From the outbreak of 2019 novel coronavirus disease in December 2019 to Mar 27, 2020 , and the number of confirmed patients and deaths outside of China is increasing rapidly all around the world 1 . The autopsy of a patient who died from severe infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) showed evident desquamation of pneumocytes, hyaline membrane formation and pulmonary edema, suggesting acute respiratory distress syndrome (ARDS) 2 . Xun et al. reported that all of 25 patients with COVID-19 died of SARS-CoV-2 infection complicated by respiratory failure, suggesting that lung is the main target organ, followed by multiple organ dysfunction, including heart, kidney and liver 3 . Therefore, refractory hypoxemia and ARDS are the leading causes of death for critically ill patients with COVID-19.
Pneumothorax is a common complication of ARDS. The incidence of pneumothorax varies from 1.7% to 77%, significantly increasing the mortality of patients 4-7 . However, there are no detailed reports on pneumothorax in critically ill patients with COVID-19, but a report by Yang et al. mentioned that 1 of 37 patients treated with mechanical ventilation developed pneumothorax, indicating a low incidence of pneumothorax in critically ill patients with COVID-19 8 . Nonetheless, this is inconsistent with what we have found in clinical observations. Meanwhile, the clinical characteristics of the patients with COVID-19 complicated by pneumothorax have not been clarified. Therefore, we have summarized the clinical characteristics of 5 critically ill COVID-19 patients with pneumothorax in our center, which may shed light on early prevention and identification of pneumothorax in critically ill patients with COVID-19 and reduce the mortality.
The diagnosis of COVID-19 was performed according to New Coronavirus Pneumonia Diagnosis and Treatment Program (Trial Fifth Edition). Two negative nucleic acid tests of respiratory tract specimens (with an interval of at least 1 day) were considered the virus was eliminated 9 . Diagnosis of ARDS was based on Berlin standards 10 . According to the mechanism of pneumothorax of patients with ARDS, the risks of pneumothorax are classified into four aspects, including increased alveolar pressure, increased negative pressure of the pleural cavity, shear stress, and changes of lung structure and function. Probability of the risk was defined as irrelevant, possible and probable (Table 1) . This study was approved by the Medical Ethical Committee of the First Affiliated Hospital of Chongqing Medical University (approval number 20200601). Due to the special reasons of the epidemic, the patients' informed consent was not obtained.
From January 23, 2020 to March 15, 2020, we retrospectively screened 248 COVID-19 patients, and collected detailed medical records, laboratory findings, chest CT scan and X-ray images of critically ill COVID-19 patients complicated by pneumothorax at Chongqing Three Gorges Central Hospital.
Continuous variables were presented with range. Categorical variables were presented with percentage.
From January 23, 2020 to March 15, 2020, a total of 248 patients with COVID-19 were admitted to the hospital, and 49 of them met the diagnostic criteria of ARDS. Twenty-one of these patients were treated with mechanical ventilation, and 9 of them received invasive mechanical ventilation (IMV), 5 of whom developed pneumothorax. The overall incidence of pneumothorax was 2.01% (5/248), 10% (5/49) in patients with ARDS, 24% (5/21) in patients receiving mechanical ventilation, and 56% (5/9) in patients requiring IMV. Four of the 5 patients died during hospitalization, with a mortality as high as 80% (4/5), and the remaining one was still in hospital with a prolonged length of stay of 39 days ( Figure 1 ).
The 5 patients were all male, their age ranging from 54 to 79 years old. The time from onset to dyspnea ranged from 3 to 9 days, and the interval from dyspnea to the occurrence of pneumothorax varied from 15 to 40 days. PO 2 /FiO 2 on admission varied between 127-200 mmHg according to arterial blood gas (ABG) tests, which, in combination with history and chest radiography, was consistent with the diagnostic criteria of ARDS. None of the 5 patients had chronic lung diseases or smoking history. The emphysema showed in the chest CT images at admission of case 1 was considered as senile emphysema, as the patient has no history of chronic coughing, sputum or dyspnea. They received treatment of mechanical ventilation with protective ventilation strategies. Chest CT scan and X-ray images of the 5 patients showed remarkably heterogenic distribution, with patchy glass-ground opacification, interspersed with normal-appearing areas or consolidation, especially distributing in gravity dependent lung regions.
The fibrosis of cases 3 and 4, consolidation of case 2, 3 and 5, and pulmonary cysts and emphysema of case 3 were newly developed during the treatment. Case 1 and 4 developed right pneumothorax after reducing the usage of neuromuscular blocking agents,with increased respiratory rates (RR) and paradoxical thoracoabdominal motion. Right pneumothorax of case 2 occurred after an ineffective recruitment maneuver when he was treated by IMV combined with venous-venous extracorporeal membrane oxygenation (VV-ECMO). Pneumothorax of case 3 occurred after a consecutively and severely coughing, although he was already weaning from IMV Table 2 ).
Pneumothorax is a potentially fatal complication in patients with ARDS, especially in those who receives mechanism ventilation. However, the incidence of pneumothorax varies widely, from 1.7% to 10% 7, 11 , according to previous literature, with an astonishing 77% in an early report 6 . In our study, the incidence of pneumothorax was 10% (5/49) in COVID-19 patients with ARDS, 24%
(5/21) in patients receiving mechanical ventilation , 56% (5/9) in patients treated with IMV, significantly higher than 2.70% (1/37) as reported by Yang X et al. in COVID-19 patients with mechanical ventilation 8 and 1.7% (6/356) as reported by Sihoe et al. in severe acute respiratory syndrome (SARS) patients with ARDS 7 . Pneumothorax has been known to increase the mortality in patients with ARDS. In a study of 84 patients with severe ARDS by Gattinoni et al., the incidence of pneumothorax was 48.8% (40/84), and the mortality was higher in patients with pneumothorax than those without it (66% vs. 46%) 5 . On the basis of our data, pneumothorax is a frequent and fatal complication in critically ill COVID-19 patients with ARDS, resulting in a mortality rate as high as 80% (4/5) and prolonged length of hospital stay. Therefore, prevention, prompt recognition and treatment of pneumothorax are very important to minimize the mortality of critically ill COVID-19 patients with ARDS, especially those who require mechanical ventilation.
The occurrence of pneumothorax in patients with ARDS is associated with multiple factors, including chronic pulmonary diseases , smoking, severity and duration of ARDS, mechanical ventilation settings, changes of lung structure and function during ARDS 12 . While, none of the 5 patients in the current study had a history of smoking or chronic pulmonary diseases.
Several ventilation parameters are considered significant in the pathology of pneumothorax, including peak inspiratory pressure, PEEP, RR and V T . Lung-protective ventilation strategies were applied in all 5 patients while they were on mechanical ventilation, with V T set according to predicted body weight (<6ml/kg) and static P plat less than 30 cm H 2 O 13 . All patients except case 5 were treated with neuromuscular blockers to reduce oxygen consumption, RR, nagetive pressure in pleural cavity, transpulmonary pressure and human-machine confrontation during IMV 14, 15 .
However, case 2 developed right pneumothorax after ineffective recruitment maneuver when he was on IMV combined with VV-ECMO treatment. Recruitment maneuver may increase alveolar pressure and lead to pneumothorax, in line with previous reports 16 . Case 1 and 4 developed pneumothorax in the process of reducing neuromuscular blocker dose. Moreover, paradoxical thoracoabdominal motion and increased RR appeared in case 1, 4 and 5, suggesting forced inhalation while they suffered from severe ARDS. Pneumothorax occurred in case 3 due to a severely coughing when he was treated by COT after extubated. Severe cough and forced inhalation significantly increase the negative pressure in the pleural cavity 16 and transpulmonary pressure, thereby leading to alveolar overdistension 18 and causing pneumothorax.
However, pneumothorax is more common in intubated patients with ARDS than in those without ARDS 19 . Therefore, in addition to mechanical ventilation parameters, there are many other factors promoting pneumothorax, such as formation of pulmonary cysts and emphysema-like changes 20, 21 . The autopsy of COVID-19 patients showed pulmonary consolidation, fibrosis and lung lobe dilation 22 . These signs were also partially shown in the CT images of the 5 patients, similar to SARS-related ARDS 23 . Fibrosis was seen in 3 of the 5 patients, which seems more common compared to patients with SARS (3/8) 23 . Moreover, the fibrosis of cases 3 and 4, consolidation of case 2, 3 and 5 and pulmonary cysts and emphysema of case 3 were newly developed during the treatment. Chest CT images of the 5 patients showed heterogenic distribution, with patchy glass-ground opacification interspersed with areas of normal-appearing or consolidation, especially distributing in gravity dependent lung regions. The shear stress at the junction between aerated and collapsed lung aggravates the structural damages during the recruitment and de-recruitment of lung units 18 . Hence, the abnormal alveolar pressure and negative pressure of the pleural cavity induce increased transpulmonary pressure, which, together with shear stress and changes of lung structure and function, contributes to the pathology of pneumothorax in patients with ARDS ( Figure 4) . Furthermore, the incidence of pneumothorax is related to the duration of ARDS. The pneumothorax of the 5 critically ill COVID-19 patients occurred 2 weeks after the beginning of dyspnea. Gattinoni L et al. reported an incidence of pneumothorax of 87% in patients with late ARDS (more than 2 weeks), which is much higher than the 30% incidence in patients with early ARDS (less than 1 week) 5 .The aforementioned complicating factors increase the incidence of pneumothorax in critically ill COVID-19 with ARDS. The evaluation of probability of the risk in the 5 patients is listed in Table 3 .
The literature on the treatment of ARDS with pneumothorax is very limited. Treatment options vary from observation, traditional tube thoracostomy, pleurodesis, open thoracotomy to thoracoscopic surgery. Observation was used in 2 patients with small-amount pneumothorax, and traditional tube thoracostomy was performed in the other 3 patients with large pneumothorax and severe dysnea. Persistent air leaks exist in 2% of patients with ARDS, increasing the mortality rate by 26% 24 . In our study, air leaks persisted in 2 of the 4 dead patients until their death. 
Pneumothorax is a frequent complication of critically ill COVID-19 patients and related to poor prognosis, and therefore the prevention and prompt recognition of pneumothorax are particularly important. Protective ventilation-the prevision of P plat less than 30cmH 2 O and V T normalized to predicted body weight-reduces the alveolar pressure, overdistension alveolus, and strongly risk of pneumothorax and persistent air leak in patient s with ARDS 27 . In addition, the use of neuromuscular blockers reduces the negative pressure in pleural cavity, shear stress and changes of lung structure, and then is associated with lower incidence of pneumothorax in patients with severe ARDS (4% vs 11.7%) 15 , which was also confirmed in a systematic evaluation . Cases 1 and 4 developed pneumothorax while reducing the dose of neuromuscular blocker, indicating the need of close monitor for RR, paradoxical thoracoabdominal motion or other signs of forced inhalation. Furthermore, antivirus and prone ventilation may facilitate the recovery and recruitment of lung before stopping using neuromuscular blocker. But the use of recruitment maneuver requires careful consideration, given the circumstance of case 2 and previous literatures 16 . Although protective ventilation strategies and neuromuscular blocker have been widely applied, high incidence of pneumothorax remains in critically ill COVID-19 patients with ARDS treated by mechanical ventilation. Cases 3 suggested prompt use of ECMO in patients with rapidly progressing ARDS to allow the reduction of peak and mean airway pressure, V T , ventilator rate and oxygen concentration, risk of acute lung injury and forced inhalation, which may reduce the incidence of pneumothorax and mortality. Of course, management of cough after ECMO decannulation and weaning from ventilator are also very important. Combes A et al. reported that extracorporeal carbon dioxide removal (ECCO 2 R) to facilitate ultra-protective ventilation (V T 4mL/kg and P plat ≤ 25 cmH 2 O) in patients with moderate ARDS was feasible and safe 28 . Hence, timely use of ECMO or ECCO 2 R combined by ultra-protective ventilation may play an important role in the prevention of pneumothorax in critically ill patients with severe ARDS, particularly in who newly developed emphysema, fibrosis or pulmonary cysts in chest CT images.
There are several problems which remain to be answered by future studies with larger sample size.
Firstly, the optimal time and manner for the retreat of neuromuscular blockers remains to be clarified. Secondly, suitable treatment options for COVID-19 patients with persistent air leaks are still unclear. Thirdly, the difficulty to obtain timely CT images for critically ill COVID-19 patients calls for monitoring with more portable means of examination, such as bedside lung ultrasound bedside CT, but the value of these is uncertain. Fourthly, the risks and advantages of recruitment maneuver in critically ill COVID-19 patients with severe ARDSshould be further studied. Fifthly, early use of ECMO or ECCO 2 R needs to be weighed against rescue therapy on the effect of lower incidence of pneumothorax and mortality of critically ill COVID-19 with ARDS.
In summary, pneumothorax remains a frequent and fatal complication of COVID-19 patients with ARDS despite the use of protective ventilation strategies. Our findings indicate that pneumothorax is most likely to occur 2 weeks after the beginning of dyspnea and associated with many factors, including the reduction of neuromuscular blocking agents, recruitment maneuver, severely coughing, changes of lung structure and function during ARDS over time. Apart from traditional protective ventilation and use of neuromuscular blockers, timely treatment of ECMO or ECCO 2 R combined by ultra-protective ventilation may provide new option for the prevention of pneumothorax in critically ill COVID-19 patients with severe ARDS, especially in whom with newly developed emphysema, fibrosis or pulmonary cysts in CT images. Although our study is limited by the small sample size and retrospective nature, we believe the findings reported is important for reducing the incidence of pneumothorax and mortality, and improving the prognosis for critically ill COVID-19 patients. 