Understanding of Patients with Severe COVID-19 Using Lung Ultrasound
Article information
Abstract
Background
Lung ultrasound (LUS) has proven valuable in the initial assessment of coronavirus disease 2019 (COVID-19), but its role in detecting pulmonary fibrosis following intensive care remains unclear. This study aims to assess the presence of pulmonary sequelae and fibrosis-like changes using LUS in survivors of severe COVID-19 pneumonia one month after discharge.
Methods
We prospectively enrolled patients with severe COVID-19 who required mechanical ventilation in the intensive care unit (ICU) and conducted LUS assessments from admission to the outpatient visit after discharge. We tracked changes in key LUS findings and applied our proprietary LUS scoring system. To evaluate LUS accuracy, we correlated measured LUS values with computed tomography scores.
Results
We evaluated B-line presence, pleural thickness, and consolidation in 14 eligible patients. The LUS scores exhibited minimal changes, with values of 19.1, 19.2, and 17.5 at admission, discharge, and the outpatient visit, respectively. Notably, the number of B-lines decreased significantly, from 1.92 at admission to 0.56 at the outpatient visit (p<0.05), while pleural thickness increased significantly, from 2.05 at admission to 2.48 at the outpatient visit (p≤0.05).
Conclusion
This study demonstrates that LUS can track changes in lung abnormalities in severe COVID-19 patients from ICU admission through to outpatient follow-up. While pleural thickening and B-line patterns showed significant changes, no correlation was found between LUS and high-resolution computed tomography fibrosis scores. These findings suggest that LUS may serve as a supplementary tool for assessing pulmonary recovery in severe COVID-19 cases.
Introduction
The coronavirus disease 2019 (COVID-19) pandemic has imposed a significant global health burden, with a substantial subset of affected individuals requiring intensive care unit (ICU) treatment, estimated at up to 16% of cases [1]. Emerging data from the pandemic have raised concerns about the potential long-term consequences of COVID-19 pneumonia, particularly in relation to pulmonary fibrosis. While many COVID-19 survivors experience gradual recovery over time, a significant proportion may face the daunting prospect of irreversible pulmonary fibrosis, a condition more commonly observed in elderly patients or those necessitating mechanical ventilation [2]. Pulmonary fibrosis following severe pneumonia, such as that induced by COVID-19, presents a formidable clinical challenge, as there is currently no definitive treatment available [3]. Effective management strategies for post-COVID-19 pulmonary complications remain a subject of intense research and clinical interest.
To address this challenge, it becomes imperative to establish proper and periodic evaluations of lung lesions during the convalescent phase of severe COVID-19. Chest computed tomography (CT) has traditionally served as the ‘gold standard’ for diagnosing pulmonary fibrosis. However, its utility as a continuous follow-up tool is limited due to the associated costs, radiation exposure concerns, and challenges associated with assessing lung lesions using conventional X-ray images [4].
A promising alternative to address these limitations is lung ultrasound (LUS), a non-invasive imaging technique that offers distinct advantages in monitoring post-COVID-19 pulmonary complications [5]. Given that COVID-19 pneumonia typically initiates in the distal alveoli, leading to lesions in close proximity to the pleura, LUS provides a high-resolution imaging modality ideally suited for visualizing these lesions with precision and without the concerns associated with radiation exposure.
In prior studies, B-lines and pleural line thickness have been recognized as reliable indicators of lung deaeration in patients with interstitial lung disease [6]. Building upon these insights, our study seeks to comprehensively track the trajectory of LUS findings in patients with severe COVID-19, spanning from their initial admission to the ICU to subsequent outpatient visits.
We aim to investigate significant changes in LUS findings over this critical period. Notably, this study marks a significant advancement, being the first to prospectively evaluate and longitudinally follow severe COVID-19 survivors using LUS, transitioning seamlessly from inpatient to outpatient settings. Such an approach holds the potential to offer valuable insights into the dynamic course of post-COVID-19 pulmonary sequelae, laying the foundation for more effective clinical management and treatment strategies.
Materials and Methods
1. Patient group and study design
This prospective study was conducted by enrolling adult patients who needed mechanical ventilation and were admitted in the ICU due to COVID-19 for 6 months from July 1 to December 31, 2021. Among patients with radiologically confirmed pneumonia, those classified as ‘Severe’ or ‘Critical’ according to the World Health Organization clinical classification were included. Thirteen patients were recruited from a tertiary university hospital and two patients from a national public hospital. This study was approved by the ethical committee of the Seoul National University Bundang Hospital (approval number: B-2107-694-302; NMC-2021-06-083) and conducted in accordance with the amended Declaration of Helsinki. Written informed consent was obtained from all patients or their families. This research was supported by the Research of the Korea Centers for Disease Control and Prevention (grant number: 2021ER190400).
2. LUS examination
Ultrasound examinations were performed at three key time points to monitor the progression of the patient’s lung changes. It was performed immediately after intubation in the ICU (within 48 hours), at the time of transfer from the ICU to a general ward after tracheal extubation, and on an outpatient visit day 1 month after discharge. ICU discharge, which also marked the transfer to the general ward, was determined by the patient’s ability to transition to a nasal prong following tracheal extubation, with an oxygen requirement of less than 6 L and SpO2 of 92% or more. Hospital discharge criteria included either no oxygen requirement or an oxygen requirement of less than 3 L that could be managed with home oxygen therapy. An outpatient visit was scheduled 30 days post-discharge for follow-up blood tests, imaging tests, and to assess the patient’s overall condition. Bedside LUS was performed by three sonographers with 2–10 years of experience in ultrasound. The machine used in the isolation ICU was a GE VENUE GO iq ultrasound (GE Healthcare, Seoul, Korea) equipped with a convex C1-5-RS probe, with a frequency of 3.5 MHz, a depth of 10 cm [7]. According to international evidence-based recommendations for point-of-care LUS in the emergency setting [8], a complete eight-zone LUS examination was performed with the patients in the supine position. The machine used for outpatient treatment after discharge was a dual-probe V-scan iq ultrasound (GE Healthcare), equipped with a linear probe, with a frequency range of 3.4 to 8 MHz and a depth of 8 cm to minimize inconsistencies in imaging views. The patient underwent LUS in 12 zones, including posterior imaging, while in a sitting or supine position (Figure 1). The captured images and videos were recorded and stored in the picture archiving and communication system (PACS) for subsequent offline analysis. Pleural thickness and the number of B-lines were recorded as actual numerical values in millimeters, which were considered for additional analysis to provide a comprehensive assessment of lung pathology.
Thoracic areas for lung ultrasound examination protocol. PSL: parasternal line; AAL: anterior axillary line; PAL: posterior axillary line.
3. LUS scores
In 12 pulmonary zones, typical lung findings were observed, and the number of B-lines, degree of pleural thickening, and presence or absence of consolidation that could suggest lung fibrosis were checked. The LUS scoring system used in our study was developed by our team to assess pulmonary fibrosis in postCOVID-19 acute respiratory distress syndrome (ARDS) patients. It combines key ultrasound indicators—pleural thickening, B-lines, and consolidation—based on existing literature [9-11]. The final score was obtained using the LUS scoring system. The maximum B-line was set at 2 points, the degree of pleural thickening at 2 points, and, when present, consolidation at 1 point. When 12 pulmonary zones were applied, 30 points on each left and right side were calculated as the maximum score (Figure 1, Supplementary Table S1, Supplementary Figure S1).
4. Analysis of high-resolution computed tomography findings
Due to logistical constraints, high-resolution computed tomography (HRCT) could not be performed at ICU admission or during quarantine. Instead, HRCT examinations were scheduled during routine outpatient visits, typically 1 month after discharge. These scans were conducted either the day before or on the same day as the outpatient visit, with the LUS examination performed immediately after the face-to-face consultation. Using the lung fibrosis texture-based automatic quantification analysis technique, we measured the extent of reticulation, honeycombing, consolidation, and ground-glass opacity on HRCT. This approach involves whole-lung segmentation and texture quantification to evaluate the presence of fibrotic and inflammatory features. Typically, fibrosis in interstitial lung disease includes reticular structures, honeycombing, sclerosis, and ground-glass opacities. The term ‘mixed disease pattern’ refers to the coexistence of multiple abnormalities, such as consolidation and ground-glass opacities, in the same patient, indicating overlapping inflammatory and fibrotic processes. In this study, fibrotic changes after severe COVID-19 pneumonia were not accompanied by honeycombing or reticulation. Therefore, we defined the HRCT fibrosis score as the sum of consolidation and ground-glass opacity, reflecting this mixed disease pattern [12-14]. The HRCT fibrosis score used in this study is calculated as the sum of ground-glass opacity and consolidation, measured using quantitative CT imaging. This scoring method is designed to assess the extent of post-COVID-19 fibrotic changes in the lungs. A higher fibrosis score reflects a greater degree of lung abnormalities, indicating more extensive fibrotic sequelae. All HRCT images were interpreted and scored by radiologists who were blinded to the clinical data, ensuring an objective and unbiased evaluation of the fibrosis extent.
5. Statistical analysis
Dichotomous variables are expressed as frequency (%) and continuous variables are expressed as median (interquartile range [IQR]). The relationship between the LUS and CT scores was studied using Pearson correlations. Statistical significance was set at p<0.05. A linear mixed model was used to analyze the trends in the average LUS score, B-line number, and pleural thickness over time. Ultrasound was performed in eight areas during the initial stage and in 12 areas at the time of leaving the ICU and at the time of discharge. However, to maintain consistency, the analysis was conducted using data from the eight areas that were consistently examined across all time points. This approach ensured a valid comparison of trends over time.
Results
1. Dermographic and medical history of the study group
Clinical data were collected from 15 consecutive patients hospitalized for COVID-19 infection during the study period. Three patients were excluded due to refusal and two due to a ‘do not resuscitate’ status. The study group included 12 COVID-19 patients who underwent LUS evaluation (Figure 2). Table 1 shows the baseline characteristics and treatments administered to all study participants. The average patient age was 53±10 years, and 57% were men. The most common comorbidity was hypertension, followed by diabetes and heart disease. None of them had an underlying pulmonary disease, and the majority were non-smokers. The average PaO2/FiO2 ratio was 79.13, indicating relatively severe respiratory failure, and the average duration of mechanical ventilation was 8.5 days.
Flowchart of patient selection process. COVID-19: coronavirus disease 2019; ICU: intensive care unit.
Baseline demographics and treatments for enrolled patients (n=14)
2. Ultrasound measurements in 12 lung zones
The LUS score was calculated by assigning points to the degree of B-lines and pleural thickness, along with the presence of consolidation. Due to the conflicting trends observed between B-lines and pleural thickness, the combined score for these parameters did not show significant variation. The sum of LUS scores across the eight examined zones was 19.1 (IQR, 13.0 to 26.5) at admission, 19.2 (IQR, 16.5 to 23.5) at discharge, and 17.5 (IQR, 15.5 to 19.25) in the outpatient setting, and there was no statistically significant difference (p=0.658). The HRCT fibrosis score did not show a statistically significant correlation with the actual pleural thickness (mm) measured using LUS (see Supplementary Tables S2, S3 for details).
Consequently, we conducted a trend analysis using the actual measured values, specifically the number of B-lines and the degree of pleural thickness in millimeters. This approach allowed for a more precise evaluation of changes in LUS findings. The mean values of B-lines for each lung area were 2.3±1.20 at admission, 0.45±0.19 at ICU discharge, and 0.15±0.23 at the outpatient visit approximately 1 month post-discharge. Similarly, the mean values of pleural thickness for each lung area were 2.05±0.19 at admission, 2.30±0.17 at ICU discharge, and 2.40±0.20 at the outpatient visit. The number of B-lines decreased significantly (confidence interval [CI], –1.35 to –0.62; p<0.001), and pleural thickness increased significantly (95% CI, 0.89 to 0.35; p=0.001). These measurements were taken to monitor the progression and resolution of lung abnormalities over time (Figure 3).
The change trend was evaluated with the number of B-lines and the measured values of the pleural thickness. The number of B-lines decreased significantly (95% confidence interval [CI], –1.35 to –0.62; p<0.001). The pleural thickness increased significantly (95% CI, 0.89 to 0.35; p=0.001). Only patients with all serial results at each intervention point were included. OPD: outpatient department.
Discussion
This study was conducted to investigate the usefulness of LUS for the initial assessment and follow-up of patients with severe COVID-19, particularly those with limited mobility during the initial evaluation. In patients with severe COVID-19 pneumonia requiring tracheal intubation, LUS examinations were conducted at key time points: upon admission, at ICU discharge, and during outpatient visits (Supplementary Figure S2). Our observations revealed distinct patterns in LUS findings during the course of severe COVID-19 and its recovery.
Initially, we observed a predominance of multiple B-line findings, particularly during the acute phase of respiratory failure under mechanical ventilation. This initial B-line pattern was often accompanied by small subpleural consolidations, which correlated with higher oxygen requirements. As patients transitioned into the recovery phase, we noted a significant decrease in the number of B-lines. This reduction likely reflects an improvement in lung aeration and overall recovery. This findings was also very similar with many other LUS studies [15-17].
Our study unveiled a noteworthy trend in pleural changes among severe COVID-19 patients, characterized by a progressive increase in pleural thickness from the initial acute phase to the recovery phase. This phenomenon highlights the persistence of pleural abnormalities even as patients exhibit clinical improvements and transition to outpatient care. The observed pleural thickening suggests the possibility of underlying chronic inflammatory or fibrotic processes that merit further investigation.
During recovery period, patients demonstrated significant improvements in their overall clinical status, enabling them to transition to outpatient care. However, despite these positive clinical developments, the persistence of pulmonary complications on radiological tests, notably the prominent pleural thickening observed, raises critical questions. These lingering pulmonary abnormalities, especially pleural thickening, may have multifaceted clinical implications. They could potentially signify slowly progressing inflammation or fibrotic processes even when patients exhibit improved lung function and symptoms. These findings underscore the need for a comprehensive understanding of post-COVID-19 pulmonary sequelae, emphasizing the importance of continued monitoring and evaluation beyond the acute phase to guide long-term patient care strategies effectively [18]. Further research is warranted to unravel the mechanistic underpinnings of these pleural changes and their impact on patient outcomes.
Our findings align with a previous LUS study [19-21] involving patients with severe COVID-19 pneumonia characterized by high respiratory rates, severe dyspnea, and low oxygen saturation. In these patients, we frequently observed pleural thickening and irregularities. We hypothesized that these pleural changes might be indicative of fibrotic-like changes during the recovery phase [22]. Notably, pleural thickening persisted even one month after discharge, especially in patients with reduced lung compliance during ventilator treatment. However, despite our hypothesis, no statistically significant correlation between pleural thickening on LUS and HRCT fibrosis score was observed in this study. The lack of correlation between HRCT fibrosis scores and LUS findings may be due to differences in imaging capabilities, as HRCT detects finer structural changes that LUS cannot fully capture. COVID-19–related fibrosis may also follow unique pathways involving angiotensin-converting enzyme 2 (ACE2) receptor interactions, distinct from other infections, potentially resulting in different imaging patterns.
The pathophysiology of early and late pulmonary fibrosis caused by COVID-19 has not yet been elucidated. However, it is believed to be clinically different from ARDS caused by other lung infections. Some hypotheses suggest that distinct interactions of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) with the ACE2 receptor and other cellular mechanisms may lead to distinct inflammatory and fibrotic pathways [14,23]. Future research should further clarify these differences and explore LUS’s role in understanding COVID-19 ARDS sequelae.
To our knowledge, this is the first prospective study to evaluate and monitor severe COVID-19 survivors using LUS from their hospital admission to outpatient basis. An increase in the B-line and a small consolidation of the subpleural cavity were confirmed. These properties were clearly visible on LUS and may enable continuous LUS evaluation in situations where the initial CT cannot be obtained. In addition, these parameters can be easily calculated to form semiquantitative scores [7].
Several limitations should be considered when interpreting our findings. First, our study’s sample size is absolutely small, a limitation that reflects the high mortality rate among critically ill COVID-19 patients in this prospective study. While the small sample restricts the statistical power to detect significant correlations, the study provides valuable insights into LUS and HRCT fibrosis score patterns in severe COVID-19 cases.Second, patient selection bias may exist, as our hospital’s infectious disease beds are often managed by the state, leading to the transfer of more critically ill patients. Thus, our findings may differ from studies involving less severely ill patient populations. Additionally, the initial LUS assessments were conducted in the supine position, which limited observations of the posterior lung areas due to the challenges associated with repositioning critically ill patients.
Finally, in comparing the correlation between LUS and CT, we ensured that the anatomical regions compared on LUS and CT were aligned as closely as possible. A standardized region was used to ensure that the LUS matched the anatomical region assessed by HRCT. Although differences in imaging modalities make precise anatomical correspondence difficult, we believe that our approach provides valuable insight into the correlation between LUS and HRCT scores. We investigated the potential correlation between the LUS score—which integrates B-line count, pleural thickness, and consolidation—and the HRCT fibrosis score at the outpatient visit (Supplementary Tables S2, S3). However, no significant correlation was found between the LUS score and HRCT fibrosis score. The ultrasound and CT regions were divided as follows: (1) right upper zone in the R1 and R3 regions; (2) right middle zone in the R2 and R4 regions; and (3) right lower zone in the R4 and R6 regions. These pairings were used to determine whether there was a correlation, but no significant correlation was found. This lack of correlation may result from anatomical discrepancies between the regions assessed by ultrasound and CT. These findings highlight the potential of LUS to provide insights into post-ARDS changes, and further studies are warranted to explore its role in understanding the pathophysiology of pulmonary sequelae.
Another limitation of our study is the lack of comprehensive pulmonary function test (PFT) data; although PFTs were included in our follow-up protocol, only a limited number of patients were able to complete these tests, preventing a thorough analysis of functional respiratory outcomes. Future studies should aim to include more complete PFT data to better understand the impact of COVID-19 on long-term pulmonary function.
In conclusion, our study sheds light on the evolving LUS landscape of pulmonary sequelae in severe COVID-19 patients during the critical phase of recovery. The observed pleural changes, notably the progressive thickening, suggest the presence of ongoing pathological processes that extend beyond the acute phase of the disease. Future research with larger sample sizes, longer follow-up periods, and a more comprehensive evaluation of imaging and clinical parameters may provide a more nuanced understanding of these sequelae and guide tailored management strategies.
Notes
Authors’ Contributions
Conceptualization: Yang SH, Cho YJ. Methodology: Yang SH, Park EJ, Cho YJ. Formal anlaysis: Yang SH, Park EJ, Cho YJ. Data curation: all authors. Validation: Yang SH, Cho YJ. Investigation: all authors. Writing - original draft preparation: Yang SH. Writing - review and editing: Yang SH, Cho YJ. Approval of final manuscript: all authors.
Conflicts of Interest
Jin Woo Song is an associate editor of the journal, but he was not involved in the peer reviewer selection, evaluation, or decision process of this article. No other potential conflicts of interest relevant to this article were reported.
Funding
This research was supported by the Seoul National University Bundang Hospital research fund (No. 14-2022-0031), and the Research of the Korea Centers for Disease Control and Prevention (grant number: 2021ER190400).
Supplementary Material
Supplementary material can be found in the journal homepage (http://www.e-trd.org).
Lung ultrasound scoring.
The correlation of pleural thickness (mm) measured by lung ultrasound and high-resolution computed tomography fibrosis scores (right lung).
The correlation of pleural thickness (mm) measured by lung ultrasound and high-resolution computed tomography fibrosis scores (left lung).
Examples of each detailed area (B-line, consolidation, pleural thickness) in the scoring system used in this study.
Examples of pulmonary ultrasonography performed in a 47-year-old female patient at each follow-up time point.