Masatoki Sato

Global burden of respiratory infections due to seasonal influenza in young children: a systematic review and meta-analysis

BACKGROUND The global burden of disease attributable to seasonal influenza virus in children is unknown. We aimed to estimate the global incidence of and mortality from lower respiratory infections associated with influenza in children younger than 5 years. METHODS We estimated the incidence of influenza episodes, influenza-associated acute lower respiratory infections (ALRI), and influenza-associated severe ALRI in children younger than 5 years, stratified by age, with data from a systematic review of studies published between Jan 1, 1995, and Oct 31, 2010, and 16 unpublished population-based studies. We applied these incidence estimates to global population estimates for 2008 to calculate estimates for that year. We estimated possible bounds for influenza-associated ALRI mortality by combining incidence estimates with case fatality ratios from hospital-based reports and identifying studies with population-based data for influenza seasonality and monthly ALRI mortality. FINDINGS We identified 43 suitable studies, with data for around 8 million children. We estimated that, in 2008, 90 million (95% CI 49-162 million) new cases of influenza (data from nine studies), 20 million (13-32 million) cases of influenza-associated ALRI (13% of all cases of paediatric ALRI; data from six studies), and 1 million (1-2 million) cases of influenza-associated severe ALRI (7% of cases of all severe paediatric ALRI; data from 39 studies) occurred worldwide in children younger than 5 years. We estimated there were 28,000-111,500 deaths in children younger than 5 years attributable to influenza-associated ALRI in 2008, with 99% of these deaths occurring in developing countries. Incidence and mortality varied substantially from year to year in any one setting. INTERPRETATION Influenza is a common pathogen identified in children with ALRI and results in a substantial burden on health services worldwide. Sufficient data to precisely estimate the role of influenza in childhood mortality from ALRI are not available. FUNDING WHO; Bill & Melinda Gates Foundation.

Genetic diversity of enterovirus 71 associated with hand, foot, and mouth disease epidemics in Japan from 1983 to 2003

Background: Enterovirus 71 (EV71) is one of the major etiologic agents of hand, foot and mouth disease (HFMD). The surveillance data indicate that EV71 infection follows an epidemic mode of transmission, causing large outbreaks and then becoming quiescent for a few years. Methods: We investigated the genetic diversity of a total of 121 EV71 strains isolated from patients with HFMD in Fukushima, Japan, from 1983 to 2003 and compared their genetic relation with the 164 EV71 strains isolated in the world using phylogenetic analysis based on the VP4 sequence. Results: We observed EV71-related HFMD outbreaks in Fukushima in 1984, 1987, 1990, 1993, 1997, 2000 and 2003. Phylogenetic reconstruction of EV71 strains isolated in Fukushima demonstrated 8 genetically distinct clusters, including 6 subgroups previously designated as B-1, B-2 and 3, B-4, C-1, C-2, and C-3 and 2 subgroups newly designated as B-5 and C-4. Additional 2 indistinct clusters belonged to genogroup C and were named C-U1 and C-U2. Of those subgroups, B-1, C-U1, C-U2, C-2, B4, and C-4 and B-5 dominantly related to epidemics that occurred in the years 1984, 1987 and 1990, 1993, 1997, 2000 and 2003, respectively. EV71 strains derived from each outbreak in Fukushima formed a single cluster with those isolated during almost the same time period in other area of Japan and in other countries. Conclusions: Our results suggested that the repeated EV71 outbreaks might be the result of the worldwide transmission of the newly introduced genetically divergent EV71 strains.

Viral shedding in children with influenza virus infections treated with neuraminidase inhibitors.

We examined the efficacy of neuraminidase inhibitors for reducing the duration of virus shedding after naturally occurring influenza virus infection. The duration of fever was significantly shorter in patients treated with neuraminidase inhibitors than in untreated patients. The durations of virus shedding from patients treated with neuraminidase inhibitors were not significantly shorter than those of untreated patients.

Genetic Diversity of Coxsackievirus A16 Associated with Hand, Foot, and Mouth Disease Epidemics in Japan from 1983 to 2003

ABSTRACT To clarify the chronologic genetic diversity of coxsackievirus A16 (CV-A16) strains associated with hand, foot, and mouth disease (HFMD) epidemics in a restricted area and their genetic relation with those isolated in other areas, we investigated the genetic diversity of the 129 CV-A16 strains associated with HFMD epidemics in Fukushima, Japan, from 1983 to 2003, and compared their genetic relation to 49 CV-A16 strains isolated in other areas of Japan and in China by using phylogenetic analysis based on the VP4 sequences. Phylogenetic reconstruction of the CV-A16 strains isolated in Fukushima from 1983 to 2003 demonstrated three distinct genetically divergent clusters related to HFMD epidemics that occurred from 1984 to 1994 (including the 1985 and 1991 outbreaks), HFMD epidemics from 1987 to 1998 (including the 1988 and 1998 outbreaks), and HFMD epidemics from 1995 to 2003 (including the 1995 and 2002 outbreaks). CV-A16 strains isolated during each period in Fukushima formed a single cluster with those isolated during essentially the same time period in other areas of Japan and in China. Our results demonstrated that prevalent CV-A16 strains causing HFMD in Fukushima, Japan, genetically changed twice during 21 epidemics, and changes were also observed in the CV-A16 strains causing HFMD epidemics in other areas. We concluded that repeated outbreaks of CV-A16-related HFMD in Japan were caused, in part, by the introduction of genetically changed CV-A16 strains, which might be transmitted overseas.

Current Status of Vaccines for Parainfluenza Virus Infections

Parainfluenza viruses (PIV) have been generally disregarded as pathogens in spite of their importance in pediatric lower respiratory illness. Because PIVs account for 17% of hospitalized illness associated virus isolation, the development of PIV vaccine would be a major advance in preventing lower respiratory tract infection in infants and young children. We will review in detail several PIV vaccine candidates and recent newer approaches to PIV vaccine development. Intranasally administered bovine PIV3 (bPIV3) vaccine and cold-adapted PIV3 vaccine have been evaluated throughout the pediatric age spectrum. BPIV3 does not give a robust response to the heterotypic human strain although seroconversion rate to bPIV3 is 57-65%. However, bPIV3 vaccine is being used as an attenuated backbone for insertion of human PIV3 hemagglutinin-neuraminidase and fusion (F) proteins and a surface protein, F, of respiratory syncytial virus. The effectiveness of this vaccine against both PIV3 and RSV challenge has been demonstrated in African green monkeys. The cold-adapted PIV3 vaccine has been extensively evaluated and is safe and immunogenic in seronegative children with a seroconversion rate of 79%. These promising candidates deserve to enter into efficacy trials both for their ability to prevent PIV3 disease and as a model of protection against respiratory illness by mucosal vaccination.

Application of PCR for various neurotropic viruses on the diagnosis of viral meningitis.

BACKGROUND Epidemiological studies have indicated that the majority of cases of aseptic meningitis result from viral infections. However, specific viral pathogens for aseptic meningitis can be identified in only some cases even if consistent conventional diagnostic methodologies rare used. OBJECTIVES To clarify the etiological agents of aseptic meningitis by means of polymerase chain reaction (PCR) for various neurotropic viruses. STUDY DESIGN Cerebrospinal fluid (CSF) samples were collected from 73 children suspected of having meningitis from November 1991 to December 1994. The samples were examined for infectious viruses by cell culture and for viral genomes by PCR. RESULTS AND CONCLUSIONS Of 45 samples from patients diagnosed with aseptic meningitis, positive PCR results for enterovirus, mumps virus, cytomegalovirus, and varicella-zoster virus were obtained from respectively 25, 14, 1, and 1. Viral pathogens were thus identified in 41 (91.1%) of the 45 CSF samples. By the combination of PCR methods with conventional virological methods, the diagnosis of viral meningitis was established in 97.8% of the 45 cases. Our findings prove that the application of PCR methods is useful for etiological study of aseptic meningitis, and that the vast majority of cases of aseptic meningitis result from viral infection.

Rhinovirus load and disease severity in children with lower respiratory tract infections

It has not been clarified if there is a correlation between rhinovirus (RV) load and disease severity in the lower respiratory tract infections of hospitalized children. This study was undertaken to elucidate the contribution of the viral load to the development of disease severity in 412 children ≤3 years of age who were hospitalized with lower respiratory tract infections. The RV load in nasopharyngeal aspirates obtained from the patients at the time of admission was measured by real‐time quantitative reverse‐transcription polymerase chain reaction (PCR), and the clinical symptoms of the patients were assessed using a severity scoring system. Of the 412 patients, 43 (10.4%) were diagnosed with RV infections only, and 15 were determined to have high severity scores. When all patients infected with RV were assessed, there was no correlation between the viral load and the disease severity. However, there was a significant negative correlation between the disease severity and age among children <11 months of age (n = 15, ρ = −0.677, P = 0.006) and a significant positive correlation between the viral load and the disease severity among children ≥11 months of age (n = 28, ρ = 0.407, P = 0.032). Among the patients infected with RV <11 months of age, the disease severity may be associated with an immature immune response and the small diameter of their airways rather than viral load. By contrast, in the patients ≥11 months of age, viral load may contribute to the development of disease severity. J. Med. Virol. 84: 1135–1142, 2012.

The effectiveness of trivalent inactivated influenza vaccine in children over six consecutive influenza seasons

OBJECTIVE To estimate the effectiveness of two doses of trivalent inactivated influenza vaccine (TIV) over six consecutive influenza seasons in a small community in Japan. PATIENTS AND METHODS A prospective, non-randomized, observational study of TIV effectiveness was performed involving children aged 6 months to 6 years accessing pediatric services in Soma and Shinchi, Japan. The total number of children under observation was 14,788. Each fall from 2002 to 2007 TIV was offered to all children with an average uptake of 52.9%. Influenza rapid diagnostic tests were performed to all children with respiratory symptoms and a temperature >38°C during each surveillance period. The efficacy of two doses of TIV was estimated by the relative risk of influenza illness and influenza associated hospitalizations and effectiveness by reduction in all respiratory illness in vaccinated and unvaccinated children. RESULTS Influenza A occurred each year resulting in approximately one in five children in the unvaccinated group having an influenza A related clinic visit. For influenza A, two doses of TIV showed yearly efficacies that ranged from 42% to 69% with the highest efficacy during the 2002/2003 influenza season when the vaccine strains were well matched with the circulating viruses. The overall efficacy of two doses of TIV against influenza A and B associated illness was 52% and 59%, respectively. TIV also reduced the rate of the influenza associated hospitalizations attributable to both influenza A and B. CONCLUSIONS Vaccination with two doses of TIV was consistently effective in preventing influenza-associated clinic visits and hospitalizations.

RSV replication is attenuated by counteracting expression of the suppressor of cytokine signaling (SOCS) molecules.

Human RSV causes an annual epidemic of respiratory tract illness in infants and in elderly. Mechanisms by which RSV antagonizes IFN-mediated antiviral responses include inhibition of type I IFN mRNA transcription and blocking signal transduction of JAK/STAT family members. The suppressor of cytokines signaling (SOCS) gene family utilizes a feedback loop to inhibit cytokine responses and block the activation of the JAK/STAT signaling pathway. To evaluate the potential of SOCS molecules to subvert the innate immune response to RSV infection, eight SOCS family genes were examined. RSV infection up-regulated SOCS1, SOCS3, and CIS mRNA expression in HEp-2 cells. Suppression of SOCS1, SOCS3 and CIS by short interfering ribonucleic acid (siRNA) inhibited viral replication. Furthermore, inhibition of SOCS1, SOCS3, or CIS activated type I IFN signaling by inducing STAT1/2 phosphorylation. These results suggest that RSV infection escapes the innate antiviral response by inducing SOCS1, SOCS3 or CIS expression in epithelial cells.

Differences in serum cytokine levels between influenza virus A and B infections in children

OBJECTIVE To investigate differences in cytokine production between influenza A and B. MATERIALS AND METHODS thirty one patients with influenza A and 16 with influenza B were enrolled in this study. We measured soluble tumor necrosis factor receptor (sTNFR) 1, interleukin (IL)-6, interferon (IFN)-gamma and IL-4 concentrations in serum obtained from all patients during the acute and convalescence phases of their illnesses. RESULTS the sTNFR1 and IL-6 serum concentrations of patients with influenza A and B were equivalently elevated in the acute phase of their illness. However, the acute phase concentrations of IFN-gamma and IL-4 were significantly higher in patients with influenza A than in patients with influenza B. The concentration of all cytokines in influenza A and sTNFR1 in influenza B significantly decreased from the acute to convalescent phase. Plotted from the onset of symptoms it appeared that all of the cytokines peaked within 24h after onset. DISCUSSION the production pattern of the inflammatory cytokines - TNF and IL-6 - were the same between influenza A and B. However, a Th2 predominant cytokine pattern was induced after natural influenza virus A infection, notably IL-4 that differed from that to influenza B.