The following review focuses on pulmonary manifesta- tions of granulomatous diseases (sarcoidosis), connective tissue diseases, vasculitis (Wegener granulomatosis and Church-Strauss), and Goodpasture syndrome. Rare pul- monary manifestations associated with other diseases, such as tuberous sclerosis and lymphangioleiomyomato- sis, Erdheim-Chester disease (rare non-Langerhans cell histiocytosis), storage diseases (Gaucher, Niemann Pick), systemic amyloidosis, and relapsing polychondritis, as well as manifestations of neoplastic diseases (e.g., lym- phoma) are not considered herein. Langerhans cell histi- ocytosis shows a pulmonary involvement that is associa- ted with a systemic manifestation only in children and not in adults.
Granulomatous Diseases Pulmonary Sarcoidosis
Sarcoidosis is a systemic disorder of unknown origin. It is characterized by non-caseating epitheloid-cell granulo- mas in multiple organs; however, morbidity and mortali- ty are closely related to pulmonary manifestations, which occur in >90% of patients. The CT appearance of pul- monary sarcoidosis varies greatly and is known to mim- ic many other diffuse infiltrative lung diseases. These in- clude Loffgren syndrome (fever, bilateral adenopathy, eythema nodosum, and arthralgia) and lupus pernio (cu- taneous lesions, bone cysts and pulmonary fibrosis).
The histology of pulmonary sarcoidosis consists of noncaseating granulomas rimmed by lymphocytes and fi- broblasts in a perilymphatic distribution, which may re- solve or cause fibrosis. The disease may occur at any age, but mostly affects individuals between 20 and 40 years of age, and only rarely those over 65 years of age. Females are affected more often than males. The prognosis is mostly good, with disease resolution occurring in <2 years; mortality is 1-5%.
The chest X-ray shows lymphadenopathy, reticulonodu- lar opacities predominantly in the upper lobes (rarely, larg- er nodules), and fibrosis with honeycombing and volume loss, predominantly in the upper lobes and segment 6.
Staging based on chest X-ray is as follows:
Stage 0 Normal chest radiograph (>50% at presentation) Stage I Bilateral hilar and paratracheal lymphadenopathy Stage II Lymphadenopathy and nodular opacities Stage III Nodular opacities without lymphadenopathy or
signs of fibrosis
Stage IV Signs of fibrosis with or without lympha- denopathy.
Computed tomography (CT) and high-resolution CT (HRCT) show small, well defined nodules in a characteris- tic perilymphatic distribution in relation to the subpleural surface. The nodules are located adjacent to the major fis- sures, along thickened interlobular septa, and adjacent to vessels in the lobular core. There may also be even distrib- ution of the nodules throughout both lungs, with a predom- inance in the upper and middle lung zones. However, in most cases they are clustered in the perihilar and peribron- chovascular region, with relative sparing of the lung periph- ery, or they are grouped in small areas uni- or bilaterally.
Confluence of granulomas results in larger nodules (1-4 cm, nodular sarcoid, galaxy sign) or ill-defined opacities (ground-glass or consolidations, up to 10 cm, alveolar sar- coidosis). There may be irregular thickening of the bronchial wall, with narrowing of the large and small airways (mosa- ic pattern). Lymphadenopathy is noted in up to 50% of pa- tients on CT. Calcifications may be bilateral, more focal than complete, eggshell-like, or with an amorphous cloud- like pattern. In up to 20% of patients, pulmonary fibrosis with septal thickening, traction bronchiectasis, and honey combing (stage IV) may be observed. Conglomerate mass- es mostly in a perihilar location represent areas of fibrosis with characteristic traction bronchiectasis.
Important take-home points regarding pulmonary sar- coidosis are:
• Caveat complications: Aspergilloma in cavitations with hemoptysis (stage IV) and pneumothorax (more common with alveolar sarcoid).
• Sarcoidosis may present with very characteristic HRCT features, obviating further invasive diagnosis.
• Sarcoidosis may also present less typically, e.g., lower lobe predominance mimicking idiopathic pulmonary fi- brosis (IPF), subpleural consolidations mimicking eosinophilic pneumonia, thus requiring further diagnosis.
IDKD 2007
Pulmonary Manifestations of Systemic Diseases
C. Schaefer-Prokop
Department of Radiology, Academic Medical Center, Amsterdam, The Netherlands
• Sarcoid is a frequent differential diagnosis when ana- lyzing diffuse lung disease.
• Airflow obstruction is common and occurs in associa- tion with fibrotic changes, especially in the large air- ways, but also in earlier disease stages (small-airway obstruction).
Connective-Tissue Disorders
Involvement of the respiratory system in rheumatology or connective-tissue disorders (CTDs) is common and re- sults in significant morbidity and mortality. Many of the diseases are characterized by a specific serological anti- body (Table 1). The underlying mechanism of that group of autoimmune mediated diseases is still unknown. The most important factor contributing to poor outcome in patients with CTD is the presence of lung fibrosis. Early HRCT screening for lung involvement in patients with CTD is therefore justified.
The histological pattern is like that of usual interstitial pneumonia (UIP), the most frequent pattern in biopsies
from patients with IPF. Cryptogenic fibrosing alveolitis ap- pears to be relatively rare in patients with CTD. The pres- ence of a combination of radiological and histological pat- terns, e.g., those of nonspecific interstitial pneumonia (NSIP), lymphocytic interstitial pneumonia (LIP)/follicu- lar bronchiolitis and organizing pneumonia, should initiate further diagnostic work-up for a CTD. Recent publications suggested a prevalence of distinct histological patterns be- tween the various CTDs: NSIP in systemic sclerosis, orga- nizing pneumonia in polymyositis/dermatomyositis, follic- ular bronchiolitis and UIP in rheumatoid arthritis, and chronic bronchiolitis in Sjögren’s syndrome (Table 2).
Diffuse alveolar damage can complicate the clinical course of patients with CTD. The outcome is critical, es- pecially for those with preexisting interstitial lung dis- ease.
Pulmonary Scleroderma
Progressive systemic sclerosis is a generalized CTD af- fecting multiple organ systems (skin, lungs, arteries, heart and kidneys), but it has the highest incidence of lung fi-
Table 1. Serological markers of connective tissue disorders (modified from Sperber M [1999])
ANA Rheumatoid factor ACA Anti DNA Anti RNA CPK
Rheumatoid arthritis x
Systemic lupus erythematosus x x
Systemic sclerosis) x x
Polymyositis/dermatomyositis x
Mixed connective-tissue disease x x
Sjögren’s syndrome x x
ANA, Anti-nuclear antigen; ACA, anticentromere; CPK, creatinin phosphokinase
Table 2. Prevalence of patterns in connective-tissue disorders (modified from Hansell DM et al. [2005])
Pattern Progressive Rheumatoid Polymyositis/ Sjögren’s Mixed Systemic
systemic arthritis dermatomyositis syndrome connective-tissue lupus
sclerosis disease erythematosus
Usual interstitial pneumonia + +++ + + + +
Nonspecific interstitial pneumonia ++++ + ++ + ++ +
OP + +++ +++ + +
Diffuse alveolar damage + ++ ++ +++
LIP + ++
Alveolar hemorrhage + + ++ + +++
Upper-lobe fibrosis +
Aspiration ++ ++ +
Pulmonary hypertension +++ + + +
Bronchiectasis +++ ++
Obliterative bronchiolitis +++ +
Necrobiotic nodules +++
Pleural effusion + +++ +++
Diaphragm dysfunction ++ + +
OP, Organizing pneumonia; LIP, lymphocytic interstitial pneumonia
brosis. In this case, it is referred to as fibrosing alveolitis of systemic sclerosis. The lung is the fourth most common organ involved, after skin, arteries and esophagus. Patients can be of any age, but are mostly middle-aged The 5-year survival of patients with progressive systemic sclerosis is 70%. Most commonly, death is from aspiration pneumo- nia and respiratory failure.
The histology of progressive systemic sclerosis con- sists of overproduction and tissue deposition of collagen.
Lung fibrosis presents with a pattern typical of either NSIP (80%, cellular or fibrotic) or UIP (20%). The de- mographics of the disease reveal a 3:1 preponderance in women.
The chest X-ray findings include symmetric reticulon- odular densities, small cystic destruction and honey- combing, with a predominantly basal location. The ob- served volume loss is disproportionate to the symptoms.
The hemidiaphragms are elevated due to muscle atrophy.
Patients also show signs of recurrent infection due to as- piration. Esophageal dilatation is seen as a fluid-air-lev- el. Pleural effusion is found in <15% of patients.
On CT/HRCT, the spectrum of fibrotic changes ranges from ground-glass with or without fine intralobular retic- ular densities (NSIP pattern) to honeycombing associat- ed with traction bronchiectasis (UIP pattern). These changes show a subpleural and basal predominance.
Frequently, the findings remain consistent over a period of years, with no or very little progression. The esopha- gus is dilated and the lung parenchyma shows postinfec- tious changes. There is mild lymphadenopathy, which is usually not seen on chest X-ray, as well as mild pleural thickening (pseudoplaques). In addition, signs of pul- monary hypertension (enlarged pulmonary artery), inde- pendent of interstitial fibrosis and reflecting small-vessel disease (intimal proliferation, medial hypertrophy, myxo- matous changes), is present. Cardiomyopathy, due to is- chemia or based on infiltrative cardiomyopathy is anoth- er component of progressive systemic sclerosis.
Important take-home points to consider in patients with progressive systemic sclerosis are:
• Dilated esophagus should be looked for in patients with a newly diagnosed fibrosis.
• Systemic sclerosis should be considered in patients with newly diagnosed, fine reticular and microcystic parenchymal changes.
• Signs of pulmonary hypertension (out of proportion to the extent of lung disease) and reflecting vasculopathy should be noted.
• There is an increased risk of cancer, generally by a fac- tor of 1.8-6.5, in patients with this disease. Moreover, for lung cancer there is an 18-fold increased risk for adenocarcinoma and bronchoalveolar carcinoma.
• Scleroderma features (clinical and radiological) are seen in CREST (limited cutaneous systemic sclerosis:
calcinosis, Raynaud, esophageal dysmotility, sclero- dactyly, teleangiectasis), mixed connective tissue dis- ease), graft vs. host disease, carcinoid syndrome, and drug reactions. Up to 25% of all patients showing sys-
temic sclerosis-like features suffer from an overlap syndrome, with symptoms of one or more CTDs.
• In progressive systemic sclerosis, the outcome is sim- ilar for patients with UIP and NSIP, and is more strongly linked to the disease severity at presentation.
Rheumatoid Arthritis
This disease consists of subacute or chronic inflammato- ry polyarthropathy of unknown cause. Associated lung findings include fibrosis (mostly UIP pattern), organizing pneumonia, airways disease (bronchitis and bronchiolitis), pleural disease (pleuritis sicca) and (large) cavitating nod- ules (pulmonary nodules are always associated with sub- cutaneous nodules). Pleural involvement is the most com- mon thoracic manifestation of rheumatoid arthritis.
Histologically, rheumatoid nodules (pathognomonic), lymphoid follicles, UIP and NSIP patterns of fibrosis, and signs of organizing pneumonia are seen. The incidence of rheumatoid arthritis shows a 3:1 female to male predom- inance. However, extra-articular disease is more common in men, and more common in smokers. While patients may be of any age, the disease mostly occurs in middle- aged individuals. The 5-year survival is 40%, with death from infection, respiratory failure, or cor pulmonale.
Chest X-ray findings indicative of rheumatoid arthritis include signs of pleural disease, such as thickening or an effusion which may be transient, persistent over months, or relapsing, but is usually asymptomatic. Pleural find- ings are more commonly seen in men than in women.
Other findings include lower-zone fibrosis (honeycomb- ing) and volume loss. Pulmonary involvement may also include a cryptogenic organizing pneumonia (COP) pat- tern of disease. Nodules (5 mm-7cm) show signs of cav- itation in 50% of affected patients, may be PET positive, and are a more frequent finding in smokers. They also represent an increased risk for pneumothorax.
Airway disease is also evident radiographically, pre- senting as bronchial wall thickening and bronchiectasis.
Consolidations are present in patients with organizing pneumonia. Signs of recurrent infectious disease are also observed.
CT/HRCT findings of rheumatoid arthritis include pleural disease (thickening, effusion, empyema), pul- monary fibrosis with honeycombing, traction bronchiec- tasis, and parenchymal distortion (UIP pattern, indistin- guishable from that of IPF). Ground-glass and reticular densities (NSIP pattern) and features of a COP pattern of disease are seen. Nodules (up to 7cm in size) may mim- ic neoplasm, are frequently subpleural, and cavitate in
>50% of affected patients. obliterative bronchiolitis with a mosaic pattern is rarely seen. There are also signs of follicular bronchiolitis (subpleural, centrilobular, unsharp nodules <1 cm). While systemic vasculitis affecting the small vessels, usually in the skin, is found in rheumatoid arthritis, pulmonary vasculitis is exceptionally rare.
Cardiac signs include cor pulmonale and pericarditis.
Sclerosing mediastinitis is very rare.
Important take-home points concerning rheumatoid arthritis are:
• Pleural abnormalities are the most common abnormal thoracic findings.
• Parenchymal fibrosis is evident in 5% of chest X-rays but in up to 40% of HRCT findings. It is mostly of the UIP pattern and indistinguishable from IPF.
• Associated nodules and pleural disease help to differ- entiate rheumatoid arthritis from IPF.
• There is an increased risk for empyema in patients with pleural disease.
• Patients with (cavitating) nodules are at increased risk for pneumothorax.
• Many of the available treatment options for rheuma- toid arthritis are associated with lung toxicity (see www.pneumotox.com).
Pulmonary Dermatomyositis/Polymyositis
This idiopathic, immune-mediated, inflammatory myo- pathic disorder has multiple systemic manifestations.
Females are affected twice as often as males. Patients may be of any age but are mostly middle-aged. Pulmonary in- volvement is associated with a poorer prognosis. The 5- year survival rate ranges from 35 to 77%. Findings con- sistent with diffuse alveolar damage are predictive of poor prognosis.
In the lungs, the histological findings have prognos- tic implications. Most typical is a mix of various find- ings that include UIP and NSIP pattern (cellular and fi- brotic type) patterns of fibrosis and organizing pneu- monia.
The chest X-ray of patients with pulmonary dermato- myositis/polymyositis shows fibrotic changes, with a subpleural and basal distribution. Volume loss can be observed. Other findings include sequelae after recur- rent aspiration pneumonia and consolidations. The dif- ferential diagnosis includes aspiration or organizing pneumonia.
The CT/HRCT findings depend on the nature of the parenchymal changes. Ground-glass (diffuse alveolar damage), fine reticular densities (NSIP pattern) honey- combing and traction bronchiectasis (UIP pattern), and consolidations (COP pattern) may be present simultane- ously.
There disease shows a basal and subpleural predomi- nance. Frequently, sequelae of aspiration pneumonia and/or opportunistic pneumonia are seen.
Important take-home points to keep in mind when evaluating patients with suspected pulmonary dermato- myositis/polymyositis are:
• A mixture of radiological and histological findings, in- cluding NSIP-, UIP-, COP-, and diffuse alveolar-type damage, is suggestive of pulmonary dermatomyositis/
polymyositis.
• The disease is sometimes associated with other collagen- vascular diseases (systemic lupus erythematosus, sclero- derma, rheumatoid arthritis, Sjögren’s syndrome).
• There is an increased risk for malignancy (especially of the breast, lung, ovary, and stomach) which is concur- rently diagnosed within 1 year in up to 20% of patients.
• Whole-body magnetic resonance imaging (short tau inversion recovery, STIR) is used to demonstrate in- flammatory soft-tissue burden.
Sjögren’s Syndrome
Primary Sjögren’s syndrome is a systemic inflammatory disorder affecting exocrine glands (dry mouth and dry eye). The incidence of extraglandular involvement of the lung varies from 9 to 75%. The secondary form of Sjögren’s syndrome is associated with collagen-vascular disease (systemic lupus erythematosus, rheumatoid arthritis, and pulmonary dermatomyositis/polymyositis).
There is a well-established association with LIP and an overlap between LIP, amyloid deposition, sarcoid- like reactions, and Sjögren’s syndrome. Middle-aged women are affected much more often than men, the ra- tio being 9:1.
Histologically, the tissues of patients with Sjögren’s syndrome show widespread tissue infiltration by poly- clonal B lymphocytes.
The chest X-ray findings in this disease consist of bi- lateral interstitial opacities, consolidations, bilateral nod- ules, and pleural effusion (when associated with cardio- vascular disease, such as systemic lupus erythematosus, or rheumatoid arthritis).
CT/HRCT findings include pulmonary fibrosis with either a UIP or a LIP pattern. The latter consists of dif- fuse ground-glass opacities and thin-walled cysts, that, while widely distributed, show a subpleural predomi- nance. Airway disease, e.g., bronchiolitis with air-trap- ping, tree-in-bud sign, and bronchitis, is common.
Additional findings are organizing pneumonia and pul- monary hypertension.
Important take-home points in evaluating patients with Sjögren’s syndrome are:
• Generally, the risk for malignoma is doubled, and there is an up to 40 times increased risk for developing a lymphoma. In this context, mediastinal lym- phadenopathy (visible on chest X-ray) and new intra- pulmonary consolidations are suggestive for the devel- opment of nodular lymphoid hyperplasia or a malig- nant lymphoma.
• Pleural effusion suggests an association with a colla- gen-vascular disease (rheumatoid arthritis or systemic lupus erythematosus).
Systemic Lupus Erythematosus
This chronic collagen vascular disease involves blood vessels (vasculitis with and without pulmonary hyperten- sion), serosal surfaces, joints (pericardiac effusion, pleur- al effusion), kidneys, central nervous system, and skin.
Thoracic manifestations are seen in up to 70% of pa-
tients. The disease occurs ten times more often in women
than in men. The etiology is unknown. The most common causes of death related to this chronic (10 years) disease are sepsis and renal failure.
Histologically, hematoxylin bodies are pathognomonic but they are rarely seen in the lungs. Alveolar hemor- rhage reflects endothelial damage.
Chest X-ray shows evidence of (painful) pleural dis- ease, with thickening or effusion (usually small).
Consolidations may be of various origin. Consequently, the differential diagnosis should consider opportunistic infection, hemorrhage, pneumonitis, organizing pneumo- nia, and infarcts. The diaphragm may be elevated due to muscle dysfunction, with plate-like atelectasis and signs of shrinking lung syndrome. Other findings are cardiac enlargement (pericardial effusion) and lung fibrosis (seen in <5% of patients).
CT/HRCT will reveal mild adenopathy in 20% of pa- tients. Ground glass and/or consolidations, due to hem- orrhage, pneumonia, pneumonitis, are seen. Airway dis- ease manifests as tree-in-bud sign, bronchiectasis, and bronchial wall thickening. Fibrosis (UIP pattern) is seen in up to 15% of patients, and in autopsy in up to 30%.
Pulmonary hypertension occurs primary to vasculitis and secondary to chronic embolism. Cavitating nodules indicate areas of infarct.
Important take-home points in the diagnosis of sys- temic lupus erythematosus include:
• Acute pneumonitis with diffuse hemorrhage is rare but has a very high mortality. It is mostly associated with renal infiltration and multi-organ failure.
• Patients are at increased risk for opportunistic infec- tions.
• There is increased risk for pulmonary embolism; in- creased levels of antiphospholipid antibodies are pre- sent in 40% of patients.
• Patients with drug-induced systemic lupus erythe- matosus have a better prognosis.
Pulmonary Vasculitis/Diffuse Alveolar Hemorrhage
Non-infectious systemic necrotizing vasculitides are a large and varied group of disorders characterized by in- flammation and necrosis of blood vessels (Table 3).
Pulmonary involvement is seen in Wegener granulomato- sis, Goodpasture syndrome, Church-Strauss disease, mi- croscopic polyangiitis, Behçet disease, and Takayasu dis- ease. The combined involvement of the lungs and kidneys by some of these diseases is also described as pulmonary- renal syndrome.
Wegener Granulomatosis
The classic form of Wegener granulomatosis affects the sinuses, kidneys, and lungs resulting in a frequent triad of symptoms comprising sinusitis and/or tracheobronchitis, pathological chest X-ray (with or without signs of he- moptysis), and microhematuria. However, any part of the body may be affected. Females and males are affected equally and at any age (mostly age 40-55). Airway in- volvement is more frequent in men. The most common cause of death is renal failure. With treatment, the 24- month survival is 80%.
Histologic findings include necrotizing granulomatous vasculitis of the small to medium-sized vessels, without associated infection. Serologically, up to 90% of patients are positive for c-ANCA (circulating antineutrophil cyto- plasmic antibodies). However, c-ANCA findings should not replace histological confirmation!
The chest X-ray findings in Wegener granulomatosis include the presence of single or multiple nodules, 50%
of which are cavitating. The cavitations may be thick- walled. There are multifocal, non-segmental, or diffuse consolidations, the latter due to hemorrhage and/or vas- cular necrosis. Pleural effusion is seen in 20% of patients.
Table 3. CT findings associated with pulmonary vasculitis syndromes (modified from Marten K et al. [2005])
Vasculitis Size of involved Pulmonary-renal Pulmonary Pulmonary
vessels
a, bsyndrome hemorrhage hypertension
Wegener Small 50-75% In up to 8%, diffuse –
Church Strauss Small Up to 25% Very rare, diffuse –
Microvascular polyangiitis Small In 75-100% Very rare, diffuse –
Polyarteritis nodosa Medium – Very rare, diffuse –
(associated with hepatitis B)
Giant-cell arteritis Large – Rare, focal Rare
Takayasu Large – Rare, focal Rare
Rheumatoid arthritis CTD – Very rare, diffuse Up to 60%
Systemic sclerosis CTD – Rare, diffuse, 10-60%
with necrotizing vasculitis
Mixed connective-tissue disease CTD – Rare, diffuse Up to 45%
Systemic lupus erythematosus CTD Up to 60%, late In 4% (but potentially 5-45%
more frequent), diffuse
a
According to the Chapel Hill classification, 2000
b