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[[File:Microfluidic chip for point-of-care medical devices.jpg|right|thumb|400px|Example of a microfluidic chip used in point-of-care medical devices]]On September 28, 2020, the WHO published its blueprint for what they call Target Product Profiles (TPP), which "describe the desirable and minimally acceptable profiles" for four different COVID-19 test categories.<ref name="WHOCOVIDTarget20">{{cite web |url=https://www.who.int/publications/m/item/covid-19-target-product-profiles-for-priority-diagnostics-to-support-response-to-the-covid-19-pandemic-v.0.1 |title=COVID-19 Target product profiles for priority diagnostics to support response to the COVID-19 pandemic v.1.0 |author=World Health Organization |publisher=World Health Organization |date=28 September 2020 |accessdate=08 September 2021}}</ref> Addressing POC testing, the WHO recommends that such assays<ref name="WHOCOVIDTarget20" /><ref name="PeplowRapid20">{{cite web |url=https://cen.acs.org/analytical-chemistry/diagnostics/Rapid-COVID-19-testing-breaks/98/web/2020/08 |title=Rapid COVID-19 testing breaks free from the lab |author=Peplow, M. |work=Chemical & Engineering News |date=10 August 2020 |accessdate=12 August 2020}}</ref>:
As the pandemic has progressed and test manufacturers have become more experienced with SARS-CoV-2 test development, multiplex testing has become an option. The multiplex assay—an immunoassay test able to measure multiple analytes in a single test—is certainly not new in itself. In 1989, R. Ekins developed the ambient analyte theory, which stated that miniaturizing an immunoassay can lead to an improved limit of detection (LOD). That work influenced the future development of microarray multiplex technology principles.<ref name="TigheELISA15">{{Cite journal |last=Tighe |first=Patrick J. |last2=Ryder |first2=Richard R. |last3=Todd |first3=Ian |last4=Fairclough |first4=Lucy C. |date=2015-04 |title=ELISA in the multiplex era: Potentials and pitfalls |url=https://onlinelibrary.wiley.com/doi/10.1002/prca.201400130 |journal=PROTEOMICS – Clinical Applications |language=en |volume=9 |issue=3-4 |pages=406–422 |doi=10.1002/prca.201400130 |issn=1862-8346 |pmc=PMC6680274 |pmid=25644123}}</ref> By 2013, development of multiplex protein immunoassays was becoming increasingly prominent.<ref name="TigheELISA15" />


* have a sensitivity (true positive rate) of at least 80 percent, with 90 percent or better being desirable;
As of September 2021, eighteen "multi-analyte" ''in vitro'' molecular diagnostic tests are shown as receiving EUAs by the FDA, four of them even authorized for CLIA waived testing.<ref name="FDAInVitroEUAs21">{{cite web |url=https://www.fda.gov/medical-devices/coronavirus-disease-2019-covid-19-emergency-use-authorizations-medical-devices/in-vitro-diagnostics-euas-molecular-diagnostic-tests-sars-cov-2 |title=In Vitro Diagnostics EUAs - Molecular Diagnostic Tests for SARS-CoV-2 |publisher=U.S. Food and Drug Administration |date=07 September 2021 |accessdate=07 September 2021}}</ref> Common additional targets for analysis among the various kits include influenza A, influenza B, and respiratory syncytial virus (RSV).<ref name="FDAInVitroEUAs21" /> However, several multiplex test kits cover an even broader array of respiratory-affecting organism types and subtypes such as adenovirus and a few other coronavirus types, to name a few. Kits include the ePlex Respiratory Pathogen Panel 2<ref name="HintonePlex20">{{cite web |url=https://www.fda.gov/media/142902/download |format=PDF |title=ePlex Respiratory Pathogen Panel 2 (ePlex RP2 Panel) |author=Hinton, D.M. |publisher=U.S. Food and Drug Administration |date=07 October 2020 |accessdate=19 September 2021}}</ref>, the NxTAG Respiratory Pathogen Panel + SARS-CoV-2<ref name="HintonNxTAG21">{{cite web |url=https://www.fda.gov/media/146492/download |format=PDF |title=NxTAG Respiratory Pathogen Panel + SARS-CoV-2 |author=Hinton, D.M. |publisher=U.S. Food and Drug Administration |date=03 March 2021 |accessdate=19 September 2021}}</ref>, the QIAstat-Dx Respiratory SARS-CoV-2 Panel<ref name="HintonQIAstat21">{{cite web |url=https://www.fda.gov/media/136569/download |format=PDF |title=QIAstat-Dx Respiratory SARS-CoV-2 Panel |author=Hinton, D.M. |publisher=U.S. Food and Drug Administration |date=29 July 2021 |accessdate=19 September 2021}}</ref>, and the BioFire Respiratory Panel 2.1-EZ.<ref name="HintonBioFireRes21">{{cite web |url=https://www.fda.gov/media/142693/download |format=PDF |title=BioFire Respiratory Panel 2.1-EZ (RP2.1-EZ) |author=Hinton, D.M. |publisher=U.S. Food and Drug Administration |date=30 August 2021 |accessdate=19 September 2021}}</ref> (Of the four, the BioFire panel is approved for CLIA waived testing.<ref name="FDAInVitroEUAs21" />) Adding multiplex testing of SARS-CoV-2 plus other organisms to your laboratory will largely revolve around your lab's CLIA status and assessment of the available options.
* have a specificity (true negative rate) of at least 97 percent, with greater than 99 percent being desirable;
* provide results in less than 40 minutes, with less 20 minutes or less being desirable;
* have "a cost that allows broad use, including in low- and middle-income countries";
* be simple enough that only a half day to, optimally, a few hours of training are required to run the test; and
* operate reliably outside a clean laboratory environment.


Though at the time of the announcement few of the available test systems could likely meet all these requirements, it's clear this and other urgencies have put pressure on manufacturers to expand COVID-19 testing to the point of care setting.<ref name="PeplowRapid20" /><ref name="KriegerCorona20">{{cite web |url=https://www.mercurynews.com/2020/08/10/coronavirus-how-to-test-everyone-all-the-time/ |title=Coronavirus: How to test everyone, all the time |author=Krieger, L.M. |work=The Mercury News |date=10 August 2020 |accessdate=12 August 2020}}</ref><ref name="BrownPoint20">{{cite web |url=https://www.mcknights.com/news/point-of-care-testing-could-be-biggest-advance-in-covid-19-fight/ |title=Point-of-care testing could be ‘biggest advance’ in COVID-19 fight |author=Brown, D. |work=McKnight's |date=10 August 2020 |accessdate=12 August 2020}}</ref><ref name="WissonCOVID20">{{cite web |url=https://www.healtheuropa.eu/covid-19-and-effective-cohorting-rapid-point-of-care-triage-testing/101696/ |title=COVID-19 and effective cohorting: Rapid point of care triage testing |author=Wisson, J. |work=Health Europa |date=28 July 2020 |accessdate=12 August 2020}}</ref> Additional incentives were offered by the U.S. National Institutes of Health's Rapid Acceleration of Diagnostics (RADx) funding program, which sought to speed up innovation in COVID-19 testing and promote "truly nontraditional approaches for testing that have a slightly longer horizon."<ref name="TrombergRapid20">{{cite journal |title=Rapid Scaling Up of Covid-19 Diagnostic Testing in the United States — The NIH RADx Initiative |journal=New England Journal of Medicine |author=Tromberg, B.J.; Schwetz, T.A.; Pérez-Stable, E.J. et al. |year=2020 |doi=10.1056/NEJMsr2022263}}</ref> In August 2020, RADx had chosen to fund seven biomedical diagnostic companies making new lab-based and POC tests that could significantly ramp up overall testing in the U.S. into September 2020. Four of those offerings were lab-based (from Ginkgo Bioworks, Helix OpCo, Fluidigm, and Mammoth Biosciences) and three were POC tests (from Mesa Biotech, Quidel, and Talis Biomedical), all using varying technologies and methods such as next-generation sequencing, CRISPR, microfluidic chips, nucleic acid testing, antigen testing, and saliva testing.<ref name="NIHDelivering20">{{cite web |url=https://www.nih.gov/news-events/news-releases/nih-delivering-new-covid-19-testing-technologies-meet-us-demand |title=NIH delivering new COVID-19 testing technologies to meet U.S. demand |author=National Institutes of Health |publisher=National Institutes of Health |work=News Releases |date=31 July 2020 |accessdate=12 August 2020}}</ref> On October 28, 2020, RADx added an additional 15 biomedical diagnostics projects for funding, for a total of 22.<ref name="NIHRADxTech20">{{cite web |url=https://www.nih.gov/research-training/medical-research-initiatives/radx/funding#radx-tech-atp-funded |title=Funded Projects - RADx Tech/ATP |publisher=National Institutes of Health |date=28 October 2020 |accessdate=19 November 2020}}</ref> As of September 2021, some of those 22 programs have come to fruition, garnering FDA EUAs, including Mesa Biotech's rapid cartridge-based RT-PCR Accula System, Quidel's rapid Sofia SARS Antigen FIA test, Mammoth Bioscience's SARS-CoV-2 DETECTR Reagent Kit, and Visby Medical's COVID-19 Point of Care Test.<ref name="FDAInVitroEUAs21">{{cite web |url=https://www.fda.gov/medical-devices/coronavirus-disease-2019-covid-19-emergency-use-authorizations-medical-devices/in-vitro-diagnostics-euas-molecular-diagnostic-tests-sars-cov-2 |title=In Vitro Diagnostics EUAs - Molecular Diagnostic Tests for SARS-CoV-2 |publisher=U.S. Food and Drug Administration |date=07 September 2021 |accessdate=07 September 2021}}</ref>
Multiplexing provides a variety of benefits for laboratories and patients. In their 2015 paper on ELISA and multiplex technologies, Tighe ''et al'' find that multiplexed immunoassays have the potential to decrease diagnosis times and reduce assay costs. "At the same time, such multiplexing offers more comprehensive analysis whether for research purposes, differential diagnoses, or monitoring of therapeutic interventions."<ref name="TigheELISA15" /> They also note the potential for improved health surveillance of patients, catching early-onset diseases by looking for informative biomarkers.<ref name="TigheELISA15" /> From the perspective of diagnosing infections of SARS-CoV-2 or influenza, the CDC adds that multiplexing helps preserve testing supplies that may be in short supply, conduct more tests in a given time period, and paint a clearer picture of both viruses and their prevalence in a given population.<ref name="CDCInflu21">{{cite web |url=https://www.cdc.gov/coronavirus/2019-ncov/lab/multiplex.html |title=CDC’s Influenza SARS-CoV-2 Multiplex Assay and Required Supplies |author=Centers for Disease Control and Prevention |publisher=Centers for Disease Control and Prevention |date=13 July 2021 |accessdate=19 September 2021}}</ref>
 
Outside the RADx program, enterprising researchers in other parts of the world are also attempting non-traditional approaches to improving COVID-19 testing options. Examples include<ref name="EsbinOver20">{{cite journal |title=Overcoming the bottleneck to widespread testing: a rapid review of nucleic acid testing approaches for COVID-19 detection |journal=RNA |author=Esbin, M.N.; Whitney, O.N.; Chong, S. et al. |volume=26 |issue=7 |pages=771–83 |year=2020 |doi=10.1261/rna.076232.120 |pmid=32358057 |pmc=PMC7297120}}</ref><ref name="WissonCOVID20" /><ref name="Leichman10Ways20">{{cite web |url=https://www.israel21c.org/how-israeli-scientists-are-improving-corona-testing/ |title=10 ways Israeli scientists are improving corona testing |author=Leichman, A.K. |work=Isael21c |date=27 July 2020 |accessdate=11 August 2020}}</ref><ref name="UNRCOVID20">{{cite web |url=https://www.sciencedaily.com/releases/2020/10/201014141032.htm |title=COVID-19 rapid test has successful lab results, research moves to next stages: Engineers and virologists team up for novel approach |author=University of Nevada, Reno |work=ScienceDaily |date=14 October 2020 |accessdate=19 November 2020}}</ref>:
 
* a method of DNA nanoswitch detection of virus particles;
* a dual biomarker-based finger-stick test for acute respiratory infections;
* a rapid breath test to detect volatile organic chemicals from the lungs;
* an affordable, hand-held spectral imaging device to detect virus in blood or saliva in seconds;
* an ultrahigh frequency spectroscopic scanning device to see virus particles resonating;
* a method that combines optical devices and magnetic particles to detect virus RNA;
* an RNA extraction protocol that uses magnetic bead-based kits;
* a nanotube-based electrochemical biosensor for detecting biomarkers in a sample in less than a minute;
* the additional use of an [[artificial intelligence]] (AI) application to better scrutinize test results; and
* the miniaturization of PCR technology to make it more portable and user-friendly.
 
Of course, most of these are largely experimental technologies, and realistically getting them into the lab may be far out. But they represent out-of-the-box ideas that have some kind of chance at playing a greater role in the clinical laboratory or in point-of-care settings in the future.


==References==
==References==
{{Reflist|colwidth=30em}}
{{Reflist|colwidth=30em}}

Revision as of 19:29, 3 February 2022

As the pandemic has progressed and test manufacturers have become more experienced with SARS-CoV-2 test development, multiplex testing has become an option. The multiplex assay—an immunoassay test able to measure multiple analytes in a single test—is certainly not new in itself. In 1989, R. Ekins developed the ambient analyte theory, which stated that miniaturizing an immunoassay can lead to an improved limit of detection (LOD). That work influenced the future development of microarray multiplex technology principles.[1] By 2013, development of multiplex protein immunoassays was becoming increasingly prominent.[1]

As of September 2021, eighteen "multi-analyte" in vitro molecular diagnostic tests are shown as receiving EUAs by the FDA, four of them even authorized for CLIA waived testing.[2] Common additional targets for analysis among the various kits include influenza A, influenza B, and respiratory syncytial virus (RSV).[2] However, several multiplex test kits cover an even broader array of respiratory-affecting organism types and subtypes such as adenovirus and a few other coronavirus types, to name a few. Kits include the ePlex Respiratory Pathogen Panel 2[3], the NxTAG Respiratory Pathogen Panel + SARS-CoV-2[4], the QIAstat-Dx Respiratory SARS-CoV-2 Panel[5], and the BioFire Respiratory Panel 2.1-EZ.[6] (Of the four, the BioFire panel is approved for CLIA waived testing.[2]) Adding multiplex testing of SARS-CoV-2 plus other organisms to your laboratory will largely revolve around your lab's CLIA status and assessment of the available options.

Multiplexing provides a variety of benefits for laboratories and patients. In their 2015 paper on ELISA and multiplex technologies, Tighe et al find that multiplexed immunoassays have the potential to decrease diagnosis times and reduce assay costs. "At the same time, such multiplexing offers more comprehensive analysis whether for research purposes, differential diagnoses, or monitoring of therapeutic interventions."[1] They also note the potential for improved health surveillance of patients, catching early-onset diseases by looking for informative biomarkers.[1] From the perspective of diagnosing infections of SARS-CoV-2 or influenza, the CDC adds that multiplexing helps preserve testing supplies that may be in short supply, conduct more tests in a given time period, and paint a clearer picture of both viruses and their prevalence in a given population.[7]

References

  1. ↑ 1.0 1.1 1.2 1.3 Tighe, Patrick J.; Ryder, Richard R.; Todd, Ian; Fairclough, Lucy C. (1 April 2015). "ELISA in the multiplex era: Potentials and pitfalls" (in en). PROTEOMICS – Clinical Applications 9 (3-4): 406–422. doi:10.1002/prca.201400130. ISSN 1862-8346. PMC PMC6680274. PMID 25644123. https://onlinelibrary.wiley.com/doi/10.1002/prca.201400130. 
  2. ↑ 2.0 2.1 2.2 "In Vitro Diagnostics EUAs - Molecular Diagnostic Tests for SARS-CoV-2". U.S. Food and Drug Administration. 7 September 2021. https://www.fda.gov/medical-devices/coronavirus-disease-2019-covid-19-emergency-use-authorizations-medical-devices/in-vitro-diagnostics-euas-molecular-diagnostic-tests-sars-cov-2. Retrieved 07 September 2021. 
  3. ↑ Hinton, D.M. (7 October 2020). "ePlex Respiratory Pathogen Panel 2 (ePlex RP2 Panel)" (PDF). U.S. Food and Drug Administration. https://www.fda.gov/media/142902/download. Retrieved 19 September 2021. 
  4. ↑ Hinton, D.M. (3 March 2021). "NxTAG Respiratory Pathogen Panel + SARS-CoV-2" (PDF). U.S. Food and Drug Administration. https://www.fda.gov/media/146492/download. Retrieved 19 September 2021. 
  5. ↑ Hinton, D.M. (29 July 2021). "QIAstat-Dx Respiratory SARS-CoV-2 Panel" (PDF). U.S. Food and Drug Administration. https://www.fda.gov/media/136569/download. Retrieved 19 September 2021. 
  6. ↑ Hinton, D.M. (30 August 2021). "BioFire Respiratory Panel 2.1-EZ (RP2.1-EZ)" (PDF). U.S. Food and Drug Administration. https://www.fda.gov/media/142693/download. Retrieved 19 September 2021. 
  7. ↑ Centers for Disease Control and Prevention (13 July 2021). "CDC’s Influenza SARS-CoV-2 Multiplex Assay and Required Supplies". Centers for Disease Control and Prevention. https://www.cdc.gov/coronavirus/2019-ncov/lab/multiplex.html. Retrieved 19 September 2021. 
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