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.

Cutaneous manifestation during COVID-19 pandemic.

BACKGROUND: The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic, causing COVID-19, is rapidly spread across the world, by posing novel challenges for all physicians. Cutaneous manifestations of COVID-19 may be present in 20% of patients, but they are still now poorly characterized. METHODS: We search literature to describe all the various cutaneous manifestation observed during COVID-19 pandemic. RESULTS: Different cutaneous clinical patterns were described, showing a wide polymorphism. CONCLUSION: We provided an overview of all the various cutaneous manifestations of COVID-19 described in the literature today, to improve our knowledge and lead a more prompt and accurate diagnosis, especially in asymptomatic or paucisymptomatic cases.

Prevalence and Clinical Relevance of IgE Sensitization to Profilin in Childhood: A Multicenter Study.

BACKGROUND: Little is known about the prevalence and clinical relevance of hypersensitivity to the plant panallergen profilin in children. OBJECTIVES: The present study aimed to investigate prevalence, risk factors and clinical relevance of profilin sensitization in a large cohort of Italian children of different ages living in different geographic areas. METHODS: Children with pollen allergy enrolled by 16 pediatric outpatient clinics sited in three main geographic areas of Italy were studied. SPT were carried out with commercial pollen extracts and a commercial purified date palm pollen profilin. IgE specific for allergenic pollen molecules, Phl p 12 (grass profilin) and Pru p 3 (peach lipid transfer protein) were tested by ImmunoCAP FEIA. RESULTS: IgE to Phl p 12 (≥0.35 kU/l) was observed in 296 of the 1,271 participants (23%), including 17 of the 108 (16%) preschool children. Profilin SPT was positive (≥3 mm) in 320/1,271 (25%) participants. The two diagnostic methods were concordant in 1,151 (91%, p < 0.0001) cases. Phl p 12 IgE prevalence declined from northern to southern Italy and was directly associated with IgE to Phl p 1 and/or Phl p 5 and Ole e 1. Among children with IgE to Phl p 12, OAS was provoked by kiwi, melon, watermelon, banana, apricot and cucumber. CONCLUSIONS: Profilin sensitization is very frequent among pollen-allergic children, occurs at a very young age and contributes to the development of childhood OAS with a typical pattern of offending foods. Pediatricians should always consider IgE sensitization to profilin while examining pollen-allergic children, even if they are at preschool age.

The effect of component-resolved diagnosis on specific immunotherapy prescription in children with hay fever.

BACKGROUND: Sensitization to profilins and other cross-reacting molecules might hinder proper specific immunotherapy (SIT) prescription in polysensitized patients with pollen-related allergic rhinitis (AR). In these patients, component-resolved diagnosis (CRD) might modify SIT prescription by improving the identification of the disease-eliciting pollen sources. OBJECTIVES: We sought to measure the effect of CRD on SIT prescription in children with pollen-related AR. METHODS: Children (n = 651) with moderate-to-severe pollen-related AR were recruited between May 2009 and June 2011 in 16 Italian outpatient clinics. Skin prick test (SPT) reactivity to grass, cypress, olive, mugwort, pellitory, and/or Betulaceae pollen was considered clinically relevant if symptoms occurred during the corresponding peak pollen season. IgE sensitization to Phl p 1, Phl p 5, Bet v 1, Cup a 1, Art v 1, Ole e 1, Par j 2, and Phl p 12 (profilin) was measured by using ImmunoCAP. SIT prescription was modeled on SPT responses first and then remodeled considering also CRD according to GA(2)LEN-European Academy of Allergology and Clinical Immunology guidelines and the opinions of 14 pediatric allergists. RESULTS: No IgE to the respective major allergens was detected in significant proportions of patients with supposed clinically relevant sensitization to mugwort (45/65 [69%]), Betulaceae (146/252 [60%]), pellitory (78/257 [30%]), olive (111/390 [28%]), cypress (28/184 [15%]), and grass (56/568 [10%]). IgE to profilins, polcalcins, or both could justify 173 (37%) of 464 of these SPT reactions. After CRD, the SPT-based decision on SIT prescription or composition was changed in 277 (42%) of 651 or 315 (48%) of 651 children according to the European or American approach, respectively, and in 305 (47%) of 651 children according to the opinion of the 14 local pediatric allergists. CONCLUSIONS: In children with pollen-related AR, applying CRD leads to changes in a large proportion of SIT prescriptions as opposed to relying on clinical history and SPT alone. The hypothesis that CRD-guided prescription improves SIT efficacy deserves to be tested.

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.

New Directions in Understanding Atopic March Starting from Atopic Dermatitis.

Recent evidence showed that the postulated linear progression of the atopic march, from atopic dermatitis to food and respiratory allergies, does not capture the heterogeneity of allergic phenotypes, which are influenced by complex interactions between environmental, genetic, and psychosocial factors. Indeed, multiple atopic trajectories are possible in addition to the classic atopic march. Nevertheless, atopic dermatitis is often the first manifestation of an atopic march. Improved understanding of atopic dermatitis pathogenesis is warranted as this could represent a turning point in the prevention of atopic march. In this review, we outline the recent findings on the pathogenetic mechanisms leading to atopic dermatitis that could be targeted by intervention strategies for the prevention of atopic march.

Narrative review on the management of moderate-severe atopic dermatitis in pediatric age of the Italian Society of Pediatric Allergology and Immunology (SIAIP), of the Italian Society of Pediatric Dermatology (SIDerP) and of the Italian Society of Pediatrics (SIP).

Currently, there are a few detailed guidelines on the overall management of children and adolescents with moderate-severe atopic dermatitis. AD ​​is a complex disease presenting with different clinical phenotypes, which require an individualized and multidisciplinary approach. Therefore, appropriate interaction between primary care pediatricians, pediatric allergists, and pediatric dermatologists is crucial to finding the best management strategy. In this manuscript, members of the Italian Society of Pediatric Allergology and Immunology (SIAIP), the Italian Society of Pediatric Dermatology (SIDerP), and the Italian Society of Pediatrics (SIP) with expertise in the management of moderate-severe atopic dermatitis have reviewed the latest scientific evidence in the field. This narrative review aims to define a pathway to appropriately managing children and adolescents with moderate-severe atopic dermatitis.

Atopic dermatitis and atopic march: which link?

There is a long standing debate on the atopic march in childhood. The natural progression of allergic manifestations may be considered as comorbidities, which occur more frequently in a specific evolutive age. On the other hand, the natural history of allergies in children may follow trajectories that may be heterogeneous. The effects of atopic march in clinical practice have also been reported.

Food allergy and probiotics in childhood.

Food allergy is a frequent problem in childhood and its prevalence is increasing. In most cases food allergy is an IgE-mediated hypersensitivity response that cause skin reactions as urticaria. Subacute or chronic disorders have generally a not IgE mediated mechanism. Milk is the most common food allergen in USA and UK followed by egg, peanut and walnuts. Sensitization to milk or egg in infancy is associated with an increased risk to develop house dust mite sensitization and asthma later in childhood. Commensal gut flora play a role in induction of oral tolerance and the importance of the intestinal microbiota in the development of food allergy is essential in early ages, when the mucosal barrier and immune system are still immature. Probiotics interact with the mucosal immune system by the same pathways as commensal bacteria. Recent study show that probiotic bacteria induced in vivo increased plasma levels IL-10 and total IgA in children with allergic predisposition. Many clinical studies reporting significant benefits by probiotics supplementation in food allergy prevention and management but not everyone agree on their effectiveness. These differences are probably related to differences in selected populations and in probiotic strains used.

Formoterol, montelukast, and budesonide in asthmatic children: effect on lung function and exhaled nitric oxide.

BACKGROUND: It has been proposed that asthma control may be achieved in part by minimizing airway inflammation. The simultaneous effects of inhaled steroids associated with long-acting beta-agonists and leukotriene antagonists on pulmonary function and airway inflammation are still largely unexplored in children with moderate persistent asthma. OBJECTIVES: The aim of this study was to investigate the effects of add-on therapy with long-acting beta-agonists and leukotriene antagonists on FEV1 and exhaled nitric oxide levels (FENO) in children. METHODS: Forty-eight steroid-naïve atopic asthmatic children, 7-11 years of age, were randomly treated in four groups for two consecutive one-month periods, as follows: (1) first month: budesonide 200 microg twice daily; second month: budesonide 400 microg twice daily; (2) first month: budesonide 200 microg twice daily+formoterol 9 microg twice daily; second month: budesonide 200 microg twice daily+montelukast 5mg once daily; (3) first month: budesonide 200 microg twice daily+montelukast 5mg once daily; second month budesonide 200 microg+formoterol 9 microg twice daily; (4) first and second month: budesonide 400 microg twice daily. RESULTS: All treatments resulted in a significant increase in lung function and a decrease in FENO compared with values at baseline. Budesonide+montelukast in combination was the most effective treatment for reducing FENO levels. CONCLUSION: This study demonstrates that add-on therapy with montelukast plus low-dose budesonide is more effective than the addition of long-acting beta-agonists or doubling the dose of budesonide for controlling FENO in asthmatic children.

Bifidobacterium mixture (B longum BB536, B infantis M-63, B breve M-16V) treatment in children with seasonal allergic rhinitis and intermittent asthma.

BACKGROUND: Allergic rhinitis (AR) and allergic asthma are caused by an IgE-mediated inflammatory reaction. Probiotics may exert anti-inflammatory and immune-modulatory activity. Thus, this study aimed at investigating whether a Bifidobacteria mixture could be able to relieve nasal symptoms, and affect quality of life (QoL) in children with AR and intermittent asthma due to Parietaria allergy. MATERIALS AND METHODS: The present study was conducted as placebo-controlled, double-blinded, and randomized. Globally, 40 children (18 males; mean age 9 ± 2.2 years) were enrolled. They were treated with probiotics or placebo: 1 sachet/day for 4 weeks. AR symptoms, and QoL were assessed at baseline and after treatment. Use of rescue medications, such as cetirizine syrup and salbutamol spray, was also permitted and recorded. RESULTS: Children treated with probiotic mixture achieved a significant improvement of symptoms (p < 0.005), and QoL ((p < 0.001). Placebo group had worsening of symptoms (p < 0.005) and QoL (p < 0.001). The use of rescue medications was overlapping in the two groups. The intergroup analysis showed that probiotic mixture was significantly superior than placebo for all parameters. CONCLUSIONS: The current study demonstrated that a Bifidobacteria mixture was able of significantly improving AR symptoms and QoL in children with pollen-induced AR and intermittent asthma. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov ID NCT02807064 .

Consensus Conference on Clinical Management of pediatric Atopic Dermatitis.

The Italian Consensus Conference on clinical management of atopic dermatitis in children reflects the best and most recent scientific evidence, with the aim to provide specialists with a useful tool for managing this common, but complex clinical condition. Thanks to the contribution of experts in the field and members of the Italian Society of Pediatric Allergology and Immunology (SIAIP) and the Italian Society of Pediatric Dermatology (SIDerP), this Consensus statement integrates the basic principles of the most recent guidelines for the management of atopic dermatitis to facilitate a practical approach to the disease. The therapeutical approach should be adapted to the clinical severity and requires a tailored strategy to ensure good compliance by children and their parents. In this Consensus, levels and models of intervention are also enriched by the Italian experience to facilitate a practical approach to the disease.

Flavor, relative palatability and components of cow's milk hydrolysed formulas and amino acid-based formula.

BACKGROUND: Both extensively hydrolysed formulas (eHF) and amino acid-based formula (AAFs) have been demonstrated effective for the treatment of CMA. However, in clinical practice, parents complain that hydrolysates are rejected by children due to their bad taste. Flavor of hydrolysed formulas has been poorly investigated although it affects the acceptance of milk over all the other attributes. The aim of the present study was to understand the factors underlying the unpleasant flavor of hydrolysed 25 formulas and amino acid-based formula. SUBJECTS AND METHODS: One hundred and fifty trained panelists performed a randomized-double-blind test with different milks. The smell, texture, taste and aftertaste of each formula were evaluated on a scale ranging from -2 (worst) to 2 (best). RESULTS: Formulas showed significant difference, as compared to cow's milk, in smell, texture, taste and aftertaste. Overall, whey eHFs were judged of better palatability than casein eHF and the AAFs (p < 0.05). Whey eHF showed significant differences among them for sensory attributes, especially for taste and aftertaste. CONCLUSIONS: These results suggest that a broad range of flavor exists among the hydrolysed formulas. Further studies, adequately designed to investigate the relationship between milks' flavor and nutrient profile of hydrolysed formulas are warranted.

Resveratrol plus carboxymethyl-ß-glucan reduces nasal symptoms in children with pollen-induced allergic rhinitis.

OBJECTIVE: Allergic rhinitis (AR) is caused by an IgE-mediated inflammatory reaction consequent to the exposure to causal allergen. Resveratrol is a natural non-flavonoid polyphenol, exerting anti-inflammatory activity; ß-glucan is a polysaccharide with immuno-modulatory properties. Thus, this study aimed to investigate whether these combined compounds are able of relieving nasal symptoms in children with AR due to pollen allergy. RESEARCH DESIGN AND METHODS: The present study was conducted as placebo-controlled, double-blinded, and randomized. Globally, 68 children (36 males; mean age 7.9 years) were treated with resveratrol plus ß-glucan or placebo (the diluent of active drug) two sprays (100 µL/spray) in each nostril three times/day for 2 months. Nasal symptoms, including itching, sneezing, rhinorrhea, and obstruction, were assessed at baseline and after treatment. Use of rescue medication, such as cetirizine syrup, was also evaluated. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov ID NCT02130440. RESULTS: Children treated with active drug achieved a significant reduction in all nasal symptoms: itching (p = 0.0001), sneezing (p = 0.0009), rhinorrhea (p = 0.009), and obstruction (0.002) as well as antihistamine use (p = 0.003). Placebo did not affect nasal complaints and cetirizine use. The intergroup analysis showed that active treatment was significantly superior to placebo about reduction of AR symptoms and rescue medication use. CONCLUSIONS: The present preliminary study firstly showed that intranasal resveratrol plus carboxymethyl-ß-glucan is capable of significantly improving nasal symptoms in children with pollen-induced AR.

Microbiota in healthy skin and in atopic eczema.

The Italian interest group (IG) on atopic eczema and urticaria is member of the Italian Society of Allergology and Immunology. The aim of our IG is to provide a platform for scientists, clinicians, and experts. In this review we discuss the role of skin microbiota not only in healthy skin but also in skin suffering from atopic dermatitis (AD). A Medline and Embase search was conducted for studies evaluating the role of skin microbiota. We examine microbiota composition and its development within days after birth; we describe the role of specific groups of microorganisms that colonize distinct anatomical niches and the biology and clinical relevance of antimicrobial peptides expressed in the skin. Specific AD disease states are characterized by concurrent and anticorrelated shifts in microbial diversity and proportion of Staphylococcus. These organisms may protect the host, defining them not as simple symbiotic microbes but rather as mutualistic microbes. These findings reveal links between microbial communities and inflammatory diseases such as AD and provide novel insights into global shifts of bacteria relevant to disease progression and treatment. This review also highlights recent observations on the importance of innate immune systems and the relationship with normal skin microflora for the maintenance of healthy skin.

Autoimmunity in atopic dermatitis: biomarker or simply epiphenomenon?

The idea that a mechanism of autoimmunity could play a role in the pathogenesis of atopic dermatitis gained support from the observation that patients with atopic dermatitis display IgE reactivity to a variety of human protein antigens, several of which have been characterized at molecular level. A broad spectrum of at least 140 IgE-binding self-antigens associated with atopic dermatitis has been demonstrated; they might promote, perpetuate, or both, skin inflammation by binding IgE antibodies or activating specific T cells. Even if the presence of autoreactivity seems to be associated with the severity of the disease and may be used as a parameter reflecting chronic tissue damage, at the state of art the role of autoimmunity in atopic dermatitis is far from clear. Data from the literature show that the use of autoantibodies as biomarkers of atopic dermatitis are still limited by the evidence that the epiphenomenon of autoreactivity is detectable only in a percentage of patients and that the involved self-allergens often are not the same; further longitudinal case-control studies are needed to investigate and to clarify the pathogenethic role of autoimmunity in the course of atopic dermatitis.