Respiratory Muscle Dysfunction in COVID-19 Patients with Persistent Symptoms

In a cross-sectional analysis, we have identied a high prevalence of respiratory muscle dysfunction in persistently symptomatic patients after COVID-19 (‘Long COVID’). Respiratory muscle impairment in these patients was associated with exercise-induced deoxygenation, impaired exercise tolerance, activity and functional outcomes after COVID-19.

longest lasting sequelae [7,8]. As recently reported in the Journal, fatigue, exertional intolerance and dyspnea can also be observed in Long COVID patients with preserved lung function [9]. In this light, besides the growing body of evidence regarding pulmonary parenchymal and cardiac sequelae [10][11][12][13][14], fatigue and dyspnea in convalescent COVID-19 patients might have additional causes related to respiratory muscular dysfunction.
In a cross-sectional approach, we have therefore prospectively investigated respiratory drive and effort in convalescent COVID-19 patients presenting to our outpatient department (OPD) with persisting respiratory symptoms.
Sixty-seven adult convalescent COVID-19 patients (30 female, 37 male, mean age: 49 yrs, baseline characteristics are given in Table 1) after mild to critical disease (according to WHO classi cation) completed general symptom, activity and productivity (modi ed WPAI score) questionnaires before undergoing complete pulmonary function testing (PFT) including spirometry, body plethysmography, capillary blood gas analyses (CBG) at rest and after performing a six-minute walk test (6MWT) including assessment of dyspnea intensity at rest and during 6MWT using the Modi ed BORG Dyspnea Scale (Borg CR10). In addition, respiratory muscle testing to assess respiratory drive and effort was conducted following current guidelines, which also de ned pathological cut-off values [15,16]. PRISM 9 (GraphPad Inc, San Diego, CA) and R for macOS version 3.6.3 (https://cran.r-project.org) with RStudio 1.3 (RStudio, Boston, MA) was used for the following statistical analyses: One-sample t-test and Pearson correlation analysis for normally distributed data (D'Agostino-Pearson Test); Mann-Whitney, Spearman correlation and Fisher's exact test for non-parametric data.
At time of presentation to our OPD (median of 152 days, IQR: 65 -260), convalescent patients which initially had to be hospitalized due to COVID-19 (55% of cohort) showed reduced PFT parameters compared with non-hospitalized COVID-19 patients. In addition, initially hospitalized COVID-19 patients walked 92.3 m (15.2%) less in 6MWT and showed a more pronounced decrease in P a O 2 during 6MWT (median: +1.5 mmHg vs. -7.8 mmHg). No differences were found in dyspnea perception, functional impairment, daily activity or productivity. While hospitalized patients were older, had a higher Body-Mass-Index and more co-morbidities, history of lung disease was rare and did not differ between hospitalized and non-hospitalized patients (Table 1).
While no patient was hypoxemic at rest, convalescent COVID-19 patients with elevated P 0.1 showed a signi cant decrease in arterial oxygen partial pressure (P a O 2 ) during 6MWT (DP a O 2 : -6.6 mmHg,p=0.0134; Figure 1F). In all patients with exertional deoxygenation pulmonary thromboembolic disease was ruled out by subsequent V/Q scans.
In our cross-sectional pilot study of convalescent COVID-19 patients with persistent exertional dyspnea and fatigue we have identi ed a high prevalence of impaired respiratory muscle function at ~5 months after diagnosis. Functionally, this was associated with impaired exercise tolerance and daily activity/productivity in connection with exercise-induced deoxygenation.
Recently published PFT data of COVID-19 patients show mildly reduced TLC and DLCO at discharge, three-or six-months convalescence mostly in patients with severe disease [12,18]. This is in line with our data showing patients initially hospitalized for COVID-19 had signi cantly lower PFT parameters including TLC and DLCO up to 5 months after infection. This was also associated with reduced exercise capacity in hospitalized patients after COVID-19 as measured by 6MWD.
Our study extends these ndings as we newly report a high prevalence of increased respiratory drive and impaired respiratory muscle capacity in convalescent, persistently symptomatic COVID-19 patients. In our cohort, patients requiring hospitalizations including ICU treatment also had impaired respiratory muscle strength consistent with recently reported ndings of brotic diaphragm remodeling in patients deceased due to COVID-19-related ARDS [14]. Even though central dyspnea processing shows high interindividual variability [19], in line with our results, elevated P 0.1 is strongly associated with heightened dyspnea perception [20]. This was also the case in our cohort as shown by elevated BORG-CR scores and everyday activity, productivity and COVID-related functional impairment (PCFS). In keeping with persistent respiratory pump impairment convalescent yet persistently symptomatic COVID-19 patients with elevated P 0.1 also featured an increase in P 0.1 /MV supporting our ndings of clinically relevant inspiratory muscle weakness. Prevalence of elevated P 0.1 in our Post-COVID-19 cohort was comparable to that in acutely ill COVID-19 patients on ICU [21] possibly pointing towards a persistent COVID-19-associated phenomenon.
Our data support that, pathophysiologically, elevated P 0.1 might be a function of exercise-induced deoxygenation in convalescent, persistently symptomatic COVID-19 patients. While pulmonary thromboembolic disease was not detected by V/Q scan (as described above), six patients showed signs of ground-glass opacity and (mostly minor) brotic changes. Systematic analysis of these changes, however, was out of the scope of the present study which is a limitation. Also, due to unavailability of data in some patients, we cannot exclude pre-existing changes in respiratory drive and effort sustained from before SARS-CoV-2 infection. Additional limitations include a putatively biased patient selection as most patients reported to our OPD with persistent symptoms after COVID-19 with very few patients referred for a routine follow-up after COVID-19. Patients and staff were also not blinded to the overall testing, possibly inserting additional bias in the measurement as does lack of historical PFT data. We also cannot speci cally attribute the detected changes in respiratory drive and inspiratory muscle function to SARS-CoV-2 as we cannot rule out a general effect of viral infections. Although it is not possible to differentiate inspiratory muscle impairment from generalized muscle weakness or postinfection myopathy, in our cohort, creatine kinase and myoglobin serum levels did not differ between patients with normal or abnormal respiratory muscle function (p=0.202 and p=0.075, respectively). Regardless of SARS-CoV-2 speci city, high prevalence in our pilot study points towards a relevant healthcare burden given the pandemic nature of COVID-19.
Thus, in our cohort respiratory drive (P 0.1 ) was most likely increased due to impaired inspiratory muscle function (PI max ) which was present in approx. 90% of patients. In addition, to deoxygenation-triggered central chemoreceptors, there might be other explanations for increased neuromuscular activity in Long COVID patients such as dysfunctional thoracic receptors or altered cortical and emotional central feedback loops (as reviewed in [22]). The latter would also be in line with Long COVID patients reporting heightened stress and anxiety levels [23] which is another well characterized trigger of respiratory drive [24].
As there is strong evidence that chronic fatigue syndrome (CFS) is associated with COVID-19 [7,8,25], it is compelling to speculate to what extend heightened neuroventilatory activity as documented by P 0.1 in our cohort contributes to COVID-19-CFS. Particularly, as incapability to adequately increase respiratory effort upon increased respiratory drive is known to worsen respiratory distress [26]. Therefore, more invasive techniques such as twitch interpolation might help to further characterize dysregulation of respiratory drive and effort in Long COVID patients.

Conclusion
We were able to detect increased respiratory drive as well as inspiratory muscle dysfunction in persistently symptomatic patients months after COVID-19. Notwithstanding the small sample size, our ndings reveal a previously unidenti ed neuromuscular component of COVID-19 sequelae.
Given the wide accessibility of respiratory muscle testing as a relatively low-cost approach (in particular in comparison with imaging and immunological laboratory studies), we strongly advocate for systematic respiratory muscle testing in the diagnostic workup of persistently symptomatic, convalescent COVID-19 patients. Availability of data and materials. Data analyzed during this study are available from the corresponding authors upon reasonable request.

Competing interests
The authors declare no competing interests.