy Mills Sutherland, MPH, Hodan Guled, MPH, Minneapolis, MN; John Grabau, PhD, MPH, Wilson Miranda, MBBS, MPH, Albany, NY; Rachel Royce, PhD, Carol Dukes-Hamilton, MD, Juani Munoz Sanchez, Durham, NC; Connie Haley, MD, MPH, Tamara Chavez-Lindell, MPH, Original Research
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Nashville, TN; Edward Graviss, PhD, MPH, Smita Chatterjee, MS, Houston, TX; David E. Griffith, MD, Tyler, TX; Michael Kimerling, MD, MPH, Ashutosh Tamhane, MD, DPH, MSPH, Birmingham, AL; Monika Naus, MD, MSc, Mark Fitzgerald, MD, DM, Victoria Cook, MD, Maya Nakajima, BSc, Vancouver, BC; Earl Hershfield, MD, Barbara Roche, BScN, MPH, Winnipeg, MB; Nandini Selvam, MPH, PhD, Newark, NJ; Stephen Weis, MD, Guadalupe Munguia, MD, MPH, Jingsheng Yan, PhD, MPH, Heidi L. Venegas, MS, Sarah Brown, MS, Fort Worth, TX; Mike Jones, MS, Bethesda MD. In addition, we thank Richard O’Brien, MD, for inspiration and encouragement in the development of this study.
References 1. American Thoracic Society, Centers for Disease Control and Prevention. Targeted tuberculin testing and treatment of latent tuberculosis infection. This official statement of the American Thoracic Society was adopted by the ATS Board of Directors, July 1999. This is a Joint Statement of the American Thoracic Society (ATS) and the Centers for Disease Control and Prevention (CDC). This statement was endorsed by the Council of the Infectious Diseases Society of America. (IDSA), September 1999, and the sections of this statement. Am J Respir Crit Care Med. 2000;161(4 pt 2):S221-S247. 2. Centers for Disease Control (CDC). A strategic plan for the elimination of tuberculosis in the United States. MMWR Morb Mortal Wkly Rep. 1989;38(16):269-272. 3. Geiter L. Ending Neglect. The Elimination of Tuberculosis in the United States. Washington, DC: National Academy Press; 2000. 4. Sterling TR, Bethel J, Goldberg S, Weinfurter P, Yun L, Horsburgh CR; Tuberculosis Epidemiologic Studies Cosortium. The scope and impact of treatment of latent tuberculosis infection in the United States and Canada. Am J Respir Crit Care Med. 2006;173(8):927-931. 5. Bennett DE, Courval JM, Onorato I, et al. Prevalence of tuberculosis infection in the United States population: the national health and nutrition examination survey, 1999-2000. Am J Respir Crit Care Med. 2008;177(3):348-355. 6. Marks SM, Taylor Z, Qualls NL, Shrestha-Kuwahara RJ, Wilce MA, Nguyen CH. Outcomes of contact investigations of infectious tuberculosis patients. Am J Respir Crit Care Med. 2000;162(6):2033-2038. 7. Gilroy SA, Rogers MA, Blair DC. Treatment of latent tuberculosis infection in patients aged . or =35 years. Clin Infect Dis. 2000;31(3):826-829. 8. Sprinson JE, Flood J, Fan CS, et al. Evaluation of tuberculosis contact investigations in California. Int J Tuberc Lung Dis. 2003;7(12)(suppl 3):S363-S368. 9. Bock NN, Metzger BS, Tapia JR, Blumberg HM. A tuberculin screening and isoniazid preventive therapy program in an inner-city population. Am J Respir Crit Care Med. 1999;159(1):295-300. 10. Khoury SA, Theodore A, Platte VJ. Isoniazid prophylaxis in a slum area. Am Rev Respir Dis. 1969;99(3):345-353. 11. Hirsch-Moverman Y, Daftary A, Franks J, Colson PW. Adherence to treatment for latent tuberculosis infection: systematic review of studies in the US and Canada. Int J Tuberc Lung Dis. 2008;12(11):1235-1254. 12. LoBue PA, Moser KS. Use of isoniazid for latent tuberculosis infection in a public health clinic. Am J Respir Crit Care Med. 2003;168(4):443-447. 13. McNeill L, Allen M, Estrada C, Cook P. Pyrazinamide and rifampin vs isoniazid for the treatment of latent tuberculosis: improved completion rates but more hepatotoxicity. Chest. 2003;123(1):102-106. www.chestjournal.org
14. Morisky DE, Ebin VJ, Malotte CK, Coly A, Kominski G. Assessment of tuberculosis treatment completion in an ethnically diverse population using two data sources. Implications for treatment interventions. Eval Health Prof. 2003;26(1): 43-58. 15. Jasmer RM, Saukkonen JJ, Blumberg HM, et al; Short-Course Rifampin and Pyrazinamide for Tuberculosis Infection (SCRIPT) Study Investigators. Short-course rifampin and pyrazinamide compared with isoniazid for latent tuberculosis infection: a multicenter clinical trial. Ann Intern Med. 2002;137(8):640-647. 16. Shukla SJ, Warren DK, Woeltje KF, Gruber CA, Fraser VJ. Factors associated with the treatment of latent tuberculosis infection among health-care workers at a midwestern teaching hospital. Chest. 2002;122(5):1609-1614. 17. Parsyan AE, Saukkonen J, Barry MA, Sharnprapai S, Horsburgh CR Jr. Predictors of failure to complete treatment for latent tuberculosis infection. J Infect. 2007;54(3):262-266. 18. Menzies D, Dion M-J, Rabinovitch B, Mannix S, Brassard P, Schwartzman K. Treatment completion and costs of a randomized trail of rifampin for 4 months versus isoniazid for 9 months. Am J Respir Crit Care Med. 2004;170(4):445-449. 19. Lardizabal A, Passannante M, Kojakali F, Hayden C, Reichman LB. Enhancement of treatment completion for latent tuberculosis infection with 4 months of rifampin. Chest. 2006;130(6):1712-1717. 20. Page KR, Sifakis F, Montes de Oca R, et al. Improved adherence and less toxicity with rifampin vs isoniazid for treatment of latent tuberculosis: a retrospective study. Arch Intern Med. 2006;166(17):1863-1870. 21. Shieh FK, Snyder G, Horsburgh CR, Bernardo J, Murphy C, Saukkonen JJ. Predicting non-completion of treatment for latent tuberculous infection: a prospective survey. Am J Respir Crit Care Med. 2006;174(6):717-721. 22. Brick JM, Morganstein D. Computing Sampling Errors from Clustered Unequally Weighted Data Using Replication: WesVarPC. Bulletin of the International Statistical Institute. Proceedings, Book 1. 2007:479-482. 23. Maloney SA, Fielding KL, Laserson KF, et al. Assessing the performance of overseas tuberculosis screening programs: a study among US-bound immigrants in Vietnam. Arch Intern Med. 2006;166(2):234-240. 24. Cohen T, Murray M. Incident tuberculosis among recent US immigrants and exogenous reinfection. Emerg Infect Dis. 2005;11(5):725-728. 25. Nolan CM, Elarth AM. Tuberculosis in a cohort of Southeast Asian refugees. A five-year surveillance study. Am Rev Respir Dis. 1988;137(4):805-809. 26. Cain KP, Benoit SR, Winston CA, Mac Kenzie WR. Tuberculosis among foreign-born persons in the United States. JAMA. 2008;300(4):405-412. 27. Goldberg SV, Wallace J, Jackson JC, Chaulk CP, Nolan CM. Cultural case management of latent tuberculosis infection. Int J Tuberc Lung Dis. 2004;8(1):76-82. 28. Whalen CC, Johnson JL, Okwera A, et al; Uganda-Case Western Reserve University Research Collaboration. A trial of three regimens to prevent tuberculosis in Ugandan adults infected with the human immunodeficiency virus. N Engl J Med. 1997;337(12):801-808. 29. Schechter M, Zajdenverg R, Falco G, et al. Weekly rifapentine/isoniazid or daily rifampin/pyrazinamide for latent tuberculosis in household contacts. Am J Respir Crit Care Med. 2006;173(8):922-926. 30. Tuberculosis Trials Consortium, Division of TB Elimination, Centers for Disease Control and Prevention. The Tuberculosis Trials Consortium: a model for clinical trials collaborations. Public Health Rep. 2001;116(suppl 1):41-49. CHEST / 137 / 2 / FEBRUARY, 2010
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Original Research LUNG INFECTION
Latent TB Infection Treatment Acceptance and Completion in the United States and Canada C. Robert Horsburgh Jr, MD; Stefan Goldberg, MD; James Bethel, PhD; Shande Chen, PhD; Paul W. Colson, PhD; Yael Hirsch-Moverman, MPH; Stephen Hughes, PhD; Robin Shrestha-Kuwahara, MPH; Timothy R. Sterling, MD; Kirsten Wall, MHS; Paul Weinfurter, BA; and the Tuberculosis Epidemiologic Studies Consortium
Background: Treatment of latent TB infection (LTBI) is essential for preventing TB in North America, but acceptance and completion of this treatment have not been systematically assessed. Methods: We performed a retrospective, randomized two-stage cross-sectional survey of treatment and completion of LTBI at public and private clinics in 19 regions of the United States and Canada in 2002. Results: At 32 clinics that both performed tuberculin skin testing and offered treatment, 123 (17.1%; 95% CI, 14.5%-20.0%) of 720 subjects tested and offered treatment declined. Employees at healthcare facilities were more likely to decline (odds ratio [OR], 4.74; 95% CI, 1.75-12.9; P 5 .003), whereas those in contact with a patient with TB were less likely to decline (OR, 0.19; 95% CI, 0.070.50; P 5 .001). At 68 clinics starting treatment regardless of where skin testing was performed, 1,045 (52.7%; 95% CI, 48.5%-56.8%) of 1,994 people starting treatment failed to complete the recommended course. Risk factors for failure to complete included starting the 9-month isoniazid regimen (OR, 2.08; 95% CI, 1.23-3.57), residence in a congregate setting (nursing home, shelter, or jail; OR, 2.94; 95% CI, 1.58-5.56), injection drug use (OR, 2.13; 95% CI, 1.04-4.35), age ⱖ 15 years (OR, 1.49; 95% CI, 1.14-1.94), and employment at a health-care facility (1.37; 95% CI, 1.00-1.85). Conclusions: Fewer than half of the people starting treatment of LTBI completed therapy. Shorter regimens and interventions targeting residents of congregate settings, injection drug users, and employees of health-care facilities are needed to increase completion. CHEST 2010; 137(2):401–409 Abbreviations: BCG 5 bacillus Calmette-Guérin; CDC 5 Centers for Disease Control and Prevention; INH 5 isoniazid; LTBI 5 latent tuberculosis infection; TBESC 5 Tuberculosis Epidemiologic Studies Consortium
of latent TB infection (LTBI) has been Treatment identified by the Centers for Disease Control
and Prevention (CDC), the Advisory Council for the Elimination of Tuberculosis, the American Thoracic Society, and the Institute of Medicine of the National Academy of Sciences as the major strategy for elimination of TB in the United States.1-3 It is estimated that 10 to 15 million people in the United States have LTBI, and roughly 300,000 Americans are treated for LTBI each year.4,5 In both the United States and Canada, LTBI treatment is a cornerstone of national programs to reduce the burden of TB. Factors that limit the effectiveness of this strategy are failure of persons with LTBI to accept or com-
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plete treatment. Although there are anecdotal reports that most persons offered treatment accept it, there have been no systematic studies of treatment acceptance. Individual clinics have reported completion by 5% to 60% of persons receiving the 6-month regimen of isoniazid (INH),6-17 and 19% to 76% of persons receiving the 9-month INH regimen.18-21 However, the data for the 9-month regimen were from subjects enrolled in research studies and may not reflect completion achieved under program conditions. A more precise estimate of the proportion of persons declining and failing to complete treatment and identification of predictors of these outcomes would facilitate the development of interventions to CHEST / 137 / 2 / FEBRUARY, 2010
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improve acceptance and completion. In a previous study, we asked clinics to estimate the number of subjects treated for LTBI, but we were not able to determine acceptance or completion of such treatment. Therefore, in this study, we performed a randomized retrospective evaluation of the frequency of and risk factors for declining and failing to complete therapy for LTBI in the United States and Canada.
Methods
of the CDC determined that the study involved minimal risk to participants and approved waivers of Privacy Rule authorization and informed consent according to federal regulations. Definitions Completion of LTBI treatment was based on a specified number of doses to be completed within a specified period of time for each regimen, as previously defined.1 For the 9-month daily isoniazid regimen, completion was defined as 270 doses within 12 months; for 6 months of daily isoniazid completion was 180 doses within 9 months; for 4 months of daily rifampin, completion was 120 doses within 6 months; and for 2 months of daily rifampin/ pyrazinamide, completion was 60 doses within 3 months.
Study Sites
Data Analysis
The study was conducted at the 19 sites of the Tuberculosis Epidemiologic Studies Consortium (TBESC), each of which represents a partnership between an academic institution and a state or local TB control program.4 Each TBESC site was asked to examine practice sites in their catchment area that provided LTBI treatment to at least 10 persons in 2002 and could provide access to records of patients.
The analysis considered two end points: acceptance and completion of LTBI treatment. We analyzed risk factors for failure to accept (ie, declining) treatment only in clinics where we were able to identify and sample subjects who had been offered treatment. The analysis of the second end point, treatment completion, was based on all patients started on treatment at any clinic. Frequencies and descriptive statistics used x2 tests and confidence intervals to assess statistical significance; logistic regression was used to identify and evaluate risks associated with declining and failing to complete treatment. Data analyses were weighted to adjust for nonresponse and unequal selection probabilities due to the two-stage sample design. The sampling weights were adjusted for nonparticipation of sampled clinics and for charts that were sampled within clinics but could not be located for abstraction. Weighted frequencies, proportions, other descriptive statistics, and logistic regression analyses were performed using WesVar (Westat; Rockville, MD).22 Multivariate models for declining and failing to complete treatment were constructed by including all variables associated with the outcome of interest that had a P value of .15 or less, and then removing variables by stepwise elimination to arrive at the most parsimonious model; a significant P value was defined as , .05.
Study Design The study design was a random stratified two-stage cluster sample survey with 1-year follow-up; all persons who were offered and/or started treatment of LTBI during 2002 at a participating clinic were eligible. This design permits adjustment for nonresponse and unequal selection probabilities in clinics of differing size. Outcomes were evaluated during 1 year of follow-up from the date of starting treatment. Patient charts were sampled using a random, stratified two-stage cluster sample survey. In the first stage, clinics were sampled across the sites, stratified by clinic type; in the second stage, charts were selected at random from within the clinics using predesignated sampling intervals. In addition to abstraction of individual patient charts, a clinic characteristic survey was performed by interviewing the clinic director or staff designated by the clinic director. The Institutional Review Board
Results Study Clinics and Study Subjects
Manuscript received June 9, 2009; revision accepted August 4, 2009. Affiliations: From the Department of Epidemiology (Dr Horsburgh), Boston University School of Public Health, Boston, MA; Centers for Disease Control and Prevention (Dr Goldberg, Ms Shrestha-Kuwahara, Mr Weinfurter), Atlanta, GA; Westat (Dr Bethel), Rockville MD; Department of Biostatistics (Dr Chen), University of North Texas Health Science Center, Fort Worth, TX; Columbia University (Dr Colson, Ms HirschMoverman), New York, NY; New York State Department of Health (Dr Hughes), Albany, NY; Division of Infectious Diseases (Dr Sterling), Vanderbilt University School of Medicine, Nashville, TN; and the Denver Health and Hospital Authority (Ms Wall), Denver CO. Funding/Support: This study was supported by the Centers for Disease Control and Prevention, Contract Number 200-200100082. Correspondence to: C. Robert Horsburgh Jr, MD, Department of Epidemiology, Boston University School of Public Health, 715 Albany Street, T3E, Boston, MA 02118; e-mail: rhorsbu@ bu.edu © 2010 American College of Chest Physicians. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (www.chestjournal.org/ site/misc/reprints.xhtml). DOI: 10.1378/chest.09-0394
Sixty-eight (68%) of the 100 clinics randomly selected for chart abstraction within the 19 catchment areas participated in the study. There were some differences between responding and nonresponding clinics. The response rate was substantially higher among public health clinics (82%) than among other types of clinics (26%); the latter group included private clinics, HIV clinics, and clinics serving homeless persons, immigrants, and refugees. There were also differences by size of clinic, with response rates of 50%, 75%, and 81%, respectively, among clinics reporting 100 or fewer, 100 to 249, and 250 or more LTBI patients. Finally, there were differences by region, with response rates of 76%, 59%, and 52% in the South, Northeast, and Midwest/West (combined). In summary, our sample somewhat overrepresents larger clinics, public health clinics, and clinics in the South. Because of the small sample size overall, we were unable to adjust for all these factors in weighting, Original Research
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Table 1—Risk Factors for Declining LTBI Treatment Variable
Categories
Patient Characteristics Age, y
Sex Race/ethnicity
Recent contact with an active TB patient TST converter Ever homeless Ever incarcerated (jail or prison) Resident in a congregate setting (nursing home/ shelter/jail/prison) Foreign born Employee at health-care facility (hospital/nursing home) Years of residence in United States/Canadae HIV seropositive Immunosuppressive therapy Fibrotic lesions (class 4) Diabetes mellitus (type 1 or type 2) Injection drug user Received the BCG vaccinee Clinic Characteristics Written educational materials about LTBI are provided Clinician reviews chest radiograph film directly with the patient Blood specimens required
Number of d/wk open Walk-ins available
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,5 5-9 10-14 15-24 25-44 45-64 65 or older Male Female Hispanic White, nonHispanic Black, nonHispanic Asian Other/unknown Yes No/unknown Yes No/unknown Yes No/unknown Yes No/unknown Yes (ever) Never/unknown Yes No/unknown Yes No/unknown .5 y ⱕ5 y Yes No/unknown Yes No/unknown Yes No/unknown Yes No/unknown Yes No/unknown Yes No/unknown At least most of the time Half the time or less All the time Most, seldom, or no All patients Selected patients or no Less than 5 d 5 d or more Yes No or sometimes yes
Treatment Declined/Total
Weighteda % Declined
P Value
Odds Ratio
Lower Limit
Upper Limit
1/22 3/44 1/50 24/137 64/286 25/157 5/24 67/382 56/338 44/332 18/84
3.9 16.0 4.5 22.7 24.8 20.3 23.6 20.5 21.4 15.2 36.0
.1882 … … … … … … .8811 … .3895 …c
0.308b … … … … … … 0.945 … … 0.525
0.050 … … … … … … 0.311 … … 0.173
1.915 … … … … … … 2.870 … … 1.596
22/153
22.0
…d
2.440
0.752
7.916
11/101 28/50 10/212 113/508 15/107 108/613 15/51 108/669 16/58 107/662 16/58 107/662 78/440 45/280 22/53 101/667 37/242 25/158 0/18 123/702 0/6 123/714 1/15 122/705 0/24 123/696 0/8 123/712 41/230 37/210
11.9 50.8 6.3 25.5 22.7 20.6 37.0 20.0 42.3 18.7 34.5 20.1 23.4 17.7 51.7 18.5 21.2 19.9 0.0 21.4 0.0 21.0 9.1 21.1 0.0 21.5 0.0 21.1 18.3 27.6
… … .0140 … .7611 … .3285 … .2728 … .4878 … .5279 … .0381 … .9615 … .2075 … .0363 … .3043 … .0185 … .0357 … .1325 …
… … 0.197 … 1.135 … 2.354 … 3.181 … 2.097 … 1.418 … 4.722 … 1.079 … NC … NC … 0.375 … NC … NC … 0.588 …
… … 0.050 … 0.378 … 0.614 … 0.955 … 0.401 … 0.409 … 1.945 … 0.269 … NC … NC … 0.025 … NC … NC … 0.156 …
… … 0.799 … 3.410 … 9.024 … 10.589 … 10.959 … 4.924 … 11.464 … 4.072 … NC … NC … 5.718 … NC … NC … 3.601 …
119/668
21.5
.2927
4.212
0.673
26.377
4/52
6.2
…
…
…
…
26/343 96/376
11.0 27.1
.2772 …
0.332 …
0.057 …
1.948 …
13/45 110/675
25.3 20.3
.8067 …
1.306 …
0.185 …
9.210 …
18/108 105/612 110/495 13/225
24.0 20.0 25.8 6.8
.8090 … .2208 …
1.237 … 4.638 …
0.270 … 0.416 …
5.668 … 51.693 …
(Continued)
CHEST / 137 / 2 / FEBRUARY, 2010
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Table 1—(Continued) Variable
Categories
Time to schedule an initial appointment Time to complete evaluation Reschedule if arriving late Required to return for follow-up Reminders for upcoming follow-up Clinic is easily accessible for patients
Interpretation for first most common language Other primary care services, on site, most often
Less than a wk, same d A wk or longer ,4 h ⱖ4 h Yes No Yes, all Some, or none Yes No, or sometimes Car and public transport Neither, or one , 15 min . 15 min, rarely/ never On site, most often Not on site, most often
Treatment Declined/Total
Weighteda % Declined
P Value
Odds Ratio
Lower Limit
Upper Limit
30/295
9.0
.0366
0.233
0.059
0.913
93/425 51/222 72/498 73/342 50/378 121/639 2/81 73/348 50/371 107/630
29.7 17.3 22.1 23.1 18.9 22.1 2.3 21.3 20.7 19.9
… .7979 … .8085 … .0002 … .9715 … .7861
… 0.717 … 1.348 … 12.309 … 1.051 … 0.779
… 0.074 … 0.257 … 3.263 … 0.180 … 0.147
… 6.940 … 7.075 … 46.436 … 6.132 … 4.133
16/90 112/688 11/32
24.6 19.9 39.2
… .5336 …
… 0.391 …
… 0.076 …
… 5.987 …
55/286
23.8
.7031
1.434
0.282
7.296
68/434
17.5
…
…
…
…
Univariate analysis of patient-level variables and clinic characteristics among 720 patients seen at clinics that performed tuberculin skin testing and offered LTBI treatment. BCG 5 bacillus Calmette-Guérin; LTBI 5 latent tuberculosis infection; NC 5 not calculable; TST 5 tuberculin skin test. aThe sampling weights were adjusted for nonparticipation of sampled clinics and for charts that were sampled within clinics but could not be located for abstraction. bComparing aged 14 y and younger with aged 15 y and older. cWhite, non-Hispanic vs other. dBlack, non-Hispanic vs other. eAmong foreign-born only; 40 persons did not provide information about time of residence.
but we did adjust for type of clinic, which had the greatest disparity in response rates. Reasons for failure to participate included inability to identify records of persons tested or treated for LTBI (5), administrative refusal to participate (8), failure to obtain local institutional review board approval (11), and other reasons (8). Of the clinics, 61/68 (90%) were general public health clinics, 2/68 (3%) were immigrant/ refugee clinics, 2/68 (2%) were correctional clinics, one was an HIV clinic, one was a homeless clinic, and one was defined as other. At the 68 clinics, 3,540 charts were selected for review, of which 2,395 (67.7%) were located and abstracted, 797 (22.5%) were ineligible, and 348 (9.8%) could not be located or were not abstracted for some other reason. Of the 68 clinics, only 32 both performed skin testing and offered treatment. Thus, only patients sampled at these 32 clinics who had testing done on site were included in the analysis of declining treatment. Declining LTBI Treatment Of 720 patients at the 32 clinics, 123 (17.1%; 95% CI, 5.8%-36%) declined initiation of treatment (Table 1). Of the 440 foreign-born persons, 232 (52.7%) were from Mexico, 46 (10.5%) were from the Philippines, 20
(4.5%) were from Vietnam, and 142 (32.3%) were from other countries. In multivariate analysis (Table 2), employees at a health-care facility were more likely to decline treatment, whereas contacts of a case of TB were less likely to decline. The proportion of persons declining treatment was not different between US/Canada-born and foreign-born persons, nor was it different between foreign-born persons in the United States/Canada for 5 years or less compared with those in the United States/ Canada for more than 5 years. The proportion declining treatment was less among foreign-born persons in the United States/Canada 1 year or less (11.4%) compared with all others (25.7%), but this was not statistically significant (odds ratio, 0.373; 95% CI, 0.113-2.471; P 5 .464). Failure to Complete LTBI Treatment At the 68 clinics that provided treatment to those tested on site or elsewhere, 1,994 persons started treatment (Table 3). Of the 1,177 foreign-born persons, 482 (41.0%) were from Mexico, 146 (12.4%) were from the Philippines, 55 (4.7%) were from Vietnam, and 495 (42.0%) were from other countries, each of which represented less than 3% of the total. A regimen of 9 months of INH was prescribed for 1,674 (84.0%) of them, 6 months of INH for 181 Original Research
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Table 2—Multivariate Analysis of Risk Factors for Declining and Failing to Complete Treatment of LTBI Group Risk factors for declining treatment Risk factors for failing to complete treatment
Odds Ratio
Employee of a health-care facilitya Contact with a person with TB Resident in a congregate settingb 9-mo INH regimen Injection drug use Employee of a health-care facilitya Age ⱖ 15
4.74 0.19 2.94 2.08 2.13 1.37 1.49
95% CI
P Value
1.75-12.9 0.07-0.50 1.58-5.56 1.23-3.57 1.04-4.35 1.00-1.85 1.14-1.94
.003 .001 .001 .008 .038 .049 .004
INH 5 isoniazid. aHospital or nursing home. bNursing home, homeless shelter, jail, or prison.
(9.1%), 4 months of rifampin for 91 (4.6%), and 2 months of rifampin and pyrazinamide for 13 (0.7%). Overall, 1,054 (52.5%; 95% CI, 45.8%-59.2%) of the 1,994 patients did not complete treatment. Univariate analysis of characteristics associated with failure to complete treatment is shown in Table 3 and Figure 1. Of patients who were prescribed 9 months of INH but failed to complete the 9-month course, 21.9% failed to complete 6 months, whereas 78.1% completed 6 months but failed to complete the final 3 months. Thus, for the 9-month regimen, if failure had been defined as not taking at least 6 months of INH, the overall noncompletion rate would have been 42.9%. In multivariate analysis, failure to complete therapy was associated with being a resident in a congregate setting, initiating the 9-month INH regimen compared with all others, being an injection drug user, age ⱖ 15, and being an employee of a congregate setting (Table 2). As shown in Figure 2, more than 20% of persons initiating one of the three main LTBI treatment regimens stopped taking it in the first month. This was a significantly greater percentage than in all other months (P , .001). Failure to complete treatment was not different between US/Canada-born and foreign-born persons, nor was it different between foreign-born persons in the United States/Canada for 5 years or less compared with those in the United States/Canada for greater than 5 years. However, failure to complete treatment was significantly less among foreign-born persons in the United States/Canada 1 year or less (48.0%), compared with all others (55.3%; relative risk, 0.824; 95% CI, 0.671-0.975; P 5 .0262). Discussion This study shows that although acceptance of LTBI treatment is relatively high (83%), the proportion completing is low (47%). When the product of these two proportions is calculated, we see that completion was achieved by only 39% of persons who were offered LTBI treatment. The major risk factor for noncompletion was being prescribed the 9-month www.chestjournal.org
INH regimen. As shown in Figure 1, when the proportions completing the three most commonly prescribed regimens are compared, it can be seen that there is an inverse relationship between length of the regimen prescribed and the proportion completing treatment. The increased completion that we observed with the 4-month rifampin regimen is consistent with previous reports.18-20 It is of interest to note that if completion of the 9-month regimen were defined as completion of at least 6 months of INH, the noncompletion rate of the 9-month regimen, 42.9%, would have been almost identical to that of the 6- month regimen, 44.8%. Thus, prescribing the longer course seems neither to greatly encourage nor discourage patients from completing 6 months of INH. In addition to using regimens of shorter duration, another strategy for increasing completion suggested by the results of this study is targeting of populations at higher risk of failing to complete treatment. Such populations include residents in congregate settings (nursing homes, homeless shelters, jails, and prisons), injection drug users, and employees of hospitals and nursing homes. Some of these populations are recognized to include many difficult-to-reach subjects,1 but health-care workers could be targeted by adherence programs in the workplace. Unfortunately, only 336/1994 (16.9%) of the patients receiving LTBI treatment in this study were members of these groups, so improvement in completion among these populations might not translate to a substantial overall improvement. On the other hand, if strategies to improve completion in populations with low rates of completion cannot be implemented, focusing screening efforts on populations with better rates of completion might more efficiently use program resources. Such populations include those in contact with patients with infectious TB, persons younger than 15 years of age, and foreignborn persons during their first year in the United States/Canada. Such a strategy would have the additional advantage of targeting the group with the highest rates of TB disease of all foreign-born persons in the United States.23-26 Moreover, specialized programs CHEST / 137 / 2 / FEBRUARY, 2010
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Table 3—Risk Factors for Failure to Complete LTBI Treatment
Variable
Category
Patient Characteristics Age, y
Sexc Race/ethnicity
Recent contact with an active TB patient TST converter Ever homeless Ever incarcerated (jail or prison) Resident in congregate setting (nursing home/shelter/jail/prison) Foreign born . 2 wk in a TB-endemic area in previous year Employee at health-care facility, (hospital/nursing home) Years of residence in United States/ Canadaf HIV-infected Immunosuppressive therapy Fibrotic lesions (class 4) Diabetes mellitus (type 1 or type 2) Chronic renal failure Injection drug user Received the BCG vaccine Regimen
Clinic Characteristics Written educational materials about LTBI are provided Clinician reviews chest radiograph film directly with the patient
,5 5-9 10-14 15-24 25-44 45-64 65 or older Male Female Hispanic White, non-Hispanic Black, non-Hispanic Asian, non-Hispanic Other/unknown Yes No/unknown Yes No/unknown Yes No/unknown Yes No/unknown Yes (ever) No/unknown Yes United States/unknown Yes No/unknown Yes No/unknown .5 y ⱕ5 y Yes No/unknown Yes No/unknown Yes No/unknown Yes No/unknown Yes No/unknown Yes No/unknown Yes No/unknown 9 mo of INH 6 mo of INH 2 mo Rifampin/ pyrazinamide 4 mo Rifampin Other/unknown At least most of the time Half the time or less All the time Most, seldom, or no
Treatment Not Completed/Total
Weighteda % Not Completed
P Value
Lower Limit
Upper Limit
0.755 … … … … … … 0.879 … … 0.832 0.830 … … 0.820 … 0.903 … 0.916 … 0.909 … 1.013 … 0.847 … 0.753 … 0.929 … 0.800 … 0.632 … 0.544 … 0.441 … 0.701 … 0.271 … 0.986 … 0.809 … 0.849 … …
1.073 … … … … … … 1.145 … … 1.115 1.148 … … 1.171 … 1.182 … 1.445 … 1.404 … 1.392 … 1.174 … 1.319 … 1.243 … 1.207 … 1.575 … 1.906 … 1.688 … 1.211 … 3.944 … 1.360 … 1.218 … 1.612 … …
34/71 51/120 60/156 238/430 454/807 178/351 30/59 522/1,007 523/985 375/753 162/313 229/408 226/433 53/87 208/401 837/1,593 175/314 870/1,680 44/59 1,001/1,935 67/99 978/1,895 78/102 967/1,892 606/1,177 439/817 93/178 951/1,816 125/209 920/1,785 241/460 330/661 14/29 1,031/1,965 8/16 1,037/1,978 10/27 1,035/1,967 31/75 1,014/1,919 8/14 1,037/1,980 19/25 1,026/1,969 312/618 294/559 915/1,674 84/181 5/13
48.3 40.8 42.4 56.0 55.9 51.2 52.1 52.9 52.5 49.6 50.2 55.3 54.1 62.4 50.7 53.1 56.1 52.0 72.0 52.2 68.8 51.9 76.7 51.6 52.5 52.9 52.2 52.7 60.9 51.6 53.2 52.1 52.4 52.7 54.9 52.6 37.7 52.9 43.9 53.0 56.8 52.6 73.2 52.2 52.0 52.9 54.8 44.8 41.8
… … .5739 … .2481 … .0549 … .0697 … .0035 … .9327 … .9445 … .0087 … .3717 … .9807 … .8817 … .2719 … .1134 … .8360 … .0751 … .8072 … .0122g … …
0.785b … … … … … … 1.007 … … 0.917 0.945 … … 0.954 … 1.078 … 1.380 … 1.324 … 1.486 … 0.993 … 0.991 … 1.181 … 0.960 … 0.995 … 1.043 … 0.712 … 0.828 … 1.080 … 1.401 … 0.983 … 1.435 … …
32/91 9/35
31.2 23.9
… …
… …
… …
… …
52.8 53.8 51.9 54.0
.7924 … .6425 …
0.982 … 0.960 …
0.860 … 0.822 …
1.145 … 1.175 …
948/1,820 97/174 435/872 590/1,087
.1738 … … … … … … .8850 … .2788
Relative Risk
d e
(Continued)
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Table 3—(Continued)
Variable
Category
Blood specimens required How many d/wk open Walk-ins available Time to schedule an initial appointment Time to complete evaluation Reschedule if arriving late Required to return for follow-up Reminders for upcoming follow-up Clinic is easily accessible for patients Interpretation for first most common language Other primary care services, on site, most often
Treatment Not Completed/Total
All patients Selected patients or no Less than 5 d 5 d or more Yes No or sometimes yes Less than 1 wk, same d 1 wk or longer ,4 h ⱖ4 h Yes No Yes, all Some, or none Yes No, or sometimes Car and public transport Neither, or one , 15 min . 15 min, rarely/never On site, most often Not on site, most often
119/217 926/1,777 172/342 873/1,652 423/823 222/443 494/932 551/1,062 377/679 668/1,315 356/687 689/1,307 952/1,810 93/184 579/1,122 466/872 917/1,758 128/236 937/1,793 101/190 431/833 614/1,161
Weighteda % Not Completed 57.2 52.3 49.8 53.5 53.1 52.5 52.8 53.1 54.4 52.0 51.4 53.5 53.1 50.2 51.5 54.7 52.6 56.1 52.6 55.7 52.2 53.5
P Value
Relative Risk
Lower Limit
Upper Limit
.4883 … .4569 … .9169 … .9537 … .5951 … .7033 … .5396 … .4833 … .5776 … .6524 … .7794 …
1.094 … 0.931 … 1.010 … 0.995 … 1.047 … 0.960 … 1.058 … 0.941 … 0.937 … 0.943 … 0.977 …
0.819 … 0.780 … 0.819 … 0.845 … 0.862 … 0.784 … 0.830 … 0.822 … 0.772 … 0.747 … 0.840 …
1.320 … 1.205 … 1.232 … 1.178 … 1.207 … 1.231 … 1.265 … 1.155 … 1.224 … 1.272 … 1.166 …
Univariate analysis of patient-level variables and clinic characteristics among 1,994 patients seen at clinics that offered LTBI treatment. See Table 1 for expansion of abbreviations. aThe sampling weights were adjusted for nonparticipation of sampled clinics and for charts that were sampled within clinics but could not be located for abstraction. bComparing aged 14 y and younger to aged 15 y and older. cTwo persons had unknown gender. dWhite, non-Hispanic vs other. eBlack, non-Hispanic vs other. fAmong foreign-born only; 56 persons had unknown duration of residence. gNine-month regimen vs other regimens.
that are designed to be culturally sensitive have been shown to be successful in reaching such populations.27 We did not find significant differences in completion of LTBI treatment by race, sex or birth outside the United States, or between those who had received bacillus Calmette-Guérin (BCG) vaccination and those who had not, as has been reported by others.12,14,16,17 Moreover, characteristics of the treating clinic and the patient experience at the clinic were not associated with completion. Thus, factors that have been reported to be associated with completion in single-clinic studies may not be generalizable to the United States as a whole. More than 20% of those initiating treatment stopped it within 1 month of starting; this amounts to one-third of all those who failed to complete treatment. It is possible that some of those failing to complete in the first month may have been individuals who were unwilling to refuse the offer of treatment, but who never intended to initiate it. Thus, acceptance rates may not be as encouraging as they appear. In addition, because more than one-half of those who did not complete stopped within 2 months after www.chestjournal.org
starting, close follow-up of patients during the first 2 months with prompt intervention to encourage completion among those stopping treatment might pay substantial dividends. Our study has several limitations. First, not all clinics that were selected for the study agreed to participate, and clinics that did not participate differed from those that did participate. Although we were able to adjust for some of these differences in the analysis, our results may still reflect unmeasured or uncorrected bias. Second, clinics that treated fewer than 10 persons per year for LTBI were excluded. Thus, it is possible that large numbers of small clinics and practices, each treating a small number of persons each year, could represent a substantial number of LTBI diagnoses and courses of treatment that were missed by our survey. Based on our informal understanding of the relative importance assigned to LTBI treatment by primary care physicians and infectious diseases specialists, we doubt that this is the case. Third, some charts were ineligible or could not be located. Such charts might be expected to have been more likely to represent patients who declined or did CHEST / 137 / 2 / FEBRUARY, 2010
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rifampin has only been conclusively demonstrated to be effective in HIV-infected persons,28 and is not recommended for use in the United States. Another 3-month regimen, once weekly rifapentine plus INH, has been shown to be well tolerated and lead to improved completion.29 The efficacy of this regimen compared with the 9-month INH regimen is currently being studied by the Tuberculosis Trials Consortium.30 If this regimen is as effective as the 9-month INH regimen, its widespread adoption might lead to substantially improved treatment completion rates and result in prevention of more cases of TB. Figure 1. Percent LTBI treatment completion by duration of treatment. Shorter treatment duration was associated with increased completion (P , .001). Vertical lines indicate standard errors. 4R 5 4 months of rifampin; 6H 5 6 months of INH; 9H 5 9 months of INH; INH 5 isoniazid; LTBI 5 latent tuberculosis infection.
not complete treatment. To the extent that this occurred, our proportions of acceptance and completion may be overestimates. We conclude that the most important advance that could improve the effectiveness of LTBI treatment would be a regimen of shorter duration. The 4-month rifampin regimen and the 3-month regimen of daily INH plus rifampin are both shorter regimens with better completion rates, but the 4-month rifampin regimen has not had efficacy evaluated in a large prospective trial, whereas the 3-month regimen of INH plus
Figure 2. Failure to complete LTBI treatment, by month in which last dose was taken, as a percent of all persons taking treatment at the beginning of that month (among those taking the 9-month INH regimen, the 6-month isoniazid regimen, or the 4-month rifampin regimen only). See Figure 1 legend for expansion of abbreviations.
Acknowledgments Author contributions: Dr Horsburgh Jr: contributed to the design of the study, abstraction of study data, and analysis of the data, and wrote the first draft of the manuscript. Dr Goldberg: contributed to the design of the study, analysis of the data, and preparation of the manuscript. Dr Bethel: contributed to the design of the study, analysis of the data, and preparation of the manuscript. He had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Dr Chen: contributed to the creation of the study database, analysis of the data, and preparation of the manuscript. Dr Colson: contributed to the design of the study, abstraction of study data, analysis of the data, and preparation of the manuscript. Ms Hirsch-Moverman: contributed to the design of the study, abstraction of study data, analysis of the data, and preparation of the manuscript. Dr Hughes: contributed to the design of the study, abstraction of study data, analysis of the data, and preparation of the manuscript. Ms Shrestha-Kuwahara: contributed to the design of the study, analysis of the data, and preparation of the manuscript. Dr Sterling: contributed to the design of the study, abstraction of study data, analysis of the data, and preparation of the manuscript. Ms Wall: contributed to the design of the study, abstraction of study data, analysis of the data, and preparation of the manuscript. Mr Weinfurter: contributed to the design of the study, analysis of the data, and preparation of the manuscript. Financial/nonfinancial disclosures: The authors have reported to CHEST the following conflicts of interest: Dr Sterling has received grant money from Pfizer and Oxford/Immunotec. Mr Weinfurter has a sibling who works for and owns stock in Amgen. Drs Horsburgh, Goldberg, Bethel, Chen, Colson, and Hughes, and Mss Hirsch-Moverman, Shrestha-Kuwahara, and Wall have reported that no potential conflicts exist with any companies/ organizations whose products or services may be discussed in this article. Role of sponsor: The findings and conclusions in this report are those of the authors and do not necessarily represent the official position of the Centers for Disease Control and Prevention. Other contributions: We thank the investigators and staff at all the participating TBESC sites: James McAuley, MD, MPH, Judith Beison, Chicago, IL; Frank Wilson, MD, Cheryl LeDoux, MT, MPH, Little Rock, AR; Jennifer Flood, MD, MPH, Sumi Sun, MPH, Berkeley, CA; Hugo Ortega, New York, NY; Randall Reves, MD, MSc, Denver, CO; Henry M. Blumberg, MD, Jane Tapia, BSN, Atlanta, GA; Jessie Wing, MD, Sara Jacobson, MPH, Honolulu HI; Cara Endyke-Doran, RN, BSN, MPH, Baltimore MD; Sue Etkind, RN, MPH, Sharon Sharnprapai, MPH, Boston MA; Wendy Mills Sutherland, MPH, Hodan Guled, MPH, Minneapolis, MN; John Grabau, PhD, MPH, Wilson Miranda, MBBS, MPH, Albany, NY; Rachel Royce, PhD, Carol Dukes-Hamilton, MD, Juani Munoz Sanchez, Durham, NC; Connie Haley, MD, MPH, Tamara Chavez-Lindell, MPH, Original Research
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Nashville, TN; Edward Graviss, PhD, MPH, Smita Chatterjee, MS, Houston, TX; David E. Griffith, MD, Tyler, TX; Michael Kimerling, MD, MPH, Ashutosh Tamhane, MD, DPH, MSPH, Birmingham, AL; Monika Naus, MD, MSc, Mark Fitzgerald, MD, DM, Victoria Cook, MD, Maya Nakajima, BSc, Vancouver, BC; Earl Hershfield, MD, Barbara Roche, BScN, MPH, Winnipeg, MB; Nandini Selvam, MPH, PhD, Newark, NJ; Stephen Weis, MD, Guadalupe Munguia, MD, MPH, Jingsheng Yan, PhD, MPH, Heidi L. Venegas, MS, Sarah Brown, MS, Fort Worth, TX; Mike Jones, MS, Bethesda MD. In addition, we thank Richard O’Brien, MD, for inspiration and encouragement in the development of this study.
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