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INTRODUCTION: Experimental studies in animals have yielded conflicting results on the role of Tumor Necrosis Factor (TNF) in sepsis and endotoxemia, with some reporting adaptive and others inappropriate effects. A meta-analysis of the available literature was performed to determine the factors explaining this discrepancy. METHODS: The study followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. The protocol was registered with PROSPERO (CRD42020167384) prior to data collection. PubMed and Embase were the databases queried. Risk of bias was evaluated using the SYRCLE Risk of Bias Tool. All animal studies investigating sepsis-related mortality and modified TNF signaling were considered eligible. The exclusion criteria were: lack of mortality data, 7-day mortality rates below 10% in both wild type and TNF-altered pathway animals, and absence of an English abstract. To determine the role of TNF according to the experimental protocol, three approaches were used: first an approach based on the statistical significance of each experiment, then the pooled mortality was calculated, and finally the weighted risk ratio for mortality was assessed. RESULTS: A total of 175 studies were included in the analysis, comprising a total of 760 experiments and involving 19,899 animals. The main species used were mice (77%) and rats (21%). The most common method of TNF pathway modulation was TNF pathway inactivation that was primarily associated with an inappropriate secretion of TNF. At the opposite, TNF injection was associated with an adaptive role of TNF. Lipopolysaccharide (LPS) injection was the most used stimulus to establish an infectious model (42%) and was strongly associated with an inappropriate role of TNF. Conversely, live bacterial models, especially the cecal ligation and puncture (CLP) model, pneumonia, meningitis, and gastrointestinal infection, were associated with an adaptive role. This was particularly evident for Listeria monocytogenes, Streptococcus pneumoniae. CONCLUSION: The role of TNF during infection varies depending on the experimental model used. Models that mimic clinical conditions, based on virulent bacteria that cause high mortality even at low inocula, demonstrated an adaptive role of TNF. Conversely, models based on LPS or low-pathogenic live bacteria, administered at doses well above physiological thresholds and combined with early antibiotic therapy, were associated with an inappropriate role.
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Sepse , Fator de Necrose Tumoral alfa , Animais , Modelos Animais de DoençasRESUMO
BACKGROUND: Drug challenge is the gold standard for identifying causative agents of drug allergies. Although clinical guidelines have recently been published, they do not recommend neuromuscular blocking agent (NMBA) drug challenges. NMBA challenges are rendered difficult by the lack of homogeneity of routine allergy work-ups and the necessity of a specialised setting. Several scenarios support NMBA challenges, such as an ambiguous allergy work-up, a high suspicion of a false-positive skin test or identification of a well tolerated alternative NMBA strategy. Furthermore, routine allergy work-ups may not recognise non-IgE mechanisms, such as IgG or MRGPRX2, whereas drug challenges may reveal them. Finally, if the culprit NMBA is not identified, subsequent anaesthesia regimens will be challenging to implement, resulting in increased risk. OBJECTIVES: This literature review discusses the indications, strategies, doses, monitoring methods, limitations, and unresolved issues related to drug challenges for NMBAs. DESIGN: The literature review included randomised controlled trials, observational studies, reviews, case reports, series, and comments on humans. DATA SOURCES: Studies were retrieved from databases (PubMed) and electronic libraries (OVID, EMBASE, Scopus, etc.). ELIGIBILITY CRITERIA: All studies that referred to the NMBA challenge were included without publication date limitations. RESULTS: NMBA challenge may be considered in NMBA anaphylaxis patients with inconclusive or ambivalent IgE diagnostic work-up under controlled conditions (presence of anaesthetists and allergists with continuous monitoring in a secured environment). To illustrate its utility, a case report of a double NMBA challenge in a patient with NMBA cross-reactivity is presented, along with biological explorations to detect subclinical cellular activation, a novel aspect of this procedure. CONCLUSION: Drug challenges could be implemented during the NMBA allergy work-up under strict safety conditions at specialised centres with close collaboration between anaesthetists and allergists. This could decrease uncertainty and contribute to defining a safer strategy for subsequent anaesthetic drug regimens.
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Hipersensibilidade a Drogas , Bloqueadores Neuromusculares , Humanos , Bloqueadores Neuromusculares/efeitos adversos , Hipersensibilidade a Drogas/diagnóstico , Hipersensibilidade a Drogas/imunologia , Testes Cutâneos/métodos , Imunoglobulina E/sangue , Imunoglobulina E/imunologiaRESUMO
IgG is the predominant antibody class generated during infections and used for the generation of therapeutic antibodies. Antibodies are mainly characterized in or generated from animal models that support particular infections, respond to particular antigens or allow the generation of hybridomas. Due to the availability of numerous transgenic mouse models and the ease of performing bioassays with human blood cells in vitro, most antibodies from species other than mice and humans are tested in vitro using human cells and/or in vivo using mice. In this process, it is expected, but not yet systematically documented, that IgG from these species interact with human or mouse IgG receptors (FcγRs). In this study, we undertook a systematic assessment of binding specificities of IgG from various species to the families of mouse and human FcγRs including their polymorphic variants. Our results document the specific binding patterns for each of these IgG (sub)classes, reveal possible caveats of antibody-based immunoassays, and will be a useful reference for the transition from one animal model to preclinical mouse models or human cell-based bioassays.
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Imunoglobulina G , Receptores de IgG , Animais , Proteínas de Transporte/metabolismo , Humanos , Hibridomas , Camundongos , Camundongos TransgênicosRESUMO
Acute hypersensitivity reactions (AHRs) occurring in present-day anaesthesia can have severe, sometimes fatal, consequences and their incidence is increasing. The most frequent allergens responsible for AHR during anaesthesia are neuromuscular blocking agents (NMBAs) (70% of the cases) followed by antibiotics (18%), patent blue dye and methylene blue dye (5%), and latex (5%). Following an AHR, strategies for subsequent anaesthetic procedures (especially the choice of an NMBA) may be difficult to formulate due to inconclusive diagnostic analysis in up to 30% of AHRs. Current diagnosis of AHR relies on the detection of mast cell degranulation products and drug-specific type E immunoglobulins (IgE) in order to document an IgE-mediated anaphylaxis (IgE endotype). Nonetheless, other IgE-independent pathways can be involved in AHR, but their detection is not currently available in standard situations. The different mechanisms (endotypes) involved in peri-operative AHR may contribute to the inconclusive diagnostic work-up and this generates uncertainty concerning the culpable drug and strategy for subsequent anaesthetic procedures. This review provides details on the IgE endotype; an update on non-IgE related endotypes and the novel diagnostic tools that could characterise them. This detailed update is intended to provide explicit clinical reasoning tools to the anaesthesiologist faced with an incomplete AHR diagnostic work-up and to facilitate the decision-making process regarding anaesthetic procedures following an AHR to NMBAs.
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Anafilaxia , Anestesia , Bloqueadores Neuromusculares , Humanos , Imunoglobulina E/efeitos adversos , Anafilaxia/induzido quimicamente , Anafilaxia/diagnóstico , Bloqueadores Neuromusculares/efeitos adversos , Anestesia/efeitos adversos , Alérgenos/efeitos adversos , Testes Cutâneos/efeitos adversos , Testes Cutâneos/métodosRESUMO
BACKGROUND: The bacille Calmette-Guérin (BCG) tuberculosis vaccine has immunity benefits against respiratory infections. Accordingly, it has been hypothesized to have a protective effect against coronavirus disease 2019 (COVID-19). Recent research found that countries with universal BCG childhood vaccination policies tend to be less affected by the COVID-19 pandemic. However, such ecological studies are biased by numerous confounders. Instead, this paper reports on a rare nationwide natural experiment that occurred in Sweden in 1975, where discontinuation of newborns' BCG vaccination led to a dramatic decrease in BCG coverage rate, thus allowing us to estimate BCG's effect without the biases associated with cross-country comparisons. METHODS: Numbers of COVID-19 cases and hospitalizations were recorded for birth cohorts born just before and just after 1975, representing 1 026 304 and 1 018 544 individuals, respectively. We used regression discontinuity to assess the effect of BCG vaccination on COVID-19-related outcomes. On such a large population, this method allows for a precision that would be hard to achieve using a randomized controlled trial. RESULTS: The odds ratios (95% CI) for COVID-19 cases and COVID-19-related hospitalizations were 1.0005 (.8130-1.1881) and 1.2046 (.7532-1.6560), allowing us to reject fairly modest effects of universal BCG vaccination. We can reject with 95% confidence that universal BCG vaccination reduces the number of cases by 19% and the number of hospitalizations by 25%. CONCLUSIONS: While the effect of a recent vaccination must be evaluated, we provide strong evidence that receiving the BCG vaccine at birth does not have a protective effect against COVID-19 among middle-aged individuals.
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Vacina BCG , COVID-19 , Vacinação , COVID-19/prevenção & controle , Estudos de Coortes , Humanos , Lactente , Recém-Nascido , Pessoa de Meia-Idade , Pandemias , SARS-CoV-2 , Suécia/epidemiologiaRESUMO
Increased blood fibrocytes are associated with a poor prognosis in fibrotic lung diseases. We aimed to determine whether the percentage of circulating fibrocytes could be predictive of severity and prognosis during coronavirus disease 2019 (COVID-19) pneumonia. Blood fibrocytes were quantified by flow cytometry as CD45+/CD15-/CD34+/collagen-1+ cells in patients hospitalized for COVID-19 pneumonia. In a subgroup of patients admitted in an intensive care unit (ICU), fibrocytes were quantified in blood and bronchoalveolar lavage (BAL). Serum amyloid P (SAP), transforming growth factor-ß1 (TGF-ß1), CXCL12, CCL2, and FGF2 concentrations were measured. We included 57 patients in the hospitalized group (median age = 59 yr [23-87]) and 16 individuals as healthy controls. The median percentage of circulating fibrocytes was higher in the patients compared with the controls (3.6% [0.2-9.2] vs. 2.1% [0.9-5.1], P = 0.04). Blood fibrocyte count was lower in the six patients who died compared with the survivors (1.6% [0.2-4.4] vs. 3.7% [0.6-9.2], P = 0.02). Initial fibrocyte count was higher in patients showing a complete lung computed tomography (CT) resolution at 3 mo. Circulating fibrocyte count was decreased in the ICU group (0.8% [0.1-2.0]), whereas BAL fibrocyte count was 6.7% (2.2-15.4). Serum SAP and TGF-ß1 concentrations were increased in hospitalized patients. SAP was also increased in ICU patients. CXCL12 and CCL2 were increased in ICU patients and negatively correlated with circulating fibrocyte count. We conclude that circulating fibrocytes were increased in patients hospitalized for COVID-19 pneumonia, and a lower fibrocyte count was associated with an increased risk of death and a slower resolution of lung CT opacities.
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Antígenos CD/sangue , Células Sanguíneas/metabolismo , COVID-19/sangue , Citocinas/sangue , SARS-CoV-2/metabolismo , Proteína Amiloide A Sérica/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Contagem de Células Sanguíneas , COVID-19/diagnóstico , COVID-19/diagnóstico por imagem , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Índice de Gravidade de Doença , Tomografia Computadorizada por Raios XRESUMO
BACKGROUND: Patients with primary biliary cholangitis who have an inadequate response to therapy with ursodeoxycholic acid are at high risk for disease progression. Fibrates, which are agonists of peroxisome proliferator-activated receptors, in combination with ursodeoxycholic acid, have shown potential benefit in patients with this condition. METHODS: In this 24-month, double-blind, placebo-controlled, phase 3 trial, we randomly assigned 100 patients who had had an inadequate response to ursodeoxycholic acid according to the Paris 2 criteria to receive bezafibrate at a daily dose of 400 mg (50 patients), or placebo (50 patients), in addition to continued treatment with ursodeoxycholic acid. The primary outcome was a complete biochemical response, which was defined as normal levels of total bilirubin, alkaline phosphatase, aminotransferases, and albumin, as well as a normal prothrombin index (a derived measure of prothrombin time), at 24 months. RESULTS: The primary outcome occurred in 31% of the patients assigned to bezafibrate and in 0% assigned to placebo (difference, 31 percentage points; 95% confidence interval, 10 to 50; P<0.001). Normal levels of alkaline phosphatase were observed in 67% of the patients in the bezafibrate group and in 2% in the placebo group. Results regarding changes in pruritus, fatigue, and noninvasive measures of liver fibrosis, including liver stiffness and Enhanced Liver Fibrosis score, were consistent with the results of the primary outcome. Two patients in each group had complications from end-stage liver disease. The creatinine level increased 5% from baseline in the bezafibrate group and decreased 3% in the placebo group. Myalgia occurred in 20% of the patients in the bezafibrate group and in 10% in the placebo group. CONCLUSIONS: Among patients with primary biliary cholangitis who had had an inadequate response to ursodeoxycholic acid alone, treatment with bezafibrate in addition to ursodeoxycholic acid resulted in a rate of complete biochemical response that was significantly higher than the rate with placebo and ursodeoxycholic acid therapy. (Funded by Programme Hospitalier de Recherche Clinique and Arrow Génériques; BEZURSO ClinicalTrials.gov number, NCT01654731 .).
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Bezafibrato/uso terapêutico , Colangite/tratamento farmacológico , Hipolipemiantes/uso terapêutico , Adulto , Bezafibrato/efeitos adversos , Ácidos e Sais Biliares/sangue , Colangite/etiologia , Método Duplo-Cego , Feminino , Humanos , Hipolipemiantes/efeitos adversos , Cirrose Hepática Biliar/complicações , Cirrose Hepática Biliar/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Placebos/uso terapêutico , Falha de Tratamento , Ácido Ursodesoxicólico/uso terapêuticoRESUMO
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 (ß 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.
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Armadilhas Extracelulares/metabolismo , Neutrófilos/metabolismo , Pneumonia/sangue , Síndrome do Desconforto Respiratório/sangue , Adulto , Idoso , Líquido da Lavagem Broncoalveolar , Estudos de Coortes , Armadilhas Extracelulares/imunologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neutrófilos/imunologia , Pneumonia/imunologia , Pneumonia/terapia , Estudos Prospectivos , Respiração Artificial/tendências , Síndrome do Desconforto Respiratório/imunologia , Síndrome do Desconforto Respiratório/terapiaAssuntos
Oxigenação por Membrana Extracorpórea , Transplante de Pulmão , Adsorção , Citocinas , Humanos , ImunoterapiaRESUMO
Polymorphonuclear neutrophils (PMN) play a central role in inflammation and participate in its control, notably by modulating dendritic cell (DC) functions via soluble mediators or cell-cell contacts. Neutrophil extracellular traps (NETs) released by PMN could play a role in this context. To evaluate NET effects on DC maturation, we developed a model based on monocyte-derived DC (moDC) and calibrated NETs isolated from fresh human PMN. We found that isolated NETs alone had no discernable effect on moDC. In contrast, they downregulated LPS-induced moDC maturation, as shown by decreased surface expression of HLA-DR, CD80, CD83, and CD86, and by downregulated cytokine production (TNF-α, IL-6, IL-12, IL-23), with no increase in the expression of tolerogenic DC genes. Moreover, the presence of NETs during moDC maturation diminished the capacity of these moDC to induce T lymphocyte proliferation in both autologous and allogeneic conditions, and modulated CD4(+) T lymphocyte polarization by promoting the production of Th2 cytokines (IL-5 and IL-13) and reducing that of Th1 and Th17 cytokines (IFN-γ and IL-17). Interestingly, the expression and activities of the lymphoid chemokine receptors CCR7 and CXCR4 on moDC were not altered when moDC matured in the presence of NETs. Together, these findings reveal a new role for NETs in adaptive immune responses, modulating some moDC functions and thereby participating in the control of inflammation.
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Células Dendríticas/imunologia , Armadilhas Extracelulares/imunologia , Monócitos/imunologia , Células Th1/imunologia , Células Th17/imunologia , Imunidade Adaptativa , Antígenos CD/genética , Antígenos CD/metabolismo , Diferenciação Celular , Células Cultivadas , Citocinas/genética , Citocinas/metabolismo , Células Dendríticas/citologia , Regulação para Baixo , Antígenos HLA-DR/genética , Antígenos HLA-DR/metabolismo , Humanos , Mediadores da Inflamação/metabolismo , Lipopolissacarídeos/imunologia , Monócitos/citologiaAssuntos
Asma , Armadilhas Extracelulares , Asma/diagnóstico , Biomarcadores , Eosinófilos , Humanos , NeutrófilosAssuntos
Colangite , Gastroenterologia , Cirrose Hepática Biliar , Antipruriginosos , Bezafibrato , Humanos , Reino UnidoRESUMO
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.
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Neutrófilos/imunologia , Neutrófilos/metabolismo , Animais , Doenças Autoimunes/imunologia , Exocitose/imunologia , Espaço Extracelular/imunologia , Espaço Extracelular/metabolismo , Humanos , Imunidade Inata , Infecções/imunologia , Inflamação/imunologia , Neutrófilos/patologia , Trombose/imunologiaRESUMO
BACKGROUND: The first line of prevention of surgical site infection relies on the timely administration of antibiotic prophylaxis. First- and second-generation cephalosporins are the most recommended antibiotics in elective surgery. The incidence of cefazolin allergy has increased worldwide over the years. The sensitization mechanism of cefazolin is currently unknown, and data supporting cross-reactivity between penicillins and cephalosporins are lacking. Sensitization could occur through previous exposure either to cefazolin or to structurally related chemical agents. The objective of this study was to evaluate sensitization agents towards cefazolin. METHODS: The OpenBabel chemoinformatics toolbox was used to search for similarities between cefazolin and other molecules in an extensive drug database. Using the pholcodine-rocuronium similarity score as a threshold, we selected drugs with the most similar structure to that of cefazolin. Exposure to those drugs and cefazolin was assessed in a cohort of patients with skin test-proven cefazolin allergy at a specialized allergy centre via a self-administered anonymous questionnaire. RESULTS: Using the pholcodine-rocuronium similarity score as a threshold (score≥0.7), 42 molecules were found to be similar to cefazolin (all cephalosporins). Only 8 were marketed in France. None of the 14 cefazolin-allergic patients who answered the questionnaire (65% female, median age 56 years) reported exposure to any identified antibiotics. In contrast, 11 (78%) had at least one previous surgery requiring cefazolin before the index case. CONCLUSION: Direct previous cefazolin exposure was identified in 78% of cefazolin-allergic patients. Cefazolin started to take a central place in antibiotic prophylaxis after 2010, when cefamandole usage decreased drastically. Changes in antibiotic prophylaxis over the past 14 years in France could have been the turning point for the increased incidence of cefazolin allergy.
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Hipersensibilidade a Drogas , Hipersensibilidade , Humanos , Feminino , Pessoa de Meia-Idade , Masculino , Cefazolina/efeitos adversos , Antibioticoprofilaxia/efeitos adversos , Rocurônio , Estudos Retrospectivos , Antibacterianos/efeitos adversos , Hipersensibilidade a Drogas/epidemiologia , Hipersensibilidade a Drogas/etiologia , Hipersensibilidade a Drogas/prevenção & controle , Cefalosporinas/uso terapêutico , Hipersensibilidade/complicações , Hipersensibilidade/tratamento farmacológicoRESUMO
OBJECTIVES: To compare the performance of anticitrullinated peptides/protein antibodies (ACPA) detected by three immunoassays in the French ESPOIR cohort of patients with early rheumatoid arthritis (RA) and undifferentiated arthritis (UA) and to study the relationship between ACPA and disease activity. METHODS: A diagnosis of RA (1987 American College of Rheumatology (ACR) criteria) was established at baseline in 497 patients and after a 2-year follow-up in 592 patients. At baseline, antibodies to citrullinated fibrinogen (AhFibA), antimutated citrullinated vimentin (anti-MCV) and anticyclic citrullinated peptide (anti-CCP2) were assayed and the individual and combined diagnostic sensitivities and predictive values of the tests were determined. Relationships between ACPA positivity and the 28-joint disease activity score and Health Assessment Questionnaire scores were analysed. RESULTS: At a diagnostic specificity of at least 98%, the three tests exhibited similar diagnostic sensitivities (47-48.5%). When considering as positive patients with at least one positive test, the sensitivity increased to 53.5% with a probable loss of specificity. Among the patients classified as having UA at baseline, 30% were positive for one ACPA, the positive predictive values for RA of the three tests ranging from 73% to 80% but increasing when two tests were associated. Whatever the test used, the addition of ACPA positivity to the 1987 criteria enhanced their sensitivity by 6%, close to that of the 2010 ACR/European League Against Rheumatism (EULAR) criteria. CONCLUSIONS: In early arthritis, AhFibA, anti-MCV and anti-CCP2 showed similar diagnostic sensitivity with a high diagnostic specificity and a similar high positive predictive value for RA. Adding ACPA to the 1987 ACR criteria significantly increased the number of patients classified as having RA, confirming the validity of the recent inclusion of the serological criterion in the ACR/EULAR criteria.