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Thymic stromal lymphopoietin (TSLP), a cytokine involved in severe asthma treatment, was never studied in non-severe asthma.Among 969 adults from a large epidemiological study, cross-sectional analyses showed that plasma TSLP levels were associated with increased age and BMI, male sex, smoking and high TSLP levels (one IQR increase) with current asthma and poor lung function. High TSLP levels were also associated with persistence of asthma attacks (aOR=2.14 (95% CI 1.23 to 3.72)) and dyspnoea (aOR=2.71 (95% CI 1.39 to 5.28)) 10 years later.Our results suggest that TSLP could be a cytokine of interest in non-severe asthma, and its determinants of circulating levels could be considered in asthma management.

Added data on circulating IL-6 levels can predict COVID-19 severity and IL1RA efficiency.

Neutrophils are key players in the hyperinflammatory response upon SARS-CoV-2 infection. We have previously described that cytosolic proliferating cell nuclear antigen (PCNA) controls neutrophil survival and NADPH oxidase-dependent ROS production. We here show that both PCNA and S100A8 expression and interaction were elevated in neutrophils from patients with COVID-19 compared to healthy donors and this was correlated with disease severity. Increased PCNA expression was accompanied by a decreased apoptosis and increased NADPH-oxidase activity in neutrophils from COVID-19 patients compared to healthy donors. These effects, as well as the interaction between PCNA and S100A8, were potently counteracted by T2 amino alcohol (T2AA), a PCNA inhibitor, demonstrating that the PCNA scaffold orchestrated neutrophil activation. Notably, the interaction between PCNA-S100A8 was more intense in the CD16high-CD62Llowactivated neutrophil subset. We propose that PCNA-S100A8 complex acts as potential driver for neutrophil dysregulation in COVID-19 and show for the first time that the PCNA scaffold is a decisive component of both neutrophil activation and heterogeneity.

Thymus and Activation Regulated Chemokine (TARC) and Thymic Stromal Lymphopoeitin (TSLP) are involved in the pro-Th2 inflammatory response. To date, there is no epidemiological studies that have simultaneously investigated TARC and TSLP with various asthma characteristics and allergy in adults. We investigated the associations between TARC/TSLP and various asthma and allergic characteristics in the Epidemiological study on the Genetics and Environment of Asthma (EGEA). Cross-sectional analyses were performed at EGEA2 (second survey, 2003-2007). Asthma characteristics were defined by standardized questionnaires and lung function tests. Allergy was defined by positive skin prick test. Plasma TARC and TSLP levels were measured by enzyme-linked immunosorbent assay. Generalized logistic models adjusted (a) for age, sex, smoking habits, body mass index and taking into account familial dependence were used. The correlation between TARC and TSLP in the 958 adults (43 years old, 48% men, 43% current asthmatics, 56% with allergy) was 0.11 (p=0.0009). High TSLP level was associated with an increased risk of current asthma (aOR [CI95%]=1.37 [1.11-1.68]). Among current asthmatics (n=380), TSLP level was negatively correlated with FEV1 (r=-0.23, p Results suggest that TARC and TSLP are associated with different asthma characteristics but not with allergy. Longitudinal analyses between TARC/TSLP levels and changes in asthma characteristics are on-going.

Editor’s Perspective What We Already Know about This Topic What This Article Tells Us That Is New Background Neutrophil extracellular traps have been associated with tissue damage. Whether these are involved in the pathogenesis of human acute respiratory distress syndrome (ARDS) and could be a potential therapeutic target is unknown. The authors quantified bronchoalveolar and blood neutrophil extracellular traps in patients with pneumonia-related ARDS and assessed their relationship with ventilator-free days. Methods Immunocompetent patients with pneumonia and moderate or severe ARDS (n = 35) and controls (n = 4) were included in a prospective monocentric study. Neutrophil extracellular trap concentrations were quantified (as DNA–myeloperoxidase complexes) in bronchoalveolar lavage fluid and serum by enzyme-linked immunosorbent assay. The relationship between bronchoalveolar lavage neutrophil extracellular trap concentrations and the primary clinical endpoint (i.e., the number of live ventilator-free days at day 28) was assessed using linear regression analyses. Results There was no significant relationship between bronchoalveolar lavage neutrophil extracellular trap concentrations and ventilator-free days by multiple regression analysis (β coefficient = 2.40; 95% CI, −2.13 to 6.92; P = 0.288). Neutrophil extracellular trap concentrations were significantly higher in bronchoalveolar lavage than in blood of ARDS patients (median [first to third quartiles]:154 [74 to 1,000] vs. 26 [4 to 68] arbitrary units, difference: −94; 95% CI, −341 to −57; P < 0.0001). Bronchoalveolar concentrations of patients were higher than those of controls (154 [74 to 1,000] vs. 4 [4 to 4] arbitrary units, difference: −150; 95% CI, −996 to −64; P < 0.001) and associated with bronchoalveolar interleukin-8 (Spearman’s ρ = 0.42; P = 0.012) and neutrophil concentrations (ρ = 0.57; P < 0.0001). Intensive care unit mortality (12%, n = 2 of 17 vs. 17%, n = 3 of 18; P > 0.99) and the number of ventilator-free days at day 28 (22 [14 to 25] vs. 14 [0 to 21] days; difference: −5; 95% CI, −15 to 0; P = 0.066) did not significantly differ between patients with higher (n = 17) versus lower (n = 18) bronchoalveolar neutrophil extracellular trap concentrations. Conclusions Bronchoalveolar neutrophil extracellular trap concentration was not significantly associated with mechanical ventilation duration in pneumonia-related ARDS.

Fondée au VIe siècle, l’abbaye bénédictine féminine de Saint-André-le-Haut (Vienne, Isère) est l’une des plus anciennes fondations monastiques de la ville. À la fin du XVIe siècle, l’église abbatiale devient paroissiale et les paroissiens investissent le sous-sol de la nef comme lieu d’inhumation. Depuis 2003, la nef de Saint-André-le-Haut a été fouillée aux deux tiers et a livré 317 sépultures datées de l’époque moderne, parmi lesquelles 102 sont celles d’individus immatures, dont 30 sont décédés avant l’âge d’un an. La présence de ces derniers au sein de la communauté paroissiale, à plus forte raison dans l’église, semble signifier une intégration à part entière au monde chrétien. Deux rassemblements d’individus immatures se distinguent, le premier autour d’un pilier vers l’entrée de l’église, le second contre le mur gouttereau nord. Il est possible que la présence d’aménagements liturgiques particuliers à ces deux endroits soit en rapport avec le regroupement de ces immatures. The Abbey of Saint-André-le-Haut (Vienne, Isère, France), founded by Benedictine nuns in the 6th century, is one of the city’s oldest monastic buildings. In the 16th century, the abbey church became a parish church and the parishioners consecrated the floor of its nave as a burial site. Since 2003, two-thirds of the nave of Saint-André-le-Haut have been excavated, revealing 317 burials from the early modern period. Of these, 102 are of immature individuals, including 30 in the [0] class. The presence of these individuals within the parish community, particularly inside the church, points to full integration into the Christian world. Two groups of small children stand out: the first around a pillar at the church entrance, the second beside the north lateral wall. It is possible that the presence of distinctive liturgical details in these two places is related to these groups of small children.

COVID-19 can cause acute respiratory distress syndrome (ARDS), leading to death in a significant number of individuals. Evidence of a strong role of the innate immune system is accumulating, but the precise cells and mechanism involved remain unclear. In this study, we investigated the links between circulating innate phagocyte phenotype and functions and severity in COVID-19 patients. Eighty-four consecutive patients were included, 44 of which were in intensive care units (ICU). We performed an in-depth phenotyping of neutrophil and monocyte subpopulations and measured soluble activation markers in plasma. Additionally, myeloid cell functions (phagocytosis, oxidative burst, and NETosis) were evaluated on fresh cells from patients. Resulting parameters were linked to disease severity and prognosis. Both ICU and non-ICU patients had circulating neutrophils and monocytes with an activated phenotype, as well as elevated concentrations of soluble activation markers (calprotectin, myeloperoxidase, neutrophil extracellular traps, MMP9, sCD14) in their plasma. ICU patients were characterized by increased CD10low CD13low immature neutrophils, LOX-1+ and CCR5+ immunosuppressive neutrophils, and HLA-DRlow CD14low downregulated monocytes. Markers of immature and immunosuppressive neutrophils were strongly associated with severity and poor outcome. Moreover, neutrophils and monocytes of ICU patients had impaired antimicrobial functions, which correlated with organ dysfunction, severe infections, and mortality. Our study reveals a marked dysregulation of innate immunity in COVID-19 patients, which was correlated with severity and prognosis. Together, our results strongly argue in favor of a pivotal role of innate immunity in COVID-19 severe infections and pleads for targeted therapeutic options.One Sentence SummaryOur study reveals a marked dysregulation of innate immunity in COVID-19 patients, which correlates with severity and prognosis.

BackgroundEosinophil-derived neurotoxin (EDN) and eosinophil cationic protein (ECP) are proteins released by activated eosinophils whose role in adult asthma remains unclear.ObjectiveTo study associations between ECP, EDN and various asthma characteristics in adults from the Epidemiological Study on the Genetics and Environment of Asthma (EGEA).MethodsPlasma ECP and EDN levels were measured by ELISA. Cross-sectional analyses were performed in 941 adults (43±16 years old, 39% with asthma) at EGEA2 (2003–2007). Longitudinal analyses investigated the associations between EDN level at EGEA2 and changes in asthma characteristics between EGEA2 and EGEA3 (2011–2013, n=817). We used generalised estimated equations adjusted for age, sex, smoking status and body mass index to take into account familial dependence.ResultsAt EGEA2, both high ECP and EDN levels were associated with current asthma (adjusted OR (aOR) (95% CI): 1.69 (1.35–2.12) and 2.12 (1.76–2.57)). Among asthmatics, high EDN level was associated with asthma attacks (aOR: 1.50 (1.13–1.99)), wheezing and breathlessness (aOR: 1.38 (1.05–1.80)), use of asthma treatments (aOR: 1.91 (1.37–2.68)) and bronchial hyper-responsiveness (aOR: 2.03 (1.38–2.97)), even after further adjustment on ECP. High ECP level was associated with high neutrophil count and tended to be associated with chronic bronchitis. High EDN level at EGEA2 was associated with persistent asthma (aOR: 1.62 (1.04–2.52)), nocturnal symptoms (aOR from 2.19 to 3.57), worsening wheezing and breathlessness (aOR: 1.97 (1.36–2.85)) and nocturnal shortness of breath (aOR: 1.44 (1.04–1.98)) between EGEA2 and EGEA3.ConclusionsEDN and ECP were associated with different asthma expression in adults. EDN could be a potential biomarker to monitor asthma evolution in adults.

Eosinophil derived neurotoxin (EDN) and Eosinophil cationic protein (ECP) are two granule proteins released by activated eosinophils. Although their potential benefit as markers of asthma severity has been well-established in childhood asthma, studies in adults are scarce. We aimed to study the associations between ECP/EDN and various asthma characteristics in adults from the Epidemiological study on the Genetics and Environment of Asthma (EGEA). Cross-sectional analyses were performed in 941 adults at EGEA2 (second survey, 2003-2007). Asthma characteristics were defined by standardized questionnaire and lung function tests. Plasma ECP and EDN levels were measured by enzyme-linked immunosorbent assay. Longitudinal analyses investigated the associations between EDN level at EGEA2 and changes in asthma characteristics at EGEA3 (follow-up, 2011-2013). Generalized logistic models taking into account familial dependence and adjusted for age, sex, smoking and body mass index were used. At EGEA2, ECP and EDN were statistically associated with increased risk of current asthma, poorly controlled asthma, chronic bronchitis, asthma treatments use and bronchial hyperresponsiveness. (adjusted(a) OR ranging from 1.35 to 2.12). Associations with EDN were stronger and remained after further adjustment on ECP. Increased risk of asthma attacks was specifically associated with EDN. High EDN level at EGEA2 was associated with the onset and/or the persistence of current asthma and nocturnal symptoms at EGEA3 (aOR ranging from 1.61 to 2.47). Results suggest that both ECP and EDN are associated with asthma expression and that EDN could be a potential biomarker to monitor asthma evolution in adults.

Background Prompt diagnosis of intra-anaesthetic acute hypersensitivity reactions (AHR) is challenging because of the possible absence and/or difficulty in detecting the usual clinical signs and because of the higher prevalence of alternative diagnoses. Delayed epinephrine administration during AHR, because of incorrect/delayed diagnosis, can be associated with poor prognosis. Low end-tidal CO2 (etCO2) is known to be linked to low cardiac output. Yet, its clinical utility during suspected intra-anaesthetic AHR is not well documented. Methods Clinical data from the 86 patients of the Neutrophil Activation in Systemic Anaphylaxis (NASA) multicentre study were analysed. Consenting patients with clinical signs consistent with intra-anaesthetic AHR to a neuromuscular blocking agent were included. Severe AHR was defined as a Grade 3–4 of the Ring and Messmer classification. Causes of AHR were explored following recommended guidelines. Results Among the 86 patients, 50% had severe AHR and 69% had a confirmed/suspected IgE-mediated event. Occurrence and minimum values of arterial hypotension, hypocapnia and hypoxaemia increased significantly with the severity of AHR. Low etCO2 was the only factor able to distinguish mild [median 3.5 (3.2;3.9) kPa] from severe AHR [median 2.4 (1.6;3.0) kPa], without overlap in inter-quartile range values, with an area under the receiver operator characteristic curve of 0.92 [95% confidence interval: 0.79–1.00]. Among the 41% of patients who received epinephrine, only half received it as first-line therapy despite international guidelines. Conclusions An etCO2 value below 2.6 kPa (20 mm Hg) could be useful for prompt diagnosis of severe intra-anaesthetic AHR, and could facilitate early treatment with titrated doses of epinephrine. Clinical trial registration NCT01637220.

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

Background Glucocorticoid-induced leucine zipper (GILZ) is a potent anti-inflammatory protein involved in neutrophil apoptosis and the resolution of inflammation. Given the numerous pathophysiologic roles of neutrophils in the acute respiratory distress syndrome (ARDS), we postulated that neutrophil GILZ expression might be induced during ARDS, to modulate the inflammatory process and participate in lung repair. Methods This single-center, prospective, observational cohort study took place in the surgical intensive care unit of Bichat Hospital (Paris, France) and involved 17 ARDS patients meeting the Berlin criteria at inclusion, and 14 ventilated controls without ARDS. Serial blood samples were obtained every 2 days until extubation or death (from 1 to 9 samples per patient). GILZ protein and gene expression was quantified in blood neutrophils, along with markers of inflammation (CRP, extracellular DNA) or its resolution (Annexin A1). Results Neutrophil GILZ expression was detected at the transcriptional and/or translational level in 9/17 ARDS patients (in particular 7/10 severe ARDS) and in 2/14 ventilated controls. The highest mRNA levels were observed in the most severely ill patients (p

Neutrophil extracellular traps (NETs) are extracellular DNA filaments formed during neutrophil activation. This process, called netosis, was originally associated with neutrophil antibacterial properties. However, several lines of evidence now suggest a major role for netosis in thrombosis, autoimmune diseases, and cancer. We demonstrate here that highly purified human blood monocytes are also capable of extracellular trap (ET) release in response to several stimuli. Monocyte ETs display a morphology analogous to NETs and are associated with myeloperoxidase (MPO), lactoferrin (LF), citrullinated histones, and elastase. Monocyte ET release depends on oxidative burst but not on MPO activity, in contrast to neutrophils. Moreover, we demonstrate procoagulant activity for monocyte ETs, a feature that could be relevant to monocyte thrombogenic properties. This new cellular mechanism is likely to have implications in the multiple pathologic contexts where monocytes are implicated, such as inflammatory disorders, infection, or thrombosis.

Introduction Venous thrombo-embolic events (VTE) occur frequently in patients with pancreatic cancer and contribute to elevated morbidity and mortality. Clinical risk factors for thrombosis such as cancer stage and tumor grade have been clearly identified. Recently, several biomarkers have been proposed which may help identifying cancer patients at high risk of thrombosis. Those biomarkers have been studied in heterogeneous cohorts of patients with different cancer types. Aim To compare pro-thrombotic biomarkers in pancreatic cancer and in chronic pancreatitis to determine whether these biomarkers are related to cancer or inflammation and to validate their association with thrombotic risk in a pancreatic cancer population. Materials and Methods 45 patients with pancreatic cancer, 49 with intraductal papillary mucinous tumor of the pancreas (IPMN), a precancerous lesion, and 50 with chronic pancreatitis were recruited. Plasma levels of factor VIII, D-dimers, thrombin-antithrombin complexes, soluble p-selectin, tissue factor-dependent procoagulant activity of MP (TF-MP), free Tissue Factor Pathway Inhibitor (TFPI) and extracellular DNA were measured. Thrombin generation triggered by 1pM of TF was evaluated with the Calibrated Automated Thrombogram assay. Results Levels of factor VIII, D-dimers, TF-MP, TFPI and extracellular DNA were significantly higher in cancer patients compared to IPMN or chronic pancreatitis (Table 1). Patients with metastatic cancer (n = 27) presented higher levels of D-dimers (mean ± sd 1.77 ± 1.28 vs 0.80 ± 0.96 μg/ml, p = 0.004) and MP-TF (54.3 ± 53.2 vs 15.8 ± 10.4 fM, p = 0.02) compared to patients with localized lesions (n = 18). Among cancer patients, 42 were followed for a median duration of 187 days (min 21-max 802 days). VTE occurred in 10 (23%) patients. All had metastatic cancer at the time of thrombosis. Only D-dimers were significantly elevated in cancer patients with VTE compared to patients without VTE (median 1.85 vs 0.7 μg/ml, p = 0.02). Table 1 . Pancreatic cancer (n = 45) IPMN (n = 49) Chronic pancreatitis (n = 50) p-value Factor VIII (%) 197 ± 62 150 ± 43 146 ± 66 D-dimers (μg/ml) 0.9 (0.22-4) 0.27 (0.22-3.07) 0.38 (0.17-4) Thrombin-antithrombin (ng/ml) 3.9 (2-39) 3.2 (2-6.1) 3.6 (2.2-57)* 0.003 sP-selectin (ng/ml) 28 (6.5-157) 27 (8-63) 30 (4-67) 0.7 TF-MP (fM) 22 (0-198) 12 (0-51) 16 (0-66) 0.03 Free TFPI (ng/ml) 21 ± 12 12 ± 4 13 ± 7 Extracellular DNA (ng/ml) 16.6 (0-408) 0 (0-193) 0 (0-197) Thrombin peak (nM) 209 ± 59 240 ± 90 198 ± 80 0.02 Results presented as mean ± SD for data with Gaussian distribution or median (min-max) for skewed variables; p-value for one-way analysis of variance or Kruskal-Wallis test Conclusions Elevation of factor VIII, D-dimers, TF-MP, TFPI and extracellular DNA seems to be related to cancer process, not to local or systemic inflammation as these parameters differentiate cancer from chronic pancreatitis. Interestingly, D-dimers and TF-MP are related to the disseminated cancer stage, suggesting that vascular invasion is a prerequisite to the release of TF-MP from the primary tumor into the bloodstream and to coagulation activation. However, only D-dimers are associated with the occurrence of future VTE. We propose that D-dimers could be a useful tool to predict thrombotic events in pancreatic cancer patients. This should be confirmed in a larger population.

Neutrophil extracellular traps (NET) account for a new mechanism of anti-infectious innate immunity that may lead to important tissue damages. Indeed, a growing number of studies demonstrate the involvement of NET in the pathogenesis of several human diseases as diverse as autoimmune diseases, thrombotic disorders or some inflammatory diseases. After a short description of molecular mechanisms of NETosis and its host-defense function, we will review their detrimental effects. We will then examine the potential therapeutic approaches for modulating excessive or inappropriate NETosis and thereby minimize tissue injury.

International audience; Platelets are key regulators of vascular integrity; however, their role in anaphylaxis, a life-threatening systemic allergic reaction characterized by the loss of vascular integrity and vascular leakage, remains unknown. Anaphylaxis is a consequence of inappropriate cellular responses triggered by antibodies to generally harmless antigens, resulting in a massive mediator release and rapidly occurring organ dysfunction. Human platelets express receptors for immunoglobulin G (IgG) antibodies and can release potent mediators, yet their contribution to anaphylaxis has not been previously addressed in mouse models, probably because mice do not express IgG receptors on platelets. We investigated the contribution of platelets to IgG-dependent anaphylaxis in human IgG receptor-expressing mouse models and a cohort of patients suffering from drug-induced anaphylaxis. Platelet counts dropped immediately and markedly upon anaphylaxis induction only when they expressed the human IgG receptor FcγRIIA/CD32A. Platelet depletion attenuated anaphylaxis, whereas thrombocythemia substantially worsened its severity. FcγRIIA-expressing platelets were directly activated by IgG immune complexes in vivo and were sufficient to restore susceptibility to anaphylaxis in resistant mice. Serotonin released by activated platelets contributed to anaphylaxis severity. Data from a cohort of patients suffering from drug-induced anaphylaxis indicated that platelet activation was associated with anaphylaxis severity and was accompanied by a reduction in circulating platelet numbers. Our findings identify platelets as critical players in IgG-dependent anaphylaxis and provide a rationale for the design of platelet-targeting strategies to attenuate the severity of anaphylactic reactions.