TREATMENT PROFILES AND RISK FACTORS FOR CLINICAL OUTCOMES OF CONFIRMED COVID-19 AND PNEUMONIA PATIENTS AT FATMAWATI GENERAL HOSPITAL JAKARTA

Objectives: This study aimed to investigate the treatment profiles and the risk factor for clinical outcomes of confirmed coronavirus disease-19 (COVID-19) and pneumonia patients at Fatmawati General Hospital Jakarta. Methods: This research was conducted using a cross-sectional design at Fatmawati General Hospital Jakarta. A total of 72 adults COVID-19 confirmed patients with pneumonia diagnosis from March to December 2020 were included in our study. Data were collected retrospectively by the patients’ medical record. Results: The percentage of critical or severe confirmed COVID-19 with pneumonia inpatients (66.7%) was higher than those who were having non-severe diseases (33.3%). 36 (50%) death were reported in our patient population. Patients received antiviral, antibiotics, and steroids during a treatment period. The most common antibiotic regimens were levofloxacin intravenous (IV) (18.8%) and azithromycin per oral (PO) (13.9%). Oseltamivir (83.3%) was the most frequently prescribed antiviral for the patients. A total of 41.7% of patients used steroids. In multivariable logistic regression analyses, the severity of COVID-19 disease was the only predictive factor of death in COVID-19 and pneumonia patients (p<0.001, OR=26.714, 95% confidence intervals: 5.526–129.135). Conclusion: Some drugs (antiviral, antibiotics, and steroids) have been prescribed to the confirmed COVID-19 with pneumonia patients. Oseltamivir and levofloxacin were the widely used antiviral and antibiotic agents in this study. The analysis showed that the disease severity was statistically associated with patient’s clinical outcomes. COVID-19 patients with the severe illness have a greater risk of death.


INTRODUCTION
Coronavirus disease-19 (COVID-19) pandemic has drastically affected global health. From December 2019 to August 6, 2021, the disease caused 4,265,903 (2.12%) deaths from 200,840,180 confirmed COVID-19 patients worldwide [1], while the number of COVID-19 cases in Indonesia reached 3,666,031 confirmed cases and 107,096 death cases till August 8, 2021 [2]. COVID-19 is an infectious disease by a new type of coronavirus, severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) [3]. It was more dangerous if pneumonia attacks COVID-19 patients as a complication. The mortality rate of COVID-19 patients with pneumonia was 7.3-8.2% [4]. The rapidly increasing of patients brought a big challenge to public health. Nowadays, definitive therapy for COVID-19 has not been found yet. However, some drugs that have been used for other indications, or new drugs that are still in trials are being researched in various parts of the world. Based on the new WHO COVID-19 guideline (2021), empiric therapy with an antiviral should be considered for patients with severe disease or at risk for severe influenza. Antibiotics also have been used to prevent and treat bacterial coinfection in COVID-19 [5,6]. Profile treatment and the association between demographic or clinical risk factors on the clinical outcomes of COVID-19 and pneumonia patients in Indonesia have been described in only a few studies. Rozaliyani et al. found that mortality was correlated with older age, male, and comorbidity (pre-existing hypertension) [7]. Thus, the purpose of this study was to investigate the treatment profiles and the risk factor for clinical outcomes of confirmed COVID-19 patients and pneumonia at Fatmawati Hospital Jakarta.

Study site
The study was conducted in Fatmawati General Hospital Jakarta, Indonesia, from October 2020 through June 2021. The hospital is one of the referral hospitals for COVID-19 patients in Indonesia with a total of 1165 COVID-19 inpatients from March to December 2020.

Study population description
The study was carried out among COVID-19 confirmed patients with pneumonia diagnosis from March to December 2020 at Fatmawati General Hospital Jakarta.

Study design
The study design was cross-sectional to collect information about the demographic and clinical characteristics, treatments, and the risk factor of COVID-19 with pneumonia patients.

Inclusion criteria
Inclusion criteria included confirmed COVID-19 patients diagnosed with pneumonia by the doctor based on clinical examination and chest X-ray results and adult patients (aged ≥18 years).

Exclusion criteria
Exclusion criteria were patients with incomplete medical record data, pregnant, and breastfeeding women.

Data collection
Data were collected by patient's medical records.

Data analysis
Data analysis was performed using Statistical Product and Service Solutions (SPSS) program version 23. Descriptive analysis for patient characteristics and the treatment profiles was presented in frequency or percentage. The analysis of the correlation between age, gender, comorbidities, COVID-19 severity, and clinical outcomes was carried out by the Chi-square test and assuming that there is a significant difference if p<0.05. Logistic regression was performed to determine the risk factors for patient's clinical outcomes. Crude, adjusted odds ratios (OR), and 95% confidence intervals (CI) are provided as estimates of risk for each outcome.

Ethical issues
The Ethics Committee of the Fatmawati Central General Hospital has approved this study with the number: 23/KEP/XII/2020.

RESULTS
The results showed that of 118 patients diagnosed with confirmed COVID-19 and pneumonia from March to December 2020, 72 patients met the inclusion criteria, and 46 patients were excluded (44 patients medical records were inaccessible, and two pediatric patients).

DISCUSSION
Our study's median length of stay as 15.50 days (IQR 9-20.75) was not much different from the median length of stay of positive COVID-19 patients with CAP and VAP pneumonia, which was 14.5 days (IQR 9.5-28.1) [8]. However, the proportion of deaths in this study was higher (50%) than the previous study in positive COVID-19 patients with pneumonia in Russia (18.75%) [4]. SARS-CoV-2 infection can increase an individual's susceptibility to secondary bacterial infections such as pneumonia. Lung cells infected by SARS-CoV-2 causes damage to the infrastructure of the lung through suppression of the host immune system. Suppression of the immunity by the virus through upregulation of membrane surface proteins expression of the host cell, induction of type I interferon overproduction resulting in dysregulation of cytokines and chemokines, and impaired phagocytic function of alveolar macrophages (AM). This virus-induced lung epithelial damage can cause bacteria to attach, proliferate, and attack lung cells [5,9].
During treatment, antiviral, antibiotics, and steroids were prescribed to patients. According to the COVID-19 protocol by the Indonesian Doctor Association, the recommendations of the antiviral for mild to severe/ critical COVID-19 disease were oseltamivir (Tamiflu), favipiravir (Avigan), or remdesivir [10]. The results showed that oseltamivir was the most common antiviral used in patients. Oseltamivir is indicated for the treatment and prevention of influenza. The mechanism of action of oseltamivir is through neuraminidase inhibition (neuraminidase inhibitor) [11]. Influenza viruses require the enzyme neuraminidase to release newly formed viruses from infected cells at the end of the replication process. Oseltamivir carboxylate as the active metabolite of oseltamivir will interact with neuraminidase. This causes a conformational change in the active site of the enzyme so that enzyme activity is inhibited and the spread of the virus in the respiratory tract decreases [12].
Based on the new WHO COVID-19 management guidelines (2021), empiric antimicrobial therapy is recommended for patients with suspected or confirmed severe COVID-19. The selection of empirical antimicrobial administration should consider the clinical diagnosis, local epidemiology, susceptibility data, and national treatment guidelines [6]. The most common antibiotic regimens were levofloxacin intravenous (IV) (18.8%) and azithromycin per oral (PO) (13.9%). Based   (2021), the prevalence of COVID-19 patients with pneumonia who received antibiotics (single/combination) was 43.8%. However, the main antibiotics used for COVID-19 patients with CAP or HAP in that study were amoxicillin-clavulanate (22.2%), piperacillin/ tazobactam (18.5%), and ceftriaxone (8.6%) [8]. The use of levofloxacin and azithromycin was suitable with the COVID-19 treatment protocol recommended by the Indonesian Doctor Association. The use of azithromycin or levofloxacin IV/PO for 5-7 days can be given if the bacterial infection is suspected in COVID-19 patients [10]. Patients also received steroid therapy in this study. This result is supported by Liu et al. study that 25.9% of COVID-19 patients in Wuhan were also given glucocorticoids. Antiviral was negatively associated with mortality in severe COVID-19 patients (OR: 0.17, p: 0.008). Oseltamivir reduces the risk of death in severe COVID-19 patients, while glucocorticoids increase the risk of progressivity COVID-19 from mild to severe (OR: 3.79; p<0.001) [13].
This research indicates that the COVID-19 severity was statistically associated with the clinical outcome of COVID-19 confirmed and pneumonia patients (p<0.001, OR=26.714, 95% CI: 5.526-129.135). Confirmed COVID-19 with severe or critical diseases has a greater risk for death than non-severe patients in this study. Those results are supported by Rahmani et al. which states that the mortality rate of COVID-19 patients depends on the severity of the disease [14]. The estimated mortality rate of COVID-19 patients with severe disease was greater (32.5%) than COVID-19 patients with the non-severe disease (1.1%) [15].
The severe COVID-19 disease makes patients are more susceptible to severe symptoms and a higher mortality rate, especially for patients with comorbidities, including hypertension, cardiovascular disease, and diabetes [16]. Severe disease in COVID-19 patients is characterized by massive alveolar damage and progressive respiratory failure that may be associated with cytokine storm events. Cytokine storm events are characterized by an increase in pro-inflammatory cytokines such as interleukin-6 (IL-6). IL-6 is a multifunctional cytokine that is involved in the pathogenesis of acute lung injury. These cytokines are produced mainly by pulmonary AM and act as functional mediators for recruiting lymphocytes into lung lesions. The secretion of these cytokines can exacerbate lung injury and accelerate mortality [17].
In this study, comorbidity had a significant effect (p<0.05) according to the bivariate analysis with an odds ratio value of 4, which means that COVID-19 patients with pneumonia who have comorbidities have 4 times greater chance of dying than patients who have no comorbidities. This result is consistent with the previous research that

Harahap et al.
comorbidities can increase the risk of death and disease severity in COVID-19 patients [18].
The variables of age and gender did not affect the clinical outcome of the research subjects. The results of this study differ from a cohort study in China which states that age significantly affects mortality in COVID-19 patients [19]. Another study by Zheng et al. also stated that a greater proportion of patients aged >65 years died and had a critical illness [20]. Elderly COVID-19 patients experience decreased T and B cell function and cytokine overproduction resulting in a deficiency in controlling viral replication and prolonging the pro-inflammatory response [21].
A meta-analysis of 13 studies showed that male was a risk factor for COVID-19 disease progression [21]. Male patients were higher in a critical illness (p<0.001) [20]. Biological, immunological, and endocrine differences explain the reasons for the different outcomes in the two sexes [22]. Women are at lower risk for viral infections because estrogen and progesterone can help enhance innate and adaptive immune responses. Women also have many X-chromosome-related immune genes. Therefore, women had high immune reactivity after viral infection and the viral clearance process will be accelerated [23].
The limitations of this research were the small sample size. Second, the research data collection was retrospective by patient medical records in one referral hospital for COVID-19 patients in Indonesia. Further research is needed with larger sample size or area to represent the population. Third, the effect of therapy on clinical outcomes was not analyzed in this research. Hence, the most effective therapy cannot be known for COVID-19 patients.

CONCLUSION
This research demonstrated that the risk factor for clinical outcomes of the confirmed COVID-19 with pneumonia patients was disease severity. Patients with severe illness have a greater risk to die. Patients received antiviral, antibiotics, and steroids during a treatment period. The most common antibiotics were levofloxacin IV and azithromycin per oral, while oseltamivir was the most frequently prescribed antiviral for the patients. The percentage of patients that used steroids was 41.7%. Future research is needed to find the most effective treatment for COVID-19 patients.