Campylobacter jejuni and Campylobacter coli: Dose Response Models

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Campylobacter jejuni and Campylobacter coli

Author: Kyle S. Enger
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If you want to download the excel spreadsheet of tables, please click the captions of tables. If you want to download a specific figure, just click on the figure


Overview

Campylobacter are microaerophilic gram-negative curved or spiral rods with a polar flagellum. Gastroenteritides are typically caused by C. jejuni and C. coli.(Havelaar et al. 2009) It can cause acute self-limited diarrhea in healthy humans with an incubation period of 2-3d, and appears very common worldwide. It is mainly a zoonosis, being primarily associated with birds (especially poultry). They do not grow in water and (like Escherichia coli) are an indicator of post-treatment contamination in water distribution systems.

According to feeding studies with chickens, strains of C. jejuni that have been passaged many times in the laboratory tend to have a lower ID50 than strains that are isolated from infected hosts and then used to infect new hosts, with minimal passage (Chen et al. 2006). Minimally passaged strains also had more variation in ID50 (Chen et al. 2006). Given safety concerns, strains used for human studies may be passaged and studied more, possibly underestimating infectiousness in actual human exposure scenarios (Chen et al. 2006).

Campylobacter epidemiology varies greatly between the developed and underdeveloped world, probably due to development of immunity early in life. Illness is rare after about 5 years of age (or earlier) in developing countries, but occurs among adults in industrialized countries, probably because they avoided exposure (and therefore immunity) in childhood.(Havelaar et al. 2009) However, immunity appears to protect against disease rather than infection, and asymptomatic shedding is common.(Havelaar et al. 2009) In a comparison of Mexican children <4y and Swedish patients (ages not given), Swedish patients tended to carry only 1 Campylobacter serotype, while mixed serotypes were common among Mexican children (42%).(Sjögren et al. 1989)




Summary of data

Blaser et al. (1983) experimentally infected adult female HA-ICR mice intragastrically with 3 different serotypes of C. jejuni (strains T1, T2, and T3).

Chen et al. (2006) describe dose response models fitted to data from feeding studies in chickens with 19 different strains (18 C. jejuni, 1 C. coli). They found that isolates that had been passaged multiple times in the laboratory were more infectious than isolates taken from infected animals and reused with minimal passaging. Also, one passaged strain (11168) was substantially less infectious than the other passaged strains, which all had very similar dose response curves.

Black et al. (1988) fed human volunteers 2 different strains (81-176 and A3249) of C. jejuni suspended in 150 mL nonfat milk. Neither strain showed an increasing trend of illness with dose. The A3249 strain showed an increasing trend of infection with dose; however, all volunteers became infected with the 81-176 strain regardless of dose. The data describing infection with the A3249 strain were fit by Medema et al. (1996). Teunis et al. (1999) pooled all illness data from Black et al. (1988) to fit a model for strains 81-176 and A3249, which remained similar to Medema et al. (1996). This model was later elaborated by Teunis et al. (2005) by including information from 2 outbreaks of C. jejuni in contaminated milk.

Tribble et al. (2009) fed healthy adult human volunteers with the CG8421 strain of C. jejuni, along with bicarbonate. However, only 2 doses were used, and all but 1 volunteer became ill.

Tribble et al. (2010) experimentally infected humans with strain 81-176 of C. jejuni, one of the strains used by Black et al. (1988). Although Black et al. (1988) administered the dose in milk, Tribble et al. (2010) administered the dose in a solution containing 2g of bicarbonate. All volunteers were infected, but a dose response trend was seen in the development of disease.

See also Stellbrink & Dahms 2004, in German, for other model fits.

Table 3.1: Summary of dose response models
Experiment number Reference Host type Pathogen type Route Dose units Response Best Fit Model Optimized parameters ID50
1 Blaser et al., 1983 Mouse T1 strain intragastric CFU Infection Exponential k = 9.01E-07 7.69E+05
2 Blaser et al., 1983 Mouse T2 strain intragastric CFU Infection Beta-Poisson α = 0.32

N50 = 6.68E+04

6.68E+04
3 Blaser et al., 1983 Mouse T3 strain intragastric CFU Infection Beta-Poisson α = 0.12

N50 = 3.14E+04

3.14E+04
4 Black et al. 1988

Medema et al. 1996

Human A3249 strain oral (in milk) CFU Infection Beta-Poisson α = 0.14

N50 = 890.38

890.38
5 Tribble et al. 2010 Human 81-176 strain oral (with NaHCO3) CFU Disease Beta-Poisson α = 0.17

N50 = 1.23E+05

1.23E+05



Optimized Models and Fitting Analyses

Optimization Output for experiment 1

Table 3.2. T1 strain for serotype PEN 1 data
Dose Infected Non-infected Total
1.00E+08 5 0 5
1.00E+06 3 2 5
1.00E+04 0 5 5
1.00E+02 0 5 5
1.00E+00 0 5 5
Blaser et al. 1983.


Table 3.3. Goodness of fit and model selection
Model Deviance Δ Degrees
of Freedom
χ20.95,1
p-value
χ20.95,m-k
p-value
Exponential 0.092 6.00E-04 4 3.84
0.981
9.49
0.999
Beta Poisson 0.092 3 7.81
0.993
Exponential is best fitting model
Table 3.4: Optimized parameters for the best fitting (exponential), obtained from 10,000 bootstrap iterations
Parameter or value MLE estimate Percentiles
0.50% 2.5% 5% 95% 97.5% 99.5%
k 9.01E-07 4.61E-08 2.21E-07 2.21E-07 4.61E-06 4.61E-06 4.61E-06
ID50 7.69E+05 1.51E+05 1.51E+05 1.51E+05 3.14E+06 3.14E+06 1.51E+07


Figure 3.1 Parameter histogram for exponential model (uncertainty of the parameter)
Figure 3.2 Exponential model plot, with confidence bounds around optimized model




Optimized Models and Fitting Analyses

Optimization Output for experiment 2

Table 3.5. T2 Strain for serotype PEN 2 model data
Dose Infected Non-infected Total
1.00E+08 5 0 5
1.00E+07 4 1 5
1.00E+06 4 1 5
1.00E+05 3 2 5
1.00E+04 1 4 5
Blaser et al. 1983.


Table 3.6. Goodness of fit and model selection
Model Deviance Δ Degrees
of Freedom
χ20.95,1
p-value
χ20.95,m-k
p-value
Exponential 25.43 24.46 4 3.84
0
9.49
0
Beta Poisson 0.97 3 7.81
0.809
Beta Poisson is best fitting model
Table 3.7: Optimized parameters for the best fitting (beta Poisson), obtained from 10,000 bootstrap iterations
Parameter MLE estimate Percentiles
0.5% 2.5% 5% 95% 97.5% 99.5%
α 0.32 -- -- -- -- -- --
N50 6.68E+04 -- -- -- -- -- --
LD50(spores) 6.68E+04 2.97E+02 5.03E+03 1.04E+04 3.41E+05 4.52E+05 7.76E+05


Figure 3.3. Parameter scatter plot for beta Poisson model ellipses signify the 0.9, 0.95 and 0.99 confidence of the parameters.
Figure 3.4 beta Poisson model plot, with confidence bounds around optimized model




Optimized Models and Fitting Analyses

Optimization Output for experiment 3

Table 3.8. T3 strain for serotype PEN 3 data
Dose Infected Non-infected Total
1.00E+08 5 0 5
1.00E+07 3 2 5
1.00E+06 2 3 5
1.00E+05 4 1 5
1.00E+04 2 3 5
Blaser et al. 1983.


Table 3.9. Goodness of fit and model selection
Model Deviance Δ Degrees
of Freedom
χ20.95,1
p-value
χ20.95,m-k
p-value
Exponential 45.64 40.23 4 3.84
0
9.49
2.92E-09
Beta Poisson 5.41 3 7.81
0.144
Beta Poisson is best fitting model
Table 3.10: Optimized parameters for the best fitting (beta Poisson), obtained from 10,000 bootstrap iterations
Parameter MLE estimate Percentiles
0.5% 2.5% 5% 95% 97.5% 99.5%
α 0.12 -- -- -- -- -- --
N50 3.14E+04 -- -- -- -- -- --
LD50(spores) 3.14E+04 3.29E-09 2.55E-05 2.25E-02 4.16E+05 9.07E+05 3.28E+06


Figure 3.5 Parameter scatter plot for beta Poisson model ellipses signify the 0.9, 0.95 and 0.99 confidence of the parameters.
Figure 3.6 beta Poisson model plot, with confidence bounds around optimized model



Optimized Models and Fitting Analyses

Optimization Output for experiment 4

Table 3.11 Strain A3249 model data
Dose Infected Non-infected Total
8.10E+02 5 5 10
8.10E+03 6 4 10
9.10E+04 11 2 13
8.10E+05 8 3 11
1.10E+06 15 4 19
1.10E+08 5 0 5
Black et al. 1988.


Table 3.12. Goodness of fit and model selection
Model Deviance Δ Degrees
of Freedom
χ20.95,1
p-value
χ20.95,m-k
p-value
Exponential 110.11 107.68 5 3.84
0
11.07
0
Beta Poisson 2.43 4 9.49
0.658
Beta Poisson is best fitting model
Table 3.13 Optimized parameters for the best fitting (beta Poisson), obtained from 10,000 bootstrap iterations
Parameter MLE estimate Percentiles
0.5% 2.5% 5% 95% 97.5% 99.5%
α 0.14 -- -- -- -- -- --
N50 890.38 -- -- -- -- -- --
LD50(spores) 890.38 1.44E-09 2.17E-04 1.23E-01 6.89E+03 9.13E+03 1.62E+04


Figure 3.7 Parameter scatter plot for beta Poisson model ellipses signify the 0.9, 0.95 and 0.99 confidence of the parameters.
Figure 3.8 beta Poisson model plot, with confidence bounds around optimized model.



Optimized Models and Fitting Analyses

Optimization Output for experiment 5

Table 3.14 Strain 81-176 model data
Dose Infected Non-infected Total
1.00E+05 3 2 5
1.00E+07 2 3 5
1.00E+09 33 3 36
Tribble et al. 2010.


Table 3.15. Goodness of fit and model selection
Model Deviance Δ Degrees
of Freedom
χ20.95,1
p-value
χ20.95,m-k
p-value
Exponential 50.14 46.63 2 3.84
0
5.99
0
Beta Poisson 3.51 1 3.84
0.061
Beta Poisson is best fitting model
Table 3.16 Optimized parameters for the best fitting (beta Poisson), obtained from 10,000 bootstrap iterations
Parameter MLE estimate Percentiles
0.5% 2.5% 5% 95% 97.5% 99.5%
α 0.17 -- -- -- -- -- --
N50 1.23E+05 -- -- -- -- -- --
LD50(spores) 1.23E+05 3.69E-10 6.14E-05 7.58E-01 2.00E+06 7.07E+06 3.96E+07


Figure 3.9 Parameter scatter plot for beta Poisson model ellipses signify the 0.9, 0.95 and 0.99 confidence of the parameters.
Figure 3.10 beta Poisson model plot, with confidence bounds around optimized model




References

Black, R.E. et al., 1988. Experimental Campylobacter jejuni infection in humans. The Journal of Infectious Diseases, 157(3), pp.472-479.  

Blaser, M.J. et al., 1983. Experimental Campylobacter jejuni infection of adult mice. Infection and Immunity, 39(2), pp.908-916.  

Chen, L. et al., 2006. Dose response for infectivity of several strains of Campylobacter jejuni in chickens. Risk Analysis: An Official Publication of the Society for Risk Analysis, 26(6), pp.1613-1621.  

Havelaar, A.H. et al., 2009. Immunity to Campylobacter: its role in risk assessment and epidemiology. Critical Reviews in Microbiology, 35(1), pp.1-22.  

Medema, G.J. et al., 1996. Assessment of the dose-response relationship of Campylobacter jejuni. International Journal of Food Microbiology, 30(1-2), pp.101-111.  

Sjögren, E., Ruiz-Palacios, G. & Kaijser, B., 1989. Campylobacter jejuni isolations from Mexican and Swedish patients, with repeated symptomatic and/or asymptomatic diarrhoea episodes. Epidemiology and Infection, 102(1), pp.47-57.  

Stellbrink, E. & Dahms, S., 2004. Dose-response-models and their implications for quantitative risk assessment for Campylobacter infections. Berliner Und Münchener Tierärztliche Wochenschrift, 117(5-6), pp.207-213.  

Teunis, P. et al., 2005. A reconsideration of the Campylobacter dose-response relation. Epidemiology and Infection, 133(4), pp.583-592.  

Teunis, P.F., Nagelkerke, N.J. & Haas, C.N., 1999. Dose response models for infectious gastroenteritis. Risk Analysis: An Official Publication of the Society for Risk Analysis, 19(6), pp.1251-1260.  

Tribble, D.R. et al., 2009. Campylobacter jejuni strain CG8421: a refined model for the study of Campylobacteriosis and evaluation of Campylobacter vaccines in human subjects. Clinical Infectious Diseases: An Official Publication of the Infectious Diseases Society of America, 49(10), pp.1512-1519.  

Tribble, D.R. et al., 2010. Assessment of the duration of protection in Campylobacter jejuni experimental infection in humans. Infection and Immunity, 78(4), pp.1750-1759.