written by Phil Rasmussen

Post-viral fatigue is emerging as a frequent problem, with a somewhat alarming proportion of Covid-19 patients experiencing ongoing symptoms and especially fatigue for several weeks or months after recovery from the acute infection.  Due to high rates of infection with the SARS-CoV-2 (Covid-19) as well as influenza and other viruses such as respiratory syncytial virus in Aotearoa New Zealand this year, complaints of a slow or incomplete recovery have been running high.

Exact definitions of ‘Long Covid’ (Post-Covid Syndrome or Post Acute Covid syndrome) remain elusive and continue to be evaluated and debated^{(1, 2)}. The term “Post Covid Conditions” is possibly a better reflection of the diversity of how the delayed recovery syndrome(s) presents in different individuals. However, Long Covid is commonly used to describe signs and symptoms that continue or appear at least four weeks after an acute Covid-19 infection, and that weren’t present beforehand. While most people make a full recovery within twelve weeks, some continue to have symptoms beyond this period^{(3, 4)}. These are hugely variable and still not completely characterised, but fatigue is most common. Other symptoms include ongoing shortness of breath, cough, chest pain, headache, loss of smell, muscle aches and decreased mental and cognitive abilities, including problems with memory and concentration.

Those who have had relatively severe cases of the acute illness or had at least one pre-existing medical condition, seem more likely to develop post-infective syndromes.  Emerging evidence also suggests that gender may also be a factor, with women being more likely than men to experience Long-Covid complications such as fatigue and depression^(5-7). The elderly, Māori and Pasifika people also seem more at risk, given they are at higher risk of contracting serious forms of Covid-19 initially, as are those with type 2 diabetes. Cognitive and cardiovascular complications are also more likely to manifest in these population groups. However, residual Post-Covid symptoms can affect people at all levels of disease severity, even younger adults, children, and those not hospitalized.

Fatigue, brain fog and headaches

Fatigue and ‘brain fog’, headache, cognitive impairment and sleep disturbances, are some of the most disturbing manifestations of long Covid, and can affect the ability to undertake normal daily activities. Apart from anecdotal reports and personal experiences, accumulating data suggests a high prevalence of such prolonged neurological symptoms following an acute Covid-19 infection ^(8-10).

A recent meta-analysis of 68 studies found that 32% of patients experienced fatigue, twelve or more weeks after Covid-19 diagnosis; a meta-analysis of 43 studies found 22% complained of cognitive impairment⁽³⁾. Elevated levels of inflammatory cytokines and other markers, and significant functional impairment, is also seen in a proportion of individuals. While some of these studies may have over-estimated the extent of these symptoms due to the lack of appropriate comparator groups, they paint an alarming picture⁽¹¹⁾.

Long Covid headache can present either through the worsening of a pre-existing primary headache, or, more commonly, as a new intermittent or daily headache starting during the acute infection or soon afterwards. It often accompanies other long Covid symptoms such as loss of the sense of smell. It can be migrainous in type, but is more often a tension-type headache⁽⁹⁾.

Residual symptoms and feelings of fatigue are nothing new when it comes to the post-viral infection period, with long Covid symptoms being similar to those seen in myalgic encephalomyelitis or chronic fatigue syndrome (ME/CFS)⁽²⁾. This is a chronic multi-system illness characterized by profound fatigue, sleep disturbances, neurocognitive changes and feeling unwell after exercise which occurs in the absence of any significant clinical or laboratory findings^(12-14). Although not exclusively considered a post-infectious entity, ME/CFS has been associated with several infectious agents including Epstein-Barr Virus, Q fever, influenza, and other coronaviruses^{(15, 16)}.

An Australian study reported prolonged illness characterised by disabling fatigue, musculoskeletal pain, neurocognitive difficulties, and mood disturbance in 12% of Australian patients at 6 months following acute infection with Epstein-Barr virus (glandular fever), Q fever or Ross River virus⁽¹⁷⁾.

Multiple pre-disposing and pathophysiological factors seem to be involved.  The incredibly complex cross talk between numerous components of the nervous system and immune system functions, and the ability of viruses including Covid-19 to cross the blood brain barrier, are undoubtedly contributory.

Given the increase in mental unwellness and anxiety associated with the many impacts of the Covid-19 pandemic over the past nearly three years, accompanying issues such as insomnia, cognitive deficits and fatigue, are to be expected. Prolonged or poorly managed stress, can also lead to burnout, fatigue, and cognitive issues such as poor memory and anxiety or depression.

The role of inflammation including neuroinflammation in the symptomatology of many viral infections and involvement of the gut microbiome to immune functions and chronic inflammatory conditions, are only now starting to be better understood. Just as the so-called ‘cytokine storm’ can cause severe symptoms in acute Covid-19 infections, elevated levels of inflammatory cytokines in the cerebrospinal fluid⁽¹⁸⁾ and the presence of damaging autoantibodies or ongoing dysregulation of the immune system, may lead to chronic inflammation and long term effects on tissues the brain, lungs and heart. An association between Covid-19 infection and demyelination in both the peripheral and central nervous systems, has also been implicated⁽¹⁹⁾.

Management

The presence of ongoing fatigue and poor health following a Covid-19 infection can be very distressing. Social media and the state of the world at times, sometimes also doesn’t help.

However recovery time from many illnesses is often protracted, and adequate rest, good nutrition, and healthy sleep routines, are integral to making a steady recovery. Eating nutritious foods with lots of vegetables, and trying to exercise regularly even if only gentle activities are possible to build up stamina and strength, can really help.  Full recovery will usually take longer if there were pre-existing health challenges such as cardiovascular or respiratory tract conditions, if the person is elderly or their cognition was already somewhat compromised, or they were experiencing a significant amount of stress prior to being infected.

Typical conventional treatment interventions involve the use of analgesics and anti-inflammatories such as paracetamol, ibuprofen and other NSAID’s, as well as vitamin C, lemon and honey. Keeping a daily symptom diary can be helpful for some, to identify which symptoms impact them most, and to monitor how things are progressing.

Herbal Help

While a huge volume of research has taken place and thousands of papers published into the use and potential efficacy of complementary and herbal medicines for the treatment of Covid-19^(20-26) few studies have taken place to date into the potential impacts of natural health product interventions on long Covid symptomatology. This is disappointing given the enormous impact this condition(s) is having on people’s health and its huge potential future healthcare burden, although characterising the syndrome and determining and validating outcome measures in such studies, are challenges for researchers.

There is, however, compelling evidence that various plant based medicines have the potential to greatly help with overcoming the debilitating symptoms of fatigue, headaches and compromised cognitive functions.

Fatigue is of course multi-faceted and broadly defined, which makes understanding its cause(s) especially difficult in conditions such as post-viral syndromes or autoimmune diseases, with their complex pathologies.

Where prolonged or poorly managed stress is likely to have been contributory to sleep disruption and tiredness, anxiolytic, stress insulating and sleep promoting plant medicines can produce marked improvements. Residual damage to the respiratory tract and thus a compromised ability to ensure adequate oxygenation of bodily tissues, may also contribute to ongoing lethargy and constitutional ill health. Addressing this through exercise and bronchial herbal medicines such as Kumerahou, Elecampane, Horseradish and many more, can sometimes help facilitate a return to normal energy levels.

Adaptogens

Adaptogens are a category of medicinal plants that increase the body’s ability to cope with stress, helping to restore balance.  Most if not all adaptogens can play a valuable contribution in a post-viral or convalescence situation where someone has been knocked back by a protracted and debilitating viral infection.

They include well known herbal medicines such as Korean Ginseng (Panax ginseng), American ginseng (Panax quinquefolium), Astragalus (Astragalus membranaceous), Andrographis (Andrographis paniculata), Aswaghandha (Withania somnifera) Bupleurum (Bupleurum falcatum), Eleutherococcus (Eleutherococcus senticosus) and Schisandra (Schisandra chinensis).  Apart from being traditionally used in formulations and treatments taken by the elderly and during convalescence, one of their main indications is for fatigue. In the case of American and Korean ginsengs, clinical trials have shown their potential to help reduce fatigue in cancer patients^{(27, 28)}. A recent clinical trial reported efficacy against Covid-19 infection and reduced levels of inflammatory markers following administration of a product containing Withania and Holy Basil (Ocimum sanctum)⁽²⁹⁾.

Adaptogens have multiple mechanisms of action, such as the ability to increase and modulate innate and adaptive immunity, and exhibit anti-inflammatory actions. Many show direct antiviral actions against a range of viruses, and Withania and Schisandra contain various compounds which act as in vitro protease inhibitors against the SARS-2 coronavirus^(30-32).

A recent clinical trial involving two weeks use of a formulation containing the adaptogens Rhodiola, Eleutherococcus and Schisandra reported improvements in symptoms of fatigue, cognitive function and anxiety, and enabled an increase in daily workout times⁽³²⁾.

Medicinal fungi

Medicinal fungi also possess the ability to act as powerful adaptogens, and most have traditionally been used as tonics to increase energy and physical stamina. The ‘caterpillar fungus’ Cordyceps, one of the most highly sought after natural health products in China, has been termed a mitochondrial adaptogen due to its ability to increase oxygen utilisation and protect mitochondria from adverse events^{(34, 35)}. Its adaptogenic properties and antifatigue activities reported in mice⁽³⁵⁾, together with anti-inflammatory and cardioprotective properties, supports potential benefits as a treatment for Long Covid symptoms such as fatigue. Reishi (Ganoderma lucidum) improved cancer related fatigue in a clinical trial involving breast cancer patients⁽³⁷⁾. Both Reishi^{(38, 39)} and Cordyceps or its active constituent cordycepin^{(40, 41)}, have also shown efficacy in laboratory and animal studies, against the Covid-19 virus.

Like medicinal plants such as Astragalus and Echinacea, medicinal fungi such as Cordyceps, Reishi, Turkey Tail, Shiitake and Maitake exhibit multiple actions on the immune system, and many have pronounced antiviral effects^(42-44). Some of their terpenoid compounds in particular seem to possess anti-inflammatory and antiviral properties, including inhibiting viral enzymes such as neuraminidase and HIV-protease^(45-47).

Finally, the neuroprotective and tonifying effects on nerve cells that seem to be a feature of most medicinal fungi, are highly relevant in the management of post-viral fatigue and cognitive impairment.  Lions Mane (Hericium erinaceus) produces many nurturing effects on the nervous system, showing neuroprotective activity in many animal models, and enhancing Nerve Growth Factor, a neuropeptide involved in regulating nerve cell growth and survival ⁽⁴⁸⁾. Results from clinical trials have also reported improved sleep quality and reduced feelings of depression and anxiety after Lions Mane treatment^(48-50).

Cognition and Headaches

Through addressing the immune dysregulation and nervous system manifestations of Long Covid with some of the targeted herbal treatments already discussed, issues such as a poor memory, a foggy brain and headaches are likely to be at least partially resolved. Adaptogenic plants and medicinal fungi, all have relevant actions in this area, and should generally be part of all Long Covid treatments. Kawakawa as a daily beverage or included in a herbal formulae, can also help with both headaches and other aspects of post-viral recovery.

Where these symptoms are particularly debilitating or distressing, Ginkgo and Bacopa are two phytomedicines for which there is now convincing evidence of their benefits to cognitive function. Improved cognition or relevant neuroprotective effects have also been reported for Cinnamon, Cordyceps, Green tea, Gotu kola, Lemon balm, Lion’s Mane, Nigella, Rosemary, Sage, Turmeric and Valerian.

Apart from the medicinal plants and fungi I’ve already mentioned, there are many others which I’ve discussed in previous blogs^(20-23) that may also assist with overcoming the debilitating symptoms of Long Covid and facilitating a return to good health.

References:

1. Michelen M, Manoharan L, Elkheir N, et al. Characterising long COVID: a living systematic review. BMJ Glob Health. 2021;6(9):e005427.
2. Tirelli U, Taibi R, Chirumbolo S. Post COVID syndrome: a new challenge for medicine. Eur Rev Med Pharmacol Sci. 2021;25(12):4422-4425.
3. Ceban F, Ling S, Lui LMW, et al. Fatigue and cognitive impairment in Post-COVID-19 Syndrome: A systematic review and meta-analysis. Brain Behav Immun. 2022;101:93-135.
4. d’Ettorre G, Gentilini Cacciola E, Santinelli L, et al. Covid-19 sequelae in working age patients: A systematic review. J Med Virol. 2022;94(3):858-868
5. Bucciarelli V, Nasi M, Bianco F, et al. Depression pandemic and cardiovascular risk in the COVID-19 era and long COVID syndrome: Gender makes a difference. Trends Cardiovasc Med. 2022;32(1):12-17.
6. Maglietta G, Diodati F, Puntoni M, et al. Prognostic Factors for Post-COVID-19 Syndrome: A Systematic Review and Meta-Analysis. J Clin Med. 2022;11(6):1541. 
7. López-Sampalo A, Bernal-López MR, Gómez-Huelgas R. Persistent COVID-19 syndrome. A narrative review. Rev Clin Esp (Barc). 2022;222(4):241-250.
8. Stefanou MI, Palaiodimou L, Bakola E, et al. Neurological manifestations of long-COVID syndrome: a narrative review. Ther Adv Chronic Dis. 2022;13:20406223221076890.
9. Tana C, Bentivegna E, Cho SJ, et al. Long COVID headache. J Headache Pain. 2022;23(1):93.
10. Damiano RF, Guedes BF, de Rocca CC, et al. Cognitive decline following acute viral infections: literature review and projections for post-COVID-19. Eur Arch Psychiatry Clin Neurosci. 2022;272(1):139-154.
11. Alkodaymi MS, Omrani OA, Fawzy NA, et al. Prevalence of post-acute COVID-19 syndrome symptoms at different follow-up periods: a systematic review and meta-analysis. Clin Microbiol Infect. 2022;28(5):657-666.
12. Fukuda K, Straus SE, Hickie I, Sharpe MC, Dobbins JG, Komaroff A. The chronic fatigue syndrome: a comprehensive approach to its definition and study. International Chronic Fatigue Syndrome Study Group. Ann Intern Med. 1994;121(12):953-959.
13. Heyll U, Wachauf P, Senger V, Diewitz M. Definitionen des “Chronic Fatigue Syndrome” (CFS) [Definition of “chronic fatigue syndrome” (CFS)]. Med Klin (Munich). 1997;92(4):221-227.
14. Mawle AC. Chronic fatigue syndrome. Immunol Invest. 1997;26(1-2):269-273.
15. Moldofsky H, Patcai J. Chronic widespread musculoskeletal pain, fatigue, depression and disordered sleep in chronic post-SARS syndrome; a case-controlled study. BMC Neurol. 2011;11:37. doi: 10.1186/1471-2377-11-37
16. Poenaru S, Abdallah SJ, Corrales-Medina V, Cowan J. COVID-19 and post-infectious myalgic encephalomyelitis/chronic fatigue syndrome: a narrative review. Ther Adv Infect Dis. 2021;8:20499361211009385.
17. Hickie I, Davenport T, Wakefield D, et al. Post-infective and chronic fatigue syndromes precipitated by viral and non-viral pathogens: prospective cohort study. BMJ. 2006;333(7568):575.
18. Vanderheiden A, Klein RS. Neuroinflammation and COVID-19. Curr Opin Neurobiol. 2022;76:102608.
19. Ismail II, Salama S. Association of CNS demyelination and COVID-19 infection: an updated systematic review. J Neurol. 2022;269(2):541-576.
20. Rasmussen PL, Culinary herbs and spices to know about, in infectious times. www.herbblurb.com 20 March 2020.
21. Rasmussen PL, Echinacea in the time of a pandemic. www.herbblurb.com 30 October 2020.
22. Rasmussen PL, Propolis – amazing stuff made by bees from nature. www.herbblurb.com 9 April 2021
23. Rasmussen PL, Omicron – the latest Covid-19 chapter. www.herbblurb.com 29 Jan 2022.
24. Jeon, S. R., Kang, J. W., Ang, L., Lee, H. W., Lee, M. S., & Kim, T. H. (2022). Complementary and alternative medicine (CAM) interventions for COVID-19: An overview of systematic reviews. Integrative medicine research, 11(3), 100842.
25. Ang L, Song E, Hu XY, Lee HW, Chen Y, Lee MS. Herbal Medicine Intervention for the Treatment of COVID-19: A Living Systematic Review and Cumulative Meta-Analysis. Front Pharmacol. 2022;13:906764. Published 2022 Jun 20.
26. Prajapati SK, Malaiya A, Mishra G, et al. An exhaustive comprehension of the role of herbal medicines in Pre- and Post-COVID manifestations. J Ethnopharmacol. 2022;296:115420.
27. Barton DL, Liu H, Dakhil SR, et al. Wisconsin Ginseng (Panax quinquefolius) to improve cancer-related fatigue: a randomized, double-blind trial, N07C2. J Natl Cancer Inst. 2013;105(16):1230-1238.
28. Kim JW, Han SW, Cho JY, et al. Korean red ginseng for cancer-related fatigue in colorectal cancer patients with chemotherapy: A randomised phase III trial. Eur J Cancer. 2020;130:51-62
29. Devpura G, Tomar BS, Nathiya D, et al. Randomized placebo-controlled pilot clinical trial on the efficacy of ayurvedic treatment regime on COVID-19 positive patients. Phytomedicine. 2021;84:153494.
30. Patil VS, Hupparage VB, Malgi AP, Deshpande SH, Patil SA, Mallapur SP. Dual inhibition of COVID-19 spike glycoprotein and main protease 3CLpro by Withanone from Withania somnifera. Chin Herb Med. 2021;13(3):359-369.
31. Qi JH, Dong FX, Wang K, et al. Feasibility analysis and mechanism exploration of Rhei Radix et Rhizome-Schisandrae Sphenantherae Fructus (RS) against COVID-19. J Med Microbiol. 2022;71(5):10.
32. Kushwaha PP, Singh AK, Prajapati KS, Shuaib M, Gupta S, Kumar S. Phytochemicals present in Indian ginseng possess potential to inhibit SARS-CoV-2 virulence: A molecular docking and MD simulation study. Microb Pathog. 2021;157:104954.
33. Karosanidze I, Kiladze U, Kirtadze N, et al. Efficacy of Adaptogens in Patients with Long COVID-19: A Randomized, Quadruple-Blind, Placebo-Controlled Trial. Pharmaceuticals (Basel). 2022;15(3):345.
34. Li XT, Li HC, Li CB, Dou DQ, Gao MB. Protective effects on mitochondria and anti-aging activity of polysaccharides from cultivated fruiting bodies of Cordyceps militaris. Am J Chin Med. 2010;38(6):1093-1106.
35. Bai X, Tan TY, Li YX, et al. The protective effect of cordyceps sinensis extract on cerebral ischemic injury via modulating the mitochondrial respiratory chain and inhibiting the mitochondrial apoptotic pathway. Biomed Pharmacother. 2020;124:109834.
36. Song J, Wang Y, Teng M, et al. Studies on the Antifatigue Activities of Cordyceps militaris Fruit Body Extract in Mouse Model. Evid Based Complement Alternat Med. 2015;2015:174616.
37. Zhao H, Zhang Q, Zhao L, Huang X, Wang J, Kang X. Spore Powder of Ganoderma lucidum Improves Cancer-Related Fatigue in Breast Cancer Patients Undergoing Endocrine Therapy: A Pilot Clinical Trial. Evid Based Complement Alternat Med. 2012;2012:809614.
38. Jan JT, Cheng TR, Juang YP, et al. Identification of existing pharmaceuticals and herbal medicines as inhibitors of SARS-CoV-2 infection. Proc Natl Acad Sci U S A. 2021;118(5):e2021579118.
39. Yeh H, Vo DNK, Lin ZH, et al. GMI, a protein from Ganoderma microsporum, induces ACE2 degradation to alleviate infection of SARS-CoV-2 Spike-pseudotyped virus. Phytomedicine. 2022;103:154215.
40. Jędrejko KJ, Lazur J, Muszyńska B. Cordyceps militaris: An Overview of Its Chemical Constituents in Relation to Biological Activity. Foods. 2021;10(11):2634.
41. Verma AK. Cordycepin: a bioactive metabolite of Cordyceps militaris and polyadenylation inhibitor with therapeutic potential against COVID-19. J Biomol Struct Dyn. 2022;40(8):3745-3752.
42. Elhusseiny SM, El-Mahdy TS, Awad MF, et al. Proteome Analysis and In Vitro Antiviral, Anticancer and Antioxidant Capacities of the Aqueous Extracts of Lentinula edodes and Pleurotus ostreatus Edible Mushrooms. Molecules. 2021;26(15):4623.
43. Shahzad F, Anderson D, Najafzadeh M. The Antiviral, Anti-Inflammatory Effects of Natural Medicinal Herbs and Mushrooms and SARS-CoV-2 Infection. Nutrients. 2020;12(9):2573.
44. Rahman MA, Rahman MS, Bashir NMB, et al. Rationalization of Mushroom-Based Preventive and Therapeutic Approaches to COVID-19: Review. Int J Med Mushrooms. 2021;23(5):1-11
45. El Dine RS, El Halawany AM, Ma CM, Hattori M. Inhibition of the dimerization and active site of HIV-1 protease by secondary metabolites from the Vietnamese mushroom Ganoderma colossum. J Nat Prod. 2009;72(11):2019-2023.
46. Zhu Q, Bang TH, Ohnuki K, Sawai T, Sawai K, Shimizu K. Inhibition of neuraminidase by Ganoderma triterpenoids and implications for neuraminidase inhibitor design. Sci Rep. 2015;5:13194. 
47. Sillapachaiyaporn C, Chuchawankul S. HIV-1 protease and reverse transcriptase inhibition by tiger milk mushroom (Lignosus rhinocerus) sclerotium extracts: In vitro and in silico studies. J Tradit Complement Med. 2019;10(4):396-404. 
48. Zhang CC, Yin X, Cao CY, Wei J, Zhang Q, Gao JM. Chemical constituents from Hericium erinaceus and their ability to stimulate NGF-mediated neurite outgrowth on PC12 cells. Bioorg Med Chem Lett. 2015;25(22):5078-5082.
49. Nagano M, Shimizu K, Kondo R, et al. Reduction of depression and anxiety by 4 weeks Hericium erinaceus intake. Biomed Res. 2010;31(4):231-237. 
50. Chong PS, Fung ML, Wong KH, Lim LW. Therapeutic Potential of Hericium erinaceus for Depressive Disorder. Int J Mol Sci. 2019;21(1):163.
51. Vigna L, Morelli F, Agnelli GM, et al. Hericium erinaceus Improves Mood and Sleep Disorders in Patients Affected by Overweight or Obesity: Could Circulating Pro-BDNF and BDNF Be Potential Biomarkers?. Evid Based Complement Alternat Med. 2019;2019:7861297.