JeanAnne Ware

Marked and persistent eosinophilia in the absence of clinical manifestations

BACKGROUND Although most patients with hypereosinophilic syndromes (HES) present with clinical signs and symptoms attributable to eosinophilic tissue infiltration, some untreated patients remain asymptomatic or have signs and symptoms, such as allergic rhinitis, for which the relationship to peripheral eosinophilia is unclear (hypereosinophilia of unknown significance [HEUS]). OBJECTIVE To identify and characterize subjects with HEUS of 5 years duration or more as compared to untreated patients with symptomatic HES and healthy normal volunteers. METHODS All subjects with eosinophilia underwent yearly evaluation, including a standardized clinical evaluation, whole blood flow cytometry to assess lymphocyte subsets and eosinophil activation, and serum collection. Peripheral blood mononuclear cells were cultured overnight with and without phorbol 12-myristate 13-acetate/ionomycin. Cytokines and chemokines were measured in serum and cell supernatants, and mRNA expression was assessed by using quantitative real-time PCR. RESULTS Eight of the 210 subjects referred for the evaluation of eosinophilia (absolute eosinophil count [AEC] > 1500/μL) met the criteria for HEUS of 5 years duration or more (range, 7-29 years). Peak eosinophil count and surface expression of eosinophil activation markers were similar in subjects with HEUS and in untreated subjects with platelet-derived growth factor alpha-negative HES (n = 28). Aberrant or clonal T-cell populations were identified in 50% of the subjects with HEUS as compared to 29% of the subjects with HES (P = .12). Increased levels of IL-5, GM-CSF, IL-9, and IL-17A were also comparable in subjects with HEUS and HES. Serum levels of IgE and IL-13 were significantly increased only in subjects with HES. CONCLUSIONS A small number of patients with persistent peripheral eosinophilia (AEC > 1500/μL) appear to have clinically benign disease.

Clinical features predict responsiveness to imatinib in platelet-derived growth factor receptor-alpha-negative hypereosinophilic syndrome

With the exception of the presence of the FIP1L1‐PDGFRA fusion gene, little is known about predictors of imatinib response in clinically‐defined hypereosinophilic syndrome (HES).

Long-Term Clinical Outcomes of High-Dose Mepolizumab Treatment for Hypereosinophilic Syndrome

BACKGROUND Conventional therapies for hypereosinophilic syndromes (HES) have variable efficacy and carry significant long-term toxicities. Anti-IL-5 (mepolizumab) therapy has a glucocorticoid (GC)-sparing effect in GC-sensitive HES, but the efficacy of mepolizumab in treatment-refractory HES patients with severe disease has not been examined to date. OBJECTIVE To identify predictors of response to mepolizumab in subjects with severe treatment-refractory HES and compare long-term outcomes in these subjects with HES subjects treated with conventional therapies. METHODS Retrospective analysis of clinical and laboratory data from 35 HES subjects treated with mepolizumab and 55 HES subjects on conventional therapy, all followed at a single center, was performed. RESULTS Peak eosinophilia, GC sensitivity, pulmonary involvement, HES clinical subtype, and pretreatment serum IL-5 were correlated with mepolizumab response. Despite evidence of more severe disease at baseline, mepolizumab-treated subjects had comparable long-term clinical outcomes to HES subjects treated with conventional therapies and reported improvements in therapy-related comorbidities. Subjects managed with mepolizumab monotherapy had fewer disease flares than HES subjects on conventional therapies or mepolizumab-treated HES subjects requiring additional HES therapies. CONCLUSIONS This study confirms that mepolizumab is an effective and well-tolerated therapy for HES, but suggests that response is more likely in GC-responsive subjects with idiopathic or overlap forms of HES. A primary benefit of treatment is the reduction of comorbidity due to discontinuation or the reduction of conventional HES therapies. Although subjects who completely discontinued GC had the most benefit, high-dose mepolizumab was a safe and effective salvage therapy for severe, treatment-refractory HES.

Dexpramipexole as an oral steroid-sparing agent in hypereosinophilic syndromes

Hypereosinophilic syndromes (HESs) are a heterogeneous group of disorders characterized by peripheral eosinophilia and eosinophil-related end organ damage. Whereas most patients respond to glucocorticoid (GC) therapy, high doses are often necessary, and side effects are common. Dexpramipexole (KNS-760704), an orally bioavailable synthetic aminobenzothiazole, showed an excellent safety profile and was coincidentally noted to significantly decrease absolute eosinophil counts (AECs) in a phase 3 trial for amyotrophic lateral sclerosis. This proof-of-concept study was designed to evaluate dexpramipexole (150 mg orally twice daily) as a GC-sparing agent in HESs. Dual primary end points were (1) the proportion of subjects with ≥50% decrease in the minimum effective GC dose (MED) to maintain AEC <1000/μL and control clinical symptoms, and (2) the MED after 12 weeks of dexpramipexole (MEDD) as a percentage of the MED at week 0. Out of 10 subjects, 40% (95% confidence interval [CI], 12%, 74%) achieved a ≥50% reduction in MED, and the MEDD/MED ratio was significantly <100% (median, 66%; 95% CI, 6%, 98%; P = .03). All adverse events were self-limited, and none led to drug discontinuation. Affected tissue biopsy samples in 2 subjects showed normalization of pathology and depletion of eosinophils on dexpramipexole. Bone marrow biopsy samples after 12 weeks of dexpramipexole showed selective absence of mature eosinophils in responders. Dexpramipexole appears promising as a GC-sparing agent without apparent toxicity in a subset of subjects with GC-responsive HESs. Although the exact mechanism of action is unknown, preliminary data suggest that dexpramipexole may affect eosinophil maturation in the bone marrow. This study was registered at www.clinicaltrials.gov as #NCT02101138.

Natural History of Patients With Perilesional Edema Around Taenia solium Calcified Granulomas

Background The transient development of perilesional edema (PE) around ≥1 calcification (defined as 1 episode) occurs in about 50% of the patients with recurrent seizures in calcified neurocysticercosis (NCC). We determined the long-term clinical and radiological course of persons undergoing PE episodes. Methods Twenty-one persons with NCC who experienced ≥1 PE episode were followed for a median of 10.6 years (range, 0.4-29.2 years). Clinical evaluations and magnetic resonance imaging (MRI) were performed at the time of suggestive symptoms and during routine follow-up. Results PE episodes were documented 78 times, involving 50 of 729 calcifications. Episodes reoccurred in all but 3 persons. The pattern, rate, and number of episodes were variable, commonly chronic, and not significantly associated with time from treatment, number of calcifications, or sex. Seizure was the most common symptom, but almost 30% of episodes were asymptomatic and detected by MRI during routine follow-up. Persons with delayed recurrent episodes were significantly older (age, 42.3 vs 28.8 years; P = .045). Seizures continued to occur in 37.5%, and 2 persons had a severe disabling clinical course. Conclusions The number and timing of PE episodes in individuals with calcified NCC are variable and commonly chronic, sometimes recurring over decades. A minority of patients developed significant disability.

Intraventricular Neurocysticercosis: Experience and Long-Term Outcome from a Tertiary Referral Center in the United States

Abstract. Ventricular involvement in neurocysticercosis (NCC), a common serious manifestation of NCC, has distinct clinical presentations, complications, and treatments primarily because of partial or complete obstruction of the cerebrospinal fluid (CSF) flow by Taenia solium cysts. We review the clinical course, treatments, and long-term outcomes in 23 of 121 (19.0%) total NCC patients with ventricular cysts referred to the National Institutes of Health from 1985 to the October 2017. Patients had a median age of 31.8 (range: 22.4–52.6 years), were 60.9% male, diagnosed a median of 6.5 years (range: 0.17–16 years) after immigration, and were followed for a median of 3.6 years (range: 0.1–30.5 years). Other forms and manifestations of NCC were present in 73.9% (17/23). The fourth ventricle was involved in a majority (15/23, 65.2%) resulting in hydrocephalus (73.9%), ventriculitis, and periventricular edema (7/23, 30.4%). Cystectomy was accomplished in 60.9%, usually by removal of a fourth ventricular cyst through a suboccipital craniotomy. Nonresectable cysts were treated medically. Ventriculoperitoneal shunts were inserted in 43.5% (10/23) and failed in four, three from infection. Other complications included surgically induced injuries (4/23, 17.4%) and entrapment of a lateral ventricle (2/23, 8.7%). Despite a common severe early course, 90.9% (20/22) stabilized without recurrence, 15% (3/20) complained of mild-to-moderate neurological complaints, and 15% (3/20) were significantly disabled. Four patients who underwent removal of ventricular cysts without significant other NCC and who received with no cysticidal treatment became CSF cestode antigen negative without recurrence indicating that after successful extraction of cysts, additional cysticidal treatment may not be needed.