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Latent tuberculosis infections in hard-to-reach drug using population – detection, prevention and control
Tuberculosis 89 (2009) S1, S41–S45
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Tuberculosis journal homepage: http://intl.elsevierhealth.com/journals/tube
Latent tuberculosis infections in hard-to-reach drug using population – detection, prevention and control Lu-Yu Hwanga, *, Carolyn Z. Grimesa , R. Palmer Beasleya , Edward A. Gravissa,b a Center
for Infectious Diseases, Division of Epidemiology and Disease Control, School of Public Health, University of Texas Health Science Center at Houston, Houston, TX, USA Research Laboratory, Department of Pathology, The Methodist Hospital Research Institute, Houston, TX, USA
b Tuberculosis
article info
summary
Keywords: Latent tuberculosis infection Drug users Interferon gamma release assay QFT T-SPOT
Interferon-gamma release assays (IGRAs) need be evaluated for effectiveness as screening tests for tuberculosis (TB) infection in drug users. These tests have demonstrated improved sensitivity and specificity, but have not been studied in drug users. These one step blood tests are intended to replace the tuberculin skin test (TST), which is difficult to use and requires 48 hour follow-up, so they are expected to be particularly suitable for risk groups, like drug users, in whom follow-up is problematic. Drug users have traditionally been identified as being at increased risk for acquiring TB disease. The results of our pilot study using the TST and simpler and more sensitive interferongamma release assays showed that about 45% of current drug users in Houston tested have at least one test positive for latent tuberculosis infection (LTBI). These preliminary data suggest that there is an important reservoir of LTBI in drug using populations, and the risk of progression to active TB disease with other infections is great. However, LTBI in drug using populations has not been studied in depth and deserves further investigation. We need to evaluate the validity of IGRAs for detection of latent TB infection, the factors associated with LTBI, the incidence and risk for developing active TB disease in drug users and the effectiveness of early treatment of LTBI. We believe that using better tuberculosis screening tools will allow us to more accurately measure the prevalence of latent TB infection and incidence of active TB disease in drug using populations and develop more effective TB prevention and treatment interventions in the community. © 2009 Elsevier Ltd. All rights reserved.
1. Tuberculosis, HIV and drug users The Centers for Disease Control and Prevention (CDC) have identified individuals who are contacts of tuberculosis cases, infected with HIV, homeless, jail or prison detainees, foreignborn, or drug users, both injecting and non-injecting, as having the greatest risk of tuberculosis infection.1 The high risk of TB among drug users is amplified by exposure to other high-risk groups with whom they interact, such as homeless individuals in shelters, incarcerated populations, and those with HIV infection.2–4 A high proportion of TB infections in drug users are latent, but progress to active TB. The prevalence of latent tuberculosis infection in injecting and non-injecting drug users has been estimated at 15–25%,5–7 easily justifying screening and ongoing assessment in this population. The dissemination of HIV among drug users, knowing that HIV is the most potent risk factor for TB disease progression among adults, makes drug users a critical risk-group to target for TB screening.8 Although it has been shown that TB screening and isoniazid (INH) preventive therapy * Corresponding author. Lu-Yu Hwang, MD, Professor of Epidemiology and Disease Control, 1200 Herman Pressler E717, Houston, TX 77030, USA. Tel.: +1 713 500 9382; fax: +1 713 500 9359. E-mail address: [email protected] (L.-Y. Hwang). 1472-9792 /$ – see front matter © 2009 Elsevier Ltd. All rights reserved.
can be successfully implemented in drug abuse treatment and syringe exchange programs,3,9 only 10–20% of drug users participate in any of these programs at any given time.8 The low rate of participation in drug treatment or syringe exchange programs by drug users suggests that other methods should be employed to reach drug users for TB screening and intervention. Drug users with latent tuberculosis are an important reservoir and source of transmission to family and other contacts in their social networks. In a recently studied drug using population in Houston, Texas, we observed a 10% prevalence of HIV, meaning that an estimated 120 HIV-positive drug users would be at risk for TB infection and progression to active disease. Several studies have calculated the incidence of active TB in drug using, HIVpositive, tuberculin skin test (TST)-positive study participants to be 0.73–4.46 per 100 person years, with one study estimating active TB in HIV positives with TST anergy to be 6.6 per 100 person years.10 Out of ten studies, four studies showed active TB case rates over 4 per 100 person years (4.01–4.46),11–14 and another four showed active TB case rates from 1 to 2.4 per 100 person years in populations of recovering and active drug users or homeless populations with drug users.15–18 Overall incidence rates of active TB disease in drug users have been calculated at 1–2 cases per 100 person years.12,13,15,17,18
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Drug users in methadone treatment centers in the above studies were offered INH prophylaxis for latent TB infection (LTBI). However, the isoniazid completion rates for the study participants in these studies remained below 50% (34–49%).12,15,17,18 Reasons for noncompliance were hepatotoxicity, refusal, and loss to followup. Furthermore, some of these studies have demonstrated that drug users may be at such high risk that the development of active TB has occurred even after they completed treatment with INH.12,15,17,19,20 From the Houston Tuberculosis Initiative (HTI) project, under Dr. Ed Graviss, data showed that out of 33 active TB cases, 26 completed INH prophylaxis treatment, which is higher compared to other studies mentioned above. Since these studies focused mostly on injecting drug users in methadone treatment centers, that have been offered INH prophylaxis treatment, the actual incidence of active TB is probably higher among not-in-treatment drug users. Furthermore, sampling in methadone treatment programs would not have accessed important groups of drug users, like crack cocaine smokers, who are likely to be at extremely high risk of TB infection because of smoking in crack houses.
Drug users are exposed not only to tuberculosis, but other serious infectious diseases that may complicate or help facilitate tuberculosis transmission. HIV is probably the most important facilitating infection, but others, including hepatitis B and C and STDs, may also play a role. Some studies have found high prevalence rates of hepatitis C in populations at high risk for tuberculosis, such as prison systems and homeless individuals.26,27 Since drug users are often incarcerated and transient, similar high risks may also be found in drug using cohorts. Yet the relationship of diseases other than HIV to TB infection is far from clear. These diseases have behavioral and network factors in common. This suggests that factors that facilitate the transmission of one are likely to facilitate transmission of others. Hepatitis B and C infections may complicate the treatment course of TB because of the effects that TB medications and hepatitis infections have on the liver, or force the drug user to quit treatment because of side effects of the TB medications. These drug users will continue to be reservoirs for continued transmission. Studies are needed to understand the role of infectious diseases, like hepatitis, for TB transmission and how it might be affected by the structure of drug users’ social networks. 3. Diagnosis of latent TB infection
2. Social networking and infectious disease transmission in drug users A social network paradigm is a powerful tool for studying transmission in diseases having behavioral factors as major determinants. Social network structures enhance or diminish the effect of personal behavior on disease transmission, including tuberculosis.21–23 Open or “fuzzy” networks, defined as members connected to more than one personal network, are associated with the highest risk, while closed personal networks, no members connected to other personal networks, are found to be associated with the lowest risk. Dense areas of social networks are associated with places of social aggregation, providing an environment in which larger numbers of individuals can congregate, e.g., crack houses and shooting galleries. These points of social aggregation are associated with a fuzzy network structure and facilitate an environment of higher levels of risk behavior.24 Since tuberculosis infection may be associated with places and personal relationships, the traditional social networking concept has to be reworked. Outbreak networking is the most appropriate term to be used when trying to track tuberculosis in the community. Traditionally tuberculosis outbreaks have been tracked by contact tracing. Recently, the definition of contact tracing in TB outbreaks has been expanded to include not just persons, but also places and other inanimate/animate objects that facilitate transmission that can be linked together epidemiologically. A Houston population studied by Yaganehdoost et al.,25 and again by Klovdahl et al.,23 revealed an outbreak of tuberculosis that had been previously undetected. By utilizing both social network methods and ethnographic field work coupled with molecular characterization of M. tuberculosis isolates, the source of the outbreak was found to be men who were having sex with men and frequenting a small number of bars. The important factor in identifying the source was place. Once places frequented by those who had tested positive for TB were factored into the social network structure, easily identifiable links between individuals in the outbreak were revealed. By examining connection to place, unknown cases, which could not have been identified using traditional contact tracing, also became evident. This study demonstrates the importance of investigating places TB cases and their contacts frequent as part of a social network structure (location-based surveillance). This is especially true with drug users, as the only link to a TB case may be the crack house or other “hangout” where the exposure to a TB case occurred.
The tuberculin skin test (TST), first described for detecting latent TB infection a century ago by von Pirquet, has long been the standard TB screening test for infection.28 But the TST has low sensitivity and specificity and is difficult to use. The results are compromised by: (1) BCG immunization, routinely administered at birth in most countries of the world; (2) cross-reactivity with atypical mycobacteria infections which may exist in the same communities; (3) boosting phenomenon; (4) high loss of people who fail to return for required 48 hour readings; (5) subjective quantitative measurements, and; (6) multiple causes of immunosuppression.29 Diagnosing LTBI in drug users with the TST is notoriously difficult because drug users are often homeless, transient, and binge users, all of which contribute to low return rates for TST reading. Drug users also have health problems that affect TST interpretation, such as HIV infection. With the TST there are also risks for boosting phenomenon due to the immunologic recognition of TST antigens by the human body after frequent exposures. These problems, along with the rapid expansion of tuberculosis molecular genomics, have led to the development of interferongamma release assays (IGRA), which have significantly improved sensitivity and specificity compared to the TST for active TB disease and for latent TB infection prevalence. An extensive review and meta-analyses of studies of these tests for the diagnosis of latent TB infections was published in March 2007.30 Boosting effects have not been found to interfere with the QuantiFERON® -TB Gold® (QFT-G) test.31 In most populations, the IGRAs are superior to the TST, especially in drug users. However, significant differences between IGRAs and TST have not been seen in all studies or subpopulations.31–36 The CDC recommends that one IGRA blood draw and test could be used in place of the previously recommended two-step TST format for TB infection screening, particularly in high-risk populations, including contact investigations, evaluation of recent immigrants who have had BCG vaccination, and TB screening of health-care workers and others undergoing serial evaluation for M. tuberculosis infection.37 The United States Food and Drug Administration (US FDA) has approved the QuantiFERON® -TB Gold® (QFT-G) (Cellestis Limited, Carnegie, Victoria, Australia), which is an ELISA-based, whole blood, indirect cytokine-based IGRA and also a newly simplified version of the QFT-G, QuantiFERON® -TB Gold In-Tube® (QFT-GIT) which allows for additional transport time needed to the laboratory. A second IGRA test, the T-SPOT.TB (Oxford Immunotec Limited, Abingdon, Oxon, UK) has also been approved by the US FDA,
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and utilizes the same basic mycobacterial antigens as the QFT-G, but employs a different methodology of measuring the interferongamma response known as the enzyme-linked immunospot (ELISPOT). The T-SPOT.TB measures the direct release of interferongamma from the peripheral blood mononuclear cells (PBMCs) and the enumeration of the interferon gamma element released from a stimulated T-lymphocyte. No studies have been reported comparing the two IGRA assays versus TST, in drug using cohorts. Until recently, there had been no studies evaluating IGRA tests of serial specimens and their results in subjects at high risk for tuberculosis. The T-SPOT.TB assay is a simplified variant of the enzyme-linked immunospot (ELISPOT) assay technique for the determination of effector T-cells which secrete interferon-gamma in response to stimulation by antigens specific for M. tuberculosis. There are no published studies of the T-SPOT.TB in the United States or studies using cohorts of drug users anywhere. The published data for T-SPOT.TB come from studies in Europe, Africa and Asia.38–45 The cumulative reported sensitivity for IGRA tests was estimated as approximately 87%, better than TST.30 Accuracy of the test has not been determined per se because the standard being used is the TST, which again has a significant number of false positive results. The specificity of the T-SPOT.TB is estimated to be 92%, a significant improvement over the TST.30 There have been nine studies published on the sensitivity of the QuantiFERON-TB Gold.42–51 The reported cumulative sensitivity for these studies is approximately 80%.30 Accuracy of the test has not been determined because there is no “gold standard”, as the TST produces a significant number of false positives due to cross-reactivity with BCG vaccination and atypical mycobacterium, TST reader errors and the lack of a delayed hypersensitivity response in immunocompromised individuals (specifically HIVseropositive individuals with low CD4 levels). The specificity of the QuantiFERON-TB Gold is about 96%.30 Conclusions by Menzies et al. indicate that the sensitivity of the T-SPOT.TB is superior to the TST or QFT-G/QFT-GIT when using active TB as a surrogate for latent TB infection.30 Sensitivity estimates are difficult because of the lack of a true gold standard for latent TB infection. However, the specificities of the IGRAs are excellent because the BCG vaccine does not interfere with test results, but the effect of exposure to non-tuberculous mycobacteria (infections with M. marinum or M. kansasi) has not been extensively studied with regards to IGRA performance, and will need to be further assessed. Menzies et al. recommend large-scale cohort studies that estimate risk for progression to active disease in persons who have had TST and IGRA, especially in persons with discordant reactions. No link to any “gold standard” for IGRA results is a legitimate concern, but in fact, the TST is the standard of practice. The problem is the same as that for any new test irrespective of whether a socalled “gold standard” exists or not. Ultimately any test must be evaluated against the biology, clinical realities, and epidemiology of the problem. The CDC has recommended that the QuantiFERON-TB Gold (QFT-G) be used under any condition that a TST is used,37 but the practicality of using QFT in public health practice as a screening tool in the US is currently being debated. At least in Houston, the HDHHS, Bureau of TB Control currently does not utilize QFT except under the strictest conditions, including allergic responses to the PPD antigenic solution. As part of our latent TB infection (LTBI) definition, any HIV-negative individual with a TST that is positive is considered positive for LTBI, as long as an IGRA is also positive. Under the clinical conditions that an IGRA is positive and the TST is negative then the patient (participant) would be considered to have LTBI. To be considered free of LTBI the patient (participant) would need to be negative on both the IGRA and the TST. In HIVseropositive (and immunocompromised) individuals a physician’s clinical impression plays a major role in the determination of LTBI,
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inherent with HIV T-cell depletion, where the number of available memory cells and thus the potential cells for interferon gamma release are reduced. CD4 levels below 200 mg/dl can cause a TH1 anergic response and little if any immunological response. Thus, the individuals would present as a negative IGRA and/or TST, but be truly infected with M. tuberculosis. Additional data have shown that the T-SPOT.TB assay may be more sensitive and specific in the immunocompromised individual than the QFT, although there may be moderate agreement between the TST and T-SPOT.TB and the TST with the QFT.52 A recent study from San Francisco that evaluated and screened 818 persons using the QFT to evaluate LTBI in TB clinics over a 16-month period found 7 of 20 TB suspects were diagnosed as TB cases within 90 days of a positive IGRA.53 However, a study by Rangaka found little agreement between the interferon gamma release assay (QFT and T-SPOT.TB) and the Mantoux TST in HIV seropositive individuals, highlighting the need for prospective studies to determine which test may predict subsequent risk of tuberculosis.38 4. Rationale for proposing studies among drug users in Houston Houston, Texas, is the nation’s fourth largest city and according to the CDC was in the top 10 US cities for highest tuberculosis rates in 2006 (9.1/100,000) with 29% of the TB cases occurring in African Americans. Over the past three years, the greater Houston area had an average tuberculosis rate that is 1.5–2 times higher than the average Texas tuberculosis rate. The Texas Department of State Health Services indicates that 18% of the tuberculosis cases in 2005 had HIV or AIDS, 9% were non-injection drug users, 0.5% were injection drug users and 11% had been in jail within the past two years (www.dshs.state.tx.us/idcu/disease/tb/statistics, accessed October 2008). Our pilot study reflected these statistics. The majority of participants were African American (75%), male (77%), crack cocaine users (91%), or had been incarcerated (66%).54 Over one third was positive for LTBI.54 The Houston Tuberculosis Initiative (HTI) project, directed by Dr. Graviss, supports the rationale for studying African-American drug users as a high-risk population for TB. According to HTI statistics, 53% of the tuberculosis cases were crack cocaine smokers, and 26% of these tuberculosis cases had a history of injection drug use. In summary, African-American drug users in Houston, Texas, are a high-risk population that would be appropriate for targeting tuberculosis screening and prevention. The Houston area ranked 8th among US cities in cumulative AIDS cases reported through 2006. The number of AIDS cases among African American and Hispanic Houstonians now outnumbers that among Whites. The reason for the change in focus of the epidemic in Houston from men who have sex with men to African Americans is related to the use of crack cocaine. Our own studies of the prevalence of STD/HIV among injection drug users and crack smokers in Houston support this conclusion.55–57 Houston thus constitutes a major HIV epicenter both in terms of the number of African-American drug users already infected with HIV and the number of those at risk for contracting and transmitting the virus, and tuberculosis. 5. Significance We have begun to undertake the first large-scale prospective study of IGRAs (QFT-GIT and T-SPOT.TB) for the detection of LTBI in a drug using cohort, and compare the IGRA performance to the tuberculin skin test (TST), the best current standard test available. It will evaluate the effectiveness of these new tests in drug users, notably whether IGRAs will detect TB infections missed by the standard TST, thus leading to earlier detection of infections, reduction of early transmission and fewer infections
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which progress to clinical disease. The FDA has licensed the QFT-G, QFT-GIT, and T-SPOT.TB. The CDC has already recommended QFT-G as a replacement for TST in most circumstances, including contact investigations, evaluation of recent immigrants who have had BCG vaccination, and TB screening of health-care workers and others undergoing serial evaluation for M. tuberculosis infection. This study will help determine whether that list should be expanded to include drug users, as well as to determine if current cut points used for the QFT-GIT or T-SPOT.TB are applicable to drug using populations. Finally, earlier diagnosis and treatment of TB may be an important part of the strategy to minimize the development and spread of extensively drug resistant TB (XDR-TB) which is becoming an increasing problem and potentially a major health threat. We are optimistic about achieving the goal of this project because our preliminary data suggest that these tests will improve early case detection and, perhaps even more important, a higher rate of test completion. The newly available IGRA tests (QFT-GIT and T-SPOT.TB) and their ability to predict progression to active TB disease have not been effectively studied in high-risk groups with high rates of latent TB infection. If we have a better screening and diagnostic tool for latent and active TB in drug users we can implement more effective TB prevention and treatment programs in the community. Acknowledgements: This project was supported in part by a grant from the National Institute on Drug Abuse, R01 DA 017505. The research and opinions herein are solely those of the authors. Competing interests: Dr. Edward Graviss has served as a consultant to both Oxford Immunotec, Ltd. and Cellestis, Ltd, and portions of this work have been sponsored by Oxford Immunotec, Ltd. Remaining authors of this manuscript do not have commercial or any other associations that might pose a conflict of interest. References 1. Guidelines for the investigation of contacts of persons with infectious tuberculosis. Recommendations from the National Tuberculosis Controllers Association and CDC. MMWR Recomm Rep 2005;54:1–47. 2. Reichman LB, Felton CP, Edsall JR. Drug dependence, a possible new risk factor for tuberculosis disease. Arch Intern Med 1979;139:337–9. 3. Selwyn PA, Hartel D, Lewis VA, Schoenbaum EE, Vermund SH, Klein RS, et al. A prospective study of the risk of tuberculosis among intravenous drug users with human immunodeficiency virus infection. N Engl J Med 1989;320:545–50. 4. Perlman DC, Salomon N, Perkins MP, Yancovitz S, Paone D, Des Jarlais DC. Tuberculosis in drug users. Clin Infect Dis 1995;21:1253–64. 5. Malotte CK, Hollingshead JR, Rhodes F. Monetary versus nonmonetary incentives for TB skin test reading among drug users. Am J Prev Med 1999;16:182–8. 6. Durante AJ, Selwyn PA, O’Connor PG. Risk factors for and knowledge of Mycobacterium tuberculosis infection among drug users in substance abuse treatment. Addiction 1998;93:1393–401. 7. Howard AA, Klein RS, Schoenbaum EE, Gourevitch MN. Crack cocaine use and other risk factors for tuberculin positivity in drug users. Clin Infect Dis 2002;35: 1183–90. 8. Salomon N, Perlman DC, Friedmann P, Ziluck V, Des Jarlais DC. Prevalence and risk factors for positive tuberculin skin tests among active drug users at a syringe exchange program. Int J Tuberc Lung Dis 2000;4:47–54. 9. Gourevitch MN, Wasserman W, Panero MS, Selwyn PA. Successful adherence to observed prophylaxis and treatment of tuberculosis among drug users in a methadone program. J Addict Dis 1996;15:93–104. 10. Selwyn PA, Sckell BM, Alcabes P, Friedland GH, Klein RS, Schoenbaum EE. High risk of active tuberculosis in HIV-infected drug users with cutaneous anergy. JAMA 1992;268:504–9. 11. Golub JE, Saraceni V, Cavalcante SC, Pachecho AG, Moulton LH, King BS, et al. The impact of antiretroviral therapy and isoniazid preventive therapy on tuberculosis incidence in HIV-infected patients in Rio de Janeiro, Brazil. AIDS 2007;21:1441–8. 12. Jansa JM, Serrano J, Cayla JA, Vidal R, Ocana I, Espanol T. Influence of the human immunodeficiency virus in the incidence of tuberculosis in a cohort of intravenous drug users: effectiveness of anti-tuberculosis chemoprophylaxis. Int J Tuberc Lung Dis 1998;2:140–6. 13. Klein RS, Gourevitch MN, Teeter R, Schoenbaum EE. The incidence of tuberculosis in drug users with small tuberculin reaction sizes. Int J Tuberc Lung Dis 2001;5: 707–11.
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48. Kang YA, Lee HW, Yoon HI, Cho B, Han SK, Shim YS, et al. Discrepancy between the tuberculin skin test and the whole-blood interferon gamma assay for the diagnosis of latent tuberculosis infection in an intermediate tuberculosis-burden country. JAMA 2005;293:2756–61. 49. Connell TG, Curtis N, Ranganathan SC, Buttery JP. Performance of a whole blood interferon gamma assay for detecting latent infection with Mycobacterium tuberculosis in children. Thorax 2006;61:616–20. 50. Brock I, Munk ME, Kok-Jensen A, Andersen P. Performance of whole blood IFNgamma test for tuberculosis diagnosis based on PPD or the specific antigens ESAT-6 and CFP-10. Int J Tuberc Lung Dis 2001;5:462–7. 51. Ferrara G, Losi M, Meacci M, Meccugni B, Piro R, Roversi P, et al. Routine hospital use of a new commercial whole blood interferon-gamma assay for the diagnosis of tuberculosis infection. Am J Respir Crit Care Med 2005;172:631–5. 52. Mandalakas AM, Hesseling AC, Chegou NN, Kirchner HL, Zhu X, Marais BJ, et al. High level of discordant IGRA results in HIV-infected adults and children. Int J Tuberc Lung Dis 2008;12:417–23. 53. Dewan PK, Grinsdale J, Liska S, Wong E, Fallstad R, Kawamura LM. Feasibility, acceptability, and cost of tuberculosis testing by whole-blood interferon-gamma assay. BMC Infect Dis 2006;6:47. 54. Grimes CZ, Hwang LY, Williams ML, Austin CM, Graviss EA. Tuberculosis infection in drug users: interferon-gamma release assay performance. Int J Tuberc Lung Dis 2007;11:1183–9. 55. Williams ML, Elwood WN, Weatherby NL, Bowen A, Zhao Z, Saunders L, et al. An assessment of the risks of syphilis and HIV infection among a sample of not-in-treatment drug users in Houston, Texas. AIDS Care 1996;8:671–82. 56. Ross MW, Hwang LY, Leonard L, Teng M, Duncan L. Sexual behaviour, STDs and drug use in a crack house population. Int J STD AIDS 1999;10:224–30. 57. Hwang LY, Ross MW, Zack C, Bull L, Rickman K, Holleman M. Prevalence of sexually transmitted infections and associated risk factors among populations of drug abusers. Clin Infect Dis 2000;31:920–6.
Contents lists available at ScienceDirect
Tuberculosis journal homepage: http://intl.elsevierhealth.com/journals/tube
Latent tuberculosis infections in hard-to-reach drug using population – detection, prevention and control Lu-Yu Hwanga, *, Carolyn Z. Grimesa , R. Palmer Beasleya , Edward A. Gravissa,b a Center
for Infectious Diseases, Division of Epidemiology and Disease Control, School of Public Health, University of Texas Health Science Center at Houston, Houston, TX, USA Research Laboratory, Department of Pathology, The Methodist Hospital Research Institute, Houston, TX, USA
b Tuberculosis
article info
summary
Keywords: Latent tuberculosis infection Drug users Interferon gamma release assay QFT T-SPOT
Interferon-gamma release assays (IGRAs) need be evaluated for effectiveness as screening tests for tuberculosis (TB) infection in drug users. These tests have demonstrated improved sensitivity and specificity, but have not been studied in drug users. These one step blood tests are intended to replace the tuberculin skin test (TST), which is difficult to use and requires 48 hour follow-up, so they are expected to be particularly suitable for risk groups, like drug users, in whom follow-up is problematic. Drug users have traditionally been identified as being at increased risk for acquiring TB disease. The results of our pilot study using the TST and simpler and more sensitive interferongamma release assays showed that about 45% of current drug users in Houston tested have at least one test positive for latent tuberculosis infection (LTBI). These preliminary data suggest that there is an important reservoir of LTBI in drug using populations, and the risk of progression to active TB disease with other infections is great. However, LTBI in drug using populations has not been studied in depth and deserves further investigation. We need to evaluate the validity of IGRAs for detection of latent TB infection, the factors associated with LTBI, the incidence and risk for developing active TB disease in drug users and the effectiveness of early treatment of LTBI. We believe that using better tuberculosis screening tools will allow us to more accurately measure the prevalence of latent TB infection and incidence of active TB disease in drug using populations and develop more effective TB prevention and treatment interventions in the community. © 2009 Elsevier Ltd. All rights reserved.
1. Tuberculosis, HIV and drug users The Centers for Disease Control and Prevention (CDC) have identified individuals who are contacts of tuberculosis cases, infected with HIV, homeless, jail or prison detainees, foreignborn, or drug users, both injecting and non-injecting, as having the greatest risk of tuberculosis infection.1 The high risk of TB among drug users is amplified by exposure to other high-risk groups with whom they interact, such as homeless individuals in shelters, incarcerated populations, and those with HIV infection.2–4 A high proportion of TB infections in drug users are latent, but progress to active TB. The prevalence of latent tuberculosis infection in injecting and non-injecting drug users has been estimated at 15–25%,5–7 easily justifying screening and ongoing assessment in this population. The dissemination of HIV among drug users, knowing that HIV is the most potent risk factor for TB disease progression among adults, makes drug users a critical risk-group to target for TB screening.8 Although it has been shown that TB screening and isoniazid (INH) preventive therapy * Corresponding author. Lu-Yu Hwang, MD, Professor of Epidemiology and Disease Control, 1200 Herman Pressler E717, Houston, TX 77030, USA. Tel.: +1 713 500 9382; fax: +1 713 500 9359. E-mail address: [email protected] (L.-Y. Hwang). 1472-9792 /$ – see front matter © 2009 Elsevier Ltd. All rights reserved.
can be successfully implemented in drug abuse treatment and syringe exchange programs,3,9 only 10–20% of drug users participate in any of these programs at any given time.8 The low rate of participation in drug treatment or syringe exchange programs by drug users suggests that other methods should be employed to reach drug users for TB screening and intervention. Drug users with latent tuberculosis are an important reservoir and source of transmission to family and other contacts in their social networks. In a recently studied drug using population in Houston, Texas, we observed a 10% prevalence of HIV, meaning that an estimated 120 HIV-positive drug users would be at risk for TB infection and progression to active disease. Several studies have calculated the incidence of active TB in drug using, HIVpositive, tuberculin skin test (TST)-positive study participants to be 0.73–4.46 per 100 person years, with one study estimating active TB in HIV positives with TST anergy to be 6.6 per 100 person years.10 Out of ten studies, four studies showed active TB case rates over 4 per 100 person years (4.01–4.46),11–14 and another four showed active TB case rates from 1 to 2.4 per 100 person years in populations of recovering and active drug users or homeless populations with drug users.15–18 Overall incidence rates of active TB disease in drug users have been calculated at 1–2 cases per 100 person years.12,13,15,17,18
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Drug users in methadone treatment centers in the above studies were offered INH prophylaxis for latent TB infection (LTBI). However, the isoniazid completion rates for the study participants in these studies remained below 50% (34–49%).12,15,17,18 Reasons for noncompliance were hepatotoxicity, refusal, and loss to followup. Furthermore, some of these studies have demonstrated that drug users may be at such high risk that the development of active TB has occurred even after they completed treatment with INH.12,15,17,19,20 From the Houston Tuberculosis Initiative (HTI) project, under Dr. Ed Graviss, data showed that out of 33 active TB cases, 26 completed INH prophylaxis treatment, which is higher compared to other studies mentioned above. Since these studies focused mostly on injecting drug users in methadone treatment centers, that have been offered INH prophylaxis treatment, the actual incidence of active TB is probably higher among not-in-treatment drug users. Furthermore, sampling in methadone treatment programs would not have accessed important groups of drug users, like crack cocaine smokers, who are likely to be at extremely high risk of TB infection because of smoking in crack houses.
Drug users are exposed not only to tuberculosis, but other serious infectious diseases that may complicate or help facilitate tuberculosis transmission. HIV is probably the most important facilitating infection, but others, including hepatitis B and C and STDs, may also play a role. Some studies have found high prevalence rates of hepatitis C in populations at high risk for tuberculosis, such as prison systems and homeless individuals.26,27 Since drug users are often incarcerated and transient, similar high risks may also be found in drug using cohorts. Yet the relationship of diseases other than HIV to TB infection is far from clear. These diseases have behavioral and network factors in common. This suggests that factors that facilitate the transmission of one are likely to facilitate transmission of others. Hepatitis B and C infections may complicate the treatment course of TB because of the effects that TB medications and hepatitis infections have on the liver, or force the drug user to quit treatment because of side effects of the TB medications. These drug users will continue to be reservoirs for continued transmission. Studies are needed to understand the role of infectious diseases, like hepatitis, for TB transmission and how it might be affected by the structure of drug users’ social networks. 3. Diagnosis of latent TB infection
2. Social networking and infectious disease transmission in drug users A social network paradigm is a powerful tool for studying transmission in diseases having behavioral factors as major determinants. Social network structures enhance or diminish the effect of personal behavior on disease transmission, including tuberculosis.21–23 Open or “fuzzy” networks, defined as members connected to more than one personal network, are associated with the highest risk, while closed personal networks, no members connected to other personal networks, are found to be associated with the lowest risk. Dense areas of social networks are associated with places of social aggregation, providing an environment in which larger numbers of individuals can congregate, e.g., crack houses and shooting galleries. These points of social aggregation are associated with a fuzzy network structure and facilitate an environment of higher levels of risk behavior.24 Since tuberculosis infection may be associated with places and personal relationships, the traditional social networking concept has to be reworked. Outbreak networking is the most appropriate term to be used when trying to track tuberculosis in the community. Traditionally tuberculosis outbreaks have been tracked by contact tracing. Recently, the definition of contact tracing in TB outbreaks has been expanded to include not just persons, but also places and other inanimate/animate objects that facilitate transmission that can be linked together epidemiologically. A Houston population studied by Yaganehdoost et al.,25 and again by Klovdahl et al.,23 revealed an outbreak of tuberculosis that had been previously undetected. By utilizing both social network methods and ethnographic field work coupled with molecular characterization of M. tuberculosis isolates, the source of the outbreak was found to be men who were having sex with men and frequenting a small number of bars. The important factor in identifying the source was place. Once places frequented by those who had tested positive for TB were factored into the social network structure, easily identifiable links between individuals in the outbreak were revealed. By examining connection to place, unknown cases, which could not have been identified using traditional contact tracing, also became evident. This study demonstrates the importance of investigating places TB cases and their contacts frequent as part of a social network structure (location-based surveillance). This is especially true with drug users, as the only link to a TB case may be the crack house or other “hangout” where the exposure to a TB case occurred.
The tuberculin skin test (TST), first described for detecting latent TB infection a century ago by von Pirquet, has long been the standard TB screening test for infection.28 But the TST has low sensitivity and specificity and is difficult to use. The results are compromised by: (1) BCG immunization, routinely administered at birth in most countries of the world; (2) cross-reactivity with atypical mycobacteria infections which may exist in the same communities; (3) boosting phenomenon; (4) high loss of people who fail to return for required 48 hour readings; (5) subjective quantitative measurements, and; (6) multiple causes of immunosuppression.29 Diagnosing LTBI in drug users with the TST is notoriously difficult because drug users are often homeless, transient, and binge users, all of which contribute to low return rates for TST reading. Drug users also have health problems that affect TST interpretation, such as HIV infection. With the TST there are also risks for boosting phenomenon due to the immunologic recognition of TST antigens by the human body after frequent exposures. These problems, along with the rapid expansion of tuberculosis molecular genomics, have led to the development of interferongamma release assays (IGRA), which have significantly improved sensitivity and specificity compared to the TST for active TB disease and for latent TB infection prevalence. An extensive review and meta-analyses of studies of these tests for the diagnosis of latent TB infections was published in March 2007.30 Boosting effects have not been found to interfere with the QuantiFERON® -TB Gold® (QFT-G) test.31 In most populations, the IGRAs are superior to the TST, especially in drug users. However, significant differences between IGRAs and TST have not been seen in all studies or subpopulations.31–36 The CDC recommends that one IGRA blood draw and test could be used in place of the previously recommended two-step TST format for TB infection screening, particularly in high-risk populations, including contact investigations, evaluation of recent immigrants who have had BCG vaccination, and TB screening of health-care workers and others undergoing serial evaluation for M. tuberculosis infection.37 The United States Food and Drug Administration (US FDA) has approved the QuantiFERON® -TB Gold® (QFT-G) (Cellestis Limited, Carnegie, Victoria, Australia), which is an ELISA-based, whole blood, indirect cytokine-based IGRA and also a newly simplified version of the QFT-G, QuantiFERON® -TB Gold In-Tube® (QFT-GIT) which allows for additional transport time needed to the laboratory. A second IGRA test, the T-SPOT.TB (Oxford Immunotec Limited, Abingdon, Oxon, UK) has also been approved by the US FDA,
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and utilizes the same basic mycobacterial antigens as the QFT-G, but employs a different methodology of measuring the interferongamma response known as the enzyme-linked immunospot (ELISPOT). The T-SPOT.TB measures the direct release of interferongamma from the peripheral blood mononuclear cells (PBMCs) and the enumeration of the interferon gamma element released from a stimulated T-lymphocyte. No studies have been reported comparing the two IGRA assays versus TST, in drug using cohorts. Until recently, there had been no studies evaluating IGRA tests of serial specimens and their results in subjects at high risk for tuberculosis. The T-SPOT.TB assay is a simplified variant of the enzyme-linked immunospot (ELISPOT) assay technique for the determination of effector T-cells which secrete interferon-gamma in response to stimulation by antigens specific for M. tuberculosis. There are no published studies of the T-SPOT.TB in the United States or studies using cohorts of drug users anywhere. The published data for T-SPOT.TB come from studies in Europe, Africa and Asia.38–45 The cumulative reported sensitivity for IGRA tests was estimated as approximately 87%, better than TST.30 Accuracy of the test has not been determined per se because the standard being used is the TST, which again has a significant number of false positive results. The specificity of the T-SPOT.TB is estimated to be 92%, a significant improvement over the TST.30 There have been nine studies published on the sensitivity of the QuantiFERON-TB Gold.42–51 The reported cumulative sensitivity for these studies is approximately 80%.30 Accuracy of the test has not been determined because there is no “gold standard”, as the TST produces a significant number of false positives due to cross-reactivity with BCG vaccination and atypical mycobacterium, TST reader errors and the lack of a delayed hypersensitivity response in immunocompromised individuals (specifically HIVseropositive individuals with low CD4 levels). The specificity of the QuantiFERON-TB Gold is about 96%.30 Conclusions by Menzies et al. indicate that the sensitivity of the T-SPOT.TB is superior to the TST or QFT-G/QFT-GIT when using active TB as a surrogate for latent TB infection.30 Sensitivity estimates are difficult because of the lack of a true gold standard for latent TB infection. However, the specificities of the IGRAs are excellent because the BCG vaccine does not interfere with test results, but the effect of exposure to non-tuberculous mycobacteria (infections with M. marinum or M. kansasi) has not been extensively studied with regards to IGRA performance, and will need to be further assessed. Menzies et al. recommend large-scale cohort studies that estimate risk for progression to active disease in persons who have had TST and IGRA, especially in persons with discordant reactions. No link to any “gold standard” for IGRA results is a legitimate concern, but in fact, the TST is the standard of practice. The problem is the same as that for any new test irrespective of whether a socalled “gold standard” exists or not. Ultimately any test must be evaluated against the biology, clinical realities, and epidemiology of the problem. The CDC has recommended that the QuantiFERON-TB Gold (QFT-G) be used under any condition that a TST is used,37 but the practicality of using QFT in public health practice as a screening tool in the US is currently being debated. At least in Houston, the HDHHS, Bureau of TB Control currently does not utilize QFT except under the strictest conditions, including allergic responses to the PPD antigenic solution. As part of our latent TB infection (LTBI) definition, any HIV-negative individual with a TST that is positive is considered positive for LTBI, as long as an IGRA is also positive. Under the clinical conditions that an IGRA is positive and the TST is negative then the patient (participant) would be considered to have LTBI. To be considered free of LTBI the patient (participant) would need to be negative on both the IGRA and the TST. In HIVseropositive (and immunocompromised) individuals a physician’s clinical impression plays a major role in the determination of LTBI,
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inherent with HIV T-cell depletion, where the number of available memory cells and thus the potential cells for interferon gamma release are reduced. CD4 levels below 200 mg/dl can cause a TH1 anergic response and little if any immunological response. Thus, the individuals would present as a negative IGRA and/or TST, but be truly infected with M. tuberculosis. Additional data have shown that the T-SPOT.TB assay may be more sensitive and specific in the immunocompromised individual than the QFT, although there may be moderate agreement between the TST and T-SPOT.TB and the TST with the QFT.52 A recent study from San Francisco that evaluated and screened 818 persons using the QFT to evaluate LTBI in TB clinics over a 16-month period found 7 of 20 TB suspects were diagnosed as TB cases within 90 days of a positive IGRA.53 However, a study by Rangaka found little agreement between the interferon gamma release assay (QFT and T-SPOT.TB) and the Mantoux TST in HIV seropositive individuals, highlighting the need for prospective studies to determine which test may predict subsequent risk of tuberculosis.38 4. Rationale for proposing studies among drug users in Houston Houston, Texas, is the nation’s fourth largest city and according to the CDC was in the top 10 US cities for highest tuberculosis rates in 2006 (9.1/100,000) with 29% of the TB cases occurring in African Americans. Over the past three years, the greater Houston area had an average tuberculosis rate that is 1.5–2 times higher than the average Texas tuberculosis rate. The Texas Department of State Health Services indicates that 18% of the tuberculosis cases in 2005 had HIV or AIDS, 9% were non-injection drug users, 0.5% were injection drug users and 11% had been in jail within the past two years (www.dshs.state.tx.us/idcu/disease/tb/statistics, accessed October 2008). Our pilot study reflected these statistics. The majority of participants were African American (75%), male (77%), crack cocaine users (91%), or had been incarcerated (66%).54 Over one third was positive for LTBI.54 The Houston Tuberculosis Initiative (HTI) project, directed by Dr. Graviss, supports the rationale for studying African-American drug users as a high-risk population for TB. According to HTI statistics, 53% of the tuberculosis cases were crack cocaine smokers, and 26% of these tuberculosis cases had a history of injection drug use. In summary, African-American drug users in Houston, Texas, are a high-risk population that would be appropriate for targeting tuberculosis screening and prevention. The Houston area ranked 8th among US cities in cumulative AIDS cases reported through 2006. The number of AIDS cases among African American and Hispanic Houstonians now outnumbers that among Whites. The reason for the change in focus of the epidemic in Houston from men who have sex with men to African Americans is related to the use of crack cocaine. Our own studies of the prevalence of STD/HIV among injection drug users and crack smokers in Houston support this conclusion.55–57 Houston thus constitutes a major HIV epicenter both in terms of the number of African-American drug users already infected with HIV and the number of those at risk for contracting and transmitting the virus, and tuberculosis. 5. Significance We have begun to undertake the first large-scale prospective study of IGRAs (QFT-GIT and T-SPOT.TB) for the detection of LTBI in a drug using cohort, and compare the IGRA performance to the tuberculin skin test (TST), the best current standard test available. It will evaluate the effectiveness of these new tests in drug users, notably whether IGRAs will detect TB infections missed by the standard TST, thus leading to earlier detection of infections, reduction of early transmission and fewer infections
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which progress to clinical disease. The FDA has licensed the QFT-G, QFT-GIT, and T-SPOT.TB. The CDC has already recommended QFT-G as a replacement for TST in most circumstances, including contact investigations, evaluation of recent immigrants who have had BCG vaccination, and TB screening of health-care workers and others undergoing serial evaluation for M. tuberculosis infection. This study will help determine whether that list should be expanded to include drug users, as well as to determine if current cut points used for the QFT-GIT or T-SPOT.TB are applicable to drug using populations. Finally, earlier diagnosis and treatment of TB may be an important part of the strategy to minimize the development and spread of extensively drug resistant TB (XDR-TB) which is becoming an increasing problem and potentially a major health threat. We are optimistic about achieving the goal of this project because our preliminary data suggest that these tests will improve early case detection and, perhaps even more important, a higher rate of test completion. The newly available IGRA tests (QFT-GIT and T-SPOT.TB) and their ability to predict progression to active TB disease have not been effectively studied in high-risk groups with high rates of latent TB infection. If we have a better screening and diagnostic tool for latent and active TB in drug users we can implement more effective TB prevention and treatment programs in the community. Acknowledgements: This project was supported in part by a grant from the National Institute on Drug Abuse, R01 DA 017505. The research and opinions herein are solely those of the authors. Competing interests: Dr. Edward Graviss has served as a consultant to both Oxford Immunotec, Ltd. and Cellestis, Ltd, and portions of this work have been sponsored by Oxford Immunotec, Ltd. Remaining authors of this manuscript do not have commercial or any other associations that might pose a conflict of interest. References 1. Guidelines for the investigation of contacts of persons with infectious tuberculosis. Recommendations from the National Tuberculosis Controllers Association and CDC. MMWR Recomm Rep 2005;54:1–47. 2. Reichman LB, Felton CP, Edsall JR. Drug dependence, a possible new risk factor for tuberculosis disease. Arch Intern Med 1979;139:337–9. 3. Selwyn PA, Hartel D, Lewis VA, Schoenbaum EE, Vermund SH, Klein RS, et al. A prospective study of the risk of tuberculosis among intravenous drug users with human immunodeficiency virus infection. N Engl J Med 1989;320:545–50. 4. Perlman DC, Salomon N, Perkins MP, Yancovitz S, Paone D, Des Jarlais DC. Tuberculosis in drug users. Clin Infect Dis 1995;21:1253–64. 5. Malotte CK, Hollingshead JR, Rhodes F. Monetary versus nonmonetary incentives for TB skin test reading among drug users. Am J Prev Med 1999;16:182–8. 6. Durante AJ, Selwyn PA, O’Connor PG. Risk factors for and knowledge of Mycobacterium tuberculosis infection among drug users in substance abuse treatment. Addiction 1998;93:1393–401. 7. Howard AA, Klein RS, Schoenbaum EE, Gourevitch MN. Crack cocaine use and other risk factors for tuberculin positivity in drug users. Clin Infect Dis 2002;35: 1183–90. 8. Salomon N, Perlman DC, Friedmann P, Ziluck V, Des Jarlais DC. Prevalence and risk factors for positive tuberculin skin tests among active drug users at a syringe exchange program. Int J Tuberc Lung Dis 2000;4:47–54. 9. Gourevitch MN, Wasserman W, Panero MS, Selwyn PA. Successful adherence to observed prophylaxis and treatment of tuberculosis among drug users in a methadone program. J Addict Dis 1996;15:93–104. 10. Selwyn PA, Sckell BM, Alcabes P, Friedland GH, Klein RS, Schoenbaum EE. High risk of active tuberculosis in HIV-infected drug users with cutaneous anergy. JAMA 1992;268:504–9. 11. Golub JE, Saraceni V, Cavalcante SC, Pachecho AG, Moulton LH, King BS, et al. The impact of antiretroviral therapy and isoniazid preventive therapy on tuberculosis incidence in HIV-infected patients in Rio de Janeiro, Brazil. AIDS 2007;21:1441–8. 12. Jansa JM, Serrano J, Cayla JA, Vidal R, Ocana I, Espanol T. Influence of the human immunodeficiency virus in the incidence of tuberculosis in a cohort of intravenous drug users: effectiveness of anti-tuberculosis chemoprophylaxis. Int J Tuberc Lung Dis 1998;2:140–6. 13. Klein RS, Gourevitch MN, Teeter R, Schoenbaum EE. The incidence of tuberculosis in drug users with small tuberculin reaction sizes. Int J Tuberc Lung Dis 2001;5: 707–11.
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