SARS-CoV-2 infection sequelae on exercise response: persistent or reversible? A 2-year perspective

To the Editor:

SARS-CoV-2 and the related disease COVID-19 have had a dramatic impact on the global healthcare system since their appearance in December 2019 [1]. The evidence of long-lasting sequelae in COVID-19 survivors has rapidly grown, leading to the current definition of “long COVID”, an entity defined as the persistence or development of new symptoms 3 months after the acute infection, lasting ≥2 months [2]. Nevertheless, recent literature has showed how some patients still presented SARS-CoV-2 sequelae with clinical and functional impairment even at a 2-year follow-up [3]. Cardiopulmonary exercise testing (CPET), which is the gold standard for the evaluation of pathophysiological response during exercise [4], allowed the unveiling of mechanisms of exercise intolerance in the early post-acute phase, mainly involving deconditioning and peripheral oxygen utilisation impairment, but also alteration of the breathing pattern and possibly chronotropic incompetence [5, 6]. However, data on the long-term outcome of patients presenting altered exercise capacity as a post-acute sequela of COVID-19 are still lacking.

In this observational, monocentric study, we prospectively enrolled consecutive patients who presented a reduced exercise capacity (V′_O2Low) on CPET 3–6 months after hospital discharge (peak oxygen consumption (V′_O2peak) <85% predicted) [4] and who repeated, at our post-COVID-19 clinic, CPET ≥18 months following discharge. We also included a group of patients who already presented a normal exercise capacity (V′_O2Normal) at the 3–6-month evaluation, for descriptive reasons. Other inclusion criteria were: 1) age >18 years; and 2) previous microbiological diagnosis of SARS-CoV-2 infection. Definition of diagnosis of SARS-CoV-2 infection, severity of the disease and SARS-CoV-2-related pneumonia were as previously described [7]. Exclusion criteria were the absence of signed informed consent, acute respiratory exacerbation in the previous 4 weeks and the presence of medical conditions contraindicating CPET (i.e. acute or unstable cardio-respiratory conditions, osteomuscular impairment compromising exercise performance) [4].

All patients had already been evaluated in our previous study on exercise capacity at 3–6 months after COVID-19 [7]. The Italian version of modified Medical Research Council dyspnoea during daily living scale (mMRC) was administered for quantification of dyspnoea. The International Physical Activity Questionnaire (IPAQ) was administered to assess daily physical activity [8]; the questionnaire identifies three levels of physical activity: low, moderate and high. Pulmonary function testing and CPET procedures were previously described [7]. We defined an abnormal chronotropic response as <80% of the adjusted heart rate index (AHRI) calculated as: where HR_peak­ and HR_rest are peak and resting heart rate, respectively. Deconditioning was defined as reduced exercise capacity with normal breathing reserve, no evidence of cardiocirculatory pathology (assessed by ECG, ventilation (V′_E)/carbon dioxide output (V′_CO2) slope and oxygen pulse curve) with normal or low V′_O2 at the anaerobic threshold and/or the presence of a reduced slope or late plateau of the V′_O2 trajectory (i.e. a V′_O2/work rate relationship ≤8) [9, 10]. Dysfunctional breathing identification was based on visual pattern recognition [11].

All tests were performed at the Respiratory Unit at ASST Santi Paolo e Carlo, Milan, Italy (March–June 2022). Written informed consent was obtained from each participant. The study was approved by Milan Area 1 Ethics Committee with the registration number 2022/ST/127.

The primary objective was to assess the change in peak exercise capacity, expressed as V′_O2peak, in a population of subjects who had a reduced exercise capacity 3–6 months after acute SARS-CoV-2 infection. We hypothesised an improvement of ≥10% of V′_O2peak over time as a significant outcome in respiratory patients [12]. A post hoc analysis of V′_O2peak confirmed a statistical power >85% (α-error of 5%) for such an outcome in our population. Student's t-test for two independent or paired groups and Mann–Whitney test or Wilcoxon signed-rank test were used when appropriate. Qualitative data were analysed with Pearson's chi-squared test. A p-value <0.05 was considered statistically significant.

Three patients were excluded for submaximal test (one V′_O2Normal patient), new diagnosis of atrial fibrillation during the test (one V′_O2Low patient) and excessive air loss through the mouthpiece (one V′_O2Normal patient). We eventually included 20 V′_O2Low patients and 19 V′_O2Normal patients at 3–6 months. Mean±sd time from hospital discharge was 24±1 months for both groups. No patient had undergone a structured programme of rehabilitation after discharge. IPAQ scores of physical activity were comparable between the V′_O2Low and V′_O2Normal groups (low/moderate/high: 4/8/8 versus 4/6/9; p=0.853). One V′_O2Low and one V′_O2Normal patient reported a new asymptomatic SARS-CoV-2 infection between tests.

The most frequent comorbidities were arterial hypertension (41%), asthma (13%) and diabetes (5%). One V′_O2Normal patient had a major medical event between tests (non-ST elevation myocardial infection treated with revascularisation and stent placement).

V′_O2Low patients significantly improved their peak exercise capacity, while V′_O2Normal patients reported comparable values at the repeated test. CPET and functional parameters are reported in table 1.

V′_O2Low patients had a significant improvement in V′_O2peak, although they still had lower levels of exercise capacity compared to V′_O2Normal patients (V′_O2peak 88±12% versus 98±14% predicted, p=0.021). At 24 months, 13 (65%) V′_O2Low patients had recovered to a preserved exercise capacity. Among the seven patients who still presented a reduced exercise capacity, four had an increase in V′_O2peak (range 4–12% predicted), while three presented a decrease (range −1– −4% predicted). The final diagnoses for exercise intolerance were five patients with deconditioning and two with chronotropic incompetence. Three (16%) patients in the V′_O2Normal group presented a V′_O2peak <85% predicted at 24 months. Out of the eight (40%) V′_O2Low and nine (47%) V′_O2Normal patients who showed dysfunctional breathing at the early evaluation, one and two had a complete resolution, two and three had a significant improvement in their breathing pattern, and five and four showed an unchanged pattern at 24 months, respectively, resulting in 14 (35%) patients still presenting dysfunctional breathing in the combined cohort. Overall, five (12%) patients with preserved exercise capacity at 24 months reported an mMRC score ≥1 with no evident sign of altered physiology on CPET, pointing to a final diagnosis of long COVID, as per the World Health Organization definition.

This is, to our knowledge, the first study assessing peak exercise capacity in COVID-19 survivors 24 months after hospital discharge. In our study, we report a significant improvement in anaerobic threshold, V′_O2/work slope and peak oxygen pulse in V′_O2Low patients, although they reached the same load at peak as at 3–6 months. We interpreted this response as an overall improvement in the transport/peripheral utilisation of oxygen, which was found to be impaired in our cohort, as well as in several studies, in the early post-acute phase [6, 7, 13]. Previously, Cassar et al. [14] had showed an initial improvement in V′_O2peak between 3 and 6 months. Recently, Ingul et al. [9] demonstrated that V′_O2peak increases from 3 to 12 months post-COVID-19, as well as a proportion of patients considered as normal of 77%. Further studies, including invasive CPET, may be of use in understanding the limitation in those still presenting an overt impairment, particularly the role of a true residual myopathy beyond recovery from the disease-related limitation of activity and consequent deconditioning [13]. Although already above the limit of normal, our group showed a further improvement in ventilatory and gas exchange responses. We interpreted this improvement as likely further resolution of parenchymal abnormalities still observed on computed tomography at 3–6 months [15]. However, the evidence of a residual ventilatory inefficiency in COVID-19 survivors is mixed in the literature [5, 6]; Noureddine et al. [16] have shown a prevalence ranging 50–56% of intensive care unit-admitted patients presenting a V′_E/V′_CO2 slope above normal even at 12 months from the infection, independently of a preserved or reduced peak exercise capacity. Of note, as previously pointed out also at earlier time-points from the infection, some degree of dysfunctional breathing was still present in our cohort [11]. Interestingly, our V′_O2Low patients showed an increase in Borg scale for dyspnoea at peak, despite a better performance. This could be related to the resolution of a blunted perception of dyspnoea that characterises the acute and early phases of recovery from the disease [17].

The main limitations of our study are the monocentric nature, which impacts the generalisability of our data, and the absence of a baseline pre-COVID-19 assessment.

In conclusion, our study shows that patients with an impairment in exercise capacity at 3–6 months recover to a normal exercise capacity in most cases, even without a specific rehabilitating intervention, through an overall improvement in the physiology of oxygen transport/peripheral utilisation of oxygen with a more efficient ventilatory response to exercise. Further studies are warranted to confirm our findings on the long-term consequences of SARS-CoV-2 infection.