Persistent Mitochondrial and Endothelial Dysfunction in Non-Hospitalized Patients with Long COVID, 2026, Ono et al.

[Chandelier]

Persistent Mitochondrial and Endothelial Dysfunction in Non-Hospitalized Patients with Long COVID

Spoiler: Authors

Rie Ono Shin Takayama Shin Takayama M Michiaki Abe Ryutaro Arita Ryutaro Arita K Koh Onodera K Kota Ishizawa T Takeshi Kanno Natsumi Saito Natsumi Saito Akiko Kikuchi Akiko Kikuchi T Takaaki Abe See less Tadashi Ishii Tadashi Ishii

Abstract​

Long COVID, a major post-acute infection syndrome (PAIS), characterized by prolonged or new-onset symptoms following acute COVID-19, critically affects patients' quality of life.
Establishing easily measurable and objective biomarkers that reflect disease severity is essential for clinical management.
This retrospective cohort study evaluated serum levels of growth differentiation factor 15 (GDF-15), a mitochondrial stress marker, and vascular cell adhesion molecule-1 (VCAM-1), a vascular endothelial stress marker, in 32 patients with Long COVID who presented with persistent systemic or neurological symptoms and had not required acute-phase hospitalization.
Serum GDF-15, VCAM-1, and inflammatory cytokine levels were measured at the initial visit and at 3 and 6 months.
Differences between patients who recovered at 6 months and those who did not (non-improved group) were analyzed using linear mixed-effects models (LMMs).
Most inflammatory cytokines remained near their lower detection limits and were excluded from the longitudinal analysis.
The LMMs revealed sustained elevation of both GDF-15 (p = 0.02) and VCAM-1 (p = 0.03) levels in the non-improved group.
These findings suggest that longitudinal tracking of these two markers may offer clinically relevant insights into disease activity and treatment-resistant pathophysiology in mild acute-phase Long COVID.

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[Hutan]

A Japanese study. Currently only the abstract is available. Good that they excluded hospitalised patients. It would have been good if they had been more specific in the abstract about the 'persistent systemic or neurological symptoms'.

The p values for GDF-15 and VCAM-1 aren't stunning, but they only had 32 Long COVID patients at the initial visit, and they don't say how many improved. So, the sample size is small, and possibly the distinction between who improved and who did not was a bit murky. Some healthy controls who recovered from Covid-19 would have been nice.

One to watch out for, when the full paper is released.

 

[Mij]

I wonder if getting a Covid vaccine the day after I contracted Covid saved me from getting worse? I was asymptomatic and didn't know I had contracted Covid. I recovered around the six month period.

 

[SNT Gatchaman]

Now published.

 

[SNT Gatchaman]

This single-center, retrospective, longitudinal cohort study was conducted at the Department of General Medicine at Tohoku University Hospital. In accordance with the National Institute for Health and Care Excellence (NICE) guidelines, Long COVID was defined as symptoms persisting for more than 4 weeks after the onset of COVID-19. We enrolled non-hospitalized patients who met these criteria and visited our department between January 2022 and August 2024

To evaluate the systemic pathophysiology, patients presenting with fatigue, neurocognitive impairment (e.g., brain fog), or myalgia/arthralgia were included. In contrast, those with exclusively localized symptoms (e.g., taste or smell disorders, cough) were excluded.

The analysis was restricted to patients who were followed up for at least 3 months and had paired banked serum samples available at both the initial visit and the 3-month follow-up visit. For patients with a 6-month follow-up visit, serum samples obtained at the 6month follow-up visit were also included in the analysis, if available.

“Clinical recovery” was defined as the resumption of pre-COVID-19 social and daily activities, including returning to work or school, as documented in medical records, without using standardized criteria derived from symptom questionnaires. This functional outcome was prioritized because, from a clinical perspective, subjective metrics such as the Visual Analog Scale (VAS) exhibit significant interindividual variability and frequently dissociate from actual social functioning.

That sounds eminently sensible.

 

[SNT Gatchaman]

Among the patients who visited our department during the study period, 32 met the inclusion criteria and were included in this study. Among the 32 participants, 14 (44%) were female, and the median age was 37 years [interquartile range (IQR), 30–49].

Not an ideal sex ratio though.

Based on their 6-month clinical outcomes, 18 patients were assigned to the recovered group and 14 to the non-improved group.

Patients typically presented with multiple concurrent symptoms (median 4; IQR, 3–5), with fatigue being the most prevalent (29 patients, 91%). Although the prevalence of specific symptoms and baseline QOL scores did not differ significantly between the two groups, brain fog (64 vs. 33%, p = 0.08) and cough (36 vs. 6%, p = 0.06) were more common in the non-improved group.

In terms of the levels of inflammatory cytokines (IL-6, TNF-α, and IL-10), the measured levels were predominantly near the lower limit of the standard curve at all time-points. […] these markers were deemed unsuitable for evaluation of their association with Long COVID and were excluded from further longitudinal statistical analyses.

the levels [of GDF-15] were higher in the non-improved group, with the difference approaching statistical significance at 6 months (median: 680 vs. 410 pg/ml, p = 0.07).

The longitudinal GDF-15 trajectories, evaluated using LMM [linear mixed-effects models], are shown in Figure 2A. The LMM analysis revealed a significant main effect of group (F = 5.27, p = 0.02), indicating that GDF-15 levels were significantly higher in the non-improved group than in the recovered group throughout the observation period (estimated mean difference: 108 pg/ml, 95% confidence interval [CI]: 14 to 201).

results indicate that GDF-15 levels remained relatively stable over time in both groups, and that the non-improved group exhibited a consistently elevated trajectory without significant divergence over time.

the non-improved group exhibited significantly higher levels [of VCAM-1] at 6 months (median: 1,043 vs. 663 ng/ml, p = 0.004). The longitudinal VCAM-1 trajectories, evaluated using LMM, are shown in Figure 2B. The LMM analysis revealed a significant main effect of group (F = 4.68, p = 0.03), indicating that the overall VCAM-1 levels were significantly higher in the non-improved group than in the recovered group throughout the observation period (estimated mean difference: 138.7 ng/ml, 95% CI: 11.0 to 266.4).

Although previous studies have highlighted the importance of systemic inflammatory markers, such elevations were rarely observed in our cohort. In contrast, we demonstrated that the longitudinal trajectories of GDF-15 and VCAM-1 remained persistently elevated in the non-improved group compared with those in the recovered group.

 

[SNT Gatchaman]

because all patients in our study received treatment, these biomarker trends might not simply predict the natural prognosis of Long COVID; rather, they may reflect the pathophysiological differences between treatmentresistant and treatment-responsive groups or the effectiveness of the treatment.

the therapeutic interventions during the observation period were not standardized, and potential biases arising from differences in symptomatic treatments cannot be excluded.

GDF-15 is a stress-responsive cytokine that is produced primarily in response to mitochondrial stress and contributes to energy metabolism and immune regulation

Taken together, these findings suggest that underlying mitochondrial dysfunction, as well as a prolonged impairment in mitochondrial homeostasis or repair processes, are involved in the pathophysiology of Long COVID. […] Furthermore, such mitochondrial dysfunction is associated with the pathophysiology of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and chronic pain disorders.

In circulation, VCAM-1 exists as a soluble form and serves as a marker of endothelial injury

in our previous study, we did not observe an elevation of syndecan1—a marker reflecting glycocalyx damage—in patients during the acute phase and at 3 months post-onset. Therefore, we consider that the persistently elevated trajectory of VCAM-1 observed in the non-improved group suggests a prolonged state of functional endothelial activation and dysfunction, without overt structural damage.

VCAM-1 is involved in BBB disruption and increased permeability […] the persistent increase in VCAM-1 may closely reflect ongoing vascular pathology extending to the central nervous system.