The role of drug, dose and the tolerance/intolerance of new drugs in multiple drug hypersensitivity syndrome (MDH).

BACKGROUND Multiple drug hypersensitivity syndrome (MDH) is used to describe persons with a drug hypersensitivity reaction (DHR) to at least two chemically unrelated drugs, confirmed by skin test or in vitro assay. METHODS Medical records of 25 patients with MDH, tested and confirmed at our allergy division were retrospectively evaluated in terms of clinical course, involved drugs, daily drug dose, latency periods, test results of skin test and cellular assays and tolerated drugs in subsequent pharmacological treatments. RESULTS MDH almost exclusively appeared as a delayed, often severe DHR and started in 14/25 with a drug reaction with eosinophilia and systemic symptoms (DRESS). Penicillins (13/25, 52.0%) and cephalosporins (6/25, 24.0%), typical high dose drugs, were most often identified as elicitors of MDH, especially at the first DHR, followed by aromatic antiepileptics (7/25, 28.0%), vancomycin (4/25, 16.0%) and antibiotic sulfonamides (4/25, 16.0%). Cephalosporins, clindamycine and radio contrast media (RCM) were mainly involved in subsequent DHR. The median daily drug dose of all drug trigger was 1875.0 mg (662.5; 2100.0) at the first DHR and 600.0 mg (300.0; 1300.0) at subsequent DHR, p=0.0420. CONCLUSION High dose drugs, especially betalactam antibiotics, RCM and clindamycin are common elicitors of subsequent DHR in patients with MDH. Macrolides, quinolones, doxycycline, non-aromatic antiepileptics and paracetamol were often tolerated. As the same drugs elicited both flare-up reactions and real DHR, drug induced flare-up reactions may be precursors of a possible second DHR and MDH. The administration of highly dosed drugs should be avoided in patients at risk for MDH

Treatment with IL5-/IL-5 receptor antagonists in drug reaction with eosinophilia and systemic symptoms (DRESS).

Purpose Drug reaction with eosinophilia and systemic symptoms (DRESS) is a severe delayed drug hypersensitivity reaction with exanthema, eosinophilia, and organ manifestations. After culprit drug withdrawal, systemic corticosteroids (CS) are the most widely used treatment, often requiring high doses for months. Blocking the IL-5/IL‑5 receptor axis with mepolizumab, reslizumab, and benralizumab is a promising targeted treatment with a good safety profile and no immunosuppressive effect. The aim of this study is to summarize current experience with the anti-IL5/IL-5-receptor therapy in DRESS. Methods A retrospective analysis of all patients diagnosed with DRESS and treated with mepolizumab, reslizumab, or benralizumab in DRESS was performed. In addition, a PubMed-Medline search for publications on DRESS with anti-IL-5/IL‑5 receptor treatment was performed. Results Of the 14 cases identified, 6 patients were treated with mepolizumab, 6 with benralizumab, 1 patient with reslizumab, and 1 patient was switched from benralizumab to mepolizumab. The main indication for an IL‑5 blockade was a therapy-refractory course (7/14 [50.0%]), recurrent relapses (3/14 [21.4%]), and severe organ dysfunction (2/14 [14.3%]). In 13/14 (93%) cases, a rapid clinical improvement with suppression of eosinophilia and reduction of CS could be achieved. In all but two cases under mepolizumab (dose 100-600 mg) or reslizumab (dose according to body weight), two or more doses were necessary until resolution of DRESS. In 4/7 cases under benralizumab, a single 30 mg dose was sufficient. Conclusion Blockade of the IL-5/IL‑5 receptor axis appears to be a promising treatment in DRESS with fast clinical improvement, which may allow more rapid reduction of CS, and a good safety profile. In addition, a summary of recommendations on when to use blockade of the IL-5/IL‑5 receptor axis in DRESS treatment is provided

Use of epinephrine in anaphylaxis: a retrospective cohort study at a Swiss university emergency department.

AIMS OF THE STUDY Anaphylaxis is a medical emergency and requires prompt treatment to prevent life-threatening conditions. Epinephrine, considered as the first-line drug, is often not administered. We aimed first to analyse the use of epinephrine in patients with anaphylaxis in the emergency department of a university hospital and secondly to identify factors that influence the use of epinephrine. METHODS We performed a retrospective analysis of all patients admitted with moderate or severe anaphylaxis to the emergency department between 1 January 2013 and 31 December 2018. Patient characteristics and treatment information were extracted from the electronic medical database of the emergency department. RESULTS A total of 531 (0.2%) patients with moderate or severe anaphylaxis out of 260,485 patients admitted to the emergency department were included. Epinephrine was administered in 252 patients (47.3%). In a multivariate logistic regression, cardiovascular (Odds Ratio [OR] = 2.94, CI 1.96-4.46, p <0.001) and respiratory symptoms (OR = 3.14, CI 1.95-5.14, p<0.001) were associated with increased likelihood of epinephrine administration, in contrast to integumentary symptoms (OR = 0.98, CI 0.54-1.81, p = 0.961) and gastrointestinal symptoms (OR = 0.62, CI 0.39-1.00, p = 0.053). CONCLUSIONS Less than half of the patients with moderate and severe anaphylaxis received epinephrine according to guidelines. In particular, gastrointestinal symptoms seem to be misrecognised as serious symptoms of anaphylaxis. Training of the emergency medical services and emergency department medical staff and further awareness are crucial to increase the administration rate of epinephrine in anaphylaxis

Climate data, localisation of the sting, grade of anaphylaxis and therapy of hymenoptera stings.

International epidemiological studies indicate that around 1-7% of the population respond with an allergic reaction to a hymenoptera sting, which is frequently associated with admission to an emergency department. This retrospective study included patients admitted between 2009 and 2013 to an emergency department after a hymenoptera sting. In all, 86 (60.1%) men and 57 (39.9%) women were included in the study. The mean age was 43 years, with a range from 19 to 84 years. The most common localisations of a sting were the head (n = 33; 22.5%), the hands (n = 32; 21.9%) and the arms (n = 26; 17.8%). In women, we recorded significantly more stings in distal extremities (p = 0.033) and in men stings in the rump and head were most frequent. Local swellings were observed in 67.1% (n = 96) of patients and 34.3% (n = 49) patients exhibited an anaphylactic reaction. Of these, 21.7% (n = 31) suffered from a grade I, 6.3% (n = 9) grade II, 4.2% (n = 6) grade III and 2.1% (n = 3) grade IV anaphylactic reactions. 46% (66) of the patients were given antihistamines, 45% (64) intravenous glucocorticoids and only 12.5% (16) epinephrine. Most stings were recorded on days without rainfall (p = 0.013), with more hours of sunshine (p = 0.001), low relative humidity (p = 0.006), with mean air pressure above 954.3 hPa and on days with mean temperature above 24.2 °C (p = 0.001). In conclusion, the most hymenoptera stings induced local swelling only; severe reactions were rare. The most dangerous stings are enoral and result from inattentive drinking. Epinephrine was rarely used in anaphylactic reactions

Humoral response to mRNA vaccines against SARS-CoV-2 in patients with humoral immunodeficiency disease.

OBJECTIVES Although mRNA-based vaccines against SARS-CoV-2 induce a robust immune response and prevent infections and hospitalizations, there are limited data on the antibody response in individuals with humoral immunodeficiency. The aim of this study was to evaluate the humoral immune response after two vaccine doses with BNT162b2 or mRNA-1273 in patients with humoral immunodeficiency disease. METHODS This cross-sectional study assessed 39 individuals with hypogammaglobulinemia under immunoglobulin replacement therapy. IgG anti-SARS-CoV-2 spike protein antibodies (anti-S) were measured 4 weeks to 4 months after two doses of an mRNA vaccine against SARS-CoV-2. The proportion of patients, who developed a humoral immune response to the spike protein were evaluated and compared to 19 healthy controls. RESULTS After vaccination with two vaccine doses, 26/39 patients (66.7%) with humoral immunodeficiency disease and all healthy controls developed anti-S. In subjects with baseline IgG 5 g/l: 151.5 AU/ml (95%CI 109.0-400.0), healthy controls 250.0 AU/ml (95%CI 209.0-358.0), p = 0.007. CONCLUSION In most patients with mild to moderate humoral immunodeficiency we found only slightly lower anti-S antibodies compared with healthy controls after two vaccine doses with BNT162b2 and mRNA-1273. However, in patients with a decreased baseline IgG below 3 g/l and/or under immunosuppressive drugs, we found severely impaired humoral immune responses

Efficacy of omalizumab in mastocytosis: allusive indication obtained from a prospective, double-blind, multicenter study (XOLMA Study)

BACKGROUND: Patients with mastocytosis often suffer from a variety of symptoms caused by mast cell mediators where treatments remain difficult, showing various success rates. Omalizumab, a monoclonal anti-IgE antibody, has been postulated to have a positive impact on mastocytosis-associated symptoms such as flush, vertigo, gastrointestinal problems, or anaphylaxis. OBJECTIVE: To investigate the efficacy and safety of omalizumab in systemic mastocytosis. METHODS: Patients with histologically proven mastocytosis were investigated in a multicenter prospective double-blind placebo-controlled trial to receive either omalizumab or placebo, dosed according to IgE and body weight. The primary endpoint was change in the AFIRMM activity score after 6 months of treatment. Different laboratory parameters were analyzed. RESULTS: Sixteen patients were analyzed: 7 to omalizumab and 9 to placebo (mean age 47.7 ± 13.8 vs. 45.4 ± 8.8 years; 66.6 vs. 85.7% were female; mean disease duration 10.0 ± 5.1 vs. 4.5 ± 2.9 years, respectively). After 6 months the median AFIRMM score decreased 50% from 52.0 to 26.0 in the omalizumab group versus 104.0-102.0 in the placebo group (p = 0.286); however, the difference was not significant (p = 0.941). Secondary endpoints, including the number of allergic reactions, changes in major complaints, wheal-and-flare reaction due to mechanical irritation (Darier's sign), and frequency of the use of mastocytosis-specific drugs improved in the omalizumab group, but not significantly. Adverse events like urticaria, bronchospasm, and anaphylactic shock showed no significant difference between the groups. No severe adverse events occurred. FcεRI (Fc-epsilon receptor) expression on basophils decreased after receiving omalizumab versus placebo. CONCLUSION: Omalizumab was safe and showed a tendency to improve mastocytosis-related symptoms, in particular diarrhea, dizziness, flush, and anaphylactic reactions, including the AFIRMM score and secondary endpoints; however, the difference was not significant. Due to the small study size and difference at baseline between the study groups, further studies are required to confirm our findings

Autoimmunity and immunodeficiency associated with monoallelic LIG4 mutations via haploinsufficiency

BACKGROUND: Biallelic mutations in LIG4 encoding DNA-ligase 4 cause a rare immunodeficiency syndrome manifesting as infant-onset life-threatening and/or opportunistic infections, skeletal malformations, radiosensitivity and neoplasia. LIG4 is pivotal during DNA repair and during V(D)J recombination as it performs the final DNA-break sealing step. OBJECTIVE: We explored whether monoallelic LIG4 missense mutations may underlie immunodeficiency and autoimmunity with autosomal dominant inheritance. METHODS: Extensive flow-cytometric immune-phenotyping was performed. Rare variants of immune system genes were analyzed by whole exome sequencing. DNA repair functionality and T cell-intrinsic DNA damage tolerance was tested with an ensemble of in vitro and in silico tools. Antigen-receptor diversity and autoimmune features were characterized by high-throughput sequencing and autoantibody arrays. Reconstitution of wild-type vs. mutant LIG4 were performed in LIG4 knock-out Jurkat T cells and DNA damage tolerance was subsequently assessed. RESULTS: A novel heterozygous LIG4 loss-of-function mutation (p.R580Q), associated with a dominantly inherited familial immune-dysregulation consisting of autoimmune cytopenias, and in the index patient with lymphoproliferation, agammaglobulinemia and adaptive immune cell infiltration into nonlymphoid organs. Immunophenotyping revealed reduced naïve CD4$^{+}$ T cells and low TCR-Vα7.2$^{+}$ T cells, while T/B-cell receptor repertoires showed only mild alterations. Cohort screening identified two other non-related patients with the monoallelic LIG4 mutation p.A842D recapitulating clinical and immune-phenotypic dysregulations observed in the index family and displaying T cell-intrinsic DNA damage intolerance. Reconstitution experiments and molecular dynamics simulations categorize both missense mutations as loss-of-function and haploinsufficient. CONCLUSION: We provide evidence that certain monoallelic LIG4 mutations may cause human immune dysregulation via haploinsufficiency