key: cord-0949305-ap72gg3x
authors: Emanuele, Pivetta; Alberto, Goffi; Maria, Tizzani; Stefania M, Locatelli; Giulio, Porrino; Isabel, Losano; Dario, Leone; Gilberto, Calzolari; Matteo, Vesan; Fabio, Steri; Ardito, Arianna; Marialessia, Capuano; Maria, Gelardi; Giulia, Silvestri; Stefania, Dutto; Maria, Avolio; Rossana, Cavallo; Alice, Bartalucci; Cristina, Paglieri; Fulvio, Morello; Lorenzo, Richiardi; Milena M, Maule; Enrico, Lupia
title: Lung ultrasound for the diagnosis of SARS-CoV-2 pneumonia in the Emergency Department
date: 2020-10-13
journal: Ann Emerg Med
DOI: 10.1016/j.annemergmed.2020.10.008
sha: 035c9c7a21b21c389eff70955fa1b7e9b74372aa
doc_id: 949305
cord_uid: ap72gg3x

Objective Accurate diagnostic testing to identify SARS–CoV-2 infection is critical. Although highly specific, SARS–CoV-2 reverse transcription polymerase chain reaction (RT-PCR), has shown, in clinical practice, to be affected by a non-insignificant proportion of false negative results. The study sought to explore whether the integration of lung ultrasound (LUS) with clinical evaluation is associated with increased sensitivity for the diagnosis of COVID-19 pneumonia, and therefore may facilitate the identification of false negative SARS-CoV-2 RT-PCR results. Methods This prospective cohort study enrolled consecutive adult patients with symptoms potentially related to SARS-CoV-2 infection admitted to the emergency department (ED) of an Italian academic hospital. Immediately after the initial assessment, a LUS evaluation was performed and the likelihood SARS-CoV-2 infection, based on both clinical and LUS findings (“integrated” assessment), was recorded. RT-PCR SARS-CoV-2 detection was subsequently performed. Results We enrolled 228 patients; 107 patients (46.9%) had SARS-CoV-2 infection. Sensitivity and negative predictive value of the clinical-LUS integrated assessment were higher than first RT-PCR [94.4% (95% CI 88.2-97.9), vs. 80.4% (95% CI 71.6-87.4); 95% (95% CI 89.5-98.2), vs. 85.2% (95% CI 78.3-90.6)]. Among the 142 patients who initially had negative RT-PCR, 21 resulted positive at a subsequent molecular test performed within 72 hours. All these false negative cases were correctly identified by the integrated assessment. Conclusion This study suggests that, in patients presenting to the ED with symptoms commonly associated with SARS-CoV-2 infection, the integration of LUS with clinical evaluation has high sensitivity and specificity for COVID-19 pneumonia and it may help to identify false negative results occurring with RT-PCR.

Accurate diagnostic testing to identify individuals presenting with symptoms associated with Severe Acute Respiratory Syndrome CoronaVirus 2 (SARS-CoV-2) infection is critical, not only for appropriate patient management but also for effective and judicious implementation of infection prevention and control strategies [1] [2] [3] . A test unable to accurately identify individuals affected by coronavirus disease of 2019 (COVID-19) (i.e., false negative result) would generate a significant risk of disease transmission and further propagation of the infection in the community and healthcare settings 1, 4, 5 . As SARS-CoV-2 tests become more available, understanding how they perform in "real world" settings (e.g., busy Emergency Departments) and developing integrated diagnostic pathways able to identify or minimize false negative results represent a priority as we prepare for a second wave of infection 1, 5 .

Currently, the most commonly used diagnostic test for the diagnosis of SARS-CoV-2 infection is the reverse transcription polymerase chain reaction (RT-PCR) performed using nasopharyngeal swabs 3,6-8 . Although highly specific, this test has shown, in clinical practice, to be affected by a non-insignificant proportion of false negative results 1, 9 , potentially related to insufficient viral copies, deficient sampling, inappropriate timing in relation to illness onset, or different location of viral replication (e.g., lower respiratory tract) 9, 10 .Considering the unsatisfactory results obtained with RT-PCR 3,9 , many experts recommend 1) to continue to isolate patients with a high clinical suspicion 11-13 , an intervention often problematic given limitations in appropriate isolation spaces and shortages in personal protective equipment, and 2) to conduct further testing, either timeconsuming (e.g., serial RT-PCRs) or logistically challenging (e.g., bronchoscopy for bronchoalveolar lavage [BAL] or chest Computed Tomography [CT]) scan 10 ).

Lung ultrasound (LUS) is a non-invasive bedside tool that has been shown to be useful for the assessment of patients presenting with acute respiratory failure 14 , as well as for the diagnosis of several pleural and pulmonary diseases, including acute heart failure, pleural effusion, pneumonia and pneumothorax [15] [16] [17] . Preliminary reports have been published on the use of LUS in the evaluation of patients with SARS-CoV-2 infection [18] [19] [20] .

In this study, we sought to explore, in a population of adult patients presenting to the emergency department (ED) with symptoms potentially related to SARS-CoV-2 infection, whether the integration of LUS with the initial clinical evaluation was associated with increased sensitivity for the diagnosis of COVID19 pneumonia, therefore facilitating the identification of false negative RT-PCR results.

This was a prospective cohort study held at the Emergency Department of the "Città della Salute e della Scienza di Torino" University Hospital, Turin, Italy, an urban, university-affiliated ED with an approximate annual volume of 75,000 visits/year and main site of the University of Turin Emergency Medicine Residency Program. The protocol was approved by the "Città della Salute e della Scienza di Torino" institutional review board (authorization n. CS3/23). All patients or their substitute decision makers provided informed consent and all data were immediately de-identified.

The study was conducted in accordance with the principles of the Declaration of Helsinki for clinical research involving human subjects.

We considered eligible all adult patients (age≥18 years) who, at triage, screened positive for acute symptoms commonly associated with SARS-CoV2 infection (i.e. fever, dyspnea, new or worsening cough, sore throat, diarrhea, ageusia, anosmia, asthenia) during the study period. Screening positive patients were cohorted in a dedicated area of the ED, and subsequently evaluated and approached for study enrollment by the treating physician, regardless of their primary language. Patients known to be infected by SARS-CoV2, requiring an urgent psychiatric assessment, or those already intubated at the time of ED arrival were excluded. Conversely, patients who required non-invasive mechanical ventilation were included in the study. Availability of an attending physician with expertise in LUS (i.e., completion of a LUS training course accredited by the Italian Society of Emergency Medicine 21 and performance and interpretation of at least 40 LUS examinations) was also required for enrollment. All physicians received a training module describing study, scanning protocol, and COVID-19/viral pneumonia LUS findings known at the time of study initiation 18 .

Immediately after the initial clinical evaluation (i.e., past medical history, history of present illness, physical examination, and ECG, but not laboratory analyses and chest radiography), the treating physician (i.e. the attending physician responsible for the patient care) postulated and recorded in a (Table S1) . 

Descriptive results are presented as median and interquartile range (IQR) for continuous data, or as number and percentage for ordinal data.

The diagnostic accuracies of clinical evaluation alone, clinical-LUS integrated assessment and first RT-PCR were calculated through sensitivity, specificity, positive predictive values (PPV) and

negative predictive values (NPV), positive and negative likelihood ratios (LR+ and LR-), and area under the receiving-operator curve (AUC) 31 .We compared the difference in accuracies by using the McNemar test for paired data 32 . Net reclassification index (NRI) 33 was used to evaluate the clinical usefulness of the different assessments/diagnostic tests.

We estimated that a sample size of 228 patients was necessary to achieve a power of 90% to observe an absolute difference of 8% in sensitivity between clinical-LUS integrated evaluation and RT-PCR, with 1% alpha error (one-sided test). 

The absence of a true "gold standard" for the diagnosis of SARS-CoV-2 infection is a limitation of our study. We assumed that patients who tested positive at RT-PCR were true positive cases, as only occasional false positive results have been described 8, 34 . However, as previously discussed, false negative results with RT-PCR are not uncommon. In our study, an incorporation bias (and, possibly, a verification bias) may have occurred for patients with negative results for RT-PCR and clinical-LUS integrated assessment and for whom further investigations were not pursued. We 

Our study demonstrates that, in adult patients presenting to the ED with symptoms potentially related to SARS-CoV-2 infection, an integrated clinical and pulmonary sonographic approach has high sensitivity and specificity for COVID-19 pneumonia and may therefore help to identify false negative results occurring with nasopharyngeal specimens, analyzed with RT-PCR. To our knowledge, this is the first study to demonstrate, in a cohort of patients with suspected SARS-CoV-2 infection, an improvement of sensitivity with the implementation of LUS with clinical evaluation.

Although in laboratory settings SARS-CoV-2 RT-PCR has been shown to be extremely sensitive and specific 34 , "real world" clinical sensitivity of RT-PCR has been reported to be significantly lower 5 , likely related to multiple factors, including sampling errors or inappropriate timing of sample collection(either too early or late in the clinical course of the disease 34,38 ). In our study, clinical sensitivity was similar or even higher to what previously reported 5, 38, 39 , although a recently published meta-analysis comparing chest CT and initial RT-PCR sensitivity suggested higher sensitivity [89% (95% CI, 81-94%)] 40 . However, in this meta-analysis, substantial heterogeneity was identified (I 2 =90%), most of the studies had retrospective design, details on RT-PCR procedures were not provided, and often the reference standard was considered the RT-PCR itself 39 .

Nevertheless, even with RT-PCR sensitivity as high as 89% 40 Table S3 , were all affected by diseases that could mimic the pathological findings detected by LUS in COVID-19 patients, leading the treating physician, during the pandemic outbreak, to choose COVID-19 as the most likely final diagnosis. It is well known, indeed, that LUS alone is neither able to discriminate different forms of diffuse interstitial syndrome (e.g. interstitial lung disease, acute decompensate heart failure, ARDS, interstitial pneumonia) nor of lung parenchymal consolidations. On the contrary, the integration of LUS with clinical data would increase its diagnostic accuracy in all these conditions 24, 54, 55, 15 . The ability to perform LUS at the bedside, the short time required to complete it, the lower costs, and the absence of radiation exposure represent other significant strengths of our integrated approach when compared with other proposed diagnostic strategies, such as integration with chest CT scan 10, 42 .

In our study the median duration of LUS evaluation was 5 minutes (IQR 5-8 minutes and 5-10 minutes for SARS-CoV-2 negative and positive patients, respectively). This duration is consistent with what has been reported in other studies 35, 36 . However, providers with limited expertise may take longer to perform the 12-zone LUS examination.

In conclusion, the results of our study suggest that, in patients presenting to the ED with symptoms 

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The Authors would like to acknowledge Butterfly Network Inc (New York, NY, USA) for supporting our ED during the SARS-CoV-2 pandemic with four Butterfly iQ devices.

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