Severity of the Omicron SARS‐CoV‐2 variant compared with the previous lineages: A systematic review

Abstract The Omicron variant was first detected in October 2021, which evolved from the original SARS‐CoV‐2 strain and was found to possess many mutations. Immune evasion was one of the notable consequences of these mutations. Despite Omicron exhibiting increased transmissibility, the rates of hospitalizations and deaths among patients infected with this variant were substantially lower when compared to other strains. However, concluding that the Omicron variant is less severe than other variants of SARS‐CoV‐2 requires consideration of multiple factors, including the vaccination status of infected patients as well as any previous infections with other variants. This review compiled data about any reported indicators of severity in Omicron‐infected patients, including studies comparing Omicron with other variants while adjusting for confounders. A comprehensive search was conducted using different databases to target any studies about Omicron. In total, 62 studies met our inclusion criteria and were included in this study. Many studies reported a significantly reduced risk of hospitalization, ICU admission, need for oxygenation/ventilation, and death in Omicron‐infected patients compared to patients infected with other variants, such as Delta. Some studies, however, reported comparable severity in Omicron infected patients as to other variants emphasizing a substantial risk for severe illness. Furthermore, the COVID‐19 vaccines were less effective against Omicron relative to previous lineages, except after receiving the booster dose. One study recommended vaccination during pregnancy, which may help prevent future cases of severe SARS‐CoV‐2 pneumonia in neonates and young infants due to the transfer of humoral response from the mother.


SARS-CoV-2 is a virus that emerged in
pandemic. Since its emergence, there have been nearly 45 million confirmed cases and over 6 million deaths. 1 As of December 2021, five variants of concern have been identified by the World Health Delta variant is one of special interest and concern as it might cause more severe illness. 2 The Omicron variant was first detected in South Africa on 24 October, 2021, 3 45 mutations in comparison to the original strain. 3 One of the most concerning consequences of these mutations is that they render the virus to evade the immune response and recognition by T lymphocytes. 3 Despite Omicron exhibiting increased transmissibility, the rates of hospitalizations and deaths are substantially lower relative to other strains. 4

| ME THODS
The preferred reporting items for systematic reviews and metanalysis (PRISMA) statement was used to develop the protocol of this systematic review. 5

| Eligibility criteria
We conducted a comprehensive literature search of medical studies that reported any clinical data related to COVID-19 infections with the Omicron variant. No restrictions were made based on country, age or gender. Any articles that did not have primary data, such as review articles, were excluded from the study after removing the duplicates. Furthermore, studies that were not in English were excluded. During the full-text screening, any studies that reported positive Omicron infection were included, whether the subjects were symptomatic or asymptomatic. Only studies that stratified the data based on the type of SARS-CoV-2 variant were included.

| Study selection and data collection
Title and abstract screening, full-text screening and data extraction were conducted by two independent reviewers for each study using Covidence and disagreements were resolved by consensus.

| Data items
Demographic and clinical data, including age, sex, comorbidities, treatments and outcomes, were collected. Continuous variables were expressed as mean ± standard deviation or range of results.
Categorical variables were expressed as percentages.

| Data analysis
Indicators of severity were classified based on the following criteria: Hospitalization, intensive care unit (ICU) admission, the need for oxygenation or ventilation, cardiovascular and haematological complications, other complications and death. The other complications included any of the above categories that were reported by some studies without separating the data of each category or those that described the symptoms as severe without specifying the symptoms or type of intervention. Furthermore, emergency department (ED) visits, respiratory failure, pneumonia, new renal replacement therapy (NRRT), lung filtrates on chest X-ray/CT scan (CXR/CT), the use of vasopressors or the loss/impairment of smell and/or taste, were reported in this review under the category of other complications. Figure 1 shows the flow diagram of our protocol. After removing the duplicates, the titles and abstracts of 2397 studies were screened, of which 663 were selected for full-text screening. Only 62 studies met our inclusion criteria. Of the 601 excluded studies, 443 were irrelevant, 18 did not have enough data, 117 had no primary data, 3 were not in English, 19 used animal models, and 1 was a duplicate of another study. Tables S1 and S2 summarize the demographic and clinical data of the included subjects who had reported vaccination statuses (regardless of the dose).   Table S3 summarizes the demographic and clinical data of the subjects in studies that did not report vaccination statuses.

| Types of studies and demographic data
Among the 62 included studies, 23  We, therefore, reported the data as rates of incidence of certain severe symptoms, outcomes or interventions among each cohort.

| Clinical data
Tables S2 and S3 summarize the clinical data of the subjects that took part in each study, including comorbidities and any reported clinical manifestations associated with Omicron infections such as symptomatic and asymptomatic infections. We also noted any clinical data related to COVID-19 infections with other variants whenever reported. Micheli et al., 19 Piersiala et al., 23  Any data reported specifically for Omicron is found in Tables S1-S9.
As not all studies reported the statistical significance of differences between the cohorts, Table 1 summarizes the studies that tested the statistical significance of the differences between the cohorts infected with Omicron compared with other variants, whether the results were significant or not.    Figure 5 illustrates the rates of incidence of cardiovascular and/ or haematological events among patients infected with Omicron compared to other variants of SARS-CoV-2. Figure 4A illustrates the rates among unvaccinated patients infected with Omicron, Alpha, or Delta as reported by one study, which presented lower rates of myocardial infarction (MI) and stroke in Omicron-infected patients compared to both Alpha and Delta. 10 Lower rates of venous thromboembolic event (VTEE) in Alpha patients were reported compared with both Omicron and Delta. However, the statistical significance of these differences was not reported. Figure 4B illustrates the rates among fully vaccinated or boosted patients infected with Omicron, Alpha, or Delta as reported by Lauring et al., which showed lower rates of MI in Omicron-infected patients compared with both Alpha and Delta. 10 Higher rates of stroke and venous thromboembolism (VTE) were reported in the Omicroninfected patients compared to Delta. However, the statistical significance of the differences was not reported.

| Other complications
Some studies reported the rates of combined events without separating the data of each category, such as ICU admission and death, and others described the symptoms as severe without specifying the type of symptoms or intervention. This, in addition to ED visits, respiratory failure, pneumonia, NRRT, lung infiltrates on CXR/CT or the use of vasopressors, were reported in this review under the category of other complications (Table S9). Whenever Omicron was compared with other variants, lower or similar rates were reported for the Omicron-infected patients compared to the patients infected with other variants. However, the statistical significance of the differences between the variants was tested only in a few studies. For example, Viellard-Baron et al. reported a significantly lower rate of pneumonia among Omicron-infected patients compared to Delta-infected patients (p < 0.01, partially, fully vaccinated and boosted). 13 Jassat et al. reported a significantly lower rate of severe symptoms in Omicron-infected patients compared to Delta, Beta, and the D614G variants (p < 0.001, vaccination status NR). 41 Similarly, Martin et al. 43 and Auvigne et al. 59 found that the rate of incidence of severe symptoms among Omicron-infected patients was significantly lower than those in pre-Omicron and Delta patients, without reporting the vaccination status (p < 0.001). Some other complications such as ED visits, respiratory failure, pneumonia, NRRT, lung infiltrates on CXR/CT and the use of vasopressors were mentioned for Omicron infected patients in some studies without comparing them with other variants, all of which are summarized in Table S9. Loss/impairment of smell and/or taste in Omicron infected patients has been reported by 9 studies. 30 , mixed data for partially and fully vaccinated patients (D) and those who did not have known/reported vaccination status (E for Omicron vs. Delta, F for Omicron vs. multiple variants). All the studies showed lower admission rates among Omicron-infected patients compared to the other variants, regardless of the vaccination status or doses. Some studies reported the significance of the difference between the Omicron variant and the other variants. Specifically, p < 0.0001 and 0.00007 were reported for fully vaccinated (B) and boosted patients (C), respectively (Fall et al. 5 ). Goga et al. 6 reported significantly lower admission rates among the J&J fully vaccinated and boosted patients (D) infected with Omicron compared to those infected with Delta (p < 0.001). Krutikov et al., 47 Houhamdi et al. 61 (E) and Maslo et al. 40 (F). reported significantly lower rates of hospitalization among Omicron-infected patients with unknown/unreported vaccination status compared to Delta patients (p < 0.0001, p < 0.0001 and p < 0.001, respectively). When Omicron was compared with other variants (including Delta, F), the rates of hospital admissions were also reported to be significantly lower among Omicron-infected patients by Christensen et al. 60 (p < 0.0001 for Omicron and either Delta or Alpha), Jassat et al. 41 (p < 0.001 for Omicron and either Delta or Beta or D614G) and Dinh et al. 35 (p < 0.0001 for Omicron and Alpha). In Figure F, no values are shown for some variants because the variants were not reported by these studies, not because the admission rate was 0% as illustrated in Table S4. *Rate is significantly lower for Omicron as compared to other variants (specified in the legend). experiencing these symptoms ranged from 1.2% to 24% of the cohorts. They were either known to be vaccinated or their vaccination status was not reported.

F I G U R E 3 ICU admissions among patients infected with Omicron compared to other variants of SARS-CoV-2. (A-F) Illustrate the rates in unvaccinated patients (A), fully vaccinated patients (B), vaccine-boosted patients (C), mixed data for partially and fully vaccinated patients (D)
and those who did not have known/reported vaccination status (E for Omicron vs. Delta, F for Omicron vs. multiple variants). All the studies showed lower admission rates among Omicron-infected patients compared to other variants regardless of the vaccination status or the number of doses, except for Marks et al., 15 who reported a higher admission rate among fully vaccinated Omicron-infected patients without reporting the significance of the difference. Most studies did not report the statistical significance of the difference between different variants. However, Modes et al. 20 and Fall et al. 5 reported that the differences were not significant for unvaccinated patients (A). Similarly, there was no significant difference between the ICU admissions in boosted Omicron and Delta-infected patients (C, Fall et al. 5 ). Significantly lower admission rates were reported among fully vaccinated and boosted Omicron-infected patients compared with Delta-infected patients (D, Goga et al., 6 p < 0.001; Modes et al., 20 p = 0.01). Furthermore, among the studies that did not report the vaccination status of the included subjects, significantly lower ICU admission rates were reported by Houhamdi et al. 61 (E, p < 0.0001 for Omicron and Delta), Dinh et al. 35 (F, p < 0.0001 for Omicron and Alpha), Iuliano et al. 42 (p < 0.05 for Omicron and Delta and Omicron and the variants of the winter period), Maslo et al. 42 (F, p < 0.001 for Omicron and Delta) and Jassat et al. 41 (F, p < 0.001 for Omicron and either Delta or Beta or D614G). In Figure F, some values are not shown for some variants (except Omicron) because the variants were not reported by these studies, and not because the admission rate was 0%. However, sometimes no values are shown for Omicron because either the value is very low or 0% as illustrated in Table S5. *Rate is significantly lower for Omicron as compared to other variants (specified in the legend). **Vieillard-Baron et al. 13 3 (C) who reported a significantly higher rate of need for oxygenation among vaccinated Omicron-infected patients (dose NR) as compared to Beta and Delta and Lewnard et al., who reported similar rates of UMV in the Omicron and Delta infected patients without reporting their vaccination status. While some studies did not report the statistical significance of the difference between the different variants, Modes et al. 20 showed that the difference in the rate of IMV was not significant between the unvaccinated Omicron and Delta patients. A significantly lower rate of ventilation was reported by Goga et al. 3 (C) among fully vaccinated or boosted Omicron patients compared to the Delta variant (p < 0.001), while the rate of need for oxygenation was significantly higher among Omicron patients relative to Delta patients (Goga et al. 3 p < 0.001). The need for IMV was significantly lower among Omicron patients compared to Delta patients (C, Modes et al., 20 p = 0.03). Significantly lower rates were reported by Maslo et al. 40 (E, p < 0.001 for USO and UMV in Omicron and Delta patients). Jassat et al. 41 (E, p < 0.001 for USO in Omicron and D614G) and Christensen et al. 60 (E, p < 0.0001 for LFOT, HFOT, NIV, IMV and ECMO in Omicron vs. either Delta or Alpha variants). In Figure E, values are not shown for some variants (except Omicron) because the variants were not reported by the corresponding studies, and not because the rate was 0%. However, sometimes no values are shown for Omicron because the value is very low as illustrated in Table S6. *Rate is significantly lower for Omicron as compared to other variants (specified in the legend). # Rate is significantly higher for Omicron. **Vieillard-Baron et al. 13 Abdullah

| Rates of death among Omicron infected patients compared to other variants
Ward et al. conducted a retrospective cohort study that assessed the risk of mortality, as identified by death certification records, attributed to COVID-19 in patients who contracted Omicron or Delta in the UK. 31 After adjusting for a spectrum of possible confounders such as age and vaccination status, there was a 67% reduction (HR = 0.33, 95% CI: 0.24-0.45) of mortality attributed to COVID-19 with Omicron compared to Delta. When vaccination status was considered, the risk reduction of mortality between the 2 variants was even more significant in individuals who received a booster compared to those who received the primary vaccination F I G U R E 5 Rates of incidence of cardiovascular and/or haematological events among patients infected with Omicron compared to other variants of SARS-CoV-2 with different vaccination statuses as reported by the included studies. (A) Rates among unvaccinated patients infected with Omicron, Alpha, or Delta as reported by one study (Lauring et al. 10 ), which showed lower rates of MI and stroke in Omicroninfected patients compared to both Alpha and Delta. Lower rates of VTEE in Alpha-infected patients were reported compared with both Omicron and Delta. However, the statistical significance of the differences was not reported. (B) Rates among fully vaccinated and boosted patients infected with Omicron, Alpha, or Delta as reported by Lauring et al., 10 which showed lower rates of MI in Omicron-infected patients compared with both Alpha and Delta-infected patients. Higher rates of strokes and VTE were reported among Omicron-infected patients compared to Delta-infected patients. However, the statistical significance of the differences was not reported. More details are reported in Table S7. CVST, cerebral venous sinus thrombosis; MI, myocardial infarction; NR, not reported; VTEE, venous thromboembolic events. series (2 doses) only, regardless of age. Therefore, the study results provide strong evidence that Omicron is associated with a significantly reduced risk of mortality compared to Delta in the UK.

| Severity (different severe hospital events) of Omicron compared with other variants
Peralta-Santos et al. reported that the Omicron variant was associated with 75% and 86% risk reduction of hospitalization and death, respectively, compared to the Delta variant. 54 20 (D) reported no significant difference in the death rates in the unvaccinated patients of Omicron and Delta; however, the rate was significantly lower in the fully vaccinated Omicron-infected patients (p = 0.02). Furthermore, the death rate among Omicron-infected patients (vaccination status NR) was reported to be significantly lower than other variants by Houhamdi et al. 61 (E, p < 0.0001, for Omicron and Delta), Krutikov et al. 47 (E, p < 0.0001, for Omicron and Delta), Jassat et al. 41 (F, p < 0.001 for Omicron and either Delta, Beta or D614G), Christensen et al. 60 (F, p < 0.0001 for Omicron and Delta, p < 0.0001 for Omicron and Alpha) and Abdullah et al. 36 (F, p < 0.00001 for Omicron and Delta). In Figure F, values are not shown for some variants (except Omicron) because the variants were not reported by these studies, and not because the death rate was 0%. However, sometimes no values are shown for Omicron because the value is very low or 0% as illustrated in Table S8. *Rate is significantly lower for Omicron as compared to other variants (specified in the legend).

TA B L E 1
Studies that tested the significance of the severity difference between Omicron and the other variants.

| Studies reporting comparable severity in patients infected with Omicron or other variants
Unlike many studies that reported lower severity in Omicron cohorts reported that patients hospitalized in the Omicron period had lower severity but still had a substantial risk for severe illness. There was a 29% reduction in ED visits, 67% in hospitalizations, 68% in ICU admissions and 71% in MV. Since the study population was unvaccinated and not previously infected, the potential effects of preexisting immunity do not confound the results. Hence, this suggests that Omicron is integrally milder than Delta in the study population.

| S TU DY LI M ITATI O N S
There are some limitations for this study, which are related to the types of reported data in the included studies. The statistical significance of the differences in rates of infection, hospitalization, ICU admission, mortality, etc. between Omicron and the other variants were not reported by many studies. To overcome this problem, we compiled all the data that were statistically tested in Table 1, whether they were significant or not. The extraction of data from different databases may account for some overlap between studies in case the data was published to multiple databases. To overcome this problem, we presented the data that compares the severity among the different variants separately as reported in each study without compiling them. In some studies, when the rates of certain events (such as hospital admissions or death) were calculated, It was not clear whether they were caused directly by the COVID-19 infections or by other factors. This limitation was also observed in the initial global reports of COVID-19 clinical data. Some studies described some symptoms as mild, moderate, or systemic without specifying the types of events. In such cases, non-objective data was excluded and we focused instead on the well-defined events that were described in the 'data analysis' section. Another challenge was the overlap between the rates of some reported events, such as ICU admission and ventilation. For this reason, we avoided discussing the relative rates of incidence of certain events within each cohort as the percentages do not add to 100% due to the overlap.

| CON CLUS ION AND RECOMMENDATIONS
The compiled results demonstrated that the severity of the in Omicron-infected patients were rare, it was suggested by one study that there is a need to study anticoagulation and d-dimer measurement in infants with severe SARS-CoV-2 pneumonia. The study also suggested that antenatal vaccination is protective to the foetus due to the transfer of humoral response from the mother.
Therefore, vaccination during pregnancy is recommended and may help prevent future cases of severe SARS-CoV-2 pneumonia in neonates and young infants.

S U PP O RTI N G I N FO R M ATI O N
Additional supporting information can be found online in the Supporting Information section at the end of this article.