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Pulmonary vasculitides in children
PAEDIATRIC RESPIRATORY REVIEWS (2006) 7S, S243–S244
Pulmonary vasculitides in children Victor Chernick* Children’s Hospital, 840 Sherbrook St., Winnipeg , Manitoba, Canada R3A1S1
The pulmonary vasculitides are one component of a variety of systemic disorders in which there is vascular inflammation. This inflammation may lead to a progressive destruction of the pulmonary circulation, granuloma formation, tissue necrosis and end-organ failure. The vasculitides are uncommon conditions and they involve the lung with variable frequency (Table 1). The true incidence of the systemic vasculitides in children is not known but is probably around 2–5 cases per million population per annum. Only a small proportion of these cases proceed to pulmonary involvement that is clinically significant. However, there is a paucity of lung biopsy examination in most cases so that the incidence of pulmonary involvement may be higher than we think it is on purely clinical grounds. The clinical presentation of vasculitis depends on the size of vessel involved. If medium or large size vessels are affected this will result in infarction, necrosis and end-organ dysfunction. When smaller vessels such as arterioles, capillaries or venules are affected there is leakage of blood into the tissues. In the lung this causes diffuse alveolar hemorrhage. Wegener’s Granulomatosis (WG), first described in l935, involves small and medium size vessels where, in addition to vascular inflammation and tissue necrosis, there is an adjacent granulomatous process. These are areas of central necrosis surrounded by acute and chronic inflammatory cells, histiocytes and giant cells. The lung is involved in the majority of cases and focal segmental glomerulonephritis involving small vessels often causes substantial renal impairment. Often the first manifestation of the disease is in the upper airway including the nose (septal perforation, saddle nose deformity) and in the sinuses (pansinusitis). Diffuse * Tel.: +1 2047871380. E-mail address: [email protected]. 1526-0542/$ – see front matter ß 2006 Elsevier Ltd. All rights reserved. doi:10.1016/j.prrv.2006.04.190
alveolar hemorrhage can occur in a minority of patients. The disease may involve the tracheobronchial tree and cause upper airway obstruction and stridor as a result of stenosis. Churg-Straus Syndrome (CSS) (allergic granulomatous angiitis) was first described in l951. It is a rare disorder consisting of asthma, allergic rhinitis/sinusitis, fever and eosinophilia. Vasculitis occurs after several years of atopy, involves pulmonary and systemic small and medium vessels, and is associated with eosinophil infiltration of tissues and lung, extravascular granulomas and necrotizing lesions. Recently an increase in the incidence of this disorder was associated with the use of Zafirlukast and Montelukast, probably related to a decreased use of steroids in asthmatic patients rather than a drug reaction. Polyarteritis Nodosa (PAN) is an inflammatory disorder of the medium and small muscular arteries. There is intimal proliferation, destruction of the elastic lamina, aneurism formation, secondary thrombosis and destruction of the target organ. This is a rare disorder in children and is a diagnosis of exclusion: hypersensitivity angiitis, WG, allergic granulomatosis and Kawasaski disease must be ruled out. Hepatitis B surface antigen may be positive but serum ANCA is negative. A variant of PAN, called Microscopic Polyangiitis (MPA), which involves small vessels, is associated with rapidly progressive glomerulonephritis and alveolar hemorrhage. It is associated with a preceeding upper respiratory tract infection in most cases and also a positive perinuclear- ANCA or cytoplasmic-ANCA (see below). Pathogenensis Two pathogenetic pathways have been proposed. The first involves antibodies to nuclear cytoplasmic components of neutrophils(ANCA). In WG the vast majority of patients have a serum antibody to neutrophil cytoplasmic serine proteinase (proteinase-3) or cANCA. In patients with CSS and MPA most have antibodies to the neurtrophil perinuclear meyeloperoxidase or
S244
Table 1
V. CHERNICK
Some Vasculitides
A. Pulmonary involvement common Wegener’s Granulomatosis* Goodpasture’s Syndrome* Idiopathic pulmonary hemosiderosis Kawasaki disease B. Pulmonary involvement uncommon Henoch-Shonlein Purpura Churg-Strauss Vasculitis* Polyarteritis Nodosa* Takayasu Arteritis Temporal Arteritis Hypersensitivity Angiitis Serum Sickness Cryoglobulinemia *
Positive serum anti-neutrophil cytoplasmic antibody (ANCA).
p-ANCA. Some patients with PAN have antibodies to cANCA. It is thought that an antigen-antibody reaction results in fragmentation of neutrophils and the release of toxic oxygen radicals and proteases into the surrounding tissue causing vascular injury. The other proposed mechanism is related to the deposition of immune complexes which are found in patients with Goodpasture’s Syndrome, Henoch-Schonlein purpura, systemic lupus erythematosis, mixed connnective tissue disease and rheumatoid arthritis. Immune complexes are not found in patients with WG, CSS or PAN and these disorders are describes as pauci-immune. Treatment Treatment is non specific and involves the use of high dose steroids, cyclophosphamide,azothioprine, methotrexate or intravenous immunogloblin, either alone or in various combinations. Plasmapheresis has been used
in Goodpasture’s syndrome but is not effective in WG, CSS or PAN.
FURTHER READING 1. Platzker ACG. Pulmonary Involvement in Rheumatoid Disorders of Childhood. In: Chernick V, Boat T, Wilmott R, Bush A, eds: Chapter 67 in Kendig’s Disorders of the Respiratory Tract in Children. 7th Edition. Philadelphia: Elseveir-Saunders. 2. Chandler DB, Fulmer JD. Pulmonary Vasculitis. Lung 1985; 163: 257– 273. 3. Jennette JS, Falk RJ. Small vessel vasculitis. N Eng J Med 1997; 337: 1512– 1523. 4. Schwarz MI, Brown KK. Small vessel vasculitis of the lung. Thorax 2000; 55: 502–520. 5. Schwarz M. Pulmonary Vasculitis and Hemorrhage. In: Albert RK, Spiro SG, Jett JR, eds: Chapter 55 in Clinical Respiratory Medicine. 2nd edition. Philadelphia: Mosby. 6. Dinwiddie R, Sonnappa S. Systemic Diseases and the Lung. Paediatr Respir Rev 2005; 6: 181–189. 7. Wegener F. Uber eiene eigenartrige rhinogene Granulomatose mit besonderer Bereiligung des Arterienesystems und er. Nieren Beitr Pathol 1939; 102: 32–68. 8. Rottem M, Fauci AS, Hallahan CW et al. Wegener granulomatosis in children and adolescents. Clinical presentation and outcome. J Pediatr 1993; 122: 26–31. 9. Adlakha A, Roa K, Adlaka K, Ryu JH. A case of pediatric Wegener’s granulomatosis with recurrent venous thromboses treated with intravenous immunoglobulin and laryngotracheoplasty. Pediatr Pulmonol 1995; 20: 265–268. 10. Ozen S, Anton J, Arisoy N et al. Juvenile polyarteritis. Results of a multicenter survey of 110 children. J Pediatr 2004; 145: 517–522. 11. Churg J, Strauss L. Allergic granulomatosis, allergic angiitis and periarteritis nodosa. Am J Pathol 1951; 27: 277–301. 12. Churg, Andrew: Churg-Strauss Syndrome in I Remember. . .ReflecReflections on the American Thoracic Society’s First Century. ATS publication 2005. pp 24–27. (a son’s reflection on the syndrome described by his father Jacob Churg and Lotte Strauss). See www.cssassociation.org.
Pulmonary vasculitides in children Victor Chernick* Children’s Hospital, 840 Sherbrook St., Winnipeg , Manitoba, Canada R3A1S1
The pulmonary vasculitides are one component of a variety of systemic disorders in which there is vascular inflammation. This inflammation may lead to a progressive destruction of the pulmonary circulation, granuloma formation, tissue necrosis and end-organ failure. The vasculitides are uncommon conditions and they involve the lung with variable frequency (Table 1). The true incidence of the systemic vasculitides in children is not known but is probably around 2–5 cases per million population per annum. Only a small proportion of these cases proceed to pulmonary involvement that is clinically significant. However, there is a paucity of lung biopsy examination in most cases so that the incidence of pulmonary involvement may be higher than we think it is on purely clinical grounds. The clinical presentation of vasculitis depends on the size of vessel involved. If medium or large size vessels are affected this will result in infarction, necrosis and end-organ dysfunction. When smaller vessels such as arterioles, capillaries or venules are affected there is leakage of blood into the tissues. In the lung this causes diffuse alveolar hemorrhage. Wegener’s Granulomatosis (WG), first described in l935, involves small and medium size vessels where, in addition to vascular inflammation and tissue necrosis, there is an adjacent granulomatous process. These are areas of central necrosis surrounded by acute and chronic inflammatory cells, histiocytes and giant cells. The lung is involved in the majority of cases and focal segmental glomerulonephritis involving small vessels often causes substantial renal impairment. Often the first manifestation of the disease is in the upper airway including the nose (septal perforation, saddle nose deformity) and in the sinuses (pansinusitis). Diffuse * Tel.: +1 2047871380. E-mail address: [email protected]. 1526-0542/$ – see front matter ß 2006 Elsevier Ltd. All rights reserved. doi:10.1016/j.prrv.2006.04.190
alveolar hemorrhage can occur in a minority of patients. The disease may involve the tracheobronchial tree and cause upper airway obstruction and stridor as a result of stenosis. Churg-Straus Syndrome (CSS) (allergic granulomatous angiitis) was first described in l951. It is a rare disorder consisting of asthma, allergic rhinitis/sinusitis, fever and eosinophilia. Vasculitis occurs after several years of atopy, involves pulmonary and systemic small and medium vessels, and is associated with eosinophil infiltration of tissues and lung, extravascular granulomas and necrotizing lesions. Recently an increase in the incidence of this disorder was associated with the use of Zafirlukast and Montelukast, probably related to a decreased use of steroids in asthmatic patients rather than a drug reaction. Polyarteritis Nodosa (PAN) is an inflammatory disorder of the medium and small muscular arteries. There is intimal proliferation, destruction of the elastic lamina, aneurism formation, secondary thrombosis and destruction of the target organ. This is a rare disorder in children and is a diagnosis of exclusion: hypersensitivity angiitis, WG, allergic granulomatosis and Kawasaski disease must be ruled out. Hepatitis B surface antigen may be positive but serum ANCA is negative. A variant of PAN, called Microscopic Polyangiitis (MPA), which involves small vessels, is associated with rapidly progressive glomerulonephritis and alveolar hemorrhage. It is associated with a preceeding upper respiratory tract infection in most cases and also a positive perinuclear- ANCA or cytoplasmic-ANCA (see below). Pathogenensis Two pathogenetic pathways have been proposed. The first involves antibodies to nuclear cytoplasmic components of neutrophils(ANCA). In WG the vast majority of patients have a serum antibody to neutrophil cytoplasmic serine proteinase (proteinase-3) or cANCA. In patients with CSS and MPA most have antibodies to the neurtrophil perinuclear meyeloperoxidase or
S244
Table 1
V. CHERNICK
Some Vasculitides
A. Pulmonary involvement common Wegener’s Granulomatosis* Goodpasture’s Syndrome* Idiopathic pulmonary hemosiderosis Kawasaki disease B. Pulmonary involvement uncommon Henoch-Shonlein Purpura Churg-Strauss Vasculitis* Polyarteritis Nodosa* Takayasu Arteritis Temporal Arteritis Hypersensitivity Angiitis Serum Sickness Cryoglobulinemia *
Positive serum anti-neutrophil cytoplasmic antibody (ANCA).
p-ANCA. Some patients with PAN have antibodies to cANCA. It is thought that an antigen-antibody reaction results in fragmentation of neutrophils and the release of toxic oxygen radicals and proteases into the surrounding tissue causing vascular injury. The other proposed mechanism is related to the deposition of immune complexes which are found in patients with Goodpasture’s Syndrome, Henoch-Schonlein purpura, systemic lupus erythematosis, mixed connnective tissue disease and rheumatoid arthritis. Immune complexes are not found in patients with WG, CSS or PAN and these disorders are describes as pauci-immune. Treatment Treatment is non specific and involves the use of high dose steroids, cyclophosphamide,azothioprine, methotrexate or intravenous immunogloblin, either alone or in various combinations. Plasmapheresis has been used
in Goodpasture’s syndrome but is not effective in WG, CSS or PAN.
FURTHER READING 1. Platzker ACG. Pulmonary Involvement in Rheumatoid Disorders of Childhood. In: Chernick V, Boat T, Wilmott R, Bush A, eds: Chapter 67 in Kendig’s Disorders of the Respiratory Tract in Children. 7th Edition. Philadelphia: Elseveir-Saunders. 2. Chandler DB, Fulmer JD. Pulmonary Vasculitis. Lung 1985; 163: 257– 273. 3. Jennette JS, Falk RJ. Small vessel vasculitis. N Eng J Med 1997; 337: 1512– 1523. 4. Schwarz MI, Brown KK. Small vessel vasculitis of the lung. Thorax 2000; 55: 502–520. 5. Schwarz M. Pulmonary Vasculitis and Hemorrhage. In: Albert RK, Spiro SG, Jett JR, eds: Chapter 55 in Clinical Respiratory Medicine. 2nd edition. Philadelphia: Mosby. 6. Dinwiddie R, Sonnappa S. Systemic Diseases and the Lung. Paediatr Respir Rev 2005; 6: 181–189. 7. Wegener F. Uber eiene eigenartrige rhinogene Granulomatose mit besonderer Bereiligung des Arterienesystems und er. Nieren Beitr Pathol 1939; 102: 32–68. 8. Rottem M, Fauci AS, Hallahan CW et al. Wegener granulomatosis in children and adolescents. Clinical presentation and outcome. J Pediatr 1993; 122: 26–31. 9. Adlakha A, Roa K, Adlaka K, Ryu JH. A case of pediatric Wegener’s granulomatosis with recurrent venous thromboses treated with intravenous immunoglobulin and laryngotracheoplasty. Pediatr Pulmonol 1995; 20: 265–268. 10. Ozen S, Anton J, Arisoy N et al. Juvenile polyarteritis. Results of a multicenter survey of 110 children. J Pediatr 2004; 145: 517–522. 11. Churg J, Strauss L. Allergic granulomatosis, allergic angiitis and periarteritis nodosa. Am J Pathol 1951; 27: 277–301. 12. Churg, Andrew: Churg-Strauss Syndrome in I Remember. . .ReflecReflections on the American Thoracic Society’s First Century. ATS publication 2005. pp 24–27. (a son’s reflection on the syndrome described by his father Jacob Churg and Lotte Strauss). See www.cssassociation.org.