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The topic of This Month Vol.36 No.2(No.420)

Syphilis 2008-2014

(IASR 36: 17-19, February 2015)

Syphilis is a bacterial infectious disease caused by Treponema pallidum.  T. pallidum is a highly motile spirochete bacterium sized 0.1-0.2 μm in diameter and 6-20 μm in length.  It can be observed microscopically by staining or by using dark field microscopy. The pathogenicity of T. pallidum has not been fully elucidated.

In Japan, notification of all detected syphilis cases began in 1948 under the Venereal Diseases Prevention Law.  In April 1999, syphilis was classified as category V notifiable infectious disease under the Infectious Diseases Control Law.  A physician who diagnoses a syphilis case must notify it to the nearby health center within 7 days (see http://www.niid.go.jp/niid/images/iasr/36/420/de4201.pdf for notification criteria).

Routes of infection and clinical manifestations:  Generally, the infection is acquired through sexual contact with a person in the early stage of syphilis.  Transmission occurs when T. pallidum present in lesion exudate penetrates the skin through mucous membrane or damaged skin.  Placental infection of a fetus from the infected mother causes abortion, stillbirth or congenital syphilis.  There is no evidence of transmission of syphilis through breast-feeding.

Three to six weeks after infection, an infected person usually develops initial sclerosis and hard chancres at the infected sites (primary symptomatic syphilis).  During the latency period of a few weeks to months that follows, the bacteria spreads via blood circulation, and the infection becomes generalized giving rise to rashes appearing on the skin or on the mucous membrane (secondary symptomatic syphilis).  Primary and secondary symptomatic syphilis are collectively called “early symptomatic syphilis”.  A few years to some decades after infection, gummas, cardiovascular and/or neurological symptoms characteristic of “late symptomatic syphilis” appear. Infected persons are often asymptomatic during the period between the early and late symptomatic phases, which often results in delayed diagnosis and treatment.

Congenital syphilis consists of early and late congenital syphilis.  Early congenital syphilis is characterized by development of skin lesions, hepatosplenomegaly and osteochondritis, shortly after birth.  After a latent period without clinical manifestations, late congenital syphilis, characterized by development of Hutchinson’s triad, parenchymatous keratitis, inner ear deafness and Hutchinson teeth, appear during childhood.

Laboratory diagnosis and therapy:  Laboratory diagnosis consists of direct identification of the causative agent, T. pallidum, under an optical microscope and/or detection of antibodies against Treponemal antigen or cardiolipin antigen (see p. 20 of this issue). PCR detection of the bacterial genome from skin lesions is used as a test to supplement the antibody tests when the patients have yet to seroconvert (see p. 21 of this issue).  Penicillin is the first choice for therapy, and no penicillin-resistant strains have been yet reported.

National Epidemiological Surveillance of Infectious Diseases:  The law governing surveillance of syphilis was switched from the Venereal Diseases Prevention Law to the Infectious Diseases Control Law in April 1999 (indicated by an asterisk in Fig. 1). Overall, the number of reported syphilis cases continuously decreased from 1948 until 2010, though with slight fluctuations (Fig. 1). Since 2010, however, notification has been on the rise (Fig. 1).  The total number of reported syphilis cases in 2008-2014 was 6,745, which consisted of 5,262 males and 1,483 females (as of 15 January 2015).  Among them, 3,740 were early symptomatic syphilis (1,290 primary and 2,450 secondary; average annual notification rate: 0.42 per 100,000 population), 399 late symptomatic syphilis, 2,567 asymptomatic syphilis, and 39 congenital syphilis (Table 1).  The average annual notification rate of total syphilis cases in 2008-2014 was 0.75 per 100,000 population.  Cases from Tokyo, Osaka, Aichi, Kanagawa and Fukuoka prefectures occupied 62% of cases (Table 2 in p.19).

Fig. 2 shows the age distribution of cases.  The age distribution of early symptomatic syphilis showed a broad range from 20 years to 44 years.  Among the early symptomatic syphilis cases, the number of male patients in their 20’s-40’s increased from 2012 to 2014, while the number of female patients, particularly in their 10’s-20’s, doubled from 2013 to 2014 (Fig. 3 left).  The number of early symptomatic syphilis cases under the age of 18 years was 57 from 2008 to 2014 (14, 4, 5, 4, 6, 10, and 14 in respective years); among them 21 were males and 36 females.  As for transmission routes, among males, there was a notable increase in cases associated with homosexual contact since 2008, though heterosexual contact have also been increasing; among females, the main transmission route was heterosexual contact (Fig. 3 right).

In 2014, the incidence of congenital syphilis (per 100,000 live births) was 1.0, which was the highest in the last 7 years (Table 1).  From 2008 to 2013, the annual incidence was 0.8, 0.5, 0.1, 0.6, 0.4 and 0.4 per 100,000 live births, respectively (birth data derived from Vital Statics, the Ministry of Health, Labour, and Welfare’s demographic survey; 2014 data based on tentative estimate).

Reported number of asymptomatic syphilis increased, which was detected during such times as clinical consultations on ailments related to other sexually transmitted diseases, blood testing before blood donation, prenatal checkups, and laboratory tests before surgical operations (Table 1).

Prevention and control:  Frequent sexual contact with casual partners, particularly without using condoms, is a high risk behavior.  Genital ulcers caused by syphilis increase the risk of infection by other sexually transmitted diseases including HIV.  The co-infection of HIV and syphilis enhances the progress of both infections (see p. 22 of this issue).  Infection through blood transfusion, which was a serious problem in the past, has almost disappeared owing to the advancement of blood screening technology.  Needle-stick injury- or laboratory-acquired infection risks persist, however.

The risk of congenital syphilis increases when a fetus is infected after the formation of placenta, i.e., the 16th week of gestation.  It is therefore important to instruct expectant mothers to receive a syphilis test in the early stage of pregnancy, and receive appropriate therapy if she is found to be infected.  It is also important that women take measures to prevent syphilis infection during pregnancy (IASR 34: 113-114, 2013). 

In recent years, increase in asymptomatic and early symptomatic syphilis have been reported not only in Japan but also from abroad (see p. 24 of this issue).  Providing young and sexually active people with appropriate information is a crucial public health measure.  Such information should include: (i) transmissibility of syphilis through oral or anal sex (see p. 23 of this issue); (ii) absence of life-long immunity to syphilis; and (iii) progression of the disease when the infected are not treated during the asymptomatic phase between the early and late symptomatic phases.  Physicians who have diagnosed syphilis should not only notify and treat the case but also educate and/or test his/her sexual partner(s).  National guidance on the prevention of sexually transmitted infections emphasizes the importance of early detection and early treatment as effective measures for preventing infection and spread of sexually transmitted diseases.


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The topic of This Month Vol.36 No.1(No.419)

Hepatitis A in Japan, 2010-2014, as of November 2014

(IASR 36: 1-2, January 2015)

Hepatitis A is an acute infectious disease caused by hepatitis A virus (HAV), which belongs to genus Hepatovirus of Picornaviridae.  There is only one serotype known, which is classified into 6 genotypes, I-VI.  Genotypes I-III have been detected from man so far, with each of these genotypes further grouped into A or B.  HAV is shed via the infected person’s stool, and spreads fecal-orally through contaminated food or water causing occasionally large outbreaks.  According to the WHO Fact Sheet (N° 328, June 2014, http://www.who.int/mediacentre/factsheets/fs328/en/), globally an estimated 1.4 million hepatitis A cases occur each year.  The improved water supply and sewage system, along with improved environmental hygiene, have greatly reduced the number of large-scale HAV outbreaks in developed countries.  Nevertheless, Japan continuously reports more than 100 HAV infections per year (Fig. 1).

HAV infection is a category IV infectious disease under the Law Concerning the Prevention of Infectious Diseases and Medical Care for Patients of Infectious Diseases (the Infectious Diseases Control Law) amended in November, 2003.  All diagnosed cases, including asymptomatic carriers, must be notified.  The notification criteria are found in http://www.niid.go.jp/niid/images/iasr/36/419/de4191.pdf.

The incubation period is 2-6 weeks (average of 4 weeks).  Early clinical signs and symptoms include high fever (38°C or above), general malaise, headache, anorexia, myalgia, and abdominal pain, which is followed by appearance of signs characteristic of hepatitis, such as jaundice and hepatomegaly.  Fulminant type or death is rare, though its frequency increases with age particularly among those with no anti-HAV antibody.  The prognosis is generally good (case fatality rate <0.5%); it does not becomes chronic and patients recover in 2-3 months.  No specific therapeutics are available and patients are kept in rest and treated symptomatically.  Among children under five years of age, 90% are asymptomatic.  Among adults, 90% are symptomatic and 60% among them develop jaundice.  Once infected, symptomatically or asymptomatically, life-long immunity is acquired. 

HAV infected cases release virus from 1 week after infection to several months after the onset, during which time they remain as the infectious source.

National Epidemiological Surveillance of Infectious Diseases
HAV epidemiology in Japan used to display seasonality with the high season during winter to spring (January-May).  With reduced notifications since 2004, the clear seasonality has become restricted to peak years (see IASR 31: 284-285, 2010 for data before 2004).

From 2004 to 2014, there were three such years, 2006, 2010 and 2014, which respectively reported 320, 347 and 421 (as of week 48) cases; number of reported cases during other years during this period ranged from 115-176 (Fig. 1).  During 2010 to 2014 (as of week 48), twenty asymptomatic cases (ranging from 2 to 6 cases per year) and six fulminant hepatitis cases (ranging in age from 56-67 years) were reported.

Suspected place of infection:  There was no regional clustering of the hepatitis A cases (Fig. 2).  The majority of patients (80%) were infected in Japan, though there were also annually 40-50 cases infected abroad (Table 1).  Among 228 patients suspected to have been infected abroad, reported travel countries included the Philippines (n=34), India (n=33), Pakistan (n=17), the Republic of Korea (n=14) and Indonesia (n=12).

Suspected route of infection:  Among 1,229 cases that were notified from 2010 to the 48th week of 2014, 987 were attributed to foodborne routes, among which 41% (405/987) were due to ingestion of contaminated oyster or other shellfish and seafood products.  The infection source was unknown for 49% (486/987) of cases.  There were 9 cases suspected of transmission via sexual routes.

Sex and age distribution of cases:  As shown in Fig. 3, 59% (723/1,229) of cases were male and 41% (506/1,229) female.  The cases’ age distribution ranged broadly from 20 to 60 years, with a large proportion of cases occurring among those 40-64 years of age, particularly among males.  The median age of cases has been rising; from 41 years in 2000, 44 years in 2004, 47 years in 2010, and 49 years in 2014 (as of week 48).

Laboratory diagnosis and detected genotypes:  Laboratory confirmation of cases notified from 2010 to the 48th week of 2014 consisted of IgM antibody detection (1,205 cases, 98%) and HAV genome detection by PCR (105 cases, 9%) (some cases were tested for more than one method).  Specimens used for PCR detection were stool (65 cases), blood (38 cases) and both stool and blood (2 cases).  Among 333 cases reported to the Infectious Agents Surveillance Report (IASR), 175 cases were genotype IA (as of 8 December 2014) (Table 2).The proportion of cases that were genotyped increased remarkably since 2012.

Epidemiologic situation in 2014
Concerned by the sudden increase of HAV cases in February 2014, the Ministry of Health, Labour, and Welfare (MHLW) issued a note “Trends in hepatitis A infections and a warning regarding the hepatitis A epidemic” on 14 March 2014.  MHLW asked the local governments, according to the notice on 26 April 2010 (IASR 31: 140, 2010) to ensure collection of stool specimens from notified cases for molecular epidemiological investigations and to conduct active surveillance.  National Institute of Infectious Diseases (NIID) and prefectural and municipal public health institutes (PHIs) jointly genotyped HAV specimens obtained from 159 cases in 2014, and found that 137 cases were IA, 18 cases IIIA, and 4 cases IB (see pp. 3 to 7 of this issue).  Seventy-five percent of the IA type isolates obtained, ranging from Miyagi prefecture in the north to the southern prefecture of Kagoshima, shared almost identical nucleotide sequences, which was named “2014 Japan epidemic strain (2014JapanEPM)”.  As the “2014JapanEPM” gave false negative results when assayed by using the real-time PCR method described in the HAV detection manual (August 2006), conventional RT-PCR or a real-time PCR using modified primers is now recommended (see p. 7 of this issue, IASR 35: 154-156, 2014).

Preventive measures
Special attention should be paid to the fact that HAV is resistant to acid or drying, and cases’ discharges and foods contaminated by HAV should be handled with care.  Implementation of hand washing and other hygienic practices, sufficient heating of foods (85°C for at least 1 minute), and disinfection using chlorine agents are indispensable for interrupting transmission.

Long-term protection against hepatitis A can be achieved by three shots of the available vaccine.  Inactivated HAV vaccine produced in Japan had been used for vaccinating adults (16 years of age or above) on a voluntary basis, but since March 2013, voluntary vaccination was expanded to children younger than 16 years of age (see p. 10 of this issue).  The vaccination, though voluntary, is strongly recommended for those with higher risk of HAV infection, such as long-term travelers going to HAV endemic areas, medical practitioners with a high chance of coming in contact with HAV patients, people with underlying chronic hepatic disease(s) without HAV antibody, and men who have sex with men.

According to the 2003 national serological survey, while more than 70% of the Japanese population aged 70 years or older have anti-HAV antibody, almost none of those 50 years or younger have immunity (https://idsc.niid.go.jp/iasr/31/368/graph/df36811.gif).  Therefore, a large proportion of the Japanese population is at risk of HAV infection.  Among reported cases, an estimated 10% of the HAV infections occurred among household members (does not necessarily mean person-to-person transmission and may include exposure to a common infection source) (see p. 8 of this issue).  Due to HAV’s long incubation period, identifying the infection source or route is difficult, but using molecular epidemiology tools are helpful for analysis (IASR 32: 78-79, 2011; and IASR 34: 311-312, 2013).  Due to long-term shedding of the virus, notification of cases and information-sharing among medical institutions, health centers, PHIs and NIID is important for interrupting HAV transmission.


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The topic of This Month Vol.35 No.12(No.418)

Carbapenem-resistant Enterobacteriaceae Infection, Japan

(IASR 35: 281-282, December 2014)

Carbapenem-resistant Enterobacteriaceae (CRE) is a group of Enterobacteriaceae, such as Escherichia coli and Klebsiella pneumoniae that are resistant to both carbapenems and broad-spectrum β-lactams.  CREs cause respiratory tract infections such as pneumonia, urinary tract infections, surgical site infections, catheter-related bacteremia, sepsis and meningitis. While more common among immune compromised patients, postoperative patients or patients treated with antimicrobials for an extended period of time, CREs may also cause infection in otherwise healthy patients.  CREs are often the cause of nosocomial infections.

So far in Japan, the prevalence of CRE has been relatively low.  For example, in 2013, meropenem-resistant isolates occupied less than 1% of the various representative Enterobacteriaceae bacteria isolates (Table 1).  Meanwhile, in many other countries, the proportion of carbapenem resistance is increasing, and in the United States, 10.4% of the isolates belonging to the genus Klebsiella were carbapenem-resistant [MMWR, 62(9): 165-170, 2013].  The World Health Organization (WHO) considers strengthening the surveillance of antimicrobial resistance as a critical priority for member states (WHO, Antimicrobial resistance: global report on surveillance 2014, http://www.who.int/drugresistance/documents/surveillancereport/en/).

Carbapenem resistance mechanisms
Mechanism of carbapenem resistance includes production of various carbapenemases, production of AmpC type or extended-spectrum β-lactamases combined with mutation(s) resulting in the decreased permeability of the cellular membrane (see p. 283 of this issue).  Carbapenemase-producing bacteria are clinically important as they are often resistant not only to broad-spectrum β-lactams but also to other classes of antimicrobials (see p. 284 of this issue).

Carbapenemase producers isolated in Japan are mostly of IMP genotype (see p. 285 of this issue), which can be easily detected by the sodium mercaptoacetic acid (SMA) disk method widely used in medical facilities in Japan.  Isolates abroad, however, carry carbapenemases of NDM, KPC, or OXA-48 genotypes, whose detection requires use of methods other than SMA disk method (see p. 285 of this issue).  As nosocomial infections due to CRE are more frequent abroad, patients who were treated in foreign medical facilities should be investigated for possible carriage of CREs so as to prevent the spread from such imported cases in Japan (see p. 287 of this issue, IASR 35: 200-201, 2014, IASR 34: 237-238, 2013 and IASR 34: 238-239, 2013).

National Epidemiological Surveillance of Infectious Diseases–reporting criteria and current trends
CRE infection is a category V infectious disease under the Infectious Diseases Control Law.  Physicians who make the diagnosis of CRE infection must notify all cases (see http://www.niid.go.jp/niid/images/iasr/35/418/de4181.pdf for reporting criteria).  Only infections determined to be caused by CRE are notifiable; asymptomatic CRE carriers are not.  For determining carbapenem resistance, resistance to meropenem or resistance to both imipenem and cefmetazole are methods currently used (Table 2).  Among them, use of meropenem is most recommended on account of its sensitivity and specificity (IASR 35: 156-157, 2014).  Imipenem resistance was included in the reporting criteria because imipenem has been widely used as an indicator in the clinical setting.  However, in order to exclude those that are resistant to imipenem but susceptible to other cephem antimicrobials and do not produce carbapenemase (e.g. Genus Proteus), reporting is limited to those resistant to both imipenem and cefmetazole.

Since compulsory reporting of all cases started in week 38 (19 September 2014), 113 CRE infection cases were notified through week 44, among whom 66 were male and 47 female (see p. 288 of this issue).  The age of the patients ranged from 0 year to 97 years; among them 88 (78% of all the cases) were aged 65 years or above (Figure).  CRE was isolated from 47 (42%) aseptic specimens, such as blood, ascites, and cerebrospinal fluid; the isolation was most frequent from blood (n=27).

Among 113 cases, 109 cases were reported as domestically acquired and one case abroad.  Twenty three cases were considered as healthcare-associated infections, such as infection due to medical devices or surgical site infections.  Among 113 cases diagnosed as CRE infection, 31 cases were based on resistance to meropenem, 41 cases by resistance to both imipenem and cefmetazole and 39 cases based on both methods.

Half of the reported CRE cases were infections by Enterobacter spp. (Table 3).  Most carbapenem resistance of Enterobacter spp. was not due to production of carbapenemases but rather due to production of class C β-lactamase associated with reduced cellular membrane permeability.  The current practice of notifying carbapenemase non-producing bacteria resistant to broad-spectrum β-lactams is being reviewed with regards to implications for public health.

Horizontal gene transfer and nosocomial infection
In most cases, the carbapenemase gene is found on plasmids.  It is transmitted to other bacteria belonging to Enterobacteriaceae by conjugation or other horizontal gene transfer mechanisms.  Some Enterobacteriaceae bacteria possessing carbapenemase gene may be phenotypically susceptible to carbapenems.  Such bacteria may become carbapenem-resistant through elevated expression of the drug resistance gene(s) or through cellular membrane change and capable of transmitting the resistance gene(s) to other bacteria of other species.  As such events may go unnoticed, such possibilities should be kept in mind for surveillance.  In fact, dissemination of the carbapenem resistance gene to multiple bacteria species in the clinical setting has already been reported (see pp. 289 & 290 of this issue).

Asymptomatic CRE carriers are not rare.  Although they are not notifiable, if they are hospitalized and a nosocomial outbreak is suspected, such carriers should be reported to health centers according to the notice issued by the Director of Guidance of Medical Service Division, Health Policy Bureau, Ministry of Health, Labour and Welfare (17 June 2011: Isei-shi-hatsu 0617 No.1), and necessary measures taken promptly with assistance of an existing local network of medical institutions.  Though this notice will be updated soon, the requirements for notification will remain unchanged.  If genotyping or further analysis of resistance gene(s) is deemed necessary for infection control purposes, research institutes, including the National Institute of Infectious Diseases, should be consulted.


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The topic of This Month Vol.35 No.11(No.417)

2013/14 influenza season, Japan

(IASR 35: 251-253, November 2014)

In the 2013/14 season (from week 36/September of 2013 to week 35/August of 2014), influenza A(H1N1)pdm09 (AH1pdm09) became the main strain for the first time in past 3 seasons; other epidemic strains were influenza virus type B followed by the subtype AH3.  The number of patients reached the peak in January as usual.

Incidence of Influenza patients:  Under the National Epidemiological Surveillance of Infectious Diseases (NESID), 5,000 influenza sentinels (3,000 pediatric and 2,000 internal medicine clinics) report influenza cases at weekly basis (http://www.niid.go.jp/niid/images/iasr/34/405/de4051.pdf).  The number of patients/week/sentinel (epidemic index) exceeded 1.0 in the national level (a sign of start of the epidemic season) in week 51 of 2013 and the level was maintained for 21 weeks till week 19 of 2014 (http://www.niid.go.jp/niid/en/10/2096-weeklygraph/2572-trend-week-e.html).  The epidemic reached its peak in week 5 of 2014 with the incidence of 34.4 cases/sentinel (Fig. 1), whose level was the same as that of the previous season (36.4 per sentinel in week 4 of 2013).  The total number of patients per sentinel for the whole season was 301.0 (239.0 in 2012/13 season).

In prefecture levels, the epidemic index exceeded 10.0 first in Okinawa in the 1st week of 2014.  The number of prefectures with the epidemic index exceeding 10.0 increased to 30 in week 3 of 2014 and to 47 all prefectures in week 5, and then the influenza epidemic expanded nationwide.  In 2013/14 season, Okinawa Prefecture didn’t experience the summer season influenza that occurred every year since 2005 (see p. 262 of this issue).

The total number of influenza patients visiting medical institutions, which was estimated from sentinel reports, was about 15,720,000 from week 36 of 2013 to week 21 of 2014 (September 2, 2013-May 25, 2014).

The hospitalization surveillance started in September 2011 for estimating number of severe influenza cases.  According to its report, total 9,905 patients were hospitalized in about 500 “designated hospital sentinels with ≥300 beds” in this season.  The number of hospitalized patients was 5% less than in the previous season (10,373 in 2012/13) (see p. 261 of this issue).

Isolation/detection of influenza virus:  In 2013/14 season, the prefectural and municipal public health institutes (PHIs) reported total 8,230 isolation/detections (6,345 isolations and 1,885 detections without virus isolation) (Table 1).  Among them, 6,738 were reported from influenza sentinels and 1,492 from elsewhere (Table 2 and see p. 258 of this issue).

Influenza virus isolated/detected in the 2013/14 season consisted of AH1pdm09 (43%), subtype AH3 (21%) and type B (36%). AH1pdm09 became dominant for the first time since 2010/11 season.  Among type B viruses, ratio of Yamagata lineage to Victoria lineage was 7:3 (Table 1).  The subtype AH3 reached the peak in week 4 of 2014, and then declined.  Type B exceeded type A in week 10 of 2014 (Fig. 1; Fig. 2).  The peak age was 5-9 years both for AH1pdm09 and type B Yamagata lineage (Fig. 3 and see p. 258 of this issue).

Antigenic characteristics of the 2013/14 season isolates and their drug resistance (see p. 254 of this issue):  National Institute of Infectious Diseases conducted detailed antigen analysis of isolates from Japan and other Asian countries.  All of the 255 AH1pdm09 isolates, except one antigen variant, were antigenically similar to the vaccine strain A/California/7/2009.  All of the 244 subtype AH3 isolates were antigenically similar to the vaccine strain A/Texas/50/2012.  All of the 163 Yamagata lineage isolates were all antigenically similar to vaccine strain B/Massachusetts/02/2012; among them 28% of the isolates belonged to the clade 2 genetic type (same as 2013/14 season vaccine strain), and 72% to the clade 3 genetic type (represented by B/Wisconsin/1/2010, a 2012/13 season vaccine strain).  All of the 104 Victoria lineage isolate were antigenically similar to the vaccine strain B/Brisbane/60/2008.

Among 2,524 AH1pdm09 isolates in Japan, 105 isolates (4.2%) had the H275Y mutation, a marker of the oseltamivir/peramivir resistance.  Sapporo City in Hokkaido experienced a local epidemic of the H275Y mutant from November 2013 to February 2014; as a consequence, the mutant occupied 28% of all the isolates in Hokkaido.  So far tested, subtype AH3 and type B isolated in Japan were all sensitive to oseltamivir, zanamivir, peramivir, and laninamivir.

Immunological status of Japanese population (see p. 264 of this issue):  According to the sero-surveillance conducted under the National Epidemiological Surveillance of Vaccine-Preventable Diseases (FY2013), among 6,571 sera collected before the 2013/14 season (from July to September in 2013), the HI antibody positives (≥1:40) to A/California/7/2009[A(H1N1)pdm09] were ≥70% in the population in their teens and early twenties, and 20-30% among population younger than 4 years or older than 55 years.  The population HI antibody positive to A/Texas/50/2012 [A(H3N2)] was around 40-50% or more in all the age groups except age group <4 years and 60-64 years whose antibody positive rate was relatively low (~30%).  Antibody positives to B/Massachusetts/ 02/2012 (B Yamagata lineage) occupied >50% among population aged 15-29 years (highest among 20-24 year olds) and ~10% among the population younger than 4 years.  The percentage of the antibody positives to B/Brisbane/60/2008 (B Victoria lineage) was the highest (~50%) among population aged 35-44 years, and ~20% among <4 year and 60-64 year aged groups.

Influenza vaccine:  The quantity of trivalent vaccines produced for 2013/14 season was 33,880,000 vials (1ml/vial), of which estimated 25,810,000 vials were used.

The vaccine strain selected for 2014/15 season for the AH1 subtype was A/California/7/2009pdm09 (X-179A) which was the same as for 2010/11-2013/14 seasons, whereas the vaccine strain for AH3 was changed to A/New York/39/2012 (X-233A) strain.  The vaccine strain for type B was B/Massachusetts/2/2012 (BX-51B) (Yamagata lineage) as in 2013/14 season (see pp. 267 & 269 of this issue).

Avian influenza A(H7N9):  In China, influenza virus A(H7N9) broke out late in March 2013.  So far, total 454 confirmed cases including 171 deaths have been reported.  The epidemic consisted of two waves, the second wave (since October 2013) being larger in scale than the first (before October 2013).  The number of patients in the second wave was 318 and that of deaths 127 (see p. 271 of this issue).

The avian influenza H7N9 was classified as “designated infectious disease” on 26 April, 2013 in Japan.  Its laboratory diagnosis is now possible in 74 PHIs and 16 quarantine laboratories in Japan.  All the laboratories have already received the H7N9 detection manual and the test kits (reagents for PCR tests, primers, probes, and a positive reference, etc.).

Avian influenza A(H5N1):  In 2014, total 13 cases including 6 deaths (9 cases including 4 deaths in Cambodia; 2 cases and zero deaths in China, and 2 cases including 2 deaths in Vietnam) were reported (as of 17 October) (http://www.wpro.who.int/emerging_diseases/AvianInfluenza/en/).

Avian influenza in Japan:  In April 2014, there was an outbreak of the highly pathogenic avian influenza in a meat poultry farm in Kumamoto Prefecture.  On the 22nd day after the completion of the preventive measures, the setting of the movement restriction area has been released.  The genotype of the virus was identical to that H5N8 subtype isolated in the Republic of Korea suggesting its Korean origin.

Act on special measures against the new type influenza:  The act was issued on 11 May 2012 and enforced on 13 April 2013 with the objectives of protecting life and health of Japanese citizens and minimizing the adverse effects on the daily life and economy.  The Japanese government produced a government action plan and all the prefectures in Japan completed prefecture level action plan in June 2013.

Additional comments:  Trends of influenza outbreaks should be monitored continuously by sentinel surveillance, school out-break surveillance, hospitalization surveillance and other possibilities.  The virus isolation should be conducted throughout the year and the antigenic and genetic changes of the epidemic strains should be monitored so as to secure vaccine candidate strains.  Monitoring of the resistance to anti-influenza drugs among isolates and the antibody level of Japanese population should be continued for risk management in future.

Flash reports on the isolation and detection of influenza viruses in 2013/14 season are found in see p. 272 of this issue and http://www.niid.go.jp/niid/en/iasr-inf-e.html.


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The topic of This Month Vol.35 No.10(No.416)

Invasive Haemophilus influenzae and Streptococcus pneumoniae infections, as of August 2014

(IASR 35: 229-230, October 2014)

The amendment of the Infectious Diseases Control Law on 1 April 2013 brought invasive Haemophilus influenzae disease/infection and invasive pneumococcal disease/infection into the category V infectious diseases.  Physicians who have made the diagnosis of these infections must notify within 7 days of diagnosis (see http://www.niid.go.jp/niid/images/iasr/34/401/de4011.pdf and http://www.niid.go.jp/niid/images/iasr/35/416/de4161.pdf for notification criteria).  Invasive infection is defined as infection of sterile sites. 

Invasive Haemophilus influenzae disease (IHD)
H. influenzae is a gram-negative bacillus belonging to the genus Haemophilus in the Pasteurellaceae family.  It causes invasive infections (e.g. meningitis and bacteremic pneumonia) and non-invasive infections (e.g. otitis media).  Strains having capsular polysaccharide are resistance to phagocytosis by neutrophils in antibody-free conditions, and frequently cause invasive infections.  H. influenzae having capsules are grouped into six serotypes, from a to f, determined by bacterial agglutination tests using polysaccharide antisera.  Infection caused by the Hib strain with b type capsule is vaccine-preventable.  Strains devoid of capsule are classified as “non-typable H. influenzae (NTHi)”.

National Epidemiological Surveillance of Infectious Diseases (NESID):  From April 2013 to 20 August 2014, 235 IHD cases were reported (male to female ratio of 1.6:1).  Children less than 5 years of age occupied 17% and those aged 65 years or older 57% of the reported IHD cases (Fig. 1).  Among patients younger than 5 years, bacteremic pneumonia occupied 33% (13/39), meningitis 23% (9/39) and bacteremia 44% (17/39) of the cases.  Relative to adults, meningitis was more frequent among children, particularly among infants less than 6 months of age (63%; 5/8).  Bacteremic pneumonia occupied more than half of those older than 65 years (61%; 82/134).  No clear seasonality was observed; there was a peak in June in 2013 and two peaks in January and in April in 2014 (Fig 2).  Among 235 IHD cases, 16 died-13 cases were 65 years of age or older and 2 cases were less than 1 year of age.  The incidence per 100,000 population was 0.13 for the total population, 0.52 for the population under 5 years of age and 0.29 for the population 65 years of age or older (Table).

Vaccine:  Vaccination for Hib vaccine for serotype b H. influenzae began in December 2008 on a voluntary basis for children less than 5 years of age; it was incorporated in the government supported “Program of accelerated vaccination with cervical cancer and other vaccines” in November 2010, and included in the routine immunization program in April 2013.  According to “Research on evidence and recommended policies on better use of vaccinations” (Ihara-Kamiya Research Project that started in 2007), while the incidence per 100,000 population under 5 years of age of Hib-related meningitis was 7.71 and that of Hib-related non-meningitis was 5.15 before introduction of Hib vaccine (2008-2010), the respective figures fell to 0.17 and 0.10 after Hib vaccine introduction (2013) (see pp. 231 & 233 of this issue).  Notably, with inclusion of IHD in the category V infectious diseases, reported data through NESID revealed that NTHi caused bacteremic pneumonia among adults (see p. 232 of this issue).

Invasive pneumococcal disease (IPD)
Streptococcus pneumoniae is a gram-positive diplococcus.  It causes non-invasive infections among infants and the elderly (e.g. otitis media and non-bacteremic pneumonia).  Once it enters the blood stream, it causes meningitis, bacteremic pneumonia, bacteremia/septicemia and other IPDs.  The capsular polysaccharide is an important pathogenic factor, and S. pneumoniae is classified into more than 90 serotypes according to its antigenicity type. 

NESID:  From April 2013 to 20 August 2014, 2,210 IPD cases were reported (male to female ratio of 1.4:1).  Children younger than 5 years of age occupied 23% (510/2,210), and adults aged 65 years or older occupied 50% (1,106/2,210) of the reported IPD cases (Fig. 3). Among patients younger than 5 years of age, bacteremia associated with pneumonia occupied 18% (92/510) and bacteremia unassociated with meningitis or pneumonia occupied 70% (355/510) of the cases.  Among patients older than 65 years, bacteremic pneumonia occupied 46% (506/1,106) and meningitis 19% (206/1,106) of the cases.  Among IPD patients 20-64 years of age, meningitis was most frequent (36%; 190/534).  The number of IPD cases tended to slightly increase from winter to early summer (Fig 4).  There were 154 fatal cases reported, among which 112 cases were older than 65 years of age and 3 cases younger than 5 years of age.  The incidence of IPD was 1.18 per 100,000 total population, 6.32 for the population under 5 years of age and 2.41 for the population 65 years of age or older (Table).

Vaccine:  Japan approved the heptavalent pneumococcal conjugate vaccine (PCV7) for children in February 2010 on a voluntary basis; it was incorporated in the government supported “Program of accelerated vaccination with cervical cancer and other vaccines” in November 2010 for children less than 5 years of age, and included into routine immunization program in April 2013.  In November 2013, PCV7 was replaced with PCV13, which incorporated additional 6 serotype polysaccharide antigens.

For adults, a 23-valent pneumococcal polysaccharide vaccine (PPSV23) was approved in 1988.  PCV13 was approved for immunization of adults aged 65 years or older in June 2014. Routine immunization of PPSV23 for adults 65 years or older is planned from October 2014 (see p. 240 of this issue).

According to the Ihara-Kamiya Research Project, while the incidence per 100,000 population under 5 years of age was 2.81 for meningitis IPD and 22.18 for non-meningitis IPD before the government supported implementation of PCV7 vaccination, after its incorporation into the routine vaccination program, respective incidences decreased to 1.10 and 9.71 (see p. 233 of this issue).  With introduction of pneumococcal vaccines, the frequency of IPDs caused by the PCV7-covered serotypes was reduced from 77% (201/261) to 4% (4/94) in 2013.  However, IPD due to serotypes that are not covered by the vaccines increased (serotype replacement) (see p. 234 of this issue).

According to a research project conducted in 10 prefectures, among the S. pneumoniae isolates detected since April 2013 during the past one year, serotypes covered by PCV13 occupied 46% (38/83) and those covered by PPSV23 60% (50/83) of the isolates (see p. 236 of this issue); prior to the introduction of PCV7 in 2006-2007, serotypes covered by PCV13 occupied 61% (185/301) and those covered by PPSV23 85% (257/301) of the isolates (Chiba N, et al., Epidemiol Infect 138: 61-68, 2010).  The proportion of serotypes included in PCV13 and PPSV23 are expected to further decline in 2014 and over the coming years.  Serotype replacement, observed overseas among adult IPD cases following PCV introduction in children, is also becoming apparent in Japan (IASR 35: 179-181, 2014).  Serotype replacement is similarly being observed among non-bacteremic pneumococcal pneumonia in adults (see p. 238 of this issue).

Conclusion:  Since November 2010, the government has been supporting immunization of children with Hib vaccine and PCV.  Starting in October 2014, vaccination of PPSV23 for adults 65 years or older will begin as a routine immunization.  In addition to collection of epidemiological data of IHD and IPD, enhanced pathogen surveillance and analysis of serotypes will be important for assessing the vaccination program. 


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The topic of This Month Vol.35 No.9(No.415)

HIV/AIDS in Japan, 2013

(IASR 35: 203-204, September 2014)

Japan started HIV/AIDS surveillance in 1984.  From 1989, it was conducted in compliance with the AIDS Prevention Law and since April 1999, it has been conducted in compliance with the Infectious Diseases Control Law.  Physicians must notify all diagnosed HIV/AIDS cases (reporting criteria found in http://www.niid.go.jp/niid/images/iasr/34/403/de4031.pdf).  Under the scheme, the patients are notified either as “HIV” or as “AIDS” (*see footnote below for definitions).  The data in this article are derived from the National AIDS Surveillance Committee 2013 Annual Report [released by the Specific Disease Control Division, the Ministry of Health, Labour and Welfare (MHLW), http://api-net.jfap.or.jp/status/2013/13nenpo/nenpo_menu.htm].

Around 1,500 new HIV/AIDS cases have been reported annually since 2007.  Since then, through 2013, the cumulative number of reported HIV/AIDS cases reached a total of 23,000 (Fig. 1).  Globally, there are an estimated 35 million HIV/AIDS cases, and every year, an estimated 2.3 million new HIV infections and 1.6 million deaths (2013 UNAIDS announcement, http://www.unaids.org/en/). 

Recent information on HIV/AIDS testing and diagnosis, HIV-associated neurocognitive dysfunctions and other ailments under long-term antiretroviral therapy, and other articles on HIV/AIDS in Japan are found in pp. 205-217.

1. Trends in HIV/AIDS during 1985-2013:  In 2013, 1,106 HIV cases (1,060 males and 46 females) and 484 AIDS cases (466 males and 18 females) were reported.  The year 2013 recorded the second highest number of HIV cases (since 2007, annually reported number of HIV cases ranged from 1,002-1,126) and the highest number of AIDS cases since HIV/AIDS surveillance started (Fig. 2).  Since 1985 to 2013, excluding infections that occurred through administration of coagulants, the cumulative number of reported HIV and AIDS cases were, respectively, 15,812 (13,578 males and 2,234 females) and 7,203 (6,488 males and 715 females).  Based on population size estimates as of October 1, 2013, this corresponds to 12.4 HIV and 5.7 AIDS cases per 100,000 population.  The above data do not include 1,439 HIV infections caused by HIV-contaminated coagulation factor products (none since 2008), among whom 691 have died (as of May 31, 2013) (“Nationwide Survey of Blood Coagulation Anomalies”).

Nationality and gender:  In 2013, among a total of 1,106 HIV cases, 996 (963 males and 33 females) were of Japanese nationality and 110 (97 males and 13 females) were of non-Japanese nationality.  Eighty-seven percent (963/1,106) of HIV cases and 91% (438/484) of AIDS cases were Japanese males. 

Transmission route and age distribution among HIV cases:  Among 1,106 HIV cases, 780 (71%) acquired infection through male homosexual contact (men who have sex with men: MSM); among Japanese males 75% (726/963) acquired infection through MSM (Fig. 3, Fig.) and the majority were in their 20’s to 40’s (Fig. 4).  Among 46 female HIV cases, 33 were of Japanese nationality, and 79% (26/33) acquired infection through heterosexual contact.  One case of mother-to-child infection was reported in 2013.  Incidence of reported HIV infections per 100,000 population increased in all age groups, and particularly in the 25-29 year old age group.

Suspected place of infection among HIV cases:  Infection occurred mostly outside of Japan until 1994 but the majority have been domestic since then.  In 2013, 85% (939/1,106) of all HIV cases and 90% of HIV cases among those of Japanese nationality (893/996) occurred in Japan.

Place of notification based on physician report:  Majority of HIV and AIDS cases were reported from the Kanto-Koshinetsu, Kinki and Tokai areas (Table 1).

2. HIV-antibody-positive rates among blood donors:  In 2013, among a total of 5,205,819 donated blood specimens, 63 were HIV positive (61 males, 2 females), or 1.210 HIV positive specimens (1.690 for males and 0.125 for females) per 100,000 blood donations, which was lower than that reported in 2012 (1.290) (Fig. 5).

3. HIV antibody tests and consultation provided by local governments:  The number of people receiving HIV tests at health centers and other facilities managed by local government units was 136,400 (131,235 tests in 2012), and has been relatively stable over the years (peaked in 2008) (Fig. 6).  Among those tested, 453 were HIV positive in 2013 (469 positives in 2012), corresponding to 0.33% positivity (0.36% in 2012).  While the HIV positivity rate among specimens tested in health centers was 0.26% (273/105,531), the positivity rate in facilities other than health centers was 0.58% (180/30,869), considerably higher than in health centers.  The number of counseling cases provided by local governments continued to decrease, following the same trend as in the preceding 5 years (145,401 in 2013 and153,583 in 2012).

Conclusion:  The number of HIV/AIDS cases reported in 2013, 1, 590 cases, was the highest in the history of Japanese HIV/AIDS surveillance (1,449 cases in 2012).  Increase in AIDS cases, which occupied 30% of the total, was remarkable; it may indicate that many HIV-infected persons were unaware of their own HIV infection for a long time.  For early detection and diagnosis of HIV, information on the characteristics of the current HIV/AIDS epidemic, such as high HIV incidence among young male adults and increasing AIDS cases among those over 60 years of age, should be shared not only at the national level but also at local levels.  A policy should be established and appropriate measures should be taken in order to prevent further spread of HIV/AIDS and facilitate early HIV treatment.  Making HIV testing and medical consultations more accessible in time and place for those such as male homosexuals (MSM), adolescents and young adults, and commercial sex workers and their clients, are examples of such measures.  It is important to note that implementing any measure requires consideration of human rights and coordination with appropriate partners, such as, corporations, NGOs, and educational and/or medical staff. 

The national HIV/AIDS control policy should include enhancing understanding of the HIV/AIDS trends and continuing activities regarding public awareness, early diagnosis and early therapeutic intervention.  The national policy should be such that it also contributes to global HIV/AIDS control.  While effective in preventing progression to AIDS, anti-HIV chemotherapy necessitates life-long treatment as it does not cure the patients of the virus.  In addition, life-long treatment is associated with occurrence of drug-resistant HIV variants and appearance of neurological, bone-related (e.g. osteoporosis), cardiovascular and other ailments due to proviral latency of HIV.

 *HIV surveillance in Japan counts a case as an “HIV case” if the case is laboratory diagnosed with HIV infection (but without manifestation of AIDS symptoms), and as an “AIDS case” if a case is laboratory diagnosed with HIV infection and manifests AIDS symptoms at the time of initial diagnosis and report.  An HIV infected case once registered as an “HIV case” is not registered as an “AIDS case” even if he/she subsequently develops AIDS.

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The topic of This Month Vol.35 No.8(No.414)

Cryptosporidiosis and Giardiasis as of July 2014

(IASR 35: 185-186, August 2014)

Cryptosporidiosis and giardiasis are intestinal protozoan infectious diseases that often manifest as non-bloody watery diarrhea.  The parasites are transmitted fecal-orally as oocysts or cysts.  Under the Infectious Diseases Control Law, they are classified as category V infectious diseases requiring reporting of all the cases.  Physicians who make a diagnosis of these infections must notify within 7 days of diagnosis (http://www.niid.go.jp/niid/images/iasr/35/414/de4141.pdf, http://www.niid.go.jp/niid/images/iasr/35/414/de4142.pdf).  Notification requires laboratory diagnosis, via microscopic detection of pathogens or its antigens or genes (see p. 197 of this issue).  In the laboratory, Cryptosporidium must be handled as a class 4 pathogen under the Infectious Diseases Control Law.

The disease is caused by Cryptosporidium, an enteric, protozoan coccidian parasite.  C. hominis (formerly classified as C. parvum genotype 1 or anthroponotic genotype) mainly infects humans and C. parvum (formerly classified as C. parvum genotype 2 or bovine genotype) mainly mammals.  While C. meleagridis (avian type) does not commonly infect humans, infections, including outbreaks, have been reported (IASR 29: 22-23, 2008).

Oocysts, spherical in shape and 5μm in diameter (see Fig. 1 in p. 198 of this issue), are shed via stools.  Oocytes are resistant to chlorine disinfectants, and outbreaks that occur through contamination of tap water, swimming pools, or fountains tend to become large-scale.  Ministry of Health, Labour and Welfare issued the ”Guidelines on prevention of cryptosporidiosis caused by contaminated tap water (Ken-sui-hatsu No. 0330005, 30 March 2007)”, which recommend implementation of necessary measures such as appropriate filtration or UV light treatment (see p. 187 of this issue).  Other modes of transmission include consumption of contaminated foods, contact with infected patients (including sexual contact) or animals, and opportunistic infections.

The median incubation period is 6 days (range 4 to 8 days) (see p. 190 of this issue).  While watery diarrhea may continue for about 10 days, there are no effective treatments.  Prevention of dehydration is the standard treatment for otherwise healthy patients.  Immunocompromised patients may develop persistent, refractory, and wasting diarrhea which may be fatal if proper treatment to recover immune function is not provided.

The largest outbreak documented in Japan occurred in Ogose-cho in Saitama Prefecture in 1996.  Caused by contaminated tap water, as many as 8,800 people (approximately 70% of the habitants), fell ill (IASR 17: 217-218, 1996).  Other large outbreaks include an outbreak in a multi-tenant building (due to contamination of the water tank) (IASR 15: 248-249, 1994) and an outbreak associated with the use of a swimming pool (IASR 26: 167-168, 168-169, 169-170 & 170-171, 2005).  An outbreak affecting more than 10 persons receiving on-site training at a cattle ranch has also been reported (IASR 30: 319-321, 2009)

National Epidemiological Surveillance of Infectious Diseases (NESID):  Reported surveillance data through 2005 are found in IASR 26: 165-166, 2005.  From 2006 to 2013, annually 6 to 19 cases were reported (Table 1).  Common modes of transmission included contact with cattle, travel abroad to developing countries (where contaminated food or water consumption were suspected), sexual contact among men who have sex with men (MSM), and food poisoning (Table 2).  Among outbreaks associated with cattle contact, one was due to contact with calves during on-site training for students at a farm (see p. 188 of this issue) and another due to an outdoor event that included contact with cattle (see p. 189 of this issue).  Typical food poisoning cases include those such as the one reported in 2006, caused by consumption of raw beef (“yukhoe”) and/or raw liver (IASR 28: 88-89, 2007).  A large-outbreak involving tens of primary school students and teachers during on-site training was occurred in June 2014, but the source and mode of transmission are still under investigation.

Some cryptosporidiosis cases were co-infected with other pathogens, such as Giardia or Entamoeba histolytica (IASR 28: 298-299, 2007).  Several cases among MSM were infected with both Cryptosporidium and HIV (see p. 192 of this issue).  Among reported Cryptosporidiosis cases, males in their twenties were most frequent (Fig. 1).

No large scale waterborne outbreak has been reported in Japan since 2006.  Outside of Japan, however, from 2004 to 2010, there were at least 120 waterborne outbreaks reported (see p. 194 of this issue), including the largest ever documented outbreak (an estimated 27,000 cases in 2010) in Europe (see p. 195 of this issue).

The disease is caused by an intestinal protozoan parasite, Giardia.  Human infection is caused by G. lamblia (syn. G. duodenalis or G. intestinalis), which is classified into 8 genotypes (assemblages from A to H), among which assemblages A and B are most frequently isolated from humans.  The cysts of Giardia, although resistant to chlorine, can be relatively easily removed by filtration that can remove Cryptosporidium because the cysts of Giardia (5-8×8-12µm) are larger than the oocysts of Cryptosporidium (see Fig 2 in p. 199 of this issue).  Giardiasis is effectively treated with metronidazole, which is covered by the national health insurance since 2012.

NESID:  From 2006 to 2013, 578 giardiasis cases were notified (Table 1) and in 2010, an outbreak, uncommon in recent years in Japan, was reported (see p. 191 of this issue).  Among reported giardiasis cases, males in their twenties were most frequent (Fig. 2).  Common modes of transmission included travel abroad to developing countries, sexual contact (42 of 71 were among MSM), and exposures to sewage or stool (Table 3).  Twenty-six cases (4.5% of the total cases) were co-infected with other pathogens, such as Entamoeba histolytica, Cryptosporidium, Salmonella Typhi, S. Paratyphi, Shigella, or HIV (see p. 192 of this issue).

Although giardiasis is usually accompanied by diarrhea, 17% of the patients (98/578) had no diarrhea but experienced abdominal discomfort and 2.2% (13/578) were asymptomatic.  It should be noted that the asymptomatic carriers exist as sources of infection although they do not require notification under the Infectious Diseases Control Law.  Notably, Giardia was detected from duodenal, bile and pancreatic excretes of 63 cases (11%) who received gastrointestinal endoscopy.  Giardia has been occasionally detected from patients with cholecystitis symptoms (see p. 194 of this issue).

Cryptosporidiosis, giardiasis, and other protozoan infections, such as infection with Cyclospora (see p. 196 & Fig 3 in p. 199 of this issue), Isospora, Entamoeba histolytica, occur widely throughout the world.  Measures that should be taken for these protozoan infections are similar to those that are taken for Cryptosporidium and Giardia, such as infection control, adequate hand washing, and proper heating and/or treatment of food and water.  For cases of diarrhea of unknown etiology, Cryptosporidium and Giardia should be included in the laboratory differential diagnosis.

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The topic of This Month Vol.35 No.7(No.413)

Epidemiology of Norovirus in Japan, 2010/11-2013/14 seasons

(IASR 35: 161-163, July 2014)

Norovirus (NoV) is an RNA virus with 5 genogroups GI-GV, among which GI and GII cause human infection.  GI genogroup contains at least 9 genotypes and GII genogroup is composed of 22 genotypes (see p. 173 of this issue).  Persons infected with norovirus shed large quantities of virus in stool and vomit; virus is present in patients’ stool for 10-21 days (occasionally for >1 month) after disappearance of clinical signs and symptoms (IASR 31: 319-320, 2010).  NoV causes food poisonings. Person-to-person transmission occurs through contact (often via contaminated fingers) or inhalation of droplets of fresh vomit or dried-up vomitus (IASR 28: 84, 2007 & 29:196, 2008).

1. Notification of infectious gastroenteritis reported under the National Epidemiological Surveillance of Infectious Diseases (NESID) and detection/isolation of NoV:  Infectious gastroenteritis that includes NoV infection is reported from approximately 3,000 pediatric sentinels in Japan (http://www.niid.go.jp/niid/images/iasr/35/409/de4091.pdf).  Each year, the number of infectious gastroenteritis cases increase towards the end of the calendar year forming a sharp peak at week 49 to 51, with approximately 18 cases reported per sentinel per week; after a temporary decline, NoV activity increases again, forming a broad arch shaped curve, from week 5 to 25 of the next year (Fig. 1; http://www.niid.go.jp/niid/en/10/2096-weeklygraph/1647-04gastro.html).

Prefectural and municipal public health institutes (PHIs) report isolation/detection of causative agents of infectious gastro-enteritis, including NoV, to NESID using a case-based reporting form (IASR 31: 75-76, 2010).  Among the reported pathogens, NoV is the most commonly reported, followed by rotavirus and sapovirus.  NoV is dominant from November/December and continues to be reported through May, although rotavirus becomes more common from February (Fig. 1) (IASR 35: 63-64, 2014).

Among pathogens reported to NESID as causative agents of sporadic cases of infectious gastroenteritis, NoV occupies about one third of the pathogens detected from children 3 years old or younger (Fig. 2).  With increase in age, the proportion of NoV increases.

NoV detected during the 2010/11-2013/14 seasons was mostly of GII type (Fig. 1 & https://nesid4g.mhlw.go.jp/Byogentai/Pdf/data11e.pdf).  Among NoVs detected from infectious gastroenteritis patients 0-15 years of age, GII/4 was dominant in the 2006/07-2009/10 seasons but GII/3 became the most frequent (50%) in the 2010/11 season (Table 1 in p. 163 of this issue & IASR 31: 312-314, 2010).  Since the 2011/12 season, GII/4 once again became more dominant, and made up nearly 80% of the NoV detected during the 2012/13 season; many of the outbreaks during this season were due to the GII/4 variant (Sydney 2012) (see p. 165, 167, 168 & 169 of this issue and IASR 33: 333-334 & 334-335, 2012), which was epidemic abroad (IASR 34: 45-49, 2013).

2. NoV detected from outbreak cases:  Information of pathogen detection in food poisonings, complaints attributed to foods, as well as outbreaks of gastroenteritis due to person-to-person transmission are reported from PHIs as outbreak events.

During the 2010/11-2013/14 seasons, 517-815 outbreaks were reported annually (Table 2 in p.163 of this issue). November and December were high seasons (Fig. 3).  Among outbreaks with known genotype information, GII/3 was the most common during the 2010/11 season, while GII/4 became dominant since the 2011/12 season.

For the 2010/11-2013/14 seasons, foods were responsible for 700 outbreaks, person-to-person for 1,256 and 593 outbreaks were of unknown cause.  The place most frequently suspected as the source of infection was nursery schools, followed by restaurants, nursing homes for the elderly, and primary schools.  Person-to-person transmission was frequent in nursery and primary schools and nursing homes for the elderly.  Foodborne infection was most frequently attributed to restaurants (Table 2 in p. 163 of this issue).

During the 2010/11 season, foods were suspected in 141 of the 648 outbreaks. Person-to-person transmission was most common and suspected for 355 outbreaks, accounting for more than half of the outbreaks; frequently suspected locations were nursery schools, restaurants and primary schools.  GII/3 was frequently found in nursery and primary schools while nursing homes for the elderly was more associated with GII/4.

For the 2011/12-2013/14 seasons, person-to-person transmission was suspected for 212, 394, and 295 outbreaks in each respective season.  During the 2012/13 season, nursing homes for the elderly were suspected for 141 outbreaks.  GII/4 was dominant and responsible for 500 outbreaks; among them, 176 and 86 outbreaks occurred in nursing homes for the elderly and nursery schools, respectively, where person-to-person transmission is suspected as the main route of infection.  There were 59 outbreaks associated with restaurants.

3. Statistics of Food Poisoning: Statistics for food poisoning managed by the Ministry of Health, Labour and Welfare (MHLW) contains data on NoV-related events (IASR 32: 352-353, 2011, https://idsc.niid.go.jp/iasr/32/382/tpc382.html).  The number of NoV-related events was 293 (8,086 patients) in 2010/11, 317 (10,969 patients) in 2011/12, 437 (19,709 patients) in 2012/13, and 228 (8,903 patients) in 2013/14 (as of June 2, 2014).  In the 2012/13 season, the number of patients per outbreak exceeded 500 in three events (2,035, 1,442 and 526, respectively).  In the 2013/14 season, there was a large-scale outbreak involving 8,027 persons, causing food poisoning in 1,271 persons (see p. 164 of this issue).

During the 2010/11-2013/14 seasons, the most frequent number of patients per event was 17-32 (327 events) followed by 9-16 (310 events) and 33-64 (226 events)(Fig. 4).  The place most frequently suspected as the source infection was restaurants (906 events), followed by hotels (111 events) and caterers (85 events).

4. Preventive measures and challenges: In order to improve and promote prevention of norovirus infection, MHLW issues a public notice every season (in November 20, 2013 for the 2013/14 season) (http://www.mhlw.go.jp/topics/syokuchu/dl/131120_1.pdf).  For NoV prevention, attention should be paid to trends in infectious gastroenteritis and NoV detection informa-tion.

Infection control including hand washing, proper clothing and use of gloves in food handling areas and other standard hygienic measures should be implemented (IASR 33: 137-138 & 334-335, 2012).  Health condition of food handlers should be monitored and maintained through implementation of regular health checks (IASR 34: 265-266, 2013).  These measures should be maintained throughout the year as NoV activity is continuous.  For rapidly identifying the cause of food poisoning and for preventing further spread, standardized methods for detecting virus from foods need to be established.

Development of NoV vaccine is identified as a high priority for the MHLW’s master plan for immunization (MHLW, notification number 121, 2014; see http://www.mhlw.go.jp/stf/seisakunitsuite/bunya/kenkou_iryou/kenkou/kekkaku-kansenshou/kihonteki_keikaku/index.html).  Effective vaccine development requires comprehensive information, such as pathogen information obtained through NESID, knowledge on antigen variability and mutation/evolution of the major antigen determinant gene(s) (see p. 170 of this issue), and computational prediction of virus evolution (see p. 171 of this issue).

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The topic of This Month Vol.35 No.6(No.412)

Respiratory syncytial virus infection, as of May 2014

(IASR 35: 137-139, June 2014)

Respiratory syncytial virus (RSV) is an RNA virus belonging to Pneumovirus in Paramyxoviridae family (see p. 148 of this issue).  It is propagated as droplet or contact infections.  Estimatedly, more than 50% of infants acquire primary infection during the first year of life and nearly 100% before their second birthday.  No first infection confers lifelong immunity (see p. 141 of this issue). 

RSV infection occupies 50% of pneumonia and 50-90% of bronchiolitis among infants (see p. 139 & 142 of this issue).  The clinical manifestation is indistinguishable from other respiratory virus infections.  Therefore, laboratory diagnosis is indispensable for differential diagnosis.Clinical treatment of the patients is basically supportive.

Newborn, infant and immunocompromised cases tend to become serious (see pp. 139 & 150 of this issue) with development of apnea, syndrome of inappropriate antidiuretic hormone (SIADH), acute encephalopathy and other complications.  Adult cases are generally mild (with flu-like symptoms) though they may transmit RSV to others.  Aged cases may develop pneumonia as severe as that associated with influenza, and their case fatality rate is high (see p. 147 of this issue).  Preventive measures against nosocomial RSV infection including early diagnosis should be implemented in facilities for elderlies or persons with developmental disabilities, as RSV outbreaks have been reported from such facilities (see pp. 145 & 146 of this issue). 

Currently, no preventive vaccines against RSV infection are available, though a humanized monoclonal antibody to RSV F glycoprotein, palivizumab, (developed in the USA and commercially available in Japan since 2002) is administered to high risk groups, such as, premature babies, patients with chronic pulmonary or congenital heart disease(s) for preventing RSV infection.

RSV infection is a category V infectious disease under the Infectious Diseases Control Law since its amendment in 2003.  In compliance with the Law and under the framework of the National Epidemiological Surveillance of Infectious Diseases (NESID), pediatric sentinels report the notified RSV cases every week to the local public health centers.  Notification requires laboratory diagnosis including RSV antigen detection (notification criteria in http://www.niid.go.jp/niid/images/iasr/35/412/de4121.pdf).  Though it had been limited to hospitalized patients before 17 October 2011, the medical insurance now covers RSV antigen detection testing of infants and other outpatients, to whom palivizumab is indicated (see p. 143 of this issue).  Among approximately 3,000 pediatric sentinels (hospitals and clinics), now about 80% of them report RSV infection.  In particular, clinics without beds increasingly report RSV infection cases in recent years, and the number of RSV infection reporting from such clinics doubled from 2008 to 2012 (Fig. 1).

RSV infections under NESID: During 2012-2013, the RSV infection epidemic started in July; the patients increased rapidly in September; the epidemic reached the peak towards the end of the year; and it continued till spring (Fig. 2).  Osaka Prefecture continuously reported the highest number of patients (IASR 29: 271-273, 2008), followed by Hokkaido, Tokyo, Aichi and Fukuoka prefectures; they are all prefectures with high annual number of births. The epidemic season started earlier in Kyushu region.  Okinawa Prefecture, differently from other regions, had the epidemic peak in summer (Fig. 3).  From 2012 to 2013, there were 105,174 male patients (54%) and 89,370 female patients (46%).  Infants under 2 years of age occupied 90% of the patients; the frequency proportion among <2 year patients was in the order of 0 year, 1 year and 2 years (Fig. 4 in p. 139 of this issue).

Since 2008, 22 RSV-related acute encephalopathy cases including 2 fatal cases (10 males, 12 females; 17 patients less than 2 years of age) have been reported.  The patients’ age ranged from 5 months to 13 years (median 2 years), which corresponds to the age groups whose RSV infection tends to be serious (Table 1).

Detection of RSV and other respiratory infectious viruses: Prefectural and municipal public health institutes (PHIs) isolate/detect virus from specimens sent from pathogen sentinels [corresponding about 10% of influenza sentinels (3,000 pediatric and 2,000 internal medicine clinics) and 500 sentinel hospitals].  Until 2009/10 influenza season, RSV was the second highest in detection frequencies following influenza, but since 2010/11 season, rhinovirus detections exceeded RSV detections (Table 2 in p. 139 of this issue).  RSV was isolated/detected from autumn to winter; influenza in winter; and rhinovirus throughout the year (Fig. 5 in p. 139 of this issue).  Human metapneumovirus and parainfluenza viruses (see p. 157 of this issue), though small in number, were isolated/detected most frequently from spring to summer.

In 2008/09-2013/14 season, 57 PHIs in 44 prefectures isolated/detected RSV from 5,441 cases (as of 20 May 2014).  The most frequent RSV-positive specimens were throat swab (5,358 specimens, 98%) and the most frequent detection method applied was PCR (4,959 cases, 91%) followed by cell culture isolation (932 cases, 17%), and antigen detection (49 cases, 1%) (detection by more than one method included).  The most frequent respiratory disease-related diagnosis of the cases from which the specimens were collected was lower respiratory tract inflammation (2,371 cases, 44%) followed by RSV infection (1,746 cases, 32%) and upper respiratory tract inflammation (495 cases, 9%).

Challenges in future: RSV infection is associated with high incidence of pneumonia among aged groups and serious complications among infants.  To reduce the disease burden, the RSV surveillance system should be strengthened to make evidence based intervention possible. 

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The Topic of This Month Vol.35 No.5 (No.411)

Enterohemorrhagic Escherichia coli infection in Japan as of April 2014

(IASR 35: 117-118, May 2014)

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

Prefectural and municipal public health institutes (PHIs) conduct isolation of EHEC, serotyping, and toxin [vero-/Shigatoxin: (VT)/(Stx)] typing and report the result to the National Epidemiological Surveillance of Infectious Diseases (NESID) system (see p. 119 of this issue).  When necessary, the Department of Bacteriology I, National Institute of Infectious Diseases (NIID), conducts confirmatory tests for sero- and toxin-typing and also conducts multiple-locus variable-number tandem repeat analysis (MLVA), pulsed-field gel electrophoresis (PFGE) and other molecular epidemiological analysis to analyze outbreaks (including sporadic cases part of diffuse outbreaks).  These results are informed back to PHIs and made available through the National Epidemiological Surveillance of Foodborne Disease (NESFD) system (see p. 128 of this issue).

Cases notified under NESID: During January to December 2013, a total 4,046 EHEC infections, composed of 2,624 symptomatic and 1,422 asymptomatic (detected during active surveillance of outbreaks or routine stool testing of food preparation staff) cases, were reported (Table 1).  The number of symptomatic infections remained stable from 2009 to 2012 (2,602, 2,719, 2,659 and 2,363, respectively).  As in previous years, a large peak occurred in summer (Fig. 1).  Reported number of cases (including asymptomatic cases) was the highest in Tokyo (382), followed by Fukuoka (271), Kanagawa (218), Aichi (211), and Hokkaido (207).  Incidence (cases per 100,000 populations) was the highest in Miyazaki Prefecture (8.35) followed by Saga Prefecture (8.19) and Toyama Prefecture (7.95) (Fig. 2, left).  Among those 0-4 years of age, more cases were reported from Miyazaki, Nagasaki and Shimane Prefectures (Fig. 2, right).  The young (<30 years of age) and the elderly (≥60 years of age) had a greater proportion of reported cases that were symptomatic relative to those in their 30’s, 40’s and 50’s (Fig. 3).

Hemolytic uremic syndrome (HUS): A total of 87 hemolytic uremic syndrome (HUS) cases (3.3% of symptomatic cases), were reported in 2013 (see p. 130 of this issue).  EHEC was isolated from 55 cases, among which 48 were O157, three were O26, and one each of O76, O111, O121 and O165.  Among the 55 isolates, 54 were positive for VT2 or VT1 & 2 (98%).  One isolate was unknown for VT type.  Four fatal cases were reported, among which one had HUS complication (5 years of age) and the others were elderly (one in her 70’s and two in their 90’s).

EHEC isolated by PHIs: In 2013, number of EHEC isolated by PHIs was 2,086 (see p. 119 of this issue), which was far less than the reported number of 4,046 EHEC cases (Table 1).  This discrepancy is due to the current situation where clinical or commercial laboratories do not always send specimens to PHIs.  The most frequent O-serogroup was O157 (52%), followed by O26 (25%) and O111 (7.2%).  Among O157 isolates, those positive for both VT1 and VT2 genes were predominant (63%) as in previous years.  Of the O26 isolates, 95.7% were positive only for VT1 and 78.1% of O111 were positive for both VT1 and VT2.  Signs and symptoms frequent among the O157-isolated symptomatic cases (n=1,044), were abdominal pain (60%), diarrhea (60%), bloody diarrhea (50%), and fever (22%).

Outbreaks: In 2013, PHIs reported to NESID 34 EHEC outbreaks. Outbreaks involving ten or more EHEC-positive cases are shown in Table 2.  Several outbreaks were believed to have occurred via human to human transmissions at nursery schools (pp. 123, 124, 126 and 127 of this issue).  In 2013, prefectures reported a total of 13 EHEC incidents involving 105 symptomatic patients (cases that were negative for isolation included) in compliance with the Food Sanitation Law (25 incidents and 714 patients in 2011; 16 incidents and 392 patients in 2012) (see p. 120 of this issue).  Although epidemiological linkage was not demonstrated, Department of Bacteriology I, NIID reported that EHEC cases showing the same PFGE pattern was isolated from sporadic cases that occurred diffusely and widely (see p. 128 of this issue).

Prevention and measures to be implemented: In response to persistent food poisonings caused by raw beef, MHLW revised the standards of beef marketed for raw consumption and issued the MHLW notice No. 321 in October 2011.  Further, upon the detection of EHEC O157 in the inner part of beef liver, MHLW banned marketing of beef liver for raw consumption (notice No. 404 in July 2012) (IASR 34: 123-124, 2013).  As a consequence, the incidence of O157 cases related to consumption of raw beef or raw beef liver decreased considerably in one year from 2011 and that level has been maintained through 2013.  In response to O157 outbreaks caused by pickled vegetables, MHLW further modified the hygiene standards of pickled vegetables (Shoku-An-Kan-Hatsu 1012 No.1, 12 October 2012).  The basics for preventing EHEC infections are to observe the principles of food poisoning prevention and to avoid consumption of raw or undercooked beef (http://www.gov-online.go.jp/useful/article/201005/4.html).  Although Japan experienced no large-scale food poisoning events in 2013, food safety measures, including the assurance of personal hygiene of food handlers, should be further strengthened.

Similar to dysentery bacilli, EHEC establishes infection even at minute doses and can spread from person to person rather easily.  The year 2013 experienced many EHEC outbreaks in nursery schools (Table 2, pp. 123, 124, 126 and 127 of this issue).  Preventing such outbreaks needs appropriate hygienic practice, such as routine hand washing and sanitary use of children’s pools during summer (see “Infection Control Guidelines for Nurseries” revised in 2012).  To prevent the spread of EHEC within patients’ families and to the wider community, health centers should provide instructions on prevention to relevant persons.

Copyright 1998 National Institute of Infectious Diseases, Japan

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