hypereosinophilia in allergic diseases and parasitosis

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http://tjh.dergisi.org/text.php3?id=396

 

Turkish Journal of Haematology

2005, Volume 22, Number 3, Page(s) 107-116

 

In the light of recent advances: eosinophil, eosinophilia and

idiopathic hypereosinophilic syndrome

Ali & #351;an YILDIRAN, Aydan & #304;K & #304;NC & #304;O & #286;ULLARI

 

Department of Pediatric Immunology and Allergy, Ankara University

School of Medicine, Ankara, TURKEY

 

Introduction

Eosinophil is a different cell containing highly toxic substances the

functions of which are still incompletely understood. Eosinophilia is

a condition where the eosinophil concentrations in the blood and some

tissues increase to unusual high levels in some abnormal conditions

and disease states. Being a common finding in clinical practice, in

the majority of cases, it can be ascribed to an underlying disease[1].

 

The role of interleukin- 5 (IL-5) in the induction of

hypereosinophilia in allergic diseases and parasitosis has been

established recently[2]. It is an important task for clinicians to

distinguish these conditions from the very rare, but more serious

idiopathic hypereosinophilic syndrome (IHES), characterized by

persistent eosinophilia in peripheral blood, bone marrow and

eosinophilic infiltration of multiple organs leading to severe organ

dysfunction[3]. Recently, with the discovery of different

well-characterized underlying molecular defects that ultimately lead

to eosinophil expansion in some patients, the term " idiopathic " has

become outdated in many cases[1].

 

In the light of recent advances, we made an attempt to review the

eosinophil, eosinophilia, IHES and the evaluation and management of

the latter.

 

THE EOSINOPHIL

The eosinophil was first recognized 125 years ago as a distinct

cellular element through the pioneering work of Paul Erlich. The ruddy

dye, eosin, was named after the Greek goddess of the morning sun, for

use in histologic staining by Erlich[4].

 

Eosinophils are derived from myeloid progenitors (GEMM-CFU) in bone

marrow[1]. Eosinophil production, maturation and survival are under

the control of some cytokines and growth factors, including IL-2,

IL-3, IL-5, IL-13 and granulocyte macrophage colony stimulating factor

(GM-CSF)[5]. IL-5 is the major growth factor for eosinophils.

Morphologically, eosinophils in the peripheral blood are approximately

the same size as polymorphonuclear leukocytes (PMNLs), 12 to 15 µm in

diameter, having mostly bilobed nuclei. The cytoplasm is normally

filled with approximately 200 large, eosin-staining unique granules

containing a central crystalloid core and high concentrations of

hydrolases, cationic and basic proteins. There are also several

smaller, enzyme-rich non-eosinophilic granules present in the

cytoplasm. With an appropriate stimulus, the number of specific

granules in the average eosinophil significantly declines, and the

cell often becomes vacuolized[4]. They are primarily a tissue cell,

with only 1-2% of them found in the circulation. They have a life span

of 8 to 12 hours in circulation and then remain another 1 to 2 weeks

in destination tissues[6].

 

Normal functions of eosinophils resemble to those of other circulatory

phagocytes (such as PMNLs and monocytes): chemotaxis, chemokinesis,

phagocytosis, cytotoxicity, antiparasitic activity, bactericidal

activity, effector of immediate hypersensitivity, modulation of

inflammatory response. Unlike PMNLs, when stimulated, they also

possess the capacity to elaborate substances that are toxic to a wide

variety of multicellular parasites. Eosinophils also act as

immunomodulators, particularly in their ability to dampen the host's

immediate allergic response[7]. Although, it is unclear whether they

are innocent bystanders or agents adding to tissue injury, in other

disease states, they are involved directly with critical pathologic

events. Their most virulent effects are seen in conditions like

Loeffler disease (eosinophilic fibroplastic endocarditis) and the IHES

in which permanent deleterious tissue injuries is due to their

presence[8].

 

EOSINOPHILIA

The normal absolute eosinophil count for both adults and children is & #8804;

350/µL. A level of 500 to 1500/µL is considered as mild; 1500 to

5000/µL as moderate; and > 5000/µL as severe eosinophilia. Eosinophils

are cells that mainly reside in tissues. For every one blood

eosinophil, there are 100 tissue eosinophils[9]. In the normal

individual, a circadian rhythm can be noted in peripheral blood

absolute eosinophil count due to normal fluctuation in glucocorticoids

seen during the day. Besides, relative eosinophilia is often noted

during the convalescent phase of a variety of systemic infectious

processes[4].

 

There is an association in children between total eosinophil counts in

the peripheral blood, and age. Eosinophil concentrations are elevated

at birth; continue to rise subsequently for several weeks. Then, by 8

weeks of age, eosinophil counts begin to decline to the levels at

which they are normally seen throughout the rest of life[10]. As many

as 70%, of premature babies may show at least mild eosinophilia.

Infants with high eosinophil counts (> 700/µL) at 3 months of age and

beyond are at risk of developing atopic diseases[11].

 

Mature eosinophils are released into the bloodstream and rapidly

migrate to peripheral tissues, namely gut and bronchial mucosa and

skin, where they soon undergo apoptosis and are cleared by

macrophages, unless survival factors such as IL-3, IL-5 and/or GM-CSF

are present. Thus, overproduction of one or more of these cytokines is

sufficient to induce normal or abnormal blood or tissue eosinophilia,

which accounts for hypereosinophilia in various disorders[12].

 

Mild and Moderate Eosinophilia

There are many conditions associated with mild to moderate

eosinophilia (500 to 5000/µL) (Table 1). Moreover, a wide variety of

pharmaceutical agents are associated with mild or moderate, sometimes

profound eosinophilia in children.

 

Table 1: Causes of mild to moderate eosinophilia in children[4]

 

The most common cause of eosinophilia worldwide is helminthic

infection and, in industrialized countries, atopic disease[13,14].

 

In general, gastrointestinal parasites lacking a tissue-invasive phase

tend to produce only mild eosinophilia. On the other hand,

tissue-invasive parasites often produce severe eosinophilia like

toxocara[15]. Nonparasitic infections capable of producing a

granulomatous tissue reaction such as mycobacterial or fungal

infections (including histoplasmosis, blastomycosis, and

coccidiomycosis) or chronic bacterial infections (brucellosis,

tularemia) can be associated with eosinophilia[16].

 

Loeffler syndrome, in distinction to the fibroplastic endocarditis

termed Loeffler disease, refers to a rather common condition

characterized by eosinophilia associated with cough and transient

pulmonary infiltrates. The most common cause of the syndrome is

migration through the lungs of the larval stages of certain intestinal

parasites like ascaris. Occasionally, some children may develop this

picture without evidence of parasitic infection. One such entity is

allergic bronchopulmonary aspergillosis. Another similar condition can

be seen after the inhalation of certain foreign antigens by a

sensitized individual. Such antigens may be household environmental

substances; chemicals encountered occupationally, animal products, or

plant materials. The patient develops diffuse pulmonary infiltrations

with alveolar-capillary block resulting in hypoxia[17].

 

Asthma, an atopic condition, is wellknown to be associated with mild

or moderate peripheral eosinophilia. Eosinophilia is commonly seen in

young infants who have milk intolerance caused by either milk protein

allergy or disaccaharidase deficiency[4]. Any condition with low

levels of functional corticosteroids is associated with a degree of

eosinophilia[4].

 

The study of Mehrizi suggested that children who have some congenital

heart defects, such as coarctation of aorta, ventricular septal

defect, frequently demonstrate unexplained mild to moderate

eosinophilia[18]. There is also a well-known relation between

eosinophilia and postpericardiotomy syndrome. But, the most serious

cardiac condition associated with eosinophilia is Loeffler disease

(eosinophilic endocardial fibroelastosis). Eosinophilic endocardial

fibroelastosis has been observed in children who have a wide variety

of underlying eosinophilic conditions, including severe asthma,

eosinophilic leukemia, acute lymphocytic leukemia (ALL), and acute

myeloid leukemia (AML), as well as a complication of the IHES[8].

 

Profound Eosinophilia

Profound (> 5000/µL) eosinophilia is a rarely encountered condition.

Visceral larva migrans, AML, ALL, eosinophilic leukemia, toxic oil

syndrome, ingestion of L-tryptophan byproduct, IHES, periarteritis

nodosa and other conditions may be associated with profound eosinophilia.

 

Visceral larva migrans is caused by infection with the larval stages

of the common pet nematode Toxocara canis and catii. Patients have

cough, prominent organomegaly, generalized lymphadenopathy, rash,

hypergammaglobulinemia, hypoalbuminemia and sometimes extremely high

levels of isohemagglutinins[4].

 

Eosinophilic leukemia is exceedingly rare in children. The patients

may develop rapid loss of cardiac functions. Profound eosinophilia may

be seen rarely in ALL and AML, confusing identification of the truly

malignant cell line[19]. As much as one quarter of patients who have

Hodgkin disease have profound eosinophilia[20].

 

Patients who have periarteritis nodosa usually present with

nonlocalizing systemic symptoms, including fever of unknown origin,

abdominal pain, arthritis, rash, leukocytosis, hematuria and

eosinophilia. Definitive diagnosis can only be made by muscular artery

biopsy[21].

 

Two major epidemics of profound eosinophilia have occurred in the

past. People who ingested olive oil mixed rapeseed oil suffered toxic

oil syndrome, and those who ingested an undetermined toxin in an

adulterated product contaminated with L-tryptophan suffered

eosinophilia-myalgia syndrome[22,23].

 

Some dermatologic conditions are also associated with severe

eosinophilia in children and adults. Gleich syndrome is a distinct

patient subpopulation of IHES, many of whom are children, have

extremely high eosinophil counts, and additionally suffer frequent

episodes of severe angioedema associated with weight gain, hypotension

and shock[4].

 

Eosinophilic End-Organ Damage

Sustained hypereosinophilia, whether reactive or clonal, can lead to

eosinophilic endorgan damage, but does not always do so, even after

many years. Therefore, other factors, possibly cytokines, genetic

propensity, T-cell clones, neutrophil and eosinophil activation, and

tyrosine kinases, may be necessary to cause the end-organ damage.

Regardless of the cause of activation, eosinophilia generates

cytokines which in turn produce an autocrine IL-2/IL-2R loop which

further activates Th2 type cells, leading to continued eosinophil

degranulation and activation[24].

 

Cardiac involvement is the most important cause of morbidity and

mortality due to end-organ damage of eosinophilia. This condition

generally evolves in three stages. The early necrotic stage, rarely

symptomatic, is followed by a thrombotic stage in which intracavitary

thrombi develop along the damaged endocardium. In the final fibrotic

stage, endomyocardial fibrosis and damage to atrioventricular valves

result in congestive heart failure[12]. Since, cardiac involvement

does not correlate with the level of blood eosinophilia, careful

follow-up is essential. Measurement of serum concentrations of cardiac

troponin T is thought to be a sensitive non-invasive marker of

involvement[25].

 

Evaluating an Eosinophilic Patient

When dealing with a child who has eosinophilia, the actual presence of

eosinophilia needs to be confirmed with repeated counts. If the

eosinophil counts remain elevated, a focused history and physical

examination should be performed (Table 2).

 

Table 2: Evaluation of eosinophilic patient[4]

 

In their study, Bridgen et al showed that eosinophilia noted on a

single complete blood cell count (CBC) is common and should be no

cause for alarm[26]. A CBC was performed in 195.000 outpatients, 225

(0.1%) were found to have an absolute eosinophil count > 700/µL. Less

than 9% of them had a serious systemic problem (parasitemia, collagen

vascular disease, malignancy) as the cause of their eosinophilia[25].

 

IDIOPATHIC HYPEREOSINOPHILIC SYNDROME (IHES)

Although increased peripheral blood and bone marrow eosinophilia is

the hallmark of IHES, the clinical presentations are extremely varied,

ranging from asymptomatic eosinophilia to life-threatening organ

damage. Recent studies clearly indicate that many patients fulfilling

the diagnostic criteria of this syndrome can now be classified as

presenting one of two major disease variants: the myeloproliferative

or the lymphocytic variant[1]. To understand the clinical

heterogeneity of IHES, one should review chronologic advances in

definition and pathogenesis.

 

Chronologic Advances in Definition and Pathogenesis of IHES

In 1912, the idiopathic proliferation of eosinophils was initially

recognized by Stillman. Since then, designations as eosinophilic

leukemia, disseminated eosinophilic collagen disease, endomyocardial

disease and eosinophilia have been used to describe this disorder[27].

Hardy and Anderson draw attention to the interrelationships among

these disorders in 1969[28]. Some authors have considered the syndrome

as a form of leukemia, while others doubted that the syndrome was a

neoplastic proliferation[27]. In 1975, Chusid et al established the

three empirical diagnostic criteria of IHES that are still in use

today: (1) blood eosinophilia exceeding 1500/µL for more than six

consecutive months; (2) absence of an underlying cause of

hypereosinophilia despite extensive diagnostic evaluations; and (3)

presence of organ damage or dysfunction related to

hypereosinophilia[29]. Flaum et al reported elevation of serum vitamin

B12 levels in 1981[27]. The prognosis of the patients has been poor in

the literature prior to 1976, and then a more favourable course has

been noted with a regimen of Parillo and Fauci that includes

prednisone or hydroxyurea[30]. Because of the expanded eosinophilic

and neutrophilic pool and the absence of an identifiable cause in

IHES; Zittoun suggested including this syndrome in myeloproliferative

disorders[31].

 

Clinical heterogeneity of IHES has complicated the understanding of

its etiology and pathogenesis even in 1994[12]. In 1994, Cogan et al

showed a T-cell population able to produce IL-5 and IL-4, and bearing

a unique CD3-CD4(+) surface phenotype[32]. Simon et al reported an

alternative mechanism of hypereosinophilia in 1996, via failure of

apoptosis of Fas-deficient T-cells or secretion of soluble Fas

receptor on a population of CD4-CD8(-) T-cells in two patients[33].

 

Emerging evidence is suggesting that IHES may be either a reactive

condition or a chronic myeloproliferative disorder[29]. Bain signalled

the relationship among tyrosine kinase gene and myelodsyplastic

syndrome in the study of Wlodarska and postulated that the location of

genes including IL-3, IL-4, IL-5 and GM-CSF in chromosome 5 is

relevant in the pathogenesis of IHES[34]. Then, De Vries et al

presented two patients with rapidly evolving cardiac and respiratory

failure, moreover, some patients experience normalization of

eosinophil levels before the defined six month interval is completed,

and thus do not fulfil Chusid' criteria although they clearly present

IHES. This means that there were some clinical pitfalls in the

diagnosis of IHES based on Chusid criteria[35]. This condition has led

several authors to suggest that these criteria be revised to include

such patients. In the same year, the increasing availability of

detecting techniques of clonality led to think that IHES could be a

T-cell disorder secreting eosinokines or failure of eosinophil

apoptosis[24]. Thus, in 1999, Simon et al reported that clonal

populations of T-cells with an abnormal immunophenotype (such as CD3+,

CD4-, CD8-) that secrete IL-5 are present in some patients with IHES.

These subsets generally display an activated (HLA-DR+ and/or CD25+)

memory (CD45RO+) phenotype[33]. They could not demonstrate clonality

by conventional techniques but, the presence of a uniform population

of T-cells expressing an aberrant phenotype suggested clonality.

Therefore, the diagnosis of IHES requires the exclusion of occult

cytokine-secreting T-cell clones.

 

However, pathogenic diversity of the striking clinical heterogeneity

of patients and occasional development of malignancy involving either

the myeloid or the lymphoid lineage was still a problem. Cools et al

demonstrated that many patients who would previously have been

categorized as having IHES actually have chronic eosinophilic leukemia

since they can be demonstrated to have a clonal molecular genetic

abnormality, specifically a FIP1L1-PDGFRA fusion gene resulting from a

cryptic deletion of part of the long arm of chromosome 4[36]. Other

groups confirmed this fusion gene both on patient samples and EOL-1

cell line[37,38]. The central role of this fusion gene in IHES

pathogenesis is supported by its disappearance in most patients

successfully treated with imatinib mesylate[39].

 

Therefore, accumulation of eosinophils in peripheral blood and tissues

can either be the result of an acquired abnormality involving the

myeloid lineage (myeloproliferative variant), or be due to the

production of eosinophilopoietic cytokines by nonmyeloid cells

(lymphocytic variant). In primary eosinophilia, clonal eosinophil

expansion may occur late in the process of differentiation, in which

case the rare diagnosis of " eosinophilic leukemia " is currently

thought to be appropriate. Secondary eosinophilia is a reactive

cytokine-driven process with the accumulation of polyclonal eosinophils.

 

Pediatric IHES

Pediatric IHES has only a slight male predominance whereas adult IHES

is reported to be more common among males than females, at a ratio of

9 to 1. Katz et al reported an IHES patient and reviewed long-term

prognosis of pediatric cases in the literature; 15 patients were

reported to be alive at that time their cases were published, whereas

21 have expired[40]. In this recent review, there were 38 pediatric

IHES cases; 17 female and 21 male. Their ages were ranged between 1 to

16 years, with a mean of 8.2. Presenting symptoms of them [n, (%)]

were fever in 20 (58.8), arthralgias in 8 (23.5), fatigue in 8 (23.5),

rash in 8 (23.5), cough in 7 (20.6), neurologic symptoms in 6 (17.6),

dyspnea in 6 (17.6), diarrhoea in 5 (14.7), abdominal pain in 4

(11.8), vomiting in 4 (11.8), headache in 4 (11.8), sore throat in 4

(11.8). Involved organs were heart in 27 (71.0), lungs in 21 (55.3),

skin in 13 (34.2), nervous system in 10 (26.3), gastrointestinal in 8

(21.0) cases. Pediatric IHES associated with ALL in 14 (36.8) of them.

Of 28 pediatric IHES patients, 11 responded to corticosteroids.

FIP1L1-PDGFRA fusion gene has not been reported to date in pediatric

cases.

 

Management of Patients with IHES

Patients diagnosed as IHES should be referred to experienced teams as;

optimal management depends on the ability to classify the disease

variant both technically and clinically. Distinction of myeloid vs.

lymphoid variants is the critical first step (Table 3). Identification

of patients with l-IHES is based on showing aberrant T-cell population

and analysis of TCR gene rearrangement patterns using Southern Blot

and PCR amplification[1]. Negative findings may reflect true absence

of clonality, or clonality may be undetected[33]. Analysis of cytokine

profiles must be performed for assessment of underlying T-cell

disorder. Cytokine concentrations can be measured in supernatants of

cultured peripheral blood mononuclear cells or purified aberrant

lymphocyte subsets by enzyme-linked immuno-sorbant assay, in the

absence or presence of T-cell stimulating agents, or by determining

the proportion of cytokinepositive cells within a given lymphocyte

subset by flow-cytometry[1]. Conventional cytogenetic analysis and

detection of F/P must be performed systematically in IHES patients.

Certain translocations [i.e. t (5;12) (q33;q13) or t (8;13)] or

chromosomal abnormalities may actually change the diagnosis from IHES

to eosinophilic leukemia[1,41]. Also, CHIC2 deletion could serve as a

surrogate marker for F/P[39]. Bone marrow sampling will disclose

existence of an underlying lymphoma in a patient with

hypereosinophilia. Tryptase staining may reveal the presence of

increased numbers of dysplastic spindle-shaped mast cells and

reticulin staining may show degrees of myelofibrosis in m-IHES[37].

Following the diagnostic workup, classification of an IHES patient can

be made (Table 3)[1]. In the lack of a primitive myeloid or lymphoid

disorder, a third truly `idiopathic' HES group could be defined.

Instead of these difficult and expensive techniques, diagnostic

markers to distinguish variants of IHES are being explored. Increased

serum tryptase appears to be a good marker for m-IHES associated with

the F/P[1,3]. Increased serum TARC levels may represent a highly

discriminative diagnostic test for l-IHES[42]. In the follow-up of

IHES patients, clinicians should expect development of peripheral

T-cell lymphoma in lymphocytic variant and AML in myeloid variant. As

expected, therapeutic perspectives have radically changed in the past

several years with the description of aberrant lymphocyte subsets and

F/P. The new therapeutic strategies in IHES variants are shown in

Table 4. It should not be forgotten that congestive heart failure,

even relapse may develop while receiving imatinib therapy[38,43].

 

Table 3: Investigation steps for IHES[1]*

 

Table 4: Therapeutic strategies in IHES variants[1]

# Top

# Introduction

# References

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