Delayed hypersensitivity after skin prick test in patients with chronic spontaneous urticaria: safety of allergen immunotherapy—a report of two cases

Introduction

Background

The skin prick test (SPT) is the most common and is usually the first-choice test in the diagnosis for allergic disorders because of its reliability, safety, convenience and low cost. SPT is minimally invasive and has the advantage of testing several allergens in 15 to 20 min (1).

A delayed hypersensitivity response, known as a late phase reaction (LPR), is an infrequent adverse event following SPT (2). This LPR represents an IgE-dependent consequence of the initial immediate reaction (IR), characterized by sustained eosinophilic inflammation and the release of arachidonic acid metabolites from the mast cells (3).

Mast cell degranulation triggers a complex cascade of immunological responses, resulting in a biphasic reaction: the IR and the LPR. Additional mediators released by mast cells, including leukotrienes C4, B4, D4, prostaglandin D2, and/or platelet-activating factor, are detectable in the skin during the LPR. Principally, histamine doses contribute to LPR formation, and antihistamines are ineffective in preventing LPR development (3).

LPR is characterized by edematous and erythematous areas, with a diameter of at least 5 mm, that appear 3–6 hours after the IR at the site of SPT. The initial wheal-and-flare response begins within one minute post-test, peaks around 15 minutes, and resolves within 30–60 minutes. In contrast, the edema and erythema of the LPR manifest 1 hour after the IR, reach a peak at 3–6 hours, and persist for 6–8 hours, gradually diminishing within 24–48 hours (3). Isolated late reactions (ILRs) to SPT were observed in 36% of pediatric patients. The clinical significance of those responses remains unclear (4).

The LPR (oedema and erythema) graded as: grade I, less than 10 mm (1 cm); grade II, 10 to 20 mm (1–2 cm); grade III, 20 to 30 mm (2–3 cm); grade IV, more than 30 mm (>3 cm) (3).

Rationale and knowledge gap

Allergen-specific immunotherapy is a unique form of therapy capable of altering the course of allergic disorder through induction of T regulatory cells and subsequently peripheral tolerance along with clinical improvement (5). The potential for administering allergen immunotherapy (AIT) to patients exhibiting LPR following SPT has not been previously explored in the literature. In our clinical practice, we observed two cases where patients developed LPR after SPT but did not experience delayed-onset local reactions to subcutaneous AIT.

Objective

We aim to explain the safety of Implementation of AIT in patients exhibiting LPR following SPT. We present this article in accordance with the CARE reporting checklist (available at https://amj.amegroups.com/article/view/10.21037/amj-24-156/rc).

Case presentation

We observed two patients with chronic spontaneous urticaria (CSU) who developed LPR after SPT. Both patients received subcutaneous injections with increasing amounts of allergens, two times per week till once weekly maintenance dose (5).

Urticaria activity score, angioedema activity score, and medication scores were recorded. The scores recorded were measured before and after AIT. The urticaria activity score evaluates two symptoms, the hives count and intensity of itching. The 5-point angioedema activity scale also was used (6).

Case 1

A 48-year-old man presented with a 1-year history of severe CSU accompanied by angioedema, refractory to antihistamines and corticosteroids. SPT showed positive reactions to pollens and wheat. He then received the first dose of subcutaneous AIT (concentration of 1/million) about 4 hours after SPT but developed itching, erythema, and large wheals (about 8 mm in diameter; grade I) at the SPT site only over the course of 2 hours after starting treatment (about 6 hours after SPT) (Figure 1). So subcutaneous AIT was stopped for one week and the patient received systemic steroids to control this LPR. He restarted subcutaneous immunotherapy but developed a systemic reaction (generalized urticaria with widespread skin rash and mild lip swelling) with subsequent doses. The reaction responded to treatment with antihistamines and systemic corticosteroids. Consequently, the decision was taken to hold subcutaneous AIT again. Subsequently, the patient was tried on low concentrations (concentration of 1/10 million) of subcutaneous AIT which was well tolerated, and the patient had a clinical response without local or systemic side effects. At 1-year follow-up, he has had a reasonable response of both symptom score and medication score. (Hives score was decreased from score 3 with >50 confluent hives to score one less than 20 hives. Also, itching score was decreased from score 3 to score 1 and angioedema score decreased from score 4 to score 0) A graphical timeline of the case evolution is presented in Figure 1.

Figure 1 Timeline of late phase reaction after skin prick test in Case 1. AIT, allergen immunotherapy.

Case 2

A 30-year-old female with a history of CSU not associated with angioedema for 8 months, presented with symptoms unresponsive to antihistamines and corticosteroids. SPT was positive for pollens, house dust mites, wool, and hay dust. Three hours after SPT, the patient developed localized itching, erythema, and large wheals (about 6 mm in diameter; grade I) at the SPT site (she had not started subcutaneous AIT yet), consistent with an LPR. The patient received systemic corticosteroids to control this symptom. She then began subcutaneous AIT (1/million) and tolerated it without experiencing any local or systemic adverse reactions. Fortunately, one year after initiating the treatment, the patient demonstrated a favorable clinical response (hives score was decreased from score 3 with >50 confluent hives to score one less than 20 hives. Also, itching score was decreased from score 3 to score 0).

Ethical statement

All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee(s) and with the Declaration of Helsinki and its subsequent amendments. Written informed consent was obtained from the patients for the publication of this case report and accompanying images. A copy of the written consent is available for review by the editorial office of this journal.

Discussion

In our clinical practice, we observed two cases who developed LPR after SPT but did not develop delayed-onset local reactions to subcutaneous AIT. In the first case, systemic reaction occurred after subcutaneous AIT, which was initiated about 4 hours after SPT. In the second case, subcutaneous AIT was delayed by a few days after resolution of LPR, and the patients experienced neither local nor systemic reactions.

The early-phase reaction of allergy develops within minutes following allergen exposure. During this phase, allergens bind to IgE attached to FcεRI receptors on the surface of mast cells and basophils, resulting in the release of both preformed and newly synthesized mediators. Some of the released mediators also enhance local leukocyte recruitment and activation, which aids in the development of LPR (4).

The mechanism underlying why the LPR does not occur in all sensitized individuals remains unclear. In some cases, there may be no distinct clinical boundary between the end of early-phase reaction and the onset of LPR (7). Experimentally induced LPR typically resolves completely without therapeutic intervention, though the processes governing these responses are still not well understood (4).

Wheal and flare reaction are characteristic of type I IgE-mediated hypersensitivity in human skin. This response initiates shortly after SPT, reaches its peak within 10 to 20 minutes, and subsides within a few hours. The LPR is typically larger than the early reaction. Although histamine is not the sole mediator of the LPR, mast cells and basophils may contribute to the lesion’s formation. Notably, lymphocytes are the most predominant cells present in the LPR, although eosinophils and neutrophils, as well as increased numbers of basophils, are also present (8). Therefore, patients who exhibit LPR to SPT can benefit from treatment with topical corticosteroids (2).

Sutherland et al. (2) reported a case involving LPR after SPT. The allergist observed persistent wheals and erythema at the SPT sites of cat and dust mites. This patient has never received subcutaneous AIT as part of the treatment.

Kathuria et al. (3) reported 3 cases with respiratory allergies who developed LPR 3 hours after SPT. All three cases were given single AIT, which was safe, effective, and had long-lasting effects.

The clinical utility of subcutaneous AIT has been demonstrated over the years; however, the potential for adverse reactions remains a concern. Adverse reactions may occur as a localized reaction at the injection site or may present systemically. Systemic reaction is rare when following a conventional protocol and the prompt recognition and treatment of systemic reactions (9). Injectable epinephrine is the treatment of choice for fatal systemic reactions and all subsequent therapeutic measures depend on the initial response to epinephrine (10).

CSU is a common skin disorder characterized by the appearance of pruritic wheals lasting less than 24 hours for a period of at least 6 weeks and often for decades. Notably, studies of skin biopsies from CSU patients have shown significantly higher levels of IL-33 compared to healthy controls, thus suggesting that the expression of Th2-promoting cytokines may have an important role in whealing (11).

The case report draws attention to the possibility of administration of AIT in patients who developed LPR after SPT. However, this study is limited by the few number of reported cases. Future studies on large numbers of cases is required.

Conclusions

We highlight LPR as a known complication of SPT. The occurrence of LPR after SPT is not a contraindication for AIT, but the initiation needs to be delayed by 2 days to minimize side effects in these patients.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the CARE reporting checklist. Available at https://amj.amegroups.com/article/view/10.21037/amj-24-156/rc

Peer Review File: Available at https://amj.amegroups.com/article/view/10.21037/amj-24-156/prf

Funding: None.

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://amj.amegroups.com/article/view/10.21037/amj-24-156/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee(s) and with the Declaration of Helsinki and its subsequent amendments. Written informed consent was obtained from the patients for the publication of this case report and accompanying images. A copy of the written consent is available for review by the editorial office of this journal.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

References

1. Frati F, Incorvaia C, Cavaliere C, et al. The skin prick test. J Biol Regul Homeost Agents 2018;32:19-24.
2. Sutherland A, Ganju A, et al. Delayed type hypersensitivity in a tricenarian with skin prick testing. Annals of Allergy, Asthma & Immunology 2022;129:S107.
3. Kathuria PC, Rai M. Significance of Late Phase Reaction in Allergy Skin Testing in Polysensitized Patients-A Case Series. Archives of Surgery and Clinical Case Reports 2021;4:157.
4. Galli SJ, Tsai M, Piliponsky AM. The development of allergic inflammation. Nature 2008;454:445-54. [Crossref] [PubMed]
5. Abdelwahab HW, El-Maksoud AA, Farrag NS, et al. Association of allergen sensitization patterns with clinical outcome of subcutaneous allergen-specific immunotherapy in polysensitized allergic patients. The Egyptian Journal of Chest Diseases and Tuberculosis 2022;71:388-94.
6. Heba WA, El-Maksoud AA, El Dakrory FF. Efficacy of Allergen Immunotherapy in the Treatment of Chronic Spontaneous Urticaria. Dermatology Research and Reports 2024;3:1-5.
7. Kay AB. Allergy and Allergic Diseases. N Engl J Med 2001;344:30-7. [Crossref] [PubMed]
8. Solley GO, Gleich GJ, Jordon RE, et al. The late phase of the immediate wheal and flare skin reaction. Its dependence upon IgE antibodies. J Clin Invest 1976;58:408-20. [Crossref] [PubMed]
9. Aue A, Ho J, Zhu R, et al. Systemic reactions to subcutaneous allergen immunotherapy: real-world cause and effect modelling. Allergy Asthma Clin Immunol 2021;17:65. [Crossref] [PubMed]
10. Stephen E. Kemp. Adverse effects of allergen immunotherapy: Assessment and Treatment. Radiologic Clinics of North America 2000;20:571-91.
11. Murdaca G, Greco M, Tonacci A, et al. IL-33/IL-31 Axis in Immune-Mediated and Allergic Diseases. Int J Mol Sci 2019;20:5856. [Crossref] [PubMed]