Point-of-Care Testing in Microbiology: A Mechanism for Improving Patient Outcomes

Abstract

BACKGROUND

Increasingly, demands for improved health and quality of life conflict with the realities of delivering healthcare in an environment of higher expenditures, adherence to test utilization, and patient-centered experience. Patient-centered care is commonly identified as a goal of healthcare delivery, and yet healthcare systems struggle with delivery of care to patients, often failing to identify the seriously ill and capitalize on the predictive qualities of diagnostic testing. Point-of-care (POC) testing provides access to rapid diagnosis and predictive value key to realizing patient outcomes. An evaluation of cost-effective models and the clinical impact of POC testing for clinical microbiology is needed.

CONTENT

Accurate and rapid diagnostics have the potential to affect healthcare decisions to a degree well out of proportion to their cost. Contemporary healthcare models increasingly view POC testing as a mechanism for efficient deployment of healthcare. POC testing can deliver rapid diagnosis in environments where testing results can be used to direct management during patient visits and in areas where centralized laboratory testing may limit access to care. Nucleic acid assays, designed for POC testing, can match, or exceed, the sensitivity of conventional laboratory-based testing, eliminating the need for confirmation testing. Here, the goals of POC testing for microbiology, applications, and technologies, as well as outcomes and value propositions, are discussed.

SUMMARY

The combination of rapid reporting, an increasing array of organisms capable of causing disease, actionable resulting, and improved patient outcomes is key in the evolution of POC testing in clinical microbiology.

“They [lab tests] are to the physician just as the knife and scalpel are to the surgeon.”

William Osler, Physician-In-Chief Johns Hopkins Hospital, 1889–1905

Patient-centered care is increasingly identified as a goal of healthcare delivery, and yet, healthcare systems struggle with delivery of care to patients, often failing to identify the seriously ill and to capitalize on prediction offered through diagnostic testing. Healthcare models increasingly view point-of-care tests (POCTs)⁴ as a mechanism for efficient deployment of healthcare. The point-of-care (POC) testing market has risen by over $29 billion in global sales and is expected to surpass $38 billion by 2020 (1, 2) (Fig. 1).

Global market expenditure in POC and publication citations.

This review will assess the field of microbiology and infectious disease testing as it relates to contemporary disease states, POCT applications, technologies, evidence, and current challenges.

Redefining POCTs for Microbiology: Contemporary Perspective

Many descriptive names have characterized POCTs, including bedside testing, near-patient testing, physician office-based testing, decentralized testing, off-site testing, ancillary/alternative site testing, and testing performed by nonlaboratory trained personnel, waived testing. The College of American Pathology defines POCTs as tests designed for use at or near the site where the patient is located that do not require permanent dedicated space, and where the testing is performed outside the physical facilities of the clinical laboratories (3).

Waived testing, a US Food and Drug Administration (FDA) designation, is a regulatory designation characterizing diagnostic assays that are simple to perform, have an insignificant risk of delivering erroneous results, and require reduced regulatory oversight (4). Insight into POC testing defines a working definition as diagnostic testing that will result in a clear and actionable management decision, such as when to start treatment or to require a confirmatory test, within the same clinical encounter (5).

Although debates over a universal definition of POC exist, there is little debate regarding the intent of POC testing. For POC testing to provide tangible benefits, results should be actionable, leading to improved health outcome and increased patient satisfaction. The key objective of POCTs is to produce results more quickly than could be routinely offered by contemporary or centralized testing or within the context of discrete patient visits (6). A goal for POC testing should be to provide analytical performance that can match the performance of testing performed in larger centralized labs, allowing POCTs to serve as stand-alone or “one and done” testing without the need to question sensitivity or require follow-up testing.

Early applications of POCTs for microbiology testing focused on resource-limited settings where lack of access to medical testing is one of the major reasons for the failure of healthcare services (7). This perspective continues to permeate contemporary views on POCTs, which still focus on relatively inexpensive, instrument-free tests used in place of laboratory-based testing. Influenced by this perspective, and fueled by an emphasis on global health initiatives, the WHO proposed a general framework for POCT development based on the “ASSURED” criteria: Affordable, Sensitive, Specific, User friendly, Rapid and robust, Equipment-free, and Deliverable to end users (8).

ASSURED criteria were necessary when rapid detection assays were introduced, and many POCTs filled a needed gap in place of centralized testing, which was often inaccessible, for which collection and transport of specimens was difficult to coordinate, and delivery of results was slow. However, rigid adherence to ASSURED criteria imposes artificial restrictions on the concept of POC testing. Does location define POC, or does the technology define POC? Does a simple, inexpensive dipstick test performed in a centralized laboratory qualify for POC? Similarly, the same inexpensive dipstick test can be performed by nonlaboratory personnel, but if results are delayed until after the patient has left care, then benefits of POC testing are limited.

Pai and colleagues reexamined the working construct of POC by suggesting that POC testing address “test target profiles” (TTPs) (5). TTPs define the user, the location, and test complexity to provide a greater understanding and flexibility on how POC testing should be applied in nontraditional laboratory environments, such as clinics, pharmacies, or homes (Table 1).

Microbiology and POC Testing: Natural Evolution

Microbiology and POC testing have always been a natural fit because microbiological diagnoses are actionable, leading to antimicrobial treatments(s) and informing diagnostic differentials and management goals. Deploying rapid, laboratory-independent diagnostic tests for just 4 infections (bacterial pneumonia, syphilis, malaria, and tuberculosis) could prevent >1.2 million deaths each year in developing countries (9). Table 2 outlines advantages of POC testing for microbiology.

Balancing requirements for affordable, easy to use, sensitive POCTs is difficult. Evaluation of any POCT should require independent assessment of the relative clinical value rapid testing offers, and the value should be tied to patient outcomes. Requirements for POCTs differ when comparing application within developed and resource-limited healthcare settings. Raising the expectations for POC testing by requiring POCTs to match, or exceed, the accuracy and performance of centralized laboratory testing should be a contemporary goal. The need for highly sensitive POCTs remains a debate. Some have argued that a true POCT should place an emphasis on clinical impact over diagnostic accuracy (10). Measures of patient outcomes and efficacy are highlighted, while stressing that less sensitive testing may still positively affect large proportions of target populations (11, 12). Can a test with 70% to 80% accuracy that reaches 70% to 80% of a population still provide clinical benefit? The answer to this question is scenario dependent. In industrialized healthcare systems, poor sensitivity of a POCT negates its use because a lack of reliable sensitive testing outweighs the advantages of offering POC testing and presents increased risk related to missed diagnosis and/or increased costs associated with follow-up testing (13). From an individual patient perspective, this acknowledgment has forced new minimum standards for rapid influenza and tuberculosis testing (14, 15). However, perspective from public health and resource-limited settings indicates that some testing may be better than none at all, and even poorly performing POCTs can be effective compared with empiric approaches or failing to provide testing options. Despite debate, the goals of POC testing are clear: to provide faster diagnosis, accelerate treatment response, and identify patients who require access to additional medical treatment, including hospitalization.

Technologies for POC Testing

POC testing is generally supported by 2 types of technology: small bench-top analyzers and handheld single-use devices. Lateral flow enzyme immunoassays (EIAs) for bacterial, viral, fungal, or parasite antigens have a long history as POCTs. Lateral flow tests or strip tests rely on the binding of a microbial antigen present in the clinical sample to a primary antibody conjugated to signal, typically a gold impregnated molecule or a fluorescent marker. Bound antibody–antigen complex(es) then migrates either under the effect of a lysis buffer or by capillarity in a solid substrate to generate detectable signals (16). Lateral flow assays are generally inexpensive and easy to use but can suffer from limited sensitivity, particularly as compared with nucleic acid amplification assays (NAATs) (13).

NAAT testing offers greater sensitivity because these tests target pathogen-specific RNA or DNA sequences. NAATs include many variations of molecular chemistries, including PCR, transcription-mediated amplification, strand displacement amplification, loop-mediated isothermal amplification, and helicase-dependent amplification. Although PCR assays have emerged as gold standard testing in many applications, reliance on instrumentation, thermocycling chemistry, and high associated costs have limited their adoption for POC testing. In the US, POC testing is heavily reliant on lateral flow EIA technologies (4). Recent developments have now focused on NAAT techniques that can be performed with minimal instrumentation requirements at a single temperature (isothermal amplification).

NAATs offer the security of sensitive, reliable, specific results. However, recent experience suggests that different molecular chemistries may not perform equally well in real world experiences and that differences in test performance exist between different NAAT assays (17). Genetic diversity in target pathogens, often tied to regional differences and circulating genotypes, affects molecular-based assays. NAATs can carry risks of contamination during sample collection and extraction processes or from vaccines/environmental sources (3, 18). Many POC molecular assays incorporate single closed-tube systems that limit the risk of preprocessing and carryover contamination (19), making them suited for POC testing.

Microfluidics and Cell Phone-Based POCT

Traditional lateral flow chemistry is built around processes in which fluids move through a system and around a stationary analyte. Droplet microfluids reverse this process whereby fluids stay in place, and the analyte, or testing sample, moves through the system (20). Benefits for POC testing include reagents that can easily be applied to cartridges and low costs associated with inexpensive instrumentation. Droplet microfluid assays have been used with cell phones for use with Chlamydia trachomatis (CT) testing. The cartridge itself serves as the processing unit for isothermal amplification, and optical imaging; a mobile phone, connected to the device, then provides the link to data acquisition and reporting through the phone's camera (21).

Microbiology Applications for POCT

A total of 17 different infectious agents for 10 different diseases, encompassing 139 CLIA-waived tests, are listed as waived tests by the FDA (4).

URINARY TRACT INFECTIONS

Urinary tract infections (UTIs) represent the second most common bacterial infections seen in primary care, accounting for an enormous healthcare burden of up to 3% of all general practitioner visits (22). A 5-country study conducted across the US, UK, the Netherlands, Belgium, and Australia concluded that UTI testing among primary care physicians was the largest unmet POC need (23).

Simple nitrate tests represent some of the easiest POCTs but also demonstrate the challenges of applying POC testing to microbiology, particularly as related to their sensitivity and inclusivity of disease. A study targeting UTI among symptomatic men found urinary nitrite to have a sensitivity of 38% and a corresponding specificity of 84%. False-negative nitrate results are often affected by a lack of dietary nitrate, reduction of nitrate owing to diuresis, or because some organisms, such Enterococcus and Acinetobacter species do not reduce nitrate.

Flexicult (not approved by the FDA) POCT urine culture involves fresh urine being poured onto a chromogenic agar plate, which is then incubated at 35 °C to 37 °C overnight in a small desktop incubator located onsite in the clinic. Chromogenic plates are subdivided into 6 segments: The largest allows for the identification of species through bacterial growth on chromogenic substrate; the other 5 contain agar impregnated with antibiotics and are used to assess antibiotic susceptibility. Compared with standardized laboratory testing, Blom et al. reported a 4% error rate for assessing bacterial identification and quantification and correctly determined susceptibility in 93% of cases tested (24). Another study of the impact of providing Flexicult compared with traditional laboratory-based urine cultures revealed no differences in antibiotic utilization, recovery, patient enablement, UTI recurrences, reconsultation, or hospitalizations. However, office-based POC UTI testing using the assay was not actionable or cost-effective (25).

RESPIRATORY INFECTIONS

Influenza infection.

The CDC recommends initiating antiviral treatment within 48 h of onset of symptoms associated with influenza to prevent deaths, shorten duration of symptoms, and limit spread of secondary infections (26). The availability of antiviral therapies places importance on obtaining a rapid accurate diagnosis during patient visits to support treatment. US hospital surveys indicated that >60% of healthcare systems rely on rapid EIA testing as their sole diagnostic for influenza (27). However, concerns over poor performance of rapid lateral flow EIA influenza assay exist (13, 14), and sensitivity among published studies varies widely from <40% sensitive to upward of 80% to 90% (13, 28). Molecular assays for influenza and respiratory syncytial virus (RSV) offer highly sensitive testing equal to that of centralized labs, allowing NAAT-based POCT results to be used confidently without requirements for confirmation testing.

Hernandez et al. applied POC PCR testing to influenza/RSV in physician office and outpatient clinics, which reduced time to result by 70% and empiric antiviral prescriptions (29).

Hansen et al. demonstrated that providing reverse transcription PCR for influenza in the emergency department (ED) setting (Roche; FDA-cleared, CLIA-waived) was actionable, resulting in changes to empiric management approaches in 60% of cases (30). The impact of providing influenza diagnosis within ED visits is difficult to assess in part because many patients present with additional comorbidities that influence management decisions independent of an influenza diagnosis. Identifying patients with primary diagnosis codes for influenza and/or acute respiratory infections allowed further insight into the impact of providing the POC diagnosis and its impact on hospital admissions, medical procedures, radiology, and laboratory testing, resulting in a cost savings of $200.40 per ED visit (30).

Mycobacterium tuberculosis.

Key to control of M. tuberculosis is case detection, and microscopy continues to be central to diagnosis. Light-emitting diode (LED) microscopy is a diagnostic tool developed primarily to allow resource-poor parts of the world access to the benefits of fluorescent microscopy. Compared with conventional mercury vapor fluorescence microscopes, LED microscopes are less expensive, have lower maintenance requirements, can be operated without dedicated dark microscopy rooms, and do not require warm-up times, making them suited for POC applications. Minion et al. compared diagnostic accuracy and time to result for 2 LED technologies with that of conventional fluorescence microscope and mycobacterial culture in 195 cases submitted for M. tuberculosis testing. No differences in sensitivity or specificity between the 3 microscopic techniques were noted, and LED-based microscopy could be performed with 1.12 to 1.5 min/slide (31).

The Cepheid Xpert MTB/RIF (FDA-cleared, non-CLIA-waived) assay is currently the only FDA-cleared M. tuberculosis PCR assay. Testing uses a heminested PCR design using 5 molecular beacons that bind regions of the ribosomal polymerase-B gene in which most mutations conferring rifampin resistance are found (32). The assay has been successfully implemented as a POCT in clinics in Africa (33) and has positively affected time to M. tuberculosis diagnosis, time to therapy, and reduced transmission rates (9, 34).

Novel molecular technologies are currently in development, with a focus on handheld isothermal molecular POCTs for M. tuberculosis (35). PCR-based assays by Molbio Diagnostics (non-FDA-cleared) and Epistem (non-FDA-cleared) feature automated platforms and novel thermocycling designed to reduce costs and power requirements (36, 37). An observational cohort study examining >1600 participants is currently a registered trial with an anticipated completion date of December 2019 (38). The Epistem-Genedrive was evaluated as a multicenter, cross-sectional, blinded diagnostic accuracy study involving 336 patients (Brazil, South Africa, and Uganda). The analytical limits of detection reached 2.5 × 10⁴ colony-forming units/mL to 2.5 × 10⁵ colony-forming units/mL with a corresponding sensitivity of 45.4% compared with reference PCR and microscopy. The Genedrive assay failed to meet performance standards recommended by the WHO for a smear microscopy POCT for M. tuberculosis (39). Enthusiasm for easy-to-use portable POC testing devices needs to carefully balance requirements for ease of use with analytical performance needed to provide security and confidence in reporting.

TROPICAL FEVERS AND FEVERS OF UNKNOWN ORIGIN IN RETURNING TRAVELERS

Malaria.

POCT for malaria testing has gained acceptance in endemic areas where malaria remains a substantial health risk. The WHO recommends that parasite-based diagnosis should be used in all cases of suspected malaria before patients begin treatment (40), further supporting the need for POCTs for malaria. POC malaria tests typically target histidine-rich proteins in Plasmodium species (41) and are primarily used in resource-limited settings. No assay is cleared by the FDA as a CLIA-waived POCT.

Sensitivity of immunochromogenic assays is generally >95% in patients with blood parasitemia counts ≥0.001%, although sensitivity, compared with microscopy, may fall between 70% and 80% in patients with blood parasite counts <0.001 (42). An Ethiopian study examined 2 inexpensive malaria POCTs—the Parascreen™ and Paracheck-Pf (not FDA-cleared)—among 2422 suspected malaria patients. The study focused on cost-effectiveness models based on applying POCT malaria diagnosis and assessing the number of correctly treated cases using POC testing compared with presumptive/empiric diagnosis and treatment. Investigators calculated the cost of a diagnosis and treatment divided by the number of correctly treated cases resulting in increased cost-effectiveness (2.4× Paracheck-Pf and 6.5× Parascreen) (43). Investment in POC testing for malaria in Ethiopia facilitated targeted management of 65% more cases, compared with presumptive diagnostic approaches, for as little as $0.59/patient (43).

The BinaxNOW malaria test is currently the only FDA-approved test capable of detecting 4 Plasmodium species and is used in core microbiology laboratories alongside microscopy to provide rapid reporting. Although the BinaxNOW assay is not CLIA-waived, some investigators outside the US have examined its use as a POCT at bedside and remote clinic settings with sensitivity and specificity ranging from 85% to 88% and 97% to 99%, respectively (44, 45).

The Ebola outbreak in West Africa reported in March 2014 rapidly became the deadliest occurrence of the disease since its discovery in 1976 and highlighted the need for access to rapid diagnostics to quickly diagnose suspected patients and limit spread (37). Fever in the returning traveler is applicable for POC testing because rapid diagnosis of potentially infected individuals from tropical countries can be life-saving in some situations. Experimental POCTs for tropical diseases exist; however, no assay has been approved by the FDA. Published series examining POCTs for Borrelia species, typhus, rickettsiae, Bartonella species, and Leishmania have all been described using a combination of rapid PCR and antibody assays (46). CL Detect™ Rapid (non-FDA-cleared) and Loopamp™ Leishmania Detection Kit (non-FDA-cleared) were examined as potential POCTs for Leishmania with reported sensitivities, compared with PCR, of 35.8% and 91.4%, respectively (47). A spotted fever group Rickettsia-specific loop-mediated isothermal amplification assay based on a region of the outer surface antigen (17-kDa protein gene) demonstrated analytical sensitivity of 0.00001 ng/μL, which is 10 times more sensitive than the 17-kDa protein gene end point PCR used as the reference method, suggesting its possible future role as POCT for rickettsial diseases (48). POCTs for dengue from bodily fluids, including saliva (not FDA-cleared), exist in rapid immunogenic IgM/IgG antibody assays with overall sensitivities reported between 30% and 96% (49). IgM immune responses to single pathogens can limit sensitivity. NAAT-based testing, delivered as multiples testing, provides wider detection of potential pathogens associated with disease. A simple to use multiplex isothermal amplification assay capable of detecting Zika, chikungunya, and dengue virus (not FDA-cleared) in handheld, battery-powered devices demonstrates analytical limits of detection between 30 and 40 target gene copies and 1.22 plaque-forming units (50). Such assays may also provide a role for environmental sampling of mosquitoes as vectors for transmission and control in target areas.

STREPTOCOCCUS PHARYNGITIS

Perhaps no application of POCT for microbiology has been studied as extensively as that of Streptococcus pyogenes [group A Streptococcus (GAS)] as a causative agent of pharyngitis. Testing consists of pharyngeal swabs often tested by lateral flow antigen-based assays with reported sensitivity/specificity, compared with culture, of 86% to 95% (51). Evidence supporting the use of POCTs for GAS has been documented in pharmacy settings where patients report high satisfaction scores based on receiving same-day diagnosis and provide diagnosis-supported treatment in 33% more cases compared with non-POC control settings (52).

POCTs for GAS highlight the challenges associated with interpreting even simple lateral flow antigen assays in POC settings. Comparing test performance among trained laboratory technologists and nonlaboratory personnel, differences in performance of up to 35% were noted, and sensitivity was consistently improved when the test was performed by laboratory technologists compared with nonlaboratory personnel (53). These experiences demonstrate the role of laboratory involvement in examination, evaluation, selection of POCT, and also training needed to accurately perform testing. Digital immunoassays (e.g., Becton Dickinson Veritor and Quidel Sofia) (FDA-cleared, CLIA-waived) that incorporate bench-top analyzers that automatically detect particles conjugated with the antigen–antibody complex to minimize operator variation in test interpretation, represent another step in POC testing.

Provider education should follow POC testing programs. Palla et al. determined that only 11% of patients tested with POC GAS testing received appropriate antibiotics whereas 89% received inappropriate antibiotics in the setting of negative cases, likely suggestive of viral pharyngitis (54). This finding was also shown by Norton et al., who demonstrated physician education accompanying GAS testing reduced unnecessary testing by 24%, emphasizing the importance of physician education and adherence to test results when applying POCT in clinical practice (55).

Molecular POCTs for GAS are now FDA-cleared and available in simple to use molecular platforms. Molecular tests for GAS exhibit high sensitivity (≥95%) equal to or exceeding that of reference laboratory cultures (56). NAAT testing can provide results in 6 to 24 min and eliminate the follow-up cultures. Are molecular options for GAS POCTs the new standard? Analytical performance would suggest yes, but clinical work flow and costs often dictate a POCT decision. To date, most studies examining POC molecular testing for GAS have focused on analytical data comparisons, clinical consequences of missed diagnosis, and antibiotic stewardship benefits. Few studies have examined economic variables associated with the costs of providing POC molecular GAS testing, which in some instances can be 10 times higher for NAAT testing. Studies of the economic justification for NAAT-based GAS studies are needed and lacking, and may examine deferred costs of eliminating use of backup cultures, laboratory reporting, courier requirements, and centralized laboratory processing.

SEXUALLY TRANSMITTED DISEASES

Sexually transmitted diseases (STDs) are increasingly viewed as an opportunity in which POCTs can drive patient satisfaction while reducing the symptoms and onward transmission. A recent report on the landscape of STDs estimates 357 million people are infected annually with 1 of 4 STDs: syphilis, CT, Neisseria gonorrhoeae (NG), and Trichomonas vaginalis (TV) (57).

POCTs for the detection of syphilis at the POC have been developed and include AccuBioTech (Accu-Tell® Rapid Syphilis Test), Alere (Alere Determine™), Alere/Standard Diagnostics (SD Syphilis 3.0), The Tulip Group/Qualpro (Syphicheck®-WB), Cypress Diagnostics (Syphilis Rapid Test), and Omega Diagnostics (Visitect® Syphilis) with performance sensitivity ranging from 74% to 90% (58). However, no POCT for syphilis has received an FDA CLIA waiver (4). Cost-effectiveness of POC applications for syphilis diagnosis has been demonstrated in resource-limited settings (e.g., sub-Saharan Africa) where alternatives to POC testing are limited. In these settings, use of POCTs has been associated with significant health benefits for women and children and offered cost savings owing to reduced transmission and recurrence (59). FDA-cleared, CLIA-waived lateral flow EIAs for CT, NG, TV, and herpes simplex virus include Qcare Chlamydia TRF test, the QuickVue CT, Quick Vue TV, Alere Determine Syphilis TP, and SD BIOLINE (60). Benefits of POCTs for STDs are widely supported; however, concerns over minimum sensitivity needed for POCTs to be safely used as stand-alone tests exist (57). Sensitivity and specificity of POC NG and TV assays range from 12.5% to 100% and 38% to 98%, respectively (61). High-risk patients who test negative by POC EIAs may still require reference laboratory testing.

The Cepheid NG/CT Xpert assay (FDA-cleared, non-CLIA-waived) has been evaluated as a POC testing approach to public health screening during STD visits. Although this approach provides reliable testing in a clinic setting, one study concluded that a 1-h time to result was too long, and testing failed to provide results in time to direct management in 78.6% of patients (62). Assessing the turnaround time needed for POCT remains key; however, POC testing for STDs is an example of how POCTs can affect healthcare delivery. In February 2014, the NHS Foundation Trust opened Dean Street Express in London, offering free, walk-in, rapid STD screening (Fig. 2). POC testing coupled with innovative healthcare delivery models should further inform our understanding of how POCTs can affect delivery of care through improved access and overall reduction in healthcare costs through aversion (63).

Dean Street Express Clinic (London, UK) and example of novel healthcare delivery using POC testing for STDs.

HIV AND HEPATITIS

Sixteen different antibody, antigen, or antibody/antigen combination assays have received CLIA waivers for fingerstick whole blood, venipuncture whole blood, plasma, and oral specimens (4), making HIV one of the most successful and longest tenured applications for POCT. Rapid HIV antibody testing was approved as an over-the-counter test for use with oral fluid specimens in 2012. POC testing for HIV allows testing to occur in value-added settings, such as physician offices, and testing by non-healthcare professionals as home use and provides a direct link to initiation and retention of care cascades (64), which in turn has significantly limited transmission events (64, 65). Testing is the first and most crucial step in the HIV treatment cascade. An HIV test is the only way a person can know they have HIV. Patients who test positive are linked to specialized health and psychosocial support. Undetectable viral load is the goal for persons living with HIV, which improves overall health and diagnosis. Early treatment reduces the likelihood of transmission. Home testing, which requires laboratory confirmation testing, is effective in achieving primary goals of acquainting patients with their HIV status and facilitating entry into care and treatment.

Tun et al. examined home-based HIV testing in a largely illiterate 257-patient Nigerian cohort. Importantly, 97.7% of enrolled patients reported successful use of a home HIV testing kit, and 14 new HIV cases were identified that were all self-reported and linked to treatment within 90 days (66). POC testing for HIV provides access to testing that leads to identification of new cases, entry to care, and initiation of treatment and has been shown to be a key step in reductions in the number of new cases. Similar care-cascade models are being examined for hepatitis C virus (HCV). The Cepheid HCV assay can accurately detect HCV infection from a fingerstick sample in about 1 h, providing the opportunity for patients to receive an HCV diagnosis and receive therapy in a single visit (67).

Syndromic-Based Panel Testing

Syndromic panel testing is common among microbiology laboratories because testing can detect multiple pathogens associated with infection syndromes (respiratory, gastrointestinal, and central nervous system). Syndromic approaches to POC testing add diagnostic value because infectious causes of disease are broad and diverse, and symptoms are rarely agent specific. Rogers et al. examined the Biofire-RP assay (FDA-cleared, CLIA-waived) in pediatric ED visits, concluding that time to report was improved; however, results were not available for 50% of patients in time to be used in the ED setting (68). This finding was substantiated by Andrews et al., who found the respiratory panel, as a POC device, did not affect length of hospital stay, antibiotic prescribing, mortality, or readmission rates (69). Investigators concluded that findings were likely attributable to delays in initiating the Biofire Film Array testing. Balancing time to result and analytical performance is needed in discussions of applying POCT, and early experience with syndromic-based POCTs suggests that <15 min time to result is required to affect care (70).

Regulatory Oversight and Barriers to Implementation: Testing Is Not Enough

Discussions surrounding POC testing focus on technology as a key driver of implementation. Quicker results do not ensure success of POC testing, and evidence that POC testing can affect patient treatment, healthcare costs, and outcomes is needed. Table 3 outlines examples of various outcomes for POC testing, providing evidence that POC testing can produce desired outcomes.

Determining useful outcome measures for POCTs is dependent on identifying key stakeholders (e.g., patients, physicians, administrators, financers, and payers). Outcomes can generally fall into 1 of 4 key categories:

1. Time management (e.g., decision-making, staffing, streamlined processes, and increased physician/clinic metrics such as relative value units).

2. Consumer/patient (e.g., fewer hospital/clinic visits, improved compliance/retention to care, and increased satisfaction scores).

3. Resource management (e.g., bed use, length of stay, cost-effectiveness, and utilization gains).

4. Medical management (e.g., improved mortality, cure rates, quality of life, and time to appropriate management/therapy).

Collectively, outcomes of POCT will be balanced against greater health gains for lower costs, the health gains for lower or neutral costs, or greater health gains for additional costs that justify paying for POCT.

If the goals of POCT are to provide testing more quickly, then support for POCT should come from demonstrating that test results are used in care of patients during patient visits. Studies demonstrating clinical utility have produced conflicting results, indicating that the success of POC programs are highly dependent on variables that surround testing, such as access to therapeutics, follow-up care, reference diagnostics, and physician education. Hanrahan et al. determined that the process of sending M. tuberculosis testing to the reference laboratory was a trigger for providers to initiate therapy in patients suspected of having tuberculosis, and POCT did not affect adherence or time to therapy (71).

The infrastructure and support needed for POC testing programs are rarely discussed, and costs associated with oversight of POC testing are infrequently addressed in studies concluding cost-effectiveness. Budgetary impacts of POC testing include higher reagent costs, capital costs associated with testing analyzers, service contracts, electronic reporting systems, and associated costs needed for confirmation/follow-up testing. Labor costs associated with POC coordinators are often overlooked; centralized laboratories are frequently unwilling to incur the loss of valuable laboratory staff often needed to justify POC testing.

Whether POC testing saves money depends in part on the opposing perspectives of payers vs producers of laboratory services. Future evaluation of POCT should incorporate analyses that shift perspective away from simply providing faster testing to also consider accessibility.

Barriers to implementing POC testing have been examined using rapid HIV testing as a model (72). Concerns over test performance, including quality control, staffing, robustness, and space requirements, accounted for 51% (97 of 190) of all documented responses across all 4 levels. The evolution of NAATs in POC testing should eliminate concerns in performance of testing relative to tests performed in core laboratories but will bring stronger concerns over test oversight and quality control. POC testing placements transfer logistical responsibilities to clinics, including quality assurance, maintenance, stock control, cartridge disposal, documentation, and follow-up reporting. Thus, POC at the primary healthcare level must be accompanied by ownership and financial, operational, and logistical support (71) (Fig. 3).

Considerations and oversight associated with POC testing.

The centralized laboratory should be part of POC testing programs to guide, advise, choose, troubleshoot, and ensure testing meets the needs of the healthcare system. The American Society for Microbiology endorses oversight of POC testing programs by trained laboratorians and/or laboratory-based POC coordinators because of concern for the potential misuse, incorrect performance, and misinterpretation of POCTs (73).

Conclusion

There is little doubt that POC testing will affect microbiology because it provides increased access to care and prompt diagnosis of infectious diseases, which in turn enables timely and effective patient-centric treatment and management. Driven by support from the American Society for Microbiology (73) and the Infectious Diseases Society of America (74), POC testing is occurring in physician offices, pharmacies, and even cruise ships. Increasing emphasis for “on-demand” microbiology testing will continue to drive POC testing for microbiology, both within and external to laboratory settings. As molecular technologies advance, performance gaps between POCTs and reference laboratory testing will close, providing new opportunities for testing, and the laboratory's role in oversight and training will increase. Mortality associated with infections can be measured by time to effective therapy, exemplifying the role POC testing can have on patient outcomes.

If the importance of rapid reliable testing could be acknowledged by Sir William Osler more than a century ago, there is hope that we can improve patient access to important testing, change the way POC testing is perceived, and apply POC testing to reach patients and improve outcomes.

Footnotes

Author Contributions: All authors confirmed they have contributed to the intellectual content of this paper and have met the following 4 requirements: (a) significant contributions to the conception and design, acquisition of data, or analysis and interpretation of data; (b) drafting or revising the article for intellectual content; (c) final approval of the published article; and (d) agreement to be accountable for all aspects of the article thus ensuring that questions related to the accuracy or integrity of any part of the article are appropriately investigated and resolved.

Authors' Disclosures or Potential Conflicts of Interest: Upon manuscript submission, all authors completed the author disclosure form. Disclosures and/or potential conflicts of interest:

Employment or Leadership: None declared.

Consultant or Advisory Role: G.T. Hansen, Roche, Luminex, Chromacode.

Stock Ownership: None declared.

Honoraria: G.T. Hansen, Roche.

Research Funding: Roche.

Expert Testimony: None declared.

Patents: None declared.

References