The prevalence and risk factors for tuberculosis among healthcare workers in Yogyakarta, Indonesia.

Healthcare workers (HCWs) are at risk of contracting TB, particularly when in high tuberculosis (TB) burden settings. Routine surveillance data and evidence are limited on the burden of TB amongst HCWs in Indonesia. We aimed to measure the prevalence of TB infection (TBI) and disease among HCWs in four healthcare facilities in Yogyakarta province in Indonesia, and explore risk factors for TBI. A cross-sectional TB screening study targeted all HCWs from four pre-selected facilities (1 hospital, 3 primary care) in Yogyakarta, Indonesia. Voluntary screening included symptom assessment, Chest X-ray (CXR), Xpert MTB/RIF (if indicated) and tuberculin skin test (TST). Analyses were descriptive and included multivariable logistic regression. Of 792 HCWs, 681 consented (86%) to the screening; 59% (n = 401) were female, 62% were medical staff (n = 421), 77% worked in the one participating hospital (n = 524), and the median time working in the health sector was 13 years (IQR: 6-25 years). Nearly half had provided services for people with TB (46%, n = 316) and 9% reported ever having TB (n = 60). Among participants with presumptive TB (15%, n = 99/662), none were diagnosed microbiologically or clinically with active TB disease. TBI was detected in 25% (95% CI: 22-30; n = 112/441) of eligible HCWs with a TST result. A significant association was found between TB infection and being male (adjusted Odds Ratio (aOR) 2.02 (95%CI: 1.29-3.17)), currently working in the participating hospital compared to primary care (aOR 3.15 (95%CI: 1.75-5.66)), and older age (1.05 OR increase per year of life between 19-73 years (95%CI: 1.02-1.06)). This study supports prioritisation of HCWs as a high-risk group for TB infection and disease, and the need for comprehensive prevention and control programs in Indonesia. Further, it identifies characteristics of HCWs in Yogyakarta at higher risk of TBI, who could be prioritised in screening programs if universal coverage of prevention and control measures cannot be achieved.

Evolution of tuberculosis diagnostics: From molecular strategies to nanodiagnostics.

Tuberculosis has remained a global concern for public health affecting the lives of people for ages. Approximately 10 million people are affected by the disease and 1.5 million succumb to the disease worldwide annually. The COVID-19 pandemic has highlighted the role of early diagnosis to win the battle against such infectious diseases. Thus, advancement in the diagnostic approaches to provide early detection forms the foundation to eradicate and manage contagious diseases like tuberculosis. The conventional diagnostic strategies include microscopic examination, chest X-ray and tuberculin skin test. The limitations associated with sensitivity and specificity of these tests demands for exploring new techniques like probe-based assays, CRISPR-Cas and microRNA detection. The aim of the current review is to envisage the correlation between both the conventional and the newer approaches to enhance the specificity and sensitivity. A significant emphasis has been placed upon nanodiagnostic approaches manipulating quantum dots, magnetic nanoparticles, and biosensors for accurate diagnosis of latent, active and drug-resistant TB. Additionally, we would like to ponder upon a reliable method that is cost-effective, reproducible, require minimal infrastructure and provide point-of-care to the patients.

First evaluation of the performance of portable IGRA, QIAreach® QuantiFERON®-TB in intermediate TB incidence setting.

Diagnosis and treatment of tuberculosis infection (TBI) are the core elements of tuberculosis elimination. Interferon gamma release assays have advantages over the tuberculin skin test, although their implementation in low-resource settings is challenging. The performance of a novel digital lateral flow assay QIAreach® QuantiFERON®-TB (QIAreach QFT) against the QuantiFERON®-TB Gold Plus (QFT-Plus) assay was evaluated in an intermediate incidence setting (Malaysia) according to the manufacturer's instructions. Individuals aged 4-82 years, who were candidates for TB infection screening for contact investigation were prospectively recruited. On 196 samples, the QIAreach-QFT showed a positive percent agreement (sensitivity) was 96.5% (CI 87.9-99.6%), a negative percent agreement (specificity) 94.2% (CI 88.4% to 97.6%) and an overall percentage of agreement was 94.9% (95% CI 90.6-97.6%) with a Cohen's κ of 0,88. Out of 196, 5.6% (11/196) samples gave an error result on QIAreach-QFT and 4.1% (8/196) samples gave indeterminate result on QFT-plus. The TTR for QIAreach QFT positive samples varied from 210-1200 seconds (20 min) and significantly correlated with IFN-γ level of QFT-Plus. QIAreach QFT could be considered an accurate and reliable point-of-need test to diagnose TB infection helping to achieve the WHO End TB programme goals even in decentralised settings where laboratory expertise and infrastructure may be limited.

Changes in interferon-γ release assay readout after COVID-19 vaccination: A prospective cohort study.

OBJECTIVES: Interferon-γ release assays (IGRAs) are widely used in public health practice to diagnose latent tuberculosis. During the COVID-19 pandemic and rollout of COVID-19 vaccination, it has remained unclear whether COVID-19 vaccines interfere with IGRA readouts. METHODS: We prospectively recruited healthcare workers during their annual occupational health examinations in 2021. Baseline IGRA readouts were compared with follow-up data after the participants had received two doses of COVID-19 vaccination. RESULTS: A total of 134 baseline IGRA-negative cases (92 with ChAdOx1 vaccine, 27 with mRNA-1273 vaccine, and 15 with heterologous vaccination) and seven baseline IGRA-positive cases were analyzed. Among the baseline IGRA-negative cases, there were decreased interferon-γ concentrations over the Nil (P = 0.005) and increased Mitogen-Nil (P < 0.001) values after vaccination. For TB2-Nil value, a similar trend (P = 0.057) of increase was observed. Compared with the 0.35 IU/ml threshold, the baseline and follow-up readout differences were less than |± 0.10| IU/ml over the TB1-Nil and TB2-Nil values in >90% baseline IGRA-negative cases. No significant readout difference was observed among baseline IGRA-positive cases. CONCLUSION: COVID-19 vaccination did not change IGRA interpretation in most cases. Cases showing conversion/borderline IGRA readouts should be given special consideration.

Prevalence of latent tuberculosis infection among pre-clinical and clinical medical students using QuantiFERON-TB gold plus and tuberculin skin test at a teaching hospital in Thailand: A cross-sectional study.

BACKGROUND: Healthcare workers are considered to be at a higher risk of acquiring tuberculosis (TB) infection than the general population. Clinical medical students are part of the healthcare team and clinical practice are done during their clinical rotation. They could be exposed to similar occupational risks as the healthcare workers. Most students who become infected have latent tuberculosis infection (LTBI) and may not exhibit any clinical symptoms. Some students with LTBI can progress to TB disease during clinical rotations in the hospitals. Therefore, screening for LTBI in this population represents hospital aspect of public health strategy and infection control in medical school in high TB burden countries. OBJECTIVE: We aimed to determine the prevalence of LTBI among fourth-year medical students and sixth-year medical students by using QuantiFERON-TB Gold Plus (QFT-Plus) and Tuberculin Skin Test (TST). METHODS: A cross-sectional study of fourth-year medical students (n = 73) and sixth-year medical students (n = 85) was conducted at the School of Medicine, Chulalongkorn University, Bangkok, Thailand. The medical students (n = 158) who met the eligibility criteria were recruited into the study. LTBI was detected by using QFT-Plus and some of the participants had a tuberculin skin test (TST). The TST was interpreted after 48-72 h. The participants who tested positive by QFT-Plus were considered to have LTBI. Demographic information and data on occupational TB exposure were collected via a questionnaire. A multivariate logistic regression was used to test for associations between independent variables and results of the QFT-Plus. RESULTS: A total of 158 participants were included in this study. The overall prevalence of LTBI was 6.3% (n = 10) as determined by QFT-Plus. The LTBI prevalence was higher in the sixth-year medical students (9.4%) compared to the fourth-year medical students (2.7%). Higher risk of LTBI was associated with sixth-year medical students (odds ratio, 3.69 [95%CI, 0.75-17.96]), but this was not significant. Moreover, history of occupational TB exposure without PPE yielded an odds ratio of 2.98 [95%CI, 0.68-13.12] but it was not statistically significant due to the small sample size. One hundred thirty-nine (88%) participants were BCG vaccinated as per the national vaccination requirements. No abnormal chest X-rays were found for any of the positive participants. Of the 158 participants, 41 (25.9%) of them had TST. Of the 41 participants, 6 (14.6%) tested positive at a cut-off of ≥ 10 mm for TST, which was concordant with QFT-Plus results. The agreement between the two tests was 0.57 using kappa coefficients. CONCLUSION: The screening of TB infection in new healthcare workers (HCWs), especially medical students, is essential to reduce future nosocomial TB incidences in the hospitals. This study showed that there was a high prevalence of LTBI among sixth-year medical students compared to fourth-year medical students. Our results suggest that tendency of higher LTBI prevalence might be associated with advanced clinical years, thus tailored public health education strategy and infection control in tertiary care hospitals for new healthcare workers in TB endemic countries may prevent nosocomial TB disease from developing in the future. Therefore, active surveillance should be done for all new HCWs, and TB preventive therapy should be administered to recent converters.

Indeterminate mycobacterium tuberculosis QuantiFERON post Moderna mRNA Covid-19 vaccination.

We report an interesting case of an indeterminate MTB QuantiFERON for a 26-year-old healthy soldier planned for a routine field exercise to Brunei. Further medical history revealed that the patient had a Moderna mRNA Covid-19 vaccine the day before his MTB QuantiFERON test. The patient was subsequently asked to repeat a T-spot test which was non-reactive, there were no longer any issues with the positive control for the T-spot test. Current Covid-19 research suggests that infection causes a dysregulation of the immune system, perhaps this might also be extrapolated where a Covid-19 vaccine might provoke an immune response which might interfere with some immunological assays. In summary there should be more research invested into the immunological interactions that the newly developed Covid-19 vaccinations have with our existing immunological tests such as QuantiFERON tests which forms a key cornerstone in our fight against tuberculosis.

Predicting Airborne Infection Risk: Association Between Personal Ambient Carbon Dioxide Level Monitoring and Incidence of Tuberculosis Infection in South African Health Workers.

BACKGROUND: High rates of tuberculosis (TB) transmission occur in hospitals in high-incidence countries, yet there is no validated way to evaluate the impact of hospital design and function on airborne infection risk. We hypothesized that personal ambient carbon dioxide (CO2) monitoring could serve as a surrogate measure of rebreathed air exposure associated with TB infection risk in health workers (HWs). METHODS: We analyzed baseline and repeat (12-month) interferon-γ release assay (IGRA) results in 138 HWs in Cape Town, South Africa. A random subset of HWs with a baseline negative QuantiFERON Plus (QFT-Plus) underwent personal ambient CO2 monitoring. RESULTS: Annual incidence of TB infection (IGRA conversion) was high (34%). Junior doctors were less likely to have a positive baseline IGRA than other HWs (OR, 0.26; P = .005) but had similar IGRA conversion risk. IGRA converters experienced higher median CO2 levels compared to IGRA nonconverters using quantitative QFT-Plus thresholds of ≥0.35 IU/mL (P < .02) or ≥1 IU/mL (P < .01). Median CO2 levels were predictive of IGRA conversion (odds ratio [OR], 2.04; P = .04, ≥1 IU/mL threshold). Ordinal logistic regression demonstrated that the odds of a higher repeat quantitative IGRA result increased by almost 2-fold (OR, 1.81; P = .01) per 100 ppm unit increase in median CO2 levels, suggesting a dose-dependent response. CONCLUSIONS: HWs face high occupational TB risk. Increasing median CO2 levels (indicative of poor ventilation and/or high occupancy) were associated with higher likelihood of HW TB infection. Personal ambient CO2 monitoring may help target interventions to decrease TB transmission in healthcare facilities and help HWs self-monitor occupational risk, with implications for other airborne infections including coronavirus disease 2019.

Impact of the COVID-19 pandemic on contact tracing of patients with pulmonary tuberculosis.

BACKGROUND: The COVID-19 pandemic could have negative effects on tuberculosis (TB) control. The objective was to assess the impact of the pandemic in contact tracing, TB and latent tuberculosis infection (LTBI) in contacts of patients with pulmonary TB in Catalonia (Spain). METHODS: Contact tracing was carried out in cases of pulmonary TB detected during 14 months in the pre-pandemic period (1 January 2019 to 28 February 2020) and 14 months in the pandemic period (1 March 2020 to 30 April 2021). Contacts received the tuberculin skin test and/or interferon gamma release assay and it was determined whether they had TB or LTBI. Variables associated with TB or LTBI in contacts (study period and sociodemographic variables) were analyzed using adjusted odds ratio (aOR) and the 95% confidence intervals (95% CI). RESULTS: The pre-pandemic and pandemic periods showed, respectively: 503 and 255 pulmonary TB reported cases (reduction of 50.7%); and 4676 and 1687 contacts studied (reduction of 36.1%). In these periods, the proportion of TB cases among the contacts was 1.9% (84/4307) and 2.2% (30/1381) (P = 0.608); and the proportion of LTBI was 25.3% (1090/4307) and 29.2% (403/1381) (P < 0.001). The pandemic period was associated to higher LTBI proportion (aOR = 1.3; 95% CI 1.1-1.5), taking into account the effect on LTBI of the other variables studied as sex, age, household contact and migrant status. CONCLUSIONS: COVID-19 is affecting TB control due to less exhaustive TB and LTBI case detection. An increase in LTBI was observed during the pandemic period. Efforts should be made to improve detection of TB and LTBI among contacts of TB cases.

Is the course of COVID-19 associated with tuberculin skin test diameter? A retrospective study.

The pathogenesis of coronavirus disease 2019 (COVID-19) is still not fully understood. As severe acute respiratory syndrome coronavirus 2 (SARS-COV-2) has a similar pathogenetic pathway to Mycobacterium tuberculosis, it has been reported that there may be a relationship between Bacille Calmette-Guérin (BCG) vaccination rate and COVID-19 severity. This study investigated the relationship between tuberculin skin test (TST) induration diameter and the clinical course of COVID-19. Of 1963 adult patients who underwent TST, 76 patients with SARS-COV-2 infection confirmed by RT-PCR analysis of respiratory tract samples were included in the study. Relationships between COVID-19 clinical severity and TST positivity, induration size, and other clinical parameters were analyzed. Of the 76 patients, TST results were negative for 53 patients (69.7%) and positive for 23 patients (30.3%). COVID-19 severity was mild in 47 patients (61.8%), moderate in 22 patients (28.9%), and severe in seven patients (9.3%). All TST-positive patients had mild disease. Patients with mild disease had a significantly higher TST positivity rate (p < 0.001) and larger induration diameter (p < 0.001). The area under the receiver operating characteristic (ROC) curve of TST induration size for the differentiation of mild with moderate and severe disease was 0.768 (p < 0.001). The maximum Youden J index value was 0.522 at an induration diameter of 6.5 mm, which had a sensitivity of 66.0% and specificity of 86.2%. COVID-19 patients with positive TST showed a significantly higher rate of mild disease than those with negative TST. TST positivity is favorably associated with the course of COVID-19.

Clinical and Epidemiological Correlates of Low IFN-Gamma Responses in Mitogen Tube of QuantiFERON Assay in Tuberculosis Infection Screening During the COVID-19 Pandemic: A Population-Based Marker of COVID-19 Mortality?

Background: The clinical and epidemiological implications of abnormal immune responses in COVID-19 for latent tuberculosis infection (LTBI) screening are unclear. Methods: We reviewed QuantiFERON TB Gold Plus (QFT-Plus) results (36,709 patients) from July 2016 until October 2021 in Asturias (Spain). We also studied a cohort of ninety hospitalized patients with suspected/confirmed COVID-19 pneumonia and a group of elderly hospitalized patients with COVID-19 who underwent serial QFT-Plus and immune profiling testing. Results: The indeterminate QFT-Plus results rate went from 1.4% (July 2016 to November 2019) to 4.2% during the COVID-19 pandemic. The evolution of the number of cases with low/very low interferon-gamma (IFN-gamma) response in the mitogen tube paralleled the disease activity and number of deaths during the pandemic waves in our region (from March 2020 to October 2021). The percentages of positive QFT-plus patients did not significantly change before and during the pandemic (13.9% vs. 12.2%). Forty-nine patients from the suspected/confirmed COVID-19 pneumonia cohort (54.4%) had low/very low IFN-gamma response to mitogen, 22 of them (24.4%) had severe and critical pneumonia. None received immunosuppressants prior to testing. Abnormal radiological findings (P = 0.01) but not COVID-19 severity was associated with low mitogen response. Immune profiling showed a reduction of CD8 + T cells and a direct correlation between the number of EMRA CD8 + T-cells and IFN-gamma response to mitogen (P = 0.03). Conclusion: Low IFN-gamma responses in mitogen tube of QFT-Plus often occur in COVID-19 pneumonia, which is associated with a low number of an effector CD8 + T-cell subset and does not seem to affect LTBI screening; however, this abnormality seems to parallel the dynamics of COVID-19 at the population level and its mortality.

Targeting screening and treatment for latent tuberculosis infection towards asylum seekers from high-incidence countries - a model-based cost-effectiveness analysis.

BACKGROUND: Enhancing tuberculosis (TB) prevention and care in a post-COVID-19-pandemic phase will be essential to ensure progress towards global TB elimination. In low-burden countries, asylum seekers constitute an important high-risk group. TB frequently arises post-immigration due to the reactivation of latent TB infection (LTBI). Upon-entry screening for LTBI and TB preventive treatment (TPT) are considered worthwhile if targeted to asylum seekers from high-incidence countries who usually present with higher rates of LTBI. However, there is insufficient knowledge about optimal incidence thresholds above which introduction could be cost-effective. We aimed to estimate, among asylum seekers in Germany, the health impact and costs of upon-entry LTBI screening/TPT introduced at different thresholds of country-of-origin TB incidence. METHODS: We sampled hypothetical cohorts of 30-45 thousand asylum seekers aged 15 to 34 years expected to arrive in Germany in 2022 from cohorts of first-time applicants observed in 2017-2019. We modelled LTBI prevalence as a function of country-of-origin TB incidence fitted to data from observational studies. We then used a probabilistic decision-analytic model to estimate health-system costs and quality-adjusted life years (QALYs) under interferon gamma release assay (IGRA)-based screening for LTBI and rifampicin-based TPT (daily, 4 months). Incremental cost-effectiveness ratios (ICERs) were calculated for scenarios of introducing LTBI screening/TPT at different incidence thresholds. RESULTS: We estimated that among 15- to 34-year-old asylum seekers arriving in Germany in 2022, 17.5% (95% uncertainty interval: 14.2-21.6%) will be latently infected. Introducing LTBI screening/TPT above 250 per 100,000 country-of-origin TB incidence would gain 7.3 (2.7-14.8) QALYs at a cost of €51,000 (€18,000-€114,100) per QALY. Lowering the threshold to ≥200 would cost an incremental €53,300 (€19,100-€122,500) per additional QALY gained relative to the ≥250 threshold scenario; ICERs for the ≥150 and ≥ 100 thresholds were €55,900 (€20,200-€128,200) and €62,000 (€23,200-€142,000), respectively, using the next higher threshold as a reference, and considerably higher at thresholds below 100. CONCLUSIONS: LTBI screening and TPT among 15- to 34-year-old asylum seekers arriving in Germany could produce health benefits at reasonable additional cost (with respect to international benchmarks) if introduced at incidence thresholds ≥100. Empirical trials are needed to investigate the feasibility and effectiveness of this approach.

Management of latent TB infection in people living with HIV - AIDS.

Latent TB infection is one of the most important issues which has not been addressed well so far. As we all know, unless measures are taken to diagnose LTBI and treat it effectively, END TB strategy may not achieve its' goals in time. This article highlights the impact of LTBI particularly among PLHIV, WHO recommendations for the diagnosis and management of LTBI, various treatment options for the management of LTBI and research priorities to address LTBI better.