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. 2022 Aug 31;6:117. [Version 1] doi: 10.12688/gatesopenres.13654.1

Higher mortality associated with the SARS-CoV-2 Delta variant in the Western Cape, South Africa, using RdRp target delay as a proxy: a cross-sectional study.

Hannah Hussey 1,2,a, Mary-Ann Davies 1,3, Alexa Heekes 1,2, Carolyn Williamson 4,5,6, Ziyaad Valley-Omar 4,6, Diana Hardie 4,6, Stephen Korsman 4,6, Deelan Doolabh 4,6, Wofgang Preiser 6,7, Tongai Maponga 6,7, Arash Iranzadeh 4,6, Susan Engelbrecht 6, Sean Wasserman 5,8, Neshaad Schrueder 9, Linda Boloko 5,10, Greg Symons 10, Peter Raubenheimer 10, Abraham Viljoen 9, Arifa Parker 9, Cheryl Cohen 11,12, Waasila Jasat 11, Richard Lessells 13, Robert J Wilkinson 5,14,15, Andrew Boulle 1,3, Marvin Hsiao 4,5,6
PMCID: PMC10663174  PMID: 37994361

Abstract

Background: The SARS-CoV-2 Delta variant (B.1.617.2) has been associated with more severe disease, particularly when compared to the Alpha variant. Most of this data, however, is from high income countries and less is understood about the variant’s disease severity in other settings, particularly in an African context, and when compared to the Beta variant.

Methods: A novel proxy marker, RNA-dependent RNA polymerase (RdRp) target delay in the Seegene Allplex TM 2019-nCoV (polymerase chain reaction) PCR assay, was used to identify suspected Delta variant infection in routine laboratory data. All cases diagnosed on this assay in the public sector in the Western Cape, South Africa, from 1 April to 31 July 2021, were included in the dataset provided by the Western Cape Provincial Health Data Centre (PHDC). The PHDC collates information on all COVID-19 related laboratory tests, hospital admissions and deaths for the province. Odds ratios for the association between the proxy marker and death were calculated, adjusted for prior diagnosed infection and vaccination status.

Results: A total of 11,355 cases with 700 deaths were included in this study. RdRp target delay (suspected Delta variant) was associated with higher mortality (adjusted odds ratio [aOR] 1.45; 95% confidence interval [CI]: 1.13-1.86), compared to presumptive Beta infection. Prior diagnosed infection during the previous COVID-19 wave, which was driven by the Beta variant, was protective (aOR 0.32; 95%CI: 0.11-0.92) as was vaccination (aOR [95%CI] 0.15 [0.03-0.62] for complete vaccination [≥28 days post a single dose of Ad26.COV2.S or ≥14 days post second BNT162b2 dose]).

Conclusion: RdRp target delay, a proxy for infection with the Delta variant, is associated with an increased risk of mortality amongst those who were tested for COVID-19 in our setting.

Keywords: SARS-CoV-2, Delta, B.1.617.2, clinical severity, RdRp target delay, South Africa

Introduction

To date, the Western Cape Province of South Africa, has experienced four large waves of SARS-CoV-2 infections. The first wave caused by early ancestral clades of SARS-CoV-2 peaked in June 2020, the second wave with the Beta variant (B.1.351) peaked in December 2020, the third wave caused by the Delta variant (B.1.617.2) peaked in August 2021 and the fourth most recent wave was caused by the Omicron variant peaked in December 2021 1 .

Prior to the arrival of Omicron, Delta had been the dominant variant globally, its increased clinical severity particularly when compared to Alpha is well documented 26 . Most of the severe disease in these studies occurred in those who were unvaccinated. The concern is that in these settings with well-established vaccination programmes, there are differences between the vaccinated and unvaccinated population, largely driven by socioeconomic disparities 7 , that might contribute to the clinical severity seen and confound the association between variant and disease severity. In addition, there is only limited data on Delta disease severity within a sub-Saharan African setting.

The start of the third wave of COVID-19 in the Western Cape Province was characterized by a rapid transition from the previously dominant Beta variant to Delta 8 . Using a novel proxy marker for Delta, namely RNA-dependent RNA polymerase (RdRp) target delay (RTD) in (polymerase chain reaction) PCR positive samples, our objective was to assess mortality associated with Delta, compared to Beta, in our population which had relatively low levels of vaccine coverage as well as a high prevalence of comorbidities, including HIV and tuberculosis.

Methods

RdRP target delay

RTD, defined as a difference in cycle threshold (Ct) value of >3.5 in the RdRp relative to E gene target in the Seegene Allplex TM 2019-nCoV PCR assay (Seegene Inc, USA), has recently been described 9 . This phenomenon is due to the G15451A mutation found in Delta, resulting in a RdRp primer mismatch 9 . When evaluated against genomic data, this method had a sensitivity of 93.6% and specificity of 89.7% in detecting Delta 9 . RTD has been used to assess variant disease severity in our setting during the fourth wave 10 .

Population and statistical analysis

We included all COVID-19 cases diagnosed on the Seegene Allplex TM 2019-nCoV diagnostic PCR assay in the Western Cape public sector from 1 April to 31 July 2021, a period when both Beta and Delta were co-circulating ( Appendix Figure 1) All available cases were included without sampling. Alpha and non-variant of concern lineages accounted for a negligible number of infections at this time 8 . Follow-up ended on 31 August 2021, at which point most of the expected COVID-19 related outcomes would have occurred. Approximately 70% of the Western Cape population uses the public sector for health services and the Western Cape Provincial Health Data Centre (PHDC) collates all available electronic health data on these patients 11 . The PHDC combines laboratory data on COVID-19 tests with hospital admission and death data, as well as information on known comorbidities and where available, vaccination status. Use of de-identified linked data provided by the PHDC in COVID-19 analyses has been previously described 12 . COVID-19 deaths were defined analytically as deaths within 28 days of diagnosis of COVID-19 or 14 days after discharge from hospital (where hospital admission occurred within 21 days of the COVID-19 diagnosis), without a non-COVID-19 cause of death recorded by the health facility or COVID-19 case managers. Out-of-facility deaths were determined by civil identifier linkage of patients with COVID-19 diagnoses to the national population register.

Figure 1.

Figure 1.

Weekly frequency and distribution of SARS-CoV-2 variants circulating in the Western Cape Province, South Africa, 1 January to 31 August 2021: a) absolute count of genomes sequenced, b) proportion of genomes sequenced 9 .

We undertook logistic regression using Stata 13.1 (Stata corp, 2013) (RRID:SCR_012763) to determine the association between RTD and mortality, adjusted for age, sex, known comorbidities, prior diagnosed infection, vaccination status at time of diagnosis, sub-district of residence, month of diagnosis and hospital admission pressure (number of public sector admissions in the calendar week of diagnosis, categorized into four [weekly admission of ≤350, ≤700, ≤1000 and >1000]). All variables were included as binary or categorical variables. Prior diagnosed infections were defined as a positive COVID-19 test more than 90 days prior to the current test and classified into those with their first infection in the first wave (1 March – 30 September 2020) or second wave (1 October 2020 – 31 March 2021). Vaccination status at time of COVID-19 diagnosis was determined by the PHDC prior to de-identification by linking COVID-19 cases with the national Electronic Vaccination Data System (EVDS) through national civil identifiers in both the PHDC and EVDS databases. EVDS, a national clinical data system that is not publicly accessible, is one of the data sources integrated into the PHDC 11 . For the purposes of this study, we defined complete vaccination analytically as ≥28 days post-vaccination with Janssen/Johnson & Johnson (Ad26.COV2.S), or ≥14 days post second dose of Pfizer–BioNTech (BNT162b2). Patients were deemed partially vaccinated from the day after their (first) vaccine dose until meeting criteria for complete vaccination.

A secondary analysis was done, using the same methodology as above, but stratifying the cases into those aged less than 50 years and those aged 50 years and above.

Ethical approval

The study was approved by the University of Cape Town Research Ethics Committee (HREC 460/2020).

Results

We included 11,355 cases tested using the Seegene Allplex TM assay, which were 22% of all positive test results in the province in that time period ( Appendix Table 1). The median age was 43 years (interquartile range [IQR] 32-55) and 44% were male. RTD was present in 9106 (80%) of the cases included ( Table 1). Patient characteristics were similar in those with and without RTD. There was, however, a difference in Ct values (average of the E and N gene targets); those with RTD had lower median Ct values (26.1, IQR 22.2-30.9, vs 32.7 IQR 25.6-37.6).

Table 1. Characteristics of all COVID-19 cases (Seegene Allplex TM 2019-nCoV assay positive) in the Western Cape, April – July 2021, by presence of RNA-dependent RNA polymerase (RdRP) target delay (RTD).

All cases
(n=11,355;
700 deaths)
RdRP Target
Delay (n=9,106;
570 deaths)
No RdRP Target
(n=2,249;
130 deaths)
n % n % n %
RTD Absent 2249 19.8
Present 9106 80.2
Sex Female 6411 56.5 5143 56.5 1268 56.4
Male 4944 43.5 3963 43.5 981 43.6
Age category 20–29 years 2243 19.8 1810 19.9 433 19.3
30–39 years 2623 23.1 2149 23.6 474 21.1
40–49 years 2427 21.4 1956 21.5 471 20.9
50–59 years 2113 18.6 1701 18.7 412 18.3
60–69 years 1177 10.4 899 9.9 278 12.4
≥70 years 772 6.8 591 6.5 181 8.1
Comorbidities HIV positive 726 6.4 560 6.2 166 7.4
Diabetes 1546 13.6 1218 13.4 328 14.6
Current tuberculosis 94 0.8 66 0.7 28 1.2
Hypertension 2475 21.8 1963 21.6 512 22.8
Chronic Kidney Disease 374 3.3 299 3.3 75 3.3
Chronic Obstructive Pulmonary
Disease
876 7.7 685 7.5 191 8.5
Prior diagnosed
infection
None 11107 97.8 8914 97.9 2193 97.5
First infection in first wave 64 0.6 46 0.5 18 0.8
Second infection in second wave 184 1.6 146 1.6 38 1.7
Vaccination status at
time of diagnosis
Unvaccinated 10422 91.8 8358 91.8 2064 91.8
Partially vaccinated 694 6.1 544 6.0 150 6.7
Completely vaccinated 239 2.1 204 2.2 35 1.6

¶ Fully vaccinated was defined as ≥28 days post-vaccination with Janssen/Johnson & Johnson or ≥14 days post second dose of Pfizer–BioNTech. Patients were deemed partially vaccinated from the day after their (first) vaccine dose until meeting criteria for complete vaccination.

Amongst the Seegene Allplex TM cases in our study, there were 700 deaths meeting the above definition for COVID-19-associatedness, with a case fatality rate of 6.3% in those with RTD, compared to 5.8% in those without. After adjusting for all covariates, we found that RTD was associated with death among cases (aOR 1.45 [95% CI 1.13-1.86]) and among those admitted to hospital (aOR 1.39 [95% CI 1.03-1.88]) ( Table 2).

Prior diagnosed infection with a first infection in the Beta dominated second wave (vs no prior diagnosed infection), was protective against death (aOR 0.32 [95% CI 0.11-0.92]), whereas prior diagnosed infection with a first infection in the first wave was not (aOR: 1.56 [95% CI 0.50-4.92]). Vaccination was protective against death. The aORs (95% CI) for partial and full vaccination were 0.59 (0.45-0.77) and 0.15 (0.03-0.62) respectively.

Table 2. Logistic regression for outcome of death in a) all positive Seegene Allplex TM cases; b) restricted to those admitted to hospital only; c) stratified by age into those aged under 50 and over 50 years.

Adjusted § OR (95%CI) for outcome of death
All cases
(n=11,355; 700
deaths)
Only admitted
cases *
(n=1856; 612
deaths)
All cases < 50 years
(n=7293; 113 deaths)
All cases ≥ 50
years
(n=4062; 587
deaths)
RTD absent Ref Ref Ref Ref
present 1.45 (1.13-1.86) 1.39 (1.03-1.88) 1.32 (0.77-2.26) 1.44 (1.09-1.91)
Sex female Ref Ref Ref Ref
male 1.50 (1.25-1.80) 1.19 (0.95-1.47) 1.16 (0.78-1.72) 1.63 (1.33-2.00)
Age category 20–29 years Ref Ref Ref
30–39 years 2.75 (1.19-6.31) 2.19 (0.81-5.93) 2.49 (1.07-5.78)
40–49 years 6.89 (3.15-15.05) 5.91 (2.27-15.54) 6.48 (2.92-14.37)
50–59 years 11.49 (5.31 - 24.88) 6.86 (2.66-17.67) Ref
60–69 years 24.64 (11.36-53.42) 11.75 (4.56-30.28) 2.16 (1.68-2.79)
≥70 years 72.81 (33.54-158.06) 25.93 (10.03-67.01) 6.43 (4.96-8.33)
Comorbidities HIV positive 1.66 (1.11-2.47) 1.14 (0.69-1.88) 2.21 (1.27-3.85) 0.99 (0.53-1.85)
Diabetes 2.60 (2.14-3.16) 1.19 (0.95-1.49) 2.58 (1.55-4.32) 2.61 (2.11-3.22)
Current tuberculosis 3.62 (1.76-7.42) 1.57 (0.68-3.61) 4.90 (1.90-12.65) 2.38 (0.78-7.20)
Hypertension 1.13 (0.93-1.38) 0.95 (0.76-1.20) 1.07 (0.63-1.82) 1.16 (0.93-1.43)
Chronic Kidney Disease 2.17 (1.65-2.86) 1.76 (1.29-2.42) 9.33 (4.20-20.72) 1.87 (1.41-2.50)
Chronic Obstructive
Pulmonary Disease
1.27 (1.00-1.62) 0.91 (0.69-1.19) 1.95 (1.08-3.53) 1.17 (0.90-1.52)
Prior diagnosed
infection
None Ref Ref Ref Ref
First infection in first
wave
1.56 (0.50-4.92) 2.63 (0.51-13.64) 1.11 (0.14-78.87) 2.12 (0.49-9.17)
First infection in
second wave
0.32 (0.11-0.92) 0.34 (0.10-1.09) 0.68 (0.15-3.19) 0.14 (0.03-0.67)
Vaccination status at
time of diagnosis
Unvaccinated Ref Ref Ref Ref
Partially vaccinated 0.59 (0.45-0.77) 0.79 (0.57-1.09) 1.47 (0.32-6.66) 0.57 (0.44-0.75)
Completely vaccinated 0.15 (0.03-0.62) 0.14 (0.02-1.20) (omitted) 0.22 (0.05-0.96)

§ Adjusted for all variables in the model, as well as month of diagnosis, sub-district of residence and number of COVID-19 admissions in week of diagnosis.

* Date of hospital admission within 21 days of COVID-19 date of diagnosis.

† The reference group here is the absence of that specific comorbidity.

¶ Fully vaccinated was defined as ≥28 days post-vaccination with Janssen/Johnson & Johnson or ≥14 days post second dose of Pfizer–BioNTech. Patients were deemed partially vaccinated from the day after their (first) vaccine dose until meeting criteria for complete vaccination.

In a stratified analysis the association between RTD and death was similar in both those aged <50 and ≥50 years (aOR [95%CI] of 1.32 [0.77-2.26] and 1.44 [1.09-1.91] respectively).

Discussion

RTD, a proxy marker for the Delta variant, was associated with an increased risk for death compared to presumptive Beta variant infection, while prior diagnosed infection (with first infection in the second wave) and vaccination were strongly protective. These findings are corroborated by a recent study from the Western Cape, which is the only other study to assess mortality with the Delta variant to compared to Beta. In that analysis, the wave itself was used as a proxy for variant, and the third wave (“Delta”: 26 May - 23 June 2021) had a higher aOR for mortality when compared to the second wave (“Beta”: 25 October - 21 November 2020) of 1.79 (95%CI 1.41-2.27) 13 , which is slightly higher than this analysis. Although the confidence intervals do overlap, the possible difference might be explained by the inclusion of cases after testing restrictions were in place in this analysis.

The increased transmissibility of Delta is well established, and may be due to its higher viral load 6 . In our analysis, specimens with RTD had lower Ct values than those without, suggesting a higher viral load. This, along with immune evasion by Delta, could contribute to the increased disease severity seen 14 . Nonetheless, our results need to be interpreted in the context of our setting where not all COVID-19 cases would have accessed testing. Delta often results in mild symptoms and during wave surges, as was the case from 15 June 2021 until the end of the analysis period, in the public sector only those aged ≥45 years or with comorbidities or requiring hospital admission would be eligible for all SARS-CoV-2 testing 15 . The interpretation of our results is therefore, that among those who access a PCR test, the Delta variant is associated with worse outcomes. While it is unclear if this finding can be extrapolated to all those with COVID-19 in our setting, similar findings from countries with more widespread testing support the increased clinical severity of Delta 26 .

Hospital admission was more likely with Delta compared to Alpha in England (aHR 2.26 [95%CI 1.32-3.89]) 2 and Denmark (RR 2.83 [95%CI 2.02-3.98]) 3 . In Singapore, infection with Delta and Beta vs. wild-type SARS-CoV-2 were both associated with a composite outcome of oxygen use, intensive care admission and death (aOR 4.9 [95%CI 1.43-30.78] and 1.69 [95%CI 0.19-14.69] respectively) 4 . Similarly, a recent study from Qatar found that Delta compared to Beta had an aOR of 3.61 (1.65-7.91) for severe-critical disease, which was defined as intensive care unit admission, use of high-flow oxygen, mechanical ventilation, or death 16 . Delta (vs wild-type) was associated with mortality in Canada (aOR 2.32 [95% CI 1.47-3.30]) as were N501Y-positive variants (Alpha, Beta, Gamma) (aOR 1.51 [95%CI 1.30-1.74]) 5 .

However, most of these countries had relatively high COVID-19 vaccination coverage rates by the time the Delta variant became dominant there 17 . Since most severe COVID-19 cases would be in unvaccinated people, differences between the vaccinated and the unvaccinated population might confound associations with variant infection and disease severity. By contrast in the Western Cape by 31 July 2021, only 5.0% of all adults, mostly in older age groups, were fully vaccinated 17 . In addition, most of these studies compared the outcomes of Delta to Alpha. The Alpha variant has been shown to have worse clinical outcomes compared to wild-type, with an aHR for death of 1.73 (95%CI 1.41 - 2.13) 18 .

Despite Delta no longer being the dominant variant, it continues to circulate globally and understanding and quantifying the disease severity associated with it and its spectrum of mutations remains critical. A Delta resurgence cannot be excluded, particularly with the recent emergence of the Omicron-Delta recombinant strain (BA.1 x AY.4) that the World Health Organisation has declared to be a variant under monitoring 19 . In addition, disease severity of dominant circulating variants is often calculated relative to the previously dominant variants 20 . The Omicron variant, for instance, has been found to cause less disease than the Delta variant, but this has to be understood in the context of the Delta variant already being associated with more severe disease compared to Alpha or Beta, hence quantifying the clinical severity of different variants is important for such comparisons 10, 13 .

This study has several limitations. First, we could only include cases tested on the Seegene Allplex TM 2019-nCoV assay, excluding cases diagnosed by other PCR methods or antigen testing. However, the included cases are mostly representative of all diagnosed PCR cases in the Western Cape ( Appendix Table 1). Patients tested on this assay were similar in age, sex, known comorbidities, prior diagnosed infection and vaccination status to those who tested positive using other PCR assays. As different laboratories service different geographical regions there was a difference, however, in the district of residence. Patients who tested positive on antigen tests tended to be younger, have fewer comorbidities and fewer were admitted to hospital. This is in accordance with the Western Cape’s testing guidelines where PCR was preferred for hospital patients, while antigen testing was promoted at primary health care facilities 15 .

Second, while RTD is a reliable proxy marker for Delta, it is not as accurate as whole genome sequencing, and misclassification may have diluted the effect of Delta. Third, we could only assess the effect of prior laboratory-confirmed COVID-19 infection and seroprevalence studies suggest considerably higher numbers were infected, even after the first wave, and that prior infection prevalence differed by sub-district of residence 21 . While we did adjust for sub-district, the absence of a protective effect of prior infection in the first wave may be due to insufficient numbers of those infections being diagnosed. Fourth, the inclusion of cases after testing restrictions were introduced is likely to result in an underestimate of Delta disease severity. However, in the stratified analysis, those younger than 50 years, who would be more likely to be affected by the testing restrictions, still had a similar findings to those >50 years. Fifth, although we adjusted for COVID-19 hospital admissions to account for escalating service pressure during the wave surge, we could not adjust for non-COVID-19 admissions that might have added to pressure on facilities and contributed to mortality.

And finally, there are innate limitations in using observational data from surveillance and routine health records to assess variant disease severity, particularly as potential biases around testing patterns cannot always be fully adjusted for 20.

Conclusion

In this study we found that RTD, a useful proxy for infection with the Delta variant, is associated with an increased risk of mortality amongst those who were tested for COVID-19 in our setting. This suggests that the Delta variant is associated with an increased risk of mortality when compared with other variants, and the Beta variant in particular.

Data availability

The Western Cape Provincial Health Data Centre collates all available electronic health data on public sector patients in the province for operational service use. The underlying data in this study are routinely collected patient records that have been de-identified and pseudo-anonymised in accordance with research ethics requirements. The patients have not consented to these data being part of publicly accessible repositories considering the inherent risks of re-identification. The Western Cape Department of Health and Wellness evaluates research proposals for all research in the public health sector in the province, subject to standard research ethics, government approval and data governance prescripts. This includes those that draw on routine datasets like the current study. For more information on conducting research in health services or on data managed by the Western Cape Government Department of Health and Wellness (WCGHW), please email health.research@westerncape.gov.za.

Funding Statement

This study was funded by the Grand Challenges ICODA pilot initiative delivered by Health Data Research UK and funded by the Bill & Melinda Gates and the Minderoo Foundations (INV-017293), and by a research Flagship grant from the South African Medical Research Council. Additional support was provided by the Francis Crick Institute which receives its core funding from Cancer Research UK (FC0010218), the UK Medical Research Council (FC0010218), and the Wellcome Trust (FC0010218) as well as Wellcome (203135, 222574).

The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

[version 1; peer review: 2 approved]

Appendix

Table 1. All positive SARS-CoV-2 tests in the Western Cape public sector, April to July 2021.

Total positive tests
(n=50,768)
Seegene AllplexTM PCR
(n=11,355; 22.4%)
Other PCR tests
(n=25,042; 49.3%)
Antigen tests
(n=14,371; 28%)
n % n % n %
Month of diagnosis April 165 1.5 900 3.6 106 0.7
May 302 2.7 1260 5.0 637 4.4
June 2161 19.0 5223 20.9 2836 19.7
July 8727 76.9 17659 70.5 10792 75.1
District of residence Cape Winelands 508 4.5 2449 9.8 3125 21.8
Central Karoo 246 2.2 431 1.7 302 2.1
City of Cape Town 4975 43.8 12039 48.1 8954 62.3
Garden Route 4642 40.9 4063 16.2 961 6.7
Overberg 426 3.8 2448 9.8 522 3.6
West Coast 557 4.9 3503 14.0 486 3.4
Unallocated 1 0.0 109 0.4 21 0.2
Sex Male 4944 43.5 10602 42.3 6427 44.7
Age category 20–29 years 2243 19.8 4805 19.2 2711 18.9
30–39 years 2623 23.1 5497 22.0 3410 23.7
40–49 years 2427 21.4 5200 20.8 3025 21.1
50-59 years 2113 18.6 5104 20.4 3187 22.2
60–69 years 1177 10.4 2660 10.6 1241 8.6
≥70 years 772 6.8 1776 7.1 797 5.6
Comorbidities HIV positive 726 6.4 1586 6.3 405 2.8
Diabetes 1546 13.6 3433 13.7 1488 10.4
Current tuberculosis 94 0.8 284 1.1 60 0.4
Hypertension 2475 21.8 5357 21.4 2272 15.8
Chronic Kidney Disease 374 3.3 702 2.8 270 1.9
Chronic Obstructive Pulmonary Disease 876 7.7 2115 8.5 878 6.1
Prior diagnosed infection None 11107 97.8 24339 97.2 14245 99.1
First infection in first wave 64 0.6 202 0.8 43 0.3
First infection in second wave 184 1.6 501 2.0 83 0.6
Vaccination status at time of diagnosis * Unvaccinated 10422 91.8 22930 91.6 13223 92.0
Partially vaccinated 694 6.1 1457 5.8 904 6.3
Completely vaccinated 239 2.1 655 2.6 244 1.7
Admitted § Case admitted to hospital 1856 16.4 4964 19.8 1649 11.5

* Fully vaccinated was defined as ≥28 days post-vaccination with Janssen/Johnson & Johnson or ≥14 days post second dose of Pfizer–BioNTech. Patients were deemed partially vaccinated from the day after their (first) vaccine dose until meeting criteria for complete vaccination.

§ Admission with 21 days before or after COVID-19 diagnosis date

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Gates Open Res. 2023 Nov 21. doi: 10.21956/gatesopenres.14936.r35389

Reviewer response for version 1

Polani Rubeshkumar 1

This is a detailed and thorough investigation into the mortality rates associated with the Delta variant of SARS-CoV-2 in South Africa. The study is based on a cross-sectional analysis and utilizes the RdRp target delay in PCR testing as a proxy for identifying suspected Delta variant infections. It contributes significantly to the understanding of COVID-19 variant impacts in a lower-middle-income country setting. The study's methodology, data analysis, and contextual focus are commendable, although the limitations typical of observational studies should be considered when interpreting the findings.

Minor comment:

Just to ensure uniformity, I suggest the authors to use either mortality or deaths in the manuscript text.

Is the work clearly and accurately presented and does it cite the current literature?

Yes

If applicable, is the statistical analysis and its interpretation appropriate?

Yes

Are all the source data underlying the results available to ensure full reproducibility?

Yes

Is the study design appropriate and is the work technically sound?

Yes

Are the conclusions drawn adequately supported by the results?

Yes

Are sufficient details of methods and analysis provided to allow replication by others?

Yes

Reviewer Expertise:

Field Epidemiology; Infectious disease; Tropical medicine

I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard.

Gates Open Res. 2022 Oct 10. doi: 10.21956/gatesopenres.14936.r32523

Reviewer response for version 1

Jeannie Collins 1

This is an important paper on higher mortality associated with SARS CoV-2 Delta variant using data from the Western Cape provincial health data. The paper is well written, the conclusions are well supported and the potential limitations clearly stated. 

In brief, the cross sectional study utilised a novel proxy marker for Delta variant (RdRP target delay) and assessed the risk of mortality and hospital admissions among cases with Delta variant versus those without (assumed to be Beta which was circulating at the time).  The analyses were adjusted for key characteristics including age, known comorbidities, prior SARS CoV-2 diagnosis and vaccination status. Stratified analyses by age group had broadly similar results.  

Minor comment: 

In the methods the authors could note how the RdRP target delay tests were distributed and used (versus other PCR tests), was this randomly allocated to patients or health care facilities? As there were some variations in the district of residence, as noted in the Discussion.

Is the work clearly and accurately presented and does it cite the current literature?

Yes

If applicable, is the statistical analysis and its interpretation appropriate?

Yes

Are all the source data underlying the results available to ensure full reproducibility?

No

Is the study design appropriate and is the work technically sound?

Yes

Are the conclusions drawn adequately supported by the results?

Yes

Are sufficient details of methods and analysis provided to allow replication by others?

Yes

Reviewer Expertise:

infectious disease epidemiology

I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard.

Associated Data

    This section collects any data citations, data availability statements, or supplementary materials included in this article.

    Data Availability Statement

    The Western Cape Provincial Health Data Centre collates all available electronic health data on public sector patients in the province for operational service use. The underlying data in this study are routinely collected patient records that have been de-identified and pseudo-anonymised in accordance with research ethics requirements. The patients have not consented to these data being part of publicly accessible repositories considering the inherent risks of re-identification. The Western Cape Department of Health and Wellness evaluates research proposals for all research in the public health sector in the province, subject to standard research ethics, government approval and data governance prescripts. This includes those that draw on routine datasets like the current study. For more information on conducting research in health services or on data managed by the Western Cape Government Department of Health and Wellness (WCGHW), please email health.research@westerncape.gov.za.


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