Lorraine Nicolle Nutrition

Nutritionist

Nutrition in Long Covid

Articles, Long Covid / by

Nutritional Support in Long COVID: a Discussion Paper for Nutrition Practitioners

Lorraine Nicolle MSc (Nutr.)

[First written by Lorraine Nicolle for Lamberts Healthcare Ltd and reproduced with permission]

Long COVID is an informal term used to describe the long-term sequelae following SARS-CoV-2 infection. Sufferers are typically burdened with a range of symptoms still affecting their lives several weeks after the acute infection. In this discussion, we’re going to take a look at:

  • What Long COVID is
  • Why it happens / some of the potential underlying drivers involved
  • Some key nutritional aspects to consider in supporting the road back to better health.

What is Long COVID?

Long COVID, also known as ‘post-acute sequelae of COVID’ (PASC), is classified by the NHS into 2 subsets:

  • Ongoing symptomatic COVID: symptoms continue for more than four weeks
  • Post-COVID Syndrome: symptoms continue for more than twelve weeks and cannot be explained by any other condition.

The Office of National Statistics (ONS) has estimated 1.1 million people in private households in the UK to be currently experiencing self-reported Long COVID (as at 5 September 2021). This equates to 1.7% of the population. Hence, practitioners are likely to see individuals presenting with symptoms. Yet, the condition remains poorly understood.

Such symptoms may affect a wide range of body systems, with the NHC citing the most common symptoms as:

  • extreme tiredness (fatigue)
  • shortness of breath
  • chest pain or tightness
  • poor memory/concentration (“brain fog”)
  • difficulty sleeping (insomnia)
  • heart palpitations
  • dizziness
  • pins and needles
  • rashes
  • joint pain
  • depression and anxiety
  • tinnitus, earaches
  • feeling sick, diarrhoea, stomach aches, loss of appetite
  • a high temperature, cough, headaches, sore throat, changes to sense of smell or taste.

The ONS also gives information on the length and severity of symptoms, reporting that 77% of Long COVID sufferers first had COVID-19 at least 12 weeks previously and that as many as 37% first had COVID at least 12 months previously and have therefore been suffering for a year or more. What’s more,19% report their ability to undertake their day-to-day activities is “limited a lot”.

The more common symptoms reported in the ONS survey are fatigue, followed by shortness of breath, then loss of smell, and difficulty concentrating. And the prevalence appears to be greatest in people aged 35 to 69 years, females, people living in the most deprived areas, those working in health or social care, and those with another activity-limiting health condition or disability (https://www.ons.gov.uk/peoplepopulationandcommunity/healthandsocialcare/conditionsanddiseases/bulletins/prevalenceofongoingsymptomsfollowingcoronaviruscovid19infectionintheuk/7october2021)

Medically Unexplained Long COVID

NHS online information sources encourage a visit to the GP if symptoms of COVID-19 persist for more than four weeks. The GP will likely check blood pressure and oxygen levels and may arrange for blood tests and/or a chest x-ray to be undertaken.

Such tests look for abnormal blood coagulation and for any organ damage, such as lung scarring (‘pulmonary fibrosis’), cardiac issues (myocarditis, pericarditis) or kidney damage. Where any of these are identified, the patient can be treated with the specialist rehab team in the relevant area.

Hence, these are not the type of long-COVID cases of interest in this discussion paper. Rather, we are focusing on the ‘unexplained’ cases – those patients for whom there is no obvious cause for their symptoms according to their medical test results. These are the ‘medically unexplained Long COVIDers’.

Within the NHS, such cases can be referred to a post-COVID clinic. The clinics house multi-disciplinary teams, including doctors, nurses, physiotherapists, psychotherapists, occupational health practitioners, and more.

Medically unexplained Long COVID is still poorly understood and thus hard to manage.  It doesn’t seem to discriminate between age, nor between previously ‘healthy’ and ‘unhealthy’ individuals. And there’s no evidence that sufferers were more pre-disposed to anxiety or depression prior to becoming ill.

Underlying drivers to consider

So, why might ‘unexplained’ long COVID happen and how can this direct us to interventions that may help?

As time goes on, an increasing number of potential underlying causes are up for discussion in the scientific literature. Current proposals include:

Persistent reservoirs of SARS-CoV-2

Persistent reservoirs of the virus may remain in certain tissues after the acute infection is over, yet be hidden from detection by diagnostic tests. Alternatively, small viral fragments that the body hasn’t disabled may be left over from the infection. These situations may not make the patient infectious but may keep the immune system activated.

Aberrant blood clotting

Some patients with Long COVID appear to have higher levels of blood clotting markers even after inflammatory markers have resolved. What’s more, these elevated markers seem to be linked to persistent symptoms of breathlessness, fatigue and reduced exercise tolerance.

A study of 50 patients reviewed at a median of 68 days following SARS-CoV-2 infection found ongoing endothelial dysfunction to still be common even at this point of apparent resolution of the acute infection. The study also found that this is associated with increased levels of thrombin and other coagulation chemicals compared to controls; and that these markers correlate inversely with 6-minute walk tests in patients with ongoing symptoms after COVID-19 (Inflamm Res. 2020 Dec;69(12):1181-1189).

Re-activation of neurotropic pathogens

Infection with SARS-Cov-2 can stress the immune system such that pre-existing low levels of neurotropic viruses can surface again. These are viruses that can enter and reside in the nervous system. Following their acute infection, they persist but can be well-controlled by a fully functioning immune system. But in situations of immune system stress, such as acute infection with a new virus (including SARS-CoV-2), these dormant viruses can reactivate and cause symptoms. This is commonly seen with, for example, the appearance of cold sores when under stress due to reactivation of herpes simplex virus type 1; or chronic fatigue with the reactivation of Epstein Barr virus.

A study of 185 randomly surveyed COVID patients found the prevalence of long-COVID to be 30%, and that 66.7% of the long-COVID sufferers tested positive for EBV reactivation compared to 10% of control subjects (Pathogens. 2021 Jun 17;10(6):763).

Dysfunctional brain stem/vagal nerve signalling

Several studies have shown that the dorsal brainstem can be affected or infected by SARS-CoV-2.  This region regulates many of the nervous system functions that can go awry in long COVID, including nausea and vomiting, inflammatory pain sensitivity and autonomic control of heart rate, blood pressure and breathing (Front Microbiol. 2021 Jun 23;12:698169).

SARS-CoV-2 interactions with host microbiome/virome

It’s long been known that an immune system under stress can drive microbial dysbiosis; and recent studies have shown that SARS-CoV-2 infection can disrupt both the microbiome (bacteria, viruses, fungi, and archea), and the virome in the gut, urinary tract, pancreas, lungs, and/or oral cavity.

It’s thought that weakened immunity from viral infection can cause commensal flora to mutate into opportunistic, virilant types; and there is now evidence for SARS-CoV-2 patients developing gut and/or lung pathogenic dysbiosis via this mechanism. But pre-existing dysbiosis may also play a part, as this itself can weaken immune function, leaving the host more susceptible to the long-term effects of COVID (Front Microbiol. 2021 Jun 23;12:698169).

Given that dysbiosis appears to be a feature of so many types of chronic conditions, including inflammatory bowel diseases, metabolic disorders, fatigue disorders, neuroinflammatory and neurological conditions, it makes sense to identify and treat any microflora imbalances.

Epithelial barrier hyperpermeability 

Loss of barrier integrity, such as in ‘leaky gut syndrome’ and/or disruption of the gingiva or the blood brain barrier, allows pathogens to translocate into the bloodstream, leading to systemic inflammation.

Gingival bacteria that have been able to translocate into the circulation can drive hypercoagulation. Given that, as seen earlier, SARS-CoV-2 secretes proteins that disrupt normal blood clotting cascades, an individual who has both the viral infection and weak barrier function may be more prone to long-term ill-health: evidence suggests that having both present may drive inflammation and disrupted coagulation, leading to more microclots and related symptoms (fatigue and reduced physical fitness) (Front Microbiol. 2021 Jun 23;12:698169).

Aberrant Mast Cell Activation

One of the much discussed potential drivers of Long COVID is the ongoing activity of primed immune cells which, in turn, causes chronic oxidative stress and inflammation. This has implications for mitochondrial function (see below) and also for histamine issues.

Histamine is produced by mast cells (MCs). MCs are activated by SARS-CoV-2. What’s more, it’s estimated that approximately 17% of the population may suffer from a degree of ‘mast cell activation syndrome’ (MCAS), which is described as a chronic multisystem disorder with inflammatory and allergic themes. Evidence suggests that pre-existing MCAS, whether or not formally diagnosed, might increase the propensity for chronic post-Covid-19 illnesses. Put another way, could Long COVID be an atypical response to SARS-CoV-2 caused by pre-existing dysfunctional MCs?

A study by MCAS experts that compared the Covid-19 illness in patients with and without MCAS reported significant overlap between symptoms of Long COVID (and more severe acute COVID disease) and symptoms of MCAS. Moreover, pharmaceutical drugs with activity against MCs or their mediators were observed preliminarily as helpful in Covid-19 patients; and MCAS patients who were being treated for MCAS seemed to be less badly affected during and after the acute COVID illness (Int J Infect Dis. 2020 Nov;100:327-332).

Autoimmunity

It’s long been established that many common viruses, especially herpes viruses like HHV-6 and EBV, can be triggers and/or mediators of autoimmune conditions. The mechanism by which this occurs is known as molecular mimicry. The viral infection stimulates antibodies that may also react against self-tissues because the strings of amino acids (the epitopes) in the virus and the self-tissue are so similar to each other.

There is growing evidence that SARS-CoV-2 can cause autoimmunity by this same mechanism. In fact, the SARS-CoV-2 spike protein antibody has been shown to cross-react with (attach to) a wide range of self-proteins, including zonulin in the gut, thyroid peroxidase (TPO) in the thyroid gland, actin in muscle, mitochondrial proteins and many others.

What’s more, the longer the antibodies stay in the body, the more likely molecular mimicry may occur. So researchers are investigating not only whether existing autoimmune conditions can be exacerbated by COVID illness, but the extent to which new cases of autoimmunity can be triggered by the illness, and whether this may explain a sub-section of Long COVID cases (Clin Immunol. 2020 Aug;217:108480).

Mitochondrial dysfunction

Optimizing mitochondrial function for general health is a hot topic at the moment and so it’s no surprise that it’s also being considered as a way to improve outcomes in Long COVID. The mitochondria are responsible for energy production, and for the control of oxidative stress and inflammation, all of which are processes that go awry in Long COVID.

Our mitochondria can become dysfunctional under stress from both the viral infection itself, and also from the body’s response to the infection in the form of the cytokine storm. This type of inflammation can cause long term oxidative & inflammatory stress both to mitochondrial DNA and mitochondrial membranes, leading to loss of function. This, in turn, hampers energy production and drives more oxidative stress and inflammation (Chronic Dis Transl Med. 2021 Mar;7(1):14-26).

What’s more, there are similarities between the symptoms of Long COVID and Chronic Fatigue Syndrome (CFS), of which the latter is considered to be related, at least in part, to mitochondrial dysfunction.

Baseline interventions

Few people would argue that at, at the very least, individuals with Long COVID would likely benefit from optimising basic diet and and lifestyle activities and, in particular:

  • Taking steps to ensure 7-8 hours a night of good quality sleep
  • Appropriate management of stress, both physiological and emotional. Physiological stressors may include blood glucose disruptions and food sensititivies.
  • Regular physical activity, at a moderate level of intensity so as to better support HPA (hypothalamic-pituitary-adrenal) axis function and anti-inflammatory processes. Regular movement also supports tissue oxygenation, lymphatic and circulatory health.
  • A wholefood, low-glycaemic load, nutrient-dense, anti-inflammatory diet
  • A low-histamine diet if the case history suggests this may be helpful
  • Consideration of an elimination diet, such as an Auto-Immune Paleo diet, where autoimmunity is suspected as a key driver of the ongoing symptoms.

The importance of diet was highlight in a recent review that concluded that a ‘Standard Western Diet’, high in processed fats, sugars and starches, and low in micronutrients, acts as a potent inflammatory antecedent in the general ‘healthy’ population (Brain Behav Immun. 2020 Jul;87:53-54). Eating this way not only contributes to obesity and type 2 diabetes, but also impairs adaptive immunity, and this in turn drives chronic inflammation while simultaneously hampering defence against viruses.

Thus, living in a constant state of low-grade inflammation increases the risk of long-term inflammatory and neuroinflammatory health issues from what would otherwise be short-term, acute inflammatory triggers like viral infections.

Conversely, ‘studies show that consuming healthy foods has a rapid anti-inflammatory effect, even in the presence of obesity pathology…Thus, now more than ever, wider access to healthy foods should be a top priority & individuals should be mindful of healthy eating habits to reduce susceptibility to & long-term complications from CO-19” (Brain Behav Immun. 2020 Jul;87:53-54).

The NHS advises consuming good levels of protein and energy-rich foods, staying well-hydrated, taking a multivitamin & mineral supplement for those not consuming adequate amounts of a wide range of nutrient-dense foods and taking vitamin D for those over 65, with a darker skin tone, or those unable to spend time outside regularly.  A dedicated NHS COVID recovery website can be found at https://www.yourcovidrecovery.nhs.uk.

A Personalised Approach

The individualised nature of Long COVID suggests that different therapeutic approaches may be required for different patients with the same (i.e. ‘Long COVID’) diagnosis. Thus a personalised approach may be the most effective.

It isn’t just about the virus, it’s about the internal terrain.

One way to start is by identifying the underlying body systems that seem to be in need of the most support in the particular individual needing help. Functional laboratory investigations can be helpful here. For example, in considering what may be driving aberrant ongoing inflammation, look for the sorts of mediators discussed above, such as mast cell activation, loss of epithelial barrier function, microbiome imbalance, mitochondrial dysfunction and/or increased oxidative stress, reactivation of dormant viruses, autonomic dysfunction (sympathetic dominance) and/or central adiposity.

Examples of broad-based tests to start with may include

  • Full blood count and biochemistry, including thyroid hormones and HbA1c
  • Ferritin, CRP, ESR
  • Urinary organic acids, amino acids, blood spot membrane fatty acids
  • Stool microbiome
  • Co-infections (viruses and/or mycotoxins)
  • Salivary and urinary adrenal profile
  • Urinary sex hormones and metabolites. (Consider, for example, the extent to which the symptom profile matches that for peri-menopause.)

In his recent paper on immune rejuvenation, Dr Jeffrey Bland explains that rather than simply ‘boosting’ an already flagging immune system, a personalised approach works to reduce immunosenescence and chronic inflammation, while also improving the resilience of immune cells through, for example, optimising the processes of autophagy and mitophagy (Integr Med (Encinitas). 2020 Dec;19(6):18-22).

Some key nutraceutical interventions to consider

[Note that this information is designed for healthcare practitioners. It is not intended as a replacement for medical advice. Check with your doctor before using nutritional supplements if you are taking any prescribed medications or being monitored for a medical condition.]

Having discussed some of the likely biochemical imbalances in cases of unexplained Long COVID, we’re now going to suggest some nutritional agents to consider. But remember that, as we’ve already discussed, there is no single nutritional ‘protocol’ for Long COVID.  Like any other chronic, complex condition, the best efficacy comes with identifying and treating the client’s unique set of underlying triggers and mediators.

What’s more, clinical research on nutriceuticals in Long COVID has not yet been reported on. Hence these nutriceuticals are discussed here because they have shown efficacy in human trials in other conditions and have been shown to have relevant mechanistic effects, such as antiviral, anti-inflammatory, immune cell rebalancing, mitochondrial support, and/or support for physical and mental fatigue. Hence, hypothetically, their use be helpful in certain cases of Long COVID.

Support for Natural Killer (NK) Cell Response

NK cells drive the core immunological response to viral infection. Hence this is important to consider if persistent SARS-CoV-2 reservoirs are suspected and/or if co-infections may be a mediator of the Long COVID symptoms.

Astragalus, andrographis, reishi, black currant seed oil, zinc and vitamin C all help to support NK cell function (Integr Med (Encinitas). 2020;19(Suppl 1):8-35, Ann Nutr Metab. 2006;50(2):85-94).

It’s worth holding in mind that if overt inflammation seems to be a greater driver than any viral residue or co-infections, it would be safer and likely more effective to focus on anti-inflammatory support (see later).

Focus on Vitamin C

Although vitamin C deficiency in Long COVID isn’t evidenced, it’s likely, since infections are known to be associated with an increased consumption of vitamin C, and deficiencies in acute infections are frequent, especially for patients with pneumonia and COVID-19. Also, fatigue, pain, cognitive disorders, and depression-like symptoms are known symptoms of a vitamin C deficiency (Nutrients. 2021 Mar 31;13(4):1154).

What’s more, vitamin C may help with post-viral fatigue generally due to its antioxidant activity, it’s anti-inflammatory effects (not only through reducing oxidative stress and but also by helping to stabilise mast cells) and its ability to promote the restoration of endothelial function.

In the absence of testing, start with 1,000mg/day in divided doses or in a time release formula.

Nutrients for Balancing T-helper Cells

T-helper cells (also termed CD4+ cells) are key mediators in the adaptive immune response. They are further differentiated into various T-helper cell sub-types, such as Th1, Th2, Th17 and others.

In Long COVID, some immunological experts recommend supporting Th1 and modulating Th2, the rationale being that:

  • Th1 is anti-infective (viral/bacterial/fungal, etc)
  • Th1 cells support Natural Killer Cell function
  • Suppressed Th1 reduces innate immunity
  • Suppressed Th1 function leads to up-regulated Th2 activity, which in turn drives ‘hollow space’ infections and further suppresses Th1
  • Suppressed Th1 enables Th17 to rise, which is associated with autoimmunity

(Integr Med (Encinitas). 2020;19(Suppl 1):8-35).

Berberine and liquorice root support Th1 activity, while quercetin and astragalus modulate Th2. Quercetin has also been shown to have some antiviral activity against Coronovirus and Herpesvirus. And it works as an antioxidant, an anti-inflammatory and a mast cell-stabilising agent in post-viral healing (Integr Med (Encinitas). 2020;19(Suppl 1):8-35, IFM.org (open access COVID resources).

Nutrients that Play Dual Roles in Immunology

Certain nutrients are particularly helpful because of their ability to support immune surveillance, while also reducing inflammation.  These include vitamin D, vitamin A, vitamin C, zinc, quercetin and EPA/DHA from fish oil  (Integr Med (Encinitas). 2020;19(Suppl 1):8-35).

Interestingly, these same nutrients can be helpful in supporting gut barrier integrity, further modulating inflammation.

Focus on Vitamin A

Research concludes that vitamin A status is a major determinant of overall immune status.

‘Those deficient in vitamin A experience impaired antibody response, decreased levels of helper T cells, and impaired integrity of the mucosal linings of the respiratory and gastrointestinal tracts’ (Integr Med (Encinitas). 2020;19(Suppl 1):8-35).

Sadly, we can’t assume that dietary beta-carotene will provide sufficient vitamin A for everyone. This is because genetic SNPs in the 15,15’-monoxygenase enzyme can compromise conversion from beta-carotene to vitamin A, and such SNPs are relatively common in the population.

This is important in COVID-19 because vitamin A levels tend to drop during infections. Multiple studies show that vitamin A supplementation improves resistance and recovery rate in infections generally and that this can also reduce persistent inflammation (Integr Med (Encinitas). 2020;19(Suppl 1):8-35).

Focus on Vitamin D

Vitamin D deficiency is well evidenced to drive many processes that may be relevant in Long COVID. Deficiency impairs immune function, making infections more likely. It also drives excessive inflammation and it promotes autoimmunity.

In the acute viral phase, vitamin D is crucial for potentiating immune function: it activates macrophages to respond more effectively to infection; it supports neutrophil influx into infected tissues; and it stimulates anti-microbial peptides.

During the resolution phase of the infection, vitamin D supports immune tolerance, by modulating Th17 and inflammatory cytokines, enabling the immune system to switch off its response in a timely manner. There are also results from a meta-analysis indicating that vitamin D may protect against lung fibrosis (Integr Med (Encinitas). 2020;19(Suppl 1):8-35).

Antioxidant Support

Powerful and intense free radical activity is triggered by the immune response to an acute SARS-CoV-2 infection, in order to disable the virus. Sometimes the body needs extra support to resolve this upregulated level of oxidative stress. Antioxidants mentioned elsewhere in this discussion include vitamins A, C and E, zinc, coenzyme Q10, and the phytochemicals curcumin, quercetin and berberine.

Focus on N-acetyl cysteine (NAC)

NAC is the rate-limiting nutrient for glutathione (GSH) synthesis. Supplementing NAC can improve GSH status and can thus bring the associated benefits.

Optimal GSH status is crucial in the health of individuals with Long COVID because it supports immune surveillance, while also reducing any unresolved oxidative stress that may be a driver of ongoing symptoms.

Specifically, GSH increases the proliferative response of immune T cells, which in turn helps to disable any residual viral burden and/or reactivation of coinfections. And it inhibits the NLRP3 inflammasome pathway (IL1β and IL18 – see below) and reduces plasma TNF-ɑ. This in turn dampens any ongoing chronic inflammation triggered by the initial immune response to the virus (Chronic Dis Transl Med. 2021 Mar;7(1):14-26, Integr Med (Encinitas). 2020;19(Suppl 1):8-35).

Because of these effects, NAC has a long-established use in lung-respiratory conditions like COPD (chronic obstructive pulmonary disease) and cystic fibrosis. Nebulized forms are most commonly used but oral NAC (600mg twice a day) was reported in a controlled study of patients with COPD to significantly improve oxygen readings, symptoms like wheezing, and reduce the need for nasal oxygen support.

GSH is also crucial for supporting the detoxification of any residual viral load, inflammatory cytokines, lipopolysaccharides (from dysbiosic bacteria), histamine, mycotoxins and any other toxins that may be contributing to chronic ongoing symptoms. And NAC has been reported to lower elevated homocysteine levels. (See below for methylation in long-COVID.) (Clin Chem Lab Med. 2002 May;40(5):496-8, Integr Med (Encinitas). 2020;19(Suppl 1):8-35).

Anti-inflammatory Support

Evidence from recent studies demonstrates that the NLRP3 inflammasome has a potent role in COVID-19 and in driving the lung fibrosis that can contribute to lingering symptoms long after the acute infection.

The NLRP3 inflammasome is a protein complex that initiates an inflammatory form of programmed cell death (‘pyroptosis’) and triggers the release of proinflammatory cytokines. NLRP3 is initiated by microbial infection (including viruses and LPS) and also by other stress signals such as mitochondrial dysfunction. Hence, experts recommend intervening to downregulate inflammasome biology to reduce the risk of lingering inflammatory and fibrotic effects from COVID (Integr Med (Encinitas). 2020;19(Suppl 1):8-35).

Focus on Curcumin

This phytochemical from the turmeric root has pleiotropic effects in human health that may logically be relevant in Long COVID:

It works as an anti-inflammatory both by targeting the NLRP3 inflammasome that is upregulated in SARS-CoV-2 infection; and also by down-regulating the inflammatory transcription factor nuclear factor kappa beta (NF-kB).

Curcumin also has antiviral effects; and it has antioxidant activity by stimulating the production of the ‘antioxidant response element’ (the synthesis of endogenous antioxidant enzymes). What’s more, it has some anticoagulant effects, which is a key consideration in individuals for whom excessive blood clotting is a likely driver of the Long COVID symptoms (Integr Med (Encinitas). 2020;19(Suppl 1):8-35).

It’s worth noting that curcumin supplementation may be contraindicated with some anticoagulant medications, as well as in gallbladder disease and/or poor phase 1 detoxification function.

Focus on EPA/DHA

These highly unsaturated omega-3 fatty acids derived from fish, krill oil and algae are potently anti-inflammatory in the longer term, once levels are sufficiently accumulated within the cell membranes.

EPA and DHA are metabolised into anti-inflammatory prostaglandins and anti-thrombotic thromboxanes, as well as newly identified eicosanoids such as ‘specialised pro-resolving lipid mediators’ (SPMs). EPA is the precursor for the E series resolvins, while DHA is the precursor for the D series resolvins, neuroprotectins, and maresins. Each of these has a role in promoting the resolution phase of the inflammatory process (Nat Rev Immunol. 2010 Jun;10(6):427-39), meaning that both these long-chain fatty acids may be important in modulating long-term inflammation such as can be found in Long COVID.

Nutrients to Consider in Long Term Fatigue

Many cases of Long COVID present in a way not dissimilar to cases of other chronic unexplained conditions like Chronic Fatigue Syndrome (CFS) and Fibromyalgia (FM), sharing such symptoms as ongoing muscle pain, headache, fatigue and cognitive disruption. Hence, it may be worth trialling some of the nutrients that have shown promise in CFS and FM.

Co enzyme Q10 (CoQ10)

CoQ10 is a fat-soluble vitamin-like molecule made in the liver and used by the mitochondria to make energy within the electron transport chain. CoQ10 is also a potent antioxidant within the mitochondria and within cell membranes and other lipid compartments of the body (such as LDL-cholesterol).

A recent review includes supplemental CoQ10 as a promising agent in CFS; and CoQ10 is well-reported as helpful in FM.  FM patients using 300mg/day CoQ10 experienced reduced symptoms of tiredness and pain, as well as reduced associated biomarkers including markers of inflammation, compared to the placebo group. Another trial found the same dose of CoQ10 induced significant improvement in headache symptoms in FM patients compared to placebo (Antioxidants & Redox Signaling. 2013;19(12):1356-1361, PLoS ONE. 2012;7(4):e35677, Pharmacol Res. 2019 Oct;148:104450).

Although CoQ10 is made within the body, tissue saturation declines with age. What’s more, CoQ10 synthesis is significantly compromised by the use of statin medication.

Folate and vitamin B12

The process of methylation is crucial for healthy cell turnover, as well as for supporting immune function, brain chemistry, detoxification and many other body processes. Hence, it is a key player in making a full recovery from COVID illness.

Yet, methylation may be severely hampered by the acute infection. A recent review suggests that SARS-CoV-2 induces, ‘an increased demand for methyl-groups whilst simultaneously impairing their supply due to viral-induced oxidative stress’.

If this isn’t reason enough to look to methylation-supportive nutrients, there is also evidence that methylation support may help individuals with CFS (symptomatically similar to Long COVID, as we’ve seen above). Good responses have been reported by such patients with the use of therapeutic levels of B12 and folate (Med Hypotheses. 2021 Apr;149:110543, Proc Natl Acad Sci USA. 2016 Sep 13;113(37):E5472-80, PLoS One. 2015 Apr 22;10(4):e0124648).

A review earlier this year proposed that ,‘The diverse symptoms [of Long COVID] are reminiscent of vitamin B12 deficiency, … in which methylation status is compromised.’ The researchers go on to propose that because the viral-induced oxidative stress leads to increased methyl-group requirements, individuals with Long COVID and/or with similar conditions such as CFS, may benefit from being evaluated for functional B12 and folate status, such as by measuring homocysteine and methylmalonic acid, and then supported by supplementing these nutrients where necessary (Med Hypotheses. 2021 Apr;149:110543).

Magnesium

Magnesium is another micronutrient essential for methylation. And it also has many other roles in supporting energy metabolism and recovery from energy-sapping infections. For example, it is a co-factor in ATP synthesis; it supports adrenal gland function to help with stress-related fatigue; it aids blood glucose metabolism to prevent hypoglycaemic energy crashes; and it helps prevent inflammatory-related exhaustion by opposing excessive calcium levels. Magnesium supplementation has also been found to fight fatigue by improving sleep: 500mg/day for eight weeks has been reported to improve both subjective and objective measures of insomnia in a trial of elderly subjects. And there is some evidence for the use of magnesium in CFS and FMS, although the trials are small in scale (J Res Med Sci. 2012 Dec;17(12):1161-9, Nutrients. 2020 Jan 16;12(1):228, Rheumatol Int. 2013 Jan;33(1):167-72).

Digestive enzymes and probiotics

In one of the few randomised controlled trials of a nutritional supplement in patients with Long COVID, a combined enzyme complex and probiotic complex was given to 200 patients with post-COVID fatigue. After two weeks, a reduction in fatigue (both physical and mental) was reported by 91% in the intervention group compared to only 15% of controls (Medicines (Basel). 2021 Aug 30;8(9):47).

What’s more, if probiotics and enzymes are helping, this may indicate a need to look more routinely for functional gastrointestinal imbalances in individuals with Long COVID, especially, as we’ve seen above, the microbiome can become disrupted by viral infection. Stool and breath testing can be used to identify colonic dysbiosis, SIBO, SIFO and/or intestinal methanogen overgrowth (IMO). And any of these microbial imbalances can contribute to gut barrier dysfunction, which, as we’ve seen, can drive more inflammation.

A personalised approach to supporting gastrointestinal health may include not only probiotics and enzymes, but also, for example, prebiotic fibres, polyphenols, antimicrobials, prokinetics, liver/gallbladder support and/or anti-spasmodics, as well as a focus on the gut-brain axis and stress management.

To wrap up

Many different mechanisms are currently under investigation as potential candidates for driving ‘unexplained’ Long COVID. There is likely a different combination of underlying factors present between individuals. Hence, it’s best to adopt a personalised approach, which encompasses investigating and working to resolve each of the underlying factors.

In this discussion, we have looked at some key imbalances to consider. We’ve then explained the importance of optimising diet and lifestyle, and we’ve provided a rationale for considering the use of certain key nutraceuticals.