An international observational study to assess the impact of the Omicron variant emergence on the clinical epidemiology of COVID-19 in hospitalised patients
- ISARIC, Pandemic Sciences Institute, University of Oxford, United Kingdom
- Big Data Institute, Nuffield Department of Medicine, University of Oxford, United Kingdom
- National Institute for Communicable Diseases, South Africa; Right to Care, South Africa
- Faculty of Medicine, University of British Columbia, Canada
- MRC Population Health Research Unit, Clinical Trials Service Unit and Epidemiological Studies Unit, Nuffield Department of Population Health, University of Oxford, United Kingdom
- Institute of Infection, Veterinary and Ecological Sciences, Faculty of Health and Life Sciences, University of Liverpool, United Kingdom
- Respiratory Medicine, Alder Hey Children's Hospital, University of Liverpool, United Kingdom
- Royal Melbourne Hospital, Australia
- Centre for Integrated Critical Care, University of Melbourne, Australia
- Universidad de La Sabana, Colombia
- Clinica Universidad de La Sabana, Colombia
- Department of Computer Science, University of Oxford, United Kingdom
- Department of Biology, University of Oxford, United Kingdom
- Emergency Department. Hospital Universitario La Paz – IdiPAZ, Spain
- Department of Infectious Diseases and Clinical Microbiology, School of Medicine, Marmara University, Turkey
- Roslin Institute, University of Edinburgh, United Kingdom
- Intensive Care Unit, Royal Infirmary of Edinburgh, United Kingdom
- Critical Care and Anesthesia, Nepal Mediciti Hospital, Nepal
- King Abdullah International Medical Research Center and King Saud Bin Abdulaziz University for Health Sciences, Saudi Arabia
- Network for Improving Critical care Systems and Training, Sri Lanka
- Department of Infectious, Tropical Diseases and Microbiology (DITM), IRCCS Sacro Cuore Don Calabria Hospital, Negrar di Valpolicella, Italy
- Makati Medical Center, Makati City, Philippines
- Department of Anesthesiology, Centre hospitalier de l'Université de Montréal, Canada
- Department of Medicine, Critical Care Division, Centre hospitalier de l'Université de Montréal, Canada
- Carrefour de l'innovation et santé des populations, Centre de recherche du Centre hospitalier de l'Université de Montréal (CRCHUM), Canada
- Department of Anesthesiology and Pain Medicine, Université de Montréal, Canada
- Centre for Medical Informatics, The University of Edinburgh, Usher Institute of Population Health Sciences and Informatics, United Kingdom
- Department of Infectious Diseases, Hospital del Mar, Infectious Pathology and Antimicrobial Research Group (IPAR), Institut Hospital del Mar d'Investigacions Mèdiques (IMIM), Universitat Autònoma de Barcelona (UAB), CEXS-Universitat Pompeu Fabra, Spain
- Instituto de Infectologia Emílio Ribas, Brazil
- Lions Gate Hospital, Canada
- International Islamic University Malaysia, Malaysia
- Clinical Research Centre, Sunway Medical Centre, Selangor Darul Ehsan, Malaysia
- Digital Health Research and Innovation Unit, Institute for Clinical Research, National Institutes of Health (NIH), Malaysia
- World Health Organization, Switzerland
- Carol Davila University of Medicine and Pharmacy, Romania
- National Institute for Infectious Diseases "Prof. Dr. Matei Bals", Romania
- Fundación Cardiovascular de Colombia, Colombia
- Department of Critical Care Medicine, Sunnybrook Health Sciences Centre, Canada
- Department of Critical Care Medicine, Manipal Hospital Whitefield, India
- Department of Medical Microbiology and Infection Control, Franciscus Gasthuis & Vlietland, Netherlands
- Critical Care Asia and Ziauddin University, Pakistan
- Pandemic Sciences Institute, University of Oxford, United Kingdom
- Department of Intensive Care, Franciscus Gasthuis & Vlietland, Netherlands
- Infectious Diseases Data Observatory, Centre for Tropical Medicine and Global Health, University of Oxford, United Kingdom
Figures
Figure 1
Population-level relative frequency of Omicron variant infections by country and time.
Here, data aggregated by epidemiological week and country were used to calculate the proportions of infections caused by the Omicron variant. For analyses reported in the Results section, two …
Figure 2
Study flowchart.
In this figure, we present the numbers of observations included in analyses in the different subsections of the Results section.
Figure 3
Age distributions by study period and country.
Age distributions (x-axes show proportions; y-axes, age groups) when Omicron variant relative frequency was below 10% (blue bars) and when the frequency was 90% or higher (red bars). Data from …
Figure 4
Frequencies of symptoms and comorbidities by study period and country.
Frequencies of the five most common symptoms (A) and comorbidities (B) during the pre-Omicron (blue bars) and Omicron (red bars) periods. 95% confidence intervals are shown. Note that South Africa …
Figure 5
Risk of death (y-axes) in the first 14 days after hospital admission or disease onset, whichever occurred latest, during the pre-Omicron and Omicron periods.
In each panel, the x-axis shows countries (ISO3 codes are presented), with different periods represented by circles with different colours (blue circles for the pre-Omicron period; red circles, for …
Appendix 1—figure 1
In this figure, population-level variant data are presented for countries with clinical data included in our analysis.
The same structure of Figure 1 was used but different cut-off frequencies for Omicron variant were applied: in (A), the lower and upper threshold frequencies were 10% and 80%; in (B), these …
Appendix 1—figure 2
Frequencies of the five most common symptoms during the period before (blue bars) and after (red bars) Omicron variant frequency reached 10% and 90%, respectively.
95% confidence intervals are also shown. In (A), data from individuals aged between 18 and 60 years are shown; and (B) shows the same information for individuals older than 60 years. Data from …
Appendix 1—figure 3
Frequency of previous vaccination by study period, age category and country.
Only data from countries with at least 50 observations with information on previous vaccination during both study periods defined by Omicron variant frequency are shown. In each panel, the x-axis …
Appendix 1—figure 4
Population-level vaccination coverage.
Data from different countries are presented in different panels; x-axes show epidemiological weeks since the first epidemiological week of 2020. As in Figure 1, continuous black lines represent …
Appendix 1—figure 5
Risk of death in the first 28 days after hospital admission or disease onset, whichever occurred latest, during pre-Omicron and Omicron periods.
In each panel, the x-axis shows countries, with different periods represented by circles with different colours (blue circles for the pre-Omicron period; red circles, for period after Omicron …
Appendix 1—figure 6
Risk of death or invasive mechanical ventilation by study period.
In each panel, the x-axis shows countries, with different periods represented by circles with different colours (blue circles for the pre-Omicron period; red circles, for the Omicron period). 95% …
Appendix 1—figure 7
This figure shows similar information to that presented in Figure 3.
The legend of that figure applies to this figure, except that instead of referring to time periods, the figure shows data for Delta and Omicron variants. Only countries with at least 10 observations …
Appendix 1—figure 8
This figure shows similar information to that presented in Figure 4.
The legend of that figure applies to this figure, except that instead of referring to time periods, the figure shows data for Delta and Omicron variants. Only countries with at least 10 observations …
Appendix 1—figure 9
This figure shows similar information to that presented in Appendix 1—figure 3.
The legend of that figure applies to this figure, except that instead of referring to time periods, the figure shows data for Delta and Omicron variants. Only countries with at least 10 observations …
Appendix 1—figure 10
This figure shows similar information to that presented in Figure 5.
The legend of that figure applies to this figure, except that instead of referring to time periods, the figure shows data for Delta and Omicron variants. Only countries with at least 10 observations …
Appendix 1—figure 11
This figure shows similar information to that presented in Figure 3.
The legend of that figure applies to this figure. Here, the upper threshold frequency used to define Omicron variant dominance was 80% rather than 90%.
Appendix 1—figure 12
This figure shows similar information to that presented in Figure 4.
The legend of that figure applies to this figure. Here, the upper threshold frequency used to define Omicron variant dominance was 80% rather than 90%.
Appendix 1—figure 13
This figure shows similar information to that presented in Appendix 1—figure 3.
The legend of that figure applies to this figure. Here, the upper threshold frequency used to define Omicron variant dominance was 80% rather than 90%.
Appendix 1—figure 14
This figure shows similar information to that presented in Figure 5.
The legend of that figure applies to this figure. Here, the upper threshold frequency used to define Omicron variant dominance was 80% rather than 90%.
Tables
Table 1
Vaccination status by country and study period.
Data for period-country combinations with less than 10 observations are not presented. Data on vaccination status were not available for patients from Saudi Arabia.
| pre-Omicron period | Omicron period | |||
|---|---|---|---|---|
| Country | % Vaccinated | Total N | % Vaccinated | Total N |
| Brazil | 84.6 | 13 | 87.9 | 33 |
| Canada | 32.2 | 59 | 57.3 | 686 |
| Colombia | 42.1 | 19 | - | <10 |
| Estonia | - | <10 | ||
| Germany | - | <10 | - | <10 |
| India | 34.8 | 23 | 84.8 | 33 |
| Malaysia | 79.3 | 29 | 80.0 | 10 |
| Nepal | 25.3 | 190 | 39.3 | 183 |
| Netherlands | 60.0 | 60 | 51.0 | 51 |
| New Zealand | 5.9 | 34 | - | <10 |
| Norway | - | <10 | 82.2 | 45 |
| Philippines | 78.6 | 14 | - | <10 |
| Portugal | - | <10 | - | <10 |
| Romania | - | <10 | 78.6 | 98 |
| South Africa | 15.1 | 1605 | 27.9 | 24752 |
| Spain | 45.0 | 20 | 70.9 | 55 |
| United Kingdom | 65.4 | 6865 | 70.3 | 7846 |
| United States of America | - | <10 | - | <10 |
| Argentina | - | <10 | ||
| Australia | - | <10 | ||
| Indonesia | - | <10 | ||
| Israel | 54.5 | 11 | ||
| Kuwait | 66.7 | 18 | ||
| Turkey | 74.1 | 27 | ||
Table 2
Odds ratio for the association between study period and mortality outcome.
Results of multivariate logistic models, with random intercepts for countries, on 14-day fatality risk are presented. Different models were fit that included different variables. Model III adjusts …
| Model | I | II | III | IV |
|---|---|---|---|---|
| Number of observations | 94,077 | 39,950 | 26,728 | 56,329 |
| Odds ratio (95% CI) | Odds ratio (95% CI) | Odds ratio (95% CI) | Odds ratio (95% CI) | |
| Variables | ||||
| Omicron period* | 0.65 (0.62–0.69) | 0.67 (0.61–0.75) | 0.68 (0.60–0.77) | 0.64 (0.59–0.69) |
| Sex (male) | 1.32 (1.26–1.38) | 1.33 (1.23–1.43) | 1.36 (1.24–1.49) | 1.33 (1.25–1.42) |
| Age | ||||
| Older than 60 years | Reference | Reference | Reference | Reference |
| Aged between 18 and 60 years | 0.26 (0.25–0.27) | 0.24 (0.22–0.26) | 0.27 (0.25–0.30) | 0.30 (0.27–0.32) |
| Younger than 18 years | 0.06 (0.05–0.07) | 0.06 (0.05–0.07) | 0.07 (0.05–0.09) | 0.06 (0.05–0.08) |
| Previous vaccination | - | 0.60 (0.55–0.65) | 0.53 (0.48–0.59) | 0.59 (0.54–0.65) |
| Comorbidities | ||||
| Hypertension | - | - | 1.29 (1.16–1.42) | 1.26 (1.17–1.35) |
| Diabetes | - | - | 1.22 (1.09–1.38) | 1.22 (1.12–1.32) |
| Chronic cardiac disease | - | - | 1.50 (1.31–1.71) | 1.51 (1.39–1.65) |
-
*
Odds ratio in univariate analysis 0.65 (0.61–0.69) (N=94,524).
Appendix 1—table 1
Numbers of records contributed by partner institutions in different countries between 01/10/2021 and 28/02/2022.
| Country | Number of records |
|---|---|
| South Africa | 69766 |
| United Kingdom | 55049 |
| Pakistan | 929 |
| Canada | 919 |
| Nepal | 504 |
| Laos | 456 |
| India | 409 |
| Romania | 166 |
| Saudi Arabia | 151 |
| Spain | 151 |
| Netherlands | 134 |
| Malaysia | 90 |
| Norway | 67 |
| Turkey | 57 |
| Brazil | 54 |
| Colombia | 52 |
| New Zealand | 46 |
| Kuwait | 35 |
| United States | 32 |
| Philippines | 26 |
| Ghana | 21 |
| Ireland | 20 |
| Israel | 17 |
| Italy | 12 |
| Estonia | 7 |
| Australia | 7 |
| Indonesia | 6 |
| Portugal | 5 |
| Germany | 4 |
| Argentina | 4 |
Appendix 1—table 2
Missing data on symptoms.
Note that this information was not systematically recorded in South Africa, and for this reason data from that country are not included in this table.
| Symptoms | Yes | No | Missing data |
|---|---|---|---|
| Any cough | 20431 | 13726 | 25273 |
| Fever | 16045 | 19465 | 23920 |
| Headache | 3896 | 28398 | 27136 |
| Confusion | 5960 | 28548 | 24922 |
| Seizures | 570 | 33424 | 25436 |
| Sore throat | 2394 | 29353 | 27683 |
| Runny nose | 1639 | 30279 | 27512 |
| Vomiting | 6956 | 27734 | 24740 |
| Wheezing | 2042 | 31191 | 26197 |
| Diarrhoea | 4418 | 29989 | 25023 |
| Chest pain | 5488 | 28732 | 25210 |
| Conjunctivitis | 106 | 32606 | 26718 |
| Myalgia | 3686 | 28195 | 27549 |
| Rash | 476 | 32877 | 26077 |
| Fatigue | 11339 | 22150 | 25941 |
| Ageusia | 1682 | 28341 | 29407 |
| Inability to walk | 252 | 3797 | 55381 |
| Anosmia | 1393 | 29040 | 28997 |
| Shortness of breath | 20490 | 14030 | 24910 |
| Lymphadenopathy | 145 | 32795 | 26490 |
Appendix 1—table 3
Missing data on comorbidities.
In this table, data from all countries are included.
| Comorbidities | Yes | No | Missing data |
|---|---|---|---|
| Liver disease | 1786 | 40992 | 86418 |
| Diabetes | 12956 | 68743 | 47497 |
| Chronic cardiac disease | 13546 | 73423 | 42227 |
| Hypertension | 32052 | 57401 | 39743 |
| Current smoking | 5090 | 26674 | 97432 |
| COPD | 9304 | 77794 | 42098 |
| Active TB | 1579 | 45731 | 81886 |
| Asthma | 8720 | 79175 | 41301 |
| Chronic kidney disease | 8441 | 78453 | 42302 |
| Malignant neoplasm | 5062 | 81465 | 42669 |
| Dementia | 4646 | 38530 | 86020 |
| HIV | 5925 | 79121 | 44150 |
| Chronic neurological disorder | 5615 | 37740 | 85841 |
| Obesity | 5723 | 45367 | 78106 |
Appendix 1—table 4
Potential limitations of population-level variant data used to determine time periods when Omicron variant was dominant.
| Potential limitation | Likely impact on analyses |
|---|---|
| Population-level data come from a range of sources in each country, and for most samples it is not possible to determine whether patient was hospitalised or was a community (mild) case | If different variants are associated with different severities upon infection and if a large fraction of samples used in the estimation of population-level frequency of variants are from community cases, then it is possible that this frequency does not fully represent the frequency in the hospitalised population. In particular, if Omicron variant infection is linked to lower risk of hospitalisation, as previous studies suggest, it is possible that even during periods when community-level frequency of Omicron variant was high, the frequency of Omicron variant in the hospitalised population might have been relatively low. |
| Use of country-level data, rather than data on variant frequency in the catchment areas of clinical centres contributing data | If Omicron variant spreads asynchronously in a country, with some regions reaching high relative frequency faster than others, it is possible that country-level data, rather than data at a finer geographical level, might not reflect Omicron variant frequency in the population from which patients were recruited. |
| Delay between infection, onset of symptoms and hospitalisation | Depending on the data source used to define population-level frequency of variants, if clinical samples were obtained early during the infection, hospitalised cases might only have the same variant composition after a time lag, corresponding to average time from infection, or onset of symptoms, to hospital admission. |
Appendix 1—table 5
Numbers of records in the pre-Omicron and Omicron periods by country.
| Omicron emergence | |||
|---|---|---|---|
| Country | Before 10% | After 90% | Total |
| South Africa | 4180 | 51929 | 56109 |
| United Kingdom | 18124 | 26479 | 44603 |
| Canada | 61 | 763 | 824 |
| Nepal | 197 | 204 | 401 |
| India | 89 | 212 | 301 |
| Netherlands | 60 | 65 | 125 |
| Saudi Arabia | 2 | 121 | 123 |
| Romania | 1 | 100 | 101 |
| Spain | 21 | 56 | 77 |
| Malaysia | 42 | 11 | 53 |
| Norway | 5 | 45 | 50 |
| Brazil | 15 | 33 | 48 |
| New Zealand | 34 | 6 | 40 |
| Colombia | 26 | 5 | 31 |
| Turkey | 0 | 27 | 27 |
| Philippines | 16 | 5 | 21 |
| United States of America | 14 | 7 | 21 |
| Kuwait | 0 | 19 | 19 |
| Ghana | 4 | 15 | 19 |
| Ireland | 14 | 3 | 17 |
| Israel | 0 | 14 | 14 |
| Australia | 0 | 6 | 6 |
| Portugal | 3 | 2 | 5 |
| Indonesia | 1 | 4 | 5 |
| Germany | 2 | 2 | 4 |
| Italy | 3 | 0 | 3 |
| Argentina | 0 | 3 | 3 |
| Estonia | 1 | 0 | 1 |
Appendix 1—table 6
Medians (interquartile ranges [Q1 - Q3]) of age by study period and country.
Only countries with 10 or more observations in both study periods are shown.
| Before 10% | After 90% | |||||
|---|---|---|---|---|---|---|
| Country | Median | Q1 | Q3 | Median | Q1 | Q3 |
| Brazil | 59 | 50 | 70 | 55 | 48 | 70 |
| Canada | 63 | 50 | 71 | 62 | 35 | 76 |
| Spain | 68 | 63 | 75 | 76 | 59 | 84 |
| United Kingdom | 66 | 48 | 78 | 67 | 38 | 81 |
| India | 63 | 47 | 72 | 70 | 60 | 76 |
| Malaysia | 63 | 52 | 68 | 59 | 55 | 63 |
| Netherlands | 74 | 64 | 80 | 70 | 55 | 77 |
| Nepal | 63 | 42 | 77 | 64 | 42 | 75 |
| South Africa | 45 | 30 | 62 | 41 | 27 | 63 |
Appendix 1—table 7
Numbers of hospitalised patients admitted due to COVID-19.
For country-time period combinations with less than 10 observations, numbers are not presented.
| Before 10% | After 90% | |||||
|---|---|---|---|---|---|---|
| Country | COVID-19 as reason (N) | COVID-19 as reason (%) | Total | COVID-19 as reason (N) | COVID-19 as reason (%) | Total |
| Australia | - | - | <10 | |||
| Argentina | - | - | <10 | |||
| Brazil | 14 | 100 | 14 | 32 | 96.7 | 33 |
| Canada | 12 | 52.2 | 23 | 514 | 67.5 | 761 |
| Colombia | 2 | 7.7 | 26 | - | - | <10 |
| Germany | - | - | <10 | - | - | <10 |
| Ghana | - | - | <10 | |||
| India | 0 | 0 | 12 | 2 | 8.3 | 24 |
| Indonesia | - | - | <10 | |||
| Israel | 8 | 66.7 | 12 | |||
| Kuwait | 0 | 0 | 18 | |||
| Malaysia | - | - | <10 | - | - | <10 |
| Nepal | - | - | <10 | 0 | 0 | 15 |
| Netherlands | 49 | 81.7 | 60 | 39 | 61.9 | 63 |
| New Zealand | 30 | 90.9 | 33 | - | - | <10 |
| Norway | - | - | <10 | 34 | 75.5 | 45 |
| Philippines | 16 | 100 | 16 | - | - | <10 |
| Romania | - | - | <10 | 100 | 100 | 100 |
| Saudi Arabia | - | - | <10 | 68 | 68.7 | 99 |
| South Africa | 1433 | 71.1 | 2015 | 18306 | 69.0 | 26512 |
| Spain | 11 | 64.7 | 17 | 37 | 66.1 | 56 |
| Turkey | 27 | 100 | 27 | |||
| USA | 0 | 0 | 11 | - | - | <10 |
Appendix 1—table 8
Percentages of patients with at least one comorbidity by country and study period.
Only countries with at least 10 patients in each study period are included.
| Before 10% | After 90% | |||
|---|---|---|---|---|
| Country | % with one or more comorbidities | Total | % with one or more comorbidities | Total |
| Brazil | 78.6 | 14 | 81.8 | 33 |
| Canada | 76.7 | 60 | 74.2 | 760 |
| India | 44.9 | 89 | 56.9 | 209 |
| Malaysia | 64.3 | 42 | 72.7 | 11 |
| Nepal | 46.2 | 197 | 55.4 | 204 |
| Netherlands | 86.7 | 60 | 78.5 | 65 |
| South Africa | 53.9 | 3170 | 44.7 | 37412 |
| Spain | 76.2 | 21 | 76.8 | 56 |
| United Kingdom | 86.5 | 11820 | 84.6 | 21501 |
Appendix 1—table 9
Percentages of patients with at least one symptom by country and study period.
Only countries with at least 10 patients in each study period are included.
| Before 10% | After 90% | |||
|---|---|---|---|---|
| Country | % with one or more symptoms | Total | % with one or more symptoms | Total |
| Brazil | 100.0 | 14 | 100.0 | 32 |
| Canada | 91.7 | 60 | 91.6 | 754 |
| India | 28.1 | 89 | 18.6 | 210 |
| Malaysia | 64.3 | 42 | 90.9 | 11 |
| Nepal | 97.0 | 197 | 86.3 | 204 |
| Netherlands | 96.7 | 60 | 96.9 | 65 |
| Spain | 100.0 | 21 | 87.5 | 56 |
| United Kingdom | 97.4 | 11104 | 89.3 | 16157 |
Appendix 1—table 10
Medians (interquartile ranges [Q1 - Q3]) of time from admission or disease onset to death by study period and country.
Only countries with 10 or more observations in both study periods are presented.
| pre-Omicron period | Omicron period | ||||||
|---|---|---|---|---|---|---|---|
| Country | Median | Q1 | Q3 | Median | Q1 | Q3 | |
| Canada | 10 | 6 | 21 | 10 | 5 | 18 | |
| United Kingdom | 11 | 6 | 19 | 11 | 6 | 19 | |
| India | 6 | 3 | 8 | 7 | 3 | 12 | |
| Nepal | 6 | 5 | 12 | 4 | 2 | 8 | |
| South Africa | 6 | 2 | 12 | 5 | 2 | 10 | |
Appendix 1—table 11
Survival models.
Results of a Cox proportional hazards model, stratified by country, on time to death in the first 28 days since hospital admission or onset of symptoms, which happened latest, are shown in the …
| Hazard ratio | Subhazard ratio | ||
|---|---|---|---|
| Variables | |||
| Omicron period | 0.77 (0.71–0.84) | 0.79 (0.73–0.84) | |
| Sex (male) | 1.24 (1.17–1.32) | 1.32 (1.24–1.40) | |
| Age | |||
| Older than 60 years | Reference | ||
| Aged between 18 and 60 years | 0.41 (0.38–0.44) | 0.26 (0.24–0.28) | |
| Younger than 18 years | 0.13 (0.11–0.17) | 0.06 (0.04–0.07) |
Appendix 1—table 12
Distribution of infections with individual-level variant information by country and variant.
Only countries with at least 10 observations for Delta and Omicron variants are listed. Note that other countries had limited numbers for both or one of the two variants.
| Country | Delta | Omicron |
|---|---|---|
| Canada | 26 | 303 |
| Netherlands | 12 | 52 |
| Norway | 15 | 22 |
| South Africa | 17 | 720 |
| Spain | 10 | 16 |
