Multiorgan impairment in low-risk individuals with post-COVID-19 syndrome: A prospective, community-based study

Abstract

Objective:
To assess medium-term organ impairment in symptomatic individuals following recovery from acute SARS-CoV-2 infection.

Design:
Baseline findings from a prospective, observational cohort study.

Setting:
Community-based individuals from two UK centres between 1 April and 14 September 2020.

Participants:
Individuals ≥18 years with persistent symptoms following recovery from acute SARS-CoV-2 infection and age-matched healthy controls.

Intervention:
Assessment of symptoms by standardised questionnaires (EQ-5D-5L, Dyspnoea-12) and organ-specific metrics by biochemical assessment and quantitative MRI.

Main outcome measures:
Severe post-COVID-19 syndrome defined as ongoing respiratory symptoms and/or moderate functional impairment in activities of daily living; single-organ and multiorgan impairment (heart, lungs, kidneys, liver, pancreas, spleen) by consensus definitions at baseline investigation.

Results:
201 individuals (mean age 45, range 21-71 years, 71% female, 88% white, 32% healthcare workers) completed the baseline assessment (median of 141 days following SARS-CoV-2 infection, IQR 110-162). The study population was at low risk of COVID-19 mortality (obesity 20%, hypertension 7%, type 2 diabetes 2%, heart disease 5%), with only 19% hospitalised with COVID-19. 42% of individuals had 10 or more symptoms and 60% had severe post-COVID-19 syndrome. Fatigue (98%), muscle aches (87%), breathlessness (88%) and headaches (83%) were most frequently reported. Mild organ impairment was present in the heart (26%), lungs (11%), kidneys (4%), liver (28%), pancreas (40%) and spleen (4%), with single-organ and multiorgan impairment in 70% and 29%, respectively. Hospitalisation was associated with older age (p=0.001), non-white ethnicity (p=0.016), increased liver volume (p<0.0001), pancreatic inflammation (p<0.01), and fat accumulation in the liver (p<0.05) and pancreas (p<0.01). Severe post-COVID-19 syndrome was associated with radiological evidence of cardiac damage (myocarditis) (p<0.05).

Conclusions:
In individuals at low risk of COVID-19 mortality with ongoing symptoms, 70% have impairment in one or more organs 4 months after initial COVID-19 symptoms, with implications for healthcare and public health, which have assumed low risk in young people with no comorbidities.

Trial registration number:
NCT04369807; Pre-results.

Full text

1
DennisA, etal. BMJ Open 2021;11:e048391. doi:10.1136/bmjopen-2020-048391
Open access
Multiorgan impairment in low- risk
individuals with post- COVID-19
syndrome: a prospective, community-
based study
Andrea Dennis,1 Malgorzata Wamil,2,3 Johann Alberts,4 Jude Oben,5,6
Daniel J Cuthbertson,7 Dan Wootton,8,9 Michael Crooks,10,11 Mark Gabbay,12
Michael Brady,1,13 Lyth Hishmeh,14 Emily Attree,15 Melissa Heightman,16
Rajarshi Banerjee,1 Amitava Banerjee ,16,17,18 On behalf of COVERSCAN study
investigators
To cite: DennisA, WamilM,
AlbertsJ, etal. Multiorgan
impairment in low- risk
individuals with post-
COVID-19 syndrome: a
prospective, community-
based study. BMJ Open
2021;11:e048391. doi:10.1136/
bmjopen-2020-048391
►Prepublication history and
additional material for this
paper are available online. To
view these les, please visit
the journal online (http:// dx. doi.
org/ 10. 1136/ bmjopen- 2020-
048391).
RB and AB are joint senior
authors.
Received 26 December 2020
Revised 25 February 2021
Accepted 11 March 2021
For numbered afliations see
end of article.
Correspondence to
Dr Amitava Banerjee;
ami. banerjee@ ucl. ac. uk
Original research
© Author(s) (or their
employer(s)) 2021. Re- use
permitted under CC BY.
Published by BMJ.
ABSTRACT
Objective To assess medium- term organ impairment in
symptomatic individuals following recovery from acute
SARS- CoV-2 infection.
Design Baseline ndings from a prospective,
observational cohort study.
Setting Community- based individuals from two UK
centres between 1 April and 14 September 2020.
Participants Individuals ≥18 years with persistent
symptoms following recovery from acute SARS- CoV-2
infection and age- matched healthy controls.
Intervention Assessment of symptoms by standardised
questionnaires (EQ- 5D- 5L, Dyspnoea-12) and organ-
specic metrics by biochemical assessment and
quantitative MRI.
Main outcome measures Severe post- COVID-19
syndrome dened as ongoing respiratory symptoms and/or
moderate functional impairment in activities of daily living;
single- organ and multiorgan impairment (heart, lungs,
kidneys, liver, pancreas, spleen) by consensus denitions
at baseline investigation.
Results 201 individuals (mean age 45, range 21–71
years, 71% female, 88% white, 32% healthcare workers)
completed the baseline assessment (median of 141 days
following SARS- CoV-2 infection, IQR 110–162). The study
population was at low risk of COVID-19 mortality (obesity
20%, hypertension 7%, type 2 diabetes 2%, heart disease
5%), with only 19% hospitalised with COVID-19. 42%
of individuals had 10 or more symptoms and 60% had
severe post- COVID-19 syndrome. Fatigue (98%), muscle
aches (87%), breathlessness (88%) and headaches (83%)
were most frequently reported. Mild organ impairment
was present in the heart (26%), lungs (11%), kidneys
(4%), liver (28%), pancreas (40%) and spleen (4%), with
single- organ and multiorgan impairment in 70% and 29%,
respectively. Hospitalisation was associated with older age
(p=0.001), non- white ethnicity (p=0.016), increased liver
volume (p<0.0001), pancreatic inammation (p<0.01),
and fat accumulation in the liver (p<0.05) and pancreas
(p<0.01). Severe post- COVID-19 syndrome was associated
with radiological evidence of cardiac damage (myocarditis)
(p<0.05).
Conclusions In individuals at low risk of COVID-19
mortality with ongoing symptoms, 70% have impairment
in one or more organs 4 months after initial COVID-19
symptoms, with implications for healthcare and public
health, which have assumed low risk in young people with
no comorbidities.
Trial registration number NCT04369807; Pre-results.
INTRODUCTION
Early in the COVID-19 pandemic, research
and clinical practice focused on pulmonary
manifestations.1 There is increasing evidence
for direct multiorgan effects,2–7 as well as indi-
rect effects on other organ systems and disease
processes, such as cardiovascular diseases
and cancers, through changes in healthcare
delivery and patient behaviours.8–10 The
Strengths and limitations of this study
►This is an ongoing, prospective, longitudinal
COVID-19 recovery study with biochemical and im-
aging characterisation of organ function, starting in
April 2020 before recognition of ‘long- COVID’, prop-
er testing availability and prospective COVID-19-
related research.
►By recruiting ambulatory patients with broad inclu-
sion criteria, we focused on a real- world population
at lower risk of COVID-19 severity and mortality.
►Healthy controls were included for comparison, not
individuals with postinuenza symptoms, COVID-19
without symptoms or from general clinics, which
further studies may explore.
►The study population was not ethnically diverse
despite disproportionate COVID-19 impact in non-
white individuals.
►To limit interaction and exposure between the trial
team and the patients, pulse oximetry, spirometry,
MRI assessment of the brain and muscle function
were not included from the outset.
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2DennisA, etal. BMJ Open 2021;11:e048391. doi:10.1136/bmjopen-2020-048391
Open access
clear long- term impact on individuals and health systems
underlines the urgent need for a whole body approach
with assessment of all major organ systems following
SARS- CoV-2 infection. Quantitative MRI has recently
been used to show multiorgan impairment in individuals
post- COVID-19 hospitalisation,11 but has not been used in
non- hospitalised individuals.
COVID-19 is the convergence of an infectious disease,
undertreated non- communicable diseases and social
determinants of health, described as a ‘syndemic’.12 Pre-
existing non- communicable diseases and risk factors
predict poor COVID-19 outcomes, whether intensive
care admission or mortality.10 Research has emphasised
acute SARS- CoV-2 infection, hospitalised individuals and
COVID-19 mortality,13–15 which is likely to underestimate
the true burden of COVID-19- related disease. Among
those surviving acute infection, 10% report persistent
symptoms for 12 weeks or longer after initial infection
(‘long- COVID’, or ‘post COVID-19 syndrome’, PCS).16
However, PCS is yet to be fully defined.17–20 Neither
severity of symptoms, nor medium- term and long- term
pathophysiology across organ systems, nor the appro-
priate control populations are understood.
UK government policies have emphasised excess
mortality risk in moderate- risk and high- risk conditions,
including ‘shielding’10 and commissioning of a risk calcu-
lator to identify those at highest risk of COVID-19 severity
and mortality.21 These policies assume that younger indi-
viduals without apparent underlying conditions are at low
risk. However, unlike symptoms following critical illness22
or acute phase of other coronavirus infections,23 symp-
toms in PCS are commonly reported in individuals with
low COVID-19 mortality risk, for example, female, young
and no chronic comorbidities.14 The potential scale of
PCS in ‘lower- risk’ individuals, representing up to 80% of
the population,3 necessitates urgent policies across coun-
tries to monitor,24 treat19 and pay25 for long- term implica-
tions of COVID-19 and to mitigate impact on healthcare
utilisation and economies.
Therefore, in a pragmatic, prospective cohort study
of individuals with persistent symptoms at least 4 weeks
following recovery from acute SARS- CoV-2 infection and
at low risk of COVID-19 mortality, we investigated (1)
the prevalence of multiorgan impairment, compared
with healthy, age- matched controls; (2) the associations
between typical COVID-19 symptoms and multiorgan
impairment; and (3) the associations between hospital-
isation, severity of symptoms and multiorgan impairment.
METHODS
Patient population and study design
In an ongoing, prospective study, participants were
recruited to the study following expression of interest on
the study registration website. Participants learnt about
the study through advertisement on social media or via
recommendations from clinicians from four partici-
pant identification centres, the latter usually applied to
patients who had been hospitalised. Assessment took
place at two UK research imaging sites (Perspectum,
Oxford; and Mayo Clinic Healthcare, London) between
1 April 2020 and 14 September 2020, completing base-
line assessment by 14 September 2020 (figure 1). Partic-
ipants with laboratory- confirmed SARS- CoV-2 infection
(tested SARS- CoV-2- positive by oropharyngeal/naso-
pharyngeal swab by reverse- transcriptase PCR (n=62),
a positive antibody test (n=63), or with strong clinical
suspicion of infection with typical symptoms/signs and
assessed as highly likely to have COVID-19 by two inde-
pendent clinicians (n=73)) were eligible for enrolment.
Exclusion criteria were symptoms of active respiratory
viral infection (temperature >37.8°C or three or more
episodes of coughing in 24 hours), hospital discharge in
the last 7 days, and contraindications to MRI, including
implanted pacemakers, defibrillators, other metallic
implanted devices and claustrophobia. All participants
gave written informed consent.
Assessment of PCS
Assessment included patient- reported validated question-
naires (quality of life, EQ- 5D- 5L,26 and Dyspnoea-1227)
and fasting biochemical investigations (listed in online
supplemental methods). PCS was classified as ‘severe’
(defined as persistent breathlessness, score of ≥10 on
Dyspnoea-12, or reported moderate or greater problems
with usual activities on EQ- 5D- 5L) or ‘moderate’. These
thresholds were selected as the Dyspnoea-12 has been
correlated with the Medical Research Council (MRC)
Figure 1 Flow from recruitment to enrolment of 201 patients
with post- COVID-19 syndrome.
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Table 1 Baseline demographics and symptoms of 201 low- risk individuals with post- COVID-19 syndrome
All patients
(N=201)
Healthy
controls (n=36)
P
value
Not hospitalised
(n=163)
Hospitalised
(n=37)
P
value
Moderate PCS
(n=77)
Severe PCS
(n=116) P value
Age (years), mean (SD) 44 (11.0) 39 (12.4) 0.013 43 (10.9) 50 (10.0) 0.001 45 (12.2) 44 (10.0) 0.419
Female, n (%) 142 (70.6) 14 (38.9) 0.032 118 (72.4) 23 (62.2) 0.302 51 (66.2) 85 (73.3) 0.374
BMI (kg/m2), median (IQR) 25.7 (22.7–28.1) 23.2 (21.4–23.1) <0.001 25.3 (22.7–27.7) 27.2 (23.1–31.0) 0.063 25.8 (22.7–27.9) 25.4 (22.5–28.2) 0.639
Ethnicity
White 176 (87.6) 33 (91.7) 148 (90.8) 28 (75.7) 67 (87.0) 106 (91.4) 0.178
Mixed 3 (1.5) 0 (0) 0.904 3 (1.8) 0 (0) 0.016 1 (1.3) 2 (1.7)
South Asian 7 (3.5) 3 (8.3) 4 (2.5) 3 (8.1) 5 (6.5) 0 (0)
Black 4 (2.0) 0 (0) 1 (0.6) 2 (5.4) 2 (2.6) 2 (1.7)
Comorbidities and risks
Smoking 0.244
Never 133 (66.2) 20 (60.6) 108 (66.3) 24 (64.9) 55 (71.4) 72 (61.7)
Current 6 (3.0) 8 (24.2) <0.001 6 (3.7) 0 (0) 0.641 3 (3.9) 3 (2.6)
Ex- smoker 62 (30.8) 5 (15.2) 49 (30.1) 13 (35.1) 19 (24.7) 41 (35.3)
Healthcare worker 64 (31.8) 4 (12.1) 0.009 50 (30.7) 13 (35.1) 0.695 33 (42.9) 28 (24.1) 0.007
Asthma 37 (18.4) 0 (0) 0.002 34 (20.9) 3 (8.1) 0.099 13 (16.9) 22 (19.0) 0.849
BMI
≥25 kg/m2113 (56.5) 7 (20) 87 (53.7) 25 (67.6) 0.144 46 (60.5) 62 (53.4) 0.374
≥30 kg/m240 (20.0) 0 (0) 28 (17.3) 12 (32.4) 0.066 16 (21.1) 24 (20.7) 1.000
Hypertension 13 (6.5) 0 (0) 0.001 11 (6.7) 2 (5.4) 1.000 6 (7.8) 7 (6.0) 0.771
Diabetes 4 (2.0) 0 (0) 0.104 4 (2.5) 0 (0.0) 1.000 4 (5.2) 0 (0.0) 0.024
Previous heart disease 9 (4.5) 0 (0) 0.001 8 (4.9) 1 (2.7) 1.000 3 (3.9) 5 (4.3) 1.000
Symptoms
Fatigue 196 (98.0) 159 (97.5) 37 (100.0) 1.000 73 (96.1) 115 (99.1) 0.302
Shortness of breath 176 (88.0) 141 (86.5) 35 (94.6) 0.262 58 (76.3) 112 (96.6) <0.0001
Muscle ache 173 (86.5) 142 (87.1) 31 (83.8) 0.597 66 (86.8) 101 (87.1) 1.000
Headache 165 (82.5) 138 (84.7) 27 (73.0) 0.098 56 (73.7) 102 (87.9) 0.019
Joint pain 156 (78.0) 127 (77.9) 29 (78.4) 1.000 56 (73.7) 94 (81.0) 0.284
Chest pain 152 (76.0) 128 (78.5) 24 (64.9) 0.090 47 (61.8) 98 (84.5) 0.001
Cough 146 (73.0) 117 (71.8) 29 (78.4) 0.539 55 (72.4) 84 (72.4) 1.000
Fever 144 (72.0) 113 (69.3) 31 (83.8) 0.104 51 (67.1) 86 (74.1) 0.329
Sore throat 143 (71.5) 120 (73.6) 23 (62.2) 0.165 50 (65.8) 86 (74.1) 0.256
Continued
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4DennisA, etal. BMJ Open 2021;11:e048391. doi:10.1136/bmjopen-2020-048391
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dyspnoea grade, where level 3 warrants referral to reha-
bilitation services,27 and with EQ- 5D- 5L, less than 8% of
the general population report moderate or greater prob-
lems with usual activities.28
Multiorgan impairment in PCS compared with healthy controls
We selected MRI as the imaging modality (as in UK
Biobank) due to (1) safety (no radiation exposure, no
need for intravenous contrast and minimal contact
with the radiographer); (2) quantitative reproducibility
(>95% acquisition and image processing success rate);
(3) capacity for information sharing (digital data repos-
itory for independent analysis and research); and (4)
rapid scalability (35 min scan to phenotype lung, heart,
kidney, liver, pancreas and spleen). Multiorgan MRI data
were collected at both study sites (Oxford: MAGNETOM
Aera 1.5T; Mayo Healthcare London: MAGNETOM Vida
3T; both from Siemens Healthcare, Erlangen, Germany).
The COVERSCAN multiparametric MRI assessment typi-
cally required 35 min per patient, including the lungs,
heart, liver, pancreas, kidneys and spleen, by standardised
methodology (online supplemental file 1). In brief, we
assessed inflammation of the heart, kidneys, liver and
pancreas with quantitative T1 relaxation mapping; lung
function was characterised with a dynamic structural
T2- weighted lung scan estimating lung capacity; ectopic
fat accumulation in the liver and pancreas from proton
density fat fraction; and volume of the liver and spleen
measured from T1- weighted structural scan.
To determine impairment in each organ, we compared
MRI- derived measurements from the heart, lungs,
kidneys, liver, pancreas and spleen with reference ranges
(online supplemental table 1), which were established
as mean±2 SD from the healthy, age- matched control
subjects (n=36) and validated by scoping literature
review.11 We defined organ impairment if quantitative
T1 mapping was outside the reference ranges for the
heart, kidney, liver and pancreas, reduced estimated
lung capacity from dynamic measurements in the lungs,
or there was evidence of hepatomegaly, splenomegaly or
ectopic fat accumulation.
Symptoms and multiorgan impairment
Associations between organ impairment and symptoms
were visually assessed using a heat map, dividing those
with impairments to an organ into columns and colouring
the rows by percentage of reported symptoms.
Hospitalisation, severity and multiorgan impairment
We compared mean differences in quantitative organ
metrics for hospitalised versus not hospitalised and
moderate versus severe PCS using Kruskal- Wallis test
(Fisher’s exact test for differences in binary outcomes).
We defined multiorgan impairment as ≥2 organs with
metrics outside the reference range. We investigated the
associations between multiorgan impairment and (1)
being hospitalised and (2) severe PCS with multivariate
All patients
(N=201)
Healthy
controls (n=36)
P
value
Not hospitalised
(n=163)
Hospitalised
(n=37)
P
value
Moderate PCS
(n=77)
Severe PCS
(n=116) P value
Diarrhoea 118 (59.0) 91 (55.8) 27 (73.0) 0.065 40 (52.6) 76 (65.5) 0.097
Abnormal pain 108 (54.0) 91 (55.8) 17 (45.9) 0.361 30 (39.5) 75 (64.7) 0.001
Wheezing 98 (49.0) 75 (46.0) 23 (62.2) 0.101 30 (39.5) 64 (55.2) 0.039
Inability to walk 80 (40.0) 58 (35.6) 22 (59.5) 0.009 24 (31.6) 50 (43.1) 0.130
Runny nose 68 (34.0) 55 (33.7) 13 (35.1) 0.85 24 (31.6) 41 (35.3) 0.642
Time interval
Initial symptoms to assessment
(days), median (IQR) 141 (110–162) 141 (112–163) 138 (97–150) 0.106 121 (89–158) 145 (121–163) 0.001
COVID-19- positive to
assessment (days), median
(IQR) 71 (41–114) 68 (35–112) 105 (59–126) 0.012 60 (43–98) 78 (34–119) 0.305
Data are presented as count (%).
Comparisons between managed at home versus hospitalised and between moderate versus PCS were conducted using Fisher’s exact test
BMI, body mass index; PCS, post- COVID-19 syndrome.
Table 1 Continued
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DennisA, etal. BMJ Open 2021;11:e048391. doi:10.1136/bmjopen-2020-048391
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logistic regression models, adjusting for age, sex and body
mass index (BMI).
Patient and public involvement and engagement
Patients and the public have directly and indirectly
informed our research, from design to dissemination,
with regular updates and webinars, including question
and answer sessions with patients. Several clinician coau-
thors were indirectly informed by their patients in the
COVERSCAN study (RB, AB) or PCS clinics (DW, MH,
MC), who are members of organisations such as Long
Covid SOS (eg, LH) and UKDoctors#Longcovid (eg, EA).
LH and EA have been involved in the research, inter-
pretation of results, understanding implications of our
results and providing critical feedback to the manuscript.
Statistical analysis
We performed all analyses using R V.3.6.1, using descrip-
tive statistics to summarise baseline characteristics and
considering a p value less than 0.05 as statistically signif-
icant. Mean and SD were used for normally distributed
continuous variables, median with IQR for non- normally
distributed variables, and frequency and percentage for
categorical variables. For group- wise comparison for abso-
lute values between cases and healthy controls, we used
Kruskal- Wallis test.
RESULTS
Overall study population
Baseline characteristics
The study included 201 individuals (full details regarding
hospitalisation: n=199; full questionnaire data to assign
PCS severity: n=193). The mean age was 44.0 (range
21–71) years and the median BMI was 25.7 (IQR 23–28).
Of the individuals, 71% were female, 88% were white,
32% were healthcare workers and 19% had been hospi-
talised with COVID-19. Assessments (symptoms, blood
and MRI) had a median of 141 (IQR 110–162) days after
initial symptoms. Medical history included smoking
(3%), asthma (19%), obesity (20%), hypertension (7%),
diabetes (2%) and prior heart disease (5%). The healthy
control group had a mean age of 39 years (range 20–70),
40% were female, with a median BMI of 23 (IQR: 21–25)
(table 1).
Regardless of hospitalisation, the most frequently
reported symptoms were fatigue (98%), shortness of
breath (88%), muscle ache (87%) and headache (83%)
(table 1). Of the individuals, 99% had four or more and
42% had ten or more symptoms. Of individuals 70%
reported ≥13 weeks off paid employment. Of the inci-
dental structural findings observed on MRI (n=56), three
were cardiac (atrial septal defect, bicuspid aortic valve
and right atrial mass), one renal (hydronephrosis) and
the rest were benign cysts.
Haematological investigations, including mean corpus-
cular haemoglobin concentration (24%), and renal,
liver and lipid biochemistry, including potassium (38%),
alanine transferase (14%), lactate dehydrogenase (17%),
triglycerides (11%) and cholesterol (42%), were abnor-
mally high in ≥10% of individuals. Bicarbonate (10%),
phosphate (11%), uric acid (11%) and transferrin satu-
ration (19%) were abnormally low in ≥10% of individuals
(online supplemental table 1).
Single-organ and multiorgan impairment in PCS compared
with healthy controls
Organ impairment was more common in PCS than
healthy controls (figure 2 and online supplemental figure
Figure 2 Percentage of patients (black) and controls (grey) with individual organ measures outside of the predened normal
range. Lines represent signicant difference in the proportions between the two groups, with *p<0.05, **p<0.01, ***p<0.001. LV,
left ventricular.
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6DennisA, etal. BMJ Open 2021;11:e048391. doi:10.1136/bmjopen-2020-048391
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Table 2 Evidence of organ impairment in 201 low- risk individuals with post- COVID-19 syndrome
Measurement
All patients
(N=201)
Healthy
controls (n=36)
P
value
Not hospitalised
(n=163)
Hospitalised
(n=37) P value
Moderate
PCS (n=77)
Severe PCS
(n=116)
P
value
Heart
Left ventricular ejection fraction (%)
Normal (>51%) 190 (95.0) 35 (97.2) 0.699 155 (95.7) 33 (89.1) 0.124 72 (93.5) 111 (95.7) 0.353
Impaired (≤51%) 11 (5.0) 1 (2.8) 7 (4.3) 4 (10.1) 5 (6.4) 5 (4.3)
Left ventricular end diastolic volume (mL)
>264 mL in Men; >206 mL in Women 8 (4.0) 1 (2.8) 1.00 4 (2.5) 4 (10.8) 0.040 4 (5.2) 4 (3.4) 0.715
Evidence of myocarditis
≥3 segments with high T1 (≥1229 ms at 3T;
≥1015 ms at 1.5T) 39 (19.4)
2 (5.6)
0.053 30 (18.4) 8 (21.6) 0.647 9 (11.7) 29 (25.0) 0.027
Lungs
Deep breathing fractional area change (n=17 missing) (n=13 missing) (n=3 missing) (n=8 missing) (n=7 missing)
<31% 21 (11.4) 1 (2.8) 0.138 17 (11.3) 4 (11.8) 1 7 (10.1) 13 (11.9) 0.811
Kidneys
Kidney cortex T1 (n=3 missing) (n=3 missing) (n=2 missing)
Normal (<1652 ms at 3T; <1227 ms at 1.5T) 191 (96.5) 36 (100.0) 0.599 155 (96.9) 35 (94.6) 0.618 74 (98.7) 112 (96.6) 0.65
Impaired (≥1652 ms at 3T; ≥1227 ms at 1.5T) 7 (3.5) 0 (0.0) 5 (3.1) 2 (5.4) 1 (1.3) 4 (3.4)
Pancreas
Pancreatic inammation (T1 in ms) (n=11 missing) (n=13 missing) (n=7 missing) (n=4 missing) (n=4 missing) (n=6 missing)
Normal <803 ms 162 (85.3) 23 (100.0) 0.049 139 (89.1) 22 (66.7) 0.002 60 (82.2) 95 (86.4) 0.530
Impaired ≥803 ms 28 (14.7) 0 (0) 17 (10.9) 11 (33.3) 13 (17.8) 15 (13.6)
Pancreatic fat (n=4 missing)
Normal <4.6% 122 (62.2) 30 (93.8) <0.001 107 (66.9) 14 (40.0) 0.004 44 (57.9) 72 (63.7) 0.449
Impaired ≥4.6% 74 (37.8) 2 (6.2) 53 (33.1) 21 (60.0) 32 (42.1) 41 (36.3)
Liver
Liver inammation (cT1 in ms) (n=1 missing) (n=1 missing) (n=1 missing)
Normal <784 ms 177 (88.5) 36 (100) 0.030 148 (91.4) 28 (75.7) 0.018 69 (90.8) 101 (87.1) 0.494
Impaired ≥784 ms 23 (11.5) 0 (0) 14 (8.6) 9 (24.3) 7 (9.2) 15 (12.9)
Liver fat
Normal <4.8% 159 (79.1) 34 (94.4) 0.034 134 (82.2) 24 (64.9) 0.026 61 (79.2) 91 (78.4) 1
Impaired ≥4.8% 42 (20.9) 2 (5.4) 29 (17.8) 13 (35.1) 16 (20.8) 25 (21.6)
Liver volume (n=1 missing)
Continued
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1). Impairment was present in the heart in 26% (myocar-
ditis 19%, systolic dysfunction 9%), lung in 11% (reduced
vital capacity), kidney in 4% (inflammation), liver in 28%
(12% inflammation, 21% ectopic fat, 10% hepatomegaly),
pancreas in 40% (15% inflammation, 38% ectopic fat)
and spleen in 4% (splenomegaly) (figure 2 and table 2).
Of the individuals, 70% had impairment in at least one
organ and 29% had multiorgan impairment, with overlap
across multiple organs (figure 3). Impairment in the liver,
heart or lungs was associated with further organ impair-
ment in 63%, 62% and 48% of individuals, respectively
(figure 3).
Symptoms and multiorgan impairment
Hepatic and pulmonary impairment frequently clustered
together, with fatigue, muscle aches, fever and cough
commonly reported. Impairment in particular organs
was associated with particular symptoms—pancreas: diar-
rhoea, fever, headache and dyspnoea; heart: headache,
dyspnoea and fatigue; and kidney: wheezing, runny nose,
diarrhoea, cough, fever, headache, dyspnoea and fatigue
(figure 4).
Hospitalisation, severity and multiorgan impairment
The hospitalised group were older (p=0.001), had higher
BMI (p=0.063), and were more likely to be non- white
(p=0.016) and to report ‘inability to walk’ (p=0.009)
than non- hospitalised individuals. There were no other
statistically significant differences between risk factors
or symptoms between the groups. Impairment of the
liver, pancreas (eg, ectopic fat in the pancreas and liver,
hepatomegaly) and ≥2 organs was higher in hospitalised
individuals (all p<0.05) (figure 3 and table 2). In multi-
variate analyses, adjusting for age, sex and BMI, liver
volume remained significantly associated with hospi-
talisation (p=0.001). Hospitalised individuals had high
triglycerides (30% vs 7.2%, p=0.002), cholesterol (60%
vs 38%, p=0.04) and low- density lipoprotein- cholesterol
(57% vs 31%, p=0.01), and low transferrin saturation
(38% vs 15%, p=0.01), compared with non- hospitalised
individuals. erythrocyte sedimentation rate (ESR) (13%),
bicarbonate (12%), uric acid (16%), platelet count (13%)
and high- sensitivity C- reactive protein (CRP) (15%) were
high in ≥10% of hospitalised individuals.
Of the individuals, 60% (n=120) had severe PCS, with
52% reporting persistent, moderate problems under-
taking usual activities (level 3 or greater in the relevant
EQ- 5D- 5L question; 34% reported Dyspnoea-12 score
≥10). Of those with severe PCS, 84% were not hospitalised
and 73% were female. There were no differences in age,
BMI or ethnicity between the groups. Individuals with
severe PCS were more likely to report shortness of breath
(p<0.001), headache (p=0.019), chest pain (p=0.001),
abdominal pain (p=0.001) and wheezing (p=0.039). Of
those with ‘severe’ PCS, 25% had myocarditis compared
with 12% with moderate PCS (unadjusted: 0.023; adjust-
ment for age, sex and BMI: p=0.04; online supplemental
figure 2). Severe PCS was associated with higher mean
Measurement
All patients
(N=201)
Healthy
controls (n=36)
P
value
Not hospitalised
(n=163)
Hospitalised
(n=37) P value
Moderate
PCS (n=77)
Severe PCS
(n=116)
P
value
Normal <1935 mL 180 (89.6) 34 (97.1) 0.214 154 (94.5) 25 (67.6) <0.0001 68 (88.3) 104 (89.7) 0.816
Impaired ≥1935 mL 21 (10.4) 1 (2.9) 9 (5.5) 12 (32.4) 9 (11.7) 12 (10.3)
Spleen
Splenic volume (mL) (n=1 missing)
Normal <350 mL 194 (96.5) 32 (91.4) 0.172 160 (98.2) 33 (89.2) 0.023 74 (96.1) 112 (96.6) 1
Impaired ≥350 mL 7 (3.5) 3 (8.6) 3 (1.8) 4 (10.8) 3 (3.9) 4 (3.4)
Data are presented as count (%).
Comparisons between managed at home versus hospitalised and between moderate versus PCS were conducted using Fisher’s exact test.
PCS, post- COVID-19 syndrome.
Table 2 Continued
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8DennisA, etal. BMJ Open 2021;11:e048391. doi:10.1136/bmjopen-2020-048391
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cell haemoglobin concentration (28% vs 17%), choles-
terol (46.2% vs 32.8%), CRP (10% vs 3.8%) and ESR
(10% vs 6%) than moderate PCS, but these differences
were not statistically significant (online supplemental
table 3). Muscle aches, fever and coughing were common
in severe PCS, and headache was common in individuals
with inflammation of the pancreas (figure 4).
DISCUSSION
We report three findings in the first COVID-19 recovery
study to evaluate medium- term, multiorgan impairment.
First, in low- risk individuals, there were chronic symptoms
and mild impairment in the heart, lung, liver, kidney
and pancreas 4 months post- COVID-19, compared with
healthy controls. Second, cardiac impairment was more
common in severe PCS. Third, we demonstrate feasibility
and potential utility of community- based multiorgan
assessment for PCS.
Comparison with other studies
Common symptoms were fatigue, dyspnoea, myalgia,
headache and arthralgia, despite low risk of COVID-19
mortality or hospitalisation. COVID-19 impact models
have included age, underlying conditions and mortality,
but not morbidity, multiorgan impairment and chronic
diseases.29 30 Even in non- hospitalised individuals, up
to 10% of those infected have PCS,15 31 but studies of
extrapulmonary manifestations emphasise acute illness.32
We describe mild rather than severe organ impairment,
but the pandemic’s scale and high infection rates in lower
risk individuals signal medium- term and longer- term
COVID-19 impact, which cannot be ignored in health-
care or policy spheres.
Acute myocarditis and cardiogenic shock33 are docu-
mented in hospitalised patients with COVID-19.6 In
American athletes, recent COVID-19 was associated with
myocarditis.34 Although causality cannot be attributed
and postviral syndromes have included similar find-
ings,21 we show that a quarter of low- risk individuals with
PCS have mild systolic dysfunction or myocarditis. The
significance of these findings and the associations with
contemporaneous abnormal echocardiography findings
and long- term myocardial fibrosis and impairment are
unknown. Cardiac impairment, a risk factor for severe
COVID-19, may have a role in PCS. Two further findings
that deserve investigation are pancreatic abnormalities,
given the excess diabetes risk reported in PCS,15 and the
preponderance of healthcare workers at increased PCS
risk (as observed for COVID-19 mortality), possibly due
to higher viral burden.
PCS is likely to be a syndrome rather than a single
condition. Despite an immunological basis for individual
variations in COVID-19 progression and severity,35 predic-
tion models have high rates of bias, perform poorly,36 and
focus on respiratory dysfunction and decisions for venti-
lation in acutely unwell patients, rather than multiorgan
function. Ongoing long- term studies37 exclude non-
hospitalised, low- risk individuals. During a pandemic, we
studied subclinical organ impairment in PCS, showing
low rates of incidental findings. As specialist PCS services
are rolled out,38 39 multiorgan assessment, monitoring
and community pathways have potential roles during and
beyond COVID-19, but need to be evaluated.
Implications for research, clinical practice and public health
Our findings have three research implications. First, as
countries face second waves, COVID-19 impact models
Figure 3 Multiorgan impairment in low- risk individuals with post- COVID-19 syndrome by gender and hospitalisation.
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should include PCS, whether quality of life, healthcare util-
isation or economic effects. Second, there is urgent need
for multiorgan assessment, including blood and imaging,
as well as primary and secondary care data linkage, to
define PCS. Third, longitudinal studies of clustering of
symptoms and organ impairment will inform health
services research to plan multidisciplinary care path-
ways. There are three management implications. First,
we signal the need for multiorgan monitoring in at least
the medium term, especially extrapulmonary sequelae.
Care pathways involving MRI (with limited access in
many clinical settings) need evaluation versus other
modalities to detect organ impairment (eg, spirometry,
N- terminal pro B- type natriuretic peptide (NT- pro- BNP),
ECG, echocardiography, ultrasound and blood investi-
gations). Second, until effective vaccines and treatments
are widely available, ‘infection suppression’ (eg, social
distancing, masks, physical isolation) is the prevention
strategy. Third, whether understanding baseline risk or
multiorgan complications, PCS requires management
across specialties (eg, cardiology, gastroenterology) and
disciplines (eg, epidemiology, diagnostics, laboratory
science) (figure 5).
Limitations
There are some limitations. First, our cardiac MRI
protocol excluded gadolinium contrast due to concerns
regarding COVID-19- related renal complications, relying
on native T1 mapping to characterise myocardial inflam-
mation non- invasively (previously validated for acute
myocarditis).40 Second, for organ impairment, we show
association, not causation, and incidental findings are
possible in asymptomatic individuals41; however, our
findings are strengthened by comparison with healthy,
age- matched controls, although not matched for sex or
baseline comorbidities. Third, for pragmatic reasons, our
controls were scanned using 1.5T, but we used 3T ranges
as described in an analogous study with similar acquisi-
tion protocols. Therefore, we may be under- representing
the true proportion of impairment in those individuals
with PCS scanned at 3T. Fourth, further studies may
explore different controls, for example, individuals with
Figure 4 Percentage of reported symptoms during the acute phases of the illness within those with evidence of organ
impairment for each organ separately. Darker red indicates higher percentage of reported symptoms per impaired organ.
There are no distinct patterns of symptoms relating to each impaired organ, but a high burden of symptoms in individuals is
highlighted.
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10 DennisA, etal. BMJ Open 2021;11:e048391. doi:10.1136/bmjopen-2020-048391
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postinfluenza symptoms, COVID-19 without symptoms or
from general clinics. We will investigate duration, trajec-
tory, complications and recovery for specific symptoms
and organ impairment in the follow- up phase. Fifth,
our study population was not ethnically diverse, despite
disproportionate COVID-19 impact in non- white individ-
uals. Sixth, to limit interaction and exposure between the
trial team and the patients, pulse oximetry, spirometry,
MRI assessment of the brain and muscle function were
not included from the outset.
CONCLUSIONS
Our study suggests PCS has a physiological basis, with
measurable patient- reported outcomes and organ
impairment. Future research should address longer- term
follow- up of organ function beyond symptoms and blood
investigations, even in lower risk individuals; prioritisa-
tion for imaging, investigation and referral; and optimal
care pathways. Health system responses should emphasise
infection suppression and management of pre- COVID-19
and post- COVID-19 risk factors and chronic diseases.
Author afliations
1Perspectum, Oxford, UK
2Department of Cardiology, Great Western Hospital Foundation NHS Trust, Swindon,
UK
3Department of Cardiology, Oxford University Hospitals NHS Foundation Trust,
Oxford, UK
4Alliance Medical, Warwick, UK
5Department of Gastroenterology, Guy's and St Thomas' NHS Foundation Trust,
London, UK
6Institute for Liver and Digestive Health, University College London, London, UK
7Institute of Cardiovascular and Metabolic Medicine, University of Liverpool,
Liverpool, UK
8Institute of Infection and Global Health, University of Liverpool, Liverpool, UK
9Department of Respiratory Research, Liverpool University Hospitals NHS
Foundation Trust, Liverpool, UK
10Department of Respiratory Medicine, Hull and East Yorkshire Hospitals NHS Trust,
Hull, UK
11Institute of Clinical and Applied Health Research, University of Hull, Hull, UK
12Institute of Population Health Sciences, University of Liverpool, Liverpool, UK
13Department of Oncology, University of Oxford, Oxford, UK
14Long COVID SOS, Oxford, UK
15UKDoctors#Longcovid, London, UK
16Department of Medicine, University College London Hospitals NHS Foundation
Trust, London, UK
17Institute of Health Informatics, University College London, London, UK
18Department of Cardiology, Barts Health NHS Trust, London, UK
Twitter Amitava Banerjee @amibanerjee1
Contributors Study design: AD, RB, JA, COVERSCAN team. Patient recruitment: RB,
COVERSCAN team. Data collection: MW, COVERSCAN team. Data analysis: AD, AB,
COVERSCAN team. Data interpretation: AB, AD, MW, RB. Initial manuscript drafting:
AB, AD, RB. Critical review of early and nal versions of the manuscript: all authors
including JO and DJC. Specialist input: MW, AB (cardiology); RB, MH, DW, MC, DJC
(general medicine); MH, MC, DW (long COVID-19); MB, RB (imaging); AD (statistics);
AB (epidemiology/public health); MG (primary care); JA (healthcare management);
LH, EA (patient and public involvement).
Funding This work was supported by the UK’s National Consortium of Intelligent
Medical Imaging (Industry Strategy Challenge Fund), Innovate UK (Grant 104688)
and the European Union’s Horizon 2020 research and innovation programme
(agreement no 719445). The research was designed, conducted, analysed and
interpreted by the authors independently of the funding sources.
Competing interests AD, RB and MB are employees of Perspectum.
Patient consent for publication Not required.
Ethics approval The study has received ethical approval (20/SC/0185).
Provenance and peer review Not commissioned; externally peer reviewed.
Data availability statement Data are available upon reasonable request from the
corresponding author.
Supplemental material This content has been supplied by the author(s). It has
not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been
peer- reviewed. Any opinions or recommendations discussed are solely those
Figure 5 Natural history of post- COVID-19 syndrome, the COVERSCAN study in low- risk individuals (N=201) and policy
recommendations.
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of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and
responsibility arising from any reliance placed on the content. Where the content
includes any translated material, BMJ does not warrant the accuracy and reliability
of the translations (including but not limited to local regulations, clinical guidelines,
terminology, drug names and drug dosages), and is not responsible for any error
and/or omissions arising from translation and adaptation or otherwise.
Open access This is an open access article distributed in accordance with the
Creative Commons Attribution 4.0 Unported (CC BY 4.0) license, which permits
others to copy, redistribute, remix, transform and build upon this work for any
purpose, provided the original work is properly cited, a link to the licence is given,
and indication of whether changes were made. See:https:// creativecommons. org/
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ORCID iD
AmitavaBanerjee http:// orcid. org/ 0000- 0001- 8741- 3411
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