On Temporal Patterns and Circulation of Influenza Virus Strains in Taiwan, 2008-2014: Implications of 2009 pH1N1 Pandemic

<div><p>Background</p><p>It has been observed that, historically, strains of pandemic influenza led to succeeding seasonal waves, albeit with decidedly different patterns. Recent studies suggest that the 2009 A(H1N1)pdm09 pandemic has had an impact on the circulation patterns of seasonal influenza strains in the post-pandemic years. In this work we aim to investigate this issue and also to compare the relative transmissibility of these waves of differing strains using Taiwan influenza surveillance data before, during and after the pandemic.</p><p>Methods</p><p>We make use of the Taiwan Center for Disease Control and Prevention influenza surveillance data on laboratory-confirmed subtyping of samples and a mathematical model to determine the waves of circulating (and co-circulating) H1, H3 and B virus strains in Taiwan during 2008–2014; or namely, short before, during and after the 2009 pandemic. We further pinpoint the turning points and relative transmissibility of each wave, in order to ascertain whether any temporal pattern exists.</p><p>Results/Findings</p><p>For two consecutive years following the 2009 pandemic, A(H1N1)pdm09 circulated in Taiwan (as in most of Northern Hemisphere), sometimes co-circulating with AH3. From the evolution point of view, A(H1N1)pdm09 and AH3 were able to sustain their circulation patterns to the end of 2010. In fact, A(H1N1)pdm09 virus circulated in six separate waves in Taiwan between summer of 2009 and spring of 2014. Since 2009, a wave of A(H1N1)pmd09 occurred every fall/winter influenza season during our study period except 2011–2012 season, when mainly influenza strain B circulated. In comparing transmissibility, while the estimated per capita weekly growth rates for cumulative case numbers (and the reproduction number) seem to be lower for most of the influenza B waves (0.06~0.26; range of 95% CIs: 0.05~0.32) when compared to those of influenza A, the wave of influenza B from week 8 to week 38 of 2010 immediately following the fall/winter wave of 2009 A(H1N1) pdm09 was substantially higher at r = 0.89 (95% CI: 0.49, 1.28), in fact highest among all the waves detected in this study. Moreover, when AH3 or A(H1N1)pdm09 exhibit high incidence, reported cases of subtype B decreases and vice versa. Further modeling analysis indicated that during the study period, Taiwan nearly experienced at least one wave of influenza epidemic of some strain every summer except in 2012.</p><p>Discussion</p><p>Estimates of R for seasonal influenza are consistent with that of temperate and tropical-subtropical regions, while estimate of R for A(H1N1)pdm09 is comparatively less than countries in Europe and North America, but similar to that of tropical-subtropical regions. This offers indication of regional differences in transmissibility of influenza virus that exists only for pandemic influenza. Despite obvious limitations in the data used, this study, designed to qualitatively compare the temporal patterns and transmissibility of the waves of different strains, illustrates how influenza subtyping data can be utilized to explore the mechanism for various influenza strains to compete or to circulate, to possibly provide predictors of future trends in the evolution of influenza viruses of various subtypes, and perhaps more importantly, to be of use to future annual seasonal influenza vaccine design.</p></div

Richards model fit for waves of circulating influenza strains in Taiwan, 2008–2014 in chronological order.

<p>Richards model fit for waves of circulating influenza strains in Taiwan, 2008–2014 in chronological order.</p

Timelines of waves of circulating influenza strains in Taiwan, 2008–2014.

<p>Blue for influenza virus strain B; red for AH3 and red shaded for H3N2; green for AH1 and shaded green for A(H1N1)pdm09.</p

Number of laboratory confirmed influenza positive samples collected from patients with influenza-like-illness (ILI) from 255 TCDC-contracted healthcare facilities and laboratories in Taiwan.

<p>Number of laboratory confirmed influenza positive samples collected from patients with influenza-like-illness (ILI) from 255 TCDC-contracted healthcare facilities and laboratories in Taiwan.</p

Weekly percentage of influenza strains among all lab-confirmed positive tests reported to Taiwan CDC by the contracted laboratories.

<p>(a) week 1, 2008-week 18, 2011; (b) week 20, 2011-week 18; 2014, with virus strains B in blue, AH1 in broken green, A(H1N1)pdm09 in green, AH3 in red, and H3N2 in broken red.</p

Model fits for the Richards model with cumulative influenza subtype data for strains.

<p>(a) AH1 and A(H1N1)pdm09; (b) AH3 and H3N2; (c) B.</p

Reproduction numbers with 95% CI of circulating influenza strain waves.

<p>(a) B; (b) AH1; and (c) AH3, during 2008–2014 in Taiwan.</p

Comparison of HIV-1 viral loads, CD4 counts and percent survivial analysis between the significant SNP (rs16896970) genotypes.

<p><b>A:</b> Measurements of HIV-1 viral load after infection were shown between the AA and AG+GG genotypes. <b>B:</b> Measurements of CD4 count after infection were shown between the AA and AG+GG genotypes. <b>C:</b> Analysis between HIV-1 viral load and the AA and AG+GG genotypes (<i>p</i><0.0001; the unpaired Student t test). <b>D:</b> Analysis between CD4 count and the AA and AG+GG genotypes (p<0.0001; the unpaired Student t test). <b>E:</b> Kaplan-Meier survival analysis was performed to assess the difference between the AA and AG+GG genotypes (<i>p</i> = 0.0026, log-rank test).</p

Baseline characteristics of HIV-1 patients with or without AIDS progression in a Han Chinese population in Taiwan.

<p>Statistical significance at <i>p</i><0.05.</p>a<p>The age with HIV-1 antibody positive means the age of the person when he/she was examined with the earlist positive for HIV-1 antibody result. The HIV-1 antibody positive results were from the database of the department of medical and laboratory examination of our hospital.</p>b<p><i>p</i>-value = 0.993 by using the unpaired Student t test. The total observation time is the duration between the lastest visiting date and the date when the person was examined with the earlist HIV-1 antibody positive result.</p>c<p><i>p</i>-value <0.0001 by using the unpaired Student t test. The HIV-1 viral load was measured in peripheral blood sampled in the first 3–27 months when he/she was examined with the earlist HIV-1 antibody positive result. Any measurements taken after the start of anti-retroviral therapy were not used in any analysis.</p>d<p><i>p</i>-value <0.0001 by using the unpaired Student t test. The CD4 count at enrollment was measured in peripheral blood sampled in the first 3–27 months when he/she was examined with the earlist HIV-1 antibody positive result. Any measurements taken after the start of anti-retroviral therapy were not used in any analysis.</p>e<p><i>p</i>-value = 0.351 by using the unpaired Student t test. The CD8 count at enrollment was measured in peripheral blood sampled in the first 3–27 months when he/she was examined with the earlist HIV-1 antibody positive result. Any measurements taken after the start of anti-retroviral therapy were not used in any analysis.</p

Single nucleotide polymorphisms (SNPs) analyzed and the linkage disequilibrium (LD) pattern of the <i>ZNRD1</i> and <i>RNF39</i> genes used in this study.

<p><b>A:</b> Genomic location of SNPs present on chromosome 6p21. <b>B:</b> Linkage disequilibrium (LD) blocks in the <i>ZNRD1</i> and <i>RNF39</i> genes, estimated by using HAPLOVIEW software. Pairwise D’ values (%) are indicated in squares; red indicates linkage disequilibrium (D’ = 1, logarithm of odds (LOD) ≥2); blue indicate evidence of recombination (D’ = 1, LOD<2). <b>C:</b> Allelic distribution (%) of the significant SNP (rs16896970) in the AIDS progression and non-progression groups.</p