Severity of disease associated with Omicron variant as compared with Delta variant in hospitalized patients with suspected or confirmed SARS-CoV-2 infection

1Severity of disease associated with Omicron variant as compared with Delta variant in hospitalized patients with suspected or confirmed SARS-CoV-2 infection Severity of disease associated with Omicron variant as compared with Delta variant in hospitalized patients with suspected or confirmed SARS-CoV-2 infection ISBN 978-92-4-005182-9 (electronic version) ISBN 978-92-4-005183-6 (print version) © World Health Organization 2022 Some rights reserved. This work is available under the Creative Commons Attribution- NonCommercial-ShareAlike 3.0 IGO licence (CC BY-NC-SA 3.0 IGO; https://creativecommons.org/licenses/by-nc-sa/3.0/igo). Under the terms of this licence, you may copy, redistribute and adapt the work for non-commercial purposes, provided the work is appropriately cited, as indicated below. In any use of this work, there should be no suggestion that WHO endorses any specific organization, products or services. The use of the WHO logo is not permitted. 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In no event shall WHO be liable for damages arising from its use. iii Contents Acknowledgements................................................................................................................................ iv Abbreviations ......................................................................................................................................... iv Background.............................................................................................................................................. 1 Methods.................................................................................................................................................... 2 Results...................................................................................................................................................... 3 Interpretation............................................................................................................................................ 9 Limitations................................................................................................................................................ 9 Conclusion.............................................................................................................................................. 10 References.............................................................................................................................................. 10 Annex: List of contributing hospitals and health centres................................................................... 11 iv Acknowledgements The report was written by Dr Bharath Kumar Tirupakuzhi Vijayaraghavan (Consultant, Clinical Management Team, Health Emergencies Programme, WHO) in collaboration with Dr Ronaldo Silva (Consultant, Department of Sexual and Reproductive Health and Research, WHO), Dr Soe Soe Thwin (Department of Sexual and Reproductive Health and Research, WHO), Dr Janet Diaz (Lead, Clinical Management for COVID-19 World Health Emergencies Programme, WHO) and Dr Silvia Bertagnolio (Head, Antimicrobial Resistance Division, WHO). This report benefited from the contributions of Dr Olivier le Polain de Waroux (Acute Response Coordination Department, Health Emergencies Programme, WHO), Dr Henry Laurenson-Schafer (Acute Response Coordination Department, Health Emergencies Programme, WHO), Dr Marta Lado Castro-Rial (Clinical Management Team, Health Emergencies Programme, WHO), Dr Krutika Kuppalli (Clinical Management Team, Health Emergencies Programme, WHO) and Vanessa Cramond (Clinical Management Team, Health Emergencies Programme, WHO). Sincere thanks to Dr Waasila Jassat, National Institute for Communicable Diseases, South Africa) and to all facilities and collaborators from South Africa contributing individualized anonymized data of hospitalized patients with suspected or confirmed COVID-19 to the WHO Global Clinical Platform. Abbreviations CI confidence interval CRF case record form ECMO extracorporeal membrane oxygenation HIV human immunodeficiency virus HR hazard ratio ICU intensive care unit IQR interquartile range OR odds ratio PCR polymerase chain reaction SARS-CoV-2 severe acute respiratory syndrome corona virus 2 SGTF S-gene target failure TAG-VE Technical Advisory Group on SARS-CoV-2 Virus Evolution (WHO) TB tuberculosis VOC Variant of Concern WHO World Health Organization 1Globally, as of 23rd May 2022, there have been over 522,000,000 confirmed cases and more than 6.2 million deaths from COVID-19 (1). On 25 November 2021, South Africa reported the detection of a new variant (B.1.1.529) of severe acute respiratory syndrome corona virus 2 (SARS-CoV-2) after a sharp increase in cases in Gauteng province with the unique finding of S-gene target failure (SGTF) on polymerase chain reaction (PCR) testing. This new variant of SARS-CoV-2 was notable for having numerous mutations, with many in the spike protein, leading to concerns of increased transmissibility and antibody escape (2). The Technical Advisory Group on SARS-CoV-2 Virus Evolution (TAG-VE) of WHO convened on 26 November 2021 and designated B.1.1.529 a new Variant of Concern (VOC) and assigned the nomenclature Omicron (3). One of the key questions as Omicron variant emerged was how it affected severity of disease. Early on, data suggested that although Omicron variant may have increased transmissibility, it caused less severe disease than the Delta variant (4–6). There were also data to suggest that Omicron variant may have reduced proclivity to damage the lungs based on animal studies and increased tropism for the upper airway (7,8). However, significant uncertainty exists on the true severity and outcomes from Omicron variant due to a variety of reasons – the limited amount of data available and, crucially, challenges in disentangling the protective effects of prior infection (with different variants) and vaccination (9,10). Recent trends from Hong Kong SAR, China, show that in populations with suboptimal pre-existing immunity, Omicron variant can lead to substantial mortality and morbidity (11). Omicron variant is now the dominant global SARS-CoV-2 variant and has replaced Delta variant (12). Understanding the true severity of a VOC has several important implications – in planning the public health response, in resource allocation, in providing clinical guidance and designing clinical management protocols and, more broadly, regarding the nature of public health messaging. Since May 2020 and throughout the pandemic, many countries and research networks around the globe have contributed anonymized individual patient-level clinical data of hospitalized COVID-19 patients to the WHO Global Clinical Platform (13). To determine the severity associated with Omicron SARS-CoV-2 infection, we compared clinical severity and outcomes during a period of Omicron variant circulation with a period of Delta variant circulation in a subset of cases submitted to the WHO Global Clinical Platform. Objectives of the analysis 1. Describe the clinical characteristics and key outcomes for hospitalized patients with COVID-19 during the Omicron period compared with the Delta period. 2. Assess the difference in severity between hospitalized patients during the "Omicron period" compared with the "Delta period". Background 2Data sources Anonymized individual-level data from patients admitted to hospitals with COVID-19 in South Africa and submitted to the WHO Global Clinical Platform were used to identify the eligible study sample. Two options exist to contribute date to the platform: 1) use of the WHO case record form (CRF), which exists in both paper-based and electronic formats; and 2) data entered into a local system or database. For locally entered data (as in this report), relevant variables were mapped and aligned to the WHO CRF data dictionary and transferred to the WHO Clinical Platform hosted on REDCAP. Inclusion criteria All patients hospitalized with suspected or confirmed COVID-19 symptoms to a health care facility in the South African provinces of Eastern Cape, Free State, Gauteng, KwaZulu-Natal, Limpopo, Mpumalanga, North West, Northern Cape and Western Cape between 2 August 2021 (week 31) and 3 October 2021 (week 39) [Delta period] or 15 November 2021 to 16 February 2022 [Omicron period] were included in the analysis. Disease severity was categorized as critical, severe or non-severe where: • critical included those “ever on invasive ventilation” during hospitalization or “ever on oxygen and on high-flow nasal oxygen”, or “ever extracorporeal membrane oxygenation (ECMO)” or “admitted to intensive care unit (ICU)”; • severe included those if “ever on oxygen only”; • non-severe if none of the above conditions were met. Statistical analysis We compared patient and clinical characteristics, disease severity and outcomes of patients admitted during the Delta period with those admitted during the Omicron period. Records with missing data were excluded when determining distributions across outcome levels. Observations with missing values for death or discharge outcomes and severity classification were excluded from analysis. We used multivariable logistic regression models using generalized estimating equations to compute odds ratios (ORs) of severe or critical illness for Omicron compared with Delta patients. In addition, we developed a proportional hazards model to estimate the hazard ratio (HR) of in-hospital mortality for the Omicron period compared with Delta. For the time-to-event model data were right censored at 28 days. Additionally, we assumed that patients discharged before 28 days were considered to be alive for at least 28 days. Age and sex were included in the models as a priori confounders. Other covariates that were considered for inclusion in the models were self-reported vaccination status, number of underlying conditions (none, one or more), public or private sector, ethnic group and self-reported COVID-19 reinfection. Included covariates were retained in the final model if they were found to be significant at p < 0.05 level. All models included provinces as random effect to account for potential heterogeneity in patient care. We also undertook a sensitivity analysis by excluding patients that were not vaccinated to test the consistency of the primary results. All analyses were conducted in SAS version 9.4 (Copyright © 2016 by SAS Institute Inc., Cary, NC, USA) or R version 4.1.1 (R Core Team 2021. R Foundation for Statistical Computing, Vienna, Austria. https://www.R-project.org/). Methods 3For this report, we included data on 17 693 patients from the Omicron period and 16 749 patients from the Delta period, data extracted on 16 February 2022. Fig. 1 lists the flow of participants through the analysis. Figure 1 Flow of participants through the analysis Results Delta: n=16812 Omicron: n=19226 Analytic sample Delta: n=16749 Omicron: n=17693 N=34442 Number of subjects by period Delta: n=52166 Omicron: n=55914 N=108080 Excluded because missing on following variables: Outcome, Sex, Ethnicity N=1596 Excluded observations, by admission reason Isolation: 11369 Other: 4088 Missing reason: 56585 Admitted for COVID-19 symptoms: N=36038 4Key characteristics and outcomes Table 1 lists the key characteristics of the two groups. The median age (IQR) of the Omicron cohort was 41 years (28,62) and for Delta, was 52 years (36,66). Close to 60% of the population in both groups were female. 28.1% of Omicron patients had severe disease as compared with 49.2% of the Delta cohort. Similarly, 3.7% of the Omicron cohort and 7.7% of the Delta cohort had critical disease. Table 1 Baseline characteristics of the included population Table 2 lists the key outcomes by variant period. 15% of the Omicron cohort and 28% of the Delta cohort died during their hospital stay. Median (IQR) length of stay was 6 days (3,10) in the Omicron group and 7 days (3,10) in the Delta group. a Chi-Square test for categorical variables and Wilcoxon rank sum for continuous variables. Variable Omicron (n=17 693) Delta (n=16 749) P value a Age - median (IQR) 41 (28,62) 52 (36,66) < 0.0001 Sex (n and %) 0.0005 Male 7500 (42.4%) 6792 (40.6%) Female 10 193 (57.6%) 9957 (59.5%) Key underlying conditions (n and %) Diabetes 1629/7573 (21.5%) 2648/8752 (69.7%) < 0.0001 Hypertension 3196/8322 (38.4%) 4632/9668 (47.9%) < 0.0001 Chronic heart disease 315/6431 (4.9%) 396/7138 (5.6%) 0.0899 Chronic lung disease 178/6326 (2.8%) 127/7018 (1.8%) 0.0001 Chronic kidney disease 142/6318 (2.3%) 186/7034 (2.6%) 0.1392 Malignancy 58/6249 (0.9%) 79/6968 (1.1%) 0.2439 HIV 1982/6665 (29.7%) 1592/7132 (22.3%) < 0.0001 Current smoking 523/4492 (11.6%) 383/5462 (7.0%) < 0.0001 Current or past TB 559/6081 (9.2%) 389/6875 (5.7%) < 0.0001 Asthma 383/6537 (5.9%) 399/7206 (5.5%) 0.4159 Vaccination status (n and %) Yes 16 71(9.4%) 734 (4.4%) Unknown/No 16 022 (90.6%) 16 015 (95.6%) Severity (n and %) < 0.0001 Non-severe 12 082(68.3%) 7207 (43.0%) Severe 4964 (28.1%) 8248 (49.2%) Critical 647 (3.7%) 1294 (7.7%) Table 2 Key outcomes a Wilcoxon rank sum test. Outcome Omicron (n=17 693) Delta (n=16 749) Unadjusted effect estimate P value Death (n and %) 2643 (15%) 4689 (28%) OR: 0.45 95% CI: 0.43–0.48 < 0.0001 Length of stay (median and Q1, Q3) 6 (3,10) 7 (3,10) – < 0.0001 a Length of stay (median and Q1, Q3) Death Discharged Death Discharged < 0.0001 a 5 (2–8) 6 (3–10) 4 (2–9) 7 (4–11) 5Omicron period and risk of severe or critical disease Table 3 provides the results of the multivariable regression model for severity of disease by variant adjusted for age (ordinal variable), sex, vaccination status (vaccinated/unknown or unvaccinated), province, comorbidities (none/one or more), ethnicity (nominal) and reinfection. In this adjusted analysis, Omicron was associated with a lower odds of developing severe or critical disease (OR: 0.43; 95% CI: 0.41–0.46 and p < 0.001). Table 3 Factors associated with risk of severe or critical COVID-19 illness during hospital stay Frequencies Multivariate Logistic regression Characteristic No O2/INV, N = 19,289 1 Severe/Critical, O2/INV, N = 15,1531 OR 2,3 95% CI3 p-value Variant period Delta (wk 31-39 / 2021) 7,207 (43%) 9,542 (57%) — — Omicron (wk 46-52 / up to 16th Feb 2022) 12,082 (68%) 5,611 (32%) 0.43 0.41, 0.46 <0.001 Age 18-34 5,944 (73%) 2,157 (27%) — — <1 544 (74%) 196 (26%) 1.18 0.99, 1.41 0.065 1-4 456 (80%) 115 (20%) 0.77 0.62, 0.96 0.021 5-9 284 (79%) 74 (21%) 0.70 0.54, 0.92 0.010 10-14 343 (79%) 92 (21%) 0.69 0.54, 0.88 0.003 15-17 464 (80%) 113 (20%) 0.62 0.50, 0.77 <0.001 35-49 4,334 (58%) 3,177 (42%) 1.56 1.45, 1.67 <0.001 50-59 2,227 (44%) 2,844 (56%) 2.23 2.06, 2.41 <0.001 60+ 4,693 (42%) 6,385 (58%) 2.43 2.27, 2.59 <0.001 Sex at birth Female 11,612 (58%) 8,538 (42%) — — Male 7,677 (54%) 6,615 (46%) 1.20 1.14, 1.26 <0.001 Vaccination status Unvaccinated/unknown 18,035 (56%) 14,002 (44%) — — Vaccinated 1,254 (52%) 1,151 (48%) 0.86 0.78, 0.94 0.001 Comorbidities None 13,914 (66%) 7,293 (34%) — — One or more 5,375 (41%) 7,860 (59%) 1.97 1.87, 2.07 <0.001 Public/Private sector Public 17,989 (57%) 13,409 (43%) — — Private 1,300 (43%) 1,744 (57%) 1.40 1.27, 1.53 <0.001 Ethnic group Black African 17,011 (60%) 11,557 (40%) — — Coloured 899 (42%) 1,265 (58%) 1.03 0.92, 1.15 0.6 Indian 473 (39%) 746 (61%) 1.57 1.37, 1.79 <0.001 Other 98 (65%) 53 (35%) 1.18 0.82, 1.72 0.4 White 808 (35%) 1,532 (65%) 1.83 1.65, 2.03 <0.001 Reinfection Not reinfected/unknown 18,897 (56%) 14,946 (44%) — — Reinfected 392 (65%) 207 (35%) 0.71 0.59, 0.86 <0.001 1 n (%) for categorical; median (IQR) for continuous 2 not shown: Province included as a random effects variable 3 OR = Odds Ratio, CI = Confidence Interval Note: Data on race/ethnicity provided in categories determined by South Africa. 61 n (%) for categorical; median (IQR) for continuous 2 not shown: Province included as a random effects variable 3 HR = Hazard Ratio, CI = Confidence Interval Note: Data on race/ethnicity provided in categories determined by South Africa. Omicron period and risk of in-hospital mortality Table 4 provides the results of the Cox proportional hazards model for mortality by variant adjusted for age, sex, vaccination status, province, comorbidities, public/private facility, ethnicity and reinfection. After adjustment, Omicron was associated with lower hazards of in-hospital mortality (HR: 0.62; 95% CI: 0.59–0.65 and p < 0.001). Figs 2 and 3 are the Kaplan Maier curves for survival by variant and by severity of illness. Table 4 Factors associated with risk of in-hospital mortality Frequencies Cox mixed effects model Characteristic No O2/INV, N = 25,2501 Severe/Critical, O2/INV, N = 6,7861 OR 2,3 95% CI3 p-value Variant period Delta (wk 31-39 / 2021) 11,606 (72%) 4,408 (28%) 1.00 — Omicron (wk 46-52 / up to 16th Feb 2022) 13,644 (85%) 2,378 (15%) 0.62 0.59, 0.65 <0.001 Age 18-34 7,291 (93%) 535 (6.8%) 1.00 — <1 682 (92%) 58 (7.8%) 1.25 0.95, 1.63 0.11 1-4 556 (97%) 15 (2.6%) 0.40 0.24, 0.68 <0.001 5-9 349 (97%) 9 (2.5%) 0.38 0.20, 0.73 0.004 10-14 419 (97%) 13 (3.0%) 0.43 0.25, 0.75 0.003 15-17 550 (96%) 20 (3.5%) 0.49 0.32, 0.77 0.002 35-49 5,783 (83%) 1,149 (17%) 2.31 2.08, 2.56 <0.001 50-59 3,367 (73%) 1,216 (27%) 3.60 3.25, 4.00 <0.001 60+ 6,253 (62%) 3,771 (38%) 5.46 4.98, 5.99 <0.001 Sex at birth Female 14,934 (80%) 3,773 (20%) 1.00 — Male 10,316 (77%) 3,013 (23%) 1.14 1.09, 1.20 <0.001 Comorbidities None 16,920 (84%) 3,337 (16%) 1.00 — One or more 8,330 (71%) 3,449 (29%) 1.27 1.20, 1.33 <0.001 Public/Private sector Public 23,218 (78%) 6,485 (22%) 1.00 — Private 2,032 (87%) 301 (13%) 0.47 0.41, 0.53 <0.001 Ethnic group Black African 21,278 (80%) 5,451 (20%) 1.00 — Coloured 1,492 (73%) 540 (27%) 0.96 0.87, 1.06 0.5 Indian 784 (74%) 276 (26%) 1.05 0.92, 1.19 0.5 Other 134 (91%) 13 (8.8%) 0.57 0.33, 0.98 0.043 White 1,562 (76%) 506 (24%) 1.00 0.91, 1.11 >0.9 Reinfection Not reinfected/ unknown 24,822 (79%) 6,737 (21%) 1.00 — Reinfected 428 (90%) 49 (10%) 0.65 0.49, 0.86 0.002 7Figure 2 Survival of Delta and Omicron cohorts to day 28 of hospital stay Figure 3 Survival of the cohort by variant type and severity to day 28 of hospital stay + + p < 0.0001 Log−rank 0.00 0.25 0.50 0.75 1.00 0 7 14 21 28 Days Ov er all su rv iva l p ro ba bil ity Strata + +Delta (wk 31−39) Omicron (46−52 + 2022) 16748 13769 12589 12272 12166 17693 15987 15322 15145 15100+Omicron (46−52 2022) Delta (wk31−39) 0 7 14 21 28 Days St ra ta Number at risk + + + + p < 0.0001 Log−rank 0.00 0.25 0.50 0.75 1.00 0 7 14 21 28 Days Ov er all su rv iva l p ro ba bil ity Strata + + + +Delta, Non−severe Delta, Severe/Critical Omicron, Non−severe Omicron, Severe/Critical 7206 6352 6067 5985 5959 9542 7417 6522 6287 6207 12082 11270 10960 10874 10854 5611 4717 4362 4271 4246Omicron,Severe/Critical Omicron,Non−severe Delta, Severe/Critical Delta, Non−severe 0 7 14 21 28 Days St ra ta Number at risk 8Table 5 provides the results of the sensitivity analysis (population of unvaccinated/unknown vaccination status) for mortality using the cox proportional hazards model adjusted for the same variables as in Table 4. In this model, after adjustment, the hazards for death were lower with Omicron (HR: 0.62; 95% CI: 0.59–0.65 and p value < 0.001). 1 n (%) for categorical; median (IQR) for continuous 2 not shown: Province included as a random effects variable 3 HR = Hazard Ratio, CI = Confidence Interval Note: Data on race/ethnicity provided in categories determined by South Africa. Table 5 Factors associated with risk of in-hospital mortality Frequencies Cox mixed effects model Characteristic No O2/INV, N = 27,2661 Severe/Critical, O2/INV, N = 7,1751 OR 2,3 95% CI3 p-value Variant period Delta (wk 31-39 / 2021) 12,166 (73%) 4,582 (27%) 1.00 — Omicron (wk 46-52 / up to 16th Feb 2022) 15,100 (85%) 2,593 (15%) 0.62 0.59, 0.65 <0.001 Age 18-34 7,557 (93%) 543 (6.7%) 1.00 — <1 682 (92%) 58 (7.8%) 1.25 0.95, 1.64 0.10 1-4 556 (97%) 15 (2.6%) 0.41 0.24, 0.68 <0.001 5-9 349 (97%) 9 (2.5%) 0.38 0.20, 0.73 0.004 10-14 422 (97%) 13 (3.0%) 0.43 0.25, 0.75 0.003 15-17 556 (96%) 21 (3.6%) 0.52 0.34, 0.80 0.003 35-49 6,307 (84%) 1,204 (16%) 2.32 2.09, 2.57 <0.001 50-59 3,800 (75%) 1,271 (25%) 3.56 3.21, 3.94 <0.001 60+ 7,037 (64%) 4,041 (36%) 5.51 5.03, 6.04 <0.001 Sex at birth Female 16,160 (80%) 3,990 (20%) 1.00 — Male 11,106 (78%) 3,185 (22%) 1.14 1.09, 1.20 <0.001 Vaccination status Unvaccinated/ unknown 25,250 (79%) 6,786 (21%) 1.00 — Vaccinated 2,016 (84%) 389 (16%) 0.66 0.60, 0.74 <0.001 Comorbidities None 17,761 (84%) 3,445 (16%) 1.00 — One or more 9,505 (72%) 3,730 (28%) 1.27 1.21, 1.33 <0.001 Public/Private sector Public 24,581 (78%) 6,816 (22%) 1.00 — Private 2,685 (88%) 359 (12%) 0.45 0.40, 0.51 <0.001 Ethnic group Black African 22,817 (80%) 5,750 (20%) 1.00 — Coloured 1,598 (74%) 566 (26%) 0.97 0.88, 1.07 0.5 Indian 916 (75%) 303 (25%) 1.07 0.95, 1.21 0.3 Other 137 (91%) 14 (9.3%) 0.60 0.36, 1.02 0.060 White 1,798 (77%) 542 (23%) 1.01 0.92, 1.11 0.8 Reinfection Not reinfected/ unknown 26,721 (79%) 7,121 (21%) 1.00 — Reinfected 545 (91%) 54 (9.0%) 0.62 0.48, 0.82 <0.001 9Interpretation Our analysis of anonymized individual-level clinical data of hospitalized patients with COVID-19 from South Africa suggests evidence of reduced severity and lower mortality for the Omicron variant as compared with the Delta variant after adjusting for the confounding effects of age, sex, ethnicity, prior infection, vaccination status, comorbidities, effect of province and effect of public/private sector. A sensitivity analysis that included patients who were either unvaccinated or with unknown vaccination status was consistent with the results of the primary analysis suggesting a lower intrinsic severity for Omicron variant and enhancing our confidence in the results of the primary analysis. Our findings are supported by additional independent analyses from South African investigators (5,14,15) as well as by data from the United States of America (16), Portugal (17), Canada (18) and Denmark (19). However, unadjusted case fatality ratios remain significant at 15% in this hospitalized cohort. Understanding the severity and outcomes from a VOC has important implications for the public health response – in resource allocation, in adapting clinical management protocols, in vaccination policies and, more broadly, in the context of public health messaging. Taken along with the WHO public dashboards for COVID-19 case tracking (https://covid19.who.int/) and the WHO Global Clinical Platform for COVID-19 (20), this analysis provides additional robust information for ministries of health across the world and to all key stakeholders. Limitations Although our analysis adjusted for key potential confounding variables, there remains the possibility of residual confounding. Also, our analysis was restricted to data from South Africa and this reduces generalizability. As with other countries and jurisdictions, infections and reinfections were likely underreported in South Africa. There is also the risk of misclassification due to challenges in linking datasets related to cases and hospitalization. In addition, while we adjusted for vaccination, information on vaccination status was available for the minority of the cohort and, where available, was self-reported. While our sensitivity analysis of the unvaccinated/unknown vaccination status cohort mitigates this limitation to some extent, it does not completely exclude the confounding effects of vaccination. Also not fully factored into our analysis given the limitations of the data available, is the impact of prior infection (specifically during the larger Delta wave) and resulting immunity. While Omicron demonstrates immune escape, prior infection may offer protection against severe disease and death, which could partly explain the decoupling between cases and hospitalizations. We would also like to caution that our analysis should not be seen as supportive of the “mild” variant narrative. Nearly a third of the hospitalized Omicron patients developed severe disease and 15% died; numbers which are not insignificant. Omicron with its enhanced transmissibility has and continues to overwhelm health care systems globally (21) and international efforts to bring the pandemic to an end must continue with enhanced urgency. Among vulnerable populations, i.e. patients at the extremes of age, in populations with high comorbid burden, in frail patients and among the unvaccinated, COVID-19 (all VOCs) continues to contribute to substantial morbidity and mortality. 10 Our report demonstrates lower risk of developing severe disease as well as a lower risk of mortality among patients infected with the Omicron variant as compared with the Delta variant. While these findings are reassuring, limitations include the inability to fully adjust for the impact of vaccination and prior infection. 1. WHO Coronavirus (COVID-19) Dashboard. Geneva: World Health Organization; 2022 (https://covid19.who. int/, accessed 1 March 2022). 2. New COVID-19 variant detected in South Africa. 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Clinical outcomes among patients infected with Omicron (B.1.1.529) SARS-CoV-2 variant in southern California. medRxiv. 2022. doi: https://doi.org/1 0.1101/2022.01.11.22269045. Preprint. 17. Peralta-Santos A, Rodrigues EF, Moreno J, Ricoca V, Casaca P, Fernandes E et al. Omicron (BA.1) SARS-CoV-2 variant is associated with reduced risk of hospitalisation and length of stay compared with Delta (B.1.617.2). medRxiv. 2022. doi: https://doi.org/10.1101/ 2022.01.20.22269406. Preprint. 18. Ulloa AC, Buchan SA, Daneman N, Brown KA. Early estimates of SARS CoV-2 Omicron variant severity based on a matched cohort study, Ontario, Canada. medRxiv. 2022. doi: https://doi.org/10.1101/2021.12.24.2 1268382. Preprint. 19. Bager P, Wohlfahrt J, Bhatt S, Edslev SM, Sieber RN, Ingham AC et al. Reduced risk of hospitalisation associated with infection with SARS-CoV-2 Omicron relative to Delta: a Danish cohort study. SSRN (https:// ssrn.com/abstract=4008930, accessed 4 April 2022). 20. 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Conclusion References 11 Annex: List of contributing hospitals and health centres 1 Military Hospital 2 Military Hospital 3 Military Hospital AbaQulusi Private Hospital Aberdeen Hospital Abraham Esau Hospital Addington Hospital Adelaide Hospital Ahmed Al-Kadi Private Hospital Alan Blyth Hospital Albert Nzula District Hospital Alexandra Hospital Aliwal North Hospital All Saints Hospital Amajuba Memorial Hospital Andrew Saffy Memorial Hospital Andries Vosloo Hospital Appelsbosch Hospital Arwyp Medical Centre Aurora Hospital Aurora Rehabilitation Hospital Bambisana Hospital Barberton Hospital Bayview Private Hospital (Life) Beaufort West Hospital Bedford Hospital Beethoven Recovery Centre Belfast Hospital (HA Grove) Benedictine Hospital Bernice Samuel Hospital Bertha Gxowa Hospital Bethal Hospital Bethesda Hospital Bheki Mlangeni Hospital Biotumelo Surge Facility Bisho Hospital Bloemcare Psychiatric Hospital Boitumelo Hospital Bongani Nurses' Dormitory Surge Facility Bongani Regional Hospital Botlokwa Hospital Botshabelo Hospital Botshelong Empilweni Hospital Botshilu Private Hospital Brackengate Intermediate Care Brewelskloof Hospital Brits Hospital Bronkhorstspruit Hospital Brooklyn Chest Hospital Bryanston Subacute Burgersdorp Hospital Busamed - Paardevlei Private Hospital Busamed Bram Fischer International Airport Hospital Busamed Gateway Private Hospital Busamed Harrismith Private Hospital Busamed Hillcrest Private Hospital Busamed Modderfontein Private Hospital Orthopaedic and Oncology Centre Butterworth Hospital Cairnhall Hospital Cala Hospital Caledon Hospital Canzibe Hospital Cape Gate Mediclinic Capital Hospital Care Cure Queenstown Carewell Sub-Acute Hospital Carletonville Hospital Carnavon Community Health Centre Carolina Hospital Cathcart Hospital Catherine Booth Hospital Cecilia Makiwane Hospital Ceres Hospital Ceza Hospital Charles Johnson Memorial District Hospital Charlotte Maxeke Hospital Chris Hani Baragwanath Hospital Christ The King Hospital Christiana Hospital Church of Scotland Hospital Citrusdal Hospital Clairwood Hospital Clanwilliam Hospital Clinix Naledi Nkanyezi Hospital Clinix Solomon Stix Morewa Hospital Cloete Joubert Hospital CN Phatudi Hospital Cofimvaba Hospital Corona Sub-Acute Hospital Cradock Hospital Crescent Clinic CTICC COVID Intermediate Care Cullinan Rehabilitation Hospital Daxina Hospital Daymed Private Hospital De Aar Hospital Diamant Hospital Dihlabeng Hospital Dilokong Hospital Donald Fraser Hospital Donald Gordon Medical Centre Dora Nginza Hospital Dordrecht Hospital Doris Goodwin Hospital Douglas Community Health Centre DP Marais Santa Centre Dr George Mukhari Hospital Dr Harry Surtie Hospital Dr Js Moroka Hospital Dr Malizo Mpehle Hospital Dr S K Matseke Memorial Hospital Dr Yusaf Dadoo Hospital Duff Scott Memorial Hospital Dundee Hospital Durdoc Hospital EG and Usher Memorial Hospital Eden Gardens Private Hospital Edendale Hospital Edenvale Hospital Eerste River Hospital Ekombe Hospital Elim Hospital Elizabeth Donkin Hospital Elizabeth Ross Hospital Elliot Hospital Ellisras Hospital Elsie Ballot Hospital Emalahleni Private Hospital 12 Embhuleni Hospital Emmaus Hospital EmoyaMed Private Hospital Empilisweni Hospital Empilweni Hospital Ermelo Provincial Hospital Eshowe Hospital Eskom Academy of Learning Quarantine Site Esselenpark School of Excellence Quarantine Site Estcourt Hospital Evander Hospital Evuxakeni Hospital False Bay Hospital Far East Rand Hospital Fezi Ngubentombi Provincial Hospital FH Odendaal Hospital Fisha wellness Hospital Fort Beaufort Hospital Fort England Hospital Fort Napier Hospital Frere Hospital Frontier Hospital Ganyesa Community Hospital General Justice Gizenga Mpanza Hospital George Hospital George Masebe Hospital GJ Crooke's Hospital Glen Grey Hospital - Lady Frere Greenville Hospital Grey Hospital Grey's Hospital Greytown Hospital Greytown Specialized TB Hospital Griekwastad CHC Groblersdal Hospital Groote Schuur Hospital Hanover Park Clinic Harry Comay Hospital Hartswater Hospital Hayani Psychiatric Hospital Heidelberg Hospital Heideveld Community Day Centre Heideveld Emergency Centre Helderberg Hospital Helderberg Village, Somerset West Helen Joseph Hospital Helene Franz Hospital Hermanus Hospital Hewu Hospital Hibiscus Cato Ridge Private Hospital Hibiscus Private Hospital Highway Sub-Acute Hillandale Health Care Centre Hillcrest Hospital Hlabisa Hospital Holy Cross Hospital Hopetown Hospital Humansdorp Hospital Impungwe Hospital Indwe Hospital Inkosi Albert Luthuli Hospital Intercare Hazeldean Sub-Acute Hospital Intercare Irene Sub-Acute Hospital Intercare Sandton Sub-Acute Hospital Intercare Tyger Valley Sub-Acute Hospital Isilimela Hospital Isivivana Private Hospital Itemoheng Hospital Itshelejuba Hospital Jamestown Hospital Jan Kempdorp Community Heath Centre Jane Furse Hospital JMH Ascot Park Hospital JMH City Hospital JMH Isipingo Hospital Job Shimankana Tabane Hospital Joe Morolong Memorial Hospital Joe Slovo Community Heath Centre John Daniel Newsberry Hospital Jose Pearson TB Hospital Jubilee Hospital Kakamas Hospital Kalafong Hospital Kareedouw Hospital Karl Bremer Hospital Katleho Hospital Keimoes Community Heath Centre Kgapane Hospital Khayelitsha District Hospital Khotsong TB Hospital Kiaat Private Hospital KimMed Private Hospital King Dinuzulu Hospital King Edward VIII Hospital Klerksdorp Hospital Knysna Hospital Knysna Private Hospital Kokstad Private Hospital Komani Hospital Komga Hospital Kopanong Hospital Kuruman Hospital KwaDukuza Private Hospital Kwa-Magwaza Hospital Kwamhlanga Hospital La Verna Private Hospital Lady Grey Hospital Ladysmith Hospital Laingsburg Hospital Lapa Munnik Hospital Lebowakgomo Hospital Lenmed Ahmed Kathrada Hospital Lenmed Ethekwini Hospital and Heart Centre Lenmed Howick Private Hospital Lenmed Kathu Private Hospital Lenmed Randfontein Private Hospital Lenmed Royal Hospital and Heart Centre Lenmed Zamokuhle Private Hospital Lentegeur Hospital Leratong Hospital Letaba Hospital Life Anncron Hospital Life Beacon Bay Private Hospital Life Bedford Gardens Hospital Life Brackenview Life Brenthurst Hospital Life Carstenhof Hospital Life Carstenview Hospital Life Chatsmed Garden Hospital Life Cosmos Hospital Life Dalview Hospital Life East London Private Hospital Life Empangeni Private Hospital 13 Life Entabeni Hospital Life Eugene Marais Hospital Life Flora Hospital Life Fourways Hospital Life Genesis Clinic Saxonwold Life Glynnview Hospital Life Groenkloof Hospital Life Health Care (Faerie Glen) Life Hilton Private Hospital Life Hunters Craig Hospital Life Kingsbury Hospital Life Midmed Hospital Life Mt Edgecombe Hospital Life Pasteur Hospital Life Peglerae Hospital (pty) Ltd Life Poortview Hospital Life Queenstown Private Hospital Life Riverfield Rehab Centre Life Robinson Private Hospital Life Roseacres Hospital Life Rosepark Hospital Life Springs Parkland Hospital Life St Dominic's Hospital Life St George's Hospital Life Suikerbosrand Hospital Life The Crompton hospital Life The Glynnwood Hospital Life Vincent Pallotti Hospital Life VPH Rehabilitation Unit Life Westcoast Private Hospital Life Westville Hospital Life Wilgeheuwel Hospital Life Wilgers Hospital Livingstone Hospital Louis Pasteur Private Hospital Louis Trichardt Hospital Lydenburg Hospital Lynnmed Clinic Maclear Hospital Madadeni Hospital Madwaleni Hospital Madzikane Ka Zulu Memorial Hospital Mafube Hospital Mahatma Gandhi Memorial Hospital Mahikeng Provincial Hospital Malamulele Hospital Malmesbury Infectious Disease Hospital Mamelodi Hospital Manapo Hospital MANCOVS Surge Facility Manguzi Hospital Mankweng Hospital Manne Dipico Hospital Maphuta L Malatji Hospital Mapulaneng Hospital Margery Parkes TB Hospital Martjie Venter Hospital Maseve Field - Royal Bafokeng (public) Matatiele Private Hospital Matibidi Hospital Matikwana Hospital Matlala Hospital Mbongolwane Hospital Mccords Hospital Mecklenburg Hospital Medforum Private Hospital Medicare Private Hospital Mediclinic Bloemfontein Mediclinic Brits Mediclinic Cape Town Mediclinic Constantiaberg Mediclinic Durbanville Mediclinic Emfuleni Mediclinic Ermelo Mediclinic Geneva Mediclinic George Hospital Mediclinic Gynaecological Hospital Mediclinic Heart Hospital Mediclinic Hermanus Mediclinic Highveld Mediclinic Hoogland Mediclinic Howick Mediclinic Kimberley Mediclinic Klein Karoo Mediclinic Kloof Mediclinic Legae Mediclinic Lephalale Mediclinic Limpopo Mediclinic Louis Leipoldt Mediclinic Midstream Mediclinic Milnerton Mediclinic Morningside Mediclinic Muelmed Mediclinic Paarl Mediclinic Panorama Mediclinic Pietermaritzburg Mediclinic Plettenberg Bay Mediclinic Potchefstroom Mediclinic Sandton Mediclinic Stellenbosch Mediclinic Thabazimbi Mediclinic Tzaneen Mediclinic Upington Mediclinic Vereeniging Mediclinic Vergelegen Mediclinic Victoria Mediclinic Welkom Mediclinic Winelands Orthopaedic Hospital Mediclinic Worcester Medicross Boksburg Day Theatre Medicross Cape Town Foreshore Theatre Medicross Constantia Day Theatre Medicross Monte Vista Day Theatre Medicross Pinetown Day Theatre Medicross Procare Medicross Richards Bay Day Theatre Medicross Upington Day Theatre Medicross Wembley House Medleb Melomed Bellville Melomed Gatesville Melomed Mitchell's Plain Melomed Richardsbay Hospital Melomed Tokai Private Clinic Mercantile Private Hospital Messina Hospital Middelburg Hospital Midland Hospital Midlands Medical Centre Private Hospital Midvaal Private Hospital Mitchell's Plain District Hospital Mitchells Plain Hospital of Hope Intermediate Care Mjanyana Hospital Mmametlhake Hospital Modimolle MDR TB Hospital Mohau Hospital 14 Mokopane Hospital Molteno Hospital Montagu Hospital Montebello Hospital Mooimed Private Hospital Morehill Clinic Physical Rehab Moses Kotane Hospital Mossel Bay Hospital Mosvold Hospital Mount Ayliff Hospital Mowbray Maternity Hospital Mseleni Hospital Mthatha Private Hospital Murchison Hospital Murraysburg Hospital N17 Hospital Nababeep Community Health Centre Nala Hospital Nasrec Quarantine Site National District Hospital Nelson Mandela Academic Hospital Nelson Mandela Children's Hospital Nelspruit Medi Clinic Nessie Knight Hospital Netcare Akasia Hospital Netcare Alberlito Hospital Netcare Blaauwberg Hospital Netcare Bougainville Hospital Netcare Ceres Hospital Netcare Christiaan Barnard Memorial Hospital Netcare Clinton Netcare Constantia Day Clinic Netcare Cuyler Hospital Netcare Femina Hospital Netcare Ferncrest Hospital Netcare Garden City Hospital Netcare Greenacres Hospital Netcare Jakaranda Hospital Netcare Kingsway Hospital Netcare Kroon Hospital Netcare Krugersdorp Hospital Netcare Kuils River Hospital Netcare Lakeview Hospital Netcare Linksfield Hospital Netcare Linkwood Hospital Netcare Linmed Hospital Netcare Margate Hospital Netcare Milpark Hospital Netcare Montana Hospital Netcare Moot Hospital Netcare Mulbarton Hospital Netcare N1 City Hospital Netcare Olivedale Hospital Netcare Optiklin Hospital Netcare Parklands Hospital Netcare Pelonomi Private Hospital Netcare Pholoso Hospital Netcare Pinehaven Hospital Netcare Pretoria-East Hospital Netcare Rehabilitation Hospital Netcare Rosebank Hospital Netcare St Annes Hospital Netcare St Augustine Hospital Netcare Sunninghill Hospital Netcare Sunward Park Hospital Netcare The Bay Hospital Netcare Umhlanga Hospital Netcare Union Hospital Netcare Unitas Hospital Netcare Vaalpark Clinic Netcare Waterfall Hospital New Kensington Clinic (Life) New Somerset Hospital Newcastle Hospital Newcastle Private Hospital Ngwelezana Hospital NIC Bodenstein Hospital Niemeyer Memorial Hospital Nkandla Hospital Nketoana District Hospital Nkhensani Hospital Nkonjeni Hospital Nkqubela Chest Hospital Nompumelelo Hospital Northdale Hospital Noupoort (Fritz Visser) Community Health Centre Nurture Cape View Nurture Ilembe Nurture Newlands Nurture Queenstown Nurture Rynmed Nurture Sunnyside Nurture Vereeniging Nurture Woodlands (Mental Health Institution) ODI Community Hospital Olifantshoek Community Health Centre Orsmond TB Hospital Osindisweni Hospital Othobothini Community Health Centre Otto Du Plessis Hospital Oudtshoorn Hospital Paarl Hospital Pampierstad Health Centre Park Lane Clinic Parys Hospital Pelonomie Hospital Phekolong Hospital Philadelphia Hospital Pholosong Hospital Phumelela Hospital Phuthuloha Hospital Piet Retief Hospital Polokwane Hospital Pomeroy Community Health Centre Port Alfred Hospital Port Nolloth Community Health Centre Port Shepstone Hospital Postmasburg Hospital Potchefstroom Hospital Pretoria Eye Institute Arcadia Pretoria Urology Hospital Pretoria West Hospital Prieska (Bill Pickard) Hospital Prince Albert Hospital Prince Cyril Zulu Community Day Centre Prince Mshiyeni Hospital Prof ZK Matthews Hospital PZ Meyer TB Hospital Queen Nandi Regional Hospital Radie Kotze Hospital Rahima Moosa Mother and Child Hospital Red Cross Childrens Hospital Rev Dr Elizabeth Mamisa Chabula- Nxiweni Field Hospital RH Matjhabeng Hospital RH Phodiclinic RH Piet Retief Hospital 15 RH Rand Hospital Richmond Community Health Centre Richmond Hospital Riemland Clinic Rietvlei Hospital Riversdale Hospital RK Khan Hospital Rob Ferreira Hospital Robert Mangaliso Sobukwe Hospital Robertson Hospital Rondebosch Medical Centre Sabie Hospital Sawas Hospital Schweizer Reneke Hospital Sebokeng Hospital Sekororo Hospital Senorita Ntlabathi District Hospital Seshego Hospital Settlers Hospital PPP Shelly Beach Private Hospital Shifa Private Hospital Shongwe Hospital Siloam Hospital Sipetu Hospital Sizwe Tropical Diseases Hospital Sonstraal Hospital South Rand Hospital Springbok Hospital SS Gida Hospital St Aidan's Mission Hospital St Andrews Hospital St Apollinaris Hospital St Barnabas Hospital (Ntlaza) St Elizabeth Hospital St Francis Hospital St Francis Hospital (Aliwal North) St Helena GM Hospital St Lucy's Hospital St Margaret’s Hospital St Mary's Hospital St Mary's Hospital - Umtata St Patrick's Hospital St Rita's Hospital Standerton Hospital Standerton TB Hospital Stellenbosch Hospital Sterkfontein Hospital Sterkstroom Hospital Steve Biko Academic Hospital Steynsburg Hospital Stikland Psychiatric Hospital Stoffel Coetzee Hospital Stutterheim Hospital Sundays Valley Hospital Sunningdale Hospital Sunshine Hospital Swartland Hospital Swellendam Hospital Tafalofefe Hospital Tambo Memorial Hospital Tara H Moross Hospital Taung Hospital Tayler Bequest Hospital (Matatiele) Taylor Bequest Hospital (Mount Fletcher) TB Specialised Hospital (Barberton) Telkom Learning Centre Quarantine Site Tembisa Hospital Thabamoopo Psychiatric Hospital Thabazimbi Hospital The Fountain Private Hospital Thebe Hospital Thelle Mogoerane Regional Hospital Themba Hospital Thulasizwe Hospital Thusanong Hospital Tintswalo Hospital Tokollo Hospital Tonga Hospital Tower Psychiatric Hospital Town Hill Hospital Tshepong Hospital Tshepo-Themba Private Hospital Tshilidzini Hospital Tshwane District Hospital Tshwane Rehabilitation Hospital Tshwaragano Hospital Tygerberg Hospital UCT Private Academic Hospital Uitenhage Hospital Umlamli Hospital Umphumulo Hospital Umtata General Hospital Uniondale Hospital Universitas Hospital Universitas Private Hospital Universitas Surge Hospital Untunjambili Hospital Valkenberg Hospital Van Velden Hospital Victoria Hospital Victoria Hospital (Alice) Victoria Private Hospital Victoria West Community Health Centre Vista Clinic Voortrekker Hospital Vredenburg Hospital Vredendal Hospital Vryburg Private Hospital Vryheid Hospital Warmbaths Hospital Warrenton Community Health Centre Waterval-Boven Hospital Wentworth Hospital Wesfleur Hospital Weskoppies Hospital West Vaal Hospital Western Cape Rehabilitation Centre WF Knobel Hospital Wilhelm Stahl Hospital Williston Community Health Centre Willowmore Hospital Wilmed Park Private Hospital Winburg Hospital Winterberg TB Hospital Witbank Hospital Witbank TB Specialized Hospital Witpoort Hospital Worcester Hospital Zebediela Hospital Zeerust Hospital Zithulele hospital Zoutpansberg Private Hospital Zuid Afrikaans Hospital