What are the causes of diffuse alveolar hemorrhage?

Causes of Diffuse Alveolar Hemorrhage

Diffuse alveolar hemorrhage (DAH) results from five major categories: autoimmune/vasculitic diseases (most common), coagulation disorders, infections, cardiac/hemodynamic causes, and toxic/drug exposures. 1, 2

Autoimmune and Vasculitic Causes (Most Common)

ANCA-associated vasculitis represents the most frequent cause of DAH, accounting for approximately 25% of all cases. 3, 1

• Microscopic polyangiitis and granulomatosis with polyangiitis (Wegener's) are the leading systemic diseases causing DAH through pulmonary capillaritis. 1, 4, 2
• Approximately 90% of patients with small-vessel vasculitis have circulating MPO-ANCA or PR3-ANCA antibodies, though 10% remain ANCA-negative. 4

Anti-glomerular basement membrane (anti-GBM) disease is the most critical cause requiring immediate recognition, as delayed treatment results in 96% mortality. 1, 4

• Classically presents as pulmonary-renal syndrome with simultaneous lung and kidney injury. 4
• Positive anti-GBM antibody testing demands urgent plasma exchange without waiting for biopsy confirmation. 4

Systemic lupus erythematosus (SLE) can manifest DAH as a severe disease flare, particularly dangerous during pregnancy with high maternal morbidity and mortality risk. 1

• Active lupus nephritis or vasculitis frequently accompanies DAH in SLE patients. 1

Isolated pulmonary capillaritis can occur without systemic disease, clinical findings, or positive serologies in approximately 28% of DAH cases with biopsy-proven capillaritis. 5

• These patients are ANCA-negative with negative direct immunofluorescence studies. 5
• Prognosis is generally favorable with most patients achieving remission. 5

Coagulation-Related Causes

Anticoagulation therapy, particularly warfarin and dual antiplatelet therapy (DAPT), can precipitate DAH through INR instability and bleeding complications. 1

• Recent literature highlights increased DAH risk in COVID-19 patients treated with DAPT after percutaneous coronary intervention. 1

Uremic platelet dysfunction in renal failure contributes to hemorrhagic risk, especially when combined with volume overload from cardiac failure. 4

Cardiac and Hemodynamic Causes

Left-sided cardiac failure and pulmonary edema produce hydrostatic alveolar hemorrhage through increased left-ventricular preload and elevated capillary pressure. 4

• Renal failure compounds this through volume overload and uremic platelet dysfunction. 4

Pulmonary embolism can cause hemodynamic disturbances resulting in alveolar hemorrhage, though PE is an uncommon cause of hemoptysis. 4

Infectious Causes

Respiratory infections can precipitate DAH, though less commonly than autoimmune etiologies. 1

In immunocompetent patients, the most frequent infectious causes include:

• Influenza A (H1N1) 6
• Dengue 6
• Leptospirosis 6
• Malaria 6
• Staphylococcus aureus infection 6

In immunocompromised patients, key infectious causes are:

• Cytomegalovirus 6
• Adenovirus 6
• Invasive aspergillosis 6
• Mycoplasma and Legionella 6
• Strongyloides 6

Tuberculosis and its sequelae remain prevalent causes in developing countries. 1

Toxic and Drug-Induced Causes

Molecular-targeted therapies and immune-checkpoint inhibitors cause drug-related pneumonitis that may be accompanied by alveolar hemorrhage. 4

Radiation pneumonitis typically develops 3-12 weeks after thoracic irradiation and can present with DAH. 4

• Risk increases with combined or sequential cyclophosphamide and radiation therapy of the cardiac region. 4

Inhaled toxins represent another mechanism for DAH development. 7, 8

Critical Care-Related Causes

Diffuse alveolar damage associated with acute respiratory distress syndrome (ARDS) may manifest with pulmonary hemorrhage. 3, 4

• The pathological hallmark is diffuse alveolar damage with interstitial swelling, proteinaceous alveolar edema, hemorrhage, and fibrin deposition. 3

Diagnostic Considerations

Cryptogenic hemoptysis accounts for approximately 20% of cases despite extensive investigation. 1

• Mortality risk correlates more with the rate of hemoptysis rather than quantity, making rapid progression particularly concerning. 1, 9

Bronchoalveolar lavage retrieving increasingly bloody fluid in sequential aliquots is the best diagnostic clue for confirming DAH. 4, 9

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. 4

Key Clinical Pitfalls

• Do not exclude small-vessel vasculitis based on negative ANCA alone, as approximately 10% of AAV patients are ANCA-negative. 4
• Do not delay empiric immunosuppressive therapy when immune-mediated DAH is suspected, as delayed treatment dramatically worsens outcomes. 9
• Older age, severe kidney failure, degree of hypoxemia, and involvement of >50% of lung area at presentation are independent predictors of mortality requiring aggressive early intervention. 3, 9