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Syndromic Testing

Understanding the differences between COVID-19 and influenza-like illnesses

By Isheeta Shah, PharmD Candidate 2023
QIAGEN Medical Affairs – Infectious Diseases

Acute respiratory tract infections can affect the lungs, airways, sinuses or throat, and can be caused by one of many viral or bacterial pathogens. While respiratory infections can occur year-round, there tends to be a significant increase in these infections during the fall and winter months.

QIAstat-Dx, syndromic, respiratory, RSV, respiratory syncytial virus, antigen detection, virus isolation, PCR detection
In 2021, as public health measures are eased and society reopens, cases of ILI caused by non-COVID respiratory viruses – such as RSV – are dramatically rebounding.

The COVID-19 pandemic changed this epidemiological paradigm with influenza, respiratory syncytial virus (RSV) and other common cold pathogens essentially not seen last influenza-like illness (ILI) season. However, recent data suggests the lessening of social distancing and other public health measures is causing a quick re-emergence of many of these pathogens out of their typical seasonality.

Many of these pathogens cause similar symptoms, and it’s difficult to distinguish the culprit causing the infection based on clinical evaluation alone. With increasing cases of COVID-19 due to the Delta variant and upcoming ILI season, it’s important to know the differences between common respiratory infections and options to diagnose them.

What causes COVID-19?

COVID-19 is caused by a virus called SARS-CoV-2 and is spread when a person comes into contact with an infected person’s droplets or small particles that contain the virus. These droplets and particles can be transmitted through breathing or contact with the eyes, nose or mouth. People most likely to get infected are those that are within 6 feet of an infected person.

Viruses constantly change through the process of mutation and result in new variants of the virus to develop. Several vaccines across the globe have been approved that are able to protect against Delta and other known variants.

What causes the flu?

The flu is caused by the influenza virus and spreads easily during the winter months when people spend time together indoors. There are two common influenza viruses, Influenza A and B, which can change from year to year. Getting the influenza vaccine annually can protect you and those around you from getting the flu.

What is RSV?

RSV, also known as respiratory syncytial virus, is a common respiratory virus that is most often seen during the fall and winter months. Symptoms of RSV are typically mild for a healthy individual. However, it can cause serious illness in young children and those with weakened immune systems. RSV is the leading cause of bronchiolitis and pneumonia in infants and causes an estimated 58,000 hospitalizations in children under 5 years of age yearly.

Similarity in clinical characteristics of COVID-19 and ILIs
Distinguishing between COVID-19 and ILIs based on symptoms alone is challenging due to the similarity in clinical characteristics.

What are the symptoms of COVID-19, flu and RSV?

According to the CDC, COVID-19 and flu have overlapping and similar symptoms making it difficult to differentiate between the two. SARS-CoV-2 has an incubation period of 4-5 days, and it may take longer for people infected with SARS-CoV-2 to show symptoms. Loss of taste or smell seems to be a symptom that is unique to COVID-19; however, both viruses can cause fevers, chills, headaches, cough, fatigue, muscle aches, vomiting, diarrhea, runny nose, sore throat and shortness of breath. 

Of note, RSV can infect anyone but it is most dangerous in infants and elderly, where symptoms can be more severe, requiring hospitalization.

Corona Virus

How has the COVID-19 pandemic changed respiratory virus epidemiology?

The COVID-19 pandemic and the implementation of mask mandates, physical distancing and the stay-at-home order reduced the transmission of SARS-CoV-2 and other viral respiratory pathogens (1). In the United States, influenza activity was historically low through the summer of 2020 and remained low during October 2020–May 2021. The overall incidence of laboratory-confirmed influenza-related hospitalizations was 0.8 per 100,000 during the 2020–2021 season. This hospitalization rate was one-tenth of the previous lowest severity season in 2011–2012. Circulation of other respiratory viruses such as RSV, common human coronaviruses and parainfluenza viruses was almost non-existent from early 2020 and did not begin to re-emerge until spring 2021.

RSV activity has been increasing since April 2021, indicating an interseasonal spike in cases, prompting the CDC to publish a health advisory urging clinicians to test broadly for RSV among other respiratory pathogens in patients presenting with acute respiratory illness and negative for COVID-19.

In late March 2020, Rhinovirus/Enterovirus (RV/EV) cases were at 14.9% and continued to decrease to 3.2% by early May 2020. Most state-wide mask mandates were lifted in May 2020, and cases of RV/EV steadily increased to near pre-pandemic seasonal levels. The effect of COVID-19 has severely impacted the incidence of respiratory viruses; however, the magnitude and duration vary among each virus. As pandemic measures are adjusted, we may continue to see changes in the circulation of these viruses.

Recently, there have been increasing reports of children developing both RSV and COVID-19 simultaneously (2). It is common for children to contract two respiratory viruses at the same time. However co-infection with SARS-CoV-2 may worsen the course of the infection. In most cases, school-aged children will experience mild cold symptoms, but toddlers and babies will have a higher risk of developing respiratory distress syndrome from RSV. Pediatricians are recommending that children get tested for both RSV and SARS-CoV-2 viruses if they develop symptoms that align with either of the two infections (3).

How can you clinically distinguish between COVID-19, the flu and other respiratory illnesses?

The flu season is quickly approaching (4). Since the symptoms among viruses are very similar, the best way to determine what is causing the illness is to get tested. Several tests, including nucleic acid amplification tests and antigen tests, can detect acute infections. Additionally, there are multiplex PCR tests available that can give you multiple results with just one swab. These tests allow clinicians to efficiently differentiate between several viruses and reduce the time it takes to obtain results.

Some available options include a SARS-CoV-2/FluA/B/RSV or a “4-plex” combined test, which can determine if a person is infected with one of the four viruses on the panel. Multiplex PCR and syndromic respiratory tests are other options that allow for a variety of bacterial and viral pathogens to be identified and discriminated using just one test. Syndromic respiratory tests have fast turn-around times, providing results in about an hour. Additionally, they have the potential benefit of identifying co-infections or persons infected with more than one virus at the same time.

In comparison, antigen or rapid tests use fragments of proteins found within a certain virus to detect the presence of infection (5). Although these tests are rapid, they are only able to test for one target at a time. This would result in a time-consuming process of performing several tests individually to determine if any co-infections are present.

What does the CDC recommend is the best test for patients?

The US CDC announced in July 2021 that it would withdraw its request for emergency use authorization from the FDA for the CDC 2019-Novel Coronavirus (2019-nCoV) Real-Time RT-PCR Diagnostic Panel as of December 31, 2021. In its place, the CDC encourages laboratories to consider adoption of an FDA-authorized multiplexed method that can facilitate detection and differentiation of SARS-CoV-2 and influenza viruses (6), (7). A multiplex assay can facilitate continued testing for both influenza and SARS-CoV-2 and can increase efficiency and save both time and resources as we head into influenza season.

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  1. Changes in influenza and other respiratory virus activity during the COVID-19 pandemic – United States, 2020–2021 Centers for Disease Control and Prevention,
  2. Ries J (2021) Kids can get COVID-19 and RSV at the same time. Healthline, (accessed November 1, 2021)
  3. Cooper C (2021) We will soon be entering flu season: What it means in today’s COVID-19 world. Modern Healthcare, (accessed November 1, 2021)
  4. Flu season. Centers for Disease Control and Prevention,
  5. Groth L (2020) What is a coronavirus antigen test – and how is it different than antibody testing?, (accessed November 1, 2021) 
  6. Fraser T and Joffe-Block J (2021) CDC encourages use of new tests that detect both COVID-19 and the flu. AP News, Associated Press, (accessed November 1, 2021)
  7. 07/21/2021: Lab Alert: Changes to CDC RT-PCR for SARS-CoV-2 Testing. Centers for Disease Control and Prevention