Allergic bronchopulmonary aspergillosis (ABPA) is a complex hypersensitivity reaction to Aspergillus spp. ABPA diagnosis may be challenging due to its non-specific presentation. Standard ABPA treatment consists of systemic corticosteroids and antifungal agents. Mepolizumab, a monoclonal antibody against interleukin-5 seems to be a promising treatment for ABPA. Data about ABPA following lung transplantation (LuTx) are scarce. LuTx recipients are at higher risk for adverse effects of ABPA treatment compared to the general population. Here we present a case of a LuTx recipient who was successfully treated with mepolizumab for ABPA following LuTx. Prolonged administration of high dose prednisone was thus avoided. To our knowledge, this is the first case describing mepolizumab administration following LuTx. Mepolizumab seems particularly attractive as a corticosteroid-sparing agent or as an alternative option to antifungal treatments, because of its excellent safety profile and low risk of drug interactions.

BACKGROUND: We aimed to clarify comprehensively the safety profiles of anti-IL-5 drugs and pinpoint potential safety concerns that may arise in their post-marketing phase.
METHODS: Two researchers conducted comprehensive searches of PubMed, EMBASE, Web of Science, and the Cochrane Library from inception to September 2022. Additionally, we investigated the FDA AE Reporting System for post-marketing adverse event (AE) reports related to anti-IL-5 drugs. The outcomes fulfilled the proportional reporting rate criteria and the Bayesian confidence propagation neural network.
RESULTS: We included 24 published studies in our analysis. The anti-IL-5 treatment group showed an incidence of AEs comparable to the placebo group, and it exhibited a significantly lower frequency of serious AEs. Common AEs were asthma, nasopharyngitis, headache, upper respiratory tract infection (URTI), and bronchitis. The post-marketing data included 28,478 case reports associated with the suspect drugs and 75 suspect safety observations affecting 16 system organ classes. New suspect observations included incomplete therapeutic product effect, URTIs, and pulmonary mass in reports related to mepolizumab. Reports associated with mepolizumab and benralizumab also indicated issues with incorrect technique in device usage and product issues.
CONCLUSIONS: Individual anti-IL-5 drugs\' safety profiles largely matched their product inserts. We identified issues like improper device usage, product issue, and URTIs as potential concerns for mepolizumab and benralizumab. Additionally, all anti-IL-5 drugs showed signs of incomplete therapeutic effects.

There is a growing need for advanced treatment in children with persistent and severe asthma symptoms. As a matter of fact, between 2 and 5% of asthmatic children experience repeated hospitalizations and poor quality of life despite optimized treatment with inhaled glucocorticoid plus a second controller. In this scenario, mepolizumab, a humanized monoclonal antibody, has proven to be effective in controlling eosinophil proliferation by targeting interleukin-5 (IL-5), a key mediator of eosinophil activation pathways. Mepolizumab is approved since 2015 for adults at a monthly dose of 100 mg subcutaneously and it has been approved for patients ≥ 6 years of age in 2019. Especially in children aged 6 to 11 years, mepolizumab showed a greater bioavailability, with comparable pharmacodynamics parameters as in the adult population. The recommended dose of 40 mg every 4 weeks for children aged 6 through 11 years, and 100 mg for patients ≥ 12 years provides appropriate concentration and proved similar therapeutic effects as in the adult study group. A marked reduction in eosinophil counts clinically reflects a significant improvement in asthma control as demonstrated by validated questionnaires, reduction of exacerbation rates, and the number of hospitalizations. Finally, mepolizumab provides a safety and tolerability profile similar to that observed in adults with adverse events mostly of mild or moderate severity. The most common adverse events were headache and injection-site reaction. In conclusion, mepolizumab can be considered a safe and targeted step-up therapy for severe asthma with an eosinophilic phenotype in children and adolescents.

OBJECTIVE: GSK3511294 is a humanized anti-interleukin (IL)-5 monoclonal antibody (mAb) engineered for extended half-life and improved IL-5 affinity versus other anti-IL-5 mAbs. This study examined its safety, tolerability, pharmacokinetics (PK) and effect on blood eosinophil counts.
METHODS: This was a double-blind, parallel-group, single-ascending-dose, multicenter, Phase 1 study (205 722;NCT03287310) in patients with asthma and a blood eosinophil count ≥200 cells μL-1 . Patients were randomized 3:1 within dose cohorts to receive a single subcutaneous dose of GSK3511294 (2, 10, 30, 100 or 300 mg) or placebo and followed for up to 40 weeks to assess safety (primary endpoint), ratio to baseline in blood eosinophil count, plasma PK parameters and frequency/titers of binding antidrug antibodies (all secondary).
RESULTS: Forty-eight patients received the study drug and completed the study. Adverse events (AEs) occurred in 92% of placebo-treated and 81% of GSK3511294-treated patients. There were no AEs leading to study withdrawal or serious AEs; hypersensitivity (one event in one patient) and injection-site reaction (three events in two patients) occurred infrequently. Marked reductions (>48%) in blood eosinophil count were seen from 24 hours post-dose with all GSK3511294 doses but not placebo; suppression was maintained for longer with increasing dose (82% and 83% adjusted reductions vs placebo with 100 and 300 mg, respectively, at week 26). PK were linear and dose proportional over the dose range; terminal half-life was 38-53 days.
CONCLUSIONS: GSK3511294 was well tolerated, with linear and dose proportional PK, extended half-life and blood eosinophil count reduction, supporting less frequent dosing versus other anti-IL-5 mAbs.

Background: Lymphocytic variant hypereosinophilic syndrome is characterized by marked over-production of eosinophilopoietic factor(s) by dysregulated T cells leading to eosinophil expansion. In most cases, these T cells are clonal and express a CD3-CD4+ phenotype. As this is a rare disorder, presenting manifestations, disease course, treatment responses, and outcome are not well-characterized. Materials and Methods: In this retrospective single-center observational study, we reviewed medical files of all patients with persistent hypereosinophilia seen between 1994 and 2019 in whom CD3-CD4+ T cells were detected. Data collection included clinical and biological findings at presentation, treatment responses, disease course, and serial CD3-CD4+ T cell counts. Results: Our cohort comprises 26 patients, including 2 with hypereosinophilia of undetermined significance. All 24 symptomatic patients had cutaneous lesions and/or angioedema, and fasciitis was present in several cases. The aberrant T cell subset represented 2% or less total lymphocytes in 11 subjects. TCR gene rearrangement patterns on whole blood were polyclonal in these cases, while they all had serum CCL17/TARC levels above 1,500 pg/ml. Disease manifestations were mild and did not require maintenance therapy in roughly one third of the cohort, while two thirds required long-term oral corticosteroids and/or second-line agents. Among these, interferon-alpha was the most effective treatment option with a response observed in 8/8 patients, one of whom was cured of disease. Treatment had to be interrupted in most cases however due to poor tolerance and/or development of secondary resistance. Anti-interleukin-5 antibodies reduced blood eosinophilia in 5/5 patients, but clinical responses were disappointing. A sub-group of 5 patients had severe treatment-refractory disease, and experienced significant disease- and treatment-related morbidity and mortality, including progression to T cell lymphoma in three. Conclusions: This retrospective longitudinal analysis of the largest monocentric cohort of CD3-CD4+ T cell associated lymphocytic variant hypereosinophilic syndrome published so far provides clinicians confronted with this rare disorder with relevant new data on patient presentation and outcome that should help tailor therapy and follow-up to different levels of disease severity. It highlights the need for novel therapeutic options, especially for the subset of patients with severe treatment-refractory disease. Future research efforts should be made toward understanding CD3-CD4+ T cell biology in order to develop new treatments that target primary pathogenic mechanisms.

Gleich\'s syndrome (GS) is characterized by recurrent episodes of angioedema, increase in body weight, fever, hypereosinophilia, and elevated serum IgM. The exact etiology remains unclear. Currently, the only treatment strategy is the administration of high dose of steroids during the acute phases. We report the case of a 37-year-old man suffering from GS with recurrent episodes of angioedema, fever, hypereosinophilia [6,000/mm3 (45%)], and high eosinophil cationic protein (ECP) (>200 μg/l), treated with oral steroids during the acute phase (prednisone 50-75 mg/day), the dose of maintenance being 25 mg/day. No monoclonal components were identified, and genetic tests exclude mutations including Bcr/Abl, JAK2 V617F, c-KIT D816V, and FIP1L1-PDGFRA. Using Luminex technology, we observed higher serum levels of interleukin (IL)-5, CCL2, and CCL11 during the acute exacerbations in comparison with the clinical remission phases though CCL11 did not achieve statistical significance. The flow-cytometric analysis identified a CD3+ CD8- lymphocyte population with high frequency of IL-4-, IL-5-, and IL-13-producing cells. No clinical benefit was observed after therapeutic strategies with imatinib, interferon-α, cyclosporine-A, and azathioprine. Due to high IL-5 serum levels, an intravenous treatment with anti-IL-5 monoclonal antibody mepolizumab (750 mg every 4 weeks) was started. A reduction in the rate of exacerbation phases/year (10 ± 3 vs 2 ± 1; p < 0.005), in the eosinophils count both in percentage (28.8 ± 12.8 vs 9.8 ± 3.9; p < 0.001) and absolute value (2,737 ± 1,946 vs 782 ± 333; p < 0.001) were observed as well as the ECP serum levels (132.7 ± 62.7 vs 21 ± 14.2 μg/l; p < 0.05). The daily dose of prednisone was significantly reduced (25 vs 7.5 mg). Any adverse effects were recorded. To the best of our knowledge, this case is the first report of the disease successfully treated with mepolizumab, and it could represent a novel therapeutic strategy in GS.

Benralizumab is a monoclonal antibody that targets interleukin-5 receptor α to deplete blood eosinophils and improve the clinical outcomes of allergic asthma. We conducted a meta-analysis to evaluate the safety and efficacy of different doses of benralizumab in patients with eosinophilic asthma. All randomized controlled trials involving benralizumab treatment for patients with eosinophilic asthma, which were searched in PubMed, Embase, and the Cochrane Library published until January 2017, as well as the rate of asthmatic exacerbation, pulmonary functionality, asthma control, quality of life scores, and adverse events were included. Randomized-effect models were used in the meta-analysis to calculate the pooled mean difference, relative risks, and 95% confidence intervals. Five studies involving 1951 patients were identified. Compared with the placebo, benralizumab treatment demonstrated significant improvements in the forced expiratory volume in 1 s (FEV1), Asthma Quality of Life Questionnaire scores, decreased asthmatic exacerbation and Asthma Control Questionnaire-6 (ACQ-6) scores. Benralizumab treatment was also not associated with increased adverse events. These findings indicated that benralizumab can be safely used to improve FEV1, enhance patient symptom control and quality of life, and reduce the risk of exacerbations and ACQ-6 scores in patients with eosinophilic asthma. Furthermore, our meta-analysis showed that benralizumab with 30 mg (every eight weeks) dosage can improve the health-related quality of life and appear to be more effective than 30 mg (every four weeks) dosage. Overall, data indicated that the optimal dosing regimen for benralizumab was possibly 30 mg (every eight weeks).