Eosinophilic disorders represent a broad range of pathologic conditions that occur as a result of persistent blood eosinophilia and have the potential for end-organ damage.¹ The incidence and prevalence of all types of eosinophilic disorders is not well characterized.² The age-adjusted incidence rate of hypereosinophilic syndrome–a type of eosinophilic disorder–was approximately 0.4 cases per 1,000,000 according to the International Classification of Disease for Oncology (version 3), and coding of 9964/3, the Surveillance, Epidemiology and End Results (SEER) database from 2004 to 2015.¹

Eosinophils make up less than 5% of circulating white blood cells in healthy people, but eosinophilia or hypereosinophilia­ occurs when a higher than normal level of eosinophils are produced in the tissues or blood in the body.³ Elevated eosinophils may occur when a large number of cells are recruited by the immune system to a specific site in the body in response to allergic disorders, parasitic and fungal infections, autoimmune diseases, and other conditions.⁴ Resulting diseases and conditions are defined by organ dysfunction induced by activated eosinophils and include allergies, asthma, pneumonia, esophagitis, and others.^5,6

The abnormal growth, differentiation, and survival of eosinophils is caused by either an intrinsic defect of eosinophil-committed neoplastic progenitor cells due to PDGFR or FGFR1 mutations or overproduction of the cytokines IL-3 and IL-5, the key cytokines critical for stimulation of bone marrow production of eosinophils. Organ involvement in eosinophilic disorders is caused by the increased production and/or persistent accumulation of normal or neoplastic eosinophils and persistent activation of eosinophils. Eosinophilia can be secondary (reactive) to a variety of causes or primary hypereosinophilic syndromes after secondary causes have been ruled out based on defined characteristics.⁵

The first step to diagnosing eosinophilia leading to eosinophilic disorders is to exclude secondary (reactive) causes of eosinophilia. Secondary eosinophilia is cause by multiple factors like infections, allergy, drug reactions, pulmonary eosinophilic diseases, acute or chronic eosinophilic pneumonia, allergic bronchopulmonary aspergillosis, etc, which may require diagnostic evaluation by multiple sub-specialty consultants. Testing for secondary causes of eosinophilia are often guided by a patient’s travel history, presenting symptoms, and findings on physical examination. End-organ damage should be assessed. Specifically, lung involvement is evaluated using pulmonary function testing, bronchoscopy, and serologic tests.¹

Once any secondary causes are excluded, the workup should evaluate for primary (clonal) eosinophilia. Blood and/or bone marrow should be evaluated for serum B12 level, serum tryptase level, serum IgE level, FIPIPI-PDGFRA fusion by FISH or RT-PCR, T-cell receptor gene rearrangement by PCR, immunophenotyping, NGS myeloid gene panel, dysplasia and blast percentage, immunohistochemistry for CD117, tryptase and CD25 if serum tryptase is elevated, and standard karyotyping.¹

Treatment for eosinophilic disorders varies depending on the cause and the part of the body affected. Corticosteroids are often used if end organ damage is present.¹ Most people with hypereosinophilic syndrome require drug treatment with prednisone, hydroxyurea, or chemotherapy drugs.⁴

For patients with eosinophilic asthma, mepolizumab is shown to reduce eosinophil count and reduce exacerbation frequency when given in the stable state in both eosinophilic asthma and chronic obstructive pulmonary disease (COPD).⁷ The current ongoing phase 2/3 trial COPD-HELP compares mepolizumab 100 mg vs placebo in patients with eosinophilic COPD following hospital admission.⁸ Mepolizumab is FDA-approved for patients with idiopathic hypereosinophilic syndrome.

Imatinib is the definitive treatment for PDGFRA/B-rearranged neoplasms with eosinophilia and the FDA-recommended starting dose is 100 mg daily. This dose results in complete and durable hematologic and molecular remissions.

On May 20, 2022, the FDA approved Dupixent (dupilumab), an IL-4 receptor antibody, as the first treatment for eosinophilic esophagitis (EoE) in individuals aged 12 years or older who weigh at least 40 kilograms.⁹ In adults and adolescent patients with EoE, common symptoms include difficulty swallowing, difficulty eating, and food getting stuck in the esophagus.¹⁰ Dupilumab is a monoclonal antibody that acts to inhibit part of the inflammatory pathway.¹¹ This medication has previously been approved in 2017 for the treatment of moderate to severe atopic dermatitis, and as an add-on maintenance treatment for certain types of moderate to severe asthma and poorly controlled chronic rhinosinusitis with nasal polyposis.⁹

Current treatments for primary eosinophilia evokes a beneficial clinical response, but treatment is often short-lived and results in long-term side effects. Future treatments may involve the JAK1/2 inhibitor ruxolitinib (and other JAK inhibitors). In fact, phase 2 clinical trials of ruxolitinib in hypereosinophilic syndrome and eosinophilic neoplasms are currently enrolling patients.^1,12,13 Several antibodies are being studied to reduce eosinophils and symptoms. Notably, the IL-5 receptor antibody benralizumab is being studied in various eosinophilic disorders.¹

The diagnosis and management of eosinophilic disorders requires a multidisciplinary approach and is complex, costly, and time-consuming. Allergists, hematologists, pathologists, pulmonologists, immunologists, and infectious disease specialists are often involved in eosinophilic disorder management. Such a complex clinical picture causes difficulties in evaluation of eosinophilic syndromes clinically, which results in potentially severe disease outcomes.⁵

The pathophysiologic mechanisms of eosinophilic disorders are well characterized. Nevertheless, eosinophilic disorders are a very heterogeneous group of diseases and confusing terminology and diagnosis gaps makes some aspects of diagnosis and treatments unclear. In addition, there is a need for harmonization of terminology and classification of eosinophilic disorders along with specialized centers with multidisciplinary teams for diagnosis and management.⁵

However, the better understanding of the cellular and molecular bases of eosinophilic disorders has allowed for new therapeutic options, such as imatinib, that have reversed the poor prognosis of patients previously diagnosed as hypereosinophilic syndrome. In addition, this better understanding has allowed for more personalized treatment approaches including corticosteroids, IFN-α, hydroxyurea, and other chemotherapy and targeted antibodies. These therapies elicit benefit in eosinophilia but have short-lived responses and long-term side effects.¹ Since current therapeutic method success is often short-lived, new therapies should include more targeted molecules for the improved prognosis of eosinophilic disorders.⁵ Because of the risk of organ damage in patients with hypereosinophilic syndrome, treatment must be initiated in a timely manner.

1. Shomali W, Gotlib J. World Health Organization-defined eosinophilic disorders: 2022 update on diagnosis, risk stratification, and management. Am J Hematol. 2022;97(1):129-148. doi:10.1002/ajh.26352

2. Simon D, Simon HU. Eosinophilic disorders. J Allergy Clin Immunol. 2007;119(6):1291-1300. doi:10.1016/j.jaci.2007.02.010

3. American Partnership for Eosinophilic Disorders. What is an eosinophil-associated disease? Accessed March 14, 2022. https://apfed.org/about-ead/what-is-an-eosinophil-associated-disease/

4. Merck Manuals. Eosinophilic Disorders - Blood Disorders. Accessed March 14, 2022. https://www.merckmanuals.com/home/blood-disorders/white-blood-cell-disorders/eosinophilic-disorders

5. Leru PM. Eosinophilic disorders: evaluation of current classification and diagnostic criteria, proposal of a practical diagnostic algorithm. Clin Transl Allergy. 2019;9(1):1-9. doi:10.1186/s13601-019-0277-4

6. Mayo Clinic. Eosinophilia Causes. Accessed March 14, 2022. https://www.mayoclinic.org/symptoms/eosinophilia/basics/causes/sym-20050752 

7. Papi A, Ryan D, Soriano JB, et al. Relationship of inhaled corticosteroid adherence to asthma Eeacerbations in patients with moderate-to-severe asthma. J Allergy Clin Immunol Pract. 2018;6(6):1989-1998.e3. doi:10.1016/j.jaip.2018.03.008

8. A Randomised Controlled Trial of Mepolizumab Initiated Following Admission to Hospital for a Severe Exacerbation of Eosinophilic COPD. Clinicaltrials.gov . Published August 30, 2019. Updated January 31, 2022. Accessed March 13, 2022. Clinicaltrials.gov identifier: NCT04075331. https://clinicaltrials.gov/ct2/show/NCT04075331

9. FDA approves first treatment for eosinophilic esophagitis, a chronic immune disorder. News release. US Food and Drug Administration; May 20, 2022. https://www.fda.gov/news-events/press-announcements/fda-approves-first-treatment-eosinophilic-esophagitis-chronic-immune-disorder

10. Merck Manuals. Eosinophilic Esophagitis. Updated March 2022. Accessed March 24, 2022. https://www.merckmanuals.com/home/digestive-disorders/esophageal-and-swallowing-disorders/eosinophilic-esophagitis

11. Study to Determine the Efficacy and Safety of Dupilumab in Adult and Adolescent Patients With Eosinophilic Esophagitis (EoE). Clinicaltrials.gov. Published August 16, 2018. Updated April 28, 2022. Accessed May 24, 2022. Clinicaltrials.gov identifier: NCT03633617. https://clinicaltrials.gov/ct2/show/NCT03633617

12. Phase 2 Study of Ruxolitinib in Idiopathic Hypereosinophilic Syndrome and Primary Eosinophilic Disorders. Clinicaltrials.gov. Published January 11, 2019. Updated November 19, 2021. Accessed March 13, 2022. Clinicaltrials.gov identifier: NCT03801434.  https://clinicaltrials.gov/ct2/show/NCT03801434

13. Efficacy of Tyrosine Kinase Inhibition in Reducing Eosinophilia in Patients With Myeloid and/or Steroid-Refractory Hypereosinophilic Syndrome. Clinicaltrials.gov. Published August 26, 2002. Updated March 16, 2022. Accessed March 13, 2022. Clinicaltrials.gov identifier: NCT00044304. https://clinicaltrials.gov/ct2/show/NCT00044304