The SQ HDM SLIT‐Tablet is safe and well tolerated in patients with House Dust Mite allergic rhinitis with or without asthma: A “real‐life” French study

BackgroundThe SQ House Dust Mite (HDM) SubLingual ImmunoTherapy (SLIT)‐Tablet (Acarizax) is the only allergen immunotherapy authorized by European regulatory authorities to treat HDM‐induced allergic asthma (AA) that is not well‐controlled by inhaled corticosteroids and associated with mild‐to‐severe HDM allergic rhinitis (AR). The aim of this study was to add evidence on the safety of the SQ HDM SLIT‐Tablet in patients with AR, alone or with AA, under real‐life conditions.MethodsThis was a French “real‐life”, multicenter, non‐comparative, longitudinal, prospective study. It included patients initiating the SQ HDM SLIT‐Tablet for either persistent moderate‐to‐severe HDM AR or AA not well‐controlled by inhaled corticosteroids and associated with mild‐to‐severe HDM AR. Adverse Events (AEs) were collected at the first intake and throughout the study. Logistic regression was used to compare safety according to asthma control before treatment initiation.ResultsBetween May 09, 2018 and May 29, 2019, 1526 patients were enrolled at 185 sites and 1483 were included in the safety population (SAF). Of them, 33.6% had suspected clinical manifestations of AA. Asthma was uncontrolled for 18.2% of the patients, partially controlled for 27.9% and well‐controlled for 53.8%. Overall, 31.9% of the SAF patients experienced at least one AE. The percentage of patients with AEs was 29.9% among patients with AR alone and 35.9% among those with AA (p = 0.0193). No significant difference was observed in the rate of AE or SAE depending on asthma control at inclusion (2.2% of SAEs reported for patients with uncontrolled asthma, 1.4% for partly controlled and 1.1% for well‐controlled).ConclusionsThe overall results indicate a good SQ HDM SLIT‐Tablet safety profile consistent with that reported in previous studies, regardless of asthma control.     

MiR‐29b regulates Th2 cell differentiation in asthma by targeting inducible B7‐H3 and STAT3

BackgroundMicroRNAs play an important role in T cell responses. However, how microRNAs regulate Th cells in asthma remains poorly defined.ObjectiveIn this study, we investigated the mechanism and pathways of miR‐29b regulating Th cells in asthma, in order to find new targets for asthma.MethodsWe detected miR‐29b, B7‐H3 and STAT3 in the peripheral blood of children with asthma, explored the relationship between these molecules and their effects on T cells through in vitro cell culture, and verified it by animal model.ResultsMiR‐29b levels were decreased in the peripheral blood mononuclear cells from children with asthma. Vitro studies found that the expression of miR‐29b in macrophages was decreased and the expression of B7‐H3 and STAT3 was increased after house dust mite (HDM) stimulation. After down‐regulation of miR‐29b in macrophages, the expressions of B7‐H3 and STAT3 in macrophages were increased and T cells differentiate into Th2 cells. After the addition of B7‐H3 or STAT3 antibodies, the differentiation of naive T cells into Th2 cells was reduced. In OVA induced mice asthmatic model, after the up‐regulation of miR‐29b in lung, the expression of B7‐H3 and STAT3 decreased in the lung tissues of mice, and the expression of Th2 cells and type II cytokine decreased simultaneously. The pathological changes of lung tissues were also alleviated.ConclusionThe expression of miR‐29b is decreased in asthmatic children. MiR‐29b can inhibit Th2 cell differentiation by inhibiting B7‐H3 and STAT3 pathways at the same time, and reduce asthmatic immune inflammation.     

Allergic sensitization to lipocalins reflects asthma morbidity in dog dander sensitized children

BackgroundSensitization to dog is an important risk factor for asthma in children, but the clinical relevance of IgE to available dog‐ and furry animal allergen molecules is uncertain.MethodsSpirometry, methacholine challenge, fraction of exhaled nitric oxide, nasal challenge with dog extract and questionnaires were performed in 59 dog‐sensitized children (age 10–18 years). Serum IgE to dog‐, cat‐, horse extracts and the allergen molecules Can f 1–6, Fel d 1, Fel d 2, Fel d 4 and Equ c 1 were evaluated.ResultsMedian numbers of positive IgE results to furry animal allergen molecules among children without asthma was 3, with asthma 5.5 and with troublesome asthma 9 (asthma vs. no asthma; p = 0.039; troublesome asthma vs. no asthma; p = 0.009). The odds ratio for asthma if sensitized to any lipocalin was 7.2 (95% confidence Interval: 1.44–35.9). Children with troublesome asthma had higher IgE levels to the lipocalins Can f 2, Can f 4 and Can f 6 compared to the rest of the study population (44 vs. 4.1 kU_A/L, p = 0.015; 5.8 vs. 0.9 kU_A/L, p = 0.018 and 1.3 vs. 0.7 kU_A/L, p = 0.03 respectively). Furthermore, a positive nasal challenge was more common among children with troublesome asthma (83% vs. 36%, p = 0.036).ConclusionsPolysensitization to furry animal allergens and lipocalins is associated with asthma in dog‐sensitized children. Children with troublesome asthma have higher IgE levels to several dog lipocalins than other dog sensitized children.Key messagePolysensitization to furry animal allergens and high IgE levels to the dog lipocalins Can f 2, Can f 4 and Can f 6 is associated with asthma severity in dog dander sensitized children. Molecular allergy diagnostics may thus help the clinicians to evaluate the impact of allergic sensitization on asthma morbidity.     

Down‐regulated IL36RN expression based on peripheral blood mononuclear cells and plasma of periodontitis patients and its clinical significance

BackgroundThe role of IL‐36 receptor antagonist (IL36RN), a mutated gene expression of IL‐36 in periodontitis patients with peripheral blood mononuclear cells (PBMC) and plasma remains to be undetermined.Materials and methodsOur study discovered the IL36RN expression through GEO public databases and further validated by PBMC and plasma of periodontitis patients and healthy participants. A total of 194 participants of public datasets, consisting of 97 cases of periodontitis and 97 cases of healthy control were retrospectively evaluated and explored the gene enrichment pathways and clinical significance of IL36RN expression accompanied by three different cytokines. Furthermore, the clinical significance of IL36RN was evaluated in mild‐to‐severe patients of periodontitis by the receiver operating curve (ROC) using the area under the curve (AUC).ResultsIL36RN expressions were notably down‐regulated in PBMC and plasma of periodontitis patients. Further, a positive correlation of IL36RN expression was significantly observed between PBMC and plasma of periodontitis patients while IL36RN expression was negatively correlated to serum‐based three different cytokines of periodontitis patients. Meanwhile, the ROC‐AUCs achieved a significantly higher range from 0.80 to 0.87 with PBMC of mild‐to‐severe and moderate‐to‐severe periodontitis patients whereas similar patients with plasma obtained a significant AUC range from 0.73 to 0.83.ConclusionIL36RN can distinctively be detectable in periodontitis patients with PBMC and plasma, which can act as a down‐regulated mutated gene that might play an effective role in causing periodontitis. IL36RN may involve by other inflammatory cytokines in the pathogenesis of periodontitis.     

The clinical significance of spondin 2 eccentric expression in peripheral blood mononuclear cells in bronchial asthma

BackgroundBronchial asthma (BA) was a heterogeneous disease characterized by chronic airway inflammation. Spondin 2 (SPON2) was reported to be implicated in the integrin pathway, protein metabolism, and drug‐induced lupus erythematosus. The purpose of this study was to evaluate the significance of SPON2 in BA diagnosis and treatment.MethodsPeripheral blood samples were obtained from 137 BA pediatric patients (61 mild‐to‐moderate BA and 76 severe BA) and 59 healthy children. Subject''s information, clinical indexes, pulmonary ventilation functions were recorded in the two groups. Peripheral blood mononuclear cells (PBMCs) were isolated from patients’ samples. qRT‐PCR and ELISA assays were employed to examine the levels of SPON2 and inflammatory cytokines, respectively. Pearson''s correlation analysis confirmed the association between SPON2 and inflammatory cytokines. Receiver operating characteristic (ROC) analysis was used to evaluate the potentials of SPON2 in terms of BA detection and discriminating against the severity of BA.ResultsBioinformatics analysis showed that SPON2, OLFM4, XIST, and TSIX were significantly upregulated, while KDM5D and RPS4Y1 were reduced in BA. GO analysis verified that these six genes were mainly involved in neutrophil degranulation, neutrophil activation involved in immune response, neutrophil activation, and neutrophil‐mediated immunity. After isolating PBMCs, we found that SPON2 was remarkably increased in BA pediatric group compared with healthy children, and the relative levels of SPON2 were related to the severity of BA. The receiver operating characteristic (ROC) analysis revealed the high potentials of SPON2 in BA diagnosis (AUC was 0.8080) and severity distinctions (AUCs were 0.7341 and 0.8541, respectively). Also, we found that there were significant differences in fractional exhaled nitric oxide (FeNO), forced expiratory volume in 1 s (FEV1)%, FEV1/ forced vital capacity (FVC)%, immunoglobulin E (IgE), serum eosinophils, and serum neutrophils between mild‐to‐moderate BA group and severe BA group. Finally, SPON2 was negatively correlated with IL‐12 while positively associated with IL‐4, IL‐13, and IL‐17A.ConclusionsSPON2 was a viable biomarker for diagnosing and degree of severity in BA, providing more insight into exploring BA and treatment''s pathogenesis.     

Complex IgE sensitization patterns in ragweed allergic patients: Implications for diagnosis and specific immunotherapy

BackgroundRagweed (Ambrosia artemisiifolia) is one of the most important allergen sources, worldwide, causing severe respiratory allergic reactions in late summer and fall, in sensitized patients. Amb a 1 has been considered as the most important allergen in ragweed but 12 ragweed pollen allergens are known. The aim of our study was to investigate IgE reactivity profiles of ragweed allergic patients and to associate them with clinical symptoms.MethodsIgE sensitization profiles from clinically well‐characterized ragweed allergic patients (n = 150) were analyzed using immunoblotted ragweed pollen extract. Immunoblot inhibition experiments were performed with two Amb a 1 isoforms and CCD markers and basophil activation experiments were performed with IgE serum before and after depletion of Amb a 1‐specific IgE.ResultsBy IgE‐immunoblotting 19 different IgE reactivity patterns with and without Amb a 1‐sensitization were found. The majority of patients (>95%) suffered from rhino‐conjunctivitis, around 60% reported asthma‐like symptoms and about 25% had skin reactions. Patients with complex IgE sensitization profiles tended to have more clinical symptoms. Serum with and without Amb a 1‐specific IgE induced basophil activation.ConclusionsRagweed pollen allergic patients exhibit complex IgE reactivity profiles to ragweed allergens including Amb a 1 isoforms and cross‐reactive carbohydrates indicating the importance of Amb a 1 isoforms and additional allergens for diagnosis and allergen‐specific immunotherapy of ragweed allergy.     

MALT1 in asthma children: A potential biomarker for monitoring exacerbation risk and Th1/Th2 imbalance‐mediated inflammation

BackgroundMucosa‐associated lymphoid tissue lymphoma translocation protein 1 (MALT1) participates in the immune‐related allergic response and inflammation flare, while its clinical role in asthma children is still unknown. Herein, this study aimed to investigate MALT1 expression, and its correlation with exacerbation risk, T helper (Th)1, Th2 cells (and their secreted cytokines), as well as inflammatory cytokines in asthma children.MethodsSixty children with asthma exacerbation and 60 children with remission asthma were enrolled in this study; then their blood MALT1, Th1, Th2 cells, tumor necrosis factor‐α (TNF‐α), interleukin‐6 (IL‐6), interferon‐gamma (IFN‐γ), and interleukin‐4 (IL‐4) were detected. Besides, blood MALT1 in another 20 health controls was also determined.ResultsMucosa‐associated lymphoid tissue lymphoma translocation protein 1 was highest in children with asthma exacerbation, followed by children with remission asthma, and lowest in health controls (p < 0.001). MALT1 could distinguish children with asthma exacerbation from children with remission asthma (area under the curve (AUC): 0.757, 95% CI: 0.670–0.843). In children with asthma exacerbation, MALT1 was negatively linked with IFN‐γ (p = 0.002) and Th1 cells (p = 0.050), but positively related to Th2 cells (p = 0.027) and exhibited a positive correlation trend (without statistical significance) with IL‐4 (p = 0.066); meanwhile, MALT1 was positively correlated with exacerbation severity (p = 0.010) and TNF‐α (p = 0.003), but not linked with IL‐6 (p = 0.096). In children with remission asthma, MALT1 only was negatively associated with Th1 cells (p = 0.023), but positively linked with TNF‐α (p = 0.023).ConclusionMucosa‐associated lymphoid tissue lymphoma translocation protein 1 serves as a potential biomarker for monitoring exacerbation risk and Th1/Th2 imbalance‐mediated inflammation of asthma children.     

Leptin favors Th17/Treg cell subsets imbalance associated with allergic asthma severity

BackgroundObesity has often been associated with severe allergic asthma (AA). Here, we analyzed the frequency of different circulating CD4⁺T‐cell subsets from lean, overweight and obese AA patients.MethodsMononuclear cells from peripheral blood were obtained from 60 AA patients and the frequency of different CD4⁺T‐cell subsets and type 1 regulatory B cells (Br1) was determined by cytometry. The effect of obese‐related leptin dose on cytokine production and Treg cell function in AA‐derived CD4⁺ T cell cultures was evaluated by ELISA and 3H thymidine uptake, respectively. Leptin levels were quantified in the plasma by ELISA. According to the BMI, patients were stratified as lean, overweight and obese.ResultsAA severity, mainly among obese patients, was associated with an expansion of hybrid Th2/Th17 and Th17‐like cells rather than classic Th2‐like cells. On the other hand, the frequencies of Th1‐like, Br1 cells and regulatory CD4⁺ T‐cell subsets were lower in patients with severe AA. While percentages of the hybrid Th2/Th17 phenotype and Th17‐like cells positively correlated with leptin levels, the frequencies of regulatory CD4⁺ T‐cell subsets and Br1 cells negatively correlated with this adipokine. Interestingly, the obesity‐related leptin dose not only elevated Th2 and Th17 cytokine levels, but also directly reduced the Treg function in CD4⁺ T cell cultures from lean AA patients.ConclusionIn summary, our results indicated that obesity might increase AA severity by favoring the expansion of Th17‐like and Th2/Th17 cells and decreasing regulatory CD4⁺T cell subsets, being adverse effects probably mediated by leptin overproduction.     

Effects of early‐life exposure to dust mite allergen and endotoxin on the development of asthma and wheezing: The Japan Environment and Children's Study

BackgroundThe effects of early‐life exposure to house dust mite allergen and endotoxin on the development of asthma are unclear in the literature. We investigated the association of early‐life exposure (0–36 months old) to house dust mite allergen and endotoxin with asthma incidence.MethodsIn this novel, large‐scale, nationwide birth cohort study, 5017 participants were randomly selected from those who met the eligibility criteria. House dust was vacuum‐sampled from the children''s mattresses within homes and assayed for the presence of dust mite allergen (Der 1) and endotoxin. The participants were classified into four quartiles (Q1–Q4) according to exposure levels. We defined the incidence of asthma and wheezing using questionnaires at 12, 24, and 36 months old. Odds ratios (ORs) of the incidence of asthma and wheezing by age in Der 1 and endotoxin exposure level were estimated using logistic regression.ResultsThe cumulative incidence rates of asthma and wheezing during 0–36 months were 10.4% and 38.1%, respectively. Significant ORs were observed in asthma onset during 12–24 months old, asthma onset during 24–36 months old, and wheezing onset during 0–12 months old in the Q4 Der 1 group. In the Q4 endotoxin group, significant positive associations between endotoxin exposure and asthma (OR 2.00, 95% confidence interval [CI]: 1.03–3.85) and wheezing (OR 1.78, 95% CI: 1.01–3.12) onset during 24–36 months old were found.ConclusionsOur results indicated that high levels of early‐life exposure to Der 1 and endotoxin in mattresses may be involved in the development of asthma.     

Allergen Uptake, Activation, and IL-23 Production by Pulmonary Myeloid DCs Drives Airway Hyperresponsiveness in Asthma-Susceptible Mice

Maladaptive, Th2-polarized inflammatory responses are integral to the pathogenesis of allergic asthma. As regulators of T cell activation, dendritic cells (DCs) are important mediators of allergic asthma, yet the precise signals which render endogenous DCs “pro-asthmatic”, and the extent to which these signals are regulated by the pulmonary environment and host genetics, remains unclear. Comparative phenotypic and functional analysis of pulmonary DC populations in mice susceptible (A/J), or resistant (C3H) to experimental asthma, revealed that susceptibility to airway hyperresponsiveness is associated with preferential myeloid DC (mDC) allergen uptake, and production of Th17-skewing cytokines (IL-6, IL-23), whereas resistance is associated with increased allergen uptake by plasmacytoid DCs. Surprisingly, adoptive transfer of syngeneic HDM-pulsed bone marrow derived mDCs (BMDCs) to the lungs of C3H mice markedly enhanced lung IL-17A production, and rendered them susceptible to allergen-driven airway hyperresponsiveness. Characterization of these BMDCs revealed levels of antigen uptake, and Th17 promoting cytokine production similar to that observed in pulmonary mDCs from susceptible A/J mice. Collectively these data demonstrate that the lung environment present in asthma-resistant mice promotes robust pDC allergen uptake, activation, and limits Th17-skewing cytokine production responsible for driving pathologic T cell responses central to the development of allergen-induced airway hyperresponsiveness.     

Pru du 1, the Bet v 1‐homologue from almond,is a major allergen in patients with birch pollen associated almond allergy

BackgroundAlmond allergy is common and can manifest in two different forms. Primary almond allergy has been reported to be associated with sensitization to almond legumin Pru du 6. In birchendemic regions, there is a link between birch‐pollinosis which is likely based on a cross‐reactive Bet v 1 homologue, a yet unidentified allergen in almond. Therefore, we sought to identify and characterize a Bet v 1‐homologue in almond.MethodsThe expression of a Bet v 1 homologue in almond kernels was confirmed by mass spectrometry. The recombinant protein was produced in Escherichia coli and its cross‐reactivity and allergenic potency was analyzed by IgE quantitative and competitive ELISA, immunoblotting and basophil histamine release using sera from 17 almond allergic patients.ResultsThe identified Bet v 1 homologue received the designation Pru du 1.0101. Pru du 1.0101 bound IgE from 82 % of almond allergic patients. Bet v 1 was able to inhibit IgE‐binding to rPru du 1 by 100%, while rPru du 1 inhibited IgE binding to rBet v 1 by 48%. Pru du 1.0101 activated basophils, though 100‐ to 1000‐fold higher concentrations were required for maximum activation in comparison to rBet v 1.ConclusionConsidering the strong inhibition capacity and higher allergenic potency of Bet v 1, the results provide compelling evidence for primary sensitization to Bet v 1 in case of birch pollen associated almond allergy. Combining Pru du 6 and Pru du 1 in diagnostic approaches may help to discriminate between primary and birch‐pollen associated almond allergy.     

Aberrant expression of long non‐coding RNA PVT1 in allergic rhinitis children: Correlation with disease risk,symptoms, and Th1/Th2 imbalance

BackgroundLong non‐coding RNA plasmacytoma variant translocation 1 (lnc‐PVT1) exacerbates inflammation and induces T helper (Th) 1/Th2 imbalance in allergic diseases, but its clinical role in allergic rhinitis (AR) remains unclear. Hence, we conducted this study to compare lnc‐PVT1 expression among AR children, disease controls (DCs), and health controls (HCs), aiming to investigate its clinical application in AR children.MethodsSixty AR children, 30 DCs, and 30 HCs were enrolled in the study, and then, their lnc‐PVT1 expression in peripheral blood mononuclear cell was detected. Serum interferon‐gamma (IFN‐γ), interleukin 10 (IL‐10), Th1, and Th2 cells in AR children were also analyzed. Besides, lnc‐PVT1 was also detected at Week (W)4 after treatment in AR patients.ResultsLnc‐PVT1 was upregulated in AR children compared with DCs and HCs (both p < 0.001). Lnc‐PVT1 was positively related to nasal rhinorrhea score, itching score, congestion score, and total nasal symptom score (TNSS) in AR children (all p < 0.050), instead of sneezing score (p = 0.115). Lnc‐PVT1 negatively associated with Th1 cells in AR children (p = 0.028) also exhibited a negative correlation trend with IFN‐γ (but without statistical significance) (p = 0.065). Differently, lnc‐PVT1 was positively related to Th2 cells (p = 0.012) and IL‐10 (p = 0.021) in AR children. Besides, lnc‐PVT1 and TNSS were reduced at W4 after treatment in AR children (both p < 0.001); notably, lnc‐PVT1 expression decline was correlated with TNSS decline during treatment (p = 0.013).ConclusionLnc‐PVT1 works as a biomarker, whose aberrant expression is related to disease severity, Th1/Th2 imbalance, and its decrement can reflect treatment outcome in AR children.     

Cross‐reactivity between tick and wasp venom can contribute to frequent wasp sensitization in patients with the α‐Gal syndrome

Backgroundα‐Gal syndrome (AGS) is a food allergy with severe delayed allergic reactions, mediated by IgE‐reactivity to galactose‐α1,3‐galactose (α‐Gal). AGS is strongly associated with tick bites. An increased incidence of venom sensitization has been found in AGS patients. Here, we evaluated the frequency of wasp sensitization in Swedish AGS patients and the possible cross‐reactivity between wasp venom and tick proteins.MethodsSera from 136 Swedish AGS patients and 29 wasp‐positive non‐AGS control sera were analyzed for IgE‐reactivity against wasp venom (Vespula spp.), the European tick Ixodes ricinus (Streptavidin ImmunoCAP), α‐Gal and total IgE by ImmunoCAP. The presence of α‐Gal on wasp venom proteins (Vespula vulgaris) was investigated by western blot (WB), and possible cross‐reactivity between wasp venom and tick proteins by enzyme‐linked immunosorbent assay and WB. Involvement of cross‐reactive carbohydrate domains (CCDs) was also assessed.ResultsWasp sensitization was present in 54% of AGS patients, although the IgE levels were low. Wasp sensitized patients had higher IgE levels to α‐Gal and total IgE levels compared to non‐wasp sensitized AGS patients. α‐Gal was not detected in wasp venom, but cross‐reactivity between wasp and tick proteins was demonstrated which was not dependent on CCDs. The same cross‐reactivity was also observed in the control sera. Furthermore, 17 putative cross‐reactive peptides were identified using an in silico approach.ConclusionsFor the first time, cross‐reactivity between wasp venom and tick proteins has been described. This may be a reason why the majority of Swedish AGS patients, who have all been tick bitten, are also sensitized against wasp.     

Th1, Th2, and Th17 cells are dysregulated,but only Th17 cells relate to C‐reactive protein,D‐dimer,and mortality risk in Stanford type A aortic dissection patients

BackgroundT helper (Th) cells are closely involved in vascular inflammation, endothelial dysfunction, and atherogenesis, which are the hallmarks of aortic dissection (AD). This study aimed to evaluate the clinical value of Th1, Th2, and Th17 cell measurements in Stanford type A AD patients.MethodsStanford type A AD patients (N=80) and non‐AD patients with chest pain (N = 40) were recruited. Then, Th1, Th2, and Th17 cells in peripheral blood CD4⁺ T cells from all participants were detected by flow cytometry. The 30‐day mortality of Stanford type A AD patients was recorded.ResultsTh1 and Th17 cells were higher, while Th2 cells were lower in Stanford type A AD patients compared with non‐AD patients (all p < 0.001). Meanwhile, Th1 cells (area under curve (AUC): 0.734, 95% confidence interval (CI): 0.640–0.828), Th2 cells (AUC: 0.841, 95% CI: 0.756–0.925), and Th17 cells (AUC: 0.898, 95% CI: 0.839–0.957) could distinguish Stanford type A patients from non‐AD patients. Moreover, Th1 cells (p = 0.037) and Th17 cells (p = 0.001) were positively related to CRP, and Th17 cells (p = 0.039) were also positively associated with D‐dimer in Stanford type A AD patients. Furthermore, Th17 cells were elevated in deaths compared with survivors (p = 0.001), also, it could estimate 30‐day mortality risk in Stanford type A AD patients with an AUC of 0.741 (95% CI: 0.614–0.867), which was similar to the value of CRP (AUC: 0.771, 95% CI: 0.660–0.882), but lower than the value of D‐dimer (AUC: 0.818, 95% CI: 0.722–0.913).ConclusionTh1, Th2, and Th17 cells are dysregulated, but only the Th17 cells relate to CRP, D‐dimer, and 30‐day mortality risk in Stanford type A AD patients.     

Effects of anti‐IL5 biological treatments on blood IgE levels in severe asthmatic patients: A real‐life multicentre study (BIONIGE)

BackgroundMepolizumab and benralizumab are clinically effective biological treatments for severe eosinophilic asthmatic patients by hampering eosinophilic inflammation. The effects of these compound on the immunoglobulin (Ig)E T2 component are virtually unknown.ObjectivesTo evaluate the change in total IgE levels at 4 ± 2 months after initiation of the mepolizumab (primary outcome) or benralizumab. When available, the changes of blood inflammatory cell counts, lung function and asthma control test (ACT) were also assessed and correlated with changes in total IgE levels.MethodsObservational, retrospective, multicentre, cohort study. Severe eosinophilic atopic asthmatic patients treated with mepolizumab or benralizumab were included in the analysis.ResultsThree‐month treatment (on average) with mepolizumab (n = 104) or benralizumab (n = 82) resulted in significantly higher reduction of blood eosinophil and basophil levels in patients treated with benralizumab compared to mepolizumab. Mepolizumab did not significantly modified the levels of blood total IgE during the study period, whereas benralizumab significantly reduced (−35%, p < 0.001) total blood IgE levels. In patients treated with benralizumab the reduction of blood total Ig‐E levels correlated with the reduction of blood basophils (but not eosinophils) and weakly with the improvement of asthma control.ConclusionBenralizumab but not mepolizumab, treatment led to a significant reduction of circulating IgE level. The study provides different and specific mechanisms of action for anti‐IL5‐pathway treatments.     

Peptide immunotherapy for childhood allergy - addressing translational challenges

ABSTRACT: Allergic sensitisation usually begins early in life. The number of allergens a patient is sensitised to can increase over time and the development of additional allergic conditions is increasingly recognised. Targeting allergic disease in childhood is thus likely to be the most efficacious means of reducing the overall burden of allergic disease. Specific immunotherapy involves administering protein allergen to tolerise allergen reactive CD4+ T cells, thought key in driving allergic responses. Yet specific immunotherapy risks allergic reactions including anaphylaxis as a consequence of preformed allergen-specific IgE antibodies binding to the protein, subsequent cross-linking and mast cell degranulation. CD4+ T cells direct their responses to short "immunodominant" peptides within the allergen. Such peptides can be given therapeutically to induce T cell tolerance without facilitating IgE cross-linking. Peptide immunotherapy (PIT) offers attractive treatment potential for allergic disease. However, PIT has not yet been shown to be effective in children. This review discusses the immunological mechanisms implicated in PIT and briefly covers outcomes from adult PIT trials. This provides a context for discussion of the challenges for the application of PIT, both generally and more specifically in relation to children.     

Immunoregulatory effects of Lactococcus lactis‐derived extracellular vesicles in allergic asthma

BackgroundProbiotics have been shown to prevent various allergic diseases by producing extracellular vesicles (EVs). However, the role of EVs in allergic asthma has not yet been completely determined.MethodsGut microbial composition, mainly genera related to probiotics, was investigated in allergic asthmatic mice. Moreover, EVs were isolated from Lactococcus lactis (L. lactis, a selected bacterium) and EV proteins were identified by peptide mass fingerprinting. EV functions in immune responses were evaluated in vivo or ex vivo. Furthermore, the levels of specific IgG antibodies (an alternative marker for EV quantification) to L. lactis‐EVs were measured by ELISA in the sera of 27 asthmatic patients and 26 healthy controls.ResultsAllergic asthmatic mice showed a lower proportion of Lactococcus compared to healthy mice. L. lactis was cultured and its EVs abundantly contained pyruvate kinase. When allergic asthmatic mice were intranasally treated with EVs, airway hyperresponsiveness, eosinophil number, cytokine secretion, and mucus production were significantly decreased. Moreover, L. lactis‐EV treatment shifted immune responses from Th2 to Th1 by stimulating dendritic cells to produce IL‐12. In addition, significantly lower levels of serum specific IgG4 (but not IgG1) to L. lactis‐EVs were noted in asthmatic patients than in healthy controls. A positive correlation between the levels of EV‐specific IgG4 and FEV₁ (%), but a negative correlation between the levels of EV‐specific IgG4 and IL‐13 were observed.ConclusionThese findings suggest that L. lactis‐EVs may have immune‐regulating effects on airway inflammation mediated by dendritic cell activation, providing a potential benefit for allergic asthma.     

Gram‐negative microbiota is related to acute exacerbation in children with asthma

BackgroundThe upper‐airway microbiota may be associated with the pathogenesis of asthma and useful for predicting acute exacerbation. However, the relationship between the lower‐airway microbiota and acute exacerbation in children with asthma is not well understood. We evaluated the characteristics of the airway microbiome using induced sputum from children with asthma exacerbation and compared the microbiota‐related differences of inflammatory cytokines with those in children with asthma.MethodsWe analysed the microbiome using induced sputum during acute exacerbation of asthma in children. We identified microbial candidates that were prominent in children with asthma exacerbation and compared them with those in children with stable asthma using various analytical methods. The microbial candidates were analysed to determine their association with inflammatory cytokines. We also developed a predictive functional profile using PICRUSt.ResultsA total of 95 children with allergic sensitisation including 22 with asthma exacerbation, 67 with stable asthma, and 6 controls were evaluated. We selected 26 microbial candidates whose abundances were significantly increased, decreased, or correlated during acute exacerbation in children with asthma. Among the microbial candidates, Campylobacter, Capnocytophaga, Haemophilus, and Porphyromonas were associated with inflammatory cytokines including macrophage inflammatory protein (MIP)‐1β, programmed death‐ligand 1, and granzyme B. Both Campylobacter and MIP‐1β levels were correlated with sputum eosinophils. Increased lipopolysaccharide biosynthesis and decreased glycan degradation were observed in children with asthma exacerbation.ConclusionGram‐negative microbes in the lower airway were related to acute exacerbation in children with asthma. These microbes and associated cytokines may play a role in exacerbating asthma in children.     

Combinations of self‐reported rhinitis,conjunctivitis, and asthma predicts IgE sensitization in more than 25,000 Danes

BackgroundAllergic rhinitis (AR), allergic conjunctivitis (AC), and asthma composing multiple phenotypes and improved understanding of these phenotypes and their respective risk factors are needed.ObjectivesThe objective of this study was to define the prevalence of AR, AC, and asthma and their association with allergen‐specific immunoglobulin E (sIgE) sensitization in a large cohort of blood donors and identify risk factors.MethodsFrom the nationwide population‐based Danish Blood Donor Study, 52,976 participants completed an electronic questionnaire including AR, AC, asthma, allergic predisposition, and childhood residence. Of these, 25,257 were additionally tested for sIgE to inhalation allergens (Phadiatop).ResultsThe prevalence of sIgE sensitization, AR, AC, and asthma was 30%, 19%, 15%, and 9%, respectively. The youngest birth cohorts had the highest prevalence of sIgE sensitization and symptoms of asthma, AR, and AC, and for asthma, they apparently experienced symptoms at an earlier age. The sIgE sensitization was positively associated with male sex. The sIgE seroprevalence was higher in participants with both AR and AC (ARC) than in participants with either AR or AC. Allergic predisposition and sIgE sensitization increased the risk of the diseases, while farm upbringing was associated with reduced prevalence of ARC, however, only in sIgE sensitized participants.ConclusionBirth year, childhood residence, sIgE sensitization, and allergic predisposition were associated with asthma, AR, and AC prevalence. Individuals with self‐reported ARC represent a primarily sIgE‐positive phenotype, while those with either AR or AC represent more diverse phenotypes.     

Combined procalcitonin and hemogram parameters contribute to early differential diagnosis of Gram‐negative/Gram‐positive bloodstream infections

BackgroundHemogram parameters and procalcitonin (PCT) play auxiliary roles in the diagnosis and outcome of sepsis. However, it is not clear whether these indicators can quickly distinguish bacterial classification or guide the choice of empirical antibiotics.MethodsWe retrospectively enrolled 381 patients with bloodstream infections (BSI), divided into Gram‐positive bloodstream infections (GP‐BSI) and Gram‐negative bloodstream infections (GN‐BSI). Demographic parameters, hemogram parameters, and PCT were recorded and compared between the two groups.ResultsThe mean platelet volume (MPV), platelet distribution width (PDW), and PCT in the GN‐BSI group were significantly higher than those in the GP‐BSI group, while the platelet count (PLT), plateletcrit, platelet count‐to‐white blood cell count ratio (PWR), platelet count‐to‐neutrophil count ratio (PNR), platelet count‐to‐PCT ratio (PLT/PCT), and mean platelet volume‐to‐PCT ratio (MPV/PCT) were significantly lower in the GN‐BSI group. Multivariate stepwise logistic regression analysis revealed that the independent predictors of GN‐BSI were MPV, PWR, and PCT. The areas under the curve (AUC) for this prediction model was 0.79, with sensitivity =0.75 and specificity =0.71.ConclusionsThere were significant differences in terms of PCT, platelet parameters, and platelet‐related index‐PCT ratio between GN‐BSI and GP‐BSI. Combined PCT and hemogram parameters are more conducive to the early differential diagnosis of bacterial classification of BSI.