Publication date: Available online 21 September 2020
Source: Ultrasound in Medicine & Biology
Author(s): David Bennett, Elda De Vita, Fabrizio Mezzasalma, Nicola Lanzarone, Paolo Cameli, Francesco Bianchi, Felice Perillo, Elena Bargagli, Maria Antonietta Mazzei, Luca Volterrani, Sabino Scolletta, Serafina Valente, Federico Franchi, Bruno Frediani, Piersante Sestini
Received 16 June 2020, Revised 14 August 2020, Accepted 7 September 2020, Available online 21 September 2020.
Key words
lung ultrasound
handheld
COVID-19
SARS-CoV-2
imaging
pneumonia
acute respiratory failure
Introduction
Coronavirus disease 2019 (COVID-19), caused by infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), emerged in China in December 2019 and quickly spread all over the globe. The clinical features are fever, dyspnoea, dry cough, fatigue and diarrhoea (Wan et. 2020). Pharyngodynia, nasal congestion, rhinorrhoea and anosmia have also been reported (Chen et al. 2020, Hopkins et al. 2020, Mason 2020, Gattinoni et al. 2020). Interstitial pneumonia is very common and a high percentage of patients (9-11%) develop severe acute respiratory distress syndrome (ARDS) and require intensive care (Lovato and de Filippis 2020, Remuzzi and Remuzzi 2020, Yuan et al. 2020). Current therapeutic strategy involves agents counteracting viral invasion and replication, and inhibitors of cytokine-sustained inflammatory reactions. No specific antiviral therapy has yet been identified (Capecchi et al. 2020, Conticini et al. 2020).
Ultrasound imaging of the lung (LUS) is a promising technique in many acute and chronic parenchymal conditions that determine interstitial syndrome. These include cardiogenic and non-cardiogenic pulmonary oedema, ARDS, interstitial pulmonary fibrosis and a variety of conditions determining lung consolidations, such as pneumonia and lung cancer (Mojoli et al. 2019). In COVID-19 patients, it demonstrated clinical utility due to the typical sonographic characteristics of affected lungs by providing indications for clinical decisions and the management of associated respiratory failure and lung injury (Smith et al. 2020).
The aim of the present study was to evaluate the possibilities of a portable pocket-sized ultrasound scanner in the evaluation of lung involvement in patients with COVID-19 pneumonia.
Materilas and Methods
We conducted 34 LUS evaluations on patients admitted to the COVID Unit of Siena University Hospital with symptoms compatible with COVID-19, a positive SARS-CoV-2 nasal-pharyngeal swab and radiological evidence of interstitial pneumonia.
The patients were divided into three severity categories based on respiratory impairment: Mild PaO2/FiO2 > 300 in room air or oxygen flow; Moderate PaO2/FiO2 between 150 and 300 in room air or oxygen-therapy, CPAP, NIV or HFNC; Severe PaO2/FiO2 < 150 on oxygen-therapy, CPAP, NIV, HFNC or mechanical ventilation.
The lung ultrasound scans were performed on the same day with a high-end point-of-care ultrasound scanner (Venue GO™, GE Healthcare, Chicago, IL, USA) and a pocket-sized ultrasound scanner (Butterfly iQ, Butterfly Network Inc., Guilford, CT, USA) for clinical purposes; lung preset was used with both scanners. The portable pocket-sized ultrasound scanner we tested has a single silicon chip containing a 2D array of 9000 capacitive micromachined ultrasound transducers instead of the standard piezoelectric crystal-based transducers. The chip emulates curved, linear, or phased transducers at any time in M-mode, B-mode or colour Doppler with a 2–30 cm scan depth (Liu et al. 2019).
Up to six regions of the chest were identified: anterosuperior (A); anteroinferior (B); lateralsuperior (C); lateralinferior (D); posterosuperior (E); posteroinferior (F). One of four different aeration patterns was recorded according to a specific scoring system: A = 0 points (normal aeration, presence of lung sliding with A lines or less than two isolated B lines), B1 = 1 point (moderate loss of lung aeration, multiple well-defined B lines), B2 = 2 points (severe loss of lung aeration, multiple coalescent B lines), C = 3 points (lung consolidation and tissue-like pattern). Pleural effusion and pneumothorax were also recorded. A score of 0 was normal and 36 was the worst. Due to clinical conditions, the upper posterior region (E) could not explored in some patients, so the mean of the regions explored was calculated for the purposes of statistical analysis (total sum (0 to 36) divided by number of regions explored (5 or 6 on each side). Our step‐by‐step approach to LUS in COVID-19 patients was comparable to the CLUE protocol (Manivel V). Imaging were obtained by two different operators, both experts in lung ultrasound. The research was approved by the local ethics committee (OSS_REOS n° 12908) and informed consent was obtained from each participant.
Statistical analysis
Student's t-test was used to compare pairs of groups and ANOVA to compare three or more groups, followed by Holm-Sidak's multiple comparisons test, when the former were significant. Normal distribution of data was checked using D'Agostino-Pearson test (command sktest of Stata). The presence and possible sources of systematic bias between the two instruments was investigated in the complete dataset of the individual readings at 12 thoracic location in each patient. We used multilevel mixed-effects linear regression models with the difference in score on the same thoracic location (Butterfly-GE) as the outcome variable, changes in vertical level of the thoracic location (high vs. low), side (right vs. left), horizontal level (anterior, lateral, posterior) and severity as fixed effect variables, and the patient as a random effect variable.
The primary outcome of the study was the assessment of the bias and of Limits of Agreement (LoA) between the total patient score obtained with the two instruments, computed with the Bland Altman method (Balnd and Altman 1986). A secondary outcome was the assessment of the concordance between the two instruments. As no single measure of concordance is generally accepted (Bunting et al. 2019), we computed five different parameters: Pearson's correlation coefficient (PCC), Intraclass Correlation coefficient (ICC), Lin's Concordance Correlation Coefficient (CCC), Liao's Improved Concordance Correlation Coefficient (ICCC), and Cohen's Kappa measure of agreement (Liao 2015). Power size calculation. We calculated that 34 patients would be required for the comparison of the two methods using the Bland-Altman method (Lu et al. 2016), assuming a mean difference in total score of 1±1, a false positive rate (α) of 0.05 and a false negative rate of 0.1 (β=0.9). The analyses were performed with Stata for Windows V 16 (Stata corp, Texas College, TX) except for ICCC (package AgreementInterval of R) and power size estimation (Medcalc 19.3.1, MedCalc Software Ltd, Ostenda, B). A level of p ≤ 0.05 for a two tail distribution was considered statistically significant.
Results
The 34 paired LUS scans on 18 COVID-19 patients (14 male and 4 female; age at presentation 77.6 ± 10.0 years) produced the following results. No difference in age was found between severity groups; 16/34 scans were performed on severe, 11 on moderate and 7 on mild patients. No difference in days since onset of symptoms was observed between groups (23.29 ± 10.07, 22.91 ± 8.91, 28.56 ± 11.13 days, respectively, p=0.38).
When assessed on the full dataset of 437 paired readings in 34 LUS, no significant differences were found between LUS scores obtained with the high-end and the portable pocket-sized ultrasound, with a mean difference in score of -0.018± 0.018 points (NS). The score difference did not change significantly according to lung side (0.027 ±0.032 points), vertical level (-0.041±0.033 points), clinical severity (0.013.±0.022 points per each level). A significant difference, however, was found between the two instruments according the horizontal location of the site, with the difference between the two instruments resulting slightly but significantly greater on the posterior compared to the anterior side of the thorax (0.082 ±0.021 points, p <0.01).
Total average scores obtained with the two instruments were normally distributed, as was their difference. Average patient scores correlated with clinical severity (p<0.001, Figure 1)
Figure 1. Correlation of mean scores obtained with the two instruments, according to disease severity.
All the computed parameters showed an excellent degree of concordance between the two instruments (Table 1). The Bland-Altman plot is shown in figure 2, The absolute level of bias computed with the Bland-Altman method was -0.016 (95% CI: -0.054, 0.021), the lower LoA -0.227 (-0.291, -.0162) and the upper 0.194 (0.129, 0.259), much smaller than the minimum possible change of 1 point. Figure 3 reports images sample of different grade of severity of lung impairment obtained with the handheld scanner.
Table 1. Correlation coefficients between total average scores.
| Parameter | Coefficient (95% CI) |
|---|---|
| Pearson's Correlation Coefficient | 0.990 (0.980, 0.995) |
| Intraclass Correlation Coefficient | 0.989 (0.980, 0.994) |
| Concordance Correlation Coefficient | 0.989 (0.978, 0.994) |
| Improved Concordance Correlation C | 0.988 (0.927, 0.998) |
Figure 2. Bland-Altman plot showing the level of bias (solid line) and Limits of Agreement.
Figure 3. Images sample of different grade of severity of lung impairment obtained with the handheld ultrasound scanner. A: normal aeration, presence of A lines or less than two isolated B lines; B: moderate loss of lung aeration, multiple well-defined B lines; C: severe loss of lung aeration, multiple coalescent B lines; D: lung consolidation and tissue-like pattern.
Discussion
Lung ultrasound imaging is a non-invasive technique that provides useful indications for clinical decisions concerning COVID-19 patients (Smith et al. 2020, Wang et al. 2017). It is safe, repeatable, radiation-free and economical and can be used at the point of care. Here we evaluated the possibilities of a portable pocket-sized ultrasound scanner in COVID-19 patients with pneumonia.
We included a cohort of COVID-19 patients who were hospitalized with respiratory failure of different severity. All were scanned with a standard high-end ultrasound scanner and a portable pocket-sized ultrasound scanner.
The results of the portable scanner were practically identical to those of the high-end scanner in the assessment of lung interstitial syndrome according the BLUE protocol (Lichtenstein 2015): Bland-Altman bias was found to be close to zero, with very narrow Limits of Agreement and all the other parameters of concordance were in the range of substantial or excellent agreement. Furthermore, no systematic bias was observed according to disease severity or anatomical site of analysis, except for a statistically significant but practically negligible difference in the posterior side of the thorax, possibly a spurious finding.
Due to its easy handling and dynamic nature, LUS is increasingly used in clinical settings, especially in critical care (Mojoli et al. 2019). In SARS-CoV-2 infection, it is invaluable in clinical management, showing higher accuracy than chest radiography (Smith et al. 2019) and good correlation with CT imaging and pneumonia severity (Nouvenne et al. 2020, Zieleskiewicz et al. 2020). In experimental models of ARDS, it was found to detect lung lesions before the onset of hypoxemia (Soldati et al. 2020). Point-of-care ultrasound has great possibilities in many branches of medicine, especially emergency and critical care where it can be invaluable in the safe management of COVID-19, since it allows concomitant clinical examination and lung imaging at the bedside by the same doctor (Smith et al. 2019, Buonsenso et al. 2020). An observational study, named CORonavirus (COVID-19) Diagnostic Lung UltraSound Study (COR-DLUS) (ClinicalTrials.gov Identifier: NCT04351802), is currently ongoing. The study is designed to assess whether focused lung ultrasound examination can improve the diagnosis of COVID-19 lung disease and/or make an alternative diagnosis at a patient's initial hospital presentation.
In our study we also found a statistically significant correlation between portable scanner findings and disease severity, confirming previous reports of 68.8%, 77.8%, 100.0% sensitivity, 85.7%, 76.2%, 92.9% specificity and 76.7%, 76.7%, 93.3% diagnostic accuracy in detecting mild, moderate and severe lung lesions, respectively (Lu et al. 2020).
The main limit of our study were its retrospective nature, preventing the analysis of the effect of the order of measurements with the two instruments and the effect of different observers (both can be considered to have been random, but there was no systematic protocol), and the limited number of patients undergoing imaging, however a considerable number of lung scans were analysed and clearly demonstrated, for the first time, that the performances of the portable and high-end scanners were interchangeable. The use of portable ultrasound devices has increased in recent years, creating a flourishing market. A big advantage of portable devices is time saving at the bedside and in prehospital situations; limits are battery runtime, narrow field of vision, and low penetration (Stock et al. 2020, ESR 2019). In COVID-19 patients, these devices could be of help for triage purpose as well by providing instant and objective information of the severity of the disease and may avoid further imaging in mild patients, however findings are not specific and may not correlate to clinical outcome and qualified operators are necessary; combination with clinical and physiological data is strongly recommended. Their utility has been argued by several authors (Gibson et al. 2020, Qian et al. 2020), but this is the first study providing a demonstration of their use in daily clinical practice in COVID-19 patients.
In conclusion, our study confirms the possibilities of portable ultrasound imaging of the lung in COVID-19 patients. Portable pocket-sized ultrasound scanners are cheap, easy to handle and equivalent to standard scanners for non-invasive assessment of severity and dynamic observation of lung lesions in COVID-19 patients with pneumonia. These ultrasound scanners can play a decisive role when healthcare resources are scarce, during pandemics and in emergency situations, such as the present COVID-19 outbreak.
Funding
The present study did not receive any funding.
Disclosure Statement
Authors have no conflicts of interest to disclose.
Uncited References:
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