Diffuse alveolar hemorrhage

I. What every physician needs to know.

Diffuse alveolar hemorrhage (DAH) is a clinicopathologic syndrome resulting from the accumulation of erythrocytes, fibrin, and eventually hemosiderin-laden macrophages within the alveoli and is due to damage to the vascular structures within the lung.

II. Diagnostic Confirmation: Are you sure your patient has diffuse alveolar hemorrhage?

There is no specific diagnostic criteria for DAH. The diagnosis is established when clinical, radiographic, and bronchoscopy findings are suggestive, with or without lung biopsy.

A. History Part I: Pattern Recognition:

Clinically, DAH is characterized by hemoptysis, anemia, and hypoxemic respiratory failure. Nonspecific symptoms such as fever, dyspnea, and chest pain are often present. Hemoptysis is considered a cardinal feature, although it can be absent in up to one-third of patients.

B. History Part 2: Prevalence:

DAH occurs in patients of all ages and is often associated with infection or bronchitis. While DAH can be isolated, it can occur in association with a systemic disease. Isolated DAH can be due to pauci-immune pulmonary capillaritis or idiopathic pulmonary hemosiderosis (IPH). IPH is an uncommon condition characterized by recurrent DAH leading to iron-deficiency anemia and pulmonary fibrosis. Specific diseases associated with DAH are discussed briefly below.

Systemic lupus erythematosus (SLE): DAH occurs in approximately 4% of hospitalized SLE patients. Most of these patients are young females. When DAH occurs in SLE, it is frequently accompanied by renal failure due to glomerulonephritis. Mortality is higher than in DAH associated with other conditions, approaching 50%. Recurrences are common.

Granulomatosis with polyangiitis (GPA): DAH is identified in 25% of patients with severe GPA. Most patients with DAH are older males and have evidence of sinus and renal disease. Serum antibodies to cytoplasmic proteinase-3 (c-ANCA) levels are associated with disease activity.

Microscopic polyangiitis (MPA): MPA is a small-vessel vasculitis that affects the lower respiratory tract and kidney. DAH is common in MPA, occurring in one-third of patients and carries a 30% mortality. The pathogenesis of MPA is related to serum antibodies to perinuclear antibodies (p-ANCA) with antimyeloperoxidase specificity (anti-MPO ELISA), however disease activity does not correlate to antibody titers.

Anti-glomerular basement membrane (GBM) antibodies or Goodpasture’s syndrome: Goodpasture’s syndrome or basement membrane disease is caused by autoantibodies against type 4 collagen, a component of both glomerular and alveolar basement membrane. DAH is the pulmonary expression of Goodpasture’s syndrome and is most commonly seen in young male smokers. The diagnosis is often made by serum glomerular basement membrane antibodies, however, demonstration of linear immunoflourescence on kidney or lung biopsy is often required.

C. History Part 3: Competing diagnoses that can mimic diffuse alveolar hemorrhage.

Infectious causes of DAH should be excluded, as should other manifestations of systemic diseases such as lupus pneumonitis.

D. Physical Examination Findings.

Physical examination is nonspecific and can range from normal physical exam to crackles and upper airway pooling of blood.

E. What diagnostic tests should be performed?

Bronchoalveolar lavage (BAL) is central to the diagnosis of DAH. Although initial airway survey is unremarkable, sequential BAL revealing progressively bloody return is the characteristic finding. The finding of hemosiderin-laden macrophages on cytologic examination confirms the diagnosis if greater than 20% of macrophages stain positive for hemosiderin, although this is often absent early in the disease.

Pulmonary function tests are usually nonspecific. A characteristic finding, however, is an elevated diffusion capacity due to the presence of intra-alveolar erythrocytes.

1. What laboratory studies (if any) should be ordered to help establish the diagnosis? How should the results be interpreted?

Anemia is common, and an unexplained falling hemoglobin in the presence of cough or dyspnea should alert clinicians to the possible diagnosis.
Measurements of inflammation such as sedimentation rate and C-reactive protein (CRP) are often elevated.
Serum antinuclear antibody, ANCAs, and glomerular basement membrane (GBM) should be assessed to look for an underlying etiology of DAH.

2. What imaging studies (if any) should be ordered to help establish the diagnosis? How should the results be interpreted?

Chest radiography is nonspecific, usually demonstrating diffuse alveolar opacities. Computed tomography (CT) scan is more sensitive and used to better delineate the extent of disease.

CT angiography is rarely helpful in identifying the involved blood vessel.

F. Over-utilized or “wasted” diagnostic tests associated with this diagnosis.

N/A

III. Default Management.

Hypoxemic respiratory failure is not uncommon in DAH and care should be taken to maintain oxygenation.

A. Immediate management.

Supportive care measures to maintain oxygenation.
Endotracheal intubation is essential to maintain patent airway if the hemoptysis is massive.
Single-lung intubation may be needed if the bleeding location is known.
Appropriate venous access (large-bore IV access) for resuscitation.
High-dose corticosteroids (for example, methylprednisolone 1g/day) along with other immunosuppressive therapy, such as cyclophosphamide, rituximab, or plasmapheresis should be administered if vasculitis is suspected.

B. Physical Examination Tips to Guide Management.

Watch for worsening of airspace disease and increasing oxygen requirements as a sign of impending respiratory failure.

C. Laboratory Tests to Monitor Response To, and Adjustments in, Management.

In GPA, c-ANCA titers parallel disease activity. Inflammatory markers, such as erythrocyte sedimentation rate (ESR) and CRP, have not been adequately studied as prognostic tools.

D. Long-term management.

The underlying etiology should be identified and treated. Immunosuppressive therapy is the mainstay of treatment, with cyclophosphamide, azathioprine, and more recently, rituximab.

IV. Management with Co-Morbidities

A. Renal Insufficiency.

Immunosuppressive agents may need to be dose adjusted.

B. Liver Insufficiency.

Immunosuppressive agents may need to be dose adjusted.

E. Diabetes or other Endocrine issues

Watch for hyperglycemia with high dose corticosteroid therapy.

F. Malignancy

No change in standard management.

H. Primary Lung Disease (COPD, Asthma, ILD)

Expect exacerbations of underlying lung disease in the presence of DAH.

I. Gastrointestinal or Nutrition Issues

No change in standard management.

J. Hematologic or Coagulation Issues

Coagulopathy needs to be corrected in patients with DAH.

K. Dementia or Psychiatric Illness/Treatment

High dose steroids can exacerbate or induce psychosis or other psychiatric conditions.

V. Transitions of Care

A. Sign-out considerations While Hospitalized.

Watch for worsening oxygenation, increased work of breathing, or an unexplained drop in hemoglobin as a sign of worsening hemorrhage.

B. Anticipated Length of Stay.

Length of stay is variable, depending on the etiology and severity of the disease.

C. When is the Patient Ready for Discharge.

Patients can be discharged once oxygen requirements are stable for over 48 hours, and there has been clinical and radiographic improvement.

D. Arranging for Clinic Follow-up

1. When should clinic follow up be arranged and with whom.

Patients should follow up with a pulmonologist and/or rheumatologist, depending on the etiology of their disease. Initial follow up should be short term, in 2–3 weeks.

2. What tests should be conducted prior to discharge to enable best clinic first visit.

Serologic testing for ANCAs, GBM, etc. may take time to result. Ordering these during the hospitalization will ensure that the results are available for the first clinic visit.

3. What tests should be ordered as an outpatient prior to, or on the day of, the clinic visit.

Patients on immunosuppressive therapy will need monitoring of their complete blood count (CBC).

E. Placement considerations

F. Prognosis and Patient Counseling.

The course of DAH is variable, and progression to life-threatening respiratory failure should always be considered. Mortality is significantly worse when DAH occurs in association with SLE than with other conditions.

VI. Patient Safety and Quality Measures

A. Core Indicator Standards and Documentation.

There are no core measures for the treatment of DAH.

B. Appropriate Prophylaxis and Other Measures to Prevent Readmission.

During hospitalization, prophylactic anticoagulation should be held in the presence of life-threatening bleeding.

If patients are discharged on chronic immunosuppression, consider Pneumocystis carinii pneumonia (PCP) prophylaxis as well as vitamin D, calcium, and measures to avoid osteoporosis.

VII. What’s the Evidence?

Collard, HR, King, TE, Schwarz, MI, Broaddus, VC, Mason, RJ, Ernst, JD. “Diffuse alveolar hemorrhage and rare infiltrative disorders of the lung”. Murray & Nadel’s Textbook of Respiratory Medicine. 2016. pp. 1207

Lara, AR, Schwarz, MI. “Diffuse Alveolar Hemorrhage”. CHEST. vol. 137. 2010. pp. 1164-1171.

Collard, HR, Schwarz, MI. “Diffuse alveolar hemorrhage”. Clin Chest Med. vol. 25. 2004 Sep. pp. 583-92.

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