Quantitative susceptibility mapping at 7 Tesla in COVID-19: mechanistic and outcome associations (preprint)

Post mortem studies have shown that patients dying from severe SARS-CoV-2 infection frequently have pathological changes in their central nervous system, particularly in the brainstem. Many of these changes are proposed to result from para-infectious and/or post-infection immune responses. Clinical symptoms such as fatigue, breathlessness, and chest pain are frequently reported in post-hospitalized COVID-19 patients. We propose that these symptoms are in part due to damage to key neuromodulatory brainstem nuclei. While brainstem involvement has been demonstrated in the acute phase of the illness, the evidence of long-term brainstem change on magnetic resonance imaging (MRI) is inconclusive. We therefore used ultra-high field (7T) quantitative susceptibility mapping (QSM) to test the hypothesis that brainstem abnormalities persist in post-COVID patients and that these are associated with persistence of key symptoms. We used 7T QSM data from 30 patients, scanned 93 - 548 days after hospital admission for COVID-19 and compared them to 51 age-matched controls without prior history of COVID-19 infection. We correlated the patients QSM signals with disease severity (duration of hospital admission and COVID-19 severity scale), inflammatory response during the acute illness (C-reactive protein, D-Dimer and platelet levels), functional recovery (modified Rankin scale; mRS), depression (PHQ-9) and anxiety (GAD-7). In COVID-19 survivors the MR susceptibility increased in the medulla, pons and midbrain regions of the brainstem. Specifically, there was increased susceptibility in the inferior medullary reticular formation and the raphe pallidus and obscurus. In these regions, patients with higher tissue susceptibility had worse acute disease severity, higher acute inflammatory markers, and significantly worse functional recovery. Using non-invasive ultra-high field 7T MRI, we show evidence of brainstem pathophysiological changes associated with inflammatory processes in post-hospitalized COVID-19 survivors. This study contributes to understanding the mechanisms of long-term effects of COVID-19 and recovery.

One year health outcomes associated with systemic corticosteroids for COVID-19: a longitudinal cohort study (preprint)

BackgroundIn patients with COVID-19 requiring supplemental oxygen, dexamethasone reduces acute severity and improves survival, but longer-term effects are unknown. We hypothesised that systemic corticosteroid administration during acute COVID-19 would be associated with improved health-related quality of life (HRQoL) one year after discharge. MethodsAdults admitted to hospital between February 2020 and March 2021 for COVID-19 and meeting current guideline recommendations for dexamethasone treatment were included using two prospective UK cohort studies. HRQoL, assessed by EQ-5D-5L utility index, pre-hospital and one year after discharge were compared between those receiving corticosteroids or not after propensity weighting for treatment. Secondary outcomes included patient reported recovery, physical and mental health status, and measures of organ impairment. Sensitivity analyses were undertaken to account for survival and selection bias. FindingsIn 1,888 participants included in the primary analysis, 1,149 received corticosteroids. There was no between-group difference in EQ-5D-5L utility index at one year (mean difference 0.004, 95% CI: -0.026 to 0.034, p = 0.77). A similar reduction in EQ-5D-5L was seen at one year between corticosteroid exposed and non-exposed groups (mean (SD) change -0.12 (0.22) vs -0.11 (0.22), p = 0.32). Overall, there were no differences in secondary outcome measures. After sensitivity analyses modelled using a larger cohort of 109,318 patients admitted to hospital with COVID-19, EQ-5D-5L utility index at one year remained similar between the two groups. InterpretationSystemic corticosteroids for acute COVID-19 have no impact on the large reduction in HRQoL one year after hospital discharge. Treatments to address this are urgently needed. Take home messageSystemic corticosteroids given for acute COVID-19 do not affect health-related quality of life or other patient reported outcomes, physical and mental health outcomes, and organ function one year after hospital discharge

Enhanced immune ageing associated with increasing COVID-19 disease severity (preprint)

Background The striking increase in COVID-19 severity in older adults provides a clear example of immunesenescence, the age-related remodelling of the immune system. To better characterise the association between convalescent immunesenescence and acute disease severity, we determined the immune phenotype of COVID-19 survivors and non-infected controls.Results We performed detailed immune phenotyping of peripheral blood mononuclear cells isolated from 103 COVID-19 survivors 3–5 months post recovery who were classified as having had severe (n = 56; age 53.12 ± 11.30 years), moderate (n = 32; age 52.28 ± 11.43 years) or mild (n = 15; age 49.67 ± 7.30 years) disease and compared with age and sex-matched healthy adults (n = 59; age 50.49 ± 10.68 years). We assessed a broad range of immune cell phenotypes to generate a composite score, IMM-AGE, to determine the degree of immune senescence. We found increased immunesenescence features in severe COVID-19 survivors compared to controls including: a reduced frequency and number of naïve CD4 and CD8 T cells (p < 0.0001); increased frequency of EMRA CD4 (p < 0.003) and CD8 T cells (p < 0.001); a higher frequency (p < 0.0001) and absolute numbers (p < 0.001) of CD28− ve CD57+ ve senescent CD4 and CD8 T cells; higher frequency (p < 0.003) and absolute numbers (p < 0.02) of PD-1 expressing exhausted CD8 T cells; a two-fold increase in Th17 polarisation (p < 0.0001); higher frequency of memory B cells (p < 0.001) and increased frequency (p < 0.0001) and numbers (p < 0.001) of CD57+ ve senescent NK cells. As a result, the IMM-AGE score was significantly higher in severe COVID-19 survivors than in controls (p < 0.001). Few differences were seen for those with moderate disease and none for mild disease. Regression analysis revealed the only pre-existing variable influencing the IMM-AGE score was South Asian ethnicity (\(\beta\) = 0.174, p= 0.043), with a major influence being disease severity (\(\beta\) = 0.188, p = 0.01).Conclusions Our analyses reveal a state of enhanced immune ageing in survivors of severe COVID-19 and suggest this could be related to SARS-Cov-2 infection. Our data support the rationale for trials of anti-immune ageing interventions for improving clinical outcomes in these patients with severe disease.

Large scale phenotyping of long COVID inflammation reveals mechanistic subtypes of disease (preprint)

One in ten SARS-CoV-2 infections result in prolonged symptoms termed "long COVID", yet disease phenotypes and mechanisms are poorly understood. We studied the blood proteome of 719 adults, grouped by long COVID symptoms. Elevated markers of monocytic inflammation and complement activation were associated with increased likelihood of all symptoms. Elevated IL1R2, MATN2 and COLEC12 associated with cardiorespiratory symptoms, fatigue, and anxiety/depression, while elevated MATN2 and DPP10 associated with gastrointestinal (GI) symptoms, and elevated C1QA was associated with cognitive impairment (the proteome of those with cognitive impairment and GI symptoms being most distinct). Markers of neuroinflammation distinguished cognitive impairment whilst elevated SCG3, indicative of brain-gut axis disturbance, distinguished those with GI symptoms. Women had a higher incidence of long COVID and higher inflammatory markers. Symptoms did not associate with respiratory inflammation or persistent virus in sputum. Thus, persistent inflammation is evident in long COVID, distinct profiles being associated with specific symptoms.

Cohort Profile: Post-hospitalisation COVID-19 study (PHOSP-COVID) (preprint)

Abstract [bullet] PHOSP-COVID is a national UK multi-centre cohort study of patients who were hospitalised for COVID-19 and subsequently discharged. [bullet] PHOSP-COVID was established to investigate the medium- and long-term sequelae of severe COVID-19 requiring hospitalisation, understand the underlying mechanisms of these sequelae, evaluate the medium- and long-term effects of COVID-19 treatments, and to serve as a platform to enable future studies, including clinical trials. [bullet] Data collected covered a wide range of physical measures, biological samples, and Patient Reported Outcome Measures (PROMs). [bullet] Participants could join the cohort either in Tier 1 only with remote data collection using hospital records, a PROMs app and postal saliva sample for DNA, or in Tier 2 where they were invited to attend two specific research visits for further data collection and biological research sampling. These research visits occurred at five (range 2-7) months and 12 (range 10-14) months post-discharge. Participants could also participate in specific nested studies (Tier 3) at selected sites. [bullet] All participants were asked to consent to further follow-up for 25 years via linkage to their electronic healthcare records and to be re-contacted for further research. [bullet] In total, 7935 participants were recruited from 83 UK sites: 5238 to Tier 1 and 2697 to Tier 2, between August 2020 and March 2022. [bullet] Cohort data are held in a Trusted Research Environment and samples stored in a central biobank. Data and samples can be accessed upon request and subject to approvals.

The effects of sleep disturbance on dyspnoea and impaired lung function following COVID-19 hospitalisation: a prospective multi-centre cohort study (preprint)

Background Sleep disturbance is common following hospitalisation both for COVID-19 and other causes. The clinical associations are poorly understood, despite it altering pathophysiology in other scenarios. We, therefore, investigated whether sleep disturbance is associated with dyspnoea along with relevant mediation pathways. Methods Sleep parameters were assessed in a prospective cohort of patients (n=2,468) hospitalised for COVID-19 in the United Kingdom in 39 centres using both subjective and device-based measures. Results were compared to a matched UK biobank cohort and associations were evaluated using multivariable linear regression. Findings 64% (456/714) of participants reported poor sleep quality; 56% felt their sleep quality had deteriorated for at least 1-year following hospitalisation. Compared to the matched cohort, both sleep regularity (44.5 vs 59.2, p<0.001) and sleep efficiency (85.4% vs 88.5%, p<0.001) were lower whilst sleep period duration was longer (8.25h vs 7.32h, p<0.001). Overall sleep quality (effect estimate 4.2 (3.0-5.5)), deterioration in sleep quality following hospitalisation (effect estimate 3.2 (2.0-4.5)), and sleep regularity (effect estimate 5.9 (3.7-8.1)) were associated with both dyspnoea and impaired lung function (FEV1 and FVC). Depending on the sleep metric, anxiety mediated 13-42% of the effect of sleep disturbance on dyspnoea and muscle weakness mediated 29-43% of this effect. Interpretation Sleep disturbance is associated with dyspnoea, anxiety and muscle weakness following COVID-19 hospitalisation. It could have similar effects for other causes of hospitalisation where sleep disturbance is prevalent.

Nasal IgA wanes 9 months after hospitalisation with COVID-19 and is not induced by subsequent vaccination. (preprint)

Background Most studies of immunity to SARS-CoV-2 focus on circulating antibody, giving limited insights into mucosal defences that prevent viral replication and onward transmission. We studied nasal and plasma antibody responses one year after hospitalisation for COVID-19, including a period when SARS-CoV-2 vaccination was introduced. Methods Plasma and nasosorption samples were prospectively collected from 446 adults hospitalised for COVID-19 between February 2020 and March 2021 via the ISARIC4C and PHOSP-COVID consortia. IgA and IgG responses to NP and S of ancestral SARS-CoV-2, Delta and Omicron (BA.1) variants were measured by electrochemiluminescence and compared with plasma neutralisation data. Findings Strong and consistent nasal anti-NP and anti-S IgA responses were demonstrated, which remained elevated for nine months. Nasal and plasma anti-S IgG remained elevated for at least 12 months with high plasma neutralising titres against all variants. Of 180 with complete data, 160 were vaccinated between 6 and 12 months; coinciding with rises in nasal and plasma IgA and IgG anti-S titres for all SARS-CoV-2 variants, although the change in nasal IgA was minimal. Samples 12 months after admission showed no association between nasal IgA and plasma IgG responses, indicating that nasal IgA responses are distinct from those in plasma and minimally boosted by vaccination. Interpretation The decline in nasal IgA responses 9 months after infection and minimal impact of subsequent vaccination may explain the lack of long-lasting nasal defence against reinfection and the limited effects of vaccination on transmission. These findings highlight the need to develop vaccines that enhance nasal immunity.

Device-assessed sleep and physical activity in individuals recovering from a hospital admission for COVID-19: a prospective, multicentre study (preprint)

ObjectivesTo describe physical behaviours following hospital admission for COVID-19 including associations with acute illness severity and ongoing symptoms. Methods1077 patients with COVID-19 discharged from hospital between March and November 2020 were recruited. Using a 14-day wear protocol, wrist-worn accelerometers were sent to participants after a five-month follow-up assessment. Acute illness severity was assessed by the WHO clinical progression scale, and the severity of ongoing symptoms was assessed using four previously reported data-driven clinical recovery clusters. Two existing control populations of office workers and type 2 diabetes were comparators. ResultsValid accelerometer data from 253 women and 462 men were included. Women engaged in a mean{+/-}SD of 14.9{+/-}14.7 minutes/day of moderate-to-vigorous physical activity (MVPA), with 725.6{+/-}104.9 minutes/day spent inactive and 7.22{+/-}1.08 hours/day asleep. The values for men were 21.0{+/-}22.3 and 755.5{+/-}102.8 minutes/day and 6.94{+/-}1.14 hours/day, respectively. Over 60% of women and men did not have any days containing a 30-minute bout of MVPA. Variability in sleep timing was approximately 2 hours in men and women. More severe acute illness was associated with lower total activity and MVPA in recovery. The very severe recovery cluster was associated with fewer days/week containing continuous bouts of MVPA, longer sleep duration, and higher variability in sleep timing. Patients post-hospitalisation with COVID-19 had lower levels of physical activity, greater sleep variability, and lower sleep efficiency than a similarly aged cohort of office workers or those with type 2 diabetes. ConclusionsPhysical activity and regulating sleep patterns are potential treatable traits for COVID-19 recovery programmes.

The Investigation of Pulmonary Abnormalities using Hyperpolarised Xenon Magnetic Resonance Imaging in Patients with Long-COVID. (preprint)

Background Long-COVID is an umbrella term used to describe ongoing symptoms following COVID-19 infection after four weeks. Symptoms are wide-ranging but breathlessness is one of the most common and can persist for months after the initial infection. Investigations including Computed Tomography (CT), and physiological measurements (lung function tests) are usually unremarkable. The mechanisms driving breathlessness remain unclear, and this may be hindering the development of effective treatments. Methods Eleven non-hospitalised Long-COVID (NHLC, 4 male), 12 post-hospitalised COVID-19 (PHC, 10 male) patients were recruited from a Post-COVID Assessment clinic, and thirteen healthy controls (6 female) were recruited to undergo Hyperpolarized Xenon Magnetic Resonance Imaging (Hp-XeMRI). NHLC and PHC participants underwent contemporaneous CT, Hp-XeMRI, lung function tests, 1-minute sit-to-stand test and breathlessness questionnaires. Statistical analysis included group and pair-wise comparisons between patients and controls, and correlations between patient clinical and imaging data. Results NHLC and PHC patients were 287 {+/-} 79 [range 190-437] and 149 {+/-} 68 [range 68-269] days from infection, respectively. All NHLC patients had normal CT scans, and the PHC had normal or near normal CT scans (0.3/25 {+/-} 0.6 [range 0-2] and 7/25 {+/-} 5 [range 4-8], respectively). There was a significant difference in TLco (%) between NHLC and PHC patients (76 {+/-} 8 % vs 86 {+/-} 8%, respectively, p = 0.04) but no differences in other measurements of lung function. There were significant differences in RBC:TP mean between volunteers (0.45 {+/-} 0.07, range [0.33-0.55]) and PHC (0.31 {+/-} 0.11, [range 0.16-0.37]) and NHLC (0.35 {+/-} 0.09, [range 0.26-0.58]) patients, but not between NHLC and PHC (p = 0.26). Conclusion There are RBC:TP abnormalities in NHLC and PHC patients, with NHLC patients also demonstrating lower TLco than PHC patients despite their having normal CT scans. These abnormalities are present many months after the initial infection. Summary statement Hyperpolarized Xenon MRI and TLco demonstrate significantly impaired gas transfer in non-hospitalised long-COVID patients when all other investigations are normal.

Clinical characteristics with inflammation profiling of Long-COVID and association with one-year recovery following hospitalisation in the UK: a prospective observational study (preprint)

Background There are currently no effective pharmacological or non-pharmacological interventions for Long-COVID. To identify potential therapeutic targets, we focussed on previously described four recovery clusters five months after hospital discharge, their underlying inflammatory profiles and relationship with clinical outcomes at one year. Methods PHOSP-COVID is a prospective longitudinal cohort study, recruiting adults hospitalised with COVID-19 across the UK. Recovery was assessed using patient reported outcomes measures (PROMs), physical performance, and organ function at five-months and one-year after hospital discharge. Hierarchical logistic regression modelling was performed for patient-perceived recovery at one-year. Cluster analysis was performed using clustering large applications (CLARA) k-medoids approach using clinical outcomes at five-months. Inflammatory protein profiling from plasma at the five-month visit was performed. Findings 2320 participants have been assessed at five months after discharge and 807 participants have completed both five-month and one-year visits. Of these, 35.6% were female, mean age 58.7 (SD 12.5) years, and 27.8% received invasive mechanical ventilation (IMV). The proportion of patients reporting full recovery was unchanged between five months 501/165 (25.6%) and one year 232/804 (28.9%). Factors associated with being less likely to report full recovery at one year were: female sex OR 0.68 (95% CI 0.46-0.99), obesity OR 0.50 (95%CI 0.34-0.74) and IMV OR 0.42 (95%CI 0.23-0.76). Cluster analysis (n=1636) corroborated the previously reported four clusters: very severe, severe, moderate/cognitive, mild relating to the severity of physical, mental health and cognitive impairments at five months in a larger sample. There was elevation of inflammatory mediators of tissue damage and repair in both the very severe and the moderate/cognitive clusters compared to the mild cluster including interleukin-6 which was elevated in both comparisons. Overall, there was a substantial deficit in median (IQR) EQ5D-5L utility index from pre-COVID (retrospective assessment) 0.88 (0.74-1.00), five months 0.74 (0.60-0.88) to one year: 0.74 (0.59-0.88), with minimal improvements across all outcome measures at one-year after discharge in the whole cohort and within each of the four clusters. Interpretation The sequelae of a hospital admission with COVID-19 remain substantial one year after discharge across a range of health domains with the minority in our cohort feeling fully recovered. Patient perceived health-related quality of life remains reduced at one year compared to pre-hospital admission. Systematic inflammation and obesity are potential treatable traits that warrant further investigation in clinical trials.

Longitudinal Changes of Cardiac and Aortic Imaging Phenotypes Following COVID-19 in the UK Biobank Cohort (preprint)

Case studies conducted after recovery from acute infection with SARS-CoV-2 have frequently identified abnormalities on CMR imaging, suggesting the possibility that SARS-CoV-2 infection commonly leads to cardiac pathology. However, these observations have not been able to distinguish between associations that reflect pre-existing cardiac abnormalities (that might confer a greater likelihood of more severe infection) from those that arise as consequences of infection. To address this question, UK Biobank volunteers (n=1285; 54.5% women; mean age at baseline, 59.8 years old; 96.3% white) who attended an imaging assessment including cardiac magnetic resonance (CMR) before the start of the COVID-19 pandemic were invited to attend a second imaging assessment in 2021. Cases with evidence of previous SARS-CoV-2 infection were identified through linkage to PCR-testing or other medical records, or a positive antibody lateral flow test; n=640 in data available on 22 Sep 2021) and were matched to controls with no evidence of previous infection (n=645). The majority of these infections were milder and did not involve hospitalisation. Measures of cardiac and aortic structure and function were derived from the CMR images obtained on the cases before and after SARS-CoV-2 infection from images for the controls obtained over the same time interval using a previously validated, automated algorithm. Cases and controls had similar cardiac and aortic imaging phenotypes at their first imaging assessment. Changes between CMR imaging measures in cases before and after infection were not significantly different from those in the matched control group. Additional adjustment for comorbidities made no material difference to the results. While these results are preliminary and limited to imaging metrics derived from automated analyses, they do not suggest clinically significant persistent cardiac pathology in the UK Biobank population after generally milder (non-hospitalised) SARS-CoV-2 infection.

Symptom Persistence Despite Improvement in Cardiopulmonary Health - Insights from longitudinal CMR, CPET and lung function testing post-COVID-19 (preprint)

BackgroundThe longitudinal trajectories of cardiopulmonary abnormalities and symptoms following infection with coronavirus disease (COVID-19) are unclear. We sought to describe their natural history in previously hospitalised patients, compare this with controls, and assess the relationship between symptoms and cardiopulmonary impairment at 6 months post-COVID-19. MethodsFifty-eight patients and thirty matched controls underwent symptom-questionnaires, cardiac and lung magnetic resonance imaging (CMR), cardiopulmonary exercise test (CPET), and spirometry at 3 months following COVID-19. Of them, forty-six patients returned for follow-up assessments at 6 months. FindingsAt 2-3 months, 83% of patients had at least one cardiopulmonary symptom versus 33% of controls. Patients and controls had comparable biventricular volumes and function. Native cardiac T1 (marker of inflammation) and late gadolinium enhancement (LGE, marker of focal fibrosis) were increased in patients. Sixty percent of patients had lung parenchymal abnormalities on CMR and 55% had reduced peak oxygen consumption (pVO2) on CPET. By 6 months, 53% of patients remained symptomatic. On CMR, indexed right ventricular (RV) end-diastolic volume (-4{middle dot}3 mls/m2, P=0{middle dot}005) decreased and RV ejection fraction (+3{middle dot}2%, P=0{middle dot}0003) increased. Native T1 and LGE improved and was comparable to controls. Lung parenchymal abnormalities and peak VO2, although better, were abnormal in patients versus controls. 31% had reduced pVO2 secondary to fatigue and submaximal tests. Cardiopulmonary symptoms in patients did not associate with CMR, lung function, or CPET measures. InterpretationIn patients, cardiopulmonary abnormalities improve over time, though some measures remain abnormal relative to controls. Persistent symptoms at 6 months post-COVID-19 did not associate with objective measures of cardiopulmonary health. FundingNIHR Oxford and Oxford Health BRC, Oxford BHF CRE, UKRI and Wellcome Trust.

Adapting the UK Biobank brain imaging protocol and analysis pipeline for the C-MORE multi-organ study of COVID-19 survivors (preprint)

ABSTRACT SARS-CoV-2 infection has been shown to damage multiple organs, including the brain. Multiorgan MRI can provide further insight on the repercussions of COVID-19 on organ health but requires a balance between richness and quality of data acquisition and total scan duration. We adapted the UK Biobank brain MRI protocol to produce high-quality images while being suitable as part of a post-COVID-19 multiorgan MRI exam. The analysis pipeline, also adapted from UK Biobank, includes new imaging-derived phenotypes (IDPs) designed to assess the effects of COVID-19. A first application of the protocol and pipeline was performed in 51 COVID-19 patients post-hospital discharge and 25 controls participating in the Oxford C-MORE study. The protocol acquires high resolution T 1 , T 2 -FLAIR, diffusion weighted images, susceptibility weighted images, and arterial spin labelling data in 17 minutes. The automated imaging pipeline derives 1575 IDPs, assessing brain anatomy (including olfactory bulb volume and intensity) and tissue perfusion, hyperintensities, diffusivity, and susceptibility. In the C-MORE data, these quantitative measures were consistent with clinical radiology reports. Our exploratory analysis tentatively revealed that recovered COVID-19 patients had a decrease in frontal grey matter volumes, an increased burden of white matter hyperintensities, and reduced mean diffusivity in the total and normal appearing white matter in the posterior thalamic radiation and sagittal stratum, relative to controls. These differences were generally more prominent in patients who received organ support. Increased T 2 * in the thalamus was also observed in recovered COVID-19 patients, with a more prominent increase for non-critical patients. This initial evidence of brain changes in COVID-19 survivors prompts the need for further investigations. Follow-up imaging in the C-MORE study is currently ongoing, and this protocol is now being used in large-scale studies. The pipeline is widely applicable and will contribute to new analyses to hopefully clarify the medium to long-term effects of COVID-19. Highlights UK Biobank brain MRI protocol and pipeline was adapted for multiorgan MRI of COVID-19 High-quality brain MRI data from 5 modalities are acquired in 17 minutes Analysis pipeline derives 1575 IDPs of brain anatomy, perfusion, and microstructure Evidence of brain changes in COVID-19 survivors was found in the C-MORE study This MRI protocol is now being used in multiple large-scale studies on COVID-19

Medium-term effects of SARS-CoV-2 infection on multiple vital organs, exercise capacity, cognition, quality of life and mental health, post-hospital discharge (preprint)

BackgroundThe medium-term effects of Coronavirus disease (COVID-19) on multiple organ health, exercise capacity, cognition, quality of life and mental health are poorly understood. MethodsFifty-eight COVID-19 patients post-hospital discharge and 30 comorbidity-matched controls were prospectively enrolled for multiorgan (brain, lungs, heart, liver and kidneys) magnetic resonance imaging (MRI), spirometry, six-minute walk test, cardiopulmonary exercise test (CPET), quality of life, cognitive and mental health assessments. FindingsAt 2-3 months from disease-onset, 64% of patients experienced persistent breathlessness and 55% complained of significant fatigue. On MRI, tissue signal abnormalities were seen in the lungs (60%), heart (26%), liver (10%) and kidneys (29%) of patients. COVID-19 patients also exhibited tissue changes in the thalamus, posterior thalamic radiations and sagittal stratum on brain MRI and demonstrated impaired cognitive performance, specifically in the executive and visuospatial domain relative to controls. Exercise tolerance (maximal oxygen consumption and ventilatory efficiency on CPET) and six-minute walk distance (405{+/-}118m vs 517{+/-}106m in controls, p<0.0001) were significantly reduced in patients. The extent of extra-pulmonary MRI abnormalities and exercise tolerance correlated with serum markers of ongoing inflammation and severity of acute illness. Patients were more likely to report symptoms of moderate to severe anxiety (35% versus 10%, p=0.012) and depression (39% versus 17%, p=0.036) and a significant impairment in all domains of quality of life compared to controls. InterpretationA significant proportion of COVID-19 patients discharged from hospital experience ongoing symptoms of breathlessness, fatigue, anxiety, depression and exercise limitation at 2-3 months from disease-onset. Persistent lung and extra-pulmonary organ MRI findings are common. In COVID-19 survivors, chronic inflammation may underlie multiorgan abnormalities and contribute to impaired quality of life. FundingNIHR Oxford and Oxford Health Biomedical Research Centres, British Heart Foundation Centre for Research Excellence, UKRI, Wellcome Trust, British Heart Foundation.