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Tuberculosis screening programme using the QuantiFERON®-TB Gold test and chest computed tomography for healthcare workers accidentally exposed to patients with tuberculosis
Journal of Hospital Infection 77 (2011) 257e262
Available online at www.sciencedirect.com
Journal of Hospital Infection journal homepage: www.elsevierhealth.com/journals/jhin
Tuberculosis screening programme using the QuantiFERONÒ-TB Gold test and chest computed tomography for healthcare workers accidentally exposed to patients with tuberculosis T. Hirama*, K. Hagiwara, M. Kanazawa Department of Respiratory Medicine, Saitama Medical University, Saitama, Japan
a r t i c l e i n f o
s u m m a r y
Article history: Received 10 June 2010 Accepted 15 November 2010 Available online 12 February 2011
Healthcare workers (HCWs) have an increased incidence of tuberculosis (TB). Periodic and asneeded screenings of HCWs exposed to patients with TB are important. We integrated chest computed tomography (CT) and the QuantiFERONÒ-TB Gold (QFT-G) test into our TB screening programme for HCWs. First, contacts were tested using the QFT-G test. Those positive for the QFT-G test were investigated by CT and classified as having active, latent (LTBI), or old TB. Between April 2005 and April 2010, 11 patients who had not been diagnosed with active TB on admission were found to have the disease. A total of 512 close or high risk contacts were identified, and underwent screening. Out of those, 34 (6.64%) were QFT-G positive, whereas 478 (93.36%) were negative. Of the 34 QFT-G-positive HCWs, four had CT findings compatible with active TB and received multidrug treatment; 24 showed no findings of active TB and received isoniazid for six months. All completed their regimens without any adverse effects. The TB screening programme integrating CT and the QFT-G test was safe and feasible. The efficacy of the programme needs to be confirmed by large scale clinical trials. Ó 2010 The Hospital Infection Society. Published by Elsevier Ltd. All rights reserved.
Keywords: Chest computed tomography Healthcare workers QuantiFERONÒ-TB Gold test
Introduction Healthcare-associated transmission of tuberculosis (TB) is a serious issue.1,2 Healthcare workers (HCWs) have been reported to show a high incidence of TB, which was probably transmitted by accidental exposure to patients with TB.3e6 In turn, this creates a risk for the patients receiving care from these HCWs. Periodical or pre-employment screenings of all HCWs, in addition to as-needed screenings of HCWs accidentally exposed to patients with TB, are important.3 Tuberculosis infection may be active or latent (LTBI); the former presents symptoms or other indications of disease, whereas the latter is silent. The diagnosis of active TB is straightforward: signs and symptoms, or chest radiograph findings are confirmed by culture or polymerase chain reaction tests. However, the diagnosis of LTBI is not as simple. This is suspected as a result of an enhanced reaction to the
* Corresponding author. Address: Department of Respiratory Medicine, Saitama Medical University, 38 Morohongo, Moroyama-machi, Saitama 350-0495, Japan. Tel./fax: þ81 492761319. E-mail address: [email protected] (T. Hirama).
tuberculin skin test (TST), but there is no procedure for confirming diagnosis. The classification of TB determines the regimen of the treatment required. Active disease is treated with multiple antituberculosis drugs, whereas LTBI is treated with isoniazid (INH) monotherapy. The treatment scheme stated above has been widely acknowledged and used. Nevertheless, there is a risk of undertreatment due to insufficient sensitivity of chest radiographs for detecting active TB; patients may be diagnosed as having LTBI and treated only by INH. There is also a risk of overtreatment due to the insufficient specificity of TST for detecting LTBI; a positive TST can be either due to bacille CalmetteeGuérin (BCG) vaccination or infection with non-tuberculous mycobacteria. As a result, patients who have not been exposed to TB may be treated by INH. This is especially relevant to the countries with a high BCG vaccination rate such as Japan (96.5%).7 The addition of chest computed tomography (CT) will increase the sensitivity of TB disease detection, and replacement of the TST with the QuantiFERONÒ-TB Gold (QFT-G) will increase the specificity in detecting LTBI, thus enabling more precise treatment. We therefore integrated chest CTs and the QFT-G test into our TB screening programme for HCWs. First, contacts were tested using the QFT-G test; those who tested negative were excluded. Positive
0195-6701/$ e see front matter Ó 2010 The Hospital Infection Society. Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.jhin.2010.11.012
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contacts were investigated by CT and classified as having active, latent or old TB. Finally, those with active TB were treated with a multidrug regimen [INH, rifampicin (REF), ethambutol (EB), and pyrazinamide (PZA)], whereas those with LTBI were treated with INH monotherapy. We retrospectively investigated the utility, safety, and feasibility of this programme that has been conducted at the Saitama Medical University Hospital (SMUH) for five years. Methods Infection Control Subcommittee for Tuberculosis (ICST) The SMUH is a 712-bed general hospital for patients with acute or subacute illnesses. It does not have a ward dedicated to patients with TB. The ICST was organised in April 2005 by members of the Infection Control Team with experts on TB control, and has been responsible for the TB screening programme. TB screening programme Traced contacts The TB screening programme has been active from April 2005 to the present. The programme is conducted by the ICST: once every two years, targeting HCWs who have worked in an infectious disease ward; and each time HCWs are accidentally exposed to a patient
Infectious disease ward worker: n = 157
with TB disease. In the former case, all HCWs are considered to be close contacts (Figure 1). In the latter, the programme first assesses the infectiousness of the disease, and the closeness of contact according to the criteria summarised below.8e10 (I) Infectiousness of the disease. (a) Infectious TB: (1) disease with a pulmonary cavity on chest radiograph or (2) disease positive for sputum smear. (b) Non-infectious TB: disease other than that described above. (II) Closeness of contact. (a) A close contact: an HCW who has worked for >8 h in the room of a patient with infectious TB; an HCW who has performed an aerosol-producing procedure on the patient, including bronchoscopy, airway suction, sputum induction or administration of aerosolised medication; an HCW who has performed examination procedures on the patient (e.g. ultrasound, bedside radiogram, or laboratory examination). (b) A non-close contact: an HCW who has had contact with a patient with infectious TB but did not fit the criteria for a close contact. (c) A high risk contact: any contact who is infected with human immunodeficiency virus, has diabetes mellitus, chronic renal failure, malignancies, or who is on prolonged corticosteroid or immunosuppressive treatments.
Accidental contact: n = 355
Every two years Close contact
Close contact
High-risk contact
Non-close contact
Traced contact >10% of trace contact TB disease or LTBI?
Contact tracing procedure
NO Step 1
Inquiry
YES Terminate tracing
Step 2
{
Inquiry
QFT-G positive?
2-year annual follow-up by chest radiograph
YES CT
TB disease Step 3
NO
Antituberculosis multidrug treatment
LTBI
Old TB
INH monotherapy
Figure 1. The tuberculosis (TB) screening programme for healthcare workers. LTBI, latent tuberculosis infection; QFT-G, QuantiFERONÒ-TB Gold; CT, computed tomography; INH, isoniazid.
T. Hirama et al. / Journal of Hospital Infection 77 (2011) 257e262
When the disease is infectious, close contacts and high risk contacts are classified as traced contacts.
259
Results TB screening programme
Contact tracing procedures Contact tracing procedures are undertaken for all traced contacts. The procedures consist of three steps (Figure 1). Step 1: Just after exposure. The ICST inquires about health problems, previous history of TB, regular use of medication, and presence of respiratory symptoms. Step 2: 8e10 weeks after exposure. The ICST makes the same inquiries as in Step 1. A chest radiograph and the QFT-G test are performed. Traced contacts who are positive for the QFT-G test (i.e. ESAT-6 > 0.10 IU/mL or CFP-10 >0.10 IU/mL) are considered to have either active or latent TB; chest CT scans are taken to investigate the presence of pulmonary lesions. Traced contacts with CT findings consistent with activity are considered to have active TB.11 Traced contacts with CT findings consistent with old TB were considered to have old TB.11 All others are considered to have LTBI. If Step 2 reveals the presence of TB disease or LTBI in more than 10% of traced contacts, the patient’s disease is considered highly infectious and all non-close contacts are henceforth included in the traced contacts e the contact tracing procedures for non-close contacts are initiated from Step 2. Step 3: Drug administration. Traced contacts with active TB are treated with multiple antituberculosis drugs. Normally treatment is started with four drugs, INH, REF, EB, and PZA, for two months, followed by INH and REF for four months; these are amenable to change depending on the sensitivity of the M. tuberculosis strain isolated from the patient they have been exposed to. Traced contacts with LTBI are given INH monotherapy for six months.12 Ethical considerations The TB screening programme reported in the current study was approved by the institutional review board of the Saitama Medical University.
Between April 2005 and April 2010, 11 patients who had not been diagnosed with active TB on admission were later found to have the disease. The ICST conducted the TB screening programme for HCWs in the infectious disease ward twice, and an additional 11 times for HCWs who could have had accidental exposures (Table I). A total of 512 close contacts and high risk contacts underwent screening; 34 (6.64%) had a positive QFT-G test, and 478 (93.36%) were negative. Of the 34 QFT-G positives, four had CT findings compatible with active TB and received multidrug treatment. The chest CTs for 24 showed no indication of activity; these HCWs received INH for six months. All contacts completed their regimens without any adverse effects. Two contacts had CT findings consistent with old TB, and were put on a two-year follow-up regimen by annual chest radiography.11 The details of the four contacts who received multidrug treatments are presented below. Case 1: A 25-year-old female nurse who worked in the pulmonary disease ward The QFT-G results were ESAT-6, 0.31 IU/mL and CFP-10, 0.12 IU/mL (Figure 2). The chest CT showed centrilobular nodules in the right apex of the lung, which was difficult to detect on a chest radiograph. The subject had no previous history of TB disease or respiratory symptoms. A chest CT taken three years previously was negative for nodules. The subject received multidrug treatment for six months and the CT findings improved after treatment. Case 2: A 31-year-old male physician who worked in the pulmonary disease ward The QFT-G results were ESAT-6, 0.02 IU/mL and CFP-10, 0.11 IU/mL (Figure 3). The chest CT showed a round nodular shadow (indicated by an arrow) in the left lingula segment, which was difficult to detect with chest radiography. The subject received multidrug treatment for six months but the CT findings remained unchanged, suggesting that the subject may not have had active TB.
Table I The 355 HCWs accidently exposed to tuberculosis out of a total of 512 contacts Date of incidence
Patient’s characteristics Main lesion of tuberculosis
Aug 2005
Pulmonary
Sep 2005 Oct 2005 May 2007 Jul 2007
Endobronchial Pulmonary Systemic (miliary tuberculosis) Pulmonary
Aug 2007 Jan 2008 Mar 2008
Pulmonary Pulmonary Pulmonary
Jul 2008 Nov 2008
Pulmonary Systemic (miliary tuberculosis) Pulmonary
Jan 2009
Findings that support infectivity Cavitation in chest radiograph Positive sputum smear Positive sputum smear Positive sputum smear Cavitation in chest radiograph Positive sputum smear Positive sputum smear Cavitation in chest radiograph Positive sputum smear Positive sputum smear Positive sputum smear
Contacts Underlying disease
Close contactsa
Contact tracing procedure High risk contacts
Positive QFT-Gb
Abnormal chest CT
Received multidrug treatment
Behçet disease
41
1
2 (0)
0
0
Rheumatoid arthritis Peritonitis
41 36 (18) 17
0 1 0
2 (0) 1 (0) 1 (0)
0 0 0
0 0 0
Diabetes
27
0
3 (0)
0
0
MCTD Behçet disease Malignant rheumatoid arthritis
19 44 (14) 24 (19)
0 1 0
1 (0) 3 (0) 1 (0)
0 1 0
0 1 0
45 46 (32)
0 1
0 (0) 0 (0)
NA NA
0 0
0 4
0 (0) 14 (0)
NA 1
0 1
Arteritis temporalis Liver cirrhosis Total
11 351
CT, computed tomography; MCTD, mixed connective tissue disease; NA, not applicable. a Values in parentheses indicate HCWs who were involved in previous incidences and thus were counted more than once. b Values in parentheses indicate the number of high risk contacts in positive QuantiFERON Gold (QFT-G).
260
T. Hirama et al. / Journal of Hospital Infection 77 (2011) 257e262
Figure 2. Case 1. (A) Chest radiograph showing no findings suggestive of active tuberculosis. (B) Chest computed tomography (CT) showing centrilobular nodules in the right apex of the lung, which are difficult to visualise on a chest radiograph. (C) Chest CT taken three years before (A) was taken, showing a normal right apex. (D) Chest CT taken after a multidrug treatment revealed that the nodules seen in (B) were resolved.
Case 3: A 24-year-old female nurse who worked in the infectious disease ward The QFT-G results were ESAT-6, 0.01 IU/mL and CFP-10, 0.12 IU/mL (Figure 4). The chest CT showed centrilobular nodules (indicated by an arrow) situated right above the diaphragm. The subject received multidrug treatment for six months and the CT findings improved. Case 4: A 22-year-old female nurse who worked in the rheumatic disease ward The QFT-G results were ESAT-6, 0.12 IU/mL and CFP-10, 0.01 IU/mL (Figure 5). The subject had previously undergone the QFT-G test (ESAT-6, 0.01 IU/mL and CFP-10, 0.01 IU/mL) performed six months before the TB screening programme. The chest CT scan revealed a poorly defined nodule accompanying satellite nodules in the left upper lobe. The subject received multidrug treatment for six months and the CT findings improved.
Discussion The combination of the QFT-G test and chest CT is widely used in the clinical practice of TB diagnosis. However, there are no reported TB screening procedures that integrate both the QFT-G and chest CT in the healthcare setting. This prompted us to design the procedures reported in the current study. The QFT-G test has greater specificity than the TST in detecting current or past history of exposure to M. tuberculosis; thus, we obtained chest CT scans of all contacts with positive QFT-G test results.13 Meanwhile, there was little information regarding the sensitivity of the QFT-G test e especially regarding its sensitivity for the detection of LTBI. Therefore, all traced contacts who had negative QFT-G results underwent a two-year follow-up by chest radiography. None of them showed any active TB, suggesting that those with negative QGT-G results did not need follow-up. However, a larger scale study is necessary to confirm this, especially in the healthcare setting.
T. Hirama et al. / Journal of Hospital Infection 77 (2011) 257e262
261
Figure 3. Case 2. (A) Chest computed tomography (CT) showing a round nodular shadow in the left lingular segment, which was difficult to detect on a chest radiograph. (B) The nodule seen in (A) did not change after multidrug treatment.
Many studies have shown the superior effectiveness of chest CT to chest radiography for the diagnosis of TB disease, but CT for all traced contacts is not practicable. Therefore, we limited CT scans only to contacts with positive QFT-G test results.
Previous clinical trials have demonstrated that INH monotherapy for LTBI substantially reduces the probability of developing active TB.14,15 However, treatment of active TB with INH monotherapy is known to promote the development of INH-resistant
Figure 4. Case 3. (A) Chest computed tomography showing centrilobular nodules situated right above the diaphragm. (B) The nodules seen in (A) were resolved after a multidrug treatment.
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Figure 5. Case 4. (A) Chest radiograph showing no findings suggestive of active tuberculosis. (B) Chest computed tomography showing a poorly defined nodule accompanying satellite nodules in the left upper lobe.
TB.16 This raises a concern that misdiagnosis of contacts with active TB as LTBI creates a risk for developing INH-resistant TB. We had three cases (1, 3, and 4) in which, according to the response to the therapy, the diagnosis was likely to have been active TB. However, they would have been diagnosed as LTBI if chest CT scans had not been obtained. This confirms the utility of our TB screening programme, which integrates both the QFT-G test and CT; now there is a need for a clinical trial to demonstrate that the programme indeed suppresses the development of INH-resistant TB. In the present study, we retrospectively investigated the utility, safety, and feasibility of the TB screening programme for HCWs, which has been in effect for five years at our university hospital. Identification of three cases that were probably active TB that would have been otherwise diagnosed as having LTBI suggests the superiority of our procedure over procedures in which the QFT-G or chest CT scans are not conducted. Our procedure has been safely performed without any problems. However, a prospective study is needed to investigate whether our procedure is more effective than programmes that do not include the QFT-G test or chest CT. Conflict of interest statement None declared. Funding source This study was performed using research funds of the Saitama Medical University. References 1. Jensen PA, Lambert LA, Iademarco MF, Ridzon R. Guidelines for preventing the transmission of Mycobacterium tuberculosis in health-care settings, 2005. MMWR Recomm Rep 2005;54:1e141.
2. Guidelines for the investigation of contacts of persons with infectious tuberculosis. Recommendations from the National Tuberculosis Controllers Association and CDC. MMWR Recomm Rep 2005;54:1e47. 3. Schablon A, Harling M, Diel R, Nienhaus A. Risk of latent TB infection in individuals employed in the healthcare sector in Germany: a multicentre prevalence study. BMC Infect Dis 2010;10:107. 4. Joshi R, Reingold AL, Menzies D, Pai M. Tuberculosis among health-care workers in low- and middle-income countries: a systematic review. PLoS Med 2006;3:e494. 5. Pai M, Gokhale K, Joshi R, et al. Mycobacterium tuberculosis infection in health care workers in rural India: comparison of a whole-blood interferon gamma assay with tuberculin skin testing. J Am Med Assoc 2005;293:2746e2755. 6. Harada N, Nakajima Y, Higuchi K, Sekiya Y, Rothel J, Mori T. Screening for tuberculosis infection using whole-blood interferon-gamma and Mantoux testing among Japanese healthcare workers. Infect Control Hosp Epidemiol 2006;27:442e448. 7. Baba K, Okuno Y, Tanaka-Taya K, Okabe N. Immunization coverage and natural infection rates of vaccine-preventable diseases among children by questionnaire survey in 2005 in Japan. Vaccine 2010 Sep 23 [Epub ahead of print]. 8. Kenyon TA, Valway SE, Ihle WW, Onorato IM, Castro KG. Transmission of multidrug-resistant Mycobacterium tuberculosis during a long airplane flight. N Engl J Med 1996;334:933e938. 9. Joint Tuberculosis Committee of the British Thoracic Society. Control and prevention of tuberculosis in the United Kingdom: Code of Practice 2000. Thorax 2000;55:887e901. 10. Culver DA, Gordon SM, Mehta AC. Infection control in the bronchoscopy suite: a review of outbreaks and guidelines for prevention. Am J Respir Crit Care Med 2003;167:1050e1056. 11. Lee KS, Hwang JW, Chung MP, Kim H, Kwon OJ. Utility of CT in the evaluation of pulmonary tuberculosis in patients without AIDS. Chest 1996;110:977e984. 12. American Thoracic Society. Targeted tuberculin testing and treatment of latent tuberculosis infection. MMWR Recomm Rep 2000;49:1e51. 13. Pai M, Riley LW, Colford Jr JM. Interferon-gamma assays in the immunodiagnosis of tuberculosis: a systematic review. Lancet Infect Dis 2004;4:761e776. 14. Ferebee SH. Controlled chemoprophylaxis trials in tuberculosis. A general review. Bibl Tuberc 1970;26:28e106. 15. Akolo C, Adetifa I, Shepperd S, Volmink J. Treatment of latent tuberculosis infection in HIV infected persons. Cochrane Database Syst Rev 2010, Issue 1. Art. No.: CD000171. DOI: 10.1002/14651858.CD000171.pub3. 16. Balcells ME, Thomas SL, Godfrey-Faussett P, Grant AD. Isoniazid preventive therapy and risk for resistant tuberculosis. Emerg Infect Dis 2006;12:744e751.
Available online at www.sciencedirect.com
Journal of Hospital Infection journal homepage: www.elsevierhealth.com/journals/jhin
Tuberculosis screening programme using the QuantiFERONÒ-TB Gold test and chest computed tomography for healthcare workers accidentally exposed to patients with tuberculosis T. Hirama*, K. Hagiwara, M. Kanazawa Department of Respiratory Medicine, Saitama Medical University, Saitama, Japan
a r t i c l e i n f o
s u m m a r y
Article history: Received 10 June 2010 Accepted 15 November 2010 Available online 12 February 2011
Healthcare workers (HCWs) have an increased incidence of tuberculosis (TB). Periodic and asneeded screenings of HCWs exposed to patients with TB are important. We integrated chest computed tomography (CT) and the QuantiFERONÒ-TB Gold (QFT-G) test into our TB screening programme for HCWs. First, contacts were tested using the QFT-G test. Those positive for the QFT-G test were investigated by CT and classified as having active, latent (LTBI), or old TB. Between April 2005 and April 2010, 11 patients who had not been diagnosed with active TB on admission were found to have the disease. A total of 512 close or high risk contacts were identified, and underwent screening. Out of those, 34 (6.64%) were QFT-G positive, whereas 478 (93.36%) were negative. Of the 34 QFT-G-positive HCWs, four had CT findings compatible with active TB and received multidrug treatment; 24 showed no findings of active TB and received isoniazid for six months. All completed their regimens without any adverse effects. The TB screening programme integrating CT and the QFT-G test was safe and feasible. The efficacy of the programme needs to be confirmed by large scale clinical trials. Ó 2010 The Hospital Infection Society. Published by Elsevier Ltd. All rights reserved.
Keywords: Chest computed tomography Healthcare workers QuantiFERONÒ-TB Gold test
Introduction Healthcare-associated transmission of tuberculosis (TB) is a serious issue.1,2 Healthcare workers (HCWs) have been reported to show a high incidence of TB, which was probably transmitted by accidental exposure to patients with TB.3e6 In turn, this creates a risk for the patients receiving care from these HCWs. Periodical or pre-employment screenings of all HCWs, in addition to as-needed screenings of HCWs accidentally exposed to patients with TB, are important.3 Tuberculosis infection may be active or latent (LTBI); the former presents symptoms or other indications of disease, whereas the latter is silent. The diagnosis of active TB is straightforward: signs and symptoms, or chest radiograph findings are confirmed by culture or polymerase chain reaction tests. However, the diagnosis of LTBI is not as simple. This is suspected as a result of an enhanced reaction to the
* Corresponding author. Address: Department of Respiratory Medicine, Saitama Medical University, 38 Morohongo, Moroyama-machi, Saitama 350-0495, Japan. Tel./fax: þ81 492761319. E-mail address: [email protected] (T. Hirama).
tuberculin skin test (TST), but there is no procedure for confirming diagnosis. The classification of TB determines the regimen of the treatment required. Active disease is treated with multiple antituberculosis drugs, whereas LTBI is treated with isoniazid (INH) monotherapy. The treatment scheme stated above has been widely acknowledged and used. Nevertheless, there is a risk of undertreatment due to insufficient sensitivity of chest radiographs for detecting active TB; patients may be diagnosed as having LTBI and treated only by INH. There is also a risk of overtreatment due to the insufficient specificity of TST for detecting LTBI; a positive TST can be either due to bacille CalmetteeGuérin (BCG) vaccination or infection with non-tuberculous mycobacteria. As a result, patients who have not been exposed to TB may be treated by INH. This is especially relevant to the countries with a high BCG vaccination rate such as Japan (96.5%).7 The addition of chest computed tomography (CT) will increase the sensitivity of TB disease detection, and replacement of the TST with the QuantiFERONÒ-TB Gold (QFT-G) will increase the specificity in detecting LTBI, thus enabling more precise treatment. We therefore integrated chest CTs and the QFT-G test into our TB screening programme for HCWs. First, contacts were tested using the QFT-G test; those who tested negative were excluded. Positive
0195-6701/$ e see front matter Ó 2010 The Hospital Infection Society. Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.jhin.2010.11.012
258
T. Hirama et al. / Journal of Hospital Infection 77 (2011) 257e262
contacts were investigated by CT and classified as having active, latent or old TB. Finally, those with active TB were treated with a multidrug regimen [INH, rifampicin (REF), ethambutol (EB), and pyrazinamide (PZA)], whereas those with LTBI were treated with INH monotherapy. We retrospectively investigated the utility, safety, and feasibility of this programme that has been conducted at the Saitama Medical University Hospital (SMUH) for five years. Methods Infection Control Subcommittee for Tuberculosis (ICST) The SMUH is a 712-bed general hospital for patients with acute or subacute illnesses. It does not have a ward dedicated to patients with TB. The ICST was organised in April 2005 by members of the Infection Control Team with experts on TB control, and has been responsible for the TB screening programme. TB screening programme Traced contacts The TB screening programme has been active from April 2005 to the present. The programme is conducted by the ICST: once every two years, targeting HCWs who have worked in an infectious disease ward; and each time HCWs are accidentally exposed to a patient
Infectious disease ward worker: n = 157
with TB disease. In the former case, all HCWs are considered to be close contacts (Figure 1). In the latter, the programme first assesses the infectiousness of the disease, and the closeness of contact according to the criteria summarised below.8e10 (I) Infectiousness of the disease. (a) Infectious TB: (1) disease with a pulmonary cavity on chest radiograph or (2) disease positive for sputum smear. (b) Non-infectious TB: disease other than that described above. (II) Closeness of contact. (a) A close contact: an HCW who has worked for >8 h in the room of a patient with infectious TB; an HCW who has performed an aerosol-producing procedure on the patient, including bronchoscopy, airway suction, sputum induction or administration of aerosolised medication; an HCW who has performed examination procedures on the patient (e.g. ultrasound, bedside radiogram, or laboratory examination). (b) A non-close contact: an HCW who has had contact with a patient with infectious TB but did not fit the criteria for a close contact. (c) A high risk contact: any contact who is infected with human immunodeficiency virus, has diabetes mellitus, chronic renal failure, malignancies, or who is on prolonged corticosteroid or immunosuppressive treatments.
Accidental contact: n = 355
Every two years Close contact
Close contact
High-risk contact
Non-close contact
Traced contact >10% of trace contact TB disease or LTBI?
Contact tracing procedure
NO Step 1
Inquiry
YES Terminate tracing
Step 2
{
Inquiry
QFT-G positive?
2-year annual follow-up by chest radiograph
YES CT
TB disease Step 3
NO
Antituberculosis multidrug treatment
LTBI
Old TB
INH monotherapy
Figure 1. The tuberculosis (TB) screening programme for healthcare workers. LTBI, latent tuberculosis infection; QFT-G, QuantiFERONÒ-TB Gold; CT, computed tomography; INH, isoniazid.
T. Hirama et al. / Journal of Hospital Infection 77 (2011) 257e262
When the disease is infectious, close contacts and high risk contacts are classified as traced contacts.
259
Results TB screening programme
Contact tracing procedures Contact tracing procedures are undertaken for all traced contacts. The procedures consist of three steps (Figure 1). Step 1: Just after exposure. The ICST inquires about health problems, previous history of TB, regular use of medication, and presence of respiratory symptoms. Step 2: 8e10 weeks after exposure. The ICST makes the same inquiries as in Step 1. A chest radiograph and the QFT-G test are performed. Traced contacts who are positive for the QFT-G test (i.e. ESAT-6 > 0.10 IU/mL or CFP-10 >0.10 IU/mL) are considered to have either active or latent TB; chest CT scans are taken to investigate the presence of pulmonary lesions. Traced contacts with CT findings consistent with activity are considered to have active TB.11 Traced contacts with CT findings consistent with old TB were considered to have old TB.11 All others are considered to have LTBI. If Step 2 reveals the presence of TB disease or LTBI in more than 10% of traced contacts, the patient’s disease is considered highly infectious and all non-close contacts are henceforth included in the traced contacts e the contact tracing procedures for non-close contacts are initiated from Step 2. Step 3: Drug administration. Traced contacts with active TB are treated with multiple antituberculosis drugs. Normally treatment is started with four drugs, INH, REF, EB, and PZA, for two months, followed by INH and REF for four months; these are amenable to change depending on the sensitivity of the M. tuberculosis strain isolated from the patient they have been exposed to. Traced contacts with LTBI are given INH monotherapy for six months.12 Ethical considerations The TB screening programme reported in the current study was approved by the institutional review board of the Saitama Medical University.
Between April 2005 and April 2010, 11 patients who had not been diagnosed with active TB on admission were later found to have the disease. The ICST conducted the TB screening programme for HCWs in the infectious disease ward twice, and an additional 11 times for HCWs who could have had accidental exposures (Table I). A total of 512 close contacts and high risk contacts underwent screening; 34 (6.64%) had a positive QFT-G test, and 478 (93.36%) were negative. Of the 34 QFT-G positives, four had CT findings compatible with active TB and received multidrug treatment. The chest CTs for 24 showed no indication of activity; these HCWs received INH for six months. All contacts completed their regimens without any adverse effects. Two contacts had CT findings consistent with old TB, and were put on a two-year follow-up regimen by annual chest radiography.11 The details of the four contacts who received multidrug treatments are presented below. Case 1: A 25-year-old female nurse who worked in the pulmonary disease ward The QFT-G results were ESAT-6, 0.31 IU/mL and CFP-10, 0.12 IU/mL (Figure 2). The chest CT showed centrilobular nodules in the right apex of the lung, which was difficult to detect on a chest radiograph. The subject had no previous history of TB disease or respiratory symptoms. A chest CT taken three years previously was negative for nodules. The subject received multidrug treatment for six months and the CT findings improved after treatment. Case 2: A 31-year-old male physician who worked in the pulmonary disease ward The QFT-G results were ESAT-6, 0.02 IU/mL and CFP-10, 0.11 IU/mL (Figure 3). The chest CT showed a round nodular shadow (indicated by an arrow) in the left lingula segment, which was difficult to detect with chest radiography. The subject received multidrug treatment for six months but the CT findings remained unchanged, suggesting that the subject may not have had active TB.
Table I The 355 HCWs accidently exposed to tuberculosis out of a total of 512 contacts Date of incidence
Patient’s characteristics Main lesion of tuberculosis
Aug 2005
Pulmonary
Sep 2005 Oct 2005 May 2007 Jul 2007
Endobronchial Pulmonary Systemic (miliary tuberculosis) Pulmonary
Aug 2007 Jan 2008 Mar 2008
Pulmonary Pulmonary Pulmonary
Jul 2008 Nov 2008
Pulmonary Systemic (miliary tuberculosis) Pulmonary
Jan 2009
Findings that support infectivity Cavitation in chest radiograph Positive sputum smear Positive sputum smear Positive sputum smear Cavitation in chest radiograph Positive sputum smear Positive sputum smear Cavitation in chest radiograph Positive sputum smear Positive sputum smear Positive sputum smear
Contacts Underlying disease
Close contactsa
Contact tracing procedure High risk contacts
Positive QFT-Gb
Abnormal chest CT
Received multidrug treatment
Behçet disease
41
1
2 (0)
0
0
Rheumatoid arthritis Peritonitis
41 36 (18) 17
0 1 0
2 (0) 1 (0) 1 (0)
0 0 0
0 0 0
Diabetes
27
0
3 (0)
0
0
MCTD Behçet disease Malignant rheumatoid arthritis
19 44 (14) 24 (19)
0 1 0
1 (0) 3 (0) 1 (0)
0 1 0
0 1 0
45 46 (32)
0 1
0 (0) 0 (0)
NA NA
0 0
0 4
0 (0) 14 (0)
NA 1
0 1
Arteritis temporalis Liver cirrhosis Total
11 351
CT, computed tomography; MCTD, mixed connective tissue disease; NA, not applicable. a Values in parentheses indicate HCWs who were involved in previous incidences and thus were counted more than once. b Values in parentheses indicate the number of high risk contacts in positive QuantiFERON Gold (QFT-G).
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Figure 2. Case 1. (A) Chest radiograph showing no findings suggestive of active tuberculosis. (B) Chest computed tomography (CT) showing centrilobular nodules in the right apex of the lung, which are difficult to visualise on a chest radiograph. (C) Chest CT taken three years before (A) was taken, showing a normal right apex. (D) Chest CT taken after a multidrug treatment revealed that the nodules seen in (B) were resolved.
Case 3: A 24-year-old female nurse who worked in the infectious disease ward The QFT-G results were ESAT-6, 0.01 IU/mL and CFP-10, 0.12 IU/mL (Figure 4). The chest CT showed centrilobular nodules (indicated by an arrow) situated right above the diaphragm. The subject received multidrug treatment for six months and the CT findings improved. Case 4: A 22-year-old female nurse who worked in the rheumatic disease ward The QFT-G results were ESAT-6, 0.12 IU/mL and CFP-10, 0.01 IU/mL (Figure 5). The subject had previously undergone the QFT-G test (ESAT-6, 0.01 IU/mL and CFP-10, 0.01 IU/mL) performed six months before the TB screening programme. The chest CT scan revealed a poorly defined nodule accompanying satellite nodules in the left upper lobe. The subject received multidrug treatment for six months and the CT findings improved.
Discussion The combination of the QFT-G test and chest CT is widely used in the clinical practice of TB diagnosis. However, there are no reported TB screening procedures that integrate both the QFT-G and chest CT in the healthcare setting. This prompted us to design the procedures reported in the current study. The QFT-G test has greater specificity than the TST in detecting current or past history of exposure to M. tuberculosis; thus, we obtained chest CT scans of all contacts with positive QFT-G test results.13 Meanwhile, there was little information regarding the sensitivity of the QFT-G test e especially regarding its sensitivity for the detection of LTBI. Therefore, all traced contacts who had negative QFT-G results underwent a two-year follow-up by chest radiography. None of them showed any active TB, suggesting that those with negative QGT-G results did not need follow-up. However, a larger scale study is necessary to confirm this, especially in the healthcare setting.
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Figure 3. Case 2. (A) Chest computed tomography (CT) showing a round nodular shadow in the left lingular segment, which was difficult to detect on a chest radiograph. (B) The nodule seen in (A) did not change after multidrug treatment.
Many studies have shown the superior effectiveness of chest CT to chest radiography for the diagnosis of TB disease, but CT for all traced contacts is not practicable. Therefore, we limited CT scans only to contacts with positive QFT-G test results.
Previous clinical trials have demonstrated that INH monotherapy for LTBI substantially reduces the probability of developing active TB.14,15 However, treatment of active TB with INH monotherapy is known to promote the development of INH-resistant
Figure 4. Case 3. (A) Chest computed tomography showing centrilobular nodules situated right above the diaphragm. (B) The nodules seen in (A) were resolved after a multidrug treatment.
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Figure 5. Case 4. (A) Chest radiograph showing no findings suggestive of active tuberculosis. (B) Chest computed tomography showing a poorly defined nodule accompanying satellite nodules in the left upper lobe.
TB.16 This raises a concern that misdiagnosis of contacts with active TB as LTBI creates a risk for developing INH-resistant TB. We had three cases (1, 3, and 4) in which, according to the response to the therapy, the diagnosis was likely to have been active TB. However, they would have been diagnosed as LTBI if chest CT scans had not been obtained. This confirms the utility of our TB screening programme, which integrates both the QFT-G test and CT; now there is a need for a clinical trial to demonstrate that the programme indeed suppresses the development of INH-resistant TB. In the present study, we retrospectively investigated the utility, safety, and feasibility of the TB screening programme for HCWs, which has been in effect for five years at our university hospital. Identification of three cases that were probably active TB that would have been otherwise diagnosed as having LTBI suggests the superiority of our procedure over procedures in which the QFT-G or chest CT scans are not conducted. Our procedure has been safely performed without any problems. However, a prospective study is needed to investigate whether our procedure is more effective than programmes that do not include the QFT-G test or chest CT. Conflict of interest statement None declared. Funding source This study was performed using research funds of the Saitama Medical University. References 1. Jensen PA, Lambert LA, Iademarco MF, Ridzon R. Guidelines for preventing the transmission of Mycobacterium tuberculosis in health-care settings, 2005. MMWR Recomm Rep 2005;54:1e141.
2. Guidelines for the investigation of contacts of persons with infectious tuberculosis. Recommendations from the National Tuberculosis Controllers Association and CDC. MMWR Recomm Rep 2005;54:1e47. 3. Schablon A, Harling M, Diel R, Nienhaus A. Risk of latent TB infection in individuals employed in the healthcare sector in Germany: a multicentre prevalence study. BMC Infect Dis 2010;10:107. 4. Joshi R, Reingold AL, Menzies D, Pai M. Tuberculosis among health-care workers in low- and middle-income countries: a systematic review. PLoS Med 2006;3:e494. 5. Pai M, Gokhale K, Joshi R, et al. Mycobacterium tuberculosis infection in health care workers in rural India: comparison of a whole-blood interferon gamma assay with tuberculin skin testing. J Am Med Assoc 2005;293:2746e2755. 6. Harada N, Nakajima Y, Higuchi K, Sekiya Y, Rothel J, Mori T. Screening for tuberculosis infection using whole-blood interferon-gamma and Mantoux testing among Japanese healthcare workers. Infect Control Hosp Epidemiol 2006;27:442e448. 7. Baba K, Okuno Y, Tanaka-Taya K, Okabe N. Immunization coverage and natural infection rates of vaccine-preventable diseases among children by questionnaire survey in 2005 in Japan. Vaccine 2010 Sep 23 [Epub ahead of print]. 8. Kenyon TA, Valway SE, Ihle WW, Onorato IM, Castro KG. Transmission of multidrug-resistant Mycobacterium tuberculosis during a long airplane flight. N Engl J Med 1996;334:933e938. 9. Joint Tuberculosis Committee of the British Thoracic Society. Control and prevention of tuberculosis in the United Kingdom: Code of Practice 2000. Thorax 2000;55:887e901. 10. Culver DA, Gordon SM, Mehta AC. Infection control in the bronchoscopy suite: a review of outbreaks and guidelines for prevention. Am J Respir Crit Care Med 2003;167:1050e1056. 11. Lee KS, Hwang JW, Chung MP, Kim H, Kwon OJ. Utility of CT in the evaluation of pulmonary tuberculosis in patients without AIDS. Chest 1996;110:977e984. 12. American Thoracic Society. Targeted tuberculin testing and treatment of latent tuberculosis infection. MMWR Recomm Rep 2000;49:1e51. 13. Pai M, Riley LW, Colford Jr JM. Interferon-gamma assays in the immunodiagnosis of tuberculosis: a systematic review. Lancet Infect Dis 2004;4:761e776. 14. Ferebee SH. Controlled chemoprophylaxis trials in tuberculosis. A general review. Bibl Tuberc 1970;26:28e106. 15. Akolo C, Adetifa I, Shepperd S, Volmink J. Treatment of latent tuberculosis infection in HIV infected persons. Cochrane Database Syst Rev 2010, Issue 1. Art. No.: CD000171. DOI: 10.1002/14651858.CD000171.pub3. 16. Balcells ME, Thomas SL, Godfrey-Faussett P, Grant AD. Isoniazid preventive therapy and risk for resistant tuberculosis. Emerg Infect Dis 2006;12:744e751.