Journal of Critical Care 44 (2018) 217–222

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Journal of Critical Care

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Patterns of C-reactive protein ratio response to antibiotics in pediatric

sepsis: A prospective cohort study☆
Vanessa Soares Lanziotti a,b,c,⁎, Pedro Póvoa e,f, Arnaldo Prata-Barbosa a,d, Lucas Berbet Pulcheri g,
Ligia S.C.F. Rabello a,b, José Roberto Lapa e Silva b, Marcio Soares a,b, Jorge I.F. Salluh a,b
a
D'Or Institute for Research and Education, Rio de Janeiro, RJ, Brazil
b
Postgraduate Program in Internal Medicine, Federal University of Rio de Janeiro (Universidade Federal do Rio de Janeiro – UFRJ), Rio de Janeiro, RJ, Brazil
c
Institute of Pediatrics and Child Care Martagão Gesteira, Pediatric Intensive Care Unit, Federal University of Rio de Janeiro (Universidade Federal do Rio de Janeiro- UFRJ), Rio de Janeiro, RJ, Brazil
d
Department of Pediatrics, School of Medicine, Federal University of Rio de Janeiro (Universidade Federal do Rio de Janeiro – UFRJ), Rio de Janeiro, RJ, Brazil
e
NOVA Medical School, New University of Lisbon, Lisboa, Portugal
f
Polyvalent Intensive Care Unit, Hospital de São Francisco Xavier, Centro Hospitalar de Lisboa Ocidental, Lisboa, Portugal
g
Rios D'Or Hospital, Rede D'Or São Luiz, Rio de Janeiro, RJ, Brazil

a r t i c l e i n f o a b s t r a c t

Keywords: Purpose: Evaluate sequential C-reactive protein (CRP) measurements and patterns of CRP-ratio response to
C-reactive protein antibiotic therapy during first 7 days in Pediatric Intensive Care Unit (PICU) of septic children.
Sepsis Methods: Prospective, cohort study of children (1 month-12 years) admitted at 3 PICUs, with diagnosis of sepsis
Biomarkers
with b72 h course. CRP-ratio was calculated in relation to D0_CRP value. Children were classified according to an
Children
Pediatric intensive care unit
individual pattern of CRP-ratio response: fast – CRP_D4 of therapy was b0.4 of D0_CRP; slow – continuous but
Outcome slow decrease of CRP; non – CRP remained ≥ 0.8 of D0_CRP; biphasic – initial CRP decrease to levels b0.8 of
D0_CRP followed by secondary rise ≥0.8.
Results: 103 septic children (age-median: 2 yrs; 54% male) were prospectively included (infection focus: 65%
respiratory, 12.5% central nervous system). Overall PICU mortality was 11.7%. 102 children could be classified ac-
cording to a predefined CRP-ratio response pattern. Time-dependent analysis of CRP-ratio and CRP course of the
different patterns were significantly different. Besides, PICU mortality rate was significantly different according
CRP-ratio response patterns: fast response 4.5%; slow response 5.8%; non-response 29.4%; biphasic response
42.8%.
Conclusions: In pediatric sepsis, CRP-ratio serial evaluation was useful in early identification of patients with poor
outcome.
© 2017 Elsevier Inc. All rights reserved.

1. Introduction pediatric sepsis [5,6]. However, the assessment of the response to treatment
is still based on clinical judgment which is frequently insufficient for an
Sepsis is a major cause of admission to pediatric intensive care units early recognition of outcomes in children with sepsis [1,2]. Thus, biomarkers
(PICU) [1,2]. In the last decade, a number of initiatives were implemented have been proposed to aid physicians in the clinical decision-making process
aiming to achieve a better understanding of sepsis concepts [3,4], as well as [7-9]. C-reactive protein (CRP) is a biomarker well acknowledged for its diag-
to improve morbidity and mortality, namely through higher diagnosis aware- nostic value in pediatric sepsis, with low cost, widely available and easy to in-
ness and early antibiotic therapy and specific guidelines for treatment of terpret [9,10]. However, there is still little evidence in pediatric patients on the
use of CRP as a surrogate marker of outcomes and most available studies are
limited to neonates [10,11], infants [12,13] and adults [14-16].
Abbreviations: CRP, C-reactive protein; CRPr, C-reactive protein ratio; ICU, Intensive
Care Unit; IEC, Institutional Ethics Committee; IQR, interquartile range; LOS, length of Since CRP has 1st order elimination kinetics, relative changes could
stay; MV, mechanical ventilation; PELOD, Pediatric Logistic Organ Dysfunction; PICU, be more informative than absolute. Using CRP-ratio, that is the relative
Pediatric Intensive Care Unit. CRP changes in relation to its initial concentration, patients could be
☆ Financial support: Drs. Salluh & Soares are supported in part by individual research
classified according to different patterns of response that were shown
grants from CNPq (302963/2015-4 and 304240/2014-1) and FAPERJ (E26103.048/2012).
⁎ Corresponding author at: Rua Diniz Cordeiro, 30 – Botafogo, Rio de Janeiro, RJ 22281-
to be associated with different outcomes [15]. Besides, some studies
100, Brazil. had shown that despite its low specificity, CRP has unique characteris-
E-mail address: [email protected] (V.S. Lanziotti). tics that are advantageous for its use in critically ill patients- its

https://doi.org/10.1016/j.jcrc.2017.11.018
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concentrations are not changed by immunosupression or use of system- range, IQR) according to data distribution. Comparisons between
ic corticosteroids (including in critically adult patients with sepsis and groups were performed using the unpaired and paired t-test, or the
neutropenia, for example) and frequent therapies or interventions, as Mann-Whitney U test and Wilcoxon signed-rank test (for comparison
renal replacement therapy for instance, as occurs with other biomarkers between 2 groups) and ANOVA or Kruskal Wallis test (for comparison
as procalcitinin [17-19]. between 4 groups) for continuous variables according to data distribu-
The aim of the present study was to assess serial CRP measurements tion. The Fisher's exact test was used to carry out comparisons between
and the outcomes associated with patterns of CRP-ratio response to categorical variables. Time-dependent analysis of CRP was performed
antibiotic therapy during the first 7 days in the PICU, in children with via General Linear Model (GLM) univariate repeated-measures analysis
sepsis. using a split-plot design approach. The SPSS version 20.0 software pack-
age (Chicago, IL, USA) and Prism 7.0 (Graphpad, USA) were used for sta-
2. Materials and methods tistical analysis. In all cases, statistical significance was defined as a two-
tailed test with an alpha of 0.05.
2.1. Study design, subjects and setting
3. Results
We conducted a prospective observational cohort study in three
PICUs at tertiary hospitals in Rio de Janeiro, Brazil (Instituto de 3.1. Main characteristics of the study population
Puericultura e Pediatria Martagão Gesteira- IPPMG- Federal University
of Rio de Janeiro, Copa D'Or Hospital and Rio's D'Or Hospital). Pediatric During the study period, 103 out of the 112 patients that fulfilled the
patients (1 month to 12 years) with sepsis diagnosis with b 72 h of hos- eligibility criteria were included (Fig. 1); 9 patients were excluded since
pital admission were consecutively included between July 2013 and July they had no sequential CRP measurements (Fig. 1).
2016. The present study was strictly observational and did not interfere The main characteristics of the studied population are depicted in
with clinical management or clinical decision-process. The Institutional Table 1. The median age was 2 years old, respiratory tract was the
Ethics Committees (IECs) approved the study (D'Or Institute for main site of primary infection (65%; 3% upper respiratory infections,
Research and Education IEC – No 178.663/December 2012 and IPPMG/ 62% lung), followed by central nervous system (12.5%) and abdominal
UFRJ IEC – No 190.152/January 2013) and as no interventions were (6.8%). 71% of the patients required vasopressors during PICU stay and
performed, the need for informed consent was waived. 69% required invasive mechanical ventilation. The overall PICU and
90-day mortality rates were the same (11.7%).
2.2. Definitions and data collection 14.5% (N = 15) of infections were microbiologically documented
(54% Gram-negative bacteria, 19%, Gram-positive bacteria, 19% virus
Sepsis was diagnosed according to the international pediatric sepsis and one Mycobacterium tuberculosis). Detailed data of microbiological
consensus definitions (3). Demographic, clinical, laboratory and documentation is shown in Table 2.
outcome data were prospectively collected, using standardized case re- Considering that our overall study population was very heteroge-
port forms, including age, gender, comorbidities, primary infection site, neous, in order to provide information in a more homogeneous sub-
presence of nosocomial infection, use of vasopressors, dialysis and me- group of patients, we analysed the 64 patients with lung infections.
chanical ventilation (invasive and non-invasive). Comorbidity was de- The results were comparable to those of the overall population. Data is
fined as the presence of underlying disease and/or chronic comorbid provided in the electronic supplementary material.
conditions, such as genetic syndrome, encephalopathy, heart disease
and immunodeficiency. Pediatric Logistic Organ Dysfunction (PELOD) 3.2. C-reactive protein, organ failure course and CRP-ratio patterns of
score (20) was calculated daily using clinical and laboratory data response to antibiotic therapy in survivors and non-survivors
routinely collected during the first week of PICU stay. Empiric antibiotic
and supportive therapies were started upon PICU admission according Time course of CRP concentrations during the first week of antibiotic
to local guidelines and international guidelines for sepsis and septic therapy is shown in Fig. 2 A. Time dependent analysis of CRP values
shock (5).Patients were followed until death or hospital discharge. An from D0 to D6 between survivors and non-survivors showed a significant
additional follow-up for 90-day mortality was also performed for all decrease in survivors whereas it remained almost unchanged in non-
patients, after PICU or hospital discharge, through phone calls or survivors (P b 0.0001). As early as D2, this difference was already present,
checking hospital electronic data system. and by D4 of antibiotic therapy, this divergent evolution of CRP values was
CRP was sampled every other day from admission (D0) to D6 of PICU markedly different between survivors and non-survivors (P = 0.01).
stay (D0, D2, D4, D6). CRP-ratio was calculated in relation to the D0 CRP Time dependent analysis of the course of PELOD values from D0 to
value. Patients were retrospectively classified according to predefined D6 between survivors and non-survivors are shown in Fig. 2 B. PELOD
CRP- ratio patterns of response to antibiotics [15,16]: 1) fast response – score values were significantly different (GLM P b 0.0001) and the dif-
when CRP at D4 of therapy was ≤0.4 of D0 CRP concentration; 2) slow ference is marked since D2 of antibiotic therapy, with significantly
response – characterized by a continuous but slow decreased of CRP lower values in survivors. Patients included in the study were divided
(CRP at D4 N 0.4 and at D6 ≤ 0.8 of D0 CRP); 3) non-response – when according to the four patterns of the CRP-ratio course during antibiotic
CRP remained always N 0.8 of D0 CRP; 4) biphasic response – therapy, as previously described. Out of the 103 patients, 102 could be
characterized by an initial CRP decrease to levels ≤0.8 of D0 CRP followed classified: 43% were classified as fast response (N = 44), 33.5% as slow
by a secondary rise N 0.8 of D0 CRP. Comparisons between survivors and response (N = 34), 16.5% as non-response (N = 17) and 7% as biphasic
non-survivors and between the four different CRP-ratio patterns were response (N = 7). The time-dependent analysis of CRP-ratio of the four
performed. different patterns was significantly different (P = 0.023), as shown in
Fig. 3 A. The time-dependent analysis of PELOD values in the four differ-
2.3. Data processing and statistical analysis ent patterns of CRP-ratio response to antibiotics is shown in Fig. 3 B. We
observed that PELOD course on the first week of antibiotic therapy were
Data entry was performed by a single investigator (VSL) and consis- significantly different in the different patterns (P = 0.027). Patients
tency was assessed with a rechecking procedure of a 10% random sam- classified as fast response had a continuous and faster improvement of
ple of patients. Data were screened in detail for missing information, organ dysfunctions (decrease of PELOD value) as compared to patients
implausible and outlying values. Continuous variables were reported who were classified as slow response during the first week of antibiotic
as mean ± standard deviation (SD) or median (25% to 75% interquartile therapy. Patients classified as biphasic response had slightly increased

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 V.S. Lanziotti et al. / Journal of Critical Care 44 (2018) 217–222 219

Fig. 1. Study flow chart.

in PELOD values by D2, followed by a slight decrease. Patients classified and classified as responders (fast plus slow response) and with no CRP
as non-response had an initial increase in PELOD values (D2) followed decrease as non-responders (non-response plus biphasic) and performed
by later decrease in the values. a comparison between them (Fig. 4B) where we can observe a clear
We also compared the absolute PELOD changes during the first week graphic difference, with an evident negative and continuous PELOD vari-
of antibiotic therapy on the four different patterns of CRP-ratio response ation on responders. However, the curves were not significantly different.
that are shown in Fig. 4A. We grouped patients with initial CRP decrease CRP-ratio patterns of response presented significant different PICU
mortality rates (Fig. 5): 4.5% of mortality in patients with the fast
response; 5.8% in patients with slow response; 29.4% in non-response
patients and 42.8% in biphasic response patients (P = 0.001). When
Table 1
Clinical patients' characteristics and comparison between PICU survivors and non- we grouped the patterns of CRP-ratio response with good outcome
survivors. (responders- fast response and slow response patterns) and bad
outcome (non-responders–non-response and biphasic response) the
Characteristics All patients PICU survivors PICU P
(n = 103; (n = 91; 88%) nonsurvivors value⁎
mortality rate were, respectively, 5.1% and 33% (P = 0.0001). We also
100%) (n = 12; 12%) analyzed additional outcomes as ventilator-free days, hospital and
Age (years) 2 [0.5–5.2] 2[0,6–4.9] 0.75 [0,5–6.2] 0.602
PICU length of stay (21) in the different CRP-ratio response patterns to
Gender (male) 56 (54%) 49 (54%) 7 (58%) 0.999 antibiotics. Ventilator-free days median was calculated for each
PELOD score – D0 (points) 1 [1−11] 1 [1–10.5] 1.5 [1–11] 0.237
Sites of primary infection 0.541
Respiratory 67 (65%) 59 (65%) 8 (66%) Table 2
Central nervous system 13 (12.5%) 11 (12%) 2 (17%) Microorganisms from the 15 (14.5%) pediatric patients with sepsis.
Abdominal 7 (6.8%) 6 (6.5%) 1 (8.5%)
Microorganism N = 15 Isolated site
Urinary 4 (4%) 4 (4.5%) 0(0%)
Other 12 (11.7%) 11 (12%) 1 (8.5%) Gram-negative organisms N=8
Microbiological 15 (14.5%) 13 (14.3%) 2 (16.6%) 0.826 Escherichia coli N=4 Urine (N = 3); blood (N = 1)
documentation Neisseria meningitidis N=2 Blood (N = 2)
Comorbidity 34 (33%) 29 (32%) 5 (42%) 0.524 Acinetobacter baumannii N=1 Blood (N = 1)
Vasopressors 71 (69%) 59 (65%) 12 (100%) 0.016 Pseudomonas aeruginosa N=1 Cerebrospinal fluid (N = 1)
Dialysis 6 (6%) 1 (1%) 5 (42%) 0.001 Gram-positive organisms N=3
Non-invasive MV 38 (37%) 36 (40%) 2 (17%) 0.202 Streptoccoccus pyogenes N=2 Blood (N = 1); pleural fluid
Invasive MV 71 (69%) 59 (65%) 12 (100%) 0.016 (N = 1)
CRP (D0) (mg/dL) 6.9 7 [4.3–21.6] 5.5 [3.7–20.6] 0.751 Methicilin-resistant Staphylococcus aureus N=1 Blood (N = 1)
[4.05–21.6] Mycobacteria N=1
Mycobacterium tuberculosis N=1 Peritoneal fluid
Results expressed as median (25%–75% interquartile range) and number (%). Abbrevia-
Virus N=3 Nasopharyngeal aspirate
tions: CRP, C-reactive protein; PICU, Pediatric Intensive Care Unit; PELOD, Pediatric Logis-
Respiratory syncytial virus N=2
tic Organ Dysfunction; MV, mechanical ventilation.
Bocavirus N=1
⁎ P value for comparison among patients PICU mortality.

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220 V.S. Lanziotti et al. / Journal of Critical Care 44 (2018) 217–222

Fig. 2. 2A — C-Reactive Protein (CRP) of survivors and non-survivors pediatric septic critically ill patients. Time course of CRP concentrations (mg/dL) for survivors and non-survivors
pediatric septic critically ill patients during the first week of antibiotic therapy. The difference between the two groups was statistically significant (P b 0.0001). 2B — PELOD course of
survivors and non-survivors pediatric septic critically ill patients. Time course of PELOD values for survivors and non-survivors septic critically ill patients during the first week of
antibiotic therapy. The difference between the two groups was statistically significant (P b 0.0001).

different pattern and patients with fast response, slow response, non- in the slow response patients; 14 [9-18] in non-response patients and
response and biphasic response patterns presented a ventilator-free 13 [10-27] in biphasic response patients (P = 0.057).
days medians [IQR 25–75] of 22.5 [18.75–26.25]; 23.5 [13.75–27.5]; 16 We also analyzed the rate of nosocomial infections according to four
[0–20.37] and 19 [0–20.5], respectively, and we observed a gradient CRP-ratio patterns of response: fast response 11.3% (N = 5); slow re-
from responders to non-responders (P = 0.020). Regarding PICU length sponse 14.7% (N = 5); non-response 41.1% (N = 7); biphasic response
of stay (LOS) it was 9 [6–13.25] in the fast response patients; 10 [7–17.5] 42.8% (N = 3) (P = 0.02). Nosocomial infections rates were significantly
higher on the patterns with poor outcomes (non-response and biphasic
response). Analyzing specifically patients with biphasic response pattern
we found that the secondary rise of CRP was coincident with the day of
nosocomial infection (D4) in all biphasic patients who presented nosoco-
mial infection (N = 3).

4. Discussion

In the present study, we described the course of CRP in pediatric sep-

tic critically ill patients and observed an association between individual
patterns of CRP-ratio response and PICU mortality rates. Patients with a
substantial decrease in CRP values and with CRP-ratio patterns of fast
response and slow response presented a significant lower mortality
rate when compared to those patients with no decrease on CRP sequen-
tial values and with CRP-ratio patterns of non-response and biphasic
response.
These data suggest that persistently elevated CRP values are indica-
tive of poor response to antibiotic therapy. Although there are many
reasons for the unfavorable outcomes and the lack of recovery of
multi-organ dysfunction in sepsis, one of the potentially modifiable
reason is inadequate initial antibiotic therapy as well as the occurrence
of a nosocomial infection [16,22,23]. In those with biphasic response,
albeit very small absolute numbers, we observed that the 3 patients
that presented nosocomial infection (43% of 7 patients classified as
biphasic) during the first week of PICU admission had the secondary
CRP rise coincident with the day of diagnosis of nosocomial infection.
Future studies with larger number of patients should be performed to
corroborate this finding.
Fig. 3. 3A — Time-dependent analysis of CRP-ratio in different response patterns. Data are Several studies, especially in adults, have confirmed that sequential
presented as exactly means. Values of CRP-ratio in the different patterns were significantly
CRP measurements are a useful tool to monitor clinical course, evaluate
different (P = 0.023). 3B — Time-dependent analysis of PELOD in different response
patterns. Data are presented as means. PELOD values variation in the different patterns antibiotic efficacy and need for antibiotic changes, and mortality predic-
were significantly different (P = 0.027). tion [14-16], having better value as a prognostic predictor than using

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Fig. 4. Absolute PELOD changes during the first week of antibiotic therapy. 4A — Absolute PELOD changes during the first week of antibiotic therapy in different CRP-ratio response
patterns. 4B — Absolute PELOD changes during the first week of antibiotic therapy in patients with CRP decrease (fast and slow response patterns) and CRP no decrease (biphasic and
nonresponse patterns).

only the absolute values [24,25]. However, data using the sequential worse. This can be explained by the fact that the early reversal of
approach is scarce in pediatric sepsis. organ failure is directly related to the outcomes (26). Besides, the reso-
Considering that CRP is widely available in most of PICUs, with easy lution of the sepsis induced inflammatory response, assessed by CRP,
access and low cost and that it has been one of the best-known inflam- seems to be surrogate of the reversal organ failure. Moreover, we eval-
matory biomarkers used in clinical practice for many years, CRP can be uate the absolute PELOD changes during the first week of antibiotic
confirmed as a key biomarker of response to antibiotic therapy when therapy on the 4 different patterns of CRP-ratio response (Fig. 4A) and
dynamically analyzed. This is a relevant aspect to justify its wide imple- compared responders and non-responders (4B), trying to overcome dif-
mentation especially in low-resource settings. We also performed a ferences of PELOD values at PICU admission. Although the differences
time-dependent analysis of PELOD score variation in the different were not statistically significant, we could observe evident graphic dif-
CRP- ratio patterns of response. We found that in the patients with ferences on the curves, showing more evident negative variations of
CRP-ratio response patterns of fast or slow, PELOD score presented PELOD on the responders (fast and slow response pattern).
marked decreases. On the opposite, in biphasic response patients, Given the low mortality rates among critically ill children, alterna-
PELOD remained almost unchanged over the first 7 days of antibiotic tive endpoints such as ventilator free days, hospital and PICU length of
treatment. And, in patients with non-response pattern, we observed stay are being strongly recommended [21]. Besides the main outcome
an initial increase followed by a decrease in PELOD average value, al- (PICU mortality), we compared the secondary outcomes on the four dif-
though the CRP had no decrease and outcomes of these patients were ferent patterns of CRP-ratio responses and the patients classified as non-
response and biphasic response had less ventilation free days, longer
PICU length of stay and higher mortality rates (PICU and 90 day mortal-
ity). We could observe that PICU LOS was higher in patients with no de-
crease CRP (non-response and biphasic response). Although P value
was on the limit of the statistical significance (P = 0.057) for this com-
parison, considering that literature definition for long stay patients in
the PICU is longer than 12 days [27], we can include patients classified
as non-response and biphasic response patterns, with median PICU
LOS of 14 and 13 days, respectively, and higher mortality, as long stay
patients, which does not happen with the patients with substantial de-
crease of CRP (fast and slow response). Since literature has also shown
that patients with a longer ICU length of stay have higher mortality
[27,28], this finding must be considered, corroborating with the worst
outcomes in the nonresponder patterns that presented longer PICU
length of stay and higher mortalities.
The present study has some limitations. First, considering the rates
Fig. 5. Pediatric Intensive Care Unit (PICU) mortality in the 4 CRP-ratio (CRPr) response
of events as mortality and nosocomial infections, we have a relatively
patterns. Mortality rate was significantly different according to the CRPr pattern (P = small sample size (N = 103). However, we believe that this limitation
0.001). could be attenuated, since we included secondary outcomes as

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