Asthma management, focused on the use of oral corticosteroids: the opinions of Italian asthmatic patients.

OBJECTIVE: Patients' perceptions of asthma symptoms, and attitudes regarding diagnosis and management, can affect their ability to reach good asthma control. The aim of the study was to explore patients' perceptions of asthma management, with focus on treatment with oral corticosteroids (OCS). METHODS: A DOXAPHARMA survey was conducted. A questionnaire with 46 multiple choice questions was completed by 50 patients with severe uncontrolled asthma, and 258 with mild-moderate controlled or partly controlled asthma. Participants were representative of Italian asthmatic patients-with medium age, long asthma duration, delayed diagnosis, poor asthma control, and frequent exacerbations. RESULTS: Many asthmatics reported inadequate pharmacologic treatment. The majority but not all patients regularly used ICS/LABA. Oral treatment was common, mainly with OCS, particularly in severe asthmatics. One-fourth of patients did not regularly use inhaled therapy, and adherence was poor, resulting in frequent OCS use to treat exacerbations, which were common in mild-moderate cases. Patients were fairly satisfied with asthma therapies, but many had concerns about long-term corticosteroid use. Patients complained about poor management of comorbidities associated with asthma and OCS use, but were generally satisfied with their patient/doctor relationships. Many patients failed to achieve optimal health-related quality of life (HRQoL), mainly those with severe asthma who used OCS treatment and emphasized how OCS therapy impacted QoL. CONCLUSIONS: The survey results confirmed many problems related to mild-moderate and severe asthma management in Italy and highlighted the overuse of OCS rather than more effective and safe treatments, which had strong negative effects on HRQoL.

Thymic Stromal Lymphopoietin and Tezepelumab in Airway Diseases: From Physiological Role to Target Therapy.

Thymic stromal lymphopoietin (TSLP), is a protein belonging to a class of epithelial cytokines commonly called alarmins, which also includes IL-25 and IL-33. Functionally, TSLP is a key player in the immune response to environmental insults, initiating a number of downstream inflammatory pathways. TSLP performs its role by binding to a high-affinity heteromeric complex composed of the thymic stromal lymphopoietin receptor (TSLPR) chain and IL-7Rα. In recent years, the important role of proinflammatory cytokines in the etiopathogenesis of various chronic diseases such as asthma, chronic rhinosinusitis with nasal polyposis (CRSwNP), chronic obstructive pulmonary diseases (COPDs), and chronic spontaneous urticaria has been studied. Although alarmins have been found to be mainly implicated in the mechanisms of type 2 inflammation, studies on monoclonal antibodies against TSLP demonstrate partial efficacy even in patients whose inflammation is not definable as T2 and the so-called low T2. Tezepelumab is a human anti-TSLP antibody that prevents TSLP-TSLPR interactions. Several clinical trials are evaluating the safety and efficacy of Tezepelumab in various inflammatory disorders. In this review, we will highlight major recent advances in understanding the functional role of TSLP, its involvement in Th2-related diseases, and its suitability as a target for biological therapies.

Different aspects of severe asthma in real life: Role of Staphylococcus aureus enterotoxins and correlation to comorbidities and disease severity.

BACKGROUND: Asthma, with several phenotypes and endotypes, is considered particularly suited for precision medicine. The identification of different non-invasive biomarkers may facilitate diagnosis and treatment. Recently, Staphylococcus aureus and its enterotoxins (SE) have been found to have a role in inducing persistent type 2 airway inflammation in severe asthma, but also in such comorbidities as chronic rhinosinusitis with nasal polyposis (CRSwNP). METHODS: The aim of this retrospective study was to evaluate the prevalence of SE-IgE sensitization in a multicentric Italian cohort of severe asthmatic patients and correlate it with demographic and clinical characteristics. RESULTS: A total of 249 patients were included in the analysis, out of which 25.3% were staphylococcal enterotoxin B (SEB)-IgE positive. We found a meaningful association between SEB-IgE and female gender, a positive association was also measured between CRS and CRSwNP. No significant association was found between SEB-IgE sensitization and atopy, the occurrence of exacerbations and corticosteroid dosages. In the SEB-IgE-positive patient, blood eosinophil count does not appear to be correlated with the severity of the disease. Patients with SEB-IgE sensitization are, on average, younger and with an earlier disease onset, thus confirming the possibility to consider SEB-IgE sensitization as an independent risk factor for developing asthma. CONCLUSIONS: Our data confirm that the search for SE in the initial screening phase of these patients is helpful to better phenotype them, may predict the evolution of comorbidities and lead to a targeted therapeutic choice; in this point of view this represents a goal of precision medicine.

Effectiveness and safety of dupilumab in patients with chronic rhinosinusitis with nasal polyps and associated comorbidities: a multicentric prospective study in real life.

BACKGROUND: Biologics are currently one of the main treatment options for a number of diseases. The IgG4 monoclonal antibody dupilumab targets the Interleukin-4 receptor alpha chain, thus preventing the biological effects of the cytokines IL-4 and IL-13, that are essential for the Th2 response. Several controlled trials showed that dupilumab is effective and safe in patients with atopic dermatitis (AD), severe asthma and chronic rhinosinusitis with nasal polyps (CRSwNP), thus resulting in approval by regulatory agencies. Aim of the study was to evaluate the efficacy and safety of dupilumab in adult patients with CRSwNP stratified by common overlapping comorbid conditions. METHODS: We performed a multicenter, observational, prospective study enrolling adult patients with severe CRSwNP who had started dupilumab treatment in the context of standard care from January 2021 to October 2021. Data were collected from twentynine Italian secondary care centers for allergy and clinical immunology, all of which were part of the Italian Society of Allergy, Asthma and Clinical Immunology (SIAAIC). A number of efficacy parameters were used. Patient data were compared using the Wilcoxon test for paired data. All statistical analyses were performed with SPSS version 20 (IBM, Armonk, NY, USA). RESULTS: In total, 82 patients with nasal polyposis were identified. A significant improvement was detected for all the applied efficacy parameters, i.e. 22-item Sino-Nasal Outcome Test (SNOT-22) and bilateral endoscopic nasal polyp score (NPS) scores for CRSwNP, Rhinitis Control Scoring System (RCSS) and Rhinoconjunctivitis Quality of Life Questionnaire (RQLQ) scores for allergic perennial rhinitis, Forced Expiratory Volume in the 1st second (FEV1) and Asthma Quality of Life Questionnaire (AQLQ) scores for asthma, Eczema Area and Severity Index (EASI) and Dermatology Life Quality Index (DLQI) scores for AD. A non-significant improvement was also obtained in the Urticaria Activity Score over 7 days (UAS7) for chronic spontaneous urticaria. Treatment with dupilumab was well tolerated. CONCLUSIONS: These data suggest that dupilumab treatment in patients suffering from CRSwNP and associated comorbidities may be suitable. Such outcome, although confirmation by trials is warranted, suggests the possibility to treat different disorders with a single therapy, with favorable effects especially under the cost-effectiveness aspect.

Personalized medicine and allergen immunotherapy: the beginning of a new era?

The concept of personalized medicine as a diagnostic and therapeutic approach tailored to the medical needs of each patient is currently revolutionizing all fields of medicine and in particular allergology. Allergen immunotherapy (AIT) meets the three main needs for precision medicine: identification of molecular mechanism of disease, diagnostic tools for the mechanism and treatment blocking the mechanism itself. AIT adapts to the spectrum of specific IgE of each individual subject, changing the course and natural history of the disease, so is a clear model of precision and personalized medicine. This first step before the prescription of AIT is to define the sensitization profile of the patient; after that, the healthcare professional has numerous levers for adapting the treatment to the physio-pathological mechanisms involved. AIT allows to adapt treatments to the profile of the patients, but also to the its preferences, to ensure optimal treatment efficacy, resulting in an agile and personalized approach, with the aim to ensure adherence to the treatment, which is usually quite low. AIT also broadens the field of possibilities for healthcare professionals and patients, by allowing to choose the galenic formulation according to patient preferences and on the basis of their clinical history, adapting the product composition to the patient's sensitization profiles and the underlying biological mechanisms identified at the diagnostic stage, while guaranteeing quality of the prescribed product as the production of allergens and allergoids is today more regulated than in the past years. In the management of AIT, it is also possible to involve patients in decisions throughout their care pathway thanks to multiple services, offering personalized follow-up and support, to ensure the highest treatment efficacy levels, and recalling medication intake, medical appointments and prescription renewals.

Small airway dysfunction and poor asthma control: a dangerous liaison.

Asthma is a common chronic condition, affecting approximately 339 million people worldwide. The main goal of the current asthma treatment guidelines is to achieve clinical control, encompassing both the patient symptoms and limitations and the future risk of adverse asthma outcomes. Despite randomized controlled trials showing that asthma control is an achievable target, a substantial proportion of asthmatics remain poorly controlled in real life. The involvement of peripheral small airways has recently gained greater recognition in asthma, and many studies suggest that the persistent inflammation at these sites leads to small airway dysfunction (SAD), strongly contributing to a worse asthma control. Overall, the impulse oscillometry (IOS), introduced in the recent years, seems to be able to sensitively assess small airways, while conventional spirometry does not. Therefore, IOS may be of great help in characterizing SAD and guiding therapy choice. The aim of this article is to review the literature on SAD and its influence on asthma control, emphasizing the most recent evidence.

30 years of sublingual immunotherapy.

Allergen Immunotherapy (AIT) was introduced in clinical practice on an empirical basis more than 100 years ago. Since the first attempts, AIT was administered subcutaneously. Indeed, other routes of administration were proposed and studied, in particular to improve the safety, but only the sublingual route (SLIT) achieved a credibility based on evidence and was then accepted as a viable "alternative" option to the subcutaneous route. SLIT was largely used in clinical trials and clinical practice in this last 30 years. Thus, a large amount of data is available, coming from either controlled trials and postmarketing surveillance studies. It is clear that SLIT is overall effective, but it is also clear that the efficacy is not "class-related," as derived from meta-analyses, but restricted to each specific product. The 30-year lasting use of SLIT allowed to clarify many clinical aspects, such as efficacy, safety, use in asthma, regimens of administration, and optimal doses. In parallel, the mechanisms of action of AIT were elucidated, and new indications were proposed (eg food allergy, atopic dermatitis). In addition, the introduction of molecular-based diagnosis, allowed to better refine the prescription of SLIT, based on specific sensitization profiles. The present article will describe the origin and evolution of SLIT for respiratory allergy, taking into account the clinical context that suggested this form of treatment, the recently developed aspects, the future perspectives and unmet needs, This is not, therefore, a systematic review, rather a narrative historical description of the past history, and a look forward to the future opportunities.

Significant improvement in lung function and asthma control after benralizumab treatment for severe refractory eosinophilic asthma.

Severe eosinophilic asthma is a complex disease and much effort has been made to fully understand its mechanisms. Bronchial remodeling and loss of lung function are important features in asthma, however their key aspects are not completely clear, especially the impact that biological drugs may have on them. One of the key cytokines involved in the pathophysiology of eosinophilic asthma is interleukin-5 (IL-5), which plays a very important role together with other type 2 cytokines and chemokines in the development, transmigration and persistence of eosinophils into airways, such as eotaxin-2 and 3, thymic stromal lymphopoietin (TSLP), IL-33, as well as IL-4 and IL-13. Several monoclonal antibodies have been developed against this cytokine (mepolizumab, reslizumab) or its receptor (benralizumab). Data on the improvement of respiratory function in patients who undergo benralizumab treatment are scarce and partly conflicting. Real-life studies may play a crucial role in clarifying this important aspect. The aim of this retrospective observational real-world study was to evaluate the effect of benralizumab on lung function improvement, exacerbation rate, oral corticosteroids (OCS) reduction and asthma control questionnaire (ACQ) score before and after six months of treatment with benralizumab in a cohort of 20 consecutive patients with severe refractory asthma (SRA) treated at the Pneumology Unit of Local Health Authority, Reggio Emilia, Italy. Add-on therapy with benralizumab allowed to completely suspend OCS in 19 out of 20 patients. Notably, the number of moderate/severe exacerbations dropped significantly (p < 0,0001); as well as an improvement in ACQ score (p < 0,0001). The most relevant data concern respiratory function: the average pre-bronchodilator FEV1 increased by 21.3% (+680 ml) compared to baseline (p = 0,0006). Moreover, the improvement in morning PEF (+66,6 l/min) confirmed the benefit of benralizumab (p = 0,02). The improvement in respiratory function was significantly higher in patients with blood eosinophilia greater than 500 cells/µL and chronic rhinosinusitis with nasal polyps (CRSwNP). This study underlies a noticeable improvement in respiratory function, much higher than what has been observed in literature so far. This aspect, together with the others aforementioned, should be considered when choosing a treatment option in the context of precision medicine.

Biologics and Bronchial Thermoplasty for severe refractory asthma treatment: From eligibility criteria to real practice. A cross-sectional study.

The increasing knowledge on immuno-inflammatory pathways allowed the development of new therapeutic options in the field of severe refractory asthma (SRA). It is therefore very important to accurately identify phenotypes and endotypes of patients potentially eligible for innovative treatments. The aim of this study was to describe a cohort of patients affected by SRA referring to the Pneumology Unit of Azienda USL di Reggio Emilia/IRCCS in Reggio Emilia, Italy. It is an observational cross-sectional study, investigating the proportion of subjects with eligibility criteria for biological treatments (omalizumab, mepolizumab, benralizumab) and non-pharmacological treatment (bronchial thermoplasty, BT). We enrolled 137 patients with SRA referring to the centre from June 1st, 2017 to June 30th, 2019. The results of this study showed that 125 (91%) of patients were eligible for at least one biologic and 94 (69%) were eligible for BT. Only 6 (4%) of patients had no criteria for any available SRA treatments. Among biologics, there were only 11 (8%) patients resulting in overlap between omalizumab, mepolizumab and benralizumab, and 22 (16%) overlap of patients when BT was included. Considering eligibility criteria for BT, only 6 (4%) patients had inclusion criteria for BT, instead in real life 28% of patients were treated with BT. The major comorbidities were: bronchiectasis, chronic rhinosinusitis with nasal polyps (CRSwNP), gastro-esophageal reflux disease (GERD), and eosinophilic granulomatosis with polyangiitis (EGPA). The prevalence of bronchiectasis was much higher in the mepolizumab (45%) and benralizumab (43%) groups than in omalizumab (1%) and BT (7%), p < 0,001; CRSwNP and GERD were equally present and EGPA was only present in the mepolizumab group. Overall, our population was eligible for biologicals in almost all cases, and a significant percentage of patients showed the presence of an overlap of allergic and eosinophilic endotypes. This implies the possibility of different therapeutic options and reiterates the need for a correct characterization of patients. This study confirmed how the identification of inflammatory endotypes and phenotypes represent a key role in the selection of the right therapy for the right patient.

Analysis of the drop-out rate in patients receiving mepolizumab for severe asthma in real life.

Mepolizumab (anti IL-5, monoclonal antibody) is commercially available in Italy since more than one year for the treatment of severe hypereosinophilic asthma. Its efficacy and safety were evaluated in several regulatory trials. The characteristics of this drug in real life began to be assessed only recently. We describe herein the drop-out rate observed with mepolizumab in real life, because this datum can indirectly reflect the safety and tolerability aspects. The demographic and clinical data of patients receiving mepolizumab for severe asthma were collected, and the number and reasons for discontinuation of the treatment were analyzed. The database involves 143 patients (67 male, age range 19-80 year) who received at least one dose of mepolizumab. The observed discontinuation rate was 6/143 (4.2%). Five out of 6 discontinuations were due to lack of response, and one was an adverse event (urticaria) probably related to the treatment. There was no clinical difference between the drop-out group and the patients still ongoing. As compared to the clinical trials published the discontinuation rate was lower in our population, especially for adverse events (7% vs 23.7%). Thus, the tolerability of mepolizumab, as derived from discontinuations, seems to be better in real-life than in clinical trials.

One year of mepolizumab. Efficacy and safety in real-life in Italy.

BACKGROUND: Severe asthma is a disease with a heavy socio-economic burden and a relevant impact on the life of patients. Mepolizumab (MEP) was recently introduced in practice. The previous data were favourable as efficacy and safety are concerned. Nowadays, we can report the clinical data after more than one year of use of MEP in the real-life setting. OBJECTIVE: To evaluate the efficacy and safety of MEP in a real life framework, mainly concerning asthma exacerbations, steroid dependence, effects on respiratory function and adverse events. METHODS: This retrospective analysis was performed on 138 patients, treated with MEP for at least 12 months, and referred to eleven severe asthma clinics in Italy. All patients met the criteria for severe uncontrolled asthma according to ATS/ERS guidelines and prescribing MEP conditions according to the Italian Drug Agency (AIFA). RESULTS: We could observe 138 patients (78 female, age 58 ±â€¯10 years). The average age of onset of asthma was 34 ±â€¯16 years. The blood eosinophil count decreased from 822 ±â€¯491/µL at baseline to 117 ±â€¯96/µL (p < .0001) after 12 months of therapy. Exacerbations decreased from 3.8/year to 0.7/year (-81%; p < .0001). Steroid-dependent patients before MEP (80%) with a daily dose of 10.1 ±â€¯9.4 mg prednisone decrease at 28% after 12 months with a mean of 2.0 ±â€¯4.2 mg/day (p < .0001). The occurrence of adverse events was overall low. CONCLUSIONS & CLINICAL RELEVANCE: In this real-life setting, MEP confirmed its efficacy and safety profile, already shown in clinical trials. This was apparent concerning exacerbation rate, systemic steroids intake and safety.

Current insights in allergen immunotherapy.

OBJECTIVE: Allergen-specific immunotherapy (AIT) in its subcutaneous and sublingual forms is currently a well-established and experimentally supported treatment for respiratory allergy and hymenoptera venom allergy. There have been advances in its use linked strictly to the advancement in the knowledge of the molecular mechanisms of allergy, the production of well-characterized extracts, and diagnostic techniques. The use of AIT in asthma and the application of new approaches are expanding. We briefly review the advances and concerns in the use of AIT. DATA SOURCES: PubMed and Scopus. STUDY SELECTIONS: The most recent and clinically relevant literature was selected and reviewed. RESULTS: The introduction of high-quality products supported by large dose-finding trials has yielded better defined indications, contraindications, and modalities of use. Some specific products in tablet form have recently been approved in the United States. Sublingual immunotherapy has been found to be effective in asthma, which until recently had been a matter of debate. Another promising therapy is oral and sublingual desensitization for food allergy, for which encouraging results have recently been reported. In the near future, other options will be available, including new routes of administration (intralymphatic and epicutaneous), allergoids, engineered allergens, and peptides. The use of component-resolved diagnosis techniques will further refine and target AIT prescriptions. CONCLUSION: This condensed and updated review shows that AIT remains a viable treatment option, especially after the introduction of standardized tablets for some allergens. Food allergy and new administration routes represent a promising expansion.

IL-13 and idiopathic pulmonary fibrosis: Possible links and new therapeutic strategies.

The recent advances in the knowledge of immunological aspects of many pulmonary diseases, allowed to identify cells, biological functions, cytokines, and receptors that are preferentially involved in each disease. This is the case of asthma, where IL-13 (together with IL-4) is recognized as a central mediator. The role of IL-13 is strictly related, via complex signaling pathways, to eosinophil recruitment and activation, to mucus secretion, periostin generation and to fibrogenic processes (which are part of the remodeling process). These peculiar roles of IL-13 have suggested the hypothesis of its role in Idiopathic Pulmonary Fibrosis, and consequently of its antagonists in the treatment of such disease. We review herein the immunological roles of IL-13 in asthma and IPF, and the currently ongoing attempts to treat IPF by IL-13 antagonism strategies.

A Critical Evaluation of Anti-IL-13 and Anti-IL-4 Strategies in Severe Asthma.

Asthma is a high-prevalence disease, still accounting for mortality and high direct and indirect costs. It is now recognized that, despite the implementation of guidelines, a large proportion of cases remain not controlled. Certainly, adherence to therapy and the education of patients remain the primary objective, but the increasingly detailed knowledge about the pathogenic mechanisms and new biotechnologies offer the opportunity to better address and treat the disease. Interleukin (IL)-13 and IL-4 appear as the most suitable targets to treat the T helper 2 (TH2)-mediated forms (endotypes) of asthma. IL-13 and IL-4 partly share the same receptor and signaling pathways and both are deeply involved in immunoglobulin E (IgE) synthesis, eosinophil activation, mucus secretion and airways remodeling. Several anti-IL-13 strategies have been proposed (anrukinzumab, lebrikizunab and tralokinumab), with relevant clinical results reported with lebrikizumab. Such studies facilitate better definition of the possible predictive markers of response to a specific treatment (e.g. eosinophils, total IgE, fraction of exhaled nitric oxide and periostin). In parallel, anti-IL-4 strategies have been attempted (pascolizumab, pitakinra and dupilumab). So far, dupilumab was reported capable of reducing the severity of asthma and the rate of exacerbations. IL-13 and IL-4 are crucial in TH2-mediated inflammation in asthma, but it remains clear that only specific endotypes respond to these treatments. Although the use of anti-IL-14 and anti-IL-13 strategies is promising, the search for appropriate predictive biomarkers is urgently needed to better apply biological treatments.

Update on immunotherapy for the treatment of asthma.

PURPOSE OF REVIEW: Despite that specific immunotherapy can boast being more than a century old, there is still skepticism about its real effectiveness, and therefore it is still used too little in clinical practice. The purpose of this review was to analyze the most recent articles in the literature to highlight scientific evidence for the proper use of allergen immunotherapy (AIT). RECENT FINDINGS: In the near future, the concept of medicine for trials will have to be revised and in certain cases abandoned in favor of a personalized medicine, able to use a drug more targeted for the individual patient and not for the disease. SUMMARY: For AIT, it will become increasingly important to use products designed properly, standardized and with a well documented effectiveness in clinical studies. We must overcome the disputes of subcutaneous immunotherapy versus sublingual immunotherapy, arrive at the concept of personalized medicine regarding AIT, framing in different phenotypes of asthma patients to use the optimal preparation for each particular patient.

Benefit of SLIT and SCIT for Allergic Rhinitis and Asthma.

Allergen immunotherapy (AIT) has been in use since more than one century, when Leonard Noon experimentally proved its efficacy in hayfever (Noon, in Lancet 1:1572-3, 1911). Since then, AIT was administered only as subcutaneous injections (SCIT) until the sublingual route (SLIT) was proposed in 1986. The use of SLIT was proposed following several surveys from the USA and UK that repeatedly reported fatalities due to SCIT (Lockey et al. in J Allergy Clin Immunol 75(1): 166, 1985; Lockey et al. in J Allergy Clin Immunol 660-77, 1985; Committee on the safety of medicines. CSM update. Desensitizing vaccines. Br Med J, 293: 948, 1986). These reports raised serious concerns about the safety and the risk/benefit ratio of AIT. Many cases of life-threatening events with SCIT were due to avoidable human errors in administration, but a relevant fraction of them remained unexplained and unpredictable (Aaronson and Gandhi in J Allergy Clin Immunol 113: 1117-21, 2014). Subsequently, in a few years, SLIT gained credibility and was included in the official documents and guidelines (Table 1) (Bousquet et al. in J Allergy Clin Immunol 108(5 Supp):S146-S150, 2001; Canonica et al. in Allergy 64 (Supp 91):1-59, 2009) as a viable alternative to traditional SCIT. Of note, the local bronchial (aerosol) and the intranasal route of administration were attempted after the 1970s as alternatives to SCIT: the bronchial route was soon abandoned due to the poor efficacy and/or side effects, and the local nasal route, although effective and safe, was judged substantially impractical (Canonica and Passalacqua in J Allergy Clin Immunol 111: 437-48, 2003). In contrast to SCIT, SLIT was tested in very large clinical trials (need references), including hundreds of patients and with dose-ranging experimental designs, so that some products (tablets) for grass, mite, and ragweed were officially approved as commercial drugs by regulatory agencies such as the Food and Drug Administration and the European Medicines Agency and the optimal content for the maintenance dose was identified for selected allergens. In parallel, the knowledge on the mechanisms of action of AIT was rapidly refined, leading to further improvements, such as the chemically modified extracts and the use of adjuvants to enhance efficacy and safety. In addition, in the last 10 years, there has been an increasing scientific and clinical interest in AIT applied to food allergies, in particular in children, with the use of orally administered extracts (Albin and Nowak-Wegrzyn in Immunol Allergy Clin North Am 35: 77-100, 2015). The results are so far encouraging, at least for cow's milk, egg, and peanut, although the use of treatment is still restricted to clinical trials or within specialized centers. Finally, the introduction of molecular- or component-resolved diagnosis has allowed detailing the prescription of AIT, by better delineating true sensitization versus cross-reactivity (Canonica et al. in World Allergy Organ J 6(1):17, 2013). This latter point is also in strict relation to the use of recombinant, engineered or highly purified molecules, instead of raw extracts, for the desensitization process.