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Diffuse Alveolar Hemorrhage

by Marvin I. Schwarz, MD

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 suggests a differential diagnosis and a specific sequence of testing.

Pathophysiology

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 yr. Idiopathic pulmonary hemosiderosis is diffuse alveolar hemorrhage with no detectable underlying disorder; it occurs mainly in children < 10 yr and is thought to be due to a defect in the alveolar capillary endothelium, possibly due to autoimmune injury.

Etiology

Many disorders can cause alveolar hemorrhage; they include

  • Autoimmune disorders (eg, systemic vasculitides, Goodpasture syndrome, antiphospholipid antibody syndrome, connective tissue disorders)

  • Pulmonary infections (eg, invasive aspergillosis, 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

  • Bone marrow or solid organ transplantation

Symptoms and Signs

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 with a decreasing Hct. Children with idiopathic pulmonary hemosiderosis may have failure to thrive and iron deficiency anemia.

There are no specific physical examination findings.

Other manifestations depend on the underlying disorder (eg, diastolic murmur in patients with mitral stenosis).

Diagnosis

  • 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 if one suspects 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; serum BUN and creatinine also should be done. Other routine tests include CBC, coagulation studies, platelet counts, and serologic tests (antinuclear antibody, anti–double-stranded DNA [anti-dsDNA], antiglomerular basement membrane [anti-GBM] antibodies, antineutrophil cytoplasmic antibodies [ANCA], antiphospholipid antibody) to look for underlying disorders; perinuclear-ANCA (p-ANCA) titers are elevated in some cases of isolated pauci-immune pulmonary capillaritis. Diagnosis of idiopathic pulmonary hemosiderosis involves demonstration of iron deficiency anemia and hemosiderin-laden macrophages in BAL fluid or lung biopsy specimens when there is no evidence of small-vessel vasculitis (pulmonary capillaritis) or another diagnosis; it is confirmed by lung biopsy.

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 (DL co ) due to increased uptake of carbon monoxide by intra-alveolar Hb; however, this finding, which is consistent with hemorrhage, does not assist with establishing a diagnosis. Echocardiography may be indicated to exclude mitral stenosis. Lung or 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

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 occurs in some patients with recurrent diffuse alveolar hemorrhage secondary to microscopic polyarteritis.

Treatment

  • Corticosteroids

  • Sometimes cyclophosphamide 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. Plasma exchange may be used to treat Goodpasture syndrome. Corticosteroids are also used to treat idiopathic pulmonary hemosiderosis; immunosuppressants are added for nonresponders. 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 O 2 , bronchodilators, reversal of any coagulopathy, intubation with bronchial tamponade, protective strategies for the less involved lung, and mechanical ventilation.

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 BAL 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, plasma exchange, and/or immunosuppressants for autoimmune causes).

Resources In This Article

Drugs Mentioned In This Article

  • Drug Name
    Select Trade
  • FURADANTIN, MACROBID, MACRODANTIN
  • No US brand name
  • SINGULAIR
  • CORDARONE
  • REMICADE
  • OTREXUP
  • CYTOXAN (LYOPHILIZED)

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