Campylobacter jejuni and Campylobacter coli: Dose Response Models

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Chapter X. Campylobacter jejuni and Campylobacter coli

Author: Kyle S. Enger
If you want to download this chapter in pdf format, please click here
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


X.1 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)




X.2 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.TODO: Verify models based on chicken data. Requires pooled analysis. (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) pooledTODO: Verify. 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 dosesTODO: Pooling analysis, including smaller datasets. 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 X.X: Summary of dose response models
Experiment number Reference (data) Reference (model) Host type Pathogen type Route Dose units Response Best Fit Model Optimized parameters ID50
Animal hosts
184 Blaser et al., 1983 Mouse T1 strain intragastric CFU Infection Exponential k = 9.01E-07 7.69E+05
185 Blaser et al., 1983 Mouse T2 strain intragastric CFU Infection Beta-Poisson α = 3.19E-01

N50 = 6.68E+04

6.68E+04
186 Blaser et al., 1983 Mouse T3 strain intragastric CFU Infection Beta-Poisson α = 1.17E-01

N50 = 3.14E+04

3.14E+04
Human hosts
106 Black et al. 1988 Medema et al. 1996 Human A3249 strain oral (in milk) CFU Infection Beta-Poisson α = 1.44E-01

N50 = 8.90E+02

8.90E+02
226 .. Human A3249 strain oral (with NaHCO3) CFU Infection None (1 dose)
137 .. Human 81-176 strain oral (in milk) CFU Infection None (all were infected)
187 Tribble et al. 2009 Human CG8421 strain oral (with NaHCO3) CFU Disease None (2 doses)
188 Tribble et al. 2010 Human 81-176 strain oral (with NaHCO3) CFU Disease Beta-Poisson α = 1.66E-01

N50 = 1.23E+05

1.23E+05




X.X. Optimized models: uncertainty and fitting analyses.

MODEL 184. Campylobacter jejuni (T1 strain for serotype PEN 1) given to mouse hosts by the intragastric route; response is infection.

Table X.X. Dose response data
Dose(CFU) Infection Total
Yes No
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 X.X. Goodness of fit and model selection
Model Deviance Goodness of fit Model comparison
Value DF χ2 p χ21, DF p
exponential 0.1 4 9.5 0.999 3.8 1.000
beta-Poisson 0.1 3 7.8 0.993
Conclusion: Exponential fits better than beta-Poisson; cannot reject good fit for exponential.
Table X.X: Parameters (k) and values (ID50) for the best fit model; percentiles from 105 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
FILL IN CITATION OF MODEL FIT HERE.


Figure X.X. Histogram showing uncertainty of k parameter estimates (bootstrap realizations).
Figure X.X. Exponential model plot, with confidence bounds around optimized model.





X.X. Optimized models: uncertainty and fitting analyses.

MODEL 185. Campylobacter jejuni (T2 strain for serotype PEN 2) given to mouse hosts by the intragastric route; response is infection.

Table X.X. Dose response data
Dose(CFU) Infection Total
Yes No
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 X.X. Goodness of fit and model selection
Model Deviance Goodness of fit Model comparison
Value DF χ2 p χ21, DF p
exponential 131.5 4 9.5 0.000 3.8 0.000
beta-Poisson 1.9 3 7.8 0.809
Conclusion: Beta-Poisson fits better than exponential; cannot reject good fit for beta-Poisson.
Table X.X: Parameters (α & N50) for the beta-Poisson model, percentiles from 105 bootstrap iterations
Parameter MLE estimate Percentiles
0.5% 2.5% 5% 95% 97.5% 99.5%
α 3.19E-01 7.55E-02 1.22E-01 1.45E-01 1.64E+01 5.53E+02 1.52E+03
N50 6.68E+04 4.37E+02 5.93E+03 1.03E+04 3.49E+05 4.52E+05 9.35E+05
FILL IN CITATION OF MODEL FIT HERE.


Figure X.X. Scatterplot showing uncertainty of α & N50 parameter estimates (bootstrap realizations).
Figure X.X. Beta-Poisson model plot, with confidence bounds around optimized model





X.X. Optimized models: uncertainty and fitting analyses.

MODEL 186. Campylobacter jejuni (T3 strain for serotype PEN 3) given to mouse hosts by the intragastric route; response is infection.

Table X.X. Dose response data
Dose(CFU) Infection Total
Yes No
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 X.X. Goodness of fit and model selection
Model Deviance Goodness of fit Model comparison
Value DF χ2 p χ21, DF p
exponential 62.2 4 9.5 0.000 3.8 0.000
beta-Poisson 2.9 3 7.8 0.144
Conclusion: Beta-Poisson fits better than exponential; cannot reject good fit for beta-Poisson.
Table X.X: Parameters (α & N50) for the beta-Poisson model, percentiles from 105 bootstrap iterations
Parameter MLE estimate Percentiles
0.5% 2.5% 5% 95% 97.5% 99.5%
α 1.17E-01 1.20E-02 1.79E-02 2.53E-02 2.83E-01 3.32E-01 5.26E-01
N50 3.14E+04 3.29E-09 9.31E-05 2.53E-02 4.22E+05 9.47E+05 3.37E+06
FILL IN CITATION OF MODEL FIT HERE.


Figure X.X. Scatterplot showing uncertainty of α & N50 parameter estimates (bootstrap realizations).
Figure X.X. Beta-Poisson model plot, with confidence bounds around optimized model.




X.X. Optimized models: uncertainty and fitting analyses.

MODEL 106. Campylobacter jejuni (strain A3249) given to human hosts by the oral route (in milk); response is infection.

Table X.X. Dose response data
Dose(CFU) Infection Total
Yes No
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 X.X. Goodness of fit and model selection
Model Deviance Goodness of fit Model comparison
Value DF χ2 p χ21, DF p
exponential 86.7 5 11.1 0.000 3.8 0.000
beta-Poisson 2.1 4 9.5 0.658
Conclusion: Beta-Poisson fits better than exponential; cannot reject good fit for beta-Poisson.
Table X.X: Parameters (α & N50) for the beta-Poisson model, percentiles from 105 bootstrap iterations
Parameter MLE estimate Percentiles
0.5% 2.5% 5% 95% 97.5% 99.5%
α 1.44E-01 2.10E-02 3.68E-02 5.04E-02 2.60E-01 2.90E-01 3.56E-01
N50 8.90E+02 4.12E-10 3.27E-04 1.71E-01 6.81E+03 9.11E+03 1.55E+04
FILL IN CITATION OF MODEL FIT HERE.


Figure X.X. Scatterplot showing uncertainty of α & N50 parameter estimates (bootstrap realizations).
Figure X.X. Beta-Poisson model plot, with confidence bounds around optimized model.




X.X. Optimized models: uncertainty and fitting analyses.

MODEL 188. Campylobacter jejuni (strain 81-176) given to human hosts by the oral route (w. 2g NaHCO3); response is campylobacteriosis.

Table X.X. Dose response data
Dose(CFU) Infection Total
Yes No
1.00E+05 3 2 5
1.00E+07 2 3 5
1.00E+09 33 3 36
Tribble et al. 2010.


Table X.X. Goodness of fit and model selection
Model Deviance Goodness of fit Model comparison
Value DF χ2 p χ21, DF p
exponential 332.2 2 6.0 0.000 3.8 0.000
beta-Poisson 3.7 1 3.8 0.061
Conclusion: Beta-Poisson fits better than exponential; cannot reject good fit for beta-Poisson.
Table X.X: Parameters (α & N50) for the beta-Poisson model, percentiles from 105 bootstrap iterations
Parameter MLE estimate Percentiles
0.5% 2.5% 5% 95% 97.5% 99.5%
α 1.66E-01 2.92E-02 4.57E-02 6.44E-02 3.14E-01 4.07E-01 1.12E+00
N50 1.23E+05 6.24E-10 1.56E-04 9.12E-01 2.21E+06 7.07E+06 3.96E+07
FILL IN CITATION OF MODEL FIT HERE.


Figure X.X. Scatterplot showing uncertainty of α & N50 parameter estimates (bootstrap realizations).
Figure X.X. 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.