Evaluation of characteristics and prognosis of COVID-19 patients requiring invasive mechanical ventilation during dominance of nonvariant, alpha, delta, and omicron variants in tertiary hospitals of Japan

The omicron variant of SARS-COV-2 was first reported in South Africa in November 2022 and has since spread worldwide [1]. Omicron’s virulence and ability to escape from neutralizing antibodies are more potent than those of the alpha and delta variants, but the rates of severe illness and mortality are reported to be low [2‐4]. During the epidemic of the omicron variant, the decrease in severity of COVID-19 may be affected by the increased immunity due to vaccination and the lower ability of the omicron variant to migrate to the lungs. Despite this reduced severity, some patients become severely ill after infection with omicron variants and must undergo invasive mechanical ventilation (IMV), but there are few reports on the background and prognosis of these patients. In COVID-19 pandemic, we experienced waves I–III due to nonvariants, wave IV due to B.1.1.7 (alpha variant), wave V due to B.1.617.2 (delta variant), and waves (VI–VIII) due to B.1.1.529 (omicron variant) in Japan. In this study we compared the patient background and prognosis of COVID-19 patients who received mechanical ventilation in each period during the pandemic. Throughout all periods, risk factors affecting the prognosis of COVID-19 patients requiring IMV were also analysed and evaluated.

In this study, we compared the background and prognosis of patients with COVID-19 pneumonia requiring IMV during four viral epidemic waves in Japan (nonvariant, alpha variant, delta variant, and omicron variant). While many similar reports have included patients in whom SARS-CoV-2 was detected and who received IMV, we included patients in whom SARS-CoV-2 was detected who received IMV due only to COVID-19 pneumonia. We excluded patients who did not have COVID-19-specific pneumonia on chest CT at the time of admission. Patients with lung abnormalities on chest CT were excluded if they were diagnosed as having bacterial pneumonia, aspiration pneumonia, atelectasis, heart failure, or other causes. Since the outbreak of the omicron variant, there has been an increase in the number of patients brought to the emergency department for causes other than COVID-19 and who tested positive for SARS-CoV-2 by PCR testing prior to admission.

In addition to differences in the characteristics of each variant, factors such as the healthcare system, available drugs, and the prevalence of vaccines against SAR-CoV-2 may have influenced the comparison of patient backgrounds. Patients in the Omicron group were significantly older than those in the Alpha and Delta groups. According to data from Osaka Prefecture, in which our hospital is located, among the patients positive for SARS-CoV-2 during the omicron variant epidemic, the number of patients aged 70 years or older was 235,060 (9.0%). In comparison, 8368 (15.1%) older patients were in the alpha variant epidemic, and 4131 (4.1%) were in the delta variant epidemic [9]. One possible reason for the significant difference in the age of the groups is the large difference in the number of older patients who tested positive for SARS-COV-2 in those periods.

As the drugs used against COVID-19, corticosteroids were the treatment of choice for COVID-19 in all patients even before the guidelines recommended them [10], whereas significant differences existed between the groups for other agents administered. Among the antiviral drugs, only favipiravir, which was being investigated in Japan, could be used in the early stages of the epidemic [11]. Subsequently, after remdesivir was approved, its use increased [12]. During the omicron variant epidemic, molnupiravir was given to patients with poor renal function. As a result, one of these antivirals was administered to most patients. We had been using tocilizumab since the beginning of the epidemic [13] and then switched to baricitinib when it was approved [14]. After tocilizumab was also approved, we chose between the two depending on renal function [15]. No anti-cytokine drugs were administered in cases diagnosed as complicated by bacterial pneumonia, based on the findings of the initial CT and blood tests. In the omicron variant, the rate of anti-cytokine drugs was low (66.7%) because many of the patients were older and had bacterial pneumonia from the admission. These data showed that despite differences in the drugs, each variant group was treated similarly for COVID-19.

Initial blood test results showed that CRP, PCT, and D-dimer were significantly higher in the Omicron group. As KL-6 and LDH, which have been reported to be elevated in severe COVID-19 pneumonia [7, 16], are comparable, the elevations in CRP, PCT, and D-dimer are likely due to bacterial coinfection. Patton et al. reported that bacterial co-infection is a major risk factor for mortality, regardless of SARS-CoV-2 variants [17]. The detailed data in their report indicate that the rate of bacterial coinfection was 4.7% for the alpha variant, 5.4% for the delta variant, and 10.7% for the omicron variant. In the cases of death in our cohort, the positivity rate of βD-glucan was 49% and that of blood culture was 37.7%. The positivity rate for βD-glucan was not significantly different for each variant, although the Omicron variant had a significantly higher rate of positive blood cultures. One of the factors for the high mortality in patients with the omicron variant was likely to have been bacterial or fungal co-infection. Within the limitation of the retrospective design of this study, we could show COVID 19 pneumonia-related mortality.

In the present study, in-hospital mortality was highest in the Omicron group at 30.5%. Univariate analysis showed that the omicron variant had a significantly higher risk of death than the alpha and delta variants. A report from Brazil compared patients admitted to the ICU with nonvariant, gamma/delta variants, and omicron variants and reported that prognosis was better with omicron variants, but there was no difference in prognosis when limited to patients who required invasive ventilation [18]. A report from France showed that ICU mortality in COVID-19 patients admitted to the ICU was lower for the omicron variant than for the delta variant, but there was no difference in ICU mortality when restricted to patients admitted due to pneumonia [4]. Our study is also consistent with these studies in that the SARS-CoV-2 variant did not remain as a risk for in-hospital mortality of patients who required IMV for COVID-19 pneumonia in the multivariate analysis. The SARS-CoV-2 variant was also not a significant risk factor in a multivariate logistic regression restricting the primary endpoint to COVID-19 associated mortality (Supplementary Table 1). Importantly, our multivariate analysis of the risk of in-hospital mortality for all patients over the entire period showed age, immunodeficiency, smoking history, dialysis prior to COVID-19 infection, and high SOFA score at admission to be the significant risk factors. In the present study, the reason for more in-hospital deaths in the Omicron group may be that it included more patients who were older, immunocompromised, or had complicated bacterial infections with elevated CRP or PCT. In other words, even with omicron variant infections, which are said to have reduced rates of severe illness and mortality [2, 3], patients who are older, immunocompromised, have chronic obstructive pulmonary disease (COPD) due to smoking, or chronic renal failure on dialysis may require careful treatment and follow-up.

This study has several limitations. The major limitation is the lack of sufficient sample sizes and the use of retrospective data analysis. In addition, other factors, such as the degree of urgency in the health care system and differences in population age groups and health care supply by country may also affect prognosis. Since the emergence of the omicron variant, the number of elderly people with bacterial pneumonia following SARS-COV-2 infection has increased. In this study, patients whose main CT findings were consolidation or atelectasis possibly bacterial pneumonia were excluded. Because COVID-19 pneumonia also causes sepsis and it can be combined with bacterial coinfection, these exclusion criteria may possibly be inadequate. Further studies are needed to accurately determine risk factors affecting the prognosis of COVID-19 patients requiring IMV.

We compared the patient background and prognosis of patients with critical COVID-19 pneumonia between the SARS-CoV-2 variants. In patients with severe COVID-19 pneumonia requiring invasive ventilation, differences in the variants did not affect prognosis. Hospital mortality in critically ill COVID-19 patients was significantly higher in the older patients with bacterial coinfection, or patients with immunodeficiency, COPD, and chronic renal failure on dialysis.