Epidemiology of Sepsis in US Children and Young Adults

Shelley S Magill; Mathew R P Sapiano; Runa Gokhale; Joelle Nadle; Helen Johnston; Geoff Brousseau; Meghan Maloney; Susan M Ray; Lucy E Wilson; Rebecca Perlmutter; Ruth Lynfield; Malini DeSilva; Marla Sievers; Lourdes Irizarry; Ghinwa Dumyati; Rebecca Pierce; Alexia Zhang; Marion Kainer; Anthony E Fiore; Raymund Dantes; Lauren Epstein

doi:10.1093/ofid/ofad218

Epidemiology of Sepsis in US Children and Young Adults

Magill, Shelley S; Sapiano, Mathew R P; Gokhale, Runa; Nadle, Joelle; Johnston, Helen; Brousseau, Geoff; Maloney, Meghan; Ray, Susan M; Wilson, Lucy E; Perlmutter, Rebecca; Lynfield, Ruth; DeSilva, Malini; Sievers, Marla; Irizarry, Lourdes; Dumyati, Ghinwa; Pierce, Rebecca; Zhang, Alexia; Kainer, Marion; Fiore, Anthony E; Dantes, Raymund; Epstein, Lauren 2023-04-20 00:00:00 Open Forum Infectious Diseases MAJOR ARTICLE 1 1 1,a 2 3 3,b 4 5,6 Shelley S. Magill, Mathew R. P. Sapiano, Runa Gokhale, Joelle Nadle, Helen Johnston, Geoff Brousseau, Meghan Maloney, Susan M. Ray, 7,8 7 9 9,c, 10 10 11, 12 Lucy E. Wilson, Rebecca Perlmutter, Ruth Lynfield, Malini DeSilva, Marla Sievers, Lourdes Irizarry, Ghinwa Dumyati, Rebecca Pierce, 12 13,d 1 1,5 1,e, Alexia Zhang, Marion Kainer, Anthony E. Fiore, Raymund Dantes, and Lauren Epstein 1 2 3 Division of Healthcare Quality Promotion, Centers for Disease Control and Prevention, Atlanta, Georgia, USA, California Emerging Infections Program, Oakland, California, USA, Division of Disease Control and Public Health Response, Colorado Department of Public Health and Environment, Denver, Colorado, USA, Connecticut Emerging Infections Program, Hartford and New Haven, 5 6 7 Connecticut, USA, Department of Medicine, Emory University, Atlanta, Georgia, USA, Georgia Emerging Infections Program, Decatur, Georgia, USA, Infectious Disease Epidemiology and Outbreak Response Bureau, Maryland Department of Health, Baltimore, Maryland, USA, Department of Emergency Health Services, University of Maryland, Baltimore County, Baltimore, Maryland, USA, 9 10 11 Minnesota Department of Health, St Paul, Minnesota, USA, Epidemiology and Response Division, New Mexico Department of Health, Santa Fe, New Mexico, USA, New York Emerging Infections 12 13 Program, University of Rochester Medical Center, Rochester, New York, USA, Public Health Division, Oregon Health Authority, Portland, Oregon, USA, and Tennessee Department of Health, Nashville, Tennessee, USA Background. Most multicenter studies of US pediatric sepsis epidemiology use administrative data or focus on pediatric intensive care units. We conducted a detailed medical record review to describe sepsis epidemiology in children and young adults. Methods. In a convenience sample of hospitals in 10 states, patients aged 30 days–21 years, discharged during 1 October 2014– 30 September 2015, with explicit diagnosis codes for severe sepsis or septic shock, were included. Medical records were reviewed for patients with documentation of sepsis, septic shock, or similar terms. We analyzed overall and age group–specific patient characteristics. Results. Of 736 patients in 26 hospitals, 442 (60.1%) had underlying conditions. Most patients (613 [83.3%]) had community- onset sepsis, although most community-onset sepsis was healthcare associated (344 [56.1%]). Two hundred forty-one patients (32.7%) had outpatient visits 1–7 days before sepsis hospitalization, of whom 125 (51.9%) received antimicrobials ≤30 days before sepsis hospitalization. Age group–related differences included common underlying conditions (<5 years: prematurity vs 5–12 years: chronic pulmonary disease vs 13–21 years: chronic immunocompromise); medical device presence ≤30 days before sepsis hospitalization (1–4 years: 46.9% vs 30 days–11 months: 23.3%); percentage with hospital-onset sepsis (<5 years: 19.6% vs ≥5 years: 12.0%); and percentage with sepsis-associated pathogens (30 days–11 months: 65.6% vs 13–21 years: 49.3%). Conclusions. Our data suggest potential opportunities to raise sepsis awareness among outpatient providers to facilitate prevention, early recognition, and intervention in some patients. Consideration of age-specific differences may be important as approaches are developed to improve sepsis prevention, risk prediction, recognition, and management. Keywords. children; epidemiology; sepsis; septic shock; severe sepsis. Sepsis is recognized as an urgent global public health threat, have developed EHR definitions of sepsis for pediatric popula - with an estimated 48.9 million cases and 11.0 million deaths tions [3, 4], these definitions have not been used to estimate na - worldwide in 2017 [1]. In the United States (US), using a sepsis tional pediatric sepsis cases and deaths, and additional work is definition based on electronic health record (EHR) data, inves - needed to refine and validate a widely applicable EHR-based tigators estimated there were 1.7 million adults with sepsis and approach [5]. An analysis of administrative data from 2013 270 000 in-hospital deaths in 2014 [2]. Although investigators yielded an annual US estimate of 54 060 sepsis cases in children outside of the neonatal period and <19 years old; 3.7% of chil- dren with sepsis in this study died in the hospital [6]. Although Received 03 February 2023; accepted 19 April 2023; published online 20 April 2023 there is robust literature on the epidemiology of sepsis in US Current affiliation: Division of Global Health Protection, Centers for Disease Control and Prevention, Atlanta, Georgia, USA. adults [7–9], there are relatively few recent, multicenter studies Current affiliation: Michigan Department of Health and Human Services, Lansing, Michigan, of US pediatric sepsis epidemiology. Most previously published USA. Current affiliation: HealthPartners Institute, Bloomington, Minnesota, USA. studies used administrative data [10–13] or were focused on Current affiliation: Western Health, Melbourne, Australia. patients admitted to pediatric intensive care units [14]. Current affiliation: Atlanta Veterans Affairs Medical Center, Decatur, Georgia, USA. Correspondence: Shelley S. Magill, MD, PhD, Division of Healthcare Quality Promotion, Through the Centers for Disease Control and Prevention’s Centers for Disease Control and Prevention, 1600 Clifton Rd NE, HB16-3, Atlanta, GA 30333 (CDC) Emerging Infections Program (EIP), we conducted a (smagill@cdc.gov); Lauren Epstein, MD, MSc, Atlanta Veterans Affairs Medical Center, RIM detailed medical record review of US children and young adults 111, 1670 Clairmont Rd, Decatur, GA 30333 (lauren.epstein@va.gov). Open Forum Infectious Diseases with hospital discharge codes of severe sepsis or septic shock to Published by Oxford University Press on behalf of Infectious Diseases Society of America 2023. describe demographic and clinical characteristics, including by This work is written by (a) US Government employee(s) and is in the public domain in the US. https://doi.org/10.1093/ofid/ofad218 age group. Pediatric Sepsis Epidemiology • OFID • 1 METHODS healthcare facility (such as a hospital or long-term care facility) in the 30 or 90 days before admission. Data were also collected Hospitals and Patients on outpatient healthcare in the 7 days before sepsis hospital ad- The methods have been described previously [15]. The EIP is a mission, including the visit date and setting type (eg, primary network of 10 state health departments (California, Colorado, care or medical subspecialty clinic). Connecticut, Georgia, Maryland, Minnesota, New Mexico, In addition, data were collected on (1) infections document- New York, Oregon, and Tennessee) and academic partners ed in the medical record as present within 7 days before or after [16]. Each EIP site recruited 2–4 hospitals. Trained EIP staff sepsis diagnosis, including the subset documented to be associ- reviewed medical records of randomly selected patients with ated with sepsis at the time of sepsis diagnosis or in the hospital sepsis in these hospitals, with a goal of including approximately discharge summary; (2) vital signs and laboratory data on 100 adult (≥18 years old) and 100 pediatric patients (<18 the day before, day of, and day after sepsis diagnosis to deter- years old) per EIP site. Patients were eligible for inclusion mine the presence of the systemic inflammatory response syn- if they were discharged from a participating hospital between drome using age-specific criteria [17, 18]; (3) cultures and 1 October 2014 and 30 September 2015 and had an explicit nonculture microbiological tests collected during the 7 days be- diagnosis code for severe sepsis or septic shock (International fore and after sepsis diagnosis; and (4) outcome at hospital dis- Classification of Diseases, Ninth Revision, Clinical Modification charge. Death certificate information was gathered from state [ICD-9-CM] code 995.92 or 785.52). Only the first hospitaliza- vital statistics registries to identify patients who died within tion per eligible patient during the period of interest was includ- 90 days of sepsis diagnosis. ed. In some EIP sites there were fewer than 100 patients <18 Indicators of organ dysfunction documented in the medical years old with a sepsis-related hospital discharge during the record in the 7 days before or after sepsis diagnosis were also time frame of interest across all participating hospitals. In these collected. These indicators were generally consistent with crite- cases, sites were asked to review the records of all pediatric ria proposed by Hsu et al for consideration in an EHR defini - patients. tion of pediatric sepsis or sensitivity analyses [5], based on Patients without clinical documentation in the medical re- modifications of the pediatric Sequential Organ Failure cord of terms such as sepsis or septic shock and patients who Assessment (pSOFA) score [19]: invasive mechanical ventila- were missing a sepsis diagnosis date were excluded. Results of tion, noninvasive positive pressure ventilation, receipt of vaso- the analysis of patients ≥18 years old with sepsis have been pressor medications, systolic blood pressure <90 mm Hg, published [15]. For the current analysis, we included patients documented altered mental status, lactate ≥2 mmol/L, platelets 30 days to 21 years old. Infants <30 days old or who were never <100 000/µL, creatinine ≥2 times baseline, and total bilirubin discharged from the hospital after birth were excluded [5]. ≥2 times baseline and ≥2 mg/dL. Organ dysfunction evidenced by mechanical ventilation or noninvasive positive pressure ven- Patient Consent Statement tilation, receipt of vasopressors, systolic blood pressure The human subjects advisor in the CDC’s National Center for <90 mm Hg, or altered mental status had to be new or worsen- Emerging and Zoonotic Infectious Diseases determined the ing during the 7 days before or after sepsis diagnosis. Baseline project to be a nonresearch activity. Institutional review boards values of total bilirubin and creatinine were defined as the low- in EIP sites and participating hospitals determined the project est value during the 7 days before or after sepsis diagnosis. to be nonresearch or approved the project with waiver of in- formed consent. Analysis To determine which organisms were associated with sepsis, we Data Collection developed an algorithm based on the specimen type (sterile or EIP site staff collected medical record data using a standardized nonsterile body site), diagnostic test (culture or nonculture), or- data collection form. Data collection focused on preadmission ganism, and infection site documented in the medical record healthcare and information present in the medical record (Supplementary Table 1). This approach was adapted from the around the sepsis diagnosis date, defined as the first date a previously published analysis of adult patients with sepsis [15]. healthcare practitioner documented sepsis or a related term Sepsis cases were classified as hospital-onset, healthcare-associated in the medical record. Preadmission healthcare data collection community-onset, or community-associated. Hospital-onset included (1) prehospital treatment or procedures (receipt of cases were defined as occurring in patients with a sepsis diagnosis antimicrobial medications, chemotherapy, wound care, dialy- date on hospital day 4 or later. Healthcare-associated sis, or surgery in the 30 days before admission); (2) prehospital community-onset cases were defined as sepsis events with diagno- medical devices (urinary catheter, central line, mechanical ven- sis dates on hospital days 1–3, and occurring in (1) patients in a tilation, gastrostomy or jejunostomy tube, or tracheostomy in hospital or other healthcare facility (such as a nursing home) 4 the 30 days before admission); and (3) stays of ≥2 days in a days before admission and in a community location or 2 • OFID • Magill et al Treatment, Procedures, and Devices Before the Sepsis Hospitalization nonhospital facility immediately prior to admission; or (2) Three hundred thirteen patients (42.5%) received a treatment patients with a medical device, treatment, or procedure in or procedure in the 30 days before hospital admission, among the 30 days before sepsis hospital admission, or a ≥2-day which antimicrobial medications were the most common in all healthcare facility stay in the 90 days before sepsis hospital ad- age groups (263 patients [35.7%]). Medical devices were pre- mission. Community-associated cases were defined as sepsis sent in the 30 days before hospital admission in 264 patients events with diagnosis dates on hospital days 1–3, occurring (35.9%) overall, ranging from 23.3% in the age group 30 days in patients who were (1) in a private residence or other com- to 11 months to 46.9% in those aged 1–4 years (Table 2). munity location 4 days before the sepsis hospital admission, Among 442 patients with underlying conditions, 327 (74.0%) regardless of patient location immediately before sepsis hospi- had a medical device, treatment, or procedure in the 30 days be- tal admission; and (2) reported to have no medical devices, fore sepsis hospital admission, or a healthcare facility stay in the treatments, or procedures in the 30 days before sepsis hospital 90 days before sepsis hospital admission. admission and no ≥2-day healthcare facility stay in the 90 days Almost three-quarters of all patients with sepsis (548 before sepsis hospital admission. Patients who were in a hospi- [74.5%]) had an underlying condition, treatment, or procedure tal other than the sepsis hospital 4 days before sepsis hospital in the 30 days before admission, medical device in the 30 days admission, and also in a hospital other than the sepsis hospital before admission, or ≥2-day stay in a healthcare facility in the immediately prior to admission (such as patients transferred 90 days before admission. One hundred seventy-five patients from another hospital), with a sepsis diagnosis date on days (23.8%) had no underlying conditions and none of these 1–3 in the sepsis hospital, were considered to have sepsis of un- healthcare interactions before hospital admission (data were known onset. incomplete for 13 patients [1.8%]). We conducted a descriptive analysis of demographic and clinical variables stratified by age group: 30 days–11 months, 1–4 years, 5–12 years, and 13–21 years. Analyses were per- Outpatient Visits Before the Sepsis Hospital Admission formed using SAS version 9.4 software (SAS Institute). Two hundred forty-one patients (32.7%) were identified as hav- Data were analyzed between 1 May 2018 and 12 October ing outpatient visits from 1 to 7 days before hospital admission 2022. (not including the day of admission), with visits to a medical subspecialty (74 patients [10.1%]) or primary care clinic (74 pa- tients [10.1%]) being the most common overall (Table 2). The percentage of patients with underlying conditions who RESULTS had an outpatient visit from 1 to 7 days before hospital admis- Patient Characteristics sion (151/442 patients [34.2%]) was only slightly higher than in Among 900 patients ≤21 years old at hospital admission, 736 patients with no or unknown underlying conditions (90/294 patients in 26 hospitals met inclusion criteria. Of 164 excluded patients [30.6%]). Among the subset of patients with underly- patients, 133 were <30 days old; 13 were never discharged from ing conditions and devices, treatments, or procedures in the 30 the hospital after birth; 17 did not have documentation of sep- days before admission, or another healthcare facility stay in the sis, septic shock, or similar terms in the medical record; and 1 90 days before admission, the percentage with an outpatient was missing the sepsis diagnosis date. visit in the 7 days before admission was 37.3% (122/327 pa- Of 736 patients with sepsis who met inclusion criteria, 386 pa- tients). Among the 241 patients with outpatient visits 1 to 7 tients (52.4%) were female, 355 (48.2%) were non-Hispanic days before sepsis hospitalization, 125 (51.9%) received antimi- White, 144 (19.6%) were Hispanic, and 129 (17.5%) were crobials in the 30 days before sepsis hospitalization. non-Hispanic Black ethnicity and race. The distribution of eth- nicity and race varied by age, with a higher percentage of chil- Infections and Pathogens dren <5 years old reported to be of non-Hispanic Black At least 1 infection (including infection of unknown type) was ethnicity and race (53/235 [22.6%]) compared with older chil- reported for 712 patients (96.7%) (Table 3). Infection types var- dren (76/501 [15.2%]). Four hundred sixteen (56.5%) were re- ied by age group; among patients 30 days to 11 months old, ported to have Medicaid as the primary insurer. bloodstream infections were most common (26 [28.9%]), Most patients (442 [60.1%]) had ≥1 underlying condition whereas pneumonia was the most common infection in all oth- (Table 1). The distribution of underlying conditions varied er age groups (in 30.3% of patients 1–4 years old, 24.2% of pa- by age, with prematurity the most common condition among tients 5–12 years old, and 27.0% of patients 13–21 years old). children 30 days–11 months old (30 [33.3%]) and 1–4 years Almost all patients (732 [99.5%]) had ≥1 culture or noncul- old (34 [23.4%]), chronic pulmonary disease among children ture microbiology test in the 7 days before or after the date of 5–12 years old (51 [23.3%]), and chronic immunocompromise sepsis diagnosis; 518 (70.4%) had ≥1 positive test, and 427 among patients 13–21 years old (54 [19.1%]). (58.0%) had ≥1 positive test for a pathogen associated with Pediatric Sepsis Epidemiology • OFID • 3 Table 1. Demographic and Clinical Characteristics of Children and Young Adults With Sepsis, by Age Group Age Group Total 30 Days–11 Months 1–4 Years 5–12 Years 13–21 Years Characteristic (N = 736) (n = 90) (n = 145) (n = 219) (n = 282) State of residence California 67 (9.1) 6 (6.7) 16 (11.0) 20 (9.1) 25 (8.9) Colorado 94 (12.8) 5 (5.6) 18 (12.4) 30 (13.7) 41 (14.5) Connecticut 82 (11.1) 6 (6.7) 14 (9.7) 22 (10.0) 40 (14.2) Georgia 105 (14.3) 19 (21.1) 24 (16.6) 34 (15.5) 28 (9.9) Maryland 94 (12.8) 13 (14.4) 24 (16.6) 34 (15.5) 23 (8.2) Minnesota 87 (11.8) 20 (22.2) 13 (9.0) 28 (12.8) 26 (9.2) New Mexico 38 (5.2) 5 (5.6) 4 (2.8) 8 (3.7) 21 (7.4) New York 47 (6.4) 7 (7.8) 9 (6.2) 9 (4.1) 22 (7.8) Oregon 59 (8.0) 3 (3.3) 13 (9.0) 14 (6.4) 29 (10.3) Tennessee 63 (8.6) 6 (6.7) 10 (6.9) 20 (9.1) 27 (9.6) Sex Female 386 (52.4) 48 (53.3) 75 (51.7) 123 (56.2) 140 (49.6) Male 350 (47.6) 42 (46.7) 70 (48.3) 96 (43.8) 142 (50.4) Race/ethnicity American Indian, non-Hispanic 16 (2.2) 5 (5.6) 2 (1.4) 4 (1.8) 5 (1.8) Asian, non-Hispanic 29 (3.9) 6 (6.7) 4 (2.8) 11 (5.0) 8 (2.8) Black, non-Hispanic 129 (17.5) 21 (23.3) 32 (22.1) 33 (15.1) 43 (15.2) Hispanic/Latino 144 (19.6) 18 (20.0) 25 (17.2) 47 (21.5) 54 (19.1) Pacific Islander, non-Hispanic 4 (0.5) 1 (1.1) 0 1 (0.5) 2 (0.7) White, non-Hispanic 355 (48.2) 34 (37.8) 66 (45.5) 104 (47.5) 151 (53.5) Other or multiple races, non-Hispanic 29 (3.9) 0 9 (6.2) 13 (5.9) 7 (2.5) Unknown race, non-Hispanic 30 (4.1) 5 (5.6) 7 (4.8) 6 (2.7) 12 (4.3) Primary insurance type Medicaid 416 (56.5) 55 (61.1) 89 (61.4) 128 (58.4) 144 (51.1) Private 254 (34.5) 24 (26.7) 36 (24.8) 74 (33.8) 120 (42.6) Other 47 (6.4) 7 (7.8) 17 (11.7) 11 (5.0) 12 (4.3) Unknown 19 (2.6) 4 (4.4) 3 (2.1) 6 (2.7) 6 (2.1) Location immediately before sepsis admission Private residence 378 (51.4) 44 (48.9) 77 (53.1) 116 (53.0) 141 (50.0) Another acute care hospital or emergency department 271 (36.8) 41 (45.6) 46 (31.7) 82 (37.4) 102 (37.6) Outpatient clinic or urgent care 73 (9.9) 5 (5.6) 21 (14.5) 20 (9.1) 27 (9.6) Nursing home 4 (0.5) 0 0 0 4 (1.4) Other 6 (0.8) 0 0 1 (0.5) 5 (1.8) Unknown 4 (0.5) 0 1 (0.7) 0 3 (1.1) Location 4 days before sepsis admission Private residence 676 (91.8) 85 (94.4) 135 (93.1) 200 (91.3) 256 (90.8) Another acute care hospital 38 (5.2) 5 (5.6) 7 (4.8) 13 (5.9) 13 (4.6) Nursing home 5 (0.7) 0 1 (0.7) 0 4 (1.4) Other 11 (1.5) 0 1 (0.7) 3 (1.4) 7 (2.5) Unknown 6 (0.8) 0 1 (0.7) 3 (1.4) 2 (0.7) Underlying conditions Any underlying condition 442 (60.1) 49 (54.4) 93 (64.1) 132 (60.3) 168 (59.6) Chronic pulmonary disease 137 (18.6) 6 (6.7) 33 (22.8) 51 (23.3) 47 (16.7) Chronic cognitive deficit 118 (16.0) 8 (8.9) 31 (21.4) 40 (18.3) 39 (13.8) Chronic immunocompromise 109 (14.8) 5 (5.6) 17 (11.7) 33 (15.1) 54 (19.1) Hematologic or oncologic disease 108 (14.7) 3 (3.3) 22 (15.2) 37 (16.9) 46 (16.3) History of prematurity 90 (12.2) 30 (33.3) 34 (23.4) 14 (6.4) 12 (4.3) Congenital heart disease 63 (8.6) 23 (25.6) 17 (11.7) 10 (4.6) 13 (4.6) Hemiplegia, paraplegia, quadriplegia 42 (5.7) 0 4 (2.8) 16 (7.3) 22 (7.8) Chronic kidney disease 31 (4.2) 2 (2.2) 7 (4.8) 10 (4.6) 12 (4.3) Chronic mental illness 18 (2.4) 0 0 4 (1.8) 14 (5.0) Other cardiovascular disease 17 (2.3) 2 (2.2) 6 (4.1) 5 (2.3) 4 (1.4) Chronic liver disease 15 (2.0) 1 (1.1) 7 (4.8) 2 (0.9) 5 (1.8) 4 • OFID • Magill et al Table 1. Continued Age Group Total 30 Days–11 Months 1–4 Years 5–12 Years 13–21 Years Characteristic (N = 736) (n = 90) (n = 145) (n = 219) (n = 282) Diabetes mellitus 12 (1.6) 0 1 (0.7) 3 (1.4) 8 (2.8) Chronic wound 10 (1.4) 2 (2.2) 2 (1.4) 0 6 (2.1) Connective tissue disease 6 (0.8) 0 0 3 (1.4) 3 (1.1) Pregnancy 2 (0.3) … … 0 2 (0.7) Peptic ulcer disease 1 (0.1) 0 0 0 1 (0.4) Unknown 9 (1.2) 1 (1.1) 1 (0.7) 3 (1.4) 4 (1.4) Substance use 15 (2.0) … … 0 15 (5.3) Data are presented as No. (%). Persons with unknown ethnicity are grouped with persons reported as non-Hispanic. Including persons experiencing homelessness or incarceration. Includes any of the conditions listed. Including asthma in 91 of 137 patients. Defined as asplenia, neutropenia, hematopoietic stem cell transplant, solid organ transplant, human immunodeficiency virus infection, primary immunodeficiency, or chronic steroid or other immunosuppressive therapy. Includes type 1 and type 2 diabetes mellitus and gestational diabetes. Includes alcohol use disorder, injection drug use, and smoking. sepsis. The percentages of patients with any microbiological intensive care unit, and ≥1 indicator of organ dysfunction testing, positive tests, and positive tests for pathogens was present in the 7 days before or after sepsis diagnosis in associated with sepsis decreased as patient age increased 682 patients (92.7%). Indicators of cardiovascular dysfunction (Supplementary Table 2). For example, 65.6% of patients 30 (systolic blood pressure <90 mm Hg or receipt of vasopressors) days to 11 months old had ≥1 pathogen identified that was as - or perfusion dysfunction (lactate ≥2 mmol/L) were documented sociated with sepsis compared with 49.3% of patients 13–21 for 627 patients (85.2%). years old. Overall, 74 patients (10.1%) died during their hospitalization Among patients in whom a sepsis-associated pathogen was (71 within 90 days of sepsis diagnosis). Eighty-four patients detected, gram-positive bacteria were most common (215/427 (11.4%) died within 90 days of sepsis diagnosis; 13 of these pa- patients [50.4%]), followed by gram-negative bacteria (193/ tients (15.5%) died after discharge from their sepsis hospitaliza- 427 [45.2%]) and viruses (123/427 [28.8%]) (Supplementary tion. The youngest age group, patients 30 days to 11 months Table 2). Pathogen distribution varied by age group, although old, had the highest percentage of patients who died during Staphylococcus aureus was the most common pathogen overall their hospitalization (15.6%) or within 90 days of diagnosis (89 patients, 12.1% of all patients and 20.8% of those with a (18.9%). Patients with underlying conditions were more likely sepsis-associated pathogen) and in all age groups except pa- to die during their hospitalizations (55/442 [12.4%]) and dur- tients 1–4 years old in whom respiratory syncytial virus was ing the 90 days after sepsis diagnosis (62/442 [14.0%]) than pa- most common (13 patients, 9.0% of all patients in this age tients without or with unknown underlying conditions group and 14.0% of those with a sepsis-associated pathogen) (in-hospital death: 19/294 [6.5%]; 90 days after sepsis diagnosis: (Table 4). 22/294 [7.5%]). Patients with hospital-onset sepsis were more likely to die (in-hospital death: 26/106 [24.5%]; 90 days after sepsis diagnosis: 26/106 [24.5%]) than patients with Sepsis Hospitalization and Outcome community-onset sepsis (in-hospital death: 46/613 [7.5%]; 90 Most patients had community-onset sepsis (613/736 [83.3%]); days after sepsis diagnosis: 56/613 [9.1%]). most community-onset sepsis was healthcare associated (344/ 613 [56.1%]) (Table 5). Hospital-onset sepsis was more com- mon among patients <5 years old (46/235 [19.6%]) than among DISCUSSION older patients (60/501 [12.0%]). Patients with sepsis had prolonged hospitalizations, rang- In our analysis of medical record data from 736 children and ing from a median of 7 days (interquartile range [IQR], 4– young adults with explicit ICD-9-CM codes for severe sepsis or 17 days) in those 13–21 years old to 14 days (IQR, 7–30 septic shock during hospitalizations in 2014–2015, 60% of patients days) in those 1–4 years old (Table 5). Most patients (647 had at least 1 underlying condition and almost one-third of all pa- [87.9%]) spent at least part of their hospitalization in the tients with sepsis, including those without underlying conditions, Pediatric Sepsis Epidemiology • OFID • 5 Table 2. Healthcare Received by Children and Young Adults With Sepsis Before the Sepsis Hospitalization, by Age Group Age Group Total 30 Days–11 Months 1–4 Years 5–12 Years 13–21 Years Characteristic (N = 736) (n = 90) (n = 145) (n = 219) (n = 282) Outpatient visit in the 7 d before sepsis hospitalization Any of the included visits 241 (32.7) 33 (36.7) 52 (35.9) 71 (32.4) 85 (30.1) Medical or pediatric subspecialty 74 (10.1) 7 (7.8) 21 (14.5) 21 (9.6) 25 (8.9) Primary care 74 (10.1) 12 (13.3) 16 (11.0) 17 (7.8) 29 (10.3) Emergency department 65 (8.8) 14 (15.6) 8 (5.5) 16 (7.3) 27 (9.6) Urgent care 13 (1.8) 1 (1.1) 5 (3.4) 3 (1.4) 4 (1.4) Surgery 6 (0.8) 0 0 6 (2.7) 0 Physical, occupational, or speech therapy 3 (0.4) 0 2 (1.4) 1 (0.5) 0 Dental 1 (0.1) 0 1 (0.7) 0 0 Other 25 (3.4) 2 (2.2) 3 (2.1) 12 (5.5) 8 (2.8) Unknown type of visit 1 (0.1) 0 0 0 1 (0.4) Treatments or procedures in the 30 d before sepsis hospitalization Any of the included treatments or procedures 313 (42.5) 29 (32.2) 73 (50.3) 96 (43.8) 115 (40.8) Antimicrobial medications 263 (35.7) 27 (30.0) 62 (42.8) 78 (35.6) 96 (34.0) Cancer chemotherapy 76 (10.3) 2 (2.2) 16 (11.0) 28 (12.8) 30 (10.6) Surgery 35 (4.8) 5 (5.6) 12 (8.3) 12 (5.5) 6 (2.1) Wound care 14 (1.9) 2 (2.2) 2 (1.4) 6 (2.7) 4 (1.4) Chronic dialysis 4 (0.5) 0 2 (1.4) 1 (0.5) 1 (0.4) Devices present in the 30 d before sepsis hospitalization Any of the included devices 264 (35.9) 21 (23.3) 68 (46.9) 83 (37.9) 92 (32.6) Gastrostomy or jejunostomy tube 159 (21.6) 13 (14.4) 53 (36.6) 50 (22.8) 43 (15.2) Central line 132 (17.9) 8 (8.9) 33 (22.8) 41 (18.7) 50 (17.7) Mechanical ventilator 33 (4.5) 5 (5.6) 9 (6.2) 9 (4.1) 10 (3.5) Tracheostomy 27 (3.7) 1 (1.1) 10 (6.9) 11 (5.0) 5 (1.8) Urinary catheter 17 (2.3) 1 (1.1) 1 (0.7) 6 (2.7) 9 (3.2) Admission for ≥2 d to a healthcare facility in the 30 d before sepsis hospitalization Hospital 164 (22.3) 29 (32.2) 35 (24.1) 47 (21.5) 53 (18.8) Long-term acute care hospital 1 (0.1) 0 0 0 1 (0.4) Nursing home 4 (0.5) 0 0 0 4 (1.4) Admission for ≥2 d to a healthcare facility in the 90 d before sepsis hospitalization Hospital 217 (29.5) 39 (43.3) 52 (35.9) 65 (29.7) 61 (21.6) Long-term acute care hospital 1 (0.1) 0 0 0 1 (0.4) Nursing home 4 (0.5) 0 0 0 4 (1.4) Data are presented as No. (%). Includes outpatient encounters that occurred from 1 to 7 days before the day of admission. Excludes encounters that were reported to occur on the same day as hospital admission and encounters with missing dates. Other visits include visits to infusion clinics, laboratories, or radiology. Seven patients were reported to have visited a hospital; these were included since the specific type of location visited within the hospital was not reported and could have been an outpatient location. had an outpatient visit in the week prior to the sepsis hospitaliza- or day before sepsis hospitalization. Most of these patients tion. Although most sepsis had its onset in the community, more (80.5%) had symptoms of infection or sepsis in clinic, but 44 than half of cases of community-onset sepsis occurred in patients patients (37.3%) were either treated as an outpatient or sent who had received recent prehospital healthcare. home without intervention. Upon subsequent presentation Our finding that almost one-third of patients had an outpa- to the hospital or emergency department, 77.3% of the patients tient visit in the week before sepsis hospitalization has also been treated as an outpatient or sent home from clinic were noted to observed in studies of adult patients with sepsis [20, 21]. have worsening illness severity, compared with 37.8% of those Flannery and colleagues reviewed observational studies of adult who were referred directly to the emergency department [22]. patients with sepsis and found that an average of 32.7% of pa- These observations suggest that for some patients, there may tients had outpatient encounters in the week before sepsis hos- be opportunities to intervene earlier, although more data are pitalization [20]. In a study of 1150 adult patients with a sepsis needed [23], including studies describing the reasons for and hospital discharge and an established outpatient provider in quality of prehospital care in children who are subsequently ad- 2017, 118 patients (10.3%) were seen in clinic on the day of mitted for sepsis. 6 • OFID • Magill et al a b Table 3. Infections Present During the Period Defined by the 7 Days Before or After Sepsis Diagnosis and Documented as the Cause of Sepsis , by Age Group Age Group Infection Type Total (N = 736) 30 Days–11 Months (n = 90) 1–4 Years (n = 145) 5–12 Years (n = 219) 13–21 Years (n = 282) Pneumonia 193 (26.2) 20 (22.2) 44 (30.3) 53 (24.2) 76 (27.0) Documented as the cause of sepsis 152/193 (78.8) 17/20 (85.0) 29/44 (65.9) 46/53 (86.8) 60/76 (78.9) Bloodstream 154 (20.9) 26 (28.9) 37 (25.5) 38 (17.4) 53 (18.8) Documented as the cause of sepsis 123/154 (79.9) 22/26 (84.6) 29/37 (78.4) 34/38 (89.5) 38/53 (71.6) Undetermined or unknown 107 (14.5) 11 (12.2) 21 (14.5) 31 (14.2) 44 (15.6) Documented as the cause of sepsis 72/107 (67.3) 8/11 (72.7) 12/21 (57.1) 20/31 (64.5) 32/44 (72.7) Urinary tract 101 (13.7) 13 (14.4) 10 (6.9) 31 (14.2) 47 (16.7) Documented as the cause of sepsis 77/101 (76.2) 9/13 (69.2) 9/10 (90.0) 22/31 (71.0) 37/47 (78.7) Lower respiratory (other than pneumonia) 84 (11.4) 23 (25.6) 22 (15.2) 22 (10.0) 17 (6.0) Documented as the cause of sepsis 36/84 (42.9) 12/23 (52.2) 8/22 (36.4) 9/22 (40.9) 7/17 (41.2) Ear, eye, mouth, nose, or throat 64 (8.7) 9 (10.0) 12 (8.3) 27 (12.3) 16 (5.7) Documented as the cause of sepsis 36/64 (56.3) 4/9 (44.4) 5/12 (41.7) 16/27 (59.3) 11/16 (68.8) Skin or soft tissue 51 (6.9) 5 (5.6) 4 (2.8) 20 (9.1) 22 (7.8) Documented as the cause of sepsis 29/51 (56.9) 2/5 (40.0) 2/4 (50.0) 11/20 (55.0) 14/22 (63.6) Gastrointestinal tract (other than CDI) 50 (6.8) 5 (5.6) 7 (4.8) 14 (6.4) 24 (8.5) Documented as the cause of sepsis 36/50 (72.0) 3/5 (60.0) 3/7 (42.9) 11/14 (78.6) 19/24 (79.2) Intra-abdominal 39 (5.3) 2 (2.2) 9 (6.2) 15 (6.8) 13 (4.6) Documented as the cause of sepsis 27/39 (69.2) 2/2 (100) 5/9 (55.6) 11/15 (73.3) 9/13 (69.2) Central nervous system 36 (4.9) 10 (11.1) 10 (6.9) 8 (3.7) 8 (2.8) Documented as the cause of sepsis 27/36 (75.0) 8/10 (80.0) 7/10 (70.0) 6/8 (75.0) 6/8 (75.0) CDI 19 (2.6) NA 7 (4.8) 4 (1.8) 8 (2.8) Documented as the cause of sepsis 5/19 (26.3) NA 1/7 (14.3) 1/4 (25.0) 3/8 (37.5) Bone or joint 16 (2.2) 0 1 (0.7) 8 (3.7) 7 (2.5) Documented as the cause of sepsis 12/16 (75.0) 0 0 7/8 (87.5) 5/7 (71.4) Disseminated 16 (2.2) 0 3 (2.1) 4 (1.8) 9 (3.2) Documented as the cause of sepsis 11/16 (68.8) 0 2/3 (66.7) 2/4 (50.0) 7/9 (77.8) Cardiovascular 9 (1.2) 1 (1.1) 1 (0.7) 3 (1.4) 4 (1.4) Documented as the cause of sepsis 7/9 (77.8) 1/1 (100) 1/1 (100) 2/3 (66.7) 3/4 (75.0) Reproductive 7 (1.0) 0 0 1 (0.5) 6 (2.1) Documented as the cause of sepsis 6/7 (85.7) 0 0 0 6/6 (100) Hepatobiliary 6 (0.8) 0 3 (2.1) 0 3 (1.1) Documented as the cause of sepsis 2/6 (33.3) 0 0 0 2/3 (66.7) No infection documented 24 (3.3) 2 (2.2) 6 (4.1) 8 (3.7) 8 (2.8) Data are presented as No. (%). Abbreviations: CDI, Clostridioides difficile infection; NA, not applicable. Patients could have >1 infection type. In 14 patients, 1 infection type was reported >1 time (for example, 2 lower respiratory tract infections were reported for the same patient). Duplicate records for 8 of these patients (records with identical data) were deleted. For 6 of the 14 patients with multiple unique infections of the same type, we kept the infection that was reported to have caused sepsis and/or the infection with onset before the sepsis diagnosis date. Documented in the medical record as the cause of sepsis at the time of sepsis diagnosis or in the discharge summary. Infections were reported as undetermined site if there was medical record documentation that the source of infection was not yet known. Infections were reported as unknown site when there was insufficient or incomplete documentation in the medical record to determine the site of infection. In total, there were 106 patients with infections of undetermined site and 10 patients with infections of unknown site. Guidelines for the care of pediatric patients with sepsis and were evaluated by a pediatric emergency physician or mobile septic shock, as for adult patients, have primarily focused on medical unit, and suboptimal care was associated with in- providing recommendations for the recognition and treatment creased odds of death. Although not statistically significant, of sepsis in the emergency department and after hospital ad- children who died were also more likely to have had parental mission [24, 25], although the importance of educating the delays in seeking medical care compared with those who sur- public, including parents and healthcare providers, to improve vived [28]. Investigators are studying whether assessing the lev- sepsis early recognition and response in the prehospital setting el of parent and healthcare provider concern for severe has been acknowledged [26, 27]. In a study of 114 children with infection in the emergency department can lead to earlier rec- severe bacterial infection, 21 of whom died, children whose ini- ognition of sepsis [29]. CDC and organizations such as Sepsis tial medical contact was with a general practitioner were more Alliance and End Sepsis have developed campaigns and mate- likely to receive suboptimal care compared with those who rials to educate the public and healthcare providers about sepsis Pediatric Sepsis Epidemiology • OFID • 7 Table 4. Common Pathogens Associated With Sepsis, by Patient Age Group Age Group a b c d Pathogen Total (N = 736) 30 Days–11 Months (n = 90) 1–4 Years (n = 145) 5–12 Years (n = 219) 13–21 Years (n = 282) Staphylococcus aureus 89 (12.1) 10 (11.1) 12 (8.3) 26 (11.9) 41 (14.5) Escherichia coli 61 (8.3) 6 (6.7) 8 (5.5) 21 (9.6) 26 (9.2) Pseudomonas aeruginosa 32 (4.3) 5 (5.6) 11 (7.6) 11 (5.0) 5 (1.8) Viridans streptococci 30 (4.1) 9 (10.0) 2 (1.4) 11 (5.0) 8 (2.8) Klebsiella pneumoniae 29 (3.9) 3 (3.3) 11 (7.6) 7 (3.2) 8 (2.8) RSV 27 (3.7) 8 (8.9) 13 (9.0) 4 (1.8) 2 (0.7) Streptococcus pneumoniae 27 (3.7) 5 (5.6) 8 (5.5) 9 (4.1) 5 (1.8) Streptococcus, group A 27 (3.7) 2 (2.2) 10 (6.9) 11 (5.0) 4 (1.4) Rhinovirus 26 (3.5) 5 (5.6) 5 (3.4) 10 (4.6) 6 (2.1) Enterovirus 18 (2.4) 6 (6.7) 5 (3.4) 6 (2.7) 1 (0.4) Clostridioides difficile 15 (2.0) NA 5 (3.4) 3 (1.4) 7 (2.5) Influenza A 15 (2.0) 1 (1.1) 2 (1.4) 7 (3.2) 5 (1.8) Haemophilus influenzae 14 (1.9) 6 (6.7) 2 (1.4) 2 (0.9) 4 (1.4) Adenovirus 13 (1.8) 4 (4.4) 4 (2.8) 4 (1.8) 1 (0.4) Enterococcus faecalis 13 (1.8) 1 (1.1) 5 (3.4) 3 (1.4) 4 (1.4) Human metapneumovirus 13 (1.8) 0 6 (4.1) 5 (2.3) 2 (0.7) Data are presented as No. (%). Abbreviations: NA, not applicable; RSV, respiratory syncytial virus. Among patients 30 days to 11 months old, other organisms detected in 3 or more patients included Moraxella catarrhalis (7 [7.8%]) and Serratia marcescens (3 [3.3%]). Among patients 1–4 years old, other organisms detected in 3 or more patients included Enterobacter cloacae (5 [3.4%]), coagulase-negative staphylococci (3 [2.1%]), and Streptococcus spp (3 [2.1%]). Among patients 5–12 years old, other organisms detected in 3 or more patients included coagulase-negative staphylococci (5 [2.3%]), Streptococcus spp (4 [1.8%]), Citrobacter freundii (3 [1.4%]), cytomegalovirus (3 [1.4%]), Enterobacter cloacae (3 [1.4%]), and Enterococcus spp (3 [1.4%]). Among patients 13–21 years old, other organisms detected in 3 or more patients included Enterococcus faecium (4 [1.4%]), influenza B (4 [1.4%]), Candida albicans (3 [1.1%]), cytomegalovirus (3 [1.1%]), Enterococcus spp (3 [1.1%]), and Proteus mirabilis (3 [1.1%]). [30–32]. Further research is needed to determine whether edu- patients with sepsis who were less severely ill. Third, we relied cational efforts facilitate earlier recognition and treatment of on medical record documentation of healthcare interactions sepsis and improve patient outcomes [33]. that occurred prior to hospital admission, and this documentation We observed differences in sepsis epidemiology among chil- was likely incomplete. Fourth, we did not collect information dren in different age groups outside the neonatal period, includ- about the reason for these healthcare interactions, nor did we col- ing differences in underlying conditions, prehospital healthcare, lect information about infections diagnosed or treated before hos- common infections and pathogens, and outcomes. For example, pital admission. Fifth, we had limited data to use in determining children between 30 days and 4 years old with sepsis tended to be whether sepsis was hospital or community onset, and it is possible more medically complex with longer hospitalizations and higher some cases were misclassified. Finally, we used an algorithm to de- mortality than children ≥5 years old with sepsis. Our findings termine which organisms were likely to be associated with sepsis, suggest that different approaches to prevention, early recogni- which also may have resulted in misclassification. tion, and management of nonneonatal pediatric sepsis may be needed in children of different ages. To optimize care and out- CONCLUSIONS comes, investigators have proposed grouping patients into vari- ous subclasses of sepsis based on factors such as clinical or A large percentage of US children and young adults hospital- biological features [34]. Our findings indicate that there may ized with sepsis have underlying chronic medical conditions be sepsis subclasses in children outside the neonatal period or healthcare interactions, including visits with outpatient pro- that are dependent, at least in part, on patient age. viders, in the days or weeks leading up to their sepsis hospital This analysis has several limitations. First, we included a conve- admission. Approaches to raise awareness among outpatient nience sample of hospitals and relatively small number of patients providers of the risk of sepsis in these patients and improve ear- in a limited number of geographic areas; therefore, our results ly recognition and appropriate clinical intervention should be might not be generalizable to all children and young adults with developed and studied. In addition, our data demonstrate dif- sepsis in the US. Second, because there is currently no widely ac- ferences in the epidemiology of sepsis among children of differ- cepted pediatric sepsis surveillance definition, we identified pa- ent ages, which may be important to consider as approaches are tients with sepsis using explicit administrative codes for sepsis developed to improve sepsis prevention, risk prediction, early and septic shock. This may have resulted in the exclusion of recognition, and management. 8 • OFID • Magill et al Table 5. Characteristics of Sepsis Events and Hospitalization in Children and Young Adults, by Age Group Age Group Total 30 Days–11 Months 1–4 Years 5–12 Years 13–21 Years Characteristic (N = 736) (n = 90) (n = 145) (n = 219) (n = 282) Patient location at the time the sepsis diagnosis was first documented in the medical record ICU 324 (44.0) 48 (53.3) 79 (54.5) 94 (42.9) 103 (36.5) Emergency department 295 (40.1) 28 (31.1) 46 (31.7) 91 (41.6) 130 (46.1) Inpatient ward 104 (14.1) 12 (13.3) 19 (13.1) 32 (14.6) 41 (14.5) Other 2 (0.3) 0 0 1 (0.5) 1 (0.4) Unknown 11 (1.5) 2 (2.2) 1 (0.7) 1 (0.5) 7 (2.5) Days from admission to sepsis diagnosis, median (IQR) 0 (0–1) 0 (0–2) 0 (0–1) 0 (0–1) 0 (0–1) Epidemiologic classification of sepsis episode Community onset 613 (83.3) 65 (72.2) 112 (77.2) 182 (83.1) 238 (84.4) Community associated 254 (34.5) 28 (31.1) 38 (26.2) 71 (32.4) 117 (41.5) Healthcare associated 344 (46.7) 37 (41.1) 74 (51.0) 111 (50.7) 122 (43.3) Unknown healthcare association 15 (2.0) 4 (4.4) 1 (0.7) 7 (3.2) 3 (1.1) Hospital onset 106 (14.4) 18 (20.0) 28 (19.3) 25 (11.4) 35 (12.4) Unknown onset 17 (2.3) 3 (3.3) 4 (2.8) 5 (2.3) 5 (1.8) Admitted to the ICU during the sepsis hospitalization 647 (87.9) 80 (88.9) 129 (89.0) 197 (90.0) 241 (85.5) Days in ICU, median (IQR) 4 (2–11) 6 (3–14) 7 (2–15) 4 (2–9) 3 (2–8) Indicators of organ dysfunction Any indicator of organ dysfunction 682 (92.7) 86 (95.6) 135 (93.1) 204 (93.2) 257 (91.1) Systolic blood pressure <90 mm Hg 516 (70.1) 55 (61.1) 103 (71.0) 165 (75.3) 193 (68.4) Vasopressors 370 (50.3) 37 (41.1) 64 (44.1) 119 (54.3) 150 (53.2) Lactate ≥2 mmol/L 345 (46.9) 40 (44.4) 68 (46.9) 109 (49.8) 128 (45.4) Platelets <100 000/µL 287 (39.0) 27 (30.0) 69 (47.6) 86 (39.2) 105 (37.2) Invasive mechanical ventilation 273 (37.1) 59 (65.6) 66 (45.5) 78 (35.6) 70 (24.8) Creatinine ≥2 times baseline 252 (34.2) 33 (36.7) 52 (35.9) 66 (30.1) 101 (35.8) Altered mental status 175 (23.8) 29 (32.2) 35 (24.1) 57 (26.0) 54 (19.1) Noninvasive positive pressure ventilation 104 (14.1) 12 (13.3) 20 (13.8) 32 (14.6) 40 (14.2) Total bilirubin ≥2 times baseline and ≥2 mg/dL 72 (9.8) 7 (7.8) 12 (8.3) 14 (6.4) 39 (13.8) SIRS 727 (98.8) 88 (97.8) 144 (99.3) 217 (99.1) 278 (98.6) Days in hospital, median (IQR) 10 (5–22) 12 (5–29) 14 (7–30) 10 (6–20) 7 (4–17) Sepsis listed in the discharge summary 483 (65.6) 54 (60.0) 76 (52.4) 153 (69.9) 200 (70.9) Location to which patient was discharged from the hospital Private residence 587 (79.8) 65 (72.2) 112 (77.2) 185 (84.5) 225 (79.8) Deceased 74 (10.1) 14 (15.6) 16 (11.0) 17 (7.8) 27 (9.6) Another acute care hospital 33 (4.5) 8 (8.9) 10 (6.9) 5 (2.3) 10 (3.5) Long-term acute care hospital or long-term care facility 21 (2.9) 1 (1.1) 2 (1.4) 7 (3.2) 11 (3.9) Other or unknown 21 (2.9) 2 (2.2) 5 (3.4) 5 (2.3) 9 (3.2) Died within 90 d of sepsis diagnosis 84 (11.4) 17 (18.9) 18 (12.4) 17 (7.8) 32 (11.3) Data are presented as No. (%). Abbreviations: ICU, intensive care unit; IQR, interquartile range; SIRS, systemic inflammatory response syndrome. Three patients had sepsis diagnosis dates predating the day of admission; for 2 patients, the sepsis diagnosis date was the day before hospital admission. These were included in the analysis. For 1 patient the day of sepsis diagnosis was reported to be 6 days before admission. This appeared to be a data entry error and was changed to the day of hospital admission for analysis purposes. Admission and/or discharge dates from the ICU were missing for 11 patients: 1 patient in the age group 30 days–11 months, 3 patients in the age group 1–4 years, 5 patients in the age group 5–12 years, and 2 patients in the age group 13–21 years. During the period defined by the 7 days before and 7 days after sepsis diagnosis. Criteria of the systemic inflammatory response syndrome (SIRS) were assessed each day during the 3-day period defined by the day before sepsis diagnosis through the day after sepsis diagnosis. SIRS was defined as described by Goldstein and colleagues [17]. Patients aged 30 days–17 years had to meet either the temperature criterion (>38.5°C or <36°C) or the age-based white blood cell count criterion, plus 1 additional age-based criterion. Adult SIRS criteria were used for patients who were 18–21 years old [18]. Hospital discharge date missing for 2 patients. Data missing for 6 patients. Supplementary Data Notes Supplementary materials are available at Open Forum Infectious Diseases Author contributions. S. S. M., M. R. P. S., R. G., H. J., J. N., M. M., online. Consisting of data provided by the authors to benefit the reader, S. M. R., L. E. W., R. Pe., R. L., M. S., L. I., G. D., R. Pi., M. K., A. E. F., the posted materials are not copyedited and are the sole responsibility of R. D., and L. E. contributed to study concept and design. All authors con- the authors, so questions or comments should be addressed to the corre- tributed to data acquisition, analysis, or interpretation. S. S. M., M. R. P. S., sponding author. R. G., and L. E. drafted the manuscript. All authors contributed to Pediatric Sepsis Epidemiology • OFID • 9 9. Rhee C, Wang R, Zhang Z, et al. Epidemiology of hospital-onset versus reviewing and revising the manuscript for important intellectual content community-onset sepsis in U.S. hospitals and association with mortality: a retro- and approved the final version for submission. spective analysis using electronic clinical data. Crit Care Med 2019; 47:1169–76. Acknowledgments. The following individuals are acknowledged for their 10. Balamuth F, Weiss SL, Neuman MI, et al. Pediatric severe sepsis in US children’s contributions to data acquisition: California Emerging Infections Program hospitals. Pediatr Crit Care Med 2014; 15:798–805. (EIP): Deborah Godine, RN, Linda Frank, BSN. Colorado EIP: Sarabeth 11. Hartman ME, Linde-Zwirble WT, Angus DC, Watson RS. Trends in the epidemi- Friedman, MSN, Navjot Kaur, MPH, Tolulope Oyewumi, MBBS, Wendy ology of pediatric severe sepsis. Pediatr Crit Care Med 2013; 14:686–93. M. Bamberg, MD. Connecticut EIP: Nicole Stabach, MSN, Paula 12. Thavamani A, Umapathi KK, Dhanpalreddy H, et al. Epidemiology, clinical and Clogher, MPH. Georgia EIP: Lewis Perry, PhD, Susan Morabit, MSN, microbiologic profile and risk factors for inpatient mortality in pediatric severe Stacy Carswell, MPH. Maryland EIP: Linda Li, MPH, Elisabeth Vaeth, sepsis in the United States from 2003 to 2014: a large population analysis. MPH. Minnesota EIP: J. P. Mahoehney, RN, MPH, Jacy Walters, PhD, Pediatr Infect Dis J 2020; 39:781–8. 13. Carlton EF, Kohne JG, Hensley MK, Prescott HC. Comparison of outpatient MPH. New Mexico EIP: Emily Hancock, MS. New York EIP: Christina health care use before and after pediatric severe sepsis. JAMA Netw Open Felsen, MPH. Tennessee EIP: Raphaelle H. Rodzik, MPH, Daniel Muleta, 2020; 3:e2015214. MD, Kelley Tobey, MPH, Katherine Buechel, BSN, Patricia Lawson, 14. Giuliano JS, Markovitz BP, Brierley J, et al. Comparison of pediatric severe sepsis MPH, Vicky Reed, MPH. managed in U.S. and European ICUs. Pediatr Crit Care Med 2016; 17:522–30. Data availability. The data are not publicly available. 15. Fay K, Sapiano MRP, Gokhale R, et al. Assessment of health care exposures and Disclaimer. The findings and conclusions in this report are those of the outcomes in adult patients with sepsis and septic shock. JAMA Netw Open 2020; authors and do not necessarily represent the official position of the Centers 3:e206004. for Disease Control and Prevention or the position or policy of the 16. Centers for Disease Control and Prevention. Emerging Infections Program. Department of Veterans Affairs. Available at: https://www.cdc.gov/ncezid/dpei/eip/index.html. Accessed 30 March 2023. Financial support. This work was supported by the Centers for Disease 17. Goldstein B, Giroir B, Randolph A, et al. International pediatric sepsis consensus Control and Prevention through the Emerging Infections Program cooper- conference: definitions for sepsis and organ dysfunction in pediatrics. Pediatr Crit ative agreement CK12-1202 and CK17-1701. Care Med 2005; 6:2–8. Potential conflicts of interest. G. D.: personal fees from Seres 18. Bone RC, Balk RA, Cerra FB, et al. Definitions for sepsis and organ failure and Therapeutics. R. L.: payment for serving as Associate Editor of the guidelines for the use of innovative therapies in sepsis. Chest 1992; 101: 1644–55. American Academy of Pediatrics Red Book (donated to the Minnesota 19. Matics TJ, Sanchez-Pinto LN. Adaptation and validation of a pediatric sequential Department of Health); support for attending meetings and/or travel as a organ failure assessment score and evaluation of the Sepsis-3 definitions in criti- member of the IDWeek Program Committee; support for attending meet- cally ill children. JAMA Pediatr 2017; 171:e172352. ings and/or travel as an Executive Board Member of the Council for State 20. Flannery AH, Venn CM, Gusovsky A, et al. Frequency and types of healthcare en- counters in the week preceding a sepsis hospitalization: a systematic review. Crit and Territorial Epidemiologists; support for attending meetings and/or Care Explor 2022; 4:1–9. travel as an Executive Board Member of the National Foundation for 21. Liu VX, Escobar GJ, Chaudhary R, Prescott HC. Healthcare utilization and infec- Infectious Diseases; and support for attending meetings and/or travel tion in the week prior to sepsis hospitalization. Crit Care Med 2018; 46:513–6. from the American Academy of Pediatrics, Committee on Infectious 22. Miller HC, Liu VX, Prescott HC. The characteristics and outcomes of clinic visits Diseases. M. K.: reimbursement for time participating in the CSF Seqirus immediately preceding sepsis hospitalization. Am J Crit Care 2021; 30:135–9. Asia-Pacific Advisory Council; and compensation and travel support for 23. Klompas M, Rhee C. Missed opportunities for better sepsis care or misplaced service on the board of the Infectious Disease Consulting blame? Deconstructing patients’ encounters in the week before sepsis hospitaliza- Corporation. M. M.: recipient of Public Health Scholarship support for tions. Crit Care Med 2018; 46:644–5. meeting attendance/travel to the Society for Healthcare Epidemiology of 24. Weiss SL, Peters MJ, Alhazzani W, et al. Surviving Sepsis Campaign international guidelines for the management of septic shock and sepsis-associated organ dys- America 2019 spring meeting. 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Incidence and trends of sepsis in US hospitals 28. Launay E, Gras-Le Guen C, Martinot A, et al. Why children with severe bacterial using clinical vs claims data, 2009–2014. JAMA 2017; 318:1241–49. infection die: a population-based study of determinants and consequences of sub- 3. Weiss SL, Balamuth F, Chilutti M, et al. Identification of pediatric sepsis for ep- optimal care with a special emphasis on methodological issues. PLoS One 2014; 9: idemiologic surveillance using electronic clinical data. Pediatr Crit Care Med e107286. 2020; 21:113–21. 29. Sever Z, Schlapbach LJ, Jessup M, George S, Harley A. Parental and healthcare 4. Scott HF, Brilli RJ, Paul R, et al. Evaluating pediatric sepsis definitions designed professional concern in the diagnosis of paediatric sepsis: a protocol for a prospec- for electronic health record extraction and multicenter quality improvement. tive multicentre observational study. BMJ Open 2021; 11:e045910. Crit Care Med 2020; 48:e916–26. 30. Centers for Disease Control and Prevention. Get ahead of sepsis. Available at: 5. Hsu HE, Abanyie F, Agus MSD, et al. A national approach to pediatric sepsis sur- https://www.cdc.gov/sepsis/education/index.html. Accessed 29 March 2022. veillance. Pediatrics 2019; 144:e20191790. 31. Sepsis Alliance. Posters and infographics. Available at: https://www.sepsis.org/ 6. Prout AJ, Talisa VB, Carcillo JA, et al. Children with chronic disease bear the education/resources/posters-and-infographics/. Accessed 30 March 2022. highest burden of pediatric sepsis. J Pediatr 2018; 199:194–9. 32. End Sepsis. The Legacy of Rory Staunton. Resources. Available at: https://www. 7. Paoli CJ, Reynolds MA, Sinha M, Gitlin M, Crouser E. Epidemiology and costs of endsepsis.org/resources-2/. Accessed 30 March 2022. sepsis in the United States—an analysis based on timing of diagnosis and severity 33. Angus DC, Bindman AB. Achieving diagnostic excellence for sepsis. JAMA 2022; level. Crit Care Med 2028; 46:1889–97. 327:117–8. 8. Buchman TG, Simpson SQ, Sciarretta KL, et al. Sepsis among Medicare beneficia - 34. DeMerle KM, Angus DC, Baillie JK, et al. Sepsis subclasses: a framework for ries: 2. The trajectories of sepsis, 2012–2018. Crit Care Med 2020; 48:289–301. development and interpretation. Crit Care Med 2021; 49:748–59. 10 • OFID • Magill et al http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Open Forum Infectious Diseases Oxford University Press http://www.deepdyve.com/lp/oxford-university-press/epidemiology-of-sepsis-in-us-children-and-young-adults-UfeMHMun9O

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Publisher: Oxford University Press
Copyright: Published by Oxford University Press on behalf of Infectious Diseases Society of America 2023.
eISSN: 2328-8957
DOI: 10.1093/ofid/ofad218
Publisher site: See Article on Publisher Site

Abstract

Open Forum Infectious Diseases MAJOR ARTICLE 1 1 1,a 2 3 3,b 4 5,6 Shelley S. Magill, Mathew R. P. Sapiano, Runa Gokhale, Joelle Nadle, Helen Johnston, Geoff Brousseau, Meghan Maloney, Susan M. Ray, 7,8 7 9 9,c, 10 10 11, 12 Lucy E. Wilson, Rebecca Perlmutter, Ruth Lynfield, Malini DeSilva, Marla Sievers, Lourdes Irizarry, Ghinwa Dumyati, Rebecca Pierce, 12 13,d 1 1,5 1,e, Alexia Zhang, Marion Kainer, Anthony E. Fiore, Raymund Dantes, and Lauren Epstein 1 2 3 Division of Healthcare Quality Promotion, Centers for Disease Control and Prevention, Atlanta, Georgia, USA, California Emerging Infections Program, Oakland, California, USA, Division of Disease Control and Public Health Response, Colorado Department of Public Health and Environment, Denver, Colorado, USA, Connecticut Emerging Infections Program, Hartford and New Haven, 5 6 7 Connecticut, USA, Department of Medicine, Emory University, Atlanta, Georgia, USA, Georgia Emerging Infections Program, Decatur, Georgia, USA, Infectious Disease Epidemiology and Outbreak Response Bureau, Maryland Department of Health, Baltimore, Maryland, USA, Department of Emergency Health Services, University of Maryland, Baltimore County, Baltimore, Maryland, USA, 9 10 11 Minnesota Department of Health, St Paul, Minnesota, USA, Epidemiology and Response Division, New Mexico Department of Health, Santa Fe, New Mexico, USA, New York Emerging Infections 12 13 Program, University of Rochester Medical Center, Rochester, New York, USA, Public Health Division, Oregon Health Authority, Portland, Oregon, USA, and Tennessee Department of Health, Nashville, Tennessee, USA Background. Most multicenter studies of US pediatric sepsis epidemiology use administrative data or focus on pediatric intensive care units. We conducted a detailed medical record review to describe sepsis epidemiology in children and young adults. Methods. In a convenience sample of hospitals in 10 states, patients aged 30 days–21 years, discharged during 1 October 2014– 30 September 2015, with explicit diagnosis codes for severe sepsis or septic shock, were included. Medical records were reviewed for patients with documentation of sepsis, septic shock, or similar terms. We analyzed overall and age group–specific patient characteristics. Results. Of 736 patients in 26 hospitals, 442 (60.1%) had underlying conditions. Most patients (613 [83.3%]) had community- onset sepsis, although most community-onset sepsis was healthcare associated (344 [56.1%]). Two hundred forty-one patients (32.7%) had outpatient visits 1–7 days before sepsis hospitalization, of whom 125 (51.9%) received antimicrobials ≤30 days before sepsis hospitalization. Age group–related differences included common underlying conditions (<5 years: prematurity vs 5–12 years: chronic pulmonary disease vs 13–21 years: chronic immunocompromise); medical device presence ≤30 days before sepsis hospitalization (1–4 years: 46.9% vs 30 days–11 months: 23.3%); percentage with hospital-onset sepsis (<5 years: 19.6% vs ≥5 years: 12.0%); and percentage with sepsis-associated pathogens (30 days–11 months: 65.6% vs 13–21 years: 49.3%). Conclusions. Our data suggest potential opportunities to raise sepsis awareness among outpatient providers to facilitate prevention, early recognition, and intervention in some patients. Consideration of age-specific differences may be important as approaches are developed to improve sepsis prevention, risk prediction, recognition, and management. Keywords. children; epidemiology; sepsis; septic shock; severe sepsis. Sepsis is recognized as an urgent global public health threat, have developed EHR definitions of sepsis for pediatric popula - with an estimated 48.9 million cases and 11.0 million deaths tions [3, 4], these definitions have not been used to estimate na - worldwide in 2017 [1]. In the United States (US), using a sepsis tional pediatric sepsis cases and deaths, and additional work is definition based on electronic health record (EHR) data, inves - needed to refine and validate a widely applicable EHR-based tigators estimated there were 1.7 million adults with sepsis and approach [5]. An analysis of administrative data from 2013 270 000 in-hospital deaths in 2014 [2]. Although investigators yielded an annual US estimate of 54 060 sepsis cases in children outside of the neonatal period and <19 years old; 3.7% of chil- dren with sepsis in this study died in the hospital [6]. Although Received 03 February 2023; accepted 19 April 2023; published online 20 April 2023 there is robust literature on the epidemiology of sepsis in US Current affiliation: Division of Global Health Protection, Centers for Disease Control and Prevention, Atlanta, Georgia, USA. adults [7–9], there are relatively few recent, multicenter studies Current affiliation: Michigan Department of Health and Human Services, Lansing, Michigan, of US pediatric sepsis epidemiology. Most previously published USA. Current affiliation: HealthPartners Institute, Bloomington, Minnesota, USA. studies used administrative data [10–13] or were focused on Current affiliation: Western Health, Melbourne, Australia. patients admitted to pediatric intensive care units [14]. Current affiliation: Atlanta Veterans Affairs Medical Center, Decatur, Georgia, USA. Correspondence: Shelley S. Magill, MD, PhD, Division of Healthcare Quality Promotion, Through the Centers for Disease Control and Prevention’s Centers for Disease Control and Prevention, 1600 Clifton Rd NE, HB16-3, Atlanta, GA 30333 (CDC) Emerging Infections Program (EIP), we conducted a (smagill@cdc.gov); Lauren Epstein, MD, MSc, Atlanta Veterans Affairs Medical Center, RIM detailed medical record review of US children and young adults 111, 1670 Clairmont Rd, Decatur, GA 30333 (lauren.epstein@va.gov). Open Forum Infectious Diseases with hospital discharge codes of severe sepsis or septic shock to Published by Oxford University Press on behalf of Infectious Diseases Society of America 2023. describe demographic and clinical characteristics, including by This work is written by (a) US Government employee(s) and is in the public domain in the US. https://doi.org/10.1093/ofid/ofad218 age group. Pediatric Sepsis Epidemiology • OFID • 1 METHODS healthcare facility (such as a hospital or long-term care facility) in the 30 or 90 days before admission. Data were also collected Hospitals and Patients on outpatient healthcare in the 7 days before sepsis hospital ad- The methods have been described previously [15]. The EIP is a mission, including the visit date and setting type (eg, primary network of 10 state health departments (California, Colorado, care or medical subspecialty clinic). Connecticut, Georgia, Maryland, Minnesota, New Mexico, In addition, data were collected on (1) infections document- New York, Oregon, and Tennessee) and academic partners ed in the medical record as present within 7 days before or after [16]. Each EIP site recruited 2–4 hospitals. Trained EIP staff sepsis diagnosis, including the subset documented to be associ- reviewed medical records of randomly selected patients with ated with sepsis at the time of sepsis diagnosis or in the hospital sepsis in these hospitals, with a goal of including approximately discharge summary; (2) vital signs and laboratory data on 100 adult (≥18 years old) and 100 pediatric patients (<18 the day before, day of, and day after sepsis diagnosis to deter- years old) per EIP site. Patients were eligible for inclusion mine the presence of the systemic inflammatory response syn- if they were discharged from a participating hospital between drome using age-specific criteria [17, 18]; (3) cultures and 1 October 2014 and 30 September 2015 and had an explicit nonculture microbiological tests collected during the 7 days be- diagnosis code for severe sepsis or septic shock (International fore and after sepsis diagnosis; and (4) outcome at hospital dis- Classification of Diseases, Ninth Revision, Clinical Modification charge. Death certificate information was gathered from state [ICD-9-CM] code 995.92 or 785.52). Only the first hospitaliza- vital statistics registries to identify patients who died within tion per eligible patient during the period of interest was includ- 90 days of sepsis diagnosis. ed. In some EIP sites there were fewer than 100 patients <18 Indicators of organ dysfunction documented in the medical years old with a sepsis-related hospital discharge during the record in the 7 days before or after sepsis diagnosis were also time frame of interest across all participating hospitals. In these collected. These indicators were generally consistent with crite- cases, sites were asked to review the records of all pediatric ria proposed by Hsu et al for consideration in an EHR defini - patients. tion of pediatric sepsis or sensitivity analyses [5], based on Patients without clinical documentation in the medical re- modifications of the pediatric Sequential Organ Failure cord of terms such as sepsis or septic shock and patients who Assessment (pSOFA) score [19]: invasive mechanical ventila- were missing a sepsis diagnosis date were excluded. Results of tion, noninvasive positive pressure ventilation, receipt of vaso- the analysis of patients ≥18 years old with sepsis have been pressor medications, systolic blood pressure <90 mm Hg, published [15]. For the current analysis, we included patients documented altered mental status, lactate ≥2 mmol/L, platelets 30 days to 21 years old. Infants <30 days old or who were never <100 000/µL, creatinine ≥2 times baseline, and total bilirubin discharged from the hospital after birth were excluded [5]. ≥2 times baseline and ≥2 mg/dL. Organ dysfunction evidenced by mechanical ventilation or noninvasive positive pressure ven- Patient Consent Statement tilation, receipt of vasopressors, systolic blood pressure The human subjects advisor in the CDC’s National Center for <90 mm Hg, or altered mental status had to be new or worsen- Emerging and Zoonotic Infectious Diseases determined the ing during the 7 days before or after sepsis diagnosis. Baseline project to be a nonresearch activity. Institutional review boards values of total bilirubin and creatinine were defined as the low- in EIP sites and participating hospitals determined the project est value during the 7 days before or after sepsis diagnosis. to be nonresearch or approved the project with waiver of in- formed consent. Analysis To determine which organisms were associated with sepsis, we Data Collection developed an algorithm based on the specimen type (sterile or EIP site staff collected medical record data using a standardized nonsterile body site), diagnostic test (culture or nonculture), or- data collection form. Data collection focused on preadmission ganism, and infection site documented in the medical record healthcare and information present in the medical record (Supplementary Table 1). This approach was adapted from the around the sepsis diagnosis date, defined as the first date a previously published analysis of adult patients with sepsis [15]. healthcare practitioner documented sepsis or a related term Sepsis cases were classified as hospital-onset, healthcare-associated in the medical record. Preadmission healthcare data collection community-onset, or community-associated. Hospital-onset included (1) prehospital treatment or procedures (receipt of cases were defined as occurring in patients with a sepsis diagnosis antimicrobial medications, chemotherapy, wound care, dialy- date on hospital day 4 or later. Healthcare-associated sis, or surgery in the 30 days before admission); (2) prehospital community-onset cases were defined as sepsis events with diagno- medical devices (urinary catheter, central line, mechanical ven- sis dates on hospital days 1–3, and occurring in (1) patients in a tilation, gastrostomy or jejunostomy tube, or tracheostomy in hospital or other healthcare facility (such as a nursing home) 4 the 30 days before admission); and (3) stays of ≥2 days in a days before admission and in a community location or 2 • OFID • Magill et al Treatment, Procedures, and Devices Before the Sepsis Hospitalization nonhospital facility immediately prior to admission; or (2) Three hundred thirteen patients (42.5%) received a treatment patients with a medical device, treatment, or procedure in or procedure in the 30 days before hospital admission, among the 30 days before sepsis hospital admission, or a ≥2-day which antimicrobial medications were the most common in all healthcare facility stay in the 90 days before sepsis hospital ad- age groups (263 patients [35.7%]). Medical devices were pre- mission. Community-associated cases were defined as sepsis sent in the 30 days before hospital admission in 264 patients events with diagnosis dates on hospital days 1–3, occurring (35.9%) overall, ranging from 23.3% in the age group 30 days in patients who were (1) in a private residence or other com- to 11 months to 46.9% in those aged 1–4 years (Table 2). munity location 4 days before the sepsis hospital admission, Among 442 patients with underlying conditions, 327 (74.0%) regardless of patient location immediately before sepsis hospi- had a medical device, treatment, or procedure in the 30 days be- tal admission; and (2) reported to have no medical devices, fore sepsis hospital admission, or a healthcare facility stay in the treatments, or procedures in the 30 days before sepsis hospital 90 days before sepsis hospital admission. admission and no ≥2-day healthcare facility stay in the 90 days Almost three-quarters of all patients with sepsis (548 before sepsis hospital admission. Patients who were in a hospi- [74.5%]) had an underlying condition, treatment, or procedure tal other than the sepsis hospital 4 days before sepsis hospital in the 30 days before admission, medical device in the 30 days admission, and also in a hospital other than the sepsis hospital before admission, or ≥2-day stay in a healthcare facility in the immediately prior to admission (such as patients transferred 90 days before admission. One hundred seventy-five patients from another hospital), with a sepsis diagnosis date on days (23.8%) had no underlying conditions and none of these 1–3 in the sepsis hospital, were considered to have sepsis of un- healthcare interactions before hospital admission (data were known onset. incomplete for 13 patients [1.8%]). We conducted a descriptive analysis of demographic and clinical variables stratified by age group: 30 days–11 months, 1–4 years, 5–12 years, and 13–21 years. Analyses were per- Outpatient Visits Before the Sepsis Hospital Admission formed using SAS version 9.4 software (SAS Institute). Two hundred forty-one patients (32.7%) were identified as hav- Data were analyzed between 1 May 2018 and 12 October ing outpatient visits from 1 to 7 days before hospital admission 2022. (not including the day of admission), with visits to a medical subspecialty (74 patients [10.1%]) or primary care clinic (74 pa- tients [10.1%]) being the most common overall (Table 2). The percentage of patients with underlying conditions who RESULTS had an outpatient visit from 1 to 7 days before hospital admis- Patient Characteristics sion (151/442 patients [34.2%]) was only slightly higher than in Among 900 patients ≤21 years old at hospital admission, 736 patients with no or unknown underlying conditions (90/294 patients in 26 hospitals met inclusion criteria. Of 164 excluded patients [30.6%]). Among the subset of patients with underly- patients, 133 were <30 days old; 13 were never discharged from ing conditions and devices, treatments, or procedures in the 30 the hospital after birth; 17 did not have documentation of sep- days before admission, or another healthcare facility stay in the sis, septic shock, or similar terms in the medical record; and 1 90 days before admission, the percentage with an outpatient was missing the sepsis diagnosis date. visit in the 7 days before admission was 37.3% (122/327 pa- Of 736 patients with sepsis who met inclusion criteria, 386 pa- tients). Among the 241 patients with outpatient visits 1 to 7 tients (52.4%) were female, 355 (48.2%) were non-Hispanic days before sepsis hospitalization, 125 (51.9%) received antimi- White, 144 (19.6%) were Hispanic, and 129 (17.5%) were crobials in the 30 days before sepsis hospitalization. non-Hispanic Black ethnicity and race. The distribution of eth- nicity and race varied by age, with a higher percentage of chil- Infections and Pathogens dren <5 years old reported to be of non-Hispanic Black At least 1 infection (including infection of unknown type) was ethnicity and race (53/235 [22.6%]) compared with older chil- reported for 712 patients (96.7%) (Table 3). Infection types var- dren (76/501 [15.2%]). Four hundred sixteen (56.5%) were re- ied by age group; among patients 30 days to 11 months old, ported to have Medicaid as the primary insurer. bloodstream infections were most common (26 [28.9%]), Most patients (442 [60.1%]) had ≥1 underlying condition whereas pneumonia was the most common infection in all oth- (Table 1). The distribution of underlying conditions varied er age groups (in 30.3% of patients 1–4 years old, 24.2% of pa- by age, with prematurity the most common condition among tients 5–12 years old, and 27.0% of patients 13–21 years old). children 30 days–11 months old (30 [33.3%]) and 1–4 years Almost all patients (732 [99.5%]) had ≥1 culture or noncul- old (34 [23.4%]), chronic pulmonary disease among children ture microbiology test in the 7 days before or after the date of 5–12 years old (51 [23.3%]), and chronic immunocompromise sepsis diagnosis; 518 (70.4%) had ≥1 positive test, and 427 among patients 13–21 years old (54 [19.1%]). (58.0%) had ≥1 positive test for a pathogen associated with Pediatric Sepsis Epidemiology • OFID • 3 Table 1. Demographic and Clinical Characteristics of Children and Young Adults With Sepsis, by Age Group Age Group Total 30 Days–11 Months 1–4 Years 5–12 Years 13–21 Years Characteristic (N = 736) (n = 90) (n = 145) (n = 219) (n = 282) State of residence California 67 (9.1) 6 (6.7) 16 (11.0) 20 (9.1) 25 (8.9) Colorado 94 (12.8) 5 (5.6) 18 (12.4) 30 (13.7) 41 (14.5) Connecticut 82 (11.1) 6 (6.7) 14 (9.7) 22 (10.0) 40 (14.2) Georgia 105 (14.3) 19 (21.1) 24 (16.6) 34 (15.5) 28 (9.9) Maryland 94 (12.8) 13 (14.4) 24 (16.6) 34 (15.5) 23 (8.2) Minnesota 87 (11.8) 20 (22.2) 13 (9.0) 28 (12.8) 26 (9.2) New Mexico 38 (5.2) 5 (5.6) 4 (2.8) 8 (3.7) 21 (7.4) New York 47 (6.4) 7 (7.8) 9 (6.2) 9 (4.1) 22 (7.8) Oregon 59 (8.0) 3 (3.3) 13 (9.0) 14 (6.4) 29 (10.3) Tennessee 63 (8.6) 6 (6.7) 10 (6.9) 20 (9.1) 27 (9.6) Sex Female 386 (52.4) 48 (53.3) 75 (51.7) 123 (56.2) 140 (49.6) Male 350 (47.6) 42 (46.7) 70 (48.3) 96 (43.8) 142 (50.4) Race/ethnicity American Indian, non-Hispanic 16 (2.2) 5 (5.6) 2 (1.4) 4 (1.8) 5 (1.8) Asian, non-Hispanic 29 (3.9) 6 (6.7) 4 (2.8) 11 (5.0) 8 (2.8) Black, non-Hispanic 129 (17.5) 21 (23.3) 32 (22.1) 33 (15.1) 43 (15.2) Hispanic/Latino 144 (19.6) 18 (20.0) 25 (17.2) 47 (21.5) 54 (19.1) Pacific Islander, non-Hispanic 4 (0.5) 1 (1.1) 0 1 (0.5) 2 (0.7) White, non-Hispanic 355 (48.2) 34 (37.8) 66 (45.5) 104 (47.5) 151 (53.5) Other or multiple races, non-Hispanic 29 (3.9) 0 9 (6.2) 13 (5.9) 7 (2.5) Unknown race, non-Hispanic 30 (4.1) 5 (5.6) 7 (4.8) 6 (2.7) 12 (4.3) Primary insurance type Medicaid 416 (56.5) 55 (61.1) 89 (61.4) 128 (58.4) 144 (51.1) Private 254 (34.5) 24 (26.7) 36 (24.8) 74 (33.8) 120 (42.6) Other 47 (6.4) 7 (7.8) 17 (11.7) 11 (5.0) 12 (4.3) Unknown 19 (2.6) 4 (4.4) 3 (2.1) 6 (2.7) 6 (2.1) Location immediately before sepsis admission Private residence 378 (51.4) 44 (48.9) 77 (53.1) 116 (53.0) 141 (50.0) Another acute care hospital or emergency department 271 (36.8) 41 (45.6) 46 (31.7) 82 (37.4) 102 (37.6) Outpatient clinic or urgent care 73 (9.9) 5 (5.6) 21 (14.5) 20 (9.1) 27 (9.6) Nursing home 4 (0.5) 0 0 0 4 (1.4) Other 6 (0.8) 0 0 1 (0.5) 5 (1.8) Unknown 4 (0.5) 0 1 (0.7) 0 3 (1.1) Location 4 days before sepsis admission Private residence 676 (91.8) 85 (94.4) 135 (93.1) 200 (91.3) 256 (90.8) Another acute care hospital 38 (5.2) 5 (5.6) 7 (4.8) 13 (5.9) 13 (4.6) Nursing home 5 (0.7) 0 1 (0.7) 0 4 (1.4) Other 11 (1.5) 0 1 (0.7) 3 (1.4) 7 (2.5) Unknown 6 (0.8) 0 1 (0.7) 3 (1.4) 2 (0.7) Underlying conditions Any underlying condition 442 (60.1) 49 (54.4) 93 (64.1) 132 (60.3) 168 (59.6) Chronic pulmonary disease 137 (18.6) 6 (6.7) 33 (22.8) 51 (23.3) 47 (16.7) Chronic cognitive deficit 118 (16.0) 8 (8.9) 31 (21.4) 40 (18.3) 39 (13.8) Chronic immunocompromise 109 (14.8) 5 (5.6) 17 (11.7) 33 (15.1) 54 (19.1) Hematologic or oncologic disease 108 (14.7) 3 (3.3) 22 (15.2) 37 (16.9) 46 (16.3) History of prematurity 90 (12.2) 30 (33.3) 34 (23.4) 14 (6.4) 12 (4.3) Congenital heart disease 63 (8.6) 23 (25.6) 17 (11.7) 10 (4.6) 13 (4.6) Hemiplegia, paraplegia, quadriplegia 42 (5.7) 0 4 (2.8) 16 (7.3) 22 (7.8) Chronic kidney disease 31 (4.2) 2 (2.2) 7 (4.8) 10 (4.6) 12 (4.3) Chronic mental illness 18 (2.4) 0 0 4 (1.8) 14 (5.0) Other cardiovascular disease 17 (2.3) 2 (2.2) 6 (4.1) 5 (2.3) 4 (1.4) Chronic liver disease 15 (2.0) 1 (1.1) 7 (4.8) 2 (0.9) 5 (1.8) 4 • OFID • Magill et al Table 1. Continued Age Group Total 30 Days–11 Months 1–4 Years 5–12 Years 13–21 Years Characteristic (N = 736) (n = 90) (n = 145) (n = 219) (n = 282) Diabetes mellitus 12 (1.6) 0 1 (0.7) 3 (1.4) 8 (2.8) Chronic wound 10 (1.4) 2 (2.2) 2 (1.4) 0 6 (2.1) Connective tissue disease 6 (0.8) 0 0 3 (1.4) 3 (1.1) Pregnancy 2 (0.3) … … 0 2 (0.7) Peptic ulcer disease 1 (0.1) 0 0 0 1 (0.4) Unknown 9 (1.2) 1 (1.1) 1 (0.7) 3 (1.4) 4 (1.4) Substance use 15 (2.0) … … 0 15 (5.3) Data are presented as No. (%). Persons with unknown ethnicity are grouped with persons reported as non-Hispanic. Including persons experiencing homelessness or incarceration. Includes any of the conditions listed. Including asthma in 91 of 137 patients. Defined as asplenia, neutropenia, hematopoietic stem cell transplant, solid organ transplant, human immunodeficiency virus infection, primary immunodeficiency, or chronic steroid or other immunosuppressive therapy. Includes type 1 and type 2 diabetes mellitus and gestational diabetes. Includes alcohol use disorder, injection drug use, and smoking. sepsis. The percentages of patients with any microbiological intensive care unit, and ≥1 indicator of organ dysfunction testing, positive tests, and positive tests for pathogens was present in the 7 days before or after sepsis diagnosis in associated with sepsis decreased as patient age increased 682 patients (92.7%). Indicators of cardiovascular dysfunction (Supplementary Table 2). For example, 65.6% of patients 30 (systolic blood pressure <90 mm Hg or receipt of vasopressors) days to 11 months old had ≥1 pathogen identified that was as - or perfusion dysfunction (lactate ≥2 mmol/L) were documented sociated with sepsis compared with 49.3% of patients 13–21 for 627 patients (85.2%). years old. Overall, 74 patients (10.1%) died during their hospitalization Among patients in whom a sepsis-associated pathogen was (71 within 90 days of sepsis diagnosis). Eighty-four patients detected, gram-positive bacteria were most common (215/427 (11.4%) died within 90 days of sepsis diagnosis; 13 of these pa- patients [50.4%]), followed by gram-negative bacteria (193/ tients (15.5%) died after discharge from their sepsis hospitaliza- 427 [45.2%]) and viruses (123/427 [28.8%]) (Supplementary tion. The youngest age group, patients 30 days to 11 months Table 2). Pathogen distribution varied by age group, although old, had the highest percentage of patients who died during Staphylococcus aureus was the most common pathogen overall their hospitalization (15.6%) or within 90 days of diagnosis (89 patients, 12.1% of all patients and 20.8% of those with a (18.9%). Patients with underlying conditions were more likely sepsis-associated pathogen) and in all age groups except pa- to die during their hospitalizations (55/442 [12.4%]) and dur- tients 1–4 years old in whom respiratory syncytial virus was ing the 90 days after sepsis diagnosis (62/442 [14.0%]) than pa- most common (13 patients, 9.0% of all patients in this age tients without or with unknown underlying conditions group and 14.0% of those with a sepsis-associated pathogen) (in-hospital death: 19/294 [6.5%]; 90 days after sepsis diagnosis: (Table 4). 22/294 [7.5%]). Patients with hospital-onset sepsis were more likely to die (in-hospital death: 26/106 [24.5%]; 90 days after sepsis diagnosis: 26/106 [24.5%]) than patients with Sepsis Hospitalization and Outcome community-onset sepsis (in-hospital death: 46/613 [7.5%]; 90 Most patients had community-onset sepsis (613/736 [83.3%]); days after sepsis diagnosis: 56/613 [9.1%]). most community-onset sepsis was healthcare associated (344/ 613 [56.1%]) (Table 5). Hospital-onset sepsis was more com- mon among patients <5 years old (46/235 [19.6%]) than among DISCUSSION older patients (60/501 [12.0%]). Patients with sepsis had prolonged hospitalizations, rang- In our analysis of medical record data from 736 children and ing from a median of 7 days (interquartile range [IQR], 4– young adults with explicit ICD-9-CM codes for severe sepsis or 17 days) in those 13–21 years old to 14 days (IQR, 7–30 septic shock during hospitalizations in 2014–2015, 60% of patients days) in those 1–4 years old (Table 5). Most patients (647 had at least 1 underlying condition and almost one-third of all pa- [87.9%]) spent at least part of their hospitalization in the tients with sepsis, including those without underlying conditions, Pediatric Sepsis Epidemiology • OFID • 5 Table 2. Healthcare Received by Children and Young Adults With Sepsis Before the Sepsis Hospitalization, by Age Group Age Group Total 30 Days–11 Months 1–4 Years 5–12 Years 13–21 Years Characteristic (N = 736) (n = 90) (n = 145) (n = 219) (n = 282) Outpatient visit in the 7 d before sepsis hospitalization Any of the included visits 241 (32.7) 33 (36.7) 52 (35.9) 71 (32.4) 85 (30.1) Medical or pediatric subspecialty 74 (10.1) 7 (7.8) 21 (14.5) 21 (9.6) 25 (8.9) Primary care 74 (10.1) 12 (13.3) 16 (11.0) 17 (7.8) 29 (10.3) Emergency department 65 (8.8) 14 (15.6) 8 (5.5) 16 (7.3) 27 (9.6) Urgent care 13 (1.8) 1 (1.1) 5 (3.4) 3 (1.4) 4 (1.4) Surgery 6 (0.8) 0 0 6 (2.7) 0 Physical, occupational, or speech therapy 3 (0.4) 0 2 (1.4) 1 (0.5) 0 Dental 1 (0.1) 0 1 (0.7) 0 0 Other 25 (3.4) 2 (2.2) 3 (2.1) 12 (5.5) 8 (2.8) Unknown type of visit 1 (0.1) 0 0 0 1 (0.4) Treatments or procedures in the 30 d before sepsis hospitalization Any of the included treatments or procedures 313 (42.5) 29 (32.2) 73 (50.3) 96 (43.8) 115 (40.8) Antimicrobial medications 263 (35.7) 27 (30.0) 62 (42.8) 78 (35.6) 96 (34.0) Cancer chemotherapy 76 (10.3) 2 (2.2) 16 (11.0) 28 (12.8) 30 (10.6) Surgery 35 (4.8) 5 (5.6) 12 (8.3) 12 (5.5) 6 (2.1) Wound care 14 (1.9) 2 (2.2) 2 (1.4) 6 (2.7) 4 (1.4) Chronic dialysis 4 (0.5) 0 2 (1.4) 1 (0.5) 1 (0.4) Devices present in the 30 d before sepsis hospitalization Any of the included devices 264 (35.9) 21 (23.3) 68 (46.9) 83 (37.9) 92 (32.6) Gastrostomy or jejunostomy tube 159 (21.6) 13 (14.4) 53 (36.6) 50 (22.8) 43 (15.2) Central line 132 (17.9) 8 (8.9) 33 (22.8) 41 (18.7) 50 (17.7) Mechanical ventilator 33 (4.5) 5 (5.6) 9 (6.2) 9 (4.1) 10 (3.5) Tracheostomy 27 (3.7) 1 (1.1) 10 (6.9) 11 (5.0) 5 (1.8) Urinary catheter 17 (2.3) 1 (1.1) 1 (0.7) 6 (2.7) 9 (3.2) Admission for ≥2 d to a healthcare facility in the 30 d before sepsis hospitalization Hospital 164 (22.3) 29 (32.2) 35 (24.1) 47 (21.5) 53 (18.8) Long-term acute care hospital 1 (0.1) 0 0 0 1 (0.4) Nursing home 4 (0.5) 0 0 0 4 (1.4) Admission for ≥2 d to a healthcare facility in the 90 d before sepsis hospitalization Hospital 217 (29.5) 39 (43.3) 52 (35.9) 65 (29.7) 61 (21.6) Long-term acute care hospital 1 (0.1) 0 0 0 1 (0.4) Nursing home 4 (0.5) 0 0 0 4 (1.4) Data are presented as No. (%). Includes outpatient encounters that occurred from 1 to 7 days before the day of admission. Excludes encounters that were reported to occur on the same day as hospital admission and encounters with missing dates. Other visits include visits to infusion clinics, laboratories, or radiology. Seven patients were reported to have visited a hospital; these were included since the specific type of location visited within the hospital was not reported and could have been an outpatient location. had an outpatient visit in the week prior to the sepsis hospitaliza- or day before sepsis hospitalization. Most of these patients tion. Although most sepsis had its onset in the community, more (80.5%) had symptoms of infection or sepsis in clinic, but 44 than half of cases of community-onset sepsis occurred in patients patients (37.3%) were either treated as an outpatient or sent who had received recent prehospital healthcare. home without intervention. Upon subsequent presentation Our finding that almost one-third of patients had an outpa- to the hospital or emergency department, 77.3% of the patients tient visit in the week before sepsis hospitalization has also been treated as an outpatient or sent home from clinic were noted to observed in studies of adult patients with sepsis [20, 21]. have worsening illness severity, compared with 37.8% of those Flannery and colleagues reviewed observational studies of adult who were referred directly to the emergency department [22]. patients with sepsis and found that an average of 32.7% of pa- These observations suggest that for some patients, there may tients had outpatient encounters in the week before sepsis hos- be opportunities to intervene earlier, although more data are pitalization [20]. In a study of 1150 adult patients with a sepsis needed [23], including studies describing the reasons for and hospital discharge and an established outpatient provider in quality of prehospital care in children who are subsequently ad- 2017, 118 patients (10.3%) were seen in clinic on the day of mitted for sepsis. 6 • OFID • Magill et al a b Table 3. Infections Present During the Period Defined by the 7 Days Before or After Sepsis Diagnosis and Documented as the Cause of Sepsis , by Age Group Age Group Infection Type Total (N = 736) 30 Days–11 Months (n = 90) 1–4 Years (n = 145) 5–12 Years (n = 219) 13–21 Years (n = 282) Pneumonia 193 (26.2) 20 (22.2) 44 (30.3) 53 (24.2) 76 (27.0) Documented as the cause of sepsis 152/193 (78.8) 17/20 (85.0) 29/44 (65.9) 46/53 (86.8) 60/76 (78.9) Bloodstream 154 (20.9) 26 (28.9) 37 (25.5) 38 (17.4) 53 (18.8) Documented as the cause of sepsis 123/154 (79.9) 22/26 (84.6) 29/37 (78.4) 34/38 (89.5) 38/53 (71.6) Undetermined or unknown 107 (14.5) 11 (12.2) 21 (14.5) 31 (14.2) 44 (15.6) Documented as the cause of sepsis 72/107 (67.3) 8/11 (72.7) 12/21 (57.1) 20/31 (64.5) 32/44 (72.7) Urinary tract 101 (13.7) 13 (14.4) 10 (6.9) 31 (14.2) 47 (16.7) Documented as the cause of sepsis 77/101 (76.2) 9/13 (69.2) 9/10 (90.0) 22/31 (71.0) 37/47 (78.7) Lower respiratory (other than pneumonia) 84 (11.4) 23 (25.6) 22 (15.2) 22 (10.0) 17 (6.0) Documented as the cause of sepsis 36/84 (42.9) 12/23 (52.2) 8/22 (36.4) 9/22 (40.9) 7/17 (41.2) Ear, eye, mouth, nose, or throat 64 (8.7) 9 (10.0) 12 (8.3) 27 (12.3) 16 (5.7) Documented as the cause of sepsis 36/64 (56.3) 4/9 (44.4) 5/12 (41.7) 16/27 (59.3) 11/16 (68.8) Skin or soft tissue 51 (6.9) 5 (5.6) 4 (2.8) 20 (9.1) 22 (7.8) Documented as the cause of sepsis 29/51 (56.9) 2/5 (40.0) 2/4 (50.0) 11/20 (55.0) 14/22 (63.6) Gastrointestinal tract (other than CDI) 50 (6.8) 5 (5.6) 7 (4.8) 14 (6.4) 24 (8.5) Documented as the cause of sepsis 36/50 (72.0) 3/5 (60.0) 3/7 (42.9) 11/14 (78.6) 19/24 (79.2) Intra-abdominal 39 (5.3) 2 (2.2) 9 (6.2) 15 (6.8) 13 (4.6) Documented as the cause of sepsis 27/39 (69.2) 2/2 (100) 5/9 (55.6) 11/15 (73.3) 9/13 (69.2) Central nervous system 36 (4.9) 10 (11.1) 10 (6.9) 8 (3.7) 8 (2.8) Documented as the cause of sepsis 27/36 (75.0) 8/10 (80.0) 7/10 (70.0) 6/8 (75.0) 6/8 (75.0) CDI 19 (2.6) NA 7 (4.8) 4 (1.8) 8 (2.8) Documented as the cause of sepsis 5/19 (26.3) NA 1/7 (14.3) 1/4 (25.0) 3/8 (37.5) Bone or joint 16 (2.2) 0 1 (0.7) 8 (3.7) 7 (2.5) Documented as the cause of sepsis 12/16 (75.0) 0 0 7/8 (87.5) 5/7 (71.4) Disseminated 16 (2.2) 0 3 (2.1) 4 (1.8) 9 (3.2) Documented as the cause of sepsis 11/16 (68.8) 0 2/3 (66.7) 2/4 (50.0) 7/9 (77.8) Cardiovascular 9 (1.2) 1 (1.1) 1 (0.7) 3 (1.4) 4 (1.4) Documented as the cause of sepsis 7/9 (77.8) 1/1 (100) 1/1 (100) 2/3 (66.7) 3/4 (75.0) Reproductive 7 (1.0) 0 0 1 (0.5) 6 (2.1) Documented as the cause of sepsis 6/7 (85.7) 0 0 0 6/6 (100) Hepatobiliary 6 (0.8) 0 3 (2.1) 0 3 (1.1) Documented as the cause of sepsis 2/6 (33.3) 0 0 0 2/3 (66.7) No infection documented 24 (3.3) 2 (2.2) 6 (4.1) 8 (3.7) 8 (2.8) Data are presented as No. (%). Abbreviations: CDI, Clostridioides difficile infection; NA, not applicable. Patients could have >1 infection type. In 14 patients, 1 infection type was reported >1 time (for example, 2 lower respiratory tract infections were reported for the same patient). Duplicate records for 8 of these patients (records with identical data) were deleted. For 6 of the 14 patients with multiple unique infections of the same type, we kept the infection that was reported to have caused sepsis and/or the infection with onset before the sepsis diagnosis date. Documented in the medical record as the cause of sepsis at the time of sepsis diagnosis or in the discharge summary. Infections were reported as undetermined site if there was medical record documentation that the source of infection was not yet known. Infections were reported as unknown site when there was insufficient or incomplete documentation in the medical record to determine the site of infection. In total, there were 106 patients with infections of undetermined site and 10 patients with infections of unknown site. Guidelines for the care of pediatric patients with sepsis and were evaluated by a pediatric emergency physician or mobile septic shock, as for adult patients, have primarily focused on medical unit, and suboptimal care was associated with in- providing recommendations for the recognition and treatment creased odds of death. Although not statistically significant, of sepsis in the emergency department and after hospital ad- children who died were also more likely to have had parental mission [24, 25], although the importance of educating the delays in seeking medical care compared with those who sur- public, including parents and healthcare providers, to improve vived [28]. Investigators are studying whether assessing the lev- sepsis early recognition and response in the prehospital setting el of parent and healthcare provider concern for severe has been acknowledged [26, 27]. In a study of 114 children with infection in the emergency department can lead to earlier rec- severe bacterial infection, 21 of whom died, children whose ini- ognition of sepsis [29]. CDC and organizations such as Sepsis tial medical contact was with a general practitioner were more Alliance and End Sepsis have developed campaigns and mate- likely to receive suboptimal care compared with those who rials to educate the public and healthcare providers about sepsis Pediatric Sepsis Epidemiology • OFID • 7 Table 4. Common Pathogens Associated With Sepsis, by Patient Age Group Age Group a b c d Pathogen Total (N = 736) 30 Days–11 Months (n = 90) 1–4 Years (n = 145) 5–12 Years (n = 219) 13–21 Years (n = 282) Staphylococcus aureus 89 (12.1) 10 (11.1) 12 (8.3) 26 (11.9) 41 (14.5) Escherichia coli 61 (8.3) 6 (6.7) 8 (5.5) 21 (9.6) 26 (9.2) Pseudomonas aeruginosa 32 (4.3) 5 (5.6) 11 (7.6) 11 (5.0) 5 (1.8) Viridans streptococci 30 (4.1) 9 (10.0) 2 (1.4) 11 (5.0) 8 (2.8) Klebsiella pneumoniae 29 (3.9) 3 (3.3) 11 (7.6) 7 (3.2) 8 (2.8) RSV 27 (3.7) 8 (8.9) 13 (9.0) 4 (1.8) 2 (0.7) Streptococcus pneumoniae 27 (3.7) 5 (5.6) 8 (5.5) 9 (4.1) 5 (1.8) Streptococcus, group A 27 (3.7) 2 (2.2) 10 (6.9) 11 (5.0) 4 (1.4) Rhinovirus 26 (3.5) 5 (5.6) 5 (3.4) 10 (4.6) 6 (2.1) Enterovirus 18 (2.4) 6 (6.7) 5 (3.4) 6 (2.7) 1 (0.4) Clostridioides difficile 15 (2.0) NA 5 (3.4) 3 (1.4) 7 (2.5) Influenza A 15 (2.0) 1 (1.1) 2 (1.4) 7 (3.2) 5 (1.8) Haemophilus influenzae 14 (1.9) 6 (6.7) 2 (1.4) 2 (0.9) 4 (1.4) Adenovirus 13 (1.8) 4 (4.4) 4 (2.8) 4 (1.8) 1 (0.4) Enterococcus faecalis 13 (1.8) 1 (1.1) 5 (3.4) 3 (1.4) 4 (1.4) Human metapneumovirus 13 (1.8) 0 6 (4.1) 5 (2.3) 2 (0.7) Data are presented as No. (%). Abbreviations: NA, not applicable; RSV, respiratory syncytial virus. Among patients 30 days to 11 months old, other organisms detected in 3 or more patients included Moraxella catarrhalis (7 [7.8%]) and Serratia marcescens (3 [3.3%]). Among patients 1–4 years old, other organisms detected in 3 or more patients included Enterobacter cloacae (5 [3.4%]), coagulase-negative staphylococci (3 [2.1%]), and Streptococcus spp (3 [2.1%]). Among patients 5–12 years old, other organisms detected in 3 or more patients included coagulase-negative staphylococci (5 [2.3%]), Streptococcus spp (4 [1.8%]), Citrobacter freundii (3 [1.4%]), cytomegalovirus (3 [1.4%]), Enterobacter cloacae (3 [1.4%]), and Enterococcus spp (3 [1.4%]). Among patients 13–21 years old, other organisms detected in 3 or more patients included Enterococcus faecium (4 [1.4%]), influenza B (4 [1.4%]), Candida albicans (3 [1.1%]), cytomegalovirus (3 [1.1%]), Enterococcus spp (3 [1.1%]), and Proteus mirabilis (3 [1.1%]). [30–32]. Further research is needed to determine whether edu- patients with sepsis who were less severely ill. Third, we relied cational efforts facilitate earlier recognition and treatment of on medical record documentation of healthcare interactions sepsis and improve patient outcomes [33]. that occurred prior to hospital admission, and this documentation We observed differences in sepsis epidemiology among chil- was likely incomplete. Fourth, we did not collect information dren in different age groups outside the neonatal period, includ- about the reason for these healthcare interactions, nor did we col- ing differences in underlying conditions, prehospital healthcare, lect information about infections diagnosed or treated before hos- common infections and pathogens, and outcomes. For example, pital admission. Fifth, we had limited data to use in determining children between 30 days and 4 years old with sepsis tended to be whether sepsis was hospital or community onset, and it is possible more medically complex with longer hospitalizations and higher some cases were misclassified. Finally, we used an algorithm to de- mortality than children ≥5 years old with sepsis. Our findings termine which organisms were likely to be associated with sepsis, suggest that different approaches to prevention, early recogni- which also may have resulted in misclassification. tion, and management of nonneonatal pediatric sepsis may be needed in children of different ages. To optimize care and out- CONCLUSIONS comes, investigators have proposed grouping patients into vari- ous subclasses of sepsis based on factors such as clinical or A large percentage of US children and young adults hospital- biological features [34]. Our findings indicate that there may ized with sepsis have underlying chronic medical conditions be sepsis subclasses in children outside the neonatal period or healthcare interactions, including visits with outpatient pro- that are dependent, at least in part, on patient age. viders, in the days or weeks leading up to their sepsis hospital This analysis has several limitations. First, we included a conve- admission. Approaches to raise awareness among outpatient nience sample of hospitals and relatively small number of patients providers of the risk of sepsis in these patients and improve ear- in a limited number of geographic areas; therefore, our results ly recognition and appropriate clinical intervention should be might not be generalizable to all children and young adults with developed and studied. In addition, our data demonstrate dif- sepsis in the US. Second, because there is currently no widely ac- ferences in the epidemiology of sepsis among children of differ- cepted pediatric sepsis surveillance definition, we identified pa- ent ages, which may be important to consider as approaches are tients with sepsis using explicit administrative codes for sepsis developed to improve sepsis prevention, risk prediction, early and septic shock. This may have resulted in the exclusion of recognition, and management. 8 • OFID • Magill et al Table 5. Characteristics of Sepsis Events and Hospitalization in Children and Young Adults, by Age Group Age Group Total 30 Days–11 Months 1–4 Years 5–12 Years 13–21 Years Characteristic (N = 736) (n = 90) (n = 145) (n = 219) (n = 282) Patient location at the time the sepsis diagnosis was first documented in the medical record ICU 324 (44.0) 48 (53.3) 79 (54.5) 94 (42.9) 103 (36.5) Emergency department 295 (40.1) 28 (31.1) 46 (31.7) 91 (41.6) 130 (46.1) Inpatient ward 104 (14.1) 12 (13.3) 19 (13.1) 32 (14.6) 41 (14.5) Other 2 (0.3) 0 0 1 (0.5) 1 (0.4) Unknown 11 (1.5) 2 (2.2) 1 (0.7) 1 (0.5) 7 (2.5) Days from admission to sepsis diagnosis, median (IQR) 0 (0–1) 0 (0–2) 0 (0–1) 0 (0–1) 0 (0–1) Epidemiologic classification of sepsis episode Community onset 613 (83.3) 65 (72.2) 112 (77.2) 182 (83.1) 238 (84.4) Community associated 254 (34.5) 28 (31.1) 38 (26.2) 71 (32.4) 117 (41.5) Healthcare associated 344 (46.7) 37 (41.1) 74 (51.0) 111 (50.7) 122 (43.3) Unknown healthcare association 15 (2.0) 4 (4.4) 1 (0.7) 7 (3.2) 3 (1.1) Hospital onset 106 (14.4) 18 (20.0) 28 (19.3) 25 (11.4) 35 (12.4) Unknown onset 17 (2.3) 3 (3.3) 4 (2.8) 5 (2.3) 5 (1.8) Admitted to the ICU during the sepsis hospitalization 647 (87.9) 80 (88.9) 129 (89.0) 197 (90.0) 241 (85.5) Days in ICU, median (IQR) 4 (2–11) 6 (3–14) 7 (2–15) 4 (2–9) 3 (2–8) Indicators of organ dysfunction Any indicator of organ dysfunction 682 (92.7) 86 (95.6) 135 (93.1) 204 (93.2) 257 (91.1) Systolic blood pressure <90 mm Hg 516 (70.1) 55 (61.1) 103 (71.0) 165 (75.3) 193 (68.4) Vasopressors 370 (50.3) 37 (41.1) 64 (44.1) 119 (54.3) 150 (53.2) Lactate ≥2 mmol/L 345 (46.9) 40 (44.4) 68 (46.9) 109 (49.8) 128 (45.4) Platelets <100 000/µL 287 (39.0) 27 (30.0) 69 (47.6) 86 (39.2) 105 (37.2) Invasive mechanical ventilation 273 (37.1) 59 (65.6) 66 (45.5) 78 (35.6) 70 (24.8) Creatinine ≥2 times baseline 252 (34.2) 33 (36.7) 52 (35.9) 66 (30.1) 101 (35.8) Altered mental status 175 (23.8) 29 (32.2) 35 (24.1) 57 (26.0) 54 (19.1) Noninvasive positive pressure ventilation 104 (14.1) 12 (13.3) 20 (13.8) 32 (14.6) 40 (14.2) Total bilirubin ≥2 times baseline and ≥2 mg/dL 72 (9.8) 7 (7.8) 12 (8.3) 14 (6.4) 39 (13.8) SIRS 727 (98.8) 88 (97.8) 144 (99.3) 217 (99.1) 278 (98.6) Days in hospital, median (IQR) 10 (5–22) 12 (5–29) 14 (7–30) 10 (6–20) 7 (4–17) Sepsis listed in the discharge summary 483 (65.6) 54 (60.0) 76 (52.4) 153 (69.9) 200 (70.9) Location to which patient was discharged from the hospital Private residence 587 (79.8) 65 (72.2) 112 (77.2) 185 (84.5) 225 (79.8) Deceased 74 (10.1) 14 (15.6) 16 (11.0) 17 (7.8) 27 (9.6) Another acute care hospital 33 (4.5) 8 (8.9) 10 (6.9) 5 (2.3) 10 (3.5) Long-term acute care hospital or long-term care facility 21 (2.9) 1 (1.1) 2 (1.4) 7 (3.2) 11 (3.9) Other or unknown 21 (2.9) 2 (2.2) 5 (3.4) 5 (2.3) 9 (3.2) Died within 90 d of sepsis diagnosis 84 (11.4) 17 (18.9) 18 (12.4) 17 (7.8) 32 (11.3) Data are presented as No. (%). Abbreviations: ICU, intensive care unit; IQR, interquartile range; SIRS, systemic inflammatory response syndrome. Three patients had sepsis diagnosis dates predating the day of admission; for 2 patients, the sepsis diagnosis date was the day before hospital admission. These were included in the analysis. For 1 patient the day of sepsis diagnosis was reported to be 6 days before admission. This appeared to be a data entry error and was changed to the day of hospital admission for analysis purposes. Admission and/or discharge dates from the ICU were missing for 11 patients: 1 patient in the age group 30 days–11 months, 3 patients in the age group 1–4 years, 5 patients in the age group 5–12 years, and 2 patients in the age group 13–21 years. During the period defined by the 7 days before and 7 days after sepsis diagnosis. Criteria of the systemic inflammatory response syndrome (SIRS) were assessed each day during the 3-day period defined by the day before sepsis diagnosis through the day after sepsis diagnosis. SIRS was defined as described by Goldstein and colleagues [17]. Patients aged 30 days–17 years had to meet either the temperature criterion (>38.5°C or <36°C) or the age-based white blood cell count criterion, plus 1 additional age-based criterion. Adult SIRS criteria were used for patients who were 18–21 years old [18]. Hospital discharge date missing for 2 patients. Data missing for 6 patients. Supplementary Data Notes Supplementary materials are available at Open Forum Infectious Diseases Author contributions. S. S. M., M. R. P. S., R. G., H. J., J. N., M. M., online. Consisting of data provided by the authors to benefit the reader, S. M. R., L. E. W., R. Pe., R. L., M. S., L. I., G. D., R. Pi., M. K., A. E. F., the posted materials are not copyedited and are the sole responsibility of R. D., and L. E. contributed to study concept and design. All authors con- the authors, so questions or comments should be addressed to the corre- tributed to data acquisition, analysis, or interpretation. S. S. M., M. R. P. S., sponding author. R. G., and L. E. drafted the manuscript. All authors contributed to Pediatric Sepsis Epidemiology • OFID • 9 9. Rhee C, Wang R, Zhang Z, et al. Epidemiology of hospital-onset versus reviewing and revising the manuscript for important intellectual content community-onset sepsis in U.S. hospitals and association with mortality: a retro- and approved the final version for submission. spective analysis using electronic clinical data. Crit Care Med 2019; 47:1169–76. Acknowledgments. The following individuals are acknowledged for their 10. Balamuth F, Weiss SL, Neuman MI, et al. Pediatric severe sepsis in US children’s contributions to data acquisition: California Emerging Infections Program hospitals. Pediatr Crit Care Med 2014; 15:798–805. (EIP): Deborah Godine, RN, Linda Frank, BSN. Colorado EIP: Sarabeth 11. Hartman ME, Linde-Zwirble WT, Angus DC, Watson RS. Trends in the epidemi- Friedman, MSN, Navjot Kaur, MPH, Tolulope Oyewumi, MBBS, Wendy ology of pediatric severe sepsis. Pediatr Crit Care Med 2013; 14:686–93. M. Bamberg, MD. Connecticut EIP: Nicole Stabach, MSN, Paula 12. Thavamani A, Umapathi KK, Dhanpalreddy H, et al. Epidemiology, clinical and Clogher, MPH. Georgia EIP: Lewis Perry, PhD, Susan Morabit, MSN, microbiologic profile and risk factors for inpatient mortality in pediatric severe Stacy Carswell, MPH. Maryland EIP: Linda Li, MPH, Elisabeth Vaeth, sepsis in the United States from 2003 to 2014: a large population analysis. MPH. Minnesota EIP: J. P. Mahoehney, RN, MPH, Jacy Walters, PhD, Pediatr Infect Dis J 2020; 39:781–8. 13. Carlton EF, Kohne JG, Hensley MK, Prescott HC. Comparison of outpatient MPH. New Mexico EIP: Emily Hancock, MS. New York EIP: Christina health care use before and after pediatric severe sepsis. JAMA Netw Open Felsen, MPH. Tennessee EIP: Raphaelle H. Rodzik, MPH, Daniel Muleta, 2020; 3:e2015214. MD, Kelley Tobey, MPH, Katherine Buechel, BSN, Patricia Lawson, 14. Giuliano JS, Markovitz BP, Brierley J, et al. Comparison of pediatric severe sepsis MPH, Vicky Reed, MPH. managed in U.S. and European ICUs. Pediatr Crit Care Med 2016; 17:522–30. Data availability. The data are not publicly available. 15. Fay K, Sapiano MRP, Gokhale R, et al. Assessment of health care exposures and Disclaimer. The findings and conclusions in this report are those of the outcomes in adult patients with sepsis and septic shock. JAMA Netw Open 2020; authors and do not necessarily represent the official position of the Centers 3:e206004. for Disease Control and Prevention or the position or policy of the 16. Centers for Disease Control and Prevention. Emerging Infections Program. Department of Veterans Affairs. Available at: https://www.cdc.gov/ncezid/dpei/eip/index.html. Accessed 30 March 2023. Financial support. This work was supported by the Centers for Disease 17. Goldstein B, Giroir B, Randolph A, et al. International pediatric sepsis consensus Control and Prevention through the Emerging Infections Program cooper- conference: definitions for sepsis and organ dysfunction in pediatrics. Pediatr Crit ative agreement CK12-1202 and CK17-1701. Care Med 2005; 6:2–8. Potential conflicts of interest. G. D.: personal fees from Seres 18. Bone RC, Balk RA, Cerra FB, et al. Definitions for sepsis and organ failure and Therapeutics. R. L.: payment for serving as Associate Editor of the guidelines for the use of innovative therapies in sepsis. Chest 1992; 101: 1644–55. American Academy of Pediatrics Red Book (donated to the Minnesota 19. Matics TJ, Sanchez-Pinto LN. Adaptation and validation of a pediatric sequential Department of Health); support for attending meetings and/or travel as a organ failure assessment score and evaluation of the Sepsis-3 definitions in criti- member of the IDWeek Program Committee; support for attending meet- cally ill children. JAMA Pediatr 2017; 171:e172352. ings and/or travel as an Executive Board Member of the Council for State 20. Flannery AH, Venn CM, Gusovsky A, et al. Frequency and types of healthcare en- counters in the week preceding a sepsis hospitalization: a systematic review. Crit and Territorial Epidemiologists; support for attending meetings and/or Care Explor 2022; 4:1–9. travel as an Executive Board Member of the National Foundation for 21. Liu VX, Escobar GJ, Chaudhary R, Prescott HC. Healthcare utilization and infec- Infectious Diseases; and support for attending meetings and/or travel tion in the week prior to sepsis hospitalization. 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All authors affiliated with EIP sites report function in children. Pediatr Crit Care Med 2020; 21:e52–e106. support for their institutions from the Centers for Disease Control and 25. Davis AL, Carcillo JA, Aneja RK, et al. American College of Critical Care Prevention. All other authors report no potential conflicts. Medicine clinical practice parameters for hemodynamic support of pediatric and neonatal shock. Crit Care Med 2017; 45:1061–93. References 26. Medeiros DNM, Pizarro CF, Cardoso MP, Shibata ARO, Troster EJ. First recog- 1. Rudd KE, Johnson SC, Agesa KM, et al. Global, regional, and national sepsis in- nition, then education. Crit Care Med 2017; 45:e1307. cidence and mortality, 1990–2017: analysis for the Global Burden of Disease 27. Carcillo J, Kissoon N. We know how to stop sepsis, the leading global killer of chil- Study. Lancet 2020; 395:200–11. dren—let’s get it started!. Pediatr Crit Care Med 2010; 11:525–6. 2. Rhee C, Dantes R, Epstein L, et al. 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Open Forum Infectious Diseases – Oxford University Press

Published: Apr 20, 2023

Keywords: children; epidemiology; sepsis; septic shock; severe sepsis

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Epidemiology of Sepsis in US Children and Young Adults

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Epidemiology of Sepsis in US Children and Young Adults

Epidemiology of Sepsis in US Children and Young Adults

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