Peanut-induced anaphylaxis in children and adolescents: Data from the European Anaphylaxis Registry

Background

Peanut allergy has a rising prevalence in high-income countries, affecting 0.5%–1.4% of children. This study aimed to better understand peanut anaphylaxis in comparison to anaphylaxis to other food triggers in European children and adolescents.

Methods

Data was sourced from the European Anaphylaxis Registry via an online questionnaire, after in-depth review of food-induced anaphylaxis cases in a tertiary paediatric allergy centre.

Results

3514 cases of food anaphylaxis were reported between July 2007 - March 2018, 56% in patients younger than 18 years. Peanut anaphylaxis was recorded in 459 children and adolescents (85% of all peanut anaphylaxis cases). Previous reactions (42% vs. 38%; p = .001), asthma comorbidity (47% vs. 35%; p < .001), relevant cofactors (29% vs. 22%; p = .004) and biphasic reactions (10% vs. 4%; p = .001) were more commonly reported in peanut anaphylaxis. Most cases were labelled as severe anaphylaxis (Ring&Messmer grade III 65% vs. 56% and grade IV 1.1% vs. 0.9%; p = .001). Self-administration of intramuscular adrenaline was low (17% vs. 15%), professional adrenaline administration was higher in non-peanut food anaphylaxis (34% vs. 26%; p = .003). Hospitalization was higher for peanut anaphylaxis (67% vs. 54%; p = .004).

Conclusions

The European Anaphylaxis Registry data confirmed peanut as one of the major causes of severe, potentially life-threatening allergic reactions in European children, with some characteristic features e.g., presence of asthma comorbidity and increased rate of biphasic reactions. Usage of intramuscular adrenaline as first-line treatment is low and needs to be improved. The Registry, designed as the largest database on anaphylaxis, allows continuous assessment of this condition.

     

CD40-mediated lymphotoxin α expression in human B cells is tyrosine kinase dependent

The cytokine lymphotoxin (LT)α is known to play a role in B cell activation. As the engagement of the B cell antigen CD40 is known to lead to B cell proliferation and differentiation, we studied LTα expression in human B cells after CD40 ligation. We demonstrate that anti-CD40 monoclonal antibody (mAb) induces strong LTα mRNA and surface expression in human tonsil B cells. Induction of LTα mRNA and surface expression by CD40 ligation is inhibited by the protein tyrosine kinase (PTK) inhibitors herbimycin and genistein in a dose-dependent manner. The protein kinase C (PKC)-specific inhibitors sphingosine and bisindolylmaleimide caused negligible inhibition of anti-CD40-induced LTα mRNA and surface expression. No inhibition is observed with the protein kinase (PKA) inhibitors H89 and HA1004. Cross-linking of the transmembrane phosphatase CD45 to CD40 by using goat-anti-mouse F(ab')₂ fragments strongly inhibits CD40-mediated LTα expression in human B cells, confirming the role of PTK activation in CD40-mediated induction of LTα expression. Inhibitors of the serine/threonine protein phosphatases PP1 and PP2A, okadaic acid and calyculin induce LTα mRNA expression. In contrast, cyclosporin A, an inhibitor of the serine/threonine phosphatase calcineurin has no effect on anti-CD40-induced LTα expression. These results suggest that induction of LTα expression in B cells following engagement of CD40 involves activation of protein tyrosine kinases.     

Opposing effects on immune function and skin barrier regulation by the proteasome inhibitor bortezomib in an allergen‐induced eczema model

Proteasome inhibition (PI) has been reported to interfere with antibody‐driven autoimmune diseases. The impact of PI on the allergic immune response and on skin diseases like atopic dermatitis (AD) has not been thoroughly explored, however. Here, we examined whether the PI bortezomib interferes with the allergic immune response and the severity of AD by using an established mouse model of allergen‐driven dermatitis, to which bortezomib was applied after the establishment of systemic sensitization to ovalbumin. The treatment indeed resulted in a remarkable decrease in total and allergen‐specific plasma cells/antibody‐secreting cells, as evidenced by flow cytometry and ELISpot, respectively. This was accompanied by rapid reductions in serum antibody titres, including a prominent reduction of the IgE isotype. CD4+ and CD8+ cells were greatly diminished in lesional skin on immunohistological staining. The impressive effects at the level of immune modulation did not result in any improvement in the eczema, however. Following up on this unexpected result, we found that the skin itself was susceptible to bortezomib, by which it was instructed to lower the expression of critical skin barrier genes, especially transglutaminase‐1 and filaggrin. Together, bortezomib eliminates plasma cells and decreases immunoglobulin responses, including allergenic IgE. Although anti‐inflammatory effects are detectable in the skin, counter‐regulatory effects from PI on resident skin cells likely undermine improvement in the eczema. These results caution against the therapeutic use of bortezomib for inflammatory skin disorders, which are characterized by inherently impaired barrier function, especially AD.     

Health-related quality of life with tralokinumab in moderate-to-severe atopic dermatitis: A phase 2b randomized study

BackgroundAtopic dermatitis (AD) is associated with a substantial burden on quality of life (QoL).ObjectiveTo evaluate the effects of tralokinumab on health-related QoL in patients with moderate-to-severe AD using patient-reported outcomes.MethodsThis was a phase 2b, randomized, double-blind, placebo-controlled, dose-ranging study in adults with moderate-to-severe AD. The patients received subcutaneous tralokinumab or placebo (1:1:1:1) every 2 weeks for 12 weeks and class 3 topical corticosteroid cream or ointment at least once daily from the run-in to end of follow-up. Patient-reported outcome end points were change from baseline to week 12 in the Dermatology Life Quality Index (dermatology life quality index (DLQI); prespecified secondary objective), the Short Form 36 Health Survey (SF-36) version 2, and sleep interference numeric rating scale score (prespecified exploratory objectives).ResultsA total of 204 patients were randomized to placebo (n = 51) or tralokinumab (45 mg, n = 50; 150 mg, n = 51; 300 mg, n = 52). Tralokinumab 300 mg every 2 weeks improved total Dermatology Life Quality Index vs placebo at week 12 (placebo-adjusted mean change, ?3.51 [95% confidence interval, ?6.00 to ?1.02]). At week 12, both the mental component summary (4.23 [0.98-7.47]) and the physical component summary (4.26 [1.83-6.69]) and all 8 domains of the Short Form 36 Health Survey were improved in patients treated with tralokinumab 300 mg vs placebo. Sleep interference was improved at week 12 with all tralokinumab doses vs placebo.ConclusionTralokinumab improved health-related QoL in patients with moderate-to-severe atopic dermatitis, providing further evidence of the value of targeting interleukin-13 in such patients.Trial RegistrationClinicalTrials.gov identifier: NCT02347176; https://clinicaltrials.gov/ct2/show/NCT02347176.     

SPAK Differentially Mediates Vasopressin Effects on Sodium Cotransporters

Activation of the Na⁺-K⁺-2Cl⁻-cotransporter (NKCC2) and the Na⁺-Cl⁻-cotransporter (NCC) by vasopressin includes their phosphorylation at defined, conserved N-terminal threonine and serine residues, but the kinase pathways that mediate this action of vasopressin are not well understood. Two homologous Ste20-like kinases, SPS-related proline/alanine-rich kinase (SPAK) and oxidative stress responsive kinase (OSR1), can phosphorylate the cotransporters directly. In this process, a full-length SPAK variant and OSR1 interact with a truncated SPAK variant, which has inhibitory effects. Here, we tested whether SPAK is an essential component of the vasopressin stimulatory pathway. We administered desmopressin, a V2 receptor–specific agonist, to wild-type mice, SPAK-deficient mice, and vasopressin-deficient rats. Desmopressin induced regulatory changes in SPAK variants, but not in OSR1 to the same degree, and activated NKCC2 and NCC. Furthermore, desmopressin modulated both the full-length and truncated SPAK variants to interact with and phosphorylate NKCC2, whereas only full-length SPAK promoted the activation of NCC. In summary, these results suggest that SPAK mediates the effect of vasopressin on sodium reabsorption along the distal nephron.The furosemide-sensitive Na⁺-K⁺-2Cl⁻-cotransporter (NKCC2) of the thick ascending limb (TAL) and the thiazide-sensitive Na⁺-Cl⁻-cotransporter (NCC) of the distal convoluted tubule (DCT) are key regulators of renal salt handling and therefore participate importantly in BP and extracellular fluid volume homeostasis.¹ Loss-of-function mutants in the SLC12A1/ A3 genes encoding NKCC2 and NCC cause salt-losing hypotension and hypokalemic alkalosis in Bartter’s and Gitelman’s syndromes,^2,3 whereas their overactivity may contribute to essential hypertension.^4,5 Recently, attention has been focused on the two closely related STE20-like kinases, SPS-related proline/alanine-rich kinase (SPAK) and oxidative stress responsive kinase 1 (OSR1), which can phosphorylate NKCC2 and NCC at their N-terminal conserved threonine or serine residues (T96, T101, and T114 of mouse NKCC2 and T53, T58, and S71 of mouse NCC) and thereby activate the transporters.^6–8 Despite the high homology between SPAK and OSR1 and their overlapping renal expression patterns, distinct roles along the nephron have been suggested based on data from SPAK-deficient and kidney-specific OSR1-deficient mice: deletion of SPAK primarily impairs the function of NCC, whereas deletion of OSR1 negatively affects NKCC2.^9–11 The complex functional properties of a WNK-SPAK/OSR1-N(K)CC interaction cascade are currently being defined.¹² Recently, arginine vasopressin (AVP), signaling via the V2 receptor (V2R), has been identified as an efficient activator of both cotransporters, affecting their luminal trafficking and phosphorylation.^13–18 Because plasma AVP levels may vary not only with the sleep-wake cycle or long-term physiologic challenges, but also with pulsatile changes over the short term, distinct, time-dependent responses may occur.¹⁹ SPAK and OSR1 are well placed to regulate distal NaCl reabsorption in response to AVP. Here we tested the role of SPAK in AVP-induced activation of NKCC2 and NCC, acutely and during long-term treatment. The results suggest that SPAK is an essential kinase that modulates distal nephron function in response to AVP stimulation.