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 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 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 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 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 , Goodpasture syndrome Goodpasture Syndrome Goodpasture syndrome, a type of pulmonary-renal syndrome, is an autoimmune syndrome consisting of alveolar hemorrhage and glomerulonephritis caused by circulating anti-glomerular basement membrane... read more , antiphospholipid syndrome Antiphospholipid Syndrome (APS) Antiphospholipid syndrome is an autoimmune disorder characterized by venous and arterial thrombosis or pregnancy complications (eg, recurrent miscarriage) and persistent autoantibodies to phospholipid-bound... read more , systemic rheumatic disorders)
Coagulation disorders caused by diseases or anticoagulant medications
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
Reactions to medications (eg, propylthiouracil, amiodarone, methotrexate, nitrofurantoin, montelukast, infliximab)
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 Acute Hypoxemic Respiratory Failure (AHRF, ARDS) Acute hypoxemic respiratory failure is defined as severe hypoxemia (PaO2 (See also Overview of Mechanical Ventilation.) Airspace filling in acute hypoxemic respiratory failure (AHRF) may result... read more , 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 Mitral Stenosis Mitral stenosis is narrowing of the mitral orifice that impedes blood flow from the left atrium to the left ventricle. The usual cause is rheumatic fever. Common complications are pulmonary... read more ).
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 Bronchoscopy Bronchoscopy is the introduction of an endoscope into the airways. Flexible fiberoptic bronchoscopy (rather than rigid bronchoscopy) is used for virtually all diagnostic, and most therapeutic... 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 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 ; 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.
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 specific diagnosis.
Echocardiography Echocardiography Echocardiography uses ultrasound waves to produce an image of the heart, the heart valves, and the great vessels. It helps assess heart wall thickness (eg, in hypertrophy or atrophy) and motion... read more 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
Sometimes cyclophosphamide, rituximab, or plasma exchange
Supportive measures
Treatment involves correcting the cause. Treatment recommendations are based on the type and severity of disease (1 Treatment references 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... read more ).
Corticosteroids and possibly cyclophosphamide are used to treat vasculitides 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 , systemic rheumatic disorders, and Goodpasture syndrome Treatment Goodpasture syndrome, a type of pulmonary-renal syndrome, is an autoimmune syndrome consisting of alveolar hemorrhage and glomerulonephritis caused by circulating anti-glomerular basement membrane... read more . Rituximab has been studied primarily in ANCA-associated vasculitis and has been shown to be noninferior to cyclophosphamide for induction treatment (2 Treatment references 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... read more ) and superior to azathioprine for remission treatment (3 Treatment references 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... read more ). Rituximab has also been used to treat alveolar hemorrhage related to systemic lupus erythematosus Systemic Lupus Erythematosus (SLE) Systemic lupus erythematosus is a chronic, multisystem, inflammatory disorder of autoimmune etiology, occurring predominantly in young women. Common manifestations may include arthralgias and... read more , Goodpasture syndrome, and antiphospholipid syndrome Antiphospholipid Syndrome (APS) Antiphospholipid syndrome is an autoimmune disorder characterized by venous and arterial thrombosis or pregnancy complications (eg, recurrent miscarriage) and persistent autoantibodies to phospholipid-bound... read more .
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 defined as severe hypoxemia (PaO2 (See also Overview of Mechanical Ventilation.) Airspace filling in acute hypoxemic respiratory failure (AHRF) may result... 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 .
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 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. Emphysema 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 can occur in some patients with recurrent diffuse alveolar hemorrhage secondary to microscopic polyangiitis Microscopic Polyangiitis (MPA) Microscopic polyangiitis is a systemic necrotizing vasculitis without immune globulin deposition (pauci-immune) that affects mainly small vessels. It may begin as a pulmonary-renal syndrome... read more .
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.
Treat the cause (eg, with corticosteroids, cyclophosphamide, rituximab, plasma exchange).
Drugs Mentioned In This Article
Drug Name | Select Trade |
---|---|
propylthiouracil |
No brand name available |
amiodarone |
Cordarone, Nexterone, Pacerone |
methotrexate |
Jylamvo, Otrexup, Rasuvo, RediTrex, Rheumatrex, Trexall, Xatmep |
nitrofurantoin |
Furadantin, Macrobid, Macrodantin, Urotoin |
montelukast |
Singulair |
infliximab |
AVSOLA, INFLECTRA, Remicade, RENFLEXIS, Zymfentra |
cyclophosphamide |
Cyclophosphamide, Cytoxan, Neosar |
rituximab |
RIABNI, Rituxan, RUXIENCE, truxima |
azathioprine |
Azasan, Imuran |