Epidemics Deadly Diseases Throughout History Essay

See also: Public Health; Malaria; Influenza Outbreak of 1918-1919

Part II: Significant Infectious Diseases in North Carolina History

The following infectious diseases caused serious damage to the lives and health of North Carolinians before the discovery of successful inoculations and vaccines.

Ague. An acute form of fever that often damages nerves and is sometimes fatal, ague was present in North Carolina from colonial times until the 1930s. The term was prevalent among early colonists, although ague and malaria shared many symptoms and were often mistaken for one another. In fact, little information exists that relates specifically to ague because the histories of the diseases are so intertwined.

Early colonists coined the term "seasoning" to refer to cases of ague and similar diseases. Ague and malaria began to reach epidemic proportions among white colonists after the arrival of ships carrying infected slaves from Africa between 1682 and 1685. An abundance of marshland and an inadequate water supply exacerbated the problem as mosquitoes, the diseases' primary carrier, thrived in the region.

In the twentieth century, records of ague cases became more accurate. The disease was prevalent on the coast and in the Piedmont, whereas infections were rare in the Mountains. By the 1930s, enhancements in sanitary conditions and better medical treatment began to greatly lessen the threat of ague and similar diseases among North Carolinians.

Diphtheria. One of the dreaded diseases of both children and adults, diphtheria was present in nineteenth-century North Carolina. The disease is of bacterial origin, the toxin from which causes damage to the throat area with possible obstruction to the breathing passages and subsequent suffocation. Many cases described as croup before the germ theory of contagion were no doubt actually diphtheria, since it is one of the several infections that presents with a "croupy" cough.

In 1887 diphtheria was listed in official records as the third most important cause of death in North Carolina. During 1920-24 there were 25,460 reported cases, with 1,864 deaths attributed to this disease. It was not until the early 1920s that an effective vaccine for diphtheria was developed and not until 1939 that compulsory immunization for schoolchildren with the diphtheria vaccine was mandated by the General Assembly. By the early 2000s diphtheria was rare, not only in North Carolina but nationwide, and antibiotics were available for those cases that did occur.

Influenza. An infectious disease of viral origin that is worldwide in distribution, influenza, or "the flu," was first described by Hippocrates, the "Father of Medicine," in 412 B.C. About 29 pandemics were recorded between 1510 and 1918. In the great "Spanish" flu pandemic of 1918-19, after World War I, North Carolina lost 13,644 citizens, including Edward Kidder Graham, the new president of the University of North Carolina.

The causative virus of influenza was first isolated in 1933, and a vaccine was developed in the 1940s. The ability of the virus to shift susceptibility to the vaccine requires an annual change in its composition to ensure the inclusion of protection against the strains most likely to be encountered in that particular year.

Malaria. A major public health problem for decades, malaria was especially prevalent in coastal North Carolina during the early years of settlement. The disease is caused by a protozoan parasite named plasmodium. There are several varieties, all of which are transmitted from person to person by the bite of a female Anopheles mosquito. The year 1889 was a particularly bad one for malaria in North Carolina, probably due to an unusually mild winter with no killing frosts. Control of the disease was slow until 1898, when the mechanism of mosquito transmission was identified. Following this discovery, efforts at mosquito control began to see results.

In 1936 malaria was declared a reportable disease to the State Board of Health; a widespread attempt to obtain blood smears from persons in high-incidence areas was undertaken, and a concerted effort to drain swamps in these areas was intensified. Quinine became available for the treatment of malaria around 1820, although the use of powdered cinchona bark, from which quinine was derived, had been used by the Spanish in Peru as early as 1638 and to some extent in the United States. Since 1946, however, chloroquine has been the drug of choice, supplemented by quinine and related substances in resistant cases. Since 1970 North Carolina has reported only sporadic incidents of malaria, generally contracted by persons during travel to endemic areas in other parts of the world.

Poliomyelitis. A contagious viral infection, polio is manifested by an aseptic meningitis, often with paralytic results that may be permanent or, in the worst cases, fatal. The disease affects both children and adults, but because of its frequent occurrence in small children, it came to be known as "infantile paralysis." Perhaps its most famous victim was President Franklin D. Roosevelt.

Polio epidemics, occurring especially in the summer, struck terror into the hearts of American parents during the first half of the twentieth century. In 1948, an especially bad year for North Carolina, 2,516 cases and 143 deaths were reported. A special emergency polio hospital was set up in the Greensboro area since Guilford was the hardest hit county in the state. The National Foundation for Infantile Paralysis, whose annual fund-raising effort is called the "March of Dimes," was founded on 3 Jan. 1938 to help finance a nationwide campaign of education, research, and relief for victims of epidemics. In 1948 alone, the foundation allotted more than $1.4 million to North Carolina to mitigate the statewide tragedy.

In the prevaccine era, the so-called iron lung machine-a respirator device into which persons unable to breathe for themselves because of the effects of polio were placed and artificially ventilated-became a familiar sight in all hospitals treating polio patients. In 1955 a vaccine named after its developer, Jonas Salk, became available for injection. It was quickly put into general use across North Carolina, resulting in an almost immediate decline both in new cases and deaths from the disease. In 1959 North Carolina was the first state to add the polio vaccine to the list of immunizations mandatory for children. In 1962 the Sabin vaccine, an improved preparation that could be administered orally, was introduced and soon largely replaced the injectable vaccine. The virtual abolishment of this dreaded disease in households across the nation was one of the most dramatic medical success stories of the twentieth century.

Scarlet Fever. Also known as scarlatina, scarlet fever is a febrile illness accompanied by a characteristic red rash and sore throat caused by infection with a toxin-producing strain of Streptococcus bacteria. Before the discovery of penicillin, scarlet fever could only be treated symptomatically and allowed to run its course. To prevent its spread through household contact, strict quarantine was mandated by public health officials. Epidemics of scarlet fever were commonplace in North Carolina until the advent in the 1940s of penicillin, which has been the drug of choice in treatment of this infection.

Smallpox. Also known as variola, smallpox, one of the ancient viral illnesses of epidemic and endemic proportions, was introduced into the North American mainland by the earliest European settlers. By 1711 smallpox had become endemic among the North Carolina population, including the Indians of the region. Primitive efforts of quarantine and isolation were ineffective in preventing its spread, such as the virulent smallpox epidemic in Charlotte in 1770. In 1798 Edward Jenner, an English physician, discovered that an inoculum derived from the cowpox virus, a similar but less potent pathogen, could prevent smallpox in humans. Yet many years elapsed before this type of vaccination became generally acceptable to the public, and many more years passed before it became mandatory.

In 1836 Ashe County alone reported 70 cases of smallpox. Other North Carolina epidemics occurred in Charlotte in 1851, in Salisbury in 1863, and in Wilmington in 1865. Compulsory smallpox vaccination in schools was required in Hyde County and a portion of Washington County in 1905. The State Board of Health, created by the General Assembly in 1877, led a decades-long battle to promote vaccination against smallpox. In 1911, 113 years after Jenner's development of the vaccine, the legislature enacted a statute requiring inoculation against smallpox, and in 1918 the State Board of Health made smallpox a reportable disease. Following these important public health measures, the annual cases dropped to 3,845 by 1924 and continued to decline rapidly. The last death from smallpox reported in North Carolina occurred in 1943, and the last reported case in the state was in 1953. Due to the worldwide promotion of immunization by the World Health Organization, smallpox was eliminated as a health hazard, and consequently the requirement for smallpox vaccination in North Carolina was lifted in 1973.

Tuberculosis. Sometimes referred to as the "Great White Plague" and frequently called "consumption," tuberculosis was also introduced into North Carolina by the earliest English settlers. John Lawson, in A New Voyage to Carolina (1709), noted the apparent absence of the disease among the local Indians. By the latter half of the nineteenth century, tuberculosis was the leading cause of death in the United States. Prior to the advent of antituberculosis drugs, the preferred treatment was institutional care in facilities located in a mountainous environment with pure, cool, and dry air. In North Carolina, Asheville became famous for its large number of private sanatoriums and consequently for the many physicians who specialized in the care of tuberculosis patients drawn to the area.

Tuberculosis was made a reportable disease by the State Board of Health in 1913. The first state-supported sanatorium opened near Aberdeen in April 1908; state-supported tuberculosis hospitals were later established at Wilson, Swannanoa, and Chapel Hill to permit full coverage across North Carolina.

In 1947, 1,056 people died from tuberculosis statewide. There was no effective medicine to treat the disease until the mid-1940s, when streptomycin was discovered and began to be used. Subsequently, a number of other antituberculosis drugs were introduced and usually used in combination for optimum treatment. Following the introduction of these drugs, the number of new cases began to decline. By 1962 all county sanatoriums had been closed and the residual patients transferred to one of the state-supported institutions.

In the early 2000s tuberculosis continued to be a public health problem in North Carolina. The incidence of tuberculosis was again on the increase, especially among AIDS victims. Periodic skin testing as a means of tuberculosis case-finding remained part of careful medical practice.

Typhoid Fever. A bacterial infection depending in large part on contaminated water and food supplies for its transmission, typhoid fever was present in endemic proportions among the earliest settlers in North Carolina. Although the first description of epidemic typhoid fever was penned by Thomas Willis in 1659, it was not until 1880 that the typhoid bacillus-the causative agent of the disease-was discovered. The first inoculations with a killed bacterial suspension began in 1896, and the vaccine had a good measure of success during the World War I years of 1914-18. After that, summertime clinics providing "typhoid shots" were commonplace across the state.

A much more effective method of controlling this disease was the effort by public health departments to clean up water, milk, and food supplies. In the 1880s municipal waterworks began to replace wells and public pumps in Raleigh, Charlotte, Wilmington, and Winston-Salem. By 1894 Charlotte, New Bern, Asheville, Winston-Salem, and Raleigh had sewerage systems. After another half century, the outdoor privy had virtually disappeared.

In 1901 there were still 8,000 to 10,000 cases of typhoid fever in North Carolina annually. In 1918, when large-scale typhoid immunization programs went into effect, the number dropped to 3,461 cases and subsequently declined steadily; after 1953 fewer than 10 cases were reported annually. The first useful antibiotic for typhoid fever, chloramphenicol, was developed in 1948; this drug and new antibiotics were very helpful in controlling the disease.

Typhus. An infection caused by a Rickettsial organism transmitted by the bites of lice that have also infested rats, typhus was endemic among early North Carolina colonists, especially in port cities where ships containing many rats in the holds and among the cargo were coming and going. In 1758, during the French and Indian War, a large number of refugees flocked to the Moravian settlement of Bethabara, resulting in an outbreak of typhus that took the lives of many refugees as well as Moravians. In 1940, when 65 cases of typhus were reported in the state, the disease became a concern of public health authorities. A major effort was directed toward rodent control and rat-proofing of buildings; by 1952, only 12 cases were reported, and none occurred by 1970.

Yaws. Still a major health hazard in many Third World countries, yaws was a crippling disease for many North Carolinians in the late seventeenth and early eighteenth centuries. Yaws is contracted through infection by a spirochete, treponema pallidum, associated with primitive living conditions. It is transmitted by skin contact and manifests itself as pimples that, on sloughing off, leave mulberrylike growths of fungi. These tend to develop into malignant ulcers that may cover the body, attacking especially glands of the armpits, groin, throat, palate, and soles of the feet. Believed to have been imported into the American colonies on slave ships from Africa and the West Indies, yaws caused many North Carolina victims to lose their noses and palates.

Physicians treated yaws by the same methods used against venereal syphilis, the symptoms of which were nearly identical. Mercury, a mixture of several kinds of barks and roots (called "papaw's remedy"), "sweating boxes" to dry up ulcers, "yaws houses" to segregate infected slaves, restricted diets, and other remedies had little effect. The disease appears to have largely disappeared by 1750, although a prominent physician claimed to have found it in coastal areas of the state at the beginning of the twentieth century.

Yellow Fever. An acute viral illness characterized by high fever, jaundice, and brain disease, yellow fever is transmitted from person to person by the bite of an Aedes mosquito, which serves as the insect vector for the disease. In colonial North Carolina, yellow fever was frequently encountered in coastal settlements, especially where mosquitoes were found in abundance. For 200 years it was one of the great plagues not only of the United States but also of the entire world.

In September 1862, in the midst of the Civil War, a severe epidemic of yellow fever struck Wilmington after a blockade-running vessel from Nassau in the Bahamas loaded with supplies made its way into the Cape Fear River and docked in the port. In the zeal to off-load much-needed food and other cargo, the quarantine laws were apparently overlooked. A few days later, several Wilmington physicians reported cases suggestive of yellow fever, and it was found that there had been cases aboard the vessel from Nassau. The disease spread rapidly. Deaths numbered as high as 18 in a single day, and at one time as many as 500 cases were being treated. Physicians and nurses from as far away as Charleston, S.C., responded to the call for assistance. The epidemic lasted until 6 Nov. 1862, when a heavy snowstorm occurred. About 1,000 people died. One of the victims was James H. Dickson, a former president of the North Carolina Medical Society. The death of one of their colleagues increased the realization among North Carolina physicians that more had to be done to prevent yellow fever and other deadly contagious diseases in the state.

Progress in controlling yellow fever was slow until 1898, when it was discovered that the mosquito was the carrier for its transmission. Thereafter, widespread efforts to drain swamps and eradicate the mosquito population helped prevent infection.

There was no satisfactory vaccine against yellow fever prior to 1937. That year a substance utilizing a strain of yellow fever virus called "17D," obtained by prolonged propagation in chick embryo tissue, was found to be effective and safe for humans and used experimentally. The vaccine was available during World War II to protect troops entering areas endemic to yellow fever.

No cases of yellow fever appeared in North Carolina after the advent of modern-day reporting in 1932. In the early 2000s this disease was endemic only in South America and Africa.

Return to Infectious Diseases- Part I: Overview

References:

Thomas J. Farnham and Francis P. King, "'The March of the Destroyer': The New Bern Yellow Fever Epidemic of 1864," NCHR 73 (October 1996).

Frederick L. Hoffman, Malaria in Virginia, North Carolina, and South Carolina (1933).

Dorothy Long, ed., Medicine in North Carolina: Essays in the History of Medical Science and Medical Service, 1524-1960 (1972).

Thomas C. Parramore, "The 'Country Distemper' in Colonial North Carolina," NCHR 48 (Winter 1971).

William S. Powell, North Carolina through Four Centuries (1989).

Benjamin Earle Washburn, A History of the North Carolina State Board of Health, 1877-1925 (1966).

Jane Zimmerman, "The Formative Years of the North Carolina Board of Health, 1877-1893," NCHR 21 (January 1944).

Image Credit:

Pamphlet from Polk Diphtheria Cure Co. of Boston, Massachusetts. Image courtesy of the UNC-CH libraries. Available from http://www.lib.unc.edu/blogs/ncm/index.php/2009/05/29/a-cure-for-diphtheria/ (accessed August 20, 2012).

"Iron lung (c. 1933) used to "breathe" for polio patients until 1955." Image courtesy of Library of Congress. Available from http://www.loc.gov/pictures/resource/highsm.05216/ (accessed August 20, 2012).

Free Anti-Typhoid Treatment. The Columbus County Campaign of Protection Against Typhoid Fever Will Occur from November 1st to November 27th, 1920. Image courtesy of University of North Carolina at Chapel Hill Libraries. Available from http://docsouth.unc.edu/nc/antityph/menu.html (accessed August 20, 2012).

EMERGING INFECTIONS: CONDEMNED TO REPEAT?

Stephen S. Morse, Ph.D.1

Columbia University

We have all learned about the importance of infectious diseases throughout history, including the Plague of Justinian (541–542), the first known pandemic on record (McNeill, 1976), and the Black Death in the fourteenth century. Stanley Falkow, who is included in this volume, has extensively studied Yersinia pestis, the responsible organism, and given us important insights into its pathogenesis. Another devastating disease that was once much feared is smallpox, which is said to have killed more people than all the wars in history. The eradication of smallpox was therefore a triumph of public health. Ironically, smallpox has the unique property of being the only species to date that human beings have intentionally driven to extinction. While we have unintentionally driven so many species to extinction, it is nice to know we can actually intentionally do some good. Cholera was, of course, a very big concern in the nineteenth century and remains a concern today, especially in places like Bangladesh, as Gerald Keusch of Boston University and a member of the Forum can affirm.

The 1918 influenza pandemic is one of our paradigms of a nightmare emerging infectious disease event. It may very well have been the greatest natural disaster in the early days of the twentieth century. The “official” mortality estimates keep rising as investigators keep finding data from further away, in developing countries and more remote places. But that pandemic is thought to have accounted for about 50 million or more deaths, depending on how you want to count it, and is obviously a matter of great concern.

Despite that, we have had years of complacency about infectious diseases, partly for reasons already discussed—the antibiotic era, immunizations, improved public health measures—all of which have led to the fact that we now live longer and tend to die later of chronic diseases. Unfortunately, this has not been true everywhere. It has not been true in many developing countries. Infectious diseases remain the major causes of morbidity and mortality in much of the world.

But in this paper, I would like to concentrate on emerging infections, the ones that are not previously recognized and that seem to appear suddenly and almost mysteriously—if you will, The Andromeda Strain (Crichton, 1969). Figure WO-7 graphically shows a number of examples. Of course, there are also forgotten infections that reappear. We sometimes call those “reemerging infections.” I tend to think of most of the “reemerging” infections as reminding us that many infectious diseases in our highly mechanized modern societies, with the standard of living we enjoy, have been pushed to the margins, but have never been entirely eliminated. So when public health measures are relaxed or are abandoned because of lack of money or complacency—complacency being a very big problem—you then see forgotten infections reappearing. An example is diphtheria in the former Soviet Union and Eastern Europe in the early 1990s when those countries no longer had the money to maintain their immunization programs. It reminds us that many of these diseases may be forgotten, but they are not gone.

HIV/AIDS is, of course, the infection that got our attention initially and made it possible at least to think about shaking ourselves out of the growing complacency about infectious diseases. HIV infection and AIDS, starting from obscurity, rose to become a leading cause of death in the United States by 1993 (Figure 5-1). There are recent reports dating HIV to the early twentieth century, but it didn’t appear to take off until mid-century. You can find a molecular example of HIV in Zaire in 1969, but that is almost a one-off, and then there were reports of a few cases in the 1970s in Africa, if anyone had been paying attention. Then suddenly, in the early 1980s, it appeared in the United States and took off like the proverbial rocket to overtake all other causes of death in healthy young people. Of course, this is the same age group killed in the 1918 flu, but also the very people we generally expect to have the best survival rate. They have survived childhood and we expect that they ought to be fine. As shown in Figure 5-1, all the other causes of death were unchanged during that period.

FIGURE 5-1

Leading causes of death in young adults, United States, 1987–2005. Red line: Rise of HIV infection to become leading cause of death. SOURCE: CDC (2008).

HIV was therefore quite a surprise. When you think about it, this does seem rather like The Andromeda Strain. We had thousands of years of experience with infections, some of them historically recorded in some detail. Some of these are still unidentified, and we still argue about what they were. But a disease that actually kills by undermining the immune system directly was a novel mechanism of pathogenesis. How often does one find a new mechanism of pathogenesis in an infectious disease, considering the thousands of years of experience that we have had? I think it was quite remarkable.

Since its peak (around 1995), the HIV/AIDS death rate in the young adult population in the United States has dropped (Figure 5-1), thanks largely to the fact that a few effective drugs were finally developed, including in particular the protease inhibitors. As a result, the trend reached a plateau and has recently been going down. HIV/AIDS is now a treatable disease, with many lives saved among those who can afford the medication. But it also worries me that this fortunate situation may not last very long. Inevitably, antiviral resistance has already been identified in some patients. Another concern is that some of the younger people have now become quite complacent about this disease, not knowing the devastation that many of us witnessed in the 1980s, before it could be effectively treated. We are seeing young people now regarding this with less seriousness than they should.

So there we are, facing complacency again. If there is a bottom line to the theme of the Forum on Microbial Threats, it is that we cannot afford to be complacent anymore.

What are emerging infections? I always like informally to define emerging infections as those that would knock a really important story off the front page of the newspaper, whether the runaway bride or the Texas polygamy case, at least for a day or two. However, I do have a more formal definition: those infections that are rapidly increasing in incidence or geographic range. In some cases, these are novel, previously unrecognized diseases. But, as I am going to show you, many of them are not The Andromeda Strain. They do not come from space. Actually, in many cases, they have already existed in nature. Very often, anthropogenic causes—often as unintended consequences of things we do—are important in the emergence of these infections.

There are many examples. You can pick your favorite: Ebola in 1976; hantavirus pulmonary syndrome, which I will discuss briefly in a moment; Nipah, which Peter Daszak addressed at the workshop (and his group has done some excellent work on this); SARS; and, of course, influenza, which still continues to surprise us.

You could think of the many events shown in Figure 5-2 as “a thousand points of light” (or at least those of you who are old enough to remember the first President Bush). But these are really a lot of little fires all over the world, most of which we did not spot in time before they became big brush fires or even wild-fires. That includes many examples, such as West Nile virus entering the United States in 1999, the enteropathogenic Escherichia coli (made famous by the “Jack in the Box” case2), and a number of others, including SARS, of course.

FIGURE 5-2

Global examples of emerging and reemerging infectious diseases, some of which are discussed in the main text. Red represents newly emerging diseases; blue, reemerging or resurging diseases; black, a “deliberately emerging” disease. SOURCE: (more...)

I have divided the process of disease emergence into two steps, for analysis: (1) what I call introduction, where these “Andromeda-like” infections are coming from; and (2) establishment and dissemination, which (fortunately for us) is much harder for most of these agents to achieve. The basic lesson there is that many may be called, but few are chosen.

In this two-step process, as you all know, the opportunities are increasing thanks to ecological changes and globalization, which gives the microbes great opportunities to travel along with us, and to travel very quickly. Even medical technologies have played an inadvertent role in helping to disseminate emerging infections.

I will spend most of my time talking about what seems to be the most mysterious step—and I hope we can demystify it a bit here—and that is the introduction of a “new” infection. What we now know is that many of these infections, exotic as they may seem, are often zoonotic. Some of them do not do very much, and may cause no infection at all; while others may cause a truly dramatic infection, like Ebola.

So that zoonotic pool, if I may use that term, is not fully chlorinated, and it is a rich source of potential emerging pathogens. There is so much biodiversity out there, including a tremendous biodiversity of microbes. Some of that biodiversity—we do not know how much, even now—is still untapped.

Changes in the environment may increase the frequency of contact with a natural host carrying an infection, and therefore increase our chances of encountering microorganisms previously unknown to humans. Of course, the role of food animals, as well as wildlife (one of the subjects of Peter Daszak’s contribution to this volume), has come very much to fore in recent years.

There are a number of examples associated with activities like agriculture, food-handling practices, and, for the vector biologists, of course, changes in water ecosystems. Table 5-1 lists just some of these cases. The basic point is that there are a number of ecological changes, many of them anthropogenic, which provide new opportunities for pathogens to emerge and gain access to human populations. Think of these as a sort of microbial explorers, discovering new niches—us—and exploring new territory.

TABLE 5-1

New Opportunities for Pathogens: Ecological Changes.

It is important not to overlook the very important role of evolution as well. One role is obviously what evolution has already been doing for a long time, leading to the biodiversity of pathogens that we see existing in nature. It is remarkable, when you think about how great that biodiversity is. We don’t even know how many viruses human beings are subject to, even how many inhabit us at this very moment. But when I think about just the herpesviruses, which are pretty well studied, that number could be very large indeed. There are eight known human herpesviruses, and at least six of them—you might argue, even seven of them, except for Human herpesvirus 8, the one that causes Kaposi’s sarcoma—are ubiquitous in the human population. They can be found all over the world. Several of them are present at very high prevalence in the human population.

That just gives you an idea of some of that great biodiversity. As it happens, these herpesviruses are all specialized for humans. There are, of course, herpes-viruses of other species. So a lot of coevolution between host and pathogen goes on as well.

Of course, there is adaptation to new hosts and environments through natural selection. We see this with influenza most notably, but with many other examples—the coronaviruses, like SARS—as well. Of course, antimicrobial resistance has been mentioned so many times. If anyone needs to be convinced about the role of evolution in the world, I think this is a pretty good demonstration—one of the rare examples in which you can do in vitro exactly the same thing as what happens in the real world, just on a different scale.

There are many case studies. I’ll briefly discuss a few, just to illustrate some key points.

Hantavirus pulmonary syndrome was ironically one of the first things to happen suddenly in the United States after the original Institute of Medicine Emerging Infections report came out in October 1992. Hantavirus pulmonary syndrome suddenly appeared in the southwestern United States in the following spring and summer.

My friend Richard Preston wrote a book called The Hot Zone. He has a very philosophical chapter at the end where he talks about the “revenge of the rainforest.” I think it is a good thought, in that we should be kinder to our environment, for many good reasons. The rainforests are great sources of biodiversity and, to a great extent, that biodiversity was largely unexplored.

But an emerging infection can occur anywhere. Even the southwestern United States, which looks so dry, arid, and inhospitable to life, has its share, different from the rainforest, but just as significant.

Jim Hughes, who is a Forum member and was the director of the National Center for Infectious Diseases (NCID) at the Centers for Disease Control and Prevention (CDC) at the time of the outbreak, knows this story firsthand. Starting in the late spring and then going through the summer of 1993, people started appearing at emergency departments and clinics with respiratory distress. Many of them were hospitalized. I believe the case fatality rate at that time was about 60 percent, even with treatment. It is a little lower now, but it is still hovering near 40 to 50 percent.

The health departments did the usual investigations: There is a pocket of plague in that area, so the local health departments tested for that. Another possibility could be influenza out of season. These, and other likely possibilities, were ruled out. The state health departments then called in CDC, which did a number of tests and identified, perhaps surprisingly, a hantavirus as the most likely culprit. This was tested both by serology and, later, shedding of virus was tested by polymerase chain reaction (PCR). Of course, when you think of hantavirus, you usually think of rodents, with a few minor exceptions. So a number of rodent species trapped near patients’ homes were tested. The most frequent rodent was apparently also the most frequently infected: Peromyscus maniculatus, the deer mouse. This is a very successful and prolific rodent that is essentially the major wild rodent in this entire area. Ruth Berkelman likes to refer to this as your typical hardworking single mom, as shown in the illustration (Figure 5-3).

FIGURE 5-3

A deer mouse (Peromyscus maniculatus), natural host for the Sin Nombre (hantavirus pulmonary syndrome) virus, with her young. SOURCE: Image courtesy of Bet Zimmerman, www.sialis.org.

Of course, once a test was developed and people started looking for the virus, they were able to find it in a great number of other places, including serum and tissue samples that had been saved earlier because the etiology was unknown, but odd—cases of acute respiratory distress. There were even some cases outside the geographic range of Peromyscus maniculatus, which turned out to be hantaviruses that were natural infections of other rodent species.

This point is illustrated in Figure 5-4 (I thank C. J. Peters, then at CDC, for the illustration). Before 1993, the United States had one known hantavirus, not associated with human disease (Prospect Hill virus) and another hantavirus of rats, Seoul virus, and related variants that could be found in port cities; neither was associated with serious acute disease in the United States. After 1993, we had to add another: the virus that causes hantavirus pulmonary syndrome. Then, when people started looking for hantaviruses, there was no shortage of previously unrecognized cases. In Figure 5-4, the virus names in bold have been associated with human disease, while many others have not. So throughout North and South America, suddenly there was a whole rash of hantaviruses that nobody knew existed.

FIGURE 5-4

Hantaviruses of the Americas. Viruses associated with human disease are shown in bold. SOURCE: Adapted from Peters (1998) with permission from ASM Press and Jim Mills.

That is evolution at work. We do not know how long ago this diversification occurred. It could have been as long as 2 million years ago, when some of the rodent species separated, but I would defer to the mammalologists on that issue.

As with HIV, at first we think it is an orphan, but, of course, it has its relatives; we just hadn’t found them yet.

What about the respiratory viruses? We have been thinking about that question a great deal lately. Some of our most serious historical examples—influenza, measles, smallpox, and many others—have been respiratory viruses. Right now pandemic influenza and H5N1 avian flu are very much on our minds.

Figure WO-11 was one of Josh Lederberg’s favorite slides. It shows U.S. mortality rates. You can see an enormous peak in 1918, coinciding with the 1918 flu pandemic. It was a big event, and even in the United States it killed at least a half-million people, most of them young and previously healthy.

Several pandemics have been documented. The 1918 pandemic was by far the worst. The Asian flu of 1957—as it happened, I lived through the next two twentieth-century influenza pandemics—was not much fun, to put it mildly, but nothing was ever like 1918. I wasn’t there to experience that one, thankfully. Later, the pandemic Hong Kong flu of 1968 appeared but was relatively mild compared with 1918 and even 1957.

There have been some other events along the way: the reappearance in 1977 of H1N1, and the famous swine flu scare in 1976, which, in fact, Harvey Fineberg, now president of the IOM, wrote about when he was at Harvard (“the epidemic that never was,” as he and his coauthor Richard Neustadt dubbed it [Neustadt and Fineberg, 1983]).

Figure 5-5 shows a ward filled with patients suffering from influenza during the 1918 pandemic. These are soldiers who were about to go overseas to fight in World War I. The photo shows graphically the impact that a disease like the 1918 flu had. CDC has since recalculated the case fatality rates adjusted to today’s population, just extrapolating what the expected deaths would be. With today’s population, a 1918-like pandemic would be expected to cause almost 2 million deaths in the United States alone. If it were like the 1957 or 1968 pandemic, a much milder pandemic, it might be fewer than 100,000 deaths. In any case, it is not something to take lightly.

FIGURE 5-5

Influenza pandemic 1918 at Camp Funston, Kansas. SOURCE: Image NCP 1603 courtesy of the National Museum of Health and Medicine, Armed Forces Institute of Pathology, Washington, DC.

In pandemic influenza viruses, the novel or new genes tend to come from avian influenza viruses that then reassort, often with mammalian influenza genes (or at times the virus may possibly go directly from avian to human, although that seems to be a relatively rare event).

We hear a great deal recently about the H5N1 avian flu in humans, and about the next pandemic. These two terms, “pandemic” and “avian flu,” are really not synonymous, although nonscientists sometimes mistakenly use them that way. Rob Webster and Virginia Hinshaw discovered some years ago that the waterfowl of the world appear to be the natural reservoirs for influenza viruses. Therefore, there is certainly open territory for influenza virus dissemination along any of the Old World flyways for bird migration.

As a result of all of those movements of birds, both migratory fowl and domestic poultry, we have seen a number of outbreaks of H5N1 avian influenza, starting in Asia, but extending into Europe and Africa as well. There have been some human cases, mostly (although not all) occupational, and with a high case fatality rate. Fortunately, there have been only a few instances of human-to-human transmission so far, all apparently quite limited. Obviously, everyone is watching this closely, just in case there is a change in the ability of the virus to transmit from person to person. If this virus were able to infect people readily and transmit itself, let’s say, as well as ordinary seasonal influenza does, then it could well be the next pandemic.

I am not putting money on H5N1, however. The next pandemic is going to happen, but so far nobody in this field can predict exactly when and where, and which influenza strain will be responsible. The only people who claim they can, at least as of now, are either charlatans or great risk takers. It is safer to bet on horse races.

Let me now move on briefly to that second step in emergence—establishment and dissemination. Luckily for us, this is much harder for a newly-minted pathogen. So many infections that can get into human beings from time to time may not have a good way of transmitting or propagating themselves. We have given them some help in this regard—think about HIV, for example, spreading in the blood supply or through contaminated injection equipment—and provided some highways for what I like to call “microbial traffic”: pathogens moving into new areas or new populations. Of course, environmental changes can be important here as well.

It used to take a long time to get around the world, but now you can do it, if you make all your connections, in 24 to 48 hours. If you do not make all your connections, as happens to most of us, then you spend time in a usually crowded airport, where you have even more opportunity to infect others.

Consider SARS, for example. By the way, ironically, Hong Kong decided to embark on a new promotional campaign just before SARS started. The slogan was “Hong Kong will take your breath away.” I do not know what inspired them to come up with it just then. Maybe they are better prognosticators than we are when it comes to the flu and other respiratory diseases. They certainly have had much more direct experience.

The consequences of SARS on global travel were enormous. The usually bustling Hong Kong airport was deserted. At least the few who did arrive there did not have to worry about waiting for their luggage. And the hotel rooms were cheaper, especially at the Hotel Metropole, which, we now know, was site of the “Big Bang” of SARS.

The spread of SARS was a remarkable event, when you think about it. One infected individual—a physician, in fact—from south China treated a patient who had an unusual pneumonia. Clinicians usually assume community-acquired pneumonia is not very transmissible—a major mistake here, as this turned out to be, unfortunately, an exception. He then went to Hong Kong, where he stayed at the Hotel Metropole, a popular business hotel, and became sick. He believed he had the same disease that had killed the patient he had treated earlier. He went to the hospital, told his healthcare providers about his odd patient, and warned them to be careful. Apparently they did not pay much attention. There were 99 healthcare workers infected in Hong Kong alone.

At the same time, another dozen people were infected in the Hotel Metropole by this index patient. This is what was responsible for the dissemination of SARS essentially worldwide. Of course, everyone likes to say that it was an interesting coincidence that he stayed in Room 911. There no longer is a Room 911 at the Hotel Metropole, by the way. This is a little bit like the first Legionnaires’ outbreak and what it did to that hotel’s image, but that is another story.

We had a few near-misses with SARS. The man who went to Vietnam was actually a New York businessperson who did not go back to New York. One doctor from Singapore did go to New York, but did not get sick until he was on his way home and was put into isolation in Germany.

Just to put in a small plug for one of my favorite causes (of course, this is completely biased): ProMED-mail, the listserv for reporting and discussion of emerging infections. There was a little item that appeared there in February 2003, just questioning whether something odd was going on in China, with reports of deaths. The next day China admitted to having 305 cases of SARS.

Yi Guan, as he first reported at an IOM Forum meeting on SARS in October 2003, actually was able to find earlier cases, going back at least to November 2002. There were several different cases in perhaps five cities in southern China, but they were not reported or recognized at the time. He did a survey and found that animal slaughterers and wild animal handlers had a much greater chance of becoming seropositive. Why? Because the ultimate link to humans was another cute little animal, Paguma larvata, the palm civet, which is actually a prized food animal in south China, particularly during the winter. It is very expensive. The civets became infected, it would appear, in the live animal markets, probably from contact with bats (according to work by Peter Daszak and colleagues). Wild-caught and farmed civets—yes, they do farm them—that were tested were all negative for the SARS coronavirus.

Then, of course, SARS came to Canada, as we well know, and wreaked havoc. Those of you who know Don Low, as many do, know that he was right at the front line there; I remember that when I saw him at one of our Forum meetings just after the crisis was over, he was exhausted.

By the end of all this, there were about 8,000 cases, most of them in the original area, but a few in other widely scattered places, with over 700 deaths, or about a 10 percent case fatality rate. Not a trivial disease.

This also was the first time the World Health Organization (WHO) had really acted aggressively, which got the Canadians very annoyed, since WHO issued a travel advisory recommending that travelers avoid Toronto. But WHO acted very effectively and was able, I think, to solve some of the scientific and disease-control problems rather quickly.

There is probably a parallel story with HIV origins. We do not know how it entered the human population. It may very well have been through a similar mechanism as SARS. It came from chimpanzees, most likely, and humans may have become infected by preparing or handling infected nonhuman primates for the “bushmeat” trade.

Hospitals also provide opportunities for emerging infections. Transmission of infections by contaminated injection equipment is well known. Most of the Ebola cases arose this way.

In summary, there are some recognizable factors responsible for precipitating or enabling emergence, such as ecological factors or globalized travel and trade. This was the framework, which I had originally developed, that we used in the Emerging Infections (IOM, 1992) report. These factors have since been augmented and embellished in the new version of the IOMEmerging Infections report, titled Microbial Threats to Health, published in 2003 (Box WO-3; IOM, 2003). So there are even more of them now, but I think they are recognizable. We know what is responsible for emerging infections and should be able to prevent them.

What are we going to do about this? One thing we can do is improve disease surveillance. I will put in another plug for ProMED here. There is a sort of backhanded compliment, I guess, from a recent popular book about John Snow and cholera, The Ghost Map, by Steven Johnson (2006). On page 219, he states: “The popular ProMED-mail e-list offers a daily update on all the known disease outbreaks flaring up around the world, which surely makes it the most terrifying news source known to man.”

The reality is that we need better early-warning systems and more effective disease control, implemented without delay. If we had let SARS go the way we had let AIDS go, probably very few of us would be here to talk about it, especially the physicians.

To summarize, these are my central themes:

  • There are factors responsible for the emergence of infectious disease.

  • Often, interspecies transfer is responsible or facilitates emergence.

  • Things we do (anthropogenic changes) often increase the risk of transmission by altering the environment and interposing ourselves into an environment containing pathogens unfamiliar to humans.

  • We can manage those risks in some ways using our wits.

  • You might ask, what should we be doing to make the world safer? Effective global surveillance is one, as are better diagnostics, political will to respond to these events, and research to help understand the ecology and pathogenesis of these “new” infections and to help develop effective preventive or therapeutic measures.

I am sure the other contributors to this chapter will have additional suggestions and insights into the problem and about how we might begin to make the world safer. We must get serious about this. Our future as a species may well depend on it someday.

ECOLOGICAL ORIGINS OF NOVEL HUMAN PATHOGENS3

Mark Woolhouse, Ph.D.4

University of Edinburgh

Eleanor Gaunt, B.Sc.4

University of Edinburgh

A systematic literature survey suggests that there are 1399 species of human pathogen. Of these, 87 were first reported in humans in the years since 1980. The new species are disproportionately viruses, have a global distribution, and are mostly associated with animal reservoirs. Their emergence is often driven by ecological changes, especially with how human populations interact with animal reservoirs. Here, we review the process of pathogen emergence over both ecological and evolutionary time scales by reference to the “pathogen pyramid.” We also consider the public health implications of the continuing emergence of new pathogens, focusing on the importance of international surveillance.

Introduction

In this review, we will be particularly concerned with species of pathogen that have recently been reported to be associated with an infectious disease in humans for the first time. As discussed more fully below, not all such pathogens (possibly very few of them) will be truly “new,” at least in the sense that the pathogen has only recently discovered us rather than we have only recently discovered the pathogen. This focus on novel pathogens differs somewhat from the more general topic of “emerging infectious diseases,” which is often taken to include previously rare disease which are now on the increase, and sometimes diseases once considered to be in decline but which are now resurgent—the so-called “re-emerging” diseases. However, our focus does fairly reflect one of the major public health concerns of the early 21st century, the possible emergence of new pathogens species and novel variants (OSI 2006).

At first glance, a pre-occupation with yet-to-emerge disease problems may seem extravagant, given the massive and all too immediate health burdens imposed by malaria, tuberculosis, measles, and other familiar examples. An obvious counterargument is the relatively recent advent of HIV-1, unrecognized less than a generation ago and yet now one of the world’s biggest killers. As we shall discuss, the great majority of novel pathogens have not caused public problems on anything like this scale. However, AIDS (reinforced by knowledge of other plagues occurring throughout human history—see Diamond 2002) reminds us that the possibility that they could do so is real. In the early stages of the emergence of a new disease, it is a possibility that all too often cannot easily be dismissed as current concerns about H5N1 influenza A virus attest. A second reason for concern is that outbreaks of new diseases, and the public reaction to them, can cause economic and political shocks far greater than might be anticipated. The 2003 SARS epidemic, for example, resulted in fewer than 1000 deaths but cost the global economy many billions of dollars (King et al. 2006). Variant CJD, which has caused just over 100 deaths mostly confined to the UK, has had a global economic impact of a similar magnitude. Moreover a better understanding of the natural history of the emergence of new infectious diseases should inform our ability to combat them and, as the 2003 SARS epidemic illustrated, rapid, coordinated intervention can be highly effective.

Pathogen Diversity

Surveys of Pathogen Species

Although the existence of pathogens has been recognized for centuries, the first comprehensive list of human pathogen species was not published until 2001 (Taylor, Latham, and Woolhouse 2001). This list was generated from a comprehensive review of the secondary literature available at the time (see Taylor, Latham, and Woolhouse 2001 for full details). Each entry was a distinct species known to be infectious to and capable of causing disease in humans under natural transmission conditions. Species only known to cause infection through deliberate laboratory exposure were excluded. Species only known to cause disease in immuno-compromised patients and species only associated with a single human case of infection (e.g., Zika virus) were included. Ectoparasites such as ticks and leeches were not included. The 2001 list included species names that appeared in either (1) a text book published within the previous 10 years, or (2) standard web-based taxonomy browsers (see below), or (3) an ISI Web of Science citation index search covering the preceding 10 years. In subsequent work (e.g., Woolhouse and Gowtage-Sequeira 2005) NCBI taxonomies were used throughout (www.ncbi.nlm.nih.gov.library.vu.edu.au/Taxonomy/).

This methodology has the advantage that it is (or, at least, aspires to be) systematic, transparent and reproducible by other researchers. However, it does have its limitations and two of these in particular are worth highlighting. First, the criterion “capable of causing disease” has been variously interpreted and not all text book reports of disease-causing organisms can be confirmed from the primary literature. Second, some taxonomies have been revised since 2001, altering which pathogen variants are regarded as “species.” Further revisions can reasonably be anticipated. More fundamentally, using the species as the unit of analysis ignores a wealth of important and interesting variation that occurs within species in traits such as virulence factors, antigenicity, host specificity or antibiotic resistance. Moreover, what is meant by “species” may differ from one group to another; some pathogens have complex subspecific taxonomies (e.g., Salmonella enterica, Listeria monocytogenes, human rhinoviruses, Candiru virus complex, Trypanosoma brucei complex), making direct comparisons of different “species” potentially problematic. With these caveats noted however, a survey of recognized species represents a natural starting point for investigations of the diversity of human pathogens.

Surveys of New Pathogen Species

A subset of human pathogen species of special interest here is those that have only recently been discovered. In this context, “recently” is taken (arbitrarily) as meaning from 1980 onwards and “discovered” means recognized as causing infection and disease in humans. Thus there are several possible reasons for a pathogen to appear in the list of “new” species.

  1. Both the pathogen and the disease it causes did not occur before 1980.

  2. The disease was already recognized but the pathogen was not identified as the etiological agent before 1980.

  3. The pathogen was already recognized but had not been associated with human disease before 1980.

  4. Neither the pathogen nor the disease it causes were recognized or reported before 1980, but they did occur.

  5. What was considered to be a single pathogen before 1980 was subsequently recognized as comprising two or more species.

Strictly speaking, only the first of these possibilities constitutes an “emerging” infectious disease as defined earlier. In practice, however, most post-1980 pathogens probably fall into categories (2) to (5). For example, phylogenetic evidence has demonstrated clearly that the evolutionary origins of the human immunodeficiency viruses pre-date their discoveries in the 1980s by at least several decades (van Heuverswyn et al. 2006).

To provide a more complete picture of new pathogens the list of species described above was supplemented in early 2007 by searching the WHO, CDC, and ProMed web sites and the primary literature.

Results of Pathogen Surveys

Based on the above methodologies an updated version of the previously reported surveys generates a list of 1399 species of human pathogen. The most diverse group is the bacteria (over 500 species) with fungi, helminths and viruses making up most of the remainder (Table 5-2).

TABLE 5-2

Numbers of Pathogen Species by Taxonomic Category.

Of these 1399 species of human pathogen, 87 have been discovered from 1980 onwards (Table 5-3). The composition of the subset of new species is very different from the full list. New species are dominated by viruses, and there are relatively few bacteria, fungi or helminths (Table 5-2). Within these broad categories certain taxa stand out: human retroviruses were not reported until 1980; most of the new fungi are microsporidia; and almost half the new bacteria are rickettsia. Although the over-representation of viruses is highly statistically significant (odds ratio (OR) = 18.0, P < 0.001), it is not clear that (excluding retroviruses) particular kinds of viruses have special status. Single-stranded RNA viruses make up the largest subset of new species (45 species) but are only marginally over-represented. Similarly, bunyaviruses are the largest single family but are also only marginally over-represented in the list of new viruses.

TABLE 5-3

Dates of First Reports of Human Infection with Novel Pathogen Species.

In summary, since 1980 new human pathogen species have been discovered at an average rate of over 3 per year. Almost 75% of these have been virus species even though viruses still represent a small fraction (less than 14%) of all recognized human pathogen species.

Geographic Origins of Novel Pathogens

For those pathogen species discovered in the post-1980 period, the geographic location of the first reported human case(s) can often be determined from the primary literature, at least to within specific countries and often to specific regions or municipalities. However, this is not possible for all new pathogen species. For example, although the early history of HIV-1 has been exhaustively investigated the exact origin of the first reported human case remains unclear (Barre-Sinoussi et al. 1983). Similarly, the only reported human case of European bat lyssavirus 2 in a human could have resulted from exposure in Finland, Switzerland or Malaysia (Lumio et al. 1986). Moreover, some new human pathogens were already endemic or ubiquitous in the human population when they were first discovered; examples include human metapneumovirus and human bocavirus. For those pathogens which were discovered previously, but were only recently associated with human disease (such as commensals which have become pathogenic in patients immunosuppressed due to infection with HIV) the geographic origin is taken as the location in which the patient became sick (if the patient was not reported as having recent travel history).

Figure 5-6 shows a map of the points of origin of the first human cases of disease caused by 51 of the 87 pathogen species discovered since 1980. Data of this kind must be interpreted cautiously, not least because of likely ascertainment bias (variable likelihood of detection and identification of novel pathogens) in different parts of the world. Nonetheless, Figure 5-6 does make the important point that the emergence of new pathogens shows a truly global pattern, with multiple incidents being reported from every continent except Antarctica (with other gaps apparent in, for example, the Middle East and central Asia). There is no striking tendency for new pathogens to be more likely to be reported from tropical rather than temperate regions, or from less developed regions, or from more densely populated regions.

FIGURE 5-6

World map indicating points of origin of the first reported human cases of disease caused by 51 novel pathogen species since 1980. Locations are identified to municipality or region (occasionally country), jiggled as necessary to avoid overlap.

Process of Pathogen Emergence

Reservoirs of Infection

Relatively few human pathogens are known solely as human pathogens. The remainder also occur in other contexts: as commensals; or free-living in the wider environment; or as infections of hosts other than humans.

Overall, probably no more than 50 to 100 species are specialist human pathogens. These range from major killers such as Plasmodium falciparum, mumps virus, Treponema pallidum, smallpox and HIV-1 to those causing more minor problems such as the human adenoviruses and rhinoviruses.

Hundreds of species which can cause human disease occur naturally as “commensals” found on the skin, on mucosal surfaces, or in the gut. They are normally benign but are sometimes pathogenic, for example if introduced into the blood system via a wound or in association with AIDS or other immunosuppressive conditions. Examples include the streptococci and Candida spp.

Several hundred human pathogen species have environmental reservoirs; these are referred to as “sapronoses.” Examples include Bacillus anthracis, Legionella pneumophila, and Cryptococcus neoformans. Here, we do not take sapronotic to include pathogens which are transmitted via the fecal-oral route or via a free-living stage of a complex parasite life cycle. Most sapronoses are bacteria or fungi, plus some protozoa, and cause sporadic infections of humans. Few are highly transmissible (directly or indirectly) between humans, an important exception being Vibrio cholerae. Some human pathogens (e.g., Listeria spp.) are both sapronotic and zoonotic.

Many more pathogens—over 800 species—are capable of infecting animal hosts other than humans. These range from species where humans are largely incidental hosts—such as rabies or Bartonella henselae—to species in which the main reservoir (sensu Haydon et al. 2002) is the human population and animals may be largely incidental hosts, that is, the so-called “reverse zoonoses” such as Schistosoma haematobium, rubella virus, Mycobacterium tuberculosis, or Necator americanus. We refer to all of these as “zoonotic,” following the World Health Organization’s definition of zoonoses as “diseases or infections which are naturally transmitted between vertebrate animals and humans.” In contrast to some other authors (e.g., Hubalek 2003) we do not consider pathogens with invertebrate reservoirs, and especially pathogens which are transmitted by arthropod vectors, as zoonotic. Note that the WHO definition does not include human pathogen species which recently evolved from animal pathogens, such as HIV-1. Nor does it include pathogens with complex life cycles where vertebrate animals are involved only as intermediate hosts with humans as the sole definitive host. It does, however, include reverse zoonoses.

Few of the 87 new human pathogen species in Table 5-3 are commensals or sapronoses. The great majority—around 80%—are associated with nonhuman vertebrate reservoirs (e.g., SARS coronavirus, vCJD agent and Borrelia burgdorferi) and most of the remainder appear to be long-standing human pathogens which have only recently been identified (e.g., Hepatitis G virus). Even some of the nonzoonotic pathogens, notably HIV-1 and HIV-2, are recently evolved from pathogens of nonhuman vertebrates (Keele et al. 2006). Compared with human pathogen species reported before 1980 the new species are statistically significantly more likely to be associated (or, at least, are more likely to be known to be associated) with a nonhuman animal reservoir (OR = 2.75, P < 0.001).

The reservoirs of the new, zoonotic human pathogens are mainly mammals, although a small number are associated with birds (Figure 5-7). However, the reservoirs include a wide range of mammal groups with ungulates, carnivores, and rodents most frequently involved, but also bats, primates, marsupials and occasionally other taxa (Figure 5-7). These observations must be interpreted with some caution because our knowledge of the host range of many pathogens is still incomplete. Nevertheless, the data available give the impression that taxonomic relatedness is less important than ecological opportunity as a determinant of the reservoirs of novel human pathogens. Homo sapiens as a species is classified within primates and, beyond that, the most closely related major groups are the rodents and lagomorphs. Ungulates, carnivores, and bats are more distant relatives. One related observation is that emerging human pathogens are especially likely to have a broad host range which includes more than one of these groups (Woolhouse and Gowtage-Sequeira 2005).

FIGURE 5-7

Counts of recently discovered human pathogens species (see Table 5-3) associated with various categories of non-human animal reservoirs. Some pathogens species are associated with more than one category of reservoir. These data should be regarded as no (more...)

Drivers of Pathogen Emergence

As discussed earlier, not all the pathogens in the list of new species should be regarded as truly emerging; some have only recently been identified as the causative agents of established infectious diseases. However, for 30 or more of new species the literature suggests various drivers deemed to be associated with their emergence at the present time. These drivers can be considered within a framework originally suggested by the Institute of Medicine (IOM 2003), noting that this framework was devised with reference to all emerging and re-emerging infectious diseases, not just newly discovered pathogen species.

The most commonly cited drivers fall within the following IOM categories: economic development and land use; human demographics and behavior; international travel and commerce; changing ecosystems; human susceptibility; and hospitals. Economic development and land use, and especially changes in economic development and land use, are associated with the emergence of pathogens such as Nipah virus and Borrelia burgdorferi through activities such as intensification of farming and forest encroachment respectively. Human demographics and behavior, and especially changes in human demographics and behavior, are associated with the emergence of pathogens such as HIV-1 and Hepatitis C virus through activities such as sexual activity and intravenous drug use. International travel and trade are increasing as part of the process of globalization and are associated with the emergence of pathogens such as SARS coronavirus. Changing ecosystems covers unintended consequences of human activities such as desertification, pollution, and climate change and is associated with the emergence of pathogens such as the hantaviruses. Broadly speaking, the set of drivers listed so far are all “ecological” in nature; they are to do with the ways that humans interact with their wider environment (especially with other vertebrate animals both domestic and wild), providing opportunities for pathogens to infect humans, and with the ways that humans interact with each other, providing opportunities for pathogens to spread within human populations. A particular concern—implicit but not highlighted in the IOM’s list—is increasing use of “exotic” animal species, whether as food, farm animals or pets, and the trade that accompanies this.

The other most commonly cited drivers are to do with human population health. Human susceptibility is particularly important in the context of coinfections associated with AIDS (e.g., several species of microsporidia) but also covers the effects of malnutrition and other immunosuppressive conditions. The hospitals category covers iatrogenic transmission (e.g., vCJD), and xenotransplantation (e.g., baboon cytomegalovirus), as well as nosocomial infections (e.g., Ebola viruses and Rotavirus C).

Other categories listed by the IOM—such as “intent to harm”—have not been or are not commonly cited as associated with the emergence of novel human pathogen species. Among these is the category “microbial adaptation and change,” an observation that we expand on below.

Transmission and Disease

The 87 new species of human pathogen are associated with public health problems of hugely variable magnitudes. At one extreme is HIV-1 which has killed an estimated 25 million people since it was first reported in 1983, with 40 million more currently infected (UNAIDS 2007). HIV-1 has a high transmission potential within many human populations (combining transmission mainly by sexual contact or by needle-sharing associated with intravenous drug use with an infectious period of several years) and is highly pathogenic (with a case fatality rate close to 100% in the absence of treatment). At the other extreme, Menangle virus is known to have infected only 2 farm workers in which it may have caused a mild febrile illness (Chant et al. 1998). Menangle virus does not appear to be highly infectious to or transmissible between humans and has not so far been associated with severe disease. In the following section we consider the kinds of epidemiological and biological differences that underlie the vast difference in public health impacts between pathogens such as HIV-1 and pathogens such as Menangle virus.

Pathogen Pyramid

A useful aid to conceptualizing the process of pathogen emergence is the pathogen pyramid. The concept of the pathogen pyramid was first put forward by Wolfe et al. (2004) and developed further in Wolfe, Dunavan, and Diamond (2007). A very similar framework but with a more formal mathematical underpinning was adopted by Woolhouse, Haydon, and Antia (2005). The pyramid we use here has four levels corresponding to exposure, infection, transmission, and epidemic spread (Figure 5-8). Wolfe, Dunavan, and Diamond (2007) subdivided epidemic spread into (in their terminology): Stages 4a, b, and c, infectious diseases that exist in animals but with different balances of animal-to-human and human-to-human spread (where Stage 4c corresponds to reverse zoonoses as defined above); and Stage 5, pathogens exclusive to humans (corresponding to specialist human pathogens as defined above).

FIGURE 5-8

The pathogen pyramid (adapted from Wolfe, Dunavan, and Diamond 2007). Each level represents a different degree of interaction between pathogens and humans, ranging from exposure through to epidemic spread. Some pathogens are able to progress from one (more...)

Level 1: Exposure The first stage of the emergence of a new pathogen is the exposure of humans to that pathogen. Exposure requires “contact” between humans and the pathogen reservoir (which may be animal or environmental; exposure to commensals is implicit). The nature of “contact” is determined by the mode of transmission of the pathogen, e.g., animal bite, contamination of food with fecal material, blood-feeding by arthropod vectors or exposure to aerosols. The only barrier to exposure is insufficient overlap between habitats occupied by humans and habitats occupied by the pathogen. Changes in human ecology, particularly patterns of land use and interactions with animal reservoirs, are likely to change our exposure to potential new pathogens, as are changes in the ecology of the pathogens, their reservoirs or their vectors, e.g., as a result of climate change or other kinds of environmental change.

We do not know how many potential human pathogen species there are which we have not yet been exposed to, but we do know that human pathogens make up only a fraction of the known biodiversity of viruses, bacteria, fungi, protozoa and helminths, which in turn probably makes up only a fraction of the biodiversity which exists (Dykhuizen 1998).

Level 2: Infection The second stage of pathogen emergence is reached if the pathogen proves capable of infecting humans, possibly causing disease. As reviewed above, we know of 1399 species that have reached this stage. Others may have done so but have yet to be identified. Others may do so in the future but, to date, we have had no or insufficient exposure to them. Clearly, there will often be significant biological barriers—referred to as species barriers—preventing organisms infecting other kinds of host from infecting humans. We do not, for example, share any pathogens with plants, very few with invertebrates, and only a small number with cold-blooded vertebrates (e.g., Salmonella spp. in reptiles and amphibians—Mermin et al. 2004; helminth infections from fish—Chai et al. 2005). In contrast, we share many more of our pathogens with birds, and we share more than half with other species of mammal.

Indeed, the species barrier (at least between humans and other mammals) may not be as profound as is sometimes implied. According to Cleaveland et al. (2001) over 500 different species of pathogen are known to occur in domestic livestock and as many as 40% of these are zoonotic. The same authors report for domestic carnivores (dogs and cats) that almost 400 pathogen species are known, of which almost 70% are zoonotic. These data imply that, given the opportunities for exposure to pathogens that proximity to domestic animals must surely provide, many pathogens, perhaps even a majority, are capable of crossing the species barrier and infecting humans.

As suggested by the IOM (2003) report, an important contributor to the ability of a new pathogen to infect humans is variation in human susceptibility. In some cases this variation might have a genetic basis; for example, apparently pre-existing genetic variation in human susceptibility to HIV (Arien, Vanham, and Arts 2007). More commonly, phenotypic variation in the human population will be important, particularly factors which compromise the human immune system. The most striking examples come from the wide range of opportunistic infections associated with the immunosuppressive effects of HIV infection; these include several pathogen species, such as the microsporidia Brachiola algerae and Enterocytozoon bieneusi which were first recognized in AIDS patients.

Level 3: Transmission The third stage of pathogen emergence is reached if a pathogen that can infect humans also proves capable of transmission from one human to another. Transmission in this context need not be direct (e.g., by aerosol spread or sexual contact); it might be indirect (e.g., via contamination of food) or via an arthropod vector. The requirement is simply that an infection of one human leads ultimately to an infection of another.

In most cases the barriers preventing transmission will be biological, often reflecting tissue tropisms within the human host since pathogens normally need to access the gut, upper respiratory tract, urogenital tract or (especially for vector-borne infections) blood in order to be able to exit the body. However, sometimes such barriers can be overcome by changes in human behavior. The two best examples concern prion diseases. Kuru is only transmitted through cannibalism, which is extremely rare in most human societies. vCJD is not transmissible between humans except iatrogenically as a result of surgical procedures or blood transfusions.

Again, these barriers to human-to-human transmission are far from insuperable. Although information is lacking for many pathogen species (Taylor, Latham, and Woolhouse 2001), the literature suggests that a substantial minority—at least 500 species, over one third of the total, and possibly many more—are transmissible between humans.

Level 4: Epidemic Spread The fourth and, in our version, final level of the pathogen pyramid is reached if a pathogen is sufficiently transmissible within the human population to cause major epidemics or pandemics and/or to become endemic, without the involvement of the original reservoir. This represents a quantitative rather than qualitative distinction and it can be made more formally precise by reference to the concept of the basic reproduction number, R0. R0 can be defined as the average number of secondary cases of infection produced when a primary case is introduced into a large population of previously unexposed hosts (adapted from Anderson and May 1991). The distinction between Level 3 and Level 4 pathogens can be expressed in terms of R0. If R0 is less then one then, on average, a single primary case will fail to replace itself and although there may be chains of transmission these will be self-limiting—this corresponds to Level 3. On the other hand, if R0 is greater than one then, on average, a single primary case will produce more than one secondary case and, at least initially, there will be an exponential increase in the number of cases and ultimately a major epidemic is possible—this corresponds to Level 4. (A proviso is that, even if R0 >1, stochastic extinction of the infection chain is quite possible, especially in the early stages of the epidemic when numbers of cases are low—see May, Gupta, and McLean 2001.)

The barriers between Level 3 and Level 4 are both biological and epidemiological. The biological barriers are to do with pathogen infectivity, host susceptibility, the infectiousness of the infected host and for how long the host is infectious (whether this is terminated by recovery or death). The epidemiological barriers are to do with the rate and pattern of contacts between infectious and susceptible hosts. Here again, the nature of a “contact” reflects the mode of transmission of the pathogen (see above). The rate and pattern of contacts can increase, and hence R0 can increase, independently of the pathogen, as a result of shifts in host demography or behavior. In the context of human hosts such shifts could constitute changes in factors such as population density (e.g., urbanization), living conditions, water supply and sanitation, patterns of travel and migration, or sexual behavior and intravenous drug use, depending on the specific pathogen involved. These might be augmented by changes in host susceptibility due to the kinds of factors listed earlier. Clearly, for the same pathogen R0 can vary considerably from one human population to another. Similarly, different strains of the same pathogen species may have very different R0 values in humans, e.g., different subtypes of influenza A virus.

In principle, this barrier might seem quite fragile; the kinds of changes in host demography and behavior alluded to above are certainly occurring. In practice, it is not clear how many species of human pathogen have reached Level 4 since we have estimates of R0 values within human populations for only a handful of them. Based on earlier studies (Taylor, Latham and Woolhouse 2001; Woolhouse and Gowtage-Sequeira 2005) a plausible estimate is that 100 to 150 pathogen species are capable of causing major outbreaks within human populations, with half to two-thirds of these being specialist human pathogens and the remainder also occurring in animal reservoirs or the wider environment. This implies considerable attrition between levels 3 and 4 of the pathogen pyramid.

Status of New Pathogens

We can now consider where the 87 new human pathogen species fit within the pathogen pyramid. It is immediately clear that the majority of them are at Level 2; they can infect humans but are rarely if at all transmitted between humans. Examples include Borrelia burgdorferi, vCJD agent, most of the hantaviruses and Ehrlichia spp. At the other extreme, although there are a number that appear to be at Level 4, most of these are pathogens which are probably long established in human populations but have only recently been recognized, such as human metapneumovirus or hepatitis C virus. Only a very small number are likely to be recent additions to the repertoire of Level 4 human pathogens, namely HIV-1, HIV-2 and, arguably before its spread was contained, SARS coronavirus. In between, at Level 3, there is a significant minority of new pathogens that are somewhat transmissible between humans but which have so far been restricted to relatively minor outbreaks. These include Andes virus, human torovirus and some Encephalitozoon spp. For these species the value of the basic reproduction number R0 is of particular interest, especially if it lies close to one, the threshold for potential epidemic spread. R0 can be estimated from data on the distribution of outbreak sizes as follows.

The quantitative analysis of outbreak data used to estimate R0 is based upon a methodology developed by Jansen et al. (2003) for measles case data from the UK (to monitor the effect of changes in childhood vaccination coverage). Here, we apply the technique (see also Matthews and Woolhouse 2005) to data on human outbreaks of Andes virus (see Figure 5-9 for details). Andes virus is an emerging South American hantavirus and there are concerns that, unusually for hantaviruses, it can be transmitted directly between humans (Wells et al. 1997). Most reports of Andes virus represent sporadic cases (i.e., outbreaks of size 1) but clusters of cases also occur, ranging in size from 2 to 20 (Figure 5-9). This pattern—many small outbreaks and a few larger ones—is typical of a wide range of infectious diseases (Woolhouse, Taylor, and Haydon 2001). The best estimate of R0 based on these data lies in the range 0.22 to 0.37. This is well below one and in reality is likely to be an over-estimate since at least some of the clusters of cases may reflect exposure to a common source rather than, as is assumed in the analysis, person-to-person spread. However, the analysis does suggest that occasional larger outbreaks will occur (the R0 estimates are consistent with up to 1 in 200 outbreaks being of size 10 or more) without necessarily implying that there has been a major change in Andes virus epidemiology. This same approach can be applied to other “Level 3” pathogens to determine how close they are to reaching Level 4 of the pyramid (cf. Jansen et al. 2003).

FIGURE 5-9

Analysis of Andes virus outbreaks. Frequencies of outbreaks of different sizes (grey bars) are compared with the fit of a statistical model to the data (open bars). Outbreak data are taken from Wells et al. (1997) and Lazaro et al. (2007). The model is (more...)

Evolution and Emergence

So far we have examined the emergence of new species of human pathogens over time scales of a few decades. However, the origins of many human pathogens are considerably more ancient, extending back over time scales of thousands to millions of years. This process has been reviewed by, among others, Weiss (2001), Diamond (2002), and Wolfe, Dunavan, and Diamond (2007). Of particular interest here are examples of pathogens which have emerged in human populations as a result of successfully crossing the species barrier from an animal reservoir and reaching Level 4 status. Any analysis must be prefaced by the observation that we have good evidence for the origins of only a small minority of pathogens, plausible hypotheses (usually based on the epidemiologies of related species) for some of the remainder, and no information at all for the majority. Wolfe, Dunavan, and Diamond (2007)

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