There are, however, several limitations to this study warranting cautious interpretation of the results. First, the study relied upon a nonspecific clinical outcome (ILI) for defining pH1N1‐related illness. There are many causes of ILI, as evidenced by other contributing viruses identified through passive surveillance during the study period. We attempted to validate the ILI case definition on the basis of pH1N1‐seropositive status, but participation in the serologic survey was self‐selected, and sample size was small. Inclusion of communities where there was little or no circulation of pH1N1 would lead to outcome misclassification as evidenced by the low positive predictive value (38%) for the ILI case definition. We thus restricted analyses to households of the affected elementary school and on a reserve where pH1N1 circulation was more certain. This improved the positive predictive value of the ILI case definition in representing pH1N1‐related illness (>60%), although some misclassification may have still occurred. The effect of any persisting misclassification due to a nonspecific outcome would be to underestimate the association between TIV and pH1N1 illness (ie, to drive the OR toward a null effect).
A second limitation is that we relied on proxy report by 1 adult for all household members. Both ILI experience and TIV history may have been less well known for other household members. Third, the collection of TIV status after any ILI experience may have introduced recall bias. If recall bias related to TIV receipt were operating, it would introduce misclassification (information bias) related to exposure. Ultimately, the impact of this misclassification would depend on whether participants believed a priori that seasonal vaccine ought to have decreased or increased the risk of ILI during the study period. The lack of an immunization registry in British Colombia precluded further confirmation of immunization status.
It is noteworthy that ORs were higher among Aboriginal on‐reserve participants who also had higher rates of repeat seasonal influenza immunization. Repeated vaccination has been hypothesized to block potentially cross‐protective immunity otherwise afforded by heterotypic infection. Higher ORs among on‐reserve Aboriginals could also reflect greater susceptibility to the effects of TIV on pH1N1 risk, although an analysis for interaction did not yield statistically significant results. Some studies have reported genetic polymorphisms that favor Th2 skew among Canadian Aboriginals with higher expression of interleukin‐6 and lower production of tumor necrosis factor–α, interferon‐γ, and interleukin‐10 that may be relevant to enhanced immune‐mediated effects in this population. Other studies have suggested that Aboriginal status is an independent risk factor for more severe pH1N1 outcomes, but we did not specifically assess that hypothesis. However, higher ORs may also reflect the methodological influences of bias or confounding. Aboriginal populations are known to have higher rates of both chronic conditions and influenza vaccination. To address this, we adjusted for comorbidity and conducted sensitivity analyses restricted to on‐reserve participants without chronic conditions, resulting in similar or higher ORs. Despite these reassurances, neither residual confounding nor bias can be fully ruled out. As a final limitation, the sample sizes were small and confidence intervals were wide for stratified and serologically‐confirmed analyses so that these in particular should be interpreted cautiously.