The pathophysiology of Long Covid and traditional approaches to treatment
Since the start of the COVID-19 pandemic nearly 3 years ago millions of people worldwide have been infected and the total cumulative numbers of infections continue to rise with each new variant. Whilst the severity of infection can be said to have lessened with the newer strains, especially since the emergence of Omicron, the spectre of Long Covid is still adversely affecting huge numbers of patients.
The term Long Covid or post COVID-19 syndrome was first used in May 2020 to describe the persistence of post viral symptoms lasting for more than 12 weeks with the main ones being fatigue, shortness of breath, palpitations, chest pain, foggy head, cognitive impairment, muscle aches, and neuropathic issues. Since then there has been considerable debate about what constitutes Long Covid and the possible patho-mechanisms involved in this poorly understood condition. Parallels have been drawn between LC and other post viral conditions including Chronic fatigue syndrome (CFS) and Myalgic encephalomyelitis (ME) yet there is still much uncertainty over both aetiology and treatment.
As Chinese Medicine Practitioner I have keenly followed the discourse on COVID diagnosis and treatment from both Western and Chinese Medicine perspectives since the Pandemic began. I experienced COVID first hand in March 2020 following a trip to India and applied the principles of Chinese medicine diagnosis and treatment via self treatment. Since then, I have also been involved in the Jade Screen Project that has treated hundreds of front line workers affected by COVID and Long Covid. Considerable experience has been gained by the herbalists involved in this ground breaking initiative.
What studies have shown is that Long Covid can affect a spectrum of patients regardless of severity and duration of the initial infection. This debilitating condition continues to confound Western medics although many theories are emerging from the thousands of research papers that have been written about SARS Cov-2 and its after effects. Chinese Medicine, however, has a long history of treating epidemic diseases and has numerous diagnostic models to explain their progression and treatment. Whilst I will be exploring what we are learning about Long Covid I will try to draw some parallels with traditional understandings of its patho-physiology. Detailed explanations of Chinese medicine theory are however beyond the scope of this article.
——-
Firstly distinctions have been made between the symptoms that result from organ damage that occurred during the acute COVID infection and those that patients experience in the aftermath of even a mild infection without any evidence of organ or tissue damage.
1. Organ and tissue damage from active COVID
It is now widely recognised that SARS Cov-2 infection has five distinct phases in the acute stage of infection: the viral symptom phase, the early inflammatory phase, the secondary infection phase, the multisystem inflammatory phase, and the tail phase. The viral phase presents much the same as most viral infections with cough, runny nose, myalgia, temperature, headache, however depending on the severity of the acute phase patients can also suffer from local organ and tissue damage such as fibrosis of the lung, damage to nerves and haemolytic effects. High levels of inflammation can effect various other organs such as the brain, liver, kidneys, heart and reproductive systems but if a cytokine storm arises then hospitalisation may be required as this can lead to organ failure and death. The pathophysiology of this tissue damage is thought to be due to various factors such as direct cytotoxic effects, inflammation, dis-regulation of the immune system and apoptosis of local cells and tissues. Many of these cytotoxic effects are due to the viral spike protein which characterises SARS Cov-2. Angiotensin Converting Enzyme 2 (ACE-2) receptors act as binding sites for this spike protein and tissue damage has been observed in autopsies in a multitude of organs and vessels that are rich in ACE-2 receptor sites such as pulmonary, cardiac, renal, endocrine, hepatic, gastrointestinal and neurological systems as well as the cardio-vascular system as a whole. These wide ranging effects can persist for some considerable time post acute infection, although serious damage would seem to be most likely in those patients who have severe infection requiring hospitalisation.
Traditional Chinese medicine formulas that were developed as long ago as the Han dynasty (220 AD) have been shown to directly limit viral replication, reduce the inflammatory response and modulate the immune system in the treatment of viral epidemics. Many of these formulas were studied and employed in the treatment of both the original SARS (2003) and MERS (2012 onwards) outbreaks and most notably in the development of Qing Fei Pai Du Tang (QFPDT) for the treatment of SARS Cov-2 to reduce severity of disease and prevent hospitalisation and death. Studies have suggested that this combination of herbs reduced hospitalisation and death rates by a staggering 50%. This formula is composed of 4 traditional formulas that address the key pathological processes involved in acute COVID infection: Wind cold damp invasion of the Lung and Spleen, Heat Toxicity, Accumulation of Pathogenic Damp, Blood Stasis and Damage to Yin & Qi. They demonstrate broad anti viral and antibactial, anti-inflammatory, anti pyretic (fever reducing) and haemolytic effects as well as having the ability to block viral replication by blocking entry of the spike protein into ACE-2 receptor expressing cells. The study into compounds such as puerarin, emodin and quercetin, present in various herbal medicines that block spike protein is gaining considerable attention presently suggesting that the earlier treatment can be applied in such cases the better the outcomes are likely to be. There has been ongoing use of various other traditional formulas that have been used for thousands of years to effectively treat viral infections and considerable research collected over the course of the pandemic.
2. Ongoing inflammation
One of the key characteristics of acute SARS Cov-2 infection is inflammation.
In the acute phase of infection an inflammatory cascade is triggered & mediated by the immune system in response to viral spike protein entering cells via ACE-2 receptor sites . For most COVID patients, thankfully this inflammatory process is relatively short lived and as the immune system deals with the infection relatively effectively.
However, in LC patients there is mounting evidence that an ongoing inflammatory response can persist long after the viral phase has passed ‘impairing both the structure and function of multiple organs’. Such inflammatory responses are thought to be the main causes of the fatigue, myalgia, brain fog and neurological and tissue damage that many LC patient suffer.
This corresponds loosely with the Chinese medicine view of ‘smouldering’ low grade heat consuming body fluids and weakening patients further resulting in a deficiency of organ qi (function) and yin (structure). In the treatment of Long Covid this is often directly addressed by employing herbs that act to tonify these deficiencies. It is, however, important to note that formulas to clear residual inflammation and regulate the immune system need to be used first before tonification is attempted.
Another observed phenomenon is that many Long Covid patients present with characteristics of Mast Cell Activation Syndrome (MCAS) where there is an over production of inflammatory cytokines and histamine which has also been linked with allergies and other conditions where the immune system reacts inappropriately to stimulus. This could explain why any level of exertion can in fact cause a relapse in symptoms linked to increased inflammatory responses.
3. Viral persistence & dysregulated immune response
Ongoing viral particles have been identified in LC patients in some studies in both body tissues and the gastrointestinal tract, long after the acute infection has past. Reactivation of these viral particles and others such as Epstein-Barr and Herpes viruses may account for a persistent immune response setting the scene for ongoing inflammation and increased numbers of ‘exhausted’ T-cells (a vital component of our immune defences) suggestive of the body battling ‘unidentified invaders’. This has also been linked to low levels of cortisol which acts’ in part’ to control inflammation. Whether, this reactivation of former viruses is a direct result of a weakened immune system is currently under investigation. Many have drawn parallels between Long Covid and other chronic post viral conditions such as Chronic fatigue syndrome (CFS) and Myalgic encephalomyelitis (ME).
Chinese Medicine theory has long considered the concept of Lingering Pathogenic Factors (LPFs) following acute viral illness as a cause for ongoing symptoms that can persist for months, even years after the initial infection. This is often seen in clinic where patients ‘never feel quite right’ following an illness. Ongoing symptoms such as recurring sore throat, swollen lymph glands, myalgia (muscle aches), cough, digestive disturbances, fluctuating temperatures (mild chills and fever), skin rashes, fatigue and exhaustion can be hallmarks of these conditions but symptoms can be mild or severe and particularly varied. There may or not be actual viral or bacterial infection left but the body often reacts as if there is, so some level of immune system dysfunction also seems likely. Often patients are treated with formulas that seek to ‘vent’ these hidden pathogens and harmonise the immune response. Xiao Chai Hu Tang and San Ren Tang have long been used for this purpose and both have strong immune modulating and anti viral effects. If this ongoing immune response continues it can leads to a depletion of both Qi (function) and Blood and Yin (body fluids and structure). Once again modern research is confirming traditional medicine insights into these types of conditions.
Chinese medicine has a deep understanding of such concepts and has long treated such conditions with a complex diagnostic framework which allows practitioners to gauge which tissues and organs are most affected and at what level in the body such a LPF may be lodged. This has been invaluable in the development of treatments for our Long Covid patients.
4. Blood clotting issues
One fascinating yet worrying aspect of SARS Cov-2 has been the haemolytic and thrombotic effects that present in many patients. The more severe the acute infection is, the more likely patients are to suffer from thrombosis or blood clotting, since it is the rampant inflammation generated in the alveolar epithelium and endothelium that accompanies viral entry into ACE-2 receptors in the lung that puts patients at risk of pneumonia and death. Specifically, spike protein can also cause injury to the endothelial lining of the heart and blood vessels leading to ongoing inflammation within the cardiovascular system leading to increased fibrinogen production and hyper coagulation of the blood. This was apparent during the pandemic with the occurrence of ‘covid toes’ where the extremities would suffer reduced circulation alongside the usual headaches and body pain that accompanied infection and hyper-coagulation. More serious conditions such as lung fibrosis, myocarditis and pericarditis can also lead to permanent organ damage.
In both recovered COVID patients and those suffering from Long Covid, it has been noted in clinic that many patients are currently suffering some degree of ongoing ‘Blood Stasis’. Chinese Medicine practitioners are uniquely placed to observe such changes since tongue diagnosis is performed on every patient and a key diagnostic is the appearance of distended and dark sub lingual veins on the underside of the tongue.
Key to the treatment of Long Covid has therefore also involved herbs and formulas that have a haemolytic function to increase circulation and reduce the incidence and risk of clotting. In fact, a much greater proportion of patients regardless have needed herbal formulas and herbs that ‘move the Blood’.
The incidence of shortness of breath, chest pain, palpitations, arrhythmias are all indicative of reduced blood flow in the chest or heart and can be common in many LC patients regardless of whether or not there is heart tissue damage. The classic formula Xue Fu Zhu Yu Tang and it’s numerous variations have proved invaluable for such cases as have herbs such as Dan Shen, Tao Ren, Hong Hua, Ji Xue Teng, Hu Zhang. Since Blood Stasis is a key component of Long Covid patterns most personalised formulas will contain a number of herbs to address this aspect of the pathology.
It is also worth noting that repeat exposure to spike protein either naturally or as an intervention will increase the likelihood of inflammation and blood disorders due to its propensity for endothelial damage and micro-clotting. The effect of repeatedly instructing our bodies to produce toxic spike protein is yet to be fully understood or appreciated.
5. The role of the microbiome in COVID and Long Covid
It is now well recognised that the huge number of bacteria, viruses, fungi and other organisms that form our microbiome are crucial in many physiological processes not least modulation of the immune system and inflammation. Whilst the majority of microbes inhabit out gastrointestinal tract, many other areas of out bodies have their own microbiome. Crucially, for respiratory diseases such as COVID, our lungs have their own bacterial microbiome which has cross links with our digestive system. This notion is hard wired into Chinese Medicine thought where the Lung and Spleen (digestive system and cellular metabolism) form the crucial organ pair of the immune system. It is no coincidence that they are usually the first epithelial surfaces that come into contact with viruses and other pathogens.
Any disruption of the diversity and makeup of our microbiome has the potential to negatively affect our immune response and could be crucial in determining outcomes of acute infections.
Recent studies have shown that those who went on to develop long covid had persistent alterations in their microbiome, having a greater abundance of harmful ‘unfriendly’ bacteria and significantly fewer ‘friendly’ bacteria in their stool samples. Analysis also found that certain types of bacteria were strongly associated with particular long covid symptoms too. This is categorised as persistent ‘damp’ in Chinese Medicine and is actively treaterd with herbs that drain, dry or fascilitate transformation of damp to allow better function and circulation.
It is crucial that digestive health and microbiome diversity is considered in the treatment of long covid. Herbal formulas have been shown to strongly alter the composition of the microbiome and in part this may account for many of their pharmacological actions. It in no coincidence that many Chinese medicinals classed as ‘tonics’, which can be given in convalescence to rebuild strength and health, are potent prebiotics that foster the growth of beneficial bacteria in the gut.
Tongue diagnosis has allowed practitioners to assess the accumulation of damp in Long Covid patients throughout the pandemic. This usually presents with a greasy tongue coat in the initial stages but can change rapidly as herbs are used to treat this pathogenic ‘damp’.
6. Mitochondrial dysfunction
Many of the symptoms that characterise Long Covid are very similar to those described in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Studies into the role of the mitochondria, oxidative stress and antioxidants are currently underway to determine whether the fatigue that many long covid patients experience is due to a disruption in the energy producing pathways of the mitochondria. RCHM member Steve Woodley is involved in an exciting research project to assess the potential antioxidant role of Chinese herbal medicine and their potential to regulate mitochondrial actions. This will no doubt add to our existing knowledge and lead to further refinements of the treatment of these types of chronic fatigue patients with herbal medicine. The use of adaptogenic herbs is attracting much attention for their ability to treat multiple factors that effect the mitochondria.
7. Risk factors for Long Covid
One key consideration for Chinese Medicine practitioners is understanding what may have lead to the development of post viral conditions such as Long Covid. The results of studies are mixed but there is suggestion that, risk factors for Long Covid could include age (over 50), number of pre-existing conditions (hypertension, obesity, diabetes, asthma psychiatric conditions and immuno-supression), severity of infection and number of symptoms in the acute phase. However there are mixed factors as well. For instance, men are more at risk of severe acute symptoms of covid but women form a higher proportion of Long Covid sufferers.
Previous disease or chronic conditions can weaken a patient to the extent that a robust immune response doesn’t occur in the acute phase of a viral infection so the body is unable to ‘vent’ or neutralise the pathogen completely. Inappropriate treatment can also lead to an incomplete clearance of pathogenic factors. Most notably these can include the use of antibiotics and even paracetamol and other anti pyretic medicines in the acute phase of viral infection. It is interesting that, anecdotally, many early SARS Cov-2 patients may have been treated with antibiotics in an attempt to prevent pneumonia developing and widespread use of over the counter cold and flu remedies that contain paracetamol is still commonplace. Could this increased the likelihood of Long Covid?
What does seem likely, given the inflammatory nature of COVID and Long Covid, is that inflammatory disorders such as obesity, diabetes, heart disease are key risk factors. One could therefore also suggest that diets high in inflammatory foods (such as sugar, processed foods and vegetable oils etc) may also increase risk as would exposure to chemicals and food additives that may be pro-inflammatory. There is little or no consideration given to this in the literature. Given that the health of our microbiome is crucial for both the immune system and controlling inflammation one could argue that diet and care of our microbiome is vital. Commentary on the levels of patient antibiotic use or the prevalence of antibiotics and toxic chemicals such as glyphosate in the food chain is also strikingly absent in most of the research.
Other lifestyle considerations are also important in the management of COVID and Long Covid.
Strenuous exercise is by its very nature, inflammatory. Some studies have shown that on day 7 or 8 of Covid infection, when many symptoms of the viral replication phase are subsiding and patients may actually feel like they are recovering well, is a danger period where the secondary inflammatory stage can quickly progress. There is some thought that exercising at this stage of the disease increases the risk of an uncontrolled inflammatory response. Could this be why so many long covid patients report being fit and healthy before COVID, exercising 5 times a week or having daily strenuous workouts in the gym? Was it the return to vigorous exercise too early that caused them to suffer the debilitating effects of long covid?
Long Covid patients themselves are advised against strenuous exercise as it typically makes their fatigue worse. Even the ‘pacing’ that is often suggested in rehabilitation clinics can further exhaust an already depleted system. The gentle Qi Gong stretching and breathing exercise developed over thousands of years have been shown to be the best exercise for regaining strength and recovering from post viral fatigue.
And finally a note on emotional factors. Chinese Medicine practitioners always consider emotional states and their impact on general circulation and function of various organs. Long Covid sufferers can understandably be depressed, fearful of ongoing disfunction, angry that they aren’t improving, or simply frustrated at being poorly understood. Acupuncture and herbal medicine as well as the sympathetic ear of a practitioner that listens and understands their varied and sometimes confusing list of symptoms can go a long way to calm the spirit and begin their journey back to health.
Martin John (BHSc, BSc (Hons), MRCHM, MAAC) has been in practice in Frome, Somerset, for 12 years following on from his training in acupuncture and herbal medicine in Melbourne, Australia. He lecures on the treatment of digestive disorders with Chinese Medicine and has a particular interest in the microbiome and its effects on disease and health. As member of the Jade Screen Project project he is keen to transmit the knowledge that was gathered over the course of the pandemic by herbal practitioners worldwide into the treatment of COVID and Long Covid.
Bibliography
Castanares-Zapatero D, et al. Pathophysiology and mechanism of long COVID: a comprehensive review. Ann Med. 2022 Dec;54(1):1473-1487. doi: 10.1080/07853890.2022.2076901. PMID: 35594336; PMCID: PMC9132392.
Crook H, Raza S, Nowell J, Young M, Edison P. Long covid—mechanisms, risk factors, and management BMJ 2021; 374 :n1648 doi:10.1136/bmj.n1648
Feng F, Tuchman S, Denninger JW, Fricchione GL, Yeung A. Qigong for the Prevention, Treatment, and Rehabilitation of COVID-19 Infection in Older Adults.
Am J Geriatr Psychiatry. 2020 Aug;28(8):812-819. doi: 10.1016/j.jagp.2020.05.012. Epub 2020 May 15. PMID: 32425471; PMCID: PMC7227578.
Griffin DO, et al – The Importance of Understanding the Stages of COVID-19 in Treatment and Trials. AIDS Rev. 2021 Feb 8;23(1):40-47. doi: 10.24875/AIDSRev.200001261. PMID: 33556957.
Ho TY, Wu SL, Chen JC, Li CC, Hsiang CY.
Emodin blocks the SARS coronavirus spike protein and angiotensin-converting enzyme 2 interaction. Antiviral Res. 2007 May;74(2):92-101. doi: 10.1016/j.antiviral.2006.04.014. Epub 2006 May 15. PMID: 16730806; PMCID: PMC7114332.
Huang ST, Lai HC, Lin YC, Huang WT, Hung HH, Ou SC, Lin HJ, Hung MC. Principles
and treatment strategies for the use of Chinese herbal medicine in
patients at different stages of coronavirus infection. Am J Cancer Res. 2020 Jul 1;10(7):2010-2031. PMID: 32774998; PMCID: PMC7407358.
Jun-ling Ren, Ai-Hua Zhang, Xi-Jun Wang
Corrigendum to “Traditional Chinese medicine for COVID-19 treatment” [Pharmacol. Res. 155 (2020) 104743] Pharmacological Research, Volume 155, May 2020, Pages 104768
Kim E, Choi J, Min SY, Kim JH, Jeong A. Efficacy of traditional
herbal medicine for psychological sequelae in COVID-19 survivors: A
protocol for systematic review and meta-analysis. Medicine (Baltimore). 2021 May 21;100(20):e25609. doi: 10.1097/MD.0000000000025609. PMID: 34011025; PMCID: PMC8137070
Pan B, Fang S, Zhang J, Pan Y, Liu H, Wang Y, Li M, Liu L. Chinese herbal compounds against SARS-CoV-2: Puerarin and quercetin impair the binding of viral S-protein to ACE2 receptor. Comput Struct Biotechnol J. 2020;18:3518-3527. doi:
10.1016/j.csbj.2020.11.010. Epub 2020 Nov 11. PMID: 33200026; PMCID: PMC7657012.
Laura C. Price, Colm McCabe, Ben Garfield, Stephen J. Wort. Thrombosis and COVID-19 pneumonia: the clot thickens! European Respiratory Journal Jul 2020, 56 (1) 2001608; DOI: 10.1183/13993003.01608-2020
Liu Q, Mak JWY, Su Q, et al. Gut microbiota dynamics in a prospective cohort of patients with post-acute COVID-19 syndrome
Gut 2022;71:544-552.
Patterson BK, et al. Persistence of SARS CoV-2 S1 Protein in CD16+ Monocytes in Post-Acute Sequelae of COVID-19 (PASC) up to 15 Months Post-Infection.
Front Immunol. 2022 Jan 10;12:746021. doi: 10.3389/fimmu.2021.746021. PMID: 35082777; PMCID: PMC8784688.
Wood E, Hall KH, Tate W. Role of mitochondria, oxidative stress and the response to antioxidants in myalgic encephalomyelitis/chronic fatigue syndrome: A possible approach to SARS-CoV-2 ‘long-haulers’? Chronic Dis Transl Med. 2021 Mar;7(1):14-26. doi: 10.1016/j.cdtm.2020.11.002. Epub 2020 Nov 21. PMID: 33251031; PMCID: PMC7680046.
Pang W, Yang F, Zhao Y, Dai E, Feng J, Huang Y, Guo Y, Zhou S, Huang M, Zheng W, Ma J, Li H, Li Q, Hou L, Zhang S, Wang H, Liu Q, Zhang B, Zhang J. Qingjin Yiqi granules for post-COVID-19 condition: A randomized clinical trial. J Evid Based Med. 2022 Mar;15(1):30-38. doi: 10.1111/jebm.12465. PMID: 35416437; PMCID: PMC9114922.
Can our mitochondria help to beat long Covid? – David Cox, Sun 26 Jun 2022 14.00 BST – https://www.theguardian.com/sc…
Blood abnormalities found in people with Long Covid https://www.science.org/conten…
