key: cord-0062466-mklhl63w authors: Gupta, Prashant Kumar; Sonewane, Kishor; Rajan, Mariappan; Patil, Nitin J.; Agrawal, Trapti; Banerjee, Ena Ray; Chauhan, Nagendra Singh; Kumar, Awanish title: Scientific rationale of Indian AYUSH Ministry advisory for COVID-19 prevention, prophylaxis, and immunomodulation date: 2021-04-29 journal: ADV TRADIT MED (ADTM) DOI: 10.1007/s13596-021-00574-7 sha: 52b69807c24cd8964988b7520e5f011293d03a69 doc_id: 62466 cord_uid: mklhl63w The current outbreak of COVID-19 is caused by the SARS-CoV-2 virus that has affected > 210 countries. Various steps are taken by different countries to tackle the current war-like health situation. In India, the Ministry of AYUSH released a self-care advisory for immunomodulation measures during the COVID-19 and this review article discusses the detailed scientific rationale associated with this advisory. Authors have spotted and presented in-depth insight of advisory in terms of immunomodulatory, antiviral, antibacterial, co-morbidity associated actions, and their probable mechanism of action. Immunomodulatory actions of advised herbs with no significant adverse drug reaction/toxicity strongly support the extension of advisory for COVID-19 prevention, prophylaxis, mitigations, and rehabilitation capacities. This advisory also emphasized Dhyana (meditation) and Yogasanas as a holistic approach in enhancing immunity, mental health, and quality of life. The present review may open-up new meadows for research and can provide better conceptual leads for future researches in immunomodulation, antiviral-development, psychoneuroimmunology, especially for COVID-19. Today whole world is battling with the current pandemic of COVID-19 (Corona Virus Disease-2019) . Increasing patient trend, high extend of spread, the unpredictability of manifestation of the clinical disease spectrum, and the uncertainty of cure are some worrisome concerns behind such social and mental stress in COVID-19. Information on COVID-19 is evolving very fast and it unlikely to have any definite treatment in near future. Drug discovery is a costly and large gestational affair while repurposing can cut short both cost/gestational time and bypass the preclinical and safety studies hence a push for Hydroxychloroquine repurposing is emphasized and exhibiting with a mixed response from scientists and clinicians (Rodrigo et al. 2020) . Amid such situations, where modern medical science and traditional medicine are standing on the same platform, we must explore all possibilities to prevent, mitigate, and control this pandemic. It is the right time to integrate critical care and complication management skills of allopathy and preventive, immunomodulatory, and mental health management through traditional medicine. The development of traditional medicine with the perspectives of safety, efficacy, and quality would help not only to preserve the traditional heritage but also to rationalize the use of herbal medicine in human healthcare (Mukharjee et al. 2017) . Integration of traditional Chinese medicine and modern medicine had formed the dominant treatment strategy in all COVID-19 affected areas across China (Jia and Yunfei 2020). Following a rich heritage of traditional medicine, the Indian AYUSH (Ayurveda, Yoga, Unani, Sidha, and Homeopathy) ministry has released an advisory for preventive health and immunity-boosting measures for self-care during the COVID-19 crisis (https:// ayush. gov. in). It underscores the concept of "Prevention is better than cure". The author has screened the capacity of AYUSH-advisory in the prevention, prophylaxis, mitigations, and rehabilitation of COVID-19 cases. Advisory broadly divided into 3 categories i.e. general measures, immunity promotive measures, and the Ayurveda procedures to follow. General measures of advisory advocate drinking warm water throughout the day in COVID-19 outbreak and practice of Yogasana, Pranayaam, and Dhayana (meditation) for 30 min daily (https:// ayush. gov. in). According to Ayurveda, drinking hot water helps in digesting Aama (a proinflammatory marker of impaired metabolism) followed by Samprapti Vighatan (break of disease cascade). It is advocated in Naveen Jwara (fever) (Vaidya and Trikamji 2004) . It is a good natural remedy to treat nasal congestion. A clinical study done in 15 healthy subjects, the nasal mucus velocity was measured before and at 5 and 30 min after drinking hot water increased from 6.2 to 8.4 mm/ min five minutes after administration in patients drinking hot water by sip, again value returned to their baseline at 30 min. The above study concludes increased nasal mucus velocity might be helpful in the management of upper respiratory tract infections (Saketkhoo et al. 1978) . On the line of advisory, the author emphasized how Yoga, Dhyana, and Pranayaam practices can be helpful in fighting psychoneuroimmuno perturbation during COVID-19. Among general measures, Yoga therapy is a form of mind-body medicine that integrates an individual's physical, psychological, social, and spiritual components to enhance health, with a primary focus on stress and related illnesses (Atkinson and Permuth-Levine 2009) . Yoga therapy comprises yogic physical postures (Asanas), Yogic breathing techniques (Pranayama), meditation (Dhyana)/ Mindfulness, Yogic cleansing techniques (Kriya), Yogic gestures (Mudras), and locks (Bandhas) (Sengupta 2012) . Evidence suggests Yoga as a therapeutic tool in alleviating fear, depression, anxiety, negative thinking, and enhance the quality of sleep (Cabral et al. 2011) . With mounting scientific literature/research in the field of Yoga, it is regarded as a form of Complementary and Alternative Medicine (CAM) by National Centre for Complementary and Integrative Health (NCCIH), USA. Spices like Curcumin longa Linn. (Haldi) , Cuminum cyminum Linn. (Jeera), Coriandrum sativum Linn. (Dhaanyaka) , and Allium sativum Linn. (Lahsun) are recommended for cooking. Herbal medicines like Ocimum sanctum Linn. (Tulsi), Piper nigrum Linn. (Maricha), Dry Zingiber officinale Roscoe (Shunthi), Cinnamomum species (Tvaka), Dry Vitis vinifera Linn. (Munnaka, Raisin, dried grapes) are recommended to make herbal tea/decoction and consume twice daily. Chyawanprasha (Herbo-mineral ayurvedic preparation) 10 g daily in the morning is also advised (https:// ayush. gov. in). Herbal drug screening revealed the presence of phytoconstituents such as polyphenol, terpenoid, flavonoid, curcumin, anthocyanin, proteins like lectins or agglutinins, piperine, vitamin C, gingerols, anthraquinone, and so on. These phytochemicals showed wide pharmacological actions but here we are documenting immunomodulatory, antiviral, and antibacterial actions, co-morbidity preventive action, and their probable mechanism of action. The third section i.e. Ayurvedic procedures advocates oil pulling therapy (Kawala) by sesame or coconut oil for 2-3 min followed by the warm water rinse, nasal application (Pratimarsh Nasya) of sesame oil or coconut oil or ghee in morning and evening. Daily steam inhalation with Mentha arvensis Linn. (Pudina) or Trachyspermum ammi Linn. (Ajwain), and Syzigium aromaticum Linn. (lavang) powder with honey orally is advised for ailment like sore throat or cough (ayush.gov.in). Recently, Indian states like Kerala, Delhi, Gujarat, Goa, and so on, allowed to treat COVID-19 confirm cases through dedicated Ayurveda/integrative approach using Ayurveda and modern medicine through projects like ʻSukhayusham̕ , ʻSwasthyam̕ , and ʻAyurRaksha̕ clinics. The herbal medicines and Ayurveda procedures mentioned in the advisory are being used for the purpose of immunomodulation, antimicrobial, and stress management in various traditional medicine the system of the world since ancient period (Table 1 ). In the next section, AYUSH recommended herbs, their present antimicrobial, immunomodulatory, and antiviral actions are discussed in detail and how these medicines and procedures are vindicated in retaliation of COVID-19. The current advisory supports the scientific background of Ayurvedic plants and their phytochemicals support the immune system and have antimicrobial action (Fig. 1a,b) . Apart from that, we have also discussed the detailed role of advised herbs because each phytochemical influences The enhanced mitogeninduced proliferation of spleen cell lymphocytes Enhanced NK cell activity in normal and tumor-bearing animals, Elevated levels of IL-2, TNF-α, and IFN-γ in normal mice, Antibody-dependent cellular cytotoxicity was raised Kesavan et al. (1998) (1) Ginger given orally for the common cold in India. (2) Ginger and palm tree juice (htan-nyat) are boiled and given orally to prevent the flu in Burma. (3) Shruthi et al. (2017) the immune cells as well as microbes that could also provide useful insights to the development of potentially useful new pharmacological agents (Fig. 2) . Rasona is an Ayurvedic Sanskrit name for Garlic (Allium sativum L.; Family: Amaryllidaceae) that enhances the functioning of the immune system by stimulating macrophages, lymphocytes, natural killer (NK) cells, dendritic cells, and eosinophils, through mechanisms like modulation of cytokine secretion, immunoglobulin production, phagocytosis, and macrophage activation (Arreola et al. 2015) . Garlic compounds, like sulfur-containing components, showed a modulatory effect on T cell proliferation. Cuminum cyminum (Jiraka) possesses immune stimulatory property possibly through thymoquinone (TQ). The black cumin seeds are proved effective for the treatment of diseases such as asthma, bronchitis, rheumatism, and other inflammatory diseases (Srinivasan 2018) . Cuminum cyminum stimulated the T cells (CD4 and CD8) and Th1 cytokines expression in normal and immune-suppressed swiss albino mice (Chauhan et al. 2010) . Antibacterial activities of cumin, cardamom, and dill weed essential oils were evaluated against Campylobacter jejuni and Campylobacter coli showed inhibition of Campylobacter species by impairing the bacterial cell membrane (Ingok and Guler 2017). Coriandrum sativum (Dhaanyaka) leaves contain vitamins, minerals (phosphorous, calcium and iron) and it is a major source of lipids, petroselinic acid, and monounsaturated fatty acid (Mandal and Mandal 2015) . Plantaricin C. sativum, an antimicrobial peptide isolated from coriander leaf extract and coriander essential oil exhibited antimicrobial activities against different strains of bacteria's in two different studies (Masoud et al. 2014 ). Immunomodulatory and antimicrobial in vivo/in vitro and clinical studies of all recommended spices/herbs are summarised in Table 1 . An open level, comparative clinical study administering add-on Ayurvedic treatment with Standard of Care (SoC) in COVID-19 positive cases expressed fast recovery and early discharge in patients received Dasamooladuthrayam Kashaya and Guduchi Kwatham with SoC than SOC alone (Khedkar et al. 2020) . Results of undergoing Ayurvedic herbs trials on recovery rate, virus loads, and immunological markers of COVID-19 are awaited (Rangnekar et al. 2020 ). Ayurveda advocates Nasya (instillation of medicine through nostrils) for the prevention and mitigation of diseases. Absorption of drugs from the nasal cavity occurs through two routes i.e. paracellular (slow, passive, and aqueous route of transport) and transcellular (rate dependent, active and lipophilic route of transport) (Bale et al. 2015) . Advisory recommended applying sesame oil/ coconut oil or ghee in both the nostrils twice daily (morning and evening) called Pratimarsha nasya. This therapy cleanses, purifies, and strengthens the nasal passages, likely to act as a "physiological mask" and may prevent virus fatty acid layer adherence to moist mucosa of the nasal or oral cavity (Tillu et al. 2020 ). The sesame seed oil contains important active compounds such as major lignans, phytosterols, and vitamin E especially γ-tocopherol which has immunomodulatory and antimicrobial activity (Nonaka et al. 1997) . Advisory also recommended oil pulling therapy (Kavala or Gandusha: a traditional procedure in which the practitioner rinses or swishes oil in his mouth). It is supposed to cure oral and systemic diseases. It is a powerful detoxifying ayurvedic technique that is preventive as well as curative (Hooda et al. 2017) . Cocos nucifera Linn. (Coconut) oil is an easily available edible oil that contains predominantly medium-chain fatty acids (lauric acid) that have proven anti-inflammatory and antimicrobial effects (Peedikayil et al. 2015) . In an observermasked, randomized, volunteer-based cross-over clinical trial, coconut oil pulling seems to have similar plaque inhibition activity as 2% chlorhexidine gluconate (CHX) with less tooth staining than CHX (Sezgin et al. 2019) . Non-pharmacological procedures like Yogasan, Pranayama, and Dhyaan (meditation) have been advised routinely at least 30 min/day in AYUSH guidelines to reduce stress, anxiety, enhance immunity, etc. Every day, an instructor displays the Asanas technique on the website of the AYUSH ministry in the form of a video for the people to follow. Pranayama (breath regulation) an essential component of Yoga, positively influences the physiology of the human body. Stress hurts the immune system and prolonged exposure is linked to physical and mental health problems (Segerstrom and Miller 2004) . Yoga modulates levels of immunoglobulins and viral recognition cells (NK cells) and moderates C-reactive protein and other inflammatory cytokines in the blood (Shete et al. 2017) . Yoga practice optimizes sympathetic responses of the body to stressful stimuli and restores autonomic regulatory reflex mechanisms by inhibition of the posterior or sympathetic area of the hypothalamus. It inhibits median forebrain centers and other areas liable for Fig. 1 a Immunomodulatory and anti-microbial action of herbs advised by AYUSH, India. Advised herbs, their major phytoconstituents, and possible mechanism of actions leading to immunomodulation, anti-microbial, and anti-oxidative actions. Ab-antibodies, Th1-T helper type 1, Nk cells-natural killer cells, IgG2a-immunoglobulin G 2a, DTH-delayed-type hypersensitivity, NO-nitric oxide, CCL3-Chemokines (C-C motif) ligand 3, IL-1β-interleukin 1β, IL-6-interleukin 6, IFN-γ-interferon-gamma, WBCswhite blood cells, CD4-Cluster of differentiation 4, TNFα-tumour necrotizing factor α, MIP 1α-macrophage inflammatory protein α, and IgE-Immunoglobulin E. b Preventive, mitigation, and rehabilitation role of immunity to the viral threat ◂ fear, aggressiveness, and rage, coupled with stimulation of the rewarding pleasure centers resulting in a state of bliss and pleasure (Woodyard 2011 ) and increase multiple antidepressant neurotransmitters and hormones such as GABA, serotonin, dopamine (Stephens 2017) and decrease the levels of monoamine oxidase that breaks down neurotransmitters and cortisol (Kamble 2019) . Yoga practices may inhibit the activity of the paraventricular nuclei of the hypothalamus, resulting in reduced ACTH production and decreased synthesis of cortisol, and aldosterone lead to down-regulate stress responses (Arora and Bhattacharjee 2008) . The process and interrelation between stress, immunity, morbidity susceptibility, co-morbidities, and Yogic practices are summarised in Fig. 3 . Dhyaan (meditation) increases the expression of brainderived neurotrophic factor (BDNF) and the thickness of the left hippocampus that essentially plays a role in the resiliency to chronic stress and depressive states (Taliaz et al. 2011) . Chronic stress flare-up the aging process in association with decreased telomerase activity and telomere shortening. A big positive association between comprehensive lifestyle changes (including Yoga, meditation, breathing, healthy whole-food, and plant-based diet), and increased telomerase activity in human peripheral blood mononuclear cells was found (Ornish et al. 2008 ). An open-label cohort study performed on 54 depression patients (high serum cortisol level), subjects in the Yoga groups (Yoga alone and Yoga with drug therapy) had significant drops in their cortisol levels in comparison to the drug-only group (p < 0.008). In Yoga only group, there was a high correlation between decreased cortisol levels and lower scores on the HDRS (Hamilton Depression Rating Scale) indicating a positive antidepressant effect as well (p < 0.001) (Thirthalli et al. 2013) . A randomized controlled clinical test performed among high stressed college students assessed the consequences of sun salutations or Suryanamaskar (a series of 12 physical postures in conjunction with breathing). After 14 days of practice, the experimental group scored higher on mental calmness, joy, strength, physical relaxation and feeling at ease, and scored lower on physical fatigue, somatic stress, and negative emotional feelings in comparison with the control group (Godse et al. 2015) . Pranayama or breath regulation includes modulation of the pace of breathing, viz. slowing down or pacing the breath, manipulation of nostrils, chanting of humming sounds, retention of breath, etc. Pranayama techniques are also beneficial for treating a range of stress-related disorders. Anuloma-Viloma-Pranayama (AVP), i.e., alternate nasal breathing exercise creates negative pressure within the cavity hence improves oxygenation (better surface availability) and ventilation of the paranasal sinuses and nasal respiratory epithelium (Bhardwaj et al. 2013) . A set of 3 Pranayama breathing exercises was found to increase lung functions (PEF and FEV1) after only 6 weeks of three 10-min each practice sessions per week in healthy volunteers (Kupershmidt and Barnable 2019). The Intervention arm, COPD assessment test scores after 3 months of Pranayama practice, showed improvement in the subjective experience of health, disease severity, and functional status for COPD patients, with airflow limitation not fully reversible but usually progressive . In an observational, prospective, quasi-experimental study done on elderly COVID-19 patients (65 yrs or above) recruited from Hainan General Hospital and Huanggang central hospital, six-week respiratory rehabilitation improved respiratory function (FEV1, FVC, FEV1/FVC%, and DLCO%), Quality of life, anxiety and depression scores (Liu et al. 2020) . Yoga is effective in improving dyspnea, inflammatory markers, respiratory functions (Tidal volume, vital capacity, minute ventilation, respiratory rate, forced expiratory volume (FEV1) and forced vital capacity (FVC)), cardiac functions (blood pressure, heart rate, pulse duration, upstroke time, ejection duration index, diastolic time) and Quality of life as a standard cardiopulmonary rehabilitation Psychoneuroimmunology correlation and protective effect of Yoga in modulation of acute stress, chronic stress, equipoise immune system, and COVID-19 associated co-morbidities. Multiple stimuli exaggerate acute stress leading to chronic stress and vice versa. Stress causing immune alteration eventually morbidity susceptibility and prone to COVID-19 illness if contracted to SARS-CoV-2 virus. Yoga modulates, weakens, reduces the stress intensity through various mechanisms as shown in the figure. GABA-Gamma-aminobutyric acid, BDNF-Brain-derived neurotrophic factor, NK cells-Natural killer cells (Guleria et al. 2015) . The Yoga practice induces beneficial changes in cardiovascular function in a parallel arm, openlabel, single-blind, randomized controlled study conducted on elderly people (age above 60 yrs) with stage-I hypertension. The basal oxygen consumption is reported to be up to 15% less in regular yoga practitioners as compared to non-practitioner (Patil 2016) . 3 months of regular yoga breathing practice is reported with decreasing oxygen consumption by 36% (Tyagi 2013). The effects of yoga on pulmonary volumes and respiratory muscle strength verified in 36 elderly women showed a decrease in heart rate (HR) and respiratory rate (RR) in the yoga group (76-39 ± 8-03 vs. 74-61 ± 10.26 bpm and 18.61 ± 3.15 vs. 16.72 ± 3.12 res/ min. respectively) with improved tidal volume, minute ventilation, vital capacity, maximal inspiratory pressure, and maximal expiratory pressure (Bezerra et al. 2014) . Ayurveda and Yoga can mitigate the health and social impact of COVID-19 illness. Ayurvedic pathophysiology of COVID-19 is understood (Pandkar and Sachdeva 2020) and multiple clinical results also support the standalone or adjuvant benefits of Ayurvedic medication. In a randomized placebo-controlled pilot clinical trial, Ayurvedic oil, herbs, and herbo-mineral preparations were administered orally and intranasal. Patients were evaluated for clinical severity, viral loads, and inflammatory markers. The study concluded that Ayurveda intervention can expedite viral dissemination, equipoised inflammatory markers, and no ADR link to intervention (Devpura et al. 2021 ). Ayurveda postulates a foremost treatment of any disease is Nidan Parivarjan (eradication of causative), followed by treatment of disease (Sanshaman and Sanshodhan) and followed by do's and don'ts related to illness, food, daily regimes, and seasonal regime (Prasad 2002) . The two main factors that contribute to infection are exposure and poor immune status. In Ayurveda, the concept of Vyadhikshamatwa has many broad implications than the term "Immunity" used in modern medicine (Masram et al. 2014 ). The word Vyadhi-kshamatwa" is made up of two words; Vyadhi (disease) and Kshamatwa (suppress or overcome). It is defined as Vyadhibala-Virodhitwa (antagonistic to the strength and virulence of the disease) and Vyadhyutpada Pratibandhakatwa (capacity to inhibit and bind the causes and factors of the disease). Acharya Sushrutha has mentioned that the Ojus is the finest essence of all of our body tissue and this Ojus is said to be Bala (strength of body) (Trikam and Sharma 2002) . There is a close relation between Bala and Vyadhi-kshamatwa, when there is an increase in Bala, there is an increase in Vyadhi-kshamatwa and viceversa (Masram et al. 2014; Byadgi 2011) . The continuous accumulation of Aama (a pro-inflammatory product of impaired metabolic disorder) in the body blocks the channels of energy and nutrition, which in turn decreases the level of Bala and finally compromised the Vyadhi-kshamatwa of the body (Byadgi 2011) . Stress, pathogens, viruses, various chemicals, wrong food habits, and so on are responsible for the accumulation of Aama in the body leading to increased susceptibility to disease. Drinking hot water is a basic measure to digest Aama (Tillu et al. 2020) . Ayurveda, the science of life, is based on preventive care employing Dinacharya (daily regime) and Ritucharya (seasonal regime) to maintain the balance of Doshas (maintain homeostasis of body and mind). Self-care advisory incorporates aspects of promotion and strengthening of Vyadhikshamtwa and Bala. Through centuries, India had managed/ combat pandemics (Janpadodhwans) through the wisdom of Ayurveda and natural resources (Priya and Sujatha 2020) . Ayurveda literature promotes Rasayana therapy along with physical and social distancing from infected persons for prevention and overcomes epidemic situations (Rastogi et al. 2020) . Traditional Chinese Medicine has applied its diagnostic concept in identifying the current syndrome and treated accordingly. Ayurveda should also work on the same line of diagnosing through its diagnostic concepts following treatment according to RogiBala and Vyadhi-kshamatva. The immune components have continuing inside-out and outside-in communication at molecular, cellular, histological, and systems levels to maintain the body homeostasis. This routine house-keeping vs. concerted strategized response to an incumbent situation (altered normal) dialogue is what keeps a human body healthy and able to overcome challenging situations. Host immunity against viral is largely innate (first and second lines of defense) and also auto-regulated. Acquired or memory-directed immunity usually does not need to kick in during a virus lytic cycle. When a virus changes from lytic to lysogenic cycle (i.e. assumes a more long-term association with the body), it leads to a powerful and unregulated innate immune response leading to devastating results. For SARS-CoV-2, an unregulated cytokine storm seems to be an important watershed reaction leading to fatality. Just like in allergic response, some persons may and some may not respond to an allergen in the environment because of 'primed' dendritic and other antigen presentation cells that process and activate the allergenic circuit. Similarly, 80% of individual do not show symptoms of SARS-CoV-2 although they harbour the virus in their body and may act as carriers, while others (15%) show moderate symptoms, and only 5% show the severe form of disease requiring ventilation and these individuals (with or without co-morbidity) tend to succumb to the COVID-19. SARS-COV-2 manifestation is akin to other influenza viruses such as HKU-1, NL6, and OC43 which cause mild forms of pneumonia. SARS-COV-2 on the other hand is unusual in the sense, it quickly unlocks its replicon and usurps the host's transcriptome using its enzymes 3CLpro, RDRP, and other NSPs. ACE-2 is expressed on all blood vessel cells, monocytes, dendritic cells, and macrophages in tissue spaces that interact with spike protein of virus for internalization inside the host cell. It resulted in inflammation (innate immune response), release low levels of IFN-γ, and then the mononuclear macrophages start secreting high levels of IL-6, TNF-α, IL-1b, etc. Soon potent inflammation-inducing cytokines secreted in large quantity relentlessly and lost regulatory mechanism to stop it. A positive feedback loop seems to be the hyper-response to the viral proteins that cannot be controlled. Under these circumstances, an efficient immune system needs to have the right proportion of all cells. The signal reception nodes of all the immune circuits must be in good functioning so that once they can respond, certain stimuli be intercepted, and once mounted it must not go on for a very long-time unabated unchecked. The other important thing is the rejuvenation (regeneration, replacement, and repair) of damaged and used-up components of the immune system. The preventive, mitigation, and rehabilitation role of immunity to viral threat is shown in Fig. 1b . AYUSH advisory's phytochemicals and Yoga may induce the Th1/Th17 response for macrophage activation and elimination of SARS-COV-2 pathogens. They could support regenerating the required repertoire for the development of certain cell types to be efficiently and correctly occurring during infection (Rastogi et al. 2020; Kar et al. 2015; Das et al. 2016) . From data generated by scientific experiments, curcumin, piperine and various phenolic compounds (Paul et al. 2018; Das et al. 2015) have already shown immuneboosting not in the sense of activation but rather to maintain, regenerate, and ensure the efficiency of key immune components and their connecting circuitry in the rest of the systems (none of them exist in isolation). Nutritional ligands of PPAR-y like Curcuma Longa and others are under scrutiny as a potential candidate for cytokine storm modulation in COVID-19 (Ciavarella et al. 2020) . Pro-inflammatory innate responses are not misfired and in case there is an over-stimulation, they act as inflammation regulatory elements to bring the inflammatory cascade down. Almost 10 herbal drugs are screened for their immunomodulation effects (Fig. 1a) . Recently, a clinical trial of some Ayurveda drugs as add-on therapy and standard care for COVID-19 has been launched. The lead herbs are G. glabra Linn., W. somnifera Linn., T. cardifolia, P. longum and poly-herbal medicine. Chyawanprash, a component of advisory contains these four herbs; hence Chyawanprash could also be extended to COVID-19 care if trials post positive results. Suffice it to say, the functional food, prophylactic-therapeutic phytochemicals, Ayurvedic procedures, frequency and synchronicity of important diurnal events for maximum efficacy by the chrono-biological system of the body's cells and their bioavailability to affected tissue, may ensure transcriptomic and/or metabolomic sequestration of the required components (cellular and non-cellular) and their proper communication in the body with time to ensure optimum balance to keep the immunity (Vyadhukshamata), samprapti-vigathan (break of disease cascade), etc. in synchrony. Self-care advisory can streamline and maintain immunological, social, diurnal, and mental balance. Ayurveda fortified by Yoga, Dhyana, and Pranayaam ensure perfect rhythm and wellstocked repertoire of an already efficient and well-endowed immune system to combat the current pandemic situation. An international advisory released by WHO, welcoming innovation like drug repurposing and traditional medicine in search of a potential treatment for COVID-19. This advisory also expressed concern for safety, efficacy and adverse side effects of certain remedies like Artemisia annua Linn. (family-Asteraceae) (Sweet wormwood, Chinese nameqinghao and famous as COVID-ORGANICS) touted as possible treatment backed by several African nations. "Natural and safe" a perception linked with herbal products is not always true. Many herbs have reported toxicity and adverse drug reactions. Clinical, in vivo and in vitro safety and toxicity profile studies for advised drugs are searched, analyzed, and discussed in Table 2 , Although most of these herbs are food or dietary supplements so pharmacological vigilance is not compulsory. Sufficient works had been carried out on Chyawanprash, no evident information on toxicity has been available to date. It is considered safe in prescribed dosage (10 g/P.o. in the morning as recommended by AYUSH advisory). Agbaje et al. (2009) , concluded that indiscriminate and long-term use of Syzigium aromaticum could be hazardous to body health so must be ingested with caution. (already in below table). No study has shown any significant toxicity except few in doses much higher than therapeutic limits. We searched Uppsala Monitoring Centre (UMC) (www. vigia ccess. org) and Ayushsuraksha (AYUSH pharmacovigilance reporting site) (www. ayusu raksha. com) for adverse drug reactions (ADRs) associated with these herbs. UMC on date 23th May 2020, ADRs reported for P. nigrum, O. sanctum, C. cyminum, Cinnamomum, and M. arvensis are 2, 1, 6, 68, and 26 respectively. ADRs for A. sativum, Z. officinalis and prash, S. aromaticum, and T. ammi has no reported ADR to date. These numbers are negligible in comparison to ADRs reported of another prophylactic drug like hydroxychloroquine (23,994) and paracetamol (149,820). The above data support the safety of advisory for longer human uses. Although limited access and information are available may be due to under-reporting or less known reporting procedure. Ayursuraksha, an Indian ASU pharmacovigilance reporting site, has no available data for public access to get an idea of ADRs reported to date for a particular herb, active ingredient, and their combination. Guidelines issued are self-care, so no unsubstantial claims and no Ayurveda professional practice is promoted. Ministry of AYUSH issued a notification prohibiting the mongering of unsubstantiated and unauthenticated claims of curing COVID-19 through AYUSH medicines. It stated that all Indian states and Union Territories are directed to stop or prevent publicity and advertisement of AYUSH related claims for COVID-19 treatment in television, print media, and electronic media. This step has fairly regulated the claims made through e-platforms and print media (Anonymous 2020). More than 30 traditional medicine guidelines (for treatment alone 26 from china, 2 from South Korea) for prevention, prophylaxis, and treatment of COVID-19 have been issued till 12 May 2020. Many nations have adopted the translated version like Japan has adopted the translated version of Traditional Chinese Medicine (Lin et al. 2020) . Indian AYUSH self-care guideline is translated in 5 united nation (UN) languages and 3 other international languages; hence it was eminent to see such advisory in light of current science and public health prospect. The concept of the psychosomatic phenomenon has its roots in one of the traditional/classical Yoga texts (The Yoga Vashista, codified nearly 5000 years ago) termed as Adhija-Vyadhi. Uncontrolled, long-standing stress at Manomaya Kosha (Mental body) may lead to disturbances in the Prana (vital energy-similar to Qi), and manifest the disturbances in the Annamaya Kosa (Physical body) may result in several psychosomatic diseases. Stress, anxiety, depression, fear psychosis, sleep disturbances, loneliness (lockdown effect) are associated with the ongoing COVID-19 pandemic. Psychoneuroimmunology (PNI) studies showed correlation between the state of mind and the state of physical health . Eustress helps to cope with the demanding situation at the physical, mental or emotional level, but uncontrolled long-standing stress/chronic stress can have an immunosuppressive effect, a risk factor for COVID-19. Stress may dysregulate different immune parameters (e.g. inflammatory pathways) and lead to disease. Elevated pro-inflammatory cytokine production may generate sustained upper respiratory infection symptoms. Limited studies are carried out to evaluate the effect of Yoga on the immune system and it may decrease IL-1β, IL-6, and TNF-α in inflammatory stages and reflects immunomodulation (Falkenberg et al. 2018) . Increasing psychological resources (mindfulness, body consciousness, self-transcendence, spiritual peace, and social connectedness) may bring about salutary effects on emotional wellbeing. PNI correlation and protective effect of Yoga in modulation of acute stress, chronic stress, comorbidity, and immune system are explained in Fig. 3 . Endocrine, nervous and immune systems are interconnected, so disruption in one creates an impact on the other. Yoga activates neurohormonal mechanisms by inhibiting the posterior or sympathetic area of the hypothalamus, optimizes sympathetic responses to stressful stimuli, restores autonomic reflexes associated with stress, increases the parasympathetic activity thus reduces stress, anxiety, balances autonomic functions and hormonal secretions (Balasubramaniam et al. 2013) . Yoga therapy was also found beneficial in enhancing immunity, sleep, cardio-pulmonary fitness, and telomere length in regular practitioners (Ornish et al. 2008; McCall et al. 2013) . The above discussion supports that Yoga, Pranayaam, and Dhyaan can be a better way of managing stress in the current pandemic situation. Emerging data suggest an increased association and a heightened mortality in patients of COVID-19 with comorbidities ). Co-morbidities predispose the patients to multi-organ failure during an infection. According to a recently published study on laboratoryconfirmed cases of COVID-19, patients with any comorbidity yielded poorer clinical outcomes than those without. A systematic review and meta-analysis on the prevalence of co-morbidities and their effects in COVID-19 patients revealed that underlying disease, including hypertension, respiratory system disease, and cardiovascular disease, may be risk factors for severe patients compared with non-severe patients (Yang and Zhou 2020) . Hence advised drugs were screened for various morbidities associated with COVID-19. It was observed that all herbs protect from single or multiple co-morbidities collectively or individually. The role of advised herbs and their mechanism of action against co-morbidities associated with COVID-19 is explained in Fig. 2 and Table 3 . Yoga has also gained popularity as an adjunct therapeutic tool in the management of diabetes, hypertension, obesity, respiratory disorders, autoimmune disorders and other psychosomatic illnesses (Ornish et al. 2008; McCall et al. 2013 ) hence may equally contribute to co-morbidities management. Evidence from China has shown that recovery will be longer and more complex in COVID-19 patients due to neurological, cardiovascular, and respiratory after effects. The symptoms of COVID-19 disease can range from very mild to severe. Community-acquired pneumonia, ARDS, acute cardiac injury, stress, depression, and acute kidney injury in COVID-19 patients results in decreased activities of daily living and quality of life accompanied by decreased physical and mental function. Many research studies support that Yoga therapy is reported to relieve post-traumatic stress disorder symptoms in war veterans, tsunami survivors, hurricane refugees, and flood survivors (Tyagi 2013). Based on the above discussion, Yoga therapy may prove a beneficial rehabilitative strategy in patients having a history of severe symptoms of COVID-19 in improving dyspnea, inflammatory markers, respiratory functions, cardiac functions, quality of life, and post-traumatic stress disorder as shown in Fig. 4 . AYUSH guidelines can help to get back, improve the functioning system of the body as standard rehabilitation therapy (Fig. 5 ). There is a need to document the feedbacks of self-care advisory and in this regard, the Indian AYUSH ministry's attempt of "Ayush Sanjeevani" mobile application (covered > 100 thousand downloads and > 1 million cumulative feedbacks as of 19 June 2020) and Arogyaduta are appreciable. Advisory has streamlined the AYUSH human resources (> 7 lakh AYUSH practitioners) and associated infrastructure (near 25,000 health facilities) in India. From time to time, scientific advisory released by the national government of a country has great significance and is considered as an important medical guideline but the modern medical fraternities have some apprehension for the unconventional method like AYUSH. The information discussed in this article is the rationale behind advisory and will gradually increase the wisdom to provide an alternative to a large Indian community. The detailed immunological and other scenarios of herbal medicine are portrayed in Fig. 1a in terms of B-cell/T-cell response, cytokines release, and antimicrobial activity. It can be concluded that AYUSH-advised herbs and Yoga promote the state of immunity preparedness to threat, and equipoise the immunity in COVID-19, COVID-19 related co-morbidities (Fig. 2) and stress management. It may be a simple, safe, cost-effective, accessible, acceptable, infrastructure compatible, pragmatic for a longer duration, and sustainable preventive and prophylaxis approach for COVID-19. AYUSH ministry advisory not only supports the health of COVID-19 people but also creating a mental state that one can remain safe following home remedies (Rajkumar 2020) . It is adoptive in nature and in the long run, it will change an individual's habits that may reduce the burden of overall health care. It was an advisory release for pan India which may have a pan globe following. We have thoroughly searched the scientific domain for each component of advisory for its pharmacological relevance. We conclude can help to get back, keep, or improve the functioning system of the body as a standard rehabilitation therapy through routine procedures, meditation, Pranayama, herbs, and Asanas that this advisory comes up with a strong scientific rationale and further indicated more precise research in clinical/ observational trials concerning COVID-19 and prevention of other infections. This advisory can pave the way to overcome this pandemic and may open a new window for the effective use of traditional medicines throughout the world. Considering the properties of flora, Yoga, and procedures, this advisory encouraging us to get closer to the natural way of healing. 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We acknowledge Dr. Ethical Statement This article does not contain any studies involving animals performed by any of the authors. This article does not contain any studies involving human participants performed by any of the authors.