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.

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.

Molecular profiles of IgE to Phleum pratense in children with grass pollen allergy: implications for specific immunotherapy.

BACKGROUND: The so-called component-resolved immunotherapy of allergies proposes an immunization tailored to the molecular sensitization profiles of individual patients. OBJECTIVES: We sought (1) to investigate the profiles of IgE sensitization to Phleum pratense in children with grass pollen allergy and (2) to define the compatibility of these profiles with a mixture of recombinant allergenic molecules of P pratense previously proposed for specific immunotherapy. METHODS: We examined 200 children (age, 4-18 years; 126 boys) with allergic rhinitis, asthma, or both ascertained through validated questionnaires. Each child underwent skin prick testing (ALK-Abelló) and serum IgE assays (ImmunoCAP, Phadia) with 9 pollen extracts. Sera reacting against P pratense were tested for the individual molecules (rPhl p 1, rPhl p 2, rPhl p 4, nPhl p 4, rPhl p 5b, rPhl p 6, rPhl p 7, rPhl p 11, and Phl p 12). Through a combinatorial approach, the IgE individual sensitization profiles were matched against an experimental allergen-specific immunotherapy (SIT) preparation containing Phl p 1, Phl p 2, Phl p 5, and Phl p 6. RESULTS: Among the 176 of 200 children with IgE sensitization to P pratense extract, 39 profiles of sensitization to the 8 allergenic molecules tested (cutoff, 0.35 kU/L) were identified. This high heterogeneity was reduced by considering only 6 or 4 P pratense molecules but not by increasing the cutoff levels of IgE positivity. The molecular profile of the experimental SIT preparation matched that of 7 (4%) of 176 patients only; the remaining 169 patients were classified in 4 mismatch categories: underpowered (29%), overpowered (32%), underpowered/overpowered (32%), and unrelated (3%). CONCLUSIONS: IgE sensitization profiles to P pratense are highly heterogeneous. Molecularly designed SIT preparations tailored to patients' needs should consider this high heterogeneity and be driven by locally performed population studies.

Management of BNT162b2 mRNA COVID-19 vaccine in children aged 5-11 years with allergies, asthma, and immunodeficiency: consensus of the Italian Society of Pediatric Allergy and Immunology (SIAIP).

BNT162b2 vaccine, developed by BioNTech and Pfizer ha recently approved for use in children aged 5 to 11 years. Recent data show evidence of safety on the administration and serious adverse events have been rarely reported. However, allergic systemic reactions could occur. In some cases, a correct allergic evaluation allows identifying patients at risk of developing an anaphylactic reaction. Risk assessment of allergic reactions to COVID-19 vaccines is useful to limit contraindications to vaccination and help to safely vaccinate people supposed to be at risk of allergic reactions.

Component resolved diagnosis and risk assessment in food allergy.

Allergy testing should only be performed in the context of the clinical history as history provides the cornerstone of diagnosis. In food allergy, some allergy tests often give rise to false positive results and thus can lead to unnecessary avoidance or delay on foods introduction. The use of Component Resolved Diagnosis in combination with conventional sensitization testing improves analytical and diagnostic performance and can lead to the reduction of diagnostic oral food challenges. Component Resolved Diagnosis can be helpful in identifying some risks for the allergic child. Molecular diagnosis can help also in predicting the development of the allergy march, in severe reactions (lipid transfer protein, seed storage proteins, etc.) in food allergy and for potential clinical cross-reactivity.

Digital health in the management of allergic diseases.

In recent years there has been an important implementation in the medical field of both Mobile Health, such as the use of mobile communication devices, and of other telemedicine tools in general, with the aim of supporting the supervision of diseases from the moment of the first diagnosis to the therapeutic follow-up. In fact, Digital Health can also have a very positive impact on the management of allergic patients, who are known to have the greatest need for regular monitoring, simplifying contact between doctor and patient, but there is still a need to improve implementation regulations, define certification programs and adequate reimbursement systems, as well as to guarantee a high level of attention to the protection of sensitive data. The hope is that one positive outcome of the Covid-19 pandemic will be an acceleration, by all stakeholders involved, of the process of the modernization of health care.

United airway disease.

Nose and lungs are considered as anatomic and functional unit, as they share morphological, pathophysiological and immunological basis. Allergic rhinitis and asthma often coexist in the same individual, and the treatment of one also improves the symptoms of the other (one airway, one disease). The aim of this review is to discuss the interaction between upper and lower airways, based on recent scientific evidence and, critically, analyze the important implications the new findings have for the future therapy and prevention of these common diseases.

Analysis of a database to predict the result of allergy testing in vivo in patients with chronic nasal symptoms.

BACKGROUND: This article uses the logistic regression model for diagnostic decision making in patients with chronic nasal symptoms. We studied the ability of the logistic regression model, obtained by the evaluation of a database, to detect patients with positive allergy skin-prick test (SPT) and patients with negative SPT. The model developed was validated using the data set obtained from another medical institution. METHODS: The analysis was performed using a database obtained from a questionnaire administered to the patients with nasal symptoms containing personal data, clinical data, and results of allergy testing (SPT). All variables found to be significantly different between patients with positive and negative SPT (p < 0.05) were selected for the logistic regression models and were analyzed with backward stepwise logistic regression, evaluated with area under the curve of the receiver operating characteristic curve. A second set of patients from another institution was used to prove the model. RESULTS: The accuracy of the model in identifying, over the second set, both patients whose SPT will be positive and negative was high. The model detected 96% of patients with nasal symptoms and positive SPT and classified 94% of those with negative SPT. CONCLUSION: This study is preliminary to the creation of a software that could help the primary care doctors in a diagnostic decision making process (need of allergy testing) in patients complaining of chronic nasal symptoms.

Vitamin D, allergies and asthma: focus on pediatric patients.

In recent years, the interest of the scientific world towards vitamin D gradually increased, and several studies have been conducted to dissect its possible role in modulating the development/course of allergic diseases. Also, Vitamin D supplementation has been assessed as a beneficial approach for treating allergies in some, but not all studies. We reviewed herein the available and relevant literature concerning the possible links between Vitamin D, its supplementation and allergic diseases. A literature search was made independently by the Authors, identifying articles for a narrative review. As per literature, Vitamin D plays a key role in calcium and phosphate metabolism, and it is essential for bone health in infants, children and adolescents. However, there is presently insufficient evidence to support vitamin D supplementation for prevention or treatment of allergic diseases in infants, children and adolescents, concerning allergic rhinitis, asthma, food allergy and atopic dermatitis.

Consumption of fish, butter and margarine during pregnancy and development of allergic sensitizations in the offspring: role of maternal atopy.

It has been suggested that changes in dietary habits, particularly increased consumption of omega-6 polyunsaturated fatty acids (PUFA) and decreased consumption of omega-3 PUFAs may explain the increase in atopic disease seen in recent years. Furthermore, it seems possible that it is mainly prenatal or very early life environmental factors that influence the development of allergic diseases. It has also been suggested that intrauterine risk factors may act differently if mother themselves suffer from allergic disease. The aim of this study was to investigate whether the consumption of fish, butter and margarine during pregnancy might influence the development of allergic sensitizations in the offspring. The study population was divided into the offspring of allergic and non-allergic mothers. This was a retrospective cohort study enrolling 295 offspring of allergic mothers and 693 of non-allergic mothers. Information regarding maternal intake of fish, butter and margarine during pregnancy as well as other prenatal and perinatal confounding factors were retrospectively assessed by parental report via a standardized questionnaire. Atopy was determined by skin-prick tests (SPT) to eight prevalent inhalant allergens and two foods. In the allergic mothers' group there is no clear correlation between maternal intakes of fish, butter and margarine and sensitizations to food or inhalants. In the non-allergic mothers' group there was no correlation between butter and margarine intake and food or inhalant sensitizations. On the contrary, a protective effect of fish intake on SPT positivity was observed. In particular, frequent maternal intake ('2-3 times/wk or more') of fish reduced the risk of food sensitizations by over a third (aOR 0.23; 95% CI: 0.08-0.69). A similar trend, even if not significant, was found for inhalants. Finally, even in the whole study population, i.e. allergic group plus non-allergic group, there was a similar trend between increased consumption of fish and decreased prevalence of SPT positivity for foods. This study shows that frequent intake of fish during pregnancy may contrast the development of SPT sensitizations for foods in the offspring of mothers without atopic disease. Therefore, larger prospective studies are needed, enrolling mothers with and without allergic disease, to confirm these results.