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

Abstract

Background: The longitudinal trajectories of cardiopulmonary abnormalities and symptoms following infection with coronavirus disease (COVID-19) are unclear. We sought to describe their natural history in previously hospitalised patients, compare this with controls, and assess the relationship between symptoms and cardiopulmonary impairment at 6 months post-COVID-19.

Methods: Fifty-eight patients and thirty matched controls (single visit), recruited between 14^th March - 25^th May 2020, underwent symptom-questionnaires, cardiac and lung magnetic resonance imaging (CMR), cardiopulmonary exercise test (CPET), and spirometry at 3 months following COVID-19. Of them, forty-six patients returned for follow-up assessments at 6 months.

Findings: At 2-3 months, 83% of patients had at least one cardiopulmonary symptom versus 33% of controls. Patients and controls had comparable biventricular volumes and function. Native cardiac T₁ (marker of fibroinflammation) and late gadolinium enhancement (LGE, marker of focal fibrosis) were increased in patients at 2-3 months. Sixty percent of patients had lung parenchymal abnormalities on CMR and 55% had reduced peak oxygen consumption (pV̇O₂) on CPET. By 6 months, 52% of patients remained symptomatic. On CMR, indexed right ventricular (RV) end-diastolic volume (-4·3 mls/m², P=0·005) decreased and RV ejection fraction (+3·2%, P=0·0003) increased. Native T₁ and LGE improved and was comparable to controls. Lung parenchymal abnormalities and peak V̇O₂, although better, were abnormal in patients versus controls. 31% had reduced pV̇O₂ secondary to symptomatic limitation and muscular impairment. Cardiopulmonary symptoms in patients did not associate with CMR, lung function, or CPET measures.

Interpretation: In patients, cardiopulmonary abnormalities improve over time, though some measures remain abnormal relative to controls. Persistent symptoms at 6 months post-COVID-19 did not associate with objective measures of cardiopulmonary health.

Funding: The authors' work was supported by the NIHR Oxford Biomedical Research Centre, Oxford British Heart Foundation (BHF) Centre of Research Excellence (RE/18/3/34214), United Kingdom Research Innovation and Wellcome Trust. This project is part of a tier 3 study (C-MORE) within the collaborative research programme entitled PHOSP-COVID Post-hospitalization COVID-19 study: a national consortium to understand and improve long-term health outcomes, funded by the Medical Research Council and Department of Health and Social Care/National Institute for Health Research Grant (MR/V027859/1) ISRCTN number 10980107.

Keywords: CMR; COVID-19; CPET; SARS-CoV-2; long COVID.

Figure 1

Serial CMR findings in previously hospitalised COVID-19 patients and controls. A: Mid ventricular native T₁ (mean + SD) in patients at 2-3 months was higher than controls, and normalized by 6 months. B: Mid ventricular extracellular volume fraction (ECV, median + IQR) in patients at 2-3 months was comparable to controls, but decreased in patients by 6 months. C: Right ventricular ejection fraction (mean + SD) in patients at 2-3 months was comparable to controls, and increased by 6 months. P-values are for group differences (COVID-19 2-3 months vs COVID-19 6 months and COVID-19 6 months vs controls).

Figure 2

Serial CPET assessments in previously hospitalised COVID-19 patients and controls. A: Peak oxygen consumption (V̇O₂ peak, mean + SD) in patients improved from 2-3 months to 6 months, but remained lower than controls. B: Peak oxygen pulse (O₂ pulse, mean + SD) in patients with maximal tests at 2-3 months was lower compared to controls. By 6 months, this improved and became comparable to controls. C: The ventilatory equivalent for carbon dioxide (V̇E/V̇CO₂, median + IQR) slope in patients improved from 2-3 months to 6 months, but remained high versus controls. P-values are for group differences (COVID-19 2-3 months vs COVID-19 6 months and COVID-19 6 months vs controls).

Figure 3

Prevalence and determinants of cardiopulmonary symptoms (chest pain, palpitations, syncope, dyspnoea, or dizziness) among previously hospitalised COVID-19 patients. A: At 2-3 months, 83% of patients experienced at least one cardiopulmonary symptom. By 6 months, this improved to 52% and was comparable to controls. B: Forest plot depicts the odds ratio and 95% confidence intervals of having any cardiopulmonary symptom at 6 months given the changes on ECG, CMR, PFT, and CPET measures. An abnormal ECG was defined as rhythm abnormalities and/or the presence of bundle branch block, ST-segment elevation/depression or T wave inversion. Elevated NT-proBNP was defined as ≥125 ng/L. (OR - Odds ratio. CI - Confidence interval. ECG – Electrocardiogram. NT-proBNP - N-terminal pro b-type natriuretic peptide. LVEDVi - Left ventricular end-diastolic volume (indexed), mls/m². LVESVi - Left ventricular end-systolic volume (indexed). LVSVi - Left ventricular stroke volume (indexed), mls/m². RVEDVi - Right ventricular end-diastolic volume (indexed), mls/m². RVESVi - Right ventricular end-systolic volume (indexed), mls/m². RVSVi - Right ventricular stroke volume (indexed), mls/m². LGE - Late gadolinium enhancement, %. FEV₁ – Forced expiratory volume in 1 second, % of predicted. FVC – Forced vital capacity, % of predicted. DL_co - Diffusing capacity for carbon monoxide, % of predicted. pVO₂ - Peak oxygen consumption, % of predicted. VE/VCO₂ - Ventilatory equivalent for carbon dioxide. O₂ pulse - Oxygen pulse, % of predicted.)