Myeloperoxidase deficiency

A 74-year-old man was admitted to the hospital with a 4-day history of fatigue dyspnea and hemoptysis. Ten days before hospital admission, he began experiencing a right-sided chest pain associated with malaise, worsening dyspnea, and cough. He denied fever, night sweats, or weight loss, but his exercise capacity and stamina had declined over the most recent 2-month period. His medical history included right hemispheric stroke with minimal residual left hemiparesis and anemia of undetermined etiology. His medications included aspirin, 100 mg once daily.

Physical Examination

On physical examination, the patient appeared pale and ill. A few crackles were heard over the right lower lung field. The rest of the physical examination findings were within normal limits. The oxygen saturation was 88% while the patient was breathing room air.

Laboratory Findings

The hemoglobin level was 7.3 g/dL, the mean corpouscular volume was 72 fentoliter, the WBC count was 15,200 cells/[micro]L, and the platelet count was 406,000 cells/[micro]L. The serum iron level was 10 [micro]g/dL, the transferrin level was 175 mg/dL, and transferrin saturation was 4.5%. BUN level was 111 mg/dL, the creatinine level was 1.9 mg/dL, and the albumin was 2.4 g/dL. Urinary sediment showed microscopic, occasionally granular hematuria, and RBC casts and proteinuria of 0.56 g/d. A chest radiograph (Fig 1) revealed an infiltrate involving the entire right lung field and a left upper lobe consolidation.

[FIGURE 1 OMITTED]

Hospital Course

Therapy with IV amoxycyclin-clavulinic acid was initiated. Despite supportive therapy and antibiotic therapy, the patient remained afebrile yet tachypneic with recurrent paroxysms of hemoptysis. A repeat chest radiograph on the sixth hospital day demonstrated worsening infiltrates on the right side. His renal function also deteriorated with a creatinine level of 2.45 mg/dL and a BUN level of 129 mg/dL. Due to worsening respiratory and renal failure, the patient was transferred to the medical ICU. The antibiotic therapy was changed to levofloxacin. Despite the change in antibiotic agent, his condition continued to deteriorate, and on the third day he was intubated due to hypoxemic respiratory failure. His chest radiograph showed bilateral alveolar consolidations. There was no hemoptysis on purulence through the endotracheal tube. Numerous blood, urine, and sputum cultures were all negative.

ACT scan of the chest and sinuses (Fig 2) demonstrated diffuse alveolar consolidations affecting the entire right lung field and the left upper lobe. No masses or lymphadenopathy could be seen. The sinuses were normal. Rheumatoid factor level was 22.3 IU/mL (normal range, 0 to 20 IU/mL), antinuclear antibody was + 2 homogenous (HEP-2 cells), anti-double-strand DNA level was 15 IU/mL, C3 level was 62 mg/dL (normal range, 80 to 120 mg/dL), C4 level was 20 mg/dL (normal range, 16 to 47 mg/dL), and test results for cytoplasmic-antineutrophil cytoplasmic antibodies (c-ANCAs) and antiglomendar basement membranes were negative, while test results for perinuclear-antineutrophil cytoplasmic antibodies (p-ANCA) were positive (via immunofluorescent assay).

[FIGURE 2 OMITTED]

What diagnostic study should be performed to confirm the patient's diagnosis?

Answer: Lung biopsy to confirm a diagnosis of microscopic polyangiitis with alveolar hemorrhage.

The vasculitides are a heterogeneous group of diseases that are characterized by the inflammation of blood vessels. The clinical manifestations depend largely on the size and .type of blood vessel involved and the extent of vascular inflammation. A definitive diagnosis of vasculitis usually requires angiography or a biopsy from clinically involved tissue that shows typical histologic features. Vasculitis can affect multiple organs.

Pulmonary vasculitides are classified according to the size of blood vessels involved. Large-vessel pulmonary vasculitis includes giant cell and Takayasu arteritis, although pulmonary involvement in these entities is rare. Medium-sized blood vessel vasculitis is associated with Behcet disease, typically, in the form of pulmonary artery aneurysms. Small-vessel pulmonary vasculitis includes Wegener granulomatosis (WG), Cliurg-Strauss syndrome, isolated pauci-immune pulmonary capillaritis, and microscopic polyangiitis (MPA).

MPA is a necrotizing vasculitis that was first recognized as a distinct clinical entity in 1994. It typically involves venules, capillaries, and arterioles. The mean age of patients at presentation is 50 years. Patients may present with constitutional symptoms such as fever, anorexia, or weight loss. Arthralgias, myalgias, palpable purpura, and GI bleeding are additional manifestations. Typically, patients with MPA present with predominantly renal or pulmonary features or with well-blown pulmonary-renal syndrome. Indeed, MPA is almost always associated with necrotizing glomerulonephritis (80 to 100% of patients) and is often associated with alveolar hemorrhage (30% of patients).

The combination of hemoptysis, iron deficiency anemia, rapidly progressive glomerulonephritis, and bilateral airspace consolidation suggests pulmonary-renal syndrome. Most patients develop this condition in association with systemic autoimmune diseases such as the antineutrophil cyoplasmic antibody (ANCA)-associated systemic vasculitides (eg, WG and MPA), connective-tissue diseases (eg, systemic lupus erythematosus and rheumatoid arthritis), or anti-basement membrane antibody diseases (eg, Goodpasture syndrome). Rarely, it may be associated with Henoch-Schonlein purpura, IgA nephropathy, cryoglobulinemia, or pnemnonia-related immune complex glomerulonephritis.

The introduction of ANCA testing has greatly contributed to the diagnosis of vasculitis. ANCA tests were first introduced in the diagnosis and monitoring of disease activity in patients with WG. A c-ANCA (anti-proteinase 3) is found in up to 95% of patients with active WG. The p-ANCA pattern with antibodies to myeloperoxidase is most closely associated with MPA. A p-ANCA pattern is found in 50 to 80% of patients with MPA. The distinction between MPA mid WG may be particularly difficult in the setting of pulmonary-renal syndrome since glomerular lesions in both entities are similar. The diagnosis of WG should be limited to patients with necrotizing granulomatous disease associated with e-ANCA. Moreover, the detection of p-ANCA does not necessarily establish a diagnosis of vasculitis since it may be found in a wide variety of inflammatory and infectious diseases.

A lung biopsy is often required for a definitive diagnosis when pulmonary vasculitis or alveolar hemorrhage is suspected. It may be of great value in excluding important diagnostic considerations such as infections, neoplasms, sarcoidosis, and others. In patients with pulmonary-renal syndrome in whom there is at predominant renal involvement, renal biopsy is a preferable alternative, since it is easier to perform and often times more diagnostic. Furthermore, the addition of cytotoxic therapy (eg, cyclophosphamide) without tissue confirmation of a reversible inflammatory vasculitis is controversial and potentially dangerous. Because the introduction of cyclophosphamide has dramatically affected the course and outcome of many of the small-vessel vasculitis syndromes, early diagnostic confirmation is of importance. We recommend an aggressive approach, including a biopsy from the predominantly involved organ that has the highest probability of ,yielding a definitive diagnosis. Clinical and radiographic characteristics such as age, sex, time course, systemic and pulmonary manifestations, mad the pattern and extent of extrapulmonary involvement should be correlated with laboratory data such as p-ANCA or e-ANCA levels and histopathologic findings. These correlations are required to effectively manage these serious, yet potentially reversible, syndromes.

In the present patient, recurrent hemoptysis, iron deficiency anemia, rapidly progressive glomerulonephritis, bilateral airspace opacities, and an assay positive for p-ANCA strongly suggested MPA. The diagnosis was confirmed by an open-lung biopsy (Fig 3), which demonstrated typical histologic features and no granulomas or evidence of infectious or malignant disease. Despite therapy with IV solumedrol, 2 mg/kg/d, and cycloplaosphamide, 100 nag/d, the patient failed to respond, and developed progressive respiratory and renal failure. He died 4 weeks after hospital admission from sepsis and multiorgan failure. An autopsy revealed severe necrotizing and proliferative glomerulonephritis (Fig 4).

[FIGURES 3-4 OMITTED]

CLINICAL PEARLS

1. Pulmonary-renal syndrome is primarily associated with autoimmune rheumatic diseases and small-vessel vasculitis.

2. MPA should be suspected when pulmonary infiltrates are associated with hemoptysis, iron deficiency anemia, and rapidly progressing renal failure.

3. p-ANCA is characteristically positive in patients' with MPA. An assay that is positive for myelaperoxiidase antibodies further supports the diagnosis.

4. Diagnosis of pulmunary vasculitis should be confirmed with tissue obtained from involved organs.

5. Early diagnosis of MPA is important because patients may respond to corticosteroid and cyclophosphamide therapy.

6. Performance of a careful analysis of recently voided urine is commonly overlooked in the evaluation of patients with pulmonary-renal syndrome. The presence of RBC casts and proteinuria suggest the presence of glomerulelonephritis.

SELECTED READINGS

Davenport A, Lock RJ, Wallington TB, et al. Clinical significance of anti-neutrophil cytoplasm antibodies detected by a standardized indirect immunofluorescence assay. Q J Med 1994; 87:291-299

Eschum GM, Mink SN, Sharma S. Pulmonary interstitial fibrosis as a presenting manifestation in perinuclear antineutrophilic cytoplasmic antibody microscopic polyangiitis. Chest 2003; 123:297-301

Evans J. Antinuclear antibody testing in systemic autoimmune disease. Clin Chest Med 1998; 19:613-625

Gross WL. Antineutrophil cytoplasmic autoantibody testing in vasculitides. Rheum Dis Clin North Am 1995:21:987-1011

Guillevin L, Durand-Gasselin B, Cevallos R, et al. Microscopic polyangiitis: clinical and laboratory findings in eighty-five patients. Arthritis Rheum 1999:42:421-430

Hatipoglu U, Rubinstein I. Pulmonary vasculitis: a clinical overview. Isr Med Assoe J 2002; 4:1143-1148

Hoffman GS. Kerr GS, Leavitt RY, et al. Wegener granulomatosis: an amdysis of i58 patients. Ann Intern Med 1992; 116:488-498

Hunder GG, Arend WP, Bloch DA, at al. The American College of Rheumatology 1990 criteria for the classification of vasculitis: introduction. Arthritis Rheum 19911:33:1065-1067

Jennette JC, Falk RJ, Andrassy K, et al. Nomenclature of systemic vasenlitides: proposal of an international consensuS conference. Arthritis Rheum 1994;37:187-192

Kallenberg CC, Brouwer E, Weening JJ, et al. Anti-neutrophil cytoplasmic antibodies: current diagnostic and pathophysiological potential. Kidney Int 1994; 46:1-15

Lhote F, Guillevin L. Polyarteritis nodosa, microscopic polyangiitis, and Churg-Strauss syndrome: clinical aspects and treatment. Rheum Dis Clin North Am 1995; 21:911-947

Massachusetts General Hospital. Case records of the Massachusetts General Hospital: weekly clinicopathological exercises; case 13-1993--a 74-year-old woman with rapidly progressing renal failure alter an upper respiratory tract infecction. N Engl J Med 1993; 328:951-958

Massachusetts General Hospital. Case records of the Massachusetts General Hospital: weekly clinicopathological exercises; case 28-1998--a 64-year-old man with cranial-nerve palsies and a positive test for antinuclear cytoplasmic antibodies. N Engl J Med 1998; 339:755-763

Silverman EM, Mark EJ. Case records of the Massachusetts General Hospital: weekly clinicopathological exercises; ease 36--2002--32-year-old man with hemoptysis of nearly three decades' duration. N Engl J Med 2092; 347:1693-1701

van der Woude FJ, Rasmussen N, Lobatto S, et el. Autoantibodies against neutrophils mad monocytes: tool for diagnosis and marker of disease activity in Wegener's granulomatosis. Lancet 1985; 1:425-429

* From the Medical Intensive Care Unit (Drs. Maimon and Almog), and the Departments of Medicine D (Dr. Abu-Shakra) and Pathology (Dr. Sion-Vardi), Soroka University Medical Center, Faculty of Health Sciences, Ben-Gurion University, Beer-Sheva, Israel.

Manuscript received June 11, 2003; revision accepted August 7, 2003.

Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (e mail: permissions@ehestnet.org).

Correspondence to: Yaniv Almog, MD, MICU, Soroka University Medical Center, POB 151, Beer-Sheva, 84101, Israel; e-mail: almogya@bgumail.bgu.ac.i

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