Skin Test Reactivity Patterns in Patients Allergic to Iodinated Contrast Media: A Refined View.

BACKGROUND: Two-dimensional (2D) classifications of iodinated contrast media (ICM) are insufficient to explain the observed skin test (ST) reactivity patterns in patients with drug hypersensitivity reactions (DHRs) to ICM. OBJECTIVE: To refine the current view on allergic DHRs to ICM by analyzing ST reactivity patterns in patients with previous reactions to ICM. METHODS: Patients with a history of DHR to ICM and positive STs, who presented at the University Hospital of Montpellier between 2004 and 2022, were included in the study. The relative difference between every two ICM products was measured by Manhattan distance and odds ratios were computed for all pairs of products in the immediate reaction (IR) and non-immediate reaction (NIR) ST groups. RESULTS: A total of 181 patients were included in the study. Odds ratio analysis identified significant associations between classical cross-reactive ICM, such as iohexol-ioversol, iohexol-iomeprol, iomeprol-ioversol, and iohexol-iodixanol in the IR ST group and iohexol-ioversol, iopromide-iohexol, and iomeprol-ioversol in the NIR ST group. We also identified uncommon associations, such as ioxitalamate-amidotrizoate in the IR ST group and amidotrizoate-iopamidol and amidotrizoate-ioxitalamate in the NIR ST group. The results were reflected by the Manhattan distance, which suggested the existence of clusters containing the same classically associated ICM as well as uncommon associations, which we hypothesize to be related to similarities in the 3D structure of the respective ICM. CONCLUSIONS: Current chemical (2D) classifications cannot explain all observed ST reactivity patterns. Whether the 3D structure can be integrated into the current classifications to interpret the observed ST reactivity patterns and predict tolerance to alternative ICM requires further research.

Comparative Performance of 4 Penicillin-Allergy Prediction Strategies in a Large Cohort.

BACKGROUND: A safe and pragmatic guide for labelling and delabelling patients with suspected penicillin allergy is mandatory. OBJECTIVE: To compare the performance of 4 penicillin-allergy prediction strategies in a large independent cohort. METHODS: We conducted a retrospective study for subjects presenting between January 2014 and December 2021 at the University Hospital of Montpellier, with a history of hypersensitivity to penicillins. The outcome targeted by the study was a positive penicillin-allergy test. RESULTS: Of the 1,884 participants included, 382 (20.3%) had positive penicillin-allergy tests. The ENDA (European Network on Drug Allergy) and Blumenthal strategies yielded relatively high sensitivities and low specificities and, by design, did not misclassify any positive subjects with severe index reactions. The PEN-FAST <3 score had a negative predictive value of 90% (95% confidence interval [95% CI] 88%-91%), with a sensitivity of 66% (95% CI 62%-71%) and a specificity of 73% (95% CI 71%-75%), and incorrectly delabelled 18 subjects with anaphylaxis and 15 with other severe nonimmediate reactions. For the adapted Chiriac score, the specificity corresponding to 66% sensitivity was 73% (95% CI 70%-75%). Conversely, at a 73% specificity threshold, the sensitivity was 65% (95% CI, 61%-70%). Attempts to improve these prediction algorithms did not substantially enhance performance. CONCLUSIONS: The ENDA and Blumenthal strategies are safe for high-risk subjects, but their delabelling effectiveness is limited, leading to unnecessary avoidance. Conversely, the PEN-FAST and Chiriac scores are performant in delabelling, but more frequently misclassify high-risk subjects with positive penicillin-allergy tests. Selection of the most appropriate tool requires careful consideration of the target population and the desired goal.

Evaluation of environmental antibiotic contamination by surface wipe sampling in a large care centre.

OBJECTIVES: Exposure of healthcare workers to antibiotics may cause adverse health effects. Results of environmental contamination with antibiotics, obtained by taking surface wipe samples, can be used as an indicator for potential exposure to these sensitizing drugs. The objective was to describe the results of repeated measurements of contamination with antibiotics on multiple surfaces in hospital wards. Standardized needle and syringe preparation techniques and cleaning procedures were used. METHODS: The preparation table and the floor around the waste bin in six wards were sampled and analysed for contamination with the antibiotics amoxicillin, benzylpenicillin, cefotaxime, ceftriaxone, flucloxacillin, meropenem, piperacillin and vancomycin. Sampling was performed in four trials during 8 months. Depending on the outcome of the trials, the cleaning procedure was adapted. Liquid chromatography with tandem mass spectrometry was used for the analysis of the drugs. RESULTS: During the four trials, contamination with all eight antibiotics was omnipresent on all preparation tables and floors in the six wards. The highest contamination was found for amoxicillin (1291 ng/cm2). Changing the cleaning procedure did not reduce the level of contamination. CONCLUSIONS: Surface contamination with the antibiotics was widespread and most probably caused by spillage during the preparation in combination with an ineffective cleaning procedure. Strategies should be developed and implemented by institutions for safe handling of antibiotics to reduce environmental contamination and potential exposure of healthcare workers to these sensitizing drugs.

OTULIN haploinsufficiency predisposes to environmentally directed inflammation.

Recently, OTULIN haploinsufficiency was linked to enhanced susceptibility to Staphylococcus aureus infections accompanied by local necrosis and systemic inflammation. The pathogenesis observed in haploinsufficient patients differs from the hyperinflammation seen in classical OTULIN-related autoinflammatory syndrome (ORAS) patients and is characterized by increased susceptibility of dermal fibroblasts to S. aureus alpha toxin-inflicted cytotoxic damage. Immunological abnormalities were not observed in OTULIN haploinsufficient patients, suggesting a non-hematopoietic basis. In this research report, we investigated an Otulin+/- mouse model after in vivo provocation with lipopolysaccharide (LPS) to explore the potential role of hematopoietic-driven inflammation in OTULIN haploinsufficiency. We observed a hyperinflammatory signature in LPS-provoked Otulin+/- mice, which was driven by CD64+ monocytes and macrophages. Bone marrow-derived macrophages (BMDMs) of Otulin+/- mice demonstrated higher proinflammatory cytokine secretion after in vitro stimulation with LPS or polyinosinic:polycytidylic acid (Poly(I:C)). Our experiments in full and mixed bone marrow chimeric mice suggest that, in contrast to humans, the observed inflammation was mainly driven by the hematopoietic compartment with cell-extrinsic effects likely contributing to inflammatory outcomes. Using an OTULIN haploinsufficient mouse model, we validated the role of OTULIN in the regulation of environmentally directed inflammation.

FLT3L governs the development of partially overlapping hematopoietic lineages in humans and mice.

FMS-related tyrosine kinase 3 ligand (FLT3L), encoded by FLT3LG, is a hematopoietic factor essential for the development of natural killer (NK) cells, B cells, and dendritic cells (DCs) in mice. We describe three humans homozygous for a loss-of-function FLT3LG variant with a history of various recurrent infections, including severe cutaneous warts. The patients' bone marrow (BM) was hypoplastic, with low levels of hematopoietic progenitors, particularly myeloid and B cell precursors. Counts of B cells, monocytes, and DCs were low in the patients' blood, whereas the other blood subsets, including NK cells, were affected only moderately, if at all. The patients had normal counts of Langerhans cells (LCs) and dermal macrophages in the skin but lacked dermal DCs. Thus, FLT3L is required for B cell and DC development in mice and humans. However, unlike its murine counterpart, human FLT3L is required for the development of monocytes but not NK cells.

Paediatric perioperative hypersensitivity: the performance of the current consensus formula and the effect of uneventful anaesthesia on serum tryptase.

Background: Paired sampling of acute (aST) and basal (bST) serum tryptase has been recommended when investigating patients with a suspected perioperative hypersensitivity (POH) reaction. In the current consensus formula, an aST value exceeding (1.2×bST+2) confirms mast cell activation. The current consensus formula has been validated in adults but not in children. Methods: We prospectively included 96 children who underwent uneventful anaesthesia and sampled serum tryptase at baseline and 60-90 min after induction. Tryptase changes were then compared with those in 94 children with suspected POH who were retrospectively included from four reference centres in Belgium, France, and Denmark. Results: We observed a median decrease in serum tryptase during uneventful anaesthesia of 0.41 µg L-1 (-15.9%; P<0.001). The current consensus formula identified mast cell activation in 31.9% of paediatric POH patients. After generating receiver operating characteristic curves through 100 repeated five-fold cross-validation, aST>bST+0.71 was identified as the optimal cut-off point to identify mast cell activation. This new paediatric formula has higher sensitivity than the current consensus formula (53.2% vs 31.9%, P<0.001) with a specificity of 96.9%. Analysis in the subpopulation where a culprit was identified and in grade 3-4 reactions similarly yielded higher sensitivity for the new paediatric formula when compared with the current consensus formula (85.3% vs 61.8%; P=0.008 and 78.0% vs 48.8%; P<0.001, respectively). Internally cross-validated sensitivity and specificity were 53.3% and 93.3%, respectively. Conclusions: This is the first study suggesting the need for an adjusted formula in children to identify perioperative mast cell activation as tryptase is significantly lowered during uneventful anaesthesia. We propose a new formula (aST>bST+0.71) which performs significantly better than the current consensus formula in our multicentric paediatric population.

Heterozygous mutations in the C-terminal domain of COPA underlie a complex autoinflammatory syndrome.

Mutations in the N-terminal WD40 domain of coatomer protein complex subunit α (COPA) cause a type I interferonopathy, typically characterized by alveolar hemorrhage, arthritis, and nephritis. We described 3 heterozygous mutations in the C-terminal domain (CTD) of COPA (p.C1013S, p.R1058C, and p.R1142X) in 6 children from 3 unrelated families with a similar syndrome of autoinflammation and autoimmunity. We showed that these CTD COPA mutations disrupt the integrity and the function of coat protein complex I (COPI). In COPAR1142X and COPAR1058C fibroblasts, we demonstrated that COPI dysfunction causes both an anterograde ER-to-Golgi and a retrograde Golgi-to-ER trafficking defect. The disturbed intracellular trafficking resulted in a cGAS/STING-dependent upregulation of the type I IFN signaling in patients and patient-derived cell lines, albeit through a distinct molecular mechanism in comparison with mutations in the WD40 domain of COPA. We showed that CTD COPA mutations induce an activation of ER stress and NF-κB signaling in patient-derived primary cell lines. These results demonstrate the importance of the integrity of the CTD of COPA for COPI function and homeostatic intracellular trafficking, essential to ER homeostasis. CTD COPA mutations result in disease by increased ER stress, disturbed intracellular transport, and increased proinflammatory signaling.

Combined deficient response to polysaccharide-based and protein-based vaccines predicts a severe clinical phenotype.

OBJECTIVES: Antibody response on polysaccharide- and protein-based vaccines is useful to test B cell functionality. As only few studies have explored the value of studying immune response to both vaccines, we evaluated the clinical value of anti-polysaccharide and anti-protein Luminex-based multiplex assays in context of primary immunodeficiency (PID) diagnosis. METHODS: A 10-plex Luminex-based assay detecting antibodies to ten pneumococcal polysaccharide (PnPS) serotypes [present in unconjugated Pneumovax, not in 13-valent pneumococcal conjugated vaccine (PCV)] and a 5-plex assay detecting antibodies to five protein antigens (present in DTap/Tdap) were clinically validated in healthy individuals (n=99) and in retrospective (n=399) and prospective (n=108) patient cohorts. Clinical features of individuals with impaired response to PnPS and/or proteins were compared to those with normal response. RESULTS: Antigen-specific antibody thresholds were determined in healthy individuals. Individuals with impaired anti-PnPS responses and deficient immunoglobulin levels suffered more from autoimmune diseases and had lower B cell levels compared to individuals with impaired anti-PnPS response with normal immunoglobulin levels. Individuals with combined impaired response to PnPS and proteins showed more severe clinical manifestations compared to individuals with isolated impaired response to PnPS or proteins. Eight of the 11 individuals with severely impaired responses to both PnPS and proteins had common variable immunodeficiency. Evaluation of the anti-PnPS response to four serotypes not contained in 20-valent PCV was comparable to evaluation to ten serotypes not contained in 13-valent PCV. CONCLUSIONS: Multiplexed assessment of anti-PnPS and anti-protein responses combined with immunoglobulin quantification provides useful clinical information to support PID diagnosis.

Evaluation of skin prick location on the forearm using a novel skin prick automated test device.

Background: The skin prick test (SPT) is the gold standard for identifying allergic sensitization in individuals suspected of having an inhalant allergy. Recently, it was demonstrated that SPT using a novel skin prick automated test (SPAT) device showed increased reproducibility and tolerability compared to the conventional SPT, among other benefits. Objective: This study aimed to evaluate prick location bias using the novel SPAT device. Methods: A total of 118 volunteers were enrolled in this study and underwent SPATs with histamine (nine pricks) and glycerol control (one prick) solutions on the volar side of their forearms. Imaging of the skin reactions was performed using the SPAT device, and the physician determined the longest wheal diameter by visually inspecting the images using a web interface. Prick location bias was assessed along the medial vs. lateral and proximal vs. distal axes of the forearm. Results: In total, 944 histamine pricks were analyzed. Four medial and four lateral histamine pricks were grouped, and wheal sizes were compared. The longest wheal diameters were not significantly different between the medial and lateral prick locations (p = 0.41). Furthermore, the pricks were grouped by two based on their position on the proximal-distal axis of the forearm. No significant difference was observed among the four groups of analyzed prick locations (p = 0.73). Conclusion: The prick location on the volar side of the forearm did not influence wheal size in SPAT-pricked individuals.

Rituximab and improved nodular regenerative hyperplasia-associated non-cirrhotic liver disease in common variable immunodeficiency: a case report and literature study.

Common variable immunodeficiency (CVID) associated liver disease is an underrecognized and poorly studied non-infectious complication that lacks an established treatment. We describe a CVID patient with severe multiorgan complications, including non-cirrhotic portal hypertension secondary to nodular regenerative hyperplasia leading to diuretic-refractory ascites. Remarkably, treatment with rituximab, administered for concomitant immune thrombocytopenia, resulted in the complete and sustained resolution of portal hypertension and ascites. Our case, complemented with a literature review, suggests a beneficial effect of rituximab that warrants further research.

A Narrative Review of the Neurological Manifestations of Human Adenosine Deaminase 2 Deficiency.

Deficiency of human adenosine deaminase type 2 (DADA2) is a complex systemic autoinflammatory disorder characterized by vasculopathy, immune dysregulation, and hematologic abnormalities. The most notable neurological manifestations of DADA2 are strokes that can manifest with various neurological symptoms and are potentially fatal. However, neurological presentations can be diverse. We here present a review of the neurological manifestations of DADA2 to increase clinical awareness of DADA2 as the underlying diagnosis. We reviewed all published cases of DADA2 from 1 January 2014 until 19 July 2022 found via PubMed. A total of 129 articles describing the clinical features of DADA2 were included in the analysis. Six hundred twenty-eight patients diagnosed with DADA2 were included in the review. 50.3% of patients had at least signs of one reported neurological event, which was the initial or sole manifestation in 5.7% and 0.6%, respectively. 77.5% of patients with neurological manifestations had at least signs of one cerebrovascular accident, with lacunar strokes being the most common and 35.9% of them having multiple stroke episodes. There is a remarkable predilection for the brain stem and deep gray matter, with 37.3% and 41.6% of ischemic strokes, respectively. Other neurological involvement included neuropathies, focal neurological deficits, ophthalmological findings, convulsions, and headaches. In summary, neurological manifestations affect a significant proportion of patients with DADA2, and the phenotype is broad. Neurological manifestations can be the first and single manifestation of DADA2. Therefore, stroke, encephalitis, posterior reversible encephalopathy syndrome, mononeuropathy and polyneuropathy, and Behçet's disease-like presentations should prompt the neurologist to exclude DADA2, especially but not only in childhood.

Frequent Allergic Sensitization to Farmed Edible Insects in Exposed Employees.

BACKGROUND: Exposure to insects used in pet food, scientific research, or live fish bait can cause an occupational allergy. The recent shift toward enhanced insect production for human consumption and animal feed will likely expose more employees. OBJECTIVE: To investigate sensitization and symptoms in employees exposed to edible insects in Flanders. METHODS: Fifteen insect-exposed employees were recruited and sensitization was explored by skin prick test, basophil activation test, and immunoblotting. Lung function, FeNO, histamine provocation, and sputum induction were studied. Airborne dust sampling was performed and proteins were studied by silver stain and immunoblotting. RESULTS: Sixty percent of employees self-reported upper respiratory tract symptoms related to insect exposure. Ten employees (71.4%) had a positive histamine provocation test concentration causing a 20% drop in FEV1 less than 8 mg/mL and four (26.7%) had FeNO levels above 25 ppb. Four employees (30.7%) had a positive skin prick test for at least one insect, and seven (58.3%) had a positive basophil activation test. In eight participants with insect sensitization, four (50%) had co-occurring house dust mite sensitization. Two participants had strong IgE binding to a 50-kDa migratory locust allergen, one to a 25-kDa mealworm allergen, and one to mealworm α-amylase. In one center, facility adjustment resulted in a substantial decrease in the inhalable dust fraction. CONCLUSIONS: Insect exposure leads to high levels of sensitization among employees. Most employees reported symptoms of the upper respiratory system, and two-thirds of employees had bronchial hyperreactivity. Prevention and health surveillance will be important in the developing insect-rearing industry.

Plasma cells are not restricted to the CD27+ phenotype: characterization of CD27-CD43+ antibody-secreting cells.

Circulating antibody-secreting cells are present in the peripheral blood of healthy individuals reflecting the continued activity of the humoral immune system. Antibody-secreting cells typically express CD27. Here we describe and characterize a small population of antibody-secreting class switched CD19+CD43+ B cells that lack expression of CD27 in the peripheral blood of healthy subjects. In this study, we characterized CD27-CD43+ cells. We demonstrate that class-switched CD27-CD43+ B cells possess characteristics of conventional plasmablasts as they spontaneously secrete antibodies, are morphologically similar to antibody-secreting cells, show downregulation of B cell differentiation markers, and have a gene expression profile related to conventional plasmablasts. Despite these similarities, we observed differences in IgA and IgG subclass distribution, expression of homing markers, replication history, frequency of somatic hypermutation, immunoglobulin repertoire, gene expression related to Toll-like receptors, cytokines, and cytokine receptors, and antibody response to vaccination. Their frequency is altered in immune-mediated disorders. Conclusion: we characterized CD27-CD43+ cells as antibody-secreting cells with differences in function and homing potential as compared to conventional CD27+ antibody-secreting cells.

Endotyping of IgE-Mediated Polyethylene Glycol and/or Polysorbate 80 Allergy.

BACKGROUND: Polyethylene glycol (PEG) and polysorbate 80 (PS80) allergy preclude from SARS-CoV-2 vaccination. The mechanism(s) governing cross-reactivity and PEG molecular weight dependence remain unclear. OBJECTIVES: To evaluate PEGylated lipid nanoparticle (LNP) vaccine (BNT162b2) tolerance and explore the mechanism of reactivity in PEG and/or PS80 allergic patients. METHODS: PEG/PS80 dual- (n = 3), PEG mono- (n = 7), and PS80 mono-allergic patients (n = 2) were included. Tolerability of graded vaccine challenges was assessed. Basophil activation testing on whole blood (wb-BAT) or passively sensitized donor basophils (allo-BAT) was performed using PEG, PS80, BNT162b2, and PEGylated lipids (ALC-0159). Serum PEG-specific IgE was measured in patients (n = 10) and controls (n = 15). RESULTS: Graded BNT162b2 challenge in dual- and PEG mono-allergic patients (n = 3/group) was well tolerated and induced anti-spike IgG seroconversion. PS80 mono-allergic patients (n = 2/2) tolerated single-dose BNT162b2 vaccination. Wb-BAT reactivity to PEG-containing antigens was observed in dual- (n = 3/3) and PEG mono- (n = 2/3), but absent in PS80 mono-allergic patients (n = 0/2). BNT162b2 elicited the highest in vitro reactivity. BNT162b2 reactivity was IgE mediated, complement independent, and inhibited in allo-BAT by preincubation with short PEG motifs, or detergent-induced LNP degradation. PEG-specific IgE was only detectable in dual-allergic (n = 3/3) and PEG mono-allergic (n = 1/6) serum. CONCLUSION: PEG and PS80 cross-reactivity is determined by IgE recognizing short PEG motifs, whereas PS80 mono-allergy is PEG-independent. PS80 skin test positivity in PEG allergics was associated with a severe and persistent phenotype, higher serum PEG-specific IgE levels, and enhanced BAT reactivity. Spherical PEG exposure via LNP enhances BAT sensitivity through increased avidity. All PEG and/or PS80 excipient allergic patients can safely receive SARS-CoV-2 vaccines.

Impact of environmental nitrogen pollution on pollen allergy: A scoping review.

The current rise in the prevalence of allergies to aeroallergens is incompletely understood and attributed to interactions with environmental changes and lifestyle changes. Environmental nitrogen pollution might be a potential driver of this increasing prevalence. While the ecological impact of excessive nitrogen pollution has been widely studied and is relatively well understood, its indirect effect on human allergies is not well documented. Nitrogen pollution can affect the environment in various ways, including air, soil, and water. We aim to provide a literature overview of the nitrogen-driven impact on plant communities, plant productivity, and pollen properties and how they lead to changes in allergy burden. We included original articles investigating the associations between nitrogen pollution, pollen, and allergy, published in international peer-reviewed journals between 2001 and 2022. Our scoping review found that the majority of studies focus on atmospheric nitrogen pollution and its impact on pollen and pollen allergens, causing allergy symptoms. These studies often examine the impact of multiple atmospheric pollutants and not just nitrogen, making it difficult to determine the specific impact of nitrogen pollution. There is some evidence that atmospheric nitrogen pollution affects pollen allergy by increasing atmospheric pollen levels, altering pollen structure, altering allergen structure and release, and causing increased allergenic reactivity. Limited research has been conducted on the impact of soil and aqueous nitrogen pollution on pollen allergenic reactivity. Further research is needed to fill the current knowledge gap about the impact of nitrogen pollution on pollen and their related allergic disease burden.

Case report: Myocarditis in congenital STAT1 gain-of function.

Autosomal dominant Signal transducer and activator of transcription 1 (STAT1) gain-of-function (GOF) mutations result in an inborn error of immunity characterized by chronic mucocutaneous candidiasis, recurrent viral and bacterial infections, and diverse autoimmune manifestations. Current treatment consists of chronic antifungal therapy, antibiotics for concomitant infections, and immunosuppressive therapy in case of autoimmune diseases. More recently, treatment with Janus kinases 1 and 2 (JAK1/2) inhibitors have shown promising yet variable results. We describe a STAT1 GOF patient with an incidental finding of elevated cardiac troponins, leading to a diagnosis of a longstanding, slowly progressive idiopathic myocarditis, attributed to STAT1 GOF. Treatment with a JAK-inhibitor (baricitinib) mitigated cardiac inflammation on MRI but was unable to alter fibrosis, possibly due to the diagnostic and therapeutic delay, which finally led to fatal arrhythmia. Our case illustrates that myocarditis could be part of the heterogeneous disease spectrum of STAT1 GOF. Given the insidious presentation in our case, a low threshold for cardiac evaluation in STAT1 GOF patients seems warranted.