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Geriatr Gerontol Int 2015; 15: 1179–1184
ORIGINAL ARTICLE: EPIDEMIOLOGY, CLINICAL PRACTICE AND HEALTH
Quantiferon TB-Gold conversion can predict active tuberculosis development in elderly nursing home residents Ping-Hsien Tsou,1,2* Wei-Chang Huang,3,4* Chen-Cheng Huang,5 Chen-Fu Lin,6 Kun-Ming Wu,7 Jeng-Yuan Hsu3 and Gwan-Han Shen3,8,9 1
Division of Chest Medicine, Department of Internal Medicine, National Taiwan University Hospital, 2Department of Biological Science and Technology, National Chiao Tung University, Hsin-Chu, 3Division of Respiratory and Critical Care Medicine, Departments of Internal Medicine, 6Microbiology, Taichung Veterans General Hospital, 8Institute of Molecular Biology, National Chung Hsing University, 5 Division of Respiratory and Critical Care Medicine, Department of Internal Medicine, Taichung Hospital, Ministry of Health and Welfare, 7 Reference Medical Laboratory, 9Institute of Respiratory Therapy, China Medical University, Taichung, and 4Department of Medical Technology, Jen-The Junior College of Medicine, Nursing and Management, Miaoli, Taiwan
Aim: The study was carried out on elderly nursing home residents in Taiwan. We assessed whether the serial QuantiFERON-TB Gold (QFT-G) assay and serial tuberculin skin test (TST) were reliable tools to predict or exclude the development of active tuberculosis (TB). Methods: This prospective observational cohort study involved non-bacillus Calmette–Guérin-vaccinated 259 elderly nursing home residents free of active TB at baseline. Of these, 147 were eligible for follow up. Participants underwent serial QFT-G and TST at baseline and 2-year follow up, and were monitored for active TB over 5 years. Agreement between QFT-G and TST, incidence rate ratio, positive predictive value, and negative predictive value for progression to active TB were measured. Results: During 5-year follow up, three participants developed active TB. The agreement between these two tests was 54.13% (ĸ = 0.167, P = 0.001). The incidence rate ratio was 15.8 (P = 0.016) for the QFT-G-conversion group compared with the TST-positive group at baseline. Positive predictive value for QFT-G conversion groups was 25%. Negative predictive value was 100% for the TST-negative group at baseline. Conclusion: In the elderly nursing home residents, QFT-G conversion is a more reliable tool to predict the development of active TB. Meanwhile, TST is a valuable tool for predicting the chance of not developing active TB. Geriatr Gerontol Int 2015; 15: 1179–1184. Keywords: elderly, Mycobacterium tuberculosis, nursing home residents, Quantiferon TB-Gold assay, tuberculin skin test.
Introduction Approximately one-third of the world population is estimated to be infected with Mycobacterium tuberculosis (MTB), and Asia accounts for 60% of new cases detected globally in recent years.1 In 2010, 53% of all tuberculosis (TB) patients were aged ≥65 years in
Accepted for publication 20 September 2014. Correspondence: Dr Gwan-Han Shen PhD, Division of Respiratory and Critical Care Medicine, Department of Internal Medicine, Taichung Veterans General Hospital, 160, Sec. 3 Taichung Port Rd., Taichung 40705, Taiwan. Email: [email protected] *These authors equally contributed to this work.
© 2014 Japan Geriatrics Society
Taiwan.2 The elderly are an important reservoir of TB, and are at a high risk of progression from latent tuberculosis infection (LTBI) to active TB, particularly in settings where they come in close contact with each other.3 Therefore, the detection of TB infection in elderly individuals living in groups has become important in disease control.4 The tuberculin skin test (TST) has traditionally been used to identify LTBI in populations likely to benefit from preventive isoniazid (INH) treatment.5,6 Individuals in whom recent TST conversion has occurred had a high probability of developing active TB.7 Despite its usefulness and simplicity, the TST has test- and population-specific limitations; that is, its specificity is reduced in individuals previously vaccinated with bacillus Calmette–Guérin (BCG) or those with prior doi: 10.1111/ggi.12416
| 1179
P-H Tsou et al.
exposure to non-tuberculous mycobacteria. Furthermore, it increases the risk of anergic reactions in the elderly.7–9 The interferon-gamma release assay (IGRA) measures a surrogate marker for TB infection that represents a cellular immune response to sensitization. Recent studies showed that IGRA might be more useful than TST in diagnosing LTBI in elderly10 and nursing home residents.9 Furthermore, recent QuantiFERON conversion (a type of IGRA), as defined by negative IGRA results at baseline and positive results on subsequent testing, was a valuable tool to predict the development of active TB in a cohort of adolescents rather than in a cohort of healthcare workers.11,12 However, its usefulness in the elderly and nursing home residents remains unknown. Despite the detection and treatment of LTBI constituting the cornerstone of TB control, LTBI treatment in the elderly is challenging.13 Risks of hepatitis and other adverse events requiring hospitalization were found to increase significantly among patients aged >65 years receiving preventive treatment for LTBI.14 The American Thoracic Society guidelines recommend that LTBI should be treated regardless of age, whereas the National Institute of Excellence guidelines from the UK advise against treating LTBI in individuals aged >35 years.15 Thus, whether the risk to individuals aged >35 years justifies withholding treatment for LTBI is a controversial issue.16,17 In light of this controversy and its implications in the elderly population, we aimed to investigate whether serial QuantiFERON-TB Gold (QFT-G) assay – a type of IGRA – and serial TST were reliable tools to predict or exclude the development of active TB in elderly nursing home residents.
Methods Study participants As the aim of the present study was to investigate whether serial QFT-G assay and serial TST were reliable tools to predict or exclude the development of active TB in elderly nursing home residents, we invited all of the residents in a veteran nursing home in central Taiwan to participate in the study in 2004. These veterans were Chinese immigrants and comprised a unique ethnic group in Taiwan because they were not vaccinated (i.e. BCG vaccinationnaïve). Those who were younger than 65 years, declined participation, or had the radiological or laboratory evidence of active TB confirmed by chest specialists at enrolment were excluded from the present study. Of the 516 residents, 259 residents (mean age 79.97 ± 5.26 years) were enrolled (Fig. 1). The institutional review board and ethics committee of Taichung Veterans General Hospital approved this study, and informed consent was obtained from all participants. 1180 |
TST and QFT-G assay Baseline characteristics of study participants were collected from the residents’ medical records by the investigators. At baseline, the study nurses who were certified for TST administration carried out and read TST results, and drew blood for QFT-G assay for all study participants. Sputum smears and cultures were obtained from participants with prior pulmonary TB history, patients with fibrocalcific lesions in the upper lung fields on chest X-rays (CXR) as confirmed by chest specialists or patients positive for TST or QFT-G at baseline, to evaluate the presence of active TB. None of the participants had active TB at baseline. Again, TST was carried out in study participants who were TST-negative at baseline, and QFT-G was carried out in all the study participants at 2-year follow up. During this period of further observation for incident active TB disease, study participants were interviewed at 6-monthly intervals to determine whether they had new TB symptoms, had received screens for TB and had received a diagnosis of TB. If new TB symptoms/signs presented and active TB was suspected by the interviewers, the participants were admitted to Taichung Veterans General Hospital for definitive diagnoses and treatments. The TST was carried out using the Mantoux method. Briefly, 48−72 h after intradermal infection with 2 tuberculin units of purified protein derivative RT-23 (Staten Serum Institute, Copenhagen, Denmark), the induration size was measured. A diameter of ≥10 mm was considered an indicator of positivity. QFT-G assay was carried out according to the manufacturer’s instructions (Cellestis, Melbourne, VIC, Australia). An interferongamma (IFN-γ) level of ≥0.35 IU/mL against early secretory antigenic target 6 and culture filtrate protein 10, and ≥50% of nil was interpreted as positivity. An IFN-γ level of
Geriatr Gerontol Int 2015; 15: 1179–1184
ORIGINAL ARTICLE: EPIDEMIOLOGY, CLINICAL PRACTICE AND HEALTH
Quantiferon TB-Gold conversion can predict active tuberculosis development in elderly nursing home residents Ping-Hsien Tsou,1,2* Wei-Chang Huang,3,4* Chen-Cheng Huang,5 Chen-Fu Lin,6 Kun-Ming Wu,7 Jeng-Yuan Hsu3 and Gwan-Han Shen3,8,9 1
Division of Chest Medicine, Department of Internal Medicine, National Taiwan University Hospital, 2Department of Biological Science and Technology, National Chiao Tung University, Hsin-Chu, 3Division of Respiratory and Critical Care Medicine, Departments of Internal Medicine, 6Microbiology, Taichung Veterans General Hospital, 8Institute of Molecular Biology, National Chung Hsing University, 5 Division of Respiratory and Critical Care Medicine, Department of Internal Medicine, Taichung Hospital, Ministry of Health and Welfare, 7 Reference Medical Laboratory, 9Institute of Respiratory Therapy, China Medical University, Taichung, and 4Department of Medical Technology, Jen-The Junior College of Medicine, Nursing and Management, Miaoli, Taiwan
Aim: The study was carried out on elderly nursing home residents in Taiwan. We assessed whether the serial QuantiFERON-TB Gold (QFT-G) assay and serial tuberculin skin test (TST) were reliable tools to predict or exclude the development of active tuberculosis (TB). Methods: This prospective observational cohort study involved non-bacillus Calmette–Guérin-vaccinated 259 elderly nursing home residents free of active TB at baseline. Of these, 147 were eligible for follow up. Participants underwent serial QFT-G and TST at baseline and 2-year follow up, and were monitored for active TB over 5 years. Agreement between QFT-G and TST, incidence rate ratio, positive predictive value, and negative predictive value for progression to active TB were measured. Results: During 5-year follow up, three participants developed active TB. The agreement between these two tests was 54.13% (ĸ = 0.167, P = 0.001). The incidence rate ratio was 15.8 (P = 0.016) for the QFT-G-conversion group compared with the TST-positive group at baseline. Positive predictive value for QFT-G conversion groups was 25%. Negative predictive value was 100% for the TST-negative group at baseline. Conclusion: In the elderly nursing home residents, QFT-G conversion is a more reliable tool to predict the development of active TB. Meanwhile, TST is a valuable tool for predicting the chance of not developing active TB. Geriatr Gerontol Int 2015; 15: 1179–1184. Keywords: elderly, Mycobacterium tuberculosis, nursing home residents, Quantiferon TB-Gold assay, tuberculin skin test.
Introduction Approximately one-third of the world population is estimated to be infected with Mycobacterium tuberculosis (MTB), and Asia accounts for 60% of new cases detected globally in recent years.1 In 2010, 53% of all tuberculosis (TB) patients were aged ≥65 years in
Accepted for publication 20 September 2014. Correspondence: Dr Gwan-Han Shen PhD, Division of Respiratory and Critical Care Medicine, Department of Internal Medicine, Taichung Veterans General Hospital, 160, Sec. 3 Taichung Port Rd., Taichung 40705, Taiwan. Email: [email protected] *These authors equally contributed to this work.
© 2014 Japan Geriatrics Society
Taiwan.2 The elderly are an important reservoir of TB, and are at a high risk of progression from latent tuberculosis infection (LTBI) to active TB, particularly in settings where they come in close contact with each other.3 Therefore, the detection of TB infection in elderly individuals living in groups has become important in disease control.4 The tuberculin skin test (TST) has traditionally been used to identify LTBI in populations likely to benefit from preventive isoniazid (INH) treatment.5,6 Individuals in whom recent TST conversion has occurred had a high probability of developing active TB.7 Despite its usefulness and simplicity, the TST has test- and population-specific limitations; that is, its specificity is reduced in individuals previously vaccinated with bacillus Calmette–Guérin (BCG) or those with prior doi: 10.1111/ggi.12416
| 1179
P-H Tsou et al.
exposure to non-tuberculous mycobacteria. Furthermore, it increases the risk of anergic reactions in the elderly.7–9 The interferon-gamma release assay (IGRA) measures a surrogate marker for TB infection that represents a cellular immune response to sensitization. Recent studies showed that IGRA might be more useful than TST in diagnosing LTBI in elderly10 and nursing home residents.9 Furthermore, recent QuantiFERON conversion (a type of IGRA), as defined by negative IGRA results at baseline and positive results on subsequent testing, was a valuable tool to predict the development of active TB in a cohort of adolescents rather than in a cohort of healthcare workers.11,12 However, its usefulness in the elderly and nursing home residents remains unknown. Despite the detection and treatment of LTBI constituting the cornerstone of TB control, LTBI treatment in the elderly is challenging.13 Risks of hepatitis and other adverse events requiring hospitalization were found to increase significantly among patients aged >65 years receiving preventive treatment for LTBI.14 The American Thoracic Society guidelines recommend that LTBI should be treated regardless of age, whereas the National Institute of Excellence guidelines from the UK advise against treating LTBI in individuals aged >35 years.15 Thus, whether the risk to individuals aged >35 years justifies withholding treatment for LTBI is a controversial issue.16,17 In light of this controversy and its implications in the elderly population, we aimed to investigate whether serial QuantiFERON-TB Gold (QFT-G) assay – a type of IGRA – and serial TST were reliable tools to predict or exclude the development of active TB in elderly nursing home residents.
Methods Study participants As the aim of the present study was to investigate whether serial QFT-G assay and serial TST were reliable tools to predict or exclude the development of active TB in elderly nursing home residents, we invited all of the residents in a veteran nursing home in central Taiwan to participate in the study in 2004. These veterans were Chinese immigrants and comprised a unique ethnic group in Taiwan because they were not vaccinated (i.e. BCG vaccinationnaïve). Those who were younger than 65 years, declined participation, or had the radiological or laboratory evidence of active TB confirmed by chest specialists at enrolment were excluded from the present study. Of the 516 residents, 259 residents (mean age 79.97 ± 5.26 years) were enrolled (Fig. 1). The institutional review board and ethics committee of Taichung Veterans General Hospital approved this study, and informed consent was obtained from all participants. 1180 |
TST and QFT-G assay Baseline characteristics of study participants were collected from the residents’ medical records by the investigators. At baseline, the study nurses who were certified for TST administration carried out and read TST results, and drew blood for QFT-G assay for all study participants. Sputum smears and cultures were obtained from participants with prior pulmonary TB history, patients with fibrocalcific lesions in the upper lung fields on chest X-rays (CXR) as confirmed by chest specialists or patients positive for TST or QFT-G at baseline, to evaluate the presence of active TB. None of the participants had active TB at baseline. Again, TST was carried out in study participants who were TST-negative at baseline, and QFT-G was carried out in all the study participants at 2-year follow up. During this period of further observation for incident active TB disease, study participants were interviewed at 6-monthly intervals to determine whether they had new TB symptoms, had received screens for TB and had received a diagnosis of TB. If new TB symptoms/signs presented and active TB was suspected by the interviewers, the participants were admitted to Taichung Veterans General Hospital for definitive diagnoses and treatments. The TST was carried out using the Mantoux method. Briefly, 48−72 h after intradermal infection with 2 tuberculin units of purified protein derivative RT-23 (Staten Serum Institute, Copenhagen, Denmark), the induration size was measured. A diameter of ≥10 mm was considered an indicator of positivity. QFT-G assay was carried out according to the manufacturer’s instructions (Cellestis, Melbourne, VIC, Australia). An interferongamma (IFN-γ) level of ≥0.35 IU/mL against early secretory antigenic target 6 and culture filtrate protein 10, and ≥50% of nil was interpreted as positivity. An IFN-γ level of
