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958 Part VII: Neutrophils, Eosinophils, Basophils, and Mast Cells Chapter 62: Eosinophils and Related Disorders 959

pneumonia, drug allergy, malignancy, EGPA, and eosinophilic gas- It varies from being relatively asymptomatic to an aggressive disease
troenteritis (which could be regarded as part of the HES spectrum). leading to death within a few years if left untreated. The more severe
Etiology and Pathogenesis New insights into both the patho- complications are generally found in the myeloproliferative variant of
physiology and management of HES have been offered by the use of the disease. HES can present with nonspecific symptoms such as general
anti–IL-5 and the tyrosine kinase inhibitor imatinib mesylate to treat malaise, weight loss, aches and pains, and sweating attacks, or with one
the disease. HES appears to be a heterogenous condition with some of the organ-specific features. Cardiac complications are common in the
patients having evidence of abnormal T-cell clones, some of which myeloproliferative variant of the disease, in particular endomyocardial
overproduce IL-5 and some cases being because of somatic mutations fibrosis, which leads to a restrictive cardiomyopathy and left ventricular
leading to constitutively active tyrosine kinases. This finding has led failure. Mitral incompetence can occur. Thromboembolic complications
to the proposal that there are two broad variants of HES: myeloid and of large and small vessels are common in more severe disease some of
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lymphoid. The myeloid variant has features in common with myelo- which originate from endomyocardial clot. Many of the central neuro-
proliferative neoplasms, including raised serum vitamin B and serum logic features are embolic in origin. Respiratory symptoms, including
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tryptase, elevated neutrophil alkaline phosphatase score, clonal chro- cough that is (usually) productive of only small amounts of sputum and
mosomal abnormalities, anemia and thrombocytopenia, splenomeg- breathlessness, are common. Although airflow obstruction occurs there
aly, and circulating blast cells. The cardiac and neurologic involvement is a limited response to bronchodilators and AHR is often absent. Wheez-
that is a poor prognostic factor in HES is found mainly, but far from ing is not a prominent symptom. Pulmonary shadowing including alveo-
exclusively, in this group. A small proportion of these patients go on lar infiltration and nodules may be present. Skin symptoms are common,
to develop acute eosinophilic or myeloid leukemia (see Chaps. 88 and particularly pruritus. which is sometimes associated with erythematous
89). Demonstration of eosinophil clonality has been difficult but there papules and urticaria. A variant of HES is Gleich syndrome in which
is compelling evidence that these patients have chromosomal abnor- patients have recurring episodes of angioedema. Eosinophilic cellulitis
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malities leading to constitutive activation of growth factor associated may also be a feature. As well as embolic events, HES can be associated
tyrosine kinases. In particular, an interstitial deletion on 4q12 result- with confusion, loss of memory, and ataxia. Peripheral nervous system
ing in the encoding of a fusion protein consisting of the products of symptoms can include mononeuritis multiplex, sensorimotor neuropa-
the F/P oncogene, which has constitutive tyrosine kinase activity, was thy, multifocal neuropathy, and radiculopathy. The differential diagnosis
found in eight of 15 patients with iHES, all of whom responded to with EGPA can be difficult and may be semantic. Patients can develop
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treatment with the tyrosine kinase inhibitor imatinib. This muta- mucosal ulcerations but as with the renal system, severe complications
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tion caused the Ba/F3 cell line to become IL-3–independent and was are not usually prominent.
found in the EOL-1 cell line derived from a patient with eosinophilic Laboratory Features Investigations to exclude a reactive cause
leukemia. The presence of this mutation and the response to treat- for the eosinophilia need to be undertaken (see “Differential Diagnosis”
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ment with imatinib has been confirmed by other groups and is now below), if the neoplastic nature of the eosinophilia is not evident.
recognized as the most common clonal abnormality in CEL/myeloid Examination of stools for parasites in patients with chronic eosino-
HES. Imatinib has also been effective in other patients with iHES philia is an insensitive investigation and serology is only available for
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without this particular mutation. 159,162 A number of other rare mutated common helminths such as Strongyloides, schistosomiasis, and filar-
tyrosine kinases also cause the condition, including the JAK2 V617F iasis. Empirical treatment with broad-spectrum antihelminths can
point mutation usually associated with polycythemia vera, other sometimes be justified if there is high clinical suspicion with exposure
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partners for PDGFRα, the PDGFRβ gene, and rearrangements in the and a high total IgE. Occult fungal allergy is another common cause of
FGFR1 gene at 8p11 in which most patients progress to an aggressive hypereosinophilia and specific IgE for thermotolerant fungi which can
leukemia or lymphoma. 164,165 Karyotyping can identify these muta- colonize the host, such as A. fumigatus, C. albicans, Penicillium chrys-
tions, except the F/P mutation. The F/P mutation can be identified by ogenum, and Malassezia species, should be routinely undertaken. A
fluorescence in situ hybridization (FISH) studies (Chap. 89). A num- scheme for stepwise investigation of patients with iHES has been sug-
ber of other tyrosine kinase inhibitors with activity against CEL are in gested. These are mainly aimed at determining if there is evidence of
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clinical development. Serum tryptase appears to be a good, though clonality, or an abnormal T-cell clone. They include a complete blood
not perfect, marker of this variant of iHES, suggesting that mast cells count with examination of a blood film. Serum immunoglobulins,
are also affected by the mutation. It is, however, clinically distinct serum vitamin B and tryptase, examination of a marrow aspirate and
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from systemic mastocytosis. The lymphoid variant of HES clinically biopsy, lymphocyte phenotyping and, if available, analysis of cytok-
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generally follows a more benign course than m-HES (myeloprolofer- ine production, T-cell receptor gene rearrangement, karyotyping and
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ative HES) and there is less sex bias. Patients tend to respond well analysis of the presence of the F/P fusion protein by reverse transcrip-
to glucocorticoids and do not develop the cardiac fibrosis and other tion polymerase chain reaction or FISH analysis. A chest radiograph,
severe complications of the disease. The lymphoid variant of HES vari- spirometry, biochemical profile, troponin, cortisol, echocardiogram
ant is presumed to be a result of the overproduction of eosinophil- and abdominal ultrasound should also be considered as well as neu-
related growth factors by aberrant T cells. The eosinophils are, therefore, rologic investigations such as electromyography studies, if prior stud-
normal, unlike the m-HES variant. A number of different patterns of ies have not uncovered the explanation for the HES. Depending on
T cell abnormality have been found in association with HES the most the major site of organ damage, more detailed organ-specific inves-
common being a CD3– CD4+ CD5 subset of T cells 169–172 (reviewed tigations, such as cardiac magnetic resonance imaging, chest com-
in Ref. 173). In many cases, these clones secrete increased amounts of puterized tomography, full lung function tests, and gastrointestinal
eosinophil-related cytokines such as IL-5, IL-4, and IL-13. Clonality endoscopy, may be required.
of the phenotypically aberrant T cells has been demonstrated in many Differential Diagnosis Table 62–4 lists the reactive causes
cases and some progress to frank malignancy. of a marked eosinophilia, which causes should be excluded with
Clinical Features HES has a heterogeneous presentation with appropriate investigations. Once these causes have been excluded
the marked and persistent blood eosinophilia being the obvious hall- the differential diagnosis includes familial eosinophilia, which is
mark. 158,173,174 It is a chronic disease that usually presents in the third or a rare condition that has been mapped to a region of chromosome
fourth decade but can present at any age, including (rarely) in childhood. 5q31-q33, CEL, eosinophilia secondary to malignancy, EGPA, and
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