Restrictive Lung Disease Workup

• Intrinsic lung diseases

  • Routine laboratory evaluations often fail to reveal positive findings. However, anemia can indicate vasculitis, polycythemia can indicate hypoxemia in advanced disease, and leukocytosis can suggest acute hypersensitivity pneumonitis.
  • The decision to perform additional tests should be directed by the findings of the clinical assessment. Antinuclear antibodies and rheumatoid factor should be measured to screen for collagen vascular disorders, creatine kinase for polymyositis, antineutrophilic cytoplasmic antibodies for vasculitis, and antiglomerular basement membrane antibody for Goodpasture syndrome.
  • The presence of precipitating antibodies to an antigen may help in diagnosing hypersensitivity pneumonitis. Serum angiotensin-converting enzyme levels are often elevated in patients with sarcoidosis, but this finding has poor specificity.
• Extrinsic disorders: An elevated creatine kinase level may indicate myositis, which may cause muscle weakness and restrictive lung disease.

• Chest radiography for intrinsic lung disorders

  • The diagnosis of an interstitial lung disorder is often initially based on abnormal chest radiograph findings, which can be normal in as many as 10% of patients. All previous chest films should be reviewed.
  • The most common radiographic abnormality is a reticular pattern. Nodular, reticulonodular, or mixed patterns, such as alveolar filling (ie, ground-glass appearance), and increased interstitial markings are not unusual; however, these are not predictive of a specific pathological picture. High-resolution CT scanning can be helpful in such cases by providing an accurate assessment and is recommended before lung biopsy.^{[6, 7]}
  • Air-space opacities suggest pulmonary hemorrhage, eosinophilic pneumonia, and BOOP.
  • Upper-zone predominance on chest radiographs is observed in patients with sarcoidosis, histiocytosis X, chronic hypersensitivity pneumonitis, pneumoconiosis, or ankylosing spondylitis. Lower-zone predominance is seen in patients with idiopathic pulmonary fibrosis (IPF), asbestosis, or collagen-vascular diseases.
  • The finding of honeycombing correlates with advanced fibrosis and indicates a poor prognosis. Bilateral hilar lymphadenopathy, with or without mediastinal adenopathy, suggests sarcoidosis. See the images below. Chest radiograph of a 67-year-old man diagnosed with idiopathic pulmonary fibrosis, based on open lung biopsy findings. Extensive bilateral reticulonodular opacities are seen in both lower lobes. A chest radiograph of stage III sarcoidosis. This stage refers to pulmonary infiltrates without evidence of mediastinal lymphadenopathy. Chest radiograph from a 39-year-old woman with severe kyphoscoliosis who developed hypercapnic respiratory failure. Spirometry findings showed a severe restrictive lung disease, with a forced expiratory volume in one second of 0.4 L/s and a forced vital capacity of 0.5 L.
• CT scanning of the chest

  • High-resolution CT scanning of the chest can be helpful, but the expense and high dose of radiation makes it inappropriate for every patient.^[7] IPF can be diagnosed clinically based on the typical clinical features and CT scan findings without the need for lung biopsy.^{[8, 9]} Bibasilar peripheral lung zone involvement is seen in patients with IPF, asbestosis, connective-tissue disease, or eosinophilic pneumonia.
  • Central disease along bronchovascular bundles is indicative of sarcoidosis or lymphangitic carcinoma.
  • Upper-zone predominance is observed in patients with sarcoidosis, eosinophilic granuloma, or chronic hypersensitivity pneumonitis. Lower-zone predominance is seen in patients with IPF, asbestosis, or rheumatoid arthritis.
  • Lower-zone and peripheral infiltration is ordinarily seen in patients with IPF or asbestosis.
  • The presence of bilateral cysts and nodules, with preservation of lung volumes, may suggest a diagnosis of LAM or histiocytosis X.
  • Bibasilar reticular fibrosis with coexisting retraction bronchiectasis indicates end-stage irreversible disease, and ground-glass attenuation may result from changes in the interstitium, air spaces, or redistribution of capillary blood flow.^[10] See the images below. High-resolution CT scan of the same patient in the image below demonstrates peripheral honeycombing and several areas of ground-glass attenuation. Ground-glass opacification may correlate with active alveolitis and a favorable response to therapy. A CT scan image from a 59-year-old woman shows advanced pulmonary fibrosis. Extensive honeycombing and traction bronchiectasis are present. Restrictive lung disease may occur in stage II and stage III sarcoidosis. In this image, mediastinal lymphadenopathy is shown secondary to stage II disease. Sarcoidosis on CT scan shows nodules in midlung zones. These nodules are predominantly along the bronchovascular bundles and in a subpleural location. Restrictive lung disease secondary to sarcoidosis.
• Tests for extrinsic disorders

  • Evidence of nonmuscular diseases of the chest wall and associated deformities of the spinal column and ribs are readily appreciated on chest radiographs. The severity of kyphoscoliosis is determined by the Cobb angle, which, when greater than 100°, indicates severe deformity. Neuromuscular diseases are also diagnosed based on chest radiograph findings showing low volumes and basal atelectasis.
  • Fluoroscopy is used to assess for diaphragm paralysis.
  • A positive result from a sniff test may demonstrate paradoxical upward movement of the affected diaphragm.

• Pulmonary function testing

  • Complete lung function testing includes spirometry, lung volume, diffusing capacity, and arterial blood gas measurements. Pulmonary function test findings do not indicate a specific diagnosis or help distinguish alveolitis from fibrosis. Findings from sequential tests are invaluable for monitoring the course of the disease and assessing the response to therapy.
  • All disorders are associated with a restrictive defect with a reduction in TLC, FRC, and residual volume (RV).
  • While a reduction in the forced expiratory volume in one second (FEV₁) and the forced vital capacity (FVC) with a normal or increased FEV₁ -to-FVC ratio suggests a restrictive pattern, the diagnosis of restriction is based on a decreased TLC. The assessment of the severity of restriction is also based on TLC.
  • An obstructive airflow limitation may be observed in patients with sarcoidosis, LAM, hypersensitivity pneumonitis, and pulmonary fibrosis with concomitant chronic obstructive pulmonary disease. See the images below. Lung volume is plotted against transpulmonary pressure. Compliance is the change in volume for a given change in pressure. A patient with emphysema has much higher lung compliance compared to a patient with intrinsic lung disease. Idealized flow volume curves for normal, obstructive, and restrictive lungs. The expiratory flow volume curves of 2 patients are depicted graphically. A is a patient with restrictive lung disease (idiopathic pulmonary fibrosis), low forced vital capacity (FVC), but an increased ratio of forced expiratory volume in 1 second (FEV1) to FVC because of increased elastic recoil. B is a patient with chronic obstructive lung disease whose FEV1/FVC ratio is low but whose lung volumes are increased. Pulmonary function test results from a patient with restrictive lung disease.
• Tests for extrinsic lung disorders

  • In nonmuscular diseases of the chest wall, severe kyphoscoliosis produces a restrictive pattern. The TLC is markedly reduced, with relative preservation of the RV. The vital capacity is reduced, and the RV-to-TLC ratio is elevated. Chest wall components are reduced, and inspiratory muscle weakness may also contribute to the restrictive process. Maximal inspiratory and expiratory pressures are modestly decreased in patients with mild disease but are severely reduced in patients with advanced disease.
  • Hypoxemia is due to a ventilation-perfusion mismatch caused by the underlying atelectasis and shunt.
  • In neuromuscular diseases, the maximal inspiratory and expiratory mouth pressures vary from normal to severely reduced. When maximal inspiratory pressure falls below 30 cm of water, ventilatory failure commonly ensues.
  • Patients with chronic muscular diseases have a decreased vital capacity and FRC, but the RV is preserved. TLC is also moderately reduced. Breathing during sleep is often abnormal in these patients. They have nocturnal desaturation during rapid eye movement sleep, secondary to hypoventilation.
  • The diffusing capacity of lung for carbon monoxide (DLCO) is reduced in all patients with intrinsic lung disorders, and the severity of the reduction does not correlate well with the stage of the disease. The DLCO is the most sensitive parameter, and findings may be abnormal even when the lung volumes are preserved. A normal DLCO value excludes intrinsic lung disease and indicates a chest wall, pleural, or neuromuscular cause of restrictive lung disease.
  • Arterial blood gas values at rest may reveal hypoxemia. Arterial oxygen desaturation occurs with exercise, along with an excessive increase in the respiratory rate and a high ratio of dead-space gas volume to tidal gas volume.
  • Cardiopulmonary exercise testing with measurements of gas exchange and oxygenation is more sensitive, and findings correlate better with lung biopsy but do not help predict the prognosis. A 6-minute walk test with oximetry provides a measure of oxygen requirement and a quantifiable measure of disease progression.

• Bronchoalveolar lavage

  • In selected cases, bronchoalveolar lavage (BAL) cellular analysis may be helpful to narrow the differential diagnosis. However, the utility of BAL in the clinical assessment and management of interstitial lung diseases remains to be established.
  • Performing BAL lymphocytosis in patients with IPF may help predict steroid responsiveness. A predominance of T lymphocytes with an elevated CD4-to-CD8 ratio is characteristic but not diagnostic of sarcoidosis.
  • BAL fluid may contain malignant cells, asbestos bodies, eosinophils, and hemosiderin macrophages, which assist in making a diagnosis.
• Lung biopsy

  • A lung biopsy is not always required to make a diagnosis in patients suggested to have interstitial lung diseases. A lung biopsy can provide information that may help lead to a specific diagnosis, help assess for disease activity, exclude neoplastic and infectious processes, establish a definitive diagnosis, and predict the prognosis. Open lung biopsy can be as valuable in selected patients^[11] as high-resolution CT scanning, and the American Thoracic Society/European Respiratory Society (ATS/ERS) clinical criteria may misdiagnose patients with interstitial lung disease.^[12]
  • Fiberoptic bronchoscopy with transbronchial lung biopsy is often the initial procedure of choice, especially when sarcoidosis, lymphangitic carcinomatosis, eosinophilic pneumonia, Goodpasture syndrome, histiocytosis X, hypersensitivity pneumonitis, or infection is suggested based on clinical evidence.
• Surgical lung biopsy

  • Video-assisted thoracoscopic lung biopsy is the preferred method for obtaining lung tissue samples for analysis.
  • Histologic patterns may be helpful in narrowing the differential diagnosis.^[13] Honeycombing is seen in end-stage disease, in which the original disease process often cannot be differentiated. See the image below. Intrinsic lung disease may progress to extensive fibrosis, regardless of etiology. This is described as honeycomb lung.
  • The common histologic patterns include interstitial pneumonitis (ie, IPF). Subpleural and paraseptal inflammation is present, with an appearance of temporal heterogeneity. Patchy scarring of the lung parenchyma and normal, or nearly normal, alveoli interspersed between fibrotic areas is the hallmark of this disease. Also, the lung architecture is completely destroyed.
  • Desquamative interstitial pneumonitis is characterized by diffuse and temporally uniform involvement of the lung parenchyma. The alveoli are filled with macrophages and hyperplastic type II pneumocytes.
  • BOOP (also called proliferative bronchiolitis) is often patchy and peribronchiolar. The proliferation of granulation tissue within small airways and alveolar ducts is excessive and is associated with chronic inflammation of surrounding alveoli.
  • Diffuse alveolar damage is marked by a nonspecific reaction with diffuse temporally uniform involvement and marked thickening of the alveolar septa; inflammatory cell infiltration and type II cell hyperplasia and fibroblast proliferation are present.
  • For acute interstitial pneumonia, the pathological appearance is identical to that of diffuse alveolar damage.
  • In eosinophilic pneumonia, the eosinophils and macrophages are the predominant alveolar inflammatory cells, and they also extend into the interstitium.
  • Lymphocytic interstitial pneumonitis marked by a lymphoid infiltrate that involves both the interstitium and alveolar spaces is the prominent finding.
  • In nonspecific interstitial pneumonia, the lesions are characterized by a relatively uniform appearance consisting of mononuclear interstitial infiltrates associated with varying degrees of interstitial fibrosis.
  • Granulomatous lung diseases are marked by granulomas characterized by the accumulation of T lymphocytes, macrophages, and epithelioid cells. These may progress to pulmonary fibrosis.

The histological findings of various interstitial pneumonias include an interstitial cellular infiltrate and interstitial fibrosis, eventually leading to an end-stage honeycomb lung. These findings are described in detail in Procedures.

Table. Contrasting Clinical, Radiologic, and Histologic Features of Acute Interstitial Pneumonia (AIP), Usual Interstitial Pneumonia (UIP), Nonspecific Interstitial Pneumonia (NSIP),^[14] and BOOP^[15] (Open Table in a new window)

See the images below.