Prevalence of and Risk Factors for Latent Tuberculosis Infection among Healthcare Workers of Directly Observed Tuberculosis Treatment Centers of Kathmandu, Nepal

Introduction: The object of this study was to assess the burden of latent tuberculosis (TB) infection among the healthcare workers at centers for directly observed treatment (DOT) for TB in Nepal and to describe associated risk factors for LTBI in this population. It is very important to measure prevalence of LTBI among high risk group as WHO suggest to treat LTBI in all high risk groups to eliminate TB. BCG coverage in Nepal is 90.9% according to department of health service in 2019. Methods: This was a cross-sectional study conducted from May 2019 to March 2020 at the 113 DOT centers across Kathmandu district. With two healthcare workers per DOT center on average, the total number of study participants was 226. After obtaining written consent, the trained data collectors interviewed healthcare workers with a predesigned questionnaire for risk analysis. Those with no symptoms of TB were administered TST. The result was read in 72 hours and recorded in millimeters. To increase the sensitivity, the TST reading of ≥ 5 mm was regarded as positive TST and samples were collected for IGRA. Results: TST was used as the screening tool (30% prevalence by cut off 10mm) and IGRA as the confirmatory test, 17.6% (95% CI 13.08 - 23.44) for the healthcare workers studied had LTBI with the duration of employment as a healthcare worker as an independent risk factor LTBI (adjusted OR CI 1.01 - 1.11, p = 0.006) after adjusting for other factors. Conclusions: This study suggests that, in Nepal, IGRAs should serve as a necessary confirmatory test for diagnosis of LTBI among healthcare workers before starting preventive therapy, as TST may be false positive due to BCG vaccination and that the duration of employment as a healthcare worker is an independent risk factor for LTBI.

It is, therefore, important that the people at high risk be screened and treated for LTBI. It confers benefit by preventing the active TB disease and decreasing the reservoir population [4,5]. The WHO End TB Strategy calls for targeted screening and treatment of high-risk individuals in its quest for TB elimination by 2035 [6]. Healthcare workers, particularly those caring for patients with tuberculosis, are among the high-risk individuals due to their repeated contacts with the patients with TB as well as variable TB infection control practices in the healthcare settings. It has been found that healthcare workers have more than two times higher risk of LTBI in comparison to the general population [7]. Guidelines have recommended screening and treatment of LTBI of healthcare workers based on the background TB epidemiology, available resources and possible harms of treatment [1,8]. In Nepal, the majority of the patients with TB receive care from directly observed TB treatment centers across the country and the healthcare workers at these centers are at higher risk for tuberculosis [2].
However, limited data on the burden of TB or LTBI among the Nepalese healthcare workers have been reported.
In this study, we aim to estimate the prevalence of LTBI among the healthcare workers at directly observed TB treatment centers of Kathmandu district. We also aim to assess the risk factors for latent TB among these populations. The information obtained will provide evidence of the existing occupational risk of infection in health care settings.

Methods
This was a cross-sectional study. Study site was the directly observed TB treatment (DOT) centers under the National TB Program (NTP) are responsible for a large proportion of TB care in Nepal. Due to resource constraints, this study has been confined to the DOT centers from Kathmandu District -the country capital. There are 113 DOT centers across Kathmandu district. All these DOT centers were included in the study. Study Population was the healthcare workers at the DOT Centers of Kathmandu District Sampling unit was the healthcare workers of the DOT centers of Kathmandu District. The objective of this study is to assess the burden of latent tuberculosis among the healthcare workers at directly observed TB treatment centers and describe the risk factors for the same.
The sample size was calculated by the formula n = Z2P(1-P)/ d2 where Z is level of confidence taken as 1.96, P is expected the prevalence of LTBI among the healthcare workers taken as 41% (the pooled prevalence value corresponding to the TB incidence of Nepal) and d is the degree of precision taken as 10%. The sample size thus derived was 93. Because the cluster sampling technique was applied, it was multiplied by the design effect of 2. An additional 20% non-response rate was estimated, and the final sample size was 223. With two healthcare workers per DOT center on average, the total number of study participants was226.  There were 169 (74.7%) study participants who reported to have been vaccinated with BCG and all these participants had a BCG vaccination scar.
A majority of the study participants (195, 87%) were non-

smokers.
There were 52 (23%), study participants, with one or more of the chronic illnesses with systemic hypertension being the most common chronic illness, seen in 28 study participants.
A majority of the study participants had BMI in the range of 20 -25 with a median BMI of 24.9 (IQR 22.9 -27.5).
The median TST reading was 5 mm (IQR 0-10) with most of the study participants had < 5 mm reading (Figure 2 and Table 1). With the TST reading of 5 mm or more as a cut-off for positive TST results, 115 (50.8%) participants had positive TST results ( Figure 3).
Of the 115 study participants with positive TST results, a whole blood sample for all these participants was obtained for IGRA, 40 samples tested positive (Figure 4). The prevalence of latent TB infection was 17.6% (95% CI 13.08 -23.44).   On univariate analyses between potential risk factors and LTBI, age, duration of employment as a health worker, number of patients encountered per day and TB in colleagues were found to have a significant association with LTBI ( found to be an independent risk factor for LTBI (adjusted OR 1.06, 95% CI 1.01 -1.11, p = 0.006) ( Figure 5).

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Discussion
The prevalence of LTBI in this study was found to be lower than the pooled estimates of 39% (based on IGRA results) or 49% (based on TST results) reported in the updated systematic review and meta-analysis of the studies among healthcare workers from lowand middle-income countries [9]. Several possible explanations could be offered to account for this observed difference.
First, the algorithm for diagnosis of LTBI in this study uses TST as the screening tool to select a subset of the study population and IGRA as the confirmatory test to diagnose LTBI in this population.
The implications are twofold. While this strategy strives for higher specificity in LTBI diagnosis, the cost is the lower sensitivity in Second, though the TST cut-off of ≥ 5 mm was used to increase its sensitivity, only one-step TST was used in this study which may have failed to elicit the optimal response of remote TB infection in some individuals due to waned cell-mediated immunity.12 A second TST done 1 -3 weeks of the first TST (called two-step TST) has been shown to find additional individuals with positive TST [13][14][15]. This phenomenon, known as boosting, increases in the settings with high TB burden and high rate of BCG vaccinations [12]. Use of one-step TST in this study may have missed a subset of study participants who would have tested positive in two-step TST and thus would have been tested for IGRA subsequently, contributing to the LTBI burden estimation.
Third, there are important differences in the study populations in this study and the studies which contributed to the pooled prevalence estimates [9]. Most of the participants (63.7%) in this study were allied health professionals and none were physicians or general services staff (Figure 7). In addition, there were laboratory and public health professionals included as well in this study. The pooled estimates in the systematic-review have been obtained from the studies that had representations from physicians as well as general services staff. In the stratified analysis reported, the LTBI prevalence was lower in allied health professionals (45% versus 49% in overall healthcare workers, based on TST or 31% versus 39% in overall healthcare workers, based on IGRA). In nursing professionals, the prevalence estimates are higher (54% versus 49% in overall healthcare workers) based on TST and lower (34% versus 39% in overall healthcare workers) based on IGRA.
Estimates from laboratory or public health professionals were not available for comparison.
The duration of employment as a health worker, found to be a statistically significant risk factor in this study, has been reported as an important occupational risk factor for LTBI in earlier studies as well. In the systematic review and meta-analysis of the studies from low-and middle-income countries, eight studies reported the duration of the employment as one of the risk factors for LTBI, either by TST or IGRA [9]. This suggests that longer the duration of employment as a health worker, longer the duration of exposure with the patients with TB and therefore, higher the risk of getting

Conclusion
It is very important to treat LTBI to eliminate TB from the world.
WHO suggest to start treating LTBI in high risk groups beyond less than 5 years and HIV patients in Nepal to eliminate TB. Before starting treatment we should confirm the diagnosis of LTBI. This study suggests that, in Nepal, IGRAs should serve as a necessary confirmatory test for diagnosis of LTBI among healthcare workers before starting preventive therapy and the duration of employment as a healthcare worker is an independent risk factor for LTBI.