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
Table 104-1Categorization of Interstitial Lung Disease Into Granulomatous and Alveolitic Subtypes ||Download (.pdf) Table 104-1Categorization of Interstitial Lung Disease Into Granulomatous and Alveolitic Subtypes
Infections—tuberculosis, helminths, aspergillosis
Granulomatous vasculitides—Wegener granulomatosis and
Foreign body/Inorganic dust
Idiopathic interstitial pneumonias
Morphologically, the lung parenchyma has two general components: airspace and interstitium. The airspace is comprised of the respiratory bronchioles, alveolar ducts, and alveoli. The interstitium consists of the fibrous septa, alveolar walls, and connective tissues that surround the vascular and bronchial lumina.
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.
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 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.
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.
CT scan representative of radiographic findings seen in Wegener granulomatosis. Note the large cavitary lesion in the left lung.
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 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 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.
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
Table 104-2Ten Steps to Video-Assisted Thoracoscopic Surgery (VATS) Lung Biopsy ||Download (.pdf) Table 104-2Ten Steps to Video-Assisted Thoracoscopic Surgery (VATS) Lung Biopsy
Single-lung ventilation with either placement of double-lumen endotracheal tube or placement of a bronchial blocker together with a single-lumen endotracheal tube (see Fig. 104-5). Bronchoscopic confirmation of correct placement and auscultatory confirmation of lung isolation of the operative side is recommended.
Use the chest CT findings to plan the placement of the patient in the full lateral decubitus position with slight flexion of the operating table to widen the lung interspaces.
Placement of three 10-mm ports with the idea of triangulating the region of lung targeted for biopsy within the three ports. The camera port should be at the apex of the triangle (see Fig. 104-6).
One centimeter skin incisions should be placed in the rib interspaces with Bovie dissection through the soft tissue and intercostal muscles until the endothoracic fascia over the rib is reached. The endothoracic fascia should be divided carefully over the rib to avoid injury to the lung as the thorax is entered.
A 10-mm thoracoscopic port then is placed into the chest through this incision.
A 10-mm 30-degree camera is inserted through the port into the thoracic cavity, and the thorax is inspected.
The other two 10-mm ports then are placed in a similar fashion with direct visualization of entry into the thoracic cavity.
With the aid of atraumatic grasping instruments (e.g., O-ring forceps), the lung parenchyma is grasped, inspected, and palpated until the parenchymal lesion(s) of interest is identified (see Fig. 104-7).
Endoscopic staplers are used to resect the identified lesion. The lesion then is removed from the thorax within a specimen bag (see Fig. 104-8).
After ensuring that hemostasis has been achieved, the ports are removed from the thorax. The thoracoscopic ports then are closed with 2-0 absorbable suture for the soft tissue and 3-0 absorbable suture for the skin.
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 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.
CT scan from a patient with idiopathic pulmonary fibrosis. Note the significant fibrotic changes and characteristic honeycomb pattern.