The Atopic March
The atopic march, also known as the allergic march, describes the common sequential progression of different allergic conditions observed in individuals, particularly children, who develop IgE-antibody responses against common environmental allergens (atopy).[1]This phenomenon typically begins with eczema (atopic dermatitis) in infancy, followed by the development of other allergic diseases such as asthma and/or allergic rhinitis later in childhood.[1] While this sequence is the most recognized, various progression patterns exist, and allergic conditions can manifest in different orders.[1]Approximately 20-30% of infants with eczema experience this progression, which is associated with more severe and persistent allergic disease manifestations.[1] Of all children with eczema, 86% develop it as their first allergic condition.[1]
Biological Basis
Section titled “Biological Basis”A significant step in understanding the atopic march was the discovery offilaggrin (FLG) loss-of-function mutations. These genetic variants provide strong evidence linking a compromised skin barrier to the initial development of eczema and the subsequent progression to asthma.[1]Research, including genome-wide association studies (GWAS), has identified several susceptibility loci associated with the atopic march. A meta-analysis identified seven such loci, including known risk factors for allergic diseases and two novel variants.[1] These loci include regions such as CRNN/LCE5A (near FLG), AP5B1/OVOL1, C11orf30/LRRC32, SLC6A15/TMTC2, and IKZF3.[1]Notably, there is an overrepresentation of genes associated with eczema among these atopic march loci, suggesting that genetic factors predisposing to eczema are primary drivers of this disease trajectory.[1]
Clinical Relevance and Social Importance
Section titled “Clinical Relevance and Social Importance”The atopic march represents a critical clinical trajectory due to its association with severe and persistent allergic diseases. Understanding its molecular and genetic underpinnings is crucial for developing novel therapeutic and preventive strategies. Deciphering the specific genetic factors involved offers the potential to identify individuals at high risk and intervene early to prevent or halt the progression of allergic conditions.[1]Given the high prevalence of allergic diseases and their significant impact on quality of life for affected children and their families, the atopic march carries considerable social importance, highlighting the need for continued research into its mechanisms and effective management.
Methodological and Design Constraints
Section titled “Methodological and Design Constraints”The interpretation of findings related to the atopic march is subject to several methodological and study design limitations. Many studies, particularly genome-wide association studies (GWAS), operate under an assumption of monogenic effects, which may oversimplify the complex polygenic nature of allergic disease progression and limit the detection of true genetic risk factors.[2] Furthermore, variations in follow-up time within cohorts and the use of secondary analyses of health records from single institutions can introduce biases and influence association results, potentially limiting the generalizability of findings to broader populations.[2]Studies have also faced challenges with sample size and cohort selection, where small genotyped cohorts for certain ancestral groups or specific allergic trajectories may lack the statistical power to identify significant associations.[2]Additionally, meta-analyses incorporating cases primarily recruited through previous GWAS for specific conditions like eczema or asthma can introduce selection bias, potentially overrepresenting loci associated with those initial conditions and affecting the power to detect genes specifically involved in the broader atopic march progression.[1]The inclusion of individuals with unknown disease status or affected individuals among controls in some studies can further diminish statistical power, making it harder to discern true genetic effects.[1]
Phenotypic Definition and Measurement Challenges
Section titled “Phenotypic Definition and Measurement Challenges”The precise definition and measurement of atopic march phenotypes present significant limitations in research. Many studies adopt a reductionist approach, focusing exclusively on a predefined sequence of major allergic manifestations like eczema followed by asthma, thereby overlooking other crucial allergic conditions such as allergic rhinitis or eosinophilic esophagitis, as well as alternative progression trajectories.[2] This narrow focus can lead to results biased towards the included conditions and may miss the complex interplay and diverse pathways through which individuals develop allergies.[2]Moreover, the heterogeneity and quality of phenotypic data can impact the reliability of findings. Data on atopy status, for instance, often varies widely across studies concerning age at testing, assay methods, and allergens screened, making consistent integration difficult and potentially reducing the power to identify atopy-related genes.[1] Reliance on diagnosis codes from routine care, while practical, may be influenced by administrative or billing constraints, introducing potential biases, even if accuracy is high in subsets.[2] Furthermore, missing phenotype data for full age ranges or the use of parental reports and retrospectively collected information can lead to a loss of cases due to misclassification or recall bias, further compromising the integrity and power of genetic association studies.[1]
Generalizability and Unaccounted Confounders
Section titled “Generalizability and Unaccounted Confounders”Investigations into the atopic march are significantly limited by issues of generalizability and the inability to fully account for confounding factors. Genetic association studies often perform analyses exclusively on specific ancestral populations, such as individuals of African ancestry, due to sample size constraints for other groups.[2] This practice means that identified genetic polymorphisms may not be universally applicable and could fail to capture relevant genetic risk factors present in other populations, thus restricting the broader applicability of findings.[2] Beyond genetic differences, the concept of “race” itself, often used in demographic analyses, is a social rather than a purely biological construct, intrinsically linked to a myriad of social, environmental, institutional, and biological factors that influence health disparities.[2] The inability to fully account for these complex covariates means that observed genetic associations might be confounded by unmeasured environmental or social influences, making it challenging to disentangle the precise contributions of genetic polymorphisms versus other determinants of allergic trajectories.[2] Additionally, the method of assigning racial groups, whether self-identified or assigned by others, can introduce further biases and confounders that complicate the interpretation of ancestry-associated outcomes.[2]
Variants
Section titled “Variants”The progression of allergic diseases, often termed the atopic march, involves a complex interplay of genetic factors influencing skin barrier integrity, immune responses, and epithelial function. Several single nucleotide polymorphisms (SNPs) have been identified as susceptibility loci, demonstrating associations with the development of conditions like eczema, asthma, and allergic rhinitis, which characterize this march. These genetic variations can alter gene activity, leading to dysregulation of pathways critical for immune homeostasis and tissue barrier maintenance.
Variations affecting skin barrier and epithelial integrity are significant contributors to the atopic march. The SNPrs12081541 , located in the _LCE5A_ region, is associated with genes like _FLG_ (Filaggrin), which is crucial for skin barrier formation. Loss-of-function mutations in _FLG_are a well-established genetic link between skin barrier dysfunction, eczema, and subsequent asthma development, highlighting the “outside-in” mechanism of allergen sensitization.[1] Similarly, rs479844 near _AP5B1_ and _OVOL1_ influences epithelial differentiation. _OVOL1_is a transcription factor that plays a role in maintaining epithelial integrity, and variations here can affect skin barrier function, increasing susceptibility to allergen entry and allergic sensitization.[1] Another important locus is rs2155219 , associated with _C11orf30_ and _LRRC32_, which is a known susceptibility factor for eczema and eczema-associated asthma, also suggesting a role in disease progression from eczema to asthma.[1] Other variants impact immune regulation and ciliary function, critical for respiratory health and overall allergic responses. The SNP rs9357733 is located within _EFHC1_, a gene involved in ciliary function. In mouse models, _Efhc1_deficiency affects ciliary beating frequency, and its presence in tracheal epithelium suggests a role in defense against inhaled pathogens and allergens, thereby influencing asthma development.[1] This variant, along with rs993226 , which is located near _SLC6A15_, represents novel susceptibility loci for the atopic march.[1] _SLC6A15_ encodes a neurotransmitter transporter, _BAT2_, and its function can be modulated by antihistamines, pointing to its involvement in allergic pathways.[1] Furthermore, rs17690965 is found in the _KIF3A_ region, a gene essential for the proper formation and function of cilia, which are vital for clearing irritants and allergens from the airways. Lastly, rs10445308 within an intron of _IKZF3_is strongly associated with childhood asthma and self-reported allergy.[1] _IKZF3_ is a transcription factor crucial for lymphocyte development and immune cell differentiation, making it a key regulator of allergic inflammation.
Beyond protein-coding genes, long intergenic non-coding RNAs (lincRNAs) also play a role in the atopic march by regulating gene expression. The variantrs60242841 , located in an intergenic region near _LINC00299_, has been associated with the progression from atopic dermatitis to asthma.[2] Similarly, rs151041509 , also found in an intergenic region near _LINC02512_, shows associations with atopic dermatitis progressing to allergic rhinitis.[2]These lincRNAs can influence the expression of nearby genes involved in immune responses or tissue development, thereby contributing to the complex genetic architecture of allergic diseases and their sequential development in the atopic march.
Key Variants
Section titled “Key Variants”| RS ID | Gene | Related Traits |
|---|---|---|
| rs2155219 | EMSY - LINC02757 | allergic sensitization measurement atopic march ulcerative colitis seasonal allergic rhinitis asthma |
| rs12081541 | CCDST - LCE5A | atopic march |
| rs479844 | AP5B1 - OVOL1 | atopic march atopic eczema asthma serum IgG glycosylation measurement childhood onset asthma |
| rs993226 | RPL6P25 - SLC6A15 | atopic march |
| rs9357733 | EFHC1 | atopic march |
| rs17690965 | KIF3A | atopic march |
| rs10445308 | IKZF3 | atopic march asthma, cardiovascular disease asthma |
| rs60242841 | LINC00299 | atopic march |
| rs9565267 | RN7SL571P - KCTD12 | atopic march |
| rs151041509 | LINC02512 | atopic march |
Definition and Nomenclature
Section titled “Definition and Nomenclature”The “atopic march,” also known as the “allergic march,” describes the common sequential progression of different allergic conditions, particularly observed in children with IgE-antibody responses to common environmental allergens.[1] This conceptual framework posits that allergic diseases often manifest in a characteristic order, typically beginning in infancy and evolving throughout childhood.[1]It represents an unfavorable disease course linked to severe and persistent allergic manifestations.[1]Key terms associated with this progression include eczema (atopic dermatitis), asthma, and allergic rhinitis, with atopy broadly referring to the genetic predisposition to produce IgE antibodies in response to common environmental allergens.[1]
Clinical Trajectories and Classification
Section titled “Clinical Trajectories and Classification”The classic pattern of the atopic march typically begins with eczema in infancy, followed by the development of asthma and/or allergic rhinitis in childhood.[1]While this sequence is the most common, accounting for the largest group among children with multiple allergic conditions, studies acknowledge the existence of multiple distinct disease developmental trajectories.[1]These variations can include non-traditional orders of disease manifestation, individuals skipping certain allergic conditions, or the progression halting altogether.[2]Furthermore, less prevalent allergic manifestations such as IgE-mediated food allergy and eosinophilic esophagitis are also recognized as potential components or late manifestations of the allergic march.[2]
Operational Definitions and Diagnostic Criteria
Section titled “Operational Definitions and Diagnostic Criteria”For research and clinical studies, the atopic march requires precise operational definitions and diagnostic criteria, which can vary and impact case ascertainment.[1]A strict definition, for instance, might require early eczema to manifest by 3 years of age and childhood asthma by 16 years.[1]Such stringent criteria, while aiming for a severe phenotype, can result in a smaller number of identified cases compared to wider definitions that encompass childhood eczema and asthma at any age up to 16 years, potentially nearly doubling case numbers.[1]Diagnostic approaches often rely on actual or reported doctor’s diagnoses, though some studies may use parental reports of disease symptoms, and conditions are often identified using International Classification of Diseases (ICD) codes, sometimes requiring multiple care visits for confirmation.[1] The identification of genetic susceptibility loci, such as FLGloss-of-function mutations linking skin barrier deficiency to eczema and subsequent asthma, provides a biological basis for understanding the mechanisms underlying this progression.[1]
Sequential Progression and Phenotypes
Section titled “Sequential Progression and Phenotypes”The atopic march describes a common, sequential progression of allergic conditions, typically beginning in infancy and extending through childhood.[2]The classic presentation starts with atopic dermatitis (eczema), followed by the development of IgE-mediated food allergy, asthma, and/or allergic rhinitis.[2]While eczema is generally the initial manifestation in about 86% of cases, defining a “strict” atopic march often involves early-onset eczema (by age 3) followed by childhood asthma (by age 16), a pattern observed in the largest group of children with multiple allergic conditions.[1]This unfavorable disease course is associated with severe and persistent allergic disease manifestations, affecting 20–30% of infants with eczema.[1]However, the atopic march is characterized by significant phenotypic diversity and heterogeneity, with multiple distinct disease developmental trajectories existing beyond the traditional sequence.[2] Individuals may experience manifestations in a non-traditional order, skip certain conditions, or halt progression altogether.[2]For instance, the development of all three major conditions—eczema, asthma, and allergic rhinitis—is relatively uncommon, occurring in only 2.3% of children.[1]Eosinophilic esophagitis has also been identified as a potential late manifestation of this allergic progression.[3]
Diagnostic Assessment and Genetic Markers
Section titled “Diagnostic Assessment and Genetic Markers”Clinical diagnosis of atopic march components typically relies on actual or reported doctor’s diagnoses, though parental reports of disease symptoms are also utilized in some studies.[1] Longitudinal observational data, often derived from electronic medical records, are crucial for tracking the progression of allergic manifestations over time and identifying individual and cumulative risks.[2]For research purposes, definitions can vary, with “strict” criteria requiring early-onset eczema (up to 3 years) and childhood asthma (up to 16 years), while “wider” definitions may include eczema and asthma at any age up to 16 years, influencing case identification.[1]Genetic factors play a significant role in the predisposition and progression of the atopic march, with advanced genomic techniques like Genome-Wide Association Studies (GWAS) identifying susceptibility loci.[1] A breakthrough was the discovery of filaggrinloss-of-function mutations, which are major predisposing factors for atopic dermatitis and provide genetic evidence linking skin barrier deficiency to subsequent asthma development.[1] Other associated loci include FLG, IL4/KIF3A, OVOL1, and C11orf30/LRRC32, which are also linked to eczema, suggesting its pivotal role in the disease course.[1]Novel susceptibility loci for the atopic march includers9357733 in EFHC1 and rs993226 located between TMTC2 and SLC6A15, while IKZF3shows a stronger association with asthma alone.[1]
Variability, Severity, and Prognostic Indicators
Section titled “Variability, Severity, and Prognostic Indicators”The clinical expression and progression of the atopic march demonstrate considerable inter-individual variation, influenced by a complex interplay of environmental, genetic, and immunological factors.[2]This heterogeneity is reflected in diverse allergic trajectories, where individuals may follow unique paths of disease development.[2]Observational studies have noted demographic disparities, including an increased prevalence of males and self-identified Black individuals within allergy groups, highlighting the influence of population-level factors.[2]The severity of atopic dermatitis, particularly early-onset and persistent forms, is a significant prognostic indicator for the likelihood of progressing through the atopic march.[1] The presence of filaggrinloss-of-function mutations specifically predisposes individuals to phenotypes involved in the atopic march, linking epidermal barrier dysfunction to the subsequent development of allergic airway diseases.[1] Understanding these varied presentations, genetic predispositions, and the sequential nature of the conditions holds diagnostic value for identifying high-risk individuals and informs potential early intervention strategies to prevent or arrest the march.[1]
Causes of Atopic March
Section titled “Causes of Atopic March”The atopic march, characterized by the sequential development of allergic conditions such as eczema, asthma, and allergic rhinitis, is driven by a complex interplay of genetic predispositions, environmental factors, and immunological processes.[1]While multiple distinct disease trajectories exist, the underlying causal factors often converge on mechanisms affecting immune regulation and barrier function.[2] Understanding these multifaceted causes is crucial for developing strategies to prevent or manage the progression of allergic diseases.
Genetic Predisposition and Epidermal Barrier Dysfunction
Section titled “Genetic Predisposition and Epidermal Barrier Dysfunction”Genetic factors play a significant role in determining an individual’s susceptibility to the atopic march. A breakthrough in understanding this progression was the discovery of loss-of-function mutations in theFLG gene, which encodes the epidermal barrier protein filaggrin.[1]These common variants are a major predisposing factor for atopic dermatitis, and their presence genetically links skin barrier deficiency to eczema and subsequent asthma development.[1] The impaired skin barrier function allows increased penetration of allergens, initiating an immune response that can contribute to systemic sensitization.
Beyond FLG, genome-wide association studies (GWAS) have identified several other susceptibility loci involved in the atopic march, highlighting its polygenic nature.[1] These include novel variants such as rs9357733 on chromosome 6p12.3, which is located in a region containing genes like PAQR8, EFHC1, and TRAM2, and rs993226 on chromosome 3, near TMTC2 and SLC6A15.[1] Other identified loci, like AP5B1/OVOL1 (rs479844 ) and CRNN/LCE5A (rs12081541 ), are known risk factors for eczema, while C11orf30/LRRC32 (rs2155219 ) is associated with both eczema and eczema-associated asthma, andIKZF3 (rs10445308 ) is linked to childhood asthma.[1]The strong contribution and enrichment of eczema-related genes among the atopic march loci suggest that early skin manifestations are critical in initiating this unfavorable disease course.[1]
Environmental Influences and Early Life Programming
Section titled “Environmental Influences and Early Life Programming”Environmental factors significantly influence the manifestation and progression of the atopic march. The “hygiene hypothesis” suggests that reduced exposure to microbes and infections in early life can alter immune system development, potentially increasing susceptibility to allergic diseases.[1]While specific environmental factors such as diet, lifestyle, socioeconomic status, or geographic influences are less detailed in their direct contribution to the atopic march within current research, their collective impact on immune maturation and allergen exposure is recognized as crucial. Early life exposures, particularly during critical developmental windows, play a vital role in shaping an individual’s immunological responses and their propensity to develop allergic conditions.
Gene-Environment Interactions and Immune Dysregulation
Section titled “Gene-Environment Interactions and Immune Dysregulation”The progression of the atopic march is often a result of intricate gene-environment interactions, where genetic predispositions are triggered or modulated by environmental exposures. For instance, the genetically compromised skin barrier in individuals withFLG mutations makes them more vulnerable to environmental allergens, which can then penetrate the skin and initiate an immune cascade, leading to sensitization and subsequent allergic manifestations.[1]This interaction between a genetic defect and environmental triggers is a cornerstone of the atopic march. The involvement of Toll-like receptors in linking the atopic march to the hygiene hypothesis further underscores how environmental microbial exposure can interact with host genetics to shape immune responses and influence allergic outcomes.[1]These complex interactions contribute to the varied and distinct disease trajectories observed within the atopic march, rather than a singular linear progression.[2]
Developmental Trajectories and Multi-System Allergic Manifestations
Section titled “Developmental Trajectories and Multi-System Allergic Manifestations”The atopic march is characterized by a developmental sequence, typically beginning with atopic dermatitis (eczema) in infancy, followed by the emergence of asthma and/or allergic rhinitis in later childhood.[1] This progression is not uniform, with studies identifying multiple distinct trajectories where individuals may develop manifestations in non-traditional orders, skip certain conditions, or halt progression altogether.[2]Early life influences are critical, with eczema onset typically defined by 3 years of age and asthma by 16 years in research studies.[1]The atopic march also encompasses a broader spectrum of allergic multimorbidity, extending beyond the classical triad. Food sensitization is a significant early manifestation, with atopic dermatitis severity being a main risk factor in exclusively breastfed infants.[4]Furthermore, eosinophilic esophagitis has been identified as a late manifestation of the allergic march, indicating that the underlying immunological dysregulation can impact various organ systems over time.[3] Functional investigations of identified genetic loci, such as the potential involvement of EFHC1 in mucociliary epithelium, suggest widespread biological implications beyond localized allergic responses.[1]
Biological Background
Section titled “Biological Background”The atopic march describes a common developmental progression of allergic diseases, typically starting with atopic dermatitis (eczema) in infancy, followed by the development of asthma and/or allergic rhinitis in childhood.[1] This sequence is observed in a significant portion of children with eczema and is associated with persistent and severe allergic manifestations.[1] While the classic pattern begins with eczema, other trajectories exist, with some individuals developing manifestations in different orders, skipping certain conditions, or halting progression entirely.[2] Understanding the biological underpinnings of this phenomenon, including genetic predispositions, molecular pathways, and tissue-level interactions, is crucial for developing preventive and therapeutic strategies.
Epidermal Barrier Dysfunction and Initial Allergic Sensitization
Section titled “Epidermal Barrier Dysfunction and Initial Allergic Sensitization”The atopic march frequently commences with atopic dermatitis, a condition fundamentally linked to a compromised epidermal barrier. Key biomolecules, such as the proteinfilaggrin, are essential for maintaining the integrity of the skin. Loss-of-function mutations in the filaggrin gene (FLG) represent a major genetic predisposition for atopic dermatitis, leading to a deficient skin barrier.[5], [6]This impaired barrier function allows environmental allergens and irritants to penetrate the skin more readily, triggering immune responses and sensitizing the individual’s immune system. This initial breakdown in skin homeostasis is considered a critical pathophysiological process that primes the body for the subsequent development of allergic conditions in the airways, such as asthma and allergic rhinitis, thus initiating the characteristic progression of the atopic march.[1]
Genetic Foundations of Allergic Progression
Section titled “Genetic Foundations of Allergic Progression”Genetic mechanisms significantly influence an individual’s susceptibility to and progression through the atopic march. Genome-wide association studies (GWAS) have pinpointed several crucial susceptibility loci. For instance, variants nearCRNN/LCE5A (located close to FLG) and OVOL1have been associated with the atopic march, underscoring the genetic links to both skin barrier function and development.[1] Another important genetic factor is a variant within an intron of IKZF3, a gene previously implicated in childhood asthma and general allergy, suggesting its role in regulating immune cell development and function. Furthermore, thers9357733 variant is situated in a predicted enhancer region, which is active in critical target organs of allergic disease, including skin keratinocytes, skin fibroblasts, and lung fibroblasts.[1] This highlights how specific regulatory elements influence gene expression patterns in a tissue-specific manner, collectively shaping the regulatory networks that govern immune responses and tissue integrity, thereby predisposing individuals to the sequential manifestations of allergic diseases.
Immune System Modulation and Airway Pathophysiology
Section titled “Immune System Modulation and Airway Pathophysiology”The advancement of the atopic march involves intricate dysregulation of the immune system and distinct organ-level effects, particularly within the respiratory system. Genes likeC11orf30/LRRC32are recognized risk factors for eczema-associated asthma and hay fever, indicating common pathophysiological mechanisms underlying the development of various allergic airway conditions.[1] The EFHC1 gene, which plays a role in the function of motile cilia, is found in the tracheal epithelium. Here, it contributes to mucociliary clearance, a vital defense mechanism that protects against inhaled pathogens and allergens. Impaired mucociliary function due to EFHC1deficiency could compromise the airway’s ability to clear allergens, thereby contributing to the development of asthma.[1] Additionally, established immune-related genes such as IL6R, IL1RL1/IL18R1, RAD50, and those within the HLAregion, which are fundamental to immune signaling and antigen presentation, further contribute to the broader systemic allergic response and the overall trajectory of atopy.[1]
Cellular Transport and Metabolic Influences
Section titled “Cellular Transport and Metabolic Influences”Beyond the established roles of immune components and barrier functions, specific cellular and metabolic pathways also contribute to the complex biology of the atopic march. A novel susceptibility locus,rs993226 , is located between the genes TMTC2 and SLC6A15.[1] TMTC2 encodes a membrane protein involved in maintaining calcium homeostasis within the endoplasmic reticulum, suggesting a potential role for cellular calcium signaling in allergic processes. Concurrently, SLC6A15 encodes BAT2, a Na+/Cl—dependent membrane transporter responsible for neutral amino acids, which is highly expressed in the respiratory epithelium.[1]The observation that the antihistamine loratadine can selectively inhibit BAT2 points to a direct molecular pathway linking this transporter to the treatment of allergic diseases and, by extension, to the underlying mechanisms driving the atopic march.[1] These findings highlight the intricate interplay of molecular transport, cellular metabolic processes, and pharmacological responses in shaping the development and progression of allergic conditions.
Impaired Epithelial Barrier Function and Initial Immune Priming
Section titled “Impaired Epithelial Barrier Function and Initial Immune Priming”The atopic march often begins with atopic dermatitis, a condition fundamentally linked to a compromised skin barrier. A key mechanism involves loss-of-function mutations in theFLG(Filaggrin) gene, which predispose individuals to atopic dermatitis and subsequent asthma development.[5] This epidermal barrier dysfunction allows increased penetration of environmental allergens and irritants, initiating local immune responses in the skin. Such breaches can lead to the release of alarmins like thymic stromal lymphopoietin (TSLP), which orchestrate T-helper 2 (Th2) type inflammation, setting the stage for systemic sensitization to allergens.[7] This initial dysregulation of the skin barrier acts as a primary driver, triggering a cascade of events that primes the immune system for allergic reactions in other organ systems.
Genetic Modifiers and Regulatory Dysregulation
Section titled “Genetic Modifiers and Regulatory Dysregulation”Multiple genetic loci contribute to the susceptibility and progression of the atopic march, influencing gene regulation and protein function. Genome-wide association studies have identified seven significant loci, including novel variants such asrs9357733 in EFHC1 and rs993226 located between TMTC2 and SLC6A15.[1] The EFHC1 gene, for instance, is expressed in motile cilia of tracheal epithelium, suggesting a role in mucociliary clearance and defense against inhaled pathogens and allergens.[1] Additionally, SLC6A15encodes BAT2, a Na+/Cl-dependent membrane transporter for neutral amino acids, which is selectively inhibited by the antihistamine loratadine, pointing to its potential involvement in allergic disease mechanisms.[1] Other identified loci, including IL4/KIF3A, AP5B1/OVOL1, C11orf30/LRRC32, and IKZF3, highlight diverse regulatory pathways influencing immune responses and epithelial integrity.[1]
Immune Signaling and Inflammatory Cascades
Section titled “Immune Signaling and Inflammatory Cascades”The progression of the atopic march is characterized by the activation of specific immune signaling pathways, leading to chronic inflammation and IgE-mediated responses. Toll-like receptors (TLRs) play a role in linking the atopic march to the hygiene hypothesis, suggesting that early life microbial exposures can modulate immune development and allergic susceptibility.[8] Genetic variants in loci like IL4/KIF3Acan modulate T-helper 2 (Th2) cell differentiation and cytokine production, crucial for IgE synthesis and allergic inflammation. Dysregulated receptor activation and subsequent intracellular signaling cascades involving these pathways drive the immune system towards an allergic phenotype, contributing to the development of IgE-mediated food allergy, asthma, and allergic rhinitis.[1] This persistent Th2-skewed response, once established, underlies the clinical manifestations observed throughout the march.
Pathway Crosstalk and Systems-Level Integration
Section titled “Pathway Crosstalk and Systems-Level Integration”The atopic march exemplifies a complex systems-level integration where dysregulation in one organ system influences others, demonstrating significant pathway crosstalk. The initial epidermal barrier defects and subsequent immune priming in the skin create a systemic predisposition, linking skin inflammation to the development of respiratory allergies.[1] Genetic factors predominantly driving eczema, such as FLGmutations, are also strong contributors to the risk of the atopic march, suggesting a hierarchical regulation where primary skin issues act as a gateway for subsequent allergic manifestations.[1] This intricate network of interactions, where early-life environmental and genetic factors converge to shape immune development, results in emergent properties that define the sequential progression of allergic conditions, although individuals can exhibit distinct trajectories.[2]
Prognostic Value and Risk Stratification
Section titled “Prognostic Value and Risk Stratification”The atopic march describes a sequential progression of allergic conditions, typically beginning with atopic dermatitis (AD) in infancy, followed by IgE-mediated food allergy, asthma, and allergic rhinitis in childhood.[2]This progression has significant prognostic value, as approximately 20-30% of infants with eczema will experience this unfavorable disease course, which is associated with more severe and persistent allergic manifestations.[1]Early-onset eczema, specifically, is a strong risk factor and confers a 4.3-fold increased risk for developing asthma.[1] Identifying individuals with early eczema allows for risk stratification, enabling clinicians to monitor those at highest risk for subsequent allergic conditions.
Genetic factors, such as loss-of-function mutations in the FLGgene, are significant predisposing factors for AD and have been shown to link skin barrier deficiency to eczema and the subsequent development of asthma.[1]This genetic insight, coupled with demographic data, can refine risk assessment beyond clinical presentation alone; for example, studies indicate that self-identified Black individuals are more likely to progress from AD to asthma.[2] Such detailed risk stratification is crucial for predicting long-term outcomes, including the severity and persistence of allergic diseases, and for informing personalized medicine approaches.
Diagnostic Utility and Proactive Therapeutic Strategies
Section titled “Diagnostic Utility and Proactive Therapeutic Strategies”Understanding the atopic march provides crucial diagnostic utility by recognizing early allergic manifestations as potential harbingers of subsequent conditions, thereby guiding more proactive clinical management. Given that no cure for asthma currently exists, insights into the atopic march highlight the potential for early interventions to modify disease progression.[1]For instance, modulation of skin integrity early in infancy through strategies like skin emollient therapy has shown promising results in preventing eczema, and is being investigated for its long-term effect on preventing the atopic march in a subset of patients.[1]The identification of specific genetic loci associated with the atopic march and its component diseases (eczema, asthma) can inform targeted treatment selection and personalized medicine approaches, moving beyond a one-size-fits-all strategy.[1]Furthermore, advanced computational modeling of clinical datasets, particularly in birth cohorts, enables the identification of distinct allergic trajectories and associated demographic and genetic factors.[2] This approach can improve the ability to identify, diagnose, and treat at-risk patient populations more effectively, by developing new hypotheses for subsequent testing and tailoring monitoring strategies.
Understanding Disease Heterogeneity and Comorbidities
Section titled “Understanding Disease Heterogeneity and Comorbidities”The concept of the atopic march has evolved to acknowledge that multiple distinct disease developmental trajectories exist, meaning individuals may experience allergic manifestations in non-traditional orders, skip certain conditions, or halt progression altogether.[2]This understanding of heterogeneity is critical for clinicians, as it moves beyond a simple linear model and accounts for the varied clinical presentations and overlapping phenotypes observed in patients. While eczema followed by asthma is the single largest group among children with multiple allergic diseases, other patterns and comorbidities, such as eosinophilic esophagitis, have been identified as late manifestations of the allergic march.[3]Genetic research has revealed that some loci are specific to the atopic march phenotype, while others are associated with eczema or asthma alone, suggesting a complex interplay and heterogeneity of underlying disease mechanisms.[1]This implies that some associations may reflect independent disease processes rather than a strict causal sequence, highlighting the need for comprehensive assessment of all allergic comorbidities. The role of less prevalent allergic manifestations, particularly food allergy, in the overall atopic march trajectory remains an area of ongoing research, though mouse models point to its potential involvement.[1]
Frequently Asked Questions About Atopic March
Section titled “Frequently Asked Questions About Atopic March”These questions address the most important and specific aspects of atopic march based on current genetic research.
1. My baby has eczema; will they definitely get asthma too?
Section titled “1. My baby has eczema; will they definitely get asthma too?”Not necessarily. While eczema often precedes other allergies, about 20-30% of infants with eczema actually experience this progression to conditions like asthma or allergic rhinitis. However, for those who do, it’s often associated with more severe and persistent allergic disease.
2. If my baby has eczema, can I stop other allergies?
Section titled “2. If my baby has eczema, can I stop other allergies?”Understanding the genetic factors involved is crucial for developing potential preventive strategies. The goal of research is to identify high-risk individuals early, allowing for interventions that could prevent or halt the progression of allergic conditions.
3. Can taking care of my skin barrier prevent other allergies?
Section titled “3. Can taking care of my skin barrier prevent other allergies?”Yes, research strongly links a compromised skin barrier to the initial development of eczema and the subsequent progression to asthma. Genetic factors, such as mutations in thefilaggrin gene, play a key role in this. Maintaining a healthy skin barrier could be an important protective measure.
4. Can a DNA test predict my child’s future allergies?
Section titled “4. Can a DNA test predict my child’s future allergies?”Genetic research is identifying specific susceptibility loci associated with the atopic march. While not a simple “yes” or “no” answer, these discoveries offer the potential to identify individuals at high risk and allow for earlier, targeted interventions.
5. My eczema got better, but then I got hay fever. Why?
Section titled “5. My eczema got better, but then I got hay fever. Why?”The atopic march isn’t always a direct path from eczema to asthma. It describes a common progression of various allergic conditions, which can include allergic rhinitis (hay fever). Different progression patterns exist, and conditions can manifest in various orders.
6. My sibling’s allergies are mild, but mine are severe. Why?
Section titled “6. My sibling’s allergies are mild, but mine are severe. Why?”Genetic factors play a significant role in how severe and persistent allergic diseases become. There’s an overrepresentation of genes associated with eczema among the genetic risk factors for the atopic march, suggesting these genetic predispositions can drive a more challenging disease trajectory for some individuals.
7. Does where I live change my allergy risk?
Section titled “7. Does where I live change my allergy risk?”Environmental and social factors can definitely influence your allergy risk and how genetic predispositions manifest. It’s challenging to fully disentangle the precise contributions of genetics versus these external influences, as they often interact in complex ways.
8. Does my family’s background affect my allergy risk?
Section titled “8. Does my family’s background affect my allergy risk?”Yes, genetic risk factors can vary across different ancestral populations. Many genetic studies are performed on specific groups, meaning that identified genetic polymorphisms might not be universally applicable or capture relevant risk factors in other populations.
9. Why do doctors mainly talk about eczema and asthma, not other allergies?
Section titled “9. Why do doctors mainly talk about eczema and asthma, not other allergies?”Many studies, especially in the past, have focused on the most recognized sequence of eczema followed by asthma. However, the atopic march includes other crucial allergic conditions like allergic rhinitis, and researchers recognize that various progression patterns exist beyond this narrow focus.
10. Can I overcome my family’s history of allergies?
Section titled “10. Can I overcome my family’s history of allergies?”While genetics play a strong role in predisposing individuals to allergic conditions, understanding these specific genetic factors is the key to developing new therapeutic and preventive strategies. Early intervention is a major goal, aiming to prevent or halt the progression of allergies even with a family history.
This FAQ was automatically generated based on current genetic research and may be updated as new information becomes available.
Disclaimer: This information is for educational purposes only and should not be used as a substitute for professional medical advice. Always consult with a healthcare provider for personalized medical guidance.
References
Section titled “References”[1] Marenholz I, et al. “Meta-analysis identifies seven susceptibility loci involved in the atopic march.”Nat Commun, vol. 6, 2015, p. 8806. PMID: 26542096.
[2] Gabryszewski SJ. “Unsupervised Modeling and Genome-Wide Association Identify Novel Features of Allergic March Trajectories.” J Allergy Clin Immunol, vol. 146, no. 4, 2020, pp. 815-826.e11. PMID: 32650023.
[3] Hill DA, et al. “Eosinophilic esophagitis is a late manifestation of the allergic march.”J Allergy Clin Immunol Pract, 2018.
[4] Dharmage SC, et al. “Atopic dermatitis and the atopic march revisited.”Allergy, vol. 69, no. 1, 2014, pp. 17–27. PMID: 24117677.
[5] Palmer, C. N. et al. “Common loss-of-function variants of the epidermal barrier protein filaggrin are a major predisposing factor for atopic dermatitis.”Nat Genet, vol. 38, no. 4, 2006, pp. 441-6.
[6] Marenholz, I. et al. “Filaggrin loss-of-function mutations predispose to phenotypes involved in the atopic march.”J Allergy Clin Immunol, vol. 118, no. 4, 2006, pp. 866-71.
[7] Li, M. “Current evidence of epidermal barrier dysfunction and thymic stromal lymphopoietin in the atopic march.”Eur Respir Rev, vol. 23, no. 133, 2014, pp. 292-298.
[8] Kemeny, L., and K. Szabo. “Toll-like receptors link atopic march to the hygiene hypothesis.”J Invest Dermatol, vol. 133, no. 4, 2013, pp. 874-878.