Cardiopulmonary, functional, cognitive and mental health outcomes post COVID, across the range of severity of acute illness, in a physically active working age population

Objectives: To investigate cardiopulmonary, functional, cognitive, and mental health post-COVID-19 outcomes in a young, physically active working-age population, across the spectrum of acute COVID-19 severity. Methods: Observational cohort study of 4 groups; hospitalised, community illness with on-going symptoms (community-symptomatic), community illness now recovered (community-recovered) and controls. Participants underwent extensive clinical assessment involving cardiopulmonary imaging, submaximal and maximal exercise testing, pulmonary function, cognitive assessment, blood tests, electrocardiogram and questionnaires on mental health and physical function. Results: 113 participants (aged 39±9 and 86% male) were recruited into four groups, Hospitalised (n=35), community-symptomatic (n=34), community-recovered (n=18) and control (n=26), at 159±72days following acute illness. Hospitalized and community-symptomatic groups were older, with a higher body mass index, and worse mental health, fatigue, and quality of life scores. Hospitalised and community-symptomatic participants also performed less well on sub-maximal and maximal exercise testing. Hospitalised individuals had impaired ventilatory e�ciency (higher VE/ V̇ CO 2 slope), achieved less work at the anaerobic threshold and at peak than other groups and had a signi�cantly reduced forced vital capacity. Clinically signi�cant abnormal cardiopulmonary imaging �ndings were present in 6% of hospitalised participants. Those who recovered from COVID-19 had no signi�cant differences when compared with controls. Conclusion: Recovered individuals who suffered mild-moderate


Introduction
Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) continues to cause signi cant mortality and morbidity, with over 270 million con rmed cases, and 5 million deaths, of coronavirus disease 2019 (COVID-19) globally.. (1) Approximately 80% of SARS-CoV-2 cases are asymptomatic or mild, with many patients recovering within 2-4 weeks.(2)However, COVID-19 also causes prolonged illness, with some individuals experiencing persistent symptoms for months, including shortness of breath (SoB), fatigue and mood disturbance.(3)(4)(5)(6) The National Institute for Health and Care Excellence (NICE) have adopted time based de nitions for post COVID illness: after four weeks, 'ongoing symptomatic COVID-19', and beyond 12 weeks, 'post-COVID-19 syndrome'.An estimated 1.2 million people in the UK (population: 66 million) have ongoing symptoms at ≥4 weeks.(7) The mean age of post-COVID-19 syndrome sufferers is ~40 years, whilst approximately 20% of previously healthy 18-35 year olds report ongoing symptoms at 14-to-21 days, implying the majority of negatively affected individuals are in the working population.(8,9) This has consequences for return to work and economic recovery.Initial studies found the severity and duration of the acute COVID-19 increased the risk of chronicity, but this is now challenged.(10,11) The majority of studies investigating post-COVID-19 syndrome have focussed on hospitalised patients, with few analysing non-severe cases, and fewer still utilising a control population (3,5,(12)(13)(14)(15)(16)(17)(18)(19)(20)(21).Ongoing symptoms consistently include SoB, fatigue, pain, mood disorder and perceived cognitive impairment.(3,13) Cross-sectional cardiopulmonary imaging abnormalities, including lung brosis and myocardial in ammation (22,23) and functional limitation have been recorded.(24)(25)(26) An inability to fully recover from COVID-19 has a high impact on two diverse groups.Professional athletes and front-line emergency services (e.g., police, re ghters, paramedics, military) are exposed to high volume/intensity exercise as a core component of their role, often under challenging environmental conditions.Any enduring pathology may impair their cognitive judgement and return to high-end physical function.Alongside a speci cally commissioned clinical service, (27) the Military COVID-19 Observational Outcome in a Viral Infectious Disease (M-COVID) study was developed to describe the effects of SARS-CoV-2 on the UK Armed Forces.M-COVID allowed detailed characterisation of cardiopulmonary pathology and functional, neurocognitive and mental health status across three cohorts: hospitalised illness (H), community illness with on-going symptoms (community-symptomatic, CS) and community illness now recovered (community-recovered, CR), compared to an age, gender and job-role matched control population (CON).

Study Design
Prospective observational cohort study.Ethically approved by the Ministry of Defence research ethic committee in July 2020 (1061/MODREC/20).

Patient and public involvement
Multiple focus groups were held at the Defence Medical Rehabilitation Centre (DMRC) Stanford Hall with potential participants during the study design phase.Iterative feedback was gained on the patient information lea et, study concept and design, and study visit details.

Setting
Clinical assessments occurred over three days.Two days at DMRC for cardiopulmonary exercise testing (CPET), functional tests, cognitive assessment, spirometry, blood samples and patient reported outcome measures.The third day was at Oxford University Hospital (OUH) NHS Foundation Trust for cardiopulmonary imaging and additional pulmonary function testing (Figure 1) Participants 113 participants were categorised into 1 of 4 groups; hospitalised (n=35); community-symptomatic (n=34); community-recovered (n=18), and; control (n=26).Exposed participants were recruited via the clinical pathway.(27) Severity categories were determined pragmatically, with all hospitalised participants requiring supplementary oxygen.Recovered and control participants were recruited from military units and key occupational groups.All controls were nucleocapsid antibody negative.Two senior consultants clinically adjudicated all volunteers who met the eligibility criteria (Online Resource 1) based on positive SARS-CoV-2 antigen testing, history, blood tests and imaging.

Determining Recovery status
Non-recovery was de ned as the continued presence of one or more post-COVID-19 symptoms at recruitment (Table 1).To measure for differences in demographics, functional, neurocognitive and mental health status, and cardiopulmonary function/pathology between the four groups, a one-way analysis of variance (ANOVA) was performed on all continuous data and a chi-squared test on ordinal and categorical data.
An alpha threshold of 0.05 was taken to indicate signi cance.Post-hoc tests were carried out for any results where a signi cant between-group difference was identi ed following an ANOVA.Bonferroni corrections were applied to allow for multiple post-hoc comparisons.

Cardiopulmonary Exercise Test (CPET)
There were no differences between hospitalised and community-symptomatic individuals, or between community-recovered and controls in any CPET variable (Table 3).

Heart rate pro le
Hospitalised and community-recovered individuals had a signi cantly higher resting HR vs controls (82±11bpm and 84±13bpm vs 73±8bpm, both p<0.05) (Table 3, Figure 2).There were no other between-group differences in exercise HR parameters.

Workload (Watts)
Workloads at VT1 and peak were lower by 36% and 24% respectively in hospitalised individuals compared to controls (both p<0.001).Workloads at VT1 and peak were lower by 30% and 25% respectively in hospitalised vs community-recovered (p=0.002 and p<0.001, respectively).Workloads for VT1 and peak were also less in community-symptomatic vs controls by 22% and 16% (p=0.008 and p=0.005, respectively) (

Cardiopulmonary imaging
Imaging results were reviewed by consultants in radiology, cardiology and respiratory medicine to determine clinical signi cance (Table 4).The only clinically signi cant pathology identi ed, moderate volume ground glass changes, occurred on two HRCTs.

Cognitive function
There were no between-group differences in uid, crystallised or total composite scores (Supplementary File 2).

Mental health and quality of life
The mean scores for and depression equated to 'minimal' (0 to 4) or 'mild' (4 to 9) severity for each group (Table 2).Post-hoc analyses revealed no signi cant between-group differences for anxiety.

DISCUSSION
In a physically active working-age population, this study found that individuals who had recovered following community-based acute illness did not differ from an age, gender and job-role matched control population across a comprehensive array of cardiopulmonary, functional, neurocognitive and mental health assessments.

Participant characteristics/demographics
There were no between-group differences in highest educational attainment or rank, as proxies for socioeconomic status (Supplementary le 2), but signi cant between-group differences were demonstrated in age and body composition (p>0.05).Both hospitalised and community-symptomatic individuals were signi cantly older, had increased body mass, BMI and waist circumference vs community-recovered, consistent with increased age and BMI as risk factors for COVID-19 severity.(7,41,42) Functional limitations Hospitalised and community-symptomatic participants had reduced exercise capacity during submaximal (6MWT) and maximal testing (CPET).They also achieved signi cantly shorter 6MWT distances vs controls, with higher pre-and post-6MWT breathlessness scores.No signi cant differences in distance were observed between community-recovered and control groups.Other studies (21,43) have found similar discrepancies in 6MWT, albeit at much shorter distances, re ecting the pre-morbid tness of participants in this study.
During CPET, hospitalised and community-symptomatic participants had lower absolute and relative VȮ 2 , and workload at both VT1 and peak, with signi cantly lower peak lactate and O 2 pulse values.
Hospitalised individuals also had higher VĖ/VĊO 2 slopes, and therefore worse ventilatory e ciency compared to the other three groups.Lower VȮ 2 and higher VĖ/VĊO 2 slopes have previously been reported in individuals with more severe COVID-19 illness.(21,25,26) There were no signi cant differences demonstrated between the community-recovered and controls in VȮ 2 and VĖ/VĊO 2 values.Whilst Singh et al. (20) reported reduced VȮ 2 max with increased VĖ/VĊO 2 slopes during CPET in their 'recovered individuals', (20) their study participants were recruited from an unexplained exercise intolerance clinic, failing to meet our de nition of 'recovered'.

Organ pathology
Despite concerns regarding end-organ damage after COVID-19, (3,22,23,41,(44)(45)(46) especially in athletes, (47) this study reassuringly demonstrates an extremely low level of abnormalities in cardiopulmonary imaging, blood markers or cognitive function across the spectrum of severity.Hospitalised individuals were more likely to have pathological ndings on imaging, however, only 6% were deemed clinically signi cant, a much lower rate than the 29-60% previously reported (within methodological differences) (Table 2) (21,43,48).This could be due to the protective effect of cardiorespiratory tness and lean muscle tissue/metabolic exibility in this trained population.(49,50) Importantly, there were no differences on any endpoint measured between the community-recovered and control groups.
Neurocognitively, the uid composite score, the ability to react, analyse and process information, and the crystallised composite score, representing acquired knowledge and learning, were reviewed.The former is impacted by biological insult, while the latter is relatively preserved.Our ndings suggest no medium-term damage, with no statistically signi cant differences between composite cognitive scores in this study.
Previous work have shown cognitive symptoms improving with time.(51,52) Lung function results were also reassuring in this study.The only demonstrable effects were an 18% reduction in FVC in hospitalised vs. community-recovered, and a 15% reduction in DLCO for hospitalised vs. controls.The coincidence of relatively reduced FVC and DLCO in those hospitalised, with no difference in KCO, is suggestive that these differences result from a reduced lung volume, rather than a problem of ventilation-perfusion matching.Previous studies have highlighted the need to correlate both spirometry and diffusion capacity (21,46).

Mental health
There were between-group differences in mental health status, fatigue and QoL.The impact of the virus can be partitioned, by using a control group, to separate out the impact of social upheaval, isolation, media and other external in uences.(53,54) Those in the community-symptomatic group had the highest scores for anxiety, depression and fatigue and the lowest for QoL.Those in the hospitalised group scored highest for post-traumatic stress.There were no signi cant differences between hospitalised and community-symptomatic groups, similarly to other study populations, (42) and the 2003/4 SARS epidemic.(55,56) Community-recovered participants displayed no signi cant difference to controls.

Strengths and limitations
This is the rst study, to our knowledge, that has compared groups, across the spectrum of acute COVID-19 severity, including on-going or resolved symptom cohorts, with an age, gender and job-role matched control group, to identify ongoing organ pathology, functional limitations and mental health impact.
Whilst the sample size (n=113) is modest, this is balanced by the comprehensive assessment completed in every participant.
Non-recovery was de ned by the presence of symptoms at the time of recruitment (~5 months post illness).The most common symptoms (Table 1) are re ective of those in other studies, which supports the generalisability of other ndings here, such as objective cardiopulmonary tness and neurocognitive outcomes, which have not previously been reported in case-controlled cohorts.(42,(57)(58)(59) An additional strength is the population studied.Whilst not all ndings can be extrapolated to the wider population, the impact on COVID-19 on sportspeople and other physically demanding occupations has been a research priority.(60)The ndings of this study will reassure the majority of recovered individuals with less severe disease, and the clinicians responsible for their care.It will permit the dedication of resources to those who remain at risk of important clinical sequelae.All investigations were delivered by the same team of investigators, equipment and conditions, increasing the consistency of the data.

CONCLUSION
This study showed that those with more severe acute disease and/or prolonged symptoms were older and had a higher BMI.Within these groups, there is an increased likelihood of pathological cardiopulmonary imaging ndings (albeit at a much lower rate than other published studies) and reduced exercise capacity during sub-maximal and maximal testing.These same groups also experienced higher rates of mental health symptoms, fatigue, and a reduced QoL.
Reassuringly, this study also found that recovered community-based individuals do not differ in terms of cardiopulmonary disease, functional outcomes and mental health from a matched control population.
Our ndings do suggest that for individuals who will be exposed to high intensity physical exercise, who were either hospitalised during acute illness or experience prolonged symptoms, that a speci c, comprehensive evaluation of functional and neurocognitive capacity, mental health status and cardiopulmonary pathology is warranted.

Declarations
Ethical approval and consent to participate: Ethical approval from the Ministry of Defence ethic committee in July 2020 (1061/MODREC/20).Written informed consent was obtained from all participants included in the study.
Consent for publication: Written informed consent included consent for anonymised data to be analysed and shared (including via publication).
Data sharing: Data relate to the serving population of the Ministry of Defence and thus are sensitive.
Research teams requesting data are invited to contact the corresponding author and appropriate permissions will be sought for release.
Cognitive Assessment Cognitive assessments were performed in a quiet environment using the National Institute of Health (NIH) Cognitive Toolbox cognition battery for age 12+ years on an iPad (Apple, California, USA)(32), with the uid, crystallised and total composite scores analysed, Patient reported outcome measures Participants completed PROMs relating to depression (Patient Health Questionnaire-9, PHQ-9); (33) anxiety (General Anxiety Disorder scale-7 questions, GAD-7); (34) post-traumatic stress disorder (PTSD, National Centre for PTSD checklist, PCL-5);(35) quality of life (QoL, European QoL 5 domains,EQ5D),(36) and fatigue (Fatigue Assessment Scale, FAS).(37)Ongoing symptoms were measured using an evidence-based symptom checklist.(38,39) Data Management and Statistical Methods Study data were collected and managed using REDCap.(40)Statistical Analysis Data are presented as mean ± standard deviation.The normality of all variables was assessed using a Shapiro-Wilk test and inspection of the frequency histogram distributions and Q-Q plots.Results showed approximate normal distribution across the majority of variables.Parametric tests were applied throughout.

Figures
Figures

Table 1 :
Prevalence of symptoms across all groups Mapping sequences (ShMOLLI, Siemens) and late gadolinium imaging were obtained with a bolus injection of 0.1mmol/kg of a gadolinium contrast agent.Images were analysed with CVI 42 analysis software (Circle Cardiovascular Imaging Inc, Calgary, AB, Canada).

Table 2 :
Descriptive data demonstrating body composition, ambulatory function, mental health and fatigue status at admission to DMRC.

Table 3
, Figure2).No signi cant between-group differences were reported in RPE or SoB scores during rest, VT1 or peak exercise, or RER at peak.st ventilatory threshold; HR, heart rate; HRR, heart rate recovery; BP, blood pressure; BF, breathing frequency; OUES, oxygen uptake e ciency slope.H, hospitalised illness; CS, community illness with on-going symptoms (community-symptomatic), CR, community illness now recovered (community-recovered; CON age, gender and job-role matched control population.There was no signi cant difference between H versus CS and CR versus CON for any CPET-related parameter.†, H vs. CR; §, H vs. CON; #, CS vs. CR; ¥, CS vs. CON.Level of signi cance: * p<0.05, ** p<0.01 ***p<0.001

Table 4 :
Prevalence of participants with abnormal and clinically signi cant ndings following clinical investigations.Descriptive data detailing the total number in each group and percentage based on the number of tests performed.