INTRODUCTION — Gas in the pleural space is termed "pneumothorax." A spontaneous pneumothorax is that which occurs in the absence of an external event. Determining the etiology of pneumothorax dictates immediate and definitive management. Thus, the clinician needs to be familiar with the wide array of etiologies when faced with pneumothorax so that appropriate therapy can be administered promptly to prevent deterioration and recurrence (table 1).
In this topic review, the epidemiology and etiology of pneumothorax are discussed. Clinical presentation, diagnosis, and treatment of pneumothorax are reviewed in detail elsewhere. (See "Clinical presentation and diagnosis of pneumothorax" and "Treatment of secondary spontaneous pneumothorax in adults" and "Treatment of primary spontaneous pneumothorax in adults" and "Pneumothorax: Definitive management and prevention of recurrence".)
PRIMARY SPONTANEOUS PNEUMOTHORAX
Definition — A primary spontaneous pneumothorax (PSP) is traditionally defined as a pneumothorax which presents without a precipitating external event in the absence of clinical lung disease. Although PSP is not associated with known clinical lung disease (eg, chronic obstructive pulmonary disease [COPD]), most affected patients have unrecognized lung abnormalities (mostly subpleural blebs) that likely predispose to pneumothorax [1-5]. However, following investigation, some patients with apparent PSP may have other more serious underlying lung diseases (eg, Birt-Hogg-Dubé syndrome, thoracic endometriosis, lymphangioleiomyomatosis), thereby recategorizing them as having secondary spontaneous pneumothorax (SSP). Thus, many experts believe that the distinction between pneumothorax in patients "without" lung disease (ie, pneumothorax with subpleural blebs, also known as PSP) and pneumothorax in patients with lung diseases (ie, SSP) is somewhat artificial, and that PSP and SSP may exist on either end of a continuum [6].
Epidemiology — PSP is more common in males than females (roughly three to six times higher). The incidence of PSP in males ranges from 7.4 per 100,000 population per year in the United States to 37 per 100,000 population per year in the United Kingdom. The incidence in females ranges from 1.2 per 100,000 population per year in the United States to 15.4 per 100,000 population per year in the United Kingdom [7]. The reason for these geographic differences is unknown. Another hospital database study of emergency department visits from January 2008 to December 2014 reported that 79 percent of pneumothoraces were in males and 21 percent in females [8].
The prevalence of asymptomatic PSP is unknown, but one retrospective study of Japanese students suggested that the rate may be as high as 0.042 percent and higher in males than females [9]. Mild collapse (ie, <10 percent collapse) was present in approximately half of individuals, most of whom underwent intervention.
Pathogenesis and risk factors
Subpleural blebs — PSP is thought to be due to small apical subpleural blebs or bullae (ie, air sacs between the lung tissue and pleura) that rupture into the pleural cavity (table 2). The mechanism of bleb/bulla formation is unknown. However, since PSP classically occurs in tall, thin males between the ages of 10 and 30 years [10,11], the development of subpleural blebs is thought to be due to either increasing negative pressure or greater mechanical alveolar stretch at the apex of the lungs during growth or a congenital phenomenon in which lung tissue at the apex grows more quickly than the vasculature, thereby outstripping its blood supply. Pathologic assessment of resected specimens suggests disrupted areas of mesothelial cells, inflammation, and pores of 10 to 20 microns in diameter rather than a breach in the visceral pleural membrane [12,13]. Leakage of fluorescein seen on autofluorescence thoracoscopy also supports this theory [14].
Smoking (cigarette, cannabis) — Cigarette smoking (current or past) is a significant risk factor for PSP, probably due to airway inflammation and respiratory bronchiolitis. As an example, in an analysis of four studies that included 505 patients with PSP, 91 percent were smokers [7]. Furthermore, the risk of PSP was directly related to the amount of cigarette smoking. Compared with nonsmokers, the relative risk of PSP in males was seven times higher in light smokers (1 to 12 cigarettes per day), 21 times higher in moderate smokers (13 to 22 cigarettes per day), and 102 times higher in heavy smokers (>22 cigarettes per day) [15]. For females, the relative risk was 4, 14, and 68 times higher in light, moderate, and heavy smokers, respectively. Similarly, patients with PSP who smoke cigarettes have more respiratory bronchiolitis and higher recurrence rates than those who don't smoke [16]. Regularly smoking cannabis appears to increase the risk of PSP similarly [17,18].
Genetic predisposition — Reports have been published describing the clustering of PSP in certain families [19-25]. Autosomal dominant, autosomal recessive, polygenic, and X-linked recessive inheritance mechanisms have all been proposed [20-22]. Genetic variants associated with PSP include human leukocyte antigen (HLA) haplotype A2B40, alpha-1 antitrypsin (M1M2 mutations), and fibrillin 1 (FBN1) mutations [26,27]. The autosomal dominant Birt-Hogg-Dubé syndrome (BHD; due to mutations in the folliculin gene [especially c.1300G>C, c.250-2A>G] [28]), hyperhomocysteinemia, alpha-1 antitrypsin and Marfan syndrome are also inherited conditions associated with pneumothorax that may masquerade as PSP when the diagnosis is not known. For example, one study reported that 5 to 10 percent of patients with PSP turned out to have BHD following investigation [29]. (See "Birt-Hogg-Dubé syndrome".)
Other — Several reports suggest that drops in atmospheric pressure may be associated with an increase in the incidence of pneumothorax [30-35].
SECONDARY SPONTANEOUS PNEUMOTHORAX — Secondary spontaneous pneumothorax (SSP) is defined as pneumothorax that presents as a complication of underlying lung disease (table 2) [1,36].
SSP has a male preponderance, but in contrast with primary spontaneous pneumothorax, SSP presents in older patients (>55 years) [11]. One large hospital database of admissions reported that the rate of admissions for spontaneous pneumothorax, 61 percent of which were due to chronic obstructive pulmonary disease (COPD), has increased by 9 percent over a 48-year period from 1968 through 2016 [37]. Rates were higher in males than females (73 versus 27 percent).
Nearly every lung disease can be complicated by SSP, although the most commonly associated diseases are COPD and, in endemic areas, tuberculosis (TB). In one study of hospital admissions, up to 80 percent of SSP cases were due to emphysema/COPD, interstitial lung disease, and malignancy while TB, sarcoidosis, and cystic fibrosis (CF) were responsible for <2 percent of cases [37].
Other common causes include CF, primary or metastatic lung malignancy, and necrotizing pneumonia [36,38]. Pneumothorax typically presents as a complication of these common diseases and is rarely an initial manifestation. In contrast, pneumothorax may be the presenting feature of uncommon causes of SSP, and the diagnosis may not be known upon presentation (eg, lymphangioleiomyomatosis, Birt-Hogg-Dubé syndrome (table 3)).
Chronic obstructive pulmonary disease/emphysema — COPD is the most common cause of SSP, with 50 to 70 percent of SSP cases attributed to COPD in small case series [36,38-40]. Rupture of apical blebs or bullae is the usual cause. Patients with COPD may also be at higher risk for iatrogenic pneumothorax (eg, venous catheterization, mechanical ventilation), particularly when there is a significant amount of underlying emphysema or air trapping. (See "Chronic obstructive pulmonary disease: Diagnosis and staging".)
Severity of COPD correlates with the likelihood of developing SSP. As an example, more than 30 percent of patients with SSP due to COPD have a forced expiratory volume in one second (FEV1) less than one liter and an FEV1 to forced vital capacity (FEV1/FVC) ratio less than 40 percent [41].
Cystic fibrosis — Approximately 3 to 4 percent of patients with CF will have an episode of SSP during their lifetime, but in those who survive to age 18, the incidence is 16 to 20 percent [42,43]. CF-related SSP is usually due to rupture of apical subpleural cysts. (See "Cystic fibrosis: Clinical manifestations and diagnosis", section on 'Respiratory tract involvement' and "Cystic fibrosis: Overview of the treatment of lung disease", section on 'Spontaneous pneumothorax'.)
The risk of pneumothorax in CF increases with the severity of lung function abnormalities. In one report, nearly half of all patients with CF who had an FEV1 less than 20 percent of predicted experienced at least one SSP [42].
Other than cysts and fibrosis, other factors that may predispose to the development pneumothorax in CF include infection with Pseudomonas aeruginosa, Burkholderia cepacia complex, or Aspergillus species, as well as a prior episode of massive hemoptysis, and possibly inhaled medications or noninvasive positive pressure [44]. These factors may reflect disease severity, rather than being independent risk factors.
Lung malignancy (primary and metastatic) — Both primary and metastatic lung malignancy have been associated with SSP. Among 168 patients with SSP, malignancy was the underlying cause in 16 percent; the underlying malignancy was more commonly a lung primary than metastatic disease [38]. Potential mechanisms include tumor necrosis, endobronchial obstruction with air trapping, development of necrotizing cysts or pneumonia, and coexisting COPD/emphysema.
Less commonly, malignancies that metastasize to the lung are associated with the development of necrotic cysts, which can result in SSP. Examples include lymphoma, sarcoma, gastrointestinal or genitourinary adenocarcinoma, mesenchymal cystic hamartoma, pleuropulmonary blastoma, and angiosarcoma. (See 'Cystic lung disorders (other than emphysema)' below.)
Necrotizing lung infections — SSP can complicate the course of necrotizing pneumonia due to Pneumocystis jirovecii (ie, pneumocystis pneumonitis [PCP]), TB, bacteria, and less often fungi or other microorganisms, including severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) [38,45]. The relative frequency of these etiologies depends upon the frequency of these diseases in the population studied. The presumed common mechanism underlying pneumothorax in patients with lung infection is direct invasion and necrosis of lung tissue including the pleura by the microorganism itself.
●Pneumocystis jirovecii – Unilateral and bilateral SSP can be seen in patients with PCP, most often in patients with human immunodeficiency virus (HIV) [46-52]. In the era of antiretroviral therapy (ART), the frequency of pneumothorax complicating PCP is approximately 5 to 10 percent [50]. However, another study reported lower rates, with pneumothorax complicating only 1.2 percent of all hospital admissions in a cohort of 599 HIV-infected patients; however, over half had nonpulmonary reasons for admission [46].
In patients with HIV-related PCP, it has been hypothesized that the administration of aerosolized pentamidine may increase the likelihood for PCP to grow and cause cavitation in the peripheral parts of the upper lobe, thereby increasing the risk for pneumothorax [49,53,54]. This phenomenon may relate to the preferential delivery of the aerosolized agent to the proximal parenchyma of the lower lobes rather than upper lobes.
Unlike bacterial pneumonia, pneumothorax associated with PCP is more likely to be bilateral than unilateral [55].
The clinical presentation, diagnosis, and management of PCP are discussed separately. (See "Epidemiology, clinical presentation, and diagnosis of Pneumocystis pulmonary infection in patients with HIV".)
●Bacterial pneumonia – SSP has been associated with bacterial pneumonias caused by Staphylococcus, Klebsiella, Pseudomonas, Streptococcus pneumoniae, and anaerobic organisms. Among 168 patients with SSP, bacterial pneumonia was the etiology in 11 percent of cases [38]. SSP in the setting of bacterial pneumonia is more likely to be unilateral than bilateral and can be associated with extension of bacterial infection into the pleura and development of empyema, giving the appearance of a hydropneumothorax.
●Tuberculosis – SSP occurs in 1 to 3 percent of patients hospitalized with pulmonary TB [40,56,57]. Rates are higher in endemic areas [40]. The pneumothorax is usually due to rupture of a tuberculous cavity into the pleural space. (See "Pulmonary tuberculosis: Clinical manifestations and complications", section on 'Pneumothorax' and "Diagnosis of pulmonary tuberculosis in adults".)
●Coronavirus disease 2019 (COVID-19) – Pneumothorax has been reported with various incidences in patients with COVID-19 infections and were likely related to severity of the infection. These details are provided separately. (See "COVID-19: Epidemiology, clinical features, and prognosis of the critically ill adult", section on 'Pneumothorax and barotrauma'.)
●Others – Several other pulmonary infections have been associated with pneumothorax including fungal, viral, and mycobacterial infections other than TB [45-49,55,58-61].
Cystic lung disorders (other than emphysema) — Pneumothorax is common in lung conditions associated with cysts. However, since many of these conditions are rare, pneumothorax in this setting may masquerade as PSP when the underlying diagnosis is unknown. Disorders associated with cysts are listed in the table (table 3) and include conditions such as lymphangioleiomyomatosis, diffuse Langerhans cell histiocytosis, lymphocytic interstitial pneumonitis (eg, Sjögren's disease), and Birt-Hogg-Dubé syndrome. Further details regarding the diagnostic investigation of suspected cystic lung disease are provided separately. (See "Diagnostic approach to the adult with cystic lung disease".)
Catamenial pneumothorax — Catamenial pneumothorax refers to a pneumothorax occurring in association with menses due to thoracic endometriosis. In this condition pneumothorax is thought to relate to the development and involution of pleural implants comprised of endometrial tissue; as such, some experts consider this primary spontaneous pneumothorax since parenchymal lung disease is typically absent. Further details regarding thoracic endometriosis can be found separately. (See "Clinical features, diagnostic approach, and treatment of adults with thoracic endometriosis".)
Human immunodeficiency virus — Pneumothorax is seen in HIV due to several etiologies, particularly infections including PCP pneumonia, bacterial pneumonia, and pulmonary TB as well as toxoplasmosis, and fungal, viral, and mycobacterial infections [15,46-49,55,58,59,62,63]. Patients with HIV can also be at risk for iatrogenic pneumothorax as well as pneumothorax due to the presence of pneumatoceles (typically from old Staphylococcal or PCP infection), Kaposi sarcoma, intravenous drug abuse, and cigarette smoking [64-67].
One report suggested that the degree of immunosuppression in HIV may affect the etiology of pneumothorax: In patients with CD4 positive lymphocyte counts >200 cells/mL, pneumothorax was more likely due to bacterial pneumonia whereas in those with counts <200 cells/mL, pneumothorax was more often associated with Pneumocystis jirovecii [55].
Architectural abnormalities of pleural membrane — Pneumothorax may occur in conditions where the integrity of the pleural membrane and parenchyma is abnormal, the diagnosis of which may be or may not be known at the time of presentation. This includes:
•Marfan syndrome [68] (see "Genetics, clinical features, and diagnosis of Marfan syndrome and related disorders")
•Homocystinuria [69] (see "Overview of homocysteine")
•Ehlers-Danlos syndrome [70] (see "Clinical manifestations and diagnosis of Ehlers-Danlos syndromes")
In Marfan and Ehlers-Danlos syndrome, it is thought that abnormal elastin or collagen content of the pleural membrane and parenchyma may predispose patients to pneumothorax. Patients with Marfan syndrome may also develop parenchymal cysts that may increase the risk of developing a pneumothorax. Why patients with homocystinuria develop pneumothorax is less clear, but homocysteine plays a role in vascular homeostasis and in the regulation of smooth muscle and collagen production in the lung [71].
Others — Less common causes of SSP include ankylosing spondylitis, asthma, interstitial lung disease (eg, idiopathic pulmonary fibrosis, silicosis), granulomatous lung diseases (eg, rheumatoid arthritis, granulomatosis with polyangiitis, and sarcoidosis), and inhalation of cocaine [36,72-77]. Several case series have described pneumothorax occurring in patients with COVID-19 in the absence of noninvasive or invasive ventilation [78-80].
OTHERS
Traumatic pneumothorax — Pneumothorax is traumatic when due to blunt or more commonly, penetrating thoracic trauma. Traumatic pneumothorax can be categorized as iatrogenic or non-iatrogenic. Trauma is probably the most common cause of pneumothorax.
Iatrogenic — Pneumothorax is iatrogenic when it is induced by a medical procedure, typically procedures that have the potential to introduce air into the pleural space via the chest, neck, gut, or abdomen [81]. Most commonly, iatrogenic pneumothorax is induced by lung procedures (eg, percutaneous or transbronchial lung or mediastinal biopsy and fiducial seed placement for radiotherapy) and central venous catheterization. Other etiologies include thoracentesis, mechanical ventilation, pacemaker, hypoglossal nerve stimulation, tracheostomy, other thoracic or esophageal procedures or surgery, breast tissue expander placement, and even chest acupuncture, colonoscopy, and shoulder arthroscopy [82-85].
The prevalence of iatrogenic pneumothorax is poorly studied but likely varies with the prevalence of procedures performed, presence of risk factors such as underlying lung disease, and operator experience [81,86]. In one study of over 12,000 procedures, the prevalence of pneumothorax was 1.4 percent, among which 57 percent were due to emergency procedures [81]. The most frequent procedures associated with pneumothorax were central venous catheterization (44 percent), thoracentesis (20 percent), and barotrauma due to mechanical ventilation (9 percent). Another study reported a higher incidence of iatrogenic pneumothorax in teaching compared with nonteaching hospitals [87].
Non-iatrogenic — Non-iatrogenic pneumothorax due to external trauma may be minor or severe. It is also termed "open pneumothorax" when a penetrating traumatic chest wall defect is present, through which atmospheric air enters the pleural space during inspiration (ie, a "sucking wound") and exits during expiration, resulting in a mediastinal swing away from the affected side during inspiration and toward the affected side during expiration ("mediastinal flutter"). Further details regarding traumatic pneumothorax are provided separately. (See "Initial evaluation and management of blunt thoracic trauma in adults", section on 'Pneumothorax'.)
Miscellaneous — Several rare case reports have described pneumothorax in association with the following:
Anorexia nervosa — Patients with anorexia nervosa may develop spontaneous pneumothorax [88-91]. It is thought that the pulmonary parenchymal consequences of malnutrition (eg, emphysema) contribute to development of pneumothorax in these patients, but other unknown processes may be at play. (See "Anorexia nervosa in adults and adolescents: Medical complications and their management", section on 'Pulmonary'.)
Exercise, illicit drug use, immunosuppressant drugs — Rare case reports and anecdotes suggest a possible relationship between pneumothorax and exercise, drug abuse (eg, cocaine or heroin), or chemotherapeutic drugs [92-101]. It has been postulated that exercise and illicit drug use may cause pneumothorax by leading to deeper inhalation and Valsalva maneuvers. Some injection drug users may also develop traumatic pneumothorax from attempting to inject into the neck veins.
Air travel and scuba diving — Pneumothorax may be associated with air travel and diving, although an underlying lung disorder may increase this risk further [102]. (See "Complications of SCUBA diving", section on 'Pulmonary barotrauma' and "Pneumothorax and air travel".)
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Pneumothorax".)
INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)
●Basics topic (see "Patient education: Pneumothorax (collapsed lung) (The Basics)")
PATIENT PERSPECTIVE TOPIC — Patient perspectives are provided for selected disorders to help clinicians better understand the patient experience and patient concerns. These narratives may offer insights into patient values and preferences not included in other UpToDate topics. (See "Patient perspective: Lymphangioleiomyomatosis (LAM)".)
SUMMARY AND RECOMMENDATIONS
●Definition – Gas in the pleural space is termed "pneumothorax." Determining the etiology of pneumothorax dictates immediate and definitive management. Thus, the clinician needs to be familiar with the wide array of etiologies when faced with pneumothorax, so that appropriate therapy can be administered promptly to prevent deterioration and recurrence. (See 'Definition' above and 'Introduction' above.)
●Primary spontaneous pneumothorax – A primary spontaneous pneumothorax (PSP) is one that presents in the absence of an external event in an individual who is without underlying clinical lung disease. (See 'Primary spontaneous pneumothorax' above and 'Definition' above.)
•PSP is three to six times more common in males than females and usually presents between the ages of 10 and 40 years. (See 'Epidemiology' above.)
•Most individuals with PSP have unrecognized lung disease in the form of subpleural blebs that rupture into the pleural space (table 2). Subpleural blebs may be developmental, but cigarette smoking and genetic predisposition may also play a role. (See 'Pathogenesis and risk factors' above.)
●Secondary spontaneous pneumothorax – Secondary spontaneous pneumothorax (SSP) is that which presents as a complication of underlying lung disease (table 2). (See 'Secondary spontaneous pneumothorax' above.)
•SSP has a slight male preponderance and occurs in older patients (>55 years).
•Nearly every lung disease can be complicated by SSP, although the most common lung disorders associated with SSP are chronic obstructive pulmonary disease and, in endemic areas, tuberculosis. Other common causes include cystic fibrosis, primary or metastatic lung malignancy, and necrotizing pneumonia. Less common causes include cystic lung diseases other than emphysema (eg, lymphangioleiomyomatosis, Birt-Hogg-Dubé syndrome (table 3)), endometriosis, HIV, and architectural abnormalities of the pleural membrane (eg, Marfan syndrome, Ehlers-Danlos syndrome, homocystinuria).
●Other types of pneumothoraces – Pneumothorax, including iatrogenic pneumothorax, can also be traumatic in nature due to penetrating or nonpenetrating trauma. Pneumothorax is iatrogenic when it is induced by a medical procedure, the most common cause being central venous catheterization. Rare case reports describe pneumothorax occurring in association with anorexia, exercise, illicit or immunosuppressant drugs, or air travel and scuba diving. (See 'Others' above.)
ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Richard W Light, MD, who contributed to earlier versions of this topic review.
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