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Introduction. The onset of allergic diseases most often occurs in early childhood with the onset of food allergies, which can subsequently lead to the implementation of the atopic march. Increased intestinal permeability with high production of zonulin, the main moderator of intestinal tight junctions, can be an important link in the development of comorbid allergic diseases.Material and methods. In order to study the significance of fecal zonulin as a marker for predicting the atopic march in children with food allergy, a cross-sectional retrospective study was conducted on 73 children aged 5 years who were diagnosed with food allergy (FA) to cow’s milk proteins in the first year of life. In all children, when the diagnosis was made in the first year of life, the content of zonulin in feces was determined using the ELISA method.Results. As a result of dynamic observation, all children with food allergy were divided into 2 groups: the first group consisted of children with food allergy who developed allergic rhinitis and/or bronchial asthma within 5 years (group I, n = 39), group 2 consisted of 34 children with food allergy who did not implement the atopic march within 5 years of observation (group II, n = 34). Our study showed statistically significant differences in the fecal zonulin level in the first year of life: group I Me = 2.39 ng/ml (Q1-Q3: 1.78–2.65 ng/ml), group II Me = 1.85 ng/ml (Q1-Q3: 0.49–0.91 ng/ml), p = 0.034. Strong direct correlations were found (Spearman correlation coefficient S = 0.681 (p < 0.05)) between the zonulin level in feces at the onset of the disease and the development of allergic rhinitis and/or bronchial asthma up to 5 years of age, the data were confirmed by comparing the areas under the curves during ROC analysis, AUC in the study of fecal zonulin as a prognostic marker of the risk of atopic march in children is 0.887, the optimal threshold (cutoff point) is 1.94 ng/ml.Conclusions. Fecal zonulin level in children with food allergy can be an effective prognostic marker of atopic march development, its values in feces above 1.94 ng/ml allow us to predict with a high degree of probability the risk of atopic march development in children with food allergy to cow’s milk proteins within 5 years

Introduction: Nitric oxide (NO) is an important biological mediator of inflammation which is exhaled after being produced in the lungs. Fractional exhaled NO (FENO) is a new tool which measures the amount of NO exhaled. Aims and Objective: The objective of our study was to find the correlation between the FENO levels between atopic dermatitis and asthma patients in comparison to healthy controls and hence identify steroid responsiveness. Methodology: Our study was a cross-sectional observational study performed in a tertiary care hospital involving 150 children (>5–

Background. Atopic dermatitis (AD) is one of the most common chronic inflammatory skin diseases in children. It manifests during the first year of life in majority of cases. Early AD manifestation is a risk factor for the development of other atopic spectrum diseases in the future. Nowadays, the ability of the dupilumab, as a genetically engineered biologic drug (GEBD), to modify the disease course, to reduce the frequency of AD persistence and the possibility of multimorbid atopic phenotype development is widely discussed. Thus, dupilumab management in young children with early onset and severe course arouses specific interest. Clinical case description. This article demonstrates the experience of effective administration of GEBD dupilumab in 4-year old patient with severe AD and comorbid food allergies. Continuous therapy for 12 weeks allowed to recover disease’s skin manifestations. No adverse events were reported. Conclusion. Long-term continuous dupilumab administration in children aged from 6 months to 5 years has proven its efficacy and acceptable safety profile. The potential disease-modifying effect of dupilumab is especially significant for young and preschool children due to the high risk atopic multimorbidity developing during this period.

Background: Dupilumab is the first and only biologic agent approved for the treatment of atopic dermatitis (AD) in pediatric patients aged from 6 months to 17 years. The study aimed to evaluate the impact of dupilumab on the occurrence of comorbidities in pediatric patients with AD. Methods: In this population‐based cohort study, we utilized electronic health records from multiple healthcare organizations across the United States. Pediatric patients (<18 years of age) with a diagnosis of AD initiating dupilumab were propensity‐score matched 1:1 to those initiating other systemic agents (azathioprine, cyclosporine, methotrexate, mycophenolate mofetil, or systemic corticosteroids). The primary outcomes were new‐onset comorbidities emerging during the study period measured by the risk ratio (RR) and its confidence interval (CI). Subgroup analyses were stratified by age (0–5 years, 6–11 years, and 12–17 years), sex, and race. Results: A total of 3575 pediatric patients with AD treated with dupilumab were matched to 3575 patients treated with other systemic agents. The dupilumab cohort was associated with a lowered risk of new‐onset atopic comorbidities (including asthma [RR, 0.72; 95% CI, 0.59–0.89] and allergic rhinitis [RR, 0.62; 95% CI, 0.52–0.74]), infections (e.g., skin and soft tissue infection [RR, 0.70; 95% CI, 0.63–0.76] and respiratory tract infection [RR = 0.56; 95% CI, 0.51–0.61]), psychiatric disorders (e.g., mood disorder [RR, 0.52; 95% CI, 0.39–0.70] and anxiety [RR, 0.57; 95% CI, 0.46–0.70], sleep disturbance [RR, 0.60; 95% CI, 0.47–0.77]), neurologic and developmental disorders (e.g., attention deficit hyperactivity disorder [RR, 0.54; 95% CI, 0.38–0.75]). Furthermore, the positive effects are found to be more pronounced in younger children (aged 0–5 years) with AD. Conclusions: Treatment with dupilumab compared to systemic agents resulted in reductions in AD‐related comorbidities in pediatric patients. [ABSTRACT FROM AUTHOR]

Eosinophilic esophagitis (EoE) is a chronic inflammatory disorder of the esophagus. EoE shares a common pathogenetic mechanism with other chronic disorders pertaining to the type 2 inflammatory spectrum, such as atopic dermatitis (AD), allergic rhinitis (AR), asthma, and chronic rhinosinusitis with nasal polyps (CRSwNP). The recent advancements in EoE pathogenesis understanding have unveiled new molecular targets implied within the "atopic march" picture as well as specific to EoE. These discoveries have led to the clinical evaluation of several novel drugs (monoclonal antibodies and immune modulators), specifically aimed at the modulation of Th2 inflammation. In this comprehensive review, we have focused on the subtle mechanisms of type 2 inflammatory disorders, highlighting the similarities and differences with EoE, taking a deeper look into the evolving field of biologic therapies, already approved or under current investigation. [ABSTRACT FROM AUTHOR]

Dupilumab effectively treats atopic dermatitis (AD); however, its role in halting the atopic march remains uncertain. To investigate dupilumab's effect on atopic march in pediatric AD patients versus conventional immunomodulators. This retrospective cohort study utilized data from the TriNetX US Collaborative Network (2011-2024). Pediatric AD patients (≤18 years) were categorized into DUPI-cohort (newly prescribed dupilumab) or CONV-cohort (prescribed conventional immunomodulators without dupilumab). After 1:1 propensity-score matching, we analyzed atopic march progression, defined by the incident asthma or allergic rhinitis (AR). Cumulative incidence was plotted using Kaplan-Meier, with risk assessment via Cox regression. The study included 2192 patients in each cohort. The 3-year cumulative incidence of atopic march progression was lower in the DUPI-cohort than the CONV-cohort (20.09% vs 27.22%; P <.001). The DUPI-cohort demonstrated significant risk reduction in atopic march progression (hazard ratio [HR] 0.68, 95% CI 0.55-0.83), individual asthma (HR 0.60, 0.45-0.81), and individual AR (HR 0.69, 0.54-0.88). Younger patients on dupilumab exhibited a greater risk reduction for atopic march progression and individual asthma, contrasting with the opposite age-related pattern for individual AR. Observational study. Among pediatric AD patients, dupilumab was associated with reduced risk of atopic march progression compared with conventional therapies. [ABSTRACT FROM AUTHOR]

To the editor: The article by Geba et al., entitled “Attenuating the atopic march: Meta-analysis of the dupilumab atopic dermatitis database for incident allergic events”,1,2 published in JACI 2023 Mar; 151 (3): 756-766, offers insights into the potential of dupilumab in modulating the atopic march. The author’s comment: “…Dupilumab reduced the risk of new/worsening allergies by 34% (IRR 0.66; 95% confidence interval [CI], 0.52-0.84) and new allergies by 37% (IRR: 0.63; 95%CI: 0.48-0.83) versus placebo”, and “…These treatment benefits did not reverse on treatment discontinuation in off-treatment follow-up”. Although the results are interesting, the study presents some methodological and conceptual aspects that call to be cautious with interpreting the results. • The study's primary objective was "…to determine the rate of acquisition of new or worsened allergic events for dupilumab versus placebo in patients with AD". However, the use of dupilumab may mask symptoms of different allergic conditions, and these may only become evident after therapy discontinuation.3 Despite the authors' claim that “These treatment benefits did not reverse on treatment discontinuation in off-treatment follow-up,” when reviewing information about “off-treatment period” in Figure E3 we observe that the confidence interval of all studies crosses 1 and, additionally, the incidence rate ratio (IRR) was 0.99 (CI 95% 0.62-1.59.) Therefore, these results do not support the previous affirmation. • Table E1 reveals a follow-up time of 16 to 52 weeks in the studies. Within this short period and considering predominantly adult patients, the observed variation in allergic events between dupilumab and control groups appears more attributable to disease control than a genuine reduction in incidence. • The main result of the study present in Figure 3 “Dupilumab reduced the risk of new/worsening allergies by 34% (IRR 0.66; 95% confidence interval [CI], 0.52-0.84) and new allergies by 37% (IRR 0.63; 95% CI, 0.48-0.83) versus placebo.” Of the 12 studies included in the Forest plot A and B, 11 crosses 1. Additionally, a single study (R668-AD-1224) does not cross 1 and contributes with 47.6% of the weight, dragging down the observed significance. This may be due to the ecological fallacy, where aggregate analyses are interpreted but not the interindividual variability of patients.4 Also, lack of bias assessment and publication verification reduces the reliability of the study's findings. • It is not clear how the authors defined some terms used in the article as “allergic conditions”, “chemical allergy”, “metal allergy”, “contact dermatitis”, “asthma”, and “wheezing”. The lack of clarity in the definitions generates a risk of ambiguity fallacy.5 • It´s controversial that all conditions included in the study are really part of the atopic march. For example, authors included “pruritus” or “urticaria.” • How was pet’s allergy defined? While biologics may suppress specific IgE responses, their influence on clinical outcomes is not adequately addressed. In summary, we thank Geba et al. for raising an interesting question about the impact of dupilumab on the atopic march. The question remains largely unanswered, underscoring the importance of future studies for a comprehensive understanding of biologics' effects on the atopic march.

Introduction: Nitric oxide (NO) is an important biological mediator of inflammation which is exhaled after being produced in the lungs. Fractional exhaled NO (FENO) is a new tool which measures the amount of NO exhaled. Aims and Objective: The objective of our study was to find the correlation between the FENO levels between atopic dermatitis and asthma patients in comparison to healthy controls and hence identify steroid responsiveness. Methodology: Our study was a cross-sectional observational study performed in a tertiary care hospital involving 150 children (>5–<18 years) who were either attending the outpatient departments or were admitted as inpatients. Relevant history and physical findings were noted and severity scorings were done in the preformed pro forma. Their FENO levels were then recorded and compared. Results: The level of FENO was higher in both bronchial asthma and atopic dermatitis patients as compared to controls. The level of FENO was higher in treatment-naïve patients as compared to treated cases. There was also a strong positive correlation between the levels of FENO and disease severity in both the groups. Conclusion: FENO is a relatively new tool and as such still requires standardization and acceptance in the medical field. It can be a very useful tool in not only identifying these atopic diseases, but it can also act as a prognostic marker as well as a marker for patient compliance. There being a gap in literature related to FENO, hopefully our study will provide some insight to its usefulness. [ABSTRACT FROM AUTHOR]

Introduction: Tape‐strips, a minimally invasive method validated for the evaluation of several skin diseases, may help identify asthma‐specific biomarkers in the skin of children with allergic asthma. Methods: Skin tape‐strips were obtained and analyzed with RNA‐Seq from children with moderate allergic asthma (MAA) (n = 11, mean age 7.00; SD = 1.67), severe allergic asthma (SAA) (n = 9, mean age 9.11; SD = 2.37), and healthy controls (HCs) (n = 12, mean age 7.36; SD = 2.03). Differentially expressed genes (DEGs) were identified by fold change ≥2 with a false discovery rate <0.05. Transcriptomic biomarkers were analyzed for their accuracy in distinguishing asthma from HCs, their relationships with asthma‐related outcomes (exacerbation rate, lung function‐FEV1, IOS‐R5‐20, and lung inflammation‐FeNO), and their links to skin (barrier and immune response) and lung (remodeling, metabolism, aging) pathogenetic pathways. Results: RNA‐Seq captured 1113 in MAA and 2117 DEGs in SAA. Epidermal transcriptomic biomarkers for terminal differentiation (FLG/filaggrin), cell adhesion (CDH19, JAM2), lipid biosynthesis/metabolism (ACOT2, LOXL2) were significantly downregulated. Gene set variation analysis revealed enrichment of Th1/IFNγ pathways (p <.01). MAA and SAA shared downregulation of G‐protein‐coupled receptor (OR4A16, TAS1R3), upregulation of TGF‐β/ErbB signaling‐related (ACVR1B, EGFR, ID1/2), and upregulation of mitochondrial‐related (HIGD2A, VDAC3, NDUFB9) genes. Skin transcriptomic biomarkers correlated with the annualized exacerbation rate and with lung function parameters. A two‐gene classifier (TSSC4‐FAM212B) was able to differentiate asthma from HCs with 100% accuracy. Conclusion: Tape‐strips detected epithelial barrier and asthma‐associated signatures in normal‐appearing skin from children with allergic asthma and may serve as an alternative to invasive approaches for evaluating asthma endotypes. [ABSTRACT FROM AUTHOR]

Atopic dermatitis (AD) is thought to precede the onset of other allergic illness (OAI) in a temporal progression (ie, atopic march), yet the timing and progression has been questioned. It is also unclear how parental allergic illness impacts the development of these illnesses in offspring. (1) Explore risk of incident AD and (2) timing of allergic disease onset in children of mothers with AD compared with mothers without AD from the United Kingdom. We created a birth cohort of mother-child pairs using IQVIA Medical Research Data database and developed Cox proportional models to examine the above associations (hazard ratio, HR [95% confidence interval, CI]). Among 1,224,243 child-mother pairs, mean child (standard deviation) follow-up time was 10.8 (8.3) years and 50.1% were males (N = 600,905). Children were 59% (HR = 1.59 [1.57, 1.60]) more likely to have AD if their mothers had AD compared with no AD with mean age of first AD diagnosis at 3.3 (4.8) years. Most children with any diagnosis of AD present with AD first (91.0%); however, in those with asthma, only 67.8% developed AD first. Children born to mothers with AD are more prone to develop AD and some develop OAI first, suggesting that not all follow the same sequential pathway. • The atopic march describes the temporal association of initial onset of atopic dermatitis at an early age followed by subsequent development of other atopic illness. • We observed that whereas this may be true for some, not all patients with allergic diseases including atopic dermatitis, will follow the same "sequential" march. [ABSTRACT FROM AUTHOR]

Background: Allergic rhinitis (AR) is an IgE-mediated type I allergic chronic nasal disease common among all age groups, including the pediatric population. House dust mites (HDMs) are globally ubiquitous and the most important indoor aeroallergen. However, the recent prevalence of HDM-caused AR (AR-HDM) in Japan remains unknown, especially after the COVID-19 pandemic. Objective: The objective of this study was to investigate the current prevalence of AR-HDM, its clinical features, and the current status of medical examinations in elementary school students. Methods: A survey of 41,000 elementary school students was conducted during July 2021 in Fukui Prefecture, Japan. Parents were asked to complete a questionnaire that examined allergic disease history and clinical background. Results: A total of 17,974 subjects were analyzed in the study. The results showed that the current prevalence of AR-HDM in elementary school children is 18.8%. We found that AR-HDM had already developed before entrance into elementary school in 68.3% of affected subjects. Among these subjects, 82.3% had received some form of treatment, such as prescription medications, whereas 4.2% were treated by allergen immunotherapy. Multiple logistic regression analysis of the onset of AR-HDM revealed that male sex, being the first-born child, comorbidity of bronchial asthma, atopic dermatitis, food allergy, and allergic conjunctivitis are associated with development of AR-HDM. Conclusions: The present study revealed the prevalence of AR-HDM in elementary school children. The results emphasize the importance of appropriate diagnosis and treatment from infancy through early childhood.

BackgroundWhile numerous genetic loci associated with atopic dermatitis (AD) have been discovered, to date, work leveraging the combined burden of AD risk variants across the genome to predict disease risk has been limited.ObjectivesThis study aims to determine whether polygenic risk scores (PRSs) relying on genetic determinants for AD provide useful predictions for disease occurrence and severity. It also explicitly tests the value of including genome-wide association studies of related allergic phenotypes and known FLG loss-of-function (LOF) variants.MethodsAD PRSs were constructed for 1619 European American individuals from the Atopic Dermatitis Research Network using an AD training dataset and an atopic training dataset including AD, childhood onset asthma, and general allergy. Additionally, whole genome sequencing data were used to explore genetic scoring specific to FLG LOF mutations.ResultsGenetic scores derived from the AD-only genome-wide association studies were predictive of AD cases (PRSAD: odds ratio [OR], 1.70; 95% CI, 1.49-1.93). Accuracy was first improved when PRSs were built off the larger atopy genome-wide association studies (PRSAD+: OR, 2.16; 95% CI, 1.89-2.47) and further improved when including FLG LOF mutations (PRSAD++: OR, 3.23; 95% CI, 2.57-4.07). Importantly, while all 3 PRSs correlated with AD severity, the best prediction was from PRSAD++, which distinguished individuals with severe AD from control subjects with OR of 3.86 (95% CI, 2.77-5.36).ConclusionsThis study demonstrates how PRSs for AD that include genetic determinants across atopic phenotypes and FLG LOF variants may be a promising tool for identifying individuals at high risk for developing disease and specifically severe disease.

Background. Atopic march (AM) is the progression of atopic lesions (AL) from monoorganic phenotypes (MOPh), usually atopic dermatitis (AD), to a combination with allergic rhinitis/rhinoconjunctivitis (AR/ARC) and bronchial asthma (BA) in the full-scope polyorganic phenotype (POPh) AD + AR/ARC + BA. At the same time, AD is the initial and basic AM MOPh. The basis of AL and AM is the human genotype, in particular, single nucleotide variants (SNV) of genes that predispose to the development of AL phenotypes. Namely, these are SNV of thymic stromal lymphopoietin (TSLP) and orоsomucoid-1-like protein 3 (ORMDL3): SNV rs_11466749 TSLP and rs_7216389 ORMDL3. The purpose of this study was to detect the associations and risks of developing AM POPh AD + AR/ARC and AD + AR/ARC + BA related to baseline MOPh AD and to each other in children with different SNV rs_11466749 TSLP and rs_7216389 ORMDL3 genotypes. Materials and methods. Two hundred and thirty-two children aged 3 to 18 years took part in the study. The main group consisted of 127 patients with 3 studied AM phenotypes: one MOPh AD (n = 58) and two POPh: AD + AR/ARC (n = 43) and AD + AR/ARC + BA (n = 26). The control group included 105 children without AL, suffering from gastrointestinal diseases. All children in the study groups underwent a buccal swab of the DNA material, which then was studied using the real-time polymerase chain reaction with restriction fragment length polymorphism to determine the genotypes of SNV candidates: A/A, A/G, G/G rs_11466749 TSLP and C/C, C/T, T/T rs_7216389 ORMDL3. Pearson’s χ2 criterion and Fisher’s exact test, Bravais-Pearson contingency coefficient (r), logistic regression analysis with determination of odds ratio (OR) with 95% confidence interval (95% CI), receiver operating characteristic (ROC) analysis with calculation of the area under the ROC curve with a 95% CI and operating characteristics — sensitivity and specificity were used for statistical processing. The critical level of statistical significance of the results during testing of all hypotheses was p < 0.05, the tendency to probability was determined at p = 0.05–0.1. Results. The following statistically significant differences were detected in the occurrence of genotypes related to the control group: for POPh AD + AR/ARC: SNV rs_7216389 ORMDL3: C/C — 14.0 %, T/T — 39.5 to 27.6 and 15.2 %, respectively (p = 0.08 and p < 0.05); for POPh AD + AR/ARC + BA: SNV rs_11466749 TSLP: A/A — 77.0 %, A/G — 11.5 to 50.5 and 45.7 %, respectively (p < 0.05 and p < 0.01). Among the phenotypes of the main group, the following statistically significant differences in the genotypes incidence had been detected: AD + AR/ARC related to AD: G/G rs_11466749 TSLP — 9.3 to 1.7 % (p = 0.08), T/T rs_7216389 ORMDL3 — 39.5 to 19.0 % (p

The atopic march encompasses a sequence of allergic conditions, including atopic dermatitis, food allergy, allergic rhinitis, and asthma, that frequently develop in a sequential pattern within the same individual. It was introduced as a conceptual framework aimed at elucidating the developmental trajectory of allergic conditions during childhood. Following the introduction of this concept, it was initially believed that the atopic march represented the sole and definitive trajectory of the development of allergic diseases. However, this perspective evolved with the emergence of new longitudinal studies, which revealed that the evolution of allergic diseases is far more intricate. It involves numerous immunological pathological mechanisms and may not align entirely with the traditional concept of the atopic march. The objective of our review is to portray the atopic march alongside other patterns in the development of childhood allergic diseases, with a specific emphasis on the potential for a personalized approach to the prevention, diagnosis, and treatment of atopic conditions. [ABSTRACT FROM AUTHOR]

Background: Atopic dermatitis (AD) at a young age often precedes the development of food allergies. Although AD affects millions of infants worldwide, prenatal and postnatal risk factors, and their association with the development of food allergies later on, are not fully elucidated. This study seeks to investigate AD epidemiology in infancy and its risk factors, examining early-life factors (both prenatal and postnatal) that could contribute to the later development of food allergies. Methods: Between January 2019 and December 2019, 501 infants were included in this prospective cohort study. Longitudinal data collection was performed through maternal interviews, the first one conducted within three days after the delivery and the second within 24 to 36 months after the delivery, encompassing variables such as demographics, family history of atopy, maternal smoking, antibiotic use during pregnancy, the mode of delivery, breastfeeding history, food practices, and greenness exposure within 3 days from delivery, while they were still in the hospital. Results: Maternal smoking during pregnancy (p = 0.001) and an older sibling atopy history (p = 0.03) was significantly linked to AD incidence. Cesarean section delivery (p = 0.04) was associated with a higher risk of food allergies in infants with AD. Having a garden at home correlated with a higher likelihood of AD (p = 0.01), and food elimination without medical guidance (p = 0.02) due to AD correlated with an elevated risk of food allergies. Conclusions: Encouraging timely allergenic food introduction while promoting dietary diversity, rich in plant-based foods, maternal smoking cessation, and professional dietary guidance may help minimize AD and food allergy risk. Future studies should address the role of greenness in the development of AD and food allergies. [ABSTRACT FROM AUTHOR]

Background. The problem of atopic march (AM), namely its progression from monoorganic phenotypes of atopic dermatitis (AD), allergic rhinitis/rhinoconjunctivitis (AR/ARC), bronchial asthma (BA) to their multiorgan combinations, is one of the biggest in the modern pediatrics. One of the most important causes for the development of these pathologies are single nucleotide variants (SNV) of the causative genes, orsomucoid-1-like protein 3 (ORMDL3), in particular rs_7216389 ORMDL3. The roles of T- and C-alleles in relation to monoorganic and polyorganic AM phenotypes have not been sufficiently studied. The objective was to study associations of the SNVs rs_7216389 ORMDL3 in the development of different AM phenotypes in children. Materials and methods. There were 293 children recruited into the main group and 105 controls aged 3 to 18 years. Children of the main group had monoorganic and polyorganic phenotypes of AM: AD, AR/ARC, BA, AD+AR/ARC, BA+AR/ARC, AD+AR/ARC+BA. Children of the control group suffered from organic and functional digestive pathology without clinical or paraclinical signs of AM. All children were genotyped for C/C, T/T, C/T variants of SNV rs_7216389 ORMDL3 by allelic discrimination method based on real time polymerase chain reaction with restriction fragment length polymorphism of the buccal swab obtained from each patient. Spearman’s correlation coefficient (rs) was used to determine associations; risks and protective effects were determined using logistic regression analysis by calculating odds ratios (OR) and 95% confidence intervals (CI). The results obtained were significant at p < 0.05 according to the Student’s test. Results. Risks and associations for the monoorganic AR/ARC phenotype: C/C SNV rs_7216389 ­ORMDL3: rs = 0.197, OR = 0.33 (95% CI 0.14–0.78, p < 0.05); T/T SNV rs_7216389 ORMDL3: rs = 0.246, OR = 3.21 (95% CI 1.57–6.59, p < 0.05). For the monoorganic BA phenotype: T/T SNV rs_7216389 ORMDL3: rs = 0.192, CI = 2.97 (95% CI 1.08–8.14, p < 0.05). For the polyorganic AD+AR/ARC phenotype: C/C SNV rs_7216389 ORMDL3: rs = 0.146, OR = 0.42 (95% CI 0.16–1.11, p = 0.05–0.1); T/T SNV rs_7216389 ­ORMDL3: rs = 0.265, OR = 3.64 (95% CI 1.62–8.18, p < 0.05). For the polyorganic BA+AR/ARC phenotype: C/C SNV rs_7216389 ORMDL3: rs = 0.163, OR = 0.42 (95% CI 0.19–0.93, p < 0.05); T/T SNV rs_7216389 ORMDL3: rs = 0.255, OR = 3.34 (95% CI 1.63–6.82, p < 0.01). The C/T SNV rs7216389 ORMDL3 genotype did not reveal significant associations or impact on the development of any AM phenotypes in children. Conclusions. The T-allele SNV rs7216389 ORMDL3 has an inductive impact on the development of AM in children — the homozygous T/T genotype of SNV rs7216389 ORMDL3 is significantly associated with and increases the risk of developing the monoorganic AR/ARC and BA phenotypes, as well as polyorganic AD+AR/ARC and BA+AR/ARC phenotypes. The C-allele SNV rs7216389 ORMDL3 has a protective impact on the development of AM in children — the homozygous genotype C/C of SNV rs7216389 ORMDL3 is significantly associated with and reduces the risk of developing the monoorganic AR/AR phenotype, as well as polyorganic AD+AR/AR and BA+AR/ARC phenotypes.

Respiratory allergen sources such as house dust mites frequently contain proteases. In this study, we demonstrated that the epicutaneous application of a model protease antigen, papain, onto intact or tape-stripped ear skin of mice induced acute scratching behaviors and T helper (Th)2, Th9, Th17/Th22, and/or Th1 sensitization in a protease activity–dependent manner. The protease activity of papain applied onto the skin was also essential for subsequent airway eosinophilia induced by an intranasal challenge with low-dose papain. With tape stripping, papain-treated mice showed barrier dysfunction, the accelerated onset of acute scratching behaviors, and attenuated Th17/Th22 sensitization. In contrast, the protease activity of inhaled papain partially or critically contributed to airway atopic march responses in mice sensitized through intact or tape-stripped skin, respectively. These results indicated that papain protease activity on epicutaneous application through intact skin or skin with mechanical barrier damage is critical to the sensitization phase responses, including acute itch and Th sensitization and progression to the airway atopic march, whereas dependency on the protease activity of inhaled papain in the atopic march differs by the condition of the sensitized skin area. This study suggests that exogenous protease-dependent epicutaneous mechanisms are a target for controlling allergic sensitization and progression to the atopic march.

Allergic diseases affect many people across the globe. They significantly impact on the quality of life of the people who are affected, creating personal and economic predicaments. Some of the most commonly diagnosed allergic diseases include atopic dermatitis, rhinitis, allergic conjunctivitis and sinusitis. Allergic conjunctivitis is an allergic disease characterised by the inflammation of the conjunctiva caused by airborne allergens; it presents as itching, excessive lacrimation, discharge and pink eye. Usually it is associated with other allergic conditions such as allergic rhinitis and bronchial asthma. Allergic conjunctivitis is further divided into acute, seasonal allergic conjunctivitis (SAC), and perennial allergic conjunctivitis (PAC). Other conditions, such as eosinophilic oesophagitis, are on the rise and are being diagnosed across all continents except Africa. The diagnosis is primarily clinical. Antihistamines have been the mainstay of therapy for most allergic conditions, except for other conditions that require corticosteroids, or in severe allergic conditions such as anaphylaxis where antihistamines are ineffective as main therapy. It is important to consider first- versus second-generation options when treating allergic diseases, also bearing in mind the duration of therapy and any comorbid conditions that a patient might have. This article provides an overview of these conditions and their current management options. [ABSTRACT FROM AUTHOR]

Asthma is the most prevalent cause of chronic respiratory diseases. Herein, we evaluate the asthma burden in Mexico based on results from the Global Burden of Disease (GBD 2019) study 2019. Using data from the GBD 2019, we estimated asthma prevalence, incidence, mortality, and disability-adjusted lived years (DALYs) counts and crude and age-standardized rates per 100,000 people with a 95% uncertainty interval (UI) by sex and age at the national and subnational levels in Mexico from 1990 to 2019. At the national level, asthma affected 3.35 million (95% UI, 2.59–4.37) people, with 606.0 thousand (433.0–811.1) new incident cases and 1655 (3–1931) deaths during 2019. Asthma caused a slightly higher burden in females and affected mainly age groups between 1 and 14 years of age. The burden of asthma gradually decreased from 1990 to 2010. However, during the last decade (2010–2019), prevalence increased by 8.2%, as did incidence, by 11.3%, whereas mortality and DALYs decreased by 23.3 and 1.6%, respectively. Finally, the burden of asthma displayed a heterogeneous pattern of disease at the subnational level. In conclusion, asthma causes a significant health loss in Mexico that differentially affects the population distributed among the states of the country, thus causing health disparities that should be addressed to provide sustainable asthma diagnosis and control to reduce its burden, especially in the early stages of life. [ABSTRACT FROM AUTHOR]

Abstract Atopic dermatitis (AD) as a chronic inflammatory systemic condition is far more than skin deep. Co-morbidities such as asthma and allergic rhinitis as well as the psychological impact influence seriously the quality of life of the patients. Recent studies have shown that only 10% of atopic patients undergo full manifestation of the atopic march, while 40% demonstrate concomitant food allergy. Exposure to food allergens in the environment causes sensitization and food allergy through the disruption of the skin barrier, as in AD. Food allergy and AD are closely related. While not all AD patients have a food allergy, 20–40% of children with moderate to severe AD will have an IgE-mediated food allergy. It is known that they may coexist but it is unclear if food allergy worsens the course of AD. Experimental, clinical, and epidemiological studies have provided evidence of the primary role of an epidermal barrier defect in the development of sensitization to environmental allergens and that this process occurs in the damaged skin barrier rather than the gastrointestinal or respiratory tract. There is strong evidence for a connection between early AD onset and the development of other allergic diseases later in life.

Background: Eczema patients are commonly immunoglobulin (Ig)E polysensitized. Although atopic dermatitis (AD) phenotypes have been recognized, IgE sensitization patterns based on AD phenotypes have not been well illustrated. We aimed to investigate how eczema phenotypes impact IgE component sensitization patterns. Methods: This birth cohort study investigated a general population in the Tokyo Children's Health, Illness, and Development Study (T-Child Study) until children reached the age of 13 years. Eczema was assessed using the International Study of Asthma and Allergies in Childhood (ISAAC) questionnaire. Allergen component specific IgE antibody titers were measured using a multiplex array ImmunoCAP ISAC. Results: Persistent eczema phenotype until adolescence was strongly associated with allergic march symptoms, such as wheezing and hay fever, and oral allergy symptoms, and IgE component sensitizations of airborne (Japanese cedar, house dust mite, Timothy, cat, and dog) and cross-reactive allergens (Bet v 1 family) compared to early-remission and late-onset eczema. On the other hand, late-onset eczema did not show any strong associations with allergic symptoms and IgE sensitization. Adolescents with persistent eczema have high comorbidity of symptoms of pollen-food allergy syndrome. Conclusions: Early-onset eczema is deeply connected with the later allergic march, and late-onset eczema differs from the phenotype of allergic march. Early-onset eczema characterizing IgE sensitization was likely to be an extrinsic type, and late-onset eczema, which was not related to IgE sensitization, was likely an intrinsic type. Pollen-Food Allergy Syndrome is one of the allergic features in allergic march.

Elena Araviiskaia,1 Carlo Pincelli,2 Adele Sparavigna,3 Thomas Luger4 1Department of Dermatology and Venereal Diseases, First Pavlov State Medical University of St Petersburg, St Petersburg, Russia; 2DermoLab, Department of Surgical, Medical, Dental and Morphological Sciences, University of Modena and Reggio Emilia, Modena, Italy; 3Derming Clinical Research and Bioengineering Institute, Milan, Italy; 4Department of Dermatology, University of Munster, Munster, GermanyCorrespondence: Thomas Luger, Dermatology Clinic, University of Münster, Von-Esmarch-Straẞe 58, Münster, 48149, Germany, Email luger@uni-muenster.deAbstract: Emollients are the mainstay maintenance treatment for atopic dermatitis (AD). A novel generation of emollients, ‘emollients plus’, containing active, non-medicated substances, has softened the distinction between emollients and topical drugs. A literature search for selected key words was performed using PubMed. Additional papers were identified based on author expertise. Whilst the inclusion of five components of an ideal emollient has been proposed, no such consensus exists for emollients plus and they can vary markedly in their composition and modes of action for AD treatment. This could have a profound effect on their clinical efficacy. The efficacy of emollients plus in restoring and maintaining skin barrier function has been demonstrated on multiple levels, with evidence reported for their effects on the physical and biochemical, microbial, immunological, and neurosensory barriers. When selecting an appropriate AD treatment approach, the safety profiles of the available topical therapies must be carefully considered. There are several proposed treatment approaches for AD, including preventive, proactive, intermittent, and synergistic approaches. Emollients plus may be effective not only as maintenance therapy for AD, but also when used synergistically with anti-inflammatory pharmacological therapies.Keywords: atopic dermatitis, atopic march, emollient, emollient plus, maintenance therapy, skin barrier

Atopic dermatitis (AD) is a multifactorial inflammatory skin disease. Its pathogenetic basis is epidermal barrier dysfunction, immune system dysregulation, as well as skin microbiome diversity decrease that occurs due to genetic predisposition. Considering these factors, the skin of patients with AD requires constant care and use of medications with active regenerative properties. The inclusion of anti-inflammatory components in the composition of modern emollients (zinc sulfate and sucralfate) is crucial for restoring the microbiome and immune mechanisms controlling the skin. This article presents data on pathogenetic applicability and clinical efficacy of emollients with anti-inflammatory compounds in patients with AD.

To investigate the effect of emollient on atopic march in a murine model of atopic dermatitis (AD). Following induction of AD with topical calcipotriol (MC903) and ovalbumin (OVA), one group of mice was treated topically with a linoleic acid‐ceramide‐containing emollient, while mice without emollient treatment served as disease controls. After 28 days, clinical, histological and transcriptomic analyses were performed in the skin lesions and the lung as well as serum cytokine levels. Treatments of mice with MC903 and OVA induced a typical phenotype of AD, accompanied by increased expression levels of Th2 and basophil‐related genes in the lung. Topical emollients markedly decreased the severity of skin lesions and inflammatory cell infiltration. Moreover, emollient treatments significantly downregulated expression levels of AD‐related genes (286 of 1450 differentially expressed genes), including those related to innate inflammation (S100a8/a9, Il1b, Defb3/6, Mmp12), chemokines (Cxcl1/3, Ccl3/4) and epidermal permeability barrier (Krt2/6b/80, Serpinb12, Lce3e, Sprr2), etc. Downregulated genes were enriched in mitochondrial OXPHOS‐related pathways, while upregulated genes were mainly enriched in axon guidance and tight junctions. Moreover, topical emollient treatments decreased total serum levels of IL‐4, along with substantial reductions in IgE and thymic stromal lymphopoietin (TSLP) levels. Furthermore, 187 of 275 upregulated genes in lung tissue were also significantly downregulated, including those involved in leucocyte chemotaxis (Ccl9, Ccr2, Retnlg, Ccl3, Cxcl10, Il1r2, etc.) and basophil activation (Mcpt8, Cd200r3, Fcer1a, Ms4a2). In conclusion, topical emollient not only reduces skin inflammation, but also mitigates systemic inflammation by decreasing TSLP and IgE levels. Moreover, topical emollient reduces chemokine production and basophil infiltration and activation in the lung. [ABSTRACT FROM AUTHOR]

Background: Eczema is the most common form of dermatitis and also the starting point of atopic march. Although many eczema‐associated allergic and immunologic disorders have been studied, there remains a gap in the systematic quantitative knowledge regarding the relationships between all childhood disorders and eczema. This study aimed to systematically explore eczema‐associated childhood diseases using a real‐world, long‐term clinical dataset generated from millions of children in China. Methods: Data were collected at 8,907,735 outpatient healthcare visits from 2,592,147 children between January 1, 2013, and August 15, 2019, at the largest comprehensive pediatric medical center in Zhejiang Province of China. The period prevalence differences in various pediatric diseases between children with and without eczema were used to test the independence of various pediatric disorders and eczema using Fisher's exact test. Bonferroni correction was used to adjust the p value in multiple testing. Odds ratio >2 with 95% confidence interval not including 1 and adjusted p < 0.05 was used to identify eczema‐associated diseases. Results: Overall, 234 pediatric disorders were identified from more than 6000 different pediatric disorders. An interactive eczema‐associated disease map that has related quantitative epidemiological features called ADmap was published at http://pedmap.nbscn.org/admap. Thirty‐six of these disease associations have not been reported in previous studies. Conclusion: This systematic exploratory study confirmed the associations of many well‐known diseases with eczema in Chinese children and also identified some novel and interesting associations. These results are valuable for the development of a comprehensive approach to the management of eczema in childhood. [ABSTRACT FROM AUTHOR]

Izabela Knyziak-M&eogon;drzycka,1,2 Monika Szychta,3 Emilia Majsiak,4 Andrzej M Fal,2,5,6 Zbigniew Doniec,7 Bo&zdot;ena Cukrowska8 1Allergy Clinic, Children’s Memorial Health Institute, Warsaw, Poland; 2The Department of Allergy, Pulmonary Diseases and Internal Medicine, Central Clinical Hospital of the Ministry of Interior and Administration in Warsaw, Warsaw, Poland; 3Department of Gastroenterology, Hepatology, Nutritional Disturbances and Pediatrics, Children’s Memorial Health Institute, Warsaw, Poland; 4Department of Health Promotion, Chair of Nursing Development, Faculty Health of Sciences, Medical University of Lublin, Lublin, Poland; 5Collegium Medicum, Faculty of Medicine, Cardinal Stefan Wyszy&nacute;ski University, Warsaw, Poland; 6Department of Public Health, Wroclaw Medical University, Wroc&lstrok;aw, Poland; 7The Institute of Tuberculosis and Lung Diseases, Regional Branch in Rabka-Zdrój, Rabka-Zdrój, Poland; 8Department of Pathomorphology, Children’s Memorial Health Institute, Warsaw, PolandCorrespondence: Emilia Majsiak, Department of Health Promotion, Chair of Nursing Development, Faculty Health of Sciences, Medical University of Lublin, Staszica 4 m.6 (Collegium Maximum), Lublin, 20-081, Poland, Tel +48 81 448 6700, Fax +48 48 814 4867, Email emiliamajsiak@umlub.pl; wnoz@umlub.plAbstract: The case of a 9-month-old boy with an initial diagnosis of atopic dermatitis and confirmed allergy to hen’s egg, cow’s milk allergens with episodes of anaphylaxis who developed birch allergy whilst under observation with asthma symptoms was presented. The precision allergy molecular diagnosis (PAMD @) allowed for individualisation of dietary recommendations and observing the early progression of food sensitisation to the main birch molecule. The presented identification of major allergic molecules with PAMD@ in the preclinical phase of asthma contributes to the discussion related to early specific immunotherapy to suppress molecular spread and allergic march. However, more research is needed to verify this hypothesis.Graphical Abstract: Keywords: atopic march, allergy, anaphylaxis, sIgE, PAMD@, multiplex molecular tests

The atopic march was described more than 20 years ago on the basis of initial observations, and it is now seen in prospective studies. The concept has evolved and is now considered to be the progression of atopic dermatitis to other atopic conditions, including asthma, allergic rhinitis, food allergy, and eosinophilic esophagitis in a nonlinear fashion. The progression can include some or all of the aforementioned atopic conditions. The pathogenesis is part of the classic type 2 inflammatory process involving IL-4, IL-5, and IL-13 preceded by induction of the alarmins (thymic stromal lymphopoietin, IL-33, and IL-25), leading to production of IgE in a genetically predisposed individual. The development of new biologics that interact with T2 pathway represent possible ways to prevent or modify the atopic march. [ABSTRACT FROM AUTHOR]

[Display omitted] Atopic march refers to the sequential development of allergic diseases from infancy through adolescence, typically beginning with atopic dermatitis (AD), followed by food allergy and then airway diseases, later evolving to broader or worsened spectrum of allergic diatheses. No intervention has shown to alter its course. We sought to determine the rate of acquisition of new or worsened allergic events for dupilumab versus placebo in patients with AD. Allergy-associated events from 12 clinical trials were grouped into 17 allergy categories, and IgE changes from baseline were defined. A new/worsened event was considered one step of atopic march. Treatment effect was assessed by incidence rate ratios (IRRs), dupilumab versus placebo, by meta-analysis. The duration of pooled AD studies was 4 to 52 weeks (1359 patient-years; n = 2296 dupilumab, n = 1229 placebo, median age 35 years). The median age at AD onset was 2 years. Baseline allergic disease burden was comparable between groups. Dupilumab reduced the risk of new/worsening allergies by 34% (IRR 0.66; 95% confidence interval [CI], 0.52-0.84) and new allergies by 37% (IRR 0.63; 95% CI, 0.48-0.83) versus placebo. Including IgE category shift, the IRR for combined new/worsening allergies was reduced by 54% (IRR 0.46; 95% CI, 0.36-0.57). These treatment benefits did not reverse on treatment discontinuation in off-treatment follow-up. The acquisition/worsening of allergic conditions suggestive of atopic march was observed in a pooled adult/adolescent AD study population with inadequately controlled AD. Treatment with dupilumab reduced new/worsened allergy events versus placebo; inclusion of IgE category change increased the apparent benefit. [ABSTRACT FROM AUTHOR]

Understanding the atopic march hypothesis is important for the clinical manifestation of allergic diseases, since it determines the prognosis of whether people with early symptoms of atopy will follow the traditional atopic march. Currently, there is substantial evidence of the presence of the atopic march, but its prevalence may be exaggerated. The legitimacy of the atopic march as a model for the formation of atopic diseases is currently being discussed. Atopic dermatitis reaches its peak in early childhood, opening the door for the subsequent development of the atopic march. It is practically significant to establish risk factors that determine the start of the atopic march: early onset of atopic dermatitis, severity, persistence of the disease, presence of FLG mutation, polysensitization, atopy on the part of parents. The analysis of prospective studies of patients with atopic march from infancy to adulthood is valuable, which will allow us to develop specific programs for the timely prevention of the implementation of severe allergic diseases. The article presents a case from pediatric practice with early symptoms of atopy and the implementation of the atopic march in a 15-year-old patient. The clinical case demonstrates early symptoms and consistent development of atopic diseases: food allergy, atopic dermatitis, bronchial asthma, allergic rhinitis with the addition of allergic conjunctivitis, progressive severity of diseases, against the background of polyvalent sensitization and hereditary burden of allergic diseases. Thus, the clinical example of a 15-year-old patient demonstrates that the atopic march is a reality. On the example of a clinical case, several important factors were identified that increase the risk of developing other allergic diseases: earlier, the onset of symptoms of atopy – food allergy, then the consistent development of diseases of atopic dermatitis, bronchial asthma, allergic rhinitis, against the background of emerging polyvalent sensitization to allergens and hereditary burden of allergic diseases. This example showed that the atopic march can be realized due to sensitization through an early broken barrier of atopic dermatitis, due to common possibly genetic and environmental factors.

In the present study, a subject of atopic dermatitis (AD) is exposed progressively to allergic rhinitis (AR) and asthma (AS), which is defined as atopic march (AM). However, both the targets and compounds against AM are still largely unknown. Hence, we investigated the overlapping targets related directly to the occurrence and development of AD, AR, and AS through public databases (DisGeNET, and OMIM). The final overlapping targets were considered as key targets of AM, which were visualized by a Venn diagram. The protein–protein interaction (PPI) network was constructed using R package software. We retrieved the association between targets and ligands via scientific journals, and the ligands were filtered by physicochemical properties. Lastly, we performed a molecular docking test (MDT) to identify the significant ligand on each target. A total of 229 overlapping targets were considered as AM causal elements, and 210 out of them were interconnected with each other. We adopted 65 targets representing the top 30% highest in degree centrality among 210 targets. Then, we obtained 20 targets representing the top 30% greatest in betweenness centrality among 65 targets. The network analysis unveiled key targets against AM, and the MDT confirmed the affinity between significant compounds and targets. In this study, we described the significance of the eight uppermost targets (CCL2, CTLA4, CXCL8, ICAM1, IL10, IL17A, IL1B, and IL2) and eight ligands (Bindarit, CTLA-4 inhibitor, Danirixin, A-205804, AX-24 HCl, Y-320, T-5224, and Apilimod) against AM, providing a scientific basis for further experiments.

The atopic march encompasses a sequence of allergic conditions, including atopic dermatitis, food allergy, allergic rhinitis, and asthma, that frequently develop in a sequential pattern within the same individual. It was introduced as a conceptual framework aimed at elucidating the developmental trajectory of allergic conditions during childhood. Following the introduction of this concept, it was initially believed that the atopic march represented the sole and definitive trajectory of the development of allergic diseases. However, this perspective evolved with the emergence of new longitudinal studies, which revealed that the evolution of allergic diseases is far more intricate. It involves numerous immunological pathological mechanisms and may not align entirely with the traditional concept of the atopic march. The objective of our review is to portray the atopic march alongside other patterns in the development of childhood allergic diseases, with a specific emphasis on the potential for a personalized approach to the prevention, diagnosis, and treatment of atopic conditions.

Introduction: The progression of allergy disorders is termed “atopic march.” Having one allergic disorder increases the likelihood of acquiring others. Asthma and food allergies often coexist. There are no thresholds for specific IgE (sIgE) associated with the presence of clinical symptoms. Each allergen shows a particular trend with age. Objective: Our study and analysis aim to identify food sensitization in children with asthma and evaluate its impact on asthma attacks and clinical control. Material and methods: As a part of a bigger study, 56 children (mean age 11.07 years (5.3–17.5), 38 boys, and 18 girls) with bronchial asthma were tested for total IgE and sIgE against food and inhalator allergens. All children performed baseline and post-BD spirometry and were assessed for asthma control. Results: In the studied population of children, sIgE against several food allergens was positive in the same patient. A significant correlation was found between the positive sIgE for milk and soy (p < 0.0001), for milk and egg yolk (p = 0.01), compared to milk and peanuts (p = 0.004), compared to egg yolk and fish (p < 0.0001), compared to egg yolk and casein (p < 0.001), and soy (p < 0.0001). The children who are positive for sIgE antibodies in cats, dogs, Cladosporium, Aspergillus, wormwood from aeroallergens and soy from food allergens have a higher risk of hospitalization for exacerbation of bronchial asthma. (p < 0.05). In the studied population, sensitization to food allergens among asthmatics does not contribute to the number of asthma attacks. Conclusions: Food sensitivity is associated with eczema, while mite sensitization is strongly associated with rhinitis and asthma. Food sensitization is not a risk factor for asthma exacerbation in children older than five years old.

Allergic diseases consist of improper inflammatory reactions to antigens and are currently an important healthcare concern, especially considering their increasing worldwide development in recent decades. The "atopic march" defines the paradigm of allergic diseases occurring in chronological order and displaying specific spatial manifestations, as they usually start as atopic dermatitis (AD) and food allergies during infancy and progressively evolve into allergic asthma (AA) and allergic rhinitis (AR) or rhino-conjunctivitis in childhood. Many immune cell subtypes and inflammatory factors are involved in these hypersensitivity reactions. In particular, the T helpers 2 (Th2) subset, through its cytokine signatures made of interleukins (ILs), such as IL-4, IL-5, IL-10, and IL-13, as well as mast cells and their related histamine pathways, contribute greatly to the perpetuation and evolution of the atopic march. By providing low doses (LD) and ultra-low doses (ULD) of ILs and immune factors to the body, micro-immunotherapy (MI) constitutes an interesting therapeutic strategy for the management of the atopic march and its symptoms. One of the aims of this review is to shed light on the current concept of the atopic march and the underlying immune reactions occurring during the IgE-mediated responses. Moreover, the different classes of traditional and innovative treatments employed in allergic diseases will also be discussed, with a special emphasis on the potential benefits of the MI medicine 2LALERG® formulation in this context. [ABSTRACT FROM AUTHOR]

In the past 2 years, there continue to be advances in our understanding of the genetic and epigenetic underpinnings of atopy pertaining to disease risk and disease severity. The joint role of genetics and the environment has been emphasized in multiple studies. Combining genetics with family history, biomarkers, and comorbidities is further refining our ability to predict the development of individual atopic diseases as well as the advancement of the atopic march. Polygenic risk scores will be an important next step for the field moving toward clinical translation of the genetic findings thus far. A systems biology approach, as illustrated by studies of the microbiome and epigenome, will be necessary to fully understand disease development and to develop increasingly targeted therapeutics. [ABSTRACT FROM AUTHOR]

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Antibiotic use during pregnancy may increase the risk for asthma in children. We performed a meta‐analysis assessing prenatal antibiotic exposure and the risk for childhood wheeze or asthma, as well as for diseases associated with the atopic march. A systematic literature search protocol (PROSPERO‐ID: CRD42020191940) was registered and searches were completed using Medline, Proquest, Embase, and the Cochrane central register of controlled trials. Screening for inclusion criteria: published in English, German, French, Dutch, or Arabic, intervention (use of any antibiotic at any time point during pregnancy), and disease (reporting atopic disease incidence in children with a primary outcome of asthma or wheeze), and exclusion criteria: reviews, preclinical data, and descriptive studies, yielded 27 studies. Study quality was assessed using the Newcastle–Ottawa Assessment Scale. Quality of the evidence was assessed using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach. Our meta‐analysis demonstrates that antibiotic use during pregnancy is associated with an increased relative risk (RR) of developing wheeze RR 1.51 (95% CI: 1.17–1.94) or asthma RR 1.28 (95% CI 1.22–1.34) during childhood. Assessment of the atopic march in association with asthma or wheeze revealed that antibiotic use during pregnancy also increases the risk for eczema/dermatitis RR 1.28 (95% CI: 1.06–1.53) and allergic rhinitis RR 1.13 (95% CI: 1.02–1.25). One study found an increase in food allergy RR 1.81 (95% CI: 1.11–2.95). Maternal antibiotic use during pregnancy is associated with an increased risk for wheeze or asthma development in children, as well as for diseases involved in the atopic march. There was high heterogeneity in the data, and the certainty of the evidence was determined to be low quality, highlighting the need for more high‐quality studies on this topic. These results have importance for antibiotic stewardship throughout the prenatal period. This work was supported by the Deutsche Forschungsgemeinschaft and the Konrad Adenauer Foundation. [ABSTRACT FROM AUTHOR]

Abstract Atopic diseases are multifactorial chronic disturbances which may evolve one into another and have overlapping pathogenetic mechanisms. Atopic dermatitis is in most cases the first step towards the development of the atopic march and represents a major socio-economic burden in the industrialized countries. The treatment of atopic diseases is often long-lasting and in some cases with lower effectiveness than expected. In order to prevent the development of the atopic march, the links between the atopic diseases have to be understood. The aim of this review is to present some major points outlining the link between atopic dermatitis and asthma, through a research in the medical literature from recent years. Stratifying patient populations according to the clinical phenotype of their disease and according to specific measurable values (biomarkers) can help to establish the main etiopathogenetic mechanisms of the disease in these populations. This will add predictive value for the evolution of the disease, and will allow the use and research of more targeted therapy in order to stop this evolution and comorbidities.

IntroductionAllergic diseases are a global public health problem. Food allergy, atopic dermatitis (AD), allergic rhinoconjunctivitis, allergic rhinitis (AR) and asthma represent the natural course of allergic diseases, also known as the “atopic march”. In recent years, a large number of studies have been published on the association between greenness exposure and allergic diseases. However, systematic reviews on the association between greenness exposure and multiple allergic diseases or atopic march are lacking.MethodsIn this study, PubMed, EMBASE, ISI Web of Science, and Scopus were systematically searched. Meta-analyses were performed if at least three studies reported risk estimates for the same outcome and exposure measures.ResultsOf 2355 records, 48 studies were included for qualitative review. Five birth cohort studies, five cross-sectional studies, and one case-control study were included for asthma meta-analysis, respectively. Four birth cohort studies were included for AR meta-analysis. Our results support that exposure to a greener environment at birth reduces the risk of asthma and AR in childhood. In addition, higher greenness exposure was associated with decreased odds of current asthma in children.DiscussionThere was a large heterogeneity among the included studies and most of them did not specify the vegetation type and causative allergens. Therefore the study results need to be further validated. In addition, a small number of studies evaluated the association between greenness and food allergy, AD and allergic rhinoconjunctivitis. More research is needed to strengthen our understanding of the association between greenness and allergic diseases.

Rationale: The relationship between eczema, wheeze or asthma, and rhinitis is complex, and epidemiology and mechanisms of their comorbidities is unclear. Objectives: To investigate within-individual patterns of morbidity of eczema, wheeze, and rhinitis from birth to adolescence/early adulthood. Methods: We investigated onset, progression, and resolution of eczema, wheeze, and rhinitis using descriptive statistics, sequence mining, and latent Markov modeling in four population-based birth cohorts. We used logistic regression to ascertain if early-life eczema or wheeze, or genetic factors (filaggrin [FLG] mutations and 17q21 variants), increase the risk of multimorbidity. Measurements and Main Results: Single conditions, although the most prevalent, were observed significantly less frequently than by chance. There was considerable variation in the timing of onset/remission/persistence/intermittence. Multimorbidity of eczema+wheeze+rhinitis was rare but significantly overrepresented (three to six times more often than by chance). Although infantile eczema was associated with subsequent multimorbidity, most children with eczema (75.4%) did not progress to any multimorbidity pattern. FLG mutations and rs7216389 were not associated with persistence of eczema/wheeze as single conditions, but both increased the risk of multimorbidity (FLG by 2- to 3-fold, rs7216389 risk variant by 1.4- to 1.7-fold). Latent Markov modeling revealed five latent states (no disease/low risk, mainly eczema, mainly wheeze, mainly rhinitis, multimorbidity). The most likely transition to multimorbidity was from eczema state (0.21). However, although this was one of the highest transition probabilities, only one-fifth of those with eczema transitioned to multimorbidity. Conclusions: Atopic diseases fit a multimorbidity framework, with no evidence for sequential atopic march progression. The highest transition to multimorbidity was from eczema, but most children with eczema (more than three-quarters) had no comorbidities. [ABSTRACT FROM AUTHOR]

Starting from the "Hygiene Hypothesis" to the "Microflora hypothesis" we provided an overview of the symbiotic and dynamic equilibrium between microbiota and the immune system, focusing on the role of dysbiosis in atopic march, particularly on allergic rhinitis. The advent of deep sequencing technologies and metabolomics allowed us to better characterize the microbiota diversity between individuals and body sites. Each body site, with its own specific environmental niches, shapes the microbiota conditioning colonization and its metabolic functionalities. The analysis of the metabolic pathways provides a mechanistic explanation of the remote mode of communication with systems, organs, and microflora of other body sites, including the ecosystem of the upper respiratory tract. This axis may have a role in the development of respiratory allergic disease. Notably, the microbiota is significant in the development and maintenance of barrier function; influences hematopoiesis and innate immunity; and shows its critical roles in Th1, Th2, and Treg production, which are necessary to maintain immunological balance and promote tolerance, taking part in every single step of the inflammatory cascade. These are microbial biotherapy foundations, starting from probiotics up to postbiotics and parabiotics, in a still-ongoing process. When considering the various determinants that can shape microbiota, there are several factors to consider: genetic factors, environment, mode of delivery, exposure to antibiotics, and other allergy-unrelated diseases. These factors hinder the engraftment of probiotic strains but may be upgradable with postbiotic and parabiotic administration directly on molecular targets. Supplementation with postbiotics and parabiotics could represent a very exciting perspective of treatment, bypassing probiotic limitations. At present, this avenue remains theoretical and to be explored, but it will certainly be a fascinating path to follow. [ABSTRACT FROM AUTHOR]

Atopic eczema is the most common chronic inflammatory skin disease of early childhood and is often the first manifestation of atopic march. Therefore, one challenge is to identify the risk factors associated with atopic eczema that may also be predictors of atopic disease progression. The aim of this study was to investigate the association of SNPs in hornerin (HRNR) and filaggrin-2 (FLG2) genes with childhood atopic eczema, as well as other atopic phenotypes. Genotyping for HRNR and FLG2 was performed in 188 children younger than 2 years of age, previously screened for the FLG null mutations, and followed at yearly intervals until the age of 6. We demonstrated that risk variants of HRNR rs877776[C] and FLG2 rs12568784[T] were associated with atopic eczema, allergic sensitization, and susceptibility to the complex phenotype—asthma plus eczema. These effects seem to be supplementary to the well-known associations for FLG mutations and may be modulated by gene–gene interactions. Additionally, in children with eczema, these genetic variants may also be considered, along with FLG mutations, as predictive biomarkers for eczema-associated asthma. In conclusion, our results indicate that genetic variants in the epidermal differentiation complex gene could contribute to the pathogenesis of atopic eczema and progression to subsequent allergic disease. [ABSTRACT FROM AUTHOR]

Atopic dermatitis (AD) in early childhood often precedes the development of food sensitization and allergy, but the role of treating AD to prevent food allergy remains poorly understood. Our objective was to assess the relationship between facial dermatitis and food sensitization to cow's milk, egg whites, and peanuts in early childhood, as aggressive treatment of facial dermatitis could serve as a potential opportunity for food sensitization prevention. By 3 years of age, food sensitization levels to cow's milk, egg whites, and peanuts were 48% greater in children with facial AD than in children with no facial involvement of their AD. Additional research is needed to determine if facial involvement of AD in infants and young children is associated with increased food allergy. [ABSTRACT FROM AUTHOR]

BackgroundAsthma is one of the most common chronic diseases in children globally. In recent decades, advances have been made in understanding the mechanism, diagnosis, treatment and management for childhood asthma, but few studies have explored its knowledge structure and future interests comprehensively.ObjectiveThis scientometric study aims to understand the research status and emerging trends of childhood asthma.MethodsCiteSpace (version 5.8.R3) was used to demonstrate national and institutional collaborations in childhood asthma, analyze research subjects and journal distribution, review research keywords and their clusters, as well as detect research bursts.ResultsA total of 14,340 publications related to childhood asthma were extracted from Web of Science (core database) during January 2011 to December 2021. The results showed that academic activities of childhood asthma had increased steadily in the last decade. Most of the research was conducted by developed countries while China, as a developing country, was also actively engaged in this field. In addition to subjects of allergy and immunology, both public health aspects and ecological environmental impacts on the disease were emphasized recently in this research field. Keywords clustering analysis indicated that research on asthma management and atopy was constantly updated and became the two major research focuses recently, as a significant shift in research hotspots from etiology and diagnosis to atopic march and asthma management was identified. Subgroup analysis for childhood asthma management and atopy suggested that caregiver- or physician-based education and interventions were emerging directions for asthma management, and that asthma should be carefully studied in the context of atopy, together with other allergic diseases.ConclusionsThis study presented a comprehensive and systematic overview of the research status of childhood asthma, provided clues to future research directions, and highlighted two significant research trends of asthma management and atopy in this field.

Atopic diseases remain one of the most common childhood diseases. At the beginning of life, atopic dermatitis (AD) occurs, and only then bronchial asthma (BA). This staged development of sensitization and transformation of clinical manifestations is called the atopic march. Are the genetic factors of predisposition to AD the same for BA? There is still no definite answer to this question. Mutations in the filaggrin gene (FLG) are known to impair skin barrier function. Filaggrin is expressed not only in the skin, but also in the respiratory organs of the nasal mucosa, lungs, and bronchi. Filaggrin defects lead not only to disruption of the skin barrier, but also to an increase in the Th2 response and increased production of IgE, typical of bronchial asthma. Therefore, mutations in the FLG gene can be a risk factor for the development of not only AD, but also BA.The aim of this study was to compare the values of the association of mutations in the FLG gene with AD and BA in the Russian sample.Material and methods. Case-control study design. We used 265 blood samples from children. 4 mutations in the filaggrin gene were identified by real-time PCR. The association of mutations with disease was assessed by odds ratio.Results. We showed a strongly pronounced association of the deletion of 4 nucleotides (2282del4) with AD, but not with BA, although for patients with atopic BA the indicator of the association of this mutation with the disease was higher than for the group with symptoms of bronchial asthma identified by the ISAAC questionnaire. These results lead to the conclusion that the role of the filaggrin gene for BA is much less significant than for AD.