Int J STD AIDS 2008;19:843-847
doi:10.1258/ijsa.2008.008123
© 2008 Royal Society of Medicine Press
Original research articles |
Assessment of risk for pulmonary tuberculosis after non-reactive tuberculin skin testing among patients with HIV infection in a resource-limited setting
T Khawcharoenporn MD *,
A Apisarnthanarak MD * and
L M Mundy MD 
* Division of Infectious Diseases, Faculty of Medicine, Thammasart University Hospital, Pratumthani 12120, Thailand;
Saint Louis University School of Public Health, St Louis, MO, USA
Correspondence to: Dr Anucha Apisarnthanarak Email: anapisarn{at}yahoo.com
 |
Summary
|
|---|
A cross-sectional study of 350 patients with HIV-1 infection
was conducted to identify risks for pulmonary
Mycobacterium tuberculosis (TB) after non-reactive two-step tuberculin skin
tests (TST). Among 219 patients (62.6%) with non-reactive TST,
independent risks for active pulmonary TB were prior known TB
exposure (adjusted odds ratio [aOR] = 16.00, 95% confidence
interval [CI] = 2.00–26.36,
P = 0.008), CD4 <100 cells/µL
(aOR = 2.50, 95% CI = 1.30–6.50,
P = 0.04) and less than
secondary-school education (aOR = 2.60, 95% CI = 1.50–6.90,
P = 0.02). Our findings suggest that further diagnostic work-up
for pulmonary TB is warranted among patients with HIV infection,
non-reactive TSTs and either prior known TB exposure, CD4 counts
<100 cells/µL or limited formal education.
Key Words: risk factors • tuberculin skin test • human immunodeficiency virus • tuberculosis • resource-limited setting
|
INTRODUCTION
|
|---|
Risks and transmission dynamics for
Mycobacterium tuberculosis (TB) in persons with HIV-1 infection are complex. Persons with
HIV infection are more susceptible to both new TB infection
with disease progression and to reactivation of latent infection.
1,2 Significantly lower TB treatment success and higher mortality
have been reported worldwide in persons with HIV infection compared
with persons without HIV infection.
3 While screening tests for
TB are recommended in HIV clinical care, and the tuberculin
skin test (TST) has been widely used, studies from TB endemic
areas reported TST sensitivities of 19–74% in persons
with HIV infection compared with 51–91% in persons without
HIV infection.
2,4–9 Presumably, TST variability is due
to reduced delayed-type hypersensitivity responses, if not anergy,
among persons with advanced HIV infection and the AIDS. While
repeat TST is recommended in patients who commence antiretroviral
(ARV) regimens and achieve immune restoration, a paucity of
recommendations exists in confirmatory testing of TB in non-reactive
TST patients independent of ARV drug initiation.
4–6 Thus,
non-reactive TST results are not sufficient to exclude TB, yet
risk factors for active TB in persons with HIV/AIDS and non-reactive
TST are not well-characterized.
10–12
In Thailand, the incidence of TB has been estimated to be 3000 per 100,000 persons with HIV/AIDS compared with 164 cases per 100,000 persons in the general population.13,14 While TB mortality has been difficult to estimate, one Thai study reported one-, two-, and three-year crude mortality at 56%, 80% and 91%, respectively, in ARV-naïve patients with HIV/AIDS compared with 4%, 6% and 12% mortality in patients who were prescribed ARV therapy.15 These results implicate the clinical relevance of secure ARV drug access and delivery, along with early detection of TB. If the two-step TST is reactive, further clinical evaluation is warranted along with medical decisions regarding concomitant treatment of HIV and TB according to international guidelines.4–6,16,17 Given the limited guidance and justification for confirmatory testing of TB after a non-reactive TST, independent of ARV drug initiation, we conducted a cross-sectional study to assess risk factors for active pulmonary TB in patients with HIV infection and non-reactive, two-step TST.
|
MATERIALS AND METHODS
|
|---|
Study design, sample, and site
A cross-sectional study was conducted for HIV-infected adult patients aged 
15 years and in established care at the HIV Clinic of Thammasart University Hospital, Thailand, between 1 January 2003 and 31 December 2006. The hospital is a tertiary care, 500-bed referral hospital in central Thailand with an estimated 450 HIV-related hospital admissions and 3850 HIV-related outpatient visits annually.18,19 All eligible patients in established care who consented to study participation were included. Exclusion criteria included history of TB infection prior to the study entry. Of note, routine childhood immunization in Thailand includes Bacillus Calmette-Guérin (BCG) via standard protocol within the first six months of life.20 This study was approved by the Institutional Review Board of Thammasart University Hospital.
Study protocol and definitions
All eligible patients' charts were reviewed by two independent reviewers. Data regarding history of BCG vaccination, TST diameter and CD4 counts were obtained. The first-step TST and chest radiograph were routinely performed at the initial study visit. The second-step TST was performed two weeks later if the first test was non-reactive. Positive TST reactivity was defined as skin induration 5 mm at 72 hours after the TST. An abnormal chest radiograph had findings consistent with pulmonary TB according to American Thoracic Society, Centers for Disease Control and Prevention and Infectious Diseases Society of America guidelines.16,21 Per protocol, patients with abnormal chest radiographs underwent sputum procurement for acid-fast bacilli (AFB) examination and culture of expectorated, induced or bronchoscopic specimens, as appropriate. If sputum AFB and/or M. tuberculosis cultures were positive, the patient was treated for active pulmonary TB. If sputum AFB and M. tuberculosis cultures were negative, treatment was initiated for latent TB.
Patients with non-reactive TST were categorized as those with and without active pulmonary TB. Demographics, clinical and laboratory characteristics of the two groups were compared to identify risk factors associated with active pulmonary TB. Duration of HIV infection was calculated as the time from diagnosis of HIV infection to the initial clinic visit, which was obtained by patient interview and/or review of patients' medical records. Advanced HIV infection was defined as confirmed HIV infection and presumptive or definitive diagnosis of any stage 3 or stage 4 condition or confirmed HIV infection and CD4 count <350 cells/µL according to the World Health Organization (WHO) criteria.22 Current alcohol use was categorized by self-report of five or more drinks on a single occasion or drinking ‘several days per week’ or ‘everyday’ at any time during the study period.23 Clinical staging of HIV infection was classified according to the criteria set by the WHO.24
Statistical analysis
Data analysis was performed using SPSS Version 12 (SPSS, Chicago, IL, USA). Categorical variables were compared using 
2 or Fisher exact test, as appropriate. Continuous variables were compared using the Wilcoxon rank sum test. Multivariate analyses were used to identify variables associated with active pulmonary TB. Variables that were present in more than 10% of patients with P < 0.20 on the univariate analysis (e.g. education, age, CD4 count) and had a prior clinical significance (e.g. age, history of opportunistic infections [OI]) were entered into forward, stepwise logistic regression analysis. Significant variables that were potential covariates were grouped, and only one variable from each group was chosen for entry into the model. The final model was chosen based on biological plausibility and by selecting the logistic regression model with the lowest 2-log-likelihood function. All P values were two-tailed; P < 0.05 was considered statistically significant. Adjusted odds ratios (aOR) and 95% confidence intervals (CIs) were computed. Correlation analysis was performed by Pearson's correlation test to assess correlation between TST reaction size and CD4 counts.
|
RESULTS
|
|---|
Study population and two-step TST results
Three hundred and fifty patients, who met the inclusion criteria, were enrolled and administered with childhood BCG vaccination. Overall, 131 patients (37.4%) had reactive TSTs and 219 patients (62.6%) had non-reactive two-step TSTs (Table 1). Among the 131 patients with reactive TSTs, 13 (10%) patients were confirmed to have active pulmonary TB compared with 18% (40/219) of patients with non-reactive TSTs (P = 0.03). Patients with non-reactive TSTs were more likely to have delayed presentation to the clinic after the diagnosis of HIV infection (median, seven months vs. one month, P < 0.001) than those with reactive TST. The correlation between TST diameter and CD4 count was r = 0.69 (P = 0.02; Table 2). Proportionately more patients with higher CD4 counts, by categorical groupings, had reactive TSTs, independent of age and known history of TB exposure (Table 3).
View this table:
[in this window]
[in a new window]
|
Table 1 Demographic and clinical characteristics of 350 patients screened with two-step tuberculin skin tests (TST), stratified by TST reactivity and pulmonary tuberculosis (TB)
|
|
View this table:
[in this window]
[in a new window]
|
Table 2 Correlation between tuberculin skin test (TST) reaction size and CD4 count among 350 patients with HIV infection (r = 0.69, P = 0.02)
|
|
View this table:
[in this window]
[in a new window]
|
Table 3 Distribution of 131 tuberculin skin test (TST)-reactive patients among 350 participants screened with two-step TST, stratified by age, known TB exposure and CD4 count
|
|
Risk assessment for active pulmonary TB among patients with non-reactive TSTs
Among the 219 patients with non-reactive TSTs, the median age was 36 years (range 19–61), 134 patients (61.2%) were men, the median duration of HIV infection was 36 months (range 0–180 months), median CD4 count 139 cells/µL (range 0–953) and 151 (68.9%) had prior OIs (Table 1). Forty patients (18%) with non-reactive TSTs had evidence of active pulmonary TB, confirmed by chest radiographs and positive sputum AFB (n = 5; 12%) or sputum cultures (n = 35; 88%); the majority (n = 33, 82.5%) had both prior OIs and CD4 <100 cells/µL. In the univariate analysis of risk for active pulmonary TB, lower CD4 count (67 cells/µL vs. 156 cells/µL, P < 0.001), prior history of OI (OR = 24.16, 95% CI = 4.11–141.21, P < 0.001), advanced HIV infection (OR = 25.54, 95% CI = 10.40–62.68, P < 0.001) and known history of TB exposure (OR = 18.67, 95% CI = 7.88–44.21, P < 0.001) were predictors of active pulmonary TB. By multivariate analysis, independent risks for active pulmonary TB included known history of TB exposure (aOR = 16.00, 95% CI = 2.00–26.36, P = 0.008), CD4 count <100 cells/µL (aOR = 2.50, 95% CI = 1.30–6.50, P = 0.04) and at/below primary-school education (aOR = 2.60, 95% CI = 1.50–6.90, P = 0.02). In addition, patients with less education were more likely to have delayed presentation to clinic after the diagnosis of HIV infection (median, eight months vs. one month, P < 0.001) and had lower income (median, US$ 89 vs. US$ 195 per month, P < 0.001) than those with higher education.
|
DISCUSSION
|
|---|
There are two major findings highlighted from this study that
evaluated TB screening among 350 patients with HIV infection
in a resource-limited setting. Most importantly, almost half
(48.8%) the patients had either TB infection detected with a
reactive, two-step TST (
n = 131, 37.4%) or a non-reactive TST
with subsequent diagnostic studies that confirmed active pulmonary
TB (
n = 40, 11.4%). While a high prevalence of TB has been reported
among populations with HIV infection from several countries,
10–12,25,26 this is the first study to characterize the dual pandemic of
HIV and TB in Thailand. The higher prevalence of active pulmonary
TB among TST non-reactive patients compared to patients with
reactive TST (18% vs. 10%;
P = 0.03) may be attributed to severity
of HIV infection and loss of CD4 cells [median CD4: 67 cells/µL
vs. 150 cells/µL, respectively;
P = 0.005]. Tuberculosis
screening using TST and preventive treatment administration
were shown to reduce the incidence of TB in an area of low TB
transmission.
27 However, in patients with HIV/AIDS and non-reactive
TST, current HIV care guidelines from developed countries recommend
that providers use an individualized approach to further diagnostic
evaluation of TB.
4,6,16 Such an approach to TB screening may
not be prudent in countries with high prevalence of TB, as TST
was a poor predictor for both latent and active TB.
28,29 These
data implicate the need for other sensitive and specific screening
and confirmatory detection methods for TB. Hence, the second
major study finding is the identification of three independent
risks for active pulmonary TB in patients with non-reactive
two-step TST and HIV infection. Our data support that a subset
of TST non-reactive patients with HIV infection, who have known
prior TB exposure, low CD4 counts and limited formal education
(at/below primary school level), should proceed with chest radiograph
and if the chest radiograph is abnormal, sputum AFB staining
and culture for TB should be performed.
It is known that prior TB exposure is a major risk for active pulmonary TB.1,4,6,13,16 The clinical challenges revolve around translation of this risk into provider-patient encounters, public health messages and treatment adherence.4,16,24 In response to the TB and HIV epidemic, the Thailand Ministry of Public Health (MOPH) has declared TB control a high priority and officially adopted the WHO strategies for TB control in 1997.30 In addition, the Thailand TB Active Surveillance Network (TB-net) was established in cooperation with the Research Institute of Tuberculosis (Japan) and the Thailand MOPH-US Centers for Disease Control and Prevention Collaboration to develop an active population-based surveillance system for TB, guide public health policy and clinical practice for TB management and set up the public TB/HIV education programme.30 Programmatic goals target patient education to influence decision-making on acceptance of and adherence to the TB/HIV treatment and prevention programme.16,30 To our knowledge, this is the first study to highlight limited formal education as an independent risk factor for active pulmonary TB in persons with HIV infection and non-reactive TSTs.10–12 Comprehensive TB/HIV programmes are aimed at provision of education and early access to primary HIV care. The identification of low CD4 count as a risk for active TB in our study is consistent with two prior studies.10,11 Notably, the CD4 count threshold in this study (<100 cells/µL) was lower than that reported in previous studies (Table 4).10–12 This distinction may be temporally related to this Thai study sample having had greater access to ARV therapy in an era of improved dual HIV/TB programmes and public health messages about TB prevention.
View this table:
[in this window]
[in a new window]
|
Table 4 Published clinical studies identifying risk factors of active tuberculosis in patients with HIV infection and non-reactive tuberculin skin (TST)
|
|
There are some recognized limitations in our study. First, the
small sample size may have limited our power to detect other
plausible risk factors for active pulmonary TB in patients with
non-reactive TSTs. Secondly, informational and measurement biases
may have occurred as no prior TST results or patient recall
of TST results were available. Thirdly, there was restriction
of additional diagnostic studies to AFB smear and cultures in
our setting. Nucleic acid amplification systems were not used
and, hence our detection methods likely underestimate the burden
of pulmonary TB. Finally, we were not able to evaluate the impact
of BCG on the TST in this population, as all study patients
had BCG vaccination during childhood. Nonetheless, we identified
a high prevalence of TB infection and disease in this population,
along with identifiable risks to assist in prioritizing additional
diagnostic tests among TST-non-reactive patients.
In conclusion, physicians working in TB endemic areas should consider additional diagnostic studies for active pulmonary TB in patients with HIV infection, non-reactive TSTs, low CD4 counts, known TB exposure and low education – especially when provided with the available resources in resource-limited settings. Further studies are needed to identify the appropriate diagnostic methods for TB in high-risk populations.
|
ACKNOWLEDGEMENT
|
|---|
This study was supported by Infectious Diseases and Hospital
Epidemiology Research Unit at Thammasat University.
(Accepted May 22, 2008)
|
REFERENCES
|
|---|
- Corbett EL, Watt CJ, Walker N, et al. The growing burden of tuberculosis: global trends and interactions with the HIV epidemic. Arch Intern Med 2003; 163:1009–21[Abstract/Free Full Text]
- García-García ML, Valdespino-Gómez JL, García-Sancho C, et al. Underestimation of Mycobacterium tuberculosis infection in HIV-infected subjects using reactivity to tuberculin and anergy panel. Int J Epidemiol 2000;29:369–75[Abstract/Free Full Text]
- World Health Organization. Global Tuberculosis Control 2008: Surveillance, Planning, Financing. See http://www.who.int/tb/publications/global_report/2008/pdf/fullreport.pdf (last checked 18 April 2008) (p. 40, figure 1.17)
- Aberg JA, Gallant JE, Anderson J, et al. Primary care guidelines for the management of persons infected with human immunodeficiency virus: recommendations of the HIV Medicine Association of the Infectious Diseases Society of America. Clin Infect Dis 2004;39:609–29[Medline]
- World Health Organization. Scaling up Antiretroviral Therapy in Resources-Limited Settings: Treatment Guidelines for a Public Health Approach. 2003 trevision. Geneva: World Health Organization, 2003. See http://www.who.int/3by5/publications/documents/arv_guideline/en (last checked 14 February 2008)
- Masur H, Kaplan JE, Holmes KK, et al. Guidelines for preventing opportunistic infections among HIV-infected persons 2002. Recommendations of the U.S. Public Health Service and the Infectious Diseases Society of America. Ann Intern Med 2002;137:435–78[Abstract/Free Full Text]
- Yanai H, Uthaivoravit W, Mastro TD, et al. Utility of tuberculin and anergy skin testing in predicting tuberculosis infection in human immunodeficiency virus-infected persons in Thailand. Int J Tuberc Lung Dis 1997;1:427–34[Medline]
- Slovis BS, Plitman JD, Haas DW. The case against anergy testing as a routine adjunct to tuberculin skin testing. JAMA 2000;283:2003–7[Abstract/Free Full Text]
- Janis EM, Allen DW, Glesby MJ, et al. Tuberculin skin test reactivity, anergy, and HIV infection in hospitalized patients. Longcope Firm of the Osler Medical Housestaff. Am J Med 1996;100:186–92[Medline]
- Guelar A, Gatell JM, Verdejo J, et al. A prospective study of the risk of tuberculosis among HIV-infected patients. AIDS 1993;7:1345–9[Medline]
- Moreno S, Baraia-Etxaburu J, Bouza E, et al. Risk for developing tuberculosis among anergic patients infected with HIV. Ann Intern Med 1993;119:194–8[Abstract/Free Full Text]
- Antonucci G, Girardi E, Raviglione MC, Ippolito G. Risk factors for tuberculosis in HIV-infected persons. A prospective cohort study. The Gruppo Italiano di Studio Tubercolosi e AIDS (GISTA). JAMA 1995;274:143–8[Abstract/Free Full Text]
- Varma JK, Wiriyakitjar D, Nateniyom S, et al. Evaluating the potential impact of the new Global Plan to Stop TB: Thailand, 2004–2005. Bull World Health Organ 2007;85:586–92[Medline]
- Manosuthi W, Chaovavanich A, Tansuphaswadikul S, et al. Incidence and risk factors of major opportunistic infections after initiation of antiretroviral therapy among advanced HIV-infected patients in a resource-limited setting. J Infect 2007;55:464–9
- Manosuthi W, Chottanapand S, Thongyen S, Chaovavanich A, Sungkanuparph S. Survival rate and risk factors of mortality among HIV/tuberculosis-coinfected patients with and without antiretroviral therapy. J Acquir Immune Defic Syndr 2006;43:42–6[Medline]
- American Thoracic Society, Centers for Disease Control and Prevention, Infectious Diseases Society of America. American Thoracic Society/Centers for Disease Control and Prevention/Infectious Diseases Society of America: controlling tuberculosis in the United States. Am J Respir Crit Care Med 2005;172:1169–227[Free Full Text]
- Department of Health and Human Services. Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents (29 January 2008). See http://www.aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf (last checked 18 April 2008), pp. 52–3
- Kitkungvan D, Apisarnthanarak A, Plengpart P, Mundy LM. Fever of unknown origin in patients with human immunodeficiency virus infection in Thailand: an observation study and review of literatures. Int J STD AIDS 2008;19:232–5[Abstract/Free Full Text]
- Apisarnthanarak A, Jirayasethpong T, Sa-nguansilp C, et al. Antiretroviral drug resistance among antiretroviral-naïve persons with recent HIV infection in Thailand. HIV Med 2008;9:322–5[Medline]
- Phonboon K, Ramaboot S, Kunasol P, Preuksaraj S. Thailand Expanded Program on Immunization: a ten-years review of coverage and impact on EPI target diseases. Southeast Asian J Trop Med Public Health 1989;20:529–40[Medline]
- Lee KS, Song KS, Lim TH, Kim PN, Kim IY, Lee BH. Adult-onset pulmonary tuberculosis: findings on chest radiographs and CT scans. Am J Roentgenol 1993;160:753–8[Abstract/Free Full Text]
- World Health Organization. WHO Case Definitions of HIV for Surveillance and Revised Clinical Staging and Immunological Classification of HIV-Related Disease in Adults Aged 15 years or Older. See http://www.searo.who.int/LinkFiles/Publications_StagingCardsAdult.pdf (last checked 18 April 2008), p. 1
- Berg KM, Demas PA, Howard AA. Gender differences in factors associated with adherence to antiretroviral therapy. J Gen Intern Med 2004;19:1111–7[Medline]
- World Health Organization. Interim Policy on Collaborative TB/HIV Activities. Geneva: World Health Organization, 2004 See http://whqlibdoc.who.int/hq/2004/who_htm_tb_2004.330.pdf. (last checked 14 February 2008)
- Wood R, Maartens G, Lombard CJ. Risk factors for developing tuberculosis in HIV-1-infected adults from communities with a low or very high incidence of tuberculosis. J Acquir Immune Defic Syndr 2000;23:75–80[Medline]
- Chaisson RE, Martinson NA. Tuberculosis in Africa: combating an HIV-driven crisis. N Engl J Med 2008;358:1089–92[Free Full Text]
- Elzi L, Schlegel M, Weber R, et al. Reducing tuberculosis incidence by tuberculin skin testing, preventive treatment, and antiretroviral therapy in an area of low tuberculosis transmission. Clin Infect Dis 2007;44:94–102[Medline]
- Swaminathan S, Subbaraman R, Venkatesan P, et al. Tuberculin skin test results in HIV-infected patients in India: implications for latent tuberculosis treatment. Int J Tuberc Lung Dis 2008;12:168–73[Medline]
- Tegbaru B, Wolday D, Messele T, et al. Tuberculin skin test conversion and reactivity rates among adults with and without human immunodeficiency virus in urban settings in Ethiopia. Clin Vaccine Immunol 2006;13:784–9[Abstract/Free Full Text]
- Thailand Ministry of Public Health, Bangkok Metropolitan Administration, The Research Institute of Tuberculosis, Japan and U.S Centers for Disease Control and Prevention. Active, Population-Based Surveillance and Enhanced Control of Tuberculosis: The Thailand TB Active Surveillance Network (TB-Net), October 2005. See http://www.thaitbnet.org/TB%20Surveillance%20Protocol_%20English%20Revised%20Oct.05.pdf (last checked 17 March 2008)
- Centers for Disease Control, U.S. Department of Health and Human Services. Classification system for human T-lymphotropic virus type III/lymphadenopathy-associated virus infections. Ann Intern Med 1986;105:234–7[Abstract/Free Full Text]
CiteULike 
Complore 
Connotea 
Del.icio.us 
Digg 
Reddit 
Technorati What's this?
This article has been cited by other articles:
|
|
|
|
 
T Khawcharoenporn, A Apisarnthanarak, D Kitkungvan, P Laowansiri, and L M Mundy
Feasibility of primary HIV care in a Thai tertiary care centre
Int J STD AIDS,
September 1, 2009;
20(9):
669 - 670.
[Full Text]
[PDF]
|
|
|
Top
Summary
INTRODUCTION
