Challenging assumptions about the demographics of eosinophilic gastrointestinal diseases: A systematic review.

Background: The demographic characteristics of patients with eosinophilic gastrointestinal diseases (EGIDs) are poorly understood. Population-based assessments of EGID demographics may indicate health disparities in diagnosis. Objectives: We aimed to characterize the demographic distribution of EGIDs and evaluate the potential for bias in reporting patient characteristics. Methods: We conducted a systematic review, extracting data on age, sex, gender, race, ethnicity, body mass index, insurance, and urban/rural residence on EGID patients and the source population. Differences in proportions were assessed by chi-square tests. Demographic reporting was compared to recent guidelines. Results: Among 50 studies that met inclusion/exclusion criteria, 12 reported ≥1 demographic feature in both EGID and source populations. Except for age and sex or gender, demographics were rarely described (race = 4, ethnicity = 1, insurance = 1) or were not described (body mass index, urban/rural residence). A higher proportion of male subjects was observed for EoE or esophageal eosinophilia relative to the source population, but no difference in gender or sex distribution was observed for other EGIDs. "Sex" and "gender" were used interchangeably, and frequently only the male proportion was reported. Reporting of race and ethnicity was inconsistent with guidelines. Conclusion: Current data support a male predominance for EoE only. Evidence was insufficient to support enrichment of EGIDs in any particular racial, ethnic, or other demographic group. Population-based studies presenting demographics on both cases and source populations are needed. Implementation of guidelines for more inclusive reporting of demographic characteristics is crucial to prevent disparities in timely diagnosis and management of patients with EGIDs.

Biologic Therapy in Rare Eosinophil-Associated Disorders: Remaining Questions and Translational Research Opportunities.

Rare eosinophil-associated disorders (EADs), including hypereosinophilic syndrome, eosinophilic granulomatosis with polyangiitis and eosinophilic gastrointestinal disorders, are a heterogeneous group of conditions characterized by blood and/or tissue hypereosinophilia and eosinophil-related clinical manifestations. Although the recent availability of biologic therapies that directly and indirectly target eosinophils has the potential to dramatically improve treatment options for all EADs, clinical trials addressing their safety and efficacy in rare EADs have been relatively few. Consequently, patient access to therapy is limited for many biologics, and the establishment of evidence-based treatment guidelines has been extremely difficult. In this regard, multicenter retrospective collaborative studies focusing on disease manifestations and treatment responses in rare EADs have provided invaluable data for physicians managing patients with these conditions and helped identify important questions for future translational research. During the Clinical Pre-Meeting Workshop held in association with the July 2023 biennial meeting of the International Eosinophil Society in Hamilton, Ontario, Canada, the successes and limitations of pivotal multicenter retrospective studies in EADs were summarized, and unmet needs regarding the establishment of guidelines for use of biologics in rare EADs were discussed. Key topics of interest included: 1) clinical outcome measures, 2) minimally invasive biomarkers of disease activity, 3) predictors of response to biologic agents, and 4) long-term safety of eosinophil depletion. Herein, we report a summary of these discussions, presenting a state-of-the-art overview of data currently available for each of these topics, the limitations of the data, and avenues for future data generation through implementation of multidisciplinary and multicenter studies.

Mepolizumab incompletely suppresses clinical flares in a pilot study of episodic angioedema with eosinophilia.

BACKGROUND: Episodic angioedema with eosinophilia (EAE) is a rare multilineage cyclic syndrome of unknown etiology characterized by episodes of angioedema, myalgia, fatigue, and fever that occur every 3 to 8 weeks and resolve between episodes without therapy. Cyclic elevations in serum IL-5 levels and neutrophils precede the increase in absolute eosinophil count (AEC) in most patients. OBJECTIVE: We sought to assess the role of IL-5-driven eosinophilia in the clinical manifestations of EAE. METHODS: An open-label pilot study of mepolizumab (700 mg intravenously monthly for 3 months followed by sequential dose reduction to the Food and Drug Administration-approved dose of 300 mg subcutaneously monthly) was conducted. The primary end point was reduction in the number and severity of clinical symptoms as assessed by patient-reported symptom questionnaires. Secondary end points were greater than or equal to 75% reduction in peak AEC after 1 dose of mepolizumab and sustained reduction in AEC after 3 doses of mepolizumab. Exploratory end points included effects of mepolizumab treatment on other cell lineages (numbers and surface marker expression), levels of plasma mediators, and biomarkers of eosinophil activation. RESULTS: Four female and 1 male (median age, 45 years) participants with EAE were enrolled. None of the 5 participants experienced a reduction in the number of symptomatic flares on mepolizumab therapy, and 1 participant withdrew before study completion because of lack of improvement. Peak AEC was reduced by 75% or more in 3 participants after the first dose of mepolizumab and in 4 participants after 3 doses. CONCLUSIONS: In a small cohort of participants with EAE, mepolizumab was unsuccessful in substantially reducing clinical symptoms despite reduction in AEC.

Barriers to Timely Diagnosis of Eosinophilic Gastrointestinal Diseases.

Although eosinophilic gastrointestinal diseases, including eosinophilic esophagitis, have been described over the past 2 to 3 decades, barriers to diagnosis and treatment are common and compounded by issues related to social determinants of health, race, ethnicity, and access to care. These barriers contribute to delays in diagnosis, resulting in persistent inflammation in the gastrointestinal tract, which can have significant consequences, including fibrostenotic complications in adults, failure to thrive in children, and decreased quality of life in all affected patients. In this commentary, we summarize gaps in knowledge regarding the epidemiology of eosinophilic gastrointestinal diseases, highlight barriers to diagnosis, discuss potential approaches based on best practices in other atopic and chronic gastrointestinal diseases, and provide recommendations for reducing barriers to timely diagnosis of eosinophilic gastrointestinal diseases in underserved populations.

Distinct CRTH2+CD161+ (peTh2) memory CD4+ T-cell cytokine profiles in food allergy and eosinophilic gastrointestinal disorders.

INTRODUCTION: Although IgE-mediated food allergy (FA) and eosinophilic gastrointestinal disorders (EGID) are clinically distinct and treated differently, pathogenic effector Th2 (peTh2) cells are implicated in the pathogenesis of both FA and EGID. The aim of this study was to better characterize peTh2 cells in the context of FA and EGID and the overlap between these two conditions. METHODS: Peripheral blood peTh2 cells (CD3+CD4+CD27-CD49d+CRTH2+CD161+) were profiled by intracellular cytokine flow cytometry in the following patient cohorts: patients with FA alone (n = 8), FA and food-triggered EGID (EGID+FA+FT, n = 7), food-triggered EGID alone (EGID+FT, n = 7), EGID without FA or specific food triggers (ONLY_EGID, n = 9), and healthy volunteers (HV, n = 7). Overnight peripheral blood mononuclear cell (PBMC) culture supernatants were assessed for cytokine production by multiplex analysis. RESULTS: CRTH2+CD161+ (peTh2) memory CD4+ T cells were significantly increased in both patients with FA and those with ALL_EGID (inclusive of EGID+FA+FT, EGID+FT and ONLY_EGID) when compared to HV. However, ALL_EGID patients, particularly those with EGID+FA+FT, had significantly elevated IL-5+IL-13+ peTh2 cells, whereas FA patients had significantly elevated IFN-γ or IL-17A-expressing peTh2 cells. This finding was supported by increased spontaneous IL-5 and IL-13 production in overnight cultures of PBMC from EGID+FA+FT patients compared to spontaneous IL-10 and IFN-γ production by PBMC from FA patients. FA patients had increased IL-9, IL-10, IL-17A, and IFN-γ production in overnight cultures of stimulated PBMC. CONCLUSIONS: EGID and IgE-mediated FA share a common cell subtype defined by specific surface markers and termed CRTH2+CD161+ (peTh2) memory CD4+ T cells. However, the cytokine profiles of these CRTH2+CD161+ (peTh2) memory CD4+ T cells are markedly different between the two disorders.

Biologics and Hypereosinophilic Syndromes: Knowledge Gaps and Controversies.

Hypereosinophilic syndromes (HES) are a heterogeneous group of disorders defined by blood and/or tissue hypereosinophilia and clinical manifestations attributable to the eosinophilia. Although various clinical subtypes of HES have been described, the general approach to therapy in all subtypes has focused on the reduction of blood and tissue eosinophilia to improve symptoms and halt disease progression. Until recently, this typically involved the use of corticosteroids and/or other immunosuppressive or cytotoxic drugs with significant toxicity. Whereas imatinib, the first targeted therapy approved for treatment of HES, has dramatically changed the prognosis of patients with primary (myeloid) forms of HES, it is ineffective in patients with other HES subtypes. For these nonmyeloid patients with HES, the development of eosinophil-targeting biologics (most notably, mepolizumab, the first biologic approved for the treatment of HES) has been transformative. Nevertheless, important issues remain with respect to the efficacy and safety of these biologics in the treatment of the varied subtypes of HES. Moreover, with the increasing number of commercially available biologics with direct or indirect effects on eosinophils, questions related to the choice of initial biologic, potential reasons for biologic failure, and treatment options in the setting of incomplete response are becoming increasingly common.

False-Negative Testing for FIP1L1::PDGFRA by Fluorescence in situ Hybridization Is a Frequent Cause of Diagnostic Delay.

The imatinib-sensitive fusion gene FIP1L1::PDGFRA is the most frequent molecular abnormality identified in patients with eosinophilic myeloid neoplasms. Rapid recognition of this mutation is essential given the poor prognosis of PDGFRA-associated myeloid neoplasms prior to the availability of imatinib therapy. We report a case of a patient in whom delayed diagnosis resulted in cardiac transplantation for eosinophilic endomyocardial fibrosis. The delay in diagnosis was due, in part, to a false-negative result in fluorescence in situ hybridization (FISH) testing for FIP1L1::PDGFRA. To explore this further, we examined our cohort of patients presenting with confirmed or suspected eosinophilic myeloid neoplasms and found 8 additional patients with negative FISH results despite a positive reverse-transcriptase polymerase chain reaction test for FIP1L1::PDGFRA. More importantly, false-negative FISH results delayed the median time to imatinib treatment by 257 days. These data emphasize the importance of empiric imatinib therapy in patients with clinical features suggestive of PDGFRA-associated disease.

Benralizumab for eosinophilic gastritis: a single-site, randomised, double-blind, placebo-controlled, phase 2 trial.

BACKGROUND: In eosinophilic gastrointestinal diseases, the role of eosinophils in disease pathogenesis and the effect of eosinophil depletion on patient outcomes are unclear. Benralizumab, an eosinophil-depleting monoclonal antibody that targets the interleukin-5 receptor α, might eliminate gastric tissue eosinophils and improve outcomes in eosinophilic gastritis. We aimed to assess the efficacy and safety of benralizumab in patients with eosinophilic gastritis. METHODS: We conducted a single-site, randomised, double-blind, placebo-controlled, phase 2 trial at Cincinnati Children's Hospital Medical Center (Cincinnati, OH, USA). Individuals aged 12-60 years with symptomatic, histologically active eosinophilic gastritis (peak gastric eosinophil count ≥30 eosinophils per high-power field [eos/hpf] in at least five hpfs) and blood eosinophilia (>500 eosinophils per µL [eos/µL]) were randomly assigned (1:1, block size of four) to benralizumab 30 mg or placebo, stratified by the use of glucocorticoids for gastric disease. Investigators, study staff, and study participants were masked to treatment assignment; statisticians were unmasked when analysing data. Treatments were administered subcutaneously once every 4 weeks for a 12-week double-blind period (three total injections). The primary endpoint was the proportion of patients who achieved histological remission (peak gastric eosinophil count <30 eos/hpf) at week 12. Key secondary endpoints were the changes from baseline to week 12 in peak gastric eosinophil count, blood eosinophil count, eosinophilic gastritis histology (total, inflammatory, and structural feature scores), Eosinophilic Gastritis Endoscopic Reference System (EG-REFS) score, and patient-reported outcome symptom measures (Severity of Dyspepsia Assessment [SODA] and Patient-Reported Outcome Measurement Information System [PROMIS] short-form questionnaire). After the 12-week double-blind period, patients were eligible for entry into two open-label extension (OLE) periods up to week 88, in which all patients received benralizumab. Efficacy was analysed in the intention-to-treat (ITT) population and safety was assessed in all patients who received at least one dose of study drug. The trial was registered on ClinicalTrials.gov, NCT03473977, and is completed. FINDINGS: Between April 23, 2018, and Jan 13, 2020, 34 patients were screened, and 26 were subsequently randomly assigned to benralizumab (n=13) or placebo (n=13) and included in the ITT and safety populations (mean age 19·5 years [SD 7·3]; 19 [73%] male patients and seven [27%] female patients). At week 12, ten (77% [95% CI 50 to 92]) of 13 patients who received benralizumab and one (8% [1 to 33]) of 13 who received placebo achieved histological remission (difference 69 percentage points [95% CI 32 to 85]; p=0·0010). Changes from baseline to week 12 were significantly greater in the benralizumab group versus the placebo group for peak gastric eosinophil counts (mean -137 eos/hpf [95% CI -186 to -88] vs -38 eos/hpf [-94 to 18]; p=0·0080), eosinophilic gastritis histology total score (mean -0·31 [-0·42 to -0·20] vs -0·02 [-0·16 to 0·12]; p=0·0016), histology inflammatory score (mean -0·46 [-0·60 to -0·31] vs -0·04 [-0·22 to 0·13]; p=0·0006), and blood eosinophil counts (median -1060 eos/µL [IQR -1740 to -830] vs -160 eos/µL [-710 to 120]; p=0·0044). Changes were not significantly different between the groups for eosinophilic gastritis histology structural score (mean -0·07 [95% CI -0·19 to 0·05] vs 0·03 [-0·09 to 0·15]; p=0·23), EG-REFS score (mean -1·0 [-2·3 to 0·3] vs -0·5 [-2·0 to 1·0]; p=0·62), or in patient-reported outcomes (SODA and PROMIS). During the double-blind period, treatment-emergent adverse events occurred in 11 (85%) of 13 patients in the benralizumab group and six (46%) of 13 in the placebo group; the most common treatment-emergent adverse events were headache (six [46%] vs two [15%] patients), nausea (three [23%] vs two [15%]), and vomiting (two [15%] vs three [23%]). There were no treatment-related deaths. Two patients had serious adverse events (dizziness and rhabdomyolysis in one patient; aspiration in one patient) during the OLE periods, which were considered unrelated to study treatment. INTERPRETATION: Benralizumab treatment induced histological remission, as defined by absence of tissue eosinophilia, in most patients with eosinophilic gastritis. However, the persistence of histological, endoscopic, and other features of the disease suggest a co-existing, eosinophil-independent pathogenic mechanism and the need for broader targeting of type 2 immunity. FUNDING: AstraZeneca and the Division of Intramural Research (National Institute of Allergy and Infectious Diseases, US National Institutes of Health).

Urine eosinophil-derived neurotoxin: A potential marker of activity in select eosinophilic disorders.

BACKGROUND: Biomarkers of eosinophilic disease activity, especially in the context of novel therapies that reduce blood eosinophil counts, are an unmet need. Absolute eosinophil count (AEC) does not accurately reflect tissue eosinophilia or eosinophil activation. Therefore, the aims of this study were to compare the reliability of plasma and urine eosinophil major basic protein 1, eosinophil cationic protein, eosinophil-derived neurotoxin (EDN), and eosinophil peroxidase measurement and to evaluate the usefulness of eosinophil granule protein (EGP) measurement for the assessment of disease activity in patients with eosinophil-associated diseases treated with mepolizumab, benralizumab, or dexpramipexole. METHODS: Eosinophil granule protein concentrations were measured in serum, plasma, and urine from healthy volunteers and patients with hypereosinophilic syndrome (HES), eosinophilic granulomatosis with polyangiitis (EGPA), and eosinophilic asthma using a multiplex assay. RESULTS: Urine EGP concentrations remained stable, whereas serum and plasma EGP concentrations increased significantly with delayed processing. Plasma (p) EDN, but not urine (u) EDN, concentration correlated with AEC and negatively correlated with prednisone dose. Both pEDN and uEDN decreased significantly following treatment of HES patients with benralizumab and EGPA patients with mepolizumab. uEDN appeared to increase with clinical relapse in both patient groups. CONCLUSIONS: Measurement of EGP in urine is noninvasive and unaffected by cellular lysis. Although plasma and urine EDN concentrations showed a similar pattern following benralizumab and mepolizumab treatment, the lack of correlation between AEC or prednisone dose and uEDN concentrations suggests that measurement of uEDN may provide a potential biomarker of disease activity in patients with HES and EGPA.

Proposed refined diagnostic criteria and classification of eosinophil disorders and related syndromes.

Eosinophilia and eosinophil activation are recurrent features in various reactive states and certain hematologic malignancies. In patients with hypereosinophilia (HE), HE-induced organ damage is often encountered and may lead to the diagnosis of a hypereosinophilic syndrome (HES). A number of known mechanisms and etiologies contribute to the development of HE and HES. Based on these etiologies and the origin of eosinophils, HE and HES are divided into primary forms where eosinophils are clonal cells, reactive forms where an underlying reactive or neoplastic condition is detected and eosinophils are considered to be "non-clonal" cells, and idiopathic HE and HES in which neither a clonal nor a reactive underlying pathology is detected. Since 2012, this classification and the related criteria have been widely accepted and regarded as standard. However, during the past few years, new developments in the field and an increasing number of markers and targets have created a need to update these criteria and the classification of HE and HES. To address this challenge, a Working Conference on eosinophil disorders was organized in 2021. In this conference, a panel of experts representing the relevant fields, including allergy, dermatology, hematology, immunology, laboratory medicine, and pathology, met and discussed new markers and concepts as well as refinements in definitions, criteria and classifications of HE and HES. The outcomes of this conference are presented in this article and should assist in the diagnosis and management of patients with HE and HES in daily practice and in the preparation and conduct of clinical trials.

Approach to the patient with suspected hypereosinophilic syndrome.

Hypereosinophilic syndromes (HES) are a heterogenous group of rare disorders with clinical manifestations ranging from fatigue to life-threatening endomyocardial fibrosis and thromboembolic events. Given the broad differential diagnosis of HES, a comprehensive approach is needed to identify potential secondary (treatable) causes and define end-organ manifestations. Classification by clinical HES subtype is also useful in terms of assessing prognosis and guiding therapy. Corticosteroids remain the mainstay of initial therapy in the setting of acute, life-threatening PDGFR mutation-negative HES. Whereas the recent availability of eosinophil-targeted therapies with extraordinary efficacy and little apparent toxicity is changing the treatment paradigm, especially for idiopathic HES and overlap syndromes, questions remain unanswered regarding the choice of agent, impact of combination therapies, and long-term effects of eosinophil depletion. This review provides a case-based discussion of the differential diagnosis of HES, including the classification by clinical HES subtype. Treatment options are reviewed, including novel eosinophil-targeted agents recently approved for the treatment of HES and/or other eosinophil-associated disorders. Primary (myeloid) disorders associated with hypereosinophilia are not be addressed in depth in this review.

Recent advances in understanding the role of eosinophils.

Our understanding of eosinophil biology, development, and regulation has dramatically increased in the past decade, leading to new paradigms for the role of eosinophils in human health and disease and, perhaps more importantly, providing insights toward novel treatment strategies in the fight against eosinophil-mediated inflammation. In this review, we discuss recent advances regarding the role of eosinophils in host-viral defense, eosinophil heterogeneity, and eosinophil-targeted therapies.

No evidence of lymphatic filariasis transmission in Bamako urban setting after three mass drug administration rounds.

Lymphatic filariasis (LF) elimination activities started in Mali in 2005 in the most endemic areas and reached countrywide coverage in 2009. In 2004, the district of Bamako was endemic for LF with a prevalence of 1.5%. The current study was designed to determine LF endemicity level in the urban area of Bamako after three rounds of ivermectin and albendazole mass drug administration (MDA). A cross-sectional study was conducted in 2011 in Bamako city, consisting of human prevalence and entomological surveys. Volunteers aged 14 years and above were invited to participate and tested for evidence of Wuchereria bancrofti using night time blood thick smear microfilarial count and blood spots for LF antibodies using the SD BIOLINE Oncho/LF IgG4 Biplex rapid test (Ov16/Wb123). Mosquitoes were collected using CDC light and gravid traps and tested using molecular methods. Poolscreen software v2.0 was used to estimate vector transmission potential. Of the 899 volunteers, one (0.11%) was found to be positive for LF using the Oncho/LF IgG4 Biplex rapid test, and none was found to have Wuchereria bancrofti microfilariae. No mosquitoes were found infected among 6174 Culex spp. (85.2%), 16 Anopheles gambiae s.l. (An. gambiae s.l.) (0.2%), 26 Aedes spp. (0.4%), 858 Ceratopogonidae (11.8%) and 170 other insects not identified (2.3%) tested. Our data indicate that there was no active LF transmission in the low prevalence urban district of Bamako after three MDA rounds. These data helped the National LF programme move forward towards the elimination goal.

Changes in Onchocerciasis Ov16 IgG4 Rapid Diagnostic Test Results Over One-Month Follow-up: Lessons for Reading Timeframe and Decision-Making.

The SD Bioline® IgG4 rapid diagnostic test (RDT) detects IgG4 antibodies induced by the Onchocerca volvulus-specific antigen Ov16. We evaluated the stability of the RDT results over 1 month, at different time points after completion of each assay, using eluted dried blood spots collected in central Cameroon. Agreement coefficients regarding positivity between 30 minutes and 24 hours, 1, 2, 3, and 4 weeks were, 96.4%, 93.4%, 93.3%, 93.2%, and 93.2%, respectively. Between 30 minutes and 24 hours, 3.6% of the 15,444 tests showed inconsistent results with 81.2% of these tests changing from negative to positive, increasing O. volvulus antibody prevalence from 23.9% to 26.2% (P < 0.0001). This change from negative to positive outcome was confirmed at the subsequent timepoints. Depending on the desired accuracy of prevalence estimates, reading time may have to be redefined more strictly.

Rapid GPR183-mediated recruitment of eosinophils to the lung after Mycobacterium tuberculosis infection.

Influx of eosinophils into the lungs is typically associated with type II responses during allergy and fungal and parasitic infections. However, we previously reported that eosinophils accumulate in lung lesions during type I inflammatory responses to Mycobacterium tuberculosis (Mtb) in humans, macaques, and mice, in which they support host resistance. Here we show eosinophils migrate into the lungs of macaques and mice as early as one week after Mtb exposure. In mice this influx is CCR3 independent and instead requires cell-intrinsic expression of the oxysterol receptor GPR183, which is highly expressed on human and macaque eosinophils. Murine eosinophils interact directly with bacilli-laden alveolar macrophages, which upregulate the oxysterol-synthesizing enzyme Ch25h, and eosinophil recruitment is impaired in Ch25h-deficient mice. Our findings show that eosinophils are among the earliest cells from circulation to sense and respond to Mtb infection of alveolar macrophages and reveal a role for GPR183 in the migration of eosinophils into lung tissue.

Effect of Dupilumab on Blood Eosinophil Counts in Patients With Asthma, Chronic Rhinosinusitis With Nasal Polyps, Atopic Dermatitis, or Eosinophilic Esophagitis.

BACKGROUND: Transient increases in blood eosinophil counts have been observed in dupilumab clinical trials. OBJECTIVE: To assess eosinophil counts and eosinophilia-related treatment-emergent adverse events (TEAEs) across 11 dupilumab clinical trials, comparing adult and adolescent patients with asthma and adult patients with chronic rhinosinusitis with nasal polyps (CRSwNP), atopic dermatitis, and eosinophilic esophagitis. METHODS: Eosinophil counts, rates of eosinophilia-related TEAEs or treatment-emergent eosinophilia (>1,500 cells/µL), discontinuations, clinical symptoms, and efficacy in patients with asthma or CRSwNP with treatment-emergent eosinophilia are presented. RESULTS: Transient increases in mean eosinophil counts were observed in dupilumab-treated patients with asthma (mean range across studies at baseline: 349-370 cells/µL; week 4: 515-578 cells/µL), CRSwNP (baseline: 440-448 cells/µL; week 16: 595 cells/µL), and atopic dermatitis (baseline: 434-600 cells/µL; week 4: 410-710 cells/µL), followed by a decline starting by week 24 to baseline or lower. No increases were seen in patients with eosinophilic esophagitis (baseline: 310 cells/µL; week 4: 230 cells/µL). In dupilumab-treated patients across all studies, rates of eosinophilia TEAEs were 0% to 13.6%. Clinical symptoms associated with increased eosinophils were rare (seven of 4,666 dupilumab-treated patients, including six cases of eosinophilic granulomatosis with polyangiitis) and occurred only in patients with asthma or CRSwNP. Eosinophilia was not associated with reduced dupilumab efficacy. CONCLUSIONS: Transient increases in eosinophil counts with dupilumab treatment did not affect efficacy and were rarely of clinical consequence. It remains important for physicians to base judgment on individual patient history and baseline eosinophil counts and to be alert to hypereosinophilic symptoms.