This retrospective, observational cohort study enrolled moderate to critical illness COVID-19 patients admitted to isolation rooms from April 1 to June 30, 2022, at Taichung Veterans General Hospital. Patients aged <18 years and pregnant were excluded. The study was approved by the Taichung Veterans General Hospital Human Studies Committee.

COVID-19 patients were defined by a positive SARS-CoV-2 infection test result, confirmed by real time reverse transcriptase-polymerase chain reaction (RT-PCR) assay from nasal and pharyngeal swabs. According to COVID-19 severity definitions established by the Taiwan CDC and American College of Emergency Physicians (ACEP), moderate illness was defined as having signs and symptoms of lower respiratory disease or abnormal imaging and a SpO2 ≥ 94% at room temperature at sea level. Severe illness was defined as a SpO2 < 94% at room temperature at sea level, a PaO₂/FiO₂ < 300 mmHg, a respiratory frequency > 30 breaths/minute or having lung infiltrates > 50%. Critical illness was defined as respiratory failure, septic shock, and/or multiple organ dysfunction. The index day (day 0) was the day when a SARS-CoV-2 RT-PCR test confirmed positive, with patients followed until death in hospital or hospital discharge, whichever occurred first.

Medical chart reviews were conducted by infectious disease doctors using a standard case report form. We recorded each patient s age, gender, body mass index (BMI) and preexisting comorbidities, including cancer, CVD, diabetes, CKD, CLD and chronic liver disease. Obesity was defined as a calculated BMI ≥ 30 kg/m2. The Charlson comorbidity index (CCI), used to estimate the risk of death from comorbid diseases, was used for calculations.15 We also recorded each patient s history of COVID-19 vaccinations. In Taiwan, four types of vaccines, Moderna, AstraZeneca (AZ), Pfizer-Biontech (BNT) and the MVC-COV1901 COVID-19 Vaccine, were available during the study period. Groups of respiratory support were stratified from non-oxygen use/nasal cannula, to simple mask/non-rebreathing mask/high-flow nasal cannula (HFNC), and bilevel positive airway pressure (BiPAP)/mechanical ventilators. Time to remdesivir or dexamethasone was identified as the onset of COVID-19 symptoms to medication administration.

The demographic data regarding the survivors and non-survivors were analyzed. Descriptive statistics for patient and hospital characteristics were calculated using either mean (standard deviation (SD)), median (range or interquartile range (IQR)), or frequency count (percentage). Continuous variables were analyzed by the Wilcoxon rank-sum test and categorical variables by the Chi-square test or Fisher s exact test. All tests were two-sided, and a p value of <0.05 was considered to be statistically significant. The Kaplan-Meier method was used to determine the cumulative survival rate, category by CCI score, cancer and diabetes. Logistic regression analysis was used to determine independent predictors of hospital mortality. Model 1 was adjusted for age, gender, severity of COVID-19, cancer, CVD, diabetes, CKD, CLD, chronic liver disease, obesity, history of vaccination, remdesivir use, dexamethasone use and the cycle threshold (Ct) value at day 0. Model 2 was adjusted for age, gender, severity of COVID-19, obesity, CCI ≥ 6, history of vaccination, remdesivir use, dexamethasone use and Ct value at day 0. Variables differing between survivors and non-survivors with a p value < 0.5, according to the Chi-square test or Fisher s exact test, or the Wilcoxon rank-sum test, were entered into the multivariable regression model. Results were presented as odds ratios (ORs) with 95% confidence intervals (CI). Two-way analysis of variance (ANOVA) was used to examine the interaction between the independent risk factors for hospital mortality, including the onset of remdesivir and dexamethasone use time, history of vaccinations, cancer and diabetes. Statistical analysis were performed using SPSS software (Version 22.0).

A total of 838 patients were assessed for eligibility, with 196 children (23.39%) and 21 pregnant women (2.5%) being excluded. 416 patients were excluded due to mild COVID-19 illness. Ultimately, 205 patients experiencing moderate to critical COVID-19 illness were enrolled in the final analysis (Figure 1). Amongst them, 60 patients (29.27%) expired and 145 (70.73%) survived, with the mortality rate within the moderate to critical illness COVID-19 patients being 29.5%.

Clinical characteristics within the moderate to critical COVID-19 patients are shown in Table 1. The median age was 73.0 years for survivors and 78.5 years for non-survivors. Non-survivors were more likely to be experiencing critical illness and also have a higher proportion of cancer, diabetes and CVD. The median CCI score was significantly higher in non-survivors (7.5) compared with survivors (5.0). Only 21.7% of non-survivors received ≥ 3 doses of the COVID-19 vaccinations. With respiratory support, 40.0% of non-survivors required Bi-PAP or mechanical ventilator respiratory support. For COVID-19 treatment, oral antiviral agents included nirmatrelvir/ritonavir (Paxlovid) and Molnupiravir, with 16 patients (16/205, 7.8%) receiving Paxlovid and 31 patients (31/205, 15.12%) receiving Molnupiravir in the survivor group. In the non-survivor group, only 14 patients (14/205, 6.82%) received Molnupiravir, with no patients receiving Paxlovid. The onset of remdesivir and dexamethasone use time was more likely to be more than 2 days for non-survivors. An empirical antibiotic was used in 198 patients (198/205, 96.59%), 97.24% of survivors, and 95% of non-survivors. The overall length of hospital stay was 14.91 (7-20) days, 15.31(10-20) days for survivors, and 14.23 (1-58) days for non-survivors.

The cumulative survival rates during admission are shown in Figure 2a, Figure 2b and Figure 2c. The cumulative survival rate amongst patients with a CCI score ≥ 6 was significantly lower than those with a CCI score < 6 (P < 0.001) (Figure 2a). The cumulative survival rate amongst patients with cancer was significantly lower than those without cancer (P = 0.002) (Figure 2b). The cumulative survival rate amongst patients with diabetes was significantly lower than those without diabetes (P = 0.044) (Figure 2c).

Multivariable analysis for COVID-19 mortality risk factors is shown in Table 2. Critical illness of COVID-19 (Model 1: OR=6.55; 95% CI, 2.61–16.43; Model 2: OR=6.13; 95% CI, 2.09–17.97), underlying comorbidities of cancer (OR=2.35; 95% CI, 1.47–3.76), diabetes (OR=2.32; 95% CI, 1.23–4.37), chronic liver disease (OR=3.22; 95% CI, 1.01–10.29), and a CCI score ≥ 6 (OR=7.77; 95% CI, 2.70–22.35) were significantly associated with a higher risk of mortality. Patients who never received any vaccination (Model 1: OR=3.22; 95% CI, 1.07–9.66; Model 2: OR=3.57; 95% CI, 1.12–11.36), had an onset of remdesivir use time ≥ 2 days (Model 1: OR=6.04; 95% CI, 2.81–12.99; Model 2: OR=7.89; 95% CI, 1.34–16.40), and had an onset of dexamethasone use time ≥ 2 days (Model 1: OR=4.30; 95% CI, 1.88–9.83; Model 2: OR=4.47; 95% CI, 1.34–22.39) were all independent risk factors for mortality in both Models 1 and 2.

Table 3 shows the association between cancer, diabetes and the onset of remdesivir use time for mortality rates. An onset of remdesivir use time (≥ 2 days) was associated with an increased mortality rate, particularly amongst patients with cancer/diabetes, compared to those without cancer/diabetes (p for interaction = 0.046/0.049). Table 4 shows the association between cancer, diabetes and the onset of dexamethasone use time for mortality rates. An onset of dexamethasone use time (≥ 2 days) was associated with a higher mortality rate in patients with cancer. In addition, the impact was significant amongst patients with diabetes, compared to those without diabetes (p for interaction = 0.042). Table 5 shows the association between cancer, diabetes and COVID-19 vaccines. Compared to patients who received ≥ 3 doses of COVID-19 vaccinations, those who received < 3 doses were associated with a higher mortality rate, particularly amongst patients with cancer/diabetes, compared to those without cancer/diabetes (p for interaction = 0.038/0.048).

In this observational retrospective study, we found even during the omicron wave, in-hospital mortality was still high (29.5%) among moderate to critical illness COVID-19 patients. Cancer, diabetes, chronic liver disease and a CCI score ≥ 6 were all independent risk factors for mortality. Being COVID-19 vaccinated with ≥ 3 doses, the onset of both remdesivir and dexamethasone for < 2 days were protective factors for mortality. The protective effect of ≥ 3 doses of the vaccine, along with early administration of remdesivir and dexamethasone can greatly reduce mortality rates, particularly in patients with cancer or diabetes.

The overall in hospital mortality rate of COVID-19 ranges from 17 to 24.5% 23. Our study showed a higher in-hospital mortality rate (29.5%) than previous studies. Additionally, 30.7% of patients in this study saw progression to BiPAP or invasive mechanical ventilator, which may be due to the relatively old age (median age 74 years) of our patients and a higher percentage of underlying comorbidities, particularly cancer and diabetes. The results of our study also emphasize the relatively high mortality rate in those with multiple comorbidities despite the omicron wave.

As for the treatment of COVID-19 patients, the WHO Solidarity trial determined that remdesivir shortens the time to clinical recovery 16. Similarly, the PINETREE trial and CATCO study also demonstrated the clinical efficacy of remdesivir in hospitalized patients. The further investigation surrounding the timing of remdesivir has suggested that early-remdesivir use could prevent a progression to severe COVID-19 pneumonia 1017. One prospective, observational study indicated that early-remdesivir use (≤ 5 days from onset of symptoms) was a protective factor, and may reduce COVID-19 progression 18. Another retrospective observational study also found patients receiving remdesivir ≤ 3 days from first testing positive for SARS-CoV-2 had 1.74 times a reduction in mortality rate compared to those receiving remdesivir after > 3 days 19. Our study also demonstrated the benefits of early remdesivir administration. An onset of remdesivir use time ≥ 2 days was an independent risk factor for in-hospital mortality rates, particularly amongst patients with cancer and diabetes.

Host immune response is thought to play a central role in the pathophysiological effects of organ failure in severe COVID-19 patients. Corticosteroids have been used as immunomodulators to reduce COVID-19 related systemic inflammatory response. The RECOVERY trial demonstrated the use of dexamethasone resulted in a lower 28-day mortality rate amongst those receiving oxygen supplement 11. The benefits of early administration of dexamethasone remain controversial. One retrospective study showed that severe COVID-19 patients receiving corticosteroids within 10 days from diagnosis had a favorable outcome in the length of their hospital stay 20. Another observational study found that early administration of dexamethasone (within 24 hours of hypoxemia) was associated with a lower rate of HFNC and mechanical ventilator appliance 21, however, another observational cohort study did not show any mortality benefits 22.In our study, the onset of dexamethasone use time ≥ 2 days was also an independent risk factor for in-hospital mortality rates, particularly among patients with cancer or diabetes. Our study supported the early timing of dexamethasone use. However, the benefit was more significant for critical condition patients. Early consideration of corticosteroid use should be recommended, particularly in those patients with high-risk comorbidities, to limit the rapid progression of COVID-19.

Vaccines remain the most valuable instrument in the protection against COVID-19. In a previous study, participants being 60 years old or older showed that the rates of confirmed COVID-19 and severe illness were substantially lower amongst those receiving a booster (third) dose of the BNT162b2 vaccine 23. Even during the Omicron-dominant epidemic period, the risk of mortality decreased with each additional vaccine and protection against death among those aged > 50 years was more significant 24. Among patients with cancer, full vaccination and boosting were associated with an improvement in COVID-19 related mortality and morbidity rates compared with unvaccinated patients 13. Similarly, our study highly emphasizes the effectiveness of a booster (third) dose of a COVID-19 vaccine, as it reduced mortality rate during the omicron phase, particularly amongst patients with diabetes and cancer.

There were some limitations in our study. First, this study was a single medical center with a small patient number, selection bias existed. Secondly, our database did not contain certain patient personal information, such as smoking and alcohol drinking habits, which are associated with increased severity of disease and death for hospitalized COVID-19 patients 252627. We cannot analyze patient histories regarding smoking and alcohol consumption due to poor data quality. Finally, we only followed up with patients until discharge, so there were no long-term survival outcome results.

In summary, patients being COVID-19 vaccinated with ≥ 3 doses, and undergoing an early onset of remdesivir or dexamethasone of < 2 days can experience a greatly reduced mortality rate, particularly in patients with cancer or diabetes.