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.

Pulmonary Tuberculosis in Children: A Forgotten Disease?

Even today, tuberculosis in childhood is a disease that is often undiagnosed and undertreated. In the absence of therapy with antituberculosis drugs, children in the first years of life have a high degree of severe forms and mortality. In these children, symptoms are often not very specific and can easily be confused with other diseases of bacterial, viral or fungal etiology, making diagnosis more difficult. Nevertheless, the introduction of new diagnostic techniques has allowed a more rapid identification of the infection. Indeed, Interferon gamma release assay (IGRA) is preferred to the Mantoux, albeit with obvious limitations in children aged <2 years. While the Xpert Mtb/RIF Ultra test is recommended as an initial diagnostic investigation of the gastric aspirate and/or stools in children with signs and symptoms of pulmonary tuberculosis. The drugs used in the treatment of susceptible and resistant TB are the same as those used in adults but doses and combinations are different in the pediatric age. In children, brief therapy is preferable in both the latent infection and the active disease, as a significant reduction in side effects is obtained.

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.

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 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.

Environmental risk factors and lung diseases in children: from guidelines to health effects.

During the last decades research all over the world has highlighted the deleterious effects of outdoor and indoor pollution on respiratory health of adults and children. The World Health Organization (WHO) "Air quality guidelines for Europe" played a fundamental role in providing information and guidance to authorities involved in the air pollution field and they are considered the key source on which the European Commission's directive on air quality is based. Children appear to be most vulnerable to the harmful effects of outdoor pollutants, which can cause both acute exacerbations, as well as chronic respiratory symptoms and diseases. Possible mechanisms include the induction of oxidative stress, and/or allergic sensitization, as well as increased susceptibility to infections. Cigarette smoke is one of the environmental pollutant influencing morbidity and death rate in childhood as responsible for adverse health effects in both prenatal and postnatal. There is growing epidemiological evidence that indoor allergen exposure may contribute to the development of allergic respiratory symptoms. In Italy the housing and social situation, with regard to the aspects related to exposure to secondhand smoke or the presence of fungal spores, moisture linked to household vapor and poor ventilation of the rooms are problems still not completely resolved. From a medical point of view the field of pediatrics has certainly made great strides in promoting the health of children and pediatricians to have a central role for pursuing this objective.

Treatment of disorders characterized by reversible airway obstruction in childhood: are anti-cholinergic agents the answer?

Release of acetylcholine from parasympathetic nerves in the airways activates postjunctional muscarinic receptors present on smooth muscle, submucosal glands and blood vessels. This triggers bronchoconstriction, muscle hypertrophy, mucus secretion, and vasodilatation, respectively. The release of acetylcholine from parasympathetic nerves in lungs is induced by a variety of stimuli and downregulated by the inhibitory activity of neuronal M2 muscarinic receptors via a feedback mechanism. Increased parasympathetic nerve activity occurs in a variety of airway diseases in childhood, including viral-induced wheeze and asthma. Common to these conditions are reversible airway obstruction, mucus hypersecretion, vasodilation and enhanced vascular permeability. In animal models of airway hyperreactivity similar findings of increased acetylcholine release resulting in enhanced supply of this neurotransmitter to the postjunctional smooth muscles, submucosal glands and airway vessels, were demonstrated. While the number and function of postjunctional muscarinic receptors in the airways are unchanged in such airway disorders, inhibitory activity on the parasympathetic nerves appears to be impaired. Specifically, M2 muscarinic receptor dysfunction has been demonstrated in models of bronchial hyperreactivity induced by a variety of triggers, including viruses, atmospheric pollutants and allergens. The mechanisms leading to impairment of neuronal M2 muscarinic receptor function and their putative relevance to the pathogenesis and the treatment of airway disease in childhood are described. Finally, the available data on the activity of ipratropium bromide, a short-acting anticholinergic drug, in the most common pediatric airway disease are reported and the possible therapeutic efficacy of tiotropium bromide, a more recently introduced long-acting, selective anticholinergic compound, is discussed.

Indoor exposure to environmental tobacco smoke and dampness: respiratory symptoms in Sardinian children--DRIAS study.

Indoor exposures at home, environmental tobacco smoke (ETS) and mould/dampness adversely affect respiratory health of children. Disturbi Respiratori nell'Infanzia e Ambiente in Sardegna (DRIAS) (Respiratory Symptoms in children and the Environment in Sardegna, Italy) aims at relating the prevalence of respiratory and allergic symptoms to indoor exposures in Sardinian children. DRIAS, a cross-sectional investigation of respiratory symptoms/diseases, used a modified version of ISAAC questionnaire, included 4122 children attending 29 primary schools in the school year 2004-2005. If both parents smoke the prevalence for current wheeze and current asthma is almost doubled in comparison with never smokers, for persistent cough and phlegm a role is suggested when only mother smokes. Among mothers smoking in pregnancy, the prevalence of current wheeze and current asthma is increased. Exposure to ETS and family atopy have a joint effect resulting in an almost tripling of prevalence for current wheeze and more than four times for current asthma. Exposure to "dampness" (mould or dampness) both during the first year of life and currently is associated with increased prevalence of current wheeze, persistent cough or phlegm and current rhino-conjunctivitis; if exposure is only during the first year of life a doubling or more of prevalence is observed for current wheeze, current asthma, and persistent cough or phlegm. DRIAS results add evidence to the causal role of childhood exposure to ETS in the development of respiratory symptoms (cough, phlegm, and wheezing) and asthma. The joint effect of ETS and family atopy is corroborated. The results strengthen the evidence for a causal association between "dampness" and respiratory health, pointing to its possible independent role in causing asthma, a long-lasting exposure entails a doubled prevalence for both asthmatic and bronchitis symptoms.

IRAK-M is involved in the pathogenesis of early-onset persistent asthma.

Asthma is a multifactorial disease influenced by genetic and environmental factors. In the past decade, several loci and >100 genes have been found to be associated with the disease in at least one population. Among these loci, region 12q13-24 has been implicated in asthma etiology in multiple populations, suggesting that it harbors one or more asthma susceptibility genes. We performed linkage and association analyses by transmission/disequilibrium test and case-control analysis in the candidate region 12q13-24, using the Sardinian founder population, in which limited heterogeneity of pathogenetic alleles for monogenic and complex disorders as well as of environmental conditions should facilitate the study of multifactorial traits. We analyzed our cohort, using a cutoff age of 13 years at asthma onset, and detected significant linkage to a portion of 12q13-24. We identified IRAK-M as the gene contributing to the linkage and showed that it is associated with early-onset persistent asthma. We defined protective and predisposing SNP haplotypes and replicated associations in an outbred Italian population. Sequence analysis in patients found mutations, including inactivating lesions, in the IRAK-M coding region. Immunohistochemistry of lung biopsies showed that IRAK-M is highly expressed in epithelial cells. We report that IRAK-M is involved in the pathogenesis of early-onset persistent asthma. IRAK-M, a negative regulator of the Toll-like receptor/IL-1R pathways, is a master regulator of NF- kappa B and inflammation. Our data suggest a mechanistic link between hyperactivation of the innate immune system and chronic airway inflammation and indicate IRAK-M as a potential target for therapeutic intervention against asthma.

Measurement of body surface area in atopic dermatitis using specific PC software (ScoradCard).

In skin diseases, evaluation of involved surface area is a crucial factor in grading the degree of severity. We examined the reliability of body surface area assessment and relative inter-observer and intra-observer variability using new software (ScoraCard), specifically designed to evaluate automatically the extension of the involved area in the SCORAD index. Twenty pediatricians, untrained in the evaluation of skin disease, estimated the percentage of surface area involved in photo-tests of two children with artificial well-delimited lesions, at first by sight and then through software. As "gold standard" the exact amount of pixels was counted for the whole body surface of the children, for the different body zones and for the painted artificial lesions, expressed as percentage of the respective zone. For photo 1, gold standard was 38.06% and median percentage was 43.44% (95% CI 40.7-46.21) by sight (p = 0.002) and 37.99% (95% CI 36.04-39.94) by ScoradCard (p = 0.79). For photo 2, gold standard was 27.84%, median percentage was 30.44% (95% CI 28.25-32.63) by sight (p = 0.047) and 27.8% (95% CI 26.55-29.04) by ScoradCard (p = 0.79). The level of agreement (kappa statistic), cumulative for the two photo tests, was 0.38 (fair agreement) by sight method and 0.67 (good agreement) by ScoradCard. Among the 10 pediatricians who repeated the computer aided evaluation 3 months apart, the intra-observer variability was not significantly different: the median percentage was 31.5% (95% CI 27.0-49.4) at time 0 and 29.0% (95% CI 26.7-47.2) 3 months later (p = 0.76). This new software could be a useful tool in evaluating skin lesions extension, minimizing inter- and intra-observer variability, which is an important goal in multi-centre studies.