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3.
Chest ; 160(4): 1340-1349, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34029565

RESUMO

BACKGROUND: Tobacco smoking is associated with a reduced risk of developing sarcoidosis, and we previously reported that nicotine normalizes immune responses to environmental antigens in patients with active pulmonary sarcoidosis. The effects of nicotine on the progression of pulmonary sarcoidosis are unknown. RESEARCH QUESTION: Is nicotine treatment well tolerated, and will it improve lung function in patients with active pulmonary sarcoidosis? STUDY DESIGN AND METHODS: With local institutional review board approval, a randomized, double-blind, controlled pilot trial was conducted of daily nicotine transdermal patch treatment (21 mg daily) or placebo patch use for 24 weeks. The Ohio State University Wexner Medical Center and Cleveland Clinic enrolled 50 consecutive subjects aged ≥ 18 years with active pulmonary sarcoidosis, based on symptoms (ie, dyspnea, cough) and objective radiographic evidence of infiltrates consistent with nonfibrotic lung disease. Each study group was compared at 26 weeks based on repeated measures of FVC, FEV1, quantitative lung texture score based on CT texture analysis, Fatigue Assessment Score (FAS), St. George's Respiratory Questionnaire (SGRQ), and the Sarcoidosis Assessment Tool. RESULTS: Nicotine treatment was associated with a clinically significant, approximately 2.1% (70 mL) improvement in FVC from baseline to 26 weeks. FVC decreased by a similar amount (2.2%) in the placebo group, with a net increase of 140 mL (95% CI, 10-260) when comparing nicotine vs placebo groups at 26 weeks. FEV1 and FAS improved marginally in the nicotine-treated group, compared with those on placebo. No improvement was observed in lung texture score, FAS, St. George's Respiratory Questionnaire score, or the Sarcoidosis Assessment Tool. There were no reported serious adverse events or evidence of nicotine addiction. INTERPRETATION: Nicotine treatment was well tolerated in patients with active pulmonary sarcoidosis, and the preliminary findings of this pilot study suggest that it may reduce disease progression, based on FVC. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov; No.: NCT02265874; URL: www.clinicaltrials.gov.

4.
Chest ; 159(5): 1902-1912, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33387486

RESUMO

BACKGROUND: A Phase I, single-center investigation found that 8 weeks of antimycobacterial therapy improved sarcoidosis FVC. Safety and efficacy assessments have not been performed in a multicenter cohort. RESEARCH QUESTION: The objective of this study was to determine the safety and efficacy of antimycobacterial therapy on the physiological and immunologic end points of sarcoidosis. STUDY DESIGN AND METHODS: In a double-blind, placebo-controlled, multicenter investigation, patients with pulmonary sarcoidosis were randomly assigned to receive 16 weeks of concomitant levofloxacin, ethambutol, azithromycin, and rifabutin (CLEAR) or matching placebo to investigate the effect on FVC. The primary outcome was a comparison of change in percentage of predicted FVC among patients randomized to receive CLEAR or placebo in addition to their baseline immunosuppressive regimen. Secondary outcomes included 6-min walk distance (6MWD), St. George's Respiratory Questionnaire (SGRQ) score, adverse events, and decrease in mycobacterial early secreted antigenic target of 6 kDa (ESAT-6) immune responses. RESULTS: The intention-to-treat analysis revealed no significant differences in change in FVC among the 49 patients randomized to receive CLEAR (1.1% decrease) compared with the 48 randomized to receive placebo (0.02% increase) (P = .64). Physiological parameters such as the change in 6MWD were likewise similar (P = .91); change in SGRQ favored placebo (-8.0 for placebo vs -1.5 for CLEAR; P = .028). The per-protocol analysis revealed no significant change in FVC at 16 weeks between CLEAR and placebo. There was no significant change in 6MWD (36.4 m vs 6.3 m; P = .24) or SGRQ (-2.3 vs -7.0; P = .14). A decline in ESAT-6 immune responses at 16 weeks was noted among CLEAR-treated patients (P = .0003) but not patients receiving placebo (P = .24). INTERPRETATION: Despite a significant decline in ESAT-6 immune responses, a 16-week CLEAR regimen provided no physiological benefit in FVC or 6MWD among patients with sarcoidosis.


Assuntos
Antibacterianos/uso terapêutico , Antituberculosos/uso terapêutico , Sarcoidose Pulmonar/tratamento farmacológico , Sarcoidose Pulmonar/microbiologia , Azitromicina/uso terapêutico , Doença Crônica , Método Duplo-Cego , Quimioterapia Combinada , Etambutol/uso terapêutico , Feminino , Humanos , Levofloxacino/uso terapêutico , Masculino , Pessoa de Meia-Idade , Testes de Função Respiratória , Rifabutina/uso terapêutico , Sarcoidose Pulmonar/imunologia
5.
PLoS One ; 16(1): e0246083, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33497386

RESUMO

OBJECTIVE: Cardiac sarcoidosis is difficult to diagnose, often requiring expensive and inconvenient advanced imaging techniques. Circulating exosomes contain genetic material, such as microRNA (miRNA), that are derived from diseased tissues and may serve as potential disease-specific biomarkers. We thus sought to determine whether circulating exosome-derived miRNA expression patterns would distinguish cardiac sarcoidosis (CS) from acute myocardial infarction (AMI). METHODS: Plasma and serum samples conforming to CS, AMI or disease-free controls were procured from the Biologic Specimen and Data Repository Information Coordinating Center repository and National Jewish Health. Next generation sequencing (NGS) was performed on exosome-derived total RNA (n = 10 for each group), and miRNA expression levels were compared after normalization using housekeeping miRNA. Quality assurance measures excluded poor quality RNA samples. Differentially expressed (DE) miRNA patterns, based upon >2-fold change (p < 0.01), were established in CS compared to controls, and in CS compared to AMI. Relative expression of several DE-miRNA were validated by qRT-PCR. RESULTS: Despite the advanced age of the stored samples (~5-30 years), the quality of the exosome-derived miRNA was intact in ~88% of samples. Comparing plasma exosomal miRNA in CS versus controls, NGS yielded 18 DE transcripts (12 up-regulated, 6 down-regulated), including miRNA previously implicated in mechanisms of myocardial injury (miR-92, miR-21) and immune responses (miR-618, miR-27a). NGS further yielded 52 DE miRNA in serum exosomes from CS versus AMI: 5 up-regulated in CS; 47 up-regulated in AMI, including transcripts previously detected in AMI patients (miR-1-1, miR-133a, miR-208b, miR-423, miR-499). Five miRNAs with increased DE in CS included two isoforms of miR-624 and miR-144, previously reported as markers of cardiomyopathy. CONCLUSIONS: MiRNA patterns of exosomes derived from CS and AMI patients are distinct, suggesting that circulating exosomal miRNA patterns could serve as disease biomarkers. Further studies are required to establish their specificity relative to other cardiac disorders.


Assuntos
MicroRNA Circulante/sangue , Exossomos/metabolismo , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Infarto do Miocárdio/sangue , Sarcoidose/sangue , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/diagnóstico , Sarcoidose/diagnóstico
6.
Eur Respir J ; 57(3)2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-32943400

RESUMO

INTRODUCTION: Sarcoidosis and tuberculosis are granulomatous pulmonary diseases characterised by heightened immune reactivity to Mycobacterium tuberculosis antigens. We hypothesised that an unsupervised analysis comparing the molecular characteristics of granulomas formed in response to M. tuberculosis antigens in patients with sarcoidosis or latent tuberculosis infection (LTBI) would provide novel insights into the pathogenesis of sarcoidosis. METHODS: A genomic analysis identified differentially expressed genes in granuloma-like cell aggregates formed by sarcoidosis (n=12) or LTBI patients (n=5) in an established in vitro human granuloma model wherein peripheral blood mononuclear cells were exposed to M. tuberculosis antigens (beads coated with purified protein derivative) and cultured for 7 days. Pathway analysis of differentially expressed genes identified canonical pathways, most notably antigen processing and presentation via phagolysosomes, as a prominent pathway in sarcoidosis granuloma formation. The phagolysosomal pathway promoted mechanistic target of rapamycin complex 1 (mTORc1)/STAT3 signal transduction. Thus, granuloma formation and related immune mediators were evaluated in the absence or presence of various pre-treatments known to prevent phagolysosome formation (chloroquine) or phagosome acidification (bafilomycin A1) or directly inhibit mTORc1 activation (rapamycin). RESULTS: In keeping with genomic analyses indicating enhanced phagolysosomal activation and predicted mTORc1 signalling, it was determined that sarcoidosis granuloma formation and related inflammatory mediator release was dependent upon phagolysosome assembly and acidification and mTORc1/S6/STAT3 signal transduction. CONCLUSIONS: Sarcoidosis granulomas exhibit enhanced and sustained intracellular antigen processing and presentation capacities, and related phagolysosome assembly and acidification are required to support mTORc1 signalling to promote sarcoidosis granuloma formation.


Assuntos
Leucócitos Mononucleares , Sarcoidose , Granuloma , Humanos , Fagossomos , Transdução de Sinais , Serina-Treonina Quinases TOR
7.
Crit Care Med ; 48(12): e1375-e1376, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-33255141
8.
Respir Res ; 21(1): 321, 2020 Dec 04.
Artigo em Inglês | MEDLINE | ID: mdl-33276795

RESUMO

RATIONALE: Despite the availability of multi-"omics" strategies, insights into the etiology and pathogenesis of sarcoidosis have been elusive. This is partly due to the lack of reliable preclinical models and a paucity of validated biomarkers. As granulomas are a key feature of sarcoidosis, we speculate that direct genomic interrogation of sarcoid tissues, may lead to identification of dysregulated gene pathways or biomarker signatures. OBJECTIVE: To facilitate the development sarcoidosis genomic biomarkers by gene expression profiling of sarcoidosis granulomas in lung and lymph node tissues (most commonly affected organs) and comparison to infectious granulomas (coccidiodomycosis and tuberculosis). METHODS: Transcriptomic profiles of immune-related gene from micro-dissected sarcoidosis granulomas within lung and mediastinal lymph node tissues and compared to infectious granulomas from paraffin-embedded blocks. Differentially-expressed genes (DEGs) were profiled, compared among the three granulomatous diseases and analyzed for functional enrichment pathways. RESULTS: Despite histologic similarities, DEGs and pathway enrichment markedly differed in sarcoidosis granulomas from lymph nodes and lung. Lymph nodes showed a clear immunological response, whereas a structural regenerative response was observed in lung. Sarcoidosis granuloma gene expression data corroborated previously reported genomic biomarkers (STAB1, HBEGF, and NOTCH4), excluded others and identified new genomic markers present in lung and lymph nodes, ADAMTS1, NPR1 and CXCL2. Comparisons between sarcoidosis and pathogen granulomas identified pathway divergences and commonalities at gene expression level. CONCLUSION: These findings suggest the importance of tissue and disease-specificity evaluation when exploring sarcoidosis genomic markers. This relevant translational information in sarcoidosis and other two histopathological similar infections provides meaningful specific genomic-derived biomarkers for sarcoidosis diagnosis and prognosis.


Assuntos
Coccidioidomicose/genética , Perfilação da Expressão Gênica , Granuloma/genética , Doenças Linfáticas/genética , Sarcoidose Pulmonar/genética , Transcriptoma , Tuberculose/genética , Adulto , Idoso , Coccidioidomicose/diagnóstico , Coccidioidomicose/imunologia , Coccidioidomicose/microbiologia , Diagnóstico Diferencial , Feminino , Marcadores Genéticos , Granuloma/diagnóstico , Granuloma/imunologia , Granuloma/microbiologia , Humanos , Doenças Linfáticas/diagnóstico , Doenças Linfáticas/imunologia , Masculino , Pessoa de Meia-Idade , Sarcoidose Pulmonar/diagnóstico , Sarcoidose Pulmonar/imunologia , Tuberculose/diagnóstico , Tuberculose/imunologia , Tuberculose/microbiologia , Adulto Jovem
9.
Contemp Clin Trials Commun ; 20: 100669, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33089005

RESUMO

Introduction: Sarcoidosis is a systemic granulomatous disease of unknown cause afflicting young to middle-aged adults. The majority of patients with active pulmonary sarcoidosis complain of overwhelming fatigue, which often persists despite administration of immune-modulating drugs typically used to treat sarcoidosis. Nicotine offers an alternative to conventional treatments, which are associated with a spectrum of serious untoward effects, including diabetes mellitus, osteoporosis, bone marrow suppression, severe infections, cirrhosis. The described pilot randomized trial aims to provide preliminary data required to design subsequent Phase II/III trials to formally evaluate nicotine as a novel low-cost and highly-effective, safe treatment option for patients with active pulmonary sarcoidosis. Methods: and Design: This is a randomized double-blind controlled trial of adults with confirmed pulmonary sarcoidosis, allocated in equal proportion to sustained release transdermal nicotine or placebo patch. The primary objective outcome is the improvement in forced vital capacity at study week 26 from baseline measurement. Secondary measures include lung texture score, and self-reported outcomes including the Fatigue Assessment Scale, the St George's Respiratory Questionnaire, and the Sarcoidosis Assessment Tool. Discussion: Current therapies for active pulmonary sarcoidosis, remain either expensive and often with numerous side-effects, as with novel industry developed therapies, or with reduced quality of life, as with corticosteroids. Nicotine therapy provides promise as a safe, available, and cost-effective intervention strategy, which we expect to be acceptable to patients. ClinicalTrialsgov: NCT02265874.

12.
Front Immunol ; 11: 1719, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32849608

RESUMO

The inability to effectively model sarcoidosis in the laboratory or in animals continues to hinder the discovery and translation of new, targeted treatments. The granuloma is the signature pathological hallmark of sarcoidosis, yet there are significant knowledge gaps that exist with regard to how granulomas form. Significant progress toward improved therapeutic and prognostic strategies in sarcoidosis hinges on tractable experimental models that recapitulate the process of granuloma formation in sarcoidosis and allow for mechanistic insights into the molecular events involved. Through its inherent representation of the complex genetics underpinning immune cell dysregulation in sarcoidosis, a recently developed in vitro human granuloma model holds promise in providing detailed mechanistic insight into sarcoidosis-specific disease regulating pathways at play during early stages of granuloma formation. The purpose of this review is to critically evaluate current sarcoidosis models and assess their potential to progress the field toward the goal of improved therapies in this disease. We conclude with the potential integrated use of preclinical models to accelerate progress toward identifying and testing new drugs and drug combinations that can be rapidly brought to clinical trials.


Assuntos
Granuloma do Sistema Respiratório , Pulmão , Sarcoidose Pulmonar , Animais , Células Cultivadas , Modelos Animais de Doenças , Granuloma do Sistema Respiratório/genética , Granuloma do Sistema Respiratório/imunologia , Granuloma do Sistema Respiratório/metabolismo , Granuloma do Sistema Respiratório/patologia , Humanos , Leucócitos Mononucleares/imunologia , Leucócitos Mononucleares/metabolismo , Pulmão/imunologia , Pulmão/metabolismo , Pulmão/patologia , Macrófagos Alveolares/imunologia , Macrófagos Alveolares/metabolismo , Modelos Teóricos , Sarcoidose Pulmonar/genética , Sarcoidose Pulmonar/imunologia , Sarcoidose Pulmonar/metabolismo , Sarcoidose Pulmonar/patologia
14.
J Intensive Care ; 8: 33, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32391157

RESUMO

Background: The initial presentation of sepsis in the emergency department (ED) is difficult to distinguish from other acute illnesses based upon similar clinical presentations. A new blood parameter, a measurement of increased monocyte volume distribution width (MDW), may be used in combination with other clinical parameters to improve early sepsis detection. We sought to determine if MDW, when combined with other available clinical parameters at the time of ED presentation, improves the early detection of sepsis. Methods: A retrospective analysis of prospectively collected clinical data available during the initial ED encounter of 2158 adult patients who were enrolled from emergency departments of three major academic centers, of which 385 fulfilled Sepsis-2 criteria, and 243 fulfilled Sepsis-3 criteria within 12 h of admission. Sepsis probabilities were determined based on MDW values, alone or in combination with components of systemic inflammatory response syndrome (SIRS) or quick sepsis-related organ failure assessment (qSOFA) score obtained during the initial patient presentation (i.e., within 2 h of ED admission). Results: Abnormal MDW (> 20.0) consistently increased sepsis probability, and normal MDW consistently reduced sepsis probability when used in combination with SIRS criteria (tachycardia, tachypnea, abnormal white blood count, or body temperature) or qSOFA criteria (tachypnea, altered mental status, but not hypotension). Overall, and regardless of other SIRS or qSOFA variables, MDW > 20.0 (vs. MDW ≤ 20.0) at the time of the initial ED encounter was associated with an approximately 6-fold increase in the odds of Sepsis-2, and an approximately 4-fold increase in the odds of Sepsis-3. Conclusions: MDW improves the early detection of sepsis during the initial ED encounter and is complementary to SIRS and qSOFA parameters that are currently used for this purpose. This study supports the incorporation of MDW with other readily available clinical parameters during the initial ED encounter for the early detection of sepsis. Trial registration: ClinicalTrials.gov, NCT03145428. First posted May 9, 2017. The first subjects were enrolled June 19, 2017, and the study completion date was January 26, 2018.

15.
Am J Respir Crit Care Med ; 201(8): e26-e51, 2020 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-32293205

RESUMO

Background: The diagnosis of sarcoidosis is not standardized but is based on three major criteria: a compatible clinical presentation, finding nonnecrotizing granulomatous inflammation in one or more tissue samples, and the exclusion of alternative causes of granulomatous disease. There are no universally accepted measures to determine if each diagnostic criterion has been satisfied; therefore, the diagnosis of sarcoidosis is never fully secure.Methods: Systematic reviews and, when appropriate, meta-analyses were performed to summarize the best available evidence. The evidence was appraised using the Grading of Recommendations, Assessment, Development, and Evaluation approach and then discussed by a multidisciplinary panel. Recommendations for or against various diagnostic tests were formulated and graded after the expert panel weighed desirable and undesirable consequences, certainty of estimates, feasibility, and acceptability.Results: The clinical presentation, histopathology, and exclusion of alternative diagnoses were summarized. On the basis of the available evidence, the expert committee made 1 strong recommendation for baseline serum calcium testing, 13 conditional recommendations, and 1 best practice statement. All evidence was very low quality.Conclusions: The panel used systematic reviews of the evidence to inform clinical recommendations in favor of or against various diagnostic tests in patients with suspected or known sarcoidosis. The evidence and recommendations should be revisited as new evidence becomes available.


Assuntos
Cardiomiopatias/diagnóstico , Nefropatias/diagnóstico , Hepatopatias/diagnóstico , Sarcoidose Pulmonar/diagnóstico , Alanina Transaminase/sangue , Fosfatase Alcalina/sangue , Aspartato Aminotransferases/sangue , Biópsia , Broncoscopia , Cálcio/sangue , Cardiomiopatias/sangue , Cardiomiopatias/fisiopatologia , Creatinina/sangue , Ecocardiografia , Eletrocardiografia , Eletrocardiografia Ambulatorial , Endossonografia , Oftalmopatias/diagnóstico , Oftalmopatias/fisiopatologia , Humanos , Hipercalcemia/sangue , Hipercalcemia/diagnóstico , Hipertensão Pulmonar/diagnóstico , Hipertensão Pulmonar/fisiopatologia , Nefropatias/sangue , Hepatopatias/sangue , Linfonodos/patologia , Linfadenopatia , Imageamento por Ressonância Magnética , Mediastino , Tomografia por Emissão de Pósitrons , Pneumologia , Sarcoidose/sangue , Sarcoidose/diagnóstico , Sarcoidose/patologia , Sarcoidose/fisiopatologia , Sarcoidose Pulmonar/sangue , Sarcoidose Pulmonar/patologia , Sarcoidose Pulmonar/fisiopatologia , Sociedades Médicas , Vitamina D/sangue
16.
Am. j. respir. crit. care med ; 201(8): e26-e51, Apr. 15, 2020.
Artigo em Inglês | BIGG - guias GRADE | ID: biblio-1117227

RESUMO

The diagnosis of sarcoidosis is not standardized but is based on three major criteria: a compatible clinical presentation, finding nonnecrotizing granulomatous inflammation in one or more tissue samples, and the exclusion of alternative causes of granulomatous disease. There are no universally accepted measures to determine if each diagnostic criterion has been satisfied; therefore, the diagnosis of sarcoidosis is never fully secure. Systematic reviews and, when appropriate, meta-analyses were performed to summarize the best available evidence. The evidence was appraised using the Grading of Recommendations, Assessment, Development, and Evaluation approach and then discussed by a multidisciplinary panel. Recommendations for or against various diagnostic tests were formulated and graded after the expert panel weighed desirable and undesirable consequences, certainty of estimates, feasibility, and acceptability. The clinical presentation, histopathology, and exclusion of alternative diagnoses were summarized. On the basis of the available evidence, the expert committee made 1 strong recommendation for baseline serum calcium testing, 13 conditional recommendations, and best practice statement. All evidence was very low quality.The panel used systematic reviews of the evidence to inform clinical recommendations in favor of or against various diagnostic tests in patients with suspected or known sarcoidosis. The evidence and recommendations should be revisited as new evidence becomes available.


Assuntos
Humanos , Sarcoidose/prevenção & controle , Doenças Raras/prevenção & controle , Granuloma/prevenção & controle , Hipertensão Pulmonar/prevenção & controle , Pneumopatias/prevenção & controle
17.
Eur Respir Rev ; 29(155)2020 Mar 31.
Artigo em Inglês | MEDLINE | ID: mdl-32198218

RESUMO

Pulmonary sarcoidosis presents substantial management challenges, with limited evidence on effective therapies and phenotypes. In the absence of definitive evidence, expert consensus can supply clinically useful guidance in medicine. An international panel of 26 experts participated in a Delphi process to identify consensus on pharmacological management in sarcoidosis with the development of preliminary recommendations.The modified Delphi process used three rounds. The first round focused on qualitative data collection with open-ended questions to ensure comprehensive inclusion of expert concepts. Rounds 2 and 3 applied quantitative assessments using an 11-point Likert scale to identify consensus.Key consensus points included glucocorticoids as initial therapy for most patients, with non-biologics (immunomodulators), usually methotrexate, considered in severe or extrapulmonary disease requiring prolonged treatment, or as a steroid-sparing intervention in cases with high risk of steroid toxicity. Biologic therapies might be considered as additive therapy if non-biologics are insufficiently effective or are not tolerated with initial biologic therapy, usually with a tumour necrosis factor-α inhibitor, typically infliximab.The Delphi methodology provided a platform to gain potentially valuable insight and interim guidance while awaiting evidenced-based contributions.


Assuntos
Corticosteroides/uso terapêutico , Algoritmos , Produtos Biológicos/uso terapêutico , Tomada de Decisão Clínica , Técnicas de Apoio para a Decisão , Fatores Imunológicos/uso terapêutico , Pulmão/efeitos dos fármacos , Sarcoidose Pulmonar/tratamento farmacológico , Corticosteroides/efeitos adversos , Produtos Biológicos/efeitos adversos , Consenso , Técnica Delfos , Humanos , Fatores Imunológicos/efeitos adversos , Pulmão/fisiopatologia , Sarcoidose Pulmonar/diagnóstico , Sarcoidose Pulmonar/fisiopatologia , Índice de Gravidade de Doença
18.
Intensive Care Med ; 45(10): 1360-1371, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31576433

RESUMO

PURPOSE: Sepsis-associated immunosuppression increases hospital-acquired infection and viral reactivation risk. A key underlying mechanism is programmed cell death protein-1 (PD-1)-mediated T-cell function impairment. This is one of the first clinical safety and pharmacokinetics (PK) assessments of the anti-PD-1 antibody nivolumab and its effect on immune biomarkers in sepsis. METHODS: Randomized, double-blind, parallel-group, Phase 1b study in 31 adults at 10 US hospital ICUs with sepsis diagnosed ≥ 24 h before study treatment, ≥ 1 organ dysfunction, and absolute lymphocyte count ≤ 1.1 × 103 cells/µL. Participants received one nivolumab dose [480 mg (n = 15) or 960 mg (n = 16)]; follow-up was 90 days. Primary endpoints were safety and PK parameters. RESULTS: Twelve deaths occurred [n = 6 per study arm; 40% (480 mg) and 37.5% (960 mg)]. Serious AEs occurred in eight participants [n = 1, 6.7% (480 mg); n = 7, 43.8% (960 mg)]. AEs considered by the investigator to be possibly drug-related and immune-mediated occurred in five participants [n = 2, 13.3% (480 mg); n = 3, 18.8% (960 mg)]. Mean ± SD terminal half-life was 14.7 ± 5.3 (480 mg) and 15.8 ± 7.9 (960 mg) days. All participants maintained > 90% receptor occupancy (RO) 28 days post-infusion. Median (Q1, Q3) mHLA-DR levels increased to 11,531 (6528, 19,495) and 11,449 (6225, 16,698) mAbs/cell in the 480- and 960-mg arms by day 14, respectively. Pro-inflammatory cytokine levels did not increase. CONCLUSIONS: In this sepsis population, nivolumab administration did not result in unexpected safety findings or indicate any 'cytokine storm'. The PK profile maintained RO > 90% for ≥ 28 days. Further efficacy and safety studies are warranted. TRIAL REGISTRATION NUMBER (CLINICALTRIALS.GOV): NCT02960854.


Assuntos
Nivolumabe/farmacologia , Nivolumabe/farmacocinética , Nivolumabe/uso terapêutico , Sepse/tratamento farmacológico , Adulto , Idoso , Biomarcadores/análise , Método Duplo-Cego , Feminino , Antígenos HLA-DR/análise , Antígenos HLA-DR/sangue , Humanos , Fatores Imunológicos/farmacocinética , Fatores Imunológicos/farmacologia , Fatores Imunológicos/uso terapêutico , Masculino , Pessoa de Meia-Idade , Receptor de Morte Celular Programada 1/análise , Receptor de Morte Celular Programada 1/sangue , Sepse/imunologia , Sepse/fisiopatologia
19.
JAMA Netw Open ; 2(8): e198686, 2019 08 02.
Artigo em Inglês | MEDLINE | ID: mdl-31390038

RESUMO

Importance: Long-term immune sequelae after sepsis are poorly understood. Objective: To assess whether abnormalities in the host immune response during hospitalization for sepsis persist after discharge. Design, Settings, and Participants: This prospective, multicenter cohort study enrolled and followed up for 1 year adults who survived a hospitalization for sepsis from January 10, 2012, to May 25, 2017, at 12 US hospitals. Exposures: Circulating levels of inflammation (interleukin 6 and high-sensitivity C-reactive protein [hs-CRP]), immunosuppression (soluble programmed death ligand 1 [sPD-L1]), hemostasis (plasminogen activator inhibitor 1 and D-dimer), endothelial dysfunction (E-selectin, intercellular adhesion molecule 1, and vascular cell adhesion molecule 1), and oxidative stress biomarkers were measured at 5 time points during and after hospitalization for sepsis for 1 year. Individual biomarker trajectories and patterns of trajectories across biomarkers (phenotypes) were identified. Main Outcomes and Measures: Outcomes were adjudicated centrally and included all-cause and cause-specific readmissions and mortality. Results: A total of 483 patients (mean [SD] age, 60.5 [15.2] years; 265 [54.9%] male) who survived hospitalization for sepsis were included in the study. A total of 376 patients (77.8%) had at least 1 chronic disease, and their mean (SD) Sequential Organ Failure Assessment score was 4.2 (3.0). Readmissions were common (485 readmissions in 205 patients [42.5%]), and 43 patients (8.9%) died by 3 months, 56 patients (11.6%) died by 6 months, and 85 patients (17.6%) died by 12 months. Elevated hs-CRP levels were observed in 23 patients (25.8%) at 3 months, 26 patients (30.2%) at 6 months, and 23 patients (25.6%) at 12 months, and elevated sPD-L1 levels were observed in 45 patients (46.4%) at 3 months, 40 patients (44.9%) at 6 months, and 44 patients (49.4%) at 12 months. Two common phenotypes were identified based on hs-CRP and sPDL1 trajectories: high hs-CRP and sPDL1 levels (hyperinflammation and immunosuppression phenotype [326 of 477 (68.3%)]) and normal hs-CRP and sPDL1 levels (normal phenotype [143 of 477 (30.0%)]). These phenotypes had similar clinical characteristics and clinical course during hospitalization for sepsis. Compared with normal phenotype, those with the hyperinflammation and immunosuppression phenotype had higher 1-year mortality (odds ratio, 8.26; 95% CI, 3.45-21.69; P < .001), 6-month all-cause readmission or mortality (hazard ratio [HR], 1.53; 95% CI, 1.10-2.13; P = .01), and 6-month readmission or mortality attributable to cardiovascular disease (HR, 5.07; 95% CI, 1.18-21.84; P = .02) or cancer (HR, 5.15; 95% CI, 1.25-21.18; P = .02). These associations were adjusted for demographic characteristics, chronic diseases, illness severity, organ support, and infection site during sepsis hospitalization and were robust in sensitivity analyses. Conclusions and Relevance: In this study, persistent elevation of inflammation and immunosuppression biomarkers occurred in two-thirds of patients who survived a hospitalization for sepsis and was associated with worse long-term outcomes.


Assuntos
Imunocompetência/imunologia , Inflamação/sangue , Sepse/imunologia , Idoso , Antígeno B7-H1/sangue , Biomarcadores/sangue , Proteína C-Reativa/análise , Comorbidade , Feminino , Humanos , Inflamação/imunologia , Masculino , Pessoa de Meia-Idade , Escores de Disfunção Orgânica , Readmissão do Paciente/estatística & dados numéricos , Estudos Prospectivos , Sepse/sangue , Sepse/mortalidade
20.
Crit Care Med ; 47(8): 1018-1025, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31107278

RESUMO

OBJECTIVES: Most septic patients are initially encountered in the emergency department where sepsis recognition is often delayed, in part due to the lack of effective biomarkers. This study evaluated the diagnostic accuracy of peripheral blood monocyte distribution width alone and in combination with WBC count for early sepsis detection in the emergency department. DESIGN: An Institutional Review Board approved, blinded, observational, prospective cohort study conducted between April 2017 and January 2018. SETTING: Subjects were enrolled from emergency departments at three U.S. academic centers. PATIENTS: Adult patients, 18-89 years, with complete blood count performed upon presentation to the emergency department, and who remained hospitalized for at least 12 hours. A total of 2,212 patients were screened, of whom 2,158 subjects were enrolled and categorized per Sepsis-2 criteria, such as controls (n = 1,088), systemic inflammatory response syndrome (n = 441), infection (n = 244), and sepsis (n = 385), and Sepsis-3 criteria, such as control (n = 1,529), infection (n = 386), and sepsis (n = 243). INTERVENTIONS: The primary outcome determined whether an monocyte distribution width of greater than 20.0 U, alone or in combination with WBC, improves early sepsis detection by Sepsis-2 criteria. Secondary endpoints determined monocyte distribution width performance for Sepsis-3 detection. MEASUREMENTS AND MAIN RESULTS: Monocyte distribution width greater than 20.0 U distinguished sepsis from all other conditions based on either Sepsis-2 criteria (area under the curve, 0.79; 95% CI, 0.76-0.82) or Sepsis-3 criteria (area under the curve, 0.73; 95% CI, 0.69-0.76). The negative predictive values for monocyte distribution width less than or equal to 20 U for Sepsis-2 and Sepsis-3 were 93% and 94%, respectively. Monocyte distribution width greater than 20.0 U combined with an abnormal WBC further improved Sepsis-2 detection (area under the curve, 0.85; 95% CI, 0.83-0.88) and as reflected by likelihood ratio and added value analyses. Normal WBC and monocyte distribution width inferred a six-fold lower sepsis probability. CONCLUSIONS: An monocyte distribution width value of greater than 20.0 U is effective for sepsis detection, based on either Sepsis-2 criteria or Sepsis-3 criteria, during the initial emergency department encounter. In tandem with WBC, monocyte distribution width is further predicted to enhance medical decision making during early sepsis management in the emergency department.


Assuntos
Serviço Hospitalar de Emergência , Monócitos/metabolismo , Sepse/metabolismo , Choque Séptico/metabolismo , Adulto , Idoso , Biomarcadores/sangue , Estudos de Casos e Controles , Feminino , Humanos , Contagem de Linfócitos/métodos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Sepse/diagnóstico , Choque Séptico/diagnóstico , Adulto Jovem
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