Prevalence and patient risk factors for pneumothorax in COVID-19 and in influenza pneumonia: a nationwide comparative analysis

Introduction

Pneumothorax, a rare but deadly complication in patients with coronavirus disease 2019 (COVID-19), is more common in patients requiring mechanical ventilation (1). Studies have demonstrated the incidence of pneumothorax in hospitalized COVID-19 patients is 1–2% (2-5).

The pathogenesis of pneumothorax in COVID-19 is multifactorial. A proposed mechanism is the distortion of lung parenchyma with cyst formation and reduced lung compliance from reticulation and fibrotic changes (6). Invasive mechanical ventilation (IMV) increases the risk of barotrauma, rupture of the alveoli, and introduction of air into the pleural cavity. In a spontaneously breathing patient with COVID-19, an increased respiratory rate, severe cough, and air hunger increase alveolar shear stress, contributing to the pathogenesis of pneumothorax. The development of pneumothorax is associated with increased mortality risk in COVID-19 patients (7-9).

Although many case series and reports discuss the epidemiology of pneumothorax in COVID-19 patients, few nationwide studies establish its prevalence, risk factors, and mortality. This study comparatively analyzes the prevalence, risk factors, and associated mortality of pneumothorax in COVID-19 and in influenza pneumonia, using the National Inpatient Sample (NIS) database of the United States (US). We present this article in accordance with the STROBE reporting checklist (available at https://jtd.amegroups.com/article/view/10.21037/jtd-23-1454/rc).

Methods

Data source

The study utilized the NIS 2020 dataset. The NIS is a part of a series of databases and software tools developed for the Healthcare Cost and Utilization Project (HCUP) (10). It serves as the largest publicly available comprehensive inpatient database in the US, designed to generate regional and national estimates on various aspects of inpatient care, including utilization, access, cost, quality, and outcomes. Unweighted, it encompasses data from approximately 7 million hospital stays annually, which, when weighted, translates to approximately 35 million hospitalizations nationwide. The NIS encompasses all states participating in HCUP, representing more than 97 percent of the US population. The NIS constitutes a 20-percent stratified sample of discharges from community hospitals across the US. The current version’s self-weighting design minimizes the margin of error for estimates, resulting in more robust and precise estimations compared to earlier iterations of the NIS. The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). The study was exempt from institutional review board approval as the NIS 2020 database is comprised of previously collected, de-identified data.

Patient selection and outcomes

Our study included adult patients (age 18 years and above) with COVID-19 [International Classification of Diseases, Tenth Revision (ICD-10) code U07.1] and influenza (ICD-10 code J09.X1, J10.00, J10.01. J10.08, J11.00, J11.08) who were hospitalized between January 1^st, 2020, and December 31^st, 2020. Patients who were transferred to another acute care hospital were excluded. This exception was necessary as pneumothorax and mortality may not have occurred in the same hospitalization. Socioeconomic and comorbidity risk factors for pneumothorax in COVID-19 patients and its associated mortality were identified in the same cohort. Primary outcomes were the prevalence of pneumothorax in COVID-19 patients and the socioeconomic and comorbidity risk factors demonstrated in these patients. Secondary outcomes were the comparison of COVID-19 patients with pneumothorax and those without pneumothorax and the comparison of pneumothorax risk in influenza and in COVID-19.

Identification of variables

The NIS variables encompassed demographic characteristics of patients, comprising age, gender, insurance status, race, and income quartiles derived from zip codes. Additionally, hospital characteristics such as bed size (capacity), teaching status, and ownership were identified. Elixhauser Comorbidity Index variables, including complicated and uncomplicated hypertension, diabetes, solid cancer, chronic pulmonary disorders, liver disease, and rheumatoid arthritis/collagen vascular disorders were directly utilized. Further variables were extracted through ICD-10, Clinical Modification (ICD-10-CM) diagnosis codes (Table S1).

Statistical analysis

Descriptive analysis calculated the mean for continuous variables and the proportion for categorical variables. Initially, the distribution of socioeconomic factors, comorbidities, and complications among COVID-19 patients with and without pneumothorax was examined. Univariate logistic regression identified risk factors associated with pneumothorax in COVID-19 patients. Variables demonstrating significant P values (P<0.05) and those of particular clinical relevance were incorporated into multivariate logistic regression to determine independent predictors of pneumothorax in COVID-19. Univariate and multivariate logistic regression analyses were conducted to ascertain COVID-19 as a risk factor for pneumothorax, with influenza pneumonia serving as a reference. StataCorp. 2021, Stata Statistical Software: Release 17, StataCorp LLC (College Station, TX, USA), basic edition (BE) version was utilized for analysis. The Stata “SVY” command and appropriate weights were applied in all estimations. The overall model fit was assessed using receiver operating characteristic (ROC) curves. Sensitivity analysis was conducted using the E-value package. Additionally, survival analysis was performed, with length of stay serving as the time variable. Kaplan-Meier survival curves were generated for patients with and without pneumothorax.

Results

Patient characteristics and demographics

Of the 1,608,980 patients who tested positive for COVID-19 and were hospitalized in 2020, a cohort of 22,545 [95% confidence interval (CI): 21,491–23,598] (1.4%) developed a pneumothorax. Mean age of patients who developed pneumothorax was 64.5 years [standard deviation (SD): ±0.5 years]. Prevalence of pneumothorax increased with age. Prevalence in the 18–40 years of age group was 5.7%, 39.7% in the 41–64 years group, and highest at 52.1% in the age group >65 years. Of the COVID-19 patients in the pneumothorax cohort, 34% were females, and 66% were males. The type of insurance used included Medicare (49.8%), private insurance (27.2%), Medicaid (13.9%), self-pay (4%), and others (4.6%). Caucasians comprised 43.9% of the cohort, Hispanics 31.8%, African-Americans 12.9%, Native Americans 1.5%, and other origins 6.1%. Within the cohort, 36.6% were reported in the 0–25^th percentile of the zip code income bracket, 26.9% in the 26^th–50^th percentile, 21.3% in the 51^st–75^th percentile, and 14.9% in the 76^th–100^th percentile. Patients were admitted to large-bed (50.8%), medium-bed (30%), and small-bed capacity hospitals (19%). Patients with pneumothorax were hospitalized in urban teaching hospitals (77.5%), in urban non-teaching hospitals (17.2%), and in rural hospitals (5.1%).

Geographically, 43.7% of the patients were hospitalized in the South, 20.1% in the West, 18% in the Midwest, and 18% in the Northeast. Non-profit private hospitals admitted 69.7% of the patients with pneumothorax, private hospitals 18.6%, and government hospitals 11.5% (Table 1).

Total hospitalization charges of pneumothorax patients were significantly higher than those of patients without pneumothorax. Average hospitalization cost of a patient with pneumothorax was $437,692 (95% CI: 415,842–459,542), compared to $87,081 (95% CI: 84,858–89,304) for a patient with no pneumothorax (Table 2).

Mortality was significantly higher in patients with pneumothorax at 68.7% compared to 13% in patients without pneumothorax (Table 2).

Risk factors and mortality associated with pneumothorax

Multivariate analysis indicated females were less likely to develop pneumothorax [adjusted odds ratio (aOR): 0.68, 95% CI: 0.63–0.73, P<0.001]. Age was a significant risk factor for the development of pneumothorax: highest in patients in the 41–64-year age group (aOR: 2.45, 95% CI: 2.15–2.79, P<0.001) followed by age group ≥65 years (aOR: 2.29, 95% CI: 2.01–2.60, P<0.001). Compared to private insurance, the odds of getting pneumothorax were lower in patients with Medicare (aOR: 0.83, 95% CI: 0.76–0.91, P<0.001) and Medicaid (aOR: 0.86, 95% CI: 0.77–0.96, P<0.001). In comparison to Caucasian patients, African Americans were at a lower risk of having a pneumothorax (aOR: 0.64, 95% CI: 0.58–0.72, P<0.001), but Hispanics, Native Americans, and patients belonging to other races had a higher risk with the highest risk in Native Americans (aOR: 1.63, 95% CI: 1.25–2.13, P<0.001). Regarding median household income of the patient’s zip code of residence, patients with the highest zip code quartile income had the lowest possibility of pneumothorax: 51^st–75^th percentile (aOR: 0.87, 95% CI: 0.80–0.96, P<0.001) and 76^th–100^th percentile (aOR: 0.87, 95% CI: 0.78–0.97, P=0.01) In contrast to small-bed hospitals the risks of getting pneumothorax were higher in medium-bed hospitals (aOR: 1.18, 95% CI: 1.07–1.31, P<0.001) and highest in large-bed hospitals (aOR: 1.26, 95% CI: 1.14–1.38, P<0.001). The odds of pneumothorax were higher in urban non-teaching (aOR: 1.28, 95% CI: 1.07–1.52, P<0.001) and urban teaching hospitals (aOR: 1.48, 95% CI: 1.27–1.73, P<0.001) than in rural hospitals. Southern hospitals’ patients had higher odds of pneumothorax (aOR: 1.38, 95% CI: 1.23–1.54, P<0.001) than hospitals in the Northwest. Compared to government non-federal hospitals, a higher likelihood of pneumothorax was seen in private invest-own hospitals (aOR: 1.35, 95% CI: 1.18–1.56, P<0.001) (Table 1).

Patients with a history of stroke (aOR: 1.28, 95% CI: 1.04–1.58, P=0.02), malnutrition (aOR: 1.52, 95% CI: 1.40–1.64, P<0.001), chronic obstructive pulmonary disease (COPD) (aOR: 1.83, 95% CI: 1.52–2.20, P<0.001), bronchiectasis (aOR: 2.04, 95% CI: 1.47–2.83, P<0.001), pulmonary fibrosis (aOR: 1.84, 95% CI: 1.44–2.35, P<0.001), liver disease (aOR: 1.38, 95% CI: 1.24–1.54, P<0.001), and positive pressure ventilation, including high flow nasal cannula (HFNC), bilevel positive airway pressure (BiPAP) and continuous positive airway pressure (CPAP) (aOR: 1.82, 95% CI: 1.66–1.98, P<0.001) were more likely to develop pneumothorax. Further, the odds were extremely high in intubated (aOR: 13.6, 95% CI: 12.5–14.7, P<0.001) and extracorporeal membrane oxygenation (ECMO) patients (aOR: 7.24, 95% CI: 5.16–10.1, P<0.001) (Table 2).

Interestingly, the likelihood of developing pneumothorax was low in nicotine abuse (aOR: 0.75, 95% CI: 0.64–0.88, P<0.001), substance abuse (aOR: 0.66, 95% CI: 0.53–0.83, P<0.001), and obstructive sleep apnea (OSA) [aOR: 0.79, 95% CI: 0.69–0.90, P<0.001] (Table 2).

In patients with pneumothorax, the risks of having a cardiac arrest were very high (aOR: 7.85, 95% CI: 7.21–8.54, P<0.001), and the odds of mortality due to any cause were extremely high (aOR: 14.65, 95% CI: 13.7–15.6, P<0.001) (Table 2).

Patients with a higher Elixhauser comorbidities score had higher risks of developing pneumothorax, with the highest risk when the Elixhauser comorbidities score was >6 (aOR: 7.60, 95% CI: 7.33–7.88, P<0.001). Patients with a pneumothorax had a higher probability of having higher mean Elixhauser comorbidities scores than patients without pneumothorax (aOR: 1.19, 95% CI: 1.18–1.20, P<0.001) (Table 2).

The prevalence of pneumothorax showed an upward trend with increasing severity of COVID-19. Among patients with asymptomatic COVID-19, the prevalence was 0.3%, while in those with lower respiratory tract infection without pneumonia, it was 0.8%. In COVID-19 pneumonia cases, the prevalence was 1.7%, and in patients with COVID-19 acute respiratory distress syndrome (ARDS), it significantly increased to 9% (Table S2).

Likewise, mortality rates attributed to pneumothorax also increased with severity. In patients with asymptomatic COVID-19, the mortality rate was 38%, while it 54% in those with lower respiratory tract infection without pneumonia. Among COVID-19 pneumonia cases, the mortality rate increased to 70%, and in patients with COVID-19 ARDS, it reached 76% (Table S2).

The odds of mortality in COVID-19 patients who developed pneumothorax were higher (aOR: 5.51, 95% CI: 4.87–6.23, P<0.001) (Table S3).

Comparison with influenza

Influenza pneumonia was seen more frequently in female patients and in patients of minority races and ethnicities. Compared to COVID-19 patients, certain comorbidities were more frequently observed in influenza patients, such as chronic kidney disease (CKD), smoking, and malnutrition. Conversely, comorbidities such as uncontrolled diabetes mellitus (DM) and complications such as vasopressor therapy, cardiac arrest, and overall mortality were higher in COVID-19 patients. Of 184,980 influenza patients, 1,630 (95% CI: 1,448–1,811) (0.88%) developed pneumothorax as compared to 1.4% of COVID-19 patients. After adjusting for confounding variables, COVID-19 pneumonia had higher odds of pneumothorax than influenza pneumonia (aOR: 2.07, 95% CI: 1.73–2.49. On sensitivity analysis, this yielded an E-value (point estimate 3.55, CI 2.85) (Tables 3,4).

Kaplan-Meier survival estimates showed a clear demarcation in mortality trajectories among COVID-19 patients with and without pneumothorax, especially during prolonged stays (Figure 1).

Figure 1 Kaplan-Meier survival estimates: the probability of survival was lower in patients who developed a pneumothorax. P value <0.001.

A trend of prevalence and mortality of COVID-19-induced pneumothorax was observed in 2020. Pneumothorax prevalence decreased from March to December 2020. However, the mortality rate remained consistent during the same period (Figures S1,S2).

Discussion

This nationwide study is one of the largest on the epidemiology of pneumothorax in COVID-19 patients. No existing literature compares pneumothorax in COVID-19 and influenza cases. Key findings were (I) the prevalence of pneumothorax in COVID-19 patients was 1.4%; (II) male sex and the elderly population with COVID-19 infection, and patients with stroke, malnutrition, COPD, pulmonary fibrosis, bronchiectasis, liver disease, or requiring non-invasive, IMV and ECMO were more likely to develop pneumothorax; (III) risk of pneumothorax was higher for COVID-19 patients than for those with influenza. Pneumothorax was associated with an increased risk of cardiac arrest and all-cause mortality. Although supporting several findings of earlier smaller studies, this study has highlighted some significant differences.

The prevalence of pneumothorax in this study (1.4%) was similar to a previous study by Malik et al. of 811,065 patients in which the incidence was 1.84% in COVID-19 hospitalized patients (11). Some previous large-scale studies observed a lower incidence. In a systematic review by Chong and colleagues, the overall incidence of pneumothorax in hospitalized COVID-19 patients was 0.3% (7). In a multi-center case-control study in Spain by Miró et al. of 71,904 COVID-19 patients initially assessed in the emergency department (ED), the incidence of pneumothorax was 0.06% (12). In a multi-center retrospective cohort study of 3,948 COVID-19 patients in US veteran affairs (VA) hospitals by Cates et al., the incidence of pneumothorax was 0.6% (13). However, these studies do not describe the severity of the illness and the need for IMV or non-IMV (NIMV). In this study, pneumothorax is seen in a sicker patient population, and the previous studies may have included patients who were less critically ill. One retrospective study by McGuinness et al. assessed patients on mechanical ventilation, 9% of whom developed pneumothorax (14). Several early studies have reported an incidence of pneumothorax similar to this study (1–2%). However, the sample size of those studies was smaller (3,4,15).

In this study, 66% of the patients who developed pneumothorax were males, which is consistent with the majority of studies in the literature (66–100%) (2,6,11-14,16). Possible causes include male anthropometric characteristics and the mechanical properties of the lungs in males (17,18). Studies have observed a risk of pneumothorax increasing with age, perhaps from underlying lung conditions like emphysema, interstitial lung disease (ILD)/pulmonary fibrosis, etc. Advancing age is a well-known risk factor for severe COVID-19, which is, in turn, linked to pneumothorax. Odds of pneumothorax were highest in patients aged 41–64 years, similar to the results in the studies by Malik et al. and Chong et al. (7,11). Native Americans, Hispanics, and patients of other origins had higher odds of pneumothorax, with the highest odds in Native Americans (63% higher than Caucasians). The odds of pneumothorax were lower for African Americans (36% lower than Caucasians). The exact reason for this is unclear, but the data may be confounded by differences in socioeconomic status and access to health care (19). These racial differences could also be due to the severity of COVID-19 in non-white races (20,21).

Large and urban hospitals demonstrated a higher likelihood of pneumothorax, presumably because they are referral centers for other hospitals and care for the sickest patients. Why hospitals in the South had a high prevalence of pneumothorax remains undetermined. The southern region also had a high number of COVID-19 patients. Racial and ethnic inequities in the region might have led to delays in access to health care. The association between higher-income zip codes and better outcomes highlights socioeconomic healthcare impacts in the US (20,21). Ironically, it is unclear why Medicare or Medicaid patients had lower odds of pneumothorax than private insurance. One potential reason is that Medicare and Medicaid place a strong emphasis on preventive care, facilitating the identification and management of underlying health conditions that could contribute to the risk of pneumothorax.

Literature on COVID-19 pneumothorax and stroke is sparse. Patients with stroke are at greater risk of developing pneumothorax. Smoking and physical inactivity are well-documented common risk factors for pneumothorax and stroke (22). Chronic liver disease was the single most predictive risk factor for severe COVID-19, according to the Centers for Disease Control and Prevention (CDC). Potential causes include coagulopathy and immune dysregulation in liver disease (23). The increased severity of COVID-19 in these patients may have increased the likelihood of pneumothorax. Malnutrition was associated with a higher risk of pneumothorax, which may result from poor healing which can produce prolonged air leakage in the pleural cavity (24,25). Pre-existing lung conditions can also be risk factors for pneumothorax. Chong et al. reported that 66.7% (6/9) of observational studies described the presence of pre-existing lung diseases such as asthma, bronchiectasis, COPD, and ILD among COVID-19 patients with pneumothorax (7). Our study confirmed an increased risk of pneumothorax in COPD, bronchiectasis, and pulmonary fibrosis patients. However, the data did not indicate an association between COVID-19 patients with pneumothorax and asthma, tuberculosis, cystic fibrosis, pneumoconiosis, primary and secondary pulmonary hypertension, or lung cancer. Mechanical and positive pressure ventilation increases the risk of pneumothorax due to increased barotrauma (26). Our study demonstrated this increased risk, as have previous study in which the risk of pneumothorax was significantly high in critically ill patients (27).

CKD, ischemic heart disease, uncomplicated DM, complicated hypertension, and substance abuse were associated with a lower risk of pneumothorax. Tobacco smoking is a major risk factor for pneumothorax (28). However, in our study, nicotine abuse was associated with lower odds of pneumothorax. The reason for this is unclear. Smokers may belong to a younger age group, which had a better outcome. OSA can increase the risk of pneumothorax, especially in patients on CPAP (29-31). However, in our study, OSA patients had a lower risk of pneumothorax. Although the exact cause is unclear, the NIS 2020 database does not differentiate patients with OSA on CPAP therapy and their compliance.

Influenza-related ARDS can cause diffuse alveolar damage and sub-pleural and intrapulmonary air cysts (32). However, no studies compare the risk and prevalence of pneumothorax in COVID-19 and influenza patients. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and influenza viruses share high infectivity, incidence, rapid onset, and mutability, along with similar signs, symptoms, and hematological parameters. While their chest computed tomography (CT) findings may overlap, they also exhibit distinct characteristics (33). In this study, the risk of pneumothorax was higher in patients with COVID-19 than in influenza patients. A higher degree of inflammation and changes in lung dynamics in COVID-19 could predispose the patients to develop a pneumothorax. The higher prevalence of pneumothorax in COVID-19 in 2020 could reflect fewer flu illnesses requiring hospitalization in that year.

Limitations

This study has several limitations. NIS is an administrative database. It relies on ICD-10 codes, which are inferior to manual chart review. It is an inpatient database and does not track patients post-discharge. If a patient was discharged alive but died at home or in a rehabilitation facility, that data will not be captured. NIS data lack laboratory investigations, imaging studies, and treatment; therefore cannot record the severity of illness during pneumothorax. Data on intensive care unit (ICU) admission, invasive and non-invasive ventilator settings, and duration of pneumothorax are not collected. Since no patients in the pneumothorax group had a lung transplant, an association could not be established. Implementation of ventilation techniques to mitigate barotrauma may have reduced the prevalence of pneumothorax over time. It is plausible that in the subsequent years, various COVID-19 variants, which are recognized for their impact on the disease’s severity, may have also contributed to the incidence of pneumothorax. Unfortunately, NIS provides data through the year 2020. Although the prevalence of pneumothorax may have decreased, the risk factors remain unchanged. Lastly, this observational study cannot establish causality between COVID-19 and pneumothorax. Some cases of pneumothorax might be coincidental with COVID-19 due to invasive or non-invasive ventilation or ECMO for ARDS due to COVID-19, but this is unlikely in this study due to the simultaneous presentation of COVID-19 and pneumothorax.

Conclusions

Pneumothorax, a rare complication of COVID-19, is a grave prognostic marker associated with a high mortality risk (14). Risk factors for the development of pneumothorax in COVID-19 include advancing age, male sex, stroke, liver disease, malnutrition, certain lung conditions, and additional comorbidities. Since the risk of pneumothorax was higher in COVID-19 than in influenza pneumonia, patients with COVID-19 and with the above-mentioned risk factors should be prioritized in applying strategies to prevent pneumothorax. COVID-19 patients, particularly those on mechanical ventilation, require close monitoring for potential pneumothorax development. Timely recognition and intervention can lower mortality rates in COVID-19 patients.

Acknowledgments

We would like to express our gratitude to Linda Conry, MA, for their invaluable contributions to the editing and refinement of this manuscript.

Funding: None.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://jtd.amegroups.com/article/view/10.21037/jtd-23-1454/rc

Peer Review File: Available at https://jtd.amegroups.com/article/view/10.21037/jtd-23-1454/prf

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jtd.amegroups.com/article/view/10.21037/jtd-23-1454/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). The study was exempt from institutional review board approval as the NIS 2020 database is comprised of previously collected, de-identified data.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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