key: cord-0264326-4nyrn0mb
authors: Blair, P. W.; Siddharthan, T.; Liu, G.; Bai, J.; East, J.; Herrera, P.; Anova, L.; Mahadevan, V.; Hossen, S.; Seo, S.; Sonuga, O.; Lawrence, J.; Peters, J.; Cox, A.; Manabe, Y. C.; Fenstermacher, K.; Shea, S.; Rothman, R. E.; Hansoti, B.; Sauer, L.; Crainiceanu, C.; Clark, D. V.
title: Point-of-care lung ultrasound predicts severe disease and death due to COVID-19: a prospective cohort study.
date: 2022-01-01
journal: nan
DOI: 10.1101/2021.12.30.21268558
sha: bff3790623516eb852e98fd055472b8a313098a6
doc_id: 264326
cord_uid: 4nyrn0mb

Objective: The clinical utility of point-of-care lung ultrasound (LUS) for disease severity triage of hospitalized patients with COVID-19 is unclear. Design: Prospective cohort study Setting: A large tertiary care center in Maryland, USA between April 2020 to September 2021. Patients: Hospitalized adults (18 years of age or greater) with positive SARS-CoV-2 RT-PCR results. Interventions: None. Measurements and Main Results: All patients were scanned using a standardized protocol including 12 lung zones and followed to determine clinical outcomes until hospital discharge and vital status at 28-days. Ultrasounds were independently reviewed for lung and pleural line artifacts and abnormalities, and the mean Lung Ultrasound Score (ranging from 0 to 3) across lung zones (mLUSS) was determined. The primary outcome was time to ICU-level care, defined as high flow oxygen, noninvasive, or mechanical ventilation, within 28-days of the initial ultrasound. Cox proportional hazards regression models adjusted for age and sex were fit for mLUSS and each ultrasound covariate. A total of 264 participants were enrolled in the study; the median age was 59 years and 114 (43.2) % of participants were female. The median mLUSS was 1 (interquartile range: 0.5 to 1.3). Following enrollment, 29 (11.0%) participants went on to require ICU-level care and 14 (5.3%) subsequently died by 28 days. Each increase in mLUSS at enrollment was associated with disease progression to ICU-level care (aHR = 3.63; 95% CI: 1.23 to 10.65) and 28-day mortality (aHR = 4.50; 95% CI: 1.52 to 13.31). Pleural line abnormalities were independently associated with disease progression to ICU-level care (aHR = 18.86; CI: 1.57 to 226.09). Conclusions: Participants with a mLUSS of 1 or more or pleural line changes on LUS had an increased likelihood of subsequent requirement of high flow oxygen or greater. LUS is a promising tool for assessing risk of COVID-19 progression at the bedside.

LUS was standardized with 6-second clips from 12 lung zones with six lung zones on each side 1 3 9 as previously described.(10) All images were collected with a Lumify S4 phased array probe 1 4 0 (Philips, Amsterdam, Netherlands) using the application's lung scan settings. We employed a The pleural line was considered abnormal if it was irregular, fragmented, discontinuous, or hospitalized, study visits including lung ultrasound scans occurred on study days 0, 3, 7, and 1 5 0 weekly for up to 90 days. The first available scan was used for this analysis. Baseline 1 5 1 demographics, comorbid conditions, and oxygen requirements until discharge were determined 1 5 2 using the Hopkins Precision Medicine Analytics Platform (11), and duration of symptoms at 1 5 3 enrollment was determined through medical chart review. Date of death by 28 days from 1 5 4 enrollment was determined using the Precision Medicine Analytics Platform, medical chart 1 5 5 review, and review of the regional Maryland, Washington D.C, and Virginia health information 1 5 6 exchange (12). 1 5 7 1 5 8

As previously described (13), the LUS score was calculated for each zone with 1 point for 1 5 9 discrete B lines, 2 points for coalescent B lines, and 3 points for lung consolidation. The mean 1 6 0 . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) LUS score (mLUSS) ranges from 0 to 3, with a higher score signifying higher severity. The 1 6 1 mLUSS was calculated out of total available zones to include participants with missing zones. 1 6 2

The Pearson correlation coefficient of the mLUSS between masked ultrasound clip readers was 1 6 3 determined for the participants that were available (61 consecutive patients or 23% of the 1 6 4 cohort). Participants were divided into severity groups at baseline based on severity at the time of 1 6 5 POCUS or peak severity prior to POCUS: on room air or nasal cannula supplemental oxygen 1 6 6 (moderate disease), on HFNC or noninvasive positive pressure ventilation (NIPPV) (moderately 1 6 7 severe), or on mechanical ventilation (severe disease). Summary statistics were performed by 1 6 8 comparing baseline demographics (i.e., sex, age, race, ethnicity, medical comorbidities), and 1 6 9 duration post symptom-onset between severity groups using Kruskal-Wallis tests. Progression to ICU-level care was defined as newly requiring either high flow nasal cannula, 1 7 2 noninvasive ventilation, or mechanical ventilation during the hospitalization. To determine the 1 7 3 association between baseline LUS characteristics and future risk, this outcome was restricted to 1 7 4 study participants not requiring more than supplemental oxygen via low-flow nasal cannula at 1 7 5 baseline (among those with moderate disease at baseline, N=164) ( Figure 2 ). Secondary 1 7 6 outcomes included 28-day mortality (all baseline severity groups, N=264) and 28-day 1 7 7 progression to mechanical ventilation or 28-day death (among those with moderate or 1 7 8 moderately severe disease, N=215) ( Figure 2) . A Kaplan-Meier plot was created to compare risk 1 7 9 over time between those at the 25 th and 75 th mLUSS percentile. After checking the proportional 1 8 0 hazards assumption, Cox proportional hazards regression models were used to evaluate the 1 8 1 differences in risk of death and risk of death or subsequent mechanical ventilation plus 28-day 1 8 2 death as a function of baseline % of lung fields with A lines, % with B lines, % with 1 8 3 . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted January 1, 2022. ; https://doi.org/10.1101/2021.12.30.21268558 doi: medRxiv preprint 0 7

Baseline cross-sectional differences in POCUS findings by severity 2 0 8

At enrollment, participants with severe illness were later in their course of illness (median: 15.79 2 0 9 days post symptom onset; IQR: 10.92 to 26.70 days) compared to those with moderately severe 2 1 0 (median: 9.29 days; IQR: 7.03 to 13.92 days), or moderate illness (median 7.38 days; IQR 4.08 2 1 1 to 11.92 days) ( compared to moderately severe (median 0.0%; 0.0 to 15.6%) or moderate (median 0.0%; IQR 2 2 0 0.0 to 16.7%) disease. The mLUSS was lower for moderate disease (median 0.83; IQR, 0.33 to 2 2 1 0.80) compared to a stepwise increase in moderately severe disease (median 1.11; IQR, 1.00 to 2 2 2 1.50) followed by severe critical disease (1.25; IQR, 1.00 to 1.67). The Pearson correlation 2 2 3 coefficient of the mLUSS between readers was high at 0.77 among 61 participants with a an 2 2 4 available matched masked LUS read (Supplemental Figure S1 ). When evaluating the 28-day risk of progression to severe COVID-19, multiple baseline POCUS 2 2 8 parameters were found to be associated with severity progression using Cox proportional hazards 2 2 9 . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted January 1, 2022. ; https://doi.org/10.1101/2021.12.30.21268558 doi: medRxiv preprint regression. Each point increase in the mLUSS was associated with disease progression to ICU-2 3 0 level care (aHR = 3.61; 95% CI: 1.27 to 10.22) and 28-day mortality (aHR = 3.10; 95% CI: 1.29 2 3 1 to 7.50), but not the composite outcome of ventilation or death (aHR = 2.45; 95% CI 0.81 to 2 3 2 11.02) (Figure 3 and Figure 4) . Inference was unchanged when adjusting for total number of 2 3 3 available lung zones with an increased risk of progression to ICU-level care (aHR = 3.80; 95% 2 3 4 CI: 1.32 to 10.95) or death (aHR: 2.47; 95% CI: 1.10, 5.55), but not the composite outcome of 2 3 5 ventilation or death (aHR: 2.96; 95% CI: 0.80 to 11.01). Similarly, inference was unchanged 2 3 6 when excluding asymptomatic individuals with each increase in the mLUSS associated with risk 2 3 7 of progression to ICU-level care (aHR = 3.07; 95% CI: 1.04 to 9.07), death (aHR: 2.94; 95% CI: 2 3 8

1.21 to 7.15), but not ventilation or death together (aHR: 2.69; 95% CI: 0.66 to 11.05). Lastly, 2 3 9 when including days since symptom onset, there was an increased risk with each additional day 2 4 0 (aHR: 1.007; 95% CI: 1.001 to 1.01), but the risk associated with each increase in mLUSS was 2 4 1 similar (aHR: 3.86; 95% CI: 1.32 to 11.30) (Supplemental Table S1 ). There was no interaction 2 4 2 observed between duration of symptoms and mLUSS (p=0.48) (data not shown). CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted January 1, 2022. ; is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted January 1, 2022. ; https://doi.org/10.1101/2021.12.30.21268558 doi: medRxiv preprint . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)

The copyright holder for this preprint this version posted January 1, 2022. ; https://doi.org/10.1101/2021.12.30.21268558 doi: medRxiv preprint

Prospective Longitudinal Evaluation of