key: cord-0757413-2u4jshrn authors: Hussey, Hannah; Davies, Mary-Ann; Heekes, Alexa; Williamson, Carolyn; Valley-Omar, Ziyaad; Hardie, Diana; Korsman, Stephen; Doolabh, Deelan; Preiser, Wolfgang; Maponga, Tongai; Iranzadeh, Arash; Wasserman, Sean; Boloko, Linda; Symons, Greg; Raubenheimer, Peter; Parker, Arifa; Schrueder, Neshaad; Solomon, Wesley; Rousseau, Petro; Wolter, Nicole; Jassat, Waasila; Cohen, Cheryl; Lessells, Richard; Wilkinson, Robert J; Boulle, Andrew; Hsiao, Nei-yuan title: Assessing the clinical severity of the Omicron variant in the Western Cape Province, South Africa, using the diagnostic PCR proxy marker of RdRp target delay to distinguish between Omicron and Delta infections – a survival analysis date: 2022-02-27 journal: Int J Infect Dis DOI: 10.1016/j.ijid.2022.02.051 sha: 254b2ee15d1b7e0fa935c89ee6993c98f7ad8762 doc_id: 757413 cord_uid: 2u4jshrn Background The extent to which the reduced risk of severe disease seen with SARS-CoV-2 Omicron is due to a decrease in variant virulence, or higher levels of population immunity, is currently not clear. Methods RdRp target delay (RTD) in the Seegene AllplexTM 2019-nCoV PCR assay is a proxy marker for the Delta variant. The absence of this proxy marker in the transition period was used to identify suspected Omicron infections. Cox regression was performed for the outcome of hospital admission in those who tested positive for SARS-CoV-2 on the Seegene AllplexTM assay from 1 November to 14 December 2021 in the Western Cape Province, South Africa, public sector. Vaccination status and prior diagnosed infection, were adjusted for. Results 150 cases with RTD and 1486 cases without RTD were included. Cases without RTD had a lower hazard of admission (adjusted Hazard Ratio [aHR] of 0.56, 95%CI 0.34-0.91). Complete vaccination was protective of admission with an aHR of 0.45 (95%CI 0.26-0.77). Conclusion Omicron has resulted in a lower risk of hospital admission, compared to contemporaneous Delta infection, when using the proxy marker of RTD. Under-ascertainment of reinfections with an immune escape variant remains a challenge to accurately assessing variant virulence. 1. Lower risk of admission with Omicron compared to contemporaneous Delta cases 2. Analysis adjusted for vaccination status and prior diagnosed infection 3. Compares contemporaneous cases, which is more robust than other South African studies 4. Only the second study from a LMIC to assess Omicron with contemporaneous cases 5. Shows ongoing utility of novel proxy marker (RdRp target delay on SeegeneAllplex assay) Abstract Background The extent to which the reduced risk of severe disease seen with SARS-CoV-2 Omicron is due to adecrease in variant virulence, or higher levels of population immunity, is currently not clear. 4 Methods RdRp target delay (RTD) in the SeegeneAllplex TM 2019-nCoV PCR assay is a proxy marker for the Delta variant . The absence of this proxy marker in the transition period was used to identify suspected Omicron infections. Cox regression was performed for the outcome of hospital admission in those who tested positive for SARS-CoV-2 on the SeegeneAllplex TM Omicron has resulted in alower risk of hospital admission, compared to contemporaneous Delta infection, when using the proxy marker of RTD. Under-ascertainment of reinfections with an immune escape variant remains a challenge to accurately assessing variant virulence. With the rapid global spread of the Omicron (B.1.1.529) SARS-CoV-2 variant of concern (VOC), understanding the clinical implications of this new VOC is critical (Viana et al., 2022) . Emerging data from both South Africa and the United Kingdom suggest that it is associated with a reduced risk of severe disease (Abdullah et al., 2021; Ferguson et al., n.d.; Jassat et al., 2021; Maslo et al., 2021; Sheikh et al., 2021; Wolter et al., 2021) . The extent to which this reflects a difference in the inherent virulence of Omicron, or just higher levels of population immunity, due to previous infection and/or vaccination, is currently not clear. In November 2021 in the Western Cape Province, South Africa, following a period of very low incidence, Omicron rapidly replaced Delta (B.1.617 .2) as the dominant variant and drove the fourth wave of infections. Omicron is known to result in S-gene target failure (SGTF) on the Thermo Fisher Taqpath TM PCR assay (Scott et al., 2021) . Unfortunately, too little routine diagnostic testing is done using this assay in the Western Cape National Health Laboratory Service(NHLS) to power an SGTF analysis. RdRp target delay (RTD) is a proxy marker for the Delta varianton routine diagnostic testing with the SeegeneAllplex TM 2019-nCoV PCR assay, similar in concept to S-gene target failure. RTDhas a 93.6% sensitivity and 89.7% specificity in detecting the Delta variant when compared to genomic sequencing (Valley-Omar et al., 2022) . This proxy marker has previously successfully been used to assess the association of the Delta variant and mortality in the third wave (Hussey et al., 2021) . 6 As the SeegeneAllplex TM assayis widely usedby the Western CapeNHLS, and as Omicron rapidly displaced the Delta variantwith minimal other variants detected, the absence of RTD in SeegeneAllplex TM cases can be used to identify likely Omicron infections during the replacement period. The absence of RTD tracks well with SGTF in the province (Figure 1 ), as well as genomic sequenced data (Network for Genomic Surveillance in South Africa (NGS-SA), 2021; Viana et al., 2022) . We used this proxy marker to assess the clinical severity associated with Omicron infection. RTD is defined as a difference in cycle threshold value of RdRpgene target -E gene target> 3.5 in the SeegeneAllplex TM 2019-nCoV PCR assay (Valley-Omar et al., 2022) . Cases diagnosed using this assay have previously been found to be representative of cases diagnosed by any PCR assay in the Western Cape Province public sector (Hussey et al., 2021) . We included all COVID-19 cases, aged 15 years and older, diagnosed on the SeegeneAllplex TM 2019-nCoV diagnostic PCR assay in the Western Cape Province public sector from 1 November to 14 December 2021, a period when both Delta and Omicron were co-circulating and other lineages were negligible(Network for Genomic Surveillance in South Africa (NGS-SA), 2021; Viana et al., 2022) . Follow-up ended 6 January 2022.Children were excluded from this analysis as their testing and admission patterns are different compared to adults. admissions. If an individual tested positive for SARS-CoV-2 14 days before admission, or 7 days after the date of admission, and was not admitted to a specialized psychiatric and rehabilitation facilities, it was defined as COVID-19 related hospital admission. We undertook a survival analysis using Cox regression, assessing time from date of diagnosis to date of hospital admission, which was our outcome of interest.Those whose date of admission was on or before the date of diagnosis were assigned one day of follow-up. Intensive Care Unit (ICU) admission or mortality were not assessed as too few of these severe outcomes had occurred. We adjusted for age, sex, known comorbidities, prior diagnosed infection (two positive COVID-19 tests more than 90 days apart) and vaccination status at time of diagnosis. Analyses were conducted using Stata 13.1. Results 1 636 cases were tested on the SeegeneAllplex TM assay during the study period and were included in this analysis, representing 14% of all cases diagnosed and 24% of all cases diagnosed by PCR testing in the public sector at that time. 150 cases were with RTD (proxy for Delta) and 8 1486 cases were without RTD (proxy for Omicron/non-Delta).Patient demographic characteristics and comorbidities were similar in both groups (Table 1 ). The median age in both groups was 33 years (IQR 25-44 in those with RTD; IQR 26-44 in those without). The proportion of cases that were fully vaccinated in both groups was also similar, although more infections following partial vaccination were seen in those without RTD. The proportion of cases with a documented reinfection was 11% for both those with and without RTD. By using a stricter definition of RTD (i.e., requiring a larger difference in Ct values), a similar proportion of RTD cases that had documented reinfectionswere found (Supplementary Complete vaccination was protective of admission with an aHR of 0.45 (95%CI 0.26-0.77). The proportional hazards assumption was tested and found to have held for each variable and the model as a whole (see Supplementary Table 2) . 9 Using the proxy marker of RTD absence, suspected Omicron cases were associated with a lower risk of hospital admission when compared to contemporaneous suspected Delta cases. A study from the South African National Institute of Communicable Diseases found that using SGTF suspected Omicron cases had a lower odds of being admitted to hospital compared to non-SGTF infections (adjusted odds ratio [aOR] 0.2, 95%CI 0.1-0.3) (Wolter et al., 2021) . However, this analysis was not able to adjust for vaccination status at time of diagnosis, potentially explaining the greater reduction in observed disease severity compared to our study. Similar contemporaneous SGTF studies from the UK have also found that SGTF was associated with a lower risk of hospitalisation, with an adjusted observed/expected ratio of 0.32 (95% CI 0.19, 0.52) (Sheikh et al., 2021 ) and a 40-45% reduction in risk of admission, which is similar to our result (Ferguson et al., n.d.) . Several studies have also found less severe disease in thefourth Omicron-driven wave compared to the third wave caused by Delta in South Africa (Abdullah et al., 2021; Jassat et al., 2021; Maslo et al., 2021) , but as they are comparing non-contemporaneous cases it is difficult to account for the effect of the vaccination programme, which started too late to provide significant protection for the third wave (Mathieu et al., 2021) , as well as the fact that more individuals were previously infected, and thus had some immunity at the start of the fourth wave compared to the third. 10 Anecdotally, this fourth wave has resulted in a relatively large proportion of admissions where COVID-19 was incidentally diagnosed (Abdullah et al., 2021) . It is unfortunately not possible to tease out the primary indication for admission from our routine data and we were unable to assess severe outcomes due to the very small numbers of cases tested on the SeegeneAllplex TM assay who were recorded as having steroids prescribed electronically, being admitted to ICU or dying. The fact that full vaccination still provided substantial protection against admission, even with the contamination of incidental admissions, suggests that vaccination provides very strong protection against admission in the face of the Omicron variant, and that some of the admissions were likely due to COVID-19 disease. Vaccination itself might also be a proxy marker for higher socio-economic status, access to health care or good health seeking behaviour, such as adherence to chronic medications, and as such might confer some protection against hospital admissions, irrespective of COVID-19. Omicron is associated with an increased risk of reinfections (Pulliam et al., 2021) .Previous infection initself is protective against severe disease (Milne et al., 2021) . In this analysis, no cases with a documented reinfection required hospital admission. But seroprevalence studies indicate only a small fraction of total COVID-19 cases in the Western Cape Province are laboratory confirmed (Hsiao et al., 2020) , particularly when there have been testing restrictions during epidemic surges. Under-ascertainment of prior diagnosed infection is therefore likely, and this could considerably bias measures of disease severity for an immune escape variant 11 compared to a variant that is not associated with reinfection. The extent of this residual confounding i.e., the contribution of this under-ascertainment of reinfections to the milder disease severity seen with Omicron, is thus still uncertain in our context of very high rates of unconfirmed prior infection. At the same time, if we are diagnosing a smaller proportion of Omicron cases by missing the more mild or asymptomatic infections, or if the Omicron variant results in more incidental hospital admissions and outcome misclassification, this could bias our findings in the opposite direction, and falsely elevate the disease severity seen with this variant. An additional limitation to this study isthe low numbers of SARS-CoV-2 infections during the Delta to Omicron transition period, particularly in the public sector, where this analysis was restricted to, as well as the increasing use of SARS-CoV-2 rapid antigen tests (42% of cases in the study period were diagnosed using rapid antigen tests)from which the variant proxy markers cannot be calculated.We also useda proxy marker for Omicron and not whole genome sequencing, as only limited sequencing is feasible in our setting. A proxy marker on routine diagnostic testing is likely to result in some variant misclassification, which is evidenced by the high rate of reinfections seen in RTD cases. Attempts to narrow the definition of RTD were not able to resolve this. In addition, this analysis like many others, only compares disease severity between Omicron and Delta. Little is known of the severity of Omicron when compared to the ancestral strain and other non-Delta VOCs. Omicron has resulted in a lower risk of hospital admission, when compared to contemporaneous Delta cases using the proxy marker of RTD in the Western Cape Province. Vaccination and documented previous infection are highly protective of hospital admission. Under-ascertainment of reinfections with an immune escape variant like Omicron remains a challenge to accurately assessing variant virulence. Decreased severity of disease during the first global omicron variant covid-19 outbreak in a large hospital in tshwane, south africa Report 50 -Hospitalisation risk for Omicron cases in SARS-CoV-2 seroprevalence in the Cape Town metropolitan sub-districts after the peak of infections Higher mortality associated with the SARS-CoV-2 Delta variant in the Western Cape, South Africa, using RdRp target delay as a proxy Clinical severity of COVID-19 patients admitted to hospitals in Gauteng, South Africa during the Omicron-dominant fourth wave Characteristics and Outcomes of Hospitalized Patients in South Africa During the COVID-19 Omicron Wave Compared With 16 Previous Waves. JAMA 2021 A global database of COVID-19 vaccinations Does infection with or vaccination against SARS-CoV-2 lead to lasting immunity? Network for Genomic Surveillance in South Africa (NGS-SA). SARS-CoV-2 Sequencing Update -24 Increased risk of SARS-CoV-2 reinfection associated with emergence of the Omicron variant in South Africa Track Omicron's spread with molecular data Severity of Omicron variant of concern and vaccine effectiveness against symptomatic disease: national cohort with nested test negative design study in Scotland CoV-2 variant using routine diagnostic tests Rapid epidemic expansion of the SARS-CoV-2 Omicron variant in southern Africa Early assessment of the clinical severity of the SARS-CoV-2 Omicron variant in South Africa Thermo Fisher Taqpath TM cases and non-RdRp target delay in SeegeneAllplex TM assay cases, in the Western Cape Province public sector adults We would like to acknowledge all patients in the Western Cape and to thank the Western Cape Using the original definition of RTD (>3.5), 16 RTD cases with reinfections (10.67%) were included in the main analysis. The proportion of RTD cases that were reinfections was 2.6, 2.1 and 0.8% in the months of August, September and October 2021 respectively.By narrowing the definition of RTD to require a larger difference in Ct values, less "Delta" cases were classified as such, but the aHRfor suspected Omicron cases and admission remained similar, although the confidence intervals did widen.The stricter definition of RTD, however, was not able decrease the proportion of cases with reinfection. In November, when Delta was still dominant, there were very low case numbers. After Omicron arrived, there was a massive increase in case numbers. A small proportion of misclassification of these higher numbers of Omicron cases is therefore able to markedly change the proportion of reinfection seen in the RTD cases..