Recent Advances in the Diagnosis of Churg-Strauss Syndrome Andrew Churg, M.D

Recent Advances in the Diagnosis of Churg-Strauss Syndrome Andrew Churg, M.D. Department of Pathology, University of British Columbia, Vancouver, British Columbia, Canada Historic Definitions of Churg-Strauss Syndrome Most pathologists assume that a diagnosis of Churg- Churg-Strauss syndrome (CSS) as originally de- Strauss syndrome (CSS) requires the finding of ne- scribed (1) is a syndrome characterized by asthma, crotizing vasculitis accompanied by granulomas blood and tissue eosinophilia, and in its full-blown with eosinophilic necrosis in the setting of asthma form, eosinophilic systemic vasculitis, along with ne- and eosinophilia. However, recent data indicate crotizing granulomas centered around necrotic eosin- that this definition is too narrow and that adher- ophils. However, experience with increasing numbers ence to it leads to cases of CSS being missed. CSS of cases indicates that this definition is too narrow. has an early, prevasculitic phase that is character- Many cases of CSS, especially the early (“prevascu- ized by tissue infiltration by eosinophils without litic” or “prodromal”) phase cases readily amenable to overt vasculitis. Tissue infiltration may take the treatment, do not have overt vasculitis, but often have form of a simple eosinophilia in any organ, and a fine-needle aspirate showing only eosinophils may other, quite typical, patterns of organ involvement. As suffice for the diagnosis in this situation. The pre- well, relatively new developments in diagnostic test- vasculitic phase appears to respond particularly ing, notably ANCA, and new modes of treatment for well to steroids. Even in the vasculitic phase of CSS, asthma, have made it clear that a much broader def- many cases do not show a necrotizing vasculitis but inition is required for accurate diagnosis of CSS. Cli- often only an apparently nondestructive infiltration nicians are becoming familiar with these findings, of vessel walls by eosinophils. In modern biopsy particularly the issue of CSS and leukotriene receptor materials, granulomas frequently cannot be found. antagonist therapy. However, few pathologists are In the postvasculitic phase of CSS, healed vascular aware of these issues and CSS appears to be under- lesions resemble organized thrombi but typically diagnosed by pathologists. show very extensive destruction of elastica and, of- The first description of CSS was made by Churg ten, an absence of eosinophils. The widespread use and Strauss in 1951 (1) on 13 patients (11 autop- of steroids as therapy for asthma has led to the sied) under the title “allergic granulomatosis, aller- peculiar and confusing situation in which the ste- gic angiitis, and periarteritis nodosa.” Churg and roid therapy accidentally suppresses CSS and Strauss emphasized the findings common to all changes in steroid treatment uncover the disease; cases: history of asthma; blood and tissue eosino- this type of “formes frustes” CSS is now well recog- philia; necrotizing vasculitis; and a granulomatous nized with leukotriene receptor antagonist treat- response to eosinophilic necrosis (Table 1). Al- ment and will be seen with increasing frequency as though the cases in the original description of CSS other steroid-sparing therapies for asthma are were remarkably similar, further experience has introduced. shown that exact definition of CSS is a problem, in part because CSS is very protean in its manifesta- KEY WORDS: ANCA, Churg-Strauss syndrome, Leu- tions, a problem common to most forms of vascu- kotriene receptor antagonists, Vasculitis. litis, and in part because, as will be described, it has Mod Pathol 2001;14(12):1284–1293 become clear that there is a sequence of events in the natural history of CSS and that some relatively early cases do not demonstrate vasculitis. As well, the original cases predated the use of exogenous Copyright © 2001 by The United States and Canadian Academy of steroids, and thus represent totally untreated dis- Pathology, Inc. ease. However, most asthmatics now are treated VOL. 14, NO. 12, P. 1284, 2001 Printed in the U.S.A. Date of acceptance: August 28, 2001. with steroids for their asthma, and this treatment, Address reprint requests to: Andrew Churg, M.D., Department of Pathol- which is the preferred treatment for CSS as well, in ogy, University of British Columbia, 2211 Wesbrook Mall, Vancouver, BC, V6T 2B5, Canada; e-mail: [email protected]; fax: 604-822-7635. itself changes the clinical appearances of CSS. 1284 Current Definitions of CSS 90% of cases (11–15). There appears to be a consensus Historically, pathologic descriptions of CSS were that a properly performed ANCA test, which must relatively few (1–5), in part because CSS is a rare include an ELISA to show proteinase 3 or myeloper- disease (incidence on the order of 1–2 cases per oxidase specificity, provides strong support for a di- million persons per year in the general population agnosis of CSS, even if overt vasculitis cannot be (6)). But the recognition that CSS could be success- found. fully treated with steroids led, by the mid-1980s, to a shift in emphasis from purely pathologic diagno- Natural History of CSS sis to clinical diagnosis (7). Unfortunately, clinical diagnosis is also not simple, and thus a variety of The early (“prodromal,” “prevasculitic”) phase definitions exist in the literature as shown in Table Although the original cases of CSS all had florid 1. The original Churg and Strauss definition (1), the vasculitis, it has become apparent from clinical ob- Chapel Hill Consensus Conference definition (8), servations (3, 5, 7) that many cases pass through a and the Lanham et al. (7) criteria require overt series of stages before the development of vasculitis vasculitis, although Lanham et al. (5, 7) also stress and that identification of patients in the early phase the idea of an early, prevasculitic phase of the dis- is important because they appear to respond well to ease (see below). The broadest definition is that of steroids and to have an excellent prognosis (Table the American College of Rheumatology (ACR; 9), 2). which is notionally based on subclassifying patients The idea of a natural history of CSS was intro- thought to have clinical vasculitis but does not ac- duced by Lanham et al. (7). They summarized 138 tually require pathologic evidence of vasculitis. The cases in the literature and 16 of their own and ACR criteria instead allow tissue eosinophilia in the suggested that the typical sequence of events is, absence of pathologic vasculitis to serve as one first, the appearance of clinically overt allergic rhi- criterion for the diagnosis of CSS. Both the ACR and nitis (mean age of appearance, 28 years), followed the Lanham criteria also emphasize allergic rhinitis several years later by the development of asthma as a part of CSS. (mean age of appearance, 35 years), and, finally, the These definitions also predate the widespread use development of vasculitis (mean age of appearance, of anti-neutrophil cytoplasmic antibody (ANCA) test- 38 years). Before vasculitis appears, there is often ing, and ANCA status is not part of any of these clinically apparent infiltration of tissues by eosino- diagnostic schemes. CSS is associated with a positive phils (3), and it is this pathologic tissue eosinophilia ANCA in some reports in as many as 70% of cases that is the diagnostic hallmark of early-stage CSS. (10–15); this is usually p- (myeloperoxidase) ANCA, This sequence is by no means invariable, and all although c-ANCA–positive patients have also been manifestations may occur together; as well, some reported, and sometimes the proportion of positive patients do not have clinical allergic rhinitis, and in cases is much smaller (see Reference 11). Microscopic rare cases asthma develops after vasculitis (16). polyangiitis, one of the morphologic differentials of Allergic rhinitis was believed to be, in retrospect, CSS, is also typically p-ANCA positive in about 40– the earliest manifestation of CSS in about 70% of 80% of cases, whereas Wegener’s granulomatosis, an- the cases summarized by Lanham et al. (7) and in other morphologic differential, is generally c- (pro- 60% of the cases of Guillevin et al. (16). The rhinitis teinase 3) ANCA positive, in some studies in up to is often severe and may require repeated nasal TABLE 1. Criteria for the Diagnosis of CSS Author Group (Reference No.) Criteria Churg and Strauss (1) History of asthma Blood and tissue eosinophilia Necrotizing vasculitis Necrotizing granulomas centered on necrotic eosinophils Chapel Hill Consensus Conference (8) Asthma Eosinophilia Necrotizing vasculitis Granulomatous inflammation associated with tissue eosinophilia Lanham et al. (7) Asthma Eosinophilia Ͼ 1.5 ϫ 109/l Vasculitis involving Ն2 organs American College of Rheumatology (9) Asthma Paranasal sinus abnormalities Eosinophilia Ͼ 10% Neuropathy (mono or poly) Pulmonary infiltrates Biopsy containing a blood vessel with extravascular eosinophils Churg-Strauss Syndrome (A. Churg et al.) 1285 TABLE 2. Typical Findings in the Early (Prevasculitic, by steroid therapy. Lanham et al. (7) suggested that Prodromal) Phase of CSS eosinophilia more than 1.5 ϫ 109/L (at some point) Allergic rhinitis is a required feature for diagnosis. Care should be Asthma Blood eosinophilia taken not to confuse the eosinophilia of CSS, which Extravascular tissue infiltration by eosinophils (may be diagnosed by is often quite marked, with the low-level eosino- fine-needle aspirate), including ϫ 9 Lavage eosinophilia philia (less than 1.0 10

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