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954 Part VII: Neutrophils, Eosinophils, Basophils, and Mast Cells Chapter 62: Eosinophils and Related Disorders 955

the degree of infection. This variation is comparable to variations in damage seen in asthma and pulmonary eosinophilia, and tissue repair
IgE levels. There are no differences between ethnic groups in eosinophil characteristic of wound healing. The factors that determine which role
counts. the eosinophil adopts are unclear.
The eosinophil count in hospitalized patients is less than 0.01 ×
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10 /L in only 0.1 percent of patients, and in virtually all patients the eos-
inopenia can be ascribed to glucocorticoids or to disease activity. Acute EOSINOPHILS AND ASTHMA
infection, or treatment with glucocorticoids or adrenaline, decreases The relationship between airway inflammation and asthma is complex.
eosinophil counts. In contrast, β-blockers inhibit adrenaline-induced In particular, there is no close relationship between the severity of eos-
eosinopenia and can cause a rise in the eosinophil count. inophilic airway inflammation and either the severity of symptoms,
There have been several isolated case reports of patients with AHR, or abnormalities in forced expiratory volume in 1 second (FEV ).
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absent eosinophils in the blood and marrow. A rare disorder, eosino- The potential dissociation between an airway smooth muscle dysfunc-
phil peroxidase deficiency, may be brought to light by automatic count- tional phenotype, which leads to many of the symptoms and physiologic
ing that uses detection of eosinophil peroxidase to count eosinophils. abnormalities in asthma, and an eosinophilic inflammation- predominant
Eosinophil peroxidase deficiency does not have any adverse clinical phenotype more closely associated with severe exacerbations was
consequences. demonstrated in an examination of asthma heterogeneity using cluster
analysis techniques. This dissociation was further illustrated by clin-
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CAUSES OF AN EOSINOPHILIA ical trials of mepolizumab, an anti–IL-5 monoclonal antibody (mAb),
An eosinophilia accompanies a discrete number of diseases and a high which markedly reduced eosinophils in the blood and sputum but had
eosinophil count is always a clinically notable observation that requires no effect, either on AHR or lung function in patients with mild asthma,
36
explanation, although this is not always forthcoming. The causes of or on the late response to allergen challenge. The interpretation of
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eosinophilia can be classified according to the degree and frequency of this study and others using the anti–IL-5 antibody was complicated
occurrence (Table 62–4). Division of eosinophil counts is arbitrary, but by the observation that anti–IL-5 only partially decreases the tissue
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a mild eosinophilia could be regarded as less than 1.0 × 10 /L, a moder- eosinophilia. A dissociation between AHR and eosinophilia has also
9
ate elevation as 1.0 to 5.0 × 10 /L, and a high count as greater than 5.0 × been seen in animal models of allergen challenge. For example, anti–
9
10 /L. The most common cause of an eosinophilia worldwide is infec- VLA-4 mAb was able to block ovalbumin-induced AHR, but not airway
9
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tion with helminthic parasites, which can often result in a very high eosinophilia when given by aerosol to mice. Strikingly, in a condition
eosinophil count. The most common cause of an eosinophilia in indus- called eosinophilic bronchitis in which patients have an eosinophilic air-
trialized countries is the atopic allergic diseases, seasonal and perennial way inflammation but no evidence of asthma (no AHR or variable air-
rhinitis, atopic dermatitis, and asthma. Allergic disease generally results flow obstruction), the asthma phenotype correlated with the number of
in only a mild increase in eosinophil counts. A moderate or high eos- mast cells in the airway smooth muscle and the tissue eosinophilia did
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inophil count in asthma, especially outside a severe exacerbation, raises not differ between the asthmatic and eosinophilic bronchitis groups.
the possibility of a complication such as eosinophilic granulomatosis Large numbers of eosinophils and mononuclear cells are found in and
with polyangiitis (EGPA, formerly Churg-Strauss syndrome), allergic around the bronchi of patients who have died of asthma, and their bron-
8
fungal airway disease, or eosinophilic pneumonia. Drug allergy is not chial tissue contains large amounts of MBP. The pathology of asthma
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always straightforward to diagnose as a cause of an eosinophilia and deaths is at the extreme end of the pathology of asthma exacerbations.
less-common causes include Addison disease (although the eosino- There is increasing evidence that an airway eosinophilia is closely
philia is not usually marked). associated with the risk of having severe exacerbations. There is now
definitive evidence from two studies using mepolizumab that eosino-
phils are directly causal in the pathogenesis of severe exacerbations of
THE ROLE OF EOSINOPHILS asthma. Asthmatics with documented eosinophil airway inflammation
For years eosinophils were thought to ameliorate inflammatory were treated for up to a year with the drug with the primary outcome
responses, a view that is possibly coming back into vogue as noted above of a reduction in severe exacerbations in one study and dose of cor-
(see “Role in Immunoregulation” above); then through the 1980s and ticosteroids in another. Both demonstrated that mepolizumab was an
1990s they were believed to cause tissue damage in some situations. The effective form of treatment with response correlating with the effect on
subsequent use of anti–IL-5 and tyrosine kinase inhibitors to inhibit reducing eosinophils. 136,137 These observations were confirmed in phase
eosinophil production has suggested a complex interaction between II and III clinical trials and mepolizumab is now going through the
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eosinophilic inflammation and target organ damage. Eosinophils, licensing procedure for the treatment of asthma. 138,139 Of note, a dose of
in part through release of cytokines such as TGF-α, may also have a mepolizumab that was suboptimal for suppressing the airway eosino-
homeostatic role in certain circumstances, such as wound healing and philia was as effective in preventing exacerbations as a higher dose that
mammary gland development. 128,129 Eosinophils can certainly cause did suppress sputum eosinophils. Both doses effectively suppressed the
severe tissue damage under certain circumstances. Chronically high blood eosinophilia, suggesting this is a better biomarker of response.
eosinophil counts from many causes, including drug reactions, parasitic The exact mechanism by which mepolizumab prevents exacerbations of
infections, eosinophilic leukemia, and HES, are associated with end- asthma is therefore not entirely clear, especially as it does not obviously
omyocardial fibrosis. The observation in the mid-1970s that eosinophils suppress eosinophil activation in the airway lumen. 140
could kill parasite targets led to the hypothesis that the principal role
of eosinophils was to counter parasitic infection, although this remains
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a controversial area. Eosinophils in a mouse model had a protective EOSINOPHILS AND THE SKIN
effects against fungal growth in the lungs and eosinophils have also A large number of skin conditions are associated with infiltration of
been demonstrated in mice to protect against lethal respiratory virus the skin by eosinophils. The normal skin contains few eosinophils,
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infection. 131,132 Eosinophils are therefore associated with a number of so their presence is usually associated with pathology. The commonest
different types of pathologic and reparative processes ranging from causes of eosinophilic infiltration of the skin is atopic dermatitis where,
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the permanent tissue damage seen in HES, the partly reversible tissue as with asthma, the relationship to pathogenesis remains contentious.

Kaushansky_chapter 62_p0947-0964.indd 954 9/21/15 10:56 AM