Symptoms of long COVID, also known as post-acute sequelae of COVID-19, are well documented,1,2 but natural history is poorly characterised, either by symptoms, organ impairment or function.3–5
Among 3762 individuals with suspected or confirmed COVID-19, debilitating symptoms lasted beyond 35 weeks, with fatigue, breathlessness and cognitive dysfunction being the most frequent.6
In the UK’s largest long COVID clinic, non-hospitalised patients required specialist referral at similar rates to hospitalised patients and were more likely to report breathlessness and fatigue, with reduced health-related quality of life (HRQoL).7
A US study of 270,000 individuals post COVID-19 showed that one-third had persistent symptoms at 3–6 months (more common than post-influenza symptoms based on a matched cohort with otherwise similar risk factors), possibly due to direct organ-specific rather than general viral effects, and potentially informing development of effective treatments.8
Long COVID may be linked to severity of initial illness in some hospitalised patients, but prognostic factors are neither defined nor investigated systematically in non-hospitalised patients.7–9 To conduct trials of possible therapies for long COVID, we need stratification by symptoms or investigations.3
Our interim magnetic resonance imaging (MRI) data in 201 individuals showed mild organ impairment in the heart, lungs, kidneys, liver, pancreas and spleen, with single- and multi-organ impairment in 70% and 29%, respectively, 4 months after COVID-19.9 Clinical utility of these MRI metrics for chronic and multi-system conditions has been shown.10,11
More severe ongoing symptoms of breathlessness and fatigue were associated with myocarditis (p < 0.05)9, but symptoms and multi-organ manifestations have not been correlated.
In the UK and other countries, health system and research responses have begun at scale.12 However, clinical patient pathways are unclear and there are still no proven, evidence-based therapies, either in subgroups or in the overall long COVID population. Single- and multi-organ impairments need investigation over the medium and long term to assess resource utilisation and health system needs.
In individuals with long COVID, we therefore prospectively investigated the following:
1. Symptoms, organ impairment and function over 1 year, particularly relating to ongoing breathlessness, cognitive dysfunction and HRQoL.
2. Associations between symptoms and organ impairment.
A total of 536 individuals (mean age 45 years, 73% female, 89% white, 32% healthcare workers, 13% acute COVID-19 hospitalisation) completed baseline assessment (median: 6 months post COVID-19); 331 (62%) with organ impairment or incidental findings had follow-up, with reduced symptom burden from baseline (median number of symptoms 10 and 3, at 6 and 12 months, respectively).
Extreme breathlessness (38% and 30%), cognitive dysfunction (48% and 38%) and poor health-related quality of life (EQ-5D-5L < 0.7; 57% and 45%) were common at 6 and 12 months, and associated with female gender, younger age and single-organ impairment. Single- and multi-organ impairment were present in 69% and 23% at baseline, persisting in 59% and 27% at follow-up, respectively.
Organ impairment persisted in 59% of 331 individuals followed up at 1 year post COVID-19, with implications for symptoms, quality of life and longer-term health, signalling the need for prevention and integrated care of long COVID.
In this UK prospective study of largely non-hospitalised long COVID, we have four new findings. First, we confirm multi-organ impairment at 6 and 12 months in 29% of individuals with long COVID, with persistent symptoms and reduced function. Second, despite some associations between organ impairment and symptoms, there is currently insufficient evidence for distinct long COVID subtypes. Blood biomarkers, the current standard of care, showed no relation to clinical presentation. Third, symptoms, blood investigations and quantitative, multi-organ MRI did not predict trajectory or recovery. Fourth, we demonstrate feasibility of scalable, multi-organ assessment in non-acute settings in the pandemic context.
Several studies confirm persistence of symptoms in individuals with long COVID up to 1 year.16 We now add that three in five people with long COVID have impairment in at least one organ, and one in four have impairment in two or more organs, in some cases without symptoms. Impact on quality of life and time off work, particularly in healthcare workers, is a major concern for individuals, health systems and economies.17
Many healthcare workers had no prior illness (2% diabetes, 2% heart disease and 22% asthma, which may play a pathophysiologic role18) but of 172 such participants, 19 were still symptomatic at follow-up and off work for a median of 180 days. We need comparison with similar analyses from other long COVID studies, and other long-term conditions,19 with considerable workforce planning implications. There have been heterogenous methods to investigate long COVID, whether qualitative20,21 or quantitative,5 or symptom surveys6 versus cohort studies.4,22 Most research still focuses on individual organs.23–25 The scale of long COVID burden necessitates action to develop, evaluate and implement evidence-based investigation, treatment and rehabilitation26 (e.g. STIMULATE-ICP and other studies4).
Metabolic diseases, including non-alcoholic liver disease and diabetes, are postulated to play a role in the pathogenesis of severe COVID-19 and possibly long COVID.27 We observe associations with markers of liver dysfunction, and increased risk of symptoms in female and obese individuals with long COVID, which have been shown previously.28,29 Cognitive impairment appears to develop in the natural history of long COVID in some patients. However, the underlying mechanisms of the condition or syndrome remain elusive. We did not find evidence by symptoms, blood investigations or MRI to clearly define long COVID subtypes.
We observed symptom resolution at 12 months in 29% of individuals with long COVID, particularly with cardiopulmonary and systemic symptoms, aligning with other longitudinal studies.5,13,19 Our findings of reductions in HRQoL and time at work reinforce prior research and are concerning, despite improvement over time. Future research must consider associations between symptoms, multi-organ impairment and function in larger cohorts, enabling clearer stratification and evaluation of treatments.
The COVERSCAN study was initiated in the early COVID-19 pandemic’s first wave when face-to-face assessment and investigation, and reduced health system capacity were major concerns for patients and health professionals. In the UK and other countries, long COVID carries high burden of investigations and healthcare utilisation across specialties, and definitive care pathways are lacking. We show feasibility, acceptability and scalability of a rapid (40-min), multi-organ MRI protocol for practice and research. Alongside routine clinical assessment and blood tests, COVERSCAN can exclude organ impairment in integrated, multidisciplinary care pathways.30 Such MRI assessment has potential application beyond the pandemic for multi-system assessment and investigation, including in lower resource settings.
Trial Registration: ClinicalTrials.gov Identifier: NCT04369807
The study findings were published in the peer reviewed Journal of the Royal Society of Medicine.