Journal of Critical Care (2013) 28, 291295

Impact of serum C-reactive protein measurements in the

first 2 days on the 30-day mortality in hospitalized
patients with severe community-acquired pneumonia:
A cohort study
William Nseir a,b,, Raymond Farah b,c , Julnar Mograbi a , Nicola Makhoul b,d
a
Internal Medicine Department and Infectious Diseases Unit, Holy Family Hospital, Nazareth, Israel
b
Faculty of Medicine in the Galilee, Bar-Ilan University, Safed, Israel
c
Internal Medicine Department B, Ziv Medical Center, Safed, Israel
d
Respiratory Intensive Care Unit and Eliachar Research Laboratory, Western Galilee, Hospital- Nahariya, Israel

Keywords:
Abstract
Community-acquired
Introduction: The purpose of the study is to evaluate the impact of daily consecutive measurements of
pneumonia;
C-reactive protein (CRP) in the initial 2 days of hospitalization on the 30-day all-cause mortality in
C-reactive protein (CRP);
patients with severe community-acquired pneumonia (CAP).
Fractional decrease
Methods: We used 4 different thresholds of fractional decrease (FD) in CRP at the second day of
in CRP;
admission (CRP2) of 25%, 30%, 40%, and 60%. In addition, we studied the association of each of these
30-day mortality
thresholds with the 30-day all-cause mortality.
Results: The mean age was 64 20; males, 59%. The 30-day mortality rate was 18% (20/111). The
mean serum CRP levels at the first day of all study group and CRP2 were 203 98 vs 146 92 mg/L,
respectively, P = .05. The mean FD in CRP2 levels among the survivors was 33 %, whereas among the
nonsurvivors, was 7%, P b .001. Multiple regression analysis revealed that FD less than 25% in CRP2
was associated with 30-day all-cause mortality, odds ratio of 3.07 (95% confidence interval, 2.84-5.03),
P = .002, compared with those with FD more than 25% in CRP2.
Conclusions: Fractional decrease less than 25% in CRP levels at the second day was significantly
associated with 30-day all-cause mortality in hospitalized patients with severe CAP.
2013 Elsevier Inc. All rights reserved.

1. Introduction

Lower respiratory infections, which result in pneumonia,

Corresponding author. Department of Internal Medicine, Infectious
are the third leading cause of death worldwide [1]. The
Diseases Unit, Holy Family Hospital, Nazareth, Faculty of Medicine in the
Galilee, Bar-Ilan University, Israel, POB, 8. Tel.: +97246508942; fax:
estimated incidence of community-acquired pneumonia
+97246508942. (CAP) is 2 to 12 cases per 1000 population per year [2].
E-mail address: w.nseir@yahoo.com (W. Nseir). Most cases of CAP are managed outside hospital, but

0883-9441/$ see front matter 2013 Elsevier Inc. All rights reserved.
http://dx.doi.org/10.1016/j.jcrc.2012.09.012
292
approximately 20% require hospital admission; out of these
patients, approximately 10% develop severe CAP [3].
Accurate diagnosis and appropriate management of CAP
are crucial for reducing medical costs, length of hospital stay,
mortality rates, and antibiotic resistance; the latter has
become a public health problem on a global scale [4]. In the
absence of generally accepted criteria for determining the
severity and the ensuing management of CAP, the search has
intensified for reliable biomarkers for diagnosis, risk
prediction, and disease management [5].
C-reactive protein (CRP) is an acute phase protein
synthesized by the liver, primarily in response to interleu-
kin-6. Its measurement is inexpensive and widely accessible.
C-reactive protein levels have been shown to discriminate
between pneumonia and healthy status [6] as well as between
pneumonia and exacerbations of chronic obstructive pulmo-
nary disease, heart failure, and asthma [7-9]. Consecutive
measurements of CRP levels at days 3 and 7 also have been
shown to distinguish between causative pathogens [6,10],
including bacterial and nonbacterial causes [11]. Recently,
Ramirez et al [12] reported that inflammatory biomarkers
identified patients needing intensive care unit (ICU)
admission, including those with delayed ICU admission.
Regarding to process of medical decision in cases of severe
CAP, the timing of the CRP measurements after the fourth
day of admission seems to be delayed for making any change
in medical management. Therefore, the rationale of this
study was to examine the impact of early measurements of
CRP despite the half lifetime of CRP of 19 hours. Against
this background, the current study was to evaluate the impact
of consecutive measurements of serum CRP levels in the first
2 days of hospitalization on the 30-day all-cause mortality.
2. Patients and methods
2.1. Design and setting
This was a prospective observational cohort study that was
conducted between November 2009 and December 2010 in
internal medicine department and respiratory ICU, Western
Galilee Hospital, Nahariya, Faculty of Medicine in the
Galilee, Bar-Ilan University, Israel. All patients gave written
informed consent before the enrollment to the study. The
study was approved by the local medical ethics committee.
2.2. Selection of participants, data collection,
and definitions
Patients of either sex with severe CAP that required
admission in internal medicine department and older than 18
years were consecutively included. We excluded patients
with interstitial pneumonia, cystic fibrosis, a history of
colonization with gram-negative bacteria due to structural
damage to the respiratory tract, severe neutropenia (b0.5x
W. Nseir et al.
109 neutrophils/L), HIV infection, intravenous drug use,
presence of a severe infection other than pneumonia, on
antibiotic use, Pneumonia Severity Index (PSI) less than
class IV, CURB-65 (Confusion, Urea, Respiratory rate,
Blood pressure, and Age >65) score less than 3 points, a life
expectancy less than 1 month because of an underlying
disease, rheumatoid arthritis, an active autoimmune disease,
or patients admitted directly to an ICU.
On admission, demographic data, clinical signs, symp-
toms, and laboratory data including calculation of the
PSI class and CURB-65 score were recorded [13,14].
Community-acquired pneumonia was defined as present in
cases with at least 2 symptoms of acute lower respiratory
tract infection with onset before hospital admission and a
new or progressive pulmonary infiltrate on chest radiograph.
A standard follow-up period of 30 days was established for
all the participants.
Serum concentration of CRP was measured by particle-
enhanced immunoturbimetric assay (Tina-quant CRP latex;
Roche Diagnostics Corporation, Indianapolis, Ind). The
reference range for this assay is less than 5 mg/L. For each
patient, CRP was measured at days 1, 2, 3, 4, and 5. C-reactive
protein 1 was taken within 6 hours from the admission to
emergency department. A unique protocol was used to treat
CAP (a -lactam and macrolide). To emphasize, we did not use
steroids as adjunctive therapy in our protocol; however, we
used steroid according to the medical needs of each patient. All
patients had received the antibiotic therapy within 6 hours of
their presentation to the emergency department.
2.3. Outcome
The main outcome was to evaluate the impact of daily
consecutive measurements of CRP in the initial 2 days of
hospitalization on the 30-day all-cause mortality in patients
with severe CAP.
2.4. Data presentation and statistical analysis
The data were statistically analyzed using WinSTAT
(Kalamia, Cambridge, Mass), the statistics add-in for
Microsoft Excel. Continuous variables are expressed as the
mean SD. Initially, the study participants were divided into
2 groups: those who had survive the 30-day survivors and
those who died nonsurvivors and differences between the 2
groups were assessed by the 2 test for categorical variables
and the Student t test for continuous variables. We used 4
different thresholds of fractional decrease (FD) in CRP at the
second day of admission (CRP2) of 25%, 30%, 40, and 60%.
Fractional decrease was calculated according to the follow-
ing formula: (CRP1 CRP2)/CRP1 100%. Spearman rank
correlation and univariate regression analysis were used to
determine the strength of the relationship between the
different variables for 30-day all-cause mortality, namely,
age, sex, PSI class of 4 or higher, CURB-65 score of 3 points
Impact of serum C-reactive protein measurements
268 patients were
admitted due to CAP
157 patients were
excluded
111 patients were
included in the study
Fig. 1
or higher, the 4 thresholds of FD in CRP2, and FD in CRP5,
smoking, and chronic obstructive pulmonary disease
(COPD). A variable associated with P b .05 in univariate
analysis was used after that for feature analysis. A multiple
regression analysis was done to determine the association
between the variables and the 30-day all-cause mortality.
Statistical significance was set at 5%.
3. Results
3.1. Characteristics of the study population
A total of 268 patients with CAP were admitted to the
Internal Medicine Department during the study period; 111
patients met the study criteria (Fig. 1). We excluded 157
patients: 66 patients had PSI class less than 4, 54 patients had
CURB-65 score less than 3 points, 12 patients had terminal
illnesses, 6 patients were immunosuppressed, 8 patients had
pulmonary structural disorders, and 11 patients had refused
to participate. Demographic, clinical characteristics, and
comparisons between survivors (n = 91) and nonsurvivors
(n = 20) are presented in Table 1. The nonsurvivors were
older. There were no significant differences between the
2 groups regarding the sex, COPD as comorbidity, and
smoking. The mean PSI class, CURB-65 score, number of
positive blood cultures, the need for mechanical ventilation,
transfer to ICU, and hospital length of stay in days were
significantly differs statistically between the 2 groups. The
decline in CRP levels during the hospitalization among the
survivors vs nonsurvivors was statistically significant.
The differences in the thresholds of FD in CRP of day 2
from the initial CRP greater than 25%, 30%, 40%, and 60%
293
Reasons for exclusion:
66 patients with PSI class< IV
54 patients with CURB-65 score
<3points
12 patients had terminal
illnesses
6 patients were
immunosuppressed
8 patients with pulmonary
structural disorders
11 patients refused to
participate
Study flowchart.
between the survivors and nonsurvivors are shown in
Table 2. In 72 (79%) of 91 patients from the survivors had
reduced greater than 25% of their CRP in day 2 from the
initial CRP. In contrast, among the nonsurvivors, 1 patient
had FD in CRP2 greater than 25%; P b .001.
To the fifth day, from 111 patients, 6 patients died, 32
patients discharged, and 73 patients remained hospitalized.
3.2. Outcome analysis
The main outcome was to evaluate the impact of daily
consecutive measurements of CRP in the initial 2 days of
hospitalization on the 30-day all-cause mortality in patients
with severe CAP.
To examine the associations of the different variables
including FD in CRP at the second day of hospitalization
with the 30-day all-cause mortality, we performed multiple
regression analysis (Table 3), which revealed that age, odds
ratio (OR) of 0.44 (95% confidence interval [CI], 0.28-1.25),
P = .63; male sex, OR of 2.12 (95% CI, 1.88-2.95), P = .03;
FD in CRP2 less than 25%, OR of 3.07 (95% CI, 2.84 -5.03),
P = .002; PSI class of 4 or higher, OR of 1.45 (CI, 0.82-2.31),
P = .05; CURB-65 of 3 points or higher, OR of 5.79 (95%
CI, 5.21-6.39), P b .001, were associated with 30-day all-
cause mortality in patients with severe CAP.
4. Discussion
In this study of hospitalized patients with severe CAP, we
found that the FD less than 25% in CRP levels at the second
day of hospitalization was significantly associated with 30-
day all-cause mortality. According to our knowledge, this is
294 W. Nseir et al.

Table 1 Demographic and clinical variables of the 111 study participants and comparisons between survivors and nonsurvivors of
severe CAP
All patients (N = 111) Survivors (n = 91, 82%) Nonsurvivors (n = 20, 18%) Pa
Age, y 64 20 62 20 71 14 .03
Male sex, n (%) 66 (59%) 54 (59%) 12 (60%) .20
PSI (class) 4.5 0.55 4.37 0.55 4.8 0.41 .001
CURB-65 score ( points) 2.62 0.86 2.38 0.6 3.7 0.9 b.001
CRP mg/dL in day 1(means) 203 98 193 95 246 99 .02
CRP in day 2 (means) 146 92 128 82 228 91 b.001
CRP mg/dL in day 3 (means) 125 80 108 68 205 84 b.001
CRP mg/dL in day 4 (means) 93 71 75 56 174 74 b.001
CRP mg/dL in day 5 (means) 86 77 67 54 165 106 b.001
CRP mg/dL at discharge (means) 43 41 33 26 82 65 b.001
The FD of CRP2 from CRP1 (%) 28% 33% 7% b.001
COPD, n (%) 14 (12%) 11 (12%) 3 (15%) .07
Smoking, n (%) 47 (42%) 35 (38%) 9 (45%) .08
Positive blood cultures, n (%) 19 (17%) 11 (12%) 8 (40%) b.001
Needed MV during hospitalization, n (%) 22 (20%) 10 (11%) 12 (60%) b.001
Transfer to ICU, n (%) 27 (24%) 13 (14%) 14 (70%) b.001
Hospital LOS, in days (means) 7.5 6 6.7 4.5 11 9.3 .001
MV, mechanical ventilation; LOS, length of stay.
a
For comparisons among survivors and nonsurvivors.

the first study investigating the association of CRP levels improve the prediction of absence of severe complications of
measurements of the first 2 days and the 30-day all-cause CAP. Furthermore, Bruns et al [10] found that consecutive
mortality in patients with severe CAP. CRP measurements during the first week of hospitalization
Several studies have shown that CRP is a good marker of have demonstrated usefulness for follow-up of antibiotic
CAP diagnosis as well as an useful tool for assessing the treatment for CAP and a delayed normalization of CRP
severity and effectiveness of treatment [6,15,16]. Moreover, levels is associated with a higher risk of receiving
measurement of CRP has demonstrated effectiveness in inappropriate antibiotic treatment for severe CAP. Ruiz
distinguishing between CAP, which requires or not requires Gonzalez et al [19] found that CRP levels at day 4 were
antibiotics [5,7,8]. However, in a study of elderly hospital- useful in distinguishing between failure to respond to
ized patients with CAP, CRP at admission was not associated antibiotic treatment for CAP and slow response to treatment.
with the need for transfer to an ICU or with mortality [17]. Moreover, Chalmers et al [20] reported that a decrease in
Although singular measurements at hospital admissions have CRP levels of less than 50% within the first 4 days of
demonstrated the usefulness of CRP in the diagnosis of hospitalization was associated with an increased risk for 30-
pneumonia, consecutive measurements support the role for day mortality and a need for mechanical ventilation or
this biomarker in the therapeutic management of pneumonia. inotropic support. Previous studies based on the levels of
In a prospective study of 294 hospitalized patients with CAP, CRP at day 3 or later in making medical decision. Therefore,
Menndez et al [18] found that low levels of CRP at 72 hours we believe that our finding of this threshold of FD less than
after treatment initiation, together with clinical criteria, might 25% in CRP at day 2 may provide a useful tool for
identifying high-risk patients.
Numerous clinical reports have been published regarding
Table 2 The FDs greater than 25%, 30%, 40%, and 60% in steroid use in severe pneumonia with conflicting results
CRP levels at the second day (CRP2) from the CRP levels of
first day of hospitalization among of the survivors and
nonsurvivors and the comparisons between them in each Table 3 The results of multiple regression analysis on the
threshold of CRP2 association between the different variables and the 30-day all-
cause mortality of 111 hospitalized patients with severe CAP
Survivors, Nonsurvivors, P a
n = 91 n = 20 Variables OR (95% CI) P
FD in CRP2 N25%, n (%) 72 (79%) 1 (5%) b.001 Age 0.44 (0.28-1.25) .63
FD in CRP2 N30%, n (%) 62 (68%) 0 (0%) b.001 Male sex 2.12 (1.88-2.95) .03
FD in CRP2 N40%, n (%) 41 (45%) 0 (0%) .002 FD b25% in CRP2 3.07 (2.84-5.03) .002
FD in CRP2 N60%, n (%) 17 (19%) 0 (0%) .03 PSI class 4 1.45 (0.82-2.31) .05
a CURB-65 3 points 5.79 (5.21-6.39) b.001
For comparisons among survivors and nonsurvivors.
Impact of serum C-reactive protein measurements
[21-24]. We did not use steroid as adjuvant therapy in our
protocol therapy for CAP. However, we used steroids as
needed, especially among COPD patients (COPD patients were
12% of all patients), although the effect of steroids on CRP
levels is inconclusive. Salluh et al [25] examined the impact of
systemic corticosteroids on the clinical course and outcomes in
111 patients with severe CAP, and they found that adjuvant
corticosteroids did not influence hospital mortality. The same
results have been shown by Perren et al [26] who in addition
found that corticosteroids do not modify the time-dependent
decay of CRP in case that CAP is adequately treated.
The present study has several limitations. It was
performed in 1 center, with relatively small number of
patients, and we did not consider the causative pathogens in
our interpretation of CRP levels [27].
5. Conclusions
Fractional decrease less than 25% in CRP levels in the
second day of hospitalization was significantly associated
with 30-day all-cause mortality in patients with severe CAP.
Further prospective studies with larger number of patients are
needed to assess the clinical impact of this fall of CRP in the
second day among patients with severe CAP.
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