The Bitter Pill: COVID-19 is much worse than the flu.

Key messages

• Accurate counts of total deaths provide a clear cut measure of lethal impact of these two distinct virus diseases. COVID-19 has killed about 10-fold more people in the USA as were killed by the last bad flu epidemic that happened in 2017-2018. 
• COVID-19 pandemic death count in the USA is worse than any flu pandemic since 1919.
• COVID-19 is worse than modern influenza in 7 ways
• lumping all ages together, with COVID-19 there is at least a 10-fold higher chance of dying than if sick with flu, 
• everyone is at risk of infection (or reinfection) by SARS-CoV2 virus, 
• there is still inadequate existing vaccine coverage for COVID-19 to mitigate severe disease, 
• greater potential infectious spread throughout the community, 
• greater ability of the SARS-CoV2 virus (compared to flu) to spread through the bloodstream and damage vital organs and tissues, 
• greater risk of more severe disease, 
• and wide range of potential and realised damage to survivors of illness.
• The proportion of people with symptoms who require hospital admission is higher for SARS-CoV-2 infections than for the 2009 influenza pandemic (Petersen and colleagues 2020 Lancet Infectious Diseases)
• Risk of admission to the intensive care unit is five to six times higher in patients infected with SARS-CoV-2 than in those with the fairly mild 2009 influenza pandemic (Petersen and colleagues 2020 Lancet Infectious Diseases)
• SARS-CoV2 is new to humans, and most people have no protective immunity unless they are vaccinated. Most people are somewhat protected against flu by prior infection with older flu strains or by vaccination. The virus is evolving in real time to acquire greater transmission rates
• With both viruses, it's expensive and difficult to measure infection attack rates in the community, as many infected people don't know that they are infected, or don't seek medical treatment. 
• Careful studies of fatality rates show that 5- to 25-fold more adults die from COVID-19 than from flu, and that patient age is a key factor modulating this risk of death. Younger communities (eg. in Africa) display lower infection fatality risk from COVID-19 than do some aging industrialised countries (e.g. Italy). Good infection survey data in the USA show COVID-19 infection fatality ratio is 0.82 to 1.4 deaths per 100 infected persons.
• The Pumphandle Lecture 2021: Dr Anthony Fauci  explains in depth how COVID-19 is not like Flu

When it comes to health risks, it seems a lot of people think that Covid-19 is much like influenza.

Such an assumption of relative innocuousness  dovetails with the belief that Australian governments and news media are largely overreacting in their recent efforts to stamp out coronavirus outbreaks.

Maybe there some truth to this sentiment, which is discussed in another GMO Pundit post.

But such arguments about how to best manage the epidemic need to rest on hard-headed, evidence-based assessment of the human health dangers posed by SARS COV2 infections. 

Let's have a go at that here.

How do COVID-19 and flu compare?

First get so basic disease features out in front.

The Pundit is happy to heavily rely on Peter Doherty for this as he is a veterinary scientist by basic training and has chalked up a long and distinguished career in immunology and virology. On Twitter he says home truths on this pandemic with great clarity:

Deinhardt-Emmer and colleagues 2021 provide further details showing how COVID-19 affects multiple organs by systematic spread. A professional medical article provides further detail, and a summary diagram from it shows the scope of potential organ damage from spread of SARS-CoV2 throughout the body by the bloodstream:

To restate these points, severe COVID-19 disease may involve:

• Severe lung damage
• Heart damage or heart failure
• Injury to the kidneys
• Changes to the brain
• Blood progenitor malfunction
• Hormone organ malfunction--adrenals, pituitary gland
• Diarrhoea, liver damage

Dr Fauci says even more:

(The Pumphandle Lecture 2021: Dr Anthony Fauci )

Comparing Flu and COVID-19 outbreaks by numbers.

That said, it’s pretty useful to further compare influenza and SARS COV2 disease outbreaks to get further insight in how the diseases measure up. There's some tricky aspects to doing such a comparison though (see Hiroshi Nishiura 2010 whose triangle diagram illustrating this is reproduced below).

Context is important: we know much more about influenza, as this “old” disease has been in the human populations for at least a century or so, and we can learn much  from this historical experience. We have pre-existing immunity because of prior exposure, and we have widely deployed vaccines in the past to protect against the flu. Our immune systems have retained a memory of this exposure.

Less so with COVID-19, whose human story starts in 2019.

Everyone is susceptible.

SARS-CoV2 is a virus new to humans. Because of newness the  Covid-19 pandemic is largely unconstrained by any pre-existing immunity, and before the new Covid-19 vaccines are fully rolled out,  this virus is potentially able to affect almost everyone in any community that it enters. High attack rates are promoted by high infectiousness of disease and low pre-existing immunity. Clear evidence of high attack rates was seen in Amazonian Brazil in October 2020, where it is reported by Buss and colleagues that 76 percent of people suffered infection with SARS-CoV2.

High spread of COVID-19 infection through communities  is also illustrated by events in countries heavily predicted by vaccination. Despite high levels of vaccination protection in Israel and the UK and Israel, SARS COV2 outbreaks still occurred. They are primarily now caused by the so-called Delta variant causing particular trouble among those who haven’t yet been been vaccinated -- particularly children and young adults.

Sadly the epidemic raged extensively in Israel even after substantial vaccination was implemented and this is a grim further reminder of SARS-CoV2 Delta variant's high attack rate (documented here at Science Magazine blog.)

Influenza is a well-established human disease with much pre-existing baseline immunity.

With influenza epidemics the situation seems quite unlike what’s happening in the SARS-CoV2 pandemic.

In most modern communities there is substantial pre-existing community protection against infection because of the immunological memory induced by vaccination campaigns and previous influenza infections.

The penetration of influenza infections into the community in flu epidemics has been more limited than we are seeing with Covid-19 (with flu attack rates of 10 to 30% being quoted by various sources; Haywood 2014 gives 18 percent influenza infection of unvaccinated people per season). It contrast with COVID-19 in late June 2021 in the UK, new COVID-19 infections continued at a brisk pace even though 9/10 people already had antibody against the virus. This shows that attack rates above 90 percent are possible for SARS-CoV2 (data reported by the UK Office of National Statistics).

This past history means that even if influenza and Covid-19 had identical infection fatality risk ratio (IFR values), differences in their attack rates would make Covid-19 more dangerous because almost all people can be infected with SARS-CoV2, but with flu, not so many get infected.

Measuring fatality risks isn’t easy. To get an accurate value, we need to pin down both the numerator and the denominator.

It might seems obvious and simple to compare the two diseases by working out what percentage of infections result in death, and thus obtain accurate values for the metric called infection fatality ratio (IFR, also called infection fatality risk or even infection fatality rate).

Diagram showing why infection fatality ratio (IFR) is smaller than case fatality ratio (CFR) when not all infections display symptoms or are diagnosed (After Hiroshi Nishiura 2010) .

But number values for infection fatality ratio and case fatality ratio are not easy to measure accurately for either virus. 

A problem is that we don’t have usually have measurements of the numbers of people who are infected which is the denominator of the IFR. It’s expensive and difficult to get this number. Infected people can’t always be counted because many don’t look or behave differently from non-infected people. The surprise with Covid-19 in the early stages of the pandemic was that many people were infected without realising it. They were “asymptomatic’ as the medicos say. (In the Italian municipality of Vo' investigators found that 42.5 percent of confirmed SARS-CoV2 infections were individuals who did not have symptoms at the time of swab testing and who failed to display symptoms after testing. Careful surveys by Sullivan and colleagues (2021) suggest that only one in five SARS-CoV2 infections are reported, Irons estimates 40 percent are reported). This made the COVID-19 epidemic very dangerous and difficult to control. It also makes infection fatality ratios are difficult to pin down. Specially designed US surveys (Sullivan 2021, Irons 2021) give reliable IFR values that fall in the range of 0.83-1.4 death events per 100 SARS-CoV2 infected persons -- about 1 percent.

But what is not always realised is that the same kind of under-the-radar spread can occur with influenza. For example, after the 2009 influenza pandemic in England, antibody surveys of children indicate that 10-fold as many children had been infected as had picked up at the time by surveillance for disease symptoms (Miller and colleagues 2010 Lancet report; see also Haywood and colleagues 2014, Leung and colleagues 2015, that show there is a wide uncertainty in the fraction of flu infections that don't show symptoms).

If estimates of Covid-19 infection fatality ratio have been a bit rubbery, flu IFRs are equally rubbery.

For instance, various death rates reported in 2009 flu pandemic showed extremely wide variation, ranging between 1 up to 10,000 per 100,000 virus affected people.

It’s sobering to read a systematic review of this problem in a 2013 Epidemiology journal review by Wong and colleagues. 

They describe how different investigators didn't standardise their criteria for identifying infection numbers or influenza case numbers -- the infection rate denominator-- and thus obtained an exaggerated spread in IFR values. This lack of common statistical standards adds to the challenge of interpreting infection fatality risks.

Wong and crew concluded:

Conclusions: Our review highlights the difficulty in estimating the seriousness of infection with a novel influenza virus using the case fatality risk. In addition, substantial variability in age-specific estimates complicates the interpretation of the overall case fatality risk and comparisons among populations. A consensus is needed on how to define and measure the seriousness of infection before the next pandemic.

Measurement of total infection numbers with antibody tests gives a much lower infection risk for flu.

Using a blood test that catches people who are infected and not showing any symptoms reveals that people suffering from flu symptoms are often just the tip an iceberg of largely undetected infections during an epidemic.

Wong and colleagues (2013) summarise reports that use such blood tests to set the ratio denominators for calculating IFR values during the 2009 influenza pandemic. Those IFRs sit in a narrow low range between 1 and 10 deaths per 100,000 infections (Wong 2013, table below). 

Sickness with COVID-19 gives you around 15-fold higher chance of dying than flu if sick

It is noteworthy that most, if not all, Covid-19 infection fatality ratios are an order of magnitude higher than this, typically being 500 deaths per 100,000 people in well developed countries. In the 2021 Sydney Delta variant outbreak there were at 10 Sept 2021 170 deaths in 36374 infections even at a high vaccine first dose coverage at this stage in the outbreak or close to 470 per 100,000 infections and this is an underestimate of the IFR.  It is clear from this that on average, COVID-19 is much more likely to kill you than getting sick with recent strains of the flu.

Many people have noted that the worldwide IFR value for the current coronavirus pandemic is lower than 500 (say 150 per 100,000), but 150 is still well above the 10 of lower per 100,000 shown by modern influenza epidemics. (See also WHO 2020 whose guidance of infection fatality ratio values reinforces these conclusions.)

Both flu and COVID-19 fatality rates change greatly with patient age.

People do not always factor in the uncertainties in this global IFR value, or realise that it’s influenced by the age distribution of the communities affected. Young countries, such as many places in Africa have much lower COVID-19 infection fatality ratios than countries such as Italy with an ageing population. Marc Bevand (@zorinac at Twitter) presents some good summaries showing that from ten years of age and above, death rates from COVID-19 adjusted for age of the patient are generally many fold worse with COVID-19 that for the flu. The graph below shows the gap increases above 50 years of age. (This graph is shown here because it provides a visual comparison between flu and COVID-19 fatality at different ages, and in rests on assumptions about disease prevalence documented at the link.)

Mind the Gap (update of 21 Jun 2021)

Total death numbers provide a metric that is independent of uncertainties about infection numbers.

There is a way round these confusions about infection fatality ratio values—count up the total numbers of deaths from two different epidemics and compare total flu and COVID-19 death numbers directly.

There are reliable numbers available in many countries for total death numbers Covid-19 and alternative ways of getting numbers to crosscheck values.

One of these death count approaches is the so-called excess deaths measure.

Excess deaths is obtained by subtraction of expected deaths from measured deaths in a particular time period.  For example in the chart below, weekly excess deaths is the weekly count numbers of deaths above a threshold number (orange line) of expected number of weekly deaths. It is useful for identifying whether unusual causes of high death rates have occurred --  and it flags occurrence of epidemics. The graph below captures deaths for a US flu and the COVID-19 disease outbreaks in the one diagram.

The graph is a plot produced by the US CDC to display weekly numbers of deaths from all causes in the United States. From stats for previous years, the expected profile of deaths can be estimated for each week, as shown by the orange line that shows the upper bound for normal expected deaths numbers for each week of the year. For weeks where the counted death numbers  significantly exceed this upper bound there is a cross. 2017-2018 was a bad year for influenza as shown by 8 weeks with unexpectedly high death numbers or “excess deaths”.

Some people do not find the CDC convincing. But similar results are found in England (from week 27 2021 report):

Other calculations showed that the US deaths resulting from the 2017 to 2018 influenza pandemic caused by the flu virus were 61,000. (For example see https://www.cdc.gov/flu/about/burden-averted/2017-2018.htm ).

In contrast to the 2017-2018 period, excess deaths in 2020 - 2021 were much greater and extended over a much longer interval as shown the row of crosses in the graph. Those excess deaths were mostly caused by SARS-CoV2, as there was essentially no influenza circulating in the USA.

We don’t know the final death numbers for this COVID-19 epidemic yet, because it’s not over yet.

But just a glance at the above CDC graph show that they will much, much greater than the 61,000  dying from flu  in 2017-2018. 

At the time of writing (1 July 2021), in the USA, COVID-19 deaths are estimated by the CDC at 595,387 , so that flu and COVID clearly differ in lethality by a factor of ten-fold or so based on death counts. The previously mentioned infection fatality rate estimates revealed a similar gap between the two diseases. When adjusted for age, the gap is 5- to 25-fold.

COVID-19 is simply not just the common flu by any careful measure of lethality

Disease is not just mortality risks. There are a wide range of harms to consider.

The features of disease differ substantially between flu and COVID-19. A diagram from an article in The Lancet in mid-2020 covers some major aspects of this difference (thanks to Eric Topol on Twitter quoting Eskild Petersen and colleagues 2020).

Some of these difference reflect differences in vaccine coverage. There is (mid-2021) inadequate existing SARS-CoV2 vaccine coverage in Australia and most of the world, greater infectiousness with COVID-19 than with flu, especially with newer variants, and a wide range of potential and realised damage to survivors. It's a bitter pill to chew.

"A surprising finding of the study by Piroth and colleagues 4 was that, among patients younger than 18 years, the rates of ICU admission were significantly higher for COVID-19 than influenza. The need for intensive care was highest in patients with COVID-19 who were younger than 5 years (14 [2·3%] of 613 for COVID-19 vs 65 [0·9%] of 6973 for influenza), but mortality in the COVID-19 group was not higher than for influenza. Mortality was ten-times higher in children aged 11–17 years with COVID-19 than in patients in the same age group with influenza (5 [1·1%] of 458 vs 1 [0·1%] of 804). These findings are supported by a study of 4784 children and adolescents with COVID-19 from Brazil7 and a study of children and adolescents from Spain.8 Clearly, COVID-19 is not an innocent infection in children and adolescents." Quote from Petersen (2021). COVID-19 is not influenza. Lancet Respir Med. 

Late in the epidemic direct comparisons of hospitalisation rates became available

Post-Script.

Perhaps the 2009 flu pandemic and current seasonal flu are relatively tame by historical standards.

Haywood and colleagues 2014 provide a longer term  picture of flu pandemics:

Influenza causes roughly 250 000–500 000 deaths worldwide each year. In the 20th century there were three influenza pandemics for which there are varying mortality estimates: 1918 A/H1N1 at least 20–40 million excess deaths, 1957 A/H2N2 about 4 million excess deaths, and 1968 A/H3N2 about 2 million excess deaths. In 2009 a new pandemic virus, influenza A(H1N1) pdm09, emerged in Mexico and spread globally over 2009–10, causing an estimated 200000 respiratory deaths and 83 000 cardiovascular deaths during the first 12 months of circulation. WHO declared an end to the pandemic on Aug 10, 2010. However, a further pandemic wave occurred in some European and other countries outside North America in 2010–11 with reports of excess deaths in, for example, England.

In a follow up post we do some more detailed comparisons  of COVID-19 and the flu.

Here is the figure presented in the later post that compares death rates in different epidemics rates:

Epidemic death rates per 100,000 citizens. Vertical axis captions identifies
the time and nature of the epidemics being compared.
Bars represent deaths per 100,000 population (including infected and uninfected
in the denominator and is different from the infection fatality ratio).
Some estimates are for lung disease (P&I), others are all cause excess death above normal seasonal levels, which provide an upper bound for lethal impact.
Details in above link to a GMO Pundit Post.

This graph confirms that COVID-19 has already achieved a greater lethal impact than any other respiratory disease epidemic in the last 100 years, approaching that of the 1918 pandemic.

Selected further reading:

Blog Post 

What's the risk from COVID-19? Any takers for large scale Russian Roulette? It would be an exciting ride

Medical Literature:

Baker MG, Wilson N, Huang QS, Paine S, Lopez L, Bandaranayake D, Tobias M, Mason K, Mackereth GF, Jacobs M, Thornley C, Roberts S, McArthur C. (2009). Pandemic influenza A(H1N1)v in New Zealand: the experience from April to August 2009. Euro Surveill. 2009;14(34):pii=19319. Available online: http://www.eurosurveillance.org/ViewArticle.aspx?ArticleId=19319

Buss LF, Prete CA Jr, Abrahim CMM, Mendrone A Jr, Salomon T, de Almeida-Neto C, França RFO, Belotti MC, Carvalho MPSS, Costa AG, Crispim MAE, Ferreira SC, Fraiji NA, Gurzenda S, Whittaker C, Kamaura LT, Takecian PL, da Silva Peixoto P, Oikawa MK, Nishiya AS, Rocha V, Salles NA, de Souza Santos AA, da Silva MA, Custer B, Parag KV, Barral-Netto M, Kraemer MUG, Pereira RHM, Pybus OG, Busch MP, Castro MC, Dye C, Nascimento VH, Faria NR, Sabino EC. Three-quarters attack rate of SARS-CoV-2 in the Brazilian Amazon during a largely unmitigated epidemic. Science. 2021 Jan 15;371(6526):288-292. doi: 10.1126/science.abe9728. Epub 2020 Dec 8. PMID: 33293339; PMCID: PMC7857406.

Blackburn J, Yiannoutsos CT, Carroll AE, Halverson PK, Menachemi N. (2021). Infection Fatality Ratios for COVID-19 Among Noninstitutionalized Persons 12 and Older: Results of a Random-Sample Prevalence Study. Ann Intern Med. 2021 Jan;174(1):135-136. doi: 10.7326/M20-5352. Epub 2020 Sep 2. Erratum in: Ann Intern Med. 2020 Oct 20;173(8):684. PMID: 32877214; PMCID: PMC7505013.

Brazeau NF , R Verity, S Jenks et al. (2020). COVID-19 Infection Fatality Ratio: Estimates from Seroprevalence. Imperial College London (29-10-2020), doi https://doi.org/10.25561/83545. https://www.imperial.ac.uk/media/imperial-college/medicine/mrc-gida/2020-10-29-COVID19-Report-34.pdf

COVID-19 Response Team. Suppression of a SARS-CoV-2 outbreak in the Italian municipality of Vo'. Nature. 2020 Aug;584(7821):425-429. doi: 10.1038/s41586-020-2488-1. Epub 2020 Jun 30. Erratum in: Nature. 2021 Feb;590(7844):E11. PMID: 32604404.

CDC estimates the severe 2017-2018 US Flu season claimed 61000 lives, with 5700 deaths preventedby vaccination

Deinhardt-Emmer S, Wittschieber D, Sanft J, Kleemann S, Elschner S, Haupt KF, Vau V, Häring C, Rödel J, Henke A, Ehrhardt C, Bauer M, Philipp M, Gaßler N, Nietzsche S, Löffler B, Mall G. Early postmortem mapping of SARS-CoV-2 RNA in patients with COVID-19 and the correlation with tissue damage. Elife. 2021 Mar 30;10:e60361. doi: 10.7554/eLife.60361. PMID: 33781385; PMCID: PMC8009677.

Gavriatopoulou, M., Korompoki, E., Fotiou, D., Ntanasis-Stathopoulos, I., Psaltopoulou, T., Kastritis, E., Terpos, E., & Dimopoulos, M. A. (2020). Organ-specific manifestations of COVID-19 infection. Clinical and experimental medicine, 20(4), 493–506. https://doi.org/10.1007/s10238-020-00648-x

Glezen WP. Emerging infections: pandemic influenza. Epidemiol Rev. 1996;18(1):64-76. doi: 10.1093/oxfordjournals.epirev.a017917. PMID: 8877331.

Goldstein E, Viboud C, Charu V, Lipsitch M. Improving the estimation of influenza-related mortality over a seasonal baseline. Epidemiology. 2012 Nov;23(6):829-38. doi: 10.1097/EDE.0b013e31826c2dda. PMID: 22992574; PMCID: PMC3516362.

Guzik TJ, Mohiddin SA, Dimarco A, Patel V, Savvatis K, Marelli-Berg FM, Madhur MS, Tomaszewski M, Maffia P, D'Acquisto F, Nicklin SA, Marian AJ, Nosalski R, Murray EC, Guzik B, Berry C, Touyz RM, Kreutz R, Wang DW, Bhella D, Sagliocco O, Crea F, Thomson EC, McInnes IB. COVID-19 and the cardiovascular system: implications for risk assessment, diagnosis, and treatment options. Cardiovasc Res. 2020 Aug 1;116(10):1666-1687. doi: 10.1093/cvr/cvaa106. PMID: 32352535; PMCID: PMC7197627.

Hayward AC, Fragaszy EB, Bermingham A, Wang L, Copas A, Edmunds WJ, Ferguson N, Goonetilleke N, Harvey G, Kovar J, Lim MS, McMichael A, Millett ER, Nguyen-Van-Tam JS, Nazareth I, Pebody R, Tabassum F, Watson JM, Wurie FB, Johnson AM, Zambon M (2014). Flu Watch Group. Comparative community burden and severity of seasonal and pandemic influenza: results of the Flu Watch cohort study. Lancet Respir Med. 2014 Jun;2(6):445-54. doi: 10.1016/S2213-2600(14)70034-7. Epub 2014 Mar 17. PMID: 24717637; PMCID: PMC7164821.

Irons, Nicholas J. , Adrian E. Raftery 2021. Estimating SARS-CoV-2 infections from deaths, confirmed cases, tests, and random surveys Proceedings of the National Academy of Sciences USA Aug 2021, 118 (31) e2103272118; DOI: 10.1073/pnas.2103272118

Kalish H  et al, (2021) Undiagnosed SARS-CoV-2 seropositivity during the first six months of the COVID-19 pandemicin the United States Sci. Transl. Med. 10.1126/scitranslmed.abh3826 (2021).

Leung, N. H., Xu, C., Ip, D. K., & Cowling, B. J. (2015). Review Article: The Fraction of Influenza Virus Infections That Are Asymptomatic: A Systematic Review and Meta-analysis. Epidemiology (Cambridge, Mass.), 26(6), 862–872. https://doi.org/10.1097/EDE.0000000000000340

Levin AT, Hanage WP, Owusu-Boaitey N, Cochran KB, Walsh SP, Meyerowitz-Katz G. (2020). Assessing the age specificity of infection fatality rates for COVID-19: systematic review, meta-analysis, and public policy implications.Eur J Epidemiol. Dec;35(12):1123-1138. doi: 10.1007/s10654-020-00698-1. Epub 2020 Dec 8. PMID: 33289900; PMCID: PMC7721859.

Miller E, Hoschler K, Hardelid P, Stanford E, Andrews N, Zambon M. Incidence of 2009 pandemic influenza A H1N1 infection in England: a cross-sectional serological study. (2010). Lancet 375(9720), 1100–1108 . https://pubmed.ncbi.nlm.nih.gov/20096450/ “Around one child in every three was infected with 2009 pandemic H1N1 in the first wave of infection in regions with a high incidence, ten times more than estimated from clinical surveillance. “

Nishiura, Hiroshi (2010) The virulence of pandemic influenza A (H1N1) 2009: an epidemiological perspective on the case–fatality ratio, Expert Review of Respiratory Medicine, 4:3, 329-338, DOI: 10.1586/ers.10.24 https://doi.org/10.1586/ers.10.24

O'Driscoll M, Ribeiro Dos Santos G, Wang L, Cummings DAT, Azman AS, Paireau J, Fontanet A, Cauchemez S, Salje H. Age-specific mortality and immunity patterns of SARS-CoV-2. Nature. (2021) Feb;590(7844):140-145. doi: 10.1038/s41586-020-2918-0. Epub 2020 Nov 2. PMID: 33137809. https://pubmed.ncbi.nlm.nih.gov/33137809/

Petersen E, Koopmans M, Go U, Hamer DH, Petrosillo N, Castelli F, Storgaard M, Al Khalili S, Simonsen L. Comparing SARS-CoV-2 with SARS-CoV and influenza pandemics. Lancet Infect Dis. 2020 Sep;20(9):e238-e244. doi: 10.1016/S1473-3099(20)30484-9. Epub 2020 Jul 3. PMID: 32628905; PMCID: PMC7333991.

Petersen E. (2021). COVID-19 is not influenza. Lancet Respir Med. 2021 Mar;9(3):219-220. doi: 10.1016/S2213-2600(20)30577-4. Epub 2020 Dec 17. PMID: 33341154; PMCID: PMC7834708.

Piroth L, Cottenet J, Mariet AS, Bonniaud P, Blot M, Tubert-Bitter P, Quantin C. (2021). Comparison of the characteristics, morbidity, andmortality of COVID-19 and seasonal influenza: a nationwide, population-basedretrospective cohort study. Lancet Respir Med. 2021 Mar;9(3):251-259. doi: 10.1016/S2213-2600(20)30527-0. Epub 2020 Dec 17. PMID: 33341155; PMCID: PMC7832247.

van Asten L, Harmsen CN, Stoeldraijer L, Klinkenberg D, Teirlinck AC, de Lange M, et al. (2021). Excess Deaths during Influenza and CoronavirusDisease and Infection-Fatality Rate for Severe Acute Respiratory SyndromeCoronavirus 2, the Netherlands. Emerg Infect Dis. 2021;27(2):411-420. 

Abstract. Since the 2009 influenza pandemic, the Netherlands has used a weekly death monitoring system to estimate deaths in excess of expectations. We present estimates of excess deaths during the ongoing coronavirus disease (COVID-19) epidemic and 10 previous influenza epidemics. Excess deaths per influenza epidemic averaged 4,000. The estimated 9,554 excess deaths (41% in excess) during the COVID-19 epidemic weeks 12–19 of 2020 appeared comparable to the 9,373 excess deaths (18%) during the severe influenza epidemic of 2017–18. However, these deaths occurred in a shorter time, had a higher peak, and were mitigated by nonpharmaceutical control measures. Excess deaths were 1.8-fold higher than reported laboratory-confirmed COVID-19 deaths (5,449). Based on excess deaths and preliminary results from seroepidemiologic studies, we estimated the infection-fatality rate to be 1%. Monitoring of excess deaths is crucial for timely estimates of disease burden for influenza and COVID-19. Our data complement laboratory-confirmed COVID-19 death reports and enable comparisons between epidemics.

From <https://wwwnc.cdc.gov/eid/article/27/2/20-2999_article>

Quandelacy et al (2013) Age- and Sex-related Risk Factors for Influenza-associated Mortality in the United States Between 1997–2007 Am J Epidemiol. 2014;179(2):156–167 derive an overall mortality from influenza of 117.8 deaths per million which for the 2020 US population of 331,449,281 yields an annual death rate of  39,000 pa from influenza.

Sullivan, Patrick Sean, Aaron J Siegler, Kayoko Shioda, Eric W Hall, Heather Bradley, Travis Sanchez, Nicole Luisi, Mariah Valentine-Graves, Kristin N Nelson, Mansour Fahimi, Amanda Kamali, Charles Sailey, Benjamin A Lopman 2021. SARS-CoV-2cumulative incidence, United States, August-December 2020, Clinical Infectious Diseases, 2021;, ciab626, https://doi.org/10.1093/cid/ciab626

WHO (2020). Coronavirus disease (COVID-19): Similarities and differences with influenza 17 March 2020 | Q&A

Wong, Jessica Y.; Kelly, Heath; Ip, Dennis K. M.; Wu, Joseph T.; Leung, Gabriel M.; Cowling, Benjamin J. (2013). Case Fatality Risk of Influenza A(H1N1pdm09), Epidemiology: November 2013 - Volume 24 - Issue 6 - p 830-841 doi: 10.1097/EDE.0b013e3182a67448

V 2. (Updated 3 July 2021 with age fatality profiles graph.)

V3 . Selected further reading added

V4. Wong 2013 Table section added

V5. It's a bitter pill to chew.

V6. IFR CFR Triangle graph

V7. Age fatality profile graph updated, linked to github page

V8. Post script. Earlier flu pandemics

V9. Follow up post on hit parade of pandemics

V10. Lancet Table via Eric Topol

V11 Bargraph updated

V12 IFR evidence updated

V13 Doherty Tweets. Systematic spread link

V14 updated Israel Delta wave comments

V15 Further Grim Israel updates