Analysis of Vaccination Status of Patients Admitted to the Intensive Care Unit with Confirmed COVID-19-Related ARDS: A Retrospective Cross-Sectional Study

Introduction

Human coronaviruses, including the causative agent COVID-19 (SARS-CoV-2), lead recurrent infections. Vaccination is the most effective and essential step in preventing this viral infection. However, evidence of protection vaccinations provide is limited (1). It has been reported that unvaccinated people experience 2.34 times more reinfections than vaccinated people. COVID-19 vaccination is recommended for all eligible people, including those who have already experienced COVID-19 infection (2). A booster dose administered to fully vaccinated individuals aged 60 years and over has been reported to significantly reduce the COVID-19 infection risk and disease severity (3).

People in the risk group, including healthcare workers and individuals aged 65 and over, were actively vaccinated with the inactivated whole virus (CoronaVac, China) and messenger ribonucleic acid (mRNA) (mRNA-based, BioNTech/Pfizer, Germany)vaccineinTurkey(4). Protection rates may vary depending on the vaccine used and the dose repetition. For example, when the COVID-19 mRNA vaccine is administered in two doses 21 or 28 days apart, protection against infection in people aged 16 years and older is 94–95%, whereas two doses of the CoronaVac vaccine administered two to four weeks apart provide a protection rate of 67.7% (50.7%– 83.5%) against symptomatic COVID-19 (1, 5). On the other hand, a single randomized dose of Ad26.COV2.S vaccine was reported to provide up to 73.1% protection against COVID- 19 in adult participants (6). In studies conducted during the period when the delta variant was dominant, it was reported that viral ribonucleic acid (RNA) at the time of COVID-19 diagnosis were similar in nonvaccinated and vaccinated individuals but exhibited a more rapid decline, and viral RNA levels were lower in the upper respiratory tract mucosa in vaccinated cases (7). The vaccinated individuals were be much less likely to transmit COVID-19 variants, including delta,if infected (8–10).The study was conducted to investigate whether there were relationships between the vaccination status of patients admitted to the COVID-19 intensive care unit and APACHE II score at admission, the modified Charlson comorbidity index (11), requirement for noninvasive ventilation (NIV) and intubation, duration of intensive care unit hospitalization, first-day laboratory values, and final status.

Materials and Methods

After obtaining approval from the Ethics Committee, the data in the hospital information system and the records kept in the files of 124 patients aged 18 years and older who were admitted to the COVID-19 intensive care unit (ICU) of the Van Yüzüncü Yıl University, Faculty of Medicine between September 1 and October 31, 2021, were evaluated in this retrospective cross-sectional study. The data of 99 patients who met the inclusion criteria were assessed in this study, conducted during the period when the delta variant was prevalent. Patients with a positive polymerase chain reaction (PCR) test who were admitted to the ICU diagnosed with COVID-19-related acute respiratory distress syndrome (ARDS) or severe pneumonia and hospitalized for at least one day were included. Patients admitted to the intensive care unit and discharged to the ward within a few hours were considered to have unconfirmed COVID-19- related ARDS. Patients with a negative PCR test, unconfirmed COVID-19-related ARDS, and missing data were excluded from the study. The patients were classified into three groups according to their vaccination status. Those who had received no COVID-19 vaccine were considered nonvaccinated, those who had received only one dose of vaccine were partially vaccinated, and those who had received two or more doses were considered fully vaccinated. The demographic data, vaccination status on admission to the intensive care unit, APACHE II score, modified Charlson comorbidity index, need for NIV and intubation, time of intubation, ICUhospitalization duration,first-day laboratory values, and final status of the patients were recorded. The need for NIV and intubation indicates whether patients underwent NIV and intubation during their ICU stays. The intubation time means the day on which intubation was performed, and ICU hospitalization duration indicates the time from the ICU admission to discharge/death. Final status was considered as discharge to the ward or mortality.

Variables included age (years), gender, the modified Charlson comorbidity index, APACHE II score, ferritin(ng/L), fibrinogen(mg/L),D-dimer (µg/L), C-Reactive Protein (mg/L), white blood cells (WBC,10³/uL), hemoglobin (g/dL), platelets (10³/uL), aspartate amino transferase (AST, U/L), alanine aminotransferase (ALT, U/L), sodium (mmol/L), potassium (mmol/L), urea (mg/dL), creatinine (mg/dL), need for NIV, intubation, ICU hospitalization duration, and outcome.

Statistical Analysis

The mean, standard deviation, median, minimum, maximum, frequency, and ratio values were used in the descriptive statistics of the data. The variables' distributions were measured with the Kolmogorov-Smirnov test. The independent sample t-test, Mann-Whitney u test, and One-way ANOVA test were used to analyze independent quantitativedata. Forward Logistic Regression analysis was performed to evaluate the relationships between variables. The Tukey was used for pairwise comparisons (post-hoc analysis). The chi-square test was used to analyze independent qualitative data, and the Fischer test was used when the chi-square test conditions were not fulfilled. SPSS 28.0 software was used in the analyses.

Ethical Statement

In our study, written informed consent was obtained from the first-degree relatives of all participants following the Declaration of Helsinki. Furthermore, ethical approval was obtained from the Non-Interventional Clinical Research Ethics Committee of Van Yüzüncü Yıl University, with a decision dated 10.12.2021 and numbered 2021/13-01.

Results

The mean age of the 99 cases included in the study was 58.7±18.8 years, and 51 (51.5%) were female. 55 (56%) were nonvaccinated, 36 (36%) were fully vaccinated, and 8 (8%) were partially vaccinated (Table-1). Seventy-seven percent (n=76) of the patients hospitalized in the ICU had comorbidities (Table 2). Hypertension 33% (n=33), diabetes mellitus 20% (n=20), coronary artery disease 12% (n=12), malignancy 10% (n= 10), and chronic obstructive pulmonary disease (COPD) 9% (n=9) were the most prevalent comorbidities. Among 61 (62%) patients with COVID-19-related ARDS or severe pneumonia who died in the ICU, 34 were nonvaccinated, 23 were fully vaccinated, and four were partially vaccinated.

Age, APACHE II score on admission, modified Charlson comorbidity index, fibrinogen, CRP, urea, creatinine values, and intubation rates were statistically significantly higher in the deceased patients. The gender distribution, ferritin, D-dimer, WBC, Hb, Plt, ALT, AST, Na, K values, vaccination status, need for NIV, and ICU hospitalization durations were similar to those of the discharged patients (Table 2). Age, admission APACHE II score, the modified Charlson comorbidity index, fibrinogen, urea, creatinine values, and mortality rates were significantly higher in the intubated patients. Age, admission APACHE II score, the modified Charlson comorbidity index, fibrinogen, urea, creatinine values, and mortality rates were significantly higher in the intubated patients. On the other hand, gender distribution, admission ferritin, D-dimer, CRP, WBC, Hb, Plt, ALT, AST, Na, K values, vaccination status, need for NIV, and ICU hospitalization durations were similar to those of the non-intubated patients (Table 3). Univariate logistic regression analysis revealed significant associations among age, the APACHE II at ICU admission, the modified Charlson comorbidity index, fibrinogen and urea levels, and intubation status (p<0.05). In addition, significant independent (p<0.05) effects of the APACHE II score, the modified Charlson comorbidity index, and the fibrinogen were observed in the multivariate reduced model constructed for differentiating intubated and non-intubated patients. These parameters were statistically higher in the intubated patients (Table 4). The chi-square analysis revealed no relationships among vaccination status and gender (p=0.564), ICU hospitalization (p=0.479), need for NIV (p=0.810), intubation (p=0.639), or mortality (p=0.769). Significant differences (p< 0.05) were determined among the groups regarding age, APACHE II score on admission to the ICU, the modified Charlson comorbidity index, and laboratory values (Table-5). The post hoc (Tukey) analysis indicated that age (p=0.002), the modified Charlson comorbidity index (p=0.002), APACHE II score on admission to the ICU (p=0.039), and creatinine (p=0.036) values were higher in the fully vaccinated group than in the nonvaccinated group (Table 6).

Discussion

The principal results of this study were that age, APACHE II, modified Charlson comorbidity index, and creatinine values on admission to the ICU were higher in the fully vaccinated group. Age; APACHE II score on the day of admission to the ICU; modified Charlson comorbidity index; levels of fibrinogen, CRP, urea, and creatinine; and intubation were associated with mortality. On the other hand, no association was found between vaccination status and the need for NIV, intubation, ICU hospitalization duration, or mortality. These variables were similar in the death and discharged patients. As of July 2021, the delta variant was reported to be the dominant variant in Turkey and 60% more contagious than the alpha variant (12, 13). Severe COVID may occur in any age. However, those older than 60 with comorbidities suffer more severely from COVID-19. The need for hospitalization and mortality due to COVID-19 has increased in elderly patients. It has been reported that 80% of deaths in ICUs are seen in patients aged 65 and over; furthermore, male patients have a more severe course of COVID- 19 and a higher mortality rate (1, 14–16). Hypertension, diabetes mellitus, cardiovascular disorders, chronic kidney disease, extreme obesity, suppressed immunity, and extrapulmonary organ dysfunction on admission to ICU increase the COVID-19-related mortality risk at an advanced age. Turkish Ministry of Health data indicate that 76.4% of citizens aged ≥65 years had been vaccinated as of April 2021 (17). Most vaccinated patients were already comorbid and over 65 years of age. Therefore, the Charlson comorbidity index was higher in the vaccinated group. It has been reported that 80–88% of patients admitted to the ICU due to acute respiratory failure were intubated, and invasive mechanical ventilation was applied. The mortality rate was 31%, whereas it was 37% in early-intubated patients (18, 19). While our study’s overall comorbidity rate was 77%, it was 84% in intubated patients. The intubation rate was 65%; 75% of the intubated patients were intubated in the first three days, and invasive mechanical ventilation was initiated. While our overall mortality rate was 62%, it was 92% in intubated patients. The deceased mean age was higher than the survivors. Advanced age, comorbidities, and the need for intubation increased the mortality risk, as supported by our data. Contrary to the literature, gender was not associated with mortality and intubation. Among fully vaccinated people with the CoronaVac vaccine, adjusted vaccine efficacy was 66% protective in preventing COVID-19 infection,88%protectiveagainst hospitalization, 90% protective against the need for an ICU, and 86% protective against COVID-19-related mortality (20). In addition, the CoronaVac vaccine has been effective in people aged 60 years and older. It can be administered safely, although its effectiveness in adults aged 70 years and older has been lower (21, 22). The immune response of individuals 65 and older is lower than that of others (21). Some people might not be able to develop a sufficient immune response against the COVID-19 vaccine (1). Sevinç et al. found that COVID-19- related ICU mortality was 69% in the vaccinated group and 83% in the nonvaccinated group. They reported no difference for vaccinated and nonvaccinated patients regarding the duration of ICU and in-hospital stay and mortality rates (23). Our results were similar to Sevinç et al. No associations were determined between vaccination status, the need for NIV, and ICU hospitalization and mortality duration. Of the vaccinated cases, 58% were older than 70 years. This situation, which adversely affects vaccine efficacy, leading to an increased mortality rate. Patients hospitalized for severe COVID-19 are at a high risk of developing acute kidney injury (AKI). Numerous factors, such as hypervolemia, drug toxicity, vascular injury, and probably the direct cytotoxic effect of the virus, play roles in AKI development. AKI is COVID-19’s most prevalent extrapulmonary manifestation and has been determined to be associated with an increased risk of mortality (24). In our study, increased urea and creatinine levels, indicators of extrapulmonary involvement, were also associated with mortality.

Vaccination against COVID-19 is critical for the immunocompromised kidney transplant population (25). Unfortunately, only 18.8% were reported to develop anti-SARS-CoV-2 IgG antibodies against nucleocapsid and spike antigens in 28 days following the second dose of CoronaVac (26). In patients with a renal transplant, the CoronaVac vaccine was associated with low reactogenicity, low immunogenicity, and low incidence of COVID- 19; however, no reduction in mortality rates was reported (27). In this cross-sectional study, the mean age of the eight renal transplant patients followed up in the COVID-19 ICU was 50 years, the vaccination rate was 75%, and the mortality rate was 50%. There was no significant decrease in mortality despite the high vaccination rate. In this study, the sample size was small, and the time of the last vaccination was unclear. In addition, the patient’s current antibody levels and immune status were unknown upon admission to ICU. Therefore, these conditions were considered the study’s limitations.

Conclusion

There was no association between vaccination and the need for NIV, intubation, length of stay in the ICU, or mortality. However, mortality was associated with age, APACHE II on admission to the ICU, the modified Charlson comorbidity index, elevated fibrinogen, CRP, urea, and creatinine levels, and intubation. Our results suggest the need for comprehensive studies investigating vaccine efficacy, especially in elderly and comorbid patients.