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1.  Pancreatic stone protein (PSP) and pancreatitis-associated protein (PAP): a protocol of a cohort study on the diagnostic efficacy and prognostic value of PSP and PAP as postoperative markers of septic complications in patients undergoing abdominal surgery (PSP study) 
BMJ Open  2014;4(3):e004914.
Introduction
Major abdominal surgery leads to a postoperative systemic inflammatory response, making it difficult to discriminate patients with systemic inflammatory response syndrome from those with a beginning postoperative infectious complication. At present, physicians have to rely on their clinical experience to differentiate between the two. Pancreatic stone protein (PSP) and pancreatitis-associated protein (PAP), both secretory proteins produced by the pancreas, are dramatically increased during pancreatic disease and have been shown to act as acute-phase proteins. Increased levels of PSP have been detected in polytrauma patients developing sepsis and PSP has shown a high diagnostic accuracy in discriminating the severity of peritonitis and in predicting death in intensive care unit patients. However, the prognostic value of PSP/PAP for infectious complications among patients undergoing major abdominal surgery is unknown.
Methods and analysis
160 patients undergoing major abdominal surgery will be recruited preoperatively. On the day before surgery, baseline blood values are attained. Following surgery, daily blood samples for measuring regular inflammatory markers (c-reactive protein, procalcitonin, interleukin-6, tumour necrosis factor-α and leucocyte counts) and PSP/PAP will be acquired. PSP/PAP will be measured using a validated ELISA developed in our research laboratory. Patient's discharge marks the end of his/her trial participation. Complication grade including mortality and occurrence of infectious postoperative complications according to validated diagnostic criteria will be correlated with PSP/PAP values. Total intensive care unit days and total length of stay will be recorded as further outcome parameters.
Ethics and dissemination
The PSP trial is a prospective monocentric cohort study evaluating the prognostic value of PSP and PAP for postoperative infectious complications. In addition, a comparison with established inflammatory markers in patients undergoing major abdominal surgery will be performed to help evaluate the role of these proteins in predicting and diagnosing infectious and other postoperative complications.
Institution ethics board approval ID
KEKZH-Nr. STV 11-2009.
Trial registration
ClinicalTrials.gov: NCT01258179.
doi:10.1136/bmjopen-2014-004914
PMCID: PMC3948573  PMID: 24604486
2.  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.
Background
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.
Methods/design
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
ClinicalTrials.gov 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.
doi:10.1136/bmjopen-2010-000006
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
3.  Optimizing imaging in suspected appendicitis (OPTIMAP-study): A multicenter diagnostic accuracy study of MRI in patients with suspected acute appendicitis. Study Protocol 
Background
In patients with clinically suspected appendicitis, imaging is needed to substantiate the clinical diagnosis. Imaging accuracy of ultrasonography (US) is suboptimal, while the most accurate technique (CT) is associated with cancer related deaths through exposure to ionizing radiation. MRI is a potential replacement, without associated ionizing radiation and no need for contrast medium administration. If MRI is proven to be sufficiently accurate, it could be introduced in the diagnostic pathway of patients with suspected appendicitis, increasing diagnostic accuracy and improving clinical outcomes, without the risk of radiation induced cancer or iodinated contrast medium-related drawbacks. The multicenter OPTIMAP study was designed to estimate the diagnostic accuracy of MRI in patients with suspected acute appendicitis in the general population.
Methods/Design
Eligible for this study are consecutive patients presenting with clinically suspected appendicitis at the emergency department in six centers. All patients will undergo imaging according to the Dutch guideline for acute appendicitis: initial ultrasonography in all and subsequent CT whenever US does not confirm acute appendicitis. Then MRI is performed in all patients, but the results are not used for patient management. A final diagnosis assigned by an expert panel, based on all available information including 3-months follow-up, except MRI findings, is used as the reference standard in estimating accuracy. We will calculate the sensitivity, specificity, predictive values and inter-observer agreement of MRI, and aim to include 230 patients. Patient acceptance and total imaging costs will also be evaluated.
Discussion
If MRI is found to be sufficiently accurate, it could replace CT in some or all patients. This will limit or obviate the ionizing radiation exposure associated risk of cancer induction and contrast medium induced nephropathy with CT, preventing the burden and the direct and indirect costs associated with treatment. Based on the high intrinsic contrast resolution of MRI, one might envision higher accuracy rates for MRI than for CT. If so, MRI could further decrease the number of unnecessary appendectomies and the number of missed appendicitis cases.
Trial registration
NTR2148
doi:10.1186/1471-227X-10-19
PMCID: PMC2978143  PMID: 20961412
4.  Clinical presentation of acute appendicitis in adults at the Chris Hani Baragwanath academic hospital 
Background
Acute appendicitis is the most common surgical abdominal emergency. Delayed treatment increases the incidence of complications. The aim of this study was to investigate the presentation, incidence, and predictors of complications, and histological findings in adult patients with clinical diagnosis of acute appendicitis.
Methods
The study was a prospective observational study and included patients aged 12 years and older diagnosed with acute appendicitis. Data collected included demographic data, clinical presentation, duration of symptoms and reasons for presentation delay, diagnostic investigations, operative and histology findings, length of hospital stay, and mortality.
Results
A total of 146 patients were admitted with a mean age of 26 years (SD = 12 years). The male to female ratio was 1.6:1. Predominant presenting symptoms were right iliac fossa pain (95%), nausea (80%), and vomiting (73%), with 63% of patients presenting 2 days after onset of symptoms. Fever was present in 15% and only 31% of patients gave a typical history of acute appendicitis of vague peri-umbilical pain. The negative predictive values of white cell count and C-reactive protein for acute appendicitis were 28% and 50%, respectively. Sensitivity of the ultrasound to detect acute appendicitis was 60% with a negative predictive value of 31%; 30% of patients had complicated appendicitis. Histology results showed a normal appendix in 11% of patients. The 30-day mortality rate was 1.4%.
Conclusions
Patients with acute appendicitis rarely present with a typical history of vague peri-umbilical pain. The negative predictive values of both white cell count and ultrasound proved that neither of these measurements was accurate in the diagnosis of acute appendicitis. Most of our patients with complicated disease present late, with the most common reasons for this delay being lack of access to a medical clinics and prior treatment by general practitioners. Complications were higher in males and in those aged 45 years and above.
doi:10.1186/1865-1380-7-12
PMCID: PMC3938026  PMID: 24533851
Acute appendicitis; Complications; Delayed presentation; Negative appendicectomy
5.  Quantitative Measurement of Elasticity of the Appendix Using Shear Wave Elastography in Patients with Suspected Acute Appendicitis 
PLoS ONE  2014;9(7):e101292.
Introduction
Shear wave elastography (SWE) has not been studied for diagnosing appendicitis. We postulated that an inflamed appendix would become stiffer than a normal appendix. We evaluated the elastic modulus values (EMV) by SWE in healthy volunteers, patients without appendicitis, and patients with appendicitis. We also evaluated diagnostic ability of SWE for differentiating an inflamed from a normal appendix in patients with suspected appendicitis.
Materials and Methods
Forty-one patients with clinically suspected acute appendicitis and 11 healthy volunteers were prospectively enrolled. Gray-scale ultrasonography (US), SWE and multi-slice computed tomography (CT) were performed. The EMV was measured in the anterior, medial, and posterior appendiceal wall using SWE, and the highest value (kPa) was recorded.
Results
Patients were classified into appendicitis (n = 30) and no appendicitis groups (n = 11). One case of a negative appendectomy was detected. The median EMV was significantly higher in the appendicitis group (25.0 kPa) compared to that in the no appendicitis group (10.4 kPa) or in the healthy controls (8.3 kPa) (p<0.001). Among SWE and other US and CT features, CT was superior to any conventional gray-scale US feature or SWE. Either the CT diameter criterion or combined three CT features predicted true positive in 30 and true negative in 11 cases and yielded 100% sensitivity and 100% specificity. An EMV of 12.5 kPa for the stiffest region of the appendix predicted true positive in 28, true negative in 11, and false negative in two cases. The EMV (≥12.5 kPa) yielded 93% sensitivity and 100% specificity.
Conclusion
Our results suggest that EMV by SWE helps distinguish an inflamed from a normal appendix. Given that SWE has high specificity, quantitative measurement of the elasticity of the appendix may provide complementary information, in addition to morphologic features on gray-scale US, in the diagnosis of appendicitis.
doi:10.1371/journal.pone.0101292
PMCID: PMC4106760  PMID: 25051242
6.  High mobility group box protein-1 (HMGB-1) as a new diagnostic marker in patients with acute appendicitis 
Background
The aim of this prospective study was therefore to evaluate the diagnostic value of preoperative serum High Mobility Group Box Protein-1 (HMGB-1) levels in patients with Acute Appendicitis (AA) who show normal white blood cell count (WBC) counts.
Method
Our study was carried out from October 2010 through November 2010 and included 20 healthy control group participants and 60 patients who presented at the emergency department of Erzurum Training and Research Hospital in Turkey with acute abdominal pain complaints, who were pathologically diagnosed with AA after laparotomy, and who agreed to participate in the study.
Results
Of the 60 patients who underwent appendectomies, 36 were male and 24 were female, and of the healthy group, 12 were male and 8 female. The age averages of the patients in Groups 1, 2 and 3 were, respectively, 31.3+15.4, 34.0+16.3 and 31.0+13.1 years. The WBC averages of Groups 1, 2 and 3 were, respectively, 7.41+2.02 (x109/L), 15.71+2.85 (x109/L) and 8.51+1.84 (x109/L). The HMGB-1 levels for Groups 1 (healthy persons), 2 (AA patients with high WBC counts ) and 3 (AA patients with normal WBC counts) were, respectively, 21.71 ± 11.36, 37.28+13.37 and 36.5 ± 17.73 ng/ml. The average HMGB-1 level of the patients with AA was 36.92 ± 15.43 ng/ml while the average HMGB-1 value of the healthy group was 21.71 ± 11.36 ng/ml.
Conclusion
The significantly higher levels of HMGB-1 in AA patients compared to healthy persons infer that HMGB-1 might be useful in the diagnosis of AA. Use of HMGB-1, especially in patients with normal WBC counts, will reduce the number of unnecessary explorations.
doi:10.1186/1757-7241-19-27
PMCID: PMC3094252  PMID: 21507210
7.  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.
doi:10.1007/s12262-010-0214-1
PMCID: PMC3077170  PMID: 22468064
Procalcitonin; Appendicitis; Diagnosis
8.  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.
doi:10.7150/ijms.4733
PMCID: PMC3520016  PMID: 23236260
Appendicitis; D-dimer; Procalcitonin; C-reactive protein.
9.  The Usefulness of Procalcitonin in the Diagnosis of Appendicitis in Children: A Pilot Study 
Objective. To assess the predictive value of procalcitonin in detecting acute appendicitis (AP) in children, and to determine a cutoff value of procalcitonin which can safely include/exclude the diagnosis of acute appendicitis in children with acute abdominal pain. Methods. Prospective cohort study of children aged 5–17 years presenting to the emergency room with right lower quadrant (RLQ) tenderness and strong suspicion for acute AP. In addition to standard diagnostic workup for acute AP, a quantitative procalcitonin level was measured using immunoluminometric assay. Recursive partitioning model was used to assess the usefulness of procalcitonin in the diagnosis of appendicitis. Results. Of the 50 children studied, 48% were diagnosed to have AP. The mean procalcitonin level was higher among the children with appendicitis (P = 0.3). Using the recursive partitioning model, we identified a cutoff value of procalcitonin level of 0.39 with a likelihood ratio presence of appendicitis 3.25 and absence of appendicitis 0.8. None of the study subjects with procalcitonin level <0.39 and WBC count of <6.76 K had appendicitis. Conclusions. In conjunction with the clinical symptoms, a procalcitonin level and WBC count could be a strong predictor of acute appendicitis in children.
doi:10.1155/2012/317504
PMCID: PMC3529464  PMID: 23304513
10.  Clinical value of total white blood cells and neutrophil counts in patients with suspected appendicitis: retrospective study 
Introduction
Acute appendicitis (AA) is common surgical problem associated with acute-phase reaction. Blood tests role in decision-making process is unclear. This retrospective study aimed to determine diagnostic value of preoperative evaluation of white blood cells (WBCs) and neutrophils and its value in predicting AA severity.
Methods
Medical records of 456 patients who underwent appendectomy during 4-years period were retrospectively reviewed. Patients were subdivided according to histological finding into: normal appendix (n = 29), uncomplicated inflamed appendix (n = 350), complicated appendicitis (n = 77). Diagnostic performances of WBCs and neutrophils were analyzed using receiver operating characteristic (ROC) curves.
Results
WBCs and neutrophils counts were higher in patients with inflamed and complicated appendix than normal appendix and in complicated than inflamed appendix. In patients, WBCs count 9.400 × 103/mL had sensitivity of 76.81%, specificity of 65.52%, positive predictive value (PPV) of 97.0%, negative predictive value (NPV) of 16.1%, positive likelihood ratio [LR(+)] of 2.23, negative LR(−) of 0.35. Neutrophil count 7.540 × 103/mL had sensitivity of 70.96%, specificity of 65.52%, PPV of 96.8%, NPV of 13.3%, LR(+) of 2.06, LR(−) of 0.44. Areas under ROC curve were 0.701, 0.680 for elevated WBCs and neutrophils count.
Conclusions
Clinicians should not rely on either elevated WBCs or neutrophils count as appendicitis indicator as clinical data are superior in decision-making appendectomy.
doi:10.1186/1749-7922-7-32
PMCID: PMC3502286  PMID: 23031349
Acute appendicitis; Diagnosis; White blood cells; Histological diagnosis; Neutrophil count; Receiver operating characteristic curves
11.  Correlation of serum C-reactive protein, white blood count and neutrophil percentage with histopathology findings in acute appendicitis 
Background
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.
Results
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.
Conclusion
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.
doi:10.1186/1749-7922-7-27
PMCID: PMC3469372  PMID: 22866907
Acute appendicitis; CRP correlation; White blood count; Neutrophil percentage; Histopathology findings
12.  A hybrid decision support model to discover informative knowledge in diagnosing acute appendicitis 
Background
The aim of this study is to develop a simple and reliable hybrid decision support model by combining statistical analysis and decision tree algorithms to ensure high accuracy of early diagnosis in patients with suspected acute appendicitis and to identify useful decision rules.
Methods
We enrolled 326 patients who attended an emergency medical center complaining mainly of acute abdominal pain. Statistical analysis approaches were used as a feature selection process in the design of decision support models, including the Chi-square test, Fisher's exact test, the Mann-Whitney U-test (p < 0.01), and Wald forward logistic regression (entry and removal criteria of 0.01 and 0.05, or 0.05 and 0.10, respectively). The final decision support models were constructed using the C5.0 decision tree algorithm of Clementine 12.0 after pre-processing.
Results
Of 55 variables, two subsets were found to be indispensable for early diagnostic knowledge discovery in acute appendicitis. The two subsets were as follows: (1) lymphocytes, urine glucose, total bilirubin, total amylase, chloride, red blood cell, neutrophils, eosinophils, white blood cell, complaints, basophils, glucose, monocytes, activated partial thromboplastin time, urine ketone, and direct bilirubin in the univariate analysis-based model; and (2) neutrophils, complaints, total bilirubin, urine glucose, and lipase in the multivariate analysis-based model. The experimental results showed that the model with univariate analysis (80.2%, 82.4%, 78.3%, 76.8%, 83.5%, and 80.3%) outperformed models using multivariate analysis (71.6%, 69.3%, 73.7%, 69.7%, 73.3%, and 71.5% with entry and removal criteria of 0.01 and 0.05; 73.5%, 66.0%, 80.0%, 74.3%, 72.9%, and 73.0% with entry and removal criteria of 0.05 and 0.10) in terms of accuracy, sensitivity, specificity, positive predictive value, negative predictive value, and area under ROC curve, during a 10-fold cross validation. A statistically significant difference was detected in the pairwise comparison of ROC curves (p < 0.01, 95% CI, 3.13-14.5; p < 0.05, 95% CI, 1.54-13.1). The larger induced decision model was more effective for identifying acute appendicitis in patients with acute abdominal pain, whereas the smaller induced decision tree was less accurate with the test data.
Conclusions
The decision model developed in this study can be applied as an aid in the initial decision making of clinicians to increase vigilance in cases of suspected acute appendicitis.
doi:10.1186/1472-6947-12-17
PMCID: PMC3314559  PMID: 22410346
Hybrid decision support model; Acute appendicitis; Knowledge discovery; Decision tree; Logistic regression analysis
13.  Diagnostic values of ultrasound and the Modified Alvarado Scoring System in acute appendicitis 
Background
Making the diagnosis of acute appendicitis is difficult, and is important for preventing perforation of the appendix and negative appendectomy results. Ultrasound and clinical scoring systems are very helpful in making the diagnosis. Ultrasound is non-invasive, available and cost-effective, and can accomplish more than CT scans. However, there is no certainty about its effect on the clinical outcomes of patients, and it is operator dependent. Counting the neutrophils as a parameter of the Alvarado Scale is not routine in many laboratories, so we decided to evaluate the diagnostic value of the Modified Alvarado Scaling System (MASS) by omitting the neutrophil count and ultrasonography.
Methods
After ethical approval of methodology in Tehran University of Medical Sciences ethical committee, we collected the data. During 9 months, 75 patients with right lower quadrant pain were enrolled in the study, and underwent abdominal ultrasonography and appendectomy, with pathological evaluation of the appendix. The MASS score was calculated for these patients and compared with pathology results.
Results
Fifty-five male and 20 female patients were assessed. Of these patients 89.3% had acute appendicitis. The sensitivity, specificity, PPV, NPV and accuracy rate of ultrasonography was 71.2%, 83.3%, 97.4%, 25% and 72.4%, respectively. By taking a cutoff point of 7 for the MASS score, a sensitivity of 65.7%, specificity of 37.5%, PPV of 89.8%, NPV of 11.5% and accuracy of 62.7% were calculated. Using the cutoff point of 6, a sensitivity of 85.1%, specificity of 25%, PPV of 90.5%, NPV of 16.7% and accuracy of 78.7% were obtained.
Conclusion
Ultrasound provides reliable findings for helping to diagnose acute appendicitis in our hospital. A cutoff point of 6 for the MASS score will yield more sensitivity and a better diagnosis of appendicitis, though with an increase in negative appendectomy.
doi:10.1186/1865-1380-5-26
PMCID: PMC3410771  PMID: 22673121
Appendicitis; Ultrasonography; Modified Alvarado Scoring System (MASS)
14.  Validation and Refinement of a Prediction Rule to Identify Children at Low Risk for Acute Appendicitis 
Objective
To validate and refine a clinical prediction rule to identify which children with acute abdominal pain are at low risk for appendicitis (Low Risk Appendicitis Rule).
Design
Prospective, multi-center cross-sectional study.
Setting
Ten pediatric hospital emergency departments.
Participants
Children 3–18 years old who presented with suspected appendicitis from May 2009 – April 2010.
Main Outcome Measures
The test performance of the Low Risk Appendicitis Rule.
Results
Among 2625 patients enrolled, 1018 (38.8%; 95% confidence interval [CI] 36.9% – 40.7%) had appendicitis. Validation of the rule resulted in a sensitivity of 95.5% (95% CI 93.9 – 96.7%), specificity of 36.3% (33.9 – 38.9%) and negative predictive value (NPV) of 92.7% (90.1 – 94.6%). Theoretical application would have identified 573 (24%) as low risk, misclassifying 42 patients (4.5%; 95% CI 3.4% – 6.1%) with appendicitis. We refined the prediction rule, resulting in a model that identified patients at low risk if: a) absolute neutrophil count (ANC) ≤ 6.75 × 103/µL and no maximal tenderness in right lower quadrant (RLQ) or b) ANC ≤ 6.75 × 103/µL, maximal tenderness in the RLQ but no abdominal pain with walking/jumping or coughing. This refined rule had a sensitivity of 98.1% (97.0 – 98.9%), specificity of 23.7% (21.7 – 25.9%) and NPV of 95.3% (92.3 – 97.0%).
Conclusions
We have validated and refined a simple clinical prediction rule for pediatric appendicitis. For patients identified as low risk, clinicians should consider alternative strategies such as observation or ultrasound, rather than proceed to immediate imaging with CT.
doi:10.1001/archpediatrics.2012.490
PMCID: PMC3790639  PMID: 22869405
Appendicitis; Clinical prediction rules
15.  Discriminative Accuracy of Novel and Traditional Biomarkers in Children with Suspected Appendicitis Adjusted for Duration of Abdominal Pain 
Objectives
To assess the accuracy of novel and traditional biomarkers in patients with suspected appendicitis as a function of duration of symptoms.
Methods
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.
Results
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.
Conclusions
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.
doi:10.1111/j.1553-2712.2011.01095.x
PMCID: PMC3117273  PMID: 21676053
16.  Acute appendicitis in minority communities: an epidemiologic study. 
This study examines the incidence and epidemiological factors of acute appendicitis in various ethnic groups in an urban minority community. The charts of 278 consecutive patients who underwent appendectomy at The Bronx-Lebanon Hospital Center, Bronx, New York, between January 1988 and December 1990 were reviewed. Thirty-eight patients who underwent incidental appendectomy and one patient who had an interval appendectomy were excluded. The remaining 239 patients, all of whom had acute appendicitis, constituted the study population. The incidence of appendicitis for each ethnic group was calculated as a percentage of the total emergency surgical admissions for that group. Acute appendicitis constituted 3.1% of all emergency admissions to the surgical service over the period studied and represented 4.5% of surgical service admissions from the emergency department in Hispanics, 1.9% in African Americans, 1.5% in whites, and 21% in Asians. These differences were statistically significant except some comparisons involving whites. There were no significant differences in the pathological findings regarding the diseased appendix in different racial groups. These results indicate that acute appendicitis is responsible for a higher incidence of emergency admissions among Hispanics than among African Americans. This finding was statistically significant. High white blood cell counts indicated inflammation of the appendix, but had no predictive value for the type of pathology. Surgical findings were similar in all groups.
PMCID: PMC2608236  PMID: 9094841
17.  Diagnostic value of blood inflammatory markers for detection of acute appendicitis in children 
BMC Surgery  2006;6:15.
Background
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.
Methods
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.
Results
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.
Conclusion
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.
doi:10.1186/1471-2482-6-15
PMCID: PMC1712352  PMID: 17132173
18.  Bedside Ultrasonography as an Adjunct to Routine Evaluation of Acute Appendicitis in the Emergency Department 
Introduction
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.
Methods
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.
Results
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.
Conclusion
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.
doi:10.5811/westjem.2014.9.21491
PMCID: PMC4251223  PMID: 25493122
19.  Acute appendicitis: does removal of a normal appendix matter, what is the value of diagnostic accuracy and is surgical delay important? 
A prospective study with long-term follow-up was undertaken of 248 patients (137 males, median age 18 years (range 6-81 years), undergoing emergency appendicectomy during a 12-month period. Acute inflammation was present in 182 patients (73.4%) (males 86.1%, females 57.8%; P < 0.001). Before surgery, the positive predictive value of diagnostic accuracy was 82.0% (males 91.2%, females 67.7%). Delaying surgery did not significantly increase the proportion of perforated appendices (22.0%), hospital stay, or frequency of postoperative complications (overall 49.6%). Hospital complications were significantly more common among patients with a perforated appendix. There was no significant difference in the complication rate between patients with or without appendicitis while in hospital, during the first 18 months after operation or 8 years after operation. At 18 months, 17 of 238 patients (7.1%) continued to experience their original pain. After 8 years the original pain was still present in 10 of 155 patients (6.5%). Continued pain was more likely in patients having undergone removal of a normal appendix (P < 0.001)
PMCID: PMC2502408  PMID: 7486763
20.  Accuracy of the new radiographic sign of fecal loading in the cecum for differential diagnosis of acute appendicitis in comparison with other inflammatory diseases of right abdomen: a prospective study  
Journal of Medicine and Life  2012;5(1):85-91.
Rationale: To assess the importance of the new radiographic sign of faecal loading in the cecum for the diagnosis of acute appendicitis, in comparison with other inflammatory diseases, and to verify the maintenance of this radiographic sign after surgical treatment of appendicitis.
Methods: 470 consecutive patients admitted to the hospital due to acute abdomen were prospectively studied: Group 1 [n=170] – diagnosed with acute appendicitis, subdivided into: Subgroup 1A – [n=100] – submitted to an abdominal radiographic study before surgical treatment, Subgroup 1B – [n=70] – patients who had plain abdominal X-rays done before the surgical procedure and also the following day; Group 2 [n=100] – right nephrolithiasis; Group 3 [n=100] – right acute inflammatory pelvic disease; Group 4 [n=100] – acute cholecystitis. The patients of Groups 2,3 and 4 were submitted to abdominal radiography during the pain episode.
Results: The sign of faecal loading in the cecum, characterized by hypo transparency interspersed with multiple small foci of hyper transparent images, was present in 97 patients of Subgroup 1A, in 68 patients of Subgroup 1B, in 19 patients of Group 2, in 12 patients of Group 3 and in 13 patients of Group 4. During the postoperative period the radiographic sign disappeared in 66 of the 68 cases that had presented with the sign. The sensitivity of the radiographic sign for acute appendicitis was 97.05% and its specificity was 85.33%. The positive predictive value for acute appendicitis was 78.94% and its negative predictive value was 98. 08%.
Discussion: The radiographic image of faecal loading in the cecum is associated with acute appendicitis and disappears after appendectomy. This sign is uncommon in other acute inflammatory diseases of the right side of the abdomen.
PMCID: PMC3307086  PMID: 22574093
Appendicitis; Acute abdomen; Radiography; Cecum; Fecal loading
21.  Normal inflammatory markers in appendicitis: evidence from two independent cohort studies 
JRSM Short Reports  2011;2(5):43.
Objectives
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.
Design
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.
Setting
Two district general hospitals in the UK.
Participants
Patients undergoing appendicectomy for suspected appendicitis.
Main outcome measures
Inflammatory markers and appendix histology.
Results
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.
Conclusions
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.
doi:10.1258/shorts.2011.010114
PMCID: PMC3105453  PMID: 21637404
22.  A Prospective Bicenter Study Investigating the Diagnostic Value of Procalcitonin in Patients with Acute Appendicitis 
Background
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.
Methods
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.
Results
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.
Conclusions
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.
doi:10.1159/000232939
PMCID: PMC2790741  PMID: 19672084
Procalcitonin; Appendicitis; Diagnostic
23.  Extensive retroperitoneal and right thigh abscess in a patient with ruptured retrocecal appendicitis: An extremely fulminant form of a common disease 
As a disease commonly encountered in daily practice, acute appendicitis is usually diagnosed and managed easily with a low mortality and morbidity rate. However, acute appendicitis may occasionally become extraordinarily complicated and life threatening. A 56-year-old man, healthy prior to this admission, was brought to the hospital due to spiking high fever, poor appetite, dysuria, progressive right flank and painful swelling of the thigh for 3 d. Significant inflammatory change of soft tissue was noted, involving the entire right trunk from the subcostal margin to the knee joint. Painful disability of the right lower extremity and apparent signs of peritonitis at the right lower abdomen were disclosed. Laboratory results revealed leukocytosis and an elevated C-reactive protein level. Abdominal CT revealed several communicated gas-containing abscesses at the right retroperitoneal region with mass effect, pushing the duodenum and the pancreatic head upward, compressing and encasing inferior vena cava, destroying psoas muscle and dissecting downward into the right thigh. Laparotomy and right thigh exploration were performed immediately and about 500 mL of frank pus was drained. A ruptured retrocecal appendix was the cause of the abscess. The patient fully recovered at the end of the third post-operation week. This case reminds us that acute appendicitis should be treated carefully on an emergency basis to avoid serious complications. CT scan is the diagnostic tool of choice, with rapid evaluation followed by adequate drainage as the key to the survival of the patient.
doi:10.3748/wjg.v12.i3.496
PMCID: PMC4066078  PMID: 16489659
Acute appendicitis; Retrocecal appendicitis; Complication; Retroperitoneal abscess; Thigh abscess
24.  Diagnostic accuracy of white cell count and C-reactive protein for assessing the severity of paediatric appendicitis 
JRSM Short Reports  2011;2(7):59.
Objectives
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.
Design
Cross-sectional study.
Setting
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.
Participants
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.
Results
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.
Conclusion
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.
doi:10.1258/shorts.2011.011025
PMCID: PMC3147235  PMID: 21847441
25.  Pancreatic stone protein as an early biomarker predicting mortality in a prospective cohort of patients with sepsis requiring ICU management 
Critical Care  2012;16(4):R114.
Introduction
Biomarkers, such as C-reactive protein [CRP] and procalcitonin [PCT], are insufficiently sensitive or specific to stratify patients with sepsis. We investigate the prognostic value of pancreatic stone protein/regenerating protein (PSP/reg) concentration in patients with severe infections.
Methods
PSP/reg, CRP, PCT, tumor necrosis factor-alpha (TNF-α), interleukin 1 beta (IL1-β), IL-6 and IL-8 were prospectively measured in cohort of patients ≥ 18 years of age with severe sepsis or septic shock within 24 hours of admission in a medico-surgical intensive care unit (ICU) of a community and referral university hospital, and the ability to predict in-hospital mortality was determined.
Results
We evaluated 107 patients, 33 with severe sepsis and 74 with septic shock, with in-hospital mortality rates of 6% (2/33) and 25% (17/74), respectively. Plasma concentrations of PSP/reg (343.5 vs. 73.5 ng/ml, P < 0.001), PCT (39.3 vs. 12.0 ng/ml, P < 0.001), IL-8 (682 vs. 184 ng/ml, P < 0.001) and IL-6 (1955 vs. 544 pg/ml, P < 0.01) were significantly higher in patients with septic shock than with severe sepsis. Of note, median PSP/reg was 13.0 ng/ml (IQR: 4.8) in 20 severely burned patients without infection. The area under the ROC curve for PSP/reg (0.65 [95% CI: 0.51 to 0.80]) was higher than for CRP (0.44 [0.29 to 0.60]), PCT 0.46 [0.29 to 0.61]), IL-8 (0.61 [0.43 to 0.77]) or IL-6 (0.59 [0.44 to 0.75]) in predicting in-hospital mortality. In patients with septic shock, PSP/reg was the only biomarker associated with in-hospital mortality (P = 0.049). Risk of mortality increased continuously for each ascending quartile of PSP/reg.
Conclusions
Measurement of PSP/reg concentration within 24 hours of ICU admission may predict in-hospital mortality in patients with septic shock, identifying patients who may benefit most from tailored ICU management.
doi:10.1186/cc11406
PMCID: PMC3580689  PMID: 22748193

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