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