Original Articles: Workshop Summary Report
The relationship of asthma therapy and Churg-Strauss syndrome: NIH workshop summary report☆,☆☆

https://doi.org/10.1067/mai.2001.117176Get rights and content

Abstract

The Churg-Strauss syndrome (CSS) is a distinct form of vasculitis that is notable for its eosinophilia and frequent associations with asthma and sinusitis. Because there has been an increasing recognition that CSS can develop in patients with asthma and that CSS might be associated with specific asthma treatments, the National Heart, Lung, and Blood Institute, the National Institute of Allergy and Infectious Diseases, the Office of Rare Diseases, National Institutes of Health, and the US Food and Drug Administration jointly sponsored a workshop to consider interrelationships among CSS, asthma, and asthma therapeutics and to assess what is known about underlying mechanisms of CSS. Issues related to the criteria for defining and diagnosing CSS were reviewed, including the contemporary understanding that diagnostic biopsies need only reveal eosinophilic perivascular infiltrates and that asthma need not be present when CSS develops. From published reports and reports to the US Food and Drug Administration, treatment of patients with asthma with any of 3 cysteinyl leukotriene receptor antagonists, a 5-lipoxygenase inhibitor, and inhaled corticosteroids has been associated with CSS development. It is unknown whether these agents were eliciting CSS. A variety of physiologic and study design issues might lead to the reported associations of these drugs with CSS. Because many asthma patients receiving these therapies were able to diminish their systemic corticosteroid therapy, it is possible that incipient CSS was unmasked by lessened steroid use. The underlying pathophysiologic mechanisms of CSS, however, are unknown, and there is no means of identifying which patients with asthma might be at risk for CSS. Accordingly, investigations with the goals of defining the underlying pathophysiologic processes of CSS and establishing the relationships of asthma and its therapies to CSS are needed. (J Allergy Clin Immunol 2001;108:175-83.)

Section snippets

CSS: Historical aspects

Starting about 1940, reports began to appear identifying a subset of patients with polyarteritis nodosa who were distinct because they frequently had concomitant allergic diseases (including asthma) and characteristically developed eosinophilia and pulmonary infiltrates. In 1951, Churg and Strauss reported from autopsies of 13 patients a pathologic triad of allergic granulomatosis, allergic angiitis, and periarteritis nodosa.1 The recognition of this pathologic triad was critical in

Available definitions of CSS and their limitations

The currently available definitions of CSS are presented in Table I.

. Definitions of the Churg-Strauss syndrome

StudyCriteriaPurpose and limitations
Churg and Strauss1(1) Necrotizing vasculitis of small and medium-sized arteries and veins; (2) eosinophil infiltration around involved vessels and in tissues; and (3) extravascular granulomasIdentified CSS as a pathologically distinct form of vasculitis, but was based on autopsy examination of multiple organs of those with end-stage disease
Hammersmith2

CSS: The spectrum of disease and issues of differential diagnosis

Although limited forms of CSS have been recognized previously,12, 14 the spectrum of the syndrome has been expanded in part by the recognition of forme frustes of CSS. Churg et al20 reported 4 patients weaned from corticosteroid therapy for asthma in whom CSS developed either as obvious vasculitis (2 patients) or as suggestive vasculitis, eosinophilic lymphadenopathy, and eosino-philia. These cases were believed to represent longsmoldering CSS that was unrecognized while cortico-steroids were

The incidence of CSS

In considering the relationship of CSS to asthma and its treatments, it is reasonable to consider not only whether our diagnostic awareness of CSS might be increasing but also whether there is an increasing incidence of CSS, especially relative to the documented increases in the incidence of asthma.26 Data on the prevalence or incidence of CSS are limited. In a 10-year study of vasculitis in a defined, ethnically homogeneous population of approximately 500,000 in an eastern coastal region of

Associations of CSS with specific asthma therapies

In 1998, 8 patients with asthma were reported to have developed CSS while receiving zafirlukast31; however, other treatment modalities for asthma have been associated with CSS. When cromolyn was introduced as an asthma treatment, drug-associated eosinophilic pulmonary infiltrates were recognized.32 At that time, CSS was underappreciated, and whether some of the eosinophilic reactions associated with cromolyn treatment might have been due to CSS remains conjectural. The French Vasculitis Study

Potential pathophysiology of CSS

As is true for several other forms of vasculitis, the pathogenesis of CSS is not at all clear, but it probably derives from autoimmune mechanisms involving endothelial cells and leukocytes.57 In CSS, in contrast to other forms of vasculitis, eosinophils are the predominant and signature leukocytes, but the roles of eosinophils in driving the pathogenesis of CSS are virtually unknown. Remarkably few studies have addressed the potential pathophysiologic mechanisms of CSS. Recently, an impairment

Future research directions

There was a consensus among the workshop participants that CSS is a distinct form of vasculitis—notable for its eosinophilia and frequent association with asthma and sinusitis—whose underlying pathophysiology and relationship to asthma are very poorly understood. The workshop was organized in response to the increase in reports of CSS among patients with asthma treated with newer therapeutic agents. Potential explanations for this increased reporting include the following: (1) there might be an

Recommendations for research studies

Research to define the underlying pathophysiologic processes of CSS and establishing the relationship of asthma and its therapies to CSS should be encouraged. Investigations of the potential pathophysiology might include studies of the following: (1) lymphocyte populations active in CSS and the question of whether they overexpress particular cytokines (eg, IL-5); (2) the expression of chemokines, cytokines, or other mediators potentially active in recruiting and activating eosinophils or other

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    ☆

    Workshop supported by the National Institutes of Health: National Heart, Lung, and Blood Institute, Division of Lung Diseases; National Institute of Allergy and Infectious Diseases, Division of Allergy, Immunology, and Transplantation; and Office of Rare Diseases. The views expressed are those of the authors and do not necessarily represent the official position of the US Food and Drug Administration.

    ☆☆

    Reprint requests: Peter F. Weller, MD, Beth Israel Deaconess Medical Center, DA617, 330 Brookline Avenue, Boston, MA 02215.

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