In 1890 the German physician and bacteriologist Robert Koch set out his celebrated criteria for judging whether a given bacteria is the cause of a given disease as follows:
- The bacteria must be present in every case of the disease.
- The bacteria must be isolated from the host with the disease and grown in pure culture.
- The specific disease must be reproduced when a pure culture of the bacteria is inoculated into a healthy susceptible host.
- The bacteria must be recoverable from the experimentally infected host.
However, Koch’s postulates have their limitations and so may not always be the last word. They may not hold if:
- The particular bacteria (such as the one that causes leprosy) cannot be “grown in pure culture” in the laboratory.
- There is no animal model of infection with that particular bacteria.
It is debatable whether or to what extent Koch’s postulates are relevant to multifactorial chronic disease syndromes such as asthma, that may include a component of bacterial causation:
- Different types of asthma may have different “causes.”
- The form of the bacteria (in this case, chlamydia) that causes disease may not be cultivable.
- Not all infected individuals may demonstrate the disease (i.e., disease expression may depend on a specific host response not shared by a majority of those who are infected).
Despite such limitations, Koch’s postulates are still a useful benchmark in judging whether there is a cause-and-effect relationship between a bacteria (or any other type of microorganism) and a clinical disease.
How well does C. pneumoniae fulfill Koch’s postulates for asthma?
1. The bacteria must be present in every case of the disease.
C. pneumoniae has been implicated, indirectly by serology and directly by PCR testing, in around 50% of asthma, not in all asthma. C. pneumoniae has been associated with more severe forms of asthma, suggesting a disproportionate contribution to morbidity and mortality
2. The bacteria must be isolated from the host with the disease and grown in pure culture.
Several investigators have reported isolation of C. pneumoniae from children and adults with asthma. The isolation techniques include culture, polymerase chain reaction (PCR) testing, and intracellular staining.
3. The specific disease must be reproduced when a pure culture of the bacteria is inoculated into a healthy susceptible host.
After accidental exposure, a laboratory worker developed pneumonia with wheezing. Non-asthmatic patients have developed asthma or chronic bronchitis after naturally acquired acute C. pneumoniae infections.
Experimental inoculation of mice produces sustained bronchial hyperresponsiveness (Blasi et al. 2007), allergic airways sensitization (Horvat et al. 2007 and Schroder et al. 2008), and lung remodelling ( Chen et al. 2009), three hallmarks of asthma.
4. The bacteria must be recoverable from the experimentally infected host.
C pneumoniae has been recovered by culture of the sputum from one of the patients who developed chronic bronchitis after naturally acquired infection.
Hill’s Criteria
Hill’s 9 criteria for causal association represent a more comprehensive set of characteristics that can be applied to the question about C. pneumoniae and asthma:
1. Strength of Association: What is the relative risk?
The magnitude of the association between C. pneumoniae antibodies and asthma is large (#1) and unlikely to be explained by confounding.
2. Consistency: Agreement over time, space and method?
Associations between C. pneumoniae and asthma have been demonstrated in 11 countries on 4 continents; over 15 years; using culture, PCR, intracellular staining, MIF, slgA and lgE immunoblotting; in primary and specialty medical care settings and in population-based epidemiological studies (#35 and Johnston & Martin 2005)
3. Specificity: Is the outcome unique to the exposure?
C. pneumoniae , not C. trachomatis, is specifically associated with adult asthma (#1, #62); the majority of the adult population has been exposed to this infection and many asymptomatic individuals may be chronically infected, implying that a gene-environment interaction is needed to express disease.
4. Temporality: Does exposure precede the outcome?
Yes. Systematic clinical studies document that acute infection is followed by new-onset asthma, not the reverse (#30, #49).
5. Biologic-gradient: Is there a dose-response relationship?
Yes (#1)
6. Plausibility: Does the association make biological sense?
Yes. Chlamydial infections are known to cause chronic inflammation in target organs. C. pneumoniae infects the lung; asthma is a chronic inflammatory disease of the lung (#53).
7. Coherence: Compatible with knowlege of the disease?
Yes. Older models saw asthma as a non-infectious allergic disease; newer models acknowledge a major contribution from various infections, including chlamydiae (#53).
8. Experimentation: Does treatment improve the disease?
Case reports (#11, #36), a case-series (#31), a before-after study (#19) and a randomized controlled trial (#60) consistently suggest important clinical benefits from prolonged antibiotic treatment directed against C. pneumoniae. More research is required (#38).
9. Analogy: Does the association conform to a previously described related disease?
Yes. There are compelling analogies with other chronic human chlamydial infections such as trachoma and pelvic inflammatory disease (#61).
References:
AB Hill. The environment and disease: association or causation? 1965 Proc. R. Soc. Med; Fredericks & Relman 1996