Global burden of 288 causes of death and life expectancy decomposition in 204 countries and territories and 811 subnational locations, 1990–2021: a systematic analysis for the Global Burden of Disease Study 2021

BACKGROUND Regular, detailed reporting on population health by underlying cause of death is fundamental for public health decision making. Cause-specific estimates of mortality and the subsequent effects on life expectancy worldwide are valuable metrics to gauge progress in reducing mortality rates. These estimates are particularly important following large-scale mortality spikes, such as the COVID-19 pandemic. When systematically analysed, mortality rates and life expectancy allow comparisons of the consequences of causes of death globally and over time, providing a nuanced understanding of the effect of these causes on global populations. METHODS The Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2021 cause-of-death analysis estimated mortality and years of life lost (YLLs) from 288 causes of death by age-sex-location-year in 204 countries and territories and 811 subnational locations for each year from 1990 until 2021. The analysis used 56 604 data sources, including data from vital registration and verbal autopsy as well as surveys, censuses, surveillance systems, and cancer registries, among others. As with previous GBD rounds, cause-specific death rates for most causes were estimated using the Cause of Death Ensemble model-a modelling tool developed for GBD to assess the out-of-sample predictive validity of different statistical models and covariate permutations and combine those results to produce cause-specific mortality estimates-with alternative strategies adapted to model causes with insufficient data, substantial changes in reporting over the study period, or unusual epidemiology. YLLs were computed as the product of the number of deaths for each cause-age-sex-location-year and the standard life expectancy at each age. As part of the modelling process, uncertainty intervals (UIs) were generated using the 2·5th and 97·5th percentiles from a 1000-draw distribution for each metric. We decomposed life expectancy by cause of death, location, and year to show cause-specific effects on life expectancy from 1990 to 2021. We also used the coefficient of variation and the fraction of population affected by 90% of deaths to highlight concentrations of mortality. Findings are reported in counts and age-standardised rates. Methodological improvements for cause-of-death estimates in GBD 2021 include the expansion of under-5-years age group to include four new age groups, enhanced methods to account for stochastic variation of sparse data, and the inclusion of COVID-19 and other pandemic-related mortality-which includes excess mortality associated with the pandemic, excluding COVID-19, lower respiratory infections, measles, malaria, and pertussis. For this analysis, 199 new country-years of vital registration cause-of-death data, 5 country-years of surveillance data, 21 country-years of verbal autopsy data, and 94 country-years of other data types were added to those used in previous GBD rounds. FINDINGS The leading causes of age-standardised deaths globally were the same in 2019 as they were in 1990; in descending order, these were, ischaemic heart disease, stroke, chronic obstructive pulmonary disease, and lower respiratory infections. In 2021, however, COVID-19 replaced stroke as the second-leading age-standardised cause of death, with 94·0 deaths (95% UI 89·2-100·0) per 100 000 population. The COVID-19 pandemic shifted the rankings of the leading five causes, lowering stroke to the third-leading and chronic obstructive pulmonary disease to the fourth-leading position. In 2021, the highest age-standardised death rates from COVID-19 occurred in sub-Saharan Africa (271·0 deaths [250·1-290·7] per 100 000 population) and Latin America and the Caribbean (195·4 deaths [182·1-211·4] per 100 000 population). The lowest age-standardised death rates from COVID-19 were in the high-income super-region (48·1 deaths [47·4-48·8] per 100 000 population) and southeast Asia, east Asia, and Oceania (23·2 deaths [16·3-37·2] per 100 000 population). Globally, life expectancy steadily improved between 1990 and 2019 for 18 of the 22 investigated causes. Decomposition of global and regional life expectancy showed the positive effect that reductions in deaths from enteric infections, lower respiratory infections, stroke, and neonatal deaths, among others have contributed to improved survival over the study period. However, a net reduction of 1·6 years occurred in global life expectancy between 2019 and 2021, primarily due to increased death rates from COVID-19 and other pandemic-related mortality. Life expectancy was highly variable between super-regions over the study period, with southeast Asia, east Asia, and Oceania gaining 8·3 years (6·7-9·9) overall, while having the smallest reduction in life expectancy due to COVID-19 (0·4 years). The largest reduction in life expectancy due to COVID-19 occurred in Latin America and the Caribbean (3·6 years). Additionally, 53 of the 288 causes of death were highly concentrated in locations with less than 50% of the global population as of 2021, and these causes of death became progressively more concentrated since 1990, when only 44 causes showed this pattern. The concentration phenomenon is discussed heuristically with respect to enteric and lower respiratory infections, malaria, HIV/AIDS, neonatal disorders, tuberculosis, and measles. INTERPRETATION Long-standing gains in life expectancy and reductions in many of the leading causes of death have been disrupted by the COVID-19 pandemic, the adverse effects of which were spread unevenly among populations. Despite the pandemic, there has been continued progress in combatting several notable causes of death, leading to improved global life expectancy over the study period. Each of the seven GBD super-regions showed an overall improvement from 1990 and 2021, obscuring the negative effect in the years of the pandemic. Additionally, our findings regarding regional variation in causes of death driving increases in life expectancy hold clear policy utility. Analyses of shifting mortality trends reveal that several causes, once widespread globally, are now increasingly concentrated geographically. These changes in mortality concentration, alongside further investigation of changing risks, interventions, and relevant policy, present an important opportunity to deepen our understanding of mortality-reduction strategies. Examining patterns in mortality concentration might reveal areas where successful public health interventions have been implemented. Translating these successes to locations where certain causes of death remain entrenched can inform policies that work to improve life expectancy for people everywhere. FUNDING Bill & Melinda Gates Foundation

Inhibition of release of inflammatory mediators in rat peritoneal mast cells and murine macrophages by a Chinese herbal medicine formula (RCM-102)

RCM-102 is a Chinese herbal medicine formulation derived from a formula which was shown to be effective in treating seasonal allergic rhinitis (SAR) in a randomized placebo-controlled trial. The aim of this study was to investigate the in vitro effect of RCM-102 on the formation of inflammatory mediators, histamine, prostaglandin and nitric oxide, which are known to be involved in the pathophysiology of SAR. The effect of RCM-102 on histamine release was tested in compound 48/80-stimulated rat peritoneal mast cells. The effects of RCM-102 on the release of NO and prostaglandins (PGE 2) and the expression of inducible NO synthase (iNOS) and COX-2 were studied in lipopolysaccharide (LPS)-stimulated RAW 264.7 cells. In rat peritoneal mast cells, RCM-102 significantly reduced the compound 48/80-induced histamine release. It also significantly reduced NO and PGE 2 production as well as the expression of COX-2 and iNOS in RAW 264.7 cells. These findings indicate that RCM-102 inhibits the formation of several allergic/inflammatory mediators and thus may be used for treating related conditions such as SAR. The actions of RCM-102 are likely to be contributed by the synergistic actions of individual herbal ingredients

Inhibition of inducible nitric oxide production and iNOS protein expression in lipopolysaccharide-stimulated rat aorta and Raw 264.7 macrophages by ethanol extract of a Chinese herbal medicine formula (RCM-101) for allergic rhinitis

Aim of the study: A Chinese herbal formula (RCM-101) has shown to be effective in reducing symptoms of seasonal allergic rhinitis (SAR) in a randomised, placebo-controlled clinical trial. The aim of this study is to investigate the effects of RCM-101 on the actions and synthesis of nitric oxide (NO). l-Arginine-induced endothelium-independent relaxations were studied in rat isolated aorta which was pre-treated with lipopolysaccharide (LPS). Materials and methods: NO production and inducible nitric oxide synthase (iNOS) protein expression were studied in LPS and interferon γ-stimulated murine macrophages (Raw 264.7), measured by NO sensors and Western blotting. Results: In rat aortic preparations, RCM-101 significantly inhibited endothelium-independent relaxations to l-arginine, but not affected those to sodium nitroprusside (SNP). In Raw 264.7 cells, RCM-101 and some of its individual ingredients (e.g., Radix glycyrrhizae, Radix bupleuri, Radix saposhnikoviae and Atractylodis rhizome macrocephalae) significantly inhibited the NO production and iNOS protein expression. Conclusions: The findings indicate that RCM-101 may inhibit inducible NO production by suppressing iNOS. In addition, its inhibitory action of iNOS is likely to be mediated by several key herbal ingredients

Treatment for seasonal allergic rhinitis by Chinese herbal medicine : a randomized placebo controlled trial

Context: Chinese herbal medicine (CHM) is widely used to treat seasonal allergic rhinitis (SAR), however, evidence of efficacy is lacking. Objective: To evaluate the efficacy of a Chinese herbal formulation for the treatment of SAR. Design: Randomized, double blind, placebo controlled trial. Setting: RMIT Chinese Medicine Clinic, Patients: 55 patients with seasonal allergic rhinitis (active 28, placebo 27). Interventions: CHM extract capsule (containing 18 herbs) or placebo, given daily for 8 weeks. Main Outcome Measures: The primary measure of efficacy were changes in severity of nasal and non-nasal symptoms using a Five Point Scale (FPS) measured by both patients and the practitioner. The secondary measure was the change in score for the domains measured in the Rhinoconjunctivitis and Rhinitis Quality of Life Questionnaire (RQLQ) assessed by patients. Results: Forty-nine patients completed the study (active 24, placebo 25). After eight weeks, the severity of nasal symptoms and non-nasal symptoms were significantly less in the active treatment group than in the control group, both for measurements made by patients and those by the practitioner. Comparison of active and placebo treatment groups RQLQ scores also indicated significant beneficial effects of treatment (end point Section 1: P<0.05; Section 2: P<0.01). Intention-to-treat analyses of categorical items showed moderate to marked improvement rates were 60.7% and 29.6% for active and placebo respectively. Eleven patients reported mild adverse events including 1 withdrawn from the trial. Conclusions: This CHM formulation appears to offer symptomatic relief and improvement of quality of life for some patients with seasonal allergic rhinitis

Lack of efficacy of a herbal preparation (RCM-102) for seasonal allergic rhinitis : a double blind, randomised, placebo-controlled trial

Background: A herbal preparation, known as RMIT Chinese Medicine 102 (RCM-102) consisting of eight herbs which demonstrates inhibition of the release of key inflammatory mediators associated with seasonal allergic rhinitis (SAR) was used. This study evaluated the efficacy and safety of RCM-102 for SAR. Objective: This study evaluated the efficacy and safety of RCM-102 for SAR. Methods: This randomised placebo-controlled trial involved subjects aged between 18 and 65 who were randomly assigned to either RCM-102 or a placebo group. After a two-week baseline period, all subjects took either RCM-102 or placebo capsules (two capsules each time, three times daily with a four hour interval) for a period of eight weeks. The primary end-points were the Five-Point Scale symptom scores. Rhinoconjunctivitis Quality of Life Questionnaire, relief medication usage, adverse events, kidney and liver function tests and full blood examination were secondary end-points. Intention-to-treat analysis was applied. Results: One hundred and four subjects were randomised with 52 in each group. Ninety-five subjects (47 and 48 subjects in RCM-102 and placebo groups) completed the trial. Nine subjects withdrew from the study prior to the end of the second treatment week. At the end of the trial, there were no significant differences between the two groups with respect to all outcome measures. There were no liver or kidney function abnormalities reported. Conclusion: This mechanism-based RCM-102 was safe but not more beneficial than placebo for patients with SAR

Real-life effectiveness of omalizumab in severe allergic asthma above the recommended dosing range criteria

BackgroundOmalizumab (Xolair) dosing in severe allergic asthma is based on serum IgE and bodyweight. In Australia, patients eligible for omalizumab but exceeding recommended ranges for IgE (30-1500 IU/mL) and bodyweight (30-150 kg) may still receive a ceiling dose of 750 mg/4 weeks. About 62% of patients receiving government-subsidized omalizumab are enrolled in the Australian Xolair Registry (AXR). ObjectivesTo determine whether AXR participants above the recommended dosing ranges benefit from omalizumab and to compare their response to within-range participants. MethodsData were stratified according to dose range status (above-range or within-range). Further sub-analyses were conducted according to the reason for being above the dosing range (IgE only vs. IgE and weight). ResultsData for 179 participants were analysed. About 55 (31%) were above recommended dosing criteria; other characteristics were similar to within-range participants. Above-range participants had higher baseline IgE [812 (IQR 632, 1747) IU/mL vs. 209 (IQR 134, 306) IU/mL] and received higher doses of omalizumab [750 (IQR 650, 750) mg] compared to within-range participants [450 (IQR, 300, 600) mg]. At 6 months, improvements in Juniper 5-item Asthma Control Questionnaire (ACQ-5, 3.61 down to 2.01 for above-range, 3.47 down to 1.93 for within-range, P < 0.0001 for both) and Asthma Quality of Life Questionnaire (AQLQ mean score (3.22 up to 4.41 for above-range, 3.71 up to 4.88 for within-range, P < 0.0001) were observed in both groups. Forced expiratory volume in one second (FEV1) improved among above-range participants. There was no difference in response between above-range and within-range participants. Above-range participants due to either IgE alone or IgE and weight had similar improvements in ACQ-5, AQLQ and FEV1. Conclusions and Clinical RelevancePatients with severe allergic asthma above recommended dosing criteria for omalizumab have significantly improved symptom control, quality of life and lung function to a similar degree to within-range participants, achieved without dose escalation above 750 mg.The Australian Xolair Registry was supported by Novar-tis Pharmaceuticals Australia Pty Ltd as an investiga-tor-initiated tria

Effectiveness and response predictors of omalizumab in a severe allergic asthma population with a high prevalence of comorbidities: the Australian Xolair Registry

Background: Severe asthma is a high impact disease. Omalizumab targets the allergic inflammatory pathway; however, effectiveness data in a population with significant comorbidities are limited. Aims: To describe severe allergic asthma, omalizumab treatment outcomes and predictors of response among the Australian Xolair Registry participants. Methods: A web-based post-marketing surveillance registry was established to characterise the use, effectiveness and adverse effects of omalizumab (Xolair) for severe allergic asthma. Results: Participants (n = 192) (mean age 51 years, 118 female) with severe allergic asthma from 21 clinics in Australia were assessed, and 180 received omalizumab therapy. They had poor asthma control (Asthma Control Questionnaire, ACQ-5, mean score 3.56) and significant quality of life impairment (Asthma-related Quality of Life Questionnaire score 3.57), and 52% were using daily oral corticosteroid (OCS). Overall, 95% had one or more comorbidities (rhinitis 48%, obesity 45%, cardiovascular disease 23%). The omalizumab responder rate, assessed by an improvement of at least 0.5 in ACQ-5, was high at 83%. OCS use was significantly reduced. The response in participants with comorbid obesity and cardiovascular disease was similar to those without these conditions. Baseline ACQ-5 = 2.0 (P = 0.002) and older age (P = 0.05) predicted the magnitude of change in ACQ-5 in response to omalizumab. Drug-related adverse events included anaphylactoid reactions (n = 4), headache (n = 2) and chest pains (n = 1). Conclusion: Australian patients with severe allergic asthma report a high disease burden and have extensive comorbidity. Symptomatic response to omalizumab was high despite significant comorbid disease. Omalizumab is an effective targeted therapy for severe allergic asthma with comorbidity in a real-life setting.This work was supported by the Chungnam National University Hospital Research Fund, 2012 (to D. E. Choi