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. FUNDING: Bill & Melinda Gates Foundation

Oligoclonal T cell expansions in patients with Behçet's disease

Behçet's disease (BD) is a multisystem disorder with oral and genital ulcers, mucocutaneous, ocular, joint, vascular and central nervous system involvement. In this study, the peripheral T cell repertoire was analysed in patients with BD with MoAbs against T cell receptor (TCR) Vβ gene products in CD4+ and CD8+ T cell compartments, and these were compared with rheumatoid arthritis (RA) patients and healthy controls (HC). In the CD4+ T cell compartment, oligoclonal TCR Vβ expression was observed in 56% of BD (10/18), 71% of RA (5/7) patients and 21% (3/14) of HC. In the CD8+ T cell group 50% of BD (9/18), 57% of RA patients and 28% of HC (4/14) had an oligoclonal TCR repertoire. An increase of TCR Vβ5.1 subset was observed in five BD patients among CD8+ T cells. Other elevations of TCR Vβ subsets were heterogeneously distributed with one to three different Vβ subsets. Our results suggest an antigen-driven oligoclonal increase of T cells in BD. There was no overall increase in any Vβ group to suggest a superantigen effect. Analysis of the responsible antigens causing the increase in T cell subsets may give insights into the aetiopathogenesis of BD and immunomodulation of these T cells may lead to new treatments

Cellular and humoral immune responses to mycobacterial heat shock protein-65 and its human homologue in Takayasu's arteritis

Expression of heat shock protein (HSP)-65 as well as infiltration of T-cells in arterial lesions and raised levels of circulating antibodies against mycobacterial HSP65 (mHSP65) led us to the concept that mHSP65 or its human homologue (hHSP60) might be involved in the etiopathogenesis of Takayasu's arteritis (TA). Therefore, we investigated mHSP65 and hHSP60 reactive peripheral blood T-cell subsets by BrdU incorporation assay and flow cytometry as well as investigating the different isotypes of anti-mHSP65 and hHSP60 antibodies by ELISA. Eighty-four percent (22/26) of the TA patients were observed to show T-cell proliferation to mHSP65 and hHSP60 whereas only 16% (3/18) healthy controls showed such proliferation (P < 0·001). Both HSPs induced proliferation of exclusively CD4+ T-cells and not CD8+ T-cells. We also observed a significantly higher prevalence of only the IgG isotype reactive to mHSP65 and hHSP60 in TA as compared to HC (mHSP65: 92% TA versus 11% HC, P < 0·0001 and hHSP60: 84% versus 22%, P < 0·001). Our data show a significant correlation between mHSP65 and hHSP60 reactive T-cells (CD3+: r = 0·901; CD4+: r = 0·968) as well as anti-mHSP65 and anti-hHSP60 IgG antibodies (r = 0·814) suggesting an infection induced autoimmunity in TA, possibly induced by molecular mimicry between mHSP65 and hHSP60 or other tissue specific antigens

Cytokine mRNA repertoire of peripheral blood mononuclear cells in Takayasu's arteritis

We have investigated constitutive and phytohaemagglutinin (PHA) + phorbol 12-myristate 13-acetate (PMA)-induced gene expression of tumour necrosis factor (TNF)-α, interferon (IFN)-γ, interleukin (IL)-2, IL-3, IL-4, IL-10, IL-12 and granulocyte macrophage colony-stimulating factor (GM-CSF) in peripheral blood mononuclear cells (PBMCs) of 10 patients with Takayasu's arteritis (TA) and 10 healthy controls by semiquantitative reverse transcriptase polymerase chain reaction (RT-PCR). The constitutive mRNA expression of TNF-α (69·0 ± 4·0% versus 27·5 ± 18·0%; P = 0·001) and IL-4 (60·0 ± 10·0% versus 0%; P = 0·001) was significantly higher in patients than controls; that of IL-3 was comparable in both groups (38·0 ± 6·0% versus 32·0 ± 5·0%; P = 0·651) while no constitutive mRNA expression was observed for the other cytokines studied. The stimulated PBMCs of patients, as compared with the controls, had higher mRNA gene expression of TNF-α (127·0 ± 16·0% versus 54·0 ± 6·0%; P = 0·001), IFN-γ (93·0 ± 13·0% versus 57·0 ± 5·0%; P = 0·032), IL-2 (109·0 ± 13·0% versus 68·0 ± 6·0%; P = 0·015), IL-3 (60·0 ± 8·0% versus 21·2 ± 3·0%; P = 0·045) and IL-4 (68·0 ± 7·0% versus 27·0 ± 7·2%; P = 0·01) The mRNA expression of IL-10 was lower in patients than controls (35·0 ± 8·0% versus 75·0 ± 12·0%; P = 0·022). The GM-CSF mRNA was similar (102·0 ± 6·0% versus 89·0 ± 5·0%; P = 0·475) in both groups. Stimulation of cells with PHA + PMA showed no IL-12 expression but stimulation with lipopolysaccharide induced higher IL-12 mRNA in patients than controls (83·0 ± 14·0% versus 33·0 ± 4·0%; P = 0·005). Our data suggest that an inflammatory cytokine signature exists in TA with a key role for TNF-α, IL-4, IL-10 and IL-12 in different pathological processes of the disease

Global, regional, and national age-sex-specific burden of diarrhoeal diseases, their risk factors, and aetiologies, 1990–2021, for 204 countries and territories: a systematic analysis for the Global Burden of Disease Study 2021

Background: Diarrhoeal diseases claim more than 1 million lives annually and are a leading cause of death in children younger than 5 years. Comprehensive global estimates of the diarrhoeal disease burden for specific age groups of children younger than 5 years are scarce, and the burden in children older than 5 years and in adults is also understudied. We used results from the Global Burden of Diseases, Injuries, and Risk Factors Study 2021 to assess the burden of, and trends in, diarrhoeal diseases overall and attributable to 13 pathogens, as well as the contributions of associated risk factors, in children and adults in 204 countries and territories from 1990 to 2021. Methods: We used the Cause of Death Ensemble modelling strategy to analyse vital registration data, verbal autopsy data, mortality surveillance data, and minimally invasive tissue sampling data. We used DisMod-MR (version 2.1), a Bayesian meta-regression tool, to analyse incidence and prevalence data identified via systematic reviews, population-based surveys, and claims and inpatient data. We calculated diarrhoeal disability-adjusted life-years (DALYs) as the sum of years of life lost (YLLs) and years lived with disability (YLDs) for each location, year, and age–sex group. For aetiology estimation, we used a counterfactual approach to quantify population-attributable fractions (PAFs). Additionally, we estimated the diarrhoeal disease burden attributable to the independent effects of risk factors using the comparative risk assessment framework. Findings: In 2021, diarrhoeal diseases caused an estimated 1·17 million (95% uncertainty interval 0·793–1·62) deaths globally, representing a 60·3% (50·6–69·0) decrease since 1990 (2·93 million [2·31–3·73] deaths). The most pronounced decline was in children younger than 5 years, with a 79·2% (72·4–84·6) decrease in diarrhoeal deaths. Global YLLs also decreased substantially, from 186 million (147–221) in 1990 to 51·4 million (39·9–65·9) in 2021. In 2021, an estimated 59·0 million (47·2–73·2) DALYs were attributable to diarrhoeal diseases globally, with 30·9 million (23·1–42·0) of these affecting children younger than 5 years. Leading risk factors for diarrhoeal DALYs included low birthweight and short gestation in the neonatal age groups, child growth failure in children aged between 1–5 months and 2–4 years, and unsafe water and poor sanitation in older children and adults. We estimated that the removal of all evaluated diarrhoeal risk factors would reduce global DALYs from 59·0 million (47·2–73·2) to 4·99 million (1·99–10·0) among all ages combined. Globally in 2021, rotavirus was the predominant cause of diarrhoeal deaths across all ages, with a PAF of 15·2% (11·4–20·1), followed by norovirus at 10·6% (2·3–17·0) and Cryptosporidium spp at 10·2% (7·03–14·3). In children younger than 5 years, the fatal PAF of rotavirus was 35·2% (28·7–43·0), followed by Shigella spp at 24·0% (15·2–37·9) and adenovirus at 23·8% (14·8–36·3). Other pathogens with a fatal PAF greater than 10% in children younger than 5 years included Cryptosporidium spp, typical enteropathogenic Escherichia coli, and enterotoxigenic E coli producing heat-stable toxin. Interpretation: The substantial decline in the global burden of diarrhoeal diseases since 1990, particularly in children younger than 5 years, supports the effectiveness of health interventions such as oral rehydration therapy, enhanced water, sanitation, and hygiene (WASH) infrastructure, and the introduction and scale-up of rotavirus vaccination. Targeted interventions and preventive measures against key risk factors and pathogens could further reduce this burden. Continued investment in the development and distribution of vaccines for leading pathogens remains crucial. Funding: Bill & Melinda Gates Foundation.</p

Global fertility in 204 countries and territories, 1950–2021, with forecasts to 2100: a comprehensive demographic analysis for the Global Burden of Disease Study 2021

BackgroundAccurate assessments of current and future fertility—including overall trends and changing population age structures across countries and regions—are essential to help plan for the profound social, economic, environmental, and geopolitical challenges that these changes will bring. Estimates and projections of fertility are necessary to inform policies involving resource and health-care needs, labour supply, education, gender equality, and family planning and support. The Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2021 produced up-to-date and comprehensive demographic assessments of key fertility indicators at global, regional, and national levels from 1950 to 2021 and forecast fertility metrics to 2100 based on a reference scenario and key policy-dependent alternative scenarios.MethodsTo estimate fertility indicators from 1950 to 2021, mixed-effects regression models and spatiotemporal Gaussian process regression were used to synthesise data from 8709 country-years of vital and sample registrations, 1455 surveys and censuses, and 150 other sources, and to generate age-specific fertility rates (ASFRs) for 5-year age groups from age 10 years to 54 years. ASFRs were summed across age groups to produce estimates of total fertility rate (TFR). Livebirths were calculated by multiplying ASFR and age-specific female population, then summing across ages 10–54 years. To forecast future fertility up to 2100, our Institute for Health Metrics and Evaluation (IHME) forecasting model was based on projections of completed cohort fertility at age 50 years (CCF50; the average number of children born over time to females from a specified birth cohort), which yields more stable and accurate measures of fertility than directly modelling TFR. CCF50 was modelled using an ensemble approach in which three sub-models (with two, three, and four covariates variously consisting of female educational attainment, contraceptive met need, population density in habitable areas, and under-5 mortality) were given equal weights, and analyses were conducted utilising the MR-BRT (meta-regression—Bayesian, regularised, trimmed) tool. To capture time-series trends in CCF50 not explained by these covariates, we used a first-order autoregressive model on the residual term. CCF50 as a proportion of each 5-year ASFR was predicted using a linear mixed-effects model with fixed-effects covariates (female educational attainment and contraceptive met need) and random intercepts for geographical regions. Projected TFRs were then computed for each calendar year as the sum of single-year ASFRs across age groups. The reference forecast is our estimate of the most likely fertility future given the model, past fertility, forecasts of covariates, and historical relationships between covariates and fertility. We additionally produced forecasts for multiple alternative scenarios in each location: the UN Sustainable Development Goal (SDG) for education is achieved by 2030; the contraceptive met need SDG is achieved by 2030; pro-natal policies are enacted to create supportive environments for those who give birth; and the previous three scenarios combined. Uncertainty from past data inputs and model estimation was propagated throughout analyses by taking 1000 draws for past and present fertility estimates and 500 draws for future forecasts from the estimated distribution for each metric, with 95% uncertainty intervals (UIs) given as the 2·5 and 97·5 percentiles of the draws. To evaluate the forecasting performance of our model and others, we computed skill values—a metric assessing gain in forecasting accuracy—by comparing predicted versus observed ASFRs from the past 15 years (2007–21). A positive skill metric indicates that the model being evaluated performs better than the baseline model (here, a simplified model holding 2007 values constant in the future), and a negative metric indicates that the evaluated model performs worse than baseline.FindingsDuring the period from 1950 to 2021, global TFR more than halved, from 4·84 (95% UI 4·63–5·06) to 2·23 (2·09–2·38). Global annual livebirths peaked in 2016 at 142 million (95% UI 137–147), declining to 129 million (121–138) in 2021. Fertility rates declined in all countries and territories since 1950, with TFR remaining above 2·1—canonically considered replacement-level fertility—in 94 (46·1%) countries and territories in 2021. This included 44 of 46 countries in sub-Saharan Africa, which was the super-region with the largest share of livebirths in 2021 (29·2% [28·7–29·6]). 47 countries and territories in which lowest estimated fertility between 1950 and 2021 was below replacement experienced one or more subsequent years with higher fertility; only three of these locations rebounded above replacement levels. Future fertility rates were projected to continue to decline worldwide, reaching a global TFR of 1·83 (1·59–2·08) in 2050 and 1·59 (1·25–1·96) in 2100 under the reference scenario. The number of countries and territories with fertility rates remaining above replacement was forecast to be 49 (24·0%) in 2050 and only six (2·9%) in 2100, with three of these six countries included in the 2021 World Bank-defined low-income group, all located in the GBD super-region of sub-Saharan Africa. The proportion of livebirths occurring in sub-Saharan Africa was forecast to increase to more than half of the world's livebirths in 2100, to 41·3% (39·6–43·1) in 2050 and 54·3% (47·1–59·5) in 2100. The share of livebirths was projected to decline between 2021 and 2100 in most of the six other super-regions—decreasing, for example, in south Asia from 24·8% (23·7–25·8) in 2021 to 16·7% (14·3–19·1) in 2050 and 7·1% (4·4–10·1) in 2100—but was forecast to increase modestly in the north Africa and Middle East and high-income super-regions. Forecast estimates for the alternative combined scenario suggest that meeting SDG targets for education and contraceptive met need, as well as implementing pro-natal policies, would result in global TFRs of 1·65 (1·40–1·92) in 2050 and 1·62 (1·35–1·95) in 2100. The forecasting skill metric values for the IHME model were positive across all age groups, indicating that the model is better than the constant prediction.InterpretationFertility is declining globally, with rates in more than half of all countries and territories in 2021 below replacement level. Trends since 2000 show considerable heterogeneity in the steepness of declines, and only a small number of countries experienced even a slight fertility rebound after their lowest observed rate, with none reaching replacement level. Additionally, the distribution of livebirths across the globe is shifting, with a greater proportion occurring in the lowest-income countries. Future fertility rates will continue to decline worldwide and will remain low even under successful implementation of pro-natal policies. These changes will have far-reaching economic and societal consequences due to ageing populations and declining workforces in higher-income countries, combined with an increasing share of livebirths among the already poorest regions of the world.</p