key: cord-1008150-732hildh
authors: Alschuler, Lise; Chiasson, Ann Marie; Horwitz, Randy; Sternberg, Esther; Crocker, Robert; Weil, Andrew; Maizes, Victoria
title: Integrative Medicine Considerations for Convalescence from Mild-to-Moderate COVID-19 Disease
date: 2020-12-23
journal: Explore (NY)
DOI: 10.1016/j.explore.2020.12.005
sha: 16fc49383bc29d98e4dee002d904a9423d38b1ed
doc_id: 1008150
cord_uid: 732hildh

The majority of individuals infected with SARS-CoV-2 have mild-to-moderate COVID-19 disease. Convalescence from mild-to-moderate (MtoM) COVID-19 disease may be supported by integrative medicine strategies. Integrative Medicine (IM) is defined as healing-oriented medicine that takes account of the whole person, including all aspects of lifestyle. Integrative medicine strategies that may support recovery from MtoM COVID-19 are proposed given their clinically studied effects in related conditions. Adoption of an anti-inflammatory diet, supplementation with vitamin D, glutathione, melatonin, Cordyceps, Astragalus and garlic have potential utility. Osteopathic manipulation, Qigong, breathing exercises and aerobic exercise may support pulmonary recovery. Stress reduction, environmental optimization, creative expression and aromatherapy can provide healing support and minimize enduring trauma. These modalities would benefit from clinical trials in people recovering from COVID-19 infection.

The majority of individuals infected with SARS-CoV-2 have mild-to-moderate COVID-19 disease. Despite the non-severe nature of mild-to-moderate (MtoM) COVID-19, these infections are, nonetheless, accompanied by pathophysiological changes, acute and enduring symptoms. Convalescence from MtoM COVID-19 disease is largely overlooked and represents a prime opportunity to support health resilience and to potentially lessen enduring and late-onset sequelae with evidence-informed integrative medicine strategies. Integrative medicine (IM) approaches typically recommend a combination of practices including dietary change, breathing exercises, physical activity, supplements, etc. These authors, all IM subject matter experts, offer plausible integrative strategies to support convalescence from MtoM COVID-19. Whether this multipronged approach has synergistic advantages in COVID-19 recovery deserves further study.

Coronavirus disease of 2019 (COVID- 19) , the disease caused by the Novel SARS-coronavirus-2 (SARS-CoV-2), was first described in Wuhan, China in December 2019. SARS-CoV-2 is a large RNA virus of the coronavirus family. Its route of infection mimics other members of the Coronaviridae family, which are responsible for many common upper respiratory infections. The virus is enveloped, with a prominent spike protein ("S protein") on its surface; this protein is responsible for virion attachment. 1 The virus enters the body via common mucosal portals and attaches to the cellular ACE2 receptor. 2 The ACE2 receptor is found on diverse cell types, including endothelial and epithelial cells of the lungs, heart, blood vessels, kidneys, and gastrointestinal tract. 3, 4, 5 This broad tissue distribution of ACE2 may explain the pleiotropic effects of viral replication in different hosts.

The SARS-CoV-2 virus has demonstrated marked heterogeneity in both host symptomology and target organ pathogenicity. Viral infection of mucosal epithelial cells occurs and may be followed by aggressive replication that spreads the virus down the respiratory tree to the upper and lower lungs. Coronavirus infects both type I and II pneumocytes, which leads to a loss of surfactant and can lead to an acute respiratory distress syndrome (ARDS)-like pathology, with respiratory failure and sepsis. Compounding this issue, a concomitant immune response commonly described as a "cytokine storm" can occur. Activation of macrophages, monocytes, and lymphocytes in response to the virus leads to massive release of cytokines. 6 These cytokines contribute to overwhelming and uncontrolled inflammation, leading to septic shock and death in some patients. 7 Acute treatment of these COVID-19 patients becomes a balancing act between maintaining innate antiviral immune responses and suppressing the robust and unregulated cytokine release.

Convalescence appears to be a lengthy process relative to the initial infection. For instance, complications of macro-and micro-thromboses are relatively common, and may require prolonged anti-coagulation. 8, 9 Recovery from ARDS is a slow rehabilitative process, and supplemental oxygen is often required. Even individuals with MtoM disease -the majority of infected patients -may experience sequelae of this respiratory viral infection with few supportive conventional therapeutic options. This article will provide additional options for these patients. We will focus on integrative lifestyle-based and dietary supplement strategies. While not all-inclusive of potentially useful strategies, the recommendations outlined here reflect the expertise and experience of these authors. Additionally, while other whole systems of healing such as Asian traditional medicine 10 and Ayurvedic medicine 11 have much to offer in recovery from COVID-19 infection, inclusion is beyond the scope of this paper.

The natural course of COVID-19 recovery is variable and influenced by divergent factors including age, the baseline health of the individual, the presence of comorbid conditions, the nature and severity of infection, and socioeconomic circumstances. This variability, coupled with our incomplete understanding of this illness, presents a challenge to the development of a standard convalescence protocol.

Up to 50% of asymptomatic COVID-19 patients have atypical chest CT findings, specifically ground-glass opacities 12 , indicative of pulmonary inflammation and possibly fibrosis. Unresolved post-viral fibrosis can lead to altered lung elasticity and decreased pulmonary function as has been seen in other coronavirus infections. 13 In a cohort of patients over age 65 hospitalized for various types of infectious pneumonia, the risk of cardiovascular disease events increased 4-fold in the first year compared to age-matched controls and remained elevated for 10 years after the pneumonia. 14 Whether this will be seen with COVID-19 is not yet known but is a concern. Liver impairment is also a concern; for instance, out of 926 patients with nonsevere COVID-19 in China, elevated AST was seen in 18.2% and elevated ALT was seen in 19.8% of these patients. 15 Another complication is inflammatory activation of the coagulation cascade, evidenced by thrombocytopenia and elevated d-dimer. Although more common in severe infection, over 1/3 of all patients with COVID-19 develop these coagulation abnormalities which may impede patient recovery. 16, 17 Immune dysregulation can occur, especially in individuals over the age of 50 years, characterized by decreased lymphocytes, especially CD8+ T lymphocyte counts and impaired adaptive immunity. 18 Inflammation and other ongoing sequelae may lead to lingering fatigue. Additionally, inflammatory cytokines, such as IL-6 and TNF-alpha, which are characteristically elevated in SARS-CoV-2 infection, are implicated in mood disorders especially depression. 19 Convalescence from MtoM COVID-19 infection is not the primary concern of conventional medicine, whose resources are appropriately directed to life-saving interventions in those with severe infection. However, supporting convalescence is directly within the scope of integrative medicine. Drawing from the deep repository of research and experience in lifestyle-based strategies that optimize recovery and wellbeing after infections, there are a multitude of integrative strategies that can be employed for individuals recovering from MtoM COVID-19 illness. The strategies highlighted here are curated from the expertise of the authors as plausible integrative strategies to support convalescence from MtoM COVID-19.

Integrative medicine is defined as healing-oriented medicine that takes account of the whole person, including all aspects of lifestyle. It emphasizes the therapeutic relationship between practitioner and patient, is informed by evidence, and makes use of all appropriate therapies. 20 To be explicit, IM is a larger paradigm that includes conventional approaches. As more effective conventional treatments for COVID-19 become available, and as primary prevention with a vaccine is developed, integrative approaches are likely to remain critically important in reestablishing well-being.

A focus on restoring homeostasis plays a key role in IM. Even when diseases do not have clear treatment, practitioners can use the principles of IM to facilitate recovery. 21 Below are summaries of the evidence for selected IM approaches that can be used to combat inflammation, repair lung injury or dysfunction, replete nutritional deficiencies, reduce chronic stress, and mitigate fatigue.

In addition, IM may empower the patient to aid their recovery. This is important in chronic diseases such as diabetes and cancer to enhance individual control of the disease as well as to reduce the cost of care. 22, 23 Many of the evidence-based recommendations that follow are interventions that people can do for themselves. Incorporating these behaviors moves the locus control from external ("the doctor must prescribe medicine or treat me") to internal ("I can take actions to restore my own health.")

A low-glycemic, low-saturated fat diet can be used to modulate inflammation generally. 24 An anti-inflammatory diet combines traditional Mediterranean and Asian eating patterns and is characterized by high consumption of vegetables, fruit, legumes, fish, lean protein, whole grains, spices, nuts and seeds and low consumption of both refined grains and processed foods. Various nutrient components of an anti-inflammatory diet, such as monosaturated and polyunsaturated fatty acids 25 and plant-derived flavonoids 26 are associated with decreased activation of the NLRP3 inflammasome. The NLRP3 inflammasome is a critical cytosolic protein complex responsible for both acute and chronic inflammation in response to various pathogens 27 , including SARS-CoV-2. 28, 29 Anti-inflammatory diets are associated with improved pulmonary function in non-asthmatic Hispanic adults 30 and improved lung function and lower mortality in individuals with COPD. 31 Anti-inflammatory diets emphasize the inclusion of herbs and spices which have known antioxidant and anti-inflammatory effects and may slow the progression of COPD in which NLRP3 inflammasome activation plays a critical pathogenic role. 32, 33 With any prolonged illness, COVID-19 included, mental health can be compromised. In a period as short as 10 days, a Mediterranean style diet may result in improved mood and cognition. 34 Infection is a catabolic process which leads to transient nutrient deficiencies, particularly of protein, B vitamins, vitamin C, copper, zinc, and iron. 35 Individuals with prolonged infections, as well as those who are undernourished prior to infection, are at greatest risk for these nutrient depletions. Thus far, it has been observed that individuals with patients with COVID-19 are likely to have nutrient deficiencies, with one study reporting 76% of hospitalized patients with COVID-19 deficient in vitamin D, 42% deficient in selenium. 36 Further, among patients with respiratory distress, 91.7% were deficient in at least one nutrient while 78.9% without respiratory distress had a deficiency of at least one nutrient. With appropriate dietary support during convalescence, nutrient repletion can be expected, although it is estimated that it takes up to 3 times as long to replete nutrients than it took to become depleted. 37 Dietary intake of meat, poultry, fish, eggs, dairy, legumes, beans, nuts and seeds supply amino acids such as alanine, glutamate and glutamine which provide the substrates for nitrogenous compounds. Branched chain amino acids (namely leucine, isoleucine, and valine) improve intestinal permeability, regulate glucose metabolism, enhance endogenous protein synthesis, and fuel immune cells resulting in increased phagocytosis, NK cell activity and immunoglobulin production. 38 The global consensus for protein intake needed by healthy individuals is 0.8g/kg body weight/day. 39 Older individuals have greater protein needs associated with acute inflammatory and catabolic conditions and PROT-AGE evidence-based recommendations advise the consumption of 1.2 -1.5g protein/kg body weight/day. 40 In addition to protein, consumption of foods rich in vitamins and minerals, and avoidance of foods which may further deplete these nutrients, will support nutritional convalescence. Fruits and vegetables are the main dietary sources of vitamins and minerals and also provide antiinflammatory and antioxidant phytochemicals. Not surprisingly, consuming fruit and vegetables is associated with improved respiratory function, specifically reduced airway inflammation and oxidative stress, 41 reduced TNFα, reduced C-reactive protein and increased T-cell activation. 42 The USDA-recognizes produce subgroups as follows: dark green vegetables, red/orange vegetables, legumes, starchy vegetables, other vegetables (such as iceberg lettuce, onions, green beans), and fruit. 43 Eating produce from all subgroups is important in order to ingest a full-spectrum of these phytochemicals. The USDA MyPlate guidelines recommend that half of each meal is fruit and vegetables. 44

While dietary supplements are now being studied in acute COVID-19 infections, there are no clinical trials demonstrating the efficacy of dietary supplementation to support convalescence. The therapeutic goals of adjunctive support are prioritized differently between these phases, notably, during active infection, anti-viral support is key, while during convalescence, the primary goal is downregulation of inflammation. There are a number of supplements which may support recovery and minimize post-infectious complications; several of which are highlighted here.

Vitamin D: Vitamin D has anti-viral, anti-inflammatory, and immune enhancing actions in the lungs. 45 Among 43 consecutive older patients hospitalized for treatment of COVID-19, 17.6% of those who received oral 1000iu vitamin D3, 150mg magnesium and 500mcg vitamin B12 throughout their hospitalization required oxygen therapy compared to 61.5% of patients who did not receive the supplements. 46 Serum vitamin D levels are positively correlated with improved pulmonary function in children and adults with asthma. 47 Vitamin D deficiency is associated with reduced risk of respiratory tract infections, 48 decreased lung function, as well as increased susceptibility to, and delayed recovery from, infections and inflammatory conditions. 49 Not surprisingly, vitamin D deficiency is associated with greater COVID-19 disease severity, and vitamin D deficiency is more prevalent among severe cases compared to mild cases. 50 Vitamin D 3 supplementation is ideally based on serum 25OH vitamin D levels to achieve sufficiency and is typically recommended at a dose of 300 -4,000IU daily. 51 Those with very low levels of vitamin D, older adults, people with darkly pigmented skin, and obese patients may require higher doses.

Glutathione: Glutathione is the body's primary endogenous antioxidant and is the most abundant antioxidant in the lung epithelium. Glutathione exerts non-specific anti-viral actions, has anti-inflammatory actions, and upregulates vitamin D synthesis and vitamin D receptor activity. 52 A published report of two patients with COVID-19 pneumonia reported relief of respiratory distress using 2g of either oral or IV glutathione at the peak of their illness. 53 Various studies of patients with acute respiratory distress syndrome have shown that the intake or administration of a number of compounds, including selenium, 54 n-acetyl cysteine, 55 and ginger, 56 are associated with increased pulmonary glutathione, improved pulmonary function and reduced inflammation. Contrary to popular belief, oral glutathione increases systemic tissue levels of glutathione and natural killer cell cytotoxicity in a dose and time dependent manner. 57 Glutathione supplementation ranges from 250mg to 1000mg daily to achieve tissue increases and immune changes. 58

Melatonin: Melatonin is a potent endogenous antioxidant, anti-inflammatory and immunomodulatory molecule. 59 The natural decline in melatonin production over the lifespan 60 is one theoretical postulation for the increased susceptibility to COVID-19 infection and sequelae among the elderly. Melatonin has been shown to reduce symptoms of other viral infections. 61 Importantly, exogenous melatonin has been found to reduce inflammation, specifically IL-1 , in the face of acute systemic inflammation. 62 Given the integral role of inflammation in the symptoms of COVID-19 and its post-infection sequelae, there is compelling rationale for the use of melatonin in the convalescent population. Long term melatonin supplementation has been clinically studied at dosages ranging from 2mg to 20mg nightly. 63 Cordyceps sinensis: Cordyceps is a medicinal mushroom with a long tradition of use due to its antioxidant, antitumor, anti-inflammatory, and antimicrobial actions. 64 Cordyceps has been shown to increase Natural Killer (NK) cell activity in randomized clinical trials of healthy adults. 65 , 66 Cordyceps has also been shown to increase exercise performance -both metabolic and ventilatory capacity -in adults ages 50-75 after 12 weeks of supplementation. 67 A randomized controlled trial of adult patients with moderate chronic asthma found that Cordyceps supplementation for 2 months resulted in reduced serum markers of airway inflammation, including lower IgE, sICAM-1, IL-4 and MMP-9. 68 Long term cordyceps has been most commonly studied in doses between 1.5g -3g daily. 69 Astragalus membranaceus: The root of Astragalus membranaceus, or milkvetch, has a long tradition of use in Asian medicine (Huang-Chi) and has increasingly been incorporated into Western herbal medicine. The root extract contains polysaccharides which have been found to increase innate and T-cell adaptive immunity, to exert anti-oxidant and anti-proliferative effects, and to modulate inflammation. 70 The anti-inflammatory effects of intravenous astragalus have been documented in a DBRCT of 23 patients with metastatic cancers of various types 71 Astragalus resulted in significant quality of life improvements (reduced pain, nausea, fatigue, improved appetite and sleep) which was attributed to reduced inflammatory cytokines, notably IL-1 and IL-6. In another clinical trial of 82 patients with acute exacerbation of COPD, the addition of 15mg of astragalus granules twice daily for two weeks to conventional bronchodilator therapy resulted in significant reductions in TNF , IL-8, IL-1 and IL-32. 72 Furthermore, the astragalus group experienced improved measures of adaptive and innate immunity and improved pulmonary function tests. Astragalus root extracts standardized to 40% polysaccharides or 3% astragalosides can be dosed at 320mg -500mg daily and astragalus granules dosed between 4g -60g daily. 73 Garlic: Garlic, or Allium sativa, can be a component of the diet and also supplemented. Garlic is a source of organosulfur compounds which downregulate nuclear factor-kappa B (NFkB), thereby reducing the expression of many inflammatory cytokines. 74 Several clinical trials have demonstrated immune enhancing and anti-inflammatory effects using aged garlic extract. A DBRCT 3-month study of 120 individuals found that aged garlic extract reduced the severity and duration of cold and flu symptoms. 75 The garlic extract also improved T-cell and NK cell activity. A subsequent trial found similar results with reduced cold and flu severity as a result of aged garlic extract. 76 Garlic supplementation is also associated with reduced inflammation. In a DBRCT of 51 healthy obese adults, 3.6g of aged garlic extract resulted in significantly lower IL-6 and TNF after 6 weeks of supplementation. 77 The effective dose of garlic varies according to the formulation studied and the indication. Clinically studied daily dosages of garlic supplements range from 600-900mg dried garlic powder tablet, standardized to 1.3% alliin or 0.6% allicin) or 7.2g of aged garlic extract. 78

One historical narrative of the 1918 great influenza reports that people treated by an osteopathic physician had death rates of 10% compared to the 30% overall estimated death rate. 79 While there is no published data confirming this supposition about the 1918 flu, the wisdom that therapies such as Osteopathic Manipulation Techniques (OMT) may be of assistance in respiratory illness is long standing. 80 Noll et al. examined osteopathic manipulation as an adjunct treatment for hospitalized patients with pneumonia in a DBRCT study of hospitalized patients over age >50 with pneumonia. The researchers found significant reductions in length of stay, respiratory failure and duration of antibiotics in the conventional care plus OMT group. 81 Yao et al performed a systematic review of the literature examining OMT in patients diagnosed with pneumonia. 82 This review examined 6 RCTs of good quality and summarized their findings as 5 effective techniques that address lung function: inhalation and exhalation dysfunction, diaphragmatic and rib cage mobility, and thoracic lymphatic flow (i.e. thoracic pump). All techniques are illustrated in this review. While this review examined bacterial pneumonia, these OMT techniques address underlying issues also seen in viral pneumonia and ARDS. Based on an extensive literature review and clinical experience, Wang et al conclude that the best OMT techniques for COVID-19 recovery are modified segmental breathing, lymphatic drainage and rib cage mobility. 83 OMT may also assist with development of immunity. Jackson et al examined the effect of OMT techniques (lymphatic pump and splenic pump) during hepatitis B vaccination. 84 In this pilot study (N=20), participants received the 3 OMT sessions per week for 2 weeks after each vaccination. By week 6, the OMT intervention group had significantly higher antibody titers and this improvement continued throughout the course of the study. The authors posit that lymphatic and splenic pump techniques improved the immunologic response through the movement of lymphatic fluid.

Qigong, an ancient practice of meditation, breathing and slow movements, has been shown to improve pulmonary function and may be of benefit in COVID-19. 85 Lim et al performed a small study (N= 20) examining the effect of Qigong (20 min per day for 10 days) in normal volunteers. 86 Participants had a significant increase in ventilatory efficiency for oxygen use and carbon dioxide production (p<0.05); the authors posit that this represented a 20% increase in ventilatory efficiency, and that Qigong is an effective technique for increasing lung capacity and efficiency. Sakata et al studied the effect of a 12-week Qigong and aerobic exercise program on 72 healthy Japanese women aged 60-86 years of age. 87 The intervention consisted of 90 minutes of supervised Qigong and 25 minutes of aerobic exercise once a week, with an additional 20 minutes of home-based Qigong per day. Physical function improved, and lung capacity increased significantly in participants aged 60-69, although not in those older than 69.

Feng et al completed an extensive literature search for Qigong to examine its potential in COVID-19 prevention and rehabilitation. 88 They reviewed data for effectiveness in hypertension, asthma, COPD, mood disorders, cognitive impairment, pain relief and muscle strength. They concluded that the efficacy of Qigong is based on 4 mechanisms: management of stress and emotion, strengthening respiratory muscles, reducing inflammation, and enhancing immune function. In respiratory patients, Qigong improved pulmonary function as well as 6-minute walking distance. They specifically recommend three Qigong practices for COVID-19 prevention and rehabilitation -Diaphragmatic breathing, Ba Duan Jin (a series of 8 slow movements and stretching), and Liu Zi Jue (diaphragmatic breathing with pursed lip breathing, toning and mild-body movements.

Wayne et al did a systematic review of 22 studies on Tai Chi and Qigong with cancer related symptoms and found significant improvement in fatigue, sleep, depression, and overall quality of life. 89 Chan et al reviewed data on Qigong in two studies of chronic fatigue patients, both trials lasted between 5-8 weeks, with a minimum practice of 30 min 3 times per week. 90 They found significant decrease in depressive symptoms, fatigue, and an improvement in sleep.

Home based Qigong may also be very effective for COVID-19. A small feasibility study in China offered a 12-minute Qigong routine twice a day to COVID-19 patients while convalescing. 91 Patients kept a journal of their experiences. This pilot found 100% adherence; the authors conclude that home Qigong is a feasible at home rehabilitation program for COVID-19 recovery. Qigong can be learned through classes (including on-line); the feasibility of doing Qigong at home is promising.

Expert opinion in the recent COVID-19 literature stresses the use of breathing exercises in COVID rehabilitation, with the caveat that it must not be introduced too early; patients should be off supplemental oxygen. 92, 93 Hanada et al published a systematic review of 14 studies examining the effect of specific types of pulmonary rehabilitation (PR) on hypoxia and pulmonary function in patients with idiopathic pulmonary fibrosis (IPF). 94 The authors report that aerobic exercise plus either diaphragmatic breathing exercises or inspiratory muscle training (IMT) significantly increased 6-minute walk distance, leading the authors to conclude that breath work added to aerobic exercise may be an important addition to the treatment of pulmonary fibrosis. 95 Borge et al did a systematic review of breathing exercises including diaphragmatic breathing (DB), pursed-lip breathing (PLB), yoga breathing relaxation techniques (RT), and body position exercises (BPEs) in COPD patients. 96 The strongest evidence was for PBL, with an improvement of dyspnea found to be at 40%.

Wang et al also included breathing exercises in their recommendations for MtoM COVD-19 rehabilitation. 97 They recommend starting 10 minutes per session, 2-3 times per day, with a progression up to a total of 60 minutes per day. The techniques they suggest include DB, PLB, pranayama (a yogic breathing practice), tai chi breath work, or singing. 98 As patients are able to do this before aerobic exercise, breathing exercises are one of the first elements that can be started for COVID-19 rehabilitation. 99 Breathing techniques can be instructed virtually and may be easily added early in recovery and effective for COVID-19 rehabilitation.

Moderate exercise appears to be key for immune support and improved recovery. Many observational studies correlate exercise fitness prior to viral infection with lowering the severity of illness; interventional studies also support this finding. 100 Moderate exercise improves cytotoxic immunity 101 and reduces pulmonary fibrosis 102 in animal studies. although all the participants' regimens were overseen by a physical therapist during the course of the study. This suggests that virtual oversight could be utilized.

The Stanford Hall consensus statement for post COVID-19, created as an evidence-based set of UK guidelines, states that rehabilitation should be started after it is clear there are no cardiac complications and within 30 days in the post-acute phase. 104 For asymptomatic, mildly symptomatic and symptomatic patients not requiring hospitalization, they recommend exercise training as the core of the rehabilitation, graded to the patient's ability. For patients who were asymptomatic, they do not suggest exercise restrictions. For those with MtoM COVID-19 symptoms, once recovering, they suggest 1 week of low-level stretching, and light muscle strengthening, before returning to moderate cardiovascular exercise. They stress that high intensity training is avoided until fully recovered. 105 Wang et al structure their COVID-19 rehabilitation recommendations according to the severity of dyspnea with the Borg dyspnea score. 106 For MtoM COVID-19, they recommend initially starting with aerobic exercise (i.e. walking or biking) for 10-15 minutes, 1-2 times per day on 3-4 days each week with an intensity that keeps the Borg dyspnea score ≤ 3. Next they recommend incremental increases in intensity every 2-3 sessions to reach a Borg dyspnea score of 4-6, and to increase the duration incrementally to a maximum of 30-45 minutes per session.

Extensive literature shows that chronic stress, termed allostatic load, 107 impacts immune system function and, largely through the anti-inflammatory effects of glucocorticoids, 108, 109 leads to more frequent and severe viral infections, 110,111 reduced vaccine take-rate, 112 prolonged wound healing, 113 and speeding of chromosomal aging. 114 Mind-body interventions, such as mindfulness meditation, or those combining mindfulness with gentle exercise, such as yoga and Tai Chi, lower the brain's stress response, and also trigger the brain's relaxation response. 115 The latter, via enhancing the parasympathetic nervous system and vagus nerve release of acetylcholine, provide a brake to the stress response and boost the antiinflammatory components of the immune response. 116 All mind-body practices, including, but not limited to meditation, yoga, Tai Chi, and guided imagery, incorporate deep breathing. Deep breathing initiates the vagal parasympathetic response, as measured by heart rate variability (HRV), 117 lowers the stress response and impacts the immune response. 118, 119 In addition, these, and other, mind-body practices boost brain dopamine reward and endogenous opioid anti-pain pathways. 120

Studies have demonstrated measurable health benefits associated with creative expression in healthy individuals as well as in those with medical conditions. Improvements in mood, psychological well-being and immune system functioning have been noted. 121, 122 There have been more than 400 studies assessing the impact of expressive writing on various health conditions. 123 Although studies on the benefits of expressive writing have mixed or marginal results, expressive writing is associated with some conditions with relevance to COVID-10 convalescence. Expressive writing is associated with improvements in lung function in adults with asthma, 124 improvement in chronic pain 125 , and improvement in mental health. 126 One well-studied form of creativity is expressive writing, or journaling. A small randomized trial was conducted in which individuals with active HIV infections were assigned to one of two groups over a 4-day period. 127 One group wrote about an emotional topic, while the control group wrote about non-emotional events. The emotional writing group was noted to have decreased viral load and an associated increase in CD4 counts compared to the control writing group. Although causality is not established here, there is a suggestion that this expressive writing exercise could potentially be beneficial.

Creative writing may provide individuals with an opportunity to express their experiences without interruption by a listener, without the need to filter entries to make them acceptable to others, and without the need for special equipment or supplies. However, there may be need for caution in using this technique with those unaccustomed to any emotional expression. 128

Aromatherapy is the aerosolization of plant-derived essential oils. The volatile essential oils found in plants carry aromatic qualities, interact with the mucus membranes of the respiratory tract and affect the limbic system. There are certain clinical applications of aromatherapy which may be of benefit in the setting of convalescence from COVID-19 infection. Lavender essential oil has potential therapeutic value in convalescence due to its stress-reducing and anxiolytic effects. Lavender aromatherapy has been found, in a variety of clinical contexts, to exert anxiolytic effects and to improve sleep quality. 129, 130, 131 Reduction in anxiety correlates with self-perceived wellness, improves adherence to healthy behaviors and improves sleep -all essential to convalescence from viral infections. In another application of aromatherapy in light of the shared underlying pathophysiology between asthma, COPD and COVID-19 pulmonary disease, namely NLRP3 inflammasome activation, oxidative stress, hypoxia and mitochondrial dysfunction, 132 it is proposed that essential oils beneficial in asthma and COPD may also be beneficial in COVID-19 disease. Specifically, oral administration of 1,8-cineole, a main constituent of eucalyptus oil, at 200mg three times daily, improves pulmonary function in asthmatics. 133 1,8-Cineole improves lung function via mucolytic, anti-inflammatory, bronchodilatory, antioxidant and antimicrobial effects. However, in healthy volunteers, nebulized essential oils of peppermint, eucalyptus or rosemary did not affect spirometry readings. 134 Sleep Good sleep quality is essential for health, and the physical environment plays an important role in supporting healthy sleep. Exposure to full spectrum circadian sunlight from 8am to 12 noon reduces sleep latency (time to fall asleep), improves sleep quality and improves mood. 135 In the absence of sunlight, full spectrum light boxes can also be effective in sleep support and in reducing depressive symptoms. 136 

The physical environment can similarly play a role in either triggering the stress response and contributing to chronic stress, or in triggering the relaxation response. There are many features of the physical environment that increase stress: noise; light; foul odors; extremes of temperature and humidity; crowding; and mazes. Cumulative exposure to stressful environments can thus contribute to allostatic load and impair immune system function. Conversely elements of the physical environment that relax and counter these effects of stress include soothing nature sounds; diffuse light and full spectrum sunlight in the morning; natural fragrances from essential oils, such as lavender; social support and positive social interactions; 137 and labyrinths, which unlike mazes, can induce a state of walking meditation. Human preference for green spaces, termed biophilia, whether views of nature, being in nature, or even images of nature, reduce stress, and has even been shown to speed postsurgical recovery 138 and improve quality of life in bone marrow transplant patients. 139 Sound can also stress or calm. Spaces that are too noisy or too quiet can increase the stress response, 140 and sound abating features can help to mitigate these effects (carpets, ceiling tiles). A study in Sweden showed that changing the ceiling tiles in intensive care units reduced stress in staff and led to a better night's sleep. 141 Nature sounds, such as running water or forest sounds have also been shown to reduce stress and bring on better sleep quality. 142 Similarly calming music improves moods, reduces stress and activates dopamine reward pathways. 143, 144 Finally, relative humidity (RH) outside the 30-60% range increases stress, as measured by HRV by up to 25%, while RH in the 45% +/-5% range is optimal for reducing the stress response. 145 RH in the discomfort range (less than 30% or greater than 60%) is also associated with poorer sleep quality, due to increased stress. Relative humidity lower than 30% also increases susceptibility to viral infection, likely due to drying of mucus membranes. 146

The recommendations outlined in this review are summarized in Table 1 . below. 25 Lim(2018) 26 Han(2020) 30 Biswas(2013) 32 Nachmias (2019) 48 Gorman(2017) 45 Herr(2011) 49 Pereira ( Reiter(2020) 59 Reiter (2020) 65 Kang(2015) 66 Chen(2010) 67 Wang (2007) 78 Ruhee(2020) 74 Nantz(2012) 75 Xu(2018) 77 Osteopathic manipulation Increases pulmonary function, diaphragmatic and rib cage mobility, and thoracic lymphatic flow; increases immune response 3 OMT sessions per week of: modified segmental breathing, lymphatic drainage, rib cage motility Jackson(1998) 84 Noll(2010) 81 Yao (2014) 82 Wang (2020) 103 Barker-Davies(2020) 104 Wang (2020) 83 Stress reduction Anti-inflammatory, initiates parasympathetic response, activates endogenous opioid anti-pain pathways Meditation, yoga, Tai Chi, guided imagery Tracey(2007) 116 Thayer(2006) 118 Williams(2019) 119 Bhasin(2013) 120 Creative expression Improves mood and psychological well-being; enhances immunity; improves lung function; improves chronic pain Visual art, music, expressive writing Stuckey(2010) 121 Baikie (2005) 122 Smith(2015) 124 Trompetter (2015) 133 Ozkaraman(2018) 129 Senturk(2018) 130 Lillehei(2015) 131 Juergens(2020) 133 Environment optimization Stress reduction, improved mood, enhanced immunity, better sleep

Full spectrum Circadian light exposure; time in Nature; calming music or sounds; indoor relative humidity 30-60% Cohen(1997) 111 Ulrich(1984) 138 Levitin(2006) 143 Ellis(2010) 144 Razjouyan(2020) 145 Taylor (2016) 146

Integrative Medicine focuses on the human organism's innate capacity for healing. Convalescence from disease, like recovery from injury, places great demands on the body's mechanisms of healing. In this article, we have given specific advice based on current evidence about diet, supplements, physical activity, stress management, and other helpful therapeutic modalities. This advice will continue to evolve as we care for patients recovering from MtoM COVID-19. Ideally, a randomized a trial would confirm the value of these therapies as well as any additive, negative, or synergistic effects. Until that time, the high safety profile of these recommendations align with the first principle of medicine primum non nocere.

The most important contribution of IM is the assurance that the body's healing system is fully capable of restoring wellness. Depending on age, state of health at the onset of illness, and the severity of your illness, the process may take longer for some. Nonetheless, it is imperative to trust in the wisdom of the body and the healing power of nature.

SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor

Tissue distribution of ACE2 protein, the functional receptor for SARS coronavirus. A first step in understanding SARS pathogenesis

SARS-CoV-2 Infectivity and Neurological Targets in the Brain

Expression of the SARS-CoV-2 cell receptor gene ACE2 in a wide variety of human tissues

Molecular pathology of emerging coronavirus infections

Plasma inflammatory cytokines and chemokines in severe acute respiratory syndrome

Pulmonary Vascular Endothelialitis, Thrombosis, and Angiogenesis in Covid-19

Global COVID-19 Thrombosis Collaborative Group, Endorsed by the ISTH, NATF, ESVM, and the IUA, Supported by the ESC Working Group on Pulmonary Circulation and Right Ventricular Function. COVID-19 and Thrombotic or Thromboembolic Disease: Implications for Prevention, Antithrombotic Therapy, and Follow-Up: JACC State-of-the-Art Review

The Effects of Traditional Chinese Medicine as an Auxiliary Treatment for COVID-19: A Systematic Review and Meta-analysis

The Plausible role of Indian Traditional Medicine in combating Corona Virus (SARS-CoV 2): a mini-review

Clinical characteristics of 24 asymptomatic infections with COVID-19 screened among close contacts in Nanjing

Pulmonary fibrosis and COVID-19: the potential role for antifibrotic therapy

Coagulation disorders in coronavirus infected patients: COVID-19, SARS-CoV-1, MERS-CoV and lessons from the past

Immune environment modulation in pneumonia patients caused by coronavirus: SARS-CoV, MERS-CoV and SARS-CoV-2

COVID-19: Coagulopathy, Risk of Thrombosis, and the Rationale for Anticoagulation

Remodeling of the Immune Response With Aging: Immunosenescence and Its Potential Impact on COVID-19 Immune Response. Front Immunol

Effects of acute systemic inflammation on the interplay between sad mood and affective cognition

What is Integrative Medicine

Integrative Medicine and Patient Centered Care

Why patients should be more empowered: a European perspective on lessons learned in the management of diabetes

Self-management: Enabling and empowering patients living with cancer as a chronic illness

Cardiovascular diseases, NLRP3 inflammasome, and western dietary patterns

Fatty Acids and NLRP3 Inflammasome-Mediated Inflammation in Metabolic Tissues

Flavonoids interfere with NLRP3 inflammasome activation

The NLRP3 Inflammasome: Metabolic Regulation and Contribution to Inflammaging. Cells

Emerging role of IL-6 and NLRP3 inflammasome as potential therapeutic targets to combat COVID-19: Role of lncRNAs in cytokine storm modulation

Targeting the NLRP3 Inflammasome in Severe COVID-19. Front Immunol

Dietary Patterns, Asthma, and Lung Function in the Hispanic Community Health Study/Study of Latinos

The Association Between Dietary Intake and Phenotypical Characteristics of COPD in the ECLIPSE Cohort. Chronic Obstr Pulm Dis

Pharmacological and Dietary Antioxidant Therapies for Chronic Obstructive Pulmonary Disease

NLRP3 inflammasome activity is upregulated in an in-vitro model of COPD exacerbation

Switching to a 10-day Mediterranean-style diet improves mood and cardiovascular function in a controlled crossover study

Effect of infection on nutrient requirements

Nutritional status of patients with COVID-19

Scrimshaw 1991 op cit

Branched chain amino acids: Beyond nutrition metabolism

Dietary protein requirements and adaptive advantages in athletes

Evidence-based recommendations for optimal dietary protein intake in older people: A position paper from the prot-age study group

Effects of fruit and vegetable consumption on risk of asthma, wheezing and immune responses: A systematic review and meta-analysis

Effects of fruit and vegetable consumption on inflammatory biomarkers and immune cell populations: a systematic literature review and meta-analysis

Updated US Department of Agriculture Food Patterns meet goals of the 2010 dietary guidelines

Back to Basics: All About MyPlate Food Groups. J Acad Nutr Diet

Vitamin D supplementation of initially vitamin D-deficient mice diminishes lung inflammation with limited effects on pulmonary epithelial integrity

Cohort study to evaluate the effect of vitamin D, magnesium, and vitamin B12 in combination on progression to severe outcomes

Meta-analysis of vitamin D and lung function in patients with asthma

Vitamin D supplementation to prevent acute respiratory tract infections: systematic review and meta-analysis of individual participant data

The role of vitamin D in pulmonary disease: COPD, asthma, infection, and cancer

Vitamin D deficiency aggravates COVID-19: systematic review and meta-analysis

Endogenous Deficiency of Glutathione as the Most Likely Cause of Serious Manifestations and Death in COVID-19 Patients

Efficacy of glutathione therapy in relieving dyspnea associated with COVID-19 pneumonia: A report of 2 cases

The Effect of Intravenous Selenium on Oxidative Stress in Critically Ill Patients with Acute Respiratory Distress Syndrome

Improvement by N-acetylcysteine of acute respiratory distress syndrome through increasing intracellular glutathione, and extracellular thiol molecules and anti-oxidant power: Evidence for underlying toxicological mechanisms

Effect of enteral feeding with ginger extract in acute respiratory distress syndrome

Randomized controlled trial of oral glutathione supplementation on body stores of glutathione

Melatonin Inhibits COVID-19-induced Cytokine Storm by Reversing Aerobic Glycolysis in Immune Cells: A Mechanistic Analysis

Aging and circadian rhythms

Therapeutic Algorithm for Use of Melatonin in Patients With COVID-19

Melatonin suppresses markers of inflammation and oxidative damage in a human daytime endotoxemia model

The genus Cordyceps: An extensive review of its traditional uses, phytochemistry and pharmacology

Immunomodulatory effects of a mycelium extract of

CBG-CS-2): A randomized and double-blind clinical trial

Cordyceps Militaris Enhances Cell-Mediated Immunity in Healthy Korean Men

Effect of Cs-4® (Cordyceps sinensis) on exercise performance in healthy older subjects: A double-blind, placebo-controlled trial

Effect of Dongchong Xiacao Capsule on Airway Inflammation of Asthmatic Patients

Astragalus polysaccharide (PG2) ameliorates cancer symptom clusters, as well as improves quality of life in patients with metastatic disease, through modulation of the inflammatory cascade

Milkvetch root improves immune function in patients with acute exacerbation of COPD

Organosulfur Compounds: A Review of Their Anti-inflammatory Effects in Human Health

Supplementation with aged garlic extract improves both NK and γδ-T cell function and reduces the severity of cold and flu symptoms: A randomized, doubleblind, placebo-controlled nutrition intervention

Aged Garlic Extract Modifies Human Immunity

Aged garlic extract supplementation modifies inflammation and immunity of adults with obesity: A randomized, double-blind, placebo-controlled clinical trial

Health Effects of Garlic

The 2012-2013 Influenza Epidemic and the Role of Osteopathic Manipulative Medicine

One hundred thousand cases of influenza with a death rate of one-fortieth of that officially reported under conventional medical treatment. 1919

Efficacy of osteopathic manipulation as an adjunctive treatment for hospitalized patients with pneumonia: a randomized controlled trial

Osteopathic manipulative treatment as a useful adjunctive tool for pneumonia

Physical Medicine and Rehabilitation and Pulmonary Rehabilitation for COVID-19

Effect of Lymphatic and Splenic Pump Techniques on the Antibody Response to Hepatitis B Vaccine: A Pilot Study

The Application of Eight-Segment Pulmonary Rehabilitation Exercise in People With Coronavirus Disease

Effects of qigong on cardiorespiratory changes: a preliminary study

Positive effects of a qigong and aerobic exercise program on physical health in elderly Japanese women: an exploratory study. Environ Health Prev Med

Qigong for the Prevention, Treatment, and Rehabilitation of COVID-19 Infection in Older Adults

Chi and Qigong for cancer-related symptoms and quality of life: A systematic review and meta-analysis

Qigong exercise for chronic fatigue syndrome

Effects of controlled breathing exercises and respiratory muscle training in people with chronic obstructive pulmonary disease: results from evaluating the quality of evidence in systematic reviews

Aerobic and breathing exercises improve dyspnea, exercise capacity and quality of life in idiopathic pulmonary fibrosis patients: systematic review and meta-analysis

Positive effects of a qigong and aerobic exercise program on physical health in elderly Japanese women: an exploratory study. Environ Health Prev Med

Exercise and Respiratory Tract Viral Infections

activator associated with physical exercise potentiates the reduction of pulmonary fibrosis

A randomised controlled trial of the effectiveness of an exercise training program in patients recovering from severe acute respiratory syndrome

The Stanford Hall consensus statement for post-COVID-19 rehabilitation

Stress and the individual. Mechanisms leading to disease

Brain-immune interactions and disease susceptibility

Neural regulation of innate immunity: a coordinated nonspecific host response to pathogens

Stress-induced immune dysfunction: implications for health

Can meditation slow rate of cellular aging? Cognitive stress, mindfulness, and telomeres

The relaxation response: psychophysiologic aspects and clinical applications

Physiology and immunology of the cholinergic antiinflammatory pathway

Heart rate dynamics during three forms of meditation

Beyond heart rate variability: vagal regulation of allostatic systems

Heart rate variability and inflammation: A meta-analysis of human studies

Relaxation response induces temporal transcriptome changes in energy metabolism, insulin secretion and inflammatory pathways

The Connection Between Art, Healing, and Public Health: A Review of Current Literature

Emotional and physical health benefits of expressive writing

Randomized controlled trial of expressive writing for psychological and physical health: the moderating role of emotional expressivity

The effects of expressive writing on lung function, quality of life, medication use, and symptoms in adults with asthma: a randomized controlled trial

Internet-based guided self-help intervention for chronic pain based on Acceptance and Commitment Therapy: a randomized controlled trial

Expressive writing and positive writing for participants with mood disorders: an online randomized controlled trial

Effects of written emotional expression on immune function in patients with human immunodeficiency virus infection: a randomized trial

Aromatherapy: The effect of lavender on anxiety and sleep quality in patients treated with chemotherapy

The Effect of Lavender Oil Application via Inhalation Pathway on Hemodialysis Patients' Anxiety Level and Sleep Quality

Effect of inhaled lavender and sleep hygiene on self-reported sleep issues: A randomized controlled trial

Novel insights on the pulmonary vascular consequences of COVID-19

New Perspectives for Mucolytic, Anti-inflammatory and Adjunctive Therapy with 1,8-Cineole in COPD and Asthma: Review on the New Therapeutic Approach

Inhaled peppermint, rosemary and eucalyptus essential oils do not change spirometry in healthy individuals

The impact of daytime light exposures on sleep and mood in office workers. Sleep Health

Light therapy for preventing seasonal affective disorder

View through a window may influence recovery from surgery

Open Window': a randomized trial of the effect of new media art using a virtual window on quality of life in patients' experiencing stem cell transplantation

Using Digital Health Wearable Devices to Understand the Relationship Between Sound levels and Wellbeing: A Segmented Mixed-effects Regression Approach. Complete paper presented at workshop on Information Technology and Systems

Acoustics and psychosocial environment in intensive coronary care

Shinrin-yoku" (taking in the forest atmosphere or forest bathing) in Japan

This is your brain on music: the science of a human obsession

Music and Autonomic Nervous System (Dys)function. Music Percept

Wellbuilt for wellbeing: Controlling relative humidity in the workplace matters for our health

Is low indoor humidity a driver for healthcare-associated infections? Indoor Air, Paper 340: Session 98