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ORIGINAL ARTICLE
Year : 2022 | Volume
: 32
| Issue : 4 | Page : 200-204
Assessment of long-term sequelae of pulmonary dysfunction associated with COVID-19 using pulmonary pulse transit time
Mustafa Duran1, Turgut Uygun1, Ercan Kurtipek2
1 Department of Cardiology, Konya City Hospital, Konya, Turkey
2 Department of Pulmonology, Konya City Hospital, Konya, Turkey
Correspondence Address:
Mustafa Duran
Department of Cardiology, Konya City Hospital, Karatay, Konya 042020
Turkey
Source of Support: None, Conflict of Interest: None
CheckDOI: 10.4103/jcecho.jcecho_31_22
Background: Studies report deleterious impacts of severe acute respiratory syndrome coronavirus 2 on multiple organs in the human body, not only in the acute infection period but also in the long-term sequelae. Recently defined pulmonary pulse transit time (pPTT) was found to be a useful parameter regarding the evaluation of pulmonary hemodynamics. The purpose of this study was to determine whether pPTT might be a favorable tool for detecting the long-term sequelae of pulmonary dysfunction associated with coronavirus disease 2019 (COVID-19). Materials and Methods: We evaluated 102 eligible patients with a prior history of laboratory-confirmed COVID-19 hospitalization at least 1 year ago and 100 age- and sex-matched healthy controls. All participants' medical records and clinical and demographic features were analyzed and underwent detailed 12-lead electrocardiography, echocardiographic assessment, and pulmonary function tests. Results: According to our study, pPTT was positively correlated with forced expiratory volume in the 1st s, peak expiratory flow, and tricuspid annular plane systolic excursion (r = 0.478, P < 0.001; r = 0.294, P = 0.047; and r = 0.314, P = 0.032, respectively) as well as negatively correlated with systolic pulmonary artery pressure (r = −0.328, P = 0.021). Conclusion: Our data indicate that pPTT might be a convenient method for early prediction of pulmonary dysfunction among COVID-19 survivors.
Keywords: Coronavirus disease 2019, pulmonary pulse transit time, severe acute respiratory syndrome coronavirus 2
Since the outbreak of coronavirus disease 2019 (COVID-19), there have been several studies reporting deleterious impacts of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) on multiple organs in the human body, not only in the acute infection period but also in the long-term sequelae.[1] According to the currently available data, one of the primary target sites of infection is the respiratory system.[2],[3],[4] The underlying mechanisms associated with the long-term sequelae of pulmonary dysfunction are residual epithelial and endothelial cell damage owing to an accelerated immune response to viral entry, direct viral toxicity, and impairment of the intra-alveolar diffusion triggered by activation of profibrotic pathways.[5],[6],[7],[8] Yet, investigations are still underway to better understand long-term pulmonary complications associated with COVID-19. Despite the proven prolonged implications of SARS-CoV-2 infection on pulmonary functions, there is still no consensus among health-care workers on how to monitor COVID-19 survivors. Therefore, novel surveillance parameters are mandatory in terms of predicting disease progression after the onset of symptoms and guiding the management of subsequent adverse events.
Recently, Wibmer et al. proposed a novel echocardiographic determinant for the functional evaluation of respiratory hemodynamics, “pulmonary pulse transit time” (pPTT), characterized as the time interval needed for the systolic pressure pulse wave to travel from the right heart to the left atrium.[9] According to their study, this novel echocardiographic method was strongly associated with increased pulse wave velocity as well as decreased pulmonary artery compliance.[9] In this study, we aimed to evaluate whether pPTT might be a favorable diagnostic tool for detecting the long-term sequelae of pulmonary dysfunction associated with COVID-19.
Materials and MethodsStudy design and participants
The records of the patients who were admitted to the outpatient clinics of cardiology for cardiovascular and respiratory complaints were investigated. To be included, those identified subjects had to be hospitalized for laboratory-confirmed COVID-19 at least 1 year ago and the present complaints could not be attributed to alternative diagnoses. Patients with a prior history of severe valvular disease, congestive heart failure, atrial fibrillation, malignancy, renal failure, pregnancy, and those with poor image quality were excluded from the study. All participants' medical records and clinical and demographic features were analyzed and underwent detailed 12-lead electrocardiography (ECG) and echocardiographic evaluation. Pulmonary function tests, including forced vital capacity (FVC), forced expiratory volume in the 1st s (FEV1), peak expiratory flow (PEF), and FEV1/FVC ratio, were also performed. After exclusion, a total of 102 COVID-19 survivors and 100 age- and sex-matched controls without a prior history of COVID-19 were included in the study. All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional committee and with the 1964 Helsinki Declaration. Informed consent was obtained from all participants following a protocol approved by the local institutional review board (approval number: 03/22, date: March 3, 2022).
Echocardiographic assessment
All subjects underwent comprehensive transthoracic echocardiographic examination using a GE Vingmed Vivid 5 echocardiography device (GE Vingmed Ultrasound, Horten, Norway) by an experienced cardiologist who was blinded to patient data. During the echocardiographic examination, parasternal long-axis, short-axis, and apical four-chamber and two-chamber images were obtained and analyzed using M-mode, 2D, continuous-wave Doppler, pulse wave Doppler, and tissue Doppler methods. In addition, tricuspid annular plane systolic excursion (TAPSE), the tissue Doppler of the free lateral wall S'measurement (Sm), estimated systolic pulmonary artery pressure (sPAP), right ventricular (RV) fractional area change (FAC), and pPTT were measured. TAPSE was acquired from an M-mode cursor through the tricuspid lateral annulus by calculating the quanta of longitudinal displacement of the annulus at peak systole. RV FAC was calculated as the ([end-diastolic RV area–end-systolic RV area]/end-diastolic RV area) × 100, and sPAP was calculated by adding the Doppler-determined trans-tricuspid gradient to the estimated right atrial pressure and its respirophasic variations. To obtain tissue Doppler imaging-derived Sm, apical four-chamber images were analyzed with a tissue Doppler mode demonstrating the lateral RV free wall. All the Doppler measurements were obtained at a sweep speed of 50–100 mm/s with a simultaneous ECG. pPTT was measured using the following equation which was previously described:[9] pPTT = the estimated length of time between the R-wave peak in ECG and the corresponding peak late-systolic pulmonary vein flow velocity (R-PVs2 interval) [Figure 1]. All measurements were performed according to the American Echocardiography Society criteria.[10]
Figure 1: The time interval between the two vertical red lines was described as the time interval between the R-wave in the electrocardiogram and the corresponding peak late systolic pulmonary vein flow velocityStatistical analysis
Statistical analysis was performed using SPSS software version 16.0 for Windows (IBM Corp., Armonk, USA). In this study, data are expressed as mean ± standard deviation (SD) for continuous variables and as counts and percentages for categorical variables. Kolmogorov–Smirnov test and Shapiro–Wilk test were used to assess the distribution of continuous variables. The Chi-square test and Fisher's exact test were used to evaluate categorical variables. The Student's t-test was used for continuous variables with normal distribution, and the values were demonstrated as mean ± SD. Comparison of intergroup continuous variables without normal distribution was evaluated using Mann–Whitney U-test. Relationships between continuous variables were calculated using Pearson's correlation coefficients, and Spearman's rank correlation coefficient was performed for noncontinuous and categorical variables. P < 0.05 was considered statistically significant.
ResultsOver the period from January 2021 to January 2022, 102 eligible COVID-19 survivors and 100 age- and sex-matched healthy participants were included in the study. The baseline demographic, clinical, and laboratory characteristics of both groups are shown in [Table 1]. Both groups had similar clinical characteristics. On the other hand, there was a significantly higher prevalence of dyslipidemia among COVID-19 survivors compared to healthy control subjects (38.2% vs. 28.0%, P < 0.05). In addition, COVID survivors had significantly higher levels of serum uric acid level and neutrophil counts than healthy control subjects (5.87 ± 1.68 mg/dl vs. 5.01 ± 1.22 mg/dl and 6.35 ± 1.39 103/mm3 vs. 5.54 ± 1.33 103/mm3, P < 0.05, respectively). Regarding pulmonary function tests, COVID-19 survivors had significantly lower levels of FVC, FEV1, and PEF compared to healthy control subjects (3.60 ± 0.57 vs. 5.83 ± 0.65 and 2.84 ± 0.42 vs. 4.78 ± 0.79 and 6.49 ± 1.67 vs. 9.89 ± 1.38, P < 0.05, respectively).
Table 1: The demographic, clinical, and laboratory characteristics of the study populationThe echocardiographic outcomes of both groups are shown in [Table 2]. LV systolic functions, calculated ventricular and atrial diameters, and septum thickness were comparable in both groups (P > 0.05). However, TAPSE, RV FAC, and pPTT measurements were significantly lower among COVID-19 survivors compared to healthy control subjects (20.8 ± 0.20 mm vs. 23.3 ± 0.26 mm, 38.95 ± 3.36% vs. 45.9 ± 5.20%, and 163.10 ± 27.2 ms vs. 191.7 ± 29.4 ms, P < 0.05, respectively). In addition, the estimated sPAP measurement was significantly higher amount COVID-19 survivors compared to healthy control subjects (21.7 ± 7.7 mm/Hg vs. 19.3 ± 3.4 mm/Hg, P < 0.05). According to our study, pPTT was positively correlated with FEV1, PEF, and TAPSE (r = 0.478, P < 0.001; r = 0.294, P = 0.047; and r = 0.314, P = 0.032, respectively) as well as negatively correlated with sPAP (r = −0.328, P = 0.021) [Table 3].
Table 3: Correlation analysis between pulmonary pulse transit time and variables Discussion In the present study, we investigated the association between the pPTT and the long-term sequelae of pulmonary dysfunction in COVID-19 survivors. Our results demonstrate that there is a significantly lower level of pPTT in COVID-19 survivors compared to healthy control subjects which indicate subclinical impairment of pulmonary functions.
Compared to other respiratory viruses, SARS-CoV-2 has a high mortality rate not only in the infection period of the disease but also in the long-term sequelae.[1] In addition, there is an increased risk of long-term morbidity associated with SARS-CoV-2 reinfection due to the lack of long-term immunity and the ability of the virus to rapidly change spike proteins.[11],[12] One of the well-known long-term complications associated with COVID-19 disease is gradual loss of pulmonary functions, known as “long COVID.”[13],[14] The underlying mechanisms that lead to long COVID are diffuse alveolar injury resulting from acute respiratory distress syndrome, diffuse thrombotic alveolar damage, and airway inflammation.[3],[4] The combined effect of these deleterious pathways may result in permanent lung injury, especially in the elderly and the vulnerable.[15] Similar results were also obtained from previous studies which investigate long-term complications of SARS-CoV-1 infection. According to those studies, nearly one-third of patients had permanent pulmonary damage following SARS-CoV-1 infection.[16],[17] The underlying mechanisms of chronic pulmonary dysfunction in SARS-CoV-1 survivors were also similar to those observed in SARS-CoV-2 survivors including respiratory tract inflammation, intra-alveolar thrombosis, and development of pulmonary fibrosis triggered by procoagulant signaling pathways.[18],[19],[20]
Due to the importance of the disease, several studies have been implemented to assess the clinical, laboratory, and radiological course of COVID-19 throughout hospital admission and follow-up visits. Yet, there are insufficient data in terms of describing how to find those at risk of developing long-term complications and how that monitorization methods guide the management of long-term complications associated with COVID-19.
Recent reports proposed a novel, simplified determinant for the noninvasive evaluation of pulmonary functions known as the “pPTT.” According to these studies, this novel index not only identified the severity of pulmonary fibrosis but also acts as a potential index of pulmonary dysfunction.[9] In another study, Mueller-Graf et al. investigated the relationship between the pPTT and the estimated pulmonary artery pressure in the porcine model of pulmonary arterial hypertension and found a negative correlation between pPTT and calculated sPAP.[21] The outcomes of our study were comparable with their reports and demonstrated the strong association between pPTT and impaired pulmonary functions. According to our study, estimated TAPSE, RV FAC, and pPTT measurements were significantly lower among COVID-19 survivors compared to healthy control subjects (P < 0.05, respectively). In addition, the estimated sPAP measurement was significantly higher among COVID-19 survivors compared to healthy control subjects (P < 0.05). We also observed a significant relationship between estimated pPTT values and impaired pulmonary function tests including FEV1 and PEF (r = 0.478, P < 0.001, and r = 0.294, P = 0.047, respectively). These results were comparable to the results of previous reports, which turned out to be approximately 25% of COVID-19 survivors experienced varying degrees of worsening in pulmonary ventilation functions.[22]
ConclusionOur data indicate that there is an increased risk of pulmonary dysfunction in association with impaired RV functions in COVID-19 survivors. Due to the inverse relationship between the long-term sequelae of pulmonary dysfunction and survival in COVID-19 survivors, early detection and prompt intervention are crucial. In this context, the pPTT might be a convenient method for early prediction of pulmonary dysfunction in COVID-19 survivors.
Limitations
In this study, we evaluated pulmonary functions with conventional echocardiographic methods, but there are more sensitive echocardiographic parameters for early detection of RV and pulmonary dysfunction such as myocardial strain and the use of three-dimensional echocardiography. Yet, our major aim was to evaluate the long-term sequelae of pulmonary dysfunction of SARS-CoV-2 infection using pPTT. Although it is the first large-scale study investigating the association between the pPTT and COVID-19 disease, it has a limited number of participants. Finally, the measurement of the pPTT was limited by qualitative and quantitative analysis of pulmonary vein flow velocities.
Acknowledgment
The authors declare that no funds, grants, or other support were received during the preparation of this manuscript.
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
References
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