1. Pulmonary vasculitis Sanitra Sirithangkul M.D. Division of Pulmonary and Critical care Department of Pediatrics Phramongkutklao Hospital

2. Systemic diseases and the lung relatively rare in pediatric practice CNT diseases : SLE, dermatomyositis CNT diseases : SLE, dermatomyositis Pulmonary vasculitis Pulmonary vasculitis Inherited CNT disorders : Ehlers-Danlos Inherited CNT disorders : Ehlers-Danlos Mucopolysaccharidoses, familial Mucopolysaccharidoses, familial dysautonomia, sarcoidosis dysautonomia, sarcoidosis LCH, pulmonary lymphangiomatosis LCH, pulmonary lymphangiomatosis Pediatr Respir Rev 2005;6:181-189

3. Systemic diseases and the lung may may cause significant respiratory complications treatment : often requires corticosteroids & immunosuppressants outcome : variable outcome : variable when they affect the lung, carry a small but significant mortality Pediatr Respir Rev 2005;6:181-189

4. Systemic vasculitis true incidence in children is not known around 2-5 cases/million/year pathology of vasculitis : cellular pathology of vasculitis : cellular inflammation, vessel destruction, inflammation, vessel destruction, tissue necrosis tissue necrosis clinical features : site, size and type clinical features : site, size and type of vessel involved of vessel involved

5. 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

6. 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

7. Classification ของในโรคในกลุ่ม vasculitis (cont.) Secondary vasculitis - Classic autoimmune disease Systemic lupus erythematosus Rheumatoid arthritis Polymyositis / dermatomysitis Scleroderma Antiphospholipid antibody syndrome

8. Secondary vasculitis Essential cryoglobulinemia Inflammatory bowel disease Hypocomplementemic urticarial vasculitis Drug-induced (e.g., propylthiouracil, diphenylhydantoin) Paraneoplastic Infection

9. 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

10. โรคในกลุ่ม vasculitis ที่ทำให้เกิดพยาธิ สภาพที่ปอด A. Pulmonary involvement common - Wegener’s granulomatosis* - Goodpasture’s syndrome* - Idiopathic pulmonary hemosiderosis - Kawasaki disease * Positive serum anti-neutrophil cytoplasmic antibody (ANCA)

11. 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) โรคในกลุ่ม vasculitis ที่ทำให้เกิดพยาธิ สภาพที่ปอด (ต่อ)

12. Clinical scenarios suggestive of vasculitis 1. Diffuse alveolar hemorrhage (DAH) - hemoptysis - diffuse alveolar infiltration in CXR - a drop in hematocrit

14. สาเหตุของ Diffuse alveolar hemorrhage With pathologic capillaritis - Primary idiopathic small vessel vasculitis - Primary immune complex-mediated vasculitis - Secondary vasculitis

15. 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)

16. 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

18. 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

21. Specific testing 1. Antineutrophil cytoplasmic antibodies (ANCA) - circulating autoantibodies against intracellular antigens found in neutrophils - cytoplasmic ANCA (c-ANCA), perinuclear ANCA (p-ANCA)

22. แสดงการเปรียบเทียบ c-ANCA และ p-ANCA p - ANCA c - ANCA Antibodies to strong cations Target antigen is usually myeloperoxidase but nonspecific antigenic interactions may occur Most often positive in patients with microscopic polyangiitis or pauci immune, rapidly progressive glomerulonephritis Antibodies to neutral proteins or weak cations (e.g.,proteinase3) Target antigen is proteinase3 Highly specific for Wegener’s granulomatosis

23. แสดงการเปรียบเทียบ c-ANCA และ p-ANCA p - ANCA c - ANCA Positive in approximately 50% of patients with microscopic polyangiitis Positive in 5-30% of patients with Wegener’s granulomatosis May be positive in patients with systemic lupus erythematosus, Goodpasture’s syndrome, inflammatory bowel disease, or rheumatoid arthritis Positive in 70-90% of patients with Wegener’s granulomatosis Occasionaly positive in patients with microscopic polyangiitis or Churg-Strauss syndrome (15- 25%) Very rarely positive in patients with certain infectious diseases (e.g., amoebiasia)

24. Specific testing 2. Radiographic imaging - CT chest : cavity, nodule, diffuse ground glass opacification - CT sinus 3. Bronchoscopy - assess for infection / alveolar hemorrhage / endobronchial lesion

25. 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

26. 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

27. 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

28. 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

29. 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

30. 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

31. 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

32. 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

33. EUVAS grading of disease severity Clinical class Constitutionalsymptoms Renal function Threatened vital organ function Options for inductiontherapy LimitedNo Creatinine < 120  mol/l (1.4 mg/dl) No Corticosteroids OR methotrexate OR azathioprine EarlygeneralizedYes Creatinine < 120  mol/l (1.4 mg/dl) NoCyclophosphamide OR methotrexate+ corticosteroids

34. EUVAS grading of disease severity Clinical class Constitutionalsymptoms Renal function Threatened vital organ function Options for inductiontherapy ActivegeneralizedYes Creatinine < 500  mol/l (5.7 mg/dl) YesCyclophosphamide+corticosteroids SevereYes Creatinine > 500  mol/l (5.7 mg/dl) YesCyclophosphamide+corticosteroids+ plasma exchange RefractoryYesAnyYes Consider investigational agents

35. 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

36. Take home message Pulmonary vasculitis is one component of a variety of systemic vasculitis Early diagnosis using common clinical scenarios and appropriate investigations

37. Take home message Aggressive early treatment to minimize disease related mortality & irreversible damage Regular monitoring for disease activity and medication toxicity