“One in three survivors of severe COVID diagnosed with mental health condition” was the stark headline from The Guardian on April 7, 2021, reporting findings published in The Lancet Psychiatry the day before. This retrospective cohort study had analysed the electronic health records of 236 379 patients, mainly from the USA, and found that 34% had had psychiatric or neurological conditions in the 6 months following COVID-19 diagnosis. This finding supported a study published in The Lancet in January, detailing the long-term consequences of COVID-19 in patients discharged from Jin Yin-tan hospital (Wuhan, China) at the start of the pandemic. Evidence was mounting that COVID-19 was not only an acute disease but often manifested chronically, exhibiting a diverse and unpredictable disease course. Major efforts are now underway to understand this long-term component—also known as long COVID, post-acute sequelae of SARS-CoV-2 infection (PASC), or post-COVID-19 syndrome. What is the natural history of this disease and can specific features be identified and exploited to treat affected individuals more effectively?
The true extent of long COVID is only starting to be appreciated. On April 1, 2021, The Office for National Statistics estimated that 1.1 million people in the UK were experiencing long COVID (ie, symptoms persisting >4 weeks after the first suspected COVID-19 episode, with no alternative diagnosis). Alarmingly, an estimated 674 000 people reported that their symptoms had negatively affected their ability to undertake regular day-to-day activities. Unlike acute COVID-19, symptom prevalence at 12 weeks post-infection showed slightly higher prevalence in women compared with men and was highest among those aged 24 to 36 years. Considering the magnitude of these numbers, the potential threat to global productivity, and the additional burden on already beleaguered health-care systems, it is vital for these long-term complications to be recognised.
This task is not trivial. As long COVID is an uncharacterised disease, it does not yet have a universally accepted definition or appropriate medical terminology. The UK's National Institute for Health and Care Excellence published guidelines at the end of 2020 to help identify and manage individuals with post-COVID-19 syndrome. However, the definitions remain vague (essentially, not recovering to baseline health within 4 weeks). Another confounding factor is the heterogeneous presentation of the disease. Long COVID is a multisystem disorder that consists of a constellation of around 50 symptoms, including fatigue, so-called brain fog, and breathlessness. Some symptoms cluster, and others manifest at different phases or in a relapsing-remitting manner, making it difficult to define and unambiguously diagnose. Despite these confounding factors, a study published in Nature Medicine on April 10, 2021, found that having more than five symptoms during the first week of illness was associated with long COVID, offering a simple model to identify at-risk individuals. This model, developed by Tim Spector and colleagues (King's College London, London, UK), was based on data from people self-reporting their COVID-19 symptoms using the COVID Symptom Study app developed this group, underscoring the importance of community-led input in comprehending this enigmatic syndrome.
Understanding the biological basis of long COVID is key to identifying factors that predispose the development of long-term complications and to guide effective therapies. This quest has been led by international multi-stakeholder entities, such as the International Severe Acute Respiratory and Emerging Infection Consortium, and the Global Research Collaboration for Infectious Disease Preparedness research funders group, who have been instrumental in defining research priorities and helping to mobilise funds to pursue these efforts.
At a recent online event hosted by The Royal Society called Long COVID: an unfolding story, Paul Elliott (Imperial College London, UK, who is the Director of the REal-time Assessment of Community Transmission [REACT] study) talked about a new research strand called REACT Long COVID (REACT LC). In February, REACT LC was awarded £5.5 million by the UK Government to look specifically at long COVID in over 120 000 individuals in the UK. It is hoped that analysing reported outcomes from a large and diverse group of people will help us to understand the spectrum of recovery. Complementing this effort, the REACT-GE study (in partnership with Genomics England) aims to look for biological signatures that could be linked with the development of long COVID, and whether genes affect the severity of COVID-19 and its long-term progression.
In the USA, congress has pledged US$1.15 billion over the next 4 years to understand PASC. On Feb 23, Francis Collins, Director of NIH, announced the NIH PASC Initiative to investigate long COVID. Central to this plan is the formation of a clinical science core (ie, clinicians with expertise in post-viral syndromes), a data resource core (providing standardised datasets), and a biorepository core (comprising specimens from consenting volunteers). It is hoped that by combining these core resources with enhanced funding opportunities, the molecular basis of PASC will be revealed. These efforts might also shed light on other chronic diseases with overlapping causes.
At present, hypotheses vastly outnumber peer-reviewed articles. Low-level persistent virus, a dysregulated immune system, rogue antibodies, and chronic inflammation have all been implicated in the progression to PASC. As studies are published, the relative importance and interplay of these factors will unfold. A study published in Med on March 31, 2021, compared longitudinal lymphocyte profiles in patients during the acute stage of COVID-19 and up to 6 months of convalescence. Unlike changes in B cells that were found to be increased during the acute phase and largely restored upon convalescence, cytotoxic markers within circulating CD8+ T cells remained high in a subgroup of patients for up to 6 months, and these individuals were associated with the poorest clinical outcome. Such an altered T cell landscape might affect tissue integrity and response to subsequent pathogenic insult, offering some tantalising clues in the long COVID puzzle.
On Feb 9, Tedros Ghebreyesus, Director General of WHO, announced that recognition, research, and rehabilitation were key factors in tackling long COVID. At this crucial juncture in the pandemic there are many pressing questions that remain unanswered. Does long COVID make individuals more susceptible to other infections? What are the immunological and genetic determinants of PASC? Do vaccines affect long COVID progression? Should affected individuals be given the vaccine (some evidence suggests vaccination can ameliorate long COVID symptoms)? Will long COVID be classed as a disability to provide protection rights for people? In a backdrop of doubt is the realisation that the most effective way of minimising the societal impact of this devastating disease is global collaboration and a collective belief that every single person has a part to play.
EBioMedicine