Dupilumab Efficacy on Asthma Functional, Inflammatory, and Patient-Reported Outcomes across Different Disease Phenotypes and Severity: A Real-Life Perspective.

Dupilumab is currently approved for the treatment of Type 2 severe asthma and chronic rhinosinusitis with nasal polyps (CRSwNP). Few studies have specifically reported on dupilumab efficacy on asthma outcomes as a primary objective in a real-life setting, in patients with and without CRSwNP. Our study aimed to explore the efficacy of dupilumab on functional, inflammatory, and patient-reported outcomes in asthma patients across different disease phenotypes and severity, including mild-to-moderate asthma coexisting with CRSwNP. Data from 3, 6, and 12 months follow-up were analyzed. Asthma (FEV1%, Tiffeneau%, ACT, FeNO, oral steroid use, exacerbation rate, and blood eosinophilia) and polyposis (SNOT22, VAS, NPS) outcomes showed a rapid (3 months) and sustained (6 and 12 months) significant change from baseline, despite most of the patients achieving oral steroid withdrawal. According to the sensitivity analysis, the improvement was not conditioned by either the presence of polyposis or severity of asthma at baseline. Of note, even in the case of milder asthma forms, a significant further improvement was recorded during dupilumab treatment course. Our report provides short-, medium-, and long-term follow-up data on asthma outcomes across different diseases phenotypes and severity, contributing to the real-world evidence related to dupilumab efficacy on upper and lower airways T2 inflammation.

Adherence to Intranasal Steroids in Chronic Rhinosinusitis with Nasal Polyposis Prior to and during Biologic Therapy: A Neglected Matter.

Adherence to treatment is essential in chronic rhinosinusitis with nasal polyposis (CRSwNP). Intranasal corticosteroids (INCS) are the first-line therapy, followed by systemic corticosteroids and surgery if needed. In cases of refractory disease, biologics are added to conventional treatment, making adherence to INCS crucial in assessing eligibility for these targeted therapies. The purpose of this review is to examine INCS adherence assessment and rate, before starting and during biologic therapy. We conducted a comprehensive literature review focusing on INCS adherence in CRSwNP treated with biologics, including randomized controlled trials and real-life studies. The search extended to studies on allergic and non-allergic rhinitis to provide broader insights into tools to assess the INCS adherence. The result was that adherence to INCS in CRSwNP is underexplored, with only a few studies addressing it directly. Various tools for adherence assessment have been identified, but none are universally accepted as standard. The review also highlights the complexity of factors influencing adherence rates. Effective CRSwNP management requires a paradigm shift to prioritize adherence in treatment guidelines and clinical practice. The review advocates for improved adherence assessment tools, a deeper understanding of influencing factors, and the integration of personalized medicine approaches, especially for biologic therapies.

Safety of dupilumab in T2 airways conditions: focus on eosinophilia across trials and real-life evidence.

INTRODUCTION: Dupilumab, a monoclonal antibody targeting the IL-4 receptor alpha subunit, effectively blocks both IL-4 and IL-13 mediated pathways. Its introduction has represented a significant advancement in the treatment of severe asthma and other Type 2 (T2) conditions, including nasal polyps, atopic dermatitis, and eosinophilic esophagitis. To date, Dupilumab has demonstrated optimal efficacy and safety profile. AREAS COVERED: The safety profile of dupilumab has been extensively studied, especially for its effects on blood eosinophil count. Transient eosinophil increase during treatment is typically insignificant from a clinical point of view and related to its mechanism of action. Rare cases of hyper-eosinophilia associated with clinical conditions like eosinophilic granulomatosis with polyangiitis (EGPA) and hypereosinophilic syndrome (HES) have been reported. Those cases are often related to the drug's steroid-sparing effect or the natural trajectory of the underlying disease rather than a direct cause-effect relationship with dupilumab. EXPERT OPINION: The management of hyper-eosinophilia during dupilumab treatment requires comprehensive diagnostic work-up and strict follow-up monitoring for early detection of systemic disease progression in order to avoid unnecessary discontinuation of an effective treatment. This approach highlights the importance of a personalized treatment.

Remission in Type 2 Inflammatory Diseases: Current Evidence, Unmet Needs, and Suggestions for Defining Remission in Chronic Rhinosinusitis with Nasal Polyps.

PURPOSE OF REVIEW: The development of biological therapies for type 2 inflammatory diseases raises the possibility of addressing remission in those dis-immune conditions. No consensus exists for a definition of remission in chronic rhinosinusitis with nasal polyps (CRSwNP). This review aims to critically evaluate the published data to provide the basis for defining remission in CRSwNP. RECENT FINDINGS: The published evidence has yet to provide an unequivocal definition on remission in type 2 inflammatory diseases, in part reflecting differences in approaches to diagnosis and follow-up. A multidimensional evaluation is necessary when considering complete remission, including clinical, inflammatory, and histologic criteria, but how to combine or tailor the three perspectives according to disease severity at baseline or timing of assessment of treatment category is yet to reach consensus. We suggest defining remission starting from the approach taken in asthma and eosinophilic esophagitis, that is, including the resolution of symptoms and improvements in objective parameters of disease severity and/or inflammatory activity. Future studies and consensuses should provide validated criteria with cutoffs for the day-to-day definition of remission. The definition of remission in CRSwNP should include the following criteria, to be verified and maintained for a period of ≥ 12 months: absence of symptoms (nasal obstruction, loss of smell, rhinorrhea as the main ones); no impact of symptoms on quality of life; no need of surgery; no chronic or rescue medications (systemic corticosteroids or antibiotics); and recovery of smell function, possibly evaluated by objective test. Assessment of underlying inflammation should also be considered once accurate and feasible biomarkers are available in clinical practice.

Resensitization in suspected penicillin allergy.

BACKGROUND: The diagnosis of allergic reactions to penicillins (AR-PEN) is very complex as there is a loss of sensitization over time, which leads to negative skin tests (STs) and specific IgE in serum, and even to tolerance to the drug involved. However, STs may become positive after subsequent exposure to the culprit drug (resensitization), with the risk of inducing potentially severe reactions. The exact rate of resensitization to penicillins is unknown, ranging from 0% to 27.9% in published studies. OBJECTIVES: To analyze the rate of resensitization in patients with suggestive AR-PEN by repeating STs (retest) after an initial evaluation (IE). MATERIAL AND METHODS: Patients with suspected AR-PEN were prospectively evaluated between 2017 and 2020. They underwent STs, and a randomized group also underwent a drug provocation test (DPT) with the culprit. Only patients with negative STs and/or DPT were included. All included cases were retested by STs at 2-8 weeks. RESULTS: A total of 545 patients were included: 296 reporting immediate reactions (IRs) and 249 non-immediate reactions (NIRs). Eighty (14.7%) cases had positive results in retest (RT+): 63 (21.3%) IRs and 17 (6.8%) NIRs (p < 0.0001). The rate of RT+ was higher in anaphylaxis compared with all other reactions (45.8% vs 9.1%, p < 0.0001). The risk of RT+ was higher from the fifth week after IE (OR: 4.64, CI: 2.1-11.6; p < 0.001) and increased with the patient's age (OR: 1.02; CI: 1.01-1.04; p = 0.009). CONCLUSIONS: Due to the high rate of resensitization, retest should be included in the diagnostic algorithm of IRs to penicillins after an initial negative study, especially in anaphylaxis, to avoid potentially severe reactions after subsequent prescriptions of these drugs.

Dupilumab-induced hypereosinophilia: review of the literature and algorithm proposal for clinical management.

INTRODUCTION: Dupilumab is a human monoclonal antibody that targets both IL-4 and IL-13 signaling. It is currently indicated for the treatment of asthma, moderate-to-severe atopic dermatitis, and chronic rhinosinusitis with nasal polyps (CRSwNP). Eosinophilia has been reported as a potential adverse event in treated patients. AREAS COVERED: A selective search on PubMed and Medline up to January 2022 was performed, by focusing on dupilumab-induced hypereosinophilia described in clinical trials, real-life studies, and case reports. The possible mechanisms underlying dupilumab-induced hypereosinophilia and the eosinophil-related morbidity have also been explored. EXPERT OPINION: Dealing with dupilumab-induced hypereosinophilia represents a clinical challenge for clinicians managing patients on dupilumab therapy. An algorithm for the practical management of dupilumab-induced hypereosinophilia has been proposed, in order to properly investigate potential eosinophil-related morbidity and avoid unnecessary drug discontinuation.

Multidisciplinary management of type 2 inflammatory diseases.

Greater understanding of molecular pathophysiology has led to the recognition that an excessive type 2 inflammatory response is at the basis of the pathophysiology of several inflammatory diseases including atopic dermatitis (AD), asthma, and chronic rhinosinusitis with nasal polyps (CRSwNP). Given the availability of biological agents that can permit management of specific disease endotypes, this reinforces the need for detailed characterization of these diseases through a multidisciplinary approach. Herein, these three conditions are briefly overviewed and practical guidance for a multidisciplinary approach to management is presented. Since type 2 inflammation is suppressed by steroids, drugs such as glucocorticoids have long been the workhorse of medical therapy. However, steroids have well-known local and systemic adverse effects, especially when used at high doses over prolonged periods of time, which is problematic when treating chronic diseases such as AD, asthma, and CRSwNP. Moreover, a substantial proportion of patients remain refractive to therapy. In the attempt to overcome these limitations, greater understanding of the molecular mechanisms of type 2 inflammation have led to the development of targeted biological drugs such as dupilumab, a fully human monoclonal antibody that targets the α chain of the IL-4 receptor. Dupilumab represents a unique therapy for type 2 inflammatory diseases and to date is the only therapy approved for AD, asthma, and CRSwNP. In terms of multidisciplinary management of type 2 inflammatory conditions, the main healthcare professionals involved include a dermatologist, pneumologist or allergologist, and ENT specialist. The model proposed herein takes into account the complex management of patients with type 2 inflammatory conditions and the new biological agents available. A multidisciplinary team can provide a central point for patient management, improve outcomes and specialist referrals, reduce costs, and guarantee that the most appropriate therapeutic decisions are made, as well as aid in management of adverse events. The multidisciplinary model should be structured and dedicated, but at the same time simple and flexible in order to not risk slowing down the patient's care. At present, it is believed that a structured multidisciplinary approach is currently the best means to optimize care of patients with type 2 inflammatory conditions.

ARIA-ITALY multidisciplinary consensus on nasal polyposis and biological treatments.

In the recent years, it was recognized that type-2 inflammation links many forms of nasal polyposis with severe asthma. Thus, some biological drugs developed for severe asthma appeared to exert an effect on nasal polyposis. So far, there are several trials supporting this concept; therefore, some monoclonal antibodies for severe asthma were assessed also in polyposis, with promising results. Since different specialists are involved in the management of nasal polyposis (eg, pulmonologists, ENT, allergists), it was felt that an educational and informative document was needed to better identify the indications of biologicals in nasal polyposis. We collected the main Italian Scientific Societies, and prepared (under the Allergic Rhinitis and its Impact on Asthma, ARIA) a document endorsed by all Societies, to provide a provisional statement for the future use of monoclonal antibodies as a medical treatment for polyposis. It is the first nationwide endorsed document on this aspect. The current pathogenic knowledge and the experimental evidence are herein reviewed, and some suggestions for a correct prescription and follow-up are provided.

The Characteristics of Severe Chronic Upper-Airway Disease (SCUAD) in Patients with Allergic Rhinitis: A Real-Life Multicenter Cross-Sectional Italian Study.

BACKGROUND: There are few studies regarding severe chronic upper-airway disease (SCUAD) that represents an important socioeconomic problem for the treatment of rhinitis and associated comorbidities, particularly asthma. OBJECTIVES: The aim of our study is to evaluate the prevalence of this pathology in patients with allergic rhinitis (AR) in real life, to phenotype allergic patients with SCUAD, and to identify which factors are related to the severity of the disease. METHODS: We studied 113 patients with uncontrolled AR despite optimal adherence to therapy according to the Allergic Rhinitis and its Impact on Asthma (ARIA) guidelines in a multicenter Italian study, analyzing comorbidity, use of additional drugs, not scheduled visits, and the number of emergency room admissions. RESULTS: Our data suggest that polysensitization is the only statistically significant factor correlating with SCUAD. Asthma does not seem to represent a correlating factor. An important finding is the poor use (20%) of allergy immunotherapy (AIT), although patients were suffering from AR and the ARIA guidelines recommend the use of AIT in moderate/severe AR. CONCLUSIONS: The SCUAD population seems not to have a specific phenotype; there is a greater presence of SCUAD in polysensibilized patients, perhaps a sign of greater inflammation.

Fatal asthma; is it still an epidemic?

BACKGROUND: Asthma mortality has declined since the 1980s. Nevertheless the World Health Organization (WHO) identified asthma as responsible for 225.000 deaths worldwide in 2005, and 430.000 fatal cases are expected by 2030. Some unexpected and concentrated fatal asthma events all occurred between 2013 and 2015 in Veneto, a North Eastern region of Italy, which prompted a more in-depth investigation of characteristics and risk factors. METHODS: A web search including key words related to fatal asthma in Italy between 2013 and 2015 has been performed. Concerning the cases that occurred in Veneto, subjects' clinical records have been evaluated and details about concomitant weather conditions, pollutants and pollen count have been collected. RESULTS: Twenty-three cases of asthma deaths were found in Italy; 16 of them (69%) occurred in the Veneto Region. A prevalence of male and young age was observed. Most of patients were atopic, died in the night-time hours and during the weekends. The possible risk factors identified were the sensitization to alternaria, previous near fatal asthma attacks and the incorrect treatment of the disease. Weather condition did not appear to be related to the fatal exacerbations, whereas among the pollutants only ozone was detected over the accepted limits. Smoking habits, possible drug abuse and concomitant complementary therapies might be regarded as further risk factors. DISCUSSION: Although not free from potential biases, our web search and further investigations highlight an increasing asthma mortality trend, similarly to what other observatories report. The analysis of available clinical data suggests that the lack of treatment more than a severe asthma phenotype characterizes the fatal events. CONCLUSIONS: Asthma mortality still represents a critical issue in the management of the disease, particularly in youngsters. Once more the inadequate treatment and the lack of adherence seem to be not only related to the uncontrolled asthma but also to asthma mortality.

What lies beyond Asthma Control Test: Suggestions for clinical practice.

BACKGROUND: Asthma Control Test (ACT ™) validity relies on Global Initiative for Asthma (GINA) definition of control. It includes neither reversibility nor inflammation assessment despite their importance as hallmark of asthma, partially unrelated to symptoms. Furthermore though rhinitis may affect the patient's perception of asthma control, its impact on ACT accuracy has not been systematically evaluated. OBJECTIVE: To explore ACT validity according to a definition of control including: forced expiratory volume in 1 s (FEV1) ≥ 80%, negative reversibility test, exhaled nitric oxide at a flow rate of 50 ml/s (FeNO) < 50 ppb. RESULTS: 177 asthmatics referring to our Unit have been studied. ACT with cut-off score ≥20 showed a good positive predictive value (83.5%) but low sensitivity (47.8%), specificity (66.7%), and negative predictive value (26.5%). ROC curves analysis indicates that ACT in patients with mild intermittent rhinitis is more reliable (AUC: 0.714; p < 0.05) than in patients with nasal polyposis/chronic rhino-sinusitis (AUC: 0.176; p > 0.05). Considering asthma classification, the probability that ACT detects patients with uncontrolled asthma is significantly higher in moderate persistent asthma subgroup than in mild persistent asthma one (OR 5.464; IC 95%: 2.5-11,9; p < 0.05). CONCLUSIONS: As ACT mainly relies on patient's reported outcomes, it may not completely reflect the airways inflammation and airways obstruction. The presence and severity of rhinitis may affect ACT outcome. The awareness of the variables that could influence ACT evaluation is much more important in the primary care setting where ACT may often represent the only tool for asthma assessment.

Asthma under/misdiagnosis in primary care setting: an observational community-based study in Italy.

BACKGROUND: Published data suggest that asthma is significantly under/misdiagnosed. The present community-based study performed in Italy aims at investigating the level of asthma under/misdiagnosis among patients referring to the General Practitioner (GP) for respiratory symptoms and undergoing Inhaled corticosteroids. METHODS: A sub-analysis of a previously published observational cross-sectional study has been provided. It included subjects registered in the GP databases with at least three prescriptions of inhaled or nebulised corticosteroids during the 12 months preceding the start of the study. All subjects, independently of the diagnosis, were invited to visit their GP's office for a standardised interview and to fill the European Community Respiratory Health Survey (ECRHS) questionnaire. RESULTS: The studies involved 540 GPs in most of the Italian regions and 2090 subjects (mean age 54.9 years, 54.1 % females) were enrolled. Among them 991 cases of physician-diagnosed asthma were observed while 1099 subjects received a diagnosis other than asthma (chronic obstructive pulmonary disease, chronic upper respiratory tract infections etc.). Among the lasts, the ECRHS questionnaire was suggestive for asthma diagnosis in 365 subjects (33.2 %). CONCLUSIONS: The data suggest that there is still a large under/misdiagnosis of asthma in the Italian primary care setting, despite the spread of GINA guidelines nearly 20 years before this study. A validated tool like the ECRHS questionnaire has detected a considerable proportion of potentially asthmatic patients who should be addressed to lung function assessment to confirm the diagnosis. Further educational efforts directed to the GPs are needed to improve their diagnosis of asthma (SAM104964).

Incidence and risk factors for subcutaneous immunotherapy anaphylaxis: the optimization of safety.

Fatal reactions related to subcutaneous allergen immunotherapy are rare: one event in 2.5 million injections has been reported in the USA and none in Europe. The prevalence of very severe systemic reactions (systemic adverse events [SAEs]) is one in 1 million injections. Though the serious events rate is decreasing and the majority of SAEs (∼0.2% per injection) are moderate and reversible, they still represent a major concern. Uncontrolled asthma, long-term therapy with ß-blockers and high degree of allergen sensitivity are generally considered risk factors. The relevance of other conditions, like previous local reactions, the use of extracts conjugated with adjuvants and accelerated build-up schedules is controversial, as well as the role of preventative strategies. A careful risk assessment of patients and optimal administration procedures may significantly decrease the risk of SAEs. However, more uniform safety data are required and an accurate safety profile should be provided for every allergen product.

Balancing efficacy against safety in sublingual immunotherapy with inhalant allergens: what is the best approach?

Over the last 20 years, studies and clinical trials have demonstrated efficacy, safety and cost-effectiveness of sublingual immunotherapy (SLIT) for respiratory allergic diseases. Nevertheless, it seems to be mostly used as a second-line therapeutic option, and adherence to treatment is not always optimal. Selective literature research was done in Medline and PubMed, including guidelines, position papers and Cochrane meta-analyses concerning SLIT in adult patients. The most recent reviews confirm SLIT as viable and efficacious treatment especially for allergic rhinitis, even if the optimal dosage, duration, schedule are not clearly established for most of the products. Despite an optimal safety profile, tolerability and patient-reported outcomes concerning SLIT have received poor attention until now. Recently, new tools have been specifically developed in order to investigate these aspects. Regular assessment of tolerability profile and SLIT-related patient-reported outcomes will allow balancing efficacy with tolerability and all the other patient-related variables that may affect treatment effectiveness beyond its efficacy.

[Asthma and aspirin]. / Asma ed aspirina.

Aspirin (ASA) is an important cause of asthma so that ASA induced asthma (AIA) is considered a disease. Its prevalence is of 0.3-0.6 in the general population but it raises to 21% in the asthmatic one. Middle aged female are the most affected. AIA generally begins with a non allergic rhinitis, complicated sometimes with polyps, that evolves secondarily in asthma. The disease is often so severe to need oral corticosteroids to be controlled. It persists independently to the intake of ASA. From a pathogenetic point of view the interaction of ASA with the arachidonic acid metabolism seems to be important. The inhibition of cyclo-oxygenase (COX) induces an activation of lypo-oxygenase with an increased synthesis of leukotrienes. In ASA intolerant patients there is also an activation of LTC4 synthetase, enzyme responsible for the synthesis of leukotrienes. Clinical history is very important to diagnose the disease but to confirm the diagnosis sometimes the provocation test is mandatory. Oral and bronchial challenges can be dangerous, while nasal challenge is safer even if must be better standardized. Patients must not use antiinflammatory drugs with the same mechanism of action of ASA; COX-2 inhibitors are generally well tolerated. Antileukotrienes are useful to treat asthma, in association with steroids. Desensitization can be used in very selected patients.

Nimesulide and meloxicam are a safe alternative drugs for patients intolerant to nonsteroidal anti-inflammatory drugs.

BACKGROUND: Pseudoallergic reactions to ASA and NSAIDs in general are frequent and difficult to manage. The challenge with the suspected drug is considered unethical, therefore the only possible approach is a challenge with alternative drugs. Selective COX2 inhibitors are considered the most suitable alternative drugs. We describe the comparative results and follow-up of an oral challenge with nimesulide and meloxicam, in NSAIDs intolerant patients. METHODS: 381 patients (118 male, 263 female, mean age 53.2 years) with a well documented pseudoallergic reaction to NSAIDs underwent an oral challenge with these alternative drugs. All 381 patients were given nimesulide 88 of them were also given meloxicam. All patients were re-interviewed at six-month intervals up to two years after challenge. RESULTS: 98.4% of the patients tolerated nimesulide and 95.4% tolerated meloxicam. The reactions occurred during challenges were mild and easily manageable. Three out of the six nimesulide-intolerant patients could tolerate meloxicam, whereas only one of the four meloxicam-intolerant patients could tolerate nimesulide. At the follow-up, 96% of patients with previous negative challenge could tolerate nimesulide and within the patients which took meloxicam after challenge no pseudoallergic reaction occurred. CONCLUSIONS: The herein described challenge with alternative drugs, meloxicam and nimesulide, is a safe tool for the management of NSAIDs-intolerant patients. The two tested drug are safe and reliable alternatives for these patients.

[Alternative tests in the diagnosis of food allergies]. / Test alternativi nella diagnostica delle allergie alimentari.

In the last years an increase of allergic diseases has been observed whose prevalence is about 20-30% in general population of western countries. However there is a risk of an over diagnosis of allergic diseases as many different diseases (migraine, chronic urticaria, chronic inflammatory bowel diseases, chronic-fatigue syndrome etc.) are considered due to food allergy or intolerance. In many patients the diagnosis is based on the results of alternative diagnostic tests such as the cytotoxic test, the provocation/neutralization sublingual or subcutaneous test, the heart-ear reflex test, the kinesiology, the biorisonance, the electro-acupuncture, and the hair analysis, or on immunological tests (immunocomplex or specific food IgG). We reviewed the scientific evidences of these tests (specificity, sensibility, rationale, reproducibility). According to most studies none of them had to be recommended as useful for the diagnosis of food allergy or intolerance. Physicians should alert patients about the risk of an indiscriminate use of these test in the diagnosis of food allergy. In fact the use of an incorrect diet could be dangerous, particularly in childhood, as recently shown.