key: cord-0748970-z8x9t9pf
authors: Morin, F.; Douillet, D.; Hamel, J. F.; Savary, D.; Aube, C.; Tazarourte, K.; Marouf, K.; Dupriez, F.; Le Conte, P.; Flament, T.; Delomas, T.; Taalba, M.; Marjanovic, N.; Couturaud, F.; Peschanski, N.; Boishardy, T.; Riou, J.; Dubee, V.; Roy, P.-M.
title: Point-of-care ultrasonography for risk stratification of non-critical suspected COVID-19 patients on admission (POCUSCO): a prospective binational study
date: 2021-03-11
journal: nan
DOI: 10.1101/2021.03.09.21253208
sha: c25cd37d368dad1d732669dff6f05603c20ea5ed
doc_id: 748970
cord_uid: z8x9t9pf

Background Lung point-of-care ultrasonography (L-POCUS) is highly effective in detecting pulmonary peripheral patterns and may allow early identification of patients who are likely to develop an acute respiratory distress syndrome (ARDS). We hypothesized that L-POCUS performed during the initial examination would identify non-severe COVID-19 patients with a high risk of getting worse. Methods POCUSCO was a prospective, multicenter study. Non-critical adult patients who were admitted to the emergency department (ED) for suspected or confirmed COVID-19 were included and had L-POCUS performed within 48 hours following admission. The severity of lung damage was assessed using the L-POCUS score based on 36 points for ARDS. The primary outcome was the rate of patients requiring intubation or who died within 14 days following inclusion. Results Among 296 participating patients, 8 (2.7%) had primary outcome. The area under the curve (AUC) of the receiver operating characteristic of L-POCUS was 0.80 [95%CI:0.60-0.94]. The score values which achieved a sensibility > 95% in defining low-risk patients and a specificity > 95% in defining high-risk patients were <1 and [≥]16, respectively. The rate of patients with an unfavorable outcome was 0/95 (0%[95%CI:0-3.9]) for low-risk patients (score=0) versus 4/184 (2.17%[95%CI:0.8-5.5]) for intermediate-risk patients (score 1-15) and 4/17 (23.5%[95%CI:11.4-42.4]) for high-risk patients (score [≥]16). In patients with confirmed COVID-19 (n=58), the AUC of L-POCUS was 0.97 [95%CI:0.92-1.00]. Conclusions L-POCUS allows risk-stratification of patients with suspected or confirmed COVID-19. These results should be confirmed in a population with a higher risk of an unfavorable outcome.

The COVID-19 pandemic has developed worldwide since its emergence in China in December 2019. [1] [2] [3] The majority of patients has a mild or uncomplicated course (81%)

with minor symptoms such as headache, loss of smell, or cough. However, around 14% of patients develop respiratory symptoms and require hospitalization. [4] Median time from illness onset to dyspnea is 6 to 8 days and around 5% of the patients develop acute respiratory distress syndrome (ARDS), usually between Day 7 and Day 10. [4] [5] [6] The rapid progression of respiratory failure soon after the onset of dyspnea is a striking feature of COVID-19. [7] , [8] There is an urgent need for reliable tools which can identify patients who are likely to get worse and develop ARDS early on.

Pulmonary computed tomography (CT-scan) appears to be very sensitive (97%) and quite specific for diagnosis of COVID-19 in patients with a clinical suspicion, provided that it is not performed within the first 4 days after symptom onset. [9, 10] COVID-19 manifests itself on CT-scans as bilateral, subpleural, ground-glass opacities with air bronchograms, and illdefined margins. [11] Those patterns can precede the positivity of the Reverse Transcriptase-Polymerase Chain Reaction (RT-PCR) for SARS-CoV-2. [12, 13] Lung point-of-care ultrasonography (L-POCUS) is a simple, non-invasive, non-irradiating, inexpensive imaging tool that is available at the bedside and used more and more by emergency physicians in their everyday clinical practice. L-POCUS seems to be better than chest X-ray in detecting pneumonia and may be an alternative to the CT-scan as a screening and prognostic tool. [14] Indeed, L-POCUS is highly effective in detecting peripheral patterns and pleural abnormalities, and seems appropriate for triaging COVID-19 patients. [15] A recent review highlights its potential value in decision making for triage or follow-up. [16] Many physicians have placed their hopes in this device, as shown by the number of publications reporting personal experiences or case reports but few prospective studies have been carried out on this topic, and, to our knowledge, no robust data have been yet provided on the prognostic value of L-POCUS in COVID-19 patients.

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The copyright holder for this preprint this version posted March 11, 2021. ;  https://doi.org/10.1101/2021.03.09.21253208 doi: medRxiv preprint 5 The aim of this study is to determine the performance of L-POCUS at the time of ED admission in identifying, among patients with confirmed or highly suspected COVID-19, those who are at high-risk of adverse outcomes such as respiratory failure or death.

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The point-of-care ultrasonography for risk stratification of COVID-19 patients' study (POCUSCO) was a non-interventional, prospective, multicenter study that was conducted in 11 participating hospitals in France and Belgium.

Patients were enrolled if they met all of the following criteria: (1) adult patients (≥ 18 years old); (2) typical COVID-19 symptoms and at least one of the three following features: i) positive SARS-CoV-2 RT-PCR, ii) typical CT-scan lesions, iii) COVID-19 is the main diagnostic hypothesis by the in-charge physician; (3) no requirement for respiratory support and/or other intensive care, and not subject to a limitation of care; (4) membership of a social security scheme.

Patients for whom the follow-up at Day 14 was impossible or who had a condition making lung ultrasonography impossible (body mass index > 35 kg/m², history of pneumonectomy) were excluded.

The initial evaluation was carried out by the physician-in-charge and patients were treated as standard.

[17] All participating patients underwent L-POCUS and a score reflecting the intensity and the extension of lung involvement was determined. [18] This score was previously developed for ARDS (see below). [18, 19] For patients who were subsequently hospitalized, a second L-POCUS was performed on Day 5 ± 3 under the same conditions as the first one, whenever it was possible. . 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)

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The main objective was to assess the ability of L-POCUS to identify COVID-19 patients with a high-risk of an unfavorable outcome. The primary endpoint was the development of severe COVID-19 within the 14 days after ED admission defined as a stage of the WHO-OSCI ≥ 6.

This stage relates to a severe inpatient requiring intubation and invasive ventilation (stage 6), and/or additional organ support (stage 7) or who died whatever the cause (stage 8). The ability of L-POCUS to predict the primary outcome occurrence was evaluated by the area under the curve (AUC) of the receiver operating characteristic (ROC) curve and its 95% confidence interval (95%CI). A sensitivity analysis was performed with the 14-day all-cause mortality rate as the outcome.

The secondary objectives were: 1) To determine the threshold values of L-POCUS to perform risk stratification in three groups of patients: low-risk patients, intermediate-risk patients, and high-risk patients.

2) To assess the impact of adding the result of POCUS evaluation to two risk-stratification clinical scores: the quick Sequential Organ Failure Assessment (qSOFA) and the CRB-65. [21, 22] 3) To assess the impact of the knowledge and experience of the operator level (novice, confirmed or expert) on the L-POCUS performance.

We performed a subgroup analysis in patients for whom the diagnosis of COVID-19 was initially or subsequently confirmed by a positive RT-PCR for SARS-CoV-2.

Lung point-of-care ultrasonography L-POCUS was performed with ultrasound scanners using low frequency (2) (3) (4) (5) transductors, convex or small linear type probes. The Bedside Lung Ultrasound in an Emergency (BLUE)-Protocol was applied to patients in erect or semi-recumbent positions depending on dyspnea severity ( Figure 1 ). [19] Each chest wall was divided by the anterior and posterior axillary lines into anterior, lateral, or posterior regions. All intercostal spaces of the upper and lower parts of these regions were examined, resulting in a total of 12 areas of investigation. Each area was examined for at least one complete respiratory cycle. Four ultrasound aeration patterns were defined and scored 0 to 3, allowing calculation of the L-POCUS score, theoretically ranging from 0 to 36 ( Figure 1 ). [18, 23] Considering biological risk of infection, special protective precautions were taken to protect the operator and other patients as recommended. [24] . 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.

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This study was conducted in accordance with the Declaration of Helsinki, as amended. The protocol was approved by the Ethics Committee CPP Sud-Ouest et Outre-Mer II for France (No. 2020-A00782-37 / 2-20-025 id7566) and the Ethics Committee of the Cliniques Universitaires Saint-Luc for Belgium (No. 2020/14AVR/223). Written informed consent was obtained from all patients. The study was funded by a grant from the French Ministry of Health (PHRC-I, April 2020, COVID19_A_001). This study adheres to STROBE guidelines, and all its details have been verified before submitting the manuscript. [25] 

Continuous variables were expressed as mean and standard deviation values. Categorical variables were described using numbers, percentages and their 95% confidence intervals (95%CI). The AUCs and their 95% confidence interval were determined by the .632 bootstrap method. For the primary outcome, we determined in advance that the L-POCUS prognostic value would be considered as clinically relevant with a good level of evidence if the lower bound of the 95%CI of the AUC was equal to or greater than 0.7. To perform risk stratification in three groups of patients with a low, intermediate, or high-risk of an unfavorable outcome, two thresholds were calculated. The first maximized specificity with a sensitivity greater than or equal to 95% and the second maximized sensitivity with a specificity greater than or equal to 95%. For these threshold values, sensitivity, specificity, predictive values and likelihood ratios were assessed. To study the impact of adding the results of the L-POCUS evaluation to several risk stratification clinical rules for pulmonary infection or sepsis (qSOFA and CRB65), AUCs were compared with or without their components with a DeLong test. For this purpose, we attributed 0, 1, or 2 points in the L-POCUS result as low, moderate or high risk according to the predefined threshold values and assessed the AUC of the risk-stratification rules with and without adding the L-POCUS result value. Assuming a rate of death or tracheal intubation requirement of 10%, and expecting an AUC of 0.8, the number of patients required to achieve a lower limit of the 95%CI, more than 0.7, was estimated as 286. Taking into consideration that 5% of patients were not followed up or could not be evaluated, the sample size was defined as 300 patients. Missing data were not imputed. A descriptive analysis of missing data was performed and compared to the available data to assess a potential bias. All statistical analyzes were performed using STATA, version 14.2; StataCorp; College Station, TX.

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A total of 307 patients with suspected or confirmed SARS-CoV-2 infection were enrolled in this study. Among them, 2 were subsequently excluded and 9 were could not be followed up (2.93%) leaving 296 patients for the main analyses ( Figure 2) . The mean age of the overall population was 57 years (± 20.8), and 146 (47.6%) were men ( Table 2) 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) 1 1 

The results of the L-POCUS are outlined in Figure 3 . At Day 14, among 296 analyzable patients, the main outcome occurred in 8 (2,7%) patients (seven were dead and one patient had required intubation and invasive ventilation). The AUC of L-POCUS was 0.80 (95%CI: 0.60-0.94) (Figure 4) . The lower value of the 95% CI did not achieve the predefined value of 0.7 necessary to consider the performance of L-POCUS as clinically relevant. In the sensitivity analysis with the 14-day all-cause mortality rate as an outcome, the AUC of L-POCUS was 0.83 (95%CI: 0.66-1).

The AUC slightly increased according to the experience of the POCUS operator without 

Among 240 patients tested (78.2%), 58 (24.2%) had a positive RT-PCR for SARS-CoV2. At Day 14, 4 patients with confirmed COVID-19 were dead (4/58, 6.9%). The AUC of L-. 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.

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In our prospective POCUSCO study of non-severe patients with confirmed or suspected COVID-19, L-POCUS has had good results in predicting the occurrence of death or requirement for invasive ventilation within the 14 days following ED admission and it appears to be a promising tool for risk stratification. However, because of a lower-than-expected rate of patients with an unfavorable outcome, the confidence intervals of our estimates are wide with an upper value of the AUC not achieving the predefined value of 0.7 to consider the L-POCUS prognostic value as clinically relevant with a good level of evidence.

Based on its performance in diagnosing pneumonia and ARDS, L-POCUS ought to be a useful diagnostic and risk stratification tool in the initial assessment of suspected COVID-19

patients. [14, 26, 27] It is currently considered an alternative to physical examination for suspected COVID-19 patients in the emergency department. [27] However, this position is mainly based on expert opinion and few trials have been published. Moreover, most of them are monocentric studies assessing the correlation of L-POCUS with chest CT scans in detecting lung abnormalities suggestive of COVID-19 and/or its value in diagnosing patients with suspected COVID-19. Globally, they suggest a high sensitivity at around 90% but with a low specificity at around 25%, depending on disease prevalence. [28, 29] Those estimates are greater than the first RT-PCR value. [29] L-POCUS would provide an effective estimate of the extent of the pulmonary histological damage. [30] To our knowledge, only one previous study assessed the performance of L-POCUS in identifying patients with suspected or confirmed COVID-19 at risk of deteriorating. Indeed, Bonadia et al. conducted a prospective study in 41 COVID-19 patients and showed the higher the rate, the higher the in-hospital mortality and need for intensive care admission. [31] Our results therefore provide further important data regarding prognostication and triage with L-

Ultrasonography including L-POCUS was questioned for its lack of reproducibility, being dependent on the examiner. To avoid this pitfall, standardized procedures have been proposed. [32] We used a revised BLUE protocol previously validated in patients with ARDS. [18] Based on the screening of twelve chest areas and on weighting with four aeration patterns, this score is quick and easy to achieve, which is particularly relevant in the Emergency Department and in the context of the strain on health resources. [18] Aeration . 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 March 11, 2021. ; https://doi.org/10.1101/2021.03.09.21253208 doi: medRxiv preprint patterns are easy to recognize and the use in our study of pocket cards with the L-POCUS score ( Figure 1 ) make it easy for most emergency physicians to apply. It is important to note that in previous studies, L-POCUS were performed by experienced emergency physicians, all certified for lung ultrasound. [33, 34] In our trial, nearly a quarter of the exams were performed by novices physicians without any significant difference in terms of the AUC of L-POCUS is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) 1 5 a diagnostic tool (AUC: 0.82 [95%CI: 0.75 -0.90]) of. [37] The best result was obtained with CRB-65 + L-POCUS with an AUC of 0.82 [95%CI: 0.68 to 0.99]. However, the lower limit of the 95%CI did not achieve the prespecified level of 0.7.

To our knowledge, POCUSCO is the largest multicentric, prospective study evaluating L-POCUS to risk-stratify COVID-19 patients. Nevertheless, it has some limitations, one of the more important being the low primary endpoint rate. On the basis of the first cohorts of COVID-19 inpatients, we considered a rate of mortality or invasive ventilation requirement of 10%, at the time the protocol was written. [38] It was actually 7% in confirmed COVID-19 patients and only 2.4% in our overall cohort. Several factors may explain this discrepancy: differences in the completeness of testing and case identification, variable thresholds for hospitalization and Intensive Care Unit admission, and improvement in patients' care. [39] Moreover, only a quarter of participating patients had a positive RT-PCR for SARS-CoV-2, the other patients may have had a minor form of COVID-19 or another less severe disease.

Nevertheless, our results are in line with the 1.4% mortality rate and 2.3% rate of patients who underwent invasive mechanical ventilation in the cohort of Guan et al. [4] Finally, in the absence of a derivation model, it is not methodologically justified to assess the calibration of L-POCUS. [18] Another study must be carried out to validate our results on an independent cohort.

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