Phenotypes and Natural Course of Atopic Dermatitis: A pathway to the Atopic March

Phenotypes and Natural Course of Atopic Dermatitis: A pathway to the Atopic March | Authorea try { document.documentElement.classList.add('js'); } catch (e) { } var _gaq = _gaq || []; _gaq.push(['_setAccount', 'G-8VDV14Y67G']); _gaq.push(['_trackPageview']); (function() { var ga = document.createElement('script'); ga.type = 'text/javascript'; ga.async = true; ga.src = ('https:' == document.location.protocol ? 'https://ssl' : 'http://www') + '.google-analytics.com/ga.js'; var s = document.getElementsByTagName('script')[0]; s.parentNode.insertBefore(ga, s); })(); Skip to main content Preprints Collections Wiley Open Research IET Open Research Ecological Society of Japan All Collections About About Authorea FAQs Contact Us Quick Search anywhere Search for preprint articles, keywords, etc. Search Search ADVANCED SEARCH SCROLL This is a preprint and has not been peer reviewed. Data may be preliminary. 8 July 2025 V1 Latest version Share on Phenotypes and Natural Course of Atopic Dermatitis: A pathway to the Atopic March Authors : Cagla Karavaizoglu 0009-0005-3898-4767 [email protected] , Kazım Okan Dolu , Ayse Suleyman 0000-0002-9190-6849 , Esra Yucel 0000-0003-3712-2522 , Esra Altıntaş , Zeynep Hızlı Demirkale , Sevgi Sipahi Cimen 0000-0003-3026-0906 , Cevdet Ozdemir 0000-0002-9284-4520 , and Zeynep Tamay Authors Info & Affiliations https://doi.org/10.22541/au.175196049.94173477/v1 Published International Archives of Allergy and Immunology Version of record Peer review timeline 300 views 141 downloads Contents Abstract Information & Authors Metrics & Citations View Options References Figures Tables Media Share Abstract Background Atopic dermatitis (AD) is a chronic inflammatory skin disorder that may progress to asthma and/or allergic rhinitis (AR) in children, a progression known as the ”atopic march.” This study aimed to evaluate the natural history of AD, its clinical phenotypes, and the risk of progression to atopic march over a 10-year period. Methods A retrospective review of medical records was performed for children diagnosed with AD and those with respiratory allergies who had prior AD. Patients were categorized into early transient, early persistent, and late-onset phenotypes based on eczema onset age and disease course. Disease progression, atopic march development, and related risk factors were analyzed Results The study included 894 children (375 females, 519 males) with a mean presentation age of 3.54 ± 3.31 years and mean follow-up of 3.65 ± 2.84 years. Based on clinical phenotypes, 61% (n=545) were early transient, 15.2% (n=136) early persistent, and 23.8% (n=213) late-onset. Asthma and AR rates were 8.6–11.2% in early transient, 14.0–22.8% in early persistent, and 16.0–24.9% in late-onset phenotypes respectively. Overall, 29.9% (n=267) exhibited the atopic march; 56.3% (n=503) were in remission and 43.7% (n=391) had persistent AD. Aeroallergen sensitization was significantly associated with persistent disease (p=0.016) and atopic march progression (p=0.001). Family history of atopy correlated with disease persistence (p=0.033) Conclusion Nearly one-third of children with AD are at risk of developing additional allergic diseases constituting the atopic march. Children with AD who exhibit aeroallergen sensitization should be closely monitored for the development of respiratory allergies. Phenotypes and Natural Course of Atopic Dermatitis: A pathway to the Atopic March 1 Dr. Çağla Karavaizoğlu, 1 Dr. Kazım Okan Dolu, 1 Dr. Ayşe Süleyman, 1 Dr. Esra Yücel, 2 Dr. Esra Altıntaş, 1 Dr. Zeynep Hızlı Demirkale, 1 Dr. Sevgi Sipahi Çimen, 1,3 Dr. Cevdet Özdemir, 1 Dr. Zeynep Ülker Altınel 1Division of Pediatric Allergy and Immunology, Department of Pediatrics, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey 2 Department of Child Health and Diseases Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey 3Institute of Child Health, Department of Pediatric Basic Sciences, Istanbul University, Istanbul, Turkey Background Atopic dermatitis (AD) is a chronic inflammatory skin disorder that may progress to asthma and/or allergic rhinitis (AR) in children, a progression known as the ”atopic march.” This study aimed to evaluate the natural history of AD, its clinical phenotypes, and the risk of progression to atopic march over a 10-year period. Methods A retrospective review of medical records was performed for children diagnosed with AD and those with respiratory allergies who had prior AD. Patients were categorized into early transient, early persistent, and late-onset phenotypes based on eczema onset age and disease course. Disease progression, atopic march development, and related risk factors were analyzed Results The study included 894 children (375 females, 519 males) with a mean presentation age of 3.54 ± 3.31 years and mean follow-up of 3.65 ± 2.84 years. Based on clinical phenotypes, 61% (n=545) were early transient, 15.2% (n=136) early persistent, and 23.8% (n=213) late-onset. Asthma and AR rates were 8.6–11.2% in early transient, 14.0–22.8% in early persistent, and 16.0–24.9% in late-onset phenotypes respectively. Overall, 29.9% (n=267) exhibited the atopic march; 56.3% (n=503) were in remission and 43.7% (n=391) had persistent AD. Aeroallergen sensitization was significantly associated with persistent disease (p=0.016) and atopic march progression (p=0.001). Family history of atopy correlated with disease persistence (p=0.033) Conclusion Nearly one-third of children with AD are at risk of developing additional allergic diseases constituting the atopic march. Children with AD who exhibit aeroallergen sensitization should be closely monitored for the development of respiratory allergies. Keywords; atopic dermatitis, atopic march, children, natural course, phenotype, risk factors Key Message Most children with atopic dermatitis (AD) experience disease onset within the first two years of life, with more than half achieving remission by the age of four. Nearly one-third of children with AD develop additional allergic diseases, demonstrating the classical atopic march. Aeroallergen sensitization and a family history of atopy are significant risk factors for persistent AD and progression to the atopic march. Close monitoring of children with AD who have aeroallergen sensitization may help in early detection and management of respiratory allergies. INTRODUCTION Atopic dermatitis (AD) is a common inflammatory allergic skin disease, characterized by chronic, recurrent, inflammatory, and eczematous lesions. Typical features of AD include dry and itchy skin, with lesions varying in localization depending on the patient’s age. The onset of lesions usually occurs in childhood, with a prevalence of 15–30% 1 . The increasing prevalence of AD has been attributed not only to genetic predisposition but also to environmental factors, emphasizing the role of gene-environment interactions 2 . In some children with AD, additional atopic diseases may develop over time, a phenomenon referred to as the atopic march. The atopic march typically begins with AD as the initial clinical manifestation and a common entry point into allergic diseases, often preceeding the development of food allergies (FA) during early childhood. Allergic rhinitis (AR) and asthma, which are closely associated with sensitization to inhaled allergens, generally tend to appear later in the atopic march, typically after the age of 3 3-5 . However, it has also been suggested that an innate predisposition, influenced by shared genetic loci or early exposure to environmental irritants, may contribute to the coexistence of allergic disorders independently of a sequental progression 6 . Some of children with AD improve as they get older. In an Asian birth-cohort study conducted in Singapore 253 children with a family history of atopic diseases were followed from the prenatal period up to 5 years. Eczema prevalence in children with onset before age 2 declined from 27% to 11.9% by age five, indicating a reduction in disease persistence over time. Besides, early-onset wheezing before age 2 increased the risk of asthma by age 5, while early-onset eczema and sensitization to house dust mites were associated with an increased risk of AR at age 5 3 . Food allergy has also been strongly linked to AD and is considered an early component of the atopic march 4 . A review of 13 cohorts studying the atopic march revealed that children with early food sensitization had an increased risk of wheezing/asthma and AR between the ages of 4-8 years 7 . It has been suggested that food sensitization may serve as a marker for AD severity and could represent an endotype associated with a high risk of additional atopic comorbidities 8 . Identifying risk factors for the disease may not only guide our understanding of its natural course but also aid in clinical management and monitoring. Effective management of AD has been proposed as a strategy to prevent or at least reduce the progression of the atopic march, potentially mitigating the development of asthma and AR 9 . Classifying AD into phenotypes may be instrumental in understanding its relationship with other atopic diseases, gaining insights into remission, and guiding appropriate treatment, preventive measures, and follow-up. This approach can also serve as a roadmap for managing eczema and potentially preventing the development of other atopic diseases. The aim of this study is to evaluate the natural course of AD, its different phenotypes, factors influencing its persistence, and the risk of atopic march in these children over a 10-year observation period. METHODS Study Group and Data Collection The medical records of patients diagnosed with AD and followed up at the outpatient clinic of the Division of Pediatric Immunology and Allergy, Istanbul Faculty of Medicine, Istanbul University, between January 2013 and September 2023 were retrospectively reviewed. Additionally, medical records of patients with respiratory diseases were also reviewed for a documented diagnosis of AD or a history of AD in infancy, within the same period. Patients who could not attend follow-up visits, or with an unclear history of AD were contacted by phone, and a survey was conducted to gather information about the course of the disease. Risk factors including mode of delivery, timing of birth, presence of seborrheic dermatitis, family history of asthma and/or AR, family history of AD, breastfeeding, introduction of solid foods, exposure to tobacco smoke during pregnancy or infancy were gathered from patient files. Laboratory test results including skin prick tests (SPT) for aeroallergens and for foods, serum specific IgE levels for foods, serum total IgE levels, and peripheral eosinophil values (as percentage) were obtained from the records. Hospitalizations due to severe AD flare-ups or colonization of Methicillin-resistant Staphylococcus aureus (MRSA) in nasal swab cultures taken from patients with moderate-to-severe AD were considered complications. Information on concomitant allergic diseases or the onset of new allergic diseases, including food allergy, asthma or wheezy episodes and allergic rhinitis, during follow-up, as well as the treatment regimens for these conditions, was obtained from the patients’ medical records Definitions The diagnosis of AD was made based on the Hanifin-Rajka clinical criteria 10 . Disease severity was assessed based on the extent of involvement observed during clinical examination and the treatment regimens administered during the follow-up. Patients were categorized as having mild, moderate, or severe AD. Patients with no visible eczematous lesions were categorized as ”No”. Those with eczema limited to a single anatomical region, such as the face, neck, or flexural areas, were defined as having mild disease (1+). Involvement of two distinct body regions (e.g., face and neck, or trunk and flexural areas) was defined as moderate disease (2+). Severe disease (3+) was assigned to patients with eczema affecting three or more anatomical regions, such as the face, neck, and trunk, or a combination of trunk, flexural, and extensor areas. Wheezy episodes were defined as asthma-like symptoms requiring emergency care and lasting more than 24 hours, or episodes resulting in hospitalization. Asthma diagnosis was based on a positive asthma predictive index (API) and/or clinical symptoms consistent with asthma (e.g., recurrent cough, wheezing), responsiveness to the asthma treatment, or reversible airway obstruction on pulmonary function test if the child can cooperate 11 . AR was defined as one or more symptoms, such as nasal congestion, nasal itching, sneezing, or serous nasal discharge, lasting for two or more consecutive days and often exceeding one hour in duration, unrelated to the common cold 12 . The atopic march is defined as a clinical progression typically beginning with atopic dermatitis in early childhood, followed by the subsequent development of asthma and/or allergic rhinitis symptoms, reflecting the natural course of allergic diseases 6 . Food allergy is considered as a reproducible adverse immune reaction triggered by a particular food. The diagnosis of IgE-mediated food allergy is based on a detailed allergy-focused clinical history supported by evidence of sensitization through SPT or specific IgE measurement. When results are inconclusive, an oral food challenge considered the gold standard may be required to confirm the diagnosis 13 . Children were categorized into three groups based on the age of AD lesion onset and disease progression during follow-up: (1) Early transient group- onset before 2 years of age with resolution by 4 years of age; (2) Early persistent group- onset before 2 years of age with symptoms persisting beyond 4 years of age; (3) Late-onset group-onset after 2 years of age. Remission was defined as the absence of symptoms for at least one year, while persistence was defined as ongoing skin symptoms requiring treatment at least once per month. Based on atopic status, children were also classified into subgroups: (1) non-atopic group- those with no sensitization on SPT, low serum IgE levels, low specific IgE levels. (2) Atopic group: those with any sensitization on SPT and/or high serum IgE levels (>200 IU/mL) and/or high specific IgE levels (>0.35 IU/mL). Statistical Analysis Statistical analyses were performed using the NCSS (Number Cruncher Statistical System) 2020 Statistical Software (NCSS LLC, Kaysville, Utah, USA). Descriptive statistical methods were used to evaluate the study data, with quantative variables presented as mean, standard deviation, median, minimum, and maximum values, and qualitative variables as frequencies and percentages. The Shapiro-Wilk test and box plot graphs were utilized to assess the normality of data distribution. For comparisons among three or more groups with normally distributed data, the one-way ANOVA test was applied, and the Bonferroni test was used to identify the specific groups causing the differences. For qualitative data comparisons, Pearson’s Chi-Square test and the Fisher-Freeman-Halton test were employed. Results were evaluated within a 95% confidence interval, with statistical significance set at p<0.05. To identify the factors affecting progression, univariable and multivariable linear regression analyses were performed. We received informed consent from the parents of the patients during phone interviews. Ethics The study protocol was approved by the Ethics Committee of Istanbul University, Istanbul Faculty of Medicine (No: 2023/1888). RESULTS A total of 894 children were included in the study, with 41.9% (n=375) being female and 58.1% (n=519) male. The age at presentation ranged from 0.8 to 17.3 years, with a mean of 3.54 ± 3.31 years (median: 2.5 years). The mean follow-up period of the children was 3.65±2.84 years. Among the children, 20.8% (n=186) had food allergy (FA), 11.2% (n=100) had bronchial asthma (BA), and 16.2% (n=145) had allergic rhinitis (AR). The atopic march was identified in 29.9% (n=267) of the children. Based on clinical phenotype classification, 61.0% (n=545) of children were categorized as early transient, 15.2% in the early persistent, and 23.8% (n=213) in the late onset. Hence, 76% (n=681) of children with AD had disease onset within the first two years of life, and 61% (n=595) experienced remission before the age of four. Characteristics and other features of children were presented in Table 1. At follow-up, 56.2% of children were in remission, while 43.8% had persistent AD (Table 1). Although univariable analysis showed a significant association between the disease persistence and food sensitization, food allergy, positive allergen SPT results, family history of atopy, family history of asthma/AR or AD and complications, multivariable analysis identified only positive allergen SPT results (p=0.016) and a family history of atopy (p=0.033) as significant risk factors. Children with positive SPT results had a 1.593-fold increased risk of persistent AD. Gender, disease extent on the onset of AD, mode of delivery, gestational age at birth, and age at lesion onset were not significantly associated with the persistence of the disease (p>0.05) (Table 2). When we evaluated the early onset, early persistent and late onset phenotypes, gender, age, and age at presentation significantly differed among the subgroups. The proportion of males was higher in all three groups, with the difference being statistically significant (p=0.023 and p<0.05, respectively). Male predominance was particularly notable in the early transient group. No significant differences were found among the groups in terms of delivery mode, gestational age, or presence of seborrheic dermatitis. Similarly, there were no significant group differences regarding family history of asthma, AR, AD, timing of solid food introduction, or exposure to tobacco smoke during pregnancy or infancy (p> 0.05). However, the proportion of children breastfed up to 24 months and those with ongoing breastfeeding was significantly higher in the early transient group compared to others (p=0.001 and p<0.01, respectively) (Table 3). AR was detected in 11.2% (n=61) of the early transient, 22.8% (n=31) of the early persistent, and 24.9% (n=53) of the late-onset group. Similarly, asthma was diagnosed in 8.6% (n=47), 14.0% (n=19), and 16.0% (n=34) of these respective groups. All three allergic comorbidities (wheezing, AR, and asthma) demonstrated statistically significant differences among the groups (p<0.01). No statistically significant difference was found in the persistence of AD among the phenotypes. (p=0.202) (Table 4). All children underwent SPT for food allergens. Of these, 74.8% (n=669) showed no sensitization, while 14.4% (n=129) were sensitized to hen’s egg, 5.1% (n=46) to cow’s milk, 1.5% (n=13) to other foods, and 4.1% (n=37) were polysensitized. Rates of food sensitization differed significantly between the early transient, early persistent and late onset groups (p=0.001). No statistically significant association was found between the disease severity at onset and either clinical progression or sensitization status. However, statistically significant differences in the disease severity on onset were observed between clinical phenotype groups (p=0.037) (Table 5). SPTs with aeroallergens was performed in 599 children. Sensitization rates were as follows: 13.4% (n=80) to house dust mites, 2.5% (n=15) to grasses, 0.8% (n=5) to animal dander, 1.5% (n=9) to pollens, 7.7% (n=46) to other aeroallergens, and 22.4% (n=134) were polysensitized. In our study, the early transient group had a higher prevalence of both food allergy history and food sensitization (via SPT) than the early persistent and late-onset groups. This difference was statistically significant for both hen’s egg sensitization and for multiple food sensitizations (Table 5). However, among children exhibiting atopic march, neither food allergy nor food sensitization differed significantly (p> 0.05). The age at presentation to the outpatient clinic and the rate of preterm birth were found to be statistically significantly higher in children who developed atopic march compared to those who did not (p=0.001 and p=0.005, respectively). However, gender, mode of delivery, presence of seborrheic dermatitis, family history of atopy, asthma/allergic rhinitis, and atopic dermatitis did not show a statistically significant difference (Table 6). In cases with atopic march, the rate of positive SPT results was found to be statistically significantly higher than in those without atopic march (p=0.001). However, food sensitization and food allergies did not show a statistically significant difference between the groups (Table 6). In terms of treatment patterns, the early transient group had significantly lower rates of inhaled corticosteroids, antihistamines, montelukast, and allergen specific immunotherapy usage compared to the early persistent and late onset groups. However, no significant differences were observed between the groups for topical treatments, including topical corticosteroids, calcineurin inhibitors, and emollients (p>0.05). Due to the presence of extreme outliers in eosinophil counts and total IgE levels, logarithmic transformation was applied prior to analysis. Following transformation, eosinophil and IgE levels differed significantly between the groups. Both the early transient and early persistent groups had significantly higher eosinophil levels compared to the late onset group (p=0.009). Early transients had significantly lower total IgE levels compared to the earlypersistents and late onsets (p=0.001). DISCUSSION In this study we observed that nearly 76% of children with AD had a disease onset within the first 2 years of life, and more than half experienced remission before the age of 4, which is compatible with previous reports 14,15 . We also found that 56.2% of children were in remission, and 43.8% had persistent AD. However, in a study conducted in Republic of Korea, children were found to be in complete remission in 70.6% of cases, in the persistent group in 4.4%, while 25% of the children did not fit into either of these categories 16 . The long-term course of AD remains unclear, with studies reporting conflicting outcomes 17 . This may be attributed to variations in genetic and epigenetic factors, as well as environmental exposures across different regions and countries. Younger age of onset, family history of atopy, greater AD severity, filaggrin gene (FLG) mutations, urban environment and polysensitization and/or allergic multimorbidity have been suggested as risk factors for the persistence of AD 18 . In our study, family history of atopy and positive allergy skin test results was associated with the disease persistence. This may reflect the influence of allergic sensitization and some genetic risk factors on the natural course of AD. In our study, the atopic march was observed in 29.9% of cases. A systematic review of 9 eczema cohort studies found that children with AD had a 29.5% risk of developing asthma by the age of 6 years, which is compatible with our results 19 . Additionaly, a recent study from United Kingdom, which included two population based-birth cohorts, identified 8 latent classes using Bayesian machine learning methods. Among children with allergic symptoms, approximately 6.4% exhibited the classical atopic march pattern, while 5.5% had persistent AD accompanied by wheeze, and 9.6% had persistent AD with later onset AR, resulting in a total of 21.5% of children with AD having coexisting respiratory allergies 20 . The coexistence of AD and respiratory allergies represents a sequential progression as described in the atopic march or independent coexisting allergic conditions. Nonetheless, it is important to note that approximately one-third of children with AD may experience wheezing or go on to develop respiratory allergies later in life. We classified our study group into early transient, persistent, and late onset groups, using the same classification system defined by the PASTURE birth cohort study, based on the onset and course of AD 21 . Our frequency rates of clinical phenotypes were similar to those reported in the PASTURE study for the late-onset group (23.8% vs. 23%, respectively); higher for the early transient group (61% vs. 45%); and lower for the early persistent group (15.8% vs. 32%) compared to the PASTURE study 21 . Moreover, in our study, age and the disease severity at the time of presentation to the outpatient clinic was significantly higher in the early transient group compared to the late-onset group (p=0.001 and p=0.037, respectivey). This is expected, as more severe symptoms in the child may prompt families to seek medical attention earlier. We found that asthma and AR were significantly more frequent in the late-onset group compared to early onset of phenotypes (p=0.008, p=0.001, respectively). However, in the PASTURE study, children with the early persistent phenotype had an asthma prevalence of 17.5%, which was significantly higher than the other phenotypes 21 . This discrepancy may be attributed to our retrospective evaluation of allergic children with respiratory allergies who have AD and/or a history of AD. We observed that both a history of food allergy and food sensitization, especially with egg and polysensitization detected by SPT were more common in the early transient group compared to the early persistent and late onset groups. This may suggest that although the skin can serve as an initial entry point for food allergens in children with AD, leading to transient food sensitization, there may be alternative trajectories of the atopic march beyond food sensitization and food allergy. Detection of higher eosinophil levels in the early transient and early persistent group compared to late onset group may be due to Th2 predominancy in early childhood, beginning from the newborn period. Conversely, lower IgE levels in the early transient group, which is another pathway of atopy, may reflect a weak and transient sensitization, influenced by environmental factors. We identified positive allergen sensitization as a risk factor for the atopic march. The prevalence of AR and asthma was lower in children without any allergen sensitization. Additionally, atopy also was a risk factor for the progression to atopic march In the ORCA cohort, the presence of polysensitization, greater disease severity, and a family history of asthma were identified as risk factors for the development of asthma later in life among children with early-onset AD 22 . These findings may reflect that the Th2 allergic endotype of AD is part of the trajectory of the atopic march. We also found that a history of preterm birth was significantly more frequent in children with atopic march. Given that prematurity is an established risk factor for childhood asthma, its presence in the context of the atopic march may represent a coincidental rather than a causal relationship 23 . A limitation of our study is its retrospective design, which precluded the availability of SCORAD scores that would have enabled a consistent assessment of disease severity. Additionally, there may be some selection bias related to children with respiratory allergies who have a history of atopic dermatitis. In conclusion, our study demonstrated nearly majority of children with AD had experienced disease onset within the first two years of life, and more than half showed resolution of the condition before the age of four. Neverthless, approximately one in three children with AD went on to develop atopic march. Children with atopic dermatitis who exhibit aeroallergen sensitization should be closely monitored for the development of respiratory allergies. Author Contrıbutıons Çağla Karavaizoğlu conceptualization (lead); writing original draft (lead); formal analysis (lead); and writing review and editing (equal), Kazım Okan Dolu conceptualization (supporting); writing original draft (supporting); formal analysis (lead) and writing – review and editing (equal), Ayşe Süleyman, Esra Yücel, Zeynep Hızlı Demirkale, Esra Altıntaş and Sevgi Sipahi Çimen conceptualization (supporting); writing original draft (supporting); and writing review and editing (equal), Cevdet Özdemir drafted and revised the manuscript, Zeynep Ülker Altınel: conceptualization (equal); writing – original draft (equal); and writing, review and editing (equal). Conflıct Of Interest None. Funding Sources There is no funding. Acknowledgements There is no acknowledgement. REFERENCES 1. Raimondo A, Lembo S. Atopic dermatitis: epidemiology and clinical phenotypes. Dermatol Pract Concept. 2021 Oct 29;e2021146. 2. Celebi Sozener Z, Ozdel Ozturk B, Cerci P, Turk M, Gorgulu Akin B, Akdis M et all. Epithelial barrier hypothesis: Effect of the external exposome on the microbiome and epithelial barriers in allergic disease. Allergy. 2022 May;77(5):1418-14493. 3. Quah PL, Loo EXL, Lee GNLY, Kuo IC, Gerez I, Llanora GV, et al. Clinical phenotype and allergen sensitization in the first 2 years as predictors of atopic disorders at age 5 years. World Allergy Organization Journal. 2015;8:33. 4. Hill DA, Grundmeier RW, Ram G, Spergel JM. The epidemiologic characteristics of healthcare provider-diagnosed eczema, asthma, allergic rhinitis, and food allergy in children: a retrospective cohort study. BMC Pediatr. 2016 Dec 20;16(1):133. 5. Schoos AM. Atopic diseases-Diagnostics, mechanisms, and exposures. Pediatr Allergy Immunol. 2024 Jul;35(7):e14198 6. Paller AS, Spergel JM, Mina-Osorio P, Irvine AD. The atopic march and atopic multimorbidity: Many trajectories, many pathways. Journal of Allergy and Clinical Immunology. 2019 Jan;143(1):46–55. 7. Alduraywish SA, Lodge CJ, Campbell B, Allen KJ, Erbas B, Lowe AJ, et al. The march from early life food sensitization to allergic disease: a systematic review and meta‐analyses of birth cohort studies. Allergy. 2016 Jan 4;71(1):77–89. 8. Tsakok T, Marrs T, Mohsin M, Baron S, du Toit G, Till S, et al. Does atopic dermatitis cause food allergy? A systematic review. Journal of Allergy and Clinical Immunology. 2016 Apr;137(4):1071–8. 9. Pinart M, Benet M, Annesi-Maesano I, von Berg A, Berdel D, Carlsen KCL, et al. Comorbidity of eczema, rhinitis, and asthma in IgE-sensitised and non-IgE-sensitised children in MeDALL: a population-based cohort study. Lancet Respir Med. 2014 Feb;2(2):131–40. 10. Rudzki E, Samochocki Z, Rebandel P, Saciuk E, Gałecki W, Rączka A, et al. Frequency and significance of the major and minor features of hanifin and rajka among patients with atopic dermatitis. Dermatology. 1994;189(1):41–6. 11. Castro-Rodríguez Ja, Holberg Cj, Wrıght Al, Martınez Fd. A clinical ındex to define risk of asthma in young children with recurrent wheezing. Am J Respir Crit Care Med. 2000 Oct 1;162(4):1403–6. 12. Brożek JL, Bousquet J, Agache I, Agarwal A, Bachert C, Bosnic-Anticevich S, et al. Allergic rhinitis and its ımpact on asthma (ARIA) guidelines—2016 revision. Journal of Allergy and Clinical Immunology. 2017 Oct;140(4):950–8. 13. Santos AF, Riggioni C, Agache I, Akdis CA, Akdis M, Alvarez-Perea A, et al. EAACI guidelines on the management of IgE-mediated food allergy. Allergy. 2025 Jan;80(1):14-36 14. Weidinger S, Novak N. Atopic dermatitis. Lancet 2016; 387: 1109–22; 2. Illi S, von Mutius E, Lau S, et al, and the Multicenter Allergy Study Group. The natural course of atopic dermatitis from birth to age 7 years and the association with asthma. J Allergy Clin Immunol 2004; 113: 925–31 15. Paternoster L, Savenije OEM, Heron J, Evans DM, Vonk JM, Brunekreef B, Wijga AH, Henderson AJ, Koppelman GH, Brown SJ. Identification of atopic dermatitis subgroups in children from 2 longitudinal birth cohorts. J Allergy Clin Immunol. 2018 Mar;141(3):964-971 16. Chung Y, Kwon JH, Kim J, Han Y, Lee SI, Ahn K. Retrospective analysis of the natural history of atopic dermatitis occurring in the first year of life in korean children. J Korean Med Sci. 2012;27(7):723. 17. The Long-Term Course of Atopic Dermatitis. Abuabara K, Margolis DJ, Langan SM. Dermatol Clin. 2017 Jul;35(3):291-297;2. Spergel, J.M.; Paller, A.S. Atopic dermatitis and the atopic march. J. Allergy Clin. Immunol. 2003, 112, S118–S127.). 18. Irvine AD, Mina-Osorio P. Disease trajectories in childhood atopic dermatitis: an update and practitioner’s guide. Br J Dermatol. 2019 Nov;181(5):895-906 19. Annelies E van der Hulst 1 , Helen Klip, Paul L P Brand. Risk of developing asthma in young children with atopic eczema: A systematic review. J Allergy Clin Immunol 2007;120: 565-9 20. Belgrave DCM, Granell R, Simpson A, Guiver J, Bishop C, Buchan I, et al. Developmental profiles of eczema, wheeze, and rhinitis: two population-based birth cohort studies. PLoS Med. 2014 Oct 21;11(10):e1001748. 21. Roduit C, Frei R, Depner M, Karvonen AM, Renz H, Braun-Fahrländer C, et al. Phenotypes of atopic dermatitis depending on the timing of onset and progression in childhood. JAMA Pediatr. 2017 Jul 1;171(7):655 22. Amat F, Saint-Pierre P, Bourrat E, Nemni A, Couderc R, Boutmy-Deslandes E, et al. Early-onset atopic dermatitis in children: which are the phenotypes at risk of asthma? Results from the orca cohort. PLoS One. 2015 Jun 24;10(6):e0131369. 23. Bloom CI, Franklin C, Bush A, Saglani S, Quint JK. Burden of preschool wheeze and progression to asthma in the UK: population-based cohort 2007 to 2017. J Allergy Clin Immunol. 2021 May;147(5):1949-1958. Table 1. Demographic and Clinical Characteristics of the Children Gender Female 375 (41.9) Male 519 (58.1) Age (years) Mean ± SD 7.09 ± 4.10 Median (Min–Max) 6.5 (1.5–18.8) Age at presentation (years) Mean ± SD 3.54 ± 3.31 Median (Min–Max) 2.5 (0.8–17.3) Food Allergy No 708 (79.2) Yes 186 (20.8) Allergic Rhinitis No 749 (83.8) Yes 145 (16.2) Bronchial Asthma No 794 (88,8) Yes 100 (11.2) Atopic March No 627 (70.1) Yes 267 (29.9) Atopic Dermatitis Progress Remission 503 (56.3) Persistent 391 (43.7) Blood eosinophil counts (/mL) Mean ± SD 502.08 ± 599.37 Median (Min–Max) 350 (0–8900) Total IgE ( kU/L) Mean ± SD 607.00 ± 7926.22 Median (Min–Max) 80 (0–226000) Severity of Atopic Dermatitis* No active eczema 37 (4.1) Mild (1+) 407 (45.5) Moderate (2+) 319 (35.7) Severe (3+) 131 (14.7) Clinical Phenotypes Early transient 545 (61.0) Early persistent 136 (15.2) Late onset 213 (23.8) * Mild (1+): Eczema localized to a single body region (e.g., the face, neck, or flexural areas) Moderate (2+): Eczema involving two or more body regions (e.g., face, neck and extensor or trunk and flexural areas) Severe (3+): Eczema involving three or more body regions (e.g., face, neck, and trunk or trunk, flexural, and extensor areas) Table 2. Univariable and Multivariable Analysis of Risk Factors for Persistence of Atopic Dematitis Remission Persistence OR (95% CI) p OR (95% CI) p Gender Female 199 (39.6) 176 (45) 0.800 (0.612-1.045) 0.102 0.721 (0.512-1.014) 0.060 Male 304 (60.4) 215 (55) Food sensitization No 392 (77.9) 277 (70.8) 1.453 0.016* 0.860 0.715 Yes 111 (22.1) 114 (29.2) (1.073-1.968) (0.382-1.936) Severity of Atopic Dermatitis* No active eczema 21 (4.2) 16 (4.1) Mild (1+) 225 (44.7) 182 (46.5) 1.062 (0.538-2.094) 0.863 Moderate (2+) 175 (34.8) 144 (36.8) 1.080 (0.543-2.146) 0.826 Severe (3+) 82 (16.3) 49 (12.5) 0.784 (0.374-1.645) 0.520 Mode of Delivery Vaginal 273 (54.3) 224 (57.3) 0.368 Cesarean 230 (45.7) 167 (42.7) 0.885 (0.678-1.155) Gestational age Term 445 (88.5) 335 (85.7) 0.215 Preterm 58 (11.5) 56 (14.3) 1.283 (0.865-1.901) Food Allergy No 412 (81.9) 296 (75.7) 1.453 0.024* 1.432 0.406 Yes 91 (18.1) 95 (24.3) (1.0151-2.009) (0.614-3.339) Onset of AD lesions Mean±Ftable 19.63±29.75 1.001 0.783 Median (Min–Max) 6 (0-204) 6 (0-240) (0.996-1.005) Skin test Negative 187 (58.4) 128 (46.9) 1.593 0.005** 1.529 0.016* Positive 133 (41.6) 145 (53.1) (1.150-2.205) (1.083-2.159) Complications ( hospitalization, MRSA) No 498 (99) 372 (95.1) 0.001** 2.509 0.100 Yes 5 (1) 19 (4.9) 5.087 (1.882-13.749) (0.838-7.511) Family history of atopy No 304 (60.4) 193 (49.4) 1.567 0.001** 1.614 0.033* Yes 199 (39.6) 198 (50.6) (1.200-2.047) (1.039-2.507) Family history of Asthma/AR No 352 (70) 226 (57.8) 1.702 0.001** 1.323 0.230 Yes 151 (30) 165 (42.2) (1.290-2.245) (0.839-2.089) Family history of atopic dermatitis No 439 (87.3) 335 (85.7) 1.147 0.487 Yes 64 (12.7) 56 (14.3) (0.780-1.686) *p<0,05 **p<0,01 Table 3. Comparison of Demographic Characteristics and Selected Factors Among Atopic Dermatitis Phenotypes n (%) n (%) n (%) Gender Female 209 (38.3) 66 (48.5) 100 (46.9) a 0.023* Male 336 (61.7) 70 (51.5) 113 (53.1) Age (years) Mean ± SD 5.31 ± 3.14 10.36 ± 3.51 9.59 ± 4.08 b 0.001** Median (Min-Max) 4.4 (1.5–15.6) 9.9 (2–18.8) 9 (1.3–18.6) Onset of AD lesions (months) Mean ± SD. 7.17±7.53 6.26±6.39 60.35±31.84 b 0.001** Median (Min–Max) 4 (0.1-24) 3,5(0.1-24) 48 (26-240) Age at Presentation to the outpatient clinic (years) Mean ± SD 1.50 ± 1.11 7.42 ± 2.92 6.30 ± 3.12 b 0.001** Median (Min-Max) 1 (0.1–4) 6.8 (3–17) 6 (0.3–17.3) Mode of Delivery Vaginal 311 (57.1) 81 (59.6) 105 (49.3) a 0.092 Cesarean 234 (42.9) 55 (40.4) 108 (50.7) Timing of Birth Term 475 (87.2) 120 (88.2) 185 (86.9) a 0.926 Preterm 70 (12.8) 16 (11.8) 28 (13.1) Seborrheic Dermatitis No 505 (92.7) 126 (92.6) 201 (94.4) a 0.693 Yes 40 (7.3) 10 (7.4) 12 (5.6) Family History of Atopy No 308 (56.5) 73 (53.7) 116 (54.5) a 0.779 Yes 237 (43.5) 63 (46.3) 97 (45.5) n (%) n (%) n (%) Family History of Asthma/AR No 365 (67) 88 (64.7) 125 (58.7) a 0.428 Mother 78 (14.3) 26 (19.1) 38 (17.8) Father 43 (7.9) 11 (8.1) 24 (11.3) Sibling 28 (5.1) 7 (5.1) 13 (6.1) Multiple Members 31 (5.7) 4 (2.9) 13 (6.1) Family History of Atopic Dermatitis No 481 (88.3) 109 (80.1) 184 (86.4) c 0.065 Mother 33 (6.1) 8 (5.9) 16 (7.5) Father 17 (3.1) 12 (8.8) 7 (3.3) Sibling 10 (1.8) 6 (4.4) 3 (1.4) Multiple Members 4 (0.7) 1 (0.7) 3 (1.4) Total breastfeeding 0-6 mn 58 (10.8) 12 (9.0) 23 (10.8) a 0.001** 6-12 mn 119 (22.1) 33 (24.8) 37 (17.4) 12-24 mn 235 (43.6) 67 (50.4) 128 (60.1) Continued breastfeeding 127 (23.8) 21 (15.8) 25 (11.7) • a : Pearson’s Chi-Square Test • b: One-Way ANOVA Test with Bonferroni Post Hoc • c: Fisher Freeman Halton Test. **p<0,01 *p<0,05 Table 4: AD Phenotypes and Comorbid Atopic Diseases n (%) n (%) n (%) Prognosis of Atopic Dermatitis Remission 314 (57.6) 67 (49.3) 122 (57.3) a 0.202 Persistent 231 (42.4) 69 (50.7) 91 (42.7) Severity of Atopic Dermatitis No active eczema 16 (2.9) 5 (3.7) 16 (7.5) a 0.037* Mild (1+) 247 (45.3) 55 (40.4) 105 (49.3) Moderate (2+) 196 (36.0) 54 (39.7) 69 (32.4) Severe (3+) 86 (15.8) 22 (16.2) 23 (10.8) Complications ( hospitalization, MRSA) No 532 (97.6) 132 (97.1) 206 (96.7) a 0.772 Yes 13 (2.4) 4 (2.9) 7 (3.3) Wheezing No 454 (83.3) 94 (69.1) 163 (76.5) a 0.001** Yes 91 (16.7) 42 (30.9) 50 (23.5) Allergic Rhinitis No 484 (88.8) 105 (77.2) 160 (75.1) a 0.001** Yes 61 (11.2) 31 (22.8) 53 (24.9) Bronchial Asthma No 498 (91.4) 117 (86) 179 (84) a 0.008** Yes 47 (8.6) 19 (14) 34 (16) a: Pearson’s Chi-Square Test **p < 0.01, *p < 0.05 Table 5: Comparison of Atopic Dermatitis Phenotypes by Food Sensitization Patterns n (%) n (%) n (%) Skin Prick Tests Negative 202 (57.5) 39 (40.6) 69 (45.4) a 0.003** Positive 149 (42.5) 57 (59.4) 83 (54.6) Food Sensitization Negative 368 (67.5) 111 (81.6) 190 (89.2) a 0.001** Yes 177 (32.5) 25 (18.4) 23 (10.8) - Hen’s egg 104 (19.1) 14 (10.3) 11 (5.2) - Cow’s Milk 34 (6.2) 5 (3.7) 7 (3.3) - Other Foods 9 (1.7) 2 (1.5) 2 (0.9) - Multiple Foods 30 (5.5) 4 (2.9) 3 (1.4) Food Allergy No 393 (72.1) 115 (84.6) 200 (93.9) a 0.001** Yes 152 (27.9) 21 (15.4) 13 (6.1) a: Pearson’s Chi-Square Test p < 0.01 Table 6: Comparison of Demographic Characteristics and Diagnostic Tests of Children with and without Atopic March Gender Female 261 (41.6) 114 (42.7) a 0.767 Male 366 (58.4) 153 (57.3) Age (years) Mean ± SD 6.78±4.13 7.86±3.95 f 0.001** Median (Min-Max) 5.8 (0.5-18.6) 7.6 (1-18.8) Age at Presentation to the outpatient clinic (years) Mean ± SD. 3.23±3.27 4.27±3.32 f 0.001** Median (Min–Max) 2 (0.1-16) 4 (0.2-17.3) Mode of Delivery Vaginal 353 (56.3) 144 (53.9) a 0.514 Cesarean 274 (43.7) 123 (46.1) Timing of Birth Term 560 (89.3) 220 (82.4) a 0.005** Preterm 67 (10.7) 47 (17.6) Seborrheic Dermatitis No 579 (92.3) 253 (94.8) a 0.194 Yes 48 (7.7) 14 (5.2) Family History of Atopy No 356 (56.9) 140 (52.4) a 0.222 Yes 270 (43.1) 127 (47.6) Family History of Asthma/AR No 418 (66.7) 160 (59.9) a 0.288 Mother 94 (15.0) 48 (18.0) Father 52 (8.3) 26 (9.7) Sibling 29 (4.6) 19 (7.1) Multiple Members 34 (5.4) 14 (5.2) Family History of Atopic Dermatitis No 543 (86.6) 231 (86.5) a 0.960 Mother 41 (6.5) 16 (60) Father 25 (4.0) 11 (4.1) Sibling 12 (1.9) 7 (2.6) Multiple Members 6 (1.0) 2 (0.7) Atopy No 96 (15.4) 22 (8.3) a 0.004** Yes 529 (84.6) 244 (91.7) Skin Test Negative 226 (57.2) 88 (41.2) a 0.001** Positive 169 (42.8) 120 (58.8) Food Sensitization No 459 (73.2) 210 (78.7) a 0.399 Hen’s Egg 98 (15.6) 31 (11.6) Cow’s Milk 32 (5.1) 14 (5.2) Other Foods 9 (1.4) 4 (1.5) Multiple Foods 29 (4.6) 8 (3.0) Food Allergy No 490 (78.1) 218 (81.6) a 0.238 Yes 137 (21.9) 49 (18.4) • a Pearson’s Chi-Square Test • b One-Way ANOVA Test & Bonferroni Test • c Fisher-Freeman-Halton Test • f Student’s t-Test • **p<0.01 *p<0.05 Information & Authors Information Version history V1 Version 1 08 July 2025 Peer review timeline Published International Archives of Allergy and Immunology Version of Record 18 Nov 2025 Published Copyright This work is licensed under a Non Exclusive No Reuse License. Authors Affiliations Cagla Karavaizoglu 0009-0005-3898-4767 [email protected] Istanbul Universitesi Istanbul Tip Fakultesi View all articles by this author Kazım Okan Dolu Istanbul Universitesi Istanbul Tip Fakultesi View all articles by this author Ayse Suleyman 0000-0002-9190-6849 Istanbul Universitesi Istanbul Tip Fakultesi View all articles by this author Esra Yucel 0000-0003-3712-2522 Istanbul Universitesi Istanbul Tip Fakultesi View all articles by this author Esra Altıntaş Istanbul Universitesi Istanbul Tip Fakultesi View all articles by this author Zeynep Hızlı Demirkale Istanbul Universitesi Istanbul Tip Fakultesi View all articles by this author Sevgi Sipahi Cimen 0000-0003-3026-0906 Istanbul Universitesi Istanbul Tip Fakultesi View all articles by this author Cevdet Ozdemir 0000-0002-9284-4520 Istanbul Universitesi Istanbul Tip Fakultesi View all articles by this author Zeynep Tamay Istanbul Universitesi Istanbul Tip Fakultesi View all articles by this author Metrics & Citations Metrics Article Usage 300 views 141 downloads .FvxKWukQNSOunydq8rnd { width: 100px; } Citations Download citation Cagla Karavaizoglu, Kazım Okan Dolu, Ayse Suleyman, et al. 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