Diffuse alveolar hemorrhage is persistent or recurrent pulmonary hemorrhage that originates from the lung parenchyma (ie, the alveoli) as opposed to the airways. There are numerous causes, but autoimmune disorders are most common. Most patients present with dyspnea, cough, hemoptysis, and new alveolar infiltrates on chest imaging. Diagnostic testing is directed at the suspected cause. Treatment is with immunosuppressants for patients with autoimmune causes and respiratory support if needed.
Diffuse alveolar hemorrhage is not a specific disorder, but a syndrome that has a specific differential diagnosis and a specific sequence of testing. Some disorders that cause diffuse alveolar hemorrhage are associated with glomerulonephritis; then the disorder is defined as a pulmonary-renal syndrome.
Pathophysiology of Diffuse Alveolar Hemorrhage
Diffuse alveolar hemorrhage results from widespread damage to the small pulmonary vessels, leading to blood collecting within the alveoli. If enough alveoli are affected, gas exchange is disrupted. The specific pathophysiology and manifestations vary depending on cause. For example, isolated pauci-immune pulmonary capillaritis is a small-vessel vasculitis limited to the lungs; its only manifestation is alveolar hemorrhage typically affecting people aged 18 to 35 years.
Etiology of Diffuse Alveolar Hemorrhage
Many disorders can cause alveolar hemorrhage; they include
Autoimmune disorders (eg, systemic vasculitides, Goodpasture syndrome, antiphospholipid syndrome, systemic rheumatic disorders)
Cardiac disorders (eg, mitral stenosis)
Coagulation disorders caused by diseases or anticoagulant medications
Hematopoietic stem cell transplantation or solid organ transplantation
Isolated pauci-immune pulmonary capillaritis
Pulmonary infections (eg, hantavirus infection)
Toxic exposures (eg, trimellitic anhydride, isocyanates, crack cocaine, certain pesticides, vaping)
Symptoms and Signs of Diffuse Alveolar Hemorrhage
Symptoms and signs of milder diffuse alveolar hemorrhage are dyspnea, cough, and fever. Hemoptysis is common but may be absent in up to one third of patients. Most patients have anemia and ongoing bleeding, leading to a reduced hematocrit. Many patients present with acute respiratory failure, sometimes leading to death.
Pearls & Pitfalls
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There are no specific physical examination findings.
Other manifestations depend on the underlying disorder (eg, diastolic murmur in patients with mitral stenosis).
Diagnosis of Diffuse Alveolar Hemorrhage
Chest x-ray
Bronchoalveolar lavage
Serologic and other tests to diagnose the cause
Diagnosis is suggested by dyspnea, cough, and hemoptysis accompanied by chest x-ray findings of diffuse bilateral alveolar infiltrates and a suspicion of diffuse alveolar hemorrhage.
Bronchoscopy with bronchoalveolar lavage (BAL) is strongly recommended to confirm the diagnosis, particularly when manifestations are atypical or an airway source of hemorrhage has not been excluded. Specimens show blood with numerous erythrocytes and siderophages; lavage fluid typically remains hemorrhagic or becomes increasingly hemorrhagic after sequential sampling.
Evaluation of the cause
Further testing for the cause should be done. Urinalysis is indicated to exclude glomerulonephritis and the pulmonary-renal syndrome; serum BUN (blood urea nitrogen) and creatinine also should be measured.
Other routine tests include
Complete blood count (CBC)
Coagulation studies
Platelet count
Serologic tests (antinuclear antibody, anti–double-stranded DNA [anti-dsDNA], antiglomerular basement membrane [anti-GBM] antibodies, antineutrophil cytoplasmic antibodies [ANCA], antiphospholipid antibody, complement levels)
Serologic tests are done to look for underlying disorders. Perinuclear-ANCA (p-ANCA) titers are elevated in some cases of isolated pauci-immune pulmonary capillaritis.
By permission of the publisher. From Cohen A, Glassock R. In Atlas of Diseases of the Kidney: Glomerulonephritis and Vasculitis. Edited by R Schrier (series editor), RJ Glassock, and AH Cohen. Philadelphia, Current Medicine, 1999.
Image courtesy of Joyce Lee, MD.
Other tests depend on clinical context. When patients are stable, pulmonary function tests may be done to document lung function. They may show increased diffusing capacity for carbon monoxide (DLCO) due to increased uptake of carbon monoxide by intra-alveolar hemoglobin; however, this finding, which is consistent with hemorrhage, does not assist with establishing a specific diagnosis.
Echocardiography may be indicated to exclude mitral stenosis.
Lung biopsy or, if the urinalysis is abnormal, kidney biopsy may be needed when a cause remains unclear or the progression of disease is too rapid to await the results of serologic testing.
Treatment of Diffuse Alveolar Hemorrhage
Corticosteroids
Supportive measures
Treatment involves correcting the cause. Treatment recommendations are based on the type and severity of disease (1).
vasculitides, systemic rheumatic disorders, and Goodpasture syndrome23). Rituximab has also been used to treat alveolar hemorrhage related to systemic lupus erythematosus, Goodpasture syndrome, and antiphospholipid syndrome.
Plasma exchange may be used to treat Goodpasture syndrome.
Several studies have reported successful use of recombinant activated human factor VII in treating severe unresponsive alveolar hemorrhage, but such therapy is controversial because of possible thrombotic complications.
Other possible management measures include supplemental oxygen, bronchodilators, reversal of any coagulopathy, and intubation with protective strategies as for acute respiratory distress syndrome (ARDS) and mechanical ventilation.
Treatment references
1. Chung SA, Langford CA, Maz M, et al: 2021 American College of Rheumatology/Vasculitis Foundation Guideline for the Management of Antineutrophil Cytoplasmic Antibody-Associated Vasculitis. Arthritis Rheumatol 73(8):1366–1383, 2021. doi:10.1002/art.41773
2. Specks U, Merkel PA, Seo P, et al: Efficacy of remission-induction regimens for ANCA-associated vasculitis. N Engl J Med 369:417–427, 2013. doi: 10.1056/NEJMoa1213277
3. Guillevin L, Pagnoux C, Karras A, et al: Rituximab versus azathioprine for maintenance in ANCA-associated vasculitis. New Engl J Med 371:1771–1780. 2014. doi: 10.1056/NEJMoa1404231
Prognosis for Diffuse Alveolar Hemorrhage
Patients can require mechanical ventilation and even die as a result of hemorrhage-associated respiratory failure.
Recurrent alveolar hemorrhage causes pulmonary hemosiderosis and fibrosis, both of which develop when ferritin aggregates within alveoli and exerts toxic effects. Emphysema can occur in some patients with recurrent diffuse alveolar hemorrhage secondary to microscopic polyangiitis.
Key Points
Although diffuse alveolar hemorrhage can have various causes (eg, infection, toxins, drugs, hematologic or cardiac disorders), autoimmune disorders are the most common causes.
Symptoms, signs, and chest-x-ray findings are not specific.
Confirm diffuse alveolar hemorrhage by doing bronchoalveolar lavage to show persistent hemorrhage with sequential lavage samples.
Test for the cause by doing routine laboratory tests, autoantibody testing, and sometimes other tests.
