key: cord-0933556-lj9x85uh
authors: Huang, Luqi
title: Efficacy and Safety Assessment of Severe COVID-19 Patients with Chinese Medicine: a Retrospective Case Series Study at Early Stage of the COVID-19 Epidemic in Wuhan, China
date: 2021-01-30
journal: J Ethnopharmacol
DOI: 10.1016/j.jep.2021.113888
sha: 9419fed808166929765db8c25ef751c439fbd192
doc_id: 933556
cord_uid: lj9x85uh

ETHNOPHARMACOLOGICAL RELEVANCE: The coronavirus disease 2019 (COVID-19) has formed a global pandemic since late 2019. Benefit from the application experience of Chinese Medicine (CM) for influenza and SARS, CM has been used to save patients at the early stage of COVID-19 outbreak in China. AIM OF THE STUDY: In order to evaluate the efficacy and safety of CM, and comparing with that of Western Medicine (WM) for COVID-19, we conducted a retrospective case series study based on the patients in Wuhan Jinyintan Hospital, Wuhan, China. METHODS: The inclusion and exclusion criteria of data extraction was set for this retrospective study. All patients who were admitted by the Wuhan Jinyintan Hospital between January 17 and February 25, 2020 were considered. In addition, patients enrolled met the severe defined by the guidelines released by the National Health Commission of the People’s Republic of China. In these cases included in the study, CM or WM treatment was selected according to the wishes of the patients at the beginning of hospitalization. The patients in CM group was treated with Huashi Baidu granule (137 g po, bid) combined with the injections of Xiyanping (100 mg iv, bid), Xuebijing (100 ml iv, bid,) and Shenmai (60 ml iv, qd) according to the syndrome of epidemic toxin blocking the lung in the theory of Traditional Chinese Medicine. The WM group received antiviral therapy (including abidor capsule 0.2 g po, tid; Lopinavir–Ritonavir tablets, 500 mg po, bid), antibiotics (such as cefoperazone, 2 g iv, bid; moxifloxacin hydrochloride tablets, 0.4 g po, qd) or corticosteroid therapy (such as methylprednisolone succinate sodium, 40mg, iv, 40 mg, qd; prednisone, 30 mg po, qd). In addition, patients in both groups received routine supportive treatment, including oxygen inhalation, symptomatic therapy, and/or human intravenous immunoglobulin, and/or serum albumin, and therapy for underlying diseases. The clinical outcomes were evaluated based on changes before and after the treatment related with clinical manifestations, computer tomography (CT) scan images, and laboratory examinations. RESULTS: 55 severe COVID-19 patients, with 23 in CM group and 32 in WM group, were included for analyzed. There was no case of death, transferred to ICU, or received invasive mechanical ventilation in two groups during hospitalization. The median time of SARS-CoV-2 RNA clearance in CM and WM group were 12 days and 15.5 days (P=0.018). Further, the chest CT imaging showed more widely lung lesion opacity absorbed in the CM group (P<0.05). The C-reactive protein level, erythrocyte sedimentation rate, serum ferritin, and myoglobin decreased significantly in the CM group (P<0.05). There was no significant difference in adverse events in terms of liver function and renal function between the two groups. CONCLUSION: Based on this retrospective analysis from Wuhan Jinyintan Hospital, CM has better effects in SARS-CoV-2 RNA clearance, lung lesion opacity absorbed and reduced inflammation in severe COVID-19 patients, is effective and safe therapy for treating severe COVID-19 and reducing mortality.

In December 2019, a sudden epidemic of pneumonia occurred in Wuhan, China. The etiologic agent of the pneumonia was reported to be the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and the disease was officially named coronavirus disease 2019 (COVID-19) on February 11, 2020 (Zhu N, et al., 2019; Huang C, et al., 2020; Zhang HT, et al., 2020; Xin S, et al., 2020; WHO a, 2020) . The COVID-19 is characterized by influenza-like symptoms, including fever, cough, severe acute respiratory distress syndrome and, in some cases, death . The World Health Organization (WHO) described the ongoing epidemic as a pandemic on March 11, 2020 (WHO b, 2020 . As of 30 October, 2020, a total of 44 888 869 cases and 1 178 475 deaths had been documented globally (WHO c, 2020) . The COVID-19 pandemic has become a great threat to global health. (Arshad Ali S et al., 2020) . Unfortunately, there is still no efficacy and safety therapy.

Chinese Medicine (CM) has been used to prevent and treat new outbreaks of infectious diseases for thousands of years . With the application experience of Chinese Medicine for influenza and SARS (Li JH, et al., 2016; Wu L, et al., 2020; Leung PC, 2007; Ho TY, et al., 2007; Chen Z, et al., 2004; Jia W, et al., 2003; Lau JT, et al., 2005; Liu X, et al., 2012) , CM was applied for the treatment of COVID-19 at the beginning of the epidemic of COVID-19 in Wuhan.

China National Medical Task Force of Traditional Chinese Medicine (TCM) for COVID-19 has been formed by the State Administration of Traditional Chinese Medicine of the People's Republic of China (SATCM) on January 24, 2020. The team member of CNMGTCM-COVID19, including medical staff from the emergency and respiratory departments of Guanganmen Hospital and Xiyuan Hospital who have experienced in SARS treatment, are the member of this Task Force.

The protocol has been issued by the National Health Commission (NHC) on January 15, 2020, which has been revised periodically, and practiced throughout China. CNMGTCM-COVID-19 from China Academy of Chinese Medical Sciences took the lead in using CM to treat patients with severe COVID-19 in Wuhan Jinyintan Hospital which is the largest of an infectious disease hospital in Wuhan.

In order to objectively reflect the efficacy and safety of CM on COVID-19 at that time, CNMGTCM-COVID-19 conducted a retrospective review to evaluate the efficacy and safety of CM, comparing with that of WM treatment. The results indicate J o u r n a l P r e -p r o o f that CM has better effects in SARS-CoV-2 RNA clearance, lung lesion opacity absorbed and reduced inflammation in severe COVID-19 patients, is effective and safe therapy for treating severe COVID-19 and reducing mortality.

We also wish the data from this assessment can provide the data to the healthcare providers a choice for COVID-19 patients, especially there are no effective western medicine drugs available now worldwide.

This study was a retrospective case series study, the enrolled patients were required to met the inclusion and exclusion criteria.

Inclusion criteria including 1) all patients were admitted between January 17, 2020 and February 25, 2020; 2) all patients had complete medical records during their hospitalization. 3) all patients over 18 years old; 4) all patients with laboratory confirmed SARS-Cov-2 RNA infection; 5) all patients met the severe defined by the "Diagnosis and Treatment Protocol for Novel Coronavirus Pneumonia (7th Interim Edition)" released by NHC (NHC, 2020); 6) all patients were treated in the wards in charge of the CNMGTCM-COVID-19 in Wuhan Jinyintan Hospital; 7) CM or WM treatment was selected according to the wishes of the patients at the beginning of hospitalization, and the two treatments met the treatment protocol defined by the "Diagnosis and Treatment Protocol for Novel Coronavirus Pneumonia (7th Interim Edition)" released by NHC (NHC, 2020); 8) the clinical manifestation of the patients treated with CM were consistent with the syndrome of epidemic toxin blocking the lung in the theory of TCM.

Exclusion criteria including 1) other types of viral pneumonia; 2) mild or critical cases of COVID-19; 3) patients who need emergency surgery or other intensive care; 4) mental illness; 5) pregnant or lactating women; 6) patients participating in clinical trials for other intervention.

Patients were discharged if two repeated tests of SARS-CoV-2 virus polymerase chain reaction (PCR) test of pharyngeal swabs turned out to be negative, and the chest computed tomography (CT) imaging was improved.

The patients in CM group was treated with Huashi Baidu granule (137 g po, bid) combined with the injections of Xiyanping (100 mg iv, bid), Xuebijing (100 ml iv, bid,) and Shenmai (60 ml iv, qd) according to the syndrome of epidemic toxin blocking the lung in the theory of TCM.

The composition of Huashi Baidu granule is as follows: Ephedrae Herba (Mahuang), 6 g; Armeniacae Semen Amarum (Kuxingren), 9 g; Gypsum Fibrosum (Shigao), 15 g; Radix Rhizoma Glycyrrhizae (Gancao), 3 g; Herba Agastaches (Huoxiang), 10 g; Magnoliae Officmalis Cortex (Houpu), 10 g; Atractlodis Rhizoma (Cangzhu), 15 g; Fructus Tsaoko (Caoguo), 10 g; Pinelliae Rhizoma (Fabanxia), 9 g; Poria (Fuling), 15 g; Rhei Radix Et Rhizoma (Shengdahuang), 5 g; Astmgali Radix (Shenghuangqi), 10 g; Descurainiae Semen (Tinglizi), 10 g; Paeoniae Radix Rubra (Chishao), 10 g.

Xiyanping injection (SFDA approval number Z20026249, 50mg/piece) is made by sulfonation process of andrographis B extracted from Andrographis Herba (Chuanxinlian), was provided by Jiangxi Qingfeng Pharmaceutical Co., Ltd. (Ganzhou, China).

Xuebijing injection (SFDA approval number Z20040033 for 10ml/piece) is a combination of five herbs extraction, which are Carthamus tinctorius Linn (Honghua), Paeoniae Radix Rubra (Chishao), Chuanxiong Rhizoma (Chuanxiong), Angelicae Sinensis Radix (Danggui), and Salviae Miltiorrhizae (Danshen), was provided by Tianjin Chase Sun Pharmaceutical Co. Ltd. (Tianjin, China).

Shenmai injection (SFDA approval number Z33020020 for 20ml/piece) is made from Red Ginseng (Hongshen) and Radix Ophiopogonis (Maidong), was provided by Chiatai Qingchunbao Pharmaceutical Co., Ltd. (Hangzhou, China).

The WM group received antiviral therapy (including abidor capsule 0.2 g po, tid; Lopinavir-Ritonavir tablets, 500 mg po, bid), antibiotics (such as cefoperazone, 2 g iv, bid; moxifloxacin hydrochloride tablets, 0.4 g po, qd) or corticosteroid therapy (such as methylprednisolone succinate sodium, 40mg, iv, 40 mg, qd; prednisone, 30 mg po, qd). Supportive therapy in both groups included oxygen inhalation, symptomatic therapy, and/or human intravenous immunoglobulin, and/or serum albumin, and therapy for underlying diseases.

In view of the maximum median time of persistent SARS-CoV-2RNA infection in the two groups before the implementation of the temporary ward reconstruction plan on March 5th and a systematic review on COVID-19 length of hospital stay (Rees EM, et al., 2020) , the clinical observation period was set at 16 days. The data collected at the time of admission were baseline data. The outcome indexes about the efficacy and safety were collected from the baseline (admission) of patients to the end of 16 days of intervention, including: 1)discharge from hospital; 2) transfer to ICU, 2) the use of invasive mechanical ventilation, 3) number of death, 4) the time of viral clearance; 5) changes of the major symptoms, 6) chest CT findings, and 7) laboratory results from baseline.

CT findings were semi-quantitated based on the sign and range of pneumonia lesions on admission and throughout the observation period as an objective indicator of change of inflammation. All patients' chest CT images were independently evaluated by two radiologists. When the diagnosis was inconsistent, they reached a reasonable conclusion after discussion and/or consultation. The optimized semi-quantitative scoring system for CT signs was established based on the previous research methods (Zhao W, et al., 2020; Ajlan AM, et al, 2014) . Briefly, seven CT signs included imaging features: ground-glass opacities (GGO), consolidation, mixed GGO with consolidation, bronchial wall thickening, reticulation, sub-pleural bands, and traction bronchiectasis. Presence of any of the lesion features is scored as 1, and absence is scored as 0. Secondly, the lesion distribution in the lung is scored according to the following rule: The bilateral lung lobes were divided into 6 areas, the upper, middle, and lower. The upper-middle boundary in the CT axial section is defined at the level of the tracheal bifurcation, and the middle-lower boundary was the maximum transverse section of the right pulmonary vein. Each lung area is scored visually according to the infiltrative degree of lesions, which is divided into 0-4 points. Absence of inflammatory lesions was scored as 0, inflammatory area below 25% was scored as 1; area between 26% to 50% as 2, area between 51% to 75% as 3, and area between 76% to 100% as 4. A higher total score for a patient indicated that the pneumonia was worse.

The changes of liver and kidney function test results and the occurrence of adverse events were observed as safety outcomes.

The primary analysis in our study was descriptive or inferential statistics, and survival analysis. The continuous variables are expressed as medians (and interquartile range, IQR), and t or Wilcoxon rank sum test was used for inter-group comparison; The categorical variables are presented as frequency and percentage, and Chi-square or Fisher's exact test was used for comparison between groups. Paired t/sign rank or McNemar/McNemar-Bowker test was used within a group. Analysis of covariance or Mantel-Haenszel test was used for baseline correction. The non-nucleic acid negative conversion curve or rate was estimated using the non-parametric Kaplan-Meier method, and was compared between groups by log-rank test, giving the median time for viral shedding and 95% confidence intervals (CIs). The stratified log-rank test and Cox proportional hazards model were used to correct the baseline. In this study, R packages Stats, R companion and survival in version-3.6.2 and SPSS 20.0 were utilized for statistical analysis.

A total of 55 patients met the study conditions ( Figure. 1) . The age ranged from 26 to J o u r n a l P r e -p r o o f 77 years, with a median age of 58 years (IQR, ). The CM group included 23 patients, including 12 males and 11 females. The age ranged from 31 to 77 years, with a median age of 56 (IQR, . In CM group, 10 patients (43.5%) had underlying diseases (Table. 1). The WM group had 32 patients, including 17 males and 15 females. The age ranged from 26 to 73 years, with a median of 61.50 years (IQR, 45.75-68.00). In WM group 19 patients (61.3%) had underlying diseases (Table. 1). The baseline data of laboratory measurements of the two groups are shown in Table. 1.

In the cases included in this retrospective study, there was no patients of both groups died, were transferred to ICU, or underwent invasive mechanical ventilation.

SARS-CoV-2 RNA testing turned to negative in all patients of the CM group while in one case of WM group the viral RNA was still positive by the end of observation period. The SARS-CoV-2 RNA persisted for a median time of 12 days (IQR, 6.50-14.00; 95%CI, [9] [10] [11] [12] [13] [14] in the CM group, as compared with 15.5 days (IQR, 95%CI, (13) (14) (15) (16) (17) (18) in the WM group (P<0.01).

With the log -rank test and further stratified by using the multivariate Cox proportional hazards model calibration analysis, the time to SARS-CoV-2 RNA conversion to negative in the CM group was significantly shorter than that in the WM group (HR: 2.281, P = 0.018). The ratio of nucleic acid negative conversion of CM group at different follow-up time points was significantly higher than that of WM group by log-rank test (P=0.0026, <0.01) ( Figure. 2) 

During the observation period, 45 of the 55 patients were discharged. Among them, 20 cases (20/23, 87.0%) were discharged from the CM group, and 25 cases (25/32, 78.1%) were discharged from the WM group. The discharge rates of the two groups had no significant difference (P=0.629). The 10 patients who had not been discharged as of March 5 were transferred to other wards for treatment and were eventually discharged.

In chest CT scan images, the two groups showed typical changes of severe pneumonia, widely distributed GGO, consolidation, mixed GGO with consolidation mainly in the middle, lower and peripheral lung areas. However, these features were not significantly different between two groups except the distribution area.

The scores of pulmonary inflammatory lesions' feature, for example, consolidation sign in each group were significantly reduced, indicating that the inflammation was J o u r n a l P r e -p r o o f significantly absorbed after treatment (Table. 2). After CM group's combination therapy (what kind of combination therapy? It is new concept, sorry, please specify) , the scores of the distribution of inflammatory lesions in both lungs (except the upper right lung) were significantly reduced (Table. 3); however, the score for the lesion area in the WM group also decreased, but there was no significant difference between the scores obtained before and after treatment. The scores for total distribution and for the left upper lung were significantly decreased in CM group compared with WM group, which means that the inflammation absorption was in a wider range after combination therapy in CM group ( Figure. 3) .

On-admission lymphocytopenia was present in 52.7% (29/55) of patients, the absolute value of neutrophils/lymphocytes was abnormally increased in 87.3% (48/55) of patients. Most patients had elevated levels of erythrocyte sedimentation rate (ESR) (43/52, 82.7%), high sensitivity C-reactive protein (hsCRP) (36/55, 65.5%), interleukin-6 (IL-6) (35/51, 68.6%), amyloid A (33/49, 67.3%) and serum ferritin (43/53, 81.1%).

After treatment improvement of hs-CRP, ESR, serum ferritin (SF) and myoglobin in the CM group was better than those of the WM group (after the correction of covariate, P< 0.05) (Table. 4).

After treatment, four patients in the WM group and two patients in the CM group showed mild elevation of alanine aminotransferase, and one patient in each group showed elevation of aspartate aminotransferase, and no other adverse events were recorded. Since the virus attacks the liver, kidney and other organs in the course of the disease, the correlation between the observed adverse events and the medication is not clear yet.

In this study, a total of 55 patients met the study conditions. We compared the enrolled severe COVID-19 patients treated with CM and WM in the same period. The results showed that there was no case of death, transferred to ICU, or received invasive mechanical ventilation in two groups during hospitalization. The median time of SARS-CoV-2 RNA clearance in CM and WM group were 12 days and 15.5 days (P=0.018). Further, the chest CT imaging showed more widely lung lesion opacity absorbed in the CM group (P<0.05). The C-reactive protein level, erythrocyte sedimentation rate, serum ferritin, and myoglobin decreased significantly in the CM group (P<0.05). There was no significant difference in adverse events in terms of liver function and renal function between the two groups.

In general, the duration of positive detection of viral nucleic acid in patients is an important factor in evaluating the risk of virus transmission and prognosis. Recent clinical studies found that the RNA detection of respiratory virus in dead patients with COVID-19 continues to be positive, and the average virus shedding period of discharged patients was 20 days (Zhou F, et al. 2020) . Although there is no evidence that antiviral therapy can shorten the virus shedding time of SARS-CoV-2 (Zhou F, et al. 2020) , the results of the present study showed that CM treatment could significantly shorten the SARS-CoV-2 RNA persistence time and more quickly cleared the virus, which is of significance to reduce the risk of disease transmission and improve the prognosis of patients.

Chest CT is a valuable diagnostic tool for clinical management of COVID-19-related lung diseases (Harmon SA, et al. 2020) . The semi-quantitative CT imaging analysis in this study showed that the inflammation imaging signs and the infiltrated lung area in severe patients were basically consistent with recent COVID-19 imaging results (Chung M, et al., 2020; Kanne JP, 2020) . The major lung CT findings of the disease include extensive GGO, consolidation, and sub-pleural bands in the peripheral parts of the middle and lower lungs. Pulmonary consolidation is a well-known CT sign of the lung inflammation at the peak. The disperse of consolidation was observed in both groups, but more lung lesion opacity absorbed in CM group. Recent autopsy and lung replacement pathology reports showed that SARS-CoV-2 mainly causes inflammatory reactions characteristically in deep airway and alveolar level, producing extensive inflammatory exudation and mucus filling in the alveolar cavity. It is suggested that eliminating inflammatory exudation and mucus from the small airways is an important solution (liu Q, et al., 2020) . It has been previously verified that CM functions anti-inflammatory and expectorant effects in viral pneumonia and SARS (Zhu S, et al., 2020; Liang A, et al., 2003) .

The results in this study showed that combination therapy in CM group could improve lymphopenia and reduce inflammatory measurements such as hsCRP, SF, and ESR. A recent study also showed that integrated treatments could significantly improve the lymphocytes, serum amyloid-A (SAA), CRP and ESR (Xia W, et al., 2020) , CM could improve the immune and inflammatory response induced by SARS-Cov-2 infection.

With regard to the above results in the CM group, we think that it has a potential relationship with the pharmacological function of the CM used. A large number of previous studies have shown that some CM extracts can enhance or regulate the function of the immune system, stimulate the production of endogenous interferons, J o u r n a l P r e -p r o o f and have anti-inflammatory and anti-allergic effect (Liu J, 2020) . Previous studies have proved that the active ingredients in Chinese herbal medicine composed of Huashi Baidu granule have the effects of anti-inflammation and regulating immunity. Polysaccharide from Ephedra sinica Stapf reduced airway and pulmonary inflammation by regulating inflammatory cytokines (Liang S, et al., 2018) , andrographolide could reduce the pathological changes of lung tissue and the expression of inflammatory cytokines in mice induced by influenza A virus (Ding Y, et al., 2017) , patchouli alcohol could alleviate lipopolysaccharide-induced acute lung injury in mice through anti-inflammatory and antioxidant effects (Su Z, et al., 2016) , and stragaloside has good anti-inflammatory and immunostimulatory activities (Qi Y, et al., 2017) , which is of great significance to improve the immune function of the body. It has been reported that 7.2％ of COVID-19 patients have acute cardiac injury (Wang D, et al., 2020) . Shenmai injection is extracted from Panax ginseng and Ophiopogon japonicas. Some study has shown that Shenmai injection could protect cardiomyocytes through energy metabolism pathway (Wang S, et al., 2019) . A randomized, double-blind, multi-center, placebo-controlled clinical study showed that integrative treatment with standard medicines plus Shenmai injection can improve the chronic heart failure (CHF) (Xian S, et al., 2016) . In addition, animal experimental study showed that Shenmai injection can protect the lung from injury induced by intestinal Imax R injury, which may be mediated by inhibiting the activation of p38 MAPK (Zhao J, et al., 2019) .

Dynamic immune response plays an important role in shaping the process of COVID-19 (Ong EZ, et al., 2020) , cytokine storm (CS) is an important node of COVID-19 's transformation from mild to severe (Ma Q, et al., 2020; Coperchini F, et al., 2020; Vaninov N, 2020; Hu B, et al., 2020) , and it is also one of the causes of severe or critical death (Ma Q, et al., 2020) . Improving the immune function of patients and reducing the storm of inflammatory factors are two key links in the treatment of severe COVID-19 patients (Ma Q, et al., 2020) . The results of CM treatment in this study suggests that CM has obvious anti-inflammatory effect, and good in prevention of death and exacerbation of the disease. It is worth mentioning that the treatment scheme in the CM group has been incorporated into the national recommendations for diagnosis and treatment of pneumonia caused by 2019-nCoV (the 7th edition) by NHC (NHC, 2020), which is recommended for the treatment of severe cases of COVID-19.

This study has all the limitations of a retrospective case series study; the sample size was too small. To further evaluate the efficacy and safety of the CM treatment of COVID-19, rigorously designed prospective randomized clinical trials are warranted.

The overall results of CM treatment in this study was good in prevention of death and exacerbation of the disease at early stage of the COVID-19 epidemic in Wuhan, China. While the CM therapy shows a better effects in SARS-CoV-2 RNA clearance, lung lesion opacity absorbed and reduced inflammation in severe COVID-19 patients, is effective and safe therapy for treating severe COVID-19 and reducing mortality.

This study was approved by the Research Ethics Committee of Wuhan Jinyintan Hospital (KY-2020-43.01) and China Academy of Chinese Medical Sciences (CACM S-IRB2020-003-1). The requirement for informed consent was waived by the Ethics Committee as a retrospective study.

The authors declare that they have no conflict of interest.

This study was funded by the National Key Research and Development Project of China (Grant no. 2020YFC0841500).

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Omer SB, Malani P, del Rio C, 2020. The COVID-19 pandemic in the US: a clinical update. JAMA. 323 (18) February 2020. https://www.who.int/dg/speeches/detail /who-director-general-s-remarks-at-the-media-briefing-on-2019-ncov-on-11-february-2020.

WHO b, 2020. Weekly operational update on COVID-19 -30 October 2020. https://www.who.int/publications/m/item/weekly-operational-update---30-october-202 0.

WHO c, 2020. Director-General's opening remarks at the media briefing on COVID-19-11 March 2020. Retrieved March, 11, 2020. https://www.who.int/zh/dg/speeches/detail/who-director-general-s-opening-remarks-at -the-media-briefing-on-covid-19---11-march-2020 (2020-03-25).

Wu JT, Leung K, Leung GM, 2020 J o u r n a l P r e -p r o o f J o u r n a l P r e -p r o o f Note. CM denotes Chinese medicine; WM Western medicine. The lesions distributed morein the lower and the peripheral region.The inflammation area (except in the right upper lung) significantly reduced after Chinese medicine treatment (P<0.05).The scores of the inflammation area involving in the left upper lung and the whole lung significantly decreased in the Chinese medicine group compared with the western medicine (P=0.002,0.025). 

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The authors gratefully acknowledge all patients and health-care workers in the Wuhan Jinyintan Hospital. We also acknowledge Hongjun Yang, Xin Shen, and all research assistants participated in collection of clinical data, and technical support.J o u r n a l P r e -p r o o f