Tomohiro Oishi

Nationwide population-based surveillance of invasive pneumococcal disease in Japanese children: Effects of the seven-valent pneumococcal conjugate vaccine.

BACKGROUND In Japan, the seven-valent pneumococcal conjugate vaccine (PCV7) was introduced in 2010. PCV13 has replaced PCV7 since November 2013. METHODS The effectiveness of PCV7 in protecting against invasive pneumococcal disease (IPD) in children aged <5 years was evaluated in a nationwide active population-based surveillance of IPD in 2008-2013 in 10 prefectures in Japan. RESULTS 1181 cases were identified; 711 pneumococcal strains were analyzed for serotyping and antimicrobial resistance. Compared with the baseline IPD incidence (25.0 per 100,000), a 98% decline in IPD caused by PCV7 serotypes was found after the introduction of PCV7. This was partially offset by an increased incidence of IPD caused by PCV13 minus PCV7 and non-PCV13 serotypes, resulting in a 57% decline in overall IPD incidence. Absolute increases in the incidence rates of IPD caused by PCV13 minus PCV7 and non-PCV13 serotypes were 2.1 and 2.8 per 100,000 during the study period, respectively. The proportion of meropenem-nonsusceptible strains, especially with serotypes 19A and 15A, increased significantly after PCV7 introduction. CONCLUSIONS Our data confirmed a 98% decline in IPD incidence caused by PCV7 serotypes in children aged <5 years and serotype replacement after PCV7 introduction. This shows the importance of continuing surveillance of serotypes responsible for IPD and their antimicrobial resistance in Japan.

Role of Maternal Antibodies in Infants with Severe Diseases Related to Human Parechovirus Type 3.

Maternal antibodies may protect infants from severe illness caused by this pathogen.

Nationwide survey of the development of drug-resistance in the pediatric field: drug sensitivity of Haemophilus influenzae in Japan

We evaluated the β-lactamase-producing ability and resistance to 20 antibacterial agents of 448 clinically isolated strains of Haemophilus influenzae accumulated from October 2000 to July 2001 (phase 1) and of 376 different strains accumulated from January to June 2004 (phase 2), from institutions that participated in a nationwide Drug-Resistant Pathogen Surveillance Group in Pediatric Infectious Disease. Between phase 1 and phase 2 the proportion of β-lactamase-negative ampicillin (ABPC)-susceptible (BLNAS) strains declined from 62.9% to 34.3%; the proportions of β-lactamase-positive ABPC-resistant (BLPAR) strains were 8.3% and 6.4% in phases 1 and 2, but the proportion of β-lactamase-negative ABPC-resistant (BLNAR) strains increased from 28.8% in phase 1 to 59.3% in phase 2. Comparison of the MIC90 values of the antibacterial agents for H. influenzae in phase 1 and phase 2 showed that cefcapene, cefpodoxime, ceftriaxone, panipenem, and clarithromycin kept the same level, while cefdinir, faropenem, and rokitamycin showed 2-fold to 8-fold decreases. With the exception of the above antibiotics, all of the other antibacterial agents tested showed 2-fold to 4-fold increases. The MIC90 values of the β-lactam drugs for BLNAR were 2-fold to 32-fold higher than the values for BLNAS. The proportion of BLNAR H. influenzae strains rose dramatically over the 3 years between phases 1 and 2. In relation to age, prior administration of antibacterial agents, and attendance at a day nursery as background factors, no significant differences between BLNAS and BLNAR were detected in phase 1. In the phase 2 survey, the proportion of BLNAR strains showed significant differences between children under 3 years and those aged 3 years or more, and there were also significant differences according to whether antibacterial agents, especially β-lactams, had been administered previously. No significant difference was found in resistant bacteria according to whether or not a child had attended a day nursery.

Low opsonic activity to the infecting serotype in pediatric patients with invasive pneumococcal disease.

Serotype-specific protective immunity in pediatric patients with invasive pneumococcal disease (IPD) has not been fully investigated. To determine the protective immunity to the infecting serotype, the serotype-specific immunoglobulin G (IgG) levels and opsonization indices (OIs) were examined in 24 Japanese pediatric patients whose serum was collected within one month of an IPD episode between May 2008 and June 2011. The median age (range) of IPD patients was 17 (10-108) months and 63% were boys. In all 17 patients tested, the levels of serotype-specific IgG to the infecting serotype were higher than 0.2 μg/ml, but the OIs to the infecting serotype were <8. The avidities of 19F- or 6B-specific IgG in patients with levels higher than 5.0 μg/ml, but with undetectable OIs, were confirmed to be lower than those in patients with high OIs. Our data demonstrated that although the levels of serotype-specific IgG to the infecting serotype were higher than 0.2 μg/ml in sera of pediatric patients with IPD, the OIs were low one month after the IPD episode. Low opsonic activities in these patients may, in part, be explained by the low avidity of serotype-specific IgG.

Asymptomatic children might transmit human parechovirus type 3 to neonates and young infants.

BACKGROUND Human parechovirus type 3 (HPeV3) epidemics occur worldwide and can lead to severe disease in neonates and young infants. Little is known about the source of HPeV3 infection. OBJECTIVES To investigate the source of HPeV3 infection and the role of asymptomatic children in the families of infected children. STUDY DESIGN During a 2014 HPeV3 epidemic in Niigata, Japan, we analyzed (1) clinical information on sick contacts for 43 neonates and young infants with HPeV3-related disease diagnosed by PCR analysis of serum and/or cerebrospinal fluid and (2) stool samples from symptomatic and asymptomatic siblings/cousins of index patients. To confirm transmission, the P1 (VP0, VP3, and VP1) and 3D(pol) regions of HPeVs were sequenced and analyzed. RESULTS Sick contact with family members was confirmed for 51% (n=22) of patients. Among the 30 symptomatic family members, 67% (n=20) were siblings, 20% (n=6) were mothers, and 13% (n=4) were other relatives. Stool samples from symptomatic and asymptomatic siblings/cousins of 4 HPeV3-infected patients yielded positive results for HPeVs on PCR analysis. Furthermore, the P1 and 3D(pol) nucleotide sequences of family members were 100% identical to those of the respective index cases. CONCLUSIONS Identification of genetically identical virus from HPeV3-infected patients and asymptomatic children in their families suggests that the latter are a source of infection in neonates and young infants with HPeV3-related diseases.

Clinical utility of loop-mediated isothermal amplification for rapid diagnosis of Mycoplasma pneumoniae in children.

Loop-mediated isothermal amplification (LAMP) is a cost-effective and rapid method for identifying Mycoplasma pneumoniae (MP). We investigated the utility of the LAMP assay in diagnosing MP pneumonia among children in a clinical setting. In this prospective study, the cause of community-acquired pneumonia was evaluated in 111 patients for whom MP was the suspected pathogen. All participants were patients at a city hospital in Japan between April 2012 and September 2012. Throat swabs for the LAMP assay were obtained at admission, and paired serum samples to measure antibody titres to MP by particle agglutination were obtained at admission and during convalescence. Overall, 45 of 111 (41 %) patients had a fourfold or greater increase in MP titres and received a diagnosis of MP pneumonia. Among them, 43 (96 %) patients (median age, 9 years) were positive on the LAMP assay and had a fourfold or greater increase in MP titres. The median interval from fever onset to collection of throat swabs was 7 days (range, 4-10 days). As compared with paired serum titres, the LAMP assay enabled quicker diagnosis of MP (median interval, 13 vs. 7 days), thereby allowing early initiation of appropriate antimicrobial therapy.

Nationwide survey of the development of drug-resistant pathogens in the pediatric field: drug sensitivity of Streptococcus pneumoniae in Japan.

We evaluated the resistance to 20 different antibacterial agents of 362 clinically isolated strains of Streptococcus pneumoniae accumulated from October 2000 to July 2001 (phase 1) and of 332 different strains accumulated from January to June 2004 (phase 2), from institutions throughout Japan that participated in the surveys carried out by the Drug-Resistant Pathogen Surveillance Group in Pediatric Infectious Disease. In phase 1, the proportions of penicillin-sensitive S. pneumoniae (PSSP), penicillin-insensitive S. pneumoniae (PISP), and penicillin-resistant S. pneumoniae (PRSP) were 35.4%, 34.8%, and 29.8%, respectively, and the proportions were almost the same in phase 2: 33.1%, 37.0%, and 29.8%, respectively. Comparison of the MIC90 values of the antibacterial agents for PRSP in phase 1 and phase 2 revealed that these values for cefditoren, cefpodoxime, cefdinir, faropenem, ceftriaxone, cefotaxime, meropenem, and vancomycin increased by twofold to fourfold during the 3 years between phase 1 and phase 2. However the MIC90 of rokitamycin increased more than fourfold. The proportion of S. pneumoniae that were PISP + PRSP remained almost constant over the 3 years between phase 1 and phase 2. The background factors of patient age, previous administration of antibacterial agents, and attendance at a day nursery were examined; we found that in phase 1, the proportion of PISP + PRSP was significantly higher than that of PSSP in patients under 4 years old who had previously received antibacterial agents, but no significant differences were found in any of these background factors in the phase 2 survey. No significant difference was found in the proportions of penicillin-resistant bacteria according to whether or not the child had attended a day nursery.

Rhabdomyolysis Associated with Antimicrobial Drug-Resistant Mycoplasma pneumoniae

We describe a case of rhabdomyolysis in a patient infected with antimicrobial drug–resistant Mycoplasma pneumoniae The patient’s acute-phase serum levels of interleukin-18 and tumor necrosis factor–α were high, which suggests a pathogenic role for M. pneumoniae. In an era of increasing antimicrobial drug resistance, a system for rapidly identifying resistant M. pneumoniae would be beneficial.

Macrolide-Resistant Mycoplasma pneumoniae Infection, Japan, 2008–2015

We evaluated isolates obtained from children with Mycoplasma pneumoniae infection throughout Japan during 2008–2015. The highest prevalence of macrolide-resistant M. pneumoniae was 81.6% in 2012, followed by 59.3% in 2014 and 43.6% in 2015. The prevalence of macrolide-resistant M. pneumoniae among children in Japan has decreased.

Human parechovirus type 3 infection: Cause of apnea in infants born prematurely.

Four infants born prematurely presented with multiple apnea episodes caused by human parechovirus type 3 (HPeV3) infection. All patients required oxygen supplementation, and one patient required mechanical ventilation. HPeV3 infection might be included in the differential diagnosis of apnea in neonates and young infants, especially those born prematurely.