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INFLUENNZA VIRUS TREND

In the early 20th century, science was sufficiently sophisticated to anticipate that influenza, which had
twice reached pandemic proportions in the late 19th century, would recur, but was largely powerless to
blunt the devastating impact of the 1918 (H1N1) pandemic. Since then, mankind has gained several
advantages against the disease: experience of three better characterized pandemics (1918, 1957, and
1968); knowledge of influenza viruses; capacity to design and manufacture vaccines and antiviral drugs
to forestall (if not prevent) infection; and molecular technology that may one day pinpoint the viral
components that produce virulence, and thereby identify targets for more effective vaccines and drugs.

Yet the world is vulnerable to the next pandemic, perhaps even more than in 1918, when the pace and
frequency of global travel was considerably less than today. As the contributors to this chapter
demonstrate, there is still much to be learned from past pandemics that can strengthen defenses
against future threats. The chapter begins with a review of the events of 1918, the lessons they offer,
and the historical and scientific questions they raise. It describes the epidemiology and symptomology of
that deadly viral strain, limited efforts toward prevention and treatment, and the resulting social
disruption and its exacerbation by the actions of public officials and the media.

The ‘Great Influenza’ pandemic of 1918 remains the worst outbreak of infectious disease in history.
There is concern that highly pathogenic avian influenza viruses of the H5 and H7 subtypes may evolve to
cause similar pandemics. The chapter continues with an account of molecular studies underway to
determine the origin of the 1918 virus and the source(s) of its exceptional virulence. Clues are being
sought by examining viruses preserved in frozen and fixed tissues of victims of the 1918 flu.
Characterization of five of the eight RNA segments of the 1918 influenza virus indicates that it was the
common ancestor of both subsequent human and swine H1N1 lineages, and experiments testing models
of virulence using reverse genetics approaches with 1918 influenza genes have begun in hopes of
identifying genetic features that confer virulence in humans.

In a parallel effort, subsequently described, epidemiologists are analyzing death records and serological
data to better understand patterns of transmission, morbidity, and mortality in past influenza
pandemics. Such findings could inform planning for public health interventions to reduce the incidence
of severe outcomes in future pandemics. In particular, these studies reveal a signature change in excess
mortality from the elderly to younger age groups, a “pandemic age shift,” that occurred with each of the
three pandemics of the 20th century. If such a shift could be recognized in incipient pandemics, it might
allow sufficient time for the production and distribution of vaccine and antiviral drugs before the worst
pandemic impact occurs.
The 1918–1919 influenza pandemic killed more people in absolute numbers than any other disease
outbreak in history. A contemporary estimate put the death toll at 21 million, a figure that persists in the
media today, but understates the real number. Epidemiologists and scientists have revised that figure
several times since then. Each and every revision has been upward. Frank Macfarlane Burnet, who won
his Nobel Prize for immunology but who spent most of his life studying influenza, estimated the death
toll as probably 50 million, and possibly as high as 100 million. A 2002 epidemiologic study also
estimates the deaths at between 50 and 100 million

The pandemic in 1918 was hardly the first influenza pandemic, nor was it the only lethal one.
Throughout history, there have been influenza pandemics, some of which may have rivaled 1918's
lethality. A partial listing of particularly violent outbreaks likely to have been influenza include one in
1510 when a pandemic believed to come from Africa “attacked at once and raged all over Europe not
missing a family and scarce a person”

In 1580, another pandemic started in Asia, then spread to Africa, Europe, and even America (despite the
fact that it took 6 weeks to cross the ocean). It was so fierce “that in the space of six weeks it afflicted
almost all the nations of Europe, of whom hardly the twentieth person was free of the disease” and
some Spanish cities were “nearly entirely depopulated by the disease”

In 1688, influenza struck England, Ireland, and Virginia; in all these places “the people dyed … as in a
plague”mutated or new virus continued to plague Europe and America again in 1693 and Massachusetts
in 1699. “The sickness extended to almost all families. Few or none escaped, and many dyed especially
in Boston, and some dyed in a strange or unusual manner, in some families all were sick together, in
some towns almost all were sick so that it was a time of disease”

In London in 1847 and 1848, more people died from influenza than from the terrible cholera epidemic of
1832. In 1889 and 1890, a great and violent worldwide pandemic struck again

The 1918 virus also targeted young adults. In South African cities, those between the ages of 20 and 40
accounted for 60 percent of the deaths. In Chicago the deaths among those aged 20 to 40 nearly
quintupled deaths of those aged 41 to 60.A Swiss physician “saw no severe case in anyone over 50.”1 In
the “registration area” of the United States—those states and cities that kept reliable statistics—the
single greatest number of deaths occurred in the cohort aged 25 to 29, the second greatest in those
aged 30 to 34, and the third in those aged 20 to 24. More people died in each one of those 5-year
groups than the total deaths among all those over age 60, and the combined deaths of those aged 20 to
34 more than doubled the deaths of all those over 50.
The single group most likely to die if infected were pregnant women. In 13 studies of hospitalized
pregnant women during the 1918 pandemic, the death rate ranged from 23 to 71 percent of the
pregnant women who survived, 26 percent lost the child (As far back as 1557, people connected
influenza with miscarriage and the death of pregnant women.)

The case mortality rate varied widely. An overall figure is impossible to obtain, or even estimate reliably,
because no solid information about total cases exists. In U.S. Army camps where reasonably reliable
statistics were kept, case mortality often exceeded 5 percent, and in some circumstances exceeded 10
percent. In the British Army in India, case mortality for white troops was 9.6 percent, for Indian troops
21.9 percent.

In isolated human populations, the virus killed at even higher rates. In the Fiji islands, it killed 14 percent
of the entire population in 16 days. In Labrador and Alaska, it killed at least one-third of the entire native
population. But perhaps most disturbing and most relevant for today is the fact that a significant
minority—and in some subgroups of the population a majority—of deaths came directly from the virus,
not from secondary bacterial pneumonias.

In 1918, pathologists were intimately familiar with the condition of lungs of victims of bacterial
pneumonia at autopsy. But the viral pneumonias caused by the influenza pandemic were so violent that
many investigators said the only lungs they had seen that resembled them were from victims of poison
gas.

Then, the Army called them “atypical pneumonias.” Today we would call this atypical pneumonia Acute
Respiratory Distress Syndrome (ARDS). The Army's pneumonia board judged that “more than half” of all
the deaths among soldiers came from this atypical pneumonia (Ireland, 1928).

One cannot extrapolate from this directly to the civilian population. Army figures represent a special
case both in terms of demographics and environment, including overcrowded barracks.

Even so, the fact that ARDS likely caused more than half the deaths among young adults sends a
warning. ARDS mortality rates today range from 40 to 60 percent, even with support in modern
intensive care units (ICUs). In a pandemic, ICUs would be quickly overwhelmed, representing a major
challenge for public health planners.
The Site of Origin of this virus also necessary to know. It is very possible that we will never know with
certainty where the 1918 virus crossed into man. In the 1920s and 1930s, outstanding investigators in
several countries launched massive reviews of evidence searching for the site of origin. They could not
definitively answer the question. But they were unanimous in believing that no known outbreak in China
could, as one investigator said, “be reasonably regarded as the true forerunner” of the epidemic.

They considered the most likely sites of origin to be France and the United States, and most agreed with
Macfarlane Burnet, who concluded that the evidence was “strongly suggestive” that the 1918 influenza
pandemic began in the United States, and that its spread was “intimately related to war conditions and
especially the arrival of American troops in France” (Burnet and Clark, 1942).

My own research also makes me think that the United States was the most likely site of origin. The
unearthing of previously unknown epidemiologic evidence has led me to advance my own hypothesis
that the pandemic began in rural Kansas and traveled with draftees to what is now Fort Riley.

But whether the pandemic began in France or the United States is not really important. What does
matter is that the pandemic most likely did not begin in Asia.

This has important implications for modern surveillance efforts. Although Asia's population density and
the close proximity of humans and animals there makes the region particularly dangerous, the evidence
of 1918—confirmed by the H7N7 outbreak in Europe of 2003—demonstrates the need for surveillance
worldwide.

Something else should be addressed regarding surveillance. A physician now active in public health who
received his medical degree in Honduras in 1986 says that he and his colleagues were taught that there
was no difference between a cold and influenza. He believes physicians in Central America and possibly
elsewhere in the world routinely ignore influenza. Clearly, if we are to have an adequate surveillance
system, physicians need to be alert to the disease.

In conclusion, some of the questions that need to be addressed in pandemic influenza include the
following:
Can an entire avian influenza virus adapt directly in a human, or is reassortment necessary to generate a
pandemic strain?

Does adaptation of an avian influenza virus to humans require an intermediate host?

Can all possible subtypes of avian influenza virus reassort to form functional human pandemic strains, or
are there biological limitations to particular HA and NA subtypes?

A novel HA seems to be required for a pandemic strain; what about the other gene segments?

Can genetic changes be mapped to “virulence”?

Can features of virulence be separated from the host in question? Can the viral genetic component of
human virulence be modeled in experimental animal or in vitro systems?

What molecular changes are necessary for avian strains to adapt to mammals, and to humans in
particular?

Can host-adaptive changes (genetic fingerprints) be used to trace the evolution of a pandemic strain
through intermediate hosts?

Unless we make progress in understanding these and other issues involving the complex ecology and
biology of influenza viruses, we will face the risk of revisiting the past in our future

.REFERENCES

1. Correspondenz-Blatt fur Schweizer Aerzte, Basel, 11/5/18. 48, #40, “influenza epidemic,” E. bircher, p.
1338, quoted in JAMA 71(23):1946.

2. JAMA 71(16):1317 current comment, Vaccines in influenza.

3. October 16, 1918, minutes of Philadelphia General Hospital Woman's Advisory Council.

4.This work has been partially supported by National Institutes of Health grants, and previously by
grants from the Veterans Administration and the American Registry of Pathology, and by the Armed
Forces Institute of Pathology.

5.This work was partially supported by a research grant from the National Vaccine Program Office,
Unmet Needs. We thank Steven S. Morse and David S. Fedson for their support of this research activity,
and our many international colleagues who supplied mortality data for the Multinational Influenza
Seasonal Mortality Study (MISMS) network.

6.National Institute of Allergy and Infectious Diseases, National Institutes of Health (NIH), Bethesda, MD.

7.Columbia University, New York, NY.

8.Fogarty International Center (FIC), NIH, Bethesda, MD.

9.Under contract to National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD.

10.Entropy Research Institute, NJ, under contract to FIC, NIH, Bethesda, MD.

Links:

WHO Human-Animal Interface web page

http://www.who.int/influenza/human_animal_interface/en/

Cumulative Number of Confirmed Human Cases of Avian Influenza A(H5N1) Reported to WHO

http://www.who.int/influenza/human_animal_interface/H5N1_cumulative_table_archives/en/

Avian Influenza A(H7N9) Information

http://who.int/influenza/human_animal_interface/influenza_h7n9/en/index.html

WHO Avian Influenza Food Safety Issues

http://www.who.int/foodsafety/areas_work/zoonose/avian/en/

World Organisation of Animal Health (OIE) web page: Web portal on Avian Influenza

http://www.oie.int/animal-health-in-the-world/web-portal-on-avian-influenza/

Food and Agriculture Organization of the UN (FAO) webpage: Avian Influenza

http://www.fao.org/avianflu/en/index.html

OFFLU

http://www.offlu.net/index.html