Koch's postulates
Encyclopedia
Koch's postulates are four criteria designed to establish a causal relationship between a causative microbe and a disease
. The postulates were formulated by Robert Koch
and Friedrich Loeffler in 1884 and refined and published by Koch in 1890. Koch applied the postulates to establish the etiology
of anthrax
and tuberculosis
, but they have been generalized to other diseases.
However, Koch abandoned the universalist requirement of the first postulate altogether when he discovered asymptomatic carriers of cholera
and, later, of typhoid fever
. Asymptomatic
or subclinical infection
carriers are now known to be a common feature of many infectious diseases, especially viruses such as polio, herpes simplex
, HIV
and hepatitis C
. As a specific example, all doctors and virologists agree that poliovirus
causes paralysis in just a few infected subjects, and the success of the polio vaccine
in preventing disease supports the conviction that the poliovirus is the causative agent.
The third postulate specifies "should", not "must", because as Koch himself proved in regard to both tuberculosis
and cholera
, not all organisms exposed to an infectious agent will acquire the infection. Noninfection may be due to such factors as general health and proper immune functioning; acquired immunity from previous exposure or vaccination; or genetic immunity, as with the resistance to malaria conferred by possessing at least one sickle cell allele.
The second postulate may also be suspended for certain microorganisms or entities that cannot (at the present time) be grown in pure culture, such as prion
s responsible for Creutzfeldt–Jakob disease.
In summary, a body of evidence that satisfies Koch's postulates is sufficient but not necessary to establish causation.
s that could be isolated with the techniques of the day. Even in Koch's time, it was recognized that some infectious agents were clearly responsible for disease even though they did not fulfill all of the postulates. Attempts to rigidly apply Koch's postulates to the diagnosis of viral diseases in the late 19th century, at a time when viruses could not be seen or isolated in culture, may have impeded the early development of the field of virology
. Currently, a number of infectious agents are accepted as the cause of disease despite their not fulfilling all of Koch's postulates. Therefore, while Koch's postulates retain historical importance and continue to inform the approach to microbiologic diagnosis, fulfillment of all four postulates is not required to demonstrate causality.
Koch's postulates have also influenced scientists who examine microbial pathogenesis from a molecular point of view. In the 1980s, a molecular version
of Koch's postulates was developed to guide the identification of microbial genes encoding virulence
factors.
More recently, modern nucleic acid-based microbial detection methods have made Koch’s original postulates even less relevant. These nucleic acid-based methods make it possible to identify microbes that are associated with a disease, but in many cases the microbes are uncultivable. Also, nucleic acid-based detection methods are very sensitive, and they can often detect the very low levels of viruses that are found in healthy people without disease.
The use of these new methods has led to revised versions of Koch’s postulates: Fredricks and Relman have suggested the following set of Koch’s postulates for the 21st century:
Disease
A disease is an abnormal condition affecting the body of an organism. It is often construed to be a medical condition associated with specific symptoms and signs. It may be caused by external factors, such as infectious disease, or it may be caused by internal dysfunctions, such as autoimmune...
. The postulates were formulated by Robert Koch
Robert Koch
Heinrich Hermann Robert Koch was a German physician. He became famous for isolating Bacillus anthracis , the Tuberculosis bacillus and the Vibrio cholerae and for his development of Koch's postulates....
and Friedrich Loeffler in 1884 and refined and published by Koch in 1890. Koch applied the postulates to establish the etiology
Etiology
Etiology is the study of causation, or origination. The word is derived from the Greek , aitiologia, "giving a reason for" ....
of anthrax
Anthrax
Anthrax is an acute disease caused by the bacterium Bacillus anthracis. Most forms of the disease are lethal, and it affects both humans and other animals...
and tuberculosis
Tuberculosis
Tuberculosis, MTB, or TB is a common, and in many cases lethal, infectious disease caused by various strains of mycobacteria, usually Mycobacterium tuberculosis. Tuberculosis usually attacks the lungs but can also affect other parts of the body...
, but they have been generalized to other diseases.
The postulates
Koch's postulates are:- The microorganism must be found in abundance in all organisms suffering from the disease, but should not be found in healthy organisms.
- The microorganism must be isolated from a diseased organism and grown in pure cultureCell cultureCell culture is the complex process by which cells are grown under controlled conditions. In practice, the term "cell culture" has come to refer to the culturing of cells derived from singlecellular eukaryotes, especially animal cells. However, there are also cultures of plants, fungi and microbes,...
. - The cultured microorganism should cause disease when introduced into a healthy organism.
- The microorganism must be reisolated from the inoculated, diseased experimental host and identified as being identical to the original specific causative agent.
However, Koch abandoned the universalist requirement of the first postulate altogether when he discovered asymptomatic carriers of cholera
Cholera
Cholera is an infection of the small intestine that is caused by the bacterium Vibrio cholerae. The main symptoms are profuse watery diarrhea and vomiting. Transmission occurs primarily by drinking or eating water or food that has been contaminated by the diarrhea of an infected person or the feces...
and, later, of typhoid fever
Typhoid fever
Typhoid fever, also known as Typhoid, is a common worldwide bacterial disease, transmitted by the ingestion of food or water contaminated with the feces of an infected person, which contain the bacterium Salmonella enterica, serovar Typhi...
. Asymptomatic
Asymptomatic
In medicine, a disease is considered asymptomatic if a patient is a carrier for a disease or infection but experiences no symptoms. A condition might be asymptomatic if it fails to show the noticeable symptoms with which it is usually associated. Asymptomatic infections are also called subclinical...
or subclinical infection
Subclinical infection
A subclinical infection is the asymptomatic carrying of an by an individual of an agent that usually is a pathogen causing illness, at least in some individuals. Many pathogens spread by being silently carried in this way by some of their host population...
carriers are now known to be a common feature of many infectious diseases, especially viruses such as polio, herpes simplex
Herpes simplex
Herpes simplex is a viral disease caused by both Herpes simplex virus type 1 and type 2 . Infection with the herpes virus is categorized into one of several distinct disorders based on the site of infection. Oral herpes, the visible symptoms of which are colloquially called cold sores or fever...
, HIV
HIV
Human immunodeficiency virus is a lentivirus that causes acquired immunodeficiency syndrome , a condition in humans in which progressive failure of the immune system allows life-threatening opportunistic infections and cancers to thrive...
and hepatitis C
Hepatitis C
Hepatitis C is an infectious disease primarily affecting the liver, caused by the hepatitis C virus . The infection is often asymptomatic, but chronic infection can lead to scarring of the liver and ultimately to cirrhosis, which is generally apparent after many years...
. As a specific example, all doctors and virologists agree that poliovirus
Poliovirus
Poliovirus, the causative agent of poliomyelitis, is a human enterovirus and member of the family of Picornaviridae.Poliovirus is composed of an RNA genome and a protein capsid. The genome is a single-stranded positive-sense RNA genome that is about 7500 nucleotides long. The viral particle is...
causes paralysis in just a few infected subjects, and the success of the polio vaccine
Polio vaccine
Two polio vaccines are used throughout the world to combat poliomyelitis . The first was developed by Jonas Salk and first tested in 1952. Announced to the world by Salk on April 12, 1955, it consists of an injected dose of inactivated poliovirus. An oral vaccine was developed by Albert Sabin...
in preventing disease supports the conviction that the poliovirus is the causative agent.
The third postulate specifies "should", not "must", because as Koch himself proved in regard to both tuberculosis
Tuberculosis
Tuberculosis, MTB, or TB is a common, and in many cases lethal, infectious disease caused by various strains of mycobacteria, usually Mycobacterium tuberculosis. Tuberculosis usually attacks the lungs but can also affect other parts of the body...
and cholera
Cholera
Cholera is an infection of the small intestine that is caused by the bacterium Vibrio cholerae. The main symptoms are profuse watery diarrhea and vomiting. Transmission occurs primarily by drinking or eating water or food that has been contaminated by the diarrhea of an infected person or the feces...
, not all organisms exposed to an infectious agent will acquire the infection. Noninfection may be due to such factors as general health and proper immune functioning; acquired immunity from previous exposure or vaccination; or genetic immunity, as with the resistance to malaria conferred by possessing at least one sickle cell allele.
The second postulate may also be suspended for certain microorganisms or entities that cannot (at the present time) be grown in pure culture, such as prion
Prion
A prion is an infectious agent composed of protein in a misfolded form. This is in contrast to all other known infectious agents which must contain nucleic acids . The word prion, coined in 1982 by Stanley B. Prusiner, is a portmanteau derived from the words protein and infection...
s responsible for Creutzfeldt–Jakob disease.
In summary, a body of evidence that satisfies Koch's postulates is sufficient but not necessary to establish causation.
History
Koch's postulates were developed in the 19th century as general guidelines to identify pathogenPathogen
A pathogen gignomai "I give birth to") or infectious agent — colloquially, a germ — is a microbe or microorganism such as a virus, bacterium, prion, or fungus that causes disease in its animal or plant host...
s that could be isolated with the techniques of the day. Even in Koch's time, it was recognized that some infectious agents were clearly responsible for disease even though they did not fulfill all of the postulates. Attempts to rigidly apply Koch's postulates to the diagnosis of viral diseases in the late 19th century, at a time when viruses could not be seen or isolated in culture, may have impeded the early development of the field of virology
Virology
Virology is the study of viruses and virus-like agents: their structure, classification and evolution, their ways to infect and exploit cells for virus reproduction, the diseases they cause, the techniques to isolate and culture them, and their use in research and therapy...
. Currently, a number of infectious agents are accepted as the cause of disease despite their not fulfilling all of Koch's postulates. Therefore, while Koch's postulates retain historical importance and continue to inform the approach to microbiologic diagnosis, fulfillment of all four postulates is not required to demonstrate causality.
Koch's postulates have also influenced scientists who examine microbial pathogenesis from a molecular point of view. In the 1980s, a molecular version
Molecular Koch's postulates
Molecular Koch's postulates are a set of experimental criteria that must be satisfied to show that a gene found in a pathogenic microorganism encodes a product that contributes to the disease caused by the pathogen. Genes that satisfy molecular Koch's postulates are often referred to as virulence...
of Koch's postulates was developed to guide the identification of microbial genes encoding virulence
Virulence
Virulence is by MeSH definition the degree of pathogenicity within a group or species of parasites as indicated by case fatality rates and/or the ability of the organism to invade the tissues of the host. The pathogenicity of an organism - its ability to cause disease - is determined by its...
factors.
Koch’s postulates for the 21st century
Koch’s postulates have played an important role in microbiology, yet they have major limitations. For example, Koch was well aware that in the case of cholera, the causal agent, Vibrio cholerae, could be found in both sick and healthy people, invalidating his first postulate. Furthermore, viral diseases were not yet discovered when Koch formulated his postulates, and there are many viruses that do not cause illness in all infected individuals, a requirement of the first postulate.More recently, modern nucleic acid-based microbial detection methods have made Koch’s original postulates even less relevant. These nucleic acid-based methods make it possible to identify microbes that are associated with a disease, but in many cases the microbes are uncultivable. Also, nucleic acid-based detection methods are very sensitive, and they can often detect the very low levels of viruses that are found in healthy people without disease.
The use of these new methods has led to revised versions of Koch’s postulates: Fredricks and Relman have suggested the following set of Koch’s postulates for the 21st century:
- A nucleic acid sequence belonging to a putative pathogen should be present in most cases of an infectious disease. Microbial nucleic acids should be found preferentially in those organs or gross anatomic sites known to be diseased, and not in those organs that lack pathology.
- Fewer, or no, copies of pathogen-associated nucleic acid sequences should occur in hosts or tissues without disease.
- With resolution of disease, the copy number of pathogen-associated nucleic acid sequences should decrease or become undetectable. With clinical relapse, the opposite should occur.
- When sequence detection predates disease, or sequence copy number correlates with severity of disease or pathology, the sequence-disease association is more likely to be a causal relationship.
- The nature of the microorganism inferred from the available sequence should be consistent with the known biological characteristics of that group of organisms.
- Tissue-sequence correlates should be sought at the cellular level: efforts should be made to demonstrate specific in situ hybridization of microbial sequence to areas of tissue pathology and to visible microorganisms or to areas where microorganisms are presumed to be located.
- These sequence-based forms of evidence for microbial causation should be reproducible.