Lung Vasculitis and Alveolar Hemorrhage

The lung is one of the target organs in systemic vasculitides affecting small-sized vessels. The lung is intact in polyarteritis nodosa and other medium-sized vasculitides because vasculitis is absent in the lung parenchyma. All vasculitides, primary or secondary to any other cause, affecting capillaries, can present with lung manifestations. Two histological characteristics are found: granuloma and capillaritis. They can present together or independently. Clinical expression is linked to histological presentation: alveolar hemorrhage (AH) in cases of lung capillaritis, and nodules associated with small-sized vessels in patients with granuloma. This issue of Seminars in Respiratory and Critical Care Medicine focuses on AH, which is present in vasculitis as well as in other diseases, such as Goodpasture syndrome, which is not a vasculitis in the strictest sense but in which anti-glomerular basement membrane antibodies can be found together with anti-neutrophil cytoplasmic antibodies (ANCAs). Clinical description, complementary investigations, and therapeutic approaches are considered in most articles in this issue. It should be emphasized that lung hemorrhage is not, in all patients, an acute clinical manifestation associated with other clinical manifestations of vasculitis; it can be present several weeks or months before diagnosis, characterized only by bloody sputum. When malignant or infectious disease has not been found, these early symptoms could indicate the presence of vasculitis. Unfortunatly, when AH occurs, the kidneys are often involved and glomerulonephritis is present. Prognosis of such pneumo-renal symptoms is poor, and, when patients survive, renal insufficiency remains and sometimes leads to end-stage renal failure.

Vasculitides affecting lungs are not homogeneous, even if respiratory manifestations are not included in their phenotype. This has been shown in Churg-Strauss syndrome, in which two phenotypes coexist,[1] [2] one characterized by ANCA-associated vasculitis and predominantly renal involvement and mononeuritis multiplex, the second, without ANCAs, in which cardiomyopathy is observed more frequently than in patients without ANCAs.

The existence of different phenotypes is less clear in Wegener granulomatosis. We know from clinical practice and series published in the literature that some patients present mainly with ear, nose, and throat (ENT) involvement and other manifestations, such as lung nodules reflecting a predominant granulomatous disease. On the other hand, patients' disease can be characterized by rapid crescentic glomerulonephritis and AH reflecting a predominant vasculitis pattern. However, overlap is frequent between clinical forms, and clinical manifestations can change during follow-up or at the time of relapse. Such categorization of patients reflects different pathogenetic mechanisms that could impact treatment decisions. We could hypothesize, even though it has never been proven, that a treatment of more than 2 years would be useful for patients with a predominant granulomatous disease and that 2 years would be sufficient for patients with a predominantly vasculitic pattern. The existence of different phenotypes in Wegener granulomatosis is based only on clinical experience and is not supported by studies, including genetic studies. We hope that GWAS (genome wide-association studies) on patients with Wegener granulomatosis will be able to identify polymorphisms associated with the patients' clinical presentations. Trials are also needed to support therapeutic options.

The prognosis of AH is controversial, although it now seems more clear. When abundant AH is observed, the outcome can be life-threatening. However, if we consider all cases of AH in vasculitis, the prognosis is favorable. This is not surprising; it has been shown that patients with severe AH simultaneousely had renal insufficiency.[3] In multivariate analysis, only renal insufficiency is considered a factor of poor prognosis, not AH, because renal involvement surpasses AH as a prognostic factor.[3]

Treatment of lung manifestations is included in vasculitis treatment. The combination of corticosteroids and cytotoxic agents is prescribed in Wegener granulomatosis and in other cases of vasculitis with factors of poor prognosis. Steroids alone can be prescribed when factors of poor prognosis are absent. Plasma exchanges are considered when severe AH is present, with or without concomitant renal insufficiency. Such treatment has not been validated by controlled clinical trials, but its efficacy has been shown empirically. Rituximab has been evaluated in the treatment of systemic necrotizing vasculitis,[4] [5] but this has not been the case for all visceral manifestations, especially those involving the lungs. Future trials are needed to determine whether the therapeutic response is the same for lung diseases as for other visceral involvement, and, in cases of lung involvement, whether the response is comparable for patients with lung capillaritis and those with predominant granuloma.

I thank the authors for their contributions to this issue; and I hope that these articles will be of long-standing value to the readers.

REFERENCES

• 1 Sablé-Fourtassou R, Cohen P, Mahr A French Vasculitis Study Group et al. Antineutrophil cytoplasmic antibodies and the Churg-Strauss syndrome.  Ann Intern Med. 2005;  143 (9) 632-638
• 2 Sinico R A, Di Toma L, Maggiore U et al.. Prevalence and clinical significance of antineutrophil cytoplasmic antibodies in Churg-Strauss syndrome.  Arthritis Rheum. 2005;  52 (9) 2926-2935
• 3 Guillevin L, Pagnoux C, Seror R, Mahr A, Mouthon L, Le Toumelin P. French Vasculitis Study Group (FVSG) . The Five-Factor Score revisited: assessment of prognoses of systemic necrotizing vasculitides based on the French Vasculitis Study Group (FVSG) cohort.  Medicine (Baltimore). 2011;  90 (1) 19-27
• 4 Stone J H, Merkel P A, Spiera R RAVE-ITN Research Group et al. Rituximab versus cyclophosphamide for ANCA-associated vasculitis.  N Engl J Med. 2010;  363 (3) 221-232
• 5 Jones R B, Tervaert J W, Hauser T European Vasculitis Study Group et al. Rituximab versus cyclophosphamide in ANCA-associated renal vasculitis.  N Engl J Med. 2010;  363 (3) 211-220