SummaryBackground Drug patch tests (PTs) can reproduce delayed hypersensitivity to drugs and entail a moderate re-exposure of patients to offending drugs. Objectives To determine the value of PTs for identifying the responsible drug in severe cutaneous adverse drug reactions (SCARs) such as acute generalized exanthematous pustulosis (AGEP), drug reaction with eosinophilia and systemic symptoms (DRESS) and Stevens-Johnson syndrome ⁄toxic epidermal necrolysis (SJS ⁄TEN). Methods In a multicentre study, PTs were conducted on patients referred for DRESS, AGEP or SJS ⁄TEN within 1 year of their SCAR. All drugs administered in the 2 months prior to and the week following the onset of the SCAR were tested. Results Among the 134 patients included (48 male, 86 female; mean age 51AE7 years), positive drug PTs were obtained for 24 different drugs. These included positive tests for 64% (46 ⁄72) of patients with DRESS, 58% (26 ⁄45) of those with AGEP and 24% (4 ⁄17) of those with SJS ⁄TEN, with only one relapse of AGEP. The value of PTs depended on the type of drug and the type of SCAR (e.g. carbamazepine was positive in 11 ⁄13 DRESS cases but none of the five SJS ⁄TEN cases). PTs were frequently positive for beta lactams (22 cases), pristinamycin (11 cases) and in DRESS with pump proton inhibitors (five cases), but were usually negative for allopurinol and salazopyrin. Of 18 patients with DRESS, eight had virus reactivation and positive PTs. In DRESS, multiple drug reactivity was frequent (18% of cases), with patients remaining sensitized many years later. Conclusions PTs are useful and safe for identifying agents inducing SCAR.

A double-blind, placebo-controlled study was carried out in 85 patients with a well-documented history of perennial asthma caused by house-dust mites. Patients received either placebo or sublingual immunotherapy (SLIT) with a standardized Dermatophagoides pteronyssinus (DP)-D. farinae (DF) 50/50 extract. After a run-in period, patients received increasing doses up to 300 IR every day for 4 weeks and then three times a week for the following 24 months. The cumulative dose was about 104000 IR, equivalent to 4.2 mg Der p 1 and 7.3 mg Der f 1. Symptom and medication scores and respiratory function were assessed throughout the trial. Serum specific IgE and IgG4 were determined before SLIT (t0) and after 6 (t1), 11 (t2), 17 (t3), and 25 months (t4) of SLIT. Mite exposure was evaluated at t0, t2, and t4 by semiquantitative guanine determinations. Patients aged 15 years and older were asked to assess their quality of life (QoL) by completing the SF20 (Short Form Health Status Survey) plus two items at t0, t2, and t4. Use of inhaled corticosteroids and beta2-agonists was significantly decreased after 25 months of treatment in both groups (P<0.03). SLIT patients showed significant improvements in respiratory function at t4 (% predicted FEV1 (P = 0.01), VC (P = 0.002), morning (P = 0.01) and evening (P = 0.03) PEFR), and reduction in daytime asthma score (P = 0.02). In the SLIT group, the post-treatment PD20 was 1.75 times higher than the baseline value. There was no change in PD20 in the placebo group. Compared to the placebo group, the SLIT group showed a significant increase in specific IgE DP(P = 0.05), IgE DF(P = 0.02), IgG4 DP(P = 0.001), and IgG4 DF (P = 0.001) levels after SLIT. QoL scores were similar in both groups at t0 and t2. At t4, all scores were better in the SLIT group than in the placebo group, with the differences being most marked for the general perception of health (P = 0.01) and physical pain (P = 0.02). Adverse events were similar in the two groups. This study shows that SLIT in house-dust-mite-related asthma has a good safety profile and improves respiratory function, bronchial hyperreactivity, and QoL.

Anaphylaxis is a systemic acute hypersensitivity reaction that is considered to depend on allergen-specific immunoglobulin E (IgE) antibodies and histamine release by mast cells and basophils. Nevertheless, allergen-specific IgG antibodies have been proposed to contribute when the allergen is an abundant circulating large molecule, e.g., after infusions of therapeutic antibodies or dextran. Data from animal models demonstrate a pathway involving platelet-activating factor (PAF) release by monocytes/macrophages and neutrophils activated via their Fc gamma receptors (FcγRs). We hypothesized that such a pathway may also apply to small drugs and could be responsible for non–IgE-mediated anaphylaxis and influence anaphylaxis severity in humans. We prospectively conducted a multicentric study of 86 patients with suspected anaphylaxis to neuromuscular-blocking agents (NMBAs) during general anesthesia and 86 matched controls. We found that concentrations of anti-NMBA IgG and markers of FcγR activation, PAF release, and neutrophil activation correlated with anaphylaxis severity. Neutrophils underwent degranulation and NETosis early after anaphylaxis onset, and plasma-purified anti-NMBA IgG triggered neutrophil activation ex vivo in the presence of NMBA. Neutrophil activation could also be observed in patients lacking evidence of classical IgE-dependent anaphylaxis. This study supports the existence of an IgG-neutrophil pathway in human NMBA-induced anaphylaxis, which may aggravate anaphylaxis in combination with the IgE pathway or underlie anaphylaxis in the absence of specific IgE. These results reconcile clinical and experimental data on the role of antibody classes in anaphylaxis and could inform diagnostic approaches to NMBA-induced acute hypersensitivity reactions.

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Basophils express not only high-affinity IgE receptors, but also low-affinity IgG receptors. Which, among these receptors, are expressed by human basophils is poorly known. Low-affinity IgG receptors comprise CD32 (FcγRIIA, FcγRIIB, and FcγRIIC) and CD16 (FcγRIIIA and FcγRIIIB). FcγRIIA, FcγRIIC, and FcγRIIIA are activating receptors, FcγRIIB are inhibitory receptors, FcγRIIIB are GPI-anchored receptors whose function is poorly understood. Basophils were reported to express FcγRII, but not FcγRIII. We aimed at further identifying basophil IgG receptors. Basophils from normal donors and from patients suffering from an allergic skin disease (atopic dermatitis), allergic respiratory diseases (allergic rhinitis and asthma), or a nonallergic skin disease (chronic urticaria) were examined. We found that normal basophils contain FcγRIII transcripts and express FcγRIIIB, but not FcγRIIIA, which were detected on 24–81% basophils from normal donors and on 12–100% basophils from patients. Noticeably, the proportion of FcγRIIIB+ basophils was significantly lower in atopic dermatitis patients than in other subjects. This decreased FcγRIII expression was not correlated with an activated phenotype of basophils in atopic dermatitis patients, although FcγRIIIB expression was down-regulated upon basophil activation by anti-IgE. Our results challenge the two dogmas 1) that basophils do not express FcγRIII and 2) that FcγRIIIB is exclusively expressed by neutrophils. They suggest that a proportion of basophils may be lost during enrichment procedures in which FcγRIII+ cells are discarded by negative sorting using anti-CD16 Abs. They unravel an unexpected complexity of IgG receptors susceptible to modulate basophil activation. They identify a novel systemic alteration in atopic dermatitis.

In conclusion, the lack of significative difference in salivary opiorphin levels between iBMS and controls does not favor a direct local role for opiorphin in the etiopathogeny of iBMS. However, higher blood opiorphin levels may reflect a systemic dysregulation in iBMS. Trial registration NCT02686359 https://clinicaltrials.gov/ct2/show/NCT02686359.

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