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 Overview of Glomerular Disorders The hallmark of glomerular disorders is proteinuria, which is often in the nephrotic range (≥ 3 g/day). Glomerular disorders are classified based on urine changes as those that manifest predominantly... read more ; then the disorder is defined as a pulmonary-renal syndrome Pulmonary-Renal Syndrome Pulmonary-renal syndrome is diffuse alveolar hemorrhage plus glomerulonephritis, often occurring simultaneously. Cause is almost always an autoimmune disorder. Diagnosis is by serologic tests... read more .
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 Overview of Vasculitis Vasculitis is inflammation of blood vessels, often with ischemia, necrosis, and organ inflammation. Vasculitis can affect any blood vessel—arteries, arterioles, veins, venules, or capillaries... read more 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 Goodpasture Syndrome Goodpasture syndrome, a subtype of pulmonary-renal syndrome, is an autoimmune syndrome consisting of alveolar hemorrhage and glomerulonephritis caused by circulating anti-glomerular basement... read more , antiphospholipid antibody syndrome Antiphospholipid Antibody Syndrome (APS) Antiphospholipid antibody syndrome is an autoimmune disorder in which patients have autoantibodies to phospholipid-bound proteins. Venous or arterial thrombi may occur. The pathophysiology is... read more , connective tissue disorders)
Coagulation disorders caused by diseases or anticoagulant drugs
Drug reactions (eg, propylthiouracil, diphenylhydantoin, amiodarone, methotrexate, nitrofurantoin, bleomycin, montelukast, infliximab)
Hematopoietic stem cell transplantation Hematopoietic Stem Cell Transplantation Hematopoietic stem cell (HSC) transplantation is a rapidly evolving technique that offers a potential cure for hematologic cancers (leukemias, lymphomas, myeloma) and other hematologic disorders... read more or solid organ transplantation
Isolated pauci-immune pulmonary capillaritis
Toxic exposures (eg, trimellitic anhydride, isocyanates, crack cocaine, certain pesticides)
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 Acute Hypoxemic Respiratory Failure (AHRF, ARDS) Acute hypoxemic respiratory failure is severe arterial hypoxemia that is refractory to supplemental oxygen. It is caused by intrapulmonary shunting of blood resulting from airspace filling or... read more , 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
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 Bronchoscopy Bronchoscopy is the introduction of an endoscope into the airways. Flexible fiberoptic bronchoscopy is used for virtually all diagnostic, and most therapeutic, indications. Flexible bronchoscopes... read more 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 Overview of Glomerular Disorders The hallmark of glomerular disorders is proteinuria, which is often in the nephrotic range (≥ 3 g/day). Glomerular disorders are classified based on urine changes as those that manifest predominantly... read more and the pulmonary-renal syndromes Pulmonary-Renal Syndrome Pulmonary-renal syndrome is diffuse alveolar hemorrhage plus glomerulonephritis, often occurring simultaneously. Cause is almost always an autoimmune disorder. Diagnosis is by serologic tests... read more ; serum BUN (blood urea nitrogen) and creatinine also should be measured.
Other routine tests include
Complete blood count (CBC)
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 Overview of Tests of Pulmonary Function Pulmonary function tests provide measures of airflow, lung volumes, gas exchange, response to bronchodilators, and respiratory muscle function. Basic pulmonary function tests available in the... read more 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 Echocardiography This photo shows a patient having echocardiography. This image shows all 4 cardiac chambers and the tricupsid and mitral valves. Echocardiography uses ultrasound waves to produce an image of... read more 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 Overview of Mechanical Ventilation Mechanical ventilation can be Noninvasive, involving various types of face masks Invasive, involving endotracheal intubation Selection and use of appropriate techniques require an understanding... read more 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 (COPD) Chronic obstructive pulmonary disease (COPD) is airflow limitation caused by an inflammatory response to inhaled toxins, often cigarette smoke. Alpha-1 antitrypsin deficiency and various occupational... read more (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
Treatment involves correcting the cause.
Corticosteroids and possibly cyclophosphamide are used to treat vasculitides, connective tissue disorders, and Goodpasture syndrome Treatment Goodpasture syndrome, a subtype of pulmonary-renal syndrome, is an autoimmune syndrome consisting of alveolar hemorrhage and glomerulonephritis caused by circulating anti-glomerular basement... read more . Rituximab has been studied primarily in ANCA-associated vasculitis and has been shown to be noninferior to cyclophosphamide for induction treatment (1 Treatment references 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... read more ) and superior to azathioprine for remission treatment (2 Treatment references 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... read more ). Rituximab has also been used to treat alveolar hemorrhage related to systemic lupus erythematosus, Goodpasture syndrome, and antiphospholipid antibody syndrome.
Plasma exchange Plasma exchange Apheresis refers to the process of separating the cellular and soluble components of blood using a machine. Apheresis is often done on donors where whole blood is centrifuged to obtain individual... read more 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 Acute Hypoxemic Respiratory Failure (AHRF, ARDS) Acute hypoxemic respiratory failure is severe arterial hypoxemia that is refractory to supplemental oxygen. It is caused by intrapulmonary shunting of blood resulting from airspace filling or... read more (ARDS) and mechanical ventilation Overview of Mechanical Ventilation Mechanical ventilation can be Noninvasive, involving various types of face masks Invasive, involving endotracheal intubation Selection and use of appropriate techniques require an understanding... read more .
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
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).
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