Marco Caminati

Safety and tolerability of sublingual immunotherapy in clinical trials and real life.

Purpose of reviewSublingual immunotherapy (SLIT) is effective in allergic rhinitis and asthma. Apart from its efficacy, safety is crucial as this treatment is usually self-administered at home. Tolerability also plays a pivotal role, as mild local reactions, although not life-threatening, may represent a risk for treatment withdrawal and can therefore negatively affect clinical outcomes. The present study addresses this issue by reviewing double-blind, placebo-controlled, randomized trials and real-life studies. Recent findingsThe number of life-threatening SLIT-related reactions is negligible. SLIT-related adverse events are not always consistently reported nor uniformly classified in published studies. However, systemic reactions are rare and side effects mostly consist of mild, self-limiting local reactions. No treatment-related risk factors for adverse events have been clearly defined, as far as type of allergen, dose or schedule. SummarySLIT provides an optimal safety profile both in children and in adults. Apart from life-threatening reactions, the lack of standardization of adverse events reporting may account for the wide variability of the prevalence of side effects in clinical trials and in real-life setting. It can lead to a possible underestimation of adverse events, concerning, in particular, local reactions. Since poor tolerability may affect adherence and cause treatment discontinuation, adopting shared strategies in order to recognize, grade and manage adverse events is mandatory.

Choosing wisely: practical considerations on treatment efficacy and safety of asthma in the elderly

The prevalence of asthma in the most advanced ages is similar to that of younger ages. However, the concept that older individuals may suffer from allergic asthma has been largely denied in the past, and a common belief attributes to asthma the definition of “rare” disease. Indeed, asthma in the elderly is often underdiagnosed or diagnosed as COPD, thus leading to undertreatment of improper treatment. This is also due to the heterogeneity of clinical and functional presentations of geriatric asthma, including the partial loss of reversibility and the lower occurrence of the allergic component in this age range. The older asthmatic patients are also characterized the coexistence of comorbid conditions that, in conjunction with age-associated structural and functional changes of the lung, may contribute to complicate the management of asthma. The current review addresses the main issues related to the management of allergic asthma in the geriatric age. In particular, the paper aims at revising current pharmacological and non pharmacological treatments for allergic asthmatics of advanced ages, primarily focusing on their safety and efficacy, although most behaviors are an arbitrary extrapolation of what has been tested in young ages. In fact, age has always represented an exclusion criterion for eligibility to clinical trials. Experimental studies and real life observations specifically testing the efficacy and safety of therapeutic approaches in allergic asthma in the elderly are urgently needed.

Emerging drugs for allergic conjunctivitis

Introduction: Allergic conjunctivitis (AC) is a very common disease, especially in association with allergic rhinitis but may also occur in isolated presentation. The treatment of AC has long been based on antihistamines, cromones and topical corticosteroids, but none of these drugs completely abolishes the clinical expression of AC. Areas covered: The development of new drugs for AC is analyzed highlighting the recent insights into the pathophysiological mechanisms of the disease. The major aim of development of drugs for AC is to have agents able to prevent the inflammatory effects of the interaction between the allergen and the specific IgE antibodies on mast cell surface. This may be obtained by blocking the effects of histamine (the main mediator of early allergic response) by H1-receptor antagonists, inhibiting the release of soluble factors able to recruit inflammatory cells (that sustain prolonged inflammation) by mast-cell stabilizers, inhibiting the effects of single mediators, inducing tolerance to the allergen by specific immunotherapy or even acting on factors related to activation and differentiation of T lymphocytes such as the toll-like receptors. Expert opinion: AC is an underestimated disease for which there is a search of more effective treatments. The availability of the drugs under current evaluation will allow more refined therapeutic strategies to apply according to the characteristics and the clinical severity of AC.

COPD prevalence in a north-eastern Italian general population

BACKGROUND COPD prevalence estimates vary mostly depending on different study methodologies. We evaluated the prevalence and clinical features of COPD, as defined by GOLD and ERS/ATS recommendations in a representative sample of Northern Italy general population. METHODS A randomized cross-sectional study was performed. The study participants completed a questionnaire covering: key indicators for considering a diagnosis of COPD, self-reported physician diagnoses of respiratory disease, pharmacological treatment for respiratory disease, indirect costs, occupational and environmental exposures. They also underwent spirometry and physician assessment. RESULTS We evaluated 1236 subjects. Daily respiratory symptoms were experienced by 26.7%. Of this group, only 30.7% had previously performed a spirometry. The overall COPD prevalence was: 11.7% according to GOLD criterion; 9.1% according to LLN criterion; 6.8% according to self-reported physician diagnosis. Of note, 48,8% of subjects with a reported diagnosis of COPD had never undergone a spirometry before the study. CONCLUSIONS Our study provides an estimation of COPD prevalence in a representative sample of Northern Italy general population relying on both clinical symptoms and spirometry outcomes, and describes the different prevalence rates depending on the adopted diagnostic criterion. Spirometry underuse may account for under-diagnosis and misdiagnosis of COPD. It may result in a major impact on quality of life as well as in economic burden.

The level of control of mild asthma in general practice: an observational community-based study

Abstract Objective: The aim of the present community-based study was to evaluate the level of asthma control in patients with mild asthma, regularly treated with inhaled steroids (ICS). Method: This observational cross-sectional study included patients registered in the general practitioner (GP) database and with at least three prescriptions of ICS in the last 12 months. Patients were asked to refer to the doctor’s office for a standardised interview. The level of asthma control was self-measured by the patients using the Asthma Control Test (ACT)™ (Quality Metric, Inc.). Results: The study included 950 asthmatic patients, referred by 540 GPs: 54.5% were females, mean age was 51 (±19.1) years; 59.5% were non-smokers, 22.5% were current smokers and 18.0% were former smokers; 81.1% of the patients were on ICS in the last 4 weeks. Only 38.6% of patients had a spirometry in the last 12 months. According to the ACT, 13.7% of the asthmatic patients were totally controlled, 51.0% well controlled, and 35.3% poorly controlled. Smoking habit, older age (>60) and living in Central or Southern Italy were associated with poorer control. In the last 12 months 4.5% of patients had an asthma-related hospitalisation, 5.3% an emergency visit and 18.9% a specialist visit. Conclusions: More than one of three patients had poor asthma control, despite being considered by their GPs as mild asthmatics and treated with ICS. Asthmatic patients need to be regularly re-evaluated. Treatment is often inadequate and should be targeted to improve control and reduce asthma morbidity (SAM104964).

Fatal asthma; is it still an epidemic?

BackgroundAsthma 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.MethodsA 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.ResultsTwenty-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.DiscussionAlthough 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.ConclusionsAsthma 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.

Respiratory allergies in childhood: Recent advances and future challenges

The burden of allergic airway diseases still represents a major health problem in childhood. Despite many different options are currently available for the diagnostic work‐up and management, the overall disease control in terms of impact on quality of life, morbidity and mortality, is not yet satisfactory. The extreme variability of individual risk factors and severity determinants may account for it. On the other side, the knowledge of the multifaceted allergy background could pave the way to primary prevention, early intervention and disease course modification. In fact, most of current research is focusing on the identification of biological and clinical predictive markers of allergy and asthma onset. This review aims at summarizing the latest achievements concerning the complex inter‐relation between genetic predisposition and environmental factors, and their impact on prevention strategies and early identification of at risk subjects. An update on the diagnostic and monitoring tools as well as an insight into the newest treatments options is also provided.

Sex in Respiratory and Skin Allergies

A bulk of literature demonstrated that respiratory allergy, and especially asthma, is prevalent in males during childhood, while it becomes more frequent in females from adolescence, i.e., after menarche, to adulthood. The mechanisms underlying the difference between females and males are the effects on the immune response of female hormones and in particular the modulation of inflammatory response by estrogens, as well as the result of the activity of various cells, such as dendritic cells, innate lymphoid cells, Th1, Th2, T regulatory (Treg) and B regulatory (Bregs) cells, and a number of proteins and cytokines, which include interleukin (IL)-4, IL-5, IL-10, and IL-13. As far as sexual dimorphism is concerned, a gender difference in the expression profiles of histamine receptors and of mast cells was demonstrated in experimental studies. A critical phase of hormone production is the menstrual cycle, which often is associated with asthma deterioration, as assessed by worsening of clinical symptoms and increase of bronchial hyperresponsiveness. In asthmatic woman, there is a high risk to develop more severe asthma during menstruation. The higher prevalence of asthma in females is confirmed also in the post-menopause age, but the underlying mechanisms are not yet understood. In pregnancy, asthma may worsen but may also improve or remain unchanged, with no significant difference in frequency of these three outcomes. For allergic rhinitis, the available studies indicate, likewise asthma, a male predominance in prevalence in childhood that shifts to a female predominance in adolescence and adulthood, but further investigation is needed.

Targeting Interleukin-5 or Interleukin-5Rα: Safety Considerations

Asthma is a highly prevalent chronic disease of the airways; approximately 10% of patients with asthma will experience a severe form of the disease. New understanding of the pathogenesis of asthma has enabled the development of novel drugs and provided hope for patients with asthma. Interleukin (IL)-5 and IL-5 receptor subunit α (IL-5-Rα) plays a crucial role in the development, maturation, and operation of eosinophils so were the first important therapeutic target of these new drugs. While the results of early clinical trials of these drugs were not promising, results improved once researchers discovered the drugs worked best in patients with high eosinophil levels. Patients treated with both anti-IL-5 and IL-5-Rα experienced significant decreases in exacerbations. Trials have also demonstrated promising safety profiles; adverse events have been few and frequently only observed with placebo or considered unrelated to the study drug. The positive efficacy and safety profiles of these drugs has led to trials with interesting results in other diseases that are also secondary to the action of eosinophils: Churg–Strauss syndrome, hypereosinophilic syndrome, nasal polyposis, chronic obstructive pulmonary disease, atopic dermatitis, and esophagitis. In this review, we explore the main clinical trials of anti-IL-5 and IL-5-Rα, both in asthma and in other pathologies, with particular reference to the interesting safety and efficacy results.

Phenotyping asthma in the elderly: allergic sensitization profile and upper airways comorbidity in patients older than 65 years

BACKGROUND Data about allergic rhinitis in elderly patients with asthma are lacking. OBJECTIVE To investigate the presence of rhinitis and the role of sensitization of airborne allergens in elderly patients with asthma. METHODS This was a multicenter cross-sectional study involving subjects at least 65 years old with asthma. Demographic features, comorbidities, and the presence of allergic respiratory disease were retrieved through interview. Skin prick tests for common allergens were performed. Associations of demographic and clinical features were evaluated in relation to asthma control and forced expiratory volume in the first second less than 80% in the total population and in the subgroup with features resembling chronic obstructive pulmonary disease. RESULTS Of 368 elderly subjects with asthma, 101 had features resembling chronic obstructive pulmonary disease. Rhinitis was present in 59.0% of subjects (allergic rhinitis in 47.6%), with an age of onset significantly different from that of asthma (49 ± 18 vs 57 ± 18 years). At least 1 sensitization was observed in 52.4% of subjects, more frequently for house dust mite (HDM; 31.8%). The prevalence of poorly and partially controlled asthma was higher in patients sensitized to airborne allergens (odds ratio 1.64, 95% confidence interval 1.03-2.61), in particular to HDM (odds ratio 1.73, 95% confidence interval 1.05-2.85). CONCLUSION Approximately 60% of elderly subjects with asthma had rhinitis, mainly allergic and often untreated, whose onset preceded asthma symptoms by a mean of approximately 10 years. Nonallergic asthma was better controlled than allergic asthma. However, HDM sensitization was greater in subjects with asthma with features resembling chronic obstructive pulmonary disease (39% vs 28%). When restricting analysis to this group, the negative role of HDM in overall asthma control (forced expiratory volume in first second and Asthma Control Test) was significant.