key: cord-0915333-me1sn9f8
authors: Xin, Siyi; Cheng, Xueqi; Zhu, Bo; Liao, Xiaolong; Yang, Feng; Song, Lina; Shi, Yan; Guan, Xuefeng; Su, Renyi; Wang, Jian; Xing, Limin; Xu, Xiping; Jin, Lin; Liu, Yanping; Zhou, Wei; Zhang, Dongwei; Liang, Liang; Yu, You; Yu, Rui
title: Clinical retrospective study on the efficacy of Qingfei Paidu decoction combined with Western medicine for COVID-19 treatment
date: 2020-07-04
journal: Biomed Pharmacother
DOI: 10.1016/j.biopha.2020.110500
sha: ea54f0be8f4849679e0f300c650688b90c404592
doc_id: 915333
cord_uid: me1sn9f8

BACKGROUND: Coronavirus disease 2019 (COVID-19) has emerged as a global pandemic. However, as effective treatments for this disease are still unclear, safe and efficient therapies are urgently needed. Qingfei Paidu decoction (QPD) is strongly recommended in the Chinese Novel Coronavirus Pneumonia Diagnosis and Treatment Plan (Provisional 6th Edition). However, clinical research data on the effects of QPD on COVID-19 are scarce. Our study aimed to explore the effects of combined treatment with QPD and Western medicine on COVID-19. METHODS: In this study, 63 patients with confirmed COVID-19 were analyzed. During the first 14 days of hospitalization, patients with deteriorating symptoms were administered QPD along with Western medicine therapy (the antiviral medicine selected from interferon, lopinavir, or arbidol). The clinical characteristics and blood laboratory indices (blood routine, inflammatory factors, and multi-organ biochemical indices) were examined, and the total lung severity scores were evaluated in each patient by reviewing chest computed tomography before treatment and at the end of treatment. RESULTS: Before QPD treatment, the combined treatment group showed higher blood C-reactive protein levels and more severe pulmonary inflammation and clinical symptoms than the Western medicine treatment group. Both groups met the discharge criteria after a similar length of hospitalization. At the end of treatment, circulating white blood cells, total lymphocyte count, and glutamic-oxaloacetic transaminase levels improved dramatically in both groups (P < 0.05). In contrast, C-reactive protein, creatine kinase, creatine kinase-myocardial band, lactate dehydrogenase, and blood urea nitrogen levels were improved only in the combined treatment group (P < 0.05), and C-reactive protein and creatine kinase were the most pronounced (P < 0.01). Compared with baseline, at the end of treatment, the proportion of patients with normal values of C-reactive protein, total lymphocyte count, and lactate dehydrogenase were increased in the combined treatment group (P < 0.05), whereas no significant difference was observed in the Western medicine treatment group (P > 0.05). CONCLUSION: The combination of QPD with Western medicine demonstrated significant anti-inflammatory effects compared with those of only Western medicine in patients with mild and moderate COVID-19; however, neither mortality nor length of hospitalization was affected. Moreover, the combined treatment tended to mitigate the extent of multi-organ impairment. Long-term randomized controlled trials with follow-up evaluations are required to confirm the results presented here.

A novel coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2;

previously named provisionally as 2019 novel coronavirus or 2019-nCoV), was identified in December 2019 in China and is the cause of the coronavirus disease 2019 (COVID-19) [1] . The disease has spread rapidly to many other countries; since early March 2020, there J o u r n a l P r e -p r o o f have been far more active new cases from Europe and the Americas than from China [2] .

Thus, COVID-19 has already become a global health threat [3] .

Although China was the first country in which SARS-CoV-2 was identified [4] , no effective medicines have been developed for the treatment of SARS-CoV-2 infection; thus, safe and efficient treatments are still required urgently. Based on the practical clinical experience in the treatment of this novel coronavirus disease, the official guidelines, Novel Coronavirus Pneumonia Diagnosis and Treatment Plan (Provisional 6 th Edition) (hereinafter referred to as Treatment Plan 6 th ) [5, 6] were published in China; these were the newest version available when this study was designed. The guidelines recommend several Western antiviral medicines (e.g., interferon, lopinavir, and arbidol). In addition, the usage of traditional Chinese medicine (TCM) was proposed in SARS-CoV-2 infection [6] . Notably, the TCM Qingfei Paidu decoction (QPD) is strongly recommended for confirmed cases of different clinical categories [6] .

SARS-CoV-2 is 82%-89% genetically similar to severe acute respiratory syndrome coronavirus (SARS-CoV), which was endemic in China in 2003 [7] . Given the high homology between the viruses, the experience of treating SARS-CoV may be instructive for SARS-CoV-2. In 2003, TCM was shown to exert therapeutic effects on SARS-CoV in China [8] [9] [10] [11] [12] . QPD, as an optimized combination of classic TCM recipes, has been used widely since 200 AD for the treatment of exogenous fever in China. The effects of QPD on SARS-CoV-2 are expected to be promising [13] . QPD comprises 21 TCMs (Table 2 ) [6] , which may reflect the multi-functional protective effects, not only on the lung, but also on the spleen, stomach, heart, liver, and kidney. [13] . Moreover, five of the components (Gan Cao, Chai J o u r n a l P r e -p r o o f Hu, Zi Wan, Kuan Dong Hua, and Huang Qin) are supposed to have potential anti-SARS-CoV-2 effects, as some studies identified they were beneficial for severe SARS-CoV infection [14] [15] [16] . Consistent with this, another study found that QPD contains 948 different chemical compounds, which affect 790 potential target proteins; the interaction between these targets was identified to form a molecular network that plays a crucial role in effects on the lung and in the protection of multiple organs [17] . Therefore, QPD combined with Western medicine (WM) is expected to exert synergistic effects and improve the treatment of COVID-19.

However, to date, the clinical research data on the effects of QPD on COVID-19 are limited; most QPD therapy cases are based on local clinical experience. During our retrospective study, we considered discharge or death as the endpoint. The purpose of this study was to provide clear evidence of the combination treatment of COVID-19 with QPD and WM. 

Diagnostic standards:

Patients having any one of the clinical manifestations (respiratory symptoms with or without fever, significant radiological imaging features of COVID-19) would receive the novel coronavirus nucleic acid test (real-time fluorescence reverse transcription polymerase chain reaction (RT-PCR) detection). A patient that tested positive was considered a confirmed case [6] .

Patients with the following conditions were excluded: a) pregnant or lactating women; b) patients with other severe primary diseases; c) history of a psychiatric or neurological disorder; d) history of abuse (alcohol or drug); and e) other factors affecting the observation of curative effects, such as irregular medication and taking other TCM preparations within 2 weeks before or during treatment.

All the following criteria were required to be satisfied: a) normal body temperature for at least three consecutive days; b) improved respiratory symptoms; c) respiratory acute exudative lesions showing substantial improvement by chest radiology, and d) two consecutive negative nucleic acid tests using respiratory tract samples (taken at least 24 h apart).

J o u r n a l P r e -p r o o f Based on the aforementioned diagnostic standards, 63 patients with confirmed cases of COVID-19 were included in this retrospective analysis. All the confirmed patients were receiving general WM therapy throughout the hospitalization period, including effective oxygen therapy measures, antipyretic measures, rehydration, nutritional support, antiviral treatment, combined with antibiotic treatment in case of bacterial infection, and corticosteroids used only in case of inflammation caused by a cytokine storm.

We assessed the patient's state based on the symptom-rating scale ( Table 1 ) [18] . When the symptoms of the patients worsened (score increased) during the first 2 weeks of hospitalization (as the incubation period of clinical presentation is 1-14 days [6] ), they were administered 6 days of QPD treatment (comprising two consecutive courses, each course lasting 3 days, without a pause between the courses) in addition to WM treatment. Table 2 . The QPD dose was fixed for the administration period. To ensure quality control, all procedures from the purchase of raw materials (batch numbers are shown in Table 2 ) for mixture and boiling were performed by our hospital pharmacy. After boiling the herbs, the herbal liquid was filled into sterilized airtight bags; each bag contained one dose of QPD (200 mL). Trained nurses delivered and guided the patients at each administration of the drug. were collected and examined using the CoV-SARS-2 virus nucleic acid test with real-time RT-PCR (Liferiver Bio-Tech, Shanghai, China). CT was performed using a 64-slice scanner (Aquilion CXL, Toshiba Medical, Japan). The severity of chest CT was judged through assessment of the total lung severity score (hereinafter referred to as the CT score), as described by Bernheim et al. [19] . Briefly, each of the lobes was scored on a scale of 0-4 by evaluating 11 representative CT images; and the final score was determined by summing five lobe scores (to give a score from 0 to 20) [19] . A higher score indicated more severe pulmonary impairment. 

The results are reported as the mean ± SD (for parametric distributed variables) or median and interquartile range (for non-parametric distributed variables) or number and proportion (for counts). Data comparisons between groups were based on the independent sample 

From January 24 to February 15, 2020, 63 of the 99 confirmed patients were eligible. Thirtysix patients were excluded for the following reasons: a) 1 -pregnant, 2 -lactating; b) 16other severe primary diseases (e.g., cancer, severe heart diseases, hepatopathy, nephropathy); c) 2 -history of neurological disorder; d) 4 -history of abuse (alcohol or drugs); and e) 11taking other TCM preparations in the 2 weeks before or during treatment.

When admitted to hospital (baseline), with the exception of two mild cases in the WM group, most patients with COVID-19 were categorized into moderate form. Only CRP levels differed significantly between groups (P < 0.05), as shown in Table 3 . The proportion of J o u r n a l P r e -p r o o f patients who were normal/abnormal for each laboratory index was not different between groups (including CRP, P = 0.103, in the appendix, Table A.1) . In the QPD+WM group, CRP levels were significantly higher than those in the WM group (P = 0.018, Figure 1A ). The same was observed for CT scores (P = 0.035, Figure 1B) , which suggested that patients in the QPD+WM group had more robust responses to inflammation and more severe pulmonary impairment than those in the WM group.

With a maximum of two antibiotics allowed simultaneously during hospitalization, the number of antibiotics was not significantly different between groups (P = 0.269). Three antiviral drugs were available in our hospital; the usage of lopinavir only was lower in the QPD+WM group (P = 0.049). The usage of corticosteroids was not significantly different between groups (P = 0.390), as shown in Table 4 . 

At the endpoint, the WBC, TLC, and GOT showed significantly improved levels in both groups (P < 0.05), whereas BUN, CK, CK-MB, LDH, and CRP levels declined only in the QPD+WM group (P < 0.05), as shown in Table 5 . We assessed the improvement in the proportion of normal values at the endpoint; only CRP, TLC, and LDH showed a significant improvement in the QPD+WM group (P < 0.05), and no significant difference was found in the WM group (P > 0.05, in the appendix, Table A .2). To determine the degree of variation in the indices varying significantly, we calculated the rate of variation (revised value/baseline × 100%) as shown in Figure 2 . The levels of WBC and TLC were upregulated in both groups, and the remaining indices declined; however, there were no differences between groups (P > 0.05). Within groups, for the upregulated indices, the rates of variation of TLC were higher than those of WBC only in the QPD+WM group (P < 0.05); for the downregulated indices of the QPD+WM group, the rates of variation of CRP and CK were significantly higher than those of GOT, LDH, and BUN, as shown in Figure 2 . Bold values depict significant differences in the comparison between the baseline and endpoint within each group. 

Symptom scores were not different between the groups at baseline (Table 3) . At the point at which QPD was added, the symptom scores were significantly higher than those at baseline in the QPD+WM group (8.9 ± 2.7 vs. 6.8 ± 2.5, P < 0.001, Figure 3A ). At the endpoint, symptom scores dramatically decreased in both groups, and no differences were observed Figure 3B ).

At the endpoint, with the exception of the deaths in the WM group, all subjects were discharged. However, mortality was not significantly different between groups (P = 0.065).

Between groups, CT scores and the length of stay were not different at the endpoint (Table   6 ). 

In this study, we have provided evidence of the efficacy of QPD when used in combination with WM for the treatment of COVID-19, highlighting the roles of anti-inflammatory agents, and identified a trend of mitigating the extent of multi-organ impairment.

TCM exerted anti-inflammatory effects when used for the treatment of SARS-CoV in 2003.

TCM enabled a decrease in the dosage of glucocorticoids during initial treatment in 461 cases of SARS [10] . A meta-analysis of 1,678 patients with SARS also indicated that, compared with WM treatment alone, TCM plus WM played a greater role in pulmonary infiltrate absorption, reduced corticosteroid usage, and shortened the duration of fever; however, mortality rates or cure rates were equal between treatments [9] . Houttuynia cordata ameliorated symptoms in patients infected with SARS-CoV; in addition, it inhibited edema and attenuated the inflammatory response in rodents [11] . Yu Ping Feng San and Sang Ju Yin were shown to have beneficial immune modulatory effects on healthy people by increasing blood T-lymphocyte CD4/CD8 ratio [12] . Notably, Huangqi and Baizhu--two principal components of Yu Ping Feng San--are also two of the 21 herbs in QPD.

A strong immune response is possible in patients with COVID-19, and may cause an inflammatory storm [20] . Treatment Plan 6 th also mentions that inflammatory cytokine levels are often higher in severe and critical patients [6] . Furthermore, clinical research has identified that CRP levels [21] and CT image scores are among several factors contributing to the progression of COVID-19 [19, 22] . In our study, at baseline, although the proportion J o u r n a l P r e -p r o o f of patients with normal CRP in the QPD+WM group was equal to that in the WM group, significantly higher CRP levels and CT scores were observed, suggesting that patients in the QPD+WM group would have been better categorized as having a more severe form of COVID-19 than those in the WM group. Subsequently, we observed exacerbated symptoms in patients in the QPD+WM group, verifying the prediction of CRP levels and CT scores on COVID-19 progress.

Nevertheless, at the endpoint in our study, there was an impressive reduction in CRP levels (70%) and an increased proportion of normal values in the QPD+WM group. Improved outcomes in WBC and TLC were also found, which may have beneficial immune modulatory effects in humans. In addition, the patients experienced a similar curative effect (CT and symptoms scores, mortality rates) in both groups over the same length of hospitalization. As described above, the combination of QPD and WM appears to have a greater anti-inflammatory effect than WM alone, with significant signs of pulmonary inflammation absorption compared to those in the WM group.

In addition, a recent study demonstrated that the receptor of SARS-CoV-2 in human cells is angiotensin-converting enzyme 2 (ACE2), which is abundant in the lung and other organs [23] . Unfortunately, the extrapulmonary spread of SARS-CoV in ACE2 + organs has been observed [24, 25] . As a virus with affinity to SARS-CoV, SARS-CoV-2 can be expected to do the same. Meanwhile, extrapulmonary syndromes were observed in patients with COVID-19, such as symptoms of diarrhea in the early stages, or of the cardiac, hepatic, and renal systems, which may be an indication of poor prognosis [20] . Therefore, protection of the related organs is essential as part of antiviral therapy.

Our study also demonstrated the deteriorated blood laboratory indices, which to an extent, reflected multi-organ impairment. Gray et al. [26] have pointed out that the usage of TCM in the treatment of COVID-19 may be "potentially deleterious". In our study, at least during hospitalization, we did not observe any deleterious effects on patients who had taken QPD. .169 J o u r n a l P r e -p r o o f 

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We greatly appreciate the front-line medical staff at the Xiangyang No. 1 People's Hospital for their dedication to fighting against COVID-19. We thank the experts from the Liaoning