Cigna COVID-19: In Vitro Diagnostic Testing - (0557) Form

The following Coverage Policy applies to health benefit plans administered by Cigna Companies. Certain Cigna Companies and/or lines of business only provide utilization review services to clients and do not make coverage determinations. References to standard benefit plan language and coverage determinations do not apply to those clients. Coverage Policies are intended to provide guidance in interpreting certain standard benefit plans administered by Cigna Companies. Please note, the terms of a customer’s particular benefit plan document [Group Service Agreement, Evidence of Coverage, Certificate of Coverage, Summary Plan Description (SPD) or similar plan document] may differ significantly from the standard benefit plans upon which these Coverage Policies are based. For example, a customer’s benefit plan document may contain a specific exclusion related to a topic addressed in a Coverage Policy. In the event of a conflict, a customer’s benefit plan document always supersedes the information in the Coverage Policies. In the absence of a controlling federal or state coverage mandate, benefits are ultimately determined by the terms of the applicable benefit plan document. Coverage determinations in each specific instance require consideration of 1) the terms of the applicable benefit plan document in effect on the date of service; 2) any applicable laws/regulations; 3) any relevant collateral source materials including Coverage Policies and; 4) the specific facts of the particular situation. Each coverage request should be reviewed on its own merits. Medical directors are expected to exercise clinical judgment where appropriate and have discretion in making individual coverage determinations. Where coverage for care or services does not depend on specific circumstances, reimbursement will only be provided if a requested service(s) is submitted in accordance with the relevant criteria outlined in the applicable Coverage Policy, including covered diagnosis and/or procedure code(s). Reimbursement is not allowed for services when billed for conditions or diagnoses that are not covered under this Coverage Policy (see “Coding Information” below). When billing, providers must use the most appropriate codes as of the effective date of the submission. Claims submitted for services that are not accompanied by covered code(s) under the applicable Coverage Policy will be denied as not covered. Coverage Policies relate exclusively to the administration of health benefit plans. Coverage Policies are not recommendations for treatment and should never be used Medical Coverage Policy: 0557 as treatment guidelines. In certain markets, delegated vendor guidelines may be used to support medical necessity and other coverage determinations. This Coverage Policy discusses certain tests used to find the SARS-CoV-2 virus in the body. This virus causes COVID-19. Two types of tests help to diagnose COVID-19: molecular tests and antigen tests. Molecular tests look for the genetic material in the SARS-Co-V-2 virus while antigen tests look for the presence of small pieces of protein from the virus. An antibody test, also called a serology test, is used to identify antibodies against the SARS-CoV-2 virus. Antibodies are proteins that work to fight infection in the body. An antibody test does not help diagnose COVID-19, but may be used for public health reasons, like to estimate how much of a virus is in a community and how quickly it may spread. It may also be used to plan where to offer testing. This Policy applies to a test where results for one person are identified. It also discusses pooled sample testing, where test results for many people are reported together. Nucleic acid pathogen testing by panels is outside the scope of this Coverage Policy. For information related to that type of testing, please review CP 0530 Nucleic Acid Pathogen Testing. For the purpose of this Coverage Policy, molecular, antigen and antibody (serology) testing for the diagnosis of SARS-CoV-2 is informed by published statements by the FDA (2023), CDC (2022) and professional society recommendations (e.g., IDSA, 2021). Coverage Policy Note: For information related to nucleic acid pathogen testing panels please review CP 0530 Nucleic Acid Pathogen Testing. Medically Necessary A molecular or antigen in vitro diagnostic test for SARS-CoV-2 (COVID-19) infection is considered medically necessary when ALL of the following criteria are met: • ordered and administered by a licensed or authorized healthcare provider • • performed by a CLIA-certified high or medium-complexity or CLIA-waived laboratory if so test is FDA approved or cleared or has an Emergency Use Authorization (EUA) directed by test Instructions for Use clinical concern for a symptomatic COVID-19 infection An antibody (serology) test for SARS-CoV-2 antibodies is considered medically necessary when the following criteria are met: ordered and administered by a licensed or authorized healthcare provider • • performed by a CLIA-certified high or medium-complexity laboratory if so directed by test test is FDA approved or cleared or has an Emergency Use Authorization (EUA) Instructions for Use Medical Coverage Policy: 0557 results of a molecular or antigen test is non-diagnostic for COVID-19 and the results of the test will be used to aid in the diagnosis of a condition related to COVID-19 infection (e.g., Multisystem Inflammatory Syndrome [MIS], post-acute sequelae) Not Covered or Reimbursable Surrogate neutralization testing to determine the presence of SARS-CoV-2 antibodies is not covered or reimbursable . An in vitro test to determine COVID-19 variants is not covered or reimbursable. In vitro diagnostic testing (molecular, antigen, antibody) for COVID-19 infection is not covered or reimbursable for screening, including but not limited to BOTH of the following: asymptomatic individual, with or without exposure • general population screening An antibody (serology) test for SARS-CoV-2 antibodies is not covered or reimbursable for any other indication, not limited to the following: diagnose current or active infection • determine need for COVID-19 vaccination • assess immunity after COVID-19 vaccination In vitro testing (i.e., molecular, antigen, antibody) is not covered or reimbursable for ANY of the following indications:  purposes not primarily intended for individualized diagnosis or treatment of COVID- 19  testing done for employment purposes including testing conducted to screen for general workplace health and safety (such as employee “return to work” programs)  determine prevalence of COVID-19 infection in the community  public health surveillance for SARS-CoV-2  public health screening  screening assessment in a congregate setting (e.g., nursing home, correctional facility, school, residential dormitory) A high-throughput molecular or antigen in vitro diagnostic test for the diagnosis of SARS-CoV-2 (COVID-19) infection is not covered or reimbursable unless billed by a CLIA-certified high-complexity laboratory. If the above criteria are not met, in vitro testing (i.e., molecular, antigen, antibody) is not covered or reimbursable, including but not limited to the following indications listed below: (Where applicable and appropriate, ICD-10 diagnosis codes that may be used to reflect population or public health screening scenarios have been included. This list is not all inclusive and may not represent an exact indication match.) testing conducted to screen for general workplace health and safety (e.g., return-to-work) (Z02.79) return-to-school (Z02.0) Medical Coverage Policy: 0557 participation in sports (Z02.5) • pre-employment, (Z02.1) • routine and/or executive physicals (Z02.89) • travel • recruitment to armed forces (Z02.3) • insurance purposes (Z02.6) • disability evaluation (Z02.71) • encounter for administrative exam, unspecified (Z02.9) Please see Coding Table section for specific not covered or reimbursable ICD-10 code descriptions. An Over-the-Counter (OTC) test for SARS-CoV-2 (COVID-19) infection is not covered or reimbursable. A test for SARS-CoV-2 (COVD-19) infection that is not diagnostic and/or does not otherwise meet the criteria above is not covered or reimbursable. General Background COVID-19 is the infectious disease caused by the coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The virus is highly contagious and is believed to be spread from person to person through respiratory droplets or when aerosol is produced as an infected person coughs or sneezes. An infected individual may be asymptomatic or exhibit a variety of symptoms. Common symptoms of COVID-19 infection are fever, chills, cough and shortness of breath, persistent pain or pressure in chest, confusion, inability to wake or stay awake, cyanosis of the lips or face, fatigue, body aches or muscle pain, sore throat, new loss of taste or smell, nausea, vomiting and diarrhea (Centers for Disease Control and Prevention [CDC], 2022; Infectious Disease Society of America [IDSA], 2021). These symptoms typically appear 2–14 days after exposure. Symptoms can progress rapidly to severe respiratory distress requiring hospitalization, culminating in death. Prevalence Prevalence of disease is a measure of risk and is the proportion of persons in a population who have a particular disease or attribute at a specified point in time or over a specified period of time. It is used to characterize the occurrence of health events in a population and as a measure of public health impact of disease (CDC, 2022).Positive and negative predictive values of a test are affected by prevalence. In a high-prevalence setting, the positive predictive value increases (i.e., more likely that persons who test positive are truly positive). When a test is used in a population with low-prevalence the positive predictive value is decreased (i.e., there are more false positives). Likewise, negative predictive value is also affected by prevalence. In a high-prevalence setting, the negative predictive value declines whereas in a low-prevalence setting, it increases (CDC, 2022). At this time there is no national reference standard for the prevalence rate of COVID-19; rather, it is based on complex mathematical modeling. The CDC notes that prevalence of SARS-CoV-2 antibody in the US is expected to be low, ranging from <5% to 25%, so that testing might result in relatively more false-positive results and fewer false negative results (2022). Health Disparities According to the CDC, some racial and ethnic groups are disproportionately affected by COVID-19 (2023). The CDC recognizes five key topic areas of social determinants of health that may Medical Coverage Policy: 0557 increase risk of COVID-19 exposure, illness, hospitalization, long-term health and social consequences and death: neighborhood and physical environment health and healthcare occupation and job conditions income and wealth and education A COVID-19 Response Health Equity Strategy to outline a plan to reduce the disproportion burden of COVID-19 among racial and minority populations has been developed by the CDC. To that end, the reporting of race and ethnicity data is required of labs and testing facilities by the U.S. Department of Health and Human Services. An increasing body of evidence supports potential links between health disparity and social determinants of health as factors in rates of COVID-19 infection. According to national data tracked by the CDC (2023), people in some racial and ethnic minority groups are more likely to live in areas with high rates of new COVID-19 infection. Percent of Cases By Ethnicity/Race CDC, Data as of 1/25/2023) Race/Ethnicity Hispanic/Latino American Indian / Alaska Native, Non-Hispanic 1 Asian, Non-Hispanic Black, Non-Hispanic Native Hawaiian / Other Pacific Islander, Non- Hispanic White, Non-Hispanic Multiple/Other, Non-Hispanic Percent of Cases 24.5 4.4 12.4 0.3 53.6 3.8 Percent of US population 18.45 0.74 5.76 12.54 0.182 60.11 2.22 Likewise, the percent of deaths attributed to COVID-19 infection is dependent on ethnicity. The CDC notes a disproportionate number of deaths attributed to many individuals of color. Percent of Deaths By Race/Ethnicity (CDC, Data as of 1/25/2023) Race/Ethnicity Hispanic/Latino American Indian / Alaska Native, Non-Hispanic 1.1 3.1 Asian, Non-Hispanic Black, Non-Hispanic 13 Native Hawaiian / Other Pacific Islander, Non- Hispanic White, Non-Hispanic Multiple/Other, Non-Hispanic Percent of Deaths 16.8 0.2 63.6 2.1 Percent of US population 18.45 0.74 5.76 12.54 0.182 60.11 2.22 Karaye and Horney (2020) found that local population-level factors related to racial and ethnic minority status, language spoken, housing, transportation, household composition and disability were associated with higher rates of new COVID-19 infections. These findings further support Medical Coverage Policy: 0557 potential links between local social factors and COVID-19. Resources must be equitably available for everyone to maintain physical and mental health. Resources include easy access to information, goods and services, affordable testing, and medical and mental healthcare that are all tailored to meet the needs of people from diverse communities. Social determinants of health may also influence access to testing. Delays in testing may result in a delay seeking care when sick as well as delays in self-isolation or implementing other mitigation measures that could reduce the spread of the virus to others (CDC, 2022). A study by Rader et al. (2020) reported that the median travel time to a COVID-19 testing site was 20 minutes in April 2020. Counties with a travel time of more than 20 minutes to a COVID-19 testing site had a higher percentage of the population that were from racial and ethnic minority groups, were uninsured, and had lower population density (were rural). Data suggest differences in travel time may limit access to, and use of, testing services for those who have limited access to transportation and who live in areas with fewer public transit services and schedules. The authors note other factors that may affect both access to, and use of, testing services include lack of health insurance, concern about the costs or co-pays, occupational factors (e.g., not being able to take time off of work, lack of paid leave, lack of accessible options for people with disabilities, and distrust of the government and healthcare systems). Testing For the purpose of this Coverage Policy, molecular, antigen and antibody (serology) testing for the diagnosis of SARS-CoV-2 is informed by authoritative statements by the FDA (2023), CDC (2022) and published professional society recommendations (e.g., IDSA, 2021). To control the spread of COVID-19, it is imperative to test for and diagnose those who have been infected with COVID-19. Specimen sources used for in vitro diagnostic devices are taken from the human body, such as swabs of mucus from inside the nose or back of the throat, sputum, saliva or blood taken from a vein or finger stick. Two types of tests are used to diagnose a current COVID-19 infection: molecular nucleic acid amplification tests and antigen tests. These tests detect parts of the SARS-CoV-2 virus and can be used to diagnose infection with the SARS-CoV-2 virus. Molecular tests are not useful in distinguishing between highly infective viruses versus ones that have been neutralized by the host, and it cannot assess immunity status against SARS-CoV-2 antibody. Antibody (serology) tests cannot be used to diagnose a current infection (CDC, 2022; FDA, 2023). Any laboratory or testing site that performs diagnostic or screening testing must have a Clinical Laboratory Improvement Amendments (CLIA) certificate and meet all applicable CLIA requirements. Tests for SARS-CoV-2 (COVID-19 infection) must be approved or cleared by the U.S. Food and Drug Administration (FDA) or have received an Emergency Use Authorization from the FDA. Regarding a testing strategy for COVID-19 diagnostic testing and screening, the CDC (2022) notes the following: Diagnostic Testing: intended to identify current infection in individuals and should be performed on anyone that has signs and symptoms consistent with COVID-19 and/or following recent known or suspected exposure to SARS-CoV-2. Examples of diagnostic testing include:  Testing anyone with symptoms consistent with COVID-19 Medical Coverage Policy: 0557  Testing vaccinated and unvaccinated people who were exposed to someone with a confirmed or suspected case of COVID-19 Screening A screening test is one that is performed on an individual who is asymptomatic; that is, has no symptoms of disease. Guidance from the CDC (2022) notes screening helps to identify unknown cases so that measures can be taken to prevent further transmission. Regarding screening testing as a prevention strategy the CDC notes screening: may be incorporated as part of a comprehensive approach to reducing transmission. • • can improve detection of SARS-CoV-2. Is intended to identify people with COVID-19 who are asymptomatic and do not have known, suspected, or reported exposure to SARS-CoV-2. helps to identify unknown cases so that measures can be taken to prevent further transmission. Examples of screening include testing of all of the following:  employees in a workplace setting  students, faculty, and staff in a school setting  a person before or after travel The CDC notes that SARS-CoV-2 testing, symptom screening and contact tracing are strategies to identify people infected with SARS-CoV-2 so that actions can be taken to slow and stop the spread of the virus. The CDC (2022) and FDA (2022) published guidance regarding when an individual should be tested: If you have symptoms, test immediately. If you were exposed to COVID-19 and do not have symptoms, wait at least 5 full days after your exposure before testing. If you test too early, you may be more likely to get an inaccurate result. If you are in certain high-risk settings, you may need to test as part of a screening testing program. Consider testing before contact with someone at high risk for severe COVID-19, especially if you are in an area with a medium or high COVID-19 Community Level. An individual who has tested positive for COVID-19 using a nucleic acid amplification test (NAAT) within the past 90 days should not use a NAAT for repeat testing. Point-of care serial screening testing can provide rapid results and is critical to identifying people with COVID-19 who do not have symptoms and slowing the spread of SARS-CoV-2. This is especially important when community risk or transmission levels are substantial or high. A person’s vaccination status does not affect the results of their viral test for SARS-CoV-2 (CDC, 2022). Regarding use of at-home antigen tests when initial test result is negative, the FDA (2022) notes the following testing guidance: COVID-19 symptoms and were exposed: Medical Coverage Policy: 0557  Test again after 48 hours. Consider getting a laboratory-based molecular COVID-19 test or call your health care provider. COVID-19 symptoms and no exposure:  Test again after 48 hours. Consider getting a laboratory-based molecular COVID-19 test or call your health care provider. No COVD-19 symptoms and were exposed  Test again after 48 hours, and again 48 hours after a second negative test, for a total of 3 tests over 5 days. Consider getting a laboratory-based molecular COVID-19 test or call your health care provider. No COVID-19 symptoms and no exposure:  Test again after 48 hours, and again 48 hours after a second negative test, for a total of 3 tests over 5 days. Continue to take public health precautions to reduce your risk of getting COVID-19. Public Health Surveillance Public health surveillance is the ongoing, systematic collection, analysis and interpretation of health-related data performed to plan, implement and evaluate public health policy and practice. Surveillance testing is intended to monitor community- or population-level outbreaks of disease and to characterize the incidence and presence of disease. This testing is performed on de-identified specimens. Results are not linked to individuals; therefore, they cannot be used for individual health decisions. Tests used for SARS-CoV-2 surveillance do not meet FDA or CLIA requirements for diagnostic or screening testing (CDC, 2022). Limitations to Testing Diagnostic testing errors can result in false positives and/or false negatives that stem from improper sample collection, testing procedural errors, and variability in assay performance (sensitivity/specificity).The performance of tests is described by their analytical and clinical sensitivity, specificity, and positive and negative predictive values. Analytical sensitivity is the assay’s ability to detect the minimum concentration of a substance in a sample while clinical sensitivity measures how accurately a test identifies positive patients who are infected. Analytical specificity refers to the ability to detect only the desired analyte in a specimen without cross reacting with other substances, while clinical specificity determines how accurately a test identifies negative patients who do not have COVID-19. A test with lower sensitivity test means higher false negative results, while lower specificity means higher false positive results. A test with good analytical sensitivity and specificity does not necessarily correlate with clinical sensitivity and specificity (Chau et al., 2020). Regarding antibody (serology) testing positive predictive and negative values describe how likely it is that a person who receives a positive result from a test truly does have antibodies to SARS-CoV-2 and how likely it is that a person who receives a negative result from a test truly does not have antibodies to SARS-CoV-2 (FDA, 2023). Multiple methods are used in formation and processing of molecular, antigen and serology tests. Surveillance monitors population-level burden of disease or to characterize the incidence and prevalence of disease. Surveillance testing results are not linked to individual people; and therefore, cannot be used for individual healthcare decision-making or individual public health actions (CDC, 2022) antibody tests, including the use of different probes and reagents and interpretation and reporting standards. The FDA has established minimum validation standards for these tests, which are authorized under the Emergency Use Authorization (EUA) designation. Molecular Testing Medical Coverage Policy: 0557 Molecular tests using nucleic acid amplification methodologies are most commonly used to determine the presence or absence of SARS-CoV-2 virus and to make a diagnosis of active infection. Nucleic acid amplification tests (NAAT) such as reverse transcription-polymerase chain reaction (RT-PCR) tests, remain the “gold standard” for clinical diagnostic detection of SARS-CoV-2 (National Institutes of Health [NIH}, 2022). Molecular testing involves the in vitro qualitative detection of ribonucleic acid (RNA) from the SARS-CoV-2 virus. Analytical validity of the test is highly accurate in controlled laboratory conditions. These tests can identify and quantify the presence of infectious agents in a sample through the process of detection, amplification, and output measurement. Understanding the predictive value of molecular testing with regards to time from exposure and symptom onset is important as the assay may not have been appropriately validated against a clinically meaningful reference standard for detecting SARS-CoV-2 in the absence of symptoms, such as during earlier stages of the disease, or in asymptomatic individuals (Chau et al., 2020). Nonbinding standards from the FDA for validation of tests recommend analytical sensitivity (limit of detection [LOD]) for the virus of 95%. The LOD is defined as the lowest concentration where at least 19 of 20 viral replicates are positive. Most test developers self-report high performance statistics with their FDA submissions, with reported results ranging from 95-100%. Results may not be as robust as accuracy is dependent on when in the course of illness the sample is collected, test performance, collection technique and quality, storage and transport conditions. As an example, if the test has a 95% accuracy in its performance in the lab in detecting the virus, 50,000 individuals would be incorrectly identified as having a negative result in a sample of 1,000,000 test results. The test cannot distinguish between active virus and dead viral fragments, which may result in an incorrect diagnostic interpretation of a positive result. The FDA notes that clinical correlation with patient history and other diagnostic information is necessary to determine patient infection status. Positive results do not rule out bacterial infection or co-infection with other viruses. The agent detected may not be the definite cause of disease. Negative results do not preclude SARS-CoV-2 infection and should not be used as the sole basis for patient management decisions. Negative results must be combined with clinical observations, patient history, and epidemiological information (2022). Sensitivity, specificity, and positive and negative predictive values for each test for which an FDA EUA has been granted are reported in the individual test EUA summary or Instructions for Use and can be accessed on the FDA website at https://www.fda.gov/emergency- preparedness-and-response/mcm-legal-regulatory-and-policy-framework/emergency-use- authorization#covid19euas. The ISDA (2021) published guidelines regarding testing for COVID-19 infection, including the following: SARS-CoV-2 nucleic acid amplification test (NAAT) is recommended in symptomatic individuals in the community suspected of having COVID-19, even when the clinical suspicion for COVID-19 is low. A single SARS-CoV2 viral RNA test is suggested in symptomatic individuals with a low clinical suspicion of COVID-19. Repeated testing is not suggested for this population. When the initial viral RNA test is negative repeating the test in a symptomatic individual with an intermediate or high clinical suspicion of COVID-19 is suggested. • SARS-CoV-2 RNA testing is recommended in asymptomatic individuals who are either known or suspected to have been exposed to COVID-19. Known exposure is defined Medical Coverage Policy: 0557 as direct contact with a laboratory confirmed case of COVID-19. Suspected exposure was defined as working or residing in a congregate setting (e.g., long-term care, correctional facility, cruise ship, factory, among others) experiencing a COVID-19 outbreak. SARS-CoV-2 RNA testing is recommended in an asymptomatic individual with no known contact with COVID-19 who are being hospitalized in areas with a low prevalence of COVID-19 in the community. An asymptomatic individual is defined as an individual with no symptoms or signs of COVID-19. A low prevalence of COVID-19 in the community is defined by the IDSA as a prevalence of <2%. This recommendation does not apply to an immunocompromised individual or an individual undergoing time-sensitive major surgery or aerosol generating procedures. • SARS-CoV-2 RNA testing is recommended in asymptomatic individuals with no known contact with COVID-19, who are being hospitalized in areas with a high prevalence of COVID-19 in the community (i.e., hotspots). High prevalence of COVID-19 is defined by the IDSA as a prevalence of ≥10%. SARS-CoV-2 RNA testing is recommended in an immunocompromised asymptomatic individual who are being admitted to the hospital, regardless of exposure to COVID- 19 SARS-CoV-2 RNA testing (versus no testing) is recommended in an asymptomatic individual before hematopoietic stem cell (HSCT) or solid organ transplantation (SOT) regardless of a known exposure to COVID-19 The Panel makes no recommendations for or against SARS-CoV-2 RNA testing before initiating immunosuppressive therapy in an asymptomatic individual with cancer Pooled Sample Diagnostic Testing Pooled sample testing for the qualitative detection of nucleic acid from the SARS-CoV-2 virus has been proposed as a laboratory method to conserve testing resources. The technique allows upper or lower respiratory samples from several individuals (e.g., 4-5 test samples) to be combined and tested together in a batch. This method may be useful for diagnostic testing in a population where low-prevalence of infection is present. Use in a population with high-prevalence of COVID-19 infection would likely result in the need to perform individual testing to identify the positive sample(s) and result in the consumption of additional testing resources. There are limitations to pooled testing. In a pooling procedure, the laboratory cannot ensure the diagnostic integrity of an individual specimen because it is combined with other specimens before testing. Specimen integrity can also be affected by the quality of swab specimen collection, which can result in some swabs having limited amounts of viral genetic material for detection. Inadequate individual specimens might not be eliminated from the pooled specimen before testing (CDC, 2021). A decrease in performance is also likely with pooling strategies due to dilution of the primary clinical sample and a decrease in sensitivity may result. The FDA notes that because samples are diluted there is a greater likelihood of false negative results, particularly if the test is not properly validated (2020). In general, the larger the pool of specimens, the higher the likelihood of generating false negative results (CDC, 2021). These limitations mean that monitoring the prevalence of disease and properly validating the assay for the real world population in which the test is being used is important to limit the potential for false negative results. Negative results from pooled samples should be considered to be presumptive negatives. Although proposed as a method that consumes fewer testing resources, a unique sample collection kit, swab and reagents must be used for each specimen collection regardless of pooling technique used. If the sample is collected by someone other than the individual being tested, Medical Coverage Policy: 0557 personal protective equipment is also required. If the pooled sample is negative, it can be deduced that all individuals tested within the pool have a negative test result and the pooled test result is sufficient. However, if the pooled sample is inconclusive or positive, each sample must be tested individually to determine which sample or samples are positive, resulting in the use of additional testing resources. Antigen Testing An antigen test is an immunoassay test that detects the presence of a specific viral antigen. The antigen is generally detectable during the acute phase of infection; however, an antigen test may not detect all active infections. Positive results indicate the presence of viral antigens. Samples are collected from areas such as the nasal passage. Antigen testing is subject to the same analytic and clinical performance limitations, such as those described for molecular tests. An antigen test generally has similar specificity as a molecular test but are less sensitive than NAATs and may yield false negatives if the viral protein production is low or if there is not enough virus replication in the sampled area. FDA EUA-designated antigen assays report a clinical sensitivity of 80% when compared to an EUA-designated molecular device. Test specificity of 100% is reported. Negative results do not rule out COVID-19. Antigen tests are available for at-home (self) testing, at point of care or in the laboratory. Antigen tests should not be used as the sole basis for treatment or for patient management decisions and should be treated as presumptive and confirmed with a molecular assay if necessary. The analytic sensitivity, specificity and positive and negative predictive values of individual tests that have received an FDA EUA designation can also be accessed on the FDA website at https://www.fda.gov/emergency-preparedness-and-response/mcm-legal-regulatory- and-policy-framework/emergency-use-authorization#covid19euas. Because of the performance characteristics (e.g., sensitivity, specificity) of some antigen tests, it may be necessary to confirm some test results such as a negative test in persons with symptoms or a positive test in an individual without symptoms. The CDC has developed an Antigen Testing Algorithm to be used when confirmatory testing is needed (CDC, 2022). An advantage of antigen testing is that the methodology lends itself to the point of care testing environment and results can be delivered fairly rapidly, often within minutes. While the main advantage of these antigen tests is the speed of the test, they are often plagued with inaccurate results and have lower sensitivity and specificity than nucleic acid assays Clinical correlation with patient history and other diagnostic information is necessary to determine infection status (Chau et al., 2020). Regarding antigen tests, the CDC (2022) notes the following: In a symptomatic individual, infection with SARS-CoV-2 can be identified by the presence of a positive antigen test. A negative antigen test result for a symptomatic person should be confirmed with an FDA- authorized NAAT. CDC recommends using a NAAT that has been evaluated against the FDA reference panel for analytical sensitivity. If the person has a low likelihood of SARS-CoV-2 infection (e.g., no known exposure), clinical judgement should be used to determine whether a confirmatory NAAT should be performed. Because antigen tests perform best in symptomatic people and within a certain number of days since symptom onset, antigen tests are used frequently on people who are symptomatic. Antigen tests also may be informative in diagnostic testing situations in which the asymptomatic person has a known exposure to a person with COVID-19. Medical Coverage Policy: 0557 Antigen tests have been used for screening testing in high-risk congregate housing settings, such as nursing homes, in which repeat testing has quickly identified people with COVID-19, informing infection prevention and control measures, thus preventing transmission. Serology (Antibody) Testing Clinical utility for diagnosis using antibody testing has not been established; the relationship between the presence of antibodies and re-infection and or re-activation of the virus is unknown. Antibody testing may be used as an aid in diagnosis but is of limited value when COVID-19 infection is suspected because such testing cannot be used to rule in or rule out an active infection. Likewise, a positive test does not necessarily assure immunity. Serologic testing by itself should not be used to establish the presence or absence of SARS-CoV-2 infection or reinfection. Such testing is not recommended as a tool to establish or diagnose SARS- CoV-2 infection (FDA, 2022; CDC, 2022; National Institutes of Health [NIH], 2023). At this time, no antibody (serology) test has been validated to establish or diagnose SARS-CoV-2 infection or authorized by the FDA for diagnostic purposes (FDA, 2022; CDC, 2022). Serology tests play a role in the fight against COVID-19 by helping health care professionals identify individuals who may have developed an adaptive immune response to SARS-CoV-2 (CDC, 2022; FDA, 2022). The primary role for antibody testing is to inform on exposure to a specific pathogen by detection of the presence of antibodies to a specific virus. However, antibodies may not be present among those tested early in illness or among those who never develop detectable antibodies following infection. In addition, the presence of antibodies may reflect previous infection and may be unrelated to the current illness. In humans, three types of antibodies or immunoglobulins have been the target of COVID-19 serological tests: IgM, IgG, and IgA. Although the dynamics of the immune response in COVID-19 are not fully understood, typically IgM antibodies are produced by host immune cells during the early stages of a viral infection. IgG is often the most abundant antibody in the blood and plays a more prominent role in the later stages of infection and in establishing long-term immune memory. Recent studies show that IgA, predominately present in the mucosal tissue, may also play a critical role in immune response and disease progression (Ghafferi et al., 2020). Antibodies to SARS-CoV-2 are generally detectable in blood several days after initial infection, although the duration of time that antibodies are present post-infection is not well characterized (FDA, 2022). Asymptomatic patients may seroconvert later in the course of infection or may not at all (Chau et al. 2020). The FDA notes that a positive antibody test result is difficult to interpret for a number of reasons. For some assays both sensitivity and specificity are poor or undefined in a real-world population. Accuracy of an antibody test depends in part on the prevalence of the infection in the population. The prevalence of SARS-CoV-2 antibody positive individuals in the U.S. population is currently unknown. Prevalence may vary based on the duration of the virus, the effectiveness of mitigations and between locations and different groups of people, due to different rates of infection. In low prevalence populations, such as much of the asymptomatic general population, the result of a single antibody test is not likely to be sufficiently accurate to make an informed decision regarding whether or not an individual has had a prior infection or truly has antibodies to the virus (2022). A second test, typically one assessing for the presence of antibodies to a different viral protein, generally would be needed to increase the accuracy of the overall testing results (FDA, 2022). As a result, the clinical utility of serology testing is uncertain. Medical Coverage Policy: 0557 The positive and negative predictive values describe how likely it is that a person who receives a positive result from a test truly does have antibodies to SARS-CoV-2 and how likely it is that a person who receives a negative result from a test truly does not have antibodies to SARS-CoV-2. Different serological tests have varying levels of specificity and sensitivity. Sensitivity of antibody tests for SARS-CoV-2 are typically reported to be between 88-100%, specificity 94-100% and positive and negative predictive value at 5% prevalence: 50.4-100% and 99.4-100%, respectively. This means that a positive result may result in an incorrect finding in as much as 50% of the time if the prevalence of the disease in the general population is 5%. False positives can result from cross-reactivity with pre-existing antibodies from previous infections such as other coronaviruses that cause the common cold; SARS-CoV or MERS-CoV. Negative results may result because antibodies have not yet formed during the early stages of infections (Chau et al., 2020) Studies are underway to better inform the appropriate use of these tests, such as which antibodies may indicate a level of protection that would prevent or reduce the severity of infection or re- infection as well as the duration for which this protection may last. Large-scale validation studies on the performance of these assays are critical before they can be used in seroprevalence studies for disease surveillance. A collaborative effort by the FDA, National Institutes of Health, CDC and Biomedical Advanced Research and Development Authority (BARDA) is currently underway to conduct performance assessments and establish the validity of serological tests against a well- characterized set of clinical samples collected before and during the pandemic and correlate them with neutralization assays (Chau et al., 2020). Antibody tests that have received an FDA EUA designation are designed to detect IgA, IgM or IgG antibodies alone or a combination of some or all antibodies reported as a total result. Currently, there is no substantive performance advantage of assays whether they test for IgG, IgM and IgG, or total antibody. Thus, immunoglobulin class should not determine the assay chosen in most circumstances (CDC, 2022). Serologic testing should not be used to determine immune status in individuals until the presence, durability, and duration of immunity are established. Serologic testing can be offered as a method to support diagnosis of acute COVID-19 illness for persons who present late. For persons who present 9–14 days after illness onset, serologic testing can be offered in addition to recommended viral direct detection methods such as polymerase chain reaction or antigen detection tests. However, serologic testing should be offered as a method to help support a diagnosis when patients present with late complications of COVID-19 illness, such as multisystem inflammatory syndrome in children (MIS-C) and in adults (MIS-A) (CDC, 2022). The results of ongoing research are needed before it is known whether antibodies are associated with protection from future infection. When used for surveillance, the results can help determine how widely the virus has spread in communities. Results from tests used for surveillance only are generally not shared with individual patients. Regarding antibody (serology) testing, the CDC (2022) notes: Antibody tests can be used to:  Determine if a person has COVID-19 antibodies, which suggests past infection or vaccination.*  Aid in the diagnosis of multisystem inflammatory syndrome in children (MIS-C) and in adults (MIS-A).  Monitor and evaluate population levels of immunity Antibody tests should not be used to: Medical Coverage Policy: 0557  Diagnose current infection.**  Determine if someone can return to work or school.  Group people together in settings such as schools, dormitories, and correctional facilities; or to exempt someone from screening testing.  Exempt a person who wears personal protective equipment (PPE) at work from following site-specific requirements **Acute infection from SARS-CoV-2 is determined best by diagnostic testing using a nucleic acid amplification test (NAAT) or antigen test. The CDC (2022) also notes: Persons suspected of having COVID-19 who test positive by direct viral detection methods for SARS-CoV-2 (e.g., NAAT or antigen detection tests) typically begin to develop measurable antibody 7–14 days after illness onset, and by 3 weeks most persons will test positive for antibody. During this interval, the sensitivity of detecting infection using NAAT or antigen detection testing decreases and the sensitivity of serologic testing increases. Antibody testing may be useful to support the diagnosis of COVID-19 illness or complications of COVID-19 in the following situations:  A positive antibody test at least 7 days following acute illness onset in persons who had a previous negative antibody test (e.g., seroconversion) but did not receive a positive viral test might indicate SARS-CoV-2 infection between the dates of the negative and positive antibody tests.  A positive antibody test can help support a diagnosis when patients present with complications of COVID-19, such as multisystem inflammatory syndrome or other post-acute sequelae of COVID-19.  Antibody testing can be used for clinical and public health purposes to help differentiate antibodies produced due to past infection from those produced by vaccination by using tests that measure antibodies against different protein targets.  Antibody testing is currently not recommended to assess for immunity to SARS- CoV-2 following COCID-19 vaccination. The CDC notes that although the surrogate neutralization test exhibits correlation to a plaque reduction neutralization test, the clinical or public health applicability has not been established for this test. Although current FDA EUA indications do not preclude the use of these tests in vaccinated individuals, none of the currently authorized tests have been specifically authorized to assess immunity or protection of people who have received a COVID-19 vaccine, including people with immunocompromising conditions. Whether the test has been validated to specifically detect antibodies against the antigens employed by the test and whether the antigens cross-react with antibodies to antigens that are not employed by the test should be considered. Antibody (serology) tests that have received an FDA EUA designation can be found at https://www.fda.gov/emergency-preparedness-and-response/mcm-legal-regulatory-and-policy- framework/emergency-use-authorization#sarscov2antibody. Multisymptom Inflammatory Syndrome (MIS) Medical Coverage Policy: 0557 MIS is a rare but serious condition associated with COVID-19 in which different body parts become inflamed, including the heart, lungs, kidneys, brain, skin, eyes, or gastrointestinal organs (CDC, 2023). This rare syndrome shares common features with other inflammatory conditions such as Kawasaki disease, staphylococcal and streptococcal toxic shock syndromes, bacterial sepsis and macrophage activation syndromes. In an individual with suspected MIS-C a molecular test may be positive or negative for the SARS-CoV-2 virus. While not diagnostic of infection with SARS-CoV-2 infection, an antibody (serology) test may be considered appropriate in a symptomatic individual to aid in the diagnosis of MIS-C when results of molecular or antigen tests are non-diagnostic for COVID-19 infection. As a result of the variable performance of serology tests described in the above antibody testing section, the clinical utility of the antibody result must be interpreted in the context of the individual’s treatment history and presenting symptom complex. Several professional societies, including the American Academy of Pediatrics, the American College of Rheumatology and the Royal College of Paediatrics and Child Health (2020) and the CDC (2023) have developed a case definition for MIS in adults (MIS-A) and children (MIS-C): Adults (MIS-A) General Criteria  An individual ≥21 years hospitalized for ≥24hours or with an illness resulting in death, who meets the following clinical and laboratory criteria. The individual should not have a more likely alternate diagnosis for the illness (e.g., bacterial sepsis, exacerbation of a chronic medical condition). Clinical Criteria  Subjective fever or documented fever (≥38.0C for ≥24 hours prior to hospitalization or within the first three days of hospitalization AND at least three of the following clinical criteria occurring prior to hospitalization or within the first three days of hospitalization. At least one must be a primary clinical criterion. o Primary Clinical Criteria   severe cardiac illness rash and non-purulent conjunctivitis o Secondary Clinical Criteria  new onset neurologic signs and symptoms  shock or hypotension not attributable to medical therapy (e.g., sedation, renal replacement therapy)  abdominal pain  thrombocytopenia (platelet count <150,000/microliter Laboratory Evidence  Presence of laboratory evidence of inflammation and SARS-Co-V2 infection  Elevated levels of at least two of the following o C-reactive protein o Ferritin IL-6 o o Erythrocyte sedimentation rate o Procalcitonin  A positive SARS-Co-V2 test during the current illness by RT-PCR, serology or antigen detection Children (MIS-C): Any individual aged <21 years that’s meets certain clinical AND laboratory criteria, OR clinical and epidemiologic criteria OR vital records criteria: Clinical criteria Medical Coverage Policy: 0557 An illness characterized by all of the following, in the absence of a more likely alternative diagnosis*  Subjective or documented fever (temperature ≥38.0⁰ C)  Clinical severity requiring hospitalization or resulting in death  Evidence of systemic inflammation indicated by C-reactive protein ≥3.0 mg/dL (30 mg/L)  New onset manifestations in at least two of the following categories: o Cardiac involvement indicated by:  Left ventricular ejection fraction <55% OR  Coronary artery dilatation, aneurysm, or ectasia, OR  Troponin elevated above laboratory normal range, or indicated as elevated in a clinical note o Mucocutaneous involvement indicated by:  Rash, OR  Inflammation of the oral mucosa (e.g., mucosal erythema or swelling, drying or fissuring of the lips, strawberry tongue), OR  Conjunctivitis or conjunctival injection (redness of the eyes), OR  Extremity findings (e.g., erythema [redness] or edema [swelling] of the hands or feet) o Shock** o Gastrointestinal involvement indicated by:  Abdominal pain, OR  Vomiting, OR  Diarrhea o Hematologic involvement indicated by: o Platelet count <150,000 cells/μL, OR o Absolute lymphocyte count (ALC) <1,000 cells/μL Laboratory criteria: Detection of SARS-CoV-2 RNA in a clinical specimen*** up to 60 days prior to or during hospitalization, or in a post-mortem specimen using a diagnostic molecular amplification test (e.g., polymerase chain reaction [PCR]), OR Detection of SARS-CoV-2 specific antigen in a clinical specimen*** up to 60 days prior to or during hospitalization, or in a post-mortem specimen, OR Detection of SARS-CoV-2 specific antibodies^ in serum, plasma, or whole blood associated with current illness resulting in or during hospitalization Epidemiologic Linkage criteria: Close contact‡ with a confirmed or probable case of COVID-19 disease in the 60 days prior to hospitalization Vital Records criteria: Medical Coverage Policy: 0557 person whose death certificate lists MIS-C or multisystem inflammatory syndrome as an underlying cause of death or a significant condition contributing to death 38.0°C for ≥24 hours, or report of subjective fever lasting ≥24 hours Where feasible, SARS-Co-V2 serologic testing is suggested, even in the presence of positive results from RT-PCR or antigen testing. Serologic testing should be performed prior to administration of intravenous immunoglobulin IVIG) or any other exogenous antibody treatments. In Vitro Testing for Population or Public Health Screening Molecular, antigen and antibody (serology) testing has been proposed to determine prevalence of COVID-19 infection in a population. Testing strategies include screening and surveillance. Similar analytic and clinical performance limitations as described above apply to testing for population and public health screening; these tests have not been validated for use in the asymptomatic population. Screening for COVID-19 is looking for occurrence at the individual level even if there is no individual reason to suspect infection, such as a known exposure. This includes broad screening of asymptomatic individuals without known exposure with the intent of making individual decisions based on the test results. Screening tests are intended to identify infected individuals prior to development of symptoms or those infected individuals without signs or symptoms who may be contagious, so that measures can be taken to prevent those individuals from infecting others. Examples of screening include testing plans developed by a workplace to test all employees returning to the workplace, plans developed by a school to test all students and faculty returning to the school, testing requirements before participation in sports, pre-employment physicals and testing of residents and employees in congregate setting such as nursing homes, assisted living and dormitory residences. Testing is performed regardless of exposure or signs and symptoms, with the intent of using those results to determine who may return or what protective measures to take on an individual basis. (FDA, 2022). Surveillance for COVID-19 is not regulated by the FDA. An example of such testing may be a plan developed by a State Public Health Department to randomly select and sample 1% of all individuals in a city on a rolling basis to determine local infection rates and trends. It is generally used to monitor for an occurrence, such as an infectious disease outbreak in a population or community, or to characterize the occurrence once detected, such as looking at the incidence and prevalence of the occurrence. Surveillance testing is primarily used to gain information at a population level, rather than an individual level. Surveillance testing may be random sampling of a certain percentage of a specific population to monitor for increasing or decreasing prevalence and determining the population effect from community interventions such as social distancing (FDA, 2022). In vitro testing for the purpose of population or public health screening, including to determine prevalence of COVID-19 infection in the community or congregate setting is not necessary to diagnose the infection caused by SARS-COV-2 virus. Likewise, screening for other viral diseases does not diagnose COVID-19 infection. Testing for any of the following is not a covered benefit under most Cigna standard benefit plans. return-to-work • return-to-school • participation in sports Medical Coverage Policy: 0557 pre-employment • routine and/or executive physicals • travel • recruitment to armed forces • insurance purposes • disability evaluation • encounter for administrative exam, unspecified Other Non-Diagnostic Tests and Devices FDA EUA status has been granted for additional tests and devices that are not considered diagnostic for SARS-CoV-2 (COVID-19) infection. They may be used for population and public health screening and surveillance purposes. Testing for variants of SARS-CoV-2 is another type of testing used for surveillance. The CDC works with public health officials to monitor and track all variants. According to the CDC (2022) viral genomic sequencing is used to identify, track and monitor COVID-19 variants to protect the public’s health. The CDC’s COVID Data Tracker publishes estimates of how common variants are at national and regional levels. U.S. Food and Drug Administration (FDA) The FDA has issued Emergency Use Authorization (EUA) status to a number of molecular, antigen and antibody tests which allows for their marketing and use during the declared Public Health Emergency period for COVID-19 infection. Detailed information for all FDA EUAs related to COVID-19, including authorizations and fact sheets is available at https://www.fda.gov/emergency-preparedness-and-response/mcm-legal- regulatory-and-policy-framework/emergency-use-authorization#covid19euas. Professional Societies/Organizations American Academy of Family Physicians ([AAFP], 2020): The AAFP notes that family physicians should use their best clinical judgement to determine who should be tested. Centers for Disease Control and Prevention (CDC, 2022): The CDC published the following guidance: Testing Strategies for SARS-CoV-2 Diagnostic testing is intended to identify current infection in individuals and should be performed on anyone that has signs and symptoms consistent with COVID-19. A laboratory-based Nucleic Acid Amplification Test (NAAT) is recommended for diagnostic testing of vaccinated, asymptomatic individuals following recent known or suspected exposure to SARS-CoV-2. Examples of diagnostic testing include: Testing anyone with symptoms consistent with COVID-19 • Testing vaccinated and unvaccinated people who were exposed to someone with a confirmed or suspected case of COVID-19 Screening Testing Medical Coverage Policy: 0557 Screening tests are intended to identify unvaccinated people with COVID-19 who are asymptomatic and do not have known, suspected, or reported exposure to SARS-CoV-2. Screening helps to identify unknown cases so that measures can be taken to prevent further transmission. Examples of screening include testing: Employees in a workplace setting • Students, faculty, and staff in a school setting • A person before or after travel • Someone at home who does not have symptoms associated with COVID-19 and no known exposures to someone with COVID-19 Public Health Surveillance Testing Public health surveillance is the ongoing, systematic collection, analysis, and interpretation of health-related data essential to the planning, implementation, and evaluation of public health practice Public health surveillance testing is intended to monitor community- or population-level outbreaks of disease, or to characterize the incidence and prevalence of disease. Public health surveillance testing may sample a certain percentage of a specific population to monitor for increasing or decreasing prevalence, or to determine the population effect from community interventions such as social distancing Infectious Disease Society of America (IDSA, 2021): The IDSA published practice guidelines regarding testing for COVID-19, including the following recommendations: Molecular Diagnostic Testing: A SARS-CoV-2 nucleic acid amplification test (NAAT) is recommended in symptomatic individuals in the community suspected of having COVID-19, even when the clinical suspicion for COVID-19 is low (strong recommendation, very low certainty of evidence). • A single viral RNA test and not repeating testing is suggested in symptomatic individuals with a low clinical suspicion of COVID-19 (conditional recommendation, low certainty of evidence). Repeating viral RNA testing when the initial test is negative (versus performing a single test) is suggested in symptomatic individuals with an intermediate or high clinical suspicion of COVID-19 (conditional recommendation, low certainty of evidence). Intermediate/high clinical suspicion typically applies to the hospital setting and is based on the severity, numbers and timing of compatible clinical signs/symptoms. Using either rapid RT-PCR or standard laboratory based NAAT over rapid isothermal NAATs in symptomatic individuals suspected of having COVID-19 is suggested (conditional recommendation, low certainty of evidence). SARS-CoV-2 RNA testing in asymptomatic individuals who are either known or suspected to have been exposed to COVID-19 is suggested (conditional recommendation, very low certainty of evidence). Known exposure was defined as direct contact with a laboratory confirmed case of COVID-19. SARS-CoV-2 RNA testing in asymptomatic individuals with no known contact with COVID- 19 who are being hospitalized in areas with a low prevalence of COVID-19 in the community is suggested (conditional recommendation, very low certainty of evidence). Medical Coverage Policy: 0557 Asymptomatic individuals are defined as those with no symptoms or signs of COVID-19. A low prevalence of COVID-19 in the community was considered communities with a prevalence of <2%. Direct SARS-CoV-2 RNA testing in asymptomatic individuals with no known contact with COVID-19 who are being hospitalized in areas with a high prevalence of COVID-19 in the community (i.e., hotspots) is recommended (conditional recommendation, very low certainty of evidence). Asymptomatic individuals are defined as those with no symptoms or signs of COVID-19. A high prevalence of COVID-19 in the community was considered communities with a prevalence of ≥10%. SARS-CoV-2 RNA testing in immunocompromised asymptomatic individuals who are being admitted to the hospital regardless of exposure to COVID-19 is recommended (strong recommendation, very low certainty of evidence). Immunosuppressive procedures are defined as cytotoxic chemotherapy, solid organ or stem cell transplantation, long acting biologic therapy, cellular immunotherapy, or high-dose corticosteroids. SARS-CoV-2 RNA testing (versus no testing) in asymptomatic individuals before immunosuppressive procedures regardless of a known exposure to COVID-19 is recommended (strong recommendation, very low certainty of evidence). Immunosuppressive procedures are defined as cytotoxic chemotherapy, solid organ or stem cell transplantation, long acting biologic therapy, cellular immunotherapy, or high- dose corticosteroids. The IDSA panel makes no recommendations for or against SARS-CoV-2 RNA testing before initiating immunosuppressive therapy in asymptomatic individuals with cancer (evidence gap). The IDSA panel makes no recommendations for or against SARS-CoV-2 RNA testing before the initiation of immunosuppressive therapy in asymptomatic individuals with autoimmune disease (evidence gap). SARS-COV-2 RNA testing in asymptomatic individuals (without known exposure to COVID- 19) who are undergoing major time-sensitive surgeries is suggested (conditional recommendation, very low certainty of evidence). Time-sensitive surgery is defined as medically necessary surgeries that need to be done within three months. Testing should ideally be performed as close to the planned surgery as possible (e.g. within 48-72 hours). SARS-CoV-2 RNA testing in asymptomatic individuals without a known exposure to COVID- 19 who are undergoing a time-sensitive aerosol generating procedure (e.g., bronchoscopy) when PPE is available is not suggested (conditional recommendation, very low certainty of evidence). Time-sensitive procedures defined as medically necessary procedures that need to be done within three months. Procedures considered to be aerosol generating (i.e., bronchoscopy, open suctioning of airways, sputum induction, cardiopulmonary resuscitation, endotracheal intubation and extubation, non-invasive ventilation (e.g., BiPAP, CPAP), bronchoscopy, manual ventilation) SARS-CoV-2 RNA testing in asymptomatic individuals without a known exposure to COVID- 19 who are undergoing a time-sensitive aerosol generating procedure (e.g., bronchoscopy) when PPE is limited, and testing is available is suggested (conditional recommendation, very low certainty of evidence). Time-sensitive procedures are defined as medically necessary procedures that need to be done within three months. Testing should be performed as close to the planned procedure as possible (e.g. within 48-72 hours). Decisions about PPE will be dependent on test results because of limited availability of PPE. However, there is a risk for false negative test results, so caution should be exercised for those who will be in close contact with/exposed to the patient’s airways. Procedures considered to be aerosol generating (i.e., bronchoscopy, open suctioning of airways, sputum induction, cardiopulmonary resuscitation, endotracheal intubation and extubation, Medical Coverage Policy: 0557 non-invasive ventilation (e.g., BiPAP, CPAP), bronchoscopy, manual ventilation). The decision to test asymptomatic patients will be dependent on the availability of testing resources. This recommendation does not address the need for repeat testing if patients are required to undergo. Antigen Testing: For asymptomatic individuals with risk for exposure to SARS-CoV-2 infection, the IDSA panel suggests using a single standard NAAT (either rapid RT-PCR or laboratory-based NAAT) over a single rapid Ag test (conditional recommendation based on moderate certainty in test accuracy of rapid Ag tests and very low certainty in comparative test accuracy of rapid RT-PCR versus rapid Ag tests). For asymptomatic individuals with risk for exposure to SARS-CoV-2 infection, the IDSA panel suggests a single (i.e., one-time) standard NAAT (either rapid RT-PCR or laboratory- based NAAT) rather than a strategy of two consecutive rapid Ag tests (conditional recommendation based in moderate certainty in test accuracy of molecular testing and an evidence gap to inform the test accuracy of a strategies using repeat Ag testing). In asymptomatic individuals with risk for exposure to SARS-CoV-2 infection, the IDSA panel suggests neither for nor against using single (i.e. one-time) rapid Ag testing over no testing (evidence gap to inform the utility of Ag testing compared to no testing). In asymptomatic individuals with risk for exposure to SARS-CoV-2 infection, the IDSA panel suggests neither for nor against using repeat rapid Ag testing over no testing (evidence gap to inform the utility of a strategy of Ag testing compared to no testing). Serologic (Antibody) Testing: The IDSA panel suggests against using serologic testing to diagnose SARS-CoV-2 infection during the first two weeks (14 days) following symptom onset (conditional recommendation, very low certainty of evidence). When SARS-CoV-2 infection requires laboratory confirmation for clinical or epidemiological purposes, the IDSA panel suggests testing for SARS-CoV-2 IgG or total antibody three to four weeks after symptom onset to detect evidence of past SARS-CoV-2 infection (conditional recommendation, very low certainty of evidence). When serology is being considered as an adjunct to NAAT for diagnosis, testing three to four weeks post-symptom onset maximizes the sensitivity and specificity to detect past infection. The IDSA panel makes no recommendation either for or against using IgM antibodies to detect evidence of past SARS-CoV-2 infection (conditional recommendation, very low certainty of evidence). The ISDA panel suggests against using IgA antibodies to detect evidence of past SARS- CoV-2 infection (conditional recommendation, very low certainty of evidence). The IDSA panel suggests against using IgM or IgG antibody combination tests to detect evidence of past SARS-CoV-2 infection (conditional recommendation, very low certainty of evidence). IgM or IgG combination tests are those where detecting either antibody class is used to define a positive result. Recommendation 6: The IDSA panel suggests using IgG antibody to provide evidence of COVID-19 infection in symptomatic patients with a high clinical suspicion and repeatedly negative NAAT testing (weak recommendation, very low certainty of evidence). When serology is being considered as an adjunct to NAAT for diagnosis, testing three to four weeks post-symptom onset maximizes the sensitivity and specificity to detect past infection. In pediatric patients with multisystem inflammatory syndrome, the IDSA panel suggests using both IgG antibody and NAAT to provide evidence of current or past COVID-19 infection (strong recommendation, very low certainty of evidence). Medical Coverage Policy: 0557 The IDSA panel makes no recommendation for or against using capillary versus venous blood for serologic testing to detect SARS-CoV-2 antibodies (knowledge gap). National Institutes of Health ([NIH], 2022): The NIH published recommendations regarding testing for SAR-Co-V2: To diagnose acute infection of SARS-CoV-2, the COVID-19 Treatment Guidelines Panel (the Panel) recommends using either a nucleic acid amplification test (NAAT) or an antigen test with a sample collected from the upper respiratory tract (e.g., nasopharyngeal, nasal mid- turbinate, anterior nasal) to diagnose acute SARS-CoV-2. (AIII). A NAAT should not be repeated in an asymptomatic person (with the exception of health care workers) within 90 days of a previous SARS-CoV-2 infection, even if the person has had a significant exposure to SARS-CoV-2 (AIII). SARS-CoV-2 reinfection has been reported in people after an initial diagnosis of the infection; therefore, clinicians should consider using a NAAT for those who have recovered from a previous infection and who present with symptoms that are compatible with SARS- CoV-2 infection if there is no alternative diagnosis (BIII). The Panel recommends against diagnosing acute SARS-CoV-2 infection solely on the basis of serologic (i.e., antibody) test results (AIII). There is insufficient evidence for the Panel to recommend either for or against the use of SARS-CoV-2 serologic testing to assess for immunity or to guide clinical decisions about using COVID-19 vaccines or anti-SARS-CoV-2 monoclonal antibodies. For intubated and mechanically ventilated adults who are suspected to have COVID-19 but who do not have a confirmed diagnosis:  The Panel recommends obtaining lower respiratory tract samples to establish a diagnosis of COVID-19 if an initial upper respiratory tract sample is negative (BII).  The Panel recommends obtaining endotracheal aspirates over bronchial wash or bronchoalveolar lavage samples when collecting lower respiratory tract samples to establish a diagnosis of COVID-19 (BII). A NAAT should not be repeated in an asymptomatic person within 90 days of a previous SARS-CoV-2 infection, even if the person has had a significant exposure to SARS-CoV-2 (AIII). SARS-CoV-2 reinfection has been reported in people who have received an initial diagnosis of infection; therefore, a NAAT should be considered for persons who have recovered from a previous infection and who present with symptoms that are compatible with SARS-CoV-2 infection if there is no alternative diagnosis (BIII). The Panel recommends against the use of serologic (i.e., antibody) testing as the sole basis for diagnosis of acute SARS-CoV-2 infection (AIII). The Panel recommends against the use of serologic (i.e., antibody) testing to determine whether a person is immune to SARS-CoV-2 infection (AIII). Based on current knowledge, serologic tests should not be used to (AIII):  Make decisions about how to group persons in congregate settings (e.g., schools, dormitories, correctional facilities)  Determine whether persons may return to the workplace  Assess for prior infection solely to determine whether to vaccinate an individual  Assess for immunity to SARS-CoV-2 following vaccination, except in clinical trials Medical Coverage Policy: 0557 Rating of Recommendations: A = Strong, B = Moderate Rating of Evidence: IIa = Other randomized trials or subgroup analyses of randomized trials; IIb = Nonrandomized trials or observational cohort studies; III = Expert opinion