Journal of Investigative Surgery, 19:345–352, 2006Copyright ©c Informa HealthcareISSN: 0894-1939 print / 1521-0553 onlineDOI: 10.1080/08941930600985686

Original Research

The Role of Serum Inflammatory Markersin Acute Appendicitis and Their Success

in Preventing Negative Laparotomy

Osman Yildirim, MD,Cem Solak, MD,Belma Kocer, MD,Bulent Unal, MD,Melih Karabeyoglu, MD,and Betul Bozkurt, MD2nd Surgery Clinic, AnkaraNumune Training and ResearchHospital, Ankara, Turkey

Sabahat Aksaray, MD1st Clinical MicrobiologyDepartment, Ankara NumuneTraining and Research Hospital,Ankara, Turkey

Omer Cengiz, MD2nd Surgery Clinic, AnkaraNumune Training and ResearchHospital, Ankara, Turkey

ABSTRACT Improving the diagnosis of acute appendicitis in order toprevent unnecessary surgery is crucial. This study was intended to iden-tify the role of serum inflammatory markers in patients with preliminarydiagnosis of acute appendicitis with a retrospective design. Eighty-fivepatients with the preliminary diagnosis of acute appendicitis were re-cruited in this study within the period of November–December 2003.The avarage age was 31.8 years (ranged from 15 to 85). There were62 males (72.9%) and 23 females (27.1%). In addition to performing rou-tine tests, preoperative serum samples were obtained from the patientsto measure C-reactive protein, interleukin-6, and interleukin-10. All thepatients were operated on for a clinical suspicion of acute appendicitis.Depending on the macroscopic evidence during the operation and thehistopathological examination of the specimen, the patients were sepa-rated into two groups: the ones who did not have acute appendicitis asthe cause for acute abdomen (group I; n = 14) and the ones who hadacute appendicitis (group II; n = 71). The ones who had acute appen-dicitis (group II) were further grouped as noncomplicated appendicitis(group IIA; n = 44) and complicated appendicitis (group IIB; n = 27).Being a male with elevated levels of leukocytes (white blood cells, WBC);C-reactive protein (CRP), interleukin-6 (IL-6); and interleukin-10 in-creased the probability of having acute appendicitis in patients withevidences of acute abdomen. The risk of complication of acute appen-dicitis significantly increased when patients had increased levels of C-reactive protein, increased erythrocyte sedimentation rate, and increasedinterleukin-6 levels, had symptoms for more than 24 h, and were female.Interleukin-10 levels within normal range might be helpful in eliminat-ing the possibility of acute appendicitis. Thus, elevated levels of WBC,IL-6 and CRP might be helpful in confirming a potential diagnosis of

Received 3 May 2005;accepted 21 February 2006.

Address correspondence to BelmaKocer, Ankara Numune Training andResearch Hospital, Sedat Simavi sokak17/1 B Blok No: 32, 06550 Cankaya,Ankara, Turkey. E-mail:belmak@mailcity.com

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acute appendicitis. In addition, normal levels of IL-10 might be of additional help to possibly rule outthe diagnosis of acute appendicitis.

KEYWORDS acute appendicitis, C-reactive protein, IL-6,IL-10, white blood cells

Despite the fact that all of its features and itssurgical treatment have been described formore than 100 years, acute appendicitis is

still a surgical emergency having a high misdiagnosisrate [1]. Acute appendicitis is an important surgicalissue causing an inflammatory response. Hence, it isa relevant model for evaluating the roles of inflam-matory markers. In patients with acute appendicitis,the inflammatory markers begin to appear in bloodcirculation within hours after the initiation of symp-toms [2].

Increase in the synthesis and activation of acute-phase reactants such as C-reactive protein (CRP), fib-rinogen, haptoglobulin, and alpha-1 anti-trypsin inthe liver has been identified at inflammatory condi-tions in the studies carried out. The increase reachesits peak level within 24 to 48 h [3]. Within this period,there should be other factors affecting the synthe-sis and the activation of these acute-phase reactants.Acute-phase proteins that are synthesized rapidlygive support to the immune system of the host byneutralizing acute-phase antigens, controlling tissuedamage, and initiating the tissue repair process. CRPacts as an opsonin for the bacteria and the immunecomplexes in the blood circulation [4]. The roles ofthe levels of cytokines such as interleukin-6 (IL-6) andinterleukin-10 (IL-10) are not yet completely under-stood. Although the role of IL-6 in inflammation isnot clear, there is evidence that it has positive con-tributions to systemic anti-inflammatory responsesduring exposures to both systemic and local endo-toxins [5].

IL-6 is an inflammatory cytokine and IL-10 is aproinflammatory and suppressor cytokine; we thinkthat they might be of diagnostic value in cases ofacute appendicitis, since they induce the secretion ofacute-phase reactants from the liver and stimulate theinflammatory response in the immune system. Con-sidering all this information, we aimed to identify the

diagnostic values of the inflammatory markers IL-6,IL-10, and CRP in acute appendicitis and to assessthe predictive importance of their preoperative levelsin identifying the complications of acute appendici-tis such as perforation, periappendicular abscess, andplastron.

MATERIALS AND METHODS

Our study has been carried out from Novemberthrough December 2003 on 85 patients who wereadmitted to the emergency department of AnkaraNumune Training and Research Hospital with ab-dominal pain and who had a preliminary diagnosisof acute appendicitis. In patients who were consid-ered to have acute appendicitis, routine laboratoryinvestigations, were performed including urinalysis,white blood cells count, and obtaining erect directabdominal x-rays after learning the personal historiesof the patients and after performing physical exami-nation. Ultrasonography was also performed in crit-ical cases. In addition to those routine tests, 10-mLvenous blood samples were taken to measure ery-throcyte sedimentation rate (ESR), CRP, IL-6, andIL-10 levels.

For white blood cell counts (WBC), blood sampleswere assayed with the Celldyne 3700 system (AbbottPark, USA). For WBC, the upper limit of 12,400mm3/L was accepted as identified by receiver operat-ing characteristic (ROC) curves. For ESR, upper limitwas 18 mm/h for males and 12 mm/h for females. Tomeasure CRP, IL-6, and IL-10, blood samples werecentrifuged with the Rotina 35 system at 1200/rpmfor 5 min. The serum aliquots were then stored indeep freezers adjusted to −27◦C. The serum sam-ples of all the patients were collected and assayedtogether; CRP was measured with a nephelometricmethod (Dade Behring, Germany). For CRP, an up-per limit of 42.5 mg/L was accepted as identifiedby ROC curves. IL-6 and IL-10 concentrations inserum were measured by enzyme immunoassay (Cy-timmune Sciences, USA). For IL-6 an upper limit of310.43 pg/mL and for IL-10 an upper limit of 211.43pg/mL identified by ROC curves had been acceptedas cutoff levels.

The patients who were suspected to have acuteappendicitis were hospitalized in emergency surgery

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and operated upon. Depending on the macroscopicevidence of specimens during the operation andhistopathological examination, the patients were sep-arated into two groups: the ones who did nothave acute appendicitis as the cause for acute ab-domen (group I), and the ones who had acute ap-pendicitis (group II). The ones who had acute ap-pendicitis as the cause of acute abdomen (groupII) were further grouped as noncomplicated ap-pendicitis (group IIA) and complicated appendicitis(group IIB).

Group I (negative appendicitis group) consisted of 14patients who were operated on for a clinical suspicionof acute appendicitis but who had an uninflamed ap-pendix at appendectomy. Most patients in this groupsuffered from nonspecific abdominal pain but someof them had urolithiasis or pelvic inflammatory dis-ease as the cause of acute abdomen, yet these condi-tions cannot be differentiated from acute appendici-tis during the preoperative period.

In group II (acute appendicitis group), subgroupsfound were;

� Group IIA (noncomplicated appendicitis group):Consisted of 44 patients who were operated on fora clinical suspicion of acute appendicitis and haduncomplicated inflamed or phlegmonous appen-dicitis found at appendectomy.

� Group IIB (complicated appendicitis group): Con-sisted of 27 patients operated on for a clinical sus-picion of acute appendicitis in which complicatedappendicitis (perforation, plastron, and/or periap-pendicular abscess) was confirmed.

Statistical Study

To carry out the statistical analysis, the computerprogram SPSS for Windows (v.10.0) was used. ROCcurves were generated to identify the upper limitsof the measured parameters. Also they were consti-tuted to employ the parameters of the patients in thenegative appendicitis group (group I) and those inthe acute appendicitis group (group II). Comparisonsof the mean values for WBC, CRP, ESR, IL-6, andIL-10 between group I and group II and betweengroup IIA and group IIB were made using theKruskal–Wallis test; comparison of the number of

patients below and above the reference level weredone by using chi-square tests for univariate analy-sis. The parameters that were found to be significantbetween group I and group II and between group IIAand group IIB were further analyzed with logistic re-gression, as this is a tool for multivariate analysis. Across tab test was used to estimate the specificity, sen-sitivity, diagnostic value, positive predictive rate, andnegative predictive rate. Having a p value of less than.05 in that analysis was accepted as being statisticallysignificant.

RESULTS

The distributions of the results identified duringthe operation and the histopathological results aregiven in Table 1. Of the 85 patients, 23 were female(27.1%) and the remaining 62 were male (72.9%).The gender distribution of these patients is givenin Table 2. Female patients with acute abdomen aremore likely to have misdiagnosis of acute appendici-tis (34.7%–9.7%). Most of the male acute appen-dicitis cases are noncomplicated, although femaleshave a higher likelihood of complicated appendicitis(p = .004).

WBC, CRP, IL-6, and IL-10 levels were higher inpatients with acute appendicitis (group II) comparedto the negative appendicitis patients (group I) (p <

.05). Moreover, acute appendicitis predominantly

TABLE 1 Distributions of the results identified during theoperation and the histopathological results

Diagnosis n %

Negative laparotomy(n = 14)

Normal 7 (8.3%)

Pelvicinflammatorydiseases

5 (5.9%)

Ureterolithiasis 1 (1.2%)Peptic ulcer

perforation1 (1.2%)

Noncomplicated(n = 44)

Mucosalinflammation

11 (12.9%)

Phlegmonous 19 (22.3%)Gangrene 14 (16.4%)

Complicated (n = 27) Perforated 24 (28.2%)Plastron 2 (2.4%)Periappendicular

abscess1 (1.2%)

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TABLE 2 Gender distribution of patients in each group

Patients Negative laparatomy Noncomplicated Complicated Total

All 14 (16.5%) 44 (51.7%) 27 (31.8%) 85 (100%)Female 8 (34.7%) 6 (26.1%) 9 (39.1%) 23 (27.1%)Male 6 (9.7%) 38 (61.2%) 18 (29.1%) 62 (72.9%)

p = .004

occurs in male patients. The univariate analysis re-sults in groups I and II are demonstrated in Table 3.When the results that were found to be significantin univariate analysis were compared using the mul-tivariate logistic regression analysis, gender, numberof WBC, CRP, and IL-10 were found to significantlyaffect the probability of having acute appendicitis(Table 4). Males have 4.9 times more tendency to-ward acute appendicitis compared to women. Each1000/mm3 increase above the upper limit of WBCcount (12,400/mm3 in our study) results in 12.4times more risk of having acute appendicitis. Each10-mg/L increase above 42.5 mg/L, which is the up-per limit for CRP, increased this tendency by 4.2times. Each 100-pg/mL elevation from the value of211.43-pg/mL, which is the upper limit for IL-10, in-creased the risk of having appendicitis by 8.9 times.

When the differences in parameters of patientswith complicated appendicitis (group IIA) and non-complicated appendicitis (group IIB) were comparedto the univariate analysis, the levels of ESR, CRP,and IL-6 were significantly higher in the complicatedgroup ( p < .05) (Table 5). The patients with compli-cated acute appendicitis had been admitted to thehospital much later than the noncomplicated acuteappendicitis patients. The higher levels of CRP andthe longer period of symptoms were the independentfactors that significantly increased the risk of compli-

TABLE 3 Results of univariate analysis between acute ap-pendicitis patients (group II) and the negative laparotomygroup (group I)

Negative AcuteParameter laparotomy appendicitis p Value

WBC 11,798 ± 4957 17,167 ± 4626 .000(count/mm3)

CRP (mg/L) 53.9 ± 59.7 94.1 ± 68.1 .016IL-6 (pg/mL) 358.9 ± 102.9 448.3 ± 226.0 .032IL-10 (pg/mL) 177.6 ± 28.2 236.0 ± 163.3 .013

Note. WBC, white blood cells; CRP, C-reactive protein; IL-6,Interleukin-6; IL-10, interleukin-10.

cated acute appendicitis (Table 6). The probability ofdeveloping complications was higher among femalescompared to males. Each 10-mg/L increase above thevalue of 42.5 mg/L, which is the upper limit for CRP,increased the likelihood of developing complicationsby 21.6 times more; furthermore, after 24 h hadpassed, the complication rate increased by 6.7 timesfor every hour that the symptoms continued.

IL-10 and CRP provided us guidance while clas-sifying the patients with and without acute appen-dicitis. On the other hand, CRP and the period ofsymptoms were helpful while making a distinctionbetween complicated and noncomplicated cases.

As a result of evaluating all WBC, CRP, IL-6, andIL-10 levels together, the diagnosis of acute appen-dicitis can be less complicated. The levels of IL-10,on the other hand, can help us minimize the nega-tive laparotomy rate. IL-10 by itself has a specificityand positive prediction rate of 90% in the diagnosisof acute appendicitis, yet its sensitivity and negativepredictive values are very low. Yet if WBC, CRP, IL-6,and IL-10 are all evaluated together, then the sensitiv-ity and the negative predictive values become 100%(Table 7).

DISCUSSION

The diagnosis of acute appendicitis, even for expe-rienced surgeons, is often difficult. Delay in the di-agnosis of acute appendicitis increases the frequency

TABLE 4 Results of multivariate analysis between acute ap-pendicitis patients (group II) and the normal group (group I)

Parameter B p OR 95% CI

Gender 4867 .000 4.9 4402 3,833,742WBC 2765 .001 12.4 2331 108,073CRP 3459 .001 4.2 1633 618,491IL-10 3478 .002 8.9 1688 621,868

Note. WBC, white blood cells; CRP, C-reactive protein; IL-6,interleukin-6; IL-10, interleukin-10, OR, odds ratio; CI, confidentialintervals.

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TABLE 5 Results of univariate analysis between group IIAand group IIB

Noncomplicated ComplicatedParameter group group p Value

CRP (mg/L) 68.4 ± 63.5 135.9 ± 53.8 .000IL-6 (pg/mL) 432.2 ± 248.9 474.4 ± 184.1 .024ESR (mm/h) 15.9 ± 14.5 36.2 ± 19.1 .000Duration (h) 21.1 ± 3.7 58.2 ± 35.2 .000

Note. CRP, C-reactive protein; IL-6, interleukin-6; ESR, erythrocyte sedi-mentation rate; duration, duration of patients between onset of symp-toms and operation.

of possible complications by five times, and this re-sults in an increase in morbidity and mortality [1].However, the exploration and removal of a nonin-flamed appendix due to an incorrect diagnosis ofacute appendicitis (negative appendicitis) should betaken into consideration. Many studies have aimedto decrease the negative appendicitis rate by usingother methods such as laboratory and radiologicalstudies [6, 7].

Until puberty, the incidence of acute appendicitisis equal between males and females, but between theages of 15 and 25 years, the male to female ratio be-comes 2/1 [8]; furthermore, the diagnostic accuracyof acute appendicitis is generally lower in females andis approximately 60–70% [9, 10]. In our study, themale to female ratio in this age group was 4/1 and thediagnostic accuracy of acute appendicitis was 65.2%.The studies that have been done in this field demon-strated that being male influenced the probabilityof having acute appendicitis [11]. We found in ourstudy that the male to female ratio was 2.7. Malesappear to have a higher risk of acute appendicitis.

TABLE 7 Specificity, sensitivity, positive predictive value, negative predictive value, and diagnostic accuracy of the parameters

Parameter Specificity Sensitivity PPV NPV DA

WBC 64.3 87.3 92.5 50.0 83.5CRP 64.3 70.4 90.9 30.0 69.4IL-6 50.0 78.9 88.9 31.8 74.1IL-10 92.9 40.8 96.7 23.6 49.4WBC + CRP + IL-6 + IL-10

When at least one is (+) 85.7 11.3 80.0 16.0 23.5When at least two are (+) 64.3 39.4 84.8 17.3 43.5When at least three are (+) 50.0 71.8 87.9 25.9 68.2When all are (+) 42.9 100 89.9 100 90.5

Note. WBC, white blood cells; CRP, C-reactive protein; IL-6, interleukin-6; IL-10, interleukin-10; PPV, positive predictive value; NPV, negativepredictive value; DA, diagnostic accuracy.

TABLE 6 Results of multivariate analysis between group IIAand group IIB

Parameter B p OR 95% CI

CRP 2667 .001 21.6 1668 124,162Duration 1741 .004 6.7 1615 20,123

Note. CRP, C-reactive protein; duration, duration of patients betweenonset of symptoms and operation.

However, the risk of developing complications ishigher among females. This might be due to the mis-diagnosis or delays in being diagnosed.

In some of the studies, the levels of WBC and CRP[7, 12–20] and IL-6 and IL-10 [5, 21, 22, 24, 25] andthe duration of symptoms [23] have been reportedas being helpful parameters in differentiating the pa-tients in the negative appendicitis group (group I)from the patients with appendicitis (group II). Thereare also other results claiming that levels of WBC andCRP [11, 17, 18, 24, 25], levels of IL-6 and IL-10 [16,26–28], the ESR [23, 29], and the duration of symp-toms [18] were not effective parameters in making adistinction between the negative appendicitis groupand the acute appendicitis group. Multivariate logis-tic regression analysis performed between groups Iand II together with the fact of being male demon-strated that the increases in the levels of WBC, CRP,and IL-10 were found to increase the risk of hav-ing acute appendicitis in our study. This observation,that is, increase in the levels of WBC and CRP result-ing in an increase in the tendency of having appen-dicitis, is compatible with the previous research inthe literature [30]. However, we could not find anyclear information in the literature about the increase

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in the levels of IL-10 increasing the likelihood of hav-ing acute appendicitis, which is, in fact, identified inour study.

It is demonstrated that increased levels of WBCand CRP [12–18, 21, 31, 32], IL-6 and IL-10 [1, 16,28, 32, 33], and ESR [23, 34] were helpful to differen-tiate the complicated (group IIB) appendicitis fromthe noncomplicated acute appendicitis (group IIA).If 12 h or more passed over the initiation of symp-toms, patients had a higher risk of gangrenous andperforated appendicitis. The patients who could notbe operated on within 3 days after the initiation ofsymptoms had a perforation risk of 47.6% [l, 25]. Onthe other hand, there were also some reports stat-ing that the levels of WBC and CRP [1, 13, 16–18,25] and the levels of IL-6 and IL-10 [1] were noteffective parameters in making the distinction be-tween noncomplicated and complicated appendici-tis. According to the univariate analysis of results ofour study, WBC, CRP, IL-6, ESR, and the period ofsymptoms were helpful in making the distinction be-tween noncomplicated and complicated appendici-tis. However, IL-10 levels did not help at all. In multi-variate logistic regression analysis between group IIAand group IIB, an increase in the levels of CRP, hav-ing symptoms for more than 24 h, and being femalewere found to increase the risk of developing compli-cations. The sensitivity and specificity levels of WBCcounts were similar to those in other studies, whereasthe positive and the negative predictive values weresomewhat higher in our study than those of the oth-ers [6, 11, 23, 25, 30, 32, 34].

The negative appendectomy rate substantially re-duced after the introduction of ultrasonography(USG) and computed tomography (CT) [35]. USGis often used as the initial diagnostic imaging studyin the majority of patients when the clinical diagno-sis of appendicitis is equivocal. USG is noninvasiveand rapidly available and avoids radiation exposure.It was reported that the accuracy of USG was 92%,sensitivity 83% and specifity 95%. The positive pre-dictive value was 86%, and the negative predictivevalue was 94% [36]. However, the sonogram for ap-pendicitis is a highly operator-dependent study. CThad a sensitivity of 81–94% for the diagnosis of ap-pendicitis, with a specifity of 89–95% and accuracy

of 75–98%, in different studies [37–39]. However, itwas reported that CT was associated with lower neg-ative appendectomy rates for all female patients buthad no effects in either age group of males [40]. Alsoit was reported that the use of CT for the diagnosisof appendicitis in children does not change the neg-ative appendectomy rate [41]. In addition, despitethe potential advantages of this technique, there aresignificant disadvantages. CT scanning is expensive,exposes the patients to a significant amount of ra-diation, and cannot be used during pregnancy [38].The measurement of serum inflammatory markers inthese conditions can be useful to reduce the negativeappendectomy rate. USG and/or CT scan combinedwith the measurement of serum IL-6 and IL-10 con-centration can provide a rapid, highly sensitive, andaccurate diagnosis of acute appendicitis.

In conclusion, IL-6 is a potent proinflammatorycytokine and plays a central role in mediating cellu-lar and physiological inflammatory response. Plasmalevels of IL-6 and CRP were elevated between 8and 12 h after the onset of the infection. Anti-inflammatory cytokines like IL-10 appear to domi-nate in the plasma of patients with acute appendici-tis, within hours of the onset of symptoms. IL-10 isknown as immunmodulatuar cytokine, but its effectis mostly inhibition of Th1 secretion of IFN-γ andIL-2; it also suppresses class II MHC (major histo-compatibility complex) expression and productionof bacterial killing molecules and inflammatory cy-tokines by macrophages. Thus, although it decreasesinflammation, at the same time it might lead to asuppression of bacterial defense mechanisms. An in-creased level of IL-10 in patients with acute abdomenalso indicates the impairment of immune mecha-nism in the case of bacterial etiology. Recent studiesshowed that these cytokines can be used to diagnoseand differentiate appendicitis from other conditions.Our results demonstrated that in order to preventthe negative appendectomy on patients suspectedof acute appendicitis, IL-10 should be considered asan important inflammatory marker with high speci-ficity and positive predictive values. Having normallevels of IL-10 can help us not to consider the di-agnosis of acute appendicitis. However, in order todiagnose correctly the patients who in fact have acute

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appendicitis, we should measure the combination ofWBC count and IL-6 and CRP levels, which all havehigh sensitivity and negative predictive values. Mea-suring high levels of IL-6, CRP, and WBC in a patientwith acute abdomen might lead us to the diagnosis ofacute appendicitis. Additionally, having high levelsof IL-6 and CRP in a patient might indicate the pos-sibility of perforation and worsening complications.However, as a single on-admission test, the set of cy-tokine assays may not be, by itself, of any help to thephysician to diagnose acute appendicitis. The assayscan, however, be used with others diagnostic tests.Further prospective studies should be done to evalu-ate the efficiency of IL-6 and IL-10 in accurate diag-noses of nonperforated and perforated appendicitis,as well as other diseases that cause acute abdomen.

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