The Short Version: SARS-CoV-2/COVID-19 and influenza are very different viruses and produce a very different immune response. Even though influenza still causes severe disease and accounts for significant economic damage every season, COVID-19 has caused much greater devastation in a shorter amount of time. COVID-19 has a significantly higher case-fatality ratio, spreads much more rapidly, has a longer incubation period, and causes persistent symptoms after infection to a much greater extent than influenza. Influenza also has an effective vaccine that prevents the worst outcomes of disease. COVID-19 also seems to spare the young with respect to mortality, though MIS-C remains a problem. Most comparisons of influenza and COVID-19 are probably inappropriate, so please take care if you must use them.

Parts of this post are somewhat technical despite care being taken to maximize comprehensibility of the encoded subject matter. Reader discretion is advised. Also this post is long, and you probably won’t need to read all of it to get the information you’re looking for, so it’s divided into sections for your convenience.

If you’re in a hurry or just don’t want to read this entire thing, please do read the “Epidemiology” section at the end. That’s really the important part.

Influenza, the virus responsible for the pestilence that I thought would be my end. Influenza A and B viruses are more similar to each other than to influenza C (and D; not shown as they are relatively newly discovered) viruses. Key things to note h… — Influenza, the virus responsible for the pestilence that I thought would be my end. Influenza A and B viruses are more similar to each other than to influenza C (and D; not shown as they are relatively newly discovered) viruses. Key things to note here are that C viruses have 7 segments of RNA while A and B both have 8. Influenza A viruses are generally regarded as zoonoses (they come from animals), while B and C viruses are generally considered to be restricted to humans (though there have been documented cases of influenza B virus transmission between humans and harbor seals). C viruses also integrate the function of the hemagluttinin (HA) and neuraminidase (NA) into a single protein called Hemagluttinin-esterase fusion protein (HEF). A and B viruses also bear additional accessory proteins: PA-x (which seems to have a role in encouraging viral growth and suppressing innate immune responses) and PB1-F2 (which induces cell death).
From Cherry J, Demmler-Harrison GJ, Kaplan SL, Steinbach WJ, Hotez PJ. Feigin and cherry’s textbook of pediatric infectious diseases: 2-Volume set. 8th ed. Philadelphia, PA: Elsevier - Health Sciences Division; 2018. Figure 178.3

Many people are attempting to minimize COVID-19 because if COVID-19 isn’t a big deal, we can return to normal, and everyone misses their life pre-pandemic, or as I’ve come to call it, BGC (Before the Great Coronavirus; I need to amuse myself as I shelter at home- so do you). Not that I could ever be made to agree to such a thing, but the absolute last thing I would do if my goal were to minimize COVID-19 would be to suggest that it is just like the flu. Then again, this tactic is so popular and effective because people don’t really get what the flu is. In this case I do have a relevant anecdote. I don’t ordinarily go with anecdotes when I’m discussing scientific matters because they are riddled with problems (I can’t tell you how many times I have heard that HCQ works for COVID-19 on the basis that someone took it and got better, as though that means anything), but this particular anecdote is prototypically consistent with the data we have and thus I will make an exception.

From Cherry J, Demmler-Harrison GJ, Kaplan SL, Steinbach WJ, Hotez PJ. Feigin and cherry’s textbook of pediatric infectious diseases: 2-Volume set. 8th ed. Philadelphia, PA: Elsevier - Health Sciences Division; 2018. Table 178-2; You can cross-corr… — From Cherry J, Demmler-Harrison GJ, Kaplan SL, Steinbach WJ, Hotez PJ. Feigin and cherry’s textbook of pediatric infectious diseases: 2-Volume set. 8th ed. Philadelphia, PA: Elsevier - Health Sciences Division; 2018. Table 178-2;
You can cross-correlate my experience with what’s mentioned here for manifestations in children, which will tell you that the case I had was fairly typical. I had all the common symptoms, didn’t get the rare ones, and had a few uncommon ones.

Edward vs. The Pestilence

When I was about 11 (I don’t recall the exact age, but over a decade ago but not by much), I contracted influenza. What followed was a week where I felt sicker than I had ever been in my entire life. Patients who have influenza will often tell you they feel like they have been “hit by a train.” That is a reasonable summary of how I felt. I remember a profound exhaustion where I had to be completely bedridden for about a week. Between having to get up periodically to go to the bathroom and the intense focus I had to put into breathing which had become a profoundly laborious act, I could not muster energy for anything else. I had a persistently elevated fever of about 105 F (40.5 C; I remember that because it was so high it was frankly scary) which seemed to be unperturbed by the copious quantities of antipyretics I took. My joints felt like they were made of glass and I had myalgias reverberating all over my body. My sinuses were so filled with mucus and congested that I was forced to breathe with my mouth, and my throat had that classic, burning ache. I had pleuritic chest pain with every breath, which produced a sibilant wheeze. I was beset with paroxysmal coughing spells that all but turned me gray, as my inflamed bronchi screamed. I also might have had some GI distress but I honestly don’t remember because the totality of my focus was dedicated to ensuring my accessory muscles were optimized for gas exchange. I believed, wholly and credulously, that I was going to die. Imagine one week where it’s all you can do to remember to breathe. Does this sound like the cold or gastroenteritis you associate with influenza? This wasn’t an especially virulent strain. The case I had wasn’t particularly complicated (I was fortunate to recover without residual sequelae, to the best of my knowledge). This was a typical, run-of-the-mill, seasonal influenza. Some people do have milder cases. But some people have far worse. I didn’t die after all, which is a significant bonus. One more relevant point: I wasn’t vaccinated (but have received every flu vaccine every season since I was able to get them on my own), and it’s probable that being vaccinated would have made for a much milder course or no illness at all. Doesn’t quite jive with the whole “just the flu” narrative, now, does it? Influenza isn’t a mild disease, and even BGC, it accounted for a hundreds of thousands of hospitalizations and tens of thousands of deaths in the US every year.

You should also be aware that a non-comprehensive list of influenza complications includes (in no particular order):

myocardial infarction (commonly known as a heart attack- yes, really)
myocarditis (inflammation of the muscular layer of the heart; this varies a lot in its severity but can require a heart transplant). It is not entirely clear how common this is because a formal diagnosis of myocarditis requires a biopsy of the heart muscle which is extremely invasive and therefore almost never done.
cytokine storms (essentially an uncontrolled cascade of inflammation that causes profound damage to the tissues)
acute necrotizing encephalopathy (a condition in which brain cells start dying en masse; this is rare and it is not thought to occur from direct infection of neurons but rather from destruction of the vasculature supporting them)
Reye’s syndrome (Aspirin should NEVER be given to children unless they have a diagnosis of Kawasaki’s Disease made by a qualified medical provider)
Guillain-Barre syndrome (incidentally, though people often claim this is caused by flu vaccines, other than the 1976 vaccine, in the incidence of GBS in association with influenza vaccination is not distinguishable from background, and it is 17 times greater from influenza infection- your flu vaccines can help prevent GBS)
A toxic shock-like syndrome

It’s really frustrating for me when people don’t take influenza seriously not because I personally had a severe case, but because often the ones who do this are those who are assured in that they will have a mild case (this again goes back to people not understanding what influenza is). No one should be eager at the prospect of getting any disease, especially one that has the potential to be fatal, because no one knows in advance what their course will look like. Children generally fare very well with COVID-19. Except for the ones who don’t, like those who get MIS-C, who are far sicker than I was with influenza. There are no guarantees. There are also consequences beyond the individual with infectious diseases. I’m glad you’re assured in the quality of your immune system, really, and I genuinely do hope that if you are to get it, your case is mild and resolves quickly and without sequelae. But, it’s not fair to the people around you to ignore precautions against infection and then spread it during its incubation period (viral shedding of influenza peaks about 1 day before symptom onset; for SARS-CoV-2 the shedding occurs almost exclusively before symptom onset, but of course, there’s a lot of variation).

I have, thankfully, never had COVID-19 (as far as I am aware- I did have an antibody test months ago which was negative), so I can’t offer a direct comparison, but I’m going to guess I wouldn’t find it to be a picnic.

Krammer, F., Smith, G.J.D., Fouchier, R.A.M. et al. Influenza. Nat Rev Dis Primers 4, 3 (2018). https://doi.org/10.1038/s41572-018-0002-y Figure 3, demonstrating the emergence of novel influenza viruses into human population… — Krammer, F., Smith, G.J.D., Fouchier, R.A.M. *et al.* Influenza. *Nat Rev Dis Primers* 4, 3 (2018). https://doi.org/10.1038/s41572-018-0002-y Figure 3, demonstrating the emergence of novel **influenza** viruses into human populations across species.

Virology

One important similarity between SARS-CoV-2 and influenza viruses is that they are both RNA viruses. They also have similar mechanisms of entry into their target host cell, using class I fusion proteins (i.e. there is only one protein requires for fusion of the viral membranes and no accessory proteins, which are hemagluttinin in the influenzas, and spike in the coronaviruses) and needing low pH (coronaviruses do seem to be able to enter at neutral pHs as well). Also SARS-CoV-2 has a furin cleavage site on its spike protein, which some influenza strains also have.

Other than that though, from a virology perspective, these two viruses have relatively little in common.

Streicker DG, Gilbert AT. Contextualizing bats as viral reservoirs. Science (New York, N.Y.). 2020;370(6513):172–173. Figure 1 demonstrating the emergence of novel coronaviruses.

For SARS-CoV-2, the major viral receptor is ACE2, with entry assisted from furin, cathepsin L, or TMPRSS2, which cleave the S2 domain to trigger the fusion activity of the spike protein, but other possible receptors include neuropilin-1, and several other candidates (for whom the evidence is less definitive). The basis of S protein binding and cellular entry is reviewed thoroughly here. The receptor for influenza viruses appears to be α2,6- or α2,3-linked sialic acids (which are carbohydrates). Bat influenza viruses however use MHC Class II instead, a protein found mainly on antigen-presenting cells. It is important to note, however, that a cell bearing the receptor for a virus (susceptible) is NOT necessarily one that can facilitate viral replication (permissive). Viruses can grow ONLY in permissive AND susceptible cells. There are some dramatic illustrations of this- for example, HIV has strict metabolic requirements of the T cells it infects and absent their fulfillment, viral replication is not supported. Similarly, we should not expect every cell bearing ACE2 to be one that can support replication of SARS-CoV-2.

Hartenian E, Nandakumar D, Lari A, Ly M, Tucker JM, Glaunsinger BA. The molecular virology of coronaviruses. The journal of biological chemistry. 2020;295(37):12910–12934 Figure 1, summarizing the replication cycle of coronaviruses like SARS-CoV-2.

Influenza viruses are members of the orthomyxoviridae family, and they are grouped into influenza A, B, C, and D genera. These are distinguished from one another primarily by the structure of their genome and the hosts they can infect. Influenza A tends to originate from water fowl, where it can then infect various farm animals, and eventually ends up in humans. Influenza A viruses have a broad host range, and staggering diversity. They are commonly referred to in terms of the hemagluttinin and neuraminidase alleles they express e.g. H1N1 (which is a swine influenza). There are 18 hemagglutinin subtypes and 11 neuraminidase subtypes which allow for a total of 198 different combinations of H and N for influenza A viruses. Influenza A viruses have such diversity that they are given specific names in the scheme: A (to indicate influenza A)/ place isolated/ strain number/ year isolated/ subtype, for example: A/Sydney/05/97/H3N2. Influenza B viruses are similar, but are generally considered to be restricted to humans. There are two lineages of influenza B viruses: Victoria and Yamagata, and they have been becoming increasingly important causes of disease since 2015, for reasons not entirely clear. Influenza D and C viruses are very similar, but distinguished from each other by the fact that in reassortment studies (where a C and D virus infect the same cell) no infectious progeny are produced. In general, influenza A viruses cause the most severe disease, followed by B, and then C.

Coronaviruses are members of the Coronaviridae family, which is grouped into the alphacoronaviruses, betacoronaviruses, and gammacoronaviruses genera. There are 4 common cold coronaviruses which circulate commonly throughout the human population and account for about 10-30% of colds. Two of these are alphacoronaviruses and two are betacoronaviruses. The 3 highly pathogenic coronaviruses- SARS-CoV, MERS-CoV, and SARS-CoV-2, are all betacoronaviruses. The genera are distinguished from each other primarily by the size of certain genes and their presence or absence (it’s not as dramatic as for influenza viruses; consult the ICTV link for more details).

The genome of an RNA virus can be positive sense (sometimes just called sense, often abbreviated +ssRNA, where ss = single-stranded), negative sense (sometimes called antisense, often abbreviated -ssRNA), or ambisense (abbreviated dsRNA, ds = double-stranded). Positive sense genomes are those in which the genome can be popped right into a ribosome and viral proteins can be made by reading it. Negative sense RNA genomes on the other hand have to have an RNA-dependent RNA polymerase which makes positive sense RNA from the negative sense template and then a ribosome produces viral proteins from the positive sense. Ambisense viruses have both strands in their genome. Now to the point: influenza viruses have negative-sense genomes. Coronaviruses like SARS-CoV-2 have positive sense genomes. That’s right. In basically the second-most coarse way you could classify viruses (just a step above whether or not the genome is RNA or DNA), SARS-CoV-2 and influenza already diverge. That is, however, the tip of the iceberg. In addition to the fact that the genomes of these two viruses have literally the opposite polarity, the structure of the genome itself is dramatically different.

Hutchinson EC. Influenza Virus. Trends in microbiology. 2018. http://dx.doi.org/10.1016/j.tim.2018.05.013. doi:10.1016/j.tim.2018.05.013 This figure shows the standard replication cycle of influenza viruses. If you’re not sure what you’re looking fo… — Hutchinson EC. Influenza Virus. Trends in microbiology. 2018. http://dx.doi.org/10.1016/j.tim.2018.05.013. doi:10.1016/j.tim.2018.05.013 This figure shows the standard replication cycle of influenza viruses. If you’re not sure what you’re looking for, the differences between it and the coronaviruses replication cycle are not obvious, so please refer to the text.
One thing worth noting: influenza viruses do have a filamentous form shown in this figure (the long one) which differs from the round depiction they are often represented as having. The filamentous form may be more important in the causation of the disease than the spherical one, though it is also more fragile and thus harder to isolate in culture. This figure also shows the virus in a bacilliform shape (slightly elongated rounded rectangle basically), which also occur in addition to the spherical.
Coronaviruses by contrast generally occur in just one spherical shape.

Viral genomes can be segmented or non-segmented. Coronaviruses have unsegmented genomes, while influenza viruses carry their genome in 8 segments (7 in the case of influenza C and D viruses). That also has profound implications on the rate at which they mutate and the significance of those mutations immunologically. In general, there are two kinds of mutations that we care about with influenza. Antigenic drift refers to the progressive accumulation of variants with each replication cycle that occurs at baseline in influenza viruses which can lead to the formation of new strains as they escape from the immune system. However, far more concerning is the potential for influenza A viruses to undergo antigenic shift, which is a form of reassortment. If two influenza A viruses infect the same cell, their genome segments can recombine to give an entirely new virus, which is how pandemic strains emerge. The thing about influenza viruses is that as a group, they have extreme variability in how lethal they are. There are highly pathogenic avian influenza viruses (HPAIs e.g. H7N9, H5N1) whose case-fatality ratio approaches 60% in humans. The good news is: these viruses cannot generally effectively infect humans. Our seasonal influenzas have a case-fatality ratio tends to be much lower at about 0.1% (though this of course depends on age, comorbidities, and a host of other factors). The reason for this is simple: viruses are subject to evolutionary pressures to be able to transmit more effectively. If influenza infects birds, it adapts to productively infect them. Birds have a different pattern of glycosylation of their proteins, which occurs in our lower respiratory tract, and HPAIs gravitate towards a lower respiratory tract infection (LRTI; think pneumonia) as opposed to upper respiratory tract infections (URTI) like seasonal influenzas. However, two influenza A viruses can recombine in an antigenic shift event (owing in large part to the segmented nature of their genomes), and the concern is that there will emerge a new pandemic strain of influenza that manages to achieve the absurd case-fatality ratio of HPAIs and the ease of transmission of seasonal influenzas. This is why some have criticized the response to the 2009 influenza pandemic, which produced a novel strain, but exhibited similar case-fatality ratios to seasonal influenzas, as being overdramatic, based on concerns that this pandemic influenza could combine HPAI’s lethalities with the transmissibilities of seasonal strains. It cannot be excluded that there will still come such a virus in the future, and before COVID-19, I would have wagered that influenza would have been the next pandemic (and there will be many more pandemics). Farming practices in particular make antigenic shift events pretty much inevitable. Pigs can be infected by influenza A viruses, including avian influenzas, and their biology is much more similar to humans than are the birds that spawn HPAIs. Pigs are said to act as mixing vessels therefore, as they can acquire multiple influenza viruses, which can undergo antigenic shift and then pass them to humans, precipitating a pandemic.

By contrast, mutations in SARS-CoV-2 and related coronaviruses tend not to be nearly so dramatic (regardless of what hysteria you may have heard about D614G), because of a special quality: proofreading. As genomes replicate, you can expect errors to occur at random- like how if you type a long document there will inevitably be a few typos. RNA viruses mutate very quickly because their replication machinery is error prone (making about 1 error per 1,000 to 10,000 nucleotides, which might not sound like a lot, but for comparison, the genome replication machinery in our cells makes one error every 10,000 to 100,000 or so nucleotides, and has extensive machinery to correct these errors which viruses lack). This allows them to have many genetic variants across a population that evolutionary forces can act upon to select the ones that transmit most effectively and is generally a good thing if you’re a virus. Unless your genome gets to be too big. Then you encounter something called error catastrophe, where you make so many typos that you cannot replicate effectively. The larger your genome gets, the more likely this is to happen, and it turns out that you start to see error catastrophe when the genome size hits about 30,000 bases, which happens to be the approximate size of the coronavirus genome. To deal with this, coronaviruses have evolved an exonuclease- essentially a backspace button- which helps to protect the integrity of their genome. If this exonuclease gene is removed, the rate of errors rises by a factor of about 20 based on studies of SARS-CoV. It’s worth noting that despite having 7 or 8 segments (depending on which influenza you look at), the genome of influenza viruses is about 2.5 times smaller than that for a coronavirus. The outcome of this is that mutations are more likely to be more significant. With respect to SARS-CoV-2, it is unlikely that there will emerge multiple strains such that protection by a vaccine or infection will be strain specific, which is excellent news. That said, it isn’t as though coronaviruses don’t mutate. As stated by Su et al:

Flint J, Racaniello VR, Rall GF, Skalka AM. Principles of Virology, Fourth Edition. ASM Press; 2015. Figure 6.27

The estimated mutation rates in CoV are moderate to high compared to other single-stranded RNA (ssRNA) viruses, and the average substitution rate for CoVs was 10^-4 [(one per 10,000)] substitutions per year per site.

In fact, coronaviruses do undergo (homologous) recombination with each other, which could be a problem for live-attenuated vaccine candidates, as there could be a reversion to virulence where the vaccine strain virus that is ordinarily not pathogenic evolves inside the vaccinee to regain its pathogenic qualities (which can happen very rarely with the oral polio vaccine; this risk can be avoided completely with the use of a non-pathogenic vector) or emergence of a novel coronavirus strain. Indeed, this seems to be the most probable origin of SARS-CoV-2. Recombination in coronaviruses seems to primarily be the result of template switching (you can see an animation here). This is a consequence of how coronaviruses make their RNA during transcription and during replication. Coronaviruses can perform discontinuous (and continuous) RNA synthesis wherein they make a segment of RNA and then pause, and when this happens, there is a chance for the template strand to be switched to another, so that as the RNA is being replicated, new sequences are introduced. So, in the context of multiple coronavirus infections in the same host, you can imagine multiple RNAs packed into the cell, and the RNA-dependent RNA polymerase picks up a different template strand (an acceptor, per the figure on the right) after pausing and rather than replicate the template faithfully, goes to another strand, resulting in a progeny virus that is different from either of its “parents.” This can happen very easily in bats. Bats are commonly regarded as a major reservoir of coronaviruses (though they probably aren’t the only ones- just a very well studied example), as well as many other viruses. Bats have evolved a unique immunology however that allows them to have many viral infections, often at the same time, without any apparent ill effects. Interferons (IFNs) are among the most important substances we produce to suppress viral infection, but we don’t have them “on” all the time (constitutively) because the IFN response is profoundly disruptive to normal cellular function. Bats, however, do. This imposes a selection pressure on the viruses in bats to evolve effective machinery to disrupt IFN signaling. In a host that doesn’t have constitutive IFN expression, like humans, that can be a problem. Note that bats can also be a source of influenza virus strains.

Baloxavir for Uncomplicated Influenza | NEJM. The mechanism of action of Baloxavir. — *Baloxavir for Uncomplicated Influenza | NEJM*. The mechanism of action of Baloxavir.

Another critical difference between the two viruses is their actual replication strategy. Almost all coronaviruses replicate entirely in the cytoplasm of the cell (exception: MERS-CoV has been shown to have proteins which do end up in the nucleus, and its thought that this is related to the in vitro efficacy of ivermectin). Influenza on the other hand requires entry into the nucleus. The virus has an uncoating step mediated by a protein called the M2 ion channel, which can be antagonized with M2 inhibitors (though resistance to these drugs is widespread). Once in the cell, ribonucleoproteins attached to its genome segments contain nuclear localization signals (NLS) that facilitate entry. Once in the nucleus, influenza virus RNA performs something called cap snatching, which is where the influenza proteins steal the 5’ cap from host mRNAs to prime the production of influenza RNAs (this is why influenza is required to gain access to the nucleus), and this can be inhibited via the drug baloxavir marboxil to shorten the duration of influenza (FDA approved for those over age 12). After this, the viral RNA protein products are produced, and RNA is packaged into virions which exit the cell via the exocytic pathway. Exit from the cell also depends on a cleavage of host sugars by the influenza neuraminidase enzyme, which can be antagonized through the action of neuraminidase inhibitors like oseltamivir.

Coronaviruses on the other hand really make for a show. After getting into the cytosol of the cell, they release their genomes, which, being +ssRNA, can be immediately translated into a ribosome. The genome itself contains 28 proteins spread out along 13 genes, and there’s a bit of trickery required to get the entire genome replicated and make functional viruses. For a protein to be made, there is a site on the mRNA where the ribosome enters, and then once it reaches a stop signal, the ribosome will disassemble. That’s a problem though because being on one segment, this would mean that transcription of a single gene would occur and then the ribosome would leave and be unable to make the other protein components of the virus. Some viruses have evolved a trick called internal ribosome entry sites (IRES) which allow ribosomes to enter in the middle of the RNA strand to make the other protein components after the stop codon. Coronaviruses on the other hand evolved so that the first gene encodes a polyprotein, which is cleaved into multiple other proteins. Among these protein is the RNA-dependent RNA polymerase of the virus which goes on to make subgenomic RNAs (sgRNA) containing the other genes (it starts at the beginning of the gene and copies everything downstream so that you get a bunch of strands which show part of the genome). For each of these, only the gene on the 5’ end is translated. As a result, cells infected by coronaviruses have to make huge quantities of these or they will be unable to form functional viruses. In addition, possibly to hide from the immune system, some of the proteins in the coronavirus genome create structures called double-membrane vesicles (DMVs), which house replication factories (replication and transcription complexes, RTCs) for the RNA, likely to help hide it from the innate immune system because viral RNA is very immunogenic. It is also in these that many of the coronavirus proteins are made. Eventually, a functional virion ends up being secreted out of the host, though betacoronaviruses (like SARS-CoV-2) have a very unusual pathway for getting out of the cell, which involves trafficking of nascent viral particles into lysosomes. Lysosomes are organelles in the cell used primarily for digestion. They are little bubbles of destruction filled with enzymes that can break down virtually any biological material you can think of. In fact, it’s not totally clear why lysosomes don’t digest themselves, but the current best guess is that there’s a thick wall of sugar (the glycocalyx) that keeps that from happening.

Side note: STRONGLY recommend TWiV for virology podcasts, and Immune for immunology and their excellent coronavirus content.

Iwasaki A, Pillai PS. Innate immunity to influenza virus infection. Nat Rev Immunol. 2014;14(5):315-328 Figure 2, summarizing innate sensing mechanisms of the host in response to influenza infection. — Iwasaki A, Pillai PS. Innate immunity to influenza virus infection. *Nat Rev Immunol*. 2014;14(5):315-328 Figure 2, summarizing innate sensing mechanisms of the host in response to influenza infection.

Iwasaki A, Pillai PS. Innate immunity to influenza virus infection. Nat Rev Immunol. 2014;14(5):315-328 Table 2, summarizing genetic factors which are important to the host response against influenza. — Iwasaki A, Pillai PS. Innate immunity to influenza virus infection. *Nat Rev Immunol*. 2014;14(5):315-328 Table 2, summarizing genetic factors which are important to the host response against influenza.

Krammer F. The human antibody response to influenza A virus infection and vaccination. Nat Rev Immunol. 2019;19(6):383-397. Figure 2, demonstrating models of original antigenic sin for influenza. — Krammer F. The human antibody response to influenza A virus infection and vaccination. *Nat Rev Immunol*. 2019;19(6):383-397. Figure 2, demonstrating models of original antigenic sin for influenza.

Rydyznski Moderbacher C, Ramirez SI, Dan JM, et al. Antigen-specific adaptive immunity to SARS-CoV-2 in acute COVID-19 and associations with age and disease severity. Cell. Published online 2020. doi:10.1016/j.cell.2020.09.038 Graphical Abstract. Th… — Rydyznski Moderbacher C, Ramirez SI, Dan JM, et al. Antigen-specific adaptive immunity to SARS-CoV-2 in acute COVID-19 and associations with age and disease severity. *Cell*. Published online 2020. doi:10.1016/j.cell.2020.09.038 Graphical Abstract. The immune response to SARS-CoV-2 requires a careful collaboration along cellular and humoral immunity, and patients who fare the best in COVID-19 are those who have productive responses along all of these. With age, impairment of each of these arms occurs to varying degrees, complicating recovery.

Immune Response to Infection

Early on in the pandemic, a study compared the cytokine profiles of influenza A virus (IAV), respiratory syncytial virus (RSV), human parainfluenza virus 3 (HPIV3), and SARS-CoV-2, MERS-CoV, and SARS-CoV (the first one)- some of the most important human respiratory viruses from a public health perspective- in a culture of a human lung cell line and then in ferrets (ferrets are a classic model organism for influenza). The differences were profound. SARS-CoV-2 does an exceptional job of suppressing early interferon (IFN) responses (which isn’t all that surprising since it has multiple nonstructural proteins that disrupt IFN signaling; for essentially any pathogenic virus, there has to be some disruption of IFN signaling for productive replication to occur), as does IAV (though there is primarily 1 protein dedicated to this in influenza, which is demonstrated in the study by the effect on IFN response when the gene is knocked out). The cytokine response to SARS-CoV-2 was similar in magnitude to influenza A, but not in quality, instead resembling HPIV3 and RSV more, and this observation was consistent across both the in vitro study and in ferret animal models. The cytokine response to IAV was also significantly greater than for SARS-CoV-2 in the upper respiratory tract, though not overall, suggesting superior control of infection. Importantly, the cytokines from SARS-CoV-2 infection were enriched in signals for death and leukocyte activation compared with those for IAV. Additionally, the antiviral response from IAV was overall much greater than SARS-CoV-2’s.

Reviews by Iwasaki and Pillai, Koutsakos et al, and Krammer present a comprehensive account of the immunology of influenza infection. Influenza viruses enter via the respiratory tract, where they immediately go on to infect the respiratory epithelial cells, followed by the resident macrophages and plasmacytoid dendritic cells (pDCs). These pDCs accumulate preferentially in the lung and secrete copious IFN, which influenza is insensitive to, spurring immunopathology. Some additional evidence even goes as far as suggesting that IFN responses help influenza to spread throughout the host (though it’s important to note that this study is a mouse model and has some important limitations e.g. many mouse strains are inbred and lack functional MX1 and MX2, which are key effectors of the antiviral IFN response). Influenza A viruses induce a very strong and protracted IFN response, but HPAIs appear insensitive to the effects of the IFNs. In addition, influenza infection induces formation of RIG-I-like inflammasomes and NLRP3 inflammasomes, which cause the release of the extremely potent pro-inflammatory cytokines IL-18 and IL-1β, but these do not exhibit significant antiviral effects. Some individuals exhibit a tolerant phenotype (disease tolerance) wherein influenza virus replicates within them but has minimal pathophysiologic effects, and tolerance appears to be an important protective mechanism in both acute and chronic infection generally, which seems to be promoted by, among many things, the NLRP3 inflammasome. As pDCs are recruited to the site of infection through the actions of cytokines (proteins that tell cells what to do e.g. to make more of a certain protein) and chemokines (cytokines that instruct the cells of the immune system where to go), they are infected productively by influenza viruses, suggesting a mechanism by which the recruitment of immune system cells can worsen disease. The major targets of the antibody response to influenza are the hemagglutinin and neuraminidase proteins. Though strains are immunologically distinct, there does appear to be some cross reactivity from prior infections, but it is not clear what effects this has on disease severity. Despite this, antibodies directed at the stalk of the hemagglutinin protein appear to be neutralizing and the epitopes therein appear well conserved across strains, which makes them an attractive vaccine target. Recovery from disease depends strongly on resident CD8 T cells that secrete IFN-γ and this correlates strongly with survival in the case of avian influenza infection (patients with diminished quantities of these cells almost universally died). In particularly severe influenza, a profound lymphopenia occurs (very low levels of B and T cells in the blood), which seems to be from the result of expression of FasL on pDCs (this protein induces suicide of cells bearing the Fas protein, like CD8 T cells). The diversity of influenza strains is thought to give rise to a phenomenon called original antigenic sin (OAS), or antigenic seniority, but the existence of this phenomenon is controversial because it is not always recapitulated experimentally or at the population level. The concept is that the first influenza infection generates memory cells, and then subsequent influenza infections preferentially recall memory cells to epitopes on the virus that are similar to previously encountered ones (known as imprinting; classified into group 1 (viruses with N1, N4, N5, and N8) or group 2 (N2, N3, N6, N7, and N9) depending on the clade of the influenza viruses involved), successively building up with each new influenza strain encountered. Viruses that are markedly different on the other hand might experience a blunted immune response, which can be problematic for host survival from season to season. One way this can occur is by antigen masking, wherein antibodies cannot effectively bind neutralizing epitopes because antibodies from prior infections outcompete them and block them. Importantly, (inactivated) flu vaccines seem to be exempt from OAS (but DNA influenza vaccines, which are not in use, do seem to be associated), and OAS effects are abolished if adjuvants are provided with the second flu antigens or through repeated exposure to the second flu antigen. OAS can be a benefit to the host however if a strain of influenza arises similar to one encountered in early life (back boosting). Though immunity from influenza vaccines tends to be short-lived, immunity from infection tends to be long-lived, but strain-specific. That should not be taken as an endorsement of immunity by way of infection. Influenza infection can be brutal and immunity to a disease by getting the disease is akin to getting pregnant as a form of birth control. The fact that immunity from influenza vaccines is short-lived is likely an important contributor to their avoidance of OAS. Additionally, in any given flu season, multiple influenza strains are circulating, and thus even if a person gets influenza, after they recover, they should receive a flu vaccine if they have not during that season already, as it covers multiple strains, potentially including other circulating strains to which patients are susceptible.

The immune response to COVID-19 is still a moving target, as many things remain unclear. Antigenic diversity of SARS-CoV-2 remains low and that is unlikely to change in the immediate future, which is excellent news. Questions about immunological memory still linger, as reports emerge of reinfections (which while likely rare, are also likely being undercounted because of insufficient testing). Precedent from common cold coronaviruses suggests that immunity is short-lived, with infections reoccurring every ~6 months, about 1 year in the classic challenge study, despite relative antigenic homogeneity. Furthermore, it seems that though many have hoped for cross-reactivity from these common cold coronaviruses, the effect appears to be minimal. Coronaviruses exhibit many of the same PAMPs as do influenza viruses, though apparently exhibit superiority in subversion of IFNs. There is a very strong chemokine response in severe COVID-19 which results in pulmonary immunopathology mediated primarily by myeloid cells, in particular neutrophils, which appears superficially similar in nature to that of avian influenza infections. Additionally, profound lymphopenia does occur in severely ill COVID-19 patients, which may reflect either a cytokine-mediated immunologic consequence of infection (one proposed hypothesis is that the ultrastructure of the lymph node is disrupted profoundly from the cytokine response, impairing effective B cell responses that could mitigate viral dissemination). This is likely more probable than direct infection of lymphocytes by coronaviruses, as many patients with severe disease do not have detectable virus on PCR, suggesting that the virus has been cleared and the resultant disease state is immunopathologic in nature, and evidence supporting direct infection of leukocytes by SARS-CoV-2 is lacking. There is substantial heterogeneity in the immune response to COVID-19, however, with significant numbers of individuals managing to be only mildly symptomatic or entirely asymptomatic (between 5 and 80%, with most estimates close to 40-60%). This is complicated by the long incubation period of the virus (elaborated upon in “Epidemiology” section). Prognostic markers for severe disease suggest that there is substantial inflammasome activation in the sickest patients. The disease is also known for hypercoagulability, and platelets are known to license inflammasome activation in other cells, as well as having complex reciprocal interdependence on neutrophils, whose extracellular traps (NETs) form scaffolds for coagulation, which seems to spur further NET release. Indeed, though most emphasized in coagulation, platelets have critical supportive functions in host defense. Current data further suggests that the suppression of IFN early in the course of infection may cause a rebound response in which they contribute to immunopathology, as administration of IFNs seems to disrupt lung barrier function (a critical feature of IFNs in physiologic states is the preservation of anatomical barrier integrity, as this helps to limit pathogen spread) in a mouse model. This may be explainable by timing however, as it is probable that early, robust IFN responses result in mild or asymptomatic disease. Further evidence for the importance of IFNs comes from the lethal COVID-19 that results from antibodies against type 1 IFNs. Another hypothesis on the severity of COVID-19 that meshes well with this is the notion of inoculum size as a determinant of disease severity (which still remains to be established). Patients who receive a very large dose of virus on initial inoculation may have worse outcomes- this necessarily means a delivery of larger quantities of IFN-suppressing viral nonstructural proteins (NSPs), which can promote uncontrolled replication of the virus followed by a rebound IFN response that becomes uncontrolled and spurs immunopathology. The relationship between viral load (note that this is not the same as inoculum size- viral load refers to the total burden of virus in a patient during a given moment in disease while inoculum size refers strictly to the amount of virus delivered at initial inoculation) and disease severity is unclear, as immunocompromised patients who have difficulty effectively clearing virus seem to fare better than would be expected (though this is likely more reflective of difficulty generating an immune response robust enough to produce pathology). On the other hand, some patients seem to have persistent triggering of the immune response spurred by their high viral load, exacerbating immunopathology. Clearance of the virus seems to depend on highly coordinated actions by the lymphoid cells of the immune system, and immunosenescent changes of aging make this very difficult, which is likely a contributing factor to the severity of disease and high mortality in the elderly. Recovery from disease seems to depend strongly on a robust T cell response, which is distributed broadly, but the repertoire of naive T cells contracts significantly after thymic involution during puberty. However, similar to influenza, neutralizing antibodies to fusion proteins (in this case, the spike protein vs HA for influenza) seem to be a good correlate of protection from disease. The hyperinflammation in SARS-CoV-2 seems to induce and be driven by extrafollicular B cell responses (which do not depend on T cells for help and are generally short-lived and induced early in infection until high-affinity antibodies can be called), and because of the lack of dependence on T cell help, may be spurring autoimmune disease and immunopathology. Despite concerns about the duration of protection from reinfection, it seems that patients are generally protected for at least 8 months, which is encouraging for a vaccine. Much remains to be understood about the pathophysiology of immunologic dysregulation in COVID-19.

Clinical Picture

It’s not hard to understand why a layperson could easily conflate influenza and COVID-19, as they generally aren’t thinking about virology or immune responses, but rather what actually happens to sick people. For influenza, patients typically experience a fever, malaise, headache, muscle aches, cough, runny nose, and sore throat, typically with an abrupt onset. Recovery is often slow, as though the acute illness itself lasts about a week, it can take 2-4 weeks for cough and malaise to resolve, and influenza can have multiple complications including: bronchitis, middle ear infection, meningitis, encephalitis, pneumothorax (a collapsed lung), cardiac tamponade (an inability of the heart to contract because of a buildup of fluid in the pericardium, a sac that surrounds the heart), Guillain-Barre syndrome, Reye’s syndrome, sepsis, transaminitis, heart attack, and many more. This can sound similar to what patients with COVID-19 experience. Milder COVID-19 patients will have fever, cough, sore throat, malaise, headache, muscle pain, nausea, vomiting, diarrhea, and loss of taste and smell, which is quite similar to influenza (other than the loss of taste and smell). As it worsens in severity, individuals develop shortness of breath and hypoxia. This can then progress into respiratory failure and sepsis.

The CDC reports that influenza, RSV, and COVID-19 are the most common viral causes of pneumonia). But COVID-19’s pneumonia is generally very different from influenza’s, and indeed, for a time radiologic imaging was being used as a gold standard for diagnosis of COVID-19 because of the excellent sensitivity. This proved to be untenable, however, as a diagnostic tool because of how much time it took to disinfect a CT scanner after a COVID-19 patient had been in the room. It’s common sense at this point that you should not take antibiotics for a viral infection- they are not going to be helpful, can cause damage to the commensal species of the microbiota, and will fuel drug resistance (the use of antibiotics for any duration IS a selection factor for resistance and thus antibiotic use must be sparing, and courses should be short whenever possible, and in general longer courses do not produce better outcomes). But influenza might explain why the practice persists. Influenza is excellent at causing bacterial pneumonia, so sometimes patients who have influenza may be given antibiotics to treat the pneumonia or to prevent superinfection. It is in fact so good at this that, in the 1918 flu pandemic, the cause was though to be the bacterium Haemophilius influenzae (also called H. flu, for which there is a very effective childhood vaccine for the type B strains, which are commonly called Hib) because it was found in the lungs of the deceased. The major partners for influenza in addition to H. flu for bacterial pneumonia tend to be group A streptococci (GAS), Staphylococcus aureus, and especially Streptoccus pneumoniae. The mechanisms behind this are complex, but in brief, influenza really alters the landscape of the respiratory tract in terms of the microscopic structure (exposing surfaces that would not be exposed ordinarily), and can cause significant damage to the immune system of the respiratory tract that permits entry of bacteria into the lung, producing pneumonia. COVID-19 pneumonias rarely show bacterial superinfection (which really weakens the rationale for using azithromycin, even if you consider something something immunomodulation something something IFN-γ secretagogue, the approximate argument given for using the drug, and next to the risk of promoting antibiotic resistance, patients who have COVID-19 should probably not be given antibiotics unless there is true evidence of bacterial infection). Though rare with seasonal flu, avian influenzas are known to cause ARDS (acute respiratory distress syndrome) which is similar to other forms of ARDS, including those associated with sepsis, pneumonia, or gastric acid aspiration. ARDS is can occur in critical COVID-19, but unlike other forms of ARDS, COVID-19 ARDS appears somewhat responsive to corticosteroid therapy, despite inconsistent results with prior trials on non-COVID-19 ARDS.

Couzin-Frankel J. The long haul. Science. 2020;369(6504):614-617. COVID-19 causes persistent symptoms in many of the patients who recover which can be psychologically devastating in addition to the resultant physical disability. — Couzin-Frankel J. The long haul. *Science*. 2020;369(6504):614-617. COVID-19 causes persistent symptoms in many of the patients who recover which can be psychologically devastating in addition to the resultant physical disability.

Additionally, though profound clotting abnormalities can occur in influenza, especially in the setting of sepsis, they are generally limited to the avian influenzas. On the other hand, hypercoagulation in COVID-19 is extremely common, and so patients will require anticoagulation frequently. This is explained in part by an endothelialitis- inflammation of the endothelial cells of the blood vessels. There is still controversy over whether this reflects a cytokine-mediated process or direct viral infection (if infection of endothelial cells were a common occurrence, one might expect to be able to isolate significant levels of virus from blood, but this does not appear to be the case). However, normally endothelial cells express numerous anticoagulant substances on their surface so that clotting can only be initiated in the setting of damage to the vasculature. Endothelialitis disrupts the integrity of these cells, allowing for coagulation to occur inappropriately. One hypothesis for the profound hypoxia (low levels of blood oxygen) that occurs in COVID-19 (which is yet another distinguishing property from influenza infection) is the formation of microvascular thromboses in the vascular beds of the lungs that impede the communication of oxygen through the body.

The loss of smell, hyposmia, in COVID-19, was particularly alarming because this can presage neurologic disease, and is especially well known in Parkinson’s disease. Initially, literature seemed to suggest that the condition occurred because of infection of sustentacular cells, supporting cells in the nasal cavity, rather than neurons. However, recent studies call that into question, and do suggest the possibility of a route for direct neuroinvasion of SARS-CoV-2 into the central nervous system. Mechanisms for this are not fully understood however (in particular, how the virus manages to pass the blood-brain barrier).

In general, in the hospital setting, COVID-19 patients are sicker than influenza patients.

Epidemiology

Solomon DA, Sherman AC, Kanjilal S. Influenza in the COVID-19 era. JAMA: the journal of the American Medical Association. 2020. http://dx.doi.org/10.1001/jama.2020.14661. doi:10.1001/jama.2020.14661 Table 1

If you read only one section in this very long post, I urge it to be this one because ultimately this part is what people MUST understand about the difference between these two pathogens.

Mortality risk of COVID-19 - statistics and research. Ourworldindata.org. https://ourworldindata.org/mortality-risk-covid; You will note that the rise in risk of death is essentially monotonic and increases with age in an exponential manner.

Seasonal influenza viruses cause approximately 3–5 million severe cases and 290,000–650,000 deaths each year worldwide. That is a tremendous burden of disease, and it’s enough to cause profound economic and public health disruption. It is not even close to what COVID-19 has done in less than a year. At the time of writing this, COVID-19 has managed to cause nearly 64 million cases, and about 1.5 million deaths- it has not been a full year. Even compared to the worst seasonal influenza, COVID-19 is responsible for nearly 53 times as many cases, and 2.5 times as many deaths. In the US alone, COVID-19 is responsible for more fatalities than the last 5 flu seasons combined, even though they are likely being undercounted. Even in the best case scenario, COVID-19 is 2.5 times as fatal as seasonal influenza. However, we often don’t have the best-case scenario, with some estimates of case-fatality ratio reaching 3%. These measures are complicated a great deal by the fact that COVID-19 and influenza have very different effects on different age groups. Mortality with COVID-19 varies directly and exponentially with the age of the patient, as shown below. However, as more younger people are getting sick, more younger people are getting severe COVID-19 as well. Influenza on the other hand tends to be most severe in the very young, as well as the elderly. Though MIS-C still occurs rarely in children, COVID-19 is generally not a severe diseases in children, for reasons that are not entirely clear. COVID-19 also has a significant sex bias, with males consistently having worse outcomes. This has been explained by the fact that female sex is associated a strong, rapid T cell response, which does not readily attenuate with age, but further research is needed.

Additionally, risk factors for severe COVID-19 are more broad than those for influenza. Influenza is particularly dangerous in the immunocompromised for example, yet these patients are faring better than would be expected in COVID-19. High blood pressure is also a critical risk factor for COVID-19, but not influenza, and as many as half of adults in the US have it.

Still, as I’ve been trying to explain in detail throughout this post, death is not the only bad outcome from this disease. A very high proportion of patients reports persistent symptoms after COVID-19, which can be present for at least months, which is much rarer with influenza. This can take many forms. Patients often report a persistent sensation of fatigue and exercise intolerance. There is also an associated brain fog, where it becomes difficult to think or focus, as well as migraines. Damage to the lungs seems to be slow to heal (if it does at all) and so patients can still have significant shortness of breath months after initial infection. Accounts of dysautonomia occur as well. Some patients also seem to develop fevers intermittently after COVID-19 occurs. Disquietingly, the reasons behind this are not understood but there are a few ideas: it is possible that the virus is being retained in immunologically privileged sites and periodically emerging to trigger immune responses that produce these symptoms. Alternatively, it may reflect a lingering immunological dysregulation following initial infection. Still, more data are needed.

The protective measures against COVID-19 (masking, enhanced hygiene practices, distancing) have substantially driven down incidence of influenza (which is fantastic!), but still in spite of this, in much of the world, especially the US, the burden from COVID-19 remains unacceptably high. Some states are stretched so thin that there are no staffed hospital beds available, and to deal with this, the bar for hospitalization is likely being raised such that patients who may have benefited from hospital stay will now be unable to get it. As nice as it would be, we absolutely do not have a casedemic. Though so much of COVID-19 is supportive care, the inability to access it will doubtlessly raise mortality rates. Needless to say, seasonal influenza does not do that. COVID-19 spreads much more easily than does influenza for several reasons. COVID-19 has a far longer incubation period than influenza. Influenza patients are infectious for 1-2 days before symptom onset. COVID-19 patients are on average infectious for 5 days before onset of symptoms, but this can vary from 2-14 days. This creates a much longer opportunity for the pathogen to spread. Furthermore, because the window is so wide, outbreaks seem to be driven primarily by superspreading events, wherein small numbers of people infect huge numbers. Unfortunately, no one can know in advance whether or not they are a superspreader, though it should be noted that superspreading seems less to be a function of an individual than the event in question e.g. gathering in large groups of people without mitigation strategies. What’s more is that COVID-19’s disease severity seems to peak 2-3 weeks after initial infection occurs, whereas for influenza it occurs within the first 3-7 days of illness (and influenza infection itself generally lasts about 1 week). Additionally, though it is rarer, SARS-CoV-2 can spread by way of aerosols, which is important because aerosols can linger in the air even after an infectious individual has left a room. Consequently, a suite of mitigation strategies is required for control of SARS-CoV-2 spread, including control of humidity, limiting gatherings, wearing masks, and ensuring well-ventilated spaces.

Additionally, COVID-19 has massively exploited structural racism in our society to spread. COVID-19 disproportionately affects people of color, and many explanations have been proposed to explain this, most of which are sociological in nature rather than biological. People of color are more likely to be essential workers and thus more likely to be exposed (an inoculum size effect may contribute to their heightened disease severity). They are also more likely to be un- or under-insured. People of color also bear a disproportionate burden of many of the risk factors for severe COVID-19, including diabetes, heart disease, obesity, renal disease, and liver disease. Curiously, mortality from influenza and pneumonia for the elderly are lower among African American and Latino individuals compared with people of white background.

If I can leave you with a single point: If you see someone comparing COVID-19 and influenza, especially seeking to minimize either of them, they are probably wrong.

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COVID-19 and influenza are very different