One of the major problems with previously reported series of HES patients has been referral bias, with single centers more likely to see patients with end organ manifestations that fall within the area of expertise of a particular subspecialty interested in HES. This has been compounded by the tendency to publish cases of the most severely affected patients, a disproportionate number of whom, in retrospect, were likely FP-positive. Patients in the current series were referred to groups with international recognition in the diagnosis and treatment of HES, composed of a wide variety of subspecialty physicians. Consequently, the data compiled are more likely to represent the true spectrum of HES. The major limitation of this study was the retrospective design and resultant lack of standardization of laboratory studies between the different sites. Despite these limitations, however, a number of interesting conclusions can be drawn.
In contrast to the marked (9:1) male predominance of HES reported in the literature, the ratio of males to females in the current study was 11:8. This likely reflects the fact that FP-positive patients, who are almost exclusively male, were overrepresented in previous series and confirms data from recent studies in which FP-positive patients were excluded7
. Similarly, early assessments of the relative prevalence of end organ manifestations were gleaned from case reports and small series and tended to overestimate more serious consequences of HES, including cardiac and neurologic involvement 2
. In the current series, the most common presenting manifestations of HES were dermatologic, pulmonary and gastrointestinal. Cardiac and neurologic complications did occur, but were relatively uncommon at the initial presentation. Earlier diagnosis and the availability of better therapies likely contributed to the improved HES patient outcomes in the current series. It is important to note that 11 of the 188 patients presented with asymptomatic eosinophilia found on routine lab testing. Of these, two were found to have FP-mutation positive CEL, a condition associated with high morbidity and mortality (up to 50% at 5 years) in the absence of imatinib therapy 5
. These findings highlight the importance of a comprehensive evaluation and close follow-up of patients presenting with unexplained hypereosinophilia.
There has been considerable controversy regarding the prevalence of L-HES and the FP-mutation among patients meeting criteria for HES. Early studies likely overestimated the prevalence of these two entities due to selection bias 3, 4
. More recently, the prevalence of the FP mutation has been estimated at 14% in a retrospective analysis of 81 patients with primary eosinophilia ≥1.5 × 109
/L who underwent bone marrow examination 14
. The prevalence of FP-positive patients was slightly lower in our study (10%), possibly due to the inclusion of patients in whom a bone marrow examination was not deemed necessary (i.e. less likely to have myeloproliferative disease). The association between elevated serum vitamin B12 and tryptase levels and the presence of the FP mutation was confirmed in the present study. Of note, extremely high levels of serum vitamin B12 (>2000 pg/ml) were observed only in the FP-positive group, suggesting that this may be a more discriminating biomarker of myeloproliferative HES.
Confirmation of L-HES is complex, ideally involving both lymphocyte phenotyping and TCR analysis. Consequently, differences in technique as well as the characteristics of the population studied likely account for the variability in the reported prevalence of L-HES, ranging from 14–31% 3, 15, 16
. In the present study, 17% of patients who were tested had clonal/abnormal populations of T cells detected by PCR or flow cytometry. Although it is debatable whether L-HES can be diagnosed on the basis of a clonal population identified by PCR in the absence of a detectable aberrant phenotype by flow cytometry (8.3% of the patients in the current study), the fact that some patients with clonal TCR rearrangement patterns have strikingly elevated serum TARC and/or IgE levels 11
suggests that aberrant T cell populations not identified using current antibody panels may be responsible for the eosinophilia in these patients. Nevertheless, a prospective trial using standardized techniques is clearly necessary to obtain an accurate assessment of the prevalence of the lymphocytic variant of HES.
Early efficacy studies and extensive clinical experience have proven corticosteroids to be the first line agent for the treatment of FP-negative HES 6
. Although the previously reported association between prednisone responsiveness and elevated serum IgE levels 10
was not confirmed in this study, TARC levels were significantly higher in patients who responded to prednisone. There was no difference between the serum IL-5 levels in patients who responded to prednisone compared to those who failed to respond (data not shown). Most patients were maintained on low to moderate dose prednisone therapy (5–20 mg daily). Although this would seem to indicate that the need for alternative therapies is small, the study questionnaire was not designed to detect steroid toxicities that did not lead to drug discontinuation. Furthermore, the majority of corticosteroid-responsive patients went on to receive a second-line agent, consistent with a higher rate of steroid toxicity and/or resistance than is evident from the collected data.
In the past 5–10 years, HES subtypes have been defined and a number of new, targeted agents have been developed, including imatinib mesylate and humanized monoclonal antibodies to IL-5. The restriction of this retrospective study to patients seen after 2001 was intended to maximize inclusion of data on these newer agents. As expected, imatinib was extremely effective in FP-positive patients with resistance described in only 2 patients. The 23% response rate in FP-negative patients is more difficult to interpret as the database did not include sufficient information to distinguish patients with myeloproliferative features who may be more likely to respond to imatinib. Although anti-IL-5 therapy was well-tolerated with an overall response rate of 80%, all patients received this agent in clinical trials, the majority of which required patients to be steroid-responsive 7, 13
, or were limited to a small number of doses 17
. Consequently, conclusions regarding the long-term efficacy of anti-IL-5 therapy and the most appropriate patients for treatment await further study.
In summary, HES is a rare group of disorders for which unbiased information on demographics, clinical manifestations and treatment responses is scarce. Although the current study has limitations due to its retrospective design, it represents the largest multicenter study of unselected patients with HES to date. As such, it not only provides useful information for clinicians involved in the care of HES patients, but will hopefully stimulate carefully designed prospective trials for the treatment of this disorder.
- Classically defined hypereosinophilic syndrome is a heterogeneous group of varied disorders, the majority of which remain idiopathic.
- Corticosteroids are extremely effective in the treatment of FIP1L1/PDGFRA-negative HES, but their use may be limited by side effects.
- Carefully designed prospective trials are required to advance the diagnosis and treatment of HES.