Pulmonary Medicine

Bullous Lung Disease (includes HIV-related emphysema)

What every physician needs to know:

Bullous lung disease is characterized by the development of bullae within the lung parenchyma. A bulla is a permanent, air-filled space within the lung parenchyma that is at least 1 cm in size and that has a thin or poorly defined wall; it is bordered only by remnants of alveolar septae and/or pleura. Bullae are to be distinguished from other air-filled spaces within the lung:

  • Blebs are air-filled collections within the layers of the visceral pleura and are less than 1 cm in diameter.

  • Cystsare round, well circumscribed collections that have an epithelial or fibrous lining.

  • Cavities are usually thick-walled collections formed by focal necrosis within a consolidation, mass, or nodule.

  • Pneumatoceles are temporary rents in the lung parenchyma that usually arise from blunt trauma or over-distention of the lung.

Although typically seen in the context of chronic obstructive pulmonary disease (COPD), bullous emphysema bullae may occasionally be noted as isolated findings within normal lung parenchyma; they are not always associated with airflow obstruction.

Bullae typically grow in size over time, but both the rate and extent of growth are highly variable. If bullae grow large enough, they may limit the expansion of adjacent lung parenchyma and in severe cases may cause frank atelectasis of adjacent lung segments.

In the absence of unmanageable symptoms, bullae do not necessarily require intervention. However, in some patients who have severe impairment despite aggressive medical therapy, surgical bullectomy may be beneficial.

Classification:

Bullous lung disease can be classified into two major categories based on the condition of the surrounding lung parenchyma:

  • Bullous emphysema refers to the formation of bullae within emphysematous lung parenchyma. In this context, multiple adjacent bullae are often created as areas of severe emphysema coalesce that is due to progressive loss of alveolar attachments. Patients with bullous emphysema generally exhibit airflow obstruction on spirometry.

  • Bullae within otherwise normal lungs are often singular and surrounded by morphologically normal lung tissue. This category is far less common than bullous emphysema. The pathogenesis is not clearly established, but it likely involves a focal anatomic defect that results in progressive air-trapping. Even when symptomatic, patients with this form of disease may exhibit normal pulmonary function tests.

More detailed classification schemes (e.g., the Reid classification) have been proposed based on the number of bullae, their location, and the condition of the surrounding lung parenchyma. However, these classifications are not commonly used, and their clinical utility is not well established.

Are you sure your patient has bullous lung disease? What should you expect to find?

Although bullous lung disease is sometimes asymptomatic and found only incidentally on chest imaging, it commonly presents with symptoms. Typically, the symptoms are those of COPD, including:

  • Shortness of breath or chest tightness, particularly with exertion

  • Cough

  • Sputum production

  • Occasionally, a sense of abdominal fullness or bloating, usually associated with severe obstruction and prominent air-trapping on lung function testing

  • Rarely, chest pain that is due to air-trapping within a bulla, causing distention of the visceral pleura

Symptoms are typically insidious in onset, but sudden and severe dyspnea or chest pain in a patient with known bullous lung disease should raise suspicion for pneumothorax that is due to a ruptured bulla or bleb. Rarely, fever and malaise, with or without increased sputum production, may signal an infected bulla.

Chest imaging reveals large, air-filled spaces within the lung parenchyma that are at least 1 cm in size and that have thin or poorly defined walls. Bullae are usually found within areas of emphysematous lungs, but less often, they occur in isolation with normal surrounding lung parenchyma.

Pulmonary function testing may be normal, particularly in patients whose bullae are surrounded by normal lung parenchyma. However, pulmonary function testing usually demonstrates findings consistent with obstructive lung disease. Common lung function abnormalities include airflow obstruction, hyperinflation (i.e., elevated total lung capacity), air-trapping (i.e., elevated residual volume), and reduced diffusing capacity for carbon monoxide. Other clinical signs of bullous lung disease may include hypoxemia, particularly with exertion; hypercapnia; and reduced exercise capacity.

Beware: there are other diseases that can mimic bullous lung disease:

The differential diagnosis of bullous lung disease is relatively broad since it includes any disease that can form air-filled spaces within the lung parenchyma:

  • Blebs: Blebs are effectively "blisters" that occur within the layers of the visceral pleura, rather than within the lung parenchyma itself. They are usually less than 1 cm in diameter, apical in location, and are a frequent finding in patients with spontaneous pneumothorax. Blebs may coexist with bullous lung disease.

  • Cystic lung disease: Cysts are distinguished from bullae by their round shape, well circumscribed epithelial or fibrous lining, and their usually smaller size. Cystic lung diseases include:

    • Langerhans cell histiocytosis

    • Lymphangioleiomyomatosis

    • Tuberous sclerosis

    • Lymphocytic Interstitial pneumonitis

    • Birt-Hogg-Dube syndrome

    • Pneumocystis jiroveci pneumonia (PCP)

    • Honeycomb change in idiopathic pulmonary fibrosis

  • Cystic bronchiectasis: In the cystic bronchiectasis associated with cystic fibrosis, the air-filled spaces are actually dilated airways, rather than air spaces within the lung parenchyma.

  • Cavitary lung disease: Lung cavities may occur within a consolidation, a mass, or a nodule; in contrast to bullae, lung cavities are often thick-walled. Examples of cavitary lung diseases include:

    • Lung abscess (e.g., resulting from tuberculosis or Staphylococcal or Gram negative pneumonia)

    • Cavitary malignancy (e.g., non-small cell lung cancer)

    • Septic pulmonary emboli

    • Granulomatosis with polyangiitis (Wegener's granulomatosis)

    • Rheumatoid lung nodules

    • Sarcoidosis

    • Progressive massive fibrosis associated with pneumoconioses

    • Necrobiotic lung nodules associated with inflammatory bowel disease

  • Pneumatocele: A pneumatocele is usually differentiated from a bulla by its transience and the clinical context in which it develops (blunt chest trauma or positive pressure ventilation with high peak and plateau pressures).

  • Pneumothorax: With pneumothorax the air-filled space lies outside the visceral pleura, rather than within the lung parenchyma. Pneumothorax may be associated with ruptured blebs or bullae.

How and/or why did the patient develop bullous lung disease?

In bullous emphysema, bullae are created as areas of severe emphysema coalesce that are due to progressive loss of alveolar attachments. In contrast, bullae surrounded by normal lung likely form because of a focal anatomic defect that results in localized air-trapping.

The classic teaching has been that ball-valve physiology leads to build-up of pressure within bullae, contributing to their progressive enlargement and compressing adjacent lung. However, careful studies of the anatomy and physiology of bullae demonstrate that they typically have patent connections to the airways and no evidence of ball-valve physiology.

Further, the pressure within bullae is not positive but slightly negative, approximating intrapleural pressure. Therefore, the more likely mechanism for enlargement of isolated bullae is that their much higher compliance relative to the surrounding lung leads to their preferential inflation during inspiration; conversely, their much lower elastic recoil leads to their impaired deflation during expiration. Hence, given the available data, the more plausible explanation for development of adjacent atelectasis is that the elastic recoil of the more normal surrounding lung pulls the bulla open at the expense of its own aeration.

In general, the epidemiology of bullous lung disease closely follows that of COPD. Affected individuals tend to be older (usually more than 45 years old) and to have significant exposure to tobacco smoke (usually at least ten pack-years).

The possible exception is patients who have an isolated bulla surrounded by normal lung parenchyma. These patients may present at a younger age and may have less smoke exposure than do patients with bullous emphysema. However, there is a paucity of data to distinguish formally the epidemiology of isolated bullae from that of bullous emphysema. Risk factors for development of bullous lung disease are discussed in more detail in the following section.

Which individuals are at greatest risk of developing bullous lung disease?

In the majority of cases, bullous lung disease is caused by prolonged exposure to smoke from combustion of tobacco or other biomass fuels used for heating or cooking, such as wood, coal, peat, and kerosene. Cigarette smoke accounts for the vast majority of disease, but smoke from burning of biomass fuels in poorly ventilated stoves or open fires used for cooking and heating is an important secondary cause worldwide.

Although exposure to organic or inorganic dusts, industrial chemicals, and outdoor air pollution have all been postulated to play a role, the evidence linking these exposures to bullous lung disease is not nearly as strong as that for cigarette and biomass fuel smoke.

Genetic factors may also contribute to the development of bullous lung disease. Alpha-1 antitrypsin deficiency increases susceptibility to smoke-induced bullous emphysema and, much less commonly, may cause significant emphysema in the absence of smoking. Alpha-1 antitrypsin deficiency classically causes basilar predominant emphysema with a relatively young age of onset (often younger than 40-45 years old), but it can also cause apical-predominant or homogeneous emphysema in older individuals. Hence, the absence of basilar predominance or young age should not necessarily preclude its consideration.

Heritability studies of COPD suggest that there are likely other genetic risk factors, and a number of genetic epidemiology studies suggest new potential candidates. Inherited connective tissue disorders, such as Marfan's syndrome and Ehlers-Danlos syndrome, have also been linked to increased risk of bullous lung disease and spontaneous pneumothorax. However, these disorders more commonly cause small apical blebs, rather than large intraparenchymal bullae.

Intravenous injection of heroin or crushed oral tablets (e.g., methylphenidate) has been associated with basilar-predominant bullous lung disease. The pathophysiology of this condition is not clearly established and is confounded by a high prevalence of concomitant cigarette smoking among injection drug users.

The mechanism is thought to involve destruction of lung parenchyma associated with foreign body granulomatosis. Talc, cellulose, or corn starch, all used as cutting agents for heroin or as inert fillers for oral tablets, are injected into the bloodstream and are preferentially distributed to the lung bases because of their relatively higher blood flow compared with the apices. In chronic users, inflammation and fibrosis in response to accumulating insoluble particles may progress to parenchymal destruction and formation of bullae.

Human immunodeficiency virus (HIV) infection has also been implicated as a cause of bullous emphysema. Determining the contribution of HIV infection to development of bullous lung disease has been complicated by potential confounding influences, such as the high rates of concomitant smoking and intravenous drug use, as well as the prevalence of AIDS-related pulmonary infections, such as pneumocystis jiroveci pneumonia (PCP).

However, a large observational study of 1031 HIV-positive subjects and 740 HIV-negative controls suggested that HIV infection was associated with a higher prevalence of COPD, both self-reported and based on ICD-9 documentation. The finding was independent of age, race, pack-years of smoking, and intravenous drug use. Despite their higher rates of COPD, HIV-positive subjects in this study were slightly younger and had slightly lower levels of tobacco exposure compared with HIV-negative controls. These findings suggest that HIV may increase sensitivity to cigarette smoke.

Another study compared 114 HIV-positive subjects with 44 age-, sex-, and smoking-matched controls and demonstrated a higher rate of radiographic emphysema among HIV-positive subjects (15% compared with 2% among HIV-negative subjects), despite similar smoking histories.

The pathogenesis of emphysema occurring in conjunction with HIV infection is not clearly understood. Proposed mechanisms include development of lymphocytic alveolitis characterized by infiltration of the lung by CD8+ cells, which are interferon gamma-secreting T lymphocytes; upregulation of matrix metalloproteases within HIV-infected alveolar macrophages; oxidative stress; induction of microvascular endothelial cell apoptosis; malnutrition; and lung damage that is due to opportunistic infection, particularly PCP.

What laboratory studies should you order to help make the diagnosis, and how should you interpret the results?

Bullous lung disease is typically diagnosed by chest imaging. Although there are no specific laboratory tests that are useful in its diagnosis, laboratory testing may be of some use in exploring etiology and assessing the risk of operative intervention. The laboratory workup of a patient with bullous emphysema is not standardized, but it may include the following considerations:

  • Particularly in those with disease onset at a young age (<45 years), a strong family history of emphysema, or emphysema out of proportion to tobacco exposure, alpha-1 antitrypsin level and phenotype may be considered basilar-predominant bullous disease. Evaluation and management of alpha-1 antitrypsin deficiency are discussed separately.

  • HIV testing is indicated in patients with potential risk factors, particularly in those at a comparatively young age or with emphysema out of proportion to tobacco exposure.

  • A complete blood count may exclude anemia as a contributor to dyspnea, and, in more severely affected patients, may occasionally reveal polycythemia associated with untreated hypoxemia.

  • Pulse oximetry with exercise will reveal which patients may require supplemental oxygen.

  • Arterial blood gas analysis of room air may be helpful in evaluating for hypercapnia in those with a severe respiratory impairment; hypercapnia increases the risk of operative intervention and may alter medical management.

  • In very rare cases, genetic testing may be considered in patients with disease onset at a young age and who have characteristic physical features of inherited connective tissue diseases, such as Marfan's syndrome or Ehlers-Danlos syndrome.

What imaging studies will be helpful in making or excluding the diagnosis of bullous lung disease?

Chest imaging is the basis for diagnosing bullous lung disease. Although chest x-rays may reveal focal areas of radiolucency surrounded by thin curvilinear density, suggesting the presence of bullae, this test is not very sensitive for bullous lung disease. Cross-sectional imaging using computed tomography (CT) allows a much more detailed characterization of the number, size, and location of bullae, as well as the condition of the surrounding lung parenchyma. Characteristic findings of the chest CT include:

  • Air-filled spaces >1 cm in diameter within the lung parenchyma with poorly defined or very thin-walled borders (<1 mm).

  • Apical-predominant bullae, which are most commonly associated with emphysema in the surrounding lung parenchyma. Basilar-predominant disease may be associated with Alpha-1 antitrypsin deficiency or intravenous drug use.

  • Bilateral bullae, though asymmetric disease or even unilateral disease is not uncommon.

  • Thin, irregular, linear stranding within the bulla that represent residual strands of alveolar septae or blood vessels.

  • The presence of atelectasis adjacent to a giant bulla (occupying >30% of the affected hemithorax). This finding suggests a favorable prognosis following surgical intervention.

A number of radiographic features should prompt consideration of an alternate diagnosis:

  • Multiple, small, round, clearly demarcated air spaces in the lung parenchyma, particularly in the absence of surrounding emphysema, should raise the differential diagnosis for cystic lung disease (e.g., Langerhans cell histiocytosis, lymphangioleiomyomatosis). The clinical context and other radiographic findings may help to signal a particular disease. For example, multiple cysts in otherwise normal lungs of a young woman with a renal angiomyolipoma is highly suggestive of lymphangioleiomyomatosis. Langerhans cell histiocytosis, which may cause multiple, irregular, air-filled spaces in the upper lung zones of an older smoker, is often mistaken for the far more common bullous emphysema. The presence of multiple nodules or significant fibrosis between air-filled spaces (rather than additional emphysema) may help distinguish Langerhans cell histiocytosis from bullous emphysema.

  • Thick-walled air spaces within the lung parenchyma or the presence of an air-fluid level within the cavity should prompt consideration of cavitating infection or malignancy with central necrosis. Although bullae may (rarely) become secondarily infected, infected bullae are far less common than are lung abscesses. Lung abscesses are commonly surrounded by consolidated lung, reflecting associated pneumonia. However, cavitating lung cancers may be surrounded by otherwise normal lung tissue.

  • Focal thickening in one wall of a bulla raises the possibility of lung cancer arising in adjacent lung tissue.

  • Significant hilar or mediastinal lymphadenopathy is not seen in uncomplicated bullous lung disease, so its presence may help raise suspicion for cavitating infection, malignancy, or possibly fibrocavitary sarcoidosis.

  • On a chest x-ray, cystic bronchiectasis associated with cystic fibrosis may sometimes be mistaken for bullae, but CT scans clearly demonstrate that the air-filled spaces are dilated airways rather than holes in the parenchyma itself.

  • An x-ray in which an acute angle is observed where the edge of the air-filled space meets the chest wall may signal a pneumothorax rather than a bulla. Typically, a bulla meets the chest wall at an obtuse angle.

In a severely symptomatic patient, several radiographic features may suggest a favorable outcome from surgical intervention:

  • Bullectomy (resection of one or more giant bullae)

    • A single bulla occupying more than 30 percent of the hemithorax (more than half is even more favorable)

    • Atelectasis adjacent to the bulla

    • Absence of significant emphysema in the surrounding lung

  • Lung volume reduction surgery

    • Severe apical-predominant emphysema (even without a predominant bulla)

    • Relative preservation of parenchyma in the middle and lower lung zones

What non-invasive pulmonary diagnostic studies will be helpful in making or excluding the diagnosis of bullous lung disease?

Pulmonary function testing is not diagnostic of bullous lung disease, but it is a critical tool in evaluating its functional significance, guiding the medical therapy, and evaluating the likelihood of benefit from surgical intervention:

  • Spirometry establishes the presence or absence of airflow obstruction and reflects its severity. Some investigators have reported that patients with a forced expiratory volume in 1 second (FEV1) less than 40 percent predicted are less likely to have a durable clinical response to bullectomy; others have reported favorable long-term outcomes even in carefully selected patients with an FEV1 of 40 percent predicted. In general, patients with only moderately severe lung function impairment are thought to derive the most benefit, but no FEV1 clearly constitutes a cutoff for contraindication of bullectomy. In contrast, lung volume reduction surgery is associated with increased mortality among patients with an FEV 1 less than 20 percent predicted and either homogeneous emphysema or a diffusing capacity for carbon monoxide less than 20 percent predicted.

  • Measurement of lung volumes is used in evaluating for hyperinflation and air-trapping, features suggestive of a better outcome following bullectomy or lung volume reduction surgery. Because of the frequency of severe air-trapping in patients with bullous lung disease, gas dilution methods for lung volume measurement may underestimate true lung volumes. Consequently, plethysmography, when it is available, is the preferred method for lung volume measurement. Although published data do not support a discrete cutoff for the total lung capacity (TLC) or residual volume (RV) regarding bullectomy, in most studies that demonstrated benefit from bullectomy, subjects had a TLC greater than 100 percent predicted (often greater than 120% predicted) and an RV greater than 150 percent predicted (often greater than 200% predicted).

  • A diffusing capacity for carbon monoxide (DLCO) less than 40 percent predicted has been proposed as a contraindication to bullectomy, as it tends to predict a significant amount of emphysema in the lung tissue surrounding the bulla. However, some series have reported favorable long-term outcomes in carefully selected patients with a DLCO less than 40 percent predicted.

What diagnostic procedures will be helpful in making or excluding the diagnosis of bullous lung disease?

Diagnostic procedures like bronchoscopy and lung biopsies have essentially no role in the evaluation of bullous lung disease. In patients with a severe respiratory impairment and those being considered for bullectomy or lung volume reduction surgery, cardiac testing like echocardiography, stress testing, and cardiac catheterization may be considered, as appropriate, in evaluating for pulmonary arterial hypertension resulting from parenchymal lung disease. In addition, testing for the possibility of coexistent ischemic heart disease may be warranted.

These conditions are at least relative contraindications for bullectomy and lung volume reduction surgery.

What pathology/cytology/genetic studies will be helpful in making or excluding the diagnosis of bullous lung disease?

Testing for alpha-1 antitrypsin deficiency is often performed in patients with bullous lung disease but is not necessary in every case. Clinical context should help guide the decision concerning whether to test an individual patient. For example, in a 65-year-old with a 50 pack-year history of cigarette smoking, onset of symptoms in his or her mid-50s, and no family history of early-onset emphysema, alpha-1 antitrypsin testing is likely to be of little use.

In patients presenting with a strong family history of emphysema (especially early-onset disease), bullous lung disease out of proportion to their tobacco history, age at onset less than 45 years, or basilar-predominant bullous disease, consideration should be given to obtaining an alpha-1 antitrypsin level and phenotype. Testing for alpha-1 antitrypsin deficiency is discussed in detail in the section on alpha-1 antitrypsin deficiency.

If you decide the patient has bullous lung disease, how should the patient be managed?

When airflow obstruction is present, management of bullous lung disease is the same as that for other presentations of COPD: smoking cessation treatment; pulmonary function testing to assess the severity of airflow obstruction and air-trapping; pharmacologic therapy using short- and long-acting bronchodilators, inhaled corticosteroids, or anti-inflammatory agents as appropriate; supplemental oxygen for those with hypoxia on room air; vaccination to reduce complications of infection; and pulmonary rehabilitation for symptomatic patients with exercise limitations. These topics are discussed in detail in COPD: Clinical Manifestations and Management.

HIV-associated emphysema is treated in the same way as emphysema in non-HIV infected individuals, with one important exception: HIV-infected patients who are taking ritonavir as part of their antiretroviral regimen should not be treated with fluticasone. Ritonavir, a potent inhibitor of p450 enzymes in the liver, interferes with the metabolism of fluticasone, causing a marked increase in systemic fluticasone exposure from inhaled or intranasal delivery.

As a result, co-administration of ritonavir with either inhaled or intranasal fluticasone has been associated with reports of Cushing's syndrome and adrenal suppression. This interaction is apparently specific to fluticasone, so use of other potent inhaled or intranasal steroids appears to be safe in patients who are taking ritonavir.

In addition to standard therapies for COPD, patients with bullous lung disease that is due to severe alpha-1 antirypsin deficiency may benefit from alpha-1 antitrypsin replacement therapy. Exactly which patients are most likely to benefit and the magnitude of the benefit remain somewhat controversial. This topic is discussed in detail in the section on alpha-1 antitrypsin deficiency.

Patients with bullous lung disease of any etiology who are of appropriate age (usually less than 65 years) and who have very severe airflow obstruction (generally FEV1 at or below 25% predicted), poor quality of life despite aggressive therapy, and absence of severe comorbid disease may be candidates for lung transplantation. Indications for and outcomes following lung transplantation are covered in detail in the section on lung transplantation.

Selected patients with a severe impairment characterized by significant apical-predominant emphysema (with or without large bullae) and severe obstruction with prominent air-trapping and dynamic hyperinflation may benefit from lung volume reduction surgery. Indications for this procedure and outcomes following it are covered in detail in the section on lung volume reduction surgery.

Bullectomy involves the surgical resection or ablation of one or more bullae. In carefully selected patients, bullectomy may improve lung function, symptom control, and exercise tolerance. This section focuses primarily on bullectomy for treatment of giant bulla, defined as a single bulla occupying more than 30 percent of the affected hemithorax.

Rationale

Bullae cause symptoms via two distinct mechanisms. First, bullae may interfere with ventilation of adjacent areas of the more preserved lung, preventing them from expanding fully with inspiration or, in more severe cases, causing frank atelectasis.

Second, bullae are space-occupying lesions that take up relatively large volumes of the chest cavity without contributing to functional gas exchange. Because they may enlarge with exercise as a result of air-trapping, these lesions may contribute to dynamic hyperinflation, altering chest wall mechanics (e.g., diaphragm flattening and barrel chest) and increasing the work of breathing.

Bullectomy may reverse these effects by allowing expansion of adjacent, less diseased lung segments, allowing them to expand more fully and contribute more to gas exchange and by removing "wasted" volume from the chest cavity, thereby decreasing hyperinflation and air-trapping and restoring more normal chest wall mechanics. As the remaining lung stretches to fill the space previously occupied by the bulla, elastic recoil is increased, helping to pull open small airways and improve expiratory airflow.

In this sense, bullectomy is functionally similar to lung volume reduction surgery. However, bullectomy and lung volume reduction surgery are distinct surgical procedures with different indications and should not be thought of as synonymous.

Indications

Bullectomy should be considered in patients with severe dyspnea associated with a giant bulla (defined as a bulla occupying at least 30 percent of the affected hemithorax) and who have had an inadequate symptomatic response to aggressive medical therapy. Occasionally, bullectomy is performed in patients who present with spontaneous secondary pneumothorax in order to decrease the risk of recurrence.

Several clinical features may impact the likelihood of benefit from bullectomy:

  • Bulla size: Bullectomy may be considered for any patient with a bulla that occupies more than 30 percent of the affected hemithorax, but case series suggest that bullae that occupy more than half of the affected hemithorax may be even more likely to benefit.

  • Condition of the adjacent lung parenchyma: Patients with relative preservation of lung parenchyma adjacent to the bulla are more likely to benefit from bullectomy than are those with surrounding emphysema.

  • Signs of collapsed adjacent lung: Findings of atelectasis or vascular crowding are associated with a favorable outcome.

  • Moderate to severe obstruction: In published series, most patients who underwent bullectomy had an FEV1 40-80 percent predicted. In some series, an FEV 1 less than 40 percent predicted appears to predict a lower likelihood of benefit from bullectomy; however, other series report successful outcomes in groups with a mean FEV1 of 32-34 percent predicted. It stands to reason that those with very mild obstruction likely have less room to improve; very severe obstruction may portend higher operative risk and less likelihood of benefit because of the correlation with more diffuse emphysema surrounding the bulla. The available data do not support any specific contraindications to bullectomy based on FEV1.

  • Air-trapping: Most patients who undergo bullectomy have a total lung capacity greater than 100 percent predicted and a residual volume of at least 150 percent predicted (often greater than 200 percent predicted). A large difference between lung volumes obtained by plethysmography and those obtained by gas dilution methods suggests a large volume of air-trapping and may predict improved outcomes, but this measure is rarely used in clinical practice. Published data do not support any specific cutoffs for these measures in predicting benefit from bullectomy. However, based on the proposed mechanisms, greater degrees of air-trapping likely predict greater benefit.

  • Relatively preserved diffusing capacity: Because diffusion inversely correlates with the degree of emphysema in the surrounding lung, severe diffusion impairment is thought to predict worse outcomes. Some studies have suggested that a diffusing capacity for carbon monoxide less than 40 percent predicted should be a contraindication to bullectomy, but the data supporting this cutoff are limited at best.

Contraindications

  • Excess operative risk: As with any thoracic surgery, advanced age and severe comorbid disease (e.g., ischemic heart disease) increase the risks of surgery and may tip the risk-benefit ratio against surgery.

  • Ongoing smoking: Most programs require that potential candidates demonstrate sustained smoking cessation (e.g., four months) prior to consideration of bullectomy.

  • Multiple small or poorly defined bullae: The finding of so-called "vanishing lung" from severe emphysema without a clear, predominant giant bulla, should preclude consideration for bullectomy. In some of these cases, lung volume reduction surgery may still be a consideration.

  • Severe diffusion impairment: Although supportive data are scarce, a diffusing capacity for carbon monoxide less than 40 percent predicted has been suggested as a contraindication to bullectomy.

  • Hypercapnia: A PaCO2 greater than 45 mm Hg is often considered a contraindication to bullectomy.

  • Pulmonary hypertension: A pulmonary artery systolic pressure greater than 45 mm Hg, especially when it is associated with right ventricular dilation or dysfunction, substantially increases the risk of thoracic surgery.

Procedure

Bullectomy has been performed successfully using any of several surgical approaches. In a patient who requires bilateral intervention, median sternotomy is often used to allow access to both lungs via one incision. For those who require only unilateral intervention, both open thoracotomy and video-assisted thoracoscopic surgery (VATS) have been used. No compelling data support one approach over another, so the choice is based on individual patient factors and the surgeon's preference. Several surgical techniques have been used to treat giant bullae:

  • Stapler excision: In this, the most common technique, the surgeon applies a buttressed stapler across the base of the bulla and excises the bulla, taking care to minimize resection of relatively preserved surrounding lung.

  • Plication: The surgeon incises the bulla, isolates it from the airway using a purse-string suture around the base of the bulla, and then sews the walls of the bulla together to obliterate the space.

  • Modified Monaldi Technique: This technique is not commonly used but is sometimes used in patients thought too sick to tolerate a more definitive surgery. The technique is an adaptation of the methods used by Monaldi in the 1940s to drain tuberculous cavities. The surgeon incises the bulla, places a Foley catheter in it, closes the bulla around the catheter using purse-string sutures, and then applies suction. The bulla gradually closes by scarring and adhesion, allowing eventual removal of the catheter.

  • Lobectomy or segmentectomy: Although these methods effect an anatomic resection of the bulla and are likely to decrease air leaks (provided that the pleura is in tact), they are usually regarded as the procedures of last resort, as some functional lung is usually removed along with the bulla, reducing the clinical benefit.

  • Laser ablation: This method, which is rarely used, involves application of a laser via VATS to photocoagulate the bulla. It is unclear whether the higher complication rates observed for this method are the result of the procedure itself or the result of patients' selected having generally been considered poor candidates for definitive surgical therapy.

What is the prognosis for patients managed in the recommended ways?

Untreated, the natural history of bullous lung disease is generally one of gradual increase in the size and extent of bullae, as well as gradual progression of dyspnea and airflow obstruction.

However, both the rate and extent of progression over time are highly variable and dependent on smoking status and genetics, among other factors. Smoking cessation is the most important intervention to slow the progression of bullous lung disease. Rarely, if a bulla becomes infected, it may shrink or even disappear, probably because of cicatricial contraction associated with the inflammatory response.

Symptomatic patients often experience clinically significant improvements in symptom control and exercise tolerance from treatment with the usual modalities used to treat COPD, such as bronchodilators, inhaled corticosteroids and anti-inflammatory agents in selected patients, oxygen as needed, and pulmonary rehabilitation. (See COPD: Clinical Manifestations and Management.)

With smoking cessation and attentive treatment, many patients with bullous lung disease experience stabilization of lung function. However, even patients who are aggressively treated with these approaches may occasionally experience progressive dyspnea, airflow obstruction, exercise limitation, and poor quality of life. In these patients, procedural therapies are often considered.

Patients with bullous lung disease are at increased risk for developing spontaneous secondary pneumothorax because of rupture of blebs or bullae. This risk may be increased further by air travel, but adequate data to quantify this increase in risk are not available.

The classic teaching has been that ball-valve physiology leads to buildup of pressure within a bulla and that traveling at altitude reduces the surrounding atmospheric pressure, resulting in increased transmural pressure across the wall of the bulla and subsequent rupture. However, careful studies of the anatomy and physiology of bullae suggest that most have a patent communication with the airways and an internal pressure that is slightly negative, approximating intrapleural pressure.

Therefore, the concept of a bulla's "popping" like an overinflated balloon is likely erroneous. Despite the increased risk in patients with bullous lung disease, spontaneous pneumothorax remains a relatively rare event.

Outcomes following bullectomy

No controlled clinical trials of bullectomy have been conducted, but published case series suggest that, in carefully selected patients, bullectomy improves symptoms, pulmonary function, and exercise capacity--at least in the short-term in the majority of cases. Emphysema in the lung surrounding the bulla appears to increase the risks of bullectomy and decrease the likelihood of sustained benefit relative to bullae surrounded by relatively normal lung.

However, even patients with bullous emphysema appear to derive significant benefit from bullectomy relative to their baseline:

  • Dyspnea: Both subjective and objective assessments of dyspnea improve in the vast majority of subjects. While dyspnea appears to improve fairly uniformly among patients with normal lung surrounding their bullae, the symptomatic response in patients with surrounding emphysema is more variable.

  • Spirometry: Published series report improvements in FEV1 of 20-84 percent over baseline, corresponding to absolute increases of 350-945 mL. Improvements in FVC are less consistently reported.

  • Lung volumes: Changes in residual volume have not been reported in all series, but in two recent series, residual volumes dropped from an average of 226 percent and 262 percent predicted at baseline to 87 percent and 154 percent, predicted, respectively, corresponding to absolute decreases of 1.5-3 liters.

  • Oxygen: Improvements in oxygenation have not been consistently reported, but in two recent series, the partial pressure of oxygen in arterial blood improved by approximately 10 mm Hg on average; one series reported a decrease in the percentage of subjects requiring continuous supplemental oxygen from 42 percent to 9 percent.

  • Exercise capacity: Recent series have noted significant improvements in exercise tolerance as measured by six-minute walk distance and cardiopulmonary exercise testing.

Case series that have followed patients for between three and five years following bullectomy consistently demonstrate that the improvements in dyspnea, lung function, and exercise capacity wane over time. However, even after five years, these parameters typically remain at least marginally better than baseline values. Subjects with emphysema surrounding their bullae appear to decline faster than do those with relative preservation of the surrounding lung.

Complications of bullectomy

Reported operative mortality has ranged between 0 and 7 percent; the higher estimate includes all deaths within one year following bullectomy. Causes of death generally reflect those seen commonly in patients with severe COPD, including pneumonia, acute-on-chronic respiratory failure, pulmonary embolism, and myocardial infarction.

Patients with diffuse emphysema surrounding their bullae appear to have a higher mortality rate than those with normal surrounding lung, but published series have not been large enough to allow statistical tests of this comparison.

Prolonged air leak (longer than seven days) requiring chest tube drainage is, by far, the most common complication in the immediate post-operative period, affecting approximately half of patients. Emphysema in the lung surrounding the bulla appears to increase the risk of prolonged air leak. In a recently reported series of 43 patients, other frequently encountered complications included atrial fibrillation (11.6%), a requirement for post-operative mechanical ventilation (9.3%), massive subcutaneous emphysema (7%), hemothorax (7%), and pneumonia (4.7%).

What’s the evidence?

Aboussouan, LS, Basow, D. "Emphysema-like disease in HIV infection". UpToDate. UpToDate. 2011.

A broad overview of the etiology, characteristics, and possible mechanisms of emphysema associated with HIV infection.

Crothers, K. "Chronic obstructive pulmonary disease in patients who have HIV infection". Clin Chest Med. vol. 28. 2007. pp. 575-87.

A comprehensive review of the literature that demonstrates an association between COPD and HIV infection.

Crothers, K, Butt, AA, Gilbert, CL. "Increased COPD among HIV-positive compared to HIV-negative veterans". Chest. vol. 130. 2006. pp. 1326-33.

A large observational study demonstrating that HIV is an independent risk factor for COPD.

De Giacomo, T, Venuta, F, Rendina, EA. "Video-assisted thoracoscopic treatment of giant bullae associated with emphysema". Eur J Cardiothorac Surg. vol. 15. 1999. pp. 753-6.

A case series of thoracoscopic bullectomy with a detailed description of operative technique and an examination of the effect of disease severity on outcomes.

http://www.goldcopd.org..

A comprehensive resource on the diagnosis and treatment of COPD, including a small section on the indications for bullectomy.

Hansell, DM, Bankier, AA, MacMahon, H. "Fleischner Society: Glossary of terms for thoracic imaging". Radiology. vol. 246. 2008. pp. 697-722.

An outstanding resource that defines the terms used to describe abnormalities seen in chest imaging and provides representative images for most terms.

Karpel, JP, Basow, D. "Overview of pulmonary disease in injection drug users". UpToDate. UpToDate. 2011.

A broad overview of the pulmonary complications of drug use, including sections on bullous disease and foreign body granulomatosis.

Klingman, RR, Angelillo, VA, DeMeester, TR. "Cystic and bullous lung disease". Ann Thorac Surg. vol. 52. 1991. pp. 576-80.

An evidence-based discussion of the pathogenesis of bullae, selection of appropriate candidates for bullectomy, and surgical techniques employed.

Laros, CD, Gelissen, HJ, Bergstein, PG. "Bullectomy for giant bullae in empyhsema". J Thorac Cardiovasc Surg. vol. 91. 1986. pp. 63-70.

A case series of thoracoscopic bullectomy that examines long-term outcomes.

Martinez, FJ, Basow, D. "Bullectomy for giant bullae in COPD". UpToDate. UpToDate. 2011.

A comprehensive evidence-based review of bullectomy that covers rationale, patient selection, operative techniques, and complications.

Morgan, MD, Edwards, CW, Morris, J. "Origin and behaviour of emphysematous bullae". Thorax. vol. 44. 1989. pp. 533-8.

A seminal paper that investigates the physiology and histology of bullae and provides a rational explanation for the formation of bullae.

Neviere, R, Catto, M, Bautin, N. "Longitudinal changes in hyperinflation parameters and exercise capacity after giant bullous emphysema surgery". J Thorac Cardiovasc Surg. vol. 132. 2006. pp. 1203-7.

A case series that provides detailed outcomes data at multiple times up to two years following bullectomy.

Ohta, M, Nakahara, K, Yasumitsu, T. "Prediction of postoperative performance status in patients with giant bulla". Chest. vol. 101. 1992. pp. 668-73.

A retrospective case-control study that examines the predictors of a favorable functional response to bullectomy.

Palla, A, Desideri, M, Rossi, G. "Elective surgery for giant bullous emphysema: A 5-year clinical and functional follow-up". Chest. vol. 128. 2005. pp. 2043-50.

A case series that examines the durability of treatment response over five years following bullectomy.

Petrache, I, Diab, K, Knox, KS. "HIV-associated pulmonary emphysema: A review of the literature and inquiry into its mechanism". Thorax. vol. 63. 2008. pp. 463-9.

A detailed review of the biologic mechanisms that govern the association between HIV and emphysema.

Schipper, PH, Meyers, BF, Battafarano, RJ. "Outcomes after resection of gienat emphysematous bullae". Ann Thorac Surg. vol. 78. 2004. pp. 976-82.

A case series that documents pulmonary function, exercise, gas exchange, and complications over the three years following bullectomy.

Snider, GL. "Reduction pneumoplasty for giant bullous emphysema: Implications for surgical treatment of nonbullous emphysema". Chest. vol. 109. 1996. pp. 540-8.

A detailed review of the literature that addresses the pathophysiology of bullae and the selection of patients appropriate for bullectomy.

van Berkel, V, Kuo, E, Meyers, BF. "Pneumothorax, bullous disease, and emphysema". Surg Clin North Am. vol. 90. 2010. pp. 935-53.

A comprehensive review of the surgical management of bullae with a detailed description of surgical techniques.

Vigneswaran, WT, Townsend, ER, Fountain, SW. "Surgery for bullous disease of the lung". Eur J Cardiothorac Surg. vol. 6. 1992. pp. 427-30.

A case series that examines the pulmonary function and gas exchange responses following bullectomy.
You must be a registered member of Clinical Pain Advisor to post a comment.

Sign Up for Free e-Newsletters