Mepolizumab incompletely suppresses clinical flares in a pilot study of episodic angioedema with eosinophilia.

BACKGROUND: Episodic angioedema with eosinophilia (EAE) is a rare multilineage cyclic syndrome of unknown etiology characterized by episodes of angioedema, myalgia, fatigue, and fever that occur every 3 to 8 weeks and resolve between episodes without therapy. Cyclic elevations in serum IL-5 levels and neutrophils precede the increase in absolute eosinophil count (AEC) in most patients. OBJECTIVE: We sought to assess the role of IL-5-driven eosinophilia in the clinical manifestations of EAE. METHODS: An open-label pilot study of mepolizumab (700 mg intravenously monthly for 3 months followed by sequential dose reduction to the Food and Drug Administration-approved dose of 300 mg subcutaneously monthly) was conducted. The primary end point was reduction in the number and severity of clinical symptoms as assessed by patient-reported symptom questionnaires. Secondary end points were greater than or equal to 75% reduction in peak AEC after 1 dose of mepolizumab and sustained reduction in AEC after 3 doses of mepolizumab. Exploratory end points included effects of mepolizumab treatment on other cell lineages (numbers and surface marker expression), levels of plasma mediators, and biomarkers of eosinophil activation. RESULTS: Four female and 1 male (median age, 45 years) participants with EAE were enrolled. None of the 5 participants experienced a reduction in the number of symptomatic flares on mepolizumab therapy, and 1 participant withdrew before study completion because of lack of improvement. Peak AEC was reduced by 75% or more in 3 participants after the first dose of mepolizumab and in 4 participants after 3 doses. CONCLUSIONS: In a small cohort of participants with EAE, mepolizumab was unsuccessful in substantially reducing clinical symptoms despite reduction in AEC.

Distinct CRTH2+CD161+ (peTh2) memory CD4+ T-cell cytokine profiles in food allergy and eosinophilic gastrointestinal disorders.

INTRODUCTION: Although IgE-mediated food allergy (FA) and eosinophilic gastrointestinal disorders (EGID) are clinically distinct and treated differently, pathogenic effector Th2 (peTh2) cells are implicated in the pathogenesis of both FA and EGID. The aim of this study was to better characterize peTh2 cells in the context of FA and EGID and the overlap between these two conditions. METHODS: Peripheral blood peTh2 cells (CD3+CD4+CD27-CD49d+CRTH2+CD161+) were profiled by intracellular cytokine flow cytometry in the following patient cohorts: patients with FA alone (n = 8), FA and food-triggered EGID (EGID+FA+FT, n = 7), food-triggered EGID alone (EGID+FT, n = 7), EGID without FA or specific food triggers (ONLY_EGID, n = 9), and healthy volunteers (HV, n = 7). Overnight peripheral blood mononuclear cell (PBMC) culture supernatants were assessed for cytokine production by multiplex analysis. RESULTS: CRTH2+CD161+ (peTh2) memory CD4+ T cells were significantly increased in both patients with FA and those with ALL_EGID (inclusive of EGID+FA+FT, EGID+FT and ONLY_EGID) when compared to HV. However, ALL_EGID patients, particularly those with EGID+FA+FT, had significantly elevated IL-5+IL-13+ peTh2 cells, whereas FA patients had significantly elevated IFN-γ or IL-17A-expressing peTh2 cells. This finding was supported by increased spontaneous IL-5 and IL-13 production in overnight cultures of PBMC from EGID+FA+FT patients compared to spontaneous IL-10 and IFN-γ production by PBMC from FA patients. FA patients had increased IL-9, IL-10, IL-17A, and IFN-γ production in overnight cultures of stimulated PBMC. CONCLUSIONS: EGID and IgE-mediated FA share a common cell subtype defined by specific surface markers and termed CRTH2+CD161+ (peTh2) memory CD4+ T cells. However, the cytokine profiles of these CRTH2+CD161+ (peTh2) memory CD4+ T cells are markedly different between the two disorders.

Urine eosinophil-derived neurotoxin: A potential marker of activity in select eosinophilic disorders.

BACKGROUND: Biomarkers of eosinophilic disease activity, especially in the context of novel therapies that reduce blood eosinophil counts, are an unmet need. Absolute eosinophil count (AEC) does not accurately reflect tissue eosinophilia or eosinophil activation. Therefore, the aims of this study were to compare the reliability of plasma and urine eosinophil major basic protein 1, eosinophil cationic protein, eosinophil-derived neurotoxin (EDN), and eosinophil peroxidase measurement and to evaluate the usefulness of eosinophil granule protein (EGP) measurement for the assessment of disease activity in patients with eosinophil-associated diseases treated with mepolizumab, benralizumab, or dexpramipexole. METHODS: Eosinophil granule protein concentrations were measured in serum, plasma, and urine from healthy volunteers and patients with hypereosinophilic syndrome (HES), eosinophilic granulomatosis with polyangiitis (EGPA), and eosinophilic asthma using a multiplex assay. RESULTS: Urine EGP concentrations remained stable, whereas serum and plasma EGP concentrations increased significantly with delayed processing. Plasma (p) EDN, but not urine (u) EDN, concentration correlated with AEC and negatively correlated with prednisone dose. Both pEDN and uEDN decreased significantly following treatment of HES patients with benralizumab and EGPA patients with mepolizumab. uEDN appeared to increase with clinical relapse in both patient groups. CONCLUSIONS: Measurement of EGP in urine is noninvasive and unaffected by cellular lysis. Although plasma and urine EDN concentrations showed a similar pattern following benralizumab and mepolizumab treatment, the lack of correlation between AEC or prednisone dose and uEDN concentrations suggests that measurement of uEDN may provide a potential biomarker of disease activity in patients with HES and EGPA.

Efficacy and Tolerability of Miltefosine in the Treatment of Cutaneous Leishmaniasis.

BACKGROUND: Cutaneous leishmaniasis (CL) is a neglected tropical disease causing an estimated 1 million new cases annually. While antimonial compounds are the standard of care worldwide, they are associated with significant adverse effects. Miltefosine, an oral medication, is United States (US) Food and Drug Administration approved to treat CL caused by Leishmania braziliensis, Leishmania guyanensis, and Leishmania panamensis. Evidence of efficacy in other species and side-effect profiles in CL has been limited. METHODS: Twenty-six patients with CL were treated with miltefosine at the US National Institutes of Health. Species included L. braziliensis (n = 7), L. panamensis (n = 5), Leishmania mexicana (n = 1), Leishmania infantum (n = 3), Leishmania aethiopica (n = 4), Leishmania tropica (n = 2), Leishmania major (n = 1), and unspeciated (n = 3). Demographic and clinic characteristics of the participants, response to treatment, and associated adverse events were analyzed. RESULTS: Treatment with miltefosine resulted in cure in 77 % (20/26) of cases, with cures among all species. Common adverse events included nausea/vomiting (97%) and lack of appetite (54%). Clinical management or dose reduction was required in a third of cases. Gout occurred in 3 individuals with a prior history of gout. Most laboratory abnormalities, including elevated creatinine and aminotransferases, were mild and normalized after treatment. CONCLUSIONS: Our data suggest that miltefosine has good but imperfect efficacy to a wide variety of Leishmania species. While side effects were common and mostly mild to moderate, some resulted in discontinuation of therapy. Due to oral administration, broad efficacy, and manageable toxicities, miltefosine is a viable alternative treatment option for CL, though cost and lack of local availability may limit its widespread use.

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.

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.

Benralizumab Completely Depletes Gastrointestinal Tissue Eosinophils and Improves Symptoms in Eosinophilic Gastrointestinal Disease.

BACKGROUND: Previous studies of targeted eosinophil biologics in eosinophilic esophagitis have yielded mixed results. Possible explanations include incomplete eosinophil depletion with anticytokine (anti-IL-5) treatments and/or irreversible fibrotic tissue changes contributing to symptomatology. OBJECTIVE: To characterize the therapeutic effect of eosinophil depletion in patients with hypereosinophilic syndrome with varied eosinophilic gastrointestinal (GI) disorders. METHODS: Hematologic, histologic, endoscopic, and clinical symptoms for a subset (n = 7) of hypereosinophilic syndrome patients with GI tissue eosinophilia enrolled in a phase 2 clinical trial of benralizumab (anti-IL-5RA) were assessed before and after treatment (NCT02130882). RESULTS: Blood and GI tissue eosinophils were completely depleted in all segments of the GI tract, and all patients reported improved GI symptoms, in some cases as early as after the first monthly dose. Some patients had recurrent symptomatic flares without recurrent peripheral or tissue eosinophilia, in most cases after prolonged symptomatic remission and in the setting of liberalization of dietary restrictions and/or tapering of background therapy. Although eosinophil-associated histologic changes improved in all segments, epithelial changes persisted in the esophagus and stomach in patients with recurrent disease flares even after 1 year of treatment. Serum tryptase and GI mast cells were generally unchanged with treatment, and increases were not associated with disease flares. Serum levels of IL-4 and IL-5 increased with benralizumab treatment (both P < .05). CONCLUSIONS: Benralizumab treatment completely depleted blood and GI tissue eosinophilia in patients with eosinophilic GI disorders, but clinical response, while encouraging, was heterogeneous. Residual symptoms in some patients may reflect persistent epithelial changes in the upper GI tract.

An International, Retrospective Study of Off-Label Biologic Use in the Treatment of Hypereosinophilic Syndromes.

BACKGROUND: Treatment of hypereosinophilic syndrome (HES) often requires the use of immunomodulators with substantial side effect profiles. The emergence of biologics offers an alternative treatment modality. OBJECTIVE: To examine real-world practice data to describe the safety and consequences of various biologics suspected to directly or indirectly affect eosinophilic inflammation for the treatment of HES. METHODS: Retrospective data from 13 centers were collected via an online Research Electronic Data Capture repository. Inclusion criteria included (1) peripheral eosinophil count of 1,500/mm3 or greater without a secondary cause; (2) clinical manifestations attributable to the eosinophilia; and (3) having received mepolizumab (anti-IL-5), benralizumab (afucosylated anti-IL-5 receptor α), omalizumab (anti-IgE), alemtuzumab (anti-CD52), dupilumab (anti-IL-4 receptor α), or reslizumab (anti-IL-5) outside a placebo-controlled clinical trial. RESULTS: Of the 151 courses of biologics prescribed for 121 patients with HES, 59% resulted in improved HES symptoms and 77% enabled tapering of other HES medications. Overall, 105 patients were receiving daily systemic glucocorticoids at the time of a biologic initiation and were able to reduce the glucocorticoid dose by a median reduction of 10 mg of daily prednisone equivalents. Biologics were generally safe and well-tolerated other than infusion reactions with alemtuzumab. Thirteen of 24 patients had clinical improvement after switching biologics and nine patients responded to increasing the dose of mepolizumab after a lack of response to a lower dose. CONCLUSIONS: Biologics may offer a safer treatment alternative to existing therapies for HES, although the optimal dosing and choice for each subtype of HES remain to be determined. Limitations of this study include its retrospective nature and intersite differences in data collection and availability of each biologic.

Natural History of Treated Subarachnoid Neurocysticercosis.

Subarachnoid neurocysticercosis (SUBNCC) is usually caused by an aberrant proliferative form of Taenia solium causing mass effect and arachnoiditis. Thirty of 34 SUBNCC patients were treated with extended cysticidal and anti-inflammatory regimens and followed up a median of 4.2 years posttreatment (range: 15 for ≥ 4 years, 20 ≥ 2 years, 26 > 1 year, and 3 < 1 year). The median ages at the time of first symptom, diagnosis, and enrollment were 29.7, 35.6, and 37.9 years, respectively; 58.8% were male and 82.4% were Hispanic. The median time from immigration to symptoms (minimum incubation) was 10 years and the estimated true incubation period considerably greater. Fifty percent also had other forms of NCC. Common complications were hydrocephalus (56%), shunt placement (41%), infarcts (18%), and symptomatic spinal disease (15%). Thirty patients (88.2%) required prolonged treatment with albendazole (88.2%, median 0.55 year) and/or praziquantel (61.8%; median 0.96 year), corticosteroids (88.2%, median 1.09 years), methotrexate (50%, median 1.37 years), and etanercept (34.2%, median 0.81 year), which led to sustained inactive disease in 29/30 (96.7%) patients. Three were treated successfully for recurrences and one has continuing infection. Normalization of cerebral spinal fluid parameters and cestode antigen levels guided treatment decisions. All 15 patients with undetectable cestode antigen values have sustained inactive disease. There were no deaths and moderate morbidity posttreatment. Corticosteroid-related side effects were common, avascular necrosis of joints being the most serious (8/33, 24.2%). Prolonged cysticidal treatment and effective control of inflammation led to good clinical outcomes and sustained inactive disease which is likely curative.

Etanercept to Control Inflammation in the Treatment of Complicated Neurocysticercosis.

Manifestations of neurocysticercosis (NCC) are primarily due to host inflammatory responses directed at drug-damaged or naturally degenerating metacestodes (cysts) of the tapeworm Taenia solium. Prolonged high-dose corticosteroids are frequently required to control this inflammation in complicated disease, often causing severe side effects. Studies evaluating alternatives to corticosteroids are lacking. Here, we describe the clinical course of NCC in 16 patients prescribed etanercept (ETN), a tumor necrosis factor-alpha inhibitor to control inflammation resulting from anthelmintic treatment. Twelve patients with extraparenchymal NCC were administered ETN with corticosteroids (11/12, 91.7%) and/or methotrexate (9/12, 75.0%). The median age of the subgroup with extraparenchymal NCC was 40 years (range 26-57 years) and 66.7% were male. They were administered ETN for a median period of 311 days (range 31-461 days) and then followed for a median of 3.4 years (range 0.3-6.6 years). Among nine assessable patients, all improved clinically after starting ETN and one deteriorated transiently. Of the remaining three, one was lost to follow-up and two patients have improved but had not completed their assigned course. Four additional persons with recurrent perilesional edema (PE) episodes were given ETN for a median of 400.5 days (range 366-854 days) and followed post-ETN for a median of 1.7 years (range 0.2-2.4 years). All PE patients improved and two successfully tapered corticosteroids. Etanercept administration was associated with clinical improvement, stable disease, absence of recurrence, and lack of serious side effects. Etanercept appears to contribute to the control of inflammation and facilitate corticosteroid taper.

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

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.

The Lack of Association of Eosinophilia and Neurocysticercosis at Clinical Presentation: A Retrospective Analysis of Cases Seen at the National Institutes of Health, 1985-2015.

Eosinophilia is a common laboratory finding in helminth infections but whether it is suggestive of neurocysticercosis (NCC) is controversial and inadequately studied. We determined the presence of eosinophilia (≥ 500 eosinophils/mm3) at clinical presentation in 72 patients with a proven or probable diagnosis of NCC and who had not received corticosteroids within 2 weeks of evaluation and complete blood count. Only two persons whose last possible endemic exposures to NCC were 7 and 6 years earlier had eosinophilia of 500 eosinophils/mm3 and both had a positive antibody serology to strongyloidiasis. In the one subject where a follow-up assessment was possible, the eosinophilia resolved. The likely cause for eosinophilia in both was strongyloidiasis. Therefore, none of the subjects with newly diagnosed NCC had significant eosinophilia. Eosinophilia in newly diagnosed symptomatic NCC subjects who had remote exposure is unusual and should prompt a search for another process or infection.