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World Sepsis Day: a global agenda to target a leading cause of morbidity and mortality

2020; American Physical Society; Volume: 319; Issue: 3 Linguagem: Inglês

10.1152/ajplung.00369.2020

1522-1504

Luregn J. Schlapbach, Niranjan Kissoon, Abdulelah Alhawsawi, Maha Aljuaid, Ron Daniels, Luis A. Gorordo-Delsol, Flávia Ribeiro Machado, Imrana Malik, Emmanuel Nsutebu, Simon Finfer, Konrad Reinhart,

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EditorialWorld Sepsis Day: a global agenda to target a leading cause of morbidity and mortalityLuregn J. Schlapbach, Niranjan Kissoon, Abdulelah Alhawsawi, Maha H. Aljuaid, Ron Daniels, Luis A. Gorordo-Delsol, Flavia Machado, Imrana Malik, Emmanuel Fru Nsutebu, Simon Finfer, and Konrad ReinhartLuregn J. SchlapbachChild Health Research Centre, The University of Queensland and Queensland Children's Hospital, Brisbane, Queensland, AustraliaDepartment of Intensive Care Medicine and Neonatology, and Children's Research Center, University Children's Hospital of Zurich, University of Zurich, Zurich, Switzerland, Niranjan KissoonChildren's and Women's Global Health, University of British Columbia and British Columbia Children's Hospital, Vancouver, British Columbia, Canada, Abdulelah AlhawsawiSaudi Patient Safety Center–Director General, Riyadh, Saudi Arabia, Maha H. AljuaidKing Abdulaziz Medical City, Ministry of National Guard Health Affairs, Riyadh, Saudi Arabia, Ron DanielsDepartment of Critical Care, University Hospitals Birmingham NHS Foundation Trust, Birmingham, United Kingdom, Luis A. Gorordo-DelsolAdult Intensive Care Unit, Hospital Juárez de México, Juarez, Mexico, Flavia MachadoGlobal Sepsis Alliance, Sao Paolo, Brazil, Imrana MalikDepartment of Critical Care, The University of Texas, Anderson Cancer Center, Houston, Texas, Emmanuel Fru NsutebuInfectious Diseases Division, Sheikh Shakhbout Medical City, Abu Dhabi, United Arab Emirates, Simon FinferThe George Institute for Global Health, University of New South Wales, Sydney, New South Wales, Australia, and Konrad ReinhartDepartment of Anesthesia and Surgical Intensive Care Medicine, Charité Universitätsmedizin, Berlin, GermanyPublished Online:04 Sep 2020https://doi.org/10.1152/ajplung.00369.2020This is the final version - click for previous versionMoreSectionsPDF (98 KB)Download PDFDownload PDFPlus ToolsExport citationAdd to favoritesGet permissionsTrack citations ShareShare onFacebookTwitterLinkedInEmail WORLD SEPSIS DAYEach year, on September 13, the World Sepsis Day highlights the massive burden sepsis imposes on global health and serves to shed light on local, national, and international initiatives against sepsis. Sepsis is a devastating condition resulting from dysregulated host response to infection which leads to organ failure and death (44). Each year sepsis affects close to 50 million people of which more than 40% are among children under age 5, and the burden is concentrated in low and middle income countries. Overall, sepsis causes or contributes to over 11 million deaths each year (36). Mortality remains elevated post discharge, in particular in infants in low income settings (21, 26). Sepsis is also a leading cause of death in high income countries, despite access to effective vaccination, preventive care, and high-level health care including intensive care services. In the United States, Centers for Disease Control and Prevention (CDC) and US Department of Health data show that sepsis affects 1.76 million adults and claims 260,000 lives annually (31). In Europe, extrapolation of the population-based sepsis incidence rate in Sweden indicates that each year approximately 3.4 million people suffer sepsis resulting in 680,000 deaths (24). At present, hospital mortality rates for severe sepsis differ several fold even between high income countries such as Australia, England, the United States, and Germany (12) which is likely to relate to different epidemiology, socioeconomic population structure, and the presence and efficacy of quality improvement programs on infections and sepsis. Yet, in contrast to effective campaigns which have been well established for diseases such as acquired immunodeficiency syndrome (AIDS) caused by the human immuodeficiency virus (HIV), cancer, myocardial infarction, and stroke, efforts to tackle sepsis vary enormously and fall short in addressing the magnitude and complexity of the problem in most jurisdictions.The Global Sepsis Alliance (GSA) is dedicated to reducing the impact of sepsis on the health of children and adults, and coordinates national and international efforts against sepsis. The first World Sepsis Day and the first World Sepsis Declaration occurred in 2012 as initiatives of the GSA. At that time, there was no sepsis information on the websites of national public health entities and sepsis did not feature in the Global Burden of Disease Report. Only a small minority of citizens were familiar with the term sepsis (34). According to a recent poll in Germany only 17% of citizens were aware that vaccination may help prevent sepsis, 23% thought that sepsis results from an allergic reaction, and the majority of respondents were of the opinion that a red stripe on the arm is the key symptom of sepsis (8). As a result of strong advocacy from the GSA and key stakeholders, on May 24, 2017, the World Health Assembly (WHA) adopted a resolution urging member states to improve the prevention, diagnosis, and management of sepsis (29). This resolution was an important milestone in the fight against sepsis acknowledging that sepsis is a leading cause of mortality and long-term morbidity, both of which can be mitigated through early diagnosis and appropriate and timely clinical management. The resolution declared the need to improve measures for the prevention of infections and control of the consequences of sepsis, due to inadequate infection prevention and control, insufficient health education, and recognition in respect of early sepsis, inadequate access to affordable, timely and appropriate treatment and care, and insufficient laboratory services, as well as the lack of integrated approaches to the prevention and clinical management of sepsis. Thanks to the WHA sepsis resolution we have witnessed in the past years a shift in the level of data collection, concertation of efforts, and publications on sepsis. Yet, the manifold challenges imposed by sepsis require increased local, national, and international efforts in coming years to lead to substantial change. Unfortunately, to date, less than 10% of WHA/World Health Organization (WHO) member states have declared sepsis as a health priority.A HISTORICAL PERSPECTIVESepsis, representing the final common pathway of invasive infections overwhelming the host defense leading to death, has challenged the human species for thousands of years. The term sepsis stems from the Greek word indicating rotting or putrification. The availability of antibiotics and modern principles of hygiene, such as hand washing and anti-sepsis to reduce childbed fever during 19th century, led to a dramatic increase in survival rates. Vaccinations targeting diphtheria, pneumococcal, meningococcal, and Hemophilus influenzae type B have decreased deaths due to these vaccine-preventable bacterial infections. Large recent epidemiological studies have provided insight into the ongoing high prevalence of sepsis, indicating an increasing proportion of vulnerable patients due to extremes of age, complex comorbidities, and aggressive medical therapies. Although advanced hemodynamic, respiratory, and extracorporeal support techniques have enabled improved survival rates, mortality in recent cohorts of intensive care patients with septic shock still ranges between 10 and 50% (20, 38, 47, 49).RECENT INSIGHTS INTO THE TRUE SEPSIS BURDENA large body of epidemiological data demonstrated massive shortcomings in past estimates of sepsis incidence and outcomes (10–13, 16). Diagnostic coding has been shown to be highly unreliable (35) as sepsis may not be diagnosed by treating teams and as coders often list specific infections such as pneumonia rather than sepsis including notifications on death certificates. For the first time in 2020, the Global Burden of Disease program provided a comprehensive assessment of the burden of sepsis which demonstrated much higher sepsis incidence than previously reported (36). Using standardized methodology, the report estimated that in 2017, sepsis accounted for or was involved in 19.7% of all global deaths.Importantly, approximatively a third of sepsis survivors and their families experience substantial burden persisting after discharge from hospital (46). Post-sepsis syndrome has been increasingly recognized as a major contributor to poor long-term health after critical illness (19, 25) which includes sequelae affecting physical, mental, and psychological health in all age groups, affecting long-term development of neonates and children with an impact lasting decades (4, 37). In the United States, the inpatient admission and subsequent skilled nursing facility costs for sepsis in Medicare beneficiaries have risen up to 62 billion USD in 2018 (5). The full societal impact of sepsis due to reduced productivity of survivors, dependency on support in everyday life, and the multiplying effect on carers, siblings, and children has not been reliably assessed but is likely to exceed the direct sepsis costs several fold (27, 28). In contrast to myocardial infarction or cerebral stroke, where the benefits of early rehabilitation are well recognized, current health care systems lack structures to support and rehabilitate sepsis survivors and their families to mitigate these detrimental long-term effects.QUALITY IMPROVEMENT INITIATIVES TO PREVENT AND TREAT SEPSISThe concept of a "Golden Hour" is well established in diseases such as trauma, indicating a window of opportunity when effective and concerted interventions are more likely to alter the trajectory of the disease, save lives, and reduce subsequent disability. Accordingly, awareness and intervention campaigns serving to educate the public to promote earlier presentation to health practitioners, structured education of the health workforce to enable timely recognition, and protocolized care to improve consistency and reliability of treatment are considered best practice in these areas. Similarly, extensive evidence demonstrates substantially improved patient outcomes if sepsis and septic shock are recognized and treated within no more than one hour for septic shock and up to three hours for sepsis, respectively (32, 50). Each hour delay to delivering the sepsis treatment bundle was associated with an increase in mortality in a large cohort in New York state, where mandates for sepsis care were established in 2013, likely saving thousands of lives (41). In children, the observed effect size of sepsis bundle delivery within one hour leading was a 41% relative mortality risk reduction (9). Strikingly, the observations from the New York state, admittedly one of the health care systems with the most developed sepsis systems coupled with legislative, organizational, and financial incentives, demonstrate substantial variability of risk-adjusted care across institutions (41).Encouragingly, the WHA resolution is leading to an increasing number of countries and regions promoting systematic approaches to sepsis awareness, prevention, and intervention (39), such as the United Kingdom, United States, Canada, Brazil, Mexico, Ireland, Spain, Germany, Kingdom of Saudi Arabia, the Emirates, Sudan, Uganda, Nigeria, Malawi, and Kenya. On World Sepsis Day 2019 the Governments of Australia, France, and Sweden announced national sepsis campaigns. It is imperative that the lessons learned from these efforts can be shared and adapted to facilitate cost-effective change of practice extending to the areas where sepsis burden is highest and resources are lowest (23).SEPSIS AND ANTIMICROBIAL STEWARDSHIPTimely appropriate antimicrobial therapy represents the cornerstone of effective sepsis therapy and at the same time meets a key requirement for antimicrobial stewardship (33, 50). In adult patients, the effect of sepsis bundles on reduced mortality was attributable primarily to the delivery of antimicrobials within three hours of sepsis recognition (41). Similarly, in children with sepsis and septic shock, several cohorts reported substantially better outcomes in those who received timely intravenous antibiotics (48). The Surviving Sepsis Campaign recommends initiating treatment with broad-spectrum antibiotics covering the main likely pathogens, followed by narrowing to targeted therapy if a pathogen or source is identified, and stopping antimicrobial therapy if bacterial or fungal infection is not likely to be the etiology. Importantly, sepsis recommendations are intended for patients where infection-related organ dysfunction, in particular shock, is present, and should not be blindly applied to patients without organ dysfunction or shock—where sepsis is one of several considerations (18a). Indiscriminate administration of early antibiotics to undifferentiated cohorts of patients presenting with fever or infections to hospitals or community health services is not only unnecessary but may lead to increased costs and adverse effects on the patients or the community, such as the spread of increased antimicrobial resistance. Over the past years, a stimulating controversy about the importance of balancing measures in sepsis quality improvement initiatives has ensued (22, 30, 40, 45). A fact that has been overlooked sometimes is that the aims of sepsis campaigns in fact closely align with the global agenda on antimicrobial stewardship—delivering the right antimicrobial for the right patient and stopping antibiotics where they are no longer necessary.DECIPHERING DYSREGULATED HOST RESPONSEThe discrimination of sepsis from uncomplicated infections, and the heterogeneity of disease represent disease-related obstacles towards designing targeted therapies (42). Heterogeneity may result from patient factors (comorbidities, age, indwelling devices), pathogen factors (virulence and resistance profiles), the variable stages of disease presentation and progression, and differences in host response. The concept of dysregulated host response to infection leading to life-threatening organ dysfunction (2) has broad merit, but to date we lack clinical or biochemical markers to reliably measure a dysregulated host response and the associated dynamics in immune (dys-) regulation (17). First approaches to individualized care using monoclonal antibodies targeting specific pathways (18) demonstrate the feasibility of highly personalized treatments of host response in sepsis and carry promise for the coming decades. However, these are unlikely to become available for the majority of global patients suffering from sepsis.SEPSIS AND THE CORONAVIRUS DISEASE 2019 PANDEMICThe 2020 World Sepsis Day occurs at a time when mankind faces one of the greatest pandemics of recent times. Coronavirus disease 2019 (COVID-19), the clinical syndrome resulting from infection with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus, was recognized in late 2019. To date over half a million deaths across the globe, predominantly affecting the elderly and those with major comorbidities, have been attributed to COVID-19 (3). The COVID-19 crisis reminds the global community that infectious diseases continue to represent a leading global health threat. While the majority of patients infected with COVID-19 remain either asymptomatic or recover spontaneously without assistance (15), a proportion of patients progress to organ dysfunction with substantial risk of death. Multiple mechanisms have been identified in COVID-19 which result in organ dysfunction, such as endothelial dysfunction, hypercoagulopathy with impaired microcirculation, vasodilatory shock, depressed myocardial function, and hyperactivation of the immune system. COVID-19 tragically illustrates the pathways through which sepsis can develop as a result of both bacterial and viral infections. Severe COVID-19 disease manifests classic features of sepsis such as respiratory failure, cardio-circulatory shock, and altered mentation (1), and organ damage in severe COVID-19 disease seems to result from dysregulated host response, with anti-inflammatory strategies such as dexamethasone showing first promise (30). In addition, a substantial proportion of patients succumbing to COVID-19 develop bacterial infection, aggravating the primary insult. Accordingly, principles of sepsis management for the sickest patients with COVID apply. Tragically, the pandemic has illustrated the impact of sepsis-related organ dysfunction on patient outcomes spanning from mortality to long-term sequelae (43), and the tremendous dependency on intensive care resources pending introduction of effective vaccines and antiviral strategies.SEPSIS: A ROAD MAP FOR THE NEXT DECADEDespite an improved awareness and evidence base for sepsis subsequent to the 2017 WHA resolution, much remains to be done. Incentives and initiatives at government, industry, healthcare, and academic levels are needed to develop more effective and sustainable system improvements in prevention, treatment, and follow-up of patients with sepsis across all age groups, countries, and populations. Gaps in knowledge on sepsis genetics, pathophysiology, monitoring, and drug development represent scientific target areas to enable the shift towards personalized care (6, 7). At the same time, recognizing the tremendous gaps in resourcing across the globe, pragmatic and SMART (Isotonic Solutions and Major Adverse Renal Events Trial) goals for international efforts against sepsis are required. In the next decade, implementation of the WHO declaration of sepsis should lead to:reduced global incidence of sepsis thanks to improved prevention of infection, and through improved infection management at policy levelincreased sepsis survival rates across all age groups in all countries through the promotion and adoption of early recognition systems and standardized emergency treatmentbetter access to appropriate rehabilitation services for all patients and families with sepsis worldwideimproved public and professional understanding and awareness of sepsismore accurate measurement of the global burden of sepsis and the impact of sepsis control and management interventionsIn summary, sepsis is a potentially preventable disease the outcomes of which strongly depend on the quality and timeliness of treatment. Sepsis accounts for far more deaths than road traffic accidents or myocardial infarction. The next decade should witness a paradigm shift in sepsis prevention and care at individual, institutional, societal, and political levels.GRANTSThis work was supported in part by the National Health and Medical Research Council, Children's Hospital Foundation, and Charité Foundation.DISCLOSURESL.J.S. is supported by a National Health and Medical Research Council Practitioner Fellowship and by the Children's Hospital Foundation, Brisbane, Australia. L.A.G.-D. reports personal fees from Pfizer de México SA de CV, personal fees from Merck Sharp & Dohme S de RL de CV, personal fees from Abbott Laboratorios de México SA de CV, outside the submitted work. K.R. holds shares of InflaRx NV (Jena, Germany), a biotech company that evaluates an antibody against C5a in patients with COVID-19. All of the authors work on the Global Sepsis Alliance Executive Committee. 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