What causes alveolar hemorrhage?

Causes of Alveolar Hemorrhage

Alveolar hemorrhage results primarily from small-vessel vasculitis (particularly ANCA-associated vasculitis), anti-GBM disease, systemic lupus erythematosus, and drug-induced capillaritis, with less common causes including coagulopathies, infections, cardiac causes, and toxic exposures. 1, 2, 3

Primary Immunologic Causes

ANCA-Associated Vasculitis (Most Common)

• Granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA) are the most frequent causes of pulmonary capillaritis and diffuse alveolar hemorrhage (DAH), affecting approximately 25% of AAV patients 1, 2, 4
• Eosinophilic granulomatosis with polyangiitis (EGPA) rarely causes DAH 4
• These conditions cause pauci-immune necrotizing inflammation of small vessels (arterioles, capillaries, venules) with little immune complex deposition 1
• About 90% of patients with small-vessel vasculitis have circulating MPO-ANCA or PR3-ANCA 1

Anti-Glomerular Basement Membrane Disease

• Formerly called Goodpasture's syndrome, this presents classically as pulmonary-renal syndrome with simultaneous lung and kidney injury 1, 2
• Positive anti-GBM antibody testing suggests urgent need for plasma exchange without waiting for biopsy confirmation 1
• Delayed treatment results in 96% mortality, emphasizing the critical importance of early empiric therapy 2

Systemic Lupus Erythematosus

• SLE is a recognized cause of secondary pulmonary capillaritis and DAH 3, 4, 5
• Plasma exchange is recommended in severe DAH associated with SLE 4

Idiopathic Pauci-Immune Pulmonary Capillaritis

• When pulmonary capillaritis is not secondary to underlying systemic vasculitis, idiopathic pauci-immune pulmonary capillaritis may be diagnosed, with or without ANCA positivity 4

Drug-Induced Causes

Antithyroid Medications

• Propylthiouracil is a particularly important cause of drug-induced vasculitis and DAH 4
• Early identification and removal of the putative drug is crucial and may obviate the need for immunosuppressive therapy 4

Chemotherapy Agents

• Cyclophosphamide itself can cause pulmonary hemorrhage as an adverse effect 6
• Other cytotoxic agents may contribute to alveolar hemorrhage through various mechanisms 6

Drugs of Abuse

• Newer toxic causes from drugs of abuse may be difficult to diagnose and should be considered 4

Hemodynamic and Cardiac Causes

Increased Left Ventricular Preload

• Cardiac failure and pulmonary edema can lead to hydrostatic causes of alveolar hemorrhage 1, 5
• Hemodynamic disturbances from pulmonary embolism can result in alveolar hemorrhage, though PE is an uncommon cause of hemoptysis 1

Infectious Causes

• Various infections can cause DAH, particularly in immunocompromised patients 1, 5
• Pneumonia patterns must be distinguished from DAH through clinical features, microbiology, and response to antibiotics 1

Coagulation Disorders

• Coagulopathies can facilitate extravasation of erythrocytes into alveolar spaces 3, 5
• Circulating autoantibodies (such as antiphospholipid antibodies) may contribute to hemorrhage 7

Toxic and Physical Causes

Inhaled Toxins

• Direct toxic injury to the alveolocapillary membrane from inhaled substances 3, 5

Radiation Pneumonitis

• Temporal relationship to radiation exposure (3-12 weeks after irradiation) with potential for DAH 1
• Increased risk of hemorrhagic complications with combined or sequential cyclophosphamide and radiation therapy of the cardiac region 6

Neoplastic Causes

• Pulmonary lymphangitic carcinomatosis and other malignancies can present with alveolar hemorrhage 1, 5

Key Diagnostic Considerations

The pulmonary-renal syndrome (simultaneous lung and kidney injury) should immediately raise concern for vasculitis, with urgent serologic testing for ANCA and anti-GBM antibodies being of critical diagnostic importance 1

Cardinal Clinical Features

• Dyspnea, hemoptysis (absent in one-third of cases), chest infiltrates, and abrupt fall in hemoglobin level 4
• Bronchoalveolar lavage retrieving increasingly bloody fluid in sequential aliquots is the best diagnostic clue 2, 4

Important Pitfall

ANCA negativity does not exclude small-vessel vasculitis, as approximately 10% of patients with AAV are ANCA-negative 1