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Early on in the pandemic, while PCR was getting most of the attention, reverse transcription loop-mediated isothermal amplification (RT-LAMP), an isothermal [[Nucleic acid test|nucleic acid amplification]] technique that allows for RNA amplification, was also quietly being discussed<ref name="LambRapid20">{{cite journal |title=Rapid Detection of Novel Coronavirus (COVID-19) by Reverse Transcription-Loop-Mediated Isothermal Amplification |journal=medRxiv |author=Lamb, L.E.; Barolone, S.N.; Ward, E. et al. |year=2020 |doi=10.1101/2020.02.19.20025155}}</ref><ref name="Schmid-BurgkLAMP20">{{cite journal |title=LAMP-Seq: Population-Scale COVID-19 Diagnostics Using Combinatorial Barcoding |journal=bioRxiv |author=Schmid-Burgk, J.L.; Li, D.; Feldman, D. et al. |year=2020 |url=https://www.biorxiv.org/content/10.1101/2020.04.06.025635v2.article-info |doi=10.1101/2020.04.06.025635}}</ref>, and it has since gained more attention.<ref name="YuRapid20">{{cite journal |title=Rapid Detection of COVID-19 Coronavirus Using a Reverse Transcriptional Loop-Mediated Isothermal Amplification (RT-LAMP) Diagnostic Platform |journal=Clinical Chemistry |author=Yu, L.; Wu, S.; Hao, X. et al. |volume=66 |issue=7 |pages=975–77 |year=2020 |doi=10.1093/clinchem/hvaa102 |pmid=32315390 |pmc=PMC7188121}}</ref><ref name="ParkDevelop20">{{cite journal |title=Development of Reverse Transcription Loop-Mediated Isothermal Amplification Assays Targeting Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) |journal=Journal of Molecular Diagnostics |author=Park, G.-S.; Ku, K.; Baek, S.-H. et al. |volume=22 |issue=6 |pages=729–35 |year=2020 |doi=10.1016/j.jmoldx.2020.03.006 |pmid=32276051 |pmc=PMC7144851}}</ref><ref name="KellnerARapid20">{{cite journal |title=A rapid, highly sensitive and open-access SARS-CoV-2 detection assay for laboratory and home testing |journal=bioRxiv |author=Kellner, M.J.; Ross, J.J.; Schnabl, J. et al. |year=2020 |doi=10.1101/2020.06.23.166397}}</ref><ref name="ThiAColor20">{{cite journal |title=A colorimetric RT-LAMP assay and LAMP-sequencing for detecting SARS-CoV-2 RNA in clinical samples |journal=Science Translational Medicine |author=Thi, V.L.D.; Herbst, K.; Boerner, K. et al. |at=eabc7075 |year=2020 |doi=10.1126/scitranslmed.abc7075 |pmid=32719001}}</ref><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="HaleOxford20">{{cite web |url=https://www.fiercebiotech.com/medtech/oxford-researchers-develop-portable-covid-19-test-costing-less-than-25 |title=Oxford researchers develop portable COVID-19 test costing less than $25 |author=Hale, C. |work=Fierce Biotech |date=09 July 2020 |accessdate=07 August 2020}}</ref> In July 2020, the University of Oxford was in the process of getting a rapid, affordable, clinically-validated RT-LAMP test approved for the European market. Oxford also notes that "[a]n advantage of using LAMP technology is that it uses different reagents to most laboratory-based PCR tests."<ref name="HaleOxford20" /> Thi ''et al.'' have tested a two-color RT-LAMP assay with an N gene primer set and diagnostic validation using LAMP-sequencing, concluding that the pairing of the two "could offer scalable testing that would be difficult to achieve with conventional qRT-PCR based tests."<ref name="ThiAColor20" /> And California-based Color Genomics set up their own proprietary RT-LAMP system in the summer of 2020, capable of handling up to 10,000 tests per day.<ref name="SheridanThisCal20">{{cite web |url=https://www.statnews.com/2020/08/06/better-simpler-faster-covid-19-test/ |title=This California company has a better version of a simpler, faster Covid-19 test |author=Sheridan, K. |work=STAT |date=06 August 2020 |accessdate=08 August 2020}}</ref>
[[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>:


In most cases, LAMP-based testing is much simpler than PCR, lacking the requirement of specialized instruments. Despite LAMP generally being thought of as less sensitive than PCR<ref name="SheridanThisCal20" /><ref name="GuglielmiTheExp20">{{cite journal |title=The explosion of new coronavirus tests that could help to end the pandemic |journal=Nature |author=Guglielmi, G. |volume=583 |pages=506–09 |year=2020 |doi=10.1038/d41586-020-02140-8}}</ref><ref name="HeidtSaliva20">{{cite web |url=https://www.the-scientist.com/news-opinion/saliva-tests-how-they-work-and-what-they-bring-to-covid-19-67720 |title=Saliva Tests: How They Work and What They Bring to COVID-19 |author=Heidt, A. |work=The Scientist |date=09 July 2020 |accessdate=08 August 2020}}</ref>, the explosion of research into RT-LAMP methods for testing for the presence of SARS-CoV-2 continues to indicate that "under optimized conditions," RT-LAMP methods may actually be able to rival the sensitivity and specificity of many RT-PCR COVID-19 tests.<ref name="EsbinOver20" /> Esbin ''et al.'' add<ref name="EsbinOver20" />:
* have a sensitivity (true positive rate) of at least 80 percent, with 90 percent or better being desirable;
* 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.


<blockquote>These methods allow for faster amplification, less specialized equipment, and easy readout. LAMP methods also benefit from the ability to multiplex targets in a single reaction and can be combined with other isothermal methods, like &#91;[[recombinase polymerase amplification]]&#93; in the RAMP technique, to increase test accuracy even more. These techniques may be particularly useful for rapid, point-of-care diagnoses or for remote clinical testing without the need for laboratory equipment.</blockquote>
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" />


CRISPR methods are also being used in conjunction with RT-LAMP.<ref name="GuglielmiTheExp20" /><ref name="EsbinOver20" /><ref name="BroughtonCRISPR20">{{cite journal |title=CRISPR–Cas12-based detection of SARS-CoV-2 |journal=Nature Biotechnology |author=Broughton, J.P.; Deng, X.; Yu, G. et al. |volume=38 |pages=870–74 |year=2020 |doi=10.1038/s41587-020-0513-4 |pmid=32300245}}</ref> RT-LAMP creates complementary double-stranded DNA (cDNA) from specimen RNA and then copies (amplifies) it. Then CRISPR methods are used to detect a predefined coronavirus sequence (from a cleaved molecular marker) in the resulting amplified specimen. Though as of September 2021 approved assays using CRISPR-based detection of SARS-CoV-2 are limited to a handful of companies<ref name="FDAInVitroEUAs21" /><ref name="GuglielmiTheExp20" /><ref name="GDHCRISPR20">{{cite web |url=https://www.medicaldevice-network.com/comment/crispr-biotechnology-disrupt-covid-19-testing-market/ |title=CRISPR biotechnology set to disrupt Covid-19 testing market |author=GlobalData Healthcare |work=Verdict Medical Devices |date=14 July 2020}}</ref>, the technology has some promise as an alternative testing method. CRISPR has the additional advantage of being readily coupled with lateral flow assay technology to be deployed in the point-of-care (POC) setting<ref name="EsbinOver20" /><ref name="GDHCRISPR20" />, though it's worth noting the currently EUAed RT-LAMP-based CRISPR kits are only approved for high-complexity CLIA labs. (The current molecular diagnostic test kits running CRISPR technology are Sherlock BioSciences' Sherlock CRISPR SARS-CoV-2 Kit and Mammoth Biosciences' SARS-CoV-2 DETECTR Reagent Kit, both high-complexity.<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>)
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" /><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 19:23, 3 February 2022

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.[1] Addressing POC testing, the WHO recommends that such assays[1][2]:

  • have a sensitivity (true positive rate) of at least 80 percent, with 90 percent or better being desirable;
  • 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.[2][3][4][5] 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."[6] 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.[7] On October 28, 2020, RADx added an additional 15 biomedical diagnostics projects for funding, for a total of 22.[8] 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.[9]

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[10][5][11][12]:

  • 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

  1. ↑ 1.0 1.1 World Health Organization (28 September 2020). "COVID-19 Target product profiles for priority diagnostics to support response to the COVID-19 pandemic v.1.0". World Health Organization. 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. Retrieved 08 September 2021. 
  2. ↑ 2.0 2.1 Peplow, M. (10 August 2020). "Rapid COVID-19 testing breaks free from the lab". Chemical & Engineering News. https://cen.acs.org/analytical-chemistry/diagnostics/Rapid-COVID-19-testing-breaks/98/web/2020/08. Retrieved 12 August 2020. 
  3. ↑ Krieger, L.M. (10 August 2020). "Coronavirus: How to test everyone, all the time". The Mercury News. https://www.mercurynews.com/2020/08/10/coronavirus-how-to-test-everyone-all-the-time/. Retrieved 12 August 2020. 
  4. ↑ Brown, D. (10 August 2020). "Point-of-care testing could be ‘biggest advance’ in COVID-19 fight". McKnight's. https://www.mcknights.com/news/point-of-care-testing-could-be-biggest-advance-in-covid-19-fight/. Retrieved 12 August 2020. 
  5. ↑ 5.0 5.1 Wisson, J. (28 July 2020). "COVID-19 and effective cohorting: Rapid point of care triage testing". Health Europa. https://www.healtheuropa.eu/covid-19-and-effective-cohorting-rapid-point-of-care-triage-testing/101696/. Retrieved 12 August 2020. 
  6. ↑ Tromberg, B.J.; Schwetz, T.A.; Pérez-Stable, E.J. et al. (2020). "Rapid Scaling Up of Covid-19 Diagnostic Testing in the United States — The NIH RADx Initiative". New England Journal of Medicine. doi:10.1056/NEJMsr2022263. 
  7. ↑ National Institutes of Health (31 July 2020). "NIH delivering new COVID-19 testing technologies to meet U.S. demand". News Releases. National Institutes of Health. https://www.nih.gov/news-events/news-releases/nih-delivering-new-covid-19-testing-technologies-meet-us-demand. Retrieved 12 August 2020. 
  8. ↑ "Funded Projects - RADx Tech/ATP". National Institutes of Health. 28 October 2020. https://www.nih.gov/research-training/medical-research-initiatives/radx/funding#radx-tech-atp-funded. Retrieved 19 November 2020. 
  9. ↑ Cite error: Invalid <ref> tag; no text was provided for refs named FDAInVitroEUAs21
  10. ↑ Cite error: Invalid <ref> tag; no text was provided for refs named EsbinOver20
  11. ↑ Leichman, A.K. (27 July 2020). "10 ways Israeli scientists are improving corona testing". Isael21c. https://www.israel21c.org/how-israeli-scientists-are-improving-corona-testing/. Retrieved 11 August 2020. 
  12. ↑ University of Nevada, Reno (14 October 2020). "COVID-19 rapid test has successful lab results, research moves to next stages: Engineers and virologists team up for novel approach". ScienceDaily. https://www.sciencedaily.com/releases/2020/10/201014141032.htm. Retrieved 19 November 2020. 
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