Ladlow

Long-Term Recovery from SARS-CoV-2 (COVID-19): Exercise toleran... https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10010915/?
report=printable
J Appl Physiol (1985). 2023 Mar 1; 134(3): 622–637. PMCID: PMC10010915

Published online 2023 Feb 9. doi: 10.1152/japplphysiol.00370.2022: PMID: 36759161
10.1152/japplphysiol.00370.2022
Long-Term Recovery from SARS-CoV-2 (COVID-19)
Exercise tolerance, fatigue, mental health, and employment status at 5 and 12

months following COVID-19 illness in a physically trained population
Peter Ladlow, 1 , 2 David A. Holdsworth, 3 , 4 Oliver O’Sullivan, 1 , 5 Robert M. Barker-Davies, 1 , 6 Andrew Houston, 1
Rebecca Chamley, 3 , 4 Kasha Rogers-Smith, 1 Victoria Kinkaid, 1 Adam Kedzierski, 1 Jon Naylor, 7 Joseph Mulae, 7
Mark Cranley, 8 Edward D. Nicol, 3 , 9 , 10 and Alexander N. Bennett 1 , 11
1
Academic Department of Military Rehabilitation (ADMR), Defence Medical Rehabilitation Centre (DMRC),
Loughborough, United Kingdom
2
Department for Health, University of Bath, Bath, United Kingdom
3
Academic Department of Military Medicine, Birmingham, United Kingdom
4
Oxford University Hospitals NHS Foundation Trust, Oxford, United Kingdom
5
Headquarters Army Medical Directorate (HQ AMD), Camberley, United Kingdom
6
School of Sport, Exercise and Health Sciences, Loughborough University, Loughborough, United Kingdom
7
Royal Centre for Defence Medicine, Birmingham, United Kingdom
8
Defence Medical Rehabilitation Centre (DMRC), Loughborough, United Kingdom
9
Royal Brompton Hospital, London, United Kingdom
10
School of Biomedical Engineering and Imaging Sciences, Kings College London, London, United Kingdom
11
National Heart and Lung Institute, Imperial College London, London, United Kingdom
Corresponding author.
Correspondence: A. N. Bennett (Alexander.N.Bennett@btinternet.com).
Received 2022 Jun 30; Revised 2023 Jan 23; Accepted 2023 Jan 24.
Copyright © 2023 the American Physiological Society.
Abstract
1 of 33 7/11/2023, 3:52 PM
Long-Term Recovery from SARS-CoV-2 (COVID-19): Exercise toleran... https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10010915/?report=printable
Keywords: cardiopulmonary exercise, exercise tolerance, long COVID, post-COVID-19 syndrome,

recovery
Abstract
Failure to recover following severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) may
have a profound impact on individuals who participate in high-intensity/volume exercise as part
of their occupation/recreation. The aim of this study was to describe the longitudinal cardiopul-
monary exercise function, fatigue, and mental health status of military-trained individuals (up to
12-mo postinfection) who feel recovered, and those with persistent symptoms from two acute
disease severity groups (hospitalized and community-managed), compared with an age-, sex-,
and job role-matched control. Eighty-eight participants underwent cardiopulmonary functional
tests at baseline (5 mo following acute illness) and 12 mo; 25 hospitalized with persistent symp-
toms (hospitalized-symptomatic), 6 hospitalized and recovered (hospitalized-recovered); 28
community-managed with persistent symptoms (community-symptomatic); 12 community-
managed, now recovered (community-recovered), and 17 controls. Cardiopulmonary exercise
function and mental health status were comparable between the 5 and 12-mo follow-up. At 12
mo, symptoms of fatigue (48% and 46%) and shortness of breath (SoB; 52% and 43%) remain
high in hospitalized-symptomatic and community-symptomatic groups, respectively. At 12 mo,
COVID-19-exposed participants had a reduced capacity for work at anaerobic threshold and at
peak exercise levels of deconditioning persist, with many individuals struggling to return to
strenuous activity. The prevalence considered “fully �it” at 12 mo was lowest in symptomatic
groups (hospitalized-symptomatic, 4%; hospitalized-recovered, 50%; community-symptomatic,
18%; community-recovered, 82%; control, 82%) and 49% of COVID-19-exposed participants re-
mained medically nondeployable within the British Armed Forces. For hospitalized and sympto-
matic individuals, cardiopulmonary exercise pro�iles are consistent with impaired metabolic ef�i-
ciency and deconditioning at 12 mo postacute illness. The long-term deployability status of
2 of 33 7/11/2023, 3:52 PM
COVID-19-exposed military personnel is uncertain.
NEW & NOTEWORTHY Subjective exercise limiting symptoms such as fatigue and shortness of
breath reduce but remain prevalent in symptomatic groups. At 12 mo, COVID-19-exposed indi-
viduals still have a reduced capacity for work at the anaerobic threshold (which best predicts
sustainable intensity), despite oxygen uptake comparable to controls. The prevalence of COVID-
19-exposed individuals considered “medically non-deployable” remains high at 47%.
INTRODUCTION
Prolonged illness following severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) may
last beyond 12 mo (1, 2). Symptoms include exercise intolerance, shortness of breath (SoB), fa-
tigue, palpitations, and mental health problems (3–7). The majority of affected individuals are in
the working population, with implications for return to work (8, 9). An inability to fully recover
may have a profound impact on individuals who engage in high-volume/intensity exercise as a
core component of their recreation or occupational role (for example, front-line emergency ser-
vices, Armed Forces, and professional athletes), with physical deconditioning increasing the risk
of injury during their return (10). Functional limitations (11–13), including in cognition (14, 15),
and abnormalities on cross-sectional cardiothoracic imaging have been described (16, 17) rais-
ing concerns regarding long-term impairment of cardiopulmonary function.
The impact of severity of acute coronavirus disease 2019 (COVID-19) on long-term health re-
mains unclear (18, 19). The majority of studies investigating post-COVID-19 syndrome have fo-
cused on hospitalized, not community-managed, patients, and while some use control partici-
pants, few use contemporaneously recruited, appropriately matched control populations, or
demonstrate the condition’s longitudinal impact on cardiopulmonary function and mental
health (3, 5, 20–29).
The Military COVID-19 Observational Outcomes in a Viral Infectious Disease (M-COVID) study
was developed to describe the effects of SARS-CoV-2 on the UK Armed Forces. The study catego-
rized participants based on severity of acute illness (hospitalized or community-managed) and
recovery status (persistent symptoms or recovered), compared with an age-, sex-, and job role-
matched control population. Baseline �indings (at a mean 5 mo following acute COVID-19) found
hospitalized and community-managed individuals with persistent symptoms (community-
symptomatic) had worse outcomes in terms of cardiopulmonary investigations, mental health,
and functional capacity compared with both community-recovered and control groups (30).
In addition, community-managed individuals who felt recovered (community-recovered) had

comparable cardiopulmonary exercise pro�iles to the physically trained and active controls, sug-
gesting a readiness to return to higher intensity/volumes of exercise (15). These studies support
the requirement for ongoing monitoring, rehabilitation, and recovery of both hospitalized and
symptomatic groups beyond 5 mo, a joint clinician-patient research priority (31). Using data
from the M-COVID study, our aim was to:
3 of 33 7/11/2023, 3:52 PM
1. Characterize, and compare, the longitudinal cardiopulmonary function, mental health, and
employment status of symptomatic and recovered individuals from two different acute
disease severity groups (hospitalized and community-managed) following COVID-19 illness,
between 5 and 12 mo postacute illness.
2. Compare all COVID-19 exposed participants to an age-, sex-, and job role-matched control
group.
METHODS
Study Design
This is a prospective observational cohort study, ethically approved by the UK Ministry of

Defense research ethic committee in July 2020 (1061/MODREC/20). Figure 1 provides a dia-
grammatic study outline, with arrows depicting between- and within-group comparisons.
Within the overall MCOVID study, a 22% participant dropout occurred between baseline (n =
113 at 5 mo postacute illness) (15) and the subsequent 12-mo follow-up (n = 88). Here, we re-
port the baseline and follow-up data of 88 participants captured at both 5 and 12 mo (see Fig. 2).
Setting
Assessments, including cardiopulmonary exercise testing (CPET), functional tests, spirometry,

and patient-reported outcome measures (PROMs), were performed during a 2-day visit to
Defence Medical Rehabilitation Centre (DMRC) Stanford Hall (32).
Participants
Participants were recruited and categorized into 1 of 5 groups (Fig. 2). Eighty-eight participants
attended baseline and 12-mo follow-up assessments and had their data analyzed; hospitalized-
symptomatic (n = 25 adults); hospitalized-recovered (n = 6); community-symptomatic (n = 28);
community-recovered (n = 12); and control (n = 17). Written informed consent was gained from
all participants. Full details of the study eligibility criteria and recruitment strategy can be found
in Supplemental File S1 (see https://doi.org/10.6084/m9.�igshare.20197844) and elsewhere
(15, 30). In brief, COVID-19-exposed participants were recruited via the Defence COVID-19
Recovery Service (32) with community-recovered and control participants were serving military
personnel recruited from local military units. Control participants were COVID negative (con-
�irmed via antibody testing) upon recruitment into the trial. All controls were job role-matched
based on the physical demands of their primary role. All control participants underwent anti-
body testing, with both spike and anti-nucleocapsid (NC) testing. A negative anti-NC antibody
was used to determine that they had not had COVID. At follow-up, any control participants who
had had COVID-19 in the interim were excluded and another antibody test was performed. At
baseline, the prevalence of individuals employed in ground close combat roles (e.g., infantry and
artillery, which require a higher physical employment standard) was job role-matched in the
control group (hospitalized-symptomatic, 24%; hospitalized-recovered, 16%; community-
4 of 33 7/11/2023, 3:52 PM
symptomatic, 18%; community-recovered 17%); controls, 18%). To ensure a baseline level of

operational readiness is maintained at all times, UK military personnel are required to pass an
annual �itness test based on components of muscle strength, power, and endurance (33). Levels
of cardiorespiratory �itness are therefore expected to be supranormal compared with the gen-
eral population.
Determining Recovery Status
Nonrecovery was de�ined as the presence of one or more “new” post-COVID-19 symptom(s) re-
ported at 5 mo (baseline), using a symptom checklist (see Supplemental File S3, Tables S3.3, and
S3.4). Should a participant present with any of the listed symptoms before COVID-19 (for exam-
ple, dif�iculty sleeping due to prior musculoskeletal injury), this would not contribute toward be-
ing classi�ied as COVID-19 symptomatic.
Cardiopulmonary Functional Testing
Six-min walk test. Six-minute walk tests (6MWTs) were performed using standardized guide-
lines (34), with pretest body composition recorded (height, body mass, and hip and waist cir-
cumference). A pulse oximeter (Nonin Onyx Vantage 9590, Minnesota) measured heart rate (HR)
and Sp� . Pre- and posttest participant rate of perceived exertion (RPE, 6–20) (35) and SoB
�
(0–10) (36) were recorded.
Spirometry and pulmonary function test. Standing spirometry assessments (MicroMedical

MicroLab 3500, CA) measured forced vital capacity (FVC) and forced expiratory volume in the
�irst second of expiration (FEV1) (37).
Cardiopulmonary exercise testing. The cardiopulmonary exercise testing (CPET) protocol is de-
scribed in full elsewhere (15, 30). In brief, using an electromagnetically braked cycle ergometer
(Lode Carnival, Lobe BV, Groningen, The Netherlands) with indirect calorimetry (Metalyzer 3B,
Cortex Biophysik, Leipzig, Germany) and continuous 12-lead ECG monitoring (Custo Diagnostic
software, Custo-Med, Ottoburn, Germany), a ramp protocol to volitional fatigue was employed.
Two-minute rest period, followed by 2 min of unloaded pedaling, led to progressive increase in
workload until failure. Ventilation (V� �), oxygen consumption (V� �2), expired carbon dioxide
(V� ��2), HR, and Sp� were monitored continuously, with BP, RPE, and perceived SoB recorded
�
every 2 min.
Patient-Reported Outcome Measures
Participants completed PROMs relating to depression (Patient Health Questionnaire-9, PHQ-9)

(38), anxiety (General Anxiety Disorder scale-7 questions, GAD-7) (39), posttraumatic stress dis-
order (PTSD, National Centre for PTSD checklist, PCL-5) (40), quality of life (QoL, European QoL
5 domains, EQ5D) (41), and fatigue (Fatigue Assessment Scale, FAS) (42). An evidence-based
symptom checklist measured ongoing symptoms (43, 44).
5 of 33 7/11/2023, 3:52 PM
General well-being, activities of daily living (ADL), and occupational performance/status were
measured using the World Health Organization (WHO) Performance Status (adapted from Oken
et al.) (45), functional activity assessment (FAA) (46), and the joint medical employment stan-
dard.
Statistical Analysis
Data are presented as mean ± standard deviation. All data were assessed for homogeneity of
variances using the Shapiro Wilk’s test, in addition to inspection of the skewness and kurtosis of
each variable. Variables with a skewness of < −0.8 or > 0.8, a kurtosis of < −2 or >2, and a P value
< 0.05 on the Shapiro Wilk’s test were regarded as not normally distributed. Variables that were
not normally distributed were transformed using a logarithmic transformation before being sub-
ject to statistical analysis and their data presented as medians and interquartile ranges.
To examine differences in demographics, functional capacity, and PROMs between study visits in
exposed and nonexposed participants, one-way univariate analyses of covariance (ANCOVA)
were conducted, controlled for waist circumference (Supplemental File S2; see https://doi.org
/10.6084/m9.�igshare.20198078 contains noncontrolled statistical comparisons). Variables at
baseline that exceeded the threshold of medium effect size (partial eta-squared ≥0.06) were car-
ried forward for further analysis (partial eta-squared effect size thresholds include; small,
0.01–0.059; medium, 0.06–0.139, large ≥ 0.14). The rationale for this is both clinical and statisti-
cal. Clinically, if no differences were observed in cardiopulmonary exercise function in this physi-
cally trained working-age population 5 mo postillness, it is unlikely that such variables in�luence
COVID-19 recovery and therefore do not warrant longitudinal investigation. Statistically, given
the large number of variables, the number of statistical tests required to analyze all variables
risked introducing type I error into the results. The results in full can be found in Supplemental
File S2 (Statistical Analysis) and Supplemental File S3 (Medical History, Symptoms, and
Outcomes; see https://doi.org/10.6084/m9.�igshare.20198225).
To examine differences in demographics, functional capacity, outcomes at baseline and follow-up

between hospitalized and symptomatic participants, two-way univariate ANCOVAs were con-
ducted, controlled for waist circumference. Post hoc analyses were conducted for comparing
each combination of hospitalization and recovery status against controls. Bonferroni’s correc-
tion was applied to correct P values for multiple comparisons. To understand whether hospital-
ization or recovery status in�luences medium-term recovery, two-way univariate ANCOVAs were
performed on the functional capacity and PROMs at the follow-up assessment, controlling for
baseline. Where signi�icant differences at follow-up were found between COVID-19 and control
groups, after controlling for waist circumference, targeted post hoc analyses were conducted to
identify which COVID-19 subgroup differed from controls, grouping by both presence of symp-
toms and severity. Bonferroni corrections were applied to all P values to account for multiple
comparisons. Only descriptive (number and prevalence [%]) data of general well-being, ADL,
and occupational status (WHO performance, FAA, and JMES) will be presented.
RESULTS
6 of 33 7/11/2023, 3:52 PM
Baseline data was collected at 159 ± 7 days (5 mo) and follow-up at 345 ± 91 days (12 mo) posta-
cute illness. There were no signi�icant between-group differences in duration between study vis-
its (P = 0.537) or acute illness and follow-up (hospitalized-symptomatic, 329 ± 91 days;
hospitalized-recovered, 375 ± 70 days; community-symptomatic, 359 ± 103 days; community-
recovered 333 ± 65 days, P = 0.513).
Participant Characteristics
Pre-COVID-19 medical health status. Supplemental File S3 describes the prevalence of comor-
bidities and reason for medical downgrading based on injury severity and recovery status
(Supplemental Table S3.1) and individual groups (Supplemental Table S3.2). In summary, there
was a low prevalence of comorbidities within the COVID-19-exposed group, asthma (n = 2, 3%),
prediabetes (n = 1, 1%), chronic heart disease (n = 0), hypertension (n = 5, 7%), existing mental
health diagnosis (n = 8, 11%), and historical mental health diagnosis (n = 7, 10%).
Blood tests were completed at 5 mo and 12 mo. However, no abnormal blood tests were ob-
served in our symptomatic groups. As no signi�icant abnormalities were determined, blood re-
sults were not analyzed or reported in this follow-up manuscript. For reference, the blood re-
sults recorded at 5 mo can be found in the supplementary �ile elsewhere. (30)
Sex, age, and body composition. The distribution of sex within each group is similar, with a
greater proportion of men represented in each group (hospitalized-symptomatic, 84% male;
hospitalized-recovered, 100% male; community-symptomatic, 89% male; community-
recovered, 75% male; and control, 82% male). Hospitalized participants were older than
community-managed individuals (P = 0.013, effect size (ES) = 0.089, Table 1). Symptomatic indi-
viduals had a higher body mass index (BMI) and larger waist circumference than recovered
(both P = 0.020, ES = 0.08). Hospitalized individuals also demonstrate a higher BMI (P < 0.001,
ES = 0.15) and greater waist circumference (P < 0.001, ES = 0.14) than community-managed. No
changes in body composition variables were demonstrated between study visits in any group,
with less favorable body composition values identi�ied in the hospitalized and the symptomatic
groups both times.
Post-COVID-19 Symptoms
A full symptoms checklist is available in Supplemental File S3 Tables S3.3 and S3.4. The most
prevalent symptoms during initial onset of acute illness in “all COVID-19 exposed” groups were
fever (72%), shortness of breath (66%), persistent cough (63%), and fatigue (58%). The preva-
lence of symptom burden within symptomatic groups (hospitalized and community-managed,
respectively) at 5 mo include shortness of breath (84% and 68%), fatigue (68% and 64%), poor
concentration (48% and 50%), poor memory (32% and 46%), and exercise intolerance (28%
and 36%). The 10 most prevalent symptoms reported at 12 mo are listed in Table 2, ordered
based on symptom burden within “symptomatic” groups (any shortness of breath, 47%; fatigue,
45%; poor concentration, 34%; poor memory, 32%; dif�iculty getting to sleep, 28%; muscle
ache, 28%; joint pain, 28%; headache, 26%; chest pain, 21%; poor attention, 19%). The results
7 of 33 7/11/2023, 3:52 PM
below summarize the 10 most prevalent symptoms reported at 12 mo postacute COVID-19 ill-
ness within the two symptomatic groups.
Shortness of breath. SoB reduced by 32% (1 in 3 participants) and 25% (1 in 4 participants), re-
maining high in hospitalized-symptomatic (52%) and community-symptomatic (43%) individu-
als.
Fatigue. Symptoms of fatigue reduced by 20% and 21% (1 in 5 participants) but remained high
in hospitalized-symptomatic (48%) and community-symptomatic individuals (43%).
Poor concentration. Poor concentration reduced by 20% (1 in 5 participants) in hospitalized-

symptomatic (to 28%) and by 11% (1 in 8 participants) in community-symptomatic (to 39%).
Poor memory. Poor memory reduced by 8% (1 in 12 participants) in hospitalized-symptomatic

(to 24%) and by 7% in community-symptomatic (to 39%).
Difficulty staying asleep. Challenges associated with staying asleep increased by 12% (1 in 8 par-
ticipants) in hospitalized-symptomatic (to 32%) and reduced by 7% in community-symptomatic
(to 25%).
Muscle ache. The prevalence of muscle ache remained unchanged in hospitalized-symptomatic

(at 36%) and reduced by 4% in community-symptomatic (to 21%).
Joint pain. Joint pain reduced by 8% (1 in 12 participants) in hospitalized-symptomatic (to

28%) but increased by 11% in community-symptomatic (to 29%).
Chest pain. Chest pain reduced by 12% (1 in 8 participants) in hospitalized-symptomatic (to

16%) and by 11% (1 in 7 participants) in community-symptomatic individuals (to 25%).
Headache. Headaches increased by 16% (1 in 6 participants) in hospitalized-symptomatic (to

32%) and remained unchanged in community-symptomatic (at 21%).
Poor attention. Levels of attention were reduced by 4% in hospitalized-symptomatic (to 12%)

and by 11% in community-symptomatic (to 25%).
Patient-Reported Outcome Measures
Depression and fatigue were the only PROMs recorded at baseline (5 mo postacute illness) ex-
ceeding the medium effect size threshold and therefore were analyzed (Tables 3, 4, and 5).
Outcomes related to anxiety, PTSD, and QoL can be found in Supplemental File S2 and
Supplemental File S3 Table S3.5. No signi�icant between-group differences were seen between
study visits in any COVID-19-exposed group PROMs (P > 0.05, ES < 0.02).
Depression. Depressive symptoms reduced between study visits in both hospitalized and symp-
8 of 33 7/11/2023, 3:52 PM
tomatic groups (see Table 5). There were no differences in symptoms of depression between
COVID-19-exposed participants based on illness severity (P = 0.155, ES = 0.03). There was a
moderate difference between COVID-19-exposed participants based on recovery status (P =
0.013, ES = 0.09) at 12 mo (see Table 4).
Fatigue. Levels of fatigue were comparable between hospitalized and community-managed

groups at 12 mo postacute illness (P = 0.871, ES < 0.01). However, symptomatic individuals re-
port higher values of fatigue at 12 mo (hospitalized-symptomatic, 23 ± 8; community-
symptomatic, 22 ± 7; hospitalized-recovered, 16 ± 4; community-recovered 16 ± 3, P = 0.001, ES
= 0.14, Table 4).
Exercise Tolerance
Six-minute walk distance. At 12 mo postacute illness, comparable 6MWD were demonstrated be-
tween hospitalized and community-managed groups at 12 mo (P = 0.143, ES = 0.03). Both symp-
tomatic groups could walk >40 m farther than the distances they walked at 5 mo postacute ill-
ness (Table 4 and 5). However, this is below the minimum clinically importance difference
threshold (54 m) (47) and resulted in minimal differences between symptomatic and recovered
individuals at follow-up (hospitalized-symptomatic, 610 ± 81 m; community-symptomatic, 671
± 82 m; hospitalized-recovered, 677 ± 115 m; community-recovered 698 ± 81 m, P = 0.073, ES =
0.05). The shorter mean distances walked by COVID-19-exposed participants at 12 mo com-
pared with controls (P = 0.003, ES = 0.10) can be primarily explained by the signi�icantly shorter
distances walked by the symptomatic groups (hospitalized-symptomatic, 132 m less distance, P
< 0.001; community-symptomatic, 71 m less distance, P = 0.048). Reductions in walking distance
were smaller in the recovered groups and were not signi�icantly different from control (hospital-
ized-recovered, 65 m less distance; community-recovered, 44 m less distance, P > 0.05).
Cardiopulmonary exercise test. Baseline CPET values exceeding moderate effect size thresholds
were carried forward for further analysis (Tables 3, 4, and 5), with all other CPET (oxygen up-
take, work rate, HR, blood pressure, ventilation, and spirometry) found in Supplemental File S3
Table S3.6 to S3.9. No signi�icant “within-group” differences were observed between study visits
in any CPET-related parameter based on severity (P > 0.05, ES > 0.03) or recovery status (P >
0.05, ES < 0.04, Table 5).
Oxygen uptake. Hospitalized groups demonstrated reduced peak O2 pulse compared with
community-managed at 12-mo follow-up (P = 0.028, ES = 0.07). Hospitalized individuals demon-
strated reduced peak V� �2 (P = 0.003, ES = 0.13) and O2 pulse compared with community-
managed at 12 mo (O2 pulse; hospitalized-symptomatic, 17.5 ± 5.5; hospitalized-recovered, 18.7
± 3.5; community-symptomatic, 19 ± 4.3; community-recovered 22.9 ± 6.5, P = 0.004, ES = 0.12).
Symptomatic individuals had reduced exercise capacity (V� �2 at peak) compared with recovered
individuals at 12 mo (hospitalized-symptomatic, 30 ± 6 mL/kg/min; community-symptomatic,
36 ± 7 mL/kg/min; hospitalized-recovered, 33 ± 7 mL/kg/min; community-recovered 41 ± 5
mL/kg/min, P = 0.044, ES = 0.06, Table 4).
9 of 33 7/11/2023, 3:52 PM
COVID-19-exposed participants demonstrated reduced percent predicted V� �2 at VT1 (the anaer-

obic transition) (P = 0.028, ES = 0.06), percent predicted V� �2 at peak (P = 0.002, ES = 0.11), V� �2
at peak (P < 0.001, ES = 0.14), and percent predicted O2 pulse at peak (P = 0.005, ES = 0.09) com-
pared with controls. Post hoc analysis revealed no signi�icant differences in percent predicted
V� �2 at VT1 between any COVID-19-exposed group and controls (P > 0.05). However,
hospitalized-symptomatic individuals demonstrated signi�icantly reduced peak oxygen uptake
values versus controls (V� �2 at peak, P < 0.001; percent predicted V� �2 at peak, P = 0.007; O2 pulse
at peak, P = 0.001). Community-symptomatic individuals also demonstrated signi�icantly re-
duced peak oxygen uptake values versus controls (V� �2 at peak, P < 0.002; percent predicted V� �2
at peak, P = 0.045; O2 pulse at peak, P = 0.040). The only oxygen uptake parameter in which the
hospitalized-recovered group had signi�icantly lower values than controls was V� �2 at peak (P =
0.016). There were no signi�icant differences in oxygen uptake values between community-
recovered individuals and controls.
Work rate. At 12-mo follow-up, hospitalized groups demonstrate reduced VT1 WR (P = 0.013, ES
= 0.09), relative VT1 (P = 0.049, ES = 0.06), and peak WR (P = 0.007, ES = 0.10) compared with
community-managed groups. Hospitalized groups had reduced mean power output compared
with community-managed at 12 mo (peak WR at 12 mo; hospitalized-symptomatic, 230 ± 38 W;
hospitalized-recovered, 245 ± 25 W; community-symptomatic, 268 ± 62 W; community-
recovered 291 ± 40 W, P = 0.002, ES = 0.14). Symptomatic groups consistently exhibited reduced
relative mean peak power output (controlled for body mass) at 12 mo (hospitalized-
symptomatic, 2.40 ± 0.45 W/kg; community-symptomatic, 2.91 ± 0.61 W/kg; hospitalized-
recovered, 2.67 ± 0.58 W/kg; community-recovered 3.46 ± 0.42 W/kg, P = 0.025, ES = 0.07).
At 12 mo, COVID-19-exposed participants demonstrated reduced power output at VT1 (P =

0.021, ES = 0.06), peak (P = 0.026, ES = 0.06), percent predicted peak (P = 0.003, ES = 0.10), rela-
tive WR at VT1 (P = 0.001, ES = 0.13), and relative WR at peak (P < 0.001, ES = 0.15) compared
with controls. Post hoc analysis revealed signi�icantly reduced power output at VT1 in hospital-
ized-symptomatic versus controls (WR at VT1, P = 0.006; relative WR at VT1, P = 0.001) and be-
tween community-symptomatic versus controls (relative work rate at VT1, P = 0.007). No signi�i-
cant differences in work rate at VT1 were observed between recovered groups and controls.
Hospitalized-symptomatic individuals demonstrated signi�icantly reduced peak power outputs
versus controls (WR, P < 0.001; percent predicted WR, P = 0.003; relative WR, P < 0.001).
Community-symptomatic individuals also demonstrated signi�icantly reduced peak power out-
put values versus controls (percent predicted WR, P = 0.013; relative WR, P = 0.001).
Hospitalized-recovered individuals demonstrated signi�icantly lower relative WR at peak versus
controls (P = 0.031) and community-recovered individuals demonstrated signi�icantly lower
predicted WR at peak versus controls (P = 0.017).
Activities of Daily Living, Occupational Performance, and Occupational Status
Supplemental File S3 Tables S3.10 to S3.15 contains tables describing the in�luence of illness
severity and recovery on individual group well-being, ADL, and occupational status, at 5 mo and
12 mo post-COVID-19 according to the World Health Organization (WHO) performance status
10 of 33 7/11/2023, 3:52 PM
(Supplemental Tables S3.10 and S3.11), FAA (Supplemental Tables S3.12 and S3.13), and JMES
(Supplemental Tables S3.14 and S3.15).
Activities of daily living: World Health Organization performance status. Based on illness severity
and recovery status, the majority of participants at 12 mo demonstrated “Level 1: restricted in
physically strenuous activity but ambulatory and able to carry out work of a light or sedentary
nature, e.g., light house work, of�ice work” (hospitalized, 63%; community-managed, 38%;
symptomatic, 58%; recovered, 24%) or “Level 0: fully active, able to carry on all pre-disease per-
formance without restriction” (hospitalized, 37%; community-managed, 59%; symptomatic,
40%; recovered, 76%; control, 100%).
Within symptomatic groups, there was a 17% and 25% increase in individuals considered “fully
active” between 5 and 12 mo following COVID-19 illness (hospitalized-symptomatic, 16% to
33%; community-symptomatic, 21% to 46%). At 12 mo, one-third of hospitalized-symptomatic
patients were “fully active,” whereas approximately half of the hospitalized-recovered and com-
munity-symptomatic were considered “fully active” (46% and 50%, respectively). The preva-
lence of community-managed participants considered fully active is comparable to controls
(91% and 100%, respectively).
Functional performance: functional activity assessment. Based on illness severity, the prevalence
of participants considered “un�it for trade” at 12 mo (FAA score 3 to 5) was greater in
community-managed groups (hospitalized, 23%; community-managed, 34%), and based on re-
covery status, greater in symptomatic groups (symptomatic, 33%; recovered, 12%). Within the
symptomatic groups, the greatest change between study visits was observed in the hospitalized
group, with hospitalized-symptomatic participants considered “un�it for trade” reducing by 35%
(60% to 25%), with the community-symptomatic group remained comparable (49% to 43%).
The prevalence of participants considered “fully �it” (FAA1) at 12 mo was lowest in symptomatic
groups (hospitalized-symptomatic, 4%; hospitalized-recovered, 50%; community-symptomatic,
18%; community-recovered, 82%; control, 82%). These values were largely unchanged between
study visits, bar the community-symptomatic individuals improving by 11%.
Occupational status: joint medical employment standards. Before COVID-19 exposure, 62% of
participants were graded “fully deployable,” 16% “limited deployability,” and 23% “not medically
deployable,” and at 12 mo following COVID-19 illness, 30% were graded “fully deployable,” 21%
“limited deployability,” and 49% “not medically deployable” (Fig. 3). The main reason provided
by their local physician for “limited” or “full” medical downgrading before COVID-19 illness was
musculoskeletal injury (n = 17, 63%), medical-related (n = 7, 26%), or due to mental health (n =
3, 11%). The six medical conditions were related to otolaryngology (n = 3), ophthalmology (n =
1), rheumatology (n = 1), and other (n = 2). No respiratory-, cardiology-, or neurology-related
disorders were present. The control group had no comorbidities and was all fully deployable
(i.e., not medically downgraded). Between study visits, the prevalence of COVID-19-exposed par-
ticipants considered “medically un�it for duty and under medical care” (JMES grading of 0) de-
creased by 26% and 15% in the hospitalized and symptomatic groups, with the hospitalized-
symptomatic group decreasing 32%, and community-symptomatic group remaining static.
11 of 33 7/11/2023, 3:52 PM
Individuals graded “not medically deployable” were predominantly in symptomatic groups (hos-
pitalized-symptomatic, 64%; hospitalized-recovered, 33%; community-symptomatic, 57%;
community-recovered, 8%; control, 0%).
The deployability status of “recovered” groups remains largely the same between study visits
with the prevalence graded “fully deployable” greatest in recovered group (hospitalized, 16%;
community-managed, 40%; symptomatic, 13%; recovered, 78%).
Other Results of Interest
After controlling for each individual variables at baseline, there were no differences demon-
strated at 12 mo in relation to mental health, fatigue, or cardiopulmonary exercise performance
between individuals considered symptomatic at baseline who 1) feel recovered at 12 mo (n =
14) versus 2) reported persistent symptoms (n = 39, P > 0.05, ES < 0.06, Supplemental File S4,
Table S4; see https://doi.org/10.6084/m9.�igshare.20198462).
DISCUSSION
This study compared the medium-term within- and between-group differences in exercise toler-
ance, fatigue, mental health, and occupational status of working age, active individuals based on
acute COVID-19 severity and recovery status, compared with an age-, sex-, and job role-matched
control group. Symptom prevalence reduced between study visits, with depression and submaxi-
mal exercise comparable between COVID-19-exposed participants. Certain symptoms (particu-
larly fatigue and SoB) remained high, and discrepancies in peak CPET values, speci�ically oxygen
uptake and WR persisted between COVID-19-exposed groups. Small “within-group” differences
in PROMs and cardiopulmonary exercise function were also seen.
Signi�icant differences between COVID-19-exposed and nonexposed (control) participants per-

sist, primarily driven by the less favorable CPET pro�iles in the symptomatic groups. During the
�irst 12 mo of recovery following COVID-19, many individuals can perform ADLs and feel subjec-
tively better. However, deconditioning persists with many individuals struggling to return to the
strenuous activity required by the British Armed Forces. The implications of these �indings form
the basis of this discussion, �irst between COVID-19-exposed participants, then between exposed
and nonexposed participants, and �inally, longitudinal differences between 5 and 12 mo.
Differences between COVID-19-Exposed Participants: Severity of Acute Illness versus

Recovery Status
Influence of acute illness severity on exercise tolerance. Submaximal exercise conditions. At 12

mo, severity of acute illness does not in�luence submaximal ambulatory function (6MWD) or
oxygen uptake, but does in�luence power output, at the �irst ventilatory threshold (VT1). Less
work for the same O2 consumption demonstrates lower metabolic ef�iciency of work, with hospi-
talized individuals delivering reduced absolute and relative power output at the anaerobic
12 of 33 7/11/2023, 3:52 PM
threshold, the principal predictor of endurance capacity (48). One explanation is that prolonged
bed rest and physical inactivity lead to decreased mitochondrial density and decreased oxidative
capacity of muscle and resultant musculoskeletal capacity limitation (49).
Persistent fatigue following acute COVID-19 may be the result of individuals reaching or exceed-
ing their anaerobic threshold during ADLs. This can be estimated using an equation for energy
expenditure during cycle ergometry (50) and the compendium of physical activities (51). Using
age-adjusted results of power output at VT1 and mean body mass of all participants, the hospi-
talized and symptomatic groups reach anaerobic threshold at lower levels of work, established
in METS (see Supplemental File S3, Tables S3.14). Most ADLs have a METS of 2.0 to 4.0, such as
sweeping �loors (3.3 METs) (51), well within the groups’ anaerobic threshold (hospitalized-
symptomatic, 4.5 METS; hospitalized-recovered, 4.6 METS community-symptomatic, 5.1 METS;
community-recovered, 5.7 METS; control 6.2 METS, Supplemental File S3, Table S3.17). It is pos-
sible that the hospitalized and symptomatic individuals begin to exceed their anaerobic thresh-
old during activities which they would premorbidly have found straightforward, such as brisk
walking while carrying objects <11.4 kg (4.5 METS), or playing with children (5.0 METS).
Peak exercise conditions. Differences based on acute illness severity in oxygen uptake are evident
only at peak exercise. Hospitalized groups have reduced oxygen uptake (both peak V� �2 and O2
pulse) and lower absolute and relative peak power output when compared with community-
managed individuals. Lower peak oxygen uptakes (V� �2) and higher V� �/V� ��2 slopes have previ-
ously been reported in individuals with severe COVID-19 (12, 13, 29, 52, 53). Unlike these stud-
ies, our hospitalized participants have a comparatively “normal” percent predicted peak V� �2 at
12 mo and more ef�icient V� �/V� ��2 slopes, within the “normal” range (slope <30; hospitalized-
symptomatic, 29.0 ± 4.0; and hospitalized-recovered, 27.7 ± 3.9), likely the result of military
physical �itness standards. The impaired metabolic ef�iciency revealed by the relative reduction
in work at VT1 with sustained oxygen uptake, suggests that the reduced V� �2 at peak exercise is
most likely to result from decreased peripheral oxygen use as a result of physical deconditioning
(15), also described in an analysis of 581 individuals from 11 studies with post-COVID-19 syn-
drome (54).
Influence of recovery status on exercise tolerance. Submaximal exercise conditions. There were
small improvements in 6MWD in the symptomatic groups between study visits. Submaximal am-
bulatory function, and other markers of submaximal exercise capacity (percent predicted V� �2 at
VT1, relative and absolute VT1 WR), were comparable between COVID-19-exposed groups based
on recovery status at 12 mo, with no differences in oxygen uptake or ventilatory ef�iciency pa-
rameters in the exposed groups.
Peak exercise conditions. Differences in cardiopulmonary exercise function were only demon-
strated at peak exercise. Speci�ically, symptomatic groups demonstrate reduced oxygen uptake
(both peak V� �2 and O2 pulse) and reduced relative peak power output (WR controlled for body
mass) compared with recovered individuals. After controlling for age, sex, and body mass, there
was no difference between peak oxygen uptake and power output between hospitalized-
recovered, community-recovered, and community-symptomatic. Importantly, no ventilatory lim-
13 of 33 7/11/2023, 3:52 PM
itations were demonstrated at peak exercise (no abnormalities of V� �/V� ��2, % Sp� and breath-
�
ing reserve) at either time point (Supplemental File S3, Table S3.8). These �indings support im-
proving exercise tolerance (both sub- and maximal) over the �irst 12 mo of recovery.
Depression and fatigue status. Based on severity status, levels of depression are comparable
among all COVID-19-exposed groups (all groups scored between low to mild). Greater exposure
to physical training, outdoor work, regular routine, and team contact of service life may exert a
protective effect on mental health (55). These may have in�luenced the lower values of depres-
sive symptoms, small effect size differences in mean levels of anxiety (low to mild symptoms),
low PTSD score, and preserved QoL (Supplemental File S3, Table S3.5).
Unsurprisingly, symptomatic individuals report higher subjective levels of fatigue at 12 mo com-

pared with recovered individuals. However, levels of fatigue do not differ between groups based
on the severity of acute illness.
Differences between COVID-19-Exposed Participants at 12 Mo Postacute COVID-19 Illness

versus Controls
The cardiorespiratory �itness pro�ile demonstrated by the control group provides a surrogate
marker of the cardiorespiratory �itness demands expected by the British Armed Forces, there-
fore are high-normal when compared with the wider general population.
Exercise tolerance. Differences in cardiopulmonary exercise function between COVID-19-

exposed and nonexposed participants persist at 12 mo. Post hoc analysis revealed that differ-
ences with controls were primarily driven by exercise function impairment in the symptomatic
groups (Supplemental File S4), with the greatest differences observed at maximal exercise.
Submaximal exercise conditions. Only the symptomatic groups demonstrated signi�icantly shorter
6MWD compared with controls (Table 4). Oxygen uptake at VT1 did not differ between COVID-
19-exposed groups and controls. However, symptomatic individuals (particularly hospitalized)
continued to show reduced oxygen uptake at the anaerobic threshold, with the symptomatic
groups also having reduced power output at VT1 12 mo following acute illness (Table 4). Both
�indings are consistent with a metabolic insult resulting from bed rest and prolonged physical
inactivity following hospital admission, resulting in reduced oxidative metabolic ef�iciency.
Peak exercise conditions. The hospitalized-recovered group had signi�icantly reduced peak oxy-
gen uptake and reduced “relative” power output, and both symptomatic groups demonstrated
signi�icantly reduced oxygen uptake and power output at peak compared with controls. The au-
thors’ previous investigations highlighted the impact of dysautonomia as one of the potential
mechanisms associated with objective functional limitation (6). Using the same criteria to de�ine
dysautonomia (resting HR >75 beats/min, HR increase with exercise <89 beats/min, and HR re-
covery <25 beats/min 1 min after exercise) (56), the prevalence of participants with dysautono-
mia at 12 mo is comparable based on severity (community, 25%; hospitalized, 23%), with symp-
14 of 33 7/11/2023, 3:52 PM
tomatic participants displaying a higher prevalence compared with recovered (symptomatic,

26%; recovered, 17%). It is possible that dysautonomia, along with deconditioning, may contrib-
ute toward the reduced oxygen update at peak demonstrated in symptomatic participants at 12
mo.
PROMs. Neither hospitalized group differed from controls in levels of depression at 12 mo, with
only community-symptomatic individuals remaining different to controls. Improvements in fa-
tigue status between baseline and follow-up (particularly within symptomatic groups) resulted
in recovered groups being no different to controls by 12 mo. These improvements in mental
health at 12 mo may be related to improved excise tolerance (particularly at submaximal exer-
cise intensities) and resultant unrestricted ability to perform ADLs.
Differences over Time for COVID-19-Exposed Participants: Comparing 12-Mo Follow-Up to

5-Mo Baseline Values
Despite decreases of exercise limiting symptom prevalence such as SoB and fatigue (Table 2), no
objective changes in cardiopulmonary exercise function, or body composition, were identi�ied in
any group during the 7-mo observation period. Neither severity of acute illness nor recovery sta-
tus at 5 mo in�luenced 12-mo patient-reported outcomes or recovery of cardiopulmonary exer-
cise function (i.e., no COVID-19-exposed group was recovering faster than another).
Other longitudinal studies have demonstrated short to medium term improvements in peak V� �2
values following COVID-19. In a cohort study of hospitalized adults (mean age 59 yr), Ingul et al.
(57) report signi�icant improvements in peak V� �2 values and oxygen pulse between 3 and 12 mo
following COVID-19, with the majority of patients demonstrating normal exercise capacity at 12
mo. Although similar signi�icant changes over time were not reported in our hospitalized group,
Cassar et al. (58) describe exercise tolerance improving at 6 mo postillness, but 31% of the co-
hort (n = 46) had reduced peak oxygen consumption compared with controls, suggesting, similar
to our �indings, medium-term improvement, but not resolution, in CPET function. There are
other few prospective longitudinal studies which included hospitalized and community-
managed patients, with our �indings similar to those who observed minimal recovery (2, 59–61).
Collectively, while some evidence supports improvements in the trajectory of recovery over 6–12
mo duration, full recovery might actually be achieved after 12 mo.
Our �indings are also similar to a large UK prospective study of posthospitalized COVID-19 pa-
tients by Evans et al (2), who found minimal improvements at 12 mo postillness, after a 7-mo
clinical observation period. Their major risk factors for not feeling fully recovered at 1 yr were
female sex, obesity, and undergoing invasive mechanical ventilation. In a predominantly male co-
hort, our study concurred with obesity as a risk factor, as waist circumference was found to be
greater in symptomatic and hospitalized groups.
Although our population achieved CPET outputs considered “healthy” by wider population stan-
dards, they represent considerably substandard �itness in a trained military population. Prior to
COVID-19, no symptomatic participants had been diagnosed with a cardiorespiratory or neuro-
15 of 33 7/11/2023, 3:52 PM
logical disorder; however, 16 of them had a chronic musculoskeletal (MSK) injury. This could
have led to prolonged periods of rest or physical inactivity, and subsequent reduced �itness may
have preceded the acute illness and increased vulnerability to acute severity and aftermath. In
most cases, regardless of premorbid �itness, the reduced activity experienced during a prolonged
convalescent period, or in a tiny minority of cases, COVID-related organ pathology, will have im-
paired cardiorespiratory �itness.
ADL and Occupational Status
Given how debilitating COVID-19 has been for many members of the wider population, COVID-
19-exposed participant groups in this study performed relatively well at 12 mo, with the major-
ity graded in the top two categories of WHO performance status: Level 1 or Level 0 (i.e., “re-
stricted in physically strenuous activity but ambulatory and able to carry out work of a light or
sedentary nature” or “fully active, able to carry on all pre-disease performance without restric-
tion”). However, when assessed against military-speci�ic functional/occupational performance
tools (FAA and JMES), considerable limitations are demonstrated. At 12 mo, 23% of hospitalized
and 34% of symptomatic participants remained “un�it for trade” and 58% of hospitalized and
60% of symptomatic participants remained medically “not deployable.”
Occupational decisions are made by military physicians, based on a global assessment of the in-
dividual, including their medical history, clinical assessment, current issues, and job-role de-
mands. When considering the entire COVID-19-exposed cohort at 12 mo, 21% were graded “lim-
ited deployability” and 49% “not deployable” (Fig. 3). For UK military personnel experiencing
prolonged COVID-19 symptoms, this could create uncertainty over their ability to ful�il their job
role within their primary trade and/or their longer-term employment status within the British
Armed Forces, with a similar impact possible for other organizations responsible for the long-
term health of personnel in physically demanding job roles.
Strength and Limitations
A major strength of this study is the use of an appropriate control group, given the increased �it-
ness standards, to identify limitations objectively and to quantify exercise response, especially in
assessment of medium-term sequelae (62). Within this article, we present data corresponding to
the 88 participants who attended both their 5 mo and 12 mo postacute illness. One limitation is
the 22% participant dropout between baseline (5 mo postacute illness) (30) and the subsequent
follow-up (12 mo). The primary reason cited for nonattendance at 12-mo follow-up was the in-
creased demands of their job role and lack of availability to attend assessment sessions. It is not
clear what effect this has on the remaining population and potential bias, but suggests those in-
dividuals were fully recovered and able to return to full duty.
Our de�inition of illness severity (being hospitalized) is unable to differentiate between those
patients who were admitted to a ward and those considered critically ill. We are therefore un-
able to consider the impact of very severe disease. The majority of UK military personnel re-
ceived their vaccine in line with age-related governmental guidance, with widespread vaccina-
16 of 33 7/11/2023, 3:52 PM
tion within the Armed Forces from April 2021. As baseline data collection started in August
2020, with all acute illnesses during or before March 2021, we did not report vaccination status
and recurrent infections with new variants within this study.
While the follow-up sample size is modest (n = 88), this is balanced by the comprehensive as-
sessments and analysis methods completed. Deployability status is typically reviewed at ∼6 mo
intervals, with a corresponding lag between recovery and upgrade. The deployability status
alone is therefore not a responsive measure, so we have used the FAA, validated in the military
population (46), to re�lect immediate occupational impact.
Conclusions
While the prevalence of subjective exercise-limiting symptoms such as SoB and fatigue in symp-
tomatic groups decreased over 7 mo of follow-up, no clinically meaningful changes in cardiopul-
monary exercise function or body composition were demonstrated in any group. Acute illness
severity and recovery status at 5 mo do not appear to in�luence longer-term (12 mo) PROMs or
recovery of cardiopulmonary exercise �itness in a physically trained, COVID-19-exposed, work-
ing age population. This has signi�icant clinical and occupational implications for the medium to
long-term management of individuals with persistent symptoms and underscores the impor-
tance of �inding treatments for the management of post-COVID-19 syndrome.
At 12 mo after acute COVID-19 illness, COVID-19-exposed participants have a reduced capacity

for work at the anaerobic threshold, despite oxygen uptake comparable to controls. This re�lects
impaired metabolic ef�iciency. Despite their subjective perception of recovery, hospitalized-
recovered individuals continue to exhibit reduced oxygen uptake and power output compared
with controls at 12 mo. When compared with controls, symptomatic and hospitalized partici-
pants’ CPET pro�iles are consistent with deconditioning. There are no clear-cut features to sug-
gest pathological circulatory limitation and no features of ventilatory limitation.
At follow-up, both hospitalized groups demonstrate similar mental health pro�iles to controls,
suggesting a level of psychological recovery and preparedness that is compatible with return to
operational duties. However, feeling better (subjectively) does not mean “�it for operational
duty.” Military personnel are expected to meet physical occupational standards, with the car-
diorespiratory �itness of our participants expected to be higher than that in the general popula-
tion. Our overall �indings provide further evidence that, when compared with a control group
(matched by age, sex, and job role), hospitalized and symptomatic individuals experience
exercise-limiting symptoms that persist beyond 12 mo. Access to rehabilitation services and
monitoring of cardiopulmonary exercise function (under peak exercise conditions) may be war-
ranted beyond a year following onset of COVID-19 illness for individuals in physically demand-
ing job roles.
DATA AVAILABILITY
Data relate to the serving population of the Ministry of Defense and thus are sensitive. Research
17 of 33 7/11/2023, 3:52 PM
teams requesting data are invited to contact the corresponding author and appropriate permis-
sions will be sought for release.
GRANTS
A grant was received from the Defence Medical Services Research Steering Group.
DISCLOSURES
No con�licts of interest, �inancial or otherwise, are declared by the authors.
AUTHOR CONTRIBUTIONS
D.A.H., E.D.N., and A.N.B. conceived and designed research; P.L., D.A.H., O.O., R.M.B-D., R.C., K.R-S.,
V.K., and A.K. performed experiments; A.H. analyzed data; P.L., D.A.H., O.O., R.M.B-D., A.H., J.N.,
J.M., M.C., E.D.N., and A.N.B. interpreted results of experiments; P.L., D.A.H., and A.H. prepared �ig-
ures; P.L., D.A.H., O.O., and A.H. drafted manuscript; P.L., D.A.H., O.O., R.M.B-D., A.H., E.D.N., and
A.N.B. edited and revised manuscript; P.L., D.A.H., O.O., R.M.B-D., A.H., R.C., K.R-S., V.K., A.K., J.N.,
J.M., M.C., E.D.N., and A.N.B. approved �inal version of manuscript.
SUPPLEMENTAL DATA
Supplemental File S1: https://doi.org/10.6084/m9.�igshare.20197844.
ACKNOWLEDGMENTS
The authors thank the participants who volunteered for the Military COVID-19 Observational
Outcome in a Viral Infectious Disease (M-COVID) study for their determination and positive en-
gagement during the cardiopulmonary exercise test. We also acknowledge the tireless efforts of
all the research support staff at the UK Defense Medical Rehabilitation Centre (DMRC), Stanford
Hall for their role in ensuring this study could be delivered during challenging circumstances.
We would particularly like to thank the incredible efforts of two DMRC-based administrators,
Fiona Miller and Dawn McGuiness.
REFERENCES
18 of 33 7/11/2023, 3:52 PM
1. Alkodaymi MS, Omrani OA, Fawzy NA, Shaar BA, Almamlouk R, Riaz M, Obeidat M, Obeidat Y, Gerberi D, Taha RM,
Kashour Z, Kashour T, Berbari EF, Alkattan K, Tleyjeh IM. Prevalence of post-acute COVID-19 syndrome symptoms at
different follow-up periods: a systematic review and meta-analysis. Clin Microbiol Infect 28: 657–666, 2022. doi:
10.1016/j.cmi.2022.01.014. [PMCID: PMC8812092] [PubMed: 35124265] [CrossRef: 10.1016/j.cmi.2022.01.014]
2. PHOSP-COVID Collaborative Group. Clinical characteristics with in�lammation pro�iling of long COVID and association
with 1-year recovery following hospitalisation in the UK: a prospective observational study. Lancet Respir Med 10:
761–775, 2022. [Erratum in Lancet Respir Med 10: e85, 2022]. doi: 10.1016/S2213-2600(22)00127-8. [PMCID:
PMC9034855] [PubMed: 35472304] [CrossRef: 10.1016/S2213-2600(22)00127-8]
3. Carfı̀ A, Bernabei R, Landi F; Gemelli Against COVID-19 Post-Acute Care Study Group. Persistent symptoms in patients
after acute COVID-19. JAMA 324: 603–605, 2020. doi: 10.1001/jama.2020.12603. [PMCID: PMC7349096] [PubMed:
32644129] [CrossRef: 10.1001/jama.2020.12603]
4. O’Sullivan O, Barker-Davies RM, Thompson K, Bahadur S, Gough M, Lewis S, Martin M, Segalini A, Wallace G, Phillip R,
Cranley M. Rehabilitation post-COVID-19: cross-sectional observations using the Stanford Hall remote assessment tool.
BMJ Mil Health: bmjmilitary-2021-001856, 2021. doi: 10.1136/bmjmilitary-2021-001856. [PMCID: PMC8159670]
[PubMed: 34039689] [CrossRef: 10.1136/bmjmilitary-2021-001856]
5. Mandal S, Barnett J, Brill SE, Brown JS, Denneny EK, Hare SS, Heightman M, Hillman TE, Jacob J, Jarvis HC, Lipman MCI,
Naidu SB, Nair A, Porter JC, Tomlinson GS, Hurst JR. ‘Long-COVID’: a cross-sectional study of persisting symptoms,
biomarker and imaging abnormalities following hospitalisation for COVID-19. Thorax 76: 396–398, 2021. doi:
10.1136/thoraxjnl-2020-215818. [PMCID: PMC7661378] [PubMed: 33172844] [CrossRef: 10.1136/thoraxjnl-
2020-215818]
6. Ladlow P, O’Sullivan O, Houston A, Barker-Davies R, May S, Mills D, Dewson D, Chamley R, Naylor J, Mulae J, Bennett AN,
Nicol ED, Holdsworth DA. Dysautonomia following COVID-19 is not associated with subjective limitations or symptoms,
but is associated with objective functional limitations. Heart Rhythm 19: 613–620, 2021. doi:
10.1016/j.hrthm.2021.12.005. [PMCID: PMC8656177] [PubMed: 34896622] [CrossRef: 10.1016/j.hrthm.2021.12.005]
7. Tsamakis K, Tsiptsios D, Ouranidis A, Mueller C, Schizas D, Terniotis C, Nikolakakis N, Tyros G, Kympouropoulos S,

Lazaris A, Spandidos D, Smyrnis N, Rizos E. COVID-19 and its consequences on mental health. Exp Ther Med 21: 244,
2021. doi: 10.3892/etm.2021.9675. [PMCID: PMC7851613] [PubMed: 33603852] [CrossRef: 10.3892/etm.2021.9675]
8. Phillips S, Williams MA. Confronting our next national health disaster—long-haul Covid. N Engl J Med 385: 577–579,
2021. doi: 10.1056/NEJMp2109285. [PubMed: 34192429] [CrossRef: 10.1056/NEJMp2109285]
9. Tenforde MW, Kim SS, Lindsell CJ, Billig Rose E, Shapiro NI, Files DC, Gibbs KW, Erickson HL, Steingrub JS, Smithline
HA, Gong MN, Aboodi MS, Exline MC, Henning DJ, Wilson JG, Khan A, Qadir N, Brown SM, Peltan ID, Rice TW, Hager DN,
Ginde AA, Stubble�ield WB, Patel MM, Self WH, Feldstein LR; IVY Network Investigators, CDC COVID-19 Response Team,
IVY Network Investigators. Symptom duration and risk factors for delayed return to usual health among outpatients with
COVID-19 in a multistate health care systems network—United States, March–June 2020. MMWR Morb Mortal Wkly Rep
69: 993. 2020. doi: 10.15585/mmwr.mm6930e1. [PMCID: PMC7392393] [PubMed: 32730238] [CrossRef:
10.15585/mmwr.mm6930e1]
10. Caterisano A, Decker D, Snyder B, Feigenbaum M, Glass R, House P, Sharp C, Waller M, Witherspoon Z. CSCCa and
NSCA joint consensus guidelines for transition periods: safe return to training following inactivity. Strength &
Conditioning J 41: 1–23, 2019. doi: 10.1519/SSC.0000000000000477. [CrossRef: 10.1519/SSC.0000000000000477]
11. Brawner CA, Ehrman JK, Bole S, Kerrigan DJ, Parikh SS, Lewis BK, Gindi RM, Keteyian C, Abdul-Nour K, Keteyian SJ.
19 of 33 7/11/2023, 3:52 PM
Inverse relationship of maximal exercise capacity to hospitalization secondary to coronavirus disease 2019. Mayo Clin
Proc 96, 32–39, 2021. doi: 10.1016/j.mayocp.2020.10.003. [PMCID: PMC7547590] [PubMed: 33413833] [CrossRef:
10.1016/j.mayocp.2020.10.003]
12. Rinaldo RF, Mondoni M, Parazzini EM, Pitari F, Brambilla E, Luraschi S, Balbi M, Sferrazza Papa GF, Sotgiu G, Guazzi M,
Di Marco F, Centanni S. Deconditioning as main mechanism of impaired exercise response in COVID-19 survivors. Eur
Respir J 58: 2100870, 2021. doi: 10.1183/13993003.00870-2021. [PMCID: PMC8082950] [PubMed: 33926969]
[CrossRef: 10.1183/13993003.00870-2021]
13. Skjørten I, Ankerstjerne OAW, Trebinjac D, Brønstad E, Rasch-Halvorsen Ø, Einvik G, Lerum TV, Stavem K, Edvardsen
A, Ingul CB. Cardiopulmonary exercise capacity and limitations 3 months after COVID-19 hospitalisation. Eur Respir J 58:
2100996, 2021. doi: 10.1183/13993003.00996-2021. [PMCID: PMC8247555] [PubMed: 34210791] [CrossRef:
10.1183/13993003.00996-2021]
14. Holdsworth DA, Chamley R, Barker-Davies R, O’Sullivan O, Ladlow P, Mitchell JL, Dewson D, Mills D, May SLJ, Cranley
M, Xie C, Sellon E, Mulae J, Naylor J, Raman B, Talbot NP, Rider OJ, Bennett AN, Nicol ED. Comprehensive clinical
assessment identi�ies speci�ic neurocognitive de�icits in working-age patients with long-COVID. PloS One 17: e0267392,
2022. doi: 10.1371/journal.pone.0267392. [PMCID: PMC9187094] [PubMed: 35687603] [CrossRef:
10.1371/journal.pone.0267392]
15. Ladlow P, O’Sullivan O, Bennett AN, Barker-Davies R, Houston A, Chamley R, May S, Mills D, Dewson D, Rogers-Smith
K, Ward C, Taylor J, Mulae J, Naylor J, Nicol ED, Holdsworth DA. The effect of medium-term recovery status after
COVID-19 illness on cardiopulmonary exercise capacity in a physically active adult population. J Appl Physiol 132:
1525–1535, 2022. doi: 10.1152/japplphysiol.00138.2022. [PMCID: PMC9190734] [PubMed: 35608204] [CrossRef:
10.1152/japplphysiol.00138.2022]
16. Puntmann VO, Carerj ML, Wieters I, Fahim M, Arendt C, Hoffmann J, Shchendrygina A, Escher F, Vasa-Nicotera M,
Zeiher AM, Vehreschild M, Nagel E. Outcomes of cardiovascular magnetic resonance imaging in patients recently
recovered from coronavirus disease 2019 (COVID-19). JAMA Cardiol 5: 1265–1273, 2020. doi:
10.1001/jamacardio.2020.3557. [PMCID: PMC7385689] [PubMed: 32730619] [CrossRef:
10.1001/jamacardio.2020.3557]
17. Han X, Fan Y, Alwalid O, Li N, Jia X, Yuan M, Li Y, Cao Y, Gu J, Wu H, Shi H. Six-month follow-up chest CT �indings after
severe COVID-19 pneumonia. Radiology 299: E177–E186, 2021. doi: 10.1148/radiol.2021203153. [PMCID:
PMC7841877] [PubMed: 33497317] [CrossRef: 10.1148/radiol.2021203153]
18. Gaber T. Assessment and management of post-COVID fatigue. ProgNeurolPsychiatry 25: 36–39, 2021. doi:
10.1002/pnp.698. [CrossRef: 10.1002/pnp.698]
19. Stormorken E, Jason LA, Kirkevold M. Factors impacting the illness trajectory of post-infectious fatigue syndrome: a
qualitative study of adults’ experiences. BMC Public Health 17: 952, 2017. doi: 10.1186/s12889-017-4968-2. [PMCID:
PMC5729235] [PubMed: 29237442] [CrossRef: 10.1186/s12889-017-4968-2]
20. Chopra V, Flanders SA, O’Malley M, Malani AN, Prescott HC. Sixty-day outcomes among patients hospitalized with
COVID-19. Ann Intern Med 174: 576–578, 2021. doi: 10.7326/M20-5661. [PMCID: PMC7707210] [PubMed: 33175566]
[CrossRef: 10.7326/M20-5661]
21. Garrigues E, Janvier P, Kherabi Y, Le Bot A, Hamon A, Gouze H, Doucet L, Berkani S, Oliosi E, Mallart E, Corre F,
Zarrouk V, Moyer J-D, Galy A, Honsel V, Fantin B, Nguyen Y. Post-discharge persistent symptoms and health-related
quality of life after hospitalization for COVID-19. J Infect 81: e4–e6, 2020. doi: 10.1016/j.jinf.2020.08.029. [PMCID:
20 of 33 7/11/2023, 3:52 PM
PMC7445491] [PubMed: 32853602] [CrossRef: 10.1016/j.jinf.2020.08.029]
22. Xiong Q, Xu M, Li J, Liu Y, Zhang J, Xu Y, Dong W. Clinical sequelae of COVID-19 survivors in Wuhan, China: a single-
centre longitudinal study. Clin Microbiol Infect 27: 89–95, 2021. doi: 10.1016/j.cmi.2020.09.023. [PMCID: PMC7510771]
[PubMed: 32979574] [CrossRef: 10.1016/j.cmi.2020.09.023]
23. Townsend L, Dyer AH, Jones K, Dunne J, Mooney A, Gaffney F, O'Connor L, Leavy D, O'Brien K, Dowds J, Sugrue JA,
Hopkins D, Martin-Loeches I, Ni Cheallaigh C, Nadarajan P, McLaughlin AM, Bourke NM, Bergin C, O'Farrelly C, Bannan C,
Conlon N. Persistent fatigue following SARS-CoV-2 infection is common and independent of severity of initial infection.
PloS One 15: e0240784, 2020. doi: 10.1371/journal.pone.0240784. [PMCID: PMC7652254] [PubMed: 33166287]
[CrossRef: 10.1371/journal.pone.0240784]
24. Andrews PJ, Pendolino AL, Ottaviano G, Scarpa B, Grant J, Gaudioso P, Bordin A, Marchese-Ragona R, Leoni D, Cattelan
A, Kaura A, Gane S, Hamilton NJ, Choi D, Andrews JA. Olfactory and taste dysfunction among mild-to-moderate
symptomatic COVID-19 positive health care workers: an international survey. Laryngoscope Investig Otolaryngol 5:
1019–1028, 2020. doi: 10.1002/lio2.507. [PMCID: PMC7752034] [PubMed: 33365393] [CrossRef: 10.1002/lio2.507]
25. Carvalho-Schneider C, Laurent E, Lemaignen A, Beau�ils E, Bourbao-Tournois C, Laribi S, Flament T, Ferreira-Maldent

N, Bruyè re F, Ste�ic K, Gaudy-Graf�in C, Grammatico-Guillon L, Bernard L. Follow-up of adults with noncritical COVID-19
two months after symptom onset. Clin Microbiol Infect 27: 258–263, 2021. doi: 10.1016/j.cmi.2020.09.052. [PMCID:
PMC7534895] [PubMed: 33031948] [CrossRef: 10.1016/j.cmi.2020.09.052]
26. Horvath L, Lim JWJ, Taylor JW, Saief T, Stuart R, Rimmer J, Michael P. Smell and taste loss in COVID-19 patients:
assessment outcomes in a Victorian population. Acta Otolaryngol 141: 299–302, 2021. doi:
10.1080/00016489.2020.1855366. [PubMed: 33307905] [CrossRef: 10.1080/00016489.2020.1855366]
27. Sonnweber T, Boehm A, Sahanic S, Pizzini A, Aichner M, Sonnweber B, Kurz K, Koppelstä tter S, Haschka D, Petzer V,
Hilbe R, Theurl M, Lehner D, Nairz M, Puchner B, Luger A, Schwabl C, Bellmann-Weiler R, Wö ll E, Widmann G, Tancevski I,
Weiss G. Persisting alterations of iron homeostasis in COVID-19 are associated with non-resolving lung pathologies and
poor patients’ performance: a prospective observational cohort study. Respir Res 21: 276, 2020. doi:
10.1186/s12931-020-01546-2. [PMCID: PMC7575703] [PubMed: 33087116] [CrossRef: 10.1186/s12931-020-01546-2]
28. Singh I, Joseph P, Heerdt PM, Cullinan M, Lutchmansingh DD, Gulati M, Possick JD, Systrom DM, Waxman AB.
Persistent exertional intolerance after COVID-19: insights from invasive cardiopulmonary exercise testing. Chest 161:
54–63, 2021. doi: 10.1016/j.chest.2021.08.010. [PMCID: PMC8354807] [PubMed: 34389297] [CrossRef:
10.1016/j.chest.2021.08.010]
29. Raman B, Cassar MP, Tunnicliffe EM, Filippini N, Griffanti L, Alfaro-Almagro F, , et al.. Medium-term effects of SARS-
CoV-2 infection on multiple vital organs, exercise capacity, cognition, quality of life and mental health, post-hospital
discharge. EClinicalMedicine 31: 100683, 2021. doi: 10.1016/j.eclinm.2020.100683. [PMCID: PMC7808914] [PubMed:
33490928] [CrossRef: 10.1016/j.eclinm.2020.100683]
30. O'Sullivan O, Holdsworth DA, Ladlow P, Barker-Davies RM, Chamley R, Houston A, May S, Dewson D, Mills D, Pierce K,
Mitchell J, Xie C, Sellon E, Naylor J, Mulae J, Cranley M, Talbot NP, Rider OJ, Nicol ED, Bennett AN. Cardiopulmonary,
functional, cognitive and mental health outcomes post-COVID-19, across the range of severity of acute illness, in a
physically active, working-age population. Sports Med Open 9: 7, 2022. doi: 10.1186/s40798-023-00552-0. [PMCID:
PMC9893959] [PubMed: 36729302] [CrossRef: 10.1186/s40798-023-00552-0]
31. Houchen-Wolloff L, Poinasamy K, Holmes K, Tarpey M, Hastie C, Raihani K, , et al.. Joint patient and clinician priority
setting to identify 10 key research questions regarding the long-term sequelae of COVID-19. Thorax 77: 717–720, 2022.
21 of 33 7/11/2023, 3:52 PM
doi: 10.1136/thoraxjnl-2021-218582. [PMCID: PMC9209667] [PubMed: 35354642] [CrossRef: 10.1136/thoraxjnl-

2021-218582]
32. O'Sullivan O, Barker-Davies R, Chamley R, Sellon E, Jenkins D, Burley R, Holden L, Nicol AM, Phillip R, Bennett AN,
Nicol E, Holdsworth DA. Defence Medical Rehabilitation Centre (DMRC) COVID-19 recovery service. BMJ Mil Health
e001681, 2021. doi: 10.1136/bmjmilitary-2020-001681. [PubMed: 33547188] [CrossRef: 10.1136/bmjmilitary-
2020-001681]
33. Ladlow P, Conway D, Hayhurst D, Suf�ield C, Cassidy RP, Coppack RJ. Integration of strength training into UK Defence
Rehabilitation practice: current trends and future challenges. BMJ Military Health 168: 314–319, 2020. doi:
10.1136/bmjmilitary-2020-001590. [PMCID: PMC9340023] [PubMed: 33087537] [CrossRef: 10.1136/bmjmilitary-
2020-001590]
34. ATS Committee on Pro�iciency Standards for Clinical Pulmonary Function Laboratories. ATS statement: guidelines for
the six-minute walk test. Am J Respir Crit Care Med 166: 111–117, 2002. [Erratum in Am J Respir Crit Care Med 193: 1185,
2016]. doi: 10.1164/ajrccm.166.1.at1102. [PubMed: 12091180] [CrossRef: 10.1164/ajrccm.166.1.at1102]
35. Borg GA. Psychophysical bases of perceived exertion. Med Sci Sports Exerc 14: 377–381, 1982. [PubMed: 7154893]
36. Mahler DA, Horowitz MB. Perception of breathlessness during exercise in patients with respiratory disease. Med Sci
Sports Exerc 26: 1078–1081, 1994. [PubMed: 7808239]
37. Graham BL, Steenbruggen I, Miller MR, Barjaktarevic IZ, Cooper BG, Hall GL, Hallstrand TS, Kaminsky DA, McCarthy K,
McCormack MC, Oropez CE, Rosenfeld M, Stanojevic S, Swanney MP, Thompson BR. Standardization of Spirometry 2019
Update. An of�icial American thoracic society and European respiratory society technical statement. Am J Respir Crit Care
Med 200: e70–e88, 2019. doi: 10.1164/rccm.201908-1590ST. [PMCID: PMC6794117] [PubMed: 31613151] [CrossRef:
10.1164/rccm.201908-1590ST]
38. Kroenke K, Spitzer RL, Williams JB. The PHQ-9: validity of a brief depression severity measure. J Gen Intern Med 16:
606–613, 2001. doi: 10.1046/j.1525-1497.2001.016009606.x. [PMCID: PMC1495268] [PubMed: 11556941] [CrossRef:
10.1046/j.1525-1497.2001.016009606.x]
39. Spitzer RL, Kroenke K, Williams JB, Lowe B. A brief measure for assessing generalized anxiety disorder: the GAD-7.
Arch Intern Med 166: 1092–1097, 2006. doi: 10.1001/archinte.166.10.1092. [PubMed: 16717171] [CrossRef:
10.1001/archinte.166.10.1092]
40. Blevins CA, Weathers FW, Davis MT, Witte TK, Domino JL. The posttraumatic stress disorder checklist for DSM-5
(PCL-5): development and initial psychometric evaluation. J Trauma Stress 28: 489–498, 2015. doi: 10.1002/jts.22059.
[PubMed: 26606250] [CrossRef: 10.1002/jts.22059]
41. Group TE. EuroQol-a new facility for the measurement of health-related quality of life. Health Policy 16: 199–208,
1990. doi: 10.1016/0168-8510(90)90421-9. [PubMed: 10109801] [CrossRef: 10.1016/0168-8510(90)90421-9]
42. Michielsen HJ, De Vries J, Van Heck GL. Psychometric qualities of a brief self-rated fatigue measure: the fatigue
assessment scale. J Psychosom Res 54: 345–352, 2003. doi: 10.1016/s0022-3999(02)00392-6. [PubMed: 12670612]
[CrossRef: 10.1016/s0022-3999(02)00392-6]
43. Barker-Davies RM, O'Sullivan O, Senaratne KPP, Baker P, Cranley M, Dharm-Datta S, Ellis H, Goodall D, Gough M, Lewis
S, Norman J, Papadopoulou T, Roscoe D, Sherwood D, Turner P, Walker T, Mistlin A, Phillip R, Nicol AM, Bennett AN,
Bahadur S. The Stanford Hall consensus statement for post-COVID-19 rehabilitation. Br J Sports Med 54: 949–959, 2020.
doi: 10.1136/bjsports-2020-102596. [PMCID: PMC7418628] [PubMed: 32475821] [CrossRef: 10.1136/bjsports-
22 of 33 7/11/2023, 3:52 PM
2020-102596]
44. Menni C, Valdes AM, Freidin MB, Sudre CH, Nguyen LH, Drew DA, Ganesh S, Varsavsky T, Cardoso MJ, El-Sayed
Moustafa JS, Visconti A, Hysi P, Bowyer RCE, Mangino M, Falchi M, Wolf J, Ourselin S, Chan AT, Steves CJ, Spector TD. Real-
time tracking of self-reported symptoms to predict potential COVID-19. Nat Med 26: 1037–1040, 2020. doi:
10.1038/s41591-020-0916-2. [PMCID: PMC7751267] [PubMed: 32393804] [CrossRef: 10.1038/s41591-020-0916-2]
45. Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET, Carbone PP. Toxicity and response criteria of the
Eastern Cooperative Oncology Group. Am J Clin Oncol 5: 649–656, 1982. [PubMed: 7165009]
46. Roberts AJ, Franklyn-Miller AD, Etherington J. A new functional outcome assessment tool for military
musculoskeletal rehabilitation: a pilot validation study. PM R 3: 527–532, 2011. doi: 10.1016/j.pmrj.2011.03.009.
[PubMed: 21665165] [CrossRef: 10.1016/j.pmrj.2011.03.009]
47. Wise RA, Brown CD. Minimal clinically important differences in the six-minute walk test and the incremental shuttle
walking test. COPD 2: 125–129, 2005. doi: 10.1081/copd-200050527. [PubMed: 17136972] [CrossRef: 10.1081/copd-
200050527]
48. Tanaka K, Matsuura Y, Matsuzaka A, Hirakoba K, Kumagai S, Sun SO, Asano K. A longitudinal assessment of anaerobic
threshold and distance-running performance. Med Sci Sports Exerc 16: 278–282, 1984. [PubMed: 6748926]
49. Ferretti G, Antonutto G, Denis C, Hoppeler H, Minetti AE, Narici MV, Desplanches D. The interplay of central and
peripheral factors in limiting maximal O2 consumption in man after prolonged bed rest. J Physiol 501: 677, 1997. doi:
10.1111/j.1469-7793.1997.677bm.x. [PMCID: PMC1159468] [PubMed: 9218227] [CrossRef:
10.1111/j.1469-7793.1997.677bm.x]
50. Fletcher GF, Balady GJ, Amsterdam EA, Chaitman B, Eckel R, Fleg J, Froelicher VF, Leon AS, Piñ a IL, Rodney R, Simons-
Morton DA, Williams MA, Bazzarre T. Exercise standards for testing and training: a statement for healthcare
professionals from the American Heart Association. Circulation 104: 1694–1740, 2001. doi: 10.1161/hc3901.095960.
[PubMed: 11581152] [CrossRef: 10.1161/hc3901.095960]
51. Ainsworth BE, Haskell WL, Whitt MC, Irwin ML, Swartz AM, Strath SJ, O'Brien WL, Bassett DR, Schmitz KH,
Emplaincourt PO, Jacobs DR, Leon AS. Compendium of physical activities: an update of activity codes and MET
intensities. Med Sci Sports Exerc 32: S498–S504, 2000. doi: 10.1097/00005768-200009001-00009. [PubMed: 10993420]
[CrossRef: 10.1097/00005768-200009001-00009]
52. Aparisi A� , Ybarra-Falcó n C, Garcı́a-Gó mez M, Tobar J, Iglesias-Echeverrı́a C, Jaurrieta-Largo S, Ladró n R, Uribarri A,
Catalá P, Hinojosa W, Marcos-Mangas M, Ferná ndez-Prieto L, Sedano-Gutié rrez R, Cusacovich I, Andaluz-Ojeda D, de Vega-
Sá nchez B, Recio-Platero A, Sanz-Patiñ o E, Calvo D, Baladró n C, Carrasco-Moraleja M, Disdier-Vicente C, Amat-Santos IJ,
San Romá n JA. Exercise ventilatory inef�iciency in post-COVID-19 syndrome: insights from a prospective evaluation. J Clin
Med 10: 2591, 2021. doi: 10.3390/jcm10122591. [PMCID: PMC8230788] [PubMed: 34208271] [CrossRef:
10.3390/jcm10122591]
53. Steinbeis F, Knape P, Mittermaier M, Helbig ET, Tober-Lau P, Thibeault C, Lippert LJ, Xiang W, Mü ller-Plathe M,
Steinbrecher S, Meyer H-J, Ring RM, Ruwwe-Glö senkamp C, Alius F, Li Y, Mü ller-Redetzky H, Uhrig A, Lingscheid T, Grund
D, Temmesfeld-Wollbrü ck B, Suttorp N, Sander LE, Kurth F, Witzenrath M, Zoller T. Functional limitations 12 months after
SARS-CoV-2 infection correlate with initial disease severity: an observational study of cardiopulmonary exercise capacity
testing in COVID-19 convalescents. Respir Med 202: 106968, 2022. doi: 10.1016/j.rmed.2022.106968. [PMCID:
PMC9420203] [PubMed: 36081267] [CrossRef: 10.1016/j.rmed.2022.106968]
23 of 33 7/11/2023, 3:52 PM
54. Naeije R, Caravita S. Phenotyping long COVID. Eur Respiratory Soc 58: 2101763, 2021. doi:
10.1183/13993003.01763-2021. [PMCID: PMC8287735] [PubMed: 34244323] [CrossRef:
10.1183/13993003.01763-2021]
55. Ustun G. Determining depression and related factors in a society affected by COVID-19 pandemic. Int J Soc Psychiatry
67: 54–63, 2021. doi: 10.1177/0020764020938807. [PMCID: PMC7331110] [PubMed: 32605422] [CrossRef:
10.1177/0020764020938807]
56. Jouven X, Empana J-P, Schwartz PJ, Desnos M, Courbon D, Ducimetiè re P. Heart-rate pro�ile during exercise as a
predictor of sudden death. N Engl J Med 352: 1951–1958, 2005. doi: 10.1056/NEJMoa043012. [PubMed: 15888695]
[CrossRef: 10.1056/NEJMoa043012]
57. Ingul CB, Edvardsen A, Follestad T, Trebinjac D, Ankerstjerne OAW, Brønstad E, Rasch-Halvorsen Ø, Aarli B, Dalen H,
Nes BM, Lerum TV, Einvik G, Stavem K, Skjørten I. Changes in cardiopulmonary exercise capacity and limitations 3 to 12
months after COVID-19. Eur Respir J 61: 2200745, 2022. doi: 10.1183/13993003.00745-2022. [PMCID: PMC9515478]
[PubMed: 36137587] [CrossRef: 10.1183/13993003.00745-2022]
58. Cassar MP, Tunnicliffe EM, Petousi N, Lewandowski AJ, Xie C, Mahmod M, Samat AHA, Evans RA, Brightling CE, Ho L-P,
Piechnik SK, Talbot NP, Holdsworth D, Ferreira VM, Neubauer S, Raman B. Symptom persistence despite improvement in
cardiopulmonary health–insights from longitudinal CMR, CPET and lung function testing post-COVID-19.
EClinicalMedicine 41: 101159, 2021. doi: 10.1016/j.eclinm.2021.101159. [PMCID: PMC8527025] [PubMed: 34693230]
[CrossRef: 10.1016/j.eclinm.2021.101159]
59. Ferná ndez-de-Las-Peñ as C, Guijarro C, Plaza-Canteli S, Herná ndez-Barrera V, Torres-Macho J. Prevalence of post-
COVID-19 cough one year after SARS-CoV-2 infection: a multicenter study. Lung 199: 249–253, 2021. doi:
10.1007/s00408-021-00450-w. [PMCID: PMC8124095] [PubMed: 33993321] [CrossRef: 10.1007/s00408-021-00450-
w]
60. Maestre-Muñ iz MM, Arias A� , Mata-Vá zquez E, Martı́n-Toledano M, Ló pez-Larramona G, Ruiz-Chicote AM, Nieto-
Sandoval B, Lucendo AJ. Long-term outcomes of patients with coronavirus disease 2019 at one year after hospital
discharge. J Clin Med 10: 2945, 2021. doi: 10.3390/jcm10132945. [PMCID: PMC8269002] [PubMed: 34209085]
[CrossRef: 10.3390/jcm10132945]
61. Latronico N, Peli E, Calza S, Rodella F, Novelli MP, Cella A, Marshall J, Needham DM, Rasulo FA, Piva S; LOTO
Investigators. Physical, cognitive and mental health outcomes in 1-year survivors of COVID-19-associated ARDS. Thorax
77: 300–303, 2022. doi: 10.1136/thoraxjnl-2021-218064. [PubMed: 34588274] [CrossRef: 10.1136/thoraxjnl-
2021-218064]
62. Amin-Chowdhury Z, Ladhani SN. Causation or confounding: why controls are critical for characterizing long COVID.
Nat Med 27: 1129–1130, 2021. doi: 10.1038/s41591-021-01402-w. [PubMed: 34140704] [CrossRef:
10.1038/s41591-021-01402-w]
24 of 33 7/11/2023, 3:52 PM
Figures and Tables
Figure 1.
Diagrammatic description of study design and analysis plan, within- and between-group comparisons. The arrows depict
comparisons between and within groups for 3 outcome measures (functional exercise capacity, fatigue, and mental
health). These comparisons were made between two conditions: 1) severity of acute illness [hospitalized, community-
managed, and control (shaded green)] and 2) recovery status [symptomatic, recovered, and control (shaded yellow)].
Within-group comparisons occur at two time points following onset of acute COVID-19 illness; 5 mo and 12 mo).
25 of 33 7/11/2023, 3:52 PM
Figure 2.
CONSORT �low diagram.
26 of 33 7/11/2023, 3:52 PM
Table 1.
Participant demographics at baseline (5 mo postacute illness)
Two-Way ANOVA
Hospitalized vs. Recovered vs. Severity × Recovery

Recovery Status Community Symptomatic Status
Variable Severity Recovered Symptomatic F P Eta-sq. F P Eta-sq. F
Age, yr Hospitalized 50 ± 7 42 ± 8 6.584 0.013* 0.089 1.269 0.264 0.019 8.293
Community 36 ± 6 39 ± 11
Control 42 ± 8
Body Hospitalized 95 ± 18 96 ± 14 2.650 0.110 0.040 3.540 0.060 0.050 2.270

mass, kg Community 84 ± 12 93 ± 17
Control 79 ± 9
Height, Hospitalized 178 ± 9 176 ± 6 1.860 0.180 0.030 0.090 0.770 0.000 0.000
cm Community 180 ± 7 178 ± 10
Control 176 ± 7
BMI, Hospitalized 30 ± 3 31 ± 4 11.490 <0.001* 0.150 5.510 0.020* 0.080 2.870

2
kg/m Community 26 ± 2 29 ± 3
Control 26 ± 3
Waist Hospitalized 101 ± 11 101 ± 13 10.650 <0.001* 0.140 5.540 0.020* 0.080 4.770
size, cm Community 85 ± 11 95 ± 11
Control 87 ± 8
Waist/hip Hospitalized 0.96 ± 0.04 0.96 ± 0.11 4.470 0.040* 0.060 0.650 0.420 0.010 1.270
ratio Community 0.92 ± 0.08 0.92 ± 0.07
Control 0.91 ± 0.08
BMI, body mass index. Level of signi�icance <0.05 is highlighted in bold and with an asterisk symbol (*). Eta-squared ef-
fect sizes: <0.06 are small, ≥0.06 to <0.14 are medium, ≥0.14 are large. Medium and large effect sizes are highlighted in
bold.
27 of 33 7/11/2023, 3:52 PM
Table 2.
Ten most prevalent symptoms at 12 mo and the difference in prevalence since 5 mo post-COVID-19 illness
*Symptom prevalence may be linked to existing medical disorder, musculoskeletal injury, or ongoing mental health sta-
tus and not entirely re�lect participant response to COVID-19 illness.
28 of 33 7/11/2023, 3:52 PM
Table 3.
Mental health, fatigue, and functional outcome measures at 5 mo postacute illness
FAS, fatigue assessment scale; PHQ-9, patient health questionnaire (9 items); 6MWT, six-minute walk test. Level of signi�-
icance <0.05 is highlighted in bold and with an asterisk symbol (*). Eta-squared effect sizes: <0.06 are small, ≥0.06 to
<0.14 are medium, ≥0.14 are large. Medium and large effect sizes are highlighted in bold. aLogarithmic transformation
applied to correct for nonnormal distribution.
29 of 33 7/11/2023, 3:52 PM
Table 4.
Mental health, fatigue, and functional outcome measures at 12 mo postacute illness
FAS, fatigue assessment scale; PHQ-9, patient health questionnaire (9 item); 6MWT, six-minute walk test. Level of signi�i-
cance <0.05 is highlighted in bold and with an asterisk symbol (*). Eta-squared effect sizes: <0.06 are small, ≥0.06 to
<0.14 are medium, ≥0.14 are large. Medium and large effect sizes are highlighted in bold. aLogarithmic transformation
applied to correct for nonnormal distribution.
30 of 33 7/11/2023, 3:52 PM
Table 5.
Changes in the mental health, fatigue, and functional outcome measures between 12 mo and 5 mo postacute illness
FAS, fatigue assessment scale; PHQ-9, patient health questionnaire (9 item); 6MWT, six-minute walk test. Level of signi�i-
cance <0.05 is highlighted in bold and with an asterisk symbol (*). Eta-squared effect sizes: <0.06 are small, ≥0.06 to
<0.14 are medium, ≥0.14 are large. Medium and large effect sizes are highlighted in bold.
31 of 33 7/11/2023, 3:52 PM
Figure 3.
Deployable status of COVID-19-exposed participants preillness, 5 mo, and 12 mo postillness according to the Joint
Medical Employment Standard (JMES). The number and prevalence of participants whose employment status is “fully
deployable” pre-COVID-19, 5 mo, and 12 mo following the onset of COVID-19 illness are represented in boxes shaded
green. The number and prevalence of participants whose employment status is “limited deployability” pre-COVID-19, 5
mo, and 12 mo following the onset of COVID-19 illness are represented in boxes shaded yellow. The number and preva-
lence of participants whose employment is “not deployable” pre-COVID-19, 5 mo, and 12 mo following the onset of
COVID-19 illness are represented in boxes shaded orange. The �ixed lines/arrows re�lect the change in deployability sta-
tus of participants considered “fully deployable” at 5 mo and 12 mo. The smaller dashed lines/arrows re�lect the change
in deployability status of participants considered “limited deployability” at 5 mo and 12 mo. The larger dashed lines/ar-
rows re�lect the change in deployability status of participants considered to be “non deployable” at 5 mo and 12 mo. The
colored pie charts demonstrate the proportion of each COVID-19-exposed group meeting each deployability status (fully
deployable, limited deployability, and non-deployable) before COVID-19 illness, at 5 mo, and 12 mo postillness. The num-
bers inside each pie chart re�lect the number and prevalence (%) of all COVID-19-exposed participants who meet each
respective deployability status category.
32 of 33 7/11/2023, 3:52 PM
33 of 33 7/11/2023, 3:52 PM

Ladlow

Uploaded by

Document Information

Copyright

Available Formats

Share this document

Share or Embed Document

Sharing Options

Did you find this document useful?

Is this content inappropriate?

Copyright:

Available Formats

Ladlow

Uploaded by

Copyright:

Available Formats

Long-Term Recovery from SARS-CoV-2 (COVID-19): Exercise toleran... https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10010915/?

J Appl Physiol (1985). 2023 Mar 1; 134(3): 622–637. PMCID: PMC10010915

Long-Term Recovery from SARS-CoV-2 (COVID-19)

Exercise tolerance, fatigue, mental health, and employment status at 5 and 12

Copyright © 2023 the American Physiological Society.

Keywords: cardiopulmonary exercise, exercise tolerance, long COVID, post-COVID-19 syndrome,

COVID-19-exposed military personnel is uncertain.

In addition, community-managed individuals who felt recovered (community-recovered) had

This is a prospective observational cohort study, ethically approved by the UK Ministry of

Assessments, including cardiopulmonary exercise testing (CPET), functional tests, spirometry,

symptomatic, 18%; community-recovered 17%); controls, 18%). To ensure a baseline level of

Determining Recovery Status

Cardiopulmonary Functional Testing

Spirometry and pulmonary function test. Standing spirometry assessments (MicroMedical

Patient-Reported Outcome Measures

Participants completed PROMs relating to depression (Patient Health Questionnaire-9, PHQ-9)

To examine differences in demographics, functional capacity, outcomes at baseline and follow-up

Poor concentration. Poor concentration reduced by 20% (1 in 5 participants) in hospitalized-

Poor memory. Poor memory reduced by 8% (1 in 12 participants) in hospitalized-symptomatic

Muscle ache. The prevalence of muscle ache remained unchanged in hospitalized-symptomatic

Joint pain. Joint pain reduced by 8% (1 in 12 participants) in hospitalized-symptomatic (to

Chest pain. Chest pain reduced by 12% (1 in 8 participants) in hospitalized-symptomatic (to

Headache. Headaches increased by 16% (1 in 6 participants) in hospitalized-symptomatic (to

Poor attention. Levels of attention were reduced by 4% in hospitalized-symptomatic (to 12%)

Patient-Reported Outcome Measures

Fatigue. Levels of fatigue were comparable between hospitalized and community-managed

COVID-19-exposed participants demonstrated reduced percent predicted V� �2 at VT1 (the anaer-

At 12 mo, COVID-19-exposed participants demonstrated reduced power output at VT1 (P =

Activities of Daily Living, Occupational Performance, and Occupational Status

Other Results of Interest

Signi�icant differences between COVID-19-exposed and nonexposed (control) participants per-

Differences between COVID-19-Exposed Participants: Severity of Acute Illness versus

Influence of acute illness severity on exercise tolerance. Submaximal exercise conditions. At 12

Unsurprisingly, symptomatic individuals report higher subjective levels of fatigue at 12 mo com-

Differences between COVID-19-Exposed Participants at 12 Mo Postacute COVID-19 Illness

Exercise tolerance. Differences in cardiopulmonary exercise function between COVID-19-

tomatic participants displaying a higher prevalence compared with recovered (symptomatic,

Differences over Time for COVID-19-Exposed Participants: Comparing 12-Mo Follow-Up to

ADL and Occupational Status

Strength and Limitations

At 12 mo after acute COVID-19 illness, COVID-19-exposed participants have a reduced capacity

No con�licts of interest, �inancial or otherwise, are declared by the authors.

Supplemental File S1: https://doi.org/10.6084/m9.�igshare.20197844.

Supplemental File S2: https://doi.org/10.6084/m9.�igshare.20198078.

Supplemental File S3: https://doi.org/10.6084/m9.�igshare.20198225.

Supplemental File S4: https://doi.org/10.6084/m9.�igshare.20198462.

7. Tsamakis K, Tsiptsios D, Ouranidis A, Mueller C, Schizas D, Terniotis C, Nikolakakis N, Tyros G, Kympouropoulos S,

PMC7445491] [PubMed: 32853602] [CrossRef: 10.1016/j.jinf.2020.08.029]

25. Carvalho-Schneider C, Laurent E, Lemaignen A, Beau�ils E, Bourbao-Tournois C, Laribi S, Flament T, Ferreira-Maldent

doi: 10.1136/thoraxjnl-2021-218582. [PMCID: PMC9209667] [PubMed: 35354642] [CrossRef: 10.1136/thoraxjnl-

Figures and Tables

CONSORT �low diagram.

Participant demographics at baseline (5 mo postacute illness)

Hospitalized vs. Recovered vs. Severity × Recovery

Variable Severity Recovered Symptomatic F P Eta-sq. F P Eta-sq. F

Age, yr Hospitalized 50 ± 7 42 ± 8 6.584 0.013* 0.089 1.269 0.264 0.019 8.293

Body Hospitalized 95 ± 18 96 ± 14 2.650 0.110 0.040 3.540 0.060 0.050 2.270

BMI, Hospitalized 30 ± 3 31 ± 4 11.490 <0.001* 0.150 5.510 0.020* 0.080 2.870

Control 0.91 ± 0.08

Mental health, fatigue, and functional outcome measures at 5 mo postacute illness

Mental health, fatigue, and functional outcome measures at 12 mo postacute illness

You might also like