Occupational and Environmental History

The occupational and environmental history is of obvious importance. It should be thorough and detailed because a long latency period may occasionally exist between exposure and the appearance of clinical impairment and disability. The exposure may have been of short duration but high intensity. Hypersensitivity pneumonitis, which can manifest either as recurrent acute or subacute pneumonitis or as an insidious form with slowly progressive dyspnea, must be excluded (see Chapter 64 ). A growing list of occupational and environmental antigens can cause granulomatous pneumonitis.

Drug History

A review of the medications used in the recent and distant past is important. Uncommonly, lung disease may appear weeks to years after the drug has been discontinued (see Chapter 71 ). Aspiration (often silent) of gastric contents because of gastroesophageal reflux (GER) can lead to the insidious development of ILD, as can the nocturnal use of oily nose drops or use of mineral oil as a laxative.

Smoking History

Determining any history of tobacco use is important. More than 90% of patients with pulmonary Langerhans cell histiocytosis (PLCH) of the lung are smokers at the time of diagnosis; this is also true for respiratory bronchiolitis. Of patients with Goodpasture syndrome who smoked, 100% had diffuse alveolar hemorrhage, whereas only 20% of a nonsmoking group had pulmonary disease in addition to the renal involvement. Tobacco use also appears to enhance the development of interstitial fibrosis in an asbestos-exposed population. The risk of asbestosis in exposed smokers was 13 times that in a nonsmoking asbestos-exposed cohort. Most patients with IPF have a history of tobacco abuse. Conversely, hypersensitivity pneumonitis infrequently appears in the active smoker. Also, the incidence of sarcoidosis is lower in smokers.

Family History

Familial associations (with an autosomal dominant pattern) have been identified in cases of IPF, sarcoidosis, tuberous sclerosis, and neurofibromatosis; Niemann-Pick disease, Gaucher disease, and Hermansky-Pudlak syndrome are inherited in an autosomal recessive fashion (see “ Familial Pulmonary Fibrosis ” later).

Chest Radiography

Ziskind and coworkers classified diffuse lung diseases according to the pattern on chest radiographs—alveolar filling and primarily interstitial patterns (reticular or nodular). Although computed tomography (CT) scanning has supplanted the chest radiograph in the assessment of diffuse parenchymal lung diseases, it is still useful to recognize these radiographic patterns.

Alveolar Filling Pattern.

Alveolar filling ( Table 63-4 ) is recognized by a homogeneous opacity that can be diffuse or patchy and is characterized by confluent nodules with ill-defined outer borders, air bronchograms, and obliteration or silhouetting of normal structures such as the diaphragm, heart, and intrapulmonary blood vessels ( Fig. 63-2 ). Another feature occasionally seen with alveolar filling is the air alveologram, which represents small areas of uninvolved lung in an area of incomplete consolidation, manifesting on the chest radiograph ( Fig. 63-3 ) as small lucent areas within areas on increased lung opacity due to consolidation. So-called “acinar rosettes,” also referred to as “acinar nodules” or “air space nodules,” may be seen when alveolar filling is present and represent centrilobular or peribronchial nodules, rather than actual opacification of individual acini. Several have associated hilar adenopathy (e.g., sarcoidosis, pulmonary lymphoma). In patients with alveolar proteinosis, sparing of the lung parenchyma immediately adjacent to the diaphragm is seen. In chronic eosinophilic pneumonia, the pattern has been referred to as the radiographic negative of pulmonary edema because the alveolar opacities are most prominent in the periphery. A similar alveolar pattern has also been reported in some patients with organizing pneumonia ( Fig. 63-4 ).

Table 63-4

Interstitial Lung Diseases Producing an Alveolar Filling Pattern on Chest Radiograph

Alveolar proteinosis (proteinaceous fluid)

Adenocarcinoma with lepidic pattern or mucinous type (formerly called bronchoalveolar carcinoma) (malignant cells)

Bronchioloalveolar metastases (malignant cells from pancreas, breast)

Pulmonary lymphoma (malignant lymphocytes)

Lymphocytic interstitial pneumonia (lymphoplasmacytic cells)

Alveolar sarcoid (lymphocyte-macrophage alveolitis or confluent granuloma)

Desquamative interstitial pneumonia (macrophages)

Diffuse alveolar hemorrhage (red blood cells; hemosiderin-filled macrophages)

Eosinophilic pneumonia (eosinophils, macrophages; lymphocytes)

Alveolar microlithiasis (calcium-phosphate microliths)

Organizing pneumonia (Masson bodies)

Exogenous lipoid pneumonia (lipid-filled macrophages)

Acute hypersensitivity pneumonia (lymphoplasmacytic cells)

 

Frontal chest radiograph illustrating an alveolar filling pattern, or air-space consolidation.

This homogeneous opacity obscures vascular margins, tends to extend to the pleural surfaces and is often associated with air bronchograms ( arrow ). This patient had pneumococcal pneumonia, but an alveolar filling radiographic pattern can be seen in patients with several interstitial lung diseases (see Table 63-4 ).

(Courtesy Michael Gotway, MD.)

Detailed view of chest radiograph showing alveolar opacities with ill-defined nodules and distal air alveolograms.

This patient had adenocarcinoma (formerly called bronchoalveolar) carcinoma, but this pattern can be seen in several interstitial lung diseases (see Table 63-4 ).

Frontal chest radiograph showing subpleural, upper lobe consolidation in a patient with chronic eosinophilic pneumonia ( arrows ).

A similar pattern may be seen in organizing pneumonia.

(Courtesy Michael Gotway, MD.)

Nodular Pattern.

Nodules of varying size characterize granulomatous lung diseases. Miliary nodules accompany infectious granulomas and noninfectious granulomas (e.g., sarcoidosis, PLCH, and hypersensitivity pneumonitis) and some malignant diseases (e.g., melanoma, hypernephroma, and lymphoma) ( Fig. 63-5 ). However, linear opacities possibly representing an underlying cellular interstitial infiltrate are also visible.

Frontal chest radiograph showing circumscribed small interstitial-appearing “miliary” nodules.

A nodule is also present in the right lower lobe. This patient had metastatic malignant melanoma, but this pattern can also be seen in sarcoidosis, pulmonary Langerhans cell histiocytosis, and hypersensitivity pneumonitis.

Linear or Reticular.

Linear or reticular interstitial changes are seen in most ILDs ( Fig. 63-6 ). It is typical for many ILDs (e.g., IPF, the connective tissue diseases, asbestosis, cytotoxic drug–induced disorders) to have the greatest concentration of the reticular opacities in the lower lung zones. The term radiographic honeycomb lung refers to a reticular and cystic pattern that correlates with the histologic “honeycombing.” These small cystic structures, which are best seen in the lower and peripheral lung zones, indicate an underlying advanced fibrotic change ( Fig. 63-7 ).

Frontal chest radiograph in a patient with idiopathic pulmonary fibrosis.

Peripheral basal predominant reticulation is seen consistent with fibrotic lung disease. Note diminished lung volumes.

(Courtesy Michael Gotway, MD.)

Frontal chest radiograph showing characteristic features of honeycomb lung.

A network of 2- to 3-mm cystic spaces is distributed throughout the lung fields. This patient with end-stage idiopathic pulmonary fibrosis also had pulmonary hypertension and was receiving oxygen through a transtracheal catheter.

A criticism of the alveolar-interstitial classification is that a mixed pattern is often found. For example, interstitial fibrosis may eventually be superimposed on a disease that was primarily alveolar, such as alveolar proteinosis, diffuse alveolar hemorrhage, eosinophilic pneumonia, or organizing pneumonia. Sarcoidosis, a disease characterized by interstitial granuloma, can be alveolar in appearance due to either coalescence of granulomas with compression of adjacent lung or a lymphocyte-macrophage alveolitis. Dense fibrosis from any fibrotic lung disease can compress adjacent lung, producing homogeneous shadows. The appearance of alveolar opacities during the course of an ILD may represent renewed activity of the primary disease, superimposed infection, or development of adenocarcinoma.

Other Radiographic Features.

Several distinctive patterns may accompany the interstitial changes and may point to a diagnosis ( Table 63-5 ). There are a group of interstitial diseases, often granulomatous, in which the radiographic changes are more prominent in the upper lung zones ( Fig. 63-8 ). Some interstitial diseases are bronchiolocentric, resulting in either maintenance or expansion of the lung volume. If an ILD is superimposed on emphysema, the lung volumes are often preserved. The majority of ILD s result in a gradual reduction of the lung volumes. In fact, lower lobe volume loss and traction bronchiectasis are typical for the advanced stages of these diseases. Short horizontal lines at the lung periphery (Kerley B lines), representing thickened interlobular septa, are seen after obstruction of the pulmonary lymphatics ( Fig. 63-9 ). Pneumothorax is often the presenting manifestation of PLCH or lymphangioleiomyomatosis. Diaphragmatic pleural calcification in a patient with interstitial opacities is indicative of asbestos exposure. Pleural thickening and pleural effusion may complicate the course of the connective tissue–associated ILDs. Chronic hypoxemia results in radiographic evidence of pulmonary hypertension.

Table 63-5

Radiologic Features of Interstitial Lung Diseases

Feature	Diseases
Upper zone—predominant disease	Radiation pneumonitis; neurofibromatosis; chronic sarcoidosis; pulmonary Langerhans cell histiocytosis; silicosis; coal workers’ pneumoconiosis; chronic hypersensitivity pneumonitis; chronic eosinophilic pneumonia; ankylosing spondylitis; nodular rheumatoid arthritis; berylliosis; drug-induced (amiodarone, gold, bischloroethyl carmustine nitrosourea [carmustine]); radiation
Increased lung volumes	Lymphangioleiomyomatosis (with or without tuberous sclerosis); chronic sarcoidosis; pulmonary Langerhans cell histiocytosis; neurofibromatosis
Radiologic honeycomb lung	Idiopathic pulmonary fibrosis; connective tissue disease; asbestosis; drug-induced; lymphocytic interstitial pneumonia; chronic aspiration pneumonia; hemosiderosis; Hermansky-Pudlak syndrome
Pneumothorax	Pulmonary Langerhans cell histiocytosis; lymphangioleiomyomatosis (with or without tuberous sclerosis); neurofibromatosis
Kerley B lines	Lymphangitic carcinomatosis; lymphangioleiomyomatosis; left atrial hypertension (mitral valve disease, veno-occlusive disease); lymphoma; amyloidosis
Lymphadenopathy	Sarcoidosis; lymphoma; lymphangitic carcinomatosis; lymphoid interstitial pneumonia; berylliosis; amyloidosis; Gaucher disease
Pleural disease	Lymphangitic carcinomatosis; connective tissue disease; asbestosis (pleural calcification); lymphangioleiomyomatosis (chylous effusion); drug-induced (nitrofurantoin, radiation); sarcoidosis
Eggshell calcification of lymph nodes	Silicosis; sarcoidosis; radiation

 

Uncomplicated silicosis.

Frontal chest radiograph shows upper and mid lung predominant small nodules. Note that some of these nodules are calcified.

(Courtesy Michael Gotway, MD.)

Lymphangitic carcinomatosis.

Detailed view of right lung shows Kerley B lines ( arrow ) and pleural effusion.

Computed Tomography

Conventional chest radiographic assessment for ILD may miss up to 10% of cases. Conventional CT, obtained using 8- to 10-mm slices, offers little more for the detection of radiographic-negative ILD. HRCT, obtained with a section thickness of less than 2 mm, enables better visualization of fine parenchymal detail and therefore the detection of early air space filling or interstitial change ( Fig. 63-10 ). In cases of suspected ILD with negative conventional radiography, it is important to perform HRCT in the prone and supine positions. Dependent lung density can mask interstitial change, and vascular engorgement of the dependent portion of lung mimics septal thickening on supine imaging. Abnormalities that persist on prone imaging are indicative of disease.

Hypersensitivity pneumonitis.

A, Normal chest radiograph from a 45-year-old man with established hypersensitivity pneumonitis. At the time, his arterial oxygen pressure while breathing room air was 48 mm Hg. B, High-resolution chest CT image of the same patient demonstrates patchy ground-glass areas of air space–filling opacities.

In patients with abnormal chest radiographs, the diagnostic accuracy increases with HRCT evaluation. In cases of IPF, peripheral reticular opacities, lower zone subpleural honeycombing, and traction bronchiectasis are seen ( Fig. 63-11 ). In the connective tissue diseases, asbestosis, and some drug-induced ILD, the results on HRCT, as on chest radiography, are indistinguishable from those of IPF or nonspecific interstitial pneumonia (NSIP). In scleroderma, a disease in which the prevalence rate of ILD approaches 100% in autopsy series, HRCT detects disease in 45% to 75% of patients when conventional radiography is negative.

Advanced idiopathic pulmonary fibrosis.

High-resolution CT image shows extensive honeycomb changes.

In sarcoidosis, in addition to the hilar and mediastinal adenopathy, nodules deposited along bronchovascular bundles and interlobular septa, air space filling due to the lymphocyte-macrophage alveolitis, and linear densities secondary to fibrotic scarring can be seen ( Fig. 63-12 ). In patients with hypersensitivity pneumonitis, air space–filling centrilobular nodules and linear opacities without adenopathy are present. The HRCT can be normal in symptomatic patients with biopsy-proved hypersensitivity pneumonitis. In patients with PLCH, the combination of centrilobular nodules and cysts, most prominent in the upper lobes and occasionally accompanied by a pneumothorax, is characteristic ( Fig. 63-13 ). In earlier PLCH, coalescence of the nodules produces an air space–filling pattern.

Sarcoidosis.

High-resolution CT image shows hilar lymphadenopathy and nodular disease.

Pulmonary Langerhans cell histiocytosis.

High-resolution CT image shows centrilobular nodules ( arrow ) and cyst formation ( arrowheads ).

(Courtesy Michael Gotway, MD.)

In lymphangioleiomyomatosis, the HRCT is typical, revealing rounded, thin-walled cysts throughout ( Fig. 63-14 ). A pneumothorax or pleural effusion (chylous) may accompany this change. Identical findings are present in lymphangioleiomyomatosis associated with tuberous sclerosis. Lymphangitic carcinomatosis produces a beaded-chain appearance of the interlobular septa that correlates with Kerley B lines seen with conventional radiography. In asbestos-related disease, noncalcified pleural plaques and early ILD are often difficult to detect, and the HRCT is more sensitive than conventional chest radiography.

Lymphangioleiomyomatosis.

High-resolution CT image shows characteristic thin-walled cysts throughout the parenchyma.

Ventilatory Function

Ventilatory function tests provide an indirect index of alterations to the impedance to respiration offered by the elastic resistance to distention of the lungs and the frictional resistance to airflow in the tracheobronchial tree. Clinically, alterations of the mechanical properties of the respiratory system are also reflected in the pattern of breathing that is adopted by the patient. These patients tend to breathe rapidly and shallowly because a larger tidal volume would require an inordinate increase in work of breathing to overcome the greatly increased elastic resistance.

Elastic Resistance

ILD is associated with an increase in elastic resistance (or decreased compliance), and this can be seen in a plot of the static transpulmonary pressure (i.e., at points of no flow) at differing decrements of lung volume from total lung capacity (TLC) to residual volume. In most patients with ILD, the plot of the volume-pressure relationship of the lungs is characteristically shifted downward and to the right, with a reduced slope (i.e., compliance is low) and a markedly increased coefficient of elastic recoil (maximum elastic recoil pressure, TLC). Conversely, as is demonstrated in Figure 63-15 , there is significant variation in the position of the volume-pressure curve in patients with IPF and sarcoidosis, and the correlation between alterations of the elastic properties (and lung volume compartments) and the degree of fibrosis present is poor. This is, at least in part, a consequence of the impact of smoking, which appears to differ in the two disorders. In patients with IPF who smoke, the volume-pressure curve is shifted upward and to the left, whereas in patients with sarcoidosis who smoke, it is shifted downward and to the right.

Multiple recordings show volume-pressure characteristics in patients with idiopathic pulmonary fibrosis (IPF) (A) and sarcoidosis (B). Note the marked variation of position and shape in both disorders. TLC, total lung capacity.

(Redrawn from Hanley ME, King TE Jr, Schwarz MI, et al: The impact of smoking on mechanical properties of the lungs in idiopathic pulmonary fibrosis and sarcoidosis. Am Rev Respir Dis 144:1102, 1991.)

Measurements of lung volume reflect changes in position of the volume-pressure curve of the lungs. This is because alterations of the elastic recoil of the lung or chest wall disturb the balance between the elastic forces of the lungs, which act in an expiratory direction, and those of the chest wall, which act in an inspiratory direction. In patients with ILD, the TLC, functional residual capacity, and residual volume are generally reduced ( Fig. 63-16 ). A lower than expected TLC (and vital capacity) in association with a normal functional residual capacity and a greater than expected residual volume generally reflects a mixed restrictive and obstructive disorder. However, because maximum effort is necessary to determine the inspiratory capacity and the expiratory reserve volume, a less than maximal inspiration or expiration, either because of weak respiratory muscles or because of poor effort, leads to the same findings. Similar considerations apply to the vital capacity, which is often used as an index of alterations of elastic resistance. In addition, as can be seen in Figure 63-16, a low vital capacity is not specific for restrictive disorders because it is also lower than expected in patients with airflow limitation (because of an increased residual volume).

Bar graphs show total lung capacity (TLC) and its subdivisions in healthy persons (normal) compared with the typical abnormalities found in patients with restrictive disorders, obstructive disorders, and mixed disorders. FRC, functional residual capacity; RV, residual volume; VC, vital capacity.

(Redrawn from Cherniack RM: Pulmonary function testing. Philadelphia, 1992, WB Saunders, p 212.)

Flow Resistance

Measurement of lung volume is important when evaluating airflow resistance. This can be assessed directly from the relationship between the rate of airflow and the resistive component of the transpulmonary pressure.

In clinical practice, various indirect measures of flow resistance can be used: the forced expiratory volume in 1 second (FEV ₁ ); the mean expiratory flow rate between 25% and 75% of the forced vital capacity (FEF _25%-75%) ; the maximal expiratory flow rate ( ) at a particular proportion (such as 75%, 50%, or 25%) of the forced vital capacity (FVC) (from a flow-volume curve); the FEV ₁ /FVC ratio; or the FEV ₁ -to–vital capacity ratio. Low flow rates or a low FEV ₁ /FVC ratio (i.e., <70% of predicted) is believed to indicate expiratory airflow limitation. However, like airway resistance, values depend on the diameter of the airways, which is influenced by the lung volume. The FEV ₁ /FVC ratio will be overestimated, and the degree of flow limitation underestimated, in the patient who does not exhale fully because of severe dyspnea or muscular weakness, pain, or poor effort.

Airflow resistance is not generally thought to be increased in ILD. As is seen in Figure 63-17 , is low in ILD, not because of an increase in flow resistance but rather because of the low lung volumes at which the flow is being measured. In fact, in uncomplicated ILD, values are greater than expected at any particular lung volume because the lung elastic recoil pressure, which is the driving pressure for flow in the peripheral airways, is increased. As a corollary, a lower than expected at a particular lung volume in a patient who is suffering from a restrictive disorder indicates an increase of flow resistance in the more peripheral airways. An increase in peripheral airway resistance has been reported in patients with IPF, hypersensitivity pneumonitis, and asbestos exposure.

Schematic flow-volume curves in a healthy person ( solid line ) are compared with those in patients ( dotted lines ) with a restrictive disorder (A) and with an obstructive disorder (B). Lung volume is reduced in the restrictive disorder, and maximum expiratory flow rates are low because they are achieved at low lung volumes. Flow rates are higher than expected at low lung volumes because the driving pressure (lung elastic recoil) is increased. ERV, expiratory residual volume; IC, inspiratory capacity; RV, residual volume; , flow.

(Redrawn from Cherniack RM: Pulmonary function testing. Philadelphia, 1992, WB Saunders, p 218.)

Gas Exchange

Alterations of gas exchange are readily assessed by analysis of the arterial oxygen pressure (P o ₂ ) and carbon dioxide pressure (P co ₂ ) and calculation of the alveolar-arterial P o ₂ difference ((A−a)P o ₂ ), both at rest and during exercise.

In patients with ILD, arterial blood analysis while at rest usually reveals hypoxemia and an increased (A−a)P o ₂ , along with hypocapnia. In addition, the diffusing capacity for carbon monoxide (D l _CO ) is reduced, primarily because of a reduction in the alveolar-capillary surface available for gas exchange. The disturbance of gas exchange generally accompanies abnormalities in ventilatory function, but gas exchange may be normal at rest in a significant number of patients. Similarly, the resting D l _CO may be only slightly reduced in patients who demonstrate a mild restrictive disorder or normal gas exchange while at rest, or both.

The D l _CO is generally greater than expected in those cases associated with recent pulmonary hemorrhage because the red blood cells in the pulmonary alveoli take up carbon monoxide readily. Sequential measurements of the D l _CO within minutes may aid in the establishment of the diagnosis of alveolar hemorrhage. When there is fresh blood in the alveolar spaces, each successive D l _CO value will be lower as the hemoglobin in the alveoli becomes saturated with carbon monoxide.

Exercise

In most patients, gas exchange is disturbed during exertion, even in those with normal gas exchange at rest. Assessment of gas exchange during exercise provides the best correlation with the severity of disease and is probably the most important physiologic determination in patients with ILD (see Chapter 26 ).

In general, patients with the most severe restrictive disease have the poorest exercise tolerance. As is shown in Figure 63-18 , ventilation generally rises excessively during exercise and may approach the ventilatory ceiling. Characteristically, the respiratory frequency rises inordinately with increasing exercise loads because of the increased work that would be required to overcome the elastic resistance of the lungs if the tidal volume were to increase.

Schematic curves show the ventilatory response (A) and respiratory rate (B) during increasing exercise workloads expressed as a percentage of the predicted maximum oxygen uptake ( ) in a healthy person and in a patient with idiopathic pulmonary fibrosis.

(Redrawn from Cherniack RM: Pulmonary function testing. Philadelphia, 1992, WB Saunders, p 248.)

The excessive ventilation is frequently preferentially distributed to areas of lung that have normal compliance but diminished perfusion (i.e., high ventilation-perfusion ratio); as a result, unlike the normal response, the calculated dead space (V d ) and the ratio of dead space to tidal volume (V d /V t ) rise in association with rapid, shallow breathing. The increase in cardiac output with exercise and the rapid transit of blood through the pulmonary capillaries along with its redistribution in the lungs lead to a greater maldistribution of ventilation-perfusion ratios. This results in a rise in (A−a)P o ₂ and a fall in arterial P o ₂ ( Fig. 63-19 ). Except for heavy exercise, when the transit through the circulation is exceptionally rapid, it is unlikely that a reduced ability of oxygen to diffuse across a thickened alveolar-capillary membrane plays a significant role in the hypoxemia.

The changes in arterial P o ₂ ( circles ),alveolar-arterial P o ₂ difference ((A−a)P o ₂ , squares ), and arterial carbon dioxide pressure (P co ₂ , triangles ) during increasing exercise workloads expressed as the percentage of predicted maximum oxygen uptake ( ) in a healthy person and a patient with idiopathic pulmonary fibrosis. Testing was performed at an altitude of 5280 feet.

(Redrawn from Cherniack RM: Pulmonary function testing. Philadelphia, 1992, WB Saunders, p 249.)

Transbronchial Biopsy

As a matter of practicality, transbronchial biopsy can be performed during the bronchoscopy for BAL. Transbronchial biopsy is relatively safe and is often diagnostic of sarcoidosis, diffuse malignancy, alveolar proteinosis, or eosinophilic pneumonia. Other entities are less frequently confirmed by this procedure. A transbronchial biopsy interpretation, which describes only inflammation, fibrosis, or both, is not evidence for IPF or any other entity listed in Table 63-1 . Furthermore, even in clinically confirmed cases of connective tissue or drug-induced ILD, several different histologic patterns may evolve (see Table 63-2 ), and surgical lung biopsy is often undertaken to predict prognosis and therapeutic responsiveness, particularly if BAL and HRCT are inconclusive.

Surgical Lung Biopsy

If the transbronchial biopsy, clinical, and BAL data are inconclusive and the patient is not at high risk, a video thoracoscopic or open-lung biopsy should be performed. Moreover, there is a poor correlation between the results of transbronchial and open-lung biopsies unless the transbronchial biopsy yields a specific diagnosis. Therefore, when the transbronchial biopsy is inconclusive and a definitive diagnosis is required, open or thoracoscopic lung biopsy is indicated.

Clinical Features

IPF is a disease of middle age, usually seen in patients between 50 and 70 years of age. Patients with familial pulmonary fibrosis tend to present at a younger age; otherwise, it is quite uncommon for a patient to present before the age of 40. The typical patient presents with the insidious onset of exertional breathlessness and a nonproductive cough. Constitutional symptoms are uncommon, but weight loss, fever, fatigue, myalgias, or arthralgia is occasionally present. Although patients may present with only a nonproductive cough, all patients experience dyspnea with exertion as the disease progresses. Most patients have these symptoms for months to years before definitive evaluation, usually around 12 to 18 months.

The physical examination is rarely normal. Most patients have bibasilar late inspiratory fine crackles (Velcro crackles) on chest examination. Clubbing of the fingers is seen in 40% to 75% of patients and is a late finding in the disease course. Cardiac examination is usually normal except in the middle or late stages of the disease, when findings of pulmonary hypertension (e.g., augmented P2, right-sided lift, tricuspid regurgitation, and S3 gallop) and cor pulmonale may become evident. Similarly, cyanosis is a late manifestation indicating advanced disease. Spontaneous pneumothorax or pneumomediastinum is rare.

Blood and Serologic Studies

An elevated erythrocyte sedimentation rate, low-level antinuclear antibodies titer positivity (≥40 and <1 : 320), and elevated rheumatoid factor (>60 IU/mL) have been identified in some of these patients. Hemoglobin level along with leukocyte and differential counts are usually normal.

Chest Imaging Studies

Chest Radiography.

The typical finding in patients with IPF is peripheral reticular opacities with a netlike appearance of linear or curvilinear densities, with predominance at the lung bases ( Fig. 63-20 ). A coarse reticular pattern or multiple cystic or honeycombed areas (i.e., coarse reticular pattern with translucencies measuring 0.3 to 1 cm in diameter) are radiographic findings that correlate with advanced disease and poor prognosis (see Figs. 63-6 and 63-7 ). Chest radiographic evidence of reduced lung volumes is usually present unless there is associated obstructive airway disease, as can be seen in smokers.

Serial chest radiographs from a patient with idiopathic pulmonary fibrosis.

A, The frontal chest radiograph was obtained at the time of onset of breathlessness with exercise and mild cough. The chest appears normal. B, The follow-up film reveals progressive loss of lung volume and bibasilar, predominantly reticular opacities. The patient had stopped regular exercise because of breathlessness with exertion. C, Progressive changes are evident, with severe loss of lung volume. Predominantly in the lower lung zone are seen diffuse, bilateral, coarse reticular opacities typical of the radiographic appearance of the middle to late stage of pulmonary fibrosis. D, Continued disease progression is evident, with honeycombing and pulmonary hypertension. Open-lung biopsy revealed usual interstitial pneumonia with extensive fibrosis and histologic honeycombing. Treatment with corticosteroids and cyclophosphamide (Cytoxan) was started, but the patient experienced a progressive decline in functional status and died 6 months after lung transplantation.

Pleural abnormalities are uncommon in IPF; their presence should suggest another diagnosis, such as collagen vascular disease (especially rheumatoid arthritis or systemic lupus erythematosus), mitral valve disease, congestive heart failure, asbestosis, infection, drug-induced lung disease, or lymphangitic carcinomatosis (see Table 63-5 ).

Computed Tomography Scan.

CT plays a major role in the evaluation of pulmonary parenchymal diseases, especially IPF. HRCT is useful in the differentiation of IPF from other ILDs, the determination of the extent and severity of disease activity, and, most importantly, the detection of disease, especially in patients with normal or minimal change on chest radiography. HRCT findings in IPF include a marked peripheral (subpleural) distribution of the interstitial opacities. The involvement is patchy, with areas of reticulation intermingled with areas of normal tissue, often associated with cystic spaces 2 to 4 mm in diameter (see Fig. 63-11 ). Early disease appears as patchy, predominantly peripheral, subpleural reticular opacities ( eFig. 63-1 ) and minor degrees of honeycomb change. In more advanced disease, a more diffuse reticular pattern in the lower lung zones with thickened interlobular septa and intralobular lines progresses to traction bronchiectasis and subpleural fibrosis ( eFig. 63-2 ). The predominantly basal nature of these abnormalities is often readily appreciated with coronal imaging ( eFig. 63-3 ).

One of the key findings indicating the diagnosis of IPF is the presence of honeycomb cysts in a basilar subpleural distribution ( eFig. 63-4 ). Honeycomb changes appear on the HRCT scan as variably sized cystic spaces that share walls and frequently stack on one another in several layers. Ground-glass opacities are common but of mild severity and characteristically much less extensive than the reticular pattern. Architectural distortion, which reflects lung fibrosis, is often prominent.

Combined lower lobe pulmonary fibrosis and upper lobe emphysema has been recently described as a new CT-defined syndrome ( eFig. 63-5 ,Video 63-1 ) ( Fig. 63-21 ). Smoking appears to be the predominant risk factor for this disorder. Patients with this entity are primarily males with a mean age of 65 years who have relatively preserved lung volumes but marked reductions in D l _CO on pulmonary function testing. Limited data suggest that these patients with IPF and coexisting emphysema are more likely to require long-term oxygen therapy, to develop pulmonary hypertension, and to have a worse outcome than those without emphysema.

Combined pulmonary fibrosis and emphysema.

CT images from a 69-year-old woman with a 12-month history of worsening cough and dyspnea. She is a current heavy smoker. A, Upper zones of the lungs show emphysema and mild patchy peripheral reticular opacities. B, Lower zones of the lungs show emphysema and architectural distortion with patchy peripheral reticular opacities and extensive honeycombing lesions.

Other Imaging Techniques

Pulmonary Function Tests

The lung volumes (TLC, functional residual capacity, and residual volume) are reduced in IPF. Early on, the lung volumes may be normal, especially in patients with superimposed chronic obstructive pulmonary disease (COPD). Lung volumes are higher in smokers with IPF compared with those who have never smoked. As mentioned previously, a group of smokers develop a combined IPF and emphysema and show almost normal lung volumes, even in advanced disease. Expiratory flow rates (FEV ₁ and FVC) may be decreased because of the reduction in lung volume, but the FEV ₁ /FVC ratio is maintained. Because of the increased static elastic recoil found in these patients, flow rates (at any given lung volume) are often increased (see Figs. 63-15A and 63-17 ).

Patients with IPF are tachypneic, with rapid shallow breaths, probably because of increased work of breathing. This rapid respiratory rate presumably results from altered mechanical reflexes, caused by the increased elastic load, vagal mechanisms, or both, because no defined chemical basis for the hyperventilation has been identified (see Fig. 63-18 ).

The D l _CO is reduced, often before the loss of lung volume. The decrease in the D l _CO results from both a contraction of the pulmonary capillary volume and the presence of ventilation-perfusion abnormalities. Resting arterial blood gases are usually abnormal, revealing hypoxemia and respiratory alkalosis. The major cause of resting hypoxemia is ventilation-perfusion mismatching; it is not due to either impaired oxygen diffusion, as was originally suspected, or to anatomic shunts. With exercise, the (A−a)P o ₂ widens, and the arterial P o ₂ and oxygen saturation fall. During maximal exercise, 20% to 30% of the exercise-induced widening of the (A−a)P o ₂ may be caused by some impairment of oxygen diffusion. Importantly, the abnormalities identified at rest do not accurately predict the magnitude of the abnormalities seen with exercise (see Fig. 63-19 ). In addition, gas exchange during exercise has been demonstrated to be a sensitive parameter for following the clinical course.

In patients with IPF, a highly significant correlation has been reported between the 6-minute walk distance (6MWD) test and D l _CO , as well as ; the 6MWD is a strong predictor of mortality. The 6MWD test is difficult to perform in patients with advanced lung disease, however, and variability is common.

The 15-steps Climbing Oximetry Test has been found useful for estimating ventilatory reserve in patients with COPD and for predicting postoperative complications of lung resection. In a recent study, it was shown that the desaturation measured by the 15-steps Oximetry Test in IPF patients is comparable with the desaturation measured by the cardiopulmonary exercise test and the 6MWD test, suggesting it may be a reliable tool for monitoring IPF progression and for evaluating the need for oxygen supplementation. This test may serve as a surrogate marker of and an alternative to the 6MWD test in this setting.

During exercise, patients with IPF increase their minute ventilation primarily by increasing their respiratory frequency (see Fig. 63-18 ). This method of increase differs from that in normal subjects, in whom ventilation increases during mild exercise by an increase in the tidal volume (V t ) rather than respiratory rate. Thus, patients with IPF have elevated minute ventilation during exercise that is in part related to the increase in V d . In addition, the V d /V t ratio is increased at rest and is maintained or decreases only slightly with exercise. Occasionally, the V d /V t ratio increases in ILDs that have a prominent pulmonary vascular component, such as scleroderma or PLCH.

Pulmonary Hemodynamics

Recent evidence suggests pulmonary hypertension due to IPF (PH-IPF) is relatively common and may contribute substantially to functional status, quality of life, morbidity, and mortality. (See Chapter 59 .) The prevalence of PH complicating the course of patients with IPF has been reported in between 32% and 85% of patients, being more frequent in advanced disease. The most appropriate method to detect PH noninvasively is transthoracic (Doppler) echocardiography. Unfortunately, echocardiography may be inaccurate in estimating pulmonary arterial systolic pressure in patients with ILD. Right heart catheterization is the “gold standard” for the hemodynamic evaluation of the pulmonary circulation and diagnosis of PH but is an invasive technique. Right heart catheterization may be necessary, however, to document the severity of PH and potential right ventricular dysfunction. Abnormalities in gas exchange and exercise capacity seem to have a significant association with PH-IPF. Thus, exaggerated exercise oxygen desaturation, out-of-proportion reduction of D l _CO , and supplemental oxygen requirement should raise suspicion of (and may be a useful surrogate for) the presence of underlying PH. Brain natriuretic peptide concentrations predicted moderate to severe PH with 100% sensitivity and high specificity (89%) in a small cohort of patients with pulmonary fibrosis. This study requires further validation.

Pathologic vascular findings in IPF consist of changes in the arteries, arterioles, and venules, as well as destruction of the capillary bed. Advential thickening around the pulmonary vessels reflects an increase of connective tissue. Smooth muscle cells hypertrophy and proliferate, and collagen and elastin accumulate in the media of the small muscular pulmonary arteries. Distal pulmonary arterioles become muscularized (see Fig. 59-4E,F ). In addition, there may be extensive intimal hyperplasia, fibrosis, and reduplication of the inner elastic lamina in the small muscular pulmonary arteries in IPF. Increased hemosiderin deposition and alveolar septal capillary density have been associated with higher right ventricular systolic pressure (as assessed by transthoracic echocardiography) and may represent histologic correlates of pulmonary hypertension in IPF.

Supplemental oxygen is the most obvious choice for prevention or treatment of PH; however, there are no data supporting favorable effects of oxygen on survival in PH-IPF. Vasodilators agents are currently being studied, but one must recognize that decreased physiologic vasoconstriction in low ventilation-perfusion lung units may worsen shunt and hypoxemia in IPF.

Endothelin-1 (ET-1) receptor antagonists have been useful in patients with other types of pulmonary hyper­tension, mostly in primary PAH or PAH associated with connective tissue disease. Clinical trials in PH-IPF are ongoing ( Table 63-9 ). Prostacyclin ( prostaglandin I ₂ [PGI ₂ ]) analogues used via inhalation could maintain (or even improve) ventilation-perfusion matching and could have a beneficial effect targeting PH. In one study, inhaled iloprost decreased mean pulmonary artery pressure without changes in shunt flow, suggesting the utility of selective pulmonary vasodilation in patients with PH-IPF. Sildenafil, a phosphodiesterase-5 inhibitor, promotes vasodilation and decreases smooth muscle proliferation and vascular remodeling. In an open-label study of treatment with sildenafil for 3 months in a small cohort of patients with PH-IPF, a modest but significant improvement in 6MWD was noticed. In a subsequent randomized clinical trial, sildenafil therapy did not show a benefit for the primary outcome (increase in 6MWD of 20% or more), but a small yet significant improvement was noted in arterial oxygenation, diffusing capacity, dyspnea, and quality of life. Several other randomized clinical trials are currently ongoing (see Table 63-9 ) to learn whether any therapies will be useful in PH-IPF (see Chapter 59 ).

Table 63-9

Ongoing Clinical Trials in Patients with Idiopathic Pulmonary Fibrosis

Drug	Aim/Mechanism of Action	Sponsor	ClinicalTrials. Gov Identifier
QAX576	It may down-regulate IL-13	Novartis	NCT00532233
FG-3019	It blocks CTGF	FibroGen	NCT00074698
Macitentan	Inhibitor of ET-1	Actelion	NCT00903331
Bosentan	Indicated for PAH	UCLA; Actelion	NCT00625469
Pirfenidone	Antifibrotic effects in vitro and in experimental models	InterMune	NCT01366209
Zileuton	Inhibitor of leukotrienes	University of Michigan	NCT00262405
Gleevec (imatinib mesylate)	Tyrosine kinase inhibitor	Daniels, Craig E., MD, Novartis	NCT00131274
Octreotide (somatostatin analogue)	Anti-inflammatory and antifibrotic properties in vitro and in vivo	Institut National de la Santé et de la Recherche Médicale, France	NCT00463983
GC1008	Antibody that neutralizes TGF-β	Genzyme	NCT00125385
Inhaled IFN-γ	Antifibrotic effects	New York University School of Medicine; National Center for Research Resources, Stony Brook University; Respironics	NCT00563212
Inhaled IFN-γ	Same as previous	New York University School of Medicine	NCT00212563
Tetrathiomolybdate	Copper chelating agent	University of Michigan; Coalition for Pulmonary Fibrosis	NCT00189176
Nintedanib	Inhibits profibrotic growth factors	Boehringer Ingelheim Pharmaceuticals	NCT01335177
NAC alone	Effect of the antioxidant NAC	NHLBI	NCT00650091
Thalidomide	Indicated for cough. Suppresses functional up-regulation of sensory fibers within the respiratory tract	Johns Hopkins University	NCT00600028
Sildenafil	Indicated for PAH	UCLA and Pfizer	NCT00625079
Sildenafil	Indicated for PAH	NHLBI; Pfizer	NCT00517933
Sildenafil	Indicated for PAH	Department of Veterans Affairs	NCT00359736
Inhaled iloprost	Indicated for PAH; secondary purpose: to evaluate antifibrotic properties	Actelion	NCT00109681
CNTO 888	Phase II study	Centocor	NCT00786201
Losartan	An antagonist of angiotensin type 1 receptor	H. Lee Moffitt Cancer Center and Research Institute; NCI	NCT00879879
IFN-α lozenges	Reduce the frequency and severity of coughing	Amarillo Biosciences; Texas Tech University Health Sciences Center	NCT00690885
Inhaled carbon monoxide	Decrease serum level of MMP7	Brigham and Women’s Hospital	NCTO1214187
Tralokinumab	Binds IL-13	MedImmune	NCT01629667
Lysophosphatidic acid receptor antagonist	Antifibrotic effects in vitro and in experimental models	Bristol-Myers-Squibb	NCT01766817
Simtuzumab	Lysyl-oxidase-like 2 (LOXL2) inhibitor	Gilead Sciences	NCT01769196
SAR156597	IL-4 and IL-13 inhibitor	Sanofi	NCT01529853
STX-100	Integrin αvβ6 inhibitor	Stromedix	NCT01371305
Sirolimus	Reduces the number of circulating fibrocytes	University of Virginia	NCT01462006

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