Long COVID: When symptoms persist despite normal inflammatory markers
A new study in Scientific Reports provides an exciting contribution to the question of what could sustain Long COVID in the long term – and why we may need to differentiate more strongly between structural damage and altered function and regulation.
Many people with Long COVID are familiar with the frustrating situation: The symptoms are clearly noticeable – fatigue, brain fog, pain and reduced resilience – and yet many classic laboratory tests are largely unremarkable.
How does that fit together?
A controlled study published in Scientific Reports in 2026 provides interesting insights into this.
What was investigated?
The researchers compared 48 people with Long COVID with 48 people who had also had a SARS-CoV-2 infection but had subsequently fully recovered.
Of particular interest: The study took place a median of 69 weeks after the initial infection . It therefore did not focus on the early post-COVID-19 phase, but rather on symptoms persisting for longer.
Among other things, markers for the following were examined:
systemic inflammation such as CRP, IL-6 and TNF-α
neuronal damage such as neurofilament light chain (NfL)
astroglial activation or neuroinflammation such as GFAP
Myeloid or microglial activation via TREM2
In some cases, very sensitive measurement methods were used.
The surprising result
After statistical correction, the researchers found no significant differences between people with Long COVID and recovered control subjects in the inflammatory and neurological biomarkers examined.
In particular, these markers did not provide convincing evidence of ongoing neuronal damage or pronounced neuroinflammation.
This explicitly does not mean that people with Long COVID do not have physically based symptoms.
And it also doesn't mean that "there's nothing there".
It poses a different question:
Must persistent symptoms always be explained by ongoing structural damage or clearly measurable chronic inflammation?
The results of this study at least suggest that this is not necessarily the case for all affected individuals and not in every phase of the disease.
Notably, small differences were quite visible.
An important point is easily lost in the study's title.
Using an ultrasensitive measurement method, CRP, TNF-α, IL-6 and TREM2 were initially higher in the long-COVID patients than in the control subjects.
However, after the necessary statistical correction for multiple comparisons, these differences were no longer significant.
The authors themselves therefore discuss the possibility that a very low-grade chronic immune activation might exist, which could not be reliably detected with the methods used or with the relatively small number of participants.
This is an important distinction:
The absence of statistically significant inflammation does not automatically mean that all immunological regulatory processes are normal.
Structural damage or altered function?
The authors' discussion about brain fog is particularly interesting.
If markers for neuronal damage and astroglial activation are not elevated, why can thinking, concentration, and resilience still be so significantly altered?
The authors discuss various possible explanatory models.
Changes in mitochondrial energy metabolism
Changes in cellular energy production could affect the function of cells without necessarily resulting in structural damage or destruction of nerve cells.
We find the subsequent discussion by the scientists themselves particularly interesting. Therefore, we would like to highlight this passage.
Quote from the original publication – my own translation from English:
"Additionally, the symptoms could be due to functional changes in the network connections in the brain. In this case, the coordination between different brain regions is impaired, although the structural connections are intact."
Another possibility is that altered functional mechanisms of the central nervous system in the chronic phase – and not ongoing tissue damage – contribute to symptoms such as 'brain fog'.
This fits the concept of central sensitization, in which the processing of signals from inside the body (interoceptive signals) in the brain can become hypersensitive.
Furthermore, psychological factors such as fear-avoidance beliefs and catastrophizing appraisals of bodily sensations can contribute to maintaining complaints by promoting a state of heightened autonomic activation and hindering physical reconditioning.
Source: Omdal et al., Scientific Reports, 2026; own German translation.
Why we find this passage so interesting
These statements are noteworthy because the authors explicitly discuss the possibility that persistent symptoms need not be explained solely by ongoing tissue damage.
We place particular importance on differentiation:
Terms like central sensitization, fear avoidance, or the evaluation of bodily signals do not mean that Long COVID is "imagined" or a purely psychological illness.
Rather, it is about the complex biological communication between brain and body.
The autonomic nervous system, the perception of signals from within the body, immune processes, metabolism, and neural networks mutually influence each other. Experiences, expectations, and the evaluation of bodily signals can also be part of this regulation.
That is precisely why it is important not to equate structure and function .
A structurally intact neural network can function in a functionally altered way. And this altered function can be accompanied by very real and pronounced symptoms.
Sickness Behavior: A protective program of the organism
Another interesting aspect of the study is the so-called sickness behavior .
Sickness behavior describes a coordinated response of the organism during an illness.
This could include, for example:
Fatigue, reduced drive, withdrawal, concentration problems, pain and an increased need for rest.
During an acute infection, such a reaction is generally beneficial. The organism reduces its activity and shifts its priorities during the immune response.
However, it becomes problematic when elements of such a protection program remain in place even though the acute infection is long over.
The authors discuss both very low-level immunological signals and epigenetic mechanisms that could influence such a sickness-behavior response.
This is precisely where regulation becomes interesting.
This study is particularly exciting for us because it allows for an important change of perspective:
Not every persistent dysfunction necessarily means that tissue damage continues.
Between "healthy" and "structurally damaged" lies a vast level of biological function and regulation.
The immune system, autonomic nervous system, energy metabolism, stress response, brain and body are in constant communication with each other. These regulatory circuits can change after severe or prolonged stress.
At the Safety Retreat, we therefore do not consider complaints solely from a single perspective.
Our research focuses on, among other things, nervous system regulation, pacing, neuroplasticity, and cellular and metabolic regulatory processes, placing these within a broader context.
A scientific distinction is important to us:
The current study neither investigates the Cell Danger Response nor proves that a specific regulatory mechanism causes or maintains Long COVID.
However, it shows something else that we consider very relevant:
Persistent symptoms and a lack of evidence of ongoing structural neuronal damage can coexist.
This opens up possibilities for further scientific investigation of functional and regulatory mechanisms.
What we must not conclude from the study
As interesting as the results are, they should not be overinterpreted.
The study was relatively small, with a total of 96 participants, and only examined selected biomarkers.
Normal blood markers do not necessarily rule out changes in certain tissues or other pathophysiological processes.
Furthermore, this is a cross-sectional study. Cause and effect cannot be determined from it.
Long COVID is probably not a completely uniform disease. In individual patients or subgroups, immunological, vascular, autonomic, metabolic, or other alterations may play different roles.
The results must therefore be considered in the context of all long-COVID research.
Source: Omdal R. et al. Long-COVID: assessment of circulating markers suggests no cerebral neuronal damage, neuroinflammation or systemic inflammation – a controlled study. Scientific Reports, 2026.
Note: This article is for scientific information purposes only and does not replace individual medical diagnosis or treatment.
