David N. Fisman, MD MPH FRCP(C) Medical Epidemiologist, Ontario Public Health Laboratory

1. 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

2. Ultraviolet (U.V.) Radiation [Image source: NASA via Wikimedia commons]

3. Ultraviolet (U.V.) Radiation (2) [Image source: NASA via Wikimedia commons]

4. UVB (“sunburn”) UVC (“germicidal”) UVA (“black light”) Ultraviolet (U.V.) Radiation (3)

5. 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.

6. 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

7. 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).

8. 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 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).

9. 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 Active Tuberculosis

10. Guinea pig cages U.V. Source Effects of U.V. on Survival of M. tuberculosis in Droplet Nuclei Riley R.L. et al., American Review of Tuberculosis 1957; American Journal of Hygeine 1959. Image from Nardell and Dharmadhikari, IUATLD Vancouver 2008.

11. Seasonality, Influenza and U.V. [Hope-Simpson, 1981; reproduced in Cannell JJ et al., Epidemiology and Infection, 2006.

12. U.V. and Reduced Infection Risk • Direct damage to pathogens. • Mutagenesis. • Porphyrins (TB). • Improvement of host immune function. • Vitamin D and immune function.

13. Aberrant covalent bonds formed between adjacent cytosines. • Dimers read as “AA”, not “CC”. • Repaired with “TT” (“classical C-T mutation“). [Image source Wikimedia commons]

14. Mechanism of Finsen’s Lenses Photic stimulation leads to O radicals.

15. 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.

16. 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]. [Source: Cannell JJ et al., Epidemiol Infect 2006]

17. Vitamin D (2) [Zasloff M, Nature Medicine 2006]

18. Is it really the season? [Slide courtesy of Laura Kinlin and Alexander White] • 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

19. Seasonally Oscillating Environmental Exposures, Philadelphia 40 30 20 10 0 01/1994 01/1996 01/1998 01/2000 01/2002 01/2004 01/2006 01/2008 Date TMAX (C) MAXCIE/10 Delaware River dissolved O2 (*2)

20. 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.

21. Houston, Texas

22. Residual (Excess) Deaths, Relative to Model

23. 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.

24. Pneumococcus—Philadelphia [Source White ANJ et al., BMC Infectious Diseases, submitted]

25. Pneumococcus—Philadelphia [Source White ANJ et al., BMC Infectious Diseases, submitted]

26. 1.2 1 .8 Incidence Rate Ratio .6 .4 .2 0 to 9 40 to 49 50 to 59 70 to 79 10 to 19 20 to 29 30 to 39 60 to 69 80 and over Age Group Pneumococcus—Philadelphia [Source White ANJ et al., BMC Infectious Diseases, submitted]

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

28. Invasive Meningococcal Disease: Philadelphia [Kinlin L. et al., American Journal of Epidemiology 2009, in press]

29. 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]

30. Future directions: currently evaluating effects in 4 temperate cities in northern and southern hemispheres (Toronto, Philadelphia, London, and Sydney). Dose Response Relationship Wald chi-squared for trend, 4.14 [1 df]; P=0.04 [Kinlin L. et al., American Journal of Epidemiology 2009, in press]

31. 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?

32. 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).