Management of Alveolar Hemorrhage in Lung Vasculitides

ABSTRACT

Alveolar hemorrhage (AH) is an important pulmonary manifestation of small vessel vasculitis because severe presentations are the most common vasculitic cause of early death. Renal vasculitis is usually present with AH; the combination is known as pulmonary-renal syndrome. Early diagnosis and intensive therapy are of particular importance to reduce early mortality and improve longer-term outcomes. The commonest immune-mediated cause of AH is anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) (80%), with other vasculitides, including systemic lupus erythematosus and anti-glomerular basement membrane disease accounting for 20%. One quarter of AAV patients develop AH, which when mild is associated with a good outcome, but mortality rises to 50% for cases with respiratory failure requiring ventilator support. The prognosis of AH in the other vasculitides is generally favorable, but cases are rare and experience is limited. Treatment follows similar regimens to those for other AAV presentations, although when severe there is widespread use of parenteral glucocorticoids together with plasma exchange. These interventions have developed empirically supported by a theoretical rationale but have not been validated by randomized clinical trials. Sepsis and cardiovascular and thromboembolic events are important early complications. and long-term follow-up is required to monitor for and prevent relapse and manage disease-related damage. A minority of cases develop on a background of pulmonary fibrosis, or progressive pulmonary fibrosis develops after vasculitis has gone into remission.

KEYWORDS

Alveolar - hemorrhage - vasculitis - lung - ANCA - management

REFERENCES

• 1 Rabe C, Appenrodt B, Hoff C et al.. Severe respiratory failure due to diffuse alveolar hemorrhage: clinical characteristics and outcome of intensive care.  J Crit Care. 2010;  25 (2) 230-235
• 2 Casian A L, Berden A, Jayne D RW. Alveolar haemorrhage in ANCA associated vasculitis: a retrospective analysis from the European Vasculitis Study Group.  NDT PLUS. 2010;  3 (suppl 3) iii278
• 3 Guillevin L, Durand-Gasselin B, Cevallos R et al.. Microscopic polyangiitis: clinical and laboratory findings in eighty-five patients.  Arthritis Rheum. 1999;  42 (3) 421-430
• 4 Hashimoto H, Yano T, Yoshida M et al.. Clinical and epidemiological analysis of anti-neutrophil cytoplasmic antibodies (ANCA) associated vasculitis from a nationwide survey in 1998 in Japan, Annual Report of The Research Committee of Intractable Vasculitis Diseases, The Ministry of Health and Welfare of Japan, 1999. 
• 5 Travis W D, Carpenter H A, Lie J T. Diffuse pulmonary hemorrhage: an uncommon manifestation of Wegener's granulomatosis.  Am J Surg Pathol. 1987;  11 (9) 702-708
• 6 Travis W D, Hoffman G S, Leavitt R Y, Pass H I, Fauci A S. Surgical pathology of the lung in Wegener's granulomatosis: review of 87 open lung biopsies from 67 patients.  Am J Surg Pathol. 1991;  15 (4) 315-333
• 7 Yoshimura N, Matsubara O, Tamura A, Kasuga T, Mark E J. Wegener's granulomatosis: associated with diffuse pulmonary hemorrhage.  Acta Pathol Jpn. 1992;  42 (9) 657-661
• 8 Solans R, Bosch J A, Pérez-Bocanegra C et al.. Churg-Strauss syndrome: outcome and long-term follow-up of 32 patients.  Rheumatology (Oxford). 2001;  40 (7) 763-771
• 9 Clutterbuck E J, Pusey C D. Severe alveolar haemorrhage in Churg-Strauss syndrome.  Eur J Respir Dis. 1987;  71 (3) 158-163
• 10 Lai R-S, Lin S-L, Lai N S, Lee P C. Churg-Strauss syndrome presenting with pulmonary capillaritis and diffuse alveolar hemorrhage.  Scand J Rheumatol. 1998;  27 (3) 230-232
• 11 Della Rossa A, Baldini C, Tavoni A et al.. Churg-Strauss syndrome: clinical and serological features of 19 patients from a single Italian centre.  Rheumatology (Oxford). 2002;  41 (11) 1286-1294
• 12 Papiris S A, Manali E D, Kalomenidis I, Kapotsis G E, Karakatsani A, Roussos C. Bench-to-bedside review: pulmonary-renal syndromes—an update for the intensivist.  Crit Care. 2007;  11 (3) 213
• 13 Mark E J, Ramirez J F. Pulmonary capillaritis and hemorrhage in patients with systemic vasculitis.  Arch Pathol Lab Med. 1985;  109 (5) 413-418
• 14 Travis W D, Colby T V, Lombard C, Carpenter H A. A clinicopathologic study of 34 cases of diffuse pulmonary hemorrhage with lung biopsy confirmation.  Am J Surg Pathol. 1990;  14 (12) 1112-1125
• 15 Xiao H, Heeringa P, Liu Z et al.. The role of neutrophils in the induction of glomerulonephritis by anti-myeloperoxidase antibodies.  Am J Pathol. 2005;  167 (1) 39-45
• 16 Bansal P J, Tobin M C. Neonatal microscopic polyangiitis secondary to transfer of maternal myeloperoxidase-antineutrophil cytoplasmic antibody resulting in neonatal pulmonary hemorrhage and renal involvement.  Ann Allergy Asthma Immunol. 2004;  93 (4) 398-401
• 17 Xiao H, Heeringa P, Hu P et al.. Antineutrophil cytoplasmic autoantibodies specific for myeloperoxidase cause glomerulonephritis and vasculitis in mice.  J Clin Invest. 2002;  110 (7) 955-963
• 18 Mukhtyar C, Guillevin L, Cid M C European Vasculitis Study Group et al. EULAR recommendations for the management of primary small and medium vessel vasculitis.  Ann Rheum Dis. 2009;  68 (3) 310-317
• 19 Schwarz M I, Brown K K. Small vessel vasculitis of the lung.  Thorax. 2000;  55 (6) 502-510
• 20 Ewan P W, Jones H A, Rhodes C G, Hughes J M. Detection of intrapulmonary hemorrhage with carbon monoxide uptake: application in Goodpasture's syndrome.  N Engl J Med. 1976;  295 (25) 1391-1396
• 21 Schnabel A, Reuter M, Csernok E, Richter C, Gross W L. Subclinical alveolar bleeding in pulmonary vasculitides: correlation with indices of disease activity.  Eur Respir J. 1999;  14 (1) 118-124
• 22 Nada A K, Torres V E, Ryu J H, Lie J T, Holley K E. Pulmonary fibrosis as an unusual clinical manifestation of a pulmonary-renal vasculitis in elderly patients.  Mayo Clin Proc. 1990;  65 (6) 847-856
• 23 Bhanji A, Karim M. Pulmonary fibrosis-an uncommon manifestation of anti-myeloperoxidase-positive systemic vasculitis?.  NDT Plus. 2010;  3 (4) 351-353
• 24 Becker-Merok A, Nossent J C, Ritland N. Fibrosing alveolitis predating microscopic polyangiitis.  Scand J Rheumatol. 1999;  28 (4) 254-256
• 25 Eschun G M, Mink S N, Sharma S. Pulmonary interstitial fibrosis as a presenting manifestation in perinuclear antineutrophilic cytoplasmic antibody microscopic polyangiitis.  Chest. 2003;  123 (1) 297-301
• 26 Lauque D, Cadranel J, Lazor R et al.. Microscopic polyangiitis with alveolar hemorrhage: a study of 29 cases and review of the literature. Groupe d'Etudes et de Recherche sur les Maladies “Orphelines” Pulmonaires (GERM”O”P).  Medicine Baltimore). 2000;  79 (4) 222-233
• 27 Gal A A, Salinas F F, Staton Jr G W. The clinical and pathological spectrum of antineutrophil cytoplasmic autoantibody-related pulmonary disease: a comparison between perinuclear and cytoplasmic antineutrophil cytoplasmic autoantibodies.  Arch Pathol Lab Med. 1994;  118 (12) 1209-1214
• 28 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
• 29 Cordier J F, Valeyre D, Guillevin L, Loire R, Brechot J M. Pulmonary Wegener's granulomatosis: a clinical and imaging study of 77 cases.  Chest. 1990;  97 (4) 906-912
• 30 Akikusa B, Kondo Y, Irabu N, Yamamoto S, Saiki S. Six cases of microscopic polyarteritis exhibiting acute interstitial pneumonia.  Pathol Int. 1995;  45 (8) 580-588
• 31 Watts R, Lane S, Hanslik T et al.. Development and validation of a consensus methodology for the classification of the ANCA-associated vasculitides and polyarteritis nodosa for epidemiological studies.  Ann Rheum Dis. 2007;  66 (2) 222-227
• 32 Guillevin L, Mahr A, Cohen P. Systemic necrotizing vasculitides: classifications and therapeutic strategies [in French].  Rev Med Interne. 2003;  24 (3) 172-182
• 33 Seror R, Pagnoux C, Ruivard M French Vasculitis Study Group et al. Treatment strategies and outcome of induction-refractory Wegener's granulomatosis or microscopic polyangiitis: analysis of 32 patients with first-line induction-refractory disease in the WEGENT trial.  Ann Rheum Dis. 2010;  69 (12) 2125-2130
• 34 De Groot K, Rasmussen N, Bacon P A et al.. Randomized trial of cyclophosphamide versus methotrexate for induction of remission in early systemic antineutrophil cytoplasmic antibody-associated vasculitis.  Arthritis Rheum. 2005;  52 (8) 2461-2469
• 35 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
• 36 de Groot K, Harper L, Jayne D R EUVAS (European Vasculitis Study Group) et al. Pulse versus daily oral cyclophosphamide for induction of remission in antineutrophil cytoplasmic antibody-associated vasculitis: a randomized trial.  Ann Intern Med. 2009;  150 (10) 670-680
• 37 Jayne D R, Gaskin G, Rasmussen N European Vasculitis Study Group et al. Randomized trial of plasma exchange or high-dosage methylprednisolone as adjunctive therapy for severe renal vasculitis.  J Am Soc Nephrol. 2007;  18 (7) 2180-2188
• 38 Szpirt W M, Heaf J G, Petersen J. Plasma exchange for induction and cyclosporine A for maintenance of remission in Wegener's granulomatosis—a clinical randomized controlled trial.  Nephrol Dial Transplant. 2011;  26 (1) 206-213
• 39 Klemmer P J, Chalermskulrat W, Reif M S, Hogan S L, Henke D C, Falk R J. Plasmapheresis therapy for diffuse alveolar hemorrhage in patients with small-vessel vasculitis.  Am J Kidney Dis. 2003;  42 (6) 1149-1153
• 40 Gallagher H, Kwan J T, Jayne D R. Pulmonary renal syndrome: a 4-year, single-center experience.  Am J Kidney Dis. 2002;  39 (1) 42-47
• 41 Yamagata K, Hirayama K, Mase K et al.. Apheresis for MPO-ANCA-associated RPGN-indications and efficacy: lessons learned from Japan nationwide survey of RPGN.  J Clin Apher. 2005;  20 (4) 244-251
• 42 Levy J B, Hammad T, Coulthart A, Dougan T, Pusey C D. Clinical features and outcome of patients with both ANCA and anti-GBM antibodies.  Kidney Int. 2004;  66 (4) 1535-1540
• 43 Serratrice J, Chiche L, Dussol B et al.. Sequential development of perinuclear ANCA-associated vasculitis and anti-glomerular basement membrane glomerulonephritis.  Am J Kidney Dis. 2004;  43 (3) e26-e30
• 44 Hasegawa M, Kawamura N, Kasugai M et al.. Cytapheresis for the treatment of myeloperoxidase antineutrophil cytoplasmic antibody-associated vasculitis: report of five cases.  Ther Apher. 2002;  6 (6) 443-449
• 45 Betensley A D, Yankaskas J R. Factor VIIA for alveolar hemorrhage in microscopic polyangiitis.  Am J Respir Crit Care Med. 2002;  166 (9) 1291-1292
• 46 Henke D, Falk R J, Gabriel D A. Successful treatment of diffuse alveolar hemorrhage with activated factor VII.  Ann Intern Med. 2004;  140 (6) 493-494
• 47 Heslet L, Nielsen J D, Levi M, Sengeløv H, Johansson P I. Successful pulmonary administration of activated recombinant factor VII in diffuse alveolar hemorrhage.  Crit Care. 2006;  10 (6) R177
• 48 Ahmed S H, Aziz T, Cochran J, Highland K. Use of extracorporeal membrane oxygenation in a patient with diffuse alveolar hemorrhage.  Chest. 2004;  126 (1) 305-309
• 49 Jayne D R, Chapel H, Adu D et al.. Intravenous immunoglobulin for ANCA-associated systemic vasculitis with persistent disease activity.  QJM. 2000;  93 (7) 433-439
• 50 Brihaye B, Aouba A, Pagnoux C, Cohen P, Lacassin F, Guillevin L. Adjunction of rituximab to steroids and immunosuppressants for refractory/relapsing Wegener's granulomatosis: a study on 8 patients.  Clin Exp Rheumatol. 2007;  25 (1, suppl 44) S23-S27
• 51 Ferraro A J, Day C J, Drayson M T, Savage C O. Effective therapeutic use of rituximab in refractory Wegener's granulomatosis.  Nephrol Dial Transplant. 2005;  20 (3) 622-625
• 52 Keogh K A, Ytterbeg S R, Fervenza F C et al.. Rituximab for refractory Wegener's granulomatosis: report of a prospective, open-label pilot trial.  Am J Respir Crit Care Med. 2006;  173 (7) 815-816
• 53 Lovric S, Erdbruegger U, Kümpers P et al.. Rituximab as rescue therapy in anti-neutrophil cytoplasmic antibody-associated vasculitis: a single-centre experience with 15 patients.  Nephrol Dial Transplant. 2009;  24 (1) 179-185
• 54 Bartolucci P, Ramanoelina J, Cohen P et al.. Efficacy of the anti-TNF-alpha antibody infliximab against refractory systemic vasculitides: an open pilot study on 10 patients.  Rheumatology (Oxford). 2002;  41 (10) 1126-1132
• 55 Booth A, Harper L, Hammad T et al.. Prospective study of TNFalpha blockade with infliximab in anti-neutrophil cytoplasmic antibody-associated systemic vasculitis.  J Am Soc Nephrol. 2004;  15 (3) 717-721
• 56 Flossmann O, Baslund B, Bruchfeld A et al.. Deoxyspergualin in relapsing and refractory Wegener's granulomatosis.  Ann Rheum Dis. 2009;  68 (7) 1125-1130
• 57 Walsh M, Chaudhry A, Jayne D. Long-term follow-up of relapsing/refractory anti-neutrophil cytoplasm antibody associated vasculitis treated with the lymphocyte depleting antibody alemtuzumab (CAMPATH-1H).  Ann Rheum Dis. 2008;  67 (9) 1322-1327
• 58 Jayne D, Rasmussen N, Andrassy K European Vasculitis Study Group et al. A randomized trial of maintenance therapy for vasculitis associated with antineutrophil cytoplasmic autoantibodies.  N Engl J Med. 2003;  349 (1) 36-44
• 59 Hiemstra T F, Walsh M, Mahr A et al.. Mycophenolate mofetil vs azathioprine for remission maintenance in antineutrophil cytoplasmic antibody-associated vasculitis: a randomized controlled trial.  JAMA. 2010;  304(21) 2381-2388
• 60 Wegener's Granulomatosis Etanercept Trial (WGET) Research Group . Etanercept plus standard therapy for Wegener's granulomatosis.  N Engl J Med. 2005;  352 (4) 351-361
• 61 Walsh M, Merkel P A, Mahr A, Jayne D. A systemic review and meta-analysis of relapses in ANCA-associated vasculitis: what is the effect of low-dose corticosteroids?.  J Am Soc Nephrol. 2007;  19 PO919
• 62 Hogan S L, Nachman P H, Wilkman A S, Jennette J C, Falk R J. and The Glomerular Disease Collaborative Network . Prognostic markers in patients with antineutrophil cytoplasmic autoantibody-associated microscopic polyangiitis and glomerulonephritis.  J Am Soc Nephrol. 1996;  7 (1) 23-32
• 63 Holguin F, Ramadan B, Gal A A, Roman J. Prognostic factors for hospital mortality and ICU admission in patients with ANCA-related pulmonary vasculitis.  Am J Med Sci. 2008;  336 (4) 321-326
• 64 Khan S A, Subla M R, Behl D, Specks U, Afessa B. Outcome of patients with small-vessel vasculitis admitted to a medical ICU.  Chest. 2007;  131 (4) 972-976
• 65 Semple D, Keogh J, Forni L, Venn R. Clinical review: vasculitis on the intensive care unit, II: Treatment and prognosis.  Crit Care. 2005;  9 (2) 193-197
• 66 Gordon M, Luqmani R A, Adu D et al.. Relapses in patients with a systemic vasculitis.  Q J Med. 1993;  86 (12) 779-789
• 67 Nachman P H, Hogan S L, Jennette J C, Falk R J. Treatment response and relapse in antineutrophil cytoplasmic autoantibody-associated microscopic polyangiitis and glomerulonephritis.  J Am Soc Nephrol. 1996;  7 (1) 33-39
• 68 Savage C OS, Winearls C G, Evans D J, Rees A J, Lockwood C M. Microscopic polyarteritis: presentation, pathology and prognosis.  Q J Med. 1985;  56 (220) 467-483
• 69 Matsumoto T, Homma S, Okada M et al.. The lung in polyarteritis nodosa: a pathologic study of 10 cases.  Hum Pathol. 1993;  24 (7) 717-724
• 70 Gómez-Puerta J A, Espinosa G, Morlà R, Cid M C, Cervera R. et al. Interstitial lung disease as a presenting manifestation of microscopic polyangiitis successfully treated with mycophenolate mofetil.  Clin Exp Rheumatol. 2009;  27 (1) 166-167
• 71 Brugiere O, Raffy O, Sleiman C et al.. Progressive obstructive lung disease associated with microscopic polyangiitis.  Am J Respir Crit Care Med. 1997;  155 (2) 739-742
• 72 Komócsi A, Reuter M, Heller M, Muraközi H, Gross W L, Schnabel A. Active disease and residual damage in treated Wegener's granulomatosis: an observational study using pulmonary high-resolution computed tomography.  Eur Radiol. 2003;  13 (1) 36-42
• 73 Amital H, Rubinow A, Naparstek Y. Alveolar hemorrhage in cryoglobulinemia—an indicator of poor prognosis.  Clin Exp Rheumatol. 2005;  23 (5) 616-620
• 74 Rodríguez-Vidigal F F, Roig Figueroa V, Pérez-Lucena E et al.. Alveolar hemorrhage in mixed cryoglobulinemia associated with hepatitis C virus infection [in Spanish].  Med Interna. 1998;  15 (12) 661-663
• 75 Gómez-Tello V, Oñoro-Cañaveral J J, de la Casa Monje R M et al.. Diffuse recidivant alveolar hemorrhage in a patient with hepatitis C virus-related mixed cryoglobulinemia.  Intensive Care Med. 1999;  25 (3) 319-322
• 76 Cazzato S, Bernardi F, Cinti C et al.. Pulmonary function abnormalities in children with Henoch-Schönlein purpura.  Eur Respir J. 1999;  13 (3) 597-601
• 77 Chaussain M, de Boissieu D, Kalifa G et al.. Impairment of lung diffusion capacity in Schönlein-Henoch purpura.  J Pediatr. 1992;  121 (1) 12-16
• 78 Cream J J, Gumpel J M, Peachey R D. Schönlein-Henoch purpura in the adult: a study of 77 adults with anaphylactoid or Schönlein-Henoch purpura.  Q J Med. 1970;  39 (156) 461-484
• 79 Kathuria S, Cheifec G. Fatal pulmonary Henöch-Schonlein syndrome.  Chest. 1982;  82 (5) 654-656
• 80 Olson J C, Kelly K J, Pan C G, Wortmann D W. Pulmonary disease with hemorrhage in Henoch-Schöenlein purpura.  Pediatrics. 1992;  89 (6 Pt 2) 1177-1181
• 81 Paller A S, Kelly K, Sethi R. Pulmonary hemorrhage: an often fatal complication of Henoch-Schoenlein purpura.  Pediatr Dermatol. 1997;  14 (4) 299-302
• 82 Vats K R, Vats A, Kim Y, Dassenko D, Sinaiko A R. Henoch-Schönlein purpura and pulmonary hemorrhage: a report and literature review.  Pediatr Nephrol. 1999;  13 (6) 530-534
• 83 Tiryaki O, Buyukhatipoglu H, Karakok M, Usalan C. Successful treatment of a rare complication of Henoch-Schönlein purpura in advanced age: pulmonary hemorrhage.  Intern Med. 2007;  46 (12) 905-907
• 84 Payton C D, Allison M EM, Boulton-Jones J M. Henoch Schonlein purpura presenting with pulmonary haemorrhage.  Scott Med J. 1987;  32 (1) 26-27
• 85 Matsubayashi R, Matsubayashi T, Fujita N, Yokota T, Ohro Y, Enoki H. Pulmonary hemorrhage associated with Henoch-Schönlein purpura in a child.  Clin Rheumatol. 2008;  27 (6) 803-805
• 86 Nick J, Tuder R, May R, Fisher J. Polyarteritis nodosa with pulmonary vasculitis.  Am J Respir Crit Care Med. 1996;  153 (1) 450-453
• 87 Menon Y, Singh R, Cuchacovich R, Espinoza L R. Pulmonary involvement in hepatitis B-related polyarteritis nodosa.  Chest. 2002;  122 (4) 1497-1498
• 88 Huong Dle T, Andreu M R, Duhaut P, Godeau P, Piette J C. Intra-alveolar haemorrhage in temporal arteritis.  Ann Rheum Dis. 2003;  62 (2) 189-190
• 89 Kissin E Y, Merkel P A. Diagnostic imaging in Takayasu arteritis.  Curr Opin Rheumatol. 2004;  16 (1) 31-37
• 90 Vanoli M, Castellani M, Bacchiani G et al.. Non-invasive assessment of pulmonary artery involvement in Takayasu's arteritis.  Clin Exp Rheumatol. 1999;  17 (2) 215-218
• 91 Sharma S, Kamalakar T, Rajani M, Talwar K K, Shrivastava S. The incidence and patterns of pulmonary artery involvement in Takayasu's arteritis.  Clin Radiol. 1990;  42 (3) 177-181
• 92 Savage B J, Gupta R K, Angle J, Okusa M D. Takayasu arteritis presenting as a pulmonary-renal syndrome.  Am J Med Sci. 2003;  325 (5) 275-281
• 93 Koyabu S, Isaka N, Yada T, Konishi T, Nakano T. Severe respiratory failure caused by recurrent pulmonary hemorrhage in Takayasu's arteritis.  Chest. 1993;  104 (6) 1905-1906
• 94 Cilli A, Ozdemir T, Oğüş C. Takayasu's arteritis presenting with bilateral parenchymal consolidations and severe respiratory failure.  Respiration. 2001;  68 (6) 628-630
• 95 Afessa B, Tefferi A, Litzow M R, Peters S G. Outcome of diffuse alveolar hemorrhage in hematopoietic stem cell transplant recipients.  Am J Respir Crit Care Med. 2002;  166 (10) 1364-1368