Physical Fitness Differences, Amenable to Hypoxia-Driven and Sarcopenia Pathophysiology, between Sleep Apnea and COVID-19

Handgrip strength is an indirect indicator of physical fitness that is used in medical rehabilitation for its potential prognostic value. An increasing number of studies indicate that COVID-19 survivors experience impaired physical fitness for months following hospitalization. The aim of our study was to assess physical fitness indicator differences with another prevalent and hypoxia-driven disease, Obstructive Sleep Apnea Syndrome (OSAS). Our findings showed differences between post-COVID-19 and OSAS groups in cardiovascular responses, with post-COVID-19 patients exhibiting higher values for heart rate and in mean arterial blood pressure. Oxygen saturation (SpO2) was lower in post-COVID-19 patients during a six-minute walking test (6MWT), whereas the ΔSpO2 (the difference between the baseline to end of the 6MWT) was higher compared to OSAS patients. In patients of both groups, statistically significant correlations were detected between handgrip strength and distance during the 6MWT, anthropometric characteristics, and body composition parameters. In our study, COVID-19 survivors demonstrated a long-term reduction in muscle strength compared to OSAS patients. Lower handgrip strength has been independently associated with a prior COVID-19 hospitalization. The differences in muscle strength and oxygenation could be attributed to the abrupt onset of the disorder, which does not allow compensatory mechanisms to act effectively. Targeted rehabilitation focusing on such residual impairments may thus be indispensable within the setting of post-COVID-19 syndrome.


Introduction
COVID-19 has led to an increase in morbidity worldwide. Due to secondary respiratory failure both in the hospital and in post-COVID-19 settings, patients limit their physical activities, particularly when experiencing severe disease, as desaturation occurs even during minimal mobilization. Exposure to hypoxia and limitations in physical activity are shared features of Obstructive Sleep Apnea Syndrome (OSAS) and post-COVID-19 syndrome [1][2][3]. Bedridden patients experience functional decline and an increased risk of complications proportionately to their hospitalization time and regardless of age [4]. Even one week of hospitalization affects muscle mass and the patient's general wellness [5]. An indirect measure of patient fitness is handgrip strength [6], with prognostic utility regarding physical ability and cardiovascular status in hospitalized patients [7].
The aim of this study was to investigate physical fitness indicator differences between patients with OSAS and COVID-19, as two distinct hypoxia-driven diseases. We hypothesized that these diseases share pathophysiologic commonalities in the context of respiratory and musculoskeletal function, which could offer insights in optimizing the management of these diseases.

Study Population
The study population included adult COVID-19 survivors that had previously been hospitalized in the Respiratory Department of the University Hospital of Larisa (n = 40), versus obstructive OSAS patients (n = 40) without a history of or active infection with COVID-19. Patients were recruited between September 2020 to June 2021 (total n = 80; see Table 1 for cohort characteristics).

Inclusion and Exclusion Criteria
The following inclusion criteria were applied: (i) patients no longer requiring supplemental O 2 , (ii) patients who were fever-free for a period of at least 48 h (without medication to reduce the fever) prior to enrollment and/or (iii) patients deemed to be stable according to the National Institute of Health and Hellenic guidance criteria for COVID-19 discharge [8], and (iv) patients with at least 60 days between discharge and enrollment. The inclusion criteria for OSAS patients were the following: (i) presenting with Apnea Hypopnea Index ≥ 15 events/h, (ii) nonsmokers, aged between ≥30 and ≤60 years old, and (iii) sleep duration ≥ 300 min during polysomnography study (PSG) [9]. The exclusion criteria, for both groups, were contraindications for 6MWT [9,10], body mass index ≥40 kg/m 2 , abnormal pulmonary function test (FEV 1 ≤ 85%, FEV 1 /FVC < 80, and DLCO < 80%), and musculoskeletal disability which could impair maximum exercise capacity [9,11]. Moreover, post-COVID-19 patients with Pittsburgh Sleep Quality Index score ≤ 5 [12] and Epworth Sleep Scale score < 10 [13] were also excluded.

Study Ethics
The study's protocol was approved by the Institutional Review Board (IRB)/Ethics Committee (EC) of the University Hospital of Larissa (IRB/EC approval reference number: 15314/21-04-2021). All participants provided written informed consent, in accordance with the Helsinki declaration and personal data protection requirements under the European Parliament and the Council of the European Union legislation [14].

Physical Fitness Tests
The 6-minute walk test (6MWT) was performed according to the ATS guidelines [15] with O 2 saturation (SpO 2 ) and heart rate (HR) (Nonin 9590 Onyx Vantage, Plymouth, MN, USA) having been recorded at baseline and every one minute of the test thereafter [8,9]. Blood pressure (Sphygmomanometer Mac Check 501, Tokyo, Japan) and self-assessment for dyspnea and lower limbs fatigue [16] were recorded before and at the end of the test. Finally, the total distance during the 6MWT was used to estimate the oxygen uptake [17] according to the equation: [O 2 uptake = 4.948 + 0.023 × distance (m) ].
Handgrip strength was assessed with a standard height chair (46 cm), with the patient's elbow being by the side of the body and flexed at 90 degrees; the forearm and wrist remained in a neutral position and the handle of the electronic dynamometer (Camry, EH 101, South El Monte, CA, USA) rested on the middle of the four fingers [18]. All participants performed one maximum isometric effort for 5 s with the dominant hand. All subjects reported their dominant upper limb before the trials.
For the physical fitness test, a demonstration was performed by the clinical exercise physiologist prior to the patients' own attempts. All patients performed the physical fitness tests without encouragement, in the Laboratory of Cardio-Pulmonary Testing and Pulmonary Rehabilitation (University of Thessaly), with the environmental temperature at 24.1 ± 2.1 • C and humidity 33.8 ± 4.2%. The evaluation of patients was performed between 09:30 a.m. and 13:30 p.m.

Results
The results of multivariate analyses via BSLR are presented in Table 3.

Discussion
In our study, we aimed to assess differences in handgrip strength, an indirect measure of muscle strength, between OSAS patients and COVID-19 survivors. Our findings indicated that COVID-19 survivors (at a two month post-discharge timepoint) have reduced muscle strength compared to OSAS patients. Furthermore, we reported an independent association between lower handgrip strength and prior hospitalization due to COVID-19 ( Figure 6).

Hypoxia and Reduced Strength in COVID-19 Survivors and OSAS Patients
Our findings indicate that COVID-19 survivors present with lower oxygen saturation during mobilization compared to OSAS patients, as indicated by measurements during the 6MWT. Hypoxemia in post-COVID-19 patients has been attributed to ventilation-toperfusion (V/Q) mismatch in scattered lung units, especially in the early stages [19]. The V/Q ratio may be minimized in certain patients, as ventilation is hindered due to the lungs' low elastance and recruitability secondary to structural lung damage, whereas in others the V/Q ratio is elevated due to the superiority of ventilated non perfused lung units over non ventilated ones (shunt) [3]. As far as perfusion is concerned, microvascular thrombosis has been well-documented to occur in COVID-19 patients [20]. The implication of this process in the context of the lung represents dead space with reduced/absent pulmonary capillary flow without affecting ventilation, leading to a high V/Q ratio. Additionally, Figure 6. Physiological adaptations of exercise and reduced exercise in healthy adults (white boxes), hospitalized patients (grey boxes), and physical activity during hospitalization patients (blue boxes) and bicolor boxes show the reverse adjustments. Dotted lines: reverse, detrimental adjustments in physical fitness indicators due to hospitalization and/or long time bedridden/immobility. Continuous lines: adjustments during exercise (mild lines) and during hospitalization (bold lines).

Hypoxia and Reduced Strength in COVID-19 Survivors and OSAS Patients
Our findings indicate that COVID-19 survivors present with lower oxygen saturation during mobilization compared to OSAS patients, as indicated by measurements during the 6MWT. Hypoxemia in post-COVID-19 patients has been attributed to ventilation-toperfusion (V/Q) mismatch in scattered lung units, especially in the early stages [19]. The V/Q ratio may be minimized in certain patients, as ventilation is hindered due to the lungs' low elastance and recruitability secondary to structural lung damage, whereas in others the V/Q ratio is elevated due to the superiority of ventilated non perfused lung units over non ventilated ones (shunt) [3]. As far as perfusion is concerned, microvascular thrombosis has been well-documented to occur in COVID-19 patients [20]. The implication of this process in the context of the lung represents dead space with reduced/absent pulmonary capillary flow without affecting ventilation, leading to a high V/Q ratio. Additionally, in the early stages of infection the inflammation affects the lungs in a nonuniform manner, leading to an uneven distribution of capillary perfusion units [21]. This process leads some alveolocapillary units to higher V/Q ratios. While COVID-19 survivors are considered disease-free regarding the acute phase [22], persistent oxygen desaturation and fatigue are commonly reported in the post-acute period.
Conversely, chronic hypoxia in OSAS is characterized by intermittent hypoxia that is state-dependent-i.e., during sleep [23]. Intermittent hypoxia is characterized by cycles of hypoxemia with reoxygenation and is recognized as a potential fundamental factor contributing to the pathogenesis of OSAS-related comorbidities [24]. According to Dewan et al. [23], "OSAS patients, typically manifest short intermittent high-frequency hypoxemic episodes occurring in an approximately 8 h interval of sleep while, sustained or low-frequency hypoxemia with SaO 2 ranging between 80-85% that lasts longer, from a few minutes to hours, is witnessed primarily during rapid ascent and descent from altitude and secondary in chronic respiratory disease during sleep". The major pathophysiologic difference between the short intermittent high-frequency hypoxemia, as seen in OSAS, and sustained prolonged low-frequency hypoxemia is the cycles of reoxygenation. Intermittent hypoxia promotes increased systemic and vascular inflammation with endothelial dysfunction and sympathetic excitation during both daytime and nighttime and contributes to multiorgan comorbidity [23]. Comparing COVID-19 survivors and OSAS, we account for the differences in muscle strength and oxygenation in the abrupt onset of the disorder, which does not allow compensatory mechanisms to take action effectively.
It is worth noting that obesity was prevalent in both groups, and it is a well-known risk factor for both entities [25][26][27]. In OSAS patients, obesity contributes to V/Q mismatch by impairing ventilation, as it reduces lung compliance and volumes, decreases respiratory muscle strength and increases airway resistance. Reduced ventilation promotes a hypercapnic condition [28]. From our results, body fat percentage and neck circumference-as more accurate determinants-were substantially high in both groups. Furthermore, we may attribute their discrepancies to their state-dependence differences as COVID-19 is an acute debilitating condition with the patient becoming dehydrated, malnourished, and cachectic under the weight of the disease. Therefore, their overall weight rapidly reduces due to the loss of fluids and lean muscle mass.

Reduced Handgrip Strength as a Consequence of Loss of Muscle Mass
Sarcopenia is a complex syndrome composed of nutritional deficiency, chronic inflammation, insulin resistance, and a decline in anabolic hormones and is directly related to reductions in mobility and functional status. Prolonged periods of bed rest (>10 days) have been shown to induce substantial changes in body composition and are accompanied by overall metabolic decline [29]. Additionally, bed rest can affect potentially all body muscles, particularly postural ones, such as rectus abdominis, external oblique, internal oblique, transversus abdominis, thoracic erector spinae, as well as the lumbar multifidus muscle, vastus lateralis, and soleus [5]. Correspondingly, lean body mass and the quadriceps crosssectional area may also be affected by a loss of significant thickness and peak oxygen uptake (VO 2peak ) may also be affected, which increases the overall risk of falls and disability [30]. Severe sarcopenia refers to the most debilitating evolution of this syndrome that prevents individuals from accomplishing the simple activities of daily living, leaving them unable to self-care [31]. COVID-19 survivors may experience acute sarcopenia [32], preceded by lockdown-associated sarcopenia [33]. This connection carries over into post-COVID-19 syndrome [34]. These associations are reflected in our results and should be addressed by targeted rehabilitation.

Conclusions
Our findings suggest that COVID-19 survivors display diminished muscle strength compared to OSAS patients, as measured by handgrip. Lower handgrip strength was independently associated with a risk of COVID-19 hospitalization, and, considering its correlates, may be an important target for rehabilitation. Specifically, as COVID-19 survivors experience hypoxia during physical mobilization, indicating a combination of impaired respiratory function and sarcopenia, these residual impairments should be identified and reversed via targeted approaches.  Informed Consent Statement: Informed consent was obtained from all subjects involved in the study.
Data Availability Statement: All data are available upon request.