Chapter 46 Approach to Diagnosis of Diffuse Lung Disease

The term diffuse lung disease (DLD) includes infiltrative lung processes that involve the alveolar spaces or lung interstitium. This definition is fundamentally unsatisfactory because it groups together a variety of diverse disorders, some of which, such as cryptogenic organizing pneumonia, are not actually “diffuse,” but rather patchy and sometimes limited in extent. Furthermore, many secondary infiltrative abnormalities, including bacterial infection and malignancy, are excluded, whereas others, such as pulmonary involvement in connective tissue disease (CTD), are retained in most DLD classifications. The DLDs are grouped for historical reasons; in early series, DLDs presented most frequently with widespread clinical and chest radiographic abnormalities. However, with increasing clinician awareness of possible DLD, the diagnosis is often made when chest radiographic findings are limited, or disease is apparent only on high-resolution computed tomography (HRCT).

The diagnostic difficulties resulting from the multiple disorders within the DLDs are exacerbated by semantic confusion. Synonymous terms abound for some of the more frequently encountered DLDs, such as the following:

• Cryptogenic organizing pneumonia (bronchiolitis obliterans organizing pneumonia, proliferative bronchiolitis)

• Idiopathic pulmonary fibrosis (cryptogenic fibrosing alveolitis)

• Hypersensitivity pneumonitis (extrinsic allergic alveolitis)

This problem has been partially addressed by the reclassification of the idiopathic interstitial pneumonias by a joint American Thoracic Society/European Respiratory Society (ATS/ERS) international consensus committee, discussed in detail in Chapter 47. However, the term cryptogenic fibrosing alveolitis (CFA) continues to cause difficulties. As defined in the ATS/ERS reclassification, CFA is strictly synonymous with idiopathic pulmonary fibrosis (IPF). The diagnosis of IPF/CFA now requires the presence of usual interstitial pneumonia (UIP) at surgical biopsy or typical appearances on HRCT, in association with a compatible clinical picture. This represents a radical change; in historical series, various disorders presenting with a clinical picture of IPF were grouped together as IPF/CFA. The entity of “clinical CFA syndrome” is still necessary for epidemiologic studies but should not be viewed as a final diagnosis in clinical practice.

In routine practice, a simplified pragmatic approach to diagnosis of DLD is essential; consideration of a checklist of the more common diseases is often useful. The classification of DLD by their disease burden was addressed most definitively in a study from Bernalillo County, New Mexico, in which the incidence and prevalence of individual DLDs was quantified using a variety of methods (Table 46-1). New cases were estimated to occur in 32 : 100,000 years in males and 26 : 100,000 years in females; thus, although less common than lung infection, malignant disease or obstructive airways disease, the DLDs are responsible for a considerable disease burden. More recent evidence shows an increase in the prevalence of DLD, especially IPF, which inevitably means that the burden of disease has increased further in the previous one to two decades. Moreover, the workload for the respiratory medicine physician is disproportionate because the diagnosis of individual DLDs is often uncertain, despite more intensive investigation than is generally required in obstructive airways disease, malignancy, or chronic lung suppuration.

Table 46-1 Prevalence and Incidence of Interstitial Lung Diseases in Bernalillo County, New Mexico

A consideration of the differential diagnosis of DLD, based on prevalence alone, is merely a starting point, for two reasons. First, clinical information at initial evaluation profoundly alters diagnostic probabilities; therefore a longer checklist of the DLDs, based on the possible underlying cause, is indispensable. Second, the length to which a specific diagnosis is pursued, with particular reference to surgical biopsy, is critically dependent on the importance of discriminating between likely differential diagnoses in individual cases. This crucial point is discussed in detail in the concluding section of this chapter.

Initial Clinical Evaluation

Even before chest radiography and HRCT findings are considered, a wealth of diagnostic information can be obtained from initial evaluation. A possible underlying cause is often apparent, although environmental and drug exposures occurring many years earlier and apparently limited exposures are often difficult to interpret in isolation. Much information can often be obtained on the longitudinal behavior of disease from the evolution of symptoms, serial chest radiographic data, and less frequently, serial spirometric volumes. Associated systemic disease and prominent airway-centered symptoms both provide useful diagnostic clues. Less frequently, physical examination may serve to broaden the differential diagnosis. In addition to chest radiography and HRCT, certain noninvasive ancillary tests should be performed in select patients, including autoimmune serology, measurement of precipitins, and echocardiography.

Clinical History

The identification of an underlying cause is the single most important contribution made by clinical evaluation. Table 46-2 provides a checklist of the more important causes of DLD. A careful occupational history is essential and should include details of all previous occupations, including short-term employment. Asbestos exposure is often extensive in railway rolling-stock construction, shipyard workers, power station construction and maintenance workers, naval boilermen, garage workers (involved in brake lining), and other occupations in which asbestos exposure is overt; generally, workers in these occupations are well aware of their asbestos exposure. However, other workers, including joiners, electricians, carpenters, and construction workers, who handle asbestos in the form of roofing and insulation material, are often unaware of significant exposure. Other occupations associated with DLD include coal mining (coal worker’s pneumoconiosis), metal polishing (hard metal disease), and sandblasting (silicosis).

Table 46-2 Frequently Encountered Diffuse Lung Diseases with Identifiable Underlying Cause

Cause	Differential Diagnosis
Occupational-related or other inhalant–related
Inorganic	Aluminum oxide fibrosis Asbestosis Baritosis (barium) Berylliosis Coal worker’s pneumoconiosis Metal polisher’s lung/hard metal fibrosis Siderosis (iron oxide) Silicosis Stannosis Talc pneumoconiosis
Organic	Bird breeder’s (fancier’s) lung Bagassosis (sugar cane) Coffee worker’s lung Farmer’s (harvester’s) lung Fishmeal worker’s lung Malt worker’s lung Maple bark stripper’s lung Pituitary snuff-taker’s lung Mushroom worker’s lung Tea grower’s lung Tobacco grower’s lung
Collagen vascular disease–related	Ankylosing spondylitis Behçet syndrome Dermatomyositis Goodpasture syndrome Mixed connective tissue disease Polymyositis Primary Sjögren syndrome Rheumatoid arthritis Scleroderma Systemic lupus erythematosus
Drug-related	Amiodarone Azathioprine Bleomycin Bromocryptine Busulfan Carmustine Cephalosporins
	Chlorambucil Cyclophosphamide Cytarabine Gold Lomustine Melphalan Methotrexate Mitomycin Nitrofurantoin Penicillamine Phenytoin Propranolol Sulfasalazine Tocainide
Physical agents/toxins	Cocaine inhalation High-concentration oxygen Intravenous drug use Paraquat toxicity Radiation/radiotherapy
Neoplastic disease	Bronchoalveolar cell carcinoma Lymphangitis carcinomatosis
Vasculitis-related	Churg–Strauss syndrome Giant cell arteritis Wegener granulomatosis
Disorders of circulation	Pulmonary edema Pulmonary venoocclusive disease
Chronic infection	Aspergillosis Histoplasmosis Tuberculosis Parasites, viruses
Smoking-induced	Alveolar cell carcinoma Desquamative interstitial pneumonia Emphysema Langerhans cell histiocytosis Nonspecific interstitial pneumonia Respiratory bronchiolitis (alone and with interstitial lung disease)