A tuberculin skin test survey among healthcare workers in two public tertiary care hospitals in Bangladesh.

In Bangladesh, there is currently no data on the burden of latent TB infection (LTBI) amongst hospital healthcare workers (HCWs). This study aimed to determine the prevalence of LTBI and compare the prevalence among HCWs in two public tertiary care hospitals. Between September 2018 and August 2019, we conducted a cross-sectional study in two public tertiary care general hospitals. Using a survey and tuberculin skin test (TST), we assessed risk factors for LTBI, adjusting for known and plausible confounders. In addition, a facility assessment was undertaken to understand the implementation of relevant IPC measures. The prevalence of LTBI among HCWs was 42%. HCWs spent a median of 6 hours (SD = 1.76, IQR 2.00) per day and attended an average of 1.87 pulmonary TB patients per week. HCWs did not receive any TB IPC training, the wards lacked a symptom checklist to screen patients for TB, and no masks were available for coughing patients. Seventy-seven percent reportedly did not use any facial protection (masks or respirators) while caring for patients. In the multivariable model adjusting for hospital level clustering effect, TST positivity was significantly higher among HCWs aged 35-45 years (aOR1.36, 95% CI: 1.06-1.73) and with >3 years of service (aOR 1.67, 95% CI: 1.62-1.72). HCWs working in the medicine ward had 3.65 (95% CI: 2.20-6.05) times, and HCWs in the gynecology and obstetrics ward had 2.46 (95% CI: 1.42-4.27) times higher odds of TST positivity compared to HCWs working in administrative areas. This study identified high prevalence of LTBI among HCWs. This may be due to the level of exposure to pulmonary TB patients, and/or limited use of personal protective equipment along with poor implementation of TB IPC in the hospitals. Considering the high prevalence of LTBI, we recommend the national TB program consider providing preventative therapy to the HCWs as the high-risk group, and implement TB IPC in the hospitals.

Introduction

In 2019, the WHO estimated that 10 million people developed TB disease globally, of whom 44% were from South-East Asia [1]. Moreover, 22,314 healthcare workers (HCWs) developed TB in the same year, with most coming from high TB burden countries in Asia [1]. Hospital HCWs in high TB burden countries are at increased risk of TB infection due to their exposure to a higher number of pulmonary TB patients than the hospital HCWs working in low TB-incidence countries [2]. A recent mathematical modelling study on the global burden of latent TB infection (LTBI) estimated that around 1.7 billion people are infected with LTBI in the world [3]. In a systematic review of 18 studies from seven high TB burden countries, the prevalence of LTBI among HCWs was reported to be 47% (95% CI 34–60) [4]. This risk may be high among HCWs who work in health facilities that lack proper infrastructure and limited implementation of TB infection prevention and control (IPC) healthcare measures. The risk of LTBI among different health care workers may vary by place of work, duration of exposures, and compliance with TB IPC measures [5]. Prior studies identified considerable heterogeneity in the risk of LTBI among different occupations and reported high risk among doctors, nurses, and ancillary workers [5, 6]. HCWs that were most likely to be infected had the most prolonged duration and extent of patient contact [6, 7].

People with LTBI represent a reservoir for potential TB disease [3]. Without treatment, about 5 to 10% of infected persons may develop TB disease at some point in their lives, and the active stage frequently occurs within the first two years after infection [8, 9]. People with an impaired immune system are at increased risk of developing TB disease than persons with standard immune systems [9]. Diabetes and smoking also increase TB disease risk among the person with LTBI [10].

There is no gold-standard test to diagnose LTBI [11]. The widely available diagnostic tools are tuberculin skin test (TST) and interferon-gamma release assay (IGRA) that measure the response to in vivo or in vitro stimulation by M. tuberculosis antigens [12-14]. IGRA has some advantages over TST. IGRA does not require return visits and is not affected by Bacille Calmette-Guérin (BCG) vaccination status or infection with non-tuberculous Mycobacteria [13, 14]. However, IGRA is costly and needs a specialized laboratory for sample processing that is not widely available. Therefore, the American Thoracic Society (ATS), Infectious Diseases Society of America (IDSA), and the US Centers for Disease Control and Prevention (CDC) clinical guidelines recommend TST when an IGRA is not cost-effective or the laboratory supports required for IGRA are unavailable [15]. TST has widely been used to screen HCWs for LTBI in low- and middle-income high TB incidence countries [16, 17].

Although known pulmonary TB patients usually are not managed at public tertiary care hospital wards, a substantial number of pulmonary TB patients are admitted to these hospital wards before TB diagnosis and for other TB complications. Moreover, in health care facilities, a substantial number of pulmonary TB patients may remain undiagnosed due to a low index of suspicion and a lack of proper diagnostic evaluation. For example, in a study conducted in Thailand, 73% of patients hospitalized with clinical pneumonia were not adequately evaluated for TB, and an estimated 2%–12% of them had smear-positive, pulmonary TB [18].

Bangladesh shares 3.6% of the global total of 10 million people estimated with TB diseases in 2019 [1]. Bangladesh is one of the 22 high TB burden countries in the world with an estimated incidence for all forms of TB in 2019 was 221 (uncertainty interval: 161–291) per 100 000 population [1]. In line with the country's TB epidemiology, Bangladesh's extended program on immunization has included neonatal bacillus Calmette-Guérin (BCG) vaccination nationwide since the 1980s [19]. The national coverage of the BCG vaccine was 86% in 1991; 95% in 2000; and 99% since 2013 [19].

Public tertiary care hospitals in Bangladesh are overcrowded; lack necessary airborne IPC measures and hand washing stations; therefore, HCWs working in these hospitals are at increased risk of LTBI infection [20]. The approximate risk for persons with LTBI to develop active TB during their lifetime is 10% [21], and therefore, LTBI is considered the starting point for active TB disease [22]. Identifying HCWs workers with LTBI is an essential component of TB IPC in health settings [23]. However, there is no data on the burden of LTBI amongst HCWs from public tertiary care hospitals in Bangladesh. Therefore, we aimed to determine the prevalence of LTBI and compare the prevalence among different groups of HCWs in two public tertiary care hospitals in Bangladesh.

Materials and methods

Study design and sites

Between September 2018 and August 2019, a cross-sectional study was conducted in two 1000-bed public tertiary care hospitals (Hospital A and Hospital B) in Rajshahi and Barisal in Bangladesh. We selected these hospitals due to the following reasons: (1) these sites admit around 400 TB patients each year as inpatients, the majority of which are pulmonary; (2) there is already disease surveillance being conducted, including for MDR-TB; and (3) they are the largest tertiary care referral hospitals at the division levels and provide care to patients including those with TB.

Study definitions, participant recruitment, and screening

Any person aged ≥17 who delivered care and services to patients in the hospital and received payment was defined as a HCW. We included doctors, nurses, interns, ancillary workers (cleaners, general non-medical ward staff, female attendants [known as ayas]), laboratory staff, and administrative workers. We organized meetings with the HCWs in each of the hospitals to share the proposed study details and facilitate recruitment.

Sample size

Based on a recently completed study on the prevalence of LTBI of 54% among HCWs in TB specialty hospitals, we calculated the sample size needed for this study, allowing for a 95% confidence level and 5% absolute precision [24]. To estimate the prevalence within five percentage points of the hypothesized prevalence along with a 20% refusal, and the hospital level cluster effect as 1.5, the required sample size was 688.

Data collection

A questionnaire was used to collect data on demographics, history of BCG vaccination, duration of service, history of living with a TB positive person at home, and exposures to TB patients in the community. The tool, adopted from a previous study, was updated and pre-tested for cognitive test among five HCWs in the study hospitals [25]. In addition, participants were asked to complete a diary card for 7 days, to record their exposures to TB patients and IPC practices after the TST. To supplement the quantitative design, we conducted a TB IPC facility assessment using the WHO recommended checklist for periodic TB IPC assessment in health settings [26]. We assessed the implementation of structural, administrative, and environmental control measures through in-depth interviews with a range of stakeholders within the hospital (i.e., department heads, nursing heads, etc.), and direct observation of TB IPC practices. Finally, the team also mapped inpatient wards to describe the physical layout, including the distribution of patients' beds, doors, windows, and HCWs workstations.

TST Procedure

TST that uses purified protein derivative to elicit immune reactions is less expensive, easy to perform, and widely used for TB screening in low-and middle-income countries, including Bangladesh [27]. We used the TST for detecting LTBI according to the WHO and the International Union against Tuberculosis and Lung Disease recommendations for TST surveys in high TB burden countries [28]. We used the Mantoux technique and administered a ten-tuberculin unit dose (0.1 ml) of RT23 Purified Protein Derivatives (Arkray Healthcare Pvt. Ltd., Sachin, Gujarat, India) for study participants. The team organized a meeting in the study hospitals and informed the HCWs about our study objectives and planned activities. The team visited the hospital director's office, collected a list of HCWs, and then invited the HCWs by visiting the wards. After seeking informed written consent, a trained medical technologist administered the TST into the forearm. At 48 to 78 hours following TST placement, the technologists called each of the HCWs to know their present duty station. The team then visited the workplace and measured HCWs' transverse diameter of induration using a caliper [29]. We defined a positive TST as induration ≥10 mm as recommended by ATS, IDSA, and CDC [30, 31]. We dichotomized TST results as positive or negative.

Data entry and analysis

The research team entered the data into Microsoft Excel. We used descriptive statistics to summarize the distribution of demographic and clinical variables, along with variables measuring exposure to TB. We estimated odds ratios (ORs) with 95% confidence intervals (CIs) as a measure of association between factors (characteristics, duration of service, occupational TB exposure, community TB exposure) using univariate logistic regression. In the multivariate analysis, we used a generalized linear model adjusting for hospital level clustering effect (using ‘glm.cluster’ command from the miceadds R package). We included factors with an association with a p-value <0.20 in the unadjusted analyses with TST positivity along with LTBI risk factors identified in the prior published literature [32]. To check multicollinearity, we performed a variance inflation factor (VIF) analysis, and factors with VIF> 5, we considered them collinear and excluded from the multivariate model [33]. The open-source statistical package R version 3.6.3 (R Foundation for statistical computing, Vienna, Austria, Available at https://www.Rproject.org/) was used for analysis.

Ethics

We sought informed written consent before the TST and participation in the questionnaire or diary cards survey. The institutional review board of the International Centre for Diarrheal Diseases Research, Bangladesh (icddr,b), and the University of New South Wales ethical review committee approved the study (PR-16090 and HC # HC180517).

Results

Of the 4,057 HCWs listed in the hospital register, we approached 977 (24%) for the TST survey. Among the 977 HCWs, 84% (818/977) consented and participated in the TST survey. One hundred and fifty nine HCWs did not consent for TST due to their illness, prior history of allergic reaction to TST, unavailability for TST reading, and past history of active TB disease. The participants' median age was 28.8 years (standard deviation, SD = 10.87 years; range: 17 to 62 years), and 73% were female. The largest group was nurses (65%) followed by ancillary workers (18%), doctors (13%), and laboratory staff (4%). Eighty-one percent reported receiving the BCG vaccine as a child (Table 1). Seven percent of the participants had history of smoking. Active TB was not detected in any of the participants during the study period. Sixty-nine percent (566/818) reported known TB exposure to pulmonary TB patients. Among them, 3% (18/566) had sole exposures to TB patients in the community, and 22% (126/566) had exposures to TB patients both in community and hospital. Those who had sole exposures to known TB patients in the community, 56% (10/18) had TST positivity.

Table 1

Baseline characteristics of HCWs at two public tertiary care general hospitals in Bangladesh, 2019.

Demography and exposures	TST participants (N = 818) % (n/N)
Location of facilities
Hospital A	50 (409/818)
Hospital B	50 (409/818)
Sex
Male	27 (218/818)
Female	73 (600/818)
Education
0 to Primary	3 (24/816)
Secondary	12 (98/816)
HSC/Diploma	59(485/816)
MBBS/BA/BSC/Hons and above	26 (209/816)
Occupational group
Doctors	13 (104/818)
Nurse	65 (534/818)
Ancillary workers	18 (150/818)
Laboratory staff	4 (30/818)
Age in years
Median, IQR	28.8 (13.8)
>25	30 (245/818)
25–35	39 (321/818)
35–45	14 (112/818)
≥45	17 (140/818)
Years working as HCWS
< = 1.5	27 (224/818)
1.5–3	38 (308/818)
> = 3	35 (286/818)
Place of work
Medical ward	73 (596/814)
Gayne and Obstetric	9 (72/814)
Administration	10 (79/814)
Lab	6 (52/814)
ICU	2 (15/814)
Known exposures to TB patients
Hospital	75(422/566)
Community	03 (18/566)
Both hospital and community	22 (126/566)
History of smoking
Yes	7(60/817)
No	93 (757/817)

The overall prevalence of LTBI in the two study hospitals was 42%. The median diameter of induration among participants testing positive by TST was 13 mm (IQR 11 to 33 mm). In the bivariate analysis, the TST positivity significantly differed by age, duration of service, higher income, and medical ward work. Working as ancillary workers or laboratory workers was protective in the bivariate analysis (Table 2). HCWs in Hospital B had a higher TST positivity compared to HCWs in hospital A, although the difference was not statistically significant (odds ratio [OR] 1.19 with 95% confidence interval [CI] 0.89–1.57). Moreover, the history of BCG vaccination, education, known TB exposures to pulmonary TB patients were not statistically significantly associated with TST positivity.

Table 2

Prevalence of TST positivity and the factors associated with the positivity among HCWs in two tertiary care hospitals, Bangladesh, 2018–2019.

Demography and exposures	TST positive % (n/N)	TST negative % (n/N)	OR*(95% CI*)	aOR*(95% CI*)
	42 (347/818)	58 (471/818)
Location of facilities
Hospital A	40 (165/409)	60 (244/409)	Reference
Hospital B	45 (182/409)	52 (227/409)	1.19 (0.89–1.57)
Sex
Male	37 (81/218)	63(137/218)	Reference
Female	44 (266/600)	56 (334/600)	1.35 (0.98–1.86)	1.08 (1.01–1.18)
History of BCG vaccination
Yes	44 (289/659)	56 (370/659)	1.38 (0.93–2.08)	1.17 (0.47–2.94)
No	36 (44/122)	64 (78/122)	Reference
Don't know	38 (14/37)	62 (23/37)	1.08 (0.50–2.29)	0.95 (0.25–3.64)
History of smoking
Yes	35 (21/60)	65(39/60)	0.71 (0.40–1.22)
No	43(326/757)	57 (431/757)	Reference
Occupational group
Doctors	39 (40/104)	61 (64/104)	0.73 (0.48–1.13)
Nurse	46 (245/534)	54 (289/534)	Reference
Ancillary workers	36 (54/150)	51 (96/150)	0.66 (0.45–0.96)
Laboratory Staff	27 (8/30)	73 (22/30)	0.43 (0.18–0.94)
Education
0 to Primary	42 (10/24)	58 (14/24)	1.06 (0.44–2.49)
Secondary	39 (38/98)	61 (60/98)	0.94 (0.57–1.58)
Higher Secondary	44 (215/485)	56 (270/485)	1.18 (0.85–1.65)
Honours and above	40 (84/209)	60 (125/209)	Reference
Years working as HCWS
0–1.5	38 (85/224)	62 (139/224)	Reference	Reference
1.5–3	38 (116/308)	62 (192/308)	0.99 (0.69–1.41)	0.96 (0.60–1.55)
> = 3	51 (146/286)	49 (140/286)	1.70 (1.20–2.44)	1.67 (1.62–1.72)
Hours working per day
<6 hours	43 (15/35)	57(20/35)	Reference
6 hours and above	43(303/704)	57 (401/704)	1.01 (0.51–2.03)
Age in years
<25	33 (82/245)	67 (163/245)	Reference
25–35	40 (128/321)	60 (193/321)	1.32 (0.93–1.87)	1.27 (0.82–1.96)
35–45	50 (56/112)	50 (56/112)	1.99 (1.26–3.14)	1.36 (1.06–1.73)
≥45	58 (81/140)	42 (59/140)	2.73 (1.78–4.20)	2.27 (0.81–6.40)
Income
<10000	37 (68/184)	63 (116/184)	Reference	Reference
10001–20000	36 (88/247)	64 (159/247)	0.94 (0.63–1.40)	0.97 (0.68–1.38)
20001–30000	45 (110/245)	55 (135/245)	1.39 (0.94–2.06)	1.11 (0.91–1.35)
30001–40000	57 (58/101)	43 (43/101)	2.30 (1.41–3.79)	1.44 (1.00–2.09)
40001 and Above	56 (23/41)	44 (18/41)	2.18 (1.10–4.37)	1.89 (1.53–2.34)
Place of work
Administration	34 (27/79)	66 (52/79)	Reference	Reference
Gynae and Obs	39 (28/72)	61 (44/72)	1.22 (0.63–2.39)	2.46 (1.42–4.27)
ICU	13 (2/15)	87 (13/15)	0.29 (0.04–1.18)	0.80 (0.36–1.77)
Lab	29 (15/52)	71 (37/52)	0.78(0.36–1.65)	0.67 (0.16–2.75)
Medical Ward	46 (272/596)	54 (324/596)	1.62 (1.01–2.68)	3.65 (2.20–6.05)
Known exposure to TB
Hospital	43 (183/422)	57 (239/422)	Reference
Community	56 (10/18)	44 (8/18)	1.26 (0.85–1.89)
Both hospital and community	49 (62/126)	51 (64/126)	1.63 (0.63–4.35)
Involved in sputum collection
Yes	50 (63/126)	50 (63/126)	1.44 (0.98–2.11)	1.36 (1.08–1.72)
No	41(283/691)	59 (408/691)	Reference
Use of mask or respirator
Yes	40 (75/190)	60 (115/190)	0.85(0.61–1.19)
No	43 (271/626)	57 (355/626)	Reference

After adjusting for hospital level clustering effect, we noted an increasing trend for TST positivity with increasing age in the multivariate model. Healthcare workers aged 35–45 were statistically significantly associated with positive results (aOR 1.36, 95% CI: 1.06–1.73). A similar trend was also noted with an increasing year of working as HCWs. HCWs with more than three years of service in the hospital were 1.67 times (95% CI: 1.62–1.72) more likely to be positive with TST when compared with HCWs with less than 1.5 years of service. HCWs working in the medicine ward had 3.65 (95% CI: 2.20–6.05) times, and the HCWs working in the gynecology and obstetrics ward had 2.46 (95% CI: 1.42–4.27) times higher odds of TST positivity compared with HCWs working in administrative areas (Table 2). Females were more likely than males (44% Vs. 37%) to have positive results by TST and the difference was statistically significant (OR = 1.08, 95% CI: 1.01–1.18) in the multivariate model. HCWs involved in sputum collection had 1.36 (1.08–1.72) times higher odds of TST positivity compared with HCWs who were not involved in sputum collection.

The facility assessment findings showed that a TB infection control committee did not exist in any facility. None of the HCWs received any training on TB IPC measures. There were no symptom checklists in place to screen patients for TB and no tissues, pieces of cloth, or face masks available for coughing patients. The dairy card findings showed that HCWs spent a median of 6 hours (SD = 1.76, IQR 2.00), of which a median of 3.58 hours was spent in patient contact (SD = 2.50, IQR 2.62) in each day. Each day the HCWs attended a median of 22.5 general patients (SD: 43.02, IQR: 26.75). During a week, the HCWSs provided care to an average of 1.87 pulmonary TB patients in the study wards. We found smear-positive pulmonary TB patients were admitted in the wards, and their median duration of hospital stay was 4.5 days. Seventy-seven percent of the respondents reported that they did not use any medical mask or respirators while caring for patients in the hospital. We also found nurses' duty station inside the patient ward in the study wards that allow them longer exposures to the air space shared by pulmonary TB patients.

Discussion

The prevalence of LTBI in our study population was higher than what has been previously reported in other high burden TB countries. For example, studies of LTBI among HCWs in public tertiary care hospitals in India reported the prevalence at 20%, and in Pakistan, the prevalence at 40% [34, 35]. The occupational factors associated with TST positivity identified in our study suggest healthcare associated LTBI. The findings warrant immediate implementation of TB IPC in medicine, gynecology, and obstetrics wards. Besides, HCWs positive with TST can be targeted for preventative therapy to prevent active TB progression that may further prevent nosocomial and occupational TB transmission [36].

With the recent evidence of increasing multidrug-resistant TB worldwide, international health agencies, including WHO and the Stop TB Partnership, emphasized implementing TB IPC programs in health settings [37-39]. The WHO 2019 updated TB IPC guidelines, and the guidelines for programmatic management of LTBI recommend preventative treatment for people exposed to M. tuberculosis to reduce the burden of TB disease [40, 41]. Worryingly, a person latently infected with multi-drug resistant M. tuberculosis may be resistant to some available therapies and warrant optimal TB IPC program to limit nosocomial infection [42].

The study identified that the TST prevalence increases as the number of years working as HCWs increases. Our findings are consistent with prior studies in similar settings where more years of work as healthcare workers were associated with a higher prevalence of LTBI [43, 44]. The lower prevalence of LTBI in HCWs with lesser job duration could be due to lower cumulative exposure to pulmonary TB patients in the hospital. The findings showed public tertiary care hospitals admit pulmonary TB patients, and the patients stay in the hospital for over four days before they are diagnosed with TB, initiate TB treatment, and referred to TB specialty hospitals. The presence of pulmonary TB patients in the medicine wards and the poor implementation of TB IPC measures such as irregular use of N95 respirators and lack of training on TB IPC all are likely to have contributed to this healthcare associated LTBI [45].

Our analysis also identified a statistically significant association between an increase in age and TST positivity, which has also been reported previously in other settings [46, 47]. In the study hospitals, most HCWs joined work when they were young adults (usually between 17 to 21 years). Therefore, the increasing risk of TST positivity with increasing age could be better explained by prolonged cumulative exposure from both occupational and non-occupational exposures [47]. In our study, 22% of the respondents reported known exposures to TB patients both in the hospital and in the community. In Bangladesh, HCWs often hold dual jobs at government health facilities and private practice, including clinics and private chambers. They spend substantial time in private practices that had not been captured in our data [48, 49]. The private clinics and chambers often lack standard TB patient management practice and a limited supply of medical mask and N95 respirators that might have increased the risk of TB transmission [50, 51].

Working in gynecology/obstetrics (OR 2.46, 95% CI 1.14–5.40) wards was another significant predictor for LTBI. Our findings are consistent with prior studies where HCWs from gynecology and obstetrics wards were at increased risk of LTBI [52]. A perception exists that the gynecology and obstetrics ward has a low risk of TB transmission [52, 53]. Therefore, this false sense of security might have de-motivated HCWs following TB IPC measures and put them at increased risk of infection [53]. Also, this study further supports the findings that exposure during procedures such as sputum collection increases the risk of TST positivity among HCWs [54].

Our study suggests nurses could be at higher risk of TB exposures as their working stations were inside the medical wards for administrative work, direct and indirect patient care. The nurses spend around 6 hours daily for direct and indirect patients care. Though not statistically significant, the higher prevalence of LTBI among nurses could be due to this infrastructural barrier that provided nurses with more exposure to all types of patients, including pulmonary TB patients, than either doctors or other groups of HCWs [20].

This study has several limitations. Firstly, we used a one-step TST in this study. Suppose a person is tested with one-step TST after many years of infection with Mycobacterium tuberculosis. In that case, the person's ability to react to the TST antigen may wane over time and provide false-negative results. Therefore, our LTBI burden estimates may be an underestimate of the actual burden among HCWs in Bangladesh. Secondly, BCG vaccination might have affected TST positivity. A recent study showed that the possibility of false TST positivity might arise at a cut-off of TST>5mm as the result of BCG vaccine administered at infancy, TST indurations ≥ 10 mm appears unlikely to affect the diagnosis of LTBI [55]. Moreover, since all healthcare workers received BCG at birth, which is more than ten years prior to the TST, the result is less likely to be affected by the BCG exposures [56]. Thirdly, the study might have to overestimate TST positivity due to HCWs exposures to non-tuberculous mycobacteria, which are also prevalent in Bangladesh [11, 57]. However, in a systematic review, Farhat et al. (2006) showed that false-positive results due to non-tuberculous mycobacteria are not common in countries with high TB prevalence [56].

Conclusions

In conclusion, this study identified a high number of HCWs was infected with LTBI in the study facilities. This study represents a first step in estimating the risk of TB exposures and LTBI among HCWs in public tertiary care hospitals in Bangladesh. Our study identified the importance of preventing or interrupting the occupational risk of TB among HCWs. Considering the high prevalence of LTBI among the HCWs, we recommend that NTP consider providing preventative therapy to the HCWs as the high-risk group. Our analysis also warrants the immediate implementation of TB IPC in Bangladeshi tertiary care teaching hospitals. Our study also recommends relocation or renovation of the nursing workstation to minimize exposure for staff. Separating the nursing station with transparent curtains or glass could be an option. We recommend establishing a TB IPC program in all tertiary care teaching hospitals to ensure proper implementation of the TB IPC healthcare measures. Finally, an assessment of the HCWs private chambers and private clinics should be done to recommend context-appropriate modifiable TB IPC measures, including improving the facilities' physical layout. The study findings will assist Bangladesh’s national TB control program to effectively revise the TB IPC policy and reduce healthcare-associated TB infection.

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15 Oct 2020

PONE-D-20-30710

Are healthcare workers in public tertiary care general hospitals at risk of TB infection? A tuberculin skin test survey in two public tertiary care hospitals, Bangladesh

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6. Please revise overstated conclusions and statements that imply causal association. For example your statement that, "...poor implementation of TB IPC in public tertiary care teaching hospitals increased the risk of LTBI among HCWs...," implies causation. A cross-sectional study can not provide sufficient evidence for causal inferences should be avoided and instead indicate that associations were observed.

7.We note that you have indicated that data from this study are available upon request. PLOS only allows data to be available upon request if there are legal or ethical restrictions on sharing data publicly. For information on unacceptable data access restrictions, please see http://journals.plos.org/plosone/s/data-availability#loc-unacceptable-data-access-restrictions.

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b) If there are no restrictions, please upload the minimal anonymized data set necessary to replicate your study findings as either Supporting Information files or to a stable, public repository and provide us with the relevant URLs, DOIs, or accession numbers. Please see http://www.bmj.com/content/340/bmj.c181.long for guidelines on how to de-identify and prepare clinical data for publication. For a list of acceptable repositories, please see http://journals.plos.org/plosone/s/data-availability#loc-recommended-repositories.

We will update your Data Availability statement on your behalf to reflect the information you provide.

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Reviewer #1: Yes

Reviewer #2: Yes

**********

2. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #2: Yes

**********

3. Have the authors made all data underlying the findings in their manuscript fully available?

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Reviewer #1: No

Reviewer #2: No

**********

4. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

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Reviewer #2: Yes

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5. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: What about the incidence of tuberculosis in Bangladesh?

What about the program of BCG vaccination in Bangladesh?

Did you use the QFT-TB gold test for diagnosis of TB infection or TB disease in Bangladesh? If yes, why you didn't use QFT and TST tests for this study of screening of risk to TB infection ?

Did you have the information of participants about different risk factors like asthma, diabetes or others factors ?

Could you explain the choice of the references of each parameter for calculation of odd ratio for tables 2 and 3?

Reviewer #2: 1. Title: a long one, no need for the question included,

a. Are healthcare workers in public tertiary care general hospitals at risk of TB infection?

b. all of us know the answer, so better remove it,

c. and only keep title starting A tuberculin skin test survey in two public tertiary care hospitals, Bangladesh

d. you cannot use; Prevalence of latent tuberculosis infection among healthcare workers,

Bangladesh, since its done in two specific hospitals that does not represent Bangladesh in general

2. ABSTRACT:

a. in multivariate analysis need to remove age and work years, because of problem of colinearity

b. there should be no discussion in abstract, you mean conclusion

c. second part of conclusion is not accepted because it is not based on study results.

3. Introduction is poor, need more elaboration on LTB as a major health problem for HCWs

4. Review of literature missing key and important publications in the context

5. In results 1st paragraph, 169 refused to participate, why, need explanation on that.

6. The last part of results are comments that have no tables, where are tables for use of masks and exposure times.

7. Where is the conclusion and recommendation?

**********

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Reviewer #1: No

Reviewer #2: Yes: Prof. Mostafa Abbas Kofi

[NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files.]

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7 Nov 2020

PONE-D-20-30710

To

Frederick Quinn

Academic Editor

PLOS ONE

Dear Frederick Quinn:

We are thankful to the reviewers for their valuable feedback. We are also grateful to the editor for allowing us to respond to the comments. Based on the helpful feedback, we revised the manuscript and believe it is more precise, clear, and informative. The following is an itemized list of our specific responses to the reviewers' comments. We have highlighted the changes in the manuscript (marked) as well.

As suggested, we have also revised the data availability statements. A minimal dataset that supports the study has been attached as a supporting document. icddr,b’s department of research administration maintains a data repository anda copy of the complete dataset will remain in the repository. Interested researchers may contact Ms. Armana Ahmed, head of research administration (aahmed@icddrb.org), for approval and full data access.

We would appreciate your further review. Please contact me directly with any additional questions or comments. We look forward to hearing from you.

Sincerely

Md. Saiful Islam

Corresponding Author

saiful@icddrb.org

Comments: When submitting your revision, we need you to address these additional requirements. Please ensure that your manuscript meets PLOS ONE's style requirements, including those for file naming. The PLOS ONE style templates can be found at

https://journals.plos.org/plosone/s/file?id=wjVg/PLOSOne_formatting_sample_main_body.pdf andhttps://journals.plos.org/plosone/s/file?id=ba62/PLOSOne_formatting_sample_title_authors_affiliations.pdf

Response: Thank you. The manuscript and the authors’ affiliation have been updated according to the PLOS ONE’s style requirements.

Comments: 2. Regarding data availability, please note that PLOS journals require authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception. PLOS requires that a “minimal data set” is shared, defined as the data set used to reach the conclusions drawn in the manuscript with related metadata and methods, and any additional data required to replicate the reported study findings in their entirety. Authors do not need to submit their entire data set if only a portion of the data were used in the reported study. Also, authors do not need to submit the raw data collected during an investigation if the standard in the field is to share data that have been processed. Please submit the following data: The values behind the means, standard deviations and other measures reported; The values used to build graphs; The points extracted from images for analysis.” Please review http://journals.plos.org/plosone/s/data-availability#loc-faqs-for-data-policy. If you are unable to share the data, this may result in manuscript rejection.

Response: As recommended, we shared a minimal dataset.

Comment: 3. Please include additional information regarding the survey or questionnaire used in the study and ensure that you have provided sufficient details that others could replicate the analyses. For instance, if you developed a questionnaire as part of this study and it is not under a copyright more restrictive than CC-BY, please include a copy, in both the original language and English, as Supporting information, or include a citation if it has been published previously.

Response: As suggested, we have uploaded a copy of the questionnaire used in the survey.

Comment: 4. In the Methods, please discuss whether and how the questionnaire was validated and/or pre-tested. If these did not occur, please provide the rationale for not doing so.

Response: Thank you. We added, “The tool, adopted from a previous study, was updated and pre-tested for cognitive test among five HCWs in the study hospitals [1].” on page 6 in the manuscript (clean version).

Comment: 5. In your statistical analyses, please state whether you accounted for clustering by hospital. For example, did you consider using multilevel models?

Response: Thanks for your comment. Based on your suggestion, we have revised the method and the analysis, and updated the table 2 and the text in the manuscript. Under the method section, we added, “In the multivariate analysis, we used a generalized linear model adjusting for hospital level clustering effect (using ‘glm.cluster’ command from the miceadds R package)” on page 7.

Comments: 6. Please revise overstated conclusions and statements that imply causal association. For example your statement that, "...poor implementation of TB IPC in public tertiary care teaching hospitals increased the risk of LTBI among HCWs...," implies causation. A cross-sectional study cannot provide sufficient evidence for causal inferences should be avoided and instead indicate that associations were observed.

Response: Based on your suggestion, we have revised the conclusion as, “This study identified high prevalence of LTBI among HCWs. This may be due to the level of exposure to pulmonary TB patients, and/or limited use of personal protective equipment along with poor implementation of TB IPC in the hospitals. Considering the high prevalence of LTBI, we recommend the national TB program consider providing preventative therapy to the HCWs as the high-risk group, and implement TB IPC in the hospitals” on page 2.

Comments: 7.We note that you have indicated that data from this study are available upon request. PLOS only allows data to be available upon request if there are legal or ethical restrictions on sharing data publicly. For information on unacceptable data access restrictions, please see http://journals.plos.org/plosone/s/data-availability#loc-unacceptable-data-access-restrictions.

In your revised cover letter, please address the following prompts:

a) If there are ethical or legal restrictions on sharing a de-identified data set, please explain them in detail (e.g., data contain potentially identifying or sensitive patient information) and who has imposed them (e.g., an ethics committee). Please also provide contact information for a data access committee, ethics committee, or other institutional body to which data requests may be sent.

b) If there are no restrictions, please upload the minimal anonymized data set necessary to replicate your study findings as either Supporting Information files or to a stable, public repository and provide us with the relevant URLs, DOIs, or accession numbers. Please see http://www.bmj.com/content/340/bmj.c181.long for guidelines on how to de-identify and prepare clinical data for publication. For a list of acceptable repositories, please see http://journals.plos.org/plosone/s/data-availability#loc-recommended-repositories.

We will update your Data Availability statement on your behalf to reflect the information you provide.[Note: HTML markup is below. Please do not edit.]

Response: Now, we have revised the statements. A minimal dataset that supports the study has been attached as a supporting document.

Review Comments to the Author

Reviewer #1:

Comment: What about the incidence of tuberculosis in Bangladesh?

Response: We have added this information, “Bangladesh shares 3.6% of the global total of 10 million people estimated with TB diseases in 2019[2]. Bangladesh is one of the 22 high TB burden countries in the world with an estimated incidence for all forms of TB in 2019 was 221 (uncertainty interval: 161-291) per 100 000 population[2] on page 4 (Manuscript clean version).

Comment: What about the program of BCG vaccination in Bangladesh?

Response: Under the introduction, we have added this information, “In line with the country's TB epidemiology, Bangladesh's extended program on immunization has included neonatal bacillus Calmette-Guérin (BCG) vaccination nationwide since the 1980s [3]. The national coverage of the BCG vaccine was 86% in 1991; 95% in 2000; and 99% since 2013[3]” on page 4.

Comments: Did you use the QFT-TB gold test for diagnosis of TB infection or TB disease in Bangladesh? If yes, why you didn't use QFT and TST tests for this study of screening of risk to TB infection?

Response: Thank you for your valuable comments. QuantiFerron-Gold-in-Tube test (QFT-GIT) is expensive and is not routinely use in Bangladesh. Moreover, QFT-GIT requires a specialized laboratory for sample processing that was not widely available outside Dhaka during the time we conducted this study. Therefore, we could not use the QFT-GIT test.

Comment: Did you have the information of participants about different risk factors like asthma, diabetes or others factors?

Response: No, we did not collect data on asthma and diabetes. However we collected information on smoking history. Please see page 8 and the table 1 and table 2.

Comments: Could you explain the choice of the references of each parameter for calculation of odd ratio for tables 2 and 3?

Response: The reference category was chosen either with the highest frequency or the group with a lower risk of infection based on published literature.

Reviewer #2:

Comment: 1. Title: a long one, no need for the question included,

a. Are healthcare workers in public tertiary care general hospitals at risk of TB infection?

Response: Thank you. We have revised the title as, “A tuberculin skin test survey among healthcare workers in two public tertiary care hospitals in Bangladesh."

Comment: b. all of us know the answer, so better remove it,

Response: As suggested, we have removed “Are healthcare workers in public tertiary care general hospitals at risk of TB infection?” from the title.

Comment: c. and only keep title starting A tuberculin skin test survey in two public tertiary care hospitals, Bangladesh

Response: Thank you. We have revised the title as, ““A tuberculin skin test survey among healthcare workers in two public tertiary care hospitals in Bangladesh."

Comment: d. you cannot use; Prevalence of latent tuberculosis infection among healthcare workers, Bangladesh, since its done in two specific hospitals that does not represent Bangladesh in general

Response: We revised it as, “Prevalence of latent tuberculosis infection among healthcare workers in two public tertiary care hospitals in Bangladesh”.

Comment: 2. ABSTRACT:

a. in multivariate analysis need to remove age and work years, because of problem of colinearity

Response: Thank you. On page 7, we mentioned, “To check multicollinearity, we performed a variance inflation factor (VIF) analysis, and factors with VIF> 5, we considered them collinear and excluded from the multivariate model [4].

We checked for multicollinearity, and the variables with <5 variance inflation factors have been added in the multivariate analysis. Please see the outcome of the multicollinearity test.

Comment: b. there should be no discussion in abstract, you mean conclusion

Response: Thank you. We have revised it.

Comment: c. second part of conclusion is not accepted because it is not based on study results.

Response: We have revised the concluding sentence. The revised sentence is, “This study identified high prevalence of LTBI among HCWs. This may be due to the level of exposure to pulmonary TB patients, and/or limited use of personal protective equipment along with poor implementation of TB IPC in the hospitals. Considering the high prevalence of LTBI, we recommend the national TB program consider providing preventative therapy to the HCWs as the high-risk group, and implement TB IPC in the hospitals on pages 2 (manuscript clean version).

Comment: 3. Introduction is poor, need more elaboration on LTB as a major health problem for HCWs

Response: Thank you. We have now added more information to strengthen the introduction. On page 3 we added more information and revised it as, “In 2019, the WHO estimated that 10 million people developed TB disease globally, of whom 44% were from South-East Asia [2]. Moreover, 22,314 healthcare workers (HCWs) developed TB in the same year, with most coming from high TB burden countries in Asia [2]. Hospital HCWs in high TB burden countries are at increased risk of TB infection due to their exposure to a higher number of pulmonary TB patients than the hospital HCWs working in low TB-incidence countries [5]. A recent mathematical modelling study on the global burden of latent TB infection (LTBI) estimated that around 1.7 billion people are infected with LTBI in the world [6]. In a systematic review of 18 studies from seven high TB burden countries, the prevalence of LTBI among HCWs was reported to be 47% (95% CI 34- 60)[7]. This risk may be high among HCWs who work in health facilities that lack proper infrastructure and limited implementation of TB infection prevention and control (IPC) healthcare measures. The risk of LTBI among different health care workers may vary by place of work, duration of exposures, and compliance with TB IPC measures [8]. Prior studies identified considerable heterogeneity in the risk of LTBI among different occupations and reported high risk among doctors, nurses, and ancillary workers [8, 9]. HCWs that were most likely to be infected had the most prolonged duration and extent of patient contact [9, 10].

People with LTBI represent a reservoir for potential TB disease [6]. Overall, without treatment, about 5 to 10% of infected persons may develop TB disease at some time in their lives, and the active stage frequently occurs within the first two years after infection [11, 12]. People with an impaired immune system are at increased risk of developing TB disease than persons with standard immune systems[12]. Diabetes and smoking behavior also increase TB disease risk among the person with LTBI[13].

On page 4, we added, “Bangladesh shares 3.6% of the global total of 10 million people estimated with TB diseases in 2019[2]. Bangladesh is one of the 22 high TB burden countries in the world with an estimated incidence for all forms of TB in 2019 was 221 (uncertainty interval: 161-291) per 100 000 population[2]. In line with the country's TB epidemiology, Bangladesh's extended program on immunization has included neonatal bacillus Calmette-Guérin (BCG) vaccination nationwide since the 1980s [3]. The national coverage of the BCG vaccine was 86% in 1991; 95% in 2000; and 99% since 2013[3].”

Comment: 4. Review of literature missing key and important publications in the context

Response: Thank you. I would like to request you to see our response under the previous comment. We have updated literature review and added recent publications.

Comment: 5. In results 1st paragraph, 169 refused to participate, why, need explanation on that.

Response: On page 10, we added, “One hundred and fifty nine HCWs did not consent for TST due to their illness, prior history of allergic reaction to TST, unavailability for TST reading, and past history of active TB disease”.

Comments: 6. The last part of results are comments that have no tables, where are tables for use of masks and exposure times.

Response: We have now added the information in table 2.

Demography and exposures TST positive % (n/N) TST negative % (n/N) OR*(95% CI*) aOR*(95% CI*)

Hours working per day

<6 hours 43 (15/35) 57(20/35) Reference

6 hours and above 43(303/704) 57 (401/704) 1.01 (0.51-2.03)

Use of mask or respirator

Yes 40 (75/190) 60 (115/190) 0.85(0.61-1.19)

No 43 (271/626) 57 (355/626) Reference

Comments: 7. Where are the conclusion and recommendation?

Response: On Page 13 and 14, we described the conclusion and recommendations, " In conclusion, this study identified a high number of HCWs was infected with LTBI in the study facilities. This study represents a first step in estimating the risk of TB exposures and LTBI among HCWs in public tertiary care hospitals in Bangladesh. Our study identified the importance of preventing or interrupting the occupational risk of TB among HCWs. Considering the high prevalence of LTBI among the HCWs, we recommend that NTP consider providing preventative therapy to the HCWs as the high-risk group. Our analysis also warrants the immediate implementation of TB IPC in Bangladeshi tertiary care teaching hospitals. Our study also recommends relocation or renovation of the nursing workstation to minimize exposure for staff. Separating the nursing station with transparent curtains or glass could be an option. We recommend establishing a TB IPC program in all tertiary care teaching hospitals to ensure proper implementation of the TB IPC healthcare measures. Finally, an assessment of the HCWs private chambers and private clinics should be done to recommend context-appropriate modifiable TB IPC measures, including improving the facilities' physical layout. The study findings will assist Bangladesh’s national TB control program to effectively revise the TB IPC policy and reduce healthcare-associated TB infection.”

References:

1. Islam MS. Latent tuberculosis infection among healthcare workers in chest disease hospitals, Bangladesh. Health and Science Bulletin. 2014;12(1):1-7.

2. World Health Organization. Global Tuberculosis Report. Geneva: World Health Organization, 2020.

3. Sarkar PK, Sarker NK, Doulah S, Bari TI. Expanded Programme on Immunization in Bangladesh: A Success Story. Bangladesh Journal Of Child Health. 2015;39(2):93-8.

4. Kwon YS, Kim YH, Jeon K, Jeong BH, Ryu YJ, Choi JC, et al. Factors that Predict Negative Results of QuantiFERON-TB Gold In-Tube Test in Patients with Culture-Confirmed Tuberculosis: A Multicenter Retrospective Cohort Study. PloS one. 2015;10(6):e0129792. Epub 2015/06/13. doi: 10.1371/journal.pone.0129792. PubMed PMID: 26070207; PubMed Central PMCID: PMCPMC4466377.

5. Uden L, Barber E, Ford N, Cooke GS. Risk of Tuberculosis Infection and Disease for Health Care Workers: An Updated Meta-Analysis. Open forum infectious diseases. 2017;4(3):ofx137. Epub 2017/09/07. doi: 10.1093/ofid/ofx137. PubMed PMID: 28875155; PubMed Central PMCID: PMCPMC5575844.

6. Houben RM, Dodd PJ. The Global Burden of Latent Tuberculosis Infection: A Re-estimation Using Mathematical Modelling. PLoS medicine. 2016;13(10):e1002152. Epub 2016/10/26. doi: 10.1371/journal.pmed.1002152. PubMed PMID: 27780211; PubMed Central PMCID: PMCPMC5079585.

7. Nasreen S, Shokoohi M, Malvankar-Mehta MS. Prevalence of Latent Tuberculosis among Health Care Workers in High Burden Countries: A Systematic Review and Meta-Analysis. PloS one. 2016;11(10):e0164034. Epub 2016/10/07. doi: 10.1371/journal.pone.0164034. PubMed PMID: 27711155; PubMed Central PMCID: PMCPMC5053544.

8. Joshi R, Reingold AL, Menzies D, Pai M. Tuberculosis among health-care workers in low- and middle-income countries: a systematic review. PLoS medicine. 2006;3(12):e494. doi: 10.1371/journal.pmed.0030494. PubMed PMID: 17194191; PubMed Central PMCID: PMC1716189.

9. Gopinath K, Siddique S, Kirubakaran H, Shanmugam A, Mathai E, Chandy G. Tuberculosis among healthcare workers in a tertiary-care hospital in South India. Journal of Hospital Infection. 2004;57(4):339-42.

10. Donald PR, Helden PDv. The Global Burden of Tuberculosis — Combating Drug Resistance in Difficult Times. New England Journal of Medicine. 2009;360(23):2393-5.

11. Lillebaek T, Dirksen A, Baess I, Strunge B, Thomsen VØ, Andersen ÅB. Molecular evidence of endogenous reactivation of Mycobacterium tuberculosis after 33 years of latent infection. The Journal of infectious diseases. 2002;185(3):401-4.

12. Centers for Disease Control and Prevention. TB Risk Factors Atlanta, Georgia, USA: Centers for Disease Control and Prevention; 2016 [cited 2020 26 October]. Available from: https://www.cdc.gov/tb/topic/basics/risk.htm.

13. Gajalakshmi V, Peto R, Kanaka TS, Jha P. Smoking and mortality from tuberculosis and other diseases in India: retrospective study of 43 000 adult male deaths and 35 000 controls. The Lancet. 2003;362(9383):507-15.

Submitted filename: 2020 Nov8_Response to reviewers comments_PONE-D-20-30710.doc

Click here for additional data file.

1 Dec 2020

A tuberculin skin test survey among healthcare workers in two public tertiary care hospitals in Bangladesh

PONE-D-20-30710R1

Dear Dr. Islam,

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication.

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If your institution or institutions have a press office, please notify them about your upcoming paper to help maximize its impact. If they’ll be preparing press materials, please inform our press team as soon as possible -- no later than 48 hours after receiving the formal acceptance. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact onepress@plos.org.

Kind regards,

Frederick Quinn

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #1: All comments have been addressed

Reviewer #2: All comments have been addressed

**********

2. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Yes

Reviewer #2: Yes

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #2: Yes

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

Reviewer #2: Yes

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

Reviewer #2: Yes

**********

6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: (No Response)

Reviewer #2: questions were addressed by authors.

its important to hare your publication on research website such a research gate and LinkedIn.

**********

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If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: No

Reviewer #2: No

4 Dec 2020

PONE-D-20-30710R1

A tuberculin skin test survey among healthcare workers in two public tertiary care hospitals in Bangladesh

Dear Dr. Islam:

I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department.

If your institution or institutions have a press office, please let them know about your upcoming paper now to help maximize its impact. If they'll be preparing press materials, please inform our press team within the next 48 hours. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information please contact onepress@plos.org.

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on behalf of

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