Objectives

1. To understand the current guidelines for the classification of interstitial lung diseases.
2. To recite key historical factors in the evaluation of a patient with suspected interstitial lung disease.
3. To understand the role of high-resolution CT in the evaluation of a patient with suspected interstitial lung disease.
4. To understand the role of bronchoscopy and surgical lung biopsy in the evaluation of a patient with suspected interstitial lung disease.
5. To understand how historical features, radiographic features, and biopsy findings influence prognosis for patients with interstitial lung disease.

Abbreviations

AIP = acute interstitial pneumonia; ATS = American Thoracic Society; BOOP = bronchiolitis obliterans organizing pneumonia; CXR = chest radiograph; DIP = desquamative interstitial pneumonia; Dlco = carbon monoxide diffusing capacity of the lung; DPLD = diffuse parenchymal lung disease; ERS = European Respiratory Society; HP = hypersensitivity pneumonitis; IIP = idiopathic interstitial pneumonia; ILD = interstitial lung disease; IPF = idiopathic pulmonary fibrosis; LIP = lymphocytic interstitial pneumonia; NSIP = nonspecific interstitial pneumonia; OR = odds ratio; CI = confidence interval; RBILD = respiratory bronchiolitis interstitial lung disease; SLB = surgical lung biopsy; UIP = usual interstitial pneumonia; VC = vital capacity

Interstitial lung diseases (ILDs) are a diverse group of disorders involving the distal lung parenchyma. Although more than 200 diseases can result in interstitial involvement, the resulting clinical, physiologic, and radiographic manifestations are often similar. This can lead to confusion and frustration for the physician confronted by a patient with ILD. This lesson reviews the latest data and proposes an approach for the initial evaluation of such a patient.

Suspicion of ILD

Patients with ILDs typically present with dyspnea and/or cough. Unfortunately, as symptoms are often subtle, nonspecific, and slowly progressive, it is common for patients to realize the true duration of symptoms only in retrospect. Furthermore, some patients are without symptoms and are identified through abnormal findings on radiographs or pulmonary function studies. As such, the physician needs to maintain a suspicion of ILD to facilitate appropriate and early diagnostic testing. Maintaining a suspicion for ILD is perhaps even more critical for patients at risk of developing ILDs from environmental exposures (inhaled allergens, dusts, drugs) or concomitant systemic illnesses (such as collagen vascular disease).

Etiology

The incidence of ILD has been estimated at 31.5 per 100,000 men and 26.1 per 100,000 women. ¹ In general the pathogenesis is thought to center around injury to the lung followed by attempts to heal the injury. ² Whether this injury represents an ongoing event, a series of multiple events, or an abnormal response to an event that is no longer present remains unclear. Unfortunately, the etiology often remains elusive, with the most common type of ILD being idiopathic pulmonary fibrosis (IPF). ¹ An abbreviated list of causes of ILD is presented in Table 1.

Table 1. Potential Causes/Categories of Interstitial Lung Disease

Classification of ILD

Interstitial lung diseases, also termed diffuse parenchymal lung diseases (DPLDs), are a group of disorders that involve the space between the epithelial and endothelial basement membranes. ³ Recent guidelines for the classification of DPLD recommended the utilization of four categories: (1) DPLD of known cause (such as drugs, associated with a collagen vascular disease, environmental exposure, etc.); (2) granulomatous DPLD (such as sarcoidosis); (3) rare DPLD with well-defined clinicopathologic features (such as lymphangioleiomyomatosis, pulmonary Langerhans cell histiocytosis, pulmonary alveolar proteinosis, and eosinophilic pneumonia); and (4) the idiopathic interstitial pneumonias (IIPs). ³ The IIPs are further subdivided into usual interstitial pneumonia/idiopathic pulmonary fibrosis (UIP/IPF), desquamative interstitial pneumonia (DIP), respiratory bronchiolitis interstitial lung disease (RBILD), acute interstitial pneumonia (AIP), cryptogenic organizing pneumonia, nonspecific interstitial pneumonia (NSIP), and lymphocytic interstitial pneumonia (LIP) ³ (Fig 1).

Figure 1. ATS/ERS algorithm for diffuse parenchymal lung diseases. Diffuse parenchymal lung diseases (DPLDs) consist of disorders of known causes (collagen vascular disease, environmental, or drug-related) as well as disorders of unknown cause. The latter include idiopathic interstitial pneumonias (IIPs), granulomatous lung disorders ( eg , sarcoidosis), and other forms of interstitial lung disease (ILD) including lymphangioleiomyomatosis (LAM), pulmonary Langerhans cell histiocytosis/histiocytosis X (HX), and eosinophilic pneumonia. The most important distinction among the IIPs is that between idiopathic pulmonary fibrosis and the other interstitial pneumonias, which include nonspecific interstitial pneumonia (NSIP) (a provisional term), desquamative interstitial pneumonia (DIP), respiratory bronchiolitis-associated interstitial lung disease (RB-ILD), acute interstitial pneumonia (AIP), cryptogenic organizing pneumonia, bronchiolitis obliterans organizing pneumonia (BOOP), and lymphocytic interstitial pneumonia (LIP).

General Diagnostic Approach

The general approach to a patient with suspected ILD is to identify the most likely diagnosis in an expeditious fashion. It is also important to identify UIP/IPF given its particularly ominous prognosis. The American Thoracic Society (ATS) and European Respiratory Society (ERS) recommend an integrated clinical, radiologic, and pathologic approach to the diagnosis of DPLDs.³ This suggested integrated approach includes a comprehensive assessment of clinical history, physical examination findings, selected laboratory studies, imaging studies, and, in selected patients, transbronchial or surgical lung biopsy (SLB) (Fig 2).

Clinical History

General Characteristics

A careful history is required in the initial evaluation of patients with suspected ILD. Important features include sex, age, comorbidities, drug exposures, and assessment of living and work conditions. Age is important as some ILDs are more common in younger individuals (sarcoidosis, eosinophilic granuloma, familial idiopathic pulmonary fibrosis, and Gaucher's disease), while others are more common in older patients (IPF). Similarly, sex may affect predisposition to certain types of ILD or influence the clinical course of others. For example, lymphangioleiomyomatosis and pulmonary involvement in tuberous sclerosis are predominantly seen in premenopausal female patients, and women with IPF have an improved prognosis compared with men.4 The presence of a collagen vascular illness should heighten the suspicion of ILD, as many collagen vascular diseases are associated with pulmonary parenchymal involvement.⁵ Careful assessment of a patient's home and work environment can sometimes uncover exposures associated with ILDs (see below). Finally, risk factors for HIV infection should be identified, as infectious and noninfectious ILDs can be seen in this patient population.⁶

Symptoms

Although patients with ILD typically present with cough and dyspnea, other unusual chest symptoms may provide clues to the etiology of an ILD. For example, hemoptysis may be noted in patients with alveolar hemorrhage syndromes, pulmonary vascular diseases, lymphangioleiomyomatosis, tuberous sclerosis, and chronic mitral valve disease. Pleuritic chest pain may be seen in patients with collagen vascular illness, or a pneumothorax in patients with lymphangioleiomyomatosis, tuberous sclerosis, or eosinophilic granuloma. The tempo of symptom development can provide important clues. An acute process can be seen with atypical infections, eosinophilic pneumonia, pulmonary hemorrhage, Wegener's granulomatosis, AIP, initial hypersensitivity reactions, or bronchiolitis obliterans organizing pneumonia (BOOP).⁷ On the other hand, IPF, silica- or asbestos-related lung disease, long-standing hypersensitivity pneumonitis (HP), and many drug-induced lung diseases typically present more subacutely or chronically.

Occupational/Environmental History

A thorough occupational and environmental history is important from both a diagnostic and, potentially, therapeutic perspective. The range of occupational exposures associated with the development of ILD is vast and includes avian, animal, and fish proteins, as well as fungal spores, asbestos, silica, cobalt, beryllium, aluminum, isocyanates, and copper sulfate.⁶ Because the latency between disease onset and the development of symptoms can be quite long, a complete history must include a detailed assessment of all previous occupations and potential environmental exposures.⁸ Importantly, a recent multicenter, case-control study identified several occupational exposures that were associated with an increased likelihood of IPF,⁹ including farming [odds ratio (OR), 1.6; 95% confidence interval (CI), 1.0, 2.5], livestock (OR, 2.7, 95% CI, 1.3, 5.5), hairdressing (OR, 4.4; 95% CI, 1.2, 16.3), metal dust work (OR, 2.0; 95% CI, 1.0, 4.0), raising birds (OR, 4.7; 95% CI, 1.6, 14.1), stone cutting/polishing (OR, 3.9; 95% CI, 1.2, 12.7), and vegetable dust/animal dust exposure (OR, 4.7; 95% CI, 2.1, 10.4).

A patient's home environment may be an important source of exposure to new antigens and can potentially result in ILD, especially HP.¹⁰ The presence or absence of pets, especially birds, can narrow the differential diagnosis and be instrumental for therapy as the offending antigen can be removed. These points are highlighted by a recent multicenter study of 661 patients (400 derivation cohort, 261 validation cohort) evaluated for potential HP.¹¹ A clinical prediction rule was generated with logistic modeling that demonstrated an excellent predictive ability (area under the curve, 0.93). The six predictors incorporated in the clinical rule included exposure to a known offending antigen (OR, 38.8; 95% CI, 11.6 to 129.6), positive precipitating antibodies to the offending antigen (OR, 5.3; 95% CI, 2.7 to 10.4), recurrent episodes of symptoms (OR, 1.20; 95% CI, 1.5 to 7.5), inspiratory crackles (OR, 4.5; 95% CI, 1.8 to 11.7), symptoms 4 to 8 h after exposure to an offending antigen (OR, 7.2; 95% CI, 1.8 to 28.6), and weight loss (OR, 2.0; 95% CI, 1.8 to 28.6). Clearly, an appropriate exposure history is the most vital component suggesting a diagnosis of acute HP.

Current/Previous Medications

A detailed account of current and previous medication use should be obtained because numerous prescription medications have been associated with the development of ILD. In addition to over-the-counter medications, the history should also probe for recreational drug use such as cocaine.^12,13 An excellent Web-based resource is available to query for specific drugs and recent reports of pulmonary disease (http://www.pneumotox.com).

Smoking History

Smoking can alter both the development of ILD and the course of disease. In fact, several ILDs are seen almost exclusively in smokers, including RBILD, DIP, and eosinophilic granuloma.¹⁴ Several recent reviews have defined the clinical¹⁵ and histopathologic/imaging perspectives of these disorders.¹⁶ Interestingly, cigarette smoking has also been implicated in the development of IPF¹⁵ and can influence disease course. Two recent large series have suggested an improved survival in IPF patients who are smokers^4,17; this protective effect persisted after adjustment for other confounding factors and remains biologically unexplained. In contrast, HP is less common in smokers. On the other hand, when HP present in smokers, it follows a more chronic course with worse clinical outcome. ¹⁹

Family History

Familial types of pulmonary fibrosis are well described.²⁰ One group has recently reported familial pulmonary fibrosis manifesting as UIP in adults and cellular NSIP associated with mutations in the surfactant C gene.²¹ More recently complement receptor 1 gene polymorphisms have been associated with an increased presence of IPF,²² while transforming growth factor- b 1 gene polymorphisms have been associated with disease progression in IPF patients.²³ As such, a careful family history may be helpful in narrowing the differential diagnosis and may identify other family members with an earlier stage of disease.

Physical Examination

The physical examination findings for ILDs are generally nonspecific. The characteristic finding is dry bibasilar crackles, although inspiratory high-pitched rhonchi (“squeaks”) can be seen with bronchiolar disorders. Clubbing (most common in IPF) and signs of right heart failure can also be seen with advanced disease. The physical examination may be particularly helpful in identifying signs of underlying connective tissue disorders. As such, careful attention should be given to extrapulmonary manifestations of disease.

Laboratory Features

Routine laboratory tests and specific serologic studies can be useful in the diagnosis and management of patients with ILD. This is particularly evident in the diagnosis of HP, where the presence of precipitating antibodies to an offending antigen has proven particularly useful in a recent multicenter study.¹¹ A minimum panel of initial laboratory investigations includes a complete blood count with differential, electrolytes, renal function studies, liver function studies, antinuclear antibodies, rheumatoid factor, and a urinalysis.⁶

Physiology

Most ILDs share a common pattern of physiologic abnormalities characterized by a restrictive ventilatory defect with reduced lung volumes.²⁴ Unfortunately, these abnormalities are not specific for a particular ILD. Two groups have described atypical, physiologic presentations in patients with IPF who presented with preserved lung volumes.^25,26 Both groups implicated a positive smoking history in these patients. One group demonstrated a similar degree of fibrotic abnormality with radiographic imaging in patients with preserved vital capacity (VC) compared with those exhibiting a decreased VC; concomitant emphysema was much more likely in the group with a preserved VC. Carbon monoxide diffusing capacity of the lung (Dlco) is typically reduced in ILD to a greater extent than the lung volume at which it is measured²⁴ ; a value <39% predicted has been demonstrated to be associated with impaired survival in IPF.²⁷

Characteristic arterial blood gas abnormalities in ILD include resting hypoxemia and increased alveolar-arterial oxygen pressure difference ; gas exchange is more evident during exercise.²⁴ Two groups have confirmed the prognostic value of resting and exercise-induced hypoxemia in IIP.^28,29 Another investigative group recently presented a simple composite physiologic index that includes the FVC, FEV₁ and Dlco , accounting for the extent of emphysema on high-resolution CT (HRCT); this composite physiologic index correlated well with the extent of fibrotic abnormality on CT.³⁰ In addition, three groups have confirmed the prognostic value of serial spirometry,^31,33 Dlco,³² and arterial blood gases³² in patients with NSIP^31,33 and UIP.³¹ These investigators confirm an impaired survival with the documentation of 6- and 12-month worsening in these physiologic studies; this prognostic ability persisted after accounting for baseline severity of disease and adjusting for other variables that influence survival. As such, although the diagnostic value of pulmonary function testing is limited, the results of such testing have important prognostic value.

Radiology

Radiographic studies are usually abnormal in patients with ILD, although chest radiographs (CXRs) and HRCT scans can be normal in approximately 10% of patients.^34,35 Although some CXR features are particularly helpful,³⁶ the chest radiographic pattern is not specific, with studies demonstrating that a correct diagnosis will be made in only 50% of cases. 6 HRCT has dramatically altered the diagnostic evaluation of patients with ILD. The technique allows a detailed evaluation of the lung parenchyma by using 1- to 2-mm-thick slices reconstructed with an algorithm that maximizes spatial resolution.^37,38 Several studies have confirmed that abnormalities can be identified when they are not visible on CXR.³⁹ Furthermore, observer variability is decreased with HRCT compared with CXR and a confident diagnosis is more likely to be made with HRCT.³⁸

HRCT is particularly likely to be diagnostic in patients with IPF, lymphangitic carcinoma, sarcoidosis, silicosis, subacute HP, and pulmonary alveolar proteinosis.^6,7 Johkoh and colleagues⁴⁰ presented HRCT images from 129 patients with various interstitial disorders (UIP, 35; BOOP, 24; DIP, 23; AIP, 20; NSIP, 27) in a blinded fashion to two observers. The two observers made an accurate diagnosis in 57% of the cases; a correct diagnosis was more likely with UIP (71%), BOOP (79%), DIP (63%), and AIP (65%) than with NSIP (9%). These investigators have subsequently confirmed a high degree of accuracy in the HRCT diagnosis of UIP (80%) in 92 patients with cystic lung disease.⁴¹ Additional investigators have clarified the diagnostic value of typical HRCT findings in diagnosing UIP/IPF. In a sentinel study, Hunninghake et al⁴² examined the diagnostic value of a clinical, radiologic, and pathologic diagnosis in 91 patients evaluated at multiple centers for suspected IPF. Using pathologic diagnosis as the gold standard, the positive predictive value of an UIP/IPF diagnosis was high for the diagnosis by a core of expert radiologists (85%) and a core of expert clinicians (87%) in contrast to individual investigators at the referring institution (69%). When the analysis was confined to patients in whom radiologists felt confident in the HRCT diagnosis (~60% of the cases), the positive predictive value of an IPF diagnosis improved (96%). Similar data were reported in a single-center study in which the specificity of a clinical and radiologic diagnosis of UIP was >90%.⁴³ The most recent data addressing this issue are those of Flaherty and colleagues,⁴⁴ who examined the prognostic value of a HRCT diagnosis in contrast to a pathologic diagnosis of UIP. Using the diagnostic algorithm depicted in Figure 3, a radiologic diagnosis of definite or probable UIP was made in 27 patients; all of these patients exhibited typical pathologic features of UIP. Importantly, 46 of the patients with pathologic UIP exhibited atypical HRCT features. Patients with typical HRCT features of UIP exhibited the worst survival (Fig 4). The high degree of accuracy of typical HRCT features of UIP has resulted in their widespread acceptance in international guidelines. The ATS/ERS statement on the classification of IIPs suggests a confident radiologic diagnosis of UIP in the setting of a bilateral, predominantly basal, predominantly subpleural, reticular pattern with subpleural cysts (honeycombing) and/or traction bronchiectasis.³ In addition, this expert panel suggests that typically the abnormality gradually decreases in extent from the base to the apex of the lung and that consolidation and nodules are absent. Adherence to these features may confirm the diagnosis of UIP/IPF in up to two thirds of cases.³⁷

Figure 3. Diagnostic algorithm used to classify the HRCT pattern as definite UIP, probable UIP, indeterminate (equal probability of UIP or NSIP), probable NSIP, or definite NSIP. The algorithm reflects a theoretical continuum of distribution, degree of reticular/honeycomb change, and degree of ground-glass opacity illustrated below the algorithm. Generally, patients with a more basilar/subpleural distribution, more reticular infiltrates, and less ground glass were believed to have UIP. Patients with a more diffuse distribution, less reticular infiltrates, and more ground glass were thought to have NSIP.

The radiographic evaluation of other IIPs, particularly NSIP, has been evolving rapidly but remains controversial. Recent data have highlighted this evolution. Hartman et al⁴⁵ described the findings in 50 patients from multiple centers with biopsy-proven NSIP. Eleven of these patients had CT findings that were compatible with previous descriptions of NSIP, although 16 (32%) exhibited findings more compatible with UIP. In contrast, MacDonald and colleagues⁴⁶ contrasted CT findings identified by four expert radiologists in 21 patients with NSIP with those of 32 UIP patients. The only CT feature independently associated with an NSIP diagnosis was ground-glass attenuation. In the previously described work of Flaherty et al,⁴⁴ a radiologic diagnosis of probable or definite NSIP (Fig 3) was confirmed pathologically in only 41% of cases. These data suggest that a radiologic diagnosis of NSIP must be made with caution. The work of the ongoing ATS/ERS NSIP committee should provide additional data to refine the radiologic findings of NSIP (W.D. Travis, MD; personal communication; ATS Annual Meeting, May 16–21, 2003).

Bronchoscopy, BAL, Surgical Lung Biopsy

The role of bronchoscopy, BAL, and SLB in the diagnosis of ILD continues to be debated. BAL is straightforward to perform, confers little risk, and can be diagnostic in cases of certain occupational exposures to inorganic dusts, malignancy, hematologic disease, drug-induced lung disease, and pulmonary alveolar proteinosis.⁶ A recent discriminant diagnostic model generated from BAL counts in a population of patients with sarcoidosis, HP, and IPF was applied to a second group of patients with a similar distribution of ILDs. Importantly, the correct diagnosis was made in 94.5% of the patients.⁴⁷ The recent multicenter study of HP diagnosis heavily weighted BAL findings of lymphocytosis in assuring a diagnosis of HP¹¹; these authors highlight the high negative predictive value of an absence of lymphocytes in excluding the diagnosis of HP. Unfortunately, the positive predictive value of BAL cellularity is more problematic. For example, the finding of BAL lymphocytosis has been reported in 8 to 47% of NSIP patients. A recent comparison of BAL in patients with UIP or fibrotic NSIP, all of whom presented clinically as having IPF, revealed no differences in differential cell counts, highlighting the limitations of BAL in separating these entities.⁴⁸

Transbronchial biopsy can be performed at the same time as BAL and adds only a slight additional risk of bleeding and pneumothorax. It can be very useful in the diagnosis of some ILDs.⁴⁹ For example, the combination of BAL, transbronchial lung biopsy, and transbronchial mediastinal lymph node aspiration has proven very sensitive for the diagnosis of sarcoidosis, as demonstrated by Leonard and colleagues⁵⁰ in 13 patients with suspected sarcoidosis; the combination provided a sensitivity of 100%. Unfortunately, transbronchial biopsy is of limited value in the diagnosis of IPF owing to the small amount of tissue that is obtained. In these cases the clinician and patient together must balance the potential risks of SLB⁵¹ with the potential benefits (in terms of prognosis and in directing treatment).⁵² The use of SLB has become a bit more straightforward with the use of video-assisted thoracoscopy, a surgical procedure that can be performed in the outpatient setting.⁵³

The diagnostic findings of SLB in IIPs have become increasingly standardized with recent consensus statements.³ Nevertheless, significant interobserver disagreement remains among expert pathologists^54,55; similar data in pathologists with lesser degrees of experience is not available. The histologic finding in SLB specimens of patients evaluated for an IIP that has the greatest prognostic implication is documentation of the histologic findings of UIP. Two groups have documented that histologic findings of NSIP and UIP are frequently noted in multiple lobes (and even in the same lobe) of patients undergoing SLB.^55,56 Importantly, the presence of UIP in any lobe from a patient with IIP was associated with impaired survival (Fig 5). In addition, documentation of increasing profusion of fibroblastic foci, a key histologic finding in UIP, has been associated with worse prognosis by three investigative groups.^57-59

The histologic findings of NSIP have been described in detail,^3,60,61 although interobserver agreement remains problematic even among expert pathologists. Recently, the ATS and ERS assembled a committee of expert pathologists, clinicians, and radiologists who examined the clinical, radiologic, and histologic findings in 305 cases of suspected NSIP (W.D. Travis, MD; personal communication; ATS Annual Meeting, May 16–21, 2003); only 10 cases were thought by all pathologists to represent definite NSIP. After several face-to-face meetings to establish consensus, the pathologists believed 40 cases were definite, 141 probable, and 99 possible NSIP. Clearly, definition of the histologic features of NSIP will require peer-reviewed publications of these data. Importantly, the presence of histologic findings consistent with NSIP does not secure a specific diagnosis. Vourlekis and colleagues⁶² recently described six cases of histologic NSIP in which historical features supported a diagnosis of HP. Similarly, several groups have confirmed that NSIP is the most frequent histologic manifestation of a collagen vascular–associated ILD.^63-70 Finally, drug-induced ILD may present with a histologic picture of NSIP.^71,72 This supports the need for a comprehensive clinical, radiologic, and pathologic approach to diagnosis in the patient with ILD.^3,36

Summary of Diagnostic Approach

The diagnosis of ILD remains a challenging diagnostic dilemma. Figure 2 demonstrates a potential diagnostic algorithm for patients with suspected ILD, reflecting an adaptation of published recommendations.^3,6,43,73 In the initial evaluation, a careful history and physical examination are performed followed by selective laboratory studies, a chest radiograph, and physiologic studies. If a diagnosis can be reliably achieved by bronchoscopy with BAL and transbronchial biopsy, this may be diagnostic at this stage. If not, or if bronchoscopy is nondiagnostic, HRCT assumes a pivotal role in further diagnostic efforts. A typical history, physical examination, and HRCT picture can assure a diagnosis of UIP/IPF with a high degree of certainty, assuming no alternate etiology. If the clinical features are inconsistent with this diagnosis, or in the setting of atypical HRCT features, SLB should be considered. A histologic diagnosis of UIP in any sample should be considered diagnostic. If no alternate explanation is readily available as an etiology for this diagnosis ( eg , collagen vascular illness or exposure), then a diagnosis of IPF should be considered.^3,37 A histologic picture of NSIP should lead the clinician to intensify a search for an underlying process, including collagen vascular disease, a drug exposure, or HP.

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