Diffuse alveolar hemorrhage is persistent or recurrent pulmonary hemorrhage. 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 tests are 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 pulmonary small 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 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 antibody syndrome, connective tissue disorders)
- Pulmonary infections (eg, hantavirus infection)
- Toxic exposures (eg, trimellitic anhydride, isocyanates, crack cocaine, certain pesticides)
- Drug reactions (eg, propylthiouracil, diphenylhydantoin, amiodarone, methotrexate, nitrofurantoin, bleomycin, montelukast, infliximab)
- Cardiac disorders (eg, mitral stenosis)
- Coagulation disorders caused by diseases or anticoagulant drugs
- Isolated pauci-immune pulmonary capillaritis
- Idiopathic pulmonary hemosiderosis
- Hematopoietic stem cell transplantation or solid organ transplantation
Symptoms and Signs of Diffuse Alveolar Hemorrhage
Symptoms and signs of milder diffuse alveolar hemorrhage are dyspnea, cough, and fever; however, many patients present with acute respiratory failure, sometimes leading to death. 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.
Pearls & Pitfalls
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 syndromes; 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)
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.
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 diagnosis.
Echocardiography may be indicated to exclude mitral stenosis. Lung biopsy or, if the urinalysis is abnormal, kidney biopsy is frequently needed when a cause remains unclear or the progression of disease is too rapid to await the results of serologic testing.
Prognosis of 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. COPD (chronic obstructive pulmonary disease) occurs in some patients with recurrent diffuse alveolar hemorrhage secondary to microscopic polyarteritis.
Treatment of Diffuse Alveolar Hemorrhage
- Sometimes cyclophosphamide, rituximab, or plasma exchange
- Supportive measures
Treatment involves correcting the cause.
Corticosteroids and possibly cyclophosphamide are used to treat vasculitides, connective tissue disorders, and Goodpasture syndrome. Rituximab has been studied in ANCA-associated vasculitis and has been shown to be noninferior to cyclophosphamide for induction treatment (1) and superior to azathioprine for remission treatment (2).
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.
- 1. 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
- 2. 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
Key Points about Diffuse Alveolar Hemorrhage
- 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.
- Treat the cause (eg, with corticosteroids, cyclophosphamide, rituximab, plasma exchange, and/or immunosuppressants for autoimmune causes).
Drugs Mentioned In This Article
|Drug Name||Select Trade|
|propylthiouracil||No US brand name|
|nitrofurantoin||FURADANTIN, MACROBID, MACRODANTIN|