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Pulmonary Interstitial Emphysema

Author: Ruchi J. Sahota Editor: Fatima Anjum Updated: 4/17/2025 3:14:18 PM

Introduction

Pulmonary interstitial emphysema (PIE) is a rare and abnormal pathological condition that primarily affects neonates but can also occur in adults. Increased air pressure within the alveoli and alveolar airspaces disrupts the adjacent interstitial lung tissue, leading to structural damage and the formation of linear and cystic spaces, often complicated by air leaks.[1] The leaked air accumulates outside the normal air passages, within the interstitium or bronchovascular complexes. 

Premature infants with PIE may develop respiratory distress syndrome. The primary goal is to maintain adequate gas exchange. Without sufficient gas exchange, lung damage can occur, leading to prolonged hypoxia, respiratory acidosis, and pulmonary hypoperfusion.[2] 

PIE is diagnosed through imaging and histopathological findings.[3] The use of surfactants and high-frequency ventilation (HFV) has reduced the incidence of PIE in premature infants. The current management for respiratory distress syndrome in infants involves prophylaxis with synthetic surfactant and continuous positive airway pressure (CPAP), with or without mechanical ventilation.[4]

Etiology

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Etiology

Neonatal causes of PIE are mentioned below.[2]

  • Respiratory distress syndrome
  • Prematurity
  • Meconium aspiration syndrome
  • Positive pressure ventilation or mechanical ventilation with high peak pressures
  • Pulmonary infections (pneumonia, sepsis, and chorioamnionitis) and amniotic fluid aspiration[5]
  • Incorrect endotracheal tube placement
  • Antenatal exposure to magnesium sulfate [6]

Additional causes of PIE in adults include:

  • Asthma [7]
  • Smoking [8]
  • Barotrauma

Epidemiology

PIE is more commonly observed in premature infants during the first few weeks of life. Premature infants who develop PIE within 48 hours of birth typically have a poor prognosis. These infants may also have associated conditions such as low birth weight, premature birth, perinatal asphyxia, and sepsis.[9] Earlier studies found no significant difference in PIE incidence between sexes.[10] A retrospective study found that 24% of extremely premature infants on ventilators, who were treated with antenatal steroids, tocolysis, and postnatal surfactant, developed PIE later in their hospital course.[10][11]

The prevalence of PIE varies depending on the population studied, such as patients with low birth weight, respiratory distress syndrome, or other etiologies. A study examined infants with respiratory distress syndrome who were born prematurely at less than 30 weeks.[11] A comparison of surfactant administration as prophylaxis versus early treatment in premature infants revealed a higher incidence of PIE in both premature infants and those who received late surfactant treatment.[12][13] Premature infants born at 25 to 29 weeks of gestation who were randomly treated with surfactant at birth developed PIE in 15% of the treated infants and 26% of the control infants.[12][13] 

Premature infants with a body weight of less than 1000 grams at birth have the highest frequency of developing PIE. Among these infants, those with a body weight between 500 and 799 grams had a PIE incidence rate of 42%, those with a body weight between 800 and 899 grams had an incidence rate of 29%, and those with a body weight between 900 and 999 grams had an incidence rate of 20%.[14][15][16][17]

Pathophysiology

The pathophysiology of PIE involves alveolar hyperdistention and the formation of bronchial duct gland ectasia, leading to tissue rupture. Contributing factors to air leaks and alveolar rupture include insufflation from mechanical or positive pressure ventilation, uneven ventilation, and reduced lung compliance, particularly in underdeveloped lungs that are highly sensitive to stretch.[6][18] 

Increased transpulmonary pressure, which exceeds the tensile strength of the alveoli and airways, damages the respiratory epithelium. This epithelial injury allows air to enter the interstitium, leaking into the perivascular tissue of the lung due to high intra-alveolar pressure.[19] Air also leaks into the pleural connective tissue surrounding the peri-bronchovascular sheaths, interlobular septa, and visceral pleura.[19] The air becomes trapped in the interstitium, leading to compression atelectasis of the adjacent lung.[20][21] This results in respiratory distress syndrome in the affected infant.[19] Additionally, surface-active phospholipids are lost due to hyperinflation and overinflation.[22] 

Intrapulmonary and intrapleural pneumatosis are the 2 common types of air leaks, with the former being more common. The trapped air inside the lung is located beneath the pleura, within the interlobular septa. Intrapleural pneumatosis is more commonly seen in mature infants with normal lungs.[2][21] The abnormal air pockets are found within the visceral pleura and can also affect the mediastinal pleura.[7][8][23]

The complications of PIE range from isolated interstitial air bubbles to unilateral or bilateral lung lesions. This damages functional lung tissue and vascular structures, leading to fibrotic and inflammatory changes. The pathology may also include fibroblast foci, organizing and interstitial pneumonia, granulomatous inflammation, and, in some cases, lymphangiectasia.[24] These changes impair ventilation and perfusion, affecting systemic oxygenation and circulation, which increases morbidity and mortality in affected infants. PIE may resolve spontaneously, but this can result in complications such as pneumomediastinum, pneumothorax, or subcutaneous emphysema. In some cases, air may also leak into the pericardium or peritoneum.[8][6][25][26][24]

Histopathology

An autopsy of a previous case revealed bilateral pleural hyperinflation, which expanded upon opening the thoracic cavity. Numerous mucus plugs were present, but there were no effusions in the pleura or pericardium. Histologically, the autopsy showed thickening of the airway walls and basement membrane, along with inflammation of the airway lumens and the presence of eosinophils, resembling asthma. The airways were filled with mucus exudates. Case series revealed hyperdistention, signs of alveolar tears, parabronchial and perivascular widening, and connective tissue rupture, all of which are indicative of PIE.[7]

History and Physical

PIE is primarily diagnosed through imaging and histopathology; however, a few clinical signs in the history directly suggest this condition. Considering the risk factors for PIE is crucial, with premature birth and low birth weight being the primary factors. Some nonspecific clinical signs in infants associated with PIE include increased oxygen requirements, which may progressively and rapidly lead to carbon dioxide retention.

Specific physical examination findings are unavailable to directly diagnose PIE. However, if the condition has progressed, signs of air leaks may be present. During the physical examination, monitoring for air leaks, such as decreased breath sounds, crepitus on the affected side, or overinflation of the chest wall, is important.[27][28]

Evaluation

PIE is largely diagnosed through radiological imaging. PIE appears as the lung parenchyma filled with spherical, cystic, linear, and oval air-containing lucencies on imaging. Early changes are typically linear but gradually progress to more cystic formations in the interstitium. Linear radiolucencies measure approximately 3 to 8 mm in length and less than 2 mm in width, while cystic-like radiolucencies range from 1 to 4 mm in diameter. During inspiration, lung volumes may increase, but premature lungs exhibit decreased compliance, resulting in hyperdistention on imaging.

Air leaks may also be observed on imaging. In the presence of air leaks, the interstitial air is filled with large volumes of air, which increases the distance between the vascular bed and airspaces, thereby reducing gas exchange.[19] Pneumothorax can occur if subpleural cysts rupture. The air leak can compress the heart due to increased intrathoracic pressure, reducing venous return to the heart. Other imaging findings include linear gas collections in the periphery, typically seen with increased respiratory support demand and lung volumes, which are key diagnostic markers for PIE.

Early bronchopulmonary dysplasia is sometimes observed in the presence of partial bronchial obstructions. Histopathological findings in infants with bronchopulmonary dysplasia may reveal PIE, even if it is not evident on imaging.[3] A previous case study reported a computed tomography (CT) scan performed before autopsy, which showed pleural wall thickening and constricted airways. Imaging also revealed pulmonary hyperinflation and localized interstitial emphysema.[7]

PIE may occasionally appear on an anteroposterior supine chest x-ray, but sequential studies are necessary to monitor disease progression. Differentiating lucent bronchiole overdistention from PIE can be challenging, as distended airways are usually round and uniform. However, the radiolucencies in PIE do not align with the normal bronchial tree.

PIE can sometimes be misinterpreted as pulmonary edema or aspiration syndrome if the normally aerated lung appears surrounded by exudate. Air bronchograms are indicative of respiratory distress syndrome, not PIE. In infants on mechanical ventilation, the airways and alveoli may appear similarly distended, resembling PIE. If a chest x-ray is inconclusive, a CT scan should be considered as the next step for diagnostic imaging.[3][29][30][31]

Treatment / Management

Infants with PIE are treated in the neonatal ICU (NICU) due to the critical nature of the condition and the potential for complications, such as pneumothorax or pneumopericardium, which may require mechanical ventilation. Invasive procedures, such as thoracentesis, may also be necessary. Several management approaches exist, with varying degrees of success. A significant proportion of infants with PIE are premature. The use of surfactants in premature infants (<30-32 weeks) can help reduce the development of PIE by preventing respiratory distress syndrome.

If mechanical ventilation can be avoided, it should be, as high oxygen pressure may damage the infant's underdeveloped lungs. CPAP should be attempted first, although it can also contribute to the development of PIE. When mechanical ventilation is necessary, ventilator settings should prioritize reduced inspiratory time (Ti), prolonged expiratory time, and lower pressure when adjusting positive airway pressure (PEEP) to allow for proper airway emptying during expiration. Affected infants require close monitoring of vitals, oxygen levels, blood gases, and nutrition.[32] (B3)

Conservative Management

Several preventive measures can help reduce the risk of PIE. Prophylactic surfactant administration in preterm infants at risk of respiratory failure has been shown to decrease the likelihood of developing PIE. Early administration of surfactant, combined with brief ventilation, has been associated with a reduced incidence of air leaks in premature infants.[33](A1)

A more conservative approach involves lateral decubitus positioning, which is particularly effective in infants with unilateral PIE. A case study demonstrated that this method resolved unilateral PIE within 2 to 6 days, with low failure rates and minimal recurrence. Lateral decubitus positioning can also benefit infants with bilateral PIE if one side is significantly affected. The unaffected lung will receive improved oxygenation, which can help reduce ventilator settings.[34]

Surfactants: These are administered to premature infants as prophylactic management for respiratory distress syndrome. Surfactants are available in both natural and synthetic forms, and they are delivered via intratracheal administration. Surfactants reduce the surface tension at the air-alveolar interface, thereby preventing alveolar collapse during expiration.[11][35](A1)

Natural surfactants are usually derived from animals, with bovine sources being more common than porcine, and are similar to human surfactants. However, there are challenges associated with surfactant use, including inconsistent efficacy, risk of pathogen contamination, cost concerns, and the potential for anaphylactic reactions. The currently used surfactants include Survanta (bovine lung extract), Beractant (porcine lung extract), and Calfactant (bovine bronchoalveolar extract).[12][13](A1)

A few synthetic surfactants are considered therapeutic and may be more effective than natural ones. Colfosceril palmitate is protein-free and contains only phospholipids. Lucinactant, a newer surfactant containing protein, has been studied and shown to be more effective in certain cases.[12][13](A1)

Mechanical ventilation: Mechanical ventilation should be reserved for advanced cases that do not respond to initial conservative measures, including trials of CPAP and noninvasive respiratory support.[36] When mechanical ventilation is indicated, conventional modes such as controlled mechanical ventilation (CMV) are typically initiated using lung-protective strategies.[37][38] Recommended ventilator settings often include a low tidal volume of 4 to 6 mL/kg of ideal body weight, PEEP of 5 to 6 cm H2O, and an inspiratory time (Ti) of approximately 0.4 seconds.[39] Neonates require frequent assessment to guide further adjustment of ventilator settings and evaluate lung compliance. If conventional mechanical ventilation fails to improve respiratory status or increases the risk of pneumothorax, transitioning to alternative ventilation modes should be considered. (A1)

The use of HFV is not recommended as a first-line elective intervention due to a lack of conclusive evidence supporting its superiority. However, some studies suggest that HFV may reduce the risk of air leaks and PIE when compared to conventional mechanical ventilation.[40][41][42][43][14][44][45] Despite these potential benefits, HFV carries notable disadvantages, including rapid fluctuations in CO2 levels, hemodynamic instability, and an increased risk of brain injury. Additionally, it requires specialized equipment and care settings, which may not be readily available or cost-effective in all institutions. As a result, HFV is typically reserved for cases of refractory hypoxemia or persistent air leaks unresponsive to CMV. [46] Please see StatPearls' companion resource, "High-Frequency Oscillator in the Neonate," for more information.(A1)

Lobectomy: Lobectomy is considered a last-resort therapy due to its invasive nature. This procedure is typically performed when medical management fails and spontaneous resolution does not occur. This procedure is particularly considered for infants with severe emphysema, as previous outcomes have shown success in such cases.[47][48](B3)

Additional Methods of Management

Several rare case reports have described alternative management strategies for PIE, including artificial pneumothorax,[49][50][49] chest physiotherapy combined with oxygen therapy,[51] steroid treatment,[52] extracorporeal membrane oxygenation (ECMO),[25][53] and nitric oxide treatment.[54] However, these treatments are not commonly used.(B3)

Differential Diagnosis

PIE is diagnosed through radiological and histopathological evaluation. The following conditions should be ruled out, often with the help of a chest CT scan:

  • Pulmonary edema
  • Pulmonary embolism
  • Bronchogenic cysts
  • Congenital lobar emphysema
  • Air bronchograms associated with respiratory distress syndrome
  • Aspiration pneumonia
  • Diaphragmatic hernia
  • Congenital cystic adenomatoid malformation

Prognosis

The diagnosis of PIE is generally associated with a poor prognosis. Studies have reported high mortality rates ranging from 53% to 67%.[9][15] Studies of infants with PIE who have a low birth weight of less than 1600 grams and severe respiratory distress syndrome indicate a poor prognosis, with reported mortality rates of 80%.[55] PIE is known to cause air leaks, such as pneumothorax and mediastinal emphysema, further increasing the risk of mortality. Early-onset PIE is particularly associated with higher mortality due to the presence of severe underlying parenchymal disease.[56][55] 

PIE typically resolves over the course of a few weeks with appropriate management. However, this often necessitates prolonged mechanical ventilation, which can lead to complications such as bronchopulmonary dysplasia or chronic lobar emphysema. In some cases, these complications may require surgical intervention, including lobectomy.[57] 

A study found that 54% of PIE survivors developed chronic lung emphysema, with 50% of these infants requiring surgical lobectomies.[9] Other studies indicated that infants with PIE also experienced intraventricular hemorrhage, and that PIE remained strongly associated with increased mortality.[10]

Complications

PIE is a severe condition associated with multiple complications, including:

  • Respiratory insufficiency
  • Mediastinal emphysema
  • Other air leaks (eg, pneumomediastinum, pneumothorax, pneumopericardium, pneumoperitoneum, and subcutaneous emphysema)
  • Intraventricular hemorrhage
  • Massive air embolism
  • Chronic lung disease of prematurity
  • Periventricular leukomalacia
  • Death

Postoperative and Rehabilitation Care

Posttreatment monitoring is essential for premature infants. Key complications to monitor for include periventricular leukomalacia, intraventricular hemorrhage, and developmental delay. Infants may develop chronic lung disease, requiring long-term pulmonary care. The literature remains unclear on whether bronchodilator treatment benefits chronic lung disease in these infants.

Consultations

Management of PIE requires a multidisciplinary team approach. The following specialties are typically involved in the care of these patients:

  • Neonatology
  • Pediatric pulmonary care team
  • Critical care team
  • Pediatric surgery team

Deterrence and Patient Education

Preventive measures during pregnancy should be discussed for infants at high risk of developing PIE.[2]

  • Smoking and alcohol consumption should be avoided
  • Recreational drug use (eg, cocaine and marijuana) should be avoided
  • Proper prenatal care should be ensured

Pearls and Other Issues

Key facts to keep in mind regarding PIE include:

  • PIE is a rare condition that occurs more frequently in premature and low birth weight infants.
  • PIE is often caused by mechanical ventilation and is commonly associated with respiratory distress syndrome.
  • Clinically, PIE can progress quickly, with increased oxygen requirements and hemodynamic instability. However, diagnosis is made through imaging and histopathology.
  • PIE is usually treated with early surfactant administration and optimal mechanical ventilator settings, including high-frequency oscillation ventilation, positive end-expiratory pressure, and low inspiratory pressure. The goal is to facilitate proper expiration while managing over-distended lungs.
  • Conservative strategies, including lateral decubitus positioning and CPAP, may be beneficial when mechanical ventilation can be avoided.
  • Potential complications include pulmonary air embolisms and other air leaks.

Enhancing Healthcare Team Outcomes

Premature infants at high risk for PIE require close monitoring in the NICU. A strong interprofessional healthcare team, including pediatricians, pulmonologists, intensivists, and surgeons, is essential for coordinating care for these infants. CPAP and synthetic surfactants are the current standard of care for preventing PIE in patients with respiratory distress syndrome. After recovery, patients should be closely monitored by pediatricians and pulmonologists for any long-term effects. Effective communication and collaboration among the healthcare team allow these critically ill patients to be treated effectively.

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