key: cord-0261824-hu2lg6i7 authors: Wolter, N.; Jassat, W.; Walaza, S.; Welch, R.; Moultrie, H.; Groome, M.; Amoako, D. G.; Everatt, J.; Bhiman, J. N.; Scheepers, C.; Tebeila, N.; Chiwandire, N.; du Plessis, M.; Govender, N.; Ismail, A.; Glass, A.; Mlisana, K.; Stevens, W.; Treurnicht, F. K.; Makatini, Z.; Hsiao, N.-y.; Parboosing, R.; Wadula, J.; Hussey, H.; Davies, M.-A.; Boulle, A.; von Gottberg, A.; Cohen, C. title: Early assessment of the clinical severity of the SARS-CoV-2 Omicron variant in South Africa date: 2021-12-21 journal: nan DOI: 10.1101/2021.12.21.21268116 sha: 1c7d035896d34a8d52aec0bc40985299667bed41 doc_id: 261824 cord_uid: hu2lg6i7 Background The SARS-CoV-2 Omicron variant of concern (VOC) almost completely replaced other variants in South Africa during November 2021, and was associated with a rapid increase in COVID-19 cases. We aimed to assess clinical severity of individuals infected with Omicron, using S Gene Target Failure (SGTF) on the Thermo Fisher Scientific TaqPath COVID-19 PCR test as a proxy. Methods We performed data linkages for (i) SARS-CoV-2 laboratory tests, (ii) COVID-19 case data, (iii) genome data, and (iv) the DATCOV national hospital surveillance system for the whole of South Africa. For cases identified using Thermo Fisher TaqPath COVID-19 PCR, infections were designated as SGTF or non-SGTF. Disease severity was assessed using multivariable logistic regression models comparing SGTF-infected individuals diagnosed between 1 October to 30 November to (i) non-SGTF in the same period, and (ii) Delta infections diagnosed between April and November 2021. Results From 1 October through 6 December 2021, 161,328 COVID-19 cases were reported nationally; 38,282 were tested using TaqPath PCR and 29,721 SGTF infections were identified. The proportion of SGTF infections increased from 3% in early October (week 39) to 98% in early December (week 48). On multivariable analysis, after controlling for factors associated with hospitalisation, individuals with SGTF infection had lower odds of being admitted to hospital compared to non-SGTF infections (adjusted odds ratio (aOR) 0.2, 95% confidence interval (CI) 0.1-0.3). Among hospitalised individuals, after controlling for factors associated with severe disease, the odds of severe disease did not differ between SGTF-infected individuals compared to non-SGTF individuals diagnosed during the same time period (aOR 0.7, 95% CI 0.3-1.4). Compared to earlier Delta infections, after controlling for factors associated with severe disease, SGTF-infected individuals had a lower odds of severe disease (aOR 0.3, 95% CI 0.2-0.6). Conclusion Early analyses suggest a reduced risk of hospitalisation among SGTF-infected individuals when compared to non-SGTF infected individuals in the same time period, and a reduced risk of severe disease when compared to earlier Delta-infected individuals. Some of this reducton is likely a result of high population immunity. The SARS-CoV-2 Omicron variant of concern (VOC) almost completely replaced other variants in South Africa during November 2021, and was associated with a rapid increase in COVID-19 cases. We aimed to assess clinical severity of individuals infected with Omicron, using S Gene Target Failure (SGTF) on the Thermo Fisher Scientific TaqPath COVID-19 PCR test as a proxy. We performed data linkages for (i) SARS-CoV-2 laboratory tests, (ii) COVID-19 case data, (iii) genome data, and (iv) the DATCOV national hospital surveillance system for the whole of South Africa. For cases identified using Thermo Fisher TaqPath COVID-19 PCR, infections were designated as SGTF or non-SGTF. Disease severity was assessed using multivariable logistic regression models comparing SGTF-infected individuals diagnosed between 1 October to 30 November to (i) non-SGTF in the same period, and (ii) Delta infections diagnosed between April and November 2021. From 1 October through 6 December 2021, 161,328 COVID-19 cases were reported nationally; 38,282 were tested using TaqPath PCR and 29,721 SGTF infections were identified. The proportion of SGTF infections increased from 3% in early October (week 39) to 98% in early December (week 48). On multivariable analysis, after controlling for factors associated with hospitalisation, individuals with SGTF infection had lower odds of being admitted to hospital compared to non-SGTF infections (adjusted odds ratio (aOR) 0.2, 95% confidence interval (CI) 0.1-0.3). Among hospitalised individuals, after controlling for factors associated with severe disease, the odds of severe disease did not differ between SGTF-infected individuals compared to non-SGTF individuals diagnosed during the same time period (aOR 0.7, 95% CI 0.3-1.4). Compared to earlier Delta infections, after controlling for factors associated with severe disease, SGTF-infected individuals had a lower odds of severe disease (aOR 0.3, 95% CI 0.2-0.5). Early analyses suggest a reduced risk of hospitalisation among SGTF-infected individuals when compared to non-SGTF infected individuals in the same time period. Once hospitalised, risk of severe disease was similar for SGTF-and non-SGTF infected individuals, while SGTF-infected individuals had a reduced risk of severe disease when compared to earlier Delta-infected individuals. Some of this reducton is likely a result of high population immunity. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted December 21, 2021. ; https://doi.org/10.1101/2021.12.21.21268116 doi: medRxiv preprint Since the introduction of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) in March 2020, South Africa has experienced three epidemic waves with the Beta and Delta variants of concern (VOCs) dominating the second and third waves, respectively. The Omicron VOC has a high number of mutations, some of which are concerning due to predicted immune evasion and increased infectivity. While the Omicron variant shares a few common mutations with the C.1.2 (a highly mutated lineage previously identified in South Africa) 3 Delta variants, it also has 22 additional substitutions (including insertions and deletions) not seen in any other VOC or variant of interest (VOI) to date. Among them, the Δ69-70 amino acid deletion in the spike gene, previously observed in Alpha, is known to cause SGTF on the TaqPath COVID-19 PCR test. Data on the clinical severity of the Omicron variant compared to previous SARS-CoV-2 variants are needed to guide public health planning and response. DATCOV-Gen 4 is a prospective surveillance network linking real-time SARS-CoV-2 genome data to detailed epidemiologic and clinical data on hospitalised cases to allow rapid assessment of severity and clinical presentation of emerging SARS-CoV-2 VOCs. We aimed to assess the severity of Omicron infections compared to Delta variant using SGTF as a proxy 5 . . CC-BY-NC-ND 4.0 International license It is made available under a perpetuity. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint We linked data from four sources: (i) National COVID-19 case data reported in real-time to the National Institute for Communicable Diseases (NICD) Notifiable Medical Conditions Surveillance System (NMCSS), (ii) SARS-CoV-2 laboratory test data (test used and PCR cycle threshold (Ct) values) for the period 1 October -6 December 2021 for public sector laboratories (National Health Laboratory Service (NHLS)) reported all test data) and one large private sector laboratory (reported TaqPath PCR test only), (iii) genome data for clinical specimens sent to NICD from private and public diagnostic laboratories around the country (predominantly from Gauteng, North West, Mpumalanga and Northern Cape provinces), and collected through the pneumonia surveillance programme 6 December 2021. For hospitalisation and severity analyses, cases were censored to those with a specimen collected before 1 December 2021. Infections were classified as SGTF (as a proxy for Omicron) when an individual tested positive using the TaqPath COVID-19 PCR test with non-detectable S gene target and Ct value ≤30 for either the ORF1ab or nucleocapsid (N) gene targets 8 . Infections were classified as non-SGTF when an individual tested positive using TaqPath COVID-19 PCR test with Ct≤30 for either the ORF1ab or nucleocapsid (N) gene targets and had detectable S gene target. An individual was classified as admitted to hospital if they linked to a case on the DATCOV database with an admission date from 7 days prior to 21 days following the date of specimen collection. Severe disease was defined as a hospitalised patient meeting at least one of the following criteria: admitted to the intensive care unit (ICU), received oxygen treatment, ventilated, received extracorporeal membrane oxygenation (ECMO), experienced acute respiratory distress syndrome (ARDS) and/or died. Co-morbidity was defined as ≥1 of the following conditions: hypertension, diabetes, chronic cardiac disease, chronic kidney disease, asthma, chronic obstructive pulmonary disease (COPD), malignancy, HIV, and active or past is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted December 21, 2021. ; https://doi.org/10.1101/2021.12.21.21268116 doi: medRxiv preprint tuberculosis. The Delta variant was identified by genome sequencing. Re-infection was defined as an individual with at least one positive test >90 days prior to the current episode. Analysis was performed using Stata 14.1® (StataCorp LP, College Station, US). Categorical variables were summarised using frequency distributions and compared using Pearson's Chi-squared test. The mean Ct value (used as a proxy for viral load) for all public sector positive PCR tests (any PCR test) during the early Omicron wave period (weeks 46-48, 14 November -4 December 2021) was compared to the early Delta wave period (weeks 18-20, 2-22 May 2021) using the students t-test. The early wave periods were defined from the week before the country crossed a weekly incidence risk of 30 cases per 100,000 persons until two weeks later 9 . Where the PCR test included ≥1 gene target, the target with the lowest Ct value was used for the analysis. Severity of Omicron was assessed in two ways: (i) by comparing SGTF and non-SGTF infections diagnosed between 1 October to 30 November 2021, and (ii) by comparing Delta variant infections diagnosed during April through November 2021, to SGTF infections that were diagnosed during 1 October to 30 November 2021. Hospitalisation and severity data were obtained for cases on 21 December 2021 to allow at least three weeks follow up period for admission to hospital and inhospital outcome. Severity analyses were restricted to admissions that had already accumulated outcomes and all patients still in-hospital were excluded, because they were at risk of still developing severe outcomes or death. Among DATCOV cases hospitalised between 5 March 2020-18 December 2021, the median time from admission to in-hospital outcome was 6 days (interquartile range (IQR) 3-11 days, n=414,149); median of 5 days (IQR 2-11 days, n=94,938) for individuals that died and median of 6 days (IQR 3-10, n=304,845) for individuals that were discharged alive. Two models were generated to assess ( is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted December 21, 2021. ; https://doi.org/10.1101/2021.12.21.21268116 doi: medRxiv preprint to individuals with a known in-hospital outcome on 21 December 2021 (excluding cases still in hospital). We controlled for factors known to be associated with severity (age, presence of comorbidity, sex, province and healthcare sector) and adjusted for the number of days between the date of specimen collection and date of hospital admission, known prior SARS-CoV-2 infection and SARS-CoV-2 vaccination status. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint (Table 1 ). In addition to geographic factors, hospital admission was associated with young age (<5 years, aOR 9.3, 95% CI 5.2-16.8) and older age (≥60 years, aOR 3.1, 95% CI 1.9-5.0) compared to individuals aged 19-24 years and female sex (aOR 1.3, 95% CI 1.1-1.6), whereas individuals in the private healthcare sector were less likely to be admitted to hospital (aOR 0.8, 95% CI 0.6-1.0) compared to the public sector. Among hospitalised individuals diagnosed between 1 October -30 November 2021, 83.0% (317/382) had accumulated in-hospital outcome by 21 December. After controlling for factors associated with severe COVID-19 disease, the odds of severe disease did not differ between individuals with SGTF infection compared to non-SGTF infections (aOR 0.7, 95% CI 0.3-1.4) ( Table 2 ). The odds of severe disease varied geographically and was higher among individuals aged ≥60 years (aOR 11.5, 95% CI 2.8-47.0), compared to individuals aged 19-24 years. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted December 21, 2021. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted December 21, 2021. ; https://doi.org/10.1101/2021.12.21.21268116 doi: medRxiv preprint In November 2021, the Omicron variant emerged in South Africa, concurrent with a rapid increase in the number of reported COVID-19 cases 1 leading to the fourth epidemic wave. The identification of the new variant caused concern due to the large number of mutations present throughout the genome. In particular, mutations that are known to be associated with immune escape and increased infectivity were identified in the spike protein. While a number of studies are underway to rapidly assess phenotypic behaviour and immune escape, it is also critical to understand the clinical severity of infections caused by Omicron. We evaluated the severity of SGTF infections (as a proxy for the Omicron variant) by comparing to (i) non-SGTF infections during the same period of time, and (ii) Delta variant infections, which dominated the third wave. When compared to non-SGTF infections, we found that SGTF infections had an 80% lower odds being admitted to hospital, but did not differ in the risk of severe disease among hospitalised individuals. When compared to Delta infections, SGTF infections were associated with a 70% lower odds of severe disease. In addition, we found that early Omicron wave infections had a significantly lower mean PCR Ct-value compared to early Delta wave infections, which may reflect higher viral loads in Omicron infected individuals. Our findings correlate with DATCOV surveillance hospitalisation data showing that, among patients who had a known hospital outcome, 32% of COVID-19 admissions during the early fourth wave were severe compared to 65% during the early third wave 10 Incomplete vaccination data, and the fact that the majority of re-infections were likely not detected, resulted in incomplete adjustment for the effect of prior immunity in our analyses. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint This study has a number of limitations. Firstly, SGTF infections were only identifiable using the TaqPath PCR and only for specimens with high viral loads (Ct≤30) and therefore the number of SGTF infections is underestimated and biased towards geographic regions where this assay was more commonly used. Secondly, SGTF identified on PCR was used as a proxy for Omicron variant detection. However, SGTF may also identify the Alpha variant and occur sporadically in other variants and therefore some infections may have been misclassified as Omicron. However, we only used SGTF as a proxy for Omicron after 1 October 2021 and genome data generated by NGS-SA has not identified the Alpha variant in South Africa since August 2021 and at its peak Alpha variant was only detected in 6% of samples in May 2021 13 . In addition, Omicron has recently been classified into three sub-lineages, one (BA.2) of which does not contain the Δ69-70 deletion and which therefore will not be identifiable by the SGTF. Genome data from November 2021, showed that of 881 Omicron sequences, 872 (99.0%) were BA.1, 1 (0.1%) was BA.2 and 8 (0.9%) were BA.3 13 . Ongoing sequencing will enable definitive classification of the Omicron variant for future severity analyses. Thirdly, our analysis was conducted in the early phase of the fourth wave after the emergence of Omicron when numbers were small, patients with milder symptoms were more likely to be admitted, and there may be a lag in hospitalisations and severe outcomes caused by this new variant. We accounted for this by only including hospitalised patients with known outcomes, censoring cases to ensure at least three weeks of follow up, and adjusting for time interval between diagnosis and hospitalisation in the severity multivariable models. The inclusion of individuals only with accumulated in-hospital outcomes may have biased SGTF towards shorter hospital stay, hence this result should be interpreted with caution. Fourthly, we compared cases through the full Delta wave to cases in the ascending phase of the Omicron wave, this could bias comparisons if case characteristics differ in the ascending and descending wave phases. However, data from the DATCOV programme suggest that the proportion of severe cases does not vary substantially through the different wave phases 10 . Lastly, we had limited vaccination information only for hospitalised cases and that was based on self-report. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted December 21, 2021. ; https://doi.org/10.1101/2021.12.21.21268116 doi: medRxiv preprint population. These are early data and findings may change as the epidemic progresses, and with additional follow-up time for the more recently diagnosed SGTF-infected individuals. . CC-BY-NC-ND 4.0 International license It is made available under a perpetuity. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted December 21, 2021. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted December 21, 2021. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted December 21, 2021. ; Severe disease defined as a hospitalized patient meeting at least one of the following criteria: admitted to ICU, received oxygen treatment, ventilated, received extracorporeal membrane oxygenation (ECMO), experienced acute respiratory distress syndrome (ARDS) and/or died c Co-morbidity defined as ≥1 of the following conditions: hypertension, diabetes, chronic cardiac disease, chronic kidney disease, asthma, chronic obstructive pulmonary disease (COPD), malignancy, HIV, and active or past tuberculosis 0.790 a Cases followed-up for in-hospital outcome until 21 December 2021 b Severe disease defined as a hospitalized patient meeting at least one of the following criteria: admitted to ICU, received oxygen treatment, ventilated, received extracorporeal membrane oxygenation (ECMO), experienced acute respiratory distress syndrome (ARDS) and/or died c Co-morbidity defined as ≥1 of the following conditions: hypertension, diabetes, chronic cardiac disease, chronic kidney disease, asthma, chronic obstructive pulmonary disease (COPD), malignancy, HIV, and active or past tuberculosis Classification of Omicron (B.1.1.529): SARS-CoV-2 Variant of Concern The continuous evolution of SARS-CoV-2 in South Africa: a new lineage with rapid accumulation of mutations of concern and global detection Establishing a surveillance platform to assess the clinical impact of SARS-CoV-2 variants (DATCOV-Gen) in South Africa Track Omicron's spread with molecular data Severe influenza-associated respiratory infection in high HIV prevalence setting, South Africa Risk factors for COVID-19-related in-hospital mortality in a high HIV and tuberculosis prevalence setting in South Africa: a cohort study Investigation of novel SARS-CoV-2 variant. Variant of Concern 202012/01: Technical briefing 5 Proposed definition of COVID-19 wave in South Africa COVID-19 HOSPITAL SURVEILLANCE UPDATE COVID-19 modelling update: Considerations for a potential fourth wave SARS-CoV-2 Genomic Surveillance Update