Epidemiology , Clinical Characteristics , And Treatment Outcomes Of Patients With COVID-19 At Siriraj Hospital – Thailand ’ s Largest University-Based Super-Tertiary Referral Center


 Background: The epidemiology and outcomes of COVID-19 patients in Thailand are scarce. Methods: This retrospective cohort study included adult hospitalized patients who were diagnosed with COVID-19 at Siriraj Hospital during February 2020 to April 2020. Results: Of 1,409 patients who underwent reverse transcription polymerase chain reaction (RT-PCR) testing for SARS-CoV-2, 1,029 patients (73%) had risk factors for COVID-19 acquisition of which 107 patients had laboratory-confirmed COVID-19. Among the 104 patients who were treated with antiviral medications, 78 (75%) received 2-drug regimen (lopinavir/ritonavir or darunavir/ritonavir plus chloroquine or hydroxychloroquine), and 26 (25%) received a 3-drug regimen with favipiravir added to the 2-drug regimen. Disease progression was observed in 18 patients (16.8%). All patients with COVID-19 were discharged alive. Conclusions: The prevalence of COVID-19 was 7.5% among patients who underwent RT-PCR testing, and 10% among those having risk factors for COVID-19 acquisition. Combination antiviral therapies for COVID-19 patients were well-tolerated and produced a favorable outcome.

epidemiology and clinical characteristics of patients with COVID-19 in Thailand, and most of those publications are case series or case reports [6][7][8][9].
The aim of this study was to determine the epidemiology, clinical characteristics, and treatment and clinical outcomes of adult patients with COVID-19 at Siriraj Hospital -Thailand's largest university-based tertiary care center.

Materials And Methods
The protocol for this retrospective study was approved by the Institutional Review Board of the Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand (COA no. 319/2020). We reviewed the medical records of all hospitalized patients aged ≥ 18 years who were diagnosed with COVID-19 at Siriraj Hospital during the 1 February 2020 to 30 April 2020 study period. Siriraj Hospital is a 2300-bed national tertiary referral center that is located in Bangkok, Thailand.
Diagnosis of COVID-19 is made based on the detection of ≥ 2 SARS-CoV-2 genes by reverse transcription polymerase chain reaction (RT-PCR) from nasopharyngeal (NP) swab, throat swab, and/or any respiratory samples [10]. Brie y, after collection of the NP or throat swab, the specimen was placed into viral transport media (VTM). RNA was extracted using a magLEAD® 12gC automated extraction platform (Precision System Science, Chiba, Japan). Allplex™ 2019-nCoV Assay (Seegene, Seoul, South Korea) was used for SARS-CoV detection, which includes three gene targets (E, RdRp, and N). Brie y, 8  According to the Thailand national clinical practice guidelines for treatment of COVID-19, combined regimen of antiviral medications was selected based on disease severity and the presence of risk factors for disease progression. Patients with one or more of the following are considered to be at risk for disease progression: age > 60 years or < 5 years, chronic pulmonary disease, chronic kidney disease, cardiovascular disease, cerebrovascular disease, hypertension, diabetes mellitus, obesity (body mass index [BMI] ≥ 35 kg/m 2 ), cirrhosis, immunocompromised status, and/or lymphocyte count < 1,000 cells/mm 3 , as well as the severity of illness (mild and presence of pneumonia). Brie y, two-drug antiviral treatment with a combination of a protease inhibitor (lopinavir/ritonavir or darunavir/ritonavir) and a 4aminoquinoline agent (chloroquine or hydroxychloroquine) is considered for treatment of patients with mild disease regardless of the risk factors for disease progression. Three-drug antiviral therapy with the addition of favipiravir to the two-drug regimen is recommended for patients with COVID-19 pneumonia. Both the 2-and 3-drug combination therapies should be given for at least 5 days, but the duration can be extended to as long as 10 days based on patient's clinical response. All patients with con rmed COVID-19

Patient characteristics
Among the 107 patients with COVID-19, 101 patients (94.4%) presented with symptomatic infection, and 6 patients (5.6%) presented with asymptomatic infection. The proportion of COVID-19 among symptomatic patients was 8.4% (95% CI: 6.8-10.0%), whereas the proportion of COVID-19 among asymptomatic patients was 2.8% (95% CI: 0.6-5.2%). All patients with COVID-19 in our hospital had risk factors for acquiring SARS-CoV-2 infection. Eighty-six patients (80.4%) had a history of contact with con rmed COVID-19 patients from the clusters of COVID-19 outbreak in Thailand (boxing stadiums and must be hospitalized for at least 14 days after symptom onset, and must be isolated for another 14 days at home or at designated facilities [11]. Data that were collected from patient medical records included demographic data, clinical features, underlying illnesses, baseline laboratory parameters, chest X-ray, antiviral therapy, oxygen support, intensive care unit (ICU) stay, and outcome of treatment. The date of disease onset was de ned as the day when the rst symptom was observed. Pneumonia was de ned as fever and/or respiratory symptoms with appearance of new or progressive in ltrate on chest imaging.

Statistical analysis
Data are presented as number and percentage for categorical data, and as mean ± standard deviation for normally distributed data or median and range for non-normally distributed data. Fisher's exact test or chi-square test was used to compare qualitative variables, and t-test or Mann-Whitney U test was used to compare quantitative variables. Variables with a p-value < 0.05 were further analyzed for independent association with pneumonia using multiple logistic regression. All statistical analyses were performed using IBM SPSS Statistics version 20 (SPSS, Inc., Chicago, IL, USA). A p-value less than 0.05 was regarded as being statistically signi cant. pubs), and their families; 15 patients (14.0%) were imported infections; and, 6 patients (5.6%) had a history of visiting crowded public areas (markets, hotels, buses, and restaurants). The proportion of COVID-19 among patients with risk factors for COVID-19 infection was 10.4% (95% CI: 8.5-12.3%).
Among 102 patients with the result of their rst PCR test available, the median cycle threshold (Ct) value of PCR was 25.2 (range: 11.3-40.0), and the median time from onset of illness to specimen collection was 3 days (range: 0-16). The Ct value of rst PCR testing and timing from onset of illness to specimen collection are shown in Figure 2. Sixty-two patients (60.8%) from whom a specimen was collected within less than 5 days of symptom onset had a signi cantly lower median Ct value than the 40% of patients who had a specimen collected at 5 or more days after symptom onset (median Ct value of 21.9 [range: 11.3-37.2] vs. 27.0 [range: 15-40]; p<0.001). No signi cant difference in baseline Ct value (p=0.192) was found when compared among different clinical features on admission ( Figure 3).

Comparison of COVID-19 patients with and without pneumonia
The clinical characteristics, laboratory ndings, treatments, and outcomes of all COVID-19 patients, and compared between those with and without pneumonia are shown in Table 1 and Table 2. Of the 27 patients with COVID-19 pneumonia (25.2%), 19 were diagnosed with pneumonia at the time of admission, and 8 patients developed pneumonia during hospitalization. Median time from symptom onset to the development of pneumonia was 7 days (range: 1-18). Among the 19 patients who were diagnosed with pneumonia at the time of admission, bilateral opacities were found in 13 patients (68.4%), and the other 6 patients (31.6%) had unilateral involvement. All 8 patients who developed pneumonia thereafter had bilateral involvement on their chest X-ray. Patients with COVID-19 pneumonia were older, had a higher BMI, more likely to have comorbidity, more likely to have symptom, such as fever, cough, dyspnea and desaturation, lymphocytopenia, higher C-reactive protein (CRP), lower albumin, and higher globulin than those without pneumonia. Multivariate analysis revealed lymphocytopenia <1,000/mm 3 (odds ratio [OR]: 21.4; 95% CI: 2.8-162.9; p=0.003) and high CRP level (OR: 45.7; 95% CI: 9.4-222.2; p<0.001) to be independent predictors of pneumonia.
Respiratory virus panels and bacterial cultures from respiratory samples were sent in 20 and 13 patients with community-acquired pneumonia, respectively; however, no respiratory coinfection was identi ed. No patients with COVID-19 received concurrent oseltamivir therapy. Antibiotic treatment was given in only 13 patients with COVID-19 (12.1%), and 3 patients received >1 course of antibiotic treatment. Ten patients received empiric antibiotic therapy for community-acquired infections (azithromycin in 4 patients, ceftriaxone plus azithromycin in 4 patients, and levo oxacin in 2 patients). Six patients received antibiotic treatment for nosocomial infections. Among those 6 patients, 5 received antibiotics for treatment of nosocomial pneumonia (meropenem in 3 patients, and piperacillin/tazobactam in 2 patients), and one patient received cefdinir and metronidazole for treatment of perianal abscess. One out of six patients who received antibiotic developed antibiotic-associated diarrhea, and was treated with oral vancomycin.
At the time of hospital discharge, 88 patients (82.2%) were classi ed as mild disease (80 non-pneumonia, and 8 mild pneumonia). Nine patients (8.4%) were classi ed as severe disease due to oxygen desaturation (SpO 2 ≤93%) (1 patient had severe disease, and 8 patients had mild disease at the time of admission). The other 10 (9.3%) were classi ed as critical disease due to the development of ARDS (5 patients had severe disease, and 5 patients had mild disease at the time of admission).

Discussion
COVID-19 continues to cause a global health and economic crisis due to its uncontrolled spreading and the lack of an approved vaccine and treatment option. However, the COVID-19 situation in Thailand remains comparatively stable with a relatively lower fatality rate than many other counties. A combination of two or three antiviral drugs is recommended for all symptomatic COVID-19 patients in Thailand.
The present study revealed the following important ndings. First, the prevalence of COVID-19 at our hospital was approximately 10% among patients with risk factors for COVID-19 acquisition during the COVID-19 outbreak in Bangkok, Thailand. No COVID-19 patient was documented among those without risk factors for COVID-19 acquisition. This nding is different from the epidemiologic reports from other countries where the outbreak situation of SARS-CoV-2 is ongoing [14]. The very low prevalence of COVID-19 among patients without risk factors for disease acquisition is also good supporting evidence for effective control of disease outbreak in Thailand. It should be noted that healthcare facilities in Thailand take an approach of contact tracing, which is a critical step in stopping COVID-19 transmission. After COVID-19 cases are con rmed, healthcare personnel collaborate with public health o cials to identify all persons who have been in close proximity with the case, and those people are monitored daily for 14 days. This may explain why we always identi ed at least one risk factor for COVID-19 acquisition in COVID-19 patients.
Second, the major presenting symptoms in our patients with COVID-19 were fever or history of fever and cough. In contrast, we found rhinorrhea or sore throat to be uncommon, which is similar to many reports from other countries [12,13,15]. In addition, almost 17% of COVID-19 patients in our study presented with acute febrile illness without any respiratory symptoms, which is similar to the ndings from China [15]. This may create signi cant concerns of misdiagnosis when co-epidemics of COVID-19 and other tropical diseases, such as dengue, occur due to the similarity of clinical and laboratory ndings, such as leukopenia. Third, the majority of our patients presented with mild disease as evidenced by the fact that less than 10% of all patients had a baseline NEWS2 score ≥ 5 or qSOFA ≥ 2. However, 18% of patients still had clinical progression to severe or critical disease during hospitalization, which is similar to the ndings of a previous large study conducted in China [12,13,15].
The next important point is that the mortality rate was 0% in this study. This may be explained by several reasons. First, our patients were younger and had milder disease compared with patients included in other studies [12,15]. This can, in part, be explained by the fact that many con rmed cases in our study were linked to two major clusters of COVID-19 outbreak in Bangkok, Thailand, boxing stadiums and pubs.
Approximately 6% of our patients were also asymptomatic at the time of admission. In addition, our patients were all immediately admitted to the hospital upon detection of SAR-CoV-2 for clinical observation and management since it's mandatory in Thailand to admit all COVID-19 patients to prevent transmission to other individuals.
In addition, we found COVID-19 pneumonia to be signi cantly associated with lymphocytopenia and a high CRP level. This nding is similar to that from a previous meta-analysis [16]. In addition, subsequent disease progression was found in approximately 17% of patients in this study, and the presence of underlying disease and high CRP level were identi ed as independent factors associated with disease progression. Lastly, most of the patients with COVID-19 at our hospital received antiviral treatment, including protease inhibitor and antimalarial drugs with or without favipiravir, and both the 2-and 3-drug regimens were quite well-tolerated with no reported serious adverse events. Even though the risk of QT prolongation from hydroxychloroquine was increased in previous study (particularly when being used concurrently with azithromycin), we did not nd any serious cardiac events in our patients, which may be due to younger age, milder disease, and less comorbidity compared with previous study [17].
The strength of this study is that our research shows the clinical and laboratory data from a cohort of patients that acquired COVID-19 during the outbreak period in Thailand. Moreover, the favorable tolerability and clinical outcome of using recommended 2-or 3-drug antiviral regimens for all symptomatic COVID-19 patients according to the Thai national clinical practice guideline (CPG) was demonstrated in this study. The limitation of our study is that the medical record reviewer was not blinded, which could have introduced some unintended bias. Furthermore, we were unable to collect some data, such as EKG results, procalcitonin level, and LDH level, in all patients since these parameters were not routinely tested in patients with COVID-19. Finally, this study was conducted at a single institution, so our results may not be generalizable to other hospitals or care settings.

Conclusion
The prevalence of COVID-19 was 10% among patients with risk factors for COVID-19 acquisition at our university hospital during the outbreak period. Most COVID-19 patients had mild disease, and approximately 18% had severe or critical disease. A combination regimen of two or three antiviral drugs was administered in all symptomatic COVID-19 patients, and all prescribed regimens were well-tolerated and yielded a favorable outcome.    Cycle threshold (Ct) of rst PCR test and onset of illness