Paradigms and perspectives

Atopic dermatitis, food allergy, anaphylaxis, and

other atopic conditions
Michelle L. Hernandez, MD,a Pedro Giavina Bianchi, MD,b Richard Lockey, MD,c and Sarita U. Patil, MDd Chapel Hill, NC;
S~
ao Paulo, Brazil; Tampa, Fla; and Boston, Mass
Key words: Asthma, food allergy, atopic dermatitis, anaphylaxis FA affects approximately 2.5% of the US population, with a
higher prevalence among children,4 and it frequently occurs in pa-
Asthma, a widespread chronic condition, affects more than 260 tients with asthma and AD. FA is a risk factor for development of
million people globally. In the United States alone, it affects 6.5% asthma, which may be attributable to shared risk factors in early
of children and 8% of adults. If not properly managed, asthma can life, including parental atopy.5 Allergic sensitization to foods
lead to severe morbidity and even death. Asthma often coexists alone by age 24 months increases future asthma risk 4.9-fold,6
with other atopic diseases, such as atopic dermatitis (AD) and highlighted by food sensitization, which is a minor criterion for
food allergy (FA).1 These interconnected conditions may mani- the Modified Asthma Predictive Index. In the United States,
fest concurrently or sequentially, forming what is known as the non-Hispanic Black populations are at increased risk for both dis-
atopic march. The shared pathophysiology among these atopic eases.4 Eosinophilic esophagitis (EoE), which can begin at any
diseases underscores the need for an integrated approach to com- point in life, is driven primarily by food allergens and strongly
prehending and addressing these conditions, ultimately promot- associated with atopy.7
ing optimal health outcomes. The link between FA among individuals with asthma is of great
importance, given that the presence of FA is a risk factor for
asthma severity and morbidity. For example, the School Inner-
EPIDEMIOLOGIC EVIDENCE City Asthma Study found that 24% of children with asthma had
AD is the most common inflammatory skin disease of comorbid FA, and those children had increased health care
childhood, with a lifetime prevalence ranging from 10% to utilization and reduced lung function.8 Furthermore, individuals
20% and often manifesting in early life, although adult-onset with asthma are at higher risk of death due to anaphylaxis as a
AD also occurs.1 Early-onset, severe, persistent AD is result of their FA,5 influenced by increased baseline airway hyper-
associated with an increased risk of allergic disease, including reactivity. Thus, the diagnosis and management of comorbid
atopic respiratory disease.1 Children and adults with AD have a asthma and FA are essential to improve health outcomes.
2 to 3 times higher chance of developing asthma, whereas adults
with asthma have a 4 times higher chance of developing AD
(Table I2,3). PATHOPHYSIOLOGY AND THE INTERSECTION OF
Longitudinal studies have identified AD endotypes associated ASTHMA, AD, AND FA, INCLUDING EOE
with a higher risk for subsequent development of respiratory Studies of the immunologic mechanisms underlying atopy
allergies: sensitization and early onset of AD; polysensitization; reveal common pathophysiologic processes driving asthma, AD,
filaggrin mutation; persistent and more severe AD; and family and FA development and progression. Targeting these pathways
history of atopy.1 AD with food sensitization would represent a has led to a rapid burst in new therapies and therapeutic
specific endotype of AD, in which patients are more predisposed indications for existing therapies, leading to better management
to having or developing other atopic comorbidities. However, it is strategies for asthma and its comorbid conditions (Fig 1). These
important to note that this association between skin and respira- strategies have evolved from medications that modulate multiple
tory conditions is also observed when there is no evidence of pathways, such as corticosteroids, to more molecular-based bio-
IgE-mediated sensitization.1 This highlights the importance of logic therapies.
discerning distinct endotypes to understand the mechanisms The interaction between allergens with epithelial perturbation
driving these disease processes. of skin and mucosal surfaces results in downstream alarmin
signaling, which initiates adaptive immune responses that are key
From athe Division of Allergy and Immunology, Department of Pediatrics, University of to the process of allergic sensitization. Epithelial activation
North Carolina School of Medicine, Chapel Hill; bthe Clinical Immunology and Al-
lergy Division, University of S~ao Paulo School of Medicine; cthe Division of Allergy
specifically leads to the release of the alarmins IL-33 and thymic
and Immunology, Department of Internal Medicine, University of South Florida Mor- stromal lymphopoietin (TSLP), which propagates mucosal
sani College of Medicine, Tampa; and dthe Division of Allergy and Immunology, De- allergic responses. Large genome-wide association studies have
partments of Medicine and Pediatrics, Massachusetts General Hospital, Harvard identified associated polymorphisms in filaggrin and TSLP with
Medical School, Boston.
AD, asthma, and EoE. The research focused on alarmin blockade
Received for publication June 4, 2024; revised October 15, 2024; accepted for
publication October 16, 2024. led to the 2021 approval of anti-TSLP antibodies for the treatment
Available online October 19, 2024. of asthma, with ongoing clinical trials in EoE.
Corresponding author: Sarita U. Patil, MD, 55 Fruit St, Yawkey 4B, Boston, MA 02114. Adaptive mechanisms of allergic sensitization have focused on
E-mail: [email protected]. the central role of pathogenic TH2 cells in asthma, AD, IgE-
J Allergy Clin Immunol 2024;154:1416-8.
0091-6749/$36.00
mediated FA, and EoE. For instance, targeting the TH2 cytokines
Ó 2024 American Academy of Allergy, Asthma & Immunology IL-4 and IL-13, which are produced by these cells, results in the
https://doi.org/10.1016/j.jaci.2024.10.011 successful treatment of eosinophilic asthma, AD, and EoE.9 The

1416
J ALLERGY CLIN IMMUNOL HERNANDEZ ET AL 1417
VOLUME 154, NUMBER 6

TABLE I. Epidemiology of atopic comorbidity: Prevalence of comorbidity of asthma, AD, and FA or sensitization
Associated disease
Primary disease General population prevalence Asthma AD FA
2
Asthma 10% 100% 38% 24% (children)2
AD 20% (children) 2- to 3-fold2 100% 54.9%3
10% (adults)
Food sensitization/FA 2.5% 4.9-fold (children)3 40.7%3 100%

FIG 1. Pathophysiology of atopic comorbidities. Shared mechanisms and treatments underlying the
pathogenesis of comorbid asthma, AD, FA, and EoE. ILC2, Group 2 innate lymphoid cell; IT, immuno-
therapy; peTH2, pathogenic effector TH2. Figure created with BioRender.com.

downstream production of allergen-specific IgE, driven by TH2 specific IgG4 antibodies. The burst of new and effective therapies
cytokines, including the generation of both long-term plasma has led to many new immunomodulatory therapies, including
cells and short-term IgE-producing B cells that are sequentially anti–IL-5 therapy and Janus kinase inhibitors, which have been
switched from TH2 cytokine–primed IgG B cells, results in approved in asthma and AD, respectively, and are now in clinical
allergen-specific IgE production. In turn, IgE primes effector trials for use with EoE and FA.
cells, such as mast cells, to degranulate on binding to allergens,
resulting in both local and systemic inflammatory responses.
Translationally, depletion of IgE with anti-IgE therapy results in CLINICAL MANAGEMENT
clinical improvement in asthma and IgE-mediated FA. New ther- The ability to target the pathophysiologic intersection of
apies targeting IgE plasma cells are in the early stages of clinical multiple diseases has led to significant clinical innovation, with
trials. Allergen-specific therapies, such as allergen immuno- decreasing side effects and improved clinical outcomes. Man-
therapy, benefit allergen-driven asthma, AD, and IgE-mediated agement is therefore centered on diagnosis and phenotyping of
FA, by both suppressing effector cells and inducing allergen- asthma, AD, and FA, with a heavy focus on patient education.
1418 HERNANDEZ ET AL J ALLERGY CLIN IMMUNOL
DECEMBER 2024

Education on avoidance of both food and aeroallergen triggers is effectiveness, all while prioritizing equitable access to these
essential. With the multitude of therapeutic options now avail- exciting therapeutic options.
able, discussion of the impact of each disease individually and
collectively is essential. For instance, patients with asthma and
IgE-mediated FA should receive both FA and asthma action plans DISCLOSURE STATEMENT
highlighting the need for epinephrine administration in a timely Disclosure of potential conflict of interest: M. L. Hernandez
fashion when inadvertent exposure to a food leads to the onset of a serves on an advisory board for GSK. S. U. Patil has a consultancy
systemic allergic reaction. agreement with Buhlmann and Mabylon. The rest of the authors
Moreover, biologics targeting shared pathways can lead to a declare that they have no relevant conflicts of interest.
significant impact on patient quality of life. Anti-IgE therapy with
REFERENCES
omalizumab, which was previously approved for severe asthma in 1. Paller AS, Spergel JM, Mina-Osorio P, Irvine AD. The atopic march and atopic
individuals aged 6 years and older in the United States, is now also multimorbidity: many trajectories, many pathways. J Allergy Clin Immunol
approved to reduce allergic reactions from IgE-mediated FA for 2019;143:46-55.
children aged 1 year and older. A previous observational study of 2. Ravnborg N, Ambikaibalan D, Agnihotri G, Price S, Rastogi S, Patel KR, et al.
Prevalence of asthma in patients with atopic dermatitis: a systematic review and
children treated with omalizumab for severe asthma with comor-
meta-analysis. J Am Acad Dermatol 2021;84:471-8.
bid FA found increased quality of life and a reduced number of 3. Christensen MO, Barakji YA, Loft N, Khatib CM, Egeberg A, Thomsen SF, et al.
reactions to accidental food exposures.10 Another medication that Prevalence of and association between atopic dermatitis and food sensitivity, food
targets multiple atopic diseases is the TH2 cytokine–targeting allergy and challenge-proven food allergy: a systematic review and meta-analysis.
therapy dupilumab, which has been approved for management J Eur Acad Dermatol Venereol 2023;37:984-1003.
4. Liu AH, Jaramillo R, Sicherer SH, Wood RA, Bock SA, Burks AW, et al. National
of asthma, AD, and EoE in both children and adults. The develop- prevalence and risk factors for food allergy and relationship to asthma: results from
ment or worsening of allergic conditions indicative of the atopic the National Health and Nutrition Examination Survey 2005-2006. J Allergy Clin
march, including asthma, was observed in patients with AD who Immunol 2010;126:798-806.e13.
had poorly controlled disease. Treatment with dupilumab reduced 5. Caffarelli C, Garrubba M, Greco C, Mastrorilli C, Povesi Dascola C. Asthma and food
allergy in children: is there a connection or interaction? Front Pediatr 2016;4:34.
the occurrence of new or worsening allergy events, demonstrating
6. Alduraywish SA, Standl M, Lodge CJ, Abramson MJ, Allen KJ, Erbas B, et al. Is
that biologic treatment may prevent progression of the atopic there a march from early food sensitization to later childhood allergic airway dis-
march.9 It is also will be essential to evaluate the impact of these ease? Results from two prospective birth cohort studies. Pediatr Allergy Immunol
biologic therapies on improvement of the quality of life of indi- 2017;28:30-7.
viduals affected by multiple atopic diseases. 7. Underwood B, Troutman TD, Schwartz JT. Breaking down the complex patho-
physiology of eosinophilic esophagitis. Ann Allergy Asthma Immunol 2023;130:
28-39.
8. Friedlander JL, Sheehan WJ, Baxi SN, Kopel LS, Gaffin JM, Ozonoff A, et al.
CONCLUSIONS Food allergy and increased asthma morbidity in a school-based inner-city asthma
The discovery of shared pathophysiologic mechanisms among study. J Allergy Clin Immunol Pract 2013;1:479-84.
multiple atopic conditions has led to a steep increase in the 9. Geba GP, Li D, Xu M, Mohammadi K, Attre R, Ardeleanu M, et al. Attenuating the
number therapies with great potential to meaningfully reduce the atopic march: meta-analysis of the dupilumab atopic dermatitis database for inci-
dent allergic events. J Allergy Clin Immunol 2023;151:756-66.
burden of atopic comorbidities. Medicine in the field of allergy 10. Fiocchi A, Artesani MC, Riccardi C, Mennini M, Pecora V, Fierro V, et al. Impact
and immunology now faces the monumental task of assessing the of omalizumab on food allergy in patients treated for asthma: a real-life study.
optimal timing of interventions across the lifespan and their cost- J Allergy Clin Immunol Pract 2019;7:1901-9.e5.