Molecular analysis of genetic mutations among cross-resistant second-line injectable drugs reveals a new resistant mutation in Mycobacterium tuberculosis

Mutations causing mono and cross-resistance among amikacin, kanamycin and capreomycin of second-line injectable drugs (SLIDs) namely are not well understood.We investigated 124 isolates of Mycobacterium tuberculosis for mutations within rrs, eis, tlyA and efflux pump (Rv1258c and Rv0194) genes involved in resistance towards SLIDs. The distribution of mutations across these genes were significantly different in strains with mono-resistance or cross-resistance. A new mutation G878A was found in rrs gene, among strains with capreomycin mono-resistant, or in strains with cross-resistance of capreomycin, kanamycin and amikacin. This mutation was associated with the Euro-American X3 lineage (P b 0.0001). Mutations in the two efflux genes Rv1258c and Rv0194 were confined to strains with only capreomycin/amikacin/kanamycin cross-resistance. Wefurther investigated the minimuminhibitory concentration of capreomycin on isolateswith newG878Amutation ranging from 8 μg/mL to 64 μg/mL. Inclusion of G878A on new molecular assays could increase the sensitivity of capreomycin resistance detection.Lesibana Malinga received PhD funding from National Research foundation (Innovation Fund) and University of Pretoria.http://www.elsevier.com/locate/diagmicrobiohb2016Internal Medicin

A comparative evaluation of the new Genexpert MTB/RIF ultra and other rapid diagnostic assays for detecting tuberculosis in pulmonary and extra pulmonary specimens

Studies evaluating the new GeneXpert Ultra with other rapid diagnostic assays are limited, particularly in diferent geographical settings. The performance of the GeneXpert Ultra, the GeneXpert G4, the Line probe assays (LPA) and auramine smear microscopy in detecting TB in pulmonary and extrapulmonary samples were thus evaluated. Remnants (n=205 samples) of pulmonary (n=125 samples) and extra-pulmonary (n=80 samples) specimens from TB suspects were prospectively collected. Each sample was divided for diagnosis using microscopy, GeneXpert MTB/RIF assays, and LPA; these were all comparatively evaluated, using the MGIT 960 culture as a gold standard. The sensitivity and specifcity of microscopy, Xpert Ultra, Xpert G4 and MTBDRplus (ver 2) in pulmonary samples were respectively: 82.00% and 90.28%; 88.00% and 58.57%; 79.59% and 90.28%; 80.00% and 11.11%. For extrapulmonary specimen, the sensitivity and specifcity were respectively: 53.85% and 98.51%; 69.23% and 49.25%; 50.00% and 97.01%; 69.23% and 25.37%. The new and improved GeneXpert Ultra assay was more sensitive than GeneXpert G4 and LPA in both pulmonary and extra pulmonary samples, albeit with lower specifcity than the GeneXpert G4. The auramine and LPA tests were also highly sensitive, although the LPA was less specifc.University of Pretoria; National Research Foundation; Medical Research Council of South Africahttps://www.nature.com/sreppm2020Medical Microbiolog

Molecular investigations of Mycobacterium tuberculosis genotypes among baseline and follow-up strains circulating in four regions of Eswatini

AVAILABILITY OF DATA AND MATERIALS : The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.SUPPLEMENTARY MATERIAL. Baseline findings. SUPPLEMENTARY MATERIAL. Follow-up findings.BACKGROUND : The tuberculosis (TB) epidemic remains a major global health problem and Eswatini is not excluded. Our study investigated the circulating genotypes in Eswatini and compared them at baseline (start of treatment) and follow-up during TB treatment. METHODS : Three hundred and ninety (n = 390) participants were prospectively enrolled from referral clinics and patients who met the inclusion criteria, were included in the study. A total of 103 participants provided specimens at baseline and follow-up within six months. Mycobacterium tuberculosis (M.tb) strains were detected by GeneXpert ® MTB/RIF assay (Cephied, USA) and Ziehl -Neelsen (ZN) microscopy respectively at baseline and follow-up time-points respectively. The 206 collected specimens were decontaminated and cultured on BACTEC™ MGIT™ 960 Mycobacteria Culture System (Becton Dickinson, USA). Drug sensitivity testing was performed at both baseline and follow-up time points. Spoligotyping was performed on both baseline and follow-up strains after DNA extraction. RESULTS : Resistance to at least one first line drug was detected higher at baseline compared to follow-up specimens with most of them developing into multidrug-resistant (MDR)-TB. A total of four lineages and twenty genotypes were detected. The distribution of the lineages varied among the different regions in Eswatini. The Euro-American lineage was the most prevalent with 46.12% (95/206) followed by the East Asian with 24.27% (50/206); Indo-Oceanic at 9.71% (20/206) and Central Asian at 1.94% (4/206). Furthermore, a high proportion of the Beijing genotype at 24.27% (50/206) and S genotype at 16.50% (34/206) were detected. The Beijing genotype was predominant in follow-up specimens collected from the Manzini region with 48.9% (23/47) (p = 0.001). A significant proportion of follow-up specimens developed MDR-TB (p = 0.001) with Beijing being the major genotype in most follow-up specimens (p < 0.000). CONCLUSION : Eswatini has a high M.tb genotypic diversity. A significant proportion of the TB infected participants had the Beijing genotype associated with MDR-TB in follow-up specimens and thus indicate community wide transmission.https://bmcinfectdis.biomedcentral.comam2024Medical MicrobiologySDG-03:Good heatlh and well-bein

Cefdinir and β-lactamase inhibitor independent efficacy against mycobacterium tuberculosis

BACKGROUND : There is renewed interest in repurposing β-lactam antibiotics for treatment of tuberculosis (TB). We investigated efficacy of cefdinir, that withstand the β-lactamase enzyme present in many bacteria, against drug-susceptible and multi-drug resistant (MDR) Mycobacterium tuberculosis (Mtb). METHODS : Minimum inhibitory concentration (MIC) experiments were performed with Mtb H37Ra, eight drug-susceptible, and 12 MDR-TB clinical isolates with and without the β-lactamase inhibitor, avibactam at 15 mg/L final concentration. Next, we performed dose-response study with Mtb H37Ra in test-tubes followed by a sterilizing activity study in the pre-clinical hollow fiber model of tuberculosis (HFS-TB) study using an MDR-TB clinical strain. Inhibitory sigmoid Emax model was used to describe the relationship between the drug exposure and bacterial burden. RESULTS : Cefdinir MIC for Mtb H37Ra was 4 and 2 mg/L with or without avibactam, respectively. The MIC of the clinical strains ranged between 0.5 and 16 mg/L. In the test-tube experiments, cefdinir killed 4.93 + 0.07 log10 CFU/ml Mtb H37Ra in 7 days. In the HFS-TB studies, cefdinir showed dose-dependent killing of MDR-TB, without combination of avibactam. The cefdinir PK/PD index linked to the Mtb sterilizing efficacy was identified as the ratio of area under the concentration-time curve to MIC (AUC0–24/MIC) and optimal exposure was calculated as AUC0–24/MIC of 578.86. There was no resistance emergence to cefdinir in the HFS-TB. CONCLUSION : In the HFS-TB model, cefdinir showed efficacy against both drug susceptible and MDR-TB without combination of β-lactamase inhibitor. However, clinical validation of these findings remains to be determined.Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), University of Texas System STARS award and the Department of Pulmonary Immunology, UT Health Science Center at Tyler, Texas.http://www.frontiersin.org/Pharmacologyam2022Internal Medicin

Machine learning reveals that Mycobacterium tuberculosis genotypes and anatomic disease site impacts drug resistance and disease transmission among patients with proven extra-pulmonary tuberculosis

BACKGROUND: There is a general dearth of information on extrapulmonary tuberculosis (EPTB). Here, we investigated Mycobacterium tuberculosis (Mtb) drug resistance and transmission patterns in EPTB patients treated in the Tshwane metropolitan area, in South Africa. METHODS: Consecutive Mtb culture-positive non-pulmonary samples from unique EPTB patients underwent mycobacterial genotyping and were assigned to phylogenetic lineages and transmission clusters based on spoligotypes. MTBDRplus assay was used to search mutations for isoniazid and rifampin resistance. Machine learning algorithms were used to identify clinically meaningful patterns in data. We computed odds ratio (OR), attributable risk (AR) and corresponding 95% confidence intervals (CI). RESULTS: Of the 70 isolates examined, the largest cluster comprised 25 (36%) Mtb strains that belonged to the East Asian lineage. East Asian lineage was significantly more likely to occur within chains of transmission when compared to the Euro-American and East-African Indian lineages: OR = 10.11 (95% CI: 1.56–116). Lymphadenitis, meningitis and cutaneous TB, were significantly more likely to be associated with drug resistance: OR = 12.69 (95% CI: 1.82–141.60) and AR = 0.25 (95% CI: 0.06–0.43) when compared with other EPTB sites, which suggests that poor rifampin penetration might be a contributing factor. CONCLUSIONS: The majority of Mtb strains circulating in the Tshwane metropolis belongs to East Asian, EuroAmerican and East-African Indian lineages. Each of these are likely to be clustered, suggesting on-going EPTB transmission. Since 25% of the drug resistance was attributable to sanctuary EPTB sites notorious for poor rifampin penetration, we hypothesize that poor anti-tuberculosis drug dosing might have a role in the development of resistance.http://www.biomedcentral.com/bmcinfectdispm2020Medical Microbiolog

Global age-sex-specific mortality, life expectancy, and population estimates in 204 countries and territories and 811 subnational locations, 1950–2021, and the impact of the COVID-19 pandemic: a comprehensive demographic analysis for the Global Burden of Disease Study 2021

Background: Estimates of demographic metrics are crucial to assess levels and trends of population health outcomes. The profound impact of the COVID-19 pandemic on populations worldwide has underscored the need for timely estimates to understand this unprecedented event within the context of long-term population health trends. The Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2021 provides new demographic estimates for 204 countries and territories and 811 additional subnational locations from 1950 to 2021, with a particular emphasis on changes in mortality and life expectancy that occurred during the 2020–21 COVID-19 pandemic period. Methods: 22 223 data sources from vital registration, sample registration, surveys, censuses, and other sources were used to estimate mortality, with a subset of these sources used exclusively to estimate excess mortality due to the COVID-19 pandemic. 2026 data sources were used for population estimation. Additional sources were used to estimate migration; the effects of the HIV epidemic; and demographic discontinuities due to conflicts, famines, natural disasters, and pandemics, which are used as inputs for estimating mortality and population. Spatiotemporal Gaussian process regression (ST-GPR) was used to generate under-5 mortality rates, which synthesised 30 763 location-years of vital registration and sample registration data, 1365 surveys and censuses, and 80 other sources. ST-GPR was also used to estimate adult mortality (between ages 15 and 59 years) based on information from 31 642 location-years of vital registration and sample registration data, 355 surveys and censuses, and 24 other sources. Estimates of child and adult mortality rates were then used to generate life tables with a relational model life table system. For countries with large HIV epidemics, life tables were adjusted using independent estimates of HIV-specific mortality generated via an epidemiological analysis of HIV prevalence surveys, antenatal clinic serosurveillance, and other data sources. Excess mortality due to the COVID-19 pandemic in 2020 and 2021 was determined by subtracting observed all-cause mortality (adjusted for late registration and mortality anomalies) from the mortality expected in the absence of the pandemic. Expected mortality was calculated based on historical trends using an ensemble of models. In location-years where all-cause mortality data were unavailable, we estimated excess mortality rates using a regression model with covariates pertaining to the pandemic. Population size was computed using a Bayesian hierarchical cohort component model. Life expectancy was calculated using age-specific mortality rates and standard demographic methods. Uncertainty intervals (UIs) were calculated for every metric using the 25th and 975th ordered values from a 1000-draw posterior distribution. Findings: Global all-cause mortality followed two distinct patterns over the study period: age-standardised mortality rates declined between 1950 and 2019 (a 62·8% [95% UI 60·5–65·1] decline), and increased during the COVID-19 pandemic period (2020–21; 5·1% [0·9–9·6] increase). In contrast with the overall reverse in mortality trends during the pandemic period, child mortality continued to decline, with 4·66 million (3·98–5·50) global deaths in children younger than 5 years in 2021 compared with 5·21 million (4·50–6·01) in 2019. An estimated 131 million (126–137) people died globally from all causes in 2020 and 2021 combined, of which 15·9 million (14·7–17·2) were due to the COVID-19 pandemic (measured by excess mortality, which includes deaths directly due to SARS-CoV-2 infection and those indirectly due to other social, economic, or behavioural changes associated with the pandemic). Excess mortality rates exceeded 150 deaths per 100 000 population during at least one year of the pandemic in 80 countries and territories, whereas 20 nations had a negative excess mortality rate in 2020 or 2021, indicating that all-cause mortality in these countries was lower during the pandemic than expected based on historical trends. Between 1950 and 2021, global life expectancy at birth increased by 22·7 years (20·8–24·8), from 49·0 years (46·7–51·3) to 71·7 years (70·9–72·5). Global life expectancy at birth declined by 1·6 years (1·0–2·2) between 2019 and 2021, reversing historical trends. An increase in life expectancy was only observed in 32 (15·7%) of 204 countries and territories between 2019 and 2021. The global population reached 7·89 billion (7·67–8·13) people in 2021, by which time 56 of 204 countries and territories had peaked and subsequently populations have declined. The largest proportion of population growth between 2020 and 2021 was in sub-Saharan Africa (39·5% [28·4–52·7]) and south Asia (26·3% [9·0–44·7]). From 2000 to 2021, the ratio of the population aged 65 years and older to the population aged younger than 15 years increased in 188 (92·2%) of 204 nations. Interpretation: Global adult mortality rates markedly increased during the COVID-19 pandemic in 2020 and 2021, reversing past decreasing trends, while child mortality rates continued to decline, albeit more slowly than in earlier years. Although COVID-19 had a substantial impact on many demographic indicators during the first 2 years of the pandemic, overall global health progress over the 72 years evaluated has been profound, with considerable improvements in mortality and life expectancy. Additionally, we observed a deceleration of global population growth since 2017, despite steady or increasing growth in lower-income countries, combined with a continued global shift of population age structures towards older ages. These demographic changes will likely present future challenges to health systems, economies, and societies. The comprehensive demographic estimates reported here will enable researchers, policy makers, health practitioners, and other key stakeholders to better understand and address the profound changes that have occurred in the global health landscape following the first 2 years of the COVID-19 pandemic, and longer-term trends beyond the pandemic

Global burden and strength of evidence for 88 risk factors in 204 countries and 811 subnational locations, 1990–2021: a systematic analysis for the Global Burden of Disease Study 2021

Background: Understanding the health consequences associated with exposure to risk factors is necessary to inform public health policy and practice. To systematically quantify the contributions of risk factor exposures to specific health outcomes, the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2021 aims to provide comprehensive estimates of exposure levels, relative health risks, and attributable burden of disease for 88 risk factors in 204 countries and territories and 811 subnational locations, from 1990 to 2021. Methods: The GBD 2021 risk factor analysis used data from 54 561 total distinct sources to produce epidemiological estimates for 88 risk factors and their associated health outcomes for a total of 631 risk–outcome pairs. Pairs were included on the basis of data-driven determination of a risk–outcome association. Age-sex-location-year-specific estimates were generated at global, regional, and national levels. Our approach followed the comparative risk assessment framework predicated on a causal web of hierarchically organised, potentially combinative, modifiable risks. Relative risks (RRs) of a given outcome occurring as a function of risk factor exposure were estimated separately for each risk–outcome pair, and summary exposure values (SEVs), representing risk-weighted exposure prevalence, and theoretical minimum risk exposure levels (TMRELs) were estimated for each risk factor. These estimates were used to calculate the population attributable fraction (PAF; ie, the proportional change in health risk that would occur if exposure to a risk factor were reduced to the TMREL). The product of PAFs and disease burden associated with a given outcome, measured in disability-adjusted life-years (DALYs), yielded measures of attributable burden (ie, the proportion of total disease burden attributable to a particular risk factor or combination of risk factors). Adjustments for mediation were applied to account for relationships involving risk factors that act indirectly on outcomes via intermediate risks. Attributable burden estimates were stratified by Socio-demographic Index (SDI) quintile and presented as counts, age-standardised rates, and rankings. To complement estimates of RR and attributable burden, newly developed burden of proof risk function (BPRF) methods were applied to yield supplementary, conservative interpretations of risk–outcome associations based on the consistency of underlying evidence, accounting for unexplained heterogeneity between input data from different studies. Estimates reported represent the mean value across 500 draws from the estimate's distribution, with 95% uncertainty intervals (UIs) calculated as the 2·5th and 97·5th percentile values across the draws. Findings: Among the specific risk factors analysed for this study, particulate matter air pollution was the leading contributor to the global disease burden in 2021, contributing 8·0% (95% UI 6·7–9·4) of total DALYs, followed by high systolic blood pressure (SBP; 7·8% [6·4–9·2]), smoking (5·7% [4·7–6·8]), low birthweight and short gestation (5·6% [4·8–6·3]), and high fasting plasma glucose (FPG; 5·4% [4·8–6·0]). For younger demographics (ie, those aged 0–4 years and 5–14 years), risks such as low birthweight and short gestation and unsafe water, sanitation, and handwashing (WaSH) were among the leading risk factors, while for older age groups, metabolic risks such as high SBP, high body-mass index (BMI), high FPG, and high LDL cholesterol had a greater impact. From 2000 to 2021, there was an observable shift in global health challenges, marked by a decline in the number of all-age DALYs broadly attributable to behavioural risks (decrease of 20·7% [13·9–27·7]) and environmental and occupational risks (decrease of 22·0% [15·5–28·8]), coupled with a 49·4% (42·3–56·9) increase in DALYs attributable to metabolic risks, all reflecting ageing populations and changing lifestyles on a global scale. Age-standardised global DALY rates attributable to high BMI and high FPG rose considerably (15·7% [9·9–21·7] for high BMI and 7·9% [3·3–12·9] for high FPG) over this period, with exposure to these risks increasing annually at rates of 1·8% (1·6–1·9) for high BMI and 1·3% (1·1–1·5) for high FPG. By contrast, the global risk-attributable burden and exposure to many other risk factors declined, notably for risks such as child growth failure and unsafe water source, with age-standardised attributable DALYs decreasing by 71·5% (64·4–78·8) for child growth failure and 66·3% (60·2–72·0) for unsafe water source. We separated risk factors into three groups according to trajectory over time: those with a decreasing attributable burden, due largely to declining risk exposure (eg, diet high in trans-fat and household air pollution) but also to proportionally smaller child and youth populations (eg, child and maternal malnutrition); those for which the burden increased moderately in spite of declining risk exposure, due largely to population ageing (eg, smoking); and those for which the burden increased considerably due to both increasing risk exposure and population ageing (eg, ambient particulate matter air pollution, high BMI, high FPG, and high SBP). Interpretation: Substantial progress has been made in reducing the global disease burden attributable to a range of risk factors, particularly those related to maternal and child health, WaSH, and household air pollution. Maintaining efforts to minimise the impact of these risk factors, especially in low SDI locations, is necessary to sustain progress. Successes in moderating the smoking-related burden by reducing risk exposure highlight the need to advance policies that reduce exposure to other leading risk factors such as ambient particulate matter air pollution and high SBP. Troubling increases in high FPG, high BMI, and other risk factors related to obesity and metabolic syndrome indicate an urgent need to identify and implement interventions

Characterization of efflux pumps genes involved in second-line drug resistance of tuberculosis

In this study, we used molecular and proteomic methods to detect novel changes within drug-resistant tuberculosis (TB) strains. Our goal was to detect changes within efflux pump (EP) genes of extensively drug resistant (XDR-TB) strains using genomic and transcriptomic methods. We firstly sequenced multiple genes in discordant samples that lacked molecular markers present on the GenoType® MTBDRsl assay. Further analysis by whole genome sequencing was done on XDR-TB strains. Transcriptomic changes of EP genes were detected by RNA sequencing strains. The minimum inhibitory concentration (MIC) of second-line drugs in the presence and absence of efflux pump inhibitors was also measured. Proteomic expression by cloning and expression of three efflux pump genes (Rv1258c, Rv1634 and Rv0194) was done and effect on MICs of second-line drugs measured in the presence and absence of efflux pump inhibitors. We analysed molecular markers responsible for resistance to second-line drugs of ofloxacin (OFX), amikacin (AMK), kanamycin (KAN) and capreomycin (CAP) in 636 drug-resistant strains using GenoType® MTBDRsl. We compared GenoType® MTBDRsl with phenotypic second-line drug susceptibility testing. After comparison, 102 (14.8%) strains were discordant between the two methods. In the discordant population, genetic regions of gyrA, gyrB, rrs, eis, tlyA and EP genes (Rv1634, Rv1258c and Rv0194) were sequenced and analysed in search of mutations. Combining sequencing and GenoType® MTBDRsl significantly improved the diagnosis of XDR-TB and second-line drugs. The Rv0194 belongs to the ATP (adenosine triphosphate) binding cassette (ABC) family while Rv1258c and Rv1634 belong to the major facilitator superfamily (MFS) transporters. Since these genes are implicated in multiple drug resistance, our hypothesis was that possible mutations in these genes could confer cross-resistance. Our analysis revealed the appearance of Rv1258c and Rv0194 mutations in strains with cross-resistance to second-line injectable drugs. Further analysis revealed rrs G878A mutation that was specific to EuroAmerican X3 lineage (P<0.001) and linked to CAP resistance. The inclusion of G878A in new rapid assays might be beneficial for rapid CAP resistance detection. Whole genome sequencing with increased resolution and depth was used to study two XDR-TB strains. Drug resistant mutations were detected for all other drugs except for OFX in one strain. We further analysed EP genes for mutations. Bioinformatic prediction tools detected protein changes related to EP gene mutations belonging to Rv0987, Rv2039 and Rv0402. Two of the efflux pump genes (Rv0987, Rv2039) belong to the ABC family, while Rv0402 is of resistance nodulation-cell division (RND) family. Mutations within lipid metabolism and secretion pathways were also detected. To fully understand the role of EP gene mechanisms at a transcriptional level, we sequenced RNA molecules of 11 XDR-TB, five MDR and two susceptible strains. The RNA signatures of EP and lipid metabolism genes detected in XDR-TB strains were characterized. Further analysis of four XDR strains with MIC data with or without efflux pump inhibitors (EPIs) was performed in relation to RNA sequenced data. The ABC Rv2686/87/88c operon was significantly over-expressed in the background on strains with gyrA mutations causing OFX resistance. The Rv1258c, Rv0194 and Rv1634 EP genes were consistently over-expressed in XDR TB strains. Efflux pump inhibitor of piperine was effective in reducing MICs to hydrophilic drugs of AMK and OFX whereas verapamil reduced MIC of hydrophobic CAP drug. Protein-protein interaction pathways revealed novel associations between ABC, RND and type VII secretion (T7S) proteins. Finally, we cloned and expressed Rv1258c, Rv0194 and Rv1634 EP genes in Mycobacterium vectors. These genes have the potential to cause multidrug resistance. We did not detect increased MIC levels of second-line drugs in the presence of the clones. However, a reduction of MICs in the presence of the EPI, piperine, was observed. Bioinformatic approaches also revealed transmembrane motifs, domains and loops. Since EP genes are implicated in transport of substrates across cell membrane, we used biofilm formation assays to determine the role of each clone. Both Rv1258c and Rv0194 clones showed biofilm formation. Such discovery highlights the secretion of lipid bodies on the cell wall of the bacteria through EP genes/proteins. This information will allow us to develop novel strategies to treat drug-resistant TB. Our study emphasises the importance of EP gene mechanisms in causing drug resistance. The combination of EP and target genes is important in the detection of second-line drugs. Furthermore, it is suggested that EPIs combined with second-line drugs might be effective in the treatment of XDR-TB.Thesis (PhD)--University of Pretoria, 2017.Internal MedicinePhDUnrestricte

Meropenem-vaborbactam restoration of first-line drug efficacy and comparison of meropenem-vaborbactam-moxifloxacin versus BPaL MDR-TB regimen

DATA AVAILABILITY STATEMENT : Upon a reasonable request, the raw data for the results presented in the manuscript are available from the corresponding author.Please read abstract in the article.Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), the University of Texas System STARS award, the Department of Pulmonary Immunology, UT Health Science Center at Tyler, Texas, USA.http://www.elsevier.com/locate/ijantimicag2024-10-23hj2024Medical MicrobiologySDG-03:Good heatlh and well-bein

Global age-sex-specific mortality, life expectancy, and population estimates in 204 countries and territories and 811 subnational locations, 1950–2021, and the impact of the COVID-19 pandemic: a comprehensive demographic analysis for the Global Burden of Disease Study 2021

BackgroundEstimates of demographic metrics are crucial to assess levels and trends of population health outcomes. The profound impact of the COVID-19 pandemic on populations worldwide has underscored the need for timely estimates to understand this unprecedented event within the context of long-term population health trends. The Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2021 provides new demographic estimates for 204 countries and territories and 811 additional subnational locations from 1950 to 2021, with a particular emphasis on changes in mortality and life expectancy that occurred during the 2020–21 COVID-19 pandemic period.Methods22 223 data sources from vital registration, sample registration, surveys, censuses, and other sources were used to estimate mortality, with a subset of these sources used exclusively to estimate excess mortality due to the COVID-19 pandemic. 2026 data sources were used for population estimation. Additional sources were used to estimate migration; the effects of the HIV epidemic; and demographic discontinuities due to conflicts, famines, natural disasters, and pandemics, which are used as inputs for estimating mortality and population. Spatiotemporal Gaussian process regression (ST-GPR) was used to generate under-5 mortality rates, which synthesised 30 763 location-years of vital registration and sample registration data, 1365 surveys and censuses, and 80 other sources. ST-GPR was also used to estimate adult mortality (between ages 15 and 59 years) based on information from 31 642 location-years of vital registration and sample registration data, 355 surveys and censuses, and 24 other sources. Estimates of child and adult mortality rates were then used to generate life tables with a relational model life table system. For countries with large HIV epidemics, life tables were adjusted using independent estimates of HIV-specific mortality generated via an epidemiological analysis of HIV prevalence surveys, antenatal clinic serosurveillance, and other data sources. Excess mortality due to the COVID-19 pandemic in 2020 and 2021 was determined by subtracting observed all-cause mortality (adjusted for late registration and mortality anomalies) from the mortality expected in the absence of the pandemic. Expected mortality was calculated based on historical trends using an ensemble of models. In location-years where all-cause mortality data were unavailable, we estimated excess mortality rates using a regression model with covariates pertaining to the pandemic. Population size was computed using a Bayesian hierarchical cohort component model. Life expectancy was calculated using age-specific mortality rates and standard demographic methods. Uncertainty intervals (UIs) were calculated for every metric using the 25th and 975th ordered values from a 1000-draw posterior distribution.FindingsGlobal all-cause mortality followed two distinct patterns over the study period: age-standardised mortality rates declined between 1950 and 2019 (a 62·8% [95% UI 60·5–65·1] decline), and increased during the COVID-19 pandemic period (2020–21; 5·1% [0·9–9·6] increase). In contrast with the overall reverse in mortality trends during the pandemic period, child mortality continued to decline, with 4·66 million (3·98–5·50) global deaths in children younger than 5 years in 2021 compared with 5·21 million (4·50–6·01) in 2019. An estimated 131 million (126–137) people died globally from all causes in 2020 and 2021 combined, of which 15·9 million (14·7–17·2) were due to the COVID-19 pandemic (measured by excess mortality, which includes deaths directly due to SARS-CoV-2 infection and those indirectly due to other social, economic, or behavioural changes associated with the pandemic). Excess mortality rates exceeded 150 deaths per 100 000 population during at least one year of the pandemic in 80 countries and territories, whereas 20 nations had a negative excess mortality rate in 2020 or 2021, indicating that all-cause mortality in these countries was lower during the pandemic than expected based on historical trends. Between 1950 and 2021, global life expectancy at birth increased by 22·7 years (20·8–24·8), from 49·0 years (46·7–51·3) to 71·7 years (70·9–72·5). Global life expectancy at birth declined by 1·6 years (1·0–2·2) between 2019 and 2021, reversing historical trends. An increase in life expectancy was only observed in 32 (15·7%) of 204 countries and territories between 2019 and 2021. The global population reached 7·89 billion (7·67–8·13) people in 2021, by which time 56 of 204 countries and territories had peaked and subsequently populations have declined. The largest proportion of population growth between 2020 and 2021 was in sub-Saharan Africa (39·5% [28·4–52·7]) and south Asia (26·3% [9·0–44·7]). From 2000 to 2021, the ratio of the population aged 65 years and older to the population aged younger than 15 years increased in 188 (92·2%) of 204 nations.InterpretationGlobal adult mortality rates markedly increased during the COVID-19 pandemic in 2020 and 2021, reversing past decreasing trends, while child mortality rates continued to decline, albeit more slowly than in earlier years. Although COVID-19 had a substantial impact on many demographic indicators during the first 2 years of the pandemic, overall global health progress over the 72 years evaluated has been profound, with considerable improvements in mortality and life expectancy. Additionally, we observed a deceleration of global population growth since 2017, despite steady or increasing growth in lower-income countries, combined with a continued global shift of population age structures towards older ages. These demographic changes will likely present future challenges to health systems, economies, and societies. The comprehensive demographic estimates reported here will enable researchers, policy makers, health practitioners, and other key stakeholders to better understand and address the profound changes that have occurred in the global health landscape following the first 2 years of the COVID-19 pandemic, and longer-term trends beyond the pandemic