Considering the impact of environmental inhalational exposures, pneumoconioses, and drug-induced pulmonary reactions in the pathogenesis of restrictive lung diseases, a comprehensive medical history with a special focus on the patient's environmental and occupational history is important. So too is an evaluation of all the patient's current medications and their duration of use. Likewise, determining the tempo of progression of respiratory symptoms is helpful with respect to differential diagnostic considerations. For example, alveolar hemorrhage syndromes are likely to present in an acute manner, whereas IPF or sarcoidosis typically evolve more chronically.
By themselves, laboratory tests are of limited utility in establishing a diagnosis of ILD. Results must be integrated with clinical findings, thoracic imaging studies, and histopathological results when available. Nonetheless, focused testing can be useful in narrowing the differential diagnosis in the appropriate setting. For example, peripheral blood eosinophilia may be an important clue to the presence of an underlying eosinophilic lung disorder or drug-induced pulmonary reaction. Serological blood testing for specific connective tissue disorders such as rheumatoid arthritis and SLE is similarly helpful, whereas anti-neutrophil cystoplasmic antibody (ANCA) studies to diagnose Wegener's granulomatosis and microscopic polyangiitis, respectively, and anti-glomerular basement membrane antibody determination to diagnose Goodpasture's syndrome assist in pinpointing the cause of alveolar hemorrhage syndromes.
The classic findings of ILD are a restrictive ventilatory pattern and a decrease in the DLCO (Chap. 16). This restrictive ventilatory limitation is characterized by a dual reduction in the FEV1 and FVC with a correspondingly normal or elevated FEV1/FVC ratio. In this setting, a total lung capacity (TLC) finding ≤80% of predicted values confirms the diagnosis of restrictive lung disease. Whereas the presence of ILD is consistent with a reduction in both the TLC and the DLCO, chest wall and neuromuscular disorders are generally associated with a reduced TLC but a normal DLCO.
Arterial blood gases and specifically the Pao2 or Sao2 may be normal at rest in patients with ILD. However, respiratory alkalosis with hypocapnia and mild-to-moderate arterial hypoxemia and widening of the (A – a) Po2 gradient develop with progressive disease. In patients who have normal gas exchange at rest, cardiopulmonary exercise tests are especially useful in unmasking gas exchange abnormalities, principally exertional O2 deoxygenation by oximetry. Exercise physiology studies may further reveal an elevation in the VD/VT, a widened (A – a) Po2 gradient, and arterial hypoxemia in conjunction with progressive tachypnea.
One of the main features of ILD is an abnormal chest radiograph showing reticular, nodular, or reticulonodular opacities. Notably, the differential diagnosis should include ILD when individuals with dyspnea, cough, and an abnormal chest radiograph who are suspected of having infectious pneumonia do not respond to empiric antimicrobial therapy. However, the standard chest radiograph may appear normal in up to 10% of patients with symptomatic ILD. Thus HRCT is the imaging modality of choice in patients with suspected ILD, since it will reveal abnormalities in all patients with symptomatic ILD. These would include reticular opacities as well as honeycombing consistent with pulmonary fibrosis, and architectural distortion with traction bronchiectasis.
CLINICAL CORRELATION 24.3
The geographic regional distribution and type of radiographic abnormalities on chest imaging studies yield useful clues for diagnosis of specific forms of ILD. Thus, predominant abnormal radiographical involvement of the mid-upper lung zones should raise the possibility of sarcoidosis, pulmonary Langerhans' cell histiocytosis, silicosis, and hypersensitivity pneumonitis. In contrast, IPF usually presents with pleural-based reticular infiltrates in the lung bases. Intrathoracic lymphadenopathy is frequently encountered in patients with sarcoidosis, lymphangitic spread of lung cancer, lymphocytic interstitial pneumonia, berylliosis, and amyloidosis. Spontaneous pneumothorax associated with a cystic ILD suggests underlying LAM (Fig. 24.9) and pulmonary Langerhans' cell histiocytosis (Fig. 24.10).
Chest CT scan in a patient with lymphangioleiomyomatosis demonstrating multiple parenchymal lung cysts and a left pneumothorax.
Chest CT scan of a patient with pulmonary Langerhans' cell histiocytosis demonstrating the combination of upper lung zone parenchymal lung cysts and nodular interstitial opacities.
Fiberoptic bronchoscopy with BAL is useful in the diagnostic evaluation of several forms of restrictive lung diseases, most notably to confirm diffuse alveolar hemorrhage syndromes and eosinophilic pneumonia. It also is valuable in excluding pulmonary infections associated with diffuse infiltrates such as Pneumocystis jiroveci pneumonia. Bronchoscopy with transbronchial lung biopsy is also simpler and safer than surgical lung biopsy in selected patients suspected of having infections, and for granulomatous disorders such as sarcoidosis and berylliosis, and lymphangitic spread of lung cancer (Chap. 18). In contrast, transbronchial lung biopsy is not useful in establishing a diagnosis or discriminating among different types of idiopathic interstitial pneumonia, including IPF, because of the technique's limitations of lung sample size.
Surgical lung biopsy is a key diagnostic modality in patients with ILD and is the procedure of choice in establishing a diagnosis in patients with ILD secondary to suspected idiopathic interstitial pneumonia. The location of the surgical lung biopsy is guided by the distribution of disease on HRCT images. The larger lung specimens afforded by this technique are ideally obtained for pathological analysis from a region that is radiographically normal, as well as from an area with mild-to-moderate disease. Video-assisted thoracoscopic surgery (VATS) biopsy causes less morbidity than open thoracotomy and is better tolerated (Chap. 18). In certain instances of idiopathic interstitial pneumonia suspected of being IPF, a confident clinical diagnosis may be made without subjecting the patient to surgical lung biopsy, when both clinical findings and the HRCT features are supportive (Table 24.5). All major criteria and at least three minor criteria must be present to increase the likelihood of a correct IPF diagnosis.
Table 24.5Diagnostic criteria for IPF in the absence of a surgical lung biopsy ||Download (.pdf) Table 24.5 Diagnostic criteria for IPF in the absence of a surgical lung biopsy
|Major Criteria ||Minor Criteria |
|Exclusion of other known causes of ILD ||Age >50 years |
|PFT results showing restriction and impaired gas exchange ||Onset of otherwise unexplained dyspnea on exertion |
|Bibasilar reticular abnormalities with minimal ground glass opacities on HRCT scan ||Duration of illness >3 months |
|Transbronchial lung biopsy or BAL do not support alternative diagnosis ||Bibasilar inspiratory Velcro-like crackles |
Considering the diversity of restrictive lung diseases, treatment depends on the cause. For most restrictive disorders, mechanism-specific therapy is not available. With respect to the idiopathic interstitial pneumonias and IPF in particular, there is insufficient evidence-based support for any specific treatment to improve survival or the quality of life. Selected patients with IPF of mild-to-moderate severity receive combination therapy with corticosteroids, immunosuppressive drugs typified by azathioprine, and N-acetylcysteine. However, this approach is based on expert opinion rather than clinical trials. Since pharmacological therapy may be toxic, potential benefits may be outweighed by increased risk of treatment-related complications. This is especially likely to occur in patients >70 years of age, subjects with morbid obesity, or those having comorbidities such as cardiac disease, diabetes mellitus, osteoporosis, and end-stage honeycomb fibrotic changes that are unlikely to be reversed by any drug treatment.
It is best to enroll patients with IPF in ongoing clinical studies so that beneficial pharmacological therapy will be developed. Patients with IPF should be encouraged to enroll in a pulmonary rehabilitation program to avoid deconditioning. Severe hypoxemia (Pao2 <55 mm Hg at rest or during exercise) is managed by providing supplemental O2 therapy. Antitussive agents assist in controlling cough and avoiding complications such as rib fractures in the elderly.
Concerning other idiopathic interstitial pneumonias, the cellular form of NSIP has an excellent prognosis compared to the fibrotic subtype NSIP. In contrast to IPF, the response to steroids in cellular NSIP is good with an overall 5-year survival >80%. In the smoking-related idiopathic interstitial pneumonias (RB-ILD and DIP), the prognosis is generally good although complete recovery requires smoking cessation. Acute interstitial pneumonia has a high mortality rate, but remission is possible with high-dose corticosteroids; however, supportive data are limited. Cryptogenic organizing pneumonia (COP) shows excellent response to corticosteroid therapy.
Anti-inflammatory corticosteroid therapy occasionally combined with immunosuppressive therapy is similarly utilized in other forms of ILD with varying results, including sarcoidosis, connective tissue diseases, eosinophilic lung disorders, hypersensitivity pneumonitis, pulmonary vasculitides, alveolar hemorrhage syndromes, and drug-induced pulmonary disease. In sarcoidosis, therapy with the corticosteroid prednisone depends on a firm diagnosis of the disease with supportive clinical features, chest radiographic evidence, and noncaseating granulomas on lung biopsy with all other causes of granulomas ruled out. Initial treatment for pulmonary sarcoidosis with 20-40 mg of prednisone per day is generally begun for dyspnea, cough, and wheezing in conjunction with reductions in the FEV1 and FVC <70% of predicted values. Steroid-sparing agents including hydroxychloroquine, methotrexate, and tumor necrosis factor-α antagonists such as infliximab are also utilized in selected instances depending on disease severity and pattern of organ involvement. Pharmacological therapy is not employed in patients with pneumoconiosis.
Transplantation is considered for patients with ILD exhibiting progressive physiological deterioration who meet established criteria. Current criteria for referral of patients for single lung transplantation are age <70 years, histological or radiographic evidence of UIP, and any of the following: DLCO <39% predicted, 10% or greater decrement in the FVC during 6 months of follow-up, a decrease in pulse oximetry to <88% during a 6-MWT, and honeycombing on HRCT scan.