Effectiveness of Liu-zi-jue exercise on coronavirus disease 2019 in the patients: a randomized controlled trial

Abstract

OBJECTIVE:

The aim of this study was to examine the effect of Liu-zi-jue exercise on the respiratory symptoms, quality of life, and mental health of patients with mild coronavirus disease 2019 (COVID-19).

METHODS:

A single-center randomized controlled trial was conducted with 104 patients with mild COVID-19. The patients were randomly assigned to the Liu-zi-jue plus conventional therapy group and conventional therapy group. The outcome measures included Modified Borg Dyspnea Scale (MBDS) score, Patient Health Questionnaire-9 (PHQ-9) score, Fatigue Scale-14 (FS-14), respiratory symptoms, and vital signs. Data were collected on the first and sixth days of hospitalization and on the discharge day.

RESULTS:

Repeated-measures ANOVA revealed that the whole scales all showed a downward trend in the two groups (all P < 0.05). The results of single-group effect suggested that the whole scale score in the intervention group was significantly lower than that in the control group at the sixth day of hospitalization. Compared with the control group, only the MBDS, expectoration, and FS-14 scores showed significantly lower scores at the discharge day (P < 0.001, P = 0.011, P = 0.002). Comparison within the group showed that all the variables were significantly different at the three time points with a decreasing trend (P < 0.05), except for the PHQ-9 and expectoration scores (P = 0.331, 0.052). All patients' vital signs remained within a stable normal range throughout the hospital stay.

CONCLUSION:

The results suggested that Liu-zi-jue exercise as a complementary and alternative therapy showed beneficial effects on improving the symptoms (shortness of breath, fatigue, and cough), quality of life, and mental health of patients with mild COVID-19.

1. INTRODUCTION

Early in December 2019, an unknown acute respiratory disease, now called coronavirus disease 2019 (COVID-19), had an outbreak in Wuhan City, Hubei Province, China. ¹ The pathogen had been identified as a novel envelope RNAβ coronavirus 2 and named as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which has a genetic correlation with SARS-CoV. ^{2, 3} The World Health Organization had defined the spread of COVID-19 as a pandemic. As of April 1, 2020, the number of confirmed cases worldwide reached 754 948, of which 36 570 were fatal cases in over 202 countries or regions. ⁴ Previous data showed that the mortality rate of COVID-19 was 1%; studies reported recently that the virus can be spread by asymptomatic patients, which means that COVID-19 is difficult to control.^5,6 The disease has severely affected the global population, especially the elderlies, with particular emphasis on the patients and medical staff in Wuhan.^7,⇓-9 Fever, fatigue, and dyspnea are the common symptoms.¹⁰ Chest computed tomography usually shows a dynamic change in multiple ground glass shadows, which could further develop into poor prognosis.^11,12 The Chinese authority had proposed the Diagnostic and Treatment Protocol for Novel Coronavirus Pneumonia (7th Trial Version) as treatment program.¹³ Oxygen, antiviral, anti-inflammatory, and anti-infection therapies, as well as the prevention of complications are widely used in the clinical management of COVID-19. Supportive care is necessary for patients with severe COVID-19, but timely intensive surveillance and epidemiological screening are more important, and these strategies has already worked in China.¹⁴ Except for the basis of conventional treatment, clinicians should pay more attention to the rehabilitation of the physical and mental health of patients with mild COVID-19. Exercise training is an important part of pulmonary rehabilitation and has been shown to improve dyspnea and health status with low medical burden.¹⁵ Liu-zi-jue exercise, a low-risk traditional Chinese exercise, has been widely used for the prevention and treatment of respiratory diseases.^16,17 This exercise has been used in China for a long time; it involves whole-body movement accompanied by respiratory training and could be performed regardless of experience and age. Moreover, the exercise does not require expensive equipment and could be practiced individually or in groups.¹⁸ It includes six sets of physical and mental exercises with relatively low intensity, in which people need to focus on the coordination of the body and mind. Therefore, the purpose of this study was to assess the efficacy of Liu-zi-jue exercise plus conventional therapy for patients with mild COVID-19.

2. METHODS

2.1. Study design

The trial protocol was approved by the Ethics Committee of Yueyang Hospital of Integrated Traditional Chinese and Western Medicine (No. 2020-002). The study was retroactively registered on the China Clinical Trial Registry (No. ChiCTR2000032367). This study is a single-center randomized controlled trial. Patient recruitment was carried out in Huangshi Hospital of Traditional Chinese Medicine. Data management and analysis were conducted in Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine. Only the outcome assessors and statisticians were blinded because of the limitations of the intervention methods. The plan was to recruit 186 patients and randomly assign them to Liu-zi-jue exercise plus conventional treatment group and conventional treatment group at a 1:1 ratio. However, 52 patients were recruited in each group finally because of the constraint brought by the infectious disease and the lack of patients. Liu-zi-jue exercise was conducted twice a day from admission to discharge. The assessors who were blinded to the group assignment performed outcome evaluation and analysis at three time points (on admission day, before treatment on the 6th day of hospitalization, and the discharge day). All patients provided informed consent at the time of recruitment. The trial flow chart is shown in Figure 1.

Figure 1. Flow diagram of participant recruitment.

2.2. Participants

The recruited patients had mild COVID-19 symptoms, which were diagnosed by the criteria of the "Diagnostic and Treatment Protocol for Novel Coronavirus Pneumonia (7th Trial Version)" issued by the National Health Commission of China on March 4, 2020. The participants were recruited from inpatients of the Department of Infectious Diseases of Yueyang Hospital of Integrated Traditional Chinese and Western Medicine in Hubei Province.

2.2.1. Inclusion criteria

(a) No restrictions on age and gender; (b) patients diagnosed with mild pneumonia (i.e., slight clinical symptoms; no pneumonia manifestations on imaging but with fever, respiratory tract symptoms, etc.; imaging showed pneumonia but no multiple organ damage);¹⁹ (c) hospitalized patients; (4) patients who volunteered to join the trial and sign the informed consent; and (5) patients who promised not to perform other exercise activities.

2.2.2. Exclusion criteria

Patients who had one of the following were excluded in this test: (a) patients with severe diseases, such as cardiovascular, cerebrovascular, hematopoietic, digestive system, or mental illness; (b) pregnant and lactating women; (c) patients with respiratory rate > 30 breaths/min or with respiratory failure; (4) patients with other organ failure that requires treatment by the respiratory intensive care unit; and (5) patients who did not want to join the trial.

2.2.3. Drop out and suspension criteria

During the intervention period, patients had the right to withdraw for any reason in accordance with the Patient Management and Protection Regulations. The following conditions were considered the withdrawal criteria: (a) the patient did not implement the treatment plan as planned; (b) the patient participated in other exercise programs during the trial; (c) case data were incomplete and affect the judgement of curative effect; (4) the presence of unbearable adverse events; (5) the patient voluntarily withdrew. The trial would be immediately terminated in case of poor clinical efficacy or severe adverse events, such as respiratory failure, severe acid-base balance disorders, sepsis, and shock.

2.3. Randomization

Clinical researchers obtained random numbers, which were automatically generated by a random number generator (IBM Corp., Armonk, NY, USA), and assigned numbers to opaque envelopes, which represent the patients. The researchers opened the random allocation envelopes and assigned the participants accordingly. Eligible patients were randomly divided into the Liu-zi-jue exercise plus conventional treatment group and the conventional treatment group.

2.4. Blinding

Participants and Liu-zi-jue exercise trainers were not blinded to the group assignments because of the specific intervention, but the trainers would not know the assessment of outcomes. The evaluators, data managers, and statisticians were unaware of the group assignments in the outcome evaluation process and data analysis to reduce the risk of bias.

2.5. Sample size calculation

Length of hospital stay was used as the outcome to calculate the sample size. ²⁰ Assuming that the average length of stay in the control group was 10 days and the standard deviation was 3 d, the average length of stay in the treatment group was 8.5 d (α = 0.05, β = 0.10). Considering the 10% dropping rate, the number of subjects needed in each group was calculated to be 93; therefore, 186 patients needed to be recruited.

2.6. Interventions

Both groups of participants received routine treatment. The intervention group performed Liu-zi-jue exercise twice a day until the discharge day. The daily routine treatment plan was recorded in the electronic medical record by the doctor's system. The training method, including exercise action essentials, time, intensity, and precautions, was presented to the subjects in text and video forms to avoid cross-infection and ensure the identity of the training content. If the subject received any other exercise regimen, the changes should be recorded on the Clinical Report Form each time.

2.7. Control group (conventional treatment)

For patients with mild pneumonia, doctors strictly followed the general treatment plan, "Diagnostic and Treatment Protocol for Novel Coronavirus Pneumonia (7th Trial Version)," for symptomatic supportive treatment. The protocol includes: (a) bed rest, supportive treatment to ensure sufficient heat, water and electrolyte balance to maintain internal environment stability, and close monitoring of vital signs and oxygen saturation; (b) routine blood test, urinalysis, liver and renal function tests, myocardial enzymes, coagulation function test, and chest imaging; (c) timely effective oxygen therapy measures, including nasal catheter, mask oxygen, and transnasal high-flow oxygen therapy; (d) antiviral therapy [although no effective antiviral therapy has been confirmed, α-interferon atomized inhalation has been suggested to be used (5 million U each time for adults, add 2 mL of sterilized water for injection, two times a day)]; (e) antibiotic treatment if bacterial infection was confirmed; and (f) accurate Chinese medicine treatment.

2.8. Intervention group (Liu-zi-jue exercise)

The six movements of Liu-zi-jue exercise, namely, xū, hē, hū, xī, chuī, and xī, which were implemented in this study, were adopted from the reorganized version in 2003 stipulated by the General Administration of Sport of China; it is a 15-min exercise combined with breathing and stretching.²¹ The present study focused on symptom pattern identification of COVID-19 and the benefits of Liu-zi-jue exercise on physical and mental health. The participants were instructed to perform a systematic self-learning of the exercise for a half day before the trial began. They were be given written materials and video materials about the details of the Liu-zi-jue exercise. The researchers started a remote video conference to monitor and correct the exercises throughout the whole trail process. When the intervention officially began, the patients performed the exercise twice a day at 9 a.m. and 4 p.m. until the day of discharge. The six exercise movements are shown in Figure 2. The details are as follows. (a) Stand with feet open at the same width as the shoulders, put your hands on the sides of the waist with palms up, stretch out the right hand toward the left front by 45°, say "Xu,” and then return. Complete the mirror action with the other hand. (b) Bend your knees, raise your forearms, fold your palm down, press down, say "He," and then return. (c)Place your hands in front of the abdomen, rotate the palms inward, stretch forward with a circular trajectory, say "Hu," and then return. (4) Lift your hands naturally to your chest, raise your palms to push forward, say "Si," and finally return. (5) Place your hands in front of the abdomen, wrap your hands around your sides, press down slowly, say "Chui," and finally return. (6) Place your hands in front of your abdomen, lift your hands up to the top of your head, open your arms, pull back, press down, say "Xi," and finally return. Each set of actions was repeated three times before the next set of actions was performed. A previous study showed that certain exercise intensity can reach the patient’s benefit goals.²² Therefore, the exercise intensity was adjusted gradually according to the patient's cardiopulmonary exercise function from very low intensity [heart rate (HR) during exercise < 57%, heart rate rise (HRr) < 30%, or rating of perceived exertion (RPE) < 9/20] to low intensity (HR during exercise = 57%-63%, HR_max or HRr = 30%-39%, or RPE = 9-11/20) and to moderate intensity (HR during exercise = 64%-76%, HR_max or HRr = 40%-59%, or RPE = 12-14/20).

Figure 2. Illustration of the six Liu-zi-jue movements.

2.9. Outcome

All outcomes were managed by researchers blinded to the group assignment. The outcomes were assessed in three time points (the admission day, before treatment on the 6th day of hospitalization, and the discharge day). We focused on the symptoms of dyspnea and fatigue in patients. The degree of depression was also valued. Additionally, vital signs and common symptoms of lung disease were monitored.

2.10. Primary outcome

Modified Borg Dyspnea Scale score²³

MBDS, a modified dyspnea questionnaire with good reliability and validity, was listed as the main outcome index in this study. The scale includes 10 items about dyspnea and fatigue. The subjects selected the corresponding items that represent the severity of their symptoms to obtain different scores. The absence of difficulty of breathing and fatigue was scored 0 points. Highest scores of degree of breathlessness and fatigue were 10 points.

2.11. Secondary outcome

Patient Health Questionnaire (PHQ-9)²⁴

PHQ-9 is a tool that assesses the psychological condition of patients during illness that can lead to depressive symptoms. It is a self-administered questionnaire that has been widely used in many countries to assess the severity of depression. The subjects were instructed to fill the questionnaire at the three time points through case report forms.

2.12. Fatigue scale-14 (FS-14)²⁵

Patients would always feel tired during illness because of the psychological and physical damage caused by the disease; thus, fatigue is an important clinical symptom that should be monitored. FS-14 is a widely used self-assessment scale for the measurement of the severity of fatigue. It is applied in epidemiological studies to evaluate the extent of fatigue, and it has been proven to have good effectiveness and internal reliability.²⁶ The 14 questions were raised by various experts in the field and are divided into two aspects: physical fatigue and mental fatigue.

2.13. Respiratory symptoms

We focused on respiratory symptoms, such as cough, expectoration, chest tightness, dyspnea, and fatigue. The severity of each symptom was assigned with a score from 0 to 10 with 10 as the most severe. Each participant scored their own symptoms.

2.14. Vital signs²⁷

Blood pressure, HR, respiration, and blood oxygen saturation were be monitored three times a day by the nurse, and the average data was obtained.

2.15. Statistical analyses

Statistical analysis was performed using IBM SPSS version 25.0 (IBM Corp., Armonk, NY, USA). The normally distributed data were expressed as mean ± standard deviation ($\bar{x} \pm s$). Comparison of baseline data was performed using χ² test and two‐sample t‐test. The overall analysis was conducted by repeated-measures analysis of variance (Huynh-Feldt method was used to adjust the degree of freedom). Pairwise comparison within the group was conducted by Friedman test. Mann-Whitney U test was used in fine comparison or the comparison with the control group at the same time point. Significant difference in multiple comparison was defined as P < ά (ά = 0.05/3, corrected by Bonferroni method), and the significance in other tests was defined as P < 0.05.

3. RESULT

A total of 104 patients were included in the study (Figure 1). Ten patients had deteriorated conditions and were transferred to the intensive care unit; therefore, they were dropped forcibly from the study. In addition, 20 people refused to continue the trial and withdrew from the study. The two groups had no significant difference in demographic and disease data at baseline (Table 1). Moreover, no remarkable differences were found in their temperature, pulse rate, respiratory rate, and oxygen saturation of the two groups at baseline (Table 1).

Table 1.

Demographic characteristic of patients in the two groups ($\bar{x} \pm s$)

Variables	Control group (n = 37)	Intervention group (n = 37)	P value
	Male/Female	Male/Female
Sex (n)	M: 14, F: 19	M: 19, F: 18	0.242a
Number of patients with history of illness	9	10	0.790 a
History of circulatory system disease	5	6	0.744 a
History of respiratory diseases	2	1	0.556 a
Age (years)	44.81±14.6	42.35±10	0.401
BMI (kg/m2)	21.91±3	21.95±2.22	0.948
T (°C)	36.89±0.55	36.94±0.5	0.676
P (beats/min)	82.81±10.11	81.24±9.32	0.49
R (breaths/min)	20.65±1.78	20.51±1.63	0.734
SBP (mm Hg)	121.73±10.11	121.35±10.38	0.874
DBP (mm Hg)	73.08±11.91	74.03±12.53	0.74
SaO2 (%)	95.95±2.34	96.16±2.4	0.696

Notes: DBP: diastolic blood pressure; M: male, F: female; P: pulse rate; R: respiration rate; SBP: systolic pressure; SaO₂: arterial oxygen saturation; T: temperature. ^a Data were analyzed by Chi-square test. The rest of the data were analyzed by two‐sample t‐test. The control group was given guided routine treatment, while the treatment group was Liu-zi-jue exercise on the basis of routine treatment.

3.1. Clinical scales

The two groups had no differences in baseline scores (all P > 0.05). For the total scales, repeated-measures ANOVA showed that the interaction effect of time and group were statistically significant (all P < 0.05). The results of single group effect analysis suggested that the whole scale score in the intervention group was remarkably lower from that in the control group at T1. Compared with the control group, the MBDS, exp-ectoration, and fatigue scores were significantly lower at T2 in the treatment group (P < 0.001, P = 0.011, P = 0.002). Significant differences were observed in the remaining scales (P = 0.215, 0.378, 0.192, 0.026, 0.021 for PHQ-9, FS-14, cough, dyspnea, and chest tightness, respectively). Within-group comparison showed that except for PHQ-9 and expectoration score (P = 0.331, 0.052, respectively), all other variables were sig-nificantly different at the three time points and showed a decreasing trend (P < 0.05) (Figure 3).

Figure 3. Diagram of ANOVA for clinical scales.

A-C: the intervention group was compared with the control group in the median score of Modified Borg Dyspnea Scale (MBDS) score, the Patient Health Questionnaire-9 (PHQ-9) score and Fatigue Scale-14 (FS-14) at the three time points. D-H: the intervention group was compared with the control group in the median score of respiratory symptoms, including cough, expectoration, dyspnea, chest tightness, and fatigue.

The interaction between time and intervention was obvious in both groups. The clinical symptoms and physical and mental health scores of both groups showed a downward trend. However, the Liu-zi-jue exercise group had a lower score than the control group.

3.2. Vital signs

None of the vital signs differed significantly between the groups at baseline (P > 0.05), and no significant difference was found for the whole outcomes in both interventions, as well as in time-interaction effect (all P > 0.05).

4. DISCUSSION

4.1. Limitations

Although this experiment found some valuable results, it still has several limitations. (a) Given the limited resources available and the time sensitivity of the COVID-19 outbreak, we did not enroll enough participants according to the calculated sample size, which may result in type II error. (b) Obtaining sufficient blinding was impossible because of the physical therapy characteristics of Liu-zi-jue exercise, which might form a certain bias. (c)Bias may arise as the outcomes were based on clinical scale assessment. Moreover, follow-up is needed to verify the continued clinical effectiveness of the intervention.

4.2. Generalizability

Liu-zi-jue is a mind-body exercise focused on the health-related benefits of physical fitness and mindfulness-based practices. Several studies provided beneficial evidences for encouraging patients with chronic disease to practice traditional Chinese exercise combined with clinical guidance, which could considerably improve pulmonary function, clinical symptoms, and quality of life, particularly fatigue symptom and a variety of cardiopulmonary fitness indicators.^{28,⇓,⇓-31} This research combined COVID-19's treatment guidelines and Liu-zi-jue exercise. We focused on the improvement of the clinical symptoms of patients with mild COVID-19 during hospitalization and the patients' long-term quality of life. Cough, expectoration, chest pain, and fatigue are the common symptoms of experienced by patients with COVID-19, and dyspnea can reflect the degree of limited lung function.³² The research concluded that even short-term exercise can remarkably improve the clinical respiratory symptoms of mild COVID-19, including shortness of breath, cough, expectoration, and fatigue. Even at a low intensity, exercise capacity can be improved by aerobic exercise, including Liu-zi-jue. ³³ In addition, quality of life was considerably improved by the addition of Liu-zi-jue compared with the single guideline therapy. However, the differences between the two groups' statistics at discharge were not obvious, which could be attributed to the patients having reached a healthy physiological state. The stability of vital signs during treatment also showed that the safety of Liu-zi-jue exercise is reliable and suitable for patients with mild symptoms without causing adverse reactions. Additionally, an increasing number of studies have shown that traditional Chinese exercises have been widely used to address mental illness in patients with chronic disease, as these exercises could effectively manage patients' anxiety and negative emotions as a complementary alternative therapy.^34,⇓-36 The present research further observed that Liu-zi-jue exercise can better improve the emotional condition and mental health of patients than conventional therapy alone.

4.3. Interpretation

An investigation revalued that during the early stage of the COVID-19 outbreak in China, more than half of the respondents had moderate to severe anxiety.³⁷ A previous research proved that people are susceptible to anxiety and depression when faced with infectious diseases because of the potential risk of infection and poor prognosis.^38,39 A review indicated that traditional exercise is effective in reducing depression by activating the parasympathetic nervous system and immune system,⁴⁰ which may be associated with IgG, natural killer cells, and the redistribution of cytokine and T-lymphocyte.⁴¹ A systematic review showed the role of integrated medicine in the regulation of the immune system, which indirectly acts as an antiviral method.⁴² Therefore, it might be of great importance in the clinical intervention for patients with mild COVID-19. As the epidemic continues to worsen, restrictions on outdoor sports and the burden of medical costs are also increasing. However, Liu-zi-jue exercise is easy to learn and does not require special location and equipment; therefore, it could reduce the physical and mental burden of the family of a person with COVID-19. In addition, the underlying antiviral mechanism of exercise might be highly related to exercise immunity. For elderly people with immune-odeficiency, a 10-month endurance exercise is beneficial for a better influenza vaccination response.⁴³ A 2007 study also proved that the effectiveness of a 5-month exercise.⁴⁴ The Traditional Chinese Medicine theory believed that Liu-zi-jue exercise can reconcile the Yin and Yang Qi and coordinate physiological functions and emotions, and it has similarities with the physiological and pathological mechanisms of modern medicine. Applying Liu-zi-jue exercise to patients with mild COVID-19, a worldwide emergency, will be beneficial to human health and will broaden the scope of the intervention.

In conclusion, Liu-zi-jue exercise, as a complementary and alternative therapy, showed beneficial efficacy in the management of patients with mild COVID-19. Compared with the single guideline treatment, the exercise provided a better improvement in respiratory symptoms, including dyspnea, cough, expectoration, and fatigue, in the short term, as well as in patients' quality of life and mental health with high security, which are valuable for the management of the global COVID-19 crisis.