Introduction
This chapter discusses diffuse alveolar hemorrhage (DAH) and includes other rare infiltrative disorders of the lung. DAH is a serious condition characterized by widespread intra-alveolar hemorrhage that originates from the pulmonary microcirculation (arterioles, capillaries, and venules). DAH can be seen in many different diseases, often as the presenting manifestation.
The second section of the chapter discusses several rare infiltrative disorders of the lung, including neurofibromatosis, Hermansky-Pudlak syndrome, dyskeratosis congenita, Gaucher disease, Niemann-Pick disease, and pulmonary alveolar microlithiasis.
Diffuse Alveolar Hemorrhage
Unlike the more common forms of pulmonary hemorrhage that result from focal lesions (e.g., necrotizing pneumonia, bronchitis, bronchiectasis, malignancy, pulmonary infarction, arteriovenous malformation), DAH affects the majority of the alveolar capillary surface. DAH is a medical emergency that often results in acute respiratory failure and death. Pulmonologists must be prepared to identify DAH promptly, diagnose the underlying disease that is causing it, and institute appropriate medical therapy.
Definition
DAH is defined on clinical grounds: diffuse pulmonary opacities with varying degrees of respiratory failure, a falling hemoglobin level, and progressively bloody return (or with increasing red blood cell counts) on sequential bronchoalveolar lavage (BAL). The pathologic process is characterized by the intra-alveolar accumulation of erythrocytes ( Fig. 67-1 ). There can be evidence of chronicity with the accumulation of intra-alveolar hemosiderin-containing macrophages, erythrophagocytosis, and collections of free interstitial hemosiderin, findings that help distinguish DAH from acute biopsy-related bleeding. Other histologic features of DAH include hyperplasia of the type II alveolar epithelial lining cells, intra-alveolar organization (organizing pneumonia), mononuclear cell infiltration of the alveolar interstitium, and small thrombi in the alveolar capillaries and venules.
Patients with DAH may demonstrate neutrophilic inflammation of the alveolar interstitium known as pulmonary or alveolar capillaritis ( Fig. 67-2 ). Capillaritis is commonly associated with endothelial edema, injury, and localized fibrinoid necrosis. Characteristically there is infiltration of the alveolar septa with neutrophils, many of which are undergoing leukocytoclasis and appear fragmented and pyknotic. Fragmentation of these cells leads to accumulation of nuclear dust in the lung parenchyma. Capillaritis is a small vessel vasculitis of the lung and is central to the pathogenesis of many cases of DAH. This small vessel injury and necrosis leads to the loss of integrity of the shared epithelial-endothelial alveolar basement membrane, resulting in extravasation of red blood cells into the alveolar lumina. DAH can also result from all causes of diffuse alveolar damage (DAD) (i.e., cytotoxic drug, allogeneic [bone marrow transplantation]), and can also result from bland (noninflammatory) injuries (i.e., mitral stenosis).
Clinical Presentation
History and Physical Examination
The clinical presentation of DAH includes hemoptysis, alveolar opacities on chest radiograph, and anemia. However, there are cases that show only one or two of these features; the absence of classic features does not exclude DAH. In up to 33% of cases, hemoptysis is initially absent. Other symptoms are nonspecific (e.g., dyspnea, cough, chest pain, fever), although in some cases, disease-specific symptoms (e.g., sinusitis, rash, arthritis) may be present. In general, symptoms are usually of short duration, present from days to several weeks, and may be recurrent. The lung examination is nonspecific, with inspiratory crackles common but not universal. There may also be physical findings suggesting a systemic disease.
Radiology and Laboratory Evaluation
Laboratory evaluation usually reveals anemia and leukocytosis. Serum creatinine levels may be elevated. BAL reveals a bloody return that, with each aliquot returned from the same location, becomes progressively more bloody ( Fig. 67-3 ). BAL shows increased sequential red blood cell counts even in patients who do not present with hemoptysis. On examination of the sediment, there is a predominance of red blood cells and hemosiderin-containing macrophages.
The chest radiograph in DAH shows varying degrees of diffuse alveolar opacities ( Fig. 67-4 ; see eFig. 60-3A , eFig. 60-9A , eFig. 60-10A , and Fig. 91-4A ). High-resolution computed tomography (HRCT) imaging is more sensitive for radiographic abnormalities and generally shows bilateral ground-glass opacities or patchy consolidation, and occasionally centrilobular nodules. Nonetheless, it is important to recognize that the HRCT appearance of pulmonary hemorrhage is variable and not specific for a particular cause ( Fig. 67-5 ; see eFig. 60-3B-E , eFig. 60-9B-E , eFig. 60-10B-E , and Fig. 91-4B-D ). With recurrent and chronic disease, reticulation may appear, providing evidence of interstitial fibrosis. Interlobular septal thickening (Kerley B lines) ( eFig. 67-1 ) may occasionally be present in cases of mitral stenosis and pulmonary veno-occlusive disease. There are reports of an obstructive lung disease developing after recurrent episodes of DAH secondary to alveolar capillaritis.
Physiology
If measured, there are restriction and gas exchange abnormalities, particularly in chronic cases. In acute DAH an increase in the diffusing capacity for carbon monoxide (D l CO ) is often present, attributed to the increased binding of carbon monoxide to intra-alveolar hemoglobin. This will generally resolve in 48 to 72 hours, as hemoglobin is degraded into hemosiderin. Varying degrees of hypoxemia result from the ventilation-perfusion abnormalities produced by the alveolar hemorrhage, and patients often require ventilatory support.
Classification Schema
There is no consensus classification schema for DAH, although clinical, histopathologic, and etiologic approaches have all been suggested. One approach is presented here ( Table 67-1 ). The various causes of DAH are diverse; any source of injury to the alveolar microcirculation may contribute. The pathogenesis of DAH due to capillaritis is thought to be due to one of the following scenarios: (1) the direct effects of autoantibodies on the alveolar capillary endothelium, as in granulomatosis with polyangiitis (GPA; Wegener granulomatosis) or microscopic polyangiitis (MPA), (2) the effects of antibody directed against the alveolar basement membrane (e.g., Goodpasture syndrome or anti–glomerular basement membrane antibody [ABMA] disease), (3) immune complex–mediated injury (e.g., systemic lupus erythematosus [SLE], Henoch-Schönlein purpura), or (4) direct alveolar injury.
| VASCULITIS |
| Granulomatosis with polyangiitis (Wegener granulomatosis) |
| Microscopic polyangiitis |
| Eosinophilic granulomatosis with polyangiitis (Churg-Strauss syndrome) |
| Isolated pulmonary capillaritis |
| Mixed cryoglobulinemia |
| Behçet syndrome |
| Henoch-Schönlein purpura |
| Pauci-immune glomerulonephritis |
| Antiphospholipid antibody syndrome |
| IMMUNOLOGIC |
| Goodpasture syndrome (ABMA disease) |
| Connective tissue disease associated |
| Immune complex–associated glomerulonephritis |
| Acute pulmonary allograft rejection |
| Celiac disease |
| COAGULATION DISORDERS |
| IDIOPATHIC PULMONARY HEMOSIDEROSIS |
| OTHER |
| Drugs/toxins |
| Diffuse alveolar damage |
| Mitral stenosis |
| Pulmonary veno-occlusive disease |
| Pulmonary capillary hemangiomatosis |
| Lymphangioleiomyomatosis/tuberous sclerosis |
| DIFFUSE INFILTRATIVE LUNG DISEASES |
The most common causes of DAH are the systemic vasculitides, in particular GPA ( Fig. 67-6 ). Other vasculitides are also implicated, including MPA and isolated pulmonary capillaritis. A review of 34 cases of DAH found that vasculitis accounted for about half of the cases, followed by Goodpasture syndrome (13%), idiopathic pulmonary hemosiderosis (IPH; 13%), and connective tissue disease (13%).
Diagnostic Approach
There are two steps to the diagnosis of DAH: identification of DAH and identification of its underlying cause. Both are essential to the timely evaluation of this life-threatening condition.
Diagnosis of Diffuse Alveolar Hemorrhage
The diagnostic considerations for patients presenting with DAH are broad. A thorough history and physical examination looking for evidence of potential associated conditions (e.g., connective tissue disease, symptoms/signs of systemic vasculitis, anticoagulant medications) is essential, and initial studies should include a HRCT scan of the chest, complete blood count, and examination of the urine sediment. If DAH is a possibility, fiberoptic bronchoscopy should be performed immediately.
Bronchoscopy with BAL is essential to the accurate identification of DAH. Sequential BAL specimens should be obtained and sent for cell count and differential, with an increasing red blood cell count considered consistent with the diagnosis. Quantitative scoring of the hemosiderin concentration in alveolar macrophages obtained by BAL cytologic examination has a sensitivity for the diagnosis of DAH as well. Importantly, BAL serves to rule out other diagnostic considerations such as infection, acute hypersensitivity pneumonitis, acute eosinophilic pneumonia, and pulmonary alveolar proteinosis.
Diagnosis of Underlying Cause
Once DAH is identified, the underlying cause must be determined. Table 67-2 summarizes the differential clinical and laboratory features of some of the more common causes of DAH. In some cases, the cause is clear (e.g., history of SLE, drug exposure). In others, a detailed laboratory evaluation is required. The presence of proteinuria and an abnormal urinary sediment (red blood cells and red blood cell casts) suggests an underlying glomerulonephritis consistent with the diagnosis of systemic vasculitis, Goodpasture syndrome, some connective tissue diseases, or rarely infection. Vasculitis is associated with the presence of antineutrophil cytoplasmic antibodies (ANCAs) directed against either proteinase 3 ( cytoplasmic ANCA [c-ANCA]) or myeloperoxidase ( perinuclear ANCA [p-ANCA]). Elevation of the c-ANCA level is seen in GPA, whereas elevation of p-ANCA is seen with MPA, pauci-immune glomerulonephritis, eosinophilic granulomatosis with polyangiitis (Churg-Strauss syndrome), and sometimes isolated pulmonary capillaritis. However, there can be crossover.
| Syndrome | Renal | Arthritis | Skin | ANA | dsDNA | C | ABMA | c-ANCA (PR3) | p-ANCA (MPO) | Histopathology; IF |
|---|---|---|---|---|---|---|---|---|---|---|
| Granulomatosis with polyangiitis (Wegener granulomatosis) | + | + | + | ± | ± | Nl | − | + | − | Capillaritis; ± granular |
| Microscopic polyangiitis | + | + | + | ± | ± | Nl | − | − | + | Capillaritis; no deposits |
| Isolated pulmonary capillaritis | − | − | − | − | − | Nl | − | − | − | Capillaritis; none |
| Goodpasture syndrome (ABMA disease) | + | − | − | − | − | Nl | + | − | − | Bland or capillaritis; linear IgG |
| Systemic lupus erythematosus | + | + | ± | + | + | Low | − | − | − | Bland or capillaritis; granular IgG |
| Idiopathic pulmonary hemosiderosis | − | − | − | − | − | Nl | − | − | − | Bland; none |
The diagnosis of Goodpasture syndrome is established by the presence of serum ABMA. DAH due to SLE is accompanied by reduced serum complement levels as well as the presence of antinuclear and native anti-DNA antibodies in the serum. Henoch-Schönlein purpura is characterized by the formation of immunoglobulin A (IgA) immune complexes present in the circulation and also bound to tissue.
Role of Surgical Lung Biopsy and Renal Biopsy
For the diagnosis of DAH, BAL is generally sufficient. For identifying the underlying cause of the DAH, clinical and serologic findings are usually sufficient ; surgical lung biopsy may be useful but is often nonspecific. However, surgical lung biopsy should be considered for isolated DAH without an obvious cause.
When serologic findings are equivocal and vasculitis or Goodpasture syndrome is under consideration, renal biopsy may be appropriate because these conditions are more easily confirmed by kidney biopsy, even in the absence of clinically evident renal involvement. Moreover, renal biopsy may provide useful information regarding the activity and chronicity of renal involvement that may help guide therapy.
Therapeutic Approach
The most important first step in management is to identify the underlying cause and begin specific treatment when available, for example, by stopping suspected drugs or exposures, treating infection, and reversing excess anticoagulation. Patients with severe hemoptysis require general supportive therapy that is based on the degree of bleeding.
Systemic glucocorticoids, with additional immunosuppressive therapy, are the mainstay of therapy for the DAH syndrome associated with systemic vasculitis, connective tissue disease, ABMA disease (Goodpasture syndrome), and isolated pulmonary capillaritis. The common approach is to begin intravenous pulse methylprednisolone (500 to 1000 mg in divided doses daily) for up to 5 days followed by gradual tapering and then maintenance on an oral preparation. The decision to add immunosuppressive therapy (cyclophosphamide or azathioprine) is dependent upon the severity of the illness, the responsiveness to glucocorticoids, and the underlying disease. Our practice is to begin intravenous cyclophosphamide (0.75 g/m 2 if renal function is relatively normal). Careful attention must be given to the nadir of the peripheral white blood cell count. Oral therapy is usually started in approximately 2 weeks if neutropenia does not develop.
Plasma exchange is used in the treatment of DAD associated with ABMA disease or occasionally for refractory vasculitis syndromes or DAH associated with a connective tissue disease. A role for intravenous immunoglobulin or rituximab in patients with DAD remains to be defined. Recombinant activated factor VII (rFVIIa) has been used with variable success.
Specific Causes
Vasculitis (see Chapter 60 )
Granulomatosis with Polyangiitis (Wegener Granulomatosis).
GPA is a systemic vasculitis that commonly involves the upper and lower respiratory tracts and kidneys. Other organs (e.g., eyes, skin) may be involved. DAH secondary to pulmonary capillaritis can either complicate an established case of GPA or represent the initial manifestation of the disease. Pulmonary capillaritis can be the sole pulmonary parenchymal histologic finding, or it can be seen in combination with the more typical pathologic features of GPA. Surgical lung biopsies from 87 patients with GPA revealed capillaritis in 31%, but in only 3 was it an isolated finding. In another series, capillaritis was present in 17% of 35 patients, but never as an isolated finding. In a postmortem study of 22 patients, capillaritis was the sole histologic feature in 3 and was seen in conjunction with the more typical granulomatous vasculitis in 7 cases. The typical histologic features of GPA are granulomatous inflammation, small and medium vessel vasculitis, and parenchymal geographic necrosis. When DAH is present alone (see eFig. 60-3 ), without the characteristic histologic features, sinusitis (see eFig. 60-7 ), or nodular/cavitary lung lesions (see eFig. 60-1 , eFig. 60-2 , eFig. 60-4 , eFig. 60-5 ), differentiation from MPA is difficult.
The specific diagnosis depends on the ANCA pattern, with c-ANCA suggesting the diagnosis of GPA. The characteristic histologic and clinical features of GPA may appear months to years after the initial presentation of DAH and capillaritis. Circulating endothelial cells are present in GPA and MPA. The presence of circulating endothelial cells may serve as a novel marker of active ANCA-positive vasculitis.
Alveolar hemorrhage is often subclinical and recurrent in GPA (as well as in MPA), suggested by the presence of hemosiderin-laden macrophages on BAL. This pattern of frequently recurring DAH is more typical of the ANCA-associated vasculitides and SLE than of nonvasculitic diseases such as rheumatoid arthritis.
More than 40 cases of GPA with only DAH and pulmonary capillaritis have been described. Early mortality is 37% and is most often due to acute respiratory or renal failure. Renal disease in the form of a focal segmental necrotizing glomerulonephritis ( Fig. 67-7 ), a cutaneous leukocytoclastic vasculitis, and arthritis often accompany the DAH. Treatment with high-dose corticosteroids and cyclophosphamide has been the recommended initial therapy, which, for DAH of GPA, depending on the severity of the disease, is usually administered intravenously. The role of plasmapheresis is still unclear, but it is often initiated if renal failure is present. Azathioprine may be substituted for cyclophosphamide after remission. Recurrences of DAH and other disease manifestation with tapering of the drug are to be expected. Disease activity can be monitored by the erythrocyte sedimentation rates, ANCA levels, serial D l CO determinations, and microscopic urine examinations. The role of rituximab specifically for the treatment of DAH complicating the vasculitides has not been studied, but it is equal to any other therapy in maintaining remission. As previously stated, the differentiation of GPA with DAH from MPA is at times difficult because the clinical presentation, lung histologic features, and serologic findings can be identical. In fact, the response to treatment and the tendency for recurrences are similar. The differentiation can be established only after the development of the more typical upper airway disease and pathologic features of GPA.
Microscopic Polyangiitis.
MPA has been considered the small vessel variant of polyarteritis nodosa. When present, it is a frequent cause of pulmonary capillaritis and DAH (see eFig. 60-10 ). MPA is distinguishable from polyarteritis nodosa by the absence of medium-sized blood vessel involvement, the absence of asthma and systemic hypertension, and the relative sparing of the abdominal viscera. DAH has only rarely been documented with polyarteritis nodosa.
The most consistent pathologic feature in MPA is a focal segmental necrotizing glomerulonephritis, the renal lesion common to all systemic vasculitides. The lungs are involved by capillaritis in 20% to 30% of cases. The alveolar hemorrhage tends to be severe and is often life-threatening. Other manifestations include fever, weight loss, cutaneous vasculitis, myalgias, arthralgias, diarrhea, and gastrointestinal bleeding from mucosal vasculitis that is often visible by direct examination, peripheral neuropathy, and in a few cases, sinusitis. As with other vasculitides, the erythrocyte sedimentation rate is elevated, and nonspecific increases of serum rheumatoid factor and antinuclear antibody levels are found. Although circulating immune complexes are present in 45% of cases, tissue localization of these complexes is difficult to detect (pauci-immune). Anti-DNA antibodies and hypocomplementemia, findings suggestive of SLE, are absent. A positive serum p-ANCA strongly supports the diagnosis. Antibodies to hepatitis B and C antigens are present in 33% of cases.
Treatment consists of either oral or intravenous corticosteroids combined with cyclophosphamide or azathioprine. Adjuvant treatment with plasmapheresis is recommended by some authors, but its additional efficacy is difficult to determine. Outcome with early initiation of therapy for MPAis generally good, with a 65% rate of 5-year survival. However, the presence of DAH contributes to an early mortality rate of 25%. There is a tendency for recurrence with tapering of the medications. Factor VIIa has been used successfully with dramatic effects in cases of uncontrolled alveolar hemorrhage.
The transition to pulmonary fibrosis and restrictive ventilatory impairment after recurrent DAH has been described, and fibrotic lung disease has been reported as the presenting manifestation of MPA. There have been three cases of persistent, severe, irreversible airway dysfunction after recurrent episodes of DAH that complicated MPA. It is postulated that the combination of recurrent vascular obliteration from capillaritis and the release of neutral proteases and oxygen radicals from the overwhelming and recurrent burden of neutrophils causes permanent damage to the alveolar septa and results in emphysema.
Isolated Pulmonary Capillaritis.
Isolated pulmonary capillaritis is a small vessel vasculitis confined to the lungs and without concomitant systemic involvement. There are two forms: one with serum p-ANCA positivity and the other without any positive serologic testing. In one series the latter type was the most frequent cause of pulmonary capillaritis and DAH. Direct immunofluorescent studies of the lung in these patients have been negative (pauci-immune). Although respiratory failure necessitating ventilatory support was frequent, response to corticosteroids and cyclophosphamide was good, and only one of eight patients died. Recurrences appeared in two subjects. During a 4-year follow-up period, clinical or serologic evidence for a systemic vasculitis or connective tissue disease did not appear.
Isolated forms of pulmonary capillaritis causing DAH must be distinguished from IPH, which is not associated with pulmonary capillaritis, as well as lung-limited forms of Goodpasture syndrome, the initial presentation of a collagen vascular disease, primary antiphospholipid antibody syndrome, and mitral stenosis. All patients who present with unexplained DAH should have an echocardiogram and undergo surgical lung biopsy.
Mixed Cryoglobulinemia.
Mixed cryoglobulinemia is a systemic vasculitis that is recognized by the presence of purpura, arthritis, hepatitis, and glomerulonephritis. It is thought to be an immune complex–induced disease, with most cases linked to hepatitis C (and less commonly hepatitis B) viral infection. Cutaneous vasculitis appearing as raised purpura is the clinical hallmark of this disease. Histologically, there is a perivascular polymorphonuclear infiltration with tissue extravasation and fragmentation in the dermis (leukocytoclastic vasculitis). The renal disease is a proliferative glomerulonephritis with positive granular immunofluorescence. Interstitial lung disease consisting of inflammation and fibrosis of the alveolar walls is the most common pulmonary manifestation. There are two published cases of DAH with pulmonary capillaritis that complicated mixed cryoglobulinemia. rFVIIa failed to control DAH in a patient with cryoglobulinemic vasculitis.
Behçet Syndrome.
Behçet syndrome is a chronic relapsing illness characterized by oral and genital ulceration, iridocyclitis, thrombophlebitis, and a multisystem disease consisting of a cutaneous vasculitis, arthritis, and meningoencephalitis. Immune complexes have been identified in the serum of active cases as well as in the lung and other organs.
The thorax is involved in 5% to 10% of cases of Behçet syndrome. The pulmonary disease is typically a small vessel vasculitis affecting capillaries, venules, and arterioles. The renal disease is a focal segmental necrotizing vasculitis, as is seen in other systemic vasculitides. Immune complexes composed of IgG and complement have been identified in small pulmonary vessels in several cases. In addition to alveolar hemorrhage, involvement of larger vessels can lead to aneurysms of the pulmonary ( eFig. 67-2 ) and bronchial arteries, the latter potentially eroding into bronchi, causing massive pulmonary hemorrhage and death. Another potential cause for pulmonary hemorrhage in Behçet syndrome is pulmonary arterial occlusion with infarction. A review of 28 cases of pulmonary involvement in Behçet syndrome emphasized several points: pulmonary complaints consisting of cough, hemoptysis, chest pain, and fever were more common in men than in women; 39% of patients died of pulmonary hemorrhage, usually within 6 years of the first episode of hemoptysis. Other studies have confirmed the seriousness of this complication regardless of its cause. Treatment consists of corticosteroids and immunosuppressive therapy. Treatment with anti–tumor necrosis factor therapy has shown dramatic results in case reports.
Henoch-Schönlein Purpura.
Henoch-Schönlein purpura, primarily a disease of children, also can be seen in adults. Adults typically present with palpable purpura (leukocytoclastic vasculitis) and glomerulonephritis. The joints and gastrointestinal tract are commonly involved. Pulmonary involvement is unusual. In several large series, pulmonary disease, except for transient chest radiographic opacities, was not mentioned. There have been documented cases of DAH with pulmonary capillaritis in patients with Henoch-Schönlein purpura. In one, IgA immune complexes were present in the alveolar septa. It is postulated that IgA immune complexes, which are present in the serum and kidneys of these patients, are responsible for the tissue damage that results in the clinical syndrome. Corticosteroids were used in both cases and are generally recommended.
Pauci-immune Glomerulonephritis.
Pauci-immune glomerulonephritis is one of three types of isolated renal vasculitides (the other two being immune complex–mediated glomerulonephritis and Goodpasture syndrome). Pauci-immune glomerulonephritis lacks any immunoreaction product except for minimal accumulation of fibrin. It is histologically and immunologically similar to the glomerulonephritis of MPA and GPA and is considered to represent a form of renal-limited vasculitis. Up to 50% of affected patients develop pulmonary capillaritis and DAH, and a smaller number develop a full-blown systemic vasculitis indistinguishable from MPA. Another indication that pauci-immune glomerulonephritis represents a limited form of vasculitis is the presence of serum p-ANCA in these patients. Because clinical manifestations are often limited to the lung and kidney, it can be confused with Goodpasture syndrome. Pauci-immune glomerulonephritis is distinguished by the absence of circulating basement membrane antibodies in the serum and by the negative findings on renal immunofluorescence studies. Treatment with high-dose corticosteroids plus immunosuppressive therapy with either cyclophosphamide or azathioprine is recommended.
Immunologic
Goodpasture Syndrome.
Whether the case reported by Goodpasture in 1919 describes the syndrome that bears his name is questionable. He described an 18-year-old man who died 6 weeks after an influenza infection and was found to have DAH, pleuritis, glomerulonephritis, splenic infarctions, and vasculitis of the small intestines. In 1965 an anti-glomerular basement membrane antibody (ABMA)—now identified as an antibody against the NC1 domain of the α3 chain of type IV collagen—was identified in the kidneys and lungs of some patients with DAH and glomerulonephritis. The diagnosis of Goodpasture syndrome, also known as ABMA disease, is reserved for cases of DAH and glomerulonephritis in which this antibody appears in the serum, is bound to kidney and/or lung basement membranes in a linear manner by immunohistochemistry, or both.
At least 90% of patients with Goodpasture syndrome have circulating ABMA. The level of ABMA is not generally considered an accurate index of disease activity, although higher levels have been associated with more severe renal disease. In 60% to 80% of cases, the lung and renal disease appear simultaneously; in 5% to 10%, only the lung is affected; and in the remainder, renal disease exists by itself. It is clear that ABMA is pathogenetic; however, the stimulus for its production remains unknown. The clinical onset of Goodpasture syndrome has been temporarily related to infection with influenza A2 as well as to other respiratory infections, hydrocarbon exposure, and tobacco use. The presence of histocompatibility human leukocyte antigen (HLA)-DRw2 and HLA-B7 (90% and 60%, respectively) in patients with Goodpasture syndrome indicates that susceptible individuals are predisposed to disease that is often severe and progressive. It is interesting to note that, in some experimental models, the introduction of ABMA produces renal but not pulmonary disease; for the antibody to deposit in the lung, an additional injury is required that increases alveolar-capillary permeability.
Men are more commonly affected (60% to 80% of patients), and the concentration of cases is greatest between the ages of 20 and 30 years. In older cases, the sex distribution is equal and the disease tends to be limited to the kidney. Interestingly, DAH is more common in patients who smoke. The alveolar permeability is increased in most smokers, and this is thought to be an important factor leading to DAH. In one study, 100% of smokers with Goodpasture syndrome developed both DAH and glomerulonephritis, whereas only 20% of nonsmokers developed DAH. Resumption of cigarette smoking by patients who are in remission can result in recurrent episodes of DAH. Exposure to volatile hydrocarbons (e.g., petroleum products, turpentine, toluene, and pesticides) is associated with initiation, as well as exacerbations, of DAH.
Symptoms most often refer to the lungs and consist of hemoptysis, cough, and dyspnea. Fatigue caused by iron-deficiency anemia and renal failure may predominate. Microscopic hematuria, proteinuria, and increases in the serum creatinine level are often present, but gross hematuria with hypertension is unusual. The diffusing capacity may be increased during periods of active bleeding and is considered to be a useful monitor of new or recurrent DAH. An increase of 30% above baseline is highly suggestive of an intra-alveolar hemorrhage, and this increase may precede pulmonary symptoms or radiographic changes. Chest radiography often reveals patchy air space abnormalities ( eFig. 67-3A and B ). HRCT scanning (see eFig. 67-3C ) typically shows ground-glass opacities and consolidation and is more sensitive for DAH than is chest radiography.
Pulmonary capillaritis is present in some cases of Goodpasture syndrome, but the usual histologic appearance is bland pulmonary hemorrhage. Alveolar wall necrosis, which is seen with systemic vasculitis, is not a feature of Goodpasture syndrome. The renal histologic findings are a focal segmental necrotizing glomerulonephritis with crescent formation. The major distinction between Goodpasture syndrome and the other rapidly progressive glomerulonephritides is the presence of an uninterrupted linear deposition of immunoglobulin and complement along the glomerular basement membrane ( Fig. 67-8 ). Identical findings are present on alveolar basement membranes. Even when DAH dominates the clinical picture (i.e., there is no evidence of renal disease), renal biopsy will still reveal the typical linear staining.
In the minority of patients without clinically evident renal involvement, DAH responds to oral or intravenous corticosteroids. Glomerulonephritis, if present, appears resistant to corticosteroid monotherapy. The combination of plasmapheresis (3 to 6 L daily for 2 weeks), corticosteroids, and cytotoxic drugs is effective, particularly in patients who do not have oligoanuria and do not require dialysis. The combination of cyclophosphamide or azathioprine with corticosteroids leads to a dramatic fall in circulating ABMA, and oliguric dialysis-dependent subjects have responded to the point at which dialysis could be discontinued. Anuric patients do not respond well to this combination therapy, and dialysis and renal transplantation are often necessary. Case reports of successful treatment of refractory, life-threatening Goodpasture syndrome with mycophenolate mofetil and anti-CD20 monoclonal antibody have been reported. Bilateral nephrectomy no longer has a role in the management of Goodpasture syndrome.
Over time, the survival rate in Goodpasture syndrome has improved from 80% mortality at 6 months (half dying from DAH and the rest from renal insufficiency) to approximately 50% at 2 years. With the aggressive treatment approach described previously, it is estimated that the 5-year survival rate exceeds 80%, and fewer than 30% of patients require long-term dialysis. DAH is the usual cause of death, often being precipitated by a concomitant infection. There has been spontaneous remission in cases without clinical evidence of renal disease, although this is not usual. The most useful prognostic information comes from the kidney. Clinically, oliguric or anuric renal failure reduces the survival rate to 50% at 6 months. Histopathologically, less than 30% involvement of the glomeruli on biopsy predicts significant therapeutic response and improved survival. When 70% or more of glomeruli have formed crescents in conjunction with renal insufficiency, renal failure is progressive and often unresponsive to therapy, eventually necessitating dialysis.
Connective Tissue Disease.
Among the connective tissue diseases, DAH is most commonly seen in SLE ( eFig. 67-4 ). It is unusual for DAH to be the initial manifestation of SLE, in contrast to acute lupus pneumonitis, which is often the initial manifestation. Most patients with DAH have active lupus nephritis. The onset of alveolar hemorrhage can be dramatic, producing severe gas-exchange abnormalities and necessitating mechanical ventilation. Reduced complement levels and increased serum titers of serum antinuclear antibodies confirm the diagnosis.
DAH must be distinguished from other causes of hemoptysis in SLE, specifically acute lupus pneumonitis. Acute lupus pneumonitis presents with fever, cough, and dyspnea. In 50% of cases, this is the initial manifestation of SLE. It is an inflammatory condition, characterized histologically by organizing pneumonia, DAD, cellular nonspecific interstitial pneumonia, and occasionally, intra-alveolar hemorrhage. Although hemoptysis may accompany acute lupus pneumonitis, significant reductions of the hemoglobin level are not to be expected. Unlike DAH, pleural and pericardial effusions are common in acute lupus pneumonitis. Other diagnostic considerations in the patient with suspected DAH include infectious pneumonias and pulmonary infarction associated with deep venous thrombosis with or without a circulating lupus anticoagulant.
Histopathologic examination of DAH in patients with SLE generally reveals capillaritis, but bland pulmonary hemorrhage and DAD have been described. Granular deposits of IgG and complement (C3) are commonly found in the alveolar interstitium and within the walls of intra-alveolar blood vessels ( Fig. 67-9 ). Capillaritis and immune complex deposition do not necessarily overlap. In one series of four patients with SLE and massive DAH associated with pulmonary capillaritis, only two demonstrated immune complexes by light and electron microscopic techniques.
Treatment of DAH caused by SLE includes high-dose intravenous corticosteroids as well as azathioprine or cyclophosphamide. rFVIIa administered via local intrapulmonary route may be an effective treatment option for DAH in SLE patients. Plasmapheresis has been combined with chemotherapy in some cases, but its utility is unknown. Broad-spectrum antibiotic coverage is recommended because of some evidence that infection may trigger the hemorrhage. DAH is associated with a 50% mortality rate in SLE and can be recurrent in survivors. Death is caused by massive hemorrhage, concurrent infection, or renal or central nervous system disease.
Rarely, DAH and glomerulonephritis develop in patients with rheumatoid arthritis, scleroderma, or mixed connective tissue disease. Isolated DAH with capillaritis has also been described in polymyositis, rheumatoid arthritis, and mixed connective tissue disease. In polymyositis, DAH was the presenting manifestation, and in rheumatoid arthritis and mixed connective tissue disease, DAH and capillaritis followed the primary diagnosis (2 to 20 years). The absence of a systemic vasculitis in these cases, including glomerulonephritis, was unexpected.
Immune Complex–Related Crescentic Glomerulonephritis.
Immune complex–related crescentic glomerulonephritis is rarely accompanied by capillaritis and DAH. Although the kidneys demonstrate granular immune deposits, immune complexes are not found in lung tissue.
Acute Pulmonary Allograft Rejection.
Pulmonary capillaritis and DAH have been reported after lung transplantation for a variety of underlying diseases. The suspected acute vascular rejection can develop weeks to months after the transplantation and may be the only histopathologic manifestation of allograft rejection. This represents a serious immunologic complication that threatens survival. In addition to standard anti-inflammatory therapy with corticosteroids and cytotoxic agents, plasmapheresis may be effective.
Coagulation Disorders
Coagulation disorders associated with DAH include disseminated intravascular coagulation, idiopathic thrombocytopenic purpura, thrombotic thrombocytopenic purpura, acquired vitamin K deficiency, and antiphospholipid antibody syndrome. Uniquely among coagulation disorders, primary antiphospholipid antibody syndrome–associated DAH is often associated with capillaritis ( eFig. 67-5 ).
All anticoagulant medications have been associated with DAH, including warfarin (Coumadin) and its derivatives, thrombolytics, agents targeting the platelet glycoprotein IIb/IIIa, and clopidogrel. In most iatrogenically anticoagulated patients, correction of the coagulation defect resolves the DAH. It has been suggested that patients using coumarins with confirmed DAH are at risk for the development of fibrosing interstitial pneumonitis.
DAH is common in patients with acute leukemia who have undergone induction chemotherapy and are thrombocytopenic ( eFig. 67-6 ). Although thrombocytopenia surely contributes to the DAH, these patients also have evidence of DAD due to chemotherapy, oxygen toxicity, and infection that likely plays a central role.
Idiopathic Pulmonary Hemosiderosis
IPH is predominantly a disease of children, but adults represent about 20% of cases. It is a diagnosis of exclusion, and efforts to rule out other causes of DAH are essential. Among adults, men are more often affected, and there are reports of familial cases. Some cases have been described in the setting of celiac disease, and serum IgA levels are increased in 50% of cases. The pathogenesis of IPH is not understood. Some cases may be secondary to environmental exposures, such as Stachybotrys atra, a toxigenic fungus that has been potentially linked to several cases of otherwise idiopathic alveolar hemorrhage.
Recurrent hemoptysis due to DAH is the rule, ranging from intermittent blood-streaked sputum to life-threatening hemorrhage. Fever, cough, substernal chest pain, and fatigue secondary to iron-deficiency anemia are also reported. In selected pediatric cases, lymphadenopathy and hepatosplenomegaly are found. Renal disease is absent. In chronic recurrent disease, progressive dyspnea, finger clubbing, inspiratory crackles, and pulmonary fibrosis appear. Pulmonary function testing reveals a restrictive ventilatory defect with an increase in the D l CO during periods of active bleeding. Chest imaging reveals diffuse ground-glass opacity ( eFigs. 67-7 and 67-8 ) and ill-defined centrilobular nodules, the typical appearance of pulmonary hemorrhage of any cause. Measurements of serum antibodies reveal the absence of alternative causes.
In adult cases, lung tissue is required to exclude the entity of isolated pulmonary capillaritis. The histologic examination of the lung in IPH reveals bland alveolar hemorrhage with hemosiderin accumulation. There is hyperplasia of type II alveolar epithelial cells with capillary dilation and tortuosity. The iron content of the lung is increased, and it is the hemosiderin deposition in the interstitium that is thought to be the basis for collagen proliferation and parenchymal fibrosis. Pulmonary immune complexes are absent, differentiating IPH from isolated pulmonary Goodpasture syndrome. Electron microscopic studies indicate degeneration of type I alveolar epithelial cells with exposure of and breaks in the basement membrane and discontinuity of the alveolar capillary structure. Although nonspecific, these findings indicate a form of DAD.
Clinical benefit and recovery from the acute hemorrhage after corticosteroid therapy have been reported, but long-term benefit is unlikely. Azathioprine has been successful in several cases. Approximately 25% of patients are free of disease after the initial episode. Another 25% are free of active disease but have persistent dyspnea and anemia, and another quarter have persistent active disease that leads to fibrosis and severe restrictive lung disease. The rest have unresponsive disease with continued hemorrhage and death from respiratory failure. In those with persistent disease, the average survival is 3 to 5 years. Adults have a better prognosis than children. Lung transplantation is controversial in this disease because IPH has been reported to recur after bilateral lung transplantation.
Other Causes of Diffuse Alveolar Hemorrhage
Drugs/Toxins.
There are many drugs that have been reported to cause DAH. Anticoagulants have been discussed previously. Most DAH due to drugs or toxins is associated with DAD. This has been reported with abciximab, amiodarone, azathioprine, carbamazepine, cyclosporine, ara-C, dextran, docetaxel, fludarabine, hydralazine, methotrexate, radiographic contrast media, retinoic acid, sirolimus, tumor necrosis factor-α, and valproate.
A few drugs have been associated with DAH and capillaritis, including tretinoin, propylthiouracil, phenytoin, and mitomycin. DAH due to these drugs may also be associated with crescentic glomerulonephritis and elevated ANCA levels.
Penicillamine can result in DAH and an immune complex–mediated glomerulonephritis. Glomerular capillaries display a granular (as opposed to a linear) immunofluorescent pattern for IgG and C3. Cases have appeared after as much as 20 years of treatment. Some authors have called this a drug-induced Goodpasture syndrome, but the pattern of immunoglobulin deposition in the kidney differentiates this entity. Treatment with immunosuppressive therapy and even plasmapheresis may be required.
Trimellitic anhydride is used for the manufacture of paints, epoxy resins, and plastics. DAH has been reported after the inhalation of fumes or dry powder, generally during spraying of this product on heated surfaces. Antibodies to trimellitic anhydride in the serum and a latent period of 1 to 3 months both support an immunologic basis for this syndrome. Long-term physiologic impairment is unusual if further exposure is avoided.
Diffuse Alveolar Damage.
DAD is the underlying histopathologic feature of acute lung injury, and it has a variety of causes ( Table 67-3 ). In DAD the interstitium of the lung becomes edematous, and the type I alveolar epithelial lining cells are sloughed. There is neutrophilic inflammation and fibroblastic proliferation. Hyaline membranes (eosinophilic strands of necrotic cells, protein, and fibrin) develop adjacent to the injured alveolar walls. In severe cases, red blood cells may enter the alveolar space as a result of injury to the alveolar-capillary interface, resulting in DAH. The neutrophilic inflammation in DAD-associated DAH is not as intense as it is in pulmonary capillaritis.
