ABSTRACT

BACKGROUND

Sudden clinical deterioration in coronavirus disease 2019 (COVID 19) patients may be caused by thoracic air leaks. In this review, we aimed to identify the risk factors predisposing to the development of alveolar air leak and outcomes in COVID 19 patients.

METHOD

Analysis of 33 studies of COVID - 19 who developed air leaks, published between April 20 to Aug 27, 2020, reviewed. Result Twenty-one females (16.8%) and 104 males (83.2%) were included in this study. Their median age was 44.75 years, ranging from 27.5 to 60.0. Of the 125 patients, 100(80%) developed Spontaneous pneumothorax, 47 (37.6%) had pneumomediastinum, and 37 (29.6%) presented with subcutaneous emphysema. A chest tube was inserted in 63 (50.4%) patients, 97 (77.6%) received supplemental oxygen, 56 (44.8%) required mechanical ventilation, 64 (51.2%) were admitted to the Intensive Care Unit (ICU), 42 (33.6%) were admitted to the floor, and 35(28%) developed acute respiratory distress syndrome. The median length of hospital stay was 12 days (interquartile range=5.6-17.25), 57 (45.6%), patients were discharged with a median length of stay of 9 days (5.25-16.5), while mortality was reported in 29 patients (23.2%) after a longer hospitalization of 15 days (6.0-18.0). Of those who expired, only one was a smoker, and another had chronic obstructive pulmonary disease.

CONCLUSION

In COVID-19 disease, air leaks may cause potentially fatal outcomes even in formally stabilized non-smoker patients. Therefore, physicians should be aware of the development of occult air leak disease in rapidly deteriorating cohorts.

INTRODUCTION

Due to the heterogeneity of clinical presentation and complications, physicians faced overwhelming challenges during the coronavirus disease 2019 (COVID-19) epidemic due to the heterogeneity of clinical expression and complications ⁽¹⁾. Clinical presentation varies from asymptomatic, mild/moderate, severe, and even death. Mild/moderate symptoms include generalized body ache, headache, fever, tiredness, and cough. Severe COVID 19 patients can be predicted if they have shortness of breath, chest pain while breathing, tachypnea, cyanosis of the face and lips, and new-onset confusion. Severe COVID 19 patients may develop acute respiratory distress syndrome. This acute respiratory distress syndrome may result in severe complications like air leak syndrome ⁽²⁾. Due to exudative effusion in acute respiratory distress syndrome, thickened lung tissue makes the lung challenging to exchange gas; sustained–pressure ventilation requirement may lead to air leak syndrome ⁽³⁾. One of the reasons for sudden clinical deterioration in COVID-19 patients is thoracic air leak syndrome ⁽⁴⁾. It is defined as the presence of extra-alveolar air in the thoracic spaces and includes spontaneous pneumothorax, pneumomediastinum, pneumopericardium, subcutaneous emphysema and interstitial emphysema ⁽⁵⁾. Unravelling the clinical features of these patients would increase awareness of such complications. Herein, we systematically reviewed all COVID-19-related articles with patients presented with air leak syndrome to identify independent risk factors for its development and explore its prognosis in COVID-19 patients. We hypothesized that smoking and preexisting pulmonary diseases would accelerate the risk of developing air leak syndrome and synergistically enhance poor prognosis.

METHODS

Upon a comprehensive literature review in Web of Science (N=108), Embase (N=186), PubMed (N=260), and ScienceDirect (N=245) up to August 2020. Search terms were (pneumothorax OR pneumomediastinum OR subcutaneous emphysema) combined with (COVID-19 OR coronavirus disease 2019 OR severe acute respiratory syndrome coronavirus 2 OR SARS CoV-2). No time or language restriction was applied. Inclusion criteria were (1) Study design: peer-reviewed article of any type; (2) Population: confirmed COVID-19 patient; (3) Exposure: diagnosed clinically or radiologically with spontaneous pneumothorax, pneumomediastinum, pneumopericardium, subcutaneous emphysema or interstitial emphysema; (4) Outcome: mortality, length of stay, or complications. While in vitro and in vivo studies were excluded, data were abstracted in a predesigned excel sheet.

Clinical characteristics and outcomes were reported as frequency and percentage. Quantitative data were non-parametric and thus were reported as the median and interquartile range (IQR). Due to lacking enough data, quantitative synthesis meta-analysis was not feasible, and each patient’s results within each study were pooled. P-value was set significant at <0.05. Statistical analysis was performed using SPSS v27.0, and the plot was generated using STATA v16.0.

RESULTS

Thirty-three included articles were published between April 20 and August 27, 2020, and reported from 13 countries, mainly China, the USA, and the UK (Table 1). The analysis included the characteristics of 125 COVID-19 patients who developed air leak syndrome. Their median age was 44.75 years (IQR=27.25-60). Twenty-one females (16.8%) and 104 males (83.2%) were included in this review (Table 2). Of the 125 patients, 100 (80%) developed spontaneous pneumothorax, 47 (37.6%) had pneumomediastinum, and 37 (29.6%) presented with subcutaneous emphysema. Only 20.8% were smokers. Based on our findings, hypertension (20%) followed by diabetes (14.4%), asthma (11.2%), and chronic obstructive pulmonary disease (COPD, 7.2%) were the comorbidities reported. Apart from the high alanine transaminases reported in only two studies, no remarkable findings were found in the laboratory results.

Nearly 28% of patients developed acute respiratory distress syndrome (ARDS). Around 77.6% of the cohort required oxygen therapy, and 44.8% were mechanically ventilated. Intensive Care Unit admission (ICU) was needed in 51.2% of patients, and mortality was reported in 36%. The median length of hospital stay was 12 days (5.6-17.5); specifically, nine days (5.25–16.5) for those who recovered and 15 days (6.0-18.0) among expired patients.

Of those who died (N=29), only one was a smoker, and another had COPD. Some non- survivors developed coincident ARDS (N=6) and shock (N=6) during the hospitalization period, and 64 patients were admitted to the ICU.

DISCUSSION

This study combines evidence from multi-institutional centers for healthcare policymakers to raise awareness about the elevating number of reported thoracic air leak syndrome in COVD 19 patients across different countries.

Air leak syndrome, consisting of pneumothorax, pneumomediastinum, and subcutaneous emphysema, is caused by an increase in the intra-alveolar pressure with subsequent alveolar rupture, air leak, with the possibility of lung collapse and impairment of oxygenation. Alveolar air leaks might be spontaneous (primary or secondary), traumatic, or iatrogenic, with spontaneous pneumothorax being the most common type ⁽¹⁵⁾. Spontaneous air leak is a rare disease that commonly occurs in males between 10 to 30 years old and is rarely seen over 40. Smoking increases the risk of primary spontaneous pneumothorax twenty times in men. Smoking is one of the main triggering factors for the development of subpleural bullae. Inflammation of these bullae might obstruct the small airways, leading to excessive intraalveolar pressure, alveolar rupture, and subsequent air leak into the interstitium ⁽³⁷⁾. Secondary spontaneous pneumothorax commonly develops in patients suffering from lung diseases such as pneumonia, chronic obstructive pulmonary disease, asthma, and lung cancer ⁽³⁷⁾. In addition, it is a frequent complication in patients with ARDS, caused by pressure and volume-related alveolar rupture (38). While iatrogenic pneumothorax is commonly caused during an endoscopic procedure or following intubation and mechanical ventilation ⁽³⁹⁾.

In the current analysis, the prevalence of air leaks was five times higher in male COVID-19 patients compared to females. Their median age was over 45 years. Only 20.8% of patients were smokers, 11.2% were asthmatics, and 7.2% had COPD. There was no other pre-existing pulmonary disease or reported history of recent trauma. Around 42.4% of patients were admitted with air leaks, and 20% developed air leaks throughout the hospital course before receiving any ventilation support. 37.6% of patients have air leaks after mechanical ventilation, either invasive or non-invasive. Of the patients who died, 23.2% were found to have either pneumothorax, pneumomediastinum, or subcutaneous emphysema. Only one patient had pre-existing COPD, and another one was a smoker, so air leak syndrome in COVID-19 patients can cause severe outcomes even without preexisting pulmonary comorbidities.

Our findings were consistent with published articles that showed higher air leak syndrome incidence among males ⁽³⁶⁾. Other studies reported the development of air leaks in non-intubated COVID-19 patients during hospitalization ⁽⁴⁰⁾. However, others reported pneumothorax development in 5.9% of patients while on mechanical ventilation ⁽⁴¹⁾. Joshi et al. reported that the incidence of alveolar air leak was found to be 2.39%, with a mortality rate of 60% ⁽⁴²⁾.

Even though the mechanism of the injury is not fully understood, multiple mechanisms are suggested. In addition to the ventilator-induced barotrauma among mechanically ventilated patients, COVID-19 infection could cause an inflammatory response with additional positive pressure ventilation. Persistent cough with severe intrapulmonary strain, increased respiratory effort, injury from activated inflammatory processes, cytokine storm and exudate accumulation, and ischemic lung parenchymal injury might promote pulmonary cystic lesions within the lungs. Our analysis determined no apparent risk factors, and there was a lack of autopsy findings to delineate the etiology of pathophysiological alterations of developing such complications in our study.

We could not identify predictor risk factors for mortality in such cohorts from the collected data. There was a lack of information that could unleash putative etiology for developing air leak syndrome. Therefore, further in-depth pathological and molecular analysis of deceased COVID- 19 patients with similar presentations are recommended. This would be crucial to help countries design more effective interventions to shield vulnerable groups and reduce mortality risk.

Across the 33 eligible articles, 125 cases were recruited. Despite a limited sample size, they represented findings from multiple institutions reported in 13 countries. Most of the studies were case reports, and the available data described the presentation and outcomes at an individual level. Therefore, pairwise comparisons between patients of different presentations and associated with comorbidities were not feasible. Further additional studies are warranted to explore the etiology underlying the development of air leak syndrome in COVID 19 patients.

Table 1. Characteristics of Included Articles

Table 2. Characteristics of thoracic air leak syndrome in patients (N=125).

Data is presented as number and percentage or median and interquartile range (Q1-Q3).

CONCLUSION

In COVID-19 disease, air leak syndrome may cause fatal outcomes even in formally stabilized non-smoking patients. Physicians should be aware of the development of occult air leak disease in rapidly deteriorating patients.

AUTHOR’S CONTRIBUTION

RM: Study design, data extraction, analysis, draft manuscript; SM: Data extraction; MH: plotting the figure, review the draft, final approval; ET: Data analysis, writing the second draft, final approval. EK: Final approval.

ACKNOWLEDGMENTS

A sincere appreciation to Loula Burton from Tulane’s Research Proposal Development Office for her diligent editing and proofreading of this paper.

CONFLICTS OF INTEREST

The authors declare no conflict of interest.