Many are by now familiar with terms such as “long covid” or “long-haulers”—the notion that we need to move beyond covid-19 as an acute episode stratified into asymptomatic, mild-symptomatic, or severe disease, and start to recognise that at least as large a disease burden resides with the long aftermath. Relatively few peer-reviewed papers have formally documented the disease features of long covid, but patient groups report several months of sequelae that can involve a varying, relapsing and remitting appearance, including respiratory, cardiovascular, urological, neurological and/or gastrointestinal symptoms in unpredictable combinations. Like other features of covid-19, this is a story narrated in real-time, meaning that we currently do not know whether long covid will come to be seen as a condition typically lasting months, years, or lifelong. 

Getting to grips with the phenomenon imposes many challenges to our emerging model of this infectious disease. Not least among these, that many of the risk factors for severity of acute covid-19, such as age, male gender, obesity and ethnicity do not explicitly appear to enhance the chance of long covid. Also, there seems no clear correlation between severity of the acute disease and long-term sequelae. Indeed, many patients come from that large, hidden iceberg of those who self-isolated when they were unwell at home, did not access a PCR test, and so have no formal health record evidence of covid-19. These points highlight an uncharted pathophysiology, demanding a better answer than “post-viral syndrome” or the notion that people are bound to “feel a bit rough” coming out of hospital. 

Many estimates of long covid suggest that greater than 10% of acute cases have features that do not resolve over the subsequent months. [1,2] Extrapolated to the current global burden of covid-19, this suggests potentially over five million current “long haulers.” There are pressing biomedical research needs that now need to tackle the many challenges imposed by these estimates: formal assessment of the epidemiology, risk factors, symptoms, and pathology. Recognised criteria for a working diagnosis are needed, not least to facilitate access to appropriate services and allow healthcare provision planning.  However, moving forward our goals must move beyond the observational to the interventional. Achieving this will need some hard thinking to decode aetiological mechanisms in a confounding condition that seems to move around the body and between systems, and thus, in terms of healthcare management, between distinct clinical specialties and treatment pathways. What should our starting points be in decoding the unknowns?

Since relatively early reports from China, even of asymptomatic cases, it has been clear that infection can leave a lingering trial of changes on lung CT scans. [3] ACE-2 positive cells within the lung, heart, kidney and elsewhere are susceptible to direct SARS-Cov-2 infection, leaving the potential for a legacy of fibrosis. Initial reporting of the COVERSCAN MRI study of >200 individuals with long covid at around four months after infection shows multi-organ involvement, especially heart and lungs. [4] 

The notion of long-term, virus persistence is not one that had previously been considered for coronaviruses, so this seems to be a new textbook chapter to be written: gastrointestinal biopsies taken some four months after acute disease show persistent live virus in about a third of cases. [5] However, the presence of the virus would not be a prerequisite to account for persistent disease. There are many precedents for perturbation of immune and inflammatory responses by acute viral infection leading to long term sequelae. These range from the autoimmune/inflammatory conditions that can persist for years after Ebola virus or Chikungunya virus, to the profound immune subset perturbations that can be provoked by Epstein-Barr virus (EBV) in infectious mononucleosis. Furthermore, the status of EBV in aetiological risk of multiple sclerosis (MS) exemplifies the potential roles of viral infection in triggering autoimmunity. 

Consideration of the mechanisms underlying autoimmune diseases may offer some conceptual models relevant to considering symptom patterns in long covid. Cyclical relapsing and remitting disease is a key feature of MS. This is often taken to reflect fluxes of immune effector and regulatory cellular subsets, though consensus is lacking. Or consider the way in which lupus is the result of an autoantibody-driven disease process, yet can variably affect many different organs, so that patients may need to be seen by a rheumatologist, nephrologist, neurologist or immunologist in different care pathways. The answer is that it’s a single system disease—the immune system—yet impacts diverse organs at different times. Familiar? Chikungunya virus is a mosquito-borne virus causing acute fever, headache and myalgia, sometimes with neurological involvement, yet, here too, the precedent may be helpful in several respects: a significant minority go on to develop severe arthralgia which can persist for years. 

In countries like Brazil with a high Chikungunya case-burden, it is this aftermath which has been the most devastating with respect to individuals’ employment, quality of life, mental health, and long-term unforeseen demand on national health provision. The Chikungunya experience offers us lessons and should be sounding alarm bells. We have already heard that the Royal College of GPs is predicting a significantly increased workload due to long covid.

So, we need a clarion-call for studies that can illuminate the underlying mechanism. Surveys have shown many concerns on the wish-list of long covid patients, but among the items on that list is the need for insights into the nature of this condition, how long it’s likely to go on for, what can be done about it, and through which clinical specialties.

Daniel M Altmann is Professor of Immunology at the Department of Immunology and Inflammation, Hammersmith Hospital, Imperial College, London. 

Rosemary J Boyton is  Professor of Immunology and Respiratory  Medicine, Consultant Respiratory Physician, Department of Infectious Disease, Faculty of Medicine, Imperial College London, UK and  Lung Division, Royal Brompton & Harefield NHS Foundation Trust

The authors declare no competing interests

References:

1. Carfi A, Bernabei R, Landi F et al. Persistent symptoms in patients after acute COVID-19. JAMA 2020 324 (6). 603-605
2. Living with COVID19 – A dynamic review of the evidence around ongoing Covid19 symptoms (often called Long Covid). https://evidence.nihr.ac.uk/themedreview/living-with-covid19/
3. Long QX, Tang XJ, Shi QL. Clinical and immunological assessment of asymptomatic SARS-CoV-2 infections. Nat. Med. 2020; 26, 1200-1204
4. Dennis A, Wamil M, Kapur S et al Multi-organ impairment in low-risk individuals with long COVID. https://www.medrxiv.org/content/10.1101/2020.10.14.20212555v1.full
5. Gaebler C, Wang Z, Lorenzi JCC et al. Evolution of Antibody Immunity to SARS-CoV-2. https://www.biorxiv.org/content/10.1101/2020.11.03.367391v1