Oxidative stress in ME/CFS and long COVID

A recent study highlighted that the clinical presentation of long COVID is heterogenous (highly varied), spanning multiple organ systems, and in some cases strongly resembles ME/CFS. This overlap is not surprising, as many people with long COVID meet diagnostic criteria for ME/CFS, and the two diagnoses can co-exist, since both are currently symptom-based. “With no clinically approved treatments or diagnostic markers for these conditions, there is an urgent need to define the molecular underpinnings”.

The study led by Dr Vishnu Shankar, and including well-known researcher Professor Ron Davis within the team, explored bioenergetics (how cells produce and manage energy) in people with ME/CFS and long COVID, focusing on oxidative stress.

What is oxidative stress?

Oxidative stress happens when reactive oxygen species – unstable oxygen-containing molecules also called free radicals – are produced in excess and overwhelm the body’s antioxidant defences. This can damage cellular components such as proteins, DNA, and cell membranes. Mitochondria, the cell’s energy producers, are a major source of reactive oxygen species (which can even harm the mitochondria themselves).

Aim

The researchers aimed to identify shared molecular signatures between individuals with ME/CFS and long COVID compared to healthy controls, focusing on immune cell bioenergetics and oxidative stress. They drew on previous studies linking immune and metabolic dysfunction to these conditions, and also referenced an ME Research UK-funded study led by Dr Cara Tomas that explored the metabolic abnormalities in muscle cells from people with ME/CFS.

Methods

White blood cells, specifically peripheral blood mononuclear cells (PBMCs), from 27 ME/CFS participants, 20 long COVID participants, and 25 healthy controls were examined. “ME/CFS patients, including patients meeting the National Academy of Medicine (NAM) ME/CFS criteria before and after the start of the COVID-19 pandemic, were diagnosed by a physician using the National Academy of Medicine, Fukuda, and Canadian Consensus criteria”. Participants with long COVID were diagnosed using a “combination of the Center for Disease Control criteria for “LC or post-COVID conditions” and a symptom and functional status questionnaire”.

The researchers measured reactive oxygen species levels, markers of oxidative damage, and mitochondrial redox pathways (chemical reactions within the mitochondria) using complementary techniques for analysing cells, gene activity, molecular composition and complex chemical interactions.

Key Findings

Shared feature: Both ME/CFS and long COVID participants had higher oxidative stress in white blood cells.
Differences by sex in disease cohorts:
- Females: Higher reactive oxygen species levels, which correlate with hyperproliferation (excess division or multiplication) of T cells – a type of white blood cell that plays a crucial role in the immune system.
- Males: Normal reactive oxygen species levels but more oxidative damage to mitochondrial lipids.
Antioxidant response: In the disease cohorts, both sexes had higher glutathione – an antioxidant (a substance that neutralises reactive oxygen species thus protecting cells from damage). Nevertheless, the cells had issues within the systems that normally remove reactive oxygen species from cells, reduced levels of mitochondrial superoxide dismutase (a protective enzyme against oxidative stress), and other factors that contribute to ongoing oxidative damage.

Interpretation

The paper states that the findings suggest that the pathophysiology of ME/CFS and long COVID “are distinct between sexes”. Whilst “additional studies are needed to understand the mechanistic basis for these differences,” the researchers suggest that some of the patterns observed can be partially explained by the fact that sex hormones – such as oestrogen – can regulate antioxidant enzyme levels and activation of T cells. The effects of androgens (sex hormones that give male characteristics) could explain the differences related to lipids.

Overall, oxidative stress appears to impact energy use and immune function differently between sexes, which may help explain differences in symptoms.

Whilst not stated in the paper, it could be possible that the increase in the antioxidant – glutathione – is compensatory, but the compensatory effect is not enough to combat all of the oxidative damage. Furthermore, whilst this study has shown higher glutathione levels in ME/CFS, there are studies that suggest that glutathione levels in ME/CFS are lower – which also fits the picture of oxidative stress demonstrated.

Differences between long COVID and ME/CFS cohorts

While both groups shared oxidative stress signatures, long COVID participants showed lower levels of ATP (energy currency of cells) and the protective enzyme – mitochondrial superoxide dismutase. The researchers suggest that long COVID may represent an “intermediate but distinct state” between healthy controls and ME/CFS in terms of oxidative stress, potentially evolving with symptom duration.

Limitations

The researchers state, “Although our findings show consistent trends in [reactive oxygen species] dysfunction and can be validated using externally published data, additional studies directly measuring these changes in larger and diverse cohorts, with consideration of confounding factors, will be needed to test the generality of these conclusions further.”

It is also unclear whether each ME/CFS participant was diagnosed with all three criteria – NAM (formerly IOM), Fukuda and Canadian Consensus criteria, or whether one of the three was sufficient for diagnosis. If the latter, it is important to note a limitation of the Fukuda criteria – whilst post-exertional malaise (considered to be a cardinal feature of ME/CFS) is noted within Fukuda criteria, it is not required for diagnosis.

Discussion

This study strengthens the evidence of oxidative stress in ME/CFS and long COVID, whilst revealing important sex-specific differences. The researchers suggest that these findings could inform precision medicine approaches, including strategies to identify ME/CFS patients who might benefit from reactive oxygen species-modulating therapies aimed at reducing oxidative stress and controlling T cell hyperproliferation. The paper references, the example of a clinical trial that demonstrated that metformin lowered long COVID incidence in high-risk groups, particularly females and individuals with higher body mass index. According to the paper, the present study offers one plausible mechanism of action and that these results broadly suggest “the link between oxidative stress and T cell proliferation can be exploited to identify novel drug candidates.”