Interstitial Lung Disease

Jeffrey T. Chapman

Key Terms

asbestosis

connective tissue disease

corticosteroids

hypersensitivity pneumonitis (HP)

idiopathic pulmonary fibrosis (IPF)

interstitial lung disease (ILD)

lymphangioleiomyomatosis (LAM)

occupational ILD

organizing pneumonia (OP)

pulmonary Langerhans cell histiocytosis (PLCH)

sarcoidosis

silicosis

Interstitial lung disease (ILD) comprises a broad category of lung diseases rather than a specific disease entity.1,2 This category includes various illnesses affecting the lung parenchyma with many different causes, treatments, and prognoses. These disorders are grouped together because of similarities in their clinical presentations, appearance on plain chest radiography, and physiologic features.

With over 100 separate disorders, it is essential to group ILDs based on etiology, disease associations, or pathology. An organizational scheme is presented in Figure 24-1. When evaluating patients with an ILD, one first must consider diseases with known causes or associations, such as diseases related to specific exposures, diseases associated with systemic conditions, and diseases with a known genetic basis. Most patients do not have an ILD with a known cause, and their disorder is classified by pathologic pattern. These groups are divided into specific disease entities. Using this organizational scheme to guide a careful and complete history, one is able to understand the disease processes and work efficiently toward an accurate diagnosis.

FIGURE 24-1 Current organization of ILD. *COP,* Cryptogenic organizing pneumonia; *CTD,* connective tissue disease; *IBD,* inflammatory bowel disease; *IPF,* idiopathic pulmonary fibrosis; *LAM,* lymphangioleiomyomatosis; *LIP,* lymphocytic interstitial pneumonia; *NSIP,* nonspecific interstitial pneumonitis; *PAP,* pulmonary alveolar proteinosis; *PLCH,* pulmonary Langerhans cell histiocytosis.

As the name ILD implies, the histologic abnormalities that characterize ILD involve the pulmonary interstitium to a greater extent than the alveolar spaces or airways, although exceptions exist. Figure 24-2 illustrates the components of the normal pulmonary parenchyma. The interstitium is the area between the capillaries and the alveolar space. As Figure 24-2 shows, in the normal state, this space allows close apposition of gas and capillaries with minimal connective tissue matrix, fibroblasts, and inflammatory cells such as macrophages. The interstitium supports the delicate relationship between the alveoli and capillaries allowing for efficient gas exchange. When responding to any injury—whether from a specific exposure (e.g., asbestos, nitrofurantoin, or moldy hay), an autoimmune-mediated inflammation from a systemic connective tissue disease (e.g., rheumatoid arthritis), or unknown injury (e.g., idiopathic pulmonary fibrosis [IPF])—the lung must respond to the damage and repair itself. If the exposure or injury persists or if the injury repair process is imperfect, the lung may be permanently damaged with increased interstitial tissue replacing the normal capillaries, alveoli, and healthy interstitium.

FIGURE 24-2 A, Diagram of the pulmonary parenchyma shows the respiratory bronchiole, alveolar duct, and alveolar sacs. B, The constituents of the interstitial space, including type I and type II alveolar epithelial cells, a capillary with vascular endothelial cells and erythrocytes in transit, resident macrophages, interstitial fibroblasts, and matrix substance.

These pathologic abnormalities can lead to profound impairment in lung physiology. Gas exchange is impaired owing to mismatching, shunt, and decreased diffusion across the abnormal interstitium. Work of breathing is markedly increased because of decreased lung compliance. Together, these physiologic impairments lead to the exercise intolerance seen in all of the ILDs. If the initiating injury or abnormal repair from injury is not halted, progressive tissue damage leading to worsening physiologic impairment and death can occur.

Characteristics of Interstitial Lung Disease

Clinical Signs and Symptoms of Interstitial Lung Disease

Many ILDs have similar clinical features and are not easily distinguished based on history or examination. Symptoms are generally limited to the respiratory tract. However, extrapulmonary symptoms should not be ignored because they may point to an ILD associated with a systemic diagnosis. Exertional breathlessness (dyspnea) and a nonproductive cough are the most common reasons patients seek medical attention. Other respiratory symptoms, such as sputum production, hemoptysis, pneumothorax, or wheezing, can occur and be suggestive of specific diseases (Table 24-1). If the patient also has prominent extrapulmonary symptoms, such as myalgia, arthralgia, sclerodactyly, gastroesophageal reflux, or Raynaud phenomenon, ILD resulting from underlying connective tissue disease may be present (Table 24-2).

TABLE 24-1

Unusual Pulmonary Findings and Likely Diagnosis

Pulmonary Findings	Disease	Frequency
Hemoptysis	LAM	Rare
Chyloptysis	LAM	Rare
Pneumothorax	LAM, BHD	Common
Wheeze	Sarcoidosis, LAM	Common
Chylous pleural effusion	LAM	Common
Exudative pleural effusion	RA	Common

BHD, Birt Hogg Dubé syndrome; RA, rheumatoid arthritis.

TABLE 24-2

Extrapulmonary Findings and Likely Diagnosis

Extrapulmonary Findings	Disease	Frequency
Raynaud phenomenon	All CTD	Common
Arthralgia	All CTD	Common
Myalgia	Polymyositis	Common
Large muscle weakness	Polymyositis	Common
Sclerodactyly	Scleroderma	Common
Rheumatoid skin nodules	RA	Rare
Fingertip fissures	Antisynthetase syndrome	Common
Dorsal hand rash	Dermatomyositis	Common
Facial rash	Dermatomyositis	Common
Exudative pleural effusion	RA	Common
Shawl distribution skin nodules	TSC	Common
“Pencil eraser” facial skin nodules	BHD	Common
Central nervous system benign cortical tuber	TSC	Common
Abdominal angiomyolipoma	LAM	Common
Renal cancer	BHD	Common
Cardiomyopathy	Sarcoidosis, polymyositis	Rare
Cardiac conduction block	Sarcoidosis	Rare
Violaceous facial skin nodules	Sarcoidosis	Common
Subcutaneous nodules	Sarcoidosis	Common
Cranial neuropathy	Sarcoidosis	Rare
Small fiber neuropathy	Sarcoidosis	Rare

BHD, Birt Hogg Dubé syndrome; CTD, connective tissue disease; RA, rheumatoid arthritis; TSC, tuberous sclerosis complex.

Physical Examination

Most patients with ILD have bilateral fine inspiratory, crackles, which usually are most prominent at the lung bases. However, some diseases, such as sarcoidosis and lymphangioleiomyomatosis (LAM), may have only decreased breath sounds without adventitious sounds despite a markedly abnormal chest radiograph. Expiratory wheezing is uncommon, and its presence suggests either airway involvement as part of the primary disease process (LAM, sarcoidosis, respiratory bronchiolitis–associated interstitial lung disease [RB-ILD], desquamative interstitial pneumonitis [DIP], pulmonary Langerhans cell histiocytosis [PLCH]) or concomitant airways disease, such as emphysema or asthma. Signs of pulmonary arterial hypertension with right ventricular dysfunction, such as lower extremity edema or jugular venous distention, may occur late in the course of any ILD and are not helpful in the diagnosis of a specific ILD. Examination also may disclose features of underlying connective tissue disease, including synovitis, joint deformities, or skin rash.

Radiographic Features

ILDs manifest as abnormal lung parenchyma that cast abnormal radiographic shadows. For most ILDs, the chest radiograph reveals reduced lung volumes with bilateral reticular or reticulonodular opacities. However, the chest radiograph has limited value because the three-dimensional abnormalities are summed into a two-dimensional image with loss of spatial information. High-resolution cross-sectional imaging via computed tomography (CT) provides detailed images representing pulmonary pathology.³ High-resolution CT images allow noninvasive evaluation of ILDs and are a key element in making a confident diagnosis and managing ILD.⁴

Plain chest radiographs and high-resolution CT images of usual interstitial pneumonitis (UIP) show the prototypic fibrotic injury pattern. The chest radiograph (Figure 24-3, A) and high-resolution CT image (Figure 24-3, B) in UIP typically reveal a bilateral, patchy, peripheral (subpleural), and basilar predominant disease with reticulonodular infiltrates, often with honeycomb, cystic change. The lung architecture is distorted in patients with moderate or severe disease burden, with reduced lung volume and traction bronchiectasis, especially at the lung bases. Reticulogranular (ground-glass) abnormalities, increased attenuation of the lung tissue without distortion of the underlying blood vessels or bronchi, are absent or minimal in IPF. Pleural disease, air trapping, micronodules, and significant lymphadenopathy are not seen, although two-thirds of patients with IPF can have mild mediastinal adenopathy.⁵

FIGURE 24-3 A, Posteroanterior chest radiograph showing the characteristic features of IPF, a common ILD. Notice the bilateral lower zone reticulonodular infiltrates and the loss of lung volume in the lower lobes. B, Chest CT image shows the peripheral nature of the fibrosis.

As the burden of disease increases, the chest radiograph may reveal multiple, tiny cysts in the most markedly involved regions. This cystic pattern, called honeycombing, reflects end-stage fibrosis and is a feature of many end-stage ILDs. These fibrotic cysts represent irreversible destruction of normal alveoli; therapies are aimed at preserving the remaining normal parenchyma and reducing symptoms.

Rule of Thumb

In patients with spontaneous pneumothorax and interstitial infiltrates, LAM or PLCH should be considered.

In contrast to UIP, cellular nonspecific interstitial pneumonitis is a pattern of injury dominated by inflammation and has imaging findings distinct from UIP. Reticulogranular (ground-glass) attenuation predominates and is found centrally and peripherally in the middle and lower lung zones. If the inflammation can be reduced, these abnormalities may improve. A mixed pattern of injury with fibrotic nonspecific interstitial pneumonitis can also be seen and is suggested by ground-glass attenuation in the presence of fibrotic changes.

Rule of Thumb

Calcification along the pleura on a chest radiograph suggests previous exposure to asbestos. Although such plaques do not cause symptoms or physiologic abnormality, they can provide a clue to the cause of ILD.

Physiologic Features

Similar to the radiographic findings, there can be considerable variability among the specific diseases in the physiologic abnormalities seen. However, a restrictive physiologic impairment is the common finding.⁶ Both forced expiratory volume in 1 second (FEV₁) and forced vital capacity (FVC) are diminished, and the FEV₁/FVC ratio is preserved or even supranormal. Lung volumes are reduced, as is the diffusing capacity of the lung for carbon monoxide (DLCO). This reduction in diffusing capacity reflects a pathologic disturbance of the alveolus-capillary interface.

Although not commonly pursued, the compliance characteristics of the lungs can be evaluated with an esophageal balloon to measure intrathoracic pressure at various lung volumes. In almost all ILDs, the lungs have reduced compliance and require supranormal transpleural pressures to ventilate (Figure 24-4). This lack of compliance results in small lung volumes and increased work of breathing.

FIGURE 24-4 Static pressure-volume curve. The compliance characteristics of the lung are illustrated with a plot of lung volume against the corresponding transthoracic pressure measured during static (i.e., no flow) conditions. The *shaded area* represents the range of values expected with a normally compliant lung. The line labeled *ILD* represents an example of a patient with ILD. At any particular lung volume, the transthoracic pressure is greater than expected. For comparison, the line labeled *Emphysema* shows the compliance characteristics of patients with emphysema.

Less frequently, a pattern of physiologic obstruction may be seen. This obstruction can be the result of the primary disease process (e.g., LAM, PLCH, or sarcoidosis in some patients) or concomitant emphysema or asthma.⁷ If ILD develops in a patient with significant emphysema, the opposing physiologic effects of the two diseases may result in deceptively normal spirometry and lung volume measurements and apparently normally compliant lungs. However, because both emphysema and ILD result in impaired gas exchange, DLCO is significantly decreased.

Rule of Thumb

Among smokers with IPF, normal spirometry and lung volumes with reduced DLCO suggest the presence of coexisting emphysema.

Although the association of first-hand tobacco smoke and obstructive lung disease is common and well known, tobacco smoke is also an avoidable cause of ILD. Although the association is rarer than with obstructive lung disease, first-hand tobacco smoke inhalation can lead to three types of ILD in susceptible individuals: RB-ILD, DIP, and PLCH. The first two disorders are related. Each disease consists of increased numbers of polyclonal activated macrophages. The diseases differ by the location of these overly abundant cells. In RB-ILD, macrophages accumulate in the respiratory bronchioles leading to bronchiolar remodeling and fibrosis of adjacent alveoli. As expected for a disease with combined airway and alveolar injury, pulmonary function testing reveals mixed restriction and obstruction with frequent air trapping. High-resolution CT images show this mixed pathologic location with indistinct centrilobular nodules (Figure 24-5). In DIP, the increased macrophages fill the alveoli, manifesting as restrictive impairment on pulmonary function testing and diffuse ground-glass attenuation on high-resolution CT imaging (Figure 24-6).

FIGURE 24-5 RB-ILD. There are numerous indistinct centrilobular nodules. Air trapping can also be seen in RB-ILD but is not present in this case.

Pulmonary Langerhans cell histiocytosis (PLCH) is the third interstitial manifestation of tobacco smoke. Increased numbers of polyclonal macrophages play a prominent role. However, in PLCH, they are accompanied by fibroblasts and eosinophils in nodules concentrated around small airways. These nodules are stellate and destroy adjacent lung tissue, leading to the classic high-resolution CT image of stellate nodules associated with cysts as seen in Figure 24-7. Although adult smoking-associated PLCH is pathologically similar to childhood Langerhans cell histiocytosis, the adult form does not involve bone and has not proven to respond to chemotherapy as the childhood form does. The relationship of these two disorders has yet to be defined.

FIGURE 24-7 PLCH. Note the left upper lobe cysts and indistinct stellate-shaped nodule around an airway, which will become a cyst.

In each of these three diseases, the primary treatment is complete tobacco abstinence. With abstinence, most patients either minimally improve or remain stable,⁸ but a few progressively worsen and may require lung transplantation. Active treatment with prednisone or other immunosuppressive medications is discouraged because few, if any, patients improve.⁹

Drug-Related and Radiation-Related Interstitial Lung Disease

Many drugs have been associated with pulmonary complications of various types, including interstitial inflammation and fibrosis, bronchospasm, pulmonary edema, and pleural effusions. Drugs from many different therapeutic classes can cause ILD, most commonly chemotherapeutic agents, antibiotics, antiarrhythmic drugs, and immunosuppressive agents (Box 24-1). There are no distinct physiologic, radiographic, or pathologic patterns of drug-induced ILD, and the diagnosis is usually made when a patient is exposed to a medication known to result in lung disease, the timing of the exposure is appropriate for the development of the disease, and other causes of ILD have been eliminated. Treatment is avoidance of further exposure and systemic corticosteroids in markedly impaired or declining patients. In addition to future drug exposure, bleomycin injury is accentuated by increased fractional inspired oxygen (FiO₂), even months after last drug exposure, and supplemental oxygen (O₂) should be used only if absolutely necessary in these patients.¹⁰

Box 24-1 Drugs Associated With the Development of Interstitial Lung Disease

Antibiotics