Wong et al. Although PM10 is associated with signifi‑ cant risk of hospitalization for almost all the health outcomes under study at both the base‑ line and mean level of influenza intensity, we identified significant negative interaction only between PM10 and influenza in their effects on hospitalization for RD in males in the all‑ ages group. Influenza intensity was associated with reduction of ER of PM10. This negative interaction is in contrast to many previous stud‑ ies, which have demonstrated that exposure to PM10 increased the host susceptibility to influenza infection by upr‑egulating immuno ‑ regulatory cytokines (DiazS‑anchez 1997), by depressing pulmonary macrophage function (Yin et al. 2002) and also by increasing virus attachment to respiratory epithelial cells (Jaspers et al. 2005). We postulate that the seemingly negative interaction between effects of PM10 and influenza on hospitalization observed in this study may lie in the linkage of ultraviolet radiation (UVR) to PM10. In Hong Kong, concentrations of PM10 are negatively corre‑ lated with intensity of UVR in the ambient air (r = –0.17, p < 0.001). When the level of PM10 concentration is high, exposure to UVR is low. Exposure to erythemal doses of UVR before influenza infection has been shown to increase the influenzaa‑ssociated mortality in mice in a dosed‑ependent manner, without remarkably changing immunity response against influenza (Ryan et al. 2000). The adverse health effects of PM10 may be partially attenuated by the reduced effects due to the associated lowered levels of UVR. This attenuation may contrib‑ ute to the observed significant negative interac‑ tion between PM10 and influenza, which we found for respiratory hospitalization for males [see Supplemental Material, Table 3 (http:// www.ehponline.org/members/2008/11605/ suppl.pdf)], although both PM10 and influ‑ enza infection could independently increase the risk of hospitalization. However, the results of the laboratory studies describing the effects of UVR on immune function remain controver‑ sial and uncertain, and it was suggested that severity of respiratory viral infections could be related to radiation doses from UVR [reviewed by Cannell et al. (2006)]. Future studies may provide more insight into the role of UVR in interaction between influenza and PM10. In this study, we found significant posi‑ tive interaction between the effects of influ‑ enza and NO2 on hospitalization for COPD in the males in the ≥ 65 age group. Some labo‑ ratory studies described a positive interaction between influenza and NO2 (Chauhan et al. 2003; Frampton et al. 1989; Spannhake et al. 2002), whereas others did not detect such an interaction (Devlin et al. 1999; Frampton et al. 2002; Goings et al. 1989). We also found that the increase in influenza intensity would sig‑ nificantly raise the effects of SO2 on hospitaliza‑ tion for ARD. The damage caused by SO2 to 252 the human pulmonary defense system mainly involves nonspecific airway reactivity, such as lower mucociliary transportation rate, decreased alveolar clearance of deposited particles, and pulmonary macrophage function (Schlesinger 1999). People with hypersensitive airways, including COPD patients (Cazzola et al. 1991), have been shown to be more sensitive to SO2 than are healthy individuals (Schlesinger 1999), but we observed the marked positive interac‑ tion between SO2 and influenza only in ARD, and not in COPD or CVD. Interaction between air pollutants and influenza could have a competitive or a satu‑ ration effect, in that both need to attach to respiratory epithelial cells to cause harm. Therefore, if one factor saturates the sites on a particular pathway, there may be little room for the other to exert any additive effect. Early studies in mice showed that exposure to O3 (0.9 ppm for 3 hr) and SO2 (6 ppm for 7 days) could almost completely or partially inhibit influenza virus growth in the nasal cav‑ ity (Andersen et al. 1977; Fairchild 1977). Similarly, a high dose of NO2 (1.5 ppm) could suppress the replication and release of RSV in human bronchial epithelial cells (Becker and Soukup 1999). A small reduction in the num‑ ber of pneumonia cases was also observed after influenza‑ infected mice were exposed SO2 at a low concentration (of < 10 ppm) (Fairchild et al. 1972). Despite the increased awareness of the adverse impacts of both air pollution and influenza on human health, population‑ based studies on the potential synergistic effect or even competitive relationship between air pollutants and influenza viruses are lacking. Laboratory studies are insufficient to demon‑ strate a plausible mechanism for an interaction between influenza and air pollution on human health, and epidemiologic studies that can give support to formulation of plausible hypotheses at population level are needed. The estimated effects of air pollutants at the mean level of influenza intensity are consistent with our previous studies for the short‑term effects of air pollutants without adjustment for influenza intensity (Wong et al. 2001, 2002). In our study, the modifying effects esti‑ mated from the interaction models, in terms of changes in ER per 10‑µg/m 3 increase in concentration of an air pollutant when influ‑ enza intensity increased by 10%, say, for O3 ranged from 0.2% to 0.9%. These are substan‑ tial changes compared with the magnitude of air pollution effects of around 1% estimated in most studies (Wong et al. 2002, 2004). Our results show that the effects of air pollu‑ tion (particularly O3) varied to some extent depending on the level of influenza virus in the circulation. We also did the analysis without adjustment for effect modification of influenza. Most estimates for the effects of air pollut‑ ants were significant, with levels lying between those in the absence of influenza activity and at the mean level of influenza intensity (data not shown). Environmental protection and other public health agencies should take influenza peak seasons into account when they issue air pollution and health warnings to the public. We detected no significant modifying effects of influenza on the effects of air pol‑ lutants on mortality, except for O3 effects on mortality from RD and COPD. CVD was the only disease group of mortality and hospitaliza‑ tion in which we detected no significant inter‑ action between influenza and any air pollutant, although influenza and air pollutants have been documented to be associated with CVD in several epidemiologic studies. Influenza is believed to accelerate the coagulation process by evoking proinflammatory response, stimu‑ lating prothrombotic cytokines, and increas‑ ing plasma viscosity in human (Madjid et al. 2004). The biologic impacts of ambient air pollutants on progression of CVDs have been frequently reported, especially for PM10 and O3. Similar to influenza, these air pollutants are believed to stimulate systematic inflamma‑ tion and to increase oxidant stress, which may subsequently provoke cardiovascular events (Brook et al. 2004). However, interaction between influenza and ambient air pollutants for effects on cardiovascular mortality and hos‑ pitalization does not appear to be of sufficient strength to be detected in our model. A limitation in the interpretation of these observations is that it is implausible to reliably separate the effects of air pollutants because they frequently react with each other; for example, NO2 can be photolyzed into nitric oxide and oxygen atoms, the latter of which combine with molecular oxygen to form O3 (Brook et al. 2004). Future studies for possible interaction between influenza and combined air pollution may provide more insight into the mechanisms by which RDs and CVDs associated with exposure to ambient air pol‑ lution are enhanced or weakened by influenza infection. A further limitation in interpretation of the results relates to multiple comparisons. With 24 health outcomes in hospitalization (including analyses by sexes) to assess for each pollutant, we expect to find about one statisti‑ cally significant interaction result each at a 5% level. Thus, in the one significant effect modification we observed for SO2 or PM10, and the two significant effect modifications we observed for NO2 only with COPD (in males, and males and females combined in the ≥ 65 age group), we cannot exclude that the results may simply be attributable to chance for these two pollutants. For O3, we found eight statistically significant interactions, and two of them are significant at the 0.1% level. We believed that the results are unlikely to be attributable solely to chance at the 5% level even with Bonferroni adjustment. ovlume 117 | number 2 | February 2009 • Environmental Health Perspectives