Diffuse Lung Diseases

Idiopathic Pulmonary Fibrosis

Idiopathic pulmonary fibrosis (IPF) is the most common type of pulmonary fibrosis and is also the most common of the IIPs. As implied by its name, the cause of IPF is unknown. The imaging and histopathologic pattern of IPF is usual interstitial pneumonia (UIP). All cases of IPF are UIP, and most cases of UIP are IPF; a minority of UIP cases are caused by collagen vascular disease (usually rheumatoid arthritis [RA]), chronic HP, drug-related pulmonary fibrosis, or occupational lung disease. IPF usually affects older male patients in the sixth and seventh decades of life; two thirds are current or former smokers.

Timely diagnosis requires a high level of clinical suspicion in all adult patients presenting with chronic exertional dyspnea or dry cough with inspiratory crackles. Inspiratory crackles and digital clubbing are often present on physical examination. Hiatal hernias are common; gastroesophageal reflux disease (GERD) may worsen pulmonary fibrosis and is associated with worse patient survival. Restrictive physiology and reduced diffusion capacity are typical on pulmonary function testing. IPF has a poor prognosis with a median survival time of approximately 3 years.

The histopathologic findings of UIP are characterized by spatially and temporally heterogeneous fibrosis with adjacent spared areas of normal lung. The subpleural lung is most severely affected. Fibroblast foci are a key finding in UIP and are associated with worse survival.

The low-contrast resolution of chest radiography limits its utility in the assessment of pulmonary fibrosis. UIP most commonly presents with reduced lung volumes and reticular and linear opacities in the basilar portions of the lungs ( Fig. 18.1, A ). In severe cases, traction bronchiectasis and honeycombing may be evident even on radiography. Full characterization of lung disease is best performed on thin-section chest computed tomography (CT).

Chest CT plays a central role in the clinical workup of patients with suspected pulmonary fibrosis. A UIP pattern on chest CT is highly accurate for UIP on pathology, obviating lung biopsy. However, only half of cases of IPF have a UIP pattern on chest CT. A UIP pattern on chest CT is defined as reticulation in the peripheral and basilar aspects of the lungs with associated subpleural honeycombing without other features that are “inconsistent with UIP” ( Fig. 18.1, B ). Traction bronchiectasis or bronchiolectasis often coexists with other findings of pulmonary fibrosis. Fibrosis in UIP may be asymmetric as opposed to the distribution in nonspecific interstitial pneumonia (NSIP), which is almost always symmetric. A “possible UIP” pattern on chest CT has all the characteristics of a UIP pattern except there is no honeycombing ( Fig. 18.2 ). An inconsistent-with-UIP pattern on chest CT should be considered if there are any of the specific CT findings listed in Box 18.1 suggestive of an alternative diagnosis. In cases of possible UIP and inconsistent with UIP, biopsy should be considered for diagnosis ( Fig. 18.3 ).

Honeycombing is a finding of localized end-stage pulmonary fibrosis. Honeycombing on CT is an important finding because it is the single most specific finding of UIP and has poor prognostic ramifications. In certain cases, differentiating paraseptal emphysema from honeycombing on CT can be challenging because smoking is associated with both entities. Honeycombing usually manifests as rows or stacks of thin-walled subcentimeter lung cysts and adjacent reticulation, often in the mid and lower lung zones; paraseptal emphysema presents as longer and often larger cystic regions often in the upper lung zone and often contain subtle internal septations, which would be highly unusual for honeycombing ( Fig. 18.4 ). Unfortunately, differentiation of these two entities may be impossible in a minority of cases.

Combined pulmonary fibrosis and emphysema (CPFE) is a distinct clinical entity and is separate from the IIP classification system. Approximately one third of IPF patients have concomitant emphysema. On pulmonary function tests, lung volumes are typically normal or near-normal because of the offsetting effects of fibrosis (restriction) and emphysema (obstruction). However, diffusion capacity is typically markedly reduced. Emphysema is usually upper lung preponderant, and fibrosis is usually basilar in distribution and often has a UIP-like configuration, although other fibrotic patterns may also predominate (see Fig. 18.4 ). The majority of patients have some degree of diffuse ground-glass opacity likely reflecting superimposed smoking-related respiratory bronchiolitis (RB) or desquamative interstitial pneumonitis (DIP). Patients with CPFE are at increased risk of pulmonary hypertension and lung cancer.

Nonspecific Interstitial Pneumonia

Nonspecific interstitial pneumonia is most often secondary to an underlying condition, most often collagen vascular diseases (particularly scleroderma, myositis, and mixed connective tissue disease [MCTD]), drug-induced pneumonitis, and HP. Idiopathic NSIP is a distinct clinical entity with a good prognosis and typically responds well to steroid treatment.

The histologic features consist of various amounts of interstitial inflammation and fibrosis with a uniform appearance. There are two distinct types: cellular NSIP, with mild to moderate inflammation and little fibrosis, and fibrosing NSIP, with interstitial thickening by uniform fibrosis and preservation of alveolar architecture. The fibrosis is of the same age, unlike the temporal heterogeneity seen in UIP.

Nonspecific interstitial pneumonia is more common in women and is diagnosed at a younger age (average age of 50 years at diagnosis) than UIP and IPF. There is no strong association with smoking. The clinical presentation is nonspecific and includes dyspnea, cough, and weight loss.

The plain radiographic features consist of reticular opacities in the lower lungs without honeycombing ( Box 18.2 ). Chest CT findings are more specific. Typical findings include basilar-predominant ground-glass opacity, reticulation, and traction bronchiectasis—at times quite exuberant and above expected for the severity of adjacent lung disease ( Fig. 18.5 ). The distribution of disease is invariably symmetric in contrast to the often asymmetric distribution of UIP. The axial distribution may be central or peripheral but with subpleural sparing (see Fig. 18.5 ). Subpleural sparing is highly suggestive of NSIP and essentially excludes UIP as the predominant pattern of lung injury. Honeycombing is uncommon in NSIP and, if present, should be mild.

Organizing Pneumonia

Cryptogenic organizing pneumonia (COP), formerly known as bronchiolitis obliterans with organizing pneumonia (OP), is the idiopathic form of OP. Slightly more than half of cases of OP are idiopathic. The more common secondary causes of OP include collagen vascular disease, radiation therapy, medication, aspiration, pneumonia, and solid organ as well as stem cell transplantation. OP typically has a good prognosis and usually responds very well to corticosteroid therapy, although relapses are common. Histologically, OP is characterized by organizing cellular infiltrate and collections of young myxoid colagen with fibroblasts in the distal alveoli, which extend into the distal airways.

The imaging findings of OP are somewhat heterogeneous and diverse. Consolidation with a variable degree of ground-glass opacity is the most common finding. The changes are usually in a peripheral or peribronchovascular distribution and may be migratory. Airways within areas of lung opacity may transiently dilate. The borders of lung opacity are often “wispy” on CT, which is suggestive of the diagnosis ( Fig. 18.6 ). A reasonably specific finding for OP on imaging is a “perilobular pattern” consisting of irregular opacity with or without septal thickening that surrounds the secondary pulmonary lobule, often in the lower lung zones ( Fig. 18.7 ). Another frequent finding of OP is the atoll or reversed halo sign: a central region of ground-glass opacity with a circumferential border of consolidation ( Fig. 18.8 ). The presence of a substantial degree of reticulation in OP suggests a worse prognosis.

Acute Interstitial Pneumonia

Acute interstitial pneumonia (AIP) is essentially idiopathic acute respiratory distress syndrome (ARDS) and is most often characterized by a diffuse alveolar damage pattern. Affected patients often present with a viral-like prodrome followed by rapid respiratory decompensation. The diagnosis of AIP is that of exclusion, and secondary causes of ARDS such as pneumonia, trauma, transplant rejection, and blood transfusion must be excluded.

As in ARDS, there are typical stages of AIP. First, during the exudative phase, histology will demonstrate edema, hyaline membranes, acute lung inflammation, and alveolar hemorrhage. The organizing phase can develop within a few days with type II pneumocyte hyperplasia and organizing fibrosis. If patients survive their acute illness, some patients may progress to a chronic phase of pulmonary fibrosis.

Imaging findings mirror the histologic stages. On radiography, patchy bilateral consolidation is present during the early exudative phase. On CT, there are diffuse or dependent ground-glass opacities and consolidation ( Fig. 18.9 ). Usually the zonal distribution of disease is diffuse, although there may be a slight basilar preponderance. In the organizing stage, consolidation usually improves both on radiography and CT. A peribronchovascular distribution and bronchial dilation may be evident on CT. In patients who survive and develop fibrosis, the anterior and upper aspects of the lungs are usually more severely affected.

Respiratory Bronchiolitis–Interstitial Lung Disease

Interstitial pneumonias associated with smoking represent a spectrum of lung disease ranging from the asymptomatic RB to symptomatic respiratory bronchiolitis–interstitial lung disease (RB-ILD) to DIP. RB is very common in smokers and is found on pathology in the vast majority of patients with significant smoking history. Histologically, RB is characterized by collections of pigmented macrophages primarily within a bronchiolar distribution. In patients with RB, RB-ILD is diagnosed if patients have associated symptoms or functional impairment. Radiologic and histologic findings in RB and RB-ILD are essentially identical.

Respiratory bronchiolitis is usually not apparent on radiography, although more severe cases of may manifest as diffuse increased interstitial opacities sometimes referred to as “dirty lungs” or “dirty chest.” CT findings of RB typically include upper lung or diffuse centrilobular ground-glass nodules ( Fig. 18.10 ), similar to findings in subacute HP. A history of smoking is highly suggestive of RB as opposed to HP. The mild immunosuppressant effects of cigarette smoke protect from HP, but smoking is the causative agent in RB. Although most patients improve clinically and on imaging with smoking cessation, a substantial minority of patients will not respond or even worsen over time.

Desquamative Interstitial Pneumonia

Desquamative interstitial pneumonitis is much less common than RB, and up to 40% of patients with DIP have no history of smoking. Other less common causes of DIP include autoimmune disease, hepatitis C infection, and drug toxicity. The histologic finding in DIP is characterized by a diffuse alveolar infiltration of pigmented macrophages.

A chest radiograph may appear normal or demonstrate a subtle diffuse or basilar-predominant increased opacity in the lungs. On CT, DIP usually manifests as confluent areas of ground-glass opacity primarily in the lung periphery and at the lung bases ( Fig. 18.11, A ). In most cases, small clustered cystic lesions are superimposed on ground-glass opacity; these cysts may represent mild emphysema or very early traction bronchiolectasis caused by pulmonary fibrosis ( Fig. 18.11, B ). Indeed, a minority of cases of DIP progress to frank pulmonary fibrosis, although progression to a classic UIP pattern is not common. Given the relatively nonspecific imaging appearance of DIP, surgical lung biopsy may be necessary to achieve an accurate diagnosis.

Lymphocytic Interstitial Pneumonitis

Lymphocytic interstitial pneumonitis (LIP) is one of the rare interstitial pneumonias and is almost always secondary to an underlying condition. Most cases of LIP in adults occur in association with Sjögren syndrome. Other causes include human immunodeficiency virus (usually in children) and hematopoietic stem cell transplantation. The histologic pattern is marked by polymorphic lymphocyte infiltration in the pulmonary interstitium and lymphatics. Imaging findings on radiography are nonspecific, with most cases being normal. On chest CT, a variable degree of patchy ground-glass opacity and nodules may be present, often in the lung periphery and along the bronchovascular tree. In chronic cases, LIP manifests most commonly as a diffuse cystic lung disease, which is basilar and peribronchovascular predominant ( Fig. 18.12 ).

Idiopathic Pleuroparenchymal Fibroelastosis

Idiopathic pleuroparenchymal fibroelastosis (IPPFE) is a recent addition to the IIP classification but is poorly understood. Although it is an idiopathic condition, an association with chronic infection and stem cell transplantation has been described. On histology, there is exuberant biapical subpleural fibrosis. CT mirrors the histology; dense pleural and subpleural lung fibrosis affects the lung apices symmetrically and often extends along the superior margins of the upper lobes ( Fig. 18.13 ). A similar imaging appearance occurs in the setting of chronic lung transplant rejection, known as restrictive allograft syndrome (RAS).

Systemic Lupus Erythematosus

Interstitial lung disease is rare in systemic lupus erythematosus (SLE), although patients with SLE are predisposed to development of pulmonary hemorrhage and pulmonary infections. SLE more often presents with pleural or pericardial effusions or thickening. Pleural thickening may result in restrictive thoracic physiology that mimics pulmonary fibrosis on pulmonary function testing and can lead to substantial patient morbidity. Some patients develop diaphragmatic weakness, which leads to chronically low lung volumes—the so-called shrinking lung syndrome that may mimic mild ILD on radiography caused by vascular crowding and atelectasis.