ORIGINAL RESEARCH
Microbes, Infection and Chemotherapy ISSN: 2789 - 4274 https://doi.org/10.54034/mic.e1465
Clinical characteristics of patients hospitalized for COVID-19 vaccinated with at least two doses in a tertiary care hospital in Turkey
Ayşin Kılınç-Toker1, Ayşe Turunç-Özdemir1, Recep Civan-Yüksel2, Esma Eryilmaz-Eren1, İbrahim Toker3, İlhami Çelik4
1Attending Physician of Infectious Disease and Clinical Microbiology. Kayseri City Hospital, Department of Infectious Disease and Clinical Microbiology / Kayseri, Turkey.
2Attending Physician of Intensive Care Unit, Kayseri City Hospital, Intensive Care Units / Kayseri, Turkey.
3Attending Physician of Emergency Medicine. Kayseri City Hospital, Department of Emergency Medicine / Kayseri, Turkey.
4Professor of Infectious Disease and Clinical Microbiology. Kayseri City Hospital, Department of Infectious Disease and Clinical Microbiology / Kayseri, Turkey.
Corresponding author: E-mail:dr.aysin@gmail.com
Orcid ID: *https://orcid.org/0000-0002-6775-1234
Submitted: June 14, 2022
Reviewed : July 18, 2022
Approved: august 27, 2022
Abstract
Background. We aimed to examine the characteristics of Turkish patients hospitalized with COVID-19 despite being fully vaccinated. Method. A retrospective, single-center study was conducted in fully vaccinated patients with inactivated whole virion (CoronaVac) and/or BNT162b2 mRNA (Pfizer-BioNTech) vaccines and admitted to the hospital. We evaluated the hospitalized patients regarding the intensive care unit admission and death. A multivariate binary logistic regression analysis was used to determine the factors for mortality. Results. We conducted the study with 541 patients. The mean age was 70.2, and 52.1% of the patients were women. 73.6% of the patients were 65 years or older. The most common comorbidities were hypertension, diabetes mellitus, and COPD. The rate of the alpha variant was 54.3%, and the delta variant was 29.4%. The mortality rate was 45.8%, and the ICU admission rate was 55.3%. The delta (B.1.617.2) variant had higher ICU admission and mortality rate. Patients vaccinated with two-dose Sinovac-CoronaVac had a higher mortality rate. There was no difference between the time between the last vaccination dose to hospitalization, ICU admission, and mortality. LOS in the hospital was longer in ICU and mortality patients. In multivariate binary logistic analysis; age (odds ratio (OR), 1.06; 95% confidence intervals (95% CI) 1.04-1.08- year increase), male gender (OR, 1.57; 95% CI, 1.04-2.38), presence of comorbid diseases (OR, 4; 95% CI, 2-8) and delta variant (OR, 7.3; 95% CI, 4.4- 12.2) and vaccination with CoronaVac plus BioNTech (OR, 0.21; 95% CI, 0.07-0.62) were associated with death. Conclusion. Our results suggest administering a third and fourth dose of mRNA vaccine to subjects vaccinated primarily with two doses of CoronaVac.
Keyword: BCOVID-19, Vaccine, Hospitalization, Mortality.
Introduction
The COVID-19 pandemic has created one of the biggest health crises in recent history, with a high death rate. The pandemic has demonstrated the importance of the number of people vaccinated in Turkey and other countries(1). There are different types of vaccines in development for COVID-19 around the world. These are inactivated, live attenuated, protein-based, viral vector, m-RNA, and DNA vaccines. Inactivated and mRNA vaccines are used in Turkey. The mRNA and inactivated whole virion SARS-CoV-2 vaccines have demonstrated high efficacy in preventing symptomatic COVID-19, hospitalization, severe illness, and death (2,3). However, a small proportion of fully two or more doses of vaccinated people may become infected and experience significant morbidity or mortality. Therefore, it is essential to examine the real-world effects of COVID-19 vaccines(4).
The Turkish Ministry of Health agreed with two pharmaceutical companies. Individuals received Sinovac-CoronaVac on January 14, 2021, and the Pfizer-BioNTech vaccine on April 12, 2021. We aimed to examine the characteristics of Turkish patients hospitalized with COVID-19 despite being fully two doses of vaccination by CoronaVac and BioNTech.
Method
Study Design and Patients
We conducted a retrospective analysis of hospitalized COVID-19 patients in an urban teaching hospital with a bed capacity of 1607 and 253 intensive care (ICU) beds in Turkey between August 1 and October 31, 2021. According to the NIH disease severity categories, the rRT-PCR-confirmed moderate or severe COVID-19 patients admitted to the infectious disease wards and ICU were included in the study [5]. We had only fully at least two doses of vaccinated patients in this study. The fully vaccinated patients (two doses given) were given the second dose of CoronaVac or Pfizer-BioNTech ≥14 days before hospital admission. Two chart abstractors recorded age, gender, comorbid conditions, and vaccination status data. Total hospital stays until hospital outcome (death or discharge) was calculated.
Hospitalization criteria
Bio-Speedy® SARS-CoV-2 Emerging Plus kit (Bioeksen, Istanbul, Turkey) test was used in the SARS-CoV-2 PCR test on nasopharyngeal swabs to determine the presence of SARS-CoV-2 infection. Bio-Speedy® SARS-CoV-2 Emerging Plus kit can determine Delta (B.1.617.2 and all AY lineages), Alpha (B.1.1.7 and all Q. lineages), Gamma (P.1), Mu (B. 1.621) variants.
Sample size estimation
We used the Stat Calc (Epi Info 7.2.5.0) program to perform sample size calculation, based on the assumptions of a 95% confidence level, 5% margin of error, and an estimated 60% of fully vaccinated individuals in the population, and found 369.
Statistical Analysis
The study's statistical analysis assessed frequency and percentage by categorical data. Also, the continuous data were evaluated as a mean, standard deviation, or median (minimum-maximum) value based on the data distribution. The Shapiro-Wilk test was used to control the normality of continuous measurements. Descriptive statistics for categorical variables was performed using the Chi-square test, while an independent sample t-test was used for continuous data. A multivariate binary logistic regression analysis was used to determine the influence of age, gender, presence of comorbidity, variants, vaccine status, and the time between the last vaccine and illness onset on the probability of mortality. The level of significance was considered to be 0.05.
Ethical Approval
The ethics committee approved this study of Kayseri City Hospital (Approval No. 59/11022022). The signed informed consent was exempted due to the retrospective character of the research.
Results
The study included 541 patients. The mean age of the patients was 70.2± 14.9 (min:21, max:98), and 52.1% (n=282) of the patients were women. 73.6% (n=398) of the patients were 65 years or older. One hundred thirty-one patients (24.2%) had no comorbidity. The most common comorbidities were hypertension 47.7% (n=258), diabetes mellitus 36% (n=195) and chronic obstructive pulmonary disease (COPD) 19.6% (n=106), respectively.
The number of patients with alpha variant was 294 (54.3%), and the number of patients with delta variant was 159 (29.4%). The total number of patients who died in the study was 248 (45.8%), and the number of patients hospitalized in the intensive care unit was 299 (55.3%). The day between the last dose of vaccine and hospitalization was 120.7± 56.2 days. While the mean age of non-survivors was 75.8 ± 10.3 years, that of survivors was 65.5 ± 16.5 years, which was statistically significant (p < 0.001). The age group 65 years and older showed a significantly higher than fewer 65 years old by ICU admission and mortality (all p values were < 0.001). There was no significant difference between genders regarding mortality (p= 0.109). However, female patients were less admitted to the ICU (p= 0.04).
Except for diabetes, there was a statistically significant difference in ICU admission and mortality in the comorbidities; hypertension, COPD, cardiovascular disease, chronic kidney disease, and malignancy (Table 1). When the number of comorbidities exceeded one, ICU admission and mortality rates were higher (p < 0.001).
There was a significant difference between variants in ICU admission and mortality (p values= < 0.001). Delta (B.1.617.2) variant had higher ICU admission and mortality rate.
There was no statistically significant difference in ICU admission between the vaccine product groups (p= 0.107), But the two-dose Sinovac-CoronaVac group had a higher mortality rate (p= < 0.001).
We divided patients into two groups regarding the time between the last vaccination dose and hospitalization. There was no statistically significant difference between the group over 120 days and 14-120 days in ICU admission and mortality (p= 0.973 and 0.928, respectively).
There was a significant difference between the length of stay in the hospital and ICU admission and mortality (p values= < 0.001). ICU and mortality groups had long days in the hospital than the others.
We showed the Demographic and clinical characte-ristics of patients in Table 1.
Table 1 Demographic characteristics of hospitalized and two or more doses of vaccinated patients with COVID-19
| n (%) | |||||||
|---|---|---|---|---|---|---|---|
| non-ICU | ICU | p-value | Survive | Death | Total | p-value | |
| Age. mean (± SD), y | 64.3± 16.8 | 75.1± 11 | < 0.001* | 65.5± 16.5 | 75.8± 10.3 | 70.2± 14.9 | < 0.001* |
| n (%) | 242 (44.7) | 299 (55.3) | 293 (54.2) | 248 (45.8) | 541 (100) | ||
| Age, range,y | |||||||
| < 50 | 48 (19.8) | 8 (3) | < 0.001 | 51 (17.4) | 6 (2.4) | 57 (10.5) | < 0.001 |
| 50-59 | 23 (9.5) | 18 (6) | 29 (9.9) | 12 (4.8) | 41 (7.6) | ||
| 60-69 | 65 (26.9) | 54 (18.1) | 80 (27.3) | 39 (15.7) | 119 (22) | ||
| 70-79 | 69 (28.5) | 112 (37.5) | 81 (27.6) | 100 (40.3) | 181 (33.5) | ||
| > 80 | 37 (15.3) | 106 (35.5) | 52 (17.7) | 91 (36.7) | 143 (26.4) | ||
| Age groups | |||||||
| < 65y | 100 (41.3) | 43 (14.4) | < 0.001 | 112 (38.2) | 31 (12.5) | 143 (26.4) | < 0.001 |
| >65 y | 142 (58.7) | 256 (85.6) | 181 (61.8) | 217 (87.5) | 398 (73.6) | ||
| Gender | |||||||
| Female | 138 (57) | 144 (48.2) | 0,04 | 162 (55.3) | 120 (48.4) | 282 (52.1) | 0,109 |
| Male | 104 (43) | 155 (51.8) | 131 (44.7) | 128 (51.6) | 259 (47.9) | ||
| Comorbidities | |||||||
| Hypertension | 99 (40.9) | 159 (53.2) | 0,005 | 127 (43.3) | 131 (52.8) | 258 (47.7) | 0,028 |
| Diabetes | 78 (32.2) | 117 (39.1) | 0,097 | 99 (33.8) | 96 (38.7) | 195 (36) | 0,235 |
| COPD | 37 (15.3) | 69 (23.1) | 0,023 | 45 (15.4) | 61 (24.6) | 106 (19.6) | 0,007 |
| Cardiovascular disease | 10 (4.1) | 30 (10) | 0,009 | 15 (5.1) | 25 (10.1) | 40 (7.4) | 0,028 |
| Chronic kidney disease | 16 (6.6) | 50 (16.7) | < 0.001 | 19 (6.5) | 47 (19) | 66 (12.2) | < 0.001 |
| Malignancy | 9 (3.7) | 25 (4.6) | 0,027 | 13 (4.4) | 21 (8.5) | 34 (6.3) | 0,05 |
| Number of comorbidities | |||||||
| 0 | 85 (35.1) | 46 (15.4) | < 0.001 | 92 (31.4) | 39 (15.7) | 131 (24.2) | < 0.001 |
| 1 | 78 (32.2) | 97 (32.4) | 98 (33.4) | 77 (31) | 175 (32.3) | ||
| Two or more | 79 (32.6) | 156 (52.2) | 103 (35.2) | 132 (53.2) | 235 (43.4) |
In multivariate binary logistic analysis; age (odds ratio (OR), 1.06; 95% confidence intervals (95% CI) 1.04-1.08- year increase), male gender (OR, 1.57; 95% CI, 1.04-2.38), presence of comorbid diseases (OR, 4; 95% CI, 2-8) and delta variant (OR, 7.3; 95% CI, 4.4- 12.2) and vaccination with CoronaVac plus BioNTech (OR, 0.21; 95% CI, 0.07-0.62) were associated with death among COVID-19 patients. The results of the multivariate binary logistic analysis are presented in Table 3.
Table 2 Clinical characteristics of hospitalized and two or more doses of vaccinated patients with COVID-19
| n (%) | |||||||
|---|---|---|---|---|---|---|---|
| non-ICU | ICU | p-value | Survive | Death | Total | p-value | |
| Variants | |||||||
| Alpha (B.1.1.7) | 180 (74.4) | 114 (38.1) | < 0.001 | 209 (71.3) | 85 (34.3) | 294 (54.3) | < 0.001 |
| Delta (B.1.617.2) | 31 (12.8) | 128 (42.8) | 42 (14.3) | 117 (47.2) | 159 (29.4) | ||
| Others | 31 (12.8) | 57 (19.1) | 42 (14.3) | 46 (18.5) | 88 (16.3) | ||
| Vaccinated patients. by vaccine product | |||||||
| 2 Sinovac- CoronaVac | 167 (69) | 198 (66.2) | 0,107 | 205 (70) | 160 (64.5) | 365 (67.5) | < 0.001 |
| 2 Pfizer-BioNTech | 13 (5.4) | 13 (4.3) | 19 (6.5) | 7 (2.8) | 26 (4.8) | ||
| 2 Sinovac + 1 BioNTech | 31 (12.8) | 28 (9.4) | 38 (13) | 21 (8.5) | 59 (10.9) | ||
| 2 Sinovac + 2 BioNTech | 31 (12.8) | 60 (11.1) | 31 (10.6) | 60 (24.2) | 91 (16.8) | ||
| LOS in hospital. mean (± SD), day | 8.8± 4.2 | 16± 9.6 | < 0.001* | 10.5± 6.5 | 15.4± 9.7 | 12.7± 8.5 | < 0.001* |
| n (%) | 242 (44.7) | 299 (55.3) | 293 (54.2) | 248 (45.8) | 541 (100) | ||
| By the time between the last vaccine and illness onset | |||||||
| 14-120 Days | 108 (44.6) | 133 (44.5) | 0,973 | 130 (44.4) | 111 (44.8) | 241 (44.5) | 0,928 |
| >120 Days | 134 (55.4) | 166 (55.5) | 163 (55.6) | 137 (55.2) | 300 (55.5) |
Table 3 Multivariate binary logistic regression analysis for mortality
| Factors | Odds ratio | 95% CI | p-value |
|---|---|---|---|
| Age in years | 1,06 | 1.04-1.08 | < 0.001 |
| Gender | |||
| Female | Reference | 0,031 | |
| Male | 1,57 | 1.04- 2.38 | |
| Comorbidities | |||
| Absent | Reference | < 0.001 | |
| Present | 4 | 02-ago | |
| Variants | |||
| Alpha (B.1.1.7) | Reference | ||
| Others | 2,5 | 1.4- 4.4 | 0.001 |
| Delta (B.1.617.2) | 7,3 | 4.4- 12.2 | < 0,001 |
| Vaccination | |||
| CoronoVac | Reference | ||
| BioNTech | 0,48 | 0.25- 0,91 | 0,026 |
| CoronaVac plus BioNTech | 0,21 | 0.07- 0.62 | 0,005 |
| The time between the last vaccine and illness onset, days | 0,99 | 0.99-1 | 0,833 |
Discussion
We conducted the study with 541 patients. The mean age was 70.2, and 52.1% of the patients were women. 73.6% of the patients were 65 years or older. The most common comorbidities were hypertension, diabetes mellitus, and COPD. The rate of the alpha variant was 54.3%, and the delta variant was 29.4%. The mortality rate was 45.8%, and the ICU admission rate was 55.3%. The day between the last dose of vaccine and hospitalization was 120± 56 days. Sixty-five years and older was higher ICU admission and mortality, and female patients were less admitted to the ICU. Except for diabetes, ICU admission and mortality were higher in the comorbidities. The delta (B.1.617.2) variant had higher ICU admission and mortality rate. There was no difference between the time between the last vaccination dose to hospitalization, ICU admission, and mortality. Patients vaccinated with two-dose Sinovac-CoronaVac had a higher mortality rate.
Similar to the literature, we found advanced age, male gender, and comorbidities associated with poor outcomes such as mortality and ICU admission (6). Diabetes mellitus prepare the ground for the severe course of COVID-19 and is known to increase the risk of death (7), but we did not find this result in our study.
Our study's in-hospital mortality rate was relatively high compared to the literature (8,9). We think the mortality rate is high, as our research mainly included elderly patients with moderate and severe COVID-19.
There is a higher risk of hospital admission and death for COVID-19 patients infected with the delta than the alpha variant. The delta variant causes a more significant health burden than the alpha variant, especially in unvaccinated populations (10,11). Our study included only vaccinated individuals, and the delta variant had an approximately sevenfold risk of death compared to alfa.
For approximately six months after two vaccine doses, protective antibodies decrease about five times in the BNT162b2 vaccine and six times in the CoronaVac vaccine (12,13). In our study, the average time between hospitalization after the second dose was four months and was not associated with death or ICU admission. Our research results conclude that both vaccines effectively prevent death and ICU admission.
CoronaVac, produced by the Sinovac company, is the world's most widely used COVID-19 vaccine. The CoronaVac vaccine is an inactivated vaccine that uses the killed SARS-CoV-2 virus and is less effective because it triggers an immune response against many viral proteins. In contrast, mRNA vaccines react to the spike protein the virus uses to enter human cells (14). The Chilean government has reported that, based on data from nearly two million people who received two doses of CoronaVac and the third dose of CoronaVac, Pfizer-BioNTech or Oxford-AstraZeneca vaccine, protection against COVID-19 increased from fifty percent to eighty percent after two vaccinations (15). In our study, patients were given a third or fourth dose of the Pfizer-BioNTech vaccine after two doses of the CoronaVac vaccine. CoronaVac plus BioNTech group had an approximately fivefold decreased risk of death compared to the CoronaVac group. In light of this information, we suggest administering a third and fourth dose of mRNA vaccine to subjects vaccinated primarily with two doses of CoronaVac.
Our study has several limitations. The main limitations of our study include its retrospective design, short follow-up period, and assessment of hospitalized patients only. Another limitation of the study; we only examined moderate and severe patients.
In conclusion, our study found that patients vaccinated with only two-dose CoronaVac had a higher mortality rate, and CoronaVac plus BioNTech group had about five times decreased mortality risk. Although the patients were hospitalized four months after the vaccination, there was no significant difference between the post-vaccination time and ICU/ mortality. In our study, the delta variant had higher ICU admission and mortality rate. Our study suggests a third and fourth dose of mRNA vaccine to subjects vaccinated primarily with two doses of CoronaVac.
Acknowledgments
None.
Funding
None.
Competing Interests
The authors have no commercial associations or sources of support that might pose a conflict of interest.
Author Contributions
All authors contributed to the study's conception and design. Material preparation, data collection and analysis were performed by Ayşin Kılınç Toker, Ayşe Turunç Özdemir, Recep Civan Yüksel and Esma Eryilmaz Eren. İlhami Çelik and İbrahim Toker wrote the first draft of the manuscript, and all authors commented on previous versions. All authors read and approved the final manuscript.
Data Availability
The datasets generated during and analyzed during the current study are not publicly available due to the vaccination detail of patients. However, they are available from the corresponding author upon reasonable request.
Ethics approval
The ethics committee approved this study of Kayseri City Hospital (Approval No. 59/11022022).
Consent to participate
The signed informed consent was exempted due to the retrospective character of the research.
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