COVID-19 pathophysiology: looking beyond acute disease

Careful descriptions of the clinical features of acute disease in patients infected with the novel coronavirus SARS-CoV-2 had begun to emerge before WHO declared the outbreak of COVID-19 a public health emergency of international concern on Jan 30, 2020. As the global pandemic took hold, the need for data to inform patient management drove research efforts to describe the clinical spectrum of COVID-19, the determinants of disease severity, the mechanisms underlying the multiorgan manifestations of SARS-CoV-2 infection, and the response to a range of interventions. Little more than a year on, a picture of a new disease entity is coming into focus—with a distinct range of clinical and pathophysiological features—as described by Marcin Osuchowski and colleagues in the first of a Series of four papers in The Lancet Respiratory Medicine.

The Series highlights the wealth of data pertaining to the pathophysiology of acute disease that has emerged over the past year, but emphasises that many uncertainties about the mechanisms of acute disease—and potential targets for intervention—remain. Identifying subgroups of patients who are likely to benefit from particular treatment approaches—eg, on the basis of markers of inflammation or immunosuppression—and establishing the optimum timing of treatment are among the many challenges that need to be addressed. A full understanding of risk and protective factors that explain why some individuals are prone to severe disease remains elusive and is a priority for research.

The scope of efforts to understand the pathophysiology and phenotypes of COVID-19 has expanded as attention has shifted from the acute phase of COVID-19 (the first 4 weeks from the onset of symptoms) to the subacute phase and the long-term sequelae of SARS-CoV-2 infection (the post-COVID-19 condition). The informal term “long COVID” was coined to describe signs and symptoms that continue or develop after the acute phase of disease, affecting more than 10% of community-managed cases. A wide range of symptoms has now been reported, some lasting for months after acute infection, including dyspnoea, cough, chronic fatigue, muscle weakness, pain, sleep disturbances, and impairments in cognitive and mental health. As work to improve the care of patients with acute disease continues, studies to establish the causes and pathophysiological mechanisms of the range of persistent symptoms will need to go hand in hand with the development of pathways of care after SARS-CoV-2 infection. Studies in diverse populations will be essential to identify factors that put some people at higher risk of components of the condition.

Post-acute symptoms might reflect immune-mediated or inflammatory changes commonly associated with acute infection or might be specific to SARS-CoV-2. In patients recovering after critical illness, persistent symptoms might include those arising as part of the post-intensive care syndrome. A systematic approach is needed to describe the phenotypes of the post-COVID-19 condition, including the prevalence, time course, and clustering of symptoms. Whether different mechanisms underlie persistent symptoms after mild versus severe acute disease, and in early versus later post-acute phases, needs to be further explored to guide the development of strategies for symptom prevention or amelioration.

Large follow-up studies have been launched to characterise the features of the post-COVID-19 condition. In the UK, PHOSP-COVID aims to follow for a year 10 000 patients hospitalised with COVID-19, analysing patient-reported outcomes, evidence of multiorgan damage and dysfunction, and underlying pathophysiological mechanisms. Studies with a focus on non-hospitalised patients with mild acute disease, and genomics and multi-omics studies across the spectrum of acute illness, are also underway. Pooling data related to multiple organ systems across a range of studies will be key to making rapid progress. International initiatives such as the END-COVID collaboration, which was set up with the aim of aligning or merging national initiatives in Europe with a focus on the long-term effects of COVID-19, provide a way forward.

Severe disease caused by SARS-CoV-2 has clinical and pathophysiological features unlike those of respiratory failure due to other causes, and acute disease remains a priority for research as COVID-19-associated morbidity and mortality continue to pose a huge burden globally. Long-term investment and support are now needed for national research studies and international collaborative efforts to unravel the complex pathophysiology of post-acute symptoms, which will inform clinical trials of therapeutic interventions and multidisciplinary pathways of care for the growing number of people in recovery after SARS-CoV-2 infection.