Allergic March

A child with atopic allergies (particularly early-onset atopic dermatitis) may acquire further allergic conditions in a process known as the allergic march. Early signs may lessen as others become more prominent.

The terms atopic multimorbidity or atopic cluster, rather than allergic march, may better reflect the variability in the prevalence, timing, and sequence of acquisition of atopic conditions.

Despite the variability in additive atopic disease acquisition, there is strong and abundant evidence that infants and children with 1 atopic disease are at increased risk for other atopic conditions.

A prospective cohort study found that children with eczema have 3-fold increased odds of developing asthma, compared to children without eczema. Further, they have nearly 3-fold increased odds of developing rhinitis at 5-year follow-up compared to children without eczema.

In a longitudinal study of 94 children with atopic dermatitis, children up to 7 years of age were monitored, and investigators found that atopic dermatitis is associated with other atopic conditions.

• In total, 43% of study participants developed asthma.
  • The risk of developing asthma was higher in children with a family history of eczema.
  • Asthma was far more likely in those with severe disease.
    • 70% of patients with severe atopic dermatitis developed asthma, compared to 20% to 30% of patients with mild atopic dermatitis. This is compared to 8% in the general population.
• 45% of study participants developed allergic rhinitis.
• Severe eczema was associated with an increased tendency to produce food-specific IgE.
• Early onset of eczema was associated with an increased risk of sensitization to inhalant allergens and development of urticaria.

A retrospective study of a large cohort (10,688) of infants and toddlers with atopic dermatitis revealed that the presence of food allergy in addition to atopic dermatitis by 36 months of age significantly increased the number of asthma visits between ages 5 and 11 years.

• Asthma visits between ages 5 and 11 years were more common in children who had atopic dermatitis and food allergy (47%) when compared to children who had atopic dermatitis without food allergy (30.4%).
• Eosinophilic esophagitis was significantly more common in children with atopic dermatitis and early food allergy.
• Children who had atopic dermatitis with a food allergy by 36 months of age were also more likely to have allergic rhinitis (31.6%) when compared to children who had atopic dermatitis without food allergy (13.2%).
• Children with atopic dermatitis and food allergy who progressed to asthma were more likely to have an earlier onset of atopic dermatitis.

In general, factors most associated with progression along the allergic march are

• Early onset of atopic dermatitis
• Parents with atopy
• Multiple early sensitizations (inhalants or food)
• Higher severity of atopic disease
• Presence of filaggrin gene (FLG) mutation
• Environmental stressors (eg, pollutants, endotoxins, viruses)

In a study of infants who received a diagnosis of atopic dermatitis at younger than 1 year, patient-related risk factors for the development of allergic march diseases included

• Male sex
• Severe atopic dermatitis
• Cesarean delivery
• Maternal antibiotic use during pregnancy

Thus, genetic predisposition is a key driver of the allergic march, which can manifest as early atopic dermatitis, coupled with additional risk factors. Environmental factors may further influence the march, as does exposure of the immune system to antigens. If the skin barrier is disrupted, antigen exposure via the skin (instead of the normal exposure through the gut) may result in allergic sensitization and potentially clinical allergic disease.

The sequence of the allergic march often follows a progression from the skin to the gut and the respiratory tract.

The sequence of allergic conditions in the allergic march is variable. However, atopic dermatitis is considered to be the most common initial condition.

In a large retrospective cohort study of more than 82,000 infants and children, investigators examined the relationship among 4 of the major conditions of the allergic march over 8 years (atopic dermatitis, food allergy, allergic rhinitis, and asthma).

The results showed that early atopic dermatitis was associated with asthma, allergic rhinitis, and food allergy; atopic dermatitis was the most common initial atopic condition. Additionally, fewer than 2.5% of children had an atopic condition that developed before early atopic dermatitis.

The most common temporal progression of the allergic march in children who developed all 4 major allergic conditions followed 1 of 2 tracks.

Although the 2 sequences outlined in the exemplar progression (Figure) are the most common, other sequences are also relevant.

• Approximately 12% of infants with atopic dermatitis before 12 months of age developed asthma as their second atopic condition, and 11% next developed an early food allergy.
  • When food allergy occurred as a second atopic condition, the lapse between diagnosis of atopic dermatitis and food allergy was short (weeks to months, rather than years).
• A child who acquires multiple atopic morbidities may also have airway allergic disease or food allergy as the initial condition.

Multiple atopic morbidities arising from common underlying mechanisms, each with a specific range of typical expression, might be a more accurate conceptual model than a rigid, linear progression.

Key Clinical Considerations for Pediatricians

Extensive research is focused on preventing atopic conditions; only a few strategies appear to be effective.

The primary prevention of atopic conditions is mainly targeted at preventing early atopic dermatitis and food allergy. Children with both atopic dermatitis and food allergy are at higher risk for other atopic conditions. Good evidence exists that early introduction of allergenic foods (eg, peanut) can prevent the development of allergy—a systematic review and meta-analysis noted that both early peanut and egg ingestion had a role in food allergy prevention.

Current research into the prevention of atopy include the following strategies:

Breastfeeding

• Some research shows that being breastfed exclusively for 3 to 4 months reduces the risk of atopic dermatitis before 2 years of age and reduces the risk of allergic rhinitis for those younger than 5 years, though the evidence is not conclusive.
  • No short- or long-term advantages are evident for being exclusively breastfed beyond 3 to 4 months for preventing atopic disease.
  • Breastfeeding of any duration is not associated with reducing the risk of developing a specific food allergy.
  • Maternal diet restriction is not effective for preventing atopic diseases and food allergies.
• A systematic review and meta-analysis of 42 studies showed that breastfeeding duration and the level of exclusivity of the breastfeeding is associated with a reduction in wheezing or asthma in children younger than 7 years.
• Strong evidence supports the early introduction of allergenic foods—around 4 to 6 months, once the infant is developmentally ready. This may help lower the risk of developing food allergies, especially for peanut and egg. This is based on randomized trials and multiple guideline updates.

Dust Mite Avoidance

A 2015 systematic review and meta-analysis of mono-faceted and multifaceted dust mite avoidance techniques found:

• Avoiding dust mites was generally effective at reducing exposure to dust mites, but it was ineffective at preventing both sensitization to dust mites and atopic dermatitis.
• One trial had significantly increased sensitization to dust mites in the intervention group, despite having the most extensive dust interventions of all reviewed trials. Interventions were
  • Removing carpet and placing vinyl flooring in an infant’s room
  • Using mattress encasings and cots
  • Using acaricides
  • Using a high-filtration vacuum cleaner
  • Washing bedding in hot water

Vitamin D Supplementation

The World Allergy Organization reviewed evidence regarding vitamin D and allergy prevention and concluded that there is no support for providing vitamin D to mothers or infants to prevent allergic disease. (Vitamin D is often appropriately recommended for other indications.)

Immunotherapy

Allergy immunotherapy is a method of desensitization (tolerization) that can be either administered subcutaneously or dissolved sublingually. Allergy immunotherapy may reduce the risk of developing asthma in patients with allergic rhinitis and may prevent new sensitizations. While national allergy associations suggest a possible preventive effect, evidence is mixed and not yet definitive.

Diet

The timing and type of complementary food introduction has recently been of great interest, given multiple studies (LEAP, LEAP-On, EAT) that have demonstrated specific food avoidance may prevent normal tolerization pathways, encouraging early introduction of foods commonly known to cause allergy.

Dietary Diversity

Ongoing studies are exploring the idea that a diverse diet of complementary foods in infants older than 6 months may lead to the prevention of allergic diseases.

• The US Department of Agriculture (USDA) and Department of Health and Human Services (HHS) Pregnancy and Birth to 24 Months (P/B-24) study showed insufficient evidence linking food diversity and risk of allergic diseases.
  • Further, limited evidence supports a lack of association between allergic diseases and exposure to a variety of fruits, vegetables, and meats.
• A European Academy of Allergy and Clinical Immunology (EAACI) systematic review of diet diversity used a modified Delphi method to achieve expert consensus that diet diversity in infancy may be associated with reduced allergy outcomes but stated that additional studies are required to investigate this association more clearly.
• A 2024 study found that both higher maternal diet index during pregnancy and higher infant diet diversity at 12 months were independently associated with reduced risk of combined allergic disease outcomes between ages 1 and 4 years.

Specific Dietary Components

A 2019 systematic review known as P/B-24 was a collaborative effort by the USDA and HHS and investigated, among other things, the effect of diet on atopic dermatitis, food allergy, asthma, and allergic rhinitis. A review of 51 studies concluded the following regarding allergic disease and diet:

Atopic Dermatitis

• Limited evidence suggests that introducing fish in the first year after birth (after 4 months of age) may reduce the risk of atopic dermatitis (eczema).
• Limited evidence suggests there is no relationship between age of introduction of cow milk products, egg, peanuts, tree nuts, or sesame and the risk of atopic dermatitis.
• Limited evidence from observational studies suggests that introducing foods not commonly considered to be allergens (eg, fruits, vegetables, meat) between 4 and 12 months is not associated with risk of atopic dermatitis.

Food Allergy

• Strong evidence suggests that the introduction of peanut between 4 and 12 months is protective against peanut allergy.
• Moderate evidence supports a relationship between introducing egg between 4 and 12 months and a reduced risk of egg allergy.

Asthma

• Limited evidence suggests that there is no relationship between consuming egg, peanut, tree nuts, or sesame seeds during the complementary feeding period and risk of asthma.
• Limited evidence from observational studies suggests that introducing foods not commonly considered to be allergens (eg, fruits, vegetables, meat) between 4 and 12 months is not associated with risk of asthma.

Treating atopic dermatitis may interrupt the allergic march.

Most patients with mild-to-moderate atopic dermatitis may be successfully treated with skin care, topical anti-inflammatory medications, and avoidance of skin irritants. See specific summary information on the treatment of atopic dermatitis.

Young children with severe or treatment-refractory atopic dermatitis may require other therapies if typical skin-care routines and topical anti-inflammatory medications are ineffective.

Emollients

Moisturizers are critical for the care of atopic dermatitis. The best moisturizers are ones that patients will use regularly. The American Academy of Allergy, Asthma and Immunology (AAAAI)/American College of Allergy, Asthma and Immunology (ACAAI) Joint Task Force on Practice Parameters (JTFPP) 2023 guidelines suggest not using prescription moisturizers. Rather, a fragrance-free over-the-counter moisturizer is preferable.

Emollients can also reduce the risk of epicutaneous sensitization. While the use of moisturizers may not prevent atopic dermatitis from ever manifesting, it can be used to prevent or reduce flares in patients with a genetic predisposition to atopic dermatitis. An American Academy of Pediatrics clinical report provides information on the use of emollients in preventing skin flares of infants and children who already have atopic dermatitis.

Topical Treatment

In patients with uncontrolled atopic dermatitis that is refractory to moisturizer alone, the following topical treatments are recommended:

• In cases of mild disease, calcineurin inhibitors can be used twice daily on small areas of skin for infants and children at least 3 months of age.
  • Tacrolimus is approved for children at least 2 years of age, and for younger children it has been used off-label effectively, with a good safety profile.
  • Pimecrolimus is a prescription, topical calcineurin inhibitor cream that can be used to treat mild-to-moderate atopic dermatitis.
• Topical corticosteroids can be used for atopic dermatitis in infants younger than 3 months. They are often recommended for use twice daily. Numerous topical corticosteroids of varying levels of potency are available.
• Topical phosphodiesterase 4 (PDE4) inhibitors, such as crisaborole 2% ointment, are recommended for mild-to-moderate dermatitis.
• In 2024, the US Food and Drug Administration (FDA) approved roflumilast cream 0.15% for mild-to-moderate atopic dermatitis in children at least 6 years of age. Roflumilast is a selective PDE4 inhibitor. Ongoing studies are looking at alternate dosing in younger age-groups.
• Topical Janus kinase (Jak) inhibitors, such as ruxolitinib, can be considered in certain patients at least 2 years of age. However, in the 2023 AAAAI/ACAAI JTFPP guidelines, in adolescent and adult patients with mild-to-moderate atopic dermatitis that was refractory to moisturization alone, the JTF panel suggested against adding topical ruxolitinib over continued usual care alone. Concerns about systemic absorption with topical Jak inhibitors are sufficient to limit the application of ruxolitinib to less than 20% body surface area. Additionally, the FDA has placed a boxed warning label on all Jak inhibitors owing to a study in rheumatoid arthritis with an oral pan-Jak inhibitor, tofacitinib.
• In December 2024, tapinarof cream was approved for children with atopic dermatitis aged at least 2 years. Tapinarof cream is an aryl hydrocarbon receptor agonist that suppresses the immune system primarily by interfering with inflammatory signaling via the NF-κB pathway.
• Wet wraps can be used with a topical low- to mid-potency steroid, for a limited period and body surface area.

Systemic Therapies

• Allergen immunotherapy is recommended in moderate and severe atopic dermatitis if the child’s condition is refractory or if the child has an intolerance or is unable to use mid-potency topical treatments.
• Biologics (monoclonal antibodies)
  • With a high certainty of evidence, dupilumab is recommended in infants and children at least 6 months of age who have moderate or severe atopic dermatitis whose condition is refractory or who have an intolerance or are unable to tolerate mid- to high-potency topical treatments.
  • With a high certainty of evidence, tralokinumab is recommended for use in children and adolescents at least 12 years of age who have moderate or severe atopic dermatitis and whose condition is refractory or who have an intolerance or are unable to tolerate mid- to high-potency topical treatments.
  • Lebrikizumab was recently approved to treat moderate-to-severe atopic dermatitis in children and adolescents at least 12 years of age.
• Phototherapy treatment. Clinic-based, narrow-band UV-B treatment can be offered to older children with moderate-to-severe atopic dermatitis who are able to safely receive phototherapy treatment whose condition is refractory or who have an intolerance or are unable to tolerate mid- to high-potency topical treatments inclusive of an appropriate biologic agent.
• Oral Jak inhibitors are suggested, with low certainty of evidence, in patients with moderate-to-severe atopic dermatitis whose condition is refractory or who have an intolerance or are unable to tolerate mid- to high-potency topical treatments inclusive of an appropriate biologic agent.
  • Agents include abrocitinib and upadacitinib. Agents vary in age of approval, between 12 and 18 years of age.
  • As noted earlier, these agents carry an FDA boxed warning. The clinician must consider comorbidities, risk factors, values and preferences, and exceptional circumstances.
• Immunosuppressant therapy can be considered when other options are not optimal choices, are not tolerated, or are ineffective.

Recommendations against specific therapies for children include:

• Baricitinib 1 mg daily
• Azathioprine
• Cyclosporine
• Methotrexate
• Mycophenolate
• Systemic corticosteroids

Biologics and Risk Reduction for Allergic March

Biologics are molecularly targeted drugs derived from living organisms. Monoclonal antibodies are 1 type of biologic used to treat allergic disease.

Examples of biologics used to treat atopic disease in children in the United States are shown in the following table:

Skin Microbiome Research

The microbiome of normal skin benefits the host by:

• Providing barrier protection against pathobiological invasion
• Educating the immune system to respond to microbes that may break through the skin barrier
  • Diverse microbiota are needed to appropriately educate the immune system. 

The skin of patients with atopic dermatitis is characterized by a defective barrier, which leads to overstimulation of the immune system. There is increased activation of the T_H2 immune response, leading to:

• Increased infiltration of CD4⁺ cells
• Increased levels of prototypical T_H2 cytokines
• Impaired function of important skin barrier proteins such as FLG and loricrin, worsening the impaired skin barrier
• Microbiome alterations, including:
  • A reduction in microbial diversity
  • Reduction of Staphylococcus epidermidis
  • Overgrowth of Staphylococcus aureus

Patients with FLG mutations have an increase in skin pH level that leads to the overgrowth of S aureus. In a study of children and adolescents with atopic dermatitis (2–18 years), overgrowth of S aureus correlated with severe atopic dermatitis flares.

The translation of microbiome research into treatment options is still in its infancy. Options currently under investigation include:

• Phages that infect S aureus strains selectively (leaving S epidermidis)
• Synthetic peptides that target biofilms formed by S aureus
• Topical application of mixed microbiota

Currently, these treatment options are not available in clinical practice. However, at least 2 therapies have been shown to alter the skin microbiota.

• Phototherapy (UV-B) results in skin microbiota diversity in adults with atopic dermatitis.
• Dupilumab has been shown to decrease S aureus abundance and increase microbial diversity.

Interestingly, bleach baths have not been shown to correct overgrowth of S aureus or change the skin microbiota, although they can reduce itch and increase barrier function.

Further research into correcting alterations in the skin microbiome may be useful in treating children with atopic dermatitis and, thus, in interrupting the allergic march.

Genomic Studies

Genomic studies may have clinical relevance in helping to identify the children most at risk for atopic disease.

Recently, researchers defined a polygenic score for increased IgE levels.

• Polygenic score models specify a set of single nucleotide polymorphisms and their weights. These statistical models are used to create algorithms that can be used in clinical practice to calculate a risk score.
• Polygenic scores are a potential tool for early prediction and intervention for food allergies and other IgE-mediated diseases, although they are not currently recommended in clinical practice for this purpose.

Pediatricians should consider referral to subspecialists when:

• The diagnosis of atopic dermatitis is uncertain.
• Moderate or severe eczema is present.
• Moderate or severe eczema is not well controlled with skin-directed therapies.
• Concerns arise regarding the amount and side effects of topical steroids and calcineurin inhibitors.
• Recurrent skin infections occur.
• A child has a life-threatening asthma exacerbation or intensive care admission.
• The asthma is difficult to control.
• Additional diagnostic tests are needed for uncontrolled asthma (eg, allergy skin testing).
• Suspected food allergies arise.
• Severe effects on quality of life occur, including poor school attendance, sleep disturbances, and/or caregiver distress.
• Discomfort or inexperience in treating atopic eczema is present.
• Any potential signs of eosinophilic esophagitis, as endoscopy and biopsy may be needed to establish a diagnosis.

Pediatric subspecialists include:

• Allergists/immunologists
• Dermatologists
• Gastroenterologists
• Pulmonologists
• Eating disorder specialists
• Registered dieticians and feeding specialists (eg, speech-language pathologists, occupational therapists)
• Mental and behavioral specialists (eg, clinical or school psychologists, licensed social workers, clinical therapists)

Treatment that subspecialists may consider include:

• Phototherapy
• Systemic medications
  • Biologics
  • Allergen immunotherapy
  • Immunosuppressants

• Atopic Dermatitis (Eczema) Guidelines: 2023 American Academy of Allergy, Asthma and Immunology/American College of Allergy, Asthma and Immunology Joint Task Force on Practice Parameters GRADE– and Institute of Medicine–Based Recommendations
• Consensus-Based European Guidelines for Treatment of Atopic Eczema (Atopic Dermatitis) in Adults and Children: Part I
• Consensus-Based European Guidelines for Treatment of Atopic Eczema (Atopic Dermatitis) in Adults and Children: Part II
• Management of Food Allergy in Schools: Clinical Report
• Atopic Dermatitis: Update on Skin-Directed Management: Clinical Report
• Anaphylaxis Definition, Overview, and Clinical Support Tool: 2024 Consensus Report—a GA2LEN Project