Table 4 Summary of findings related to impact of VOC on mortality

Alpha

• An increase of 0.1 in the proportion of Alpha in the population was related with a 15.3% increase in the total number of deaths (Jablońska et al., Europe, Jan-Feb 2021, low quality)[27]

• The mortality hazard ratio for people with Alpha compared to those with wild-type was 1.64 (95% CI 1.32 to 2.04). In this community-based, relatively low-risk group, there was a 32 to 104% increased risk of death (Challen et al., UK, Oct 2020-Feb 2021, high quality)[54]

• The estimated hazard ratio for Alpha was 1.55 (95% CI 1.39– 1.72), indicating that the risk of mortality in the 28 days following a positive test was 55% (95% CI 39– 72%) higher for Alpha than non-Alpha. Correcting for misclassification and missing SGTF status, this increased to 61% (95% CI 42–82%); however, this was not consistent across age groups, with a greater risk in older age groups (70+) (Davies et al., UK, Nov 2020-Feb 2021, no appraisal )[78]

• Alpha was associated with 73% increased risk of death within 28 days compared to non-Alpha cases with the hazard ratio at 1.73 (95% CI 1.41–2.13, p < 0.0001) (Grint et al., England, Nov 2020-Jan 2021, high quality)[58]

• There is an 18% increase in fatality risk for Alpha compared to non-Alpha with a Case Fatality Rates (CFR) at 1.18 (95% CI 0.40-3.28) (Zhao et al., UK, Sep 2020-Jan 2021, no appraisal)[79]

• There was a 33% increase in mortality when considering the effect of Alpha in England (Ackland et al., UK, Sep 21-Nov 5 2020, no appraisal)[80]

• The Alpha wave had 39.8% mortality, although the proportion of death in people over 80 was lower: 67.0% compared to 70.9% in across the whole pandemic (Area et al., Spain, March-April 2021, high quality)[62]

• There was a marked increase in mortality between pre-Alpha and Alpha wave. The adjusted mortality was 59% (9%5 CI 39–82) higher in high dependency unit and 88% (95% CI 62–118) higher in ICU for the Alpha wave (Dennis et al., UK, March 2020-January 2021, high quality)[56]

• VOC-infected patients (primarily Alpha) exhibited higher 30-day risks of death (aOR 1.67, 95% CI 1.13-2.48] in Alberta and aOR 1.52, 95% CI 1.27-1.81] in Ontario) than non-VOC patients (McAlister et al., Canada, March 2020-March 2021, medium quality)[35]

• Alpha was associated with a higher risk of death within 28 days than wild-type variants (aHR: 1.59, 95% CI1.44-1.74)) (Nyberg et al., England, Nov 2020-Jan 2021, high quality)[61]

• Significantly more hospitalized Alpha patients died (15.4%), compared to 12.9% of non-Alpha patients (Vassallo et al., France, Oct 2020-Apr 2021, medium quality)[38]

• There was an increase in 28-day mortality risk for Alpha compared to non-Alpha patients in both the adjusted and unadjusted model (Adjusted HR: 1.65, 95% CI 1.36-2.01). In the critical care cohort, after adjusting for confounders, critical care mortality did not differ significantly between Alpha and non-VOC Alpha groups (adjusted HR: 0.93, 95% CI 0.76-1.15). Neither cohort had evidence of an interaction between Alpha and ethnic group, age group, or sex (Patone et al., England, Nov 2020-Jan 2021, high quality)[68]

• Alpha patients had a slightly higher case-fatality-rate than the non-Alpha patients for younger (e.g. ≤ 70) aged patients, whereas the non-Alpha patients has a higher case-fatality-rate in older ages (Cetin et al., Turkey, April 2020-March 2021, medium quality)[46]

• Patients admitted during the Alpha wave had a (crude) mortality rate 25% lower than that of patients admitted during the first wave (IRR 0.75, 95% CI 0.64-0.86). However, in the adjusted analysis, the hazard of death during the Alpha wave was 1.62 times higher (95% CI 1.26-2.08) than during the pre-Alpha wave, considering age, sex, dexamethasone, oxygen requirement, symptoms at admission, and Charlson Comorbidity Index (Cusinato et al., UK, January 2020-March 2021, high quality)[55]

• Crude mortality rates were higher during the Alpha wave; however, case fatality rates were lower (Moore et al., Israel, March 2020-Feb 2021, low quality)[26]

• There was no difference in the percentage of patients with and without Alpha who died within 28 days (16% Alpha vs. 17% non-Alpha, p = 0.74). In both the unadjusted and adjusted analysis (controlling for hospital, sex, age, comorbidities, and ethnicity), there was no increased risk of mortality or severe disease with Alpha compared to non-Alpha (Frampton et al., UK, Nov-Dec 2020, high quality)[57]

• In a matched cohort analysis, there was no evidence of an association between Alpha and non-Alpha on death within 28 days of COVID-19 positive test (OR 0.90, 95% CI 0.57-1.41, p = 0.64). After adjusting for confounders (sex, age, ethnicity, residential property classification, week of specimen date and testing Pillar), there was no difference in risk of death among Alpha cases compared to non-Alpha (HR 1.06, 95% CI 0.82-1.38, p = 0.65) (Dabrera et al., UK, Oct-Dec 2020, medium quality )[31]

• There was no difference found in the death rate between Alpha (0.6%) and non-Alpha individuals (0.9%), p = 0.64 (Loconsole et al., Italy, Dec 2020-Mar 2021, medium quality)[48]

• There was no increased risk of 28 day mortality after hospitalization between Alpha and wild-type (Martin-Blondel, France, Jan-Feb 2021, medium quality)[34]

• There was no difference in mortality between Alpha patients and wild-type (Martinez-Garcia, Spain, Jan-April 2021, medium quality)[50]

• Alpha was not associated with increased mortality at 28 days (OR 1.04, 95% CI: 0.67-1.59) (Pascall et al., Scotland, Nov 2020-Jan 2021, high quality)[67]

• Alpha was not associated with increased mortality at 28 days overall (HR 1.01, 95% CI 0.79-1.28, p = 0.94) (Stirrup et al., UK, Nov 2020-Jan 2021, high quality)[69]

• There was no statistically significant difference between Alpha patients (9%) and non-VOC patients (6%) in terms of mortality (Whittaker et al., Norway, Dec 2020-Apr 2021, high quality)[73]

Beta

• Compared to Alpha, the odds of COVID-19 death were 1.57-fold (95% CI 1.03-2.43) higher for Beta (Abu-Raddad, Qatar, Jan-May 2021, medium quality )[75]

• Adjusting for weekly COVID-19 hospital admissions, there was a 31% increased risk of in-hospital mortality in the Beta wave (aOR 1.31, 95% CI 1.28–1.35) (Jassat et al., South Africa, March 2020-March 2021, high quality)[60]

• Beta was highly associated with 60-day mortality in patients admitted to the ICU compared to both Alpha and wild-type (OR 5.67, 95% CI 1.04–30.81) (Louis et al., France, Feb-March 2021, medium quality )[49]

• Patients infected with the Beta variant had a higher 28-day in-hospital mortality (32.5%), compared to patients infected with wild-type (22.2%, p = 0.1). This excess mortality was confirmed after matching for comorbidities and initial severity (30.6% vs. 19.4%, p = 0.04). (Puech et al., France, March 2020-April 2021, medium quality)[36]

• There was no difference in overall mortality between the two waves (36.4% vs. 32.3%), however, ICU mortality was higher in the Beta wave (74.4%) compared to the pre-Beta wave (57.1), p = 0.002 (Maslo et al., South Africa, June-Dec 2020, medium quality)[44]

No data

Gamma

• There was an 8.2% increase in CFR (15.6% for Gamma from 7.5% wild-type) in maternal deaths out of maternal cases, with the first three months of 2021 accounting for 46.2% of deaths thus far. There was no significant difference in terms of age, type of residence, COVID-19 diagnostic criteria, cardiovascular disease, or diabetes, but the proportion of white women was higher in 2021 (Takemoto et al., Brazil, Mar 2020-Apr 2021, medium quality)[52]

• While there were no changes in CFR in children or adolescents, all other groups above 20 years of age had statistically significant increases in CFR when diagnosed in Feb 2021 (Gamma) as opposed to Jan 2021 (non-Gamma). For individuals between 20 and 29 years of age, there was a 3-fold higher risk of death when diagnosed in Feb 2021 compared to Jan 2021 (RR 3.15, 95% CI 1.52-6.53, p < 0.01). This risk of death was also higher in other age groups, although to a lesser extent (de Oliveira et al., Brazil, Jan-Feb 2021, low quality)[25]

• Each geographical region of Brazil varied in terms of their mortality over the three periods, with the North region being the hardest hit, experiencing a collapse in the provision of healthcare in the first and last periods (Gamma) with high mortality in all age groups (de Andrade et al., Brazil, Feb 2020-Feb 2021, low quality )[24]

• The proportion of women who died from COVID-19 increased from 34% in the first wave (non-VOC) to 47% in the second wave (Gamma). There were no significant differences for mortality in males, but the risk of death for men aged 20-39 was more than double in the second wave than the first wave 2.1 (95% CI 1.6-2.8, p < 0.0001) and was higher in men aged 40-59 years 1.42 (95% CI1.3-1.6, p < 0.0001). Additionally, there was an increase in proportion of deaths for individuals in all age groups (20-59 years) in both sexes (Freitas et al., Brazil, Apr 2020-Jan 2021, low quality)[28]

• The CFR was higher across all groups after the emergence of Gamma, with age groups of 20-39 and 40-59 having a higher proportional increase in the second wave than the first wave because of Gamma prevalence. Additionally, people without pre-existing conditions experienced a higher proportional increase in death in the second wave (22%) than the first (13%) (Freitas et al., Brazil, Nov 2020-Feb 2021, medium quality)[30]

• 28-day mortality from hospital admission was significantly higher in patients with Gamma than non-Gamma (aHR 3.72; 95% CI 1.19–11.65) (Zavascki et al., Brazil, June 2020-May 2021, medium quality)[39]

No data

No data

Delta

• Mortality (25%) was higher among people > 60 years compared to other age group (20-40 years (2%), 40-60 years (14%)) during Delta spread (p < .05). Mortality was significantly higher among unvaccinated patients having comorbid conditions than vaccinated patients (p < 0.05) (Agrawal et al., India, Dec 2020-June 2021, medium quality)[40]

• Mortality during the Delta wave was nearly 40% higher than in pre-Delta wave (10.5% vs. 7.2%, p < 0.001), across all age groups, with patients under 45 experiencing the greatest increase (Budhiraja et al., India, April 2020-June 2021, medium quality)[29]

• In-hospital deaths were significantly higher in the Delta wave (19.3%), compared to pre-Delta (11.5%) (OR 1.84, 95% CI 1.32-2.55), which did not change significantly with adjustment for age, sex, and comorbidities (Khedar et al., India, March 2020-July 2021, medium quality)[43]

No data

No data

Combined VOC

• VOC (Alpha, Beta, Gamma) were associated with higher odds of mortality for both the general COVID-19 population (OR 1.75, 95% CI 1.47-2.09) and hospitalized cases (OR 1.62; 95% CI 1.23-2.15) (Erman et al., Canada, January-April 2021, medium quality)[32]

• Increased rates of mortality were seen in VOC infections (all four) relative to non-VOC. Adjusted risk was 61% (95% CI 40-87) higher for VOC (Alpha, Gamma, Beta) mortality than with non-VOC and 137% (95% CI 50-230) higher for mortality due to Delta than non-VOC. Increased mortality was seen between Delta and other VOC: 59% (95% CI 39-84) (Fisman et al., Canada, Feb-June 2021, medium quality)[33]

No data

• There was no difference in mortality between individuals with Alpha or Beta compared to non-VOC (Garvey et al., England, Dec 15-31, 2021, high quality)[64]

• There was no increased risk of death for any of the VOC (Alpha, Beta or Gamma) compared to non-VOC (Funk et al., Europe, Sep 2020-Mar 2021, high quality)[63]