Subcutaneous and sublingual allergen-specific immunotherapy: a tale of two routes.

Summary: Specific immunotherapy is the only treatment acting on the causes and not only on symptoms of respiratory allergy. It was first introduced as subcutaneous immunotherapy (SCIT) with the aim to induce immunological tolerance to the administered allergen(s). In the 1980s, sublingual immunotherapy (SLIT) was developed, mainly to improve the safety, which was a critical issue at that time. This article reviewed the available literature, including a large number of randomized controlled trials, meta-analyses, and real-life studies as well, on the outcomes of SCIT and SLIT concerning the treatment critical issues of the two routes, that are efficacy, safety, cost-effectiveness, and compliance to treatment. The efficacy of SCIT and SLIT is similar in respiratory allergy, providing, based on the induction of typical changes in the immunologic response, an early control of symptoms that steadily increases during the treatment and its efficacy lasts after the recommended duration of three years. Such results are the reason why SCIT and SLIT have economic advantage over symptomatic drugs.

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.

Allergic reactions to genus Morus plants: a review.

Mulberry is a plant belonging to the family Moraceae, and genus Morus. Allergic sensitization to mulberries has been reported as both food allergy or respiratory allergy, and cross-reactivity between mulberries and other pollens or fruits was described. Clinically, in the articles reporting mulberry allergy, the reactions included respiratory allergy, airborne contact urticaria, anaphylaxis, oral allergy syndrome, and food induced urticaria. As far as cross-reactivity is concerned, the allergens identified thus far in mulberries include pathogenesis-related (PR)10 proteins, with sequence identity to Bet v 1 from birch, lipid transfer (LTP)1 proteins with identity with LTPs from Rosaceae family plants, panallergens groups, and also ubiquitin-like protein and cystatin-like protein. The two latter proteins account for cross-reactions with Parietaria judaica and Olea europaea. Such large cross-reactivity warrants to pay particular attention to the risk of systemic reactions to foods, particularly in subjects sensitized to birch, parietaria or olive pollens. In fact, the increasing use of mulberry as a food product, which is encouraged by its remarkable antioxidant power, expose sensitized patients to possible reactions after ingesting foods, dietary supplements or nutraceuticals containing mulberry. Mulberry allergenicity can vary according to the processing methods used since some allergens are thermostable and other loss their reactivity during heating.

A bio-psycho-social approach in elderly population: outcome of adapted physical activity in patients with osteoarthritis.

BACKGROUND: The beneficial effect of physical activity on a large spectrum of diseases is well known, with particular importance for elderly people. Among the different types of activity, adapted physical activity (APA) has been applied in a number of disease-related physical deficit. OBJECTIVE: The purpose of this study is to determine the outcome of a six months APA program in elder patients with osteoarthritis concerning physical and functional health and as second endpoint to determine the potential effect of AFA on reducing the risk of institutionalization. METHODS: The clinical indexes used to assess the outcome included the Blaylock Risk Assessment Screening Score (BRASS), the Psychological General Well Being Index (PGWBI), the Cumulative Illness Rating Scale (CIRS), the Short Physical Performance Battery (SPPB), and the visual analogue scale (VAS). RESULTS: A significant difference (p = 0.047) between the pre-APA and the post-APA value was found for BRASS, and highly significant differences (p <0.0001) were found for SPBB and VAS. CONCLUSIONS: These findings show that a six months APA program in elder patients with osteoarthritis improves physical function, reduces pain intensity and decreases the risk of institutionalization. Moreover the positive outcome of APA we found in elder patients with osteoarthritis suggests a more frequent use of such rehabilitation approach, also evaluating its economic impact on this disease.

Atopic Keratoconjunctivitis: Pharmacotherapy for the Elderly.

Among the different forms of allergic conjunctivitis, atopic keratoconjunctivitis has distinct characteristics, defined by a more common onset in late adolescence or early adulthood, but also affecting the elderly, and with a higher prevalence in male individuals. However, the prevalence of atopic keratoconjunctivitis is scarcely investigated, and the data are often uncertain because other allergic nasal or respiratory disorders occur concomitantly. Mast cells, eosinophils, basophils, and T cells are involved in the pathogenesis of atopic keratoconjunctivitis. Despite its denomination as atopic, negative responses to skin tests or in-vitro immunoglobulin E tests are common. In fact, atopic keratoconjunctivitis can be attributed to a combination of T-helper-1 and T-helper-2 responses, but a higher prominence for T-helper-1 cells was found. The most common symptoms of atopic keratoconjunctivitis are bilateral ocular itching, burning, and tearing with a perennial presentation, although some patients may have seasonal exacerbations in winter or summer. Other symptoms such as photophobia, blurred vision, and mucous chewy discharge, owing to the accumulation of cells and mucin, may occur. The diagnosis of atopic keratoconjunctivitis is mainly clinical, as accepted diagnostic criteria or laboratory tests are not available. The treatment of atopic keratoconjunctivitis is aimed at controlling symptoms, decreasing relapse and exacerbations, and reducing vision loss. Therapeutic options comprise topical ophthalmic drops, including cromones, antihistamines, corticosteroids, and calcineurin inhibitors. Topical ointments are also available for corticosteroids and calcineurin inhibitors. Severe forms may require systemic medications including antihistamines, corticosteroids, and calcineurin inhibitors. Atopic keratoconjunctivitis therapy in the elderly does not differ from the adult population, but the occurrence of multi-morbidities and concomitant drug treatment, which are common in this age group, requires a careful evaluation to determine appropriate and personalized treatment.

The growing importance of real-life studies in allergen immunotherapy.

Summary: Real-life studies offer the opportunity of obtaining outcomes suitable in clinical practice, as controlled trials do not mirror the real patients' population observed in clinical practice. This concept is particularly appropriate for allergen immunotherapy (AIT). Therefore, the current review will present and discuss the most recent and relevant studies published on this topic. Globally, 15 real-life studies on AIT efficacy are available until now, the total of patients amounts to 9090, with an average number of 699 patients per study. This high number significantly decrease the possibility that the observations from real-life study are casual, and confers to such studies a key role in the next years to assess issues other than efficacy and safety, especially those scantly investigated thus far.

Molecular diagnostics improves diagnosis and treatment of respiratory allergy and food allergy with economic optimization and cost saving

Background: Component resolved diagnosis (CRD) allows to precisely identify the sensitization to specific molecules of a given allergenic source, resulting in an important improvement in clinical management, particularly of polysensitized subjects. This will end in the correct prescription of allergen immunotherapy (AIT) for respiratory allergy and in adequate avoidance diets or prescription of self-injectable adrenaline in food allergy. Objective: The aim of this multicenter, real life study is to evaluate the percentage change of the diagnostic-therapeutic choice in polysensitized patients with respiratory allergy and in patients with food allergy, after using CRD compared to a first level diagnosis, along with an economic analysis of the patient's overall management according to the two different approaches. Methods: An overall number of 462 polysensitized patients, as suggested by skin prick tests (SPT), and with clinical symptoms related to a respiratory (275 pts) or food (187 pts) allergy, were recruited. All patients underwent CRD for specific IgE against food or inhalant recombinant molecules, which were chosen according to medical history and positivity to SPT. The first diagnostic-therapeutic hypothesis, based only on medical history and SPT, was recorded for each patient while the final diagnostic-therapeutic choice was based on the results from CRD. The rate of change of the diagnostic-therapeutic choice from the first hypothesis to the final choice was statistically evaluated. The economic impact of CRD on the overall management of the allergic patients was analyzed to evaluate whether the increase in the diagnostic costs would be compensated and eventually exceeded by savings coming from the improved diagnostic-therapeutic appropriateness. Results: An approximate 50% change (k index 0.54) in the prescription of AIT for respiratory allergy as well as a change in the prescription of self-injectable adrenaline (k index 0.56) was measured; an overall saving of financial resources along with a higher diagnostic-therapeutic appropriateness was also detected. Conclusion: There is moderate agreement concerning prescription of AIT and self-injectable adrenaline before and after performing CRD: this highlights the usefulness of CRD, at least in polysensitized patients, in indicating the risk assessment and therefore the correct therapy of respiratory and food allergy, which results in a cost-saving approach

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Molecular diagnostics improves diagnosis and treatment of respiratory allergy and food allergy with economic optimization and cost saving.

BACKGROUND: Component resolved diagnosis (CRD) allows to precisely identify the sensitization to specific molecules of a given allergenic source, resulting in an important improvement in clinical management, particularly of polysensitized subjects. This will end in the correct prescription of allergen immunotherapy (AIT) for respiratory allergy and in adequate avoidance diets or prescription of self-injectable adrenaline in food allergy. OBJECTIVE: The aim of this multicenter, real life study is to evaluate the percentage change of the diagnostic-therapeutic choice in polysensitized patients with respiratory allergy and in patients with food allergy, after using CRD compared to a first level diagnosis, along with an economic analysis of the patient's overall management according to the two different approaches. METHODS: An overall number of 462 polysensitized patients, as suggested by skin prick tests (SPT), and with clinical symptoms related to a respiratory (275 pts) or food (187 pts) allergy, were recruited. All patients underwent CRD for specific IgE against food or inhalant recombinant molecules, which were chosen according to medical history and positivity to SPT. The first diagnostic-therapeutic hypothesis, based only on medical history and SPT, was recorded for each patient while the final diagnostic-therapeutic choice was based on the results from CRD. The rate of change of the diagnostic-therapeutic choice from the first hypothesis to the final choice was statistically evaluated. The economic impact of CRD on the overall management of the allergic patients was analyzed to evaluate whether the increase in the diagnostic costs would be compensated and eventually exceeded by savings coming from the improved diagnostic-therapeutic appropriateness. RESULTS: An approximate 50% change (k index 0.54) in the prescription of AIT for respiratory allergy as well as a change in the prescription of self-injectable adrenaline (k index 0.56) was measured; an overall saving of financial resources along with a higher diagnostic-therapeutic appropriateness was also detected. CONCLUSION: There is moderate agreement concerning prescription of AIT and self-injectable adrenaline before and after performing CRD: this highlights the usefulness of CRD, at least in polysensitized patients, in indicating the risk assessment and therefore the correct therapy of respiratory and food allergy, which results in a cost-saving approach.

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.

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.

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.

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.

Could seasonal allergy be a risk factor for acute rhinosinusitis in children?

OBJECTIVE: To evaluate the incidence of acute rhinosinusitis in children with grass pollen induced rhinitis during the period of grass pollinosis. METHODS: Children with nasal symptoms from grass pollen induced rhinitis but without rhinosinusitis symptoms were selected. Their parents were asked to complete a diary during pollen exposure to report nasal symptoms and drugs used daily. When rhinosinusitis was suspected, the confirmatory diagnosis of acute rhinosinusitis was made by fibro-endoscopy. Children without inhalant allergy served as controls. RESULTS: Seventeen out of 242 children (7.0 per cent) had a diagnosis of acute rhinosinusitis, confirmed by fibro-endoscopy, during grass pollination, compared to 3 out of 65 (4.6 per cent) in the control group (p = 0.49). Among allergic children, those with acute rhinosinusitis had symptoms for a greater number of days and/or a higher symptoms score than children without acute rhinosinusitis. CONCLUSION: Children with grass pollen induced rhinitis during exposure to pollen have an incidence of endoscopically confirmed acute rhinosinusitis comparable to non-allergic children. This suggests that grass pollen induced rhinitis is a negligible risk factor for acute rhinosinusitis.

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.

Periostin: The bone and beyond.

In recent years the relationship between bone, metabolism and many pathophysiologic mechanisms involving other organs and the immune system, was increasingly apparent. This observation concerns vitamin D, osteopontin and periostin (PO). PO is expressed in the periosteum of long bones but also in many other tissues and organs, including heart, kidney, skin and lungs, being enhanced by mechanical stress or injury. PO has a relevant physiological function in promoting injury repair in a large number of tissues. However, its overexpression was observed in different diseases characterized by inflammation, fibrosis and tumorigenesis. Here we review the current knowledge on the role of PO in physiologic and pathologic pathways of different diseases. A specific focus regards the correlation between the level of PO and lung diseases and the identification of PO also as an inflammatory key effector in asthma, strongly associated with airways eosinophilia. In fact PO seems to be a useful biomarker of "Th2-high" asthma compared to "Th2-low" asthma phenotype and a predictor of response to therapeutic agents. Currently, a growing number of studies suggests a possible role of PO as a new diagnostic marker and/or therapeutic target for different diseases and its usefulness in clinical practice should be supported and confirmed by further and larger studies.

Scoliid wasp sting: a new cause of anaphylaxis

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Comparing the compliance to a short schedule of subcutaneous immunotherapy and to sublingual immunotherapy during three years of treatment.

BACKGROUND: Allergen immunotherapy (AIT) in its two forms of subcutaneous immunotherapy (SCIT) and sublingual immunotherapy (SLIT) is an effective treatment of respiratory allergy, but is particularly concerned by the issue of compliance. OBJECTIVE: We aimed a real-life study at evaluating the compliance to SLIT and to SCIT administered by a short-course of four injections during a 3-year period of observation. METHODS: A group of 145 patients (79 males, 66 females, age ranging from 14 to 69 years), suffering from pollen-induced rhino-conjunctivitis with or without asthma, were included in the study. Following adequate education on AIT and according to patient's preference, 72 patients chose to be treated with short-course SCIT and 73 chose to be treated with SLIT. The latter was performed by allergen extracts from different manufacturers according to the suggested schedules. RESULTS: The rate of withdrawal was as follows: after one year, 15.6% for SCIT and 33.4 for SLIT; after two years, 25.6% for SCIT and 44.8% for SLIT; after three years, 26.7 for SCIT and 46% for SLIT. There was no significant difference in the rate of withdrawal between males and females. Regarding the safety, no systemic reaction requiring medical treatment was observed either in SCIT or SLIT group. CONCLUSION: The findings of this study confirm that involving the patient in the choice of the route of administration is associated to a satisfactory compliance to AIT. In particular, more than 70% of patients treated with a short schedule of SCIT completed the three-years course of treatment that is recommended for AIT, while this goal was reached by 54% of SLIT treated patients.

Allergic rhinitis: pharmacotherapy in pregnancy and old age.

INTRODUCTION: Allergic rhinitis (AR) affects 20-30% of women in reproductive age and may worsen during pregnancy. About 10% of the elderly suffer from AR, and it could be under-diagnosed in these patients. Many drugs are currently available, however AR treatment during pregnancy and old age represents a challenging issue. AREAS COVERED: A review of the literature on the topic has been performed. Expert commentary: In pregnancy, drug avoidance should be carefully balanced with the need for AR optimal control. Topical drugs are suggested as a first approach. The safety and tolerability profile of second-generation antihistamines is well supported. If allergen immunotherapy (AIT) is ongoing and well tolerated, there is no reason for stopping it. AIT initiation in pregnancy is not recommended. For elderly patients, no specific concerns have been highlighted regarding topical treatments, except from nasal decongestionants. Second generation antihistamines are generally well tolerated. Old age should not preclude AIT.

Factors associated with different results of allergy tests in children with dust mite-induced atopic dermatitis

BACKGROUND: Atopic dermatitis (AD) is a public health problem, with an increasing prevalence worldwide. AD is a chronic inflammatory disease characterised by skin lesions and severe itching. Immunologically, AD has two forms, IgE-mediated and cell-mediated, but it may also be idiopathic. In the pathogenesis of AD, the gene mutations for filaggrin, a filament-aggregating protein present in the epidermis, are of pivotal importance, but other genetic factors are also operating, including those linked to family atopy. METHODS: We evaluated the role of family atopy, and of the results of the atopy patch test (APT) in parents, in children with mite-induced AD. 64 children, 38 males and 26 females, mean age 4.97 years, were included for the diagnosis of AD and underwent APT and skin prick test (SPT) with dust mite extracts, with evaluation of atopy and result of APT also in parents. RESULTS: A positive family history of atopy was shown for children with positivity to both APT and SPT compared to those with negative or only one positive result to APT or SPT (p = 0.08). Significant associations were found concerning APT results in children and parents. In particular, children of a positive-APT parent had an 18-fold higher risk of APT-positivity in comparison with children of negative-APT parents, while the risk was 6.6-fold higher if APT was positive in father. CONCLUSION: Family atopy and a positive APT in fathers are risk factors to develop cell-mediated AD, as assessed by the APT, in children

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