Difference between revisions of "User:Shawndouglas/sandbox/sublevel33"

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===2.3 Current test kits and their differences===
===2.3 Current test kits and their differences===
''NOTE: Information shown here may rapidly become outdated given how quickly response to pandemic testing can change. A full attempt to keep the content relavent will be made.''  
''NOTE: Information shown here may rapidly become outdated given how quickly response to pandemic testing can change. A full attempt to keep the content relavent will be made.''  
Before continuing, it should be noted that many elements of the prior-mentioned COVID-19 testing guidance have governmental public health laboratories in mind. However, as the scale of the epidemic has grown, the need for commercial laboratories and assay developers to get involved with increasing analytical testing throughput—through a more rigorous public-private partnership—has become abundantly clear. Even so, turnaround times have been slow due to a variety of factors, from lack of in-house laboratory resources to handle high test volumes and a slower-than-expected ramping up of test kit production, to actually getting test kits that are more rapid (yet still accurate) in their diagnosis.<ref name="MadrigalPrivate20">{{cite web |url=https://www.theatlantic.com/health/archive/2020/03/next-covid-19-testing-crisis/609193/ |title=Private Labs Are Fueling a New Coronavirus Testing Crisis |author=Madrigal, A.C.; Meyer, R. |work=The Atlantic |date=31 March 2020 |accessdate=07 April 2020}}</ref><ref name="HaleFDAOpens20">{{cite web |url=https://www.fiercebiotech.com/medtech/fda-opens-gates-to-commercial-coronavirus-testing-without-agency-review |title=FDA opens the gates to commercial coronavirus testing without agency review |author=Hale, C. |work=FierceBiotech |date=17 March 2020 |accessdate=07 April 2020}}</ref><ref name="ApplebyWhyIt20">{{cite web |url=https://www.npr.org/sections/health-shots/2020/03/28/822869504/why-it-takes-so-long-to-get-most-covid-19-test-results |title=Why It Takes So Long To Get Most COVID-19 Test Results |author=Appleby, J. |work=NPR - Health Shots |date=28 March 2020 |accessdate=07 April 2020}}</ref><ref name="Nguyen2019_20">{{cite journal |title=2019 novel coronavirus disease (COVID-19): Paving the road for rapid detection and point-of-care diagnostics |journal=Micromachines |author=Nguyen, T.; Bang, D.D.; Wolff, A. |volume=11 |issue=3 |at=306 |year=2020 |doi=10.3390/mi11030306 |pmid=32183357}}</ref><ref name="YangPoint20">{{cite journal |title=Point-of-care RNA-based diagnostic device for COVID-19 |journal=Diagnostics |author=Yang, T.; Wang, Y.-C.; Shen, C.-F.; Cheng, C.-M. |volume=10 |issue=3 |at=165 |year=2020 |doi=10.3390/diagnostics10030165}}</ref>


* https://www.ecdc.europa.eu/en/all-topics-z/coronavirus/threats-and-outbreaks/covid-19/laboratory-support/questions
* https://www.ecdc.europa.eu/en/all-topics-z/coronavirus/threats-and-outbreaks/covid-19/laboratory-support/questions

Revision as of 17:18, 7 April 2020

2. Diagnostic testing of COVID-19

2.1 Testing conducted on previous coronaviruses

2.1.1 Severe acute respiratory syndrome (SARS)

Severe acute respiratory syndrome, otherwise known as SARS, arose in South China in late 2002. Caused by the SARS caronavirus (SARS-CoV) and believed to have originated from horseshoe bats[1], SARS eventually was contained in the summer of 2003. The last known infection was in April 2004, due to a laboratory accident.[2] During that time, the following sample collection and test procedures evolved from the related outbreaks (note that this is only a summary; consult the cited literature directly for full details)[3][4][5][6][7]:

  • Determine that the patient is indicating clinical and/or epidemiological evidence of SARS (meets case definitions). As Knobler et al. put it: "SARS-CoV testing should be considered if no alternative diagnosis is identified 72 hours after initiation of the clinical evaluation and the patient is thought to be at high risk for SARS-CoV disease (e.g., is part of a cluster of unexplained pneumonia cases)."[5]
  • Collect multiple specimen types at different time points of the patient's illness. Respiratory and plasma or serum specimens should be collected early into the first week of illness. Respiratory samples should be from nasopharyngeal aspirates and swabs in the upper respiratory tract, or in some cases fluids from the lower respiratory tract using bronchoalveolar lavage, tracheal aspiration, or a pleural tap. (Sputum can also be collected.) Whole blood (5 to 10 ml) is collected into either a serum separator tube for blood serum or EDTA tube for blood plasma. Stool samples are also of import early on for virus isolation or detection and are useful in at least the first and second weeks of the illness. Blood serum is usefull in weeks two and three for detecting a rising titre. Additionally, the literature also makes reference to methods of collecting specimens post-mortum.
  • Conduct testing. At the time, the two primary test types used were enzyme immunoassay (EIA; today more commonly known as ELISA[8]) for detection of serum antibody and reverse transcription polymerase chain reaction (RT-PCR) for detection of the virus' RNA. The U.S. Centers for Disease Control and Preventions had this to say about these tests in May 2004[4]:

Both the EIA and the RT-PCR tests are sensitive and highly specific for SARS-CoV. The ability to diagnose SARS-CoV infection in a patient is often limited, however, by either the low concentration of virus in most clinical specimens (RT-PCR assays) or the time it takes a person to mount a measurable antibody response to SARS-CoV (serologic assays). The likelihood of detecting infection is increased if multiple specimens (e.g., stool, serum, respiratory tract specimens) are collected at several times during the course of illness.

The literature also makes reference to an immunofluorescence assay (IFA) for detecting antibody, with the CDC calling its results "essentially identical to those for the EIA for SARS antibody."[4] Tangentially, isolation of SARS-CoV in cell culture from a clinical specimen is also referenced, though such activity is reserved for Biosafety Level 3 (BSL-3) laboratories.
  • Confirm the results. Laboratory confirmation is based on one of 1. initial local lab detection and subsequent national reference lab confirmation of a validated serology-based test detection; 2. isolation of SARS-CoV in cell culture with subsequent confirmation from a validated test; or 3. initial local lab detection and subsequent national reference lab confirmation of SARS-CoV RNA from a validated RT-PCR test which used either two clinical specimens from different sources or two same-source clinical specimens from two different days.
Additionally, in the case of serology, one of the following must be true:
  1. SARS-CoV serum antibodies are detected in a single serum specimen; or,
  2. a "four-fold or greater increase in SARS-CoV antibody titer between acute- and convalescent-phase serum specimens tested in parallel"[4] is detected; or,
  3. a "negative SARS-CoV antibody test result on acute-phase serum and positive SARS-CoV antibody test result on convalescent-phase serum tested in parallel"[4] is detected.
Of note is the WHO's January 2004 cautionary message about serological diagnostics in not only SARS-CoV but other types of coronaviruses. At that time, they showed a level of unsureness in regards to how coronaviruses elicited serological cross-reactions and generated antigenic recall. They also preached caution in interpreting serological results in non-epidemic periods and when no viral sequence data are available. Finally, they also mentioned the added difficulties of rate cases when coinfection with a related human coronavirus occurs, "although the use of expressed proteins in Western blots may help to sort this out."[6] More than 15 years later, Loeffelholz and Tang put this concept into clearer terms, indicating that while "serological assays are not routinely used for diagnosis of [human coronavirus] infections due to the lack of commercial reagents," they still have important value "for understanding the epidemiology of emerging [human cornaviruses], including the burden and role of asymptomatic infections," as well as for antibody detection of novel and emerging coronaviruses.[9]
  • Arrange for confirmatory testing to be performed by an appropriate test site in the case of a positive RT-PCR test.
  • Report to state or local health departments details of patients radiographically confirmed with pneumonia with at least one SARS-CoV risk factor for exposure, clusters of healthcare workers with unexplained pneumonia, and any positive SARS-CoV test results. Additional international reporting of SARS by WHO Member States in regards to probable and laboratory-confirmed cases is also requested.
  • Send off for an additional verification by an external member of the WHO's SARS Reference and Verification Laboratory Network before internationally announcing results as a laboratory-confirmed case.


2.1.2 Middle East respiratory syndrome (MERS)

Unlike SARS, Middle East respiratory syndrome, or MERS, continues to appear in the human population. Since its appearance in 2012, several thousand laboratory-confirmed cases of MERS have been reported to the WHO.[10] The virus MERS-CoV is believed to have originated from bats, which at some unknown point spread to Dromedary camels. Approximately 55 percent of MERS-CoV infections have come from direct contact with such camels, thought it's not entirely clear how the rest of known cases have been caused[11] (Alshukairi et al. suggest asymptomatic or mildly symptomatic camel workers may serve as a possible transmission source[12]). The following sample collection and test procedures have evolved from working with the MERS-CoV virus (note that this is only a summary; consult the cited literature directly for full details)[13][14][15][16][17]:

  • Determine that the patient is indicating clinical and/or epidemiological evidence of MERS (meets case definitions). "Testing for other respiratory pathogens using routinely available laboratory procedures, as recommended in local management guidelines for community-acquired pneumonia, should also be performed but should not delay testing for MERS-CoV."[15]
  • Collect at a minumum both lower respiratory and upper respiratory tract samples. Lower respiratory tract specimens are typically the most revealing, as they have been shown to contain the highest viral load (due to the expression of the virus's cellular receptor DPP4 in the lower respiratory system). Bronchoalveolar lavage, tracheal aspiration, or a pleural tap can be used to collect specimens from the lower respiratory tract. (Sputum can also be collected.) Upper respiratory tract specimens (in this case, both a nasopharyngeal and an oropharyngeal swab are recommended) are also valuable in diagnosis, though extra care should be taken to ensure nasopharyngeal swabs gather secretions from the nasopharynx and not just the nostril. Nasopharyngeal aspiration is also an acceptable sample collection method for the upper respiratory tract.
Regarding serum specimens, slight differences in guidance appear between WHO guidance and CDC guidance. The WHO appears to differentiate between symptomatic and asymptomatic patient testing, wheras the U.S. CDC seems to only indirectly differentiate the two. The WHO suggests if testing symptomatic patients, stick with lower and upper respiratory tract specimens, which will be tested using nucleic acid amplification (molecular) testing (NAAT). Serological testing of serum specimens should be used for symptomatic patients "only if NAAT is not available."[15] If this is the case, the WHO recommends paired samples, one collected within the first week of illness and the second about three to four weeks later. For asymptomatic patients in high-contact outbreak scenarios, the WHO recommends all three sample types (with respiratory samples taken preferably within 14 days of last documented contact).
The current CDC guidance differentiates between molecular testing for active infections and serology for previous infections. The CDC adds that "MERS-CoV serology tests are for surveillance or investigational purposes and not for diagnostic purposes."[13] Whether or not to collect a serum specimen in MERS diagnostics may depend on the assay used, however. For example, the CDC, in its Version 2.1 guidance, indicates that testing using the CDC MERS rRT-PCR assay requires collection of serum in addition to upper and lower respiratory tract specimens. For that specific assay, the CDC differentiates between patients who've had symptom onset less than 14 days prior and those who've had it 14 days or later: if prior, serology is for the rRT-PCR test, and if later, serology is for antibody testing. In either case, 200 µL of serum is required.
  • Conduct testing. NAAT methods like real-time reverse-transcription polymerase chain reaction (rRT-PCR) assays have been the most common tool for diagnosing MERS-CoV infection due to their high sensitivity. According to late 2018 research by Kelly-Cirino et al., at least 11 commercial single assay and five commercial multiplex assay kits are available (see Table S1, a PDF file, from their highly relevant paper), perhaps more as of April 2020. Serological antibody detection is performed using ELISA, indirect immunofluorescence (IIF), and microneutralization.
  • Confirm the results. Laboratory confirmation of MERS-CoV infection is the same for both the WHO and the CDC: one of either a validated NAAT test providing a positive result for at least two different genomic targets, or a validated NAAT test providing a positive result for a specific genomic target along with sequencing confirmation of a separate genomic target. Persons under investigation who receive one negative NAAT result on a recommended specimen is considered to be negative for active MERS-CoV infection. The laboratory should consider testing additional specimens after the first negative. The CDC considers known MERS patients to be negative for active MERS-CoV infection after two consecutive negative NAAT tests on all specimens. The WHO adds: "A patient with a positive NAAT result for a single specific target without further testing but with a history of potential exposure and consistent clinical signs is considered a probable case."[15] The WHO also has additional guidance on using serology for confirming MERS-CoV infection for purposes of reporting under the International Health Regulations.
  • Report using national reporting requirements. More broadly, state or local health departments should receive details about received specimens to be tested for MERS-CoV, even before testing begins. Regardless of result, the final positive or negative laboratory confirmation should also be reported to national authorities. If the infection becomes widespread, updates for each new confirmed case or suspected positive should also be made.


2.1.3 The common cold

Approximately 10 to 15 percent of cases of what we call the "common cold" are associated with an endemic coronavirus, of which are two distinct groups: HCoV-229E and HCoV-OC43.[18] Disease symptoms associated with these coronaviruses—typically in the form of respiratory infection and the symptoms that come with it—by themselves are typically mild[9], and laboratory testing isn't necessarily indicated for those immunocompetent individuals capable of self-limiting.[19] However, symptom overlap with pharyngitis and bronchitis, as well as the complication of pharyngitis and sinusitis also potentially having bacterial origin, can complicate clinical diagnosis. Additionally, as more antivirals that target a specific virus are created, and as concerns of unnecessarily using antibiotics to treat viral diseases grows[20][21], laboratory methods of respiratory virus diagnosis—particularly for those who are immunocompromised—have value.[18][19]

RT-PCR, a molecular method, have been used for well over a decade for detecting coronaviruses.[18][22] However, as molecular methods of analysis have expanded over the years, more rapid solutions for testing have been developed. For example, the GenMark ePlex rapid multiplex molecular diagnostics instrument and the ePlex Respiratory Pathogen Panel were evaluated in a multicenter trial by Babady et al. in 2017.[19] The panel is capable of testing for the presence of 15 viral types—including the -229E, -OC43, and two other coronaviruses—and two bacterial types in nasopharyngeal swab specimens, with results in typically less than two hours.[19] The costs associated with these sorts of tests, compared to their benefits, likely limits ubiquitous use at the first sign of a cold[19], but as molecular diagnostic technologies become more compact and easy-to-use, testing for infection by endemic human coronaviruses may become slightly more commonplace. However, as the authors point out, with no treatment for these endemic coronaviruses, any additional utility beyond diagnosing an illness as viral rather than bacterial would primarily be found in epidemiological studies of the associated genotyping data.[19]


2.2 Organizational and agency guidance on COVID-19 testing

NOTE: Information shown here may rapidly become outdated given how quickly response to pandemic testing can change. A full attempt to keep the content relavent will be made.

Laboratory guidance for testing for SARS-CoV-2 has been relatively quick to evolve. The timely development and organized use of accurate assays and meaningful screening protocols, however, has been inconsistent worldwide, with some countries more urgently and agilely responding than others.[23][24][25] Of course with any novel virus, clinicians and public health experts are dealing with unknown factors. However, public health organizations and agencies have had a base to work from when creating laboratory testing guidance for a novel coronavirus, with more than 40 years of experience with coronavirus biology, pathogenesis, and diagnosis.[26] And while there are fundamental differences between SARS-CoV-2 and its predecessor SARS-CoV, they still share approximately 70 to 80 percent of their genetic code.[27][28] In fact, the WHO had draft guidance for laboratory testing out as early as January 10, 2020, before gene sequencing was even completed.[29] This guidance and similar draft guidance from national public health organizations and agencies has received steady revisions since as understanding of the virus has grown.

Similar to its predecessors SARS-CoV and MERS-CoV, RT-PCR is being recommended in guidance for detecting SARS-CoV-2's RNA in specimens and thus laboratory confirmation of COVID-19 cases. Serology has its place in testing as well, though with similar lessons from SARS and MERS that it's best used to test for past infection (typically after 14 days of suspected contact with a carrier, or mild symptoms) and thus potential short-term immunity due to the presence of antibodies in blood. In its March 19 guidance, the WHO said: "In cases where NAAT assays are negative and there is a strong epidemiological link to COVID-19 infection, paired serum samples (in the acute and convalescent phase) could support diagnosis once validated serology tests are available."[30] On April 3, the U.S. Food and Drug Administration approved the countries first COVID-19 serology test created by Cellex, though Mayo Clinic was also on the verge of rolling out its own in-house serology test as well[31] (Note: Johns Hopkins appears to be maintaining a page tracking approved serology tests around the world.)

The following sample collection and test procedures have evolved from the COVID-19 pandemic (note that this is only a summary; consult the cited literature directly for full details)[30][32][33][34][35]:

  • Determine that the patient is indicating clinical and/or epidemiological evidence of COVID-19 (meets case definitions). Case definitions and testing criteria have initially been strict, but as the CDC notes, as test kit availability ramps up, it "will allow clinicians to consider COVID-19 testing for a wider group of symptomatic patients."[32] However, clinicians are still encouraged to consider other causes for respiratory illness. The CDC provides a priority list, making hospitalized patients and symptomatic healthcare workers the top priority, followed by "those who are at highest risk of complication of infection," then "individuals in the surrounding community of rapidly increasing hospital cases." In the future, as more serology options and other resources become available, serological surveys of people who have never been diagnosed (asymptomatic or otherwise) may begin.[36][37]
  • Collect at a minumum upper respiratory tract specimens and, whenever possible, lower respiratory tract specimens. Although early to say with certainty, it appears lower respiratory tract specimens such as sputum and bronchoalveolar lavage fluid are typically the most reliable specimen type for RT-PCR applications, as they have been shown to contain the highest viral load, in comparison to upper respirator tract specimens.[38][39] As Wang et al. point out, "testing of specimens from multiple sites may improve the sensitivity and reduce false-negative test results,"[38] which is largely reflected in WHO, CDC, Public Health England (PHE), and Public Health Laboratory Network (PHLN; Australia) testing guidance.
Slight differences in upper respiratory tract specimen collection procedures can be found between the WHO/CDC and PHE/PHLN. Both the WHO and CDC offer nasopharyngeal and oropharyngeal swabs as options. The WHO doesn't appear to give a preference, wheras the CDC has a preference for nasopharyngeal swabs but maintains oropharyngeal as still remaining "an acceptable specimen type."[33] In comparison, the latest PHE and PHLN guidance prefer the approach of collecting from both pharynx locations—even with the same swab—"to optimise the chances of virus detection."[35] Nasopharyngeal aspiration is also an acceptable sample collection method for the upper respiratory tract according to all mentioned entitites, though the PHLN specifies that it is a substitution for only the nasopharyngeal (they now refer to it as "deep nasal") specimen.[35]
Regarding serum specimens, statements differ slightly. The WHO notes serology to be useful for retrospective case definition, using paired specimens from the acute and convalescent phases of the disease. The CDC doesn't make reference to serum or serology in their clinical specimen guidance. The PHE suggests hospital patients have "a sample for acute serology" taken but say little else.[34] The PHLN gives similar advice as the WHO, while emphasizing a need "to facilitate retrospective testing, if this is relevant, once serology tests become available."[35]
  • Conduct testing. NAAT methods like rRT-PCR have been the primary tools for diagnosing SARS-CoV-2 infection due to their high sensitivity. The PHLN provides the most background about PCR in their guidance, noting that laboratories in its network are confirmong positive infections "either with RT-PCR assays detecting a different target gene, or broadly reactive PCR tests with sequencing of amplicons."[35] The latter option is less common due to long turnaround time. They also note that other zoonotic viruses such as SARS-CoV are capable of being detected from PCR assays, though endemic coronaviruses like -229E won't be. The WHO, CDC, and PHLN underscore the idea that viral cultures for routine diagnoses are not practical and, if attempted, should only be performed in Biosafety Level 3 (BSL-3) laboratories. As of April 5, no specific methods have been suggested for serological antibody detection, though the current set of approved serology tests from around the world appear to use lateral flow immunoassay or neutralization methods.[37]
  • Confirm the results. The strongest public guidance for considering a potential case as being laboratory-confirmed for SARS-CoV-2 infection comes from the WHO. In their guidance, they differentiate between cases by NAAT "in areas with no known COVID-19 virus circulation" and "in areas with established COVID-19 virus circulation." In the first case, one of these conditions must apply: either a validated NAAT test providing a positive result for at least two different genomic targets, or a validated NAAT test providing a positive result for the presences of betacoronavirus along with sequencing confirmation of a separate genomic target, "as long as the sequence target is larger or different from the amplicon probed in the NAAT assay used."[30] In the latter case of established virus circulation, the WHO notes that "a simpler algorithm might be adopted in which, for example, screening by rRT-PCR of a single discriminatory target is considered sufficient."[30] However, if testing produces one or more negative results, that doesn't necessarily rule out SARS-CoV-2 infection. If suspicion of infection remains high, particularly if only upper respiratory tract specimens were collected, additional specimens from the lower respiratory tract should be collected and analyzed. They also emphasize that both external and internal controls should be applied to NAAT runs.
  • Report using national reporting requirements. Regardless of result, the final positive or negative laboratory confirmation should also be reported to state and national authorities. In the U.S., for example, this means reporting to the state health department using the CDC's PUI and Case Report Form. In Canada, reports are sent to the Public Health Agency of Canada (PHAC) via their Coronavirus Diseases (COVID-19) Case Report Form.


2.3 Current test kits and their differences

NOTE: Information shown here may rapidly become outdated given how quickly response to pandemic testing can change. A full attempt to keep the content relavent will be made.

Before continuing, it should be noted that many elements of the prior-mentioned COVID-19 testing guidance have governmental public health laboratories in mind. However, as the scale of the epidemic has grown, the need for commercial laboratories and assay developers to get involved with increasing analytical testing throughput—through a more rigorous public-private partnership—has become abundantly clear. Even so, turnaround times have been slow due to a variety of factors, from lack of in-house laboratory resources to handle high test volumes and a slower-than-expected ramping up of test kit production, to actually getting test kits that are more rapid (yet still accurate) in their diagnosis.[40][41][42][43][44]

Be sure: "if you can address the differences between covid testing in a POC setting like a POL and testing in a pubic health or reference lab."


2.4 Regulatory and recommended requirements for reporting test results

References

  1. McKie, R. (9 December 2017). "Scientists trace 2002 Sars virus to colony of cave-dwelling bats in China". The Guardian. https://www.theguardian.com/world/2017/dec/10/sars-virus-bats-china-severe-acute-respiratory-syndrome. Retrieved 03 April 2020. 
  2. Normile, D. (2004). "Mounting Lab Accidents Raise SARS Fears". Science (5671): 659–61. doi:10.1126/science.304.5671.659. PMID 15118129. 
  3. New York State Department of Health (February 2004). "Laboratory Testing for SARS". State of New York. https://www.health.ny.gov/diseases/communicable/sars/sars_reporting/attachment_6_dear_doctor_lab.htm. Retrieved 03 April 2020. 
  4. 4.0 4.1 4.2 4.3 4.4 Centers for Disease Control and Prevention (21 May 2004). "Public Health Guidance for Community-Level Preparedness and Response to Severe Acute Respiratory Syndrome (SARS), Version 2 - Supplement F: Laboratory Guidance" (PDF). Centers for Disease Control and Prevention. https://www.cdc.gov/sars/guidance/f-lab/downloads/F-lab-full.pdf. Retrieved 03 April 2020. 
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  6. 6.0 6.1 World Health Organization (23 January 2004). "WHO SARS International Reference and Verification Laboratory Network: Policy and Procedures in the Inter-Epidemic Period". World Health Organization. http://www.who.int/csr/resources/publications/en/SARSReferenceLab.pdf. Retrieved 03 April 2020. 
  7. Liang, G.; Chen, Q.; Xu, J. et al. (2004). "Laboratory Diagnosis of Four Recent Sporadic Cases of Community-acquired SARS, Guangdong Province, China". Emerging Infectious Diseases 10 (10): 1774–81. doi:10.3201/eid1010.040445. PMC PMC3323270. PMID 15504263. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3323270. 
  8. Lequin, R.M. (2005). "Enzyme Immunoassay (EIA)/Enzyme-Linked Immunosorbent Assay (ELISA)". Clinical Chemistry 51 (12): 2415–18. doi:10.1373/clinchem.2005.051532. PMID 16179424. 
  9. 9.0 9.1 Loeffelholz, M.J.; Tang, T.-W. (2020). "Laboratory diagnosis of emerging human coronavirus infections – The state of the art". Emerging Microbes & Infections 9 (1): 747–56. doi:10.1080/22221751.2020.1745095. PMID 32196430. 
  10. Bernard-Stoecklin, S.; Nikolay, B.; Assiri, A. et al. (2019). "Comparative Analysis of Eleven Healthcare-Associated Outbreaks of Middle East Respiratory Syndrome Coronavirus (Mers-Cov) from 2015 to 2017". Scientific Reports 9: 7385. doi:10.1038/s41598-019-43586-9. PMC PMC6517387. PMID 31089148. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6517387. 
  11. Banerjee, A.; Kulcsar, K.; Misra, V. et al. (2019). "Bats and Coronaviruses". Viruses 11 (1): E41. doi:10.3390/v11010041. PMC PMC6356540. PMID 30634396. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6356540. 
  12. Alshukairi, A.N.; Zheng, J.; Zhao, J. et al. (2018). "High Prevalence of MERS-CoV Infection in Camel Workers in Saudi Arabia". mBio 9 (5): e01985-18. doi:10.1128/mBio.01985-18. PMC PMC6212820. PMID 30377284. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6212820. 
  13. 13.0 13.1 Centers for Disease Control and Prevention (2 August 2019). "CDC Laboratory Testing for Middle East Respiratory Syndrome Coronavirus (MERS-CoV)". Centers for Disease Control and Prevention. https://www.cdc.gov/coronavirus/mers/lab/lab-testing.html. Retrieved 04 April 2020. 
  14. Centers for Disease Control and Prevention (2 August 2019). "Interim Guidelines for Collecting, Handling, and Testing Clinical Specimens from Persons Under Investigation (PUIs) for Middle East Respiratory Syndrome Coronavirus (MERS-CoV) – Version 2.1". Centers for Disease Control and Prevention. https://www.cdc.gov/coronavirus/mers/guidelines-clinical-specimens.html. Retrieved 04 April 2020. 
  15. 15.0 15.1 15.2 15.3 World Health Organization (January 2018). "Laboratory testing for Middle East Respiratory Syndrome Coronavirus: Interim guidance". WHO/MERS/LAB/15.1/Rev1/2018. World Health Organization. https://www.who.int/csr/disease/coronavirus_infections/mers-laboratory-testing/en/. Retrieved 04 April 2020. 
  16. Al-Abdely, H.M.; Midgley, C.M.; Alkhamis, A.M. et al. (2019). "Middle East Respiratory Syndrome Coronavirus Infection Dynamics and Antibody Responses among Clinically Diverse Patients, Saudi Arabia". Emerging Infectious Diseases 25 (4): 753-766. doi:10.3201/eid2504.181595. 
  17. Kelly-Cirino, C.; Mazzola, L.T.; Chua, A. et al. (2019). "An updated roadmap for MERS-CoV research and product development: focus on diagnostics". BMJ Global Health 4 (Suppl. 2): e001105. doi:10.1136/bmjgh-2018-001105. PMC PMC6361340. PMID 30815285. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6361340. 
  18. 18.0 18.1 18.2 Wat, D. (2004). "The common cold: A review of the literature". European Journal of Internal Medicine 15 (2): 79–88. doi:10.1016/j.ejim.2004.01.006. PMID 15172021. 
  19. 19.0 19.1 19.2 19.3 19.4 19.5 Babady, N.E.; England, M.R.; Jurcic Smith, K.L. et al. (2018). "Multicenter Evaluation of the ePlex Respiratory Pathogen Panel for the Detection of Viral and Bacterial Respiratory Tract Pathogens in Nasopharyngeal Swabs". Journal of Clinical Microbiology 56 (2): e01658-17. doi:10.1128/JCM.01658-17. PMC PMC5786739. PMID 29212701. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5786739. 
  20. Jenison, R. (30 November 2016). "Rapid lab tests can help reduce antibiotic resistance". STAT. https://www.statnews.com/2016/11/30/antibiotic-resistance-molecular-diagnostics/. Retrieved 03 April 2020. 
  21. Roy, K. (26 September 2018). "Rapid test for viral infections reduces unnecessary antibiotic prescribing". Healio. https://www.healio.com/infectious-disease/antimicrobials/news/online/%7B226c31f3-1d8e-4ffe-82b1-654cb37303c4%7D/rapid-test-for-viral-infections-reduces-unnecessary-antibiotic-prescribing. Retrieved 03 April 2020. 
  22. Mahoney, J.B. (2008). "Detection of Respiratory Viruses by Molecular Methods". Clinical Microbiology Reviews 21 (4): 716–47. doi:10.1128/CMR.00037-07. PMC PMC2570148. PMID 18854489. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2570148. 
  23. Subbaraman, N.; Callaway, E. (23 March 2020). "Coronavirus tests: Researchers chase new diagnostics to fight the pandemic". Nature - News Explainer. doi:10.1038/d41586-020-00827-6. https://www.nature.com/articles/d41586-020-00827-6. Retrieved 05 April 2020. 
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