Diffuse alveolar hemorrhage: Diagnosing it and finding the cause

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The diagnostic evaluation in diffuse alveolar hemorrhage usually includes bronchoscopic examination,10 which serves two purposes:

  • To document alveolar hemorrhage by bronchoalveolar lavage and to exclude airway sources of bleeding by visual inspection
  • To exclude an associated infection.

Based on experience with nonmassive hemoptysis of all causes (but not exclusively diffuse alveolar hemorrhage), the diagnostic yield of bronchoscopy is higher if the procedure is performed within the first 48 hours of symptoms rather than later. Evidence supporting diffuse alveolar hemorrhage is persistent (or even increasing) blood on three sequential lavage aliquots from a single affected area of the lung.

Figure 1. This biopsy specimen shows blood-filled alveolar spaces and hemosiderin-laden macrophages (arrows). Alveolar septae show widening due to a chronic inflammatory infiltrate of lymphocytes and plasma cells (arrowheads). (Hematoxylin and eosin stain, × 4)

In subacute or recurrent episodes of diffuse alveolar hemorrhage, counting the hemosiderin-laden macrophages (siderophages) as demonstrated by Prussian blue staining of a pooled lavage specimen centrifugate may be useful for diagnosis. Bronchoalveolar lavage specimens should be sent for routine bacterial, mycobacterial, fungal, and viral stains and cultures, as well as for Pneumocystis stains.

Figure 2. Hemosiderin pigment is visible in both alveolar macrophages (arrows, AM) and within connective tissue of alveolar septae (arrowheads, CT). (Hematoxylin and eosin stain, × 10)

Transbronchial biopsy is unlikely to establish a diagnosis of diffuse alveolar hemorrhage because the specimens are small. Thus, trans-bronchial biopsy should be reserved for situations in which the alternative cause that is being considered (eg, sarcoid) actually can be diagnosed by this method.

Figure 3. A stain for iron highlights hemosiderin within the alveolar macrophages in the alveolar spaces (Prussian blue stain × 20).

The histologic appearance of diffuse alveolar hemorrhage (Figures 1–3) is relatively uniform, whatever the underlying cause. Changes of acute or chronic organizing hemorrhage, sometimes with hyaline alveolar membranes, may accompany findings of small-vessel vasculitis or changes associated with the underlying pathology, such as granulomatous vasculitis in Wegener granulomatosis (Table 1).


Once the diagnosis of diffuse alveolar hemorrhage is established, the clinician must ascertain whether an underlying cause is present. Serologic studies may prove important, although the results are generally not available in a manner timely enough to guide immediate management.

When a pulmonary-renal syndrome is suggested by accompanying hematuria or renal dysfunction, antiglomerular basement membrane antibody and antineutrophil cytoplasmic antibody (ANCA) levels should be checked. Tests for complement fractions C3 and C4, anti-double-stranded DNA, and antiphospholipid antibodies should be ordered if an underlying condition such as lupus or antiphospholipid antibody syndrome is suspected (Table 2).11

If the underlying cause remains elusive after a thorough clinical evaluation that includes imaging studies, serologic studies, and bronchoscopy, then surgical biopsy should be considered.1 Which organ to biopsy (eg, lung, sinus, kidney) depends on the level of suspicion for a specific cause. For example, suspicion of Wegener granulomato-sis with hematuria or renal dysfunction might prompt renal biopsy. However, lung biopsy often needs to be performed with video-assisted thoracoscopy, especially when disease is confined to the lung (as in idiopathic pulmonary hemosiderosis or pauci-immune pulmonary capillaritis). Renal biopsy specimens should also undergo immunofluores-cence staining, which may reveal linear deposition of immunoglobulins and immune complexes along the basement membrane in patients with Goodpasture syndrome, or of granular deposits in patients with systemic lupus erythematosus.

Table 2 offers a guide to diagnosis for most common causes of diffuse alveolar hemorrhage, while Table 3 outlines the differential diagnosis of underlying conditions.12–62


In general, the clinician will be confronted by one of two scenarios: a patient with diffuse alveolar hemorrhage and associated systemic findings, or a patient with hemorrhage and no associated systemic findings.

Hemorrhage with associated systemic findings

Certain clues from the history raise suspicion of diffuse alveolar hemorrhage:

  • Recent infection suggests Henoch-Schönlein purpura or cryoglobulinemic vasculitis
  • Use of a possibly offending drug such as an anticoagulant, D-penicillamine (Cuprimine, Depen), nitrofurantoin (Furadantin, Macrobid, Macrodantin), amiodarone (Cordarone), propylthiouracil, cocaine, or sirolimus (Rapamune, Rapamycin)
  • Exposure to toxic agents such as trimellitic anhydride, insecticides, and pesticides
  • A known comorbid condition such as vasculitis, connective tissue disease, mitral valve disease, or solid organ or stem cell transplantation.

If asthma, eosinophilia, pulmonary infiltrates, and diffuse alveolar hemorrhage coexist, consideration should be given to Churg-Strauss syndrome. If sinus disease, skin manifestations, pulmonary parenchymal nodules, and cavitary lesions coexist with positivity for antiproteinase 3 c-ANCA and biopsy-proven granulomata, then Wegener granulomatosis should be considered. Similarly, diffuse alveolar hemorrhage with glomerulonephritis and skin manifestations, positivity for p-ANCA, and necrotizing nongranulomatous lesions on end-organ biopsy may lead to a diagnosis of microscopic polyangiitis. In a young smoker with glomeru-lonephritis and diffuse alveolar hemorrhage presenting as either bland alveolar hemorrhage or pulmonary capillaritis, Goodpasture syndrome or antiglomerular basement membrane antibody disease should be considered.

Hemorrhage with no associated systemic findings

When the above conditions have been considered but no suggestive findings are found, the following four conditions should be considered:

  • Antiglomerular basement membrane antibody disease in limited pulmonary form or onset: positivity to the antibody with linear deposits in the lungs would be diagnostic in such a case
  • Pulmonary-limited microscopic polyangiitis positive for p-ANCA (a positive anti-myeloperoxidase p-ANCA test makes the diagnosis)
  • Pauci-immune isolated pulmonary capillaritis, when the biopsy shows evidence of neutrophilic pulmonary capillaritis
  • Idiopathic pulmonary hemosiderosis, a diagnosis of exclusion, when the biopsy shows evidence of acute, subacute, and chronic bland diffuse alveolar hemorrhage and no evidence of vasculitis.

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