Trial Report Clinical and Laboratory Characteristics of Fatigue-dominant Long-COVID subjects: A Cross-Sectional Study, 2024, Lee

Dolphin · Feb 9, 2024

https://www.amjmed.com/article/S0002-9343(24)00057-3/fulltext

CLINICAL RESEARCH STUDY|ARTICLES IN PRESS

Clinical and Laboratory Characteristics of Fatigue-dominant Long-COVID subjects: A Cross-Sectional Study

Jin-Seok Lee, PhD

Yujin Choi, MD

Jin-Yong Joung, MD, PhD

Chang-Gue Son, MD, PhD

Published:February 06, 2024DOI:https://doi.org/10.1016/j.amjmed.2024.01.025

Abstract

Background
Long-COVID is defined by persistent symptoms following COVID-19 infection. Approximately 71% of individuals with long-COVID experience ongoing fatigue, post-exertional malaise, and cognitive impairments, which share pathological similarities with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). This similarity has prompted studies to explore the characteristics of long-COVID to gain a better understanding of ME/CFS. To gain insights, we investigated the clinical and laboratory characteristics of individuals with fatigue-dominant long-COVID.

Methods
We enrolled 100 subjects (36 males, 64 females) with long-COVID who had a higher score than 60 in modified Korean version of the Chalder Fatigue Scale (mKCFQ11) and higher than 5 in fatigue-focused Visual Analogue Scale (VAS). To investigate fatigue symptoms, the mKCFQ11, the Multidimensional Fatigue Inventory (MFI-20), and VAS for fatigue and brain-fog, along with the Short Form Survey (SF-12) were employed. We also measured three cytokines and cortisol levels for immunological and endocrinological indicators. As a cross-sectional observational study, the data were collected at a single point in time.

Results
The mean scores on the measurements showed severe fatigue, and these scores were significantly correlated, with no differences based on sex, the post-COVID period, or age. Among the laboratory tests, plasma cortisol levels had a significant negative correlation with fatigue scores and a positive correlation with living quality. The negative correlation between cortisol levels and mKCFQ11 scores appeared to be more specific to mental fatigue than physical, which conflicted with other measurements.

Conclusion
Our findings provide the first insights into the characteristics of fatigue in individuals with long-COVID, particularly in terms of fatigue severity and cortisol levels. These results serve as valuable reference data for clinicians dealing with fatigue symptoms in long-COVID patients and for researchers exploring post-viral fatigue symptoms, including ME/CFS, in the future.
Keywords

Long-COVID

ME/CFS

Fatigue

HPA-axis

Cortisol

Hutan · Feb 9, 2024

Korean team, there's a paywall.

It appears to be more cortisol nonsense. We know that cortisol levels vary, within normal ranges, with physical activity levels and that these adapted levels can change in a matter of weeks. If someone is routinely having physical stress, they will have higher cortisol levels than someone who is not. Someone with severe Long Covid /ME/CFS won't be rushing about, and so doesn't have a need for cortisol levels at the high end of normal. They are more likely to have a level at the low end of normal.

The fact that the authors don't report in the abstract a finding of abnormal cortisol levels for this population (i.e. relative to healthy populations) suggests to me that there wasn't one.

SNT Gatchaman · Feb 10, 2024

This study has some limitations as follows: 1) lack of comparison with healthy controls or ME/CFS patients, 2) relatively small-scale and a limited diversity of subjects, and 3) the absence of long-term follow-up data. Despite these limitations, our study conducted a thorough analysis of the clinical characteristics of fatigue symptoms in individuals with long-COVID, along with laboratory features related to three typical immunologic cytokines and cortisol.
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Yet —

In conclusion, the present results will serve as crucial reference data for clinicians dealing with fatigue symptoms in long-COVID patients and for researchers exploring post-viral fatigue symptoms, including ME/CFS, in the future.
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SNT Gatchaman · Feb 10, 2024

three cytokines (immunology) and one hormone (endocrinology) were determined to investigate their correlation with symptoms. Blood was collected using a vacutainer system containing ethylenediamine tetraacetic acid (EDTA) under 12 h fasting condition, and plasma was isolated by centrifugation at 4 ℃ for 10 minutes.
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That suggests it was an early morning fasted sample for the cortisol, but it's not specified.

The plasma levels of inflammatory cytokines, including interferon-γ (IFN-γ, cat. No. 555142), tumor necrosis factor-α (TNF-α, cat. No. 555212) and transforming growth factor-β1 (TGF-β1, cat. No. 559119) were determined using a commercial ELISA kit (BD Biosciences, San Diego, CA, USA). In addition, plasma cortisol levels were measured with a cortisol parameter assay kit
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SNT Gatchaman · Feb 10, 2024

The average of cortisol levels was 124.7 ± 41.2 ng/mL in plasma of long-COVID subjects, which is higher than known range of healthy controls generally. It was significantly higher in male (139.3 ± 53.7 ng/mL) than in female (116.5 ± 29.3 ng/mL) (p < 0.05).
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Significant correlation of cortisol levels with scores of mKCFQ11 (R-squared -0.206, p < 0.05), MFI-20 (R-squared -0.269, p < 0.05), and SF-12 (Rsquared 0.195, p < 0.05) was showed, but not in Fatigue VAS and Brain-fog VAS (Fig. 3A to F).
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Levels of immune-related cytokines (IFN-γ, TNF-α, and TGF-β1) and general blood/urinary parameters were in normal range (Table S2), but not significant correlation with symptoms scales.
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SNT Gatchaman · Feb 10, 2024

Sub-types of fatigue were scored in mKCFQ11 (physical: 46.9 ± 7.2 and mental: 25.1 ± 6.3), MFI-20 (physical: 42.0 ± 6.9 and mental: 25.8 ± 5.2), and SF-12 (physical: 47.6 ± 18.7 and mental: 46.2 ± 16.3) (Table S2). As unexpected, significant correlations were indicated between cortisol levels and mental fatigue in mKCFQ11 (R-squared -0.199, p < 0.05), whereas cortisol was significantly correlated with physical sub-type in both MFI-20 (R-squared -0.296, p < 0.01) and SF-12 (R-squared -0.250, p < 0.05) (Fig. 4A to F).
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SNT Gatchaman · Feb 10, 2024

I think those outliers are doing a lot of heavy lifting for the correlation. As usual cortisol doesn't seem particularly helpful.

Distinguishing features of Long COVID identified through immune profiling (2023, Nature) had said —

Participants with LC from two sites had significantly decreased systemic cortisol levels; this remained significant after accounting for variations in demographics and sample-collection times. Notably, the decreased cortisol did not associate with a compensatory increase in ACTH levels, suggesting that the hypothalamic–pituitary axis response to regulate cortisol may be inappropriately blunted.
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Hutan · Feb 10, 2024

The average of cortisol levels was 124.7 ± 41.2 ng/mL in plasma of long-COVID subjects, which is higher than known range of healthy controls generally. It was significantly higher in male (139.3 ± 53.7 ng/mL) than in female (116.5 ± 29.3 ng/mL) (p < 0.05).
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Yeah, so the more common claim (as exemplified in that 2023 Nature paper SNT quoted above) is that cortisol is slightly lower in LC and ME/CFS compared to healthy controls. And yet, in this one they report higher levels than normal. But they didn't have healthy controls, so maybe the supposedly higher cortisol was just the product of a bias in the analysis.

I'm not even sure that the average levels the authors report really are 'higher than the known range of healthy controls generally'. See this, for example, from the NIH:

Normal serum levels of cortisol vary on a diurnal cycle from 30 to 140 ng/ml (100 to 500 nM), peaking in early morning.
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If the techniques are the same, and it is a morning sample, then the reported levels aren't high.

Among the laboratory tests, plasma cortisol levels had a significant negative correlation with fatigue scores and a positive correlation with living quality
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.
I agree, those charts shown in post 6 suggest that the claim of a negative correlation between cortisol with fatigue is simply an artefact of those few outliers.

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