Legionella pneumophila
Author: Mark H. Weir
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 ^{[1]}
Summary Data
Muller et al. (1983)^{[2]} exposed outbred, specific pathogenfree, Hartley strain Guinea pigs to aerosols of Legionella Philadelphia 1 strain in a modified aerosol in fection chamber (TriR Instruments, Rockville Centre, N.Y.).
Fitzgeorge et al. (1983)^{[3]} challenged Female DunkinHartley Guineapigs with aerosols of Legionella pneumophila Strain 74/81.
Breiman and Horwitz (1987)^{[4]}
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.
Experiment serial number 
Reference 
Host type 
Agent strain 
Route 
# of doses 
Dose units 
Response 
Best fit model 
Optimized parameter(s) 
LD_{50}/ID_{50}

241* 
^{[2]} 
guinea pig 
Philadelphia 1 
inhalation 
4 
CFU 
infection 
exponential 
k = 5.99E02 
1.16E+01

242 
^{[3]} 
mice 
strain 74/81 
inhalation 
4 
CFU 
death 
exponential 
k = 6.48E05 
1.07E+04

243 
^{[4]} 
guinea pig 
Philadelphia 1 
inhalation 
5 
CFU 
death 
exponential 
k = 4.17E05 
1.66E+04

242, 243 
^{[3]}^{[4]} 
mice 
strain 74/81 
Inhalation 
9 
CFU 
death 
exponential 
k = 4.99E05 
1.39E+04

*This model is preferred in most circumstances. However, consider all available models to decide which one is most appropriate for your analysis.


^{*}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.
Optimization Output for experiment 241
Guinea pigs/ Philadelphia 1 strain data ^{[2]}
Dose 
Infected 
Noninfected 
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 
χ^{2}_{0.95,1} pvalue 
χ^{2}_{0.95,mk} pvalue

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 betaPoisson; 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 
5.99E02 
3.26E02 
3.90E02 
4.18E02 
1.11E01 
1.31E01 
1.57E01

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
Optimization Output for experiment 242
mice/ Strain 74/81 data ^{[3]}
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 
χ^{2}_{0.95,1} pvalue 
χ^{2}_{0.95,mk} pvalue

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 betaPoisson; 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 
6.48E05 
5.45E05 
5.45E05 
5.45E05 
9.71E05 
9.71E05 
1.24E04

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
Optimization Output for experiment 243
Guinea pigs/ Philadelphia 1 Strain model data ^{[4]}
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 
χ^{2}_{0.95,1} pvalue 
χ^{2}_{0.95,mk} pvalue

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 betaPoisson; 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 
4.17E05 
2.29E05 
2.68E05 
3.00E05 
5.87E05 
6.78E05 
7.86E05

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
Optimization Output for experiment 242, 243
Dose response data ^{[3]}^{[4]}
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 
χ^{2}_{0.95,1} pvalue 
χ^{2}_{0.95,mk} pvalue

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 betaPoisson; 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 
4.99E05 
3.55E05 
3.87E05 
3.95E05 
6.48E05 
6.76E05 
7.46E05

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
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.
References
 ↑ Armstrong, T. W. (2005). A Quantitative Microbial Risk Assessment Model for Human Inhalation Exposure to Legionella. Department of Civil, Architectural and Environmental Engineering. Philadelphia, Drexel University. PhD thesis. "[1]" .
 ↑ ^{2.0} ^{2.1} ^{2.2} Muller, D., M. L. Edwards and D. W. Smith (1983). "Changes in iron and transferrin levels and body temperature in experimental airborne legionellosis." Journal of Infectious Diseases 147: 302307.
 ↑ ^{3.0} ^{3.1} ^{3.2} ^{3.3} ^{3.4} Fitzgeorge, R. B., A. Baskerville, M. Broster, P. Hambleton and P. J. Dennis (1983). "Aerosol infection of animals with strains of Legionella pneumophila of different virulence: comparison with intraperitoneal and intranasal routes of infection." Epidemiology and Infection 90(1): 8189.
 ↑ ^{4.0} ^{4.1} ^{4.2} ^{4.3} ^{4.4} Breiman, R. F. and M. A. Horwitz (1987). "Guinea pigs sublethally infected with aerosolized Legionella pneumophila develop humoral and cellmediated immune responses and are protected against lethal aerosol challenge. A model for studying host defense against lung infections caused by intracellular pathogens." Journal of experimental medicine 165(3): 799811.