RISK FACTORS ASSOCIATED WITH IN-HOSPI-TAL MORTALITY IN PATIENT WITH SEVERE COVID-19 INFECTION

journal-imab-bg


BACKGROUND
Coronavirus disease (COVID-19) is a pandemic disease, infecting more than 673 million people.Approximately 10 percent of persons with SARS-CoV-2 infection are hospitalized because they develop severe/critical coronavirus disease.Since there is no specific and effective treatment, accurate prediction of the risk of progression of COVID-19 is needed at the time of hospitalization.Clarifying the risk factors for severe illness or mortality presents a clinical puzzle.Individuals with cardiovascular disease (CVD) face heightened susceptibility to infections, with elevated mortality rates in the context of infectious diseases.Notably, comorbidities, particularly age and CVD, have consistently emerged as significant contributors to adverse outcomes in COVID-19 patients, as evident in initial reports [1][2][3][4] and corroborated by European cohorts [5][6].As the number of COVID-19 patients increased, an association was quickly observed between cardiovascular disease (CVD) and COVID-19.[7] Analysis of patients with COVID-19 in critical condition demonstrated that 20-35% of COVID-19 mortalities occurred in those with pre-existing CVD and risk factors.[8] Understanding the burden of CVD amongst COVID-19 mortality can help predict risks and outcomes in specific populations and encourage thoughtful allocation of resources.Our analysis uses national-level data to highlight the patterns of various CVD that contribute to mortality in patients with COVID-19.

METHODS
A total of 165 patients admitted with severe COVID-19 infection above the age of 18 years were enrolled in this study.The study was conducted between December 2020 and December 2021.The data were collected from the electronic medical records of Alexandrovska Hospital.Patient diagnoses relied on positive results from reverse transcription-polymerase chain reaction assays conducted on nasopharyngeal swabs.Standard care was administered to the patients in accordance with the protocols outlined by the Ministry of Health of Bulgaria.All participants signed informed consent.Patients with COVID-19 are considered to have severe illness if they have SpO2 <94% on room air at sea level, PaO2/FiO2 <300 mm Hg, a respiratory rate >30 breaths/min, or lung infiltrates >50%.https://doi.org/10.5272/jimab.2024301.5369

Statistical Analysis
The collected data underwent analysis employing descriptive statistical methods such as mean and standard deviation.Independent samples t-tests were utilized for continuous data comparisons.Categorical data, differentiating between survivors and non-survivors, were subjected to the χ2 test or Fisher's exact test for discerning differences.When comparing the differences between groups, the Mann-Whitney U and t-test were performed for continuous variables.Mortality risk factors were analyzed by multivariate Cox's proportional-hazard model in which variables resulting as significant from the univariate analysis, or those considered relevant from the clinical point of view or previously published literature, were included in a stepwise manner.A multivariate logistic regression model with a stepwise forward selection process was applied to identify the final risk factors from the previous step.A one-tailed p<0.05 was considered statistically significant.Statistical analyses were performed using SPSS Version 23.
Compared with survivors, non-survivors were older, had a higher heart rate and respiratory rate, and had a greater proportion of oxygen saturation (SpO2) reduction on admission.Laboratory results showed that the frequencies of abnormal indicators reflecting tissue and organ necrocytosis, inflammation, liver dysfunction, cardiac dysfunction, kidney dysfunction, and coagulation dysfunc-tion were higher in the death group than in the non-death group (Table 2).Consequently, patients in the death group required more active treatments, including oxygen inhalation, mechanical ventilation, ICU admission and systemic corticosteroid.We also found that the patients with higher levels of blood glucose, which require insulin therapy during hospitalization, have poor outcomes of 25.0% vs. 11.5% (p<0.005).

DISCUSSION
In this study, we systematically analyzed the clinical characteristics, disease progression and risk factors of hospitalized COVID-19 patients.This study evaluated the risk of critical or fatal coronavirus disease among patients with underlying comorbidities.The median age of patients from our setting was similar to those informed in other series from the USA or Europe; [9][10][11] notwithstanding, nonsurvivors were ten years older than survivors.Even though the Bulgarian general population had a high prevalence of comorbid conditions such as hypertension and diabetes, hospitalized patients with COVID-19, particularly those who died, had a remarkably higher frequency of such risk factors than those who survived.The pooled analysis revealed older age is associated with a higher risk of mortality which may be due to lower levels of immune response in these patients.Older age is associated with declined immune competence.[12] We found that age e" 69 was a potential risk factor for COVID-19 death.Comparatively, the progression from non-severe to severe status was more closely correlated with coagulation disorder (D-dimer) and secondary bacterial infection (increased procalcitonin).In addition, we identified and differentiated sets of risk factors that predicted mortality and progression to severe conditions.We found that indicators suggesting the impairment of respiratory function (SpO2 < 95% and increased respiratory rate), impaired renal function (reduced GFR) and glucose metabolism dysregulation (increased blood glucose) were closely associated with disease progression from nonsevere to severe conditions.In addition, we noticed severe bacterial infections, as indicated by procalcitonin levels, largely increased the risk of developing severe cases.Once indicators suggested that multi-organ damage increased at baseline, including increased ALAT, CK levels and reduced GFR, as well as increased blood glucose levels, the rate of mortality increased dramatically.It is interesting that the progression and mortality of COVID-19 are closely associated with multiple organ injuries.The indicators reflecting impaired liver, kidney, and cardiac functions were closely associated with the progression of COVID-19 at admission to death.These organ damages likely involve multiple mechanisms, including direct attacks from SARS-CoV-2, the cytokine storm, hypoxemia, or drug interventions.It has been reported that ACE2, the primary receptor of SARS-CoV-2, is detectable in the heart, vasculature, and kidneys [13].Recent studies have found new receptors (CD147-spike protein, neuropilin-1) that facilitate the entry of SARS-CoV-2 into human cells, which may increase the direct damage of the virus.[14][15] In addition to direct virus attacks, increased leukocyte counts, especially neutrophil counts, may lead to excessive cytokine production, resulting in a cytokine storm and systematic organ injury.[16] For patients with a non-severe status at admission but who progressed to severe disease during hospitalization, apart from patients with severe bacterial infections, those with coagulation disorder (increased D-dimer) had increased odds of disease progression.The increase in Ddimer may be attributed to the new coronavirus damaging vascular endothelial cells, followed by triggering the formation of microthrombi.[17] We also investigated the relationship between existing comorbidities and mortality due to COVID-19.The most prevalent comorbidity among the studied cohorts was hypertension, with a pooled prevalence of 71.6%.Hypertension was associated with a significantly greater risk of critical or fatal outcomes from COVID-19.[18] The findings from the present study become of paramount importance owing to the ongoing global pandemic and the staggering prevalence of hypertension.Hypertensive patients constitute a high-risk population for severe COVID-19 illness and should be prioritized for healthcare services in future waves of this pandemic for greater public health impact in the reduction of mortality due to COVID-19.Furthermore, the presence of comorbid coronary artery disease (CAD), chronic kidney disease, and cerebrovascular diseases was linked to an augmented mortality risk in COVID-19.Surprisingly, chronic lung disease did not show a significant association with an increased risk of death.This contrasts with a prior study, where hospitalized COVID-19 patients with comorbid chronic obstructive pulmonary disease exhibited higher mortality (adjusted odds ratio [aOR]: 1.26, 95% CI: 1.15-1.38,p < 0.0001).[19] Top of Form HF, MI, ischaemic stroke, and AF are prevalent conditions with the highest mortality rates; all with evidencebased therapies.The current study confirms that older age and prior CVD [20,21] are significant risk factors for mortality in COVID-19 disease.We observed strong associations of CAD with COVID-19 mortality risk.Unlike previous studies [22][23][24], we found that having diabetes prior to a positive test was not a significant risk factor for 60-day mortality [25] but might increase the risk of a new onset of heart disease.[26] In the current study, the administration of in-hospital oxygen therapy was correlated with an elevated mortality rate.This finding aligns with a recent study conducted in China, where non-survivors demonstrated a higher likelihood of having received oxygen therapy, including high-flow nasal cannula (89%, p < 0.001), noninvasive mechanical ventilation (57%, p < 0.001), and invasive mechanical ventilation (35%, p < 0.001).[27]

CONCLUSION
This study emphasized specific baseline characteristics as predictive factors for COVID-19 mortality in Bulgaria.Older age, hypertension, cardiovascular disease (CVD), cerebrovascular conditions, and chronic kidney disease (CKD) were notably associated with an elevated risk of death in hospitalized COVID-19 patients.Recog-

Table 1 .
Percentage of lung parenchyma affected by COVID-19 lesions

Table 2 .
Baseline demographic, clinical and laboratory characteristics of the study population

Table 3 .
Current and previous diseases of our cohort