Book:COVID-19 Testing, Reporting, and Information Management in the Laboratory/Diagnostic testing of COVID-19 and other coronaviruses/Organizational and agency guidance on COVID-19 testing

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2.3 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NOTE: Information shown here may rapidly become outdated given how quickly response to pandemic testing can change.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 relevant will be made.

CDC 2019-nCoV Real-time RT-PCR Panel (Research Use Only)

Early in the COVID-19 pandemic, laboratory guidance for testing for SARS-CoV-2 was relatively quick to evolve. The timely development and organized use of accurate assays and meaningful screening protocols, however, has been inconsistent but improving worldwide, with some countries more urgently and agilely responding than others.[1][2][3] 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.[4] 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predecessor SARS-CoV, they still share approximately 70 to 80 percent of their genetic code.[5][6] In fact, the WHO had draft guidance for laboratory testing out as early as January 10, 2020, before gene sequencing was even completed.[7] This guidance and similar draft guidance from national public health organizations and agencies have received steady revisions since as understanding of the virus has grown.

Similar to its predecessors SARS-CoV and MERS-CoV, RT-PCR has largely been the predominant diagnostic method used in guidance for detecting SARS-CoV-2's RNA in specimens and thus laboratory confirmation of COVID-19 cases. Other diagnostic methods such as isothermal amplification (e.g., LAMP) and antigen testing have also emerged as the pandemic has progressed. 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. It also has other uses; in its September 2020 guidance, the WHO said: "If negative NAAT results are obtained from a patient in whom SARS-CoV-2 infection is strongly suspected, a paired serum specimen could be collected."[8] On April 3, the U.S. Food and Drug Administration (FDA) approved the country's 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[9] As of September 2021, the U.S. FDA has granted emergency use authorizations (EUA) for 88 serology/antibody tests.[10] (Note: Johns Hopkins also appears to be maintaining a page tracking approved serology tests around the world.)

Primary testing guidance

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)[8][11][12][13][14]:

  • Determine that the patient is indicating clinical and/or epidemiological evidence of COVID-19 (meets case definitions). Early on in the pandemic, case definitions and testing criteria were initially strict due to lack of test kits[15][16][17], but test kit availability has ramped up since, allowing for testing a wider group of symptomatic patients, as well as asymptomatic patients. However, clinicians are still encouraged to consider other causes for respiratory illness.[11]
  • Collect at a minimum an upper respiratory tract (URT) specimen. Some guidance like that found in the U.K. also suggests collecting lower respiratory tract (LRT) specimens, whenever possible.[13] Broadly, it appears lower respiratory tract specimens such as sputum and bronchoalveolar lavage fluid are a more reliable specimen type for RT-PCR applications, as they have been shown to contain the highest viral load, in comparison to upper respiratory tract specimens.[18][19] In most cases, a URT will be sufficient; however, an LRT is especially useful when a patient tests negative with a URT but is still high suspicious of having COVID-19. Yet, as Wang et al. point out, "testing of specimens from multiple sites may improve the sensitivity and reduce false-negative test results,"[18] 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, whereas the CDC has a preference for nasopharyngeal swabs but maintains oropharyngeal as still remaining "an acceptable specimen type."[12] In comparison, the latest PHE and PHLN guidance prefer the approach of collecting from both pharynx locations—even with the same swab—"to optimize the chances of virus detection."[14] Nasopharyngeal aspiration is also an acceptable sample collection method for the upper respiratory tract according to all mentioned entities except the PHLN, which appears to have removed mention of nasopharyngeal aspirate from its guidance sometime in 2021.[14]
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 used to suggest hospital patients have "a sample for acute serology" taken, but that appears to have been removed from 2021 guidance.[13] The PHLN initially provided similar advice as the WHO, but in late April they expanded their guidance to discuss the value of serology.[14] They have also added collection recommendations for serology, in separate guidance, indicating that "serological testing before two weeks from the onset of symptoms may result in false negative results."[20]
Finally, and more recently, potential evidence of saliva having diagnostic value for detecting SARS-CoV-2 has arisen. Xu et al. noted in published April 2020 research that the "diagnostic value of saliva specimens for ... nucleic acid examination remains limited but promising."[21] Another paper published in September 2020 provided similar thoughts, though was generally more optimistic than the paper published by Xu et al., suggesting saliva from the opening of the mouth (in contrast to Xu et al. and their finding of better results from saliva in the throat) may be viable specimen.[22] In fact, an April 2020 EUA by the FDA had been made for the first saliva-based COVID-19 test, produced by Vault Health, Inc.[23]
As these and similar studies have been peer reviewed and methods validated, saliva has increasingly looked like a viable sample type. The CDC updated their guidance in October 2020 regarding saliva as a testing substrate. The CDC now notes: "Collect 1-5 ml of saliva in a sterile, leak-proof screw cap container. No preservative is required."[12] This is presumably in conjunction with tests approved for the use of saliva. Australia's PHLN updated their guidance in 2021 to include a full section on saliva testing and how to approach it, though cautioning it "does not advise routine use of saliva for diagnostic testing except in specific situations."[14]
  • Conduct testing. NAAT methods like qRT-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 "RT-PCR or TMA are the methods of choice to detect SARS-CoV-2 during the acute illness."[14] Viral cultures are little mentioned, though the PHLN underscores the idea that viral cultures for routine diagnoses are "of limited utility" and, if attempted, should only be performed in Biosafety Level 3 (BSL-3) laboratories.[14] As of August 2020, only the PHLN has made any specific recommendations for how serological testing should be conducted for testing past cases of COVID-19.[14] The current set of approved serology tests from around the world appear to use lateral flow immunoassay, ELISA, or neutralization methods.[17] Also note that at least in the U.S., the FDA in October 2020 discontinued review and approval of laboratory developed tests (LDTs), in favor of tests that would be more likely to increase access to testing or overall test capacity.[24]
  • Confirm the results. The WHO notes that optimally a positive result should come from a NAAT method "with at least two independent targets on the SARS-CoV-2 genome." However, they recognize that "in areas with widespread transmission of SARS-CoV-2, a simple algorithm might be adopted with one single discriminatory target," though monitoring of potential mutations is recommended.[8] Most guidance notes that 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 to limit the chance of incorrect results.
  • Report using state and, if applicable, national reporting requirements. (See the next chapter for more on reporting.) 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 local or state health department using the CDC's COVID-19 Worksheet. In Canada, reports are sent to the Public Health Agency of Canada (PHAC) via their Coronavirus Diseases (COVID-19) Case Report Form.

Additional considerations for point-of-care testing and self-collection

One of the long-term goals of healthcare professionals, governments, and test kit manufacturers has been to develop and increase access to point-of-care (POC) testing solutions for COVID-19. This has come with many challenges, but it is largely being realized. The CDC continues to update its Guidance for SARS-CoV-2 Point-of-Care and Rapid Testing[25], and, after the first "collect and test" at-home kit—the Lucira COVID-19 All-In-One Test Kit—was approved by the FDA in November 2020[26], many more were eventually approved for emergency use.[27] However, while these easy-use or quick-result tests are promising and welcome, a few additional testing considerations come with them. For example, the CDC has indicated that though FDA-authorized POC tests are approved for symptomatic individuals, "CLIA will temporarily allow CLIA-certified laboratories and other testing sites to use SARS-CoV-2 point-of-care and rapid antigen tests on asymptomatic people for the duration of the COVID-19 public health emergency."[25] Other recommendations include not reusing test devices or components, changing gloves at strategic points, and limiting opening of test materials until ready to begin testing.[25]

In some cases, such as drive-through testing sites, patient self-collection of a sample may be required. In these cases, it's vital that the patient is given clear and concise instructions on how to collect the sample before they begin the process. The American Association for Clinical Chemistry (AACC) notes that false-negative results are more likely with poor instruction and recommends healthcare providers provide patients with written or video instructions, along with any verbal instructions. Less invasive nasal swabs are typically being used in this case. During self-collection, the patient inserts the entire swab tip in one nasal cavity, makes four to five sweeping circles along the nasal wall for about 10 to 15 seconds, and then repeats the process in the opposite nostril.[28]

In the case of at-home test kits, instructions for sample collection and system use should be followed carefully. For example, the Lucira All-In-One Test Kit can be used in a CLIA-certified lab or "for prescription home use," meaning a healthcare provide must approve a prescription in order for the patient can use the test at home. Additionally, the healthcare provider will still be held responsible for reporting the test results they receive from the patient using the kit at home.[29]

Mitigating risk associated with false negatives

Before moving on, words of caution should be issued in regard to any COVID-19 testing conducted: false-negative results can be problematic.[30][31] One of the primary reasons they are problematic is that it may leave an otherwise asymptomatic individual to continue to unknowingly spread the virus further. Those individuals may relax physical distancing measures and become lax with their mask wearing, affecting others outside the clinical setting. Inside a clinical setting, a patient with a false negative "may be sent to the frontlines of care and inadvertently transmit the virus to patients and colleagues, further straining the already precarious ability of the health care system to respond to the pandemic."[31]

In a perspective piece published in Mayo Clinic Proceedings, West et al. of the Mayo Clinic offer four critical recommendations for society as we attempt to mitigate the risk associated with false negatives when performing clinical testing for COVID-19. Those recommendations are[31]:

1. Continue protective and preventative measures inside and outside the testing facility. This includes efforts such as physical distancing, regular hand-washing, regular disinfection of surfaces, and adequate personal protective equipment (PPE) for clinical staff (as well as the encouragement of proper mask wearing by others).
2. Develop and improve PCR and serological assays to be more sensitive and specific. The development and improvement process must include methodologically rigorous studies designed to limit the risk of biased results, as well as clearly reported test performance characteristics.
3. Assess patients carefully for their potential risk level for being infected. Confidence in negative test results may need to be lowered for health care workers and individuals in other high-risk groups. In general, given the uncertainty around viral load, asymptomatic transmission, and other disease characteristics, caution should be used with negative results in general.
4. Establish risk-based protocols for managing negative COVID-19 results. Truly low-risk individuals may not be a major concern when results come back negative. However, individuals in higher-risk categories may require more judicious protocols, e.g., delaying a return to a workplace (for self-isolation) despite receiving a negative and having no symptoms. (This may require a more sensitive follow-up test or at least a second negative in a repeat test, particularly among clinical workers.)

2.3.1 Regulatory considerations: HIPAA and CLIA

HIPAA Screenshot.png


The Health Insurance Portability and Accountability Act (HIPAA) is a set of U.S. federal regulatory requirements that attempts to modernize the flow of healthcare information, stipulate how personally identifiable information (PII) (often referred to as "protected health information" or "PHI") maintained by healthcare providers and insurers should be protected from fraud and theft, and address limitations on healthcare insurance coverage in the U.S. HIPAA spans five sections or "titles," mandating health care information access, portability, privacy, and security, as well as stipulations on medical savings accounts, group health insurance requirements, and other tax- and legal-status-related issues.

Normally, HIPAA regulations would put strict requirements on how and when PII can be managed, used, shared, and stored. However, the COVID-19 pandemic has seen a relaxation of some of those requirements by the U.S. Department of Health and Human Services' (HHS) Office for Civil Rights (OCR). The HHS is currently maintaining a list of announcements, notifications, guidance documents, bulletins, and other resources as they relate to HIPAA and the public health emergency. Important notes pulled from that information reveal[32]:

  • Family, friends, and others identified by the patient as being involved in their care may receive PHI from a covered health care provider, particularly when they deem that sharing in the patient's best interest. Additionally, "[a] covered entity also may share information about a patient as necessary to identify, locate, and notify family members, guardians, or anyone else responsible for the patient’s care, of the patient’s location, general condition, or death."
  • "Covered health care providers will not be subject to penalties for violations of the HIPAA Privacy, Security, and Breach Notification Rules that occur in the good faith provision of telehealth during the COVID-19 nationwide public health emergency. This Notification does not affect the application of the HIPAA Rules to other areas of health care outside of telehealth during the emergency." This exercising of enforcement discretion will last until OCR provides a notice otherwise. Telehealth should optimally be performed in a private setting, whenever possible, using non-public facing communication technologies. Providers should opt to use the most secure services possible, "but will not be penalized for using less secure products in their effort to provide the most timely and accessible care possible to patients during the public health emergency."
  • The OCR extended its enforcement discretion to include business associates of covered health care providers, allowing them to share PHI data "without risk of a HIPAA penalty." The OCR adds that "[s]ome HIPAA business associates have been unable to timely participate in these efforts [to ensure the health and safety of the public] because their BAAs do not expressly permit them to make such uses and disclosures of PHI." Like the enforcement discretion of telehealth provision by covered health care providers, the business associate must still make a good-faith effort in the "use or disclosure of the covered entity’s PHI" for public health and health oversight activities. Similarly, this exercising of enforcement discretion will last until OCR provides a notice otherwise.
  • The OCR also extended its enforcement discretion to include covered health care providers and business associates operating community-based COVID-19 testing sites (CBTS)—"which includes mobile, drive-through, or walk-up sites that only provide COVID-19 specimen collection or testing services to the public"—during the public health emergency. This enforcement discretion, however, "does not apply to covered health care providers or their business associates when such entities are performing non-CBTS related activities, including the handling of PHI outside of the operation of a CBTS."
  • Additionally, the OCR extended its enforcement discretion to "covered health care providers or their business associates in connection with the good faith use of online or web-based scheduling applications ... for the scheduling of individual appointments for COVID-19 vaccinations during the COVID-19 nationwide public health emergency."
  • "[T]he HIPAA Privacy Rule permits a covered entity to disclose the protected health information (PHI) of an individual who has been infected with, or exposed to, COVID-19, with law enforcement, paramedics, other first responders, and public health authorities1 without the individual’s HIPAA authorization, in certain circumstances." OCR provides numerous examples, including: "when the disclosure is needed to provide treatment," "when such notification is required by law," when a public health authority must be notified "to prevent or control spread of disease," "when first responders may be at risk of infection," when preventing or lessening "a serious and imminent threat to the health and safety of a person or the public," and when responding to a law enforcement inquiring concerning a lawfully detained inmate or other individual.
  • "The HIPAA Privacy Rule permits HIPAA covered entities (or their business associates on the covered entities’ behalf) to use or disclose PHI for treatment, payment, and health care operations, among other purposes, without an individual’s authorization." ICR provides more details in its guidance, noting however that reasonable effort must still be made to protect PHI, and that this does not apply to activities that constitute marketing.
  • Similarly, the HIPAA Privacy Rule "permits covered entities or their business associates to disclose PHI to [a health information exchange (HIE)] for the HIE to report PHI to a [public health authority (PHA)] conducting public health activities" in a variety of circumstances. For more on those circumstances, see the December 2020 guidance].
  • The public health emergency does not change restrictions on disclosing PHI to the media. This includes the prohibition of media crews in, for example, emergency departments where COVID-19 patients are being treated, as PHI is found everywhere in that setting. Only when every patient who is or will be in a potentially filmed area has signed a HIPAA authorization form can this be done.


The Clinical Laboratory Improvement Amendments (CLIA) are a set of U.S. federal regulatory requirements applied to all non-research-based clinical laboratory testing performed on humans. These requirements are intended to further ensure a higher standard of quality in clinical laboratory testing, focusing in on improving the accuracy, reliability, and timeliness of tests. (The implications of these requirements on U.S. clinical labs and their ability to test for COVID-19 are discussed later, in the next section.)

CLIA uses seven different criteria to gauge and assign one of three complexity levels to laboratory devices and assays: high, moderate, and waived.[33][34] Additionally, CLIA mandates clinical laboratories handling specimens originating from the U.S. and its territories to apply for a CLIA certificate that is appropriate for the type of testing it performs. Labs using complex devices and assays would have to apply for a high complexity certificate, and so on. Waived tests are recognized as simple to perform with a low risk of erroneous results and include among others urinalysis for pregnancy and drugs of abuse, blood glucose and cholesterol tests, and fertility analysis.

Anything but waived testing requires meeting "the CLIA quality system standards, such as those for proficiency testing, quality control and assessment, and personnel requirements. The standards for moderate and high complexity testing differ only in the personnel requirements."[33] As the Centers for Medicare and Medicaid Services (CMS) points out in a frequently asked questions (FAQ) document—and as can be verified on the FDA's EUA page[10]—a huge majority of COVID-19 tests are only authorized for moderate or high complexity testing, and thus labs certified to do that sort of testing.[35] As of September 2021, only 14 of 260 FDA EUAed molecular diagnostic tests are approved to be performed in a CLIA-waived laboratory setting.[10]

CMS' FAQ, as well as their March 2020 guidance document, provides additional insight in regards CLIA and COVID-19[35][36]:

  • CLIA regulations remain firmly in effect during the U.S.-declared public health emergency; a Section 1135 waiver, under the Social Security Act, that modifies or suspends CLIA requirements is not within the authorizing jurisdiction of the CLIA program. Additionally, CMS in general does not have the authority "to grant waivers or exceptions that are not established in statute or regulation."
  • Laboratories choosing to use temporary testing sites for remotely (from home or another temporary location) viewing and reporting on cytology slides and images may do so if certain defined conditions are met. (Consult the memo for those defined conditions.)
  • Proficiency testing (PT) is still required if a CLIA-certified lab is still performing testing and issuing patient results. However, should a PT provider need to postpone, suspend, or cancel a proficiency testing event, "[l]aboratories will not be penalized for lack of PT results ... so long as the cancelation is documented (including the notification from the PT program), and PT is conducted in a timely manner after the public health emergency ends. However, labs should consider performing their own self-assessment to ensure reliable testing."
  • Alternate specimen collection devices (e.g., viral transport media, flocked nasopharyngeal swabs) used outside the manufacturer's instructions still require the establishment of performance specifications and assay validation prior to patient use. The FDA provides additional guidance on this topic.
  • Laboratories performing laboratory developed tests (LDTs) are still required to be CLIA-certified and meet the requirements for high complexity testing. However, if the state government of such a laboratory has opted to take responsibility for authorizing an LDT (in order to expedite COVID-19 testing), then engagement with the FDA is not required.
  • "CMS will temporarily exercise enforcement discretion under CLIA for the duration of the COVID-19 public health emergency for the use of authorized SARS-CoV-2 molecular and antigen POC tests on asymptomatic individuals outside of the test’s authorization."[37]
  • As of May 2021[38], a CLIA specialty or subspecialty has not yet been assigned to COVID-19 testing authorized under the EUA pathway. Testing may be performed by laboratories based on intended use and by CMS specialty and subspecialty assigned to similar FDA-cleared or -approved tests with similar characteristics to the EUA being used.


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