MANEJO DE LA NEUTROPENIA FEBRIL EN EL … a hematooncologia. Dr... · Utilitat de la Procalcitonina...

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Utilitat de la Procalcitonina en el maneig de la neutropènia febril postquimioteràpia Francesc Ferrés Serrat Cap de secció dUrgències Pediàtriques Hospital Son Espases, Palma de Mallorca

Transcript of MANEJO DE LA NEUTROPENIA FEBRIL EN EL … a hematooncologia. Dr... · Utilitat de la Procalcitonina...

Utilitat de la Procalcitonina en el

maneig de la neutropènia febril

postquimioteràpia

Francesc Ferrés Serrat

Cap de secció d’Urgències Pediàtriques

Hospital Son Espases, Palma de Mallorca

Introducció (1)

Els pacients oncohematològics que reben quimioteràpia presenten en algun moment neutropènia i febre

Les causes més greus són les bacterièmies, especialment si són gèrmens multirresistents

Taxes elevades de morbimortalitat

La INFECCIÓ és la principal causa de mort no relacionada amb l’evolució de la malaltia en els pacients oncològics

Neutropènia febril: URGÈNCIA MÈDICA

Introducció (2)

Aquests pacients no presenten els símptomes usuals d’infecció localitzada i sistèmica

La febre pot ésser l’únic indicador de l’inici d’una infecció greu

Un percentatge significatiu d’aquests pacients es recuperen satisfactòriament sense que es trobi un focus infecciós aparent o es documenta només una infecció vírica

Introducció (3)

Tots els pacients amb neutropènia febril (NF) reben tractament antibiótic d’ampli espectre i generalment ingressen

Les estratègies de tractament precoç de la febre relacionada amb la neutropènia han millorat la supervivència

Però de vegades poden rebre tractaments antibiòtics inadequats, de duració excessiva i poden estar hospitalitzats més temps del necessari

Introducció (4)

Això comporta:

◦ Un impacte en l'ecologia microbiològica del pacient i de l’hospital

◦ Un augment de les resistències bacterianes

◦ Un augment de sobreinfeccions intercurrents

◦ Una disminució de la qualitat de vida del pacient i de la seva família

Introducció (5)

Recerca de dades clíniques i de laboratori que permetin estratificar el risc d’infecció greu, classificant la NF como d’Alt o Baix risc, amb l'objectiu de:

◦ Detectar precoçment les infeccions més greus de cara a la estratègia terapèutica

◦ Identificar adequadament les NF de Baix risc de cara a plantejar-se un maneig ambulatori i/o reduir els temps d’hospitalització

Introducció (6)

És coneguda la producció selectiva de PCT en infeccions bacterianes i potencialment greus en el pacient inmunocompetent

Hi ha una alteració en la producció de PCT en pacients oncològics amb neutropènia:

◦ Neutròfils productors de PCT

◦ Dany hepàtic secundari a la Quimioteràpia

No es coneix bé el valor de la PCT en la predicció i monitorització de la infecció greu en el pacient oncològic sotmès a quimioteràpia

Introducció (7)

Interès en la recerca de factors validats de l’alt o baix risc de les NF i específicament de la contribució dels biomarcadors d’infecció, principalment PCR i PCT, en l'estratificació del risc d'infecció greu i en la monitorització de l’evolució d’aquests pacients

Causes de febre en el pacient

oncològic (1)

Causes infeccioses: ◦ Víriques

◦ Bacterianes

◦ Fúngiques

◦ Parasitàries

Causes no infeccioses: ◦ Reaccions transfusionals

◦ Administració de fàrmacs antitumorals (Ara C)

◦ Febre d’origen tumoral

◦ Leucopènia severa

Causes de febre en el pacient

oncològic (2) IDM: Infecció Documentada Microbiològicament

IDC: Infecció Documentada Clínicament

FSF/FOD: FSF inicial i FSF després de 3 dies amb resultats microbiològics negatius i sense evidència clínica de l’origen de la febre:

◦ Causes no infeccioses

◦ Infeccions víriques no documentades

Edat > 12 anys

Infecció nosocomial

Recaiguda malaltia

Transplantament al·logènic de PH

Quimioteràpia < 7 dies

Hospitalització < 7 dies

Neutropènia > 7 dies

Comorbiditat

Leucèmia mieloide aguda

Afectació estat general

Febre > 39ºC

Calfreds

Hipotensió

Mucositis

Infiltrat pneumònic

Neutròfils < 100/mm3

Monòcits < 100/mm3

Plaquetes < 50000

PCR > 9 mg/dl

Necessitat d'expansió amb líquids IV

Criteris d’alt risc

de infecció greu

Què li demanem a un biomarcador ?

Que ens ajudi a estratificar el baix o alt risc d’una NF

Que ens orienti a decidir iniciar o no Tr antibiòtic en la NF

Que ens orienti en el Tr antibiòtic a administrar

Que ens orienti en la duració del Tr antibiòtic hospitalari

Que ens orienti en l’estratègia diagnòstica en pacients amb febre persistent

Que ens orienti en l’evolució clínica del pacient

Semeraro 2010 (1)

Fins al 60% de les NF son FOD

Objectiu: Valor de PCT en predir evolució de les FOD

FOD evolució favorable: si dia 3 afebril amb 1ª o 2ª línia de tr ATB empíric i si apirèxia persisteix durant la neutropènia o fins el dia 7 de tr ATB

FOD evolució desfavorable: si febre persisteix o reapareix el dia 3 o posterior o si acaba en IDM o IDC

72 episodis, 49 pacients. Tumors Sòlids i Linfomes

PCT cut-off de 0.12ug/L:

◦ Sen 80%, Esp 64% i VPN 82%

Conclou: ◦ Pacients amb una PCT < 0.12 es podrien beneficiar

d’un maneig ambulatori a partir de les 48 hores

◦ Que el 18% d’evolucions desfavorables possibles obliguen a una estreta vigilància clínica.

◦ Que s’han de buscar altres biomarcadors que juntament amb la PCT puguin predir millor l’evolució

Semeraro 2010 (1)

Martínez 2009 (1)

Objectiu: Avaluar valor de PCT i PCR a l’ingrés en identificar evolucions d’alt risc en NF

54 episodis/pacients, 29 LA

Descripció d’Alt Risc (18, 33.3%): 1 o més de:

◦ Signes clínics de sèpsia greu o shock sèptic

◦ Cultius positius de sang o orina

◦ Inici febre < de 7 dies de la darrera Quimioteràpia

4 èxitus (7.4%)

Martínez 2009 (2)

PCR Cut-off de 9.06 mg/dL:

◦ Sens 77.7%, Esp 72.2%

◦ VPP 51%, VPN 96.2%

PCT Cut-off de 0.67 ng/mL:

◦ Sen 72.2%, Esp 80.5%

◦ VPP 68.7%, VPN 89.4%

Conclou:

◦ PCR és un millor screening a Urgències

◦ PCT més específic predictor de IBG a l’inici de la NF

Fleischhack 2000 (1) Objectiu: valor de la PCT en l’avaluació del NF:

◦ Predir la bacterièmia, especialment en BGN

◦ Monitorització del procés febril

376 episodis, 120 pacients (210 L, 166 TS):

◦ 208 FOD (55%)

◦ 125 IDM

◦ 43 IDC

Fleischhack 2000 (2)

A l’ingrés, Cut-off per predir bacterièmia x BGN:

◦ PCT 0.5 ug/L, Sens 60%, Esp 85%

◦ PCT > 5 mg/dl, Sens 40%, Esp 99%

A l’ingrés i durant l’hospitalització:

◦ Els valors més alts de PCT s’associen a bacterièmia x BGN i x GP.

◦ 3 pacients críticament greus x bacterièmia x BGN tenien pic PCT> 100 ug/L (1 EXITUS)

◦ 1 pacient amb fungèmia: pic PCT de 25.8 ug/L (EXITUS)

Fleischhack 2000 (3)

Durant tota l’hospitalització:

◦ La disminució de PCT s'associa a:

Desaparició de la febre

Milloria clínica i/o resposta al tractament antibiòtic

◦ Els increments de PCT acompanyen:

Complicacions sèptiques

Infeccions fúngiques sistèmiques (sobretot després del 3er dia)

◦ Una PCT persistentment elevada:

Representa una infecció activa, encara que estigui controlada

Fleischhack 2000 (4)

Fleischhack 2000 (5)

Conclouen:

◦ PCT és el marcador biològic més útil en NF

◦ Mesures seriades de PCT en NF són útils per:

Predir IBG

Avaluar resposta al tractament antibiòtic

Detecció precoç de complicacions

Monitoritzar pacients críticament malalts

Reitman 2012 (1)

Objectiu: Avaluar els valors seriats de PCT com a predictors de bacterièmia

PCT a l’ingrés i a les 12-24 hores

89 NF

18 hemocultius positius

◦ 6 GP

◦ 12 GN

Clinical Pediatrics

51(12) 1175 –1183

© The Author(s) 2012

Reprints and permission:

sagepub.com/journalsPermissions.nav

DOI: 10.1177/0009922812460913

http://cpj.sagepub.com

Introduction

This article reports on a small-to-medium sized, prospec-

tive, single-center study on the prediction of bacteremia

by serial procalcitonin (PCT) measurements in children

with fever and chemotherapy-induced neutropenia.

Patients undergoing chemotherapy for cancer will have

periods of neutropenia, and during these times, febrile

patients are at a higher risk for developing bacteremia.1

Over the past 3 decades, clinicians have attempted to

identify children with fever and neutropenia to be at

either high or low risk for a serious bacterial infection.

The hopes of risk classification were to decrease the rate

of hospital admissions, to prevent the emergence of anti-

microbial resistance,2 to avoid in-hospital complica-

tions, and to decrease the impairment of quality of life to

patients and their families. Oncologists have categorized

high- and low-risk adult patients for the development of

bacteremia, but their recommendations have been lim-

ited.3-6 Similarly, high- and low-risk classification stud-

ies have been evaluated in pediatric patients. Even

though there have been retrospective,7-14 prospec-

tive,15-19 and validation studies20 for high- and low-risk

patients, the majority of the pediatric oncologists have

been slow to adapt risk classifications for serious bacte-

rial infections in this high-risk population.

Regardless of risk, pediatric patients undergoing che-

motherapy continue to be routinely hospitalized for

fever and neutropenia. The current treatment consensus

for fever and neutropenia in pediatric patients has been

hospital admission, initiation of broad-spectrum antibi-

otics, and maintenance until the blood culture results are

negative for bacterial growth.21 Kara et al22 showed that

pediatric blood cultures may not produce growth for the

first 48 hours. Their study had bacterial growth in 54%

of children by day 3, 77% by day 4, and 89% by day 5.22

Furthermore, even when the clinical picture depicts a

patient who is septic, the blood culture may not produce

bacterial growth.23 Several studies have shown this to be

evident in pediatric patients because the blood volume

obtained is inadequate for bacterial growth.22,24,25 On the

contrary, blood cultures are widely known to have false

positives. Although blood cultures are not perfect, it is

still the gold standard for detecting bacteremia.

460913CPJ XXX10.1 177/0009922812460913 Clinical PediatricsReitman et al

1University of California, San Francisco-Fresno, Fresno, CA, USA2Children’s Hospital Central California, Madera, CA, USA

Corresponding Author:

Aaron J. Reitman, Children’s Hospital Los Angeles, 4650 Sunset Blvd,

Los Angeles, CA 90027

Email: [email protected]

Serial Procalcitonin Levels to Detect

Bacteremia in Febrile Neutropenia

Aaron J. Reitman, DO1,2, Rhonda M. Pisk, MS2, John V. Gates III, MD1,2, and J. Daniel Ozeran, MD, PhD1,2

Abstract

Background. Our objective was to evaluate serial procalcitonin (PCT) levels compared with an initial PCT level at

admission in predicting bacteremia in pediatric febrile neutropenic oncology patients. Procedure. Serum PCT levels

were measured at admission (t0) and within 24 hours of admission (t1) in pediatric oncology patients presenting

with fever and neutropenia. A blood culture was collected at t0 and monitored for 5 days for bacterial growth. PCT

value of 0.5 ng/mL at either t0 or t1 was considered predictive for bacteremia. Results. PCT levels were significantly

higher in children with positive blood cultures than with negative blood cultures. Serial PCT values mirrored t1

values. Serial PCT showed 76% specificity and negative predictive value of 93% in ruling out bacteremia. Conclusion.

Elevated PCT levels are predictive of bacteremia. Using serial PCT levels within 24 hours allowed a better prediction

of bacteremia than the PCT level at t0.

Keywords

procalcitonin, febrile, neutropenia, oncology, pediatric

Reitman 2012 (2) 1178 Clinical Pediatrics 51(12)

ruling out bacteremia. Using the ROC curve analysis,

the area under the curve (AUC) was determined at t0, t1,

and serial draws (0.77, 0.88, and 0.88, respectively;

Figure 2). The AUC of 0.88 indicates serial PCT draws

to be a better biomarker than a single PCT draw for bac-

teremia in this population.

The prevalence of bacteremia in the study population

was 20% or 1 in 5 patients. Using the positive likelihood

ratio, there is an 85% probability that the patients found

to have a positive serial PCT result will have bactere-

mia. Likewise, the negative likelihood ratios can be

used to determine that a patient with a negative serial

PCT level has less than a 1% chance of having bactere-

mia. These results again suggest that PCT is a useful

diagnostic test in this patient population (Table 3).

In the attempt to establish the optimal PCT cutoff

value to be used in our specific population, the diagnos-

tic sensitivity and specificity of PCT were explored using

the ROC results. The best combination of sensitivity and

specificity in this population was achieved at a cutoff

value of 0.4 ng/mL at both t0 and t1 time points.

Discussion

Children undergoing chemotherapy for cancer will most

certainly have episodes with fever and neutropenia dur-

ing treatment. This association occurs with greater fre-

quency with the growing intensity of chemotherapy.

The rapid progression of bacterial infections in neutro-

penic pediatric patients to sepsis is one reason why

these patients are frequently admitted to the hospital

and broad-spectrum antibiotics are initiated.

The precise volume of blood needed to adequately

detect bacteremia in children has not been established as

in adults.24,43,44 Blood cultures may not yield bacterial

growth for several days. Nonetheless, blood cultures are

still considered the gold standard for the detection of

bacteremia. The presence of a reliable sepsis marker

could assist in clinical decision making.

In children presenting with fever and neutropenia,

PCT has been shown to be a useful biomarker in detect-

ing serious bacterial infections.19,27-30,35-39 This study

confirms the results from previous studies as well as

demonstrates the importance of serial PCT levels in the

detection of bacteremia. This study showed serial PCT

draws to be better at detecting bacteremia than a single

PCT level, with the average increase in sensitivity

Figure 1. Patient flow diagram

Table 1. Evaluation of Procalcitonin at 2 Time Pointsa

Mean PCT

t0 (ng/mL) t1 (ng/mL) P

Bacteremic 4.090 11.600 <.05

Nonbacteremic 0.542 0.715 .22

P .001 .0001

Abbreviations: PCT, procalcitonin; t0, PCT draw at admission; t1, PCT

second draw.aSerial results mirror t1 results.

Table 2. Serial Blood Draws

PCT Serial

(t0/t1)

Blood Culture

Negative (n)

Blood Culture

Positive (n)

Neg/Neg 54 4

Pos/Pos 15 9

Pos/Neg 0 0

Neg/Pos 2 5

Abbreviations: PCT, procalcitonin; t0, PCT draw at admission; t1,

PCT second draw; Neg, negative PCT ≤0.5 ng/mL; Pos, positive

PCT >0.5 ng/mL.

Clinical Pediatrics

51(12) 1175 –1183

© The Author(s) 2012

Reprints and permission:

sagepub.com/journalsPermissions.nav

DOI: 10.1177/0009922812460913

http://cpj.sagepub.com

Introduction

This article reports on a small-to-medium sized, prospec-

tive, single-center study on the prediction of bacteremia

by serial procalcitonin (PCT) measurements in children

with fever and chemotherapy-induced neutropenia.

Patients undergoing chemotherapy for cancer will have

periods of neutropenia, and during these times, febrile

patients are at a higher risk for developing bacteremia.1

Over the past 3 decades, clinicians have attempted to

identify children with fever and neutropenia to be at

either high or low risk for a serious bacterial infection.

The hopes of risk classification were to decrease the rate

of hospital admissions, to prevent the emergence of anti-

microbial resistance,2 to avoid in-hospital complica-

tions, and to decrease the impairment of quality of life to

patients and their families. Oncologists have categorized

high- and low-risk adult patients for the development of

bacteremia, but their recommendations have been lim-

ited.3-6 Similarly, high- and low-risk classification stud-

ies have been evaluated in pediatric patients. Even

though there have been retrospective,7-14 prospec-

tive,15-19 and validation studies20 for high- and low-risk

patients, the majority of the pediatric oncologists have

been slow to adapt risk classifications for serious bacte-

rial infections in this high-risk population.

Regardless of risk, pediatric patients undergoing che-

motherapy continue to be routinely hospitalized for

fever and neutropenia. The current treatment consensus

for fever and neutropenia in pediatric patients has been

hospital admission, initiation of broad-spectrum antibi-

otics, and maintenance until the blood culture results are

negative for bacterial growth.21 Kara et al22 showed that

pediatric blood cultures may not produce growth for the

first 48 hours. Their study had bacterial growth in 54%

of children by day 3, 77% by day 4, and 89% by day 5.22

Furthermore, even when the clinical picture depicts a

patient who is septic, the blood culture may not produce

bacterial growth.23 Several studies have shown this to be

evident in pediatric patients because the blood volume

obtained is inadequate for bacterial growth.22,24,25 On the

contrary, blood cultures are widely known to have false

positives. Although blood cultures are not perfect, it is

still the gold standard for detecting bacteremia.

460913CPJ XXX10.1 177/0009922812460913 Clinical PediatricsReitman et al

1University of California, San Francisco-Fresno, Fresno, CA, USA2Children’s Hospital Central California, Madera, CA, USA

Corresponding Author:

Aaron J. Reitman, Children’s Hospital Los Angeles, 4650 Sunset Blvd,

Los Angeles, CA 90027

Email: [email protected]

Serial Procalcitonin Levels to Detect

Bacteremia in Febrile Neutropenia

Aaron J. Reitman, DO1,2, Rhonda M. Pisk, MS2, John V. Gates III, MD1,2, and J. Daniel Ozeran, MD, PhD1,2

Abstract

Background. Our objective was to evaluate serial procalcitonin (PCT) levels compared with an initial PCT level at

admission in predicting bacteremia in pediatric febrile neutropenic oncology patients. Procedure. Serum PCT levels

were measured at admission (t0) and within 24 hours of admission (t1) in pediatric oncology patients presenting

with fever and neutropenia. A blood culture was collected at t0 and monitored for 5 days for bacterial growth. PCT

value of 0.5 ng/mL at either t0 or t1 was considered predictive for bacteremia. Results. PCT levels were significantly

higher in children with positive blood cultures than with negative blood cultures. Serial PCT values mirrored t1

values. Serial PCT showed 76% specificity and negative predictive value of 93% in ruling out bacteremia. Conclusion.

Elevated PCT levels are predictive of bacteremia. Using serial PCT levels within 24 hours allowed a better prediction

of bacteremia than the PCT level at t0.

Keywords

procalcitonin, febrile, neutropenia, oncology, pediatric

Reitman 2012 (3)

1178 Clinical Pediatrics 51(12)

ruling out bacteremia. Using the ROC curve analysis,

the area under the curve (AUC) was determined at t0, t1,

and serial draws (0.77, 0.88, and 0.88, respectively;

Figure 2). The AUC of 0.88 indicates serial PCT draws

to be a better biomarker than a single PCT draw for bac-

teremia in this population.

The prevalence of bacteremia in the study population

was 20% or 1 in 5 patients. Using the positive likelihood

ratio, there is an 85% probability that the patients found

to have a positive serial PCT result will have bactere-

mia. Likewise, the negative likelihood ratios can be

used to determine that a patient with a negative serial

PCT level has less than a 1% chance of having bactere-

mia. These results again suggest that PCT is a useful

diagnostic test in this patient population (Table 3).

In the attempt to establish the optimal PCT cutoff

value to be used in our specific population, the diagnos-

tic sensitivity and specificity of PCT were explored using

the ROC results. The best combination of sensitivity and

specificity in this population was achieved at a cutoff

value of 0.4 ng/mL at both t0 and t1 time points.

Discussion

Children undergoing chemotherapy for cancer will most

certainly have episodes with fever and neutropenia dur-

ing treatment. This association occurs with greater fre-

quency with the growing intensity of chemotherapy.

The rapid progression of bacterial infections in neutro-

penic pediatric patients to sepsis is one reason why

these patients are frequently admitted to the hospital

and broad-spectrum antibiotics are initiated.

The precise volume of blood needed to adequately

detect bacteremia in children has not been established as

in adults.24,43,44 Blood cultures may not yield bacterial

growth for several days. Nonetheless, blood cultures are

still considered the gold standard for the detection of

bacteremia. The presence of a reliable sepsis marker

could assist in clinical decision making.

In children presenting with fever and neutropenia,

PCT has been shown to be a useful biomarker in detect-

ing serious bacterial infections.19,27-30,35-39 This study

confirms the results from previous studies as well as

demonstrates the importance of serial PCT levels in the

detection of bacteremia. This study showed serial PCT

draws to be better at detecting bacteremia than a single

PCT level, with the average increase in sensitivity

Figure 1. Patient flow diagram

Table 1. Evaluation of Procalcitonin at 2 Time Pointsa

Mean PCT

t0 (ng/mL) t1 (ng/mL) P

Bacteremic 4.090 11.600 <.05

Nonbacteremic 0.542 0.715 .22

P .001 .0001

Abbreviations: PCT, procalcitonin; t0, PCT draw at admission; t1, PCT

second draw.aSerial results mirror t1 results.

Table 2. Serial Blood Draws

PCT Serial

(t0/t1)

Blood Culture

Negative (n)

Blood Culture

Positive (n)

Neg/Neg 54 4

Pos/Pos 15 9

Pos/Neg 0 0

Neg/Pos 2 5

Abbreviations: PCT, procalcitonin; t0, PCT draw at admission; t1,

PCT second draw; Neg, negative PCT ≤0.5 ng/mL; Pos, positive

PCT >0.5 ng/mL.

Clinical Pediatrics

51(12) 1175 –1183

© The Author(s) 2012

Reprints and permission:

sagepub.com/journalsPermissions.nav

DOI: 10.1177/0009922812460913

http://cpj.sagepub.com

Introduction

This article reports on a small-to-medium sized, prospec-

tive, single-center study on the prediction of bacteremia

by serial procalcitonin (PCT) measurements in children

with fever and chemotherapy-induced neutropenia.

Patients undergoing chemotherapy for cancer will have

periods of neutropenia, and during these times, febrile

patients are at a higher risk for developing bacteremia.1

Over the past 3 decades, clinicians have attempted to

identify children with fever and neutropenia to be at

either high or low risk for a serious bacterial infection.

The hopes of risk classification were to decrease the rate

of hospital admissions, to prevent the emergence of anti-

microbial resistance,2 to avoid in-hospital complica-

tions, and to decrease the impairment of quality of life to

patients and their families. Oncologists have categorized

high- and low-risk adult patients for the development of

bacteremia, but their recommendations have been lim-

ited.3-6 Similarly, high- and low-risk classification stud-

ies have been evaluated in pediatric patients. Even

though there have been retrospective,7-14 prospec-

tive,15-19 and validation studies20 for high- and low-risk

patients, the majority of the pediatric oncologists have

been slow to adapt risk classifications for serious bacte-

rial infections in this high-risk population.

Regardless of risk, pediatric patients undergoing che-

motherapy continue to be routinely hospitalized for

fever and neutropenia. The current treatment consensus

for fever and neutropenia in pediatric patients has been

hospital admission, initiation of broad-spectrum antibi-

otics, and maintenance until the blood culture results are

negative for bacterial growth.21 Kara et al22 showed that

pediatric blood cultures may not produce growth for the

first 48 hours. Their study had bacterial growth in 54%

of children by day 3, 77% by day 4, and 89% by day 5.22

Furthermore, even when the clinical picture depicts a

patient who is septic, the blood culture may not produce

bacterial growth.23 Several studies have shown this to be

evident in pediatric patients because the blood volume

obtained is inadequate for bacterial growth.22,24,25 On the

contrary, blood cultures are widely known to have false

positives. Although blood cultures are not perfect, it is

still the gold standard for detecting bacteremia.

460913CPJ XXX10.1 177/0009922812460913 Clinical PediatricsReitman et al

1University of California, San Francisco-Fresno, Fresno, CA, USA2Children’s Hospital Central California, Madera, CA, USA

Corresponding Author:

Aaron J. Reitman, Children’s Hospital Los Angeles, 4650 Sunset Blvd,

Los Angeles, CA 90027

Email: [email protected]

Serial Procalcitonin Levels to Detect

Bacteremia in Febrile Neutropenia

Aaron J. Reitman, DO1,2, Rhonda M. Pisk, MS2, John V. Gates III, MD1,2, and J. Daniel Ozeran, MD, PhD1,2

Abstract

Background. Our objective was to evaluate serial procalcitonin (PCT) levels compared with an initial PCT level at

admission in predicting bacteremia in pediatric febrile neutropenic oncology patients. Procedure. Serum PCT levels

were measured at admission (t0) and within 24 hours of admission (t1) in pediatric oncology patients presenting

with fever and neutropenia. A blood culture was collected at t0 and monitored for 5 days for bacterial growth. PCT

value of 0.5 ng/mL at either t0 or t1 was considered predictive for bacteremia. Results. PCT levels were significantly

higher in children with positive blood cultures than with negative blood cultures. Serial PCT values mirrored t1

values. Serial PCT showed 76% specificity and negative predictive value of 93% in ruling out bacteremia. Conclusion.

Elevated PCT levels are predictive of bacteremia. Using serial PCT levels within 24 hours allowed a better prediction

of bacteremia than the PCT level at t0.

Keywords

procalcitonin, febrile, neutropenia, oncology, pediatric

Reitman 2012 (4)

Reitman et al 1179

Table 3. Diagnostic Values at Different Cutoff Values to Predict Bacteremia

Draw PCT Value Sensitivity (%) Specificity (%) NPV (%) PPV (%)

Positive Likelihood

Ratio (Weighted)

Negative Likelihood

Ratio (Weighted)

Draw 1 (t0) 0.2 78 49 90 28 0.39 0.11

0.3 72 65 90 34 0.52 0.11

0.4 72 70 91 38 0.62 0.10

0.5 50 79 86 38 0.60 0.16

1 44 89 86 50 1.0 0.16

2 22 94 83 48 1.0 0.21

5 22 99 83 85 4.0 0.20

Draw 2 (t1) 0.2 100 45 100 31 0.46 <0.00

0.3 89 56 95 34 0.52 0.05

0.4 89 68 96 41 0.70 0.04

0.5 78 76 93 45 0.82 0.07

1 67 86 91 55 1.2 0.10

2 61 92 90 66 1.8 0.11

5 44 97 87 79 4.0 0.14

Seriala 0.2 100 45 100 31 0.46 <0.00

0.3 89 56 95 34 0.52 0.05

0.4 89 68 96 41 0.70 0.04

0.5 78 76 93 45 0.82 0.07

1 67 86 91 55 1.2 0.10

2 61 92 90 66 1.8 0.11

5 44 97 87 79 4.0 0.14

Abbreviations: PCT, procalcitonin; t0, PCT draw at admission; t1, PCT second draw; NPV, negative predictive value; PPV, positive predictive value.aSerial results mirror t1 results.

Figure 2. Receiver operating characteristic cur ve

Clinical Pediatrics

51(12) 1175 –1183

© The Author(s) 2012

Reprints and permission:

sagepub.com/journalsPermissions.nav

DOI: 10.1177/0009922812460913

http://cpj.sagepub.com

Introduction

This article reports on a small-to-medium sized, prospec-

tive, single-center study on the prediction of bacteremia

by serial procalcitonin (PCT) measurements in children

with fever and chemotherapy-induced neutropenia.

Patients undergoing chemotherapy for cancer will have

periods of neutropenia, and during these times, febrile

patients are at a higher risk for developing bacteremia.1

Over the past 3 decades, clinicians have attempted to

identify children with fever and neutropenia to be at

either high or low risk for a serious bacterial infection.

The hopes of risk classification were to decrease the rate

of hospital admissions, to prevent the emergence of anti-

microbial resistance,2 to avoid in-hospital complica-

tions, and to decrease the impairment of quality of life to

patients and their families. Oncologists have categorized

high- and low-risk adult patients for the development of

bacteremia, but their recommendations have been lim-

ited.3-6 Similarly, high- and low-risk classification stud-

ies have been evaluated in pediatric patients. Even

though there have been retrospective,7-14 prospec-

tive,15-19 and validation studies20 for high- and low-risk

patients, the majority of the pediatric oncologists have

been slow to adapt risk classifications for serious bacte-

rial infections in this high-risk population.

Regardless of risk, pediatric patients undergoing che-

motherapy continue to be routinely hospitalized for

fever and neutropenia. The current treatment consensus

for fever and neutropenia in pediatric patients has been

hospital admission, initiation of broad-spectrum antibi-

otics, and maintenance until the blood culture results are

negative for bacterial growth.21 Kara et al22 showed that

pediatric blood cultures may not produce growth for the

first 48 hours. Their study had bacterial growth in 54%

of children by day 3, 77% by day 4, and 89% by day 5.22

Furthermore, even when the clinical picture depicts a

patient who is septic, the blood culture may not produce

bacterial growth.23 Several studies have shown this to be

evident in pediatric patients because the blood volume

obtained is inadequate for bacterial growth.22,24,25 On the

contrary, blood cultures are widely known to have false

positives. Although blood cultures are not perfect, it is

still the gold standard for detecting bacteremia.

460913CPJ XXX10.1 177/0009922812460913 Clinical PediatricsReitman et al

1University of California, San Francisco-Fresno, Fresno, CA, USA2Children’s Hospital Central California, Madera, CA, USA

Corresponding Author:

Aaron J. Reitman, Children’s Hospital Los Angeles, 4650 Sunset Blvd,

Los Angeles, CA 90027

Email: [email protected]

Serial Procalcitonin Levels to Detect

Bacteremia in Febrile Neutropenia

Aaron J. Reitman, DO1,2, Rhonda M. Pisk, MS2, John V. Gates III, MD1,2, and J. Daniel Ozeran, MD, PhD1,2

Abstract

Background. Our objective was to evaluate serial procalcitonin (PCT) levels compared with an initial PCT level at

admission in predicting bacteremia in pediatric febrile neutropenic oncology patients. Procedure. Serum PCT levels

were measured at admission (t0) and within 24 hours of admission (t1) in pediatric oncology patients presenting

with fever and neutropenia. A blood culture was collected at t0 and monitored for 5 days for bacterial growth. PCT

value of 0.5 ng/mL at either t0 or t1 was considered predictive for bacteremia. Results. PCT levels were significantly

higher in children with positive blood cultures than with negative blood cultures. Serial PCT values mirrored t1

values. Serial PCT showed 76% specificity and negative predictive value of 93% in ruling out bacteremia. Conclusion.

Elevated PCT levels are predictive of bacteremia. Using serial PCT levels within 24 hours allowed a better prediction

of bacteremia than the PCT level at t0.

Keywords

procalcitonin, febrile, neutropenia, oncology, pediatric

Reitman 2012 (5)

Conclou: ◦ La utilització de 2 determinacions de PCT en les 1es 24

hores pot ésser utilitzada en la detecció precoç de bacterièmies

◦ L’òptim cut-off de PCT és de 0.4 ng/ml (S 89%, E 68%, VPP 41% i VPN 96%)

◦ Una sensibilitat i VPN del 100% s’aconsegueix amb un cut-off de 0.2 ng/ml, que podria ésser utilitzat per un alta hospitalària precoç, en pacients clínicament bé abans de que els hemocultius siguin definitivament negatius

◦ La incorporació del nivells de PCT seriats de forma rutinària en aquests nins pot permetre intervencions més precoces davant elevacions dels valors de la PCT

Clinical Pediatrics

51(12) 1175 –1183

© The Author(s) 2012

Reprints and permission:

sagepub.com/journalsPermissions.nav

DOI: 10.1177/0009922812460913

http://cpj.sagepub.com

Introduction

This article reports on a small-to-medium sized, prospec-

tive, single-center study on the prediction of bacteremia

by serial procalcitonin (PCT) measurements in children

with fever and chemotherapy-induced neutropenia.

Patients undergoing chemotherapy for cancer will have

periods of neutropenia, and during these times, febrile

patients are at a higher risk for developing bacteremia.1

Over the past 3 decades, clinicians have attempted to

identify children with fever and neutropenia to be at

either high or low risk for a serious bacterial infection.

The hopes of risk classification were to decrease the rate

of hospital admissions, to prevent the emergence of anti-

microbial resistance,2 to avoid in-hospital complica-

tions, and to decrease the impairment of quality of life to

patients and their families. Oncologists have categorized

high- and low-risk adult patients for the development of

bacteremia, but their recommendations have been lim-

ited.3-6 Similarly, high- and low-risk classification stud-

ies have been evaluated in pediatric patients. Even

though there have been retrospective,7-14 prospec-

tive,15-19 and validation studies20 for high- and low-risk

patients, the majority of the pediatric oncologists have

been slow to adapt risk classifications for serious bacte-

rial infections in this high-risk population.

Regardless of risk, pediatric patients undergoing che-

motherapy continue to be routinely hospitalized for

fever and neutropenia. The current treatment consensus

for fever and neutropenia in pediatric patients has been

hospital admission, initiation of broad-spectrum antibi-

otics, and maintenance until the blood culture results are

negative for bacterial growth.21 Kara et al22 showed that

pediatric blood cultures may not produce growth for the

first 48 hours. Their study had bacterial growth in 54%

of children by day 3, 77% by day 4, and 89% by day 5.22

Furthermore, even when the clinical picture depicts a

patient who is septic, the blood culture may not produce

bacterial growth.23 Several studies have shown this to be

evident in pediatric patients because the blood volume

obtained is inadequate for bacterial growth.22,24,25 On the

contrary, blood cultures are widely known to have false

positives. Although blood cultures are not perfect, it is

still the gold standard for detecting bacteremia.

460913CPJ XXX10.1 177/0009922812460913 Clinical PediatricsReitman et al

1University of California, San Francisco-Fresno, Fresno, CA, USA2Children’s Hospital Central California, Madera, CA, USA

Corresponding Author:

Aaron J. Reitman, Children’s Hospital Los Angeles, 4650 Sunset Blvd,

Los Angeles, CA 90027

Email: [email protected]

Serial Procalcitonin Levels to Detect

Bacteremia in Febrile Neutropenia

Aaron J. Reitman, DO1,2, Rhonda M. Pisk, MS2, John V. Gates III, MD1,2, and J. Daniel Ozeran, MD, PhD1,2

Abstract

Background. Our objective was to evaluate serial procalcitonin (PCT) levels compared with an initial PCT level at

admission in predicting bacteremia in pediatric febrile neutropenic oncology patients. Procedure. Serum PCT levels

were measured at admission (t0) and within 24 hours of admission (t1) in pediatric oncology patients presenting

with fever and neutropenia. A blood culture was collected at t0 and monitored for 5 days for bacterial growth. PCT

value of 0.5 ng/mL at either t0 or t1 was considered predictive for bacteremia. Results. PCT levels were significantly

higher in children with positive blood cultures than with negative blood cultures. Serial PCT values mirrored t1

values. Serial PCT showed 76% specificity and negative predictive value of 93% in ruling out bacteremia. Conclusion.

Elevated PCT levels are predictive of bacteremia. Using serial PCT levels within 24 hours allowed a better prediction

of bacteremia than the PCT level at t0.

Keywords

procalcitonin, febrile, neutropenia, oncology, pediatric

Niño Jesús 2015 (1)

Objectiu: Avaluar el valor predictiu de PCT i PCR en detectar infecció greu en les NF que acudeixen a Urgències (2013-2014)

Definició d’infecció greu: ◦ Bacterièmia ◦ Inestabilitat hemodinàmica ◦ Ingrés a la UCI

75 NF

Utilidad de PCR y PCT para y ppredecir infección grave en niños con neutropenia febril.

J L Al d S R d i M Ji M J M tíJ.L. Almodovar, S. Rodriguez, M. Jimenez, M.J. Martín

Niño Jesús 2015 (2)

Conclou: en la NF no està clar el el valor predictiu de PCT i PCR en en detectar infecció greu

ResultadosResultadosNº caso Hemocultivo Expansión Drogas UCI PCT (ng/ml) PCR (mg/dl)

1 S. hominis 0,58 9,6

2 SI 0 4,2

3 SI 0,07 0,5

4 S.epidermidis 0,07 1,6

5 C.guilliermondi 0,1 0,9

De los 19 pacientes: PCT 0 39 / l ( di 0 32)

g , ,

6 SI 0,09 0,6

7 SI 0,29 3,5

8 S.epidermidis 0,06 2,8

9 SI 0 25 0 8

‐PCT: 0,39 ng/ml (mediana 0,32)‐PCR: 3,7 mg/dl (mediana 2,8)

9 SI 0,25 0,8

10 SI 0,24 5

11 SI 0,8

12 SI SI 1,17 3,2

13 SI 0 32 14 4, g/ ( , )

13 SI 0,32 14,4

14 S. aureus SI SI SI 2,46 14

15 SI 3,1

16 S. epidermidis SI 0,21 1,1

17 S. aureus 0,5

18 S. epidermidis 0,22 3,4

19 SI 0,11 0,5

Utilidad de PCR y PCT para y ppredecir infección grave en niños con neutropenia febril.

J L Al d S R d i M Ji M J M tíJ.L. Almodovar, S. Rodriguez, M. Jimenez, M.J. Martín

Son Espases 2015 (1)

Objectiu: ◦ Avaluar el valor predictiu de PCT i PCR en detectar

infecció sistèmica en NF que acudeixen a Urgències (2011-2015)

Definició de infecció sistèmica: ◦ Creixement de bacteri o fong a l’hemocultiu

40 NF:

◦ 13 FSF ◦ 7 febres documentades clínicament (cap sèpsia clínica) ◦ 6 infeccions víriques documentades ◦ 6 infeccions bacterianes localitzades documentades ◦ 7 bacterièmies i 1 candidèmia (cap sèpsia clínica o

severa)

Son Espases 2015 (2)

Conclou: una sola determinació de PCR i PCT a l’ingrés no ajuda a identificar infecció sistèmica

Shu-Guang 2012 (1)

Objectiu: Avaluar el rol de la PCT en el diagnòstic de sèpsia bacteriana en la NF

Avaluen:

◦ 10 estudis de PCT

◦ 8 de PCR

PCT i PCR: 304 SB de 1031 NF (29.5%)

PCR: 741 SB de 1316 NF(56.3%)

Role of Procalcitonin in the Diagnosis of Severe

Infection in Pediatric Patients With Fever and

Neutropenia—A Systemic Review and Meta-analysis

Shu-Guang Lin et al.

The Pediatric Infectious Disease Journal – October 2012

Shu-Guang 2012 (2)

Role of Procalcitonin in the Diagnosis of Severe

Infection in Pediatric Patients With Fever and

Neutropenia—A Systemic Review and Meta-analysis

Shu-Guang Lin et al.

The Pediatric Infectious Disease Journal – October 2012

Shu-Guang 2012 (3)

Conclou:

◦ La PCT i la PCR tenen un valor comparable i complementari en el diagnòstic de SB

◦ La PCT es més específica i que la PCR es més sensible

◦ Recomanen per la PCT el cut-off de 0.5 ng/ml

◦ Suggereixen que amb una 2ª mostra de PCT a les 24 hores de la 1ª augmentaria en gran mesura la sensibilitat de la PCT

Role of Procalcitonin in the Diagnosis of Severe

Infection in Pediatric Patients With Fever and

Neutropenia—A Systemic Review and Meta-analysis

Shu-Guang Lin et al.

The Pediatric Infectious Disease Journal – October 2012

Dificultats en l’avaluació del paper

dels biomarcadors Les sèries estudiades corresponen a pacients

heterogenis (malaltia de base, nº de neutròfils,

etc.)

No estan ben definides les definicions de NF

d’evolució desfavorable

L’agrupació de diagnòstics finals de les NF no és

uniforme i en alguns casos agrupa quadres clínics i

situacions clíniques ben diferents

Causes de NF

Febre sense focus o FOD

Infecció vírica documentada

Infecció fúngica documentada: ◦ Localitzada

◦ Sistèmica

Infecció bacteriana documentada: ◦ Localitzada

◦ Bacterièmia

◦ Bacterièmia amb criteris clínics de sèpsia

Infecció clínicament documentada: ◦ Infecció localitzada

◦ Sèpsia clínica

Coinfeccions

Què ens pot oferir la PCT?

Descartar inicialment infecció greu?: ◦ NO, especialment en una sola determinació

Orientar a decidir iniciar Tr antibiòtic en NF?: ◦ NO, sempre tractarem les NF

Orientar en el Tr antibiòtic a administrar?: ◦ Sí, valors alts de PCT poden decidir-nos a ampliar la cobertura ATB

Orientar en la duració del Tr antibiòtic hospitalari?: ◦ Sí, valors persistentment baixos de PCT poden decidir-nos a escurçar

el tr antibiòtic hospitalari

Orientar en l’estratègia diagnòstica en NF persistent?: ◦ Sí, PCT persistentment altes o normals poden influir-nos en la nostra

estratègia diagnòstica

Orientar en l’evolució clínica del pacient?: ◦ Sí, ens pot ser molt útil

Conclusions (1) Resultats no coincidents a la literatura

No existeixen uns punts de tall òptims validats

Els valors inicials de PCT i PCR a les NF NO es poden utilitzar per descartar inicialment infeccions greus

La combinació de determinacions seriades PCT i PCR pot ser MOLT ÚTIL en el maneig de les NF

Conclusions (2) Fa falta un esforç per tal de millorar el

rendiment diagnòstic de la combinació d’ambdós biomarcadors i trobar adequats punts de tall que ens ajudin a les decisions clíniques

Calen treballs col·laboratius amb una ADEQUADA i CONSENSUADA tipificació dels pacients, de les agrupacions de diagnòstics finals i de les definicions d’evolució desfavorable de les NF