New lung lesion in immunocompromised host--correct diagnosis despite a false positive ANCA.

Pulmonary vasculitides are rare, yet occur frequently enough that the clinician must be adequately aware of their clinical manifestations and laboratory features. Unrecognized, the consequences can be devastating, since untreated patients with vasculitis syndrome can suffer significant morbidity and mortality. More devastating is the scenario where, because of suspected vasculitis, an infection is treated with immunosuppression without the cover of antibiotics, leaving the host open to the devastation of the offending organism due to the lack of protection from the immune system.

Antineutrophil cytoplasmic antibodies (ANCA) are antibodies directed against cytoplasmic granules in neutrophils and monocytes. (1) ANCA-associated vasculitis includes a spectrum of entities, including Wegener granulomatosis, Churg-Strauss syndrome, microscopic polyangiitis, as well as pauciimmune glomerulonephritis (2)

Wegener granulomatosis (WG) is the most common of these primary vasculitides, the clinical presentation of which can be easily recollected using the acronym ELKS-E for ENT involvement, L for lung involvement, K for kidney involvement, and S for skin involvement. Predictors of adverse outcomes in WG include age > 50 years, kidney involvement and lung involvement. (3) Patients with upper respiratory involvement may have improved outcomes. (4) In the right clinical setting, the presence of circulating C-ANCA, with confirmatory antimyeloperoxidase (MPO) antibodies, have a high sensitivity and specificity for the diagnosis of WG. As well as being useful for diagnosing WG, ANCA may be an indicator of disease activity as well. (5) There is mounting evidence to suggest that ANCA plays a pathogenetic role in disease causation (6) and ANCA levels may become undetectable during sustained remissions of ANCA-associated vasculitis. (7)

Immunosuppression is the standard treatment for WG, with cyclophosphamide being the preferred agent, along with corticosteroids. (3,4) Although most patients achieve a complete or partial remission, relapse is common, and warrants reintroduction of immunosuppression to induction levels. Other than direct toxicity, intercurrent infections due to immunosuppression are also common, with pneumonia being the most common infection. (3)

Fungal infections, including histoplasmosis, (8) and even Pneumocystis jiroveci, have been reported in patients with WG. (9) Aspergillus species are ubiquitous molds that are present in vegetation, soil and water, with no demonstrable geographic predilection. The spectrum of interaction of Aspergillus with a human host includes airway colonization, allergic bronchopulmonary aspergillosis, hypersensitivity pneumonitis, aspergilloma and the much dreaded invasive pulmonary aspergillosis. Diagnostic strategy includes a high index of suspicion, surveillance using the galactomannan assay and obtaining timely tissue sampling. (10)

False positive ANCA has been reported in various conditions, including lymphoma, idiopathic pulmonary fibrosis, lung cancer, etc. (11,12) The molecular mechanism for ANCA false-positivity is largely unknown, but speculations of B-cell activation, with or without hypergammaglobulinemia, exist.

In this issue of the Journal, Vahid and colleagues report on a patient with known WG, immunosuppressed into remission with the usual cyclophosphamide/prednisone combination. When the patient returned with a new lung lesion, relapse of WG was initially suspected, given the high titer positivity of C-ANCA. Further workup yielded a high titer positive P-ANCA as well, but the confirmatory MPO and PR-3, (antiproteinase 3) antibodies were negative. Bronchoscopy was negative, and an open lung biopsy yielded a microbiologic diagnosis of Aspergillus infection, with no evidence of WG.

This case illustrates the importance of appropriate workup of a new infiltrate in an immunosuppressed host. The differential diagnosis in this situation includes: 1. Relapse of the original process, 2. Intercurrent infection, 3. Manifestation of drug toxicity, and 4. Emergence of an unrelated new process. Each of these possibilities should be systematically evaluated as needed, using noninvasive and invasive techniques. Antibiotic treatment of recurrent vasculitis, or immunosuppressive treatment of an infection can lead to disastrous consequences for the patient. Neutropenia is not necessary to suspect an Aspergillus infection, although the invasive form of this infection is more common in the neutropenic host. False positive ANCA can occur in this setting, as illustrated in this case, but the molecular mechanism of such tests are still poorly understood.

References

1. van der Woude FJ, Daha MR, van Es LA. The current status of neutrophil cytoplasmic antibodies. Clin Exp Immunol 1989;78:143-148.

2. Niles JL. Antineutrophil cytoplasmic antibodies in the classification of vasculitis. Annu Rev Med 1996;47:303-313.

3. Reinhold-Keller E, Beuge N, Latza U, et al. An interdisciplinary approach to the care of patients with Wegener's granulomatosis: long-term outcome in 155 patients. Arthritis Rheum 2000;43:1021-1032.

4. Bligny D, Mahr A, Toumelin PL, et al. Predicting mortality in systemic Wegener's granulomatosis: a survival analysis based on 93 patients. Arthritis Rheum 2004;51:83-91.

5. Van Der Woude FJ. Taking anti-neutrophil cytoplasmic antibody (ANCA) testing beyond the limits. Nephrol Dial Transplant 2002;17:2081-2083.

6. Falk RJ, Jennette JC. ANCA are pathogenic: oh yes they are! J Am Soc Nephrol 2002;13:1977-1979.

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

8. Manepalli AN, Rush L. Disseminated histoplasmosis and Wegener's granulomatosis. South Med J 1998;91:1156-1158.

9. Ullmer E, Mayr M, Binet I, et al. Granulomatous Pneumocystis carinn pneumonia in Wegener's granulomatosis. Eur Respir J 2000;15:213-216.

10. Sarosi GA, DS. Fungal Diseases of the Lung. Third edition. Lippincott Williams & Wilkins, 2000, p 322.

11. Lee AS, Wiesner O, Gillespie DJ. et al. A 70-year-old man with pulmonary infiltrates and a positive antineutrophil cytoplasmic autoantibody test result. Chest 2005;127:1045-1050.

12. Vassilopoulos D. Niles JL, Villa-Forte A, et al. Prevalence of antineutrophil cytoplasmic antibodies in patients with various pulmonary diseases or multiorgan dysfunction. Arthritis Rheum 2003;49:151-155.

I would feel more optimistic about a bright future for man if he spent
less time proving that he can outwit Nature and more time tasting her
sweetness and respecting her seniority.
--E.B. White

Muthiah P. Muthiah, MD, FCCP

From the Division of Pulmonary and Critical Care and Sleep Medicine, University of Tennessee Health Science Center, Memphis, TN.

Reprint requests to Muthiah P. Muthiah, MD, FCCP, University of Tennessee Health Science Center, 956 Court Avenue, H 314, Memphis, TN 38163. Email: [e-mail]

Accepted April 12, 2006.