Diagnostic Characteristics of S100A8/A9 in a Multicenter Study of Patients With Acute Right Lower Quadrant Abdominal Pain

Authors

  • Angela M. Mills MD,

    1. From the Department of Emergency Medicine, University of Pennsylvania (AMM), Philadelphia, PA; the Department of Emergency Medicine, Newton-Wellesley Hospital (DSH), Newton, MA; the Department of Emergency Medicine, Harbor UCLA Medical Center (HK, RJL), Torrance, CA; the Department of Emergency Medicine, Cooper University Hospital (BMB), Camden, NJ; the Department of Pediatrics Division of Emergency Medicine, Cincinnati Children’s Hospital Medical Center (RMR), Cincinnati, OH; the Department of Emergency Medicine, Johns Hopkins University (RER), Baltimore, MD; the Department of Emergency Medicine, MetroHealth Medical Center (JWS), Cleveland, OH; the Department of Emergency Medicine, Maricopa Medical Center (FL), Phoenix, AZ; the Departments of Pediatrics and Emergency Medicine, Long Island Jewish Medical Center (WIK), New Hyde Park, NY; the Department of Emergency Medicine, Bay State Health Center (AH), Springfield, MA; and AspenBio Pharma, Inc. (RC, BC), Castle Rock, CO.
    Search for more papers by this author
  • David S. Huckins MD,

    1. From the Department of Emergency Medicine, University of Pennsylvania (AMM), Philadelphia, PA; the Department of Emergency Medicine, Newton-Wellesley Hospital (DSH), Newton, MA; the Department of Emergency Medicine, Harbor UCLA Medical Center (HK, RJL), Torrance, CA; the Department of Emergency Medicine, Cooper University Hospital (BMB), Camden, NJ; the Department of Pediatrics Division of Emergency Medicine, Cincinnati Children’s Hospital Medical Center (RMR), Cincinnati, OH; the Department of Emergency Medicine, Johns Hopkins University (RER), Baltimore, MD; the Department of Emergency Medicine, MetroHealth Medical Center (JWS), Cleveland, OH; the Department of Emergency Medicine, Maricopa Medical Center (FL), Phoenix, AZ; the Departments of Pediatrics and Emergency Medicine, Long Island Jewish Medical Center (WIK), New Hyde Park, NY; the Department of Emergency Medicine, Bay State Health Center (AH), Springfield, MA; and AspenBio Pharma, Inc. (RC, BC), Castle Rock, CO.
    Search for more papers by this author
  • Heemun Kwok MD,

    1. From the Department of Emergency Medicine, University of Pennsylvania (AMM), Philadelphia, PA; the Department of Emergency Medicine, Newton-Wellesley Hospital (DSH), Newton, MA; the Department of Emergency Medicine, Harbor UCLA Medical Center (HK, RJL), Torrance, CA; the Department of Emergency Medicine, Cooper University Hospital (BMB), Camden, NJ; the Department of Pediatrics Division of Emergency Medicine, Cincinnati Children’s Hospital Medical Center (RMR), Cincinnati, OH; the Department of Emergency Medicine, Johns Hopkins University (RER), Baltimore, MD; the Department of Emergency Medicine, MetroHealth Medical Center (JWS), Cleveland, OH; the Department of Emergency Medicine, Maricopa Medical Center (FL), Phoenix, AZ; the Departments of Pediatrics and Emergency Medicine, Long Island Jewish Medical Center (WIK), New Hyde Park, NY; the Department of Emergency Medicine, Bay State Health Center (AH), Springfield, MA; and AspenBio Pharma, Inc. (RC, BC), Castle Rock, CO.
    Search for more papers by this author
  • Brigitte M. Baumann MD, MSCE,

    1. From the Department of Emergency Medicine, University of Pennsylvania (AMM), Philadelphia, PA; the Department of Emergency Medicine, Newton-Wellesley Hospital (DSH), Newton, MA; the Department of Emergency Medicine, Harbor UCLA Medical Center (HK, RJL), Torrance, CA; the Department of Emergency Medicine, Cooper University Hospital (BMB), Camden, NJ; the Department of Pediatrics Division of Emergency Medicine, Cincinnati Children’s Hospital Medical Center (RMR), Cincinnati, OH; the Department of Emergency Medicine, Johns Hopkins University (RER), Baltimore, MD; the Department of Emergency Medicine, MetroHealth Medical Center (JWS), Cleveland, OH; the Department of Emergency Medicine, Maricopa Medical Center (FL), Phoenix, AZ; the Departments of Pediatrics and Emergency Medicine, Long Island Jewish Medical Center (WIK), New Hyde Park, NY; the Department of Emergency Medicine, Bay State Health Center (AH), Springfield, MA; and AspenBio Pharma, Inc. (RC, BC), Castle Rock, CO.
    Search for more papers by this author
  • Richard M. Ruddy MD,

    1. From the Department of Emergency Medicine, University of Pennsylvania (AMM), Philadelphia, PA; the Department of Emergency Medicine, Newton-Wellesley Hospital (DSH), Newton, MA; the Department of Emergency Medicine, Harbor UCLA Medical Center (HK, RJL), Torrance, CA; the Department of Emergency Medicine, Cooper University Hospital (BMB), Camden, NJ; the Department of Pediatrics Division of Emergency Medicine, Cincinnati Children’s Hospital Medical Center (RMR), Cincinnati, OH; the Department of Emergency Medicine, Johns Hopkins University (RER), Baltimore, MD; the Department of Emergency Medicine, MetroHealth Medical Center (JWS), Cleveland, OH; the Department of Emergency Medicine, Maricopa Medical Center (FL), Phoenix, AZ; the Departments of Pediatrics and Emergency Medicine, Long Island Jewish Medical Center (WIK), New Hyde Park, NY; the Department of Emergency Medicine, Bay State Health Center (AH), Springfield, MA; and AspenBio Pharma, Inc. (RC, BC), Castle Rock, CO.
    Search for more papers by this author
  • Richard E. Rothman MD, PhD,

    1. From the Department of Emergency Medicine, University of Pennsylvania (AMM), Philadelphia, PA; the Department of Emergency Medicine, Newton-Wellesley Hospital (DSH), Newton, MA; the Department of Emergency Medicine, Harbor UCLA Medical Center (HK, RJL), Torrance, CA; the Department of Emergency Medicine, Cooper University Hospital (BMB), Camden, NJ; the Department of Pediatrics Division of Emergency Medicine, Cincinnati Children’s Hospital Medical Center (RMR), Cincinnati, OH; the Department of Emergency Medicine, Johns Hopkins University (RER), Baltimore, MD; the Department of Emergency Medicine, MetroHealth Medical Center (JWS), Cleveland, OH; the Department of Emergency Medicine, Maricopa Medical Center (FL), Phoenix, AZ; the Departments of Pediatrics and Emergency Medicine, Long Island Jewish Medical Center (WIK), New Hyde Park, NY; the Department of Emergency Medicine, Bay State Health Center (AH), Springfield, MA; and AspenBio Pharma, Inc. (RC, BC), Castle Rock, CO.
    Search for more papers by this author
  • Jon W. Schrock MD,

    1. From the Department of Emergency Medicine, University of Pennsylvania (AMM), Philadelphia, PA; the Department of Emergency Medicine, Newton-Wellesley Hospital (DSH), Newton, MA; the Department of Emergency Medicine, Harbor UCLA Medical Center (HK, RJL), Torrance, CA; the Department of Emergency Medicine, Cooper University Hospital (BMB), Camden, NJ; the Department of Pediatrics Division of Emergency Medicine, Cincinnati Children’s Hospital Medical Center (RMR), Cincinnati, OH; the Department of Emergency Medicine, Johns Hopkins University (RER), Baltimore, MD; the Department of Emergency Medicine, MetroHealth Medical Center (JWS), Cleveland, OH; the Department of Emergency Medicine, Maricopa Medical Center (FL), Phoenix, AZ; the Departments of Pediatrics and Emergency Medicine, Long Island Jewish Medical Center (WIK), New Hyde Park, NY; the Department of Emergency Medicine, Bay State Health Center (AH), Springfield, MA; and AspenBio Pharma, Inc. (RC, BC), Castle Rock, CO.
    Search for more papers by this author
  • Frank Lovecchio DO, MPH,

    1. From the Department of Emergency Medicine, University of Pennsylvania (AMM), Philadelphia, PA; the Department of Emergency Medicine, Newton-Wellesley Hospital (DSH), Newton, MA; the Department of Emergency Medicine, Harbor UCLA Medical Center (HK, RJL), Torrance, CA; the Department of Emergency Medicine, Cooper University Hospital (BMB), Camden, NJ; the Department of Pediatrics Division of Emergency Medicine, Cincinnati Children’s Hospital Medical Center (RMR), Cincinnati, OH; the Department of Emergency Medicine, Johns Hopkins University (RER), Baltimore, MD; the Department of Emergency Medicine, MetroHealth Medical Center (JWS), Cleveland, OH; the Department of Emergency Medicine, Maricopa Medical Center (FL), Phoenix, AZ; the Departments of Pediatrics and Emergency Medicine, Long Island Jewish Medical Center (WIK), New Hyde Park, NY; the Department of Emergency Medicine, Bay State Health Center (AH), Springfield, MA; and AspenBio Pharma, Inc. (RC, BC), Castle Rock, CO.
    Search for more papers by this author
  • William I. Krief MD,

    1. From the Department of Emergency Medicine, University of Pennsylvania (AMM), Philadelphia, PA; the Department of Emergency Medicine, Newton-Wellesley Hospital (DSH), Newton, MA; the Department of Emergency Medicine, Harbor UCLA Medical Center (HK, RJL), Torrance, CA; the Department of Emergency Medicine, Cooper University Hospital (BMB), Camden, NJ; the Department of Pediatrics Division of Emergency Medicine, Cincinnati Children’s Hospital Medical Center (RMR), Cincinnati, OH; the Department of Emergency Medicine, Johns Hopkins University (RER), Baltimore, MD; the Department of Emergency Medicine, MetroHealth Medical Center (JWS), Cleveland, OH; the Department of Emergency Medicine, Maricopa Medical Center (FL), Phoenix, AZ; the Departments of Pediatrics and Emergency Medicine, Long Island Jewish Medical Center (WIK), New Hyde Park, NY; the Department of Emergency Medicine, Bay State Health Center (AH), Springfield, MA; and AspenBio Pharma, Inc. (RC, BC), Castle Rock, CO.
    Search for more papers by this author
  • Aaron Hexdall MD,

    1. From the Department of Emergency Medicine, University of Pennsylvania (AMM), Philadelphia, PA; the Department of Emergency Medicine, Newton-Wellesley Hospital (DSH), Newton, MA; the Department of Emergency Medicine, Harbor UCLA Medical Center (HK, RJL), Torrance, CA; the Department of Emergency Medicine, Cooper University Hospital (BMB), Camden, NJ; the Department of Pediatrics Division of Emergency Medicine, Cincinnati Children’s Hospital Medical Center (RMR), Cincinnati, OH; the Department of Emergency Medicine, Johns Hopkins University (RER), Baltimore, MD; the Department of Emergency Medicine, MetroHealth Medical Center (JWS), Cleveland, OH; the Department of Emergency Medicine, Maricopa Medical Center (FL), Phoenix, AZ; the Departments of Pediatrics and Emergency Medicine, Long Island Jewish Medical Center (WIK), New Hyde Park, NY; the Department of Emergency Medicine, Bay State Health Center (AH), Springfield, MA; and AspenBio Pharma, Inc. (RC, BC), Castle Rock, CO.
    Search for more papers by this author
  • Robert Caspari MD,

    1. From the Department of Emergency Medicine, University of Pennsylvania (AMM), Philadelphia, PA; the Department of Emergency Medicine, Newton-Wellesley Hospital (DSH), Newton, MA; the Department of Emergency Medicine, Harbor UCLA Medical Center (HK, RJL), Torrance, CA; the Department of Emergency Medicine, Cooper University Hospital (BMB), Camden, NJ; the Department of Pediatrics Division of Emergency Medicine, Cincinnati Children’s Hospital Medical Center (RMR), Cincinnati, OH; the Department of Emergency Medicine, Johns Hopkins University (RER), Baltimore, MD; the Department of Emergency Medicine, MetroHealth Medical Center (JWS), Cleveland, OH; the Department of Emergency Medicine, Maricopa Medical Center (FL), Phoenix, AZ; the Departments of Pediatrics and Emergency Medicine, Long Island Jewish Medical Center (WIK), New Hyde Park, NY; the Department of Emergency Medicine, Bay State Health Center (AH), Springfield, MA; and AspenBio Pharma, Inc. (RC, BC), Castle Rock, CO.
    Search for more papers by this author
  • Beth Cohen,

    1. From the Department of Emergency Medicine, University of Pennsylvania (AMM), Philadelphia, PA; the Department of Emergency Medicine, Newton-Wellesley Hospital (DSH), Newton, MA; the Department of Emergency Medicine, Harbor UCLA Medical Center (HK, RJL), Torrance, CA; the Department of Emergency Medicine, Cooper University Hospital (BMB), Camden, NJ; the Department of Pediatrics Division of Emergency Medicine, Cincinnati Children’s Hospital Medical Center (RMR), Cincinnati, OH; the Department of Emergency Medicine, Johns Hopkins University (RER), Baltimore, MD; the Department of Emergency Medicine, MetroHealth Medical Center (JWS), Cleveland, OH; the Department of Emergency Medicine, Maricopa Medical Center (FL), Phoenix, AZ; the Departments of Pediatrics and Emergency Medicine, Long Island Jewish Medical Center (WIK), New Hyde Park, NY; the Department of Emergency Medicine, Bay State Health Center (AH), Springfield, MA; and AspenBio Pharma, Inc. (RC, BC), Castle Rock, CO.
    Search for more papers by this author
  • Roger J. Lewis MD, PhD

    1. From the Department of Emergency Medicine, University of Pennsylvania (AMM), Philadelphia, PA; the Department of Emergency Medicine, Newton-Wellesley Hospital (DSH), Newton, MA; the Department of Emergency Medicine, Harbor UCLA Medical Center (HK, RJL), Torrance, CA; the Department of Emergency Medicine, Cooper University Hospital (BMB), Camden, NJ; the Department of Pediatrics Division of Emergency Medicine, Cincinnati Children’s Hospital Medical Center (RMR), Cincinnati, OH; the Department of Emergency Medicine, Johns Hopkins University (RER), Baltimore, MD; the Department of Emergency Medicine, MetroHealth Medical Center (JWS), Cleveland, OH; the Department of Emergency Medicine, Maricopa Medical Center (FL), Phoenix, AZ; the Departments of Pediatrics and Emergency Medicine, Long Island Jewish Medical Center (WIK), New Hyde Park, NY; the Department of Emergency Medicine, Bay State Health Center (AH), Springfield, MA; and AspenBio Pharma, Inc. (RC, BC), Castle Rock, CO.
    Search for more papers by this author

  • Presented at the Society for Academic Emergency Medicine annual meeting, Boston, MA, June 2011.

  • This study was funded by AspenBio Pharma, Inc. RC and BC are consultants for AspenBio Pharma, Inc. All authors’ institutions received funding for this study. RC owns shares in AspenBio Pharma, Inc. RJL has an ongoing consultancy relationship with AspenBio Parma, Inc.; remuneration is to his institution. The rest of the authors claim no further disclosures or conflicts of interest.

  • Supervising Editor: Richard Sinert, DO.

Address for correspondence Angela M. Mills, MD; e-mail: millsa@uphs.upenn.edu. Reprints will not be available.

Abstract

ACADEMIC EMERGENCY MEDICINE 2012; 19:48–55 © 2012 by the Society for Academic Emergency Medicine

Abstract

Objectives:  Over the past decade, clinicians have become increasingly reliant on computed tomography (CT) for the evaluation of patients with suspected acute appendicitis. To limit the radiation risks and costs of CT, investigators have searched for biomarkers to aid in diagnostic decision-making. We evaluated one such biomarker, calprotectin or S100A8/A9, and determined the diagnostic performance characteristics of a developmental biomarker assay in a multicenter investigation of patients presenting with acute right lower quadrant abdominal pain.

Methods:  This was a prospective, double-blinded, single-arm, multicenter investigation performed in 13 emergency departments (EDs) from August 2009 to April 2010 of patients presenting with acute right lower quadrant abdominal pain. Plasma samples were tested using the investigational S100A8/A9 assay. The primary outcome of acute appendicitis was determined by histopathology for patients undergoing appendectomy or 2-week telephone follow-up for patients discharged without surgery. The sensitivity, specificity, negative likelihood ratio (LR–), and positive likelihood ratio (LR+) of the biomarker assay were calculated using the prespecified cutoff value of 14 units. A post hoc stability study was performed to investigate the potential effect of time and courier transport on the measured value of the S100A8/A9 assay test results.

Results:  Of 1,052 enrolled patients, 848 met criteria for analysis. The median age was 24.5 years (interquartile range [IQR] = 16–38 years), 57% were female, and 50% were white. There was a 27.5% prevalence of acute appendicitis. The sensitivity and specificity for the investigational S100A8/A9 assay in diagnosing acute appendicitis were estimated to be 96% (95% confidence interval [CI] = 93% to 98%) and 16% (95% CI = 13% to 19%), respectively. The LR− ratio was 0.24 (95% CI = 0.12 to 0.47), and the LR+ was 1.14 (95% CI = 1.10 to 1.19). The post hoc stability study demonstrated that in the samples that were shipped, the estimated time coefficient was 7.6 × 10−3 ± 2.0 × 10−3 log units/hour, representing an average increase of 43% in the measured value over 48 hours; in the samples that were not shipped, the estimated time coefficient was 2.5 × 10−3 ± 0.4 × 10−3 log units/hour, representing a 13% increase on average in the measured value over 48 hours, which was the maximum delay allowed by the study protocol. Thus, adjusting the cutoff value of 14 units by the magnitude of systematic inflation observed in the stability study at 48 hours would result in a new cutoff value of 20 units and a “corrected” sensitivity and specificity of 91 and 28%, respectively.

Conclusions:  In patients presenting with acute right lower quadrant abdominal pain, we found the investigational enzyme-linked immunosorbent assay (ELISA) test for S100A8/A9 to perform with high sensitivity but very limited specificity. We found that shipping effect and delay in analysis resulted in a subsequent rise in test values, thereby increasing the sensitivity and decreasing the specificity of the test. Further investigation with hospital-based laboratory analyzers is the next critical step for determining the ultimate clinical utility of the ELISA test for S100A8/A9 in ED patients presenting with acute right lower quadrant abdominal pain.

Ancillary