NAAT TESTING Nucleic acid amplification testing (NAAT) to detect SARS- CoV-2 RNA from the upper respiratory tract is the preferred initial diagnostic test for COVID-19 when available 3 . Among the available classes of diagnostic tests, NAAT has the highest sensitivity and specificity for acute COVID-19, although variability exists amongst different NAAT testing platforms. Rapid NAAT assays, defined as those assays that generate results in under an hour including the Abbott ID NOW and Cepheid GeneXpert Xpress Assays, are generally less sensitive and specific thanmore time-intensive standard laboratory-based NAAT methods, including RT-PCR or transcription mediated amplification (TMA) assays, which yield results within 8 to 48 hours 3 . A positive NAAT PCR for SARS-CoV-2 in a symptomatic patient generally confirms the diagnosis of COVID-19 with no additional diagnostic testing required. In some cases, an inconclusive or indeterminate result indicates that only one of the two or more genes targeted by NAAT testing was identified. These results can be considered presumptive positive results, given the high specificity of NAAT assays. In a symptomatic patient where suspicion for COVID-19 is low, a single negative rapid or standard NAAT assay is sufficient to exclude the diagnosis. In a symptomatic patient where suspicion for COVID-19 is high or the prevalence is >10% in the general population, testing should be repeated between 24-48 hours later with a standard NAAT assay such as RT-PCR if the initial rapid diagnostic is negative 3 . Of note, detectable virus in asymptomatic patients following resolved infection does not usually indicate relapsed or new infection. Patients with COVID-19 can shed detectable SARS-CoV-2 RNA either continuously or intermittently in upper respiratory tract specimens for weeks after the resolution of symptoms (5). Prolonged viral RNA detection after symptom resolution does not indicate that a patient is contagious as this virus shed is unlikely to still be transmissible 6 . ANTIGEN TESTING Antigen tests are immunoassays that detect the presence of a specific viral antigen, which implies active viral infection. They are usually rapid, inexpensive, and can be performed at the point of care, yielding greater accessibility with a faster turnaround time than most NAAT assays. Antigen tests are typically less sensitive than NAAT assays and are most accurate in confirming a diagnosis in the early stages of infection when viral replication is high. Given their rapid turnaround time, low cost, and high specificity, antigen testing is often utilized in serial screening of congregate settings or other sites of localized outbreaks. When used in clinical diagnosis in symptomatic patients, positive antigen tests can be interpreted as indicative of SARS-
CoV-2 infection. Negative antigen tests could represent a false negative given their reduced sensitivity and should generally be confirmed using a more sensitive NAAT RT- PCR assay if clinical suspicion is high. When used for serial testing in congregate settings, negative antigen tests do not need to be confirmed 4 . In general, antigen tests should be used in settings where prevalence is moderate and early in disease onset to yield the most accurate results. SEROLOGIC (ANTIBODY) TESTING Serologic tests detect antibodies to either the SARS- CoV-2 spike protein or nucleocapsid in the blood. They identify patients who have been previously infected with SARS-CoV-2 as well as patients with active infection with prolonged symptoms that extend for enough time to generate a humoral immune response (i.e., typically about three weeks). False positive serologic testing was described early in the pandemic due to cross-reactivity with other human coronaviruses when using low specificity assays in low prevalence areas 7 . Therefore, to be of value, FDA- approved anti-SARS-CoV-2 antibody tests are required to have high sensitivity and specificity (i.e., >99.5%) and should be used in areas of moderate to high prevalence. Because serologic tests are less likely tobe reactive in thefirst several days to weeks of infection while the host humoral response is generated, they have very limited utility in the diagnosis of acute infection 8 . As such, the IDSA discourages their use for confirmation of infection in the first two weeks following symptom onset 7 . Checking serologic testing with IgG or total antibody (rather than IgM, IgA or IgG/IgMassays) three to four weeks after the onset of symptoms optimizes the accuracy of testing for evidence of recent infection (7).
Commercially approved antibody assays detect both neutralizing antibodies that confer active immunity to repeat SARS-CoV-2 infection and binding antibodies that lack this protective ability. Therefore, current commercially available serologic assays cannot determine whether antibodies detected are protective against future SARS- CoV-2 infection. Confirmed and suspected cases of reinfection with the virus in seropositive patients, although rare, have been reported, confirming that these assays should not be used to demonstrate immunity 4 . The CDC recommends that results of antibody testing not be used to determine housing arrangements in congregate settings such as dormitories or prisons, to make decisions about returning to work, or to alter work and personal protective equipment requirements for health care workers and first responders 4 . Additionally, the effectiveness and durability of anti-SARS-CoV-2 antibody responses have not yet been defined. As such, serologic testing cannot be used to determine immune status since they are unable to define whether detectable antibody is able to effectively neutralize 14
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