CHAPTER 101 Pulmonary Hemorrhage and Vasculitis

A large number of conditions may result in pulmonary hemorrhage (Table 101-1). Broadly speaking, pulmonary hemorrhage may originate in the airways or lung parenchyma. Airway-related pulmonary hemorrhage is commonly the result of bronchitis, bronchiectasis, or malignancy, whereas parenchymal hemorrhage may result from pulmonary infarction, necrotizing pneumonias, toxic inhalational injury, malignancy, or causes of diffuse alveolar hemorrhage, with or without pulmonary vasculitis.

TABLE 101-1 Differential Diagnosis of Pulmonary Hemorrhage

Cause	Features
Airway	Bronchitis Bronchiectasis Endobronchial lesions (benign or malignant) Malignancy
Parenchyma
Diffuse alveolar hemorrhage with capillaritis	Wegener’s granulomatosis Microscopic polyangiitis Goodpasture syndrome Connective tissue diseases Systemic lupus erythematosus Antiphospholipid antibody syndrome Behçet syndrome Henoch-Schönlein purpura Pauci-immune glomerulonephritis Drug-induced Mixed cryoglobulinemia
Diffuse alveolar hemorrhage without capillaritis	Idiopathic pulmonary hemosiderosis Systemic lupus erythematosus Coagulation disorders Pulmonary veno-occlusive disease Pulmonary capillary hemangiomatosis Diffuse alveolar damage Mitral stenosis Drug-induced (penicillamine) Lymphangioleiomyomatosis Tuberous sclerosis Hematopoietic stem cell transplantation Leukemia
Other	Pulmonary arteriovenous malformation

DIFFUSE ALVEOLAR HEMORRHAGE

Etiology and Pathophysiology

Diffuse alveolar hemorrhage (DAH) is present when the cause of the hemorrhage primarily affects the alveolar capillary surface. Causes of DAH may be divided into conditions associated with inflammation of the pulmonary capillaries, referred to as capillaritis, and those without capillaritis, so-called bland DAH (see Table 101-1). Pulmonary capillaritis refers to alveolar interstitial inflammation consisting of neutrophil accumulation associated with fibrinoid necrosis, producing injury to the basement membrane and resulting in leaky capillaries. Repeated bouts of inflammation and hemorrhage result in the deposition of hemosiderin-laden macrophages. In patients with bland DAH, red blood cells fill the alveoli in the absence of capillary inflammation. Note that there is occasionally some overlap in this classification system; Goodpasture syndrome, collagen vascular disease, and systemic lupus erythematosus may be associated with pulmonary hemorrhage with or without pulmonary capillaritis. For DAH with capillaritis, autoantibodies directed against the alveolar basement membrane produces direct damage or basement membrane injury results from immune complex deposition.

Manifestations of Disease

Clinical Presentation

The clinical manifestations of DAH with or without capillaritis are relatively similar, and consist of cough, dyspnea, and hemoptysis, usually over a few days’ or weeks’ duration. Note that the absence of hemoptysis does not exclude DAH because hemoptysis may occur later in the course of a patient’s presentation, or occasionally will not be seen at all, even with extensive alveolar bleeding. However, at least with extensive bleeding, the patient’s hematocrit usually falls; when combined with extensive thoracic imaging findings and the proper clinical context, this should suggest the correct diagnosis. As a result of repeated hemorrhage, iron deficiency anemia may be present. In patients with DAH associated with connective tissue or rheumatologic syndromes, inflammation in other organ systems, such as sinusitis, arthritis, and glomerulonephritis, may be present. Increasingly bloody sequential bronchoalveolar lavage, often with hemosiderin-laden macrophages, confirms the diagnosis of DAH, but is not specific for the underlying insult producing the hemorrhage. In particular, when pulmonary-renal syndromes are responsible for DAH, red cell casts and proteinuria are often found in the urine. The erythrocyte sedimentation rate is frequently elevated in patients with DAH, but is a nonspecific finding.

Diagnosis

The diagnosis of DAH is usually suspected on the basis of the rapid interval appearance of bilateral pulmonary opacities in an anemic patient with cough, shortness of breath, and hemoptysis, often in the context of a condition known to be associated with alveolar hemorrhage. Diffusing capacity of carbon monoxide is characteristically elevated and may specifically suggest the diagnosis of DAH, but the diagnosis usually requires confirmation with progressively bloody fluid on bronchoalveolar lavage. Occasionally DAH may be the manifestation of an underlying condition, and further diagnostic testing will then be directed at identifying the cause of DAH. A number of specific diseases associated with DAH will be discussed in the remainder of this chapter.

Imaging Techniques and Findings

Radiography

Chest radiography in patients with DAH of any cause will show focal, multifocal, or diffuse ground-glass opacity and/or consolidation, usually in the presence of a normal heart size and without pleural effusion. Findings often predominate in the dependent regions of lung and, in most patients, appear relatively quickly. A reverse bat wing appearance may occasionally be seen. Shortly after the appearance of lung opacities, a linear and reticular network may be evident superimposed on the regions of ground-glass opacity, representing interlobular septal thickening. The pulmonary opacities clear slowly over a period of 7 to 14 days if there are no superimposed processes or repeated episodes of alveolar hemorrhage. Recurrent bouts of alveolar hemorrhage may produce areas of fibrosis and scarring, manifesting on chest radiography as areas of coarse linear and reticular opacity with architectural distortion.

CT

CT and high-resolution CT (HRCT) typically show multifocal or diffuse bilateral ground-glass opacity and consolidation. Ground-glass attenuation poorly defined nodules (Fig. 101-1) may occur. Often, a network pattern of smooth interlobular septal thickening is superimposed in the regions of ground-glass opacity.

FIGURE 101-1 Diffuse alveolar hemorrhage: centrilobular nodules. This axial CT scan shows diffuse ground-glass opacity centrilobular nodules found to represent pulmonary hemorrhage on biopsy.

VASCULITIS

The histopathologic hallmark of vasculitis is the presence of angiocentric inflammation, usually extending through all layers of blood vessel walls. Fibrinoid necrosis and perivascular fibrosis are also commonly present, and may ultimately lead to vascular obliteration and occlusion. Both leukocytoclastic (neutrophil-predominant) and granulomatous (lymphocyte-predominant) vasculitic patterns may occur. Most pulmonary vasculitides share the common pathogenesis of immune complex deposition in the vessel wall, with activation of complement and cellular chemotaxis, leading to an enzymatic and inflammatory cascade that ultimately produces vascular damage. The whole process may be antigen-driven, which may explain the association of a number of vasculitides with viral infections and collagen vascular disorders. However, some granulomatous vasculitides may be the result of cell-mediated immunity rather than immune complex deposition. A number of vasculitides may affect the thorax, the lung in particular. The main histopathologic derangement of vasculitides affecting the lung is capillaritis, perhaps associated with inflammation of slightly larger vessels (Table 101-2).

TABLE 101-2 Common Causes of Pulmonary Vasculitis

Location	Cause
Large vessels (aorta and major branch vessels)	Takayasu arteritis Giant cell (temporal) arteritis Behçet syndrome *
Medium-sized vessels (visceral arteries)*^†	Polyarteritis nodosa Kawasaki disease Behçet syndrome *
Small vessels (arterioles, capillaries, venules, distal intraparenchymal small arteries leading to arterioles)	Wegener’s granulomatosis Microscopic polyangiitis Isolated pulmonary capillaritis Churg-Strauss syndrome Henoch-Schönlein purpura Mixed cryoglobulinemia

* Some overlap in level of involvement may occur, particularly with either large or small vessel vasculitides involving medium-sized vessels.

† Visceral arteries = coronary, hepatic, mesenteric, and renal arteries

WEGENER’S GRANULOMATOSIS

First described in 1936, Wegener granulomatosis (WG) is a clinical syndrome characterized by a necrotizing granulomatous vasculitis involving the upper and lower respiratory tract and kidneys. WG is the most common vasculitis to affect the lungs.

Prevalence and Epidemiology

WG is a rare condition that occurs more commonly in whites but with an almost equal gender incidence, perhaps slightly more common in men. WG may occur at any age, even adolescence, but is most commonly encountered in patients between 35 and 55 years of age.

Manifestations of Disease

Clinical Presentation

Patients with WG typically present with fever and upper respiratory symptoms, such as nasal discharge and sinus symptoms. Constitutional symptoms, such as fatigue, weight loss, and malaise, are common. Cough, hemoptysis, shortness of breath and chest pain are common in patients with pulmonary involvement. Skin lesions, hearing loss, and ulcers in the oral and nasal cavities may occur. C-ANCA antibodies (antineutrophil cytoplasmic autoantibodies) with PR-3 specificity are elevated in more than 90% of patients with WG. C-ANCA antibodies are relatively specific for WG, but may be seen in microscopic polyangiitis, although protoplasmic-staining antineutrophil cytoplasmic antibodies (p-ANCA) is more suggestive of the latter. P-ANCA antibodies are seen in about 25% of patients with WG.

Imaging Techniques and Findings

Radiography

Chest radiographs are abnormal in up to 85% of patients with WG at some point during the course of the illness. The most characteristic imaging manifestation of WG is multiple, usually bilateral, nodules or masses typically measuring 2 to 4 cm, often associated with cavitation (Fig. 101-2). Pulmonary opacities and cavities in patients with WG may occasionally be much larger. WG-related pulmonary cavities often have a rather thick, irregular internal wall, and air-fluid levels are occasionally seen. Ground-glass opacity surrounding the cavities is a frequent finding and is usually caused by adjacent alveolitis or pulmonary hemorrhage.

FIGURE 101-2 Wegener’s granulomatosis, lung cavities. This frontal chest radiograph shows multiple cavities of variable wall thickness. Solid nodules are also present bilaterally.

CT

Thoracic CT scanning in patients with WG also typically shows multiple bilateral nodules and/or masses,¹ and is far more sensitive for the detection of cavitation than chest radiography. In fact, most nodules measuring more than 2 cm in patients with WG will show cavitation on CT (Fig. 101-3). Nodules and cavities in patients with WG have no particular zonal predilection, and are somewhat randomly distributed throughout the lungs.

FIGURE 101-3 Wegener’s granulomatosis, lung cavity. This axial CT scan shows an irregular-appearing subpleural right lung cavity of indeterminate wall thickness.

Patchy multifocal or diffuse ground-glass opacities, often with areas of consolidation,¹ is the second most common thoracic imaging manifestation of WG, and may occur in the absence of pulmonary nodules. These opacities are usually the result of pulmonary hemorrhage. Occasionally, areas of consolidation may be subpleural or peribronchiolar in distribution, simulating organizing pneumonia; the so-called atoll or reverse halo sign may also be seen (Fig. 101-4).

FIGURE 101-4 Wegener’s granulomatosis, atoll sign. This axial CT scan shows bilateral subpleural opacities with central ground-glass attenuation and peripheral consolidation, consistent with the atoll or reverse ground-glass halo sign. The appearance is suggestive of organizing pneumonia.

Tracheobronchial wall thickening and narrowing may be present in patients with WG,¹ and may even lead to atelectasis. Typically, airway involvement in patients with WG predominates in the subglottic region and extends a variable distance caudally (Fig. 101-5). The airway wall thickening is circumferential and often nodular and irregular, occasionally resulting in tracheobronchial stenosis. The tracheobronchial thickening may occasionally calcify.

FIGURE 101-5 Wegener’s granulomatosis, diffuse tracheobronchial thickening. This axial CT scan shows circumferential, noncalcified tracheal thickening.

Pleural effusions and lymphadenopathy may occur in patients with WG, but are nonspecific findings and are relatively uncommon overall.

Pulmonary parenchymal opacities in patients with WG may resolve during treatment. Cavities may occasionally even enlarge during treatment, although wall thickness usually becomes progressively thinner and the internal wall character becomes smoother.

Differential Diagnosis

From Clinical Presentation

A number of serologic abnormalities may be seen in patients with WG, including anemia, elevated rheumatoid factor, and elevated erythrocyte sedimentation rate, and other uncommon serologic test results. Most of these laboratory findings are fairly nonspecific. Recurrent alveolar hemorrhage is common in patients with WG, is often subclinical and may lead to the detection of hemosiderin-laden macrophages on bronchoscopy with lavage. The most useful test for the evaluation of patients with WG is the c-ANCA antibody, which is elevated in more than 90% of patients with WG. C-ANCA antibody titers may also be used to follow disease course. Although c-ANCA antibody titers may be elevated in other diseases, in the proper clinical context and with suggestive radiologic features, the diagnosis of WG can be confidently established when c-ANCA antibodies are present.

The term limited Wegener’s granulomatosis refers to a clinical syndrome essentially identical to the full-blown WG syndrome but without systemic (especially renal) involvement clinically; upper respiratory tract manifestations are usually present. Histopathologically, WG manifestations are often present in the viscera of patients with limited WG, and therefore it is probably appropriate to consider limited WG as one end of the spectrum of WG rather than as a separate condition.

MICROSCOPIC POLYANGIITIS

Microscopic polyangiitis is a small-vessel vasculitis ² that closely resembles polyarteritis nodosa, except that the latter usually involves medium-sized vessels, often involves abdomen viscera, and rarely produces DAH.