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

Background The COVID-19 pandemic has led to significant morbidity and mortality, with the former impacting and limiting individuals requiring high physical fitness, including sportspeople and emergency services. Methods Observational cohort study of 4 groups: hospitalised, community illness with on-going symptoms (community-symptomatic), community illness now recovered (community-recovered) and comparison. A total of 113 participants (aged 39 ± 9, 86% male) were recruited: hospitalised (n = 35), community-symptomatic (n = 34), community-recovered (n = 18) and comparison (n = 26), approximately five months following acute illness. Participant outcome measures included cardiopulmonary imaging, submaximal and maximal exercise testing, pulmonary function, cognitive assessment, blood tests and questionnaires on mental health and function. Results Hospitalised and community-symptomatic groups were older (43 ± 9 and 37 ± 10, P = 0.003), with a higher body mass index (31 ± 4 and 29 ± 4, P < 0.001), and had worse mental health (anxiety, depression and post-traumatic stress), fatigue and quality of life scores. Hospitalised and community-symptomatic participants performed less well on sub-maximal and maximal exercise testing. Hospitalised individuals had impaired ventilatory efficiency (higher VE/V̇CO2 slope, 29.6 ± 5.1, P < 0.001), achieved less work at anaerobic threshold (70 ± 15, P < 0.001) and peak (231 ± 35, P < 0.001), and had a reduced forced vital capacity (4.7 ± 0.9, P = 0.004). Clinically significant abnormal cardiopulmonary imaging findings were present in 6% of hospitalised participants. Community-recovered individuals had no significant differences in outcomes to the comparison group. Conclusion Symptomatically recovered individuals who suffered mild-moderate acute COVID-19 do not differ from an age-, sex- and job-role-matched comparison population five months post-illness. Individuals who were hospitalised or continue to suffer symptoms may require a specific comprehensive assessment prior to return to full physical activity. Supplementary Information The online version contains supplementary material available at 10.1186/s40798-023-00552-0.

An inability to fully recover from COVID-19 has a high impact on populations who require a high level of physical fitness and decision-making, such as professional athletes and front-line emergency services (e.g. police, firefighters, paramedics, military). These populations are exposed to high volume and/or intensity exercise, often under challenging environmental conditions, and enduring pathology would impair their return to high-end physical and cognitive function in high-pressure situations.
Alongside a specifically commissioned clinical service [29], the Military COVID-19 Observational Outcomes in a Viral Infectious Disease (M-COVID) study was developed to describe the longitudinal effects of SARS-CoV-2 on the UK Armed Forces in three groups: hospitalised illness (H), community illness with on-going symptoms (community-symptomatic, CS) and community illness now recovered (community-recovered, CR).
This study aims to describe cardiopulmonary, functional, and neurocognitive outcomes five months post-illness, comparing the post-COVID-19 groups with each other and an age-, gender-and job-role-matched comparison group (COM), with the hypothesis that those with more severe initial or prolonged disease have worse outcomes.

Study Design
MCOVID is a cross-sectional observational cohort study, five months post-acute illness. Ethical approval was granted 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 (June and July 2020). Iterative feedback was gained on the patient information leaflet, study concept and design, and study visit details.

Setting and Study Overview
Initial visits occurred over three days between August 2020 and July 2021. There were two days at DMRC for cardiopulmonary exercise testing (CPET), 6-min walk test (6MWT), cognitive assessment, spirometry, blood samples and patient-reported outcome measures (PROMs) and a third at Oxford University Hospital (OUH) NHS Foundation Trust for cardiopulmonary imaging and additional pulmonary function testing (Fig. 1).

Participants
A total of 370 participants were screened, with 150 approached and 119 consented (Fig. 2). Two consultants adjudicated consenting volunteers meeting eligibility criteria (Table 1) based on positive SARS-CoV-2 antigen, history, blood tests and imaging, excluding four for previously undiagnosed medical conditions. Two participants withdrew mid-study visit.
A total of 113 participants were categorised into 1 of 4 cohorts; hospitalised (n = 35); community-symptomatic (n = 34); community-recovered (n = 18) and comparison (n = 26). Exposed participants were recruited via the clinical pathway established in August 2020 for those with initially severe or prolonged COVID-19 illness to ensure safe return to duty [29].
Hospitalisation during acute illness was used pragmatically as a marker of severity. All hospitalised participants required supplementary oxygen. Recovered and comparison participants (frequency-matched by the study team to age, gender and job-roles) were identified and recruited using word-of-mouth. All comparisons were SARS-CoV-2 nucleocapsid antibody negative (positive if prior illness).

Determining Recovery Status
Non-recovery was defined as the continued presence of one or more of the below post-COVID-19 symptoms at recruitment ( Table 2).

Job Role and Rank
Participant job role was recorded, to ensure that those in Ground Close Combat roles (subject to higher physical activity standards) had appropriate matched  comparators. Rank was used as a proxy for socioeconomic status (SES) [30,31].

Venous Blood Sampling
Samples for full blood count, liver function, urea and electrolytes, C-reactive protein, creatine kinase, thyroid function, ferritin and iron studies, vitamin D, and COVID-19 antibodies (spike and nucleocapsid) were taken.

Cardiopulmonary Exercise Testing (CPET)
CPET was conducted on an electromagnetically braked cycle ergometer (Lode Carnival, Lobe BV, Groningen, Netherlands) using indirect calorimetry (Metalyzer 3B, Cortex Biophysik, Leipzig, Germany) with continuous 12-lead ECG monitoring (Custo Diagnostic software, Custo-Med, Ottoburn, Germany). A ramp protocol to volitional fatigue was employed, with a maximal test that was defined by a respiratory exchange ratio, RER, of > 1.1 and a plateau in VȮ2 over 30-s despite increasing workload [36]. The protocol started with a two-minute rest period, then two-minutes of unloaded pedalling, followed by progressive increase in workload based on a workload/ min ramp to achieve 8-12 min of loaded exercise. Ventilation (VĖ), oxygen consumption (VȮ2), expired carbon dioxide (VĊO2), HR and SpO2 were monitored continuously [36], with BP, RPE and perceived SoB recorded every two minutes.

Spirometry and Pulmonary Function Test
Standing spirometry assessments (MicroMedical Micro-Lab 3500, CA, USA) were taken to measure forced vital capacity (FVC) and forced expiratory volume in the first second of expiration (FEV1) [35]. The diffusing capacity of the lungs for carbon monoxide (DLCO) was measured over a 10-s breath hold, using methane as a tracer gas.

Cardiopulmonary Imaging Cardiothoracic Imaging
High-resolution computed tomography (HRCT) chest and dual-energy CT pulmonary angiography (DECTPA) were performed on a dual-source CT (Siemens SOMATOM Drive, Siemens Healthineers, Erlangen, Germany), using a HRCT protocol of inspiratory 1 mm sections with 10 mm gap, and expiratory 1 mm sections with a 30-mm gap. DECTPA perfusion map and reconstructed 1 mm slice thickness were analysed on Siemens Syngo, CT CE Lung Analysis software. Comparison participants did not undergo CT imaging.

Cardiac Magnetic Resonance Imaging (CMR)
CMRs were acquired on Siemens MR scanners at 3 Tesla (Siemen Medical Solutions, Erlangen, Germany), assessing myocardial mass, volumes and ejection fraction with precordial ECG gating, in held end-expiration. Mapping sequences (ShMOLLI, Siemens) and late gadolinium imaging were obtained with a bolus injection of 0.1 mmol/kg of a gadolinium contrast agent. Images were analysed with CVI 42 analysis software (Circle Cardiovascular Imaging Inc, Calgary, AB, Canada).

Cognitive Assessment
Cognitive assessments were performed using the National Institute of Health (NIH) Cognitive Toolbox cognition battery for age 12+ years on an iPad (Apple, California, USA) [37], with the fluid, crystallised and total composite scores analysed. Highest educational level was recorded during this and also used as a proxy for SES [30].

Data Management and Statistical Methods
Study data were collected and managed using REDCap [45].

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, except the PROMs, namely GAD-7, PHQ-9, PCL-5, EQ5D and FAS. Parametric tests were applied for all variables except PROMs, when nonparametric tests were applied.
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, where the groups were used as the columns and the independent variable as the rows for the Chi-squared analysis. To measure for differences in the neurocognitive and mental health status between the four groups, Kruskal-Wallis tests were applied.
An alpha threshold of 0.05 was taken to indicate significance. Post hoc tests were carried out for any results where a significant between-group difference was identified following an ANOVA. Bonferroni corrections were applied to allow for multiple post hoc comparisons.

Results
At review (159 ± 72 days following acute illness), hospitalised and community-symptomatic individuals had a mean of 2 ± 2 and 2 ± 1 symptoms, respectively ( Table 2). Hospitalised individuals were significantly older than both community-symptomatic and community-recovered (Table 3).
Community-symptomatic individuals were not statistically different to community-recovered or comparisons.

Cardiopulmonary Exercise Test (CPET)
There were no differences between hospitalised and community-symptomatic individuals or between communityrecovered and comparisons in any CPET variable (Table 4).

Workload (Watts)
Workloads at VT1 and peak were lower by 36% and 24%, respectively, in hospitalised individuals compared to comparisons (both P < 0.001). Workloads at VT1 and peak were lower by 30% and 25%, respectively, in hospitalised versus community-recovered (P = 0.002 and P < 0.001, respectively). Workloads for VT1 and peak were also less in community-symptomatic vs comparisons by 22% and 16% (P = 0.008 and P = 0.005, respectively) (Table 4, Fig. 3). No significant betweengroup differences were reported in RPE or SoB scores during rest, VT1 or peak exercise, or RER at peak.

Body Composition
Hospitalised and community-symptomatic individuals demonstrate the least favourable body composition (Table 3). There were no significant between-group differences in height or waist-to-hip ratio. However, hospitalised and community-symptomatic individuals both had significantly greater body mass index (BMI) values versus community-recovered and comparisons (H, 31 ± 4 kg m 2 ; CS, 29 ± 4 kg m 2 ; CR, 26 ± 2 kg m 2 ; COM, 25 ± 3 kg m 2 ). Body mass was greater in hospitalised and community-symptomatic individuals, and reviewing waist circumference scores, this can be attributed to increased abdominal fat (H, 101 ± 13 cm; CS, 96 ± 13 cm; CR, 85 ± 10 cm; COM 86 ± 7 cm). There was no difference in body composition between community-recovered and comparisons.

Cardiopulmonary Imaging
Imaging results were reviewed by consultants in radiology, cardiology and respiratory medicine to determine clinical significance ( Table 5). The only clinically significant pathology identified, moderate volume ground glass changes, occurred on two HRCTs.

Mental Health and Quality of Life
The mean scores for anxiety and depression equated to 'minimal' (0-4) or 'mild' (4-9) severity for each group (Table 3). Post hoc analyses revealed a significant difference between community-symptomatic and comparisons for anxiety (P = 0.006). Additionally, there were significant differences for depression between hospitalised and community-recovered (P < 0.001), hospitalised and comparisons (P < 0.001), community-symptomatic and community-recovered (P < 0.001) and communitysymptomatic and comparisons (P < 0.001). The number of hospitalised and community-symptomatic participants scoring 'none or minimal' or ' ≥ moderate symptoms' differed vs community-recovered and comparisons (Table 3). Only half of hospitalised individuals reported 'none or minimal' anxiety, and one third 'none or minimal' depression, vs ~ 90% of comparisons. 29% and 18% of hospitalised and community-symptomatic individuals reported ' ≥ moderate depression' vs 4% of comparisons. PTSD scores were higher in the hospitalised and community-symptomatic vs community-recovered and comparisons (P < 0.05). Hospitalised and communitysymptomatic participants had lower QoL vs communityrecovered and comparisons (P < 0.05).

Cognitive Function
There were no between-group differences in fluid, crystallised or total composite scores (Additional file 1).

Discussion
In a physically active working-age population, this study found that individuals who were symptomatically recovered following community-based acute illness did not differ from an age-, gender-and job-role frequencymatched comparison population across a comprehensive array of cardiopulmonary, functional, neurocognitive and mental health assessments. There were multiple clinically and statistically significant differences between comparisons and those with initially severe illness and ongoing symptomatic illness, including in functional, cardiopulmonary and mental health outcomes.

Functional Limitations
Hospitalised and community-symptomatic participants had reduced exercise capacity during sub-maximal testing, as seen by shorter distances in the 6MWT, in excess of the minimal clinically significant difference [48], and reduced workload at VT1. The value of sub-maximal testing is that it reflects the ability to perform sustained low-level exercise, including activities of daily living, and therefore may provide an objective insight into an individual's ability to manage with everyday tasks and likelihood of developing fatigue-as seen by half and twothirds of these groups reporting fatigue as a symptom (Table 2). Other studies [23,49] have found similar discrepancies in 6MWT, albeit at much shorter distances (reflecting the pre-morbid fitness of participants in this study), with one of those studies repeating the CPET 3 months later [50]. Whilst this showed improvement, but not resolution, of limitations, the inter-visit time interval was short, perhaps not reflecting the time that a full recovery from COVID-19 takes.
There were also limitations seen at maximal exertion (as defined by RER > 1.1) in the same groups (hospitalised and community-recovered), with reduction in absolute and relative VȮ 2 , and workload at both VT1 and peak, with significantly lower peak lactate and O 2 pulse values. This inability to fully perform is significant for populations who rely on physical performance, preventing a full return to occupational requirements. CPET has been demonstrated to be helpful in identifying limitations and potential causes, including dysfunctional states (such as ventilatory), organ pathology, dysautonomia and deconditioning [6,51,52], and the M-COVID study allows us to further investigate some of these potential causes.
Unsurprisingly, given the high prevalence of SoB symptoms (63%), ventilatory inefficiencies were seen in hospitalised individuals, with higher VĖ/VĊO 2 slopes compared to the other three groups, a consistent finding for individuals with more initially severe COVID-19 illness [23,27,28]. Singh et al. [22] also reported reduced VȮ 2 max with increased VĖ/VĊO 2 slopes in individuals recruited from an unexplained exercise intolerance clinic. Possible reasons include ventilation-perfusion mismatch, organ pathology, or hyperventilation, with previous work highlighting the need to correlate both spirometry and diffusion capacity [23,53] to understand this effect. In this study, lung function results were reassuring, with the only demonstrable effects an 18% reduction in FVC in hospitalised vs. community-recovered, and a 15% reduction in DLCO for hospitalised vs. comparisons. 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.
Despite concerns regarding end-organ damage after COVID-19 [3,24,25,46,[53][54][55], especially in athletes [56], this study reassuringly demonstrates an extremely low level of abnormalities in cardiopulmonary imaging, excluding this as a cause for reduced cardiopulmonary functional ability. Hospitalised individuals were more likely to have pathological findings on imaging, however, only 6% were deemed clinically significant (requiring clinical follow up), a much lower rate than the 29-60% previously reported (within methodological differences) (Table 3) [23,49,57]. This could be due to the protective effect of cardiorespiratory fitness and lean muscle tissue/ metabolic flexibility in this trained population [57,58].

Mental Health and Neuro-cognition
There were multiple between-group differences in mental health status, fatigue and QoL. Those in the communitysymptomatic group had the highest scores for anxiety, depression and fatigue and the lowest QoL. Those in the hospitalised group scored highest for post-traumatic stress. The clinical significance of this, with higher proportions of moderate and severe symptoms, is seen in Table 3. The impact of the virus can be partitioned using the comparison group, to separate out the impact of social upheaval, isolation, media and other negative effects of the pandemic, including repeated lockdown [59][60][61][62]. In particular, for this population, an inability to perform everyday and/or maximal tasks might lead to perceived fear of loss of job, contributing further to the high levels of mental health symptoms. Given the global effect of anxiety, this might also contribute to hyperventilation during CPET, as seen by increased breathing frequencies in the hospitalised and community-symptomatic groups. These findings are similar to those in other study populations [47], and the 2003/4 SARS epidemic [63,64].
Neurocognitively, the ability to react, analyse and process information (reflected by the 'fluid composite score'), and acquired knowledge and learning ('crystallised composite score'), were reviewed. The former is impacted by biological insult, whilst the latter is relatively preserved. Despite work in a similar population displaying significant changes,(30) our findings suggest no medium-term damage, with deficits most evident in the communitysymptomatic group and no statistically significant differences seen. Previous work has demonstrated significant improvement with time [8,66].

Participant Demographics
There were no between-group differences in highest educational attainment or rank, as proxies for SES (Additional file 1), but significant between-group differences were demonstrated in age and body composition (P > 0.05). Hospitalised individuals were older than community based groups, and both hospitalised and community-symptomatic individuals had increased body mass, BMI and waist circumference vs community-recovered, consistent with increased age and BMI as risk factors for COVID-19 severity [9,46,47]. These demographic differences may have influenced study outcomes. However, given all military personnel are required to meet the same fitness standards, including the comparison group, and relative CPET measurements are age and weight calculated, this effect should be mitigated.

Strengths and Limitations
This is the first 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 frequencymatched comparison group, to identify ongoing organ pathology, functional limitations and mental health impact in a young, working-age population required to undertake high levels of physical activity. Whilst the sample size (n = 113) is modest, this is balanced by the comprehensive assessment completed in every participant.
An additional strength is the population studied. Although having a predominantly male, younger population might be a risk of participant bias, this tightly-defined and generally healthy population reduce confounders and allow the effect of COVID-19 to be seen. Whilst not all findings can be extrapolated to the wider population, which is a limitation, the impact on COVID-19 on sportspeople and other physically demanding occupations has been a research priority [70]. Steps were taken to minimise selection bias during recruitment, with consecutive eligible participants approached until the study was filled. Initial sample size calculations were unable to be performed in Summer 2020 due to the unknown quality of COVID-19, therefore no power calculations are possible. Throughout this study, all investigations were delivered by the same team of investigators, equipment and conditions, increasing the consistency of the data.
There are limitations to this study. A key limitation is that of the differences between age and BMI between the groups, which might have independently impacted on the cardiopulmonary and functional outcomes, as well as increasing the risk of initial severe and worse prognosis. Armed Forces fitness standards should be met by all individuals, and CPET measurements are age and weight calculated, so it is hoped that might mitigate the effect. A further limitation is lack of pre-COVID-19 participant data, which prevents the partitioning of effect pre-and post-disease.

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 findings (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. The most common symptoms ( Table 2) are reflective of those in other studies, which supports the generalisability of other findings here, such as objective cardiopulmonary fitness and neurocognitive outcomes, which have not previously been reported in case-controlled cohorts [47,[67][68][69].
Reassuringly, this study also found that recovered community-based individuals do not differ from a matched comparison population in any parameter, which 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, as our findings 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 specific, comprehensive evaluation of functional and neurocognitive capacity, mental health status and cardiopulmonary pathology is warranted [29,71,72].
Additional file 1. Education, rank, cognitive, and blood test results for the MCOVID participants.