EMERGING INFECTIOUS DISEASES

Overview

Microbes: Friend and Foe

Infectious Disease Process

Ancient Enemies

Modern Menace: Emerging and Re-Emerging Infectious Diseases

Fighting Back

Prevention and Control

About the College of Physicians of Philadelphia

WHEN THE PRESIDENT IS THE PATIENT

Fighting Back

Medical breakthroughs have assisted in combating infectious diseases. Smallpox is perhaps the most dramatic. It took nearly two centuries following Edward Jenner's demonstration in 1796 of the efficacy of vaccination to rid the world of this affliction. No treatment for smallpox has ever been found. Yet it is the first disease for which an effective method of prevention was discovered.

The Golden Age of Microbiology (1857-1914) included discoveries both of the microbial agents causing disease and the role of immunity in prevention and cure. Robert Koch, Louis Pasteur and Joseph Lister spearheaded the rapid advances that led to the establishment of microbiology as a science. Pasteurization, aseptic surgery, and advances in hygiene have been important tools in the battle against emerging infectious diseases Once the relations between microorganisms and disease were established, microbiologists focused on the search for substances that could destroy the disease-causing microorganisms without harming the infected animal or human. The antibiotic penicillin was discovered in the l930s, revolutionizing the way bacterial diseases were treated. Many other antibiotics have subsequently been discovered or developed. Unfortunately, a major problem associated with antimicrobial drugs is the emergence and spread of new varieties of microorganisms that are resistant to them. Scientists continue to explore and develop new ways to fight back against the microbial agents that cause us harm.

Ali Maow Maalin

Ali Mao Maalin, a cook in Merca, Somalia was the last person to naturally contract smallpox. Smallpox is the first infectious disease to be eradicated through an international program of the World Health Organization, which culminated with the isolation of the last remaining cases in Ethiopia and Somalia, in 1976. This was possible due to the low mutation rate of the smallpox virus, and the fact that it is passed from person to person with no troublesome animals or insects to control.

Vaccination

Unlike antibiotics for bacterial or fungal infections, it has been difficult to develop drugs to kill viruses. Viruses take over the normal cells of the host, making it difficult to develop drugs that do not harm the host. Instead we have used the normal immune system to protect against viruses through vaccination and immunization.

It was over 200 years ago that Edward Jenner demonstrated that the technique of vaccination offered a reliable defense against smallpox. Smallpox is believed to have appeared around 10,000 BC in northeastern Africa and spread along trade routes. Smallpox affected all ages and classes with a fatality rate between 20% and 60% leaving most survivors with disfiguring scars.

Smallpox epidemics were greatly feared. The disease periodically swept through Europe killing thousands. It became a major scourge when it was brought by Spanish Conquistadors to the New World in the 1500s where it did not previously exist. Many illnesses such as smallpox pass through the body quickly and kill the infected host rapidly before immunity can develop. Those that survive are permanently immunized against the disease through natural immunity. This type of infection means that there must be large, dense populations of people to keep the smallpox virus in circulation. Smaller, less dense populations (such as those originally present in the New World) were not large enough to sustain an infection like smallpox. Native Americans were completely unexposed and unprotected by any natural immunity when first contact was made by the Spanish - with devastating consequences.

An Inquiry into the Causes and Effects of the Variole Vaccinae, a Disease Discovered in Some of the Western Countries of England

Before even understanding that such a thing as viruses existed, Jenner developed a vaccine against smallpox by drawing on its known similarity to a disease of cows called cowpox. Jenner observed that milkmaids who got cowpox from infected cows were protected against subsequent exposure to smallpox. He decided to deliberately introduce the cowpox disease into a patient to see if the disease could be artificially produced. Afterward he inoculated the patient with smallpox and discovered that the cowpox vaccine effectively prevented smallpox. In June of 1798, Jenner published his 75- page Inquiry describing his experiments, using his own meager resources.

Adult arm showing smallpox nine days after infection (Wax Model)

The first sign of the smallpox rash is small papules, which become fluid-filled vesicles, and then pustules. These dry up and become scabs, which fall off. In severely infected individuals, the pustules run together as shown in this model.

Vaccination is the process of introducing a small amount of cowpox into the skin, so as to cause a mild case of cowpox that will provide immunity against smallpox. Various techniques and instruments have been used. Most often, a lancet of the type used for bloodletting would pick up vaccine lymph from a vesicle on one person's arm, and transfer it to the arm of an uninfected person by making a slight puncture and inserting the lymph under the skin. Another technique was to make the punctures or scratches first, with sharp pins, combs, or needles, and then rub the lymph into the raw surface.

Lymph could be transferred directly from arm to arm, or preserved by dipping a lancet or an ivory point into the lymph and letting it dry, or by storing dried scabs in envelopes or small tin boxes and wetting them with water or glycerin when needed.

In May 1980, the World Health Organization announced the successful completion of its campaign to eradicate smallpox. One of the keys to that campaign's success was the invention of the bifurcated needle by Dr. Benjamin Rubin of Wyeth Laboratories. It picks up the precise amount of vaccine needed and deposits it in the skin, after which the points are pressed into the skin to introduce the vaccine. Relatively untrained field workers in developing countries where smallpox was most widespread could easily use this technique.

The introduction of vaccination into America was largely due to an English Quaker physician, John Coakley Lettsom, who sent a copy of Jenner's booklet to Harvard Professor, Dr. Benjamin Waterhouse. Waterhouse, excited by what he read, requested and received from Lettsom a supply of vaccine. He engaged President Thomas Jefferson's help in redistributing vaccine to physicians in the United States. Jefferson, who had been inoculated at age 23 by Dr. Richard Shippen of Philadelphia, had his entire family vaccinated, including his slaves. Dr. John Redmond Coxe (1773-1864) of Philadelphia also received vaccines from President Jefferson for use in large-scale vaccination programs that he started on November 9, 1801.

Thomas Jefferson was quick to grasp the immense importance of vaccination. Receiving a delegation of North American Indian Chieftains in Washington in the winter of 1801-1802, he persuaded them all to be vaccinated and to take back to their tribes supplies of vaccine. He further promoted vaccination among the Indians, directing Meriwether Lewis and William Clark to "carry with you some matter of the kinepox (cowpox), inform those of them with whom you may be of its efficiency as a preservative from the smallpox, and instruct and encourage them in the use of it."

Lady Mary Wortley Montagu. 1689-1762

From ancient times, China, India. Persia and parts of Africa promoted the practice of inoculating persons with infectious material from mild smallpox cases, which would then prevent a more serious bout with smallpox. Inoculation was introduced into Constantinople around 1672, apparently having arrived overland from China or Persia. The Lady Montagu, wife of the British Ambassador in Constantinople, popularized the practice of inoculation in England when she had her three-year-old daughter inoculated in London in 1721. This was the first professional inoculation in England. The Princess of Wales learned of this successful inoculation resulting in the first Royal inoculations, taking place on April 17, 1722. Inoculation soon became an acceptable medical practice in England, though it was not widely utilized as it entailed some risk to the inoculated individuals. Approximately 3% of inoculated persons died of smallpox, became the source of new epidemic or developed other illnesses from the donor, such as tuberculosis or syphilis. Edward Jenner's cowpox vaccine would eventually replace inoculation as a preferred method of protection against smallpox.

Child with Smallpox

This image was on a flyer used by the World Health Organization in educating populations about the smallpox eradication campaign begun in 1966.

Antibacterials

The fact that many kinds of disease are related to microorganisms was unknown until the middle of the 19th Century. Before the time of Pasteur, effective treatments for many diseases were discovered by trial and error, but the causes of the diseases were unknown. The realization that yeasts play a critical role in fermentation alerted scientists to the possibility that microorganisms might cause disease. This idea, known as the germ theory of disease, was a difficult concept for many people to accept. For centuries disease was believed to be a punishment for an individual's crimes or misdeeds. People born in Pasteur's time found it inconceivable that "invisible" microbes could travel through the air to infect plants and animals. Gradually, scientists collected the information they needed to support the new germ theory.

Louis Pasteur, 1822-1895

Pasteur proved that microorganisms are present in the air and can contaminate seemingly sterile solutions, but air itself does not create microbes. He championed changes in hospital practices to minimize the spread of disease by microbes. Pasteur also found that rabies was transmitted by agents so small they could not be seen under a microscope thus revealing the world of viruses. As a result he developed techniques to vaccinate dogs against rabies, and to treat humans bitten by rabid dogs. Pasteur also developed "pasteurization," a process by which harmful microbes in perishable food products are destroyed using heat without destroying the food.

Robert Koch, 1843-1910

The first proof that bacteria actually caused disease came from Robert Koch, a German physician, in 1876. Koch discovered rod-shaped bacteria now known as Bacillus anthracis in the blood of cattle that had died of anthrax. He established a sequence of experimental steps for directly relating a specific microbe to a specific disease, known today as Koch's postulates. During the past 100 years these criteria have been invaluable in the investigations proving that specific microorganisms cause many diseases. In 1878 Koch demonstrated the usefulness of steam for sterilizing surgical instruments and dressings. Koch was awarded the Nobel Prize in Medicine in 1905 for his investigations and discoveries in relation to tuberculosis.

Joseph Lister, 1827-1912

By the middle of the 19th century, post-operative infection accounted for the death of almost half of the patients undergoing major surgery. In 1858, Joseph Lister, influenced by the work of Pasteur, proposed that wound infection was a form of decomposition initiated by microbes. To reduce the presence of these microbes Lister used a solution of carbolic acid called phenol that was known to destroy bacteria. He sprayed the air in the operating room with a fine mist of phenol, soaked surgical instruments with phenol and had surgeons wash their hands with it. Death from surgical infection declined dramatically as a result of using carbolic acid to combat infections.

Antibiotics: From Magic Bullets To Friendly Fire

Once scientists in the late 1800s identified particular bacteria as the causes of specific diseases, it eventually became possible to develop drugs to combat the bacteria that cause infections. Before the creation of penicillin and other antibiotics, bacterial diseases simply ran their course. Either the immune system fought the microbes off or the patient died. Doctors also relied on toxic compounds like arsenic and mercury that could kill bacterial cells, but were also very harmful to the normal cells of the infected person. In 1906, when a drug was developed that allowed the killing of a bacteria - in this case syphilis - without killing normal cells, it was called a "magic bullet."

Face showing chancre of the lip of primary syphilis (Wax Model)

A chancre is the characteristic lesion caused by the spirochete Treponema pallidum where it first enters the body. Shortly after the primary chancre disappears, the rash of secondary syphilis develops. In 1838, Joseph Rollet of Lyons observed that glass-blowers sharing a blowpipe would pass syphilis if one member of the team had evidence of secondary syphilis about the mouth. It was determined that secondary syphilis was also contagious and its incubation period was approximately three weeks.

Madonna and Child with Syphallis Sufferers (Woodcut from Tractatus de Pestilentiali Scorra Sive Mala de Francos)

Authorities are unsure when venereal syphilis first appeared but they are certain that an epidemic struck Europe around 1493. In only a few decades the disease had spread to most areas of the world. The illustration in this book by Grunpeck shows the earliest image of syphilis known. Hideous symptoms persuaded sufferers to try all kinds of remedies. One of the most effective was mercury.

Syphilis lesions from a tattoo

The subject, a 16-year-old machinist, was tattooed by an itinerant artist in Reading, Pennsylvania in May, 1877. The artist had himself contracted syphilis in February of that year, and developed lesions in his mouth. He infected his clients through his saliva, which he used to moisten the pigments. He would also sometimes spit on the completed tattoo and rub it with his hand or a dirty cloth.

Syphilis before and after treatment

Mercury was rubbed on, applied to the body in plasters, and swallowed in pills. Since it is toxic to the bacteria Treponema, it was sometimes curative in the early stages of the disease. However, for use in later phases, the dose had to be so great that it was extremely toxic to human tissue as well. Side effects included profuse salivation, loosening of teeth, diarrhea, anemia, mental changes and kidney damage, which often led to death. These types of treatment prompted Oliver Wendell Holmes, Sr., well-known physician and author, to state, "I firmly believe that if the whole materia medica, as now used, could be sunk to the bottom of the sea, it would be all the better for mankind ó and all the worse for the fishes." (Address before the Massachusetts Medical Society, Boston, May 30, 1860).

Paul Ehrlich, German immunologist and Nobel Prize winner for his work with diphtheria and serum technology began searching for a cure for malaria. Ehrlich observed that certain cells and chemicals are particularly sensitive to one another. Working in the new field of chemotherapy (using chemicals to attack a particular disease), Ehrlich tested over 900 different compounds to find the 'magic bullet" that would kill the microbe but not the person. His 606th manipulation, an arsenic compound, didn't cure sleeping sickness, but it did kill the microbe which causes syphilis. In 1910, the drug, called Salvarsan, was released and was an immediate success.

The development of penicillin made possible an easy-to-administer cure for syphilis. By 1957 the incidence of the disease hit an all-time low. However, a lack of awareness of the disease along with prostitution, drug use, and the development of antibiotic resistance, have kept syphilis a continuing threat.

Penicillin

Prior to World War II, infections rather than the wounds themselves were the major cause of wartime deaths. In 1928, Alexander Fleming (1881-1955), a Scottish physician, was working on identifying ways to kill bacteria isolated from infected wounds in order to find a way to treat wounds and prevent infections. He left the lid off a culture of an infection-causing bacteria. Weeks later he discovered that the culture had become contaminated with green mold which he recognized as penicillin - a mold that was often found on spoiling bread and fruit. He also noticed that no bacteria appeared around the fuzz. The mold had prevented the bacteria from spreading. His untidy work habits lead to the creation of a new weapon against infection ó penicillin.

Ten years later, scientists Howard Florey, Ernst Chain and Norman Heatley used Fleming's findings to assist them in the isolation, purification and characterization of penicillin. In its pure form, penicillin was a million times more potent. In 1940 they published the results of their successful treatment of white mice.

Albert Alexander, a police constable who had been scratched by a thorn around the mouth was the first human volunteer to test penicillin on February 12, 1941. The wound had developed into infections about the head and face. His lungs were infected and one eye had been removed.

Less than a day after the first dose of penicillin was administered, Alexander's health improved. After five days, his fever had disappeared, his appetite returned and the infection was nearly gone. But the supply of penicillin ran out and the infection took over his body. Alexander lingered for a month and died.

Although the patient died, the experiment was a success. Florey and his colleagues knew that the treatment would be successful with the manufacture of larger quantities of penicillin. While the purification and testing occurred in England, entry into World War II and the fear of bombing raids moved the entire process for the production of penicillin to the United States. Wyeth pioneered the commercial production of penicillin at a plant in West Chester, Pennsylvania, using technology developed by G. Raymond Rettew.

Antibiotic Abuse

Just as any organism adapts to changes in its environment, so the use of antibiotics has become a feature of the environment in which bacteria breed. Because bacteria multiply rapidly, there are many opportunities for mutations to occur under the selective pressure of antibiotics. As such, many strains of bacteria have now developed resistance to many common antibiotics. The routine use of antibiotics in breeding cattle, for example, is one probable source of resistant bacteria.

Many infectious diseases, once curable by antibiotics, are reappearing in forms that are difficult and sometimes impossible to treat with conventional drugs. Scientists warn that measures are not taken now to slow their spread, the day of untreatable common infections may return.

New antibiotics are constantly being developed to combat the problem of antibiotic resistance. Research on the genetics of bacteria using advanced molecular genetic technologies may provide new opportunities to develop specific antibiotics for certain bacteria.