IgE to cyclophilins in pollen-allergic children: Epidemiologic, clinical, and diagnostic relevance of a neglected panallergen.

BACKGROUND: Cyclophilins are ubiquitous panallergens whose epidemiologic, diagnostic, and clinical relevance is largely unknown and whose sensitization is rarely examined in routine allergy practice. OBJECTIVE: We investigated the epidemiologic, diagnostic, and clinical relevance of cyclophilins in seasonal allergic rhinitis and its comorbidities. METHODS: We examined a random sample of 253 (25%) of 1263 Italian children with seasonal allergic rhinitis from the Panallergens in Pediatrics (PAN-PED) cohort with characterized disease phenotypes. Nested studies of sensitization prevalence, correlation, and allergen extract inhibition were performed in patients sensitized to birch pollen extract but lacking IgE to Bet v 1/2/4 (74/1263) or with highest serum level of IgE to Bet v 1 (26/1263); and in patients with sensitization to various extracts (ragweed, mugwort, pellitory, Plantago, and plane tree), but not to their respective major allergenic molecule, profilins, and polcalcins. IgE to cyclophilin was detected with recombinant Bet v 7, and extract inhibition tests were performed with the same rBet v 7. RESULTS: IgE to rBet v 7 was detected in 43 (17%) of 253 patients. It was associated with asthma (P < .028) and oral allergy syndrome (P < .017) in univariate but not multivariate analysis adjusted for IgE to profilins (Phl p 12), PR-10s (Bet v 1), and lipid transfer proteins (Pru p 3). IgE to rBet v 7 was also highly prevalent (47/74, 63%) among patients with unexplained sensitization to birch pollen extract. In patients with unexplained sensitization to ragweed, mugwort, pellitory, Plantago and plane tree pollen, the levels of IgE to those extracts correlated with the levels of IgE to rBet v 7, and they were also significantly inhibited by rBet v 7 (inhibition range 45%-74%). CONCLUSIONS: IgE sensitization to cyclophilin is frequent in pollen-allergic patients living in temperate areas and can produce "false" positive outcomes in skin prick and IgE tests to pollen extracts. Molecular diagnostic guidelines should include this panallergen family.

IgE to cross-reactive carbohydrate determinants (CCD) in childhood: Prevalence, risk factors, putative origins.

BACKGROUND: IgE antibodies to cross-reactive carbohydrate determinants (CCD) are usually clinically irrelevant but they can be a cause of false positive outcomes of allergen-specific IgE tests in vitro. Their prevalence and levels have been so far cross-sectionally examined among adult allergic patients and much less is known about their origins and relevance in childhood. METHODS: We examined CCD with a cross-sectional approach in 1263 Italian pollen allergic children (Panallergen in Paediatrics, PAN-PED), as well as with a longitudinal approach in 612 German children (Multicenter Allergy Study, MAS), whose cutaneous and IgE sensitization profile to a broad panel of allergen extracts and molecules was already known. The presence and levels of IgE to CCD were examined in the sera of both cohorts using bromelain (MUXF3) as reagent and a novel chemiluminescence detection system, operating in a solid phase of fluorescently labelled and streptavidin-coated paramagnetic microparticles (NOVEOS, HYCOR, USA). RESULTS: IgE to CCD was found in 22% of the Italian pollen allergic children, mainly in association with an IgE response to grass pollen. Children with IgE to CCD had higher total IgE levels and were sensitized to more allergenic molecules of Phleum pratense than those with no IgE to CCD. Among participants of the German MAS birth cohort study, IgE to CCD emerged early in life (even at pre-school age), with IgE sensitization to group 1 and 4 allergen molecules of grasses, and almost invariably persisted over the full observation period. CONCLUSIONS: Our results contribute to dissect the immunological origins, onset, evolution and risk factors of CCD-sIgE response in childhood, and raise the hypothesis that group 1 and/or 4 allergen molecules of grass pollen are major inducers of these antibodies through an antigen-specific, T-B cell cognate interaction.

IgE-Mediated and Non-IgE-Mediated Fish Allergy in Pediatric Age: A Holistic Approach-A Consensus by Diagnostic Commission of the Italian Society of Pediatric Allergy and Immunology.

Fish is one of the "big nine" foods triggering allergic reactions. For this reason, fish allergens must be accurately specified on food labels. Fish allergy affects less than 1% of the world population, but a higher prevalence is observed in pediatric cohorts, up to 7%. Parvalbumin is the main fish allergen found in the muscles. In childhood, sensitization to fish allergens occurs most frequently through the ingestion of fish, rarely transcutaneously or by inhalation. Fish allergy symptoms usually appear within two hours of the allergen contact. The diagnosis begins with the collection of the history. If it is suggestive of fish allergy, prick tests or the measurement of serum-specific IgE should be performed to confirm the suspicion. The oral food challenge is the gold standard for the diagnosis. It is not recommended in case of a severe allergic reaction. It is important to make a differential diagnosis with anisakiasis or scombroid poisoning, which have overlapping clinical features but differ in pathogenesis. Traditionally, managing fish allergy involves avoiding the triggering species (sometimes all bony fish species) and requires an action plan for accidental exposures. The present review will analyze IgE- and non-IgE-mediated fish allergy in children from epidemiology, pathogenesis to clinical features. Moreover, clinical management will be addressed with a particular focus on potential nutritional deficiencies.

Phenotypes and Endotypes of Peach Allergy: What Is New?

Peach allergy is emerging as a common type of fresh-fruit allergy in Europe, especially in the Mediterranean area. The clinical manifestations of peach allergy tend to have a peculiar geographical distribution and can range from mild oral symptoms to anaphylaxis, depending on the allergic sensitization profile. The peach allergen Pru p 7, also known as peamaclein, has recently been identified as a marker of peach allergy severity and as being responsible for peculiar clinical features in areas with high exposure to cypress pollen. This review addresses the latest findings on molecular allergens for the diagnosis of peach allergy, the clinical phenotypes and endotypes of peach allergy in adults and children, and management strategies, including immunotherapy, for peach allergy.

The Role of Gut and Lung Microbiota in Susceptibility to Tuberculosis.

Tuberculosis is one of the most common infectious diseases and infectious causes of death worldwide. Over the last decades, significant research effort has been directed towards defining the understanding of the pathogenesis of tuberculosis to improve diagnosis and therapeutic options. Emerging scientific evidence indicates a possible role of the human microbiota in the pathophysiology of tuberculosis, response to therapy, clinical outcomes, and post-treatment outcomes. Although human studies on the role of the microbiota in tuberculosis are limited, published data in recent years, both from experimental and clinical studies, suggest that a better understanding of the gut-lung microbiome axis and microbiome-immune crosstalk could shed light on the specific pathogenetic mechanisms of Mycobacterium tuberculosis infection and identify new therapeutic targets. In this review, we address the current knowledge of the host immune responses against Mycobacterium tuberculosis infection, the emerging evidence on how gut and lung microbiota can modulate susceptibility to tuberculosis, the available studies on the possible use of probiotic-antibiotic combination therapy for the treatment of tuberculosis, and the knowledge gaps and future research priorities in this field.

Role of in vitro testing in food allergy.

Oral food challenges remain the gold standard for the diagnosis of food allergy. Nevertheless, the allergy workup is based on the presence of a clinical history, which is evocative of an immune-allergic reaction, and the first assessment is usually the performance of skin prick tests. Based on these results, allergists are used to evaluate the presence of serum-specific IgE, which are today the most commonly prescribed in vitro test for the evaluation of a possible food allergy. Other in vitro tests include the basophil activation test, that is becoming more and more employed by clinicians and not only by researchers, and the evaluation of serum IgG4, which is still an issue of debate in the allergy community. The present paper reviews the use of these in vitro tests for the diagnosis of food allergy.

Consensus statement of the Italian society of pediatric allergy and immunology for the pragmatic management of children and adolescents with allergic or immunological diseases during the COVID-19 pandemic.

The COVID-19 pandemic has surprised the entire population. The world has had to face an unprecedented pandemic. Only, Spanish flu had similar disastrous consequences. As a result, drastic measures (lockdown) have been adopted worldwide. Healthcare service has been overwhelmed by the extraordinary influx of patients, often requiring high intensity of care. Mortality has been associated with severe comorbidities, including chronic diseases. Patients with frailty were, therefore, the victim of the SARS-COV-2 infection. Allergy and asthma are the most prevalent chronic disorders in children and adolescents, so they need careful attention and, if necessary, an adaptation of their regular treatment plans. Fortunately, at present, young people are less suffering from COVID-19, both as incidence and severity. However, any age, including infancy, could be affected by the pandemic.Based on this background, the Italian Society of Pediatric Allergy and Immunology has felt it necessary to provide a Consensus Statement. This expert panel consensus document offers a rationale to help guide decision-making in the management of children and adolescents with allergic or immunologic diseases.

Management of chronic urticaria in children: a clinical guideline.

The aim of this guidance is to provide recommendations to clinicians and other interested parties on chronic urticaria in children. The Italian Society for Pediatrics (SIP), the Italian Society for Allergy and Immunology (SIAIP), the Italian Society for Pediatric dermatology (SIDerP) convened a multidisciplinary panel that prepared clinical guidelines for diagnosis and management of chronic urticaria in childhood. Key questions on epidemiology, natural history, diagnosis, and management were developed. The literature was systematically searched and evaluated, recommendations were rated and algorithms for diagnosis and treatment were developed. The recommendations focus on identification of diseases and comorbidities, strategies to recognize triggering factors, improvement of treatment by individualized care.

Three contaminated sites in southern Italy. The Neonatal Environment and Health Outcomes cohort: protocol for a longitudinal birth cohort study.

INTRODUCTION: Exposure to environmental contaminants during pregnancy is one of the determinants of child's future health outcomes. The effect of environmental pollution on pregnant women living in heavily polluted areas is of special interest and, in this context, the Neonatal Environment and Health Outcomes (NEHO) cohort will focus on the investigation of (1) toxicants transferred from the environment to the mother and from the mother to the developing fetus and (2) the influence of toxicants on pregnancy outcomes, fetal development and health status during infancy. Because the human placenta is positioned at the interface between the maternal/external environment and the embryo, it can be considered a highly informative matrix regarding many key pregnancy events that can shape infant's future health. METHODS AND ANALYSIS: The NEHO cohort will enrol an estimated total of 800 pregnant women in three selected National Priority Contaminated Sites in southern Italy. Epidemiological data, concerning maternal health status, lifestyle and pregnancy, are obtained through questionnaires provided to the mother starting from the last 2 months of pregnancy. At delivery, maternal blood, umbilical cord blood and placenta tissue are collected to assess contaminant levels and to clarify how toxicants interact with the placental domain. Furthermore, placental transcriptome is studied in order to explore the interferences of toxicants on the role of the placenta in maternal/fetal interplay. Regular follow-up is planned at 6, 12 and 24 months. ETHICS AND DISSEMINATION: The study has been approved by all the Ethics Committees of the three National Priority Contaminated Sites involved: the Ethics Committee of the University Hospitals of Messina (18 September 2017, n. 9/2017); the Ethics Committee 'Catania 2' (11 July 2017, n. 38/2017/CECT2); the Ethics Committee of the Region of Calabria (20 July 2017, n. 173). Findings will be disseminated in the scientific community and on a regional basis for appropriate policy actions.

SIAIP position paper: provocation challenge to antibiotics and non-steroidal anti-inflammatory drugs in children.

Drug hypersensitivity reactions (DHRs) in childhood are mainly caused by betalactam or non-betalactam antibiotics, and non-steroidal anti-inflammatory drugs (NSAIDs). Laboratory tests for identifying children who are allergic to drugs have low diagnostic accuracy and predictive value. The gold standard to diagnose DHR is represented by the drug provocation test (DPT), that aims of ascertaining the causative role of an allergen and evaluating the tolerance to the suspected drug. Different protocols through the administration of divided increasing doses have been postulated according to the type of drug and the onset of the reaction (immediate or non immediate reactions). DPT protocols differ in doses and time interval between doses. In this position paper, the Italian Pediatric Society for Allergy and Immunology provides a practical guide for provocation test to antibiotics and NSAIDs in children and adolescents.

Prevalence of Arnold Nerve Reflex in Adults and Children With Chronic Cough.

BACKGROUND: Cough originates from stimulation of structures innervated by the vagus nerve, including the airways and distal esophagus. Arnold nerve reflex describes the induction of cough by stimulation of the external auditory canal, which is innervated by the auricular branch of the vagus. Historically, the prevalence of this reflex has been reported in the range of 2% to 3% on the basis of studies of outpatients in otolaryngology practices, but has not been investigated in healthy volunteers or in patients with chronic cough. METHODS: Two hundred adults and 100 children with chronic cough, as well as 100 adult and 100 pediatric volunteers, underwent evaluation consisting of stimulation of the external auditory canal of each ear with a cotton-tipped applicator. Cough occurring within 10 seconds of stimulation was considered induced by the intervention. RESULTS: Arnold nerve reflex was present in 25.5% of adults and 3% of children with chronic cough. The prevalence of the reflex was 2% among healthy adults and children. In adults with chronic cough, Arnold nerve reflex was observed more commonly in women (31.6%) than men (12.5%) and was unilateral in the majority of patients (90.2%). CONCLUSIONS: The greater than 12 fold prevalence of Arnold nerve reflex in adults with chronic cough compared with healthy volunteers supports the concept of cough hypersensitivity syndrome (CHS), in which vagal hypersensitivity is proposed to underlie chronic refractory cough. The absence of increased prevalence among children with chronic cough suggests that cough hypersensitivity syndrome is an acquired condition, perhaps triggered by viral respiratory infection or other environmental factor.

Inter-society consensus document on treatment and prevention of bronchiolitis in newborns and infants.

Acute bronchiolitis is the leading cause of lower respiratory tract infection and hospitalization in children less than 1 year of age worldwide. It is usually a mild disease, but some children may develop severe symptoms, requiring hospital admission and ventilatory support in the ICU. Infants with pre-existing risk factors (prematurity, bronchopulmonary dysplasia, congenital heart diseases and immunodeficiency) may be predisposed to a severe form of the disease. Clinical diagnosis of bronchiolitis is manly based on medical history and physical examination (rhinorrhea, cough, crackles, wheezing and signs of respiratory distress). Etiological diagnosis, with antigen or genome detection to identify viruses involved, may have a role in reducing hospital transmission of the infection. Criteria for hospitalization include low oxygen saturation (<90-92%), moderate-to-severe respiratory distress, dehydration and presence of apnea. Children with pre-existing risk factors should be carefully assessed.To date, there is no specific treatment for viral bronchiolitis, and the mainstay of therapy is supportive care. This consists of nasal suctioning and nebulized 3% hypertonic saline, assisted feeding and hydration, humidified O2 delivery. The possible role of any pharmacological approach is still debated, and till now there is no evidence to support the use of bronchodilators, corticosteroids, chest physiotherapy, antibiotics or antivirals. Nebulized adrenaline may be sometimes useful in the emergency room. Nebulized adrenaline can be useful in the hospital setting for treatment as needed. Lacking a specific etiological treatment, prophylaxis and prevention, especially in children at high risk of severe infection, have a fundamental role. Environmental preventive measures minimize viral transmission in hospital, in the outpatient setting and at home. Pharmacological prophylaxis with palivizumab for RSV bronchiolitis is indicated in specific categories of children at risk during the epidemic period. Viral bronchiolitis, especially in the case of severe form, may correlate with an increased incidence of recurrent wheezing in pre-schooled children and with asthma at school age.The aim of this document is to provide a multidisciplinary update on the current recommendations for the management and prevention of bronchiolitis, in order to share useful indications, identify gaps in knowledge and drive future research.

Pollen-induced allergic rhinitis in 1360 Italian children: comorbidities and determinants of severity.

BACKGROUND: Pollen-induced allergic rhinoconjunctivitis (AR) is highly prevalent and rapidly evolving during childhood. General practitioners may not be fully aware of the nature and severity of symptoms experienced by patients and might underestimate the prevalence of moderate or severe disease. Thus, the relevance of early diagnosis and intervention may be overlooked. OBJECTIVES: To investigate the severity of pollen-induced AR and its determinants in Italian children referred to allergy specialists and who had never received specific immunotherapy (SIT). METHODS: Children (age 4-18 yr) affected by pollen-induced AR who had never undergone SIT were recruited between May 2009 and June 2011 in 16 pediatric outpatient clinics in 14 Italian cities. Recruited children's parents answered standardized questionnaires on atopic diseases (International Study of Allergy and Asthma in Childhood, Allergic Rhinitis and its Impact on Asthma, Global Initiative for Asthma). The children underwent skin-prick test (SPT) with several airborne allergens and six food allergens. Information on socio-demographic factors, parental history of allergic diseases, education, perinatal events, breastfeeding, nutrition and environmental exposure in early life was collected through an informatics platform shared by the whole network of clinical centers (AllergyCARD™). RESULTS: Among the 1360 recruited patients (68% males, age 10.5 ± 3.4 yr), 695 (51%) had moderate-to-severe AR, 533 (39%) asthma, and 325 (23.9%) oral allergy syndrome (OAS). Reported onset of pollen-induced AR was on average at 5.3 ± 2.8 yr, and its mean duration from onset was 5.2 ± 3.3 yr. Only 6.2% of the patients were pollen-monosensitized, and 84.9% were sensitized to ≥3 pollens. A longer AR duration was significantly associated with moderate-to-severe AR symptoms (p 0.004), asthma (p 0.030), and OAS comorbidities (p < 0.001). CONCLUSIONS: This nationwide study may raise awareness of the severity of pollen-induced AR among Italian children who have never received pollen SIT. The strong association between pollen-induced AR duration and several markers of disease severity needs replication in longitudinal studies, while suggesting that countrywide initiatives for earlier diagnosis and intervention should be planned.

Chronic cough in preschool children.

Cough may be the first overt sign of disease of the airways or lungs when it represents more than a defense mechanism, and may by its persistence become a helpful pointer of potential disease for both patient and physician. On the other hand, impairment or absence of the coughing mechanism can be harmful and even fatal; this is why cough suppression is rarely indicated in childhood. Pediatricians are concerned more with the etiology of the cough and making the right diagnosis. Whereas chronic cough in adults has been universally defined as a cough that lasts more than 8 weeks, in childhood, different timing has been reported. Many reasons support defining a cough that lasts more than 4 weeks in preschool children as chronic, however; and this is particularly true when the cough is wet. During childhood, the respiratory tract and nervous system undergo a series of anatomical and physiological maturation processes that influence the cough reflex. In addition, immunological response undergoes developmental and memorial processes that make infection and congenital abnormalities the overwhelming causes of cough in preschool children. Cough in children should be treated on the basis of etiology, and there is no evidence in support of the use of medication for symptomatic cough relief or adopting empirical approaches. Most cases of chronic cough in preschool age are caused by protracted bacterial bronchitis, tracheobronchomalacia, foreign body aspiration, post-infectious cough or some combination of these. Other causes of chronic cough, such as bronchiectasis, asthma, gastroesophageal reflux, and upper respiratory syndrome appear to be less frequent in this age group. The prevalence of each depends on the population in consideration, the epidemiology of infectious diseases, socioeconomic aspects, and the local health system.

Pediatric allergy and immunology in Italy.

In Italy, according to the International Study on Asthma and Allergies in Childhood study, the prevalence of current asthma, allergic rhinoconjunctivitis, and atopic eczema in 2006 was 7.9%, 6.5%, and 10.1% among children aged 6-7 and 8.4%, 15.5%, and 7.75% among children aged 13-14 yr. University education in this field is provided by the Postgraduate Schools of Pediatrics and those of Allergology and Clinical Immunology, as well as several annual Master courses. The Italian Society of Pediatric Allergology and Immunology (SIAIP) was founded in 1996 and counts about 1000 members. SIAIP promotes evidence-based management of allergic children and disseminates information to patients and their families through a quite innovative website and the National Journal 'Rivista Italiana di Allergologia Pediatrica'. In the last decade, four major regional, inter-regional, and national web-based networks have been created to link pediatric allergy centers and to share their clinical protocols and epidemiologic data. In addition, National Registers of Primary Immune-deficiencies and on Pediatric HIV link all clinical excellence centers. Research projects in the field of pediatric allergy and immunology are founded by the Italian Ministry of Education, University and Research (MIUR) and by the National Research Council (CNR), but the overall investments in this research area are quite low. Only a handful Italian excellence centers participate in European Projects on Pediatric Allergy and Immunology within the 7th Framework Program. The European Academy of Allergy and Clinical Immunology currently hosts two Italians in its Executive Committee (EC) and one in the EC of the Pediatric Section; moreover, major European Academy of Allergy and Clinical Immunology meetings and courses in the area of pediatrics (e.g., PAAM, Venice, 2009) have been held in Italy in the last 3 yr. Italian hallmarks in the management of allergic diseases in childhood are a quite alive and spread interest in Molecular Allergology and a remarkable predominance of sublingual (SLIT) compared to the subcutaneous (SCIT) immunotherapy.

Clinical effects of a Long-term Educational Program for children with asthma - Aironet. A 1-yr randomized controlled trial.

Educational self-management programs for children with asthma have now become a routine feature in the management of the disease, as international guidelines underline. We designed this trial to find out whether Aironet, an educational program developed for children with asthma, influenced asthma severity and improved parents' knowledge of the disease. In a multicenter, prospective, randomized controlled trial we enrolled 123 children, 72 boys, mean age 8.78 yr (+/-2.33 s.d.), with intermittent or mild persistent asthma. Participants were randomly assigned to an education group, who received Aironet at baseline and 2 months later (60 children), or to a control group who did not (63 children). Follow-up lasted 12 months and included out-patient clinic visits and spirometry at 2, 4 and 12 months. At baseline and at 12 months follow-up, parents were questioned about their knowledge of asthma, and their children's asthmatic attacks, use of systemic corticosteroids, family physician or hospital emergency room visits, hospitalizations and asthma-related school absences. Questionnaire replies at 12-month follow-up reported significantly fewer asthma attacks in patients who received the program than in those who did not (1.65 +/- 1.21 vs. 2.34 +/- 1.73; p < 0.05). For the subgroup of children who had > or =3 asthma attacks at baseline, parents' knowledge improved significantly more in the educational group than in the control group. The out-patient educational program Aironet reduces the number of asthma attacks in children with intermittent or mild persistent asthma and improves knowledge of the disease.