Epidemiological and clinical factors associated with post-exertional malaise severity in patients with ME/CFS. Ghali et al. 2020

[John Mac]

Background
Post-exertional malaise (PEM), the cardinal feature of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), occurs generally after exposure to a stressor. It is characterized by the worsening of ME/CFS symptoms and results in aggravating the course of the disease and the quality of life of patients. Due to its unpredictable onset, severity, and recovery time, identifying patients with higher risk for severe PEM would allow preventing or reducing its occurrence. We thus aimed at defining possible factors that could be associated with PEM severity.

Methods
Adult patients fulfilling ME international consensus criteria who attended the internal medicine department of University hospital Angers-France between October 2011 and December 2019 were included retrospectively. All patients were systematically hospitalized for an etiological workup and overall assessment. We reviewed their medical records for data related to the assessment: epidemiological data, fatigue features, clinical manifestations, and ME/CFS precipitants. PEM severity was appreciated by the Center for Disease Control self-reported questionnaire. The study population was classified into quartiles according to PEM severity scores. Analyses were performed with ordinal logistic regression to compare quartile groups.

Results
197 patients were included. PEM severity was found to be positively associated with age at disease onset ≥ 32 years (OR 1.8 [95% CI 1.1–3.0] (p = 0.03)), recurrent infections during the course of the disease (OR 2.1 [95% CI 1.2–3.7] (p = 0.009)), and when ME/CFS was elicited by a gastrointestinal infectious precipitant (OR 5.7 [1.7–19.3] (p = 0.006)).

Conclusion
We identified some epidemiological and clinical features, which were positively associated with PEM severity in subsets of ME/CFS patients. This could help improving disease management and patients’ quality of life.

https://translational-medicine.biomedcentral.com/articles/10.1186/s12967-020-02419-4

 

[rvallee]

Smart study by people who seem to understand the nature of the illness.

After adjustment for previously identified variables associated with PEM severity (age at disease onset and susceptibility to viral infections, Table 2), and non-infectious precipitants, gastrointestinal (GI) infectious precipitants were strongly associated with PEM severity (OR 5.7 [1.7–19.3] (p = 0.006)) (Table 4). PEM severity groups Q2, Q3 and Q4 differed from the reference group Q1.

The enteroviral trigger has been subject of much discussion, especially lately. What it looks like is that enteric origin may be a higher risk factor but is not necessary. It also shows the difficulty, basically the same as with COVID-19, that the infections can only be categorized under Influenza-like, i.e. flu-like, because it's impossible to tell one apart from the other in individual cases based on symptoms alone.

PEM was divided into 4 quartiles and is distributed as such:

Mild: 23 (11.7%)
Moderate: 74 (37.6%)
Severe: 73 (37.1%)
Very severe: 27 (13.7)​

Anyone tried the CDC questionnaire?

PEM severity was assessed in all patients by the standardized CDC SI self-reported questionnaire

This plainly suggests PEM is a much more reliable assessment than fatigue, something obvious but dismissed by our BPS overlords, especially the last part:

Fatigue assessment showed high median levels of reported fatigue in the whole population with no significant difference between quartiles. This could be explained by the subjective nature of fatigue and the fact that current available fatigue scales would not accurately reflect fatigue severity in chronic fatigue patients [23].

The first finding of our study is that older age at onset, ≥ 32 years, was positively associated with PEM severity. To the best of our knowledge, the influence of age at ME/CFS onset on PEM severity was not reported before.

Technically incorrect in that it has been known for a long time that youth offers better outcomes for recovery, but somehow the conclusions arising from that fact did not consider the other side of the coin.

The association of recurrent viral infections with severe PEM led us to examine ME/CFS precipitants in our study population, especially infectious precipitants. Amongst the different ME/CFS precipitants, only GI precipitants were associated with more severe PEM (OR 5.7 [1.7–19.3] (p = 0.006)), as shown by an adjusted analysis. A recent study including a large cohort of patients observed an association between all types of GI infections and CFS [38]. Giardia lamblia gastritis [39], gastroenteritis [2], chronic intestinal candidiasis [40], and enteroviruses [41], especially coxsackie viruses [42], were reported to have a causative role in triggering CFS.

This suggests that significant harm will arise out of the current attempts to psychologize IBS, as GI infections present a higher risk of ME. The interaction between invading pathogens and the enteric microbiome may be quite relevant here.

Mucosal barrier dysfunction and an increase in gut permeability were reported in ME/CFS resulting in bacterial translocation and consequently a rise in serum endotoxin concentrations, which leads to triggering the immune response [43]. Intestinal microbiota is also found to be altered in ME/CFS patients and thus could contribute to ME/CFS symptoms via increased LPS translocation from gram-negative enterobacteria [44].

Lots of talks over the years of "leaky gut", perhaps a less formal term for something that needs further research. Circulating bacteria have been found in the blood of ME patients following exertion challenges, this may explain their origin.

GI manifestations are common in ME/CFS and many patients report a previous diagnosis of IBS [45]. Interestingly, both ME/CFS and IBS are sharing many similarities. They may follow bacterial and parasite-induced gastroenteritis, as well as viral disease [39], and gut dysbiosis was reported in both conditions [12]. ME/CFS patients with comorbid IBS may constitute a distinct ME/CFS subgroup, characterized by more severe fatigue and GI symptoms [44]. Dysbiosis could thus trigger autoimmunity, which in turn might be responsible for mitochondrial dysfunction identified as having a role not only in PEM pathophysiology [12, 13], but also in terms of PEM severity as we have recently demonstrated [14].

Consequently, ME/CFS-related GI anomalies could explain increasing PEM severity observed in patients in whom the disease onset was preceded by the occurrence of GI infection.

Every time I see discussions of GI symptoms in ME I can't help but think of Peter White's outraged reaction at the suggestion that GI symptoms were common in ME, something that in his opinion, as one of the foremost experts on CFS, is simply not true. This was in response to pleas for the 2007 NICE committee to include them. White was wrong. White is always wrong.

Accordingly, this will allow adapting and individualizing the disease management, especially in the absence of curative treatment. Hence older patients should be advised to adhere more strictly to pacing strategies, and specific measures against infections together with pacing should be recommended for those who display recurrent and/or persistent infections. The aim is to prevent PEM occurrence, or at least reducing its severity, to help improving disease course and patients’ quality of life.

No GET. No CBT. They are literally the worst possible advice.

It's refreshing to see research exploring symptoms by people who know their stuff. Hopefully larger studies give us better information and more reliable findings.

 

[ME/CFS Skeptic]

There were only 11 patients with a gastrointestinal infectious onset, so not sure if this is a robust finding.

The most interesting finding is probably that fatigue scores were similar among the PEM severity groups. That seems to show that these are independent constructs.

 

[Ravn]

PEM studies always catch my attention, especially ones that give a very good description of PEM in the introduction like this one does (it also uses an ICC cohort so all patients should by definition experience PEM).We sure need to know much, much more about PEM, how to identify and measure it, and what its relevance and implications really are.

Yet reading through this study the main take-away is that we also need much, much better instruments to study PEM.

PEM severity over the past month was assessed by means of the PEM item from the standardized self-reported questionnaire of Center for Disease Control and Prevention Symptom Inventory (CDC SI) [20]. Perceived frequency of PEM was rated on a 4-point scale (1 = a little of the time, 2 = some of the time, 3 = most of time, 4 = all of the time), and its intensity was measured on a 3-point scale (1 = mild, 2 = moderate, 3 = severe). The intensity score was converted into equidistant score (0 = symptom not reported, 1 = mild, 2.5 = moderate, 4 = severe). The frequency and intensity scores were then multiplied to create the PEM severity score ranging from 0 to 16.

1) So they used the "PEM item from the standardized self-reported questionnaire of Center for Disease Control and Prevention Symptom Inventory (CDC SI) [20]." The reference [20] is this paper: https://pophealthmetrics.biomedcentral.com/articles/10.1186/1478-7954-3-8 which discusses the "CDC CFS Symptom Inventory" which mentions "unusual fatigue after exertion" (table 2) amongst a whole raft of other symptoms like sore throat and unrefreshing sleep. It seems to be primarily designed to ascertain whether you have CFS, not whether you have PEM. In fact, there's no actual mention of PEM in this referenced study so I don't understand what the "PEM item" in the present study is supposed to be, the whole questionnaire or just the item "unusual fatigue after exertion"? Looking at the scoring section, the latter - "unusual fatigue after exertion" - appears to be the most likely. If so, I'm sorry but "unusual fatigue after exertion" ain't no measure of PEM, not by itself anyway. Which the authors know very well going by how they describe PEM in the intro - so why use "unusual fatigue after exertion" as a measure of PEM (if I haven't misunderstood something)?

2) They only asked about the last month, and they only asked about frequency and severity of PEM. One month is surely too short a period to assess frequency - or anything much, really - and they completely fail to take into account the impact of pacing on frequency and severity of PEM despite the fact that they discuss patients using pacing to reduce PEM.

3) Importantly they fail to investigate how much/little exertion is needed to set off PEM. Or if there's a link between the level of overexertion and the severity of PEM.

Infections were reported to be one of the PEM stressors [10, 12], therefore recurrent infections will result in more frequent and severe PEM and worsening of ME/CFS baseline symptoms.

Not sure about this one. How do you decide whether your symptoms are those of an infection or of PEM? Do you simply have an infection or do you first have an infection which then sets off PEM? My personal sense is that infection and PEM are separate phenomena but that having an infection lowers PEM threshold, i.e. it takes less exertion to set off PEM when also having an infection. But it's hard to disentangle given that both infections and PEM present with flu-like malaise.

PEM severity was assessed in all patients by the standardized CDC SI self-reported questionnaire [20], which is a reliable and valid instrument for assessing symptoms associated with CFS including PEM, and one of the two tools proposed by the IOM for PEM assessment [4].

The second of the two tools proposed by the IOM for PEM assessment is the De Paul symptom questionnaire*. I wonder why they didn't use that? Unlike the CDC SI self-reported questionnaire it was specifically designed for PEM though it still doesn't account for the impact of pacing, nor assesses the amount of exertion that leads to PEM.

*https://www.leonardjason.com/wp-con...st-Exertional-Malaise-Questionnaire-DPEMQ.pdf

And the CDC SI self-reported questionnaire can be downloaded here: https://www.cdc.gov/me-cfs/pdfs/symptom-inventory-questionnaire-508.pdf

Is this something we could do better as a patient group? Many of the patient associations have good descriptive information on PEM but there don't seem to be any better scales than the two above to use in research.

ETA: Fixed plural of phenomenon (= phenomena). I do hope that once we find a cure for ME that the brain fog at least is reversible. I would really like to have my former command of language back!

Moderator note: This post has been copied and the following discussion of PEM has been moved to a new thread:
Defining and Measuring Post-Exertional Malaise - a discussion

 

[dave30th]

The most interesting finding is probably that fatigue scores were similar among the PEM severity groups. That seems to show that these are independent constructs.

yes, that's a useful finding.

 

[Hoopoe]

Maybe the lack of correlation between fatigue and PEM is because fatigue questionnaires are useless for measuring absolute fatigue.