FormalPara Current knowledge

After COVID-19 infection, persistent exercise intolerance and changes in lung functions have been shown. The relationship between IOS parameters and exercise capacity using incremental and endurance shuttle walk tests has not been investigated.

FormalPara What this paper contributes to our knowledge

Small airway disease with normal spirometric functions could be related to decreased exercise capacity in COVID-19 survivors regardless of concomitant disease, BMI, smoking history, time since COVID-19 diagnosis. Even if FEV1 and FVC values are normal, limited exercise capacity can be established without the use of the cardiopulmonary exercise test (CPET) by using field exercise tests such as ISWT and ESWT, and IOS would be recommended.

Introduction

The infection caused by the new type of coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), was named as coronavirus disease 2019 (COVID-19) and declared as a pandemic by the World Health Organization (WHO) [1]. After acute disease, it has been found that 60–70% of patients report persistent symptoms for several weeks to months [2, 3]. The primary reported symptoms are fatigue, exercise intolerance, dyspnea, depression/anxiety, neuropsychological disorders and cognitive disturbances [2, 3]. In recent studies, the exercise intolerance by using cardiopulmonary exercise tests (CPET) has been shown among patients following COVID-19 infection [4,5,6,7].

Changes in lung functions have also been studied, and investigations have revealed that following COVID-19 infection patients have altered diffusion capacity, restrictive and obstructive patterns. Spirometry, lung volumes, and diffusion capacity were the most commonly used measures to evaluate COVID-19 patients’ respiratory function [8,9,10]. Impulse oscillometry (IOS) parameters are increasingly being used because IOS is a practical, noninvasive approach that can be administered easily and has the added benefit of having a high sensitivity to evaluate peripheral airway disease [11]. It has been shown that IOS parameters may predict poor exercise tolerance due to not only airflow limitation but also dyspnea or early detection of lung function change in patients with chronic obstructive pulmonary disease (COPD) [12, 13]. To our best knowledge, in patients following COVID-19 disease, none of the studies have looked into the relationship between IOS parameters and exercise capacity using incremental and endurance shuttle walk tests (ISWT, ESWT), which are simple, valid, reliable, reproducible, and safe and correlate more strongly with maximal oxygen uptake [14].

Our aim is to investigate the correlation between IOS parameters and exercise capacity by using ISWT, ESWT and investigate the factors and parameters which might have an effect on both IOS parameters and exercise capacity tests.

Method

Study population

The patients who had history of COVID-19 infections and symptoms, referred to our pulmonary rehabilitation center were enrolled into the study between February 2021 and June 2021 according to inclusion criteria (Fig. 1).

Fig. 1
figure 1

Flow-diagram

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Inclusion criteria: recent (at least 1 month after) infection with COVID-19 confirmed by PCR, no acute infection or pulmonary embolism (confirmed by history, serum C‑reactive protein, x‑ray) at the same time of evaluation, negative PCR test in last 72 h.

Exclusion criteria: refusal to participate and sign informed consent, acute myocardial infarction, unstable angina, uncontrolled arrhythmia, hemodynamic instability, syncope, active endocarditis, acute myocarditis or pericarditis, symptomatic severe aortic stenosis, uncontrolled heart failure, acute pulmonary embolism or pulmonary infarction, lower extremity thrombosis, dissected aneurysm, uncontrolled asthma, pulmonary edema, acute respiratory failure, mental disorder, unable to cooperate with shuttle walk tests or questionnaires, neurological or rheumatological disorders.

Written informed consent and ethical approval (Ankara Keciören education and research hospital ethics committee, number: 2012-KAEK-15/2211, date: 26.01.2021) was obtained.

Study design

This was a cross-sectional study.

Measurements

Age, gender, presence of lung disease, cardiovascular disease, diabetes mellitus (DM), IOS parameters, exercise tests, forced vital capacity (FVC), forced expiratory volume in one second (FEV1), smoking status, usage of long-term oxygen treatment (LTOT), body mass index (BMI), fat-free mass index (FFMI), dyspnea, anxiety and depression, fatigue scores, time since COVID-19 diagnosis, presence of hospitalization, length of hospital stay were recorded.

Impulse oscillometry technique: an impulse consisting of a mixture of sound waves of different frequencies is produced by the speaker in the mouth. As this wave passes into the lungs, it causes changes in pressure as well as airflow. The frequencies of the transmitted waves in IOS vary between 5 and 30 Hz. While frequencies higher than 30 Hz may disturb the patient, parameters measured at < 5 Hz are affected by breath dynamics. A pressure transducer and a pneumochromatograph are available in the mouthpiece to measure pressure and flow, respectively. The IOS evaluates the impedance (Z), resistance (R), and reactance (X) parameters at multiple frequencies from 5–35 Hertz, based on breaths at tidal volume [15].

  • Resonance frequency (Fres): the frequency at which the inertance and peripheral capacitance of lungs are equal and their total reactance is zero. Fres can be higher in both obstructive and restrictive lung disorders.

  • The area of reactance (AX): the area under the reactance curve from lowest frequency to Fres [16]. AX determines small airway function and increased values of AX have been found to be associated with decreased lung compliance and peripheral airway resistance [17].

  • Resistance: R5 shows the total airway resistance due to fact that the 5 Hz frequency signals reach distal airways while R20 shows central airways. The difference between them (R5–20) determines small airway functions.

  • Reactance (X) at low frequencies (5 Hz) determines the elastic and interstitial features of the lungs.

Disorders influencing the elasticity of the lung, such as interstitial lung diseases, will increase the capacitance negatively and X5 become more negative [16].

Although the reference values for IOS parameters have not been identified, they have been investigated in some studies. The R20 values were considered abnormal when ≥ 150% of the predicted value [18]. The cut-off values defining small airway disease have been found as 0.30 kPa/L/s for R5, 0.015 kPa/L/s for R5–R20, 0.30 kPa/L for AX and 11.23 Hz for Fres [19]. In another study, it was shown that R5–20 Hz ≥ 0.07 was predictor for small airway disease [20].

Patients were assessed by using impulse oscillometer (Carefusion Vyntus Jaeger IOS, Hochberg, Germany). The IOS device was checked and calibrated on each day. During the test, the patient was seated in a neutral or slightly extended position with the nose clip as it is recommended that the patient firmly supported their own cheeks during test.

Exercise capacity was evaluated using the incremental shuttle walking test (ISWT) and endurance shuttle walking test (ESWT). The tests were performed on a 10 m course identified by 2 cones placed 0.5 m from each end point. The patients walked around the course according to the speed dictated by an audio signal. The initial walking speed was 0.5 m/s and it increased by 0.17 m/s each minute. The distance walked was recorded. The incremental shuttle was employed to predict peak oxygen uptake (VO2 peak); 85% VO2 peak was used to determine the walking speed for the ESWT. The duration of the test was also recorded [21].

Spirometry was performed to determine FVC, FEV1 and FEV1/FVC in accordance with the American Thoracic Society-European Respiratory Society (ATS-ERS) guidelines [22]. Body composition by using bioelectrical impedance (BIA model TBF-300; Tanita Corporation, Tokyo, Japan). BMI and FFMI were calculated using the formula of weight (body mass for BMI, fat-free mass for FFMI) in kilograms divided by the square of the height in meters. Dyspnea was assessed using the modified Medical Research Council (mMRC) scale [23]. The validated Turkish version of hospital anxiety and depression (HAD) scores for assessing psychological status was recorded [24]. Fatigue was evaluated with the validated Turkish version of fatigue severity scale (FSS). The FSS is a self-administered scale used to evaluate the severity of fatigue. It consists of nine items; each item is scored between 1–7, where 1 means that the individual does not completely agree with the stated statement, and 7 means that they completely agree [25].

All measurements were made by the research coordinator and were made in a well-ventilated room, using protective personal equipment, while maintaining the necessary distance. Hospital data were used to confirm and query the history of hospitalization and length of stay.

The IOS parameters and the values of ISWT, ESWT were compared. Then, IOS parameters, ISWT, ESWT values were compared with continuous variables (age, FEV1, FVC, BMI, FFMI, mMRC, HAD scores, FSS, time since COVID-19 diagnosis, length of hospital stay) and compared according to categorical variables, the presence of concomitant disease (lung, cardiovascular disease, DM), LTOT, hospitalization and smoking status.

Statistical analyses

Statistical analyses were performed using the Statistical Package for the Social Sciences version 18.0 (SSPS, Chicago, IL, USA) software package. According to 80% power, the correlation coefficient was accepted as r = 0.34 [13], and the sample size was computed as 66 (two-sided alpha level of 0.05, beta level of 0.2). First, the variables were analyzed to assess the normality of distribution using the Shapiro-Wilk test. Data are given as mean ± standard deviation or median (min:max). The Kruskal-Wallis H or Mann-Whitney U test was used or comparing IOS parameters and ISWT, ESWT values according to categorical variables. Spearman correlation analyses were used for investigating relationships.

Results

The study comprised 72 patients, 71% of whom were male, with a mean age of 54 ± 10 years. There were 51 (71%) individuals who did not have any respiratory disease, 18 (25%) had concomitant cardiovascular illness and 16 (22%) had diabetes mellitus. Of the patients 30 (42%) were never smokers, others were current and former smokers (Table 1). After COVID-19 diagnosis, the median duration was 3 (1:5) months. 51 (71%) of the patients were hospitalized. The median length of stay in the hospital was 10 (5:70) days. The oxygen therapy was prescribed to 23 (32%) of the patients. The median value of m MRC scale was 2 (0:4). The mean value of BMI was 29 ± 5 kg/m2 with an anxiety score of 7 ± 3, depression score of 8 ± 3. The median value of ISWT was 400 (70:580) m, ESWT was 10 (2:20) min and fatigue severity score was 5 (1:7) (Table 1). The mean predicted % value of FEV was 84 ± 20, FVC was 87 ± 21, FEV1/FVC was 77 ± 11. IOS parameters are given in Table 2.

Table 1 Recorded parameters
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Table 2 Conventional pulmonary functional tests and IOS parameters
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When IOS parameters and ISWT, ESWT were compared, R5 was found to be correlated with ISWT (p = 0.001, r = −0.380). Fres, AX, X20, R5–20 correlated with both ISWT (p < 0.001, r = −0.416/p < 0.001, r = −0.443/p < 0.001, r = 0.459/p < 0.001, r = −0.381) and ESWT (p = 0.008, r = −0.312/0.030, −0.256/< 0.001, 0.469/0.047, −0.285).

When ISWT, ESWT were compared with other parameters, ISWT also correlated with age (p < 0.001, r = −0.403), mMRC (p < 0.001, r = −0.412), FEV1 (p = 0.006, r = 0.321), FVC (p = 0.012, r = 0.293). ESWT also correlated with mMRC (p = 0.001, r = −0.372), FEV1 (p = 0.003, r = 0.350), FVC (p = 0.009, r = 0.307). Both ISWT and ESWT values were statistically different according to presence of LTOT (p = 0.041 and p = 0.004, respectively).

When IOS parameters were compared with other parameters, FEV1 was correlated with all IOS parameters, R5 predicted (p = 0.012, r = −0.300), R5 (p = 0.024, r = −0.266), R 5–20 predicted (p = 0.025, r = −0.265), R5–20 (p = 0.003, r = −0.347), AX (p < 0.001, r = −0.405), X5 (p = 0.010, r = 0.301), X20 (p = 0.003, r = 0.348), Fres (p = 0.007, r = −0.317). FVC was only with correlated with R 5–20 predicted (p = 0.013, r = −0.292), R5–20 (p = 0.029, r = −0.257), AX (p = 0.046, r = −0.236), X20 (p = 0.026, r = 0.263). AX was found to be correlated with age (p = 0.037, r = 0.246) and FFMI (p = 0.037, r = −0.246), also X5 was correlated with FFMI (p = 024, r = 0.267) and X5 values were statistically different according to hospitalization (p = 0.02). Other IOS parameters were found to be similar or did not correlate with other variables.

Discussion

These findings revealed a correlation between IOS parameters and exercise capacity in COVID-19 survivors. FEV and FVC levels were shown to be correlated to both IOS parameters and exercise capacity. Furthermore, neither IOS nor exercise capacity differed according to the presence of concomitant disease, smoking status, and time since COVID-19 diagnosis, length of hospital stay, BMI, anxiety, depression, and fatigue scores.

In COVID-19 survivors, pulmonary function abnormalities have been shown in several studies [8,9,10]. Additionally, COVID-19 may have reduced lung function for months or possibly years, according to preliminary research [26, 27]. According to the studies, in coronavirus infections like SARS and Severe Acute Respiratory Syndrome (SARS) and Middle East respiratory syndrome (MERS), long-term damage has been shown months or even years after discharge [28, 29]. Performing pulmonary functional tests and also follow-up tests are recommended [30]. In another study IOS parameters have been predictors for low exercise capacity by using 6MWT [13]. Similarly, in our study the correlation was found between IOS parameters and exercise capacity. It was shown that exercise capacity was linked to pulmonary function in patients after COVID-19. It was suggested that decreased exercise capacity could be due to ventilatory limitation in these patients.

Impulse oscillometry has recently grown to prominence due to its practicality and convenience of usage. IOS resistance values can be useful for mild COPD diagnosis and small-airway changes [17]. R5–20 or AX are markers of small airway function and AX has been found to be associated with decreased lung compliance and peripheral airway resistance. Fres can be higher in both obstructive and restrictive lung disorders [16]. In our study, AX value was 0.45 cm H2O/L/s, Fres was 17 Hz, R5–20 was 0.08 Hz, X5 had negative value, 96% predicted value of R20 and FEV1, FVC > 80%. These findings suggested that there was small airway disease with preserved central airway disease in our patients according to previous studies [16, 18]. It was suggested that after COVID-19 small airway disease may be the cause of ventilatory limitation resulting in reduced exercise capacity even with normal value of FEV1. In a recent study, R5–20 Hz and AX, were inversely correlated with FEV1 [31]. In our study, all IOS parameters were found to be correlated with FEV1 but the correlation was weak. We suggest that the reason of this finding might be due to the high baseline FEV1 values of the patients after COVID-19 infection.

After COVID-19, dyspnea and exercise intolerance has been frequently seen. In another study, COVID-19 survivors were found to be dyspneic, with normal pulmonary function and reduced exercise capacity after 3 months from discharge and VO2 max values were not found to be correlated with FEV1 or FVC [32]. In the present study, our patients were dyspneic and had reduced exercise capacity but not similar to the previous study, FEV1, FVC correlated with exercise capacity. It could be due to different tests for assessing exercise capacity. Furthermore, in present study, regardless of the concomitant lung disease, cardiovascular disease, BMI, anxiety, depression and fatigue scores, smoking history, IOS parameters were correlated with exercise capacity. It was suggested that in COVID-19 survivors the reason of reduced exercise capacity might fundamentally be due to ventilator limitation. In a recent study, it was showed that performing invasive CPET in COVID-19 survivors, O2 delivery was normal and associated with reduced peripheral O2 extraction, resulting in reduced peak VO2, indicating lower diffusive O2 delivery to the mitochondria [5].

This study included a heterogeneous group of patients in terms of concomitant disorders and time since COVID-19 diagnosis but none of these variables played a significant influence in association analyses. Vaccination status could have been questioned in order to reveal the effects on pulmonary functions.

Despite the fact that it was a single-center study, there are a limited number of IOS machines in the respiratory area, and IOS is not commonly utilized in outpatient clinics. Furthermore, IOS parameters have not been studied enough in the English literature in these patients. This study may help to better understand the pulmonary functions and mechanisms of exercise intolerance by using practical and easy to perform tests in individuals with a history of COVID-19 infections.

Conclusion

In this study we showed that small airway disease with normal spirometric functions could be related with decreased exercise capacity in COVID-19 survivors regardless of concomitant disease, BMI, smoking history, time since COVID-19 diagnosis. We think that even if FEV1 and FVC values are normal, limited exercise capacity can be established without the use of CPET by using field exercise tests, such as ISWT and ESWT, and IOS would be recommended.