Searching for sharp drops in the incidence of pandemic A/H1N1 influenza by single year of age

Abstract

Background: During the 2009 H1N1 pandemic (pH1N1), morbidity and mortality sparing was observed among the elderly population; it was hypothesized that this age group benefited from immunity to pH1N1 due to cross-reactive antibodies generated from prior infection with antigenically similar influenza viruses. Evidence from serologic studies and genetic similarities between pH1N1 and historical influenza viruses suggest that the incidence of pH1N1 cases should drop markedly in age cohorts born prior to the disappearance of H1N1 in 1957, namely those at least 52-53 years old in 2009, but the precise range of ages affected has not been delineated.

Methods and findings: To test for any age-associated discontinuities in pH1N1 incidence, we aggregated laboratory-confirmed pH1N1 case data from 8 jurisdictions in 7 countries, stratified by single year of age, sex (when available), and hospitalization status. Using single year of age population denominators, we generated smoothed curves of the weighted risk ratio of pH1N1 incidence, and looked for sharp drops at varying age bandwidths, defined as a significantly negative second derivative. Analyses stratified by hospitalization status and sex were used to test alternative explanations for observed discontinuities. We found that the risk of laboratory-confirmed infection with pH1N1 declines with age, but that there was a statistically significant leveling off or increase in risk from about 45 to 50 years of age, after which a sharp drop in risk occurs until the late fifties. This trend was more pronounced in hospitalized cases and in women and was independent of the choice in smoothing parameters. The age range at which the decline in risk accelerates corresponds to the cohort born between 1951-1959 (hospitalized) and 1953-1960 (not hospitalized).

Conclusions: The reduced incidence of pH1N1 disease in older individuals shows a detailed age-specific pattern consistent with protection conferred by exposure to influenza A/H1N1 viruses circulating before 1957.

Figure 1. Laboratory confirmed hospitalized cases.

A The smoothed risk ratio of laboratory confirmed hospitalized cases in a single year age group compared to the overall risk in all age groups. Smoothed curves for each location were created by a locally weighted polynomial regression with fixed bandwidth of 4. B The smoothed weighted risk ratio (WRR) of laboratory confirmed hospitalized cases in a single year compared to the risk in all age groups combined using a fixed bandwidth of 4. The single year of age WRR used to create the smoothed curve are plotted as open circles and the 95% confidence bounds are shaded. The inset figure shows the truncated WRR from 0 to 29 years of age while the larger figure focuses on the ages from 30–100. C SiZer plot of the first derivative of the WRR by age. The X axis represents age while the Y axis corresponds to the log of the bandwidth (h). For example, log(0.6) corresponds to the fixed bandwidth of 4 used to create Figures A and B and a black horizontal line identifies this bandwidth. The shading corresponds to the significance and direction of the slope (first derivative) of the WRR by age: red is significantly decreasing, purple is possibly zero, blue is significantly increasing, and light grey represents areas where there is insufficient data to generate a smoothed curve. The grid lines correspond to 1 year of age intervals. D SiZer plot of the second derivative of the WRR by age, where the shading corresponds to that described for Figure 1C.

Figure 2. Laboratory confirmed cases that were not hospitalized.

A The smoothed risk ratio of laboratory confirmed cases that were not hospitalized in a single year age group compared to the overall risk in all age groups. Smoothed curves for each location were created by a locally weighted polynomial regression with fixed bandwidth of 4. B The smoothed weighted risk ratio of cases that were not hospitalized in a single year compared to the risk in all age groups combined using a fixed bandwidth of 4. The single year of age weighted risk ratios used to create the smoothed curve are plotted as open circles and the 95% confidence bounds are shaded. The inset figure shows the truncated WRR from 0 to 29 years of age while the larger figure focuses on the ages from 30–100. C SiZer plot of the first derivative of the weighted risk ratio by age. The X axis represents age while the Y axis corresponds to the log of the bandwidth (h). For example, log(0.6) corresponds to the fixed bandwidth of 4 used to create Figures A and B and a black horizontal line identifies this bandwidth. The shading corresponds to the significance and direction of the slope (first derivative) of the weighted risk ratio by age: red is significantly decreasing, purple is possibly zero, blue is significantly increasing, and light grey represents areas where there is insufficient data to generate a smoothed curve. The grid lines correspond to 1 year of age intervals. D SiZer plot of the second derivative of the weighted risk ratio by age, where the symbols are as described for Figure 2C .

Figure 3. Differences by sex in hospitalized cases.

A Hospitalized Men. The smoothed risk ratio of laboratory confirmed hospitalized cases among men in a single year age group compared to the overall risk in all male age groups. Smoothed curves were created by a locally weighted polynomial regression with fixed bandwidth of 4. The single year of age weighted risk ratios used to create the smoothed curve are plotted as open circles and the 95% confidence bounds are shaded. The inset figure shows the truncated WRR from 0 to 29 years of age while the larger figure focuses on the ages from 30–100. B Hospitalized Men. SiZer plot of the second derivative of the weighted risk ratio by age among male hospitalized cases. C Hospitalized Women. The smoothed risk ratio of laboratory confirmed hospitalized cases among women in a single year of age compared to the overall risk in all female age groups. Smoothed curves were created by a locally weighted polynomial regression with fixed bandwidth of 4. The single year of age weighted risk ratios used to create the smoothed curve are plotted as open circles and the 95% confidence bounds are shaded. The inset figure shows the truncated WRR from 0 to 29 years of age while the larger figure focuses on the ages from 30–100. D Hospitalized Women. SiZer plot of the second derivative of the weighted risk ratio by age among female hospitalized cases.

Figure 4. Differences by sex in cases that were not hospitalized.

A Men not hospitalized. The smoothed risk ratio of cases among men who were not hospitalized in a single year age group compared to the overall risk in all age groups. Smoothed curves were created by a locally weighted polynomial regression with fixed bandwidth of 4. The single year of age weighted risk ratios used to create the smoothed curve are plotted as open circles and the 95% confidence bounds are shaded. The inset figure shows the truncated WRR from 0 to 29 years of age while the larger figure focuses on the ages from 30–100. B Men not hospitalized. SiZer plot of the second derivative of the weighted risk ratio by age among men who were not hospitalized. C Women not hospitalized. The smoothed risk ratio of cases among women who were not hospitalized in a single year of age compared to the overall risk in all female age groups. Smoothed curves were created by a locally weighted polynomial regression with fixed bandwidth of 4. The inset figure shows the truncated WRR from 0 to 29 years of age while the larger figure focuses on the ages from 30–100. The single year of age weighted risk ratios used to create the smoothed curve are plotted as open circles and the 95% confidence bounds are shaded. D Women not hospitalized. SiZer plot of the second derivative of the weighted risk ratio by age among women who were not hospitalized.