Differentiation of Prior SARS-CoV-2 Infection and [PASC] by Standard Clinical Laboratory Measurements in the RECOVER Cohort, 2024, Erlandson+

SNT Gatchaman

SNT Gatchaman

Senior Member (Voting Rights)
Staff member
Differentiation of Prior SARS-CoV-2 Infection and Postacute Sequelae by Standard Clinical Laboratory Measurements in the RECOVER Cohort
60 authors ; on behalf of the RECOVER-Adult Cohort

BACKGROUND
There are currently no validated clinical biomarkers of postacute sequelae of SARS-CoV-2 infection (PASC).

OBJECTIVES
To investigate clinical laboratory markers of SARS-CoV-2 and PASC.

DESIGN
Propensity score–weighted linear regression models were fitted to evaluate differences in mean laboratory measures by prior infection and PASC index (≥12 vs. 0). (ClinicalTrials.gov: NCT05172024)

SETTING
83 enrolling sites.

PARTICIPANTS
RECOVER-Adult cohort participants with or without SARS-CoV-2 infection with a study visit and laboratory measures 6 months after the index date (or at enrollment if >6 months after the index date). Participants were excluded if the 6-month visit occurred within 30 days of reinfection.

MEASUREMENTS
Participants completed questionnaires and standard clinical laboratory tests.

RESULTS
Among 10 094 participants, 8746 had prior SARS-CoV-2 infection, 1348 were uninfected, 1880 had a PASC index of 12 or higher, and 3351 had a PASC index of zero. After propensity score adjustment, participants with prior infection had a lower mean platelet count (265.9 × 109 cells/L [95% CI, 264.5 to 267.4 × 109 cells/L]) than participants without known prior infection (275.2 × 109 cells/L [CI, 268.5 to 282.0 × 109 cells/L]), as well as higher mean hemoglobin A1c (HbA1c) level (5.58% [CI, 5.56% to 5.60%] vs. 5.46% [CI, 5.40% to 5.51%]) and urinary albumin–creatinine ratio (81.9 mg/g [CI, 67.5 to 96.2 mg/g] vs. 43.0 mg/g [CI, 25.4 to 60.6 mg/g]), although differences were of modest clinical significance. The difference in HbA1c levels was attenuated after participants with preexisting diabetes were excluded. Among participants with prior infection, no meaningful differences in mean laboratory values were found between those with a PASC index of 12 or higher and those with a PASC index of zero.

LIMITATIONS
Whether differences in laboratory markers represent consequences of or risk factors for SARS-CoV-2 infection could not be determined.

CONCLUSIONS
Overall, no evidence was found that any of the 25 routine clinical laboratory values assessed in this study could serve as a clinically useful biomarker of PASC.

Primary Funding Source: National Institutes of Health.

Link | PDF (Annals of Internal Medicine)
 
Laboratory studies that were done were complete blood count with differential, complete metabolic panel, international normalized ratio, D-dimer, lipid panel, 25-hydroxyvitamin D, thyroid-stimulating hormone, free thyroxine, hemoglobin A 1c (HbA1c ), high-sensitivity CRP (hsCRP), cystatin C, N-terminal pro–B-type natriuretic peptide, troponin, urinalysis, and urinary albumin–creatinine ratio (uACR).
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Subphenotypes of PASC were previously defined as cluster 1, representing high frequency of impairments in smell and taste; cluster 2, representing high frequency of postexertional malaise (PEM) (defined as worsening of symptoms after even minor physical or mental effort) and fatigue; cluster 3, representing high frequency of brain fog, PEM, and fatigue; and cluster 4, representing high frequency of fatigue, PEM, dizziness, brain fog, gastrointestinal symptoms, and palpitations (8).
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Our study has many strengths as the first large study to prospectively assess a broad battery of clinical laboratory biomarkers with standardized systematic evaluation for symptoms, which reduced ascertainment bias. We had large and robust control groups, and our participants were diverse in terms of demographic characteristics, geographic distribution, SARS-CoV-2 variant, and vaccination status. We used a rigorously derived, concrete, and reproducible research definition of PASC, enabling the cohort to be well characterized.
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In summary, our findings suggest that even highly symptomatic PASC may have no clinically observable objective findings on routine laboratory testing. Understanding the basic biological underpinnings of persistent symptoms after SARS-CoV-2 infection will likely require a rigorous focus on investigations beyond routine clinical laboratory studies (for example, transcriptomics, proteomics, metabolomics) to identify novel biomarkers.
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Had they studied ME/CFS they could have known all of this.

Long time ago (1997) I had a 24-hour urine test that did show differences. Well monitored?
So much so that it came back with 2 pages of supplements to take.
My partner was doing fine on the same (healthy) diet. More than fulltime, stressful job, 200km on his bike weekly and many other things.
From creatine mmol/mol Lactic acid 14.11, pyruvic acid 0.07 pyroglutamic 4 and succinic 63 (3x upper limit). Something to do with the Krebs Cycle?
I was still working 5x4 hours, with 2 hours travel time on public transport.

Over 10.000 participants tested for what? And at what costs?
 
SNT Gatchaman said:
Differentiation of Prior SARS-CoV-2 Infection and Postacute Sequelae by Standard Clinical Laboratory Measurements in the RECOVER Cohort
60 authors ; on behalf of the RECOVER-Adult Cohort

BACKGROUND
There are currently no validated clinical biomarkers of postacute sequelae of SARS-CoV-2 infection (PASC).

OBJECTIVES
To investigate clinical laboratory markers of SARS-CoV-2 and PASC.

DESIGN
Propensity score–weighted linear regression models were fitted to evaluate differences in mean laboratory measures by prior infection and PASC index (≥12 vs. 0). (ClinicalTrials.gov: NCT05172024)

SETTING
83 enrolling sites.

PARTICIPANTS
RECOVER-Adult cohort participants with or without SARS-CoV-2 infection with a study visit and laboratory measures 6 months after the index date (or at enrollment if >6 months after the index date). Participants were excluded if the 6-month visit occurred within 30 days of reinfection.

MEASUREMENTS
Participants completed questionnaires and standard clinical laboratory tests.

RESULTS
Among 10 094 participants, 8746 had prior SARS-CoV-2 infection, 1348 were uninfected, 1880 had a PASC index of 12 or higher, and 3351 had a PASC index of zero. After propensity score adjustment, participants with prior infection had a lower mean platelet count (265.9 × 109 cells/L [95% CI, 264.5 to 267.4 × 109 cells/L]) than participants without known prior infection (275.2 × 109 cells/L [CI, 268.5 to 282.0 × 109 cells/L]), as well as higher mean hemoglobin A1c (HbA1c) level (5.58% [CI, 5.56% to 5.60%] vs. 5.46% [CI, 5.40% to 5.51%]) and urinary albumin–creatinine ratio (81.9 mg/g [CI, 67.5 to 96.2 mg/g] vs. 43.0 mg/g [CI, 25.4 to 60.6 mg/g]), although differences were of modest clinical significance. The difference in HbA1c levels was attenuated after participants with preexisting diabetes were excluded. Among participants with prior infection, no meaningful differences in mean laboratory values were found between those with a PASC index of 12 or higher and those with a PASC index of zero.

LIMITATIONS
Whether differences in laboratory markers represent consequences of or risk factors for SARS-CoV-2 infection could not be determined.

CONCLUSIONS
Overall, no evidence was found that any of the 25 routine clinical laboratory values assessed in this study could serve as a clinically useful biomarker of PASC.

Primary Funding Source: National Institutes of Health.

Link | PDF (Annals of Internal Medicine)
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I’m pretty sure this is the first study published from the central tranche of RECOVER - a huge observational study with tens of thousands of participants. And it’s completely worthless. The cohort is incredibly large and heterogenous - there’s absolutely no attempt at phenotyping, which is actually made more difficult by the number of people involved, lots of patients who participated in this study have complained about how poorly it was organised. And they only used standard blood tests.

The good news is that this study is a relic of 2021 - it was designed at a time when the NIH and RECOVER had no idea what Long Covid was (largely due to their neglect of ME), and therefore decided to study Long Covid from scratch, with this monstrosity of a $500 million investment the main product.
 
As commented above, all this is previously well established in ME/CFS and adds nothing new. A frustrating waste of valuable resources: patient health and effort, time, money; with attendant opportunity costs. Trying to take a more optimistic view and also to meet them where they are/were, as opposed to where they damn well should have been, there are some positives.

Big numbers (patients, authors/institutions, money). This paper will be easily referenced whenever the introductory point needs to be made that routine clinical tests are normal. It is also up-to-date in terms of current technology for the routine tests.

They specifically do not then go off down the path of psychosomatics / anxiety / BPS. No mention of anxiety, depression or "psych-". Instead a call for more advanced biological investigations.

Their concluding statement is —

In summary, our findings suggest that even highly symptomatic PASC may have no clinically observable objective findings on routine laboratory testing. Understanding the basic biological underpinnings of persistent symptoms after SARS-CoV-2 infection will likely require a rigorous focus on investigations beyond routine clinical laboratory studies (for example, transcriptomics, proteomics, metabolomics) to identify novel biomarkers.
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It would have been much worse if the lead authors were Walitt/Nath.

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The only reference that itself contains "anxiety, depression" (34) is used in discussion of platelet findings and is also the only direct mention of ME/CFS in the text —

among participants with a PASC index of 12 or higher, both platelet count and hsCRP level tended to be higher than among those with a PASC index of zero, suggesting an ongoing inflammatory state, which is consistent with prior literature (33-36). Platelet and clotting abnormalities are more complex than simply the total number of platelets, and abnormalities have been widely recognized during acute COVID-19, including in vitro studies showing internalization of SARS-CoV-2 virion by platelets and rapid cell death (37). Some evidence supports a role of clotting and platelet abnormalities in PASC (38), although other studies have not found convincing evidence of microclots (39, 40). […] Other studies have demonstrated markers of platelet activation in PASC (42). Among a subset of 80 symptomatic participants in a long COVID/PASC registry, microthrombi and platelet abnormalities (hyperactivity) were seen in nearly all participants (38, 43). Platelet abnormalities have also been described among patients with myalgic encephalomyelitis/chronic fatigue syndrome or postural orthostatic tachycardia syndrome (44, 45). Clinical quantitation of platelet count is not a reliable biomarker for PASC, and more specific markers of platelet biology will likely be needed to detect platelet dysfunction related to PASC.
 
Just to add a positive note.:nailbiting:

I think this study is awesome. It validates, in an enormous cohort, that you can be sick as hell even if all the standard normal blood tests say you're fine.

1. It extinguishes the argument that you must be fine because the blood tests says so.
2. It proves the need for tests that find what's actually wrong.
3. It reminds everyone in the field of medicine the job of understanding the human body has only just begun.
 
It would have been much worse if the lead authors were Walitt/Nath.


Could the paper summary have been worse if the Walitt/Nath study had not received so much criticism?
It all breathes not seek and find, but research only what you don't want to find.
 
NIH press release here:

Routine lab tests are not a reliable way to diagnose long COVID

A National Institutes of Health (NIH)-supported study has found that routine lab tests may not be useful in making a long COVID diagnosis for people who have symptoms of the condition. The study, part of NIH’s Researching COVID to Enhance Recovery (NIH RECOVER) Initiative(link is external) and published in the Annals of Internal Medicine, highlights how challenging it can be to identify and diagnose a novel illness such as long COVID.
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My goodness. They needed to waste time and money figuring this out? If routine blood tests could diagnose ME/CFS aka Long Covid, we wouldn't be here.
 
Murph said:
I think this study is awesome. It validates, in an enormous cohort, that you can be sick as hell even if all the standard normal blood tests say you're fine.

1. It extinguishes the argument that you must be fine because the blood tests says so.
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I wish. The NIH posted this study on their twitter feed and the interpretation from healthy trolls in replies was along the lines of "of course all their lab tests are normal, it's a psychological condition".
 
The Guardian's story on this was subtitled "Four-year study of patients finds ‘markedly few’ differences between people who have long Covid and those who do not” :banghead:

I emailed the readers' editor and it's now been changed to "...'markedly few' differences in test results between people who have long Covid and those who do not”, which is slightly less dreadful but still misleading.

https://www.theguardian.com/society/article/2024/aug/14/long-covid-test
 
succinic 63 (3x upper limit). Tested in 1997!
Slow as a turtle. It took me 27 years to figure this out.
Yesterday I found out high succinic acid could also be caused bij C.difficile.
I don't even remember being treated for that, no medication for sure, I certainly was never retested.
When diagnosed with ME/CFS the "normal" ailments become less important?
 
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Turtle said:
succinic 63 (3x upper limit). Tested in 1997!
Slow as a turtle. It took me 27 years to figure this out.
Yesterday I found out high succinic acid could also be caused bij C.difficile.
I don't even remember being treated for that, no medication for sure, I certainly was never retested.
When diagnosed with ME/CFS the "normal" ailments become less important?
Click to expand...
Yep. Did an organic acids test and gut test privately after daughter had H Pylori years ago.high succinate one of the findings.
C Difficile found ( seemingly not uncommon after treatment for H Pylori ) but no " symptoms" so GP didn't offer anything .
 
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