The Functional Status of Patients with Post COVID-19: from Resting and Exertional Assessment to Therapeutic Approach

Introduction During the first 3 years of the pandemic coronavirus disease 2019 (COVID-19), survivors experienced different clinical recovery and long-term impact on lung, related to residual respiratory symptoms with functional impairment, since in its initial common presentation the disease summarized features of interstitial viral pneumonia. Clinicians were primarily focused on post-acute lung function assessment to better describe the pathological mechanisms of lung sequelae and to manage appropriately post COVID-19 condition. The first part of the research project is aimed to evaluate the lung clinical and functional impact of pulmonary disease. After describing the common gas exchanges alterations and ventilation inhomogeneity as related to higher lung damage on acute phase, rather than restrictive dysfunctional defects, for which pulmonary function tests appeared insufficient to clearly explain prolonged breathlessness after COVID-19, our research interest has been directed to unexplained long-lasting dyspnoea and fatigue on exertion in Long-COVID (LC) syndrome. In this context, cardiopulmonary exercising test (CPET) could comprehensively and objectively assess the disorders of breathing pattern in dyspnoeic LC population with normal pulmonary function by means of TI/TTOT (fractional inspiratory time of the duty cycle) and VT/TI (mean inspiratory flow) at rest and during maximal exercise compared to healthy subjects. Finally, in terms of ventilatory abnormalities of CPET deconditioning with higher diaphragm intolerance and lower efficiency, our research aimed to pulmonary rehabilitation (PR) as a means to improve uncomfortable dyspnoea and fatigue due to a higher diaphragm intolerance and lower efficiency by means of Active Cycle of Breathing Techniques (ACBT) combined with a moderate daily physical activity (PA). Moreover, in our research we evaluated if respiratory impairments could be related to small airways dysfunction and could be improved after rehabilitation protocol. Materials and Methods Firstly, we analysed the clinical parameters of post COVID-19 outpatient participants from University Hospital of Parma (Italy) that significantly correlated with radiological (HRCT) score in the acute phase, clustering the population study into two significant different groups according to normal/abnormal lung function at follow-up. Subsequently, we identified the independent variable that best significantly discriminated subjects with radiological residual features at follow-up. Finally, we elaborated a predictive score (COSeSco- COVID-19 Sequelae Score) to identify individuals at higher risk of pulmonary sequelae at HRCT at follow-up. During the second part of our research, by means of CPET, we analysed the pattern of breathing by recording TI/TTOT and VT/TI at baseline and on exercise in a LC population complained of unexplained dyspnoea lasting at least 3 months after SARS-CoV-2 infection, from outpatient clinic of University Hospital of Parma (Italy) and the Hospital of Piacenza, Italy. As control group, we recruited routine outpatient clinic healthy, age, sex and BMI-matched subjects (HS). Lastly, in the third part of 3-year research project, we assessed the benefits of a 6-week independent home respiratory rehabilitation programme, consisted of an ACBT 10-min session twice a day and at least 6000 steps per day in LC patients from University Hospital of Parma (Italy), who complained of dyspnoea, asthenia and cough at least 24 weeks after acute viral infection. The VAS scale, the mMRC dyspnoea and the Leicester Cough Questionnaire (LCQ), were all administered to the patients at baseline and at follow-up, as well as participants performed spirometry, oscillometry (IOS) and multiple-breath nitrogen washout before and after the rehabilitation. Results In the first part of our research, we confirmed that most of 121 post COVID-19 patients showed radiological and lung function changes expressed as diffusing capacity of the lung for carbon monoxide (DLCO) and total lung capacity (TLC) approximately 4 months after acute phase. Moreover, by clustering the study population according to the normal/abnormal values of DLCO they showed specific features. Finally, we elaborated the COSeSco score, which was able to significantly discriminate COVID-19 survivors at higher risk of residual HRCT score >10% in the follow-up. From the second research study, we found that 42 LC patients were characterised by significantly greater values of TI/TTOT at rest and at the peak of exercise, and lower values in VT/TI at peak, compared to 41 HS. Most LC participants with TI/TTOT > 0.38, as cut-off value, showed lower values in oxygen uptake and in maximal workload, associate with ventilatory inefficiency. Regarding the third part of research project, in which we analysed data from 33 LC patients, it should be noted that the most statistically findings after the PR concerned dyspnoea by mMRC, health status by VAS scale (0-100) and cough by LCQ (p= 0.0032, p= 0.0416, p=0.0001, respectively). Considering peripheral airway function, R5-R20 (measure of distal airway resistance) (0.074 +/- 0.097 vs 0.053 +/- 0.071 KPa s l-1), AX index (reactance) (0.62 +/- 0.88 vs. 0.53 +/- 0.59 KPa s l-1), and LCI (8.51 +/- 2 vs. 8.39 +/- 1.77), all improved after the rehabilitation course, although not statistically (p= 0,1737, p=0,4243, p=0.9056, respectively). At baseline, about one third of study population is characterised by small airway dysfunction (R5-R20 ≥ 0.07 KPa s l -1) and the average baseline score of R5-R20 at baseline was above normal limits and improved after rehabilitation. Contrasting data are obtained in terms of FEF25-75 e FEF75 (forced expiratory flow at 25% and 75% of the pulmonary volume and at 25%, respectively) showing a functional worsening, while expiratory dynamic lung volumes (FVC and FEV3) improved at follow-up. Among different functional parameters (questionnaires, spirometry, IOS or MBNW) mMRC only correlates with R5-R20 (r= 0.4084, p= 0.0183) and AX (r = 0.3953, p = 0.0228). Conclusion We confirmed that resting and exertional lung functional consequences after 3 months are related to the lung acute involvement during COVID-19 and patients with higher lung damage during the acute phase had worse lung diffusing capacity on the follow-up as abnormal gases exchange and ventilation heterogeneity. An impaired breathing pattern at rest and on exercise may explain long-lasting breathlessness related to deconditioning in LC syndrome with normal spirometry, due to a higher diaphragm intolerance and lower efficiency than the reference controls. Finally, rehabilitation programme including breathing control exercises and a moderate physical activity can improve dyspnoea, healthy status and cough. While the efficacy of non-pharmacologic options is still being investigated, it is likely that LC individuals will be best served by an integrative multidisciplinary approach.