Prognosis of Critically Ill Patients With Acute Respiratory Failure Due To The SARS-CoV-2 501Y.V2 Variant: A Multicenter Retrospective Matched Cohort Study

Background The aim of this study was to compare the prognosis of patients with acute respiratory failure (ARF) due to the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variant 501Y.V2 to that of patients with ARF due to the original strain. Methods This retrospective matched cohort study included all consecutive patients who were hospitalized for ARF due to SARS-CoV-2 in Reunion Island University Hospital between March 2020 and March 2021. Twenty-eight in hospital mortality was evaluated before and after matching.


Introduction
An outbreak of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that started in China in December 2019 began to spread globally in January 2020. 1 Reunion Island (845,000 inhabitants), a French overseas department located in the Indian Ocean, was relatively spared by the SARS-CoV-2 pandemic until February 2021. 2 From the rst detected case of SARS-CoV-2 infection on 19 March 2020 until 4 February 2021, only 10,330 cases and 5,4 deaths per 100,000 inhabitants were reported on the island. 2These gures are likely due to the protective effects of climatic and environmental factors against SARS-CoV-2 transmission [3][4][5] and to the geographical characteristics of Reunion Island (i.e. an insular territory with the international airport as its only entry point).To this is added the fact the local health care system meets European standards (16 extracorporeal membrane oxygenation supports, coronary angiography, all type of surgeries, etc.), and was therefore able to handle all cases without reaching saturation.
In recent months, several SARS-CoV-2 variants of concern have been spreading worldwide.These are a source of worry as they may lead to: reinfection of SARS-CoV-2 recovered individuals; 6 lower effectiveness of vaccines; 7,8 a higher transmission rate; 9 and more severe pathogenicity. 9,10The 501Y.V2 variant, which has three mutations to the spike protein, rst appeared in the Eastern Cape Province of South Africa in October 2020 and then spread to other countries. 11,12In Reunion Island, the rst case of the 501Y.V2 variant was isolated on 4 January 2021 in a patient transferred from the Comoros for acute respiratory failure (ARF).Since then, the incidence of SARS-CoV-2 infection has increased 3-fold on the island. 2In Mayotte, another French overseas department in the Indian Ocean, the incidence has increased 17-fold since the 501Y.V2 variant was rst detected in January. 2,13The 501Y.V2 variant is now the most common variant in Reunion Island, Mayotte, and the neighboring islands of the Comoros archipelago. 2,13t present, no clinical data are available on the pathogenicity of ARF due to SARS-CoV-2 variant 501Y.V2.
The aim of this study was to compare the prognosis of patients with ARF due to the 501Y.V2 variant to that of patients with ARF due to the original strain.

Methods
All methods were performed in accordance with the French legislation on non-interventional studies.This study was registered with the National Institute of Health Data under the number MR4-04 (2206739) and approved by the Ethics Committee of the French Society of Infectious Disease and Tropical Medicine (CER-MIT 2021-N°00011642).Written and oral Informed Consent was obtained from all participants after they were given a written information notice about the process of data collection.All methods were performed in accordance with the relevant guidelines and regulations.This study complies with the Strengthening the Reporting of Observational studies in Epidemiology recommendations statement. 14lection of the study sample All consecutive patients with ARF due to SARS-CoV-2 who were hospitalized in one of the three intensive care units (ICUs) of Reunion Island University Hospital between 1 March 2020 and 18 April 2021 were included in the study ((Félix Guyon University Hospital, Saint-Pierre University hospital and Saint-Paul Hospital).
Acute respiratory failure was de ned as bilateral pulmonary in ltrates on chest X-ray or computed tomography scan and need for high-ow nasal cannula oxygenation or invasive mechanical ventilation.
All patients with a nasopharyngeal or respiratory sample that tested positive for SARS-CoV-2 by real-time reverse transcription-polymerase chain reaction (RT-PCR) targeting the IP2 and IP4 regions and the N gene were evaluated.All positive samples were analyzed using NucliSens easyMAG system (BioMérieux).From 1 January 2021 onwards, positive samples were also analyzed by genome sequencing using Oxford Nanopore technology, as per the Artic Network's overlapping amplicon protocol. 15,16erapeutic management In accordance with our protocol, all patients with ARF due to SARS-CoV-2 were treated with: (1)   dexamethasone at a dosage of 6 mg/day for 10 days; 17 (2) deworming with ivermectine or albendazole; and (3) enhanced anticoagulation, as per the guidelines of the French Society of Thrombosis and Hemostasis and the French Society of Anesthesia and Intensive Care . 18gh-ow nasal cannula oxygenation was initiated in patients requiring standard oxygen ≥ 9 L/min to maintain peripheral arterial oxygenation saturation ≥ 92%.The timing of intubation and mechanical ventilation was not protocolized but determined by the ICU team on a case-by-case basis.
The exclusion criteria were: too high cycle threshold value in RT-PCR assay for variant screening; ARF due to 501Y.V1; and ARF due to 501Y.V3.

Data collection and study outcomes
Information was collected on the following: demographic characteristics; comorbidities; organ failure during ICU stay requiring venovenous extracorporeal membrane oxygenation, renal replacement therapy, invasive or non-invasive mechanical ventilation, use of catecholamines; prognosis (mechanical ventilation duration, length of stay in hospital and in ICU, and in-hospital and in-ICU mortality); and morbidity (coinfection, thromboembolic complications, and hospital-acquired pneumonia).
The primary outcome was 28-day in-hospital mortality.
The secondary outcomes were the occurrence of pulmonary embolism, the occurrence of hospitalacquired pneumonia, the need for venovenous extracorporeal membrane oxygenation support, and in-ICU length of stay.

Statistical analysis
Categorical variables were expressed as total number (percentages).Continuous variables were expressed as median [25 th -75 th percentiles].The study cohort was divided into patients infected with the 501Y.V2 variant and patients infected with the original strain.As the study was not randomized, unbalanced covariates could have introduced selection and confusion biases.Moreover, the number of covariates was large relative to the number of primary outcomes.These two problems were addressed by using a matching process based on a propensity score and a prognostic score in which one patient infected with the 501Y.V2 variant was matched with one patient infected with the original strain. 19,20The propensity score was determined by tting a logistic regression to estimate the probability of being infected with the 501Y.V2 variant. 21The prognostic score was determined by tting a logistic regression to estimate the probability of the primary outcome occurring in patients infected with the original strain (and unlikely to be infected with the 501Y.V2 variant since they were hospitalized between 13 March 2020 and 31 December 2020), and then by applying the generated model to the entire cohort. 22Patients were matched based on the two scores using a Mahalanobis distance with a caliper width of 0.5. 19,20,23No replacement was allowed, and all patients were matched only once.Baseline characteristics were compared before and after matching.Quantitative variables were compared using the Student's t-test or Mann-Whitney U test, as appropriate.Qualitative variables were compared using the chi-square test or Fisher's exact test, as appropriate.The marginal effect of being infected with the 501Y.V2 variant on the primary outcome (with 95% con dence interval) was estimated by applying the Doubly Robust Matching Estimator (DRME) on the matched cohort with proper control of confounding. 20The advantage of this approach being that only one of the two score models needs to be correct to obtain a consistent estimator. 20Lastly, the odds ratios of the primary and secondary outcomes (with 95% con dence intervals) were estimated using a conditional logistic regression.A P-value < 0.05 was considered signi cant.All analyses were performed at a two-tailed alpha level of 0.05.Statistical analyses were conducted with SAS 9.4 (SAS Institute, Cary, NC).

Results
Over the study period, 284 patients tested positive for SARS-CoV-2 were hospitalized in one of the two ICUs of Reunion Island University Hospital.Of these, 66 were excluded: 16 because they did not develop ARF, 5 had ARF due to 501Y.V1 variant and 45 because the cycle threshold values obtained in the RT-PCR assay were too high for variant of concern screening.The remaining 218 patients formed the cohort (Fig. 1).
Matching resulted in two well-matched groups of 62 patients each (Fig. 1).

Characteristics Of The 218 Pre-matched Patients
Of the 218 pre-matched patients, 50 (22.9%)were transferred to Reunion Island from Mayotte or the Comoros.Patient characteristics on ICU admission are shown in Table 1.In summary, 83 (38.1%) patients had ARF due to the 501Y.V2 variant.The median Simpli ed Acute Physiology Score was 32 [25-43], and the median number of days between the onset of symptoms and hospitalization in ICU was 8 [5-11] day.

Characteristics And Prognosis Of The 124 Matched Patients
After matching, there were no signi cant differences in characteristics between the group of patients infected with the 501Y.V2 variant and the group of patients infected with the original strain (Table 2).
Our study has several limitations.Biases may have been introduced due to the retrospective nature of the study.In particular, a selection bias may have occurred as a signi cant proportion of patients infected with the 501Y.V2 variant were transferred from Mayotte, whose population is younger and presents fewer comorbidities than the Reunionese population.1][22][23] In addition, mortality due to the 501Y.V2 variant was probably underestimated as several samples could not be screened for variants of concern.While our study sample may seem small (n = 218), it should be noted that all patients hospitalized in our two ICUs for ARF due to SARS-CoV-2 were evaluated, which also helped to reduce the selection bias.Moreover, patient management was the same in both ICUs, and unlike what was the case in many in other studies on the subject, it was optimal throughout the study period. 24,26

Conclusion
In Reunion Island, where SARS-CoV-2 incidence remained low until February 2021 and the health care system was never saturated, mortality was higher in patients infected with the 501Y.V2 variant than in patients infected with the original strain.These results are in line with reports on other SARS-CoV-2 variants of concerns, and should be considered in the future management of the pandemic.
Abbreviations SARS-CoV-2 Severe acute respiratory syndrome coronavirus 2 ARF Acute respiratory failure ICU Intensive care unit RT-PCR Real-time reverse transcription-polymerase chain reaction DRME Doubly robust matching estimator

Figures
Figures

Figure 1 Selection
Figure 1

Table 2
Baseline patient characteristics in propensity-matched groups

Table 3
Outcome of the 124 matched patients during intensive care unit stay *OR and 95%CI were estimated using univariate conditional logistic regression Doubly Robust Matching Estimator : 0.12 (95%CI: 0.01-0.24)