Pathogenesis, immunology, and immune-targeted management of the multisystem inflammatory syndrome in children (MIS-C) or pediatric inflammatory multisystem syndrome (PIMS): EAACI Position Paper.

Multisystem inflammatory syndrome in children (MIS-C) is a rare, but severe complication of coronavirus disease 2019 (COVID-19). It develops approximately 4 weeks after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and involves hyperinflammation with multisystem injury, commonly progressing to shock. The exact pathomechanism of MIS-C is not known, but immunological dysregulation leading to cytokine storm plays a central role. In response to the emergence of MIS-C, the European Academy of Allergy and Clinical Immunology (EAACI) established a task force (TF) within the Immunology Section in May 2021. With the use of an online Delphi process, TF formulated clinical statements regarding immunological background of MIS-C, diagnosis, treatment, follow-up, and the role of COVID-19 vaccinations. MIS-C case definition is broad, and diagnosis is made based on clinical presentation. The immunological mechanism leading to MIS-C is unclear and depends on activating multiple pathways leading to hyperinflammation. Current management of MIS-C relies on supportive care in combination with immunosuppressive and/or immunomodulatory agents. The most frequently used agents are systemic steroids and intravenous immunoglobulin. Despite good overall short-term outcome, MIS-C patients should be followed-up at regular intervals after discharge, focusing on cardiac disease, organ damage, and inflammatory activity. COVID-19 vaccination is a safe and effective measure to prevent MIS-C. In anticipation of further research, we propose a convenient and clinically practical algorithm for managing MIS-C developed by the Immunology Section of the EAACI.

Skin Barrier Function Assessment: Electrical Impedance Spectroscopy Is Less Influenced by Daily Routine Activities Than Transepidermal Water Loss.

BACKGROUND: Skin barrier function assessment is commonly done by measuring transepidermal water loss (TEWL). An important limitation of this method is the influence of intrinsic and extrinsic factors. Electrical impedance spectroscopy (EIS) is a lesser-established method for skin barrier function assessment. Some influential factors have been described, but no guidelines exist regarding the standardization of these measurements. OBJECTIVE: To evaluate the effect size of daily routine activities on TEWL and EIS, as well as their correlation with age and anatomical differences. METHODS: Healthy participants (n=31) were stratified into three age groups (18-29, 30-49, and ≥50 years). In a climate-controlled room, EIS and TEWL measurements were performed on the left and right volar forearm and abdomen. RESULTS: Body cream application decreased TEWL and EIS values after 15 and 90 minutes. Skin washing decreased TEWL for 15 minutes and EIS values for at least 90 minutes. TEWL was increased 5 minutes after moderate to intense exercise. Coffee intake increased TEWL on the abdomen after 60 minutes. TEWL and EIS values did not correlate with participants' age and no anatomical differences were observed. No correlation was observed between TEWL and EIS. CONCLUSION: Body cream application and skin washing should be avoided at least 90 minutes prior to measurements of TEWL and EIS. Exercise and coffee intake should also be avoided prior to TEWL measurements. EIS may be a promising tool for skin barrier function assessment as it is less affected by daily routine activities than TEWL.

Mast cell FcϵRI density and function dissociate from dependence on soluble IgE concentration at very low and very high IgE concentrations.

OBJECTIVE: The contribution of affinity, clonality, and concentration of individual IgE species to effector cell response has recently been characterized in a model with recombinant human IgE on passively sensitized basophils. This study extends the dependence of effector cell degranulation on IgE concentration to mast cells cultured with IgE for 2 weeks. METHODS: Human mast cells cultured for 7 weeks from peripheral blood stem cells were matured for 2 weeks with interleukin-4 (IL-4) and recombinant human IgE consisting of two clones specific for Dermatophagoides pteronyssinus 2 (Derp2) (7% + 7%) and unspecific IgE at 0.8, 8, 80, and 800 kU/L. The density of the IgE receptor, FcϵRI, and mast cell function were measured after challenging with recombinant Derp2 at 14 concentrations from 10 fg/mL to 100 pg/mL. CD63 expression, histamine release, and Prostaglandin D2 (PGD(2)) synthesis were measured, and maximal expression and mast cell sensitivity were calculated. RESULTS: At 800 kU/L IgE, FcϵRI expression varied more than at 80, 8, and 0.8 kU/L IgE. There was a trend toward increased maximal expression of CD63, histamine release, and PGD(2) secretion with increasing IgE concentration. At 0.1 kU/L specific IgE, the LC50 increased up to fivefold, least so for PGD(2). CONCLUSIONS: Human mast cells cultured with rhIgE of known composition are a sensitive model for studying factors governing effector cell degranulation that is close to the in vivo situation. This model can be used to study effects of IgE concentration, clonality, and affinity and may help predict the optimal immunologic treatment for a given patient.

Increasing time interval and decreasing allergen dose interval improves ex vivo desensitization of human blood basophils.

BACKGROUND: Desensitization is a method for inducing temporary tolerance to allergen. The mechanism underlying desensitization is yet to be established. METHODS: Basophil granulocytes in whole blood from grass pollen allergic subjects were desensitized ex vivo by sequential addition of increasing allergen concentrations. At each step basophil activation (CD193 + CD63+ ) was monitored with and without (background activation) allergen challenge at optimal concentration. The sequential desensitization protocol was compared to two single-dose desensitization protocols with threshold and subthreshold allergen concentrations. Incubation intervals and allergen concentrations were varied in order to optimise the protocol. RESULTS: Sequential desensitization effectively reduced basophil response. The single-dose subthreshold protocol and single-dose threshold protocol did not reduce basophil activation with optimal allergen challenge from a mean 57.1 (95% CI: 32.7 - 81.5) to 50.4% (95% CI: 16.3 - 84.4; n = 5; P = 0.43) and 45.0% (95% CI: 23.1 - 66.9; P = 0.14) respectively, while the sequential desensitization protocol reduced activation to a mean 37.2% (95% CI: 16.3 - 58.1; P = 0.018). Reducing incubation time from 10 to 5 minutes increased mean background activation from 22.4 (95% CI: 11.7 - 33.1) to 30.0% (95% CI: 19.7 - 40.3; n = 5; P = 0.026). Increasing time intervals from 10 to 20 minutes reduced background activation from 30.9 (95% CI: 22.8 - 39.0) to 21.9% (95% CI: 16.0 - 27.7; n = 5; P = 0.020). Increasing allergen concentration intervals from 2-fold to 5- and 10-fold did not have significant effect on basophil activation. CONCLUSIONS: Sequential desensitization ex vivo effectively attenuates the basophil response to allergen. Increasing the time spent at each step improves desensitization. This protocol could be valuable for investigation the mechanism of desensitization. © 2016 International Clinical Cytometry Society.