Giardia duodenalis: Dose Response Models

Giardia duodenalis

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Overview

Giardia is a flagellated protozoan parasite of vertebrates. It attaches noninvasively to the small intestinal wall and absorbs nutrients (Miliotis & Bier 2003). Cysts are intermittently excreted in the stools of infected people; they are infectious immediately, with a low ID₅₀ of approximately 35 cysts. Giardiasis often presents with diarrhea and flatulence, with foul-smelling foamy stools (Miliotis and Bier 2003). It can often last for 6 to 10 weeks or more without treatment; furthermore, the disease may appear to resolve, only to return later (Miliotis & Bier 2003). Partial immunity appears to develop, and infections are often asymptomatic (Miliotis & Bier 2003). Immunity is incomplete and appears to apply more to symptomatic disease than actual infection (Valentiner-Branth et al. 2003).

The taxonomy of the genus Giardia is somewhat unclear. There have been a variety of species names assigned to pathogenic Giardia in humans, including G. intestinalis, G. enterica, and G. lamblia. The currently accepted name is G. duodenalis (Monis et al. 2009). Although it has been commonly considered a zoonosis, recent evidence indicates that G. duodenalis assemblages A and B (with B sometimes referred to as G. enterica) are specific to humans (Monis et al. 2009). Dose response relationships vary depending on assemblage and host. It is difficult to distinguish Giardia assemblages morphologically; molecular methods are required (Monis et al. 2009).

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Summary of Data

Rendtorff (1954) conducted a series of feeding studies in adult male prisoners. The dose response model that best fits these data is an exponential model with an ID₅₀ of 35 cysts. Essentially the same model fit was obtained by Rose et al. (1991). This model has been found to be consistent with results from an epidemiological study in France of diarrhea and drinking water quality (Zmirou-Navier et al. 2006).

Erlandsen et al. (1969) experimentally infected wild beavers and muskrats with human-derived Giardia cysts. Giardia was much less potent in these experiments (compared to Rendtorff (1954)). This illustrates the necessity of considering assemblage and host when applying a Giardia dose response model.

Another dataset describing Giardia dose response in humans during an outbreak at a ski resort in Colorado has been published (Istre et al. 1984). However, dose is described subjectively as glasses of water consumed, and the concentration of cysts in the water was not measured, so it is not possible to tie the response directly to the numbers of cysts consumed.

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Recommendations

For most risk applications in humans, the model fit to the data published by Rendtorff (1954) is preferable. However, the other models may be useful for describing zoonotic Giardia infection.

Table 3.1: Summary of dose response data. Experiment number Reference Host type Pathogen type Route Dose units Response Best fit model Optimized paremeters ID50 1 Rendtorff 1954 Male human prisoners Unknown human strain Oral Cysts Infection Exponential k = 0.020 34.81 2 Erlandsen et al. 1969 Muskrats Unknown human strain Stomach tube Cysts Infection Exponential k = 3.68E-06 188,558 3 Erlandsen et al. 1969 Beavers Unknown human strain Oral Cysts Infection Beta-Poisson α = 0.14, N50 = 14,598 14,598

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Optimized Models and Fitting Analyses

Optimization Output for experiment 1

Table 3.2. Dose response data Dose Infected No-infected Total 1.00E+00 0 5 5 1.00E+01 2 0 2 2.50E+01 6 14 20 1.00E+02 2 0 2 1.00E+04 3 0 3 1.00E+05 3 0 3 3.00E+05 3 0 3 1.00E+06 2 0 2 Rendtorff 1954.

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 8.37 5.00E-04 7 3.84 0.983 14.07 0.301 Beta Poisson 8.37 6 12.59 0.212 Exponential is best fitting model

Table 3.4 Optimized parameters for the best fitting (exponential), obtained from 10,000 bootstrap iterations Parameter MLE estimate Percentiles 0.5% 2.5% 5% 95% 97.5% 99.5% k 0.020 0.0085 0.010 0.013 0.029 0.033 0.042 ID50 34.81 16.61 21.07 23.76 54.94 66.03 81.50

Figure 3.1 Parameter histogram for exponential model (uncertainty of the parameter)

Figure 3.2 Exponential model plot, with confidence bounds around optimized model

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Optimized Models and Fitting Analyses

Optimization Output for experiment 2

Table 3.5 Dose response data Dose Infected No-infected Total 3.00E+02 0 7 7 3.00E+04 0 6 6 1.25E+05 2 1 3 5.00E+05 4 1 5 Erlandsen et al. 1969.

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 2.49 0.042 3 3.84 0.838 7.81 0.477 Beta Poisson 2.45 2 5.99 0.294 Exponential is best fitting model

Table 3.7 Optimized parameters for the best fitting (exponential), obtained from 10,000 bootstrap iterations Parameter MLE estimate Percentiles 0.5% 2.5% 5% 95% 97.5% 99.5% k 3.68E-06 1.13E-06 1.35E-06 1.70E-06 9.61E-06 9.61E-06 9.61E-06 ID50 188,558 72,149 72,149 72,149 408,581 513,715 613,609

Figure 3.3 Parameter histogram for exponential model (uncertainty of the parameter)

Figure 3.4 Exponential model plot, with confidence bounds around optimized model

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Optimized Models and Fitting Analyses

Optimization Output for experiment 3

Table 3.8. Dose response data Dose Infected No-infected Total 4.80E+01 0 6 6 4.54E+02 2 4 6 4.46E+03 1 2 3 5.50E+05 2 1 3 Erlandsen 1969.

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 22.50 21.28 3 3.84 0 7.81 1.00E-04 Beta Poisson 1.22 2 5.99 0.544 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 0.14 -- -- -- -- -- -- N50 14,598 -- -- -- -- -- -- LD50 14,598 509 820 1064 1.71E+08 8.25E+11 3.65E+22

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

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References

Erlandsen, S.L. et al., 1988. Cross-species transmission of Giardia spp.: inoculation of beavers and muskrats with cysts of human, beaver, mouse, and muskrat origin. Appl. Environ. Microbiol., 54(11), pp.2777-2785.  

Istre, G.R. et al., 1984. Waterborne giardiasis at a mountain resort: evidence for acquired immunity. American Journal of Public Health, 74(6), pp.602-604.  

Miliotis, M., & Bier, J., eds. 2003. International Handbook of Foodborne Pathogens, New York: M. Dekker.  

Monis, P.T., Caccio, S.M. & Thompson, R.C.A., 2009. Variation in Giardia: towards a taxonomic revision of the genus. Trends in Parasitology, 25(2), pp.93-100.  

Rendtorff, R.C., 1954. The experimental transmission of human intestinal protozoan parasites. II. Giardia lamblia cysts given in capsules. American Journal of Hygiene, 59(2), pp.209-220.  

Rose, J.B., Haas, C.N. & Regli, S., 1991. Risk assessment and control of waterborne giardiasis. American Journal of Public Health, 81(6), pp.709-713.  

Valentiner-Branth, P. et al., 2003. Cohort study of Guinean children: incidence, pathogenicity, conferred protection, and attributable risk for enteropathogens during the first 2 years of life. Journal of Clinical Microbiology, 41(9), pp.4238-4245.