Radiological-pathological signatures of patients with COVID-19-related pneumomediastinum: is there a role for the Sonic hedgehog and Wnt5a pathways?

A total of 1,098 consecutive patients with COVID-19 pneumonia were reviewed and 54/1,098 (4.9%) had an unenhanced CT scan of the thorax and met the eligibility criteria. There was a 44.6% PM-associated mortality rate, making it a severe complication of the disease, whilst the study population mortality rate of hospitalized patients was 22.8% (p-value=0.002). The median age of patients with PM was 73 years (IQR, 64-77), 40 (74.1%) were males (29.2% smokers), and most patients (n=43, 81.1%) had comorbidities (cardiopathy 52.8%, hypertension 50.9%, obesity 31.4%, diabetes 30.2%, cancer 17.3%, COPD 16.6%, immune depression 3.2%). Pneumomediastinum alone was detected in 40 patients (74%), while the remaining 14 patients had associated pneumothorax (10 mono-lateral partial, 3 mono-lateral complete, 1 bi-lateral pneumothorax). The prevalent lung parenchyma CT scan pattern was ground glass in 20 patients (37%), alveolar filling 11 patients (20.4%), mixed 10 patients (18.5%), crazy paving 7 (13%), and reticular/fibrotic pattern 6 patients (11.1%). Spontaneous PM occurred in 4 patients (7.4%), 1 patient (1.8%) received HFNC while had PM, 30 patients (55.6%) NIV/CPAP, and 19 patients (35.2%) were invasively ventilated. We observed no statistical significant differences regarding clinical characteristics, co-morbidity, and CT scan features between deceased and surviving patients. Only invasive mechanical ventilation was significantly associated with death. There was a 9 day median duration (IQR, 3-13) of mechanical ventilation from intubation to PM. An autopsy was carried out on the 23 patients with PM who died and 100% of them had tracheal/large airway lesions. A control group of 8 patients who died of non-COVID-19 ARDS were also pathologically studied. Autopsy showed that most of the COVID-19 PM patients had full thickness tracheal/large airway lesions (29 patients, 53.7%), two had tracheal fistula (Fig. 1A) while the remaining 16 PM patients had tracheal mucosal ulcers and/or cartilage lesions. All the autopsies showed peculiar findings of the tracheal/airways cartilage, specifically fibrous-hyaline degeneration (Fig. 1B and 1C), that were not present in the trachea and main bronchi of control ARDS subjects. The immunohistochemistry staining evidenced a strong Wnt5a expression (labelling score 3.69 0.55) and a weak SHH expression (labelling score 2.21 0.90) in the cartilage cells of the tracheal/bronchial rings of the COVID-19 patients with PM. Controls were negative for both Wnt5a and SHH for cartilage regeneration biomarkers (labelling score 0.25 0.46 for both SHH and Wnt5a, p=0.0001).