key: cord-0822098-x4pr6e4w
authors: Chong, Woon H.; Saha, Biplab K.; Hu, Kurt; Chopra, Amit
title: The Incidence, Clinical Characteristics, and Outcomes of Pneumothorax in Hospitalized COVID-19 Patients: A Systematic Review
date: 2021-05-01
journal: Heart Lung
DOI: 10.1016/j.hrtlng.2021.04.005
sha: 2daf7256b03d2800236d675f41546298d718850e
doc_id: 822098
cord_uid: x4pr6e4w

BACKGROUND: : Pneumothorax has been frequently described as complication of COVID-19 infections. OBJECTIVE: : In this systematic review, we describe the incidence, clinical characteristics, and outcomes of COVID-19-related pneumothorax. METHODS: : Studies were identified through MEDLINE, Pubmed, and Google Scholar databases using keywords of “COVID-19,” “SARS-CoV-2,” “pneumothorax,” “pneumomediastinum,” and “barotrauma” from January 1(st), 2020 to January 30(th), 2021. RESULTS: : Among the nine observational studies, the incidence of pneumothorax is low at 0.3% in hospitalized COVID-19 patients. However, the incidence of pneumothorax increases to 12.8-23.8% in those requiring invasive mechanical ventilation (IMV) with a high mortality rate up to 100%. COVID-19-related pneumothorax tends to be unilateral and right-sided. Age, pre-existing lung diseases, and active smoking status are not shown to be risk factors. The time to pneumothorax diagnosis is around 9.0-19.6 days from admission and 5.4 days after IMV initiation. COVID-19-related pneumothoraces are associated with prolonged hospitalization, increased likelihood of ICU admission and death, especially among the elderly. CONCLUSION: : COVID-19-related pneumothorax likely signify greater disease severity. With the high variability of COVID-19-related pneumothorax incidence described, a well-designed study is required to better assess the significance of COVID-19-related pneumothorax.

Conclusion: COVID-19-related pneumothorax likely signify greater disease severity. With the high variability of COVID-19-related pneumothorax incidence described, a well-designed study is required to better assess the significance of COVID-19-related pneumothorax.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus is known to cause coronavirus disease 2019 (COVID- 19) , resulting in the ongoing global pandemic 1 . COVID-19 presents with a wide variety of respiratory complications that range from self-limiting upper respiratory tract infection to acute respiratory failure from acute respiratory distress syndrome (ARDS) and pleural diseases such as pleural effusion and pneumothorax. 2 Pneumothorax is a common complication of invasive mechanical ventilation (IMV) in critically ill patients, with reported incidence up to 15%. 3 Additionally, the overall incidence of hospitalized COVID-19 patients requiring IMV is around (17-42%) with increasing frequency in non-survivors (57-59%) compared to survivors (1-15%). 4, 5 Generally, critically ill patients with pneumothorax experienced a 2-fold increase in the risk of ICU and hospital mortality than those without pneumothorax. [6] [7] [8] Among those who develop pneumothoraces, the mortality and recovery rate are poor in the setting of IMV, septic shock, and the evidence of tension physiology compared to those with procedure-related pneumothorax. 9 The significance of pneumothorax in COVID- 19 infections, initially limited to several case reports/series, has been increasingly described and analyzed in multiple observational studies during the ongoing pandemic. A post-mortem examination of 91 deceased COVID-19 patients observed that ARDS was responsible for 80.2% of death, followed by cardiac injury (34.1%), hepatic and renal injury (31.9%), and pneumothorax (1.1%). 10 The purpose of our systematic review is to discuss the incidence, characteristics, and outcomes of pneumothorax in patients with COVID-19 infections based on the current evidence available in the medical literature.

This systematic review was conducted and presented in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Ethical approval and informed consent were not required for this study as it was a systematic review of previously published studies.

A literature search was performed through MEDLINE, Pubmed, and Google Scholar databases using keywords of "coronavirus disease 2019 (COVID- 19) ," "severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)," "pneumothorax," "pneumomediastinum," and "barotrauma" from January 1 st , 2020 to January 30 th , 2021. All specified keywords were combined using the "OR" operator and "AND" operator for searching the literature. Moreover, to detect additional studies, any cited references were reviewed to identify relevant literature that met our inclusion criteria.

Inclusion Criteria:

Articles that met the following criteria were included in our study: 1) studies that described pneumothorax on chest imaging [using either chest radiography or chest computed tomography (CT)] in hospitalized adults and children due to COVID-19 infections; 2) observational studies, including cohort, case-control, and cross-sectional studies; 3) studies written in English language; 4) studies in which diagnosis of COVID-19 infections was made via real-time reverse transcription-polymerase chain reaction (RT-PCR) from nasopharyngeal or oropharyngeal swab; 5) published between January 1 st , 2020 to January 30 th , 2021 in a peerreview journal; and 6) studies addressing at least one of the following issues: a) incidence, b) risk factors, c) onset, and/or d) outcome of COVID-19-related pneumothorax.

Exclusion Criteria:

The exclusion criteria were specified as follows: 1) studies with less than 40 patients (defined as case series) and/or case reports; 2) studies that only reported signs of barotraumas such as pneumomediastinum and subcutaneous emphysema in the absence of pneumothorax in hospitalized COVID-19 patients; and 3) studies describing iatrogenic causes (e.g., from central venous catheter insertion) of pneumothorax in COVID-19 patients.

Two researchers (W.C. and B.S.) independently screened the titles and abstracts, and reviewed the full texts of articles to identify studies that evaluated the incidence, risk factors, onset, and outcomes of pneumothorax in patients with COVID-19 infections. Any disagreements were resolved by discussion or with a third researcher (K.H.). The extracted data from full texts of included studies was added into a standardized Excel (Microsoft Corporation) form. All included studies were analyzed for: study design (e.g., retrospective or prospective; cross-sectional, case-control, or cohort; single-or multi-center); study type (clinical or radiologic characteristic); month/year; country; number of patients; patient type (hospitalized or intensive care unit [ICU]); incidence of pneumothorax; age of the patient (e.g., mean +/-standard deviation or median [interquartile range]); gender; the location of pneumothorax; chest tube requirement; co-existing pneumomediastinum; time to pneumothorax development from initial admission; co-existing lung diseases; smoking status; IMV; mortality; and requirement of ECMO support were presented in Table 1 . In Table 4 requiring IMV. We also included observational studies (40 and more patients) that described pneumothoraces among patients with severe acute respiratory syndrome (SARS) and middle east respiratory syndrome (MERS) infections that were available in the current literature for comparison (Table 3) .

Two researchers performed quality assessment using the Newcastle-Ottawa Scale (NOS), containing nine items, for the cohort and case-control studies. In NOS, the total score ranged from 0 to 9 and was categorized into three groups: Low quality "0-3", moderate quality "4-6", and high quality "7-9". 11 For cross-sectional studies, the Prevalence Critical Appraisal Instrument (PCAI), containing 10 items was used, and the total score ranged from 1 to 10. 12 During the quality assessment of the included studies, any disagreements were resolved by discussion or a third researcher.

Study Selection:

A total of 200 studies were identified in the initial search. After removal of duplicates (n = 80) and those not meeting the inclusion criteria (by title, abstract, and full text: n = 111), nine eligible articles (including five cohorts, two cross-sectional and case-control studies) were included in this review ( Figure 1 ). Study Characteristics: Table 1 19, 20 Incidence of COVID-19-Related Pneumothorax:

In hospitalized patients with COVID-19 infections, the overall incidence of pneumothoraces reported in hospitalized COVID-19 patients was 0.3% (242/79,510) in nine observational studies included in our review (Table 1 ). However, according to a single-center, case-control radiological study by McGuinness et al., which was the only study assessing 601 critically ill COVID-19 patients who required IMV, the incidence of pneumothorax increased up to 12.8%. 13 The largest study included was a multi-center, case-control study by Miro et al. conducted in Spain that described 71,904 COVID-19 patients who were initially assessed in the emergency departments (ED) with a reported incidence of pneumothoraces at 0.06%. 14 [14] [15] [16] 19, 20 Among the four observational studies describing the locality of pneumothorax, COVID-19related pneumothorax was commonly unilateral and predominantly right-sided in 56.9%

(74/130) of cases. 13, 14, 19, 20 Moreover, chest tube insertion was required in up to 64.0% (87/136) of COVID-19 patients who developed pneumothoraces for the management of pneumothoraces according to five observational studies. [14] [15] [16] 19, 20 According to three observational studies, less than 20% of hospitalized COVID-19 patients developed pneumomediastinum concurrently with pneumothoraces (Table 1) . 14, 16, 19 Risk Factors for COVID-19-Related Pneumothorax:

According to the nine observational studies, the mean/median age groups of COVID-19 patients were between 55 to 70 years of age. About 66.7% (6/9) of observational studies described the presence of pre-existing lung diseases such as asthma, bronchiectasis, chronic obstructive pulmonary disease (COPD), and interstitial lung disease (ILD) among COVID-19 patients (Table   1 ). However, most COVID-19 patients and even those diagnosed with pneumothoraces did not have pre-existing lung diseases, with a reported frequency of less than 30%. Moreover, four observational studies revealed that less than 34% of COVID-19 patients diagnosed with pneumothoraces were smokers. [13] [14] [15] [16] Two retrospective observational studies (Table 4) 16, 19 Discussion:

The incidence of pneumothorax is low at 0.3% among the nine studies included in our review but increases up to 12.8-23.8% in critically ill COVID-19 patients requiring IMV. COVID-19related pneumothorax, when present, tends to be unilateral and right-sided. Age, pre-existing lung diseases, and active smoking status are not risk factors for developing pneumothoraces.

Although COVID-19 patients who developed pneumothoraces have a higher baseline respiratory rate, ventilator parameters (e.g., peak inspiratory pressure, plateau pressure, PEEP, and TV) did not alter their frequency of pneumothorax diagnosis among mechanically patients in which all of them required IMV with a mortality rate up to 57.0% (343/601), signifying a severe course of COVID-19 disease that likely explains the high incidence rate of 12.8% (77/608) observed. 13 Furthermore, the incidence of pneumothoraces was higher in mechanically ventilated COVID-19 patients (12.8% versus 0.5%; P < 0.001) than mechanically ventilated non-COVID-19 patients over the same study duration, indicative of severe COVID-19 disease among the enrolled patients. Martinelli 19 These findings demonstrate that COVID-19 disease severity likely plays a vital role in explaining the high incidence of pneumothorax reported, consistent with greater IMV requirements and poor mortality rates observed.

The largest study among VA patients compared 3,948 COVID-19 patients with 5,4533 influenza patients over the same timeframe. 17 In that study, a significant higher proportion of COVID-19 patients developed pneumothoraces (0.6% versus 0.2%; P < 0.001) than influenza A patients.

According to six observational studies among SARS patients, the incidence of pneumothorax was 3.4% (31/921) [ Table 3 ]. However, two observational studies by Kao 23 Compared to MERS patients, the high incidence of pneumothoraces at 11.2% (14/125), observed in two observational studies were likely secondary to the severity of illness in which 54.5-70% required IMV and reported mortality rate was high at 52.7-60%. 24, 25 Furthermore, a retrospective cohort study by Das aged between 60-74 years old, and those aged 75 years and older observed no difference in the incidence of pneumothoraces. 18 Although chronic lung diseases such as asthma, COPD, and ILD, are known predisposing factors for developing pneumothorax in critically ill patients, even in the absence of IMV, our review did not show any correlation between pre-existing lung diseases and the risk of developing pneumothorax among COVID-19 patients. 37 13, 14 Miro et al. even observed that non-smokers were at a 5.5-fold increased risk of developing pneumothoraces. Compared to SARS patients, a case-control study by Chu et al. reported that no difference in smoking status was observed between patients who developed pneumothoraces and those that did not. 23 In light of the poor correlation between pre-existing lung diseases and active smoking status, pneumothorax should be considered a potential complication of hospitalized COVID-19 patients during the assessment of worsening respiratory symptoms even in the absence of pulmonary comorbidities.

In addition, IMV can be a lifesaving intervention in many critically ill COVID-19 patients, and in some cases, IMV was applied before the development of pneumothoraces (Table 1 ). However, similar to any other invasive interventions, it carries its own risk and complications that can lead to ventilator-induced lung injuries (VILI) such as volutrauma and barotrauma, especially in ARDS patients due to the overdistension of normal non-dependent lung regions with relatively higher compliance than dependent lung regions. 20, 38 Although only two observational studies in our review described the respiratory variables involving peak inspiratory pressure, plateau pressure, PEEP, and TV among mechanically ventilated COVID-19 patients, these variables were not elevated. 19, 20 A case series by Udi et al. observed that COVID-19 patients who developed barotrauma (e.g., pneumothorax, pneumomediastinum, and subcutaneous emphysema) had lower ventilator variables of peak inspiratory pressure, plateau pressure, and TV than those who did not develop barotrauma. 26 In a similar fashion, another case series by Abdallat et al. noted that critically ill COVID-19 patients receiving IMV experience a higher rate of barotrauma at a PEEP of 10-15 cmH20 as opposed to a PEEP of 15 cmH20 and more. 30 patients with ARDS demonstrated that high peak inspiratory pressure, plateau pressure, and PEEP did not increase the risk of developing barotraumas despite prolonged ICU length of stay and shorten ventilator-free days. 6, 39, 40 Similarly, ARDS Network study showed a decrease in mortality of critically ill ARDS patients without affecting the incidence of barotraumas during low tidal volume ventilation. 41 Therefore, barotrauma in the form of pneumothorax is likely related to underlying lung disease severity than lung compliance and ventilator settings.

Moreover, it is possible that tachypnea on admission signifies an increase in the respiratory effort to compensate for lung disease of greater severity and greater risk of developing autopositive end-expiratory pressure (auto-PEEP) from insufficient expiratory time, contributing to pneumothorax development. This likely explains the high RR observed by Miro et al. that is associated with a 5.37-fold increased risk of developing pneumothoraces. 14 Compared to SARS patients, a case-control study by Kao et al. demonstrated that those who developed pneumothorax had higher respiratory rate on admission and more pronounced hypoxia with lower PaO2/FiO2 ratio and higher PaCO2 during hospitalization. 21 Furthermore, in that study, a high PaCO2 and lower PaO2/FiO2 ratio during hospitalization were suggested to indicate an increase in dead space and shunting from ventilation-perfusion mismatch, and diffusion impairment from severe respiratory disease that predisposes to the development of pneumothoraces. However, these parameters (lowest PaO2/FiO2 ratio and higher PaCO2) were not measured during the hospitalization of COVID-19 patients included in our review as all observational studies included were retrospective in nature (Table 4 ). Current guidelines recommend a low TV of 4-8 ml/kg (ideally 6ml/kg) during IMV for management of critically ill COVID-19 patients. However, conflicting consensus exists on the use of a high PEEP strategy due to the low lung recruitment observed in COVID-19-induced ARDS. [42] [43] [44] The pathophysiologic changes of COVID-19 infections that revolve around dysregulation of immune response with high inflammatory markers may play a role in developing pneumothorax and pneumomediastinum independent of ventilator-induced barotrauma (e.g., pneumothorax and pneumomediastinum). 20, 45, 46 These are likely related to the lung histopathological development of diffuse alveolar damage seen in autopsies of deceased COVID-19 patients that weakens the alveolar walls and gives rise to dilated, cystic and bullous airspaces (pneumatocele) in the lung parenchyma that rupture during intense coughing (sudden rise in intrathoracic pressure) or when receiving positive pressure ventilation causing leakage of air into the pleura resulting in pneumothorax and/or traveling along the bronchovascular bundles (Macklin effect)/interstitium into the mediastinum (pneumomediastinum) with or without disrupting the mediastinal parietal pleural. 16, 26, 35, [47] [48] [49] In those receiving IMV during the time of development of pneumothoraces, this can simply reflect that the gas exchange was severely compromised in the more critically-affected lungs and that the alveoli were more readily prone to rupture even in response to a minor increase in thoracic pressure. 19, 36 Several studies have even noted incidental radiologic findings of cystic lung changes, including bulla before the development of pneumothorax in hospitalized patients with COVID-19 infections that is not present on admission and likely associated with the resorptive process of consolidation. 19, 47, [50] [51] [52] [53] Similar findings are noted in observational studies of patients with influenza A pneumonia and SARS, known to cause diffuse alveolar inflammation with cysts formation regardless of IMV requirement with only inciting event for pneumothorax is forceful coughing episodes. 35, [54] [55] [56] Observational study by Gattinoni et al. observed that the number of bullae detected in the dependent lung regions on high-resolution chest CT was significantly higher in critically ill patients who developed pneumothoraces, and among those with ARDS and required prolong IMV. 8 The utility of follow-up chest imaging to evaluate for the atypical complication of bulla and associated pneumothorax formation during COVID-19 infections needs to be better studied.

The overall time to pneumothorax diagnosis was shown to be between 9.0-19.6 days from admission and 5.4 days after IMV (Table 1) following IMV initiation with an increasing incidence of 1.4% on day 5, 2.1% on day 10, and 3.0% on day 30. 7 Similarly, among critically ill non-COVID-19 patients requiring IMV for moderate-to-severe ARDS, the incidence of pneumothorax increases significantly at 30% for early ARDS (IMV for up to a week), 46% for intermediate ARDS (IMV between 1-2 week), and up to 87% in late ARDS (IMV 2 weeks and more). 8 The onset of pneumothorax that occurs after admission suggest a sustained period of lung inflammation with extensive parenchymal injury and likely a severe course of COVID-19 infection. The typical radiologic findings in COVID-19 patients are inflammation of the lung parenchyma that predominantly affects the peripheries that will progress and eventually involve the overlying pleura that possibly explain the late onset of pneumothorax. 52, 57, 58 In a similar fashion, these findings also explain the delayed onset of other pleural diseases such as pleural effusions that are frequently observed ten days and more from the start of COVID-19 symptoms. [13] [14] [15] Additionally, according to Miro et al., COVID-19 patients with pneumothoraces had 12.9, 4.2, and 15.7-folds increased in the risk of ICU admission, prolonged hospitalization, and higher inhospital mortality than those without pneumothoraces. 14 15, 16 Our review has several limitations. First, the available data on pneumothoraces in COVID-19

infections is often limited due to the highly variable frequency reported across many observational studies included compared to other common CT chest findings (Table 1) Fourth, in several observational studies, we included, pleural effusions were observed to be a bystander (minor secondary outcome) result or identified incidentally during subgroup analysis while assessing the many characteristics, risk factors, and outcomes of hospitalized COVID-19 patients which explains their low score. 2, 17, 18, 20, 60 Fifth, as the majority of studies included were retrospective (Table 1) , real-time data such as ventilator parameters were likely difficult to obtain and limited to few studies as described in Table 4 . Lastly, premature death associated with COVID-19 infections may be an independent competing risk factor for the development of delayed pneumothoraces, leading to an unintended underestimation of the actual risk in nondeceased COVID-19 patients. 15, 16 Conclusion:

The overall incidence of Covid-19-related pneumothorax is low at 0.3% but increases to 12.8-23.8% in those who are critically ill and require IMV. COVID-19-related pneumothorax is commonly unilateral and right-sided. The onset is around 9.0-19.6 days from admission and 5.4 days after IMV. COVID-19-related pneumothorax is likely a sequela of COVID-19 disease progression due to the inflammatory insult from COVID-19-induce immune dysfunction and increase in respiratory effort that may inflict changes within the lung parenchyma. COVID-19related pneumothoraces are associated with prolonged hospitalization, increased likelihood of ICU admission and death, especially among the elderly. With increasing incidence observed among those requiring IMV, COVID-19-related pneumothorax signifies a severe course of infection. As our clinical understanding of COVID-19 continues to expand, it is crucial for healthcare providers to recognize this uncommon presentation of COVID-19 infections in which a causal relationship between COVID-19 and pneumothorax cannot be concluded from our review as it is limited by many variables as described above. Therefore, we hope that more well-designed studies will be performed to describe the incidence, risk factors, onset, and outcomes in COVID-19 patients with pneumothoraces. Abbreviations: PEEP : positive end-expiratory pressure, TV : tidal volume, ml : milliliters, RR : respiratory rate, PaO2/FiO2 : partial pressure of oxygen/fraction of inspired oxygen, PaCO2 : partial pressure of carbon dioxide

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