Clinical Yield of a Molecular Diagnostic Panel for Enteric Pathogens in Adult Outpatients With Diarrhea and Validation of Guidelines-Based Criteria for Testing

Open Forum Infectious Diseases MAJOR ARTICLE Clinical Yield of a Molecular Diagnostic Panel for Enteric Pathogens in Adult Outpatients With Diarrhea and Validation of Guidelines-Based Criteria for Testing Stephen D. Clark,1 Michael Sidlak,2 Amy J. Mathers,2,3 Melinda Poulter,2 and James A. Platts-Mills3, 1 Background. Molecular diagnostic panels for enteric pathogens offer increased sensitivity and reduced turnaround time. However, many pathogen detections do not change clinical management, and the cost is substantial. Methods. We performed a retrospective chart review of adult outpatients with diarrhea at the University of Virginia who had samples tested by the FilmArray Gastrointestinal Panel (BioFire Diagnostics, Salt Lake City, UT) to identify the clinical yield and to validate the clinical criteria for testing recommended in the 2017 Infectious Diseases Society of America (IDSA) guidelines. Results. We analyzed 629 tests sent from adult outpatients with diarrhea between March 23, 2015, and July 18, 2016. A pathogen was detected in 127 of 629 specimens (20.2%). The most common pathogens were enteropathogenic Escherichia coli (47, 7.5%), norovirus (24, 3.8%), enteroaggregative E. coli (14, 2.2%), Campylobacter (9, 1.4%), and Salmonella (9; 1.4%). The clinical yield of testing was low, with antimicrobial treatment clearly indicated for only 18 subjects (2.9%) and any change in clinical management indicated for 33 subjects (5.2%). Following the clinical criteria for diagnostic testing from the 2017 IDSA guidelines, which suggest diagnostic testing for patients with fever, abdominal pain, blood in stool, or an immunocompromising condition, would have reduced testing by 32.3% without significantly reducing the clinical yield (sensitivity, 97.0%; 95% confidence interval [CI], 84.2%–99.9%; negative predictive value, 99.5%; 95% CI, 97.3%–100.0%). Conclusions. The clinical yield of molecular diagnostic testing in this population was low. Compliance with IDSA guidelines in adult outpatients with diarrhea could reduce testing by approximately one-third. Keywords. diarrhea; guidelines; molecular diagnostics; PCR. The evaluation and management of infectious diarrhea remain a common problem in the outpatient setting, with a broad range of etiologies accounting for 37.2 million cases per year in the United States [1]. Although most infectious diarrhea is self-limited, detection of the underlying pathogen can be of value where antimicrobial therapy would be indicated, where antimicrobial therapy should be explicitly withheld (ie, for shiga toxin–producing Escherichia coli [STEC]), when the patient’s degree of immunosuppression can be modified, and for public health reasons, for example, identification and control of outbreaks. The Infectious Disease Society of America (IDSA) published updated guidelines in October 2017 on the evaluation and management of infectious diarrhea [2]. With the Received 16 January 2019; editorial decision 22 March 2019; accepted 26 March 2019. Correspondence: J. A. Platts-Mills, MD, Division of Infectious Diseases and International Health, University of Virginia, PO Box 801340, Charlottesville, VA 22908 (). Open Forum Infectious Diseases® © The Author(s) 2019. Published by Oxford University Press on behalf of Infectious Diseases Society of America. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited. DOI: 10.1093/ofid/ofz162 exception of outbreak investigations, because most diarrhea is self-limited, these guidelines recommend restricting stool diagnostic testing to patients with either severe diarrhea (ie, signs of sepsis) or with fever, bloody or mucoid stools, severe abdominal cramping or tenderness, or an immunocompromising condition. This recommendation is supported by observational studies that have found an association between fever, abdominal pain, or blood and detection of a pathogen that would warrant a change in clinical management [3–5], although immunocompromised patients have the potential for severe and complicated disease or prolonged illness [2]. The detection of a broad array of potentially offending agents has traditionally required a combination of microbiologic approaches, including bacterial culture, antigen detection, microscopy, and polymerase chain reaction (PCR). However, these tests are time intensive, expensive, and in many cases the sensitivity is poor [6, 7]. Several Food and Drug Administration– approved molecular diagnostic panels have recently become available that offer increased sensitivity and reduced time to identification of pathogens while investigating for a broad range of causes [8, 9]. The IDSA guidelines recommend the use of these panels when testing is to be performed [2, 10]. However, Molecular Diagnostic Panel for Diarrhea • ofid • 1 Cecil G. Sheps Center for Health Services Research and Division of General Medicine and Clinical Epidemiology, Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina; 2Clinical Microbiology, Department of Pathology, University of Virginia Health System, Charlottesville, Virginia; 3Division of Infectious Diseases and International Health, University of Virginia, Charlottesville, Virginia the cost to the patient is significant, especially in the outpatient setting [10, 11]. Further, Medicare reimbursement for these tests has been restricted in the southeastern United States [12]. Our institution introduced the FilmArray gastrointestinal (GI) panel (BioFire Diagnostics, Salt Lake City, UT) in 2015, which tests for 20 enteropathogens. We sought to describe the clinical yield of testing in adult outpatients with diarrhea and to validate the IDSA recommendations for diagnostic testing in this population. METHODS Study Design and Population 2 • ofid • Clark et al Stool was collected at outside clinical laboratories and transported to the central laboratory for processing daily. Stool was placed in Cary-Blair Transport Media (Remel, Lenexa, KS) at the time of collection or at the time of receipt in the central laboratory and was processed within 24 hours. For outpatients, the Clostridioides difficile result on the panel was suppressed. Interpretation of Test Results We classified positive test results in 3 ways: (a) detection of any pathogen included on the card; (b) detection of a pathogen for which antimicrobial therapy was indicated (“pathogen warranting antimicrobial therapy”); and (c) detection of a pathogen that could lead to a change in management (“clinicallyrelevant pathogen”), which additionally included detection of STEC or detection of viral pathogens in immunocompromised patients, where titration of immunosuppression is often indicated (Table 1). We did not consider avoidance or discontinuation of inap (...truncated)