Cardiorespiratory Exercise & Chinese Medicine for Rehabilitation of Discharged Coronavirus Disease (COVID-19) Patients (Covid19Reh)

Cardiorespiratory Exercise & Chinese Medicine for Rehabilitation of Discharged Coronavirus Disease (COVID-19) Patients

Would Cardiorespiratory Exercise and Chinese Herbal Medicine Facilitate Rehabilitation Among Post-discharge Patients With COVID-19? Clinical Efficacy and Mechanisms

The University of Hong Kong, Chinese University of Hong Kong, The Hong Kong Polytechnic University, University of South Wales, Yale University, University of California, San Diego

Rehabilitation interventions can help to address the consequences of COVID-19, which include medical, physical, cognitive, and psychological related problems. The specific aims of this project are to investigate the effects of a 12-week exercise program on pulmonary fibrosis in recovering COVID-19 patients. A further aim will be to examine how Chinese herbal medicines, gut microbiome, and metabolites regulate immune function and possibly autoimmune deficiency in the rehabilitation process.

The study will develop a new paradigm for patient rehabilitation needed now and in the future. The specific aims of this project are to investigate the effects of a 12-week program with cardiorespiratory exercise and Chinese herbal medicine on recovering COVID-19 patients and to collect qualitative and quantitative data to examine loneliness, anxiety, depression, quality of life, and mental health. A further aim will be to examine how Chinese herbal medicines, gut microbiome, and the metabolites regulate immune function, intestinal permeability, and possibly autoimmune deficiency (AID) in the pathological recovery/rehabilitation process. In this multicenter, triple-blinded, randomized, parallel groups, controlled clinical trial, the investigator will recruit adult patients with COVID-19 and have been discharged from the hospital in Hong Kong and the Chinese Mainland. A total of 172 eligible patients will be randomized 1:1:1:1 into four groups: cardiorespiratory exercise plus Chinese herbal medicines group, cardiorespiratory exercise group, Chinese herbal medicines group, and waiting list group for 12-week (3 months) with 12-week follow-up period. A 4-week pilot study will be conducted to test patient recruitment and maintenance, data collection, instrumentation, and observing the adaptability and practicality of the intervention. Amendments will be made if necessary.

A triple-blinded, randomized, parallel groups, controlled clinical trial. A total of 172 eligible patients will be randomized 1:1:1:1 into four groups: cardiorespiratory exercise plus Chinese herbal medicines group, cardiorespiratory exercise group, Chinese herbal medicines group and waiting list group for 12-week (3 months) with 12-week follow-up period.

Both patients and investigators will be blinded to the assigned groups. Patients will be allocated at a ratio of 1:1:1:1, the randomization will be carried out by Statistical Analysis System 9.3 (SAS 9.3) statistical software. (Descript how the blinding works here) One copy of the blind codes will be held by the project responsible unit. The statistician will be blinded throughout the study.

Includes: 1.12-week progressive & individualized exercise, 60mins/session, 3 sessions/week, total 36 exercise sessions. Components: a set of home-based tele-exercise sessions with remote monitoring of vital signs; individualized action plan to perform various daily physical activities; educational sessions on self-management & habit formation; access to a call center; & counselling sessions to enhance motivation to regularly engage in daily physical activities. 2.Chinese herbal formula of Modified Bai He Gu Jin Tang prescribed in granules, 10g/day (5g dissolved in 200ml of hot water, b.i.d), twice/day after breakfast & dinner, 7days/week for 12 weeks.

Includes: A 12-week progressive & individualized exercise, 60mins/session, 3 sessions/week, total 36 exercise sessions. Components: a set of home-based tele-exercise sessions with remote monitoring of vital signs; individualized action plan to perform various daily physical activities; educational sessions on self-management & habit formation; access to a call center; & counselling sessions to enhance motivation to regularly engage in daily physical activities.

Includes: Chinese herbal formula of Modified Bai He Gu Jin Tang prescribed in granules, 10g/day (5g dissolved in 200ml of hot water, b.i.d), twice/day after breakfast & dinner, 7days/week for 12 weeks.

The waiting list control sign will be adopted to conceal allocation results from the patients and further to reduce selection and confounding bias and increase their adherence to the study. Patients in the waiting list control group will receive no treatment in the study period (including a 12-week intervention period and a 12-week follow-up period). However, they will receive Chinese herbal medicines after the completion of the study (i.e., after the 3rd wave of measurements in the 25th weeks).

Each exercise session (40-60 minutes) will include warm-up, aerobic training, resistance training, cool-down, as well as inspiratory muscle training

The Chinese herbal formula of Modified Bai He Gu Jin Tang will be prescribed in granules. A dose of 10g a day (5g, b.i.d) will be ingested. Patients will dissolve a sachet of granules (5.0g) in 200ml of hot water, twice a day after breakfast and dinner, seven days a week for three months.

To assess the functional exercise capacity that reflects daily physical activities and to measure the distance the participant is able to walk over six minutes on a hard, flat surface. Items measured during 6MWT are: Distance Walked (m) Number of Rests

The Borg Category Ratio 10 (CR10) Scale® (Borg Dyspnea Scale), will be used to rate the patients' dyspnea and overall fatigue level. At the beginning and end the end of the 6 MWT. The scale will also be used during Cardiopulmonary Exercise Test (CPET). Scale: 0=Rest; 0.5=Really Really Easy; 1=Really Easy; 2=Easy; 3=Moderate; 4=Sort of Hard; 5,6=Hard; 7,8,9=Really Hard; 10=Maximal

Bio-impedance analysis approach will be used to assess patient's segmental muscle mass in percentage (%).

A stadiometer will be used to measure stature (in metres) and weight is measured in kg to calculate body mass index (BMI) . Body Mass Index (BMI): weight (in kilograms) divided by the square of your height (in metres)

Anatomical circumferences - waist (cm) & Hip (cm) will be measured using a steel measuring tape, to calculate the Waist-to-Hip Ratio.

Forced vital capacity test (FVC) will be measured and used to calculate FEV1/FVC ratio to assess the functional severity and capacity of the patient's lung.

Forced expiratory volume (FEV1) will be measured and used to calculate FEV1 /FVC ratio to assess the functional severity and capacity of the patient's lung.

Maximal Voluntary Ventilation (MVV) measures peak performance of the lungs and respiratory muscles to assess overall pulmonary ventilation.

Fractional exhaled Nitric Oxide (FeNO), the results will be in parts per billion (ppb) of nitric oxide in patient's breath, will be used to assess inflammatory response to exercise and medicinal intervention.

Diffusing capacity of the lungs for carbon monoxide (DLCO), measured in millilitre/minute/Kilopascal (ml/min/kPa), will be used to evaluate gas diffusion in the lungs.

CPET provides information concerning the level of exercise that the patient can perform without undue stress. The test results will guide the research team regarding exercise prescription for physical rehabilitation methodologies, and provides quantitative evidence of the benefits of a rehabilitation program as well as information on the mechanism(s) involved. Work Rate(WR), an incremental ergometry exercise test, will be used to assess the cellular, cardiovascular, and ventilatory systems' responses under precise conditions of metabolic stress

Breath by breath measurements of minute ventilation (VE) in L/min will be measured and used to calculate ventilatory efficiency - VE/VCO2 and VE/VO2, ventilatory equivalents for carbon dioxide and oxygen.

CO2 output (VCO2) in L/min, will be measured and used to calculate ventilatory efficiency - VE/VCO2, ventilatory equivalents for carbon dioxide.

O2 uptake (VO2) in L/min, will be measured and used to calculate ventilatory efficiency - VE/VO2, ventilatory equivalents for oxygen.

Change in Chinese Medicine (CM) Diagnostic Pattern & Clinical Characteristics using CM Syndrome Differentiation Assessment

The changes in participants' health as characterized by CM diagnostic pattern & clinical characteristics using CM Syndrome Differentiation according to the Guidelines for Chinese Medicine New Drug Clinical Study (China Medical Science Press, 2002) will be assessed.

The changes in participants' health as characterized by body constitution scores using the Body Constitution Questionnaires for the nine specific types of body constitutions will be assessed on each visit during the treatment and follow up period.

Venous blood will be drawn & after coagulation at room temperature for 30 minutes, the samples will be centrifuged at 3000 rpm for 20 minutes. Serum as supernatant will be extracted & stored at -80˚C until assay. Serum levels of insulin will be assessed by a commercially available Enzyme-linked immunosorbent Assay (ELISA) kit (Merck).

The Prothrombin time test will be used to measure blood coagulation. Venous blood will be collected by venepuncture in a tube with sodium citrate. Plasma will be isolated after centrifugation at 1000rpm for 30 min, 4°C. Thromboplastin will be added into the plasma and kept at 37°C for two minutes. Calcium chloride will be added to the mixture, and the plasma is allowed to coagulate. The time needed for the coagulation will be recorded as the Prothrombin Time.

Quality of life (QoL) will be measured using the Personal Well-being Index-Chinese Version (PWI-C). It is a subjective QoL measure with questionnaires that have been translated and validated. Questions included are: How satisfied are you with…?" your standard of living ? your health ? what you are achieving in life ? your personal relationships ? how safe you feel ? feeling part of your community ? your future security ? Answers are measured using scale from zero to 10 (0...1…2...3...4…5...6...7...8...9…10). Zero means feel no satisfaction at all; 10 means feel completely satisfied.

Anxiety and stress will be measured using the Chinese version of the Depression Anxiety Stress Scale (DASS-21). The scale will discriminate between the negative emotional syndromes of depression, anxiety, and stress in Chinese populations. Only the subscales of anxiety and stress will be used. The anxiety scale assesses autonomic arousal, skeletal muscle effects, situational anxiety, and subjective experience of anxious affect. The stress scale is sensitive to levels of chronic nonspecific arousal. It assesses difficulty relaxing, nervous arousal, and being easily upset/agitated, irritable/over-reactive & impatient. The rating scale is as follows: 0=Did not apply to me at all Applied to me to some degree, or some of the time Applied to me to a considerable degree or a good part of time Applied to me very much or most of the time Scores are calculated by summing the scores for the relevant items. Higher scores indicate greater degrees of anxiety and stress.

Loneliness will be measured using the Revised UCLA Loneliness Scale (R-UCLA). It consists of 20 items and participants are to indicate how often they feel the way described by placing a check in the space provided, using the following scale: Never Rarely Sometimes Often Score scale for item 1,5,6,9,10,15,16,19,20 are reversed, and score for each item then summed together. Higher scores indicate greater degrees of loneliness.

General mental health will be measured using the General Health Questionnaire (GHQ), which is commonly used to screen minor psychiatric symptoms (Hu 2007). It consists of 12 items, beginning by asking "Have you recently…", each assessing the severity of a mental problem over the past few weeks using a 4-point scale of: (always) 0...1…2…3 (never). The score was used to generate a total score ranging from 0 to 36, with higher scores indicating worse conditions.

Patient is to self-sample morning first feces & immediately freeze it in a home freezer (-20℃) & transport to facilities in a provided freezer pack stored at -80℃. Total DNA of 200 mg fecal samples will be extracted & purified. The DNA concentration & size distribution will be estimated by a Nano drop instrument & agarose gel electrophoresis respectively. The DNA one paired-end (PE) library will be prepared using a DNA high-throughput (HT) Sample Prep Kit, & whole-genome shotgun sequencing of samples will be carried out by the Illumina platform. The high quality sequences will be mapped with the published gene catalog of reference genes in the human gut microbiome (Li 2014). Taxonomic assignment of the predicted genes and Kyoto Encyclopedia of Genes & Genomes (KEGG) analysis will be performed as described (Feng 2015). Relative abundances of phyla, genera, species, & Kegg Orthology (KOs) will be calculated from the relative abundances of the respective genes.

Metabolomics analysis of selected neurotransmitters as potential markers of depression: Ultra-performance liquid chromatography triple quadrupole mass spectrometry will be used to quantitatively measure the metabolites selected (neurotransmitters) as potential markers of depression. Briefly, an aliquot of 40 μl of urine or plasma will be spiked with 10 μL of internal standard (L-4-chlorophenylalanine in water, 30 μg/mL), and extracted with 200 μL of acetonitrile and methanol (9:1, v/v). The mixture will be vortexed and centrifuged. After centrifugation, the supernatant will be transferred to the sampling vials and subject to analysis. The raw data generated will be processed using the Target Lynx Applications Manager Version 4.1 (Waters Corp., Milford, MA) for targeted metabolite annotation and to obtain calibration equations and the concentration of each metabolite in the samples Metabolomics analysis

Inclusion Criteria: aged 18 years and above; a percentage of predicted forced vital capacity (FVC) <90%, and/or a percentage of predicted carbon monoxide diffusing capacity < 90% (King 2014); able to communicate in Cantonese. Exclusion Criteria: having acute exacerbations in the 12-week preceding recruitment patients; having any contraindications for exercise (e.g., physical disability, uncontrolled mental disorders, unstable heart disease, unable to perform muscle strength tests) Female - Pregnant or plan to become pregnant in the next 1 year Unable to communicate in Cantonese or Mandarin Currently participating in other similar rehabilitation programs or research

All individual participant data collected during the trial will be deidentified and available for anyone who wish to access the data immediately following publication.

Gao Y, Zhong LLD, Quach B, Davies B, Ash GI, Lin ZX, Feng Y, Lau BWM, Wagner PD, Yang X, Guo Y, Jia W, Bian Z, Baker JS. COVID-19 Rehabilitation With Herbal Medicine and Cardiorespiratory Exercise: Protocol for a Clinical Study. JMIR Res Protoc. 2021 May 26;10(5):e25556. doi: 10.2196/25556.