Covariates associated with HI titer

Post-pandemic elevated HI titer can be explained by a pre-pandemic elevated titer, a recent increase in titer due to an infection by the pandemic virus or to another antigenic stimulation (e.g., pandemic vaccination), or by any combination of these different factors. We review our findings in light of other studies on the same topic.

The global multivariate model including pandemic vaccination gave information on the association of this factor with the GMT. Adjustment on this factor in the same model allowed us to study factors that may have an impact on GMT increase after either vaccination or infection, whereas stratified analyses according to this vaccination intended to focus more specifically on factors associated with other causes of elevated GMT.

We found a lower anti-H1N1pdm GMT in older subjects in the univariable analysis and in the multivariable model run among pandemic vaccine recipients. This covariate did not remain in the other multivariate models mainly because of the adjustment on duration of contacts at school (age was significantly associated with the GMT in all models when we excluded this covariate). Older age was also associated with a lower risk of probable infection in the case-control analysis.

These results are consistent with other cross-sectional post-pandemic studies worldwide, including modeling [35] and serological [14] studies in France, which reported a much higher infection rate in children and young adults [16], [19], [20], [36]–[44].

As expected, a reported history of ILI was associated with an elevated GMT, which indicates that some of these ILIs were probably caused by H1N1pdm infection. Though this factor lacks sensitivity and specificity to be considered as a good correlate of infection, its coefficient in selected multivariable models gives more information on the relative role of infections among all causes leading to a GMT increase. Its association with the GMT in vaccinated subjects indicates that the GMT was also caused by H1N1pdm infections. Indeed, as most vaccinations occurred at the end of the pandemic course (Figure 3), we could not distinguish whether the increased GMT in vaccine recipients was caused by vaccination itself or by previous infection.

Asthma and COPD were associated with a higher GMT and possible risk factors in the case-control analysis. Asthmatics may have increased susceptibility for H1N1pdm infection [45], possibly because of alterations in the airway architecture [46], [47] and impairment of innate immunity [47]. Another hypothesis to explain a higher GMT in subjects with such medical conditions, regardless of their susceptibility to infection, would be a more severe illness [48] involving a greater immune response [49].

We found that smoking history was associated with a lower GMT. Although several studies already found an association between cigarette smoking and risk to contract influenza infection [50]–[52], smokers have a well-known diminished serological response to influenza infection or vaccination [52], the immunosuppressive mechanism is still unclear [53]–[56].

Seasonal vaccination for any season since 2006–2007 was associated with an increase in the GMT, maybe because of a cross-reactive immune response with seasonal vaccination H1N1 strains [57]though studies investigating this association were all inconclusive [3], [58]. Another hypothesis would consider that elevated post-seasonal titer might be a consequence of an increased risk of pandemic infection in seasonal vaccine recipients [59], though conflicting results were reported about this association [60]–[64].

In covariates related to the environmental characteristics of the housing, only the association between presence of an air humidifier in the living room and lower risk remained in the case-control multivariable model, which may be consistent with the possible impact of relative humidity on influenza aerosol transmission [65], [66].

The multivariable analysis retained no covariate related to attitudes, beliefs and risk perception, except the belief that not going to work may protect against H1N1pdm infection, associated with a higher risk in the case-control analysis. We have no clear interpretation for this finding, except that this covariate may be a correlate of more general characteristics of risk perception, which affect the transmission patterns of pandemic influenza.

Increasing GMT and a higher risk of probable infection associated with duration of meetings at school were not surprising since schools are identified as places with high meeting rates between influenza susceptible subjects [67]. Interestingly, we did not find a significant association of GMT with daily duration of meetings with children younger than 10 years old regardless of location, suggesting that school favors transmissions by a particular pattern of contacts or environmental characteristics [67], [68].

The multivariable analysis retained no covariate related to the characteristics of the surrounding area, except the proportion of workers using public transportation to go to work, which also appeared as a possible risk factor.

The important pairwise OR we found in the case-control analysis for subjects living in the same household suggests a common environmental exposure or susceptibility for these subjects who often belong to the same family, or more probably an elevated intra-household secondary attack rate (estimated 4 to 37% in previous household studies [10]).