Prevalence and predictors of long COVID among non-hospitalised adolescents and young adults: a prospective controlled cohort study, 2022, Wyller et al

[Dolphin]

Link to post with link to published paper

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Preprint:
https://assets.researchsquare.com/f...-4a36-49f7-9a59-b63be81a30c2.pdf?c=1663177822

Prevalence and predictors of long COVID among non-hospitalised adolescents and young adults: a prospective controlled cohort study

Vegard Wyller (v.b.b.wyller@medisin.uio.no)
University of Oslo

Joel Selvakumar
Akershus University Hospital
https://orcid.org/0000-0002-9970-8011

Lise Havdal
Akershus University Hospital

Martin Drevvatne
University of Oslo

Elias Brodwall
University of Oslo

Lise Berven
University of Oslo

Tonje Stiansen-Sonerud
Akershus University Hospital

Gunnar Einvik
University of Oslo

Truls Leegaard
University of Oslo

Trygve Tjade
Fürst Medical Laboratory

Annika Michelsen
University of Oslo

Tom Mollnes
Rikshospitalet University Hospital

Fridtjof Lund-Johansen
Univ of Oslo and Oslo Univ Hospital
https://orcid.org/0000-0002-2445-1258

Trygve Holmøy
University of Oslo

Henrik Zetterberg
University of Gothenburg
https://orcid.org/0000-0003-3930-4354

Kaj Blennow
University of Gothenburg
https://orcid.org/0000-0002-1890-4193

Carolina Sandler
Western Sydney University

Erin Cvejic
The University of Sydney

Andrew Lloyd
Kirby Institute for Infection and Immunity
https://orcid.org/0000-0001-6277-8887

Article
Keywords: Long COVID, post-COVID-19 condition, post-acute sequelae of COVID-19, adolescents, SARSCoV-2, post-infective fatigue syndrome
Posted Date: September 14th, 2022
DOI: https://doi.org/10.21203/rs.3.rs-2021203/v1

Abstract

The prevalence and predictors of long COVID in young people remain unresolved. We aimed to determine the point prevalence of long COVID in non-hospitalised adolescents and young adults six months after the acute infection, to determine the risk of developing long COVID adjusted for possible confounders, and to explore a broad range of potential risk factors (prespecified outcomes).

We conducted a prospective controlled cohort study of 404 SARS-CoV-2-positive and 105 SARS-CoV-2-negative nonhospitalised individuals aged 12–25 years (ClinicalTrial ID: NCT04686734). Data acquisition was completed February 2022.

Assessments included pulmonary, cardiac and cognitive functional testing, biomarker analyses, and completion of a questionnaire, and were performed at inclusion (early convalescent stage) and six months follow-up.

The WHO case definition of long COVID was applied.

The point prevalence of long COVID at six months was 49% and 47% in the SARS-CoV-2-positive and negative group, respectively. SARS-CoV-2-positivity did not predict development of long COVID (relative risk 1.06, 95% CI 0.83 to 1.37).

The main predictor was symptom severity at inclusion, which correlated strongly to personality traits.

Low physical activity and loneliness were also predictive, while biological markers were not.

In conlusion, our study aims were met, and the findings suggest that persistent symptoms were not driven by the infection, but were associated with psychosocial factors.

 

[Hutan]

In conlusion, our study aims were met, and the findings suggest that persistent symptoms were not driven by the infection, but were associated with psychosocial factors.

That typo is not Dolphin's fault, it's in the original. It's hard to work out if it was meant to be 'in conclusion, our study aims were met' or 'in collusion, our study aims were met'.

The main predictor was symptom severity at inclusion, which correlated strongly to personality traits.

This was the study aim, to reach this conclusion. We have seen at least one paper co-authored by Erin Cvejic that tortured the data to produce a similar answer - and I mean seriously tortured it, and then when it still didn't admit to what the authors wanted, they went ahead and put words in its mouth.

The point prevalence of long COVID at six months was 49% and 47% in the SARS-CoV-2-positive and negative group, respectively. SARS-CoV-2-positivity did not predict development of long COVID (relative risk 1.06, 95% CI 0.83 to 1.37).

This alone suggests that the way they implemented the definition of Long Covid was a problem. They seem to have magicked away the whole idea of Long Covid. Nothing to see here folks, just a bunch of young people making a big deal about nothing, move along.

 

[Hutan]

First point is the selection. Look at the huge drops along the way, increasing selection bias.

A total of 151,110 RT-PCR-tests of SARS-CoV-2 were carried out on individuals 12–25 years old at the collaborating microbiological laboratories during the recruitment period (Fig. 1). A total of 5,912 individuals (3.9%) were SARS-CoV-2-positive, of whom 2,251 (50% males) were invited into the study. Of this group 404 (39% males, mean age 17.8 years) were enrolled (Table 1, Supplementary Table S1). Among the SARS-CoV-2-negative individuals, a total of 105 were enrolled (35% males, mean age 17.7 years), and their negative status was conrmed by the absence of anti-nucleocapsid antibodies at baseline.

Then, the 404 Covid-19 positive group reduced to 382 at the 6 month mark. The 105 Covid-19 negative group reduced to 85 at the 6 month mark.

Second point is the criteria. Check out what they are saying is the WHO definition of Long Covid. If that is correct, then the definition is meaningless. Remember that the relatively small number of controls were tested for Covid-19 for some reason, perhaps it was because they had another medical cause for their symptoms. Also, 21% of the Covid-19 positive group had co-morbidities, while 35% of the Covid-19 negative group had co-morbidities.

Whereas case denitions of long COVID diverge and lack validation, studies of PIFS have benetted from an international case-denition13. This denition is centred around the symptom of fatigue, which should be persistent from onset of the acute infectious event, severely affect daily activities, and not be caused by any other condition; also, cases must experience at least four of eight additional symptoms (such as headache and concentration/memory problems). In contrast, the case denition of long COVID established by the World Health Organisation (WHO) encompasses any symptom, not only fatigue, occurring in the aftermath of acute COVID-19; does not require symptom persistence since the infectious event; does not stipulate exclusions of other explanatory conditions; and does not stipulate signicant disability1.

Edit to add - the supplementary material confirms that everyone was tested for Covid-19 for a reason, because of symptoms consistent with Covid-19 or exposure. So, some of the Covid-19 negative people may have had another infection challenge, or some other symptom-causing condition.

 

[Hutan]

These components, representing symptom severity and emotional maladjustment, were strongly associated with both long COVID and PIFS in bivariate regression analyses (Supplementary Table S15). Other notable risk factors for both conditions were female sex, low self-reported level of physical activity before infection, loneliness and negative life events during the preceding year. The majority of biological markers, including immunological markers and markers of CNS impairment, did not show any predictive value (Supplementary Table S15).

Okay, so that's a lovely thing, isn't it.

Additionally, loneliness and low levels of physical activity predicted long COVID.

Loneliness is made to be quite a big thing- it gets mentioned in the abstract.
If we go to the actual finding, here it is. The relative risk of having "WHO defined Long Covid" (i.e. the authors tell us that that is at least one symptom persisting after Covid-19) is 1.00 if you aren't lonely and 1.00 to 1.02 if you are lonely. The gap at the right is because loneliness didn't turn out to be relevant to the risk of Post-Infective Fatigue Syndrome, the other definition they looked at.



So, the risk of getting "WHO defined Long Covid" was about 48%. The risk of getting WHO defined Long Covid if you were lonely was 48% to 48.96% - according to the study with the relatively small number of controls. And this is a result worth presenting? Of course if someone is lonely, they might make a little more of a symptom, because they have to cope on their own. I'm surprised there isn't a bigger result. But to claim loneliness is predictive of Long Covid from this is silly.



Here's another result. 'Negative life events prior to last year' didn't turn out to be relevant at all to whether someone had WHO-defined Long Covid. But look, a higher score on the 'negative life events prior to last year' was protective against post-infective fatigue syndrome!! 60 young people were assessed as meeting the criteria for PIFS, out of a total of 464. That's about 13%. But the young people who had experienced negative life events prior to last year had a lower rate of around 11.6%. So, should we be ensuring that all young people have negative life events, so that they are protected from PIFS? But wait? How does this fit with the idea that all people with PIFS have suffered child abuse, or was it sexual abuse, or sexual harassment... And where are the figures in this study for 'Negative life events in the last year' which surely must have been measured - could it be that they had no effect on PIFS or WHO-defined Long Covid at all?

Could it be that a lot of this is just psychosocial researchers grasping at the noise in the data that suits them and ignoring the noise in the data that doesn't suit them?

Also, the results from the present study question the utility of the WHO-denition of long COVID, and suggests that a modication of existing PIFS denitions may be more useful.

That is from the discussion, and I don't disagree with it if the WHO definition is as these authors have presented it. But, my, there's a lot of very nasty stuff in that discussion. The things that we have come to expect like, and I'm of course paraphrasing, 'we aren't saying these young people don't have a real problem, it's just that we can fix their problems with behavioural approaches'.

Lots more that could be said.

 

[Hutan]

@dave30th - there's happy hunting ground here.

 

[Hutan]

Furthermore, certain dimensions of fatigue (e.g. post-exertional malaise) were more common in the SARS-CoV-2-positive group. These observations suggest that further analysis of the phenomenon of fatigue following COVID- 19 might be of value.

I went to see what the prevalence of post-exertional malaise was, and found the Supplementary Table S11. These are the 'Fatigue and post-exertional malaise' symptoms that were assessed. PEM isn't even there. There are actually quite big differences in the percentage of people reporting fatigue depending on Covid-19 status. I'm not surprised to see no difference for unrefreshing sleep - it's such a vague term, it should be got rid of in ME/CFS criteria I think.

They did assess for PEM using the De Paul Symptom Questionnaire at baseline. It was not very predictive - there was a risk score 1.01 for WHO defined Long Covid and 1.04 for PIFS (P values indicated significance). (I would like to point out that, although not very good, it was a better predictor of PIFS than loneliness was of WHO defined Long Covid - and yet it wasn't mentioned in the abstract.)

Also, vaccination against COVID-19 did not appear to be a protective factor against prolonged illness, in contrast to previous reports7

Risk ratios (95% confidence intervals) for WHO-defined Long Covid and PIFS

That one is interesting.

The 95% confidence intervals are very large and so are the P values, so there's almost certainly nothing to it, but the data suggest that having one or more vaccinations was not protective for PIFS. If the risk of PIFS at 6 months was say 13%, then the risk of having PIFS having had one or more vaccinations was 33%. It's an indication that there is so much noise in this data that there are few worthwhile conclusions to draw from it, but there is no hint there that vaccinations are preventing the development of PIFS.

Edit: The supplementary table says, with respect to the vaccination data,

Received vaccination against COVID-19 (number of dosages, manufacturer; only asked at follow-up)

It's possible that the data is confounded by the collection time being at the 6 month followup. It's not clear if the responses included vaccinations received post-baseline.

 

[Hutan]

Participants who met criteria for fatigue caseness at six months (Chalder Fatigue Questionnaire total sum score ≥ 4, bimodal (0-0-1-1) scoring of single items, cf. paragraph 1.6 below) were recalled for a second follow-up investigation at 12 months. The present paper reports data from baseline and six months follow-up only.

Oh, joy, there is more to come. And they did fMRIs and a qualitative studying hope.

And this is yet to come too:

A computerised test of attention bias towards illness-related words were implemented as described by Hughes and co-workers.10 This test measured reaction times to illness-related words and neutral word pairs; faster reaction times to probes replacing (appearing in the location of) illness-related words relative to probes replacing neutral words indicate an attentional bias. Results from the attention bias test is not reported in the present paper.

and this:

The computerised Function Acquisition Speed Test (FAST) of cognitive fusion (ie., to what extent behaviour is overly regulated by thoughts and perceptions rather than external contextual clues) was implemented as described by O’Reilly and co-workers.11 The FAST assesses the differential rate at which relations between classes of words are acquired in two differing training configurations. Results are not reported in the present paper.

 

[Hutan]

What's the criteria used for post-infection fatigue syndrome?

Fukuda, K. et al. The chronic fatigue syndrome: a comprehensive approach to its denition and study. International Chronic Fatigue Syndrome Study Group. Ann. Intern. Med. 121, 953–959 (1994).

So, yeah.

The authors say that they are willing to make the data available to researchers. I'm not sure yet, but PEM data may have been collected at the 6 month mark, so an analysis could be made of people meeting a modern ME/CFS criteria. If anyone is up for it, I'd love to be involved.

 

[Sid]

The point prevalence of long COVID at six months was 49% and 47%

GTFOOH. This study is utter nonsense.

 

[SNT Gatchaman]

So, some of the Covid-19 negative people may have had another infection challenge, or some other symptom-causing condition.

Also there's a high likelihood of control group contamination - which seems to have been a bugbear through much of this pandemic, starting with the infamous French JAMA paper.

This paper looks to have used PCR, but it's been established that seronegativity (sub-) acutely is more associated with long COVID, with later demonstration of prior infection via non-routine T cell interrogation.

The objective was to set up a T-cell based assay to determine evidence of previous SARS-CoV-2 infection in patients with symptoms in keeping with Long COVID but were seronegative for both anti-Spike and anti-Nucleocapsid IgG.

We identified that 42–53% of patients with Long COVID, but without detectable SARS-CoV-2 antibodies, nonetheless have detectable SARS-CoV-2 specific T cell responses.

Our findings are consistent with other coronaviruses where cellular immunity is also important. T cell responses were detectable >10 years after infection with SARS-CoV-1 despite undetectable IgG in 2/23 patients, suggesting that with the passage of time, T cell-based assays such as our fluorospot approach are more effective and sensitive than antibody serology.

 

[Sean]

Could it be that a lot of this is just psychosocial researchers grasping at the noise in the data that suits them and ignoring the noise in the data that doesn't suit them?

Par excellence.

 

[ME/CFS Skeptic]

Do they really think that half of all young people who got infected with sars cov-2, developed Long Covid? Or am i misunderstanding something in the abstract?

 

[Hutan]

And half of all young people who didn't get infected with sars cov-2 (notwithstanding @SNTGatchaman's good point) also developed "Long Covid".

Partly these authors are using that to make the point that Long Covid isn't that bad and isn't immunological, which is rubbish. But they are also making the point that the WHO Long Covid definition is overstating the prevalence of Long Covid, which is right because someone with a single symptom of altered taste, or headaches qualifies.

This is the WHO definition:
https://www.who.int/publications/i/...-19_condition-Clinical_case_definition-2021.1

Post COVID-19 condition occurs in individuals with a history of probable or confirmed SARS- CoV-2 infection, usually 3 months from the onset of COVID-19 with symptoms that last for at least 2 months and cannot be explained by an alternative diagnosis. Common symptoms include fatigue, shortness of breath, cognitive dysfunction but also others* and generally have an impact on everyday functioning. Symptoms may be new onset following initial recovery from an acute COVID-19 episode or persist from the initial illness. Symptoms may also fluctuate or relapse over time. A separate definition may be applicable for children.
There is no minimal number of symptoms required for the diagnosis; though symptoms involving different organs systems and clusters have been described.
*A full list of described symptoms included in the surveys can be found in Annexes 2 .

 

[Sly Saint]

Vegard Wyller

Paul Garners chum
https://www.s4me.info/threads/event...ous-diseases-8th-sept-2022.29173/#post-436199

 

[Sid]

Do they really think that half of all young people who got infected with sars cov-2, developed Long Covid? Or am i misunderstanding something in the abstract?

I keep thinking I must be misinterpreting it because there's no way in hell something so absurd would pass peer review. But then again, as we've seen before, anything goes when it comes to publishing research that makes ME/CFS patients look stupid or insane.

 

[rvallee]

The point prevalence of long COVID at six months was 49% and 47% in the SARS-CoV-2-positive and negative group

That's obviously absurd. I keep seeing absurd numbers like that in BPS land that completely fly in the face of reason, like claims that 1/5 of the population has an anxiety disorder or 10% of the population has severe clinical depression. Those numbers are obviously wrong, and yet somehow it's normal and good to massively exaggerate prevalence because otherwise it's "stigmatizing" to mental health? What nonsense.

Somehow this is actually even lower quality than usual. As if personality traits are a reliable thing, and somehow taking the normal logic entirely on its head: yes, there is a common factor to all, horsies, but no, it's not significant, what is is clearly those coconuts-clopping people in the corner over there.

Like PACE, this is a cruise ship of a "study". Not an exploration vessel, it's a leisure cruise that had its destination pre-planned.

 

[Hutan]

I keep thinking I must be misinterpreting it because there's no way in hell something so absurd would pass peer review. But then again, as we've seen before, anything goes when it comes to publishing research that makes ME/CFS patients look stupid or insane.

I keep seeing absurd numbers like that in BPS land that completely fly in the face of reason,

They aren't just claiming these type of numbers for Long Covid:

Post- infective fatigue states may occur in the aftermath of a diverse array of infections9–12. Across multiple prospective cohort studies, almost one half of the subjects report post-infective fatigue states six months after the infectious event, and 10–15% suffer from moderate to severe disability meeting diagnostic criteria for a post-infective fatigue syndrome (PIFS), in line with current studies of long COVID 9–11.

9. Hanevik, K. et al. Irritable bowel syndrome and chronic fatigue 6 years after giardia infection: a controlled prospective cohort study. Clin. Infect. Dis. Off. Publ. Infect. Dis. Soc. Am. 59, 1394–1400 (2014).

10. Hickie, I. et al. Post-infective and chronic fatigue syndromes precipitated by viral and non-viral pathogens: prospective cohort study. BMJ 333, 575 (2006).

11.Pedersen, M. et al. Predictors of chronic fatigue in adolescents six months after acute Epstein-Barr virus infection: A prospective cohort study. Brain. Behav. Immun. 75, 94–100 (2019).

I haven't looked at those references, but I find it hard to believe that half of everyone who gets e.g. glandular fever has a 'post-infective fatigue state' 6 months after. There does seem to be quite a bit of evidence for around 10% to have something like ME/CFS 6 months after the top of infections that seem to be ME/CFS triggers though.

 

[Hutan]

As if personality traits are a reliable thing

Indeed. As I've commented before, my first pre-ME/CFS Myers-Briggs rating was a gratifying thing with wisdom and other good stuff. My second go, post-ME/CFS, turned out to be something like a cheerleader. Make of that what you will.

Assessments of anxiety and depression came from HADS surveys, which we know overstate mental health issues for people with physical illness.

Depression and anxiety symptoms

Hospital Anxiety and Depression Symptoms (HADS)

A total of 14 items addressed different symptoms of depression and anxiety on 4-point Likert scales scored 0 – 3; for eight of the items, scoring were reversed, after which total sum score was computed ranging from 0 to 42, where higher scores indicate more symptoms of depression and anxiety.23 Accordingly, separate indexes for depression and anxiety were computed as sum scores across relevant items (seven each).

Here's the huge number of measures that potentially could contribute to a suggestion of emotional maladjustment. So many opportunities for cherry picking - it would be interesting to go through each and work out what they latched on to and what they didn't.

Negative affect
Positive and Negative Affect Schedule, short-form (PANAS-SF)
A total of five items addressing negative affects (shameful, anxious, nervous, hostile, offended) on 5-point Likert scales, where 1 is “disagree completely” and 5 is “agree completely”; total sum score was computed ranging from 5-25, where higher scores indicate more negative affects.24

Illness perception
Brief Illness Perception Questionnaire (BPIQ)
A total of eight items addressing perceived impact of acute COVID-19 were scored on 10-point Likert scale scored 1 – 10; total sum score was computed ranging from 8 to 80, where higher scores indicate more perceived impact.25 Due to a mistake in the questionnaire design process, we did not apply the original scoring procedure as proposed by Broadbent et al., which is based on 11-point Likert scales. At follow-up, the questions were slightly rephrased in order to address ‘symptoms following COVID-19’.

Quality of life
Pediatric Quality of Life (PedsQL)
A total of 23 items addressing different aspects of quality of life (QoL) were scored on 5-point Likert scales where 0 is “never” and 4 is “almost always”; scores were multiplied with 25 to get a 100 point scale and then averaged across all items, implying that higher scores indicate better QoL.26 In addition, separate indexes for four QoL subdomains (health related, emotional, social, school) were computed as average scores across relevant items. In order to fit the age span of the participants in the present study, a few items were slightly rephrased; for instance, “school” was substituted with “school/work”.

Interoceptive attention
Body Vigilance Scale (BVS)
A total of four items addressing interoceptive phenomena were scored on 11-point Likert scales.27 One of the items asks the respondent to indicate percent of time (from 0 to 100) spent on monitoring internal bodily states; scores were divided by 10 to obtain a 0–10 point scoring scale. Another item asks the respondent to score the amount of attention directed towards a total of 14 different bodily sensations; answers were averaged across all these sensations. Finally, a total sum score across the four items were computed ranging from 0 to 40, where higher scores imply more interoceptive attention

Miscellaneous
Not applicable
· One item addressed avoidance behavior on a 10-point Likert scale, where higher scores indicate more avoidance tendency.
· One item addressed school/work absenteeism as number of totally absent days during the last month.

Neuroticism
NEO Five-Factor Inventory-30 (NEO-FFI-30)
A total of six items making up the neuroticism axis were included and scored on 5-point Likert scales where 0 is “disagree completely” and 4 is “agree completely”; total sum score across all items were computed ranging from 0 to 24, where higher scores indicate stronger neuroticism tendencies.28

Worrying tendencies
Penn State Worry Questionnaire (PSWQ)
A total of 16 items addressing worrying tendencies were scored on 5-point Likert scales where 1 is “disagree completely” and 5 is “agree completely”; scoring were reversed on five items, after which the total sum score across all items was computed ranging from 16 to 80, where higher scores indicate stronger worrying tendencies.29

Emotional awareness
Toronto Alexithymia Scale (TAS-20)
A total of seven items making up the index of Difficult identifying feelings were included and scored on 5-point Likert scales where 1 is “disagree completely” and 5 is “agree completely”; total sum score was computed across all items ranging from 7 to 49, where higher scores indicate poorer emotional awareness (ie. more difficulties identifying feelings).30

Loneliness
UCLA Loneliness Scale
A total of 20 items addressing loneliness were scored on 4-point Likert scales where 1 is “never” and 4 is “always”; scorings were reversed on nine items, after which the total sum score was computed ranging from 20 to 80, where higher scores indicate more loneliness.31

Self-efficacy
General Self-Efficacy Scale, short form (GSE-6)
A total of six items addressing self-efficacy was scored on 4-point Likert scales where 1 is “disagree completely” and 4 is “agree completely”; total sum across all items was computed ranging from 6 to 24, where higher scores indicate better self-efficacy.32

Life events
Life Events Checklist (LEC)
A total of 48 prespecified life events were presented; for each of them, and the respondents were expected to indicate whether they had encountered the specific event during the last year, and if so, whether they considered the event to be good or bad and assess its subjective impact on a 4-point Likert scale where 0 is “no impact” and 3 is “large impact”.33 Also, the respondents were allowed to list additional events. Finally, an identical procedure was undertaken for events having occurred any time in the past. Number of positive and negative life events were computed separately for ‘last year’ and ‘any time in the past’; accordingly, sum scores for subjective impact were computed.

Miscellaneous
Child-Adolescent Perfectionism Scale (CAPS); Highly Sensitive Person Scale (HSP); Parenting Dimension Inventory (PDI).
· One item (“Others always expect me to be perfect”) was picked from the CAPS inventory in order to address socially prescribed perfectionism; the item is scored on a 5-point Likert scale where 1 is “disagree completely” and 5 is “agree completely”.34
· Two items were included from the HSP: Startling tendencies and tendencies to be affected by other people’s emotions.35 Both items were scored on 5-point Likert scales where 1 is “disagree completely” and 5 is “agree completely”.
· Two items were included from the PDI, both addressing parental control.36 They were scored on 4-point Likert scales where 1 is “disagree completely” and 5 is “agree completely”.
· A total of four self-invented items addressing interoceptive awareness and positive expectancies were included; all were scored on 5-point Likert scales where 1 is “disagree completely” and 5 is “agree completely.

Re the unreliability of these, for example, the NEO Five-Factor Inventory-30 (NEO-FFI-30) which was used to assess neuroticism has been found to be influenced, specifically the neuroticism and extraversion measures, by brief priming for happy or sad emotions at time of answering the survey. More on that here:
Personality Trait measures
If watching a 10 minute emotion inducing film and a bit of thinking sad thoughts can influence personality as measured by a survey, then what would having a debilitating illness do?

The baseline measures in this Wyller study were taken between 10 and 28 days after the Covid-19 test. I think people with lingering symptoms, especially something like changed taste or smell or cognition issues, would already be feeling worried after a few weeks of that. And, for sure, the selection bias would have contributed to people who were most concerned about their ongoing symptoms and wanting some answers being over-represented in the study.

 

[Hutan]

I've just looked at the detail of how the WHO definition of Long Covid and Fukuda for PIFS were operationalised (in the supplementary material). There's devil in the detail, but they were a bit better than I expected.

There was good screening to eliminate other obvious causes for symptoms. The Fukuda operationalism actually required an aspect of PEM to be at least occasionally present (as measured using the De Paul questionnaire) - it was not optional.

I think anyone thinking of formally commenting on this study needs to get their head around how the criteria were operationalised. And that could take some detailed poking around. For example, from memory, sleep problems turned out to be protective for PIFS, but the researchers eliminated people reporting the highest level of sleep problems from the PIFS category on the grounds that they had a primary sleep disorder.

 

[Sean]

Nice work, @Hutan.