Infectious parotitis is characterized by the diffuse tender swelling of parotid glands and fever.  It is called “Otafuku Flu” in Japan because the patient’s face resembles the face of the folkloric full-cheeked woman Otafuku, who may bring us good fortune.  The causative agent mumps virus is a single stranded RNA virus of the negative polarity, and belongs to the family Paramyxoviridae, sub-family Paramyxoviridae, genus Rubulavirus.  The 2012 WHO’s proposal classifies mumps virus into 12 genotypes from A to N (note: previous E and M are now classified as C and K, respectively, and E and M are absent) (see p. 224 of this issue).

Mumps virus is transmitted by droplet infection or direct contact with saliva.  The basic reproduction number: R₀ (the average number of cases among the susceptible population, which one case can directly infect over the course of its infectious period) is 4-7 (R₀ is 12-18 for measles and 5-8 for rubella).  The incubation period is usually 16-18 days.  The communicability lasts from a few days before onset of the disease until disappearance of swelling of the parotid gland.  School Health and Safety Act designates mumps infection as a category 2 school infectious disease and prohibits the school attendance for at least 5 days after the appearance of the swelling of parotid, submandibular and sublingual gland and until full recovery of general condition of the health.  Asymptomatic infection cases occupying 30-35% of infections shed the virus and can become infection sources.

Cases notified under the National Epidemiological Surveillance of Infectious Diseases:  Infectious parotitis is a category V infectious disease under the Infectious Diseases Control Law (http://www.niid.go.jp/niid/images/iasr/34/402/de4021.pdf).  It is monitored at about 3,000 pediatric sentinel clinics, which reports the cases on weekly basis (Fig. 1). 

Though the immunization started in 1981 on voluntary basis, the coverage remained low.  As a consequence, the large scale epidemic occurred at 3-5 year intervals.  In April 1989, measles-mumps-rubella (MMR) vaccine became a choice in the routine immunization.  Accordingly the mumps vaccination coverage increased and mumps incidence was significantly reduced.  However, the MMR vaccination was discontinued in April 1993 on account of many post-vaccination aseptic meningitis cases, which became an object of public concern (see p. 230 of this issue).  Though mumps monovalent vaccine was used thereafter, large mumps epidemics recurred at 4-5 year intervals (2001-2002, 2005-2006 and 2010-2011).

According to an investigation supported by Health and Labour Sciences Research Grant (Chief Investigators: Taniguchi, K and Nagai, M), the current annual incidence of mumps infection in Japan is estimated to be between 1.356 million, which was reported in the peak year 2005 (95% confidence interval: 1.272-1.440 million) and 0.431 million, which was reported in the bottom year 2007 (95% confidence interval: 0.355-0.508 million). 

Fig. 2 shows the age distribution of mumps patients reported from the pediatric sentinel clinics.  The 4-year-old cases were the largest in number, followed by 5-year-old and 3-year-old cases; 0-1 year-old cases were few.  The cases aged less than 6 years accounted for 60% and cases aged less than 10 years occupied 90% of the total.  Since 2010, the proportion of cases less than 6 years of age has been decreasing and that of those above 10 years of age has been increasing.

Mumps virus isolation/detection:  During January 2000 through June 2013, prefectural and municipal public health institutes (PHIs) have reported 2,462 cases, from which mumps virus was detected (as of July 18, 2013).  Clinical diagnosis of them was infectious parotitis for 1,397 cases and aseptic meningitis for 764 cases (Fig. 3).  Infectious parotitis cases were reports from pathogen sentinels (corresponding about 10% of pediatric sentinel clinics), and aseptic meningitis were reports from the sentinel hospi-tals (consisting of about 500 hospitals each with more than 300 beds). 

The genotypes of the epidemic mumps virus strains change overtime in Japan.  The epidemic strain in 1980’s was genotype B and that in 1990’s was the mixture of J and B.  In 1999, it suddenly changed to the mixture of G and L and since 2000 genotype G has been predominant (see pp. 224 & 226 of this issue).

Prognosis of mumps and its complications:  Prognosis of mumps is generally good, but occasionally it develops complications, such as, aseptic meningitis, sensorineural hearing loss, encephalitis, orchitis, ovaritis, pancreatitis, etc. (see p. 222 of this issue).  About 1-2% of the diagnosed infectious parotitis patients develop meningitis that requires hospitalization (see pp. 222 & 230 of this issue).  Hearing impairment is observed among 0.1-1% of the mumps patients, and estimatedly 700-2,300 cases of hearing impairment occur in Japan every year (see pp. 227 & 228 of this issue).  Though severe bilateral sensorial hearing impairment is rare, unilateral hearing loss is frequent and such cases are often left unnoticed during the childhood.  They need hearing aids and cochlear implants, and, if the disease onset is before the entry to the junior high school, speech instruction is needed (see p. 228 of this issue). 

Efficacy and safety of mumps vaccine:  Mumps vaccine is introduced into the routine immunization in 117 countries globally, among them 110 countries adopt two-shot schedule and 7 countries one-shot schedule.  There are 76 countries that have not introduced the mumps vaccine in the routine immunization.  Japan is among them and the sole developed country that is conducting mumps immunization on voluntary basis.  WHO recommends the two-shot schedule rather than the one-shot schedule, because comparative studies have indicated that the two-shot schedule was more effective.  However, a recent mumps outbreak in the United States among those who had received two shots necessitated the third shot to control the epidemic (see p. 232 of this issue).

More than ten mumps strains are currently used as vaccine seeds, i.e., Jeryl-Lynn (JL) strain and its derivative RIT-4385 strain with the genotype A, Leningrad-3 strain and Leningrad-Zagreb strain with the genotype N, Urabe AM9 strain with the genotype B, etc.  In Japan Hoshino strain and Torii strain both with the genotype B are used as the vaccine seed virus (Urabe AM9 strain has been abandoned and Miyahara strain discontinued) (see pp. 221 & 224 of this issue). 

It has been suggested that vaccine effectiveness and safety were variable among vaccine strains.  Vaccine effectiveness has been found comparable among Urabe AM9, Torii, Hoshino and Miyahara strains.  Data obtained in the Western countries have suggested that Urabe AM9 strain has higher effectiveness than JL strain (Fact sheets on mumps: http://www.mhlw.go.jp/stf/shingi/2r9852000000bx23-att/2r9852000000bybc.pdf).  As for vaccine-associated adverse effects, incidence of aseptic meningitis was reportedly lower for the JL strain than for Urabe AM9, Leningrad-3, Hoshino and Torii strains.  As the subclinical infection is more frequent among younger children and complication rate increases with advancement of the age in natural infections, the first dose should be given during one year of age so as to reduce the frequency of the adverse effects (see p. 221 of this issue). 

Current and future challenges:  The infectious parotitis has been considered as an infection with a slight ailment.  Aseptic meningitis occurs in 1-2 % of the patients and total 700-2,300 sensorial hearing impairment cases occur in Japan due to the mumps infection, however.  The present situation should not be left as it is.

The second recommendation from Immunization Committee of the Infectious Diseases Branch of the Ministry of Health Labour and Welfare (MHLW) Council, which was issued in May 2012, proposed further strengthening of the prevention of infectious parotitis, together with that of varicella, hepatitis B and adult pneumococcal infection.  The additional resolution to the revision of the Preventive Vaccination Law declared that decision as to the incorporation of the mumps vaccine into the routine immunization should be made before the end of FY2013.

Effective control of mumps virus infection needs surveillance of child and adult patients including their vaccination history, nationwide pathogen surveillance, investigation of antibody positive rates of the Japanese population, investigation of vaccine coverage, and surveillance of vaccine-associated adverse effects.  Further strengthening of collaboration between MHLW, National Institute of Infectious Diseases, PHIs, health centers and medical institutions is in need.

 

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The statistics in this report are based on 1) the data concerning patients and laboratory findings obtained by the National Epidemiological Surveillance of Infectious Diseases undertaken in compliance with the Law Concerning the Prevention of Infectious Diseases and Medical Care for Patients of Infections, and 2) other data covering various aspects of infectious diseases.  The prefectural and municipal health centers and public health institutes (PHIs), the Department of Food Safety, the Ministry of Health, Labour and Welfare, and quarantine stations, have provided the above data.

 

Haemophilus influenzae is a small Gram-negative bacillus.  It is carried by many infants in their nasopharyngeal cavities (see p. 193 of this issue).  There are two clinical types; the one is systemic invasive type and the other is localized non-invasive type.  The systemic invasive type is generally severe and the bacteria can be found in otherwise aseptic sites, such as, blood, cerebrospinal fluid, etc.  Haemophilus influenzae is classified into the encapsulated strains and the non-typable strains.  Haemophilus influenzae with capsular type b (Hib) is the major cause of the infantile invasive H. influenzae infections (see p. 187 of this issue).  Non-typable H. influenzae (NTHi) is a major cause of non-invasive bacterial infections among infants and adults (e.g. otitis media and exacerbation of chronic obstructive pulmonary diseases, etc.).

Capsular type and Hib vaccine:  Encapsulated strains are classified into 6 capsular types from a to f.  Capsular type is determined by bacterial agglutination test using capsular antigen-specific antibodies or by capsular type-specific gene amplification using polymerase chain reaction (PCR) (see p. 192 of this issue) (see Laboratory Manual for Bacterial Meningitis in Pathogen Detection Manual, http://www.niid.go.jp/niid/images/lab-manual/hib-meningitis.pdf).

In Japan, a tetanus toxoid conjugated Hib vaccine (Hib vaccine in short) has been used since December 2008.  Since November 2010, the Hib vaccine to children of less than 5 years of age has been paid by the public under the "Program of accelerated vaccination with cervical cancer and other vaccines".  In April 2013, the immunization act was revised to include Hib vaccine in the routine immunization.  The routine vaccination consists of three shots to children aged two months to less than seven months, which is followed by the fourth booster shot one year after the third shot (see p.199 of this issue).

The antigen determinants are capsular polysaccharides (polyribosylribitol phosphate: PRP) present on the bacterial surface.  Protection from infection is mediated by antibodies against serotype-specific PRP.  The immunogenicity of Hib vaccine is evaluated by ELISA titration of serum anti-PRP IgG or by serum bactericidal assay (SBA), which measures bactericidal activity of serum by using Hib as a target (see p.190 of this issue).

Epidemiological situation:  Until April 2013 when the Enforcement Regulations for the Infectious Diseases Control Law were revised, meningitis caused by H. influenzae had been reported as "bacterial meningitis" together with other bacterial meningitis.  They were reported from about 500 sentinel hospitals in Japan.  Total 347-477 bacterial meningitis cases were reported annually from 2006 to 2010, among which 56-83 were due to H. influenzae (Table 1).  Among the total 400 H. influenzae meningitis cases reported in 2006-2012, 372 cases (93%) were patients younger than 5 years.  Thanks to the public payment of Hib vaccine, the frequency of H. influenzae meningitis decreased to 49 cases in 2011 and to 14 cases in 2012.  The reduction was found mainly among patients younger than 2 years of age (Fig. 1).

After the revision of the Enforcement Regulations for the Infectious Diseases Control Law, invasive infections by H. influenzae, Neisseria meningitidis and Streptococcus pneumoniae became category V infectious diseases, which require reporting of all the cases.  Accordingly, these infections are now excluded from the category of “bacterial meningitis”.

The notification criterion for “invasive H. influenzae infection” (including Hib meningitis) is the case, from whose cerebrospinal fluid or blood H. influenzae is detected by isolation of bacteria or by detection of bacterial DNA (http://www.niid.go.jp/niid/images/iasr/34/401/de4011.pdf).

Table 2 lists 31 invasive H. influenzae infection cases notified under the National Epidemiological Surveillance of Infectious Diseases (NESID) since April 2013 (14^th to 23^rd week).  In Fig. 2 that shows the age distribution, there are two peaks, the one in young children and the other in adults above 60 years of age.  Most cases in the aged group were H. influenzae pneumonia associated with bacteremia.  Three among them died.Capsular type was determined only in one case, which was capsular type b. 

According to the data from 10 prefectures in Japan (Ihara-Kamiya Research Group: “Research on evidence and recommended policies on better use of vaccinations” started in 2007), the frequency of invasive H. influenzae infection per 100,000 population under 5 years of age was 7.7 for meningitis type and 5.1 for non-meningitis type in 2008-2010.  In 2012 the frequency went down to 0.6 for meningitis type (reduction by 92%) and to 0.9 (reduction by 82%) for non-meningitis type (see p. 194 & 195 of this issue).  The similar tendency was noted in the nation-wide surveillance data obtained by Japan Nosocomial Infections Surveillance: JANIS (see p. 197 of this issue).

Emergence of drug-resistant strain:  There are two types of drug resistant H. influenzae strains known, β-lactamase producers and β-lactamase non-producers.  The frequency of the β-lactamase-non-producing ampicillin-resistant (BLNAR) isolate is increasing in recent years (see p. 192 & 195 of this issue), which should be further monitored (see IASR 31: 92-93, 2010; https://idsc.niid.go.jp/iasr/31/362/tpc362.html & IASR 23: 31-32, 2002; https://idsc.niid.go.jp/iasr/23/264/tpc264.html).

Measures to be taken:  Increase of invasive H. influenzae infection caused by non-b type H. influenzae (including NTHi) after introduction of Hib vaccine has been reported in abroad.  In Japan, a meningitis case of H. influenzae capsular type f was reported among those who had received three Hib vaccine shots (see p. 195 of this issue).  Invasive NTHi infections have been reported among infants and adults (see p. 188 & 189 of this issue).  Accordingly, surveillance of invasive H. influenzae infections after introduction of routine immunization of Hib vaccine should be directed not only to Hib itself but also to H. influenzae of other capsular types and NTHi.  Pathogen surveillance of H. influenzae, including capsular type analysis, is planned as an activity of the National Epidemiological Surveillance of Vaccine Preventable Diseases infection source investigation from 2013FY.

 

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The statistics in this report are based on 1) the data concerning patients and laboratory findings obtained by the National Epidemiological Surveillance of Infectious Diseases undertaken in compliance with the Law Concerning the Prevention of Infectious Diseases and Medical Care for Patients of Infections, and 2) other data covering various aspects of infectious diseases.  The prefectural and municipal health centers and public health institutes (PHIs), the Department of Food Safety, the Ministry of Health, Labour and Welfare, and quarantine stations, have provided the above data.

 

 

Enterohemorrhagic Escherichia coli (EHEC) infection is a category III notifiable infectious disease in the National Epidemiological Surveillance of Infectious Diseases (NESID) under the Law Concerning the Prevention of Infectious Diseases and Medical Care for Patients of Infections (Infectious Diseases Control Law).  All the cases must be notified by a physician who has made the diagnosis (http://www.niid.go.jp/niid/en/iasr-sp/2251-related-articles/related-articles-399/3534-de3991.html).  When an EHEC infection is notified as food poisoning by physicians or judged as such by the director of the health center, the local government investigates the incident and submits the report to the Ministry of Health, Labour and Welfare (MHLW) in compliance with the Food Sanitation Law.  Accordingly, there are two related but independent systems of notification, the one in compliance with the Infectious Diseases Control Law and the other in compliance with the Food Sanitation Law.

Prefectural and municipal public health institutes (PHIs) conduct isolation of EHEC, serotyping, and verotoxin (VT) typing and report the result to Infectious Disease Surveillance Center (IDSC) in National Institute of Infectious Diseases (NIID).  The Department of Bacteriology I, NIID conducts molecular epidemiological analysis, whose result is made available through the PulseNet Japan (see p. 139 of this issue). 

Cases notified under NESID:  In 2012 (January-December), total 3,768 EHEC infections, 2,362 symptomatic and 1,406 asymptomatic, were reported (Table 1).  Asymptomatic infections are detected during the active surveillance of outbreaks or regular stool test of cooks.  As in previous years, a large peak of epidemics occurred in summer (see weekly reports summarized in Fig. 1).  The incidence (cases per 100,000 population) was highest in Saga Prefecture (9.21) followed by Okayama (8.71) and Iwate Prefecture (8.14) (Fig. 2, left).  As in previous years, incidence of EHEC infection was highest among the age group of 0-4 years followed by 5-9 year age group (Fig. 3).  When prefectures were compared for the EHEC incidence (cases per 100,000 population) among 0-4 year age group, Okayama, Kagoshima and Miyazaki Prefectures were the highest (Fig. 2, right).  Symptomatic cases were relatively high in young and aged groups and relatively low in population in their 30’s, 40’s and 50’s (Fig. 3).  Total 94 hemolytic uremic syndrome (HUS) cases, corresponding to 4.0% of symptomatic cases, were reported in 2012 (see p. 140 of this issue).  Among 94 HUS cases, EHEC were isolated from 70 cases (the remaining 24 cases were EHEC isolation negative but LPS antibody positive or VT positive).  Among the 70 cases, there were 58 O157, four O111, two O26, two O145 and one each for O25, O165, O174 and O183.  Sixty-six isolates among 70 were positive for VT2 or VT1&2 (94%).  Fifteen fatal cases were reported, among which three were HUS and two EHEC-related encephalopathy. 

EHEC isolated in PHIs:  In 2012, number of EHEC isolates that PHIs reported to the IDSC, NIID, was 1,957, which was far less than the reported number of EHEC infection cases, 3,768 (Table 1).  This discrepancy is due to the current situation where isolates in clinical or commercial settings are not always sent to PHIs.  The most frequent O-serogroup was O157 (53%), followed by O26 (27%) and O103 (5.2%) (see Table on p. 125 of this issue).  Among the O157 isolates double positives for VT1 and VT2 genes were predominant (68%) as in previous years (53-78% in 1997-2011).  Among O26 and O103, 94% and 97%, respectively, were single positive for VT1.  Information on clinical symptoms were available for 973 cases among 1,040 cases of O157.  Major symptoms were abdominal pain (64% of the cases), diarrhea (62%), bloody diarrhea (46%), and fever (21%) (see Table on p. 125 of this issue).

Outbreaks:  In 2012, PHIs reported to IDSC twenty-three EHEC outbreaks, including six outbreaks caused by O157.  Sixteen outbreaks involving ten or more EHEC-positive cases are shown in Table 2.  Five outbreaks were suspected to be food-borne, and ten were suspected for person-to-person transmission.  In 2012, prefectures reported 17 EHEC incidents with 398 symptomatic patients (isolation negative cases included) in compliance with the Food Sanitation Law (25 incidents and 714 patients in 2011).

In 2012, there was an EHEC O157 outbreak caused by lightly pickled vegetables (see pp. 126 & 127 of this issue).  The outbreak mainly affected an elderly facility in Sapporo City, but as the product was distributed to supermarkets, hotels and restaurants as many as 169 persons fell ill and eight died.

Prevention an measures to be implemented:  The basics for preventing EHEC infections are to observe the principles of food poisoning prevention and to avoid consumption of raw or undercooked beef.  In response to persistent food poisonings caused by raw beef, MHLW revised the standards of the beef marketed for eating raw and put it into operation by issuing the MHLW notice No. 321 on October 2011.  Further, upon the detection of EHEC O157 in the inner part of cattle livers, MHLW banned marketing of the cattle liver for eating raw (notice No. 404 in July 2012).  As a consequence, the incidence of O157 cases related to consumption of raw beef or raw cattle liver significantly decreased in one year from 2011 to 2012 (see p. 129 of this issue). 

In response to O157 outbreaks caused by pickled vegetables, MHLW modified the hygiene standards of pickled vegetables (Shoku-An-Kan-Hatsu 1012 No.1, 12 October 2012) (see p. 128 of this issue).

Like dysentery bacilli, EHEC establishes infection even at minute doses and can spread from person to person rather easily.  The year 2012 experienced several EHEC outbreaks in nursery schools (Table 2).  Preventing such outbreaks needs appropriate hygienic practice, such as routine hand washing and sanitary use of children’s padding pools during summer (see “Infection Control Guidelines for Nurseries” revised in November 2012 that recommends confirmation of appropriate concentration of chloride ions and disinfection of water used for swimming baths).

To prevent spread of EHEC within patients’ families, the health center should give full instructions to the families concerning prevention of secondary infections.

Update 2013 :  In 1-15 weeks of 2013, 188 EHEC infections have been reported (Table 1).  As EHEC infection increases in summer season, increased level of vigilance is necessary.

 

The principal symptoms of rubella are fever, rash and lymphadenopathy.  As some cases show only a part of these symptoms and as not a few other diseases show similar symptoms, definitive diagnosis requires laboratory data.  The virus when infecting a pregnant woman within 20 weeks of gestation occasionally　causes congenital rubella syndrome (CRS) in newborns such as cataract, congenital heart disease (very frequently patent ductus arteriosus), hearing loss, low birth weight, thrombocytopenic purpura etc.　 (Note, however,that more than 40% of infected fetuses develop CRS.)  To avoid such consequences, preventive measures including vaccination are necessary (pp. 92, 93, 95 & 97 of this issue). 

The National Epidemiological Surveillance of Infectious Diseases (NESID): Rubella had been a sentinel surveillance infectious disease before 2008, when it was classified as a Category V infectious disease requiring notification of all the cases (IASR 32: 250-251, 2011) (http://www.mhlw.go.jp/bunya/kenkou/kekkaku-kansenshou11/01-05-14-02.html).  

Until recently nationwide epidemics used to occur every five years, e.g., 1982, 1987-1988, and 1992-1993.  Since April 1995 when rubella vaccine to children of both sexes was included in the routine immunization in, no nationwide epidemic has been reported (IASR 21: 1-2, 2000 & 24: 53-54, 2003, https://idsc.niid.go.jp/iasr/24/277/graph/f2771.gif).  The 2004 epidemic was regionally limited but accompanied with estimatedly 39,000 cases.  However, in 2011 after 7 years of silence, rubella cases started to increase (Fig. 1), and reported number during the weeks 1-12 of 2013 exceeded the total number in 2012.  Considering the possibility that some patients failed to consult doctors or to be properly diagnosed, the reported number can be a low estimate (p. 100 of this issue). 

 Large cities reported more cases (Fig. 2 on p. 89) (pp. 101 & 102 of this issue), and the weekly report in 2013 indicated spread of rubella from the Metropolitan areas to its surrounding prefectures (http://www.niid.go.jp/niid/images/idsc/disease/rubella/2013pdf/rube13-13.pdf). 

As for age distribution in 2013, most frequent were those in 30’s (33%) followed by those in 20’s (28%), 40’s (21%), ≥50 years (8.0%), 15-19 years (5.5%) and <15 years (4.8%).  Thus, adults occupied about 90% of the patients.  Among males, the most frequent were those in 20-40’s, while among females the most frequent were those in 20’s (Fig. 3).  Ratio of male patients to female patients was 3.0 in 2012 and was 3.7 in the first 14 weeks of 2013.  The gender ratio appears increasing.  Vaccination history was zero for 29% and unknown for 65% of the total cases. 

CRS was classified as a Category V infectious disease requiring notification of all the cases (http://www.mhlw.go.jp/bunya/kenkou/kekkaku-kansenshou11/01-05-10.html).  Since enforcement of the Infectious Diseases Control Law in April 1999, 27 CRS cases have been reported in Japan (pp. 95 & 97 of this issue), 10 cases from the 2003-2004 epidemic and 8 cases from the 2012 epidemic (Table 1 on p. 89).  Among these incidents, 19 mothers were diagnosed as rubella during pregnancy.  Only one case had a clear vaccination record of the mother.  Eight cases reported from the week 42 of 2012 to the week 12 of 2013 were all infected in Japan and many of them were from prefectures that reported rubella cases at frequencies higher than 10 per million population in 2012. 

Transition of vaccination schedule: The 2012-2013 rubella epidemic that principally affected age groups 20’s-40’s can be explained firstly by vaccination schedule from August 1977 focusing on female students (Group 2 in Table 2 on p. 89) and males born in FY1962-FY1979 were not included in the junior high school immunization.

In 1994, Preventive Vaccination Law was amended to the effect that the mass vaccination was replaced by strongly recommended vaccination on individual basis.  The target population was set to 12-90 months old boys and girls (Group 5 in Table 2).  Male and female junior high school students were given the first chance of vaccination during the period of FY1995-FY2001 (Group 3 in Table 2), but the coverage of this age cohort was low on account of requirement of accompaniment of a guardian for immunization (http://www.mhlw.go.jp/topics/bcg/other/5.html).

In FY2006, the one dose rubella vaccination was replaced by the two dose measles-rubella (MR) combined vaccine immunization, the first at one year of age and the second within 1 year before primary school entrance.  In addition, as a 5 year program from FY2008 to FY2012, the second chance of immunization was given to the children in the first year class of junior high schools and those in the third year class of the high schools.  However, the coverage of the latter cohort was found low in prefectures, which reported higher number of rubella cases (p. 103 of this issue).

Antibody prevalence rate among the population (National Epidemiological Surveillance of Vaccine Preventable Diseases):  Fourteen prefectural public health institutes in Japan jointly surveyed rubella hemagglutination inhibition (HI) antibody level of 5,094 healthy individuals (Fig. 4).  The percentage of antibody positives (HI titer ≥8 HI) was 30% among zero year babies, increased in one year children and attained ≥90% in ≥2 year children. 

Among adults in their 30’s and 40’s, antibody positive rate was 73-86% in males in contrast to 97-98% in females (11-25 point lower in males than in females).  However, there was little　gender gap among people in 20’s and ≥50 years of age (p. 105 of this issue). 

Woman whose antibody level is found lower than HI titer ≤16 in the prenatal checkups are advised to receive MR vaccine on in an earliest occasion after the delivery in preparation to the next possible pregnancy (p. 93 of this issue).

Rubella virus and laboratory diagnosis: There are 13 genotypes specified by the E1 protein coding gene.  In Japan, the dominant genotype including that of the 2004 epidemic was genotype 1j, which was replaced in 2011 by genotypes 1E and 2B of the South-, East- and Southeast-Asia origins (pp. 91, 95, 96, 97 & 99) (http://www.niid.go.jp/niid/en/iasr-rubella-e.html). 

Laboratory diagnosis of rubella consists of virus isolation/identification or PCR detection of viral genome from throat swab, blood or urine specimens from the acute phase patients, detection of IgM antibody in the serum of acute phase, or increase of antibody titer in the serum of recovery phase compared with the acute phase.  Currently, 70-80% of the reported rubella cases are laboratory diagnosed (Fig. 1).  The IgM test, while widely used, often gives false negative data if the specimen is obtained earlier than three days after appearance of rash.  Therefore, PCR test is recommended for earlier diagnosis (pp. 96 & 97 of this issue).  The most sensitive is the PCR test using throat swabs obtained on the next day of the rash appearance.  When the PCR test is done with the blood samples, however, it may become negative several days after appearance of rash. 

HI antibody test uses goose red blood cells.  In case of short supply of goose red blood cells, EIA can be used by converting EIA titer to HI titer by using the conversion table proposed by the Ministry of Health Labour and Welfare (MHLW) working group (pp. 93 & 107 of this issue). 

Challenges in future: MHLW issued a notice “Strengthening Measures for Prevention and Control of Rubella and Congenital Rubella Syndrome” on January 29, 2013 and partially revised on Febuary 26, 2013 (http://www.niid.go.jp/niid/en/iasr-sp/2250-related-articles/related-articles-398/3427-de3981.html).  National Institute of Infectious Diseases and MHLW, supported by　academic societies, made campaign posters for rubella control and sent them to local governments and medical institutions in Japan (http://www.niid.go.jp/niid/ja/rubella-poster2013.html).  

Currently, in order to provide correct information on CRS, consulting services are provided to obstetricians and gynecologists by the Research Group of MHLW (p.93 of this issue).  

Technical Advisory Group to Western Pacific Regional Office of WHO has recommended inclusion of rubella vaccine in the routine immunization particularly to countries which have not yet done so.  It also recommended to maintain the vaccine coverage ≥80% (p. 91 of this issue). 

As of the week 14 of 2013, rubella incidence in Japan was 28 cases per million population, and 8 CRS cases have been reported since October 2012.  As the peak season of rubella is often early summer, the rubella patients are expected to increase from now.  Once pregnant, women cannot receive the live rubella vaccine on account of potential infection to the fetus.  Therefore necessary information including MR vaccination prior to conception should be provided to every woman who is planning to bear a baby and to her husband and family members.  For further improvement of rubella control, it is important to provide adults with chance of receiving rubella vaccine, which may require collaboration with various stakeholders including industry physicians. 

 

Streptococcus pneumoniae is a gram-positive diplococcus causing respiratory infections.  The capsular polysaccharide (CPS) that encapsulates the microorganism is an important virulence factor and, at the same time, the antigenic determinant of the serotype.  Ninety-three serotypes are known.  The complement-dependent opsonization induced by the serotype-specific antibody is the major host defense mechanism. 

Many children carry S. pneumoniae in the nasopharyngeal cavity (see p. 57 of this issue), which often causes otitis media and pneumonia (see p. 58 of this issue).  Most of the adult cases of community-acquired pneumonia are not associated with bacteremia, and S. pneumoniae is responsible for 20-40% of such cases (see p. 59 of this issue).  Once it invades the blood stream, S. pneumoniae causes invasive pneumococcal disease (IPD) (see pp. 61 & 62 of this issue).  IPD is defined as any condition in which S. pneumoniae is present in blood, cerebrospinal fluid or another normally sterile body site.  IPD consists of meningitis and “non-meningitis bacteremia” associated with pneumonia, sepsis, etc. 

Vaccines and serotypes: Two types of pneumococcal vaccines have been approved in Japan, i.e., 23-valent CPS vaccine (PPV23) and 7-valent conjugate vaccine (PCV7).  The antigen contained in PPV23 is CPS, a T-cell independent antigen, which cannot induce memory B cells and is devoid of booster effect upon the second shot.  The antigen contained in PCV7 is CPS conjugated with diphtheria toxin mutant CRM₁₉₇.  It induces serotype-specific (i.e., anti-CPS) IgG antibody even in young children, as it induces antibody production in T-cell dependent manner.

PPV23 obtained the pharmaceutical approval in Japan in 1988.  Previous studies demonstrated that “PPV23 reduced the risk of IPD caused by vaccine serotypes in immunocompetent aged persons” (Jackson LA, et al., Clin Infect Dis 47: 1328-1338, 2008).  More recent studies in Japan demonstrated that PPV23 protected the aged persons from pneumococcal pneumonia and reduced their medical cost (Maruyama T, et al., BMJ 340: c1004, 2010, Kawakami K, et al., Vaccine 28: 7063-7069, 2010). 

PCV7 obtained the pharmaceutical approval in Japan in October 2009.  Since November 2010, when “vaccination promotion program of cervical cancer and other vaccine preventable diseases” started, immunization of PCV7 among children less than 5 years of age has been subsidized by public money. 

According to “Research report on evidence of and measures for improvement of usefulness of vaccination” (Ihara-Kamiya Research Project that started in 2007), incidence of IPD per 100,000 population under the age of five decreased significantly owing to the immunization program.  Namely, meningitis decreased from 2.8 in 2008-2010 to 0.8 in 2012 (decrease by 71%), and non-meningitis IPD from 22.2 to 10.6 (decrease by 52%) (see p. 62 of this issue). 

About 70% of the S. pneumoniae isolates from pediatric IPD cases have been determined for the serotype.  Before the start of the public subsidy, predominant serotypes were 6B followed by 14, 23F and 19A.  Later than April 2011 (about 5 months after the start of subsidy), the order was changed to 19A, followed by 6B, 14, and 23F.  During the same period, serotypes 19A, 15A, 15B, 15C, 22F and 6C that were not included in the antigens of PCV7 increased in proportion and in number (see p. 64 of this issue), while PCV7 serotypes as a whole decreased in proportion (from 78.3% to 44.4%) and in number.  These findings suggest that the serotype replacement occurred within 2 years after the introduction of PCV7. 

National Epidemiological Surveillance of Infectious Diseases (NESID): Surveillance of S. pneumoniae infections has not been conducted as such.  It has been done as surveillance of bacterial meningitis including S. pneumoniae infection (category V infectious disease that requires weekly report from sentinel hospitals*) and penicillin-resistant S. pneumoniae (PRSP) infections (category V infectious disease that requires monthly report from sentinel hospitals*).  For criteria of notification, see http://www.mhlw.go.jp/bunya/kenkou/kekkaku-kansenshou11/01.html. 

 *There are about 500 sentinel hospitals in Japan, which are selected from those equipped with departments of pediatrics and internal medicine and with more 300 beds. 

1) Bacterial meningitis caused by S. pneumoniae: From 2006 to 2012, the total number of reports from sentinel hospitals remained in the same level, 40-60 cases per year, though patients in 2-3 years of age decreased in 2012.  The age of patients is distributed widely from 0 to ≥80 years (Fig. 1). 

 2) PRSP infections: From 2006 to 2011, annual report from sentinel hospitals was around 5,000.  In 2012, it decreased to 3,500 owing particularly to the decrease of patients less than 5 years of age (Fig. 2).  The age distribution was wide from 0 to ≥90 years.  There were two seasonal peaks in May and December every year since NESID of PRSP infections started in 1999 (See Fig. 3, which shows the trend since 2003).  In 2012, when the total annual incidence decreased dramatically, the two peaks disappeared. 

 Laboratory diagnosis:S. pneumoniae is identified by hemolytic pattern on the blood agar (α-hemolysis), bile solubility test, optochin test, etc.  The serotyping is usually done by capsule quellung reaction, but serotyping using multiplex PCR is also useful as a screening method (see p. 67 of this issue).  Quantification of serotype-specific IgG (μg/ml) using ELISA for assaying the humoral immunity and the multiplex opsonization assay (MOPA) for assaying the serotype-specific opsonization activity are available in some research institutes (see p. 66 of this issue).

Therapy: The first choice is penicillin antibiotics.  However, the proportion of PRSP among S. pneumoniae isolates increased from 1985 and reached 63% in 2009.  Eighty-eight percent of S. pneumoniae isolates are now resistant to macrolide antibiotics. However, a high dose of β-lactam antibiotic is effective to most cases of community-acquired pneumonia or of non-meningitis infections caused by PRSP.  A high dose of β-lactam antibiotic in combination with vancomycin is recommended for treatment of meningitis cases caused by PRSP.  

Future Challenges: In March 2013, the government submitted a bill to the Diet to modify the Preventive Vaccination Law to include PCV7, Haemophilus influenzae type b (Hib) and human papilloma virus (HPV) vaccines in the routine immunization.  From April 1 of 2013, “invasive S.pneumoniae infection”, together with “invasive H. influenzae infection”, becomes a category V infectious disease that requires the notification of all the cases.  At the same time, “meningococcal meningitis”, a category V infectious disease that required notification of all the cases will be revised to “invasive meningococcal infection” including non-meningitis meningococcal bacteremia.

Medical institutions, health centers, prefectural and municipal public health institutes, and National Institute of Infectious Diseases should intensify the infectious agent surveillance of S. pneumoniae including serotyping. 

WHO Western Pacific Region to which Japan belongs targeted measles elimination by 2012 (see p. 24 of this issue).  The current verification criterion of measles elimination of the Region is “the absence of endemic measles transmission* of endemic virus for more than three years in the presence of a well performing surveillance system, which is supported by genotype analysis of the isolates.” 

*Endemic measles transmission is defined as “the existence of continuous transmission of indigenous or imported measles virus that persists for ≥12 months in any defined geographic area” (WHO, WER, 85: 490-495, 2010). 

Measles incidence under the National Epidemiological Surveillance of Infectious Diseases: Infectious Diseases Control Law requests notification of all measles cases since January 2008 (IASR 29: 179-181, 2008 & 29: 189-190, 2008).  From week 1 to week 52 of 2012, total 293 cases were reported, among which 216 cases including 75 “modified” measles were supported by laboratory diagnosis but 77 cases were supported by clinical diagnosis (as of January 8, 2013).  In 2012, measles cases were reduced to 2/3 of those in 2011 (from 434 cases or 3.58 per million population in 2011 to 293 cases or 2.32 per million population in 2012) (Fig. 1). 

In 2012, the largest number of measles cases were reported from Tokyo (84 cases) followed by Aichi (39 cases), Saitama (32 cases), Kanagawa (29 cases) and Chiba (23 cases).  The total cases in four prefectures within the metropolitan area, Tokyo, Saitama, Kanagawa and Chiba, occupied 57% of all the reported cases. Twenty-one prefectures reported zero cases (Fig. 2 in p. 23), among which 12 prefectures reported zero cases in successive two years (see p. 37 of this issue).  In 2012, 32 prefectures, in contrast to 19 prefectures in 2011, reported <1/million population, the target as a measure of near measles elimination (WHO, WER 85: 490-495, 2010).

The sex ratio was 158 males vs. 135 females.  As for age distribution (Fig. 3), one year olds were the highest in number (29 cases) followed by zero year olds (16 cases).  The teens that occupied 43% of the total in 2008 occupied only 13% in 2012.  In contrast, 20s and 30s increased in proportion, and as a consequence adults occupied 58% of the total measles cases in 2012.

Among the measles patients, 84 had received no dose, 78 only one dose and 17 two doses.  The vaccination history of the remaining 114 was unknown.  The all 16 zero-year-old cases had received no vaccination.  Among 29 one-year-old cases, 15 had received no dose and 13 only one dose.  Among the 132 cases in their 20s and 30s, 22 had received no dose, 35 only one dose and 3 two doses.Two schools, a primary school and a secondary school, temporarily closed in September 2012 in Miyazaki Prefecture on account of measles outbreaks (see p. 33 of this issue).

Isolation and detection of measles virus: The measles virus genotype D5 that had been endemic in Japan during 2006-2008 has not been detected later than May 2010.  Since 2009, measles viruses whose genotypes are those of foreign-origin were detected (Table 1 and Table 2 in p. 23).  In 2012, 45 D8 strains were isolated, among which 24 were derived from an outbreak in Aichi (IASR 33: 66, 2012) and 8 were from an outbreak in Miyazaki (see p. 33 of this issue). Other isolates were 10 D9 strains, among which 5 were from an outbreak in Okayama (IASR 33: 166-167, 2012); 7 H1 strains, among which 5 were from an outbreak in Fukushima (IASR 33: 242-244, 2012); and 6 D4 strains, which were all from sporadic cases.

The National Epidemiological Surveillance of Vaccine-Preventable Diseases (see p. 25 of this issue): WHO considers that measles elimination requires 95% population immunnity against measles virus in each birth cohort.  In Japan, gelatin particle agglutination (PA) assay is conducted and the titers above 1:16 are considered positive.  In 2012, the antibody-positive rate became ≥95% in all the age groups ≥2 years for the first time, which proved effectiveness of the two routine doses (Fig. 4).  However, as the antibody-positive rate in 1-year age group was 67%, earliest vaccination after attaining 12 months of age is desired.

It has been considered that protection of individuals from symptomatic measles infection requires titer 1:128 or higher.  However, the antibody titer of more than 15% of age groups of 0, 1, 4 and 5 years was less than 1:128.

Vaccination rate (see p. 28 of this issue): Since FY2006, routine immunization in Japan has adopted measles-rubella combined vaccine, which is administered in two doses, the first dose to children of one year (1st vaccination) and the second dose to children preceding one year before the school entry (2nd vaccination)(IASR 27: 85-86, 2006).  In addition, from 2008 to 2012, supplementary vaccination was conducted to children whose age corresponds to the age of the first year class of the secondary school (3rd vaccination) and to those whose age corresponds to the age of the third year class of the high school (4th vaccination) to ensure two doses in these age groups too (IASR 29: 189-190, 2008).

The vaccination rate of measles-containing vaccines (M, MR) in FY2011 was 95% for the 1st (96% in 2010), 93% for the 2nd (92% in 2010), 88% for the 3rd (87% in 2010) and 81% for the 4th (79% in 2010).  The coverage of the 1st vaccination exceeded 95% (targeted coverage rate) successively in 2011 and in 2012.

For further increase of vaccination coverage: Consequent to the introduction of the 3rd and 4th vaccinations, there was a great reduction of measles cases under 20 years of age (Fig. 3).  So as to achieve the measles elimination, local governments are requested to make further efforts to attain ≥95% vaccine coverage not only for 1st but also for 2nd, 3rd and 4th vaccination.  According to the questionnaire-based survey destined to municipalities, towns and villages, which was conducted by a research group supported by Ministry of Health Labour and Welfare (MHLW), factors that played an important role in attaining coverage ≥95% were (1) timely reporting on the vaccine coverage in the community level, (2) identification of unimmunized children so as to recommend each unvaccinated child to go to vaccination by mail and (3) preparatory health check conducted in October and November in previous year of the school entry, where immunization is recommended to children with insufficient vaccine doses (see p. 31 of this issue).

Unvaccinated persons belonging to target cohorts of the 2nd, 3rd and 4th vaccinations in FY2012 are advised to be vaccinated before March 31, 2013, as public expense will not cover the vaccination after this date.  During “the Children’s Immunization Week”, from March 1 (Friday) to March 7 (Thursday) in 2013, some local medical association will open clinics on Saturday, Sunday and evenings for vaccination.  The eligible persons are advised to be vaccinated at the earliest occasion before the end of March this year.

Importance of laboratory diagnosis: In 2012, one fourth of the notified cases were diagnosed by symptoms without laboratory confirmation.  More than half of the laboratory diagnosis was based on IgM tests.  Measles cases weakly positive for IgM or clinically suspected measles are often cases infected by rubella virus, B19 virus, HHV-6, HHV-7, enteroviruses, etc, which occasionally develop skin rash (see p. 34 of this issue).  Therefore, direct detection of measles virus genome, such as by PCR or virus isolation, is important.  Prefectural and municipal public health institutes (PHIs) and National Institute of Infectious Diseases (NIID) have established the collaboration network for laboratory diagnosis based on PCR testing.  In 2011-2012, 40% of the laboratory-diagnosed specimens were PCR-tested by PHIs (see p. 36 of this issue).  Physicians are requested to obtain clinical specimens in appropriate timing and the person in charge of transportation should keep the samples under the appropriate temperature.  The PHIs should observe the required temperature control of the received specimens during the storage and testing (IASR 33: 309-310, 2012).

Measures to be taken from now: In 2012, the “foreign strains” were isolated not only from the imported cases but also from sporadic cases without history of overseas travel (Table 2 in p. 23, see p. 36 of this issue and http://www.niid.go.jp/niid/en/iasr-measles-e.html).  For measles elimination, important are maintenance of high vaccine coverage and a system that allows tracing of an outbreak back to the infection source and immediate interruption of virus transmission.  The principle of “immediate response to any one measles-suspected case” should be applied to all the cases.  The response includes active epidemiological investigation supported by laboratory and prompt measures against virus spread, which requires coordination between medical facilities, health centers, PHIs and NIID.  So as to prevent importation, people including adults are advised to complete measles vaccination before going abroad.  It is also important to conduct a vaccination campaign to those going abroad.

Japanese government recently revised the “Special Infectious Disease Prevention Guidelines on Measles (MHLW, December 28, 2007)”.According to the revised guidelines adopted in April 2013, Japan targets elimination of measles by FY2015 to obtain WHO’s certificate of measles elimination and projects maintenance of the measles elimination status thereafter.  According to the Guidelines, a measles elimination verification committee will be established (see p. 39 of this issue).  Cases notified by a physician will be examined for clinical symptoms, laboratory findings, vaccine histories, and possibility of contact with measles patients.  If the possibility of measles is excluded as a consequence, the doctor in charge will be requested retraction of the notification.  In order to prove measles elimination status, it is imperative to obtain clinical specimens in timely manner and to examine the possibility of endemic circulation through genotyping.