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General Overview

'Legionella pneumophila (L. pneumophila) causes both Pontiac Fever and an aggressive form of pneumonia. L. pneumophila is a facultative gram negative aerobic rod, commonly found in drinking water distribution systems, cooling tower basin waters, premise plumbing, surface waters, and other engineered water systems.

Legionellosis includes Legionnaires’ disease and a milder febrile illness called Pontiac Fever. Legionnaires’ disease, an atypical pneumonia caused by bacteria of the genus Legionella, is most commonly caused illness by the species L. pneumophila (Lp). Legionnaires' disease has an incubation period commonly cited as of 2 to 10 days from exposure to the appearance of clinical symptoms, but the upper end of the incubation period may be at least 19 days. Symptoms of Legionnaires include: a high fever, chills, headache, muscular pains, dry cough, difficulty breathing and diarrhea, but not all symptoms occur in all in cases. 

Summary Data

Muller et al. (1983) exposed outbred, specific pathogen-free, Hartley strain Guinea pigs to aerosols of Legionella Philadelphia 1 strain in a modified aerosol in- fection chamber (Tri-R Instruments, Rockville Centre, N.Y.).

Fitzgeorge et al. (1983) challenged Female Dunkin-Hartley Guinea-pigs with aerosols of Legionella pneumophila Strain 74/81.

Breiman and Horwitz (1987) exposed Hartley strain Guinea pigs to aerosols of Legionella Philadelphia 1 strain in an aerosol chamber constructed of lucite measuring 13 X 24 X 18 in.

Recommended Model

It is recommended that experiment 241 should be used as the best dose response model. Infection as the endpoint is more protective and useful for disease transmission modeling over other endpoints such as illness and death.

Exponential and betapoisson model.jpg

Summary

By increasing the number of data points, the pooling narrows the range of the confidence region of the parameter estimates and enhances the statistical precision.

ID Exposure Route # of Doses Agent Strain Dose Units Host type Μodel LD50/ID50 Optimized parameters Response type Reference
241 inhalation 4.00 Philadelphia 1 CFU guinea pig exponential 1.16E+01 k = 5.99E-02 infection
Fitzgeorge, R. B., Baskerville, A. ., Broster, M. ., Hambleton, P. ., & Dennis, P. J. (1983). Aerosol infection of animals with strains of Legionella pneumophila of different virulence: comparison with intraperitoneal and intranasal routes of infection. Epidemiology & Infection, 90.
242 inhalation 4.00 strain 74/81 CFU mice exponential 1.07E+04 k = 6.48E-05 death
Breiman, R. F., & Horwitz, M. A. (1987). Guinea pigs sublethally infected with aerosolized Legionella pneumophila develop humoral and cell-mediated immune responses and are protected against lethal aerosol challenge. A model for studying host defense against lung infections caused by intracellul. The Journal of Experimental Medicine, 165, 3.
242, 243 inhalation 9.00 strain 74/81 CFU mice exponential 1.39E+04 k = 4.99E-05 death
Fitzgeorge, R. B., Baskerville, A. ., Broster, M. ., Hambleton, P. ., & Dennis, P. J. (1983). Aerosol infection of animals with strains of Legionella pneumophila of different virulence: comparison with intraperitoneal and intranasal routes of infection. Epidemiology & Infection, 90.
243 inhalation 5.00 Philadelphia 1 CFU guinea pig exponential 1.66E+04 k = 4.17E-05 death
Saslaw, S. ., & Carlisle, H. N. (1966). Aerosol infection of monkeys with Rickettsia rickettsii. Bacteriological Reviews, 30, 3.
Highest quality
Exposure Route:
inhalation
# of Doses:
4.00
Agent Strain:
Philadelphia 1
Dose Units:
CFU
Host type:
guinea pig
Μodel:
exponential
LD50/ID50:
1.16E+01
Optimized parameters: k = 5.99E-02
Response type:
infection
Reference:
Aerosol infection of animals with strains of Legionella pneumophila of different virulence: comparison with intraperitoneal and intranasal routes of infection
Guinea pigs/ Philadelphia 1 strain data 
Dose Infected Non-infected Total
1 0 4 4
5 4 10 14
50 17 1 18
100 8 0 8

 

Goodness of fit and model selection
Model Deviance Δ Degrees 
of freedom		 χ20.95,1 
p-value 		χ20.95,m-k 
p-value
Exponential 0.582 0.000479 3 3.84 
0.983 		7.81 
0.9
Beta Poisson 0.582 2 5.99 
0.748
Exponential is preferred to beta-Poisson; cannot reject good fit for exponential.

 

Optimized k parameter for the exponential model, from 10000 bootstrap iterations
Parameter MLE estimate Percentiles
0.5% 2.5% 5% 95% 97.5% 99.5%
k 5.99E-02 3.26E-02 3.90E-02 4.18E-02 1.11E-01 1.31E-01 1.57E-01
ID50/LD50/ETC* 1.16E+01 4.42E+00 5.28E+00 6.25E+00 1.66E+01 1.78E+01 2.13E+01
*Not a parameter of the exponential model; however, it facilitates comparison with other models.

 

Parameter histogram for exponential model (uncertainty of the parameter)

Exponential model plot, with confidence bounds around optimized model

Exposure Route:
inhalation
# of Doses:
4.00
Agent Strain:
strain 74/81
Dose Units:
CFU
Host type:
mice
Μodel:
exponential
LD50/ID50:
1.07E+04
Optimized parameters: k = 6.48E-05
Response type:
death
Reference:
Guinea pigs sublethally infected with aerosolized Legionella pneumophila develop humoral and cell-mediated immune responses and are protected against lethal aerosol challenge. A model for studying host defense against lung infections caused by intracellul
mice/ Strain 74/81 data
Dose Dead Survived Total
200 0 10 10
4000 1 9 10
5E+04 12 0 12
4E+05 16 0 16

 

Goodness of fit and model selection
Model Deviance Δ Degrees 
of freedom		 χ20.95,1 
p-value 		χ20.95,m-k 
p-value
Exponential 2.34 -0.00145 3 3.84 
1 		7.81 
0.506
Beta Poisson 2.34 2 5.99 
0.311
Exponential is preferred to beta-Poisson; cannot reject good fit for exponential.

 

Optimized k parameter for the exponential model, from 10000 bootstrap iterations
Parameter MLE estimate Percentiles
0.5% 2.5% 5% 95% 97.5% 99.5%
k 6.48E-05 5.45E-05 5.45E-05 5.45E-05 9.71E-05 9.71E-05 1.24E-04
ID50/LD50/ETC* 1.07E+04 5.57E+03 7.14E+03 7.14E+03 1.27E+04 1.27E+04 1.27E+04
*Not a parameter of the exponential model; however, it facilitates comparison with other models.

 

Parameter histogram for exponential model (uncertainty of the parameter)

Exponential model plot, with confidence bounds around optimized model

Exposure Route:
inhalation
# of Doses:
9.00
Agent Strain:
strain 74/81
Dose Units:
CFU
Host type:
mice
Μodel:
exponential
LD50/ID50:
1.39E+04
Optimized parameters: k = 4.99E-05
Response type:
death
Reference:
Aerosol infection of animals with strains of Legionella pneumophila of different virulence: comparison with intraperitoneal and intranasal routes of infection
Dose response data
Dose Dead Survived Total
200 0 10 10
4000 1 9 10
1E+04 1 4 5
15000 0 3 3
2E+04 5 2 7
5E+04 12 0 12
5E+04 3 0 3
1E+05 5 0 5
4E+05 16 0 16

 

Goodness of fit and model selection
Model Deviance Δ Degrees 
of freedom		 χ20.95,1 
p-value 		χ20.95,m-k 
p-value
Exponential 8.92 -0.000282 8 3.84 
1 		15.5 
0.349
Beta Poisson 8.92 7 14.1 
0.258
Exponential is preferred to beta-Poisson; cannot reject good fit for exponential.

 

Optimized k parameter for the exponential model, from 10000 bootstrap iterations
Parameter MLE estimate Percentiles
0.5% 2.5% 5% 95% 97.5% 99.5%
k 4.99E-05 3.55E-05 3.87E-05 3.95E-05 6.48E-05 6.76E-05 7.46E-05
ID50/LD50/ETC* 1.39E+04 9.29E+03 1.03E+04 1.07E+04 1.75E+04 1.79E+04 1.95E+04
*Not a parameter of the exponential model; however, it facilitates comparison with other models.

 

Parameter histogram for exponential model (uncertainty of the parameter)

Exponential model plot, with confidence bounds around optimized model

Exposure Route:
inhalation
# of Doses:
5.00
Agent Strain:
Philadelphia 1
Dose Units:
CFU
Host type:
guinea pig
Μodel:
exponential
LD50/ID50:
1.66E+04
Optimized parameters: k = 4.17E-05
Response type:
death
Reference:
Aerosol infection of monkeys with Rickettsia rickettsii
Guinea pigs/ Philadelphia 1 Strain model data
Dose Dead Survived Total
1E+04 1 4 5
15000 0 3 3
2E+04 5 2 7
5E+04 3 0 3
1E+05 5 0 5

 

Goodness of fit and model selection
Model Deviance Δ Degrees 
of freedom		 χ20.95,1 
p-value 		χ20.95,m-k 
p-value
Exponential 5.85 -0.000131 4 3.84 
1 		9.49 
0.211
Beta Poisson 5.85 3 7.81 
0.119
Exponential is preferred to beta-Poisson; cannot reject good fit for exponential.

 

Optimized k parameter for the exponential model, from 10000 bootstrap iterations
Parameter MLE estimate Percentiles
0.5% 2.5% 5% 95% 97.5% 99.5%
k 4.17E-05 2.29E-05 2.68E-05 3.00E-05 5.87E-05 6.78E-05 7.86E-05
ID50/LD50/ETC* 1.66E+04 8.82E+03 1.02E+04 1.18E+04 2.31E+04 2.59E+04 3.03E+04
*Not a parameter of the exponential model; however, it facilitates comparison with other models.

 

Parameter histogram for exponential model (uncertainty of the parameter)

Exponential model plot, with confidence bounds around optimized model

References

  • Armstrong, T. W. (2005). A quantitative microbial risk assessment model for human inhalation exposure to legionella.
  • Muller, D. ., Edwards, M. L., & Smith, D. W. (1983). Changes in Iron and Transferrin Levels and Body Temperature in Experimental Airborne Legionellosis. The Journal of Infectious Diseases, 147, 2. https://doi.org/https://doi.org/10.1093/infdis/147.2.302
  • Fitzgeorge, R. B., Baskerville, A. ., Broster, M. ., Hambleton, P. ., & Dennis, P. J. (1983). Aerosol infection of animals with strains of Legionella pneumophila of different virulence: comparison with intraperitoneal and intranasal routes of infection. Epidemiology & Infection, 90.
  • Breiman, R. F., & Horwitz, M. A. (1987). Guinea pigs sublethally infected with aerosolized Legionella pneumophila develop humoral and cell-mediated immune responses and are protected against lethal aerosol challenge. A model for studying host defense against lung infections caused by intracellul. The Journal of Experimental Medicine, 165, 3.