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Int J Med Sci. =
2005; 2(2): 87=E2=80=9390.=20
Published online 2005 May =
15.=20
|
PMCID:=20
PMC1145139 |
An Avian Connection as a Catalyst to the =
1918-1919=20
Influenza Pandemic
Indiana University, 247 Life Science =
Building, New=20
Albany, IN 47150, USA
Received March 15, 2005; Accepted May 12,=20
2005.
|
|
Abstract
The 1918 Influenza =
pandemic was=20
one of the most virulent strains of influenza in history. This =
strain=20
quickly dispatched previously held theories on influenza. World =
War One=20
introduced new environmental stresses and speed of dissemination =
logistics=20
never experienced by humans. In light of new phylogenic evidence =
the cause=20
of this influenza outbreak is now being considered to have linkage =
to the=20
avian influenza. Animals act as reservoirs for this influenza =
virus and=20
research indicates the influenza virus often originates in the =
intestines=20
of aquatic wildfowl. The virus is shed into the environment, which =
in=20
turns infects domestic poultry, which in turn infects mammalian =
hosts.=20
These animals, usually pigs, act as a transformer or converters; =
creating=20
a strain that can more readily infect humans. Therefore swine can =
be=20
infected with both avian and human influenza A viruses and serve =
as a=20
source for infection for a number of species as the incidents of =
direct=20
infection from birds to humans have been rare. Increased human =
habitation=20
near poultry and swine raising facilities pose greater influenza =
outbreak=20
risk. It was this combination of environmental factors that may =
have=20
contributed to the greatest pandemic of recent times, and, =
moreover,=20
similar conditions exist throughout Southeast Asia today.
Keywords: Influenza, pandemic, epidemiology, avian =
influenza, swine=20
influenza, Spanish Influenza, =
vaccination |
|
1. Introduction
The death toll of the =
First World=20
War failed to inflict the human casualty rate that the 1918-1919 =
Influenza=20
Pandemic did. Little progress has yet been made toward =
understanding the=20
condition responsible for the extreme virulence of the =
=E2=80=9C1918 type=E2=80=9D, and or=20
the conditions necessary to prevent the reappearance of this =
influenza.=20
Unlike the typical =E2=80=9Cflu=E2=80=9D that strikes the very =
young, chronically ill and=20
elderly; this flu would attack and kill healthy young adults. =
Taubenberger=20
1 that reported deaths resulting from the =
influenza and=20
pneumonia for the 15-34-year-old cohort was 20 times higher in =
1918 than=20
any previous time, and 99% of excess deaths among people under 65 =
years of=20
age. This strain of influenza killed so many people that it =
reduced the=20
life expectancy of the United States ten years during its course. =
The=20
focus of this paper is to examine the cause of this influenza =
outbreak and=20
explain why the linkage to the avian influenza is=20
doubtful. |
|
2. History of the =
Disease
The influenza virus is of =
animal origin=20
and its infection of humans may date back as early as 2000 B.C.E. =
when=20
humans began to domesticate animals. Hippocrates described an =
epidemic=20
with =E2=80=9Cflu-like=E2=80=9D symptoms in 412 B.C.E and later =
Livy in ancient Rome=20
described a similar outbreak of a sudden =E2=80=9Cmalady=E2=80=9D =
2. Early=20
hypothesis of the origins of influenza occurrences were quite =
varied.=20
Garret 3 lists proposed factors that would initiate =
the onset=20
of influenza to include =E2=80=9Cnakedness, dirt, unclean pajamas, =
dust, open=20
windows, closed windows, old books, fish contaminated by the =
Germans in=20
1918, Chinese people and cosmic influences=E2=80=9D. Other =
possible causes were=20
attributed to =E2=80=9Cbad air=E2=80=9D, rotting corpses venting =
through the earth to=20
rotten garbage in the streets. The primal source for all influenza =
=E2=80=9CA=E2=80=9D=20
virus in mammals and domestic avian species is aquatic bird=20
reservoirs. 4,5 The common denominator in every influenza =
outbreak=20
was its ability to follow the travel routes from city to city and =
sicken=20
large numbers quickly and killing the very young and very =
old. The association of avian influenza =
with the 1918=20
pandemic has not been determined; however, a more probable link =
still=20
exists with the swine influenza. Oldstone 2 link the 1918 reports and the observations =
of J.S.=20
Koen, a veterinarian and inspector for the U.S. Bureau of Animal =
Industry=20
in Fort Dodge, Iowa. He observed in pigs a disease that resembled =
the=20
raging human influenza of 1918-1919: =E2=80=9CLast fall and winter we were =
confronted with a=20
new condition, if not a new disease. I believe that have as much =
to=20
support this diagnosis in pigs, as the physicians have to support =
a=20
similar diagnosis in man. The similarity of the epidemic among =
people and=20
the epidemic in pigs was so close, the reports so frequent that an =
outbreak in the family would be followed immediately by an =
outbreak among=20
the hogs, and vice versa, as to present a most striking =
coincidence if not=20
suggesting a close relationship between the two conditions. It =
looked like=20
the =E2=80=9Cflu=E2=80=9D and until proven it was not the =
=E2=80=9Cflu,=E2=80=9D I shall stand by that=20
diagnosis=E2=80=9D 2, 5. Koen's observations were unpopular, =
especially=20
among farmers raising pigs. Ten years later researchers with the =
U. S.=20
Bureau of Animal Industry reported the successful transmission of=20
influenza from pig to pig by taking mucus from the secretions from =
the=20
upper respiratory tract of infected pigs to healthy pigs. Richard =
Shope,=20
working with the Rockefeller Institute of Comparative Anatomy =
repeated the=20
study and was able to reproduce the disease in healthy pigs with =
material=20
taken from sick pigs and passed through a Pasteur-Chamberland =
filter.=20
Shope provided the first evidence of virus transmitted by swine =
2. In 1923, Richard Shope showed that people =
who were=20
alive during the 1918-1919 epidemics had antibodies against the =
=E2=80=9Cpig=E2=80=9D=20
virus, but those born after 1920 lacked such antibodies 3, 6. According to Shope's conclusion, =
which would be=20
the dominant hypothesis, was that the source of the pandemic was =
an animal=20
virus, which crossed from one species to another to eventually =
infect=20
humans. Supporting Shope's hypothesis of trans-species infection =
an=20
incident occurred in an unrelated study in 1928, of canine =
distemper, with=20
ferrets being used as the study animals, at the United Kingdom's =
Medical=20
Research Council's laboratory. Unexpectedly, the ferrets became =
ill with=20
symptoms of human influenza, when one of the researchers became =
ill with=20
the flu. Washings were obtained from the researcher's throat and =
sprayed=20
the filtrate into healthy ferrets' respiratory tracts. The ferrets =
became=20
ill with the same symptoms 2, 5. This provided the first evidence that a =
virus caused=20
human influenza, and that it could be a trans-species virus =
fulfilling=20
Koch's postulates on the transmission disease. There are two major classes of =
influenza virus,=20
type A and B. these two classes have similar structures, but all A =
virus=20
proteins are different from B as far as the immune system is =
concerned.=20
Type A infects pigs, horses, seals, whales, and many types of =
birds as=20
well as humans. This can be a trans-species virus.
Type B infects only humans 8. Animals act as reservoirs for this =
influenza virus=20
and Gelbalt 7 cited research that indicates the virus =
often=20
originates in the intestines of aquatic wildfowl. The virus is =
shed into=20
the environment, which in turns infects domestic poultry, which in =
turn=20
infects mammalian hosts. These animals, usually pigs, act as a =
transformer=20
or converters; creating a strain that can more readily infect =
humans. Pigs=20
can be infected with both avian and human influenza A viruses. =
Human=20
influenza viruses have been detected in pigs in Asia, Europe, and =
Africa=20
10. Regions of the world such as Southeast =
Asia offer=20
a close environment, which is shared between fowls, pigs and =
humans. Some=20
of these human and avian influenza viruses might become adapted to =
pigs=20
and circulate in that population. The co-circulation of the =
viruses in=20
swine, avian and human populations it enhances the likelihood of =
genetic=20
exchange, or =E2=80=9Creassortment=E2=80=9D of the genetic =
material between these viruses.=20
The mechanism of this reassortment or conversion is not =
understood, and=20
has not been replicated in a lab. None the less the probability of =
this=20
process is not to be dismissed casually. Wild Aquatic birds are believed to =
shed influenza=20
=E2=80=9CA=E2=80=9D virus through their fecal wastes, which is =
readily picked up by other=20
avian and mammal species. Water fowl are believed to be the source =
of many=20
of the influenza viruses and are responsible for their =
re-emergence prior=20
to pandemics 8, 12, 20. With the difficulties of =
antigenic=20
shift, drift, and animal reservoirs, it is not surprising that =
making an=20
effective influenza vaccine is near impossible to achieve. Garrett =
3 lists the virulence of a virus is =
determined by: the=20
efficiency of the hemagglutinin ability to drift; functional =
ability of=20
the nueraminidase, and the immunity of the host it infects to =
fight the=20
virus. The first two factors are influenced by the genetics of the =
virus.=20
The last factor is dependent on the health of the host to regulate =
a=20
response to the virus. Garrett 3 reported that Dr. Edwin Kilburn, Mount =
Sinai School=20
of Medicine in New York City has shown that influenza viruses =
unusually=20
rich in neuraminidase proteins were more contagious, and was able =
to take=20
pieces of their host's cellular membranes to allow them to evade =
the=20
immunological responses of their host. |
|
3. The 1918-1919 =
Pandemic
The onset of the 1918-1919 influenza =
pandemic=20
occurred in three waves. The first wave, in the spring of 1918, =
was=20
relatively mild, starting from the Midwest and spreading along the =
rail=20
lines with soldiers from Ft. Funston, Kansas, modern day Ft. =
Riley.=20
3, 4 Patient zero was recorded cleaning pig pens =
prior to=20
his infection. There is no mention of the presence of poultry in =
the=20
reports. From Ft. Funston the mild influenza spread to cities and =
other=20
military bases throughout the United States. This mild strain =
received=20
very little attention from the press; after all there was a war to =
occupy=20
people's attention. The spring outbreak was not even noted in the =
index in=20
the 1918 volumes of the Journals of the American Medical=20
Association. Influenza was not a reportable disease: the only =
evidence of the early occurrence was the registration of deaths =
reported=20
as uncomplicated cases of pneumonia by physicians to various =
public health=20
departments 11. Medical researchers at the time =
offered the=20
following hypothesis what had happen to the influenza when it went =
to=20
France. The first theory that was offered was that this =
=E2=80=9CSpanish flu=E2=80=9D was=20
actually a different disease. Decades later phylogenic testing =
will find=20
this to be false. Other theories were that presence of gas =
warfare, and=20
chemicals used in explosives along with the number of corpses left =
unburied had created a new =E2=80=9Csuper germ=E2=80=9D. The =
potential of an airborne=20
disease was enhanced because of the crowded conditions, closed in =
living=20
quarters with less hygienic conditions and rapid transport systems =
that=20
allowed the ill individuals to pass the disease while in =
contagious stages=20
12. The crowded hospitals with hurried =
medical care=20
procedures and mass transport of sick and dying soldiers, in their =
late=20
teens and twenties, compounded the likelihood of an emerging =
infectious=20
disease or a possible mutation of an existing disease that would =
target=20
this age group. Those who had suffered from the earlier =
spring=20
influenza generally suffered less discomfort in the fall outbreak. =
Despite=20
the obvious differences between the strains, it is suggested that =
the more=20
virulent form of influenza was genetically derived from the spring =
influenza 13. This cannot be proven and the antigenic=20
composition of the 1918 virus is believed to be related to the =
H1N1 viral=20
group. Phylogenetic studies indicate that the virus responsible =
for the=20
1918 influenza and viruses that provided gene segments for the =
Asian/57=20
and Hong Kong/68 pandemics are still circulating in wild birds, =
with few=20
or no mutations 4. The extreme virulence of fall influenza =
strain has=20
so far not been satisfactory explained. Patterson, K. D., and =
Pyle, F. G.=20
13, Crosby 11 and many other researchers believe that a =
strain of=20
pneumonia bacteria accompanied the virus. Noyes 15 noted that the nation's people were =
stricken and=20
died from the illness at differing rates, just as the cities were =
hit at=20
differing rates. There was no correlation between populations, or =
even=20
geographical demographics. Sex and age both played a major factor =
in=20
determining the susceptibility to the disease of the individual. =
Females=20
were stricken in rates greater than males, and young adults were =
sickened=20
in greater numbers that other age cohorts 14. Climatic conditions may have =
had a role=20
in the spread and severity of influenza. Cities in more harsh and =
cold=20
climates tended to have somewhat lower death rates than those in =
more=20
temperate climates 14. Most severe outbreaks would tend to =
occur during=20
warm spells, followed by sudden drops in temperature. This trend =
was=20
observed numerous times during the course of the=20
epidemic. |
|
4. The Genetics of the =
Disease
Unlike most viruses, the =
influenza=20
virus may exist in many different shapes. The virus is well =
protected by a=20
tough lipid coat made up of two layers of viral enveloping: one =
layer is=20
composed of cholesterol, and the other layer of two proteins:=20
hemagglutinin [HA] and nueraminidase [NA]. Both proteins are =
recognized by=20
antibodies. The two proteins are unique in structure and in =
function. Over=20
700 of these tiny spike-like proteins protrude from the envelope =
of the=20
virus. Hemagglutinin will attach on the cell membranes through =
receptors=20
on the cell, containing sialic acid and fuse on the membrane, =
allowing the=20
RNA of the virus to enter the host cell. The neuraminidase removes =
the=20
sialic acid receptors from the host cell membrane and from newly =
made=20
viruses which enable the virus to continue to infect other cells =
if=20
neuraminidase is blocked the viruses =E2=80=9Cclump=E2=80=9D =
together on cell surfaces and=20
are unable to complete their cycle 8. Influenza types can be subdivided =
into subgroups=20
according to the types of surface proteins located on the surface =
of their=20
protein coats. Presently, 15 different H and 9 different N =
antigens have=20
been identified. Type A influenza viruses are made up of various=20
combinations of H and N antigens but only a few of these =
combinations:=20
H1N1, H2N2, H3N2 and H5N1 have been found to cause human illness =
6, 8. However, other H and N virus combinations =
have been=20
found in other infected animals. A change in the NA amino sequence may =
allow a=20
=E2=80=9Cback-door=E2=80=9D to HA cleavage, leading to systemic =
infection. This mutant NA=20
will bind to plasminogen a normal precursor in the blood clotting =
system.=20
If plasminogen is converted to plasmin, the active form, it =
functions as a=20
protease to cleave HA which creates a systemic infection as well =
1. Taubenberger 1 reported that this transformation was not =
observed in=20
the1918 strain, or in strains =E2=80=9Ccaptured=E2=80=9D in =
nature. The influenza virus is changing all =
the time.=20
Major antigenic =E2=80=9Cshifts=E2=80=9D occur in influenza type =
A, creating the=20
=E2=80=9Cemergence=E2=80=9D of new flu viruses. The virus =
undergoes a series of small=20
changes in the NA and HA proteins called =E2=80=9Cdrift.=E2=80=9D =
Experiments have=20
demonstrated that drift results from mutations in the pieces of =
RNA coding=20
of hemagglutinin and nueramindase. These cause small alterations =
in the=20
regions [epitopes] on the NA and HA molecules that bind antibodies =
to the=20
viruses 2, 7, 8. This mutation permits the viruses to =
=E2=80=9Cescape=E2=80=9D and=20
infect the victim, who might be previously immune. Three major hypotheses have been =
offered by=20
Oldstone 2 to explain antigenic shifts:
- A new virus can come forth from a re-assortment in =
which an=20
avian virus gene is substituted for one of the human influenza =
virus=20
genes.
- Viruses that infect other birds and mammals become =
infectious=20
to humans. This is the commonly accepted explanation of the =
1918-1919=20
Pandemic.
- The newly emerging virus has actually remained hidden =
and=20
unchanged somewhere but suddenly come forth to cause an epidemic =
against=20
an unprotected population with little to no =
immunity.
The influenza virus is able to =
initiate these=20
shifts because it follows an evolutionary process of natural =
selection=20
that acts in a method called =E2=80=9Cpositive selection=E2=80=9D. =
This allows the codons=20
in the HA genes to change. Researchers have ample evidence to =
trace the=20
non-silent mutations of the influenza virus amino acid as the =
strains that=20
show the greatest numbers of mutations are more likely to the =
progenitors=20
for future generations of the virus 15. Knowing this we may be able to predict =
which=20
strains may be likely to be the progenitors for future strains in =
future=20
outbreaks. The predictor for the future strains rest with ability =
of the=20
codons to combine with antibodies, and associate with sialic acid =
receptor=20
binding sites of the antibodies. The work of=20
Fitch, et. al. 6, 15 was utilized by researchers at the St. =
Jude=20
Children's Research Hospital in Memphis, Tennessee studying the =
1983 avian=20
flu virus before and after it became virulent. They discovered =
that a=20
single base change in the RNA segment coding the HA spike caused a =
single=20
amino acid sequence in the hemagglutinin to produce a killer =
virus. This=20
drift occurs in both types A and B, the major shifts, however, =
occur in=20
type A. This may be due to the factor of the multiple =
host/reservoirs for=20
type A. However the likelihood of the avian influenza being the =
direct=20
cause of the 1918 Influenza Pandemic is not very plausible. Prior =
to the=20
1997 H5N1 outbreak in Hong Kong, avian influenza was reported =
rarely and=20
was believed to be highly restrictive 16. There is no evidence that the H5N1 virus =
has been=20
adapted to humans. Influenza virus is protein specific to their =
binding=20
sites and humans and birds lack a common sialic acid receptor on =
host=20
cells. In order for the avian influenza virus to infect humans, =
domestic=20
pigs must act as immediate hosts and =E2=80=9Cmix=E2=80=9D or =
=E2=80=9Cconvert=E2=80=9D the virus to a=20
human virus 17. This hypothesis is consistent with the =
observation=20
that many pandemics occur in areas where duck, swine and humans =
are in=20
close contact. The role of swine as a converter is still not =
completely=20
understood 6, 14. The evidence for direct =
human infection=20
by fowl is not strong and considering that the influenza virus is =
shed=20
through their feces makes prove of human infection even more =
difficult to=20
prove. The case against swine in transmitting the avian influenza =
is not=20
proven either. One, how does an intestinal virus change to that of =
a=20
respiratory airborne-virus that is adapted to the mammalian lung? =
Second,=20
the viruses must adapt to environmental changes, able to withstand =
temperate, moisture and ph changes. Finally, the surface proteins =
as=20
discussed prior must be adapted. |
|
5. Control of the =
Disease
Presently, the only effective measure we =
have to=20
combat influenza is isolation and culling of infected fowls as=20
demonstrated by the government of China, Vietnam, and Thailand. As =
human=20
populations continue to increase and interactions between animals =
and=20
humans become more proximate, the emergence of new influenza =
strains will=20
occur 10, 18. Traditionally pigs will continue to be =
reared=20
along poultry in densely settled rural regions. Agricultural =
reforms in=20
China are moving pigs away human living quarters 4. In the United States this practice is =
being reversed=20
as the animal industry continues to develop highly dense animal =
population=20
feed lot concepts for raising swine and poultry near populated =
regions. In=20
areas that are climatically similar to southern China, the =
conditions of=20
mixing humans, aquatic birds, poultry, and swine provide excellent =
conditions for interspecies transfer and genetic exchange among =
influenza=20
viruses 5, 8. Robert Webster, M.D. of the St. Jude's =
Children=20
Hospital of Memphis, has concluded that all the genes of influenza =
reside=20
in the world's population of aquatic birds, in ducks and gulls, =
and are=20
periodically transmitted to pigs and humans 19. Pigs act as the =E2=80=9Ctransformers or =
converters=E2=80=9D for=20
the various influenza viruses and let loose the world new =
=E2=80=9Cstrains=E2=80=9D of the=20
influenza virus. The intervening passage continues to be through =
the=20
domesticated pig. The genetic structure of influenza continues to =
be=20
unstable and many different influenza =E2=80=9CA=E2=80=9D strains =
can exchange subunits of=20
DNA to produce numerous sub-strains. Generally these new =
combinations are=20
minor, with few virulent strains emerging. The=20
question when will the next influenza pandemic occur still =
remains? Every=20
influenza pandemic since 1850, [other than the 1918 pandemic] has=20
originated in China 4, 8, 15. With the recent occurrences of the new =
=E2=80=9Cbird=E2=80=9D=20
influenza and the accidental release of the 1957 H2N2 influenza =
strains to=20
labs, time may be running short until the next =
pandemic. |
|
Biography
| =E2=80=A2 |
James E. =
Hollenbeck, Ph.D. (University of Iowa) is an =
assistant=20
professor and the coordinator of Secondary Science Education =
at=20
Indiana University. Dr. Hollenbeck has taught microbiology =
and human=20
biology at various higher education institutions prior to =
his=20
dedication to developing high quality secondary science =
educators at=20
Indiana University. He is interested in the role of science =
in the=20
human experience and has lectured internationally on topics=20
concerning issues in public health and Science, Technology =
and=20
Society (STS) in =
education. | |
|
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Oldstone MBA. Viruses, Plaques=20
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3.
Koen JS. A Practical Method for Field =
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Webster RG. Predictions for Future Human =
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Bush RM. Influenza as a Model System for =
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Creation of New Pandemic Influenza Viruses. Medical Principles Practice. 1990;2:65=E2=80=9371.
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McMichael AJ. Environmental and Social =
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Taubenberger J, Reid A, Kraft A. Initial =
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