Asthma severity: the patient's point of view.

Objective: Initiated by the Severe Asthma Network Italy (SANI), this study aims to explore asthma patients' perceptions of disease severity, differentiating between mild and severe asthma. The objective is to identify factors influencing tailored treatment strategies for varying disease severities and to provide insights into asthma care in Italy. Methods: Conducted between November 2020 and January 2021, a survey using Computer-Assisted Personal Interviewing (CAPI) collected data from 308 Italian adults, representing the population. A 25 item multiple choice questionnaire covered asthma diagnosis, symptoms, treatment approaches, associated conditions, and quality of life. Results: Among participants, 83.8% reported having mild asthma, while 16.2% had severe asthma. Severe asthma patients had longer disease durations, more severe symptoms, frequent exacerbations, and higher hospital/ER visits. Although treatment adherence and symptom profiles generally aligned with international guidelines for self reported severe asthma, 22% of self identified mild asthmatics experienced severe respiratory symptoms. Oral corticosteroid (OCS) use was observed in 50% of severe cases and 22% of mild cases. Adherence was higher in severe asthma patients (76%) versus mild asthma patients (28%). Both groups experienced comorbidities, with 96% of severe asthmatics and 72% of mild asthmatics reporting impaired quality of life. Conclusion: This study highlights the disparity between clinical categorization and patient perceptions of asthma severity. The prevalence of self reported severe asthma exceeds literature data. The burden of mild asthma remains significant, with treatment approaches not fully aligned, particularly regarding disproportionate OCS use. Addressing this gap requires enhancing patient education, improving diagnostic practices, and promoting adherence.

Food triggered anaphylaxis in adults.

PURPOSE OF REVIEW: Adult food allergy, either unresolved from childhood, or new-onset in adult-life, is known to be increasingly prevalent. Although much of the reported anaphylaxis in adults is due to drug reactions, foods are becoming an increasingly important trigger, affecting adults of all ages, with a wide variation in food triggers which are often quite different to those reported in children. RECENT FINDINGS: Peanuts are well known to cause anaphylaxis in some adult populations, but other legumes such as soy may be more relevant in others. Reactions to natto, fermented soybeans, are currently mainly reported in Japan, but changing dietary practices and an increase in plant-based eating mean natto, other forms of soy and other legumes are increasingly linked to anaphylaxis in Western countries. Anaphylaxis to red meat, caused by sensitization to galactose-α-1,3-galactose and first reported in North America, is now a more world-wide concern. Co-factor induced anaphylaxis is increasingly associated with both wheat allergy and lipid transfer protein allergy. SUMMARY: More research is urgently needed to characterize adult food allergy, its triggers and symptom severity. Unusual food triggers and potential co-factors should be considered, so that anaphylaxis in adults can be correctly managed, not merely labelled as idiopathic.

The Diagnosis of Allergy to Lipid Transfer Proteins.

PURPOSE OF REVIEW: To provide an update on the diagnosis of non-specific Lipid Transfer Protein (nsLTP) allergy. RECENT FINDINGS: More publications report the presence of nsLTP allergy in Northern European countries and nsLTP sensitisation in children. Individuals are more likely to have severe reactions if there is recognition of increasing numbers of LTP components. Diagnosis is problematic; not all those with nsLTP allergy will have a positive test to a peach extract containing Pru p 3, the peach nsLTP. Sensitisation to nsLTP is being reported in more countries, including to the nsLTP in Cannabis Sativa in North America. Meals containing multiple nsLTP foods are more likely to be involved in co-factor reactions. Component-resolved diagnostics are superior to skin prick tests, to determine sensitisation to the individual nsLTP allergens causing symptoms and, in the future, the Basophil Activation test may best discriminate between sensitization and clinical allergy.

The combination of allergen immunotherapy and biologics for inhalant allergies: Exploring the synergy.

The development of monoclonal antibodies that selectively target IgE and type 2 immunity has opened new possibilities in the treatment of allergies. Although they have been used mainly as single therapies found to have efficacy in the management of asthma and other T2-mediated diseases, there is a growing interest in using these monoclonal antibodies in combination with allergen immunotherapy (AIT). AIT has transformed the treatment of allergic diseases by aiming to modify the underlying immune response to allergens rather than just providing temporary symptom relief. Despite the proven efficacy and safety of AIT, unmet needs call for further research and innovation. Combination strategies involving biologics and AIT exhibit potential in improving short-term efficacy, reducing adverse events, and increasing immunologic tolerance. Anti-IgE emerges as the most promising therapeutic strategy, not only enhancing AIT's safety and tolerability but also providing additional evidence of efficacy compared with AIT alone. Anti-interleukin-4 receptor offers a reduction in adverse effects and an improved immunologic profile when combined with AIT; however, its impact on short-term efficacy seems limited. The combination of cat dander subcutaneous immunotherapy with anti-thymic stromal lymphopoietin was synergistic with enhanced efficacy and altered immune responses that persisted for 1 year after discontinuation compared with AIT alone. Long-term studies are needed to evaluate the sustained benefits and safety profiles of combination strategies.

Utility of silver birch and house dust mite extracts derived from licensed sublingual tablets for nasal allergen challenge.

BACKGROUND: Nasal allergen challenge (NAC) is used to investigate the effects of allergen exposure and assess treatment efficacy in allergic rhinitis (AR). This study aims to establish dose-responses to NAC using licensed silver birch (SB) pollen and house dust mite (HDM) sublingual tablets as sources of the allergen extracts in participants with AR. METHODS: Sixteen volunteers with HDM-induced perennial AR and 15 volunteers with SB pollen-induced seasonal rhinitis underwent a graded up-dosing NAC with extracts derived from HDM allergen (Acarizax®) and SB (Itulazax®) tablets, respectively. Total nasal symptom score (TNSS, range 0-12) and peak nasal inspiratory flow (PNIF) were recorded before, at 10 min and at the end of the NAC. The dose of each allergen that provoked a TNSS of at least 7 ("provoking dose 7") in most allergic participants was identified. NACs using the "provoking dose 7" were performed on 5 non-allergic individuals to test for irritant effects. The "provoking dose 7" of HDM extract was used in a subgroup of two SB allergic, non-HDM allergic, volunteers, and vice versa for SB extract, to test for allergen specificity of the responses. RESULTS: Most patients experienced a TNSS of at least 7/12 at a median concentration of 1500 AU/mL for both SB pollen and HDM. The average decline in PNIF at this dose was 63.15% for SB and 63.99% for HDM. NACs using the 1500 AU/mL concentrations were performed on 5 non-allergic individuals with no symptomatic or PNIF response. 1500 AU/mL of HDM extract produced no symptoms in SB allergics nor 1500 AU/mL SB extract in HDM allergics. CONCLUSION: For both SB and HDM extracts, the optimal allergen dose for NAC to cause a moderate-severity response ("provoking dose 7/12") was 1500 AU/mL. Licensed sublingual allergen tablets provide a readily available and inexpensive source of SB and HDM extracts for use in future interventional studies in AR.

Mast cell conditions and drug allergy: when to suspect and how to manage.

PURPOSE OF REVIEW: Patients with mast cell disorders frequently experience symptoms from excessive mediator release like histamine and tryptase, ranging from mild flushing to severe anaphylactic responses. Hypersensitivity reactions (HRs) to drugs are a major cause of anaphylaxis in these patients, who often worry about triggering mast cell degranulation when taking medications. The aim of this review is to explore the complex interactions between mast cell disorders and drug HRs, focusing on the clinical challenges of managing these conditions effectively to enhance understanding and guide safer clinical practices. RECENT FINDINGS: Among the drugs most commonly associated with hypersensitivity reactions in patients with mast cell disorders are non-steroidal anti-inflammatory drugs, antibiotics, and perioperative agents. Recent studies have highlighted the role of Mas-related G-protein coupled receptor member X2 (MRGPRX2) - a receptor involved in non-immunoglobulin E mediated mast cell degranulation - in exacerbating HRs. Investigations reveal varied drug tolerance among patients, underscoring the need for individual risk assessments. SUMMARY: Tailored diagnostic approaches are crucial for confirming drug allergies and assessing tolerance in patients with mastocytosis, preventing unnecessary medication avoidance and ensuring safety before acute situations arise.

Alpha-gal syndrome: when treatment of hypovolemic shock can lead to anaphylaxis.

Delayed anaphylaxis after ingestion of red meat because of galactose-alpha-1,3-galactose (alpha-gal) syndrome has increased in recent years. The mechanism involves an immunoglobulin E reaction to alpha-gal, a molecule found in mammalian meat, dairy products, medications and excipients containing mammalian-derived components, and tick salivary glycans. Sensitization occurs due to the bite of a lone star tick and the transmission of alpha-gal molecules into person's bloodstream. We describe a case of alpha-gal syndrome with severe food, drug, and perioperative allergy in which anaphylaxis with hypovolemic shock occurred immediately after an emergency surgical procedure, when a gelatin-containing drug was injected. This case study confirms that the clinical manifestations of alpha-gal syndrome could be different depending on the route of administration, with immediate reactions if an alpha-gal-containing drug is injected and delayed type allergic manifestations occurring several hours after oral intake. The purpose of this report is to highlight the importance of risk communication in case of exposure to medical products and surgical procedures of patients with alpha-gal syndrome and to encourage drug manufacturers to indicate clearly the origin of excipients in product literature.

Exploring the Utility of Circulating Endothelial Cell-Derived Extracellular Vesicles as Markers of Health and Damage of Vasal Endothelium in Systemic Sclerosis Patients Treated with Iloprost.

Endothelial cell-derived extracellular vesicles (eEVs) are released from endothelial cells, signifying endothelial integrity. Systemic Sclerosis (SSc) is a rare disease causing skin and organ fibrosis with early vascular damage. Iloprost, an SSc treatment, might affect eEV release, showing long-term benefits. We aimed to study eEVs in SSc, potentially serving as disease markers and linked to Iloprost's impact on organ involvement. We included 54 SSc patients and 15 healthy donors. Using flow cytometry on platelet-poor plasma (PPP) with specific antibodies (CD144, CD146, AnnexinV), we detected endothelial extracellular vesicles. Results showed fewer eEVs from apoptotic or normal cells in SSc patients than healthy controls. Specifically, patients with diffuse cutaneous SSc and lung issues had reduced eEVs from apoptotic endothelial cells (CD146+ AnnV+). No notable differences were seen in CD144 endothelial markers between patients and controls. After 1-day Iloprost infusion, there was an increase in eEVs, but not after 5 days. These findings suggest circulating eEVs reflect endothelial health/damage, crucial in early SSc stages. A 1-day Iloprost infusion seems effective in repairing endothelial damage, critical in scleroderma vasculopathy. Differences in marker outcomes may relate to CD146's surface expression and CD144's junctional location in endothelial cells.

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.

New arrivals in anaphylaxis to foods.

PURPOSE OF REVIEW: More people are excluding wheat from their diet, or turning to a more sustainable diet in which includes meat substitutes or is mainly or wholly plant-based. This increases the availability of new foods and with it the increasing likelihood of novel allergens. RECENT FINDINGS: There is a growing body of evidence which suggests that allergies to seeds and legumes are increasing potentially due to their use in concentrated form in vegan or health foods. Insects can be a sustainable source of protein, but mealworm could provoke symptoms in individuals sensitized or allergic to shellfish or house dust mite. Novel plant food allergens such as gibberellin-regulated proteins and thaumatin-like proteins are increasingly being reported as significant causes of severe reactions to fruits. SUMMARY: these findings make it even more imperative to take a full dietary history to ensure apparent idiopathic anaphylaxis is not in reality due to a novel food, especially in cases where other forms of the food are tolerated. Given the lack of diagnostic tests for these novel foods, a prick-to-prick skin prick test should be performed with the suspected food. There is currently more work needed to define and sequence many of the allergens involved.

Relative Humidity and Its Impact on the Immune System and Infections.

Relative humidity (RH) represents an underestimated outdoor and indoor environmental parameter. Conditions below and above the optimal range could facilitate infectious transmission as well as the exacerbation of respiratory diseases. The aim of this review is to outline the consequences for health of suboptimal RH in the environment and how to limit this negative impact. RH primarily affects the rheological properties of the mucus, modifying its osmolarity and thus the mucociliary clearance. The integrity of the physical barrier, maintained by mucus and tight junctions, is critical for protection from pathogens or irritants. Moreover, the control of RH seems to be a strategy to prevent and control the spread of viruses and bacteria. However, the imbalance of RH in the outdoor and indoor environments is frequently associated with the presence of other irritants, allergens, and pathogens, and therefore the burden of a single risk factor is not clearly defined in different situations. Nonetheless, RHmay have a synergistic negative effect with these risk factors, and its normalization, if possible, may have a positive impact on a healthier environment.

Allergen-specific immunotherapy and COVID-19: What happened?

BACKGROUND: The COVID-19 infection played a key role in the discontinuation of patient treatment, such as allergen-specific immunotherapy, in chronic diseases. OBJECTIVES: We conducted a retrospective observational study at Verona University Hospital, Verona, Italy, to assess the level of adherence to sublingual immunotherapy (SLIT) in patients affected by allergic rhinitis and mild asthma. MATERIALS AND METHODS: We compared and analysed data related to first prescription and collection of 5-grass-pollen 300-index of reactivity (IR) SLIT and tablet lyophilisate, containing 75,000 standardized quality tablet units (SQ-T) allergen extract of grass-pollen from Phleum pratense L, for the five-year period 2017-2021.In particular we considered the group of naïve patients from 2017 who completed pre-COVID treatment (2017-2019) and the group of naïve patients from 2019 who completed treatment during the COVID period (2019-2021). The significance test used was Student's t-test, and P ˂ 0.05 was considered as statistically significant. RESULTS: In the three-year period 2017-2019, 264 naïve patients began treatment in 2017, of these 181 continued in 2018, 135 continued in 2019. Instead, for the period 2017-2019, there were 226 naïve patients in 2019; of these 139 continued in 2020, and 102 in 2021. CONCLUSIONS: COVID-19 did not seem to influence adherence to SLIT, which declined independently even in during the pre-pandemic 3-year period.

Hidden Comorbidities in Asthma: A Perspective for a Personalized Approach.

Bronchial asthma is the most frequent inflammatory non-communicable condition affecting the airways worldwide. It is commonly associated with concomitant conditions, which substantially contribute to its burden, whether they involve the lung or other districts. The present review aims at providing an overview of the recent acquisitions in terms of asthma concomitant systemic conditions, besides the commonly known respiratory comorbidities. The most recent research has highlighted a number of pathobiological interactions between asthma and other organs in the view of a shared immunological background underling different diseases. A bi-univocal relationship between asthma and common conditions, including cardiovascular, metabolic or neurodegenerative diseases, as well as rare disorders such as sickle cell disease, α1-Antitrypsin deficiency and immunologic conditions with hyper-eosinophilia, should be considered and explored, in terms of diagnostic work-up and long-term assessment of asthma patients. The relevance of that acquisition is of utmost importance in the management of asthma patients and paves the way to a new approach in the light of a personalized medicine perspective, besides targeted therapies.

Allergen-specific immunotherapy and COVID-19: What happened?

Background: The COVID-19 infection played a key role in the discontinuation of patient treatment, such as allergen-specific immunotherapy, in chronic diseases. Objectives: We conducted a retrospective observational study at Verona University Hospital, Verona, Italy, to assess the level of adherence to sublingual immunotherapy (SLIT) in patients affected by allergic rhinitis and mild asthma. Materials and Methods: We compared and analysed data related to first prescription and collection of 5-grass-pollen 300-index of reactivity (IR) SLIT and tablet lyophilisate, containing 75,000 standardized quality tablet units (SQ-T) allergen extract of grass-pollen from Phleum pratense L, for the five-year period 2017-2021.In particular we considered the group of naïve patients from 2017 who completed pre-COVID treatment (2017-2019) and the group of naïve patients from 2019 who completed treatment during the COVID period (2019-2021). The significance test used was Student’s t-test, and P ˂ 0.05 was considered as statistically significant. Results: In the three-year period 2017-2019, 264 naïve patients began treatment in 2017, of these 181 continued in 2018, 135 continued in 2019. Instead, for the period 2017–2019, there were 226 naïve patients in 2019; of these 139 continued in 2020, and 102 in 2021. Conclusions: COVID-19 did not seem to influence adherence to SLIT, which declined independently even in during the pre-pandemic 3-year period (AU)

Anaphylaxis across Europe: are pollen food syndrome and lipid transfer protein allergy so far apart?

PURPOSE OF REVIEW: Traditionally pollen-food syndrome (PFS) is considered to be a mild cross-reacting food allergy affecting only Northern Europe, with lipid transfer protein (LTP) allergy being more severe and mainly occurring in Southern Europe. This review seeks to update the reader on both types of plant food allergy and to determine whether the stereotypical presentations of these plant food allergies remain the same, with a particular focus on reaction severity. RECENT FINDINGS: Recent findings suggest that both these types of plant food allergy occur in children and adults. Although it is true that PFS allergy is more prevalent in Northern Europe and LTP allergy is more well known in Southern Europe, these conditions are not hidebound by geography, and the increasing spread and allergenicity of pollen due to global warming continues to change their presentation. Both conditions have a spectrum of symptom severity, with PFS sometimes presenting with more severe symptoms, including anaphylaxis and LTP allergy with milder reactions. SUMMARY: It is important to consider that in many parts of Europe, reactions to plant foods, especially fruits or vegetables, could be mediated either by pollen cross-reactivity or primary sensitization to LTP allergens. All those presenting with symptoms to plant foods will benefit from a detailed clinical history and appropriate tests so that an accurate diagnosis can be made, and correct management implemented.

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.

Identification of a Novel Serological Marker in Seronegative Rheumatoid Arthritis Using the Peptide Library Approach.

Rheumatoid arthritis (RA) is a systemic autoimmune disease characterized by chronic inflammation mainly affecting the joints leading to cartilage and bone destruction. The definition of seropositive or seronegative RA is based on the presence or absence of rheumatoid factor (RF) and anti-citrullinated peptide antibodies (ACPAs). Other autoantibodies have been identified in the last decade such as antibodies directed against carbamylated antigens, peptidyl-arginine deiminase type 4 and v-Raf murine sarcoma viral oncogene homologue B. In order to identify relevant autoantigens, we screened a random peptide library (RPL) with pooled IgGs obtained from 50 patients with seronegative RA. Patients' sera were then used in an ELISA test to identify the most frequently recognized peptide among those obtained by screening the RPL. Sera from age- and sex-matched healthy subjects were used as controls. We identified a specific peptide (RA-peptide) recognized by RA patients' sera, but not by healthy subjects or by patients with other immune-mediated diseases. The majority of sera from seronegative and seropositive RA patients (73.8% and 63.6% respectively) contained IgG antibodies directed against the RA-peptide. Interestingly, this peptide shares homology with some self-antigens, such as Protein-tyrosine kinase 2 beta, B cell scaffold protein, Liprin-alfa1 and Cytotoxic T lymphocyte protein 4. Affinity purified anti-RA-peptide antibodies were able to cross react with these autoantigens. In conclusion, we identified a peptide that is recognized by seropositive and, most importantly, by seronegative RA patients' sera, but not by healthy subjects, conferring to this epitope a high degree of specificity. This peptide shares also homology with other autoantigens which can be recognized by autoantibodies present in seronegative RA sera. These newly identified autoantibodies, although present also in a percentage of seropositive RA patients, may be considered as novel serum biomarkers for seronegative RA, which lacks the presence of RF and/or ACPAs.