The Reason Why People Died So Young In The Middle Ages

The Reason Why People Died So Young In The Middle Ages

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Reasons why such low estimates for life expectancy during the MIddle Ages are often tossed around. From infant mortality skewing the stats, to the risks of childbirth and disease.

10 Reasons That Prove Living in the Middles Ages Was Truly Bad

Not for nothing is the Medieval period often referred to as the ‘Dark Ages&rsquo. Not only was it incredibly gloomy, it was also quite a miserable time to be alive. Sure, some kings and nobles lived in relative splendor, but for most people, everyday life was dirty, boring and treacherous. What&rsquos more, after the fall of the Western Roman Empire in 476AD, things only really started getting better for normal people some 1,000 years later, with the start of the Renaissance and the dawn of the Age of Discovery.

Of course, life wasn&rsquot all that bad. People were in touch with nature and stayed close to their loved ones. Family values were strongly embraced, and the everyday drudgery was often eased with the occasional festival or party. But, on the whole, life was a grim as we think it was. Few people lived to a good age, which might have been something of a blessing given how hard they had to work and the stresses and dangers they faced on an everyday basis. Here are just ten hardships the average man or woman had to put up with in the Middle Ages:

In the Middle Ages, many people never left their home villages. Lost Kingdom.

Solving the Mystery Flu That Killed 50 Million People

Y ears ago the environmental historian Alfred Crosby was at Washington State University, where he was teaching at the time, when on a whim he decided to pick up an old almanac from 1917. (This is apparently the kind of thing historians like to do in their spare time.) He looked up the U.S. life expectancy in that year&mdashit was about 51 years. He turned to the 1919 almanac, and found about the same figure. Then Crosby picked up the almanac from 1918. The U.S. life expectancy in 1918 had fallen to 39 years. “What the hell happened?” Crosby told the New York Times writer Gina Kolata in her book Flu: The Story of the Great Influenza Pandemic of 1918. “ The life expectancy had dropped to what it had been fifty years before.”

What happened was the 1918 influenza pandemic. A virus that usually does little more than make people feel awful for a few days killed an estimated 50 million people worldwide, if not far more, with 650,000 people dying in the U.S. alone. The flu killed more people in a year than the bubonic plague killed in a century in the Middle Ages. Worst of all, this flu disproportionately took the lives of men and women in their 20s and 30s, while often sparing the very old and the very young&mdashtwo population groups that are especially vulnerable to the flu in most years.

This has confounded scientists for almost a century, but a new study in the Proceedings of the National Academy of Sciences (PNAS) puts forward a fresh answer to one of the enduring mysteries of medical science. Researchers led by Michael Worobey of the University of Arizona reconstructed the origins of the 1918 pandemic, concluding that the pathogen arose when an existing human H1 flu virus acquired genetic material from a bird flu virus. That new H1N1 flu virus was able to evade immune systems, which helps explain why it infected more than a quarter of the U.S. population at the time. But it was young adults between the ages of 20 and 40 that died in the greatest number&mdashand Worobey’s study suggests that the unusual death pattern was due as much to flus of the past as it was to the flu of 1918. “Prior immunity, or lack of it, seems to be the decisive factor,” says Worobey.

Flu viruses are constantly changing and mutating, which is why we can’t develop a lifelong vaccine for it the way we can for more stable viruses, like the ones that cause smallpox or the measles. A flu virus has two parts: hemagglutinin and neuraminidase proteins, shortened to HA and NA (and just H and N when naming a virus). It’s the HA protein that seems to drive our immune system response, as Worobey put it in a statement:

Imagine a soccer ball studded with lollipops. The candy part of the lollipop is the globular part of the HA protein, and that is by far the most potent part of the flu virus against which our immune system can make antibodies. If antibodies cover all the lollipop heads, the virus can’t even infect you.

Worobey and his colleagues looked back at the kinds of flu viruses that were in circulation in the decades preceding the 1918 pandemic by examining antibodies found in old blood samples. (Your immune system will produce customized antibodies in response to a flu infection, and those antibodies will remain in your body, which allows scientists to identify the genetic makeup of the virus that led to their creation.) It turns out people born between 1880 and 1900&mdashthe generation hit hardest by the 1918 flu&mdashwere mostly exposed during childhood to a H3N8 flu virus that began circulating during an earlier pandemic in 1889, but not to an H1 virus, which meant that generation had virtually no antibodies to fight it off.

By reconstructing the genetic origins of the 1918 flu, Worobey found that a version of that H1N1 flu virus was circulating for years before the pandemic began. Because flu strikes most commonly in childhood, those born after 1900 were more likely to have had previous exposure to an H1N1-like flu virus, which would have offered them some protection. Meanwhile those born before 1880 were more likely to have been exposed to the H1N8 flu strain that was prevalent when they were children. In both the very young and the old, having earlier exposure to an H1 flu&mdasheven one different from the strain that caused the 1918 pandemic&mdashoffered a level of protection not present in those who had never been infected by an H1 strain. That could explain the unusual mortality curve in the 1918 pandemic.

Thankfully, no flu pandemic since 1918 has been anywhere near as deadly. The 2009 swine flu pandemic killed an estimated 284,000 people worldwide, comparable to flu deaths in a non-pandemic year. But two avian flu viruses &mdash H5N1 and H7N9 &mdash have for years been periodically jumping the species barrier and infecting human beings. And like the 1918 flu, H5N1 and H7N9 are unusually deadly, particularly for the young and elderly, respectively. “Lots of different age groups might be exposed to these viruses, but the virus that kills them is the one that’s mismatched to the virus they encountered as a child,” says Worobey.

The PNAS paper suggests that this might be due to past flu patterns as well, with both groups having been exposed to flu viruses in their youth that offered them little protection against the new pathogens. If either virus were to mutate to the point where it could spread easily in the human population, the results could be catastrophic.

But the PNAS paper offers hope that doctors could begin to design flu vaccination strategies that compensate for the strains that different age groups never experienced as children. Down the line, scientists may even be able to develop a universal flu vaccine that targets parts of the virus that almost never change from strain to strain. “This work is encouraging that possibility,” says Worobey. If we’re smart, the global catastrophe that was the 1918 pandemic will remain confined to the history books.

Why Did the 1918 Flu Kill So Many Otherwise Healthy Young Adults?

Vaccination is underway for the 2017-2018 seasonal flu, and next year will mark the 100-year anniversary of the 1918 flu pandemic, which killed roughly 40 million people. It is an opportune time to consider the possibility of pandemics – infections that go global and affect many people – and the importance of measures aimed at curbing them.

The 1918 pandemic was unusual in that it killed many healthy 20- to 40-year-olds, including millions of World War I soldiers. In contrast, people who die of the flu are usually under five years old or over 75.

The factors underlying the virulence of the 1918 flu are still unclear. Modern-day scientists sequenced the DNA of the 1918 virus from lung samples preserved from victims. However, this did not solve the mystery of why so many healthy young adults were killed.

I started investigating what happened to a young man who immigrated to the U.S. and was lost during World War I. Uncovering his story also brought me up to speed on hypotheses about why the immune systems of young adults in 1918 did not protect them from the flu.

The 1918 flu and World War I

Certificates picturing the goddess Columbia as a personification of the U.S. were awarded to men and women who died in service during World War I. One such certificate surfaced many decades later. This one honored Adolfo Sartini and was found by grandnephews who had never known him: Thomas, Richard and Robert Sartini.

The certificate was a message from the past. It called out to me, as I had just received the credential of certified genealogist and had spent most of my career as a scientist tracing a gene that regulates immune cells. What had happened to Adolfo?

An Italian immigrant to the U.S., Adolfo Sartini died from the flu while in the military. (Courtesy of Robert Sartini)

A bit of sleuthing identified Adolfo’s ship listing, which showed that he was born in 1889 in Italy and immigrated to Boston in 1913. His draft card revealed that he worked at a country club in the Boston suburb of Newton. To learn more, Robert Sartini bought a 1930 book entitled “Newton War Memorial” on eBay. The book provided clues: Adolfo was drafted and ordered to report to Camp Devens, 35 miles from Boston, in March of 1918. He was later transferred to an engineer training regiment.

To follow up, I posted a query on the “U.S. Militaria Forum.” Here, military history enthusiasts explained that the Army Corps of Engineers had trained men at Camp A. A. Humphreys in Virginia. Perhaps Adolfo had gone to this camp?

While a mild flu circulated during the spring of 1918, the deadly strain appeared on U.S. soil on Tuesday, Aug. 27, when three Navy dockworkers at Commonwealth Pier in Boston fell ill. Within 48 hours, dozens more men were infected. Ten days later, the flu was decimating Camp Devens. A renowned pathologist from Johns Hopkins, William Welch, was brought in. He realized that “this must be some new kind of infection or plague.” Viruses, minuscule agents that can pass through fine filters, were poorly understood.

With men mobilizing for World War I, the flu spread to military installations throughout the U.S. and to the general population. It hit Camp Humphreys in mid-September and killed more than 400 men there over the next month. This included Adolfo Sartini, age 29½. Adolfo’s body was brought back to Boston.

His grave is marked by a sculpture of the lower half of a toppled column, epitomizing his premature death.

The legacy of victims of the 1918 flu

The quest to understand the 1918 flu fueled many scientific advances, including the discovery of the influenza virus. However, the virus itself did not cause most of the deaths. Instead, a fraction of individuals infected by the virus were susceptible to pneumonia due to secondary infection by bacteria. In an era before antibiotics, pneumonia could be fatal.

Recent analyses revealed that deaths in 1918 were highest among individuals born in the years around 1889, like Adolfo. An earlier flu pandemic emerged then, and involved a virus that was likely of a different subtype than the 1918 strain. These analyses engendered a novel hypothesis, discussed below, about the susceptibility of healthy young adults in 1918.

The tombstone of Adolfo Sartini in Saint Michael Cemetery in Boston (Courtesy of Michael Sheehan, Manager of St. Michael Cemetery, Boston.)

Exposure to an influenza virus at a young age increases resistance to a subsequent infection with the same or a similar virus. On the flip side, a person who is a child around the time of a pandemic may not be resistant to other, dissimilar viruses. Flu viruses fall into groups that are related evolutionarily. The virus that circulated when Adolfo was a baby was likely in what is called “Group 2,” whereas the 1918 virus was in “Group 1.” Adolfo would therefore not be expected to have a good ability to respond to this “Group 1” virus. In fact, exposure to the “Group 2” virus as a young child may have resulted in a dysfunctional response to the “Group 1” virus in 1918, exacerbating his condition.

Support for this hypothesis was seen with the emergence of the Hong Kong flu virus in 1968. It was in “Group 2” and had severe effects on people who had been children around the time of the 1918 “Group 1” flu.

To 2018 and beyond

What causes a common recurring illness to convert to a pandemic that is massively lethal to healthy individuals? Could it happen again? Until the reason for the death of young adults in 1918 is better understood, a similar scenario could reoccur. Experts fear that a new pandemic, of influenza or another infectious agent, could kill millions. Bill Gates is leading the funding effort to prevent this.

Flu vaccines are generated each year by monitoring the strains circulating months before flu season. A time lag of months allows for vaccine production. Unfortunately, because the influenza virus mutates rapidly, the lag also allows for the appearance of virus variants that are poorly targeted by the vaccine. In addition, flu pandemics often arise upon virus gene reassortment. This involves the joining together of genetic material from different viruses, which can occur suddenly and unpredictably.

An influenza virus is currently killing chickens in Asia, and has recently killed humans who had contact with chickens. This virus is of a subtype that has not been known to cause pandemics. It has not yet demonstrated the ability to be transmitted from person to person. However, whether this ability will arise during ongoing virus evolution cannot be predicted.

The chicken virus is in “Group 2.” Therefore, if it went pandemic, people who were children around the time of the 1968 “Group 2” Hong Kong flu might have some protection. I was born much earlier, and “Group 1” viruses were circulating when I was a child. If the next pandemic virus is in “Group 2,” I would probably not be resistant.

It’s early days for understanding how prior exposure affects flu susceptibility, especially for people born in the last three to four decades. Since 1977, viruses of both “Group 1” and “Group 2” have been in circulation. People born since then probably developed resistance to one or the other based on their initial virus exposures. This is good news for the near future since, if either a “Group 1” or a “Group 2” virus develops pandemic potential, some people should be protected. At the same time, if you are under 40 and another pandemic is identified, more information would be needed to hazard a guess as to whether you might be susceptible or resistant.

This article was originally published on The Conversation.

Ruth Craig, Emerita Professor, Pharmacology and Toxicology, Dartmouth College

The princes in the Tower: why was their fate never explained?

A deafening silence surrounded the disappearance of Edward V and his brother, Richard, Duke of York. But why? As Leanda de Lisle writes, both Richard III and Henry Tudor had good reasons not to talk publicly about the princes.

This competition is now closed

Published: October 1, 2013 at 5:51 pm

An insecure king

A surviving prince?

The players in the princes’ downfall

Henry VI (1421–71)

Succeeding his father, Henry V, who died when he was a few months old, Henry VI’s reign was challenged by political and economic crises. It was interrupted by his mental and physical breakdown in 1453 during which time Richard, 3rd Duke of York, was appointed protector of the realm. Both men were direct descendants of Edward III and in 1455 Richard’s own claim to the throne resulted in the first clashes of the Wars of the Roses – fought between supporters of the dynastic houses of Lancaster and York over the succession.

Richard died at the battle of Wakefield in 1460 but his family claim to the throne survived him and his eldest son became king the following year – as Edward IV. Richard’s younger son would also be king, as Richard III. Henry VI was briefly restored to the throne in 1470 but the Lancastrians were finally defeated at Tewkesbury in 1471 and Henry was probably put to death in the Tower of London a few days later.

Edward IV (1442–83)

Edward succeeded where his father Richard, the third Duke of York failed – in overthrowing Henry VI during the Wars of the Roses. He was declared king in March 1461, securing his throne with a victory at the battle of Towton. Edward’s younger brother Richard became Duke of Gloucester. Later, in Edward’s second reign, Richard played an important role in government. Edward married Elizabeth Woodville in 1463 and they had 10 children: seven daughters and three sons. The eldest, Elizabeth, was born in 1466. Two of the three sons were alive at the time of Edward’s death – Edward, born in 1470, and Richard, born 1473. Edward is credited with being financially astute and restoring law and order. He died unexpectedly of natural causes on 9 April 1483.

Elizabeth, Queen Consort (c1437–92)

Edward IV’s marriage to Elizabeth Woodville, a widow with children, took place in secret in 1464 and met with political disapproval. The king’s brother, Richard, Duke of Gloucester, was among those allegedly hostile to it. The preference the Woodville family received caused resentment at court, and there was friction between Elizabeth’s family and the king’s powerful advisor, Hastings. On Edward IV’s death in 1483, Gloucester’s distrust of the Woodvilles was apparently a factor in his decision to seize control of the heir, his nephew. Elizabeth sought sanctuary in Westminster, from where her younger son, Richard, Duke of York, was later removed. The legitimacy of her marriage and her children was one of Gloucester’s justifications for usurping the throne on 26 June.

Once parliament confirmed his title as Richard III, Elizabeth submitted in exchange for protection for herself and her daughters – an arrangement he honoured. After Richard III’s death at the battle of Bosworth, her children were declared legitimate. Her eldest, Elizabeth of York, was married to Henry VII, strengthening his claim to the throne.

Edward V (1470–83) & Richard, Duke of York (1473–83)

Edward IV’s heir was his eldest son, also named Edward. When the king died unexpectedly, his will, which has not survived, reportedly named his previously loyal brother, Richard, Duke of Gloucester, as lord protector. On hearing of his father’s death, the young Edward and his entourage began a journey from Ludlow to the capital. Gloucester intercepted the party in Buckinghamshire. Gloucester, who claimed the Woodvilles were planning to take power by force, seized the prince.

On 4 May 1983, Edward entered London in the charge of Gloucester. Edward’s coronation was scheduled for 22 June. On 16 June, Elizabeth was persuaded to surrender Edward’s younger brother, Richard, apparently to attend the ceremony. With both princes in his hands, Gloucester publicised his claim to the throne. He was crowned as Richard III on 6 July and a conspiracy to rescue the princes failed that month. By September, rebels were seeing Henry Tudor as a candidate for the throne, suggesting the princes were already believed to be dead.

Richard III (1452–85)

Richard was the youngest surviving son of Richard, 3rd Duke of York, and was still a child when his 18-year-old brother became Edward IV after Yorkist victories. Unlike his brother George (executed for treason in the Tower in 1478 – allegedly drowned in a butt of malmsey wine), Richard was loyal to Edward during his lifetime. On his brother’s death, he moved swiftly to wrest control of his nephew Edward from the boy’s maternal family, the Woodvilles. At some point in June 1483 his role moved from that of protector to usurper. He arrested several of the previous king’s loyal advisors, postponed the coronation and claimed Edward IV’s children were illegitimate because their father had been pre-contracted to marry another woman at the time of his secret marriage to Elizabeth. Richard was crowned, but he faced rebellion that year and further unrest the next. Support for the king decreased as it grew for Henry Tudor, the rival claimant who returned from exile and triumphed at the battle of Bosworth in 1485.

Henry VII (1457–1509)

Henry Tudor was the son of Margaret Beaufort (great-great-granddaughter of Edward III) and Edmund Tudor, half-brother of Henry VI. In 1471, after Edward IV regained the throne, Henry fled to Brittany, where he avoided the king’s attempts to have him returned. As a potential candidate for the throne through his mother’s side, Henry became the focus for opposition to Richard III. After the failed 1483 rebellion against the king, rebels, including relatives of the Woodvilles and loyal former members of Edward IV’s household, joined him in Brittany. In 1485 Henry Tudor invaded, landing first in Wales, and triumphed over Richard III at Bosworth on 22 August.

Henry was crowned on the battlefield with Richard’s crown. The following year he further legitimised his right to rule by marrying Elizabeth of York. When the king died in 1509, his and Elizabeth’s son came to the throne as Henry VIII.

The 1918 flu and World War I

Certificates picturing the goddess Columbia as a personification of the U.S. were awarded to men and women who died in service during World War I. One such certificate surfaced many decades later. This one honored Adolfo Sartini and was found by grandnephews who had never known him: Thomas, Richard and Robert Sartini.

The certificate was a message from the past. It called out to me, as I had just received the credential of certified genealogist and had spent most of my career as a scientist tracing a gene that regulates immune cells. What had happened to Adolfo?

A bit of sleuthing identified Adolfo’s ship listing, which showed that he was born in 1889 in Italy and immigrated to Boston in 1913. His draft card revealed that he worked at a country club in the Boston suburb of Newton. To learn more, Robert Sartini bought a 1930 book entitled “Newton War Memorial” on eBay. The book provided clues: Adolfo was drafted and ordered to report to Camp Devens, 35 miles from Boston, in March of 1918. He was later transferred to an engineer training regiment.

To follow up, I posted a query on the “U.S. Militaria Forum.” Here, military history enthusiasts explained that the Army Corps of Engineers had trained men at Camp A. A. Humphreys in Virginia. Perhaps Adolfo had gone to this camp?

While a mild flu circulated during the spring of 1918, the deadly strain appeared on U.S. soil on Tuesday, Aug. 27, when three Navy dockworkers at Commonwealth Pier in Boston fell ill. Within 48 hours, dozens more men were infected. Ten days later, the flu was decimating Camp Devens. A renowned pathologist from Johns Hopkins, William Welch, was brought in. He realized that “this must be some new kind of infection or plague.” Viruses, minuscule agents that can pass through fine filters, were poorly understood.

With men mobilizing for World War I, the flu spread to military installations throughout the U.S. and to the general population. It hit Camp Humphreys in mid-September and killed more than 400 men there over the next month. This included Adolfo Sartini, age 29½. Adolfo’s body was brought back to Boston.

His grave is marked by a sculpture of the lower half of a toppled column, epitomizing his premature death.

The life expectancy myth, and why many ancient humans lived long healthy lives

It is not uncommon to hear talk about how lucky we are to live in this age of scientific and medical advancement where antibiotics and vaccinations keep us living longer, while our poor ancient ancestors were lucky to live past the age of 35. Well this is not quite true. At best, it oversimplifies a complex issue, and at worst it is a blatant misrepresentation of statistics. Did ancient humans really just drop dead as they were entering their prime, or did some live long enough to see a wrinkle on their face?

According to historical mortality levels from the Encyclopaedia of Population (2003), average life expectancy for prehistoric humans was estimated at just 20 – 35 years in Sweden in the 1750s it was 36 years it hit 48 years by the 1900s in the USA and in 2007 in Japan, average life expectancy was 83 years. It would appear that as time went on, conditions improved and so did the length of people’s lives. But it is not so simple.

What is commonly known as ‘average life expectancy’ is technically ‘life expectancy at birth’. In other words, it is the average number of years that a newborn baby can expect to live in a given society at a given time. But life expectancy at birth is an unhelpful statistic if the goal is to compare the health and longevity of adults. That is because a major determinant of life expectancy at birth is the child mortality rate which, in our ancient past, was extremely high, and this skews the life expectancy rate dramatically downward.

The early years from infancy through to about 15 was perilous, due to risks posed by disease, injuries, and accidents. But those who survived this hazardous period of life could well make it into old age.

Drawing upon archaeological records, we can indeed see evidence of this. The "Old Man of La Chapelle", for example, is the name given to the remains of a Neanderthal who lived 56,000 years ago, found buried in the limestone bedrock of a small cave near La Chapelle-aux-Saints, in France in 1908. Scientists estimate that he had reached old age by the time he died, as bone had re-grown along the gums where he had lost several teeth, perhaps decades before. He lacked so many teeth in fact that scientists suspect he needed his food ground down before he was able to eat it. The old man's skeleton indicates that he also suffered from a number of afflictions, including arthritis.

Facial reconstruction from the skull of ‘The Old Man of La Chapelle’. Photo source .

If we look again at the estimated maximum life expectancy for prehistoric humans, which is 35 years, we can see that this does not mean that the average person living at this time died at the age of 35. Rather, it means that for every child that died in infancy, another person might have lived to be 70. The life expectancy statistic is, therefore, a deeply flawed way to think about the quality of life of our ancient ancestors.

So is modern society more beneficial for health and longevity than, say, the hunter-gatherer lifestyle? To help gain an answer to this question, scientists have compared the life span of adults in contemporary hunter-gatherer tribes (excluding the infant mortality rate). It was found that once infant mortality rates were removed, life span was calculated to between 70 and 80 years, the same rate as that found in contemporary industrialised societies. The difference is that, in the latter, most individuals survive childhood (Kanazawa, 2008).

It is certainly true that improvements in food availability, hygiene, nursing care, medical treatments, and cultural innovations have resulted in far fewer deaths caused by external injuries, infections, and epidemics, but on the other hand, we face a global cancer crisis that our ancient ancestors never had to contend with on such a scale. Are we just replacing one form of death with another?

A summary of major causes of death over time. S. Horiuchi, in United NaEons, Health and Mortality: Issues of Global Concern, 1999

Archaeologists and anthropologists face a real challenge in trying to unravel reliable information about the age structure of ancient populations, largely due to the lack of a sufficient number ancient samples, as well as the difficulties in determining exact age. Nevertheless, we can safely say that our ancient ancestors were not dropping dead at 35, and some would have even been blessed with long and healthy lives.

What was the average marriage age for people living in the Middle Ages?

More specifically, did girl's truly marry as young as 13 or 12 years old? Were boys pressured to marry young as well as girls, or was it for adults only?

My answer concerns Western European Christians in the later Middle Ages.

As you might expect, the answer varies depending on gender, time, place, and social class. Generally speaking: girls marry younger than boys, upper class girls marry younger than middle and lower class ones, marriage age for both girls and boys creeps upward towards the end of the Middle Ages, the most systematized example of girls marrying super-young like you cite is late medieval Italy, and economic considerations are a big driver of these trends.

Canon law following Gratian (12th century) set the lower limit on marriage at 12 for girls, 14 for boys. This didn't actually mean priests never married younger people: in 1364, Alice de Routclif of York was either ten or eleven when she married John Marrays (whose age is not noted). What it did mean, however, was that if a particular partnership came under dispute later--as did Alice and John's union, from one of Alice's male relatives--a Church court (which were in charge of marriage law) would have real grounds to annul the marriage. As a result, 12 and 14 remained frequently observed lower boundaries on marriage age. Although the licit betrothal age of 7 was, shall we say, flexible (with the Church's intention that parents could betrothe their children all they wanted, but when the kid reached the age of consent, he or she could break off the potential marriage if desired. Yes, this was absolutely a power struggle between the Church and secular nobility.)

Beyond the very highest levels of royalty and nobility, typical marriage age was very tied to economic circumstances. The two most important were a woman's dowry and a man's ability to support his family. (Lower and middle class women certainly worked, but typically in support of their husband's occupation and sometimes with work on the side, such as brewing ale for market instead of just for their own household). I'll talk about a couple different ways each of those factors could play out.

In northern cities, young men needed to be able to work on their own to support their family before they could be married. For the artisan class, this meant having moved beyond apprenticeship status in their profession agricultural peasants should generally have been able to form their own household. As guilds grew more powerful and flexed their ability to regulate the honing of their craft, the age for journeyman status increased from fourteen to eighteen. Thus the typical lower bound of marriage age for artisan-level boys also rose, with many not marrying right away so as to establish themselves with a bit more money first.

In Italy--urban and rural alike, although the pattern is much sharper in the cities--men tended to remain in their fathers' households much longer. While they would often get married eventually, still living in their natal home, they tended to delay marriage further due to inheritance laws. Staying single would held preserve their father's--the family's--patrimony (wealth and holdings) intact, increasing everyone's social status. That practice heavily favored late age of first marriage for Italian men.

Dowry concerns played a big role in regulating age of marriage for girls. Lower and middle class women in northern Europe, and to a much lesser extent Italy, frequently spent quite some time working to build up their dowry before marriage--to make themselves a more attractive partner, or simply to make the rest of their life more economicall comfortable. We don't have good demographics, unfortunately, but apparently it was fairly standard by the fifteenth into the sixteenth century for girls to spend a period of time working as domestic servants (to wealthy peasant families as well as noble one) to earn themselves a dowry. This pushed the typical marriage age for girls increasingly later--almost approaching the same early/mid-20s average marriage age of men.

Upper-class Italy, though, is the case you're thinking about of systematic early marriage for girls, OP. Social norms and economic concerns pushed the "desirable" age of first marriage for girls as low as legally licit. We can track this by dowry statistics: the older his daughter was at marriage, the bigger the dowry the father would have to provide. (While the dowry was technically the daughter's inheritance, it was legally controlled by the paterfamilias of the household she moved into, typically her father-in-law's).

In fact, some Italian cities were quite concerned to get women married and reproducing (although it may seem odd to us thinking about the Renaissance, late medieval Italian cities perpetually perceived themselves as experiencing a demographic crisis of rapidly falling population). Florence famously established the Monte delle dotti--think of today's "college fund" where parents invest a certain amount each year that accrues interests to help fund higher education, except the purpose was to ensure girls would have an acceptable dowry. Oh, yeah, and did I mention how fathers would lie about their daughters' ages on this 'marriage market', to make them appear younger and thus more desirable prospects? Yup.

In Italy as north of the Alps, however, social class played a mitigating factor. Lower class Italian women, like their German and English counterparts, would increasingly spend some time as a domestic servant before marriage, raising their marriage age. One presumes that in both the north and Mediterranean, rural girls were also more economically productive to their natal households--i.e. helping on farm--making it more financially desirable for their parents to keep them around longer.

Framing marriage age in such stark economic terms does have a way of painting medieval parents as callous and money-driven at the expense of actually caring about their children. It's important to point out that parents' actions, within the socio-economic system set up, actually demonstrated deep concern for their children's well-being. For example, when a father manipulated records of his daughter's age to secure her the best marriage match, or was willing to pay a higher dowry for an older daughter, that's still a sign that he wanted the best future he could get for her. It does not necessarily mean an older daughter was a burden he was willing to pay extra to be rid of.

And there is one final factor to consider in the Italian situation in particular. Gratian set the lower marriage ages to 12 and 14 based on the idea that girls and boys were then intellectually able to understand and consent to marriage. (Earlier medieval writers had used the same ages, but with respect to physical puberty.) The eventual acceptance of this standard marks a watershed in the definition of what made a marriage: from consummation to consent. However, the significance of consummation never really died out, especially in Italy. As a result, to protect their ability to control the dowry after marriage, new husbands' families would insist upon immediate consummation of the marriage--as in, in the bride's home, right after the ceremony was performed. When twelve-year-olds faced the prospect of marrying thirty-year-olds, it's no wonder some parents were willing to lie about their daughter's age.

Suicides peak in middle age. So why do we call it a young person’s tragedy?

While we most often think of suicide as a tragedy of the young it’s their parents’ generation who seem most at risk.

The Office for National Statistics (ONS) released its annual summary of data on deaths by suicide in the UK recently – in the run-up to World Suicide Prevention Day – and the data shows that in 2016 people aged between 40 and 44 had the highest prevalence of suicide, a rate of 15.1 deaths per 100,000 people. Split by gender, the highest prevalence was for men aged 40 to 44 (23.7 deaths per 100,000 in 2016) and women between the ages 50 and 54 (6.4 deaths per 100,000 in 2016).

How we view and understand suicide is shaped by who we think is important. The narrative of suicide as the lost potential of a life yet to be lived is strong because it comforts us even as it fills us with sadness. With the horrible loss of young people, we are confident in our assertion that things could have been better if they had stayed around. With adults, we are less convinced. Young suicides are politically blameless in a way that adult ones are not.

At present, British society is uncomfortable with making the individual tragedies of suicide into a case for collective change. Considering suicide as a problem of the young allows us to tell ourselves a simplified story where despair is a passing personal crisis rather than an endemic condition. We want suicide to be related to naivety and immaturity and to excessive emotional acting out. We want those who die to be worthy and innocent victims, not imperfect, multifaceted beings negotiating complex personal, social, economic and political factors.

The idea of suicide offends and disturbs so much we will do almost anything to defuse it of its power. In the UK it was illegal until 1961. This legacy lives on as a ghost in the phrase “committed suicide”.

Popular rhetoric is always looking for clean and simple stories. We want so much to focus on prevention in mental health that we can sometimes ignore the people who already have problems. Middle-aged people are wrestling with the same social and economic changes as young people, often in situations where there will be no grand change for the better in the future.

In their Men on the Ropes campaign, which began in 2010, the Samaritans focus explicitly upon making contact with men over the age of 25, noting that “men from poorer backgrounds, those who are unemployed or in manual jobs, and those who have experienced difficult times such as financial worries or breakdowns in their family relationships were more likely to take their own lives”.

There is no similar campaign for women in their 50s.

In his book Why People Die By Suicide,Thomas Joiner, a psychologist, identifies common factors in those with suicidal feelings who are most at risk: a sense of disconnection from others a lack of belonging a belief they have become a burden to those around them and the ability to overcome the instinct to self-preservation and harm themselves, combined with knowing suicide techniques.

The zero suicide approach gaining traction in the UK is a shift from accepting that suicide for some people may be inevitable and impossible to catch in time. It is an aspiration to build structures and services to prevent every suicide, ending a public services culture where people don’t ask and people don’t always feel comfortable to say.

Disturbing Execution Methods From The Middle Ages

All right, so this is an article about extremely disturbing execution methods of the Middle Ages, a period that lasted in Europe from around the 5th to the 15th centuries. Be advised that the methods outlined below are truly horrific and awful, and some of you may simply not want these ideas to occupy space in your brains. That’s OK you can go read something else. (Here’s an awesome article about puppies. You’re welcome.) But I know that many of you saw the title of this article and thought, “YES. I will click on that. Old-school torture and execution sounds fascinating.” I know, because that’s precisely the reaction I would have.

I feel like, in a perfect world, we would study these centuries-old execution methods purely as cautionary tales about the potential of human cruelty, as distasteful, but useful examples of what happens when you give people too much power over the bodies and lives of others. But the truth is, people enjoy finding out about torture methods, and murder, and the horrible things that can happen to the human body. That enjoyment, that weird feeling of simultaneous repulsion and fascination, is why we watch gratuitously gruesome forensic shows (ahem, Bones ), and it’s why people are still obsessed with Jack the Ripper 127 years after the Whitechapel Murders, and it’s why people went to see all those awful Saw movies .

Why do people (and I’m including myself here) like this stuff? Is it because, by looking at the cruelty of the Middle Ages, we somehow absolve ourselves of the violence of our own time? Does learning about archaic torture methods satisfy some deep, lizard brain desire for carnage? Are we drawn in by the transgression of physical boundaries when the body is torn apart? And does the fact that these execution methods are centuries old somehow make them approachable, or comprehensible, in a way they wouldn’t be if they were practiced today? I’M ASKING.

Read on for 7 disturbingly creative ways that people killed other people in the Middle Ages. Er … enjoy? (Is that what we’re calling it?)

1. Sawing

In this method of execution, victims were sawn in half lengthwise, from groin to head or head to groin. If a victim was tied upside down, as in the image above, blood would stay in the head and chest, and it could take several hours for him or her to finally die.

2. Judas Cradle

The Judas Cradle was a torture device that looked like a pyramid on a stool. Victims would have the pointed end inserted into their orifices (anus or vagina), and then they would be pressed onto the device. The Judas Cradle would kill victims either through impalement, or through causing so much muscle and tissue damage that the victim would become septic and die.

3. Breaking Wheel

The breaking wheel was used as a form of capital punishment during the medieval period. Victims would be strapped across the wheel, and then pummeled with iron cudgels to break their bones. After being “broken,” they would be left out to die, which could take a matter of days.

4. Burning at the Stake

Burning at the stake is a very old, very painful way to kill people. In medieval Europe, burning at the stake was a common way to execute heretics. A bit later, in the Early Modern period, this method would be a common execution route for witches.

5. Flaying alive

Flaying people alive (stripping off their skin) is an ancient method of torture and execution that was used long past the Middle Ages. During the Middle Ages, the method was used to punish witches, criminals, and traitors.

6. Hanged, Drawn, and Quartered

A medieval punishment for high treason, hanging, drawing, and quartering involved having the victim first tied to a horse and dragged to the site of execution. Then he would be hanged almost to the point of death, then, while still alive, disemboweled. After burning his entrails, executioners would finally behead the victim and quarter the body (i.e., cutting or pulling it into four pieces).

7. The Head Crusher

The head crusher is exactly what it sounds like: a torture device that worked by crushing the skull. Used as a way to extract confessions, the crusher would slowly and painfully press the jaw and crown of the head toward each other, breaking the jaw, teeth, and facial bones and squeezing the eyes out of the sockets. If the victim wasn’t killed, he or she could nevertheless suffer from permanent bone and brain damage.

OK, so now that we are all completely disturbed, let’s take a moment to clear our minds and look at puppies:


Jeffery K. Taubenberger 4

Department of Molecular Pathology

Armed Forces Institute of Pathology


Influenza A viruses are negative strand RNA viruses of the genus Orthomyxoviridae. They continually circulate in humans in yearly epidemics (mainly in the winter in temperate climates) and antigenically novel virus strains emerge sporadically as pandemic viruses (Cox and Subbarao, 2000). In the United States, influenza is estimated to kill 30,000 people in an average year (Simonsen et al., 2000 Thompson et al., 2003). Every few years, a more severe influenza epidemic occurs, causing a boost in the annual number of deaths past the average, with 10,000 to 15,000 additional deaths. Occasionally, and unpredictably, influenza sweeps the world, infecting 20 to 40 percent of the population in a single year. In these pandemic years, the numbers of deaths can be dramatically above average. In 1957�, a pandemic was estimated to cause 66,000 excess deaths in the United States (Simonsen et al., 1998). In 1918, the worst pandemic in recorded history was associated with approximately 675,000 total deaths in the United States (U.S. Department of Commerce, 1976) and killed at least 40 million people worldwide (Crosby, 1989 Patterson and Pyle, 1991 Johnson and Mueller, 2002).

Influenza A viruses constantly evolve by the mechanisms of antigenic drift and shift (Webster et al., 1992). Consequently they should be considered emerging infectious disease agents, perhaps 𠇌ontinually” emerging pathogens. The importance of predicting the emergence of new circulating influenza virus strains for subsequent annual vaccine development cannot be underestimated (Gensheimer et al., 1999). Pandemic influenza viruses have emerged three times in this century: in 1918 (“Spanish” influenza, H1N1), in 1957 (𠇊sian” influenza, H2N2), and in 1968 (“Hong Kong” influenza, H3N2) (Cox and Subbarao, 2000 Webby and Webster, 2003). Recent circulation of highly pathogenic avian H5N1 viruses in Asia from 1997 to 2004 has caused a small number of human deaths (Claas et al., 1998 Subbarao et al., 1998 Tran et al., 2004 Peiris et al., 2004). How and when novel influenza viruses emerge as pandemic virus strains and how they cause disease is still not understood.

Studying the extent to which the 1918 influenza was like other pandemics may help us to understand how pandemic influenzas emerge and cause disease in general. On the other hand, if we determine what made the 1918 influenza different from other pandemics, we may use the lessons of 1918 to predict the magnitude of public health risks a new pandemic virus might pose.

Origin of Pandemic Influenza Viruses

The predominant natural reservoir of influenza viruses is thought to be wild waterfowl (Webster et al., 1992). Periodically, genetic material from avian virus strains is transferred to virus strains infectious to humans by a process called reassortment. Human influenza virus strains with recently acquired avian surface and internal protein-encoding RNA segments were responsible for the pandemic influenza outbreaks in 1957 and 1968 (Scholtissek et al., 1978a Kawaoka et al., 1989). The change in the hemagglutinin subtype or the hemagglutinin (HA) and the neuraminidase (NA) subtype is referred to as antigenic shift. Because pigs can be infected with both avian and human virus strains, and various reassortants have been isolated from pigs, they have been proposed as an intermediary in this process (Scholtissek, 1994 Ludwig et al., 1995). Until recently there was only limited evidence that a wholly avian influenza virus could directly infect humans, but in 1997 18 people were infected with avian H5N1 influenza viruses in Hong Kong, and 6 died of complications after infection (Claas et al., 1998 Subbarao et al., 1998 Scholtissek, 1994 Ludwig et al., 1995). Although these viruses were very poorly transmissible or non-transmissible (Claas et al., 1998 Subbarao et al., 1998 Scholtissek, 1994 Ludwig et al., 1995 Katz et al., 1999), their isolation from infected patients indicates that humans can be infected with wholly avian influenza virus strains. In 2003�, H5N1 outbreaks in poultry have become widespread in Asia (Tran et al., 2004), and at least 32 people have died of complications of infection in Vietnam and Thailand (World Health Organization, 2004). In 2003, a highly pathogenic H7N7 outbreak occurred in poultry farms in The Netherlands. This virus caused infections (predominantly conjunctivitis) in 86 poultry handlers and 3 secondary contacts. One of the infected individuals died of pneumonia (Fouchier et al., 2004 Koopmans et al., 2004 World Health Organization, 2004). In 2004, an H7N3 influenza outbreak in poultry in Canada also resulted in the infection of a single individual (World Health Organization, 2004), and a patient in New York was reported to be sick following infection with an H7N2 virus (Lipsman, 2004). Therefore, it may not be necessary to invoke swine as the intermediary in the formation of a pandemic virus strain because reassortment between an avian and a human influenza virus could take place directly in humans.

While reassortment involving genes encoding surface proteins appears to be a critical event for the production of a pandemic virus, a significant amount of data exists to suggest that influenza viruses must also acquire specific adaptations to spread and replicate efficiently in a new host. Among other features, there must be functional HA receptor binding and interaction between viral and host proteins (Weis et al., 1988). Defining the minimal adaptive changes needed to allow a reassortant virus to function in humans is essential to understanding how pandemic viruses emerge.

Once a new virus strain has acquired the changes that allow it to spread in humans, virulence is affected by the presence of novel surface protein(s) that allow the virus to infect an immunologically naïve population (Kilbourne, 1977). This was the case in 1957 and 1968 and was almost certainly the case in 1918. While immunological novelty may explain much of the virulence of the 1918 influenza, it is likely that additional genetic features contributed to its exceptional lethality. Unfortunately not enough is known about how genetic features of influenza viruses affect virulence. The degree of illness caused by a particular virus strain, or virulence, is complex and involves host factors like immune status, and viral factors like host adaptation, transmissibility, tissue tropism, or viral replication efficiency. The genetic basis for each of these features is not yet fully characterized, but is most likely polygenic in nature (Kilbourne, 1977).

Prior to the analyses on the 1918 virus described in this review, only two pandemic influenza virus strains were available for molecular analysis: the H2N2 virus strain from 1957 and the H3N2 virus strain from 1968. The 1957 pandemic resulted from the emergence of a reassortant influenza virus in which both HA and NA had been replaced by gene segment closely related to those in avian virus strains (Scholtissek et al., 1978b Schafer et al., 1993 Webster et al., 1995). The 1968 pandemic followed with the emergence of a virus strain in which the H2 subtype HA gene was exchanged with an avian-derived H3 HA RNA segment (Scholtissek et al., 1978b Webster et al., 1995), while retaining the N2 gene derived in 1957. More recently it has been shown that the PB1 gene was replaced in both the 1957 and the 1968 pandemic virus strains, also with a likely avian derivation in both cases (Kawaoka et al., 1989). The remaining five RNA segments encoding the PA, PB2, nucleoprotein, matrix and non-structural proteins, all were preserved from the H1N1 virus strains circulating before 1957. These segments were likely the direct descendants of the genes present in the 1918 virus. Because only the 1957 and 1968 influenza pandemic virus strains have been available for sequence analysis, it is not clear what changes are necessary for the emergence of a virus strain with pandemic potential. Sequence analysis of the 1918 influenza virus allows us potentially to address the genetic basis of virulence and human adaptation.

Historical Background

The influenza pandemic of 1918 was exceptional in both breadth and depth. Outbreaks of the disease swept not only North America and Europe, but also spread as far as the Alaskan wilderness and the most remote islands of the Pacific. It has been estimated that one-third of the world's population may have been clinically infected during the pandemic (Frost, 1920 Burnet and Clark, 1942). The disease was also exceptionally severe, with mortality rates among the infected of more than 2.5 percent, compared to less than 0.1 percent in other influenza epidemics (Marks and Beatty, 1976 Rosenau and Last, 1980). Total mortality attributable to the 1918 pandemic was probably around 40 million (Crosby, 1989 Johnson and Mueller, 2002 Patterson and Pyle, 1991).

Unlike most subsequent influenza virus strains that have developed in Asia, the 𠇏irst wave” or “spring wave” of the 1918 pandemic seemingly arose in the United States in March 1918 (Barry, 2004 Crosby, 1989 Jordan, 1927). However, the near simultaneous appearance of influenza in March𠄺pril 1918 in North America, Europe, and Asia makes definitive assignment of a geographic point of origin difficult (Jordan, 1927). It is possible that a mutation or reassortment occurred in the late summer of 1918, resulting in significantly enhanced virulence. The main wave of the global pandemic, the �ll wave” or “second wave,” occurred in September–November 1918. In many places, there was yet another severe wave of influenza in early 1919 (Jordan, 1927).

Three extensive outbreaks of influenza within 1 year is unusual, and may point to unique features of the 1918 virus that could be revealed in its sequence. Interpandemic influenza outbreaks generally occur in a single annual wave in the late winter. The severity of annual outbreaks is affected by antigenic drift, with an antigenically modified virus strain emerging every 2 to 3 years. Even in pandemic influenza, while the normal late winter seasonality may be violated, the successive occurrence of distinct waves within a year is unusual. The 1890 pandemic began in the late spring of 1889 and took several months to spread throughout the world, peaking in northern Europe and the United States late in 1889 or early 1890. The second wave peaked in spring 1891 (over a year after the first wave) and the third wave in early 1892 (Jordan, 1927). As in 1918, subsequent waves seemed to produce more severe illness so that the peak mortality was reached in the third wave of the pandemic. The three waves, however, were spread over more than 3 years, in contrast to less than 1 year in 1918. It is unclear what gave the 1918 virus this unusual ability to generate repeated waves of illness. Perhaps the surface proteins of the virus drifted more rapidly than other influenza virus strains, or perhaps the virus had an unusually effective mechanism for evading the human immune system.

The influenza epidemic of 1918 killed an estimated 675,000 Americans, including 43,000 servicemen mobilized for World War I (Crosby, 1989). The impact was so profound as to depress average life expectancy in the United States by more than 10 years (Grove and Hetzel, 1968) (Figure 1-1) and may have played a significant role in ending the World War I conflict (Crosby, 1989 Ludendorff, 1919).


Life expectancy in the United States, 1900�, showing the impact of the 1918 influenza pandemic. SOURCES: U.S. Department of Commerce (1976) Grove and Hetzel (1968) Linder and Grove (1943).

Many individuals who died during the pandemic succumbed to secondary bacterial pneumonia (Jordan, 1927 LeCount, 1919 Wolbach, 1919) because no antibiotics were available in 1918. However, a subset died rapidly after the onset of symptoms often with either massive acute pulmonary hemorrhage or pulmonary edema, often in less than 5 days (LeCount, 1919 Winternitz et al., 1920 Wolbach, 1919). In the hundreds of autopsies performed in 1918, the primary pathologic findings were confined to the respiratory tree and death was due to pneumonia and respiratory failure (Winternitz et al., 1920). These findings are consistent with infection by a well-adapted influenza virus capable of rapid replication throughout the entire respiratory tree (Reid and Taubenberger, 1999 Taubenberger et al., 2000). There was no clinical or pathological evidence for systemic circulation of the virus (Winternitz et al., 1920).

Furthermore, in the 1918 pandemic most deaths occurred among young adults, a group that usually has a very low death rate from influenza. Influenza and pneumonia death rates for 15- to 34-year-olds were more than 20 times higher in 1918 than in previous years (Linder and Grove, 1943 Simonsen et al., 1998) (Figure 1-2). The 1918 pandemic is also unique among influenza pandemics in that absolute risk of influenza mortality was higher in those younger than age 65 than in those older than 65. Strikingly, persons less than 65 years old accounted for more than 99 percent of all excess influenza-related deaths in 1918� (Simonsen et al., 1998). In contrast, the less-than-65 age group accounted for only 36 percent of all excess influenza-related mortality in the 1957 H2N2 pandemic and 48 percent in the 1968 H3N2 pandemic. Overall, nearly half of the influenza-related deaths in the 1918 influenza pandemic were young adults aged 20 to 40 (Simonsen et al., 1998) (Figure 1-2). Why this particular age group suffered such extreme mortality is not fully understood (see below).


Influenza and pneumonia mortality by age, United States. Influenza and pneumonia specific mortality by age, including an average of the interpandemic years 1911� (dashed line), and the pandemic year 1918 (solid line). Specific death rate is (more. )

The 1918 influenza had another unique feature: the simultaneous infection of both humans and swine. Interestingly, swine influenza was first recognized as a clinical entity in that species in the fall of 1918 (Koen, 1919) concurrently with the spread of the second wave of the pandemic in humans (Dorset et al., 1922�). Investigators were impressed by clinical and pathological similarities of human and swine influenza in 1918 (Koen, 1919 Murray and Biester, 1930). An extensive review by the veterinarian W.W. Dimoch of the diseases of swine published in August 1918 makes no mention of any swine disease resembling influenza (Dimoch, 1918�). Thus, contemporary investigators were convinced that influenza virus had not circulated as an epizootic disease in swine before 1918 and that the virus spread from humans to pigs because of the appearance of illness in pigs after the first wave of the 1918 influenza in humans (Shope and Lewis, 1931).

Thereafter the disease became widespread among swine herds in the U.S. midwest. The epizootic of 1919� was as extensive as in 1918�. The disease then appeared among swine in the midwest every year, leading to Shope's isolation of the first influenza virus in 1930, A/swine/ Iowa/30 (Shope and Lewis, 1931), 3 years before the isolation of the first human influenza virus, A/WS/33 by Smith, Andrewes, and Laidlaw (Smith et al., 1933). Classical swine viruses have continued to circulate not only in North American pigs, but also in swine populations in Europe and Asia (Brown et al., 1995 Kupradinun et al., 1991 Nerome et al., 1982).

During the fall and winter of 1918�, severe influenza-like outbreaks were noted not only in swine in the United States, but also in Europe and China (Beveridge, 1977 Chun, 1919 Koen, 1919). Since 1918 there have been many examples of both H1N1 and H3N2 human influenza A virus strains becoming established in swine (Brown et al., 1998 Castrucci et al., 1993 Zhou et al., 2000), while swine influenza A virus strains have been isolated only sporadically from humans (Gaydos et al., 1977 Woods et al., 1981).

The unusual severity of the 1918 pandemic and the exceptionally high mortality it caused among young adults have stimulated great interest in the influenza virus strain responsible for the 1918 outbreak (Crosby, 1989 Kolata, 1999 Monto et al., 1997). Because the first human and swine influenza A viruses were not isolated until the early 1930s (Shope and Lewis, 1931 Smith et al., 1933), characterization of the 1918 virus strain previously has had to rely on indirect evidence (Kanegae et al., 1994 Shope, 1958).

Serology and Epidemiology of the 1918 Influenza Virus

Analyses of antibody titers of 1918 influenza survivors from the late 1930s suggested correctly that the 1918 virus strain was an H1N1-subtype influenza A virus, closely related to what is now known as 𠇌lassic swine” influenza virus (Dowdle, 1999 Philip and Lackman, 1962 Shope, 1936). The relationship to swine influenza is also reflected in the simultaneous influenza outbreaks in humans and pigs around the world (Beveridge, 1977 Chun, 1919 Koen, 1919). Although historical accounts described above suggest that the virus spread from humans to pigs in the fall of 1918, the relationship of these two species in the development of the 1918 influenza has not been resolved.

Which influenza A subtype(s) circulated before the 1918 pandemic is not known for certain. In a recent review of the existing archaeoserologic and epidemiologic data, Walter Dowdle concluded that an H3-subtype influenza A virus strain circulated from the 1889� pandemic to 1918, when it was replaced by the novel H1N1 virus strain of the 1918 pandemic (Dowdle, 1999).

It is reasonable to conclude that the 1918 virus strain must have contained a hemagglutinin gene encoding a novel subtype such that large portions of the population did not have protective immunity (Kilbourne, 1977 Reid and Taubenberger, 1999). In fact, epidemiological data collected between 1900 and 1918 on influenza prevalence by age in the population provide good evidence for the emergence of an antigenically novel influenza virus in 1918 (Jordan, 1927). Jordan showed that from 1900 to 1917, the 5 to 15 age group accounted for 11 percent of total influenza cases in this series while the 㹥 age group similarly accounted for 6 percent of influenza cases. In 1918 the 5- to 15-year-old group jumped to 25 percent of influenza cases, compatible with exposure to an antigenically novel virus strain. The 㹥 age group only accounted for 0.6 percent of the influenza cases in 1918. It is likely that this age group accounted for a significantly lower percentage of influenza cases because younger people were so susceptible to the novel virus strain (as seen in the 1957 pandemic [Ministry of Health, 1960 Simonsen et al., 1998]), but it is also possible that this age group had pre-existing H1 antibodies. Further evidence for pre-existing H1 immunity can be derived from the age-adjusted mortality data in Figure 1-2. Those individuals 㹵 years had a lower influenza and pneumonia case mortality rate in 1918 than they had for the prepandemic period of 1911�.

When 1918 influenza case rates by age (Jordan, 1927) are superimposed on the familiar “W”-shaped mortality curve (seen in Figure 1-2), a different perspective emerges (Figure 1-3). As shown, those 㰵 years of age in 1918 accounted for a disproportionately high influenza incidence by age. Interestingly, the 5 to 14 age group accounted for a large fraction of 1918 influenza cases, but had an extremely low case mortality rate compared to other age groups (Figure 1-3). Why this age group had such a low case fatality rate cannot yet be fully explained. Conversely, why the 25 to 34 age group had such a high influenza and pneumonia mortality rate in 1918 remains enigmatic, but it is one of the truly unique features of the 1918 influenza pandemic.


Influenza and pneumonia mortality by age (solid line), with influenza morbidity by age (dashed line) superimposed. Influenza and pneumonia mortality by age as in Figure 1-2. Specific death rate per age group, left ordinal axis. Influenza morbidity presented (more. )

One theory that may explain these data concerns the possibility that the virus had an intrinsically high virulence that was only tempered in those patients who had been born before 1889. It can be speculated that the virus circulating prior to 1889 was an H1-like virus strain that provided partial protection against the 1918 virus strain (Ministry of Health, 1960 Simonsen et al., 1998 Taubenberger et al., 2001). Short of this cross-protection in patients older than 29 years of age, the pandemic of 1918 might have been even more devastating (Zamarin and Palese, 2004). A second possibility remains that the high mortality of young adults in the 20 to 40 age group may have been a consequence of immune enhancement in this age group. Currently, however, the absence of pre-1918 human influenza samples and the lack of pre-1918 sera samples for analysis makes it impossible to test this hypothesis.

Thus, it seems clear that the H1N1 virus of the 1918 pandemic contained an antigenically novel hemagglutinin to which most humans and swine were susceptible in 1918. Given the severity of the pandemic, it is also reasonable to suggest that the other dominant surface protein, NA, also would have been replaced by antigenic shift before the start of the pandemic (Reid and Taubenberger, 1999 Taubenberger et al., 2000). In fact, sequence and phylogenetic analyses suggest that the genes encoding these two surface proteins were derived from an avian-like influenza virus shortly before the start of the 1918 pandemic and that the precursor virus did not circulate widely in either humans or swine before 1918 (Fanning et al., 2002 Reid et al., 1999, 2000) (Figure 1-4). It is currently unclear what other influenza gene segments were novel in the 1918 pandemic virus in comparison to the previously circulating virus strain. It is possible that sequence and phylogenetic analyses of the gene segments of the 1918 virus may help elucidate this question.


Phylogenetic tree of the influenza virus hemagglutinin gene segment. Amino acid changes in three lineages of the influenza virus hemagglutinin protein segment, HA1. The tree shows the numbers of unambiguous changes between these sequences, with branch (more. )

Genetic Characterization of the 1918 Virus

Sequence and Functional Analysis of the Hemagglutinin and Neuraminidase Gene Segments

Samples of frozen and fixed lung tissue from five second-wave influenza victims (dating from September 1918 to February 1919) have been used to examine directly the genetic structure of the 1918 influenza virus. Two of the cases analyzed were U.S. Army soldiers who died in September 1918, one in Camp Upton, New York, and the other in Fort Jackson, South Carolina. The available material consists of formalin-fixed, paraffin-embedded autopsy tissue, hematoxylin and eosin-stained microscopic sections, and the clinical histories of these patients. A third sample was obtained from an Alaskan Inuit woman who had been interred in permafrost in Brevig Mission, Alaska, since her death from influenza in November 1918. The influenza virus sequences derived from these three cases have been called A/ South Carolina/1/18 (H1N1), A/New York/1/18 (H1N1), and A/Brevig Mission/1/18 (H1N1), respectively. To date, five RNA segment sequences have been published (Basler et al., 2001 Reid et al., 1999, 2000, 2002, 2004). More recently, the HA sequences of two additional fixed autopsy cases of 1918 influenza victims from the Royal London Hospital were determined (Reid et al., 2003). The HA sequences from these five cases show 㺙 percent sequence identity, but differ at amino acid residue 225 (see below).

The sequence of the 1918 HA is most closely related to that of the A/ swine/Iowa/30 virus. However, despite this similarity the sequence has many avian features. Of the 41 amino acids that have been shown to be targets of the immune system and subject to antigenic drift pressure in humans, 37 match the avian sequence consensus, suggesting there was little immunologic pressure on the HA protein before the fall of 1918 (Reid et al., 1999). Another mechanism by which influenza viruses evade the human immune system is the acquisition of glycosylation sites to mask antigenic epitopes. The HAs from modern H1N1 viruses have up to five glycosylation sites in addition to the four found in all avian HAs. The HA of the 1918 virus has only the four conserved avian sites (Reid et al., 1999).

Influenza virus infection requires binding of the HA protein to sialic acid receptors on the host cell surface. The HA receptor binding site consists of a subset of amino acids that are invariant in all avian HAs, but vary in mammalian-adapted HAs. Human-adapted influenza viruses preferentially bind sialic acid receptors with α(2-6) linkages. Those viral strains adapted to birds preferentially bind α(2-3) linked sugars (Gambaryan et al., 1997 Matrosovich et al., 1997 Weis et al., 1988). To shift from the proposed avian-adapted receptor-binding site configuration (with a preference for α(2-3) sialic acids) to that of swine H1s (which can bind both α(2-3) and α(2-6)) requires only one amino acid change, E190D. The HA sequences of all five 1918 cases have the E190D change (Reid et al., 2003). In fact, the critical amino acids in the receptor-binding site of two of the 1918 cases are identical to that of the A/swine/Iowa/30 HA. The other three 1918 cases have an additional change from the avian consensus, G225D. Because swine viruses with the same receptor site as A/swine/Iowa/30 bind both avian- and mammalian-type receptors (Gambaryan et al., 1997), A/ New York/1/18 virus probably also had the capacity to bind both. The change at residue 190 may represent the minimal change necessary to allow an avian H1-subtype HA to bind mammalian-type receptors (Reid et al., 1999, 2003 Stevens et al., 2004 Gamblin et al., 2004 Glaser et al., 2004), a critical step in host adaptation.

The crystal structure analysis of the 1918 HA (Stevens et al., 2004 Gamblin et al., 2004) suggests that the overall structure of the receptor binding site is akin to that of an avian H5 HA in terms of its having a narrower pocket than that identified for the human H3 HA (Wilson et al., 1981). This provides an additional clue for the avian derivation of the 1918 HA. The four antigenic sites that have been identified for another H1 HA, the A/PR/8/34 virus HA (Caton et al., 1982), also appear to be the major antigenic determinants on the 1918 HA. The X-ray analyses suggest that these sites are exposed on the 1918 HA and thus they could be readily recognized by the human immune system.

The principal biological role of NA is the cleavage of the terminal sialic acid residues that are receptors for the virus's HA protein (Palese and Compans, 1976). The active site of the enzyme consists of 15 invariant amino acids that are conserved in the 1918 NA. The functional NA protein is configured as a homotetramer in which the active sites are found on a terminal knob carried on a thin stalk (Colman et al., 1983). Some early human virus strains have short (11-16 amino acids) deletions in the stalk region, as do many virus strains isolated from chickens. The 1918 NA has a full-length stalk and has only the glycosylation sites shared by avian N1 virus strains (Schulze, 1997). Although the antigenic sites on human-adapted N1 neuraminidases have not been definitively mapped, it is possible to align the N1 sequences with N2 subtype NAs and examine the N2 antigenic sites for evidence of drift in N1. There are 22 amino acids on the N2 protein that may function in antigenic epitopes (Colman et al., 1983). The 1918 NA matches the avian consensus at 21 of these sites (Reid et al., 2000). This finding suggests that the 1918 NA, like the 1918 HA, had not circulated long in humans before the pandemic and very possibly had an avian origin (Reid and Taubenberger, 2003).

Neither the 1918 HA nor NA genes have obvious genetic features that can be related directly to virulence. Two known mutations that can dramatically affect the virulence of influenza virus strains have been described. For viral activation, HA must be cleaved into two pieces, HA1 and HA2, by a host protease (Lazarowitz and Choppin, 1975 Rott et al., 1995). Some avian H5 and H7 subtype viruses acquire a mutation that involves the addition of one or more basic amino acids to the cleavage site, allowing HA activation by ubiquitous proteases (Kawaoka and Webster, 1988 Webster and Rott, 1987). Infection with such a pantropic virus strain can cause systemic disease in birds with high mortality. This mutation was not observed in the 1918 virus (Reid et al., 1999 Taubenberger et al., 1997).

The second mutation with a significant effect on virulence through pantropism has been identified in the NA gene of two mouse-adapted influenza virus strains, A/WSN/33 and A/NWS/33. Mutations at a single codon (N146R or N146Y, leading to the loss of a glycosylation site) appear, like the HA cleavage site mutation, to allow the virus to replicate in many tissues outside the respiratory tract (Li et al., 1993). This mutation was also not observed in the NA of the 1918 virus (Reid et al., 2000).

Therefore, neither surface protein-encoding gene has known mutations that would allow the 1918 virus to become pantropic. Because clinical and pathological findings in 1918 showed no evidence of replication outside the respiratory system (Winternitz et al., 1920 Wolbach, 1919), mutations allowing the 1918 virus to replicate systemically would not have been expected. However, the relationship of other structural features of these proteins (aside from their presumed antigenic novelty) to virulence remains unknown. In their overall structural and functional characteristics, the 1918 HA and NA are avian-like, but they also have mammalian-adapted characteristics.

Interestingly, recombinant influenza viruses containing the 1918 HA and NA and up to three additional genes derived from the 1918 virus (the other genes being derived from the A/WSN/33 virus) were all highly virulent in mice (Tumpey et al., 2004). Furthermore, expression microarray analysis performed on whole lung tissue of mice infected with the 1918 HA/ NA recombinant showed increased upregulation of genes involved in apoptosis, tissue injury, and oxidative damage (Kash et al., 2004). These findings were unusual because the viruses with the 1918 genes had not been adapted to mice. The completion of the sequence of the entire genome of the 1918 virus and the reconstruction and characterization of viruses with 1918 genes under appropriate biosafety conditions will shed more light on these findings and should allow a definitive examination of this explanation.

Antigenic analysis of recombinant viruses possessing the 1918 HA and NA by hemagglutination inhibition tests using ferret and chicken antisera suggested a close relationship with the A/swine/Iowa/30 virus and H1N1 viruses isolated in the 1930s (Tumpey et al., 2004), further supporting data of Shope from the 1930s (Shope, 1936). Interestingly, when mice were immunized with different H1N1 virus strains, challenge studies using the 1918-like viruses revealed partial protection by this treatment, suggesting that current vaccination strategies are adequate against a 1918-like virus (Tumpey et al., 2004). In fact, the data may even allow us to suggest that the human population, having experienced a long period of exposure to H1N1 viruses, may be partially protected against a 1918-like virus (Tumpey et al., 2004).

Because virulence (in the immunologically naïve person) has not yet been mapped to particular sequence motifs of the 1918 HA and NA genes, what can gene sequencing tell us about the origin of the 1918 virus? The best approach to analyzing the relationships among influenza viruses is phylogenetics, whereby hypothetical family trees are constructed that take available sequence data and use them to make assumptions about the ancestral relationships between current and historical influenza virus strains (Fitch et al., 1991 Gammelin et al., 1990 Scholtissek et al., 1993) (Figure 1-5). Because influenza viruses possess eight discrete RNA segments that can move independently between virus strains by the process of reassortment, these evolutionary studies must be performed independently for each gene segment.


Change in hemagglutinin (HA) and neuraminidase (NA) proteins over time. The number of amino acid changes from a hypothetical ancestor was plotted versus the date of viral isolation for viruses isolated from 1930 to 1993. Open circles, human HA closed (more. )

A comparison of the complete 1918 HA (Figure 1-5) and NA genes with those of numerous human, swine, and avian sequences demonstrates the following: Phylogenetic analyses based on HA nucleotide changes (either total or synonymous) or HA amino acid changes always place the 1918 HA with the mammalian viruses, not with the avian viruses (Reid et al., 1999). In fact, both synonymous and nonsynonymous changes place the 1918 HA in the human clade. Phylogenetic analyses of total or synonymous NA nucleotide changes also place the 1918 NA sequence with the mammalian viruses, but analysis of nonsynonymous changes or amino acid changes places the 1918 NA with the avian viruses (Reid et al., 2000). Because the 1918 HA and NA have avian features and most analyses place HA and NA near the root of the mammalian clade (close to an ancestor of the avian genes), it is likely that both genes emerged from an avian-like influenza reservoir just prior to 1918 (Reid et al., 1999, 2000, 2003 Fanning and Taubenberger, 1999 Fanning et al., 2000) (Figure 1-4). Clearly, by 1918 the virus had acquired enough mammalian-adaptive changes to function as a human pandemic virus and to form a stable lineage in swine.

Sequence and Functional Analysis of the Non-Structural Gene Segment

The complete coding sequence of the 1918 non-structural (NS) segment was completed (Basler et al., 2001). The functions of the two proteins, NS1 and NS2 (NEP), encoded by overlapping reading frames (Lamb and Lai, 1980) of the NS segment, are still being elucidated (O'Neill et al., 1998 Li et al., 1998 Garcia-Sastre et al., 1998 Garcia-Sastre, 2002 Krug et al., 2003). The NS1 protein has been shown to prevent type I interferon (IFN) production by preventing activation of the latent transcription factors IRF-3 (Talon et al., 2000) and NF-㮫 (Wang et al., 2000). One of the distinctive clinical characteristics of the 1918 influenza was its ability to produce rapid and extensive damage to both the upper and lower respiratory epithelium (Winternitz et al., 1920). Such a clinical course suggests a virus that replicated to a high titer and spread quickly from cell to cell. Thus, an NS1 protein that was especially effective at blocking the type I IFN system might have contributed to the exceptional virulence of the 1918 virus strain (Garcia-Sastre et al., 1998 Talon et al., 2000 Wang et al., 2000). To address this possibility, transfectant A/WSN/33 influenza viruses were constructed with the 1918 NS1 gene or with the entire 1918 NS segment (coding for both NS1 and NS2 [NEP] proteins) (Basler et al., 2001). In both cases, viruses containing 1918 NS genes were attenuated in mice compared to wild-type A/WSN/33 controls. The attenuation demonstrates that NS1 is critical for the virulence of A/WSN/33 in mice. On the other hand, transcriptional profiling (microarray analysis) of infected human lung epithelial cells showed that a virus with the 1918 NS1 gene was more effective at blocking the expression of IFN-regulated genes than the isogenic parental mouse-adapted A/WSN/33 virus (Geiss et al., 2002), suggesting that the 1918 NS1 contributes virulence characteristics in human cells, but not murine ones. The 1918 NS1 protein varies from that of the WSN virus at 10 amino acid positions. The amino acid differences between the 1918 and A/WSN/33 NS segments may be important in the adaptation of the latter virus strain to mice and likely account for the observed differences in virulence in these experiments. Recently, a single amino acid change (D92E) in the NS1 protein was associated with increased virulence of the 1997 Hong Kong H5N1 viruses in a swine model (Seo et al., 2002). This amino acid change was not found in the 1918 NS1 protein.

Sequence and Functional Analysis of the Matrix Gene Segment

The coding region of influenza A RNA segment 7 from the 1918 pandemic virus, consisting of the open reading frames of the two matrix genes, M1 and M2, has been sequenced (Reid et al., 2002). Although this segment is highly conserved among influenza virus strains, the 1918 sequence does not match any previously sequenced influenza virus strains. The 1918 sequence matches the consensus over the M1 RNA-binding domains and nuclear localization signal and the highly conserved transmembrane domain of M2. Amino acid changes that correlate with high yield and pathogenicity in animal models were not found in the 1918 virus strain.

Influenza A virus RNA segment 7 encodes two proteins, the matrix proteins M1 and M2. The M1 mRNA is colinear with the viral RNA, while the M2 mRNA is encoded by a spliced transcript (Lamb and Krug, 2001). The proteins encoded by these mRNAs share their initial 9 amino acids and also have a stretch of 14 amino acids in overlapping reading frames. The M1 protein is a highly conserved 252-amino-acid protein. It is the most abundant protein in the viral particle, lining the inner layer of the viral membrane and contacting the ribonucleoprotein (RNP) core. M1 has been shown to have several functions (Lamb and Krug, 2001), including regulation of nuclear export of vRNPs, both permitting the transport of vRNP particles into the nucleus upon infection and preventing newly exported vRNP particles from reentering the nucleus. The 97-amino-acid M2 protein is a homotetrameric integral membrane protein that exhibits ion-channel activity and is the target of the drug amantadine (Hay et al., 1985). The ion-channel activity of M2 is important both during virion uncoating and during viral budding (Lamb and Krug, 2001).

Five amino acid sites have been identified in the transmembrane region of the M2 protein that are involved in resistance to the antiviral drug amantadine: sites 26, 27, 30, 31, and 34 (Holsinger et al., 1994). The 1918 influenza M2 sequence is identical at these positions to that of the amantadine-sensitive influenza virus strains. Thus, it was predicted that the M2 protein of the 1918 influenza virus would be sensitive to amantadine. This was recently demonstrated experimentally. A recombinant virus possessing the 1918 matrix segment was inhibited effectively both in tissue culture and in vivo by the M2 ion-channel inhibitors amantadine and rimantadine (Tumpey et al., 2002).

The phylogenetic analyses suggest that the 1918 matrix genes, while more avian-like than those of other mammalian influenza viruses, were mammalian adapted (Reid et al., 2002). For example, the extracellular domain of the M2 protein contains four amino acids that differ consistently between the avian and mammalian clades (M2 residues #14, 16, 18, and 20). The 1918 sequence matches the mammalian sequence at all four of these residues (Reid et al., 2002), suggesting that the matrix segment may have been circulating in human virus strains for at least several years before 1918.

Sequence and Functional Analysis of the Nucleoprotein Gene Segment

The nucleoprotein gene (NP) of the 1918 pandemic influenza A virus has been amplified and sequenced from archival material (Reid et al., 2004). The NP gene is known to be involved in many aspects of viral function and to interact with host proteins, thereby playing a role in host specificity (Portela and Digard, 2002). NP is highly conserved, with a maximum amino acid difference of 11 percent among virus strains, probably because it must bind to multiple proteins, both viral and cellular. Numerous studies suggest that NP is a major determinant of host specificity (Scholtissek et al., 1978a, 1985). The 1918 NP amino acid sequence differs at only six amino acids from avian consensus sequences, consistent with reassortment from an avian source shortly before 1918. However, the 1918 NP nucleotide sequence has more than 170 differences from avian consensus sequences, suggesting substantial evolutionary distance from known avian sequences. Both the 1918 NP gene and protein sequences fall within the mammalian clade upon phylogenetic analysis.

Phylogenetic analyses of NP sequences from many virus strains result in trees with two main branches, one consisting of mammalian-adapted virus strains and one of avian-adapted virus strains (Gammelin et al., 1990 Gorman et al., 1991 Shu et al., 1993). The NP gene segment was not replaced in the pandemics of 1957 and 1968, so it is likely that the sequences in the mammalian clade are descended from the 1918 NP segment. The mammalian branches, unlike the avian branch, show a slow but steady accumulation of changes over time. Extrapolation of the rate of change along the human branch back to a putative common ancestor suggests that this NP entered the mammalian lineage sometime after 1900 (Gammelin et al., 1990 Gorman et al., 1991 Shu et al., 1993). Separate analyses of synonymous and nonsynonymous substitutions also placed the 1918 virus NP gene in the mammalian clade (Reid et al., 2004). When synonymous substitutions were analyzed, the 1918 virus gene was placed within and near the root of swine viruses. When nonsynonymous viruses were analyzed, the 1918 virus gene was placed within and near the root of the human viruses.

The evolutionary distance of the 1918 NP from avian and mammalian sequences was examined using several different parameters. There are at least three possibilities for the origin of the 1918 NP gene segment (Reid et al., 2004). First, it could have been retained from the previously circulating human virus, as was the case with the 1957 and 1968 pandemic virus strains, whose NP segments are descendants of the 1918 NP. The large number of nucleotide changes from the avian consensus and the placement of the 1918 sequence in the mammalian clade are consistent with this hypothesis. Neighbor-joining analyses of nonsynonymous nucleotide sequences or of amino acid sequences place the 1918 sequence within and near the root of the human clade. The 1918 NP has only a few amino acid differences from most bird virus strains, but this consistent group of amino acid changes is shared by the 1918 NP and its subsequent mammalian descendants and is not found in any birds, resulting in the 1918 sequence being placed outside the avian clade (Reid et al., 2004). One or more of these amino acid substitutions may be important for adaptation of the protein to humans. However, the very small number of amino acid differences from the avian consensus argues for recent introduction from birds� years after 1918, the NP genes of human influenza virus strains have accumulated more than 30 additional amino acid differences from the avian consensus (a rate of 2.3 amino acid changes per year). Thus it seems unlikely that the 1918 NP, with only six amino acid differences from the avian consensus, could have been in humans for many years before 1918. This conclusion is supported by the regression analysis that suggests that the progenitor of the 1918 virus probably entered the human population around 1915 (Reid et al., 2004).

A second possible origin for the 1918 NP segment is direct reassortment from an avian virus. The small number of amino acid differences between 1918 and the avian consensus supports this hypothesis. While 1918 varies at many nucleotides from the nearest avian virus strain, avian virus strains are quite diverse at the nucleotide level. Synonymous/nonsynonymous ratios between 1918 and avian virus strains are similar to the ratios between avian virus strains, opening the possibility that avian virus strains may exist that are more closely related to 1918. The great evolutionary distance between the 1918 sequence and the avian consensus suggests that no avian virus strain similar to those in the currently identified clades could have provided the 1918 virus strain with its NP segment.

A final possibility is that the 1918 gene segment was acquired shortly before 1918 from a source not currently represented in the database of influenza sequences. There may be a currently unknown influenza host that, while similar to currently characterized avian virus strains at the amino acid level, is quite different at the nucleotide level. It is possible that such a host was the source of the 1918 NP segment (Reid et al., 2004).

Future Work

Five of the eight RNA segments of the 1918 influenza virus have been sequenced and analyzed. Their characterization has shed light on the origin of the virus and strongly supports the hypothesis that the 1918 virus was the common ancestor of both subsequent human and swine H1N1 lineages. Sequence analysis of the genes to date offers no definitive clue as to the exceptional virulence of the 1918 virus strain. Thus, experiments testing models of virulence using reverse genetics approaches with 1918 influenza genes have begun.

In future work it is hoped that the 1918 pandemic virus strain can be placed in the context of influenza virus strains that preceded it and followed it. The direct precursor of the pandemic virus, the first or “spring” wave virus strain, lacked the exceptional virulence of the fall wave virus strain. Identification of an influenza RNA-positive case from the first wave would have tremendous value in deciphering the genetic basis for virulence by allowing differences in the sequences to be highlighted. Identification of pre-1918 human influenza RNA samples would clarify which gene segments were novel in the 1918 virus.

In many respects, the 1918 influenza pandemic was similar to other influenza pandemics. In its epidemiology, disease course, and pathology, the pandemic generally was different in degree but not in kind from previous and subsequent pandemics. Furthermore, laboratory experiments using recombinant influenza viruses containing genes from the 1918 virus suggest that the 1918 and 1918-like viruses would be as sensitive to the Food and Drug Administration-approved anti-influenza drugs rimantadine and oseltamivir as other virus strains (Tumpey et al., 2002). However, there are some characteristics of the pandemic that appear to be unique: Mortality was exceptionally high, ranging from 5 to 20 times higher than normal. Clinically and pathologically, the high mortality appears to be the result of a higher proportion of severe and complicated infections of the respiratory tract, not with systemic infection or involvement of organ systems outside the influenza virus's normal targets. The mortality was concentrated in an unusually young age group. Finally, the waves of influenza activity followed each other unusually rapidly, resulting in three major outbreaks within a year's time. Each of these unique characteristics may find their explanation in genetic features of the 1918 virus. The challenge will be in determining the links between the biological capabilities of the virus and the known history of the pandemic.

Research Agenda for the Future

The work on the 1918 influenza virus, especially its origin, has led to the support of more comprehensive influenza virus surveillance and genomics initiatives for both human and animal influenza A viruses. We believe significant advancement in the understanding of influenza biology and ecology can be made by the generation of full genomic sequences of a large number of influenza viruses from different hosts. In conclusion, some of the questions that need to be addressed in pandemic influenza include the following:

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