Correspondence
Hypereosinophilic Syndrome and Mepolizumab
N Engl J Med 2008; 358:2838-2840June 26, 2008
- Article
To the Editor:
Rothenberg and colleagues (March 20 issue)1 provide data on the use of mepolizumab, an anti–interleukin-5 monoclonal antibody, for corticosteroid sparing in patients with non–life-threatening hypereosinophilic syndrome who were negative for FIP1L1–PDGFRA. Although the corticosteroid dose and the eosinophil count were significantly lowered in patients in the mepolizumab group, as compared with those in the placebo group, the safety of corticosteroid tapering with mepolizumab was not clearly demonstrated. For example, in the mepolizumab group, dyspnea and asthma occurred in 16% and 5% of patients, respectively, and one patient died from cardiac arrest. Since cardiac involvement and pulmonary involvement represent major causes of mortality and morbidity2,3 in the hypereosinophilic syndrome, and since the authors note that some adverse events might have been due to prednisone withdrawal, what clinical elements differentiate such adverse events from disease progression and lack of efficacy of treatment?
3 ReferencesFederico Verzegnassi, M.D.
University Burlo Garofolo, 34100 Trieste, Italy
fverzegnassi@yahoo.com 1
Rothenberg ME ,Klion AD ,Roufosse FE , et al. Treatment of patients with the hypereosinophilic syndrome with mepolizumab. N Engl J Med 2008;358:1215-1228
Full Text | Web of Science | Medline2
Roufosse FE ,Goldman M ,Cogan E . Hypereosinophilic syndromes. Orphanet J Rare Dis 2007;2:37-37
CrossRef | Web of Science | Medline3
Ogbogu PU ,Rosing DR ,Horne MK III . Cardiovascular manifestations of hypereosinophilic syndromes. Immunol Allergy Clin North Am 2007;27:457-475
CrossRef | Web of Science | Medline
To the Editor:
Rothenberg et al. report the finding of a corticosteroid-sparing effect of mepolizumab in patients with the hypereosinophilic syndrome. Although this finding is encouraging, we question whether it can be taken to mean that mepolizumab would have a positive effect on end-organ involvement, an important end point, given the natural history of the hypereosinophilic syndrome, but one that was not assessed in this study. The authors chose the blood eosinophil count as a key secondary end point; however, using the blood eosinophil count as a surrogate for end-organ involvement is problematic. Although blood eosinophilia is the hallmark of the hypereosinophilic syndrome, the relationship between the absolute eosinophil count and tissue damage in this syndrome is inconsistent.1 Also the risk–benefit assessment of the corticosteroid-sparing effect needs to be placed in the context of the risk of mepolizumab treatment versus that of corticosteroid treatment, a comparison that has not been performed in patients with the hypereosinophilic syndrome. We hope that the encouraging results of this study, based on a surrogate end point, will lead to additional studies to investigate the effect of mepolizumab with respect to improvement of end-organ involvement in the hypereosinophilic syndrome.
1 ReferencesRobert M. Boucher, M.D., M.P.H.
Lydia Gilbert-McClain, M.D.
Badrul Chowdhury, M.D., Ph.D.
Food and Drug Administration, Silver Spring, MD 20993-0002
robert.boucher@fda. hhs. gov 1
Klion AD ,Bochner BS ,Gleich GJ , et al. Approaches to the treatment of hypereosinophilic syndromes: a workshop summary report. J Allergy Clin Immunol 2006;117:1292-1302
CrossRef | Web of Science | Medline
To the Editor:
One concern about the safety of mepolizumab use, beyond the safety of its use in a clinical trial, is the importance of ruling out occult parasitic infections, especially infection with Strongyloides stercoralis. Suppression of eosinophilia with corticosteroids causes life-threatening strongyloides hyperinfection.1 Whether anti–interleukin-5 therapy carries this same iatrogenic risk of death is unknown. One in eight Americans is foreign-born, and up to 75% of immigrants with asymptomatic eosinophilia have a parasitic infection.2 Seybolt et al. found that 12% of arriving refugees had eosinophilia, and although 71% had negative stool examinations for ova and parasites, 39% and 22% had serologic evidence of strongyloidiasis and schistosomiasis, respectively, when tested2; among Sudanese refugees, the rates were 46% and 44%.3 We have reported that practicing U.S. physicians and physicians-in-training have inadequate knowledge of strongyloidiasis, which places immigrants at iatrogenic risk.4 Since standard stool examination is notoriously insensitive for detecting strongyloides (<50% sensitivity), serologic screening or presumptive treatment is often necessary.4,5 Before the initiation of therapy for hypereosinophilia, all persons with previous exposure must be tested for parasites commonly causing chronic infections and eosinophilia, such as strongyloides, schistosoma, and filaria parasites.
5 ReferencesDavid R. Boulware, M.D., M.P.H.
William M. Stauffer, III, M.D., M.S.P.H.
Patricia F. Walker, M.D., D.T.M.&H.
University of Minnesota, Minneapolis, MN 55455
boulw001@umn.edu 1
Newberry AM ,Williams DN ,Stauffer WM ,Boulware DR ,Hendel-Paterson BR ,Walker PF . Strongyloides hyperinfection presenting as acute respiratory failure and gram-negative sepsis. Chest 2005;128:3681-3684
CrossRef | Web of Science | Medline2
Seybolt LM ,Christiansen D ,Barnett ED . Diagnostic evaluation of newly arrived asymptomatic refugees with eosinophilia. Clin Infect Dis 2006;42:363-367
CrossRef | Web of Science | Medline3
Posey DL ,Blackburn BG ,Weinberg M , et al. High prevalence and presumptive treatment of schistosomiasis and strongyloidiasis among African refugees. Clin Infect Dis 2007;45:1310-1315
CrossRef | Web of Science | Medline4
Boulware DR ,Stauffer WM III ,Hendel-Patterson BR , et al. Maltreatment of Strongyloides infection: case series and worldwide physicians-in-training survey. Am J Med 2007;120:545-551
CrossRef | Web of Science | Medline5
Loutfy MR ,Wilson M ,Keystone JS ,Kain KC . Serology and eosinophil count in the diagnosis and management of strongyloidiasis in a non-endemic area. Am J Trop Med Hyg 2002;66:749-752
Web of Science | Medline
Author/Editor Response
Verzegnassi inquires about clinical elements that differentiate adverse events from disease progression and lack of treatment efficacy. By design, our study selected patients with the hypereosinophilic syndrome whose condition was clinically stable with corticosteroid monotherapy. Although the clinical condition of our patients was stable, we could not definitively distinguish adverse events from disease progression. However, there were no differences in adverse events between the groups, and no serious adverse events were deemed to be related to mepolizumab therapy.
Boucher et al. are concerned that the effects of mepolizumab therapy on end-organ involvement were not presented as end points, and they stress the importance of assessing the risks and benefits of corticosteroid-sparing versus those of mepolizumab and corticosteroids. Our study was not designed to directly compare the risks of corticosteroids with those of mepolizumab. Notably, we found no differences in the prevalences of adverse effects between the mepolizumab group and the placebo group, and in response to the point made by Boucher et al. about tissue damage, we found no progression of tissue damage in patients receiving mepolizumab, despite reduced corticosteroid doses. We designed our study with patient safety as a primary factor, managing the care of patients to ensure their clinical stability. Other, open-label studies have shown clinical benefits of mepolizumab treatment in patients with the hypereosinophilic syndrome.1,2 Although eosinophil levels in given patients do not predict whether severe disease will develop,3 once end-organ damage occurs in patients with the hypereosinophilic syndrome, clinical manifestations are typically reflected by the blood eosinophil counts.
Boulware et al. recommend that all persons with potential exposures be tested for parasitic causes of eosinophilia before mepolizumab therapy is started. We fully concur. Central to the diagnosis of the hypereosinophilic syndrome is the exclusion of underlying helminthic infection. Although studies in eosinophil-deficient mice have not supported a requirement for eosinophils in protective immune responses to schistosomiasis4 and other parasitic infections, the role of eosinophils in the latency of infection, the capacity for sustained internal autoinfection, and the risk of disseminated hyperinfection with S. stercoralis are uncertain. Since corticosteroids, more than other immunosuppressive agents, confer a predisposition to hyperinfection,5 occult strongyloidiasis must be ruled out in any patient with eosinophilia before treatment for the hypereosinophilic syndrome is initiated. Given potential difficulties in diagnosing strongyloidiasis, we agree with the recommendation of serologic testing to help rule out occult infection with S. stercoralis before the initiation of corticosteroid therapy or other treatment approaches in patients with the hypereosinophilic syndrome.
5 ReferencesMarc E. Rothenberg, M.D., Ph.D.
Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229
rothenberg@cchmc.org Peter F. Weller, M.D.
Beth Israel Deaconess Medical Center, Boston, MA 02215Amy Klion, M.D.
National Institutes of Health, Bethesda, MD 208921
Plotz SG ,Simon HU ,Darsow U , et al. Use of an anti-interleukin-5 antibody in the hypereosinophilic syndrome with eosinophilic dermatitis. N Engl J Med 2003;349:2334-2339
Full Text | Web of Science | Medline2
Garrett JK ,Jameson SC ,Thomson B , et al. Anti-interleukin-5 (mepolizumab) therapy for hypereosinophilic syndromes. J Allergy Clin Immunol 2004;113:115-119
CrossRef | Web of Science | Medline3
Klion AD ,Bochner BS ,Gleich GJ , et al. Approaches to the treatment of hypereosinophilic syndromes: a workshop summary report. J Allergy Clin Immunol 2006;117:1292-1302
CrossRef | Web of Science | Medline4
Swartz JM ,Dyer KD ,Cheever AW , et al. Schistosoma mansoni infection in eosinophil lineage-ablated mice. Blood 2006;108:2420-2427
CrossRef | Web of Science | Medline5
Keiser PB ,Nutman TB . Strongyloides stercoralis in the immunocompromised population. Clin Microbiol Rev 2004;17:208-217
CrossRef | Web of Science | Medline
- Citing Articles (2)
Citing Articles
1
Yanhua Liang, Rosemarie E Seymour, John P Sundberg. (2011) Inhibition of NF-κB Signaling Retards Eosinophilic Dermatitis in SHARPIN-Deficient Mice. Journal of Investigative Dermatology 131:1, 141-149
CrossRef2
Bruce S. Bochner, Gerald J. Gleich. (2010) What targeting eosinophils has taught us about their role in diseases. Journal of Allergy and Clinical Immunology 126:1, 16-25
CrossRef
