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 Table of Contents  
ORIGINAL ARTICLE
Year : 2019  |  Volume : 6  |  Issue : 4  |  Page : 429-432

Serum amyloid A versus C-reactive protein in sepsis: new insights in an Egyptian ICU


1 Department of Pediatrics, Intensive Care and Pain Management, Faculty of Medicine, Mansoura University, Mansoura, Egypt
2 Department of Medical Microbiology and Immunology, Intensive Care and Pain Management, Faculty of Medicine, Mansoura University, Mansoura, Egypt
3 Department of Anesthesia, Intensive Care and Pain Management, Faculty of Medicine, Mansoura University, Mansoura, Egypt

Date of Submission01-Jul-2019
Date of Acceptance21-Aug-2019
Date of Web Publication06-Jan-2020

Correspondence Address:
MD Nevert A Abdel Ghaffar
Department of Anesthesia, Intensive Care and Pain Management, Faculty of Medicine, Mansoura University, 35516 Mansoura
Egypt
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/roaic.roaic_58_19

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  Abstract 

Background Early diagnosis of sepsis is a challenge. Several biomarkers are available for early diagnosis of sepsis. Serum amyloid A (SAA) and C-reactive protein (CRP) are examples of sepsis biomarkers.
Settings and design We conducted a cohort study in a university-affiliated ICU in Mansoura, Egypt during the period from May 2018 to May 2019, including 50 children with sepsis.
Patients and methods We subjected all patients to full history taking and clinical examination for age, sex, pediatric risk of mortality (PRISM) III and predicted death rate, symptoms and signs of sepsis, length of ICU stay, and invasive procedures. All patients were subjected to complete blood count, CRP, blood culture, and SAA level assay.
Statistical analysis We used Student t-test, χ2, and Mann–Whitney tests.
Results Twenty-three (46%) sepsis cases survived, whereas 27 (54%) cases died. SAA was more sensitive and specific than CRP in sepsis detection in children (sensitivity of 74.1 vs. 66.7% and specificity of 69.6 vs. 56.5%, respectively). Higher levels of SAA and CRP were observed in nonsurvivors when compared with survivors (P<0.001and 0.01, respectively).
Conclusion SAA is a more sensitive and specific sepsis biochemical marker than CRP among critically ill children. Combined usage of SAA and CRP is helpful in predicting sepsis-related mortality.

Keywords: children, C-reactive protein, sepsis, serum amyloid A


How to cite this article:
Yahia S, El-Assmy MM, Eldars W, Mahmoud M, Abdel Ghaffar NA, Wahba Y. Serum amyloid A versus C-reactive protein in sepsis: new insights in an Egyptian ICU. Res Opin Anesth Intensive Care 2019;6:429-32

How to cite this URL:
Yahia S, El-Assmy MM, Eldars W, Mahmoud M, Abdel Ghaffar NA, Wahba Y. Serum amyloid A versus C-reactive protein in sepsis: new insights in an Egyptian ICU. Res Opin Anesth Intensive Care [serial online] 2019 [cited 2020 Apr 6];6:429-32. Available from: http://www.roaic.eg.net/text.asp?2019/6/4/429/275143


  Introduction Top


Sepsis is a common and serious pediatric problem characterized by abnormal body response to infection leading to serious organ dysfunction. Annually, there are ∼19 million cases of sepsis and five million deaths from sepsis. Most cases are reported in developing countries [1].

Early diagnosis of sepsis is a challenge. Several biomarkers are available for early diagnosis of sepsis. Of course, early sepsis detection could reduce mortality and hospital stays [2]. Among these markers, serum amyloid A (SAA) is emerging as an early accurate sepsis predictor. It is a precursor protein first described in reactive amyloidosis and is considered as a member of apolipoproteins family synthesized in liver and adipocytes in response to cytokines released by activated macrophages and monocytes. Level of SAA increases shortly after inflammatory agent exposure, and the degree of increase may be more than that of C-reactive protein (CRP). Moreover, SAA response occurs after relatively trivial inflammatory stimuli. Regarding inflammation, SAA is believed to share in chemotaxis, immunomodulation, and tissue regeneration. During sepsis, a 1000-fold increase in SAA level has been reported [3]. There are several studies denoting sensitivity, early diagnostic, and prognostic values of SAA when compared with other commonly used biomarkers as CRP [4],[5].

Despite several studies having been conducted about the role of SAA in predicting sepsis in neonatal period [3],[6],[7],[8],[9], its role in pediatric age group is not clear. From this point, we conducted our study to assess the accuracy of SAA versus CRP in sepsis diagnosis in children admitted in a surgical pediatric university-affiliated ICU, Mansoura, Egypt. Moreover, we assessed the relation between these serum biomarkers and sepsis-related mortality.


  Patients and methods Top


Study settings and design

We conducted our cohort study in a surgical pediatric university-affiliated ICU, Mansoura, Egypt during the period from May 2018 to May 2019, including 50 children with sepsis. We defined sepsis as systemic inflammatory response syndrome as a result of or in the presence of suspected or proven infection (positive blood culture). Systemic inflammatory response syndrome is defined by the presence of at least two of the following criteria, one of which must be abnormal leukocytes count or temperature: core temperature more than 38.5°C or less than 36°C; tachycardia/bradycardia; tachypnea; leukocytes count decreased or increased for age but not chemotherapy induced; or more than 10% immature neutrophils [10],[11]. We further classified our sample according to their outcome into two groups: survivor and nonsurvivor groups.

Exclusion criteria were chronic diseases as amyloidosis, atherosclerosis, systemic lupus erythematosus, rheumatoid arthritis, pericarditis, and inflammatory bowel disease that might increase SAA and CRP serum levels.

Sample size calculation

The power of this study was calculated using MedCalc software. Using the positive predictive values of serum amyloid A versus C-reactive protein in diagnosis of early onset sepsis (100% and 62.5% respectively) [12] and assuming alpha error = 0.05 and beta error = 0.2, a total sample size of 42 patients was estimated. To avoid drop-out of cases, we added eight patients.


  Methods Top


We subjected all patients to full history taking including age, sex, Pediatric Risk of Mortality (PRISM) III and predicted death rate to evaluate disease severity, symptoms suggestive of sepsis (abnormal temperature, poor feeding, abdominal distension, vomiting, not doing well, and jaundice), length of ICU stay, and invasive procedures (central venous catheterization, chest tube, and endotracheal intubation). Full clinical examination was done focusing on vital signs and sepsis signs such as abdominal enlargement, jaundice, and signs of chest infection. We withdrew 3 ml of venous blood from all patients for complete blood count, CRP, SAA level assay (ELISA technique), and blood culture.

Outcome

Primary outcome was detection of the accuracy of SAA and CRP in diagnosis of sepsis in children in ICU.

Secondary outcome was to assess risk factors associated with sepsis-related mortality.

Ethical approval

Our study was approved by Institutional Research Board of Faculty of Medicine, Mansoura University (Code number: 15.08.40) and followed the 2008 Helsinki Declaration ethical standards. Written informed consents were obtained from all the participants’ parents or guardians who agreed to be enrolled in the research.

Statistical analysis

We used SPSS version 23 (IBM Corporation, Armonk, NY, USA). We assessed the normality of continuous data using Kolmogorov–Smirnov test. Nonparametric data were expressed as median and range (minimum–maximum), whereas parametric data were presented as mean±SD. Categorical data were expressed as numbers and percent. We used Mann–Whitney and Student t-tests for statistical analysis of nonparametric and parametric data, respectively. We analyzed categorical variables using χ2-test. P value up to 0.05 was considered statistically significant.


  Results Top


Our study included 50 (20 females and 30 males) children with sepsis, with median age of 18 months (12–36 months). [Table 1] shows the descriptive data of our studied cases. Twenty-three (46%) cases survived, whereas 27 (54%) cases died. Among our studied cases, 14 (28%) cases yielded positive blood culture. The most common isolated organism was Staphlyococcus aureus (20%).
Table 1 Descriptive data of the study participants

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[Table 2] and [Figure 1] describe the accuracy of SAA and CRP in sepsis diagnosis. Regarding SAA, at cutoff value of 68.54 µg/ml, the area under the curve (AUC) was 78.7%, and the diagnostic accuracy was 72% with specificity of 69.6%, sensitivity of 74.1%, negative predictive value of 69.56%, and positive predictive value of 74.07%. However, for CRP, at cutoff value of 20.5 mg/dl, AUC was 70.5%, and diagnostic accuracy was 62%, with specificity of 56.5%, sensitivity of 66.7%, negative predictive value of 59.09%, and positive predictive value of 64.28%.
Table 2 The accuracy of serum amyloid A and C-reactive protein in diagnosis of sepsis

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Figure 1 Receiver operating characteristic (ROC) curve of C-reactive protein and serum amyloid A in the diagnosis of sepsis.

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Regarding the comparison between nonsurvivors and survivors, higher levels of SAA and CRP were observed among nonsurvivors (P<0.001 and 0.01, respectively; [Table 3]).
Table 3 Comparison between survivors and nonsurvivors regarding different studied variables

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  Discussion Top


In the past few decades, attention has been paid for sepsis biomarkers in ICUs. In this study, we investigated SAA for the first time in children admitted with sepsis in a surgical pediatric university-affiliated ICU, Mansoura, Egypt. The higher sensitivity and specificity of SAA when compared with CRP is an important finding in our study, which supports the neonatal report of Arnon et al. [9]. Moreover in a later study, authors reported a better diagnostic accuracy of SAA than CRP for early prediction of late-onset sepsis in preterm infants. They reported sharper and earlier elevation of SAA level than CRP [8]. In a recent study by Yuan et al. [13], authors found that AUC of SAA test for neonatal sepsis diagnosis is more than that for CRP (0.95 vs. 0.91) and concluded that SAA is a promising diagnostic biomarker in neonatal sepsis.

In contrast to our results, Cetinkaya et al. [14] reported that CRP and SAA had the same diagnostic efficiency and the same AUC in neonatal sepsis detection. In another study, authors reported poor performance of SAA with AUC of 0.61 and sensitivity of 24%, although the specificity was 93% [7]. The discrepancy between results could be explained by difference in study design, study participants, and sample size.

An interesting finding in our study was about the cutoff values of both SAA and CRP that yielded the best specificity and sensitivity for differentiating children with sepsis from those without sepsis. In this study, the cutoff value of SAA was 68.54 µg/ml, whereas that of CRP was 20.5 mg/dl. These values differ completely from the study of Higazi et al. [15] who found lower cutoff values of SAA and CRP (8.85 µg/ml and 5.5 mg/dl, respectively). These findings confirm that there are no fixed cutoff values for these sepsis biomarkers and there is a need for further studies to find the best cutoff value for each age group.In this study, the higher levels of both SAA and CRP among nonsurvivors indicate the importance of these biomarkers as predictors for sepsis-related mortality in critically ill children. On reviewing literature, the relation between SAA and mortality was extensively investigated among neonates [3],[6],[8],[9], adults with sepsis [16], vascular atherosclerosis [17], type 2 diabetes mellitus [18],[19], renal failure [20], and malignancies as osteosarcoma [21]. Regarding sepsis-related mortality, Yu et al. [16] reported that SAA, nitric oxide, and CRP are positively correlated with an increased mortality among adults. To our knowledge, this study is the first to assess such relation among critically ill children.

Study limitations

Our research is a single-center study with a relatively small sample size and limited studied clinical variables.


  Conclusion Top


SAA is a sensitive and specific sepsis biochemical marker among critically ill children. Combined usage of SAA and CRP is helpful in predicting sepsis-related mortality. The cutoff values of both SAA and CRP are age specific. We recommend further studies including extended biochemical markers for early diagnosis of sepsis and to aid in predicting sepsis outcome.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

 
  References Top

1.
Fleischmann C, Scherag A, Adhikari NKJ, Hartog CS, Tsaganos T, Schlattmann P et al. Assessment of global incidence and mortality of hospital-treated sepsis. Current estimates and limitations. Am J Respir Crit Care Med 2016; 193:259–272.  Back to cited text no. 1
    
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Kelly BJ, Lautenbach E, Nachamkin I, Coffin SE, Gerber JS, Fuchs BD et al. Combined biomarkers predict acute mortality among critically ill patients with suspected sepsis. Crit Care Med 2018; 46:1106–1113.  Back to cited text no. 2
    
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Eras Z, Oğuz S, Dizdar EA, Sari FN, Dilmen U. Serum amyloid-A levels in neonatal necrotizing enterocolitis. J Clin Lab Anal 2011; 25:233–237.  Back to cited text no. 3
    
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Malle E, De Beer FC. Human serum amyloid A (SAA) protein: a prominent acute-phase reactant for clinical practice. Eur J Clin Invest 1996; 26:427–435.  Back to cited text no. 4
    
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McPherson RA, Pincus MR. Henry’s clinical diagnosis and management by laboratory methods E-Book. 23rd ed 2017; 929–943.  Back to cited text no. 5
    
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Edgar JD, Gabriel V, Gallimore JR, McMillan SA, Grant J. A prospective study of the sensitivity, specificity and diagnostic performance of soluble intercellular adhesion molecule 1, highly sensitive C-reactive protein, soluble E-selectin and serum amyloid A in the diagnosis of neonatal infection. BMC Pediatr 2010; 10:22.  Back to cited text no. 7
    
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Arnon S, Litmanovitz I, Regev R, Bauer S, Lis M, Shainkin-Kestenbaum R et al. Serum amyloid A protein is a useful inflammatory marker during late-onset sepsis in preterm infants. Neonatology 2005; 87:105–110.  Back to cited text no. 9
    
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Remick DG. Pathophysiology of sepsis. Am J Pathol 2007; 170:1435–1444.  Back to cited text no. 10
    
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Rossi P, Botgros R, Tibby S. Report on the expert meeting on neonatal and paediatric sepsis. https://www.ema.europa.eu/documents/report/report-expert-meeting-neonatal-paediatric-sepsis_en.pdf. Accessed December 16, 2010.  Back to cited text no. 11
    
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Higazi AM, Mahrous DM, Sayed SZ, Mohamed OG, Aly SS. Assessment of urinary interleukin-18 and serum amyloid a efficacies against C-reactive protein in diagnosis and follow-up of neonatal sepsis. J Clin Cell Immunol 2016; 7:2.  Back to cited text no. 12
    
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Yuan H, Huang J, Lv B, Yan W, Hu G, Wang J et al. Diagnosis value of the serum amyloid A test in neonatal sepsis: a meta-analysis. Biomed Res Int 2013;520294.  Back to cited text no. 13
    
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Cetinkaya M, Özkan H, Köksal N, Celebi S, Hacimustafaoğlu M. Comparison of serum amyloid A concentrations with those of C-reactive protein and procalcitonin in diagnosis and follow-up of neonatal sepsis in premature infants. J Perinatol 2009; 29:225–231.  Back to cited text no. 14
    
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Higazi AM, Mahrous DM, Sayed SZ, Mohamed OG, Aly SS, Farag NM et al. Assessment of urinary interleukin-18 and serum amyloid a efficacies against C-reactive protein in diagnosis and follow-up of neonatal sepsis. J Clin Cell Immunol 2016; 7:446–456.  Back to cited text no. 15
    
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Yu MH, Chen MH, Han F, Li Q, Sun RH, Tu YX. Prognostic value of the biomarkers serum amyloid A and nitric oxide in patients with sepsis. Int Immunopharmacol 2018; 62:287–292.  Back to cited text no. 16
    
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Mayer FJ, Binder CJ, Krychtiuk KA, Schillinger M, Minar E, Hoke M. The prognostic value of serum amyloid A for long-term mortality among patients with subclinical carotid atherosclerosis. Eur J Clin Invest 2019; 49:e13095.  Back to cited text no. 17
    
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Saulnier PJ, Dieter BP, Tanamas SK, McPherson SM, Wheelock KM, Knowler WC et al. Association of serum amyloid A with kidney outcomes and all-cause mortality in American Indians with type 2 diabetes. Am J Nephrol 2017; 46:276–284.  Back to cited text no. 18
    
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Dieter BP, McPherson SM, Afkarian M, de Boer IH, Mehrotra R, Short R et al. Serum amyloid a and risk of death and end-stage renal disease in diabetic kidney disease. J Diabetes Complications 2016; 30:1467–1472.  Back to cited text no. 19
    
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Agilli M, Aydin FN. Evaluation of serum amyloid-A as mortality predictor in continuous ambulatory peritoneal dialysis patients. Ren Fail 2015; 37:914.  Back to cited text no. 20
    
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Flores RJ, Kelly AJ, Li Y, Chen X, McGee C, Krailo M et al. The prognostic significance of circulating serum amyloid A and CXC chemokine ligand 4 in osteosarcoma. Pediatr Blood Cancer 2017; 64:e26659.  Back to cited text no. 21
    


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    Tables

  [Table 1], [Table 2], [Table 3]



 

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