Novel Coronavirus Disease 2019 (COVID-19) - Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2)

Coronaviruses are a large family of respiratory viruses. Common coronaviruses usually cause mild illness. Rarer coronaviruses, including severe acute respiratory syndrome coronavirus (SARS-CoV), Middle East respiratory syndrome coronavirus (MERS-CoV), and the recently discovered coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which causes novel coronavirus disease 2019 (COVID-19), can lead to more severe illness.

SARS-CoV-2 is widespread in the United States and many other countries. Spread of infection has been person-to-person through the respiratory route of transmission, similar to other respiratory viruses. Identification of patients with SARS-CoV-2 can help to isolate cases and prevent further person-to-person transmission, thus limiting the number of cases, slowing the spread of infection, and mitigating the impact on healthcare resources. 

Viral detection is recommended for COVID-19 diagnosis. The gold standard is molecular (nucleic acid amplification) testing.  Testing decisions should be based on local epidemiology, clinical signs and symptoms, and the course of illness. Serology (antibody) testing is recommended for evaluating exposure to SARS-CoV-2; it is not recommended for the diagnosis of acute illness.

The environment surrounding COVID-19 testing is evolving rapidly. Clinicians are advised to consult the CDC's Overview of Testing for SARS-CoV-2  and ARUP’s Coronavirus Disease 2019 (COVID-19) resource site for the most up-to-date testing information.

Quick Answers for Clinicians

How is SARS-CoV-2 infection diagnosed?

Viral detection of SARS-CoV-2 by nucleic acid amplification or antigen testing is used to diagnose infection. Nucleic acid amplification testing (NAAT), which includes polymerase chain reaction (PCR), is performed on a nasopharyngeal (NP) swab, oropharyngeal (OP) swab, nasal swab, or saliva specimen that is sent to a laboratory for analysis. NAAT is the gold standard for SARS-CoV-2 detection.  

Antigen testing requires a nasal or throat swab. This testing is frequently performed at the point of care and delivers more rapid results, but lacks the sensitivity and specificity of NAAT. 

What is serology testing used for in COVID-19?

Serology (also known as antibody) testing is used to evaluate exposure to the virus that causes COVID-19. Although antibody testing should not be used as an initial diagnostic test, there are circumstances in which this testing might be useful for diagnosing later-stage disease. For example, antibody testing can be used to evaluate individuals presenting with COVID-19-like disease but late in the course of the illness (when the sensitivity of molecular diagnostic testing is decreased) and individuals with late complications of suspected COVID-19 disease (eg, multisystem inflammatory syndrome in children [MIS-C]). 

Two types of serology tests are available—laboratory-based immunoassays and rapid lateral flow immunoassays that can be used near the point of care. Some tests detect total antibodies, whereas others detect specific isotypes (immunoglobulin G [IgG], IgM, IgA).

In much of the United States, the prevalence of SARS-CoV-2 is relatively low. False-positive results are possible in low-prevalence settings, even when an antibody test has >98.0% specificity. To reduce the likelihood of a false-positive result and to maximize the positive predictive value (PPV) of a test, the CDC Interim Guidelines for COVID-19 Antibody Testing  suggest testing individuals with a high pretest probability, choosing a test with a high specificity, or using an orthogonal testing algorithm so that individuals who are positive by one antibody test are retested with a second antibody test. To satisfy the orthogonal testing algorithm approach, the two antibody tests should have unique design characteristics (eg, different targets). 

Which specimens are acceptable for COVID-19 testing?

Nasopharyngeal (NP) specimens are the gold standard for COVID-19 viral detection. Some laboratories may accept alternative specimen types such as saliva, oropharyngeal (OP) swab, mid turbinate swab, or anterior nares swab specimens.   Clinicians are advised to check with their performing laboratories for specific specimen requirements.

Recent studies, including one performed by researchers at ARUP and University of Utah Health, found that self-collected saliva and NP swabs collected by healthcare providers are equally effective for detecting SARS-CoV-2.  Both saliva and NP swabs are superior to anterior nasal swabs. The study, published in the Journal of Clinical Microbiology, represents one of the largest COVID-19 specimen-type comparisons to date. 

Detection rates in specimen types vary from patient to patient and may change over the course of the illness.  For example, because of potentially discordant shedding of virus in the upper versus the lower respiratory tract, patients with pneumonia may have negative nasal or OP samples but positive lower airway samples.  

Point-of-care antibody tests use fingerstick whole blood samples. Serum or plasma specimens are generally required for antibody tests that are analyzed in a laboratory. 

Which collection media is preferred for COVID-19 respiratory samples?

Swab specimens should be collected with nasopharyngeal (NP) ultrafine or equivalent swabs. Dacron, polyester-tipped, or any other flocked swabs are acceptable alternatives. Calcium alginate swabs or swabs with wooden shafts are NOT acceptable due to test interference. Viral transport media and universal transport media (VTM/UTM) are the preferred collection systems for swabs. Media types that are equivalent to VTM/UTM are also acceptable. For alternative transport media, refer to the FDA’s guidance on specimen collection for SARS-CoV-2 molecular diagnostic testing. 

Do existing respiratory virus panels detect SARS-CoV-2?

Yes, some multipathogen molecular assays can detect severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).  For example, ARUP offers a multipathogen assay that detects and differentiates COVID-19, influenza A/B, and respiratory syncytial virus (RSV). Clinicians are advised to confirm which respiratory viruses are detected by an assay before ordering. The U.S. Food and Drug Administration (FDA) maintains a list of COVID-19 assays with Emergency Use Authorization (EUA).

When is it appropriate to perform combined testing (cotesting) for SARS-CoV-2, respiratory syncytial virus, and influenza?

Laboratory testing is the only way to distinguish between severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and the flu. Importantly, laboratory testing is also the only way to determine cases of viral coinfection.  Infection with one respiratory virus does not exclude the possibility of infection with another because patients may be infected with more than one virus at the same time.   When SARS-CoV-2, influenza, and respiratory syncytial virus (RSV) are cocirculating (eg, during flu season), the National Institute of Health (NIH) recommends cotesting to determine proper medical management.  

How does COVID-19 affect children differently than adults?

Children of all ages are at risk for COVID-19 infection, but there are relatively fewer cases of COVID-19 among children compared with adults. Children appear to present with more mild signs and symptoms than adults.  Although severe disease is uncommon, children are still at risk of developing severe illness and complications from COVID-19. Early case studies and reports suggest that infants may be at a higher risk for severe illness from COVID-19 when compared with older children. 

It is unclear whether children are as susceptible to SARS-CoV-2 infection compared with adults. Children can transmit the virus, but data are limited as to whether they can transmit the virus as effectively as adults. Recent studies have suggested that young children (those younger than 5 years) have higher viral loads in their nasopharynxes as compared with adults  and that children can spread the virus effectively in households and camp settings. 

Due to early community mitigation efforts and school closures, transmission of SARS-CoV-2 to and among children may have been reduced in the United States during the pandemic in the spring and early summer of 2020. It is possible that comparing trends in pediatric infections before and after the return to in-person school and other activities may provide additional understanding about infections in children.

What is multisystem inflammatory syndrome in children (MIS-C), and how is it related to COVID-19?

The CDC is investigating reports of multisystem inflammatory syndrome in children (MIS-C), a serious condition marked by inflammation that may be related to resolved COVID-19 infection.

At this time, there is limited information available about risk factors, pathogenesis, and clinical course. The CDC has issued a health advisory instructing clinicians to watch for signs and symptoms, which may include a persistent fever, elevated inflammatory markers, and multiorgan (eg, cardiac, gastrointestinal, renal) involvement.  For more information, refer to the CDC’s case definition for MIS-C. 

Indications for Testing

The CDC and the Infectious Diseases Society of America (IDSA) offer the following recommendations for viral detection of SARS-CoV-2 in symptomatic and asymptomatic groups.

Viral Detection

Diagnosis

Diagnostic testing for SARS-CoV-2 identifies current infection in symptomatic individuals and asymptomatic individuals with or without consistent symptoms. 

The CDC and IDSA recommend that all symptomatic individuals with signs or symptoms consistent with COVID-19 be tested by nucleic acid amplification testing (NAAT) or antigen testing.   NAAT is the gold standard for detection of SARS-Cov-2 virus. 

Diagnostic testing for asymptomatic individuals with known or suspected recent exposure to SARS-CoV-2 may also be advised. 

In the event of overwhelming demand and diminished capacity for testing, the IDSA recommends prioritizing the following groups for testing :

  • Hospitalized patients (especially critically ill patients with unexplained respiratory illness)
  • Symptomatic individuals who are healthcare workers or first responders; who have risk factors for severe disease; or who work or reside in congregate living settings

A rapid increase in test demand could exceed the capacity of laboratories as well as the ability of manufacturers to supply test kits and reagents and lead to further guidance from local and regional health authorities on testing prioritization.

Screening

The goal of screening is to identify individuals who may be contagious so that further transmission can be prevented. Both NAAT and antigen testing can be used for this purpose.  

The CDC recommends that all individuals, including those who are asymptomatic, who live or work in a long-term care facility or nursing home undergo testing for SARS-CoV-2 virus. 

The IDSA recommends screening individuals who :

  • Have had no known exposure to COVID-19 but are being hospitalized in areas with a high prevalence of COVID-19 in the community (eg, hotspots)
  • Are immunocompromised and are being admitted to the hospital
  • Are undergoing an immunosuppressive procedure, regardless of a known exposure to COVID-19
  • Are undergoing major time-sensitive surgeries, but have no known exposure to COVID-19
  • Are undergoing a time-sensitive aerosol-generating procedure (eg, bronchoscopy) when personal protective equipment (PPE) is limited and testing is available, but have no known exposure to COVID-19

Surveillance

Surveillance testing is used to gain information at a population level in order to inform public health planning. NAAT or antigen testing may be used for this purpose. 

Antibody Testing

Exposure to COVID-19 can be assessed by antibody (serology) testing. This testing is not recommended for diagnosis and should not be used for patients in the acute phase of infection.

Although antibody testing is not currently central to COVID-19 clinical management, it can be used to study the seroprevalence of the virus in the general population.  

Antibody testing is also useful for vetting candidates interested in donating convalescent plasma, evaluating individuals who present with COVID-19-like disease but late in the course of the illness (when the sensitivity of molecular diagnostic testing is decreased), and in individuals with late complications of suspected COVID-19 disease. For example, SARS-CoV-2 serologic testing is suggested for children who present with suspected MIS-C. 

Laboratory Testing

Diagnosis

Viral Detection

Molecular Diagnostic Testing

Molecular diagnostic assays, such as NAATs, are used to detect SARS-CoV-2 in respiratory specimens of patients suspected of having COVID-19.  

A negative result indicates that SARS-CoV-2 RNA was not present in the specimen above the limit of detection. However, a negative result does not exclude the possibility of COVID-19 and should not be used as the sole basis for treatment or patient management. The possibility of a false-negative result should be considered if the patient’s recent exposures or clinical presentation suggests that COVID-19 is likely. Retesting may be advisable in symptomatic individuals with an intermediate or high clinical suspicion of COVID-19, and should be considered based on clinical judgment in combination with the recommendation of public health authorities.  

Overall test sensitivity may be reduced if optimal sample collection is not followed. Early data suggest that some specimens, including nasal swab specimens, may lead to reduced test sensitivity as compared with saliva and NP swab specimens. 

In some situations, it may be advisable to obtain a lower respiratory tract specimen for diagnostic testing because these specimens are thought to carry a higher viral load than upper respiratory tract specimens.  Due to the high specificity of NAAT, a positive result based on an upper respiratory tract specimen is generally adequate to establish a COVID-19 diagnosis. For this reason, the IDSA panel suggests initially obtaining an upper respiratory tract sample rather than a lower respiratory sample when testing hospitalized patients with suspected COVID-19 lower respiratory tract infections. However, if the initial upper respiratory sample result is negative and the suspicion for disease remains high, the panel suggests collecting a lower respiratory tract sample rather than collecting another upper respiratory sample. 

In intubated and mechanically ventilated patients with unknown COVID-19 status, the National Institutes of Health (NIH) recommends carefully collecting a lower respiratory tract specimen for diagnostic testing.

Antigen Testing

Antigen testing, performed on nasal or throat swab specimens, can also be used to detect SARS-CoV-2 infection. Antigen testing is often performed at the point of care, allowing for quicker results. 

In the early stage of infection (within the first 5 days symptoms are experienced), antigen testing can be used to detect SARS-CoV-2 infection. This testing can also be used to screen individuals with known exposure to confirmed COVID-19 cases and individuals in high-risk congregate settings.

Antigen testing is less sensitive than NAAT and is associated with an increased risk of false-negative results. Because antigen testing requires a higher viral load for detection of SARS-CoV-2, it is recommended for use early in the course of illness when viral load is higher.  

Clinicians should consider the performance characteristics of antigen tests when interpreting results. Negative and positive test results should be considered in the context of clinical observations, patient history, and local epidemiologic information. Confirmation testing by NAAT may be advised in some situations.   However, it is not necessary to perform confirmatory testing in the event of a negative result for an individual who is asymptomatic without known exposure, or in patients with a negative result obtained during routine screening or surveillance.  

Testing for Exposure

Serology Testing

Serology testing, also known as antibody testing, is used to detect antibodies against SARS-CoV-2 in serum or plasma. Early studies suggest the majority of patients with COVID-19 seroconvert approximately 2 weeks after symptom onset; because of this natural delay, serology testing is not recommended for COVID-19 diagnosis.    Furthermore, there are not enough data available to determine if protective immunity is consistently achieved in all patients after infection and if that immunity wanes and/or disappears over time.   

Recent studies suggest that SARS-CoV-2 immunoglobulin G (IgG) concentrations tend to decline faster than concentrations of antibodies associated with other viral infections, particularly in individuals with mild COVID-19 illness. Thus, testing someone several months after infection may provide a false-negative result.  

Although antibody testing is not recommended to diagnose infection or to infer an individual’s immunity to the virus, it may aid in determining the rate of exposure in a given population. Antibody testing is useful for vetting candidates interested in donating convalescent plasma, evaluating individuals who present with COVID-19-like disease but late in the course of the illness (when the sensitivity of molecular diagnostic testing is decreased), and individuals with late complications of suspected COVID-19 disease (eg, multisystem inflammatory syndrome in children [MIS-C]).

COVID-19 convalescent plasma is currently being researched as a possible treatment for individuals who are critically ill with COVID-19 and as a prophylactic means of protecting individuals at high risk of exposure. 

Serology testing should be interpreted in the context of expected predictive values. False-positive results are possible in low-prevalence settings, even when an antibody test has >98% specificity. To reduce the likelihood of a false-positive result, the CDC recommends maximizing overall specificity by using a combination of one or more of the following strategies :

  • Testing individuals with a high pretest probability of having antibodies (eg, individuals who have a history of illness consistent with COVID-19 infection)
  • Choosing a test with very high specificity
  • Using an orthogonal testing algorithm so that individuals who are positive by one antibody assay are retested with a second antibody test that is directed toward a different SARS-CoV-2 antigenic target

ARUP offers two tests for IgG antibodies that target different SARS-CoV-2 proteins. One test detects IgG against the nucleocapsid protein, and the other test detects IgG against the S1 domain of the spike protein. These two tests can be used in the orthogonal testing algorithm, as described above, to minimize the number of false-positive results in low-prevalence settings.

Other Testing

Cytokine Testing

Early data suggest that in some patients, COVID-19 may trigger cytokine storm syndrome, a phenomena marked by hyperinduction of proinflammatory cytokine production.

Cytokine testing is used primarily for research and to support attempts to understand the pathogenesis of immune, infectious, allergic, or inflammatory disorders. There are currently no well-defined guidelines on how the results should be interpreted and/or used to guide treatment decisions in COVID-19.

Hemostasis Testing

Increased venous thromboembolism (VTE) and arterial thrombotic events (eg, myocardial infarction, stroke) have been described in patients with severe COVID-19.  However, the exact contributing factors to the observed increase in thrombotic risk are not yet fully understood.     The most likely mechanism behind most of the thrombotic risk and coagulation test abnormalities appears to be endothelial damage within the lungs, which triggers inflammatory and coagulation cascades. 

Disseminated intravascular coagulation (DIC) is another thrombotic mechanism that affects some patients, particularly those who are critically ill. Elevated D-dimer has been described in patients with COVID-19 infection who require intensive care unit (ICU) admission, but the elevation is not always to the very high level expected with DIC.    In one single-center study from Wuhan, China, approximately 70% of patients who died as a result of COVID-19 met current diagnostic criteria for DIC as set forth by the International Society of Thrombosis and Haemostasis (ISTH).  Prothrombin time (PT) may be mildly prolonged at admission in patients with COVID-19.   Thrombocytopenia has been reported in some but not all patients with COVID-19.  

Hyperfibrinogenemia has been reported in individuals with COVID-19, which may lead to increased fibrin formation and polymerization, increased thrombotic risk, and elevated D-dimer. 

Lupus anticoagulant and antiphospholipid antibodies have been reported in patients with COVID-19, but the significance of this finding is uncertain, given that transient antiphospholipid antibodies (present for <12 weeks) are described with other acute infections and do not necessarily represent a thrombotic risk factor.  

Bleeding complications have not been widely reported in those with COVID-19.  Platelet counts are variable in patients with COVID-19. One meta-analysis indicated that thrombocytopenia was more prominent in patients with more severe COVID-19.  Low platelet counts have not been observed in all case series of patients with COVID-19. 

The therapeutic implications and prognostic relevance of the abnormal hemostasis laboratory findings in COVID-19 are as yet unclear, and additional studies are needed. Prophylactic or even therapeutic anticoagulation has been used in hospitalized patients with COVID-19, and recommendations around this are currently evolving. 

Mental Health Testing

Mental health issues that have been exacerbated by the pandemic include stress, depression, and anxiety. Drugs used to treat mental health conditions such as major depressive disorder are some of the most widely prescribed drugs in the U.S. However, these medications are highly variable in terms of patient response and are associated with undesirable side effects. Pharmacogenetic testing and/or therapeutic drug monitoring may assist in the mental health care and management of patients with COVID-19.

Pharmacogenetic testing assesses genetic variations associated with drug response or drug disposition that may predispose a patient to be at risk for drug-related toxicity, nonstandard dose requirements, or lack of therapeutic benefit. Refer to the ARUP Consult Pharmacogenetics topic for examples of antidepressant testing.

Therapeutic drug monitoring is the clinical practice of measuring specific drugs or their metabolites at designated intervals to maintain a therapeutic concentration in a patient’s bloodstream and optimize individual dosage regimens. Refer to the ARUP Consult Therapeutic Drug Monitoring topic for examples of antidepressant and antipsychotic tests.

ARUP Laboratory Tests

Molecular Diagnostic Testing

Detects and differentiates SARS-CoV-2, influenza A/B virus, and RSV RNA in individuals with clinical indications of respiratory viral infection consistent with COVID-19

Specimen types include NP swab, OP swab, and nasal swab

Detects the 2019 novel coronavirus (SARS-CoV-2)

Specimen types include NP swab, saliva (self-collected while observed by a health care provider), OP swab, and/or nasal swab; for more information, refer to ARUP’s COVID-19 Specimen Collection Guide

ARUP is accepting new COVID-19 molecular test orders from clients with prior authorization; for more information about the authorization process, please contact Client Services at (800) 522-2787

Serology Testing for Exposure

Detects IgG antibodies against the nucleocapsid protein of SARS-CoV-2 to evaluate exposure

To reduce the likelihood of a false-positive result, the CDC suggests using an orthogonal testing algorithm so that individuals positive by one antibody test are retested with a second antibody test directed toward a different antigenic target (refer to COVID-19 IgG by ELISA)

Results are reported as “negative” or “positive”

Not recommended for COVID-19 diagnosis

This test is available under the FDA’s Emergency Use Authorization (EUA)

Detects IgG antibodies against the spike protein (S1) of SARS-CoV-2 to evaluate exposure

To reduce the likelihood of a false-positive result, the CDC suggests using an orthogonal testing algorithm so that individuals positive by one antibody test are retested with a second antibody test directed toward a different antigenic target (refer to COVID-19 IgG, Qualitative by CIA)

Results are reported as “negative,” “positive,” or “indeterminate” and will include an index value

Not recommended for COVID-19 diagnosis

This test is available under the FDA’s Emergency Use Authorization (EUA)

Cytokine Testing

Primarily used for research and to support attempts to understand the pathogenesis of immune, infectious, allergic, or inflammatory disorders

Medical Experts

Contributor

Barker

Adam Barker, PhD
Assistant Professor of Clinical Pathology, University of Utah
Medical Director, Microbiology, Reagent Laboratory, and R&D Special Operations
Director, ARUP Institute for Clinical & Experimental Pathology® (R&D)
Contributor

Couturier

Marc Roger Couturier, PhD, D(ABMM)
Associate Professor of Clinical Pathology, University of Utah
Medical Director, Parasitology/Fecal Testing, Infectious Disease Antigen Testing, Bacteriology, and Molecular Amplified Detection, ARUP Laboratories
Contributor
Medical Reviewer
Contributor

McMillin

Gwendolyn A. McMillin, PhD
Professor of Clinical Pathology, University of Utah
Scientific Director, Mass Spectrometry Platform; Medical Director, Clinical Toxicology and Pharmacogenomics, ARUP Laboratories
Contributor

Moser

Karen A. Moser, MD
Associate Professor of Clinical Pathology, University of Utah
Medical Director, Hemostasis/Thrombosis, ARUP Laboratories
Contributor
Contributor

Rychert

Jenna Rychert, PhD, ABMM
Adjunct Assistant Professor of Clinical Pathology, University of Utah
Medical Director, Microbial Immunology, ARUP Laboratories
Contributor

Slev

Patricia R. Slev, PhD
Associate Professor of Clinical Pathology, University of Utah
Section Chief, Immunology; Medical Director, Immunology Core Laboratory, ARUP Laboratories
Medical Director, Serologic Hepatitis and Retrovirus and Immunology Core Laboratory
Co-Medical Director, Microbial Immunology, at ARUP Laboratories
Contributor

Smock

Kristi J. Smock, MD
Professor of Clinical Pathology, University of Utah
Medical Director, Hemostasis/Thrombosis, ARUP Laboratories

References

Additional Resources