Global-, Regional-, and National-Level Impacts of the COVID-19 Pandemic on Tuberculosis Diagnoses, 2020-2021.

Evaluating cross-country variability on the impact of the COVID-19 pandemic on tuberculosis (TB) may provide urgent inputs to control programs as countries recover from the pandemic. We compared expected TB notifications, modeled using trends in annual TB notifications from 2013-2019, with observed TB notifications to compute the observed to expected (OE) ratios for 170 countries. We applied the least absolute shrinkage and selection operator (LASSO) method to identify the covariates, out of 27 pandemic- and tuberculosis-relevant variables, that had the strongest explanatory power for log OE ratios. The COVID-19 pandemic was associated with a 1.55 million (95% CI: 1.26-1.85, 21.0% [17.5-24.6%]) decrease in TB diagnoses in 2020 and a 1.28 million (0.90-1.76, 16.6% [12.1-21.2%]) decrease in 2021 at a global level. India, Indonesia, the Philippines, and China contributed the most to the global declines for both years, while sub-Saharan Africa achieved pre-pandemic levels by 2021 (OE ratio = 1.02 [0.99-1.05]). Age-stratified analyses revealed that the ≥ 65-year-old age group experienced greater relative declines in TB diagnoses compared with the under 65-year-old age group in 2020 (RR = 0.88 [0.81-0.96]) and 2021 (RR = 0.88 [0.79-0.98]) globally. Covariates found to be associated with all-age OE ratios in 2020 were age-standardized smoking prevalence in 2019 (ß = 0.973 [0.957-990]), school closures (ß = 0.988 [0.977-0.998]), stay-at-home orders (ß = 0.993 [0.985-1.00]), SARS-CoV-2 infection rate (ß = 0.991 [0.987-0.996]), and proportion of population ≥65 years (ß = 0.971 [0.944-0.999]). Further research is needed to clarify the extent to which the observed declines in TB diagnoses were attributable to disruptions in health services, decreases in TB transmission, and COVID-19 mortality among TB patients.

Community Mitigation Strategies, Mobility, and COVID-19 Incidence Across Three Waves in the United States in 2020.

BACKGROUND: Summarizing the impact of community-based mitigation strategies and mobility on COVID-19 infections throughout the pandemic is critical for informing responses and future infectious disease outbreaks. Here, we employed time-series analyses to empirically investigate the relationships between mitigation strategies and mobility on COVID-19 incident cases across US states during the first three waves of infections. METHODS: We linked data on daily COVID-19 incidence by US state from March to December 2020 with the stringency index, a well-known index capturing the strictness of mitigation strategies, and the trip ratio, which measures the ratio of the number of trips taken per day compared with the same day in 2019. We utilized multilevel models to determine the relative impacts of policy stringency and the trip ratio on COVID-19 cumulative incidence and the effective reproduction number. We stratified analyses by three waves of infections. RESULTS: Every five-point increase in the stringency index was associated with 2.89% (95% confidence interval = 1.52, 4.26%) and 5.01% (3.02, 6.95%) reductions in COVID-19 incidence for the first and third waves, respectively. Reducing the number of trips taken by 50% compared with the same time in 2019 was associated with a 16.2% (-0.07, 35.2%) decline in COVID-19 incidence at the state level during the second wave and 19.3% (2.30, 39.0%) during the third wave. CONCLUSIONS: Mitigation strategies and reductions in mobility are associated with marked health gains through the reduction of COVID-19 infections, but we estimate variable impacts depending on policy stringency and levels of adherence.

Progress towards the 2020 milestones of the end TB strategy in Cambodia: estimates of age and sex specific TB incidence and mortality from the Global Burden of Disease Study 2019.

BACKGROUND: Cambodia was recently removed from the World Health Organization's (WHO's) top 30 high tuberculosis (TB) burden countries. However, Cambodia's TB burden remains substantial, and the country is on the WHO's new global TB watchlist. We aimed to examine the levels and trends in the fatal and non-fatal TB burden in Cambodia from 1990 to 2019, assessing progress towards the WHO End TB interim milestones, which aim to reduce TB incidence rate by 20% and TB deaths by 35% from 2015 to 2020. METHODS: We leveraged the Global Burden of Disease 2019 (GBD 2019) analytical framework to compute age- and sex-specific TB mortality and incidence by HIV status in Cambodia. We enumerated TB mortality utilizing a Bayesian hierarchical Cause of Death Ensemble modeling platform. We analyzed all available data sources, including prevalence surveys, population-based tuberculin surveys, and TB cause-specific mortality, to produce internally consistent estimates of incidence and mortality using a compartmental meta-regression tool (DisMod-MR 2.1). We further estimated the fraction of tuberculosis mortality among individuals without HIV coinfection attributable to the independent effects of alcohol use, smoking, and diabetes. RESULTS: In 2019, there were 6500 (95% uncertainty interval 4830-8680) deaths due to all-form TB and 50.0 (43.8-57.8) thousand all-form TB incident cases in Cambodia. The corresponding age-standardized rates were 53.3 (39.9-69.4) per 100,000 population for mortality and 330.5 (289.0-378.6) per 100,000 population for incidence. From 2015 to 2019, the number of all-form TB deaths decreased by 11.8% (2.3-21.1), while the age-standardized all-form TB incidence rate decreased by 11.1% (6.3-15.6). Among individuals without HIV coinfection in 2019, alcohol use accounted for 28.1% (18.2-37.9) of TB deaths, smoking accounted for 27.0% (20.2-33.3), and diabetes accounted for 12.5% (7.1-19.0). Removing the combined effects of these risk factors would reduce all-form TB deaths by 54.2% (44.2-62.2). DISCUSSION: Despite significant progress in reducing TB morbidity and mortality since 1990, Cambodia is not on track to achieve the 2020 WHO End TB interim milestones. Existing programs in Cambodia can benefit from liaising with risk factor control initiatives to accelerate progress toward eliminating TB in Cambodia.

Spurious early ecological association suggesting BCG vaccination effectiveness for COVID-19.

BACKGROUND: Several ecologic studies have suggested that the bacillus Calmette-Guérin (BCG) vaccine may be protective against SARS-CoV-2 infection including a highly-cited published pre-print by Miller et al., finding that middle/high- and high-income countries that never had a universal BCG policy experienced higher COVID-19 burden compared to countries that currently have universal BCG vaccination policies. We provide a case study of the limitations of ecologic analyses by evaluating whether these early ecologic findings persisted as the pandemic progressed. METHODS: Similar to Miller et al., we employed Wilcoxon Rank Sum Tests to compare population medians in COVID-19 mortality, incidence, and mortality-to-incidence ratio between countries with universal BCG policies compared to those that never had such policies. We then computed Pearson's r correlations to evaluate the association between year of BCG vaccination policy implementation and COVID-19 outcomes. We repeated these analyses for every month in 2020 subsequent to Miller et al.'s March 2020 analysis. RESULTS: We found that the differences in COVID-19 burden associated with BCG vaccination policies in March 2020 generally diminished in magnitude and usually lost statistical significance as the pandemic progressed. While six of nine analyses were statistically significant in March, only two were significant by the end of 2020. DISCUSSION: These results underscore the need for caution in interpreting ecologic studies, given their inherent methodological limitations, which can be magnified in the context of a rapidly evolving pandemic in which there is measurement error of both exposure and outcome status.

Estimating the population at high risk for tuberculosis through household exposure in high-incidence countries: a model-based analysis.

BACKGROUND: Household contacts of people with pulmonary tuberculosis (TB) have greater risk of developing TB. Recent guidelines conditionally recommended TB preventive treatment (TPT) for household contacts of any age living in TB high-incidence countries, expanding earlier guidance to provide TPT to household contacts under five. The all-age population of household contacts has not been estimated. METHODS: Our model-based estimation included 20 countries with >80% of incident TB globally in 2019. We developed country-specific distributions of household composition by age and sex using bootstrap resampling from health surveys and census data. We incorporated age-, sex-, year-, and location-specific estimates of pulmonary TB incidence from the Global Burden of Diseases, Injuries, and Risk Factors Study 2019 to estimate the population in each country sharing a household with someone with incident pulmonary TB, and quantified uncertainty using a Monte Carlo approach. FINDINGS: We estimate that 38 million [95% uncertainty interval (UI) 33- 43 million] individuals lived in a household with someone with incident pulmonary TB in 2019 in these 20 countries. Children under five made up 12% of the population with household exposure, while adults were 65%. Zimbabwe, Mozambique, Zambia, and Pakistan had the highest proportion of the population with household exposure, while India had the highest number of contacts (11·4 million, 95% UI 9·7-13·4 million). INTERPRETATION: Expanding TPT evaluation to household contacts of all ages in high-incidence countries could include a population more than 7-times larger than the under-5 contacts previously prioritized. This would substantially increase the impact of household contact investigation on reducing TB morbidity and mortality. FUNDING: JMR is supported by the National Institute of Allergy and Infectious Diseases (K01 AI138620). This research was funded in part by a 2020 developmental grant from the University of Washington / Fred Hutch Center for AIDS Research, an NIH funded program under award number AI027757 which is supported by the following NIH Institutes and Centers: NIAID, NCI, NIMH, NIDA, NICHD, NHLBI, NIA, NIGMS, NIDDK. This work was funded in part by the National Science Foundation (DMS-1839116).

Interferon-gamma release assay levels and risk of progression to active tuberculosis: a systematic review and dose-response meta-regression analysis.

BACKGROUND: Identifying and treating individuals with high risk of progression from latent tuberculosis infection to active tuberculosis (TB) disease is critical for eliminating the disease. We aimed to conduct a systematic review and meta-regression analysis to quantify the dose-response relationship between interferon-gamma release assay (IGRA) levels and the risk of progression to active TB. METHODS: We searched PubMed and Embase from 1 January 2001 to 10 May 2020 for longitudinal studies that reported the risk of progression from latent to active TB as a function of baseline IGRA values. We used a novel Bayesian meta-regression method to pool effect sizes from included studies and generate a continuous dose-response risk curve. Our modeling framework enabled us to incorporate random effects across studies, and include data with different IGRA ranges across studies. The quality of included studies were assessed using the Newcastle-Ottawa scale (NOS). RESULTS: We included 34 studies representing 581,956 person-years of follow-up with a total of 788 incident cases of TB in the meta-regression analysis. Higher levels of interferon-gamma were associated with increased risk of progression to active tuberculosis. In the dose-response curve, the risk increased sharply between interferon-gamma levels 0 and 5 IU/ml, after which the risk continued to increase moderately but at a slower pace until reaching about 15 IU/ml where the risk levels off. Compared to 0 IU/ml, the relative risk of progression to active TB among those with interferon-gamma levels of 0.35, 1, 5, 10, 15, and 20 IU/ml were: 1.64 (1.28-2.08), 2.90 (2.02-3.88), 11.38 (6.64-16.38), 19.00 (13.08-26.90), 21.82 (14.65-32.57), and 22.31 (15.43-33.00), respectively. The dose-response relationship remains consistent when limiting the analysis to studies that scored highest in the NOS. CONCLUSION: The current practice of dichotomizing IGRA test results simplifies the TB infection disease continuum. Evaluating IGRA test results over a continuous scale could enable the identification of individuals at greatest risk of progression to active TB.

Global variation in bacterial strains that cause tuberculosis disease: a systematic review and meta-analysis.

BACKGROUND: The host, microbial, and environmental factors that contribute to variation in tuberculosis (TB) disease are incompletely understood. Accumulating evidence suggests that one driver of geographic variation in TB disease is the local ecology of mycobacterial genotypes or strains, and there is a need for a comprehensive and systematic synthesis of these data. The objectives of this study were to (1) map the global distribution of genotypes that cause TB disease and (2) examine whether any epidemiologically relevant clinical characteristics were associated with those genotypes. METHODS: We performed a systematic review of PubMed and Scopus to create a comprehensive dataset of human TB molecular epidemiology studies that used representative sampling techniques. The methods were developed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). We extracted and synthesized data from studies that reported prevalence of bacterial genotypes and from studies that reported clinical characteristics associated with those genotypes. RESULTS: The results of this study are twofold. First, we identified 206 studies for inclusion in the study, representing over 200,000 bacterial isolates collected over 27 years in 85 countries. We mapped the genotypes and found that, consistent with previously published maps, Euro-American lineage 4 and East Asian lineage 2 strains are widespread, and West African lineages 5 and 6 strains are geographically restricted. Second, 30 studies also reported transmission chains and 4 reported treatment failure associated with genotypes. We performed a meta-analysis and found substantial heterogeneity across studies. However, based on the data available, we found that lineage 2 strains may be associated with increased risk of transmission chains, while lineages 5 and 6 strains may be associated with reduced risk, compared with lineage 4 strains. CONCLUSIONS: This study provides the most comprehensive systematic analysis of the evidence for diversity in bacterial strains that cause TB disease. The results show both geographic and epidemiological differences between strains, which could inform our understanding of the global burden of TB. Our findings also highlight the challenges of collecting the clinical data required to inform TB diagnosis and treatment. We urge future national TB programs and research efforts to prioritize and reinforce clinical data collection in study designs and results dissemination.