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.

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!