key: cord-0707593-wfpdlb6k authors: Espersen, Caroline; Platz, Elke; Alhakak, Alia Saed; Sengeløv, Morten; Simonsen, Jakob Øystein; Johansen, Niklas Dyrby; Davidovski, Filip Søskov; Christensen, Jacob; Bundgaard, Henning; Hassager, Christian; Jabbari, Reza; Carlsen, Jørn; Kirk, Ole; Lindholm, Matias Greve; Kristiansen, Ole Peter; Nielsen, Olav Wendelboe; Jeschke, Klaus Nielsen; Ulrik, Charlotte Suppli; Sivapalan, Pradeesh; Iversen, Kasper; Stæhr Jensen, Jens Ulrik; Schou, Morten; Skaarup, Søren Helbo; Højbjerg Lassen, Mats Christian; Skaarup, Kristoffer Grundtvig; Biering-Sørensen, Tor title: Lung ultrasound findings following COVID-19 hospitalization: A prospective longitudinal cohort study date: 2022-04-02 journal: Respir Med DOI: 10.1016/j.rmed.2022.106826 sha: 4ed92c7ad781afb7080d2f067ba230759b252bf7 doc_id: 707593 cord_uid: wfpdlb6k BACKGROUND: Lung ultrasound (LUS) is a useful tool for diagnosis and monitoring in patients with active COVID-19-infection. However, less is known about the changes in LUS findings after a hospitalization for COVID-19. METHODS: In a prospective, longitudinal study in patients with COVID-19 enrolled from non-ICU hospital units, adult patients underwent 8-zone LUS and blood sampling both during the hospitalization and 2–3 months after discharge. LUS images were analyzed blinded to clinical variables and outcomes. RESULTS: A total of 71 patients with interpretable LUS at baseline and follow up (mean age 64 years, 61% male, 24% with ARDS) were included. The follow-up LUS was performed a median of 72 days after the initial LUS performed during hospitalization. At baseline, 87% had pathologic LUS findings in ≥1 zone (e.g. ≥3 B-lines, confluent B-lines or subpleural or lobar consolidation), whereas 30% had pathologic findings at follow-up (p < 0.001). The total number of B-lines and LUS score decreased significantly from hospitalization to follow-up (median 17 vs. 4, p < 0.001 and 4 vs. 0, p < 0.001, respectively). On the follow-up LUS, 28% of all patients had ≥3 B-lines in ≥1 zone, whereas in those with acute respiratory distress syndrome (ARDS) during the baseline hospitalization (n = 17), 47% had ≥3 B-lines in ≥1 zone. CONCLUSION: LUS findings improved significantly from hospitalization to follow-up 2–3 months after discharge in COVID-19 survivors. However, persistent B-lines were frequent at follow-up, especially among those who initially had ARDS. LUS seems to be a promising method to monitor COVID-19 lung changes over time. CLINICALTRIALS.GOV ID: NCT04377035. COVID-19 pneumonia is associated with substantial lung involvement. Lung ultrasound (LUS) is a useful tool in the acute care setting to detect and grade the severity of lung involvement in patients with COVID-19 as LUS is a portable, rapid, non-invasive examination that can be performed at the bedside. The typical findings on LUS frequently detected in patients with COVID-19 pneumonia include pleural line irregularities, multiple and at times confluent B-lines and consolidations (1) (2) (3) (4) (5) . The LUS findings observed in patients with COVID-19 correlate well with findings on chest computed tomography (CT) (1, 6, 7) . LUS has higher sensitivity than chest X-ray for the diagnosis of COVID-19 pneumonia (8, 9) and provides prognostic information regarding adverse outcomes in some studies (10) (11) (12) (13) , although there are heterogenous results regarding the prognostic utility of LUS in the inpatient setting (14, 15) . The COVID-19 worsening score including clinically relevant data in addition to LUS findings has proven to accurately identify patients who are less likely to require treatment in the intensive care unit (16) . Moreover, deep-learning based methods for LUS have also shown promising results for detecting COVID-19 pneumonia (17, 18) . Several studies have also assessed the dynamic changes in LUS findings during a COVID- 19 infection and found that LUS can be used to monitor disease progression during hospitalization (1, 19, 20) . However, whether the LUS findings detected during the initial COVID-19 infection resolve or persist after hospital discharge is less well investigated. Indeed, pathologic findings on CT have been shown to persist in a substantial number of COVID-19 survivors several months after hospitalization (21) (22) (23) (24) . In contrast to CT, LUS can be used for rapid & radiation-free monitoring in the outpatient setting. Moreover, B-lines on LUS are also a common measure of pulmonary congestion in patients with acute heart failure (AHF) (25, 26) . LUS findings in patients with COVID-19 pneumonia and AHF may thus overlap, further complicating accurate diagnosis of pulmonary congestion in the acute setting after a prior COVID-19 infection. Therefore, it is important to understand the trajectory of LUS findings after discharge in patients with COVID-19. In this longitudinal J o u r n a l P r e -p r o o f cohort study, we sought to investigate the changes in LUS findings from hospitalization for COVID-19 to 2-3 months after discharge. J o u r n a l P r e -p r o o f Adult patients hospitalized with laboratory-confirmed SARS-CoV-2 infection at 8 different hospitals in eastern Denmark were enrolled in a prospective, observational, multicenter study (the ECHOVID-19 study) from March 30 th to June 3 rd , 2020. Patients were enrolled from dedicated COVID-19 non-ICU hospital units. The study design has been described in detail previously (15, (27) (28) (29) . Upon inclusion, patients underwent LUS, laboratory testing and answered a questionnaire. Surviving participants were invited by telephone for a follow-up examination 2-3 months after hospital discharge. If participants did not respond after 3 attempts of contact on 3 separate days, they were excluded from the follow-up study. At the follow-up examination, participants underwent another LUS examination and laboratory testing. Participants also underwent echocardiography at the time of LUS during hospitalization and at follow-up. These results have been published elsewhere (27, 29, 30) . For this analysis, we only included participants who had ≤1 missing zone on the LUS during hospitalization and at follow-up. Clinical and baseline data as well as in-hospital events were retrieved from the participants' electronic health records after inclusion in the study. The definitions of hypertension, diabetes mellitus, hypercholesterolemia, heart failure and ischemic heart disease have been described previously (27) . Development of acute respiratory distress syndrome (ARDS) during hospitalization was defined according to the Berlin Criteria (31) . Venous thromboembolic events consisted of CT-confirmed pulmonary embolism and/or ultrasound-verified deep vein thrombosis (29). All included patients provided written informed consent. The study was conducted in accordance with the 2 nd Declaration of Helsinki. The ECHOVID-19 Study is registered at Clinicaltrials.gov (NCT04377035). The LUS examinations were performed with standard echocardiographic equipment using a A LUS score was constructed to integrate the above LUS findings in a single parameter, similar to the aeration score previously reported (5, 10, 32, 33) . The LUS score has been described in detail previously (15) . Briefly, ≥3 B-lines in a single zone corresponded to a score of 1, confluent B-lines to a score of 2 and subpleural or lobar consolidation to a score of 3. The total LUS score ranged from 0-24. The total number of B-lines was calculated as the sum of the maximum number of B-lines in a single frame in each of the 8 zones. Confluent B-lines were counted as 7 B-lines (the highest number of B-lines in a single zone in this dataset) for the parameter total number of B-lines. The mean intra-operator total Bline difference across all 8 zones from the baseline measurements was -1.6 (95% limits of agreement -6,3 to 3.1) in 15 randomly selected patients (15) . Continuous variables were summarized with mean and standard deviation or median and interquartile range for normally and non-normally distributed variables, respectively. Categorical variables were listed as frequencies with percentages. For comparison between groups (ARDS vs. no ARDS during hospitalization), continuous variables were compared using Student's t-test or Wilcoxon rank sum test as appropriate, and categorical variables J o u r n a l P r e -p r o o f Initially, 215 hospitalized patients with COVID-19 were included in the study. Among 171 surviving participants invited for a follow-up examination, 91 participants completed the follow-up examination, and 20 of these had ≥1 missing or uninterpretable zone on the LUS at hospitalization or at follow-up and were thus excluded. Therefore, ultimately 71 participants were included in this study of follow-up LUS findings in patients hospitalized for COVID-19. Figure 2 illustrates the inclusion and exclusion process. Baseline characteristics of patients who participated in the follow-up examination and those who did not have been published previously (30) . The initial LUS examination was performed a median of 3 days (IQR 2-6) after hospital admission, and the follow-up LUS was performed a median of 72 days (IQR 72-92) after the initial LUS. The baseline characteristics of the study sample and complications during the hospitalization are outlined in Table 1 . Overall, 61% of participants were male with a mean age of 64 years, 46% had hypertension and 19% had diabetes. The median length of stay in the hospital was were admitted to the ICU. These complications include events during the entire hospitalization; both before and after the LUS. Those who developed ARDS during the hospitalization (n=17) were older and treated with higher oxygen levels compared to those who did not develop ARDS during the hospitalization (n=54). In the Supplemental Material, Table 1 ). Laboratory findings also differed significantly from hospitalization to follow-up. CRP-levels, NT-proBNP-levels and the neutrophil counts were significantly higher at baseline compared to follow-up, whereas lymphocyte counts were significantly lower at baseline compared to follow-up (Table 2) . LUS findings at baseline and follow-up in patients who developed ARDS during the hospitalization (both before and after the LUS examination) and those who did not are listed in Table 3 . Patients who developed ARDS during the hospitalization had a higher LUS score A prior study demonstrated the ability of LUS to detect chest CT-confirmed interstitial lung disease in 38 COVID-19 survivors three months after discharge from the ICU (34), thereby underscoring the correlation between LUS findings and chest CT findings for detecting residual lung injury. LUS may therefore be useful as a non-invasive screening tool to monitor changes and improvement in lung density after discharge in patients hospitalized for COVID- 19 . As such LUS could be used to identify subjects with residual lung injury requiring additional follow-up. In this cohort, 87% of patients hospitalized for COVID-19 had at least one zone with a pathologic LUS finding, and this number decreased significantly to 30% at follow-up. In Prior prospective studies investigating the serial changes in LUS findings during and after a COVID-19 infection, have reported similar findings regarding the gradual decrease in pathologic LUS findings from hospitalization to follow-up 1-4 months after discharge (35, 38) . However, the proportion of patients with pathologic LUS findings post-discharge was higher in these serial LUS studies (35, 38) as well as in another non-serial LUS study among COVID-19 survivors (34) compared to ours. This could in part be explained by the fact that these studies employed a more extensive LUS protocol with 12-13 zones including the posterior lung areas, whereas we used a simplified 8-zone LUS protocol including only the anterior and lateral zones. Lastly, in two studies (34, 38) , all enrolled patients had been admitted to the ICU with severe COVID-19 infection, whereas only a subset of patients had been admitted to the ICU during the hospitalization in our study. In comparison, our study was a multicentre, prospective study investigating serial LUS examinations in patients hospitalized for COVID-19 independent of the severity of COVID-19 infection. Although LUS is useful for monitoring changes in lung density after discharge in patients hospitalized for COVID-19, the long-term evolution in lung density as well as the association with pulmonary function and symptoms should be investigated further in future longitudinal follow-up studies. LUS could potentially be implemented in a strategy to characterize the longer-term effects of COVID-19 infection on lung density. The results of this study should be interpreted in the context of its limitations. First, the initial (41) . However, the quality and therefore also interpretation of the LUS exam is dependent on the operator's expertise and the equipment used. Moreover, LUS may not allow for detection of centrally located pulmonary involvement (42) . Although only a subset of patients had NT-proBNP measurements at baseline and follow-up, we have previously shown that NT-proBNP and the total number of B-lines and LUS score were not correlated in this cohort (15) . Finally, although the follow-up period was relatively short, most participants demonstrated resolution of pathologic LUS findings at follow-up. Among survivors following a hospitalization for COVID-19, LUS findings improved significantly from baseline to follow-up, including the total number of B-lines and LUS score. However, multiple B-lines in at least one zone on LUS were a frequent finding at follow-up, J o u r n a l P r e -p r o o f especially among those who had ARDS during the hospitalization. LUS seems to be a promising method to monitor changes in lung density after a COVID-19 hospitalization. J o u r n a l P r e -p r o o f TBS reports receiving research grants from Sanofi Pasteur and GE Healthcare, is a Steering Committee member of the Amgen financed GALACTIC-HF trial, on advisory boards for Sanofi Pasteur and Amgen, and speaker honorariums from Novartis and Sanofi Pasteur. EP has received research support from the NIH, and consulting fees from scPharmaceuticals outside the submitted work. Her employer has received support from Novartis for consulting work outside the submitted work. 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The Lancet Respiratory Medicine NT-proBNP: Nterminal pro B-type natriuretic peptide *Pathologic LUS findings correspond to ≥3 B-lines, confluent B-lines, subpleural or lobar consolidations