Sensitization to Gibberellin-Regulated Protein (Peamaclein) Among Italian Cypress Pollen-Sensitized Patients.

BACKGROUND AND OBJECTIVES: Peach gibberellin-regulated protein (peamaclein) has recently emerged as a relevant food allergen in cypress pollen-hypersensitive patients. Objective: We investigated monosensitization to peamaclein among Italian cypress pollen-allergic patients. MATERIAL AND METHODS: A total of 835 cypress pollen-hypersensitive patients from 28 Italian allergy centers underwent a thorough work-up to determine food-allergic reactions and performed skin prick testing with a commercial peach extract containing peamaclein. IgE to rPru p 3 was measured in peach reactors, and those with negative results were enrolled as potentially monosensitized to peamaclein. IgE reactivity to rPru p 7 was evaluated using immunoblot and an experimental ImmunoCAP with rPru p 7. RESULTS: Skin prick tests were positive to peach in 163 patients (19.5%); however, 127 (77.9%) were excluded because they reacted to Pru p 3. Twenty-four patients (14.7%) corresponding to 2.8% of the entire study population) were considered potentially monosensitized to peamaclein. No geographic preference was observed. Seventeen of the 24 patients (70.8%) had a history of food allergy, mainly to peach (n=15). Additional offending foods included other Rosaceae, citrus fruits, fig, melon, tree nuts, and kiwi. On peach immunoblot, only 3 of 18 putative peamaclein-allergic patients reacted to a band at about 7 kDa; an additional 4 patients reacted at about 50-60 kDa. Ten of 18 patients (56%) had a positive result for Pru p 7 on ImmunoCAP. CONCLUSION: Allergy and sensitization to peamaclein seem rare in Italy. Most patients react to peach, although other Rosaceae fruits and several citrus fruits may also be offending foods. Peach and cypress pollen probably also share cross-reacting allergens other than peamaclein.

The role of allergoids in allergen immunotherapy: from injective to sublingual route.

Summary: Summary Allergen immunotherapy (AIT) is aimed at inducing tolerance to allergens, such as pollens, dust mites or moulds, by administering increasing amounts of the causative allergen through subcutaneous or sublingual route. The evidence of efficacy of AIT is high, but the issue of safety, especially for the subcutaneous route, must be taken into account. The search for safer AIT products aimed at reducing the allergenicity, and thus adverse reactions, while maintaining the immunogenicity, that is essential for effectiveness, gave rise to the introduction of allergoids, which were conceived to fulfill these requirements. In the first allergoids glutaraldehyde or formaldehyde were used as cross-linking agent to polymerize allergens, this resulting in high molecular weight molecules (200,000 to 20,000,000 daltons) which were significantly less allergenic due to a decreased capacity to bridge IgE on its specific receptor, while maintaining the immunogenicity and thus the therapeutic efficacy. In recent years further agents, acting as adjuvants, such as L-tyrosine, monophosphoryl lipid A, aluminium hydroxide, were added to polymerized extracts. Moreover, a carbamylated monomeric allergoid was developed and, once adsorbed on calcium phosphate matrix, used by subcutaneous route. At the same time, in virtue of its peculiarities, such allergoid revealed particularly suitable for sublingual administration. A lot of clinical evidences show that it is well tolerated, largely safer and effective. Importantly, the higher safety of allergoids allows faster treatment schedules that favor patient compliance and, according to pharmaco-economic studies, they might be more cost-effective than other AIT options.

Mechanisms of allergic diseases in Otorhinolaryngology.

Allergic Rhinitis (AR) is an IgE-mediated hypersensitivity disease caused by inhalation of an allergen to which the patients is sensitized. Etiopathogenesis of AR comprises a sensitization phase, an immediate phase and a late phase. In the sensitization phase, inhaled allergens are processed in peptides and come into contact with the nasal mucosa cells. Antigen-Presenting Cells (APCs), especially represented by Dendritic Cells (DCs), capture them through the interaction with their own MHC class II complexes and migrate to lymph nodes. Then, allergenic peptides are presented to naïve CD4+ T lymphocytes and a differentiation of T cells in Th2 subset takes place. After Th2 lymphocyte induction due to allergen exposure, the most relevant cytokines that are produced are represented by IL-3, IL-4, IL-5, IL-9, IL-10, and IL-13 that are able to promote IgE synthesis and mast cell proliferation. The allergen reaction, when allergen meets its specific IgEs on mast cells surface, causes an early inflammatory reaction determined by mast cells and basophils degranulation with release of preformed mediators from the intracellular granules, resulting in symptoms such as rhinorrhea, itching and sneezing. This phase is followed by a late phase characterized by the release of newly formed mediators, like leukotrienes, chemokines and adhesion molecules, and by the recruitment of eosinophils, neutrophils, macrophages, mast cells, lymphocytes B and T in the nasal mucosa. Such mechanism is responsible for continuing inflammation sustained by chemoattractants, cytokines and adhesion receptors that induce cellular infiltration of eosinophils, basophils, Th2 lymphocytes and mast cells and is clinically mirrored by the prevalence of nasal congestion over sneezing, itching and rhinorrhea.

Role of imaging in allergic rhinology.

Rhinitis is an underestimated clinical condition, which has a considerable impact on the quality of life of the affected patients. The subject of this review focuses on three fundamental aspects: the development of knowledge concerning anatomic landmarks, the development of radiological imaging technology, and developments that can make a difference in the treatment of allergic rhinitis. The anatomical study of paranasal sinuses has been conducted since the time of the ancient Egyptians. Development of radiological equipment from the early 1900s has helped to improve information on the morphology of paranasal sinuses, sufficient to be considered valuable information regarding frontal anatomy and its variability. Imaging has become increasingly important in the diagnosis and treatment of inflammatory diseases of the paranasal sinuses. In recent decades, radiology has helped to study this region as we have progressed from plain radiography to high-resolution Computed Tomography (HRCT). Subsequently, from radiologic imaging, digital volume tomography (DVT) has been developed, in high resolution and narrow section width. Currently, experience with third generation Cone-Beam Computed Tomography (CBCT) technologies provides useful information about bones, and it is now possible to highlight anatomical variants that involve bone structures. We still lack the ability to make a qualitative evaluation of soft tissues, as there are no Hounsfield levels in CBCT. However, this is a new area of research, and its application is evolving in an interesting manner, especially for soft-tissue allergic-inflammatory diseases.

Omalizumab a new prospective: a nasal polyposis.

Omalizumab, a monoclonal antibody against IgE, may be effective on nasal polyps, but its use is not currently authorized to treat that disease. We report the cases of three patients who were given omalizumab for asthma after undergoing nasal surgical polypectomy. Although such procedure is frequently followed by polyp recurrence, none of the three patients developed this complication, and in one subject the regression of initial polyp return was registered after starting omalizumab. Our data support the hypothesis that omalizumab may be useful to treat nasal polyposis.

New scientific synergies to manage patients with severe Rhinitis: allergy diagnosis and treatment for ENT specialists.

INTRODUCTION: Allergic rhinitis (AR) is a global health problem because of its steadily increasing incidence and prevalence that currently concerns about 30% of the world’s population. Although AR is not a disease that reduces the life expectancy, it is a disorder with a major impact on the quality of life of patients, resulting from an impaired social life, school performance and work productivity. Furthermore, AR produces significant costs for its treatment.

Human nasal immune system: a special site for immune response establishment.

The mucosal immune system located in correspondence to the olfactory organs in adult humans is not well identifiable but has proven important in establishing an effective immune response against inhaled antigens, including the generation of Helper 1 (TH1)- and TH2-cells, cytotoxic T lymphocytes (CTLs), plasma cells (PCs) and memory B cells. It is constituted by a diffused network of cells of epithelial and immune origin, as well as organized lymphoid tissue, where each component has a role in the initiation and maintenance of a long-lasting immune response, which is evoked not only in the oral and nasal cavities but also in the respiratory, intestinal and genito-urinary tracts. These peculiarities, in association to the easy anatomical accessibility of such immunological site, render the nasal mucosa a good candidate for the development of vaccine, even if a better understanding of the mechanism of the immune response induction as well as finding a safe adjuvant are necessary.

Laboratory tests for allergy diagnosis.

The introduction of highly purified natural and recombinant single allergenic molecules represented an important improvement in the diagnosis of IgE sensitization. The identification of specific IgE against cross-reacting molecules such as profilin, lipid transfer proteins, calcium binding proteins or against “genuine molecules”, represents an added value and allows to distinguish between true and false polysensitization. In vitro tests add information to recognize patients with sensitization to genuine molecules that cause allergic diseases and to evaluate in childhood the spreading of sensitization for each molecule in order to choose the best treatment and to identify the ideal patient for allergen immunotherapy. Also, in order to detect patients with sensitization to pan-allergens it is important to manage the risk of anaphylaxis for patients allergic to latex and to identify IgE to particular molecules involved in occupational allergy. In patients with negative skin prick tests (SPT), that results in a lower sensitivity compared with in vitro tests, the negative test may be caused by the lack of some important allergenic molecules in the extract used for SPT.

Pollens causing allergy and their monitoring by aerobiology and phenology.

Allergies caused by inhalant allergens, particularly pollens, are steadily increasing in urban centers. It is known that atmospheric pollution is strongly related to the inflammatory disease of the upper and lower airways but it is equally important in the development of sensitization towards pollens. Particulate Matter (PM), sulfur dioxide (SO2) and nitrogen dioxide (NO2) have an enhancement function on the persistence of pollens in the air, increasing the concentration and duration of pollinosis. It is therefore essential to use air quality control methods in urban centers to monitor the presence of pollen and fine dust that can drive the doctor and the patient to improve prevention, a step of primary importance in the treatment of allergies. Aerobiology and phenology are essential tools to monitor pollen production. The opportunity for the patients to use social media as information sources, including teletext, sms, mail and social networks, as well as a wide range of apps, allows to have reliable information on the air we breathe and therefore to better manage the methods of prevention at our disposal.

ENT tests for assessing the allergic patient.

Allergic rhinitis (AR) is a disease that afflicts a large percentage of the world population. It concerns both allergists and otolaryngologists, therefore it is important for both specialists to be aware of the characteristics of a patient who suffers from AR. Often, patients complain of nasal breathing difficulty only, initially not reporting any other symptoms typical of AR. In this brief review, the most important investigations, physical examination, nasal endoscopy, nasal peak flow and rhinomanometry, are described. All these investigations allow us not only to make the correct diagnosis, but also to monitor the course of the disease and the effects of therapy.

Allergic rhinitis.

Allergic rhinitis (AR) was long considered a quite trivial disease, but the advance in epidemiological and clinical knowledge, with a major role for Allergic rhinitis and its Impact on Asthma (ARIA) initiative, substantially changed the scene. Now we know that AR has significant effects on patients’ quality of life and also has a relevant economic burden. The ARIA phenotypes related to the duration of symptoms and to the severity of AR are very useful in establishing the optimal strategy in each patient with AR, also according to the kind of allergens that cause rhinitis. When traditional allergy testing, including skin prick tests and in vitro of specific IgE antibodies are not sufficient for the diagnosis, modern techniques such as molecular diagnostics may be used. Also the management of AR may be tailored to single patients according to the clinical expression of AR, that may vary from mild to moderate-severe stage, with the aim of achieving the best possible control of the disease.

Asthma associated to rhinitis.

A large amount of data show that AR and asthma are associated both epidemiologically and clinically, introducing the definition of “united airway disease”. The mechanisms underlying such association were initially suggested to start from the nose, including the loss of the protective and homeostatic effects of nasal function, the activation of a naso-bronchial reflex and the spread of allergic inflammation from the nose to the lower airways. Later, other factors such as microbial stimuli and systemic inflammatory mechanisms, involving bloodstream and bone marrow, were advocated. The advance in knowledge made it clear that the link between asthma and AR is multifactorial, with particular importance for inflammatory cells and especially eosinophils. By the model of nasal challenge, important immunological responses were revealed, with particular importance for the increased expression of adhesion molecules (ICAM-1, VCAM-1 and E-selectin) and of cytokines such as interleukin (IL)-13, that was accompanied by a rise of eosinophils in blood and developement of bronchial hyper-responsiveness. The occurrence in AR of a concomitant sinusitis is frequently associated with worse asthma outcomes, as assessed by a lower pulmonary function, increased asthma symptoms and poorer quality-of-life compared to patients with asthma alone.

Should omalizumab be used in severe asthma/COPD overlap?

A large number of patients suffering from asthma or chronic obstructive pulmonary disease (COPD) can show overlapping features of both diseases. Several subjects affected by asthma-COPD overlap (ACO) may be at a severe stage, poorly responsive to triple therapy including inhaled corticosteroids, long-acting ß2 agonists and muscarinic antagonists. This review tries to explore whether omalizumab can be used in poorly controlled severe ACO patients. According to the few studies available, omalizumab may improve asthma outcomes in ACO, although the magnitude of improvements may be lower in comparison to those obtained in subjects affected only by severe asthma. Omalizumab, by acting on IgE, might improve the eosinophilic pattern which is characteristic of the ACO asthma inflammation component. It can be hypothesized that a prevalence of Th1/Th17 airway inflammation pathways can modulate a lower response to anti-IgE while a Th2 pattern can lead to a higher effectiveness to omalizumab in ACO. High levels of IgE, FeNO and blood eosinophil count may be markers of a better response to omalizumab. In conclusion, on the basis of the few studies available, omalizumab could be effective in poorly-controlled severe ACO, although to a reduced extent in comparison to patients affected only by asthma.

The skin prick test.

The skin prick test (SPT) is the most common test for the diagnosis of allergy. SPT is performed by pricking the skin, usually in the volar surface of the forearm, with a lancet through a drop of an allergen extract and is usually the first choice test in the diagnostic workup for allergic diseases because of its reliability, safety, convenience and low cost. SPT is minimally invasive and has the advantage of testing multiple allergens in 15 to 20 min. In children, SPT is far less disturbing than venipuncture and is used to obtain a sample of serum to measure specific IgE through in vitro tests. There is a good correlation (about 85-95%) between SPT and in vitro tests. Globally, SPT is an excellent diagnostic tool, with a positive predictive value ranging from 95-100%. SPTs can identify sensitivity to inhalants, foods, some drugs, occupational allergens, hymenoptera venom and latex. However, the relevance of such sensitivity to allergens should always be carefully interpreted in the light of the clinical history, because sensitization and clinical allergy may not coincide. In regards to safety, though the reports of systemic reactions, and particularly anaphylaxis, are very rare, in vitro IgE tests should be preferred if previous severe reactions emerge from the patient’s clinical history.

Is lingual tonsil a preferential target for processing sublingually administered materials?

The oral cavity is a site of pivotal importance in the immune response to foreign antigens, ensuring tolerance induction to harmless agents but reactivity to potentially noxious antigens. Tolerance or reactivity are driven by a number of secondary lymphoid organs, all belonging to the Waldeyer ring, that include adenoids, tubal, palatine and lingual tonsils. Waldeyer's ring tissues were acknowledged as implicated not only in the adaptive immune system but also in the innate immune system modulation, involving the toll-like receptors. In particular, findings from animal studies suggested that the lingual tonsil can be considered as an inductive site sampling and processing antigens to stimulate naïve T and B lymphocytes. According to a recent study showing that immunologically active or inactive materials placed under the tongue of allergic subjects rapidly reach the lingual tonsil, such a role seems likely also in humans, and warrants to be investigated in-depth for possible applications in medical treatments.

Cypress pollen: an unexpected major sensitizing agent in different regions of Italy.

OBJECTIVES: In this multicenter survey, we assessed the impact of sensitization to cypress in atopic patients in Italy and determined whether cypress pollen concentration changed over time. METHODS: Allergists were required to collect the results of 100-200 consecutive skin prick tests (SPTs) performed during 2012. Seasonal symptoms were also recorded, as were airborne cypress pollen concentrations (data from the Italian Aerobiology Association) in 1998-2000 and 2010-2012. RESULTS: We examined 2258 atopic outpatients (56% females; age, 2-84 years) sensitized to at least 1 of the aeroallergens tested (Dermatophagoides species, grass, pellitory, olive, cypress, birch, Alternaria tenuis, and dog and cat dander). We found that 62.9%, 16.1%, and 32.7% of patients living in central, northern, and southern Italy, respectively, were sensitized to cypress (P < .0001). The cypress pollen concentration peak was delayed from February to March in 1998-2000 and 2010-2012 in all 3 regions, with a shift in pollination towards spring. Patients who were monosensitized to cypress reported mainly rhinitis (90.7%-97.6%) and conjunctivitis (38.1%-100%). In polysensitized patients, the prevalence of rhinitis, conjunctivitis, and asthma increased progressively (P < .0001) from southern to northern Italy. The same trend was observed for the prevalence of reported winter symptoms typical of cypress allergy (28%-65%). CONCLUSIONS: Today, cypress pollen is the most frequent sensitizing aeroallergen (assessed by SPT) in several areas of central Italy. Variations in the timing of the cypress pollination period may have favored this increased sensitization. Rhinitis and conjunctivitis are the predominant symptoms. The clinical impact of this allergy was poor in southern Italy and increased in central areas before reaching its peak in northern regions.

Evaluation of stability of allergen extracts for sublingual immunotherapy during transport under unfavourable temperature conditions with an innovative thermal insulating packaging.

Many pharmaceutical and biotechnological products are temperature-sensitive and should normally be kept at a controlled temperature, particularly during transport, in order to prevent the loss of their stability and activity. Therefore, stability studies should be performed for temperature-sensitive products, considering product characteristics, typical environmental conditions, and anticipating environmental extremes that may occur during product transport in a specific country. Staloral products for sublingual immunotherapy are temperature sensitive and are labelled for maintenance under refrigerated conditions (2-8°C). Given the peculiar climatic context of Italy and the great temperature fluctuations that may occur during transport, this study was aimed at evaluating the impact of a new engineered thermal insulating packaging for Staloral. In particular, the purpose was to assess whether the new packaging could create a container condition able to preserve the stability and immunological activity of the product during the transport phase throughout Italy. The results showed that the range of temperatures that can affect the product, in the area surrounding the product packaging, may reach a peak of 63°C during transport under the most unfavourable climatic conditions, i.e. in a non-refrigerated van during the summer season, from the site of production in France to the patient's house in Catania, the city with the highest temperatures in Italy. However, the highest temperature reached inside the vaccine did not exceed 45°C over a period of about 2 h. The ELISA inhibition test on samples subjected to the extreme temperature conditions previously defined (45°C) showed an immunological activity higher than 75% of that initially measured and was comparable to those obtained with samples stored at controlled temperature (5°C). This means that, even in the worst case scenario, the structure of the allergen extracts is not influenced and the vaccine potency is preserved.

The POLISMAIL lesson: sublingual immunotherapy may be prescribed also in polysensitized patients.

Polysensitization is a feature of allergic rhinitis (AR) that significantly impairs the quality of life (QoL) of AR patients. Allergen-specific immunotherapy is the only causal therapy for AR. However, the polysensitization phenomenon may represent a crucial obstacle as far as it concerns the choice of the allergen extract which should be used for immunotherapy. Therefore, a real-life based multi-centre study, named POLISMAIL, has been designed which aims at evaluating the behaviour of some allergists managing polysensitized AR patients. The effect of two-year SLIT treatment in those patients was also evaluated. A single allergen extract was used for two-thirds of patients, whereas a mix of two allergens was chosen for the remaining patients. The severity grade of AR and the type of diagnosis were significantly improved by 2-year SLIT. In addition, SLIT significantly improved QoL. Both outcomes confirm that SLIT with one or two allergen extracts achieves a significant improvement in polysensitized patients. In conclusion, the POLISMAIL study demonstrates that polysensitization should not represent a counter-indication for prescribing immunotherapy. The choice to limit SLIT to 1-2 allergen extracts was sufficient and effective in improving symptoms and QoL.