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1.  The diagnostic value of white cell count, C-reactive protein and bilirubin in acute appendicitis and its complications 
Inflammatory markers such as white cell count (WCC) and C-reactive protein (CRP) and, more recently, bilirubin have been used as adjuncts in the diagnosis of appendicitis. The aim of this study was to determine the diagnostic accuracy of the above markers in acute and perforated appendicitis as well as their value in excluding the condition.
A retrospective analysis of 1,169 appendicectomies was performed. Patients were grouped according to histological examination of appendicectomy specimens (normal appendix = NA, acute appendicitis = AA, perforated appendicitis = PA) and preoperative laboratory test results were correlated. Receiver operating characteristic (ROC) curve area analysis (area under the curve [AUC]) was performed to examine diagnostic accuracy.
ROC analysis of all laboratory variables showed that no independent variable was diagnostic for AA. Good diagnostic accuracy was seen for AA when all variables were combined (WCC/CRP/bilirubin combined AUC: 0.8173). In PA, the median CRP level was significantly higher than that of AA (158mg/l vs 30mg, p<0.0001). CRP also showed the highest sensitivity (100%) and negative predictive value (100%) for PA. CRP had the highest diagnostic accuracy in PA (AUC: 0.9322) and this was increased when it was combined with WCC (AUC: 0.9388). Bilirubin added no diagnostic value in PA. Normal levels of WCC, CRP and bilirubin could not rule out appendicitis.
CRP provides the highest diagnostic accuracy for PA. Bilirubin did not provide any discriminatory value for AA and its complications. Normal inflammatory markers cannot exclude appendicitis, which remains a clinical diagnosis.
PMCID: PMC4165248  PMID: 23827295
White cell count; C-reactive protein; Bilirubin; Appendicitis; Perforated appendicitis; Normal appendix
2.  Discriminative Accuracy of Novel and Traditional Biomarkers in Children with Suspected Appendicitis Adjusted for Duration of Abdominal Pain 
To assess the accuracy of novel and traditional biomarkers in patients with suspected appendicitis as a function of duration of symptoms.
This was a prospective cohort study, conducted in a tertiary care emergency department (ED). The authors enrolled children 3 to 18 years old with acute abdominal pain of less than 96 hours, and measured serum levels of Interleukin-6 (IL-6), Interleukin-8 (IL-8), C - reactive protein (CRP), white blood cell count (WBC), and absolute neutrophil count (ANC). Final diagnosis was determined by histopathology or telephone follow-up. Trends in biomarker levels were examined based on duration of abdominal pain. The accuracy of biomarkers was assessed with receiver operating characteristic (ROC) curves. Optimal cut-points and test performance characteristics were calculated for each biomarker.
Of 280 patients enrolled, the median age was 11.3 years (IQR 8.6 to 14.8), 57% were male, and 33% had appendicitis. Median IL-6, median CRP, mean WBC, and mean ANC differed significantly (p < 0.001) between patients with non-perforated appendicitis and those without appendicitis; median IL-8 levels did not differ between groups. In non-perforated appendicitis, median IL-6, WBC, and ANC levels were maximal at less than 24 hrs of pain, while CRP peaked between 24 and 48 hours. In perforated appendicitis, median IL-8 levels were highest by 24 hours, WBC and IL-6 by 24 to 48 hours, and CRP after 48 hours of pain. The WBC appeared to be the most useful marker to predict appendicitis in those with fewer than 24 or more than 48 hours of pain, while CRP was the most useful in those with 24 to 48 hours of pain.
In this population, the serum levels and accuracy of novel and traditional biomarkers varies in relation to duration of abdominal pain. IL-6 shows promise as a novel biomarker to identify children with appendicitis.
PMCID: PMC3117273  PMID: 21676053
3.  A Prospective Bicenter Study Investigating the Diagnostic Value of Procalcitonin in Patients with Acute Appendicitis 
Procalcitonin (PCT) is an established laboratory marker for disease severity in patients with infection and sepsis. In addition, PCT has been shown to be an effective marker for a limited number of localized infections. However, whether or not PCT has any diagnostic value for acute appendicitis, still remains unclear. The purpose of this prospective bicenter study was, therefore, to determine whether or not the PCT levels in the serum of patients with acute appendicitis have any diagnostic value.
This prospective study included 103 patients who received an appendectomy, based on the clinical diagnosis of acute appendicitis, in a surgical department of an academic teaching hospital in Germany or in a county hospital in Spain. White blood cell count (WBC), C-reactive protein (CRP) and procalcitonin (PCT) values were determined preoperatively. All appendectomy specimens were sent for routine histopathological evaluation. Based on this information, the patients were assigned to 1 of 5 groups that reflected the severity of the appendicitis.
Of the 103 patients who were included in the study, 98 had appendicitis. Fourteen (14.3%) showed an increase in PCT values. Of those 14, 4 had a serum PCT >0.5 ng/ml, 9 had a PCT value >2–10 ng/ml and 1 had a PCT value >10 ng/ml. The sensitivity of PCT was calculated to be 0.14. The mean WBC value was 13.0/nl (± 5.2, 3.4–31), and for CRP it was 8.8 mg/dl (± 13, 0–60.2). The values of CRP, WBC and PCT increased with the severity of the appendicitis.
PCT is potentially increased in rare cases of severe inflammation and, in particular, after appendiceal perforation or gangrenous appendicitis. However, its remarkably low sensitivity prohibits its routine use for the diagnosis of appendicitis.
PMCID: PMC2790741  PMID: 19672084
Procalcitonin; Appendicitis; Diagnostic
4.  Correlation of serum C-reactive protein, white blood count and neutrophil percentage with histopathology findings in acute appendicitis 
Acute appendicitis is one of the most common surgical emergencies. Accurate diagnosis of acute appendicitis is based on careful history, physical examination, laboratory and imaging investigation. The aim of the study is to analyze the role of C-reactive protein (CRP), white blood count (WBC) and Neutrophil percentage (NP) in improving the accuracy of diagnosis of acute appendicitis and to compare it with the intraoperative assessment and histopathology findings.
Materials and methods
This investigation was a prospective double blinded clinical study. The study was done on 173 patients surgically treated for acute appendicitis. The WBC, NP, and measurement of CRP were randomly collected pre-operatively from all involved patients. Macroscopic assessment was made from the operation. Appendectomy and a histopathology examination were performed on all patients. Gross description was compared with histopathology results and then correlated with CRP, WBC, and NP.
The observational accuracy was 87,3%, as compared to histopathological accuracy which was 85.5% with a total of 173 patients that were operated on. The histopathology showed 25 (14.5%) patients had normal appendices, and 148 (85.5%) patients had acutely inflamed, gangrenous, or perforated appendicitis. 52% were male and 48% were female, with the age ranging from 5 to 59 with a median of 19.7. The gangrenous type was the most frequent (52.6%). The WBC was altered in 77.5% of the cases, NP in 72.3%, and C-reactive protein in 76.9% cases. In those with positive appendicitis, the CRP and WBC values were elevated in 126 patients (72.8%), whereas NP was higher than 75% in 117 patients (67.6%). Out of 106 patients with triple positive tests, 101 (95.2%) had appendicitis. The sensitivity, specificity, and positive predictive values of the 3 tests in combination were 95.3%, 72.2%, and 95.3%, respectively.
The raised value of the CRP was directly related to the severity of inflammation (p-value <0.05). CRP monitoring enhances the diagnostic accuracy of acute appendicitis. The diagnostic accuracy of CRP is not significantly greater than WBC and NP. A combination of these three tests significantly increases the accuracy. We found that elevated serum CRP levels support the surgeon's clinical diagnosis.
PMCID: PMC3469372  PMID: 22866907
Acute appendicitis; CRP correlation; White blood count; Neutrophil percentage; Histopathology findings
5.  Diagnosing Appendicitis: Evidence-Based Review of the Diagnostic Approach in 2014 
Acute appendicitis is the most common abdominal emergency requiring emergency surgery. However, the diagnosis is often challenging and the decision to operate, observe or further work-up a patient is often unclear. The utility of clinical scoring systems (namely the Alvarado score), laboratory markers, and the development of novel markers in the diagnosis of appendicitis remains controversial. This article presents an update on the diagnostic approach to appendicitis through an evidence-based review.
We performed a broad Medline search of radiological imaging, the Alvarado score, common laboratory markers, and novel markers in patients with suspected appendicitis.
Computed tomography (CT) is the most accurate mode of imaging for suspected cases of appendicitis, but the associated increase in radiation exposure is problematic. The Alvarado score is a clinical scoring system that is used to predict the likelihood of appendicitis based on signs, symptoms and laboratory data. It can help risk stratify patients with suspected appendicitis and potentially decrease the use of CT imaging in patients with certain Alvarado scores. White blood cell (WBC), C-reactive protein (CRP), granulocyte count and proportion of polymorphonuclear (PMN) cells are frequently elevated in patients with appendicitis, but are insufficient on their own as a diagnostic modality. When multiple markers are used in combination their diagnostic utility is greatly increased. Several novel markers have been proposed to aid in the diagnosis of appendicitis; however, while promising, most are only in the preliminary stages of being studied.
While CT is the most accurate mode of imaging in suspected appendicitis, the accompanying radiation is a concern. Ultrasound may help in the diagnosis while decreasing the need for CT in certain circumstances. The Alvarado Score has good diagnostic utility at specific cutoff points. Laboratory markers have very limited diagnostic utility on their own but show promise when used in combination. Further studies are warranted for laboratory markers in combination and to validate potential novel markers.
PMCID: PMC4251237  PMID: 25493136
6.  Novel Serum and Urine Markers for Pediatric Appendicitis 
Academic Emergency Medicine  2012;19(1):56-62.
To describe the association between two novel biomarkers, calprotectin and leucine-rich alpha glycoprotein-1 (LRG), and appendicitis in children.
This was a prospective, cohort study of children 3 to 18 years old presenting to a pediatric emergency department with possible appendicitis. Blood and urine samples were assayed for calprotectin and LRG via enzyme-linked immunosorbent assay. Final diagnosis was determined by histopathology or telephone follow-up. Biomarker levels were compared for subjects with and without appendicitis. Recursive partitioning was used to identify thresholds that predicted appendicitis.
Of 176 subjects, mean age was 11.6 years (SD ±4.0 years) and 52% were male. Fifty-eight patients (34%) were diagnosed with appendicitis. Median plasma calprotectin, serum LRG, and urine LRG levels were higher in appendicitis versus non-appendicitis (p < 0.008). When stratified by perforation status, median plasma calprotectin and serum LRG levels were higher in non-perforated appendicitis vs. non-appendicitis (p < 0.01). Median serum LRG, urine LRG, and plasma calprotectin levels were higher in perforated appendicitis as compared to non-perforated appendicitis (p < 0.05). Urine calprotectin did not differ among groups. A serum LRG < 40,150 ng/ml, a urine LRG < 42 ng/ml, and a plasma calprotectin < 159 ng/ml, each provided a sensitivity and negative predictive value of 100% to identify children at low risk for appendicitis, but with specificities ranging from 23% to 35%. The standard white blood cell (WBC) count achieved 100% sensitivity at a higher specificity than both novel biomarkers.
Plasma calprotectin and serum/urine LRG are elevated in pediatric appendicitis. No individual marker performed as well as the WBC.
PMCID: PMC3261304  PMID: 22221321
7.  The Diagnostic Value of D-dimer, Procalcitonin and CRP in Acute Appendicitis 
BACKGROUND: The early diagnosis of acute abdomen is of great importance. To date, several inflammatory markers have been used for the diagnosis of acute abdominal conditions, including acute appendicitis. The aim of this study was to evaluate the diagnostic utility of D-dimer, Procalcitonin (PCT) and C-reactive protein (CRP) measurements in the acute appendicitis.
METHODS: This prospective study was conducted between March 1st, 2010 and July 1st, 2011. In this period, seventy-eight patients were operated with the diagnosis of acute appendicitis, and D-dimer, PCT and CRP levels of the patients were measured. The patients were grouped as phlegmonous appendicitis (Group 1), gangrenous appendicitis (Group 2), perforated appendicitis (Group 3) and negative appendectomy (Group 4) according to the surgical findings and histopathological results.
RESULTS: Of 78 patients, 54 (69.2 %) were male and 24 (30.8 %) were female, and the mean age was 25.4 ± 11.1 years (range, 18 to 69 years). 66 (84.6 %) patients had increased leukocyte count (white blood cell count). The PCT values were higher than the upper normal limit in 20 (25.6%) patients, followed by D-dimer in 22 (28.2 %) patients and CRP in 54 (69.2 %) patients. The diagnostic value of leukocyte count and CRP in acute appendicitis was higher than that of the other markers, whereas leukocyte count showed very low specificity. CRP values were higher in perforated appendicitis when compared with the phlegmonous appendicitis (p<0.05). However, PCT and D-dimer showed lower diagnostic values (26% and 31%, respectively).
CONCLUSION: An increase in CRP levels alone is not sufficient to make the diagnosis of acute appendicitis. However, CRP levels may differentiate between phlegmonous appendicitis and perforated appendicitis. Due to their low sensitivity and diagnostic value, PCT and D-dimer are not better markers than CRP for the diagnosis of acute appendicitis.
PMCID: PMC3520016  PMID: 23236260
Appendicitis; D-dimer; Procalcitonin; C-reactive protein.
8.  Acute appendicitis: relationships between CT-determined severities and serum white blood cell counts and C-reactive protein levels 
The British Journal of Radiology  2011;84(1008):1115-1120.
The aim of this study was to evaluate the relationships between the severity of appendicitis as depicted on CT and blood inflammatory markers of serum white blood cell (WBC) count and C-reactive protein (CRP).
CT images in 128 patients (109 surgically proven and 19 with clinically excluded appendicitis) were retrospectively reviewed. Two radiologists by consensus evaluated and scored (using a 0, 1 or 2 point scale) severities based on CT-determined appendiceal diameters, appendiceal wall changes, caecal changes, periappendiceal inflammatory stranding and phlegmon or abscess formation. We investigated whether CT findings were significantly related to elevated WBC counts or CRP levels and performed the correlations of WBC counts and CRP levels with CT severity scores. Patients were also subjectively classified using four grades from normal (Grade I) to perforated appendicitis (Grade IV) on the basis of CT findings to evaluate differences in WBC counts and CRP levels between grades.
Only appendiceal wall changes and the phlegmon or abscess formation were related to elevated WBC counts and CRP levels, respectively (p<0.05). CT severity scores were found to be more strongly correlated with CRP levels (r = 0.669) than with WBC counts (r = 0.222). On the basis of CT grades, the WBC counts in Grade I were significantly lower than in other grades (p<0.001), whereas CRP levels in Grade IV were significantly higher than in other grades (p<0.001).
CRP levels were found to correlate with CT-determined acute appendicitis severity and could be a useful predictor for perforated appendicitis, whereas WBC counts might be useful to detect early acute appendicitis.
PMCID: PMC3473821  PMID: 21123307
9.  Comparison of pre-operative bilirubin level in simple appendicitis and perforated appendicitis 
Delay in diagnosis and treatment of perforated appendicitis may cause life-threatening complications.The aim of this study was to determine and compare pre-operative total and direct bilirubin levels incases of simple and perforated acute appendicitis in order to improve the clinical decision making.
This prospective observational study included eighty patients who underwent open appendectomy,during a one-year period from March 2010 to March 2011 in the surgical department of Hazrat-e-Rasool AkramHospital, an academic teaching hospital in Tehran- Iran. Pre-operative total and direct levels of bilirubin werecompared in two groups of histologically proved appendicitis (simple and perforated), each including 40 patients.
Eighty patients who underwent open appendectomy including 70% men and 30% women with a meanage of 34±11 years in Group I (perforated appendicitis) and 47.5% women and 52.5% men with a mean age of33±14 in Group II (simple appendicitis) were included in this study. The mean bilirubin levels were higher forpatients with perforated acute appendicitis compared to those with a non-perforated simple appendicitis(1.04±05 mg/dl vs 0.7±0.1 mg/dl) and this difference is highly significant (p<0.01).
Assessment of preoperative total bilirubin is useful for the differential diagnosis of perforatedversus acute simple appendicitis and total bilirubin should be used as an independent parameter in the early diagnosisof appendix perforation
PMCID: PMC3917482  PMID: 24791119
Appendicitis; Bilirubin; Hyperbilirubinemia; Perforated appendicitis
10.  The value of hyperbilirubinaemia in the diagnosis of acute appendicitis 
No reliably specific marker for acute appendicitis has been identified. Although recent studies have shown hyperbilirubinaemia to be a useful predictor of appendiceal perforation, they did not focus on the value of bilirubin as a marker for acute appendicitis. The aim of this study was to determine the value of hyperbilirubinaemia as a marker for acute appendicitis.
A retrospective analysis of appendicectomies performed in two hospitals (n=472). Data collected included laboratory and histological results. Patients were grouped according to histology findings and comparisons were made between the groups.
The mean bilirubin levels were higher for patients with simple appendicitis compared to those with a non-inflamed appendix (p<0.001). More patients with simple appendicitis had hyperbilirubinaemia on admission (30% vs 12%) and the odds of these patients having appendicitis were over three times higher (odds ratio: 3.25, p<0.001). Hyperbilirubinaemia had a specificity of 88% and a positive predictive value of 91% for acute appendicitis. Patients with appendicitis who had a perforated or gangrenous appendix had higher mean bilirubin levels (p=0.01) and were more likely to have hyperbilirubinaemia (p<0.001). The specificity of hyperbilirubinaemia for perforation or gangrene was 70%. The specificities of white cell count and C-reactive protein were less than hyperbilirubinaemia for simple appendicitis (60% and 72%) and perforated or gangrenous appendicitis (19% and 36%).
Hyperbilirubinaemia is a valuable marker for acute appendicitis. Patients with hyperbilirubinaemia are also more likely to have appendiceal perforation or gangrene. Bilirubin should be included in the assessment of patients with suspected appendicitis.
PMCID: PMC3291137  PMID: 21477433
Appendicitis; Diagnosis; Bilirubin
11.  Diagnostic value of blood inflammatory markers for detection of acute appendicitis in children 
BMC Surgery  2006;6:15.
Acute appendicitis (AA) is a common surgical problem that is associated with an acute-phase reaction. Previous studies have shown that cytokines and acute-phase proteins are activated and may serve as indicators for the severity of appendicitis. The aim of this study was to compare diagnostic value of different serum inflammatory markers in detection of phlegmonous or perforated appendicitis in children.
Data were collected prospectively on 211 consecutive children. Laparotomy was performed for suspected AA for 189 patients. Patients were subdivided into groups: nonsurgical abdominal pain, early appendicitis, phlegmonous or gangrenous appendicitis, perforated appendicitis.
White blood cell count (WBC), serum C-reactive protein (CRP), interleukin-6 (IL-6), tumor necrosis factor α (TNF-α), acid α1-glycoprotein (α1GP), endotoxin, and erythrocyte sedimentation reaction (ESR) were estimated ad the time of admission. The diagnostic performance was analyzed using receiver operating characteristic (ROC) curves.
WBC count, CRP and IL-6 correlated significantly with the severity of appendiceal inflammation. Identification of children with severe appendicitis was supported by IL-6 or CRP but not WBC. Between IL-6 and CRP, there were no significant differences in diagnostic use.
Laboratory results should be considered to be integrated within the clinical assessment. If used critically, CRP and IL-6 equally provide surgeons with complementary information in discerning the necessity for urgent operation.
PMCID: PMC1712352  PMID: 17132173
12.  Does This Child Have Appendicitis? 
Evaluation of abdominal pain in children can be difficult. Rapid, accurate diagnosis of appendicitis in children reduces the morbidity of this common cause of pediatric abdominal pain. Clinical evaluation may help identify (1) which children with abdominal pain and a likely diagnosis of appendicitis should undergo immediate surgical consultation for potential appendectomy and (2) which children with equivocal presentations of appendicitis should undergo further diagnostic evaluation.
To systematically assess the precision and accuracy of symptoms, signs, and basic laboratory test results for evaluating children with possible appendicitis.
Data Sources
We searched English-language articles in MEDLINE (January 1966—March 2007) and the Cochrane Database, as well as physical examination textbooks and bibliographies of retrieved articles, yielding 2521 potentially relevant articles.
Study Selection
Studies were included if they (1) provided primary data on children aged 18 years or younger in whom the diagnosis of appendicitis was considered; (2) presented medical history data, physical examination findings, or basic laboratory data; and (3) confirmed or excluded appendicitis by surgical pathologic findings, clinical observation, or follow-up. Of 256 full-text articles examined, 42 met inclusion criteria.
Data Extraction
Twenty-five of 42 studies were assigned a quality level of 3 or better. Data from these studies were independently extracted by 2 reviewers.
In children with abdominal pain, fever was the single most useful sign associated with appendicitis; a fever increases the likelihood of appendicitis (likelihood ratio [LR], 3.4; 95% confidence interval [CI], 2.4-4.8) and conversely, its absence decreases the chance of appendicitis (LR, 0.32; 95% CI, 0.16-0.64). In select groups of children, in whom the diagnosis of appendicitis is suspected and evaluation undertaken, rebound tenderness triples the odds of appendicitis (summary LR, 3.0; 95% CI, 2.3-3.9), while its absence reduces the likelihood (summary LR, 0.28; 95% CI, 0.14-0.55). Midabdominal pain migrating to the right lower quadrant (LR range, 1.9-3.1) increases the risk of appendicitis more than right lower quadrant pain itself (summary LR, 1.2; 95% CI, 1.0-1.5). A white blood cell count of less than 10 000/μL decreases the likelihood of appendicitis (summary LR, 0.22; 95% CI, 0.17-0.30), as does an absolute neutrophil count of 6750/μL or lower (LR, 0.06; 95% CI, 0.03-0.16). Symptoms and signs are most useful in combination, particularly for identifying children who do not require further evaluation or intervention.
Although the clinical examination does not establish a diagnosis of appendicitis with certainty, it is useful in determining which children with abdominal pain warrant immediate surgical evaluation for consideration of appendectomy and which children may warrant further diagnostic evaluation. More child-specific, age-stratified data are needed to improve the utility of the clinical examination for diagnosing appendicitis in children.
PMCID: PMC2703737  PMID: 17652298
13.  The Role of Mean Platelet Volume in the Diagnosis of Acute Appendicitis: A Retrospective Case-Controlled Study 
The level of platelet volume (MPV) has been reported to be a laboratory marker in inflammatory cases.
The aim of this study was to seek whether MPV has a role in the diagnosis of acute appendicitis. It was also aimed to show the relationship of MPV with leukocyte count and C-reactive protein (CRP) level.
Materials and Methods:
This study was conducted via retrospective assessment of the hospital records of the adult patients who were operated for acute appendicitis between January 2010 and December 2012 and had a pathology report that confirmed the diagnosis of acute appendicitis. The patients in the control group were selected from healthy adults of similar age who applied to check-up clinic. The number of essential cases was defined by performing power analysis. Age, gender, leukocyte count, CRP, and MPV values were recorded. This study is a case controlled retrospective clinical study.
A total of 503 patients in the acute appendicitis group and 121 patients in the control group were included, making up a total of 624 subjects. The median MPV levels were 7.92 ± 1.68 fL in the acute appendicitis group, while 7.43 ± 1.34 fL in the control group. CRP, leukocyte count, and MPV level were significantly higher in the acute appendicitis group (P < 0.001). MPV, leukocyte count, and CRP had a sensitivity and specificity of 66% and 51%; 91% and 74%; and 97% and 41%, respectively. No correlation was found between MPV, CRP, and leukocyte count.
MPV level was higher in patients with acute appendicitis. MPV may guide the diagnostic process of acute appendicitis. However, we detected that the sensitivity and specificity of leukocyte count and CRP were superior to those of MPV in the diagnosis of acute appendicitis.
PMCID: PMC3955502  PMID: 24693387
Appendicitis; C-Reactive Protein; Leukocytes; Blood Platelets
14.  Diagnostic accuracy of white cell count and C-reactive protein for assessing the severity of paediatric appendicitis 
JRSM Short Reports  2011;2(7):59.
Simple investigations like white cell count (WCC) and C-reactive protein (CRP) may help to improve the accuracy of diagnosis in paediatric appendicitis. We evaluated the diagnostic accuracy of WCC and CRP for the severity of acute appendicitis in children.
Cross-sectional study.
This study was conducted on all children who underwent open appendectomy from January 2007 to December 2008 at a District General Hospital. Data regarding demographics, WCC, CRP, histology and postoperative complications were analysed.
All children who underwent open appendectomy during the study period.
Main outcome measures
Diagnostic accuracy of WCC and CRP for simple acute appendicitis and a perforated appendix.
Out of 204 patients, 112 (54.9%) were girls. At surgery, appendix was grossly inflamed in 175 of which 32 had perforation. Histology revealed simple acute appendicitis in 135 (66.2%) and gangrenous appendicitis in 32 (15.7%). The rest were normal. The duration of symptoms, temperature, length of stay, WCC and CRP were significantly worse in the perforated group (P value <0.05). Postoperative complications included wound infection (n = 18), pelvic collection (n = 5) and intestinal obstruction (n = 6); and were more common among patients with a perforated appendix (P value <0.05). WCC had a higher diagnostic accuracy and higher sensitivity than CRP in diagnosing simple acute appendicitis. The combined sensitivity of WCC and CRP increased to 95% and 100% for the diagnosis of simple acute appendicitis and a perforated appendix, respectively.
Accuracy of WCC is higher than CRP for diagnosing simple acute appendicitis. The combined sensitivity of WCC and CRP increases for simple acute appendicitis as well as a perforated appendix.
PMCID: PMC3147235  PMID: 21847441
15.  The NOTA study: non-operative treatment for acute appendicitis: prospective study on the efficacy and safety of antibiotic treatment (amoxicillin and clavulanic acid) in patients with right sided lower abdominal pain 
BMJ Open  2011;1(1):e000006.
Case control studies that randomly assign patients with diagnosis of acute appendicitis to either surgical or non-surgical treatment yield a relapse rate of approximately 14% at one year. It would be useful to know the relapse rate of patients who have, instead, been selected for a given treatment based on a thorough clinical evaluation, including physical examination and laboratory results (Alvarado Score) as well as radiological exams if needed or deemed helpful. If this clinical evaluation is useful, the investigators would expect patient selection to be better than chance, and relapse rate to be lower than 14%. Once the investigators have established the utility of this evaluation, the investigators can begin to identify those components that have predictive value (such as blood analysis, or US/CT findings). This is the first step toward developing an accurate diagnostic-therapeutic algorithm which will avoid risks and costs of needless surgery.
This will be a single-cohort prospective observational study. It will not interfere with the usual pathway, consisting of clinical examination in the Emergency Department (ED) and execution of the following exams at the physician's discretion: full blood count with differential, C reactive protein, abdominal ultrasound, abdominal CT. Patients admitted to an ED with lower abdominal pain and suspicion of acute appendicitis and not needing immediate surgery, are requested by informed consent to undergo observation and non operative treatment with antibiotic therapy (Amoxicillin and Clavulanic Acid). The patients by protocol should not have received any previous antibiotic treatment during the same clinical episode. Patients not undergoing surgery will be physically examined 5 days later. Further follow-up will be conducted at 7, 15 days, 6 months and 12 months. The study will conform to clinical practice guidelines and will follow the recommendations of the Declaration of Helsinki. The protocol was approved on November 2009 by Maggiore Hospital Ethical Review Board (ID CE09079).
Trial Registration identifier: NCT01096927.
Article summary
Article focus
Acute appendicitis can have severe complications including perforation and generalised peritonitis.
The appendix is found to be free of disease in 15–30% of appendectomies.
As surgery carries various risks, conservative non-surgical treatment with antibiotics for suspected appendix inflammation may avoid needless surgery, in particular as the relapse rate is low and the rate of complications is similar.
Key messages
Case control studies that randomly assign patients with acute appendicitis to either surgical or non-surgical treatment show a relapse rate of approximately 14% at 1 year.
The relapse rate of patients who are treated based on a thorough clinical evaluation should be below 14%.
Once factors predictive of outcome and/or the need of surgery are identified, an accurate diagnostic-therapeutic algorithm which will help avoid the risks and costs of needless surgery can be developed.
Strengths and limitations of this study
This non-randomised controlled study will evaluate the effectiveness and short and long term outcomes of non-operative antibiotic treatment of acute appendicitis.
Amoxicillin and clavulanic acid are common and easily managed low cost drugs, available both for intravenous and oral use.
Better analysis of clinical data might lead to better decision-making in patients with right iliac fossa pain and suspected acute appendicitis.
The study also aims to evaluate the Alvarado score, which is used to diagnose acute appendicitis and discriminate patients needing immediate surgery from patients who may safely undergo observation and antibiotic treatment.
A large sample of patients undergoing non-operative antibiotic treatment will allow a statistically powerful evaluation of safety, efficacy and cost.
An additional objective is to identify clinical, laboratory and imaging findings that are predictive of failure of conservative treatment and/or relapse of appendicitis and need for appendectomy within 1 year.
As efficacy can not be reliably determined in the absence of a control group, a case series observation determining ‘efficacy’ has limited value.
The Alvarado score is used to separate those with acute appendicitis from those with similar symptoms but no appendicitis and there is no evidence that this score can identify those who would benefit from antibiotic treatment.
PMCID: PMC3191386  PMID: 22021722
Lower abdominal Pain; right iliac fossa pain; acute appendicitis; antibiotic therapy; conservative Management; appendectomy; recurrence; length of hospital stay; sick leave time; short and long Term abdominal pain evaluation; study protocol; case control study
16.  Plasma total anti-oxidant capacity correlates inversely with the extent of acute appendicitis: a case control study 
The role of free oxygen radicals in inflammatory conditions is well known. Free radicals cause lipid peroxidation of cellular membranes resulting in cell death. The purpose of this study was to investigate the levels of total anti-oxidant status (TAS), as a marker of anti-oxidant defense system and malondialdehyde (MDA), as a marker of oxidative stress, in the plasma of patients with acute appendicitis.
Fifty-one adult patients with a median age of 31 years who underwent operations with a preoperative diagnosis of acute appendicitis were included in this prospective study. Blood samples for C-reactive protein (CRP), MDA and TAS were collected preoperatively. Groups were compared by using the Mann-Whitney U test.
There were 27 patients with acute phlagmenous appendicitis and 19 patients with advanced appendicitis (10 gangrenous and 9 perforated appendicitis), while 5 negative explorations were documented. No significant differences in WBC counts and MDA levels between groups were encountered. Plasma CRP was significantly higher in patients with perforated appendicitis, but not in the other groups. In advanced appendicitis group, TAS level was significantly lower than the other groups. On the other hand, plasma TAS level in acute phlagmenous appendicitis group was significantly higher.
A decrease in plasma total anti-oxidant capacity might be a predictor of the progression of inflammation to the perforation in acute appendicitis.
PMCID: PMC1475839  PMID: 16759345
17.  Evaluation of procalcitonin as a biomarker of diagnosis, severity and postoperative complications in adult patients with acute appendicitis 
Background: Delay in diagnosis and treatment of acute appendicitis (AA) results in an increased rate of perforation, postoperative morbidity, mortality and hospital length of stay. Several biochemical parameters including white blood cell (WBC) count, C-reactive protein (CRP), interleukin-6 (IL6) and Procalcitonin (PCT) have been used to further improve the clinical diagnosis of AA. The aim of this study was to assess the value of procalcitonin as a predictor of diagnosis and severity of appendicitis in order to improve the clinical decision making, since other studies have been unable to demonstrate a diagnostic value for PCT elevation in acute appendicitis.
Methods: One-hundred patients who underwent open appendectomy, including 75 men and 25 women with a mean age of 28 years were included in this study. Procalcitonin values were measured by an immunofluorescent method). Serum PCT>0.5 ng/ml was considered positive. The PCT serum values were measured in four different categories, including ˂0.5ng/ml, 0.5-2 ng/ml, 2-10ng/ml and more than 10ng/ml.
Results: The sensitivity and specificity of PCT level measurement for acute appendicitis diagnosis were 44% and 100% respectively. The value of PCT increased with the severity of appendicitis and also with the presence of peritonitis and infection, at the site of surgery.
Conclusions: Procalcitonin measurement cannot be used as a diagnostic test for adult patients with acute appendicitis and its routine use in such patients is not cost effective and conclusive. Procalcitonin values can be used as a prognostic marker and predictor of infectious complications following surgery and it can help to carry out timely surgical intervention which is highly recommended in patients with PCT values more than 0.5ng/ml.
PMCID: PMC4219879  PMID: 25405116
Appendicitis; Procalcitonin; Diagnosis; Prognosis
18.  The role of red cell distribution width in the diagnosis of acute appendicitis: a retrospective case-controlled study 
The aim of this study was to seek whether red cell distribution width (RDW) has a role in the diagnosis of acute appendicitis. It was also aimed to show the relationship of RDW with leukocyte count and C-reactive protein (CRP) level.
This study was conducted via retrospective assessment of the hospital records of the adult patients who were operated for acute appendicitis between January 2010 and February 2013 and had a pathology report that confirmed the diagnosis of acute appendicitis. The patients in the control group were selected from healthy adults of similar age who applied to check-up clinic. Age, gender, leukocyte count, CRP, and RDW values were recorded. This study is a case controlled retrospective clinical study.
A total of 590 patients in the acute appendicitis group and 121 patients in the control group were included, making up a total of 711 subjects. The mean RDW levels were 15.4 ± 1.5% in the acute appendicitis group, while 15.9 ± 1.4% in the control group. CRP, leukocyte count were significantly higher in the acute appendicitis group, and RDW level were significantly lower in the acute appendicitis group (p < 0.001, p < 0.001, p = 0.001, respectively). RDW, leukocyte count, and CRP had a sensitivity and specificity of 47% and 67%; 91% and 74%; and 97% and 41%, respectively in acute appendicitis. RDW was not correlated with CRP and leukocyte levels. However, we found a correlation between CRP and leukocyte levels.
RDW level was lower in patients with acute appendicitis. The magnitude of difference in RDW seen between acute appendicitis and controls was so slight as to be of no utility in diagnostic testing.
PMCID: PMC3826504  PMID: 24216220
Acute appendicitis; C-reactive protein; Leukocyte; Red cell distribution width
19.  Normal inflammatory markers in appendicitis: evidence from two independent cohort studies 
JRSM Short Reports  2011;2(5):43.
Acute appendicitis is a common surgical condition which can lead to severe complications. Recent work suggested that patients experiencing right lower abdominal pain, with normal white cell count (WCC) and C-reactive protein (CRP) are unlikely to have acute appendicitis and can be discharged. We present two independent data-sets that suggest that this strategy may not be risk-free.
Retrospective cohort study of consecutive patients from two district general hospitals. Sensitivity and specificity of CRP, WCC and neutrophil count (NC) in predicting appendicitis were calculated. Markers were analysed using Fisher's exact test and Kruskul-Wallace test.
Two district general hospitals in the UK.
Patients undergoing appendicectomy for suspected appendicitis.
Main outcome measures
Inflammatory markers and appendix histology.
A total of 297 patients were included. Appendicitis occurred in four patients with normal CRP, WCC and NC in centre A and 13 patients in centre B. The sensitivity of all three markers combined was 94% (centre A) and 92% (centre B). The specificity was 60% (centre A) and 64% (centre B). No single marker could differentiate uncomplicated and complicated appendicitis, but a raised NC or a CRP >35.5 mg/l predicted complicated appendicitis. CRP, WCC and NC combined differentiated between patients with a normal appendix, uncomplicated appendicitis and complicated appendicitis.
Appendicitis in the presence of normal inflammatory markers is not uncommon. We disagree with the view of Sengupta et al. who suggest that patients with normal WCC and CRP are unlikely to have appendicitis, and recommend that clinicians be wary of normal inflammatory markers in patients with a high clinical suspicion of appendicitis.
PMCID: PMC3105453  PMID: 21637404
20.  C-Reactive protein is an independent surgical indication marker for appendicitis: a retrospective study 
This study is an attempt to clarify the role of C-reactive protein (CRP) as a surgical indication marker for appendicitis.
One hundred and fifty patients who underwent appendectomies and had pathologically confirmed appendicitis were reviewed between May 1, 1999 and September 31, 2007. The correlation between preoperative clinical factors and the actual histological severity, and identify surgical indication markers were assessed by univariate and multivariate analyses.
Univariate analysis showed that only the CRP level significantly differ between the surgical treatment necessary group (gangrenous appendicitis) and the possible non-surgical treatment group (catarrhalis and phlegmonous appendicitis). Multivariate analysis indicated only the CRP level to be a surgical indication marker for acute appendicitis. The receiver-operating characteristic (ROC) curve indicated that the cutoff value of CRP for surgical indication of appendicitis is 4.95 mg/dl.
Only the CRP level is consistent with the severity of appendicitis, and considered to be a surgical indication marker for acute appendicitis.
PMCID: PMC2775727  PMID: 19878592
21.  Procalcitonin as the Biomarker of Inflammation in Diagnosis of Appendicitis in Pediatric Patients and Prevention of Unnecessary Appendectomies 
The Indian Journal of Surgery  2010;73(2):136-141.
Numerous diseases mimic appendicitis, and it is often difficult to rule it out on the basis of clinical presentation. Concentration of procalcitonin selectively increases in inflammatory conditions and determination of its level can help in the diagnosis of acute appendicitis. A prospective, single centre based observational study carried out at our tertiary care institute. Twenty eight patients were admitted with preliminary diagnosis of acute appendicitis. The control group involved around 12 healthy children. Serum Procalcitonin concentration was measured in all patients using the ‘Immunoluminometric Method’ (LUMI- Test PCT), besides carrying out clinical examination and other investigations. The serums PCT comes out to be a better diagnostic test than serum CRP measurement as serum PCT was able to differentiate patients who came with abdominal pain but were having normal appendix from the patients who were actual cases of acute appendicitis. In patients with histologically confirmed acute appendicitis the level of PCT was above the normal value of 0.5 ng/ml in most cases. The analysis of procalcitonin in different groups of patients showed the serum procalcitonin test having high sensitivity of 95.65% and a specificity of about 100% on the basis of histopathological diagnosis of the removed appendix taking as the standard. The serum procalcitonin test when combined with reliable clinical signs and symptoms is an excellent diagnostic marker of the disease and should be done in the patients of pediatric appendicitis so that proper handling of the patient can be done and we can prevent unnecessary appendectomies.
PMCID: PMC3077170  PMID: 22468064
Procalcitonin; Appendicitis; Diagnosis
22.  Integrated clinical-ultrasonographic diagnosis in acute appendicitis 
Journal of Ultrasound  2007;10(4):175-178.
Acute appendicitis is one of the commonest diseases encountered in the field of emergency surgery. If untreated, it can rapidly develop severe complications such as perforation and peritonitis. Surgeons therefore often choose early surgical treatment also when the diagnosis is only probable, facing the risk of performing an elevated amount of unnecessary appendectomies. The aim of this study is to analyse our experience with integrated clinical-ultrasonographic diagnosis in acute appendicitis.
Material and methods
From January 1999 to December 2006, 1447 patients underwent clinical examination, leucocyte count, evaluation of C-reactive protein level, and abdominal ultrasonography using graded compression technique and a high frequency probe.
In 368 patients (25%) ultrasonographic diagnosis was acute appendicitis; 8 patients were operated on the basis of clinical evaluation only. Ultrasonography yielded false positive results in 7 cases. In 1079 patients (75%) diagnosis was negative for acute appendicitis; 173 of these patients (12%) received a different diagnosis. The remaining 906 patients underwent clinical follow-up until the symptoms disappeared; there were no complications. In our study, sensitivity of ultrasonography was 98%, specificity 99%, positive predictive value 98%, and negative predictive value 99%. Overall diagnostic accuracy was 99%.
Integrated diagnosis of acute appendicitis based on clinical evaluation, laboratory tests and ultrasonography is safe and saves resources by preventing unnecessary operations.
PMCID: PMC3553179  PMID: 23396678
Ultrasonography; Acute appendicitis
23.  Risk factors of converting to laparotomy in laparoscopic appendectomy for acute appendicitis 
Laparoscopic appendectomy (LA) for acute appendicitis has several advantages over open appendectomy (OA). In cases of complicated appendicitis, LA is converted to OA at a constant rate, though converting appendectomy (CA) has several disadvantages. We retrospectively determined preoperative risk factors for failure of LA and subsequent conversion to OA.
Consecutive cases of preoperative computed tomography (CT) and attempted LA were retrieved from our hospital database and grouped by procedure (LA versus CA). Patients with negative appendectomies (n = 28), opened appendectomy (n = 210), delayed interval appendectomy (n = 3), or who were <14 years of age were excluded.
Average patient age, preoperative C-reactive protein (CRP) level, and diffuse peritonitis were significantly different between the groups. CT inflammation and occurrence of complicated appendicitis were significantly higher in CA than LA. Conversion to OA was mostly because of dense adhesions, diffuse peritonitis, and difficulties in excision of the appendix due to perforation or severe inflammation from surgical point of view. Postoperative complications were significantly lower in LA than CA, although the rate of intraoperative abscess was not different.
Most patients with acute appendicitis can be successfully treated with LA. We identified the following significant risk factors of CA: CT inflammation grade 4 or 5; complicated appendicitis; higher preoperative CRP level; and diffuse peritonitis.
PMCID: PMC3706257  PMID: 23869174
laparotomy; laparoscopic appendectomy; acute appendicitis
24.  Bedside Ultrasonography as an Adjunct to Routine Evaluation of Acute Appendicitis in the Emergency Department 
Appendicitis is a common condition presenting to the emergency department (ED). Increasingly emergency physicians (EP) are using bedside ultrasound (BUS) as an adjunct diagnostic tool. Our objective is to investigate the test characteristics of BUS for the diagnosis of appendicitis and identify components of routine ED workup and BUS associated with the presence of appendicitis.
Patients four years of age and older presenting to the ED with suspected appendicitis were eligible for enrollment. After informed consent was obtained, BUS was performed on the subjects by trained EPs who had undergone a minimum of one-hour didactic training on the use of BUS to diagnose appendicitis. They then recorded elements of clinical history, physical examination, white blood cell count (WBC) with polymophonuclear percentage (PMN), and BUS findings on a data form. We ascertained subject outcomes by a combination of medical record review and telephone follow-up.
A total of 125 subjects consented for the study, and 116 had adequate image data for final analysis. Prevalence of appendicitis was 40%. Mean age of the subjects was 20.2 years, and 51% were male. BUS was 100% sensitive (95% CI 87–100%) and 32% specific (95% CI 14–57%) for detection of appendicitis, with a positive predictive value of 72% (95% CI 56–84%), and a negative predictive value of 100% (95% CI 52–100%). Assuming all non-diagnostic studies were negative would yield a sensitivity of 72% and specificity of 81%. Subjects with appendicitis had a significantly higher occurrence of anorexia, nausea, vomiting, and a higher WBC and PMN count when compared to those without appendicitis. Their BUS studies were significantly more likely to result in visualization of the appendix, appendix diameter >6mm, appendix wall thickness >2mm, periappendiceal fluid, visualization of the appendix tip, and sonographic Mcburney’s sign (p<0.05). In subjects with diagnostic BUS studies, WBC, PMN, visualization of appendix, appendix diameter >6mm, appendix wall thickness >2mm, periappendiceal fluid were found to be predictors of appendicitis on logistic regression.
BUS is moderately useful for appendicitis diagnosis. We also identified several components in routine ED workup and BUS that are associated with appendicitis generating hypothesis for future studies.
PMCID: PMC4251223  PMID: 25493122
25.  Hyperbilirubinemia Is a Significant Indicator for the Severity of Acute Appendicitis 
This study aims to reveal more effective clinical or laboratory markers for the diagnosis of acute appendicitis and to score the severity based on a sufficiently large number of patients with acute appendicitis.
We identified 1,195 patients with acute appendicitis after excluding those with other causes of hyperbilirubinemia among the 1,271 patients that underwent a laparoscopic or an open appendectomy between 2009 and 2010. A retrospective chart review of the medical records, including laboratory and histologic results, was conducted. We then analyzed the data using univariate and multivariate analyses.
Among the 1,195 patients, a laparoscopic appendectomy was performed in 685 cases (57.32%), and an open appendectomy was performed in 510 cases (42.68%). The univariate analysis demonstrated significant differences for white blood cell count (P < 0.0001), segmented neutrophils (P = 0.0035), total bilirubin (P < 0.0001), and systemic inflammatory response syndrome (SIRS) score between groups (P < 0.0001). The multivariate analysis demonstrated that total bilirubin (odds ratio, 1.772; 95% confidence interval, 1.320 to 2.379; P = 0.0001) and SIRS score (odds ratio, 1.583; 95% confidence interval, 1.313 to 1.908; P < 0.0001) have statistically significant diagnostic value for perforated appendicitis.
Hyperbilirubinemia is a statistically significant diagnostic marker for acute appendicitis and the likelihood of perforation.
PMCID: PMC3499425  PMID: 23185704
Appendicitis; Appendicitis, Perforated; Appendectomy; Hyperbilirubinemia

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