Molecular epidemiology of human respiratory syncytial virus among children in Japan during three seasons and hospitalization risk of genotype ON1

<div><p>We investigated the genetic diversity, the circulation patterns, and risk for hospital admission of human respiratory syncytial virus (HRSV) strains in Japan between 2012 through 2015. During the study period, 744 HRSV-positive cases were identified by rapid diagnostic test. Of these, 572 samples were positive by real-time PCR; 400 (69.9%) were HRSV-A, and 172 (30.1%) were HRSV-B. HRSV-A and -B alternated as the dominant strain in the subsequent seasons. Phylogenetic tree analysis of the second hyper-variable region of the G protein classified the HRSV-A specimens into NA1 (n = 242) and ON1 (n = 114) genotypes and the HRSV-B specimens into BA9 (n = 60), and BA10 (n = 27). The ON1 genotype, containing a 72-nucleotide duplication in the G protein’s second hyper-variable region, was first detected in the 2012–2013 season but it predominated and replaced the older NA1 HRSV-A in the 2014–2015 season, which also coincided with a record number of HRSV cases reported to the National Infectious Disease Surveillance in Japan. The risk of hospitalization was 6.9 times higher for the ON1 genotype compared to NA1. In conclusion, our data showed that the emergence and predominance of the relatively new ON1 genotype in Japan was associated with a record high number of cases and increased risk for hospitalization.</p></div

Effectiveness of four types of neuraminidase inhibitors approved in Japan for the treatment of influenza.

BACKGROUND:Neuraminidase inhibitors (NAIs) effectively treat influenza. The clinical effectiveness of four NAIs (oseltamivir, zanamivir, laninamivir, and peramivir) was evaluated against influenza A/H1N1pdm09, A/H3N2, and B viruses. Additionally, fever duration in patients infected with oseltamivir-resistant influenza A/H1N1pdm09 with the H275Y mutation was evaluated. METHODS:Patients aged <20 years who visited outpatient clinics in Japan with influenza-like illnesses were enrolled during 4 influenza seasons from 2012/2013 to 2015/2016. After obtaining informed consent, patients who tested positive for influenza with rapid tests received one of the four NAIs. Patients recorded their body temperature daily for 8 days from the first visit. The influenza strain was identified using real-time polymerase chain reaction. Univariate and multivariable analyses were used to evaluate factors influencing fever duration. In children aged ≤5 years treated with oseltamivir, fever duration in oseltamivir-resistant A/H1N1pdm09-infected patients was compared to that in oseltamivir-sensitive A/H1N1pdm09-infected patients. RESULTS:Of the 1,368 patients analyzed, 297 (21.7%), 683 (49.9%), and 388 (28.4%) were infected with influenza A/H1N1pdm09, A/H3N2, and B, respectively. In multivariable analysis factors associated with significantly prolonged fever duration included: treatment with laninamivir (hazard ratio [HR]: 0.78, p = 0.006, compared to oseltamivir), influenza B (HR: 0.58, p<0.001, compared to influenza A/H1N1pdm09), and a higher body temperature at the clinic visit (HR: 0.87 per degree Celsius, p<0.001). Increasing age was associated with a significantly shorter duration of fever (HR: 1.31 for 6-9 years old, p<0.001; and HR: 1.65 for 10-19 years old, p<0.001, respectively, compared to 0-5 years old). Following treatment with oseltamivir, fever duration was significantly longer for oseltamivir-resistant A/H1N1pdm09-infected patients (n = 5) than for oseltamivir-sensitive A/H1N1pdm09 infected patients (n = 111) (mean, 89 versus 40 hours, p<0.001). CONCLUSIONS:Our results revealed characteristic information on the effectiveness of the four NAIs and also on oseltamivir-resistant viruses that may affect patients' clinical care

Univariate analysis of the baseline characteristics and HRSV genotypes of hospitalized and non-hospitalized patients.

<p>Univariate analysis of the baseline characteristics and HRSV genotypes of hospitalized and non-hospitalized patients.</p

Phylogenetic trees of HRSV-A (A) and HRSV-B (B) strains.

<p>The tree was constructed by the neighbor-joining method using the Maximum Composite Likelihood for substitution model and complete deletion for gap or missing data treatment (MEGA, version 6). Bootstrap value was determined for 1000 iterations. Only values greater than 70% are shown. Strains detected during the 2012–2013 season are indicated by closed triangle (▲), those during the 2013–2014 season by closed circle (●), and those during the 2014–2015 season by closed square (■). Reference sequences of HRSV-A and HRS-B strains downloaded from GenBank (<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0192085#pone.0192085.s002" target="_blank">S2 Table</a>) were compared with strains detected in this study (<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0192085#pone.0192085.s001" target="_blank">S1 Table</a>).</p

Monthly distribution of HRSV cases by location during the three seasons.

<p>Data is shown for the six prefectures where specimens were collected during three seasons besides Okinawa. Left y-axis shows the number of HRSV specimens by genotype detected in this study and the right y-axis represents the number of HRSV cases reported to National Infectious Disease Surveillance in each prefecture.</p

Sequences of primers and probes used in this study.

<p>Sequences of primers and probes used in this study.</p

Monthly distribution of HRSV cases and genotypes in Japan.

<p>The bar graph shows the number of HRSV cases by genotype detected in this study and the line graph represents the number of HRSV cases reported to National Infectious Disease Surveillance.</p

Subgroup of HRSV divided by prefecture during the 2012–2013 through the 2014–2015 seasons.

<p>Subgroup of HRSV divided by prefecture during the 2012–2013 through the 2014–2015 seasons.</p