Physical, cognitive, & social triggers of symptom fluctuations in people living with long COVID: an intensive longitudinal cohort study,2024,Greenwood

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https://www.thelancet.com/journals/lanepe/article/PIIS2666-7762(24)00249-7/fulltext

Articles Volume 46 101082 November 2024 Open access

Physical, cognitive, and social triggers of symptom fluctuations in people living with long COVID: an intensive longitudinal cohort study

Darren C. Greenwood,a,b,u,∗ Maedeh Mansoubi,c,d,e,u Nawar D. Bakerly,f Aishwarya Bhatia,d Johnny Collett,g Helen E. Davies,h Joanna Dawes,d,i Brendan Delaney,j Leisle Ezekiel,k Phaedra Leveridge,e Ghazala Mir,l Willie Muhlhausen,m Clare Rayner,n Flo Read,o Janet T. Scott,p,q Manoj Sivan,r Ian Tucker–Bell,n Himanshu Vashisht,m Tomás Ward,s Daryl B. O’Connor,t and Helen Dawes,c,d,e for the LOCOMOTION consortiumv

Summary

Background
Symptom fluctuations within and between individuals with long COVID are widely reported, but the extent to which severity varies following different types of activity and levels of exertion, and the timing of symptoms and recovery, have not previously been quantified. We aimed to characterise timing, severity, and nature of symptom fluctuations in response to effortful physical, social and cognitive activities, using Ecological Momentary Assessments.

Methods
We recorded activity, effort, and severity of 8 core symptoms every 3 h for up to 24 days, in cohorts from both clinic and community settings. Symptom severities were jointly modelled using autoregressive and moving average processes.

Findings
Consent was received from 376 participants providing ≥1 week's measurements (273 clinic-based, 103 community-based). Severity of all symptoms was elevated 30 min after all categories of activity. Increased effort was associated with increased symptom severity. Fatigue severity scores increased by 1.8/10 (95% CI: 1.6–1.9) following the highest physical exertions and by 1.5 (1.4–1.7) following cognitive efforts. There was evidence of only mild delayed fatigue 3 h (0.3, 0.2–0.5) or one day later (0.2, 0.0– 0.5). Fatigue severity increased as the day progressed (1.4, 1.0–1.7), and cognitive dysfunction was 0.2 lower at weekends (0.1–0.3).

Interpretation
Cognitive, social, self-care and physical activities all triggered increased severity across every symptom, consistent with associated common pathways as potential therapeutic targets. Clear patterns of symptom fluctuations emerged that support more targeted self-management.

Funding
National Institute for Health and Care Research.

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Merged - published opinion on the paper

https://www.thelancet.com/journals/lanepe/article/PIIS2666-7762(24)00276-X/fulltext

Comment Volume 46 101109 November 2024 Open access
Physical and cognitive stressors exacerbate symptoms in long COVID: more evidence triggering new research and therapeutic needs

Danilo Buonsenso a,b,∗ and Lael M. Yonker c,d



Post-exertional malaise is not a new symptom, but the incidence has increased dramatically in recent years. A well-known symptom of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome, post-exertional malaise occurs when exercise elicits profound, lasting fatigue in affected individuals. Now, we are seeing troves of individuals with post-exertional symptoms, an unfortunate and lasting reminder of the impact of the COVID pandemic. The symptoms of long COVID, including post-exertional malaise, fluctuate and vary markedly between individuals. These symptoms have not previously been systematically measured, limiting clinicians' ability to diagnose diseases characterized by post-exertional malaise, and impacting patients’ opportunity to receive care or research interventions.

That has changed now, thanks to a paper published in The Lancet Regional Health—Europe by Greenwood and colleagues who systematically characterized timing, severity, and nature of long COVID symptom fluctuations in response to effortful physical, social and cognitive activities, using Ecological Momentary Assessments.1 They recorded activity, effort, and severity of 8 core symptoms (fatigue, pain or discomfort, dizziness, palpitations, cognitive dysfunction, anxiety and depression) every 3 h for up to 24 days in a cohort of 376 participants with long COVID, making this study the largest and most rigorous to characterize post-exertional symptoms in long COVID. Importantly, the authors demonstrated that not only physical efforts, but also cognitive, social and self-care activities all can trigger increased severity across every symptom. In particular, fatigue severity scores increased by 1.8/10 (95% CI: 1.6–1.9) following the highest physical exertions and by 1.5 (1.4–1.7) following cognitive efforts. For the most part, symptoms escalated shortly after exertion (usually by 30 min), however, in some cases, symptoms could escalate days after the activity. And not unexpectedly, the greater the effort, the worse the symptom exacerbation.

This study has important implications. First, it validates the fluctuating nature of the symptoms seen in long COVID. People with long COVID, similar to those with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome, suffer stigma due to the under recognition of their conditions from both healthcare professionals and the society, as their symptoms are frequently labeled as “functional”.2,3 While many COVID symptoms like fatigue are considered non-specific, Greenwood's study reinforces the concept that the increase/worsening of fatigue, and other symptoms, after even minor physical or cognitive efforts, is the key diagnostic clue to suspect long COVID, therefore supporting clinicians' ability to recognize and appropriately refer patients. Of note, these fluctuations of symptoms after minor efforts are also reported in children and adolescents.4

Secondly, Greenwood's study bears strong implications from a research perspective. Most of the long COVID studies are based on surveys capturing symptoms reported in days prior to survey administration,5 when individuals may have been self-regulating stimuli to minimize symptoms. As a result, most studies report no or only minor differences in persisting symptoms between long COVID patients and controls, thus fueling the erroneous concept that long COVID may be extremely rare. Greenwood's study demonstrates that studies need to take into account symptoms fluctuations and potential triggers. This raises the question: should outcomes in long COVID studies be measured at rest/baseline or after cognitive or physical exertion? Important to the success of Greenwood's study, the group benefited from input from people affected by long COVID; future studies should also elicit patient input to optimize feasibility and capture meaningful endpoints. Additionally, the observation that cognitive efforts may worsen physical and neuropsychiatric symptoms bolsters concern that the central nervous system is directly impacted by long COVID pathobiology.6

The findings from Greenwood and colleagues have strong implications for daily lives of people with long COVID as well. To avoid isolation, loss of employment, and social and educational setbacks, we advocate for patients to adapt timelines and schedules, although these recommendations can be met with skepticism and resistance by employers and schools. This study provides strong evidence that any kind of efforts may trigger clinical worsening to patients with long COVID,1 supporting our requests for adapted schedules. In fact, Greenwood and colleagues mention that their results are consistent with current recommendations.7

Research is urgently needed to define physical conditioning and limitations around long COVID, and ultimately to find effective therapeutic strategies. Avoidance of activities and daytime resting periods hold people back from fully engaging in things that they previously enjoyed, consequentially shifting career and educational goals with substantial long-term implications. With millions of people affected by long COVID, and evidence of thromboinflammation, immune dysregulation, T-cell infiltration, autoantibodies, mitochondrial dysfunction, viral persistence,8,9 well designed, ambitious interventional trials are needed now. Otherwise, patients with long COVID will continue to suffer in silence against skepticism and hold back from mental and physical exertion.

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Research in context

Evidence before this study

We searched Medline using search terms “Post-Acute COVID19 Syndrome” and “physical exertion” or “cognitive exertion”, including MeSH terms and synonyms, between 1st January 2020 and 31st March 2021, restricted to English language. We found no previous intensive longitudinal cohorts examining exertion and subsequent symptom severity. One after that date only investigated physical activity and fatigue. Most evidence for delayed symptom response was largely anecdotal.

Added value of this study

The present study is the first to quantify the immediate time of the activity, and delayed increases later that day or the following day. We have shown that these associations are much the same for physical and cognitive exertions, and extend to effortful social and self-care activities.

Implications of all the available evidence

Our findings are consistent with current symptom management advice, but underline the importance of managing all types of effortful activity, not just physical. The wide range of symptoms with associated increased severity suggest common pathways as potential therapeutic targets

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InitialConditions said:
This is quite a bizzare comment piece, given that neither of the phrases 'myalgic encephalomyeltitis', 'chronic fatigue syndrome', or 'post-exertional malaise' appears in the study.
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I should go to bed, because this has really wound me up: A whole study on symptom exacerbation/fluctuations in LC and, as far as I can tell, they've avoided any mention of ME/CFS or PEM (or related terms).
 
Methods said:
A detailed protocol for the current work has been published previously, 18 and is summarised here focusing on our primary objective of quantifying the extent to which activities predict subsequent symptoms using Ecological Momentary Assessments (EMAs).
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[18] is Digital home monitoring for capturing daily fluctuation of symptoms; a longitudinal repeated measures study: Long Covid Multi-disciplinary Consortium to Optimise Treatments and Services across the NHS a LOCOMOTION study (2023, BMJ Open)

Protocol paper said:
The primary objectives of the study are:

1. To quantify the extent to which total (per day and week) and specific (at each time point) cognitive, physical, and social activities, sleep and rest predict subsequent incidence, severity, number and duration of Long Covid symptoms, including postexertional malaise (PEM). By total activities, this project refers to the overall engagement in cognitive, physical and social activities over a given period. Specific activities encompass the individual types of cognitive, physical and social activities conducted at each specific time point.

2. To identify different groups or classes of people who respond to physical or mental effort (based on their response to questionnaires, app surveys and accelerometer result) differently in regard to PEM, other symptom incidences, duration, number and severity. Responding to physical or mental effort relates to the participant’s response or experience following engagement in activities that require physical or mental exertion. This can include fatigue, symptom exacerbation or any other subjective or objective measures of response to effort.
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Protocol paper said:
The secondary objectives of the study are to:

3. Quantify the extent to which the prevalence or severity of specific symptoms predicts subsequent activity.

4. Quantify the relationship between sleep duration and quality with Long Covid symptoms.

5. Explore the relationship between different component contributions to the overall level of physical activity (frequency, intensity, recovery, duration) and subsequent symptoms.

6. Explore the associations between different timing or degree of exposure to (cognitive, physical and social) activities in terms of cumulative exposure (eg, multiple triggers in a short space of time or repeated triggers over the day), along with the time-lagged onset of symptoms or exacerbation of symptom severity.

7. Determine the extent of the relationship between physiological variables and activity and symptom severity for different groups of activities and symptoms (substudy 1).

8. Describe the stability of the activity, symptoms and the interrelationship in people with Long Covid.

9. Describe the variability in activities, dose of activities and symptom severity.

10. Explore the moderating effects of living with physical health and/or mental health conditions (including depression and anxiety) on the relationships between the triggers and symptoms of Long Covid (as outlined in objectives 1 and 2).

11. Describe the concurrent validity of components of the home monitoring system (substudy 1).

12. Investigate usability and acceptability of home monitoring system and explore patient experiences of Long Covid (substudy 2).
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This raises the question: should outcomes in long COVID studies be measured at rest/baseline or after cognitive or physical exertion?

Both. It is the compare and contrast the provides the critical data.

Also, might have missed it, but did not see the word convalescence or similar in there. For some, maybe many, it is not going to be enough to merely scale back activity. They are going to have more-or-less cease it, at least initially, for sustained long-term benefit.
 
Seems like a pretty important paper to me. Hopefully it will lead to more studies about PEM, triggers and delays, and maybe some patients won't get their complaints about "I feel much worse x hours after doing Y" dismissed.
 
Just on the 'trial report' prefix, a response from the moderation team:

The trial report prefix is used for interventional studies, so, where a treatment has been trialled. It is fine to have no prefix, plenty of papers don't need a prefix.

We understand that there is a grey area, where the effect of activity/exercise is assessed e.g. in CPETs. The test is if the activity is trialled as a treatment.

We are considering if the prefixes need renaming to be clearer (e.g. Treatment Trial) and will make a Moderation News item to clarify the use of prefixes. If you have comments about this, you can send us a message or wait to respond to the Moderation News item.

We've removed the prefix from this thread.
 
The paper said:
Avoidance of activities and daytime resting periods hold people back from fully engaging in things that they previously enjoyed, consequentially shifting career and educational goals with substantial long-term implications
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This is minor but substantial progress. As in it is very small step, but it is a step. But they still frame it as exercise and while the editorial is far more informed about PEM than the paper, this sentence above massively understates the consequences. The disability is so much more invasive and all-encompassing than simply not being able to engaging in things we enjoy or or shifting career goals. I have no career, it ended over a decade ago. This is the norm, there are so many who are even worse than me. This is like framing the worst that can happen in a car accident as bumps and bruises.

But at least it validates everything we have been saying for decades, even if it takes great pains to minimize it. Will it matter, though? I doubt it. I have no confidence in this profession to do the right thing if it means disputing the reign of error of psychosomatic ideology. That they go to such lengths to many any mention whatsoever of ME/CFS in the paper actually emphasizes the very stigma mentioned in the editorial, which again is misleading as this is not stigma but actually blatant discrimination based on an illness state.

This is a good example of the confusion:
This study provides strong evidence that any kind of efforts may trigger clinical worsening to patients with long COVID,1 supporting our requests for adapted schedules
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They note that 'any kind of efforts', despite the paper framing that effort as exercise, but talk of adapted schedules, either missing or covering up the fact that 'any kind of efforts' goes all the way to total disability, which any kind of scheduling adaptation won't matter one damn bit. They are entirely focused on the mildest end, and still it adds up to a major disability burden for society and health care systems.

This is really all about convalescence, but just like the other elephant in the room, ME/CFS, it is completely missing from the paper itself. As much as this is better than average, it still means zero substantial progress for patients for many decades, barring a complete game-changer like a research breakthrough or, more likely sooner, AI just upending all of society and doing the work for them.
 
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