Update on diagnosis and management of sepsis in cirrhosis: Current advances

Sepsis and septic shock are catastrophic disease entities that portend high mortality in patients with cirrhosis. In cirrhosis, hemodynamic perturbations, immune dysregulation, and persistent systemic inflammation with altered gut microbiota in the background of portal hypertension enhance the risk of infections and resistance to antimicrobials. Patients with cirrhosis develop recurrent life-threatening infections that progress to multiple organ failure. The definition, pathophysiology, and treatment options for sepsis have been ever evolving. In this exhaustive review, we discuss novel advances in the understanding of sepsis, describe current and future biomarkers and scoring systems for sepsis, and delineate newer modalities and adjuvant therapies for the treatment of sepsis from existing literature to extrapolate the same concerning the management of sepsis in cirrhosis. We also provide insights into the role of gut microbiota in initiation and progression of sepsis and finally, propose a treatment algorithm for management of sepsis in patients with cirrhosis.     

Community-acquired pneumonia and sepsis

Sepsis is a frequent and often fatal complication of pneumonia. This article discusses the epidemiology, pathophysiology, and treatment of sepsis in the setting of pneumonia. Particular consideration is given to the role of mechanical ventilation in amplifying organ dysfunction in sepsis and to treatments that have positive effects on sepsis mortality and respiratory dysfunction.     

Sepsis and septic shock: current approaches to management

Sepsis, defined as life‐threatening organ dysfunction due to a dysregulated host response to infection, is recognised by the World Health Organization as a global health priority. Each year, 5000 of the 18 000 adults with sepsis treated in Australian intensive care units die, with survivors suffering long‐term physical, cognitive and psychological dysfunction, which is poorly recognised and frequently untreated. There are currently no effective pharmacological treatments for sepsis, making early recognition, resuscitation and immediate treatment with appropriate antibiotics the key to reducing the burden of resulting disease. The majority of sepsis, around 70–80%, is community acquired making emergency departments and primary care key targets to improve recognition and early management. Case fatality rates for sepsis are decreasing in many countries with the reduction attributed to national or regional screening and quality improvement programmes focused on early identification and immediate treatment. The optimum approach to treating established sepsis has been informed by high‐quality, multicentre investigator initiated randomised trials with much of the valuable data coming from National Health and Medical Research Council‐funded trials run from Australia. While early recognition and improved management of the acute episode are important steps in reducing death and disability from sepsis, a substantial reduction in the burden of sepsis‐related disease requires action across the entire healthcare system. In this narrative review, we provide a summary of current knowledge on epidemiology of sepsis and septic shock and recommendations on the optimum approach to the management of these conditions in adults.     

Improving the outcome of septic shock in children

Sepsis is an important cause of pediatric morbidity and mortality. Improving the outcome of pediatric sepsis requires diverse efforts, including prevention, early recognition, improvements in early management and transport, and physiology-directed care. Awareness that septic shock represents a pathophysiologic host response to infection has prompted investigation of immune mediators and coagulation factors as potential targets for anti-sepsis therapies. Advancements thus far include: the potential prevention of neonatal sepsis with granulocyte colony-stimulating factor; recognition of clindamycin as a potential inhibitor of endotoxin release; improved outcome from meningococcal disease in children treated with bactericidal/permeability-increasing protein (rBPI21); and improved outcome from sepsis in premature infants treated with pentoxifylline. Further randomized controlled studies of immunomodulatory agents are indicated and a few are in progress. Current studies on genetic propensities in cytokine and coagulation protein expression may explain variability in patient outcomes and eventually lead to genomics-based therapeutics.     

Metabolic syndrome in children and adolescents: doubts about terminology but not about cardiometabolic risks

Metabolic syndrome (MS) has been a condition involved in considerable controversy, starting with the terminology. Gerald Reaven himself, the author who proposed the term MS, advised against the use of this terminology because the definition implies in at least three metabolic alterations, and it is never clear to which group of alterations we are referring to when we say that a patient has MS. In children, the problem is even more complicated, since there are many different adaptations to the criteria used in adults. On the other hand, independent of the terminology, cardiovascular risks are well-established and it is very clear that even children may present metabolic disturbances which predict future metabolic problems. The role of the pediatric endocrinologist or the general pediatrician is to investigate, especially in overweight/obese children, conditions that if treated early, may prevent future complications that today, unfortunately, are being diagnosed only in adult life. In this review, we discuss problems on the definition, epidemiology, pathophysiology, and complications of MS in children and adolescents.     

Septic shock,multiple organ failure,and acute respiratory distress syndrome

In 1914, Schottmueller wrote "Septicemia is a state of microbial invasion from a portal of entry into the blood stream which causes signs of illness." In the last few decades, the evidence that sepsis results from an exaggerated systemic inflammatory host response induced by infecting organisms is compelling; inflammatory mediators are the key players in the pathogenesis of septic shock and multiorgan failure. Sepsis and its sequelae represent a continuum of clinical syndrome encompassing systemic inflammation, coagulopathy, and hemodynamic abnormalities. Severe sepsis and septic shock continue to be the major causes of morbidity and mortality in the United States; sepsis deaths currently match mortality from myocardial infarction. Despite significant advances in our understanding of the pathophysiology and technological innovations in the supportive management, mortality from septic shock remains excessive. After many disappointments with strategies to manipulate the inflammatory response, modulation of coagulation cascade to decrease sepsis mortality has become a clinical reality. This review will highlight and discuss recent advances in the pathophysiology and management of sepsis.     

The management of pediatric systemic lupus erythematosus

Most children and adolescents with systemic lupus erythematosus (SLE) now survive into adulthood, leading the pediatric rheumatology community to focus on preventing long-term complications of SLE, including atherosclerosis, obesity, and osteoporosis, and their treatment. Unfortunately, because of the paucity of data in pediatric SLE, little is known about epidemiology, long-term outcome, and optimal treatment. Most research focuses on adults with SLE, but pediatric SLE differs significantly from adult SLE in many aspects, including disease expression, approaches to pharmacologic intervention, management of treatment toxicity, and psychosocial issues. Children and adolescents with SLE require specialized, multidisciplinary care. Treatment can be optimized by early recognition of disease flares and complications, minimizing medication toxicity, educating families about prevention, promoting school performance, addressing concerns about reproductive health, and negotiating the transition to adult-centered medical care. Developmentally appropriate concerns about pain, appearance, and peers often affect treatment adherence and must be addressed by the health-care team. Research in pediatric SLE is desperately needed and provides a unique opportunity to understand how developmental immunology and the hormonal changes associated with puberty affect the pathophysiology of SLE.     

New developments in childhood celiac disease

Celiac disease (CD) is one of the most common lifelong disorders in Europe and the United States, in both children and adults. It is an immune-mediated enteropathy triggered by the ingestion of gluten in genetically susceptible individuals. This review addresses new developments in CD with respect to pediatric patients and emphasizes the need for awareness among health-care professionals. The epidemiology, pathophysiology, diagnosis, and clinical spectrum of CD in children are highlighted.     

Primary thrombocytosis in children

Myeloproliferative neoplasms are uncommon disorders in children, for which we have limited understanding of the pathogenesis and optimal management. JAK2 and MPL mutations, while common drivers of myeloproliferative neoplasms in adult patients, are not clearly linked to pediatric disease. Management and clinical outcomes in adults have been well delineated with defined recommendations for risk stratification and treatment. This is not the case for pediatric patients, for whom there is neither a standard approach to workup nor any consensus regarding management. This review will discuss thrombocytosis in children, including causes of thrombocytosis in children, the limited knowledge we have regarding pediatric primary thrombocytosis, and our thoughts on potential risk stratification and management, and future questions to be answered by laboratory research and collaborative clinical study.     

Recent Developments in Pediatric Community-Acquired Pneumonia

Community-acquired pneumonia (CAP) is the most common acute infectious cause of death in children worldwide. Consequently, research into the epidemiology, diagnosis, treatment, and prevention of pediatric CAP spans the translational research spectrum. Herein, we aim to review the most significant findings reported by investigators focused on pediatric CAP research that has been reported in 2014 and 2015. Our review focuses on several key areas relevant to the clinical management of CAP. First, we will review recent advances in the understanding of CAP epidemiology worldwide, including the role of vaccination in the prevention of pediatric CAP. We also report on the expanding role of existing and emerging diagnostic technologies in CAP classification and management, as well as advances in optimizing antimicrobial use. Finally, we will review CAP management from the policy and future endeavors standpoint, including the influence of clinical practice guidelines on clinician management and patient outcomes, and future potential research directions that are in the early stages of investigation.     

Management of sepsis in neutropenic patients: 2014 updated guidelines from the Infectious Diseases Working Party of the German Society of Hematology and Medical Oncology (AGIHO)

Sepsis is a major cause of mortality during the neutropenic phase after intensive cytotoxic therapies for malignancies. Improved management of sepsis during neutropenia may reduce the mortality of cancer therapies. Clinical guidelines on sepsis treatment have been published by others. However, optimal management may differ between neutropenic and non-neutropenic patients. Our aim is to give evidence-based recommendations for haematologist, oncologists and intensive care physicians on how to manage adult patients with neutropenia and sepsis.     

Promotion of vascular integrity in sepsis through modulation of bioactive adrenomedullin and dipeptidyl peptidase 3

Sepsis represents one of the major medical challenges of the 21st century. Despite substantial improvements in the knowledge on pathophysiological mechanisms, this has so far not translated into novel adjuvant treatment strategies for sepsis. In sepsis, both vascular tone and vascular integrity are compromised, and contribute to the development of shock, which is strongly related to the development of organ dysfunction and mortality. In this review, we focus on dipeptidyl peptidase 3 (DPP3) and adrenomedullin (ADM), two molecules that act on the vasculature and are involved in the pathophysiology of sepsis and septic shock. DPP3 is an ubiquitous cytosolic enzyme involved in the degradation of several important signalling molecules essential for regulation of vascular tone, including angiotensin II. ADM is a key hormone involved in the regulation of vascular tone and endothelial barrier function. Previous studies have shown that circulating concentrations of both DPP3 and ADM are independently associated with the development of organ failure and adverse outcome in sepsis. We now discuss new evidence illustrating that these molecules indeed represent two distinct pathways involved in the development of septic shock. Recently, both ADM-enhancing therapies aimed at improving endothelial barrier function and vascular tone and DPP3-blocking therapies aimed at restoring systemic angiotensin responses have been shown to improve outcome in various preclinical sepsis models. Given the current lack of effective adjuvant therapies in sepsis, additional research on the therapeutic application of these peptides in humans is highly warranted.     

Sepsis in Older Adults in Long‐Term Care Facilities: Challenges in Diagnosis and Management

Despite the current understanding of the pathophysiology of sepsis and advances in its treatment, the rate of sepsis is increasing globally. Sepsis is a common cause of hospitalization in older adults, and infections are among the most common diagnoses among residents transferred to the hospital from long‐term care facilities (LTCFs). LTCFs and hospitals are facing financial and regulatory requirements to reduce potentially preventable emergency department visits, hospitalizations, and hospital readmissions due to infections and other causes. In addition, the human and financial costs of these events are substantial. Current criteria for early identification of sepsis have low sensitivity and specificity among LTCF residents. Early diagnosis must focus on changes in clinical, mental, and functional status, and vital signs including pulse oximetry. Laboratory data can increase the suspicion of sepsis, but the availability of testing and timing of results limits its usefulness in most LTCFs.While new diagnostic criteria for sepsis are being developed and validated in the LTCF setting, clinical practice and decision support tools are available to guide management. Most LTFCs do not have the capabilities to manage sepsis based on current guidelines despite availability of qualified nursing staff and clinicians. Thus excluding circumstances in which a resident's desire is palliative or hospice care without transfer to a hospital, most LTCFs will continue to transfer residents with severe infections at risk for evolving into sepsis to an acute hospital setting. J Am Geriatr Soc 67:2234–2239, 2019     

Anatomical and functional evaluation of pulmonary veins in children by magnetic resonance imaging

Pulmonary vein pathologies often present a diagnostic challenge. Among the different imaging modalities used for the evaluation of pulmonary veins, magnetic resonance is the most comprehensive in assessing anatomy and pathophysiology at the same time. Bright blood cine sequences and contrast-enhanced magnetic resonance angiography outline the course and connections of the pulmonary veins. Phase-contrast velocity mapping measures flow patterns, velocities, and volumes throughout the pulmonary circulation. This paper reviews contemporary utilization of magnetic resonance in the evaluation of pulmonary venous abnormalities in children, based on our experience over the last 5 years and on that of other investigators. We summarize how magnetic resonance imaging enhances our understanding of pulmonary vein physiology and how it can influence the diagnostic approach to children and adults with a pulmonary venous pathology, and we discuss its limitations.     

Anatomical and functional evaluation of pulmonary veins in children by magnetic resonance imaging.

Pulmonary vein pathologies often present a diagnostic challenge. Among the different imaging modalities used for the evaluation of pulmonary veins, magnetic resonance is the most comprehensive in assessing anatomy and pathophysiology at the same time. Bright blood cine sequences and contrast-enhanced magnetic resonance angiography outline the course and connections of the pulmonary veins. Phase-contrast velocity mapping measures flow patterns, velocities, and volumes throughout the pulmonary circulation. This paper reviews contemporary utilization of magnetic resonance in the evaluation of pulmonary venous abnormalities in children, based on our experience over the last 5 years and on that of other investigators. We summarize how magnetic resonance imaging enhances our understanding of pulmonary vein physiology and how it can influence the diagnostic approach to children and adults with a pulmonary venous pathology, and we discuss its limitations.     

Clostridium difficile in children: colonisation and disease

Clostridium difficile is the commonest cause of hospital acquired diarrhoea in adults and is associated with significant mortality and morbidity. The clinical significance of C. difficile in children, however, is less certain. In this article we discuss colonisation and infection and describe C. difficile in childhood in terms of risk factors, epidemiology and management.     

Adult Hyperglycemic Crisis: A Review and Perspective

Hyperglycemic crisis, which includes Diabetic Ketoacidosis and Hyperglycemic Hyperosmolar State, is a common diagnosis in high acuity hospital units and admission rates continue to increase despite preventive strategies. While diabetic ketoacidosis remains a common cause of death in children and adolescents with type 1 diabetes, in adults reported mortality is variable and depends on the severity of metabolic derangement and the presence of other acute and chronic conditions. Hyperosmolar hyperglycemic state, and the overlap syndrome of hyperosmolar ketoacidosis, have a higher overall mortality though outcomes are improving. We discuss the diagnosis, epidemiology, and management strategies with particular reference to commonly encountered pitfalls in care and provide an updated perspective on the shifts in the epidemiology and novel management strategies for these important disorders.     

Epidemiology of sepsis: Recent advances

Sepsis, as defined by an expert consensus definition, is the development of the systemic inflammatory response syndrome in the presence of infection. Using this clinically applicable definition, several studies have evaluated the epidemiology of sepsis over the past decade. The current incidence of sepsis is at least 240 patients per 100,000 people in the United States population, whereas for severe sepsis it is between 51 and 95 patients per 100,000 people. The incidence rate for sepsis has been increasing over the past two decades, driving an increase in the number of deaths despite a decline in case-fatality rates. Sepsis is the tenth leading cause of death in the United States and accounts for more than 17 billion dollars in direct healthcare expenditures.     

How I manage haematology patients with septic shock

Patients with a variety of haematological conditions are at risk of infection and its most serious complication: septic shock. Mortality for septic shock remains high and especially so in patients with haematological malignancy and following bone marrow transplantation. However, advances in the treatment of severe sepsis have improved mortality rates even though evidence for the management of severe sepsis in haematology patients is limited. Wherever possible this review will concentrate on evidence directly applicable to haematology patients but inevitably will have to extrapolate evidence from other patient groups. The Surviving Sepsis Guidelines 2008 provide information on best practice in the management of patients with severe sepsis and septic shock and are broadly applicable though not specific to haematology patients. This review summarizes a practical approach to the management of severe sepsis in haematology patients and highlights areas of research which may bring new treatments in the future. The review is limited to the management and initial resuscitation of septic shock in adult haematology patients and will not address the detailed intensive care management of these patients or the management of severe sepsis in children.     

小儿脓毒症心肌损伤机制的研究进展

脓毒症是由感染引起的严重威胁儿童生命的危重症之一，临床救治困难，已成为影响脓毒症患儿预后的重要影响因素。近年对其发生机制进行了深入探讨，本文从免疫学、细胞代谢等角度对脓毒症患儿心肌损伤的分子生物学机制研究新进展做一综述。