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Hematology Instruments and Reagents

POC testing continues to narrow the gap

As the industry shifts toward an increasingly patient-centered healthcare delivery system, point-of-care (POC) diagnostics will make rou­tine health testing more convenient, afford­able, and actionable for connected consumers.

The need for rapid POC diagnostics is now becoming more evident due to the increasing need for timely results and improvement in healthcare service. With the recent COVID-19 pandemic outbreak, POC has become critical in managing the spread of disease. Applicable diagnostics should be readily deployable, easy to use, portable, and accurate so that they fit mobile laboratories, pop-up treatment centers, field hospitals, secluded wards within hospitals, or remote regions, and can be operated by staff with minimal training. Complete blood count (CBC), however, has not been available at the POC in a simple-to-use device until recently.

POC testing is becoming more common, popular, and accepted due to increasing need for more timely results, i.e., better turnaround time (TAT), improvement in healthcare services, and mitigating delays in treatment and reducing overcrowding in areas such as the emergency department. Advances in technology play a major role in meeting these needs. Complex tests that were performed only in clinical laboratories a decade ago are now becoming available at the POC.

An unmet area of need is the complete blood count (CBC) with a 5-part white blood cell (WBC) differential (diff), which is the most frequently ordered blood test in clinical pathology. Although the CBC is a standard of care for use in diagnosis, monitoring, and guiding treatment of a diverse variety of disorders, the test has been essentially confined to laboratory settings.

Benchtop hematology analyzers designed for POC operation have a rather large footprint, require substantial maintenance, and frequent calibration procedures that must be performed by trained laboratory personnel. Furthermore, due to the more basic technology employed by benchtop analyzers, they are less adept in coping with pathological samples and raise more flags, indicating further review is required.

Availability of a small, easy-to-use CBC analyzer with WBC 5-part differential would shorten TAT and likely benefit patients in ICUs, operating rooms (ORs), and emergency departments (EDs). In the ICU and OR, hemorrhage is a major concern that is controlled, apart from surgical procedures, by transfusion of blood constituents. Transfusion management is based, in part, on a combination of hematocrit (HCT), hemoglobin (HGB), red blood cell (RBC), and platelet (PLT) counts, yet total laboratory TAT is in most cases 60 minutes or more. Thus, treatment is frequently administered based on hemoglobin values only. Immediate CBC results would substantially improve transfusion management and allow better use of blood resources.

Another example of a healthcare setting that would substantially benefit from decentralized CBC testing is oncology outpatient clinics. These are centers where patients are administered treatments such as chemotherapy and where patients in remission are monitored. Here patients must be tested for neutropenia prior to administering treatment to ensure its safety as well as adjusting dosage. In most cases, the patient’s wait time is largely due to having their blood tested in a central laboratory. This prolongs their clinic stay and delays treatment in the clinic. Immediate CBC with 5-part differential would improve workflow, use of resources, such as the pharmacy, and, most importantly, patient experience.

Father of hematology is now revered!

The history of hematology dates back to ancient Egypt and the use of blood-letting tools. A major breakthrough in the study of blood occurred in 1642 when Anthony van Leeuwenhoek built a microscope and identified blood cells. In 1770, William Hewson, the Father of Hematology, introduced the clotting features of blood and shared his knowledge of leukocytes, or white blood cells. It was not until 1818 that James Blundell successfully completed the first recorded blood transfusion between humans, but the world would have to wait almost another hundred years before Reuben Ottenberg used blood typing to conduct transfusions and identified the universality of type O blood.

Hewson’s major contribution was in isolating fibrin, a key protein in the blood coagulation process. He also contributed work on the lymphatic system by showing the existence of lymph vessels in animals and explaining their function (work for which he was awarded the Copley Medal by the Royal Society in 1769), and demonstrated that red blood cells were flat rather than spherical as had been previously supposed by Anton van Leeuwenhoek. In 1773 he produced evidence for the concept of a cell membrane in red blood cells – however, this last work was largely ignored.

Today, 232 years after his death, Hewson can now be seen not only as a popular lecturer but a charismatic teacher; an all-round clinician and a brilliant, innovative researcher who identified priorities, developed new techniques, and knew how best to present his findings; a successful man who was yet able to apologize for mistakes; a caring, family man who attracted friends.

There have been several attempts to develop miniature simple-to-use analyzers that would fit the POC setting and standard operator profile including the Chempaq XBC, Ativa, SpinIt, HemoCue WBC, and QBC Star. However, the development has either been abolished or ended with instruments that only provide a subset of the CBC parameters. The reasons that the CBC is missing from the large variety of POC tests lie in the complexity of this test. First, it is a cellular-based measurement, in which several types of cells need to be differentiated, based on nuances in their size and morphology. Moreover, cell maturity and staining vary between blood samples; as cells mature their appearance changes, creating a continuous spectrum of characteristics in a single sample for the same type of cells. Further, a major concern in analytical hematology is interference; a variety of interferences affect different measurement parameters depending on the underlying technique. For example, preanalytical errors, such as hemolysis and platelet clumps, may cause laser or impedance-based techniques to confound debris/clumps with other cells. Other known interferences include cold agglutination, microcytosis, bilirubin, nucleated RBC, high lipid content, etc., all of which arise from limitations in the measurement method.

To overcome these challenges, imaging-based analysis has been introduced that reduces susceptibility to interferences and improves quality control on the measurement by extracting far more information from individual cells compared to traditional techniques. This information is then used to differentiate between cell types and subtypes as well as to detect preanalytical and analytical errors. The first digital analysis system was the Cydac scanning microscope system that was developed more than 50 years ago. The major limitation of this technology is that it was too slow and proved to be inferior to manual microscopy examinations. Since then, dramatic advances in machine vision and machine learning (AI) have disrupted many fields, from facial recognition and autonomous cars to FDA-cleared breast cancer diagnostics, and measurement of coronary artery calcification.

Leveraging the dynamic benefits from monitoring the flow of cells through a measurement region, as is done in flow cytometry, has made a breakthrough opportunity by offering superior stability, repeatability, and accuracy and has become the standard practice.

Scientists of the EU-funded HemoScreen project have developed a hematology analyzer suitable for POC use with no need for extensive maintenance and expensive consumables. HemoScreen can deliver laboratory-quality CBC results within 6 min with just one drop of capillary blood, finally making this crucial test simple and accessible. It measures red blood cells, platelets, and white blood cells, estimates hemoglobin levels and flags any cell morphological abnormalities. The innovation behind this is the combination of viscoelastic focusing (VEF) technology with AI. VEF is a novel microfluidics-based technology that allows cells to align perfectly into a single layer, facilitating their optical analysis. Importantly, VEF is not sensitive to clogging or vibrations that can cloud results in the traditional hematology analyzers. This new approach to hematology testing allows for simplifying instrumentation and miniaturization, and thereby has the potential to improve workflow, and, in some cases, patient outcome, in a variety of settings.

How is appropriate quality control assessment and results interpretation ensured with POC testing? Laboratory quality is ensured by quality-control procedures and adherence to good practice as outlined in the ISO15189 Standard. It is important that the use of POC testing does not compromise that quality. When selecting and validating POC analyzers, the laboratory should be involved to ensure that it is the optimal solution and to assist in ongoing operations. The routine running procedures of the analyzer should conform to the required standards and the design of the analyzer should contribute to this by having automatic checks, quality control files, password protection, reagent logs, result files, and other auditable functions.

It is important that the company providing the POC device also supplies control materials for all parameters and that instruments will flag any values outside the expected ranges to the operator so that the appropriate action can be taken. It is also recommended that all instruments are enrolled in external quality-control schemes plus offers quality control program where the day-to-day control results can be uploaded online and compared with peer groups in real time, locally, nationally, and internationally.

Instrument software should provide a clear interface with the user and provide flags, alarms, and interpretive messaging to assist the operator. This is an important area of development and of particular interest in POC, where additional interpretive information is provided from instrument raw data or by assessing results in combination. The interrelation of FBC results lends itself to this development.

Analyzer, reagent, and software development need to be backed up by support from the supplier. The importance of good and ongoing training and support cannot be over-emphasized, both for the optimal operation of the instrument and for quality control and results interpretation.

Improved extraction, microfluidics, miniaturization, and data processing techniques are bringing POC test sensitivity and specificity in line with lab-based tests. The COVID-19 pandemic has transformed the healthcare industry, sparking an unprecedented pace of innovation. As the industry shifts toward an increasingly patient-centered healthcare delivery system, POC diagnostics will make routine health testing more convenient, affordable, and actionable for connected consumers – ensuring that everyone who needs a test can receive one.

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