Effective treatment of COVID-19 pneumonia with the Chinese herbal decoction FeiDuQing: A retrospective cohort study

The coronavirus disease (COVID-19) pandemic has had catastrophic consequences globally. Nevertheless, the of the has not been against the and available are limited. (FDQ), a Chinese widely used for COVID-19 in City, has a cure rate of 98.21%. Therefore, evaluating the role in successfully


Results
In contrast to patients who received FDQ, 12 patients who did not receive FDQ (8.45%) developed severe conditions, and one of them died. Furthermore, FDQ treatment was associated with a shortened duration of hospitalization (18.2 vs. 22.1 days, P < 0.0001), even in elderly patients aged > 60 years (18.0 days vs. 26.1 days, P < 0.0001). At discharge, three (1.40%) patients treated with FDQ had mild symptoms, whereas 16 (11.19%) patients not treated with FDQ had various symptoms. The cumulative survival rates of patients treated with FDQ and those not treated with FDQ were 79.04% and 32.60%, respectively (hazard ratio: 0.210, 95% con dence interval: 0.123-0.357, P < 0.001). Additionally, FDQ had no severe adverse effects.

Conclusions
Our ndings suggest that FDQ is a potential therapeutic candidate for ghting COVID-19.

Background
The coronavirus disease  pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has become a serious global health threat. As of May 27, 2021, COVID-19 had spread to 220 countries and territories and caused 3,524,490 deaths worldwide [1]. Currently, no drug has been approved by the Food and Drug Administration for the treatment of COVID-19, except remdesivir, which was authorized only for emergency use in hospitalized patients [2]. However, a recent review of pharmacological, preclinical, and clinical studies has revealed mixed results and various side effects associated with remdesivir [3].
In China, the pandemic has been controlled through strict control measures, vast surveillance systems, and integrated treatment with both Western and traditional Chinese medicine. Although the theories underlying traditional Chinese medicine may appear obscure or complicated by the standards of Western medicine, it has played an important role in controlling epidemics since ancient China [4] and was used extensively during the outbreaks of severe acute respiratory syndrome [5] and in uenza A H1N1 [6].
In this study, we retrospectively examined the use of FeiDuQing (FDQ), a Chinese herbal decoction, for treating hospitalized patients with COVID-19 in Xianning City, Hubei Province, China, using historical data.
Xianning City, known as the South Gate of Wuhan, is a prefecture-level city located 50 miles away from Wuhan, where the original SARS-CoV-2 infections were rst reported. Xianning City has 3 million permanent residents [7], with 200,000 migrant workers who returned from Wuhan before the lockdown [8].
FDQ is composed of 12 herbal components, including divaricate Shaposhnikov root, stir-fried Atractylodes macrocephala, Houttuynia cordata Thunb, Radix Paeoniae Rubra, Chinese thorowax root, Platycodon grandi orum, Fritillaria acuminate, winter mulberry leaf, Ramulus cinnamomi, stir-fried white paeony root, Radix isatidis, and Glycyrrhiza uralensis [9]. It was rst developed at the beginning of the COVID-19 outbreak in Wuhan on January 20, 2020. After successfully curing a 70-year-old woman with a long history of diabetes and a cluster of infection involving ve people, use of FDQ was included in the o cial COVID-19 treatment guidelines in several counties of Xianning City [10].
On March 17, 2020, Xianning City became the rst prefecture-level city in Hubei Province to discharge all of its patients diagnosed with COVID-19, with a cure rate as high as 98.21% [10]. There are seven tertiarylevel hospitals in Xianning City, and more than half of the patients managed at these hospitals were treated with FDQ. This cohort study aimed to assess the role of FDQ in treating COVID-19 pneumonia and to investigate whether it may be an effective therapy for COVID-19.

Study design and patients
In this retrospective cohort study, we reviewed all patients with COVID-19 pneumonia who were admitted to the seven tertiary hospitals in Xianning City, Hubei Province, China, between January 15, 2020 and February 18, 2020. The study duration was not predetermined but represents the period between the rst COVID-19 pneumonia admission to our hospitals and the initiation of FDQ treatment in all patients with NCP in Xianning City. After February 18, 2020, no control patients (non-FDQ treated) were available for the cohort study.
Our inclusion criteria included patients aged 10-90 years who were diagnosed with COVID-19 according to the World Health Organization's interim guidelines [11] and had at least one COVID-19 pneumonia-related symptom. Patients in the FDQ treatment group were required to have received in-hospital FDQ treatment for at least ve consecutive days. We excluded patients who were infected but without signs and symptoms, pregnant, those who received FDQ treatment for < 5 days, and those who were critically ill with organ dysfunction due to other underlying medical conditions. Based on these eligibility criteria, 355 patients with COVID-19 pneumonia were included in this cohort study, with 213 in the FDQ-treatment group and 142 in the non-FDQ-treatment group. All patients provided written informed consent for data collection. The Ethics Committee of The Second A liated Hospital of Hubei College of Science and Technology granted ethical approval for the study (approval # 202002005).
The study was performed in accordance with the tenets of the Declaration of Helsinki.

Procedures
At the time of hospital admission, all patients in both groups received the recommended standard treatments based on the Diagnosis and Treatment Protocol for COVID-19 published by the Chinese National Health Commission (4th to 7th editions) [12]. In addition, FDQ, an herbal decoction composed of 12 herbs, was administered orally twice daily (150 mL per dose) to patients in the FDQ-treatment group. FDQ was provided by the Department of Medication Preparation of each hospital with a Decoctable Packaging Machine (Samyam, LCK2000).
Upon discharge, the patients were required to have met the following criteria: no fever for > 3 days, signi cantly improved respiratory symptoms, obvious resolution of in ammation on chest radiography or computed tomography, and two consecutive negative results for COVID-19 reverse transcription polymerase chain reaction tests performed at > 24-h interval.

Study variables and assessments
We retrospectively collected data related to patient demographics, symptoms, admission and discharge dates, laboratory values, and therapies from patients' medical records. For symptom assessments and laboratory examinations, only values at admission and discharge were available for analyses.
The following features were analyzed: age, sex, hospitalization days, ratio of patients who developed severe conditions and required ventilator support during the treatment course, and symptoms and laboratory values at admission and at discharge.

Statistical analyses
Continuous variables are reported as means and standard deviations if they were normally distributed or as medians and interquartile ranges if they were non-normally distributed. Categorical variables are described as numbers (%) and compared using the chi-square test.
The Kaplan-Meier method and Cox proportional-hazard model were used to analyze the effects of each variable on the outcome of interest (discharged or not discharged by February 26, 2020). Hazard ratios (HR) with 95% con dence intervals (CI) were reported. The differences in the outcome between the two groups were assessed using a Cox regression survival curve and HR.
The threshold for signi cance was set at a P-value of ≤ 0.05. Statistical analyses were performed with SPSS version 24.0 (IBM Corp, Armonk, NY, USA), and graphs were plotted using Prism version 8.0 (GraphPad Software Inc, La Jolla, CA, USA).

Demographic characteristics
A total of 355 patients with COVID-19 pneumonia were included in this study. Among the patients, 142 received only the standard treatment recommended in the Diagnosis and Treatment Protocol for COVID-19, provided by the Chinese National Health Commission [9]. A total of 213 patients were treated with FDQ in addition to the standard treatment protocol. The demographic characteristics of both groups are summarized in Table 1. The average ages and sexes of patients in the FDQ and non-FDQ groups were similar. The average age of the FDQ group was 45.65 ± 14.22 years (range, 13-82 years), and 60.1% were men. The average age of the non-FDQ group was 47.74 ± 13.44 years (range, 15-79 years,) and 60.6% were men (Table 1). We further divided the patients into the following three subgroups by age: ≤30 years, 31-60 years, and ≥ 61 years, and there were no signi cant differences in age or sex observed between these subgroups. Clinical presentations At admission, the most common symptoms were fever, cough, fatigue, and poor appetite. The prevalence rates of these common symptoms (such as fever and cough) were either similar in the FDQ and non-FDQ groups or higher in the FDQ group (such as fatigue and poor appetite) ( Table 2). Less common symptoms included chest pain or pressure, soreness, chills, headache, diarrhea, congested or runny nose, throat discomfort, dizziness, and nausea or vomiting. Other symptoms, including abdominal pain and palpitation, were rare (< 1%).  At discharge, the rate of symptomatic improvement was signi cantly different between the FDQ and non-FDQ groups (P = 0.000). While only three (1.41%) of the 213 patients treated with FDQ had symptoms, 16 (11.19%) patients in the non-FDQ group continued to experience symptoms, including cough (10; 7.0%), fatigue (4; 2.8%), poor appetite (1; 0.7%), shortness of breath (2; 1.4%), nausea (1; 0.7%), palpitation (1; 0.7%), and insomnia (1, 0.7%) ( Table 2). In addition, during the treatment course, 12 (8.45%) of the 142 patients who did not receive FDQ treatment became severely ill, and one patient died. However, no patients in the FDQ group developed any severe conditions, although their clinical manifestations at admission did not signi cantly differ from those who did not receive FDQ treatment (Table 3).  Laboratory tests were performed at admission and discharge. The white blood cell count, lymphocyte count, and neutrophil count were within the normal ranges in most patients in both groups. The C-reactive protein (CRP) and high-sensitivity CRP levels varied widely between individuals, especially at admission (Table 4).  Cox proportional-hazard model analysis We conducted univariate and multivariate Cox proportional-hazard model analyses to further assess the impact of various factors on the event outcome. We de ned the event outcome as "not discharged" from the hospital as of February 26, 2020. Our analysis identi ed treatment without FDQ as the only risk factor for the event outcome in this study (univariate analysis: HR, 0.20; 95% CI: 0.13-0.32; multivariate analysis: HR, 0.21; 95% CI: 0.12-0.36) ( Table 6). Treatment groups were also compared using a Cox regression survival curve. Survival curves were plotted for all patients, as well as for those in different age subgroups. This analysis showed a signi cantly higher survival rate in patients treated with FDQ than in patients not treated with FDQ (P < 0.001) ( Fig. 2A). The cumulative probabilities estimated for all patients who received or did not receive FDQ treatment were 79.04% and 32.60%, respectively. The same conclusions were drawn in the age subgroups: 98.36% vs. 86.11% (P = 0.041) in patients aged ≤ 30 years (Fig. 2B); 80.56% vs. 36.17% (P < 0.001) in patients aged 31-60 years (Fig. 2C); and 51.19% vs. 7.36% (P = 0.017) in patients aged ≥ 61 years (Fig. 2D).

Discussion
This retrospective study evaluated the safety and e cacy of FDQ, a Chinese herbal decoction, in the treatment of patients with NCP. Clinical data showed an association between FDQ treatment and symptomatic improvement, as well as a shortened duration of hospitalization. Symptomatic improvement has also been observed in a separate study, which examined the use of FDQ to treat a big cluster infection in a special population (manuscript submitted for publication by Wang W and Fu B [unpublished data]), in which the most common COVID-19 related symptoms, such as cough and fever, improved or disappeared within 48 hours of FDQ administration. Additionally, FDQ treatment was well tolerated and was not associated with any serious adverse events during the study period. Some patients reported mild diarrhea or abdominal pain, which usually disappeared within 2-3 days.
Several studies have suggested that the risk of severe illness in patients with COVID-19 increases with age, with the highest risk in older adults [13,14]. Consistent with the results of other studies [15,16], we found that the duration of hospitalization increased with age, especially in patients who were not treated with FDQ. However, a similar trend was not observed in patients treated with FDQ who were aged ≥ 31 years. With FDQ treatment, the average length of hospital stay among patients aged ≥ 61 years was only 18.0 days, which did not signi cantly differ from that of 18.7 days in patients aged 31-60 years (P = 0.525), indicating the effectiveness of FDQ for treating NCP. However, the overall duration of hospitalization observed in this cohort study was longer than the median length of 10-13 days that has been reported previously [15]. This discrepancy may have been due to differences in the thresholds for hospitalization.
In addition, on Cox proportional-hazard model analysis, a higher estimated survival rate was observed in patients of all age groups who received FDQ treatment versus those who did not receive FDQ. Moreover, the effects of FDQ were more notable in elderly patients than in young patients, which is important to consider when establishing an effective therapeutic plan for the former patient population.
Recent studies have associated elevated CRP levels with poor outcomes [17,18]. However, we did not nd a correlation between high CRP levels and an increased risk of developing more severe disease in our study. This discrepancy may have been due to the limited sample size or the bene ts of FDQ treatment.
Our study had some limitations because of its retrospective, observational design. First, we did not perform a randomized comparison; therefore, assignment of treatment and patient biases cannot be ruled out.  [19,20]. In addition, FDQ is inexpensive and easy to administer (drinking twice daily), and only minimal side effects have been observed as a result of its use. This observational study suggests that the use of FDQ may provide clinical bene t, although these ndings require validation by randomized controlled trials in the future.

Conclusions
In conclusion, although we cannot rule out the impact of potentially important confounding factors, it is noteworthy that patients who received FDQ recovered faster and had a lower risk of a severe prognosis than did those who did not receive FDQ. We believe that this study shows that FDQ is a promising Availability of data and materials: The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request. Comparison of the lengths of hospitalization between patients treated and those not treated with FDQ.
(A) All patients treated or not treated with FDQ; (B) All patients treated or not treated with FDQ within agestrati ed subgroups: patients aged ≤30 years, 31-60 years, and ≥61 years. FDQ: FeiDuQing