Proposal of 0.5 mg of protein/100 g of processed food as threshold for voluntary declaration of food allergen traces in processed food-A first step in an initiative to better inform patients and avoid fatal allergic reactions: A GA²LEN position paper.

BACKGROUND: Food anaphylaxis is commonly elicited by unintentional ingestion of foods containing the allergen above the tolerance threshold level of the individual. While labeling the 14 main allergens used as ingredients in food products is mandatory in the EU, there is no legal definition of declaring potential contaminants. Precautionary allergen labeling such as "may contain traces of" is often used. However, this is unsatisfactory for consumers as they get no information if the contamination is below their personal threshold. In discussions with the food industry and technologists, it was suggested to use a voluntary declaration indicating that all declared contaminants are below a threshold of 0.5 mg protein per 100 g of food. This concentration is known to be below the threshold of most patients, and it can be technically guaranteed in most food production. However, it was also important to assess that in case of accidental ingestion of contaminants below this threshold by highly allergic patients, no fatal anaphylactic reaction could occur. Therefore, we performed a systematic review to assess whether a fatal reaction to 5mg of protein or less has been reported, assuming that a maximum portion size of 1kg of a processed food exceeds any meal and thus gives a sufficient safety margin. METHODS: MEDLINE and EMBASE were searched until 24 January 2021 for provocation studies and case reports in which one of the 14 major food allergens was reported to elicit fatal or life-threatening anaphylactic reactions and assessed if these occurred below the ingestion of 5mg of protein. A Delphi process was performed to obtain an expert consensus on the results. RESULTS: In the 210 studies included, in our search, no reports of fatal anaphylactic reactions reported below 5 mg protein ingested were identified. However, in provocation studies and case reports, severe reactions below 5 mg were reported for the following allergens: eggs, fish, lupin, milk, nuts, peanuts, soy, and sesame seeds. CONCLUSION: Based on the literature studied for this review, it can be stated that cross-contamination of the 14 major food allergens below 0.5 mg/100 g is likely not to endanger most food allergic patients when a standard portion of food is consumed. We propose to use the statement "this product contains the named allergens in the list of ingredients, it may contain traces of other contaminations (to be named, e.g. nut) at concentrations less than 0.5 mg per 100 g of this product" for a voluntary declaration on processed food packages. This level of avoidance of cross-contaminations can be achieved technically for most processed foods, and the statement would be a clear and helpful message to the consumers. However, it is clearly acknowledged that a voluntary declaration is only a first step to a legally binding solution. For this, further research on threshold levels is encouraged.

Current treatment strategies for seasonal allergic rhinitis: where are we heading?

INTRODUCTION: Allergic rhinitis (AR) is very commonly caused by pollens. The symptoms of AR consist of sneezing, nasal congestion, rhinorrhea, nasal itching and airflow obstruction. The diagnosis has long been based on clinical history, skin prick tests and in vitro measurement of specific IgE, but the innovative approach of precision medicine has made diagnostic tools of much greater accuracy available. AREAS COVERED: This review covers the advances in the treatment of seasonal AR concerning the drugs to be used according to the grade of disease and the characteristics of the patients, and the role of allergen immunotherapy (AIT), which is the only treatment capable of acting, in addition to the symptoms, on the cause of AR and therefore to modify its natural history. EXPERT OPINION: Drug treatment of AR include a large number of agents, the choice of which depends on the severity of the disease. AIT has high evidence of efficacy demonstrated by meta-analyses, and further improvement is currently apparent, as for diagnosis, applying the means of precision medicine. However, when AIT is performed in current practice, without the strict rules of controlled trials, long-term low adherence is a major problem to be solved.

Diagnostic performance of nasal cytology.

PURPOSE: Nasal pathologies are characterized by a symptomatology that hardly allows to distinguish allergic rhinitis (AR), non-allergic rhinitis (NAR), and chronic rhinosinusitis (CRS). Nasal cytology (NC) has shown increasing importance in helping the clinician to differentiate the various phenotypes of rhinitis. NC allows us to evaluate nasal cellularity by distinguishing AR and various types of NAR. The objective of the study is to assess the diagnostic performance of the NC by evaluating its sensitivity, specificity, and predictive value. METHODS: We recruited 387 patients with persistent rhinitis symptoms, and nasal cytology was performed. The rhinocytogram was obtained by reading for fields and the cellular count was made using quantitative and semi-quantitative grading together. RESULTS: Two hundred and fifteen patients (55.5%; 38 had acute rhinitis, 24 acute sinusitis, 153 chronic rhinosinusitis) out of 387 referred nasal symptoms. Cytological specimen showed a mean of 94 ± 4% ciliated cells, 29 ± 0.2% mucinous cells, 16 ± 0.1% neutrophils, 11 ± 0.08% eosinophils, 4 ± 0.03 lymphocytes, 4 ± 0.03% mast cells, and 4 ± 0.01% other cells. NC was positive in 271 cases (70%). After revision of medical history, 153 patients (39%) were considered positive for NAR. Test sensibility was 100% (95% CI 97-100), specificity was 49.6% (95% CI 43-56%). Positive predictive value (PPV) was 56% (95% CI 50-62%), and negative predictive value (NPV) was 100% (95% CI 96-100%). The positive likelihood ratio was 1.98 (95% CI 1.75-2.25). Accuracy of the test was 69.5% (95% CI 64.6-74.0%). CONCLUSION: Our data showed ability to identify the true-positive patients with NAR but a low ability to identify the true-negative patients, with a global accuracy of 69.5%.

Personalized medicine for allergy treatment: Allergen immunotherapy still a unique and unmatched model.

The introduction of personalized medicine (PM) has been a milestone in the history of medical therapy, because it has revolutionized the previous approach of treating the disease with that of treating the patient. It is known today that diseases can occur in different genetic variants, making specific treatments of proven efficacy necessary for a given endotype. Allergic diseases are particularly suitable for PM, because they meet the therapeutic success requirements, including a known molecular mechanism of the disease, a diagnostic tool for such disease, and a treatment blocking the mechanism. The stakes of PM in allergic patients are molecular diagnostics, to detect specific IgE to single-allergen molecules and to distinguish the causative molecules from those merely cross-reactive, pursuit of patient's treatable traits addressing genetic, phenotypic, and psychosocial features, and omics, such as proteomics, epi-genomics, metabolomics, and breathomics, to forecast patient's responsiveness to therapies, to detect biomarker and mediators, and to verify the disease control. This new approach has already improved the precision of allergy diagnosis and is likely to significantly increase, through the higher performance achieved with the personalized treatment, the effectiveness of allergen immunotherapy by enhancing its already known and unique characteristics of treatment that acts on the causes.

Personalized medicine and allergen immunotherapy: the beginning of a new era?

The concept of personalized medicine as a diagnostic and therapeutic approach tailored to the medical needs of each patient is currently revolutionizing all fields of medicine and in particular allergology. Allergen immunotherapy (AIT) meets the three main needs for precision medicine: identification of molecular mechanism of disease, diagnostic tools for the mechanism and treatment blocking the mechanism itself. AIT adapts to the spectrum of specific IgE of each individual subject, changing the course and natural history of the disease, so is a clear model of precision and personalized medicine. This first step before the prescription of AIT is to define the sensitization profile of the patient; after that, the healthcare professional has numerous levers for adapting the treatment to the physio-pathological mechanisms involved. AIT allows to adapt treatments to the profile of the patients, but also to the its preferences, to ensure optimal treatment efficacy, resulting in an agile and personalized approach, with the aim to ensure adherence to the treatment, which is usually quite low. AIT also broadens the field of possibilities for healthcare professionals and patients, by allowing to choose the galenic formulation according to patient preferences and on the basis of their clinical history, adapting the product composition to the patient's sensitization profiles and the underlying biological mechanisms identified at the diagnostic stage, while guaranteeing quality of the prescribed product as the production of allergens and allergoids is today more regulated than in the past years. In the management of AIT, it is also possible to involve patients in decisions throughout their care pathway thanks to multiple services, offering personalized follow-up and support, to ensure the highest treatment efficacy levels, and recalling medication intake, medical appointments and prescription renewals.

Cardiac rehabilitation outcome after transcatheter aortic valve implantation.

Patients with severe aortic stenosis are increasingly treated with transcatheter aortic valve implantation (TAVI) as a safer option to surgical aortic valve replacement (sAVR).  Similar to many other heart diseases, after the specific therapeutic intervention patients are eligible for cardiac rehabilitation (CR) for the purpose of functional recovery. Thus far, CR after both sAVR and TAVI has been used to a limited extent, as shown by the availability of only two meta-analyses including 5 studies and 6 studies, respectively. Recent observational studies reported a significant improvement in functional indexes such as the Barthel scale and the 6-minute walk test (6MWT). We evaluated the outcome of CR in patients after TAVI treatment by measuring changes in the commonly used Barthel scale and 6MWT and adding the short physical performance battery (SPPB) scale as an index to assess lower extremity function. All indexes demonstrated a significant improvement, namely p<0.001 with the Barthel scale, p=0.043 for the 6MWT, and p=0.002 for SPPB. These results confirm the significant improvement of the Barthel scale and 6MWT reported in the previous meta-analysis and suggest the utility of SPPB as a further index of efficacy of CR in patients with severe aortic stenosis treated with TAVI.

Near-fatal anaphylaxis with Kounis syndrome caused by Argas reflexus bite: a case report.

BACKGROUND: The pigeon tick Argas reflexus is a temporary parasite of pigeons. It bites during night hours and lies briefly on its prey, as long as it takes the blood meal. When pigeons are not accessible, ticks look for other hosts, invading nearby flats and biting humans. CASE PRESENTATION: We present the case of a woman aged 46 years who experienced severe anaphylaxis during the night which required emergency medical treatment, tracheal intubation and hospitalization in intensive care unit. Kounis syndrome was documented by transient ST depression and elevation of troponin. The allergological work up ruled out hypersensitivity to drugs, latex and foods containing alpha-gal, which is a cause of anaphylaxis. Basal serum tryptase was in normal range (8.63 ng/ml). When questioned about the presence of ticks, the patient brought into view various specimens of ticks that were recognized by an entomologist as Argas reflexus. CONCLUSIONS: An in vitro diagnosis of allergy to Argas reflexus is currently not feasible because, though the major allergen Arg r 1 has been isolated, allergen extracts are not commercially available. Therefore, the diagnosis of anaphylaxis from Argas reflexus, when other causes of anaphylaxis are excluded, must rely only on history and clinical findings, as well as on the presence of pigeons and/or pigeon ticks in the immediate domestic environment.

SIRM-SIAAIC consensus, an Italian document on management of patients at risk of hypersensitivity reactions to contrast media.

Hypersensitivity reactions (HRs) to contrast media (CM) can be distinguished in immune-mediated (including allergic reactions) and non-immune-mediated reactions, even if clinical manifestations could be similar. Such manifestations range from mild skin eruptions to severe anaphylaxis, making it important for radiologists to know how to identify and manage them. A panel of experts from the Società Italiana di Radiologia Medica e Interventistica (SIRM) and the Società Italiana di Allergologia, Asma e Immunologia Clinica (SIAAIC) provided a consensus document on the management of patients who must undergo radiological investigations with CM. Consensus topics included: the risk stratification of patients, the identification of the culprit CM and of a safe alternative by an allergy workup, as well as the use of premedication and the correct procedure to safely perform an elective (i.e., scheduled) or urgent examination. The most important recommendations are: (1) in all patients, a thorough medical history must be taken by the prescribing physician and/or the radiologist to identify at-risk patients; (2) in patients with hypersensitivity reactions to CM, the radiologist must consider an alternative, non-contrast imaging study with a comparable diagnostic value, or prescribe a different investigation with another class of CM; (3) if such options are not feasible, the radiologist must address at-risk patients to a reference centre for an allergy evaluation; (4) if timely referral to an allergist is not viable, it is recommended to use a CM other than the responsible one, taking into account cross-reactivity patterns; in the case of patients with histories of severe reactions, the presence of an anesthesiologist is also recommended and a premedication is suggested.

Urticaria: recommendations from the Italian Society of Allergology, Asthma and Clinical Immunology and the Italian Society of Allergological, Occupational and Environmental Dermatology.

BACKGROUND: Urticaria is a disorder affecting skin and mucosal tissues characterized by the occurrence of wheals, angioedema or both, the latter defining the urticaria-angioedema syndrome. It is estimated that 12-22% of the general population has suffered at least one subtype of urticaria during life, but only a small percentage (estimated at 7.6-16%) has acute urticaria, because it is usually self-limited and resolves spontaneously without requiring medical attention. This makes likely that its incidence is underestimated. The epidemiological data currently available on chronic urticaria in many cases are deeply discordant and not univocal, but a recent Italian study, based on the consultation of a national registry, reports a prevalence of chronic spontaneous urticaria of 0.02% to 0.4% and an incidence of 0.1-1.5 cases/1000 inhabitants/year. METHODS: We reviewed the recent international guidelines about urticaria and we described a methodologic approach based on classification, pathophysiology, impact on quality of life, diagnosis and prognosis, differential diagnosis and management of all the types of urticaria. CONCLUSIONS: The aim of the present document from the Italian Society of Allergology, Asthma and Clinical Immunology (SIAAIC) and the Italian Society of Allergological, Occupational and Environmental Dermatology (SIDAPA) is to provide updated information to all physicians involved in diagnosis and management of urticaria and angioedema.

Recovery of smell sense loss by mepolizumab in a patient allergic to Dermatophagoides and affected by chronic rhinosinusitis with nasal polyps.

BACKGROUND: Chronic rhinosinusitis with nasal polyps (CRSwNP) frequently presents with dysfunction or loss of the sense of smell, resulting in a significant impairment in quality of life. The medical treatments currently available may improve the olfactory function in patients with CRSwNP, but such an outcome is generally only transitory. We report the case of a patient with CRSwNP who completely recovered from smell sense loss by treatment with mepolizumab. CASE PRESENTATION: The patient was a 62-year-old female who has severe asthma induced by allergy to Dermatophagoides and concomitant CRSwNP. Any treatment for the latter, including oral and injective corticosteroids, was unsuccessful in the loss of smell. Due to the satisfaction of admission criteria to mepolizumab treatment for severe asthma, treatment was initiated on March 2018, resulting in good clinical control of both asthma and CRSwNP, and particularly in complete recovery of the smell loss after 4 months of treatment and still persisting. CONCLUSION: In this case report, the treatment with mepolizumab in a patient allergic to Dermatophagoides and affected by CRSwNP was associated with an improvement of anosmia. That finding may be explained by a reduction of the nasal obstruction by nasal polyps.

Importance of hypersensitivity in adverse reactions to drugs in the elderly.

BACKGROUND: The use of drugs in the elderly is very extensive because of the frequent occurrence of chronic diseases. Adverse drug reactions (ADRs) commonly occur in geriatric patients receiving multiple therapeutic regimens. In the literature, little attention has been given to ADRs in the elderly, and particularly to allergic reactions. OBJECTIVE: The aim of the present study is to provide data on possible inappropriate prescriptions in the elderly in relation to allergic reactions and to identify a list of drugs which are likely inducers of allergic reactions. METHODS: We retrospectively evaluated ADRs in patients referring to Immunoallergy Unit of Hospital Policlinico in Bari on the basis of Beers criteria. Among adverse reactions, hypersensitivity reactions were extracted and a comparison between different age groups was assessed. RESULTS: Out of 823 patients with ADRs, in 30.6% hypersensitivity drug reactions (HDR) were diagnosed. Data about drug intake, comorbidities and clinical presentation were collected, aiming to identify possible risk factors. An evaluation of drugs most commonly involved was assessed. CONCLUSIONS: HDR are reported to represent 5-10% of all ADRs, while in our study population the prevalence was about 30%. This suggests the need to develop strategies to minimize the incidence of drug allergy in the elderly, as well to reduce the phenomenon of inappropriate prescriptions.

Low incidence of pneumonia in COPD patients treated with inhaled corticosteroids undergoing pulmonary rehabilitation.

BACKGROUND: Based on meta-analyses results, it is currently acknowledged that there is an increased risk of pneumonia in patients with chronic obstructive pulmonary disease (COPD) undergoing inhaled corticosteroids (ICS) treatment. However, this is not found to be true in those with asthma. No data on this risk are available for COPD patients involved in pulmonary rehabilitation program (PR). METHODS: For 1 year, we prospectively studied 2 cohorts of COPD patients-undergoing PR and not undergoing PR. The first group included 438 patients undergoing PR of which 353 were treated with ICS, and 85 were treated with bronchodilators only. The second group was comprised of 76 COPD patients who were treated with ICS, but not PR. The control group consisted of 49 ICS-treated patients with asthma. The diagnosis of pneumonia, when suspected, had to be confirmed with a chest x-ray. RESULTS: Overall, 6 cases of pneumonia were diagnosed in the first study group: 5 ICS-treated patients and 1 patient treated only with bronchodilators. This corresponded to a rate of 1.41 and 1.17%, respectively, compared to a rate of 6.6% in COPD patients not treated with PR, which was significantly higher (p = 0.029) than that in the first study group. No case of pneumonia was registered among patients with asthma. CONCLUSIONS: These findings suggest that a significantly lower incidence of pneumonia is found in COPD patients treated with ICS and PR than in patients treated with ICS but not with PR. This observation deserves to be investigated in large populations of PR-treated COPD patients, possibly in multi-centric cohort studies.

The Role of the Microbiome in Asthma: The Gut⁻Lung Axis.

Asthma is one of the most common chronic respiratory diseases worldwide. It affects all ages but frequently begins in childhood. Initiation and exacerbations may depend on individual susceptibility, viral infections, allergen exposure, tobacco smoke exposure, and outdoor air pollution. The aim of this review was to analyze the role of the gut⁻lung axis in asthma development, considering all asthma phenotypes, and to evaluate whether microbe-based therapies may be used for asthma prevention. Several studies have confirmed the role of microbiota in the regulation of immune function and the development of atopy and asthma. These clinical conditions have apparent roots in an insufficiency of early life exposure to the diverse environmental microbiota necessary to ensure colonization of the gastrointestinal and/or respiratory tracts. Commensal microbes are necessary for the induction of a balanced, tolerogenic immune system. The identification of commensal bacteria in both the gastroenteric and respiratory tracts could be an innovative and important issue. In conclusion, the function of microbiota in healthy immune response is generally acknowledged, and gut dysbacteriosis might result in chronic inflammatory respiratory disorders, particularly asthma. Further investigations are needed to improve our understanding of the role of the microbiome in inflammation and its influence on important risk factors for asthma, including tobacco smoke and host genetic features.

Allergen immunotherapy and respiratory infections in children: an encouraging experience.

BACKGROUND: Allergic inflammation may promote respiratory infections (RI). House dust mite (HDM) sensitization is common in childhood. Allergen immunotherapy may cure allergy as it restores a physiological immune and clinical tolerance toward the causal allergen and exerts anti-inflammatory activity. This study retrospectively investigated whether 3 year high-dose HDM-sublingual immunotherapy (SLIT) could affect respiratory infections in children with allergic rhinitis. METHODS: Globally, 33 HDM allergic children (18 males, mean age 9.3 years) were subdivided in 2 groups: 20 treated with symptomatic drugs alone (group 1) and 13 by high-dose SLIT, titrated in mcg of major allergens (group 2) for 3 years. RESULTS: SLIT-treated children had significantly (P=0.01) less RI episodes (3.6) than symptomatically-treated children (5.4). In addition, SLIT-treated children had less fever (P<0.01) and took fewer medications, such as antibiotics (P<0.05) and fever-reducers (P<0.01), than symptomatically-treated children. CONCLUSIONS: This preliminary study suggests that high-dose 3-year SLIT might lessen RI in allergic children.

Parietaria Allergy: An Intriguing Challenge for the Allergist.

Parietaria pollen is the most important cause of pollen allergies in the Mediterranean area, as Parietaria is widespread in this region. Many issues are associated with Parietaria allergy, including the duration of the pollen season (many doctors in fact believe that it lasts throughout the year), pollen load (which seems to be increasing over time), the impact of age (on IgE production and symptom severity), inflammatory changes (after pollen exposure), and the choice of allergen immunotherapy (AIT). In addition, molecular diagnostics allows for the defining of a correct diagnosis, differentiating between mere sensitization and true allergy. This review considers these topics and will hopefully help the allergist in clinical practice. Parietaria allergy is an intriguing challenge for the allergist in clinical practice, but it may be adequately managed by knowing the peculiarities of respective territories and the clinical characteristics of each patient.

Preventive actions of allergen immunotherapy: the facts and the effects in search of evidence.

Allergen immunotherapy (AIT) is the only treatment that works on the causes of allergy. Available AIT nowadays are subcutaneous immunotherapy (SCIT) and sublingual immunotherapy (SLIT) for allergic rhinitis and asthma, while for allergy to Hymenoptera venom only subcutaneous route is recommended. A bulk of trials and meta-analyses demonstrated that efficacy and safety of AIT in decreasing allergic clinical symptoms and use of rescue medications, while its preventive capacity is yet under investigation. The most important of these effects is the prevention of potentially fatal anaphylactic reactions to Hymenoptera stings by venom immunotherapy (VIT). A certain number of studies thus far available showed that AIT, in both forms, is able to prevent the progress of allergic rhinitis into asthma and the development of new sensitizations. These effects should be related to the mechanisms of action of AIT. In fact, it has been demonstrated that both SCIT and SLIT are able to modify the allergen presentation by dendritic cells, with result in modification of the phenotype of allergen-specific T cells, switching from the typical of allergic inflammation Th2-type response to a Th1-type one. Also allergen-specific T regulatory (Treg) cells play a pivotal role by producing suppressive cytokines, such as IL-10 and TGF-beta. However, the only plain evidence of a preventive effect concerns VIT, while the other outcomes need to be furtherly investigated.

A survey on the perception of allergy specialists about the reimbursed grass pollen tablets for seasonal allergic rhinitis in Italy.

BACKGROUND: Sublingual immunotherapy (SLIT) is a feasible option to classical subcutaneous immunotherapy to treat respiratory allergy and is increasingly prescribed in Europe. However, the lack of reimbursement may limit its prescription. In 2015, the 5-grass pollen tablets was authorized by the European Medicine Agency to treat grass-pollen induced rhinitis and was approved in Italy for full reimbursement. We evaluated the opinions of allergy specialists after the availability of the reimbursed 5-grass pollen tablets. METHODS: A multiple choice questionnaire composed by six questions was used to assess the specialists opinion. The questionnaire was uploaded on the free access online platform SurveyMonkey. The link to access the platform was sent to all members of the Società Italiana di Asma, Allergologia e Immunologia Clinica (SIAAIC). The access to the questionnaire was anonymous. At survey ending, the access was closed and data were downloaded directly from SurveyMonkey website. RESULTS: The questionnaire was filled by 70 allergists. The majority of allergists felt as most important the concept of SLIT as a drug, the content of allergen extract mirroring the natural exposure, the pre-coseasonal schedule as the most patient's oriented, the very good profile of tolerability and safety, the importance of the build-up phase, and the importance of checking the patient after starting immunotherapy. CONCLUSIONS: The opinions of the Italian allergy specialists about the reimbursed 5-grass-pollen tablets are very positive and make likely an appropriate prescription of SLIT for grass-pollen induced rhinitis in the next years.

Pharmacoeconomics of sublingual immunotherapy with the 5-grass pollen tablets for seasonal allergic rhinitis.

Allergic rhinitis has a very high burden regarding both direct and indirect costs. This makes essential in the management of AR to reduce the clinical severity of the disease and thus to lessen its costs. This particularly concerns allergen immunotherapy (AIT), that, based on its immunological action on the causes of allergy, extends its benefit also after discontinuation of the treatment. From the pharmacoeconomic point of view, any treatment must be evaluated according to its cost-effectiveness, that is, the ratio between the cost of the intervention and its effect. A favorable cost-benefit ratio for AIT was defined, starting from the first studies in the 1990s on subcutaneous immunotherapy (SCIT) in AR patients, that highlighted a clear advantage on costs over the treatment with symptomatic drugs. Such outcome was confirmed also for sublingual immunotherapy (SLIT), that has also the advantage on SCIT to be free of the cost of the injections. Here we review the available literature on pharmacoeconomic data for SLIT with the 5-grass pollen tablets.