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:
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.
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.
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.
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).
|Occupational-related or other inhalant–related|
|Collagen vascular disease–related|
|Disorders of circulation|
A careful history will also disclose exposure to organic antigens known to cause hypersensitivity pneumonitis. The two most prevalent forms of hypersensitivity pneumonitis are farmer’s (harvester’s, thresher’s) lung disease, in which the offending antigen, thermophilic actinomycetes (Thermoactinomyces vulgaris) is contained within moldy hay, and pigeon (bird) breeder’s lung disease (bird fancier’s lung), in which avian proteins are inhaled by those breeding birds, or more often, those who keep birds as domestic pets. However, a wide range of other exposures also cause hypersensitivity pneumonitis, and particular attention should be paid to molds (often arising in sites of water damage); bathroom molds (as in “basement shower syndrome” and “hot-tub lung” are easily overlooked. Hobbies should also be considered (e.g., cheese-maker’s lung, winemaker’s lung). There are now more than 100 known causes of hypersensitivity pneumonitis, and an up-to-date list (e.g., see Bertorelli et al.) of the 50 more frequent causes of hypersensitivity pneumonitis is highly useful.
A detailed drug history is also essential. The drugs most frequently causing DLD are probably amiodarone, methotrexate (at doses used in CTD), and antineoplastic agents, especially bleomycin. However, a wide variety of other agents (>200 at present) cause DLD, although often in only a small number of patients, and the list increases yearly. Fortunately, an international website is now devoted to drug-induced lung disease (www.pneumotox.com), through which all medications should be routinely checked in patients with DLD.
Other therapeutic modalities causing DLD include radiotherapy and exposure to high concentrations of oxygen (especially in those previously receiving bleomycin). Paraquat ingestion (causing acute or delayed proliferative bronchiolitis), inhalation of crack cocaine or heroin (causing eosinophilic pneumonia, diffuse alveolar hemorrhage, organizing pneumonia or pulmonary edema), and intravenous drug use (causing venoocclusive disease) are also relevant.
Smoking-related DLD is increasingly diagnosed; diseases other than chronic obstructive pulmonary disease caused by smoking include Langerhans cell histiocytosis, respiratory bronchiolitis associated with interstitial lung disease (RBILD), desquamative interstitial pneumonia, and nonspecific interstitial pneumonia. Recently, HRCT evaluation has shown that all these processes may coexist in the same patient. Further, both sarcoidosis and hypersensitivity pneumonitis are rare in current smokers. Because RBILD and hypersensitivity pneumonitis often have overlapping clinical and HRCT features, the smoking history is an important discriminator between these two disorders.
Information on likely longitudinal behavior often helps distinguish between acute and chronic disease, because acute infection, heart failure, and disseminated malignancy may all simulate DLD clinically and radiologically. The duration of dyspnea and cough, pattern of symptomatic progression, and previous responsiveness (or nonresponsiveness) to corticosteroid therapy may provide valuable diagnostic clues. Variable dyspnea and cough over several years, responding to steroid therapy, is compatible with hypersensitivity pneumonitis or sarcoidosis, whereas inexorably progressive dyspnea for 2 to 3 years, not responding to steroid therapy, is typical of IPF. Previous chest radiographs may be useful, with unchanging appearances over many years a frequent finding in sarcoidosis, but not in IPF. Previous full pulmonary function tests are seldom available, but serial spirometry may be performed in general practice, because asthma is often suspected when the first symptoms of DLD occur. Thus, useful conclusions may be drawn from the rapidity of decline, or conversely the duration of stability, of spirometric volumes.
Relevant systemic diseases associated with DLD include malignancy (lymphangitis carcinomatosis or multiple metastases) and CTDs complicated by DLD, especially rheumatoid arthritis, systemic sclerosis, systemic lupus erythematosus (SLE), polymyositis or dermatomyositis, and Sjögren syndrome. Lung disease may precede systemic manifestations in all the CTDs (most frequently in polymyositis/dermatomyositis) or may develop concurrently with systemic manifestations. Thus, a full history should include details of arthritis/arthralgia, myositis, skin disorders, Raynaud’s phenomenon, and dryness of the eyes or mouth. A subgroup of patients with autoimmune disease who fail to meet formal criteria for an individual disorder are considered to have “undifferentiated connective tissue disease” but may nonetheless develop DLD.
Airway-centered symptoms may help to refine the differential diagnosis. Cough occurs frequently in IPF, but prominent wheeze is more suggestive of hypersensitivity pneumonitis or, less frequently, sarcoidosis. Wheezing is also an important feature of some of the pulmonary vasculitides, especially Churg-Strauss syndrome and occasionally Wegener granulomatosis. Hemoptysis is the most frequent pulmonary symptom at presentation in Goodpasture syndrome; however, the volume is not a good guide to disease severity, because hemoptysis may be trivial or even absent, despite considerable alveolar hemorrhage.
Physical examination tends to be less fruitful than the history and HRCT findings in refining the differential diagnosis of DLD. Bilateral predominantly basal crackles on auscultation are a defining feature of IPF and are also common in other forms of idiopathic interstitial pneumonia and asbestosis, but seldom present in sarcoidosis. Digital clubbing is a useful sign strongly indicating IPF or asbestosis; clubbing is rare in sarcoidosis, hypersensitivity pneumonitis, or pulmonary fibrosis associated with connective tissue (except possibly rheumatoid arthritis). However, no diagnostic conclusions can be drawn from the absence of clubbing. Mid- to late-inspiratory “squawks,” an underrecognized sign, are strongly indicative of an underlying bronchiolitic disorder, including hypersensitivity pneumonitis, in which the bronchiolitic component may be prominent. Central cyanosis, tachypnea, and pulmonary hypertension are nonspecific findings in end-stage DLD. When pulmonary hypertension is associated with limited DLD, underlying CTD, especially systemic sclerosis and SLE, should be suspected.
In most cases, specific diagnostic tests for DLD are confined to autoimmune serology and precipitins against organic antigens. Serologic evidence of rheumatoid arthritis and the other major CTDs should be sought in any patient with apparently idiopathic DLD in whom the diagnosis is uncertain. This is particularly important when the diagnosis appears to be cryptogenic organizing pneumonia, because underlying connective disease is common; when present, prognosis is not always good, and prolonged treatment may be required. In the antisynthetase syndrome, characterized by Jo1 antibody positivity, polymyositis or dermatomyositis, and progressive pulmonary fibrosis, lung disease often precedes systemic manifestations. However, although antibodies to extractable nuclear antigens tend to be disease specific, levels of antinuclear antibodies and rheumatoid factor are often moderately increased in idiopathic pulmonary fibrosis and are less useful diagnostically unless titers are greatly elevated.
The presence of precipitins to organic antigens increases the likelihood of hypersensitivity pneumonitis but should never be considered diagnostic in isolation. Positive precipitins denote exposure to an antigen, with immune recognition, but alone are not indicative of clinically significant DLD; pigeon and other bird breeders often have avian precipitin positivity without overt lung disease. Moreover, in many patients with convincing exposure histories and a histologic diagnosis of hypersensitivity pneumonitis, the appropriate precipitins are not present; avian antigens, for example, vary between bird species and even between individual birds.
Most DLDs are characterized by a restrictive ventilatory defect, a reduction in gas transfer, and variable hypoxia at rest or on exercise. A purely obstructive defect is often present in Langerhans cell histiocytosis and lymphangioleiomyomatosis and is sometimes a feature of fibrotic pulmonary sarcoidosis. A mixed ventilatory defect, which usually denotes an airway-centered component, is often present in hypersensitivity pneumonitis, sarcoidosis, and CTD (in which bronchiolitis or bronchiectasis may coexist with pulmonary fibrosis). Paradoxically, normal lung volumes in association with severe reduction in gas transfer levels are the hallmark of the combination of emphysema and pulmonary fibrosis. The often-cited phenomenon of a marked increase in gas transfer (measured using single-breath techniques) caused by diffuse alveolar hemorrhage is rarely clinically useful because this abnormality persists for only 36 hours after hemorrhage.
The most diagnostically useful pulmonary function pattern is preservation of gas transfer in association with irreversible airflow obstruction, a combination that points strongly toward intrinsic airways disease (i.e. bronchiolitis) rather than emphysema. However, the pattern of pulmonary function impairment seldom makes a major diagnostic contribution.
With recent attention focused on the diagnostic value of HRCT, it is often forgotten that the plain chest x-ray film provides invaluable information in diffuse lung disease. The chest radiograph points strongly toward a specific diagnosis in some patients. Sarcoidosis, the most prevalent DLD encountered in clinical practice, can be diagnosed with confidence from the clinical and chest radiographic features at presentation in many patients. HRCT seldom adds useful diagnostic information in this context.
Several radiographic features have useful positive predictive values (PPVs). The presence of hilar lymphadenopathy on chest radiography is particularly strongly predictive of sarcoidosis in the correct clinical context, although the radiographic differential diagnosis includes tuberculosis and malignancy, especially when hilar lymphadenopathy is asymmetric. Pleural effusions