Seminars in Roentgenology
Volume 45, Issue 1 , Pages 22-28, January 2010

Interstitial Lung Disease in the Setting of Collagen Vascular Disease

  • C. Isabela S. Silva, MD, PhD
    • ,
  • Nestor L. Müller, MD, PhD

      Affiliations

    • Corresponding Author InformationAddress reprint requests to Nestor L. Müller, MD, PhD, Department of Radiology, Vancouver General Hospital, University of British Columbia, 3350–950 W 10th Ave, Vancouver, BC, Canada V5Z 4E3

Department of Radiology, Vancouver General Hospital, University of British Columbia, Vancouver, British Columbia, Canada

Article Outline

 

Collagen vascular diseases (CVDs) are a group of acquired immunologically mediated inflammatory disorders that affect the connective tissue of many organs, including the lungs. The frequency of intrathoracic manifestations and the pattern of abnormality vary, depending on the underlying CVD (Table 1).1, 2, 3, 4 Pulmonary abnormalities seen in these patients may be due to the underlying CVD or may be due to complications of treatment, such as opportunistic infection and drug toxicity. The most important intrathoracic manifestations of CVDs are diffuse interstitial lung disease (ILD) and pulmonary hypertension, which together account for most of the morbidity and mortality in these patients.2 The most common CVDs associated with diffuse ILD are rheumatoid arthritis (RA), progressive systemic sclerosis and/or scleroderma, systemic lupus erythematosus (SLE), polymyositis and/or dermatomyositis (PM/DM), mixed connective tissue disease, and Sjögren syndrome. The ILD may precede the clinical and laboratory manifestations of the CVD for several months or years, be present together with systemic manifestations at the time of diagnosis of CVD or, more commonly, manifest later in the course of the disease.5 In one recent study, 17 (15%) of 114 patients with ILD were diagnosed with a new CVD as a direct consequence of their ILD evaluation.6

Table 1. Relative Frequency of Interstitial Lung Diseases in Collagen Vascular Disease
PatternRAPSSDM/PMSjögrenMCVDSLE
UIP++++++++++
NSIP+++++++++++++++
OP++++—++
LIP+——+++++
DAD++++—++

RA indicates rheumatoid arthritis; PSS, progressive systemic sclerosis/scleroderma; DM/PM, dermatomyositis and polymyositis; MCVD, mixed collagen vascular disease; SLE, systemic lupus erythematosus; UIP, usual interstitial pneumonia; NSIP, nonspecific interstitial pneumonia; OP, organizing pneumonia; LIP, lymphocytic interstitial pneumonia; DAD, diffuse alveolar damage.

+++ Indicates most common pattern seen in this collagen vascular disease; ++, second most common pattern; +, less common pattern; —, rarely seen or not described.

The most common histopathologic patterns of ILD seen in the setting of CVDs are nonspecific interstitial pneumonia (NSIP), usual interstitial pneumonia (UIP), organizing pneumonia (OP), and lymphocytic interstitial pneumonia (LIP). High-resolution computed tomography (CT) is superior to chest radiography in the detection of ILD and is more accurate in the differential diagnosis and distinction of potentially reversible abnormalities from irreversible fibrosis. High-resolution CT is therefore commonly used in the initial evaluation and follow-up of patients with CVD and clinically suspected or proven ILD.

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Chronic ILD 

The CVDs most commonly associated with chronic ILD are RA, progressive systemic sclerosis, and PM/DM. In some CVDs, such as progressive systemic sclerosis, ILD is common, eventually developing in 70%-100% of patients, while in other CVDs particularly SLE, ILD occurs in <10% of patients.1, 7 The prevalence of the individual type of chronic ILD depends on the underlying CVD (Table 1), but overall the prevalence of a NSIP pattern in these patients is considerably higher than that seen in patients with idiopathic interstitial pneumonia (IIP).2, 8 The high-resolution CT manifestations of chronic ILD seen in patients with CVD are similar to those seen in idiopathic interstitial pneumonia.2, 8, 9 Patients with CVD, however, are more likely to have >1 histologic and radiologic pattern. The most common combination of patterns is that of NSIP and OP seen particularly in patients with PM/DM and mixed connective tissue disease.3 Other findings seen more commonly in patients with CVD include pleural effusion and/or thickening, pericardial effusion and, particularly in patients with progressive systemic sclerosis, esophageal dilatation.8 Mediastinal lymphadenopathy may be seen in association with ILD, particularly NSIP and UIP in the setting of CVD, but is uncommon in OP. The prevalence of mediastinal lymphadenopathy in patients with ILD associated with CVD (24%) is similar to that of idiopathic ILD (26%).8 The nodal enlargement is usually mild, with lymph nodes measuring 10-15 mm in short-axis diameter and involving only 1 or 2 nodal stations (most commonly the right lower paratracheal or subcarinal region). The likelihood of lymphadenopathy increases with greater extent of ground glass and fibrosis. Overall, patients with ILD associated with CVD have a better prognosis than patients with IIP and this difference is not solely because of the predominance of the NSIP pattern.3, 10 The prognosis of patients with UIP pattern in CVD is also better than those with idiopathic pulmonary fibrosis (IPF).11, 12, 13 The prognosis of a NSIP pattern associated with CVD, however, is similar to that of idiopathic NSIP.11 According to recent data, the median survival for patients with limited systemic sclerosis and NSIP is 15 years.14

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Nonspecific Interstitial Pneumonia 

NSIP is the most common histopathologic and high-resolution CT pattern of ILD seen in patients with CVD.8, 15, 16 It is particularly prevalent in progressive systemic sclerosis, PM/DM, and mixed connective tissue disease.8, 14 NSIP is characterized histologically by relatively homogenous expansion of the alveolar walls by inflammation, fibrosis, or both.15 The high-resolution CT findings are identical to those seen in idiopathic NSIP and typically consist of bilateral symmetric ground-glass opacities, irregular linear (reticular) opacities, and traction bronchiectasis and bronchiolectasis involving mainly the lower lobes.2, 17 At presentation, the ground-glass opacities are typically the predominant and occasionally the only abnormality evident on CT (Fig. 1). With progression of disease reticulation, traction bronchiectasis and bronchiolectasis develop or increase in extent (Fig. 2). The abnormalities are commonly diffuse in the transverse plane but in approximately one-third of patients involve mainly the peripheral regions. Lower lobe volume loss is frequent, and relative sparing of the immediate subpleural lung in the dorsal regions of the lower lobes is often present (Fig. 2).18, 19 Areas of consolidation may be seen but rarely are the main abnormality in NSIP. When chronic consolidation is present in a patient with NSIP, it most commonly reflects a component of associated OP (Fig. 3). Acute consolidation in patients with NSIP usually is due to pneumonia or aspiration; occasionally it may result from acute exacerbation.20 Honeycombing may be seen but is uncommon at presentation. When present it tends to be mild, but may increase in size and extent with progression of the disease.18 Because NSIP is a very common histologic pattern in CVD and it may precede other clinical manifestations, the presence of a CT or histologic pattern of NSIP should prompt a search for an underlying CVD.

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  • Figure 1. 

    (A) Axial high-resolution CT image shows bilateral ground-glass opacities involving mainly the dorsal lung regions. Mildly dilated air-filled esophagus is also noted. (B) Coronal reformation demonstrates marked lower lobe predominance of the ground-glass opacities. The patient was a 40-year-old woman with mixed collagen vascular disease and nonspecific interstitial pneumonia.

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  • Figure 2. 

    (A) Axial high-resolution CT image shows bilateral symmetric ground-glass opacities and mild superimposed reticulation. Relative subpleural sparing is evident in the dorsal region of the right lower lobe (short arrows). (B) High-resolution CT image 3 years later demonstrates progression of the fibrosis with more extensive reticulation, traction bronchiectasis (arrows), and bronchiolectasis. The esophagus is dilated and contains an air-fluid level. The patient was a 61-year-old woman with progressive systemic sclerosis and nonspecific interstitial pneumonia.

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  • Figure 3. 

    (A) Axial high-resolution CT image shows bilateral ground-glass opacities, areas of consolidation, and relative subpleural sparing (arrows). (B) High-resolution CT image 2 years later demonstrates resolution of the areas of consolidation. The patient was a 51-year-old woman with Sjögren syndrome and nonspecific interstitial pneumonia plus organizing pneumonia on surgical biopsy performed the day after the initial CT.

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Usual Interstitial Pneumonia 

UIP is the second most common pattern of chronic ILD in CVD, being seen most frequently in patients with systemic sclerosis and RA.17, 21 The reported prevalence of UIP in patients with progressive systemic sclerosis and RA ranges from 8%-44%16, 22 and 1%-4%, respectively.2, 23 Although the overall prevalence of UIP in patients with progressive systemic sclerosis is greater than that in patients with RA, the prevalence of UIP in progressive systemic sclerosis is considerably lower than that of NSIP. In patients with RA, a UIP pattern is slightly more common than NSIP on high-resolution CT.24 In general, the pathologic findings of UIP in CVD are similar to those seen in the idiopathic counterpart and typically consist of patchy heterogeneous pattern with foci of normal lung, interstitial inflammation, fibrosis, and honeycombing.2 Fibroblastic foci, another characteristic histologic feature of UIP, are less extensive in CVD than in IPF; this feature presumably accounts for the better prognosis in these patients.25, 26

The high-resolution CT manifestations of UIP in the setting of CVD, similar to those seen in IPF, consist mainly of reticulation and honeycombing involving predominantly the subpleural regions and lung bases, traction bronchiectasis, and traction bronchiolectasis (Fig. 4).8, 21 However, compared with patients who have UIP in the setting of IPF, those with UIP and CVD are less likely to have honeycombing evident on CT.8 The distribution is also most commonly bilateral and symmetric, although it can sometimes be asymmetric, particularly if there is associated bronchiolitis obliterans, another relatively common complication in patients with RA. Ground-glass opacity is commonly visible on CT in patients who have UIP pattern, but is not a prominent feature. Mild mediastinal lymph node enlargement is also common.8

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  • Figure 4. 

    Axial high-resolution CT image at the level of the lung bases demonstrates subpleural reticulation and mild honeycombing (arrows). The patient was a 64-year-old man with rheumatoid arthritis and usual interstitial pneumonia pattern on CT.

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Organizing Pneumonia 

The most common CVD associated with OP is PM/DM, and OP is the second most common form of ILD in PM/DM.3 OP also occurs with increased frequency in RA21 and has been described in SLE9 and in Sjögren syndrome.27 The patients usually respond well to corticosteroid therapy and have a good prognosis. However, patients with OP associated with CVD seem to have a greater tendency to develop fibrosis and a higher mortality than patients with cryptogenic OP.2, 4

The histologic findings of OP consist of intraluminal plugs of granulation tissue within alveolar ducts and surrounding alveoli associated with chronic inflammation of the surrounding lung parenchyma.15 Granulation tissue polyps may be also present in the respiratory bronchioles. The characteristic high-resolution CT manifestations of OP consist of patchy bilateral consolidation, which in 60%-80% of cases has a subpleural and/or peribronchial distribution (Fig. 5).24, 28 It most commonly involves the lower lung zones to a greater degree than the upper lung zones. Poorly defined band-like opacities that are of greater thickness than those encountered in thickened interlobular septa and that have an arcade-like or polygonal appearance (perilobular pattern) are also common.29 Other findings include ground-glass opacities usually seen in association with areas of consolidation, ill-defined peribronchial or centrilobular nodules, large nodular or mass-like areas of consolidation, areas of ground-glass opacity surrounded by a ring-like or crescent-shaped opacities (reversed halo sign) and, occasionally, irregular linear opacities.28, 30

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  • Figure 5. 

    Axial CT image shows bilateral ground-glass opacities and peripheral consolidation. The patient was a 46-year-old woman with dermatomyositis and organizing pneumonia.

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Lymphocytic Interstitial Pneumonia 

LIP is an uncommon condition characterized histologically by a diffuse interstitial lymphoid infiltrate consisting mainly of polyclonal lymphocytes and varying numbers of plasma cells.2, 15 It usually occurs in patients with underlying immunologic disorders, such as CVD, although it may rarely be idiopathic.2, 15 The CVD typically associated with LIP is Sjögren syndrome; however, LIP may also occasionally be seen in SLE and RA.24

The main abnormalities on high-resolution CT consist of patchy or confluent bilateral ground-glass opacities and poorly defined centrilobular nodules.28 Thin-walled cysts, usually few in number, are seen in 60%-80% of patients usually associated with ground-glass opacities, but occasionally as an isolated finding (Fig. 6).28, 31 Nodules occasionally seen in association with the cysts in patients with LIP usually represent amyloid deposits that may calcify (Fig. 7).32

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  • Figure 6. 

    Axial high-resolution CT image shows bilateral ground-glass opacities and several thin-walled cysts of various sizes (arrows). The patient was a 50-year-old woman with Sjögren syndrome and lymphocytic interstitial pneumonia.

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  • Figure 7. 

    Axial high-resolution CT image demonstrates nodules (arrows) in the left upper lobe and thin-walled cyst (arrowhead) adjacent to one of the nodules. A few cysts with adjacent nodules and ground-glass opacities were present in the lower lobes (not shown). The patient was a 60-year-old man with Sjögren syndrome, lymphocytic interstitial pneumonia and amyloid nodules.

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Acute Interstitial Lung Diseases 

Acute Exacerbation of Chronic ILD 

Patients with CVD and chronic ILD, similar to those with idiopathic ILD, may develop acute exacerbation.20, 33, 34 Acute exacerbation is most common in chronic ILD associated with RA, but may be seen in progressive systemic sclerosis, DM/PM, and primary Sjögren syndrome.20, 34, 35 Patients with acute exacerbation typically present with acute respiratory deterioration and severe hypoxemia. The overall incidence of acute exacerbation of ILD in the setting of CVD has been estimated at 7.2%.35

The histologic findings of acute exacerbation are those of acute lung injury, and usually consist of a diffuse alveolar damage (DAD) pattern superimposed on a background of UIP or NSIP.20, 35 Patients may have OP as the pattern of acute lung injury, which is less common, and have a better prognosis than those with DAD.20 The high-resolution CT findings of acute exacerbation consist of newly developed bilateral ground-glass opacities with or without areas of consolidation, superimposed on a reticular pattern or honeycombing (Fig. 8). The disease is typically diffuse but may be multifocal.20, 35 Despite intensive anti-inflammatory and immunosuppressive therapies, the prognosis of acute exacerbation of CVD associated with ILD is poor, with mortality ranging from 75% to 100%.20, 33, 35

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  • Figure 8. 

    Axial high-resolution CT image shows extensive bilateral ground-glass opacities and mild subpleural reticulation and honeycombing (arrows). A hiatus hernia is also noted. The patient was a 72-year-old man with long standing rheumatoid arthritis and acute exacerbation of usual interstitial pneumonia with histologic findings of diffuse alveolar damage.

Diffuse Alveolar Damage Without Associated Chronic ILD 

Occasionally, patients with CVD and no evidence of prior ILD may present with clinical and radiologic findings of acute respiratory distress syndrome and histologic findings of DAD.9, 24 This pattern may be the initial manifestation of lung involvement in these patients and may mimic idiopathic acute interstitial pneumonia with rapid progression to respiratory failure. This presentation has been described most commonly in patients with SLE and PM/DM.9, 24

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Differential Diagnosis 

Drug-Induced Lung Disease 

ILDs, particularly NSIP, OP, and DAD may also be a reaction pattern to many drugs.36 Because most patients with CVD are treated with anti-inflammatory or immunosuppressive medications, drug-induced lung disease should always be considered in the differential diagnosis as a potential cause of the parenchymal abnormalities (Fig. 9).

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  • Figure 9. 

    Axial high-resolution CT image shows extensive bilateral ground-glass opacities and mild reticulation. The patient was a 64-year-old woman with rheumatoid arthritis and nonspecific interstitial pneumonia drug reaction pattern secondary to methotrexate.

Pulmonary Infection 

Because of their immunologic abnormalities and therapy with corticosteroids or other immunosuppressive drugs, patients with CVD are at increased risk of bacterial pneumonia and opportunistic infection. The prevalence of pneumocystis pneumonia seems to be particularly increased in patients with CVD and ILD who are being treated with corticosteroids.37, 38 Therefore, pneumocystis pneumonia should be in the differential diagnosis of new extensive ground-glass opacities on CT in these patients (Fig. 10).

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  • Figure 10. 

    (A) Axial high-resolution CT image shows bilateral ground-glass opacities and mild reticulation mainly in the lower lobes. A relative subpleural sparing in the dorsal region of the left lung is noted (arrowheads). (B) High-resolution CT image 3 months later, when the patient presented with acute worsening of the dyspnea and hypoxemia demonstrates marked increase in extent of the bilateral ground-glass opacities. The patient was a 45-year-old woman with undifferentiated collagen vascular disease, nonspecific interstitial pneumonia, and pneumocystis pneumonia.

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Conclusion 

ILD is a major cause of morbidity and mortality in patients with CVD. High-resolution CT plays an important role in the diagnosis and follow-up of ILD in these patients. The ILD most commonly develops in patients with prior diagnosis of CVD, but in some cases may precede the systemic manifestations of CVD by several months or years. The pattern of abnormality on CT correlates well with the histologic findings and has important implications for treatment and prognosis. Although diffuse ILD in these patients usually is related to the underlying CVD, similar findings may also result from drug reaction or infection.

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PII: S0037-198X(09)00069-8

doi:10.1053/j.ro.2009.07.005

Seminars in Roentgenology
Volume 45, Issue 1 , Pages 22-28, January 2010

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