COVID-19 and the Flu

Aug. 1, 2020

The COVID-19 pandemic has created monumental imbalance to our accepted way of life, removed the illusion of host dominance and thrown a glaring spotlight on some of the tiniest members of society —viruses. As time dutifully marches on, many are all-too-cognizant of the risks associated with a circulating, pandemic respiratory virus, for which there currently remains no adequate treatment or cure, clashing with a flu season that is imminent and unavoidable. In order to predict how these 2 heavy-hitting viruses might interact with one another, let’s take a look at what we know about each virus and the diseases they inflict.

Virology

Comparison of influenza virus and SARS-CoV-2 virus properties.
Comparison of influenza virus and SARS-CoV-2 virus properties.
Source: American Society for Microbiology

Genome

Coronaviruses and influenza viruses are both enveloped, single-stranded RNA viruses, and both are encapsidated by nucleoprotein. However, the genomes of these 2 viruses differ in polarity and segmentation. Influenza virus is comprised of 8 single-stranded negative-sense, viral RNA segments. SARS-CoV-2 has single-stranded, non-segmented, positive-sense, viral RNA. 

Surface Proteins

Both viruses possess distinguishing surface proteins that serve as important virulence factors for infection. SARS-CoV-2 is covered in spike (S) proteins that facilitate invasion of host cells. S proteins bind to the host cell receptor, angiotensin-converting enzyme 2 (ACE2), which regulates blood pressure and fluid-salt balances and is expressed by multiple organ systems throughout the body, including the lungs, heart, kidneys, liver, intestines, brain and adipose tissues. Upon binding, SARS-CoV-2 injects its RNA into the infected cell and uses host cell machinery to replicate its genome. Newly synthesized virus particles are then released to infect additional host cells.
 
Influenza viruses rely on the collaborative functions of 2 viral surface proteins, haemagglutinin (HA) and neuraminidase (NA) to enter and exit host cells. The host cell receptor for influenza viruses is sialic acid, a sugar chain that is fairly ubiquitous and attached to surface lipids and proteins of most host cells, as well as soluble proteins. HA preferentially binds to sialic acid on the surface of respiratory epithelial cells, and mediates entry of the virus to host cells. Once inside, influenza virus also releases its RNA to be copied and synthesized into new virus particles. However, as long as HA remains bound to sialic acid on cell surfaces, newly synthesized virus particles are unable to exit the infected cells. NA cleaves sialic acid from the cell surface, which releases HA and allows progeny viruses to exit infected cells and continue spreading. 
 
Viral Protein Function Influenza SAR-CoV-2
Entry into host cells HA S
Exit from host cells NA Not applicable

Strains and Subtypes

Another important difference between SARS-CoV-2 and influenza is that, while there is only 1 strain of SARS-CoV-2, there are 4 different strains (A, B, C and D), and many different subtypes, of influenza virus. The 2 most important strains, when it comes to human disease, are influenza A and influenza B, which both cause annual seasonal flu outbreaks. 
 
Influenza A virus is further divided into subtypes based on its HA and NA surface proteins. There are 18 possible HA subtypes and 11 NA subtypes, which means 198 combinations are possible. However, only 131 subtypes have been detected in nature, to date.

Pandemic Probability

SARS-CoV-2 is a novel virus, which means that we had no available treatments or immunity to the pathogen when it emerged in late 2019. Because of this, the virus was able to spread, unrestrained from host to host, and it didn’t take long for the SARS-CoV-2 outbreak to become a pandemic. 

Even though the flu is not a new pathogen, influenza virus is constantly evolving and experiencing varying levels of antigenic drift (and shift) that can make it less recognizable to our immune systems. This has made the development of a universally effective flu vaccine particularly challenging and explains the constant underlying threat that new zoonotic influenza strains might emerge and become pandemic. All cases of pandemic flu in the U.S. have been caused by zoonotic subtypes of influenza A, including the Flu of 1918 (H1N1), the 2005 Avian flu (H5N1) and the 2009 Swine flu (H1N1).

Coinfection Dynamics

We know that coinfection with multiple respiratory viruses is possible. More specifically, coinfection has been reported for SARS-CoV-2 and respiratory syncytial virus (RSV), rhinovirus, other Coronaviridae and the flu. A study recently published in the Journal of Medical Virology showed that coinfection of SARS-CoV-2 and influenza virus was common during the initial COVID-19 outbreak in Wuhan, China, and patients who experienced coinfection had a higher risk of poor health outcomes.

However, the reported incidence of seasonal influenza has been uncharacteristically low in the southern hemisphere so far this year. In July 2019 (peak influenza season in the southern hemisphere), most regions were reporting greater than 10% test positivity for seasonal influenza, with the most heavily hit areas reporting greater than 30% test positivity. But as of July 20, 2020, no region has reported more than 10% test positivity, and several regions, including Southeast Asia, and parts of South America and Africa have reported 0 cases of the flu.

The reason for this is unclear. It may be that the case load simply appears lower because of insufficient testing and reporting, or that the social distancing meausres put in place to help stop the transmission of SARS-CoV-2 have reduced the transmission of influenza virus as well. Whether either virus causes viral interference (competitively suppresses replication of the other virus) or modulates disease severity is of great interest. Because SARS-CoV-2 and influenza virus both infect cells of the respiratory tract, they might have to compete for resources (including cells to infect) during coinfection. As previously noted, the host cell receptors are unique for each of these viruses. Sialic acid is more prevalent than ACE2, but the binding affinity of S protein to ACE2 is remarkably strong. It is possible, but remains uncertain, whether either of these factors contributes a competitive advantage.
 
The host immune response presents another variable worth considering. Does a host’s immune response to one virus make it more difficult for the other to cause infection? Or is an already immunocompromised host left more vulnerable to secondary infection? Only time and experience will tell. But taking a closer look at disease characteristics can help inform diagnosis and treatment plans as we move forward.

Comparison of COVID-19 and the flu disease dynamics. Updated August 18, 2020.
Comparison of COVID-19 and the flu disease dynamics. Updated August 18, 2020.
Source: American Society for Microbiology

Transmission

The flu and COVID-19 are both primarily spread via small, virus-laced particles called respiratory droplets that are released when an infected person coughs, sneezes, talks or simply exhales. Someone who is nearby may inhale these droplets or become infected through physical contact, like handshaking or hugging, followed by touching their own nose or mouth.
 
Importantly, individuals do not need to exhibit symptoms to be contagious. Both COVID-19 and the flu can be transmitted by presymptomatic, asymptomatic and mildly symptomatic individuals. 
 
Influenza virus can remain infectious on surfaces outside of the body for up to 48 hours, which means that it’s possible to get sick by touching an object or surface that has recently been coughed on, sneezed on or touched by someone who has the flu. There is evidence suggesting that SARS-CoV-2 RNA may remain present on objects and surfaces for extended periods of time, but how long the virus remains infectious outside of the body has yet to be definitively determined.
 
According to the Centers for Disease Control and Prevention (CDC), COVID-19 is more contagious in vulnerable populations and age groups and has shown more superspreading activity than the flu (defined as an instance in which an individual has at least 8 transmissions of the disease to other people). 
 
Flu season occurs in the fall and winter. In the U.S., that means October-March, and in the southern hemisphere, June-September. Although the reason for this seasonality is not entirely understood, influenza virus has been shown to survive longer at low temperatures and low humidity. Other suggested explanations include weakened host immunity due to decreased sunlight and vitamin D and increased exposure to the virus due to indoor cohabitation in the winter. We’ve been asking for months whether SARS-CoV-2 would exhibit flu-like seasonality and temperature sensitivity. But the persistence of COVID-19 cases throughout the summer has reminded us that these are, indeed, 2 separate viruses. 

Fortunately, both SARS-CoV-2 and influenza virus are sensitive to alcohol-based sanitizers and soap, and good hand hygiene is an effective way to reduce transmission.

Incubation

The incubation period for the flu is typically 1-4 days after infection, but the incubation period for COVID-19 is considerably more variable. Most people develop symptoms within 5 days of exposure, however incubation periods of as little as 2 days and up to 14 days or more have been reported.

Symptoms 

Respiratory viruses primarily infect cells of the lungs and respiratory tract. As a result, symptoms and modes of transmission are tightly linked to respiration processes. Both SARS-CoV-2 and influenza cause fever, cough, shortness of breath, fatigue, sore throat, runny nose, body aches, vomiting and diarrhea. SARS-CoV-2 also causes loss of taste or smell, and additional, less common, COVID-19 symptoms and complications are continuing to be observed, reported and evaluated.

In serious cases, both the flu and COVID-19 cause pneumonia, respiratory failure, acute respiratory distress syndrome, sepsis, heart attack or stroke, multiple organ failure, severe inflammation and even death. 

While most respiratory viruses, including RSV, adenovirus and parainfluenzavirus, exhibit some symptom overlap, that does not mean that the disease progression, severity or pathogenesis of each virus is the same. Symptoms of the flu typically resolve within 5-7 days of onset, but it takes longer to recover from COVID-19 (about 2 weeks for mild cases and up to 6 weeks or more for severe cases). 

Diagnosis

Because COVID-19 and the flu present very similarly, they are nearly impossible to differentiate based on symptoms alone. Accurate diagnosis requires laboratory testing to identify genetic or molecular components of the infecting virus. 
 
There are a number of Food and Drug Administration (FDA)-approved diagnostic tests available for the flu, including viral culture, serology, rapid antigen testing, molecular tests and immunofluorescence assays. And the FDA has issued Emergency Use Authorizations (EUAs) for molecular tests, serology assays and rapid antigen testing to diagnose COVID-19 (note that EUAs do not confer FDA approval). 
 
Molecular assays diagnose acute infections by testing for viral RNA in the respiratory specimens of suspected individuals. This type of test continues to be the most accurate way to diagnosis COVID-19 and the flu. Molecular assays rely on a laboratory technique called reverse transcription polymerase chain reaction (RT-PCR), in which viral RNA is extracted from patient specimens, converted to DNA and amplified with primers that are specific to the virus of interest (in this case, either influenza virus or SARS-CoV-2). Because there are so many subtypes of influenza virus, viral culture, along with molecular testing, may be necessary for accurate influenza diagnostics.  
 
Rapid antigen tests detect virus-specific proteins, called antigens, from patient specimens (most notably nasopharyngeal or nasal swabs). Rapid influenza diagnostic tests (RIDTs) are immunoassays that detect influenza A and B viral nucleoprotein antigen and produce results in less than 15 minutes. On May 9, 2020, the  FDA issued the first EUA for a COVID-19 rapid antigen test. Sofia 2 SARS Antigen FIA detects SARS-CoV-2-specific nucleocapsid protein (N) antigens and also produces results within 15 minutes. These tests are efficient, cost effective and highly specific. However, they do not distinguish between influenza virus subtypes and they have low-moderate sensitivity (50-70% for RIDTs), which means the chances of false negatives are higher. For both viruses, molecular tests are the more accurate method of diagnosis. 
 
Serology tests primarily test for immune responses to infection. These tests screen for virus-specific antibodies in the blood of patients who are suspected to have had previous exposure to COVID-19 or the flu. In most cases, serology testing should not be used to diagnose acute infections, but serological data can be used for contact tracing, epidemiologic studies and public health investigations.

Treatment & Prevention

Remdesivir, an antiviral drug that targets RNA-dependent RNA polymerase, the enzyme responsible for replicating the SARS-CoV-2 genome, has received EUA from the FDA for the treatment of COVID-19. Convalescent plasma therapy has also shown great promise in reducing COVID-19 mortality rates and is considered a safe treatment at any stage of illness. Many other candidate drugs and vaccines are being moved through clinical trials. However, there is currently no FDA-approved treatment for COVID-19, and supportive care continues to be critical to the management of severe COVID-19 infection.
 
A number of antiviral medications may be prescribed to treat influenza, including NA inhibitors such as oseltamivir (Tamiflu), zanamivir (Relenza) or peramivir (Rapivab), and a polymerase acidic endonuclease inhibitor, baloxavir (Xofluza). All of these medications inhibit, but do not completely eliminate, influenza virus. An annual seasonal flu vaccine is the best way to protect against the flu. 

As we move toward fall, the best things we can do to prepare for the coinciding flu season and global COVID-19 pandemic are get vaccinated against the flu and practice good hand hygiene and social distancing measures. Find out where the flu vaccine is available near you.
 

Author: Ashley Hagen, M.S.

Ashley Hagen, M.S.
Ashley Hagen is a science communications specialist at ASM.