Patients present with hemoptysis, fever may be seen, on serum examination antineutrophil cytoplasmic antibodies (ANCA) may be present; antibodies are a sign of the underlying vasculitis. Examination of ANCA antibodies will show more common anti-proteinase 3 (PR3) [2]. On X-ray and CT scan, classical GPA will show infarct with less dense center parts (Fig. 11.2). Several infarcts can be present. If only small vessels are affected, the CT scan is less characteristic with diffuse interstitial infiltrates. Usually both lungs are involved. In these cases hemoptysis will be more pronounced, and on BAL alveolar hemorrhage will be diagnosed.

For a clinical diagnosis, the following features are required: histopathological evidence of granulomatous inflammation, upper airway involvement, laryngo-tracheo-bronchial involvement, pulmonary involvement (X-ray/CT), antineutrophilic cytoplasmic antibody positivity, and renal involvement [3].

If infarcts are present, these will have a similar cuneiform appearance as in hemorrhagic infarct; however, the cut surface is yellowish white with a hemorrhagic border. If only small vessels are involved, the cut surface shows hemorrhage without any further characteristics (Fig. 11.3).

The vasculitis is characterized by a destructive infiltration of the vessel wall by neutrophils, rarely also by eosinophils (Fig. 11.4). The vasculitis causes fibrinoid necrosis of the endothelium and bleeding, which depending on the size of the vessels can be focal or massive. The necrosis of endothelia is the most important sign of vasculitis, because in the differential diagnosis, transmigration of neutrophils in infections can be very prominent and therefore cannot be regarded as the proof of vasculitis. More often vasculitis causes thrombosis and vascular occlusion, which consequently lead to infarction and necrosis of the parenchyma. Since most often there is arterial occlusion, the infarcts are ischemic.

Epithelioid cell granulomas should be present in this new classification, as granulomatosis is now a requisite of the diagnosis (Fig. 11.5). Cases which present exclusively with vasculitis including those with capillaritis are now included into microscopic polyangiitis (see below).

In later stages, and under therapy, the neutrophils might be replaced by lymphocytes. In these cases, one has to exclude an infectious, mainly viral-induced secondary vasculitis (Fig. 11.6).

GPA usually presents with PR3 antibodies. ANCA testing nowadays is a routine in clinical practice. But be aware that ANCA can be negative in early stages of GPA, and ANCA can be positive in some infectious secondary vasculitis.

GPA can start with unspecific syndromes, even organizing pneumonia without vasculitis [4]; in these cases the patients should be observed until specific features will be present.

GPA patients will be treated primarily with corticosteroids; if non-responding, an immunosuppressive treatment with drugs like cyclophosphamide is the second choice.

GPA can be regarded as an autoimmune disease. ANCA directed against proteinase 3 (PR3) are preferentially associated with GPA. Anti-PR3 antibodies can activate neutrophils in vitro. A significant association of PR3-ANCA and HLA-DP and the genes encoding alpha-1 antitrypsin and PR3 have been found [2]. How these are associated with the production of autoantibodies is not understood. Lymphocytes are also involved in GPA, mainly lesional T cells, which exhibit pro-inflammatory properties and promote granuloma formation. Apart from T cells, dendritic cells are abundantly present at the sites of inflammation and locally orchestrate the immune response [5].

EGPA was first described in 1951 as a small- and medium-sized vessel vasculitis, characterized by an almost constant association with asthma and eosinophilia. Vasculitis typically develops in a previously asthmatic middle-aged patient. Asthma is severe, associated with eosinophilia and extrapulmonary symptoms. Some patients report allergic rhinitis without asthma. Most frequently EGPA involves the peripheral nerves and skin (allergic superficial eosinophilic vasculitis). Other organs such as the heart, kidney, and gastrointestinal tract, if affected, confer a poorer prognosis. In about 30–40 % of the patients, anti-myeloperoxidase (MPO) antineutrophil cytoplasm antibodies (ANCA) are present [2]. EGPA patients with anti-MPO ANCA suffered more, albeit not exclusively, from vasculitis symptoms, such as glomerulonephritis, mononeuritis multiplex, and alveolar hemorrhage, whereas ANCA-negative patients more frequently develop heart involvement [6, 7]. In recent time EGPA has been linked to new antiasthmatic drugs such as montelukast. However, new investigations have ruled out this as a possible cause of the disease [8].

Elevated IgG4 levels were found in active EGPA patients compared to controls. Serum IgG4 correlated with the number of eosinophils. During treatment and in disease remission, both IgG4 level and IgG4/IgG ratio dropped [9].

The major findings at X-ray and CT scan are diffuse interstitial infiltrates; hemorrhage will be seen on CT scans (Fig. 11.7). If eosinophilic pneumonia is present, this will cause more density and focally also ground glass changes.

On cut surface, pneumonia (consolidations) and hemorrhage are the major, however, unspecific findings.

The hallmark is an eosinophilic vasculitis, again with destruction of the vessel wall and fibrinoid necrosis of the endothelium. Besides numerous eosinophils, also macrophages and histiocytes can be seen within these infiltrations. This causes focal bleeding if capillaries are affected and hemorrhage if larger vessels are involved. In older lesions or in patients under therapy, an eosinophilic infiltrate can persist up to 1 month, and hemosiderin-laden macrophages tell the story about previous bleeding. In florid cases there might be also an eosinophilic pneumonia with parenchymal necrosis. Granulomas are not associated with the vasculitis. In areas with parenchymal necrosis, a foreign body giant cell granulomatous reaction can be seen around the necrosis (Fig. 11.8).

A strong association with IL10 promoter polymorphisms was detected in EGPA. Other associations, including CTLA4, CD226, and copy number polymorphisms of FCGR3B need to be validated in further investigations [10].

In most cases patients will respond to corticosteroid treatment, rarely an immunosuppressive therapy might be necessary. Encouraging results have been reported for the treatment of EGPA with rituximab or with the eosinophil-targeted antiinterleukin-5 agent mepolizumab [11].

The nomenclature remains a source of confusion: (1) Is vessel inflammation or the presence of ANCAs essential for the diagnosis of EGPA? (2) Are granulomas required for the diagnosis, and what type of granulomas should be seen? (3) Is eosinophilic pneumonia in EGPA another disease or just a variant? (4) Is hypereosinophilic syndrome a variant of EGPA?

As the understanding of the relation between the vasculitis and the eosinophilic proliferation is profoundly lacking, these questions so far cannot be answered.

In a VATS biopsy, there is hemorrhage without any specific morphology other than bleeding. The specimen should be sectioned in a 90° angle to the axis of the blood vessels to get the best cross sections of the larger vessels.

In MPA small vessels are involved. There is a neutrophilic rarely eosinophilic granulocytic infiltration within capillary walls, also arterioles and venules can be affected. Since necrosis of the endothelial cells will cause disruption of the vessel walls, focal bleeding (alveolar hemorrhage) will result. As this process recurs, macrophages are following and ingest the blood. The histological picture is not easy to interpret; however, a strictly to the capillary wall-associated granulocytic infiltration, and no outside accumulation within alveoli, as well as the scattered hemosiderin-laden macrophages will guide to the correct diagnosis (Fig. 11.9). Granulomas as well as infarct are absent.

A higher mortality is seen in patients with MPA-associated fibrosing interstitial lung disease (ILD) compared to those with peripheral nervous system involvement [19]. This was also confirmed in the study by Katsumata et al [20].