Theories of Disease causation Development of understanding in Pathogenesis

Dr. Bhoj R singh, Principal Scientist (VM)I/C Epidemiology; Centre for Animal Disease Research and

DiagnosisIndian Veterinary Research Institute, Izatnagar-243122, Bareilly,

UP, India. TeleFax +91-581-2302188

Disease CausationA disorder of structure or function in a human, animal, or plant, especially one that produces specific symptoms or that affects a specific location and is not simply a direct result of physical injury.

A disease is a particular abnormal, pathological condition that affects part or all of an organism. It is often construed as a medical condition associated with specific symptoms and signs.

Death due to disease is called death by natural causes. There are four main types: pathogenic disease, deficiency disease, hereditary disease, and physiological disease. Diseases may be communicable or non-communicable.

A particular quality or disposition regarded as adversely affecting a person/ animal or group of people/ animals.

"we are suffering from the British disease of self-deprecation"

Theories of Disease Causation• Pre-modern era theories of Disease causation: Religions often attributed

disease outbreaks or other misfortunes to divine retribution - punishment for mankind's sins.

and imbalance among four vital "humors“ within us. Hippocrates; Yellow Bile, Black Bile, Phlegm and Blood

• Miasma Theory: 500 BC Miasmas are poisonous emanations from putrefying carcasses, vegetables, molds and also the invisible particles. This theory led to explanation of several outbreaks of cholera, plague and malaria (Mal-aria= bad air).

• Fracastoro's contagion theory of disease (1546)• Germ theory: Louis Pasteur , Lister and others introduced the germ theory

in 1878. In 1890 Robert Koch proposed specific criteria that should be met before concluding that a disease was caused by a particular bacterium. Only single germ is responsible for causation of a specific disease.

• Webs of Causation: Epidemiological concept

Pre Modern Era (Before 1850) theories

• Devil & Witchcraft ( Demonic Theory)• Punishing from God (Punitive Theory)• Metaphysical Theory• Miasma – “Bad Air” (Miasmatic Theory)

DEMONIC THEORY

• Attributed disease to supernatural powers, the product of animism which imbued all

moving things with a spirit• In this 'spirit-world', disease could be produced by witches,

superhuman entities and spirits of the dead.

• Treatment therefore included: placation, for example by sacrifice; exorcism (forcible expulsion) etc.

DIVINE WRATH/ PUNITIVE THEORY

• Monotheistic in origin• Disease was the product of a displeased

supreme being• Disease was punishment.

Metaphysical Theory

• Development did not assume the existence of a supreme being, either demonic or divine• Assumed the presence of occult forces beyond the

physical universe.• 'Doctrine of Signatures' which suggested a similarity between the disease and its cure – for

example using toads to treat warts - were notable metaphysical developments

Religious disease concepts

Hippocratic disease concepts

Fracastoro's contagion theory of disease

Germ Theory

Web of Disease Causation

Association and CausesAssociation: An association exists if two variables appear to be related by a

mathematical relationship; that is, a change of one appears to be related to the change in the other. Association is necessary for a causal relationship to exist but association alone does not prove that a causal relationship exists. A correlation coefficient or the risk measures often quantify associations.

– Negative Association (Inverse Relationship): The magnitude of one variable appears to move in the opposite direction of the other associated variable. The correlation coefficient is negative and, if the relationship is causal, higher levels of the risk factor are protective against the outcome.

– Positive Association (Direct Relationship): The magnitudes of both variables appear to move together up or down. The correlation coefficient is positive and, if the relationship is causal, higher levels of the risk factor cause more of the outcome.

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Cause: The combination of necessary and sufficient factors (e.g., attributes and exposures) the presence of which, alone or in combination, at some time during an individual’s life, inevitably result in disease in that individual.

CausesEtiology: The study of disease causes and their modes of operation.Causal Pathway (Causal Web, Cause and Effect Relationships): The actions of

risk factors acting individually, in sequence, or together that result in disease in an individual. These pathways are often different with different sets of risk factors for individuals in different situations. Understanding these pathways and their differences is necessary to devise effective preventive or corrective measures (interventions) for a specific situation. What is effective in one pathway may not be in another because of the differences in the component risk factors. (e.g., bronchopneumonia in a housed calf vs. in a feedlot calf).

Necessary Cause: A risk factor that must be, or have been, present for the disease to occur (e.g., a specific infectious agent for a particular infectious disease). Although necessary, few infectious agents cause disease by themselves alone.

Sufficient Cause: The minimal combination of risk factors acting on the individual, on the etiologic agent if one is involved, or in the environment whose occurrence in an individual’s life inevitably results in disease. A disease can often be caused by more than one set of sufficient causes and thus different causal pathways for individuals contracting the disease in different situations.

Disease Causation– Henle-Koch Postulates: (1877) A set of 4 criteria to be met before the

relationship between a particular infectious agent and a particular disease is accepted as causal. These postulates enabled the germ theory of disease to achieve dominance in medicine over other theories, such as humors and miasma. They are insufficient for multi-causal and non-infectious diseases because the postulates presume that an infectious agent is both necessary and sufficient cause for a disease. Fulfilling the postulates experimentally can be surprisingly difficult, even when the infectious process is thought to be well understood. Now archaic and superseded by the Hill's-Evans Postulates.

– Hill-Evans Postulates: (1965) A set of 9 or 10 criteria (depending on interpretation of original papers) that each contribute a different amount of strength to the likelihood that a relationship between a potential risk factor and a disease is causal. The entire set constitutes very strong evidence of causality when fulfilled. As noted above, these supersede the Henle-Koch Postulates and are extensions of Mill’s Methods of inductive inference.

Inductive Inference for discovering causal relationships

• Mill's Eliminative Methods of Induction (System of Logic, 1843):

– Method of Agreement: "If two or more instances of the phenomenon have only one circumstance in common, the circumstance in which alone all instances agree is the cause or effect of the given phenomenon."

– Method of Difference: "If an instance in which the phenomenon under investigation occurs, and an instance in which it does not occur, have every circumstance in common save one, that one occurring in the former, the circumstance in which alone the two instances differ, is the effect, or the cause, or an indispensable part of the cause, of the phenomenon."

– Method of Residues: "Subduct from any phenomenon such part as is known by previous inductions to be the effect of certain antecedents, and the residue of the phenomenon is the effect of the remaining antecedents."

– Method of Concomitant Variations: "Whatever phenomenon varies in any manner whenever another phenomenon varies in some particular manner, is either a cause or an effect of that phenomenon, or is connected with it through some fact of causation.“

– Method of Analogy: If it happens like that the similar other event should also take the same route. Through comparison of patterns of the diseases.

Koch's postulates are

The postulates were formulated by Robert Koch and Friedrich Loeffler in 1884 and refined and published by Koch in 1890.

• 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 culture.

• The cultured microorganism should cause disease when introduced into a healthy organism.

• The microorganism must be re-isolated 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 and, later, of typhoid fever.

Koch's postulates for 21st Century:

The use of new methods in disease diagnosis has led to revised versions of Koch’s postulates: Fredricks and Relman (1996) 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.

Hill's Criteria of Causation (1965)In 1965 Austin Bradford Hill detailed criteria for assessing evidence of causation. These guidelines are

sometimes referred to as the Bradford-Hill criteria, but this makes it seem like it is some sort of checklist. For example, Phillips and Goodman (2004) note that they are often taught or referenced as a checklist for assessing causality, despite this not being Hill's intention. Hill himself said "None of my nine viewpoints can bring indisputable evidence for or against the cause-and-effect hypothesis and none can be required sine qua non".

• Strength: A small association does not mean that there is not a causal effect, though the larger the association, the more likely that it is causal

• Consistency: Consistent findings observed by different persons in different places with different samples strengthens the likelihood of an effect.

• Specificity: Causation is likely if a very specific population at a specific site and disease with no other likely explanation. The more specific an association between a factor and an effect is, the bigger the probability of a causal relationship.

• Temporality: The effect has to occur after the cause (and if there is an expected delay between the cause and expected effect, then the effect must occur after that delay).

• Biological gradient: Greater exposure should generally lead to greater incidence of the effect. However, in some cases, the mere presence of the factor can trigger the effect. In other cases, an inverse proportion is observed: greater exposure leads to lower incidence.

• Plausibility: A plausible mechanism between cause and effect is helpful (but Hill noted that knowledge of the mechanism is limited by current knowledge).

• Coherence: Coherence between epidemiological and laboratory findings increases the likelihood of an effect. However, Hill noted that "... lack of such [laboratory] evidence cannot nullify the epidemiological effect on associations".

• Experiment: "Occasionally it is possible to appeal to experimental evidence".• Analogy: The effect of similar factors may be considered.

Evan's Postulates (1976)

1. Prevalence of the disease should be significantly higher in those exposed to the risk factor than those not.

2. Exposure to the risk factor should be more frequent among those with the disease than those without.

3. In prospective studies, the incidence of the disease should be higher in those exposed to the risk factor than those not.

4. The disease should follow exposure to the risk factor with a normal or log-normal distribution of incubation periods.

5. A spectrum of host responses along a logical biological gradient from mild to severe should follow exposure to the risk factor.

6. A measurable host response should follow exposure to the risk factor in those lacking this response before exposure or should increase in those with this response before exposure. This response should be infrequent in those not exposed to the risk factor.

7. In experiments, the disease should occur more frequently in those exposed to the risk factor than in controls not exposed.

8. Reduction or elimination of the risk factor should reduce the risk of the disease.9. Modifying or preventing the host response should decrease or eliminate the disease.10. All findings should make biological and epidemiological sense.

References

• Fredericks DN, Relman DA (1996). "Sequence-based identification of microbial pathogens: a reconsideration of Koch's postulates". Clin Microbiol Rev 9 (1): 18–33.

• Hill, Austin Bradford (1965). "The environment and disease: association or causation?". Proceedings of the Royal Society of Medicine 58: 295–300. PMC 1898525. PMID 14283879.

• Phillips, Carl V.; Karen J. Goodman (October 2004). "The missed lessons of Sir Austin Bradford Hill". Epidemiologic Perspectives and Innovations 1 (3): 3.