COVID-19 or the Flu? Preparing for the Overlap

The upcoming flu season has many healthcare professionals especially worried this year.

COVID-19 alone has stretched the healthcare system to its breaking point in many places, and it remains to be seen whether we will face another surge of infections during the peak of the flu season.

To make matters worse, influenza and COVID-19 are both upper respiratory illnesses with similar presentations, and the possibility of co-infection further increases the chances of misdiagnosis.

In this article, we’ll help you prepare for the overlap by getting you up to date on the available tests and reviewing the clinical aspects of the diseases.

COVID-19 testing

Two types of tests are currently available to diagnose active infection with COVID-19:

1. Antigen tests: Antigen tests are CLIA-waived, point-of-care tests that provide results in about 15 minutes. Like the influenza antigen test, they provide high specificity but low sensitivity. The sensitivity of the approved tests is 84% and 97% when compared to molecular testing. However, these tests are most effective early in the course of illness, when viral load is highest, and antigen levels in patients who have been symptomatic for more than five days may be lower than the detection threshold of the test.

Because of this, the CDC recommends using clinical judgement to determine whether or not to follow up with a molecular test when the antigen test is negative.

Considerations include:

• The length of illness: Remember, after 5 days of symptoms, low antigen levels might lead to a false negative.
• Patient history: Recent contact with someone who has COVID-19 or frontline workers at high risk are good examples of cases when a molecular test might be warranted.
• Symptoms: Despite the negative antigen test, the patient has symptoms consistent with COVID-19.

2. Molecular tests: Molecular tests are nucleic acid amplification tests performed in a laboratory and are both highly sensitive and highly specific. However, molecular tests often take too long to make a meaningful impact in containing the spread of COVID-19. There could be several factors at play here, such as surges in testing combined with limited laboratory capacity, shortages of supplies and qualified laboratory personnel, and lack of an infrastructure for collaboration and communication among laboratories.

The CDC states that results can take up to a week, and one survey of 19 058 respondents conducted in July 2020 found that for 10% of individuals surveyed, test results took 10 days or longer.

Influenza testing

There are currently 2 categories of rapid tests available for influenza testing:

1. Rapid molecular assays: Rapid molecular assays use polymerase chain reaction (PCR) or other nucleic acid amplification techniques and provide >95% specificity and sensitivity rates. Many are CLIA-waived tests, meaning they can be performed in an office or clinic without having to send them to a laboratory for results. They produce results in 15-30 minutes. Rapid molecular assays are the best tests for influenza to use in clinical practice because of their accuracy and their ability to produce in-office results.
2. Rapid influenza diagnostic tests (RIDT): RIDTs are influenza antigen tests and, while they have high specificity (98.2-100%, depending on the virus type), they have low sensitivity (0-33.3%, depending on the virus type) compared to rapid molecular assays. For this reason, they are not a preferred testing method and their clinical utility has been called into question. RIDTs produce results in 10-15 minutes and are also available as CLIA-waived tests.

A variety of laboratory tests are available as well, including those that use immunofluorescence assay and cell culturing techniques. While these tests can be highly sensitive and specific, unfortunately it can take up to 10 days to produce results so they are not useful in clinical practice. They do allow for extensive characterization of the virus, so for this reason are helpful tools for public health surveillance and research.

Distinguishing between COVID-19 and influenza clinically

Unfortunately, influenza and COVID-19 have similar presentations and differentiating between the two can be challenging.

According to the CDC, both COVID-19 and influenza can cause:

• Fever
• Cough
• Shortness of breath
• Fatigue
• Sore throat
• Runny or stuffy nose
• Muscle aches
• Headache
• In some cases, vomiting and diarrhea

The primary differentiating symptom may be a change in, or loss of, sense of taste and/or smell, which is indicative of COVID-19, although not all persons with COVID-19 will experience these.

Symptom onset for COVID-19 ranges from 2-14 days (average around 5 days) after exposure, while onset for influenza ranges from 1-4 days after exposure. This similar onset makes it of limited value when trying to distinguish between the two.

An important and worrying possibility this flu season is co-infection with COVID-19 and influenza. There have been tests approved to test for both COVID-19 and influenza at the same time. The CDC has developed one they are distributing to public health laboratories, and there are several tests available to commercial labs as well; however, there are not currently any available point-of-care tests that will test for both with a single sample.

Finally, remember these tips from the CDC to prepare for the upcoming season:

• Get a flu vaccine: It’s more important than ever to protect you and your patients by getting your flu vaccine.
• Wear appropriate PPE when vaccinating: In addition to screening patients for COVID-19, this season the CDC recommends wearing facemasks and eye protection (depending on the level of community transmission).

References:

1. Centers for Disease Control and Prevention. Coronavirus Disease 2019. CDC website. https://www.cdc.gov/coronavirus/2019-ncov/. Accessed September 8, 2020.

2. Centers for Disease Control and Prevention. Flu – Information for Healthcare Professionals 2020. CDC website. https://www.cdc.gov/flu/professionals/. Accessed September 8, 2020.

3. Centers for Disease Control and Prevention. Influenza (Flu). CDC website. https://www.cdc.gov/flu/symptoms/. Accessed September 8, 2020.

4. Benirschke RC, McElvania E, Thomson RB Jr, Kaul KL, Das S. Clinical impact of rapid point-of-care PCR influenza testing in an urgent care setting: a single-center study. J Clin Microbiol. 2019;57:e01281-18.

5. Trombetta VK, Chan YL, Bankowski MJ. Are rapid influenza antigen tests still clinically useful in today's molecular diagnostics world? Hawaii J Med Public Health. 2018;77:226-230.