UNIVERSIDAD DE CUENCA

FACULTAD DE CIENCIAS MÉDICAS

PROGRAMA DE INTERNADO MEDICINA
ROTACIÓN DE CIRUGÌA

TEMA: “REVISIÓN BIBLIOGRÁFICA”

NOMBRE:
MARILYN SOFÍA GONZÁLEZ CHIRIBOGA

FECHA DE ENTREGA:
15 DE MAYO DE 2023

DOCENTE:
DR. ANDRÉS PALOMEQUE

PÉRIODO LECTIVO:
MAYO 2023 – ABRIL 2024

CUENCA – ECUADOR
 IDENTIFICACIÓN OPORTUNA DE SEPSIS EN EL PACIENTE DE TRAUMA:
UNA REVISIÓN BIBLIOGRÁFICA
TIMELY IDENTIFICATION OF SEPSIS IN THE TRAUMA PATIENT: A
LITERATURE REVIEW
Marilyn Sofía González Chiriboga1
1Escuela de Medicina, Facultad de Ciencias Médicas, Universidad de Cuenca,
Cuenca

RESUMEN:
La sepsis es un síndrome de ABSTRACT
disfunción orgánica potencialmente
mortal producido por una respuesta Sepsis is a life-threatening syndrome
inmunitaria desregulada del huésped of organ dysfunction caused by a
frente a la infección, en el que dysregulated host immune response
subyace disfunción orgánica to infection, underlying organ
reconocida por aumento en al menos dysfunction recognized by increases
dos de los parámetros de la in at least two of the parameters of
puntuación de Evaluación the Sequential Organ Failure
Secuencial de Falla Orgánica Assessment (SOFA) score. Timely
(SOFA). El reconocimiento oportuno recognition leads to effective and
conlleva a un manejo eficaz y precoz early management of sepsis, which
de la sepsis, lo que reduce la reduces mortality and adverse
mortalidad y los eventos adversos events derived from its natural
derivados de su curso natural. course.

El interés por el estudio de esta The interest in the study of this

patología yace de la necesidad de un pathology lies in the need for an
diagnóstico oportuno a través del opportune diagnosis through the
reconocimiento de manifestaciones recognition of clinical manifestations
clínicas y escalar pronósticas de and scaling mortality prognoses. It is
mortalidad. Es importante porque important because its complications
sus complicaciones inciden have a negative impact, increasing
negativamente, incrementando las hospital morbidity and mortality
tasas de morbimortalidad rates. In the following article, a brief
hospitalaria. En el siguiente artículo review of sepsis, clinical
se realiza una breve revisión de la presentation, comparison of
sepsis, la presentación clínica, prognostic scales and treatment is
comparación de escalas pronósticas carried out. In this way, it is intended
y tratamiento. De esta forma se to provide professionals and
pretende brindar a los profesionales students in the health area with the
y estudiantes del área de salud, el basic knowledge of this pathology.
conocimiento básico de esta Keywords: sepsis, epidemiology,
patología. prognostic scales, qSOFA, SIRS.
Palabras claves: sepsis,
epidemiología, escalas pronósticas,
qSOFA, SIRS. INTRODUCCIÓN
El término sepsis se remonta artículos originales, alojados en
inicialmente a la concepción de esta bases digitales como PubMed y BVs.
como descomposición o Se utilizó algoritmos de búsqueda a
putrefacción, dada por una partir de las siguientes palabras
interacción compleja entre claves: sepsis, etiology, clinical
microorganismo patógenos y el manifestations, epidemiology y, sus
sistema inmunitario del huésped. respectivas traducciones al español.
Actualmente, se reconoce como un Se restringió la búsqueda a
síndrome caracterizado por la publicaciones en los idiomas español
alteración de la respuesta e inglés de los últimos cinco años
inflamatoria sistémica en respuesta a (2018 – 2023).
un patógeno que puede conllevar a
desregulación o falla orgánica (1). EPIDEMIOLOGÍA

La sepsis constituye una entidad que La Organización Mundial de la Salud

acarrea elevada morbimortalidad, (OMS) y la Alianza Global de Sepsis
por lo que su reconocimiento en mayo del 2017, declaran a la
oportuno es la pauta esencial para la sepsis como una entidad de
disminución de estas tasas. Sin prioridad sanitaria a nivel mundial en
embargo, para tales objetivos no adultos y niños. La evidencia señala
existen pruebas de detección que en el año 2016 la tasa de
rápidas que sean consideradas incidencia fue de 437 por 100 000
predictores confiables para su habitantes al año para sepsis y 270
diagnóstico. En la última guía spsis- de 100 000 personas al año para la
3 se recomienda el empleo de la forma grave en países del primer
evaluación rápida de insuficiencia mundo, a lo que se suma mortalidad
orgánica relacionada con sepsis hospitalaria del 17% - 26%. Existe
(qSOFA), ya que este es un mejor escasos estudios sobre la incidencia
predictor de mortalidad en de esta en los países de bajos
comparación con el Síndrome de ingresos económicos, sin embargo
Respuesta Inflamatoria Sistémica se estima que 31.5 millones de
(SIRS) (2). personas son casos leves de sepsis
y 19.4 millones presentan sepsis
El objetivo de esta revisión es 1) grave, con una mortalidad igual a 5.3
conocer epidemiología y millones de personas al año (1).
etiopatogenia involucrada; 2)
describir la clínica frecuente y El estudio llevado a cabo por Tan, et
comparar sus escalas diagnósticas; al., señala que la tasa de mortalidad
3) orientar el diagnóstico temprano y en países de primer mundo es de
medidas terapéuticas para el manejo 19% en comparación con la de los
oportuno en el área de emergencia. países tercer mundistas en los que
Así mismo, busca llegar a la meta de esta tasa alcanza el 32%, lo que
actualización del conocimiento a permite dilucidar que la esfera
través de la búsqueda exhaustiva de socioeconómica es un determinante
la literatura disponible. o predictor de sepsis en las
poblaciones específicas. Por su
METODOLOGÍA parte en al año 2017 se estimó 48.9
millones de casos y 11 millones de
El presente trabajo se llevo a cabo muertes por esta causa,
realizando una búsqueda y revisión representando el 19.7% de muertes
de artículos científicos, casos globales al año (1).
clínicos, revisiones de literatura y
ETIOPATOGENIA junto con la activación de células
endoteliales a través de la barrera
La sepsis constituye una entidad hematoencefálica. El estrés del
caracterizada por una respuesta retículo endoplásmico se da por
inflamatoria sistémica mediada por la acumulación de proteínas
alteración del sistema inmunitario, y desplegadas o mal plegadas, lo que
cambios en la función de múltiples provoca estrés oxidativo y trastornos
órganos. Su patogenia se explica a graves del calcio. Finalmente, la
través del desequilibrio de autofagia representa un mecanismo
inflamación generada por bacterias, protector, puesto que actúa mediante
hongos, parásitos y virus, que son la eliminación de patógenos,
reconocidos por macrófagos que neutralización de toxinas
activan la liberación de citoquinas microbianas, regulación de la
proinflamatorias que despiertan el liberación de citoquina y descenso
sistema inmunitario innato a través de la apoptosis (3).
de la tormenta de citoquinas como
interleuquina-1, interleuquina-6,
factor de necrosis tumoral alfa, factor
regulador 7 de interferón y proteína PRESENTACIÓN CLÍNICA
adaptadora 1-. Consecuentemente En el área de emergencias no está
se produce disfunción inmune a esclarecido el uso de herramientas
través de la depleción de linfocitos, de detección; sin embargo, se
muerte celular programada, alza de considera que pueden ayudar al
la expresión de moléculas reconocimiento oportuno de esta
antiinflamatorias y regulación entidad y por ende generar un
positiva de ligandos y receptores tratamiento eficaz y oportuno.
asociados a la célula (3).
La sepsis fue inicialmente
Además, el daño mitocondrial catalogada en términos de Síndrome
favorece al desarrollo de trastornos de Respuesta Inflamatoria Sistémica
metabólicos celulares, menor fuente aunada a una fuente sospechosa de
de energía y estrés oxidativo, lo que infección de acuerdo a las guías
promueve apoptosis celular de los sepsis-1 y 2. A partir de la cual se
órganos y células inmunitarias, emplean los términos de sepsis
generando la denominada graves y shock séptico, refiriéndose
insuficiencia multiorgánica. Por su a la primera como a la sepsis con
parte, la sepsis altera la activación uno o más fallo de órganos diana,
de la coagulación al actuar sobre mientras que la segunda involucra
inhibidor de la vía del factor tisular, el inestabilidad hemodinámica a pesar
sistema de proteína C activada y el de la reposición de volumen
sistema antitrombótico (3). intravascular. Objetivamente, se
Las anomalías de la red debía cumplir con dos de los
neuroendocrina-inmune constituyen siguientes criterios: 1) temperatura
otro punto clave en la etiopatogenia corporal superior de 38 o inferior de
de la sepsis, a través del cual el 36 grados centígrados; 2) frecuencia
sistema nervioso autónomo cardíaca superior a 90 latidos por
desencadena activación de minuto; 3) Frecuencia respiratoria
citoquinas inflamatorias a través de superior a 20 respiraciones por
los nervios vago y trigémino; El plexo minuto o presión parcial de CO2
coroideo y órganos ventriculares a inferior a 32 mmHg; 4) recuento de
su vez dan mediadores inflamatorios leucocitos superior a 12000 o inferior
a 400 microlitros o superior al 10% En el estudio observacional
en formas o bandas inmaduras (4). retrospectivo llevado a cabo por
Brink, et al. Se constato que la
En la nueva guía Sepsis-3 se puntuación NEWA fue superior a
introdujo la evaluación rápida de qSOFA y SIRS en el servicio de
insuficiencia orgánica relacionada urgencia en referencia a la
con la sepsis (qSOFA), misma que predicción de mortalidad a los 10 y
consta de tres parámetros: presión 30 días e identificar a los pacientes
arterial sistólica baja menor o igual de alto y bajo riesgo. A pesar de esta
100 mmHg. taquipnea mayor o igual premisa, qSOFA tiene la mayor
a 22 respiraciones por minuto y especificidad (84-96%) y baja
estado mental alterado con Escala sensibilidad (13-53%) con respecto a
de Coma de Glasgow menor 15. las otras escalas. Esta última se
Este permite identificar de manera explica ya que se emplean
oportuna a pacientes con sospecha constantes vitales que son síntomas
de infección con riesgo de mal tardíos deterioro como el estado
pronóstico. Esta está basada en la mental alterado debido a una
puntuación SOFA y fue desarrollada hipoperfusión cerebral inadecuada
con el objetivo de pronosticar el (5).
curso de la sepsis, predecir la
mortalidad y los eventos adversos, CONCLUSIÓN
pues se determinó que un resultado,
mayor o igual de dos puntos La sepsis es un proceso patológico
aumenta tres veces la mortalidad complejo y multifactorial que
hospitalaria (5). conlleva a una disfunción orgánica
potencialmente letal debido a la
Otra de las escalas empleadas en el respuesta inmunitaria alterada frente
reconocimiento inicial de este a patógenos externos. Por tanto,
trastorno es el Puntaje Nacional de representan una gran problemática
Alerta Temprana (NEWS), ya que para el sistema de salud debida a la
permite la detección temprana de elevada mortalidad que esta carrea a
pacientes con riesgo de deterioro, nivel mundial y sobre todo a las
sin embargo, tiene baja consideraciones socioeconómicas
especificidad. Se compone de: implicadas. De tal manera la
frecuencia respiraría, saturación de identificación temprana y el manejo
oxígeno, oxígeno suplementario, adecuado en las primera horas de
temperatura corporañ, presión presentación del cuadro son los
arterial sistólica, frecuencia cardíaca puntales para mejorar las cifras
y puntaje AVPU. Los códigos de epidemiológicas en los países de
corte son de 1-4 para riesgo bajo, de bajos y altos ingresos.
5-6 riesgo moderado y mayor o igual
a 7 para riesgo alto (5).
En la actualidad la herramienta SIRS BIBLIOGRAFÍA
no se considera una herramienta 1. Jaramillo-Bustamante JC,
detección ideal dado a du elevada Piñeres-Olave BE, González-
sensibilidad y baja especificidad, por Dambrauskas S. SIRS or not
lo que se ha propuesto esl uso de SIRS: Is that the infection? A
qSOFA junto con el puntaje nacional critical review of the sepsis
de alerta temprana NEWS (5). definition criteria. Bol Med Hosp
Infant Mex. 2020;77(6):293-302.
2. Usman OA, Usman AA, Ward MA. StatPearls Publishing; 2023
Comparison of SIRS, qSOFA, and [citado 13 de mayo de 2023].
NEWS for the early identification Disponible en:
of sepsis in the Emergency http://www.ncbi.nlm.nih.gov/books
Department. Am J Emerg Med. /NBK547669/
agosto de 2019;37(8):1490-7.
5. Brink A, Alsma J, Verdonschot
3. Huang M, Cai S, Su J. The RJCG, Rood PPM, Zietse R,
Pathogenesis of Sepsis and Lingsma HF, et al. Predicting
Potential Therapeutic Targets. Int mortality in patients with
J Mol Sci. 29 de octubre de suspected sepsis at the
2019;20(21):5376. Emergency Department; A
retrospective cohort study
4. Chakraborty RK, Burns B. comparing qSOFA, SIRS and
Systemic Inflammatory Response National Early Warning Score.
Syndrome. En: StatPearls PloS One. 2019;14(1):e0211133.
[Internet]. Treasure Island (FL):
 RESEARCH ARTICLE

Predicting mortality in patients with

suspected sepsis at the Emergency
Department; A retrospective cohort study
comparing qSOFA, SIRS and National Early
Warning Score
Anniek Brink ID1☯*, Jelmer Alsma ID1☯, Rob Johannes Carel Gerardus Verdonschot2,
Pleunie Petronella Marie Rood2, Robert Zietse1, Hester Floor Lingsma3, Stephanie
Catherine Elisabeth Schuit1,2
a1111111111
a1111111111 1 Department of Internal Medicine, Erasmus University Medical Center, Rotterdam, the Netherlands,
a1111111111 2 Department of Emergency Medicine, Erasmus University Medical Center, Rotterdam, the Netherlands,
a1111111111 3 Department of Public Health, Erasmus University Medical Center, Rotterdam, the Netherlands
a1111111111
☯ These authors contributed equally to this work.
* [email protected]

OPEN ACCESS Abstract

Citation: Brink A, Alsma J, Verdonschot RJCG,
Rood PPM, Zietse R, Lingsma HF, et al. (2019)
Predicting mortality in patients with suspected Objective
sepsis at the Emergency Department; A In hospitalized patients, the risk of sepsis-related mortality can be assessed using the quick
retrospective cohort study comparing qSOFA,
Sepsis-related Organ Failure Assessment (qSOFA). Currently, different tools that predict
SIRS and National Early Warning Score. PLoS ONE
14(1): e0211133. https://doi.org/10.1371/journal. deterioration such as the National Early Warning Score (NEWS) have been introduced in
pone.0211133 clinical practice in Emergency Departments (ED) worldwide. It remains ambiguous which
Editor: Juan Carlos Lopez-Delgado, Hospital screening tool for mortality at the ED is best. The objective of this study was to evaluate the
Universitari Bellvitge, SPAIN predictive performance for mortality of two sepsis-based scores (i.e. qSOFA and Systemic
Received: July 19, 2018 Inflammatory Response Syndrome (SIRS)-criteria) compared to the more general NEWS
score, in patients with suspected infection directly at presentation to the ED.
Accepted: January 8, 2019

Published: January 25, 2019

Methods
Copyright: © 2019 Brink et al. This is an open
We performed a retrospective cohort study. Patients who presented to the ED between
access article distributed under the terms of the
Creative Commons Attribution License, which June 2012 and May 2016 with suspected sepsis in a large tertiary care center were included.
permits unrestricted use, distribution, and Suspected sepsis was defined as initiation of intravenous antibiotics and/or collection of any
reproduction in any medium, provided the original culture in the ED. Outcome was defined as 10-day and 30-day mortality after ED presenta-
author and source are credited.
tion. Predictive performance was expressed as discrimination (AUC) and calibration using
Data Availability Statement: Data are available Hosmer-Lemeshow goodness-of-fit test. Subsequently, sensitivity, and specificity were
from the RePub, Erasmus University Repository of
the Erasmus University Medical Center, Rotterdam
calculated.
(http://hdl.handle.net/1765/113273). The Erasmus
University Medical Center has a restrictive policy in Results
sharing de-identified data on third party servers,
which is a result of the General Data Protection In total 8,204 patients were included of whom 286 (3.5%) died within ten days and 490
Regulation. (6.0%) within 30 days after presentation. NEWS had the best performance, followed by

PLOS ONE | https://doi.org/10.1371/journal.pone.0211133 January 25, 2019 1 / 14

 Predicting mortality in patients at the Emergency Department suspected for sepsis

Funding: The authors received no specific funding qSOFA and SIRS (10-day AUC: 0.837, 0.744, 0.646, 30-day AUC: 0.779, 0.697, 0.631).
for this work. qSOFA (�2) lacked a high sensitivity versus SIRS (�2) and NEWS (�7) (28.5%, 77.2%,
Competing interests: The authors have declared 68.0%), whilst entailing highest specificity versus NEWS and SIRS (93.7%, 66.5%, 37.6%).
that no competing interests exist.

Abbreviations: AUC, Area Under the Curve; AVPU, Conclusions

Level of consciousness scale Alert, Verbal, Pain,
Unresponsive; ED, Emergency Department; GCS,
NEWS is more accurate in predicting 10- and 30-day mortality than qSOFA and SIRS in
Glasgow Coma Scale; HR, Heart Rate; ICU, patients presenting to the ED with suspected sepsis.
Intensive care unit; IQR, Interquartile range; LR,
Likelihood Ratio; MTS, Manchester Triage System;
NEWS, National Early Warning Score; qSOFA,
quick Sepsis-related Organ Failure Assessment;
SBP, Systolic Blood pressure; SD, Standard
deviation; SIRS, Systemic Inflammatory Response Introduction
Syndrome; SOFA, Sepsis-related Organ Failure
Sepsis is a syndrome characterised by both signs of infection and manifestations of a systemic
Assessment; Χ2, Chi-squared.
host response [1]. Sepsis is the primary cause of mortality from infection. The definition of
sepsis has changed throughout the last decades. In February 2016 the Third International Con-
sensus Definition for Sepsis (Sepsis-3) replaced the Sepsis-2 definition dating from 2001 [1–3].
Sepsis is currently defined as a “life-threatening organ dysfunction caused by a dysregulated
host response to infection”, in which organ dysfunction is represented by an increase of at
least two points in the Sequential Organ Failure Assessment (SOFA) score [1]. The Systemic
Inflammatory Response Syndrome (SIRS) score, which was part of the definition in Sepsis-1
and -2, has been abandoned.
The quick Sepsis-related Organ Failure Assessment (qSOFA) was introduced with the new
Sepsis-3 definition [4]. However, not all medical societies support this new definition[5, 6].
The qSOFA consists of three parameters (i.e. low systolic blood pressure (�100 mmHg),
tachypnea (�22 /minute) and altered mental status (Glasgow Coma Scale (GCS) <15 /
AVPU<Alert)), with a maximum score of three points. qSOFA is a bedside prompt to identify
patients with a suspected infection who are at greater risk for a poor outcome. It is a simplified
score based on the SOFA score. Early identification of these patients potentially results in ear-
lier adequate treatment and a decrease in mortality. qSOFA aims to prognosticate the course
of sepsis and intends to predict sepsis-related mortality and adverse events; a score of two
points or higher gives a three to 14-fold increase in in-hospital mortality [4]. The qSOFA score
is claimed to be more accurate than SOFA in departments outside the intensive care unit
(ICU), however the use of qSOFA in the Emergency Department (ED) is questionable [4, 7–
10]. The authors of Sepsis-3 also consider qSOFA as a prompt to identify possible infection
[1].
In many patients admitted to the ED with sepsis the severity of their illness is not directly
clear. The presence of a life-threatening infection can easily be overlooked. The use of screen-
ing tools in the ED can aid in early recognition of patients with sepsis, resulting in early initia-
tion of effective and complete treatment. This requires screening tools with a high sensitivity.
SIRS has been criticized for being too sensitive, while lacking specificity in recognizing sepsis,
and it is therefore not an ideal screening tool. As qSOFA performed better than SIRS in hospi-
talized patients, it has been proposed that qSOFA is preferred to SIRS. Alternatively, early
warning scores, such as the National Early Warning Score (NEWS), are already recommended
for use in the ED, and should therefore also be considered [11]. NEWS was introduced in 2012
by the Royal College of Physicians, who aimed to provide a standardised early warning score.
This score is used for early detection of patients at risk for deterioration but is not specific for
sepsis. NEWS comprises of seven parameters (i.e. respiratory rate, oxygen saturation, supple-
mental oxygen, body temperature, systolic blood pressure, heart rate, AVPU score) with a

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 Predicting mortality in patients at the Emergency Department suspected for sepsis

maximum of twenty points. In clinical practice cut-off values of 1–4, 5–6 and �7, respectively
for low, medium and high risk are used. NEWS was primarily developed for use on the wards,
however NEWS was also tested for use in the ED and in the prehospital setting [12, 13]. For
use in the ED a cut-off value of �7 is suggested.
The aim of this study was to determine the prognostic value of qSOFA in predicting mortal-
ity in comparison to SIRS and NEWS in patients presenting to the ED with suspected sepsis.

Methods
Study design and setting
This was a retrospective cohort study nested in a large anonymous database of patients visiting
the ED of the Erasmus University Medical Center, Rotterdam, the Netherlands (Erasmus
MC), which is the largest tertiary referral center in The Netherlands. The ED is an open access
department with approximately 30,000 annual visits. Patients are strongly encouraged to see a
general practitioner before visiting the ED. The database of the ED consists of all patients
presenting to the ED. This database holds information of patients from January 2012 and
onwards, on both clinical and vital parameters, laboratory results, other diagnostic procedures
and treatments. The data was extracted from the electronic health records every two weeks
through May 2017. Random samples were manually checked for concordance.

Selection of participants
In our consecutive cohort, we included patients with suspected sepsis visiting the ED
between June 1st 2012 and May 31st 2016. Suspected sepsis was defined as either the initia-
tion of non-prophylactic intravenous antibiotic therapy during their ED visit or the collec-
tion of any culture (i.e. blood cultures, urine cultures, wound cultures, throat swabs, sputum
cultures and cultures of cerebrospinal fluid) or viral diagnostics (i.e. polymerase chain reac-
tion (PCR) on blood and stool samples, on throat swabs and on cerebrospinal fluids) during
the index visit. Rapid diagnostic testing for viral or bacterial infections was not possible dur-
ing the study period. Patients who presented with symptoms directly related to trauma were
excluded. A comprehensive search in the database identified all patients who met this
definition.

Measurements and outcomes

Demographic data (i.e. age, sex), vital parameters (i.e. blood pressure, body temperature, respi-
ratory rate, peripheral oxygen saturation, consciousness level according to AVPU scale or
GCS), laboratory testing performed, acuity level according to Manchester Triage System
(MTS) category, and supplemental oxygen therapy were derived from the database.
The AVPU scale is a system to score the mental status and is an acronym of ‘Alert, Verbal,
Pain, Unresponsive’ [14]. When AVPU was not scored, GCS was used, and vice versa. Only
the first vital parameters were retrieved as the aim of the study was to assess the ability of the
different prompts to screen for short-term mortality at ED presentation. White blood cell
count was retrieved for all patients when available. Data on all-cause mortality was obtained
from patient records and 10- and 30-day mortality was calculated. Mortality data was retrieved
from the patient records, which are linked to municipal mortality data. Subsequently, we
assessed whether mortality was directly sepsis-related or not.
We calculated qSOFA, SIRS and NEWS and formed groups using cut-off values most indic-
ative for poor outcome (qSOFA�2, SIRS�2, and NEWS�7)(Table 1) [2, 4, 11]. The Medical
Ethics Committee of the Erasmus MC reviewed the study and deemed exempt.

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 Predicting mortality in patients at the Emergency Department suspected for sepsis

Table 1. Variables within NEWS, qSOFA and SIRS criteria.

NEWSa qSOFAb SIRSc
3 2 1 0 1 2 3 1 0 1 1 0 1
Body temperature (˚C) �35.0 35.1–36.0 36.1–38.0 38.1–39.0 �39.1 <36.0 36.0–38.0 >38.0
Heart rate (bpm) �40 41–50 51–90 91–110 111–130 �131 �90 >90
Systolic blood pressure (mmHg) �90 91–100 101–110 111–219 �220 �100 >100
Respiratory rate (per minute) �8 9–11 12–20 21–24 �25 <22 �22 �20 >20
Oxygen saturation (%) �91 92–93 94–95 �96
Supplemental oxygen Yes No
AVPU score / GCS A/15 V,P,U/<15 A/15 V,P,U/<15
WBC (� 109/L) �4.0 4.0–12.0 >12.0

Variables within the National Early Warning Score, quick Sepsis-related Organ Failure Assessment and Systemic Inflammatory Response Syndrome criteria. Each
variable is measured and summed up.
a
NEWS ranges from 0 to 20, wherein 1 to 3 points are given for aberrant values in the following variables: body temperature, heart rate, systolic blood pressure,
respiratory rate, oxygen saturation, supplemental oxygen and AVPU score.
b
qSOFA ranges from 0 to 3, in which 1 point is assigned to abnormal values in the following variables: systolic blood pressure, respiratory rate and AVPU score.
c
SIRS ranges from 0 to 4 points, wherein 1 point is allocated to aberrant values in the following variables: body temperature, heart rate, respiratory rate and WBC. The
total score within NEWS, qSOFA, and SIRS corresponds with a risk for mortality. Abbreviations: NEWS, national early warning score; qSOFA, quick sepsis-related
organ failure assessment; SIRS, systemic inflammatory response syndrome;˚C, degrees centigrade; bpm, beats per minute; mmHg; millimetre of mercury; AVPU, alert,
verbal, pain, unresponsive; WBC, white blood cell count.

https://doi.org/10.1371/journal.pone.0211133.t001

Statistical analysis
Data was summarized using mean, median, interquartile range (IQR) and standard deviation
(SD) when appropriate. Missing or clinically implausible data was replaced by multiple im-
putation. This method is valid even when large sets of data are missing[15]. Missing values
within the parameters were imputed five times using non-missing parameters. Furthermore,
imputation was based on a distribution of the observed data to preclude that implausible values
would replace the missing value. After imputation, five complete datasets were available. In
each dataset the SIRS, qSOFA and NEWS scores were recalculated using the imputed variables.
Whenever possible, results were pooled. When pooling was not possible, single imputation
was used. The primary outcome was all-cause mortality within 10- and 30-days after ED
presentation.
Patient characteristics were compared using the two-sampled t-test, Mann-Whitney U test,
and chi-squared test based on the distribution of the data. Univariate regression analysis was
used for association between the different parameters and 10- and 30-day mortality to deter-
mine which variable is the best predictor. This predictor is characterized by the largest LRχ2
and a high explained variance (i.e. R2 close to one).
Logistic regression was used to obtain the odds for 10- and 30-day mortality based on indi-
vidual scores. The predictive performances of qSOFA, SIRS, and NEWS were expressed as dis-
crimination (area under the Receiver Operating Characteristic-curve) and calibration.
Calibration represents how mortality predictions resemble the observed mortality, which was
measured by the Hosmer-Lemeshow goodness-of-fit test and expressed as a χ2-value and
accessory p-value. Subsequently, sensitivity, specificity and positive- and negative predictive
values were calculated for the different cut-off points. The Youden’s J statistic was calculated to
assess the optimal cut-off point for the different scores. A p-value <0.05 was considered statis-
tically significant. Analyses were undertaken using Statistical Package for the Social Science
(SPSS) version 21 and R statistics version 3.1.3. (2015-03-09).

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 Predicting mortality in patients at the Emergency Department suspected for sepsis

Results
Patient characteristics
A total of 120,177 ED visits in 75,428 unique patients were recorded between June 1st 2012 and
May 31st 2016. 21,326 patient records were excluded as their ED visits were related to trauma,
leaving 54,102 patients for analysis. 3,351 patients received intravenous antibiotic therapy in
the ED. Bacterial cultures and viral diagnostics were collected from 7,302 patients during their
ED visit. In total, 8,204 patients were analyzed (Fig 1). The majority of patients were male
(55.9%), and the median age was 57.0 (IQR 41.0–67.0). In total, 74.6% of patients were hospi-
talized (Table 2). 10-day and 30-day mortality was 3.5% (286) and 6.0% (490), respectively. Of
the 490 deceased patients, 64,7% died in the hospital. Patients who died were significantly

Fig 1. Subject inclusion flowchart. Flowchart of patients who met inclusion/exclusion criteria.
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 Predicting mortality in patients at the Emergency Department suspected for sepsis

older, and had higher heart rates, lower systolic blood pressures, lower oxygen saturation and
higher respiratory rates during ED presentation. 18,4% of the deceased patients had positive
cultures. The cause of death could be retrieved from the patient records in all 490 deceased
patients. In 63.4% of patients their death was directly related to sepsis.

Performance of the models

Univariate regression analysis showed that oxygen therapy during ED presentation—a variable
within NEWS—was the best predictor for mortality (LRχ2 = 335.73), although the explained
variation was low (r2 = 0.110). Other strong predictors included systolic blood pressure and
mental status (Table 3).
NEWS performed substantially better than qSOFA and SIRS in predicting both 10-day
mortality (AUC [95% CI]: 0.837 [0.812, 0.861], 0.744 [0.708, 0.78] and 0.646 [0.613, 0.679]

Table 2. Patient characteristics.

N (% missing) All patients Died within ten days Died within 30 days Alive P-value
N (%) 8,204 286 (3.5) 490 (6.0) 7,714 (94.0)
Male, N (%) 8,204 (0) 4,581(55.8) 182 (63.6) 321 (65.5) 4,260 (55.2) <0.0001�
Age, median (IQR) 8,204 (0) 57.0 (41–68) 68.0 (58.75–78) 67.0 (58–77.25) 56.0 (41–67) <0.0001†
Body temperature in˚C, mean (SD) 7,945 (3.2) 37.6 (1.3) 36.9 (1.7) 37.2 (1.5) 37.7 (1.2) <0.0001‡
HR in bpm, mean (SD) 7,858 (4.2) 97.9 (21.4) 103.7 (26.5) 104.9 (26.1) 97.5 (21.0) <0.0001‡
SBP in mmHg, mean (SD) 7,764 (5.4) 131.7 (26.1) 119.6 (36.2) 121.3 (34.0) 132.3 (25.4) <0.0001‡
RR per minute, mean (SD) 4,796 (41.5) 21.3 (8.5) 25.0 (9.1) 24.5 (9.1) 21.0 (8.3) <0.0001‡
Oxygen saturation in %, mean (SD) 7,578 (7.6) 96.0 (3.6) 93.9 (5.9) 93.9 (5.6) 96.2 (3.4) <0.0001‡
AVPU, N (%) 6,643 (19.0) <0.0001§
Alert 6,104 (91.9) 152 (64.7) 291 (72.6) 5,813 (93.1)
Verbal 385 (5.8) 39 (16.6) 57 (14.2) 328 (5.3)
Pain 69 (1.0) 12 (5.1) 16 (4.0) 53 (0.8)
Unresponsive 85 (1.3) 32 (13.6) 37 (9.2) 48 (0.8)
Supplemental oxygen, N (%) 8,204 (0) 2,472 (30.1) 223 (78.0) 338 (69.0) 2,134 (27.7) <0.0001�
Laboratory testing performed, N (%) 8,204 (0) 6,980 (86.9) 251 (87.8) 437 (89.2) 6,690 (86.7) 0.118�
9
�
WBC in 10 /L, mean (SD) 7,036 (14.2) 11.84 (12.88) 17.03 (30.70) 15.37 (24.22) 11.58 (11.58) <0.0001‡
SIRS�2, N (%) 4,387 (46.5) 2,940 (67.0) 178 (62.2) 298 (78.6) 2,642 (65.9) <0.0001�
qSOFA�2, N (%) 4,318 (47.4) 369 (4.5) 59 (20.6) 87 (17.8) 282 (7.0) <0.0001�
NEWS�7, N (%) 4,243 (48.3) 1,895 (44.7) 135 (77.1) 212 (70.0) 1,683 (42.7) <0.0001�
MTS, N (%) 7,786 (5.1) <0.0001§
Immediate 168 (2.2) 47 (18.2) 53 (11.8) 115 (1.6)
Very urgent 1,002 (12.9) 87 (33.7) 148 (32.9) 854 (11.6)
Urgent 5,451 (70.0) 115 (44.6) 230 (51.1) 5,221 (71.2)
Standard 1,144 (14.7) 9 (3.5) 19 (4.2) 1,125 (15.3)
Non urgent 16 (0.2) 0 (0.0) 0 (0.0) 16 (0.2)
Admission, N (%) 8,204 (0) 6,117 (74.6) 273 (95.5) 455 (92.9) 5,662 (73.4) <0.0001�

Patient characteristics. Abbreviations: N, number; SBP, systolic blood pressure; RR, respiratory rate; HR, heart rate; AVPU, Alert, Verbal, Pain, Unresponsive), WBC
white blood cell count; SIRS, systemic inflammatory response syndrome; qSOFA, quick sepsis-related organ failure assessment; NEWS, national early warning score;
MTS, Manchester Triage System; IQR, interquartile range (25–75 percentile); SD, standard deviation; bpm, beats per minute; mmHg, millimetre of mercury; L, litre;˚C,
degrees centigrade.
�
Chi-squared test
†
median test
‡
independent samples t-test
§
Mann-Whitney U test.

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 Predicting mortality in patients at the Emergency Department suspected for sepsis

Table 3. Univariate regression on the outcome 30-day mortality.

LRχ2 R2
SIRS Body temperature 0.51 0.000
Heart rate 24.05 0.008
Respiratory rate 28.13 0.013
WBC 60.50 0.022
qSOFA Respiratory rate 22.50 0.010
Systolic blood pressure 133.49 0.045
AVPU 142.03 0.060
NEWS Oxygen therapy 335.73 0.110
Oxygen saturation 44.54 0.016
Respiratory rate 30.32 0.014
Body temperature 17.13 0.006
Systolic blood pressure 103.87 0.035
Heart rate 43.04 0.015
AVPU 144.17 0.059

30-day mortality univariate regression. The best parameter in the univariate model has the highest likelihood
function (LRχ2). R2 is the proportion of the variance in outcome 30-day mortality explained by the univariate model.

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respectively) and 30-day mortality (0.779 [0.755, 0.804], 0.697 [0.667, 0.726] and 0.631 [0.605,
0.656] respectively) (Figs 2 and 3).
Calibration for NEWS showed a χ2 = 10.743 and p-value = 0.217, compared to χ2 = 6.915
and p-value = 0.032 for qSOFA, and χ2 = 22.827 and p-value = 0.004 for SIRS. The non-signifi-
cant p-value indicates that the mortality rates between the observed and the predicted values
were statistically equivalent.
qSOFA showed the highest specificity, followed by NEWS and SIRS. Sensitivity was highest
in SIRS, followed by NEWS and qSOFA. Using Youden’s J statistic, the optimal cut-off points
for 10-day mortality were qSOFA �1, SIRS�2 and NEWS�7, and for 30-day qSOFA �1,
SIRS�3 and NEWS�7 (Table 4).

Discussion
In this retrospective observational study of patients visiting the ED with a suspected sepsis we
found that NEWS was superior to qSOFA and SIRS in predicting 10- and 30-day mortality for
both discrimination and calibration. The different prompts all have different sensitivities and
specificities for mortality. qSOFA has the highest specificity and lowest sensitivity, SIRS has
the lowest specificity and highest sensitivity. NEWS has both an intermediate sensitivity and
specificity, but is the best overall predictor in distinguishing high risk from low risk patients.
NEWS has a lower sensitivity resulting in a significant number of false negatives, i.e. not all the
patients who eventually died were identified with NEWS. NEWS was the only model with a
good agreement between the expected and observed outcomes, i.e. calibration. However, none
of the prediction models succeeded to fulfil all performance assessments, which would ideally
be the case. Subsequent measurements of NEWS (e.g. hourly) will potentially identify patients
who deteriorate during the stay in the ED and may improve sensitivity. We conclude that at
presentation to the ED NEWS can be used as an alternative screening tool for patients with
suspected sepsis who are at risk for deterioration, multi-organ failure, and subsequently death.
Our findings support the increasing data that suggests that the NEWS score is a useful
screening tool in the ED, although its use has not fully been validated in the ED setting. Jo

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 Predicting mortality in patients at the Emergency Department suspected for sepsis

Fig 2. ROC curve 10-day mortality.

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et al. studied the NEWS combined with serum lactate in predicting mortality in the general
adult ED population and found an excellent discrimination (AUC = 0.96) for predicting two-
day mortality [16]. The NEWS score as measured in the prehospital setting showed good cor-
relation (p<0.001) with hospital disposition [17]. Our study confirms the findings by Churpek
et al. which support the introduction of the NEWS score in the ED. However, they studied
patients outside the ICU and not only ED patients. And they primarily measured the perfor-
mance of the different prompts based on the worst vital signs. NEWS had the highest perfor-
mance in predicting in-hospital mortality in ED patients compared to qSOFA and SIRS
(AUC = 0.77, AUC = 0.69 and AUC = 0.65 respectively). We used vital parameters at presenta-
tion in the ED and found similar results. In the Churpek et al. study a NEWS threshold of �7
is suggested. This threshold is also recommended by the Royal College of Physicians[11]. We
were able to confirm this threshold using our data. In a cohort study by Sbiti-Rohr et al. in
patients with community-acquired pneumonia, the NEWS score in the ED was significantly
higher for those who died within 30 days after presentation than for survivors [18]. These
results are similar to a study of patients presenting to the ED with acute dyspnea; survivors had
significantly lower NEWS scores at ED presentation [19].
The NEWS was also studied in patients suspected of sepsis. Corfield et al. found that an
increased NEWS on arrival at the ED was associated with mortality in patients who met the
sepsis criteria as defined by Bone et al. (odds ratio 1.95 to 5.64) [20].

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 Predicting mortality in patients at the Emergency Department suspected for sepsis

Fig 3. ROC curve 30-day mortality.

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Most prediction scores include measurements which are subject to interpretation. A study
on the interrater agreement of GCS assessed at the ED yielded low agreement [21]. Semler
et al. showed that in hospitalized patients recorded respiratory rates were higher than directly
observed measurements. Also, the recorded rates were more likely to be 18 or 20 breaths/min-
ute [22]. We expect that parameters that are not acquired automatically are subject to con-
founding by disease severity and were more likely to be measured and noted when one would
expect a deviant result [23, 24]. Therefore, for the proper use of the NEWS, qSOFA and SIRS
these measurements should be routinely performed in a structural way.
Specific scoring systems are used as an alternative to the NEWS to predict sepsis-related
mortality in ED patients. The SIRS criteria, as introduced by Bone in 1992, were studied as a
prediction tool for mortality and most studies show that an increase in SIRS items reflects an
increased risk of mortality, ranging from 1.4% to 12% when no SIRS criteria were met and
increasing to approximately 36% for four SIRS items [25, 26]. In Sepsis-3, the qSOFA was
introduced as a simple tool to detect deterioration and predict mortality in departments out-
side the ICU. Simultaneously, SIRS criteria were abandoned from the new sepsis definition
after criticism of its low specificity. The qSOFA�2 resembles a three to 14-fold increase in
mortality risk[4].
qSOFA has been challenged as a prompt in the ED to identify patients with an increased
risk for sepsis-related mortality ever since its introduction. Despite a high specificity (84–

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 Predicting mortality in patients at the Emergency Department suspected for sepsis

Table 4. Sensitivity, specificity, PPV, NPV and Youden’s index for different cut-off values for 10- and 30-day mortality.
10-day Sensitivity Specificity PPV NPV Youden’s 30-day Sensitivity Specificity PPV NPV Youden’s
mortality (%) (%) (%) (%) index mortality (%) (%) (%) (%) index
SIRS
�1 98.0 12.2 3.9 99.4 0.102 96.3 12.4 6.5 98.1 0.087
�2║ 80.4 37.3 4.4 98.1 0.177¶ 77.2 37.6 7.3 96.3 0.148
�3 50.4 67.0 5.2 97.3 0.174 48.1 67.3 8.5 95.3 0.154¶
4 15.0 90.8 5.5 96.7 0.058 14.9 90.9 9.4 94.4 0.058
qSOFA
�1 77.2 59.1 6.5 98.6 0.362¶ 69.9 59.5 10.0 96.9 0.294¶
�2║ 33.1 93.3 15.3 97.4 0.264 28.5 93.7 22.6 95.3 0.222
3 7.8 99.3 28.2 96.7 0.071 5.5 99.3 34.0 94.2 0.048
NEWS
�3 98.3 17.8 4.2 99.7 0.161 95.6 18.1 7.0 98.5 0.137
�4 94.5 26.0 4.5 99.2 0.205 90.6 26.3 7.3 97.8 0.169
�5 89.1 42.1 5.3 99.1 0.312 83.0 42.5 8.5 97.5 0.255
�6 82.1 57.0 6.5 98.9 0.391 75.5 57.6 10.2 97.3 0.33
�7║ 76.3 65.9 7.6 98.7 0.421¶ 68.0 66.5 11.5 97.0 0.345¶
�8 59.6 77.1 8.7 98.1 0.367 55.0 77.8 13.7 96.4 0.328
�9 45.8 84.0 9.5 97.7 0.298 42.0 84.5 14.9 95.8 0.266
�10 35.1 89.4 10.8 97.4 0.245 31.3 89.8 16.5 95.3 0.211
�11 22.8 94.5 13.2 97.1 0.173 20.9 94.8 20.7 94.9 0.158
�12 9.4 98.3 17.3 96.7 0.078 14.7 96.8 22.6 94.6 0.114
�13 9.4 98.3 17.3 96.7 0.078 8.1 98.5 25.3 94.3 0.066
�14 4.2 99.3 17.9 96.6 0.035 3.9 99.4 28.5 94.1 0.033
�15 1.2 99.7 14.1 96.5 0.009 1.0 99.7 20 94.0 0.007
�16 0.3 99.9 15.4 96.5 0.003 0.4 99.9 11.25 94.1 0.004

Sensitivity, specificity, positive predictive value, negative predictive value and Youden’s index for different cut-off values for 10- and 30-day mortality, respectively.
║ are the predefined cut-off values which are most indicative for a poor outcome.
¶ representing the optimal cut-off points. Abbreviations: PPV, positive predictive value; NPV, negative predictive value; SIRS, systemic inflammatory response
syndrome; qSOFA, quick sepsis-related organ failure assessment; NEWS, national early warning score.

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96%), the qSOFA has low sensitivity (13–53%) [8, 27]. This low sensitivity can be explained by
the fact that the qSOFA is composed of vital parameters representing late symptoms of deterio-
ration (e.g. altered mental status due to inadequate perfusion of the brain) [28, 29]. In addition,
qSOFA was derived in a cohort of critically ill patients, in which 11% of the patients were
admitted in the ICU [4]. These patients represent a selected population compared to all
patients who visit the ED, therefore, selection bias may be present. Furthermore, qSOFA was
developed on the most aberrant results in serial vital parameter measurements. This approach
may ameliorate the ability to predict mortality, but it restricts the utility as a prompt for early
identification of patients at risk directly at ED presentation. All these arguments mainly affect
the sensitivity and can influence the predictive performance of qSOFA. To increase sensitivity,
Park et al. proposed the use of the qSOFA cut-off point of �1 instead of 2 for patients in the
ED, resulting in an increase in sensitivity from 53.0% to 82.0%. This is in line with our find-
ings. Changing the cut-off to 1 would increase the usability of qSOFA as a screening tool at
cost of specificity. However, NEWS still has a higher sensitivity and a better predictive
performance.

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 Predicting mortality in patients at the Emergency Department suspected for sepsis

Strengths and limitations

This study has a number of strengths and limitations. The major strength of our study is that
we used a large consecutive dataset with many relevant parameters directly derived from elec-
tronic patient records with mortality data directly acquired from municipality data.
Our study also has several limitations. The first limitation of this study is its retrospective
design using data from a single tertiary care center. In our center we treat many patients with
congenital and acquired immunodeficiencies (e.g. patients with organ or bone marrow trans-
plantation, chemotherapy), which may limit the generalizability. The database contained miss-
ing values, which were replaced by multiple imputation. Multiple imputation has also been
used in other sepsis-related studies [4, 8, 30]. Respiratory rate was most frequently missing
and, as mentioned earlier, availability of respiratory rate might be an indicator of confounding
by indication, as it is more often measured in patients who are deemed more critically ill[23].
A second limitation is the definition of the study population. As there is no gold standard for
defining an infection, the study population was difficult to determine. We based our inclusion
criteria on the definition of Seymour et al. [4] but modified the criteria to incorporate the larg-
est group of patients who were suspected for infection and at risk for sepsis. Both microbial
diagnostics and initiation of antibiotics were used as a proxy for a clinically suspected sepsis.
These inclusion criteria could possibly bias against people with viral disease, as no antibiotics
given and cultures are not routinely performed. However, in the most critically ill patients cul-
tures are taken and antibiotics are started empirically in clinical practice, regardless of the sus-
pected pathogen (e.g. virus, bacteria). Furthermore, we also included viral cultures such as
throat swabs and stool cultures, but these were a minority as compared to blood cultures (289
and 46 vs. 6552). Therefore, the chance of bias due viral sepsis is limited.
Last, to determine the best screening tool at presentation in the ED, we chose to use only
the first recorded vital signs for calculation of NEWS, qSOFA and SIRS. We are aware that
rapid changes in vital parameters could be indicative for a higher risk for mortality and that
people may deteriorate during their ED visit. However, the duration of ED stay is intended to
be very limited. Choosing to only use the first vital parameters may limit the predictive ability
of the different models. However, in clinical practice the first vital parameters are used to
determine the severity of the patient’s condition and, therefore, to triage patients in urgent and
non-urgent. Using first available parameters in this study actually reflects clinical practice and
in our opinion is a valid method to test predictive performance upon ED presentation, with
results comparable to using the worst vital parameters[31].

Conclusions
In conclusion, the NEWS is more accurate in predicting 10- and 30-day mortality than qSOFA
and SIRS in patients suspected of sepsis on initial presentation to the ED. Our finding suggests
that the introduction of the NEWS in the ED with subsequent measurements should be further
studied. This will potentially aid the early detection of all patients at risk for deterioration in
the ED including those at risk of sepsis-related mortality.

Supporting information
S1 Table. Sensitivity (95% CI), specificity (95% CI), positive predictive value, negative pre-
dictive value and Youden’s index for different cut-off values for 10- and 30-day mortality.
║ are the predefined cut-off values which are most indicative for a poor outcome. ¶ represent-
ing the optimal cut-off points. Abbreviations: CI, confidence interval; PPV, positive predictive
value; NPV, negative predictive value; SIRS, systemic inflammatory response syndrome;

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 Predicting mortality in patients at the Emergency Department suspected for sepsis

qSOFA, quick sepsis-related organ failure assessment; NEWS, national early warning score.
(DOCX)

Author Contributions
Conceptualization: Anniek Brink, Jelmer Alsma, Stephanie Catherine Elisabeth Schuit.
Data curation: Anniek Brink, Rob Johannes Carel Gerardus Verdonschot.
Formal analysis: Anniek Brink, Hester Floor Lingsma.
Investigation: Anniek Brink.
Methodology: Anniek Brink, Rob Johannes Carel Gerardus Verdonschot, Pleunie Petronella
Marie Rood, Hester Floor Lingsma, Stephanie Catherine Elisabeth Schuit.
Resources: Rob Johannes Carel Gerardus Verdonschot, Stephanie Catherine Elisabeth Schuit.
Software: Hester Floor Lingsma.
Supervision: Jelmer Alsma, Robert Zietse, Stephanie Catherine Elisabeth Schuit.
Validation: Anniek Brink, Hester Floor Lingsma.
Writing – original draft: Anniek Brink, Jelmer Alsma.
Writing – review & editing: Rob Johannes Carel Gerardus Verdonschot, Pleunie Petronella
Marie Rood, Robert Zietse, Hester Floor Lingsma, Stephanie Catherine Elisabeth Schuit.

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