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Background Severe anaphylaxis (SA) in Hymenoptera venom allergy has been associated with a number of risk factors. However, the effect of several of those risk factors on the severity of anaphylaxis is poorly defined. Objective To evaluate risk factors for SA in Hymenoptera venom allergy. Methods We evaluated data from 500 patients who were referred to our department for the diagnosis of Hymenoptera venom allergy during a period of 11 years to identify risk factors for SA. Results Six significant risk factors for SA were identified (P Conclusion Apart from BST and older age, male sex, short interval from sting to reaction, and absence of U/A are also risk factors for SA. The association between elevated BST level and SA was largely confined to those who had an absence of U/A after field sting, possibly because of the higher risk of concurrent systemic mastocytosis. Patients with an SA after a field sting do not have an elevated risk of systemic reactions during the initiation of venom immunotherapy compared with patients with mild anaphylaxis; therefore, additional preventive measures are not necessary.

Defects of filaggrin (FLG) compromise epidermal barrier function and represent an important known genetic risk factor for atopic dermatitis (AD), but also for systemic atopy, including allergic sensitization and asthma. The flaky tail mouse model, widely used to address mechanisms of atopy induction by barrier-defective skin, harbors two mutations that affect the skin barrier, the mutation Flgft, resulting in near-complete loss of FLG expression, and the matted mutation inactivating transmembrane protein 79 (Tmem79). Upon separation of the two mutant loci, which are closely linked on chromosome 3, mice defective only for Tmem79 featured pronounced dermatitis and systemic atopy. Upon extensive backcross to BALB/c, also Flgft/ft mice (assumed to be wild type for Tmem79), developed AD-like dermatitis and reproduced the human ‘atopic march’, with high IgE levels and spontaneous asthma, suggesting a key role for functional Flg in protection from atopy also in mice. In contrast, BALB/c mice congenic for a targeted Flg knock out mutation did not develop skin inflammation or atopy. To resolve this discrepancy, we generated Flg-deficient mice on a pure BALB/c background by inactivating the Flg gene in BALB/c embryos. These animals feature an ichthyosis phenotype, but do not develop spontaneous dermatitis or systemic atopy. We sequenced the genome of the atopic Flgft BALB/c congenics and discovered that they were unexpectedly homozygous for the atopy-causing Tmem79matted mutation. In summary, we show that Flg-deficiency does not cause atopy in mice. This finding is in line with lack of atopic disease in a fraction of Ichthyosis vulgaris patients carrying two FLG null alleles. However, absence of FLG may promote and modulate dermatitis caused by other genetic barrier defects, as skin inflammation in Tmem79ma/maFlgft/ft BALB/c congenics is qualitatively different compared to Tmem79ma/ma mice.

Severe anaphylaxis (SA) in Hymenoptera venom allergy has been associated with a number of risk factors. However, the effect of several of those risk factors on the severity of anaphylaxis is poorly defined.To evaluate risk factors for SA in Hymenoptera venom allergy.We evaluated data from 500 patients who were referred to our department for the diagnosis of Hymenoptera venom allergy during a period of 11 years to identify risk factors for SA.Six significant risk factors for SA were identified (P.05): short interval from sting to reaction, absence of urticaria or angioedema (U/A) during anaphylaxis, older age, male sex, elevation of baseline serum tryptase (BST) level, and diagnosis of systemic mastocytosis. Moreover, elevation in BST level was significantly associated with the absence of U/A and older age. No association could be established between SA and comorbidities, concurrent cardiovascular medication, or the severity of the systemic reaction during the initiation of venom immunotherapy.Apart from BST and older age, male sex, short interval from sting to reaction, and absence of U/A are also risk factors for SA. The association between elevated BST level and SA was largely confined to those who had an absence of U/A after field sting, possibly because of the higher risk of concurrent systemic mastocytosis. Patients with an SA after a field sting do not have an elevated risk of systemic reactions during the initiation of venom immunotherapy compared with patients with mild anaphylaxis; therefore, additional preventive measures are not necessary.

Loss of FLG causes ichthyosis vulgaris. Reduced FLG expression compromises epidermal barrier function and is associated with atopic dermatitis, allergy, and asthma. The flaky tail mouse harbors two mutations that affect the skin barrier, Flgft, resulting in hypomorphic FLG expression, and Tmem79ma, inactivating TMEM79. Mice defective only for TMEM79 featured dermatitis and systemic atopy, but also Flgft/ft BALB/c congenic mice developed eczema, high IgE, and spontaneous asthma, suggesting that FLG protects from atopy. In contrast, a targeted Flg-knockout mutation backcrossed to BALB/c did not result in dermatitis or atopy. To resolve this discrepancy, we generated FLG-deficient mice on pure BALB/c background by inactivating Flg in BALB/c embryos. These mice feature an ichthyosis phenotype, barrier defect, and facilitated percutaneous sensitization. However, they do not develop dermatitis or atopy. Whole-genome sequencing of the atopic Flgft BALB/c congenics revealed that they were homozygous for the atopy-causing Tmem79matted mutation. In summary, we show that FLG deficiency does not cause atopy in mice, in line with lack of atopic disease in a fraction of patients with ichthyosis vulgaris carrying two Flg null alleles. However, the absence of FLG likely promotes and modulates dermatitis caused by other genetic barrier defects.