The Influenza story has parallels with the search for the origin of many other infections. Cholera, still present in Europe at the turn of the twentieth century, was the subject of huge debate about its origins. Dr John Snow’s methodical approach in the 1850s solved the mystery of its transmission, laying the way open for future microbiological discoveries, culminating in the publication, in August 2000, of the cholera pathogen sequence (Nature, 3 August)
Dr John Snow would have been delighted, although little realising that it would take this long and that cholera would still be a major infection problem in many countries in the late 20th century. In reaching a full understanding of the pathogen, it is not so much an end to cholera as an ‘end to the beginning’. Snow’s major contribution in cholera was, of course, the demonstration of the water link. Water plays a part in the Influenza story too, not least in its origins. Influenza was possibly an early example of a virus jumping between species. It appears to have moved from an aquatic bird to humans around 10,000 years ago.
By the late nineteenth century, ‘flu was a familiar winter visitor although the viral cause was not understood. The epidemic of 1899 was known as “Russian Flu” and coincided with another wave of cholera in Europe. Recently Professor Oxford and his colleagues have been given permission to exhume some of the victims of the 1899 epidemic, to attempt to identify the nature of the Influenza virus responsible. This is not merely an academic exercise: no laboratory samples survive from the 1899 wave of the disease. This makes it very difficult to be precise about the specific virus responsible.
Most of the epidemics and pandemics are due to shifts or drifts in the Influenza A virus types, and the modern issue is when or whether another major shift will occur, causing widespread illness, since neither vaccination nor immunity to previous Influenza types would afford adequate protection. The 1918 pandemic, following so closely the exhausting end of the First World War, was devastating in its effects. In epidemiological terms, it was a huge natural experiment, and its study helps in the understanding of this pandemic disease, just as Dr John Snow’s scientific approach assisted in the control of cholera. To help us to imagine the times of the “Forgotten Plague”, Professor Oxford showed the page of deaths from the London Hospital’s children’s ward in November 1918, at the start of the pandemic. In addition to deaths from ‘marasmus’ (severe malnutrition), there were several listed as “Influenza-pneumonia”. One, Ivy Goddard, was only eight when she succumbed to the disease. The combination of widespread malnutrition and a new infection was inevitably lethal for this East London population, as in many other countries hit by the pandemic. Typically, death was heralded by cyanosis (blue appearance) of the lips and ears. This was matched by grave pathology in the lungs, resembling the effects of gassing, a problem familiar to the pathologists of the time from examination of war victims. The predominant theory was that the disease was due to a bacterial infection. The rapid deterioration of victims was also a reminder of the bubonic and pneumonic plague years of the distant past: a Breughal painting from the time of the Black Death (Plague), The Triumph of Death, showed Death on a pale horse, striking randomly with his scythe. The 1918 pandemic inspired many such images in cartoons and contemporary reports; it was also vividly described in the novel, ‘Pale Horse, Pale Rider’ by Katherine Anne Porter. Families were parted by death, including many couples who married shortly after the First World War, leaving widows and widowers all over the world. Worldwide, it is estimated that the pandemic caused 40 million deaths, the largest outbreak ever experienced.
The death toll did not stop with the decline of the pandemic: the ‘drift year load’ of subsequent epidemics, with slightly different types of the virus, also had high fatality. The famous actress and royal mistress, Lily Langtree, was one of the later victims. A cartoon of the Millennium Dome being punctured with needles was a reminder of the continuing drift year loads: around 19,000 deaths were attributed to Influenza over the 1999-2000 New Year period.
In 1933, there was a major breakthrough in understanding Influenza, when Charles Stuart Harris, Wilson Smith and their team isolated the virus in North London. This meant that physicians and scientists could now go back and examine fixed specimens from previous epidemics, as well as investigating the possibility of exhuming people who had died. Because the virus deteriorates rapidly in dead tissue, this latter route produced little initial success. What was needed was deep frozen tissue, where the virus might have survived or to have persisted, at least, in a state to allow identification. So began the story of the research into a group of miners who died from the pandemic in Spitzbergen, in the far north of Norway. Spitzbergen was a small mining community well used to Arctic hazards: citizens kept rifles to hand in case of attacks by polar bears and accident-related mortality was high. In October 1918, a ship arrived with miners to serve in the mines in the area. They caught ‘flu en route and seven of the miners died before arrival, 10% of those on board. These victims were hurriedly buried in the frozen ground. Decades later, a Canadian researcher, Dr Kirsty Duncan identified the probable location of the graves. Ground penetrating radar was used to pinpoint the site, picking up signals from the victims’ bones.
The next step was to obtain sponsorship and permission to exhume the bodies. A project of this type required considerable sensitivity and respect for the deceased miners, as well as permission from surviving relatives and the Norwegian authorities: it also needed research sponsorship of around £250,000. An international team returned to the site with 17 tons of equipment, and with expertise ranging from virology to professional grave digging. Local people were amused to find that the equipment taken to this polar region included a large fridge: but this was not a case of ‘coals to Newcastle’: any specimens would need to be kept at a constant low temperature (-20°C) during the research and return journey. A BBC documentary showed the disappointment of this team when they discovered that the Influenza victims had not been buried as far down as the permafrost, the permanently frozen layer. The bodies were higher up, in a layer that froze and thawed each year. But all was not lost. Previous experience with exhumations had shown that viruses could survive in identifiable form within sealed lead coffins, in formalin fixed specimens and in frozen bodies. Despite the deterioration during the thaws, some tissue had survived. In later examinations of specimens, signals of RNA – the nucleic acid of the virus – were detected. The celebration of this, in an issue of Esquire as “Virus beaters: the answer is buried in the ice”, belied the months of painstaking research required to uncover the secrets of the 1918 virus. While the RNA signal was detected in parts of the lungs and kidneys, the best signal was from brain samples. Research is underway to see whether the 1918 virus (Influenza A HA1/HA2) had an extra ‘pathogenic’ sequence giving it additional virulence. A sample from a surviving victim of the encephalitis lethargica epidemic of the 1920s (as fictionalised in the 1990 film ‘Awakenings’), suggested that this virus could have caused the strange disease, with its propensity for the brain. Because of the widespread pathology and severe pneumonia, possible early outbreaks of this strain were not attributed to ‘flu. Thus an outbreak in France in 1917 was described as “purulent bronchitis”: the virus responsible was Influenza and, to match the Spanish Lady of 1918, this one has been dubbed “The French Lady”. The strain that hit the Spitzbergen miners in October 1918 was particularly lethal: it may be no coincidence that the bodies of victims in Alaska and Carolina, also exhumed for viral study, relate to deaths in the same month.
Articles on emerging diseases often include the possibility of another pandemic. If it comes, have we made sufficient progress? What, in short, have we been doing to fight ‘flu since 1918? This is a question that perhaps the victims, like little Ivy Goddard, would have asked. Apart from vaccination, which necessarily has to be based on previous circulating strains, there have been developments that offer hope of effective treatment. The neuraminidase molecule was identified in the 1970s, leading to the development of a drug against Influenza, acting by binding to the amino acid on the neuraminidase spike of the virus. Its safety is still being tested on a large scale, but animal and human studies already suggest it could act as a prophylactic (preventing infection in around 90% of cases) as well as a treatment. In general, we are also far better nourished than the victims of 1918, so that the progress of the disease would be less rapid and less fatal in its course.So, vaccines and advanced drug therapy may be the future ‘Pump Handle’ for this virus, along with the established public health lessons regarding respiratory transmission in crowded spaces and the need to keep up surveillance and early warning systems. This was a worthy topic and lecture in the John Snow Society tradition, and Professor Oxford concluded the talk with the accustomed ritual of removing the Handle from the Society’s ceremonial Pump. The Handle was then returned to the Pump, as neither Influenza, nor many other diseases, have been vanquished yet. The meeting ended with another regular ritual: celebrating the memory of Dr John Snow at the John Snow Pub in Soho.