April 8, 2024

expert reaction to study looking at long Covid subtypes and inflammatory signs in people with long Covid after Covid hospitalisation

A study published in Nature Immunology looks at long Covid subtypes and inflammatory signs. 

Prof Eleanor Riley, Professor Emerita, Immunology and Infectious Disease, University of Edinburgh, said:

“This is a very timely and important publication.  The strengths of the study are its size (over 700 hospitalized COVID-19 patients were included) and its very detailed clinical characterization, which allows the superficially heterogeneous presentations of long-COVID to be categorised into 5 or 6 distinct syndromes with specific underlying abnormalities.

“Although there is quite a lot of “noise” in the data – i.e. there is a lot of overlap in values between those with long-COVID and those who have fully recovered – because the study is so large, the differences between the groups are highly statistically significant, meaning they are very, very unlikely to have arisen by chance.  This means that although the measurement of any one of these serum proteins (or even a group of proteins) in any individual patient is not particularly helpful in terms of their diagnosis, the data do allow us to identify the shared underlying pathways of disease and to target these for therapy.

“As the authors quite rightly say, these data should usher in a series of clinical trials for treatment of long-COVID.  And, as we already have several licensed drugs that target some of these pathways, the trials could start quite quickly.

“Some of the syndromes identified here overlap with features of myalgic encephalitis/chronic fatigues syndrome (ME/CFS), the aetiology of which is currently very poorly understood.  This study thus opens up new avenues for investigation of – and possible therapies for – ME/CFS.

“Finally, this study is a resounding endorsement of the collaborative, long-term research strategy supported by various UK government bodies, prior to and during the COVID-19 pandemic, that brings together blue skies discovery research with the amazing clinical resource provided by our National Health Service.  There are few countries in the world that are able to bring together such a diverse array of skills and resources in such a short time, to tackle such globally relevant problems.”

Dr Emily Fraser, Consultant in Respiratory Medicine, Oxford University Hospitals NHS Foundation Trust, and clinical lead of the Post COVID clinic in Oxford, said:

“This is an interesting study with a large patient cohort demonstrating an ongoing inflammatory signature in those struggling with prolonged symptoms after hospitalisation with Covid.  My main comment is that severe illness/infection requiring hospitalisation per se is likely to create long lasting physiological disturbance and many patients will require a prolonged recovery period.  The definition of long Covid described by NICE/WHO is broad and I question whether prolonged fatigue/cognitive impairment etc. after severe illness at 6 months is always a Long Covid symptom or just the body recovering from being severely unwell in hospital.  Similarly, the mechanism of breathlessness in these patients is likely to be driven by lung damage sustained through Covid pneumonia and therefore persisting breathlessness at 6 months not necessarily surprising.  It would be interesting to see the results of soluble mediators in patients after hospitalisation with severe flu/other infection at 6 months as these signals may not be specific to Covid but rather the result of severe illness.

“Although the authors have made it clear that this is a hospitalised cohort, the labelling of Long Covid (rather than prolonged recovery from severe infection) is likely to then be extrapolated to the non-hospitalised cohort where the demographic is very different, initial illness often fairly mild, and where the mechanisms driving symptoms are likely to be multifaceted and complex.  I am therefore not sure if this study adds much more to our understanding of Long Covid as we see it in clinic now.”

Prof Kevin McConway, Emeritus Professor of Applied Statistics, Open University, said:

“Long COVID is an important health problem.  It arises in a large minority of people infected with the SARS-CoV-2 virus, and cases continue to occur.  It’s also clearly quite complicated – different people with long COVID report different patterns of symptoms, and there’s still a long way to go in the search for effective treatments.

“This new study is very good in my opinion, in terms of the statistical approach and the statistical methods used.  (I’m in no position to comment on the immunology.)  But its findings can’t yet do more than suggest possible ways to look for treatments, that might well be different for different types of patients.

“The study used blood samples from 659 adults who had been hospitalised with confirmed COVID at least 3 months previously (on average, about 6 months previously), where on a standard scale their original COVID had been at least moderate and, usually, severe.  The researchers tested blood samples and compared the levels of proteins involved in inflammation and the immune system between patients who said they had fully recovered, and those who hadn’t recovered and had various different types of long COVID symptoms.  They analysed these results statistically, also taking into account various characteristics of the patients such as their age, sex, pre-existing health conditions, and how severe their initial COVID was.

“The main, broad, overall finding was that there was good evidence that those who were still reporting long COVID had features in their blood proteins that are indicative of inflammation, to a greater extent than those who had recovered.  Also, the researchers found differences in the patterns of blood protein levels between patients with different types of symptoms, though there were large overlaps between the symptom groups.

“This was inevitably an observational study, and with observational studies there are always questions about what causes what.  I think it’s pretty clear from the results that the differences in blood protein levels do exist – but questions remain as to how the differences arise from the infection, in what way they might or might not actually cause the symptoms, and how this might lead to effective treatments.

“That’s no criticism of this study.  Its findings are very likely to lead to more focused and helpful research on exactly how the long COVID symptoms arise, how and why they differ between people, and to productive research on treatments.  Indeed the research paper points out that some drugs that are already being trialled do fit in with the findings of this study.  However, it’s important to mention that the new study does not itself provide any evidence on whether these drugs will actually be effective – we will need the trial results for that, and clinical trials take time.

“The research paper (and the press release) point out a potentially important limitation – although currently most people with long COVID developed it without ever having been hospitalised for COVID infection, all the patients who provided the data for this new study had been hospitalised for COVID (and indeed had had symptoms in their original infection that went beyond mild ones).  So it remains possible that the findings don’t apply to people who were never hospitalised for COVID.

“The research paper does give arguments as to why things may in fact not be very different in non-hospitalised people – for instance, in the patients that were included, the research found no association between the severity of their original COVID and their long COVID symptoms.  But the study itself provides no relevant data for non-hospitalised people, and the researchers say explicitly that their findings ‘require validation in large cohorts’ of people who were not hospitalised.  I hope that will happen.”

‘Large-scale phenotyping of patients with long COVID post-hospitalization reveals mechanistic subtypes of disease’ by Felicity Liew et al. was published in Nature Immunology at 16:00 UK time on Monday 8 April 2024.

DOI: 10.1038/s41590-024-01778-0

Declared interests

Prof Eleanor Riley: “Eleanor Riley is an Emeritus Professor at the University of Edinburgh; she had no involvement whatsoever with the conduct of this research but was a member of the UKRI COVID-19 Research and Innovation Taskforce that funded the PHOSP-COVID study.”

Dr Emily Fraser: “No interests.”

Prof Kevin McConway: “I am a Trustee of the SMC and a member of its Advisory Committee.  My quote above is in my capacity as an independent professional statistician.”

This Roundup was accompanied by an SMC Briefing.