# Comparison of C-Reactive Protein and Serum Amyloid A Protein in Septic Shock Patients

Authors: Domingos Dias Cicarelli; Joaquim Edson Vieira; Fábio Ely Martins Benseñor
Journal: Mediators of Inflammation
 (2008)

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## Abstract

Septic shock is a severe inflammatory state caused by an infectious agent. Our purpose was to investigate serum amyloid A (SAA) protein and C-reactive protein (CRP) as inflammatory markers of septic shock patients. Here we evaluate 29 patients in postoperative period, with septic shock, in a prospective study developed in a surgical intensive care unit. All eligible patients were monitored over a 7-day period by sequential organ failure assessment (SOFA) score, daily CRP, SAA, and lactate measurements. CRP and SAA strongly correlated up to the fifth day of observation but were not good predictors of mortality in septic shock.


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## Body

## 1. Introduction

Severe sepsis and septic
shocks are a common cause of mortality in
intensive care unit (ICU) [1]. They are a state of systemic inflammation in response
to infectious agents that can lead to multiple organ system failure and death.The systemic inflammatory response to infection involves the release of several mediators, which has led
to the suggestion that some of these mediators could be used as markers of
sepsis severity [2]. Among the acute-phase proteins that participate in
the inflammatory response, C-reactive protein (CRP) is a component of the
innate immune system that binds phosphocoline and recognizes some foreign pathogens as well as phospholipid
constituents of damage cells; serum amyloid A (SAA) protein is an
apolipoprotein that rapidly binds to high-density lipoprotein after their synthesis, influencing
cholesterol metabolism during inflammatory states, causing adhesion and chemotaxis of
phagocitic cells and lymphocytes [3, 4]. In some patients with chronic inflammation, the net
effect of increased SAA production may be deleterious due to tissue deposition
of its fragments and the development of systemic amyloidosis [3, 5].CRP and SAA display a similar
pattern in most inflammatory diseases, reaching a maximum serum concentration
about 24 hours after the inflammatory process sets in and slowly decreasing [6]. CRP is
commonly used as a marker of an acute inflammatory state, produced by the liver
in response to tissue injury or infection [7]. Its
plasma concentration has been reported to parallel the clinical course of
infection and the fall of the protein level indicates the resolution of
infection [1]. SAA is the other major acute-phase protein in humans, with the earliest
and highest increase rate of all acute-phase proteins, including CRP [4, 8]. SAA
concentrations usually parallel those of CRP. Some authors have been reported
that SAA appears to be a clinically useful marker of inflammation in bacterial
or viral infection likewise CRP [9]. Although some studies suggest that SAA is a more
sensitive marker of inflammatory disease, assays for SAA are not widely
available at present [4].Until now, no study has compared daily CRP to SAA plasma concentrations in postoperative patients with
septic shock, or has correlated them to the severity of
patients represented by SOFA score. This study aimed to evaluate CRP and SAA
measurements as markers of severity of septic shock patients during postoperative period.


## 2. Methods

This study was prospective at
a surgical ICU. After approval by a local ethics committee, informed consent
was obtained from patients or from their next of kin prior to enrollment [10].
Twenty-nine patients admitted into the surgical ICU of
the Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo had taken part in the study. Additional three patients were excluded
after their next of kin gave up the signed consent.
Patients with septic shock diagnosed during ICU stay were eligible for the
study. We used the American College of Chest Physicians/Society of Critical
Care Medicine Consensus Conference definition of sepsis and septic shock [11]. Patients
under 18 were excluded.Severity of illness at the
baseline was assessed based on theacute physiology
and chronic health evaluation II (APACHE II) score [12]. Patients
were assessed daily for 7 consecutive days using the sequential organ failure assessment score (SOFA) or until their
discharge from the ICU when occurring in less than 7 days [13–15].
C-reactive protein and serum amyloid A protein were also measured daily.The patients received
conventional therapy regarding antibiotic regimens, serial blood cultures
(whenever that body temperature >38°C), and discharge criteria. Relevant clinical and
laboratory tests were conducted daily throughout the study.Blood samples for CRP and SAA
dosage were thawed and assayed in batches in an automated analyzer (Behring
Nephelometer Analyzer II, Dade Behring, Marburg, Denmark) for particle-enhanced
immunonephelometry using commercial kits. The analytical sensitivity and
accuracy for CRP was 0.0175 mg/L (coefficient of variation (CV) 7,6%). The
analytical sensitivity and accuracy for SAA was determined by the lower limit
of the reference curve and thus depended on the concentration of the protein in
SAA standard test (CV between 5.4% and 6.4%).Statistical analysis was
performed using commercial available package. Multiple logistic regressions were performed to test mortality of 7 or 28 days follow-up. A distribution analysis was made by the Kolmogorov-Smirnov test, Pearson correlation coefficients were determined, and repeated measures were tested by ANOVA.  AP value < .05 was considered
significant.


## 3. Results

The mean (±SD) age of the 29 patients was 65 ± 13.9 years (range, 34 to 88 years). The study
involved 13 males and 16 females (45%/55%). The APACHE II score of these
patients was19.8±4.5 (Table 1). Table 2 represents the microbiological
characteristics of the studied patients.Table 1
Baseline characteristics of the patients.
Characteristicsn = 29Age (years)65±13.9Male sex45%Weight (kg)63.5±11.7APACHE II score19.8±4.5SOFA score9.6±2.3Prior or preexisting conditions(%)Hypertension31Myocardial infarction13.7Diabetes13.7Liver
disease6.9COPD6.9Cancer20.7Surgery(%)Multiple trauma (excluding head trauma)3.4Gastrointestinal surgery75.9Major vascular surgery6.9Thoracic surgery3.4Urologic surgery10.4Other indicators of disease severity(days)Mechanical ventilation4.0±3.2Shock (use of vasopressor)4.2±1.9APACHE: acute physiology and chronic health
evaluation, SOFA: sequential organ failure
assessment, COPD: chronic obstructive pulmonary disease.Table 2
Microbiological characteristics of patients.
PatientSurgery/phatologyAntibioticsType of organismType of culture1Cholecistectomy/biliary abscessVanco + cefepimeS. aureusAbscess culture2Empyema pleural drainageCeftriaxone + clindamycinS. pyogenesPleural abscess culture3Cholecistectomy/biliary abscessCeftriaxone + metronidazole—Negative cultures4Cystectomy/pyuriaCeftriaxone + metronidazole—Negative cultures5Aortic bypass/leg amputationCeftazidime + clindamycinP. aeruginosaSurgical site culture6Colectomy/cavity contaminationCeftriaxone + metronidazole—Negative cultures7Calcaneal exposure fractureCiprofloxacinE. faecalisSurgical site culture8Pyonephrosis drainageCeftriaxoneK. pneumoniaeUrinary culture9SigmoidectomyCeftriaxone + metronidazoleA. baumaniiBlood culture10HemicolectomyCeftriaxone + metronidazoleCandida albicansBlood culture11Enterectomy/mesenteric ischemiaCeftriaxone + metronidazole—Negative cultures12Pancreatic-duodenal resectionCeftriaxoneSerratia marcesensBAL13Pancreatic-duodenal resectionCeftriaxone + metronidazoleS. coag negativeBlood culture14Retroperitoneal abscess drainageCefepime + vanco + imipenemP. aeruginosaBlood culture15Abdominal aneurysm repairVanco + imipenemS. aureusBlood culture16Sigmoidectomy/perforative lesionCeftriaxone + metronidazoleSerratia marcesensAscite culture17ColectomyCefepime + vancoS. aureusBlood culture18Gastric ulcerCeftriaxone + metronidazole—Negative cultures19CholecistectomyCipro + metronidazoleEscherichia coliUrinary culture20HemicolectomyCefepime + vanco + metroE. cloacaeBlood culture21Enterectomy/cavity contaminationVanco + imipenem—Negative cultures22ColectomyCeftriaxone + metronidazoleA. baumaniiBlood culture23ColectomyCeftriaxone + metronidazoleP. aeruginosaBlood culture24Enterectomy/cavity contaminationCeftriaxone + metronidazole—Negative cultures25Cervical abscess drainageImipenem + vanco + metroK. pneumoniaeBlood culture26Sigmoidectomy/perforative lesionCeftriaxone + metronidazoleP. aeruginosaBlood culture27SigmoidectomyCefepime + metronidazoleS. aureusBlood culture28Pyonephrosis drainageCefepime + metronidazole—Negative cultures29ColectomyCeftriaxone + metronidazoleP. aeruginosaBALVanco: vancomycin, Cipro:
ciprofloxacin, Metro: metronidazole, S. aureus: Staphylococcus aureus, S.
pyogenes: Streptococcus pyogenes, P. aeruginosa: Pseudomonas aeruginosa, E.
faecalis: Enterobacter faecalis, K. pneumoniae: Klebsiella pneumoniae, A.
baumanii: Acinetobacter baumanii, S. coag negative: Staphylococcus coagulase
negative, E. cloacae: Enterobacter cloacae, BAL: bronchoalveolar lavage.SOFA did
not show increase from Day
0 to Day 7 of
observation (P = .589, ANOVA) while CRP reduced significantly from Day 0 till the end of
observation period (P < .001, ANOVA followed by Holm-Sidak test) as
well as SAA (P < .001, ANOVA followed by Holm-Sidak test) (Table 3).Table 3
SOFA, CRP, and SAA during the study period (mean ± SD).
Day 0Day 1Day 2Day 3Day 4Day 5Day 6Day 7SOFA9.6±2.310±2.69.4±4.19.8±4.49.4±4.29.9±3.78.7±4.18.6±3.5CRP19.8±8.420.9±9.116.3±6.213.2±5.911.8±7.712.7±11.211.9±8.310.0±4.4SAA47±39.837.2±28.129±21.4822.7±18.418.6±20.824.7±25.822.2±20.521.7±16.8SOFA: sequential organ failure assessment, CRP: C-reactive
protein, SAA: serum amyloid A. ANOVA. Equal variance test: SOFAP = .956,
CRP P = .062, SAA P = .055.CRP and SAA concentrations did not present any correlation with SOFA.On the other hand, CRP
and SAA have shown a good correlation from Day 0 till Day 5 (Table4).Table 4
Pearson coefficient for SAA and CPR.
rP-valueDay 00.682.0001Day 10.660.0004Day 20.464.034Day 30.529.024Day 40.651.0062Day 50.778.0028Day 60.578.628Day 70.081.822Mortality of these patients
in 7 days was 44.8% (13 in 29) and in 28 days was 65.5% (19 in 29). CRP and SAA
concentrations were not associated with  Day 7 mortality (Table5).Table 5
Maximum likelihood, Wald statistic (P-value).
APACHE IISOFACPRSAADay 03.46 (.06)2.46 (.11)0.02 (.89)1.91 (.17)Day 13.06 (.08)3.50 (.06)1.01 (.31)0.03 (.86)Day 30.00 (.98)0.00 (.98)0.00 (.98)0.00 (.98)CRP and SAA concentrations
evolution during the first week comparing survivors and nonsurvivors were not
statistically significant (Figures1 and 2).Figure 1
CRP evolution of survivors and nonsurvivors during the
first week (NS). NS: not statistically significant.Figure 2
SAA evolution of survivors and nonsurvivors
during the first week (NS). NS: not statistically significant.


## 4. Discussion

The present study revealed
significant positive correlation between SAA and CRP in postoperative septic
shock patients. SOFA or APACHE II did not correlate
with those serum measurements. Neither marker nor index was associated with mortality rate.SAA has been considered by
some authors to be equivalent to CRP in patients with bacterial infectious
diseases in clinical practice [16]. Other authors suggest that
SAA is a more sensitive marker than CRP in infections with low inflammatory activity (including many
viral infections) and in other clinical conditions, especially those involving
the lung tissue [16, 17]. Yet other studies have confirmed the role of SAA and
CRP in diagnosis and management of neonatal infections [2, 18].The patterns of cytokine
production and the acute-phase response differ for different inflammatory
conditions. Acute-phase changes reflect the presence and intensity of
inflammation and they have long been used as a clinical guide for diagnosis and
management. Among patients with plasma CRP concentrations higher than 10 mg/dL, 80-to-85
percent have bacterial infections [4, 19]. In our study, all the patients were in septic shock
with documented infection. We could observe that all patients during the 7-day
period of observation presented plasma CRP concentrations greater than 10 mg/dL,
according to results that Gabay et al. in a review article cited [4]. This
fact could indicate that sepsis is secondary to bacterial infections. In
relation to plasma SAA concentrations, a cutoff value has not been determined
from previous studies. We observed a level higher or
closer to 20 mg/dL, but more studies were
needed to find a cutoff value for SAA as an early diagnostic tool for patients with infection.We did not observe difference
between CRP and SAA early (Day 1) concentrations
in patients who survived compared with those who died. Other authors have found
that these proteins were not prognostic markers in patients with septic shock [7, 19]. This
fact is in concordance with our results.Previous reports have observed that CRP level was associated with organ failure in critically ill
patients, although not specifically under septic shock [14]. This study could not find any good correlation between CRP or SAA with SOFA,
probably not in agreement with other authors [20]. They believe that both CRP and SAA are good markers of organ
dysfunction, considering the established diagnostic
of septic shock.Study limitations are attributed primarily to the small sample size and the age of
the patients that could influence CRP levels. Some authors believe that the older the patient is, the higher CRP levels that can be observed [21].In conclusion, SAA protein and CRP are strongly correlated, but were not good
predictors of organ dysfunction and mortality in septic shock.



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