Value of Echocardiography Combined with Lung Ultrasound in The Diagnosis and Treatment of Coronavirus Disease 2019 (COVID-19) Pneumonia

Purpose: To investigate relationships between echocardiography results and lung ultrasound score (LUS) in COVID-19 pneumonia patients, and the value of their combined application for evaluating COVID-19 pneumonia in diagnosis and treatment. Methods: Hospitalized patients underwent lung ultrasound and echocardiography daily. Patients with tricuspid regurgitation within 3 days after admission were collected, and the correlations and differences between pulmonary artery pressures and LUS on days 3, 8, and 13 were compared. The inner diameter of the pulmonary artery root and the sizes of the atria and ventricles were observed. Results: Pulmonary artery pressure within 3 days was positively correlated with LUS (r = 0.448, p = 0.003; r = 0.738, p = 0.000; r = 0.325, p = 0.036). On day 8 the values of both were higher than the corresponding values on days 3 and 13 (p < 0.01). On day 8 the positive rate for increased pulmonary artery pressure was 92.9%(39/42), the positive rate for increased LUS was 90.5%(38/42), and the combined positive rate for the two was 97.6%(41/42). On day 8 the inner diameters of the right atrium, right ventricle, and pulmonary artery differed signicantly from the corresponding values on days 3 and 13 (p < 0.05). Conclusions: Pulmonary arterial pressure is positively correlated with LUS. The two should be combined for more informative assessment of the status of recovery from COVID-19 pneumonia.


Introduction
On February 11, 2020, the disease caused by the severe acute respiratory syndrome coronavirus 2 which broke out in Wuhan, Hubei, China, was named coronavirus disease (COVID-19) by the World Health Organization (WHO) [1] With the rapid worldwide spread of COVID-19 [2,3] , real-time reverse transcriptase polymerase chain reaction (RT-PCR) and high-resolution chest CT have been increasingly unable to meet the demands of diagnosis. Many countries and regions have gradually adopted ultrasonography as a basic examination method [4][5][6] , especially Italy [7] . Improvements in the diagnostic value of ultrasound for COVID-19 pneumonia are required. To date there have been no reports describing the combined evaluation of changes in pulmonary arterial pressure and LUS when assessing the progression of COVID-19 pneumonia. The aim of the present study was to provide useful information in this regard for the diagnosis and treatment of COVID-19 pneumonia.

Study design
This work was supported by the ministry of science and technology of the people's republic of china (grant number 2020YFC0844900). The study was approved by the Ethics Committee of Beijing You An Hospital a liated to the Capital Medical University ([2020]020). The consents were signed by all patients.
In the current study 42 hospitalized COVID-19 pneumonia patients (the diagnosis was con rmed by RT-PCR and CT) underwent dynamic echocardiographic and lung ultrasound observation. The combined use of the two modalities for evaluating lung lesions was assessed, and correlations between the two were calculated. All patients underwent dynamic lung ultrasound and echocardiographic observation upon admission to the hospital. The proportion with tricuspid valve regurgitation was increased by day 3 after admission, therefore we selected patients in whom tricuspid regurgitation was evident within 3 days as study subjects, and thereafter LUS and echocardiographic examinations were conducted daily. The mean hospital stay length was 15 days, Literature studies and our own previous research suggest that the length of time between the appearance of symptoms and the most severe stage of disease is approximately 10 days [8,9] , and that the length of time between the appearance of symptoms and hospitalization is approximately 2 days. Accordingly, days 3, 8, and 13 were selected for comparisons of LUS, pulmonary arterial pressures, and atrial and ventricular diameters. General symptoms including fever, cough, dyspnea, and history of underlying heart and lung disease were recorded.

Lung Ultrasound
Rouby [10] proposed to divide a unilateral lung into six zones for examination. With the anterior and posterior axillary lines as the boundaries, the lung was divided into three zones, namely anterior, lateral, and posterior (Fig. 1). Each zone was further divided into upper and lower parts. The worst sign of each zone in the examination was considered as the nal judgment sign of the zone, and the results were recorded as the following four basic types (Fig. 2): type N: the ultrasonographic features were A line sign or ≤ 2 independent B lines, indicating good lung in ation; type B1: the ultrasonographic features were multiple B lines, with an interval of about 7 mm between the B lines (B7 lines); type B2: the ultrasonographic features were multiple B lines, and the interval between B lines was ≤ 3 mm, (B3 lines); and type C: the ultrasonographic features were hepatization or fragment sign of the lung tissue, with dynamic bronchial in ation sign, with or without a small amount of pleural effusion, indicating consolidation of the lung. The scoring of lung ultrasonography was based on the above four types as: N = 0, B1 = 1, B2 = 2, and C = 3. All patients underwent lung ultrasonographic examination, and the sum of scores of the 12 zones was recorded. All lung ultrasound images were performed by two experienced sonologists.

Echocardiography
All patients underwent echocardiographic examination daily. Routine parasternal, apical, and other cardiac section scans were performed. Spectral Doppler was used to record the peak velocity of tricuspid regurgitation. The transvalvular pressure difference was calculated. Right atrial pressure plus the transvalvular pressure difference was calculated as the right ventricular pressure. The right ventricular pressure is approximately equal to the pulmonary artery systolic pressure [11] . When the right atrium was mildly, moderately, or severely enlarged, the respective pressures therein were 5 mm Hg, 10 mm Hg, and 15 mm Hg, where 1 mm Hg = 0.133 kPa [12] .

Statistical analysis
Page 4/13 SPSS 26.0 statistical software was used for data analysis. Continuous data were expressed as means ± the standard deviation. Non-parametric tests were used to assess data that were not normally distributed. The Mann-Whitney U test was used for comparisons of two independent samples. The Kruskal-Wallis test was used for testing multiple independent samples. Pearson's correlational analysis was used to assess correlations between LUS and pulmonary artery pressures. p < 0.05 was deemed to indicate statistical signi cance.

Results
Forty-two patients were included in the cohort, 24 were males and 18 were females, with an average age of 47.8 ± 10.8 years. All patients had no history of heart disease or chronic respiratory disease. Their general characteristics, clinical features, and related medical history are shown in Table 1. differed signi cantly as the disease progressed. The two parameters were positively correlated within 3 days, and the correlation was higher in patients with more severe disease(r = 0.448, p = 0.003; r = 0.738, p = 0.000; r = 0.325,p = 0.036), Fig. 1(a,b,c).
LUS directly re ected the degree of lung disease, whereas pulmonary arterial pressure was an indirect indicator of lung disease. Increased pulmonary arterial pressure can directly cause dilation of the pulmonary artery trunk with corresponding enlargement of the right ventricle and right atrium, and lead to exacerbation of tricuspid regurgitation. One such patient is shown in Fig. 2 (a,b,c), which illustrates the relationships between pulmonary artery changes and tricuspid regurgitation on days 3, 8, and 13. There were signi cant differences in the LUS of the 42 COVID-19 pneumonia patients within 3 days. Differences in the inner diameters of the atria, ventricles, and pulmonary artery are shown in Tables 2 and 3. The 42 patients exhibited overall increases in both pulmonary arterial pressure and LUS on day 8, but at that timepoint there were 4 patients without signi cant increases in pulmonary arterial pressure and 3 without signi cant increases in LUS. Comparisons of computed tomography (CT) ndings on day 8 revealed increased severity compared to day 3 in 6 patients, suggesting that these 6 patients were false negatives. Only one(1/7) patient there was no substantial difference between CT ndings acquired on day 3 and those acquired on day 8, indicating a negative result in the case. There were 41 42 cases in which the two in combination were positive (Table 4).

Discussion
In the present study LUS was positively correlated with pulmonary arterial pressure, and the correlation was stronger with increased disease severity. There are many reasons for increased pulmonary arterial pressure [12][13][14] . Patients with a history of underlying cardiopulmonary disease were excluded from the present study, and the observed changes in pulmonary arterial pressure were believed to be related to lung disease. During lung in ammation, in ammatory in ltration and alveolar exudate reduce the alveolar surface area available for diffusion, and diffusion time is prolonged. Hypoxic acidosis can cause swelling of pulmonary endothelial cells and pulmonary vasospasm, leading to pulmonary hypertension [12,15] .
The COVID-19 pneumonia outbreak and the 2003 severe acute respiratory syndrome outbreak were both caused by members of the coronavirus family. Angiotensin-converting enzyme-2 is a component of the renin-angiotensin system that protects blood vessels, and it is thought to be a functional receptor for coronaviruses on epithelial cells [16][17][18] . Another component of the renin-angiotensin system is angiotensin II, which causes alveolar epithelium in ammation and damage. The lung injury associated with coronavirus disease 2019 may be due to upregulation of angiotensin II and reduced angiotensinconverting enzyme-2 levels resulting in increased pulmonary vasoconstriction. The results of the present study suggest that these factors are associated with higher LUS and higher pulmonary arterial pressure.
Many studies [12][13][14] have investigated pulmonary arterial hypertension caused by pneumonia, but there are no reports of the use of pulmonary arterial pressure to predict LUS. In the present study LUS were dynamically evaluated, and echocardiography was performed simultaneously. LUS increased with worsening condition, and decreased with improving condition. Echocardiography indicated that the amount of tricuspid regurgitation increased with worsening condition, and pulmonary arterial pressure and the inner diameters of the pulmonary artery, right ventricle, and right atrium also increased. All of these parameters exhibited statistically signi cant changes, and all of them decreased with improving condition (Tables 2 and 3). These results suggest that changes in LUS and pulmonary arterial pressure can re ect lung lesions.
Hemodynamic characteristics indicate that increased pulmonary arterial pressure leads to increased right ventricular ejection resistance, which results in increased inner diameter of the right atrium, right ventricle, and pulmonary artery. Dynamic echocardiography can be used to monitor changes in pulmonary arterial pressure and the size of each chamber of the heart in real time, such that disease development can be assessed in a timely manner. The positive correlation between pulmonary arterial pressure and LUS in the current study also indicates a tendency in LUS. There were no signi cant changes in left heart size during the entire course of disease, indicating a low probability of left heart involvement, which is consistent with previous studies.
In the present study the rate of positivity for increased pulmonary arterial pressure in the 42 patients on day 8 was 92.9%. 3(3/42) patient was stable, which may be related to compensation by pulmonary blood vessels [12,15] . The rate of positivity for LUS on day 8 was 90.5%, and the scores of 4 patients did not increase with worsening condition. In conjunction with CT ndings this suggests that the region of lesion exacerbation did not involve the edge of the lung, which is outside the detection range of ultrasound and is consistent with the principles of lung ultrasound. The positivity rate for the combination of the two was 97.6%, which constitutes an improvement in the accuracy of disease progression evaluation. To date there have been no comparable previous reports.
The current study had some limitations. Some patients could not undergo oxygen therapy due to dyspnea. Compared with patients who did not undergo oxygen therapy, the estimation of pulmonary arterial pressure may be biased. Because the frequency of CT examination was not as high as that of ultrasound, not all patients have corresponding CT data at the three study timepoints utilized, and there is a lack of a basis for comparison. Fortunately, corresponding CT data were available for 7 negative patients, which provided a strong basis for diagnosis.

Conclusions
In conclusion, in COVID-19 pneumonia patients pulmonary arterial pressure and LUS positively correlated. The combination of the two can improve the rate of diagnosis of lung disease progression, and has an important guiding role with respect to monitoring disease progression, as making treatment decisions. Availability of data and materials: We con rm the data and material availability in our manuscript.
Competing interests: Not applicable.