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(Chest. 1999;116:1480-1483.)
© 1999 American College of Chest Physicians

Eosinophilia in Wegener’s Granulomatosis*

Mark B. Potter, MD; Roger K. Fincher, MD and David R. Finger, MD

* From the Department of Medicine (Drs. Potter and Fincher) and Rheumatology Service (Dr. Finger), Madigan Army Medical Center, Tacoma, WA.

Correspondence to: David R. Finger, MD, Assistant Chief, Rheumatology Service, Madigan Army Medical Center, Tacoma, WA 98431


   Abstract
TOP
 Abstract
Introduction
 Report of Cases
 Discussion
 References
 
Significant eosinophilia is a prominent feature in Churg-Strauss syndrome but has only rarely been described in Wegener’s granulomatosis (WG). We describe two Wegener’s granulomatosis patients with > 30% eosinophilia on their initial presentations. Other etiologies that could account for their eosinophilia were excluded. Both patients had pulmonary alveolar hemorrhage, sinusitis, arthritis, high-titer cytoplasmic antineutrophil cytoplasmic antibodies (cANCA), and proteinase-3 antibodies, but no evidence of renal disease. Herein we discuss eosinophilia, the differential diagnosis of pulmonary infiltrates and eosinophilia, the role of cANCA in vasculitis and autoimmune disease, compare Wegener’s granulomatosis and Churg-Strauss syndrome, and review possible pathogenic mechanisms.

Key Words: eosinophilia • vasculitis • Wegener’s granulomatosis


   Introduction
TOP
 Abstract
 Introduction
Report of Cases
 Discussion
 References
 
Significant eosinophilia is a prominent feature of conditions such as Churg-Strauss syndrome (CSS), atopic disorders, helminthic infections, Loeffler’s syndrome, and allergic bronchopulmonary aspergillosis. Mild eosinophilia has also been reported previously in Wegener’s granulomatosis (WG) in the peripheral blood,1 2 3 on lung biopsy,4 5 and in both.6 We describe two patients with WG who had > 30% peripheral blood eosinophilia along with pulmonary tissue eosinophilia. Other common etiologies for their eosinophilia were excluded. Both presented with pulmonary alveolar hemorrhage, sinusitis, arthritis, and high-titer cytoplasmic antineutrophil cytoplasmic antibody (cANCA) and proteinase-3 antibodies. Renal disease was absent in both patients, and their illnesses were quite responsive to therapy.


   Report of Cases
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 Abstract
 Introduction
 Report of Cases
Discussion
 References
 
Case 1
A 29-year-old previously healthy white man presented with a 1-month history of migratory polyarthralgias, sinus congestion, cough, and epistaxis. He also noted fatigue, night sweats, fevers, and occasional hemoptysis. He lacked a history of atopic disease or asthma, had no risk factors for communicable diseases such as HIV infection, and had an unremarkable travel or family history. Examination revealed the following: normal vital signs; synovitis of his right elbow, both wrists, right knee, and left ankle; mid-lung field crackles bilaterally; nontender sinuses; and no nasal ulcerations. Laboratory studies revealed normal urinalysis and creatinine, an elevated level of C-reactive protein at 6.38 mg/dL (normal < 0.8 mg/dL), an erythrocyte sedimentation rate of 60 mm/h (normal 0–15 mm/h), normal WBC count of 8,500 mg/dL with 33% eosinophils (total eosinophil count 2,805 cells/µL), hematocrit 30%,41–49 with a baseline level of 45% in 1994, negative rheumatoid factor and antinuclear antibodies, negative stool hemoccult as well as ova and parasite testing on three occasions, high-titer cANCA (> 1:640) and proteinase-3 antibodies, and negative perinuclear antineutrophil cytoplasmic antibody (pANCA). Chest radiography revealed patchy bilateral alveolar infiltrates (Fig 1 , top), and sinus films showed bilateral maxillary mucosal thickening. Measures of spirometry, lung volumes, diffusion of carbon monoxide, and methacholine challenge were normal.



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  		Figure 1. Frontal chest radiographs (patient 1) showing patchy bilateral alveolar infiltrates (top), with subsequent clearing after 4 weeks of therapy (bottom).

 
Results of initial blood, sputum, and stool cultures were negative. Rhinoscopy revealed nasal ulcerations, but the biopsy was nondiagnostic. BAL with transbronchial biopsy revealed negative cultures, alveolar hemorrhage, and nondiagnostic tissue histopathology. Open lung biopsy revealed alveolar hemorrhage, eosinophilic pneumonitis, and eosinophilic vasculitis, although no granulomas were noted. No fungal or atypical bacterial elements were found with special stains. Therapy was initiated with prednisone, 60 mg/d; methotrexate, 25 mg/wk, subcutaneously; and trimethoprim/sulfamethoxazole bid. The patient’s symptoms resolved 1 month into therapy, as did his anemia and eosinophilia, and repeat chest radiography showed complete resolution of alveolar infiltrates (Fig 1 , bottom). He was maintained on a therapy of alternate-day prednisone for 6 months and methotrexate for a total of 1 year and was in remission 5 months after discontinuing all immunosuppressive therapy.

Case 2
A previously healthy 39-year-old woman presented with the subacute onset of cough, dyspnea, polyarthralgias, sinus congestion, and hemoptysis. She had no significant travel or family history, and she denied an earlier history of asthma or atopic disease. Initially, she received a diagnosis of community-acquired pneumonia and was treated with antibiotics without improvement. Physical examination revealed normal vital signs, joint tenderness with mild synovitis, no cutaneous or nasal lesions, but bibasilar lung crackles were present. Laboratory testing revealed the following: WBC count of 11,800 cells/µL with 38% eosinophils (total eosinophil count of 4,484 cells/µL), elevated levels of C-reactive protein of 3.36 mg/dL (normal < 0.8 mg/dL), normal hematocrit, negative rheumatoid factor and antinuclear antibodies, normal creatinine and urinalysis, negative hepatitis B and C antibodies, stool negative for ova and parasites, highly positive cANCA (> 1:640) and proteinase-3 antibodies, negative pANCA, and negative glomerular basement membrane antibody. Of note, the eosinophilia was observed before the initiation of antibiotic therapy. Chest radiography and CT revealed bibasilar and right middle lobe focal alveolar consolidation without adenopathy or pleural effusions (Fig 2 ), while sinus films were normal.



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  		Figure 2. Chest CT scan (patient 2) revealing predominantly bibasilar focal alveolar infiltrates.

 
Bronchoscopy with transbronchial biopsy revealed alveolar hemorrhage, no evidence of infection, and nondiagnostic inflammatory tissue histopathology. A thoracoscopic lung biopsy was notable for alveolar hemorrhage with chronic eosinophilic inflammatory tissue changes, although granulomas and definitive necrotizing vasculitic changes were not identified. Special tissue stains for fungus, bacteria, parasites, and acid-fast bacilli were negative. The patient was started on prednisone 60, 60 mg/d; methotrexate, 15 mg/wk; and trimethoprim/sulfamethoxazole. Her pulmonary symptoms diminished rapidly, with resolution of her eosinophilia and improvement in her chest radiograph. Methotrexate was ultimately discontinued because of persistently elevated transaminase levels, but oral cyclophosphamide and alternate-day prednisone therapy has kept her disease in remission thus far for 1 year.


   Discussion
TOP
 Abstract
 Introduction
 Report of Cases
 Discussion
References
 
Eosinophils usually comprise only 1 to 3% of peripheral WBCs, but when excessive, eosinophilia is arbitrarily defined as mild (351 to 1,500 cells/µL), moderate (1,500 to 5,000 cells/µL), and severe (> 5,000 cells/µL). Eosinophilia is found in many conditions, including atopic disorders (the most common cause in industrialized nations), neoplasms, helminthic infections (the most common cause worldwide), various hematologic and autoimmune rheumatic disorders, and as secondary effects of medications.7

Eosinophilic pulmonary disorders can be categorized into parenchymal, airway-based, or a mixture of both. The differential diagnosis of parenchymal eosinophilic lung diseases include simple pulmonary eosinophila, chronic eosinophilic pneumonia (CEP), acute eosinophilic pneumonia, CSS, idiopathic hypereosinophilic syndrome, allergic bronchopulmonary aspergillosis, bronchocentric granulomatosis, certain parasitic infections, and drug-induced disorders.8 Infectious etiologies were thoroughly excluded in our patients with negative findings on blood, sputum, and BAL cultures, as well as negative findings on tissue stains for fungal and acid-fast organisms.

We do not feel that our patients had CEP. Although the presence of pulmonary infiltrates and eosinophilia was seen in patients with both WG and CEP, a review of the medical literature revealed that the presence of a high-titer, proteinase-3-directed cANCA has not been described in CEP. Furthermore, our patients did not have a history of asthma, which is noted in half of patients with CEP, and they had alveolar hemorrhage, which is uncommonly seen in patients with CEP.9 10 Mild eosinophilia has also been noted to occur uncommonly in various autoimmune rheumatic diseases such as scleroderma, rheumatoid arthritis, polyarteritis, and Sjogren’s syndrome, but peripheral blood eosinophilia > 5% is seen in > 90% of patients with CSS.11

Peripheral blood and tissue eosinophilia have been previously described in WG, but are uncommon. Mild eosinophilia has been reported in <= 12% (6/50) of WG patients,12 but tissue eosinophilia in WG has also been described. Fahey and Chrug1 reported 1 of 7 WG patients with tissue eosinophilia on lung biopsy, and Fienberg6 reported this in 2 of 12 patients. Yousem and Lombard4 reported four WG patients with lung biopsies notable for prominent eosinophilic infiltration in the absence of peripheral blood eosinophilia. Many of these cases were reported before the onset of ANCA testing, and the cases may have represented CSS.

The emergence of ANCA testing has helped the classification of systemic vasculitis, with two indirect immunofluorescence patterns being cytoplasmic (cANCA), directed against proteinase-3, and perinuclear (pANCA), directed primarily against myeloperoxidase.12 It has been reported13 that 81% of cANCA-positive WG sera contain antibodies against proteinase-3, compared with 8% of CSS patients.14 15 In a recent large meta-analysis, Rao and coworkers16 reported the specificity of cANCA to be 88 to 100%, with pooled specificity of active and inactive patients of 98%, and an overall specificity of 95%.

We feel the diagnosis in our patients was most likely WG with eosinophilia rather than CSS or another eosinophilic pulmonary disorder. Both patients lacked a history of asthma or atopic disease, including a negative methacholine challenge in one. Infection was excluded in both patients by BAL, and fungal and acid-fast organisms were excluded by tissue staining. High-titer cANCA and proteinase-3 antibodies, uncommon in CSS and other disorders, were present in both patients. Neither patient had allergic rhinitis or nasal polyposis commonly seen in CSS, while patient 1 had epistaxis and nasal ulcerations typical of WG. Although lung biopsies failed to reveal classic granuloma formation, patient 1 had eosinophilic vasculitis, patient 2 had perivascular eosinophilic inflammatory infiltrates, and both had alveolar hemorrhage, a finding more commonly seen in WG than CSS. These cases may represent an overlap between CSS and WG, which has been previously described.17

Classic necrotizing granulomatous vasculitis on tissue biopsy is not an absolute requirement for the diagnosis of WG, nor is it required to initiate therapy. Hoffman and Specks18 point out that, with infectious etiologies excluded and in the setting of characteristic clinical findings such as sinusitis, pulmonary infiltrates, and/or glomerulonephritis, the presence of a high-titer cANCA directed against proteinase-3 is highly specific for WG. They further points out that the need for definitive tissue confirmation is not required in this setting before initiating therapy.

WG associated with eosinophilia may portend a more favorable prognosis, given the rapid response to therapy and lack of renal involvement in our patients. However, one third of all previously reported cases had significant renal disease and did not seem to have more favorable outcomes.1 2 3 4 5 6 While the clinical significance of eosinophilia in WG is uncertain, it has been suggested that this may represent a reaction toward an extrinsic allergen or a host response to material released by the injured lung from the vasculitic process.5

In summary, we describe two patients with responsive WG involving the lungs and sinuses associated with significant peripheral blood and tissue eosinophilia. Clinicians should recognize the differential diagnosis for eosinophilia and should, in the appropriate clinical setting, consider ANCA-positive vasculitis such as CSS and WG.


   Footnotes
 
Abbreviations: cANCA = cytoplasmic antineutrophil cytoplasmic antibody; CEP = chronic eosinophilic pneumonia; CSS = Churg-Strauss syndrome; pANCA = perinuclear antineutrophil cytoplasmic antibody; WG = Wegener’s granulomatosis

The opinions and assertions contained herein are those of the authors and not to be construed as official policy of the Department of the Army or Department of Defense.

Received for publication January 26, 1999. Accepted for publication July 7, 1999.


   References
TOP
 Abstract
 Introduction
 Report of Cases
 Discussion
 References
 

  1. Fahey, Jl, Chrug, J (1954) Wegener’s granulomatosis. Am J Med 17,168-178
  2. DeRemee, RA, McDonald, TJ, Harrison, EG, Jr (1976) Wegener’s granulomatosis; anatomical correlates, classification. Mayo Clin Proc 51,777-781[ISI][Medline]
  3. Krupsky, M, Landau, Z, Lifschitz-Mercer, B, et al (1993) Wegener’s granulomatosis with peripheral eosinophilia. Chest 104,1290-1292[Abstract/Free Full Text]
  4. Yousem, SA, Lombard, CM (1988) The eosinophilic variant of Wegener’s granulomatosis. Hum Pathol 19,682-688[CrossRef][ISI][Medline]
  5. Yousem, SA, Hochholzer, L (1989) Overlap Syndromes. Wegener’s granulomatosis and Churg-Strauss syndrome. Semin Respir Med 10,162-166
  6. Fienberg, R (1981) The protracted superficial phenomenon in pathergic (Wegener’s) granulomatosis. Hum Pathol 12,458-467[CrossRef][ISI][Medline]
  7. Rothenberg, ME (1998) Eosinophilia. N Engl J Med 338,1592-1600[Free Full Text]
  8. Allen, JN, Davis, WB (1994) Eosinophilic lung diseases. Am J Respir Crit Care Med 150,1423-1438[ISI][Medline]
  9. Naughton, M, Fahey, J, FitzGerald, M (1993) Chronic eosinophilic pneumonia: a long-term follow-up of 12 patients. Chest 103,162-165[Abstract/Free Full Text]
  10. Jederlinic, P, Sicilian, L, Gaensler, E (1988) Chronic eosinophilic pneumonia: a report of 19 cases and a review of the literature. Medicine 67,154-162[Medline]
  11. Lanham, JG, Elkon, KB, Pusey, CD, et al (1984) Systemic vasculitis with asthma and eosinophilia: a clinical approach to the Churg-Strauss syndrome. Medicine 63,65-81[Medline]
  12. Falk, RJ, Jennefte, JC (1988) Anti-neutrophil cytoplasmic autoantibodies with specificity for myeloperoxidase in patients with systemic vasculitis and idiopathic necrotizing and crescentic glomerulonephritis. N Engl J Med 318,1651-1657[Abstract]
  13. Hauschild, S, Schmitt, WH, Csernok, E, et al (1993) ANCA in Wegener’s granulomatosis and related vasculitides. Gross, WL eds. ANCA-associated vasculitides: immunological and clinical aspects ,245-251 Plenum Press New York, NY.
  14. Cohen, RD, Tevaert, JW, van der Woude, FJ, et al (1989) Association between active Wegener’s granulomatosis and anticytoplasmic antibodies. Arch Intern Med 149,2461-2465[Abstract]
  15. Guillevin, L, Visser, H, Noel, LH, et al (1993) Antineutrophilic cytoplasm antibodies in systemic polyarteritis nodosa with and without hepatitis B virus infection and Churg-Strauss syndrome: 62 patients. J Rheumatol 20,1345-1350[ISI][Medline]
  16. Rao, JK, Weinberger, M, Oddone, EZ, et al (1995) The role of antineutrophil cytoplasmic antibody (cANCA) testing in the diagnosis of Wegener’s granulomatosis. Ann Intern Med 123,925-932[Abstract/Free Full Text]
  17. Henochowicz, S, Eggensperger, D, Pierce, L, et al (1986) Necrotizing systemic vasculitis with features of both Wegener’s granulomatosis and Churg-Strauss vasculitis. Arthritis Rheum 29,565-569[ISI][Medline]
  18. Hoffman, G, Specks, U (1998) Antineutrophil cytoplasmic antibodies. Arthritis Rheum 41,1521-1537[ISI][Medline]



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