1918 Spanish Influenza Pandemic

The Spanish Influenza pandemic is the catastrophe against which all modern pandemics are measured. This pandemic (caused by an H1N1 swine influenza virus) is now known to have been the most deadly in recorded history, with an estimated death toll of 40 million people in less than a year. There were on the order of 34 million combat deaths in all the wars of the twentieth century combined. have Before the 1918 epidemic, one has to go back to the black death (bubonic plague) of 1346 to find a similarly devastating epidemic in terms of total numbers of deaths. The "Spanish" attribution of the epidemic, common in the literature, is thought to be a result of the fact that the press in neutral Spain was not censored during World War I, and therefore some early printed reports of the flu originated from Spain. The spread of influenza in the US during the second wave of the 1918 pandemic began in Mid-Septebmer, and within three weeks, influenza had spread across the entire country.

Given the empirical infuenza epidemic curve and infection rates observed in the United States in 1918, it has been estimated that a very large proportion of the population was infected with the Spanish Flu in 1918, and thereafter immune to the virus. According to these estimates, only a very small proportion of the population remained susceptible to influenza after the pandemic {too small to support the initiation of another epidemic the following season. But another influenza epidemic that did in fact occur in 1919, is a puzzle. The virus may have evolved to such an extent in 1918 that could re-infect individuals in 1919. Or the virus could have persisted in 1919 due to heterogeneities in the host population and "pockets" of remaining susceptibles. Or perhaps the virus may have evolved a greater ability to spread, allowing it to persist despite the small number of susceptible hosts to support it.

As expected, many of the deaths in 1918 were from pneumonia caused by secondary bacterial infections, a complication of influenza now treatable with antibiotics. But an unknown number succumbed to the flu itself. Spanish flu caused a form of primary viral pneumonia, with extensive hemorrhaging of the lungs, that could kill the perfectly fit within 48 hours or less. Many people died from this very quickly. Some people who felt well in the morning became sick by noon, and were dead by nightfall. Those who did not succumb to the disease within the first few days often died of complications from the flu (such as pneumonia) caused by bacteria.

The male death rates in 1918 far exceed the female death rates among adults. One of the most unusual aspects of the Spanish flu was its ability to kill young adults. The reasons for this remain uncertain. In general the rate of death is highest for the very young and older persons. The 1918 pandemic followed a strikingly different pattern, with the highest mortality in young persons 25-30 years old. With the Spanish flu, mortality rates were high among healthy adults as well as the usual high-risk groups. The attack rate and mortality was highest among adults 20 to 50 years old. The severity of that virus has not been seen again in humans.

The reasons for this difference are still poorly understood. It is believed that a subset of victims experienced a primary viral pneumonia which caused a very rapid clinical decline and death. It is widely belived that cytokine storming [Immune-complexes-mediated pathogenesis] could be one of the mechanisms that resulted in damaging the lung tissue. Normally, when the lungs are under attack from a virus, T-cells, defenders from the immune system, are then sent to the site of the infection. The presence of T-cells initiate a second immune system attack by chemicals, known as cytokines, that cause inflammation. A cytokine is a small protein released by cells that has a specific effect on the interactions between cells, on communications between cells or on the behavior of cells. The cytokines includes the interleukins, lymphokines and cell signal molecules, such as the interferons, which trigger inflammation and respond to infections. When the lungs are infected with the flu virus, the T cells release chemical signals that cause them to stay longer in the lungs. The systemic symptoms of seasonal flu are caused by cytokine release, which is part of the human immune response.

A Cytokine storm [a systemic inflammatory response syndrome] -- immune system "friendly fire" -- is believed to be the underlying reason for the high death rate among young adults. It results when too many immune cells are in an endless loop of calling even more cytokines. During the flu infection the immune system has an "all hands on deck" attitude to the viral assault. More T cells are always arriving, and they in turn release more signal and stay longer, leading to a build up of T cells and chemical signals. The exaggerated immune response produces inflammatory molecules that lead to too many cells clogging up the airways and preventing efficient transfer of oxygen into the bloodstream. This Acute Respiratory Distress Syndrome [ARDS] is what makes the Cytokine storm so deadly in pandemic flu. It is suggested that the high death rate among healthy young adults was due to their strong immune systems producing a cytokine storm. The very young and very old would have had weaker immune systems, and thus weaker immune responses that would not result in a cytokine storm.

One researcher suggested that many of the apparently healthy young adults who died in 1918 were in fact infected with tuberculosis, explaining the unusually high mortality rates among young adults. Tuberculosis death rates plummeted after 1918, which can be explained by the fact that many TB sufferers died of the flu and therefore were not around to die later, nor to pass the TB bacillus to others. Just after 1918, TB death rates experience their steepest decline of the century, and this decline is much more pronounced for males than for females. [Fortunately, tuberculosis prevalence is much lower than in 1918, which bodes well for our potential susceptibility to a repeat of 1918.]

It is estimated that approximately 20 to 40 percent of the worldwide population became ill during the Spanish Flu. The number of worldwide dead due to the 1918 pandemic was initially reported as 20,000,000. A consensus has formed among experts now that the death toll was at least 40 million, and possibly much higher. Nobel laureate Frank MacFarlane Burnet believed deaths were at least 50 million, and may bave reached 100 million. Between September 1918 and April 1919, approximately 500,000 to 675,000 deaths from the flu occurred in the US alone. Western Samoa and Iceland avoided the 1918 flu entirely through the use of travel restrictions.

Though the identification of aetiology of the pandemic was not possible at that time, modern day molecular biological techniques have tried to unravel its mystery. Modern techniques have permitted a reconstitution of some parts of the genome of the 1918 agent by amplifying fragments of viral RNA obtained from different sources. One of them was anatomopathologic samples of lungs from patients who died of the disease in 1918. Other samples were obtained after the exhumation of victims of Spanish flu in Alaska and in Svalberg whose bodies had been buried in permafrost ground. Genetic sequences were obtained by genic amplification of viral RNA extracted from the lung fragments and were compared to recent human and animal viruses. The comparison showed that the hemagglutin of the 1918 virus was of the H1 subtype belonging to a subgroup of strains infecting human and pigs, but also sharing avian determinants. Sequence analysis indicates that many avian characteristics are present in critical locations of the hemagglutinin gene such as receptor, antigenic and glycosylation sites suggesting an avian relationship. However, the virus is closely related to human and swine viruses. Equivalent findings were obtained from the study of the neuraminidase gene: the enzymatic site is preserved but avian characteristics are found in antigenic and glycosylation sites. These results suggest that the 1918 virus borrowed determinants from avian strains but was already present in mammals for a prolonged period before the pandemic started.