Q:

3/26/2013
I recently saw a 4 year old male patient referred for persistent eosinophilia.

He has a history of congenital hypthyroidism and iron deficiency anemia, so he has had monthly blood work since 1 year of age. Every single month, his eosinophils have been elevated. The highest they reached was 1800, but that was one time at 13 months of age. Since then, they have ranged from 700-1300.

He has had negative blood and stool work up for parasitic infections, and for good measure, his pediatrician treated him with a single dose of mebendazole. He has no chronic GI symptoms.

The only medications he is taking are Synthroid and Fer-in-sol.

He has no history of asthma, eczema, allergic rhinitis or food allergy. His mother and sister both have asthma and allergic rhinitis.

He has no history of recurrent infections. IgGAM were checked years ago (unclear why) and were normal, no total IgE has been done.

He is slightly dysmorphic and has a history of developmental delay and FTT. He has sparse hair and mildly peg-shaped teeth. Genetic work up was unrevealing. He is otherwise quite healthy without chronic respiratory, GI, neurologic or skin symptoms.

Interestingly, a recent CBC on his sister showed an eosinophil count of 900, no other CBCs available.

Could this be benign eosinophilia? Is there any further work up that should be done?

I appreciate your help. Thank you.

A:

Thank you for your inquiry.

First, let me refer you to a nice review of eosinophilia in children, the abstract of which is copied below. The reason for this is that in this venue, it would be hard to do justice to the complete workup of eosinophilia in the space normally utilized.

In addition, I would call your attention to numerous entries regarding eosinophilia on our Ask the Expert website.

Finally, there are two chapters in Middleton's text which go into the mechanisms of eosinophilia and its clinical management and evaluation. They are noted in the entry mentioned above that was previously posted on our website.

Having said that, I will make some comments pertinent to your patient.

In direct answer to your question, yes, this could be a benign eosinophilia, and furthermore, it may well be that you will not be able to find the etiology. Fortunately, his eosinophilia, except for the one occasion at which time it was 1,800, has been mild (under 1,500). This means that there it is less likely for there to be end-organ damage related to the eosinophilia itself.

One can proceed in depth in evaluating a patient with eosinophilia, but in a child his age, as noted, you may not find the cause regardless of how vigorously it is pursued.

You have probably put the issue of parasitosis "to bed," but sometimes parasites will not be present in the stool, and therefore you could consider parasite serology. These are readily available to a number of different parasites, and as noted, I would consider ordering these.

I would also do an IgE. A normal IgE would mitigate against parasites as a cause, and an elevated IgE in the presence of eosinophilia would suggest a a separate set of conditions (See: The Journal of Allergy and Clinical Immunology Vol. 122, Issue 6, Pages 1054-1062).

Other causes of secondary eosinophilia such as drugs would of course not apply. I looked up the contents of the Fer-in-sol, and neither the sorbitol nor the metabisulfite have been known to cause eosinophilia - at least there are no reports that I could find in the literature.

This leaves us with looking at primary eosinophilias which can be divided into three types: Idiopathic, cytokine-mediated, and those due to tyrosine-kinase mutations. I do not think any of these except "idiopathic" fits his case, but you can measure IL5 since one form is related to overproduction of IL5 by T cells, and you can also measure, in the peripheral blood, tyrosine-kinase mutations including the fusion gene FIP1L1-PDGFR. Other studies such as tryptase and vitamin B12 can be ordered to look at whether or not there is any suggestion that he may have a malignant type eosinophilia. However, as noted, I would not expect any of these tests to shed much light on the etiology in your patient.

Finally, the NIH under the direction of Dr. Amy Klion, has a program to evaluate patients with unexplained eosinophilia, and your patient may be one that fits under a protocol. Dr. Klion can be contacted. For your convenience, her contact information is noted below:

Amy Klion, MD
Eosinophil Pathology Unit
Laboratory of Parasitic Diseases
Bldg 4/Rm B1-28
Bethesda, MD 20892
(301) 435-8903
(301) 451-2029 (FAX)

Thank you again for your inquiry and we hope this response is helpful to you.

Amy D. Klion et al: Familial eosinophilia: a benign disorder? Blood June 1, 2004 vol. 103 no. 11 4050-4055
Familial eosinophilia (FE) is an autosomal dominant disorder characterized by marked eosinophilia and progression to end organ damage in some, but not all, affected family members. To better define the pathogenesis of FE, 13 affected and 11 unaffected family members (NLs) underwent a detailed clinical evaluation at the National Institutes of Health (NIH). No clinical abnormalities were more frequent in the family members with FE compared with the NLs. There was, however, a decreased prevalence of asthma in family members with FE compared with unaffected family members. Eosinophil morphology as assessed by either light or transmission electron microscopy was normal in family members with and without FE. Although levels of eosinophil-derived neurotoxin (EDN) and major basic protein (MBP) were elevated in patients with FE compared with NL, levels of both granule proteins were lower than in nonfamilial hypereosinophilic syndrome (HES). Similarly, increased surface expression of the activation markers CD69, CD25, and HLA-DR was detected by flow cytometry on eosinophils from patients with FE compared with NL, albeit less than that seen in HES. These data suggest that, despite prolonged marked eosinophilia, FE can be distinguished from HES by a more benign clinical course that may be related to a relative lack of eosinophil activation.

Leuk Res. 2012 Oct;36(10):1249-54. doi: 10.1016/j.leukres.2012.05.025. Epub 2012 Jun 22.
Hypereosinophilic syndrome in children.
van Grotel M, de Hoog M, de Krijger RR, Beverloo HB, van den Heuvel-Eibrink MM.
Source
Department of Pediatric Oncology-Hematology, Erasmus Medical Center-Sophia Children's Hospital, Rotterdam, The Netherlands.
Abstract
Recently, according to the Hypereosinophilic Diseases Working Group of the International Eosinophil Society, six variants of hypereosinophilic syndrome have been proposed, i.e. (1) myeloproliferative, (2) lymphoproliferative, (3) idiopathic/undefined, (4) overlapping, (5) associated and (6) familial variant. Hypereosinophilic syndrome is a rare disorder in children and can occur at any age during childhood. Corticosteroids are the treatment of choice, whereas other treatment options are hydroxyurea, IFNá, imatinib, vincristine, mepolizumab. We present a fulminant fatal case of hypereosinophilic syndrome in a teenager with an initial presentation of an idiopathic thrombocytopenia (ITP) and present a narrative review of literature.

Sincerely,
Phil Lieberman, M.D.

AAAAI - American Academy of Allergy Asthma & Immunology