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Drug reaction with eosinophilia and systemic symptoms (DRESS) is a potentially life-threatening adverse drug reaction with a mortality rate of 10%. Interstitial nephritis, pneumonitis, myocarditis, meningitis, thyroiditis and pancreatitis are major causes of morbidity and mortality in this syndrome. Cessation of offending medication is paramount. There is paucity in high quality prospective studies guiding the treatment of DRESS, and there are no published therapeutic clinical trials in the treatment of corticosteroid refractory hypersensitivity myocarditis. The authors present a unique case of ciprofloxacin-induced DRESS with concurrent thyroiditis and refractory eosinophilic myocarditis that required mepolizumab and multiple immunosuppressants for successful treatment.

Background Anti-interleukin-5 (IL-5) therapy has been proposed as a novel treatment option for patients with chronic obstructive pulmonary disease (COPD). However, its efficacy for preventing COPD exacerbation remains unclear. Methods A literature review was conducted to August 26th 2019. Only randomized controlled trials (RCTs) that investigated the clinical efficacy and adverse effects of anti-IL-5 therapy were included in the meta-analysis. The primary outcome was the risk of COPD exacerbation. Results A total of 3 articles containing 5 RCTs were included in the study. Overall, 2837 and 1442 patients received anti-IL-5 therapy (mepolizumab, n = 865; benralizumab, n = 1972) and placebo, respectively. In the pooled analysis, anti-IL-5 therapy was associated with a lower risk of COPD exacerbation compared with the placebo (rate ratio, 0.92; 95% CI, 0.86–0.97, I2 = 0%). In addition, no significant differences in the changes in SGRQ scores and FEV1 from baseline were found between the anti-IL-5 therapy and placebo (SGRQ, mean difference, −0.86, 95% CI, −1.92 – 0.19, I2 = 0%; FEV1, mean difference, 0.01, 95% CI, −0.01 – 0.03, I2 = 0%). Anti-IL-5 therapy had a similar risk of any adverse event (risk ratio, 1.02; 95% CI, 0.99–1.05), an event leading to treatment discontinuation (risk ratio, 1.04; 95% CI, 0.72–1.48) and any serious adverse events (risk ratio, 0.93; 95% CI, 0.85–1.01) when compared with the placebo. Conclusion Anti-IL-5 therapy was associated with a lower rate of COPD exacerbation compared with placebo. In addition, anti-IL-5 therapy was well tolerated for COPD patients.

Background Eosinophilic granulomatosis with polyangiitis (EGPA) is a relapsing disease with frequent glucocorticoid dependence. Mepolizumab has been demonstrated to reduce flares and spare glucocorticoids (GC). However, EGPA is a heterogeneous condition and the effects of mepolizumab on specific disease manifestations has not been completely delimitated. Objectives To analyse the impact of mepolizumab on manifestations derived from small-vessel vasculitis, ENT (ear, nose and throat) symptoms, asthma, eosinophilic tissue infiltration and anti-neutrophil cytoplasmic antibody (ANCA) status in a single-centre cohort of EGPA patients. Methods Medical charts of EGPA patients treated with mepolizumab were retrospectively reviewed by the authors to describe demographics, clinical characteristics, steroid dose at the initiation of mepolizumab and during follow-up, flares, disease activity, damage accrual and laboratory results. Results and conclusions Among 56 patients with EGPA regularly controlled at our department, 11 patients were treated with mepolizumab because of corticodependence and unsatisfactory disease control. The mean time of treatment was 38 months (range: 3-66 months). Patients with persistent symptoms improved their asthma control, but 3 of them persisted with recurrent ENT symptoms in spite of treatment with mepolizumab. None of the patients developed vasculitic manifestations (cutaneous, neurological, gastrointestinal, renal) during treatment. All patients achieved a Birmingham Vasculitis Activity Score (BVAS) of 0 points at 12 months or earlier. In general, patients reduced the number of flares, which tended to be milder, and all related to asthma or ENT manifestations. The improvement in disease activity allowed notable glucocorticoid tapering.

Background Little is known on the persistence of asthma biologic use in clinical practice. Objective To evaluate the persistence of asthma biologic use and time to clinical response in clinical practice. Methods A cohort of people with asthma who used at least 1 asthma biologic was constructed using data from 2003 to 2019 in the OptumLabs Data Warehouse. Treatment persistence was defined by the length of time that a person continuously used an asthma biologic, allowing for a lapse in use up to 4 months before confirming that a person stopped. Clinical response to treatment (defined as a decline in asthma exacerbations of at least 50% compared with the 6 months before starting an asthma biologic) was described over time and in relation to biologic persistence. Results There were 9575 people who had at least 1 episode of asthma biologic use. There were 5319 people (64%, 95% confidence interval, 63%-65%) who completed 6 months or more on an asthma biologic and 3284 (45%, 95% confidence interval, 44%-46%) who completed 12 months or more. Of people with 1 or more asthma exacerbation 6 months before index biologic use, 63%, 76%, 80%, and 81% realized a 50% or more reduction in postindex asthma exacerbations in the first 6 months, 6 to 12 months, 12 to 18 months, and 18 to 24 months, respectively. Conclusion Between 48% and 64% of people remained on an asthma biologic for 6 months or more after first use. Most people who achieved a reduction in asthma exacerbations did so in the first 6 months of treatment.

Patients with severe chronic rhinosinusitis with nasal polyps represent an unmet clinical need in terms of recurrent disease despite current medical and surgical therapy. Targeting type 2 inflammatory cytokines (IL4/5/13) appears to be a promising therapeutic approach for such patients akin to what has already been seen in severe asthma. An indirect comparison from phase 3 placebo-controlled trials has shown relative improvements in the coprimary end point of nasal polyp score (NPS) ranging from a 15% reduction (-0.8 units) with mepolizumab, 18% with omalizumab (-1.14 units), and 35% (-2.06 units) with dupilumab. This trend was mirrored by relative improvements in health status with the 22-item Sinonasal Outcome Test score showing a 21% reduction (-13.7 units) with mepolizumab, 27% (-16.1 units) with omalizumab, and 43% (-21.1 units) with dupilumab, all exceeding the minimal clinically important difference of 8.9 units. All biologics improved the coprimary end point of nasal airway blockage and also reduced the need for rescue medical and/or surgical polypectomy. We advocate performing real-life studies looking at the response to biologics in patients who are at increased risk for disease recurrence, including initial optimal medical and surgical polyp clearance before commencing biologics.

Introduction: Asthma and hypereosinophilia have been treated with different therapeutics in the past. Some of them appear to be more effective in symptoms resolution and decreasing eosinophilic count. Case Presentation: We report here an unusual case of asthma with hypereosinophilia secondary to Chronic Myeloid Leukemia (CML) with high prevalence of eosinophilic infiltrate, treated simultaneously with an anti-IL-5 antibody (Mepolizumab) and Tyrosine-kinase Inhibitors (TKI: Imatinib and Bosutinib) for three years. The patient showed a promising reduction of pulmonary exacerbations and good control of CML without developing side effects. Conclusion: We hope that this finding could inspire further studies on the efficacy and safety of the concomitant use of anti-IL-5 and TKI.

Objectives To evaluate the efficacy and safety of anti-interleukin-5 class therapy agents in the treatment of eosinophilic asthma and the financial impact of these drugs on the Brazilian and Mato Grosso public health systems. Methods The literature review in important databases was guided by a structured research question including patient or population, intervention, comparator, outcome and type of study. The retrieved studies went through a screening, selection, data extraction, and methodological quality assessment process. A model with two scenarios, one with mepolizumab and the other with benralizumab, was created for budget impact analysis. Results Evidence indicated that anti-interleukins-5 have an acceptable safety profile and can reduce exacerbation rates by up to 50% in the population with eosinophilic asthma; however, they showed no significant difference in quality of life. The adoption of these drugs in the Brazilian health system can impact the budget from R$ 40,379,731.50 to R$ 140,301,211.34 depending on the drug incorporated, considering a time horizon of 5 years. From the perspective of the state of Mato Grosso, the budget impact may reach, in the fifth year, an amount of R$ 1,301,210.58 and R$ 2,050.687.62 for the scenarios with mepolizumab and benralizumab, respectively. Conclusion Anti-interleukins-5 are promising treatments for eosinophilic asthma because they minimise exacerbations and are well tolerated and safe. The financial impact is large, implying that technology costs may be a barrier to accessing this treatment class.

Introduction There is an ongoing debate as to the role of acute SARS-CoV-2 infection on asthma exacerbation, and its long-term impact on the lung function of individuals with asthma. In contrast, the potential impact of COVID -19 vaccination on asthma is entirely unexplored. Case Study We are shedding light on this critical topic by examining a challenging case of severe asthma exacerbation that a 28-year-old female patient developed after receiving two doses of mRNA-based vaccine BNT162b2 (Pfizer-BioNTech) at our Hospital, IRCCS Policlinico San Matteo of Pavia, in Northern Italy. The patient is a fourth year resident at the hospital, and like all health care workers at the facility, has been vaccinated since early 2021. She was an occasional smoker with a 10-year history of asthma and seasonal allergic rhinitis. She also tested negative for SARS-CoV-2 on several negative molecular swabs and serology tests. Results After receiving the second vaccine dose, she started experiencing a worsening of respiratory symptoms. Following several episodes, and a severe asthma attack, the patient required treatment with mepolizumab, a biologic drug [interleukin-5 (IL-5)] antagonist monoclonal antibody. Conclusion This single case study is insufficient to draw conclusions about the association between asthma exacerbation and the COVID-19 vaccine. While the cause-effect link between vaccination against SARS-CoV-2 and worsening of asthmatic disease might only be suggested, we consider the present case as a valuable prompt for further investigations. This is particularly true from the perspective of mass vaccination of adolescents and children currently underway across the globe.

Purpose To report the case of a patient with refractory chronic eosinophilic pneumonia who developed rheumatoid arthritis during anti-interleukin (IL)-5 therapy. Case Report The case of a 66-year-old male ex-smoker with allergic rhinitis who had dyspnea and chronic cough for 6 months and who was ultimately diagnosed with chronic eosinophilic pneumonia is reported. Long-term corticosteroid therapy was necessary due to recurrence of the chronic eosinophilic pneumonia during tapering of the corticosteroid. As a steroid sparing strategy, mepolizumab was initiated, and the steroid was tapered gradually. When the dose of prednisolone was 2 mg/day, he developed polyarthralgia. Mepolizumab was changed to benralizumab considering the possibility that arthralgia was a side effect of mepolizumab; however, the arthralgia continued and he was ultimately diagnosed with rheumatoid arthritis. Methotrexate was initiated and his arthritis improved. Thereafter, benralizumab was discontinued after 5 injections, and he subsequently required neither systemic corticosteroids nor biologics. Conclusion The present case may suggest that suppression of IL-5 induces rheumatoid arthritis in certain patients; however, it is also possible that initial steroid therapy improved subclinical RA and made it remain undiagnosed, and the parallel OCS tapering during IL-5 therapy could have contributed to unveil the underlying RA. Further studies are required to establish guidelines on the optimum use of anti-IL-5 therapy and to understand the interactions between chronic eosinophilic pneumonia, anti-IL-5 therapy, tapering of corticosteroid and development of rheumatoid arthritis.

Introduction: Compared with the placebo, biologics are beneficial in reducing nasal polyp mass and safe in patients with chronic rhinosinusitis with nasal polyps (CRSwNP). However, there lacks a head-to-head randomized trial comparing biologics. We aimed to determine the best biologic for CRSwNP. Methods: We performed a systematic review and network meta-analysis (NMA), which was registered with PROSPERO (No. CRD42021226766). A comprehensive search was performed in PubMed, Embase, Web of Science, and the Cochrane Library on December 29, 2020. Only randomized controlled trials (RCTs) assessing biologics in adult patients for CRSwNP were included. Results: Nine RCTs with 1,190 patients comparing 3 different biologics (dupilumab, omalizumab, and mepolizumab) and the placebo were included. Dupilumab had the best efficacy in terms of nasal polyp score (NPS), Sino-Nasal Outcome Test-22 (SNOT-22) score, University of Pennsylvania Smell Identification Test (UPSIT) score, and nasal congestion score (NCS) for surface under the cumulative ranking curve (SUCRA) values of 0.900, 0.916, 1.000, and 0.807, respectively. Omalizumab ranked second in efficacy in terms of SNOT-22, UPSIT, and NCS for SUCRA values of 0.606, 0.500, and 0.693, respectively. Mepolizumab ranked second in efficacy in terms of NPS for SUCRA values of 0.563 and had the highest risk of adverse events (AEs) for SUCRA values of 0.746. Conclusion: This is the first NMA that compared different biologics in patients with CRSwNP. Based on the efficacy (NPS) and safety (AEs), dupilumab is the best choice and omalizumab is the second best option for CRSwNP. Although mepolizumab ranked second in efficacy, it had the highest risk of AEs.

Sever e and difficult asthma in a low- and middle-income country (LMIC) can relate to (a) lack of availability of basic medications; (b) potentially reversible factors such as poor adherence or comorbidities such as obesity inhibiting a good response to treatment; and (c) (rarely) true severe, therapy-resistant asthma. However, definitions of severity should encompass not merely doses of prescribed medication, but also underlying risk. The nature of asthmatic airway disease shows geographical variation, and LMIC asthma should not be assumed to be phenotypically the same as that in high-income countries (HICs). The first assessment step is to ensure another diagnosis is not being missed. Largely, political action is needed if children with asthma are to get access to basic medications. If a child is apparently not responding to low dose, simple medications, the next step is not to increase the dose but perform a detailed assessment of what factors (for example co-morbidities such as obesity, or social factors like poor adherence) are inhibiting a treatment response; in most cases, an underlying reason can be found. An assessment of risk of future severe asthma attacks, side-effects of medication and impaired lung development is also important. True severe, therapy-resistant asthma is rare and there are multiple underlying molecular pathologies. In HICs, steroid-resistant eosinophilia would be treated with omalizumab or mepolizumab, but the cost of these is prohibitive in LMICs, the biomarkers of successful therapy are likely only relevant to HICs. In LMICs, a raised blood eosinophil count may be due to parasites, so treating asthma based on the blood eosinophil count may not be appropriate in these settings.

Background: Chronic rhinosinusitis with nasal polyps affects approximately 2–4% of the general population, and long-term use of systemic corticosteroids is associated with adverse effects. The aim of this study was to assess the efficacy and safety of mepolizumab in adults with recurrent, refractory severe bilateral chronic rhinosinusitis with nasal polyps. Methods: SYNAPSE was a randomised, double-blind, placebo-controlled, parallel-group, phase 3 trial done at 93 centres, mainly hospitals, in 11 countries. Eligible patients were aged 18 years or older with recurrent, refractory, severe, bilateral nasal polyp symptoms (nasal obstruction symptom visual analogue scale [VAS] score of >5), were eligible for repeat nasal surgery (overall symptoms VAS score >7 and endoscopic nasal polyps score of ≥5, with a minimum score of 2 in each nasal cavity) despite standard of care treatment, and had to have at least one nasal surgery in the past 10 years. Patients were randomly assigned (1:1), using permuted block design, to receive either 100 mg mepolizumab subcutaneously or placebo once every 4 weeks, in addition to standard of care (mometasone furoate intranasal spray for at least 8 weeks before screening and during the study, saline nasal irrigations, systemic corticosteroids or antibiotics, or both), as required, for 52 weeks. Site staff, the central study team, and patients were masked to study treatment and absolute blood eosinophil counts. The coprimary endpoints were change from baseline in total endoscopic nasal polyp score at week 52 and in mean nasal obstruction VAS score during weeks 49–52, assessed in the intention-to-treat population (ITT). This study is registered with ClinicalTrials.gov, NCT03085797. Findings: From May 25, 2017, to Dec 12, 2018, 854 patients were screened for eligibility. 414 patients were randomly assigned with 407 included in the ITT population; 206 received mepolizumab and 201 received placebo. Total endoscopic nasal polyp score significantly improved at week 52 from baseline with mepolizumab versus placebo (adjusted difference in medians −0·73, 95% CI −1·11 to −0·34; p

Benralizumab is an anti-eosinophilic monoclonal antibody that reduces exacerbations and improves lung function for patients with severe, uncontrolled asthma with eosinophilic inflammation. We evaluated the impact of baseline factors on benralizumab efficacy for patients with severe asthma. This analysis used pooled data from the SIROCCO (ClinicalTrials.gov identifier NCT01928771) and CALIMA (ClinicalTrials.gov identifier NCT01914757) Phase III studies. Patients aged 12–75 years with severe, uncontrolled asthma receiving high-dosage inhaled corticosteroids plus long-acting β2-agonists received benralizumab 30 mg subcutaneously every 8 weeks (Q8W, first three doses every 4 weeks (Q4W)), Q4W or placebo. Baseline factors that influenced benralizumab efficacy were evaluated, including oral corticosteroid (OCS) use, nasal polyposis, pre-bronchodilator forced vital capacity (FVC), prior year exacerbations and age at diagnosis. Efficacy outcomes included annual exacerbation rate and change in pre-bronchodilator forced expiratory volume in 1 s at treatment end relative to placebo. Benralizumab Q8W treatment effect was enhanced with each baseline factor for all patients and those with ≥300 eosinophils·μL−1 relative to the overall population. OCS use, nasal polyposis and FVC, Key baseline factors can aid in identifying patients who may respond to benralizumab http://ow.ly/uPVX30ltHTF

Background The efficacy of mepolizumab is well documented in severe eosinophilic asthma (SEA), although the stringent selection criteria adopted by SEA clinical trials limits the generalizability of results. Objective Our study evaluated the effectiveness and safety of mepolizumab in patients with SEA in Spain. The primary efficacy endpoint was the change in the rate of clinically significant asthma exacerbations 12 months after starting mepolizumab compared to the baseline rate in the 12 months prior to treatment. Patients were stratified by baseline blood eosinophil counts. Methods We conducted a multicentric observational cohort study of SEA patients treated with mepolizumab across 24 specialized hospital asthma units in Spain. Severe exacerbation rate, lung function, oral corticosteroid use (OCS) and asthma control test (ACT) were retrospectively collected and compared during the 12-month pre- and post-mepolizumab treatment. Adverse events were also investigated. Results A total of 318 patients with SEA were included (mean age: 56.6 years, 69.2% female). Exacerbation rates decreased by 77.5%, and 50.6% of patients did not suffer any exacerbations during the 12 months of treatment. The difference in forced expiratory volume in 1 s (FEV1) pre- and post-bronchodilator after starting mepolizumab was 0.21 (0.46) L (95% CI 0.14–0.27) (p < 0.001). Exacerbations and lung function significantly improved across all eosinophil subgroups. Among the 98 patients on OCS, 47.8% were able to discontinue this treatment and the mean daily dose was decreased by 59.9%. The baseline ACT score was 14.1, increasing by a mean (SD) of 6.7 points (1.9) at 12 months. Adverse events related to mepolizumab were uncommon. Conclusions This real-world study of SEA patients confirms that mepolizumab is effective in reducing clinically meaningful exacerbations, improving lung function, and decreasing OCS dependence and mean OCS dose at 12 months, irrespective of baseline eosinophil counts. Supplementary Information The online version contains supplementary material available at 10.1007/s40265-021-01597-9.

Eosinophilic granulomatosis with polyangiitis (EGPA), which belongs to the anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitides, is characterised by eosinophil-rich granulomatous inflammation and small- to medium-sized vessel vasculitis associated with bronchial asthma and eosinophilia. It sometimes causes severe organ damage, of which myocardial damage is one of the most important for determining the prognosis. A case of EGPA-associated myocarditis that was refractory to glucocorticoid therapy and responded successfully to rituximab (RTX) and mepolizumab (MPZ) combination therapy is presented. A 46-year-old woman was diagnosed with EGPA-associated myocarditis due to pre-existing asthma, eosinophilia, mononeuritis multiplex, and eosinophilic myocarditis by myocardial biopsy. Transthoracic echocardiography showed thickening of the cardiac wall, pericardial effusion, and left ventricular hypokinesis. Although the myocarditis was refractory to methylprednisolone pulse therapy followed by oral high-dose prednisolone, the disease activity reached remission with the successful tapering of glucocorticoid after initiation of the RTX and MPZ combination therapy. Combination therapy with RTX and MPZ can be a good treatment option for EGPA-associated myocarditis for which it is difficult to give intravenous cyclophosphamide due to cardiac dysfunction.

Background: Acute exacerbations of chronic rhinosinusitis (AECRS) are associated with significant morbidity and decreased quality of life. There are sparse data assessing the real-world impact of biologics on AECRS. Objectives: We sought to determine the impact of type 2‐targeting biologics on the frequency of medication use for AECRS episodes. Methods: Antibiotic and/or systemic corticosteroid courses for AECRS were identified in a retrospective study from November 2015 to February 2020, at a single academic health system. The estimated yearly rates for antibiotic and corticosteroid courses were evaluated before and after initiation of type 2 biologics. Results: One-hundred and sixty-five patients with chronic rhinosinusitis (CRS) had received either omalizumab (n = 12), mepolizumab (n = 42), benralizumab (n = 44), dupilumab (n = 61), or reslizumab (n = 6). Seventy percent had CRS with nasal polyps, and 30% had CRS without nasal polyps. All the patients had asthma. When all the biologics were combined, the estimated yearly rate for antibiotics for AECRS decreased from 1.34 (95% confidence interval [CI], 1.12‐1.59) to 0.68 (95% CI, 0.52‐0.88) with biologic use (49% reduction, p < 0.001). Those with frequent AECRS (three or more courses of antibiotics in the 1 year before biologic use) had a larger degree of reduction, with an estimated yearly rate of 4.15 (95% CI, 3.79‐4.55) to 1.58 (95% CI, 1.06‐2.35) with biologic use (n = 27; 62% reduction; p < 0.001). Within the total cohort, the estimated yearly rate for systemic corticosteroids for AECRS decreased from 1.69 (95% CI, 1.42‐2.02) to 0.68 (95% CI, 0.53‐0.88) with biologic use (60% reduction; p < 0.001). Conclusion: Type 2‐targeting biologics reduced medication use for AECRS. This suggested that biologics may be a therapeutic option for patients with frequent AECRS.

A 45-year-old man with allergic bronchopulmonary aspergillosis (ABPA) was treated with oral prednisolone (PSL) (30 mg/day), inhaled corticosteroids, and long-acting beta2-agonists. After confirmation of a PSL-dependent status (8 mg/day), subcutaneous injection with anti-interleukin (IL)-5 antibody (mepolizumab, 100 mg/month) was performed, and the PSL dose was tapered to 5 mg/day. However, ABPA recurred and proved refractory to oral itraconazole (200 mg/day). Alternative subcutaneous injection therapy with dupilumab (induction dose of 600 mg followed by a maintenance dose of 300 mg/2 weeks) enabled the successful withdrawal of oral PSL without clinical deterioration. This case demonstrates the potential utility of dupilumab for steroid-dependent ABPA via the synergistic suppression of IL-4 and IL-13 compared to monotherapy with anti-IL-5 antibody.

Background: Asthma is characterized by a chronic airway inflammation, usually sustained by type 2 immunity. Bronchial and peripheral eosinophilia are biomarkers for type 2 asthma. Biologicals are the most effective treatment for severe asthma at present. Mepolizumab is an antagonist of interleukin-5 (IL-5), the most relevant cytokine involved in eosinophilia.Objective: This case report evaluated the effectiveness of mepolizumab in two girls with severe eosinophilic non-allergic asthma.Materials and methods: Two female children with severe eosinophilic nonallergic asthma were treated with mepolizumab for two years. Clinical findings, lung function, peripheral eosinophils, asthma control, and bronchial endoscopy were performed.Results: Biologicals reduced the eosinophilia, asthma exacerbations, and improved lung function in both patients. The treatment was also safe and well-tolerated.Conclusion: Mepolizumab represents an effective therapeutic option in the management of severe pediatric asthma.

Die Global Initiative for Asthma (GINA) hat in den Jahren 2019–2021 einige substanzielle Änderungen für das Management von Patienten mit Asthma empfohlen, die auch Schulkinder und Jugendliche betreffen. Eine sehr wesentliche neue Empfehlung ist, dass kurzwirksame Betamimetika (SABA) aus Sicherheitsgründen nur mehr in Kombination mit inhalativen Steroiden (ICS) gegeben werden sollten. Bei Jugendlichen werden GINA-Stufe 1 und 2 zusammengezogen und bei Asthmaproblemen eine Bedarfsinhalation mit niedrig dosierter ICS-Formoterol-Kombination empfohlen. Als Alternative wird die Trennung in Stufe 1 mit Inhalation von SABA und einem ICS bei Bedarf und in Stufe 2 wie bisher die tägliche Inhalation eines ICS und SABA bei Bedarf empfohlen. Dieser Weg wird auch als der bevorzugte bei Kindern von 6 bis 11 Jahren vorgeschlagen. Diese neuen GINA-Empfehlungen wurden jedoch nicht von allen nationalen oder internationalen Leitlinien übernommen, da vor allem für Kinder die Evidenz dafür gering ist. Tiotropium, Mepolizumab und Dupilumab wurden in die Therapie des schweren Asthmas aufgenommen. Kinder mit Asthma erkranken nicht häufiger oder schwerer an COVID-19 als Kinder ohne Asthma. Verschiedene Mechanismen wie ein möglich protektiver Effekt der Typ-2-Inflammation, die antivirale und immunmodulierende Wirkung von ICS und die Niederregulierung von ACE2-Rezeptoren durch die allergische Sensibilisierung könnten dafür verantwortlich sein.

Francesco Menzella,1 Matteo Fontana,1 Carla Galeone,1 Maria D’Amato,2 Giorgio Walter Canonica,3 Giulia Ghidoni,1 Silvia Capobelli,1 Chiara Scelfo,1 Anna Simonazzi,1 Chiara Catellani,1 Patrizia Ruggiero,1 Nicola Facciolongo1 1Pulmonology Unit, Arcispedale Santa Maria Nuova, Azienda USL di Reggio Emilia- IRCCS, Reggio Emilia, 42123, Italy; 2Department of Pulmonology, AO “Dei Colli” Federico II University, Naples, 80131, Italy; 3Personalized Medicine, Asthma and Allergy - Humanitas Clinical and Research Center, IRCCS - Rozzano, Milan, ItalyCorrespondence: Francesco MenzellaPulmonology Unit, Arcispedale Santa Maria Nuova, Azienda USL di Reggio Emilia- IRCCS, Reggio Emilia, 42123, ItalyEmail francesco.menzella@ausl.re.itBackground: The important progress made on asthma phenotyping encouraged the development of new therapeutic strategies, such as monoclonal antibodies (mAbs) and bronchial thermoplasty (BT). The aim of this study is to compare patients diagnosed with severe refractory asthma (SRA) who are currently being treated with omalizumab, mepolizumab, benralizumab or BT and to evaluate the efficacy of these treatments over a 12-month observation period.Methods: Overall, 199 consecutive patients with SRA were included. The cohort was selected referring to the eligibility criteria for all available biologics and BT.Results: Among 32 patients treated with benralizumab, we found a 16.7% reduction in hospitalizations, a 66.6% reduction in exacerbations (p = 0.0001) and the greater improvement in FEV1 (+ 37.4%, p < 0.0001). Among omalizumab group (54 patients), there was a 85.7% (p = 0.012) reduction in hospitalizations and a 88.8% (p < 0.0001) reduction in exacerbations. In the mepolizumab group (83 patients), we found a 89.5% (p = 0.02) reduction in hospitalizations and a 92.1% (p < 0.0001) reduction in exacerbations. BT subgroup (30 patients) showed a 93.7% (p = 0.001) reduction in hospitalizations and a 73.5% (p < 0.0001) reduction in exacerbations. The best results in terms of OCS sparing effect were obtained by BT (- 76%, p < 0.0001) and mepolizumab (- 90.2%, p = 0.002). Omalizumab showed the highest percentage of super responder patients.Conclusion: To our knowledge, this is the first study to compare all marketed mAbs with BT, ending in more comprehensive and applicable results to clinical practice. All biologics, to varying degrees, reduced hospitalizations, exacerbations, and OCS use. The starting point for patients in the BT group was worse regarding hospitalizations, exacerbations and OCS, but despite this, even this non-pharmacological option obtained positive results, comparable to biologics.Keywords: severe asthma, biologics, bronchial thermoplasty, oral corticosteroids, exacerbations

Adverse drug reactions involving the skin are commonly known as drug eruptions. Severe drug eruption may cause severe cutaneous adverse drug reactions (SCARs), which are considered to be fatal and life-threatening, including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), acute generalized exanthematous pustulosis (AGEP), and drug reaction with eosinophilia and systemic symptoms (DRESS). Although cases are relatively rare, approximately 2% of hospitalized patients are affected by SCARs. There is an incidence of 2 to 7 cases/million per year of SJS/TEN and 1/1000 to 1/10,000 exposures to offending agents result in DRESS. However, the mortality rate of severe drug eruptions can reach up to 50%. SCARs represent a real medical emergency, and early identification and proper management are critical to survival. The common pathogenesis of severe drug eruptions includes genetic linkage with HLA- and non-HLA-genes, drug-specific T cell-mediated cytotoxicity, T cell receptor restriction, and cytotoxicity mechanisms. A multidisciplinary approach is required for acute management. Immediate withdrawal of potentially causative drugs and specific supportive treatment is of great importance. Immunoglobulins, systemic corticosteroids, and cyclosporine A are the most frequently used treatments for SCARs; additionally, new biologics and plasma exchange are reasonable strategies to reduce mortality. Although there are many treatment methods for severe drug eruption, controversies remain regarding the timing and dosage of drug eruption. Types, dosages, and indications of new biological agents, such as tumor necrosis factor antagonists, mepolizumab, and omalizumab, are still under exploration. This review summarizes the clinical characteristics, risk factors, pathogenesis, and treatment strategies of severe drug eruption to guide clinical management.

Objective To provide evidence-based recommendations and expert guidance for the management of antineutrophil cytoplasmic antibody-associated vasculitis (AAV), including granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA), and eosinophilic granulomatosis with polyangiitis (EGPA). Methods Clinical questions regarding the treatment and management of AAV were developed in the population, intervention, comparator, and outcome (PICO) format (47 for GPA/MPA, 34 for EGPA). Systematic literature reviews were conducted for each PICO question. The Grading of Recommendations Assessment, Development and Evaluation methodology was used to assess the quality of evidence and formulate recommendations. Each recommendation required ≥70% consensus among the Voting Panel. Results We present 26 recommendations and 5 ungraded position statements for GPA/MPA, and 15 recommendations and 5 ungraded position statements for EGPA. This guideline provides recommendations for remission induction and maintenance therapy as well as adjunctive treatment strategies in GPA, MPA, and EGPA. These recommendations include the use of rituximab for remission induction and maintenance in severe GPA and MPA and the use of mepolizumab in nonsevere EGPA. All recommendations are conditional due in part to the lack of multiple randomized controlled trials and/or low-quality evidence supporting the recommendations. Conclusion This guideline presents the first recommendations endorsed by the American College of Rheumatology and the Vasculitis Foundation for the management of AAV and provides guidance to health care professionals on how to treat these diseases.

Background Asthma and chronic obstructive pulmonary disease (COPD) are the most common respiratory diseases, presenting overlapping prevalence with age. Mepolizumab is a humanized monoclonal antibody targeting interleukin-5. In major randomized clinical trials, this antibody reportedly reduced the circulating eosinophil count, exacerbation rate, and oral corticosteroid (OCS) dosage in patients with severe eosinophilic asthma. However, data regarding the efficacy of mepolizumab in elderly patients with asthma and overlapping COPD are limited. Methods This was a single-center, retrospective, observational study. Elderly patients (age ≥65 years) administered mepolizumab between August 2016 and March 2019 were enrolled and the effects of mepolizumab on the eosinophil level, exacerbation numbers, OCS dosage, and lung functions were assessed. We compared treatment responses in patients with asthma and COPD overlap (ACO) with responses observed in patients with severe asthma alone. Adverse events were also evaluated. Results Twenty patients (10 men and 10 women), with a mean age of 77.5 ± 1.3 years, were included. Mepolizumab significantly reduced the blood eosinophil count, as well as significantly decreased clinically significant exacerbation, in both populations. The OCS dosage was significantly reduced in patients treated receiving maintenance OCS therapy. However, mepolizumab did not improve lung function in either population, and no significant difference was observed in treatment responses between patients with asthma alone and ACO. Conclusions Mepolizumab may be effective in elderly patients with eosinophilic asthma and ACO.

SUMMARY OBJECTIVE: A small portion of the asthmatic population (3.6%) has severe asthma (SA), presenting high morbimortality rates and demanding more financial resources than other asthmatic populations. The use of immunobiological therapy is an effective tool in controlling symptoms, decreasing the number of exacerbations, and reducing the use of systemic corticosteroids in these patients. In Brazil, epidemiological data regarding this asthmatic population using immunobiologicals and their evolution are scarce. METHODS: This is an observational, analytical, cross-sectional, and retrospective study. The sample consisted of adult patients with SA in follow-up at the pulmonology service of the Complexo Hospital de Clínicas of the Federal University of Paraná, from January 2011 to August 2019. The analyzed variables were as follows: the number of exacerbations that required hospitalization in the previous year, forced expiratory volume in one second (FEV1), and asthma control test (ACT) scores before and after the start of immunobiological therapy. RESULTS: We studied 20 patients with SA using omalizumab or mepolizumab. We observed an increase in the mean ACT score of 4.8 points, a nonsignificant reduction in the number of exacerbations that required hospitalization, and a slight improvement in the FEV1. Regarding the patients using chronic systemic corticosteroid therapy, 14.2% (n=1) of patients had the medication discontinued and 57% (n=4) of patients had the dose reduced by half. CONCLUSION: The use of omalizumab and mepolizumab as additional therapy in SA provided a significant improvement in the ACT and allowed the dose reduction of systemic corticosteroids, without significant improvement in FEV1 and in the frequency of severe exacerbations.

The management of pediatric patients with asthma continues to be a major health issue. For many patients, traditional therapies have been very effective, but for a large number of patients asthma remains poorly controlled. This leads to significant morbidity and impairment to quality of life. Recently, several new biologics, as well as new dosage forms of combination inhaled drugs, have been made available for use adding to the armamentarium of therapy for specific asthma phenotypes. Biologics have shown promise in the more difficult to manage asthma patient. Approved in children, omalizumab, an anti–immunoglobulin E (anti-IgE) antibody, has been available for several years. New agents, like mepolizumab and benralizumab, directed against interleukin (IL) 5, have indications for children >6 and >12 years of age, respectively. Dupilumab, an IL-4– and IL-13–directed antibody, has been studied as well in eosinophilic asthma, with positive results. A thorough understanding of the clinical data of these agents is key, as they may greatly improve the quality of life in children with difficult-to-manage asthma.

Lymphocyte-variant hypereosinophilic syndrome (L-HES) is a rare disease driven by immunophenotypically aberrant T cells producing eosinophilopoetic cytokines such as interleukin-5 (IL-5). Treatment is challenging because L-HES is relatively steroid resistant and not amenable to tyrosine kinase inhibitors. We searched the literature for clinical trials and observational studies, including case reports, of patients treated for L-HES. In all, 25 studies were selected; two were randomised controlled trials of IL-5 blockade, which included some patients with L-HES, and the rest were observational studies. Corticosteroids are often used as first-line therapy, but patients with L-HES have lower response rates than other types of HES. Treatments that reduce symptoms and steroid dependence in some patients include interferon-alpha (IFN-α), anti-IL-5 monoclonal antibodies, cyclosporine and mycophenolate. These drugs target T-cell activation and proliferation, or IL-5 directly. Although effective, IFN-α and cyclosporine were commonly reported to cause side-effects resulting in discontinuation. Alemtuzumab can induce remissions, but these are generally short lived. The anti-IL-5 monoclonal antibodies mepolizumab and benralizumab are effective and well tolerated, but with a high rate of relapse once withdrawn. Hydroxyurea, methotrexate, imatinib were unsuccessful in most patients studied. More prospective clinical trials are needed for patients with L-HES.

Background Severe asthma is associated with a broad range of phenotypes and clinical characteristics. This analysis assessed whether select baseline patient characteristics could prognosticate mepolizumab efficacy in severe eosinophilic asthma. Methods This was a post hoc meta-analysis of data from the Phase III MENSA (NCT01691521/MEA115588) and MUSCA (NCT02281318/200862) studies. Patients aged ≥ 12 years with severe eosinophilic asthma and a history of exacerbations were randomised to receive placebo (MENSA/MUSCA), mepolizumab 75 mg intravenously (MENSA) or 100 mg subcutaneously (SC) (MENSA/MUSCA) every 4 weeks for 32 (MENSA) or 24 (MUSCA) weeks. The primary endpoint was the annual rate of clinically significant exacerbations; other outcomes included the proportion of patients with no exacerbations and changes from baseline in pre-bronchodilator forced expiratory volume in 1 s (FEV1), St George’s Respiratory Questionnaire (SGRQ) total score and Asthma Control Questionnaire (ACQ)-5 score. Analyses were performed by baseline age of asthma onset (1 ≤ 60; 60–80; > 80); airway reversibility (reversible [≥ 12% change in FEV1]; non-reversible [1]); perennial and/or seasonal allergen sensitivity (yes/no); asthma control (uncontrolled [ACQ-5 score ≥ 1.5]; partial/complete control [ACQ-5 score Results Overall, 936 patients received mepolizumab 100 mg SC or placebo. Across age at asthma onset, lung function and airway reversibility subgroups, mepolizumab reduced the rate of clinically significant exacerbations by 49–63% versus placebo. Improvements in lung function, SGRQ total score and ACQ-5 score were also seen with mepolizumab versus placebo across most age and lung function subgroups. Clinically significant exacerbations were reduced with mepolizumab versus placebo irrespective of season or allergen sensitivity; SGRQ total and ACQ-5 scores were generally improved across seasons. Conclusions Mepolizumab efficacy was consistent for patients with varying age at asthma onset, lung function, airway reversibility and allergen sensitivities at baseline. Our results indicate that mepolizumab is likely to be beneficial for patients with severe eosinophilic asthma with a broad range of baseline clinical characteristics; large-scale real-world studies are needed to confirm the external validity of these findings. Trial registration Post hoc meta-analysis of data from MENSA (NCT01691521/MEA115588) and MUSCA (NCT02281318/200862)

Background Comorbidities can complicate the management of severe asthma; therefore, the presence of comorbid conditions or traits often need to be considered when considering treatment options for patients with severe asthma. The aim of this analysis is to investigate the efficacy of mepolizumab in patients with severe eosinophilic asthma and comorbidities. Methods This was a post hoc analysis (GSK ID:209140) of data from the Phase IIb/III studies DREAM, MENSA, SIRIUS, and MUSCA. Patients aged ≥ 12 years with severe eosinophilic asthma were randomized to: mepolizumab 750, 250, or 75 mg intravenously or placebo (DREAM); mepolizumab 75 mg intravenously or 100 mg subcutaneously or placebo (MENSA); or mepolizumab 100 mg subcutaneously or placebo (SIRIUS and MUSCA) every 4 weeks for 24 weeks in SIRIUS and MUSCA, 32 weeks in MENSA or 52 weeks in DREAM. In this analysis the primary endpoint was the annual rate of clinically significant exacerbations; secondary endpoints were Asthma Control Questionnaire-5 score, St George’s Respiratory Questionnaire total score, and pre-bronchodilator forced expiratory volume in 1 s at study end. Subgroups were based on comorbidities at baseline. Results Overall, 1878 patients received placebo (n = 689) or mepolizumab (n = 1189). Across all comorbidity subgroups mepolizumab reduced the rate of clinically significant exacerbations by 44–68% versus placebo, improved Asthma Control Questionnaire-5 score by 0.27–0.59 points, and improved St George’s Respiratory Questionnaire total score by 5.0–11.6 points. Pre-bronchodilator forced expiratory volume in 1 s was improved by 27.1–286.9 mL in all but one comorbidity subgroup, the diabetes mellitus subgroup. Conclusions Mepolizumab reduces exacerbations, and improves asthma control, health-related quality of life, and lung function in patients with severe eosinophilic asthma despite comorbid conditions, including upper respiratory conditions, psychopathologies, cardiovascular conditions, gastroesophageal reflux disease, diabetes mellitus, and obesity. Trial registration: https://clinicaltrials.gov/ DREAM, MEA112997/NCT01000506; MENSA, MEA115588/NCT01691521; SIRIUS, MEA115575/NCT01842607; MUSCA, 200862/NCT02281318.

Background A pre-specified meta-analysis of individual patient data from the 52-week METREX and METREO trials, which investigated mepolizumab for chronic obstructive pulmonary disease (COPD) in patients with blood eosinophil counts ≥150 cells/µL (screening) or ≥300 cells/µL (prior year) and frequent exacerbations, enables more robust characterization of mepolizumab efficacy in COPD and exploration of the relationship between blood eosinophil count and treatment responses. Methods In METREX (117106/NCT02105948) and METREO (117113/NCT02105961), randomized patients received mepolizumab or placebo added to existing inhaled corticosteroid (ICS)–based triple maintenance therapy. The annual rate of moderate/severe exacerbations (primary endpoint) was compared between subcutaneous (SC) mepolizumab 100 mg versus placebo (primary comparison of interest) and all doses (100 mg and 300 mg SC) versus placebo in patients with blood eosinophil counts ≥150 cells/µL at screening or ≥300 cells/µL in the prior year. Secondary/other endpoints included time to first moderate/severe exacerbation, exacerbations leading to emergency department visit/hospitalization and health-related quality of life (HRQoL). A predictive model of the relationship between screening blood eosinophil counts and exacerbation rates included data from all randomized patients. Results In total, 1510 patients were randomized in METREX and METREO and 1136 patients were included in the pre-specified meta-analysis. From the meta-analysis, mepolizumab 100 mg SC significantly reduced annual moderate/severe exacerbation rates versus placebo by 18% (rate ratio: 0.82; 95% confidence interval: 0.71, 0.95; p=0.006) and delayed time to first moderate/severe exacerbation (hazard ratio: 0.80 [0.68, 0.94]; p=0.006). Mepolizumab 100 mg SC versus placebo numerically reduced exacerbations leading to ED visits/hospitalization and improved HRQoL. A modelling approach demonstrated increasing efficacy for moderate/severe exacerbations with increasing screening blood eosinophil count; this relationship was more pronounced for exacerbations requiring oral corticosteroids (post hoc). The all-doses comparison had similar results. Conclusion Mepolizumab reduces exacerbations in patients with eosinophil-associated COPD. Results suggest that blood eosinophil counts (≥150 cells/µL at screening or ≥300 cells/µL in the prior year) allow for identification of patients with COPD who experience exacerbations while treated with maximal ICS-based triple maintenance therapy who are likely to benefit from mepolizumab., Video abstract Point your SmartPhone at the code above. If you have a QR code reader the video abstract will appear. Or use: https://youtu.be/YCq1mqQ5Xl4

A 39-year-old man presented with peripheral eosinophilia, pulmonary eosinophilic infiltrate, and renal failure due to acute tubulointerstitial nephritis (TIN). He had experienced childhood asthma and was negative for anti-neutrophil cytoplasmic antibody (ANCA). He was tentatively diagnosed with ANCA-negative eosinophilic granulomatous polyangiitis (EGPA) or idiopathic hypereosinophilic syndrome (HES). Renal involvement of isolated TIN with eosinophil infiltration is rare in EGPA and HES and does not seem to have a good prognosis in the literature. However, his condition improved well with corticosteroids and mepolizumab. The revised classification of EGPA based on the etiology should dictate the proper treatment in suspected EGPA patients with nonsystemic vasculitis.

Asthma is a heterogeneous disease, characterised by different phenotypes and endotypes. Precision medicine in asthma refers to the implementation of a targeted therapy for each individual child, based on the identification of treatable traits, including environmental, immunological and genetic factors. Severe asthma in children is associated with increased hospitalisation rates, a lower quality of life, increased healthcare costs and an increased mortality. In the era of new molecular biologics treatments, it is essential to improve deep phenotyping of children with severe asthma in order to deliver the most effective treatment to each individual child. In this review, we discuss the personalised approach to the assessment and management of severe asthma. We explore the indications and use of the currently licensed biologics, as well as the potential of other emerging treatments.

Allergic Bronchopulmonary Aspergillosis (ABPA) is a pulmonary disease characterized by recurrent pulmonary opacities and bronchiectasis caused by Type 1 hypersensitivity to A. fumigatus. Asthma is an important part of the disease and is generally in severe form. It is thought that immunoglobulins against A. fumigatus, Th2-derived cytokines such as IL-4, IL-5 and IL-13 and eosinophilic inflammation play a role in the pathogenesis of the disease. Monoclonal antibody treatments targeting IL-4, IL-5, IL-13 and IgE, which are involved in pathogenesis, have been used in asthmatic patients before. The main treatment of ABPA for exacerbations and remissions is oral corticosteroids (OCS). However, in cases where the corticosteroid dose cannot be reduced or side effects develop, monoclonal agents may be added to the treatment. Monoclonal agents such as omalizumab, mepolizumab, benralizumab and dupilumab targeting cytokines involved to the patogenesis have been used in patients with ABPA. Omalizumab has shown a reduction in exacerbations and OCS requirements, improvement in asthma symptoms and improvement in pulmonary function parameters. With mepolizumab, a decrease in OCS dose, decrease in blood eosinophil count, clinical improvement and radiological improvement were observed. Benralizumab reduced, the number of eosinophil or even almost nullified as well as clinical recovery alongside with radiological improvement. With dupilumab, improvement in symptoms, discontinuation of OCS, but increase in eosinophil count at the beginning of treatment was reported. As a result, monoclonal antibodies were generally found to be successful and safe in patients with ABPA.

A 26-year-old woman presented with abdominal pain, diarrhoea, vomiting, fever, and progressive paralysis in the lower limbs. She had a history of bronchial asthma and experienced sinusitis, progressive peripheral neuropathy, polyarthritis, and leukocytosis with prominent eosinophilia. The patient was diagnosed with eosinophilic granulomatosis with polyangiitis (EGPA). Abdominal pain was considered to be an ischaemic enteritis associated with EGPA. She was administered 1,000 mg/day of methylprednisolone for 3 days and intravenous immunoglobulin (400 mg/kg/day of γ-globulin for 5 days) followed by 50 mg (1 mg/kg)/day of oral prednisolone due to rapidly progressing peripheral neuropathy. Her symptoms temporarily improved; however, peripheral neuropathy recurred after a week, and the eosinophil count increased. Eighteen days after following the resumed treatment, 300 mg of mepolizumab, a humanised monoclonal antibody, was administered. Subjective symptoms, nerve conduction velocity, and skin perfusion pressure (an index of peripheral circulation in the lower extremities) improved after 4 weeks. Although mepolizumab has been approved for EGPA, there is no evidence of its efficacy against peripheral neuropathy. Early introduction of mepolizumab may contribute to an the early improved progressive peripheral neuropathy with eosinophilia.

The global COVID-19 pandemic has brought respiratory disease to the forefront of public health, but asthma prevalence has been rising globally for decades. Asthma is mediated by errant immune activation and airway remodeling, but the influences of environment, nutrition, and comorbidities (e.g., asthma-chronic obstructive pulmonary disorder-overlap [ACO]) are still poorly understood. Even as a new generation of biologic-based treatments offer better airway control and reductions in mortality, a lack of prophylactic treatments and mechanistic understanding complicates efforts to prevent pathogenesis. This review will explicate and synthesize current knowledge on the effect of ACO and biologics (omalizumab, mepolizumab, reslizumab, benralizumab, and dupilumab) on pathogenesis, treatment, and prognosis.

Background: The majority of patients with uncontrolled severe CRSwNP, asthma and atopic dermatitis share a similar T helper 2 type inflammation linked to their underlying phenotype. This discovery has triggered new research around treatments targeting specific cytokines driving inflammation in CRSwNP like IL-4, IL-13, IL-5 and IgE. Biologicals are increasingly tested as additional tre- atment for patients suffering from severe chronic rhinosinusitis with nasal polyps (CRSwNP). Their efficacy has been demonstrated in multiple studies. All studies differ in terms of baseline characteristics of included patients and outcome parameters analysed. Aims: A comparative analysis of the efficacy of reported biologicals for CRSwNP based on the published data for phase 2 and 3 studies. The aim was to provide a comprehensive overview across the different biologicals and outcome parameters. Methods: In a first step we critically selected out of all available phase 2 and 3 clinical trials the ones containing the most rigorous and compatible study designs. Meaning studies that comply with a need for a clear definition of CRSwNP, at least two administra- tion doses, comparable timeframes and the same outcome parameters studied. This assessment was performed using a PRISMA search. We retained 7 studies with significant data for dupilumab, mepolizumab and omalizumab. In a second step the effect-sizes of treatment with those biologicals were compared for the most important outcome parameters both patient relevant (nasal con- gestion, smell loss and SNOT-22 scores) and patient irrelevant (CT scan Lund-Mackay, smell test and nasal polyp scores). Therapy duration of 16 to 25 weeks was chosen for evaluation of efficacy. Results: A direct comparison of efficacy between dupilumab, mepolizumab and omalizumab is challenging given differences in inclusion criteria, outcome parameters and time-points of analyses. We have been able to conclude that effect sizes of dupilumab, mepolizumab and omalizumab seem large enough to reflect a major reduction in symptom burden as experienced by patients suffering from refractory CRSwNP. The effect size of dupilumab on both patient relevant and patient irrelevant parameters of smell loss are clearly significant and reflect the clinical experience of major reduction of smell impairment in treated patients. Conclusion: Despite the heterogeneity of protocols, dosages and time-points of analyses of biological trials in CRSwNP, this over- view highlights outcomes of biological treatment in CRSwNP in a comprehensive way. Real-life registries, comparative trials and/ or endotype-driven treatment plans are needed to provide the answers to the multiple questions that are still open today.

Introduction: In recent years, the advent of immunotherapy has remarkably improved the management of IgE-mediated food allergy. However, some barriers still exist. Therefore, the effort of researchers aims to investigate new perspectives in the field of non-allergen specific therapy, also based on the current knowledge of the pathogenesis of this disease.Areas covered: This review aims to focus on the role of biologics as a treatment option in patients with IgE-mediated food allergy. These agents are characterized by their ability to inactivate the Th2 pro-inflammatory pathways. Biologics can be used both alone and in association with immunotherapy. Monoclonal antibodies targeting IgE, the IL-4/IL-13 axis, IL-5, and alarmins have been proposed and investigated for treating food allergy.Expert opinion: The clinical efficacy and safety of biologics have been demonstrated in several preclinical studies and randomized controlled trials. Future studies are still required to address current unmet needs, including the identification of the optimal dose to be used by ensuring the effectiveness of therapy.

A case of eosinophilic granulomatosis with polyangiitis (EGPA) in which chronic rhinosinusitis (CRS) was improved with a reduction in the myeloperoxidase-antineutrophil cytoplasmic antibody (MPO-ANCA) titer after the addition of mepolizumab is reported. A 55-year-old woman with EGPA receiving prednisolone 5 mg/day developed CRS with increases in the eosinophil count and the MPO-ANCA titer. Although it improved with prednisolone 15 mg/day in addition to mizoribine 150 mg/day, because azathioprine could not be taken orally due to side effects, it relapsed after prednisolone was tapered to 5 mg/day. There was no exacerbation of other vasculitis symptoms such as mononeuropathy multiplex. The patient was treated with additional mepolizumab 300 mg every 4 weeks, which resulted in the improvement of CRS and marked reductions of the eosinophil count and MPO-ANCA titer, and the reduction of prednisolone to 2 mg/day. Furthermore, even after tapering mepolizumab to 200 mg every 4 weeks, her condition remained stable without relapse of EGPA and without increases in the eosinophil count and MPO-ANCA titer. The clinical course of mepolizumab treatment in this patient suggests that the IL5-dependent inflammatory cascade is one of the factors contributing to the increase in MPO-ANCA in EGPA.

Add-on therapy with monoclonal antibodies is the recommended therapy for severe asthmatic patients refractory to maintenance treatment. In randomized control trials, mepolizumab reduced the number of exacerbations, the need of oral corticosteroids (OCS), increased asthma control, and lung function in a population of uncontrolled severe eosinophilic asthmatic patients. In this piece of work, we aimed to assess mepolizumab efficacy and safety in a cohort of patients with severe eosinophilic asthma in real-life conditions.A retrospective study was carried out at eight hospitals from Asturias (Spain). The sample included patients treated with mepolizumab from 1 January 2016 to 31 March 2019. Demographic and clinical variables were collected, including OCS use, asthma control, lung function, and exacerbation rate.Sixty-nine patients (72% women) with mean age 56 ± 13 years were included. Annual exacerbation rate decreased from 4.7 (SD 3.7) to 1.3 (SD 2.5) (Overall, this study demonstrates mepolizumab efficacy and safety in a cohort of patients with uncontrolled severe eosinophilic asthma in routine clinical practice.

Idiopathic hypereosinophilic syndrome is a rare disease which is diagnosed after excluding other conditions. The syndrome is characterized by multiple organ involvement including the heart, nervous system, lungs, and gastrointestinal tract. The disease is suspected if there is peripheral blood eosinophilia and no clear etiology. The main treatment is corticosteroids. Patients who do not respond to corticosteroids can be treated with imatinib, immunomodulatory agents, myelosuppressive therapy, or mepolizumab. Alemtuzumab can be considered in severe cases that are unresponsive to other therapies. In this paper, we describe a case of idiopathic hypereosinophilic syndrome with mainly cardiac system involvement and left ventricular thrombus formation which was complicated by cerebral thromboemboli while on warfarin with international normalized ratio in the therapeutic range. Our patient responded well to steroids appreciated by improvement in clinical symptoms and decrease in eosinophil count.

Background/aims The efficacy and safety of mepolizumab in patients with severe eosinophilic asthma has been evaluated in a global clinical trial programme. This post hoc analysis assesses the efficacy and safety of mepolizumab in Korean patients. Methods Data from Korean patients in the Phase III, placebo-controlled, randomised DREAM (MEA112997/NCT01000506) and MENSA (MEA115588/ NCT01691521) studies were included. Patients ≥ 12 years old with severe eosinophilic asthma received mepolizumab (DREAM: 75, 250 or 750 mg intravenously [IV]; MENSA: 75 mg IV or 100 mg subcutaneously [SC]), or placebo every 4 weeks for 52 weeks (DREAM) or 32 weeks (MENSA). The primary outcome was the rate of clinically significant asthma exacerbations. Secondary outcomes included forced expiratory volume in 1 second (FEV1), Asthma Control Questionnaire (ACQ) and St George's Respiratory Questionnaire (SGRQ) scores (MENSA only). Blood eosinophil counts (BEC) and safety were assessed throughout. Results Reductions in the rate of clinically significant asthma exacerbations were observed with the approved (100 mg SC) and bioequivalent (75 mg IV) doses of mepolizumab in Korean patients who participated in DREAM and MENSA. In MENSA, trends for improvements from baseline at week 32 in pre-bronchodilator FEV1 (75 mg IV group), ACQ-5 and SGRQ scores (in both treatment groups) were seen versus placebo in Korean patients. Incidence of on-treatment adverse events was similar in Korean patients versus non-Korean patients as were observed reductions from baseline in BEC. Conclusions Mepolizumab treatment provided clinical benefits for Korean patients with severe eosinophilic asthma; the safety profile is consistent with the overall population.

Background Mepolizumab (MPZ), an anti-interleukin-5 antibody, is effective for the treatment of eosinophilic granulomatosis with polyangiitis (EGPA). However, its effectiveness has not been adequately evaluated in real-world clinical practice. In this study, we assessed the effectiveness and safety of MPZ (300 mg) for relapsing/refractory EGPA resistant to corticosteroids (CS) for 1 year in real-world settings. Methods We administered MPZ (300 mg) to 16 patients with relapsing/refractory EGPA resistant to CS (Post-MPZ). We also retrospectively collected data from the same patients for the 12 months before the administration of MPZ (Pre-MPZ). The primary endpoint was the 12-month remission rate after MPZ administration and the secondary endpoints were the Birmingham vasculitis activity score (BVAS), vasculitis damage index (VDI), eosinophil counts, changes in concomitant CS doses/concomitant immunosuppressant use, MPZ retention rate, and incidence of adverse events. The clinical course was compared between Pre-MPZ and Post-MPZ. Results The 12-month remission rate after the initiation of MPZ was 75%. No change was observed in BVAS, eosinophil count, or concomitant CS dose over time in the Pre-MPZ group, whereas all these parameters were significantly decreased over time in the Post-MPZ group. The number of patients using concomitant immunosuppressant also decreased over time in the Post-MPZ group. VDI did not increase in either group. The MPZ retention rate was 100% and only three patients (18.8%) had infections. Changes in BVAS, eosinophil count, and cumulative concomitant CS dose were significantly lower in the Post-MPZ group than in the Pre-MPZ group. There was no significant difference in the changes in VDI between the groups. Conclusion This study demonstrated that MPZ is effective and safe for EGPA. Furthermore, MPZ decreases disease activity, increases remission rate, and has a CS-sparing effect.

Biologic agents, including anti-immunoglobulin E (omalizumab) and anti-interleukin 5 (mepolizumab), target different mediators involved in the inflammatory process and may work synergistically to decrease symptoms in patients with severe asthma. Here we describe a 12-year-old female on 2 biologic agents, omalizumab and mepolizumab, to control severe persistent asthma. Omalizumab was started years earlier with an initial response; however, her asthma again became uncontrolled and mepolizumab was added. Both biologics were administered concomitantly for over 6 months with marked improvement of asthma symptoms without significant side effects. A combination of biologic agents may be a potential therapy for pediatric patients with severe persistent asthma that remains uncontrolled on a single agent.

Objective. Currently, the issues of the effect of anti-B cell therapy or inhibitor of interleukin 5 on the risk of COVID-19 infecting and outcomes in patients with ANCA-associated vasculitis (AAV) has not been completely studied. We present an analysis of the COVID-19 course and outcomes in AAV patients treated with rituximab or mepolizumab from one rheumatology center registry. Methods. From November 11 to November 15, 2020, a cross-sectional study was conducted using telephone and online surveys, and information was collected from all 128 AAV patients treated with rituximab in V.A. Nasonova Research Institute of Rheumatology. Patients mean age was 51 (20–81) years, 61.7% were women. Granulomatosis with polyangiitis (GPA) was diagnosed in 58 patients, microscopic polyangiitis (MPA) – in 38, eosinophilic granulomatosis with polyangiitis (EGPA) – in 24 (including 54.2% of ANCA-negative cases), and AAV with uncertain nosological affiliation – in 8 patients. Due to the disease activity or a high risk of AAV recurrence during the pandemic rituximab was prescribed in 60/126 (47.6%) patients, and mepolizumab – in 6 cases. Results. In the spring of the pandemic (until May 2020), the incidence of COVID-19 in AAV patients treated with rituximab was 4.3%, the disease course was relatively favorable. All patients recovered. At month 3–6, antibodies to SARS-CoV-2 IgG persisted in only 1 out of 4 patients. Since September 2020, the incidence has increased 3-fold, with a more severe course of COVID-19. In total, in the period until November 11, 2020, COVID-19 was diagnosed in 17.2% (22/128); the mean age of patients was 55 (25–81) years; 54.5% were women. 21/22 patients were on rituximab therapy, 2 patients had mepolizumab therapy (including 1 case after previous rituximab therapy). COVID-19 incidence was lower in patients with GPA (15.5%) vs MPA and EGPA (21.1% and 20.8% respectively). The mortality rate was 13.6%, including 2 patients with MPA and 1 patient with GPA. When analyzing the 5-year survival rate according to the registry of AAV patients treated with rituximab, prognosis worsening was noted; in 2020 there were 3 deaths due to COVID-19, in the previous 5 years – only 2 deaths. Discussion. Taking into account the fact the mechanisms of AAV and severe COVID-19 are largely synergistic (primarily in the context of microvascular COVID-19 lung vessels obstructive thromboinflammatory syndrome as manifestation of the acute inflammatory syndrome), the activity of AAV can potentially contribute to the disease onset and a severe course of COVID-19. Given the previously published information on the use of rituximab during the COVID-19 pandemic for various diseases, it seems that B cell depletion, without reducing the risk of infection, may have a protective effect with regard to the risk of severe/catastrophic COVID-19, which, however, can be insufficient in AAV patients. Further analysis of COVID-19 cases in patients with AAV and other immuno-inflammatory rheumatic diseases is exceptionally important.

Recently, mepolizumab, an interleukin (IL)-5 inhibitor, has been indicated for the treatment of eosinophilic granulomatosis with polyangiitis (EGPA) refractory to standard therapies. However, no reports have compared the efficacy of mepolizumab according to symptoms and organ lesions. Herein, we report two cases in which mepolizumab was highly effective in the management of EGPA with lung lesions and otitis media refractory to treatment with multiple immunosuppressive agents. These two cases suggest that mepolizumab is effective in treating pulmonary and ear lesions in EGPA.

Background Asthma and some chronic rhinosinusitis (CRS) subtypes are mediated by similar pathophysiologic mechanisms. The purpose of this study was to evaluate the effects of biologic therapy for asthma on co-existent CRS in the "real-world" setting. Methods A review of electronic health records (2016-2019) at Mayo Clinic was conducted to identify asthma patients treated with biologics who had co-existent CRS. Matched-pair analyses compared pretherapy and posttherapy Lund-Mackay computed tomography (CT) scores and 22-item Sino-Nasal Outcome Test (SNOT-22) scores. Performance of endoscopic sinus surgery (ESS) after initiating biologics was studied. Results We identified 247 patients who received anti-asthma biologic therapy and had co-existent CRS. Of these, 181 patients (73.3%) had CRS with nasal polyposis (CRSwNP) and 66 (26.7%) had CRS without nasal polyposis (CRSsNP). The biologics utilized were omalizumab (51.0%), mepolizumab (46.6%), benralizumab (10.5%), reslizumab (1.6%), and dupilumab (2.4%). Anti-interleukin-5 (anti-IL-5) intervention was associated with significant improvement in CT scores (CRS overall, CRSwNP subgroup, CRSsNP subgroup) and SNOT-22 scores (CRS overall, CRSwNP subgroup). Patients on omalizumab had a decrease in CT scores, but not SNOT-22 scores. ESS was performed in 206 patients (84.1%); 55 (22.3%) underwent surgery post-biologic intervention (anti-IL-5: 16.5%; omalizumab 27.8% of patients). Conclusion Anti-IL-5 agents were associated with improved CT and SNOT-22 scores in the overall CRS group and in CRSwNP subgroup; CRSsNP patients showed improved CT scores only. Omalizumab improved CT but not SNOT-22 scores. ESS was performed in 22% of patients after initiating biologics. These real-world results may influence future trial designs and clinical applications of biologics for CRS. ©2021 ARSAAOA, LLC.

Eosinophils are a type of granulocyte with eosinophilic granules in the cytoplasm that play an important role in allergic and parasitic diseases. Eosinophils are important in the pathogenesis of asthma, and many studies have examined the relationship between them. In allergic eosinophilic asthma, eosinophils act not only as important effector cells but also as antigen-presenting cells in allergic inflammatory reactions. In nonallergic eosinophilic asthma, type 2 innate lymphoid cells in the airways play an important role in eosinophil activation. Direct methods, including bronchial biopsy, bronchoalveolar lavage, and the induced sputum test, are used to evaluate eosinophilic inflammatory reactions in patients with asthma, however, because of difficulty with their implementation, they are sometimes replaced by measurements of blood eosinophils, fraction of exhaled nitric oxide, and serum periostin level. However, these tests are less accurate than direct methods. For the treatment of patients with severe eosinophilic asthma, anti-interleukin-5 preparations such as mepolizumab, reslizumab, and benralizumab have recently been introduced and broadened the scope of asthma treatment. Although eosinophils are already known to play an important role in asthma, we expect that further studies will reveal more details of their action.

Anti-neutrophil cytoplasmic antibodies-associated vasculitides (AAVs) are a heterogenous group of inflammatory diseases which primarily involve small vessels and include granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA) and eosinophilic granulomatosis with polyangiitis (EGPA). They present heterogeneous clinical manifestations, while their diagnosis and management still remain a challenge for clinicians. Nowadays, the treatment is based on two different regimens: the remission-induction treatment and the remission-maintenance treatment. The therapeutic armamentarium has grown over the years, with the aim to lessen adverse effects, improve quality of life of patients and maintain the disease under control. Biological treatments are the future: they act on different pathogenic pathways and may offer in the future a personalized management approach tailored to actual clinical manifestations. The latest guidelines were published in 2015 by the European League Against Rheumatism (EULAR) and still represent the vade mecum for the management of AAVs. In this review, we will focus on the principal strategies to treat AAVs. We discuss the remission-induction therapy and the remission- maintenance therapy; we have also distinguished the management of GPA and MPA from that of EGPA, because of their different clinical pictures.

Background Immune checkpoint inhibitors have potential applications in treating various cancers but are associated with immune-related adverse events, such as inflammation, in a wide range of organs; however, allergic inflammation caused by these agents has not been extensively studied. Case presentation A 65-year-old man was diagnosed with a kidney neuroendocrine carcinoma. Three months after kidney resection surgery, the tumor cells had metastasized to his liver and lymph nodes. Subsequently, the patient started chemotherapy; however, regardless of treatment, the tumor grew, and the patient experienced a series of adverse effects, such as taste disorder, anorexia, and general fatigue. Finally, he was administered a programmed cell death (PD)-1 inhibitor, nivolumab (biweekly, toal 200 mg/body), which was effective against kidney carcinoma. However, the patient had a bronchial asthma attack at 22 cycles of nivolumab treatment and chest computed tomography (CT) revealed an abnormal bilateral shadow after 37 cycles of nivolumab treatment. Bronchoscopy findings revealed eosinophil infiltration in the lungs along with severe alveolar hemorrhage. Paranasal sinus CT scanning indicated sinusitis and nerve conduction analysis indicated a decrease in his right ulnar nerve conduction velocity. Based on these findings, the patient was diagnosed with eosinophilic granulomatosis with polyangiitis; he was treated with prednisolone, which alleviated his bronchial asthma. To restart nivolumab treatment, the dose of prednisolone was gradually tapered, and the patient was administered a monthly dose of mepolizumab and biweekly dose of nivolumab. To date, there have been no bronchial attacks or CT scan abnormalities upon follow up. Conclusions We present a rare case in which a patient with cancer was diagnosed with eosinophilic granulomatosis with polyangiitis following treatment with a PD-1 inhibitor. Blockade of PD-1 and the programmed cell death ligand (PD-L) 1/PD-1 and PD-L2/PD-1 signaling cascade may cause allergic inflammation. Further studies are needed to identify the specific mechanisms underlying allergic inflammation after PD-1 blockade.

Background: In some patients with eosinophilic granulomatosis with polyangiitis (EGPA), remission cannot be induced, despite treatment with corticosteroids and immunosuppressants. We evaluated the clinical features of patients with EGPA in whom mepolizumab was effective. Methods: There were 59 EGPA patients treated at Hiratsuka City Hospital, Japan, between April 2018 and September 2020, and 30 of them received mepolizumab. Twenty (66.7%) experienced a “marked effect” (the daily dose of corticosteroid or immunosuppressant could be decreased, or the interval between intravenous immunoglobulin (IVIG) treatments could be prolonged) and 10 (33.3%) experienced a “weak effect” (these measures were not achieved). Eosinophil numbers, serum IgG levels, daily doses of corticosteroids and immunosuppressants, and the interval between IVIG treatments at diagnosis and before and after mepolizumab initiation were determined. Results: Eosinophil numbers at diagnosis were significantly higher in the marked-effect group than in the weak-effect group (p < 0.05) but not before mepolizumab initiation or at the last visit. Birmingham Vasculitis Activity Scores (BVASs) before mepolizumab initiation (p < 0.05) and at last visit (p < 0.01), and frequency of relapse before treatment initiation (p < 0.05) were significantly higher, and the serum IgG level before mepolizumab treatment was significantly lower in the weak-effect group than in the marked-effect group. The weak-effect group received higher doses of corticosteroids, even if the corticosteroid dose could be reduced for a while after mepolizumab initiation. Conclusion: High peripheral blood eosinophil numbers at EGPA diagnosis were suggestive of a positive clinical response to mepolizumab.

In the past years, we have seen a paradigm shift from symptomatic to disease-modifying approach to the treatment of chronic diseases. The treatment of asthma, which is a chronic disease, is no exception to this shift. Although the available therapies for asthma have been traditionally identified as either “controllers” or “relievers”, this dichotomous classification does not address the therapeutic potential to modify the underlying disease. The disease-modifying therapy for asthma can be defined either as airway remodeling or as modifying the disease's natural course. Among the biological therapies, the disease-modifying effect of omalizumab was studied most comprehensively. Some studies of other biological therapies for severe asthma (mepolizumab, benralizumab) also addressed the airway remodeling effect. A further study of the disease-modifying therapy should help gain a deeper understanding of its potential in managing asthma.