The Effects of a Comprehensive Rehabilitation Program Involving Traditional Chinese Medicine in Severe and Critical COVID-19 Patients: a Clinical Study

Background: A year ago, a new type of coronavirus emerged. Once treated for severe and critical COVID-19 infections, patients are discharged from the hospital for further treatment and rehabilitation. The aim of this study was to evaluate the ecacy and safety of a newly developed comprehensive rehabilitation program based on traditional Chinese medicine (TCM) in the rehabilitation of patients with severe and critical COVID-19. Methods: We recruited a total of 72 patients who had suffered from severe and critical COVID-19 infections and were undergoing rehabilitation in Chongqing, China. A comprehensive rehabilitation program was formulated according to the TCM syndromes of these patients. Specic treatments included oral TCM, Baduanjin, Moxibustion, Acupoint application, and foot baths. Prior to the initiation of treatment, and four weeks after the initiation of treatment, we carried out a range of assessments, including the TCM Syndrome curative effect score, the modied Medical Research Council (mMRC) dyspnea score, the St. George's Respiratory Questionnaire, the Short Form (SF)-36 Quality of Life Scale, and the 6-minute walking test. We also carried out CT scans, serology tests. Statistical analysis was also conducted to evaluate the ecacy and safety of TCM on severe and critical COVID-19 patients. Results: Analysis showed that there were signicant differences (P < 0.05) when compared before and after four weeks of TCM treatment, in terms of the TCM syndrome curative effect score, mMRC dyspnea score, St. George's Respiratory Questionnaire score, SF-36 Quality of Life Scale score, and the 6-minute walking test. We also identied signicant differences (P < 0.05) between these two timepoints, with regards to the neutrophil ratio, lymphoid cell ratio, lymphocytes, platelets, red blood cells, and hemoglobin. There were no signicant differences when compared between the two timepoints with regards to white blood cells and neutrophils (P > 0.05). The ecacy of chest CT scans was 83.9%. Logistic regression showed that the CT scans of patients who did not take the TCM decoction did not improve signicantly. The higher a patient’s score on the 6-minute walking test, the higher the probability of no signicant improvement on the CT scan. Conclusions: A comprehensive rehabilitation program based on TCM improved a number of clinical parameters in patients suffering from severe and critical COVID-19 infections, including quality of life, clinical symptoms, exercise endurance, and respiratory function. TCM also enhanced lymphocytes, lymphocyte ratio, platelet, red blood cell (RBC) count, and hemoglobin content. TCM also appeared to contribute to the absorption of lung lesions.


Introduction
A year ago, a new type of viral infection emerged. Initial genomic sequencing data of this virus do not match with previously sequenced CoVs, thus indicating a novel CoV strain (2019-nCoV). Although COVID-19 is suspected to have originated from an animal host (zoonotic origin) followed by human-to-human transmission, the possibility of other routes should not be ruled out. There are no anti-viral drugs at present that can be used to treat or prevent COVID-19. In severe cases, blood oxygen saturation will decrease and hypoxia will occur; critical cases require mechanical ventilation, and can suffer from shock or multiple organ dysfunction syndrome. Once treated for severe and critical COVID-19 infections, patients are discharged from the hospital for further treatment and monitoring. During this critical period, it is vital to provide patients with rehabilitation treatment and evaluate the e cacy of such treatment. Consequently, research focused on the development and application of and rehabilitation programs has become a critical factor in our efforts to reduce the impact of the current pandemic. Most patients diagnosed with severe or critical COVID-19 infection tend to be older and have existing earlier primary diseases and other characteristics. Typically, the lungs of patients show faded and patchy brosis on computed tomography (CT) scans [1] . A previous study acquired lung biopsies from four patients who died of COVID-19 and showed that hours after their deaths, there was evidence of extracellular matrix and brin formation and hyperplasia of the ber cells [2] . Prior to death, these brotic changes in pulmonary function led to a signi cant reduction in lung function and a consequential reduction in the patient's ability to breathe and tolerate exercise; collectively, these factors lead to a severe reduction in the quality of life. The key aspect underlying the use of traditional TCM for severe and critical COVID-19 patients during their rehabilitation period is to improve lung function and their quality of life.
At present, there is very little information relating to the use of TCM in patients with severe and critical COVID-19 during their rehabilitation period. In the present study, we investigated the clinical e cacy of a comprehensive rehabilitation program, based on TCM, in patients with severe and critical COVID-19 infection during their rehabilitation period in Chongqing.

Diagnostic criteria
The diagnostic criteria used in this study were based on the diagnosis and treatment protocol for COVID-19 (Trial version 7) that was issued by the National Health Commission and the State Administration of Traditional Chinese Medicine [3] . Adult patients were classi ed as having a 'severe' infection if they experienced any of the following criteria: (1) onset of shortness of breath, respiratory rates (RR) ≥ 30 times/min; (2) an oxygen saturation ≤ 93% at rest; (3) a partial pressure of blood oxygen (PaO 2 )/oxygen absorption concentration (FiO 2 ) ≤ 300 mmHg; or (4) pulmonary imaging showing signi cant progression of lesions within 24 to 48 hours. In total, 50% of the patients recruited into this study were treated as severe. Adult patients were classi ed as having a 'critical' infection if they experienced any of the following criteria: (1) respiratory failure and the need for mechanical ventilation; (2) shock; or (3) the patient experienced other organ failure and needed to be monitored in the intensive care unit (ICU).

Inclusion criteria
In order to be included in this study, patients needed to (1) meet all of the COVID-19 diagnostic criteria; (2) be clinically classi ed as severe or critical, based on clinical symptoms and laboratory test indicators; (3) show improvement following treatment involving a combination of TCM and western medicine treatment, and who had attained the indications for discharge indications; and (4) provide their signatures on informed consent forms and were able to cooperate with rehabilitation treatment in an active and diligent manner.

Exclusion criteria
Patients were excluded from the present study for the following reasons: (1) severe liver and kidney function impairment (serum alanine aminotransferase was 3-fold higher than the normal upper limit and/or a serum creatinine level ≥ 265 µmol/L); (2) severe cerebrovascular diseases, disorders of the blood system, nervous system diseases, and malignant tumors; (3) combined acute myocardial infarction and cardiogenic shock; (4) pregnant or lactating women; (5) mental disorders or unwillingness to cooperate; and (6) patients involved in other research studies.

Demographic information
Patients were recruited after discharge from the hospital. All 72 patients (41 males and 31 females) who suffered from severe or critical COVID-19 during the experimental period were treated in four centralized centers in Chongqing, China, including 28 patients from the municipal public health center, 10 patients from the Yongchuan district treatment center, 32 patients from the Wanzhou District treatment center, and 2 patients from the Qianjiang District treatment center. Patient age ranged from 25 to 89 years, with a mean of 56 years, and a median age of 69 (56-79).

Treatment protocol
All of the patients included in this study were given comprehensive rehabilitation treatment based on TCM for four weeks after discharge from hospital care. TCM was taken orally once in the morning and evening and Baduanjin(a type exercise of traditional Chinese medicine) was applied once a day for 15 minutes each time. The points of application included the bilateral Dingchuan, bilateral Shenshu, Shenque, and Danzhong; these were treated once a week for four to six hours. Moxibustion was selected for Qi Hai, Guan Yuan, bilateral Zusanli, and bilateral yuji, each for 10-15 minutes once every week. A Chinese herbal medicine foot bath was used once a day for approximately 20-30 minutes but not less than 5 times a week. We considered the clinical manifestations of patients with severe and critical COVID-19 following discharge into Yin and Yang syndrome types (Qi and Yin de ciency: phlegm and blood stasis syndrome; Yang Qi de ciency: phlegm and blood stasis syndrome). Patients experiencing the Yin syndrome type were administered with the following decoction: Radix Astragali 15g, Codonopsis pilosula 15 g , Lily 15 g, Ophiopogon japonicas 15 g, Pinellia ternata 10 g, thunberg fritillary bulb 10 g, Angelica 10 g, red peony root 10 g, Ligusticum wallichii 10 g, Alisma 10 g, Zedoary turmeric 6 g, and licorice root 6 g.
Patients needed to be differentiated into one of the two syndromes before they were discharged from their hospital. This differentiation was carried out by two attending doctors. The patients were then given the decoction that corresponded to their respective syndrome type.
We acquired instructional videos relating to Baduanjin, Acupoint sticking therapy, Moxibustion therapy, and application of the Chinese herbal medicine foot bath. At the time of their discharge, our researchers gave each patient a "rehabilitation bag" that included including the relevant TCM decoction and videos on a USB ash drive.
Since COVID-19 is a highly infectious disease, the researchers conducted rehabilitation guidance with social distancing and via remote digital methods. We recorded the WeChat numbers and telephone numbers of all convalescent patients were prior to their discharge from hospital. The researchers conducted regular follow-ups regularly (once a week) using WeChat or mobile phones and provided instruction with regards to rehabilitation exercise. E cacy and safety evaluation E cacy evaluation E cacy was evaluated by administering a range of questionnaires. Patients were asked to complete the Traditional Chinese Medicine Syndrome curative effect score scale, the mMRC dyspnea scale, the St.
George's respiratory questionnaire, the SF -36 quality of life scale, and the 6-minute walking test a speci c website (https://www.wjx.cn/jq/62881624.aspx.) We also carried out a chest CT scan, and laboratory tests for routine blood routine parameters, C-reactive protein, and erythrocyte sedimentation rate. These tests and the questionnaires were carried out two months after discharge.

Safety evaluation
With regards to patient safety, we acquired the following information: general condition, liver function, renal function, adverse reactions, and adverse events (two months after discharge).

Statistical methods
Data were analyzed by IBM SPSS Statistical Software version 22.0 was used in this research. If measurement data were normally distributed with the K-S test, we carried out statistical comparisons using the student's t-test and analysis of variance (ANOVA). However, if data was not normally distributed, we used non-parametric analyses (the rank sum test) for comparisons. The Chi-squared test was used to compare counting data while logistic regression analysis was conducted to compare indicators, mean scale values, and the chest CT-scans.

Results
After four weeks, 62 patients had completed the TCM syndrome curative effect score scale, the mMRC dyspnea scale, the St. George's respiratory questionnaire scale, the SF-36 quality of life scale, the 6minute walking test, and had undergone a chest CT scan. Of these 62 patients, there were 43 cases with de ciency of Qi and Yin-Phlegm and blood stasis, and 19 cases with de ciency of Yang Qi-Phlegm and blood stasis. In total, 56 patients completed serological examinations, including routine blood examinations, liver function tests, and kidney function tests. Fifty-seven of the included patients took the TCM decoction; ve patients did not take the decoction due to their own personal reasons.
Changes on chest CT scans Chest CT scans were performed before the rehabilitation program and for weeks after the program had commenced. We considered the pre-and post-rehabilitation CT scans with regards to the patient's lesions and graded these changes as follows: (1) obvious absorption: disappearance of the lesion by ≥ 70%; (2) improvement: a reduction in the area of the lesion by ≥ 30%; (3) no change; and (4) aggravation: the lesion area was increased by ≥ 30%. We then calculated the e cacy rate (%) using Eq. (1), Cases of obvious absorption are eight, proportion is 12.9%; Cases of improvement are forty-three, proportion is 69.35%; Cases of no change are eight, proportion is 12.9%; Cases of aggravation are three, proportion is 4.84%; E cacy rate of CT scans is 82.26%. as shown in Table 1.
Equation (1): E cacy rate = (basic absorption + improvement) / total number of patients × 100%. Consequently, non-parametric tests were used for data analysis and quartiles were used to re ect the distribution of each characteristic between the two groups of data, and before and after four weeks of the rehabilitation program. Two groups of data were then analyzed before and 4 weeks after their inclusion. The TCM Syndrome Curative effect score of prior to the treatment is 6 (2.5-10) and 4 weeks after is 2 (1-6.5); mMRC Dyspnea Score of prior to the treatment is 2 (1-2) and 4 weeks after is 21 (1-2); St George's Respiratory Questionnaire Score of prior to the treatment is 23 (12-32) and 4 weeks after is 11 (5-8); SF-36 Quality of Life Scale Score of prior to the treatment is 100 (87-110) and 4 weeks after is 114 (98-122.5). Difference was statistically signi cant (P<0.05), as shown in Table 2. Chi-square analysis showed that there were signi cant differences (P < 0.05) between the two timepoints (before and four weeks after the commencement of the rehabilitation program), There are 21 normal, 19 mild, 9 moderate, 9 severe, 5 extremely severe at prior to treatment, and there are 33 normal, 21 mild, 3 moderate, 5 severe, 1 extremely severe at prior to treatment. Difference was statistically signi cant(P<0.05), as shown in Table 3.

Changes in serological parameters
Several blood parameters (before and four weeks after commencement of the rehabilitation program) were not normally distributed, including leukocytes, neutrophils, neutrophil ratio, lymphocytes, lymphocyte ratio, and platelets. Consequently, we used non-parametric tests to compare this data before and after the rehabilitation program. Quartiles were used to re ect the distribution characteristics of the two groups of data. There were no signi cant differences between the two timepoints with regards to white blood cell and neutrophil (P > 0.05). However, there were signi cant differences between the two timepoints with regards to neutrophil ratio, lymphocyte, lymphocyte ratio, and platelet (P < 0.05), as shown in Table 4. Data relating to red blood cells and hemoglobin were normally distributed; the Student's t-test identi ed signi cant differences when these data were compared between the two timepoints (P < 0.05), as shown in Table 5. Next, we carried out logistic regression analysis, using a range of independent variables: age, gender, TCM syndrome curative effect score, whether the patient took the TCM decoction, 6 minute-walk test, mMRC dyspnea score, St. George's respiratory questionnaire score, SF-36 quality of life scale score, white blood cells, neutrophils, neutrophil ratio, ratio of lymphoid cells, lymphocytes, red blood cells, hemoglobin, and platelets. Chest CT scan acted as the dependent variable in this analysis. The analysis aimed to identify factors that might be associated with an improvement in chest CT scan, "Whether taking TCM decoction" and "6-minute walk test" were statistically signi cant (P < 0.05), as shown in Table 6. None of the included patients with severe and critical COVID-19 infection who were treated by TCM-based rehabilitation intervention experienced any signi cant adverse reactions or damage to liver and/or kidney function during the four weeks of analysis.

Discussion
Pulmonary rehabilitation is a comprehensive form of intervention that is based on the comprehensive assessment of a patient followed by treatments that are in accordance with the individual patient's speci c condition. The aim of these interventions is to improve the physical and psychological status of patients with respiratory diseases while promoting long-term adherence to health-promoting behavior [4] .
In combination with the modern concept of pulmonary rehabilitation, this strategy can help patients with severe and critical COVID-19 infection to return to their normal life from numerous aspects, such as exercise tolerance, appetite, sleep quality, etc.
The results of this study demonstrated that comprehensive TCM-based rehabilitation programs can improve the quality of life of patients suffering from severe or critical COVID-19 infection and improve their clinical symptoms, exercise endurance, and respiratory function. This strategy also helps to increase the total count of red blood cells, hemoglobin, lymphocytes, and lymphocytes, and can also reduce the total count of platelets and neutrophils. Research has shown that most COVID-19 patients exhibit reduced lymphocyte counts, hemoglobin counts, as well as thrombocytopenia [5] . Lymphocyte and platelet counts have also been shown to reduce gradually in patients with mild, severe, and critical COVID-19 infection [6] . After four weeks of comprehensive TCM-based rehabilitation, we found that our patients had signi cantly higher lymphocytes, lymphocyte ratio, and hemoglobin; although there was a signi cant reduction in platelet count. The factors and mechanisms underlying these observations need to be investigated in future research.
Logistic regression showed that patients who did not take the TCM decoction did not show a signi cant improvement in their CT scans. This indicates that the administration of TCM decoctions can signi cantly improve the e cacy rate of chest CT scans. The higher a patient's score on the 6-minute walking test, the higher the probability of them not showing an improvement on CT scans. According to the clinical data, the higher a patient scored on the 6-minute walking test, and the shorter the distance walked, the larger the lesions would be on chest CT scans, thus implying poor levels of absorption. Therefore, the 6-minute walking test could be used to predict chest CT scan results in this patient population. The worse the exercise endurance is, the more severe the lesions might appear on chest CT scans. Conversely, the better the exercise endurance is, the milder the lesions might be on chest CT scans. Therefore, it is evident that the improvement of clinical symptoms and serological parameters may differ from the improvements shown on CT scans of the chest.
The clinical manifestations of severe and critical COVID-19 patients are Qi de ciency of the lungs and spleen, de ciency of Yin and body uid, and de ciency of Yang. During the course of clinical treatment, and due to the serious condition and long disease duration, some patients developed pathological products, such as phlegm turbidity and blood stasis; this creates accumulation in the lungs and can block the lungs and bronchi. We divided patients with severe and critical COVID-19 upon discharge from hospital into Yin and Yang syndromes. We then administered a comprehensive TCM-based rehabilitation program. Via body movement, the administration of Baduanjin can lead to improvements in breathing and mental status, can alleviate symptoms, increase exercise endurance, and improve the quality of life [7] . Therefore, a comprehensive TCM-based rehabilitation program can alleviate the symptoms of fatigue, shortness of breath, poor appetite, and insomnia.
The study still has some limitations that need to be considered, including a small sample size and a short follow-up time. Because this disease is contagious, the rehabilitation program could not be strictly monitored by the researchers. Future studies should involve an appropriate control group. However, our current results do show that those who followed the comprehensive rehabilitation program of TCM did receive bene t. Thus, a comprehensive rehabilitation program involving TCM might be a useful way to help severe and critical patients with COVID-19.

Conclusion
Based on the results of this study, we were able to demonstrate that the modern concept of pulmonary rehabilitation and a comprehensive TCM-based rehabilitation program can improve the quality of life for patients with severe and critical COVID-19 infection. This program also helped to improve clinical symptoms, exercise endurance, respiratory function, while also helping to facilitate the absorption of lung lesions.

Declarations
Availability of data and materials The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.
Ethics approval and consent to participate All participants gave signed informed consent to participate in the study, which was approved by the local Ethics Committees(No.2020-ky-ks-ZDP).

Authors' contributions
Guo-Qing Zuo designed the research, Yi Ren performed the research and wrote the manuscript; Yu-Jin Wang evaluated the endpoints and performed statistical analysis; Hua-Bao LIU, Fang-Zheng Mou, Xiao-Feng Yan and Li-Lin Tang collected the clinical data. All the authors read and approved the nal manuscript.