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1.  Prevalence and Incidence of Latent Tuberculosis Infection in Georgian Healthcare Workers 
PLoS ONE  2013;8(3):e58202.
Background
Tuberculosis is a major occupational hazard in low and middle-income countries. Limited data exist on serial testing of healthcare workers (HCWs) with interferon-γ release assays (IGRAs) for latent tuberculosis infection (LTBI), especially in low and middle-income countries. We sought to evaluate the rates of and risk factors for LTBI prevalence and LTBI test conversion among HCWs using the tuberculin skin test (TST) and QuantiFERON-TB Gold In-tube assay (QFT-GIT).
Methods
A prospective longitudinal study was conducted among HCWs in the country of Georgia. Subjects completed a questionnaire, and TST and QFT-GIT tests were performed. LTBI testing was repeated 6-26 months after baseline testing.
Results
Among 319 HCWs enrolled, 89% reported prior BCG vaccination, and 60% worked in TB healthcare facilities (HCFs). HCWs from TB HCFs had higher prevalence of positive QFT-GIT and TST than those from non-TB HCFs: 107/194 (55%) vs. 30/125 (31%) QFT-GIT positive (p<0.0001) and 128/189 (69%) vs. 64/119 (54%) TST positive (p = 0.01). There was fair agreement between TST and QFT-GIT (kappa = 0.42, 95% CI 0.31–0.52). In multivariate analysis, frequent contact with TB patients was associated with increased risk of positive QFT-GIT (aOR 3.04, 95% CI 1.79–5.14) but not positive TST. Increasing age was associated with increased risk of positive QFT-GIT (aOR 1.05, 95% CI 1.01–1.09) and TST (aOR 1.05, 95% CI 1.01–1.10). High rates of HCW conversion were seen: the QFT-GIT conversion rate was 22.8/100 person-years, and TST conversion rate was 17.1/100 person-years. In multivariate analysis, female HCWs had decreased risk of TST conversion (aOR 0.05, 95% CI 0.01–0.43), and older HCWs had increased risk of QFT-GIT conversion (aOR 1.07 per year, 95% CI 1.01–1.13).
Conclusion
LTBI prevalence and LTBI test conversion rates were high among Georgian HCWs, especially among those working at TB HCFs. These data highlight the need for increased implementation of TB infection control measures.
doi:10.1371/journal.pone.0058202
PMCID: PMC3607575  PMID: 23536789
2.  Latent tuberculosis in nursing professionals of a Brazilian hospital 
Tuberculosis (TB) is considered an occupational disease among health-care workers (HCWs). Direct contact with TB patients leads to an increased risk to become latently infected by Mycobacterium tuberculosis. The objective of this study is to estimate the prevalence of latent M. tuberculosis minfection among nursing professionals of a hospital in Rio Grande do Sul, Brazil, assessed by tuberculin skin test (TST). From November 2009 to May 2010, latent M. tuberculosis infection was assessed by TST in 55 nursing professionals. Epidemiological information was collected using a standardized questionnaire. A positive TST result (> or = 10 mm) was observed in 47.3% of the HCWs tested. There was no significant difference in TST positivity when duration of employment or professional category (technician or nurse) was evaluated. The results of this work reinforce the need for control measures to prevent latent M. tuberculosis infection among nursing professionals at the hospital where the study was conducted.
doi:10.1186/1745-6673-6-15
PMCID: PMC3118213  PMID: 21575267
Tuberculosis; Tuberculin Skin Test; Health-Care Workers
3.  Administrative measures for preventing Mycobacterium tuberculosis infection among healthcare workers in a teaching hospital in Rio de Janeiro, Brazil 
Summary
Tuberculosis (TB) is an occupational disease of healthcare workers (HCWs). Administrative and engineering interventions simultaneously implemented in hospitals of developed countries have reduced the risk of nosocomial transmission of M. tuberculosis. We have studied the impact of administrative infection control measures on the risk for latent TB infection (LTBI) among HCWs in a resource-limited, high-burden country. An intervention study was undertaken in a university-affiliated, inner-city hospital in Rio de Janeiro, where routine serial tuberculin skin test (TST) is offered to all HCWs. From October 1998 to February 2001, the following administrative infection control measures were progressively implemented: isolation of TB suspects and confirmed TB inpatients, quick turnaround for acid-fast bacilli sputum tests and HCW education in use of protective respirators. Among 1336 initially tested HCWs, 599 were retested. The number of TST conversions per 1000 person-months during and after the implementation of these measures was reduced from 5.8/1000 to 3.7/1000 person-months (P = 0.006). The most significant reductions were observed in the intensive care unit (from 20.2 to 4.5, P < 0.001) and clinical wards (from 10.3 to 6.0, P < 0.001). Physicians and nurses had the highest reductions (from 7.6 to 0, P < 0.001; from 9.9 to 5.8, P = 0.001, respectively). We conclude that isolated administrative measures for infection control can significantly reduce LTBI among HCWs in high-burden countries and should be implemented even when resources are not available for engineering infection control measures.
doi:10.1016/j.jhin.2009.01.016
PMCID: PMC2737465  PMID: 19278753
Infection control; Health personnel; Nosocomial infection; Occupational exposure; Tuberculin test; Tuberculosis
4.  Determining the Latent Tuberculosis Infection by IFN - γ Elispot Assay in Healthcare Workers From University Hospitals of Shiraz, South West of Iran 
Background
Classical screening methods are incapable to properly detect LTBI (Latent TB Infection) and HCWs (Healthcare Workers) are at the high risk of exposure. Only few reports estimated the prevalence of LTBI among Iranian HCWs and they mostly used the TST (Tuberculin Skin Test), rather than assessing the response against TB-specific antigens.
Objectives
The current study aimed to determine the frequency of IFN - γ producing blood cells of microbiology and radiology ward technicians by an in-house IFN - γ ELISPOT assay in the University hospitals of Shiraz University of Medical Sciences (SUMS) against recombinant ESAT - 6 and PPD antigens.
Materials and Methods
89 HCWs from medical laboratory and radiology departments of Shiraz University of Medical Sciences’ hospitals, South of Iran, were screened for LTBI. To achieve the goal, an in-house IFN - γ (Interferon - gamma) ELISPOT (Enzyme Linked ImmunoSpot) assay was used to detect the reactivity against ESAT - 6 (Early Secreted Antigen Target protein - 6) and the PPD (Purified Protein Derivate).
Results
Almost 8% of the personnel showed positive TST (over 10 mm) reaction while 29% of them had considerable T - cell reactivity against PPD in ELISPOT assays. However, the ESAT - 6 reactivity was found only in one case of HCWs. No correlation was found between the patterns of the reactions and the age or the duration of the employment or previous vaccination history of the participants. The ELISPOT results were not correlated with the TST results.
Conclusions
Considering the hindrance of TST, the IFN - γ ESAT - 6 ELISPOT assay, even in forms of in-house tests, could replace traditional methods to properly spot the LTBI among the high risk groups from Iran’s health system.
doi:10.5812/ircmj.3635
PMCID: PMC3840834  PMID: 24349745
Latent tuberculosis; Tuberculin test; Interferon - gamma; Enzyme-Linked Immunospot Assay; Iran
5.  Multicytokine Detection Improves Latent Tuberculosis Diagnosis in Health Care Workers 
Journal of Clinical Microbiology  2012;50(5):1711-1717.
In a low-incidence setting, health care workers (HCW) are at a higher risk of tuberculosis than the general population. The suboptimal sensitivity of the QuantiFERON-TB Gold In-Tube (QFT) test remains a critical issue when identifying occupational latent tuberculosis infection (LTBI) in HCW. The aim of this study was to identify additional biomarkers in order to overcome the limits of gamma interferon (IFN-γ) release assays (IGRAs) and improve the performance of LTBI diagnosis within this population. Seventy Bacille Calmette-Guérin-vaccinated HCW regularly exposed to Mycobacterium tuberculosis were grouped according to QFT results into an LTBI-positive group (positive QFT, n = 8), an LTBI-negative group (normal QFT and negative tuberculin skin test [TST], n = 21), and an undetermined group (subpositive QFT and/or positive TST, n = 41). The secretion of 22 cytokines in response to QFT-specific stimulation was quantified using a multiparameter-based immunoassay. As a result, thresholds discriminating LTBI-positive from LTBI-negative HCW were established by comparing areas under the receiver operating characteristic curves for interleukin-2 (IL-2), IL-15, IFN-γ-induced protein 10 (IP-10), and the monokine induced by IFN-γ (MIG), which are biomarkers differentially secreted by the two groups. The combination of IL-15 and MIG provided a sensitivity of 100% and a specificity of 94.1% in distinguishing LTBI-positive from LTBI-negative HCW. When using IL-15 and MIG among the undetermined group, 6/45 HCW could be classified in the LTBI-positive group. The use of additional biomarkers after IGRA screening could improve the diagnosis of LTBI. The performance of these biomarkers and their use in combination with TST and/or QFT, as well as the cost-effectiveness of such a diagnostic strategy, should be evaluated in further larger clinical trials.
doi:10.1128/JCM.00117-12
PMCID: PMC3347142  PMID: 22403417
6.  Prevalence and Risk Factors for Tuberculosis Infection among Hospital Workers in Hanoi, Viet Nam 
PLoS ONE  2009;4(8):e6798.
Background
Transmission of tuberculosis (TB) to health care workers (HCWs) is a global issue. Although effective infection control measures are expected to reduce nosocomial TB, HCWs' infection has not been assessed enough in TB high burden countries. We conducted a cross-sectional study to determine the prevalence of TB infection and its risk factors among HCWs in Hanoi, Viet Nam.
Methodology/Principal Findings
A total of 300 HCWs including all staff members in a municipal TB referral hospital received an interferon-gamma release assay (IGRA), QuantiFERON-TB Gold In-TubeTM, followed by one- and two-step tuberculin skin test (TST) and a questionnaire-based interview. Agreement between the tests was evaluated by kappa statistics. Risk factors for TB infection were analyzed using a logistic regression model. Among the participants aged from 20 to 58 years (median = 40), prevalence of TB infection estimated by IGRA, one- and two-step TST was 47.3%, 61.1% and 66.3% respectively. Although the levels of overall agreement between IGRA and TST were moderate, the degree of agreement was low in the group with BCG history (kappa = 0.29). Working in TB hospital was associated with twofold increase in odds of TB infection estimated by IGRA. Increased age, low educational level and the high body mass index also demonstrated high odds ratios of IGRA positivity.
Conclusions/Significance
Prevalence of TB infection estimated by either IGRA or TST is high among HCWs in the hospital environment for TB care in Viet Nam and an infection control program should be reinforced. In communities with heterogeneous history of BCG vaccination, IGRA seems to estimate TB infection more accurately than any other criteria using TST.
doi:10.1371/journal.pone.0006798
PMCID: PMC2728839  PMID: 19710920
7.  Prevalence of latent tuberculosis infection among health care workers in a hospital for pulmonary diseases 
Background
Little is known about the prevalence of latent tuberculosis infections (LTBI) in health care workers (HCW) in low-incidence countries especially in hospitals for pulmonary diseases. With Interferon-gamma release assays (IGRA), a new method for diagnosis of LTBI is available which is more specific than the tuberculin skin test (TST).
Objectives
The study was designed to estimate prevalence of LTBI among 270 HCW in a Hospital of Pulmonary Diseases routinely screened for TB.
Methods
LTBI was assessed by the QuantiFERON-Gold In Tube (QFT-IT). Information on gender, age, workplace, job title, BCG vaccination and history of both TB and TST were collected using a standardised questionnaire. Adjusted odds ratios for potential risk factors for LTBI were calculated.
Results
The prevalence of LTBI was 7.2%. In HCW younger than 30 years LTBI prevalence was 3.5% and in those older than 50 years 22%. Physicians and nurses showed a higher prevalence rate than other professions (10.8% to 4.5%). The putative risk factors for LTBI were age (>50 year OR 9.3, 95%CI 2.5–33.7), working as physicians/nurses (OR 3. 95%CI 1.2–10.4) and no previous TST in medical history (OR 4.4, 95%CI 1.01–18.9) when compared to those with a negative TST.
Conclusion
Prevalence of LTBI assessed by QFT-IT is low, this indicates a low infection risk even in hospitals for pulmonary diseases. No statement can be made regarding the occupational risk as compared to the general population because there are no LTBI prevalence data from Germany available. The higher LTBI prevalence rate in older HCWs might be due to the cohort effect or the longer time at risk.
doi:10.1186/1745-6673-4-1
PMCID: PMC2631010  PMID: 19134168
8.  Discordant QuantiFERON-TB Gold Test Results Among US Healthcare Workers With Increased Risk of Latent Tuberculosis Infection: A Problem or Solution? 
OBJECTIVE
In late 2006, our hospital implemented use of the QuantiFERON-TB Gold (QFT-G) assay, a whole-blood interferon-γ release assay, for detection of tuberculosis infection. All newly hired healthcare workers (HCWs) with positive Mantoux tuberculin skin test (TST) results were routinely tested with the QFT-G assay, to take advantage of its higher specificity. We then undertook a quality assurance review to evaluate the QFT-G test results in HCWs with multiple risk factors for latent tuberculosis infection (LTBI).
METHODS
The clinical records for TST-positive HCWs tested with the QFT-G assay were reviewed. HCWs with 2 or more risk factors commonly associated with LTBI were classified as “increased risk” (IR). IR HCWs who had negative QFT-G test results underwent repeat QFT-G testing and were offered testing with a different interferon-γ release assay (T-SPOT.TB) and with extended T cell stimulation assays.
RESULTS
Of 143 TST-positive HCWs tested with the QFT-G assay, 26 (18%) had positive results, 115 (81%) had negative results, and 2 (1%) had indeterminate results. Of 82 IR HCWs, 23 (28%) had positive QFT-G test results, and 57 (70%) had negative results. Of the 57 IR HCWs with negative results, 43 underwent repeat QFT-G testing: 41 had negative results again, and 2 had positive results. These 43 HCWs were also offered additional testing with the T-SPOT.TB diagnostic, and 36 consented: 31/36 tested negative, and 5/36 tested positive. Extended assays using the antigens ESAT-6 and CFP-10 confirmed the positive results detected by the overnight assays and yielded positive results for an additional 7/36 (19%) of individuals; strikingly, all 36 HCWs had strongly positive test results with assays using purified protein derivative.
CONCLUSIONS
The extreme discordance between the results of our clinical diagnostic algorithm and the results of QFT-G testing raises concern about the sensitivity of the QFT-G assay for detection of LTBI in our HCWs. Results of extended stimulation assays suggest that many of our IR HCWs have indeed been sensitized to Mycobacterium tuberculosis. It is possible that the QFT-G assay identifies those at higher reactivation risk rather than all previously infected, but, in the absence of long-term follow-up data, we should interpret negative QFT-G results with some caution.
doi:10.1086/590262
PMCID: PMC3578293  PMID: 18713053
9.  Results of five-year systematic screening for latent tuberculosis infection in healthcare workers in Portugal 
Introduction
The risk of tuberculosis (TB) in healthcare workers (HCWs) is related to its incidence in the general population, and increased by the specific risk as a professional group. The prevalence of latent tuberculosis infection (LTBI) in HCWs in Portugal using the tuberculin skin test (TST) and the interferon-γ release assays (IGRA) was analyzed over a five-year period.
Methods
A screening programme for LTBI in HCWs was conducted, with clinical evaluations, TST, IGRA, and chest radiography. Putative risk factors for LTBI were assessed by a standardised questionnaire.
Results
Between September 2005 and June 2009, 5,414 HCWs were screened. The prevalence of LTBI was 55.2% and 25.9% using a TST ≥ 10 mm or an IGRA test result (QuantiFERON-TB Gold In-Tube) INF-γ ≥0.35 IU/mL as a criterion for LTBI, respectively. In 53 HCWs active TB was diagnosed. The number of HCWs with newly detected active TB decreased from 19 in the first year to 6 in 2008. Risk assessment was poorly related to TST diameter. However, physicians (1.7%) and nurses (1.0%) had the highest rates of active TB.
Conclusions
LTBI and TB burden among HCWs in Portugal is high. The screening of these professionals to identify HCWs with LTBI is essential in order to offer preventive chemotherapy to those with a high risk of future progression to disease. Systematic screening had a positive impact on the rate of active TB in HCWs either by early case detection or by increasing the awareness of HCWs and therefore the precautions taken by them.
doi:10.1186/1745-6673-5-22
PMCID: PMC2921383  PMID: 20659314
10.  Performance of QuantiFERON-TB Gold In-Tube test and Tuberculin Skin Test for diagnosis of latent tuberculosis infection in BCG vaccinated health care workers 
Background
Tuberculin skin test (TST) has been used for years as an aid in diagnosing latent tuberculosis infection (LTBI) but it suffers from a number of well-documented performance and logistic problems. Quantiferon-TB Gold In Tube test (QFT-GIT) has been reported to have better sensitivity and specifity than TST. In this study, it was aimed to compare the performance of a commercial IFN-γ release assay (QFT-GIT) with TST in the diagnosis of HCWs at risk for latent TB infection in BCG vaccinated population.
Material/Methods
Hundred healthy volunteer health care workers were enrolled. All were subjected to TST and QFT-GIT. Results were compared among Health Care Workers (HCWs) groups in terms of profession, workplace, working duration.
Results
TST is affected by previous BCG vaccinations and number of cases with QFT-GIT positivity is increased in accordance with the TST induration diameter range. QFT-GIT result was negative in 17 of 32 TST positive (≥15 mm) cases and positive in 4 of 61 cases whose TST diameters are between 6–14 mm, that is attritutable to previous BCG vaccination(s). It was negative in all cases with TST diameters between 0–5 mm.
HCWs with positive QFT-GIT results were significantly older than the ones with negative results. Furthermore duration of work was significantly longer in QFT-GIT positive than in negative HCWs.
Conclusions
There was a moderate concordance between QFT-GIT and TST, when TST result was defined as positive with a ≥15 mm diameter of induration. We suggest that QFT-GIT can be used as an alternative to TST for detection of LTBI, especially in groups with high risk of LTBI and in population with routine BCG vaccination program.
doi:10.12659/MSM.889943
PMCID: PMC3976198  PMID: 24681806
Skin Tests; Quantiferon-TB Gold In-Tube; Latent Tuberculosis; Tuberculin Test
11.  Tuberculosis examination using whole blood interferon-gamma release assay among health care workers in a Japanese hospital without tuberculosis-specific wards 
SpringerPlus  2013;2:440.
Occupational latent tuberculosis infection (LTBI) among health care workers (HCWs) is an important public health issue. The objective of this study is to assess prevalence and risk factors of LTBI among Japanese HCWs by Quantiferon-TB Gold in Tube (QFT-GIT) and the structured questionnaire. This is a cross-sectional study involving HCWs from a hospital without tuberculosis-specific wards, receiving QFT-GIT for LTBI screening. We reviewed medical records of HCWs and questioned HCWs about exposure to M. tuberculosis and employment length in health care industries. 165 HCWs, approximately 80% of the total hospital staff, were enrolled in this study.18 out of 165 subjects had positive results, suggesting LTBI prevalence rate of 11%. Multiple regression analysis revealed a significant association between the positive or intermediate QFT-GIT results and history of contact investigation for tuberculosis. QFT-GIT positivity rate among HCWs is higher than among general population in Japan.
doi:10.1186/2193-1801-2-440
PMCID: PMC3790903  PMID: 24102039
Latent tuberculosis infection; Quantiferon-TB gold in tube; Latent tuberculosis infection baseline screening; Health care workers
12.  The effect of introducing IGRA to screen French healthcare workers for tuberculosis and potential conclusions for the work organisation 
Introduction
In France, pre-employment screening for tuberculosis (TB) is performed for healthcare workers (HCW). Screening is repeated when exposure to TB patients or infectious material occurs. The results of these TB screenings were analysed in a retrospective analysis.
Method
Tuberculin skin tests (TST) and interferon-gamma release assays (QuantiFERON® Gold In-Tube – QFT) were used to perform the TB screenings. The screening results of 637 HCWs on whom QFT was performed were taken from the records of the University Hospital of Nantes.
Results
In three (0.5%) HCW, the QFT was indeterminate. In 22.2%, the QFT was positive. A second QFT was performed in 118 HCWs. The reversion rate was 42% (5 out of 17). The conversion rate was 6% (6 out of 98). A TST was performed on 466 (73.5%) of the HCWs. Results for TST > 10 mm were 77.4%. In those with a TST < 10 mm, QFT was positive in 14% and in those with a TST ≥ 10 mm, QFT was positive in 26.7%. Depending on the definition for conversion in the QFT, the annual attack rate was 4.1% or 7.3%. X-ray and pneumology consultation was based on positive QFT rather than TST alone (52 out of 56). No active TB was detected.
Conclusion
The TST overestimated the prevalence of LTBI in this cohort. The decision about X-ray and consultation regarding preventive treatment should be based on the QFT rather than the TST results. The high reversion rate should be taken into consideration when consulting with HCWs regarding preventive treatment. The high conversion rate seems to indicate that preventive measures such as wearing masks should be improved.
doi:10.1186/1745-6673-8-12
PMCID: PMC3651707  PMID: 23647777
Tuberculosis; Healthcare workers; Interferon-gamma release assay
13.  Screening for tuberculosis and prediction of disease in Portuguese healthcare workers 
Introduction
Results of systematic screening of healthcare workers (HCWs) for tuberculosis (TB) with the tuberculin skin test (TST) and interferon-γ release assays (IGRA) in a Portuguese hospital from 2007 to 2010 are reported.
Methods
All HCWs are offered screening for TB. Screening is repeated depending on risk assessment. TST and QuantiFERON Gold In-Tube (QFT) are used simultaneously. X-ray is performed when TST is > 10 mm, IGRA is positive or typical symptoms exist.
Results
The cohort comprises 2,889 HCWs. TST and IGRA were positive in 29.5%, TST-positive but IGRA-negative results were apparent in 43.4%. Active TB was diagnosed in twelve HCWs - eight cases were detected during screening and four cases were predicted by IGRA as well as by TST. However, the progression rate in IGRA-positive was higher than in TST-positive HCWs (0.4% vs. 0.2%, p-value 0.06).
Conclusions
The TB burden in this cohort was high (129.8 per 100,000 HCWs). However, the progression to active TB after a positive TST or positive IGRA was considerably lower than that reported in literature for close contacts in low-incidence countries. This may indicate that old LTBI prevails in these HCWs.
doi:10.1186/1745-6673-6-19
PMCID: PMC3132202  PMID: 21658231
14.  Persistently elevated T cell interferon-γ responses after treatment for latent tuberculosis infection among health care workers in India: a preliminary report 
Background
T cell-based interferon-γ (IFN-γ) release assays (IGRAs) are novel tests for latent tuberculosis infection (LTBI). It has been suggested that T cell responses may be correlated with bacterial burden and, therefore, IGRAs may have a role in monitoring treatment response. We investigated IFN-γ responses to specific TB antigens among Indian health care workers (HCWs) before, and after LTBI preventive therapy.
Methods
In 2004, we established a cohort of HCWs who underwent tuberculin skin testing (TST) and a whole-blood IGRA (QuantiFERON-TB-Gold In-Tube [QFT-G], Cellestis Ltd, Victoria, Australia) at a rural hospital in India. HCWs positive by either test were offered 6 months of isoniazid (INH) preventive therapy. Among the HCWs who underwent therapy, we prospectively followed-up 10 nursing students who were positive by both tests at baseline. The QFT-G assay was repeated 4 and 10 months after INH treatment completion (i.e. approximately 12 months and 18 months after the initial testing). IFN-γ responses to ESAT-6, CFP-10 and TB7.7 peptides were measured using ELISA, and IFN-γ ≥0.35 IU/mL was used to define a positive QFT-G test result.
Results
All participants (N = 10) reported direct contact with smear-positive TB patients at baseline, during and after LTBI treatment. All participants except one started treatment with high baseline IFN-γ responses (median 10.0 IU/mL). The second QFT-G was positive in 9 of 10 participants, but IFN-γ responses had declined (median 5.0 IU/mL); however, this difference was not significant (P = 0.10). The third QFT-G assay continued to be positive in 9 of 10 participants, with persistently elevated IFN-γ responses (median 7.9 IU/mL; P = 0.32 for difference against baseline average).
Conclusion
In an environment with ongoing, intensive nosocomial exposure, HCWs had strong IFN-γ responses at baseline, and continued to have persistently elevated responses, despite LTBI treatment. It is plausible that persistence of infection and/or re-infection might account for this phenomenon. Our preliminary findings need confirmation in larger studies in high transmission settings. Specifically, research is needed to study T cell kinetics during LTBI treatment, and determine the effect of recurrent exposures on host cellular immune responses.
doi:10.1186/1745-6673-1-7
PMCID: PMC1481589  PMID: 16722616
15.  Predictors of persistently positive Mycobacterium-tuberculosis-specific interferon-gamma responses in the serial testing of health care workers 
BMC Infectious Diseases  2010;10:220.
Background
Data on the performance of Mycobacterium-tuberculosis-specific interferon-(IFN)-γ release assays (IGRAs) in the serial testing of health care workers (HCWs) is limited. The objective of the present study was to determine the frequency of IGRA conversions and reversions and to identify predictors of persistent IGRA positivity among serially tested German HCWs in the absence of recent extensive tuberculosis (TB) exposure.
Methods
In this observational cohort-study HCWs were prospectively recruited within occupational safety and health measures and underwent a tuberculin skin test (TST) and the IGRA QuantiFERON®-TB Gold In-Tube (QFT-GIT) at baseline. The QFT-GIT was repeated 18 weeks later in the median. QFT-GIT conversions (and reversions) were defined as baseline IFN-γ < 0.35 IU/ml and follow-up IFN-γ ≥ 0.35 IU/ml (and vice versa). Predictors of persistently positive QFT-GIT results were calculated by logistic regression analysis.
Results
In total, 18 (9.9%) and 15 (8.2%) of 182 analyzed HCWs were QFT-GIT-positive at baseline and at follow-up, respectively. We observed a strong overall agreement between baseline and follow-up QFT-GIT results (κ = 0.70). Reversions (6/18, 33.3%) occurred more frequently than conversions (3/162, 1.9%). Age and positive prior and recent TST results independently predicted persistent QFT-GIT positivity. Furthermore, the chance of having persistently positive QFT-GIT results raised about 3% with each additional 0.1 IU/ml increase in the baseline IFN-γ response (adjusted odds ratio 1.03, 95% confidence interval 1.01-1.04). No active TB cases were detected within an observational period of more than two years.
Conclusions
The QFT-GIT's utility for the application in serial testing was limited by a substantial proportion of reversions. This shortcoming could be overcome by the implementation of a borderline zone for the interpretation of QFT-GIT results. However, further studies are needed to clearly define the within-subject variability of the QFT-GIT and to confirm that increasing age, concordantly positive TST results, and the extend of baseline IFN-γ responses may predict the persistence of QFT-GIT positivity over time in serially tested HCWs with only a low or medium TB screening risk in a TB low-incidence setting.
doi:10.1186/1471-2334-10-220
PMCID: PMC2916913  PMID: 20653946
16.  Evaluation of Interferon-Gamma Release Assays in the Diagnosis of Recent Tuberculosis Infection in Health Care Workers 
PLoS ONE  2009;4(8):e6686.
Background
Health care workers (HCWs) are a group at risk of latent tuberculosis infection (LTBI). The aims of this study were to determine IFN-γ response by QuantiFERON-TB GOLD In Tube (QFN-G-IT) and T-SPOT.TB in HCWs, comparing the results with tuberculin skin test (TST); and to analyze the capacity of IFN-γ tests to detect recent versus remote LTBI with a prolonged stimulation test (PST).
Methodology/Principal Findings
A total of 147 HCWs were enrolled; 23 of whom were BCG vaccinated. 95 HCWs (64.6%) had a previous positive TST and were not retested; and 52 HCWs had a previous negative TST or were tested for the first time. When we analysed individuals without previous positive TST, the number of positive results for T-SPOT.TB was 12/52 (23.1%); and for QFN-G-IT, 9/52 (17.3%). The global concordance (κ) between T-SPOT.TB and QFN-G-IT with TST was 0.754 and 0.929 respectively. Of individuals with previous positive TST, T-SPOT.TB and QFN-G-IT were negative in 51.6% (49/95) and 62.1% (59/95) respectively, decreasing the concordance to 0.321 and 0.288, respectively. In non-BCG vaccinated HCWs with previous positive TST a positive IFN-γ test was associated with degree of exposure and diameter of TST. PST was performed in 24 HCW with previous positive TST and negative IFN-γ tests. PST was developed in 3 cell cultures stimulated with medium alone, ESAT-6 and CFP-10, respectively. In the third and sixth day of incubation period, part of the supernatants were replaced with complete medium supplemented with (rIL)-2. On day 9, ELISPOT assay was performed. In 14 samples PST was not valid due to not having enough cells. In 8 cases, the response was negative, and in 2 cases positive, suggesting that these patients were infected with Mycobacterium tuberculosis in some point in the past.
Conclusions
Both IFN-γ tests showed a similar number of positive results, and concordance between the tests was excellent. None of the tests was affected by prior BCG vaccination. IFN-γ tests are a useful tool for detecting recent infection in HCW population.
doi:10.1371/journal.pone.0006686
PMCID: PMC2726945  PMID: 19701460
17.  Prevalence and Risk Factors for Latent Tuberculosis Infection among Health-care Workers in the Country of Georgia 
SUMMARY
BACKGROUND
Tuberculosis (TB) is a major public health problem in Georgia, but few TB infection control measures have been implemented in health-care facilities.
OBJECTIVE
To assess the prevalence and risk factors for latent TB infection (LTBI) among Georgian health-care workers (HCWs) using two diagnostic tests, the tuberculin skin test (TST) and the QuantiFERON-TB in-tube-test (QFT-3G), an interferon-γ release assay.
METHODS
A cross-sectional study was conducted between June-August 2006 among HCWs at the Georgian National TB Program.
RESULTS
265 HCWs were enrolled; 177 (67%) had a positive TST and 159 (60%) had a positive QFT-3G. 203 (77%) had a positive result for at least one of the tests and 50% tested positive for both tests. There was moderately good agreement between the tests (74%, κ=0.43 95% CI 0.33-0.55). In multivariate analysis, employment for >5 years was associated with increased risk of a positive TST (OR=5.09; 95% CI, 2.77-9.33) and QFT-3G (OR=2.26; 95% CI, 1.27-4.01); age >30 years, was associated with an increased risk of a positive QFT-3G (OR=2.91; 95% CI, 1.32-6.43).
DISCUSSION
A high prevalence of LTBI was found among Georgian HCWs and longer duration of employment was associated with increased risk. These data highlight the need for effective TB infection control measures and provide important baseline information as TB infection control measures are implemented.
PMCID: PMC2742226  PMID: 18419886
tuberculosis infection; interferon-γ assay; nosocomial transmission; skin test
18.  Repeat IGRA Testing in Canadian Health Workers: Conversions or Unexplained Variability? 
PLoS ONE  2013;8(1):e54748.
Background
Although North American hospitals are switching from tuberculin testing (TST) to interferon-gamma release assays (IGRAs), data are limited on the association between occupational exposure and serial QuantiFERON-TB Gold In-Tube (QFT) results in healthcare workers (HCWs).
Methods
In a cohort of Canadian HCWs, TST and QFT were performed at study enrolment (TST1 and QFT1) and 1 year later (TST2 and QFT2). Conversion and reversion rates were estimated, and correlation with TB exposure was assessed.
Results
Among 258 HCWs, median age was 36.8 years, 188/258 (73%) were female and 183/258 (71%) were Canadian-born. In 245 subjects with a negative QFT1 we found a QFT conversion rate of 5.3% (13/245, 95% CI 2.9–8.9%). Using more stringent definitions, QFT conversion rates ranged from 2.0 to 5.3%. No TST conversions were found among the 241 HCWs with negative TST1, and no measure of recent TB exposure was associated with QFT conversions. In the 13 HCWs with a positive QFT1, 62% reverted.
Conclusion
Using the conventional QFT conversion definition, we found a higher than expected rate of conversion. Recent occupational exposures were not associated with QFT conversions, and no TST conversions occurred in this cohort, suggesting the ‘conversions’ may not reflect new TB infection.
doi:10.1371/journal.pone.0054748
PMCID: PMC3561382  PMID: 23382955
19.  Annual Risk of Tuberculosis Infection in Hellenic Air Force Recruits 
Background:
The annual risk of Tuberculosis infection (ARTI) is a key indicator in epidemiology, of the extent of transmission in a community. There have been several suggested methods in order to evaluate the prevalence of Tuberculosis infection using tuberculin skin data. This survey estimates the ARTI in young Hellenic air force recruits. The effect of BCG vaccination has also been investigated.
Materials and Methods:
During the period November 2006-November 2007 tuberculin skin tests were conducted to estimate the prevalence of mycobacterium tuberculosis infection and also to determine the ARTI. Tuberculin PPD-RT 23, dose 2 IU was used in 7.492 Greek air force military recruits with a mean age of 23.57 years. All recruits were examined for previous bacill Calmette-Guérin vaccination through BCG scar. A vast number of personal, epidemiological significance, data of the participants was collected.
Results:
The ARTI was 0.2%, in those who were not previously BCG vaccinated; this was derived from a tuberculin skin test cut-off point of 10 mm. There were not any statistically significant differences, neither between urban and rural population concerning the positivity of the tuberculin skin test, nor among the population in recent contact with immigrants from high-incidence countries.
Conclusion:
The estimated ARTI among non BCG vaccinated young Greek men is 0.2%.
doi:10.2174/1874306401307010077
PMCID: PMC3899589  PMID: 24459536
Tuberculosis; tuberculin skin test; epidemiology; Greece.
20.  Use of interferon gamma-based assay to diagnose tuberculosis infection in health care workers after short term exposure 
Background
We intended to assess the risk for health care workers (HCWs) of acquiring M. tuberculosis infection after exposure to patients with sputum-smear positive pulmonary tuberculosis at three University Hospitals (Ullevål, Akershus, and Haukeland) in Norway.
Methods
We tested 155 exposed health care workers and 48 healthy controls both with a tuberculin skin test (Mantoux) and the T-SPOT.TB test, a recently developed interferon-γ release assays based on the M. tuberculosis-specific ESAT-6 and CFP10 antigens, to investigate if this test might improve infection control measures.
Results
Among the 155 exposed HCWs tested in this study, 27 individuals were defined as newly infected cases by TST after recent exposure, while only 3 of these had a positive T-SPOT.TB test. The number of T-SPOT.TB positives represents 11% of the individuals defined as recently infected by TST after exposure (3/27) and 2% of the total number of exposed people tested (3/155). In addition, 15 individuals had been previously defined as infected by TST before exposure of whom 2 subjects were T-SPOT.TB positive. All individuals detected as T-SPOT.TB positive belonged to the TST positive group (> 15 mm), and the percentage concordance between T-SPOT.TB and TST, including both previously and newly infected subjects, was 12% (5/42). The 48 control participants used in the study were all T-SPOT.TB negative, but 3 of these subjects were TST positive.
Conclusion
Our data indicate that the frequency of latent TB in the total cohort of HCWs is 3%, whereas the rate of transmission of TB to exposed individuals is approximately 2% and occurs through exposure periods of short duration. Thus, the risk of TB transmission to HCWs following TB exposure in a hospital setting in Norway is low, and improved screening approaches will benefit from the application of specific interferon-γ release assays.
doi:10.1186/1471-2334-9-60
PMCID: PMC2690599  PMID: 19432995
21.  Prevalence of Abnormal Radiological Findings in Health Care Workers with Latent Tuberculosis Infection and Correlations with T Cell Immune Response 
PLoS ONE  2007;2(8):e805.
Background
More than half of all health care workers (HCWs) in high TB-incidence, low and middle income countries are latently infected with tuberculosis (TB). We determined radiological lesions in a cohort of HCWs with latent TB infection (LTBI) in India, and determined their association with demographic, occupational and T-cell immune response variables.
Methodology
We obtained chest radiographs of HCWs who had undergone tuberculin skin test (TST) and QuantiFERON-TB Gold In Tube (QFT), an interferon-γ release assay, in a previous cross-sectional study, and were diagnosed to have LTBI because they were positive by either TST or QFT, but had no evidence of clinical disease. Two observers independently interpreted these radiographs using a standardized data form and any discordance between them resolved by a third observer. The radiological diagnostic categories (normal, suggestive of inactive TB, and suggestive of active TB) were compared with results of TST, QFT assay, demographic, and occupational covariates.
Results
A total of 330 HCWs with positive TST or QFT underwent standard chest radiography. Of these 330, 113 radiographs (34.2%) were finally classified as normal, 206 (62.4%) had lesions suggestive of inactive TB, and 11 (3.4%) had features suggestive of active TB. The mean TST indurations and interferon-γ levels in the HCWs in these three categories were not significantly different. None of the demographic or occupational covariates was associated with prevalence of inactive TB lesions on chest radiography.
Conclusion/Significance
In a high TB incidence setting, nearly two-thirds of HCWs with latent TB infection had abnormal radiographic findings, and these findings had no clear correlation with T cell immune responses. Further studies are needed to verify these findings and to identify the causes and prognosis of radiologic abnormalities in health care workers.
doi:10.1371/journal.pone.0000805
PMCID: PMC1950085  PMID: 17726535
22.  High Annual Risk of Tuberculosis Infection among Nursing Students in South India: A Cohort Study 
PLoS ONE  2011;6(10):e26199.
Background
Nurses in developing countries are frequently exposed to infectious tuberculosis (TB) patients, and have a high prevalence of TB infection. To estimate the incidence of new TB infection, we recruited a cohort of young nursing trainees at the Christian Medical College in Southern India. Annual tuberculin skin testing (TST) was conducted to assess the annual risk of TB infection (ARTI) in this cohort.
Methodology/Principal Findings
436 nursing students completed baseline two-step TST testing in 2007 and 217 were TST-negative and therefore eligible for repeat testing in 2008. 181 subjects completed a detailed questionnaire on exposure to tuberculosis from workplace and social contacts. A physician verified the questionnaire and clinical log book and screened the subjects for symptoms of active TB. The majority of nursing students (96.7%) were females, almost 84% were under 22 years of age, and 80% had BCG scars. Among those students who underwent repeat testing in 2008, 14 had TST conversions using the ATS/CDC/IDSA conversion definition of 10 mm or greater increase over baseline. The ARTI was therefore estimated as 7.8% (95%CI: 4.3–12.8%). This was significantly higher than the national average ARTI of 1.5%. Sputum collection and caring for pulmonary TB patients were both high risk activities that were associated with TST conversions in this young nursing cohort.
Conclusions
Our study showed a high ARTI among young nursing trainees, substantially higher than that seen in the general Indian population. Indian healthcare providers and the Indian Revised National TB Control Programme will need to implement internationally recommended TB infection control interventions to protect its health care workforce.
doi:10.1371/journal.pone.0026199
PMCID: PMC3192164  PMID: 22022565
23.  In-hospital contact investigation among health care workers after exposure to smear-negative tuberculosis 
Background
Smear-negative pulmonary tuberculosis (TB) accounts for a considerable proportion of TB transmission, which especially endangers health care workers (HCW). Novel Mycobacterium-tuberculosis-specific interferon-γ release assays (IGRAs) may offer the chance to define the burden of TB in HCW more accurately than the Mantoux tuberculin skin test (TST), but the data that is available regarding their performance in tracing smear-negative TB in the low-incidence, in-hospital setting, is limited. We conducted a large-scale, in-hospital contact investigation among HCW of a German university hospital after exposure to a single case of extensive smear-negative, culture-positive TB with pulmonary involvement. The objective of the present study was to evaluate an IGRA in comparison to the TST and to identify risk factors for test positivity.
Methods
Contacts were prospectively enrolled, evaluated using a standardized questionnaire, the IGRA QuantiFERON®-TB Gold in Tube (QFT-GIT) and the TST, and followed-up for two years. Active TB was ruled out by chest x-ray in QFT-GIT-positive subjects. Independent predictors of test positivity were established through the use of logistic regression analysis.
Results
Out of the 143 subjects analyzed, 82 (57.3%) had close contact, but only four (2.8%) experienced cumulative exposure to the index case >40 hours. QFT-GIT results were positive in 13 subjects (9.1%), while TST results were positive in 40 subjects (28.0%) at an induration >5 mm. Overall agreement was poor between both tests (kappa = 0.15). Age was the only predictor of QFT-GIT-positivity (Odds ratio 2.7, 95% confidence interval 1.32–5.46), while TST-positivity was significantly related to Bacillus Calmette-Guérin vaccination and foreign origin. Logistic regression analysis showed no relation between test results and exposure. No secondary cases of active TB were detected over an observational period of two years.
Conclusion
Our findings suggest a low contagiosity of the particular index case. The frequency of positive QFT-GIT results may in fact reflect the pre-existing prevalence of latent TB infection among the study population. TB transmission seems unlikely and contact tracing not generally warranted after cumulative exposure <40 hours. However, the substantially lower frequency of positive QFT-GIT results compared to the TST may contribute to enhanced TB control in health care.
doi:10.1186/1745-6673-4-11
PMCID: PMC2698921  PMID: 19505310
24.  Prevalence of Latent Tuberculosis Infection among Health Care Workers in South Korea: A Multicenter Study 
Background
We investigated the prevalence of latent tuberculosis infection (LTBI) among the health care workers (HCWs) and analyzed its risk factors in South Korea.
Methods
A standard questionnaire regarding the baseline demographics and risk factors for LTBI was given to each participant and tuberculin skin test (TST), QuantiFERON-TB GOLD In-Tube (QFT-GIT) assay, and chest radiography were performed.
Results
A total of 493 participants, 152 (30.8%) doctors and 341 (69.2%) nurses were enrolled in eight tertiary referral hospitals. The mean age of the subjects was 30.6 years old, and 383 (77.7%) were female. Of the 152 doctors, 63 (41.4%) and 36 (23.7%) were positive by TST and by QTF-GIT, respectively, and among the 341 nurses, 119 (34.9%) and 49 (14.4%) had positive TST and QFT-GIT results, respectively. Overall, the agreement between the two tests was 0.22 by the chance corrected proportional agreement rate (kappa coefficient) in 493 subjects. Experience of working in tuberculosis (TB)-related departments was significantly associated with positive LTBI test results by QFT-GIT assay, not by TST. In multivariate analysis, only age was independently associated with increased risk of a positive TST result, while age and experience of working in TB-related departments (odds ratio, 2.29; 95% confidence interval, 1.01-5.12) were independently associated with increased risk of a positive QFT-GIT result.
Conclusion
A high prevalence of LTBI was found among South Korean HCWs. Considering the association between the experience of working in TB-related departments and high risk of LTBI, QFT-GIT may be a better diagnostic test for LTBI than TST in HCWs.
doi:10.4046/trd.2013.75.1.18
PMCID: PMC3741469  PMID: 23946754
Latent Tuberculosis; Health Personnel; Tuberculin Test; Interferon-gamma Release Tests; Republic of Korea
25.  Tuberculosis among Health-Care Workers in Low- and Middle-Income Countries: A Systematic Review 
PLoS Medicine  2006;3(12):e494.
Background
The risk of transmission of Mycobacterium tuberculosis from patients to health-care workers (HCWs) is a neglected problem in many low- and middle-income countries (LMICs). Most health-care facilities in these countries lack resources to prevent nosocomial transmission of tuberculosis (TB).
Methods and Findings
We conducted a systematic review to summarize the evidence on the incidence and prevalence of latent TB infection (LTBI) and disease among HCWs in LMICs, and to evaluate the impact of various preventive strategies that have been attempted. To identify relevant studies, we searched electronic databases and journals, and contacted experts in the field. We identified 42 articles, consisting of 51 studies, and extracted data on incidence, prevalence, and risk factors for LTBI and disease among HCWs. The prevalence of LTBI among HCWs was, on average, 54% (range 33% to 79%). Estimates of the annual risk of LTBI ranged from 0.5% to 14.3%, and the annual incidence of TB disease in HCWs ranged from 69 to 5,780 per 100,000. The attributable risk for TB disease in HCWs, compared to the risk in the general population, ranged from 25 to 5,361 per 100,000 per year. A higher risk of acquiring TB disease was associated with certain work locations (inpatient TB facility, laboratory, internal medicine, and emergency facilities) and occupational categories (radiology technicians, patient attendants, nurses, ward attendants, paramedics, and clinical officers).
Conclusions
In summary, our review demonstrates that TB is a significant occupational problem among HCWs in LMICs. Available evidence reinforces the need to design and implement simple, effective, and affordable TB infection-control programs in health-care facilities in these countries.
A systematic review demonstrates that tuberculosis is an important occupational problem among health care workers in low and middle-income countries.
Editors' Summary
Background.
One third of the world's population is infected with Mycobacterium tuberculosis, the bacterium that causes tuberculosis (TB). In many people, the bug causes no health problems—it remains latent. But about 10% of infected people develop active, potentially fatal TB, often in their lungs. People with active pulmonary TB readily spread the infection to other people, including health-care workers (HCWs), in small airborne droplets produced when they cough or sneeze. In high-income countries such as the US, guidelines are in place to minimize the transmission of TB in health-care facilities. Administrative controls (for example, standard treatment plans for people with suspected or confirmed TB) aim to reduce the exposure of HCWs to people with TB. Environmental controls (for example, the use of special isolation rooms) aim to prevent the spread and to reduce the concentration of infectious droplets in the air. Finally, respiratory-protection controls (for example, personal respirators for nursing staff) aim to reduce the risk of infection when exposure to M. tuberculosis is unavoidably high. Together, these three layers of control have reduced the incidence of TB in HCWs (the number who catch TB annually) in high-income countries.
Why Was This Study Done?
But what about low- and middle-income countries (LMICs) where more than 90% of the world's cases of TB occur? Here, there is little money available to implement even low-cost strategies to reduce TB transmission in health-care facilities—so how important an occupational disease is TB in HCWs in these countries? In this study, the researchers have systematically reviewed published papers to find out the incidence and prevalence (how many people in a population have a specific disease) of active TB and latent TB infections (LTBIs) in HCWs in LMICs. They have also investigated whether any of the preventative strategies used in high-income countries have been shown to reduce the TB burden in HCWs in poorer countries.
What Did the Researchers Do and Find?
To identify studies on TB transmission to HCWs in LMICs, the researchers searched electronic databases and journals, and also contacted experts on TB transmission. They then extracted and analyzed the relevant data on TB incidence, prevalence, risk factors, and control measures. Averaged-out over the 51 identified studies, 54% of HCWs had LTBI. In most of the studies, increasing age and duration of employment in health-care facilities, indicating a longer cumulative exposure to infection, was associated with a higher prevalence of LTBI. The same trend was seen in a subgroup of medical and nursing students. After accounting for the incidence of TB in the relevant general population, the excess incidence of TB in the different studies that was attributable to being a HCW ranged from 25 to 5,361 cases per 100, 000 people per year. In addition, a higher risk of acquiring TB was associated with working in specific locations (for example, inpatient TB facilities or diagnostic laboratories) and with specific occupations, including nurses and radiology attendants; most of the health-care facilities examined in the published studies had no specific TB infection-control programs in place.
What Do These Findings Mean?
As with all systematic reviews, the accuracy of these findings may be limited by some aspects of the original studies, such as how the incidence of LTBI was measured. In addition, the possibility that the researchers missed some relevant published studies, or that only studies where there was a high incidence of TB in HCWs were published, may also affect the findings of this study. Nevertheless, they suggest that TB is an important occupational disease in HCWs in LMICs and that the HCWs most at risk of TB are those exposed to the most patients with TB. Reduction of that risk should be a high priority because occupational TB leads to the loss of essential, skilled HCWs. Unfortunately, there are few data available to indicate how this should be done. Thus, the researchers conclude, well-designed field studies are urgently needed to evaluate whether the TB-control measures that have reduced TB transmission to HCWs in high-income countries will work and be affordable in LMICs.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0030494.
• US National Institute of Allergy and Infectious Diseases patient fact sheet on tuberculosis
• US Centers for Disease Control and Prevention information for patients and professionals on tuberculosis
• MedlinePlus encyclopedia entry on tuberculosis
• NHS Direct Online, from the UK National Health Service, patient information on tuberculosis
• US National Institute for Occupational Health and Safety, information about tuberculosis for health-care workers
• American Lung Association information on tuberculosis and health-care workers
doi:10.1371/journal.pmed.0030494
PMCID: PMC1716189  PMID: 17194191

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