Risk factors for fatigue severity in PASC: A prospective controlled cohort study of nonhospitalised adolescents and young adults, 2025, Selvakumar MD

Mij

Mij

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Abstract
Long COVID is a global health concern, leading to persistent symptoms and disability long after the acute SARS-CoV-2 infection in most age groups. The condition can manifest even following mild COVID-19, and in young people, it may have serious adverse consequences for educational attainment and transition to adulthood. Fatigue is the most prevalent symptom, but the underlying mechanisms remain poorly understood.

In this prospective study of 404 SARS-CoV-2-positive and 105 SARS-CoV-2 negative, non-hospitalized youth (ages 12-25, female 62%), we investigated which factors in the early convalescent stage (< 28 days since test) were associated with the severity of persistent fatigue at 6 months after infection.

Participants completed questionnaires regarding clinical symptoms, social factors and psychological traits, and were subject to clinical and functional testing and biomarker analyses. Variables with significant (p <0.2) associations to the outcome in simple linear regression were chosen for multivariable modelling, together with potential confounders. In the final multivariable model, SARS-CoV-2-positivity was a minor risk factor for fatigue severity at six months. Baseline severity of symptoms was the main risk factor and correlated with psychosocial factors such as loneliness and neuroticism, rather than biomarkers.

Our results suggest that factors not related to infection are major risk factors for persistent fatigue in this age group.
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Not surprising from those authors. The LOTECA controls could also be close contacts to the covid positive participants, and even have respiratory infection symptoms as long as they did not test positive for covid-19. Despite the author team having been told repeatedly by multiple persons that antibody testing is in no way a definite way of saying someone has not had a covid-19 infection, they still seem unable to include this information in their studies.
 
I’ve pasted some of the relevant bits below. There are some arguments and in-lobby-referencing that I’ve skipped past.

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SARS-CoV-2-positive individuals were more severely fatigued compared to -negative individuals at baseline, though median severity was similar at six months. However, the distribution was right-skewed and a greater proportion of SARS-CoV-2-positive individuals had severity scores above the upper quartile (Figure 1).
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Caption: Fatigue severity assessed by the Chalder fatigue scale (Chalder, 1993), range 0-33, where higher scores imply more severe fatigue. Three participants had missing fatigue scores at baseline.

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In bivariate analyses (Figure 2, Supplemental Table S4), SARS-CoV-2 was not a risk factor of six-month fatigue severity. All baseline symptoms were strong risk factors, most notably that of fatigue (coefficient of determination (R2) 27.5%; regression coefficient (B) 0.0057, 95% confidence interval (CI) 0.0049 to 0.0066). Psychological traits were moderate risk factors, particularly neuroticism (R2 12.2%; B 0.021, CI 0.016 to 0.026) and worrying tendencies (R211.2%; B 0.00086, CI 0.00063 to 0.0011).

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Figure 2. Baseline risk factors and their univariate associations to fatigue severitya*. Caption: Linear regression. Only associations with p<0.5 are shown for brevity. Values for all variables are given in Supplemental table S5.

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In multivariable regression, the final model retained baseline symptom severity as the main risk factor (Table 2), as well as the baseline inflammatory markers interleukin (IL)-4, IL-7 and C3bc (the activation product of complement C3). SARS-CoV-2 was a significant independent variable in the final model. Post-hoc analyses showed that in models controlling for higher-order confounders only, SARS-CoV-2 status remained significant (ΔR2 0.6%; B 0.09, CI 0.003 to 0.2); p = 0.04), while IL-4, IL-7, and C3bc did not. This could imply that the latter three’s inclusion in the final multivariable model could be due to residual confounding from the symptom severity variable. In sensitivity analyses, results were comparable to those of the main analyses (Supplemental Tables S5, S6, S7 and S8).

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The main results from the present study were; (1) SARS-CoV-2 infection was a statistically significant risk factor for fatigue severity at six months, however explained only a small portion of the variance and thus was a minor risk factor(2) Symptom severity at baseline was the strongest risk factor for fatigue severity at 6 months; (3) Psychological, behavioural, and environmental factors were also associated with fatigue at 6 months.

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While the median severity [of fatigue] remains similar between groups, a greater proportion of SARS-CoV-2-positive individuals remain in the upper quartile. However, even with the use of a measure for outcome severity, infection with SARS-CoV-2 remained a minor risk factor and explains only a small fraction of the variance. Thus, although incorporating severity criteria could improve the specificity of future long COVID case definitions, our findings suggest that fatigue unrelated to infection remains a significant concern in this age group.

Baseline symptom severity, the major risk factor in the current study, interestingly correlated only weakly with SARS-CoV-2 status. Rather, it correlated with psychosocial factors not specific to infection (Supplemental Fig. S1), such as personality traits, loneliness, and recent negative life events.

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Though intriguing, it should be noted that personality traits explained a modest portion of the variance of fatigue in the present study, and thus a low score on e.g. neuroticism did not preclude persistent fatigue, nor did a high score implicate fatigue.

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As mentioned above, baseline psychosocial variables (e.g. emotional maladjustment, loneliness) and baseline symptom severity variables correlated with the outcome, but also with each other. Since both groups of variables were recorded at the same timepoint in the present study (after infection / PCR-testing), we cannot readily infer that the former are a cause of the latter.

(…)

Taken together, our study found that SARS-CoV-2 was a minor risk factor for post-COVID-19 fatigue. Baseline symptom severity was the main risk factor, and correlated with social and psychological factors, rather than markers of infection and immune activation. Our findings underscore the need for a broad, multidisciplinary approach in the research and treatment of post-COVID-19 fatigue.
 
Participants
Individuals aged 12-25 undergoing SARS-CoV-2 reverse-transcription polymerase chain reaction-testing (RT-PCR) were recruited consecutively from two accredited microbiological laboratories (Fürst Medical Laboratories and Dept. of Microbiology and Infection Control, Akershus University Hospital).

Individuals had been tested either due to symptoms, or due to being close contacts of infected individuals. The alpha (B.1.1.7) variant of SARS-CoV-2 was dominant throughout the recruitment period of December 2020 to May 2021. Individuals testing positive were eligible for enrolment after undergoing quarantine (10 days), while individuals testing negative were recruited as controls.

Exclusion criteria were: a) greater than 28 days since onset of symptoms or SARS-CoV-2 test; b) hospitalisation due to COVID-19; c) pregnancy; d) serological evidence of previous infection (in the SARS-CoV-2-negative group).
 
One thing that stands out to me is the fact that they recruited the control group from patients that had taken a PCR test and tested negative. A fair share of them presumably had symptoms that made them take the test in the first place. They did not recruit controls and made them take a PCR test - it was the other way around.

It is therefore not surprising that non-infection-related variables correlated with symptom severity, because some of them had symptoms that wasn’t caused by an infection!

Another thing that I can’t remember that they mention is the fact that they didn’t know the pre-infection symptoms of the positive participants. The symptoms are not post-covid-symptoms if they existed before the infection, so it is no wonder that some of the correlated with non-infection-related variables.

Because of these factors, I’m unsure about how much a study with this design can tell us.
 
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Variables with significant (p <0.2) associations to the outcome

That is not what I understand to be the threshold for (statistically) significant.

Utsikt said:
Because of these factors, I’m unsure about how much a study with this design can tell us.
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About the purported aims of the study? Very little. About the competence and integrity of the authors of the study? Possibly quite a bit.
 
Full title of paper, Risk factors for fatigue severity in the post-COVID-19 condition: A prospective controlled cohort study of nonhospitalised adolescents and young adults
 
Midnattsol said:
I do like rain cloud plots though
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Yes it's quite helpful to see the distribution of fatigue scores. The mean was no different between groups: both around 13 which is rather low for the Chalder Fatigue Scale (0-33). In comparison participants of the PACE trial had a score near 28.

But the Sars-Cov-2 positives seem to have higher proportion with substantial fatigue scores. Would perhaps be more interesting to focus on this group, for example using a CFQ threshold of 20.
 
This study is a further analysis of the following work:
Prevalence and predictors of long COVID among non-hospitalised adolescents and young adults: a prospective controlled cohort study.
That study has been discussed at length on the other thread.

The title with "PASC" is of course somewhat obscure given according to their own work 50% of people here have "PASC" (which of course does not consitute a meaningful definition) and that authors have at the same time criticised the vagueness of the WHO criteria themselves but are keen to apply it whenever it fits, but most prominently they don't even seem to be using any definition of PASC here in this study at all. I think everyone agrees that meaningless definitions in this context remain meaningless. The authors show that if you have fatigue you are more likely to have fatigue a couple of months later. If you were to want to meaningfully study PASC you would probably want to know what happens in people that have no fatigue and suddenly develop very severe fatigue.

Apart from what ME/CFS Skeptic mentions above these results are also what you would expect if for example your cohort is driven by pre-existing medical conditions (it seems some comorbidities, but seemingly not all for example autoimmune diseases, were assessed by questionnaires but none seem to have been assessed by medical exams) which seemingly were not ruled out in the study.
 
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