Major Allergen Content in Allergen Immunotherapy Products: The Limited Value of Numbers.

The prevalence of allergic disorders has increased drastically over the last 50 years to the extent that they can be considered epidemic. At present, allergen-specific immunotherapy (AIT) is the only therapy that targets the underlying cause of allergic disorders, and evidence of its superiority is based on data accumulated from clinical trials and observational studies demonstrating efficacy and safety. However, several aspects remain unresolved, such as harmonization and standardization of manufacturing and quantification procedures across manufacturers, homogeneous reporting of strength, and the establishment of international reference standards for many allergens. This article discusses issues related to the measurement of major allergen content in AIT extracts, raising the question of whether comparison of products from different manufacturers is an appropriate basis for selecting a specific AIT product. Allergen standardization in immunotherapy products is critical for ensuring quality and, thereby, safety and efficacy. However, lack of harmonization in manufacturing processes, allergen quantification (methodologies and references), national regulatory differences, clinical practice, and labeling shows that the comparison of AIT products based solely on major allergen amounts is not rational and, in fact, impossible. Moreover, when rating the information given for a specific product, it is necessary to take into account further inherent characteristics of products and their application in clinical practice, such as the state of extract modification, addition of adjuvant or adjuvant system, route of administration (sublingual/ subcutaneous), and cumulative dose as per posology (including the volume per administration). Finally, only convincing clinical data can serve as the basis for product-specific evaluation and cross-product comparability of individual products.

Management of patients with severe asthma: results from a survey among allergists and clinical immunologists of the Central Italy Inter-Regional Section of SIAAIC.

BACKGROUND: Asthma, and severe asthma in particular, is often managed within a specialized field with allergists and clinical immunologists playing a leading role. In this respect, the National Scientific Society SIAAIC (Società Italiana di Allergologia, Asma ed Immunologia Clinica), structured in Regional and Inter-Regional sections, interviewed a large number of specialists involved in the management of this respiratory disease. METHODS: A survey entitled "Management of patients with asthma and severe asthma" based on 17 questions was conducted through the SIAAIC newsletter in 2019 thanks to the collaboration between GlaxoSmithKline S.p.A. and the Inter-Regional Section of SIAAIC of Central Italy. RESULTS: Fifty-nine allergists and clinical immunologists participated to the survey, and 40 of them completed the entire questionnaire. Almost all of the specialists (88%) reported that asthma control was achieved in above 50% of their patients, even if only one third (32%) actually used validated clinical tools such as asthma control test (ACT). Poor adherence to inhaled therapy was recognized as the main cause of asthma control failure by 60% of respondents, and 2-5 min on average is dedicated to the patient inhaler technique training by two-thirds of the experts (65%). Maintenance and as-needed therapy (SMART/MART) is considered an appropriate approach in only a minority of the patients (25%) by one half of the respondents (52%). A high number of exacerbations despite the maximum inhalation therapy were recognized as highly suspicious of severe asthma. Patients eligible for biological therapies are 3-5% of the patients, and almost all the responders (95%) agreed that patients affected by severe asthma need to be managed in specialized centers with dedicated settings. Biological drugs are generally prescribed after 3-6 months from the initial access to the center, and once started, the follow-up is initially programmed monthly, and then every 3-6 months after the first year of treatment (96% of responders). After phenotyping and severity assessment, comorbidities (urticaria, chronic rhinosinusitis with or without nasal polyps, vasculitis, etc.) are the drivers of choice among the different biological drugs. In the management of severe asthma, general practitioners (GPs) should play a central role in selecting patients and referring them to specialized centers while Scientific Societies should train GPs to appropriately recognize difficult asthma and promote public disease awareness campaigns. CONCLUSIONS: This survey which collects the point of view of allergists and clinical immunologists from Central Italy highlights that asthma control is still not measured with validated instruments. There is a general consensus that severe asthma should be managed only in dedicated centers and to this aim it is essential to encourage patient selection from a primary care setting and develop disease awareness campaigns for patients.

Diagnostic approach to hypersensitivity reactions to iodinated contrast media: a single-center experience on 98 patients.

Summary: Adverse reactions to iodinated contrast media (ICM) are reported in 1%-3% of diagnostic procedures. They represent a relevant problem involving patients' safety as well as relevant costs for healthcare systems. Premedication with antihistamines and corticosteroids is still widely used, but evidence of its efficacy is lacking and there is a risk for under-estimation of possible severe adverse reactions to ICM in those who undergo premedication. Data from 98 patients with a previous reaction to ICM that consecutively referred to our unit between 2015 and 2018 were retrospectively analyzed. They underwent an allergologic workup comprehending skin tests and drug provocation tests (DPT) with ICM. The skin test showed a very high negative predictive value (NPV) compared to DPT in patients with a previous immediate adverse reaction, while the NPV in patients with a previous delayed adverse reaction was lower. After completion of the allergologic workup, 94 patients (95.9%) could tolerate a DPT with the culprit or alternative ICM. Subsequently, 90 patients were reached by phone to assess if they had been re-exposed to ICM for radiologic procedure. Thirty-nine patients had been re-exposed, without any premedication in 13 cases: 12 of them had tolerated the ICM, while one reacted again despite a negative DPT with the same ICM. Overall, the NPV of this protocol was elevated (92.3%) for patients undergoing DPT and subsequent exposure to the same ICM in a real-life setting. Collaboration between the prescribing physician, the radiologist and the allergist, and an accurate allergologic workup are essential to ensure maximum safety for the patient.

A new framework for the interpretation of IgE sensitization tests.

IgE sensitization tests, such as skin prick testing and serum-specific IgE, have been used to diagnose IgE-mediated clinical allergy for many years. Their prime drawback is that they detect sensitization which is only loosely related to clinical allergy. Many patients therefore require provocation tests to make a definitive diagnosis; these are often expensive and potentially associated with severe reactions. The likelihood of clinical allergy can be semi-quantified from an IgE sensitization test results. This relationship varies though according to the patients' age, ethnicity, nature of the putative allergic reaction and coexisting clinical diseases such as eczema. The likelihood of clinical allergy can be more precisely estimated from an IgE sensitization test result, by taking into account the patient's presenting features (pretest probability). The presence of each of these patient-specific factors may mean that a patient is more or less likely to have clinical allergy with a given test result (post-test probability). We present two approaches to include pretest probabilities in the interpretation of results. These approaches are currently limited by a lack of data to allow us to derive pretest probabilities for diverse setting, regions and allergens. Also, cofactors, such as exercise, may be necessary for exposure to an allergen to result in an allergic reaction in specific IgE-positive patients. The diagnosis of IgE-mediated allergy is now being aided by the introduction of allergen component testing which may identify clinically relevant sensitization. Other approaches are in development with basophil activation testing being closest to clinical application.

Kidney biopsy in pregnancy: evidence for counselling? A systematic narrative review.

BACKGROUND: Kidney diseases, which have a prevalence of 3% in women of childbearing age, are increasingly encountered in pregnancy. Glomerulonephritis may develop or flare up in pregnancy, and a differential diagnosis with pre-eclampsia may be impossible on clinical grounds. Use of kidney biopsy is controversial, but a systematic review has not been carried out to date. OBJECTIVES: To review the literature on kidney biopsy in pregnancy, with a focus on indications, risks and timing. SEARCH STRATEGY: Medline, Embase, CHINAL and the Cochrane Library were searched in September 2012, with 'pregnancy' and 'kidney biopsy' used as MESH and free terms, for the period 1980-2012. Results were filtered for 'human' if this option was available. SELECTION CRITERIA: Biopsies during pregnancy and within 2 months after delivery. Case reports (fewer than five cases) and kidney grafts were excluded. Paper selection was performed in duplicate. DATA COLLECTION AND ANALYSIS: Data were extracted in duplicate. The high heterogeneity in study design necessitated that the review be narrative, except for data on adverse events, which were analysed with regard to the timing of kidney biopsy. MAIN RESULTS: Of 949 references, 39 were selected, providing data on 243 biopsies in pregnancy and 1236 after delivery (timing was unclear in 106 women). The main aims of the studies were to define morphology in pre-eclampsia (23 studies), to carry out a risk-benefit analysis of kidney biopsy (11 studies), and to investigate pregnancy-related acute kidney injury (five studies). Four cases of major bleeding complications occurred at 23-26 weeks of gestation. Relevant complications were observed in 7% of women during pregnancy and 1% after delivery (P = 0.001). Kidney biopsy performed for the diagnosis of glomerulonephritis or pre-eclampsia led to therapeutic changes in 66% of cases. AUTHORS' CONCLUSIONS: The evidence on kidney biopsy in pregnancy is heterogeneous, but a significantly higher risk of complications (relative to postpartum biopsy) was found, with a possible peak at around 25 gestational weeks.

Italian study on buckwheat allergy: prevalence and clinical features of buckwheat-sensitized patients in Italy.

Buckwheat allergy is considered a rare food allergy outside of Asia. In Europe, buckwheat has been described mainly as a hidden allergen. Data on the prevalence of buckwheat hypersensitivity in non-Asian countries is very poor. The aim of this multicenter study was to evaluate the prevalence of buckwheat sensitization and its association with other sensitizations among patients referred to allergy clinics in different geographic areas of Italy. All patients referred to 18 Italian allergy clinics from February through April 2011 were included in the study and evaluated for sensitization to buckwheat and other allergens depending on their clinical history. A total of 1,954 patients were included in the study and 61.3 percent of them were atopic. Mean prevalence of buckwheat sensitization was 3.6 percent with significant difference between Northern (4.5 percent), Central (2.2 percent) and Southern (2.8 percent) regions. This is, to our knowledge, the largest epidemiological survey on buckwheat allergy reported outside of Asia. Buckwheat is an emerging allergen in Italy, being more frequently associated to sensitization in Northern regions.

NEMO syndrome (incontinentia pigmenti) and systemic lupus erythematosus: a new disease association.

Congenital diseases are increasingly being recognised in adults because of clinical mimicry, variable clinical picture or rarity of the disease; pregnancy is a valuable diagnostic occasion. The present case is the first report of an association report between NEMO syndrome (an acronym of the mutated, non-functioning gene, NF-kB essential modulator), a rare X-linked disease, characterised by developmental anomalies, immunodepression and skin lesions, and systemic lupus erythematosus (SLE). A 35-year-old patient affected by SLE sought clinical advice in the 8th week of gestation. The diagnosis of SLE dated back to the age of 24, when multisystemic manifestations (pleuropericarditis, weight loss, alopecia, skin involvement, joint pain, kidney involvement) were observed. She had been treated with steroids since 1999; immunosuppressive drugs had been added for short periods. Developmental anomalies were present, including oligodontia, retinal problems, anomalies of the corpus callosum and pes planovalgus. Family history included multiple miscarriages, dental malformations and oligodontia and skin blistering in the first months of life. On these bases, incontinentia pigmenti (IP; or NEMO syndrome) was diagnosed and confirmed by genetic testing. The NEMO gene is implicated in immune deficiencies as well as in autoimmune diseases. This report may suggest a role for NF-kB essential modulator in the pathogenesis of SLE, in the context of the complex immunologic deficiencies increasingly associated with autoimmune diseases.

Natural killer cell deficiencies in a consecutive series of children with herpetic encephalitis.

Natural killer (NK) cells play a fundamental role in innate and early phases of adaptive immunity against viral infections, both in humans and in animal models. To date, NK cell deficiencies in patients with severe herpetic infections have been reported in single cases, and their role as predisposing factor is still controversial. Five children affected by herpetic encephalitis were consecutively admitted to the Anna Meyer Children's Hospital in Florence (Italy) between 2003 and 2005. We therefore investigated the presence of NK cell deficiencies in a consecutive series of children with herpetic encephalitis. Five healthy children were included in the study as controls. Differential WBC counts, main Ig and IgE class serum analysis, cytofluorimetric analysis of circulating T, B and NK cells were performed on our study population. Sequencing of a selected region of CD16A gene transcript was carried out in two patients. All patients resulted to be affected by deficiencies related to NK cells in respect to controls. One patient was also affected by lymphopenia, while no other significant deficits of immunity were detected in the study population. To date, this is the first survey that demonstrates isolated NK cell deficiencies in a cohort of consecutive patients affected by severe herpes simplex infections. These findings suggest a role for NK cell deficiencies as a predisposing factor for increased susceptibility and severe course of disease in these patients.

The treatment of myotonia: evaluation of chronic oral taurine therapy.

A double-blind, single crossover study of chronic oral taurine administration versus placebo was conducted on nine patients with dystrophia myotonica. The severity of myotonia was assessed by clinical and electromyographic criteria and by testing the sensitivity of myotonic muscles to the intra-arterial infusion of potassium chloride. Confirming the antimyotonic effect of acute parenteral taurine, chronic treatment induced significant improvement of myotonia and a decreased sensitivity to the arterial potassium load as well as an enhancement of electrolyte movements across the membrane of the studied muscles. No significant side effects were noted.

Epileptic laughter: electroclinical and cinefilm report of a case.

A woman, aged 30, experienced attacks of pathological laughter which began during the first months of life; they meet the qualifying criteria of epileptic laughter. Several attacks were recorded by polygraphy and cinefilm. The attack begins with a feeling of unreality associated with a forced, involuntary smile progressing to full laughter. The patient tried to mask the laughter which was not accompanied by euphoria but was followed by loss of consciousness and automatisms. Only during the latter phase of the previously normal EEG did an ictal discharge appear over the right hemisphere. On the basis of the electroclinical pattern and of a review of the literature, the seizure is tentatively explained in terms of a progressive ictal involvement of temporodiencephalic structures.

The effects of the increase of arterial potassium upon the excitability of normal and dystrophic myotonic muscles in man.

Progressively increasing concentrations of potassium chloride were administered intra-arterially to patients affected with dystrophia myotonica (Steinert's disease) and to healthy volunteers before and after parenteral taurine treatment. Changes in the excitability of thenar eminence muscles were related to plasma potassium concentrations. A rise in the plasma potassium brought about a parallel increase of muscular excitability in normal individuals whilst in dystrophic myotonic patients it was associated with a two-phase phenomenon: the severity of myotonia first decreased and then, at higher plasma potassium levels, greatly worsened with the occurrence of spontaneous myotonic discharges. The administration of taurine, a membrane-stabilizing drug, considerably lowered the excitability of both normal and dystrophic myotonic muscles. The effects of potassium and taurine on muscular membrane conductance may explain the observed changes in muscular excitability.

The quantification of myotonia. A problem in the evaluation of new antimyotonic drugs.

The evaluation of an antimyotonic drug is often difficult since the severity of myotonia is itself hard to assess. The rise in arterial potassium level produced by the infusion of increasing concentrations of potassium chloride brought about reproducible changes in the excitability level of myotonic muscles proportional to the plasma potassium concentration. The excitability changes were assessed by three methods commonly used for evaluating antimyotonic drugs. The duration of the electromyographic relaxation time after maximal voluntary effort proved to be the only test which reliably assessed the variations of muscular excitability proportional to the increased plasma potassium. By contrast, the duration of percussion- or electrically-induced myotonic after-discharges was extremely variable and independent of plasma potassium.

Chemical reagents as potential impurities of pharmaceutical products: investigations on their genotoxic activity.

The genotoxic activity of chemical reagents and intermediates as potential impurities of final pharmaceutical products have been investigated by the AFI Mutagenesis Study Group. A number of compounds employed in the synthesis of beta-lactam (12), quinolone (6), antiviral (3), and other drugs (11) were analyzed. The information reported in this article was mainly obtained experimentally in our laboratories. In addition, attempts were made to obtain reference data; however, these were available for only a few compounds. The genetic end-point taken into account was principally gene mutation in bacteria. All chemical reagents used in the synthesis of quinolones and antivirals were negative in the Ames test. As far as reagents employed in beta-lactam synthesis were concerned, genotoxic activity was shown by the alkylating agents bromomethanol acetate and chloromethanol acetate, by carbon disulfide, and by the different dimethylanilines. The other chemicals generically considered as involved in "other syntheses" did not induce gene mutation, except for 2,5-dibromopentyl acetate, which was positive in the Ames test. For this compound, as for the halogenated methanol acetates, genotoxic activity was expected in view of its alerting chemical structure.

[Mutagenicity study of gadobenate dimeglumine formulation (E7155) (1)--Reverse mutation assays in S. typhimurium and E. coli tester strains].

The ability of gadobenate dimeglumine formulation (E7155) to cause gene mutations was assessed in five strains of Salmonella typhimurium (TA100, TA1535, TA98, TA1538, and TA1537) and a strain of Escherichia coli (CM891; WP2, uvrA-, pKM101) using the Ames test (agar plate assay). The results suggest that E7155 is non-mutagenic towards these bacterial tester strains.

[Mutagenicity study of gadobenate dimeglumine formulation (E7155) (3)--Micronucleus test in rat bone marrow cells].

The mutagenic potential of gadobenate dimeglumine formulation (E7155) was studied by the micronucleus test in rats. Single intraperitoneal injection of E7155 to Sprague Dawley rats at the dose of 5295.2 mg/kg (5 mmol/kg) did not induce any statistically significant increase in the frequency of micronucleate cells in the bone marrow sampled after 18, 42 and 66 hr from time of administration.

[Epidemiological surveillance of nursery school children in the Hérault for the evaluation of maternal and infant health and welfare services]. / Surveillance épidémiologique des enfants des écoles maternelles de l'Hérault lors des bilans de santé du service de protection maternelle et infantile.

A random sample of 4-5 years old children born in the same year was taken from the infant schools of the Herault (France) and examined by pediatricians during a systematic check carried out by the Mother and Child Protection Department of the Health Service. This gave and estimation of the prevalence of the most widespread health problems: language, motricity, eyesight, hearing, obesity and asthma. Differences according to social and familial factors were found for language and motricity problems, as well as for access to preventive care.

[Increase in the prevalence of obesity among children aged 4-5 years in a French district between 1988 and 1993]. / Accroissement de la prévalence de l'obésité chez les enfants de 4-5 ans dans un département français entre 1988 et 1993.

Two cross-sectional studies were performed on probabilistic samples in the Hérault "département"--respectively in 1987-1988 on children born in 1983 and in 1992-1993 on children born in 1988--to measure the evolution of the prevalence of obesity. A greater proportion of high weight for height (Z score of 1.0 and more, international reference population) has been observed in comparison with the first year. A major increase in the prevalence of obesity (setting a Z score of 2 as limit) has been recorded between the two periods (odds ratio = 2.51 (1.57 to 4.02)). It cannot be explained by structural changes of the population as regards factors known to be associated with obesity (urbanization, mother's occupation, family composition, social status, unemployment, distribution according to the country of origin). The possible influence of changes in the way of life is discussed in relation with the literature. This first representative sample study confirms--at least for the district studied--the findings in various populations, suggesting that the prevalence of obesity is increasing in France. The causes of this phenomenon remain to be defined.

[Bisynchronous discharge of symmetrical cortical epileptogenic foci and thaurine resistence (author's transl)]. / Resistenza alla taurina della bisincronia di scarica di foci epilettogeni corticali simmetrici

The possible preventive action of taurine administered through a cortical perfusion, has been studied in bilateral and simmetrical foci with bisynchronous discharge. The data obtained showed that: 1)taurine preventive action is less remarkable in bilateral and simmetrical foci; 2) when administered trough the appropriate route, taurine always has a preventive antiepileptic effect. Our data, compared to those of Marcus e al., confirme that bisynchronous discharge, resistant to taurine preventive and terapeutic action, is the obligatory expression of interactions of bilateral and simmetrical foci.