Bright Ideas?
Ultraviolet Radiation, Weather, and the Seasonality
of Invasive Bacterial Disease in North America
David N. Fisman, MD MPH FRCP(C)
Medical Epidemiologist, Ontario Public Health Laboratory
Scientist, Research Institute of the Hospital for Sick Children
TIBDN Research Day, Mt. Sinai Hospital, November 27, 2008
Ultraviolet (U.V.) Radiation
[Image source: NASA via Wikimedia commons]
Ultraviolet (U.V.) Radiation (2)
[Image source: NASA via Wikimedia commons]
Ultraviolet (U.V.) Radiation (3)
UVC
UVB
(“germicidal”) (“sunburn”)
UVA
(“black light”)
U.V. Radiation: Protection Against
Invasive Bacterial Disease?
• Historical perspectives (sunlight=health).
• Apparent linkages between U.V. radiation and
(prevention of) infection:
– U.V. and tuberculosis (Finsen, Riley).
– U.V. and “flu season”.
• Biological mechanisms:
– Effects on pathogens, effects on hosts.
• Approaches to epidemiological links.
– Confounding and ecological fallacy.
– IGAS, IPD, IMD.
Historical Perspectives
• Notion of season and
weather in disease
causation central to
Hippocratic medicine (ca.
400 B.C.).
– Interaction between
environment and
individual constitutions
results in disease.
– Tracts include Airs,
Waters, Places; Epidemics
Image: National Library of
Medicine
Darkness=Disease
• An English word falls upon the ear almost
with a sense of shock...In the midst of it all
there is a sudden wild scattering, a hustling
of things from the street into dark cellars…
– Jacob Riis in How the Other Half Lives (1890) on
visits by NYC Health Inspectors to Lower East Side,
1890. Quoted in Markel, Quarantine! (1997), page 35.
Jacob Riis, ca. 1890. Museum of the City
of New York. Reproduced from Markel,
Quarantine! (1997).
Light (and Enlightenment)=Health
• Sanitorium movement: Dr. E.L. Trudeau founds first
N. American “TB san” in Saranac Lake, NY ca. 1875.
– Treatment focuses on outdoor exposure, fresh air,
sunlight.
• Parallels between sanitorium movement and
Victorian “improvement” movement generally:
– “You have no zymotic [infectious] disease, no poverty, no
drunkenness…what human society might be, were it all
light, with no suffering and dark corners.”
– William James, on the Chautauqua Institution (for improvement of
Sunday School teachers), 1896. Quoted in Markel, Quarantine!
(1997).
Source: University of Virginia Health Sciences Library. Available via the Internet at:
http://www.hsl.virginia.edu/historical/medical_history/alav/assets/Trudeau_porch.jpg
Effects of U.V. on Active Tuberculosis
• E.L. Trudeau (U.S.) and Nils
Finsen (Denmark):
– Empirical observations of
behavior of own illnesses lead
to experimentation with
outdoor exposure (ELT) and
direct application of U.V.
radiation (NF).
• Finsen’s “phototherapy”
effective in cure of “lupus
vulgaris” (cutaneous T.B.).
– Recent investigation indicates
lenses resulted in UVA dosing.
– Nobel Prize for Medicine or
Physiology, 1903.
Phototherapy at Finsen’s Institute,
1897. Source: Møller K et al.,
Photodermatol Photoimmunol
Photomed 2005.
Effects of U.V. on Survival of M.
tuberculosis in Droplet Nuclei
U.V. Source
Guinea
pig
cages
Riley R.L. et al., American Review of Tuberculosis 1957; American Journal of Hygeine 1959.
Image from Nardell and Dharmadhikari, IUATLD Vancouver 2008.
Seasonality, Influenza and U.V.
[Hope-Simpson, 1981; reproduced in Cannell JJ et al., Epidemiology and Infection, 2006.
U.V. and Reduced Infection Risk
• Direct damage to pathogens.
– Mutagenesis.
– Porphyrins (TB).
• Improvement of host immune function.
– Vitamin D and immune function.
•Aberrant covalent bonds formed between adjacent cytosines.
•Dimers read as “AA”, not “CC”.
•Repaired with “TT” (“classical C-T mutation“).
[Image source Wikimedia commons]
Mechanism of Finsen’s Lenses
Photic
stimulation leads
to O radicals.
Effects of Light on Immune Response
• Dowell [2001] reviews association between
seasonality and photoperiod.
– Numerous physiological changes (psychological,
sexual, immunological, pathological) associated
with shortened (wintertime) photoperiods in
humans and animals.
• “For example, Siberian hamsters exposed to short-day
photoperiod demonstrate…phagocytosis and oxidative
burst.”
– Dowell, Emerging Infectious Diseases 2001.
Vitamin D
35
30
25(OH)D(ng/ml)
25
20
15
10
5
0
Au
g
Se
p
Oc
No t
v
De
c
Ja
n
Fe
b
M
ar
Ap
r
M
ay
Ju
n
Ju
Au l
g
• Steroid hormone, synthesis
depends on cleavage of DHC
from skin in response to U.V.
• Vitamin D deficiency associated
with numerous defects of
macrophage maturation and
function.
• Relative deficiency associated
with numerous adverse health
outcomes in observational
studies (cancer, heart disease).
• Recently described relationship
between Toll-like receptor,
vitamin D, and cathelicidin [Liu P
et al., Science 2006].
Month
[Source: Cannell JJ et al.,
Epidemiol Infect 2006]
Vitamin D (2)
[Zasloff M,
Nature
Medicine
2006]
Is it really the season?
• Establishing causal links between environmental factors and
disease occurrence may be difficult when the disease is seasonal.
• Relationships may be confounded with underlying factors
– e.g. increased incidence during certain types of weather might just reflect
population risk behaviour
– Strong correlation is necessary but NOT sufficient
• Aggregation of exposures may lead to “ecological fallacy”.
10
[Slide
courtesy
of Laura
Kinlin and
Alexander
White]
R² = 0.9389
0
0
2
4
6
Cases per week
8
10
12
0
10
20
30
40
Seasonally Oscillating Environmental
Exposures, Philadelphia
01/1994 01/1996
01/1998
01/2000 01/2002
01/2004 01/2006
Date
TMAX (C)
MAXCIE/10
Delaware River dissolved O2 (*2)
01/2008
Seasonality, Environment, and
Infectious Disease
• 2 year project funded by U.S. NIAID (R21-AI065826).
• Cooperative work performed by SickKids,
Philadelphia Department of Public Health, and
Ontario Public Health Laboratory.
• Evaluate weekly or monthly disease incidence using
Poisson models with “smoothers” (de-trended).
• Use of novel “case-crossover” method to evaluate
acute effects of exposures on disease risk.
– Both methods should largely control for confounding by
nonspecific seasonal oscillation in exposures and disease
incidence.
– Evaluate effects over different time scales.
Houston, Texas
Residual (Excess) Deaths, Relative to
Model
Supplementary Figure: Schematic diagram of control selection strategy for casecrossover study. Each row represents a 3-week time block. Hazard and control
periods (matched by day-of-week) are selected from the 3-week time block, resulting
in random directionality of control selection.
25
8
20
6
15
4
10
2
5
0
Jan-02
0
Cases
10
Dec-02
Dec-03
Dec-04
Dec-05
Date
[Source White ANJ et al., BMC Infectious Diseases, submitted]
Dec-06
Annualized Incidence per 100,000
Pneumococcus—Philadelphia
Pneumococcus—Philadelphia
Multivariable
Univariable Models
Modelsa
Meteorological Element
IRR
(95% CI)
P
Cooling-degree Days (oC)
0.97
0.92
(0.90
(0.94– –0.94)
1)
<0.001
0.06
Mean Temperature (oC)
0.96
...
(0.95...
– 0.97)
<0.001
...
Relative Humidity (%)
0.98
...
(0.97 ..– 0.99)
0.002
...
UV Index
0.74
0.89
(0.59
(0.87 – 0.83)
0.92)
<0.001
0.01
Sulphur Oxides (ppm x 100)
1.73
...
(1.27...
– 2.37)
0.002
...
Average Wind Speed (km/h)
1.01
...
(1.006...
– 1.015)
<0.001
...
[Source White ANJ et al., BMC Infectious Diseases, submitted]
1
.8
.6
.2
.4
Incidence Rate Ratio
1.2
Pneumococcus—Philadelphia
[Source White ANJ et al., BMC
Infectious Diseases, submitted]
Age Group
Invasive Meningococcal Disease
18
Philadelphia
16
Sydney(shifted by 6 months)
Toronto
Percentage of cases
14
London
12
10
8
6
4
2
0
1
2
3
4
5
6
7
8
9
10
11
12
Month
[Slide courtesy of Ms. Laura Kinlin, Hospital for Sick Children/University of Toronto SPH]
Invasive Meningococcal Disease:
Philadelphia
Environmental Exposure
Multivariable
Models
Splines
Univariable
modelsCubic
Multivariable
ModelsIncluding
Including
Oscillatory
SeasonalIRR
Smoothers
(95% CI) and Annual Trend
P
IRR (95% CI)
P
1.14 (1.06-1.23)
0.98 (0.96-0.996)
0.97 (0.95-0.99)
≤0.001
1.04- 1.08)
(1.003-1.07)
1.05
1.04 (1.01
(1.004-1.08)
0.01
0.03
0.03
1.05 (1.02-1.07)
0.92 (0.86-0.99)
≤0.001
0.02
-
0.06
-
Carbon monoxide, ppm
0.85 (0.72-1.01)
2.25 (1.18-4.27)
0.01
-
Oxides of nitrogen, ppm
1.72 (1.23-2.39)
-
0.002
-
-
Oxides of sulphur, ppm
2.52 (1.34-4.74)
-
0.004
-
-
Wind speed, km/h
Mean temperature, °C
Maximum relative humidity
Snowfall, mm
UV Index Unit
Total ozone, ppm
[Kinlin L. et al., American Journal of Epidemiology 2009, in press]
-
≤0.001 0.02
-
Results – Case-Crossover Analysis
• An acute protective association was identified for UV index during the period 1-4
days prior to onset of cases (OR, 0.55 [95% CI, 0.36-0.84])
- A significant dose-response relationship between UV index and disease risk was
detected at this lag (Wald chi-squared for trend, 4.22 [1 df]; P = 0.04)
Clear Sky UV Index (UV Index Unit / 25mW·m-2)
Odds Ratio
2.00
1.00
0.50
0.25
15
14
13
12
11
10 9
8
7
6
5
4
Days Prior to Case Occurrence
3
[Kinlin L. et al., American Journal of Epidemiology 2009, in press]
2
1
0
Dose Response Relationship
Quintile of
UV Radiation
Odds ratio
(95% CI)
1st (referent)
1
2nd
0.82
3rd
0.91
4th
0.68
5th
0.62
• Future directions:
currently evaluating
effects in 4 temperate
cities in northern and
southern hemispheres
(Toronto, Philadelphia,
London, and Sydney).
Wald chi-squared for trend, 4.14 [1 df]; P=0.04
[Kinlin L. et al., American Journal of Epidemiology 2009, in press]
Summary
• Ambient U.V. radiation has harmful effects
(mutagenesis) but may also have salubrious effects
related to infectious diseases.
• Biologically plausible relationships: effects on
pathogens and hosts.
• U.V. associated with reduced risk of invasive bacterial
disease (IPD, IMD) in Philadelphia, after controlling
for seasonality.
• Effects over both short and long time-scales: direct
effects on pathogen and vitamin D related effects?
Acknowledgements
• Funders: U.S. NIAID, SickKids SSuRE and SickKids
Foundation, Ontario Early Researcher Program.
• The (Dream) Team: Amy Greer, Victoria Ng, Laura
Kinlin, Alexander N.J. White.
• Co-investigator: Dr. Caroline Johnson (PDPH).
• Collaborators: Frances Jamieson, Natasha Crowcroft,
Elizabeth Brown (OAHPP/OPHL), C. Victor Spain
(PDPHMerck Frosst), Graham Fraser, Julia
Granerod (UK HPA), Murray Mittleman, Greg
Wellenius (Harvard SPH).