Children at risk: Conditions which can increase the occurrence of allergic disease

Within the pages of this issue, several articles are presented which focus on factors which uniquely predispose children to the development of allergic disease. These papers provide considerable insight into important clinical clues that lead to the expressions of allergic, cutaneous and respiratory disorders afflicting pediatric patients whom the allergist-immunologist is frequently called upon to serve.

Cuppari et al¹ examine the scientific literature relating to the mode of childbirth and how it may affect the risk for development of atopic diseases in children. There have been several recent scientific advances linking the mode of delivery, i.e., vaginal or Cesarean, with the infant gastrointestinal microbiome which in turn is now known to be a critical driver of the maturation and function of the immune system in the developing infant. However studies evaluating the relationship between mode of delivery and the development of atopy have produced conflicting findings. The authors performed a comprehensive literature search exploring in detail how the mode of delivery links both the microbiome and its effects on immune development with the risk of allergy and suggest potential strategies for altering microbial exposures in early life to prevent childhood allergy.

Wi et al² continue the discourse of risk with a paper evaluating the effects of herpes zoster in children with asthma. The authors had previously reported an increased risk of vaccine-preventable diseases such as herpes zoster (HZ) among children with asthma as defined by predetermined asthma criteria (PAC). Given the heterogeneity of asthma, it is unknown whether this association exists if asthma status is defined by different asthma criteria such as the Asthma Predictive Index (API). Using this definition, the authors assessed the consistency of the association between asthma and the risk of HZ in children and report finding a consistent association.

Consistent with prior descriptions of asthma risk factors and associations found within previous issues of the Proceedings,^3–5 two articles appear in this issue which address the risk of asthma and allergic disease in relation to other inflammatory diseases. Peng et al⁶ investigated the association of inflammatory bowel disease with asthma risk in a cohort of 5,260 patients with newly diagnosed inflammatory bowel disease compared to controls. The authors report that patients with inflammatory bowel disease (IBD) were associated with a higher subsequent risk of asthma. Lai et al⁷ investigated the association of rheumatoid arthritis with allergic disease in a cohort of 170,570 patients diagnosed with allergic disease compared to controls. The authors report that significant associations between common allergic diseases and incident rheumatoid arthritis (RA) were found in this population-based cohort study. Together with the report of Peng et al, these findings support the hypothesis that inflammatory conditions (such as RA and IBD) might share a similar underlying etiologic pathway with allergic disease.

Continuing with the theme of disease risk in children, Guvenir et al⁸ provide a review of nonsteroid anti-inflammatory drugs (NSAID) hypersensitivity among children. NSAIDs are the second most frequent drugs causing hypersensitivity reactions among children. These investigators evaluated 123 children with suspected NSAID hypersensitivity, performing skin tests and oral provocation tests. They report that the most commonly observed type of NSAID-induced urticaria/angioedema was non-cross reactive (single-NSAID-induced urticaria/angioedema) and the most common responsible drug was ibuprofen.

Atopic dermatitis is yet another disorder for which atopic children are at greater risk.^4,9–14 To further investigate this risk, Sybilski et al¹⁵ investigated the prevalence of sensitization to inhalant allergens in children suffering from atopic dermatitis. They analyzed data from the Epidemiology of Allergic Disorders in Poland study, which included over 9,000 children, 25% of whom were skin tested. They report that urban dwelling and positive atopic history are more frequent in children with atopic dermatitis. House dust mite and grass pollen proved to be the most common relevant aeroallergens identified in this pediatric population. The authors conclude that aeroallergens may play an essential role in pathogenesis of eczema in children.

The treatment of acute pediatric respiratory disorders is next examined in a report by, Beigelman et al¹⁶ who provide a current update on the utility of corticosteroids in the treatment of patients with various wheezing phenotypes which present most commonly in preschool children. They highlight the current gaps-of-knowledge relating to the utility of this intervention and focus on the identification of specific wheezing phenotypes which might benefit from systemic corticosteroid treatment.

Continuing further the theme of risk factors and childhood allergic disease, the management of immunodeficiency disorders is next evaluated in the most recent installment of the Patient-Oriented Problem Solving “POPS” series. This feature of the Proceedings, as per tradition, is written by an allergy-immunology fellow-in-training from one of the US allergy-immunology training programs. The purpose of the POPS series is to provide an innovative and practical learning experience for the novice allergist-immunologist in-training using a didactic format of clinical presentation and deductive reasoning. In this issue's POPS, Abul et al¹⁷ lead the reader through this process, describing the evaluation of a 15-year old male with X-linked severe combined immune deficiency (SCID), fungal infection and weight gain. This case report illustrates the complexity of the differential diagnostic process for this disease and the importance of a detailed history, physical exam and appropriate laboratory assessment in arriving at a correct diagnosis.

Moving the focus of risk to that associated with upper respiratory disease, Li and Peters¹⁸ provide a comprehensive review of CRS management beyond intranasal steroids and saline irrigations, highlighting the two treatment modalities for which “grade A” evidence for treatment exists. They review the evidence which supports these therapies and discuss novel treatment approaches. Because of the high prevalence of CRS and the significant beneficial clinical implications, the article by Li and Peters was chosen for this issue's “For the Patient” section. This segment, found in the final pages of the print version of this issue and also available online, consists of a one page synopsis of a selected article, that is written in a readily comprehensible fashion to help patients better understand the content of the full article and its diagnostic and therapeutic implications. It is printed in a format to allow reproduction on the practitioner's letterhead for distribution to patients.

Shifting from the upper to the lower airways, three papers appear in this issue, which return the focus to the topics of asthma control and treatment.^19,20 Cowden et al²¹ studied the effectiveness of a protocol of customized asthma instructions, recorded by the pediatrician on an inexpensive audio chip contained in a card, on pediatric asthma control. The authors report that this novel audio communication tool was associated with improved asthma control and was deemed highly-desirable by parents and children struggling to control asthma.

Asthma treatment, is next presented with reports of two asthma equivalence trials, the results of which are important to clinicians who are attempting to better understand the comparative safety, efficacy and therapeutic role of generic drugs. Kuna et al²² performed a randomized equivalence trial to compare the efficacy and safety of fluticasone propionate/salmeterol (FP/Sal) delivered via a novel multidose dry powder inhaler (mDPI) versus an originator device in 555 adolescent and adult patients with moderate-to-severe persistent asthma. In their analysis of primary and secondary efficacy measures (including change in FEV1 from baseline and area under the 12-hour serial FEV1 curve), the authors report that the novel FP/Sal mDPI demonstrated equivalent efficacy and safety profile to the originator device and suggest it may be an acceptable alternative treatment in this patient group.

In another asthma comparative trial, Gillespie et al²³ studied the pharmacokinetics of a novel fluticasone propionate (FP) dry powder inhaler (DPI) versus an FP originator DPI device and FP metered-dose inhaler (MDI). The authors report the results of a single-center, open-label, randomized, 3-period crossover, single-dose pilot study in 18 healthy adults. Single-dose administration of Fp MDPI 800 μg produced systemic exposure comparable with those for Fp originator DPI 1000 μg and Fp MDI 880 μg.

Turning the focus from treatment to diagnosis, Ta et al²⁴ report on a study of skin test reactivity to pollens in the Pollen Food Allergy Syndrome (PFAS) versus allergic rhinitis. The PFAS, also called the Oral Allergy Syndrome (OAS), occurs in a subset of patients with pollen allergy and its underlying pathophysiology is attributed to antigenic similarity between certain pollen and food allergens. The authors studied the size of skin test reactions in a group of pollen sensitive subjects with PFAS compared to a group of pollen sensitive subjects without PFAS. Although they found that subjects with PFAS had significantly larger skin-prick tests specific to pollens, despite larger-sized skin-prick tests, subjects with allergic rhinitis and PFAS reported milder nasal symptoms in relation to pollen skin tests size when compared to allergic rhinitis controls without PFAS.

Moving the focus of this issue to urticaria and angioedema, Mathias et al²⁵ report on the minimal important difference for measures of urticarial disease activity. More specifically they investigated the Urticaria Patient Daily Diary (a validated patient-reported outcome that captures key measures of urticarial disease activity) to update estimates of the minimal important difference (MID) for urticarial disease activity measures. Their analysis provides confirmation of the previous MID estimates for the urticaria disease activity measures in the Urticaria Patient Daily Diary.

Finally, Longhurst et al²⁶ conducted a posthoc analysis of data from an ongoing observational study monitoring the safety and effectiveness of icatibant treatment (a selective bradykinin β2 receptor antagonist) for hereditary angioedema (HAE) to determine the characteristics associated with reinjection of icatibant. In this real-world setting, most HAE attacks (89.1%) resolved with one icatibant injection. However the authors go on to state that because new attacks were not distinguished from the recurrence of symptoms, reinjection rates may be slightly higher.

In summary, the collection of articles found within the pages of this issue provides yet another insight into important allergic, cutaneous and respiratory disorders afflicting patients whom the allergist-immunologist serves. In keeping with the overall mission of the Proceedings, which is to distribute timely information regarding advancements in the knowledge and practice of allergy, asthma, and immunology to clinicians entrusted with the care of patients, it is our hope that the articles found within this issue will continue to achieve this goal and will help foster enhanced patient management through efficient workup and optimal therapy for a great diversity of clinical problems. On behalf of the editorial board, we hope you will enjoy the diversity of literature offered in this issue of the Proceedings.