73 Influenza

Influenza, also known as flu, grip, and grippe, is a disease of humans, pigs, horses, and several other mammals, as well as of a number of species of domes­ticated and wild birds.

There is at present no specific cure that is effective against this viral disease. In mild cases the acute symptoms disappear in 7 to 10 days, although gen­eral physical and mental depression may occasion­ally persist. Influenzal pneumonia is rare, but often fatal. Bronchitis, sinusitis, and bacterial pneumonia are among the more common complications, and the last can be fatal, but seldom is if properly treated. Influenza is generally benign, and even in pandemic years, the mortality rate is usually low — 1 percent or less-the disease being a real threat to life for only the very young, the immunosuppressed, and the elderly. However, this infection is so contagious that in most years multitudes contract it, and thus the number of deaths in absolute terms is usually quite high. Influenza, combined with pneumonia, is one of the 10 leading causes of death in the United States in the 1980s. The sequelae of influenza are often hard to discern and define - prolonged mental depression, for instance - but there is evidence that the global pandemic of encephalitis Iethargica (par­kinsonism) of the 1920s had its origin in the great pandemic of 1918-19.

Distribution and Incidence

In seemingly every year, there are at least some cases of influenza in every populated continent and in most of the large islands of the world. During epidemics, which occur somewhere almost annually, the malady sweeps large regions, even entire conti­nents. During pandemics, a number of which have occurred every century for several hundred years, the disease infects a large percentage of the world’s

population and, ever since the 1889-90 pandemic, in all probability a majority of that population. Not everyone so infected becomes clinically sick, but nonetheless influenza pandemics are among the most vast and awesome of all earthly phenomena. The disease strikes so many so quickly and over such vast areas that the eighteenth-century Italians blamed it on the influence of heavenly bodies and called it influenza.

Etiology and Epidemiology

The causative agents of influenza are three myxovi- ruses, the influenza viruses A, B, and C. The B and C viruses are associated with sporadic epidemics among children and young adults, and do not cause pandemics. The A virus is the cause of most cases during and between pandemics. It exists and has existed in a number of subtypes, which usually do not induce cross-immunity to one another. In most instances, influenza viruses pass from person to per­son by breath-borne droplets, and from animal to animal by this and other routes. Although the dis­ease can spread in warm weather, its epidemics among humans in the temperate zones usually ap­pear in the winters, when people gather together in schools, houses, buses, and so forth under conditions of poor ventilation. Geographically, the malady spreads as fast as its victims travel, which in our time can mean circumnavigation of the globe in a few months, with the pandemic veering to the north and south of the tropics with the changing seasons.

Immunology

Influenza A virus is distinctive in its genetic instabil­ity, which probably makes permanent immunity to the disease impossible, no matter how many times it is contracted.

The cause of the major changes in the virus that set off the pandemics is still a matter of mystery. Many theories have been devised, including those pertaining to the influence of sun spots and such. Currently the three most plausible theories are the following:

1. The influenza A virus currently circulating through the human population undergoes a se­ries of mutations, which rapidly and radically transform the virus into an infection-producing organism for which human immune systems are unprepared.

2. An animal influenza virus abruptly gains the abil­ity to cause disease in humans, with the same results.

3. A human influenza virus and an animal influenza virus recombine (“cross-breed”) to produce a new virus that retains its capacity to infect humans but has a surface with which human immune systems are unfamiliar.

In the present state of research, the first of these three seems the least likely and the last the most likely explanation. Nothing, however, is certain yet, and the cause of influenza pandemics remains unknown.

History and Geography

Through the Eighteenth Century

The origins of influenza are unknown. It is not an infection of our primate relations, and so it is proba­bly not a very old human disease. It has, as far as we know, no latent state, and it does create a usually effective (though short-lived) immunity, and so it was imlikely to have been common among our Paleo­lithic ancestors or those of our herd animals before the advent of agriculture, cities, and concentrated populations of humans and domesticated animals. In small populations, it would have burnt itself out by killing or immunizing all available victims quickly. But because the immunity engendered is ephemeral, it does not require the large populations that mea­sles and smallpox do to maintain itself.

Although influenza could be among the older dis­eases of civilization, acquired from pigs or ducks or other animals thousands of years ago, there is no clear evidence of its spread among humans until Europe’s Middle Ages, and no undeniable evidence until the fifteenth and sixteenth centuries. Yet, since that time, the malady has been our unfailing companion, never absent for more than a few de­cades, if that. The association of the disease with Old World domesticated animals, and the extreme vul­nerability to it of isolated peoples such as Amerindi­ans, suggest that it was restricted to the Old World until the end of the fifteenth century. In that and the following centuries it spread overseas with Europe­ans and their livestock, and may account for much of the clinically undefined morbidity and mortality among the indigenes of Europe’s transatlantic and transpacific empires. Large-scale epidemics of influ­enza did roll over Europe in 1510, 1557, and 1580. The last, the first unambiguously pandemic explo­sion of the disease, extended into Africa and Asia as well. There were further epidemics in Europe in the seventeenth century, but seemingly of only a re­gional nature.

At least three pandemics of influenza occurred in Europe in the eighteenth century - 1729-30, 1732­3, and 1781-2 - and several epidemics, two of which - 1761-2 and 1788-9 - may have been exten­sive enough to be termed pandemics.

Nineteenth Century

By the end of the eighteenth century, accelerating population growth, urbanization, and improvements in transportation were changing the world in ways that enhanced the transmission of microbes across long distances. There were at least three influenza pandemics in the nineteenth century: 1830-1, 1833, and 1889-90, and a number of major epidemics as well. Even so, one of the most intriguing aspects of the history of influenza in this century was the long hiatus between the second and third pandemics. In fact, in Europe, from the epidemic of 1847-8 (de­fined a pandemic by some) to 1889, there were only a few minor upsurges of this disease.

When influenza rose up again in 1889, most physi­cians had only a textbook acquaintance with the disease, but by this time the medical sciences were making rapid advances, and public health had be­come a matter of governmental concern. The 1889­90 pandemic was the first for which we have de­tailed records. It reached Europe from the east (hence its nickname, the Russian flu), and such was the efficiency of transatlantic shipping that it swept over western Europe and appeared in North Amer­ica in the same month, December of 1889. It struck Nebraska, Saskatchewan, Rio de Janeiro, Buenos Aires, Montevideo, and Singapore in February, Aus­tralia and New Zealand in March. By spring the pandemic was firmly established and widespread in Asia and Africa. Some Africans, who had never seen the disease in their lifetimes, called it a “white man’s disease.” Waves of this infection continued to roll across large regions of the world for the rest of the century, and although the mortality rates in this pandemic were quite low, the total of deaths was high. By conservative estimate, 250,000 died in Eu­rope, and the world total must have been at the very least two or three times greater.

Early Twentieth Century

Its history for the first 17 years of the next century reinforced this view. Although rarely absent for long, influenza attracted little attention until 1918­19, when a pandemic of unprecedented virulence appeared. What was probably its first wave rose in the spring of 1918, perhaps first in the United States, attracting little attention because its death rate was low. Its most ominous characteristic was that many of the dead were young adults, in contra­distinction to the malady’s previous record. That spring and summer, this new influenza circumnavi­gated the globe, infecting millions and killing hun­dreds of thousands, and making ever more difficult the waging of wars in Europe and the Middle East. The name given this new disease was the Spanish flu, not because morbidity and mortality were higher there than elsewhere, but because Spain was not a belligerent and thus the ravages of the malady in that country were not screened from world atten­tion by censorship. As in previous pandemics and epidemics, morbidity rates were vastly greater than mortality rates, and the latter, as a percentage of the former, were not impressive.

In August, that changed, as death rates doubled, tripled, and more. A second wave arose, sending hundreds of millions to sickbeds, as if they were as immunologically inexperienced as children, and kill­ing millions. This wave tended to subside toward the end of the year, but returned again in a third wave in the winter and spring. In both the fall and winter waves, about half the deaths were in the 20- to 40- year-old group. Fully 550,000 died in the United States, about 10 times the number of battle deaths of Americans in World War I.

In remote parts of the world, where influenza had never or rarely reached before, the death rate was often extremely high. In Western Samoa, 7,542 died out of a population of 38,302 in the last 2 months of 1918. The total of deaths in the world was in excess of 21 million, that number being an estimate made in the 1920s before historians and demographers sifted through the records of Latin America, Africa, and Asia, adding many more - millions, certainly — to the world total. It is possible that the 1918-19 pandemic was, in terms of absolute numbers, the greatest single demographic shock that the human species has ever received. The Black Death and World Wars I and II killed higher percentages of the populations at risk, but took years to do so and were not universal in their destruction. The so-called Spanish flu did most of its killing in a 6-month period and reached almost every human population on Earth. Moreover, its impact was even greater than these numbers indicate because so many young adults died. To this day, we do not know what made the 1918-19 influenza such a killer. Theories about wartime deprivation are clearly invalid because the death rates in well-fed America and Australasia were approximately the same as in the nations im­mediately engaged in the fighting. Perhaps as has been suggested, a chance synergy of viral and bacte­rial infection produced an exceptionally deadly pneu­monia, or perhaps the 1918 virus was so distinctive antigenically that it provoked a massive immune response, choking the victims with inflammation and edema. We have no way of proving or disproving these theories.

In 1920, another wave of the disease rolled over the world, and in the United States this was, with the exceptions of the two preceding years, the worst for influenza mortality of all time. But morbidity and mortality rates soon shrank back to normal lev­els, and the disease lost most of its power to kill young adults. The medical profession, however, has subsequently worried about a resurgence of the killer virus, and has devoted great energy to identify­ing it, learning its secrets, and how to disarm it.

Prevention and Control

The medical profession, grappling with the great pandemic, labored under three major disadvan­tages: First, in the 1890s one of the premier bacteri­ologists of the world, Richard F. J. Pfeiffer, thought he had discovered the causative organism, common in his time and again in the fall of 1918. Unfortu­nately, Pfeiffer’s bacillus was not the cause, al­though it doubtlessly played a role in many secon­dary infections. Its chief significance is probably that it inveigled many scientists into wasting a lot of time discovering its insignificance. Second, influ­enza was believed to be an exclusively human dis­ease, making it very awkward to work with in the laboratory. Third, bacteriologists of the early de­cades of the twentieth century had no means by which to see anything as small as the true cause of the disease, the influenza virus.

About 1930, Richard E. Shope discovered that he could transfer a mild influenza-like disease from one pig to another via a clear liquid from which all visible organisms had been filtered. (If Pfeiffer’s ba­cillus was also present in the pigs, they became much sicker, a phenomenon that is one of the sources of the theory that the 1918 influenza may have been the product of synergistic infections.) In 1933, W. Smith, C. H. Andrewes, and P. P. Laidlaw succeeded in infecting ferrets with a filtrate obtained from a human with influenza, and after these events, re­searchers knew what to look for. In the following years, the A, B, and C viruses were isolated and identified and, thanks to the new electron micro­scope, seen and photographed.

It is possible that more is now known about the influenza virus than about any other virus, but its changing nature has defeated all efforts thus far to make a vaccine against the disease that will be effec­tive for more than a few years at most. Vaccines were produced in the 1940s to protect the soldiers of World War II from a repetition of the pandemic that had killed so many of them in World War I, and influenza vaccines developed since have enabled mil­lions, particularly the elderly, to live through epi­demics without illness or with only minor illness. But the ability of the A virus to change and some­times to change radically - as at the beginning of the 1957-8 and 1968 pandemics - and to race around the globe faster than suitable vaccines can be produced and delivered to large numbers of peo­ple, has so far frustrated all efforts to abort pan­demics. Vaccines were effective in damping neither the pandemic of the so-called Asian flu of 1957-8 nor the Hong Kong flu of 1968.

At present, a worldwide network of 100 or so cen­ters, most of them national laboratories, cooperate under the direction of the World Health Organiza­tion to identify new strains of influenza virus as quickly as they appear in order to minimize the time between the beginning of epidemics and the ρroduc- tion and distribution of relevant vaccines. The effi­ciency of this organization has been impressive, and certainly has saved many lives, but influenza is not yet under control. The frustration of flu fighters of the United States reached a peak in 1976, when a virus closely resembling Shope’s swine virus and that of the 1918 pandemic began to spread among soldiers at Fort Dix, New Jersey. The medical profes­sion and the U.S. government mobilized in order to prevent a recurrence of the disaster that had oc­curred 60 years before. Scores of millions of dollars were spent to devise a vaccine, to produce it in quan­tity, and to deliver it into the arms of millions of Americans. No pandemic appeared, not even an epi­demic, and the single long-lasting medical result of this enormous effort seems to have been a number of cases of Guillain-Barre syndrome, a paralytic and occasionally fatal disorder, which were associated with the vaccinations. The number of these cases was tiny, relative to the tens of millions of doses of the vaccine administered, but the result in litigation has been massive.

Alfred W. Crosby

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