Antiviral treatment could not provide clinical benefit in management of mild COVID-19: A Retrospective Experience from Field hospital.

BACKGROUND: Coronavirus disease 2019 (COVID-19) has affected over 145 million infected people and 3 million deaths worldwide. There has been limited data to recommend either for or against use of antiviral regimens in mild COVID-19 patients. This study aimed to compare clinical outcomes between mild COVID-19 patients receiving antiviral drugs and those without.
METHOD: Thai patients diagnosed with COVID-19 at field hospital affiliated to Thammasat University Hospital, Thailand were evaluated between January 1, 2020 and April 13, 2021. Patients' data, clinical presentation, past medical history, laboratory results, and treatment outcomes were extensively reviewed.
RESULTS: Five hundred patients with positive tests were included in the study. The mean age was 35.9 years; 46% males. There were 225 (45%), 207 (41.4%), 44 (8.8%), 18 (3.6%), 6 (1.2%) patients with asymptomatic, mild, moderate, severe, and critical COVID-19, respectively. Of 207 mild COVID-19 patients, 9 (4.3%) received lopinavir/ritonavir or darunavir/ritonavir, 17 (8.2%) received favipiravir, while 175 (84.5%) had only supportive care. Mild COVID-19 patients receiving antiviral treatment had longer median length of hospital stay [13 days (IQR 11-14) vs. 10 days (IQR 8-12), p < 0.001] than patients having only supportive treatment. Antiviral drug use was significantly associated with longer hospital stay (>10 days) in mild COVID-19 patients (OR 5.52; 95%CI 2.12-14.40, p < 0.001). Adverse drug reactions such as diarrhea, abdominal pain, and hepatitis were also demonstrated in our COVID-19 patients with antiviral treatments. Majority of patients (97.6%) recovered without any complications and were discharged home. Two deaths were caused by acute respiratory distress syndrome from severe COVID-19 pneumonia.
CONCLUSION: Antiviral treatment could not provide superior clinical outcomes to supportive care in mild COVID-19 patients. Mild COVID-19 patients receiving antiviral medication had longer length of hospital stay than those without. Standard supportive care and regular monitoring of disease progression might be keys for successful management of mild COVID-19.

Introduction

The high transmissibility of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused the coronavirus disease 2019 (COVID-19) pandemic declared by the World Health Organization (WHO) since March 11, 2020 [1]. Border shutdowns, travel restrictions, and lockdowns inevitably spark fears of an impending economic crisis. For Thailand, the pandemic severely staggers the economy as the tourism sector since March 2020, contributing to 15% of gross domestic product (GDP) [2]. Apart from economy, there has been health controversy to recommend either for or against the use of antiviral regimen in mild COVID-19 patients [3]. Potential antiviral drugs have been recently evaluated in clinical trials in search of effective treatment for the coronavirus outbreak [4,5]. Some trials provided promising results that novel regimen could shorten recovery time or hospital stay [4,6], while another study showed no difference from standard treatment [5]. As researchers have continued to investigate new treatment options, each country needs to develop its own treatment guideline depending on the country’s epidemic situation and resource before specific treatment becomes available.

The first COVID-19 field hospital in Thailand was opened in March 2020 in order to receive referrals from teaching hospitals in the capital and nearby provinces. The field hospital is affiliated to Thammasat University Hospital, the main tertiary hospital located north of Bangkok. In order to establish the field hospital, isolation system between patients and surrounding community must be reassured to the public. Patient transfer process to the field hospital, general wastewater treatment and additional sanitation systems such as utilizing autoclave, chlorination, ultraviolet, and ozone treatment need to be well-designed to ensure sanitation [7]. So far, this field hospital has been reopened and upgraded to 470 beds for patients from the recent outbreak.

As the number of COVID-19 patients were rising, the Ministry of Public Health of Thailand released guideline for management of COVID-19 regarding severity of symptoms. However, there has been limited information about treatment outcomes in this country. This study aimed to compare clinical outcomes between mild COVID-19 patients receiving antiviral drugs and those without antiviral treatment.

Methods

Study design

This retrospective study was conducted at the Thammasat University Hospital and Thammasat University Field Hospital, Thailand between January 1, 2020, and April 13, 2021. Patients over 15 years old diagnosed with COVID-19 were included in this study. Demographic data, clinical presentation, past medical history, laboratory results including a complete blood count and a comprehensive metabolic panel, and treatment outcomes were extracted from medical database and reviewed. Data were analyzed and interpreted by the authors.

Definition

The diagnosis of COVID-19 was defined as a confirmed positive result of real-time reverse transcription-polymerase chain reaction (RT-PCR) of SARS-CoV-2 in either upper or lower respiratory tract samples. The upper respiratory tract samples could be from nasopharyngeal wash/aspirate, nasal wash/aspirate, or nasal swab, while the lower respiratory tract specimens were from tracheal aspirate or bronchoalveolar lavage [8].

Comorbidity was defined as the presence of one or more underlying medical conditions (e.g., diabetes mellitus, hypertension, dyslipidemia, etc.) in addition to the current diagnosis of COVID-19.

Classification of disease severity

Patients were classified into 5 groups by disease severity according to the National Institutes of Health (NIH) as follows [3]:

Asymptomatic infection: Patients who had positive test for SARS-CoV-2 without symptoms.

Mild illness: Patients who had signs and symptoms of COVID-19 (e.g., fever, cough, sore throat, malaise, headache, muscle pain, nausea, vomiting, diarrhea, loss of taste and smell) but did not have dyspnea, or abnormal chest radiograph.

Mild COVID-19 patients were further classified into 2 groups as stated by the updated Thai national guideline for treatment of COVID-19 on June 25, 2021 [9]:

2.1 Mild COVID-19 without risk factor for severe disease

Patients should be isolated at the hospital for at least 14 days from symptom onset and received symptomatic treatment or favipiravir based on clinical decision.

2.2 Mild COVID-19 with risk factor for severe disease

Risk factors include age >60 years, chronic obstructive pulmonary disease, chronic kidney disease, cardiovascular disease, cerebrovascular disease, uncontrolled diabetes, obesity, cirrhosis, immunodeficiency, and lymphocyte <1000 cells/mm3. Patients should receive favipiravir for ≥5 days and be isolated at the hospital for at least 14 days.

The previous national guideline published on May 1, 2020 recommended lopinavir/ritonavir or darunavir/ritonavir for mild COVID-19, which was not stated in the current guideline.

Moderate illness: Patients who had clinical or radiographic evidence of lower respiratory infection and an oxygen saturation (SpO2) ≥94% on room air at sea level.

Severe illness: Patients who had SpO2 <94% on room air at sea level, respiratory rate >30 breaths/min, or lung infiltrates >50%.

Critical illness: Patients who developed respiratory failure, septic shock, and/or multiple organ dysfunction.

Symptom resolution was defined as the time from symptom onset to resolution of symptoms.

Lymphopenia was defined as lymphocyte count of less than 1.5 × 109/L [10] or percentage of lymphocytes less than 20% [11].

Statistical analysis

All data were analyzed by using SPSS version 22 (SPSS Inc., Chicago, IL, USA). The demographic data were analyzed by Fisher’s exact test, or Chi-square test where appropriate. P-value of less than 0.05 was defined as statistical significance.

Results

Baseline characteristics

Total of 500 patients with COVID-19 were studied including 230 men and 270 women with the mean age of 35.9 ± 13.4 (range 15–91) years. All 500 patients were admitted to Thammasat University Hospital or Thammasat University Field Hospital, Thailand. There were 225 (45%), 207 (41.4%), 44 (8.8%), 18 (3.6%), 6 (1.2%) patients with asymptomatic, mild, moderate, severe, and critical COVID-19, respectively. Thailand experienced several waves of COVID-19 spreading. The first outbreak started in early March 2020 and overall cases rapidly declined after lockdown. The second began at the central shrimp market in Samut Sakhon (mid-December 2020) and Pornpat market in Pathumthani province (February 2021) which increased approximately 7 times of previous COVID-19 cases. Recently, the third outbreak has started spreading in entertainment venues in Thonglor, Bangkok in April 2021. The emerging virus was SARS-CoV-2 lineage B.1.1.7, a new variant from the UK, displaying higher transmissibility than the prior two waves as demonstrated in Fig. 1 . Baseline characteristics of each COVID-19 wave were shown in Table 1 . The most common presenting symptoms were fever (35.8%), cough (35.4%), and rhinorrhea (18.6%). Patients in second wave tended to be more asymptomatic than other waves due to active case screening from market vendors and residents in high-risk area. The proportion of critical COVID-19 cases was approximately the same in the first (2.2%) and the third wave (1.4%) as demonstrated in Fig. 2 . Of 207 mild COVID-19 patients, 9 (4.3%) received lopinavir/ritonavir or darunavir/ritonavir, 17 (8.2%) received favipiravir, while 175 (84.5%) had only supportive care.

Fig. 1

Daily new cases and cumulative confirmed COVID-19 cases in Thailand.

Table 1

Baseline characteristics and clinical course classified by waves of COVID-19 spreading.

Characteristics	1st wave (N = 45)	2nd wave (N = 316)	3rd wave (N = 139)	P-value
Mean age (years ± SD)	30.2 ± 9.0	39.0 ± 14.0	30.7 ± 10.8	<0.001
Male, n (%)	20 (44.4%)	151 (47.8%)	59 (42.4%)	0.561
Comorbidity, n (%)	7 (15.6%)	57 (18.0%)	14 (10.1%)	0.098
Exposure, n (%)
Contact of confirmed case	16 (35.6%)	39 (12.3%)	80 (57.6%)
Visit high-risk area	7 (15.6%)	261 (82.6%)	57 (41.0%)
International travel	6 (13.3%)	8 (2.5%)	0 (0%)
Unknown	16 (35.6%)	8 (2.5%)	2 (1.4%)
Alcohol use, n (%)	2 (4.4%)	21 (6.6%)	33 (23.7%)	<0.001
Smoking, n (%)	0 (0%)	17 (5.4%)	22 (15.8%)	<0.001
Clinical manifestations, n (%)
Fever	28 (62.2%)	66 (20.9%)	85 (61.2%)	<0.001
Cough	28 (62.2%)	65 (20.6%)	84 (60.4%)	<0.001
Sore throat	20 (44.4%)	18 (5.7%)	38 (27.3%)	<0.001
Rhinorrhea	16 (35.6%)	44 (13.9%)	33 (23.7%)	<0.001
Anosmia/hyposmia	a	38 (12.0%)	11 (7.9%)	0.027
Myalgia	11 (24.4%)	20 (6.3%)	19 (13.7%)	<0.001
Headache	4 (8.9%)	14 (4.4%)	9 (6.5%)	0.374
Dyspnea	7 (15.6%)	27 (8.5%)	16 (11.5%)	0.267
Nausea/vomiting	7 (15.6%)	6 (1.9%)	3 (2.2%)	<0.001
Diarrhea	6 (13.3%)	14 (4.4%)	12 (8.6%)	0.033

Anosmia and hyposmia were not recorded during the 1st wave of COVID-19.

Fig. 2

Percentage of COVID-19 cases according to severity and wave of spreading.

Clinical course of COVID-19 patients

The median incubation period of patients with mild symptoms [4 days (IQR 2–6)] was not different from those with moderate [3 days (IQR 2–4)], or severe disease [6 days (IQR 3–8.3)]. The mean age and risk factor for severe disease as stated in Thai national guideline were not different between mild COVID-19 patients receiving antiviral therapy or symptomatic treatment. Mild COVID-19 patients receiving antiviral treatment had significantly longer length of hospital stay [13 days (IQR 11–14) vs. 10 days (IQR 8–12), p < 0.001], and a trend of longer time to symptom resolution [11 days (IQR 6–14) vs. 8 days (IQR 5–12), p = 0.067] than patients having only supportive treatment as demonstrated in Table 2 and Fig. 3 . Multivariate analysis, adjusted for age and gender, demonstrated that antiviral drug use was significantly associated with longer hospital stay (>10 days) in mild COVID-19 patients (OR 5.52; 95%CI 2.12–14.40, p < 0.001), while comorbidity, obesity, and lymphocyte <1000 cell/mm3 were not, as shown in Table 3 . Two patients with comorbidity stayed longer in hospital due to adverse effects from antiviral drug which were drug-induced hepatitis, and drug-induced acute gouty arthritis. The duration of viral detection [19 days (IQR 16–22) vs. 16 days (IQR 12.5–28), p = 0.502] was not different between mild COVID-19 patients receiving antiviral drugs and those without. The median time from symptom onset to development of pneumonia in severe COVID-19 patients was 4 days (IQR 3–7). Seven patients developed pneumonia at >7 days after symptom onset. Lymphopenia was more significantly associated with severe/critical COVID-19 than mild/moderate symptom (54.2% vs. 14.7%; OR 6.84, 95%CI 2.85–16.41, p < 0.001).

Table 2

Baseline characteristics and clinical course classified by severity of COVID-19 and treatment received in mild COVID-19.

Characteristics	Mild COVID-19 with symptomatic treatment (N = 175)	Mild COVID-19 with antiviral treatment (N = 32)	Moderate COVID-19 (N = 44)	Severe/critical COVID-19 (N = 24)	P-value between mild symptom group
Mean age (years ± SD)	31.9 ± 12.2	34.3 ± 12.5	44.4 ± 13.7	51.2 ± 13.4	0.307
Male, n (%)	67 (38.3%)	20 (62.5%)	21 (47.7%)	17 (70.8%)	0.011
Comorbidity, n (%)	24 (13.7%)	10 (31.3%)	10 (22.7%)	16 (66.7%)	0.014
Mean BMI, (kg/m2 ± SD)	23.9 ± 4.7	24.8 ± 5.2	26.0 ± 4.9	28.4 ± 4.7	0.588
Risk factor for severe disease	34 (19.4%)	8 (25.0%)	21 (47.7%)	18 (75.0%)	0.471
Clinical course
Incubation period	3.5 (2-5.3)	5 (4-7)	3 (2-4)	6 (3-8.3)	0.046
Symptom onset to admission	4 (3-6)	6 (2-12)	3 (2-5)	4 (2-7)	0.231
Symptom resolution	8 (5-12)	11 (6-14)	10 (8-14)	16 (10.8-23.3)	0.067
Length of hospital stay	10 (8-12)	13 (11-14)	14 (11.3-16)	15.5 (10.3-25)	<0.001
Duration of viral detectiona	16 (12.5-28)	19 (16-22)	18.5 (10.8-25.5)	21.5 (8-23.8)	0.502
Symptoms
Fever (≥37.5 °C)	21 (12.0%)	12 (37.5%)	21 (47.7%)	14 (58.3%)	<0.001
Cough	106 (60.6%)	20 (62.5%)	32 (72.7%)	19 (79.2%)	0.837
Anosmia/hyposmia	38 (21.7%)	2 (6.3%)	6 (13.6%)	3 (12.5%)	0.042
Diarrhea	11 (6.3%)	6 (18.8%)	12 (27.3%)	2 (8.3%)	0.030
Oxygen saturation (%)	98.4 ± 1.2	98.0 ± 1.0	97.2 ± 1.5	87.4 ± 6.3	0.114
Lymphocyte (×109/L)	2.2 ± 0.6	1.8 ± 0.6	1.9 ± 0.8	1.3 ± 0.7	0.006
Medication
LPV/r or DRV/r	-	9 (28.1%)	11 (25%)	17 (70.8%)	<0.001
Favipiravir	-	17 (53.1%)	42 (95.5%)	24 (100%)	<0.001
Dexamethasone	-	1 (3.1%)	20 (45.5%)	20 (83.3%)	0.155
Remdesivir	-	-	-	6 (25.0%)	-

BMI = body mass index, LPV/r = lopinavir/ritonavir, DRV/r = darunavir/ritonavir.

N = 45 due to no longer repeated test for SARS-CoV-2 in patients in the second and third waves of COVID-19 spreading.

Fig. 3

Clinical course of mild COVID-19 patients classified by treatment received.

Table 3

Multivariate analysis of risk factors affecting on longer length of stay in mild COVID-19 patients adjusted by age and gender.

Factors	Longer length of hospital stay (>10 days)
	Odds ratio (95% CI)		P-value
Risk factor for severe disease	0.99	(0.46-2.12)	0.981
Severe comorbiditya	0.68	(0.12-3.97)	0.671
BMI ≥25 kg/m2b	0.81	(0.36-1.81)	0.603
Lymphocyte count <1000 cell/mm3	1.88	(0.16-21.92)	0.614
Antiviral drug use	5.52	(2.12-14.40)	<0.001

Severe comorbidity included either one of the followings: chronic obstructive pulmonary disease, chronic kidney disease, cardiovascular disease, cerebrovascular disease, uncontrolled diabetes, obesity, cirrhosis, immunodeficiency.

BMI = body mass index, BMI ≥ 25 kg/m2 was considered as obesity according to Asian BMI criteria.

Treatment outcomes and complications

The majority of patients (97.6%) recovered without any complications and were discharged home after a median of 9 days (IQR 7–12). Complications were observed in 12 COVID-19 patients: 3 with COVID-19 complications, 5 with adverse drug reactions, 2 with ventilator-associated pneumonia, one with recurrent stroke, and one with acute kidney injury. A 37-year-old woman had acute respiratory failure and myocarditis as complications of COVID-19. She received darunavir/ritonavir, favipiravir, hydroxychloroquine, and azithromycin for severe COVID-19 along with methylprednisolone for myocarditis. Her symptoms improved and later discharged from the hospital. Five adverse drug reactions included one with acute gouty arthritis, one with acute gouty arthritis and drug-induced hepatitis, one with drug-induced hepatitis, and two with diarrhea from darunavir/ritonavir. A 36-year-old man with a history of gout had COVID-19 pneumonia. He had no episode of arthritis in the last 3 years but developed acute attacks of gouty arthritis 4 days after favipiravir was started. The serum uric acid was high (11.9 mg/dL) suspected to be caused by favipiravir-induced hyperuricemia. Moreover, he had elevated transaminase levels which peaked at 9 days after receiving darunavir and decreased to normal level 1 month after drug discontinuation. Two deaths were caused by acute respiratory distress syndrome from severe COVID-19 pneumonia.

Discussion

SARS-CoV-2 has posed global health threat since the beginning of 2020. Until now, there has been no proven effective treatment against the virus. Supportive therapy and monitoring disease progression remain the mainstay of treatment for mild COVID-19 [3]. This retrospective study evaluated clinical outcomes between mild COVID-19 patients receiving antiviral treatment and those without. Patients receiving antiviral drugs had significantly longer median length of hospital stay than patients who had only symptomatic treatment. Moreover, adverse effects from antiviral drugs resulted in extended length of hospital stay in two patients with comorbidity. There was no significant difference in duration of viral detection in respiratory specimen between groups. These could represent the nature of mild COVID-19 which could be recovered without antiviral treatment. Our study result was in concordance with the randomized placebo-controlled trial of lopinavir-ritonavir in hospitalized COVID-19 patients conducted in the UK [12]. However, they included both mild and severe COVID-19 in the RECOVERY trial, while ours observed disadvantages of using antiviral drugs in patients with mild symptoms. Another trial concluded that no clinical benefit was observed in patients receiving lopinavir-ritonavir over standard management, but there were differences regarding the severity of COVID-19 and drugs used in treatment group [5]. The recent study with similar severity of COVID-19 patients as ours demonstrated shorter hospital stay and duration of viral shedding in triple antiviral therapy group than lopinavir–ritonavir control group, but this study did not have a placebo control group [6]. Apart from protease inhibitors, hydroxychloroquine is another drug capable of inhibiting SARS-CoV-2 infection by blocking endosomal transport of viruses as demonstrated in prior in vitro study [13]. Therefore, hydroxychloroquine is included in our prior national treatment regimen for both mild and severe COVID-19. However, as another large observational study indicated hydroxychloroquine might not be efficacious for improving disease outcomes, this medication was no longer use in the current Thai guideline for COVID-19 patients [14].

Risk factors associated with severe COVID-19 were identified in several studies. This study revealed that patients with comorbidities tended to have more severe disease which was similar to the previous study [15]. Prior studies demonstrated better therapeutic response from favipiravir than lopinavir/ritonavir or darunavir/ritonavir in severe [16] and non-severe groups [17]. However, we could not demonstrate difference of disease outcome between these two drugs because favipiravir was used in almost all cases (95–100%) according to our national guideline. Remdesivir was another antiviral drug with proven benefit for shortening recovery time in COVID-19 pneumonia as reported in prior large clinical trial [18]. However, we only used remdesivir in small number of patients with severe COVID-19 pneumonia. The median time from symptom onset to development of severe COVID-19 was 4 days which was shorter than another study [19]. Nevertheless, 7 patients developed pneumonia at more than 1 week after symptom onset. This suggests that mild COVID-19 patients should be regularly monitored for at least 2 weeks from symptom onset as they can develop severe symptoms in this period. In addition to monitoring symptoms for severe disease, laboratory abnormalities such as lymphopenia may be useful in predicting severe COVID-19 [10]. The proportion of severe COVID-19 with lymphopenia in our study (54.2%) was lower than the previous study (96.1%) [20]. This could be because our study population had less severe symptoms than those in the prior study.

Antiviral drugs might be possible causes of complication in 5 patients in this study. Diarrhea is a common side effect of boosted protease inhibitors such as lopinavir–ritonavir and darunavir–ritonavir as demonstrated in 2 patients in this study [21]. Moreover, darunavir and lopinavir are associated with elevated transaminases (>5 times of upper limit of normal) in 3–10% of patients [22]. Two patients in this study had asymptomatic hepatitis which was possibly due to protease inhibitors. Favipiravir can induce hyperuricemia and should be cautiously used in patients with history of gout [23]. Our study revealed two patients with acute gouty arthritis which might be caused by this drug.

Conclusion

In conclusion, antiviral treatment could not provide superior clinical outcomes to supportive care in mild COVID-19 patients. Mild COVID patients receiving antiviral medication had significantly longer length of hospital stay without difference in duration of viral detection. Standard supportive care and regular monitoring of disease progression might be keys for successful management of mild COVID-19.

Conflicts of interest

The authors declare that they have no conflicts of interest.

Ethical approval

Ethical approval for this study was obtained from the Human Research Ethics Committee of Thammasat University, Thailand. The research was conducted according to the good clinical practice guideline, as well as the Declaration of Helsinki. The project number of ethical approval was MTU-EC-IM-0-091/63.