Patients with COVID-19 infection are at risk of acute respiratory disease syndrome (ARDS) and death. The tissue receptor for COVID-19 is ACE2, and higher levels of ACE2 can protect against ARDS. ...Angiotensin receptor blockers and statins upregulate ACE2. Clinical trials are needed to determine whether this drug combination might be used to treat patients with severe COVID-19 infection.
Summary Pneumococcus remains the most common cause of community-acquired pneumonia worldwide. Streptococcus pneumoniae is well adapted to people, and is a frequent inhabitant of the upper airways in ...healthy hosts. This seemingly innocuous state of colonisation is a dynamic and competitive process in which the pathogen attempts to engage the host, proliferate, and invade the lower airways. The host in turn continuously deploys an array of innate and acquired cellular and humoral defences to prevent pneumococci from breaching tissue barriers. Discoveries into essential molecular mechanisms used by pneumococci to evade host-sensing systems that are designed to contain the pathogen provide new insights into potential treatment options. Versatility of the genome of pneumococci and the bacteria's polygenic virulence capabilities show that a multifaceted approach with many vaccine antigens, antibiotic combinations, and immunoadjuvant therapies will be needed to control this microbe.
The seemingly inexorable spread of antibiotic resistance genes among microbial pathogens now threatens the long-term viability of our current antimicrobial therapy to treat severe bacterial ...infections such as sepsis. Antibiotic resistance is reaching a crisis situation in some bacterial pathogens where few therapeutic alternatives remain and pan-resistant strains are becoming more prevalent. Non-antibiotic therapies to treat bacterial infections are now under serious consideration and one possible option is the therapeutic use of specific phage particles that target bacterial pathogens. Bacteriophage therapy has essentially been re-discovered by modern medicine after widespread use of phage therapy in the pre-antibiotic era lost favor, at least in Western countries, after the introduction of antibiotics. We review the current therapeutic rationale and clinical experience with phage therapy as a treatment for invasive bacterial infection as novel alternative to antimicrobial chemotherapy.
IMPORTANCE: Definitions of sepsis and septic shock were last revised in 2001. Considerable advances have since been made into the pathobiology (changes in organ function, morphology, cell biology, ...biochemistry, immunology, and circulation), management, and epidemiology of sepsis, suggesting the need for reexamination. OBJECTIVE: To evaluate and, as needed, update definitions for sepsis and septic shock. PROCESS: A task force (n = 19) with expertise in sepsis pathobiology, clinical trials, and epidemiology was convened by the Society of Critical Care Medicine and the European Society of Intensive Care Medicine. Definitions and clinical criteria were generated through meetings, Delphi processes, analysis of electronic health record databases, and voting, followed by circulation to international professional societies, requesting peer review and endorsement (by 31 societies listed in the Acknowledgment). KEY FINDINGS FROM EVIDENCE SYNTHESIS: Limitations of previous definitions included an excessive focus on inflammation, the misleading model that sepsis follows a continuum through severe sepsis to shock, and inadequate specificity and sensitivity of the systemic inflammatory response syndrome (SIRS) criteria. Multiple definitions and terminologies are currently in use for sepsis, septic shock, and organ dysfunction, leading to discrepancies in reported incidence and observed mortality. The task force concluded the term severe sepsis was redundant. RECOMMENDATIONS: Sepsis should be defined as life-threatening organ dysfunction caused by a dysregulated host response to infection. For clinical operationalization, organ dysfunction can be represented by an increase in the Sequential Sepsis-related Organ Failure Assessment (SOFA) score of 2 points or more, which is associated with an in-hospital mortality greater than 10%. Septic shock should be defined as a subset of sepsis in which particularly profound circulatory, cellular, and metabolic abnormalities are associated with a greater risk of mortality than with sepsis alone. Patients with septic shock can be clinically identified by a vasopressor requirement to maintain a mean arterial pressure of 65 mm Hg or greater and serum lactate level greater than 2 mmol/L (>18 mg/dL) in the absence of hypovolemia. This combination is associated with hospital mortality rates greater than 40%. In out-of-hospital, emergency department, or general hospital ward settings, adult patients with suspected infection can be rapidly identified as being more likely to have poor outcomes typical of sepsis if they have at least 2 of the following clinical criteria that together constitute a new bedside clinical score termed quickSOFA (qSOFA): respiratory rate of 22/min or greater, altered mentation, or systolic blood pressure of 100 mm Hg or less. CONCLUSIONS AND RELEVANCE: These updated definitions and clinical criteria should replace previous definitions, offer greater consistency for epidemiologic studies and clinical trials, and facilitate earlier recognition and more timely management of patients with sepsis or at risk of developing sepsis.
Sepsis definitions: time for change Vincent, Jean-Louis, Prof; Opal, Steven M, Prof; Marshall, John C, Prof ...
Lancet,
03/2013, Letnik:
381, Številka:
9868
Journal Article
Recenzirano
Odprti dostop
...some degree of host response is actually inherent to the infection; indeed, this is an important component of the difference between infection and mere colonisation. ...the 1991 criteria for ...sepsis continue to be used.
IMPORTANCE: Sepsis is a heterogeneous syndrome. Identification of distinct clinical phenotypes may allow more precise therapy and improve care. OBJECTIVE: To derive sepsis phenotypes from clinical ...data, determine their reproducibility and correlation with host-response biomarkers and clinical outcomes, and assess the potential causal relationship with results from randomized clinical trials (RCTs). DESIGN, SETTINGS, AND PARTICIPANTS: Retrospective analysis of data sets using statistical, machine learning, and simulation tools. Phenotypes were derived among 20 189 total patients (16 552 unique patients) who met Sepsis-3 criteria within 6 hours of hospital presentation at 12 Pennsylvania hospitals (2010-2012) using consensus k means clustering applied to 29 variables. Reproducibility and correlation with biological parameters and clinical outcomes were assessed in a second database (2013-2014; n = 43 086 total patients and n = 31 160 unique patients), in a prospective cohort study of sepsis due to pneumonia (n = 583), and in 3 sepsis RCTs (n = 4737). EXPOSURES: All clinical and laboratory variables in the electronic health record. MAIN OUTCOMES AND MEASURES: Derived phenotype (α, β, γ, and δ) frequency, host-response biomarkers, 28-day and 365-day mortality, and RCT simulation outputs. RESULTS: The derivation cohort included 20 189 patients with sepsis (mean age, 64 SD, 17 years; 10 022 50% male; mean maximum 24-hour Sequential Organ Failure Assessment SOFA score, 3.9 SD, 2.4). The validation cohort included 43 086 patients (mean age, 67 SD, 17 years; 21 993 51% male; mean maximum 24-hour SOFA score, 3.6 SD, 2.0). Of the 4 derived phenotypes, the α phenotype was the most common (n = 6625; 33%) and included patients with the lowest administration of a vasopressor; in the β phenotype (n = 5512; 27%), patients were older and had more chronic illness and renal dysfunction; in the γ phenotype (n = 5385; 27%), patients had more inflammation and pulmonary dysfunction; and in the δ phenotype (n = 2667; 13%), patients had more liver dysfunction and septic shock. Phenotype distributions were similar in the validation cohort. There were consistent differences in biomarker patterns by phenotype. In the derivation cohort, cumulative 28-day mortality was 287 deaths of 5691 unique patients (5%) for the α phenotype; 561 of 4420 (13%) for the β phenotype; 1031 of 4318 (24%) for the γ phenotype; and 897 of 2223 (40%) for the δ phenotype. Across all cohorts and trials, 28-day and 365-day mortality were highest among the δ phenotype vs the other 3 phenotypes (P < .001). In simulation models, the proportion of RCTs reporting benefit, harm, or no effect changed considerably (eg, varying the phenotype frequencies within an RCT of early goal-directed therapy changed the results from >33% chance of benefit to >60% chance of harm). CONCLUSIONS AND RELEVANCE: In this retrospective analysis of data sets from patients with sepsis, 4 clinical phenotypes were identified that correlated with host-response patterns and clinical outcomes, and simulations suggested these phenotypes may help in understanding heterogeneity of treatment effects. Further research is needed to determine the utility of these phenotypes in clinical care and for informing trial design and interpretation.
Remarkable progress has been made during the last decade in defining the molecular mechanisms that underlie septic shock. This rapidly expanding field is leading to new therapeutic opportunities in ...the management of severe sepsis.
To provide the clinician with a timely summary of the molecular biology of sepsis and to better understand recent advances in sepsis research.
Medline search of relevant publications in basic mechanisms of sepsis/severe sepsis/septic shock, and selected literature review of other manuscripts about the signalosome, inflammasome, apoptosis, or mechanisms of shock. DATA SYNTHESIS AND FINDINGS: The identification of the toll-like receptors and the associated concept of innate immunity based upon pathogen- or damage-associated molecular pattern molecules allowed significant advances in our understanding of the pathophysiology of sepsis. The essential elements of the inflammasome and signal transduction networks responsible for activation of the host response have now been characterized. Apoptosis, mitochondrial dysfunction, sepsis-related immunosuppression, late mediators of systemic inflammation, control mechanisms for coagulation, and reprogramming of immune response genes all have critical roles in the development of sepsis.
Many of these basic discoveries have direct implications for the clinical management of sepsis. The translation of these "bench-to-bedside" findings into new therapeutic strategies is already underway. This brief review provides the clinician with a primer into the basic mechanisms responsible for the molecular biology of sepsis, severe sepsis, and septic shock.
The role of biomarkers for detection of sepsis has come a long way. Molecular biomarkers are taking front stage at present, but machine learning and other computational measures using bigdata sets ...are promising. Clinical research in sepsis is hampered by lack of specificity of the diagnosis; sepsis is a syndrome with no uniformly agreed definition. This lack of diagnostic precision means there is no gold standard for this diagnosis. The final conclusion is expert opinion, which is not bad but not perfect. Perhaps machine learning will displace expert opinion as the final and most accurate definition for sepsis.
In the past 50 years, the potential benefit of corticosteroids in treating sepsis or acute respiratory distress syndrome (ARDS) has been evaluated in many randomised controlled trials (RCTs). ...Corticosteroids significantly increased ventilator-free days during the first 28 days, but there was no benefit on 28-day mortality or length of stay in intensive care units, both tested as secondary endpoints. ...in Metcovid,10 a large phase 2b double-blind RCT with 416 patients with COVID-19, corticosteroids had no effect on mortality.
The emergence of multi-drug resistant (MDR) microbial pathogens threatens the very foundation upon which standard antibacterial chemotherapy is based. We must consider non-antibiotic solutions to ...manage invasive bacterial infections. Transition from antibiotics to non-traditional treatments poses real clinical challenges that will not be easy to solve. Antibiotics will continue to reliably treat some infections (e.g., group A streptococci and Treponema pallidum) but will likely need adjuvant therapies or will need to be replaced for many bacterial infections in the future.
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