Predictive Factors of Mortality in Patients with Severe COVID-19 Treated in the Intensive Care Unit: A Single-Center Study in Vietnam

COVID-19, a disease caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has emerged as a global pandemic with severe consequences and has placed tremendous pressure on healthcare systems in numerous countries worldwide,, especially in emerging countries [1, 2]. According to Worldometers statistics, the SARS-CoV-2 virus infected more than 290 million people, with 5.4 million deaths globally by the end of 2021 [3]. The continuous emergence of new strains of the SARS-CoV-2 virus has posed crucial challenges for healthcare systems in terms of disease prevention and treatment. Delta variant, or B.1.167.2, first detected in India in December 2020, was considered the deadliest variant with more infectious and virulent, and it can reduce the vaccine’s effectiveness [4‐7]. Studies have shown that the delta variant is associated with being two times more contagious and more likely to cause severe illness compared to older strains. Specifically, it is 60% more transmissible than the alpha variant and has a shorter incubation period, around 2–3 days [8‐11].

In addition, people infected with the delta strain had a nasal viral load 1000 times higher than those infected with the original strain [12, 13]. Even the viral load in an unvaccinated person is equivalent to that of a fully vaccinated person when infected with this strain [14, 15], or in some cases, asymptomatic infected people have a higher viral load than hospitalized patients and become a mobile source of infection in the community [16]. As a result, the delta variant quickly became popular in most countries worldwide, and the dominant variant overwhelmed all other strains globally. The lethality of the delta variant was also confirmed by increased risk of hospitalization (120%) and intensive care unit (ICU) admission (287%), and 137% higher risk of death compared with the original variant [13, 17].

People with COVID-19 with the delta variant have a nonspecific clinical presentation or have symptoms ranging from mild fever, fatigue, cough, and shortness of breath [18, 19] to severe cases such as lower respiratory tract infections, pneumonia, and some cases progressed to severe acute respiratory distress syndrome (ARDS), or multi-organ failure leading to death [20, 21]. High mortality rates have been reported in Latin America and Europe, ranging from 13.9% to 21.0% in hospitalized patients, particularly in severe and critical cases [22‐24] and up to 25% in elderly patients [25]. Therefore, it is crucial to have an appropriate approach to patients with early symptoms of severe COVID-19 for helping to classify correctly the disease severity to reduce the healthcare burden and to choose the correct treatment [26].

The delta variant of SARS-CoV-2 virus has caused the COVID-19 pandemic to re-emerge, creating a new wave of infection that can increase patients’ severity and mortality risk. During the fourth wave of COVID-19 pandemic, the delta variant gave the healthcare burden in many countries worldwide. Thus, Vietnam had no exception, with the fourth wave started at the end of April 2021 [27]. According to a survey study in 23 countries on COVID-19 prevention policies in May 2020, Vietnam has a satisfaction level of people up to 77%, just behind China [28]. Indeed, Vietnam has been considered one of the most effective response countries to the COVID-19 pandemic. In the more than 15 months since the pandemic began in January 2020, the total number of officially recorded COVID-19 infections in Vietnam has been less than 3000 cases and 35 deaths out of a population of ~ 100 million. However, when delta variant arrived, the number of new cases increased to thousands of patients per day in July 2021 and continuously set new peaks. The highest record was set on August 8, 2021, with 9684 cases/day and 220,000 total infections, with 3757 deaths in Vietnam [29, 30].

However, during the fourth wave of the pandemic in Vietnam, some clinical studies on patients with severe–critical COVID-19 were also conducted, but the results have been limited and unpublished. Thus, the present study aimed to describe the clinical and laboratory characteristics and predictive factors of mortality in patients with severe and critical COVID-19 in Vietnam during the fourth wave of the COVID-19 pandemic.

COVID-19 is a highly dangerous infectious disease with significant morbidity and mortality rates globally. Therefore, it is crucial to comprehend the disease's characteristics and severity to facilitate informed decision-making in selecting appropriate care and enhancing treatment effectiveness. These measures are essential for reducing mortality rates and alleviating the burden on healthcare systems. Like other viral respiratory pathogens, without vaccination, COVID-19 presents in most cases with a rapidly progressive course of common symptoms such as fever, cough, and shortness of breath to ARDS. In the present study (Table 1), the clinical symptoms of patients with severe and critical COVID-19 were dyspnea (97.4%), fatigue (89.4%), and cough (76.8%). Some other extra-respiratory symptoms in these patients were also recognized, including a loss of smell (48.3%), loss of taste (39.1%), and headaches (21.2%). These symptoms are common in both alpha and delta variants of SARS-CoV-2 but more severe with the delta variant. Our results are also consistent with the clinical manifestations reported in a meta-analysis of 55 studies within 10,014 severe COVID-19 patients who had fever, cough, fatigue, anorexia, dyspnea, chest tightness, hemoptysis, diarrhea, and abdominal pain [19]. The study conducted by Wang et al. in the clinical characteristics of 138 COVID-19 patients in Wuhan, China, showed similar results. However, in Wang’s study, the onset of symptoms was fever (98.6%), followed by fatigue and dry cough (69.6 and 59.4%, respectively) [18]. Another study published by Shang et al. [26] demonstrated the symptoms of severe COVID-19 included fever (81.7%), cough (65.4%), dyspnea (51.5%), fatigue (38.3%), and expectoration (35.1%). Thus, the frequency of dyspnea, fatigue, and cough in our study was significantly higher than in previous studies. This difference might be due to the patient's initial severity on admission or the degree of response during treatment with different variants of the SARS-CoV-2 [26]. Dyspnea, or shortness of breath, fatigue, and cough has consistently been reported as common symptoms in severe and critical COVID-19 cases. While the exact rate may vary due to factors such as study design, population characteristics, and geographic location, it is generally recognized as a prominent symptom in severe cases.

The present study showed that there were some laboratory abnormalities such as leukopenia with mainly lymphocytopenia, anemia, thrombocytopenia, and abnormal arterial blood gas related to hypoxia, hypercapnia, and acidosis (Table 2). Thus, these laboratory characteristics might help clinicians in identifying COVID-19 patients with severe–critical illness in early stage, because most patients with severe and critical COVID-19 might present with rapid progression to multi-organ dysfunction. The present study also revealed that in comparison to survival COVID-19 patients, the common complications of dead patients were septic shock, cardiogenic shock, and embolism (Table 1). These complications might be related to nosocomial infections, cardiomyopathy, and coagulation compromised due to SARS-CoV-2 infection [32, 33]. Also, it has been found that stool and urine samples of COVID-19 patients were positive for SARS-CoV-2 nucleic acid and angiotensin-converting enzyme 2 (ACE2) expression in small intestinal epithelial cells and biliary and pancreatic cells, suggesting SARS-CoV-2 infection can cause multi-organ damage in COVID-19 patients [34‐36].

In the present study, the patients with severe and critical COVID-19 were mainly treated with enoxaparin, vasopressors, and remdesivir (Table 1). However, remdesivir was not recommended for severe COVID-19 patients due to conflicting reports on its efficacy for improving clinical status, reducing the duration of mechanical ventilation, as well as morbidity and mortality for these patients [18, 37, 38]. The use of corticosteroids with different doses, including dexamethasone with doses of 6 mg/day (73.5%), 6–12 mg/day (7.9%), and 12–20 mg/day (16.6%) was also demonstrated in the present study. While the treatment with a high dose of corticosteroids (12–20 mg/day of dexamethasone or ≥ 4 mg/kg/day of methylprednisolone) was associated with a low survival after 3 weeks, the treatment with the dose of dexamethasone of 6-12 mg/day (or > 2-3 mg/kg/day of methylprednisolone) had a low probability of survival after 4 weeks in comparison to the dose of dexamethasone of 6 mg/day (Fig. 4D). Interestingly, the treatment with dexamethasone > 6 mg/day (or methylprednisolone > 2 mg/kg/day) was significantly associated with better survival than the conventional dose of dexamethasone (6 mg/day or equivalent dose of methylprednisolone) during first 3 weeks (Fig. 4D). This result was consistent with the recommendations which suggest that low-dose and short-term treatment of dexamethasone may be used for symptomatic treatment of patients with severe and critical COVID-19 [37, 39, 40]. In fact, the efficacy of dexamethasone 6 mg/day used for 10 consecutive days to reduce hospital stay and mortality in COVID-19 patients who required oxygen or invasive mechanical ventilation has been demonstrated previously [41‐43]. However, it has also been reported that the abuse of dexamethasone or methylprednisolone with high doses might increase the patient mortality and slow down the clearance of viral RNA in severe COVID-19 patients [44, 45]. Thus, the identification of predictive mortality and survival factors is critical in choosing the appropriate treatment regimen in patients with severe and critical COVID-19.

The results of our study clearly demonstrated that deceased patients were older and predominantly female. Additionally, they exhibited a higher prevalence of cardiovascular diseases, elevated levels of LDH and urea, lower levels of PaO₂ and pH, as well as lower platelet counts compared to the patients who survived (Tables 3 and 4). Inversely, the surviving patients had a higher percentage of remdesivir treatment, a lower percentage of vasopressin use, and had no complications related to septic shock or cardiac shock during hospitalization (Table 3). However, the results of our study demonstrated that the sensitivity and specificity of the cut-off of age, PaO₂ or PaCO₂, and pH was not relevant for predicting the probability of mortality and survival (Fig. 2A, B). Previous studies have suggested that age, low oxygen saturation, and co-morbid chronic diseases were also risk factors for the increased prevalence of mortality in COVID-19 patients [46‐48]. By univariate regression analysis, the present study also indicated that age > 65 years, history of cardiovascular disease, thrombocytopenia (< 137.10⁹/l), hypoxia (PaO₂ < 63 mmHg), or acidosis (pH < 7.28) were the relative risks of mortality in patients with severe–critical COVID-19 (Table 4). This result was also confirmed by analyzing the mortality and survival of study patients via Kaplan–Meier curves (Fig. 4A, B, and C). Recently, Lavrentieva et al. have reported that the survival rates inside the ICU for the four main COVID-19 variants are 54.9, 50.3, 39.7, and 50% for the alpha, beta, delta, and omicron variants, respectively [49]. These authors also demonstrated the parameters that have been independently associated with ICU survival are SOFA (Sequential Organ Failure Assessment)–day 1, remdesivir use, AKI (acute kidney injury), sepsis, enteral insufficiency, duration of ICU stay and white blood cells. Our previous reports also revealed the severity of patients hospitalized in ICU who needed to have the optimal treatment with mechanical ventilation or therapeutic plasma exchange were related to AKI, pregnancy, and acute neurological complications [50‐53].

Finally, the present study has some main limitations, as described in the following order: a small number of study subjects; patients were included only for a descriptive study without a control group; the choice of low to high corticosteroid doses was dependent on the physicians’ decisions. However, this study does give some relevant information, which elucidates the predictive factors of mortality and survival for severe–critical COVID-19 patients and provides the primary data for clinicians to classify COVID-19 patients on admission and have appropriate treatment.

Common clinical symptoms, laboratory features, and death-related complications of critical-severe COVID-19 patients were found in Vietnamese patients during the fourth wave of the COVID-19 pandemic. This population might have some clinical characteristics and predictive factors of high risk of death and survival for those with severe and critical COVID-19. Thus, the present study suggests that during the fourth wave of the COVID-19 pandemic, the patients with severe and critical COVID-19 who were older or had the medical history of cardiovascular disease or treatment with high dose of corticosteroids, might increase the rate of mortality during hospitalization. In addition, some laboratory features such as thrombocytopenia at admission, significant hypoxia, or blood acidosis under optimal treatment in patients with severe and critical COVID-19 might also be considered as the relevant predictive factors of mortality. Therefore, these findings may provide valuable insights into developing effective treatment regimens and prognostic indicators for the survival of patients with severe and critical COVID-19.