Wegener's Granulomatosis Presenting with Diffuse Alveolar Hemorrhage and Negative Antineutrophilic Cytoplasmic Antibody Test

Tony S Han and Richard T Mahon
Military Medicine

Jul 31, 2006 20:00 EDT

Introduction

Diffuse alveolar hemorrhage (DAH) is a syndrome of accumulation of red blood cells in the alveolar airspaces because of leakage of alveolar capillaries. The loss of capillary integrity may be attributable to inflammation or changes in the pressure gradient. DAH may be associated with mild cough and scant hemoptysis or may progress to respiratory failure in morefulminant cases.

Clinically, DAH is manifested by cough, hemoptysis, and diffuse fleeting infiltrates on chest radiographs. Hemoptysis can be absent, scant, or massive, depending on the degree of involvement, but there is invariably some degree of anemia.1 Pulmonary infiltrates sometimes can be mistaken for infection, but they tend to be fleeting and they do not respond to antibiotics. Bronchoscopy with lavage shows hemosiderin-laden macrophages in DAH. An increased diffusion capacity for carbon monoxide (DLCO) can be seen with pulmonary function testing.

The main histopathologic finding in DAH is red blood cells, arising from the alveolar-capillary membrane rather than the bronchial vessels. The hemorrhage is diffuse, without a discrete source. There may be associated inflammation, which is known as capillaritis. Capillaritis is characterized by neutrophil invasion and destruction of the alveolar-capillary membrane, with subsequent edema, extravasation of red blood cells, and accumulation of neutrophils, known as leukocytoclasis. Necrotic flbrosis and granuloma formation may occur in later stages. This pattern is seen in small-vessel systemic vasculitides such as Wegener's granulomatosis (WG), Churg-Strauss (CS) syndrome, and microscopic polyangiitis (MPA). This pattern is also seen in drug-induced vasculitis, cryoglobulinemia, Henoch-Schoenlein purpura (HSP), systemic lupus erythematosis (SLE), and antibasement membrane antibody (ABMA) disease. We report a case of WG presenting with hemoptysis, anemia, pulmonary infiltrates, and glomerulonephritis. Antineutrophilic cytoplasmic antibody (ANCA) testing was negative.

Case Report

A 20-year-old Caucasian man was transferred from another hospital to our facility with recurrent pulmonary infiltrates, persistent hemoptysis of 5 to 10 mL/day, and anemia. He had been experiencing cough, hemoptysis, fever, chills, night sweats, and malaise for 4 months before presentation. He was treated with three courses of outpatient antibiotic therapy for bilateral lower lobe opacities but did not exhibit improvement.

On further evaluation, the patient was found to have profound anemia, with a hematocrit value of 17 mg/dL, with hematuria and persistent pulmonary infiltrates. He underwent negative esophagogastroduodenoscopy and colonoscopy for evaluation of the anemia and received transfusion of two units of blood before transfer to our facility.

The patient reported no previous nasal ulcers, arthritis, Raynaud's syndrome symptoms, uveitis, or urethritis. He did not have any sicca symptoms, such as dry eyes or mouth. He did report some mild, chronic, rhinitis symptoms. The patient was active and healthy while growing up in the Midwest and had no previous pulmonary disease. He had undergone an appendectomy 2 years earlier. He recently began taking iron and vitamin C supplements but was taking no other medications. The patient was a lifetime nonsmoker, with no exposure to fuels, and was training to be a U.S. Marine before his illness.

Examination revealed an alert, cooperative, male patient with a pulse of 87 beats per minute, blood pressure of 141/71 mm Hg, respiration rate of 18 breaths per minute, oxygen saturation of 97%, weight of 82 kg, and body temperature of 99

The initial hemoglobin level was 5.6 g/dL, hematocrit level was 17.3%, white blood cell count was 8,800 cells per mL (differential), and platelet count was 572,000 platelets per mL. Urinalysis showed much blood, with many red blood cells, and trace protein levels. Chest radiographs showed diffuse, bibasilar, patchy opacities (Fig. 1), with a chest computed tomographic scan confirming diffuse, ground-glass opacities in all lobes. Metabolic panel, coagulation profile, C-reactive protein, liver enzyme, and electrocardiographic results were all normal. The blood urea nitrogen level was 13 mg/dL, and the creatinine level was 1.2 mg/dL. Pulmonary function testing showed borderline low lung volumes, with a total lung capacity of 85% and a measured DLCO of 99%, which corrected to 130% for the hemoglobin level of 8.2 g/dL at the time of testing. A transthoracic echocardiogram revealed no valvular disease, with an ejection fraction of 65%.

Cytoplasmic and perinuclear ANCA (proteinase-3 and myeloperoxidase) testing through enzyme immunoassays was negative. Antinuclear antibody and ABMA tests were also negative. A percutaneous native kidney biopsy revealed segmentai necrosis and crescents involving 50 to 70% of glomeruli. Immunofluorescence staining for complement and immunoglobulin was negative.

The patient was diagnosed as having WG on the basis of renal biopsy findings and started combination therapy with prednisone (7 mg/kg per day, bolus, for 3 days, followed by 80 mg daily) and pulse cyclophosphamide (0.5 g/m^sup 2^ for the first month and then 1 g/m^sup 2^ monthly). The patient also began Pneumocystis corinii prophylaxis and alendronate therapy, because of the anticipated long-term steroid therapy.

Lung opacities resolved on repeat radiographs obtained 1 month later, with no further hemoptysis. Anemia also improved. Renal function remained intact, with a significant decrease in hematurta. The patient's symptoms of malaise and fatigue improved. Repeat ANCA testing remained negative.

Discussion

This patient exhibited the classic presentation of DAH, with chronic hemoptysis, transient opacities on radiographs, anemia, and elevated DLCO. Even in the absence of a tissue examination, the presence of diffuse infiltrates, hemoptysis, and elevated DLCO suggest DAH.2 The patient's initial symptoms and radiographs were first thought to represent bacterial pneumonia, but his lack of response to antibiotics, marked anemia, and hematuria prompted an evaluation for a pulmonary-renal syndrome. His prolonged initial presentation with fever, malaise, cough, hemoptysis, and pulmonary infiltrates for 4 months is also fairly typical of pulmonary-renal syndromes.1,2 Valvular heart disease and congestive heart failure were excluded with echocardiograms. The renal biopsy showed pauci-immune, focal, crescentic, necrotizing glomerulonephritis characterized by glomerular inflammation and necrosis, with no deposition of immunoreactants such as lmmunoglobulins and complement. Although this finding is somewhat nonspecific, the lack of immunoreactants makes SLE and ABMA disease unlikely. The patient also had no rash, arthritis, or pleuritis to suggest SLE. There are five major types of small-vessel vasculitides that cause pulmonary-renal syndromes, namely, CS syndrome, HSP, MPA, WG, and drug-induced. CS syndrome, also described as allergic granulomatosis, usually presents with preexisting asthma and eosinophilia, which progress to pulmonary opacities and renal involvement. This patient had no previous asthma symptoms or eosinophilia to suggest CS syndrome. HSP, or anaphylactoid purpura, usually has prominent skin vasculitis manifesting as purpura and immunoglobulin A deposits in the kidneys, which were not present In this case. MPA is very similar to WG; however, the DAH is often more severe in MPA. The vasculitis Is often more generalized, with cutaneous, musculoskeletal, and gastrointestinal involvement. A positive perinuclear ANCA test also suggests MPA, whereas WG is associated with cytoplasmlc ANCA. Early steroid therapy was initiated on the basis of the renal biopsy findings, because untreated WG can progress rapidly to renal failure. In fact, this case might have been a morefulminant variant of WG with more-prominent DAH and renal involvement, rather than the more-typical upper airway findings.3

DAH

DAH is extravasation of blood Into alveoli in the acinar portion of the lungs because of disruption of the capillary and alveolar walls. Because the bleeding is at the alveolar level, hemoptysis may be minimal. Inflammatory cells in systemic vasculitis and drug-induced DAH mediate disruption of the alveolar-capillary barrier. Iron is taken up by macrophages and is not effectively recycled, thus leading to iron deficiency and anemia. Opacities on radiographs are commonly seen in DAH (Fig. 1). They can be unilateral, bilateral, diffuse, or focal. They tend to resolve faster than in pneumonia but persist for days longer than in cardiogenic pulmonary edema. ABMA disease, also known as Goodpasture syndrome, is the pulmonary-renal syndrome most commonly associated with DAH. ABMA disease is characterized by the presence of circulating specific antibody as well as linear deposits of IgG and complement in alveoli and glomeruli, as seen with immunofluorescence.3 Rarely, SLE may present with DAH. There is usually other evidence of active SLE, such as fever, arthritis, or pleuritis, already present. There is usually a high antlnuclear antibody titer. The initial diffuse alveolar hemorrhage in SLE can be quite severe, with a high Initial mortality rate.3 There is also a group of related systemic vasculitides, such as CS syndrome, WG, and MPA, involving small vessels. These latter syndromes are associated with positive ANCA tests. CS syndrome is a small-vessel vasculitis associated with granulomatous inflammation, asthma, and positive ANCA test results. It can be differentiated by the presence of asthma and eosinophilia. MPA is another ANCA-related vasculitis of the small vessels. It is very similar to WG except for the absence of granulomatous lesions and the greater association with perinuclear ANCA versus cytoplasmic ANCA.

WG

WG is a systemic vasculitis of small arteries and veins involving the upper and lower respiratory tracts that can be associated with glomerulonephritis. There is a limited form that spares the kidneys but has greater involvement of the upper respiratory tract. Although the mean age of presentation is 40 years, cases involving patients < 18 years of age are not uncommon. Classically, upper respiratory tract involvement is seen, with nasal mucosal ulceration and epistaxis. Necrotizing granulomas are classically associated with WG; however, they can be difficult to document. Some studies found only small granulomas in autopsies, with poor yield from initial biopsies.4 Nonspecific prodromal symptoms such as fever, malaise, and weight loss can last up to 3 to 4 months.1,2 Subglottic stenosis can be seen, especially in the pediatric population. Renal function is generally preserved initially; however, many patients eventually develop glomerulonephritis.

Patients with WG usually have positive cytoplasmic ANCA tests, but there is a clear subset of cases with negative ANCA tests.5-7 Although a positive ANCA test has good specificity, the sensitivity was as low as 28% in previous reports.8 In limited forms of the disease, where renal involvement is not as prominent, many cases of WG may be ANCA-negative. Therefore, the absence of ANCA does not exclude the diagnosis of WG.4,5,8 The ANCA test involves visually interpreting an indirect immunofluorescence pattern when the serum of the patient is incubated with ethanol-fixed human neutrophils.5 A perinuclear ANCA pattern indicates a staining pattern around the nucleus, and a cytoplasmic ANCA pattern indicates diffuse staining of the cytoplasm. The target antigens are proteinase-3 and myeloperoxidase, but the antibodies seldom coexist.5,9 Staining patterns are compared with known control samples with positive antibodies, and the results are expressed as serial dilutions of the patient's serum. The test is inherently subjective and should not be the only basis for diagnosis. A less-sensitive but more-specific modality is the enzyme-linked immunosorbent assay method.

Before the discovery of effective therapy, the median survival time for WG was 5 months. The early institution of cyclophosphamide and prednisone has led to a 80 to 100% remission rate, with preservation of renal and lung function.I0 Although our patient did not meet the 1990 American College of Rheumatology criteria for WG, those criteria were intended for research purposes,8 and therapy was not delayed. The diffuse alveolar hemorrhage, along with the renal biopsy findings, strongly suggests either WG or MPA. There is considerable overlap between WG and MPA, with similar treatments and outcomes.

In summary, this case illustrates that DAH can be the initial presentation of a severe illness that can go unrecognized for months. It is crucial to recognize DAH and pulmonary-renal syndromes early to start therapy. The definitive diagnosis can be difficult, even with a tissue biopsy. The clinical and serologie criteria for WG can be misleading. WG, MPA, and systemic vasculitis may represent a group of closely related disorders, as noted in previous reports.4,5,8 A biopsy should not be delayed if the patient is in stable condition, because early therapy seems to preserve organ function.

© 2006 Association of Military Surgeons of the United States Provided by ProQuest LLC. All Rights Reserved.

Source: Military Medicine

 

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