THE NEXT INFLUENZA PANDEMIC

Each year at this time, as the Fall approaches and we prepare to inoculate high risk individuals with influenza vaccine, there is speculation in the media about whether the coming influenza season will be marked by major outbreaks in either epidemic or pandemic proportions. During the past century, indisputable pandemics of influenza occurred in 1918, 1957 and 1968, with significant morbidity and mortality in both high risk and normal children and adults. These pandemics tend to occur at unpredictable intervals, while epidemics tend to occur more frequently (every 1-3 years) with varying degrees of severity. There appear to be no patterns of influenza illness that allow one to predict the occurrence of the next epidemic or pandemic. All one can say is that as each year passes, we get one year closer to the next pandemic. In the 1918 pandemic, while the highest death rates occurred in infants and older individuals, the greatest absolute numbers of deaths occurred in the 20-39 year old age group. This would translate into 760,000 deaths among the 20-39 year olds in today's population. Because of the rapid spread of a future influenza pandemic due to changes in worldwide transportation and commerce we must be prepared globally to provide sufficient supplies of vaccine and be organized enough to administer these vaccines to as many people as possible.

Why so much fuss about an unpredictable event?

Past experience has indicated that pandemics have the potential to be true public health emergencies even when they resemble the 1957 and 1968 episodes which were less severe than the more infamous 1918 experience. The global danger of emerging and re-emerging microbial pathogens cannot be under-estimated. The rate of spread in the last two pandemics was quite alarming and it seems certain that the next will spread even faster. If China is considered to be the likely source of the next pandemic, the relaxation of trade and tourism restriction in that country would surely spread the virus to other countries more quickly than in the past. Furthermore the vastly increased air passenger services between countries must mean that the virus will spread around the globe more quickly than before. The least that we can do is be prepared for the next pandemic.

What are the clinical manifestations of influenza when it occurs in an epidemic or pandemic form?

Disease caused by epidemic or pandemic influenza A is unique in that people of all age groups are afflicted, usually with the acute onset of a febrile respiratory tract illness. The outbreak occurs because of a more pronounced antigenic change within the influenza virus that results in the absence of protective antibody levels in a significant proportion of both adults and children. Fever and a dry cough associated with intense malaise are found in more than 90% of cases in all age groups. The degree of prostration is generally out of proportion to the respiratory symptoms. The fever and malaise last 3 to 4 days and then diminish over this time period while the respiratory symptoms peak during this time and then resolve slowly. The main complication of influenza virus is that of pneumonia which accounts for a large degree of the morbidity and mortality; primary viral influenza pneumonia is not a complication but a manifestation of the disease at the more severe end of the spectrum. Secondary bacterial pneumonia associated with influenza occurs most commonly in those patients with underlying pulmonary or cardiac disease or other chronic illnesses, which makes them more susceptible to this complication. Influenza viruses by themselves can kill. This was true in 1918; it was true in 1957 and in 1968. Recent evidence points to the possible participation of bacteria not only as opportunistic invaders of virus damaged bronchioles but as enhancers of virus virulence. This makes the next anticipated pandemic very scary because we appear to be slipping backward, with the emergence of antibiotic resistant bacteria, towards a preantibiotic era reminiscent of 1918.

What epidemiological data are known about influenza?

Influenza A, B and C viruses are known to cause disease in humans. While influenza B and C viruses are strictly human pathogens, influenza A viruses are readily isolated from avian species, pigs and other animals. Influenza A viruses are divided into subtypes based on differences in their surface glycoprotein antigens, hemagglutinin (HA) and neuraminidase (NA). There are 14 recognized HA subtypes and 9 recognized NA subtypes. All of these subtypes have been isolated in birds but only 3 different HA and two different NA subtypes have been isolated in humans (See table 1)

The influenza viruses are unique amongst the respiratory viruses in that they undergo significant antigenic variation. Antigenic drift involves minor antigen changes from one season to the next and may result in epidemic spread of the new strain. Antigenic shift involves major antigenic changes of the HA and NA molecules and occurs only with Influenza A viruses. These changes can result in the appearance of pandemic viruses.

What are the biologic origins of pandemic influenza strains?

It is now thought that new subtypes of influenza that cause pandemics in humans arise because of the acquisition of a gene from an animal or avian virus as the result of a genetic reassortment event. In the last two decades it has become accepted that influenza viruses from aquatic birds, particularly ducks, and more recently pigs, are the primary host of influenza A viruses. Birds are thought to be the direct source of virus for reassortment in humans; however it appears more likely that there is an intermediate host such as the pig which may act as "a mixing vessel" and transmit the virus to humans. There is no doubt that influenza viruses from pigs can infect humans and cause disease. The first documented outbreak of an animal influenza virus in humans was demonstrated at Fort Dix in the United States in 1976 with the outbreak of influenza which caused infection in 230 military personnel (with one fatal outcome) which was clearly derived from swine influenza virus.

What are the geographic origins of pandemic influenza?

The most recent pandemics are thought to have arisen in China which has become known as the "epicenter" for the origin of pandemic influenza viruses. Living conditions in China seem to make it particularly feasible for animal to human transmission of influenza virus. In the villages of rural China pigs are sometimes raised in the same living quarters as their owners. This close contact is thought to promote interspecies transmission of the virus. The 1957 epidemic (H2N2) became known as the "Asian Flu" pandemic. The 1968 (H3N2) pandemic became known as the "Hong Kong flu". Only the 1918 influenza pandemic which was caused by the H1N1 subtype is thought not to have arisen in China but in Europe and has become known as the legendary "Spanish Flu". Each of these pandemics has been characterized by a major shift in one or both of the hemagglutinin or neuraminidase subtypes.

How can we (globally) best be prepared for an unpredictable influenza pandemic?

The two primary goals of a global prevention program are to gain an understanding of the epidemiology of influenza and to promptly isolate influenza virus from new outbreaks and distribute them for vaccine production. Once a new variant is detected, large quantities of vaccine will have to be produced since this is the most effective way of limiting the spread of influenza. Should a pandemic occur in the next couple of years, then the current inactivated muitivalent vaccine would the mainstay of prevention. Live attenuated influenza virus vaccines are currently being developed and appear to be promising. The advantages of the live attenuated vaccine include the administration of only a single intranasal innoculation which would induce local mucosal immunity and also be more cost effective than the other alternatives. The use of DNA vaccines for influenza control remain somewhat theoretical but its potential in the pandemic situation is so great that intense research is being conducted in this direction. Antiviral agents such as Amantadine and Rimantadine have their limitations but would be useful as short-term prophylaxis during an outbreak of Influenza A until sufficient vaccine can be produced and administered.

How can we best be prepared for the next, more predictable, influenza epidemic?

Influenza epidemics occur at 1-3 year intervals usually in the late fall. Annual inoculations with the current influenza vaccine for that particular year should be administered to all high risk children and adults as well as health care professionals, where it has been shown to significantly reduce both morbidity and mortality. If physicians were more successful at vaccinating high risk individuals, than the current annual 10% rate for children and 40% rate for adults then we would be much better prepared for the next unpredictable pandemic which could come as soon as the fall of 1997 or 1998 or……….

References:

1. Pandemic Influenza Plan.The Journal of Infectious Diseases 1997; 176 (Suppl)

S1-90

2. Ryan-Poirier K, Influenza Virus infection in Children, in Advances in Pediatric

Infectious Diseases, Mosby, St Louis, 1995;125-156.