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Diagnostic accuracy of the APPY1 Test in patients aged 2–20 years with suspected acute appendicitis presenting to emergency departments
  1. Juan González del Castillo1,2,
  2. Francisco Javier Ayuso1,
  3. Victoria Trenchs3,
  4. Mikel Martinez Ortiz de Zarate4,
  5. Carmen Navarro5,
  6. Kinda Altali6,
  7. Cristina Fernandez7,
  8. David Huckins8,
  9. Francisco Javier Martín-Sánchez1,2,
  10. representing INFURG-SEMES group
    1. 1Emergency Department, Hospital Universitario Clínico San Carlos, Madrid, Spain
    2. 2Health Research Institute, Hospital Universitario Clínico San Carlos, Madrid, Spain
    3. 3Emergency Department, Hospital Universitario Sant Joan de Deu, Barcelona, Spain
    4. 4Emergency Department, Hospital Universitario de Basurto, Bilbao, Spain
    5. 5Emergency Department, Hospital Universitario Virgen de la Macarena, Sevilla, Spain
    6. 6Pediatric Department, Hospital Universitario Clínico San Carlos, Madrid, Spain
    7. 7Research Unit, Preventive Medicine Department, Hospital Universitario Clínico San Carlos, Madrid, Spain
    8. 8Division of Emergency Medicine, Newton-Wellesley Hospital, Newton, Massachusetts, USA
    1. Correspondence to Dr Juan González del Castillo, Emergency Department, Hospital Universitario Clínico San Carlos, Calle Professor Martín-Lagos s/n, Madrid 28040, Spain; jgonzalezcast{at}gmail.com

    Abstract

    Objective Evaluate the diagnostic accuracy of the APPY1 Test alone and in combination with the Alvarado score (AS) to rule out acute appendicitis (AA) in patients presenting to EDs with abdominal pain suspicious for AA.

    Methodology Observational study in a prospective consecutive cohort including all patients from 2 to 20 years with abdominal pain suggestive of AA in four EDs. The APPY1 Test was performed and AS was calculated to determine risk stratification for each patient.

    Results 321 patients enrolled (mean age 11.8 (SD 3.8) years, 52.0% male), with 32.4% low risk, 23.7% intermediate risk and 43.9% high risk according to the AS. 111 (34.6%) had AA, of whom 1 (0.9%) had a false-negative APPY1 Test result. The APPY1 Test had a sensitivity (Se) of 99.1% (95% CI 94.4% to 99.9%), specificity (Sp) of 32.9% (95% CI 26.6% to 39.7%), negative predictive value (NPV) of 98.6% (95% CI 91.2% to 99.9%) and negative likelihood ratio (LHR−) of 0.03 (0.00 to 0.19) in this population. For patients at low risk by AS, the APPY1 Test had a Se of 100% (95% CI 62.9% to 100%), NPV of 100% (95% CI 91.1% to 100%) and LHR− of 0.0 (not calculable), and for patients at intermediate risk by AS, the APPY1 Test had a Se of 94.4% (95% CI 70.6% to 99.7%), NPV of 94.7% (95% CI 71.9% to 99.7%) and LHR− of 0.18 (0.0 to 1.2), respectively.

    Conclusions APPY1 Test is a potentially useful diagnostic tool to rule out AA in this population, with clinical utility primarily in those patients classified as having low clinical risk of appendicitis according to the AS.

    • abdomen
    • diagnosis
    • paediatrics

    https://doi.org/10.1136/emermed-2015-205259

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      Key messages

      What is already known on this subject?

      • Abdominal pain is one of the leading causes of visits to EDs. The diagnosis of appendicitis is based on clinical and analytical data of classical inflammatory biomarkers, and according to the risk stratification an abdominal imaging study may be performed. Paediatric patients can be a clinical challenge since children present more frequently with atypical clinical manifestations. White blood cells (WBC) and C reactive protein (CRP) values have limited diagnostic accuracy because of their moderate sensitivity. Imaging tests also have limitations. New lines of investigation based on biomarkers are currently being developed with the aim of rapidly, objectively and safely ruling out appendicitis.

      What might this study add?

      • The APPY1 Test uses three individual markers (WBC, CRP and calprotectin) as single separate continuous variables combined into a single value, which is compared with a cut-off for a final result of negative or inconclusive. The present study shows that the APPY1 Test is a useful diagnostic tool to rule out the diagnosis of appendicitis in patients aged 2–20 years presenting with abdominal pain suggestive of appendicitis, particularly in those classified with low clinical risk. The combination of the APPY1 Test and a clinical scoring system (Alvarado score) improves the diagnostic accuracy of the use of Alvarado score alone, which can be translated into safer and more efficient management of this process.

      Introduction

      Abdominal pain is one of the leading causes of visits to EDs.1 Acute appendicitis (AA) is one of the main differential diagnoses to consider in paediatric and adolescent patients,2 ,3 as it represents the most frequent cause of emergency surgery at these ages.4

      The diagnosis of AA in paediatric patients is a clinical challenge even for experienced emergency physicians.5 The Alvarado score (AS) describes eight predictive factors including signs, symptoms and laboratory findings useful in making the diagnosis of AA.6 The clinical history and physical examination may be less useful compared with adults,7 since children present more frequently with atypical clinical manifestations.5 ,8 A recent meta-analysis showed that the white blood cells (WBC) and C reactive protein (CRP) values have limited diagnostic accuracy because of their moderate sensitivity (Se) (62% and 57%, respectively) and dependence on clinical course.9 Imaging tests also have limitations, again being influenced by the time of clinical onset.10 Ultrasound (US) is most useful to confirm AA rather than to exclude it.5 CT is both sensitive and specific but has secondary effects such as the risk of ionising radiation and nephrotoxicity due to the contrast medium.11 ,12 There is also cost associated with these scans.

      New lines of investigation based on biomarkers are currently being developed with the aim of rapidly, objectively and safely ruling out AA at the bedside, thereby reducing the number of imaging tests, inappropriate interventions, unnecessary surgery, time in the ED, hospital admissions, diagnostic errors and possible cases of mal praxis.13

      Calprotectin (S100A8/A9 or MRP 8/14) is an intracellular calcium-binding protein expressed by neutrophils, monocytes, some epithelial cells and keratinocytes, which is key for calcium signal transduction during inflammation.14 Compared with controls, levels of this protein are elevated in patients with AA and showed calprotectin to have a high Se (96%) and low specificity (Sp) (16%).15 ,16 However, the use of this protein alone for the diagnosis of AA has not been demonstrated to be more effective than classical inflammatory markers.15 ,17 A recent observational prospective study which enrolled consecutive subjects with <72 hours of abdominal pain with appendicitis suspected showed that the combination of three markers related to inflammation, WBC, CRP and calprotectin, had a high Se (96.5%), a high negative predictive value (NPV) (96.9%) and a low negative likelihood ratio (LHR– 0.08) for the diagnosis of AA with a low-to-moderate Sp (43.2%).18

      The APPY1 Test uses a multimarker approach that measures calprotectin and CRP concentrations by lateral flow immunoassay and provides qualitative (negative or inconclusive) test result in approximately 20 min upon manually entering WBC into the APPYReader Instrument (Venaxis). With high NPV, the APPY1 Test could be a rapid, safe bedside biomarker panel to rule out AA. Currently, no study has determined the diagnostic accuracy of the APPY1 Test alone or in combination with a risk stratification score for clinical decision making to identify patients at low risk of AA. The main objective of the present study was to evaluate the diagnostic accuracy (Se, NPV and LHR–) of the APPY1 Test to rule out AA in children aged 2–20 years presenting to the ED with abdominal pain with suspicion of AA. The secondary objective was to study the diagnostic accuracy of the APPY1 Test stratified by clinical risk of AA according to the AS and to determine whether the combination of the APPY1 Test with the AS improves the diagnostic accuracy of this clinical scoring system to rule out AA.

      Materials and methods

      Study design and setting

      We performed an observational prospective study consecutively enrolling children and adolescents presenting for abdominal pain suspected of AA in EDs of four Spanish Tertiary Academic Centres (Hospital Clínico San Carlos of Madrid, Hospital de Basurto of Bilbao, Hospital Virgen de la Macarena of Sevilla and Hospital Sant Joan de Déu of Barcelona) from June to December 2014. The study was approved by the Ethical Committee of the reference centre and was carried out according to the principles of Good Clinical Practice. Informed consent was obtained from the adolescents and from the parents of the children included in the study. The assent was also obtained from children capable of providing it.

      Population

      All patients aged 2–20 years with abdominal pain of <72 hours of symptoms onset clinically suspected of AA by attending physician were consecutively enrolled in the study prior to any advanced imaging (US or CT). The exclusion criteria were patients with an abdominal US or CT prior to consent, pregnancy, history of appendectomy, inflammatory disease or active cancer, abdominal trauma, surgery or invasive abdominal procedure within the previous 7 days, use of systemic steroids in the last 14 days, receipt of any other immunosuppressive treatment or chemotherapy within the previous 29 days and participation in the present investigation at any time or another clinical trial in the previous 30 days.

      Study protocol

      The patients were assessed by the attending physician following the standard protocol of usual clinical practice, that is, collecting the clinical history and performing a physical examination and routine laboratory tests, and, if necessary, an imaging test, and evaluation by a surgeon on duty. The laboratory and imaging tests and surgical consultation were requested at the discretion of the attending physician, independent of the participation in the study. Therefore, clinicians were aware of the WBC and CRP values but they were blinded to the APPY1 results.

      In patients undergoing appendectomy, the diagnosis of AA was made from the resected appendix by a pathologist blinded to the APPY1 Test result, based on the report of the histopathological study, or via a telephone call in 2 weeks to confirm the absence of AA. This was histologically demonstrated by mucosal neutrophil infiltration of the appendix with or without local peritonitis. All patients discharged without surgery were successfully contacted at 14 days.

      Plasma measures

      In addition to the standard blood draw, an additional 5 mL of blood was collected from all patients in EDTA tubes at the time of blood draw at presentation in ED for the APPY1 Test. These samples were centrifuged according to a double centrifuge protocol within 2 hours at 1300 g and then frozen at −70°C until measurement by the laboratory of each centre.

      The plasma samples were analysed by the APPY1 Test on the APPYReader Instrument. The APPY1 Test determines the concentrations of calprotectin and CRP of the sample by lateral flow immunoassay. The WBC values were obtained by the standard laboratory method of clinical analysis and were manually entered into the APPYReader prior to initiating the test. The APPY1 Test uses each of these three individual markers as single separate continuous variables combined into a single value. This algorithm is mathematically expressed as A=2.4372+0.1177 (WBC k/μL)+0.0202 (CRP μg/mL)+1.6 (MRP 8/14 μg/mL). The cut-off of 4 was selected for clinical utility maximising the number of true-negative test results while minimising the number of false-negative test results and it was set near the fourth percentile of the distribution of scores for positive participants. The composite values of the mathematical algorithm exhibited a final result defined as either negative (<4) or inconclusive (≥4).18

      The samples were analysed by trained laboratory technicians according to the manufacturer's instructions. The laboratory personnel were blinded to the clinical data and the final clinical diagnosis and the results of the APPY1 Test were not revealed to either the attending physician or the pathologist.

      Measures

      The investigators of each centre prospectively collected the following identical data on a standardised case report form for each patient upon patients arrival at ED: demographic (age and gender), symptoms (periumbilical pain with migration to lower right quadrant, anorexia, nausea and vomiting), signs (fever, lower right quadrant tenderness, rebound and percussion tenderness, rigidity and Rovsing’s sign) and time of onset (hours), analytical (WBC and CRP) and radiological (abdominal ultrasonography and/or CT) and, if necessary, surgical and histopathological data. The forms were reviewed by the coordinating investigator of each centre. All items of the AS were prospectively collected by each centre investigator blinded to the outcome and registered in the case report form. Then, AS was calculated by coordinating researchers and the patients were classified as low (0–4 points), intermediate (5–6 points) or high (7–10 points) risk of AA.6 The primary outcome was the diagnostic accuracy of the APPY1 Test to rule out AA. The secondary outcome measures were the increase in the diagnostic accuracy of the AS when combined with the APPY1 Test and the diagnostic characteristic of APPY1 Test in low and intermediate risk groups stratified using AS.

      Calculation of sample size

      The sample size was calculated based on the study by Huckins et al,18 considering the Se and Sp of the lower value of the CI (Se 92% and Sp 38%) and a frequency of AA of 30%. It was estimated that a sample size of 308 patients was necessary for a confidence level of 95% and a precision of 6.5%.

      Primary data analysis

      Categorical variables are expressed as numbers and percentages and the continuous variables as means and SDs (as medians and IQR if the distribution was not normal). Normality was tested using the Kolmogorov-Smirnov test. Categorical variables were compared with the Pearson's χ2 test or Fisher's exact test and continuous variables using the Student's t-test (or the Mann-Whitney U test if the distribution was not normal). The values of Se, Sp, positive predictive value and NPV, positive likelihood ratio and LHR− were calculated for the APPY1 Test. A stratified analysis by AS was performed and analysis of the AS was also performed using the Pearson's χ2 test. A p value of <0.05 was considered to be statistically significant. Statistical analyses were performed using SPSS software (SPSS Inc., Chicago, Illinois, USA) and STATA V.12.0 (StataCorp LP, College Station, Texas, USA) for Windows V.18.0. The STARD statement for reporting studies of diagnostic accuracy was used in this study.19

      Results

      Patient characteristics

      Of the 331 enrolled patients, 321 patients suspected of AA were included in the analysis (figure 1). Of the seven patients with invalid APPY1 Test results, five patients were stratified as high risk and two as low risk of AA according to AS. All high-risk patients had AA and none of the low-risk patients had AA. The other three patients were excluded due to invalid consent.

      Figure 1
      Figure 1

      Flow diagram of the patients included in the study.

      The mean age was 11.8 (SD 3.8) years and 167 (52.0%) were males. The median time of clinical course was 24 (IQR 9–48) hours. Only one patient received antibiotic in the previous 24 hours to ED visit. According to AS, 104 (32.4%) were at low risk, 76 at (23.7%) intermediate risk and 141 (43.9%) at high risk of AA. At least one imaging test was performed in 185 (57.4%) cases: 169 (52.6%) ultrasonographies, 6 (1.9%) CTs and both in 10 (3.1%) cases. Appendectomy was carried out during the index visit in 114 (35.5%) patients, 105 (92.1%) of whom had a histopathological diagnosis of AA. At the end of the 2-week follow-up, 111 (34.6%) had confirmed histopathological diagnosis of AA, 105 in the first ED visit and 6 within 2 weeks of discharge.

      Table 1 shows the characteristics of the sample and the univariate analysis based on the presence or not of appendicitis. Statistically significant differences were observed in the age, gender, time of onset, associated symptoms and physical examination, WBC, CRP values, risk staging according to the AS and the performance of exploratory surgery.

      View this table:
      Table 1

      Characteristics of the patients included in the study based on the diagnosis of appendicitis

      Primary data analysis

      In 1 (0.9%) of the 111 patients with AA the APPY1 Test result was negative. Of the 210 patients without AA, 69 (32.9%) cases had a negative APPY1 Test result and in 141 (67.1%) the test result was inconclusive. The Se of the APPY1 Test for the diagnosis of AA was 99.1% (95% CI 94.4% to 99.9%), with an NPV of 98.6% (95% CI 91.2% to 99.9%) and an LHR− of 0.03 (0.00 to 0.19) (table 2). A negative test result reduced the probability of AA from 44% to 1.7%.

      View this table:
      Table 2

      Diagnostic characteristics of APPY1 Test, Alvarado score in all samples and APPY1 Test in the low and intermediate risk groups using Alvarado score

      Secondary data analysis

      Table 2 and figure 2 show the diagnostic accuracy of the APPY1 Test in the different risk groups based on the AS. In 50 of 104 patients (48.1%) at low risk and in 18 of 76 patients (23.7%) with intermediate risk, AA was correctly ruled out by the APPY1 Test. The APPY1 Test had a Se of 100%, NPV of 100% and LHR− of 0.0 in the patients at low risk, and 94.4%, 94.7% and 0.18, respectively in those with intermediate risk. Figure 3 represents the probability of AA considering the biomarker results stratified by AS.

      Figure 2
      Figure 2

      Diagnostic accuracy of the APPY1 Test for diagnosing acute appendicitis (AA) stratified by clinical risk according to the Alvarado score.

      Figure 3
      Figure 3

      Fagan normogram of the APPY1 Test stratified by Alvarado score (AS) for appendicitis diagnosis.

      Discussion

      The present study shows that the APPY1 Test is a potentially useful diagnostic tool to rule out the diagnosis of AA in patients aged 2–20 years presenting with abdominal pain suggestive of AA, particularly in those classified with low clinical risk of AA according to the AS, although it is not useful to rule in AA or to diagnose other inflammatory conditions.

      These results confirm previous reports on the diagnostic accuracy of a panel of inflammatory biomarkers including WBC, CRP and calprotectin to rule out AA in children and adolescents.18 In the present study, the APPY1 Test showed a high Se (99.1%) and NPV (98.6%) and a low LHR− (0.03) comparable to the results of Huckins et al18 (Se 96.5%, NPV 96.9%, LHR−0.08). The novelty of the present study was that the determination was made using the APPY1 Test, which provides a qualitative result and not three individual quantitative results, thereby facilitating the interpretation of results in daily clinical practice. This would allow bedside determination to rule out AA in paediatric and adolescent populations and thereby reduce the number of complementary studies, consultations with specialists, unnecessary admissions and even hospital transfers from emergency centres where imaging tests are not available.20 Each test has a cost of about €85–100. Although its determination could avoid other diagnosis tests and hospitalisation, there are no studies about its cost-effectiveness.

      The most important feature of a biomarker is its potential to change clinical decision making. Likelihood ratios and post-test probabilities are relevant for clinicians. They provide information about the likelihood that a patient with a positive or negative test actually has appendicitis or not. In our study, both LHR– and changes in post-test probability were clinically relevant. An LHR– of 0.03 reduces the post-test probability of appendicitis from 44.0% to 1.7%.

      The strategy of combining the APPY1 Test with the clinical scoring system showed an improvement in the diagnostic accuracy over the AS used alone. One systematic review reported that the heterogeneity of the studies carried out in patients aged 17 years or less does not allow the conclusion that the AS alone is a valid decision-making tool in this age group.21 These data confirm the limitation of the AS and the need to combine this clinical scoring system with a diagnostic test such as the APPY1 Test in order to identify patients aged 2–20 years with a low probability of AA. The APPY1 Test has the advantage of being an objective diagnostic test, in which there is no interobserver variability in identifying the symptoms and signs that are used in the clinical scoring systems.22 It is also safe for ruling out AA in children and adolescents since ultrasonography is only recommended as a confirmatory test due to its limited Se, and CT has adverse effects and costs that limit its use.5

      The APPY1 Test demonstrated a better diagnostic accuracy, especially in low-risk patients, and therefore adding the APPY1 Test would facilitate a more efficient management of hospital resources. Patients at high risk should be directly referred to surgery and those without high risk would potentially be candidates for an APPY1 Test. According to the current findings, patients in the low risk group, defined by negative APPY1 with low risk AS, could be discharged directly from the ED without further diagnostic testing, although with the precaution that if the symptoms persist or worsen the patient should return.5 ,21 ,23 The results show that APPY1 Test in intermediate risk group is less useful compared with the low risk group, but a negative result may help to make a decision avoiding imaging tests, surgeries and unnecessary admissions. However, the discharge decision should not be taken considering only the result of the APPY1 Test. In our study, if decision making had only been based on the AS recommendations, without taking into account the APPY1 Test, nine patients with final diagnosis of AA would have been discharged, with the potential clinical13 and economical consequences24 and the attendant quality of care implications.25

      There was one false negative in our study (negative APPY1 Test and histology report of AA without signs of perforation). The patient was a male aged 16 years and 70 kg in weight with intermediate risk of AA without fever or an elevation of inflammatory markers and with a clinical onset of <2 hours at the time of obtaining the sample. This is consistent with the results described by Huckins et al,18 who reported that the diagnostic accuracy of a three-marker panel (WBC, CRP and calprotectin) was lower in patients with a clinical course of <24 hours, and were, therefore, in a very early phase of the disease process. Previous studies have reported that classical biomarkers may modify the diagnostic certainty based on the time of course of appendicitis.22 This may indicate that in cases of low or intermediate risk with a negative APPY1 Test result but a brief time of clinical course, more conservative management may be applied with either hospital observation or close follow-up if discharged.

      The present study has several limitations. First, the percentage of AA differed according to the centre (20%–45%), which may indicate a certain discrepancy in the population included in the study, although the prevalence of appendicitis in our sample was similar to that of other studies.21 Nonetheless, a stratified analysis was performed based on the clinical risks of AA. We must consider that while the study is adequately powered to evaluate the diagnostic values of APPY1 for the entire cohort, it is inadequately powered to evaluate the diagnostic values of APPY1 once the cohort is stratified according to clinical risks, hence the low precision of the results. Second, the sample size was limited to do stratified analyses based on the time of sample obtainment for the APPY1 Test (at presentation in ED) in relation to the onset of the symptomatology (≥ or <24 hours), and thus, future studies are needed to determine the relation between duration of symptoms with the presence of a false negative result. Third, this was an observational study and, thus, we cannot demonstrate that the APPY1 Test reduces the number of imaging tests, unnecessary surgical procedures, the times of hospital stay or the associated costs. The fourth limitation is a possible detection bias in the reference test on the index visit. To avoid this, we used a 2-week follow-up for patients discharged without surgery to confirm their correct classification. Finally, we did not evaluate interobserver agreement in the AS calculation because this is a validated model for predicting AA and all data necessary to calculate AS were prospectively collected.

      Despite this, the results strongly suggest that with the APPY1 Test, patients aged 2–20 years presenting to the ED with abdominal pain suggestive of AA can be safely ruled out when the APPY1 Test result is negative, and this test is especially useful in patients at low clinical risk. In addition, the combination of the APPY1 Test and the AS improves the diagnostic accuracy of the use of AS alone, which can be translated into safer and more efficient management of this process. Regarding the generalisability of the results, we would like to highlight that this study included patients aged 2–20 years from four ED sited in different geographic areas across Spain. Future studies are necessary to demonstrate that the APPY1 Test together with risk models such as the AS will help to identify patients at low risk of AA who can be directly and safely discharged from the ED without the need for imaging tests or exploratory surgery.

      References

      1. ↵
        1. Powers RD,
        2. Guertler AT
        . Abdominal pain in the ED: stability and change over 20 years. Am J Emerg Med 1995;13:301–3. doi:10.1016/0735-6757(95)90204-X
        OpenUrlCrossRefPubMedWeb of Science
      2. ↵
        1. Tseng YC,
        2. Lee MS,
        3. Chang YJ, et al
        . Acute abdomen in pediatric patients admitted to the pediatric emergency department. Pediatr Neonatol 2008;49:126–34. doi:10.1016/S1875-9572(08)60027-3
        OpenUrlCrossRefPubMed
      3. ↵
        1. Martínez Ortiz de Zárate M,
        2. González Del Castillo J,
        3. Julián Jiménez A, et al
        . Epidemiology of infections treated in hospital emergency departments and changes since 12 years earlier: the INFURG study of the Spanish Society of Emergency Medicine (SEMES). Emergencias 2013;25:368–78.
        OpenUrlWeb of Science
      4. ↵
        1. Rothrock SG,
        2. Pagane J
        . Acute appendicitis in children: emergency department diagnosis and management. Ann Emerg Med 2000;36:39–51. doi:10.1067/mem.2000.105658
        OpenUrlCrossRefPubMedWeb of Science
      5. ↵
        1. Howell JM,
        2. Eddy OL,
        3. Lukens TW, et al
        ., American College of Emergency Physicians. Clinical policy: critical issues in the evaluation and management of emergency department patients with suspected appendicitis. Ann Emerg Med 2010;55:71–116. doi:10.1016/j.annemergmed.2009.10.004
        OpenUrlCrossRefPubMed
      6. ↵
        1. Alvarado A
        . A practical score for the early diagnosis of acute appendicitis. Ann Emerg Med 1986;15:557–64. doi:10.1016/S0196-0644(86)80993-3
        OpenUrlCrossRefPubMedWeb of Science
      7. ↵
        1. Bundy DG,
        2. Byerley JS,
        3. Liles EA, et al
        . Does this child have appendicitis? JAMA 2007;298:438–51. doi:10.1001/jama.298.4.438
        OpenUrlCrossRefPubMedWeb of Science
      8. ↵
        1. Becker T,
        2. Kharbanda A,
        3. Bachur R
        . Atypical clinical features of pediatric appendicitis. Acad Emerg Med 2007;14:124–9. doi:10.1197/j.aem.2006.08.009
        OpenUrlCrossRefPubMedWeb of Science
      9. ↵
        1. Yu CW,
        2. Juan LI,
        3. Wu MH, et al
        . Systematic review and meta-analysis of the diagnostic accuracy of procalcitonin, C-reactive protein and white blood cell count for suspected acute appendicitis. Br J Surg 2013;100:322–9. doi:10.1002/bjs.9008
        OpenUrlCrossRefPubMed
      10. ↵
        1. Bachur RG,
        2. Dayan PS,
        3. Bajaj L, et al
        ., Pediatric Emergency Medicine Collaborative Research Committee of the American Academy of Pediatrics. The effect of abdominal pain duration on the accuracy of diagnostic imaging for pediatric appendicitis. Ann Emerg Med 2012;60:582–90. doi:10.1016/j.annemergmed.2012.05.034
        OpenUrlCrossRefPubMed
      11. ↵
        1. Stoker J,
        2. van Randen A,
        3. Laméris W, et al
        . Imaging patients with acute abdominal pain. Radiology 2009;253:31–46. doi:10.1148/radiol.2531090302
        OpenUrlCrossRefPubMedWeb of Science
      12. ↵
        1. Menoch MJ,
        2. Hirsh DA,
        3. Khan NS, et al
        . Trends in computed tomography utilization in the pediatric emergency department. Pediatrics 2012;129:e690–7. doi:10.1542/peds.2011-2548
        OpenUrlAbstract/FREE Full Text
      13. ↵
        1. Naiditch JA,
        2. Lautz TB,
        3. Daley S, et al
        . The implications of missed opportunities to diagnose appendicitis in children. Acad Emerg Med 2013;20:592–6. doi:10.1111/acem.12144
        OpenUrlCrossRefPubMedWeb of Science
      14. ↵
        1. Bealer JF,
        2. Colgin M
        . S100A8/A9: a potential new diagnostic aid for acute appendicitis. Acad Emerg Med 2010;17:333–6. doi:10.1111/j.1553-2712.2010.00663.x
        OpenUrlCrossRefPubMed
      15. ↵
        1. Schellekens DH,
        2. Hulsewé KW,
        3. van Acker BA, et al
        . Evaluation of the diagnostic accuracy of plasma markers for early diagnosis in patients suspected for acute appendicitis. Acad Emerg Med 2013;20:703–10. doi:10.1111/acem.12160
        OpenUrlCrossRefPubMed
      16. ↵
        1. Mills AM,
        2. Huckins DS,
        3. Kwok H, et al
        . Diagnostic characteristics of S100A8/A9 in a multicenter study of patients with acute right lower quadrant abdominal pain. Acad Emerg Med 2012;19:48–55. doi:10.1111/j.1553-2712.2011.01259.x
        OpenUrlCrossRefPubMed
      17. ↵
        1. Horner D,
        2. Long AM
        . Towards evidence-based emergency medicine: best BETs from the Manchester Royal Infirmary. BET 3: super calprotectin will not expedite your discharge. Emerg Med J 2013;30:691–3.
        OpenUrlAbstract/FREE Full Text
      18. ↵
        1. Huckins DS,
        2. Simon HK,
        3. Copeland K, et al
        . A novel biomarker panel to rule out acute appendicitis in pediatric patients with abdominal pain. Am J Emerg Med 2013;31:1368–75. doi:10.1016/j.ajem.2013.06.016
        OpenUrlCrossRefPubMed
      19. ↵
        1. Bossuyt PM,
        2. Reitsma JB,
        3. Bruns DE, et al
        ., Standards for Reporting of Diagnostic Accuracy. Towards complete and accurate reporting of studies of diagnostic accuracy: the STARD initiative. BMJ 2003;326:41–4. doi:10.1136/bmj.326.7379.41
        OpenUrlAbstract/FREE Full Text
      20. ↵
        1. Tudela P,
        2. Mòdol JM
        . La saturacion en los servicios de urgencias hospitalarios. Emergencias 2015;27:113–20.
        OpenUrl
      21. ↵
        1. Ohle R,
        2. O'Reilly F,
        3. O'Brien KK, et al
        . The Alvarado score for predicting acute appendicitis: a systematic review. BMC Med 2011;9:139. doi:10.1186/1741-7015-9-139
        OpenUrlCrossRefPubMed
      22. ↵
        1. Kharbanda AB,
        2. Stevenson MD,
        3. Macias CG, et al
        ., Pediatric Emergency Medicine Collaborative Research Committee of the American Academy of Pediatrics. Interrater reliability of clinical findings in children with possible appendicitis. Pediatrics 2012;129:695–700. doi:10.1542/peds.2011-2037
        OpenUrlAbstract/FREE Full Text
      23. ↵
        1. Ebell MH,
        2. Shinholser J
        . What are the most clinically useful cutoffs for the Alvarado and Pediatric Appendicitis Scores? A systematic review. Ann Emerg Med 2014;64:365–72.e2. doi:10.1016/j.annemergmed.2014.02.025
        OpenUrlCrossRefPubMed
      24. ↵
        1. Rice-Townsend S,
        2. Barnes JN,
        3. Hall M, et al
        . Variation in practice and resource utilization associated with the diagnosis and management of appendicitis at freestanding children's hospitals: implications for value-based comparative analysis. Ann Surg 2014;259:1228–34. doi:10.1097/SLA.0000000000000246
        OpenUrlCrossRefPubMed
      25. ↵
        1. Busca P,
        2. Ortiz E,
        3. Alba L, et al
        . Effect of a strategy for improving quality of care based on systematic measurement of and feedback on quality indicators in 3 highly prevalent emergency department situations. Emergencias 2014;26:179–87.
        OpenUrl

      Supplementary materials

      • Abstract in Spanish

        This web only file has been produced by the BMJ Publishing Group from an electronic file supplied by the author(s) and has not been edited for content.

      Footnotes

      • Collaborators Other members of the Infectious Disease Group of Spanish Emergency Medicine Society are as follows: Lorena Algarrada Vico (Emergency Department, Hospital Sant Joan de Déu Barcelona), Arantxa Aparicio Coll (Emergency Department, Hospital Sant Joan de Déu Barcelona), Marta Batllori Tragant (Emergency Laboratory, Hospital Sant Joan de Déu Barcelona), Alejandro Torres Sampedro (Hospital Universitario de Basurto), Joseba Rementeria Radigales (Hospital Universitario de Basurto), Tarik Chaoui El Kaid (Laboratory Department, Hospital Universitario de Basurto), Jose Gallardo Bautista (Emergency Department, Hospital Universitario Virgen de la Macarena), Mª José Carpio Linde (Emergency Department, Hospital Universitario Virgen de la Macarena), Catalina Sánchez Mora (Laboratory Department, Hospital Universitario Virgen de la Macarena), Jorge García Lamberechts (Emergency Department, Hospital Universitario Clínico San Carlos), Diego Lopez de Lara, Andres Bodas-Pinedo, José Tomas Ramos-Amador (Pediatric Department, Hospital Universitario Clínico San Carlos), María Dolores Ortega (Laboratory Department, Hospital Clínico Universitario San Carlos), Pablo Martinez Camblor (Epidemiology and Preventive Department, Hospital Universitario Central de Asturias).

      • Contributors All authors contributed to the development of the study protocol. JGdC and FJM-S planned the study concept and design. JGdC obtained ethics committee approval and performed the study supervision. FJA, VT, MMOdZ, CN, KA and the members of the Infectious Disease Group of Spanish Emergency Medicine Society collected all data. FJM-S, CF and JGdC analysed and interpreted the data. FJM-S and JGdC prepared the first manuscript draft. All authors contributed to manuscript revision and all approved of the final manuscript. DH made a critical revision of the manuscript.

      • Funding This study had financial support from Infectious Disease Group of Spanish Emergency Medicine Society (INFURG-SEMES). This group has received financial support from Merck, Tedec Meijii, Pfizer, TermoFisher, Laboratorios Rubio and Novartis in the last year to organise conferences and group meetings. The Infection Diseases Group has no direct relationship with Venaxis Inc., the manufacturer of the APPY1 Test, yet has received support from Laboratorios Rubio, the company distributing the APPY1 Test in Spain. Laboratorios Rubio has participated as a sponsor of SEMES meetings in the past two years and offered the APPY1 Test free of charge for the development of this study. The promoter of this study has been INFURG-SEMES. None of the authors has received direct financial compensation from Venaxis Inc. or Laboratorios Rubio, except DH who has participated as an external reviewer of the study and to whom Venaxis Inc. has paid consulting fees and reimbursed for travel expenses to FDA meetings and conferences.

      • Competing interests None of the authors has received direct financial compensation from Venaxis Inc., the manufacturer of the APPY1 Test, or Laboratorios Rubio, the company distributing the APPY1 Test in Spain. DH, who has participated as an external reviewer of the study, has received consulting fees and reimbursed for travel expenses to FDA meetings and conferences by Venaxis Inc. Neither Venaxis Inc. nor Laboratorios Rubio has participated in the development of this study, including funding or writing.

      • Patient consent Obtained.

      • Ethics approval Ethical Committee of Hospital Clínico San Carlos, Madrid, Spain.

      • Provenance and peer review Not commissioned; externally peer reviewed.