Noriko Katsushima

Clinical Features of Influenza C Virus Infection in Children

BACKGROUND Seroepidemiological studies have revealed that influenza C virus is widely distributed globally. However, because the isolation of this virus is difficult, there have been few reports on its clinical features. METHODS Between December 1990 and November 2004, 84,946 respiratory-tract specimens were obtained from patients < or = 15 years old. On the basis of the results of isolation of virus, we examined the clinical data on children infected with influenza C virus. RESULTS Of 170 children infected with influenza C virus, 157 (92.4%) were < 6 years old. Fever (frequency, 90.0%), cough (frequency, 74.1%), and rhinorrhea (frequency, 61.8%) were the most frequent symptoms. The mean duration of fever was 2.88 days (standard deviation, 1.66 days). Of the 170 children, 29 were hospitalized, and 21 (72.4%) of these 29 had lower-respiratory-tract illness such as pneumonia, bronchitis, and bronchiolitis. The rate of hospital admission was significantly higher in children < 2 years old than in children 2-5 years old (30.4% vs. 11.9%; P = .0043). CONCLUSIONS Influenza C virus is a significant cause of upper-respiratory-tract illness in children < 6 years old, and the risk of complications with lower-respiratory-tract illness is particularly high in children < 2 years old.

Cross-antigenicity among EV71 strains from different genogroups isolated in Yamagata, Japan, between 1990 and 2007.

We isolated and identified six subgenogroups (B2, B4, B5, C1, C2, and C4) of enterovirus 71 (EV71) between 1990 and 2007 in Yamagata, Japan. We measured neutralizing antibody (NT Ab) titers against those subgenogroup strains and the BrCr reference strain for antigenic analysis. Serological analysis of 83 residents in Yamagata in 2004 showed that differences in the NT Ab titer of each individual against the different subgenogroups were mostly within 4-fold. Furthermore, sera from guinea pigs, immunized with the B2 and C1 strains indicated cross-antigenicity among the seven different subgenogroups. In conclusion, our results showed that cross-antigenicity exists among EV71 strains from different subgenogroups circulating in the community through genomic evolution. Our results also suggest that eliciting neutralizing antibodies against one genotype is likely to confer cross-neutralization against other genotypes.

Human SCARB2-Dependent Infection by Coxsackievirus A7, A14, and A16 and Enterovirus 71

ABSTRACT Human enterovirus species A (HEV-A) consists of at least 16 members of different serotypes that are known to be the causative agents of hand, foot, and mouth disease (HFMD), herpangina, and other diseases, such as respiratory disease and polio-like flaccid paralysis. Enterovirus 71 (EV71) and coxsackievirus A16 (CVA16) are the major causative agents of HFMD. CVA5, CVA6, CVA10, and CVA12 mainly cause herpangina or are occasionally involved with sporadic cases of HFMD. We have previously shown that human scavenger receptor class B, member 2 (SCARB2) is a cellular receptor for EV71 and CVA16. Using a large number of clinical isolates of HEV-A, we explored whether all clinical isolates of EV71 and other serotypes of HEV-A infected cells via SCARB2. We tested this possibility by infecting L-SCARB2 cells, which are L929 cells expressing human SCARB2, by infecting human RD cells that had been treated with small interfering RNAs for SCARB2 and by directly binding the viruses to a soluble SCARB2 protein. We showed that all 162 clinical isolates of EV71 propagated in L-SCARB2 cells, suggesting that SCARB2 is the critical receptor common to all EV71 strains. In addition, CVA7, CVA14, and CVA16, which are most closely related to each other, also utilized SCARB2 for infection. EV71, CVA14, and CVA16 are highly associated with HFMD, and EV71 and CVA7 are occasionally associated with neurological diseases, suggesting that SCARB2 plays important roles in the development of these diseases. In contrast, another group of viruses, such as CVA2, CVA3, CVA4, CVA5, CVA6, CVA8, CVA10, and CVA12, which are relatively distant from the EV71 group, is associated mainly with herpangina. None of these clinical isolates infected via the SCARB2-dependent pathway. HEV-A viruses can be divided into at least two groups depending on the use of SCARB2, and the receptor usage plays an important role in developing the specific diseases for each group.

Community-acquired influenza C virus infection in children

To clarify the epidemiologic and clinical features of community-acquired influenza C infection in children, we took specimens throughout the year from a larger number of patients with acute respiratory illnesses in a pediatric clinic in Yamagata, Japan. During a 2-year survey, 20 strains of influenza C virus were isolated from 13,426 specimens. These isolates were recovered throughout the year. The ages of patients with influenza C virus isolates ranged from 2 months to 11 years and peaked at the age of 1 year. The clinical diagnosis of patients with influenza C virus infection included bronchitis in one child and pneumonia in four. Community-acquired influenza C infection in children can cause a variety of respiratory illnesses that cannot be clinically differentiated from those caused by other viruses.

A human melanoma cell line highly susceptible to influenza C virus

The relative amounts of influenza C virus-specific receptors of 25 established lines of mammalian cells including four lines of human malignant melanoma origin were compared by virus binding experiments. All the human melanoma cell cultures studied possessed two to four times more receptors than were found on MDCK cells, a cell line known to be highly susceptible to influenza C virus. It may therefore be a feature common to human melanoma cells that O-acetylsialic acid, a determinant for the attachment of influenza C virus, exists in large quantities on their surface. This is not specific to melanoma cells, however, since several human cell lines derived from lung cancer, gastric cancer, and placenta specimens also exhibited high levels of virus binding. Twenty of 25 virus-binding cell cultures were further examined for their ability to support the replication of influenza C virus. In the presence of trypsin (5 to 20 micrograms/ml), the virus was found to undergo multiple cycles of replication much more efficiently in the HMV-II line of human melanoma cells than in MDCK cells. Additionally, by using HMV-II cells as a host, we succeeded in isolating two influenza C strains (C/Yamagata/1/88, C/Yamagata/2/88) from 241 throat swabs collected from patients with acute respiratory illness.

Sinus histiocytosis with massive lymphadenopathy. A histogenic analysis of histiocytes found in the fourth Japanese case.

The present paper deals with immunohistochemical and ultrastructural study of the lymph nodes of sinus histiocytosis with massive lymphadenopathy (Rosai and Dorfman, SHML) of a 12‐year‐old Japanese boy. This is the fourth case in Japan. Osseous manifestation was also found in the bilateral ulnae. With hallmarks of S‐100 protein and interdigitating cytoplasmic extensions, the phagocytizing histiocytes proliferating in the sinuses were considered to be derived mostly from interdigitating cells in the paracortex or T cell dependent area, which have heretofore been regarded as nonphagocytizing. Furthermore, it is most interesting that lymphoid cells bearing thymic cortical cell‐antigen (OKT 6) were increasingly recognized in the patients peripheral blood. These results suggested that SHML is a specialized reactive histiocytosis analogous to histiocytosis X and histiocytic medullary reticulosis.

Epidemiological information regarding the periodic epidemics of influenza C virus in Japan (1996–2013) and the seroprevalence of antibodies to different antigenic groups

BACKGROUND Although influenza C virus is widely distributed throughout the world, epidemiological information, based on long-term surveillance, has not yet been acquired. OBJECTIVES To clarify the epidemiological features of influenza C virus infection, and to examine whether the prevalence of the antibodies against the influenza C virus is associated with the epidemics. STUDY DESIGN Between 1996 and 2013, 36,973 respiratory specimens were collected from two pediatric outpatient clinics in Yamagata, Japan. The specimens were examined for the presence of influenza C virus using cell culture methods. Isolated viruses were antigenically analyzed. The differences in seropositivity, with respect to the different antigenic groups, were examined using serum samples collected in 2001 and 2011 by a hemagglutination inhibition assay. RESULTS Influenza C viruses were isolated from 190 specimens during an 18-year period. Most influenza C viruses were isolated from winter to early summer in even-numbered years, and the frequency of virus isolation per year ranged from 0.43% to 1.73%. An antigenic analysis revealed that the dominant antigenic groups were the C/Yamagata/26/81 from 1996 to 2000, the C/Kanagawa/1/76 in 2002 and 2004, and the C/Sao Paulo/378/82 from 2006 to 2012. When compared to the other antigenic groups, the seroprevalence of the C/Sao Paulo/378/82 group was lower in 2001 for individuals older than 5 years and was higher in 2011 in individuals younger than 40 years. CONCLUSIONS The results from our study suggest that epidemics of influenza C virus infection periodically occur and the replacement of the dominant antigenic group may be caused by immune selection within older children and/or adults in the community.

Endemicity of human metapneumovirus subgenogroups A2 and B2 in Yamagata, Japan, between 2004 and 2009

To clarify a longitudinal epidemiology, we isolated 280 hMPV strains from patients with acute respiratory infections in Yamagata, Japan, between 2004 and 2009. We observed that the high season for hMPV was from winter to spring (between January and May) and the low season was in the fall (around September and October). A further molecular analysis revealed that subgenogroup A2 (A2) strains were the most commonly isolated (151/280; 53.9%), followed by B2 (108/280; 38.6%) and B1 (19/280; 6.8%). Our results suggested that A2 and B2 have been endemically in circulation as the major types almost every year, whereas other subgenogroups have appeared less frequently.

Molecular epidemiology of Coxsackievirus A16 strains isolated from children in Yamagata, Japan between 1988 and 2011.

To clarify the longitudinal molecular epidemiology of coxsackievirus A16, phylogenetic analysis based on the VP1 region of 220 isolates in Yamagata, Japan was performed. The resultant phylogenetic tree indicates that the Yamagata isolates and reference strains can be readily genotyped into three genogroups, and 0, 12 and 208 isolates belonged to the first, second, and third genogroups, respectively. The first genogroup includes only the prototype strain, the second strains that had disappeared by the end of the 20th century and the third comprises those that have been circulating since then in local communities, such as Yamagata.

The Herald Waves of Influenza Virus Infections Detected in Sendai and Yamagata Cities in 1985-1990

The community surveillance of respiratory virus infections performed during 1985–1987 in Sendai and 1988–1990 in Yamagata has identified a total of five herald waves of influenza virus infections: A/H3N2 virus infections in 1985 and 1989, A/H1N1 virus infections in 1986 and 1988, and type B virus infections in 1989. To investigate the antigenic and genetic relationships between the herald wave and epidemic strains, influenza A/H1N1 viruses isolated during the 1986 and 1988 herald waves were compared with those isolated during the 1986–1987 and 1988–1989 epidemic seasons, respectively, utilizing hemagglutination inhibition tests with anti‐hemagglutinin monoclonal antibodies and oligonucleotide mapping of total viral RNAs. The results showed that multiple variants differing in antigenic and genetic properties were cocirculating during the 1986 herald wave as well as during each of the two epidemics (only one strain was isolated in the 1988 herald wave). It was also observed that viruses which had the antigenic and/or genetic characteristics closely similar to those of the viruses circulating in the 1986 and 1988 herald waves, were isolated during the winters of 1986–1987 and 1988–1989, respectively.