key: cord-0688350-r07x8kq0 authors: Arenas-De Larriva, Marisol; Martín-DeLeon, Roberto; Urrutia Royo, Blanca; Fernández-Navamuel, Iker; Gimenez Velando, Andrés; Nuñez García, Laura; Centeno Clemente, Carmen; Andreo García, Felipe; Rafecas Codern, Albert; Fernández-Arias, Carmen; Pajares Ruiz, Virginia; Torrego Fernández, Alfons; Rajas, Olga; Iturricastillo, Gorane; Garcia Lujan, Ricardo; Comeche Casanova, Lorena; Sánchez-Font, Albert; Aguilar-Colindres, Ricardo; Larrosa-Barrero, Roberto; García García, Ruth; Cordovilla, Rosa; Núñez-Ares, Ana; Briones-Gómez, Andrés; Cases Viedma, Enrique; Franco, José; Cosano Povedano, Javier; Luis Rodríguez-Perálvarez, Manuel; Joaquin Cebrian Gallardo, Jose; Nuñez Delgado, Manuel; Pavón-Masa, María; del Mar Valdivia Salas, Mª; Flandes, Javier title: The role of bronchoscopy in patients with SARS-CoV-2 pneumonia date: 2021-06-04 journal: ERJ Open Res DOI: 10.1183/23120541.00165-2021 sha: 531f1af04ff34d66cc0338476850ce24cc7024f6 doc_id: 688350 cord_uid: r07x8kq0 BACKGROUND: The role of bronchoscopy in coronavirus disease 2019 (COVID-19) is a matter of debate. Patients and methods: This observational multicenter study aimed to analyse the prognostic impact of bronchoscopic findings in a consecutive cohort of patients with suspected or confirmed COVID-19. Patients were enrolled at 17 hospitals from February to June, 2020. Predictors of in-hospital mortality were assessed by multivariate logistic regression. RESULTS: A total of 1027 bronchoscopies were performed in 515 patients (age 61.5±11.2; 73% men), stratified into a clinical suspicion cohort (n=30) and a COVID-19 confirmed cohort (n=485). In the clinical suspicion cohort, the diagnostic yield was 36.7%. In the COVID-19 confirmed cohort, bronchoscopies were predominantly performed in the intensive care unit (n=961; 96.4%) and major indications were: difficult mechanical ventilation (43.7%), mucus plugs (39%) and persistence of radiological infiltrates (23.4%). One hundred forty-seven bronchoscopies were performed to rule out superinfection, and diagnostic yield was 42.9%. There were abnormalities in 91.6% of bronchoscopies, the most frequent being mucus secretions (82.4%), haematic secretions (17.7%), mucus plugs (17.6%), and diffuse mucosal hyperemia (11.4%). The independent predictors of in-hospital mortality were: older age (Odds ratio [OR]=1.06; p<0.001), mucus plugs as indication for bronchoscopy (OR=1.60; p=0.041), absence of mucosal hyperemia (OR=0.49; p=0.041) and the presence of haematic secretions (OR=1.79; p=0.032). CONCLUSIONS: Bronchoscopy may be indicated in carefully selected patients with COVID-19 to rule out superinfection and solve complications related to mechanical ventilation. The presence of haematic secretions in the distal bronchial tract may be considered a poor prognostic feature in COVID-19. , the supporting scientific background is scarce and is mainly composed by short series [5] [6] [7] . The main endpoint of the present nationwide study was to evaluate the impact of endoscopic findings on outcomes among patients with COVID-19. Secondary outcomes were: a) to describe the indications for bronchoscopy and procedures; b) to analyze the diagnostic yield of bronchoscopy in patients with suspected SARS-CoV-2 pneumonia. The Potential study candidates were screened among patients admitted to the hospital with suspected or confirmed COVID-19. Those patients with compatible clinical symptoms and typical radiological findings [8] with two negative RT-PCR of nasopharyngeal swab specimens could undergo bronchoscopy to obtain a lower respiratory tract specimen and they formed the clinical suspicion cohort. Patients with previous positive RT-PCR of SARS-CoV-2 in nasopharyngeal swab specimens who underwent bronchoscopy to rule out superinfection or for therapeutic purposes formed the RT-PCR-confirmed cohort. Data was recorded in an anonymized electronic datasheet using the REDCap (Research Electronic Data Capture) platform [9] . Study investigators received online training at baseline to homogenize the data collection, and they were granted access with a unique username/password. All clinical information was extracted from reliable electronic medical data sources. were recorded. Blood tests and radiological features were considered within the 48 hours prior to bronchoscopy. Imaging findings obtained in chest computed tomography (CT) were reported according to the COVID-RADS classification as typical, fairly typical, atypical or normal [11] . Bronchoscopic findings and procedures were also registered. Patients were followed until hospital discharge or death. The main outcome evaluated was in-hospital mortality at 90 days after bronchoscopy. The sample size was calculated using EPIDAT version 4.2 (Xunta de Galicia, Spain). The following assumptions were made to study a theoretical relationship between endoscopic findings and outcomes: -The prevalence of an endoscopic feature indicating poor prognosis: 20%. -In-hospital mortality in patients showing an endoscopic feature indicating poor prognosis: 40% (obtained from the upper range of mortality reported in previous series of critically ill patients [12, 13] ). -In-hospital mortality in patients without an endoscopic feature indicating poor prognosis: 25% (obtained from the lower range of mortality reported in previous series of critically ill patients [12, 13] ). -Statistical power: 80% -Alpha error: 5% -Incomplete or unavailable data: 5% Under these premises, the minimum sample size required was 483 patients with RT-PCRconfirmed COVID-19. The study finally comprised 515 patients, including 488 RT-PCR confirmed cases. Categorical variables were described as frequency tables and percentages. Continuous variables were described using mean and standard deviation, except for those with an asymmetric distribution, in which median and interquartile range (IQR) were used. To identify clinical, radiological and endoscopic features associated with in-hospital mortality at 90 days, the first bronchoscopy performed in each patient with RT-PCR-confirmed COVID-19 was considered. Univariate and multivariate logistic regression was used. Variables with a p<0.30 in the univariate analysis were entered the initial multivariate model. Endoscopic features with a prevalence ≥5% were also included in the initial multivariate model irrespective of their univariate p value. Non-significant co-variates were removed in a backward stepwise process. All possible interactions were tested. Clinically meaningful variables were also kept in the final model even if they did not reach statistical significance. Kaplan-Meier curves were used for survival analysis, being patients censored at hospital discharge or on October 30 th , 2020. The statistical analysis was performed using SPSS version 22.0 (IBM Corp, Armonk, NY). Every hypothesis tested was two-tailed and considered significant if p <0.05. The All patients with RT-PCR-confirmed COVID-19, either in nasopharyngeal swab or in lower respiratory tract specimens, were included to evaluate clinical, radiological and endoscopic features associated with mortality (n=496). Univariate and multivariate logistic regression analyses to predict in-hospital mortality at 90 days are shown in 2 ). The present study was carried out in the largest cohort published to date and provides key evidence regarding potential indications for bronchoscopy in patients with suspected or confirmed COVID-19, both for diagnostic or therapeutic purposes. Interestingly, some bronchoscopic findings were independently associated with in-hospital mortality after controlling for potential confounders. This information could be used to refine health care pathways and to reduce heterogeneity in clinical practice, in order to improve outcomes in patients with severe COVID-19. The diagnosis of SARS-CoV-2 pneumonia is challenging when RT-PCR is negative in conventional nasopharyngeal swabs. Previous studies have suggested that lower respiratory tract specimens could increase sensitivity and allow diagnosis in patients with reduced viral load [3] , while others recommend to avoid bronchoscopy for diagnostic purposes [14] . The selection of candidates for diagnostic bronchoscopy is paramount as this is an invasive procedure, not without risk of complications, and there is also a potential risk of spreading the infection to the medical staff due to the aerosols generated therein [15] . Only patients with high clinical suspicion of COVID-19 and typical radiological findings who test negative in two consecutive nasopharyngeal swabs may be considered for diagnostic bronchoscopy. The diagnostic yield of lower respiratory tract samples in the present study was 36.7% for SARS-CoV-2 (53% if alternative microbiological agents were considered), which was lower than in previous reports (55%-71%) [3, 5] . This may be due to different selection criteria including the number of prior negative swabs and CT findings. In our study, patients with positive and negative results had a similar clinical presentation and laboratory findings, suggestive of high clinical suspicion of COVID-19 in this cohort. Gastrointestinal symptoms could identify a subgroup of candidates for diagnostic bronchoscopy. Another way to optimize the selection of candidates would be to avoid patients with atypical radiological findings [16] . According to our results, bilateral involvement in the chest X-ray and typical or fairly typical findings in the CT as previously defined [11] , may help to achieve better selection of patients, thus refining clinical pathways. International Scientific Societies and expert panels have issued recommendations to safely perform bronchoscopy in patients with suspected or confirmed COVID-19 [17] [18] [19] [20] . However, statements regarding the optimal approach to obtain microbiological samples are vague. This may explain the heterogeneity in clinical practice, as illustrated in the present study. According to our results, BAS alone should be avoided but other options including BAL, bronchial washing or BAL in combination with BAS, would be equally valid. In contrast, guidelines are broadly homogeneous regarding protocols to protect health care personnel [17, 20, 21] . In brief, bronchoscopies in patients with suspected or confirmed COVID-19 should be performed in negative-pressurized or in adequately ventilated rooms. The involved healthcare personnel may be experienced and reduced to the minimum (2 or 3 people depending on the procedure). Disposable bronchoscopes are advised. Individual enhanced third-degree protection elements are required (protective glasses or face shield, FFP3 face masks, protective clothing, gloves…). Unfortunately, some of these recommendations are difficult to implement in real clinical practice, particularly in secondary hospitals which were overwhelmed during the peak of the pandemic. Negative-pressurized rooms are anecdotal in ICUs where most therapeutic endoscopies need to be performed. These structural deficiencies should be urgently amended by the health care authorities to protect the medical staff from COVID-19 transmission. In any case, the decision to perform (or not) a bronchoscopy in a patient with COVID-19 should be taken after a careful weighting of potential benefits against the potential risk of disease transmission to healthcare personnel. Critically ill patients with COVID-19 usually require prolonged mechanical ventilation. Bronchoscopy may help to prevent, diagnose or resolve ventilator-related complications. This is the first multicenter study describing the indications and procedures in this setting. The presence of mucus plugs was the only indication independently associated with worse outcomes (60% increased mortality rates as compared with other indications), although it is tightly related to other indications such as atelectasis, superinfection and difficult mechanical ventilation. It is paramount to optimize ventilation to prevent excess secretions and to perform frequent aspirations through the endotracheal tube [20] . There are well established clinical, analytical and radiological predictors of poor outcomes in patients with COVID-19 including (but not limited to) older age, men, increased comorbidities, lymphopenia, increased D dimer and serum ferritin, and extent of pneumonia in the chest CT [22, 23] . This is the first study sufficiently powered to analyze the impact of bronchoscopic findings on outcomes among hospitalized patients with COVID-19. The presence of diffuse mucosal hyperemia was associated with reduced in-hospital mortality rates, as it is likely a typical feature of an earlier phase of COVID-19, indicating acute inflammation [24] . This situation may still be reversible with or without anti-inflammatory drugs such as corticosteroids [25] . However, the disappearance of this endoscopic sign under persistent respiratory insufficiency may indicate a poor prognosis. The presence of haematic secretions in the distal bronchial tract was an independent predictor of increased in-hospital mortality. In contrast to diffuse mucosal hyperemia, haematic secretions could translate into irreversible damage of the capillaries and the interstitial/alveolar space, which characterizes the most advanced and severe forms of COVID-19 [26] [27] [28] . Indeed, the presence of haematic secretions identified a subgroup of very sick patients (16%) with in-hospital mortality above 60%. Further studies focused on this subpopulation are needed to delineate more aggressive and life-saving therapies. The present study is limited by its ambispective design which precluded a protocolized clinical management of the study population. Although laboratory and radiological assessment of patients with COVID-19 varied among different institutions, making it difficult to extract solid conclusions regarding these parameters, the study adequately captured the heterogeneity in real clinical practice. On the other hand, the number of patients in the clinical suspicion cohort was limited as this indication is uncommon and not accepted by some experts [14] . Finally, a potential relationship between ventilator-derived trauma and some bronchoscopic findings in critically ill patients could not be ruled out. In conclusion, bronchoscopy is pivotal as part of the armamentarium against COVID-19. In carefully selected patients with clinical and radiological suspicion of SARS-CoV-2 pneumonia who test negative in nasopharyngeal swabs, a lower respiratory tract specimen may provide an acceptable diagnostic yield, also including the identification of alternative microbiological agents or superinfection. In critically ill patients with COVID-19, bronchoscopy allows removal of mucus plugs and intrabronchial clots, and the resolution of atelectasis, thereby improving mechanical ventilation. Finally, haematic secretions in the respiratory tract and absence of diffuse mucosal hyperemia are poor prognostic features. 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Classification of aerosol-generating procedures: a rapid systematic review Correlation of Chest CT and RT-PCR Testing for Coronavirus Disease The Use of Bronchoscopy During the Coronavirus Disease 2019 Pandemic: CHEST/AABIP Guideline and Expert Panel Report Pandemic: Practice Statement from an International Expert Panel Safe performance of diagnostic bronchoscopy/EBUS during the SARS-CoV-2 pandemic Expert panel consensus statement on the applications and precaution strategies of bronchoscopy in patients with COVID-19 SEPAR and AEER consensus recommendations on the Use of Bronchoscopy and Airway Sampling in Patients with Suspected or Confirmed COVID-19 Infection Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study Qualitative and quantitative chest CT parameters as predictors of specific mortality in COVID-19 patients Pulmonary pathology of ARDS in COVID-19: A pathological review for clinicians Impact of Corticosteroids in Coronavirus Disease 2019 Outcomes: Systematic Review and Meta-analysis Pulmonary and cardiac pathology in African American patients with COVID-19: an autopsy series from New Orleans Histopathology and ultrastructural findings of fatal COVID-19 infections in Washington State: a case series Postmortem examination of COVID-19 patients reveals diffuse alveolar damage with severe capillary congestion and variegated findings in lungs and other organs suggesting vascular dysfunction The present study was funded by the Spanish Society of Pulmonology and Thoracic Surgery (SEPAR): extraordinary grant PII 2020 for research in COVID-19.We acknowledge Ms. Donna Pringle for professional English language polishing. Marisol Arenas-De Larriva has received lecture fees from Ferrer and Novartis.Manuel Rodríguez-Perálvarez has received lecture fees from Astellas, Novartis and Intercept Pharma.Javier Cosano has received a travel grant form Izasa Scientific.Enrique Cases: has received lecture fees from Ambu.The remaining co-authors have no conflict of interest to disclose. Supplementary