Commentary From the Section on Allergy and Immunology

Figure 1. Protein electrophoresis of normal serum (top), and of the agammaglobulinemia patient before (P.T.) and after (AFTER Rx) receiving gammaglobulin.¹

This article in Pediatrics was the first recognition of a congenital disease of immunity and set the framework for the establishment of the field of primary immunodeficiency disease (PIDD). At that time, clinicians had only a rudimentary understanding of the immune system. Although the concept of antibodies was being established, T and B lymphocytes were not recognized until 20 years later.

PIDDs, now called inborn errors of immunity (IEI), are diagnosed and studied mostly by pediatricians, when children present with infections or inflammatory manifestations that raise the suspicion of an abnormal immune response. The field of IEI has grown exponentially. Currently there are greater than 475 defined genetic conditions, with more identified every year (Figure 2). Agammaglobulinemia or severe hypogammaglobulinemia may result from pathogenic mutations in 20 different genes, of which the most common is a deficiency of Bruton’s tyrosine kinase (BTK), responsible for the form with X-linked inheritance.^2,3

Figure 2. Exponential increase in the number of genes associated with immune defects.²

Bruton’s report of the use of intravenously administered gammaglobulins to prevent or reduce the frequency of infections was also the first therapeutic intervention aimed to correct a defective immunological function. The recognition of the therapeutic use of serum proteins had started decades earlier with the demonstration of anti-diphtheria and anti-tetanus antibodies in serum of immunized rabbits by Kitasato and von Behring in 1890.⁴ Serum was then used to treat and prevent specific infectious diseases, such as tetanus, measles, and rabies. Human rather than animal sera became preferred because of the risk of serum sickness consequent to the use of hyperimmune animal sera. In the 1940s, Cohn and others⁵ had developed purification methods for the gammaglobulin fraction of serum proteins. Bruton confirmed that antibodies were present in the gammaglobulin fraction.

Progress in the diagnosis and treatment of agammaglobulinemic patients was followed by discoveries in the fields of immunology and genetics (Figure 3). Bruton’s case report inspired others to treat agammaglobulinemic patients, and many subsequently reported the success of gammaglobulin treatment in preventing severe infections and childhood death. Early in this work, it became clear that the majority of cases exhibited an X-linked inheritance. Not until 2 decades later did investigators describe the hallmark absence of B cells in this condition, and the specific gene defect responsible for X-linked agammaglobulinemia (XLA) eluded identification until 1993.

Even considering the exceptional progress in immunological disorders, there remain pathways to improve the outcomes in the lives of XLA patients. For early diagnosis, screening for severe T cell defects is currently performed in the United States for all newborns by detecting T cell receptor excision circles (TRECs) in dried blood spots.⁶ This test permits the diagnosis of severe combined immunodeficiencies in newborns before life-threatening infections occur. Moreover, it has proven to be an approach for the screening of other immunological defects. The detection of kappa-deleting recombination circles (KRECs) for the presence of B cells, in an analog manner to TRECs, can screen for infants born with absent mature B cells. Strategies for definitive treatment of IEIs in the form of gene therapy are in development.⁷

Figure 3. Milestones in the diagnosis and treatment of X-linked agammaglobulinemia (XLA).

Bruton’s seminal report remains an inspiration for young and old pediatricians as an example of how astute clinical observations in one patient might stimulate other research that soon coalesces into a body of medical knowledge that can reduce morbidity and mortality and improve the quality of life for our patients.

References

1. Bruton OC. Agammaglobulinemia. Pediatrics 1952; 9:722-728
2. Tangye SG, Al-Herz W, Bousfiha A, et al. Human inborn errors of immunity: 2022 update on the classification from the International Union of Immunological Societies Expert Committee. J Clin Immunol. 2022;42:1473-1507
3. El-Sayed ZA, Abramova I, Aldave JC, et al. X-linked agammaglobulinemia (XLA): phenotype, diagnosis, and therapeutic challenges around the world. World Allergy Organ J. 2019;12:100018
4. Von Behring E, Kitasato S. Ueber das zustandekommen der diphtherie-immunitat and der tetanus-immunitat bei thieren. Dtsch Med Wochenschr. 1890:16:1113-1114
5. Cohn EJ, Oncley JL, Strong LE, Hughes WL, Armstrong SH. Chemical, clinical, and immunological studies on the products of human plasma fractionation. I. The characterization of the protein fractions of human plasma. J Clin Invest. 1944;23:417-432
6. Blom M, Bredius RGM, van der Burg M. Future perspectives of newborn screening for inborn errors of immunity. Int J Neonatal Screen. 2021;7(4):74
7. Shillitoe B, Gennery A. X-linked agammaglobulinaemia: outcomes in the modern era. Clin Immunol. 2017;183:54-62

Understanding the Growing Food Allergy Epidemic

J. Andrew Bird, MD, FAAP¹, Julie Wang, MD, FAAP²

Affiliations: ¹Department of Pediatrics, Division of Allergy and Immunology, University of Texas Southwestern Medical Center, Dallas, TX; ²Jaffe Food Allergy Institute, Department of Pediatrics, Division of Allergy and Immunology, Icahn School of Medicine at Mount Sinai, New York, NY

Highlighted Articles From Pediatrics

• Sicherer SH, Burks AW, Sampson HA. Clinical features of acute allergic reactions to peanut and tree nuts in children. Pediatrics. 1998;102(1):e6
• Gupta RS, Springston EE, Warrier MR, Smith B, Kumar R, Pongracic J, Holl JL. The prevalence, severity, and distribution of childhood food allergy in the United States. Pediatrics. 2011;128(1):e9-17

Critical landmark publications have helped pediatricians to understand more thoroughly the role of food allergy in the lives of their patients and to appreciate the true prevalence of food allergies in the general population. Two examples of instrumental publications affecting practice worldwide are the 1998 publication by Sicherer, et al that defined the clinical characteristics of peanut and tree nut allergic patients and the 2011 publication by Gupta, et al that established the prevalence, severity, and distribution of childhood food allergy in the United States.

Critical landmark publications have helped pediatricians to understand more thoroughly the role of food allergy in the lives of their patients and to appreciate the true prevalence of food allergies in the general population. Two examples of instrumental publications affecting practice worldwide are the 1998 publication by Sicherer, et al that defined the clinical characteristics of peanut and tree nut allergic patients and the 2011 publication by Gupta, et al that established the prevalence, severity, and distribution of childhood food allergy in the United States.

At the beginning of the food allergy epidemic in the 1990s, the medical literature lacked a well-defined, accurate description of patients with peanut and tree nut allergies, although it was recognized these were typically life-long allergies and carried the greatest risk of fatality. The highlighted report by Sicherer, Burks, and Sampson created a basis from which numerous AAP clinical reports were produced, creating the framework for the standard of care for children with peanut and tree nut allergies. Dr. Sicherer describes the genesis of the report and its impact in the following commentary.

“As a fellow in allergy in 1995, I picked up the phone and the FDA was on the line, asking me about the nature of peanut and tree nut allergies because “what if a food accidentally had peanut or tree nut in it but was not labelled correctly”? Are people allergic to peanut but not tree nut? How bad are these allergies? I had no answers and neither did my mentors, so we created a study. Working with Hugh Sampson and Wesley Burks, 2 pioneers in the field, we constructed a simple survey whose results identified issues that would be a focus of research and management for decades. Indeed, reactions were often severe, but being allergic to peanut did not mean there was necessarily allergy to tree nuts and vice versa. We found that a first allergic reaction occurred on the first known ingestion of the food, often after age 1 year. We pondered why that would have happened, how were they pre-exposed? Now we know the children, most of them with atopic dermatitis, were probably sensitized pre-ingestion through the skin, and we teach early introduction to avoid this (as reflected in an AAP clinical report¹). We found that accidental exposures with reactions usually occurred outside of the home, bringing attention to school avoidance measures (and a related clinical report from the AAP²). We learned that reactions were often severe, and that self-injectable epinephrine was under-underutilized, which became the focus for many future studies and education and advice to rectify this issue (and related clinical reports from the AAP^3,4). The study also reflected limitations to allergy testing, showing that history is key and serum tests are helpful but not typically useful as a sole diagnostic method (as reflected in another clinical report⁵). We had not realized what had been uncovered in this little survey and all that was to follow!”

Gupta et al’s 2011 publication established the striking prevalence of childhood food allergy in the United States with its report that 8% of US children have a food allergy (approximately 1 in 13 US children), higher than previous estimates. This publication summarized the results of a population-based, cross-sectional survey that was administered to nearly 40,000 US households with children. It rigorously assessed the date of onset of the food allergy, the method of diagnosis, and the reaction history for each reported allergen as well as provided detailed demographic information. Here Dr. Gupta describes the impetus for this study and the impacts of these findings:

“As in the story related above by Dr. Sicherer, when I was starting my career in academic medicine in 2005, I too found myself facing far more questions than answers around the issue of childhood food allergy. However, in my case, the questions were of a more personal nature—coming not only from my patients, but also my own family. For years, a constant refrain echoed in my exam room: “when I was a kid, nobody had food allergies, and now it seems like everyone does.” As a general pediatrician with training in epidemiology, I was disappointed at the lack of food allergy surveillance data—especially compared to asthma, which was my research focus at the time. Data on national food allergy prevalence simply didn’t exist. Around the time I first became aware of this dearth of epidemiologic data, my daughter was diagnosed with multiple food allergies, including peanut, tree nuts, and egg. From that moment on, food allergy became a round-the-clock focus of my personal and professional life. It became imminently clear that a comprehensive, national study was needed to characterize the public health burden of food allergy. I hoped that such an effort—which was eventually published in Pediatrics in 2011—would establish a solid foundation for future epidemiologic surveillance efforts. Little did I know it would also catalyze the food allergy community and my own career in food allergy public health research.”

As reflected in the authors’ own words, these studies have stimulated tremendous advancements across the field of food allergy, including prevention strategies and improved diagnostic testing. They have highlighted the daily impact food allergies have on children, families, and their communities. Furthermore, these are just 2 articles that illustrate how study ideas stemming from seemingly simple clinical questions can generate knowledge that is influential at many levels, from clinical care to research and education to advocacy and legislation.

References

1. Greer FR, Sicherer SH, Burks AW, Committee on Nutrition, Section on Allergy and Immunology. The effects of early nutritional interventions on the development of atopic disease in infants and children: the role of maternal dietary restriction, breastfeeding, hydrolyzed formulas, and timing of introduction of allergenic complementary foods. Pediatrics. 2019;143(4):e20190281
2. Sicherer SH, Mahr T, Section on Allergy and Immunology. Management of food allergy in the school setting. Pediatrics. 2010;126(6):1232-1239
3. Wang J, Sicherer SH, Section on Allergy and Immunology. Guidance on completing a written allergy and anaphylaxis emergency plan. Pediatrics. 2017;139(3)e20164005
4. Sicherer SH, Simons FE, Section on Allergy and Immunology. Epinephrine for first-aid management of anaphylaxis. Pediatrics. 2017;139(3):e20164006
5. Sicherer SH, Wood RA, Section on Allergy and Immunology. Allergy testing in childhood: using allergen-specific IgE tests. Pediatrics. 2012;129(1):193-197

Landmark Allergy & Immunology Articles in Pediatrics (bolded articles selected for commentaries)

First Quarter Century: 1948–Oct 1973

• Buckley RH, Wray BB, Belmaker EZ. Extreme hyperimmunoglobulinemia E and undue susceptibility to infection. Pediatrics. 1972;49(1):59-70
• Bruton OC. Agammaglobulinemia. Pediatrics. 1952;9(6):722-728
• Fudenberg H, Good RA, Goodman HC, et al. Primary immunodeficiencies: report of a World Health Organization committee. Pediatrics. 1971;47(5):927-946
• Goldman AS, Anderson DW Jr, Sellers WA, Saperstein S, Kniker WT, Halperin SR. Milk allergy. I. Oral challenge with milk and isolated milk proteins in allergic children. Pediatrics. 1963;32:425-443

Second Quarter Century: Nov 1973–Oct 1998

• Murray AB, Ferguson AC. Dust-free bedrooms in the treatment of asthmatic children with house dust or house dust mite allergy: a controlled trial. Pediatrics. 1983;71(3):418-422
• Eigenmann PA, Sicherer SH, Borkowski TA, Cohen BA, Sampson HA. Prevalence of IgE-mediated food allergy among children with atopic dermatitis. Pediatrics. 1998;101(3):e8
• Sicherer SH, Burks AW, Sampson HA. Clinical features of acute allergic reactions to peanut and tree nuts in children. Pediatrics. 1998;102(1):e6

Third Quarter Century: Nov 1998–Present

• Nowak-Wegrzyn A, Sampson HA, Wood RA, Sicherer SH. Food protein-induced enterocolitis syndrome caused by solid food proteins. Pediatrics. 2003;111(4):829-835
• Gupta RS, Springston EE, Warrier MR, Smith B, Kumar R, Pongracic J, Holl JL. The prevalence, severity, and distribution of childhood food allergy in the United States. Pediatrics. 2011;128(1):e9-17
• Gupta RS, Warren CM, Smith BM, et al. The public health impact of parent-reported childhood food allergies in the United States. Pediatrics. 2018;142(6):e20181235