Pneumothorax—Time for New Guidelines?

Rob Hallifax, DPhil, MRCP, BMCh; Julius P. Janssen, MD, PhD

Disclosures

Semin Respir Crit Care Med. 2019;40(3):314-322. 

In This Article

Etiology

Primary Spontaneous Pneumothorax

Although, typically PSP is defined as occurring in the absence of lung disease, it is increasingly evident that these patients do not have "normal lungs."[2,3] PSP is more common in taller patients with low body mass index (BMI) and smokers.[4–6] Sadikot et al studied risk of recurrence in 153 PSP patients over a 4-year period and found that height was significantly associated with greater risk of recurrence, but only in males.[4] In this study, female height and lower BMI in either sex, was not associated with increased risk. Large-scale data of 5,604 cases of pneumothorax in Japan, found a significantly lower weight:height ratio (using Kaup index) in individuals with pneumothorax compared to healthy individuals.[5]

While PSP may occur in patients without overtly recognized lung pathology, most patients have emphysema-like changes (ELCs), that is, blebs and bullae, in the lungs on CT scans (see Figure 1).

Figure 1.

Computed tomography (CT) image showing blebs or emphysema-like changes (ELCs). Arrows show three contiguous blebs (sometimes referred to as paraseptal emphysema).

One study found these changes bilaterally in the upper lung zones in 81% of nonsmoking patients with PSP but not in healthy controls.[7] Thoracoscopic investigation of 250 healthy individuals with no prior history of pleural disease (treated with thoracoscopic sympathectomy) demonstrated a 6% incidence of apical blebs. These were more prevalent in slim individuals (BMI < 22 kg/m2) who smoked.[8]

However, it is unclear how often these lesions are the actual site of air leakage. A landmark paper examined patients with PSP at thoracoscopy using inhaled fluorescein-enhanced autofluorescence.[9] Autofluorescence allows visualization of gas under ultraviolet light. In these patients, it demonstrated areas in the visceral pleura at which the inhaled gas comes (abnormally) close to the pleural surface. These areas appear normal on plain white light thoracoscopy, and do not necessarily correspond to areas with blebs and bullae, but are areas of parenchymal abnormality or "pleural porosity."[10] The true nature of these lesions is unclear, but is thought to be areas of disrupted mesothelial cells at the visceral pleura replaced by an inflammatory elastofibrotic layer with increased porosity, allowing air leakage.

Abnormal Elastosis

The reason why airways inflammation should result in degradation of elastic fibers, and hence formation of a porous elastofibrotic layer, is not clear. One theory is that there is an imbalance in the protease–antiprotease and oxidant–antioxidant systems. Matrix metalloproteinases (MMPs) are a group of zinc- and calcium-dependent endopeptidases that can damage the basement membrane (between pulmonary epithelium and alveoli).[11] MMP-2 and MMP-9, two interstitial collagenases, have been postulated to be pathogenic in other lung diseases,[12] including asthma and chronic obstructive pulmonary disease (COPD).[13] Two Taiwanese groups examined surgical resection specimens from patients undergoing surgery for PSP and demonstrated overexpression of MMPs.[11,14] The first compared lung tissue from 15 PSP patients with that from 20 patients with stage I nonsmall cell lung cancer who were used as controls.[11] Immunohistochemistry showed overexpression of MMP-2, MMP-7, and MMP-9 in the tissue of PSP patients compared to controls.[11] The second noncomparative study of 91 patients also found high MMP-2 and MMP-9 expression; additionally, higher levels were more frequent in those patient presenting with a recurrent pneumothorax compared to the first episode.[14] The same group of patients was examined for expression of nuclear factor erythroid 2-related factor 2 (Nrf2) in alveolar type I pneumocytes. Nrf2 is a regulator of redox homeostasis and inflammatory response. It is believed to play a cytoprotective role in detoxification and chemoprevention.[15] High Nrf2 expression was seen in those patients without previous recurrence, suggesting a protective effect.[15]

Familial Causes

Although the majority of PSPs occur "sporadically," it is estimated that around 10% of PSP will have a significant family history.[16,17] However, this estimate is based upon two small studies in specific geographical locations: 15 families identified from a survey of males in the Israeli Defense Force,[16] and 102 patients (and 21 family members) in Jiangsu Province, China.[17]

A number of important inherited conditions predispose to pneumothorax including Marfan syndrome,[18] Birt-Hogg-Dubé (BHD) syndrome,[19] other mutations of the folliculin gene (FLCN), alpha-1 antitrypsin deficiency,[20] and homocystinuria.[21] Although rare, familial patterns of inheritance of SP, particularly autosomal dominance, should be investigated as they may herald an unrecognized connective tissue disorder (Marfan syndrome or Ehlers–Danlos syndrome), metabolic disorder (homocystinuria), or skin disease (BHD) with the need for potential lifelong surveillance for severe extrapulmonary complications (e.g., renal cancer or aortic rupture). Therefore, clinicians should be vigilant for PSP being the first manifestation of a systemic disease, and should have a low threshold for onward referral. However, CT scan of the chest and pulmonary function testing are not standard after uncomplicated treatment of a first episode of PSP.

Secondary Spontaneous Pneumothorax

A host of airway and lung diseases can be complicated by SSP. In the U.K., the most common of these is the COPD.[22] The most common cause worldwide is tuberculosis. Other common causes include cystic fibrosis, lung cancer, necrotizing pneumonias, and human immunodeficiency virus-related Pneumocystis jiroveci lung infection. Two rare infiltrative lung diseases are notoriously associated with SSP; namely, pulmonary Langerhans cell histiocytosis and lymphangioleiomyomatosis, with or without other features of tuberous sclerosis.[23] Thoracic endometriosis is a recognized cause for recurrent "catamenial" pneumothorax phenomenon.[24,25] Table 1 summarizes the causes of SSP.

Epidemiology

SP is a common pathology. Estimates of the incidence of SP were based on studies which are often small, many years old, and from single centers,[26,27] and two national databases each covering 4 years (1991–1994[3] and 2008–2011[4]). These have reported an overall incidence of SP of 17 to 24 per 100,000 population per annum for men and 1 to 6 per 100,000 for women.[26–29]

These data have recently been updated using a large data set of 50 years' hospital admissions in England.[30] Covering over 170,000 admissions, these data show an increase in the incidence of pneumothorax from 1968 to 2016. In 2016, overall, there were 14.1 pneumothorax admissions per 100,000 population aged 15 years and over: higher for men (20.8) than for women (7.6 per 100,000).[30] This study confirmed the previously described bimodal age distribution (with a first peak aged 15–34 years and an increasing incidence beyond 60 years in both males and females), which was remarkably not found in the French epidemiological study.[29] This study also described the admission rates by PSP and SSP. In 2016, 60.8% of patients had chronic lung disease.

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