During the past 100 years, three worldwide (pandemic) influenza outbreaks have occurred. Each differed from the others with respect to etiologic agents, epidemiology, and disease severity. The first was the “Spanish flu” (influenza A [H1N1]) of 1918. The origin of this pandemic has always been disputed and may never be resolved. It is estimated that approximately 20% to 40% of the world population became ill and over 20 million people died. Between September 1918 and April 1919 approximately 500,000 deaths from influenza occurred in the United States alone. Many people died very quickly. The Spanish flu was unique because the causative agent was very deadly. One of the most unusual aspects of the Spanish flu was its ability to kill young adults. The reasons for this remain uncertain. 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. ⁶

In February 1957 the Asian influenza, (influenza A [H2N2]) 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 about 3 months after the first outbreaks occurred in China, and health officials increased surveillance for flu outbreaks. By June 1957, it had spread to the United States and subsequently caused approximately 70,000 deaths with the highest mortality among the older adult population. Infection rates were highest among school children, young adults, and pregnant women. By December 1957, the worst seemed to be over. However, during January and February 1958, there was another wave of illness among older adults. 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. ⁶

The pandemic of 1957 provided the first opportunity to observe vaccination response in that large part of the population that had not previously been primed.

The third pandemic and the most recent, “Hong Kong flu” (influenza A [H3N2]), occurred in 1968. The first cases were detected in Hong Kong in early 1968. The pandemic, which was milder than 1957, is thought to have caused around 1 million deaths worldwide, and nearly 34,000 deaths in the United States. Those over the age of 65 were most likely to die. There could be several reasons why fewer people in the United States died as a result of 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, as pandemic influenza had in the previous two pandemics, this pandemic did not gain momentum until near the school holidays in December. Because 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. In the 1968 pandemic, vaccines became available 1 month after the outbreaks peaked in the United States. ⁶

It is difficult to predict when the next influenza pandemic will occur or how severe it will be. Wherever and whenever a pandemic starts, everyone around the world is at risk. Countries might, through measures such as border closures and travel restrictions, delay arrival of the virus, but cannot stop it.

In January 1976 an outbreak of respiratory disease was identified at Ft. Dix, New Jersey. On February 12 the Centers for Disease Control and Prevention (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 March 24, 1976, President Ford met with representatives from the CDC, Food and Drug Administration (FDA), and National Institutes of Health (NIH), as well as other experts. There was a unanimous recommendation to initiate mass immunization. The first vaccine dose was given 7½ months after the virus was identified. Within 9½ months, 150 million doses of vaccine had been produced under a federal contract. The first vaccine was shipped to state health departments on September 22, 1976, and the first injections were given on October 1, 1976. Vaccination programs continued based on state plans and capacities, with some states aggressively implementing mass vaccinations 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—a severe neurologic condition associated with paralysis that may include the respiratory muscles and may be fatal—were reported from Minnesota. On December 16, 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. ⁴

In May 1977 influenza A(H1N1) viruses, isolated in northern China, spread rapidly and caused epidemic disease in children and young adults (less than 23 years of age) worldwide. The 1977 virus was similar to other influenza A(H1N1) viruses that had circulated before 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 1977-1978 season; however, the virus was included in the 1978-1979 vaccine. ¹²

Box 39-1 describes a more recent outbreak of influenza A(H1N1).

Of all influenza viruses that circulate in birds, the H5N1 virus is of greatest present concern for human health for two main reasons. First, the H5N1 virus has caused the greatest number of human cases of very severe disease and the greatest number of deaths. It has crossed the species barrier to infect humans. Since 2003 the World Health Organization (WHO) has reported 319 human cases of avian influenza A(H5N1) with 192 deaths. ¹⁸ As more humans become infected with the H5N1 virus, transmissibility to humans improves. ¹⁵

The virus can improve its transmissibility among humans via two principal mechanisms. The first is a reassortment event, in which genetic material is exchanged between human and avian viruses during co-infection of a human or pig. Reassortment could result in a fully transmissible pandemic virus, announced by a sudden surge of cases with explosive spread. ¹⁷

The second mechanism is a more gradual process of adaptive mutation, whereby the capability of the virus to bind to human cells increases during subsequent infections of humans. Adaptive mutation, expressed initially as small clusters of human cases with some evidence of human-to-human transmission, would probably give the world some time to take defensive action, if detected sufficiently early. ¹⁷

A second concern for human health is the risk that the H5N1 virus will develop the characteristics it needs to start an influenza pandemic. The virus has met all prerequisites for the start of a pandemic except one: the ability to spread efficiently and develop sustainability among humans. Although H5N1 is presently the virus of greatest concern, the possibility that other avian influenza viruses, known to infect humans, might cause a pandemic cannot be ruled out. ¹⁷

Current available data indicate that close contact with dead or sick birds is the principal source of human infection with the H5N1 virus. Especially risky behaviors include the slaughtering, defeathering, butchering, and preparation for consumption of infected birds. At present, H5N1 avian influenza remains largely a disease of birds. Investigations of all the most recently confirmed human cases, in China, Indonesia, and Turkey, have identified direct contact with infected birds as the most likely source of exposure. ¹⁷