104: Role of the Thoracic Surgeon in the Diagnosis of Interstitial Lung Disease

Interstitial lung disease (ILD) represents over 200 diagnostic entities. Some are distinct clinicopathologic disorders, whereas others belong to a broader class of clinical syndromes, such as the connective tissue diseases. ILD is characterized by a progressive and diffuse inflammation of the pulmonary interstitium often leading to fibrosis. Patients typically present with chronic respiratory complaints, including dyspnea, and chest radiographic findings that demonstrate pronounced “reticular markings.” The distinct clinicopathologic disorders that constitute ILD can vary widely in presentation. Examples include sarcoidosis, eosinophilic pneumonias, idiopathic pulmonary fibrosis, and infectious processes, including tuberculosis. Pulmonary fungal infections are reviewed in Chapter 102.

The primary goal of the thoracic surgeon in the evaluation of patients with symptoms and radiologic findings consistent with ILD is to facilitate an expedient diagnosis. The least invasive diagnostic modalities include bronchoscopy, bronchoalveolar lavage, and chest CT scanning. However, lung biopsy by transbronchial, open, or video-assisted thoracic surgery (VATS) techniques remains the most definitive and expeditious means of establishing the diagnosis. Development of VATS techniques has greatly reduced the morbidity associated with lung biopsy. This chapter provides an overview of the spectrum of disease and diagnostic approach to ILD from the surgical perspective.

The inflammatory response observed in ILD targets the interstitium, which is comprised of the fibrous septa and alveolar walls that give structure to the lungs. Within the interstitium lie the pulmonary vessels, lymphatics, and bronchi. The inflammatory response may be expressed against cells in any or all of these structures (Fig. 104-1). Often it is focused on one component of the interstitium, permitting a loose categorization of two patterns of injury: granulomatous and alveolitic (Table 104-1).^1,2

Granulomatous Pattern

The pattern of disease injury denoted as granulomatous is initiated by a cell-mediated immune response to a foreign or self-protein, that is antigen, which may or may not be known. The response is initiated by a release of inflammatory cytokines. Activated immune cells, typically macrophages, encircle and engulf the protein that the immune system has failed to recognize in an antigen-specific fashion. The antigen is sequestered and granulomata are formed. This inflammatory process, once activated, can spread to the alveoli, which renders the pattern of injury difficult to discern in end-stage disease. The granulomatous mechanism is expressed in several pulmonary diseases, which are described briefly below.

Infection

Mycobacterium tuberculosis infection is the most common cause of granulomatous lung disease worldwide.^3,4 Aspergillus and certain helminths also can lead to pulmonary granulomatous disease (see Chapter 102).^1,2 Diagnosis relies on history, a positive purified protein derivative test, and sputum culture.

Sarcoidosis

Sarcoidosis is a chronic systemic disorder characterized by the presence of granulomata in certain affected organs. The disorder remains poorly understood and the responsible antigen has not yet been identified. Patients with sarcoidosis may have variable and fluctuating symptoms. Classically, patients present with fever, myalgias, chills, fatigue, and weight loss. Angiotensin-converting enzyme levels are often elevated. Diagnosis is often suspected radiographically by the appearance of bilateral hilar and mediastinal lymph node enlargement on plain chest films, sometimes accompanied by a reticulonodular pulmonary pattern. Most patients diagnosed by chest radiography alone are asymptomatic. In patients with mediastinal lymphadenopathy, tissue diagnosis can be made via cervical mediastinoscopy. The rare patient with only interstitial lung pathology, or in patients with progressive lung lesions despite treatment, VATS lung biopsy may be helpful to establish the diagnosis and rule out other etiologies.

Granulomatous Vasculitides

In Wegener granulomatosis and Churg–Strauss syndrome – two representative granulomatous vasculitides – the granulomata form around the pulmonary vessels. Wegener granulomatosis is characterized by the presence of necrotizing granulomata within the pulmonary parenchyma, which often become cavitary and can be confused radiographically with squamous cell lung cancer or other infectious etiologies (Fig. 104-2). The renal vasculature also may be involved, and 90% of patients have antibodies to antineutrophil cytoplasmic antibodies against the PR3 serine proteinase (c-ANCA).^3,5–10 Churg–Strauss syndrome is a rare systemic disorder characterized by eosinophilia and eosinophilic granulomata of the pulmonary vasculature. Diagnosis of both these diseases rests on clinical suspicion, along with the laboratory studies and pathologic findings on lung biopsy or other sites of disease involvement.

Hypersensitivity Pneumonitis

Hypersensitivity pneumonitis is caused by repeated inhalation of dust-containing organic antigens, which leads to diffuse inflammation of the lung parenchyma and airways in previously sensitized patients.^11–13 The most common types of hypersensitivity pneumonitis are Farmer's lung due to chronic exposure to moldy hay, straw, or grain, or Bird fancier's lung due to exposure to avian proteins in feathers and droppings. Although many other antigens have also been implicated, with diseases named after various interesting occupations (e.g., bagassosis derived from bagasse, or sugarcane dust, cheese washer's lung from handling cheese mold, compost lung), hypersensitivity pneumonitis has also been described following exposure to fungi or bacteria in humidifiers, heaters, or air conditioning units. Diagnosis lies in careful history taking, especially when a known occupational exposure is suspected. Early parenchymal changes are characterized by neutrophil and macrophage infiltration of the distal bronchioles and alveoli. Progression to granuloma formation and interstitial fibrosis occurs with continued exposure to the antigen. Diagnosis is suspected by exposure history, but tissue biopsy may be required if disease progresses despite contact avoidance.

Foreign Body/Inorganic Dust

Exposure to small foreign particulate matter or dust, whether organic or inorganic, can lead to a spectrum of pulmonary disease processes such as those associated with chronic exposure to metal dusts (e.g., beryllium, aluminum, and zirconium) or small organic particles leading to hypersensitivity pneumonitis. A common example is silicosis caused by inhalation of crystalline silica dust by miners or sandblasters, or even desert sand, as in Desert lung or Desert storm pneumonitis described in personnel serving in the Gulf War.^14,15 Although now relatively rare in the United States after the introduction of respirator masks and other occupational safety measures, silicosis is still considered to be the most common occupational lung disease worldwide.¹⁶ It is characterized by nodular lesions predominantly in the upper lobes. Patients may be asymptomatic to the initial exposure but later develop symptoms secondary to occult lung injury. Again, diagnosis is based on exposure history but may require tissue to make a definitive diagnosis or for worker's compensation claims.

Eosinophilic Pneumonias

Eosinophilic pneumonia is a pulmonary process characterized by the accumulation of eosinophils within the parenchymal tissues. Eosinophilic pneumonias can be caused by helminth infections, such as Strongyloides stercoralis and Ancylostoma duodenale, and drug allergies.^8,17 More often than not, the etiology is unknown. Idiopathic eosinophilic pneumonias have three forms: simple, acute, and chronic. Simple eosinophilic pneumonias are rare, characterized pathologically by an interstitial edema that is abundant with eosinophils and typically resolves spontaneously, particularly with smoking cessation. Patients with acute eosinophilic pneumonia present in severe respiratory distress. Their prognosis is poor. The chronic form is more indolent and often found in patients with a history of asthma. Chronic eosinophilic pneumonia is similar in both histology and, in most cases, radiographic appearance to the simple and acute forms. Diagnosis of all these syndromes requires the demonstration of peripheral blood eosinophilia and often a tissue biopsy.^17,18 The disease clears rapidly with steroid treatment, although there is a higher rate of relapse with the acute form.^8,14

Histiocytosis X

Histiocytosis X is a rare disorder characterized by the peribronchial accumulation of specialized antigen-presenting cells known as Langerhans cells. Long-standing disease, also known as eosinophilic granulomatosis, can lead to interstitial fibrosis and also may present with skeletal involvement. Tissue biopsy is often required for diagnosis.¹⁹ Spontaneous remission can occur, particularly with smoking cessation, although treatment with steroids may be required.

Alveolitic Pattern

The alveolitic categorization of ILD applies when the injury is directed primarily toward the alveolar wall, resulting in airspace disease. Cellular and humoral components of the immune system may both be involved. Alveolitic mechanisms have been implicated in a variety of pulmonary diseases, summarized below (see Table 104-2).^1,2

Goodpasture Syndrome

Goodpasture syndrome is a systemic disease process characterized by pulmonary hemorrhage and glomerulonephritis in the setting of anti-glomerular basement membrane antibodies. It is a rare disorder diagnosed predominantly in young males and is linked to the presence of the HLA-DRw2 allele, but it can present in later years with equal sex distribution and a lower incidence of lung hemorrhage. The disease is caused by antibodies directed against a collagen protein found in the alveolar and glomerular membrane, resulting in an antibody-mediated injury.^20–22 Patients present with both hemoptysis and hematuria. Diagnosis is based on clinical symptomatology and usually renal biopsy.^21,22

Drug-induced Injury

Drug-induced lung injury often results in an alveolitic pattern of injury, whether the mechanism of injury is due to a direct cytotoxic, immune-mediated injury, or the dysregulation of cytokine regulated inflammatory cascades. Numerous drugs have been implicated in this disease process, including bleomycin, nitrofurantoin, and amiodarone.^20,23 Drug induced ILD has also been reported with erlotinib and other tyrosine kinase inhibitors used in the treatment of nonsmall cell lung cancer.^24,25 The diagnosis rests on clinical suspicion and correlation with prior drug exposure. Lung biopsy may or may not be helpful as fibrosis becomes apparent in late-stage disease.

Idiopathic Interstitial Pneumonias

Idiopathic interstitial pneumonias encompass a range of pulmonary disorders characterized by infiltration of the pulmonary interstitium with immune cells, leading to alveolitic changes. Continued inflammation eventually results in end-stage pulmonary fibrosis (Fig. 104-3). The multiple terms used in association with this disease reflect the diagnostic confusion that surrounds it, including Hamman–Rich disease, idiopathic pulmonary fibrosis, usual interstitial pneumonitis, and diffuse pulmonary alveolar fibrosis. Several subclassification schemes have been proposed, which many argue are superfluous because this disorder can be viewed as a continuum. The most common subclassification, proposed by Averill Liebow, divides idiopathic interstitial pneumonias into six categories: (1) usual interstitial pneumonia/idiopathic pulmonary fibrosis, (2) desquamative interstitial pneumonia, (3) nonspecific interstitial pneumonia, (4) acute interstitial pneumonitis, (5) respiratory bronchiolitis-associated ILD, and (6) cryptogenic organizing pneumonia. Patients with this continuum of disorders present with progressive dyspnea in the setting of reticular opacities on plain chest films. Diagnosis of the idiopathic interstitial pneumonia rests on the exclusion of other known disorders and histologic analysis of sufficient lung tissue, making open or VATS lung biopsy usually the preferred approach to tissue diagnosis.^22,26–30 Often, a clear-cut distinction cannot be made between the various subclasses, even with adequate lung tissue. Lymphocytic interstitial pneumonia is often misidentified as belonging to this category because chest radiographs of patients with lymphocytic interstitial pneumonia often show an “interstitial” pattern of disease. However, lymphocytic interstitial pneumonia is a lymphoproliferative disorder with no alveolar injury, and a lung biopsy may be required to exclude this disorder in some patients.^31,32 Patients with progressive disease refractory to immunosuppressive therapy can be treated only by lung transplantation.

Patients with ILD typically present with progressive dyspnea, a persistent nonproductive cough, fatigue, and weight loss. Wheezing, hemoptysis, and pleuritic chest pain are rare symptoms in early ILD. Hemoptysis typically is associated with diffuse alveolar hemorrhage syndromes and the granulomatous vasculitides, but not with other forms of ILD. These symptoms occur in the setting of radiographic evidence of interstitial opacities. Although symptoms are typically chronic, an acute presentation is possible, with the allergic responses seen with hypersensitivity pneumonitis, eosinophilic pneumonia, or drug-induced alveolitis.

A thorough history and physical examination are of paramount importance for patients with suspected ILD (Fig. 104-4). The diagnosis is often suggested by a history of environmental/occupational exposures or connective tissue disease. Laboratory studies are used to identify antibodies that might suggest a specific connective tissue disease or the presence of elevated angiotensin-converting enzyme in sarcoidosis.³³ Pulmonary function tests are used to assess the extent of pulmonary dysfunction. ILD is characterized by a restrictive pulmonary physiology with a reduced total lung capacity, functional residual capacity, and residual volume. The diffusing capacity of the lung for carbon monoxide (DLCO) is also impaired. Forced vital capacity and expiratory volume also may be decreased secondary to a low total lung capacity. Chest x-ray and chest CT scan may be helpful in separating “interstitial” from consolidative patterns of disease and in identifying lymphangitic spread of malignancy when additional mass(es) is present.³⁴ However, chest radiographic findings are nonspecific and are not helpful in discerning the various forms of ILD. Bronchoalveolar lavage can be a useful diagnostic aid for some diseases, including eosinophilic pneumonias and histiocytosis X (Langerhans cells), where a predominant cell type is found in the lavage fluid. However, most patients require lung biopsy to make a definitive diagnosis.^18,29,35

Lung biopsy can be performed by open, VATS, or transbronchial technique. Transbronchial biopsy typically is attempted first to rule out an infectious etiology or confirm an obvious clinical diagnosis (e.g., Goodpasture syndrome or sarcoidosis), but provides inadequate tissue for diagnosing idiopathic interstitial pneumonia. If the diagnosis remains unclear or if the clinical course or radiographic evidence dictate more aggressive management, surgical biopsy is warranted and is the most effective means of establishing the diagnosis and prognosis. In general biopsy should be obtained from two distinct disease sites, preferably from two different lobes with a margin of normal tissue for comparison to assure adequate sampling of areas of active disease and not just end-stage fibrosis. Some investigators report that lingual or middle lobe biopsy may overrepresent fibrosis and vasculopathy. Others disagree, reporting that lingual or right middle lobe biopsy is equivalent to biopsy of other pulmonary segments, provided that the area selected for biopsy is representative of the disease process present elsewhere in the lung.^36–42 Generally speaking, areas of localized fibrosis or scarring should be avoided and more representative areas selected for biopsy. If an adequate biopsy is performed early in the disease course, before the onset of end-stage fibrosis, the diagnostic accuracy approaches 90%.⁴³ Other than ruling out infectious etiologies, biopsies of late-stage disease or areas of dense fibrosis are much less helpful.

VATS biopsy has proved in most series to be as accurate in establishing a diagnosis as is open-lung biopsy performed through a minithoracotomy.^44,45 VATS lung biopsy typically is done with the patient in the full lateral decubitus position, with single-lung ventilation accomplished through either a double-lumen endotracheal tube or, if not available, insertion of a bronchial blocker through a traditional endotracheal tube (Fig. 104-5). Ports are placed with the goal of triangulating the area of interest in the lung (Fig. 104-6). Atraumatic graspers are used to localize the representative lesion, and a representative sample of disease lung tissue is resected using endoscopic staplers (Fig. 104-7). It is preferable to divide the lung where the tissue is less involved and compliant, while still including representative active disease in the specimen, in order to avoid subsequent air leaks from the lung parenchyma as positive pressure ventilation and the frequent use of steroids for these conditions can make management of this complication difficult. The lesion then is removed from the thorax within a specimen bag (Fig. 104-8).

After biopsy, hemostasis is achieved and the incisions closed. An outline of the VATS biopsy technique is presented in Table 104-2. Contraindications to performing a VATS biopsy include (1) acutely ill patients or patients with late-stage ILD with severe fibrosis (for whom definitive diagnosis on biopsy is low), who often have decreased pulmonary compliance and decreased DLCO, precluding general anesthesia even with two-lung ventilation and (2) patients with advanced-stage disease who may not be able to tolerate single-lung ventilation or a full lateral decubitus position. For these later patients, an expedient open-lung biopsy through a minithoracotomy is the best option. As a general principle, lung biopsy is ideally performed during the early stages of ILD because diffuse fibrosis makes both diagnosis and ventilation much more difficult and may even preclude single-lung ventilation and VATS biopsy. The ideal candidate for VATS is an ILD patient who is symptomatic but ambulatory with preserved lung function.

Treatment options are varied and dependent upon the medical condition of the patient and specific diagnoses suggested clinically and/or included and excluded on histologic analysis. Environmental and drug exposures potentially responsible for the underlying disease are investigated and avoided. Appropriate antimicrobials are started for infectious diseases or superimposed pulmonary infections. However, the mainstay of treatment is directed at suppressing the inflammatory response with immunomodulatory medications, such as corticosteroids. Newer agents, such as pirfenidone, have been developed to modulate and downregulate the fibrosis associated with these inflammatory disorders. A recent randomized clinical trial in patients with idiopathic pulmonary fibrosis demonstrated that pirfenidone resulted in significant clinical benefit for these patients, indicating that this agent will be a mainstay of therapy in the future.^46,47 Gastrointestinal reflux disease has been shown to occur with greater frequency in those with chronic lung disease, particularly idiopathic pulmonary fibrosis.

Consideration of antireflux surgery in this cohort is appropriate, particularly if significant reflux is detected by esophageal pH monitoring and symptom analysis despite being on medical therapy, as it has been suggested that surgery can improve exercise capacity, decrease oxygen requirements and potentially delay disease progression.^48–50 For other appropriate patients with end-stage disease, lung transplantation remains a viable option as described in Chapter 106.

The thoracic surgeon plays a vital role in the treatment of patients with ILD by safely obtaining the necessary lung tissue to establish a definitive diagnosis, if possible. Although ILD, as a group of over 200 disease entities, is a relatively rare disorder, the symptoms can significantly limit a patient's quality of life, employment options, and future plans, thus warranting a swift and expeditious diagnosis. The number of possible diagnostic entities calls for a thorough understanding of the etiology of ILD and a careful clinical and laboratory evaluation. Although other diagnostic modalities are available, including chest x-ray, CT scan, and bronchoalveolar lavage, lung biopsy preferably done via a VATS approach delivers the most definitive answer in the shortest period of time.

The group of ILD involves over 200 disease entities that present with overlapping symptomatic and radiographic presentations. Tissue biopsies not only provide positive diagnostic information about the specific disease process, but also negative information that excludes many alternative diagnoses. Even when the histologic findings preclude easy classification, the exclusion of infectious or malignant processes can make a significant clinical contribution and is an underappreciated contribution of surgical biopsies.