Approach Considerations
Diffuse alveolar hemorrhage represents a medical emergency, and clinicians must have an expedient approach to its identification. [24] In the appropriate clinical setting (ie, alveolar hemorrhage and urinary findings suggestive of an acute glomerulonephritis), the detection of circulating anti–glomerular basement membrane (anti-GBM) antibodies allows the clinician to make a firm diagnosis of anti-GBM disease. This obviates lung or kidney biopsy.
When the diagnosis remains in doubt, renal biopsy is the best method for detecting anti-GBM antibodies in tissues. Patients in whom the diagnosis of diffuse alveolar hemorrhage remains uncertain should undergo diagnostic bronchoscopy.
Urinalysis and blood studies
Urinalysis findings are characteristic of acute glomerulonephritis, usually demonstrating low-grade proteinuria, gross or microscopic hematuria, and red blood cell casts.
On the complete blood cell count, anemia may be observed secondary to iron deficiency caused by intrapulmonary bleeding. Leukocytosis is commonly present.
Elevated blood urea nitrogen (BUN) and serum creatinine levels secondary to renal dysfunction may be present.
Elevation of the erythrocyte sedimentation rate (ESR) is commonly observed in patients with vasculitis, but it is uncommon in anti-GBM disease.
Anti–GBM Antibody Testing
Serologic assays for anti-GBM antibodies are valuable for confirming the diagnosis and monitoring the adequacy of therapy. Radioimmunoassays or enzyme-linked immunosorbent assays (ELISAs) for anti-GBM antibodies are highly sensitive (>95%) and specific (>97%) but are performed in only a few laboratories. Positive results should be confirmed by Western blotting on collagenase-solubilized human GBM, especially if a kidney biopsy is not being performed.
In a comparison study of 4 immunoassay-based anti-GBM antibody kits, all the assays showed comparably good sensitivity (94.7-100.0%), whereas specificity varied considerably (90.9-100.0%). The recombinant antigen fluorescence immunoassay demonstrated the best sensitivity/specificity. [25]
Healthy individuals may have circulating antibodies against GBM belonging to IgG2 and IgG4 subclasses. With onset of clinical disease, IgG1 and IgG3 subclasses increase and levels may correlate with disease severity. [7]
A study by Yang et al indicated that higher levels of circulating anti-GBM antibodies against the epitopes EA and EB occurred in patients whose renal disease was more severe and that these patients had a worse prognosis. Correlation was noted between the levels of anti-GBM antibodies and the serum creatinine at diagnosis and the presence of oliguria. Correlation existed between the percentage of crescents on biopsy and levels of antibodies, but it was significant only for anti-EA antibodies (P< .05). [26]
Cases of anti-GBM antibody–negative anti-GBM disease have been reported. Kidney biopsy is required to diagnose this atypical presentation. [27, 28]
Antineutrophilic Cytoplasmic Antibody Testing
At some time during the course of illness, as many as one third of patients with Goodpasture syndrome have circulating antineutrophilic cytoplasmic antibodies (ANCAs) in addition to anti-GBM antibody. [23] In most cases, the ANCA antibodies precede the development of anti-GBM antibodies by months to years. [29] It is postulated that the renal involvement in ANCA vasculitis leads to the exposure of antigens from the basement membrane and the formation of antibodies. These patients are referred to as double-positive.
Cytoplasmic ANCA (c-ANCA) and perinuclear ANCA (p-ANCA) are seen in the images below.
Cytoplasmic antineutrophilic cytoplasmic antibodies (c-ANCA), which can appear in Goodpasture syndrome, are also commonly observed in Wegener granulomatosis and other vasculitides.
Perinuclear antineutrophilic cytoplasmic antibodies (p-ANCA), which can appear in Goodpasture syndrome, are also observed in Churg-Strauss vasculitis and occasionally in Wegener granulomatosis.
In the majority of double-positive patients, the ANCAs have specificity for myeloperoxidase (MPO-ANCA). [30, 31] In patients with both anti-GBM antibodies and MPO-ANCAs, histological findings differ from those of patients with anti-GBM antibodies only. The renal survival in these patients is similar to anti-GBM–positive patients and is worse compared with patients with MPO-ANCAs only.
In an analysis of the diagnostic performance of two rapid ANCA and anti-GBM test methods in 260 patients with suspected ANCA-associated small vessel vasculitis, de Joode and colleagues found that both the Dotblot and Phadia ELiA on anti-GBM, anti-PR3(s) and anti-MPO(s) performed well. Results with these tests were almost identical to those achieved with routine ELISA. [32]
Chest Radiograph
Characteristically, the chest film shows patchy parenchymal consolidations, which are usually bilateral, symmetric perihilar, and bibasilar. The apices and costophrenic angles are usually spared (see the image below). However, as many as 18% of patients may have normal findings on chest radiographs.
The consolidation resolves over 2-3 days, and it gradually progresses to an interstitial pattern as patients experience repeated episodes of hemorrhage. Pleural effusions are unusual.
Goodpasture syndrome. A 35-year-old man who previously smoked cigarettes heavily, developed massive hemoptysis. The blood work showed positive anti–glomerular basement membrane antibodies.
Pulmonary Function Testing
Routine pulmonary function testing is not helpful in the clinical evaluation of the patients with anti-GBM disease. Spirometry and lung volume tests may reveal evidence of restriction.
The diffusing capacity for carbon monoxide (DLCO) is elevated secondary to binding of carbon monoxide to intra-alveolar hemoglobin. Recurrent pulmonary hemorrhage may be diagnosed with new opacities observed on chest radiographs and a 30% rise in DLCO.
Biopsy
In patients with evidence of diffuse alveolar hemorrhage and renal involvement, kidney biopsy should be considered to identify the underlying cause and to help direct therapy. Percutaneous kidney biopsy is the preferred invasive procedure to substantiate the diagnosis of anti-GBM disease. Kidney biopsy provides a significantly higher yield than lung biopsy, but transbronchial or open lung biopsy may be performed in cases where renal biopsy cannot be performed.
The biopsy tissue must be processed for light microscopy, immunofluorescence, and electron microscopy. Light microscopy demonstrates nonspecific features of a proliferative or necrotizing glomerulonephritis with cellular crescents (as seen in the image below). Over time, the crescents become fibrotic, and frank glomerulosclerosis, interstitial fibrosis, and tubular atrophy may be observed.
This is a renal biopsy slide of a patient who presented with hemoptysis and hematuria. The renal biopsy revealed crescentic glomerulonephritis, which may be caused by systemic lupus erythematosus, vasculitis, or Goodpasture syndrome.
Immunofluorescence stains are confirmatory. These show bright linear deposits of immunoglobulin G (IgG), as seen in the image below, and complement (C3) along the glomerular basement membranes. Subclass IgG-1 predominates. [33]
Immunofluorescence staining for immunoglobulin (IgG) reveals diffuse, high-intensity, linear staining of the glomerular basement membrane in a patient with anti–glomerular basement membrane (GBM) disease. Courtesy of Glen Markowitz, MD, Department of Pathology, Columbia University.
Lung biopsy shows extensive hemorrhage with accumulation of hemosiderin-laden macrophages within alveolar spaces. Neutrophilic capillaritis, hyaline membranes, and diffuse alveolar damage may also be found. Medium-vessel or large-vessel vasculitis is not a feature. [34] Immunofluorescence staining may be diagnostic, but performing this study on lung tissue is technically difficult.
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Goodpasture syndrome. A 45-year-old man was admitted to the intensive care unit with respiratory failure secondary to massive hemoptysis and acute renal failure. The antiglomerular basement membrane antibodies were strongly positive. The autopsy showed consolidated lung from extensive bleeding, which led to asphyxiation.
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Goodpasture syndrome. Close-up view of gross pathology in a 45-year-old man admitted to the intensive care unit with respiratory failure secondary to massive hemoptysis and acute renal failure. The antiglomerular basement membrane antibodies were strongly positive. The autopsy showed consolidated lung from extensive bleeding, which led to asphyxiation.
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Cytoplasmic antineutrophilic cytoplasmic antibodies (c-ANCA), which can appear in Goodpasture syndrome, are also commonly observed in Wegener granulomatosis and other vasculitides.
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Perinuclear antineutrophilic cytoplasmic antibodies (p-ANCA), which can appear in Goodpasture syndrome, are also observed in Churg-Strauss vasculitis and occasionally in Wegener granulomatosis.
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This is a renal biopsy slide of a patient who presented with hemoptysis and hematuria. The renal biopsy revealed crescentic glomerulonephritis, which may be caused by systemic lupus erythematosus, vasculitis, or Goodpasture syndrome.
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Goodpasture syndrome. A 35-year-old man who previously smoked cigarettes heavily, developed massive hemoptysis. The blood work showed positive anti–glomerular basement membrane antibodies.
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Immunofluorescence staining for immunoglobulin (IgG) reveals diffuse, high-intensity, linear staining of the glomerular basement membrane in a patient with anti–glomerular basement membrane (GBM) disease. Courtesy of Glen Markowitz, MD, Department of Pathology, Columbia University.
