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BACKGROUND: Strongly elevated ferritin levels have been proposed to reflect systemic hyperinflammation in patients admitted to the intensive care unit. Knowledge of the incidence and pathophysiological implications of hyperferritinemia in patients with acute infection admitted to a non-intensive care setting is limited. METHODS: We determined the association between hyperferritinemia, defined by 2 cutoff values (500 and 250 ng/mL), and aberrations in key host response mechanisms among patients with community-acquired pneumonia (CAP) on admission to a general hospital ward (clinicaltrials.gov NCT02928367; trialregister.nl NTR6163). RESULTS: Plasma ferritin levels were higher in patients with CAP (nâ =â 174; median [interquartile ranges], 259.5 [123.1-518.3] ng/mL) than in age- and sex-matched controls without infection (nâ =â 50; 102.8 [53.5-185.7] ng/mL); Pâ <â .001); they were ≥500 ng/mL in 46 patients (26%) and ≥250 ng/mL in 90 (52%). Measurements of 26 biomarkers reflective of distinct pathophysiological domains showed that hyperferritinemia was associated with enhanced systemic inflammation, neutrophil activation, cytokine release, endothelial cell activation and dysfunction, and activation of the coagulation system. Results were robust across different cutoff values. CONCLUSIONS: Hyperferritinemia identifies patients with CAP with a broad deregulation of various host response mechanisms implicated in the pathogenesis of sepsis. This could inform future therapeutic strategies targeting subgroups within the CAP population.
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Infecções Comunitárias Adquiridas , Hiperferritinemia , Pneumonia , Ferritinas , Humanos , Unidades de Terapia Intensiva , Pneumonia/complicaçõesRESUMO
BACKGROUND: Viruses and bacteria from the nasopharynx are capable of causing community-acquired pneumonia (CAP), which can be difficult to diagnose. We aimed to investigate whether shifts in the composition of these nasopharyngeal microbial communities can be used as diagnostic biomarkers for CAP in adults. METHODS: We collected nasopharyngeal swabs from adult CAP patients and controls without infection in a prospective multicenter case-control study design. We generated bacterial and viral profiles using 16S ribosomal RNA gene sequencing and multiplex polymerase chain reaction (PCR), respectively. Bacterial, viral, and clinical data were subsequently used as inputs for extremely randomized trees classification models aiming to distinguish subjects with CAP from healthy controls. RESULTS: We enrolled 117 cases and 48 control subjects. Cases displayed significant beta diversity differences in nasopharyngeal microbiota (Pâ =â .016, R2 = .01) compared to healthy controls. Our extremely randomized trees classification models accurately discriminated CAP caused by bacteria (area under the curve [AUC] .83), viruses (AUC .95) or mixed origin (AUC .81) from healthy control subjects. We validated this approach using a dataset of nasopharyngeal samples from 140 influenza patients and 38 controls, which yielded highly accurate (AUC .93) separation between cases and controls. CONCLUSIONS: Relative proportions of different bacteria and viruses in the nasopharynx can be leveraged to diagnose CAP and identify etiologic agent(s) in adult patients. Such data can inform the development of a microbiota-based diagnostic panel used to identify CAP patients and causative agents from nasopharyngeal samples, potentially improving diagnostic specificity, efficiency, and antimicrobial stewardship practices.
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Infecções Comunitárias Adquiridas , Microbiota , Infecções Respiratórias , Adulto , Bactérias/genética , Estudos de Casos e Controles , Infecções Comunitárias Adquiridas/diagnóstico , Humanos , Microbiota/genética , Nasofaringe/microbiologia , Estudos Prospectivos , Sistema Respiratório/microbiologiaRESUMO
OBJECTIVES: Lymphopenia at hospital admission occurs in over one-third of patients with community-acquired pneumonia (CAP), yet its clinical relevance and pathophysiological implications remain underexplored. We evaluated outcomes and immune features of patients with lymphopenic CAP (L-CAP), a previously described immunophenotype characterized by admission lymphocyte count <0.724 × 109 cells/L. METHODS: Observational study in 149 patients admitted to a general ward for CAP. We measured 34 plasma biomarkers reflective of inflammation, endothelial cell responses, coagulation, and immune checkpoints. We characterized lymphocyte phenotypes in 29 patients using spectral flow cytometry. RESULTS: L-CAP occurred in 45 patients (30.2%) and was associated with prolonged time-to-clinical-stability (median 5 versus 3 days), also when we accounted for competing events for reaching clinical stability and adjusted for baseline covariates (subdistribution hazard ratio 0.63; 95% confidence interval 0.45-0.88). L-CAP patients demonstrated a proportional depletion of CD4 T follicular helper cells, CD4 T effector memory cells, naïve CD8 T cells and IgG+ B cells. Plasma biomarker analyses indicated increased activation of the cytokine network and the vascular endothelium in L-CAP. CONCLUSIONS: L-CAP patients have a protracted clinical recovery course and a more broadly dysregulated host response. These findings highlight the prognostic and pathophysiological relevance of admission lymphopenia in patients with CAP.
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Infecções Comunitárias Adquiridas , Linfopenia , Pneumonia , Humanos , Inflamação , HospitalizaçãoRESUMO
The lipidome of immune cells during infection has remained unexplored, although evidence of the importance of lipids in the context of immunity is mounting. In this study, we performed untargeted lipidomic analysis of blood monocytes and neutrophils from patients hospitalized for pneumonia and age- and sex-matched noninfectious control volunteers. We annotated 521 and 706 lipids in monocytes and neutrophils, respectively, which were normalized to an extensive set of internal standards per lipid class. The cellular lipidomes were profoundly altered in patients, with both common and distinct changes between the cell types. Changes involved every level of the cellular lipidome: differential lipid species, class-wide shifts, and altered saturation patterns. Overall, differential lipids were mainly less abundant in monocytes and more abundant in neutrophils from patients. One month after hospital admission, lipidomic changes were fully resolved in monocytes and partially in neutrophils. Integration of lipidomic and concurrently collected transcriptomic data highlighted altered sphingolipid metabolism in both cell types. Inhibition of ceramide and sphingosine-1-phosphate synthesis in healthy monocytes and neutrophils resulted in blunted cytokine responses upon stimulation with lipopolysaccharide. These data reveal major lipidomic remodeling in immune cells during infection, and link the cellular lipidome to immune functionality.
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Monócitos , Pneumonia , Humanos , Neutrófilos , Lipidômica , LipopolissacarídeosRESUMO
BACKGROUND: Increased production of chemokines by adipose tissue and defective adipose tissue oxygenation as a result of obesity may induce leucocyte infiltration and subsequent systemic inflammation. OBJECTIVES: 1-To determine the relation between the amount of visceral and subcutaneous adipose tissue and the chemokine interferon-γ-inducible protein 10 (IP-10) and angiogenic factor hepatocyte growth factor (HGF). 2-To determine the relation between the metabolic syndrome and IP-10 as well as HGF. METHODS: Patients originated from the Secondary Manifestations of ARTerial disease (SMART) cohort. In this study, a cohort of 1251 patients with manifest vascular disease was included. Subcutaneous and visceral adipose tissue thickness (SAT and VAT respectively) were measured ultrasonographically. IP-10 and HGF concentrations were measured with Luminex multiplex immuno assay in addition to fasting metabolic parameters. Linear regression analyses with adjustments for age, gender, smoking, estimated glomerular filtration rate, type 2 diabetes mellitus and medication use were applied to quantify the relations between adiposity or metabolic syndrome and IP-10 and HGF concentrations. RESULTS: VAT was significantly associated with (log)IP-10 and (log)HGF, reflected by significant higher ß-values in VAT quartile 4 compared with VAT quartile 1 (reference): ß0.155 (95%CI:0.073-0.237) for IP-10 and ß0.147 (95%CI:0.076-0.218) for HGF. Per standard deviation increase in VAT, (log)IP-10 levels increased with 0.057 pg/mL (95%CI:0.027-0.087) and (log)HGF increased with 0.051 pg/mL (95%CI:0.025-0.077). Effect estimates were not affected by including body mass index(BMI) in the model. In contrast, SAT was not associated with IP-10 and HGF. Furthermore, the presence of the metabolic syndrome was associated with IP-10 and HGF. CONCLUSIONS: Visceral adipose tissue but not subcutaneous adipose tissue is significantly associated with circulating levels of IP-10 and HGF, irrespective of BMI.
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Quimiocina CXCL10/metabolismo , Fator de Crescimento de Hepatócito/metabolismo , Gordura Intra-Abdominal/metabolismo , Síndrome Metabólica/metabolismo , Idoso , Índice de Massa Corporal , Feminino , Humanos , Inflamação/complicações , Inflamação/metabolismo , Masculino , Síndrome Metabólica/complicações , Pessoa de Meia-Idade , Análise de Regressão , Gordura Subcutânea/metabolismoRESUMO
BACKGROUND: We investigated whether plasma ferritin levels through the pro-inflammatory effects of free iron are associated with adipose tissue dysfunction in a relevant population of patients with manifest vascular disease who would potentially benefit the most from further aetiological insights. MATERIALS AND METHODS: In a cohort of 355 patients with vascular diseases, the association between plasma ferritin and adiponectin levels was quantified using linear regression analysis. Interleukin-6 and adiponectin levels were measured in medium from pre-adipocytes and adipocytes after incubation with increasing concentrations of Fe(III)-citrate and after co-incubation with iron chelators or radical scavengers. RESULTS: Increasing ferritin plasma concentrations were not related to plasma adiponectin levels in patients without (ß -0·13; 95% CI -0·30 to 0·04) or with the metabolic syndrome (ß -0·04; 95% CI -0·17 to 0·10). Similar results were found in patients who developed a new cardiovascular event in the follow-up period. In vitro, incubation with increasing concentrations of Fe(III)-citrate-induced inflammation in pre-adipocyte cultures as witnessed by increased IL-6 secretion at 30 µm Fe(III)-citrate vs. control (500 ± 98 pg/mL vs. 194 ± 31 pg/mL, P = 0·03). Co-incubation of pre-adipocytes with iron chelators or radical scavengers prevented this inflammatory response. Incubation of adipocytes with 30 µm Fe(III)-citrate did not influence adiponectin secretion compared with control. CONCLUSIONS: In patients with vascular disease, there is no association between plasma ferritin and adiponectin levels. In vitro, free iron induces an inflammatory response in pre-adipocytes, but not in adipocytes. This response was blocked by co-incubation with iron chelators or radical scavengers. Adiponectin secretion by adipocytes was not influenced by free iron.
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Tecido Adiposo/fisiologia , Aterosclerose/fisiopatologia , Ferritinas/metabolismo , Adipócitos/metabolismo , Adiponectina/metabolismo , Aterosclerose/sangue , Estudos de Casos e Controles , Células Cultivadas , Feminino , Compostos Férricos/farmacologia , Sequestradores de Radicais Livres/farmacologia , Humanos , Interleucina-6/biossíntese , Quelantes de Ferro/farmacologia , Masculino , Síndrome Metabólica/sangue , Síndrome Metabólica/fisiopatologia , Pessoa de Meia-Idade , Obesidade Abdominal/sangue , Obesidade Abdominal/fisiopatologia , Estudos ProspectivosRESUMO
Background: Community-acquired pneumonia (CAP) represents a major health burden worldwide. Dysregulation of the immune response plays an important role in adverse outcomes in patients with CAP. Methods: We analyzed peripheral blood mononuclear cells by 36-color spectral flow cytometry in adult patients hospitalized for CAP (n=40), matched control subjects (n=31), and patients hospitalized for COVID-19 (n=35). Results: We identified 86 immune cell metaclusters, 19 of which (22.1%) were differentially abundant in patients with CAP versus matched controls. The most notable differences involved classical monocyte metaclusters, which were more abundant in CAP and displayed phenotypic alterations reminiscent of immunosuppression, increased susceptibility to apoptosis, and enhanced expression of chemokine receptors. Expression profiles on classical monocytes, driven by CCR7 and CXCR5, divided patients with CAP into two clusters with a distinct inflammatory response and disease course. The peripheral immune response in patients with CAP was highly similar to that in patients with COVID-19, but increased CCR7 expression on classical monocytes was only present in CAP. Conclusion: CAP is associated with profound cellular changes in blood that mainly relate to classical monocytes and largely overlap with the immune response detected in COVID-19.
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COVID-19 , Infecções Comunitárias Adquiridas , Pneumonia , Adulto , Humanos , Leucócitos Mononucleares , Receptores CCR7 , ImunidadeRESUMO
Neutrophils are potent immune cells with key antimicrobial functions. Previous in vitro work has shown that neutrophil effector functions are mainly fueled by intracellular glycolysis. Little is known about the state of neutrophils still in the circulation in patients during infection. Here, we combined flow cytometry, stimulation assays, transcriptomics, and metabolomics to investigate the link between inflammatory and metabolic pathways in blood neutrophils of patients with community-acquired pneumonia. Patients' neutrophils, relative to neutrophils from age- and sex- matched controls, showed increased degranulation upon ex vivo stimulation, and portrayed distinct upregulation of inflammatory transcriptional programs. This neutrophil phenotype was accompanied by a high-energy state with increased intracellular ATP content, and transcriptomic and metabolic upregulation of glycolysis and glycogenolysis. One month after hospital admission, these metabolic and transcriptomic changes were largely normalized. These data elucidate the molecular programs that underpin a balanced, yet primed state of blood neutrophils during pneumonia.
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Human studies describing the immunomodulatory role of the intestinal microbiota in systemic infections are lacking. Here, we sought to relate microbiota profiles from 115 patients with community-acquired pneumonia (CAP), both on hospital admission and following discharge, to concurrent circulating monocyte and neutrophil function. Rectal microbiota composition did not explain variation in cytokine responses in acute CAP (median 0%, IQR 0.0%-1.9%), but did one month following hospitalization (median 4.1%, IQR 0.0%-6.6%, p = 0.0035). Gene expression analysis of monocytes showed that undisrupted microbiota profiles following hospitalization were associated with upregulated interferon, interleukin-10, and G-protein-coupled-receptor-ligand-binding pathways. While CAP is characterized by profoundly distorted gut microbiota, the effects of these disruptions on cytokine responses and transcriptional profiles during acute infection were absent or modest. However, rectal microbiota were related to altered cytokine responses one month following CAP hospitalization, which may provide insights into potential mechanisms contributing to the high risk of recurrent infections following hospitalization.
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BACKGROUND: Community-acquired pneumonia (CAP) is responsible for a high morbidity and mortality worldwide. Monocytes are essential for pathogen recognition and the initiation of an innate immune response. Immune cells induce intracellular glycolysis upon activation to support several functions. OBJECTIVE: To obtain insight in the metabolic profile of blood monocytes during CAP, with a focus on glycolysis and branching metabolic pathways, and to determine a possible association between intracellular metabolite levels and monocyte function. METHODS: Monocytes were isolated from blood of patients with CAP within 24 h of hospital admission and from control subjects matched for age, sex and chronic comorbidities. Changes in glycolysis, oxidative phosphorylation (OXPHOS), tricarboxylic acid (TCA) cycle and the pentose phosphate pathway were investigated through RNA sequencing and metabolomics measurements. Monocytes were stimulated ex vivo with lipopolysaccharide (LPS) to determine their capacity to produce tumor necrosis factor (TNF), interleukin (IL)-1ß and IL-10. RESULTS: 50 patients with CAP and 25 non-infectious control subjects were studied. When compared with control monocytes, monocytes from patients showed upregulation of many genes involved in glycolysis, including PKM, the gene encoding pyruvate kinase, the rate limiting enzyme for pyruvate production. Gene set enrichment analysis of OXPHOS, the TCA cycle and the pentose phosphate pathway did not reveal differences between monocytes from patients and controls. Patients' monocytes had elevated intracellular levels of pyruvate and the TCA cycle intermediate α-ketoglutarate. Monocytes from patients were less capable of producing cytokines upon LPS stimulation. Intracellular pyruvate (but not α-ketoglutarate) concentrations positively correlated with IL-1ß and IL-10 levels released by patients' (but not control) monocytes upon exposure to LPS. CONCLUSION: These results suggest that elevated intracellular pyruvate levels may partially maintain cytokine production capacity of hyporesponsive monocytes from patients with CAP.
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Monócitos , Pneumonia , Citocinas/metabolismo , Humanos , Interleucina-10/metabolismo , Espaço Intracelular , Lipopolissacarídeos/farmacologia , Monócitos/metabolismo , Pneumonia/metabolismo , Piruvato Quinase/metabolismo , Ácido Pirúvico/metabolismo , Ácidos Tricarboxílicos , Fator de Necrose Tumoral alfa/metabolismoRESUMO
BACKGROUND: Community-acquired pneumonia (CAP) can be caused by a variety of pathogens, of which Streptococcus pneumoniae, Influenza and currently SARS-CoV-2 are the most common. We sought to identify shared and pathogen-specific host response features by directly comparing different aetiologies of CAP. METHODS: We measured 72 plasma biomarkers in a cohort of 265 patients hospitalized for CAP, all sampled within 48 hours of admission, and 28 age-and sex matched non-infectious controls. We stratified the biomarkers into several pathophysiological domains- antiviral response, vascular response and function, coagulation, systemic inflammation, and immune checkpoint markers. We directly compared CAP caused by SARS-CoV-2 (COVID-19, n=39), Streptococcus pneumoniae (CAP-strep, n=27), Influenza (CAP-flu, n=22) and other or unknown pathogens (CAP-other, n=177). We adjusted the comparisons for age, sex and disease severity scores. FINDINGS: Biomarkers reflective of a stronger cell-mediated antiviral response clearly separated COVID-19 from other CAPs (most notably granzyme B). Biomarkers reflecting activation and function of the vasculature showed endothelial barrier integrity was least affected in COVID-19, while glycocalyx degradation and angiogenesis were enhanced relative to other CAPs. Notably, markers of coagulation activation, including D-dimer, were not different between the CAP groups. Ferritin was most increased in COVID-19, while other systemic inflammation biomarkers such as IL-6 and procalcitonin were highest in CAP-strep. Immune checkpoint markers showed distinctive patterns in viral and non-viral CAP, with highly elevated levels of Galectin-9 in COVID-19. INTERPRETATION: Our investigation provides insight into shared and distinct pathophysiological mechanisms in different aetiologies of CAP, which may help guide new pathogen-specific therapeutic strategies. FUNDING: This study was financially supported by the Dutch Research Council, the European Commission and the Netherlands Organization for Health Research and Development.
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COVID-19 , Infecções Comunitárias Adquiridas , Influenza Humana , Pneumonia , Antivirais , Biomarcadores , Humanos , Inflamação , Pneumonia/etiologia , SARS-CoV-2 , Streptococcus pneumoniaeRESUMO
BACKGROUND: Visceral adiposity is associated with cardiovascular risk factors and increased cardiovascular risk. Thyroid-stimulating hormone (TSH) levels in the normal range are associated with a higher risk of fatal coronary artery disease. We hypothesize that TSH levels in the normal range are associated with an increase in visceral adipose tissue (VAT) in patients with vascular diseases. DESIGN: In 2419 patients with vascular diseases, visceral fat thickness was analysed with ultrasonography. The association between TSH and VAT was quantified using linear regression analysis. Results are expressed as beta (ß) regression coefficients with 95% confidence intervals. Adjustments were made for age, sex, current smoking and weight. Separate analyses were performed per quartile of age. RESULTS: ß-coefficients for the relation between TSH and VAT (change per SD of 2·55 cm) was 0·085 (95% CI 0·012-0·157) in the highest quartile of age (range 67-80 years) when adjusted for age, gender and current smoking and remained statistical significant after further adjustment for weight (ß 0·096 95% CI 0·034-0·157). Per SD change, the ß-coefficient for TSH and VAT tissue was larger than for other measures of adiposity. CONCLUSIONS: In conclusion, higher TSH plasma levels in the normal range are associated with more VAT in patients with manifest vascular disease above the age of 66 years. No association was found between plasma TSH levels and weight or BMI. The relation between TSH levels and VAT may provide an explanation for the increased cardiovascular risk associated with elevated TSH plasma concentrations within the normal range.
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Doença da Artéria Coronariana/etiologia , Gordura Intra-Abdominal/metabolismo , Obesidade/complicações , Tireotropina/sangue , Adiposidade/fisiologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Modelos Biológicos , Valor Preditivo dos Testes , Fatores de Risco , Adulto JovemRESUMO
Background Bacterial intestinal communities interact with the immune system and may contribute to protection against community-acquired pneumonia (CAP). Intestinal viruses are closely integrated with these bacterial communities, yet the composition and clinical significance of these communities in CAP patients are unknown. The aims of this exploratory study were to characterise the composition of the rectal bacteriome and virome at hospital admission for CAP, and to determine if microbiota signatures correlate with clinical outcomes. Methods We performed a prospective observational cohort study in CAP patients, admitted to a university or community hospital in the Netherlands between October 2016 and July 2018, and controls. Rectal bacteriome and virome composition were characterised using 16S ribosomal RNA gene sequencing and virus discovery next-generation sequencing, respectively. Unsupervised multi-omics factor analysis was used to assess the co-variation of bacterial and viral communities, which served as primary predictor. The clinical outcomes of interest were the time to clinical stability and the length of hospital stay. Findings 64 patients and 38 controls were analysed. Rectal bacterial alpha (p = 0â¢0015) and beta diversity (r2 =0â¢023, p = 0â¢004) of CAP patients differed from controls. Bacterial and viral microbiota signatures correlated with the time to clinical stability (hazard ratio 0â¢43, 95% confidence interval 0â¢20-0â¢93, p = 0â¢032) and the length of hospital stay (hazard ratio 0â¢37, 95% confidence interval 0â¢17-0â¢81, p = 0â¢012), although only the latter remained significant following p-value adjustment for examining multiple candidate cut-points (p = 0â¢12 and p = 0â¢046, respectively). Interpretation This exploratory study provides preliminary evidence that intestinal bacteriome and virome signatures could be linked with clinical outcomes in CAP. Such exploratory data, when validated in independent cohorts, could inform the development of a microbiota-based diagnostic panel used to predict clinical outcomes in CAP. Funding Netherlands Organization for Scientific Research and Netherlands Organization for Health Research and Development.
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BACKGROUND: The plasticity of monocytes enables them to exert multiple roles during an immune response, including promoting immune tolerance. How monocytes alter their functions to convey immune tolerance in the context of lower respiratory tract infections in humans is not well understood. Here, we sought to identify epigenetic and transcriptomic features of cytokine production capacity in circulating monocytes during community-acquired pneumonia (CAP). METHODS: Circulating CD14+ monocytes were obtained from the blood of CAP patients included in a longitudinal, observational cohort study, on hospitalization (acute stage, n=75), and from the same patients after a 1-month follow-up (recovery stage, n=56). Age and sex-matched non-infectious participants were included as controls (n=41). Ex vivo cytokine production after lipopolysaccharide (LPS) exposure was assessed by multiplex assay. Transcriptomes of circulating monocytes were generated by RNA-sequencing, and DNA methylation levels in the same monocytes were measured by reduced representation bisulfite sequencing. Data were integrated by fitting projection-to-latent-structure models, and signatures derived by partial least squares discrimination. RESULTS: Monocytes captured during the acute stage exhibited impaired TNF, IL-1ß, IL-6, and IL-10 production after ex vivo stimulation with LPS, relative to controls. IL-6 production was not resolved in recovery monocytes. Multivariate analysis of RNA-sequencing data identified 2938 significantly altered RNA transcripts in acute-stage monocytes (fold expression ≤-1.5 or ≥1.5; adjusted p ≤ 0.01), relative to controls. Comparing DNA methylation levels in circulating monocytes of CAP patients to controls revealed minimal differences, specifically in DNAse hypersensitive sites (HS) of acute-stage monocytes. Data integration identified a cholesterol biosynthesis gene signature and DNAse HS axis of IL-1ß and IL-10 production (R2 =0.51). CONCLUSIONS: Circulating monocytes obtained from CAP patients during the acute stage exhibited impaired cytokine production capacities, indicative of reprogramming to a state of immune tolerance, which was not fully resolved after 1 month. Our split-sample study showed that 51% of the immune tolerance phenotype can be explained, at least in part, by coordinated shifts in cholesterol biosynthesis gene expression and DNAse HS methylation levels. A multi-scale model identified an epigenetic and transcriptomic signature of immune tolerance in monocytes, with implications for future interventions in immunosuppression. TRIAL REGISTRATION: NCT number NCT02928367.
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Epigênese Genética , Epigenômica , Regulação da Expressão Gênica , Tolerância Imunológica/genética , Monócitos/imunologia , Monócitos/metabolismo , Transcriptoma , Comorbidade , Biologia Computacional/métodos , Citocinas/genética , Citocinas/metabolismo , Epigenômica/métodos , Feminino , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Mediadores da Inflamação/metabolismo , Masculino , Análise de Sequência de DNARESUMO
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Background: The nature and timing of the host immune response during infections remain uncertain and most knowledge is derived from critically ill sepsis patients. We aimed to test the hypothesis that community-acquired pneumonia (CAP) is associated with concurrent immune suppression and systemic inflammation. Methods: Blood was collected from 79 CAP patients within 24 h after hospitalization and 1 month after discharge; 42 age- and sex-matched subjects without acute infection served as controls. Blood leukocytes were stimulated with lipopolysaccharide (LPS) or Klebsiella pneumoniae, and cytokines were measured in supernatants. Fifteen plasma biomarkers reflective of key host response pathways were compared between CAP patients with the strongest immune suppression (lowest 25% blood leukocyte tumor necrosis factor (TNF)-α production in response to LPS) and those with the least immune suppression (highest 25% of LPS-induced TNF-α production). Results: Blood leukocytes of CAP patients (relative to control subjects) showed a reduced capacity to release TNF-α, interleukin (IL)-1ß, IL-6 and IL-10 upon stimulation with LPS or K. pneumoniae, with a concurrently enhanced ability to release the anti-inflammatory mediator IL-1 receptor antagonist, irrespective of the presence of sepsis (18.9% of cases). Low (relative to high) TNF-α producers displayed higher plasma levels of biomarkers reflecting systemic inflammation, neutrophil degranulation, endothelial cell activation, a disturbed vascular barrier function and coagulation activation. Conclusion: CAP replicates a common feature of immune suppression in sepsis. The coexistence of immune suppression and hyperinflammation in CAP argues against the theory of two distinct phases during the host response to sepsis.
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Infecções Comunitárias Adquiridas/imunologia , Inflamação/imunologia , Infecções por Klebsiella/imunologia , Klebsiella pneumoniae/imunologia , Leucócitos Mononucleares/imunologia , Pneumonia Bacteriana/imunologia , Idoso , Idoso de 80 Anos ou mais , Células Cultivadas , Citocinas , Feminino , Humanos , Tolerância Imunológica , Masculino , Pessoa de Meia-IdadeRESUMO
This study analyzes the social and geographic distribution of ecological hazards across 368 communities in the Commonwealth of Massachusetts. Combining census data with a variety of environmental data, we tested for and identified both income-based and racially based biases to the geographic distribution of 17 different types of environmentally hazardous sites and industrial facilities. We also developed a composite measure of cumulative exposure to compare the relative overall risks characteristic of each community. To the best of our knowledge, this point system makes this the first environmental justice study to develop a means for measuring and ranking cumulative exposure for communities. The study also controls for the intensity of hazards in each community by accounting for the area across which hazards are distributed. The findings indicate that ecologically hazardous sites and facilities are disproportionately located and concentrated in communities of color and working-class communities. The implication of this research for policymakers and citizen advocates is that cumulative exposure of residents to environmentally hazardous facilities and sites should receive greater consideration regarding community demographics and environmental health indicators. We conclude that the provision of additional resources for environmental monitoring and ranking, as well as yearly progress reports, is necessary for communities and state agencies to achieve equal access to clean and healthy environments for all residents.
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Exposição Ambiental , Poluentes Ambientais/efeitos adversos , Grupos Minoritários , Pobreza , Preconceito , Monitoramento Ambiental , Geografia , Resíduos Perigosos , Humanos , Indústrias , Massachusetts , Política Pública , Eliminação de Resíduos , Medição de RiscoRESUMO
AIMS: To investigate whether levels of thyroid-stimulating hormone (TSH) within the normal range are associated with an increased risk of new vascular events and mortality in patients with clinical manifest vascular diseases and whether this relation is influenced by adiposity. METHODS AND RESULTS: Prospective cohort study in 2443 patients (1790 men and 653 women) with clinical manifest vascular disease and TSH levels in the normal range. Median follow up was 2.7 (interquartile range 1.4-3.9) years. Clinical endpoints of interest were: myocardial infarction, stroke, vascular death, and all-cause mortality. In patients with manifest vascular disease, the prevalence of (subclinical) hypothyroidism was 5.7%, while 3.6% had (subclinical) hyperthyroidism. An increase in 1 unit of TSH was associated with a 33% higher risk (HR 1.33; 95% CI 1.03-1.73) for the occurrence of myocardial infarction, adjusted for age, gender, renal function, and smoking. In patients with a body mass index (BMI) below the median of 26.7 kg/m(2) the HR per unit TSH for myocardial infarction was 1.55 (95% CI 1.08-2.21) compared to 1.18 (95% CI 0.81-1.71) in patients with a BMI ≥26.7 kg/m(2). Visceral adipose tissue thickness below the median (≤8.8 cm) was associated with higher HR per unit TSH for myocardial infarction (HR 1.69; 95% CI 1.21-2.35) compared to visceral adipose tissue thickness >8.9 cm (HR 1.00; 95% CI 0.66-1.49). There was no relation between TSH and risk of stroke, vascular death, the combined endpoint, or all-cause mortality. CONCLUSION: Higher TSH levels within the normal range are associated with an increased risk of myocardial infarction, in patients with clinical manifest vascular disease. This relation is most prominent in patients without visceral obesity.
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Doenças Cardiovasculares/epidemiologia , Hipertireoidismo/epidemiologia , Hipotireoidismo/epidemiologia , Tireotropina/sangue , Doenças Vasculares/epidemiologia , Adiposidade , Idoso , Análise de Variância , Biomarcadores/sangue , Doenças Cardiovasculares/sangue , Doenças Cardiovasculares/mortalidade , Doenças Cardiovasculares/fisiopatologia , Feminino , Humanos , Hipertireoidismo/sangue , Hipertireoidismo/mortalidade , Hipertireoidismo/fisiopatologia , Hipotireoidismo/sangue , Hipotireoidismo/mortalidade , Hipotireoidismo/fisiopatologia , Gordura Intra-Abdominal/fisiopatologia , Masculino , Pessoa de Meia-Idade , Países Baixos/epidemiologia , Obesidade/sangue , Obesidade/epidemiologia , Obesidade/fisiopatologia , Prevalência , Modelos de Riscos Proporcionais , Estudos Prospectivos , Medição de Risco , Fatores de Risco , Fatores de Tempo , Doenças Vasculares/sangue , Doenças Vasculares/mortalidade , Doenças Vasculares/fisiopatologiaRESUMO
OBJECTIVE: Physical exercise has multiple beneficial health effects. Yearly, over five million persons walk a pilgrimage in various parts of the World, and this number is increasing. Here we report the effects on vascular function and cardiovascular risk factors of a 12-day pilgrimage to Santiago de Compostela in Spain. METHODS: Twenty-nine healthy male and female subjects between 40 and 70 years were included in the intervention group. The intervention consisted of the last 280 km of the pilgrim route to Santiago de Compostela. Twenty-nine control subjects were age- and gender-matched. Measures of endothelial function, vascular stiffness, autonomic function, and cardiovascular risk factors were measured 2 months and 2 weeks before the pilgrimage and 2 weeks and 2 months afterwards. During the pilgrimage cardiovascular risk factors, including weight, lipids, glucose and blood pressure were measured every other day. RESULTS: The mean daily walking distance during the pilgrimage was 23.42±0.80 km taking 5.39±0.36 h/day. From start to end, HDL-cholesterol increased (0.20±0.30 mmol/L; +15%), while LDL-cholesterol (-0.6±0.6 mmol/L; -17%) and weight (-1.4±1.8 kg; -2%) decreased. After an initial rise, blood pressure came back to baseline. Two months after the pilgrimage a 2.0 kg weight loss persisted compared to the controls. There was no change in any vascular function parameter compared to the controls. CONCLUSION: Walking a pilgrimage immediately influences major cardiovascular risk factors as a consequence of (strenuous) exercise and, likely, dietary changes. Two months after the pilgrimage these changes came back to baseline, except for weight loss. There was no effect on vascular function.
Assuntos
Sistema Cardiovascular/metabolismo , Exercício Físico , Caminhada , Adulto , Idoso , Antropometria/métodos , Pressão Sanguínea , Feminino , Frequência Cardíaca , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de Risco , EspanhaRESUMO
BACKGROUND: Obesity is related to the development of vascular diseases and metabolic complications. Low grade inflammation is a key feature of central obesity, characterized by elevated plasma levels of C-reactive protein (CRP). We hypothesize that visceral adipose tissue contributes to systemic concentrations of CRP. METHODS: In 2410 patients (1729 men and 681 women) with vascular diseases, subcutaneous and visceral fat masses were analyzed with ultrasonography. Metabolic parameters and CRP were measured in a fasting state. The association between fat measurements and plasma CRP was quantified using linear regression analysis. CRP levels were logarithmically transformed. Adjustments were made for age, smoking, type 2 diabetes mellitus, insulin resistance (HOMA-IR) and medication use. RESULTS: Visceral fat was categorized into quartiles (Q) ranging from 3.2 to 7.8 cm in Q1 (reference) to 11.0-19.8 cm in Q4 in men and 2.7-6.0 cm in Q1 (reference) to 9.0-17.4 cm in Q4 in women. beta-coefficients gradually increased across the quartiles from 0.07 (0.01-0.13) in Q2 to 0.25 (0.19-0.31) in Q4 in men and 0.17 (0.07-0.26) in Q2 to 0.42 (0.32-0.52) in Q4 in women, indicating 0.25 and 0.42 mg/l higher logarithmically transformed (log)CRP levels in Q4 compared to Q1 in respectively men and women. Per standard deviation increase of visceral fat, logCRP levels increased with 0.10 mg/l (0.07-0.12) in men and with 0.11 (0.15-0.19) in women. Likewise, in separate analyses waist circumference and body mass index showed a positive, but weaker association with logCRP levels across quartiles (in men: beta 0.21 (0.15-0.27) in Q4 for waist circumference and beta 0.23 (0.17-0.30) in Q4 for body mass index; in women: beta 0.32 (0.22-0.42) in Q4 for waist circumference and beta 0.32 (0.22-0.42) in Q4 for body mass index). In men subcutaneous fat was not associated with logCRP (beta-coefficients relative to Q1: -0.01 (-0.07 to -0.05), -0.01 (-0.07 to -0.05) and 0.05 (-0.01 to -0.11) in Q2 to Q4 respectively). CONCLUSIONS: In conclusion, visceral fat thickness is the strongest contributor to the systemic CRP concentrations in patients with vascular diseases.