Spanish flu…remembering and considering if such a thing could happen again

Spanish flu a bigger Grim Reaper than the First World War
2018 is the centenary of the most deadly killer in recent memory……. You may be surprised to hear that this statement isn’t referring to the First World War but the pandemic infection known as the Spanish flu. Spanish flu came in three waves in the Spring, Summer and Autumn/Winter of 1918, the second wave more deadly than the first, and only by the third wave was it clear that it was losing its grip, finally subsiding in late 1919. Spanish flu continues to capture our imagination, not least because it claimed an estimated 100 million lives worldwide.

Spanish flu is forever wrongly, and pejoratively, attributed to Spain, when actual Ground Zero for infection was likely to be Camp Funston in Kansas, USA a training camp for US soldiers before shipping to Europe to fight.

Spanish flu – a question of biology
Biologically, flu boils down to a single strand of pathogenic RNA, enclosed in a nutshell (or a pathogenic lipid shell at least) composed of two ingredients hemagluttanin A (HA) and neuraminidase A (NA). There are 18 types of HA (1-18) and 11 types of NA (1-11). It is the combination of H and N, and where they are derived from, that determines how effectively the body recognises the virus and launches a protective immune attack.
Flu is considered a zoonotic infection, in that it can ‘jump’ or transfer from species to species, most typically from birds to pigs to humans altering its genetic material and often its killing power with each transfer. Every year, the H and N characteristics of flu change so every year seasonal flu varies very slightly. In these instances, the make-up of flu echoes previous versions so is not completely novel, explaining why it isn’t always so pathogenic. The pandemic in 1918 was characterised by an H1N1 strain of flu.

Why was the strain of pandemic flu in 1918 so brutal and effective compared to other years?
In 2005 it was found by researchers Jeffrey Taubenberger and Anne Reid that the 1918 flu virus may have potentially jumped from birds, most probably waterfowl, straight to humans, bypassing the normal pig vector – a phenomenon known as spillover. Humans infected with this strain would have no immune point of reference and so no effective immune strategies to combat infection. This may explain the pattern of deaths seen with Spanish flu. Typically, deaths from flu are in the young or the elderly who may be immunocompromised, but healthy young/middle aged people can usually expect to shake off infection and carry on. The 1918 H1N1 flu differed from other flu strains seen before and since, in not killing just the elderly, young and immunocompromised but surprisingly healthy adults. Half of all victims were aged 20-40 years.

Death from Spanish flu was particularly gruesome, characterised by blackened cyanotic bodies and bleeding from mouths and eyes. The phenomena are known to be due to the action of two effects: a cytokine storm – an overwhelming inflammatory response launched by the body in a vain attempt to combat infection and bacterial infection. Remember, this was before the advent of antibiotics and for many patients co-infection with bacteria led to pneumonia and death was effectively by drowning.

Future flu pandemic – could it happen again?
The answer is most probably. A flu strain with H1 derived directly from birds would be as dangerous as that in 1918, as we have no immunity to avian H1 and if overall population immunity to H1 decreases significantly then we have no immune reference point so infection could be as deadly as 100 years ago. We also live in a fully globalised society, so we might expect the spread of any new H1N1 variant, or another strain transmitted directly from birds like H5N1 or H7N9, to spread faster from Ground Zero across the world. In preparation for another lethal pandemic we need to consider the impact of globalisation and how spread can be limited through public health efforts.

It isn’t all gloom however. With modern medicine it is likely that mortality rates due to pandemic flu will reduce to just 1% (still a million people however if the flu takes grip as it did in 1918/19) as survival is dependent on supportive care as well as effective medications. We do need to ask ourselves however, even if medicine can theoretically cope and ensure survival, can healthcare systems across the world handle the sheer patient numbers? In 2009, the swine flu epidemic was caused by an H1N1 variant, and whilst lethal for some was not like 1918, but has helped test public health plans and expose the gaps.

Looking forward to the next 100 years, we have in place effective seasonal flu vaccines, which if taken every year improve immunity, as well as antivirals, like Tamiflu. Tamiflu targets the N component of flu and is effective, if taken early enough, although viral resistance is emerging. New entrants on the horizon differ in their mechanisms to Tamiflu and include nitazoxanide and DAS181 – both of which target the host – faviparavir (T-705), the recently approved baloxavir marboxil (S-033188) and pimodivir (JNJ63623872) which target the flu virus in a different way.

It is unlikely we can prevent the next pandemic, so the focus should perhaps be one of risk management to develop effective public health plan measures to slow down viral spread to give time for vaccine development. For those infected, we need to continue development of a range of antivirals, flu is a tricky customer after all and a one size fits all approach is unlikely to suffice.