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Diffuse Alveolar Hemorrhage (DAH) Internal Medicine Lecture Howard M. Mintz, M.D. October 14, 2004 Slide 2 Slide 3 Hallmarks of DAH Hemoptysis (may be absent in 1/3 of cases) Diffuse pulmonary infiltrates Anemia Hypoxemic respiratory failure Slide 4 Etiologies of DAH Many causes and clinical syndromes Slide 5 Slide 6 Pathology of DAH 3 Broad histologic patterns identified Pulmonary capillaritis Bland pulmonary hemorrhage Diffuse alveolar damage Slide 7 Pulmonary Capillaritis I Most common of the histologic patterns First described by Spencer in 1957 Neutrophilic interstitial infiltrate with fragmentation of neutrophils (leukocytoclasis) and pyknotic neutrophils with release of cytokines Nuclear dust in interstitium and alveolar spaces Slide 8 Pulmonary Capillaritis II Disruption of the interstitium and capillaries with leakage of blood and fibrin into alveolar spaces Edema of basement membrane with subsequent necrosis of interstitium and eventual fibrosis Neutrophils are seen lining the interstitium Slide 9 Slide 10 Slide 11 Diffuse Alveolar Damage Hyaline membrane formation, alveolar and interstitial edema, microthrombi, and capillary congestion are present See slide Slide 12 Slide 13 Bland Alveolar Hemorrhage RBCs in the alveolar spaces, but alveolar walls appear normal except for type II epithelial cell hyperplasia See slide Slide 14 Slide 15 Slide 16 Clinical Presentation of DAH I Patients often have an underlying known condition Hemoptysis can be acute or subacute, but typically presents within one week of onset Majority of patients are less than forty years old 1/3 do not have hemoptysis, but present with dyspnea and cough Slide 17 Clinical Presentation DAH II In patients without hemoptysis, diagnosis is confirmed by the presence of blood on serial BAL Anemia Pulmonary infiltrates Chest pain, nonspecific Symptoms of underlying disease processes Slide 18 History in DAH Careful drug history Smoking history History of underlying illnesses such as valvular heart disease, cytotoxic agents, drugs Social history, in particular cocaine usage History of any renal, skin, or eye diseases Slide 19 Physical Findings in DAH Nonspecific Fevers, rales, signs of consolidation Synovitis, iridocyclitis, myositis, palpable purpura Slide 20 Slide 21 Radiographic Findings in DAH Nonspecific, focal or generalized infiltrates Rapidly progressive bilateral infiltrates Interstitial fibrosis in presence of recurrent disease Kerleys B line suggestive of valvular etiology, also in conditions associated with myocarditis, venoocclusive disease Slide 22 Slide 23 Slide 24 Slide 25 Laboratory Findings in DAH I Low or falling hematocrit or hemoglobin In the setting of chronic or recurrent episodes, low serum iron Nonspecific elevations of white count Thrombocytopenia Elevation of ESR Proteinuria, microscopic hematuria, casts suggest glomerulonephrits Slide 26 Laboratory Findings in DAH II Hypoxemia Elevation of DLCO Restrictive pattern associated with fibrosis or obstructive patterns with marked emphysematous changes ANCA ABMA, IgG Slide 27 ANCA in DAH Diagnosis Antineutrophilic cytoplasmic antibodies (ANCA)first described in 1982 in association with pauci-immune glomerulonephritis ANCA described in association with Wegeners granulomatosis in 1985 Subsequently described in microscopic polyangitis (MPA) and limited renal vasculitis Slide 28 Slide 29 ANCA Testing Indirect immunofluorescence assay (IIA) is more sensitive Enzyme link immunosorbent assay (ELISA) is more specific Best used in conjunction with IIA for screening and ELISA for confirmation Two relative antigens in vasculitic diseases, proteinase 3 (PR3) and myeloperoxidase (MPO) Antigens are found in neutrophils and monocytes PR3-ANCA and MPO-ANCA Slide 30 Immunofluorescence Patterns In Vasculitis Sera from patients with suspected ANCA related vasculitis are incubated in ethanol fixed neutrophils Two distinct patterns of fixation identified, c-ANCA with cytoplasmic pattern and p-ANCA with perinuclear pattern c-ANCA pattern is typically associated with antibodies against PR3 p-ANCA is typically associated with antibodies against MPO See photographics Slide 31 Slide 32 Slide 33 Immunofluorescence Utility and Errors Tests are visually graded and inspected Tests are not specific and false positives and negatives can occur IIA testing should be confirmed with ELISA testing for PR3 and MPO Slide 34 Slide 35 Specific Examples of DAH Capillaritis-Microscopic Polyangiitis Diffuse Alveolar Damage-Crack Cocaine Bland Hemorrhage-Amiodarone Slide 36 Microscopic Polyangiitis (MPA) I Rare disease with prevalence estimated 3 cases per million Etiology is unknown Small vessel involvement including arterioles, venules, and or capillaries Immune complexes are not demonstrated Typical presentation is that of renal failure with glomerulonephritis and hemoptysis with capillaritis Histopathologically segmental distribution, neutrophilic infiltration, and fibrinoid necrosis (See slide) Slide 37 MPA II ANCA is positive in about 75% of patients p-ANCA is present with MPO by ELISA in 85% of patients c-ANCA is rare with PR3 by ELISA Systemic disease Skin manifestations including splinter hemorrhages and purpura Musculoskeletal with arthralgias, myalgias, arthritis Gastrointestinal with abdominal pain and GI hemorrhage Neurological with peripheral neuropathy Slide 38 MPA II ANCA is positive in about 75% of patients p-ANCA is present with MPO by ELISA in 85% of patients c-ANCA is rare with PR3 by ELISA Systemic disease Skin manifestations including splinter hemorrhages and purpura Musculoskeletal with arthralgias, myalgias, arthritis Gastrointestinal with abdominal pain and GI hemorrhage Neurological with peripheral neuropathy Slide 39 MPA III Prominent gastrointestinal signs and symptoms and lack of upper airway disease helps distinguish from Wegeners Classical polyarteritis nodosa rarely involves the lung 45% of patients have circulating immune complexes but tissue localization is rare, pauci-immune disease 33% of patients have antibodies to hepatitis C or B Treatment same as for Wegeners Survival about 65% with recurrence associated with tapering of therapy Case report in which MPA eventually developed features of WG Slide 40 Maimon, N. et al. Chest 2003;124:2384-2387 The histologic section from a right middle lobe open lung biopsy showed extensive hemorrhaging in the alveolar spaces Slide 41 Pulmonary Interstitial Fibrosis & MPA Report of six cases of PIF in which patients were ANCA positive and eventually diagnosed with MPA The diagnosis of PIF may precede that of MPA by many years See CT Slide 42 Slide 43 Maimon, N. et al. Chest 2003;124:2384-2387 Diffuse alveolar consolidation with air bronchogram involving the entire right lung field Slide 44 Slide 45 Cocaine History & Mechanisms of Action First isolated from coca leaves in 1859 Part of the original formulation of Coke, removed in 1906 First reported deaths occurred in 1893 Potent sympathomimetic and CNS stimulant based on its ability to block reuptake of catecholamines & serotonin Cocaine HCL boiled with baking soda and extracted with ether or alcohol, yields heat stable Crack or Rock Smoked and reaches the CNS within seconds with half life of 60-90 minutes Frequently mixed with marijuana or tobacco Slide 46 Crack Cocaine with Diffuse Alveolar Damage Cocaine is abused in two forms, cocaine HCl and cocaine alkaloidal The alkaloidal form or crack cocaine is lipid soluble and resistant to thermal breakdown Rapidly absorbed from the lung via pulmonary capillary network Euphoria is similar to that of intravenous usage Smoking of crack is also associated with absorption of impurities, ignition products and thermal breakdown products of cocaine Slide 47 BAL in Crack Lung Users Up to 40% of of crack cocaine users have hemosiderin stained alveolar macrophages.