RATIONALE: Severe cases of Coronavirus Disease 2019 (COVID-19) are frequently associated with the development of Acute Respiratory Distress Syndrome (ARDS) which can be complicated by the appearance of pneumothorax and/or pneumomediastinum (PaoP). This single-network, multi-hospital study examines PaoP in a retrospective COVID-19 cohort, including patient characteristics and overall incidence. In addition, risk factor determination is conducted using case-matched COVID-19 controls, hypothesizing that the need for mechanical ventilation and pulmonary comorbidities are associated with PaoP. METHODS: This is an IRB-exempt, retrospective case-control study involving patients with COVID-19 diagnosed by polymerase chain reaction and admitted to the hospital network 03/01/2020-11/30/2020. A total of 25 patients who developed PaoP were matched to COVID-19 patients without PaoP in 1:4 ratio according to age, gender and APACHE 2 score. Detailed chart review included patient demographics, BRIXIA, MuLBSTA, supplemental oxygen use, mechanical ventilation, inflammatory markers (CRP, ferritin, IL-6), pulmonary comorbidities (asthma, COPD, OSA, tobacco use), nonpulmonary comorbidities (diabetes, morbid obesity, malignancy, cardiovascular and renal diseases), and hospitalization characteristics (hospital length of stay or HLOS, ICU admission). Univariate results (Table 1) with significance level of P<0.20 were included in subsequent binary logistic regression to determine factors independently associated with PaoP.RESULTS: A total of 125 patients were evaluated (25 PaoP cases and 100 matched controls). Group characteristics included median age of 72 years [IQR 58-80];84% male sex;56% Caucasian;Median APACHE II 15.6 [6.8-41.0]. There were no significant differences in terms of CRP, ferritin, or IL-6 between the two groups. Patients with PaoP underwent chest tube placement in 76% cases and had significantly higher mortality (68% vs. 43%, p<0.025). In our multivariate analysis, factors independently associated with PaoP included longer hospitalization (OR 1.047, 95%CI 1.001-1.096) and mechanical ventilation (OR 3.271, 95%CI 1.066-10.035). CONCLUSION: Our data demonstrate that longer HLOS and the requirement for mechanical ventilation are independently associated with PaoP. However, our data do not support the hypothesis that pulmonary comorbidities (asthma, COPD, OSA, tobacco use) are significantly associated with PaoP. This, combined with the finding that the level of PEEP did not appear to be a significant risk factor for PaoP, highlights the need for better understanding of the underlying pulmonary pathology. The current series is among the largest studies of this important phenomenon in COVID-19 patients, and provides important insight into our understanding of this rare but prognostically important complication.