Hymenoptera venom allergy is a potentially life-threatening condition; therefore, an accurate diagnosis is essential to establish appropriate and effective treatment. This process presents several difficulties, including the heterogeneity in venom composition, the limitations of conventional diagnostic tests, the interpretation of double sensitizations, and the involvement of non-traditional species.^1,2 Furthermore, in patients with anaphylaxis due to Hymenoptera venom, especially in the most severe cases, it is fundamental to investigate the possible presence of clonal mast cell activation syndrome (CMAS), the detection of which is key for management and prognosis.³

This clinical case addresses and illustrates three of these difficulties: the identification of the insect, the management of double sensitizations, and the screening for CMAS.

Case Report

A 37-year-old male, a gardener (a high-risk profession), presented in July 2023 with a systemic reaction following an insect sting in a public area in Taramundi (Asturias). The patient initially identified the insect as a bee (Nomada flava), reporting having seen a small nest on wood on the ground after being stung. Ten minutes after the event, he began to manifest clinical signs compatible with an anaphylactic reaction: cardiovascularly, loss of consciousness without sphincter relaxation; cutaneously, mild labial angioedema; and gastrointestinally, nausea and vomiting. He was attended by a mobile ICU, where blood pressure was observed at 60/35 mmHg, heart rate at 60 bpm, and a decreased level of consciousness. He received treatment with intramuscular adrenaline (0.5 mg in the anterolateral aspect of the thigh), dexchlorpheniramine (5 mg), and methylprednisolone (80 mg), with complete resolution of the clinical picture.

In the consultation, the patient completed the HiCaV (quality of life) test, obtaining a score of 3.78 (moderate impairment).⁴

An allergologic study was performed using skin tests and laboratory studies. Prick and intradermal (ID) skin tests against Vespula spp. showed positivity in ID 0.1 mg/mL (7 × 5 mm) and against Polistes dominula in ID 0.1 mg/mL (5 × 5 mm), while skin tests for Apis mellifera were negative. Specific IgE determination was performed using ImmunoCAP^® (Thermo Fisher Scientific) and a blot study for venoms using IMMULITE^® 2000/2000XPi 3gAllergy™, which reported double sensitization to Vespula spp. and Polistes dominula, with the absence of sensitization against Apis mellifera and absence of sensitization to cross-reactive carbohydrate determinants (CCDs). Table 1

Additionally, an immunoblot was performed against venoms of the main Hymenoptera of allergologic relevance (Hymnox^®/Venenox^®, Roxall Medicina España S.A.), which revealed a predominant immunoreactive band in the Polistes dominula extract in the range of ~34–38 kDa, consistent with Pol d 1, whose theoretical molecular weight is ~36 kDa, which may appear increased under electrophoretic conditions due to glycosylation. Figure 1

A diagnosis of Polistes dominula allergy was established, and species-specific immunotherapy (SIT) was prescribed, with good tolerance and clinical response. Medical treatment in the event of a new sting was explained to the patient, and he was instructed on the use of an adrenaline autoinjector. After one year of starting SIT, he suffered a new accidental wasp sting in a public area without manifesting a systemic reaction, which supported the clinical efficacy of the treatment.

Due to a REMA score (Spanish Network on Mastocytosis) of +3 (high probability of clonal mast cell syndrome), a bone marrow study was performed. Cytology showed mast cell hyperplasia, mostly with atypical morphology (88% of the total). Flow cytometry detected 0.016% of aberrant mast cells, findings compatible with CMAS. The D816V mutation of the KIT gene, analyzed by digital PCR, was negative. Likewise, bone marrow densitometry and abdominal ultrasound were performed, with no pathological findings. Treatment with disodium cromoglycate (200 mg every 12 hours) was prescribed, with good subsequent clinical progression.⁵

Nomada flava is a small cleptoparasitic bee belonging to the Apidae family, whose morphology can complicate visual identification and favor confusion with other hymenoptera of allergological relevance such as Apis mellifera or Polistes dominula. To date, there are no documented descriptions of allergic reactions to this species nor characterization of its allergens, which limits the availability of specific diagnostic tests. This situation forces reliance on integrating clinical history and available immunological techniques to identify the culprit insect.^6–8

In our patient, the initial suspicion of a Nomada flava sting was inconsistent with the immunological findings, which showed predominant recognition against Pol d 1. This is the main allergen of Polistes dominula venom, and its detection is associated with clinically relevant sensitization.

In the ImmunoCAP^® currently available in Spain, it is not possible to determine Pol d 1; therefore, complementary techniques (IMMULITE^® and immunoblot) were used. These showed detectable concentrations of Pol d 1 (0.54 kU/L) and a predominant band in the expected range.

The predominant identification of Pol d 1, together with the absence of CCD-mediated cross-reactivity and negative results against Apis mellifera allergens, allowed for differentiation between serological double sensitization and clinically relevant Polistes dominula allergy. Therefore, it was considered more likely that the sting was caused by Polistes dominula, visually confused with Nomada flava due to their morphological similarity (Figure 2). The characteristics of the nest, the insect’s anatomy, and the immunological results support this hypothesis. The discovery of the stinger suggests the death of the insect after the sting, although this finding is not entirely specific. The visual difficulty in differentiating between species and the coexistence of double sensitization highlight the need for a comprehensive diagnostic approach that includes advanced techniques such as immunoblot, inhibition tests, or basophil activation tests to identify the correct species, thereby differentiating between primary sensitization and cross-reactivity.

The case presented in this study also shows that in patients with anaphylaxis due to Hymenoptera venom, especially in the most severe cases, clonal mast cell activation syndrome may coexist and go unnoticed, even with normal basal tryptase concentrations. Its detection is fundamental because it modifies clinical management, including the indication for prolonged or indefinite immunotherapy, carrying more than one adrenaline autoinjector, and the use of adjuvant treatments.

In our patient, the negative KIT D816V mutation, together with the absence of dense mast cell infiltration in the bone marrow, makes a diagnosis of indolent systemic mastocytosis less likely and supports the diagnosis of clonal mast cell activation syndrome, although both conditions can be part of a continuous spectrum and require longitudinal follow-up.

Among the limitations of the case presented is the impossibility of absolutely confirming the culprit species, since identification is based on indirect clinical and immunological findings. Likewise, as it is an isolated case, the extrapolation of the results should be performed with caution.

This case highlights the diagnostic complexity of Hymenoptera venom allergy and the importance of a multidimensional approach that integrates insect identification, assessment of cross-sensitizations, and the use of advanced diagnostic methods to ensure appropriate and effective immunotherapy. It also highlights the need to rule out clonal mast cell activation syndrome in patients with severe systemic reactions, due to its impact on prognosis and treatment.