Pandemic Influenza
Influenza pandemics can occur when a novel strain of virus causes an epidemic that spreads over a wide geographic area and affects an exceptionally high proportion of the population. Intervals between previous pandemics have varied from 11 to 42 years with no recognisable pattern. The last pandemic was in 1968/69. Prior to that pandemics occurred in 1957/58 and 1918/19. The impact of the next pandemic could have a devastating effect on the health and well being of the American public. Widespread illness in the community will also increase the likelihood of sudden and potentially significant shortages of personnel who provide other essential community services.
Influenza pandemics have occurred throughout recorded history and have been documented since the 16th century. There have been substantial differences between them, including between the three pandemics of the last century. There is therefore considerable uncertainty about both the timing of a future pandemic and its precise impact - the severity of illness caused by the new virus strain, the rapidity of its spread and the groups of the population which will be most susceptible are all unknown factors. Nonetheless, for planning purposes, reports of previous pandemics give an interesting insight into the likely range of impact.
Cause of Pandemics
Influenza pandemics occur when there is a notable genetic change (termed genetic shift) in the circulating strain of influenza. Because of this genetic shift, a large portion of the human population is entirely vulnerable to infection from the new pandemic strain.
Three virus types, influenza A, B and C, can cause respiratory illness and are easily transmitted in crowded and enclosed spaces. Regional and widespread epidemics are most often attributed to influenza A and B viruses, while type C is associated with mild illness, sporadic cases, or minor outbreaks. Influenza A causes the most severe disease in humans, and is the most likely to trigger a pandemic.
Influenza A and B possess two surface glycoprotein's: the hemagglutinin (H) and neuraminidase (N). The H subtypes are epidemiologically most important, as they govern the ability of the virus to bind to and enter cells, where multiplication of the virus then occurs. The N subtypes govern the release of newly formed virus from the cells. Influenza A viruses are further subdivided into subtypes dependent on differences in these surface glycoprotein's. Although only two influenza A subtypes currently co-circulate globally in humans (H1N1 and H3N2), at least 16 distinct antigenic subtypes of HAs (H1 to H16) and nine NAs (N1 to N9) have been identified in wild aquatic birds.
A minor change in these antigens (antigenic drift) may result in epidemics, since incomplete protection remains from past exposure to similar viruses. A major change (antigenic shift) may result in a worldwide pandemic if the virus, for which humans have no protection, is efficiently transmitted from human to human. Antigenic shift occurs only with influenza A viruses. Influenza A viruses were the cause of the three Pandemics in the 20th Century.
Difficulty in controlling illness from one flu season to the next is due to changes in virus types A and B. Both undergo constant, but relatively subtle mutations (antigenic drift), accounting for the different influenza epidemiology, strains, and vaccines seen from year to year. As they lack a proof-reading mechanism, the small errors that occur when the virus copies itself are left undetected and uncorrected. As a result, influenza A viruses undergo constant stepwise changes in their genetic make-up. This strategy, known as antigenic drift, works well as a short-term survival tactic for the virus: the speed with which slight variations develop keeps populations susceptible to infection.
Pandemics occur when an entirely new subtype of influenza A virus emerges (antigenic shift) through recombination of human and animal antigens (swine or avian). Not all antigenic shifts cause a pandemic, but if a novel subtype is virulent and easily transmitted, a pandemic is probable. Apart from being highly unstable and prone to small mutational errors, influenza viruses have a segmented genome, consisting of eight genes, that allows easy swapping of genetic material - like the shuffling of cards - coinfecting a host with two different viruses. If this new "hybrid" virus contains the right mix of genes, causing severe disease and allowing easy and sustainable human-to-human transmission, it will ignite a pandemic. This works well as a long-term survival tactic: immunologically, a new virus subtype starts from scratch and is guaranteed a very large population of susceptible hosts.
Flu Pandemics in History
Influenza pandemics are believed to have occurred for at unpredictable intervals for many centuries. Since the first well-described pandemic of influenza-like disease occurred in 1580, 31 influenza pandemics have been documented.
In 412 BC Hippocrates, the father of medicine, described a flu-like disease for the first time at Perinthus in North Greece. Diodorus Siculus recorded an epidemic that swept through the Athenian army in Sicily. Some historians have speculated that influenza may have contributed to the demise of Athens in 404 BC.
The term, influenza, from the Italian word meaning "influence", was coined 1357 AD. Popular belief at that time blamed the development of flu on the influence of the stars.
In 1485 the "sweating sickness", a flu-like malady, sickened hundreds of thousands of people in Britain. The Lord Mayor of London, his successor, and six aldermen died. The Royal Navy could not leave port due to the sickness of sailors. Doctors prescribed tobacco juice, lime juice, emetics, cathartics, and bleeding in attempts to cure their patients.
The first recorded global spread of flu swept out of Asia in 1580, then infected Africa, Europe and ultimately America, where over 90 percent of the populace was afflicted. Mortality was extremely high, with doctors treating their patients by bleeding them.
During the 18th century at least three pandemics occurred (1729-1730, 1732-1733, and 1781-1782). The 1781 pandemic was a major outbreak that caused high mortality among the elderly that spread across Russia from Asia. Other major outbreaks occured in 1889-1890 and in 1900.
The Spanish Flu of 1918 is considered the most severe of all influenza outbreaks to date, but the pandemic of 1830 through 1832 was similarly severe - it simply occurred when the world's population was smaller. Four major influenza epidemics were recorded between 1830 and 1848. The 1830-1831 epidemic may have originated in China; and in 1833 influenza advanced westward out of Russia into Europe. In 1836-1837, influenza diffusion was largely north to south, and in 1847-1848 the disease swept through the Mediterranean to southern France and thence elsewhere in Western Europe. Each of the four epidemics spread rapidly and caused very high morbidity rates. Although case-mortality rates were always low, each epidemic killed thousands of people, with most deaths being among the elderly. Many writers have described all four outbreaks as pandemics, but true pandemics, presumably caused by major new viral types, are clearly identifiable only in 1830-1831 and 1833. The status of the 1836-1837 outbreak is unclear, but there was no pandemic in 1847-1848.
The 1889 pandemic was believed to have originated in China. It rapidly spread via Russia throughout Europe (known as the "Russian Flu"). It spread thence to North America and then Japan. It reached North America in December 1889 and spread to Latin America and Asia in February of 1890. Approximately 1 million people were known to have died as a result of this pandemic.
1918 Spanish Influenza Pandemic
The Spanish Influenza pandemic is the catastrophe against which all modern pandemics are measured. Before the 1918 epidemic, one has to go back to the black death (bubonic plague) of 1346 to find a similarly devastating epidemic in terms of total numbers of deaths. The "Spanish" attribution of the epidemic, common in the literature, is thought to be a result of the fact that the press in neutral Spain was not censored during World War I, and therefore some early printed reports of the flu originated from Spain. The spread of influenza in the US during the second wave of the 1918 pandemic began in Mid-Septebmer, and within three weeks, influenza had spread across the entire country.
Given the empirical infuenza epidemic curve and infection rates observed in the United States in 1918, it has been estimated that a very large proportion of the population was infected with the Spanish Flu in 1918, and thereafter immune to the virus. According to these estimates, only a very small proportion of the population remained susceptible to influenza after the pandemic {too small to support the initiation of another epidemic the following season. But another influenza epidemic that did in fact occur in 1919, is a puzzle. The virus may have evolved to such an extent in 1918 that could re-infect individuals in 1919. Or the virus could have persisted in 1919 due to heterogeneities in the host population and "pockets" of remaining susceptibles. Or perhaps the virus may have evolved a greater ability to spread, allowing it to persist despite the small number of susceptible hosts to support it.
As expected, many of the deaths in 1918 were from pneumonia caused by secondary bacterial infections. But Spanish flu also caused a form of primary viral pneumonia, with extensive hemorrhaging of the lungs, that could kill the perfectly fit within 48 hours or less. Many people died from this very quickly. Some people who felt well in the morning became sick by noon, and were dead by nightfall. Those who did not succumb to the disease within the first few days often died of complications from the flu (such as pneumonia) caused by bacteria.
The male death rates in 1918 far exceed the female death rates among adults. One of the most unusual aspects of the Spanish flu was its ability to kill young adults. The reasons for this remain uncertain. In general the rate of death is highest for the very young and older persons. The 1918 pandemic followed a strikingly different pattern, with the highest mortality in young persons 25-30 years old. With the Spanish flu, mortality rates were high among healthy adults as well as the usual high-risk groups. The attack rate and mortality was highest among adults 20 to 50 years old. The severity of that virus has not been seen again in humans.
The reasons for this difference are still poorly understood. It is believed that a subset of victims experienced a primary viral pneumonia which caused a very rapid clinical decline and death. It is widely belived that cytokine storming [Immune-complexes-mediated pathogenesis] could be one of the mechanisms that resulted in damaging the lung tissue. Normally, when the lungs are under attack from a virus, T-cells, defenders from the immune system, are then sent to the site of the infection. The presence of T-cells initiate a second immune system attack by chemicals, known as cytokines, that cause inflammation. A cytokine is a small protein released by cells that has a specific effect on the interactions between cells, on communications between cells or on the behavior of cells. The cytokines includes the interleukins, lymphokines and cell signal molecules, such as the interferons, which trigger inflammation and respond to infections. When the lungs are infected with the flu virus, the T cells release chemical signals that cause them to stay longer in the lungs. The systemic symptoms of seasonal flu are caused by cytokine release, which is part of the human immune response.
A Cytokine storm [a systemic inflammatory response syndrome] -- immune system "friendly fire" -- is believed to be the underlying reason for the high death rate among young adults. It results when too many immune cells are in an endless loop of calling even more cytokines. During the flu infection the immune system has an "all hands on deck" attitude to the viral assault. More T cells are always arriving, and they in turn release more signal and stay longer, leading to a build up of T cells and chemical signals. The exaggerated immune response produces inflammatory molecules that lead to too many cells clogging up the airways and preventing efficient transfer of oxygen into the bloodstream. This Acute Respiratory Distress Syndrome [ARDS] is what makes the Cytokine storm so deadly in pandemic flu. It is suggested that the high death rate among healthy young adults was due to their strong immune systems producing a cytokine storm. The very young and very old would have had weaker immune systems, and thus weaker immune responses that would not result in a cytokine storm.
One researcher suggested that many of the apparently healthy young adults who died in 1918 were in fact infected with tuberculosis, explaining the unusually high mortality rates among young adults. Tuberculosis death rates plummeted after 1918, which can be explained by the fact that many TB sufferers died of the flu and therefore were not around to die later, nor to pass the TB bacillus to others. Just after 1918, TB death rates experience their steepest decline of the century, and this decline is much more pronounced for males than for females. [Fortunately, tuberculosis prevalence is much lower than in 1918, which bodes well for our potential susceptibility to a repeat of 1918.]
It is estimated that approximately 20 to 40 percent of the worldwide population became ill during the Spanish Flu. The number of worldwide dead due to the 1918 pandemic was initially reported as 20,000,000. A consensus has formed among experts now that the death toll was at least 40 million, and possibly much higher. Nobel laureate Frank MacFarlane Burnet believed deaths were at least 50 million, and may bave reached 100 million. Between September 1918 and April 1919, approximately 500,000 to 675,000 deaths from the flu occurred in the US alone. Western Samoa and Iceland avoided the 1918 flu entirely through the use of travel restrictions.
Though the identification of aetiology of the pandemic was not possible at that time, modern day molecular biological techniques have tried to unravel its mystery. Modern techniques have permitted a reconstitution of some parts of the genome of the 1918 agent by amplifying fragments of viral RNA obtained from different sources. One of them was anatomopathologic samples of lungs from patients who died of the disease in 1918. Other samples were obtained after the exhumation of victims of Spanish flu in Alaska and in Svalberg whose bodies had been buried in permafrost ground. Genetic sequences were obtained by genic amplification of viral RNA extracted from the lung fragments and were compared to recent human and animal viruses. The comparison showed that the hemagglutin of the 1918 virus was of the H1 subtype belonging to a subgroup of strains infecting human and pigs, but also sharing avian determinants. Sequence analysis indicates that many avian characteristics are present in critical locations of the hemagglutinin gene such as receptor, antigenic and glycosylation sites suggesting an avian relationship. However, the virus is closely related to human and swine viruses. Equivalent findings were obtained from the study of the neuraminidase gene: the enzymatic site is preserved but avian characteristics are found in antigenic and glycosylation sites. These results suggest that the 1918 virus borrowed determinants from avian strains but was already present in mammals for a prolonged period before the pandemic started.
1957 Asian Flu Pandemic
In 1957, which was on the whole a much milder illness than that of 1918, the global death toll was estimated to be around 2 million. In 1957, the Asian flu pandemic resulted in about 70,000 deaths in the United States. An excess 30,000 deaths occurred in England and Wales of which 6,716 were ascribed to influenza itself. Estimates in the UK ranged from 1.3 to 3.5 deaths/1,000 cases. An estimate from 29 British general practices was 2.3 deaths per 1,000 cases attended.
In February 1957, the Asian influenza pandemic was first identified in the Far East. Immunity to this strain was rare in people less than 65 years of age, and a pandemic was predicted. In preparation, vaccine production began in late May 1957, and health officials increased surveillance for flu outbreaks.
Unlike the virus that caused the 1918 pandemic, the 1957 pandemic virus was quickly identified, due to advances in scientific technology. Vaccine was available in limited supply by August 1957. The virus came to the US quietly, with a series of small outbreaks over the summer of 1957. When US children went back to school in the fall, they spread the disease in classrooms and brought it home to their families. Infection rates were highest among school children, young adults, and pregnant women in October 1957. Most influenza-and pneumonia-related deaths occurred between September 1957 and March 1958. The elderly had the highest rates of death.
During the 1957-1958 pandemic, a WHO expert panel found that spread within some countries followed public gatherings, such as conferences and festivals.16 This panel also observed that in many countries the pandemic broke out first in camps, army units and schools; suggesting that the avoidance of crowding may be important in reducing the peak incidence of an epidemic.
During the first wave of the Asian influenza pandemic of 1957-1958, the highest attack rates were seen in school aged children. This has been attributed to their close contact in crowded settings. A published study found that during an influenza outbreak, school closures were associated with significant decreases in the incidence of viral respiratory diseases and health care utilization among children aged 6-12 years.
In 1957, up to 50% of British schoolchildren developed influenza, but even those schools which were severely disorganised had returned to normal 4 weeks after the appearance of the first case. In residential schools in the UK, attack rates reached 90%, often affecting the whole school within a fortnight.
In Liverpool in 1957 12.6-19.4% of nurses were absent during the first 4 weeks of the epidemic; in one hospital, nearly a third were absent at the peak. During September and October 1957, the two main months of the epidemic in the UK, it was estimated between 25,000 and 30,000 more cases of acute respiratory infection were admitted to NHS hospitals in England and Wales than would have been expected at that time of year. Hospital admission and bed bureaux could barely cope with the demand placed upon them.
In 1957, of patients with pneumonia studied mainly in London teaching hospitals, 28% of those with staphylococcal pneumonia and 12% with non-staphylococcal pneumonia died. The death rate among patients with pneumonia fell during the course of the epidemic from around 20% to 13%. Deterioration can be very rapid and a high proportion of those hospitalised who die, do so within 48 hours of admission, ie so rapidly that antibiotics may have little or no effect.
Vaccine production for the Asian flu began about 3 months after the first outbreaks occurred in China. The first cases in the US occurred in the summer, with a peak in October following school openings. The first doses of vaccine became available in September and by mid-October at the peak of the US pandemic fewer than half of the approximately 60 million doses produced had been delivered.
By December 1957, the worst seemed to be over. However, during January and February 1958, there was another wave of illness among the elderly. This is an example of the potential "second wave" of infections that can develop during a pandemic. The disease infects one group of people first, infections appear to decrease and then infections increase in a different part of the population.
Other pandemics had a faster spread than in 1957, in general the weekly profile for these pandemics had a higher peak and a shorter base.
The conventional wisdom conveys China's Great Leap Forward famine as a man-made disaster where misguided economic policies precipitated widespread famine and world record-breaking population losses. Barbara Sands reconstructed regional population and grain availability data to find more complex patterns than those suggested by classic famine. While allowing for considerable excess mortality in this period, she suggested that portions of it were due to the influenza pandemic of 1957, an alternative explanation of the Great Leap Forward famine.
1968 Hong Kong Flu
The most recent influenza pandemic occurred in 1968 with the Hong Kong Flu (H3N2) outbreak, which resulted in nearly 34,000 deaths in the United States. The 1968/69 pandemic, which was milder than 1957, is thought to have caused around 1 million deaths worldwide. In early 1968, the Hong Kong influenza pandemic was first detected in Hong Kong. 1968. It then spread worldwide during the following two winters, causing greater morbidity in some countries the first winter and others the second. The first cases in the US were detected as early as September of 1968, but illness did not become widespread in the US until December 1968. Deaths from this virus peaked in December 1968 and January 1969. Those over the age of 65 were most likely to die. The same virus returned a year later, in late 1969 and early 1970 [peaking in the UK in January 1970] and in 1972. The number of deaths between September 1968 and March 1969 for this pandemic was 33,800, making it the mildest pandemic in the 20th century.
In the 1968 pandemic vaccine became available one month after the outbreaks peaked in the US.
There could be several reasons why fewer people in the US died due to this virus. First, the Hong Kong flu virus was similar in some ways to the Asian flu virus that circulated between 1957 and 1968. Earlier infections by the Asian flu virus might have provided some immunity against the Hong Kong flu virus that may have helped to reduce the severity of illness during the Hong Kong pandemic. Second, instead of peaking in September or October, like pandemic influenza had in the previous two pandemics, this pandemic did not gain momentum until near the school holidays in December. Since children were at home and did not infect one another at school, the rate of influenza illness among schoolchildren and their families declined. Third, improved medical care and antibiotics that are more effective for secondary bacterial infections were available for those who became ill.
1976 Swine Flu Pandemic Scare
On 27 January 1976, an outbreak of respiratory disease was identified at Ft. Dix, New Jersey. On February 12 the CDC influenza laboratory notified the CDC Director that a swine influenza virus strain (H1N1) had been isolated from patients that possessed hemagglutinin and neuraminidase subtypes that had not circulated for more than 50 years. Experience had led scientists to conclude that introduction of a new strain inevitably resulted in a pandemic. On 24 March 1976 President Ford met with CDC, FDA, and NIH representatives and other experts. There was a unanimous recommendation to initiate mass immunization.
The first vaccine dose was given 7.5 months after the virus was identified. By 9.5 months, 150 million doses of vaccine had been produced under a federal contract. The first vaccine was shipped to State Health Departments on 22 September 1976 and the first injections were given on 01 October 1976. Vaccination programs proceeded based on state plans and capacities, with some aggressively implementing mass vaccination and others implementing more limited programs. Overall, between October 1 and December 16, more than 40 million civilians were vaccinated. In November 1976, several cases of Guillain-Barré syndrome (GBS) - a severe neurological condition associated with paralysis that may include the respiratory muscles and may be fatal - were reported from Minnesota. On 16 December 1976, based on CDC's recommendation and after consultation with the President, the Assistant Secretary for Health announced the suspension of the swine influenza vaccination program.
Recent Pandemic Flu Scares
The Russian Flu scare began in May 1977, when influenza A/H1N1 viruses isolated in northern China spread rapidly, and caused epidemic disease in children and young adults (< 23 years) worldwide. This was a "benign" pandemic, primarily involving persons born after the 1950s. The 1977 virus was similar to other A/H1N1 viruses that had circulated prior to 1957. In 1957, the A/H1N1 virus was replaced by the new A/H2N2 viruses. Because of the timing of the appearance of these viruses, persons born before 1957 were likely to have been exposed to A/H1N1 viruses and to have developed immunity against A/H1N1 viruses. Therefore, when the A/H1N1 reappeared in 1977, many people over the age of 23 had some protection against the virus and it was primarily younger people who became ill from A/H1N1 infections. By January 1978, the virus had spread around the world, including the United States. Because illness occurred primarily in children, this event was not considered a true pandemic. Vaccine containing this virus was not produced in time for the 1977-78 season, but the virus was included in the 1978-79 vaccine.
The most recent pandemic "scares" was the Avian Flu Scare in 1997 and 1999. In 1997, at least a few hundred people became infected with the avian A/H5N1 flu virus in Hong Kong and 18 people were hospitalized. Six of the hospitalized persons died. This virus was different because it moved directly from chickens to people, rather than having been altered by infecting pigs as an intermediate host. In addition, many of the most severe illnesses occurred in young adults similar to illnesses caused by the 1918 Spanish flu virus. To prevent the spread of this virus, all chickens (approximately 1.5 million) in Hong Kong were slaughtered. The avian flu did not easily spread from one person to another, and after the poultry slaughter, no new human infections were found.
In 1999, another novel avian flu virus - A/H9N2 - was found that caused illnesses in two children in Hong Kong. Although both of these viruses have not gone on to start pandemics, their continued presence in birds, their ability to infect humans, and the ability of influenza viruses to change and become more transmissible among people is an ongoing concern.
Several novel virus alerts have been issued since 1977, none of which progressed to a pandemic. These include isolated cases and limited clusters of swine H1N1 influenza virus infections, avian H5N1 infections in 2003 (two persons hospitalized), avian H7N7 in 2003 (83 human illnesses, including one death), and avianH5N1 in 2004 (34 human illnesses, including 23 deaths as of May 2004). Control measures have included culling of poultry and protection of those who may have been exposed to the avian influenza virus, particularly those with high-level exposure (e.g., those doing the culling).
Very limited person-to-person transmission occurred during the 1976 Swine influenza outbreak in the US, the 1997 H5N1 avian influenza outbreak in Hong Kong, and also during the 2003 H7N7 avian influenza outbreak in the Netherlands. None of these outbreaks progressed to the next pandemic level possibly because none of these viruses were animal/human reassortants and, in case of the avian influenza outbreaks, aggressive efforts to eliminate the domestic animal reservoir were carried out.
