Note: The information on the coronavirus outbreak is continually evolving. The content within this activity serves as a historical reference to the information that was available at the time of this publication. We continue to add to the collection of activities on this subject as new information becomes available. It is the policy of Medscape Education to avoid the mention of brand names or specific manufacturers in accredited educational activities. However, manufacturer names related to COVID-19 vaccines, therapeutics, and diagnostic tests may be provided in this activity in an effort to promote clarity. The use of manufacturer names should not be viewed as an endorsement by Medscape of any specific product or manufacturer.

More than 60 million US households have requested free at-home COVID-19 tests through the government's website.^[1] Daniel Kuritzkes, MD, recently sat with Medscape, offering guidance to clinicians on answering patients' frequently asked questions about at-home testing. Dr Kuritzkes is an acclaimed clinical scientist, chief of infectious disease at Brigham and Women's Hospital, and a Harvard Medical School professor.

Medscape: How does an at-home rapid antigen test differ from molecular testing done at a testing facility?

Daniel Kuritzkes, MD: At-home rapid antigen tests work by detecting virus particles in samples collected from the nasal cavities of infected persons using a nasal swab.^[2] The anterior nasal swab collection method is most common, which involves putting a swab three-quarters of an inch into the nostril and twirling it around at least 4 times. These are low-complexity tests and can be performed at home by persons without any laboratory training. Typically, test results are returned in 15 to 30 minutes and tell a patient if they're infectious at the time of testing.

Antigen tests detect proteins on the surface of the SARS-CoV-2 virus, the pathogen that causes COVID-19.^[3] These tests are best used in symptomatic patients -- when the results are most sensitive. The assay reacts only to proteins contained in the test sample and so can return a false negative result when virus levels are low, as is generally the case when someone is infected but hasn't started showing symptoms.^[2] If conducted repeatedly (eg, every 3 days), antigen testing can also be a cost-effective screening method for asymptomatic infection.^[4]

Molecular testing for COVID-19 (also called nucleic acid amplification testing) is mainly processed in a laboratory using a method known as reverse transcription-polymerase chain reaction (RT-PCR).^[2,3] A healthcare professional collects a swab sample, usually from the patient's nose or throat. The RT-PCR technique tests the sample for the virus's genetic material. Trained personnel and special equipment are required to analyze the results. COVID RT-PCR results may be available in 1 to 2 days from testing.^[3]

The SARS-CoV-2 virus uses RNA as its genetic material.^[5] RT-PCR converts the viral RNA into complementary DNA (c-DNA) sequences. Primers (small pieces of DNA) attach to the viral c-DNA and build new DNA strands. This process produces millions of copies of the virus's genetic material. By copying -- or amplifying -- the DNA corresponding to the virus's RNA, RT-PCR can detect extremely small amounts of the virus, making this test highly sensitive and specific, even when patients are presymptomatic or asymptomatic.^[6]

Point-of-care rapid molecular tests used by some testing locations such as pharmacies can read results onsite -- in about 15 to 60 minutes.^[7] According to the Centers for Disease Control and Prevention (CDC), point-of-care molecular tests have a moderate to high test sensitivity -- less sensitive than RT-PCR testing, but more sensitive than antigen testing.^[2] Point-of-care molecular testing devices use an isothermal technique for nucleic acid amplification that doesn't require thermal cyclers, thus allowing for more rapid results than for RT-PCR.^[8]

Molecular RT-PCR and point-of-care test results tell a patient if they've been infected by the virus in the past few days, regardless of whether they're symptomatic. However, a positive test result could also be evidence of residual viral nucleic acid from a remote infection that's no longer capable of replicating or being transmitted to others -- these tests can be that sensitive.^[2,7] For this reason, molecular testing is not recommended as a means of clearing people for returning to work or coming out of isolation or quarantine. Table 1 summarizes some of the differences between molecular and antigen testing.

Table 1. COVID-19 Antigen and Molecular Test Differences to Consider in Diagnosis or Screening^[2]

^*At-home testing typically uses an anterior nasal swab collection method. Antigen tests are also offered in pharmacies and doctors' offices where a mid-turbinate, nasopharyngeal, or salivary collection method may be used.
^†The decreased sensitivity of antigen tests might be offset if repeated more frequently (ie, every 3 days).^[4]
‡Refers to point-of-care antigen tests only.

Medscape: Is there such a thing as at-home molecular testing?

Dr Kuritzkes: Yes, at-home molecular testing kits are available that produce test results within an hour outside of a laboratory, but they're pricey ($75 to $450+) and thus not widely accessible to most people. The kits offer telehealth services for CDC-compliant supervised testing and seem to be most frequently used as a self-test option for international travel. Two lab-quality molecular COVID-19 tests received Emergency Use Authorization (EUA) for over-the-counter (OTC) at-home use, and another has EUA for prescription home-testing.^[9-11] The home tests are low complexity but require a solid wireless connection to download the app and conduct the telehealth video call.

Medscape: Interesting. How accurate are the more commonly used at-home rapid antigen tests?

Dr Kuritzkes: At-home antigen tests are quite accurate. Still, they have some limitations. Their accuracy varies depending on the course of infection, but is generally moderate to high at times of peak viral load when patients are symptomatic.^[2] Different brands of antigen tests also have different levels of accuracy.^[3]

A test's specificity is its ability to correctly identify individuals without the disease (the true negatives) while minimizing false-positive results. A review of 64 studies from Europe and the United States showed in patients who did not have COVID-19, antigen tests correctly ruled out infection in 99.5% of people with symptoms and 98.9% without symptoms.^[3]

A test's sensitivity is its ability to correctly identify individuals with the disease (the true positives) while minimizing the number of false-negative results. In people with confirmed COVID-19, antigen tests correctly identified COVID-19 infection in 72% of people with symptoms compared to 58% without symptoms.^[3] In general, the sensitivity of antigen tests is 30% to 40% lower than for RT-PCR, depending on whether tested subjects were symptomatic or asymptomatic.^[3]

Medscape: When is it advised to go to a testing facility instead of using an at-home test?

Dr Kuritzkes: If a person tests positive for SARS-CoV-2 infection with an at-home rapid antigen test, that's a reliable result.^[2,12] However, if a person has COVID-19 symptoms and tests negative using a rapid antigen test, that doesn't exclude the possibility that they still, in fact, have COVID-19. They could either wait 24 hours (but no more than 48 hours) and re-test with an antigen test or confirm their results with the more sensitive RT-PCR tests.

The principal reason for going to a testing facility would be if you're a person who's at risk of developing severe COVID-19 and would benefit from one of the treatments available to ambulatory patients. The medications are most effective when given in the first few days after developing COVID-19 symptoms. Treatment availability is limited, and a positive COVID-19 test result is required for prescribing. International travel is another reason for getting a RT-PCR test.

Medscape: We've mentioned patients being symptomatic a few times. What are symptoms of COVID-19?

Dr Kuritzkes: It's not an exhaustive list, but COVID-19 symptoms may include fever or chills, cough, shortness of breath or difficulty breathing, fatigue, muscle or body aches, headache, new loss of taste or smell, sore throat, congestion or runny nose, nausea or vomiting, and diarrhea.^[13] There's no official guidance on which symptoms are more prevalent with certain strains of the virus (eg, Delta, Omicron).

Medscape: Does at-home testing detect the Omicron variant of SARS-CoV-2?

Dr Kuritzkes: Most at-home antigen tests can detect the Omicron variant, which is reassuring should we see a future surge in infection with a different variant. There's some dispute about whether viral shedding of the Omicron variant is higher in the saliva relative to the nose. Consequently, anecdotal advice is circulating about Omicron that oral swabs may be positive earlier than nasal swabs. There is no evidence to support oral swabbing, and the FDA has advised against using a throat swab with the rapid tests authorized in the United States.^[14] At-home antigen testing will not specify which variant is causing infection. Detecting variants requires genetic testing conducted in a laboratory.

Medscape: Any tips for patients on reducing false negatives and false positives when using at-home antigen tests?

Dr Kuritzkes: This may sound redundant, but advise patients to follow the directions carefully. They need to wash their hands before testing and avoid putting the swab down anywhere after it's taken out of its package. Inadequate sample collection can lead to a false negative; advise patients to swab as directed to maximize the chances they'll collect the virus if it is present, and put the swab directly into the test after they've swabbed to minimize the risk of contamination. Patients should also keep track of time and check results when indicated by the test's directions. Reading the result too early could result in a false negative and reading the result too late could result in a false positive. These are low-complexity tests, but they still require attention to detail and dexterity. For example, a person who has trouble with their vision or with a hand tremor, or who struggles with reading or following directions may have difficulty conducting the test themselves.

Medscape: What are the CDC's current recommendations for isolation and quarantine?

Dr Kuritzkes: The CDC decreased the recommended time for isolation for most patients from 10 days to 5 days in December 2021. The change was prompted by evidence that viral transmission occurs early in the course of COVID-19 illness, generally in the 1 to 2 days before symptom onset and 2 to 3 days after.^[15]

If the person tests positive for SARS-CoV-2 infection, they should isolate for at least 5 days, even if they don't have symptoms.^[12] Day 1 is the first full day after symptom development or test specimen collection. If the person has been in close contact with someone who has COVID-19, the recommendations for quarantine are individualized (Figure 1). According to the CDC, "a close contact is someone who was less than 6 feet away from an infected person for a cumulative total of 15 minutes or more over 24 hours." So if the infected person had completed at least 5 days of isolation prior to the exposure, they are not considered a close contact.

It's also possible that a person with COVID-like symptoms could have influenza or other respiratory infections. If a person tests negative for COVID-19 but their symptoms persist, consider testing for influenza, as well as re-testing for COVID-19.^[2]

Figure 1. CDC Guidance for Isolation and Quarantine^[2,12,15]

Medscape: Any parting words that you'd like to share with your colleagues?

Dr Kuritzkes: The fact that COVID-19 tests have been developed so rapidly and are becoming widely available is tremendous and speaks to the progress that's been made in point-of-care testing. Hopefully we can apply these learnings as a model to develop point-of-care testing for other viral infections.