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 ChildrenTIBDN 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)

UVA (“black light”)

UVB (“sunburn”)

UVC (“germicidal”)

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

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

• 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).

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

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.

U.V. Source

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• 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].

0

5

10

15

20

25

30

35

Month

25(O

H)D

(ng/

ml)

[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”.

Cases per week

[Slide courtesy of Laura Kinlin and Alexander White]

Seasonally Oscillating Environmental Exposures, Philadelphia

010

2030

40

01/1994 01/1996 01/1998 01/2000 01/2002 01/2004 01/2006 01/2008

TMAX (C) MAXCIE/10Delaware River dissolved O2 (*2)

Date

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 case-crossover 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.

Pneumococcus—Philadelphia

0

2

4

6

8

10

Jan-02 Dec-02 Dec-03 Dec-04 Dec-05 Dec-06

Date

Ca

se

s

0

5

10

15

20

25

An

nu

aliz

ed

Inc

ide

nc

e p

er

10

0,0

00

[Source White ANJ et al., BMC Infectious Diseases, submitted]

Pneumococcus—Philadelphia

Univariable Models

Meteorological Element IRR (95% CI) P

Cooling-degree Days (oC) 0.92 (0.90 – 0.94) <0.001

Mean Temperature (oC) 0.96 (0.95 – 0.97) <0.001

Relative Humidity (%) 0.98 (0.97 – 0.99) 0.002

UV Index 0.89 (0.87 – 0.92) <0.001

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

Multivariable Modelsa

IRR (95% CI) P

0.97 (0.94 – 1) 0.06

... ... ...

... .. ...

0.74 (0.59 – 0.83) 0.01

... ... ...

... ... ...

[Source White ANJ et al., BMC Infectious Diseases, submitted]

Pneumococcus—Philadelphia.2

.4.6

.81

1.2

0 to 9

Age Group

10 to 19

20 to 29

Inci

den

ce R

ate

Rat

io

30 to 39

40 to 49

50 to 59

60 to 69

70 to 79

80 and over

[Source White ANJ et al., BMC Infectious Diseases, submitted]

Invasive Meningococcal Disease

0

2

4

6

8

10

12

14

16

18

1 2 3 4 5 6 7 8 9 10 11 12

Month

Perc

enta

ge o

f cas

esPhiladelphia

Sydney(shifted by 6 months)

Toronto

London

[Slide courtesy of Ms. Laura Kinlin, Hospital for Sick Children/University of Toronto SPH]

[Kinlin L. et al., American Journal of Epidemiology 2009, in press]

Invasive Meningococcal Disease: Philadelphia

Environmental Exposure Univariable models

IRR (95% CI) P

Wind speed, km/h 1.14 (1.06-1.23) ≤0.001

Mean temperature, °C 0.97 (0.95-0.99) ≤0.001

Maximum relative humidity 1.05 (1.01 - 1.08) 0.01

Snowfall, mm 1.05 (1.02-1.07) ≤0.001

UV Index Unit 0.92 (0.86-0.99) 0.02

Total ozone, ppm 0.85 (0.72-1.01) 0.06

Carbon monoxide, ppm 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

Multivariable Models Including Oscillatory Seasonal Smoothers and Annual Trend

IRR (95% CI) P

- -

1.04 (1.004-1.08) 0.03

- -

- -

- -

- -

- -

- -

Multivariable Models Including Cubic Splines

IRR (95% CI) P

- -

0.98 (0.96-0.996) 0.02

1.04 (1.003-1.07) 0.03

- -

- -

- -

- -

- -

- -

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)

[Kinlin L. et al., American Journal of Epidemiology 2009, in press]

Dose Response Relationship

• Future directions: currently evaluating effects in 4 temperate cities in northern and southern hemispheres (Toronto, Philadelphia, London, and Sydney).

Quintile of UV Radiation

Odds ratio (95% CI)

1st (referent) 1

2nd 0.82

3rd 0.91

4th 0.68

5th 0.62

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 (PDPHMerck Frosst), Graham Fraser, Julia Granerod (UK HPA), Murray Mittleman, Greg Wellenius (Harvard SPH).