QuantiFERON-TB Gold plus testing for the detection of LTBI among health care workers in major TB hospitals of the Northern Kyrgyz Republic

Tuberculosis (TB) affects over 10 million people worldwide and it is estimated that nearly 1.8 billion people are latently infected with TB [1, 2]. Latent TB infection (LTBI) occurs when an individual develops a measurable immune response to TB bacteria, but symptoms and signs of clinical disease have not yet manifested [2]. It is estimated that about 5–15% of individuals with LTBI will progress to active TB at a certain time in their life, and those with active pulmonary TB can transmit infection to up to 15 people [2]. The land-locked Kyrgyz Republic in Central Asia is not only considered a high incidence country (2017 incidence 144/100,000; 7695 TB cases notified), but also has a high burden of drug-resistant (DR)-TB (1372 [43.5%] bacteriologically confirmed MDR/RR-TB among 3,151 bacteriologically confirmed cases in 2017) [3] increasing the importance of effective control measures. Controlling LTBI is considered a key to control the TB epidemic in a country [1, 2]. Latent TB infection can be detected by indirect immunological responses using methods such as the Tuberculin Skin Test (TST), or interferon-gamma release assays (IGRA) such as the QuantiFERON-TB Gold plus (QFT; Qiagen, Hilden, Germany). In countries where BCG vaccination (in the Kyrgyz Republic national BCG coverage from 2009 to 2019 was between 96 and 99% [4]) and interference with the TST is common, IGRA have a markedly higher specificity to detect and monitor LTBI [5, 6].

Health care workers (HCW) are at increased risk of TB infection due to their close contact with TB patients, particularly when performing high risk procedures such as cleaning, sample collection, sample testing, intubation, or resuscitation [7, 8]. Although effective training and TB infection control measures should reduce transmission of TB in medical facilities [9], the annual incidence of LTBI among HCW in high prevalence countries is estimated to be as high as 7.2% [10], which is greatly increased over the general public [8, 10, 11]. The high occupational risk to HCW is a problem not only for the individuals themselves, but also to the general public as progression to active TB leads to transmission not only in the community, but also in the hospitals during interactions with patients [11]. In order to develop and implement effective intervention strategies, it is important to determine and understand the actual prevalence and risk of LTBI among HCW in different job positions and departments within hospitals [12]. Additionally, there may be differences between hospitals depending on the effectiveness of institutional infection control measures. Therefore, it is important not only to monitor LTBI infections among HCW, but also to identify areas of increased risk of infection.

This study was conducted in the four major TB inpatient facilities of the three most Northern regions of the Kyrgyz Republic. Those were the TB hospitals of the National Tuberculosis Center (NTC) in Bishkek, Karabalta, Kemin and Karakol where 351, 104, 45, and 50 staff, respectively, were working in 2018. The NTC is larger than the three other hospitals and constitutes the central TB hospital of the country where advanced and complicated cases can be treated. The other 3 hospitals are rural and of simpler infrastructure.

Our study is the first of its kind to describe prevalence and risk factors of LTBI among HCW in Central Asia. It supports the commonly reported findings that job position in the hospital has an effect on QTF positivity, and there is a higher prevalence of LTBI among HCW than the general public [11, 13, 14]. The prevalence of 46.7% QFT positive HCW in the current study was markedly higher than the LTBI prevalence of 3.9% reported from low-incidence countries [10] and 12–28% reported from the medium-incidence country Iraq [7], but well within the range of the 34–60% LTBI among HCW reported from other high-incidence countries [11]. It should be considered that the cited studies investigated HCW in multi-disciplinary hospitals, while the participants of the current study were exclusively working with TB patients.

WHO guidelines for infection control among HCW were released in 2005, which have since been updated in 2019 [15], and have also been implemented in most health care institutions in the Kyrgyz Republic which should have had a meaningful impact on transmission and prevalence of LTBI [9, 16]. However, the current study indicates HCW may have an increased risk of LTBI, especially doctors, laboratory personnel, and those working in the drug resistance and smear-negative wards in the Kyrgyz Republic; although these differences were no longer significant when adjusting for multiple comparisons in pairwise analysis (excluding personnel in the department “laboratory”). Research conducted in Brazil, South Africa, and similar high TB burden countries have found that there is not a lack of protocols or equipment leading to gaps in infection control, but rather a lack of understanding of and adherence to infection control standards, uptake of prevention training, and efficient monitoring [17‐19]. HCW of the DR-TB and smear negative pulmonary TB departments had significantly higher odds of being QFT positive, although infection control measures should be particularly strict in the DR-TB ward, and risk of infection relatively low in the department of smear negative TB. Our findings suggest that work safety conditions might not yet be optimal in Kyrgyz TB health facilities, but also that HCW are not yet fully compliantly following the infection control standards especially where the perceived risk of transmission is presumed to be comparably low.

Of the 49 HCW that provided valid follow-up QFT during the 17-month study period, 15 (30.6%) converted from negative to positive which may reflect the high risk of infection among these professions. These results correspond to findings in previous studies whereby 11% of HCW in a medical institute in a rural area of Central India (incidence rate of over 300/100,000) converted with QFT over a period of 1 year [20] and 10% of HCW converted in Malaysia with an incidence rate around 63 per 100,000 population [21]. Although serial testing with IGRA can be influenced by various factors [20, 22], QFT has repeatedly demonstrated its superior reliability over TST in systematically BCG vaccinated populations with high incidence of TB [23]. Although there was no association with age, site, time between tests, or job position, the majority of patients that converted to positive remained positive at follow-up testing, strongly indicating new LTBI infections which may progress to active TB. In a setting with one third of TB patients having multi-drug resistant forms of the disease, active TB among HCW and their potential to spread the infection to vulnerable patient groups is of particular public health concern.

There were five individuals with tests that reverted from positive to negative at follow-up, and it has been suggested that borderline results (falling within an “uncertain range” of e.g., 0.22–0.71 IU/ml) may be more likely to change at follow-up [20, 24]; however, we did not see an association with borderline positivity of the first and the outcome of the second test. The apparent randomness and inconsistency of reversions at follow-up has been identified in previous research [25, 26] and changes have not been explained by occupational exposure in HCW [27]. Therefore, reversions identified in serial QTF testing should be interpreted with caution.

The findings of this study are of particular impact for public health and TB control projects in Central Asia as they provide the first insight in occupation specific prevalence of LTBI; however, certain limitations of the study should be kept in mind when interpreting the results. Firstly, there is a lack of information regarding the duration that the HCWs have been working in health, particularly the TB sector. It has been documented in previous research that there is an increased risk of positivity as length of employment in pulmonary hospitals increases [14]. This risk factor should be considered in future studies investigating TB transmission to HCW in Central Asia and the effectiveness of implemented control measures. There is also a lack of information regarding potential TB contacts outside the hospitals as the collection of such data was not covered by the occupational health screening program of this study. The risk of not work-related TB infection would however have been equal for all participants while we observed a clearly increased risk of LTBI only for those with regular contacts to TB patients. It should be considered that the follow-up test interval of at least one month in the current study is much shorter than most studies where investigations for serial QTF testing were conducted at intervals of three [24] to 18 months [20]. However, this effect on the results should be minimal as time between tests was not found to predict conversion status. There is likely a high amount of variability among HCW at the NTC, as the wide confidence intervals are not reflected in the smaller sample size of the three other hospitals combined. Additionally, apparent differences between job positions at the NTC for risk of QFT are no longer significant when adjusting for multiple comparison, and further research is required to fully understand HCW risk. Due to its relatively small sample size, 95% confidence intervals were large for some groups of HCW weakening statements regarding the risk of LTBI although ORs might be well above 4.0 and trends might be observable. Larger sample sizes should be considered in future studies when investigating health care facilities in Central Asia. As the baseline positivity rates of urban and rural populations are unknown for the Kyrgyz Republic, we had to use administrative staff as base group which might however bring in some bias. Our study has focussed on TB hospitals and laboratories only; population based studies would help estimate the real LTBI risk of HCW compared to the normal population in similar environment. Studies in other types of hospitals and health facilities would increase the representativeness of the results for all Kyrgyz HCWs. Simultaneous investigations of implemented and applied infection control measures would allow to measure the effectiveness and protective value of individual or bundles of measures.

This is the first international report on prevalence of LTBI among HCWs in the Kyrgyz Republic established by means of modern IGRA, and results indicate an increased risk of TB infection for TB physicians, laboratory staff, and those working in the drug resistant and smear-negative TB departments. Although all Kyrgyz hospitals have implemented infection control measures, our findings suggest that the infection control policies may be insufficient, or HCW may not be consequently adhering to the recommended standards. This research can be used to guide targeted interventions with higher efficiency, ultimately leading to a decrease in the risk of TB for HCWs and to interrupt TB infection cycles in all Central Asian Hospitals. Consideration should be made to include IGRA testing in screening algorithms among HCWs in order to monitor the success of intensified infection control efforts.