Activation and Function of Eosinophils in Conditions With Blood or Tissue Eosinophilia

• ClinicalTrials.gov Identifier: NCT00001406
• Recruitment Status: Recruiting
• First Posted: November 4, 1999
• Last Update Posted: December 14, 2020
• Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
• Information provided by (Responsible Party): National Institutes of Health Clinical Center (CC) ( National Institute of Allergy and Infectious Diseases (NIAID) )

Study Description

Brief Summary:

This study will investigate how, why and under what conditions eosinophils (a type of white blood cell) become activated and will examine their function in immune reactions. Eosinophil counts often rise in response to allergies, asthma, and parasitic worm infections. They can also go up in uncommon autoimmune conditions and, rarely, in association with tumors. Elevated levels of these cells is called eosinophilia. Usually, eosinophilia causes no apparent symptoms, but in rare cases there may be local swelling and itching, allergic lung problems, heart disease or nerve damage caused by the release of toxic substances in these cells into body tissues.

Patients 1 to 100 years of age with eosinophil counts greater than 750/ml or an abnormal accumulation of eosinophils in the skin or body tissues may be eligible for this study. All participants will have a thorough medical history, physical examination and blood tests. Depending on the person's age and symptoms, other diagnostic tests may be done, including specialized studies of the eye, lungs, skin, bone marrow, nerves or heart. This is not a treatment study, and no experimental treatments will be offered. Patients who require treatment will receive standard medical care.

Certain other procedures may be requested solely for research purposes. All participants will be asked to donate extra blood for laboratory studies investigating how immune cells and other immune substances in the blood act to stimulate a rise in eosinophils. In addition, some participants may undergo one or more of the following:

• Annual Follow-up evaluations - Physical examinations and blood tests to evaluate changes in the patient's condition and eosinophil counts over time.
• Bone marrow biopsy and aspiration will be recommended during the initial evaluation, and in certain patients at other times when it is important to look directly at the newly developing cells in the bone marrow. For this procedure an area of skin and bone is anesthetized with xylocaine (an anesthetic similar to that used by dentists), and a very sharp needle is used to sample the bone marrow for evaluation. Bone marrow biopsy and aspiration can have side effects of pain and/or bleeding into the skin and soft tissues at the site of the procedure. Rarely the area at the biopsy site can become infected, and is treated with antibiotics.
• Genetic testing: Some of the blood drawn from you as part of this study will be used for genetic tests. Genetic tests can help researchers study how health or illness is passed on to you by your parents or from you to your children. Any genetic information collected or discovered about you or your family will be confidential.
• Leukapheresis (only patients 18 years and older) to collect large numbers of certain cells - In this procedure, whole blood is collected through a needle placed in an arm vein. The blood circulates through a machine that separates it into its components. The white cells are then removed and the rest of the blood is returned to the body, either through the same needle used to draw the blood or through a second needle placed in the other arm.

Condition or disease
Immune System Diseases; Eosinophilia; Helminthiasis; Hypersensitivity; Parasitic Disease

Detailed Description:

Subjects admitted on this protocol will have elevated eosinophil counts in the peripheral blood or tissues or will be relatives of subjects with eosinophilia. Eosinophilic subjects will undergo an extensive clinical evaluation focused on the identification of the cause of eosinophilia and the presence of end organ manifestations. In addition, they will be characterized in detail immunologically, and their blood cells and/or serum will be collected to provide reagents (e.g., specific antibodies, T-cell clones, etc.) that will be used in the laboratory to address broader questions relating to the etiology of eosinophilia, its immunoregulation, the degree and source of eosinophil activation, and/or the functional role of eosinophils in the afferent arm of those immune response where they are prominent. While the protocol is not primarily designed to study treatment of patients with blood and tissue eosinophilia, the clinical and immunological responses to various medically indicated therapies will be carefully monitored. The subjects themselves will be followed over time to determine the kinetics and nature of the factors affecting their degree of eosinophilia and the level of activation or degranulation of the eosinophils at various time points and in response to various stimuli. It is anticipated that the subjects will receive a degree of clinical evaluation, care and monitoring more extensive than that generally available and that the specimens collected from them will prove to be valuable reagents for laboratory studies related to eosinophilia, eosinophil activation and function. Recognized causes of subjects hypereosinophilia will be treated appropriately either by our own clinical service or by the referring physicians. Standard of care therapy may be provided when indicated for HES variants. This protocol will also allow clinical and laboratory evaluation of family members of subjects with eosinophilia in order to help identify genetic causes of eosinophilia and to provide controls for immunologic studies. A subset of HES patients will be interviewed and/or asked to fill out questionnaires to provide information about patient signs and symptoms for use in the development of a patient-related outcomes questionnaire for use in future treatment studies. Finally, adult subjects with gastrointestinal involvement may be asked to provide stool samples for microbiome analysis and assessment of stool levels of eosinophil granule proteins to explore the role of the microbiome in eosinophilic gastrointestinal disease. Stool samples may also be obtained from adult subjects undergoing endoscopy and/or colonoscopy as part of their initial evaluation and/or assessment of response to treatment. Potential confounding variables, including body mass index, diet, stool transit time and vitamin D levels will be assessed at the time of stool collection.

Study Design

• Study Type: Observational
• Estimated Enrollment: 800 participants
• Observational Model: Cohort
• Time Perspective: Prospective
• Official Title: Eosinophil Activation and Function in Parasitic Infections and Other Conditions With Increased Tissue or Peripheral Blood Eosinophilia in Humans
• Actual Study Start Date: April 21, 1997

Groups and Cohorts

Group/Cohort
1; Volunteers with elevated eosinophil counts in the peripheral blood or tissues; or a relative of a volunteer with eosinophilia

Outcome Measures

Primary Outcome Measures :

1. Collect data and samples to enhance the understanding of the mechanisms driving eosinophilia and eosinophil activation in patients [ Time Frame: Ongoing assessment ]
   Greater understanding of the mechanisms driving eosinophilia and eosinophil activationCollect data and samples to enhance the understanding of the mechanisms driving eosinophilia and eosinophil activation in patients with a wide range of eosinophilic disorders with the ultimate goal of improving diagnostics and identifying novel treatment modalities.

Secondary Outcome Measures :

1. To explore the role of the intestinal microbiome in eosinophilic gastrointestinal inflammation [ Time Frame: Ongoing ]
2. To provide information about patient signs and symptoms for use in the development of a patient-related outcomes questionnaire for use in future treatment studies [ Time Frame: 12/31/2020 ]
3. To study and identify genetic causes of eosinophilia [ Time Frame: Ongoing ]
4. To develop a panel of laboratory and clinical tests that will aid in categorizing various conditions associated with blood and/or tissue eosinophilia and/or in monitoring response to therapy [ Time Frame: Ongoing ]
5. To study the role of inflammation associated cytokines/chemokines on the activation of eosinophils and their recruitment to the blood and tissues [ Time Frame: Ongoing ]
6. To evaluate the degree of activation of the peripheral blood and/or tissue eosinophils found in conditions characterized by elevated levels of eosinophils [ Time Frame: Ongoing ]
7. To investigate the functional role of eosinophils in immunologic and inflammatory reactions [ Time Frame: Ongoing ]
8. To determine mechanisms inducing peripheral blood and tissue eosinophil responses by evaluating these cells and other immune reactants in patients with a variety of eosinophilic conditions [ Time Frame: Ongoing ]

Eligibility Criteria

• Ages Eligible for Study: 1 Year to 100 Years (Child, Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No
• Sampling Method: Non-Probability Sample

Study Population

Participants with marked eosinophilia, eosinophilia in tissues or suspected eosinophilic end organ involvement will be seen on this protocol. Evaluation of family members may be of interest when a genetic cause of eosinophilia in suspected in a study participant.

Criteria

• INCLUSION CRITERIA (Eosinophilic Subjects):

  1. 1-100 years of age
  2. documented peripheral blood eosinophil count >1500/mm^3, tissue eosinophilia (abnormal accumulation of eosinophils in the skin or other body tissues) or suspected eosinophilic end organ involvement
  3. has a primary (non-NIH) physician for routine medical care

EXCLUSION CRITERIA (Eosinophilic Subjects):

1) medical conditions or therapies that the investigator feels put the subject at unacceptable risk for participation in the study

INCLUSION CRITERIA (Relatives):

1. 1-100 years of age
2. extended family member of a study participant in 94-I-0079

EXCLUSION CRITERIA (Relatives):

1) any condition that the investigator feels put the subject at unacceptable risk for participation in the study.

Participation of Women:

Women who are pregnant or breastfeeding will not be excluded, although procedures will be limited to those that are clinically indicated and/or pose no increased risk during pregnancy (such as echocardiopgraphy). Research blood collection will be limited in participants who are pregnant or breastfeeding.

INCLUSION CRITERIA (Hypereosinophilic Syndrome (HES) Concept Elicitation Substudy):

Each participant must meet the following criteria to be enrolled in the study:

1. Diagnosis of HES for at least 6 months
2. Documentation of symptoms for a minimum of 12 months
3. A change in symptoms that required a change in medication at least once in the past 12 months
4. Age 12 years or older
5. Adequate written and oral fluency in English
6. Willing to provide written informed consent
7. Willing to have the interview audio-recorded

EXCLUSION CRITERIA (Hypereosinophilic Syndrome (HES) Concept Elicitation Substudy):

The presence of any of the following will exclude a subject from the study:

1. Has a cognitive or physical impairment that would interfere with the subject s ability to complete the study.
2. Lack of fluency in spoken English
3. Positive for the FIP1L1-PDGFRA fusion tyrosine kinase gene translocation.

INCLUSION CRITERIA (Development of the Hypereosinophilic Syndrome Symptom Inventory (HES-SI)):

1. Have an existing diagnosis of HES
2. Be enrolled on protocol 94-I-0079
3. Age 12 or greater
4. Written and oral fluency in English
5. Willingness to provide informed consent

EXCLUSION CRITERIA (Development of the Hypereosinophilic Syndrome Symptom Inventory (HES-SI)):

Any condition that, in the investigator s opinion, places the subject at undue risk by participating in the study

Contacts and Locations

Contacts

Contact: Nicole C Holland-Thomas, R.N.; (301) 402-5969; hollandnc@mail.nih.gov

Contact: Amy D Klion, M.D.; (301) 435-8903; aklion@niaid.nih.gov

Locations

United States, Maryland

National Institutes of Health Clinical Center, 9000 Rockville Pike; Recruiting

Bethesda, Maryland, United States, 20892

Contact: For more information at the NIH Clinical Center contact Office of Patient Recruitment (OPR) 800-411-1222 ext TTY8664111010 prpl@cc.nih.gov

Sponsors and Collaborators

National Institute of Allergy and Infectious Diseases (NIAID)

Investigators

• Principal Investigator: Amy D Klion, M.D.; National Institute of Allergy and Infectious Diseases (NIAID)

More Information

Additional Information:

NIH Clinical Center Detailed Web Page 

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Stokes K, Yoon P, Makiya M, Gebreegziabher M, Holland-Thomas N, Ware J, Wetzler L, Khoury P, Klion AD. Mechanisms of glucocorticoid resistance in hypereosinophilic syndromes. Clin Exp Allergy. 2019 Dec;49(12):1598-1604. doi: 10.1111/cea.13509. Epub 2019 Oct 27.

Kuang FL, Legrand F, Makiya M, Ware J, Wetzler L, Brown T, Magee T, Piligian B, Yoon P, Ellis JH, Sun X, Panch SR, Powers A, Alao H, Kumar S, Quezado M, Yan L, Lee N, Kolbeck R, Newbold P, Goldman M, Fay MP, Khoury P, Maric I, Klion AD. Benralizumab for PDGFRA-Negative Hypereosinophilic Syndrome. N Engl J Med. 2019 Apr 4;380(14):1336-1346. doi: 10.1056/NEJMoa1812185.

Khoury P, Desmond R, Pabon A, Holland-Thomas N, Ware JM, Arthur DC, Kurlander R, Fay MP, Maric I, Klion AD. Clinical features predict responsiveness to imatinib in platelet-derived growth factor receptor-alpha-negative hypereosinophilic syndrome. Allergy. 2016 Jun;71(6):803-10. doi: 10.1111/all.12843. Epub 2016 Mar 2.

Khoury P, Herold J, Alpaugh A, Dinerman E, Holland-Thomas N, Stoddard J, Gurprasad S, Maric I, Simakova O, Schwartz LB, Fong J, Lee CC, Xi L, Wang Z, Raffeld M, Klion AD. Episodic angioedema with eosinophilia (Gleich syndrome) is a multilineage cell cycling disorder. Haematologica. 2015 Mar;100(3):300-7. doi: 10.3324/haematol.2013.091264. Epub 2014 Dec 19.

Khoury P, Zagallo P, Talar-Williams C, Santos CS, Dinerman E, Holland NC, Klion AD. Serum biomarkers are similar in Churg-Strauss syndrome and hypereosinophilic syndrome. Allergy. 2012 Sep;67(9):1149-56. doi: 10.1111/j.1398-9995.2012.02873.x. Epub 2012 Jul 9.

• Responsible Party: National Institute of Allergy and Infectious Diseases (NIAID)
• ClinicalTrials.gov Identifier: NCT00001406
• Other Study ID Numbers: 940079; 94-I-0079
• First Posted: November 4, 1999
• Last Update Posted: December 14, 2020
• Last Verified: March 10, 2020

Keywords provided by National Institutes of Health Clinical Center (CC) ( National Institute of Allergy and Infectious Diseases (NIAID) ):

Eosinophils; Helminth Parasites; Hypereosinophilia; Allergy; Asthma

Additional relevant MeSH terms:

Helminthiasis; Parasitic Diseases; Eosinophilia; Hypersensitivity; Immune System Diseases; Leukocyte Disorders; Hematologic Diseases