| 1 | Introduction |
Atopic dermatitis (AD) may manifest differently in children and adults due to genetic, immunological variables, and environmental triggers.1 These differences are important considerations for the care of AD patients of different ages. In this review, the authors compare clinically important differences in the pathophysiology, clinical presentation, and comorbidities of AD between children and adults.
| 2 | Epidemiology |
Atopic dermatitis is one of the most common diseases of childhood, affecting approximately 13% of American children overall and 15-38% of children <5 years of age worldwide.2 It was once thought that AD presented early in life in the majority of cases, with 50% of AD cases beginning in the first year of life and 85% starting at age 5 years.3 However, the majority of these findings They originated from studies of younger pediatric cohorts that did not examine adolescents or adults. Recent studies suggest that there is considerable heterogeneity in the age of onset of AD. AD can begin in adolescence or adulthood; About 1 in 4 adults with AD report onset of their disease in adulthood.4
A systematic review of 46 studies evaluated rates and risk factors for AD persistence.5 In a pooled meta-analysis, 80% of children with AD experienced a period of disease clearance observed at age 8 years and only 5% had no clearance observed after 20 years of follow-up.5 Moderate-severe and long-lasting disease was associated with more persistent AD. Little is known about the persistence of adult-onset or recurrent AD.
| 3 | Pathophysiology |
Atopic dermatitis results from a complex overlap of genetic susceptibility, skin barrier disruption, microbiome alterations, immune dysregulation with activation of T-helper (Th)-2 cells and other immune pathways, as well as environmental and behavioral factors. Several important differences are observed in the pathophysiology of AD between children and adults.
3.1 | Skin barrier dysfunction
Atopic dermatitis is associated with increased loss of transepidermal water and epidermal and proteolytic enzymes, and reduced ceramide levels. The skin barrier can be further damaged by exogenous proteases, especially from dust mites and S. aureus. 6 These defects are most striking not only in lesional skin, but also occur in non-injured skin.
Multiple terminal epidermal differentiation genes (LCE1B/1C/1E/1F/2C/2D, FLG and PSORC1C240) show downregulation in adults compared to controls, and to a lesser extent in other age groups.7 Some genes related to lipid biosynthesis/metabolism (7-dehydrocholesterol reductase and peroxisome proliferator-activated receptor gamma), perpilin 1, CIDEC and leptin, are lower in the serum of children compared to those without AD.8 Most of these genes are downregulated in children without AD lesions.7
The expression of epidermal differentiation and proliferation markers and immune cell infiltrates was studied by immunohistochemistry. All age groups show increases in epidermal hyperplasia in AD lesional skin (assessed by thickness, Ki671 cell count, K16 staining, and mRNA expression).7 Staining for the proliferation marker K16 in the skin did not lesion with AD decreases with age (infants: 14/19 [74%], children: 5/10 [50%], adolescents: 6/13 [46%] and adults: 4/13 [31%]).7
Impairment of key markers of epidermal differentiation, FLG and LOR, is more significant in adult AD.7 In general, CD31+ T cells and all DC subsets are increased in lesional skin in all age groups, including children.7 The highest eosinophil and neutrophil counts are found in children, with eosinophil counts even higher in unlesional skin of children than in lesional skin of other age groups.7
Pediatric AD shows relatively normal expression of epidermal differentiation and cornification products, which are downregulated in adults with AD.9 Defects in the lipid barrier (ELOVL fatty acid elongase 3 and diacylglycerol o-acyltransferase 2 ) and regulation of tight junctions (e.g., claudins 8 and 23) are evident in children and adults.9 However, some components of the lipid barrier (lipid acyl-CoA reductase 2 and fatty acid 2-hydroxylase) show preferential downregulation in pediatric AD.9
The FLG gene encodes filaggrin, an epidermal structural protein.10 Individuals carrying loss-of-function variants of FLG may have a skin barrier disruption characterized by dry, cracked skin.11 Twenty FLG mutations were identified in European populations and 17 in Asians, although 40% of people with the FLG mutation do not have AD.12 Variants in FLG function are associated with lower levels of natural moisturizing factors in AD.13 This facilitates the penetration of allergens, the immune dysfunction and, consequently, increases the risk of developing eczema.14,15 Children carrying the p.R501* FLG variant were reportedly more likely to fail to respond to therapies.16
FLG loss-of-function variants may be specific to early onset (<2 years) of AD.11 One study investigated the effects of 8 FLG loss-of-function variants and found prominent effects during early life (≤2 years). ).17 Another study examined FLG 222del4 and showed an association with AD developed during infancy or early childhood, but not in late childhood or adulthood.18
Other susceptibility genes, gene-environment interactions, or even acquired barrier defects may be important for the development of late-onset AD. 18 FLG gene variants are associated with early-onset, persistent, and more severe AD, and with increased risk of asthma in patients with AD.19 Although FLG gene variants confer risk of AD, they do not appear to increase the risk of allergy to foods or aeroallergens independently of AD status.20
FLG messenger RNA and protein expression in the skin may be relatively intact in children with early-onset AD (<6 months).9,21 FLG expression is similar in some children with AD and healthy controls. In contrast, tight junctions and lipid barrier genes may be downregulated in children with AD,9,21,22 possibly explaining the compromise of epidermal barrier function in children with AD, but with low levels of FLG. and preserved loricrin.23,24
Finally, children have a greater body surface area in proportion to weight, making them more prone to significant percutaneous absorption. 25
3.2 | Immune dysregulation
In children, increased expression of Th17 and IFN-gamma was observed. observed in AD lesions, and Th22 and Th17 in nonlesional skin.26 Infants ≤2 years and adult AD skin ≥18 years have the most significant dysregulations compared to other AD age groups (6-11 and 12 -17 years).7
Infants had increased circulating regulatory T cells 27,28 and greater Th17 lineage capacity versus adults,29 with greater Th1 developmental potential,29 although infants exhibit the greatest Th17-related enrichment (e.g., interleukin (IL ) 17A and IL-17F), chronic and long-term AD in adults showed more Th1 bias (e.g., interferon-gamma and chemokine ligand (CXC motif) (CXCL)9/ CXCL10/CXCL11).
Disease activity correlates with serum levels of IL-31, chemokine (CC motif) ligand (CCL) 17, CCL22, CCL27, eosinophils and IgE, and a limited range of Th2/Th1 markers using mRNA expression. 30,31 Young children with AD have increased Th2 cells but not other polar T cell subsets in peripheral blood.32
Adults with AD also have increased Th22 cells.32 Pediatric AD also shows a significant Th17/Th22 bias but lacks the Th1 upregulation that characterizes adult AD.9
Surprisingly, nonlesional skin of infants and young children with AD shows significant hyperplasia and activated cytokines at levels as high or even higher than in nonlesional skin of adults.21 At 2 months of age and before the onset of AD , the infant’s unlesional skin contains increased thymic stromal lymphopoietin, a cytokine that drives Th2 cell differentiation.33
A study of AD patients in different age groups (0–5, 6–11, 12–17, and ≥18 years) found age-related differences in systemic immune profiles. 38 Counts were higher in infants and children with AD compared to control patients, and decreased with age among AD patients.34
CLA- (systemic) Th2 subsets were higher in childhood-onset AD.34 CLA+Th1 subsets were lower in infants with AD versus all older age groups, increasing with age in patients with AD. DA, as well as controls. IL-22 levels increased from normal in infants to elevated in adolescents and adults with AD.34
AD endotyping in adults by age (18–40, 41–60, and >61 years) suggests that unique subtypes exist for younger versus older adults. Zhou et al35 described decreased Th2/TH22 activation and increased Th1/Th17 activation in parallel with increasing age.36 Adult AD patients also exhibited normalization of epithelial abnormalities with increasing age. age. The expression of terminal differentiation markers LOR, FLG and S100As increases in older AD patients, while measures of hyperplasia (thickness, K16 and Ki67) decreased.35
Serum trends in AD mimicked skin findings, with downregulation of Th2 (CCL26) and upregulation of Th1 (IFN-γ) with age. 35 These data suggest that there is an “elderly” AD phenotype (>60 years).37,38
Diverse immune signatures in different age groups of pediatric and adult AD suggest that there are key age-related differences in AD immune system mechanisms.
3.3 | Microbiome
Atopic dermatitis (AD) is associated with multiple alterations of the microbiome.
Th2 inflammation increases Staphylococcus aureus binding and colonization of the skin.39,40 IL-4 and IL-13 inhibit the production of antimicrobial peptides in the skin,39 predisposing AD skin to S. aureus infections.39 Staphylococcus aureus further exacerbates skin inflammation and barrier defects.41,42
IL-4 and IL-13 inhibit TNF-α and IFN-γ-induced human beta-defensin (HBD)-3 through activation of STAT-6 production in keratinocytes,43,44 and cathelicidin production induced by TNF-α.39 IL-17 has antimicrobial effects through upregulation of antimicrobial peptides such as HBD-2 in keratinocytes. IL-17 can be detected in AD lesions and its antimicrobial effects are inhibited by IL-4 and IL-13.45 Successful treatment of AD restores normal skin barrier function and skin microbial diversity.46
The skin microbiome differs in pediatric versus adult AD.47 Younger children had a higher abundance of Streptococcus, Granulicatella, Gemella, Rothia and Haemophilus, while adults had a higher abundance of Propionibacterium, Corynebacterium, Staphylococcus, Lactobacillus, Finegoldia and Anaerococcus. 47 Specifically, Streptococcus salivarius/thermophilus/vestibularis was more abundant in young children, while P. acnes and S. epidermidis were more abundant in adults.47
Increased host sebum production and changes in skin structure around puberty may facilitate colonization with lipophilic bacteria, for example, Propionibacterium and Corynebacterium, 48 which replace Streptococcus and become dominant with age. adult.48-50
Staphylococcus and streptococcus species in the nasal passages are replaced by lipophilic and other bacteria during late adolescence/post-adolescence, which may contribute to the reduced incidence and severity of AD with age.49 Age-specific skin commensals possess various potentials in defending against pathogens and maintaining skin health and may partly explain age differences in AD.47
| 4 | Atopic comorbidities |
AD is associated with a higher prevalence of asthma and food allergy (AA).51,52
More severe AD is associated with an even higher prevalence of asthma, more severe and persistent asthma.53-55 As mentioned above, the FLG mutation is related to the susceptibility and severity of asthma in patients with AD.56
AD is associated with a higher likelihood of developing AA compared to their healthy peers.57 Specific IgE responses to food can be detected in the first months of life of children with AD, and peak at approximately 10%. prevalence at one year of age.58 As sensitization commonly occurs before food ingestion, it was proposed that transcutaneous penetration and food sensitization occurred in the inflamed skin and not in the gastrointestinal tract.
The Childhood Origin of ASThma study is a longitudinal birth cohort that identified 3 AD phenotypes: none/transient (62%, some disease early in life that disappears), late-onset (14%, express no disease in a early stage of life, but they express it from the school age of 4 to 6 years), and early/recurrent (24%, those who present the disease early and persist throughout childhood). 59 AA was associated with the early/recurrent phenotype. Asthma was associated with late onset and early recurrence phenotypes.59
It was once postulated that there is a predictable "atopic march" with AD appearing as the first atopic disease, food allergy appearing concomitantly or shortly after, followed by asthma at school age and hay fever in adolescence and adulthood.23 ,60 Among the predisposing factors, they are characterized by Th2 effector responses, generation of specific IgE and activation of lymphocytes. This paradigm emerged from cross-sectional studies or analyzes of longitudinal studies. A more recent longitudinal study of 9801 children examined temporal relationship profiles between eczema, wheeze and rhinitis.61
They found that the longitudinal profiles of eczema, wheeze and rhinitis are heterogeneous; only a small proportion of children (~7%) have a longitudinal profile that resembles atopic gait.61 These results highlight the need to think more critically about the co-expression patterns of atopic disease and AD phenotypes rather than “gait.” atopic” per se.
| 5 | Food allergens |
Rates of food allergies reach 5 to 8 percent in children and 3 to 4 percent in adults.62,63 Prevalence rates increased by 50 percent for food allergy overall between 1999 and 2011,62 63 and more than tripled between 1997 and 2008 for peanut and tree nut allergies.64,65
In HealthNuts, a large population-based study, 1 in 5 Australian babies with AD were found to have a food allergy compared to 1 in 20 without AD (n = 4453).66 The most common food allergens in children with AD DA include cow’s milk, egg, wheat, soy, and tree nuts/peanuts.67-69
Although food allergy is very common in people with AD, foods are not triggers for AD per se in most people. Two studies examined late eczematous reactions after oral food challenges.
Many AD patients with suspected food allergies did not have positive oral food challenges, and only a minority of positive oral food challenges manifested with late eczematous reactions (12%70 and 25%71).
Food allergen triggers appear to be more common in younger children than in adults with AD, and in individuals with moderate-severe AD.72
However, patient-reported food hypersensitivity is often not confirmed with formal challenges. Common culprit foods such as carrots, celery, and hazelnuts can cross-react with aeroallergens.73
Clinical entities due to IgE sensitization to cross-reactive aeroallergens and food allergen components are described for many plant sources (pollen-food syndromes and associations, such as birch-apple, cypress-peach, and celery-sagebrush syndromes, and associations sagebrush-peach, sagebrush-chamomile, sagebrush-mustard, ragweed-melon-banana, goosefoot-melon),74 of fungal origin (Alternaria-spinach syndrome), and of invertebrate, mammalian or avian origin (syndromes mite-shrimp, cat-pig and bird-egg),74 while the food allergens classically implicated in childhood AD do not appear to have relevant cross-reactive aeroallergens.73
| 6 | Comorbid allergic contact dermatitis |
Allergic contact dermatitis ( ACD) can occur in AD patients of all ages, even among infants,75 although adults with AD are generally more likely than children to have comorbid ACD. A recent consensus guideline recommended that patch testing be considered in all patients with AD of adolescent or adult onset, because AD may occasionally present with a flexural distribution and mimic AD.75,76
Patients with AD have a higher prevalence of CAD than the general population, with notably higher rates of positive patch test reactions to ingredients in their topical medications and personal care products.77-79
The epicutaneous patch test is the gold standard for the diagnosis of DAC, but can be technically difficult to perform in children, has low sensitivity, and limited access for many patients worldwide.
Initial empirical avoidance of topical allergens has a favorable cost:benefit ratio.75 Patients and caregivers should be counseled on the safe use of topical products, including avoidance of irritants and allergens common in AD (e.g., fragrances, methylisothiazolinone/methylchloroisothiazolinone, cocamidopropyl betaine and propylene glycol).75
| 7 | Age-related differences in the clinical presentation of AD |
Symptoms of AD that are similarly prevalent in children and adults include1 pruritus, personal or family history of atopy, intolerance to foods, wool, and lipid solvents.1 Signs of AD that are similarly prevalent in pediatric and adult AD include1 xerosis, flexural, extensor involvement, immediate reactivity to skin tests, elevated total IgE, and skin infections.
Compared to adults, pediatric patients have higher prevalences of dermatitis on the eyelids, auricular area, and ventral wrists; exudative eczema; features similar to seborrheic dermatitis; and early-onset disease (defined by age of onset less than 2 years). In contrast, adults had higher pooled prevalences of lichenification, erythroderma, disease course influenced by environmental and emotional factors, ichthyosis, palmar hyperlinearity, keratosis pilaris, nonspecific dermatitis of hands and feet, dyshidrosis, nodular prurigo, and papular lichenoid lesions. .1
Other less common features that were found in similar proportions of children and adults overall included head and neck dermatitis (especially face, anterior neck, scalp, and auricular involvement), cheilitis, ophthalmic comorbidities (including orbital darkening, anterior subcapsular cataracts, , recurrent conjunctivitis and keratoconus), exfoliative keratolysis, white dermographism/delayed whitening, nummular plaques, “dirty neck”, nail involvement (pitting, shine and leukonychia), nipple eczema, cracked heels, infraglute dermatitis, genital and tongue involvement geographical.1
While head and neck involvement has a similar prevalence in children and adults (38% and 39%), there may be marked differences related to the age of presentation.1 Infants with facial dermatitis most frequently present with acute eczema with suppurating, moist lesions and with a presentation similar to seborrheic dermatitis, while facial dermatitis in adults often presents with more chronic lichenified lesions or erythematous patches reminiscent of erythematotelangiectatic rosacea.
Adults have higher prevalences of lichenification (adults: 100%; children: 48%), urticaria lesions (adults: 32%; children 20%), lichenoid papular lesions on the back of hands (adults: 46%; children 8% ), Hertoghe’s sign (thinning or loss of the lateral third of the eyebrows) (adults: 25%; children: 2%), erythroderma (adults: 29%; children: 1%) and prurigo nodules (adults: 18%; children: 4%). Of course, AD erythroderma must be distinguished from cutaneous T-cell lymphoma, contact dermatitis, and psoriasis.
Hand eczema is more common and often manifests differently in adults than in children. AD is one of the strongest risk factors for developing hand eczema in adulthood. In children, hand eczema is typically located on the back of the hands and ventral area of the wrists with more acute or subacute lesions, with light palms. While adults have more chronic lesions on the back of the hands, including dorsal lichenoid papules, lichenification and knuckle dermatitis, as well as chronic vesicular dermatitis on palms and fingers, chronic fissures and dry eczema pattern.
Exudative lesions are more common in children (61%) than in adults (42%).1 Pityriasis alba is common in children, but rare in adults.1 Follicular eczema (perifollicular accentuation) is also reportedly more common in children (37%) than in adults (21%). Follicular eczema is a particularly important morphological variant in skin of color, which must be differentiated from keratosis pilaris and folliculotrophic mycosis fungoides.1 Infraorbital Dennie-Morgan folds and seborrheic dermatitis-like lesions are also more common in children.1 Adults reportedly get the itching worse from sweating.1
In pediatric AD, a high index of suspicion for secondary infection should be maintained,80 including molluscum, herpes simplex virus, scabies, ringworm, and group A streptococci.81 Eczema herpeticum occurs in <3% of patients with AD and affects more commonly in infants and children than in adults.82,83 The risk of Epstein-Barr virus (EBV) infection may occur more commonly in adults with severe AD.84
Of interest, among children with AD, EBV infection increased slightly in mild cases but decreased in moderate to severe disease.84 One study showed an increased risk of incident herpesviruses, serious and opportunistic infections ranging from 34 200% in children and only 17 to 68% in adults with AD compared to those without AD.84
| 8 | Assessment and differential diagnosis of da in children |
When evaluating a child with probable AD, it is important to evaluate the morphology and distribution of the lesions, perform a thorough review of the systems, and whether the child has normal growth. In healthy children, the differential diagnosis includes seborrheic dermatitis, contact dermatitis, and psoriasis. Other differential diagnoses include metabolic (i.e., cystic fibrosis, severe dermatitis, multiple allergies, and metabolic wasting syndrome [MAS]) and immunodeficiency-associated dermatitis.
Grooming of the diaper area is common in babies with AD due to wet conditions and the physical barrier to scratching. Involvement of the diaper area suggests other primary diagnoses in a healthy infant, such as irritant or allergic contact dermatitis, seborrheic dermatitis, and psoriasis.
In a healthy infant with AD and diaper area involvement, secondary diagnoses should be considered, such as irritant or allergic contact dermatitis, staphylococcal or streptococcal infection, and candida infection.
Children who are otherwise unhealthy (e.g., poor growth/frequent infections) with involvement of the diaper area should be evaluated for syndromic causes with eczematous rashes, such as Netherton syndrome, cystic fibrosis presenting with zinc, leukemoid reaction of trisomy 21 and severe combined immunodeficiency due to complete RAG1/2 deficiency (Omenn syndrome). It is always advisable to monitor the child’s growth curves in case of lack of growth due to metabolic dermatitis or immunodeficiency.
| 9 | Conclusions |
Many core features of AD are similar between children and adults, including flexural eczema, comorbid atopy, and xerosis.
- Adults have more signs of chronic disease, more hand eczema and different patterns of hand eczema, and a stronger relationship of disease activity with emotional factors .
- Children have more exudative lesions, perifollicular accentuation, pityriasis alba, Dennie - Morgan folds, and presentation similar to seborrheic dermatitis.
This disease heterogeneity may be in part due to differences in genetics and immune dysregulation between children and adults with AD. Atopic diseases are common comorbidities of AD, although most children and adults with AD do not follow the “atopic march.”
