What are the main causes of alveolar hemorrhage?

Main Causes of Alveolar Hemorrhage

Alveolar hemorrhage results primarily from three mechanisms: immune-mediated capillaritis (most commonly ANCA-associated vasculitis and anti-GBM disease), coagulation/hemodynamic disturbances, and toxic/drug-induced injury. 1, 2

Immune-Mediated Causes (Most Common)

ANCA-Associated Vasculitis

• Granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA) account for approximately 25% of all diffuse alveolar hemorrhage cases, making them the leading autoimmune causes. 1, 2, 3
• These conditions cause pauci-immune necrotizing inflammation of small vessels (arterioles, capillaries, venules) with minimal immune complex deposition. 1
• Approximately 90% of patients have circulating MPO-ANCA or PR3-ANCA antibodies, though 10% remain ANCA-negative, which does not exclude the diagnosis. 1
• Eosinophilic granulomatosis with polyangiitis rarely causes alveolar hemorrhage. 3

Anti-Glomerular Basement Membrane Disease

• Presents classically as pulmonary-renal syndrome with simultaneous lung and kidney injury. 1
• Delayed treatment results in 96% mortality, making this the most urgent diagnosis to exclude. 1, 2
• Positive anti-GBM antibody testing mandates urgent plasma exchange without waiting for biopsy confirmation. 1

Other Autoimmune Conditions

• Systemic lupus erythematosus can cause alveolar hemorrhage through capillaritis. 3, 4
• Sarcoidosis is an increasingly recognized but underreported cause of alveolar hemorrhage. 5
• Antiphospholipid syndrome may cause hemorrhage through thrombotic mechanisms. 5

Hemodynamic and Cardiac Causes

Hydrostatic Mechanisms

• Cardiac failure and pulmonary edema lead to hydrostatic alveolar hemorrhage through increased left ventricular preload and capillary pressure. 6, 1, 7
• Renal failure contributes through volume overload and uremic platelet dysfunction. 6

Pulmonary Embolism

• Alveolar hemorrhage occurs when distal pulmonary artery obstruction allows influx of bronchial arterial blood into ischemic lung tissue. 2, 8
• Progression to true infarction is uncommon except in patients with pre-existing heart failure or pulmonary disease. 2
• Pulmonary embolism remains an uncommon cause of hemoptysis overall. 1

Toxic and Drug-Induced Causes

Medications

• Antithyroid drugs, especially propylthiouracil, are well-recognized causes of drug-induced vasculitis and alveolar hemorrhage. 3
• Molecular targeting agents and immune checkpoint inhibitors can cause drug-related pneumonitis with alveolar hemorrhage. 6
• Drugs of abuse represent emerging toxic causes that may be difficult to diagnose. 3

Radiation

• Radiation pneumonitis occurs 3-12 weeks after irradiation and can manifest with alveolar hemorrhage. 6, 1
• Risk increases with combined or sequential cyclophosphamide and cardiac region radiation therapy. 1

Coagulation Disorders

• Coagulopathies from anticoagulation, thrombocytopenia, or inherited bleeding disorders cause bland alveolar hemorrhage without capillaritis. 4, 7, 9
• These cases lack the inflammatory vessel injury seen in vasculitis. 9

Infectious Causes

• Various infections can cause alveolar hemorrhage, particularly in immunocompromised patients. 1
• Infection must be excluded through bronchoalveolar lavage and microbiologic testing, as it is the leading cause of death (48%) in the first year after treatment for microscopic polyangiitis. 2

Mechanical and Physical Causes

• Mechanical ventilation itself causes pulmonary hemorrhage in approximately 38% of ventilated patients (26 of 69 in autopsy series). 2
• Diffuse alveolar damage from ARDS can present with hemorrhage. 6, 9
• Lung contusion from trauma causes localized hemorrhage. 2

Critical Diagnostic Pitfall

Hemoptysis is absent in one-third to one-half of alveolar hemorrhage cases, making it an unreliable diagnostic criterion. 3, 9 The classic triad of dyspnea, anemia, and diffuse radiologic infiltrates should prompt immediate consideration of alveolar hemorrhage regardless of hemoptysis presence. 3, 9

Bronchoalveolar lavage retrieving increasingly bloody fluid in sequential aliquots is the best diagnostic clue and helps exclude infection. 1, 3 When pulmonary-renal syndrome is present, urgent serologic testing for ANCA and anti-GBM antibodies is critically important, as delayed immunosuppression dramatically worsens outcomes. 1, 2