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Communications to the Editor |

Churg-Strauss SyndromeChurg-Strauss Syndrome: Is There an Association With Leukotriene Modifiers? FREE TO VIEW

Stuart Stoloff, MD; David A. Stempel, MD
Author and Funding Information

Affiliations: Carson City, NV Seattle, WA,  Brigham and Women’s Hospital Boston, MA

Correspondence to: David A. Stempel, MD, Virginia Mason Clinic, 1100 9th Ave, Seattle, WA 98101; e-mail: immdas@vmmc.org



Chest. 2000;118(5):1515-1516. doi:10.1378/chest.118.5.1515
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Published online

The report by Wechsler and colleagues (March 2000)1addresses the question of the association of Churg-Strauss syndrome (CSS) and the use of montelukast in the treatment of patients with asthma. Their conclusion that “montelukast does not appear to directly cause the syndrome” appears to be a premature conclusion. The authors are correct to point out that asthma may be a precursor presentation for CSS, but they fail to justify why there is an increase in the number of reports of CSS since the introduction of montelukast and zafirlukast.25

Their article suggests that the tapering of systemic corticosteroids afforded by the use of these two medications allowed for the unmasking of previously controlled CSS. If this is true, why during the almost 30-year history of using inhaled corticosteroids (ICS) for asthma, a more effective drug for reducing systemic corticosteroids, were there no increases in the report of this syndrome? Wechsler and colleagues state “that no cases have been observed in steroid-naïve individuals” but then reference the report of Green and Vayonis4 describing two such patients. A further report by Villena et al2 describes another patient with CSS after beginning montelukast on a stable ICS dose with no recent use of oral corticosteroids.

Patients with CSS frequently present with signs and symptoms of asthma and are placed on asthma therapeutics; during the course of the illness and manipulation of medications, the syndrome manifests itself. CSS requires high doses of prednisone and frequently the addition of cyclophosphamide for disease control. Natural progression of the disease or the effect of the leukotriene modifiers are reasonable alternative mechanisms to corticosteroid tapering.

The authors’ rationale is inconsistent in their description of the effect of using ICS. They state that it is “well established that inhaled corticosteroids have sufficient systemic absorption to account for such suppressive effect.” If this statement is true, then maintaining a stable dose of ICS should not produce CSS. This is a confusing rationale that proposes ICS are successfully masking the disease and are then implicated as the cause of the unmasking of the illness without evidence of disease progression.

The case reports of the patients are incomplete. The four patients receiving montelukast have more extensive case histories than the two patients receiving fluticasone (the ICS patient history is presented in an abbreviated table format). Montelukast is discontinued in all of the patients in the reported cases of CSS once there is evidence of CSS. ICS are not uniformly stopped when CSS presents.5 Did the tapering of the montelukast promote the recovery? This additional information would be helpful to discern the differences between causative and unmasking.

CSS is an uncommon disease whether in the general population or in asthmatic individuals. The referenced General Practice Research Database does not prove an association of CSS and the two leukotriene modifiers. It also does not preclude the conclusion that an association does exist based on the numbers presented. The author’s statement that“ the apparent increase in case rates with the leukotriene modifiers that we obtained implies a causative role of these medications” is contradicted in the next column by their statement that “our data suggest that neither montelukast nor zafirlukast is likely to have a direct causative role in CSS pathogenesis.”1 Which statement is correct?

What is needed at this time is for the manufacturers of the leukotriene modifiers and the ICS to present to an expert panel their reports of CSS in patients on these therapies. Until then, we will have only the isolated case reports and this debate will continue without clear resolution.

Wechsler, ME, Finn, D, Gunawardena, D, et al (2000) Churg-Strauss syndrome in patients receiving montelukast as treatment for asthma.Chest117,708-713. [CrossRef] [PubMed]
 
Villena, V, Hidalgo, R, Sotelo, P, et al Montelukast and Churg-Strauss syndrome [letter]. Eur Respir J. 2000;;15 ,.:626. [CrossRef] [PubMed]
 
Wechsler, ME, Garpestad, E, Flier, SR, et al Pulmonary infiltrates, eosinophilia, and cardiomyopathy following corticosteroid withdrawal in patients with asthma receiving zafirlukast.JAMA1998;279,455-457. [CrossRef] [PubMed]
 
Green, R, Vayonis, AG Churg-Strauss syndrome after zafirlukast in two patients not receiving systemic steroid treatment.Lancet1999;353,725-726. [CrossRef] [PubMed]
 
Knoell, DL, Lucas, J, Allen, JN Churg-Strauss syndrome associated with zafirlukast.Chest1998;114,332-334. [CrossRef] [PubMed]
 
To the Editor:

While it appeared as if there had been “an increase in the number of reports of [Churg-Strauss syndrome] CSS” since the introduction of leukotriene (LT) modifiers,” recent epidemiologic data suggest that this is not the case. Prior estimates of the prevalence of CSS were made mostly in the general population and not in the population of asthma patients, which is a group that is both inherently predisposed to CSS and receives LT modifiers. In fact, recent estimates of CSS point prevalence in association with LT modifiers (approximately 60 cases per million asthma patient-years) are very similar to the estimates of point prevalence in a recent study by Martin et al1 that analyzed CSS incidence in an era prior to the availability of LT modifiers. It is likely that the incidence of CSS in the general asthma population (not necessarily associated with LT modifiers) that both we and Martin et al1 report is even higher, because the disease probably remains underdiagnosed due to its rarity, to lack of physician recognition, and to the persistent steroid masking of CSS that contributes to the perception of the disease as difficult asthma. Similarly this could account for the lower numbers reported by us regarding the General Practice Research Database. Furthermore, these estimates were based on only a “crude preliminary review” that has not been further validated.

“Tapering of systemic corticosteroid therapy” leading to “forme fruste CSS” is one mechanism that has been proposed to explain the reports of CSS in patients who are receiving LT modifiers.23 Another mechanism includes the progression of the natural course of the disease, despite inhaled or systemic corticosteroid therapy, both of which may mask CSS in some patients, but may not be sufficient in others who may require more potent immunosuppressive therapy. In the pre-LT modifier era, when patients with CSS developed worsening airway obstruction, they were given therapy with inhaled steroids that could have masked the vasculitis. When their conditions worsened, they were given therapy with systemic steroids that further masked the syndrome. In the last few years, patients with worsening airway obstruction may have been started on therapy with LT modifiers before steroids were instituted or the doses increased, which likely allowed for the previously unrecognized syndrome to become manifest.

Our claim that there have been “no cases observed in steroid-naïve individuals” still holds true. In the reports by Green and Vayonis,4and Villena et al,5 patients had long histories of asthma that required inhaled corticosteroids. This is part of the natural course of the disease as described by Lanham et al6: “indolent allergic disease that evolves into asthma with multiple exacerbations that may progress to eosinophilia and finally, multi-organ eosinophilic vasculitis.” While the absorption of inhaled steroids is often sufficient to mask or treat the syndrome, as the disease progresses to the systemic vasculitis stage these medications are often not able to quell it.

While the case histories of patients receiving fluticasone are less detailed than those of patients receiving montelukast (partly for editorial reasons), the details of several similar cases concerning patients receiving inhaled steroids recently have been reported in the literature,78 and have been listed in the Physician’s Desk Reference for years. The reason for our inclusion of these case histories was to demonstrate that other such cases exist and that other patients have similar histories to those receiving LT modifiers. While montelukast therapy was reported to be discontinued in our report, one of our patients subsequently restarted montelukast therapy without exacerbating her disease, and we have safely reinitiated LT modifier therapy in other patients that we have treated for CSS. It is clear from these patients and from a review of the literature that a “tapering of the montelukast” did not promote recovery but, rather, that the institution of corticosteroid therapy was responsible for CSS resolution.

In summary, CSS remains a rare condition that is often misdiagnosed as accelerating asthma. It appears that the association of CSS with LT modifiers, as with inhaled steroids, either is coincidental to disease progression, despite steroid therapy, or is related to steroid withdrawal, because of the efficacy of these drugs in combating airway obstruction in those patients responsive to these therapies. We agree that further case reporting and more open discussions with drug manufacturers are needed.

References
Martin, RM, Wilton, LV, Mann, RD Prevalence of Churg-Strauss syndrome, vasculitis, eosinophilia and associated conditions: retrospective analysis of 58 prescription-event monitoring cohort studies.Pharmacoepidemiol Drug Saf1999;8,179-189. [CrossRef] [PubMed]
 
Wechsler, ME, Garpestad, E, Flier, SR, et al Pulmonary infiltrates, eosinophilia, and cardiomyopathy following corticosteroid withdrawal in patients with asthma receiving zafirlukast.JAMA1998;279,455-457. [CrossRef] [PubMed]
 
Wechsler, ME, Finn, D, Gunawardena, D, et al Churg-Strauss syndrome in patients receiving montelukast as treatment for asthma.Chest2000;117,708-713. [CrossRef] [PubMed]
 
Green, RL, Vayonis, AG Churg-Strauss syndrome after zafirlukast in two patients not receiving systemic steroid treatment [letter].Lancet1999;353,725-726. [CrossRef] [PubMed]
 
Villena, V, Hidalgo, R, Sotelo, MT, et al Montelukast and Churg-Strauss syndrome [letter]. Eur Respir J. 2000;;15 ,.:626. [CrossRef] [PubMed]
 
Lanham, JG, Elkon, KB, Pusey, CD, et al Systemic vasculitis with asthma and eosinophilia: a clinical approach to the Churg-Strauss syndrome.Medicine1983;63,65-81
 
Bili, A, Condemi, JJ, Bottone, SM, et al Seven cases of complete and incomplete forms of Churg-Strauss syndrome not related to leukotriene receptor antagonists.J Allergy Clin Immunol1999;104,1060-1065. [CrossRef] [PubMed]
 
Le Gall, C, Pham, S, Vignes, S, et al Inhaled corticosteroids and Churg-Strauss syndrome: a report of five cases.Eur Respir J2000;15,978-981. [CrossRef] [PubMed]
 

Figures

Tables

References

Wechsler, ME, Finn, D, Gunawardena, D, et al (2000) Churg-Strauss syndrome in patients receiving montelukast as treatment for asthma.Chest117,708-713. [CrossRef] [PubMed]
 
Villena, V, Hidalgo, R, Sotelo, P, et al Montelukast and Churg-Strauss syndrome [letter]. Eur Respir J. 2000;;15 ,.:626. [CrossRef] [PubMed]
 
Wechsler, ME, Garpestad, E, Flier, SR, et al Pulmonary infiltrates, eosinophilia, and cardiomyopathy following corticosteroid withdrawal in patients with asthma receiving zafirlukast.JAMA1998;279,455-457. [CrossRef] [PubMed]
 
Green, R, Vayonis, AG Churg-Strauss syndrome after zafirlukast in two patients not receiving systemic steroid treatment.Lancet1999;353,725-726. [CrossRef] [PubMed]
 
Knoell, DL, Lucas, J, Allen, JN Churg-Strauss syndrome associated with zafirlukast.Chest1998;114,332-334. [CrossRef] [PubMed]
 
Martin, RM, Wilton, LV, Mann, RD Prevalence of Churg-Strauss syndrome, vasculitis, eosinophilia and associated conditions: retrospective analysis of 58 prescription-event monitoring cohort studies.Pharmacoepidemiol Drug Saf1999;8,179-189. [CrossRef] [PubMed]
 
Wechsler, ME, Garpestad, E, Flier, SR, et al Pulmonary infiltrates, eosinophilia, and cardiomyopathy following corticosteroid withdrawal in patients with asthma receiving zafirlukast.JAMA1998;279,455-457. [CrossRef] [PubMed]
 
Wechsler, ME, Finn, D, Gunawardena, D, et al Churg-Strauss syndrome in patients receiving montelukast as treatment for asthma.Chest2000;117,708-713. [CrossRef] [PubMed]
 
Green, RL, Vayonis, AG Churg-Strauss syndrome after zafirlukast in two patients not receiving systemic steroid treatment [letter].Lancet1999;353,725-726. [CrossRef] [PubMed]
 
Villena, V, Hidalgo, R, Sotelo, MT, et al Montelukast and Churg-Strauss syndrome [letter]. Eur Respir J. 2000;;15 ,.:626. [CrossRef] [PubMed]
 
Lanham, JG, Elkon, KB, Pusey, CD, et al Systemic vasculitis with asthma and eosinophilia: a clinical approach to the Churg-Strauss syndrome.Medicine1983;63,65-81
 
Bili, A, Condemi, JJ, Bottone, SM, et al Seven cases of complete and incomplete forms of Churg-Strauss syndrome not related to leukotriene receptor antagonists.J Allergy Clin Immunol1999;104,1060-1065. [CrossRef] [PubMed]
 
Le Gall, C, Pham, S, Vignes, S, et al Inhaled corticosteroids and Churg-Strauss syndrome: a report of five cases.Eur Respir J2000;15,978-981. [CrossRef] [PubMed]
 
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