09/02/2022 #2 – Host Microbe Interactions ‘the Long COVID edition’

As part of my research I’ve been involved with several studies of COVID-19 including in long COVID (LC). During the last few weeks there have been several impactful articles on LC published and pieces in The Guardian and NYT. I wanted to compare and contrast two of these and highlight some interesting findings.

To begin, what is often called long COVID in the media is also called post-acute sequelae of COVID-19 (PASC), post-acute COVID-19 syndrome, or post COVID-19 condition. It seems to affect ~5 – 30% of patients depending on the cohort and is not associated with severity, nor is it a post-intensive care syndrome (i.e. these aren’t a result of an extended stay in the ICU). The World Health Organisation provided a clinical definition of post-COVID-19 condition in October

“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 and 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.” – WHO

First up Immunological dysfunction persists for 8 months following initial mild-to-moderate SARS-CoV-2 infection – Nature Immunology.

  • Sampled up to 8 months post infection
  • Very strong study design with multiple controls
    • Unexposed healthy controls  
    • individuals who had COVID-19 but did not develop LC
    • Individuals who had been infected with a different human coronavirus. 
  • Assessed 28 analytes in the serum including six proinflammatory cytokines & flow cytometry to measure multiple immune cell types. 

Some of the serum analytes were significantly increased in both the LC and matched controls who did not develop LC indicating that the effect of COVID-19 on the immune system persists but is not necessarily associated with LC. 

They built a classification model to determine an optimal set of features predictive of LC. I like the idea but their sample size is way too limited for this type of machine learning IMO.  

Overall – Very strong study design and methodology but lack of some more global analyses left me wanting. 

Second is Long-term perturbation of the peripheral immune system months after SARS-CoV-2 infection – BMC Medicine

  • Sampled up to 6 months post infection
  • Good study design, not as strong in terms of controls as the above.
    • Unexposed healthy controls  
    • Individuals who had COVID-19 but did not develop LC
  • Performed a deeper multi-omics analysis incorporating RNASeq, Flow cytometry and serology

Found a large degree of changes in both blood gene expression, and immune cell frequency/activation that were present in all patients post-COVID-19 irrespective of if they developed LC. They found that LC was associated with changes in a number of genes related to platelet function. 

Overall – Global analyses were strong, but lacked some of the additional controls that the first study had. 

When comparing and contrasting between these two studies they agree that differences are present in the immune system following COVID-19, and that most/all of these changes are not associated with LC. The Nature Immunology study points to changes in myeloid cell activation as being associated with LC, but the BMC Medicine study doesn’t reproduce this. The BMC Med study finds changes in platelets associated with LC in their gene expression data but unfortunately neither study directly measures platelets as they focus on the PBMC fraction (no platelets/erythrocytes). 

Finally, I wanted to highlight a study published shortly after the two above. Multiple Early Factors Anticipate Post-Acute COVID-19 Sequelae – Cell. This study is a little different in that it followed 309 patients (from two independent cohorts) from diagnosis through recovery performing a range of multi-omics analyses.

They identifiedy four risk factors for developing LC at time of COVID-19 dianosis – Type 2 diabetes, SARS-CoV2 RNAemia, Epstein-Barr virius viremia and specific autoantibodies, and then subgrouped patients by these for analysis post COVID-19. Notably, they sampled only to 2-3 months post infection which if the studies above are to be believed is too early to detect any of the immunological changes associated with LC. This article is only currently available as a journal pre-proof (accepted at Cell, but needs to go through production I believe) and it seems to be missing some of the figure legends (I’m sure this will be fixed when fully published). This combined with the very different study design makes it difficult to directly compare to the studies above. There is a very strong focus here on comparing among patient groups they define rather than just LC vs matched controls that did not develop LC.

Overall – A methodologically excellent study, but I wish the authors did more to allow for more direct comparisons between this study and other work.

Also recently published.

Post-acute neurological consequences of COVID-19: an unequal burden – Nature Medicine

Studying the post-COVID-19 condition: research challenges, strategies, and importance of Core Outcome Set development – BMC Medicine

Long COVID in children – The Lancet Child Adolescent Health

I’m leading a long Covid trial – it’s clear Britain has underestimated its impact – The Guardian

New Research Hints at 4 Factors That May Increase Chances of Long Covid – The New York Times

Long COVID and kids: more research is urgently needed – Nature

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