January 18, 2024

expert reaction to study looking at blood protein signatures in Long COVID

A study published in Science looks at blood protein signatures in Long COVID.

Dr Nathan Cheetham, a Senior Postdoctoral Data Scientist at King’s College London, said:

“Previous research has shown that the actual symptoms people who are identified as having or living with long COVID are very varied. As this study’s sample was based on only 40 people with long COVID, it’s very hard to know which ‘types’ of long COVID the findings around specific biomarkers applies to. These results may only apply to a subset of people with long COVID of a certain type, and so may not be generalisable. To combat this, further work could compare people with long COVID AND different symptom profiles, vs. people without COVID-19 – to see whether different biomarkers are linked with different types of long COVID.”

“Additionally, the authors saying that the protein biomarkers have ‘predictive potential’ to predict long COVID may be somewhat overstated, as the models perform no better than standard information you would collect normally and much more easily – like age and body mass index.”

Prof Claire Steves, Professor of Ageing and Health, King’s College London, said:

“It’s great to see papers coming out now showing signals which might start to explain Long COVID.  Indeed, this study again shows similar signals to others, that complement activation may play a part.  However, I would caution that this study includes a very small number of individuals living with Long COVID and larger studies are really needed to replicate these findings.  Similarly, this study does not have a positive control group – that is, individuals with a non-COVID infection who also had symptoms, so we don’t know if these signals are specific to COVID or related to long symptoms generally.”

(from our colleagues in Australia) Prof David Lynn, Professor of Systems Immunology at Flinders University and at the South Australian Health and Medical Research Institute (SAHMRI), said:

“This paper, published by Swiss scientists in the prestigious journal Science, used advanced methods called proteomics to screen the blood (serum) of patients with and without long COVID at 6 and 12 months post-infection.

“These analyses indicate that a key component of our innate immune system, called the complement system, is dysregulated in individuals with long COVID. Importantly, this finding was replicated in an independent cohort in the USA.

“Furthermore, the research suggests that increased antibodies against other viruses (such as CMV and EBV) are evident in individuals with long COVID and could drive activation of the complement system which can lead to tissue damage. The researchers also found dysregulated platelets (cells involved in blood clotting) to be linked to long COVID, something our research in an Australian cohort first suggested, when it was published back in 2021 (see https://bmcmedicine.biomedcentral.com/articles/10.1186/s12916-021-02228-6).

“While these findings are exciting and important, it is important to note that this publication is one of several high-profile publications published in the last year or two showing that different aspects of the immune system are dysregulated in long COVID. Much work remains to be done to unify the different mechanisms that have been proposed in these different studies and more importantly to develop novel treatments based on these findings for patients suffering from this debilitating chronic condition.”

(from our colleagues in Australia) Prof Jeremy Nicholson, Professor of Medicine and Director of the Australian National Phenome Center at Murdoch University, said:

“The Science article by Cervia-Hasler et al represents a formidable application of modern high throughput proteomics to a current and important problem in medical science that is affecting millions of people worldwide – long COVID.

“As with all Science articles a huge amount of work has gone into the molecular characterisation of the abnormal protein patterns particularly in the Complement and related pathways that remain disrupted in long COVID patients.

“COVID-19 is an exceptionally complex disease that has initial respiratory targets but also has significant but hypervariable systemic organ involvement that is immunologically driven. It is the persistence of the disrupted immune responses in long COVID that gives rise to these systemic effects (which can involve all major organs systems giving neurological, cardiometabolic and a host of other side effects).

“This paper helps identify some fundamental immunological disruptions which help us understand the thrombo-inflammatory effects – affecting blood vessel linings for instance – which can give rise to more generalised systemic problems (all organs have blood vessels). This paper gives new insights into the complement protein perturbations but still does not explain the diversity of the long COVID symptoms or their differential expression between individuals.

“In fact, the work revolves around proteomic data on a relatively small number of patients so in itself is unlikely to explain everything. There are also other factors (also poorly understood) in long COVID – like the disruption of the microbiome relating to gastrointestinal effects – which are also likely to influence immune regulation and control in their own right.

“There are also known long-term disruptions in energy metabolism and regulation of the tryptophan-serotonin pathway which will also relate to the chronic fatigue that is a common long COVID feature – undoubtedly these problems also have immune-metabolic roots but how those relate to these new findings is not yet clear – this paper is another brick in the wall but the full integrative immune-metabolic picture of long COVID is yet to emerge and requires even more comprehensive studies in greater numbers of people. Sadly there is no shortage of long COVID patients to study!”

Prof Peter Openshaw, Professor of Experimental Medicine, Imperial College London, said:

“This publication describes an important new study, drawing together ideas about the causes of Long COVID, highlighting the importance of inflammation and blood clotting that appear to underlie Long COVID.

“They started by recruiting 113 COVID-19 patients, followed for up to 1 year. By the 6-month point they had 40 patients with continued symptoms. They took blood (a total of 268 longitudinal samples) and measured >6,500 serum proteins using a broad screening approach to find patterns. In these longitudinal samples, they were able to compare those who recovered fully and those who did not.

“They used machine learning algorithms to independently identify predictive markers for the development of Long COVID, highlighting substances called ‘complement’ (part of the innate immune defense) and measures of blood coagulation (known to be affected in acute COVID). They found evidence of complement activation, tissue injury and platelet activation in patients with Long COVID. These are pathways that have previously been incriminated in acute COVID, adding credence to the findings.

“This study is based on relatively small numbers of patients and the recovered cases (n=73) were younger (median 36y vs 58y), rarely had severe disease (16.4% vs. 62.5%) and were rarely admitted to ITU (4.1% vs. 30%) compared to the 6-month long COVID cases (n=40).

“While this work needs to be repeated in other cohorts, it does identify some leads which can be followed to unravel the complexity of Long COVID. Although they identify possible diagnostic markers, these are not ready to be applied clinically.

“It is important to emphasise that it would be premature to give new treatments to patients on the basis of these findings, but the study does point the way in terms of which new therapies might be tested in future trials (some of which are already underway).”

Prof Frances Williams, Professor of Genomic Epidemiology at King’s College London, said:

“The study from Switzerland and the USA found that mini blood clots contribute to long COVID. The authors compared the blood proteins of long COVID patients with long COVID people who got better as well as healthy control subjects. Multiple strands of evidence are pointing to biological clotting pathways and include activation of an immune protein pathway called complement.

“But the study did not find a protective effect of prior covid vaccination which has been reported in much larger, epidemiological studies. Additionally, while there are similarities with other rare clotting conditions, these are also a challenge to treat so while there are important new pointers, talk of new therapies is a little premature.

“Further replication of the study in other samples, particularly of different ethnicity, would be important. The study suggests complement activation is the main cause of the mini blood clots. Predicting who is at risk of long COVID may become possible now, and that is an important step towards trials of new treatments in future.”

Prof John Martin, Professor of Cardiovascular Medicine, UCL, said:

“Long Covid is a syndrome, i.e. probably made up of more than one disease.  Included may be patients with a variety of changes which may give symptoms that are classed as long Covid. The patients were selected for the Science published study by a questionnaire that I could not find attached to the supplementary material. It would be important to examine this questionnaire as it defined the patient population. Therefore the elegant molecular results are difficult to relate to a precisely defined clinical phenotype.

“That said, findings of changes in the complement system and platelets might allow design of further studies in patient populations defined by laboratory tests.

“Also the results could be used to define a population of patients which could be the subject of a clinical trial in long covid of the immune modulatory drug which was successfully trialled in severe acute Covid. The drug significantly decreased death in Covid patients, increased well-being and decreased hospital stay. This study was published in The Lancet. I was the leader of that trial.”

‘Persistent complement dysregulation with signs of thromboinflammation in active Long Covid’ by Carlo Cervia-Hasler et al. was published in Science at 19:00 UK time on Thursday 18^th January.

DOI: 10.1126/science.adg7942

Declared interests

Prof David Lynn: No conflicts

Prof Jeremy Nicholson: No conflicts

Prof Peter Openshaw: “Peter Openshaw is a Co-Lead on the Coronavirus Clinical Characterisation Consortium (ISARIC-4C) and immunology lead on PHOSP-COVID (a UKRI MRC COVID-19 Rapid Response consortium studying Long COVID, led by Chris Brightling, Leicester).  He has been a member of scientific advisory committees and/or spoken at meetings organised by Janssen, Sanofi, Moderna, Seqirus, AstraZeneca and GSK.”

Prof Frances Williams: No declarations of interest

Prof John Martin: Prof John Martin was leader of the trail references in his comment, which was written up in The Lancet, ‘A randomised, double-blind, placebo-controlled, multicentre clinical trial of AZD1656 in diabetic patients hospitalised with COVID-19: The ARCADIA Trial – implications for therapeutic immune modulation’ by Jamie Chorlton et al.

For all other experts, no reply to our request for DOIs was received.