Explore the vast range of titles available.

This proof-of-principle trial showed that imatinib treatment reduced mast-cell activation and improved airway responsiveness in patients with severe refractory asthma. Many patients with severe asthma do not have adequate disease control despite the use of high-dose inhaled or systemic glucocorticoids. 1 Severe asthma is associated with airway hyperresponsiveness — that is, an exaggerated response to a bronchoconstrictor stimulus — and airway inflammation, both of which persist despite high-dose glucocorticoid therapy. 2 , 3 Increased airway hyperresponsiveness is associated with a progressive loss of lung function, 4 and, among patients with moderate-to-severe asthma, those with airway hyperresponsiveness have a poorer quality of life than those without this trait. 5 In addition, studies have shown that treatment targeting airway hyperresponsiveness leads to more effective control of asthma . . .

Background: The diagnosis of anaphylaxis is based on clinical history since no reliable biological marker is currently available to confirm the diagnosis. Objective: It was the aim of this study to determine sequential serum tryptase concentrations during anaphylaxis and to evaluate its potential as a diagnostic marker. Methods: We performed a prospective study including patients with acute anaphylaxis (according to the National Institute of Allergy and Infectious Disease/Food Allergy and Anaphylaxis Network criteria) attending the emergency department. Demographic characteristics, anaphylactic triggers, specific risk factors, clinical characteristics and management of anaphylaxis were recorded. Serum tryptase was measured at 1–2 h (T1), 4–6 h (T2) and 12–24 h (T3) following onset of the episode and at basal conditions (TB). Results: A total of 102 patients were included (63 females, mean age 47.4 ± 19.1 years). Tryptase concentration at T1 (19.3 ± 15.4 µg/l) was significantly higher than at T2, T3 and TB (all <11.4 µg/l; p < 0.0001). Importantly, tryptase was not raised in 36.3% of cases; furthermore, in 60.6% of these patients, no changes were observed in tryptase levels comparing T1 and TB (ΔT1–TB = 0). Tryptase was more frequently elevated in more severe anaphylaxis (p < 0.0001) and positively correlated with the grades of severity (p < 0.001, r = 0.49). Anaphylaxis was more severe and tryptase concentration higher when the causative agent was a drug compared to food, both at T1 (p = 0.045) and at TB (p = 0.019). Age and coronary risk factors were associated with more severe anaphylaxis (p = 0.001). Conclusion: Tryptase is a biomarker related to the severity of anaphylaxis. However, since its concentration remains unaltered in a considerable number of patients during acute anaphylaxis, there is a need for more reliable diagnostic biological tests.

Bacterial pathogens have evolved to secrete strong anti-inflammatory proteins that target the immune system. It was long speculated whether these virulence factors could serve as therapeutics in diseases in which abnormal immune activation plays a role. We adopted the secreted chemotaxis inhibitory protein of Staphylococcus aureus (CHIPS) as a model virulence factor-based therapeutic agent for diseases in which C5AR1 stimulation plays an important role. We show that the administration of CHIPS in human C5AR1 knock-in mice successfully dampens C5a-mediated neutrophil migration during immune complex-initiated inflammation. Subsequent CHIPS toxicology studies in animal models were promising. However, during a small phase I trial, healthy human volunteers showed adverse effects directly after CHIPS administration. Subjects showed clinical signs of anaphylaxis with mild leukocytopenia and increased C-reactive protein concentrations, which are possibly related to the presence of relatively high circulating anti-CHIPS antibodies and suggest an inflammatory response. Even though our data in mice show CHIPS as a potential anti-inflammatory agent, safety issues in human subjects temper the use of CHIPS in its current form as a therapeutic candidate. The use of staphylococcal proteins, or other bacterial proteins, as therapeutics or immune-modulators in humans is severely hampered by pre-existing circulating antibodies.

Joshua Milner and colleagues show that increased TPSAB1 copy number causes a multisystem disorder marked by elevated basal serum tryptase levels. Shared symptoms in affected individuals include irritable bowel syndrome, cutaneous flushing and pruritus, connective tissue abnormalities and dysautonomia. Elevated basal serum tryptase levels are present in 4–6% of the general population, but the cause and relevance of such increases are unknown 1 , 2 . Previously, we described subjects with dominantly inherited elevated basal serum tryptase levels associated with multisystem complaints including cutaneous flushing and pruritus, dysautonomia, functional gastrointestinal symptoms, chronic pain, and connective tissue abnormalities, including joint hypermobility. Here we report the identification of germline duplications and triplications in the TPSAB1 gene encoding α-tryptase that segregate with inherited increases in basal serum tryptase levels in 35 families presenting with associated multisystem complaints. Individuals harboring alleles encoding three copies of α-tryptase had higher basal serum levels of tryptase and were more symptomatic than those with alleles encoding two copies, suggesting a gene-dose effect. Further, we found in two additional cohorts (172 individuals) that elevated basal serum tryptase levels were exclusively associated with duplication of α-tryptase–encoding sequence in TPSAB1 , and affected individuals reported symptom complexes seen in our initial familial cohort. Thus, our findings link duplications in TPSAB1 with irritable bowel syndrome, cutaneous complaints, connective tissue abnormalities, and dysautonomia.

Activation of tissue mast cells (MCs) and their abnormal growth and accumulation in various organs are typically found in primary MC disorders also referred to as mastocytosis. However, increasing numbers of patients are now being informed that their clinical findings are due to MC activation (MCA) that is neither associated with mastocytosis nor with a defined allergic or inflammatory reaction. In other patients with MCA, MCs appear to be clonal cells, but criteria for diagnosing mastocytosis are not met. A working conference was organized in 2010 with the aim to define criteria for diagnosing MCA and related disorders, and to propose a global unifying classification of all MC disorders and pathologic MC reactions. This classification includes three types of ‘MCA syndromes’ (MCASs), namely primary MCAS, secondary MCAS and idiopathic MCAS. MCA is now defined by robust and generally applicable criteria, including (1) typical clinical symptoms, (2) a substantial transient increase in serum total tryptase level or an increase in other MC-derived mediators, such as histamine or prostaglandin D 2 , or their urinary metabolites, and (3) a response of clinical symptoms to agents that attenuate the production or activities of MC mediators. These criteria should assist in the identification and diagnosis of patients with MCAS, and in avoiding misdiagnoses or overinterpretation of clinical symptoms in daily practice. Moreover, the MCAS concept should stimulate research in order to identify and exploit new molecular mechanisms and therapeutic targets.

The pathogenesis of cold urticaria (ColdU) and cold-induced anaphylaxis (ColdA) remains poorly understood, and ColdA is underrepresented in anaphylaxis literature. Laboratory features to guide management are largely unknown. This study evaluated basal serum tryptase (BST) and total immunoglobulin E (IgE) levels in ColdU and ColdA, their associations with clinical features, and the utility of testing for the p.D816V variant in blood leukocytes and hereditary α-tryptasemia (HαT). Ninety-two adults with ColdU were enrolled. ColdA was defined as a reaction involving skin and/or visible mucosal tissue with cardiovascular, respiratory, or gastrointestinal manifestations. Evaluations included patient history, standard cold stimulation testing (sCST) using an ice cube and TempTest , and laboratory tests. ColdA was diagnosed in 35.9% of patients. ColdU phenotypes based on sCST included typical ColdU (52.2%), localized cold-reflex urticaria (5.4%), and ColdU with negative sCST (42.4%). Negative sCST, compared to typical ColdU, was associated with fewer ColdA cases ( = 0.004) but more spontaneous wheals ( < 0.001). ColdA patients more frequently exhibited generalized wheals ( = 0.047), skin angioedema ( = 0.007), oropharyngeal/laryngeal manifestations ( < 0.001), and itchy earlobes ( = 0.002) than non-ColdA patients. Elevated BST levels (>11.4 ng/mL) in 9.8% of patients were attributed to p.D816V and/or HαT. p.D816V was detected in 6.6% of ColdU and 6.3% of ColdA patients. HαT prevalence was higher in ColdU (10.9%) and ColdA (15.2%) than the general population (estimated at 5.7%; = 0.041 and = 0.038). Total IgE levels were significantly higher in ColdA than non-ColdA ( = 0.021). This study confirmed clinical features linked to ColdA previously identified by the multicenter COLD-CE study, including generalized wheals, skin angioedema, oropharyngeal/laryngeal manifestations, and itchy earlobes. We identified new high-risk features. ColdA is more frequently associated with typical ColdU than with ColdU with negative sCST, the latter being linked to spontaneous wheals. ColdA is additionally associated with higher total IgE levels. Furthermore, patients with ColdU and ColdA exhibit higher prevalence of p.D816V and HαT compared to general population data, a finding not previously reported. Further research is needed to explore their clinical implications.

•Investigates research on post mortem tryptase in anaphylactic deaths.•Recommends early sampling and standardised sampling technique.•Tryptase needs to be interpreted within the wider autopsy and clinical context. Post mortem tryptase is a commonly-used ancillary test in the investigation of possible anaphylactic deaths. Ante mortem tryptase interpretation differs from post mortem interpretation due to differing priorities, biochemical behaviours and capacity for follow-up. Additionally, post mortem tryptase sampling site, method and even cut-off levels are not standardised between facilities. This review of the literature investigates the existing research and recommendations on the use of post mortem tryptase in suspected anaphylactic deaths. Currently, autopsy recommendations suggest early sampling, standardised sampling technique with clamping of and aspiration from the femoral vein, and for the results to be interpreted within the wider autopsy and clinical context. Areas in need of further research include the effects of cytolysis on tryptase levels and studies to stratify differing tryptase levels based on type of death and anaphylactic trigger.

infection is one of the most common soil-transmitted helminthiasis and IgE response to this helminth may increase the risk of asthma, bronchial hyperreactivity and atopy. There is not enough evidence showing the role of group-2 innate lymphoid cells (ILC2) in the pathogenesis of helminth infections in humans. Here, we aimed to investigate and characterize the influence of infection on circulating ILCs in endemically exposed subjects. Non-infected (NI; n=16) and Ascaris-infected (AI; n=16) subjects from an endemic area were included. Two consecutive stool samples from each subject were examined by Kato-Katz to define parasite infection. Antibodies to the ABA-1 antigen of Ascaris and Ascaris extract were measured by ELISA. ILC subsets and their activation markers (CD25, CD69, thymic stromal lymphopoietin receptor (TSLPR) were evaluated in its PBMC by flow cytometry. Proximity extension assay (PEA) was performed to explore plasma proteins associated to infection. No significant differences in the relative or absolute frequencies of total ILCs, ILC1, ILC2 and ILC3 cells were observed regarding the infection status. However, within AI group, IgE-sensitized subjects to ABA-1 had higher frequencies and counts of ILC2 (p<0.05). Frequencies of CD25+, CD69+ and TSLPR+ ILC2 were higher in AI compared to the NI (p<0.01). Additionally, egg burden was positively correlated with CD69+ ILC2 frequencies (r=0.67; p=0.005). Tryptase alpha/beta 1 (TPSAB1), GP6 and several plasma proteins associated with cell growth and granulocyte chemotaxis were highly expressed in the AI group (p<0.05). Interestingly, TPSAB1 levels were positively correlated with ILC2 expressing activation markers frequencies, egg burden and IgE levels against Ascaris. Ascaris infection is associated with increased expression of ILC2 activation markers and TPSAB1, which may contribute to the type-2 response.

Mast cells (MC) are effector cells during severe systemic reactions (SR) to Hymenoptera stings. Venom specific immunotherapy (VIT) is the treatment of choice for prevention of SR to stings. Tryptase and prostaglandin D₂ metabolites (PGD₂) are the markers of MC activation. The study design was to 1. compare baseline values of serum tryptase concentration (BST) and PGD₂ metabolites in children with/without venom sensitization, 2. to evaluate an influence of rush VIT on MC markers in treated children. Sensitized group: 25 children with SR to Hymenoptera sting. 19 healthy children. Active treatment: 5-day-rush-VIT. BST was evaluated by ImmunoCAP, PGD₂ metabolites in blood and urine by GC-NICI-MS. The baseline blood levels of MC markers were significantly higher, while urinary concentration of 9α,11β-PGF₂ was significantly lower in the whole group of venom-sensitized children compared to controls. Severity of SR showed negative correlation with urinary PGD₂ metabolites, while positive with plasma 9α,11β-PGF₂ and BST concentration The highest sensitivity was obtained for plasma 9α,11β-PGF₂ whereas the highest specificity for urinary PGD-M. In children with IgE-mediated SR to Hymenoptera stings, elevation of baseline values of PGD₂ metabolites in blood is accompanied by decreased excretion of its urinary metabolites. Assessment of stable PGD₂ metabolites might serve as an independent MC marker to identify allergic children. There is an association between urinary PGD₂ metabolites and severity of the SR to Hymenoptera stings.

Hereditary α-tryptasemia (HαT)—a genetic trait caused by increased α-tryptase-encoding typtase alpha/beta-1 (TPSAB1) copy number—is associated with adult mastocytosis. The primary objective was to assess the association between α-tryptase and pediatric mastocytosis. We also want to evaluate whether the KIT p.D816V mutation in peripheral blood leukocytes (PBLs) reliably predicts systemic mastocytosis (SM) in children. A prospective cohort of 68 children from a referral center in Slovenia with cutaneous mastocytosis (CM) underwent tryptase genotyping by droplet digital PCR and examination for KIT p.D816V in PBL using a sensitive PCR test. A significant majority of patients (57 of 68; [83.8%]) had at least one α-tryptase-encoding gene; none had HαT. 7 of the 68 (10.3%) who were positive for KIT p.D816V in PBL, one fulfilled diagnostic criteria for indolent SM, and another was diagnosed with monoclonal mast cell activation syndrome. One of those individuals had an increased basal serum tryptase (BST) level (14.5 ng/mL). We found a high presence of germline α-tryptase in children with CM, but not HαT. By employing sensitive examination for KIT p.D816V in PBL, in combination with clinical data and other examinations, our study suggests that KIT p.D816V in PBL may indicate systemic disease in children with CM.