Conceived and designed the experiments: DJC PD MP. Performed the experiments: DJC PD LA PJ BTJI BT BP. Analyzed the data: AZ MP. Contributed reagents/materials/analysis tools: DJC. Wrote the paper: DJC AZ MP. Provided funding: MP.
The authors have declared that no competing interests exist.
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
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.
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.
Tuberculosis (TB) continues to be a global killer, with over 9 million new cases of active disease diagnosed every year.
HCWs in high TB burden settings are at higher risk of developing LTBI, compared with the general population, because of their exposure to large numbers of smear-positive TB cases managed at hospitals or health care centers. Nurses, in particular, spend a lot of time caring for smear positive and smear negative pulmonary TB patients, and are particularly at risk for acquisition of LTBI
Traditionally, screening HCWs for LTBI was done with the Tuberculin Skin Test (TST), however there are some limitations for its use in serial testing HCWs, including: complications with boosting and conversions.
In an effort to better understand nosocomial TB among nursing trainees in Southern India, we initiated a cohort study among nursing students training at a large tertiary care hospital. Our earlier publication on this cohort of young nursing trainees reported a high LTBI prevalence of 47.8% using latent class analysis (95% credible interval: 17.8%–65.6%).
Our study was conducted at the Christian Medical College (CMC) in Vellore, India. Nursing students at the college were approached for enrollment in the study in the year 2007 and were followed up prospectively at yearly intervals. TST was repeated annually, but only if previously negative. Students with a positive TST result were assessed for active TB, and TST was not repeated in these individuals. Baseline demographics and results of cross-sectional testing of this cohort have been published previously.
All study participants were aged 18 or more, and all participants provided written informed consent. The study protocol was approved by the institutional review boards at both Christian Medical College Hospital, Vellore, India and McGill University, Montreal, Canada. All clinical investigations were conducted according to the principles expressed in the Declaration of Helsinki.
The CMC is a large (2200 beds) tertiary referral medical school at Vellore, a town located in the Tamil Nadu state of Southern India. The district of Vellore has an annual TB case detection rate of 148/100,000.
Student nurses from all 6 programs offered at the College of Nursing, CMC, Vellore were approached for inclusion in the study, including: Nursing diploma, BSc, Post diploma BSc courses, fellowship courses, MSc, and Doctoral (PhD) programs. Students with a past history of TB were excluded from the study at recruitment. The remaining eligible nursing students signed written consent forms to participate in the prospective cohort.
All nursing students at CMC routinely maintain detailed clinical log books, which were used to collect information regarding the students' likelihood of TB exposure. Students recorded if they had had direct contact with a smear positive TB patient, and the number of days spent working on various medical wards.
Data were ascertained from clinical log books at baseline and at testing 1 year later. Log books helped identify students who had been exposed to TB and to quantify the number of days spent caring for pulmonary TB patients, since baseline testing. Other exposure information ascertained included: days worked on isolation, pulmonary medicine, and general medicine wards, number of times performed or assisted in sputum collection, all since baseline testing. At both baseline and annual testing, students were asked about exposure to TB outside the hospital setting.
Students were tested with TST at baseline using the two step TST protocol.
Students were tested with the QuantiFERON-TB Gold In-Tube (QFT) test (Cellestis Ltd, Carnegie, Australia). QFT was performed per manufacturer's instructions, and the QFT was considered positive if the Interferon-gamma response of TB antigen minus the nil was ≥0.35 IU/mL. QFT was performed on all recruits at the annual screening in 2008. Given only one time point with QFT results we were not able to look at QFT conversions/reversions in this cohort, but such analyses will be possible with subsequent follow-up of this same cohort.
Isoniazid (INH) preventive therapy is not routinely offered to HCWs with LTBI in India because of the high background prevalence of LTBI, risks associated with drug toxicity, concern about wide-spread resistance to INH, chances of poor compliance, a high likelihood for re-exposure and re-infection, and lack of evidence that preventive therapy has long term efficacy in TB endemic populations. However, recent conversions are associated with an elevated risk of developing active TB. Therefore, students who had TST conversions upon testing at 1 year were assessed to rule out active TB and then offered preventive therapy using 4 months of Rifampicin, one of the acceptable preventive therapy regimens.
Clinical and demographic data, along with variables concerning exposure to TB for the cohort were summarized using descriptive statistics. The frequency distribution of TST measurements were displayed graphically as histograms. The main outcome was annual risk of TB infection (ARTI), with 95% confidence intervals, estimated using TST conversions as defined above. This was followed by an analysis to assess the major risk factors for TST conversions. First, univariate regression was used to assess a potential relationship between TB exposure and known clinical and occupational risk variables and a TST conversion. Finally a multivariate logistic model was fit to assess the relationship between TST conversions and known occupational risk factors for TB, variables such as age and BCG vaccination were included due to their a priori association with TST positivity despite not reaching statistical significance in univariate models. All analyses were performed using Stata 11 (Stata Corp, Texas, USA).
Nursing students who were TST negative after baseline two-step testing in 2007 were approached for repeat testing in 2008.
The cohort was predominantly female (96.7%), 83.8% were under 22 years of age, and 80% of students had evidence of BCG vaccination. All study participants were aged 18 or more. The majority of students were enrolled in the diploma or BSc nursing programs, and the mean time spent working in health care was 34.5 months (Range:13–193; Median = 28 IQR = 17–39).
Variable | N = 179 | % |
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Female | 173 | 96.65 |
Male | 6 | 3.35 |
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18 | 26 | 14.53 |
19 | 46 | 25.7 |
20 | 44 | 24.58 |
21 | 34 | 18.99 |
22 and older | 29 | 16.20 |
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< = 19 | 53 | 29.61 |
>19 | 126 | 70.39 |
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Class 12 | 162 | 90.5 |
Diploma | 12 | 6.7 |
Bachelor degree | 4 | 2.23 |
Masters degree | 1 | 0.56 |
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Diploma | 89 | 49.72 |
BSc | 77 | 43.02 |
Post Diploma BSc | 9 | 5.03 |
Post diploma specialty | 1 | 0.56 |
MSc | 3 | 1.68 |
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<5000 | 64 | 35.75 |
5000–10,000 | 62 | 34.64 |
10,000–20,000 | 28 | 15.64 |
20,000–30,000 | 12 | 6.7 |
>30,000 | 9 | 5.03 |
Refused | 4 | 2.23 |
Variable | N = 179 | % |
BCG vaccination | ||
No | 8 | 4.5 |
At birth | 140 | 78.2 |
After birth | 3 | 1.7 |
Unknown | 28 | 15.6 |
Total months in health care | Median = 28IQR: 17–39 | |
Direct contact with smear positive TB pt since last testing | ||
No | 54 | 30.2 |
Yes | 65 | 36.3 |
Yes, but unsure if smear positive | 32 | 17.9 |
Don't Know | 28 | 15.6 |
Days spent caring for pulmonary TB since last testing | Median = 4IQR: 0–9 | |
Performed or assisted with sputum collection since last testing | ||
Never | 101 | 56.4 |
<10 times | 75 | 41.9 |
>10 times | 3 | 1.67 |
Days spent working on isolation wards since last testing | Median = 4IQR: 0–6 | |
Days spent working on pulmonary medicine wards since last testing | Median = 0IQR = 0 (Range:0–14) | |
Reported contact with TB outside the hospital setting | 5 | 2.8 |
Nursing students maintained detailed clinical log books, which were used to ascertain days spent working on different wards and exposure to smear positive pulmonary patients. Sixty-five students (36.3%) had had direct contact with a smear positive TB patient as part of their nurse training since baseline testing in 2007. A further 32 students (17.9%) had had direct contact with TB patients, but were unsure if they were smear positive. Students reported a mean of 6.04 days caring for pulmonary TB patients since baseline testing (Range: 0–60 days; Median = 4 IQR = 0–9). Since baseline testing, students reported working a mean of 4.45 days on isolation wards (Range: 0–28 days; Median = 4 IQR = 0–6) and a mean of 0.76 days working in pulmonary medicine wards (Range: 0–14 days; Median = 0 IQR = 0). Almost half of the cohort (43.57%) had performed or assisted with sputum collection since last TST testing. Only five students (2.79%) recalled contact with TB outside the hospital setting since baseline testing, presumably because they were all residing in the institutional hostels (dormitories).
Using the standard ATS/CDC/IDSA definition for a TST conversion: a repeat TST induration of 10 mm or higher and an increase in induration of 10 mm over the baseline TST result, we found 14 students met the definition for TST conversion. Therefore using this definition we estimate an annual risk of TB infection (ARTI) of 7.8%, (95% CI: 4.34–12.77). Of the 14 students with conversions, 13 (93%) consented to preventive therapy and completed 4 months of daily Rifampicin therapy. No serious adverse events occurred.
QFT results were available for 177 out of 179 TST negative nursing students who underwent repeat testing in 2008. Using the manufacturer's cut-off, 131 students (74%) tested negative, 44 tested positive (24.9%) and two had indeterminate responses (1.1%).
Among the 14 students who met the ATS/CDC/IDSA definition for TST conversion, 9 (64.3%) were also positive by QFT in 2008, (range of IFN-gamma: 0.55–14.3 IU/mL). The remaining 5 TST converters, tested negative on QFT-GIT (range: 0.32–0.09 IU/mL).
Variable | OR | 95% CI |
Age (yrs) | 1.01 | (0.81–1.27) |
BCG vaccination | 0.9 | (0.1–7.67) |
BMI >19 | ||
<19 | 1 | - |
>19 | 0.93 | (0.78–1.12) |
Highest level of education completed | ||
Class 12 | 1 | - |
Diploma or higher | 1.67 | (0.34–8.16) |
Nursing Course Currently Enrolled | ||
Diploma | 1 | - |
BSc | 0.32 | (0.08–1.2) |
Post BSc diploma or MSc | 0.66 | (0.08–5.6) |
Average household monthly income (Indian Rupees) | ||
Low (<5,000) | 1 | - |
Medium (5,000–10,000) | 1.26 | (0.36–4.4) |
High (>10,000) | 0.5 | (0.09–2.7) |
Total time spent in health care (months) | 0.999 | (0.977–1.02) |
Direct contact with sputum positive TB pt | 0.93 | (0.73–1.19) |
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Days spent working on isolation wards | 0.998 | (0.90–1.11) |
Days spent working on pulmonary medicine wards | 1.12 | (0.91–1.37) |
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We also looked at the association between QFT results and TST Conversions in 2008. QFT positivity (using the manufacturer's cut-off, 0.35 IU/ml) showed the strongest association with TST conversions (OR = 4.15, 95% CI:1.55–11.13), while continuous IFN-gamma responses (measured in IU/mL) were also significantly associated with conversions (OR = 1.56, 95% CI:1.2–2.02).
Variable | OR | 95% CI |
Age (yrs) | 1.08 | (0.85–1.39) |
BCG vaccination | 0.45 | (0.04–4.62) |
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TB continues to be a major public health concern worldwide. In India, where there are more TB cases than any other country, HCWs are at higher risk for TB exposure compared to the general population. The growing concern worldwide regarding TBIC and nosocomial infection has brought attention to the problem of hospital acquired TB infection among HCWs. While our previous study
We found TST conversions were associated with the 2 variables capturing occupational TB exposure namely; days spent caring for pulmonary TB patients (OR = 1.12, 95%CI: 1.04–1.20) and having performed or assisted in sputum collection. The latter was strongly associated with TST conversions, as we would expect, given the high risk nature of the procedure (OR = 4.57, 95% CI: 1.11–18.86) and also because nursing trainees at CMC do not routinely use N95 respirators while doing the procedure. This suggests that certain occupational activities may be associated with high risk of TST conversions, even in a high TB incidence setting, and suggests areas for implementation of TBIC.
The longitudinal nature of the study, ascertainment of TB exposure data from detailed clinical log books, maintained prospectively throughout the study and the ability to associate new exposures to new TST conversions represent strengths of our study. Detailed exposure data are particularly difficult to attain in a high incidence settings such as India, and this study is one of the few that have shown that TST conversions are associated with specific occupational exposures.
One study limitation is the TST itself. False positives can happen with the TST, either because of previous BCG vaccination or by sensitization to non tuberculous mycobacteria (NTM). However, BCG vaccination in India is routinely given at birth and not repeated,
The high ARTI in this cohort indicates ongoing nosocomial transmission at CMC hospital. Health care workers are the backbone in the fight against TB and we must endeavor to protect them while they care for contagious patients. Indian healthcare providers and the Indian Revised National TB Control Programme will need to consider implementing infection control interventions in hospitals and health care centers in order to reduce nosocomial transmission and protect health care workers. With the WHO TBIC policy guidelines now available,
A recent modeling study from India examined the likely benefits of IPT as an intervention to reduce TB rates in Indian HCWs.
While testing all HCWs in India is daunting, we think a strong case can be made for at least doing annual TSTs on young HCWs and trainees – especially medical and nursing students, interns, allied health sciences students who are at risk of TB exposure, and postgraduates during their residency training.
The rate-limiting step for Indian hospitals and administrators, we suspect, is not lack of resources. After all, TST screening and isoniazid therapy are inexpensive, and most large hospitals already have the required expertise in hospital infection control committees. The real problem may be apathy, unwillingness to act on available evidence, and a fatalistic acceptance that TB risk is part and parcel of being a healthcare professional in India
We are grateful to all the student nurses at the Christian Medical College, Vellore, for their participation in our study. We also appreciate the support of College of Nursing, CMC, Vellore.