Factors influencing the prescription of allergen immunotherapy: the allergen immunotherapy decision analysis (AIDA) study.

The evidence of efficacy of allergen immunotherapy (AIT) for respiratory allergy has been demonstrated by a number of meta-analyses. However, the daily practice of AIT is quite different from controlled trials, facing challenges in terms of selection of patients, practical performance, and, of particular importance, use of allergen extracts of inadequate quality. We here performed a survey, named the Allergen Immunotherapy Decision Analysis (AIDA), to evaluate which criteria are used by specialists to choose a product for sublingual immunotherapy (SLIT) in patients with respiratory allergy. A questionnaire composed of 14 items to be ranked by each participant according to the importance attributed when choosing SLIT products was submitted to 444 Italian specialists. The responses of the 169 (38.1%) physicians, who answered all questions, were analysed. Most of the respondents were allergists (79%), followed by pulmonologists (10.8%), both allergists and pulmonologists (4.8%), and otorhinolaryngologists (3%); 59.8% of the respondents were males and 40.2% were females. The age distribution showed that 89.9% of the respondents were aged between 35 and 64 years. All respondents usually prescribed AIT products in their clinical practice: 31.4% used only SLIT, whereas 69.2% used both subcutaneous and sublingual administration. The rankings, expressed as means, attributed by physicians for each of the 14 items were as follows: level of evidence-based medicine (EBM ) validation of efficacy (3.44), level of EBM validation of safety (4.30), standardization of the product (5.37), efficacy based on personal experience (5.82), defined content(s) of the major allergen(s) in micrograms (5.96), scientific evidence for each single allergen (6.17), safety based on personal experience (6.32), ease of administration protocol (8.08), cost and terms of payment (e.g. instalments) (9.17), dose personalization (9.24), patient preference (9.25), ease of product storage (9.93), reimbursement (10.12), and availability of a helpline or on-line assistance from the manufacturer (11.89). These attitudes need to be taken into consideration by regulatory agencies as well as by producers.

The Piemonte Regional Allergy Network: a model of healthcare organization.

The Allergology Hospital Network and Regional Register for Severe Allergic Reactions (Regional Observatory) is the Piemonte Health Authority new challenge. It satisfied the need to promote and monitor the best practice among a variegated pool of specialists and to define both state of the art and evolution of efficiency and efficacy of standard working process. Harmonization in clinical daily activities and report of severe allergic reactions notified to Regional Observatory, had been gained by mean of a customized Information Technology (IT) solution. The overall target is to ensure a correct diagnostic treatment to patients with severe allergic reactions preventing possible future reactions. Statistics data as a whole, provide basilar epidemiological information to allocate both economical and human resources and to fulfill the rising of health diseases. Piemonte Allergology Medical Network with the Regional Register are an Italian unique and innovative project. It would represent a benchmark for other medical branches.

Sublingual immunotherapy in polysensitized patients: effect on quality of life.

BACKGROUND: Quality of life (QOL) is an important issue in allergic rhinitis and has been evaluated in a number of studies that have shown how it is impaired in untreated patients and improved by effective treatment. However, there are no data concerning QOL after sublingual immunotherapy (SLIT) in polysensitized patients. OBJECTIVE: To evaluate the effect, in real-life clinical practice, of SLIT on QOL in a population of polysensitized patients with allergic rhinitis. METHODS: We prospectively evaluated 167 consecutively enrolled polysensitized patients with allergic rhinitis. QOL was measured in all cases with the Rhinoconjunctivitis Quality of Life Questionnaire at baseline and after 1 year of SLIT (performed in approximately 70% of cases using single allergen extracts provided by the same manufacturer). RESULTS: The most frequent causes of sensitization were grass pollen, Parietaria, and house dust mites. The mean number of sensitizations per patient was 3.65. SLIT was performed with 1 extract in 123 patients (73.6%), with 2 extracts in 31 patients (18.6%), and with more than 2 extracts in 13 patients (7.8%). The mean values of all the QOL items improved significantly (P < .01 in all cases), with the following reductions noted: activities, 3.96 to 2.89; sleep, 2.07 to 1.56; general problems, 2.16 to 1.5; practical problems, 3.69 to 2.58; nasal symptoms, 3.57 to 2.50; eye symptoms, 2.92 to 1.83; and emotional aspects, 2.2 to 1.44. CONCLUSIONS: This study provides evidence that QOL can be improved in polysensitized patients treated with SLIT, and that the use of just 1 or 2 allergen extracts seems to be sufficient and effective in terms of improving QOL.

Sublingual immunotherapy in polysensitized allergic patients with rhinitis and/or asthma: allergist choices and treatment efficacy.

Polysensitization is very common in allergic patients and was previously reported to be associated with more severe symptoms and impaired quality of life. Polysensitization is often considered as a contraindication for specific immunotherapy (SIT). This study is aimed at evaluating the allergist attitude for decision making in choosing SIT in a cohort of Italian polysensitized patients. Moreover, the 1-year effectiveness of the prescribed sublingual immunotherapy (SLIT) in this cohort was evaluated. The study was performed on 244 patients (109 males, 135 females, mean age 28.7 years, S.D. 12.0) with allergic rhinitis (assessed by ARIA criteria) and/or mild to moderate asthma (assessed by GINA criteria) treated with SLIT for 1 year. The kind and the number of prescribed allergen extracts, type of diagnosis, severity of symptoms, use of drugs, and adverse events were evaluated at baseline and after 1 year. A total of 230 patients were treated with SLIT: 165 with a single extract, and 65 with two different extracts (mix). SLIT treatment significantly improved disease staging, and reduced symptom severity and drug use. No systemic reaction was reported. In conclusion, these findings provide preliminary evidence that SIT is effective and safe in polysensitized patients after 1 year of treatment also using single extracts, and thus does not represent an obstacle for prescribing SIT.

Specific immunotherapy for allergic rhinitis in Italy: the patients points of view.

Specific immunotherapy (SIT) is the unique causal treatment for allergy, but its use is quite limited. A perspective, cross-sectional telephone interview survey was carried out in Italy to evaluate the characteristics of 500 patients with allergic rhinitis (250 of whom treated with SIT). Relevant differences were found concerning therapeutic management of allergic rhinitis, mainly regarding the use of drugs and co-morbidities. The allergist is the most important consultant who prescribes SIT. This study therefore provides evidence that the course of allergic rhinitis may depend on the therapy prescribed by and the level of allergy awareness of the physician.

Specific immunotherapy for allergic rhinitis in Italy: the doctors points of view.

Specific immunotherapy (SIT) is the unique causal treatment for allergy, but its prescription is quite restricted. A perspective and cross-sectional survey based on telephone interviews was carried out in Italy to evaluate the profile of doctors prescribing SIT for allergic rhinitis. A total of 540 doctors were interviewed, 200 of whom are GPs, 60 allergists, 60 ENT specialists, 100 familial paediatricians, 60 hospital paediatricians and 60 pulmonologists. Significant differences concern diagnostic and therapeutic management of allergic rhinitis, mainly regarding SIT prescription. The allergist is the most important consultant who prescribes SIT, as opposed to the paediatrician. This study therefore provides the evidence that doctors behaviour towards SIT depends on the type of graduate studies.

Lack of inflammatory cells in the oral mucosa of subjects undergoing sublingual immunotherapy.

The cells involved in allergic inflammation, such as mast cells, basophils, and eosinophils, have been thoroughly studied in the nose, the lungs and the skin, demonstrating an evident increase in response to the introduction of the specific allergen, while little is known in the mucosal system and particularly in the oral mucosa. We investigated such tissue by using the model of sublingual immunotherapy (SLIT), by which high doses of the specific allergen enter the mouth. Oral biopsies were carried out on seven subjects allergic to grass pollen and treated with SLIT by a grass extract. In biopsies carried out before SLIT there was a very low number of mast cells and eosinophils both in the epithelium and subepithelium layers, and insignificant changes were detected after SLIT. These findings show the lack of allergic inflammation in the oral mucosa upon contact with the specific allergen and confirm the role of the mouth as a tolerogenic site, which is conceivable considering the different attitude of the mouth, where the antigens transit to undergo digestion, in respect to the airways or the skin, where the antigen absorption is potentially dangerous.

Comparison between continuous or intermittent schedules of sublingual immunotherapy for house dust mites: effects on compliance, patients satisfaction, quality of life and safety.

Sublingual immunotherapy (SLIT) is indicated in the treatment of allergic rhinitis and asthma. However, an issue scantly investigated is the patients satisfaction and the consequent compliance. This study is aimed at evaluating the possible differences of SLIT administered continuously or intermittently on several parameters: clinical efficacy, Quality of Life (QoL), satisfaction, compliance and safety. Forty allergic patients were treated for 12 months. The treatment was carried out by sublingual administration of an allergen extract of a 50% mixture of Dermatophagoides pteronyssinus and Dermatophagoides farinae at 10 and 300 IR/ml concentrations. Patients were randomly treated continuously or intermittently (i.e. 2 month treatment alternate to 2 month suspension). Both schedules were significantly effective in reducing allergic symptoms and improving QoL. Compliance and satisfaction were good in both groups. Local and systemic reactions were few, self-resolving, and mild in both schedules. Intergroup analysis did not reveal any difference between the two groups regarding these parameters. In conclusion, this preliminary study provides the evidence that also intermittent SLIT is as effective and safe as traditional continuous treatment. In addition, compliance and satisfaction are super-imposable in the two groups.

Doctors' and patients' educational levels affect immunotherapy prescription.

Cultural level appears to be a critical factor in the decision process of allergen-specific immunotherapy (SIT) both for doctors and patients. Thus, appropriate educational programs should be carried out to increase the number of allergic patients to be treated with SIT.

Characteristics of patients with allergic polysensitization: the POLISMAIL study.

BACKGROUND: The natural history of respiratory allergy is commonly characterized by a worsening of symptom severity, frequent comorbidity of rhinitis and asthma, and polysensitization to aeroallergens. The polysensitization phenomenon starts since childhood and is rare to find monosensitized adult patients. However, there are few studies investigating the characteristics of polysensitized patients. METHODS: This study was performed on a large cohort of patients with allergic rhinitis (assessed by ARIA criteria) and/or mild to moderate asthma (assessed by GINA). The kind and the number of sensitizations, their patterns, and the relation with quality of life (QoL) measured by the Juniper's RQLQ guestionnaire, were evaluated. RESULTS: Globally 418 patients (50.2% males, 49.8% females, mean age 26.4 years, range 3.5-65 years, 64 smokers, 371 non-smokers) were enrolled: 220 had allergic rhinitis alone, and 198 allergic rhinitis and asthma. The mean number ofsensitizations was 2.6. Three hundred-five patients (73%) had persistent rhinitis (PER), 220 of them with moderate-severe form. There was no significant derence in rate of rhinitis and asthma in monosensitized or polysensitized patients. Most patients were sensitized to pollens, whereas only 24.2% of them were sensitized to perennial allergens. Polysensitization was significantly associated with some issues of QoL, confirming previous findings, but not with number ofsensitizations. CONCLUSIONS: This study provides data confirming for poly-sensitized patients the relevance of ARIA classification of AR. PER is the most common form of AR in this cohort, symptoms are frequently moderate-severe, and asthma is present in about the half of patients with AR.

The role of health technology assessment in the comprehensive evaluation of the impact of immunotherapy on real practice.

The increasing development of new health care technologies, along with the ageing of the population and the increasing patients' expectations, cause a significant raise in medical costs, inducing in policy makers the need for well-funded information to support their decisions. The development of Health Technology Assessment (HTA), which is the systematic evaluation of properties, effects or other impacts of health technology and can be considered as a bridge between the world of research and the world of policy-making, reflects this high level of demand. HTA requires a multidisciplinary approach, that covers many different disciplines, in order to assess various aspects of health technologies, as technical properties, safety, efficacy/effectiveness, economic aspects, social, legal, ethical and political impacts. Allergic diseases show a worldwide increasing prevalence and consequent increasing costs, which result very high in recent evaluations. Specific immunotherapy is the only treatment able to alter, differently from drugs, the natural course of allergic diseases, exerting a long-lasting therapeutic effect, that persists also after stopping the therapy. This has a potential great impact in the cost of disease, which only recently was considered in properly designed studies. These issues claim for a larger use of HTA, which may provide a more comprehensive approach to the evaluation of the impact of immunotherapy on allergic patients.

Pharmacoeconomics of subcutaneous allergen immunotherapy.

The current burden of allergic diseases, estimated by both direct and indirect costs, is very relevant. In fact the cost estimation for rhinitis amount globally to 4-10 billion dollars/year in the U.S. and to an average annual cost of 1089 euros per child/adolescent and 1543 euros per adult in Europe. The estimated annual costs in Northern America for asthma amounted to 14 billion dollars. Consequently, preventive strategies aimed at reducing the clinical severity of allergy are potentially able to reduce its costs. Among them, specific immunotherapy (SIT) joins to the preventive capacity the carryover effect once treatment is discontinued. A number of studies, mainly conducted in the US and Germany demonstrated a favourable cost-benefit balance. In the nineties, most surveys on patients with allergic rhinitis and asthma reported significant reductions of the direct and indirect costs in subjects treated with SIT compared to those treated with symptomatic drugs. This is fully confirmed in recent studies conducted in European countries: in Denmark the direct cost per patient/year of the standard care was more than halved following SIT; in Italy a study on Parietaria allergic patients demonstrated a significant difference in favor of SIT plus drug treatment for three years versus drug treatment alone, with a cost reduction starting from the 2nd year and increasing to 48% at the 3rd year, with a highly statistical significance which was maintained up to the 6th year, i.e. 3 years after stopping immunotherapy, corresponding to a net saving for each patient at the final evaluation of 623 euros per year; in France a cost/efficacy analysis comparing SIT and current symptomatic treatment in adults and children with dust mite and pollen allergy showed remarkable savings with SIT for both allergies in adults and children.

Economic evaluation of sublingual immunotherapy: an analysis of literature.

Allergic rhinitis and asthma constitute a global health problem because of their very high prevalence and the consequent burden of disease, concerning medical and economical issues. Among the treatments of allergy, specific immunotherapy has the capacity to favourably alter the natural history of the disease both during and after its performance and thus to reduce the direct and indirect costs of allergic rhinitis and asthma. A number of studies reported such cost reduction for traditional, subcutaneous immunotherapy and recent data demonstrate that also sublingual immunotherapy (SLIT) is associated to economic advantages and/or monetary savings, specifically in terms of reduction of disease economic burden. Only few formal economic assessments of SLIT have been carried out so far, this article will present and discuss the published studies addressed to this issue. The data obtained, although the number of studies is still limited, provide preliminary evidence supporting a SLIT effect on sparing costs for respiratory allergy.

Practice parameters for sublingual immunotherapy.

The efficacy and safety of sublingual immunotherapy (SLIT) are currently supported by clinical trials, meta-analysis and post-marketing surveys. Practice parameters for clinical use of SLIT are proposed here by a panel of Italian specialists, with reference to evidence based criteria. Indications to SLIT include allergic rhinoconjunctivitis, asthma, and isolated conjunctivitis (strength of recommendation: grade A). As to severity of the disease, SLIT is indicated in moderate/severe intermittent rhinitis, persistent rhinitis and mild to moderate asthma (grade D). SLIT may be safely prescribed also in children aged three to five years (grade B), and its use in subjects aged more than 60 years is not prevented when the indications and contraindication are ascertained (grade D). The choice of the allergen to be employed for SLIT should be made in accordance with the combination of clinical history and results of skin prick tests (grade D). Polysensitisation, i.e. the occurrence of multiple positive response does not exclude SLIT, which may be done with the clinically most important allergens (grade D). As to practical administration, co-seasonal, pre co-seasonal, and continuous schedules are available, being the latter recommended for perennial allergens or for pollens with particularly prolonged pollination, such as Parietaria (grade D). For pollens with relatively short pollination, such as grasses and trees (cypress, birch, alder, hazelnut, olive) the pre co-seasonal and perennial schedules are preferred (grade C). The build-up phases suggested by manufacturers can be safely used (grade A), but they can be modified according to the patient's tolerance (grade C). A duration of SLIT of 3-5 years is recommended to ensure a long-lasting clinical effect after the treatment has been terminated (grade C).

Increased CD34+ cell peripheral traffic appears to be an unique feature of the allergic inflammation.

Evidence has been cumulated during the last years concerning the immaturity of the cells involved in the local and systemic aspects of allergic inflammation. Hematopoietic precursors (HPC) are mobilized from the bone matrix as multipotent cells or, more often, as progenitors that, after the initial white-lineage commitment reach through the peripheral blood (PB) their final destinations constituted by the target organs of allergy. Although several studies have investigated the CD34+ cells traffic and location at the level of the inflamed peripheral mucosae in allergic populations, limited information is available on their behaviour on the time-course of infectious diseases. The current study thus was designed to asses the peripheral traffic of CD34+ HPC during the infectious inflammation. To this end CD34+ HPCs have been enumerated, by flow-cytometric techniques, in PB of 24 adult healthy beings (Group A), 24 adult subjects with symptomatic extrinsic allergy (Group B) and in PB of 24 adult patients hospitalised for febrile infectious pathology (Group C). CD34+ cell values ranged 0.01-0.08% with a median of 0.03 in Group A. In Group B values ranged 0.17-0.75% with a median of 0.28 and in Group C values ranged 0.00-0.12% with a median of 0.07. Variance analysis test among the three groups was statistically significant (p<0.001) supporting the conclusion that CD34+ HPC mobilizing and increased peripheral traffic is an unique feature of the allergic inflammation.

Methodology and potential pitfalls in allergic diseases study designs: measurements for the assessment of the overall severity of atopic dermatitis--the four step severity score (FSSS), SCORAD-related, electronic system, for the simple and rapid evaluation of the skin and mucosal allergic inflammation.

Medical statistics may contribute to ameliorate research by improving the design of studies and identifying the optimal method for the analysis of results. Sometimes, nevertheless, it could be misemployed flawing the benefit potential. Allergic diseases pathogenesis is recognized to be systemic but global initiatives such as GINA and ARIA documents define allergic asthma and rhinitis as organ diseases; such an asymmetrical view raises a set of known and unknown confounding that could influence the quality of the process of evidence-based decision-making (topic symptomatic therapeutic interventions versus systemic pathogenetic interventions). This article shows the first scoring system for the assessment of atopic dermatitis lesions developed in the allergy-area. A four-step severity score (FSSS) was chosen in agreement with those developed for asthma and rhinitis in global initiatives, to avoid any further differences in evaluating the severity of allergic diseases. FSSS relates each step with the objective signs of the SCORAD and rates the disease course as intermittent or persistent. A devoted electronic program has been also framed to allow a quick and simple contemporary evaluation of the SCORAD Index (Section I) and of the FSSS (Section II); the program furthermore foresees a third section named ESAS (Extra Skin Allergic Signs) (Section III) in which it is possible to check whether organs other than the skin are involved by the allergic inflammation. The limitations potential generated by a misemployment of medical statistics for clinical trials designed to establish benefits rising from specific immunotherapy for allergic diseases have been also discussed extensively.

Higher frequency of early local side effects with aqueous versus depot immunotherapy for hymenoptera venom allergy.

Venom immunotherapy has proven a very effective method for the treatment of allergy to Hymenoptera venom. Aqueous instead of depot extracts are prevalently used for this immunotherapy. The advantage of using aqueous extracts has not been fully investigated. We made an open, non-controlled study on 45 subjects sensitized to either Apis mellifera or Vespula spp. Patients were assigned to either a depot (N=27) or an aqueous (N=18) immunotherapy regimen, and side effects were monitored during the induction and the 3-year maintenance phase. The effect of naturally occurring stings during the treatment and after its interruption was recorded as well. Side effects were less frequent with the depot extract both on a "per patient" (22.2% versus 50.0%) and on a "per dose" (2.9% versus 10,2%) basis (p=0.026 and p<0.000, respectively). Better tolerance was mainly due to the lower frequency of local side effects occurring at early times after vaccination. The efficacy of vaccination was comparable in the 2 cohorts, as expected. We conclude that depot immunotherapy to Hymenoptera venom should be preferred to aqueous immunotherapy for the lower occurrence of local side effects. This might influence a better compliance with this potentially life-saving treatment.

Mite antigens enhance ICAM-1 and induce VCAM-1 expression on human umbilical vein endothelium.

Although sublingual allergen-specific immunotherapy has been proved to be effective in the treatment of allergic diseases, controversy surrounds the means by which such a local therapy can induce systemic immunological changes. Adhesion molecules are critical in the regulation of leukocyte traffic. It has been hypothesized that allergenic extract, administered locally, may induce an up-regulation of the mucosal vessel vascular adhesion molecules (CAMs) resulting in local recruitment of circulating inflammatory cells. In the present study we investigated whether the mite antigens, Der p1 and Der p2, can modulate CAM expression of human endothelial cells (HEC). To do this, slices of whole human umbilical cord vein underwent short-term (8 hours) cultures in the presence or absence of mite antigen (baseline, unstimulated controls). Cryostatic sections of the specimens were then evaluated immunohistochemically for expression of intercellular adhesion molecule (ICAM-1) and vascular cell adhesion molecule (VCAM-1) molecules. The results revealed that while Der p1 is capable of significantly up-regulating ICAM-1 and VCAM-1 on HEC, Der p2 antigen moderately up-regulates ICAM-1 expression but is ineffective in modulating VCAM-1. Although preliminary, these results clearly support the hypothesis that at least some of the effects of sublingual immunotherapy may derive from inflammatory cell recruitment at the site of allergen release.

Mite antigens enhance ICAM-1 and induce VCAM-1 expression on Human Umbilical Vein Endothelium

Although sublingual allergen-specific immunotherapy has been proved to be effective in the treatment of allergic diseases, controversy surrounds the means by which such a local therapy can induce systemic immunological changes. Adhesion molecules are critical in the regulation of leukocyte traffic. It has been hypothesized that allergenic extract, administered locally, may induce an up-regulation of the mucosal vessel vascular adhesion molecules (CAMs) resulting in local recruitment of circulating inflammatory cells. In the present study we investigated whether the mite antigens, Der p1 and Der p2, can modulate CAM expression of human endothelial cells (HEC). To do this, slices of whole human umbilical cord vein underwent short-term (8 hours) cultures in the presence or absence of mite antigen (baseline, unstimulated controls). Cryostatic sections of the specimens were then evaluated immunohistochemically for expression of intercellular adhesion molecule (ICAM-1) and vascular cell adhesion molecule (VCAM-1) molecules. The results revealed that while Der p1 is capable of significantly up-regulating ICAM-1 and VCAM-1 on HEC, Der p2 antigen moderately up-regulates ICAM-1 expression but is ineffective in modulating VCAM-1. Although preliminary, these results clearly support the hypothesis that at least some of the effects of sublingual immunotherapy may derive from inflammatory cell recruitment at the site of allergen release (AU)

Aunque se ha demostrado que la inmunoterapia sublingual con alergeno específico (ITSA) es eficaz en el tratamiento de enfermedades alérgicas, se discute cómo un tratamiento local puede inducir modificaciones inmunitarias sistémicas. Las moléculas de adhesión son esenciales en la regulación leucocitaria, y se ha planteado la hipótesis de que el extracto alergénico, administrado localmente, puede inducir una estimulación de las moléculas de adhesión vascular (CAM) de los vasos de la mucosa, que se traduce en un reclutamiento local de células inflamatorias circulantes. En el presente trabajo hemos investigado si los antígenos de ácaros Der p1 y Der p2 pueden regular la expresión de células endoteliales humanas (CEH) por CAM. Para ello, se sometió a cortes de vena de cordón umbilical humano completo a cultivos a corto plazo (8 horas) en presencia o en ausencia del antígeno de ácaro (controles no estimulados basales). Después se evaluó inmunohistoquímicamente la expresión de moléculas ICAM-1 y VCAM-1 en cortes criostáticos de las muestras. Este análisis reveló que Der p1 es capaz de regular significativamente ICAM-1 y VCAM-1 sobre CEH, mientras que el antígeno Der p2 regula moderadamente la expresión de ICAM-1 pero es ineficaz para regular VCAM-1. Un que preliminares, estos resultados apoyan conclaridad la hipótesis de que al menos parte de los efectos de la inmunoterapia sublingual pueden deberse al reclutamiento de células inflamatorias en el lugar de liberación del alergeno (AU)

Lower intestinal bleeding due to aorto-enteric fistula.

The case is described of a man who complained of intermittent fever and fatigue. After three digestive endoscopies and computed tomography, a 99m technetium-HM-PAO-labelled white cell scan was usefully employed to establish diagnosis. Anaerobic aortic Graft infection and anaemia due to lower intermittent occult intestinal bleeding were found. The intestinal bleeding was caused by secondary aorto-jejunal fistula. This condition is rare, but should be suspected whenever a patient with aortic prosthesis presents with occult digestive bleeding and unexplained fever.