RadioGraphics 2007;27:637-639
Invited Commentary
Stephen K. Frankel, MD,
Steve D. Groshong, MD, PhD, and
David A. Lynch, MD
Department of Medicine and Division of Radiology, National Jewish Medical & Research Center Denver, Colorado
In this issue of RadioGraphics, Jeong et al (1) review the clinical, radiologic, and pathologic features of the eosinophilic lung diseases. In so doing, they call attention to this heterogeneous group of pulmonary disorders, which have classically been grouped together based on the presence of pulmonary infiltrates in patients with peripheral or tissue eosinophilia. Familiarity with these relatively uncommon conditions is important for the radiologist because they often manifest initially as a radiographic abnormality, and because their clinical and imaging features often overlap with those of more common disorders such as infection and malignancy. Eosinophilic lung disease often enters the differential diagnosis only upon the identification of eosinophilia. It remains unclear whether eosinophilic lung diseases are related to each other, or even whether the eosinophil is pathogenic (as opposed to a "bystander") in any or all of these diseases.
The priority for the clinician is to identify and diagnose eosinophilic lung disease as quickly and efficiently as possible, and then to institute appropriate treatment. Identification of the biomarker of blood or tissue eosinophilia should prompt an initial evaluation for "known causes," including parasitic and fungal infections, medications, asthma or atopy, allergic bronchopulmonary mycosis, systemic autoimmune disease, and malignancy. Once these diseases have been ruled out, the next logical step is to proceed down the "unknown causes" pathway. As Jeong et al (1) indicate, the primary eosinophilic disorders may be subdivided into eosinophilic vasculitis, hypereosinophilic syndromes, and organ-limited eosinophilic disorders (idiopathic CEP, AEP, SPE). However, this classification, although valuable to the clinician, may not correlate with the features identified by the pathologist, radiologist, or basic scientist.
Lung biopsy is not necessary in patients with simple or chronic pulmonary eosinophilia if the clinical and imaging features are characteristic and there is rapid response to treatment. In patients with acute respiratory failure, biopsy may be necessary to make the diagnosis of AEP. Biopsy can also be helpful in refractory and chronic cases of eosinophilia, in which the differential diagnosis includes life-threatening entities such as Churg-Strauss vasculitis, hypereosinophilic syndrome, and eosinophilic leukemia. There are several challenges in making a specific histologic diagnosis in patients with these conditions. For example, previous partial treatment with steroids may significantly alter both the number of eosinophils in a specimen and many of the associated findings. Also, some important findings in eosinophilic lung disease (such as vasculitis in Churg-Strauss syndrome) can be focal and may not be present in a small biopsy sample, leaving only the more general finding of increased tissue eosinophils. In such difficult or equivocal cases, the imaging features may help in classification. Serologic tests such as antineutrophil cytoplasmic antibody, proteinase 3, and myeloperoxidase would support the diagnosis of vasculitis, whereas the presence of a fusion protein would support the diagnosis of hypereosinophilic syndrome. It should also be remembered that not all cases of eosinophilic lung disease can be neatly classified into one of the existing categories. For example, we recently evaluated a patient with severe asthma, eosinophilic pneumonia, severe eosinophilic sinusitis, arthralgias, myalgias, and constitutional symptoms in whom there was no evidence of vasculitis at surgical lung biopsy, serologic tests for vasculitis were negative, and there was neither evidence of a fusion protein nor clonality at bone marrow biopsy. Does this patient have Churg-Strauss syndrome, a complex undefined hypereosinophilic syndrome, or some condition that falls somewhere between the two?
The importance of the eosinophil in the pathogenesis of the eosinophilic lung disorders remains unclear. Numerous studies support a pathogenic role for the eosinophil in asthma and parasitic infections (2,3), although paradoxically, the eosinophilia in these disorders is generally classified as "secondary." However, there is little objective information to support the clinical notion that eosinophilia is a dominant pathogenic feature in some of the primary eosinophilic diseases. Indeed, although Churg-Strauss vasculitis is classified as a "primary" eosinophilic disorder, its clinical behavior is more like that of other small-vessel, antineutrophil cytoplasmic antibody–associated vasculitides than that of the other eosinophilic lung diseases. Likewise, CEP may have more in common with other organ-limited eosinophilic disorders such as eosinophil-associated gastrointestinal disease than with diseases such as ABPA.
Fortunately, as our understanding of these diseases grows, so does our ability to think clearly about them. Perhaps the most prominent examples of this growing ability are recent refinements in the molecular analysis, the clinical classification, and, ultimately, the treatment of hypereosinophilic syndrome. As indicated by Jeong et al (1), hypereosinophilic syndrome has previously been defined as characterized by (a) persistent eosinophilia greater than 1500 cells per cubic millimeter for more than 6 months, (b) multiorgan involvement and dysfunction, and (c) a negative work-up for known causes of eosinophilia. However, the recent identification of the FIP1L1-PDGFR
fusion protein in up to 50% of patients with hypereosinophilic syndrome has led to the recognition that this subgroup of patients typically respond to the protein kinase inhibitor imantinib (4). The current classification scheme for hypereosinophilic syndrome incorporates a detailed analysis of cell surface markers and molecular genetic features, thereby permitting more accurate classification of (5) and, potentially, more effective treatment for these disorders.
The advent of rational biologic therapies makes accurate classification and an improved understanding of the pathophysiologic role of the eosinophil more than a simple academic matter. Anti-IgE antibodies have been approved for the treatment of subsets of asthmatic patients (6), and anti-IL5 antibodies are already being introduced into clinical trials for the treatment of asthma as well as hypereosinophilic syndrome (7–9). As additional targeted therapeutics become available, we will need to define their role in each of the eosinophilic lung diseases. We thank Jeong et al (1) for their comprehensive and well-illustrated review of eosinophilic lung diseases, which should serve to increase awareness and understanding of these uncommon and complex disorders. We anticipate that the next decade of interdisciplinary interactions will lead to substantial further advances in the classification of these disorders.
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References
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- Jeong YJ, Kim KI, Seo IJ, et al. Eosinophilic lung diseases: a clinical, radiologic, and pathologic overview. RadioGraphics 2007;27:617–639.[Abstract/Free Full Text]
- Weller PF. Human eosinophils. J Allergy Clin Immunol 1997;100:283–287.[CrossRef][Medline]
- Bochner BS, Busse WW. Allergy and asthma. J Allergy Clin Immunol 2005;115:953–959.[CrossRef][Medline]
- Klion AD, Bochner BS, Gleich GJ, et al. Approaches to the treatment of hypereosinophilic syndromes: a workshop summary report. J Allergy Clin Immunol 2006;117:1292–1302.[CrossRef][Medline]
- Gleich GJ, Leiferman KM. The hypereosinophilic syndromes: still more heterogeneity. Curr Opin Immunol 2005;17:679–684.[CrossRef][Medline]
- Strunk RC, Bloomberg GR. Omalizumab for asthma. N Engl J Med 2006;354:2689–2695.[Free Full Text]
- Garrett JK, Jameson SC, Thomson B, et al. Anti-interleukin-5 (mepolizumab) therapy for hypereosinophilic syndromes. J Allergy Clin Immunol 2004; 113:115–119.[CrossRef][Medline]
- Sutton SA, Assa’ad AH, Rothenberg ME. Anti-IL5 and hypereosinophilic syndromes. Clin Immunol 2005;115:51–60.[CrossRef][Medline]
- Klion AD, Law MA, Noel P, Kim YJ, Haverty TP, Nutman TB. Safety and efficacy of the monoclonal anti-interleukin-5 antibody SCH55700 in the treatment of patients with hypereosinophilic syndrome. Blood 2004;103:2939–2941.[Abstract/Free Full Text]
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