Special Contribution

Yonago Acta medica 2011;54:41–48

Pandemic Influenza: A Never-Ending Story
Seiji Kageyama
Division of Virology, Department of Microbiology and Immunology, School of Medicine, Tottori
University Faculty of Medicine, Yonago 683-8503, Japan

A novel pandemic influenza emerged in 2009, something that hasn’t been seen since 1977.
The following issues will be introduced and discussed in this review: the history of influenza
pandemics, the emergence of the novel pandemic influenza of 2009, epidemics in the southern and northern hemispheres after the recognition of index cases in the United States, mortality, viral characteristics, prevention in the household setting, clinical aspects, diagnosis,
treatment and immunization. Some questions have been answered. However, a number ofother questions remain. Scientific research must follow up on these unanswered questions.
Key words: influenza; pandemic; emergence; prevention; treatment
trated on an unusually young age group. The agegroup between 20 and 40 years was affected most
severely. Despite scientific and technological progress, the reasons for unexpected patterns like thisremain obscure to date (Taubenberger and Morens,2010). The high mortality associated with the 1918
virus appears to have been largely a result of bacterial pneumonia (Morens et al., 2008). Fortunately,
the situation has changed completely and antimicrobial agents are available all over the world. Spanish
influenza viruses still have an influence on recent
epidemics. Seasonal H1N1 [spread before the emergence of 2009 influenza A (H1N1)] acquired polymerase B1 (PB1), polymerase A (PA), nucleoprotein(NP) and N1 genes from 1918 pandemic H1N1
viruses. Similarly, classic swine influenza viruses
harbored three segments, PB2, matrix (M) andnon-structural (NS), originating from 1918 H1N1
viruses.

History of pandemics before 2009*
Spanish influenza of 1918 (H1N1)†More than fourteen influenza pandemics have appeared since 1500. This implies that approximately
one pandemic has occurred every 36 years. In the“microbial era” (1876 to present), there were at least
six pandemics, one each in 1889, 1918, 1957, 1968,
1977 and 2009. Possibly more pandemics have occurred. However, it is still not easy to document thelong history of influenza, because a number of techniques have only been developed recently. Indeed,
influenza viruses were not isolated until the 1930s.
The characterization of the 1918 pandemic influenza began in 1995 with the identification of a 1918
autopsy and archeological material (Taubenberger
and Morens, 2010).
The 1918 pandemic H1N1 viruses killed an
estimated 50 million people or more worldwide.
Mortality during the 1918 pandemic was concen-

Asian influenza of 1957 (H2N2)* Table 1.
† H1N1, subtype based on hemagglutinin (HA) and neuraminidase (NA) spikes.
Abbreviations: CDC, Center for Disease Control andPrevention; HA, hemagglutinin; M, matrix; NA, neuraminidase; NP, nucleoprotein; NS, non-structural; PA,
polymerase A; PB1, polymerase B1; rRT-PCR, real-time
PCR combined with reverse transcription

This was a descendant of 1918 H1N1, but acquired
three novel segments of avian-like HA (H2), NA(N2) and PB1 genes. The mortality rate during
this epidemic was as impressive as the pandemic
in 1918. After about two years the virus became
seasonally epidemic and sporadic, and disappeared41

S. Kageyama

entirely within 11 years (Taubenberger and Morens,2009).

Table 1. Influenza history and the advancementof medical technology

Hong Kong influenza of 1968 (H3N2)
Unlike the other two preceding pandemics, H3N2
Hong Kong influenza viruses are still circulating
globally. The pandemic of 1968 was modest in its
mortality. As in 1957, the epidemic size became
smaller and sporadic in its appearance. This virus
is a descendant of the H2N2-type virus with two
avian-like segments of HA (H3) and PB1. It has
been suggested that the relative mildness of the1968 pandemic resulted in the retention of the NA
segment harbored by the strains that had circulated
previously. Most of the population had at least
partial immunity to this NA (Taubenberger andMorens, 2009).

Year

Epidemics and other important medical events

1918
1928
1957
1968
1977
1987
2000
2001

Emergence of Spanish influenza (H1N1)
Discovery of penicillin by A. Fleming
Emergence of Asian influenza (H2N2)Emergence of Hong Kong influenza (H3N2)
Emergence of Russian influenza (H1N1)
Discovery of PCR
Zanamivir (drug infused by inhalation)
Oseltamivir (oral drug)
General use of antigen detection kits
Emergence of 2009 influenza (H1N1)
Peramivir (drip infusion therapy drug)
Laninavir (long-acting drug)

2009
2010

Guan et al., 2010; Taubenberger and Morens, 2010.

The severity and main symptoms of this disease
seemed similar to that of the novel influenza thatemerged and caused a pandemic in 2009.

Russian influenza of 1977 (H1N1)

Among humans

This reemergence in 1977 is unexplainable and may
represent reintroduction to humans from a laboratory source (Zimmer and Burke, 2009).

On April 17, 2009, the Center for Disease Control
and Prevention (CDC) in the United States determined two cases of febrile respiratory illness occurring in children living in two different counties insouthern California. Both of these children were infected with swine influenza A (H1N1) viruses. Neither of these children had contacts with pigs nor witheach other. The source of the infection remains unknown. The lack of known exposure to pigs in thetwo cases increases the possibility that human-tohuman transmission of this new influenza virus had
occurred. A couple of days later, the CDC reported
six additional cases. Four were in California but theother two were in Texas, far from California. Thesesix additional patients were infected by similar
strains of swine-origin influenza A (H1N1) viruses
identified in the two index cases (CDC, 2009b). As
a result, a total of 642 swine-origin influenza cases
were identified in 41 states in the United States until
May 5. The ages ranged widely, but 60% were 18
years of age or younger. The most common symptoms were fever (94%), cough (92%) and sore throat(66%). Similar to the pig-to-human cases, 25% of
patients had diarrhea (Dawood et al., 2009).

Emergence of novel influenza A
viruses in 2009
From pigs to humans
Before the emergence of novel influenza viruses
spreading among humans, there was sporadic infection with triple-reassortant swine influenza A(H1) viruses from pigs to human (one-way flow) in
the United States. Eleven cases of sporadic humaninfections with triple-reassortant swine influenza
A viruses, were recognized from December 2005
through February 2009 until just before the epidemic of swine-origin influenza A (H1N1) among
humans. Median age was 10 years (from 16 months
to 48 years). Nine cases had exposure to pigs. The
range of suspected incubation period was 3 to 9
days. Major symptoms were fever (90%), cough(100%), headache (60%) and diarrhea (30%). Fourpatients were hospitalized and two of these were under invasive mechanical ventilation. All recovered
eventually from their illness (Shinde et al., 2009).
42

Pandemic influenza

Fig. 1. Reassortment events leading to the emergence of 2009 A(H1N1) virus. Gene segments are indicated by PB2,
PB1, PA, HA, NP, NA, M and NS from top to bottom within the viral particles. The 2009 A(H1N1) viruses contained
the 6 segments originating from triple-reassortant swine strains (PB2, PB1, PA, HA, NP, and NS) and the 2 from
Eurasian swine strains (NA, M). The HA segment of a triple-reassortant swine strain was replaced by the one in a classical swine strain around 1998. H1N1, subtype based on HA and NA spikes; HA, hemagglutinin; M, matrix; NA, neuraminidase; NP, nucleoprotein; NS, non-structural; PA, polymerase A; PB, polymerase B.

Genomic analysis of the 2009 influenza A(H1N1) virus [2009 A(H1N1) virus hereafter] in humans indicates that it is closely related to common
reassortant swine influenza A viruses. The segment
coding for the polymerase complex (PB2, PB1, PA),
HA, NP and NS show high similarity to triple-reassortant swine viruses harbored by North Americanswine. The reassortment of these three segments
was generated in swine around 1990 and infected
humans sporadically since then as described above.
The segment coding for the NA and M originatedfrom the strains harbored by Eurasian swine (Fig. 1)(Smith et al., 2009; Trifonov et al., 2009).

From humans to pigs
The evolution of influenza A viruses seems to indicate that viruses among pigs change to adapt to humans, and that reversal flow (human-to-pig) doesn’t
happen. However, a reverse transmission event happened from a human to a pig after the emergence ofthe swine-origin influenza viruses. In May 2009,2009 A(H1N1) viruses were confirmed in Thailand from a person who had a history of travel to
Mexico. Shortly after this was noted, transmission
from humans to pigs was discovered on pig farms(Sreta et al., 2010).

43

S. Kageyama

Mortality

Epidemics in the southern andnorthern hemispheres

The World Health Organization stated that an assessment of the severity of a pandemic is complex,
and a single assessment of severity may not be relevant or helpful to countries at the global level (World
Health Organization, 2009). However, a graded series of responses such as closing schools and otherpublic venues, are required for addressing influenza
pandemics. The United States defined the pandemic severity index. It is calibrated to the case fatality
ratio. Mild responses are prescribed for a strain
resembling seasonal influenza, which kills around
0.1% of infected individuals, whereas stringent measures are implemented for a very severe pandemic
with a rate of 2% or more (Lipsitch et al., 2009). A
case-fatality ratio of about 0.5% was documented in
one report (Nishiura, 2010). However, an estimationof the number of infections is difficult as comparedto fatal cases. Indeed, the case fatality ratios were
estimated to be 0.4 in the United Kingdom (Pebody
et al., 2010) and 0.11 to 0.15 in Germany (Wilking
et al., 2010). Similarly, variation could be observedin the fatality ratios per one million inhabitants: 7.6
in the United Kingdom, 3.1 in Germany, 7.0 in the
United States, 13.7 in Canada, 3.7 in the Netherlands, 1.8 in Belgium, 4.8 in Austria, 6.3 in Spain,
5.1 in France (Wilking et al., 2010) and 0.7 in Japan(Kamigaki and Oshitani, 2009)

Just after the index cases of novel influenza wererecognized in southern California, countries in thesouthern hemisphere such as Australia were striken
by a strong influenza epidemic (Baker, Kelly andWilson, 2009). This happened four months earlier
than the epidemic onset in Japan. In New South
Wales the most populous state of Australia, theepidemic lasted from late June to early September(New South Wales Public Health Network, 2009).
At least one quarter of the population and one-thirdof children experienced influenza-like illnesses(Muscatello et al., 2011). The virus affected the
younger generation and caused considerable morbidity, 8.5-fold, as compared with seasonal influenza in the previous five seasons (Australian Government Department of Health and Ageing, 2009).
However, the fatality rate was not considerably highand even low (0.5–1.5%) for laboratory-confirmed
influenza cases caused by the 2009 A(H1N1) virus(Falagas et al., 2011).
The epidemic trend shifted to the northernhemisphere from September to October of that year.
Unlike the epidemic in the southern hemisphere, theepidemic size of influenza caused by 2009 A(H1N1)
viruses did not seem higher than those of regularseasonal influenza. This lower morbidity in thenorthern hemisphere is presumably attributed to the
new vaccine preparation for this pandemic. Except
for the epidemic size, findings are in accordancewith those gained during the 2009 winter season in
the southern hemisphere. The novel influenza occurred more in the younger generation as comparedto the seasonal one (Falagas et al., 2011). Most of
the epidemic was caused by 2009 A(H1N1) viruses
while a few seasonal viral strains were detected.
From April 2009 to June 12, 2010, US-CDC performed antigenic characterization of the 67,022
subtype-A viruses and identified 34 cases of seasonal influenza A (H1N1) (Russian flu type, 0.1%),
72 cases of seasonal influenza A (H3N2) (HongKong flu type, 0.1%) and 66,916 cases of the 2009
A(H1N1) virus (99.8%).

Viral load, shedding/spreadersand stability
The median incubation time was 2 days (range, 1–7)
and the duration of fever was typically 3 days (range,
1–11) (Cao et al., 2009). Viral load on the throatswab was inversely correlated with the number ofdays after the onset of fever. It was maintained at
a high level over the first 3 days during the febrile
period and then decreased over time. Patients withpneumonia had a higher viral load than those withupper respiratory tract infection (Li et al., 2010).
Median viral shedding time after the onset ofsymptoms was 6 to 9 days (Cao et al., 2009; Li etal., 2010; Ling et al., 2010). Another meta-analysis
44Pandemic influenza

reported that the average duration of shedding over
375 participants was 4.80 days (95% confidence interval: 4.31, 5.29) (Carrat et al., 2008). Independentrisk factors for prolonged viral shedding included
younger age, male sex and delayed treatment (Caoet al., 2009). Younger patients (< 13 years old) had
a longer viral shedding time than older people (≥ 13
years old) (11 days versus 7 days) (Li et al., 2010).
Asymptomatic individuals composed one-third of
total infections (Carrat et al., 2008), and caused
30% to 50% of secondary infections althoughsymptomatic patients were the main viral spreaders (Carrat et al., 2008). Another report estimateda lower transmission rate from asymptomatic individuals (14%) (Lau et al., 2010).
Influenza virus transmits through droplets(particle diameter, > 5 µm) and direct (physical contact)/indirect contact (hands, instruments, etc.). The
knowledge is supported by a number of experimental and epidemiological findings. The transmission
through the air-borne route (particle diameter < 5µm, i.e., transmission over long distance) might beunlikely for human influenza virus infection. Studies examining the particles produced during natural
coughing have shown that more than 99.9% of theaerosol volume is composed of particles with a diameter greater than 8 µm (Brankston et al., 2007).
Influenza viruses can survive in and be detected from aerosol for up to 24 h at low levelsof relative humidity and 60 min at higher levels.
Transmission of viruses has been documented tooccur from a surface to the hands of volunteers in
sufficient quantities. The contaminated surfaces
were capable of supporting viable virus transfer
for a substantially long period (up to 2 h). Viruses
were detected on 23% and 53% of objects in a daycare center in the autumn and spring, respectively.
Approximately 60% of objects swabbed in thehomes of sick children were contaminated withviruses. Although direct and indirect contact forviral transmission is important, no study has shownthat contact with contaminated surfaces could resultin transmission. Further studies should be done
(Brankston et al., 2007).

Prevention measures in daily life:
wearing masks and washing hands
Killingley and colleagues documented that remarkably little is known about models of transmissionof the influenza virus, and understanding the basic
science of influenza transmission is key to the development of evidence-based policies for prevention
and control of infections. The US Institute of Medicine, the European Center for Disease Control andthe World Health Organization have all prioritizedunderstanding the models of influenza transmission as a vital requirement for pandemic planning(Killingley et al., 2011).
Researchers in Egypt have assessed the effectof a hand-hygiene campaign and introduced a randomized control trial at 30 schools over a 12-weekperiod, while 30 different schools acted as controls.
School children in the intervention group were required to wash hands twice each day. Incidenceof laboratory-confirmed influenza (both A and B
strains) was reduced by 50% in the intervention versus control groups (P < 0.0001) (Talaat et al., 2011).
Another research group undertook a primaryprevention study in the United States. Volunteers
were divided into three groups in this study. Volunteers in the first group were assigned to wear
surgical masks (daily for 3.5 h on average), while
those in the second group wore masks and washedhands. The rest of the volunteers were in the control group. The trial lasted for six weeks. Influenza-like illnesses fell by 35% to 51% in the second
group and by 28% to 35% in the first group (Aielloet al., 2010). In households, similar studies havebeen done. One study reported that intervention
within 36 h of symptom onset reduced transmission
significantly (adjusted odds ratio 0.33) (Cowling
et al., 2009). Another study reported that risk ofinfluenza-like illness was reduced by 60% to 80%
in a subgroup of adults who used their masks mostof the time (MacIntyre et al., 2009).
Clinical aspects
Infection with the 2009 H1N1 virus causes a broad
spectrum of clinical syndromes, from afebrile up45

S. Kageyama

replicated and cause disease (Le et al., 2010). Fortunately, H275Y variants remained mostly susceptible to zanamivir. However, there emerged a 2009
A(H1N1) virus resistant not only to oseltamivir, but
to zanamivir in a immunosuppressive host due toallogeneic transplantation. This virus even resisted
peramivir (a long acting neuraminidase inhibitor)(van der Vries et al., 2010). These recent increases
in drug-resistant influenza virus variants accelerates
the need for the development of new drugs targetingother molecules and with different kinetics (Boltz etal., 2010).

per respiratory illness to severe viral pneumonia.
Fever (>38 ˚C) has been the most frequent symptom(81%–100%) among hospitalized patients. Frequencies of coughing (69%–100%), dyspnea (43%–100%,
more in children) and sore throat (4%–31%) follow.
Gastrointestinal symptoms (including nausea, vomiting and diarrhea) occur more commonly than inseasonal influenza. Rapid progression is common,
typically starting on day 4 to 5 after the onset of
illness, and intubation is often required within 24 hafter admission (Bautista et al., 2010).
Diagnosis and treatment

Prevention: non-pharmaceutical measures and immunization

In 2009, CDC conducted an evaluation of the rapid
tests for influenza diagnosis. The results showedthat overall sensitivity was low (40%–69%) among
all specimens tested and declined substantially asvirus levels decreased. This low sensitivity of therapid diagnosis system suggests that a negative result could not rule out an infection with novel influenza A (H1N1) virus although a positive result canbe used for the deciding to treat. This interpretationsuggests that treatment should be considered evenin antigen-negative cases, depending on clinical suspicion, underlying medical conditions, severity ofillness, and risk of complications. The test of realtime PCR combined with reverse transcription (rRTPCR) and/or virus isolation should be performed if
further definitive determination is required. An M
gene can be used for the target of rRT-PCR of influenza A (CDC, 2009a).
We have mainly used two anti-influenza
drugs, oseltamivir and zamanivir to date. Bothagents inhibit the neuraminidase working process.
Detailed knowledge of both pharmacokinetics
and pharmacodynamics of oseltamivir after oral
administration has been summarized elsewhere(Widmer et al., 2010). Since the outbreak of the2009 A(H1N1) virus, a number of cases of infections have been reported with oseltamivir-resistantinfluenza viruses. These strains typically containa single amino acid substitution at 275 (H275Y) of
the viral neuraminidase. The mutation of H275Y
could emerge within 48 h therapy (Inoue et al.,2010). The H275Y variant virus can be transmitted,

It has been recognized that development of strategies for mitigating the severity of a new influenza
pandemic is a top global public health priority. Influenza prevention and containment strategies canbe considered under the categories of non-pharmaceutical measures, antiviral treatment and vaccine
as partly described above. Mathematical models
have suggested that school closure can reduce peakattack rates by up to 40%, in which case isolation orhousehold quarantine has a significant impact andthat the treatment of clinical cases can reduce transmission. Household-based prophylaxis coupledwith reactive school closure could reduce clinicalattack rates by 40% to 50% (Ferguson et al., 2006).
Vaccination is the primary strategy for the prevention and control of influenza. Influenza vaccine
is trivalent, and formulated to contain three strains
representing influenza A (H1N1), A (H3N2) and
B. When human 2009 H1N1 viruses were identified in the spring of 2009, vaccine manufacturers
were already in the process of annual productionof seasonal influenza vaccine for the 2009 to 2010season. It was then decided that the production of a
vaccine against the novel virus would be produced
in addition to the seasonal vaccine. For the immediate future, priorities have been established forovercoming the rate-limiting steps in the productionof inactivated vaccines (Lambert and Fauci, 2010).
The immunogenicity of an influenza vaccine iscurrently measured by its capacity to induce func46

Pandemic influenza

tional neutralizing HA-specific antibodies in serum,
which have been proved to provide acceptable protection against influenza. Healthy adults show 70%
to 90% protection against influenza illness upon
conventional immunization, if there is a good antigenic match between the vaccine and the circulate
influenza strains. However, the protective capacity
differs depending on age and health status of population groups. Individuals at the highest risk forsevere seasonal influenza infections are the elderly,
as well as adults and children suffering of chronic
health conditions. Conventional vaccine protects
only 50% to 70% of individuals belonging to these
population groups. Lower efficacy of vaccinationin the elderly might be related to decreased immune
function, and the immune systems of small children differs from adults in that they have generated
strong immune response through frequent exposure
to influenza viruses for many years. The challenge
for future manufacturing of inter-pandemic influenza vaccine is concerned with the improvement of
immunization strategies for individuals belonging
to such high-risk populations (Fichera et al., 2009).
Although an older population has some disadvantage due to the immunological deterioration,
they have had the advantage of pre-existing crossreactive antibodies to 2009 A(H1N1) viruses acquired during the aging process through infection
and/or immunizations. On the other hand, persons
under 30 years have shown little evidence of crossreactive antibodies to the 2009 pandemic viruses
because the immunization of recent seasonal influenza vaccines induced little or no cross-reactive antibody response to 2009 A(H1N1) viruses (Hancock
et al., 2009).

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Received August 16, 2011; accepted August 22, 2011
Corresponding author: Seiji Kageyama, MD, PhD

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