Editorial

Article

Breaking the inveterate habit of starting with comments on papers on allergy topics published in the journal, in this issue we would like to highlight the paper by Mattia Moratti and Francesca Conti, who wrote an interesting review of the literature on “Lymphoproliferative Patterns as Diagnostic Dilemmas in Inborn Errors of Immunity” (p. 9).

This is a highly clinical and practical approach to patients with lymphoproliferative disorders, for which we instinctively consult an expert oncologist rather than an immunologist.

But among Inborn Errors of Immunity (IEIs) — a heterogeneous group of genetically determined disorders resulting from impaired development, function, or regulation of the immune system — tumors and lymphoproliferative disorders are far from rare. We can now consider outdated the view of IEIs as characterized exclusively by clinical and biological signs due to recurrent and severe infections. The emergence of new, increasingly complex immunodeficiencies, driven by heterogeneous immunological disorders, has led to the need for new definitions that allow us to group and classify not only immunodeficiencies, but also the very broad range of immune system regulatory defects that are responsible for other clinical manifestations, such as autoimmunity, auto-/hyperinflammation, allergies, and, indeed, tumors and lymphoproliferative disorders (LPDs). Therefore, the new definition of IEI was coined.

In this selective analysis of IEI, the authors aim to identify the diseases that are most frequently associated with lymphoproliferative complications. They seek to precisely characterize the clinical features of these diseases, also corroborated by literature data, and also attempt to frame the different forms of LPD in order to facilitate the recognition of these rare conditions. It is not easy to suspect the underlying disease because the LPDs of IEI encompass a clinical and pathological spectrum ranging from benign polyclonal hyperplasia to aggressive clonal lymphoma. Finally, the authors recommend caution in the clinical interpretation of LPD when viral infections are involved, especially if Epstein-Barr virus is isolated, whose role in inducing clinical manifestations must be correctly interpreted.

Elio Novembre’s paper: “Allergen immunotherapy in Allergic Rhinitis and Asthma” (p. 17) bridges the gap between immunology and allergy.

Allergen-specific immunotherapy (AIT) was developed over a century ago and remained largely empirical for a long time. In recent decades, however, the quality and standardization of preparations has significantly improved, leading to rigorous studies that have conclusively demonstrated the efficacy of the therapy. At the same time, molecular diagnostics have rapidly developed, allowing for better patient selection, almost to the point of personalizing therapy. Both sublingual immunotherapy (SLIT) and subcutaneous immunotherapy (SCIT) have been shown to be effective in adults and children in the treatment of allergic rhinitis and asthma. Long-term efficacy was first reported in “Preventive Allergy Treatment study”, in which a 3-year cycle of SCIT with standardized allergen extracts showed long-term clinical efficacy in children with allergic rhino conjunctivitis as well as a protective effect on the subsequent development of asthma, a preventive effect recently confirmed by a more recent review ¹. The author rightly asks why, despite these more than robust confirmations, the commercial data on the use of AIT are so disappointing: this can be explained by difficulty in adherence and costs, and perhaps also a residual skepticism deriving from the poor purity of the preparations used in the past and a certain mistrust among physicians, who are often not confident in the use of these products. Physicians should adequately inform patients about the therapeutic and preventive efficacy of this approach and actively participate in the decision-making process. At the same time, every effort should be made to remove other barriers to the use of AIT.

Regarding the problems of allergic children, the paper by Aleksandra Zomerfeld et al. entitled: “Food-Dependent Exercise-Induced Anaphylaxis: Current Insights and Future Directions” is worth mentioning (p. 3).

Food-dependent exercise-induced anaphylaxis is a rare allergic disease in which anaphylaxis is triggered by the combination of ingestion of specific foods and subsequent physical activity. In exceptional cases, the sequence can be reversed ². The most well-known predisposing factors are the use of anti-inflammatory drugs or alcohol, and the coexistence of infections that can alter intestinal permeability and increase allergen absorption. Wheat is among the most common foods that cause this condition, so much so that it can be called wheat-dependent exercise-induced anaphylaxis. It has been hypothesized that exercise activates intestinal tissue transglutaminase, which binds to dietary peptides, promoting their aggregation and increasing IgE cross-reactivity. Treatment, beyond the acute phase, which is treated with traditional anaphylaxis therapy, focuses on preventing further attacks and is based on patient education and treatment of any cofactors identified. However, when this condition significantly impairs quality of life and hinders physical performance, as in young athletes, the use of biologics, such as omalizumab or dupilumab, should be considered in specific cases, as they may be effective in controlling relapses.

Still on the topic of food allergy, we highlight the article by Arianna Giannetti et al. entitled “Allergic Reactions to Lysozyme: a Cases Report and Literature Review” (p. 22). These clinical experiences help us to understand why it is not always easy to identify an egg protein allergy, since some egg allergens (such as lysozyme) can be present in isolation in various food products and go undeclared because they are minor (hidden).

Although lysozyme is classified as a minor egg allergen, it can cause clinically significant allergic reactions in sensitized pediatric patients. Lysozyme is a thermolabile enzyme naturally present in egg white and is widely used as a food additive and preservative in products such as mature cheeses, wine, and pharmaceutical preparations. For this reason, lysozyme should also be tested in suspicious cases of food allergy, and if identified, adequate education and information should be provided to egg-allergic patients and their families.

In the Literature Pills section, we highlight a thoughtful commentary by Federica La Ciacera on the paper by Morello et al., “Role of Nutritional Supplements in Children with Post-COVID Conditions: a Preliminary Retrospective Observation and a Narrative Review” (p. 33) This is a niche topic, and precisely for this reason, we may not be adequately informed about it. Long COVID, or post-COVID, represents a clinical syndrome following SARS-CoV-2 infection with a broad spectrum of clinical manifestations involving the cardiorespiratory, neuromuscular, and cerebral systems. We still don’t know the exact reasons why only some individuals, including children, experience these late symptoms, making it more difficult to identify a possible therapeutic approach, which remains controversial. One promising approach, however, is nutritional therapy.

Last but not least (indeed!), a complex case is presented by Ifat Zerin Krase, with the paper “Infantile Aggressive Systemic Mastocytosis Complicated by Liver Fibrosis Treated with Oral Midostaurin” (p. 28) This significant clinical experience opens new therapeutic opportunities with drugs that can significantly improve the prognosis of aggressive systemic mastocytosis, even in a neonatal age.

Mastocytosis is a rare clonal disease characterized by an extreme proliferation of mast cells in the skin and other organs. The most common form is cutaneous mastocytosis (prevalence in pediatric age 1:10,000), while systemic mastocytosis represents less than 10% of cases of pediatric mastocytosis. Because bone marrow and extracutaneous organ involvement is rare, there are no FDA-approved cytoreductive therapies for aggressive systemic mastocytosis in neonates. Midostaurin, a multikinase inhibitor, is approved only for treatment in adults. The authors report a rare case of infantile aggressive systemic mastocytosis in a newborn who responded optimally to cytoreductive therapy with midostaurin.

Any rare disease can appear in our experience; in our daily practice we may visit patients with unusual symptoms that we cannot explain. We must keep an open mind and learn from the experiences of our colleagues every day, without taking anything for granted.

Happy reading!

History

Published: October 23, 2025