In a paper in Nature reviews immunology in July 2023 a group of scientists investigate the “immunology” long COVID. The authors describe the condition as the “disease entity whereby persistent symptoms ensue in a significant proportion of those who have had COVID-19″. Although the disease burden ranges from mild symptoms to “profound disability”, it is estimated that, of all COVID-19 patients in the world, at least 10% have long COVID. It is therefore a “huge, new health-care challenge”.  

What is long COVID? 

Long COVID is a “patient-coined term” that has stuck despite attempts to re-designate it. The paper acknowledges that the condition is likely “stratified” into “several more or less discrete entities”. The list of possible symptoms is “extensive, multi-organ, multisystem, and relapsing-remitting”. Despite the efforts of patients and care providers to understand the condition, we have not achieved a “coherent schema linking SARS-CoV-2 infection to the diverse array of persistent symptoms”.  

The researchers suggest that lists of symptoms were initially derived through patient group reports, which led to a survey at the end of 2020. Then, in 2021, a systematic review covering 39 studies highlighted the most common symptoms: 

  • Weakness (41%) 
  • General malaise (33%) 
  • Fatigue (31%) 
  • Impaired concentration (26%) 
  • Breathlessness (25%) 
“Long COVID is a truly multi-organ, multisystem disease, with symptoms that appear to indicate a pathological process beyond and distinct from just the ACE2-positive tissues targeted for viral ingress during the acute infection.”  

Recognising the “diversity and relapsing-remitting range” of symptoms, several studies choose to focus on the most common lists.  


The authors state that “efforts to build a mechanistic framework” have been in progress since the first noting of persistent sequelae of COVID-19. However, the field “lacks the evidence to build formal, mechanistic bridges”. The authors explore the following areas in detail, so we encourage readers to visit the paper here. 

  • Evidence for organ damage 
  • A persistent SARS-CoV-2 reservoir as a long COVID driver 
  • Association with abnormal antiviral immune response during acute infection 
  • A potential role of latent virus reactivation 
  • Perturbations in systemic immunity 
  • Induction of AABs 
  • CNS immune and pathological changes in relation to neurocognitive symptoms 
  • Endothelial activations and microclots  
  • Dysbiosis 
Disease risk after COVID-19 

Although the “clinical definition” of long COVID is “still a work in progress, the authors identify a “tendency” to draw a distinction between the “familiar spectrum of persistent symptoms” and increased risk of “overt ‘lifetime’ impacts”, like stroke or myocardial infarction. In this case, the authors encourage consideration of both sets of outcomes within the framework of long COVID.  

“If long COVID encompasses consequences of the infection beyond 4 weeks, then increased lifetime risk of neurological, cardiovascular, renal, or metabolic disease events certainly qualify within the term ‘long’.” 
Looking forward 

Despite the “huge amount of high-quality research” that has allowed “aspect of the puzzle of pathogenesis” to be put into place, the authors describe as “invidious” any attempt at mechanistic synthesis that could draw “connecting lines” between the “largely agreed” parts of the picture. Furthermore, it is apparent that it would be “premature and spurious” to “contort these into a simple pathway” in the face of “huge knowledge gaps”. 

While these discussions continue, patients who suffer long COVID feel “neglected”, say the authors, recognising impatience to see medical findings “translated into therapeutic trials”. By May 2023 there were 384 clinical trials, mostly in the US, involving patients with long COVID. However, the authors identify within this list a “lack of consensus”. They also identify a “powerful case” for large, comparative, randomised control trials. With greater clarity, the diagnosis, clinical phenotypes, and stratification of long COVID will enable “more powerful clinical trials”. 

“The biggest unknowns remain the joined-up scheme of its pathogenesis and thus the best candidate therapeutics to be trialled in randomised controlled trials, along with a better understanding of the kinetics of recovery and the factors influencing this.”  

The paper concludes with a call for “far more” investment in pilot investigations. As individual experiences evolve and data become available, we look forward to learning more about therapeutic approaches to long COVID.  

Are you involved in research into long COVID? Our COVID-19 track at the Congress in Barcelona may be of interest, so do get your tickets here. Don’t forget to subscribe for more like this.