Eosinophil-associated processes underlie differences in clinical presentation of loiasis between temporary residents and those indigenous to Loa-endemic areas.

BACKGROUND: Loa loa has emerged as an important public health problem due to the occurrence of immune-mediated severe posttreatment reactions following ivermectin distribution. Also thought to be immune-mediated are the dramatic differences seen in clinical presentation between infected temporary residents (TR) and individuals native to endemic regions (END). METHODS: All patients diagnosed with loiasis at the National Institutes of Health between 1976 and 2012 were included. Patients enrolled in the study underwent a baseline clinical and laboratory evaluation and had serum collected and stored. Stored pretreatment serum was used to measure filaria-specific antibody responses, eosinophil-related cytokines, and eosinophil granule proteins. RESULTS: Loa loa infection in TR was characterized by the presence of Calabar swelling (in 82% of subjects), markedly elevated eosinophil counts, and increased filaria-specific immunoglobulin G (IgG) levels; these findings were thought to reflect an unmodulated immune response. In contrast, END showed strong evidence for immune tolerance to the parasite, with high levels of circulating microfilariae, few clinical symptoms, and diminished filaria-specific IgG. The striking elevation in eosinophil counts among the TR group was accompanied by increased eosinophil granule protein levels (associated with eosinophil activation and degranulation) as well as elevated levels of eosinophil-associated cytokines. CONCLUSIONS: These data support the hypothesis that differing eosinophil-associated responses to the parasite may be responsible for the marked differences in clinical presentations between TR and END populations with loiasis.

Filariasis in travelers presenting to the GeoSentinel Surveillance Network.

BACKGROUND: As international travel increases, there is rising exposure to many pathogens not traditionally encountered in the resource-rich countries of the world. Filarial infections, a great problem throughout the tropics and subtropics, are relatively rare among travelers even to filaria-endemic regions of the world. The GeoSentinel Surveillance Network, a global network of medicine/travel clinics, was established in 1995 to detect morbidity trends among travelers. PRINCIPAL FINDINGS: We examined data from the GeoSentinel database to determine demographic and travel characteristics associated with filaria acquisition and to understand the differences in clinical presentation between nonendemic visitors and those born in filaria-endemic regions of the world. Filarial infections comprised 0.62% (n = 271) of all medical conditions reported to the GeoSentinel Network from travelers; 37% of patients were diagnosed with Onchocerca volvulus, 25% were infected with Loa loa, and another 25% were diagnosed with Wuchereria bancrofti. Most infections were reported from immigrants and from those immigrants returning to their county of origin (those visiting friends and relatives); the majority of filarial infections were acquired in sub-Saharan Africa. Among the patients who were natives of filaria-nonendemic regions, 70.6% acquired their filarial infection with exposure greater than 1 month. Moreover, nonendemic visitors to filaria-endemic regions were more likely to present to GeoSentinel sites with clinically symptomatic conditions compared with those who had lifelong exposure. SIGNIFICANCE: Codifying the filarial infections presenting to the GeoSentinel Surveillance Network has provided insights into the clinical differences seen among filaria-infected expatriates and those from endemic regions and demonstrated that O. volvulus infection can be acquired with short-term travel.

Relapse following discontinuation of imatinib mesylate therapy for FIP1L1/PDGFRA-positive chronic eosinophilic leukemia: implications for optimal dosing.

Although imatinib is clearly the treatment of choice for FIP1L1/PDGFRA-positive chronic eosinophilic leukemia (CEL), little is known about optimal dosing, duration of treatment, and the possibility of cure in this disorder. To address these questions, 5 patients with FIP1L1/PDGFRA-positive CEL with documented clinical, hematologic, and molecular remission on imatinib (400 mg daily) and without evidence of cardiac involvement were enrolled in a dose de-escalation trial. The imatinib dose was tapered slowly with close follow-up for evidence of clinical, hematologic, and molecular relapse. Two patients with endomyocardial fibrosis were maintained on imatinib 300 to 400 mg daily and served as controls. All 5 patients who underwent dose de-escalation, but neither of the control patients, experienced molecular relapse (P < .05). None developed recurrent symptoms, and eosinophil counts, serum B12, and tryptase levels remained suppressed. Reinitiation of therapy at the prior effective dose led to molecular remission in all 5 patients, although 2 patients subsequently required increased dosing to maintain remission. These data are consistent with suppression rather than elimination of the clonal population in FIP1L1/PDGFRA-positive CEL and suggest that molecular monitoring may be the most useful method in determining optimal dosing without the risk of disease exacerbation. This trial was registered at http://www.clinicaltrials.gov as no. NCT00044304.

Rebound eosinophilia after treatment of hypereosinophilic syndrome and eosinophilic gastroenteritis with monoclonal anti-IL-5 antibody SCH55700.

BACKGROUND: Hypereosinophilic syndrome and eosinophilic gastroenteritis with peripheral eosinophilia are characterized by sustained eosinophilia and eosinophil-mediated tissue damage. Although treatment with the humanized monoclonal anti-IL-5 antibody SCH55700 resulted in improvement of eosinophilia and clinical symptoms in 6 of 8 of patients with hypereosinophilic syndrome or eosinophilic gastroenteritis with peripheral eosinophilia for as long as 12 weeks, eosinophil counts subsequently rose above baseline levels, accompanied by an exacerbation of symptoms. OBJECTIVE: To identify the mechanism underlying this rebound eosinophilia. METHODS: Purified eosinophils from patients or normal donors were cultured with IL-5, patient serum, and/or anticytokine antibodies, and eosinophil survival was assessed by flow cytometry. Serum and intracellular cytokine levels were measured by multiplex sandwich ELISA and flow cytometry, respectively. RESULTS: Before treatment with SCH55700, in vitro eosinophil survival in media and in response to recombinant IL-5 was similar in patients and normal donors. At 1 month posttreatment, the eosinophil survival curves were unchanged in 4 of 5 patients in media and in all 5 patients in response to recombinant IL-5. Normal eosinophil survival was prolonged in cultures containing posttreatment but not pretreatment sera (pretreatment vs posttreatment, 10.74% vs 73.02% live cells; P = .01). This posttreatment serum effect on eosinophil survival was reversed by the addition of the monoclonal anti-IL-5 antibody TRFK5. Although increased levels of serum IL-5 were observed at 1 month compared with 2 to 3 days posttreatment in 5 of 6 patients ( P = .04), intracellular cytokine analysis did not reveal increased production of IL-5 by peripheral blood mononuclear cells. CONCLUSIONS: The rebound eosinophilia after SCH55700 treatment is a result of a serum factor that enhances eosinophil survival. Reversal of this effect by the addition of antibody to IL-5 suggests that this factor may be IL-5 itself.

Safety and efficacy of the monoclonal anti-interleukin-5 antibody SCH55700 in the treatment of patients with hypereosinophilic syndrome.

Four patients with hypereosinophilic syndrome (HES) refractory to or intolerant of treatment with conventional therapy were treated with a single 1 mg/kg dose of SCH55700. SCH55700 was extremely well tolerated. Two of the 4 patients responded with a fall in eosinophil counts to within the normal range within 48 hours of receiving the drug, accompanied by marked improvement in clinical signs and symptoms. Response was not predicted by serum interleukin-5 (IL-5) levels or presence of the FIP1L1/PDGFRA mutation. Eosinophil counts remained suppressed for up to 12 weeks after treatment; however, exacerbation of symptoms and eosinophilia above baseline levels occurred as drug levels waned. Reinstitution of treatment with monthly SCH55700 led to decreased eosinophilia and symptomatic improvement, albeit to a lesser degree than that seen after the initial dose. These data suggest that anti-IL-5 therapy may be useful in the treatment of HES irrespective of the underlying etiology, although the observed rebound eosinophilia and attenuation of response require further study.

Familial eosinophilia: a benign disorder?

Familial eosinophilia (FE) is an autosomal dominant disorder characterized by marked eosinophilia and progression to end organ damage in some, but not all, affected family members. To better define the pathogenesis of FE, 13 affected and 11 unaffected family members (NLs) underwent a detailed clinical evaluation at the National Institutes of Health (NIH). No clinical abnormalities were more frequent in the family members with FE compared with the NLs. There was, however, a decreased prevalence of asthma in family members with FE compared with unaffected family members. Eosinophil morphology as assessed by either light or transmission electron microscopy was normal in family members with and without FE. Although levels of eosinophil-derived neurotoxin (EDN) and major basic protein (MBP) were elevated in patients with FE compared with NL, levels of both granule proteins were lower than in nonfamilial hypereosinophilic syndrome (HES). Similarly, increased surface expression of the activation markers CD69, CD25, and HLA-DR was detected by flow cytometry on eosinophils from patients with FE compared with NL, albeit less than that seen in HES. These data suggest that, despite prolonged marked eosinophilia, FE can be distinguished from HES by a more benign clinical course that may be related to a relative lack of eosinophil activation.

Elevated serum tryptase levels identify a subset of patients with a myeloproliferative variant of idiopathic hypereosinophilic syndrome associated with tissue fibrosis, poor prognosis, and imatinib responsiveness.

Since serum tryptase levels are elevated in some patients with myeloproliferative disorders, we examined their utility in identifying a subset of patients with hypereosinophilic syndrome (HES) and an underlying myeloproliferative disorder. Elevated serum tryptase levels (> 11.5 ng/mL) were present in 9 of 15 patients with HES and were associated with other markers of myeloproliferation, including elevated B12 levels and splenomegaly. Although bone marrow biopsies in these patients showed increased numbers of CD25+ mast cells and atypical spindle-shaped mast cells, patients with HES and elevated serum tryptase could be distinguished from patients with systemic mastocytosis and eosinophilia by their clinical manifestations, the absence of mast cell aggregates, the lack of a somatic KIT mutation, and the presence of the recently described fusion of the Fip1-like 1 (FIP1L1) gene to the platelet-derived growth factor receptor alpha gene (PDGFRA). Patients with HES and elevated serum tryptase were more likely to develop fibroproliferative end organ damage, and 3 of 9 died within 5 years of diagnosis in contrast to 0 of 6 patients with normal serum tryptase levels. All 6 patients with HES and elevated tryptase treated with imatinib demonstrated a clinical and hematologic response. In summary, elevated serum tryptase appears to be a sensitive marker of a myeloproliferative variant of HES that is characterized by tissue fibrosis, poor prognosis, and imatinib responsiveness.