History of emerging infectious diseases

The discovery of new pathogens is an important activity in the field of medical science. Pathogens are organisms that cause disease through infection. Scientists have discovered viruses, bacteria, protozoa, fungi, helminthes (worms) and prions that have proven to be pathogens. A Center for Disease Control program begun in 1995 identified over a hundred patients with life threatening illnesses which were considered to be of an infectious cause, but could not be identified with any known pathogen. The association of pathogens with disease can be a complex and controversial process, in some cases requiring decades or even centuries to achieve. Factors which have been identified as impeding the identification of pathogens include the following:


 * 1. Lack of animal models: Experimental infection in animals has been used as a criterion to demonstrate an organism's disease causing ability. But animal models do not exist for many important pathogens, such as Vibrio cholerae, which cause disease only in humans. In cases where animal models were not available, scientists have sometimes infected themselves or others to determine an organism's disease causing ability.


 * 2. Pre-existing theories of disease: Before the pathogen is well-recognized, scientists may attribute the symptoms of infection to other causes, such as toxicological causes, psychological causes, or genetic causes. Once a pathogen has been associated with an illness, researchers have reported difficulty displacing these pre-existing theories.


 * 3. Variable pathogenicity: Infection with pathogens can produce varying responses in hosts, complicating the process of showing a relationship between infection and the pathogen. In some infectious diseases, the severity of symptoms has been shown to be dependent on specific genetic traits of the host.


 * 4. Organisms that look alike but behave differently: In some cases a harmless organism exists which looks identical to a disease causing organism with a microscope. Researchers have noted that this can complicate the discovery process.


 * 5. Lack of research effort: Slow progress has been attributed to the small numbers of researchers working on a pathogen.

For example, Dr. Barry Marshall was the co-discoverer of the theory that a bacterial infection with Helicobacter pylori was responsible for causing most peptic or stomach ulcers. After winning the 2005 Nobel Prize for this work, Dr. Marshall's described his difficulty in producing stomach ulcers in animals by infecting them with the bacteria. He infected piglets with the bacteria, but they did not become ill. He then infected himself by swallowing a culture. His colleague then examined him and found damage consistent with peptic ulcers which was not present previously.

Vibrio cholerae (1849-1884)
Cholera is a sometimes fatal disease caused by infection with the bacteria Vibrio cholerae, which is transmitted through contaminated water. Once ingested, the bacteria colonizes the intestinal tract of the host and produces a toxin which causes body fluids to flow across the lining of the intestine. Death can result in 2-3 hours from dehydration if no treatment is provided.

Prior to the discovery of an infectious cause, the symptoms of Cholera were thought to be caused by an excess of bile in the patient. The disease Cholera gets its name from the Greek word choler meaning bile. This was consistent with medical thought at the time, which held that four liquids or humors controlled health, and lead to such medical practices as bloodletting as a method of curing illnesses. The bacteria was first reported in 1849 by M. Gabriel Pouchet, who discovered it in stools from patients with Cholera. But he did not appreciate its significance. The first scientist to understand the significance of Vibrio cholerae was an Italian anatomist Filippo Pacini, who published detailed drawings of the organism in "Microscopical observations and pathological deductions on cholera" in 1854. He would go onto publish additional papers in 1866, 1871, 1876 and 1880, all of which were ignored by the scientific community. He correctly described how the bacteria caused diarrhea, and developed treatments that were found to be effective. But his findings did not influence medical opinion. In 1874, scientific representatives from 21 countries voted unanimously to resolve that Cholera was caused by environmental toxins from miasmatas, or clouds of unhealthy substances which float in the air. In 1884, Robert Koch re-discovered Vibrio cholerae as a causal element in Cholera. Some scientists opposed the new theory, and even drank Cholera cultures to disprove it:

Von Pettenkofer considered his experience proof that Vibrio cholerae was harmless, as he did not develop Cholera from consuming the culture. Between 1849 when Pouchet discovered Vibrio cholerae and 1891, over a million people died in Cholera epidemics in Europe and Russia. In 1995, researchers published a study in Science Magazine explaining why some persons are able to be infected with Cholera without symptoms, possibly explaining why Pettenkofer did not get sick. The study showed that a series of genetic mutations in some people provide resistance to Cholera toxin. However, these mutations come with a price. If too many of them occur in a person, they will develop Cystic Fibrosis, an incurable and often fatal genetic disorder.

Giardia lamblia (1681-1975)
Giardiasis is a disease caused by infection with the protozoan Giardia lamblia. Infection with Giardia can produce diarrhea, gas, and abdominal pain in some people. If untreated, infection can be chronic. In children, chronic Giardia infection can cause stunting (stunted growth) and lowered intelligence, Infection with Giardia is now universally recognized as a disease, and treated by physicians with anti-protozoal drugs. Since 2002, Giardia cases must be reported to the Center for Disease Control, according to the CDC’s Reportable Disease Spreadsheet. The United States National Institutes of Health Gastrointestinal Parasites Lab studies Giardia almost exclusively.

However, Giardia experienced an extraordinarily long term of emergence, from its discovery in 1681, until the 1970s when it was fully accepted that infection with Giardia was a treatable cause of chronic diarrhea:

Some of the first evidence in modern times of Giardia's pathogenicity came during World War II when soldiers were treated for malaria with the antiprotozoal Quinacrine, and their diarrhea disappeared, as did the Giardia from their stool samples. In 1954, Dr. R.C. Rendtorff performed experiments on prisoner volunteers, infecting them with Giardia. In the experiment, although some prisoners experienced changes in stool habits, he concluded that these could not be conclusively linked to Giardia infection, and also indicated that all prisoners experienced spontaneous clearance of Giardia. His experiments were described in the EPA Symposium on Waterborne Transmission of Giardiasis in 1979:

In 1954-55, an outbreak of Giardia infection occurred in Oregon (US), sickening 50,000 people. This was documented in a communication by Dr. Lyle Veazie, which wasn't published until 15 years later in the New England Journal of Medicine.  In the communication, Veazie notes that he was unable to find a publisher for his account of the epidemic. The communication was re-published in the EPA Symposium on Waterborne Transmission of Giardiasis in 1979, and that version included the following quote from the Director of the Oregon State Board of Health, suggesting that diarrhea from Giardia was still being attributed to other causes by health authorities in 1954:

Helicobacter pylori (1892-1982)
Infection with the bacteria Helicobacter pylori is the cause of most stomach ulcers. The discovery is generally credited to Australian gastroenterologists Dr. Barry Marshall and Dr. J Robin Warren, who published their findings in 1983. The pair received the Nobel Prize in 2005 for their work. Before this, nobody really knew what caused stomach ulcers, though a popular belief was that the "stress" played a role. Some researchers suggested that ulcers were a psychosomatic illness.

In H Pylori Pioneers, Dr. Marshall noted that other physicians had produced evidence of H. pylori infection as early as 1892. Marshall writes that earlier reports were disregarded because they conflicted with existing belief. The first description of H. Pylori came in 1892 from Giulio Bizzozero, who identified acid-tolerant bacteria living in a dog’s stomach. Later, a theory would be developed that no bacteria could live in the stomach. Although the theory has no scientific basis, it would become a stumbling block for scientists, discouraging them for searching for infective causes of stomach ulcers. In 1940, two physicians, Dr. A. Stone Freeberg and Dr. Louis E. Barron published a paper describing a spiral bacteria found in about half of their gastroenterology patients who had stomach ulcers. Dr. John Lykoudis, a Greek physician, was one of the first physicians to treat stomach ulcers as an infectious disease. Between 1960 and 1970, he treated over 10,000 ulcer patients in Athens with antibiotics. Lykoudis tried to publish a paper on his findings, but they conflicted with traditional theory, and his work was never published. Lykoudis' experience was followed in 1975 by a further publication in Gut magazine that included spiral bacteria living on the borders of duodonal ulcers. The medical significance of Steer’s findings was disregarded, but he “continued to publish papers on H. Pylori, mostly as a hobby."

H. pylori can infect the stomach of some people without causing stomach ulcers. In investigating asymptomatic carriers of H. pylori, researchers identified a genetic trait called Interleuik-1 beta-31 which causes increased production of stomach acid, resulting in ulcers if patients become infected with H. pylori. Patients without the trait do not develop stomach ulcers in response to H. pylori infection, but instead have increased risk from stomach cancer if they become infected. Investigation into other gastrointestinal infections has also shown that the symptoms are the result of interaction between the infection and specific genetic mutations in the host.

Pathogenic variants of Escherichia coli (1947-1983)
Enterotoxigenic Escherichia coli (ETEC) is a type of bacteria that causes illness in humans. There are different types of E. Coli, some of which are found in humans and are harmless. ETEC is a special kind of E. Coli which has a gene that allows it to manufacture a substance toxic to humans. Cattle are immune to the effects of ETEC, but when people eat food contaminated with cattle feces, the organism can cause disease. Reports of pathogenic E. Coli appear in medical literature as early as 1947. Publications regarding variants of E. Coli which cause disease appeared in medical journals regularly in the 1950s, 1960s, and 1970s. In the 1970s, reports included fatality in humans and infants. Despite the earlier reports, pathogenic E. Coli did not rise to public prominence until 1983, when Dr. Joyce Riley of the Center for Disease Control published a paper identifying ETEC as the cause of a series of outbreaks of unexplained hemorrhagic gastrointestinal illness. The New York Times account of the discovery mentions the difficulty Dr. Riley encountered in 1983 in establishing ETEC as a pathogen, despite the earlier publication of pathogenic variants of E. Coli. Since then, another type of pathogenic E. Coli has been identified in developing countries called Entero-Aggregative E. Coli (EAEC).

Human Immunodeficiency Virus (1959-1984)
AIDS was first reported June 5, 1981, when the U.S. Centers for Disease Control and Prevention recorded a cluster of Pneumocystis carinii pneumonia (now still classified as PCP but known to be caused by Pneumocystis jirovecii) in five homosexual men in Los Angeles. The discovery of the virus took several years of research, and was announced in 1984 by Dr. Gallo of the National Cancer Institute, Dr. Luc Montagnier at the Pasteur Institute in Paris, and Dr. Jay Levy at the University of California, San Francisco.

However, the HIV virus existed long before the 1981 CDC report. Three of the earliest known instances of HIV infection are as follows:
 * 1) A plasma sample taken in 1959 from an adult male living in what is now the Democratic Republic of the Congo.
 * 2) HIV found in tissue samples from a 15 year old African-American teenager who died in St. Louis in 1969.
 * 3) HIV found in tissue samples from a Norwegian sailor who died around 1976.

Two species of HIV infect humans: HIV-1 and HIV-2. HIV-1 is more virulent and more easily transmitted. HIV-1 is the source of the majority of HIV infections throughout the world, while HIV-2 is not as easily transmitted and is largely confined to West Africa. Both HIV-1 and HIV-2 are of primate origin. The origin of HIV-1 is the Central Common Chimpanzee (Pan troglodytes troglodytes) found in southern Cameroon. It is established that HIV-2 originated from the Sooty Mangabey (Cercocebus atys), an Old World monkey of Guinea Bissau, Gabon, and Cameroon.

Most experts believe that HIV probably transferred to humans as a result of direct contact with primates, for instance during hunting or butchery.

Cyclospora (1995)
Cyclospora is a gastrointestinal pathogen that causes fever, diarrhea, vomiting, and severe weight loss. Outbreaks of the disease occurred in Chicago in 1989 and other areas in the United States. But investigation by the Center for Disease Control could not identify an infectious cause. The discovery of the cause was made by Mr. Ramachandran Rajah, the head of a medical clinic's laboratory in Katmandu, Nepal. Mr. Rajah was trying to discover why local residents and visitors were becoming ill every summer. He identified an unusual looking organism in stool samples from patients who were sick. But when the clinic sent slides of the organism to the Center for Disease Control, it was identified as Blue-Green algae, which is harmless. Many pathologists had seen the same thing before, but dismissed it as irrelevant to the patient's disease. . Later, the organism would be identified as a special kind of parasite, and treatment would be developed to help patients with the infection. In the United States, Cyclospora infection must be reported to the Center for Disease Control according to the CDC's Reportable Disease Chart

Present day discoveries
The process of identifying new infectious agents continues. One study has suggested there are a large number of pathogens already causing illness in the population, but they have not yet been properly identified.

Gastrointestinal pathogens




Many recently emerged pathogens infect the gastrointestinal tract. For example, there are three gastrointestinal protozoal infections which must be reported to the Center for Disease Control. They are Giardia, Cyclospora and Cryptosporidium, and none of them were known to be significant pathogens in the 1970s.

Figure 1 shows the prevalence of gastrointestinal protozoa in studies from the United States and Canada. The most prevalent protozoa in these studies are considered emerging infectious diseases by some researchers, because a consensus does not yet exist in the medical and public health spheres concerning their importance in the role of human disease. Researchers have suggested that their treatment may be complicated by differing opinions regarding pathogenicity, lack of reliable testing procedures, and lack of reliable treatments. As with newly discovered pathogens before them, researchers are reporting that these organisms may be responsible for illnesses for which no clear cause has been found, such as Irritable Bowel Syndrome.

Dientamoeba fragilis
Dientamoeba fragilis is a single-celled parasite which infects the large intestine causing diarrhea, gas, and abdominal pain. An Australian study identified patients with symptoms of IBS who were actually infected with Dientamoeba fragilis. Their symptoms resolved following treatment. A study in Denmark identified a high incidence Dientamoeba fragilis infection in a group of patients suspected of having gastrointestinal illness of an infectious cause. . The study also suggested special methods may be required to identify infection.

Blastocystis
Blastocystis is a single-celled protozoan which infects the large intestine. Physicians report that patients with infection show symptoms of abdominal pain, constipation, and diarrhea. . One study found that 43% of IBS patients were infected with Blastocystis versus 7% of controls. An additional study found that many IBS patients from whom Blastocystis could not be identified showed a strong antibody reaction to the organism, which is a type of test used to diagnose certain difficult-to-find infections. Other researchers have also reported that special testing techniques may be necessary to identify the infection in some people. While some scientists believe the finding that IBS patients carry a protozoal infection to be significant, other researchers have reported their belief that the presence of the infection is not medically significant. Researchers report that the infection can be resistant to common protozoal treatments in laboratory culture study and in experience with patients, so identifying Blastocystis infection may not be of immediate help to a patient. A 2006 study of gastrointestinal infections in the United States suggested that Blastocystis infection has become the leading cause of protozoal diarrea in that country. Blastocystis was the most frequently identified protozoal infection found in patients in a 2006 Canadian study.