Open Access
Open Peer Review

This article has Open Peer Review reports available.

How does Open Peer Review work?

Community-onset sepsis and its public health burden: protocol of a systematic review

Systematic Reviews20154:119

DOI: 10.1186/s13643-015-0103-6

Received: 26 June 2015

Accepted: 19 August 2015

Published: 23 September 2015

Abstract

Background

Sepsis is a life-threatening condition and major contributor of public health and economic burden in the industrialised world. The heterogeneity, absence of more specific definition, and difficulties in accurate diagnosis lead to great variability in the estimates of sepsis incidence. There has been uncertainty regarding the incidence and risk factors attributable to community-onset as opposed to hospital-acquired sepsis. Community-onset sepsis has distinct host characteristics, risk factors, pathogens, and prognosis. A systematic assessment of recent evidence is warranted in light of secular changes in epidemiology, pathogens, and the uncertainties around the incidence and risk factors of community-onset sepsis.

This protocol describes a systematic review which aims to synthesise the recent empirical evidence on the incidence and risk factors of community-onset sepsis, severe sepsis, and septic shock in high-income countries.

Methods/Design

English-language publications of cohort and case-control studies reporting incidence and risk factors of community-onset sepsis will be eligible for inclusion. MEDLINE and Embase databases will be searched from 2002 and onwards. References of relevant publications will be hand-searched. Two reviewers will independently screen titles/abstracts and full texts as well as extract data and appraise the risk of bias of included studies. The data extractions and risk of bias assessments will be cross-checked. Any disagreements will be resolved via consensus.

The data on incidence and risk factors of sepsis will be organised and synthesised in text, tables, and forest plots. The evidence will be pooled given sufficient data and degree of similarity across study populations, exposures, and outcomes. The heterogeneity will be assessed through visual inspection of forest plots, Chi-square-based p value, and I2 statistic. The sources of heterogeneity will be explored via subgroup analysis.

Discussion

Timeliness and accuracy of diagnosis of sepsis are both crucial aspects for improving the patient’s outcome. The findings of this review will be discussed with a view to better inform future recommendations on improving public-facing campaigns, timely presentation, and diagnosis of sepsis in the community. The review will also discuss gaps in evidence and highlight future research and policy-making avenues for improving public health planning.

Systematic review registration

PROSPERO CRD42015023484

Keywords

Community-onset sepsis Risk factors Incidence of sepsis or severe sepsis

Background

Context for this review

The UK Department of Health allocated the task to ‘Review the evidence and make recommendations on the scope for a public-facing campaign to raise awareness of Sepsis.’ (https://www.gov.uk/government/publications/phe-remit-letter-2015-to-2016) to Public Health England in the 2015–2016 remit letter to PHE. The University of Warwick was requested to synthesise relevant evidence including estimating the burden of community-onset sepsis and groups affected by community-onset sepsis. This is the motivation for this work.

Health and economic burden

Sepsis is a complex life-threatening condition characterised by the host’s systemic anti-inflammatory immune response to infection, which may lead to organ damage, organ failure, septic shock, and death [1]. Sepsis with its associated complications remains a major public health and economic burden in the industrialised world [2]. Outcomes of sepsis may have serious short- or long-term consequences such as amputation, damage to organs, or cognitive dysfunction. In the US, treatment of a patient with sepsis may cost up to $50,000, translating to an annual nationwide economic burden of $17 billion [3, 4]. In European studies, the treatment of severe sepsis in 2002 was estimated to be approximately £25,000 [5]. Assuming the incidence of 100,000 new cases per year, the UK’s National Health System (NHS) expenditure for caring these cases would amount to £2.5 billion annually [6].

Data on global incidence of sepsis is scarce but has been growing over the past two decades, with the majority of studies identifying sepsis cases from intensive-care unit (ICU) data [4]. The estimates of sepsis incidence are highly variable. This is likely due to the heterogeneous nature, lack of a uniform definition, and difficulties in the accurate diagnosis of the condition as well as the differences in data sources (e.g. clinical registries, hospital discharge databases, or vital statistics records), periods of follow-up time, and methods of estimation used across studies. Moreover, secular changes and genuine differences in the incidence of sepsis across study populations may have additionally contributed to the observed variability. For example, one systematic review [7] reported the following ranges of annual incidence for sepsis (149–240 per 100,000 population) and severe sepsis (56–91 per 100,000 population). Another more recent systematic review of 33 epidemiologic studies conducted in 15 high-income countries [8] estimated and reported an average incidence of 427 (95 % CI 281, 648) for sepsis and 331 (95 % CI 207, 530) for severe sepsis cases per 100,000 person-years.

Large nationwide cohort studies conducted in five high-income countries (the USA, the UK, France, Australia, and New Zealand) in 1995–2002 showed a wide variation in the annual incidence of severe sepsis, ranging from 51 [9] to 300 [3] cases per 100,000 population [4, 3, 911]. The study by Padkin et al. [9] which reviewed data from 91 ICUs across England, Wales, and Northern Ireland reported an annual incidence of 51 cases of severe sepsis per 100,000 persons. These findings are in agreement with another UK-based cohort study which reported an incidence of 66 cases per 100,000 per population [12]. More recent studies conducted in Europe reported lower incidence rates of 38 [13] and 25 cases [14] per 100,000 population. Although variable, the results of these nationwide cohort studies nonetheless all indicate that severe sepsis is a common disorder [2].

Recent estimates of case-fatality rates for sepsis ranged from 14.7 % [15] to 28.6 % [3] in the US-based studies [3, 4, 15] and from 35.0 % [11] to 53.6 % [16] in European studies [11, 16, 10, 9, 5]. Almost one third of all ICU admissions in the UK are related to sepsis and about half of these patients die [9]. In their study [17], McPherson and colleagues reported that one in 20 deaths in England in 2001–2010 was associated with sepsis. These figures may underestimate the true mortality rate. Sepsis is often underreported as a cause of death because of the absence of the sepsis-specific International Classification of Diseases, 10th Revision (ICD-10) codes. Therefore, the sepsis-related deaths are often coded as deaths caused by kidney infection, pneumonia, influenza, or meningitis [17].

Over the past two decades, there has been accumulation of empirical evidence showing a gradual increase (8–13 % per year) in the incidence of sepsis in high-income countries (e.g. the UK, Australia, Croatia) [18], especially in the USA [4, 12, 19]. For example, one UK-based cohort study found an increase in annual incidence of severe sepsis from 46 (in 1996) to 66 cases per 100,000 per population between 1996 and 2003 [12]. In contrast to the incidence data, the mortality (i.e. case-fatality rate) after sepsis in high-income countries has been decreasing [15, 20]. For example, one US-based study reported the decrease in case-fatality rate of sepsis from 27.8 % (1979–1984) to 17.9 % (1995–2000) [4]. Similarly, in their ICU-based study [12], Harrison et al. showed a significant decrease in mortality rate from 48.3 % (in 1996) to 44.7 % (in 2004). The observed trends of rising incidence could be due to increased proportions of high-risk population subgroups (e.g. elderly, type-II diabetes, antibiotic resistance, cancer), improvements in methods of detection [21, 22], and the falling mortality rates due to identification of less severe forms of sepsis (in light of the improved methods of detection) [21, 22] and/or advancements in the treatment of sepsis [23, 12, 22]. In spite of the reduced case-fatality rates, the total annual number of sepsis-related deaths has been rising, perhaps owing to the increased incidence of sepsis [18]. Over the last two decades, Gram-positive bacteria have superseded Gram-negative bacteria as the most common cause of sepsis as further evidence of the changing biology of this condition [18].

Definition and diagnosis

Sepsis treatment is time-critical, which necessitates timely diagnosis and rapid provision of appropriate management options. However, this is made difficult owing to the heterogeneity of this condition, often characterised by non-specific clinical features. The current definition of ‘sepsis’ which was introduced in 1991 [24] encompasses the presence of infection and more than one of the Systemic Inflammatory Response Syndrome (SIRS) criteria including the following: a) body temperature [>38 or <36 °C], b) heart rate [>90 beats/min], c) hyper-ventilation [respiratory rate >20 breaths/min or PaCo2 < 32 mmHg], and d) white blood cell count [>12,000 cells/μL or <4000 cells/μL]. According to this definition, ‘sepsis’ with organ dysfunction and ‘sepsis’ with acute circulatory failure with arterial hypotension have been termed as ‘severe sepsis and ‘septic shock’, respectively [1]. Although the joint presence of infection and SIRS criteria has been widely adopted, their utility as a diagnostic tool for identifying sepsis has been recognised to be limited owing to high sensitivity and low specificity of these criteria (i.e. they may manifest in the absence of infection, in patients with severe trauma, burns, and other inflammatory disorders such as pancreatitis) [25, 18].

In 2001, the American College of Chest Physicians (ACCP) and the Society of Critical Care Medicine (SCCM) convened a consensus conference and updated the definition of sepsis by expanding the list of markers potentially related to sepsis (e.g. inflammatory response, hemodynamic, organ dysfunction, and tissue perfusion parameters) [1]. One important outcome of this conference was the introduction of a ‘Predisposition, Infection, Response, and Organ Dysfunction’ (PIRO) system for staging sepsis. For the purpose of improving the diagnosis of sepsis, some authors suggested that the original definition of sepsis should additionally incorporate an evidence of organ dysfunction which is a more specific sign to sepsis or severe sepsis [21, 25]. The original definition adopted in 1991 [24] is still widely used. The difficulties in case definition and variations in the definitions used substantially complicate the comparison and synthesis of findings across studies.

Risk factors and high-risk population subgroups

Several studies examined age, sex, and race disparities for developing sepsis and demonstrated that men compared to women are more likely to have sepsis or severe sepsis [4, 9, 11, 10, 26]. Similarly, African-Americans are at higher risk for developing severe sepsis compared to Caucasians (adjusted relative risk range 1.40–1.89) [4, 27, 28]. Moreover, older age [19, 29] and certain chronic medical conditions (HIV, alcohol abuse, cancer, lung/kidney disease, myocardial infarction, diabetes, stroke, deep vein thrombosis, coronary artery disease, hypertension) [29, 2, 30, 26] have also been shown to be associated with a significantly greater risk for sepsis. In their study, Hall et al. observed a 30-fold increase in the incidence rate of sepsis or septicaemia amongst people >85 years vs. those ≤65 years (271.2 per 10,000 vs. 9.5 per 10,000) [19]. In one US-based nationwide cohort study, the risk of sepsis in cancer patients was almost 10 times as high compared to the US general population without cancer (age- and sex- adjusted RR = 9.77, 95 % CI 9.67, 9.88) [30].

Community-onset and hospital-acquired sepsis

Traditionally, sepsis has been classified into community-onset and hospital-acquired (i.e. nosocomial) infection, depending on the place of the infection’s acquisition [31, 32]. The two contexts of sepsis acquisition differ in terms of the host characteristics (e.g. demographics, risk profile, resistance patterns), pathogens, and outcomes [3336]. For example, in their study, Hoenigl and colleagues observed a significantly higher 30-day (20.75 vs. 11.20 %, p = 0 · 001) and 90-day (26.83 vs. 12.63 %, p < 0 · 001) mortality rates in people with hospital-acquired vs. community-onset infection [34].

More recently, with increasing number of sepsis cases associated with outpatient treatment that takes place in communities (e.g. nursing homes, dialysis, long-term home care facilities), a new category of healthcare-associated sepsis has been recognised and introduced [37, 38]. According to the definition of healthcare-associated sepsis, the patient had to have received a medical care in the community/outpatient setting (e.g. intravenous therapy, wound care) 30 days before the bloodstream infection, hospitalisation in acute care hospital 90 days before the bloodstream infection, attendance of hospital or haemodialysis clinic, or residence in a nursing home or a long-term care facility [37]. Although nosocomial and healthcare-associated sepsis are similar with respect to source of infection, type of pathogens, susceptibility, and the outcome, emerging empirical evidence has shown them to be two distinct entities. Therefore, community-onset sepsis has been further divided into healthcare-associated and community-acquired sepsis [3739, 34, 35].

The definition of community-onset sepsis has not been consistent in the literature [39]. The most often used and widely accepted definition specifies community-onset sepsis as one that manifests (positive blood culture and systemic inflammatory response syndrome criteria) before or within 48 h after hospital admission [31, 37, 34, 40, 36, 41]. According to this definition, a nosocomial (hospital-acquired) infection is one that manifests more than 48 h after hospitalisation [37, 34, 40, 36, 41].

One important gap in the sepsis literature is the scarcity of evidence on the incidence of sepsis as opposed to severe sepsis for which evidence is more abundant [18]. Another limitation is that the majority of studies have used hospital discharge databases which do not allow to distinguish the findings between community-onset and hospital-acquired sepsis, which as noted above are different in population distribution and outcome. The evidence on incidence and risk factors of community-onset sepsis has not been systematically reviewed, an evidence-base gap of particular importance in planning for public-facing interventions.

To address these gaps, this systematic review will identify, appraise, and synthesise the empirical evidence on the incidence and risk factors of community-onset sepsis, severe sepsis, and septic shock.

Research question and aims of the systematic review

The aim of this review will be to systematically identify, appraise, and synthesise the recent evidence on incidence of community-onset sepsis, severe sepsis, or septic shock in countries of the Western industrialised world (North America, Australasia, and North/Western Europe). The review focus will be limited to more recent evidence from high-income countries (more relevant to the UK practice) given the documented longitudinal changes in the incidence, outcome, and implicated pathogens in sepsis [18] and modifications in the definition of sepsis that have taken place in 1991 [24] and 2001 [1]. Therefore, only studies reporting the evidence on data collected in 2002 or onwards will be sought.

To contribute to the aim of supporting PHE responsibilities to evaluate the evidence base for a public-facing sepsis campaign, the specific review objectives will be the following:
  1. a)

    To catalogue and map in a tabular fashion the relevant literature according to socio-demographic characteristics and clinical risk factors in relation to incidence of community-onset (e.g. healthcare-associated, community-acquired) sepsis, severe sepsis, and/or septic shock

     
  2. b)

    To document overall and stratum-specific (by socio-demographic characteristics, clinical risk factors) incidence of community-onset (e.g. healthcare-associated, community-acquired) sepsis, severe sepsis, and/or septic shock

     
  3. c)

    To compile and synthesise evidence on specific socio-demographic, clinical, or laboratory characteristics as potential risk factors for community-onset (e.g. healthcare-associated, community-acquired) sepsis, severe sepsis, and/or septic shock

     

Methods/Design

This systematic review protocol will be reported according to recommendations from the Preferred Reporting Items for Systematic Review and Meta-analysis Protocols (PRISMA-P) 2015 statement [42].

Study eligibility criteria (primary studies)

Inclusion criteria

Study design

Longitudinal prospective or retrospective cohort studies; case-control studies.

Study setting

Population- or hospital-based studies considering community-onset cases separately; studies conducted in North America, Australasia, and North/Western Europe.

Population

Community dwellers, hospitalised patients (male of female) from a defined population of any age (except for neonates) and health state with or without community-onset sepsis at study baseline. The use of relevant ICD-9/10 codes [3, 4, 43] and established criteria for the diagnoses of sepsis (e.g. the presence of infectious pathogen or bloodstream infection plus two or more SIRS criteria as a direct response to the infection), severe sepsis (e.g. sepsis complicated by organ dysfunction), and septic shock (e.g. sepsis-induced acute circulatory failure associated with persistent arterial hypotension) [24, 1, 33, 44]. will be used to determine inclusion. Those with community-onset sepsis will be eligible for inclusion regardless whether they have healthcare-associated (HCA; e.g. people receiving outpatient treatments such as dialysis) or community-acquired (CA) sepsis.

Intervention/exposure 1

Any subgroup, patient characteristic, or clinical parameter (e.g. age, sex, comorbidity, heart rate, body temperature, altered mental status, white blood cell count, creatinine, organ dysfunction score) evaluated for association with risk of sepsis, severe sepsis or septic shock.

Comparator/exposure 2

Any subgroup, patient characteristic, or clinical/laboratory parameter used as the reference category to exposures in the exposure 1 group.

Outcome

The occurrence of community-onset sepsis, severe sepsis, and/or septic shock. This will allow variations in sepsis definition including studies reporting confirmed bloodstream infections plus SIRS criteria.

Outcome measures

Odds, cumulative incidence proportion (risk), incidence rate, and/or hazard rate of sepsis, severe sepsis, and/or septic shock.

Measures of association

Odds ratio (OR), risk ratio (RR), risk difference (RD), incidence rate ratio (IRR), and/or hazard ratio.

Date of publication

Studies reporting the evidence on data collected in 2002 or onwards.

Language of publication

English.

Type of publication

Full-text report.

Exclusion criteria

Study design

Intervention studies (controlled or uncontrolled), prognostic studies (looking at associations between putative prognostic factors and subsequent outcomes or complications such as severe sepsis, septic shock, and/or mortality in participants with sepsis), cross-sectional studies, ecological studies, case series, case reports.

Publication type

Abstracts, reviews (systematic or non-systematic), editorials, letters, books, consensus statements, or opinions. Reviews will be excluded as sources of primary data but will be used to identify the original studies contributing the evidence.

Publication language

Any other than English. Non-English publications will be excluded due to limited resources. Although the inclusion of non-English studies is likely to cover this topic more comprehensively, to the best of our knowledge, we are not aware of any empirical evidence informing on effects of language bias in systematic reviews of incidence of sepsis.

Population

a) Study population with hospital-acquired (nosocomial) sepsis; b) it cannot be determined if the study population presented with community-onset or hospital-acquired sepsis; c) results on populations with community-onset and hospital-acquired sepsis are mixed (not stratified); d) bloodstream infection (BSI) not associated with sepsis/SIRS, severe sepsis (organ dysfunction), or septic shock (circulatory failure and persistent arterial hypotension); e) study population representing a specific subgroup defined by clinical condition (e.g. cancer, coronary heart disease, sepsis/severe sepsis), and f) neonates

Outcomes

Studies not reporting incidence/risk of sepsis (in absolute or relative terms), studies reporting only single site infections, or single infecting species, studies reporting only economic evaluation and/or cost-effectiveness outcomes, diagnostic accuracy or prognostic ability of biomarkers, or only mortality (including case-fatality).

Search strategy and literature sources

We will search Ovid MEDLINE and Ovid Embase from 2002 using a combination of subject headings and keywords for sepsis and related terms combined with terms for epidemiology and related concepts and finally combined this with terms for studies in community-based settings. The Ovid MEDLINE search strategy will also be adapted for Ovid Embase. The searches will be limited to English-language documents, and documents such as comments, letters, editorials, or meeting abstracts will be excluded.

Additionally, we will seek for unpublished literature through the following sources: a) hand search of reference lists of potentially eligible articles, b) relevant websites of organisations dealing with sepsis (International Sepsis Forum, Sepsis Trust UK, Sepsis Alliance, Centre for Disease Control, World Sepsis Day), c) contacting experts/researchers in the field, d) theses database (index to theses), and e) Google Scholar (government or other reports).

We will not search sources of conference proceedings, since they represent abstracts (with no corresponding full texts) which do not provide sufficient information allowing to ascertain and verify a) how sepsis was diagnosed, b) whether study population had community-onset or hospital-acquired sepsis, and c) needed details on incidence and risk factors.

More details on search strategy and sources are provided in Appendix 1.

Study selection and data management

All bibliographic records (i.e. publications) identified through our searches (electronic or hand-searched) will be compiled and then de-duplicated in a special bibliographic endnote database. Afterwards, two reviewers (AT and NM) using a pre-defined piloted screening form of the eligibility criteria will independently screen all the titles and abstracts of corresponding publications. Any disagreements regarding inclusion or exclusion of any given title/abstract will be discussed and resolved via consensus. Then, the same two reviewers will examine full-text reports of all potentially relevant publications passing the title/abstract level of screening for their eligibility. Any disagreements regarding the eligibility of the full text reports will be discussed and resolved through a consensus agreement or a third party adjudication.

Differentiation of community-onset sepsis (healthcare-associated, community-acquired) from hospital-acquired sepsis will be operationalized by relying on definitions used in individual primary studies indicating the presence of community-onset sepsis. We expect some variation across studies in definitions of community-onset sepsis so that adopting a single pre-specified fixed definition might exclude relevant data. For example, certain authors define community-onset sepsis as one that manifests before hospital admission or within 48 h after hospital admission [34, 40, 36, 41]. Other authors define community-onset sepsis if it manifests within 24–28 h of hospital admission [45, 33, 46]. Some other statements may only suggest the presence of community-onset sepsis ranging from ‘patients hospitalized with sepsis’ to ‘sepsis-related hospitalization’ [47, 28]. Alternatively, other authors may additionally report study exclusion criteria for hospital-acquired sepsis [47].

The study selection process and reasons for exclusion at full-text screening level will be presented in the PRISMA study flow diagram (Appendix 2) [48].

Data extraction

One of two reviewers (AT and NM) using pre-defined data extraction sheets will extract relevant information from included studies. The extracted data will include information on study (e.g. author name, year of publication, country of conduct, design, study setting, sample size, duration of follow-up, study quality items), potential risk factors (e.g. participant socio-demographic characteristics, comorbidities, health care procedure or intervention, laboratory marker, clinical symptom or parameter), and outcomes (e.g. definition of sepsis and related outcomes, type of pathogen, place and time of sepsis acquisition, type of health care procedure if used as outpatient treatment, the frequency of occurrence measures for sepsis, severe sepsis, and/or septic shock). Any missing statistical parameters of importance (e.g. cumulative incidence proportion, incidence rate, odds, risk ratio, incidence rate ratio, and odds ratio) and variability measures (e.g. 95 % confidence intervals, p values) will be calculated, if data permits, or authors of the primary studies will be contacted. All calculated or derived data will be denoted as ‘calculated’ and will be incorporated in the extraction sheets.

The data extracted will be cross-checked. Any disagreements regarding the extracted data will be resolved between the two reviewers or through a consensus agreement or adjudication of a third party, if needed (Appendix 3).

Quality (risk of bias) assessment

Methodological quality (or risk of bias) of included studies will be appraised by two independent reviewers (AT and NM) using two checklists developed and validated by the Scottish Intercollegiate Guidelines Network (SIGN) separately for cohort [49] and case-control studies [50]. We selected these tools based on the guidance for evidence-based decision making in infectious diseases epidemiology, prevention, and control proposed by Harder and colleagues [51].

Both the cohort (16 items) and case-control (13 items) study checklists address five domains/sources of bias: 1) study research question; 2) participant selection (e.g. sampling bias, differential non-participation, sample attrition/losses to follow-up, incomplete data assessment); 3) information (performance, detection) bias (e.g. outcome and/or exposure measurement and ascertainment, recall bias); 4) confounding, statistical analysis; and 5) an overall assessment of the study (i.e. summary judgement on internal and external validity of study findings). The response to each item can be recorded as ‘yes’, ‘no’, ‘can’t say’, or ‘doesn’t apply’. The overall methodological quality of each included study will be based on the number of satisfied items (response ‘yes’) and will be rated as follows:
  • High quality++ (≥12 items rated as ‘yes’ for cohort studies and ≥10 items rated as ‘yes’ for case-control studies = little or no risk of bias; results unlikely to be changed by further research)

  • Acceptable quality+ (6–11 items rated as ‘yes’ for cohort studies and 5–9 items rated as ‘yes’ for case-control studies = most criteria met; some flaws in the study with an associated risk of bias; conclusions may change in the light of further studies)

  • Low quality 0 (0–5 items rated as ‘yes’ for cohort studies and 0–4 items rated as ‘yes’ for case-control studies = either most criteria not met, or significant flaws relating to key aspects of study design; conclusions likely to change in the light of further studies).

The quality appraisals will be cross-checked, and any disagreements will be resolved by a consensus-based discussion or through a third party, if necessary. The overall and individual item-specific quality assessment ratings for each study will be presented in Appendix 4 (Table 1 [cohort studies] and Table 2 [case-control studies]).

Data analysis and synthesis

The collected evidence (study, participant, and outcome characteristics) will be narratively synthesised, appraised, and organised in summary tables and text. The evidence for incidence (global, national, and regional) and subgroups/risk factors in relation to the occurrence of sepsis will be presented separately. Where possible, the community-onset sepsis studies will be stratified by those of healthcare-associated and community-acquired sepsis.

The incidence and/or effect estimates with 95 % confidence intervals (95 % CIs) will be ascertained and presented in tables and figures separately for sepsis, severe sepsis, and septic shock (i.e. forest plots) as available. These outcomes will be further stratified by age, sex, study setting (e.g. hospital ward, nursing care facility, intensive-care unit), and other important characteristics, if data permits. Evidence on risk factors will be summarised separately for case-control and cohort studies.

The study results will be meta-analysed if sufficient degree of similarity exists across characteristics of populations, definitions of exposure and case-control groups, and types of outcomes of sepsis occurrence. The estimates of summary dichotomous outcome measures (e.g. risk or odds ratios) will be pooled using a DerSimonian and Laird random-effects model (no rare events, >10.0 %), Mantel-Haenszel fixed-effects model (low event rates, 5.0 %–10.0 %), or Peto fixed-effects model (very low event rates, < 5.0 % or zero events) [52]. The choice of random-effects model is based on the expectation that there will be clinical and methodological diversity across included studies.

The visual inspection of the forest plots and statistical parameters (Chi-square based p value <0.10; I2 > 50 %) will be used to judge the extent of statistical heterogeneity across the estimates of pooled studies. The heterogeneity will be explored through subgroup analysis (e.g. age, sex, underlying comorbidity) and sensitivity analysis (by study design, summary quality/risk of bias rating, study setting).

The extent of publication bias will be examined if the number of studies reporting quantitative measure(s) of the association between a risk factor and sepsis occurrence is sufficient for the inspection of funnel plot asymmetry [53].

Rating overall quality of evidence

The overall quality of the body of evidence on risk factors and frequency measures of sepsis occurrence will not be graded because there is no formal and validated grading system directly applicable to the type of evidence synthesised in this review. The widely accepted and used system suggested by the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) Working Group is ideally applicable to grading the quality of evidence, i.e. multiple patient-oriented outcomes across studies evaluating and comparing different health care interventions [54] and diagnostic accuracy of tests [55].

Discussion

This systematic review will identify and summarise the relevant evidence on the burden of community-onset sepsis in terms of incidence and risk factors. Major findings of this systematic review will be summarised in conjunction with the study methodological quality. Strengths and limitations (e.g. exclusion of non-English studies, conference abstracts) of the review will be discussed and gaps in the evidence will also be highlighted. The findings of this review and those of other similar reviews will be compared (if identified) for the degree of consistency.

Timeliness and accuracy of diagnosis of sepsis are both crucial aspects for improving the patient’s outcome. The findings will be discussed with a view to better informing PHE recommendations on public-facing campaigns to improve timely presentation and diagnosis of sepsis in the community as well as contribute more widely as a basis to future research and policy on improving public health planning.

Abbreviations

ACCP: 

American College of Chest Physicians

HIV: 

human immunodeficiency virus

ICD-10: 

International Classification of Diseases 10th revision

ICU: 

intensive-care unit

PHE: 

Public Health England

PIRO: 

Predisposition, Infection, Response, and Organ Dysfunction

SCCM: 

Society of Critical Care Medicine

SIRS: 

Systemic Inflammatory Response Syndrome

UK: 

United Kingdom

US: 

United States

Declarations

Acknowledgements

Role of the funding source

Funding source—Public Health England. The funder identified the topic and provided an initial outline specification for their research needs, but did not play any role at any stage of the manuscript development.

Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

Authors’ Affiliations

(1)
Communicable Disease Control Epidemiology and Evidence; Populations, Evidence and Technologies; Division of Health Sciences; Warwick Medical School, University of Warwick

References

  1. Levy MM, Fink MP, Marshall JC, Abraham E, Angus D, Cook D, et al. 2001 SCCM/ESICM/ACCP/ATS/SIS International Sepsis Definitions Conference. Crit Care Med. 2003;31(4):1250–6. doi:10.1097/01.CCM.0000050454.01978.3B.PubMedView ArticleGoogle Scholar
  2. Moss M. Epidemiology of sepsis: race, sex, and chronic alcohol abuse. Clin Infect Dis. 2005;41 Suppl 7:S490–7. doi:10.1086/432003.PubMedView ArticleGoogle Scholar
  3. Angus DC, Linde-Zwirble WT, Lidicker J, Clermont G, Carcillo J, Pinsky MR. Epidemiology of severe sepsis in the United States: analysis of incidence, outcome, and associated costs of care. Crit Care Med. 2001;29(7):1303–10.PubMedView ArticleGoogle Scholar
  4. Martin GS, Mannino DM, Eaton S, Moss M. The epidemiology of sepsis in the United States from 1979 through 2000. N Engl J Med. 2003;348(16):1546–54. doi:10.1056/NEJMoa022139.PubMedView ArticleGoogle Scholar
  5. Vincent JL, Sakr Y, Sprung CL, Ranieri VM, Reinhart K, Gerlach H, et al. Sepsis in European intensive care units: results of the SOAP study. Crit Care Med. 2006;34(2):344–53.PubMedView ArticleGoogle Scholar
  6. Daniels R. The incidence, mortality and economic burden of sepsis. NHS Evid Emerg & Urgent Care. 2009.Google Scholar
  7. Jawad I, Luksic I, Rafnsson SB. Assessing available information on the burden of sepsis: global estimates of incidence, prevalence and mortality. J Glob Health. 2012;2(1):010404. doi:10.7189/jogh.02.010404.PubMedPubMed CentralView ArticleGoogle Scholar
  8. Fleischmann C, Scherag A, Adhikari N, Hartog C, Tsaganos T, Schlattmann P, et al. Global burden of sepsis: a systematic review. Crit Care. 2015;19 Suppl 1:21.View ArticleGoogle Scholar
  9. Padkin A, Goldfrad C, Brady AR, Young D, Black N, Rowan K. Epidemiology of severe sepsis occurring in the first 24 hrs in intensive care units in England, Wales, and Northern Ireland. Crit Care Med. 2003;31(9):2332–8. doi:10.1097/01.CCM.0000085141.75513.2B.PubMedView ArticleGoogle Scholar
  10. Brun-Buisson C, Meshaka P, Pinton P, Vallet B, Group ES. EPISEPSIS: a reappraisal of the epidemiology and outcome of severe sepsis in French intensive care units. Intensive Care Med. 2004;30(4):580–8. doi:10.1007/s00134-003-2121-4.PubMedView ArticleGoogle Scholar
  11. Finfer S, Bellomo R, Lipman J, French C, Dobb G, Myburgh J. Adult-population incidence of severe sepsis in Australian and New Zealand intensive care units. Intensive Care Med. 2004;30(4):589–96. doi:10.1007/s00134-004-2157-0.PubMedView ArticleGoogle Scholar
  12. Harrison DA, Welch CA, Eddleston JM. The epidemiology of severe sepsis in England, Wales and Northern Ireland, 1996 to 2004: secondary analysis of a high quality clinical database, the ICNARC Case Mix Programme Database. Crit Care. 2006;10(2):R42. doi:10.1186/cc4854.PubMedPubMed CentralView ArticleGoogle Scholar
  13. Karlsson S, Varpula M, Ruokonen E, Pettila V, Parviainen I, Ala-Kokko TI, et al. Incidence, treatment, and outcome of severe sepsis in ICU-treated adults in Finland: the Finnsepsis study. Intensive Care Med. 2007;33(3):435–43. doi:10.1007/s00134-006-0504-z.PubMedView ArticleGoogle Scholar
  14. Blanco J, Muriel-Bombin A, Sagredo V, Taboada F, Gandia F, Tamayo L, et al. Incidence, organ dysfunction and mortality in severe sepsis: a Spanish multicentre study. Crit Care. 2008;12(6):R158. doi:10.1186/cc7157.PubMedPubMed CentralView ArticleGoogle Scholar
  15. Gaieski DF, Edwards JM, Kallan MJ, Carr BG. Benchmarking the incidence and mortality of severe sepsis in the United States. Crit Care Med. 2013;41(5):1167–74. doi:10.1097/CCM.0b013e31827c09f8.PubMedView ArticleGoogle Scholar
  16. Alberti C, Brun-Buisson C, Burchardi H, Martin C, Goodman S, Artigas A, et al. Epidemiology of sepsis and infection in ICU patients from an international multicentre cohort study. Intensive Care Med. 2002;28(2):108–21. doi:10.1007/s00134-001-1143-z.PubMedView ArticleGoogle Scholar
  17. McPherson D, Griffiths C, Williams M, Baker A, Klodawski E, Jacobson B, et al. Sepsis-associated mortality in England: an analysis of multiple cause of death data from 2001 to 2010. BMJ Open. 2013;3(8), e002586. doi:10.1136/bmjopen-2013-002586.PubMedPubMed CentralView ArticleGoogle Scholar
  18. Martin GS. Sepsis, severe sepsis and septic shock: changes in incidence, pathogens and outcomes. Expert Rev Anti-Infect Ther. 2012;10(6):701–6. doi:10.1586/eri.12.50.PubMedPubMed CentralView ArticleGoogle Scholar
  19. Hall MJ, Williams SN, DeFrances CJ, Golosinskiy A. Inpatient care for septicemia or sepsis: a challenge for patients and hospitals. NCHS Data Brief. 2011;62:1–8.PubMedGoogle Scholar
  20. Stevenson EK, Rubenstein AR, Radin GT, Wiener RS, Walkey AJ. Two decades of mortality trends among patients with severe sepsis: a comparative meta-analysis*. Crit Care Med. 2014;42(3):625–31. doi:10.1097/CCM.0000000000000026.PubMedPubMed CentralView ArticleGoogle Scholar
  21. Cohen J, Vincent JL, Adhikari NK, Machado FR, Angus DC, Calandra T, et al. Sepsis: a roadmap for future research. Lancet Infect Dis. 2015;15(5):581–614. doi:10.1016/S1473-3099(15)70112-X.PubMedView ArticleGoogle Scholar
  22. Rhee C, Gohil S, Klompas M. Regulatory mandates for sepsis care—reasons for caution. N Engl J Med. 2014;370(18):1673–6. doi:10.1056/NEJMp1400276.PubMedPubMed CentralView ArticleGoogle Scholar
  23. Kaukonen KM, Bailey M, Suzuki S, Pilcher D, Bellomo R. Mortality related to severe sepsis and septic shock among critically ill patients in Australia and New Zealand, 2000-2012. JAMA. 2014;311(13):1308–16. doi:10.1001/jama.2014.2637.PubMedView ArticleGoogle Scholar
  24. Bone RC, Balk RA, Cerra FB, Dellinger RP, Fein AM, Knaus WA, et al. Definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. The ACCP/SCCM Consensus Conference Committee. American College of Chest Physicians/Society of Critical Care Medicine. Chest. 1992;101(6):1644–55.PubMedView ArticleGoogle Scholar
  25. Vincent JL, Opal SM, Marshall JC, Tracey KJ. Sepsis definitions: time for change. Lancet. 2013;381(9868):774–5. doi:10.1016/S0140-6736(12)61815-7.PubMedPubMed CentralView ArticleGoogle Scholar
  26. Esper AM, Moss M, Lewis CA, Nisbet R, Mannino DM, Martin GS. The role of infection and comorbidity: factors that influence disparities in sepsis. Crit Care Med. 2006;34(10):2576–82. doi:10.1097/01.CCM.0000239114.50519.0E.PubMedPubMed CentralView ArticleGoogle Scholar
  27. Barnato AE, Alexander SL, Linde-Zwirble WT, Angus DC. Racial variation in the incidence, care, and outcomes of severe sepsis: analysis of population, patient, and hospital characteristics. Am J Respir Crit Care Med. 2008;177(3):279–84. doi:10.1164/rccm.200703-480OC.PubMedView ArticleGoogle Scholar
  28. Mayr FB, Yende S, Linde-Zwirble WT, Peck-Palmer OM, Barnato AE, Weissfeld LA, et al. Infection rate and acute organ dysfunction risk as explanations for racial differences in severe sepsis. JAMA. 2010;303(24):2495–503. doi:10.1001/jama.2010.851.PubMedPubMed CentralView ArticleGoogle Scholar
  29. Wang HE, Shapiro NI, Griffin R, Safford MM, Judd S, Howard G. Chronic medical conditions and risk of sepsis. PLoS One. 2012;7(10), e48307. doi:10.1371/journal.pone.0048307.PubMedPubMed CentralView ArticleGoogle Scholar
  30. Danai PA, Moss M, Mannino DM, Martin GS. The epidemiology of sepsis in patients with malignancy. Chest. 2006;129(6):1432–40. doi:10.1378/chest.129.6.1432.PubMedView ArticleGoogle Scholar
  31. Garner JS, Jarvis WR, Emori TG, Horan TC, Hughes JM. CDC definitions for nosocomial infections, 1988. Am J Infect Control. 1988;16(3):128–40.PubMedView ArticleGoogle Scholar
  32. American Thoracic Society, Infectious Diseases Society of America. Guidelines for the management of adults with hospital-acquired, ventilator-associated, and healthcare-associated pneumonia. Am J Respir Crit Care Med. 2005;171(4):388–416. doi:10.1164/rccm.200405-644ST.View ArticleGoogle Scholar
  33. Wang HE, Addis DR, Donnelly JP, Shapiro NI, Griffin RL, Safford MM, et al. Discharge diagnoses versus medical record review in the identification of community-acquired sepsis. Crit Care. 2015;19(1):42. doi:10.1186/s13054-015-0771-6.PubMedPubMed CentralView ArticleGoogle Scholar
  34. Hoenigl M, Wagner J, Raggam RB, Prueller F, Prattes J, Eigl S, et al. Characteristics of hospital-acquired and community-onset blood stream infections, South-East Austria. PLoS One. 2014;9(8), e104702. doi:10.1371/journal.pone.0104702.PubMedPubMed CentralView ArticleGoogle Scholar
  35. Lenz R, Leal JR, Church DL, Gregson DB, Ross T, Laupland KB. The distinct category of healthcare associated bloodstream infections. BMC Infect Dis. 2012;12:85. doi:10.1186/1471-2334-12-85.PubMedPubMed CentralView ArticleGoogle Scholar
  36. Diekema DJ, Beekmann SE, Chapin KC, Morel KA, Munson E, Doern GV. Epidemiology and outcome of nosocomial and community-onset bloodstream infection. J Clin Microbiol. 2003;41(8):3655–60.PubMedPubMed CentralView ArticleGoogle Scholar
  37. Friedman ND, Kaye KS, Stout JE, McGarry SA, Trivette SL, Briggs JP, et al. Health care—associated bloodstream infections in adults: a reason to change the accepted definition of community-acquired infections. Ann Intern Med. 2002;137(10):791–7.PubMedView ArticleGoogle Scholar
  38. Siegman-Igra Y, Fourer B, Orni-Wasserlauf R, Golan Y, Noy A, Schwartz D, et al. Reappraisal of community-acquired bacteremia: a proposal of a new classification for the spectrum of acquisition of bacteremia. Clin Infect Dis. 2002;34(11):1431–9. doi:10.1086/339809.PubMedView ArticleGoogle Scholar
  39. Cardoso T, Almeida M, Friedman ND, Aragao I, Costa-Pereira A, Sarmento AE, et al. Classification of healthcare-associated infection: a systematic review 10 years after the first proposal. BMC Med. 2014;12:40. doi:10.1186/1741-7015-12-40.PubMedPubMed CentralView ArticleGoogle Scholar
  40. Adrie C, Alberti C, Chaix-Couturier C, Azoulay E, De Lassence A, Cohen Y, et al. Epidemiology and economic evaluation of severe sepsis in France: age, severity, infection site, and place of acquisition (community, hospital, or intensive care unit) as determinants of workload and cost. J Crit Care. 2005;20(1):46–58.PubMedView ArticleGoogle Scholar
  41. Rodriguez-Bano J, Lopez-Prieto MD, Portillo MM, Retamar P, Natera C, Nuno E, et al. Epidemiology and clinical features of community-acquired, healthcare-associated and nosocomial bloodstream infections in tertiary-care and community hospitals. Clin Microbiol Infect. 2010;16(9):1408–13. doi:10.1111/j.1469-0691.2009.03089.x.PubMedView ArticleGoogle Scholar
  42. Moher D, Shamseer L, Clarke M, Ghersi D, Liberati A, Petticrew M, et al. Preferred reporting items for systematic review and meta-analysis protocols (PRISMA-P) 2015 statement. Syst Rev. 2015;4:1. doi:10.1186/2046-4053-4-1.PubMedPubMed CentralView ArticleGoogle Scholar
  43. Jolley RJ, Sawka KJ, Yergens DW, Quan H, Jette N, Doig CJ. Validity of administrative data in recording sepsis: a systematic review. Crit Care. 2015;19(1):139. doi:10.1186/s13054-015-0847-3.PubMedPubMed CentralView ArticleGoogle Scholar
  44. Balk RA. Severe sepsis and septic shock. Definitions, epidemiology, and clinical manifestations. Crit Care Clin. 2000;16(2):179–92.PubMedView ArticleGoogle Scholar
  45. Wang HE, Szychowski JM, Griffin R, Safford MM, Shapiro NI, Howard G. Long-term mortality after community-acquired sepsis: a longitudinal population-based cohort study. BMJ Open. 2014;4(1), e004283. doi:10.1136/bmjopen-2013-004283.PubMedPubMed CentralView ArticleGoogle Scholar
  46. Nygard ST, Langeland N, Flaatten HK, Fanebust R, Haugen O, Skrede S. Aetiology, antimicrobial therapy and outcome of patients with community acquired severe sepsis: a prospective study in a Norwegian university hospital. BMC Infect Dis. 2014;14:121. doi:10.1186/1471-2334-14-121.PubMedPubMed CentralView ArticleGoogle Scholar
  47. Henriksen DP, Pottegard A, Laursen CB, Jensen TG, Hallas J, Pedersen C, et al. Risk factors for hospitalization due to community-acquired sepsis—a population-based case-control study. PLoS One. 2015;10(4), e0124838. doi:10.1371/journal.pone.0124838.PubMedPubMed CentralView ArticleGoogle Scholar
  48. Moher D, Liberati A, Tetzlaff J, Altman DG, Group P. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. Ann Intern Med. 2009;151(4):264–9. W64.PubMedView ArticleGoogle Scholar
  49. Scottish Intercollegiate Guidelines Network. Checklist 3: cohort studies. In: SIGN 50: a guideline developer’s handbook, Edinburgh. 2008. http://www.sign.ac.uk/methodology/checklists.html. Accessed 01 September 2015.Google Scholar
  50. Scottish Intercollegiate Guidelines Network. Checklist 4: case-control studies. In: SIGN 50: a guideline developer’s handbook, Edinburgh. 2008. http://www.sign.ac.uk/methodology/checklists.html. Accessed 01 September 2015.Google Scholar
  51. Harder T, Takla A, Rehfuess E, Sanchez-Vivar A, Matysiak-Klose D, Eckmanns T, et al. Evidence-based decision-making in infectious diseases epidemiology, prevention and control: matching research questions to study designs and quality appraisal tools. BMC Med Res Methodol. 2014;14:69. doi:10.1186/1471-2288-14-69.PubMedPubMed CentralView ArticleGoogle Scholar
  52. Higgins JP, Green S. Cochrane handbook for systematic reviews of interventions. 510th ed. Chichester: Wiley Online Library; 2008.View ArticleGoogle Scholar
  53. Egger M, Davey Smith G, Schneider M, Minder C. Bias in meta-analysis detected by a simple, graphical test. BMJ. 1997;315(7109):629–34.PubMedPubMed CentralView ArticleGoogle Scholar
  54. Guyatt GH, Oxman AD, Vist GE, Kunz R, Falck-Ytter Y, Alonso-Coello P, et al. GRADE: an emerging consensus on rating quality of evidence and strength of recommendations. BMJ. 2008;336(7650):924–6. doi:10.1136/bmj.39489.470347.AD.PubMedPubMed CentralView ArticleGoogle Scholar
  55. Schunemann HJ, Oxman AD, Brozek J, Glasziou P, Jaeschke R, Vist GE, et al. Grading quality of evidence and strength of recommendations for diagnostic tests and strategies. BMJ. 2008;336(7653):1106–10. doi:10.1136/bmj.39500.677199.AE.PubMedPubMed CentralView ArticleGoogle Scholar

Copyright

© Tsertsvadze et al. 2015

Advertisement