key: cord-0908449-rke0ohwh
authors: Zhang, Ying; Liu, Yangyang; Li, Ming; Feng, Shaohua; Li, Xiuyang; Gao, Zezheng; Yang, Yingying; Tong, Xiaolin
title: Timely Treatment and Higher Compliance to Traditional Chinese Medicine: New Influencing Factors for Reducing Severe COVID-19 based on Retrospective Cohorts in 2020 and 2021
date: 2022-03-11
journal: Pharmacol Res
DOI: 10.1016/j.phrs.2022.106174
sha: 6e7c6c57185894eff21161448d04dc9d80bba512
doc_id: 908449
cord_uid: rke0ohwh

OBJECTIVE: From the beginning of 2020, our study team formulated a traditional Chinese medicine (TCM) prescription named Sanhanhuashi formula (SHHS) to treat COVID-19 patients. Then we conducted several studies to explore the effectiveness of SHHS formula and other influencing factors on prognosis of disease. The purpose of this study was to describe the trends of patients’ characters from 2020 to 2021 based on two separate cohorts, and to explore the influencing factors on incidence of severe COVID-19 conditions, especially the contributions of timely treatment and higher compliance to SHHS formula. METHODS: A retrospective cohort study was conducted in Wuhan, Hubei province and Tonghua, Jilin province. Participants were hospitalized mild to moderate COVID-19 consecutive enrolled patients in Wuhan hospital of traditional Chinese and western medicine (from Feb 13, 2020 to March 8, 2020) and Tonghua central hospital (from Jan 17, 2021 to Feb 5, 2021). Age, sex, time waiting to be hospitalized, medical history, initial symptoms, concomitant medication, and severity of disease were collected. Univariate and multivariate logistic regression were used to explore the associations between various exposures and the outcome, ie. the proportion of patients who were converted to severe status. E-values and its lower control limit (LCL) were calculated for sensitivity analysis. RESULTS: Totally, 176 COVID-19 patients in two hospitals were enrolled. 81 patients were from Wuhan hospital of traditional Chinese and western medicine and 95 from Tonghua central hospital. 42 patients used SHHS formula arrival or exceed 7 days, and 2 (4.8%) progressed to severe condition. Among 134 patients who were exposed SHHS less than 7 days, 18 (13.4%) were converted to severe situation. Compared with those diagnosed in 2020, cases in 2021 were characterized as lower rates of initial symptoms (88.9% vs 35.8%, P<0.001) and concomitant medications ever widely used, eg. antiviral medicine (71.6% vs 43.2%, P <0.001), antibiotics (61.7% vs 13.7%, P <0.001) and Chinese patent medicine (76.5% vs 44.2%, P <0.001). They also waited less time for hospitalization (median: 12 vs 2 days, P<0.001). The final multivariate logistic regression model showed that age (> 60 yrs) (OR: 3.943; 95% CI: 1.402-11.086; P = 0.009; E-value=7.35, LCL:2.15), diagnosis year (OR: 0.165; 95% CI: 0.050-0.551; P = 0.003; E-value=11.6, LCL: 3.03) and SHHS exposure (OR: 0.118; 95% CI: 0.014-0.992; P = 0.049; E-value=16.43, LCL:1.1) were independent risk factors for predicting severe status. CONCLUSIONS: The profile of COVID-19 patients has changed after one year. In addition to age, diagnosis year and SHHS exposure are two new factors to predict the prognosis of disease. The patients diagnosed in 2021 were mainly benefited from timely treatment. Subsequently, adhere to use SHHS formula a quite longer time reduced the number of severe cases. Therefore, both the current epidemic prevention and control measures and increasing compliance to traditional Chinese medicine are effective ways to reducing severe cases and improving public health.

At the end of December 2019, the Coronavirus disease (COVID-19) epidemic emerged in Wuhan (Hubei Province, China) [1] , and then spread rapidly around the world. Globally, as of January 7, 2022, there have been more than 298 million confirmed cases, including over 5 million deaths reported to WHO [2] . Owing to excellent management strategies and quickly social responses to foreign imported cases, the epidemic has been under well control in China. The cumulative confirmed cases in China was around 133 thousand, including 5699 deaths [2] . Because Mild or moderate was the initial status in majority of confirmed cases, to effective control the progress of disease will remarkably reduce the incidence of severe COVID-19, hereby the deaths.

As the location with the first outbreak, Wuhan is a first-line big city with a high population density. At the early time, due to limited medical resources, patients could not be diagnosed until some typical symptoms appeared. It's not worthy of doubt, there was relatively high prevalence of various initial symptoms in hospitalized patients at the beginning of 2020. Tonghua city, located in the northeastern China's Jilin province, with more than two-thirds of mountainous areas and its population ranked 5 th in Jilin. In January 12, 2021, epidemic of COVID-19 outbroke in Tonghua and mainly spread by asymptomatic carriers. Then the city government announced lockdown in January 18. The tight control mode on the patients with confirmed or suspected COVID-19, and close contacts of the confirmed cases, ensured a large number of mild to moderate cases were treated in time, reducing the possibility of becoming severe cases. Therefore, the proportion of severe cases dropped significantly.

Our team is one of the first medical teams to aid coronavirus control in Wuhan in 2020. we formulated a traditional Chinese medicine (TCM) prescription named Cold-damp Plague Formula (Hanshiyi) to prevent exacerbations of the epidemic [3] [4] [5] .

In previous cohort study of 17 quarantine stations, the results showed Hanshiyi formula (decoction or granule), renamed Sanhanhuashi (SHHS) formula in 2021, could significantly reduce the progression to severe condition in patients with mild to moderate COVID-19 [5] . But, we still don't know whether there will be notable difference when patients' compliance differs. There is also lack of quantitative evidences to show the changes of severity proportion over years. Furthermore, the analysis of whether the contributions of SHHS formula to curb disease progress will change under strictly controlled medical environments, is still needed.

Therefore, we conducted this study with the purpose to describe the trends of patients' characters from 2020 to 2021 based on two separate cohorts, and to explore the influencing factors on incidence of severe COVID-19, especially the contributions of timely treatment and higher compliance of SHHS formula.

This study is a retrospective cohort study conducted in Wuhan, Hubei province and Tonghua, Jilin province. Participants were hospitalized mild to moderate COVID-19 consecutive patients in Wuhan hospital of traditional Chinese and western medicine (from Feb 13, 2020 to March 8, 2020) and Tonghua central hospital (from Jan 17, 2021 to Feb 5, 2021). All of the participants were aged over 18 years old and ever exposed to SHHS formula, more or less. There were no any restrictions on dosage or duration of using SHHS. Data on age, sex, time waiting to be hospitalized, medical history, initial symptoms, concomitant medication, and severity of disease were collected.

The diagnosis of COVID-19 patients was conducted by Wuhan hospital of traditional Chinese and western medicine, and Tonghua central hospital. The diagnosed criteria were according to the Diagnosis and Treatment Guideline for COVID-19 released by the National Health Commission of the People's Republic of China [6] . This study was approved by the institutional ethics board of Hubei Provincial Hospital of Traditional Chinese Medicine (No. HBZY2020-C27-01) and Changchun University of Chinese Medicine (CCZYFYLL2021-001). The study was also a sub task of the Special Project for Emergency of the Ministry of Science and Technology (2020YFC0845000).

Data of consecutive hospitalized patients in two hospitals were exported from HIS (hospital information system) system to a standard electronic database. Clinical coordinating staffs from Guang'anmen hospital and Changchun University of Chinese Medicine, along with data management associates in Beijing University of Chinese Medicine completed the query generating and data cleaning, after rounds of communicating with clinicians to verify the information and ensure the accuracy of the data. The analysis and reporting of the results of the study were in accordance with the STORBE guideline [7] . Exposures All of the patients were ever prescribed SHHS formula (decoction or granule), the exposure level was categorized into high and low, which implied using time arrival 7 days or not. The patients in Wuhan and Tonghua were collected in 2020 and 2021, respectively. In China, the epidemic in 2021 differs from 2020, not only on virus mutations, but also the public health strategies. Therefore, patients in two hospitals who were diagnosed in different years were also exposed to different treatment, social and policy environments.

The outcome of the cohorts was the proportion of mild to moderate COVID-19 patients who were converted to severe or death status. The baseline covariates included age, sex, time waiting to be hospitalized, medical history, initial symptoms, concomitant medication, year of diagnosis and exposure level of SHHS. Univariate regression analysis and multivariate logistic regression were used to analyze the factors that influenced the prognosis of disease. Interaction(s) between factors were considered to add into the model when any combinations could increase the statistical power.

Data management and statistical analyses in this study were conducted using SAS 9.4 (SAS Institute Inc., Cary, NC, US) and SPSS 20.0 (IBM SPSS Inc., Chicago, IL, US). Two-sided test was used, and a P-values <0.05 were considered statistically significant. Numerical variables were summarized as mean (±SD) and median (IQR). The data of the categorical variables was described as counts and percentages.

According to the characteristics of the variables, the t-test / Wilcoxon rank-sum test J o u r n a l P r e -p r o o f was used to compare continuous data between groups, and the chi-square test / Fisher's exact test for categorical data. To construct the univariate and multivariate model, the proportion of patients who were converted to severe status was the dependent variable, age, sex, medical history, initial symptoms, concomitant medicines, year of diagnosis and level of SHHS exposure were the independent variables. To select the independent variables which could enter the model, likelihood ratio forward method was used the construct the final model. We calculated the E-values and its lower control limit (LCL) as a sensitivity analysis to quantify the potential for unmeasured confounding bias on observed associations between exposures and outcomes [8] [9] [10] . The E-value is the minimum strength of association required between an unmeasured confounder and exposure and between confounder and outcome, conditional on measured covariates, to explain away the observed exposure-outcome association [10] . A large E-value implies that considerable unmeasured confounding would be needed to explain away an effect estimate, therefore, the larger E-value means more robust of the observed associations. E-value is a sensitivity analysis without any assumptions and the calculation is straightforward. E-values for each exposure were calculated using an online calculator (website: www.evalue-calculator.com, accessed on January 1, 2021) [11] .

Totally, 176 COVID-19 patients in two hospitals were enrolled. 81 patients were from Wuhan hospital of traditional Chinese and western medicine and 95 from Tonghua central hospital. The severity of all included patients was mild or moderate. Due to the characters of epidemic in China, one city has relatively a little possibility to encounter outbreak once again over a year. For most situations, the cases were scattered in different cities and years. Therefore, patients in two hospitals could represent more differences than similarities on virus type, treatments and management strategies. 42 patients used SHHS formula arrival or exceed 7 days, and 2 (4.8%) of them was converted to severe status. Among 134 patients who were exposed SHHS less than 7 days, 40 (29.9%) had become severe situation (see figure 1 ).

In the included patients, 90 (51.1%) were female, and 39 (48.1%) were diagnosed in 2021. The median age was 55.5 years old. There was no statistical difference between year groups on age, proportion of over 60 years old and sex (P>0.05). Patients with medical history were 88 (50.0%), of which the most common medical history were hypertension (46, 26.1%), diabetes (21, 11.9%) and coronary heart disease (19, 10.8%). The proportion of gastrosis was decreased from year 2020 to 2021 (8.6% vs 0.0%, P = 0.011) and the differences on other diseases between year groups were not statistically significant (P>0.05). Among all the patients, 106 (60.2%) had initial symptoms and there was statistical significance on the decrease of proportion after one year (88.9% vs 35.8%, P<0.001). The proportion of patients with fever (25.9% vs 9.5%, P <0.001), headache or fatigue (24.7% vs 2.1%, P <0.001), expectoration (58.0% vs 25.3%, P <0.001), heart and lung symptoms (35.8% vs 7.4%, P <0.001), gastrointestinal symptoms (29.6% vs 2.1%, P <0.001), mental symptoms (34.6% vs 0.0%, P <0.001) and cacation disorders (16.1% vs 4.2%, P=0.008) was lower in 2021 than 2020 (see table 1 and figure 2) .

The patients were administered multiple medication during treating COVID-19, medicines most used included Chinese patent medicine (104, 59.1%), antiviral treatment (99, 56.3%), antibiotics (63, 35.8%) and antifebrile (29, 16.5%) etc. 47 (26.7%) patients used medicine for their concomitant diseases. There was a remarkable decline after one year on using medicine of antiviral (71.6% vs 43.2%, P <0.001), antibiotics (61.7% vs 13.7%, P <0.001) and Chinese patent medicine (76.5% vs 44.2%, P <0.001); an increase on using antifebrile (4.9% vs 26.3%, P <0.001) and hormone (2.5% vs 10.5%, P =0.035). Time from typical symptoms emerged or disease confirmed to hospitalization was shortened remarkably (median: 12 vs 2 days, P<0.001). The exposure time of SHHS was nearly equal (27.2% vs 21.1%) between years (P>0.05) (see table 1 ).

Our primary outcome was the proportion of mild/moderate COVID-19 patients turning to severe status. There was no death observed in hospitalization period in either hospital. The variations on sex, concomitant diseases, initial symptoms and SHHS exposure didn't differ the incidence of severe status (P>0.05). The difference of age category (>60yrs or not) (18.6% vs 6.6%, P =0.014) and diagnosis year (18.5% vs 5.3%, P =0.006) could significantly influence the rate of severe cases (Table 2) .

Univariate and multivariate logistic regression were used to evaluate the influencing factors on the proportion of mild to moderate COVID-19 patients turning to severe status. The dependent variable was the proportion of severe status. Age (>60yrs or not), sex, medical history, initial symptoms, SHHS exposure (>7days or not) and diagnosis year (2020 vs 2021) entered the exploratory model as independent variables. After using forward likelihood ratio model selection procedure, there were three variables and one interaction item (see Figure 3 ) included in the final model. The results showed that age (> 60 yrs) (OR: 3.943; 95% CI: 1.402-11.086; P = 0.009; E-value=7.35, LCL:2.15), diagnosis year (OR: 0.165; 95% CI: 0.050-0.551; P = 0.003; E-value=11.6, LCL: 3.03) and SHHS exposure (OR: 0.118; 95% CI: 0.014-0.992; P = 0.049; E-value=16.43, LCL:1.1) were independent risk factors of predicting severe status (Table 3) .

This cohort study showed several meaningful findings. The first, there was notable downtrend on initial symptoms (88.9% to 35.8%) and usage of several concomitant medicines, such as antiviral treatment (71.6% to 43.2%) and antibiotic (61.7% to 13.7%). The decrease of initial symptoms might largely owe to the screening strategies to suspected case and close contacts of confirmed cases. In 2021, most of the cases had been detected and then closely observed and treated before typical symptoms emerged under the strict control strategies in Tonghua city. It's worth mentioning that mental symptoms disappeared in 2021, implying psychological stability was improved among confirmed cases compared with those in 2020. The accumulating clinical experiences and evidences of diagnosis and treating COVID-19 made the prescriptions more targeted other than broad medicating in the beginning stage in 2020. In addition, lower symptoms prevalence also reduced usages of some combined medicines. The second, we found remarkable decrease on the incidence of severe cases from 2020 to 2021. These might be the results of multiple control measures in 2021, for example, virus mutations, timely treatment, longer isolation or hospitalization time etc. The third and the most, the final model demonstrated three factors could dependently influence the proportion of mild/moderate patients to severe conditions. The risk progressing to severe for the older, especially over 60 years old, was nearly fourfold (OR=3.943) to younger patients. The progressing risk for cases diagnosed in 2021 decreased 83.5% (OR=0.165) compared with those diagnosed in 2020. Although all the patients had ever taken SHHS formula, the results further found the exposure level was a potential predictor for severity status. Using SHHS with higher compliance (>=7 days) could decrease progressing risk by 88.2% (OR=0.118) compared to those with poor compliance.

The population in this study have several similarities with patients in our previous cohort which was conducted in 17 quarantine stations [5] , for example, average age (53.65 vs. 48.49 yrs), female proportion (51.1% vs. 51.9%) and medical history (50.0% vs. 46.3%). These make it possible to repeatedly validate the effectiveness of SHHS formula for mild to moderate COVID-19. An observational study our team completed in 2020 [12] , explored comprehensive intervention might be a protective factor for recurrent positive RT-PCR. SHHS formula is one part of the whole comprehensive intervention, which also included Baduanjin exercise, foot baths, moxibustion etc. At the same period, we conducted a randomized controlled trial (RCT) concluded that the use of Huoxiang Zhengqi dropping pills and Lianhua Qingwen granules combined with western medicine had clinical advantages for COVID-19 patients in improving clinical symptoms [13] . This finding confirmed the former findings that Huo Xiang (Pogostemonis Herba) could effectively inhibit the replication of influenza A (H1N1) virus [14] . Huoxiang is also one of the constituents of SHHS formula. Consistent with our previous study [5] , we found the older was still an important factor for prognosis of disease, implying differential preventive and treatment measures are needed to older population. The median of LOS in this study was 16.5 days, much longer than situations reported in outside of China which was 5 days for LOS median [15] . The most possible reason might be the unified management measures in China which generally require confirmed cases should be isolated or stayed in hospital at least 14 days.

Our study has many strengths. The first, this study might be the first attempt to explore the influence of epidemic control measures and medical environments on characters of patients and their prognosis by comparing the cohorts from 2020 to 2021. The second, other than the findings in previous study which have proved the potential benefits for COVID-19 patients from using SHHS [5] , we further evaluated the effectiveness of higher compliance to SHHS (ie. longer exposure time) which will be helpful to guide clinical prescriptions. The third, E value [9] , a novel method, was calculated to explore the robust of the associations. For age and diagnosis year, the E value was large enough, which it's unlikely any unmeasured factors could explain away the observed associations. However, the LCL of E value for SHHS exposure level is around 1 (LCL=1.1). We should consider whether there might exist any unobserved confoundings in this study could threaten current association, for example, different combined medicines or virus types. Although we got a quite strong association (OR=0.118) in the model, further studies with larger sample size are still warranted.

The main limitation of our study was its sample size. Generally, small sample size will cause lower power to detect a statistical significance, hence a higher possibility of type II error. We used model selection procedure, instead of including all of the co-variates in the model. The interaction between diagnosis year and SHHS exposure was also introduced to the final model to increase the statistical power. The second, we also found the associations of age and severe condition in our study was quite large (OR=3.943), one possible reason might relate to the special epidemic background in Tonghua city, its outbreak mainly started from the super spreader, an asymptomatic carrier, took part in a gathering which many older people were involved. Nevertheless, the prevention and treatment in older population are more challenging. The third, with the approval of "three TCM formula and three Chinese patent drugs" by China food and drug administration, there might be an increase both on patients' expectation and acceptance to TCM. In real world, patients might use other TCMs besides SHHS formula, but we could only mostly focus the SHHS, due to the complexity of the prescription data. Finally, some studies revealed the relationship between overweight (eg. BMI) and the severe outcomes. However, the data of weight and height was seriously missing in the hospitalization database, which made this analysis unpractical. Highly depending on the retrospectively collected data is also a common limitation for all retrospective studies.

The profile of COVID-19 patients has changed after one year. The reducing of severe cases could be the joint effects of multiple factors. In addition to age, diagnosis year and SHHS exposure are two new factors to predict the prognosis of disease. In this study, the patients diagnosed in 2021 were mainly benefited from timely treatment. Subsequently, adhere to use SHHS formula a quite longer time reduced the number of severe cases. Therefore, both the current epidemic prevention and control measures and increasing compliance to traditional Chinese medicine are effective ways to reducing severe cases and improving public health.

We declare no competing interests. This study was approved by the institutional ethics board of Hubei Provincial Hospital of Traditional Chinese Medicine (No. HBZY2020-C27-01) and Changchun University of Chinese Medicine (CCZYFYLL2021-001).

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 

Outbreak of pneumonia of unknown etiology in Wuhan, China: The mystery and the miracle

Notice concerning the recommendation of the prescription of traditional Chinese medicine in the treatment of COVID-19

Discussion on Traditional Chinese Medicine Prevention and Treatment Strategies of Coronavirus Disease 2019 (COVID-19) from the Perspective of "Cold-dampness Pestilence

Hanshiyi Formula, an approved medicine for Sars-CoV2 infection in China, reduced the proportion of mild and moderate COVID-19 patients turning to severe status: A cohort study

The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) Statement: guidelines for reporting observational studies

National Health Commission of the People's Republic of China, National Administration of Traditional Chinese Medicine of the People's Republic of China. Guidance for Corona Virus Disease 2019: Prevention, Control, Diagnosis and Management. People's Medical Publishing House

Sensitivity Analysis in Observational Research: Introducing the E-Value

Using the E-Value to Assess the Potential Effect of Unmeasured Confounding in Observational Studies

Web Site and R Package for Computing E-values

Positive RT-PCR Test Results in 420 Patients Recovered From COVID-19 in Wuhan: An Observational Study

Efficacy of Huoxiang Zhengqi dropping pills and Lianhua Qingwen granules in treatment of COVID-19: A randomized controlled trial

Immunologic mechanism of Patchouli alcohol anti-H1N1 influenza virus may through regulation of the RLH signal pathway in vitro

COVID-19 length of hospital stay: a systematic review and data synthesis

This work was funded by the Special Project for Emergency of the Ministry of Science and Technology (2020YFC0845000) and Special Project for Emergency Research on the Prevention and Control of COVID-19 by Traditional Chinese Medicine, supported by National Administration of Traditional Chinese Medicine (2022ZYLCYJ01-4) . We acknowledge all volunteers and health-care workers in the Wuhan, Hubei province and Tonghua, Jilin province.