Now that we are a few months into the current pandemic, there is increasing awareness of the condition known as “long covid”. This is characterised by a long recovery period or inability to recover from a primary COVID-19 infection. The phenomenon so far has no medical definition or list of symptoms shared by all patients and two people with “long covid” can have very different experiences.
Symptoms experienced are varied but include breathlessness, a cough that won’t go away, joint pain, muscle aches, hearing and eyesight problems, headaches, loss of smell and taste as well as damage to the heart, lungs, kidneys and gut. However, the most common feature is significant fatigue which occurs following infection with COVID-19, the coronavirus SARS-CoV2. Additionally, others are experiencing mental health problems such as depression, anxiety and brain fog.
It is likely that there are multiple factors responsible for symptoms associated with “long covid,” particularly as they are so varied. This blog will discuss the potential factors that are involved in “long covid” and identify potential interventions. It is worth noting that individuals will differ among which ones may be relevant to them and it is likely that multiple or all factors are relevant. This should therefore be considered individually on a case by case basis.
Damaged lung function – Complications following infections, particularly pneumonia, are not uncommon. In general, survivors of viral pneumonias are at risk of psychological and physical complications of the disease itself, as well as treatment-related lung damage and other organ injuries. Long-term lung disability is not uncommon in patients who have recovered from severe viral pneumonias. Although most survivors can return to work and normal life, a significant number of them will show residual ventilation and blood-gas diffusion abnormalities. This is most common following significant infections that are likely to have required hospitalisation and ventilation.
Evidence from previous coronavirus outbreaks indicates the risk of ongoing virus-related covideffects. Approximately 30% of survivors of global SARS and MERS outbreaks experienced persistent physiological impairment and abnormal radiology consistent with fibrotic lung disease as well as long term heart, lung, blood glucose, brain and psychological complications. A prospective cohort study of people with SARS found up to a third had persistent lung damage.
A study looking at patients infected with SARS in 2003 had shown that over 15 years pulmonary injury gradually decreased, although was significant following infections, particularly in the first year following. However, findings showed that even in patients with early complete resolution of chest CT abnormalities, pulmonary function took several years to return to normal. Highlighting that although resolution is possible, lung abnormalities, can be long-lasting and impair function for a significant amount of time.1
Although persistent lung damage will certainly be significant in people who have had severe infection of covid19, many who have experienced very mild covid symptoms are still experiencing extreme fatigue which is less associated with pulmonary damage. “There was no association between COVID-19 severity (need for inpatient admission, supplemental oxygen or critical care) and fatigue following COVID-19.”2 therefore there must be other factors at play that are contributing to these long-term issues.
Post Viral Fatigue – sometimes post viral fatigue is associated with onset of chronic fatigue syndrome (CFS) and myalgic encephalomyelitis (ME), symptoms like those of “long covid”. It is not clear exactly what happens in post viral fatigue, but it is hypothesised to be associated with increased pro-inflamamtory cytokines, neuroinflammation and potentially the virus lying dormant following infection.
Inflammation – proinflammatory cytokines may linger after a viral infection, the reason for this is poorly understood and may support the hypothesis that the virus is laying dormant in the body and has not been fully eradicated. Or it may be that the infection has disturbed normal inflammatory homeostasis placing the individual at heightened levels of inflammation. This increases oxidative damage as well as side effects of inflammation such as pain, swelling and loss of function. Leading to further tissue damage and associated symptoms.
Symptoms of “”long covid include cognitive issues such as depression, anxiety and brain fog as well as non-restorative sleep, these all have associations with neuroinflammation and should therefore be considered as important.
Neuroinflammation – Post-mortem investigations of patients who were infected and died with SARS-CoV-2 (COVID-19) have indicated the virus had crossed the blood brain barrier into the hypothalamus via the olfactory pathway. The pathway of the virus seemed to follow that previously suggested in CFS/ME patients, involving disturbance of lymphatic drainage from the microglia in the brain. One of the main pathways of the lymphatic drainage of the brain is via the perivascular spaces along the olfactory nerves through the cribriform plate into the nasal mucosa, this may explain the loss of smell in infected patients.3
It is hypothesised that this leads to a dysfunction in lymphatic (or glymphatic) drainage in the brain leading to a build-up of inflammatory cytokines including IL-7 and γIF. It is thought that build up of cytokines in the central nervous system contributes to fatigue like symptoms. It will also affect the integrity of the blood brain barrier allowing further molecules to pass into the brain, further exacerbating inflammation.
Therefore, it is essential to help attenuate inflammation both systematically and particularly within the central nervous system.
Dormant Virus – there are some suggestions that the virus may be lying dormant and hidden within the body. We can see a similar response in patients with herpes or HIV infections, this will firstly leave the body in a state of heightened inflammation but may also be directly contributing to general less specific symptoms of malaise. In the case of COVID-19 this may also explain why some people have been “re-infected” with coronavirus, it may be that it lay dormant and then reactivated. However, the research is not robust enough and there are many conflicting hypotheses, so therefore needs to be considered with caution.
However what is essential to consider in any state of post viral fatigue is that the immune system should be supported to help resilience to future infections and to help remove dormant viruses if this is in fact what is happening.
We are now seeing the relative of the hypothesis in April 2020. “I think the coronavirus will lead to many, many cases of post-infective fatigue syndrome”.4 Which highlights the importance of intervention to attenuate this condition by utilisation of the armoury we already know about to repair damages, reduce inflammation and support immunity.
Mitochondrial Dysfunction – another factor to be considered which is essential in CFS and ME and likely to be playing a role in long covid is mitochondrial dysfunction, which will be exacerbated by high inflammation and oxidative damaged discussed previously. “Together, the proinflammatory cytokines affect diverse physiological processes by driving cellular oxidative stress ROS generation. In turn, increased ROS production stimulates proinflammatory mediator release that contributes to mitochondrial dysfunction”.16
Interventions to consider
- Antioxidants – including vitamin C and NAC
- Nutrients which support epithelial tissue regeneration such as vitamin A, vitamin D and zinc.
- Nutrients to optimise cellular integrity and repair such as omega 3 fatty acids and B vitamins, particularly B12 and folate.
- Curcumin has demonstrated to reduce COX-2 expression, therefore the production of pro-inflamamtory prostaglandins, also liposomal curcumin has been shown to cross the blood brain barrier offering it up and potential to attenuate neuroinflammation6
- Quercetin – has been shown to inhibit the NRP-3 inflammasome, associated with inflammation in coronaviruses
- It is also important to consider the integrity of the gastro-intestinal tract, when there is increased permeability of the digestive system larger molecules can pass across the digestive lining and trigger inflammation. When the gut is leaky it is associated with an increased permeability of the blood brain barrier, therefore attenuates neuroinflammation. Therefore live bacteria which ferment fibre to produce short chain fatty acids such as butyrate should be supported as well as considering nutrients such as vitamin A and D, lactoferrin and glutamine
- Certain nutrients have been shown to support the integrity of the blood brain barrier which include B vitamins especially B6, resveratrol and vitamin D6-8
Support normal immune health11-14
See our other blogs (links below) for more specific information with regards to immune support. However, nutrients that should be considered include:
Vitamin C, which has multiple benefits for supporting immunity as it stimulates neutrophils and increases lymphocyte production, increases interferon production and has antioxidant and antihistamine properties.
Zinc improves cell mediated immunity by increasing production of T-Lymphocytes and regulates the function of white blood cells.
Vitamin D – is known to support healthy immune function and has been shown to be deficient in the majority of the population particularly over the winter months.
Beta Glucans are carbohydrate chains found in the cell wall of fungi, yeasts and seaweeds they have multiple effects on the immune system and have been shown to prime the immune system to help the body defend against viral and bacterial invaders. Current research suggests that they activate the immune cells macrophages.
Selenium – studies have demonstrated an enhancement of both cell-mediated and humoral immune responses by increasing levels of selenium intake. It has been shown to stimulate antibody formation and the activity of helper T cells along with the cytotoxic T and NK cells. It is also implicated in the stimulation of the phagocytic cell migration and in the phagocytosis all of which are essential processes for prevention of and fighting off infection.
Consider vitamin K
A new study review has positioned vitamin K metabolism as the “potential missing link” between lung damage and thromboembolism, both of which indicted in covid severity. It hypothesised that pneumonia-induced vitamin K depletion leads to a decrease in activated Matrix Gla protein (MGP) and protein S, aggravating pulmonary damage and coagulopathy. Therefore, if vitamin K is deficient it may be more likely that lung damage can endure therefore also increasing risk of long covid if vitamin K is sub optimal. In addition, vitamin D deficiency has a strong association with severity of COVID-19, therefore many people are considering supplementing with vitamin D. However, it is advisable to include vitamin K2 alongside vitamin D as vitamin D intake can affect vitamin K status and both are requited for healthy calcium homeostasis.15
Although this is not the main focus of this blog, it is also important to use interventions which support normal energy production therefore nutrients such as B vitamins and CoQ10 may be considered to support mitochondrial energy production.
For more information regarding nutrients which may provide an important role in protect against COVID-19see our blog Latest immune support advice from our Nutritional Therapists, and Selenium and vitamin D – the most vital nutrients in our armoury against the present threat.
- “Long covid” is a non-specific, not yet characterised condition that is experienced by individuals who have previously been infected with SARS-CoV-2 and have long lasting symptoms. Symptoms experienced are varied but include breathlessness, a cough that won’t go away, joint pain, muscle aches, hearing and eyesight problems, headaches, loss of smell and taste as well as damage to the heart, lungs, kidneys and gut.
- “Long covid” has similarities to post viral fatigue which has been shown to be a risk factor for onset of chronic fatigue syndrome and ME.
- Pathophysiology appears to be associated with persistent lung damage following severe infection particularly if patient needed to be ventilated. Leading to persisting respiratory symptoms.
- However a common symptom among people who may not have experienced a severe form of the initial infection are expiring multiple symptoms the most consistent one is significant fatigue. It is thought this may be due to increased pro-inflammatory cytokines, neuroinflammation and potentially the virus lying dormant following infection, or incomplete resolution.
Therefore interventions should aim to:
- Aid repair with antioxidant and nutrient that support epithelial and cellular repair (vitamin C, NAC, omega 3s, vitamin A and vitamin D)
- Attenuate inflammation and neuroinflammation such as quercetin, curcumin and omega 3s as well as supporting gut microflora
- Support health of blood brain barrier with B vitamins, vitamin D and resveratrol
- Support normal immune health, nutrients important for immunity include vitamin C, vitamin D, zinc, selenium and beta-glucans
- Consider vitamin K supplement (deficiency is associated with lung damage and thromboembolism, which increase severity of initial infection and therefore may contribute to persistent lung damage which is a factor in “long covid.”
If you have questions regarding the topics that have been raised, or any other health matters, please do contact me (Helen) by phone or email at any time.
Amanda Williams and the Cytoplan Editorial Team
- Salehi, Sana MD; Reddy, Sravanthi MD; Gholamrezanezhad, Ali MD Long-term Pulmonary Consequences of Coronavirus Disease 2019 (COVID-19), Journal of Thoracic Imaging: July 2020 – Volume 35 – Issue 4 – p W87-W89
- Liam Townsend et al, (2020) Persistent fatigue following SARS-CoV-2 infection is common and independent of severity of initial infection. medRxiv 2020.07.29.20164293; doi:
- Perrin R, Riste L, Hann M, Walther A, Mukherjee A, Heald A. Into the looking glass: Post-viral syndrome post COVID-19 [published online ahead of print, 2020 Jun 27]. Med Hypotheses. 2020;144:110055. doi:10.1016/j.mehy.2020.110055
- Wilson C. Concern coronavirus may trigger post-viral fatigue syndromes. New Sci. 2020;246(3278):10-11. doi:10.1016/S0262-4079(20)30746-6
- 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. Published 2011 Mar 24. doi:10.1186/1471-2377-11-37
- Yuan J, Liu R, Ma Y, Zhang Z, Xie Z. Curcumin Attenuates Airway Inflammation and Airway Remolding by Inhibiting NF-κB Signaling and COX-2 in Cigarette Smoke-Induced COPD Mice. Inflammation. 2018 Oct;41(5):1804-1814. doi: 10.1007/s10753-018-0823-6. PMID: 29961171.
- Yarlagadda A, Clayton AH. Blood brain barrier: the role of pyridoxine. Psychiatry (Edgmont). 2007;4(8):58-60.
- Wei H, Wang S, Zhen L, Yang Q, Wu Z, Lei X, Lv J, Xiong L, Xue R. Resveratrol attenuates the blood-brain barrier dysfunction by regulation of the MMP-9/TIMP-1 balance after cerebral ischemia reperfusion in rats. J Mol Neurosci. 2015 Apr;55(4):872-9. doi: 10.1007/s12031-014-0441-1. Epub 2014 Oct 21. PMID: 25330860.
- Sayeed I, Turan N, Stein DG, Wali B. Vitamin D deficiency increases blood-brain barrier dysfunction after ischemic stroke in male rats. Exp Neurol. 2019 Feb;312:63-71. doi: 10.1016/j.expneurol.2018.11.005. Epub 2018 Nov 28. PMID: 30502340.
- Butler MJ, Barrientos RM. The impact of nutrition on COVID-19 susceptibility and long-term consequences. Brain Behav Immun. 2020;87:53-54. doi:10.1016/j.bbi.2020.04.040
- Chan G, Chan W, Sze D. The effects of β-glucan on human immune and cancer cells. J Hematol Oncol. 2009;2(1):25. doi:10.1186/1756-8722-2-25
- Wessels I, Maywald M, Rink L. Zinc as a gatekeeper of immune function. Nutrients. 2017;9(12). doi:10.3390/nu9121286
- Hemilä H. Vitamin C and infections. Nutrients. 2017;9(4). doi:10.3390/nu9040339
- Hoffmann PR, Berry MJ. The influence of selenium on immune responses. Mol Nutr Food Res. 2008;52(11):1273-1280. doi:10.1002/mnfr.200700330
- Jumana Saleha, Carole Peyssonn et al. Mitochondria and microbiota dysfunction in COVID-19 pathogenesis. Mitochondrion. Volume 54, September 2020, Pages 1-7