Advancing Rapid Point-of-care Viral Diagnostics to a Clinical Setting

Kristin Weidemaier; John Carrino; Adam Curry; John H Connor; Andrea Liebmann-Vinson

Disclosures

Future Virology. 2015;10(3):313-328. 

In This Article

Abstract and Introduction

Abstract

We discuss here critical factors in ensuring the success of a viral diagnostic at the point of care. Molecular and immunoassay approaches are reviewed with a focus on their ability to meet the infrastructure and workflow limitations in clinical settings in both the developed and developing world. In addition to being low cost, easy-to-use, accurate and adapted for the intended laboratory and healthcare environment, viral diagnostics must also provide information that appropriately directs clinical treatment decisions. We discuss the challenges and implications of linking diagnostics to clinical decision-making at the point of care using three examples: respiratory viruses in the developed world, differential fever diagnosis in the developing world and HPV detection in resource-limited settings.

Introduction

The critical first step in managing patient care is accurate diagnosis of the underlying condition. For patients presenting with mild disease, treatment based upon clinical examination may be sufficient for satisfactory outcomes. However, for the conditions that are most severe, and hence most likely to have adverse outcomes, clinical diagnostic tests are the mainstay of modern medical treatment, providing definitive diagnosis, suggesting treatment paths and ruling out alternate or coexisting pathologies. In developed nations with strong supporting infrastructure, diagnostic tests may be conducted at the point of care (POC) or at a central or core laboratory. Tests conducted at doctors' offices are typically simple to operate, minimally complex, cost-effective and, most critically, provide information that helps guide the treatment decision when timely clinical intervention is important to outcome.[1] Examples of such tests include those for respiratory infections (e.g., influenza or RSV), tests that indicate likelihood of infection (e.g., complete blood counts or urinalyses) and routine diagnostics that monitor overall well-being (e.g., cholesterol levels, lead levels, or even blood pressure). In contrast, sample collection at the POC followed by central lab testing may be clinically sufficient when delayed test results are unlikely to determine the eventual clinical outcome, for example, metabolic panels or oncology tests, or when the physician can reliably contact the patient for rapid follow-up (e.g., HPV testing). Increasingly, though, there has been a trend toward moving diagnostics closer to the patient even in high infrastructure nations with minimal patient loss to follow-up. The US POC market, for example, is expected to grow from approximately US$7.8 billion in 2013 to an estimated US$9.9 billion in 2018, driven in large part by a growing demand for patient-centered care.[2,3]

The situation in developing nations, where the majority of the population lacks access to well-resourced laboratories, is entirely different.[4] Here, central lab testing is a service for only a minority of the people, with the majority often being removed from quality medical care. In rural Africa or Asia, POC testing is often the only option for diagnosis, and unfortunately, even with a high-quality POC test, results are often substandard and have little or even detrimental impact on patient care. The factors influencing diagnostic testing in low-resource, low-infrastructure settings may be profoundly different from the factors in high-resource settings typical of the industrialized world.[5] The patient population may seek medical care later in the course of a disease, relying first on self-diagnosis and treatment or delaying due to traditional teachings and local lore. Once care is sought, the nearest health center may be distant, with limited and unreliable transportation. The patient or his caregivers may travel all day to seek help, and once arrived, they all too often encounter a facility with little or no electricity or clean water, minimally trained staff, and an overall shortage of supplies and medicine. The patient is diagnosed and treated on the same visit, with no reliable means of post-visit follow-up and communication. It is due to these underlying environmental and usage conditions that WHO has coined the ASSURED criteria for POC diagnostics (Affordable, Sensitive, Specific, User-friendly, Rapid/Robust, Equipment-free and Deliverable to end users).[6]

Although the ASSURED criteria are most commonly considered in the context of the developing world, it is worth pointing out that low-infrastructure laboratories can exist in industrial nations as well. The ASSURED criteria can thus be applied generally to POC diagnostics in both the developed and developing world, although the context and emphasis may be somewhat different. Cost ('affordable') is surely an important consideration in both settings, though there is clearly a lower per-test price requirement in the developing world. Time-to-result ('rapid') may similarly be different, depending on setting. For instance, a time-to-result of 15 min or less is critical for adoption of a POC test in developed countries, where a physician spends less than 20 min with a patient, whereas time-to-result can be hours in a developing world setting where it is not unusual for a patient to wait the entire day for treatment. WHO preference for equipment-free may be appealing in the developing world but also presents a potential conflict with the need to deliver high sensitivity and specificity. In general, ASSURED demands that the resource capabilities of the end-use environment be taken into consideration at the beginning of the technology development process. We would also argue that no diagnostic test can successfully translate to the POC without a thorough consideration of not only the diagnostic test design (including design for the intended patient population and use environment, validation of test performance, and context-appropriate cost), but also the delivery and support infrastructure and the entire workflow from arrival of the patient, through diagnosis, and eventual treatment and monitoring.[1] In other words, a diagnostic test is used in a specific environment as part of a particular healthcare program. Therefore, translation to the POC requires consideration of all factors in that healthcare program, including the intended use of the test result.[7]

Given the clear need for POC testing, it is perhaps somewhat surprising that current options remain limited. Much of this is due to the genuine technical challenge of providing sensitive and specific diagnosis in complex biological fluids in an easy-to-use format. However, it is also our opinion that many technologies fail to translate successfully to clinical use not only because of the difficulty of complex biological fluids, but also because they fail to consider at the outset the entire diagnostic and treatment process. In this article, we review the translation of POC technologies to limited-resource clinical settings in the context of the ASSURED criteria. We discuss the current technology status, existing gaps and the applicability of POC diagnostics in low-, middle- and high-infrastructure environments. The term 'POC' has been used to describe testing in settings ranging from rural Africa, to doctors' offices, to well-equipped hospitals, provided that patient evaluation, test results and clinical action occur during a single encounter between the patient and healthcare provider.[7] Since much of the challenge in translating POC technologies to clinical settings occurs because those settings lack resources such as trained operators, electricity, or surrounding infrastructure, we focus our discussion on environments outside of a well-equipped hospital. We discuss diverse settings such as US doctor's offices (where diagnostics must be waived from the Clinical Laboratory Improvement Amendment, or CLIA) and rural Africa (where fresh water and electricity may be unavailable), and consider the role and future potential of POC testing in both the developed and developing worlds.

Comments

3090D553-9492-4563-8681-AD288FA52ACE

processing....