Neurological involvement among non-hospitalized adolescents and young adults 6 months after acute COVID-19, 2024, Havdal, Wyller et al.

[SNT Gatchaman]

Neurological involvement among non-hospitalized adolescents and young adults 6 months after acute COVID-19
Havdal, Lise Beier; Selvakumar, Joel; Lund Berven, Lise; Stiansen-Sonerud, Tonje; Zetterberg, Henrik; Blennow, Kaj; Holmøy, Trygve; Wyller, Vegard

The post-COVID-19 condition (PCC) is characterized by debilitating persistent symptoms, including symptoms suggesting neurological aberrations such as concentration difficulties, impaired memory, pain, and sleep disturbances. The underlying mechanisms remain elusive. This study aimed to investigate brain injury biomarkers, neurocognitive test performance, and self-reported neurological and neuropsychological symptoms in young people with PCC.

A total of 404 non-hospitalized adolescents and young adults aged 12–25 years who tested positive for SARS-CoV-2, along with 105 matched SARS-CoV-2 negative individuals, were prospectively enrolled and followed-up for 6 months (Clinical Trials ID: NCT04686734). All participants underwent comprehensive assessment encompassing clinical examinations, questionnaires, neurocognitive testing and blood sampling. Serum samples were immunoassayed for the brain injury biomarkers neurofilament light chain (Nfl) and glial fibrillary acidic protein (GFAp). At 6 months, cross-sectional analyses of serum Nfl/GFAp, neurocognitive test results and symptom scores were performed across groups based on adherence to PCC criteria as well as initial SARS-CoV-2 test results. Also, associations between Nfl/GFAp, neurocognitive test results, and symptom scores were explored.

A total of 381 SARS-CoV-2 positive and 85 SARS-CoV-2 negative were included in the final analysis at 6 months, of whom 48% and 47%, respectively, adhered to the PCC criteria. Serum levels of Nfl and GFAp were almost equal across groups and did not differ from reference values in healthy populations. Also, neurocognitive test results were not different across groups, whereas symptom scores were significantly higher in patients fulfilling PCC criteria (independent of initial SARS-CoV-2 status). No significant associations between Nfl/GFAp, neurocognitive test results, and symptom scores were found.

Normal brain injury biomarkers and neurocognitive performance 6 months after mild COVID-19 implies that the persistent symptoms associated with PCC are not concurrent with ongoing central nervous system damage or permanent disruption of cognitive functions. This finding contradicts the notion of neuroinflammation as a likely explanation for the persistent symptoms.


Link | PDF (Frontiers in Neurology)

 

[SNT Gatchaman]

Follows on from Neurological Involvement in COVID-19 Among Non-Hospitalized Adolescents and Young Adults (2022, Frontiers in Neurology)

 

[Dolphin]

I just noticed that the final author is Vegard Bruun Bratholm Wyller, a well-known biopsychosocial proponent who is prominent in the ME/CFS literature.

 

[Midnattsol]

Probably due to headlines of cognitive impairment after covid lately, this study has been pulled up as front news at a Norwegian science site today. Nothing new as as @Dolphin says it's from prominent BPS supporters.

 

[Kalliope]

Todd Davenport comments on X:

Did anyone think to ask these authors how a cohort could be COVID-negative but yet still meet the case definition criteria for Post Covid Condition, when the very first criterion for PCC is probable or confirmed SARS-COV-2 infection?

I just have no idea what’s going on with peer review sometimes.

I mean, a few cases misclassified here and there maybe because sampling variation is weird. But half the sample and equal in proportion to the infected group? That math doesn’t math. Something seems totally screwed up. Could be my understanding, but I have a decent track record.

It’s like we’re all just kind of writing up whatever came out of the hind end of Stata without really thinking it through, and reviewers and editors are all “you go, you.”

 

[Dolphin]

Paul Garner

https://twitter.com/user/status/1778034496211681498

 

[Hutan]

It's as if Wyller did this expressly to squash the idea of Long Covid as a biological issue, and instead to promote the 'there's nothing to see here, it's all in their minds' idea.

Between 24 December 2020 and 18 May 2021, a consecutive cohort of adolescents and young adults undergoing SARS-CoV-2 testing with reverse transcription-polymerase chain reaction (RT-PCR) were enrolled. All participants were recruited from one of two microbiological laboratories, Fürst Medical Laboratory or Department of Microbiology and Infection Control at Akershus University Hospital, both located in Southeast Norway. The prevailing strain of SARS-CoV-2 in this geographical area during most of the recruitment period was B.1.1.7 (Alpha). Any SARS-CoV-2 positive individuals were considered eligible for enrolment after fulfilling a 10-day quarantine. Concurrently, a SARS-CoV-2 negative control group was recruited among individuals exhibiting a similar distribution of sex and age as the SARS-CoV-2 infected cases. Within the SARS-CoV-2 negative group, some individuals had undergone testing due to acute infectious symptoms, while others were asymptomatic close contacts of confirmed cases.

Exclusion criteria at baseline encompassed the following: (1) A duration of more than 28 days since onset of symptoms; (2) Hospitalization due to COVID-19; (3) Pregnancy; and (4) Serological evidence of SARS-CoV-2 infection (in the SARS-CoV-2-negative group).

So the SARS-CoV-2 negative group consisted of young people who
1. had turned up for testing due to a suspicion that they had Covid-19 or may have been exposed to it, and/or
2. had not been tested but were close contacts of confirmed cases.

All the participants in the study were subsequently tested at 6 months for
SARS-CoV-2 nucleocapsid and receptor binding antibodies.

NIH advice - these tests are not perfect, in terms of identifying people who have has Covid-19.

SARS-CoV-2 serologic tests are authorized for detecting antibodies, but their ability to predict protective immunity has not been validated. Most of these tests are not standardized. Furthermore, as SARS-CoV-2 is not a well-conserved virus, mutations in the receptor binding domain of the virus could lead to decreased binding affinity between antibodies and SARS-CoV-2–specific antigens.

If a serologic test is performed, the result should be interpreted with caution. First, it remains unclear how long SARS-CoV-2 antibodies persist following infection or vaccination. A negative serologic test result also does not preclude prior SARS-CoV-2 infection or vaccination against COVID-19. Second, some people who are infected with SARS-CoV-2 or who are vaccinated against COVID-19 (e.g., those who are immunocompromised) may not develop measurable levels of antibodies.

So, serological testing is not 100% accurate. A person might have had a different strain of the virus, not everyone develops antibodies and, probably most importantly, 6 months after infection, the antibodies will be gone in a significant number of people, especially unvaccinated people.

Therefore, this study's Covid-19 negative cohort almost certainly had people who were actually Covid-19 positive.

 

[Hutan]

Other infections that might cause ME/CFS: e.g.

A total of 10 individuals (2.7%) in the SARS-CoV-2–positive group and 3 individuals (3.6%) in the SARS-CoV-2–negative group had a serological pattern suggesting recent EBV infection prior to enrolment or during the observational period (eTables 5 and 6 in Supplement 1).

(from an another paper on the same study, linked in post#2 above)


Case definitions
Then there is the question of who was labelled as having Post COVID-19 Condition:

The WHO definition of Post COVID-19 Condition (PCC) (9) and the modified Fukuda-case definition of Post-Infective Fatigue Syndrome (PIFS) (42) were applied and operationalized at 6-month follow-up, as thoroughly described previously (20). In brief, all participants were categorized as either case or non-case in accordance with both definitions. To enhance accuracy, a distinction was drawn between definite and uncertain classifications, considering concurrent medical and psychiatric comorbidities that could potentially account for the reported symptoms. Both clinical findings, laboratory reports and questionnaire data from baseline and at 6-month follow-up were considered in the identification of PCC and PIFS cases. Two medical doctors blinded to the participants’ initial SARS-CoV-2 status conducted the assessment independently.

Participants were stratified into four groups based on COVID status and adherence to PCC criteria as follows: (1) COVID-19 positive individuals who adhered to PCC criteria (COVID+PCC+); (2) COVID-19 positive individuals who did not adhere to PCC criteria (COVID+PCC-); (3) COVID-19 negative individuals who adhered to PCC criteria (COVID-PCC+); and (4) COVID-19 negative individuals who did not adhere to PCC criteria (COVID-PCC-). A similar categorization was undertaken based on adherence to PIFS criteria (PIFS+ or PIFS-).

At 6 month follow-up, 184 of 379 individuals in the SARS-COV-2–positive group and 40 of 85 individuals in the SARS-CoV-2–negative group were classified as having PCC

(from that other paper on the same study.)
Given that the participants were enrolled prior to knowing whether they would develop Long Covid, those incidences of about half the participants having Long Covid at 6 months are not credible. If you operationalise your criteria with such a low bar, the information you produce is useless for everything except suggesting that Long Covid is a psychosomatic phenomenon.

Participants were also evaluated against a Post-Infection Fatigue Syndrome criteria:

For PIFS, 53 individuals in the SARS-CoV-2–positive group and 7 individuals in the SARS-COV-2–negative group met the criteria (eFigure 2 in Supplement 1), corresponding respectively to a point prevalence of 14.0% (95% CI, 10.8% to 17.9%) and 8.2% (95% CI, 3.8% to 16.3%),

There's still a lot of people in the SARS-CoV-2 negative group labelled with PIFS.

This paper reports not finding any differences between individuals meeting PIFS criteria and the controls. It's probably worth looking into this more, although I expect the bias that Wyller brings seeps into the whole study - it may not be possible to identify all of the consequences of that bias from the report.

 

[Hutan]

In baseline data from our cohort, we observed a slight increase in Nfl and GFAp levels in the sub-acute phase of COVID-19 (11). Our current finding of these brain injury biomarkers returning to normal levels 6-months after mild COVID-19 infection aligns with the findings of others. Kanberg et al. found that Nfl and GFAp serum concentrations were normalized 6 months post-infection in a cohort of mild, moderate and severe COVID-19 cases (43), and Rogatzki et al. found normalization of serum levels of Nfl/GFAp as early as 1 month following mild COVID-19 infection in young adults (35).

I find it rather interesting that there is evidence of brain injury at all - it is seeming to be a consistent finding (although certainly not in all people with a Long Covid label). Some of the levels of GFAP were over 100 pg/ml, so, not insignificant, I think.