Predictive value of C-reactive protein, ultrasound and Alvarado score in acute appendicitis: a prospective pediatric cohort

American Journal of Emergency Medicine xxx (2015) xxx–xxx

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American Journal of Emergency Medicine journal homepage: www.elsevier.com/locate/ajem

Original Contribution

Predictive value of C-reactive protein, ultrasound and Alvarado score in acute appendicitis: a prospective pediatric cohort☆,☆☆,★ Mohamed Zouari, MD ⁎, Mohamed Jallouli, MD, FACS, Hamdi Louati, MD, Rim Kchaou, MD, Rahma Chtourou, MD, Ahmed Kotti, MD, Mahdi Ben Dhaou, MD, Hayet Zitouni, MD, Riadh Mhiri, MD Department of pediatric surgery, Hedi Chaker Hospital, 3029 Sfax, Tunisia

a r t i c l e

i n f o

Article history: Received 10 August 2015 Received in revised form 3 October 2015 Accepted 4 October 2015 Available online xxxx

a b s t r a c t Purpose: To evaluate whether C-reactive protein (CRP) level and ultrasound (US) results on admission could aid the diagnostic accuracy of Alvarado score. Methods: A prospective study was performed on children b14 years admitted for suspected acute appendicitis. Patients were categorized into three groups based on the Alvarado score: group I: score 7-10, group II: score 56, group III: score 0-4. Results: The difference between predictive values of Alvarado score alone and Alvarado score with CRP was not statically significant. The PPV increased from 74.29% (Alvarado score and CRP) to 93.75% (Alvarado score and US) in group 1 (P = .001) and the NPV increased from 64.86 and 79.69% (Alvarado score and CRP) to 82.6 and 88.2% (Alvarado score and US) in group 2 (P = .01) and group 3 (P = .001), respectively. Conclusions: Alvarado score and ultrasound taken together improve the predictive value of diagnosing acute appendicitis in children. © 2015 Elsevier Inc. All rights reserved.

1. Introduction

2. Materials and methods

Acute pain represents one of the most common cause for children consultation in the emergency department [1]. Clinical diagnosis of appendicitis in children is often challenging even for experienced surgeons. Different disease processes mimic the diagnosis of acute appendicitis as there are a number of causes leading to pain in the right iliac fossa particularly in female patients [2,3]. These difficulties likely contribute to the 28% to 57% rates of initially misdiagnosed appendicitis in children younger than 12 years [4–6]. Recently, different clinical scoring systems aiding in the diagnosis of appendicitis have been developed. Alvarado score is one of the most used scores in children (Table 1) [7]. It provides measurably useful diagnostic information in evaluating children with suspected appendicitis. However, Alvarado score doesn’t provide adequate predictive values to be used in clinical practice as the gold method for determination of the need for surgery [8,9]. The aim of the study was to evaluate whether C-reactive protein (CRP) level and ultrasound (US) results on admission could aid the diagnostic accuracy of Alvarado score in a prospectively identified cohort of pediatric patients with suspected appendicitis.

A prospective study was performed on children admitted for suspected acute appendicitis at the Paediatric Surgery Unit, Hedi Chaker Hospital, Sfax, Tunisia, between January 2013 and December 2014. The diagnosis of suspected appendicitis was established preoperatively by one of the consultant pediatric surgeons on the basis of clinical history and physical examination. Laboratory tests including white blood cell count and CRP were ordered on admission. C-reactive protein levels were measured by a highly sensitive immunonephelometric method; the upper reference limit for CRP was 6.0 mg/L. Decision for US evaluation was left to the discretion of the pediatric surgeon during the initial assessment. Ultrasound was performed by experienced pediatric radiologists during weekdays with all exams interpreted by a radiology resident and attending radiologist. Senior radiology residents performed and interpreted US during night-time hours (7 PM to 8 AM) and weekends. Ultrasound radiology reports were classified as positive or negative. A positive report was considered to be a maximum outer diameter of the appendix greater than 6 mm. Negative reports included those in which the appendix measured less than 6 mm and those in which there was no appendix seen on ultrasound with no indirect signs of appendicitis (large amounts of free fluid, phlegmon, or pericecal inflammatory fat changes). The Alvarado score, CRP value, and US result were correlated with the histopathological findings of the removed appendix. Patients were categorized into three groups based on the Alvarado score (Fig. 1). A score of ≥7 was indicating acute appendicitis, a score of 5 to 6 suggested the need for serial examination and follow-up

☆ Conflict of Interest: None. ☆☆ Mohamed Zouari, Mohamed Jallouli, Hamdi Louati, Rim Kchaou, Rahma Chtourou, Ahmed Kotti, Mahdi Ben Dhaou, Hayet Zitouni, and Riadh Mhiri declare that they have no conflict of interest. ★ Source of Support: Nil. ⁎ Corresponding author. Tel.: +216 97459586. E-mail address: [email protected] (M. Zouari). http://dx.doi.org/10.1016/j.ajem.2015.10.004 0735-6757/© 2015 Elsevier Inc. All rights reserved.

Please cite this article as: Zouari M, et al, Predictive value of C-reactive protein, ultrasound and Alvarado score in acute appendicitis: a prospective pediatric cohort, Am J Emerg Med (2015), http://dx.doi.org/10.1016/j.ajem.2015.10.004

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M. Zouari et al. / American Journal of Emergency Medicine xxx (2015) xxx–xxx

Table 1 The Alvarado scoring system Mnemonic (MANTRELS) Symptoms

Signs

Laboratory Total score

Value Migration Anorexia-acetone Nausea-vomiting Right iliac fossa tenderness Rebound pain Elevation of temperature N37.3°C Leukocytosis Shift to the left

1 1 1 2 1 1 2 1 10

and a score below this level meant normal appendix, but the decision to undergo surgery was purely clinical. Patients were operated by conventional method of appendectomy in 122 cases and by laparoscopy in 26 cases. Appendicitis was considered present when patients who had undergone surgery had a final histology showing acute appendicitis. Patients who did not undergo surgery were considered not to have appendicitis if they did not re-present within 2 weeks from initial discharge with acute appendicitis. Negative (NPV) and positive predictive values (PPV) of Alvarado score, CRP and ultrasound were calculated. The differences between groups are presented as 95% confidence intervals. P b .05 was considered to indicate statistical significance. All data was analyzed by SPSS version 13. 3. Results There were 402 patients admitted for suspected appendicitis from January 2013 to December 2014. One hundred and ten patients were not evaluated with US scans and were excluded from the study. Two hundred ninety-two patients were included in the study after taking informed consent. There were 170 (58.2%) males and 122 (41.8%) females. The mean age was 8.54 ± 3 years, ranging from 3 to 13.8 years. At the time of consultation, the mean duration of pain was 46.8 hours (4-168 hours). Pain was associated with nausea and vomiting in 86 patients. Right iliac fossa tenderness was found in 68 patients. Among the 292 patients, 144 were treated without surgical approaches and were then discharged from our hospital. None of these

patients has re-presented within 2 weeks from initial discharge with acute appendicitis. The rates of normal appendix, non-perforated appendicitis, and perforated appendicitis were 6.1%, 73%, and 20.9%. The final diagnoses of patients with normal appendices included colitis, functional gastrointestinal disorders, and mesenteric lymphadenopathy. The sensitivity, specificity, positive and negative predictive values of Alvarado score, CRP, and US are illustrated in Table 2. The PPV of Alvarado score ≥7 was 71.1% in group I, the NPV of Alvarado score b7 were 50.78% in group II and 68.9% in group III. The PPV of high CRP, the NPV of normal CRP, the PPV of positive ultrasound scan and the NPV of negative ultrasound result are presented in Table 3. The difference between predictive values of Alvarado score alone and Alvarado score with CRP was not statically significant (P = .453 in group 1, P = .43 in group 2, P = .08 in group 3). On the contrary, ultrasound was very helpful to diagnose acute appendicitis: The PPV increased from 74.29% (Alvarado score and CRP) to 93.8% (Alvarado score and ultrasound) in group 1 (P = .001) and the NPV increased from 64.86 and 79.69% (Alvarado score and CRP) to 82.6 and 88.2% (Alvarado score and ultrasound) in group 2 (P = .01) and group 3 (P = .001), respectively (Fig. 2). 4. Discussion Our study showed that CRP level on admission could not aid the diagnostic accuracy of Alvarado score in acute appendicitis. Despite substantial research, the diagnosis of pediatric appendicitis remains challenging. Recent studies have proposed different clinical scoring systems aiding in the diagnosis of appendicitis [8]. Ideally, a clinical score could accurately distinguish those patients that need immediate operative care from those that may benefit from further investigation or observation. Two well-studied appendicitis scores were developed by Alfredo Alvarado and Madan Samuel, with the explicit purpose of diagnosing appendicitis [10]. Several studies validated the Alvarado score as simple, practical and reproducible diagnostic tool for assessing an acute abdomen [11–15]. It has been useful both to reduce the incidence of negative appendectomy and to avoid delay in therapy [14,16,17]. However, other studies suggest that Alvarado score doesn’t provide adequate predictive values to be used in clinical practice as the sole method for determination of the need

Fig. 1. Management course and outcomes of study cohort.

Please cite this article as: Zouari M, et al, Predictive value of C-reactive protein, ultrasound and Alvarado score in acute appendicitis: a prospective pediatric cohort, Am J Emerg Med (2015), http://dx.doi.org/10.1016/j.ajem.2015.10.004

M. Zouari et al. / American Journal of Emergency Medicine xxx (2015) xxx–xxx Table 2 Sensitivity, specificity, and predictive values of AS, CRP, and US

Sensitivity Specificity PPV NPV

AS

CRP

US

AS + CRP

AS + US

AS + CRP+ US

24.24 91.88 71.11 59.51

76.98 51.63 59.12 71.17

82.73 93.46 92 58.63

50 89.29 74.29 74.26

57.69 98.51 93.75 85.71

80 97.33 92.31 92.41

for surgery [8,9]. The usefulness of inflammatory markers such as white blood cell count, CRP, and other serum markers in the diagnosis of acute appendicitis in children is still controversial. Many conditions can mimic

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no appendectomy was performed. Ultrasound radiology reports were classified as negative in cases of lack of visualization of the appendix. This was another limitation of the present study. 5. Conclusion C-reactive protein estimation does not improve accuracy in the diagnosis of acute appendicitis in pediatric patients. However, the Alvarado score and ultrasound taken together improve the predictive value of diagnosing acute appendicitis in children. We suggest that an ultrasound imaging should be performed before proceeding to appendectomy especially in patients with moderate or low Alvarado score. 6. Compliance with ethical requirements

Table 3 Predictive values of CRP and Ultrasound found for each group Group

PV

AS + CRP

AS + US

AS + CRP + US

Group 1 Group 2 Group 3

PPV NPV NPV

74.29 64.86 79.69

93.75 82.61 88.24

92.31 73.42 78.35

All human and animal studies have been approved by the appropriate ethics committee and have therefore been performed in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki and its later amendments.

Fig. 2. Variation of predictive values for single and combined diagnostic tests.

acute appendicitis and are associated with an inflammatory response. Although inflammatory markers can be helpful in the surgeon making decision, they are poorly reliable in confirming or excluding acute appendicitis [18–33]. Unlike CRP, US was very helpful in the diagnosis of acute appendicitis in our study. Because US is a low-cost option, free of ionizing radiation, anesthesia, or contrast injection, it has become a widespread initial diagnostic tool in children with suspected appendicitis [34–37]. Ultrasound improves the diagnostic accuracy of appendicitis with sensitivities and specificities ranging from 71% to 92% and from 96% to 98% [38,39]. Toprak et al [40], in their study, used Alvarado score combined with US findings in order to identify patients with a high or low probability of appendicitis. They suggested that imaging (ultrasonography and computed tomography) findings are very useful in the diagnosis of acute appendicitis in children. Our study was limited by the possibility of discharged patients presenting with appendicitis at other hospitals, the relatively small number of patients and the lack of pathological proof in those patients for whom

References [1] Pitts SR, Niska RW, Xu J, Burt CW. National Hospital Ambulatory Medical Care Survey: 2006 emergency department summary. Natl Health Stat Report 2008;6:1–38. [2] Soomro AG, Siddiqui FG, Abro AH, Abro S, Shaikh NA, Memon AS. Diagnostic accuracy of Alvarado scoring system in acute appendicitis. J Liaquat Univ Med Health Sci 2008;7:93–6. [3] Yegane R, Peyvandi H, Hajinasrollah E, Ahmadei M. Evaluation of modified Alvarado score in acute appendicitis among Iranian patients. Acta Med Iran 2008;46:501–6. [4] Rothrock SG, Skeoch G, Rush JJ, Johnson NE. Clinical features of misdiagnosed appendicitis in children. Ann Emerg Med 1991;20:45–50. [5] Curran TJ, Muenchow SK. The treatment of complicated appendicitis in children using peritoneal drainage: results from a public hospital. J Pediatr Surg 1993;28: 204–8. [6] Nance ML, Adamson WT, Hedrick HL. Appendicitis in the young child: a continuing diagnostic challenge. Pediatr Emerg Care 2000;16:160–2. [7] Alvarado A. A practical score for the early diagnosis of acute appendicitis. Ann Emerg Med 1986;15:557–65. [8] Schneider C, Kharbanda A, Bachur R. Evaluating appendicitis scoring systems using a prospective pediatric cohort. Ann Emerg Med 2007;49:778–84.

Please cite this article as: Zouari M, et al, Predictive value of C-reactive protein, ultrasound and Alvarado score in acute appendicitis: a prospective pediatric cohort, Am J Emerg Med (2015), http://dx.doi.org/10.1016/j.ajem.2015.10.004

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M. Zouari et al. / American Journal of Emergency Medicine xxx (2015) xxx–xxx

[9] Mandeville K, Pottker T, Bulloch B, Liu J. Using appendicitis scores in the pediatric ED. Am J Emerg Med 2011;29:972–7. [10] Kharbanda AB. Appendicitis: Do Clinical Scores Matter? Ann Emerg Med 2014; 64(4):373–5. [11] Bukhari SAH, Rana SH. Alvarado Score: A new approach to Acute Appendicitis. Pak Armed Forces Med J 2002;52:47–50. [12] Shrivastava UK, Gupta A, Sharma D. Evaluation of the Alvarado score in the diagnosis of acute appendicitis. Trop Gastroenterol 2004;25(4):184–6. [13] Ahmed AM, Vohra LM, Khaliq T, Lehri AA. Diagnostic Accuracy of Alvarado Score in the Diagnosis of acute Appendicitis. Pak J Med Sci 2009;25(1):118–21. [14] Khan I, Rehman A. Application of Alvarado scoring system in diagnosis of acute appendicitis. J Ayub Med Coll Abbottabad 2005;17:41–4. [15] Lone NA, Shah M, Wani KA, Peer GQ. Modified Alvarado score in diagnosis of acute appendicitis. Ind J Pract Dr 2006;3:1–4. [16] Malik AA, Wani NA. Continuing diagnostic challenge of acute appendicitis: evaluation through modified Alvarado score. Aust N Z J Surg 1998;68:504–5. [17] Al Qahtani AH, Al Qahtani DA. Utilization of diagnostic services in primary care. Saudi Med J 2004;25:1845–8. [18] Al-Abed YA, Alobaid N, Myint F. Diagnostic markers in acute appendicitis. Am J Surg 2014. http://dx.doi.org/10.1016/j.amjsurg.2014.05.024 [pii: S0002-9610(14)003602, Epub ahead of print]. [19] Beltrán MA, Almonacid J, Vicencio A, Gutiérrez J, Cruces KS, Cumsille MA. Predictive value of white blood cell count and C-reactive protein in children with appendicitis. J Pediatr Surg 2007;42(7):1208–14. [20] Stefanutti G, Ghirardo V, Gamba P. Inflammatory markers for acute appendicitis in children: are they helpful? J Pediatr Surg 2007;42(5):773–6. [21] Thirumallai S, Wijesuriya SR, Mitchell A, Delriviere L. Predictive value of C-reactive protein with Alvarado score in acute appendicitis. ANZ J Surg 2014;84(5):335–6. [22] Bundy DG, Byerley JS, Liles EA, Perrin EM, Katznelson J, Rice HE. Does this child have appendicitis? JAMA 2007;298(4):438–51. [23] Howell JM, Eddy OL, Lukens TW, Thiessen ME, Weingart SD, Decker WW. Clinical policy: critical issues in the evaluation and management of emergency department patients with suspected appendicitis. Ann Emerg Med 2010;55:71–116. [24] Vissers RJ, Lennarz WB. Pitfalls in appendicitis. Emerg Med Clin North Am 2010;28: 103–18. [25] Sengupta A, Bax G, Paterson-Brown S. White cell count and C-reactive protein measurement in patient with possible appendicitis. Ann R Coll Surg Engl 2009;91:113–5. [26] Bealer JF, Colgin M. S100A8/A9: a potential new diagnostic aid for acute appendicitis. Acad Emerg Med 2010;17(3):333–6.

[27] Mills AM, Huckins DS, Kwok H, Baumann BM, Ruddy RM, Rothman RE, et al. Diagnostic characteristics of S100A8/A9 in a multicenter study of patients with acute right lower quadrant abdominal pain. Acad Emerg Med 2012;19:48–55. [28] Dalal I, Somekh E, Bilker-Reich A, Boaz M, Gorenstein A, Serour F. Serum and peritoneal inflammatory mediators in children with suspected acute appendicitis. Arch Surg 2005;140(2):169–73. [29] Lycopoulou L, Mamoulakis C, Hantzi E, Demetriadis D, Antypas S, Giannaki M, et al. Serum amyloid A protein levels as a possible aid in the diagnosis of acute appendicitis in children. Clin Chem Lab Med 2005;43(1):49–53. [30] Kentsis A, Lin YY, Kurek K, Calicchio M, Wang YY, Monigatti F, et al. Discovery and validation of urine markers of acute pediatric appendicitis using high-accuracy mass spectrometry. Ann Emerg Med 2010;55(1):62–70. [31] Kentsis A, Ahmed S, Kurek K, Brennan E, Bradwin G, Steen H, et al. Detection and diagnostic value of urine leucine-rich α-2-glycoprotein in children with suspected acute appendicitis. Ann Emerg Med 2012;60(1):78–83. [32] Lee CC, Chen SC, Kuo TC, Chen IC, Chou WK. Usefulness of procalcitonin as a marker of appendicitis in emergency department patients. Ann Emerg Med 2008;51(4): 471–8. [33] Kharbanda AB, Rai AJ, Cosme Y, Liu K, Dayan PS. Novel serum and urine markers for pediatric appendicitis. Acad Emerg Med 2012;19:56–62. [34] Prendergast PM, Poonai N, Lynch T, McKillop S, Lim R. Acute appendicitis: investigating an optimal outer appendiceal diameter cut-point in a pediatric population. J Emerg Med 2014;46(2):157–64. [35] Garcia Peña BM, Mandl KD, Kraus SJ, Fischer AC, Fleisher GR, Lund DP, et al. Ultrasonography and limited computed tomography in the diagnosis and management of appendicitis in children. JAMA 1999;282:1041–6. [36] Hahn HB, Hoepner FU, Kalle T, Macdonald EB, Prantl F, Spitzer IM, et al. Sonography of acute appendicitis in children:7 years experience. Pediatr Radiol 1998;28:147–51. [37] Kessler N, Cyteval C, Gallix B, Lesnik A, Blayac PM, Pujol J, et al. Appendicitis: evaluation of sensitivity, specificity, and predictive values of US, Doppler US, and laboratory findings. Radiology 2004;230:472–8. [38] Kwok MY, Kim MK, Gorelick MH. Evidence-based approach to the diagnosis of appendicitis in children. Pediatr Emerg Care 2004;20(10):690–8. [39] Schulte B, Beyer D, Kaiser C, Horsch S, Wiater A. Ultrasonography in suspected acute appendicitis in childhood – report of 1285 cases. Eur J Ultrasound 1998;8(3): 177–82. [40] Toprak H, Kilincaslan H, Ahmad IC, Yildiz S, Bilgin M, Sharifov R, et al. Integration of ultrasound findings with Alvarado score in children with suspected appendicitis. Pediatr Int 2014;56(1):95–9.

Please cite this article as: Zouari M, et al, Predictive value of C-reactive protein, ultrasound and Alvarado score in acute appendicitis: a prospective pediatric cohort, Am J Emerg Med (2015), http://dx.doi.org/10.1016/j.ajem.2015.10.004