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Pulmonary vasculitis Sanitra Sirithangkul M.D. Division of Pulmonary and Critical care Department of Pediatrics Phramongkutklao Hospital Systemic diseases and the lung • relatively rare in pediatric practice • CNT diseases : SLE, dermatomyositis • Pulmonary vasculitis • Inherited CNT disorders : Ehlers-Danlos • Mucopolysaccharidoses, familial dysautonomia, sarcoidosis • LCH, pulmonary lymphangiomatosis Pediatr Respir Rev 2005;6:181-189 Systemic diseases and the lung • may cause significant respiratory complications • treatment : often requires corticosteroids & immunosuppressants • outcome : variable • when they affect the lung, carry a small but significant mortality Pediatr Respir Rev 2005;6:181-189 Systemic vasculitis • true incidence in children is not known • around 2-5 cases/million/year • pathology of vasculitis : cellular inflammation, vessel destruction, tissue necrosis • clinical features : site, size and type of vessel involved Classification ของในโรคในกลุ่ม Vasculitis Primary idiopathic vasculitis - Small vessel • Wegener’s granulomatosis • Microscopic polyangitis • Churg-Strauss syndrome • Idiopatic pauci-immune rapidly progressive glomerulonephritis • Isolated pauci-immune pulmonary capillaritis Primary idiopathic vasculitis - Medium vessel • Polyarteritis nodosa • Kawasaki disease - Large vessel • Giant cell arteritis • Takayasu’ s arteritis Primary immune complex-mediated vasculitis • Goodpasture’s syndrome • Henoch-Schonlein purpura • Behcet’s disease Classification ของในโรคในกลุม ่ vasculitis (cont.) Secondary vasculitis - Classic autoimmune disease • Systemic lupus erythematosus • Rheumatoid arthritis • Polymyositis / dermatomysitis • Scleroderma • Antiphospholipid antibody syndrome Secondary vasculitis • Essential cryoglobulinemia • Inflammatory bowel disease • Hypocomplementemic urticarial vasculitis • Drug-induced (e.g., propylthiouracil, diphenylhydantoin) • Paraneoplastic • Infection Pulmonary vasculitis • one component of systemic vasculitis • pathology : fibrin thrombi, fibrinoid necrosis • the inflammation may lead to - a progressive destruction of pulmonary circulation - granuloma formation - end – organ failure โรคในกลุ่ม vasculitis ที่ทำให้ เกิดพยำธิสภำพที่ปอด A. Pulmonary involvement common - Wegener’s granulomatosis* - Goodpasture’s syndrome* - Idiopathic pulmonary hemosiderosis - Kawasaki disease * Positive serum anti-neutrophil cytoplasmic antibody (ANCA) โรคในกลุม ่ vasculitis ทีท ่ ำให้ เกิดพยำธิ สภำพทีป ่ อด (ต่อ) B. Pulmonary involvement uncommon - Henoch-Shonlein purpura - Churg-Strauss vasculitis* - Polyarteritis nodosa* - Takayasu arteritis - Temporal arteritis - Serum sickness - Cryoglobulinemia * Positive serum anti-neutrophil cytoplasmic antibody (ANCA) Clinical scenarios suggestive of vasculitis 1. Diffuse alveolar hemorrhage (DAH) - hemoptysis - diffuse alveolar infiltration in CXR - a drop in hematocrit สำเหตุของ Diffuse alveolar hemorrhage With pathologic capillaritis - Primary idiopathic small vessel vasculitis - Primary immune complex-mediated vasculitis - Secondary vasculitis Without pathologic capillaritis (bland hemorrhage) - Idiopathic pulmonary hemosiderosis - Coagulopathy - Mitral stenosis - Inhalation injury - Goodpasture syndrome - Systemic Lupus erythematosus - Bone marrow transplantation (associated with diffuse alveolar damage) - Drug – associated disease (e.g., chemotherapeutic agents) Clinical scenarios suggestive of vasculitis 2. Acute glomerulonephritis - rapidly progressive glomerulonephritis (RPGN) - to be considered SLE, post-infectious GN, IgA nephropathy, MPGN, ANCA-associated vasculitis Clinical scenarios suggestive of vasculitis 3. Pulmonary-renal syndrome - DAH / pulmonary capillaritis + glomerulonephritis 4. Destructive upper airway lesions 5. Chest imaging findings 6. Palpable purpura 7. Mononeuritis multiplex 8. Multisystem disease Specific testing 1. Antineutrophil cytoplasmic antibodies (ANCA) - circulating autoantibodies against intracellular antigens found in neutrophils - cytoplasmic ANCA (c-ANCA), perinuclear ANCA (p-ANCA) แสดงกำรเปรียบเทียบ c-ANCA และ p-ANCA p - ANCA c - ANCA Antibodies to strong cations Antibodies to neutral proteins or weak cations (e.g.,proteinase3) Target antigen is usually myeloperoxidase but nonspecific antigenic interactions may occur Target antigen is proteinase3 Most often positive in patients Highly specific for Wegener’s with microscopic polyangiitis or granulomatosis pauci immune, rapidly progressive glomerulonephritis แสดงกำรเปรียบเทียบ c-ANCA และ p-ANCA p - ANCA Positive in approximately 50% of patients with microscopic polyangiitis Positive in 5-30% of patients with Wegener’s granulomatosis c - ANCA Positive in 70-90% of patients with Wegener’s granulomatosis Occasionaly positive in patients with microscopic polyangiitis or Churg-Strauss syndrome (1525%) May be positive in patients with Very rarely positive in patients systemic lupus erythematosus, with certain infectious diseases (e.g., amoebiasia) Goodpasture’s syndrome, inflammatory bowel disease, or rheumatoid arthritis Specific testing 2. Radiographic imaging - CT chest : cavity, nodule, diffuse ground glass opacification - CT sinus 3. Bronchoscopy - assess for infection / alveolar hemorrhage / endobronchial lesion Specific testing 4. Diagnostic biopsy - skin, sinus or upper airway lesions - renal biopsy - lung biopsy - collect tissue in saline for culture - frozen tissue for immunofluorescence - formaline-fixed tissue for H&E Wegener’s granulomatosis (WG) • the most common of the ANCA-associated vasculitis • triad : upper airway disease, lower respiratory tract disease, glomerulonephritis • abnormal CXR findings : alveolar, interstitial, mixed infiltration nodule/cavity Wegener’s granulomatosis (WG) • c-ANCA / antiPR3 positive 85-95% of active, systemic WG • poor outcomes : advanced age, severe renal involvement, alveolar hemorrhage, anti PR3 positive Microscopic polyangiitis (MPA) • long prodromal phase of constitutional symptoms → development of RPGN • pulmonary involvement seen in up to 30% • most common pulmonary involvement : DAH with pulmonary capillaritis Microscopic polyangiitis (MPA) • p-ANCA +ve 50-70%, anti MPO +ve 35-65%, c-ANCA +ve 10-15% • pathology : focal, segmental necrotizing vasculitis, mixed inflammatory infiltrate without granuloma Churg-Strauss syndrome (CSS) • to be considered when other eosinophilic lung diseases are in the differential or • difficult-to-control asthmatic patients develop significant cardiac, GI or neurologic disease • triad : asthma, hypereosinophilia, necrotizing vasculitis Churg-Strauss syndrome (CSS) • pulmonary hemorrhage and glomerulonephritis : less common • p-ANCA /anti MPO +ve 50-75%, c- NCA +ve 10% • mortality & morbidity due to cardiac complications, GI, status asthmaticus & respiratory failure Therapy • induction of remission : 12 months • maintenance : 12-18 months - cyclophosphamide → azathioprine/ methotrexate - additional agents : mycophenolate mofetil (MMF), leflunomide, cyclosporine - Pneumocystis carinii prophylaxis with trimetroprim-sulfametoxazole EUVAS grading of disease severity Constitutional symptoms Renal function Threatened vital organ function Options for induction therapy Limited No Creatinine < 120 mol/l (1.4 mg/dl) No Corticosteroids OR methotrexate OR azathioprine Early generalized Yes Creatinine < 120 mol/l (1.4 mg/dl) No Cyclophosphamide OR methotrexate+ corticosteroids Clinical class EUVAS grading of disease severity Constitutional symptoms Renal function Threatened vital organ function Options for induction therapy Active generalized Yes Creatinine < 500 mol/l (5.7 mg/dl) Yes Cyclophosphamide+ corticosteroids Severe Yes Creatinine > 500 mol/l (5.7 mg/dl) Yes Cyclophosphamide+ corticosteroids+ plasma exchange Refractory Yes Any Yes Consider investigational agents Clinical class Monitoring • to minimize morbidity & mortality of the vasculitides and their therapy • differential diagnosis in pts with clinical deterioration - infection - drug toxicity - disease relapse - a new unrelated problem Take home message • Pulmonary vasculitis is one component of a variety of systemic vasculitis • Early diagnosis using common clinical scenarios and appropriate investigations Take home message • Aggressive early treatment to minimize disease related mortality & irreversible damage • Regular monitoring for disease activity and medication toxicity