The high incidence of barotrauma in patients with COVID-19-related acute respiratory distress syndrome (ARDS) (16.1%, with a mortality rate >60%) provides rationale for considering COVID-19 ARDS a paradigm for lung frailty. The investigators recently discovered that the Macklin effect is an impressive radiological predictor of barotrauma in COVID-19 ARDS. Since lung frailty is a major issue also in non-COVID-19 ARDS (6% barotrauma, with a mortality rate of 46% ) the investigators want to confirm the importance of Macklin effect in non-COVID-19 ARDS. Using artificial intelligence-based approaches the investigators also want to identify imaging biomarkers to non-invasively assess lung frailty in a mixed cohort of COVID-19/non-COVID-19 ARDS patients. Furthermore, the investigators want to prospectively validate these biomarkers in a cohort of ARDS patients. This will provide a therapeutic algorithm for ARDS patients at high-risk for barotrauma, identifying those most likely to benefit from hyper protective strategies.

Development of barotrauma, spanning from asymptomatic air leakage within lung parenchyma to life-threatening conditions such as tension pneumothorax, is frequent in acute respiratory distress syndrome (ARDS), with a difficult, non-standardized management, resulting in high mortality rates (greater than 60% in coronavirus disease 2019 [COVID-19] ARDS patients, around 46% in non-COVID-19 ARDS patients). Of note, barotrauma occurs also in spontaneously breathing patients with COVID-19 ARDS. Frailty of lung parenchyma represents indeed a major issue in ARDS. In addition, in high-risk patients, mechanical ventilation may exacerbate pulmonary damage (ventilator-induced lung injury) and potentially induce barotrauma despite use of protective mechanical ventilation. Early assessment of lung frailty could therefore allows early risk stratification in terms of barotrauma susceptibility amongst ARDS patients, providing rationale for the deployment of lung protective management strategies in those at high-risk for barotrauma. Macklin effect, firstly intended to allow proper differentiation between respiratory and other causes of air leakage in the mediastinum (such as tracheobronchial/oesophageal injury), has been recently proved by our group to be a consistent, very accurate radiological predictor of barotrauma development in COVID-19 ARDS patients (sensitivity: 89.2%; specificity: 95.6%), anticipating by 12 days the occurrence of clinically overt barotrauma. These results have been confirmed, and even improved by multicentre findings, which report, on a large cohort of COVID-19 patients (almost 700), an impressive, almost perfect overall accuracy (99.8%) of the Macklin effect in predicting barotrauma development. Furthermore, data from our group suggest that early application of awake veno/venous extracorporeal membrane oxygenation (ECMO) without invasive mechanical ventilation in COVID-19 severe ARDS patients at high-risk for barotrauma (those with Macklin effect on chest CT imaging) is feasible and may result in no barotrauma events and low intubation rate. In this respect, confirmation of Macklin effect role and identification of further, novel quantitative imaging biomarkers could unveil biological bases of lung frailty in course of ARDS and provide instruments for early risk stratification before barotrauma occurrence.

Our group also implemented original in-house facilities consisting of densitometry, machine learning and artificial intelligence-based approaches to assess lung composition in COVID-19 patients throughout a fully automated workflow; recently, the investigators highlighted the outstanding clinical significance of this methodological approach in predicting patients' prognosis, as well as its great reproducibility. Preliminary, yet unpublished findings suggest that lung frailty has a specific densitometric signature, being a possible marker for hyper protective management strategies; few, highly robust radiomic features seem to corroborate the same result.

Accordingly, the driving hypotheses of this retrospective/prospective study are that, irrespective of COVID-19 status, in ARDS patients, i) lung frailty has a specific pattern of imaging biomarkers, and that ii) a more accurate selection of patients could limit the problem of barotrauma associated with mechanical ventilation.

Inclusion Criteria:

• Clinical and radiological signs of ARDS, according to Berlin criteria [14], requiring ICU admission;
• Obtain duly signed informed consent.

Exclusion Criteria:

• Poor quality imaging (because of motion/respiratory artefacts).

Patients with ARDS clinical suspicion or diagnosis will be enrolled; specifically, these patients will be admitted at intensive care unit. All patients enrolled in the prospective cohort will follow their normal course of diagnosis/treatment without any further requirements for the scope of this study other than those provided in the normal management of patients with this condition. Furthermore, any decision regarding drug or procedure will be made by the physician based on her/his clinical judgment in the context of clinical practice, independently from the decision to include the patient in this study. No follow-up medical and/or imaging examinations/laboratory analysis after hospital discharge are needed by the present study design.