FRONT MATTER

The American Academy of Microbiology (Academy) is the honorific branch of the American Society for Microbiology (ASM), a nonprofit scientific society with nearly 48,000 members. Fellows of the Academy have been elected by their peers in recognition of their outstanding contributions to the microbial sciences. Through its colloquium program, the Academy draws on the expertise of these fellows to address critical issues in the microbial sciences.

This report is based on the deliberations of experts who gathered for two full days to discuss a series of questions developed by the steering committee. All participants had the opportunity to provide feedback, and every effort has been made to ensure that the information is accurate and complete. The contents reflect the views of the participants and are not intended to reflect official positions of the Academy or of ASM.

The Academy acknowledges Margaret Milhous for her assistance in editing this report. In addition, the Academy thanks the efforts of Daniel Peniston for his assistance on this project.

Contents of the report may be distributed further so long as the authorship of the Academy is acknowledged and this disclaimer language is included.

BOARD OF GOVERNORS, AMERICAN ACADEMY OF MICROBIOLOGY

Michele S. Swanson, Ph.D., Chair University of Michigan Medical School

Martin J. Blaser, M.D. New York University School of Medicine

Donald A. Bryant, Ph.D. Pennsylvania State University

Arturo Casadevall, M.D., Ph.D., Chair-Elect Johns Hopkins Bloomberg School of Public Health

Nancy Craig, Ph.D. The Johns Hopkins University School of Medicine

Terence S. Dermody, M.D. Children’s Hospital of Pittsburgh of UPMC

Stanley Fields, Ph.D. University of Washington

James M. Hughes, M.D. Emory University School of Medicine

Steven Lindow, Ph.D. University of California, Berkeley

Margaret McFall-Ngai, Ph.D. Pacific Biosciences Research Center, University of Hawaii at Manoa

Mary Ann Moran, Ph.D. University of Georgia

Graham C. Walker, Ph.D. Massachusetts Institute of Technology

Alice S. Weissfeld, Ph.D. Microbiology Specialists

COLLOQUIUM STEERING COMMITTEE

Melissa B. Miller, Ph.D., Chair University of North Carolina at Chapel Hill

Kenneth Bahk, Ph.D. Three Lakes Partners

Karen C. Carroll, M.D. Johns Hopkins University School of Medicine

Keith Klugman, M.D., Ph.D. Bill & Melinda Gates Foundation

Nathan A. Ledeboer, Ph.D. Medical College of Wisconsin

PARTICIPANTS

Edina Avdic, Pharm.D., M.B.A. The Johns Hopkins Hospital

Tobias Barker, M.D. CVS Health

Steve Beuchaw, M.B.A. Morgan Stanley

Carey-Ann Burnham, Ph.D. Washington University in St. Louis School of Medicine

Sheldon Campbell, M.D., Ph.D. Yale School of Medicine

Nancy E. Cornish, M.D. Centers for Disease Control and Prevention

Scott Cunningham, M.S., M.T. (ASCP), S.M. Mayo Clinic

Charlotte A. Gaydos, M.S., M.P.H., Dr.P.H. Johns Hopkins University

Alberto Gutierrez, Ph.D. Food and Drug Administration

Alexander J. McAdam, M.D., Ph.D. Boston Children's Hospital

Jeanne Mumford, M.T. (ASCP) Johns Hopkins Medicine

Daniel D. Rhoads, M.D. Case Western Reserve University

Kristian Roth, Ph.D. Food and Drug Administration

Paul Schreckenberger, M.S., Ph.D. Loyola University Chicago

Fred C. Tenover, Ph.D. Cepheid

Dan Wattendorf, M.D. Bill and Melinda Gates Foundation

ACADEMY STAFF

Marina Moses, M.S., Dr.P.H. Director

Virginia Dolen Program Manager

Isabel Hinestrosa Board of Governors Program Assistant

Daniel Peniston Colloquium and Outreach Program Assistant

ASM LEADERSHIP

Stefano Bertuzzi, Ph.D., M.P.H. Chief Executive Officer

Approach to the Task

The Academy is the honorific leadership group within the American Society for Microbiology (ASM), the world's oldest and largest life science organization. One major role of the Academy is to convene colloquia to deliberate on issues of critical importance in the microbial sciences. On 17 to 18 October 2016, the Academy convened a group of 21 experts at ASM Headquarters to discuss changing diagnostic paradigms in microbiology, including near-patient and POC testing. A steering committee chaired by an Academy fellow was appointed prior to the colloquium and developed a comprehensive and informed agenda, including key discussion questions for the colloquium participants. The distinguished group of participants included representatives from clinical laboratories, academia, government agencies, foundations, and commercial industry with backgrounds in clinical microbiology, diagnostic and POC testing, pharmacy, medicine, laboratory medicine, public health, informatics, device development, device regulation, and investment. Colloquium participants were assigned 11 main discussion questions (see Appendix), with subquestions that covered the broad topics in the Statement of Task (see the text box). Participants were divided into working groups that consisted of individuals with varied expertise to answer the discussion questions. Groups reconvened for plenary sessions to review all answers. This report summarizes the plenary discussions during the 2-day colloquium.

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Key Terms.

This report (1) reviews characteristics and applications of near-patient and POC tests for infectious diseases, (2) provides an overview of considerations pertaining to their implementation, oversight, and evaluation, and (3) provides recommendations.

Types of Tests

Near-patient and POC tests currently exist for a number of pathogens, such as tuberculosis (TB), influenza and other respiratory viruses, group A Streptococcus (GAS), Chlamydia, and gonorrhea. These include antigen tests (most commonly lateral-flow immunochromatographic membrane-based assays) and nucleic acid tests. Due to rapid advances in technology, the field of diagnostic microbiology is shifting from antigen-based testing to nucleic acid amplification-based testing, including multiplex syndromic panels that test for a number of potential pathogens concurrently.

Nucleic Acid Amplification Tests

Nucleic acid amplification tests (NAATs) can detect RNA or DNA sequences specific to a particular target (which may be present in a specific pathogen or antimicrobial resistance determinant). NAATs include PCR (nucleic acid amplification using thermostable polymerase) or isothermal amplification methods, including transcription-mediated amplification (TMA), strand displacement amplification (SDA), loop-mediated isothermal amplification (LAMP), and helicase-dependent amplification (HDA) (Buchan and Ledeboer 2014). Although NAATs are more sensitive and specific than antigen-based tests, some limitations exist. NAATs demonstrate varied sensitivities when used in practice and may not identify clinically relevant infections in some cases. This may be due to differences between real-world experiences with these tests in clinical practice versus in controlled clinical trials performed for regulatory review or due to genetic differences in circulating strains. NAATs have a risk of contamination during nucleic acid extraction or from carryover of previously amplified material, including vaccines (Leber 2014; Mohl et al. 2016; Salimnia et al. 2012), or from leakage of test cartridges, which may affect test results. In addition, performance of NAATs may be impacted by mutations in the RNA or DNA sequences that they are designed to detect and may be falsely negative when mutations are present in the primer/probe binding sites.

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Antigen Test Considerations—Influenza.

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Nucleic Acid Amplification Test Considerations—Tuberculosis.

Figure 1

NAAT procedure.

Syndromic Panels

With the advent of molecular testing, agent-specific primers included in a particular test detect a single pathogen, but in many cases a clinical presentation may be caused by a number of possible pathogens (Schreckenberger and McAdam 2015). Multiplex NAAT panels (inclusive of pathogens that cause a common syndrome or are commonly found in a specific sample type) have been developed to investigate multiple putative causes of illness simultaneously (Schreckenberger and McAdam 2015). For example, syndromic panels exist for respiratory pathogens, for meningitis/encephalitis, and for gastrointestinal pathogens. Syndromic panels must be thoughtfully developed to provide advantages over single-pathogen tests; the clinical utility of including each pathogen should be considered to ensure that the test results are easily interpretable. Differences in sensitivity and specificity may exist between syndromic panels and the individual molecular tests. For example, one study of a meningitis/encephalitis panel found a significant number of false positives thought to be the result of contamination or some other aspect of the testing process (Leber et al. 2016). Differences in sensitivity and specificity may also exist between different multiplex assays for the same syndrome (Popowitch et al. 2013).

Concerns exist about indiscriminate deployment of syndromic panels when a nuanced approach to testing is needed. Professional judgment may be required to determine when a panel approach is warranted and to interpret the results of a syndromic panel correctly. For example, a patient’s clinical presentation might be the result of a newly recognized pathogen (in which case, it would not be identified with a panel) or an unfamiliar presentation of a known pathogen (in which case, a provider may order an uninformative panel test). If a disease included in a syndromic panel is rare in a particular setting, the number of false positives for that disease may outnumber the number of true positives, requiring further testing to confirm positive test results. In addition, multiple positive results can be obtained with a syndromic test panel, which requires the clinician to interpret which positive results are clinically significant and which might be insignificant.

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Syndromic Panel Considerations—Pharyngitis.

Sensitivity and Specificity

With increased testing being performed outside clinical microbiology laboratories, the limitations of each test with respect to sensitivity and specificity must be understood and acknowledged by those ordering and interpreting the tests. Colloquium participants affirmed that near-patient and POC tests should exhibit performance criteria for sensitivity and specificity similar to those of equivalent laboratory-based tests. Even with the best quality tests (whether performed in the laboratory or at the POC), providers need to be wary of adverse outcomes that can arise from improper interpretation of the results. Concerns exist that the results of POC tests may be automatically interpreted as correct results, even though no test has perfect sensitivity and specificity. False positives and false negatives will occur, and their likelihood needs to be evaluated when making patient care decisions. Particular concerns exist for tests with high analytical sensitivity, which may deliver positive results that are due to contamination or results that should be interpreted as asymptomatic colonization rather than infection. In addition, the pretest probabilities of a particular result and therefore of the positive predictive value of the test in that particular setting for that particular patient population need to be considered. Recommendations to guide oversight of near-patient and POC testing, such as addressing contamination and test interpretation, are provided later in this report.

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Sensitivity and Specificity Considerations—Legionella.

Regulatory Considerations

In the United States, most in vitro diagnostic tests are regulated by the Food and Drug Administration (FDA) (see the text box). CLIA regulates laboratory testing and requires clinical laboratories to be certificated by their state as well as by the Centers for Medicare and Medicaid Services (CMS) before they can accept human samples for diagnostic testing. Laboratories can obtain multiple types of CLIA certificates based on the kinds of diagnostic tests that they conduct (http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/IVDRegulatoryAssistance/ucm124105.htm). Tests that meet certain criteria may be performed in an environment that is exempt from some requirements stated in the CLIA legislation, commonly referred to as a CLIA-waived laboratory. A CLIA waiver may be granted for a test after the clearance or approval process or through a dual pathway in which the clearance and waiver occur simultaneously [known as a Dual 510(k) and CLIA Waiver Application]. Settings that perform only certain tests that are simple to use and have an insignificant risk of an erroneous result are required to obtain a certificate of waiver from the CMS. While the laboratories must follow manufacturers' instructions for the tests, they receive no routine inspections, and the tests are exempt from most CLIA requirements (https://www.cms.gov/regulations-and-guidance/legislation/clia/certificate_of_-waiver_laboratory_project.html, https://wwwn.cdc.gov/clia/Resources/WaivedTests/default.aspx).

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FDA Regulation of Medical Devices.

There are CLIA-waived nucleic acid-based tests for influenza A and B viruses, respiratory syncytial virus, and GAS and a syndromic respiratory panel that tests for Bordetella pertussis, coronaviruses, influenza A H1 virus, influenza A H3 virus, influenza A H1-2009 virus, influenza B virus, Mycoplasma pneumoniae, parainfluenza viruses, and Chlamydophila pneumoniae from a single patient sample.

Outside the United States, other regulatory paradigms exist. For example, for the European Union, Directive 98/79/EC pertains to in vitro diagnostic medical devices and provides guidance on Conformité Européene (CE) marking (https://ec.europa.eu/growth/single-market/european-standards/harmonised-standards/iv-diagnostic-medical-devices_en). The approval process and regulatory jurisdiction that apply to POC diagnostic tests must be considered as they are implemented in different settings.

New Tests and Technologies

Innovative developers and the financial community are working to leverage the latest technology to develop diagnostic tests that will have a positive impact on patient care. The field is rapidly advancing. Future tests may be able to deliver results with a faster turnaround time than currently available. Ideally, tests would be read by an instrument and electronically interfaced to reduce interpretation errors and to ensure that data are shared. Advances in technology can change the current paradigm in which healthcare systems maintain patient data. As locations of care diversify and patients undergo testing in different settings, patients may gain control of curating their own electronic health record, perhaps with information being stored in the “cloud” and shared across providers (see “Data Connectivity” side bar, page 15).

Colloquium participants discussed targets of interest for developing, improving, and implementing near-patient and POC tests. In the United States, high-priority targets include sexually transmitted infections (STIs), pharyngitis, urinary tract infections (particularly tests that distinguish between infection and noninfection), and community-acquired pneumonia (particularly tests that distinguish between viral and bacterial pneumonia). For STIs and pharyngitis, nucleic acid tests could replace currently available antigen tests. Globally, targets of highest interest include HIV, malaria (as current tests are very difficult to interpret), and TB, although low-income countries with weak healthcare infrastructures can make particularly effective use of POC diagnostics for a wide range of illnesses.

Figure 2

POC laboratory.

Future tests may also be able to provide more detailed information than is currently available through POC tests, such as antimicrobial resistance or the ability to quantitate organisms. New tests may be able to identify host biomarkers of infection to guide treatment (even when a test for the etiologic agent is not available), such as biomarkers that distinguish between viral and bacterial infection or between infection and noninfection. For example, approximately 5 to 15% of school-aged children are colonized with GAS (Speert 1998). When GAS is identified, a biomarker test might differentiate between asymptomatic colonization and signs of infection either by examining GAS gene expression or by analyzing the host immune response to GAS. Eventually, rapid tests may even be able to evaluate a patient’s microbiome to monitor health and predict disease risk, leading to “personalized microbial medicine.”

Due to their expertise and experience with diagnostic tests for infectious agents, clinical microbiology laboratory personnel can complete clinical needs assessments to guide future directions for test development (Weigl et al. 2012). For example, a survey of STD clinic clinicians regarding POC tests for STIs found that respondents valued sensitivity the most, followed by cost, specificity, and time to result (Hsieh et al. 2010; Hsieh et al. 2011; Hsieh et al. 2012). However, different practice settings can have different values because of the practice environment. The results of needs assessments can be used to inform manufacturers as to what technology they should pursue, as well as be shared with business incubators and investors who will work to develop and fund new technologies.

Regardless of the technology, it is vital to ensure that POC tests will perform accurately and reproducibly when used according to the manufacturer’s instructions. Removing the test from the laboratory removes the ability for analysis and “troubleshooting” by experienced personnel. Given the potential for limited monitoring of POC tests, engineering controls must be included when tests are developed. Some colloquium participants expressed concern that controls might not be adequate in their current format and that tests should be able to employ simple checks, such as inhibition controls to ensure that, for example, a negative result truly indicates the absence of the pathogen in question. The technological needs for enabling appropriate controls for tests that will routinely be used by nonlaboratorians must be identified. For example, colloquium participants suggested that contamination should be auto-monitored for NAATs. One way this might be accomplished is if the software accompanying the test device alerts the user when a positive threshold (as established by the user) is exceeded within a period of time, indicating the potential for false positives due to contamination. Periodic environmental monitoring to assess contamination could also be recommended.

Figure 3

Diversity of target product profiles, users, and settings within the spectrum of POC testing.

Colloquium participants asserted that developing countries should have access to the same high-quality testing as is available in developed countries. A recent Perspective in the New England Journal of Medicine called for a model list of essential diagnostics, similar to the Model List of Essential Medicines maintained by the WHO, which could include POC tests (Schroeder et al. 2016).

Effects on Clinical Practice

Near-patient and POC tests provide rapid diagnostic results outside central clinical microbiology laboratories. However, to recognize this benefit, clinical workflow needs to allow for the test to be performed and for results to be reported in a short turnaround time. This is especially true in convenient care or retail clinics, which provide services for simple acute conditions (the most common reasons for visits include upper respiratory tract infections, sinusitis, and bronchitis [27.4% of all visits] and pharyngitis [21.2%]) (Mehrotra et al. 2008). For encounters in convenient care clinics as they are currently run, diagnostic tests for infectious diseases would need to exhibit a turnaround time under 20 minutes to have an impact on clinical care decision-making during the encounter. However, redesigning workflow can allow settings to realize the benefits of rapid diagnostic tests even if the test requires 60 to 90 minutes to complete. Shifting patient flow and reorienting specimen collection may provide a way to integrate POC tests into a brief clinical encounter at a physician’s office or convenient care clinic. The workflow could begin with specimen collection ordered through a triage mechanism based on patient symptoms and accomplished through nurse-initiated provider orders. A potential model for a “flipped” patient encounter is the Dean Street clinic in London (http://dean.st/). Specimen collection might also be performed at home and testing performed at either a clinic, an emergency department (Gaydos et al. 2013), or an off-site diagnostic testing laboratory. Through a telemedicine approach, the testing may also be performed at home, with results sent electronically for secure interpretation and linkage to care (Gaydos et al. 2016). Reorienting timing of specimen collection and testing would allow the result to be available before the healthcare provider sees the patient. The decreased time to reliable results granted by the utilization of rapid NAATs can enable optimal therapeutic management to occur more quickly and can foster better adherence to clinical treatment guidelines (Gialamas et al. 2009, May et al. 2015, May et al. 2016).

One particular area in which near-patient and POC tests might impact appropriate treatment is the prescription of antibiotics. Having a test result readily available to the provider prior to providing antibiotics to a patient may allow for more-directed therapy and improve antimicrobial stewardship. Further studies are needed to examine the impact of POC testing on antibiotic prescribing. Colloquium participants observed that patients do not necessarily want an antibiotic when they come in with an illness, but they do want an answer. The results of rapid diagnostic tests could provide a basis for the provider to explain the recommended therapy (or lack thereof) to the patient. Near-patient and POC tests contributing to antimicrobial stewardship might also support requirements under Joint Commission accreditation (Joint Commission 2016) or CMS Conditions of Participation (https://www.cms.gov/Newsroom/MediaReleaseDatabase/Fact-sheets/2016-Fact-sheets-items/2016-06-13.html).

As near-patient and POC testing increases, and if workflows begin to shift in response, potential caveats must be considered. If the provider will need data from additional laboratory tests to inform diagnosis and treatment, then the time savings from performing the POC tests is lost, and the test may be performed in the laboratory to allow for greater-complexity testing and to gain benefits from batch testing, including lower costs. Some POC systems may be able to test only a limited number of samples concurrently, so scaling up test volume might be problematic for a high-volume setting. In some situations in the developing world, such as for multidrug-resistant TB, appropriate treatment may not be available even if test results are known, which provides little incentive for incurring the cost of the test. These issues must be considered when ordering diagnostic tests for a particular patient.

Effects on Patient Care

Rapid diagnostic tests have the potential to deliver timely results to make better treatment decisions. Depending on the current standard of care in the context of the patient, near-patient or POC testing may provide information more quickly than current practice, allowing a provider to make a treatment decision at the time that the patient is seen rather than to require a follow-up visit. In regions where infectious disease testing is currently unavailable, especially in developing countries, POC tests can provide critical information to inform both diagnosis and treatment.

With expansion of near-patient and POC testing, driven by provider uptake and/or patient demand, guidelines or criteria need to be available for the clinicians ordering the tests to ensure that the tests will have a positive impact on patient care. First, it is important that appropriate tests are ordered, and whether a POC test is preferable to a laboratory-based assay for the particular patient encounter should be considered. Providers must also consider how the test results will be interpreted. The practice of medicine has been described as “a science and an art,” and POC test results are only one piece of information out of many in the clinical picture that providers should consider when assessing a particular patient. It is vital that the results of POC tests are entered into the laboratory results section of the electronic medical record (EMR) of the patient, so that the laboratorian has access to the data to aid the physician in interpreting results when necessary and so that other care providers can easily identify the results upon future patient encounters.

As with all laboratory tests, providers need to be wary of adverse outcomes that can arise from improper interpretation of the results of near-patient and POC tests. Overreliance on POC test results may lead a clinician to miss a diagnosis if the test returns a false-negative result, which can lead to adverse outcomes, either in terms of progression of illness in the patient or continued spread of the untreated disease. False positives, due to contamination, colonization, or incorrect interpretation, may result in inappropriate treatment.

If near-patient and POC tests are utilized wisely as part of the clinical decision-making process, they have the potential to reduce the spread of disease by reducing the time to treatment. Their use can improve a healthcare facility use by reducing the amount of time that a patient waits in the facility and by reducing the resources needed to follow up on laboratory-based test results. Reducing the time that a patient spends in a doctor’s office or emergency room can decrease the exposure to other patients who may be contagious. Specimens for testing could even be collected at home and sent for testing to a reference laboratory, obviating the need to visit the physician’s office or emergency department altogether, if results can be returned rapidly. POC test results may also reduce the spread of disease by optimizing antimicrobial therapy earlier in the course of infection. Appropriately treating only patients with infections improves patient outcomes and improves judicious use of antimicrobial agents, which decreases adverse events and the development of antimicrobial-resistant organisms.

Examples of near-patient and POC tests that may improve patient care include those for HIV, STIs, TB (especially in high-burden developing countries), sepsis, and GAS infections. A review of POC tests for HIV mentions clinical benefits, such as earlier treatment initiation, reduced loss to follow-up, and improved linkage to care and treatment (Drain and Rousseau 2017). A review of POC tests for STIs reports findings from a mathematical model that molecular POC tests with high sensitivity can reduce the prevalence of chlamydia and gonorrhea in high-prevalence settings; even POC tests with lower sensitivity can result in additional patients being treated (Gaydos and Hardick 2014).

Utilization of near-patient and POC testing will likely impact (besides clinical outcomes) patient satisfaction, which is becoming increasingly important to providers and healthcare systems. Receiving a diagnosis and appropriate treatment at the time of service might increase patient satisfaction by decreasing diagnostic delays due to reflex testing that requires patient follow-up. More-efficient workflows as a result of increased POC testing may result in healthcare providers spending more time with their patients and addressing their questions, thus increasing satisfaction scores.

POC tests will enable much more in-home testing for infectious diseases in the future. In-home tests may lead to increased patient satisfaction due to convenience, may be an attractive option for indications for which privacy is an issue, and may reduce the spread of disease (from a mildly ill patient with a positive test who self-isolates or to a well patient with a negative test who does not present to healthcare). Currently, in-home antibody tests for HIV in saliva specimens can provide results in 20 minutes (http://www.oraquick.com/). FDA-cleared in-home sample collection kits for HIV and hepatitis C from fingerstick blood samples allow the patient to mail their specimen to a laboratory for testing. Additional kits for GAS, gonorrhea, chlamydia, and influenza will likely be available soon. Patients could collect their own samples at home and either bring the specimen into a laboratory or run the test at home.

The use of in-home tests will bring specific challenges. Clear and concise sample collection instructions will be critical for in-home testing. To ensure correct sample collection, instructions could be accompanied by QR codes that link to training videos. These videos might also be useful for nonlaboratorian staff in convenient care clinics or pharmacies who may not have extensive experience with specimen collection. Instructions should be provided in multiple languages to expand adoption of the technology. Additionally, specific in-home collection kits could be developed with specialized equipment to make sample collection easier for the public.

Effects on Public Health Response

Public health surveillance is important for monitoring the epidemiology of infectious diseases, identifying outbreaks or epidemics, and informing strategies to address the spread of disease. It is also an important way to get “feedback” on how diagnostic tests perform for the most contemporary version of a particular infection. Reporting to public health agencies, ideally automatically, should be part of a system that utilizes POC testing.

Because of the nature of near-patient and POC testing, care must be taken to ensure that public health surveillance of infectious diseases can be maintained. Pathogen characterization, such as strain typing, may be needed for public health agencies to link cases to an outbreak. Public health agencies have traditionally needed isolates in pure culture for pathogen characterization and analysis, but near-patient and POC tests are culture independent. Some near-patient and POC collection devices inactivate any pathogens present or deplete the entire specimen, making follow-up testing impossible. Thus, POC test users would need to collect another specimen to submit to public health laboratories. In some cases, strain typing is the standard of care (e.g., Salmonella typing), but in cases in which it is not, it is unclear who will pay for the additional specimen collection (if needed) and the typing necessary for public health purposes but not for the immediate care of the patient. In anticipation of increased near-patient and POC culture-independent testing, test users, clinical microbiology laboratories, and public health agencies need to develop methods to allow for continued public health surveillance (Langley et al. 2015).

With an increase in culture-independent testing and decentralized data sets, it might be more difficult to recognize outbreaks quickly, especially if testing is performed in small independent physician offices not connected to healthcare or public health systems. However, if test results are sent to a central repository for surveillance, the increase in data flow may allow outbreaks to be identified more quickly. To harness that benefit, systems that allow for data sharing, with outbreak monitoring and alert systems built in, must be implemented to enable a coordinated public health response. When relevant surveillance information is shared with public health authorities, it is important that patient confidentiality be maintained.

Clinical Microbiology Laboratory Oversight

Colloquium participants noted that when clinical microbiology expertise is available in a healthcare setting, the laboratory should retain oversight of the quality assurance of infectious disease diagnostic tests, even those that are performed outside the laboratory.

However, lack of staffing is currently a challenge for clinical microbiology laboratories. With increased diagnostic testing for infectious diseases performed outside central laboratories, additional staffing models or support may be needed to oversee competency, proficiency, and quality assurance. New staffing models may result in laboratory technologists transitioning from performing testing to overseeing tests performed outside the laboratory. Alternatively, a new type of healthcare worker certified in POC testing may be needed to fulfill the oversight functions. Most large facilities currently employ clinical laboratory scientists as POC coordinators to manage POC tests (including those for infectious indications and others). The American Association for Clinical Chemistry offers a Point-of-Care Specialist certificate program (https://www.aacc.org/store/certificate-programs/9600/point-of-care-specialist-certificate-program), and there are postbaccalaureate programs in clinical laboratory science that can provide advanced training. Specific training could be developed, with input from clinical microbiology laboratory experts, regarding competency and proficiency for infectious disease tests.

Colloquium participants felt strongly that the central laboratory should remain responsible for monitoring for environmental contamination when NAATs are used to decrease problems with false-positive results. Laboratory or site personnel can conduct “swipe testing,” in which swabs or pledgets are used to sample various areas of the test setting and then subjected to NAATs to detect any contaminating nucleic acid that may be present (Mohl et al. 2016). Clinical microbiology laboratory technicians possess expertise that can guide the procedures and schedules for swipe testing and other forms of contamination risk management and that can assist with interpretation of results or necessary decontamination.

Oversight in Other Settings

Near-patient and POC testing will also be performed in small physician-run laboratories as well as nonmedical settings. In those settings, the routine oversight afforded by regular contact with the clinical microbiology laboratory is unavailable. Voluntary frameworks for ensuring oversight and seeking relevant expertise may be useful. Clinical microbiology laboratory expertise may be obtained in these settings through employing consultants or part-time staff to review POC testing, similar to how infection control expertise may be obtained in nursing home facilities. Another option for oversight is a “self-monitoring” electronic system that assesses results from POC tests and alerts when results fall outside normal baselines, for example, when there is a strong increase in influenza-positive tests in summer, which may indicate erroneous test results. It is imperative that competent personnel review results on a regular basis to ensure that rapid action is initiated if any anomalies are identified. Site personnel would also need to monitor contamination, with consultant staff aiding with interpretation and decontamination as needed.

As the healthcare landscape changes, accreditation and state oversight may provide additional avenues for oversight of POC testing. The Joint Commission accredits hospitals, laboratories, and ambulatory healthcare settings, among others, including convenient care clinics (https://www.jointcommission.org/). COLA (an organization that “accredits almost 8,000 medical laboratories and provides the clinical laboratory with a program of education, consultation, and accreditation” [http://www.cola.org/]) is an option for reaching small physician-run laboratories. State-mandated oversight is also an option for monitoring testing, although requirements vary by state and only a small percentage of locations may be reviewed each year. In addition, the current requirement for a prescription for infectious disease diagnostic tests will provide some level of control and oversight over POC testing.

With increased infectious disease testing using more-powerful and -complex methods occurring outside clinical microbiology laboratories and in new settings, mandatory oversight of CLIA-waived tests may be considered. Colloquium participants discussed whether CLIA, as it currently exists, fits the changing paradigm of POC testing or whether it needs to be updated to conform to expanding testing and emerging technologies. Oversight would meaningfully alter what a certificate of waiver entails, but it may be beneficial, as increased testing leads to increased potential for and consequences of error. Oversight of CLIA-waived testing could be initiated through regulations or rule making but would have to balance the intended goals of quality and access.

Ordering and Interpretation

Quality assurance of test performance must be coupled with assurance that tests are properly ordered and interpreted. No test has perfect sensitivity and specificity, resulting in false positives and false negatives; the pretest probability of a particular result can vary by setting and by season, affecting where and when the test may be appropriate, and contamination or colonization may return positive results that should not result in patient treatment. Clinical microbiology laboratories are able to provide feedback regarding the tests physicians order or amend comments to the patient report to document issues that may affect interpretation, but the ability to do so is lost for near-patient and POC testing. Educated or trained personnel serving as “learned intermediaries” might be appropriate for settings without dedicated clinical microbiology laboratory expertise to inform test ordering and interpretation. As with the personnel for test oversight, this may be a position that is filled on a consultant or part-time basis.

Regardless of which methods a setting enacts to ensure proper oversight and interpretation of near-patient and POC tests, an outreach program with training and education is needed as this testing is rolled out. Both providers and patients need to be educated on the tests that are available and the appropriateness of each for a particular setting and patient population. Clinical laboratory professionals will need to acquire new skills and expand the concept of a “laboratory” to encompass and contribute to a complex network of centralized and distributed testing capabilities.

Clinical Outcome Studies

While the potential benefit to patient care of near-patient and POC tests would be rapid diagnostic results to guide treatment, there is a need for high-quality clinical outcome studies to demonstrate the actual value of these tests to patient care. Colloquium participants expressed concern that few outcome studies have been published. Published clinical trials and multicenter studies are needed to determine whether near-patient and POC tests improve patient care and clinical outcomes.

Outcome studies should examine one syndrome at a time and consider the setting, which influences the pretest probability of a particular pathogen. Clinical microbiologists can collaborate with other stakeholders, such as hospital administrators, laboratory administrators, statisticians, and mathematical modelers, to assist with study design and analysis. In particular, the U.S. Preventive Services Task Force, which grades recommendations for clinical preventive services based on the strength of the evidence and the balance of benefits and harms, might provide a model for structuring and analyzing outcome studies (https://www.uspreventiveservicestaskforce.org). Along with impacts on patient care, studies can also examine benefits to society, such as reduced disease transmission or more-judicious antibiotic use.

Funding will be needed to complete the outcome studies. Potential sources include funding related to the National Action Plan for Combating Antibiotic-Resistant Bacteria, funding from the Agency for Healthcare Research and Quality, or funding from philanthropy and foundations, such as the CDC Foundation.

Along with outcome studies by syndrome to show the benefit of near-patient and POC testing generally, there is a need to evaluate particular tests. Tests need to be accurate and safe to be FDA cleared, but not all FDA-cleared tests are the best available test for their stated indication. Colloquium participants suggested large-group evaluations of all POC tests for a particular agent as an information source to analyze tests, similar to the evaluation of rapid influenza diagnostic tests for the detection of H1N1 virus in 2009 (Balish et al. 2009). An impartial evaluator could review the tests and award a “quality seal” to tests that perform according to certain specifications. Another option is to alter practice guidelines to recommend the exclusive use of POC tests that meet a minimum threshold of sensitivity and specificity. Alternatively, data from outcomes studies could be fed into a central repository and assessed by an ongoing algorithm to determine test quality. Federal agencies, such as the CDC, FDA, NIH, or CMS, might be involved in developing criteria for such evaluations.

Box

POC Tests for Group A Streptococcus (GAS).

Cost-Effectiveness Studies

Insufficient data on the cost of implementing POC testing compared to the cost of laboratory-based diagnostic testing exist. Considering the cost of the test itself, it is almost always more expensive to do a test at the point of care than in the laboratory. The labor cost for personnel who are performing the test significantly contributes to POC testing expenses. With increased emphasis on value-based healthcare driving reimbursement decisions, facilities need to be able to demonstrate the return on investment of near-patient and POC tests.

Justification for these increasingly expensive tests may come from downstream metrics, such as improved clinical outcomes, reduction in disease transmission, better utilization of costly in-hospital testing (e.g., magnetic resonance imaging or computed tomography scans), expedited patient healthcare encounters, reduction in unnecessary or inappropriate antibiotic prescriptions, and increased patient satisfaction. Early diagnosis and treatment may avert the cost of repeat visits to the clinician, emergency room visits, or hospital admission if the disease progresses. Cost-effectiveness research is needed to determine whether the cost of a POC test is justified based on downstream effects (Hsieh et al. 2014, Hsieh et al. 2016, Soto et al. 2016).

Evaluating the true value of near-patient and POC tests may involve new methods to determine cost savings. Due to slowed and decreased budgets in healthcare systems, the cost savings (or additional reimbursement) afforded by a POC test may be realized in a department other than the one ordering or performing the test. A test performed in an emergency department may be accounted under different billing algorithms than a test performed in a laboratory. POC tests might even shift the burden of payment away from the medical system and increase the amount that patients are billed if the tests are not covered by insurance or are purchased over the counter. Healthcare economics expertise is needed to study the true costs and value of POC tests in relation to those ordering the tests, those performing the tests, the patient being tested, and the public’s health.

With the development and implementation of new technologies, the cost of each near-patient and POC test is predicted to decrease, but the overall volume and total expense of POC testing is expected to increase. Market drivers, including healthcare competition and patient expectations, may lead to increased adoption of POC testing.

Test Regulation

While a number of tests that can be utilized in near-patient and POC settings have been cleared or approved by the FDA, some may be of higher quality than others. Once a test is on the market and substantially equivalent tests are able to be cleared through the 510(k) process, it is very difficult to remove those tests from the market, even if they are no longer the best test for the stated indication. With the current regulatory paradigm, colloquium participants discussed options for reviewing tests on the market and possible regulatory considerations.

Mechanisms for tracking and identifying contamination events, such as a high frequency of test failures, including leaking test cartridges or tubes, should be developed. For example, test users could report postmarketing adverse events to the FDA. The FDA’s MedWatch website (https://www.accessdata.fda.gov/scripts/medwatch/index.cfm?action=reporting.home) explains what constitutes an “adverse event.” Some issues, however, may be mischaracterized as local problems when in fact they are more widespread. Based on the information received through adverse-event reporting, the FDA further investigates issues and takes any appropriate regulatory actions.

It is also possible to reclassify some devices when issues arise. For example, the FDA recently reclassified rapid influenza detection tests from class I to class II devices and has issued special controls for these tests (Federal Register 2014). Issues with current tests include an advance in the predicate technology (PCR, not viral culture) since approval and the poor sensitivity of some assays, especially for newly emerged influenza viruses. Special controls necessitate clinical performance criteria, annual analytical reactivity testing, and testing with newly emergent influenza viruses to ensure that the tests deliver meaningful results.