Effect of Qingfei Paidu decoction combined with Western medicine treatments for COVID-19: A systematic review and meta-analysis

Abstract

Background

Qingfei Paidu decoction (QFPDD) showed to be beneficial for the treatment of coronavirus disease 2019 (COVID-19) in China.

Purpose

This study aimed to systematically assemble the evidence on the efficacy and safety of QFPDD combined with Western medicine treatments (WMT) for COVID-19.

Study design

Systematic review and meta-analysis.

Methods

A comprehensive literature search was conducted in PubMed, Embase, Cochrane Library, CNKI, CSTJ, CBM, Wanfang Data for clinical trials with a control arm until January 13, 2022. Studies matched the selection criteria were included. Data extraction and quality assessment of the included studies were independently conducted by two reviewers. Review Manager 5.4 was used for meta-analysis.

Results

A total of 9 trials including 1108 COVID-19 patients met the selection criteria. Meta-analysis demonstrated that QFPDD combined with WMT reduced aggravation rate (AR) by 71% [risk ratio (RR) = 0.29, 95% confidence intervals (CI) (0.17, 0.51)], increased effective rate (ER) by 13% [RR = 1.13, 95%CI (1.04, 1.22)], shortened 4.78 days of viral shedding [95%CI (-5.79, -3.77)] and 4.45 days of hospital stay [95%CI (-6.05, -2.86)], also decreased the incidence of adverse events (AE) by 56% [RR = 0.44, 95%CI (0.22, 0.89)].

Conclusion

QFPDD combined with WMT might reduce the proportion of severe cases and the incidence of AE, shorten the duration of viral shedding and length of hospital stay. More randomized controlled trials (RCTs) are required to confirm our findings in the future.

Graphical abstract

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Introduction

The coronavirus disease 2019 (COVID-19) pandemic is still threatening the global public health (Khanna et al., 2021; Ma et al., 2021). Despite intense scientific effort globally for finding specific drug for treatment of COVID-19 (Cao et al., 2020a; Hariyanto et al., 2021a; 2021b; 2021c; Komoda, 2021, Pan et al., 2020), unfortunately, previous studies demonstrated that some therapeutic agents including remdesivir, hydroxychloroquine, lopinavir/ritonavir, interferon and tocilizumab had not significant clinical effects on treating patients with COVID-19 (Cao et al., 2020a; Hariyanto et al., 2021b; Pan et al., 2020). However, traditional Chinese medicine (TCM) has achieved remarkable curative effect, playing a critical role in controlling COVID-19 (Cao et al., 2020b; Hu et al., 2020; Tian et al., 2020). Recent several meta-analysis studies demonstrated that TCM could improve clinical symptoms (including fever, cough, and fatigue, etc.) and lung lesions, shorten duration of fever and course of disease, and reduce the conversion rate from mild to severe (Fan et al., 2020; Liu et al., 2020; Xiong et al., 2020). Among them, Qingfei Paidu decoction (QFPDD) has shown notable therapeutic effects to treat COVID-19. Of 214 confirmed patients treated with QFPDD from four Chinese provinces between January 27 and February 5, 2020, more than 90% total effective rate (ER) was reached, among which more than 60% of patients presented noticeable improvement in symptoms according to data reported by the State Administration of Traditional Chinese Medicine (NHC, 2020a). QFPDD has been recommended as a general prescription in China (NHC, 2020b; SATCM, 2020).It has widely used all over the country, and achieved remarkable therapeutic effect (Liu et al., 2021a; Ren et al., 2020). QFPDD consists of four classic Chinese medicine prescriptions, i.e., Shegan Mahuang decoction, Maxing Shigan decoction, Xiaochaihu decoction, and Wuling powder, and contains 21 main herbal components (Table 1 ). Previous studies reported that QFPDD has good effectiveness on COVID-19 and can effectively prevent the worse disease progress, improve clinical symptoms and absorption of lung lesions, reduce death rates, while no serious adverse reactions have been reported (Chen et al.,2020b; Ji et al., 2021; Kang et al.,2020; Luo et al.,2021; Ma et al., 2020; Ren et al., 2020; Shi et al., 2020; Wang et al.,2021b; Zhang et al.,2021) . Notably, a study from South Korea showed that QFPDD was the most prescribed herbal medicine for COVID-19 in Korea in the first days of the disease and was the second most prescribed medicine across the whole course. In addition, COVID-19 related symptoms, including fever, dry cough, sore throat, and fatigue were also improved after treatment with QFPDD (Jang et al., 2021). QFPDD is suitable for mild, moderate, severe patients, and can be used reasonably in combination with other drugs for critical patients (NHC, 2020b). Thus, we aimed to systematically assemble the evidence on the efficacy and safety of QFPDD in combination with Western medicine treatment (WMT) for COVID-19 treatment, and provide reference for clinicians in clinical practice.

Table 1.

Components of Qingfei Paidu decoction.

Chinese name(Pinyin)	English name	Latin name	Dose(gram)
Bai Zhu	Largehead Atractylodes Rhizome	Atractylodis Macrocephalae Rhizoma	9
Chai Hu	Chinese Thorawax Root	Bupleuri Radix	16
Chen Pi	Tangerine Peel	Citri Reticulatae Pericarpium	6
Fu Ling	Indian BueadTuckahoe	Poria	15
Gui Zhi	Cassiabarktree Twig	Cinnamomi Ramulus	9
Huang Qin	Baikal Skullcap Root	Scutellariae Radix	6
Huo Xiang	Wrinkled Gianthyssop Herb	Agastache rugosus	9
Jiang Ban Xia	Ternate Pinellia	Pinelliae Rhizoma	9
Kuan Dong Hua	Common Coltsfoot Flower	Farfarae Flos	9
Ma Huang	Chinese Ephedrs Herb	Ephedrae Herba	9
Shan Yao	Common Yan Rhizome	Dioscoreae Rhizoma	12
She Gan	Blackberrglily Rhizome	Belamcandae Rhizoma	9
Sheng Jiang	Fresh Ginger	Zingiberis Rhizoma Recens	15
Sheng Shi Gaoa	plaster stone	Raw Gypsum	15∼30*
Xing Ren	Ansu Apricot Seed	Armeniacae Semen Amarum	9
Xi Xin	Manchurian Wildginger Herb	Asari Radix et Rhizoma	6
Ze Xie	Oriental Waterplantain Tuber	Alismatis Rhizoma	9
Zhi Gan Cao	Liquorice Root	Glycyrrhizae Radix et Rhizoma	6
Zhi Shi	Immature Bitter Orange	Fructus Aurantii Immaturus	6
Zhu Ling	Agaric	Polyporus	9
Zi Wan	Tatarian Aster Root and Rhizome	Asteris Radix et Rhizoma	9

^aNote: Cook in advance 30 min

^⁎If the patient does not have a fever, the amount of gypsum should be little. If having a fever or an attack of fever, the amount of gypsum can be increased.

Methods

This study was conducted following the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) (Moher et al., 2009).

Search strategy

Two reviewers (S.H.L. and L.T.) independently searched PubMed, Embase, Cochrane Library by using English, China National Knowledge Infrastructure (CNKI), China Science and Technology Journal Database (CSTJ), China Biology Medicine (CBM), and Wanfang Data by using Chinese, following search terms: (“COVID-19” OR “2019-nCoV” OR “SARS-CoV-2” OR “the Novel Coronavirus Pneumonia” OR “NPC”) AND (“Qingfei Paidu decoction” OR “QPD” OR “QFPDD” OR “Lung Cleansing and Detoxifying Decoction”) AND (“clinical trial” OR “randomized controlled trial” OR “randomised controlled trial” or “random” or “trial “or “RCT”) from the inception date to January 13, 2022. References of important articles were searched manually for possible relevant studies.

Study selection

Type of studies

We included all types of clinical studies, including randomized controlled trials (RCTs), and non-randomized concurrent trials (non-RCTs).

Type of participants

Trials were considered eligible for inclusion if they were conducted in COVID-19 patients confirmed by “Diagnosis and Treatment Protocol for COVID-19” issued by the National Health Commission, participants enrolled were treated with QFPDD for at least a course (three days), in addition, without restrictions on age, gender, or nationality in the present study.

Type of interventions

We included studies in which patients were given QFPDD combined with WMT in comparison to patients who were treated with WMT alone. However, trials that involved acupuncture, moxibustion, and massage were excluded.

According to the “Diagnosis and Treatment Protocol for Novel Coronavirus Pneumonia Diagnosis and Treatment Protocol for COVID-19” released by National Health Commission & State Administration of Traditional Chinese Medicine, WMT is a therapy that comprises antivirals, antibiotics and/or other supportive treatments such as oxygen therapy, used in Western medicine. Details are shown in Supplementary Table 1.

Prescription forms of QFPDD

In our study, prescription forms of QFPDD were taken from the “Diagnosis and Treatment Protocol for Novel Coronavirus Pneumonia Diagnosis and Treatment Protocol for COVID-19” (NHC, 2020b). The detailed components and doses of QFPDD are shown in Table 1.

All studies in this review used a uniform way to administrate QFPDD, as follows: after admission, patients enrolled in each study received QFPDD, with/without an antibiotic belonging to WMT. The treatments were given twice a day (one in the morning and one in the evening), and three days a course, with a total duration of 3 days-2 weeks with an average of 10 days.

Type of outcome measures

The primary outcomes included Aggravation rate (AR) and Effective rate (ER).

AR refers to the percentage of aggravation. Aggravation was defined to meet one of the following conditions; a) patients with exacerbations during the treatment and turned to severe or critical at least one grade of clinical classification progression of the COVID-19 Treatment Protocol (6th or 7th Edition); b) Hospital transfer was considered as severe or critical COVID-19; c) Transfer to ICU; d) Respiratory failure requiring mechanical ventilation, ECMO, high-flow nasal catheter oxygen therapy, or noninvasive ventilation; e) Shock; f) Death.

ER was defined as the ratio of number of people cured or in remission per group to the total number of people in that group.

The word ‘cured’ referred to having fully recovered and being discharged from the hospitals, while “remission” meant that symptoms, signs, and laboratory indicators were improved in varying degrees. The remission of symptoms must conform to one of following conditions, a) Body temperature returned to normal for more than 1 day: temperature < 37.3 °C (under the armpit) or mouth temperature ≤ 37.5 °C, or anal or ear temperature ≤ 37.8 °C; b) Stop coughing for more than 1 day; c) Stop dry coughing for more than 1 day; d) Fatigue disappeared for more than 1 day; e) Anorexia returned to normal for more than 1 day; f) Sore throat disappeared for more than 1 day.

Secondary outcomes: duration of viral shedding, length of hospital stay and the adverse events (AE) during hospitalizations.

In addition, studies with unavailable full text or incomplete data or similar paper previously published, were excluded from this review.

Data extraction

The titles and abstracts of potentially eligible publications were independently screened by two reviewers (L.T and S.H.L) according to the search strategy. Then, full texts of the possible studies were retrieved and reviewed based on the inclusion and exclusion criteria. The process of study selection was documented using a PRISMA flow diagram (Moher et al., 2009). Data of the included trials were extracted independently by two reviewers (H.J.G and X.Y.J). The following information was retrieved: first author's name, publication year, study design, original place of patients, sample size, severity of disease, mean participant age, sex distribution, complications, diagnostic criteria, interventions in the treatment and control groups, duration, and outcome measures. Any discrepancy was discussed with the third reviewer (N.N.S).

Methodological quality assessment

The methodological quality of trials was graded by two reviewers (N.L. and R.B.C.) independently. RCTs were evaluated according to the Cochrane collaboration risk of bias tool (Higgins et al., 2020), while non-randomized experimental studies were evaluated by methodological index for non-randomized studies (MINORS) (Slim et al., 2003; Zeng et al., 2012).

Data synthesis and analysis

This meta-analysis was conducted using Review Manager 5.4 provided by the Cochrane Collaboration (Higgins et al., 2020). For dichotomous variables, the risk ratio (RR) with 95% confidence intervals (CI) were presented. For continuous variables, the weighted mean difference (MD) with 95% CI were presented. I² statistic were used to quantify the size of heterogeneity among the studies. An I² ≤ 50% indicated a low heterogeneity among studies, and fixed effects model was used to synthesize the estimates, otherwise random effects model was used (Higgins et al., 2003; Ioannidis et al., 2007). In addition, according to the type of studies, we performed subgroup analysis to minimize the heterogeneity.

Results

Study identification

According to the search strategy, 774 potentially relevant publications were searched by both electronic and manual searching approaches. After eliminating duplicates, the titles, abstracts and full text of 279 records were screened. Finally, we included 9 studies with 1108 COVID-19 patients (Chen et al., 2021; Li et al., 2020; Li and Zhang, 2020; Liu et al., 2021b; Wang et al., 2021a; Xin et al., 2020; Yu et al., 2020b; Zeng et al., 2020; Zhang and Pan, 2021). WMT in each study were shown in Supplementary Table 1. The screening process was shown in Figure 1 . Seven papers were published in Chinese and two in English (Liu et al., 2021b; Xin et al., 2020).

Fig. 1.

PRISMA flow diagram of study selection process.

Characteristics of included studies

Nine studies included were all conducted in China. Two were RCTs (Li and Zhang, 2020; Wang et al., 2021a) and the rest were non-RCTs (Chen et al., 2021; Li et al., 2020; Liu et al., 2021b; Xin et al., 2020; Yu et al., 2020b; Zeng et al., 2020; Zhang and Pan, 2021). One study was conducted in several provinces of China (Chen et al., 2021). Six studies were conducted in Hubei province (Li et al., 2020; Liu et al., 2021b; Wang et al., 2021a; Xin et al., 2020; Yu et al., 2020b; Zhang and Pan, 2021), one in Beijing (Zeng et al., 2020), and one in Shanxi province (Li and Zhang, 2020). The sample size ranged from 12 to 446 participants. Among them, 37 non-severe patients were reported in Chen et al. (2021); 55 non-severe patients in Li et al. (2020), 31 moderate patients in Yu et al. (2020b); all patients were severe cases in two studies (Li and Zhang, 2020; Zhang and Pan, 2021). Five studies reported patients had got complications (Chen et al., 2021; Li et al., 2020; Liu et al., 2021b; Xin et al., 2020; Yu et al., 2020b). All research interventions were QFPDD combined with WMT, the course of treatment was no less than 3 days in all studies. Main characteristics were shown in Table 2 .

Table 2.

Characteristics of the 9 studies included in the meta-analysis.

Study	Study design	Study sites	Sample size (T/C)	Disease severity		Gender		Age (years)	Comorbidities		Diagnostic criteria	Intervention		Duration	Outcome measures
				T	C	T (M/F)	C (M/F)	T/C	T	C		T (QFPDD +WMT)	C(WMT)
Li et al. 2020	Non-RCT	Hubei	30/30	Severe (3), Non- Severe (27)	Severe (2), Non- Severe (28)	15/15	13/17	53.60 ± 0.26/ 50.43 ± 0.34	NR	NR	Version 6	QFPDD + WMT	Oseltamivir, Abby dole, Lopinavir/ritonavir, no specific antibacterial, others	NR	AR, ER, LHS, AE
Li and Zhang. 2020	RCT	Shanxi	6/6	Severe (6)	Severe (6)	3/3	2/4	50.00 ± 10.00/ 52.00 ± 6.56	None None		Version 7	QFPDD + WMT	Alpha interferon, Ribavirin, no specific antibacterial, others	NR	ER, LHS, AE
Xin et al.2020	Non-RCT	Hubei	37/26	Moderate (37)	Mild (24), Moderate (2)	17/20	12/14	23.5 – 89.9/ 15.3 – 81.9	DM (4), HBP (7), CAD (4)	DM (3), HBP (9), CAD (1)	Version 6	QFPDD + WMT	Interferon, Abby dole, Lopinavir, No specific antibacterial, others	6d	AR, LHS
Yu et al. 2020b	Non-RCT	Hubei	43/46	Severe (29), Moderate (14)	Severe (29), Moderate (17)	22/21	28/18	64.23 ± 2.51/ 60.50 ± 2.08	HBP (5), DM (5), CAD (3)	HBP (5), DM (4), CAD (2)	Version 6	QFPDD + WMT	No specific drugs were specified, others	10-15d	DVS, LHS
Zeng et al.2020	Non-RCT	Beijing	104/125	Moderate (104)	Moderate (125)	56/48	69/57	46.65 ± 6.21/ 46.21 ± 5.62	None None		Version 7	QFPDD + WMT	Lopinavir, No specific antibacterial, others	NR	DVS, LHS, AE
Chen et al. 2021	Non-RCT	Sichuan, Heilongjiang, Shanxi, Fujian, Guangxi, Chongqing, Hebei	23/22	Severe (4), Non- Severe (19)	Severe (4), Non- Severe (18)	19/4	13/9	47.0 (40.0, 54.0) /43.5 (33.0, 48.5)	Hepatitis b (all), HBP and DM (10)	Hepatitis b (all), HBP and DM (8)	Version 3, 4, 5, 6	QFPDD + WMT	Arbidol, Lopinavir/Ritonavir, Ribavirin, Moxifloxaci, Cephalosporins, others	6d	ER, DVS, LHS
Liu et al.2021	Non-RCT	Hubei	223/223	NR	NR	111/112	113/110	59.0 (51.0 - 66.0)/ 61.0 (49.0 – 69.0)	HBP (43), DM (17), CAD (11), COPD (1), Cancer (6), CVD (5)	HBP (39), DM (10), CAD (14), COPD (1), Cancer (6), CVD (5)	Version 6	QFPDD + WMT	Version 6	3d at least	AR
Wang et al.2021a	RCT	Hubei	70/70	Moderate (70)	Moderate (70)	35/35	36/34	48 ± 13.2/ 49 ± 13.3	None None		Version 6	QFPDD + WMT	Abby dole, Moxifloxacin, others	10d	ER, LHS, AE
Zhang and Pan.2021	Non-RCT	Hubei	12/12	Severe (12)	Severe (12)	6/6	7/5	61.42 ± 13.24/ 62.25 ± 14.69	NR NR		Version 7	QFPDD + WMT	Abby dole, Alpha interferon, Moxifloxacin, others	7d	AR, ER

Abbreviations: AR: aggravation rate; AE: adverse events; C: control group; CAD: coronary artery disease; CKD: chronic kidney disease; COPD: chronic obstructive pulmonary disease; CVD: cerebrovascular disease; DM: diabetes mellitus; DVS: duration of viral shedding; Emp: emphysema; ER: effective rate; F: female; HBP: high blood pressure; LHS: length of hospital stay; M: male; NR: no reported; non-RCT: non-randomized concurrent trial; QFPDD: Qingfei Paidu decoction; RCT: randomized controlled trial; T: treatment group; Version 3: Diagnosis and Treatment Protocol for Novel Coronavirus Pneumonia (Trial Version 3); Version 4: Diagnosis and Treatment Protocol for Novel Coronavirus Pneumonia (Trial Version 4); Version 5: Diagnosis and Treatment Protocol for Novel Coronavirus Pneumonia (Trial Version 5); Version 6: Diagnosis and Treatment Protocol for Novel Coronavirus Pneumonia (Trial Version 6); Version 7: Diagnosis and Treatment Protocol for Novel Coronavirus Pneumonia (Trial Version 7); WMT: Western medicine treatments. In this review, severe patients include severe and critical patients, non-severe patients include mild and moderate patients.

Assessment of methodological quality

Among the nine studies included, two were RCTs (Li and Zhang, 2020; Wang et al., 2021a) and the other seven were non-RCTs. Both the two RCTs did not report the method of generating random sequences, and none of them reported the use of allocation concealment and blinding. However, they reported outcomes completely and no reported outcome selectively. All seven non-RCTs scored fifteen for the risk of bias, and were summarized in Table 3 . In summary, we considered the overall risk of bias of the nine included studies was moderate.

Table 3.

Risk of biases of including non-RCTs by MINORS.

Items	Li et al. (2020)	Xin et al. (2020)	Yu et al. (2020b)	Zeng et al. (2020)	Chen et al. (2021)	Liu et al. (2021)	Zhang and Pan (2021)
A clearly stated aim	2	2	2	2	2	2	2
Inclusion of consecutive patients	1	1	1	1	1	1	1
Prospective collection of data	0	0	0	0	0	0	0
Endpoints appropriate to the aim of the study	2	2	2	2	2	2	2
Unbiased assessment of the study endpoint	2	2	2	2	2	2	2
Follow-up period appropriate to the aim of the study	0	0	0	0	0	0	0
Loss to follow up less than 5%	0	0	0	0	0	0	0
Prospective calculation of the study size	0	0	0	0	0	0	0
An adequate control group	2	2	2	2	2	2	2
Contemporary groups	2	2	2	2	2	2	2
Baseline equivalence of groups	2	2	2	2	2	2	2
Adequate statistical analyses	2	2	2	2	2	2	2
Total	15	15	15	15	15	15	15

Primary outcomes

ER assessment

Five studies (Chen et al., 2021; Li et al., 2020; Li and Zhang, 2020; Wang et al., 2021a; Zhang and Pan, 2021) reported ER, involving 276 patients. We performed subgroup analysis according to different study designs. The results showed that the ER in QFPDD combined with WMT group was better than WMT group alone by 13% [pooled RR = 1.13, 95%CI (1.04, 1.22)] (Fig. 2 ). There was no heterogeneity.

Fig. 2.

Forest plot of QFPDD combined with WMT on ER in COVID-19 patients.

AR assessment

Four studies (Li et al., 2020; Liu et al., 2021b; Xin et al., 2020; Zhang and Pan, 2021) reported the AR involving 593 patients. The results demonstrated that the AR in QFPDD combined with WMT group was lower than that the WMT group by 71% [pooled RR = 0.29, 95%CI (0.17, 0.51)] (Supplementary Figure 1).

Secondary outcomes

Duration of viral shedding (days)

Two studies (Yu et al., 2020b; Zeng et al., 2020) reported the duration of viral shedding, involving 318 patients. The analysis results showed that QFPDD combined with WMT group shortened 4.78 days of viral shedding compared to WMT group alone [pooled MD = -4.78, 95%CI (-5.79, -3.77)] (Supplementary Figure 2).

Length of hospital stay (days)

Seven studies reported the length of hospital stay, of which, two studies (Chen et al., 2021; Xin et al., 2020) reported median. The rest five studies reported mean and standard deviation (Li et al., 2020; Li and Zhang, 2020; Wang et al., 2021a; Yu et al., 2020b; Zeng et al., 2020), involved 378 patients. QFPDD combined with WMT could shorten 4.45 days of hospital stay, compared with WMT alone [pooled MD = -4.45, 95%CI (-6.05, -2.86)] (Supplementary Figure 3).

We also analyzed the length of hospital stay on account of poor homogeneity based on disease severity (p < 0.00001, I² = 98%), and presence or absence of comorbidities (p < 0.00001, I² = 98%).

AE assessments

Five studies (Chen et al., 2021; Li et al., 2020; Li and Zhang, 2020; Wang et al., 2021a; Zeng et al., 2020) reported AE, involving 486 patients. The results showed that QFPDD combined with WMT decreased the occurrence of AE by 56% compared with WMT alone [pooled RR = 0.44, 95%CI (0.22, 0.89)] (Fig. 3 ). AE mainly reflected as nausea, diarrhea, pruritus, other acute respiratory illnesses, and shock.

Fig. 3.

Forest plot of QFPDD combined with WMT on AE in COVID-19 patients.

Sensitivity analyses

We further performed sensitivity analyses using RevMan 5.4 for AR and ER, and the results were not significantly difference in the primary analysis (Supplementary Tables 2-3). The sensitivity analysis for AR and ER were shown in Supplementary Figures 4-5.

Discussion

This meta-analysis showed that QFPDD combined with WMT was more effective in treating COVID-19 than WMT alone. The combination reduced the AR, increased the ER, shortened the duration of viral shedding and the length of hospital stay.

TCM therapy has been used to treat diseases for more than 5,000 years in China (Li and Kan, 2017). Additionally, TCM has a long history in prevention and treatment of infectious diseases (Ren et al., 2020; Yue, 2012). Xu et al. (2020) reported that QFPDD when used alone could regulate the body immunity, inhibit inflammatory response and reduce lung injury based on pharmacology (Xu et al., 2020). Chen et al. (2020a) and Zhong et al. (2020) found QFPDD had a protection effect on COVID-19 by regulating a complex molecular network with safety and efficacy. Part of the mechanism was associated with the regulation of antiviral, anti-inflammatory activity and metabolic programming (Chen et al., 2020a; Zhong et al. 2020). Cao et al. (2020b) and Zhao et al. (2020) demonstrated that QFPDD could exhibit immune regulation, anti-infection, anti-inflammation, and multi-organ protection (Cao et al., 2020b; Zhao et al., 2020).Therefore, QFPDD combined with WMT could improve effectively clinical ER, improve the clinical symptoms and prevent COVID-19 disease based on above reason.

A total of 9 papers were included in our study, the results showed that QFPDD combined with WMT improved clinical ER effectively (Chen et al., 2021; Li et al., 2020; Li and Zhang, 2020; Wang et al., 2021a; Zhang and Pan., 2021), in line with the reports from Jang et al. (2021), Ni et al.(2020), Shi et al. (2020), Sun et al. (2021), Wang et al. (2020), and Zhong et al. (2020). QFPDD combined with WMT shortened duration of viral shedding (Yu et al., 2020b; Zeng et al., 2020) and length of hospital stay (Li et al., 2020; Li and Zhang, 2020; Wang et al., 2021a; Yu et al., 2020b; Zeng et al., 2020), which is consistent with the studies published (Sun et al.,2021; Yu et al.,2020a). Moreover, QFPDD combined with WMT reduced the AR (Li et al., 2020; Liu et al. 2021b; Xin et al., 2021; Zhang and Pan., 2021), which had been proved in previous studies (Ma et al., 2020; Yu et al.,2020a). In addition, Zhang et al (2021) found that QFPDD was associated with a substantially lower risk of in-hospital mortality among hospitalized COVID-19 patients. Additionally, incidence rate of AE was less in QFPDD group (Chen et al. 2021; Li et al., 2020; Li and Zhang, 2020; Wang et al., 2021a; 2021b; Zeng et al., 2020), implying no serious AE related to QFPDD were found. Chen et al. (2021) and Kageyama et al. (2021) demonstrated that no serious AE were observed. Despite most above studies observed that QFPDD combined with WMT improved effective rate and had favorable treatment outcome; Xin et al. (2020) found that neither mortality nor length of hospitalization was affected.

Notably, Wang et al. (2021b) reported a systematic review and meta-analysis on efficacy and safety of QFPDD for treating COVID-19. They observed that QFPDD combined with WMT might decrease the time for nucleic acid conversion, shorten the length of hospital stay, shorten the duration of symptoms recovery of fever, cough and chest CT, improve the overall TCM symptom scores, and change the laboratory indexes. Despite 16 studies were enrolled, seven of them were pre–post studies and one study had no control group. Thus, the conclusions of that review might have more bias.

Conclusion and perspectives

There were several limitations in the present Review. First, all studies involved were conducted in China, thus, we lacked data on QFPDD use outside China. Second, among the nine studies involved, seven were in Chinese and two were in English. There might be potential publication bias. Despite above limitations, our study also has some strengths. The present study assessed efficacy and safety of QFPDD combined with WMT for the treatment of COVID-19 comprehensively and systematically. Moreover, QFPDD combined with WMT for COVID-19 presented favorable outcome, which can provide reference for doctors in clinical practice.

In summary, QFPDD combined with WMT reduces the AR, improves the clinical efficacy, shortens the duration of viral shedding and the length of hospital stay, and decreases AE. Further multi-center RCTs on efficacy and safety of QFPDD is necessary to be conducted in and outside China to confirm our findings.

Authors contributions

Y.Y.W., Y.P.W., H.M.Z., Y.M., and L.Z. designed the study. L.Z., Y.M., and N.L. carried out the statistical analysis, drew the tables and pictures. L.Z., Y.M., N.N.S., S.H.L., and L.T. drafted the manuscript, L.Z. conducted data-analysis and drafted the manuscript; S.H.L., L.T., X.Y.J., R.B.C., Y.P.F., N. L., H.J.G, G.K.C, and Y.M. searched the literature, collected the data, and assessed the methodological quality of included studies; X.Y.J., Y.W.G., and W.W. assisted with the design of PICOs and interpreted the results. Y.Y.W., Y.P.W., H.M.Z., Y.M., and L.Z. conceived the study and over sought the study implementation and provided the methodological guidance, conceived the study, designed the PICOs and interpreted the study results. All authors read and approved the final manuscript.

Funding

This study was supported by CACMS Innovation Fund (CI2021A00704), the National Key Research and Development Project (2018YFC1704401), National Natural Science Foundation of China (82105055), “COVID-19 Project of National Administration of Traditional Chinese Medicine(2020ZYLCYJ07-1), and COVID-19 project of National Administration of Traditional Chinese Medicine (GZY-KJS-2021-007).

Declaration of Competing Interest

The authors declare that they have no competing interests.