Editorials
Sepsis or SEPSIS: Does It Make a Difference?* Patricia Fontela, MD, PhD Division of Pediatric Critical Care Department of Pediatrics The Montreal Children’s Hospital McGill University Montréal, Canada Jacques Lacroix, MD, FRCPC Division of Pediatric Critical Care Department of Pediatrics Sainte-Justine Hospital Université de Montréal Montréal, Canada
I
n 2005, the International Pediatric Sepsis Consensus Conference defined sepsis as a “systemic inflammatory response syndrome (SIRS) in the presence of or as a result of suspected or proven infection” (1). Any severe infection can cause sepsis, which can then progress to “severe sepsis” and to “septic shock.” Despite severe sepsis being common in children, little is known about its epidemiology. Using 1995 U.S. hospital discharge data, Watson et al (2) reported that the prevalence rate of pediatric cases of severe sepsis was 0.56 cases/1,000 population/yr. In 1996, Proulx et al (3) diagnosed sepsis in 18% and severe sepsis in 2% of all patients in the PICU of an university-affiliated hospital. Some variation in the epidemiology of sepsis and severe sepsis reported in different articles can be expected; many causes are possible (Box 1). First, variation can be attributable to different study populations. Angus et al (4) reported that the prevalence rate of severe sepsis increases by more than 100fold with age (0.2/1,000 children to 26.2/1,000 in patients > 65 years old). Similarly, within the pediatric population, Watson et al (2) found that the American annual prevalence rate of severe sepsis in 1995 was 5.16/1,000 in infants, whereas it was 0.20/1,000 in children 10 to 14 years old. In the same study, gender was also shown to be a factor because the severe sepsis prevalence was 15% higher in boys than in girls (0.60/1,000 vs 0.52/1,000; p < 0.001). Many genes encoding bioactive
molecules such as cytokines, cell surface receptors, lipopolysaccharide ligand and shock protein are associated with increased susceptibility to contract severe sepsis (5). The prevalence rate also varies in different countries because of many reasons, including differences in the ecology of microorganisms causing sepsis. For example, malaria is a rare cause of sepsis in the United States, whereas it is frequent in Africa. Moreover, the prevalence rate might differ according to study design. Prospective cohort studies gather data in a planned, standardized fashion. In contrast, retrospective studies, especially when using large administrative databases, rely on information that was not originally collected for research purposes, which can compromise data quality. Reporting bias is a real threat because sepsis is signaled on a voluntary rather than on a mandatory basis. This can lead to falsely low prevalence rates, as seen for transfusion reactions, whose prevalence rate is higher when they are prospectively monitored on a daily basis and when reporting cases is mandatory (6, 7). A secular trend is another possible problem. In 2003, Watson et al (2) reported an increase in the prevalence rate of septic shock over time. This trend was attributed to high rates of sepsis among severely ill patients who were not seen in PICUs a few decades ago, such as very low birth weight neonates, cases of transplantation, and cases of cancer. Detection bias happens when monitoring of the outcome (i.e., sepsis) is not done optimally. The clinical findings of sepsis evolve with the progression of the disease; moreover, they can disappear quite rapidly with effective treatment. Thus, one can expect that the prevalence rate will be higher if the presence of sepsis is monitored on a daily rather than on a weekly basis.
Why Can the Incidence Rate of Sepsis Differ So Much Between Descriptive Studies?
Box 1.
Different population (age, gender, genetic predisposition, country, etc) Study design (retrospective vs prospective) Reporting bias
*See also p. 798. Key Words: critical care; diagnostic criteria; epidemiology; pediatrics; sepsis The authors have disclosed that they do not have any potential conflicts of interest. Copyright © 2014 by the Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies DOI: 10.1097/PCC.0000000000000259
Pediatric Critical Care Medicine
Secular trend Detection bias Different sets of diagnostic criteria Different sources of data Chance www.pccmjournal.org
893
Editorials
Variation in the epidemiology of sepsis can also be explained by the lack of a uniform definition and the use of different diagnostic criteria by authors (8). Many sets of criteria have been published to diagnose neonatal (9, 10) and pediatric sepsis (1, 3) that were generated by expert panels but were not validated by good prospective studies. Thereafter, it was found that their reproducibility, sensitivity, and/or specificity were not optimal. Cottineau et al (9) reported that the criteria for early onset neonatal bacterial infection were not reliable. Furthermore, European experts suggested clinical and laboratory parameters to diagnose late-onset neonatal sepsis in 2010. The prospective cohort study of Lutsar et al (10) showed that the predictive value of these criteria to recognize culture-proven late-onset neonatal sepsis was 61% (95% CI, 52–70%), which is almost equivalent to tossing a coin. As suggested by Wynn et al (11), it is crucial to revisit and/or validate diagnostic criteria of sepsis in high-quality prospective studies. Chance alone can also be a source of variation. Finally, variation in the prevalence rate of pediatric sepsis may be attributable to different data sources. In this issue of Pediatric Critical Care Medicine, Balamuth et al (12) reported the results of a retrospective cohort study conducted in 44 hospitals contributing to the Pediatric Health Information System database. It was undertaken to characterize the epidemiology of severe sepsis, using 2 diagnostic strategies. In both instances, the investigators used the International Classification of Diseases, 9th Edition, Clinical Modification. In the first strategy (combination code cohort), cases of severe sepsis were detected using codes for infection plus organ dysfunction. In the second strategy (sepsis code cohort), cases of sepsis were diagnosed combining International Classification of Diseases, 9th Edition, Clinical Modification codes for severe sepsis and septic shock. From 2004 to 2012, 176,124 hospitalizations (3.1%) with severe sepsis were detected using the combination code, whereas 25,236 (0.45%) were detected using the sepsis code, a 7-fold difference! The prevalence of severe sepsis increased from 3.7% to 4.4% in the first strategy group and from 0.4% to 0.7% in the second strategy cohort (p < 0.001). Mortality associated with strategy 2 was higher than with strategy 1. Clearly, huge variation in the prevalence rate of a disease can be observed when different data sources are used.
894
www.pccmjournal.org
Sepsis or SEPSIS? The epidemiology of a disease does not change if its name is typed with regular or capitalized letters. However, its prevalence rate can significantly change depending on the population studied, the diagnostic criteria used to detect cases, the era when the study is performed, and the data sources used. The lesson learned from they study by Balamuth et al (12)? prudence is mandatory when comparing epidemiological data using different diagnostic criteria or different data sources, even when studies are completed during the same time period in the same country and among patients with similar age and gender.
REFERENCES
1. Goldstein B, Giroir B, Randolph A; International Consensus Conference on Pediatric Sepsis: International pediatric sepsis consensus conference: Definitions for sepsis and organ dysfunction in pediatrics. Pediatr Crit Care Med 2005; 6:2–8 2. Watson RS, Carcillo JA, Linde-Zwirble WT, et al: The epidemiology of severe sepsis in children in the United States. Am J Respir Crit Care Med 2003; 167:695–701 3. Proulx F, Fayon M, Farrell CA, et al: Epidemiology of sepsis and multiple organ dysfunction syndrome in children. Chest 1996; 109:1033–1037 4. Angus DC, Linde-Zwirble WT, Lidicker J, et al: Epidemiology of severe sepsis in the United States: Analysis of incidence, outcome, and associated costs of care. Crit Care Med 2001; 29:1303–1310 5. Jaber BL, Rao M, Guo D, et al: Cytokine gene promoter polymorphisms and mortality in acute renal failure. Cytokine 2004; 25:212–219 6. Gauvin F, Lacroix J, Robillard P, et al: Acute transfusion reactions in the pediatric intensive care unit. Transfusion 2006; 46:1899–1908 7. Gauvin F, Robillard P, Hume H, et al: Transfusion-related acute lung injury in the Canadian paediatric population. Paediatr Child Health 2012; 17:235–239 8. Angus DC, Wax RS: Epidemiology of sepsis: An update. Crit Care Med 2001; 29:S109–S116 9. Cottineau M, Launay E, Branger B, et al: Diagnostic value of suspicion criteria for early-onset neonatal bacterial infection: Report ten years after the Anaes recommendations. Arch Pediatr 2014; 21:187–193 10. Lutsar I, Chazallon C, Carducci FI, et al: Current management of late onset neonatal bacterial sepsis in five European countries. Eur J Pediatr 2014; 173:997–1004 11. Wynn JL, Wong HR, Shanley TP, et al: Time for a neonatal-specific consensus definition for sepsis. Pediatr Crit Care Med 2014; 15:523–528 12. Balamuth F, Weiss SL, Neuman MI, et al: Pediatric Severe Sepsis in U.S. Children’s Hospitals. Pediatr Crit Care Med 2014; 15:798–805
November 2014 • Volume 15 • Number 9
Sepsis or SEPSIS: Does It Make a Difference?* Patricia Fontela, MD, PhD Division of Pediatric Critical Care Department of Pediatrics The Montreal Children’s Hospital McGill University Montréal, Canada Jacques Lacroix, MD, FRCPC Division of Pediatric Critical Care Department of Pediatrics Sainte-Justine Hospital Université de Montréal Montréal, Canada
I
n 2005, the International Pediatric Sepsis Consensus Conference defined sepsis as a “systemic inflammatory response syndrome (SIRS) in the presence of or as a result of suspected or proven infection” (1). Any severe infection can cause sepsis, which can then progress to “severe sepsis” and to “septic shock.” Despite severe sepsis being common in children, little is known about its epidemiology. Using 1995 U.S. hospital discharge data, Watson et al (2) reported that the prevalence rate of pediatric cases of severe sepsis was 0.56 cases/1,000 population/yr. In 1996, Proulx et al (3) diagnosed sepsis in 18% and severe sepsis in 2% of all patients in the PICU of an university-affiliated hospital. Some variation in the epidemiology of sepsis and severe sepsis reported in different articles can be expected; many causes are possible (Box 1). First, variation can be attributable to different study populations. Angus et al (4) reported that the prevalence rate of severe sepsis increases by more than 100fold with age (0.2/1,000 children to 26.2/1,000 in patients > 65 years old). Similarly, within the pediatric population, Watson et al (2) found that the American annual prevalence rate of severe sepsis in 1995 was 5.16/1,000 in infants, whereas it was 0.20/1,000 in children 10 to 14 years old. In the same study, gender was also shown to be a factor because the severe sepsis prevalence was 15% higher in boys than in girls (0.60/1,000 vs 0.52/1,000; p < 0.001). Many genes encoding bioactive
molecules such as cytokines, cell surface receptors, lipopolysaccharide ligand and shock protein are associated with increased susceptibility to contract severe sepsis (5). The prevalence rate also varies in different countries because of many reasons, including differences in the ecology of microorganisms causing sepsis. For example, malaria is a rare cause of sepsis in the United States, whereas it is frequent in Africa. Moreover, the prevalence rate might differ according to study design. Prospective cohort studies gather data in a planned, standardized fashion. In contrast, retrospective studies, especially when using large administrative databases, rely on information that was not originally collected for research purposes, which can compromise data quality. Reporting bias is a real threat because sepsis is signaled on a voluntary rather than on a mandatory basis. This can lead to falsely low prevalence rates, as seen for transfusion reactions, whose prevalence rate is higher when they are prospectively monitored on a daily basis and when reporting cases is mandatory (6, 7). A secular trend is another possible problem. In 2003, Watson et al (2) reported an increase in the prevalence rate of septic shock over time. This trend was attributed to high rates of sepsis among severely ill patients who were not seen in PICUs a few decades ago, such as very low birth weight neonates, cases of transplantation, and cases of cancer. Detection bias happens when monitoring of the outcome (i.e., sepsis) is not done optimally. The clinical findings of sepsis evolve with the progression of the disease; moreover, they can disappear quite rapidly with effective treatment. Thus, one can expect that the prevalence rate will be higher if the presence of sepsis is monitored on a daily rather than on a weekly basis.
Why Can the Incidence Rate of Sepsis Differ So Much Between Descriptive Studies?
Box 1.
Different population (age, gender, genetic predisposition, country, etc) Study design (retrospective vs prospective) Reporting bias
*See also p. 798. Key Words: critical care; diagnostic criteria; epidemiology; pediatrics; sepsis The authors have disclosed that they do not have any potential conflicts of interest. Copyright © 2014 by the Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies DOI: 10.1097/PCC.0000000000000259
Pediatric Critical Care Medicine
Secular trend Detection bias Different sets of diagnostic criteria Different sources of data Chance www.pccmjournal.org
893
Editorials
Variation in the epidemiology of sepsis can also be explained by the lack of a uniform definition and the use of different diagnostic criteria by authors (8). Many sets of criteria have been published to diagnose neonatal (9, 10) and pediatric sepsis (1, 3) that were generated by expert panels but were not validated by good prospective studies. Thereafter, it was found that their reproducibility, sensitivity, and/or specificity were not optimal. Cottineau et al (9) reported that the criteria for early onset neonatal bacterial infection were not reliable. Furthermore, European experts suggested clinical and laboratory parameters to diagnose late-onset neonatal sepsis in 2010. The prospective cohort study of Lutsar et al (10) showed that the predictive value of these criteria to recognize culture-proven late-onset neonatal sepsis was 61% (95% CI, 52–70%), which is almost equivalent to tossing a coin. As suggested by Wynn et al (11), it is crucial to revisit and/or validate diagnostic criteria of sepsis in high-quality prospective studies. Chance alone can also be a source of variation. Finally, variation in the prevalence rate of pediatric sepsis may be attributable to different data sources. In this issue of Pediatric Critical Care Medicine, Balamuth et al (12) reported the results of a retrospective cohort study conducted in 44 hospitals contributing to the Pediatric Health Information System database. It was undertaken to characterize the epidemiology of severe sepsis, using 2 diagnostic strategies. In both instances, the investigators used the International Classification of Diseases, 9th Edition, Clinical Modification. In the first strategy (combination code cohort), cases of severe sepsis were detected using codes for infection plus organ dysfunction. In the second strategy (sepsis code cohort), cases of sepsis were diagnosed combining International Classification of Diseases, 9th Edition, Clinical Modification codes for severe sepsis and septic shock. From 2004 to 2012, 176,124 hospitalizations (3.1%) with severe sepsis were detected using the combination code, whereas 25,236 (0.45%) were detected using the sepsis code, a 7-fold difference! The prevalence of severe sepsis increased from 3.7% to 4.4% in the first strategy group and from 0.4% to 0.7% in the second strategy cohort (p < 0.001). Mortality associated with strategy 2 was higher than with strategy 1. Clearly, huge variation in the prevalence rate of a disease can be observed when different data sources are used.
894
www.pccmjournal.org
Sepsis or SEPSIS? The epidemiology of a disease does not change if its name is typed with regular or capitalized letters. However, its prevalence rate can significantly change depending on the population studied, the diagnostic criteria used to detect cases, the era when the study is performed, and the data sources used. The lesson learned from they study by Balamuth et al (12)? prudence is mandatory when comparing epidemiological data using different diagnostic criteria or different data sources, even when studies are completed during the same time period in the same country and among patients with similar age and gender.
REFERENCES
1. Goldstein B, Giroir B, Randolph A; International Consensus Conference on Pediatric Sepsis: International pediatric sepsis consensus conference: Definitions for sepsis and organ dysfunction in pediatrics. Pediatr Crit Care Med 2005; 6:2–8 2. Watson RS, Carcillo JA, Linde-Zwirble WT, et al: The epidemiology of severe sepsis in children in the United States. Am J Respir Crit Care Med 2003; 167:695–701 3. Proulx F, Fayon M, Farrell CA, et al: Epidemiology of sepsis and multiple organ dysfunction syndrome in children. Chest 1996; 109:1033–1037 4. Angus DC, Linde-Zwirble WT, Lidicker J, et al: Epidemiology of severe sepsis in the United States: Analysis of incidence, outcome, and associated costs of care. Crit Care Med 2001; 29:1303–1310 5. Jaber BL, Rao M, Guo D, et al: Cytokine gene promoter polymorphisms and mortality in acute renal failure. Cytokine 2004; 25:212–219 6. Gauvin F, Lacroix J, Robillard P, et al: Acute transfusion reactions in the pediatric intensive care unit. Transfusion 2006; 46:1899–1908 7. Gauvin F, Robillard P, Hume H, et al: Transfusion-related acute lung injury in the Canadian paediatric population. Paediatr Child Health 2012; 17:235–239 8. Angus DC, Wax RS: Epidemiology of sepsis: An update. Crit Care Med 2001; 29:S109–S116 9. Cottineau M, Launay E, Branger B, et al: Diagnostic value of suspicion criteria for early-onset neonatal bacterial infection: Report ten years after the Anaes recommendations. Arch Pediatr 2014; 21:187–193 10. Lutsar I, Chazallon C, Carducci FI, et al: Current management of late onset neonatal bacterial sepsis in five European countries. Eur J Pediatr 2014; 173:997–1004 11. Wynn JL, Wong HR, Shanley TP, et al: Time for a neonatal-specific consensus definition for sepsis. Pediatr Crit Care Med 2014; 15:523–528 12. Balamuth F, Weiss SL, Neuman MI, et al: Pediatric Severe Sepsis in U.S. Children’s Hospitals. Pediatr Crit Care Med 2014; 15:798–805
November 2014 • Volume 15 • Number 9
