Seminars in Roentgenology
Volume 45, Issue 1 , Pages 4-7, January 2010

Crucial Communications

  • Jeffrey T. Chapman, MD

      Affiliations

    • Corresponding Author InformationAddress reprint requests to Jeffrey T. Chapman, MD, Department of Pulmonary and Critical Care Medicine, Cleveland Clinic, 9500 Euclid Ave., Cleveland, OH 44195

Department of Pulmonary and Critical Care Medicine, Cleveland Clinic, Cleveland, OH

Article Outline

 

High-resolution computed tomographic imaging has revolutionized the evaluation of interstitial lung disease (ILD). These noninvasive, widely available, nearly instantaneous data have allowed the radiologist to become a key physician diagnosing this diverse group of patients. However, owing to the complexity of diagnosis, overlapping diseases and radiographic patterns, and ultimately our superficial understanding of the ultimate causes of the diffuse parenchymal lung diseases, a communication between the radiologist and the chest clinician is crucial. The interactions between these physicians and, if needed, pathology interpretation by experienced pathologists, allow descriptions of image abnormalities to become accurate diagnoses and treatment plans.

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Differential Diagnosis of Interstitial Lung Disease—The Chest Clinician's Perspective 

Although more than 200 causes of ILD have been described, the diagnostic pathway can be focused to a few key questions. Figure 1 displays a diagnostic schema that serves as a framework for the clinician and radiologist to work from. Despite most patients having an idiopathic interstitial pneumonia (IIP), it is imperative that every effort be made to identify exposures, systemic diseases known to be associated with ILD, and characteristic imaging of unique genetic disorders.

  • View full-size image.
  • Figure 1. 

    The numerous unrelated ILD can be organized by exposure, associated systemic illness, or ascribed to the idiopathic category and characterized by pattern of injury. Abbreviations: Idiopathic interstitial pneumonia (IIP), Connective tissue disease (CTD), Inflammatory bowel disease (IBD), Lymphangioleiomyomatosis (LAM), Birt–Hogg–Dube (BHD), Pulmonary alveolar proteinosis (PAP), Hermansky–Pudlak Syndrome (HPS), Usual interstitial pneumonia (UIP), Nonspecific interstitial pneumonia (NSIP), Organizing pneumonia (OP), Lymphocytic interstitial pneumonia (LIP), Constrictive bronchiolitis (CB).

From a clinician's perspective, a careful history detailing work, hobby, medication, radiation, and tobacco inhalational exposure will detect the possibility of most of these diseases. The most common exposure-related ILDs are tobacco related1 [respiratory bronchiolitis-associated ILD, desquamative ILD, and pulmonary Langerhans cell histiocytosis], hypersensitivity pneumonitis2 [most commonly from birds, domestic and agricultural fungi, or small inorganic molecules (vinyl, isocyanates)], and medications3 (nitrofurantoin, amiodarone, chemotherapy, myriad others), and work-related (asbestos,4 silica,5 hard metal,6 or hypersensitivity pneumonitis antigens). After identifying a significant exposure, the chest clinician will work with the radiologist and assess whether the images support the exposure history as the cause of the ILD. Communication and combined evaluation is crucial as exposure by no means equates disease and the exposed patient may still have a systemic disease or IIP as the cause of their ILD.

After exposures are eliminated as potential causes, chest physicians must next consider whether a systemic illness is leading to parenchymal lung injury. Many patients present with a known systemic illness and the association is obvious; however, the chest physician must always carefully consider signs and symptoms as patients can present with an undiagnosed systemic disease. This vigilance should be maintained after diagnosis as patients may develop a systemic disease after the pulmonary manifestations, which may alter treatment and prognosis.

The most common systemic disease-associated ILD is sarcoidosis,7 which may present with concomitant skin, eye, cardiac, or gastrointestinal complaints. Sarcoidosis is unique in that either the clinician or radiologist may consider sarcoidosis first if the patient presents with extrapulmonary or classic radiographic findings, respectively. ILD in the setting of connective tissue disease (CTD) is commonly seen with scleroderma,8 polymyositis,9 mixed connective tissue disease,10 rheumatoid arthritis,11 and rarely lupus. Linking the ILD to the CTD is frequently difficult owing to forme fruste presentations and nondiagnostic serologic testing.12 Owing to the difficulty of establishing a firm diagnosis on clinical information alone, all patients with unexplained ILD should have serologies for antinuclear antibodies, extractable nuclear antibodies, and rheumatoid factor performed at initial evaluation and if indicated by muscle weakness or sinus symptoms, creatine kinase and antineutrophil cytoplasmic antibody determination, respectively.

Importantly, after a CTD has been determined as the cause of ILD, the chest physician must determine 2 important characteristics of the lung component. First, the pattern of injury as assessed by radiographic images, bronchoalveolar lavage, transbronchial lung biopsy, or surgical lung biopsy must be determined. The injury and repair pattern associated with CTD can be usual interstitial pneumonia (UIP), nonspecific interstitial pneumonia (NSIP), organizing pneumonia (OP), or lymphocytic interstitial pneumonia (LIP). Although the CTDs usually cause a stereotypical pattern of injury (fibrotic NSIP in scleroderma, UIP in rheumatoid arthritis, and NSIP or OP in polymyositis), exceptions are frequent enough that each case must be assessed individually. Second, the pace of parenchyma involvement assessed by symptoms, pulmonary function testing, or radiographic imaging is determined. Together, the pattern of injury and pace determines prognosis and allows development of a treatment plan, and require input clinician and radiologist.

Other systemic diseases that can cause ILD and should be considered by the chest clinician and relayed to the radiologist are inflammatory bowel diseases,13 and storage diseases14 such as Niemann-Pick.

Next to be considered are the disease that have a known genetic cause and present with either characteristic clinical or radiographic findings. Lymphangioleiomyomatosis15 (LAM) or Birt–Hogg–Dube16 are suggested by diffuse cysts without nodules on CT imaging, but the diagnosis needs to either be confirmed clinically or genetically. In LAM, the clinician confirms the diagnosis with extrapulmonary angiomyolipomas, findings of tuberous sclerosis complex (brain tubers, seizures, developmental delay, skin tubers), or via pathologic testing of LAM cells showing HMB-45 staining or abnormalities in the tumor suppressor gene tuberous sclerosis complex 2. Birt–Hogg–Dube is confirmed by finding facial skin tubers or genetic testing, confirming abnormalities in the tumor suppressor gene FLCN, which produces folliculin.

Other rare genetic disease are pulmonary alveolar proteinosis,17 which is usually suggested by the characteristic CT findings of mosaic lobular ground-glass and superimposed septal thickening (“crazy-paving”) without fibrosis and is confirmed by finding visibly increased surfactant lipid in bronchoalveolar lavage. Hermansky–Pudlak syndrome18 is a rare autosomal recessive disorder leading to oculocutaneous albinism, platelet dysfunction leading to bleeding diathesis and UIP-like ILD. Obviously, the chest clinician is typically the first to consider this rare disorder.

Recognition of familial ILD rests squarely with the chest clinician. Between 1% and 5% of all idiopathic pulmonary fibrosis (IPF) cases are familial with a first-degree relative also having ILD.19 We use the term familial ILD rather than IPF because cases within the same family having the same primary genetic defect can present with different IIP patterns, such as NSIP and UIP.20 Most kindreds identified to date have abnormalities in surfactant protein C production or telomerase maintenance.21 However, many kindreds have yet to be defined.

When exposure and systemic diseases know to cause ILD have been eliminated, the patient has an IIP and the prognosis and treatment are dictated by the pathologic pattern.22 In the absence of a history of exposure or systemic disease, radiology is the only noninvasive assessment available. This has spurred much research into utility of radiology in the IIPs.

Although there is no universally accepted list of IIPs, UIP, NSIP, cryptogenic OP, LIP, and constrictive bronchiolitis are most commonly included in the category. These disorders present with indistinguishable symptoms of cough and dyspnea, and only relative clinical differences, shown in Table 1, which cannot reliably distinguish them. Other articles describe the radiographic findings of the IIPs, and it is these findings that can lead to a secure diagnosis in many IIP cases when coupled with information from the chest physician.

Table 1. Characteristics of the Idiopathic Interstitial Pneumonias
IIPAge (yr)OnsetSteroid Responsive5-Year Survival
UIP>50ChronicNumber40%
NSIP30-60SubacuteUsually75%
OP30-60SubacuteUsually75%
LIP30-60SubacuteUsually75%
CB30-60ChronicNumberUnclear

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Integrating Radiology Into Initial Diagnosis of ILD 

An initial thorough evaluation of the images independent of clinical information should first be performed in all ILD cases to eliminate any pre-evaluation bias. Indeed, careful chest clinicians approach all cases with a blank page and gather their own primary history, physical examination, and laboratory data before assuming a previous diagnosis to be correct. Effectively integrating these evaluations is the crucial step.

Our group of radiologists, pathologists, and clinicians meets weekly with systematic case presentations of the historical, physical examination, and laboratory data followed by evaluation of available images. Over 300 patients have been evaluated at our ILD referral center in this manner. By always considering exposures, systemic diseases and known genetic causes first, we minimize the chance of overlooking these potentially improvable illnesses. However, most of our patients do not have an ILD with known cause or association and have an IIP.

The initial step to diagnose which IIP a patient has is to determine whether a confident diagnosis of UIP can be made. UIP must first be considered because it is the only IIP that can be reliably diagnosed without pathology.23 Four elements are required to make a confident diagnosis of UIP via CT imaging: basilar predominant reticular fibrotic abnormalities, subpleural predominance of reticular fibrotic abnormalities, lack of significant ground-glass or nodular abnormalities and finally subpleural honeycomb cystic changes. The presence of all 4 characteristics is diagnostic of UIP, and we define this as CT evidence of definite UIP and such patients do not require a surgical lung biopsy to confirm the diagnosis. This injury and response pattern UIP establishes a clinical diagnosis of IPF when UIP is present as an IIP. Only 40% of patients with IPF will present with diagnostic CT imaging, and the remainder will lack one of the 4 elements, most frequently the honeycomb cystic changes.23 Currently, these patients require surgical lung biopsy for definitive diagnosis.

After a surgical lung biopsy is obtained, as with radiology, it cannot be reviewed in isolation. A systematic multidisciplinary clinical, radiological, and pathologic case review enhances the chance of arriving at a correct diagnosis compared with each specialty working alone.24, 25

Importantly, IPF is not present if UIP occurs in the setting of systemic diseases (rheumatoid arthritis, scleroderma, polymyositis) or exposures (hypersensitivity pneumonitis–inducing antigens, asbestos). Rather the patient has the primary disease with an associated injury pattern of UIP. IPF and associated UIP do not have the same prognosis, with IPF having a lower 5-year survival rate.26 Associated diseases, such as hypersensitivity pneumonitis and CTD tend to have a worse prognosis if the injury and repair IIP pattern is fibrotic on imaging, mimicking UIP rather than NSIP, OP, or LIP.27

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Radiologic Information From Nonparenchymal Structures 

Nonparenchymal features can harbor important information in select patients. Pulmonary artery diameter, if normal (<29 mm) eliminates the possibility of pulmonary arterial hypertension.28 However, an increased pulmonary artery diameter has a positive predictive value of only 60% for pulmonary arterial hypertension and should not be used as a marker of such. Importantly, the lack of pulmonary arterial hypertension should be communicated to the chest clinician as its presence portends a better prognosis. Treatment of pulmonary arterial hypertension secondary to IPF is of unclear benefit at this time, although multiple trials with agents used to treat idiopathic pulmonary arterial hypertension are underway.

Pleural findings are also important diagnostic clues. Owing to the universal subpleural fibrosis and subsequent lack of lymphatic leak with elevated venous pressures, pleural effusions secondary to heart failure are never seen with IPF, and their presence argues strongly against IPF.

Mild to moderate diffuse hilar adenopathy is found in all ILD in a subset of patients and is not of diagnostic or therapeutic significance.

Recently, patients with IPF have been show to have significant risk of coronary artery disease29 and deep venous thrombosis.30 Extensive coronary artery calcifications or any hints of pulmonary emboli on contrast scans must be communicated to the chest clinician as their presence can markedly affect treatment.

Finally, patients with IPF have a significant risk of primary pulmonary malignancy given the typical smoking history and any suspicious lesions should be reported to the chest clinician.

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Conclusions 

High-resolution computed tomographic imaging of the chest allows detailed macroscopic pathologic evaluation of the pattern of injury and repair in the ILDs. Careful coordination between the radiologist and chest clinician is essential in arriving at a quick and parsimonious diagnosis. Systematic evaluation with data from both physicians addressing exposures, systemic diseases and IIPs allows patients to be diagnosed accurately and in many cases without need for invasive pathologic testing.

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References 

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PII: S0037-198X(09)00067-4

doi:10.1053/j.ro.2009.07.003

Seminars in Roentgenology
Volume 45, Issue 1 , Pages 4-7, January 2010

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