Oxford academic journal ‘Brain' has published an article entitled ‘Designing studies for post-treatment Lyme disease and other infection-associated chronic illnesses‘ (Arnaboldi et al 2026) that covers research into post infectious syndromes including ME/CFS.
Summary
- There are important clinical and pathological overlaps between ME/CFS and Long Covid
- ME/CFS still lacks a confirmed cause or biomarkers and currently there are no effective treatments.
- Research progress has been limited by inconsistent study methods & patient definitions.
- The paper argues ME/CFS research should follow more rigorous, standardised & biomedical approaches.
- The authors emphasise ME/CFS is a real, disabling biological illness.
- Conclusion: ME/CFS needs quality research to find mechanisms, diagnostics & treatments.
Abstract (2nd paragraph)
This review focuses on several diseases representative of the IACI [Infection-Associated Chronic Illness] spectrum. These are post-treatment Lyme disease syndrome (PTLDS), long COVID, myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and multiple sclerosis (MS). Their clinical and biological complexity, combined with a lack of clear diagnostic criteria and objective available laboratory biomarkers, makes them difficult to distinguish from conditions with overlapping features. This presents challenges for research studies, as well as diagnosis and clinical management. This diagnostic ambiguity, coupled with heterogeneous patient presentations, has led to challenges in research, including misclassification of study participants and inconsistent or irreproducible findings. Some PTLDS research exemplifies these issues, which also extend to other IACIs.
Extracts covering Myalgic encephalomyelitis/chronic fatigue syndrome
Historically, ME/CFS has been a highly controversial diagnosis, only gradually gaining broader acceptance within the medical community in recent years. With the emergence of long COVID, which has a clearly defined viral aetiology, the connection between chronic post-infectious diseases is receiving renewed attention. ME/CFS is a common clinical presentation in long COVID, where an estimated 4.5% or more of individuals who become infected with SARS-CoV-2 subsequently develop ME/CFS.94-98 ME/CFS also shares key neurologic features with PTLDS, particularly in its hallmark symptoms of profound fatigue, post-exertional malaise and cognitive impairment.
ME/CFS is now strongly suspected to be an IACI, and research has identified possible underlying mechanisms that align with other IACIs. Its onset has also been linked to immune dysfunction, environmental factors and traumatic events. However, in the absence of a single definitive inciting infectious agent, the disorder remains without a proven single origin or effective treatment. There may be multiple inciting or propagating infectious agents, including SARS-CoV-2.99. Diagnosis is typically delayed (sometimes years after the initial onset of symptoms), at which point evidence of cause(s) and early natural history has been lost. The diagnostic challenge mirrors those emerging in long COVID, where overlapping risk factors and related conditions are increasingly coming into focus.
Research increasingly suggests that ME/CFS may arise from a convergence of immune, neurologic, metabolic and genetic influences following an initial insult. Proposed mechanisms include immune and metabolic dysregulation, neuroendocrine abnormalities, nervous system and circulatory system dysfunction, cardiovascular defects and disturbances of the gut microbiome and intestinal barrier function. Possible aetiologies include immune system dysfunction that could be due to viral persistence, viral reactivation, B cell-, T cell- and/or NK cell-dysfunction and strong evidence for T cell exhaustion In addition, CNS dysfunction resulting in cognitive impairment or ‘brain fog’ may be due to neuroinflammation and blood–brain barrier dysfunction. Autonomic nervous system and circulatory system dysfunction result in cardiovascular manifestations (heart rate variability), endothelial dysfunction and micro-clots. There is growing evidence of genetic risk factors and/or genetic susceptibility.
MEA Comment
This review in Brain, which is a very prestigious medical journal, shows how the wider research community is starting to take a lot more interest in the cause and treatment of post infectious syndromes such as Lyme disease, ME/CFS and Long Covid.
Dr Charles Shepherd,
Trustee and Hon. Medical Adviser to the ME Association,
Member of the 2018-2021 NICE guideline on ME/CFS committee,
Member of the 2002 Chief Medical Officer's Working Group on ME/CFS
