国立感染症研究所

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The topic of This Month Vol.36 No.10(No.428)

Disseminated cryptococcal infection in Japan (2014 Week 39-2015 Week 37)

(IASR 36: 183-184, October 2015)

Cryptococcal infection is caused by infection of a fungi belonging to the genus Cryptococcus, usually present in the soil or other environments.  The route of infection is inhalation or via a skin injury.  No person-to-person infection has been reported.  Infections spreading systemically and/or to the central nervous system (CNS) are classified as disseminated cryptococcal infection (see p. 185 of this issue). 

Disseminated cryptococcal infection is a category V infectious disease under the Infectious Diseases Control Law.  All cases shall be notified within 7 days after the diagnosis.  The notification criteria, including detection of Cryptococcus in the cerebrospinal fluids, blood or otherwise sterile clinical specimens and/or presence of Cryptococcus capsular antigen in the cerebrospinal fluids, are found in http://www.niid.go.jp/niid/images/iasr/36/428/de4281.pdf.

Although disseminated cryptococcal infection can occur among otherwise healthy persons, risk factors include diabetes, malignant tumors, hematological diseases, renal diseases, collagen diseases, HIV infection, and use of steroid and other immunosuppressants.  Factors that lead to systemic infection or the mechanism of the pathogen’s high affinity to CNS have not been well elucidated.  Antifungal chemotherapy is used for treatment, but often requires a long period of time, even for healthy persons (see p. 191 of this issue).

Fungi belonging to the genus Cryptococcus have a thick capsule.  There are two species, C. neoformans and C. gattii, which are differentiated genetically.  C. neoformans is distributed worldwide and grows in bird droppings.  C. gattii is localized in tropical and subtropical regions such as Australia, and detected from trees such as Eucalyptus camaldulensis.  Compared with C. neoformans, C. gattii infections tend to be more severe and occur more frequently among otherwise healthy persons (see pp. 186 & 191 of this issue).

In Japan, C. neoformans infection cases have been reported frequently.  While C. gattii infections, associated with high case fatality and linked to environmentally-derived regional clusters, have been reported in recent years from North America (see p. 186 of this issue), environmental C. gattii colonization has not been reported in Japan.  However, with the report of a C. gattii infection case with no known travel history to an endemic region and no known suspected infection source (see p. 187 of this issue), disseminated cryptococcal infection was added as a notifiable category V infectious disease, under the Infectious Diseases Control Law on 19 September 2014; the aim was to facilitate epidemiological investigation of cryptococcal infections, including those caused by C. gattii.

National Epidemiological Surveillance of Infectious Diseases (NESID)
From week 39 of 2014 when disseminated cryptococcal infection became a category V infectious disease till week 37 of 2015, 123 cases were reported from 34 of the 47 prefectures (prefectures with the largest number of reported cases were Tokyo 12; Saitama 11; Aichi 10; Fukuoka 10; Kanagawa 9; Nagano 7; Osaka 7; Tochigi 5) (as of 17 September 2015) (Fig. 1 & Fig. 2).  The reported annual incidence per 1,000,000 population was 0.97 (prefectures with the highest reported annual incidence were Tottori 6.97; Yamanashi 3.57; Nagano 3.32; Wakayama 3.09; Miyazaki 2.69; Tochigi 2.53; Nagasaki 2.16; Fukuoka 1.96). No seasonality was observed for disseminated cryptococcal infections (Fig. 3).

Sex and age distribution: Among the 123 cases, 76 were male and 47 were female (male to female ratio: 1.6).  The median age was 74 years (range: 20-99 years).  Cases 60 years or older (106 cases) occupied 86% of all cases (82% among male cases and 94% among female cases) (Fig. 4).  Twenty cases (16%; 11 males and 9 females) had died at the time of notification; the median age was 77 years (range: 60-91 years).

Suspected infection route and underlying health conditions: Among the 123 cases, 105 cases (85%), consisting of 68 males (89% of male cases) and 37 females (79% of female cases), had underlying conditions or were immunocompromised.  Twelve cases (10%) (8 males; 4 females) had history of contact with the feces of birds such as pigeon or chicken.  Thirteen cases had no known risk factors. Seven cases had more than one suspected risk factor listed.  Though cryptococcal infection is an indicator of AIDS, there were only 8 cryptococcal infection cases with HIV/AIDS (all males; age 31-50 years) (see pp. 188 & 189 of this issue).

Clinical picture: The table lists the reported cases’ clinical signs and symptoms, as recorded on the notification form.  Sixty percent of the cases had fever.  Other reported clinical signs and symptoms included disturbance of consciousness, fungemia, central nervous system lesion, respiratory symptoms, abnormal chest roentgenogram, etc.

Laboratory diagnosis: Among the 123 cases, 108 cases (88%) were diagnosed by detection of Cryptococcus in blood and/or cerebrospinal fluid specimens, 63 cases (51%) by detection of Cryptococcus capsular antigen by latex agglutination, and 34 cases (28%) by histological and cytological detection of encapsulated yeast cells in cerebrospinal fluid (some cases were diagnosed by more than one method).  Under the current surveillance system, the respective proportion of infections caused by C. neoformans and C. gattii is unknown.

Summary
Japan has so far not experienced a cluster of epidemiologically-linked cryptococcal infection cases.  The newly established surveillance system under NESID will further elucidate the epidemiology and the clinical picture of disseminated cryptococcal infections in Japan.  It is hoped that potential risk factors may be identified, preventive measures may be developed, and early outbreak detection and intervention strategies may be established.

Latency of Cryptococcus ranges from several months to several years.  As cryptococcal infection may become serious even among otherwise healthy persons, it is critically important that clinicians suspect cryptococcal infections at an early stage, while differentiating it from other fungal infections such as Coccidioides (IASR 34: 1-2, 2013) (see p. 192 of this issue).  As cryptococcal infection treatment may occasionally fail, development of vaccines and new therapeutics are needed.

 

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The topic of This Month Vol.36 No.9(No.427)

HIV/AIDS in Japan, 2014

(IASR 36: 165-166, September 2015)

HIV/AIDS surveillance in Japan started 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, which obliges clinicians to notify all diagnosed HIV/AIDS cases (reporting criteria found in http://www.niid.go.jp/niid/images/iasr/34/403/de4031.pdf).  The data on HIV and AIDS cases (*see footnote below for definitions) are derived from the annual report of the National AIDS Surveillance Committee for year 2014 [released by the Specific Disease Control Division, the Ministry of Health, Labour and Welfare (MHLW), http://api-net.jfap.or.jp/status/2014/14nenpo/14nenpo_menu.html]. 

In Japan, around 1,500 new HIV/AIDS cases have been reported annually since 2007.  The cumulative number of reported HIV/AIDS cases reached a total of 24,000 HIV/AIDS from 1985 to 2014 (Fig.1).  Globally, there are an estimated 35 million HIV/AIDS cases, and every year, an estimated 2.1 million new HIV infections and 1.5 million deaths (according to the UNAIDS 2014, http://www.unaids.org/en/) . 

1.  Trends of HIV/AIDS during 1985-2014:  In 2014, 1,091 HIV cases (1,041 males and 50 females) and 455 AIDS cases (435 males and 20 females) were reported, which were respectively the third and the fourth highest numbers in the past (the number was 1,002-1,126 for HIV and 418-484 for AIDS in 2007-2014) (Fig. 2).  Since 1985 to 2014, total 16,903 HIV (14,619 males; 2,284 females) and 7,658 AIDS (6,923 males; 735 females) (excluding infections that occurred through administration of coagulation factor products) were reported.  The “Nationwide Survey of Blood Coagulation Anomalies” has additionally identified total 1,439 HIV infections caused by HIV-contaminated coagulation factor products including 700 deceased cases (as of May 31, 2014).

Nationality and gender:  In 2014, among a total of 1,091 HIV cases, 994 were of Japanese nationality (959 males, 35 females) and 97 were of non-Japanese nationality (82 males and 15 females).  Japanese males occupied 88% (959/1,091) of HIV cases and 90% (409/455) of AIDS cases. 

Transmission route and age distribution among HIV cases:  Infection through male homosexual contacts (men who have sex with men: MSM)** occupied 72% of total HIV cases (789/1,091) and 77% of Japanese male HIV cases (736/959) (Fig. 3, Fig.) and the majority were in their 20’s to 40’s (Fig. 4).  Among Japanese female HIV cases, the majority was infection through heterosexual contact (32 in 35 cases, 91%).  One case of mother-to-child infection was reported in 2014. There were 7 HIV/AIDS cases infected through intravenous drug use (IDU), which were all Japanese nationality, and 35 “other cases” that include blood transfusion-related cases and cases with multiple infection routes, such as, homosexual contacts and IDU.  Incidence of reported HIV infections per 100,000 population increased in almost all age groups, and particularly in the 25-29 year old age group.

Suspected place of infection:  Infection occurred mostly abroad until 1992 but the majority have been domestic since then.  In 2014, 87% of all HIV cases (951/1,091) and 91% of HIV cases among those of Japanese nationality (901/994) occurred in Japan. 

Place of notification based on physician report:  Majority of HIV and AIDS cases were reported from the Kanto-Koshinetsu area including Tokyo (HIV: 581; AIDS: 203) and Kinki area (HIV: 206; AIDS: 82) have been the top two in reporting the large numbers HIV/AIDS, followed by Tokai area. In 2014, however, Tokai area was superseded by Kyushu area (HIV: 109; AIDS: 82), which has been reporting increasingly in recent years.  In Okinawa Prefecture in the Kyushu area, number of HIV per 100,000 population was the third highest among the 47 prefectures and that of AIDS was the top of all the prefectures (Table 1). 

2.  HIV-antibody-positive rates among blood donors:  In 2014, among a total of 4,999,127 donated blood specimens, 62 were HIV positives (59 males, 3 females), or 1.240 HIV positive specimens (1.681 for males and 0.202 for females) per 100,000 blood donations (Fig. 5). 

3.  HIV antibody tests and consultation provided by local governments:  The number of people receiving the HIV tests at health centers and other facilities managed by local government units was 145,048, which was slightly higher than that in 2013 (136,400) (Fig. 6).  Among those tested, 490 were HIV positive in 2014 (453 cases in 2013), corresponding to 0.34% positivity (0.33% in 2013).  While the HIV positivity rate among specimens tested in health centers was 0.27% (298/111,743), the positivity rate in facilities other than health centers was 0.58% (192/33,305), considerably higher than in health centers.  The number of counseling cases provided by local governments was 150,993 in 2014, which was slightly higher than that in the previous year (145,401 in 2013).

Conclusion:  The number of HIV/AIDS cases reported in 2014 was 1,546 cases (1,590 in 2013), the third highest in the past.  The number of AIDS cases has not been reduced, and about 30% of the HIV/AIDS cases in 2014 were detected after development of AIDS, suggesting that many HIV-infected persons were unaware of their own HIV infection for a long time.  

With knowledge of the current characteristics of HIV/AIDS epidemic (high HIV incidence among people in their 20’s and increase of AIDS among those over 60 years of age), the central and local governments should establish an effective policy for early detection of HIV infections and effective public communications in order to prevent further spread of HIV/AIDS and facilitate early HIV treatment.  Effective preventive measures include making HIV testing and medical consultations more accessible in time and place for those such as MSM, adolescents and young adults, and commercial sex workers and their clients.  It is important to note that implementing any measure requires consideration of human rights and coordination with appropriate partners, such as, medical, educational, corporations and non-governmental organization (NGO)s.

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 serious pathological conditions due to latent infection under antiretroviral therapy, such as neurocognitive dysfunction, osteoporosis, cardiovascular disorder, and non-AIDS-defining cancers, which are new challenges for HIV/AIDS management.

 
 *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.
**Bisexual contact is counted as homosexual contact.
 

 

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The topic of This Month Vol.36 No.8(No.426)

Streptococcal Infections in Japan, 2012-2015, as of June 2015

(IASR 36: 147-149, August 2015)

Many streptococci that cause suppurative disease in humans are β-haemolytic.  They are classified according to the antigenicity of the cell wall polysaccharides; group A [Group A Streptococcus (GAS); mostly Streptococcus pyogenes], group B [Group B Streptococcus (GBS); mostly S. agalactiae], and group C or G [Group C or G Streptococcus (GCS or GGS); mostly S. dysgalactiae subsp. equisimilis (SDSE)]. GAS causes acute pharyngitis and other acute suppurative infections, such as cellulitis; scarlet fever and streptococcal toxic shock syndrome (STSS) by bacterial toxin; and rheumatic fever (see p. 160 of this issue) and acute glomerulonephritis by immunological mechanisms.  GBS causes bacteremia or meningitis in neonates and sepsis or pneumonia in adults.  SDSE causes septicemia and STSS in adults.

1.  National Epidemiological Surveillance of Infectious Diseases (NESID)
Group A streptococcal (GAS) pharyngitis:  Under the Infectious Diseases Control Law, GAS pharyngitis is a Category V infectious disease that is monitored at approximately 3,000 pediatric sentinel (see http://www.niid.go.jp/niid/images/iasr/36/426/de4261.pdf for notification criteria). 

Number of cases reported annually during 2011 to 2015 was 264,043, 276,090, 253,089, 303,160 and 202,830, respectively (as of week 24 for year 2015).  GAS pharyngitis exhibits seasonality and the number of patients increases from winter to spring each year (Fig. 1).  In 2014-2015, the number of patients began to increase from the end of 2014 and by week 24 of 2015, the weekly report per sentinel attained the highest level (3.64) in the past 10 years (Fig. 1, see p. 149 of this issue).  The cumulative reported number of patients per sentinel from the 1st week of 2014 to the 24th week of 2015 was highest in Yamagata, Tottori, Niigata, Fukuoka, Hokkaido, Ishikawa, Yamaguchi, Shimane, Kagoshima and Fukui prefectures (see p. 149 of this issue).  An outbreak in a care facility was also reported (see p. 150 of this issue).  In 2015 (as of week 24), 84% of the GAS pharyngitis patients were 9 years of age or younger, and 5-year-olds were the most reported age, occupying 9.4% of all reported cases.

Streptococcal toxic shock syndrome (STSS):  Any GAS, GBS or SDSE can cause STSS.  STSS is a Category V infectious disease that requires notification of all cases (see http://www.niid.go.jp/niid/images/iasr/36/426/de4262.pdf for notification criteria).  Since April 2006, notifications include all cases in which samples from the normally sterile sites or organs were positive for any GAS, GBS or SDSE, and manifesting shock with two or more of the following: liver failure, renal failure, acute respiratory distress syndrome, disseminated intravascular coagulation, soft tissue inflammation, acute generalized exanthema and central nervous system involvements.

The number of STSS cases has been increasing since 2011; 241, 201, and 270 cases were reported in respective years from 2012 to 2014 (Table 1).  In 2015, number of reported cases reached 204 within the first 24 weeks (see p. 153 of this issue).  During 2012-2014, STSS was reported from all 47 prefectures in Japan; prefectures that reported more than 1 patient per 100,000 population were Toyama (1.86), Tottori (1.38), Fukui (1.13) and Ehime (1.07). Median age of patients was 67 years and male to female ratio 1.1 (370 males vs. 342 females).  Among 712 patients, 207 (29%) were deceased at the time of notification (Fig. 2). The median age of deceased patients was 72 years.  Seventy-six percent of deceased patients died within 3 days after disease onset.  Group A (58%) was the most frequent causative streptococci identified among STSS in 2012-2014, followed by group G (27%), which are currently increasing (Table 1).

2.  Pathogen surveillance
Since 1992, when the first STSS case was reported in Japan, Streptococcus Reference Center (SRC), jointly established by prefectural and municipal public health institutes (PHIs) and the National Institute of Infectious Diseases (IASR 18: 25-26, 1997; IASR 31: 76-77, 2010; IASR 33: 211-212, 2012), has been conducting pathogen surveillance, including T-serotyping, genotyping of emm gene (encoding M protein responsible for pathogenicity of S. pyogenes and SDSE), and antimicrobial susceptibility tests. 

1) T-serotyping: In 2011-2014, PHIs conducted T-serotyping for 947-1,240 isolates annually from GAS pharyngitis cases (Fig. 3a in p.149 of this issue).  During 2011-2012, T1 and T12 were dominant, while in 2013-2014, T12 and TB3264 became dominant (Fig. 3a).  On the other hand, among the 321 total isolates from STSS cases, T-serotype distribution (Fig. 3b in p.149 of this issue) was as follows: 153 (48%) T1, 58 (18%) TB3264, 23 (7%) T12, and 20 (6%) T28.  T1 was dominant and occupied 60-70% in 2010-2011 (IASR 33: 209-210, 2012), although decreased to 26-49% in 2012-2014 (Fig. 3b).  Among streptococci isolates from GAS pharyngitis and STSS cases in metropolitan Tokyo, many were similarly TB3264 in 2013-2014 (see p. 151 of this issue). 

2) emm typing:  As for emm typing, which can provide epidemiologically useful information, among 243 GAS isolates from STSS cases in 2012-2014, isolates with emm1 genotype occupied 41% (100 isolates) (see p. 154 of this issue). 

3) Antimicrobial susceptibility:  The first choice for treating β-haemolytic streptococci infections is penicillin-derivatives. The 1,608 isolates from GAS pharyngitis patients in 13 prefectures from 2011 to 2014 were all susceptible to β-lactam antibiotics, although about 60% were resistant to macrolides and 25% resistant to lincomycin and tetracycline (see p. 152 of this issue).  The recommended therapy for STSS is combination of high dose administration of penicillin-derivative antibiotics and clindamycin.  The 243 isolates from STSS patients during 2012-2014 were all susceptible to penicillin G, ampicillin, cefazolin, cefotaxime, meropenem and linezolid.  However, 28 isolates (12%) were resistant to clindamycin (see p. 155 of this issue).

3. Group B Streptococcus (GBS):  GBS may cause not only STSS but also invasive streptococcal infection in neonates via vertical transmission.  Recently, invasive GBS infection cases have been increasing, with the rate of invasive GBS infection among neonates within 3 months of birth in 2014 reaching 1.8 per 10,000 births (see p. 158 of this issue).  Among bacterial meningitis cases reported from approximately 500 sentinel hospitals under NESID, GBS has been the most frequent (bacterial meningitis caused by Haemophilus influenzae and Streptococcus pneumoniae that had been dominant until 2011 are now monitored separately). 

Recently, GBS with reduced penicillin susceptibility (PRGBS) has emerged.  Among all GBS isolates, about 15% of GBS were PRGBS and 10% were PRGBS with resistance to both macrolides and fluoroquinolones (see p. 156 of this issue). 

Additional comments: The reported number of GAS pharyngitis and STSS cases has been increasing in recent years.  Several food poisoning outbreaks due to S. pyogenes have been reported (IASR 34: 266-267 & 268-269, 2013).  Pediatric sentinel-based monitoring of GAS cases and notification of all STSS cases should be further strengthened.  Pathogen surveillance should be further intensified by means of T-serotyping, emm typing and antimicrobial susceptibility monitoring.  The pathogen surveillance data should be promptly fed back to clinicians so that the information can be used for understanding of ongoing streptococcal epidemics and for early diagnosis and therapy.  Streptococcal infection caused by S. suis that claimed many lives in Southeast Asia has been reported from Japan (see p. 159 of this issue) but do not exhibit the typical β-hemolysis (IASR 26: 241-242, 2005).  Paying attention to streptococci at large beyond those associated with β-hemolysis is important.

 

 

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The topic of This Month Vol.36 No.7(No.425)

Rubella and Congenital Rubella Syndrome in Japan, as of June 2015

(IASR 36: 117-119, July 2015)

Rubella and congenital rubella syndrome (CRS) are Category V infectious diseases.  Physicians who have made a diagnosis for either rubella or CRS shall notify all cases within 7 days, and preferably within 24 hours for prompt implementation of public health measures (Guidelines for the Prevention of Specific Infections: Rubella) (Ministry of Health, Labour and Welfare notice No. 122, March 28, 2014).  Notification criteria are found in http://www.niid.go.jp/niid/images/iasr/36/425/de4251.pdf for rubella, http://www.niid.go.jp/niid/images/iasr/36/425/de4252.pdf for CRS; patients having all of the triad (small erythema/pink papule on the whole body, fever, and lymphadenopathy) without laboratory confirmation are classified as “clinically confirmed rubella” and those with at least one of the clinical symptoms and laboratory confirmation are classified as “laboratory-confirmed rubella”.

National Epidemiological Surveillance of Infectious Diseases (NESID)–Rubella:  The reported number of rubella patients increased from a total of 378 in 2011 to 2,386 in 2012 and to 14,344 in 2013 (Fig. 1, upper panel).  The reported number of rubella patients dropped to 320 in 2014. From 2011 to 2015 (through week 25), 63-78% of the reported cases were laboratory-confirmed, 80% of which were by IgM antibody detection (Fig. 1, upper panel).  Although clinical diagnosis of rubella can be assisted by epidemiological information, laboratory diagnosis is strongly recommended for differential diagnosis from other infectious diseases and syndromes, such as erythema infectiosum, measles, infectious mononucleosis, enterovirus infections, streptococcal infections, and drug rash.

From 2011 to 2015 (week 25), 13,305 male and 4,214 female rubella patients (3-fold more males than females) were notified. In the 2013 epidemic, the number of male patients (664 cases) peaked in the 19th week and that of female patients (241 cases) peaked in the 21st week (Fig. 1, lower panel).  In 2011, only a few prefectures, such as Fukuoka, Kanagawa and Osaka, reported relatively large number of rubella cases (Fig. 2 in p. 119 of this issue).  However, in 2012, all prefectures except Ishikawa, Tokushima and Miyazaki reported cases, and in 2013, all 47 prefectures reported cases (112.7/1,000,000 population).  In 2014, Tokyo and Kanagawa prefectures reported relatively large number of cases.

Among reported rubella patients, men in their early thirties and women in their early twenties were the age groups most reported in 2011-2012, while in 2013, men in their late thirties and women in their early twenties were the most reported age groups (Fig. 3).  Women in their early twenties include those who were born on or prior to April 1, 1990, when a single dose was offered as routine immunization.

NESID–CRS:  Women infected by rubella within 20 weeks of gestation are at risk of giving birth to CRS infants (see p. 125 of this issue).  A total of 45 CRS cases were reported from week 42 of 2012 to week 40 of 2014; reports of CRS cases rose substantially (>3 cases/week) 5-6 months after the peak in reported female rubella cases (Fig. 1, lower panel).  The top six prefectures with the largest number of reported CRS cases, by suspected place of infection (Fig. 4), was Saitama (6 CRS cases), Chiba (3 CRS cases), Tokyo (11 CRS cases), Kanagawa (6 CRS cases), Osaka (7 CRS cases) (see p. 120 of this issue) and Hyogo (3 CRS cases) ; the number of rubella cases during 2012-2013 for the respective prefectures were 704, 824, 4,116, 1,944, 3,600, and 1,455 cases (Fig. 2 in p. 119 of this issue).

Follow-up testing of throat swabs of 12 CRS infants revealed that the rubella virus frequently persisted for three months but up to 13 months after birth (see p. 120 of this issue).  As newborns without any signs or symptoms may develop hearing loss (see p. 123 of this issue) or cataract later, infants born to mothers infected or suspected to be infected with rubella require careful monitoring.

Routine immunization coverage:  As of May 2015, two doses of measles-rubella (MR) combined vaccine are provided as routine immunization, with the first dose at one year of age and the second dose within 1 year prior to primary school entrance. During fiscal year 2011 to 2013, the vaccination coverage was 95.3-97.5% for the first dose and 92.8-93.7% for the second dose (see p. 132 of this issue).

Rubella seropositivity in the population (National Epidemiological Surveillance of Vaccine-Preventable Diseases):  In 2014, 17 prefectural and municipal public health institutes (PHIs) in Japan surveyed 5,743 healthy individuals (2,882 males and 2,861 females) for rubella hemagglutination inhibition (HI) antibody level (Fig. 5 in p. 119 of this issue). The proportion seropositive (≥8 HI titers) was 25-27% in infants <1 year of age, 63-67% in one year olds, and ≥90% among those 2-29 years of age (93% in males and 96% in females).  The proportion seropositive was ≥90% for female adults in all age groups, but varied among male adults (82% for 35-39 years, 79% for 40-44 years, 74% for 45-49 years, and 77% for 50-54 years) (see p. 130 of this issue).  This gender difference is due to the fact that only women received routine rubella vaccination among those born between April 2, 1962 and April 1, 1979.

Rubella epidemics overseas and virus genotypes:  Globally, many countries in the world repeatedly experience large scale rubella epidemics, and WHO estimates that 110,000 CRS infants are born annually.  The World Health Assembly in 2012 adopted the resolution to eliminate rubella by 2020 in five of the six WHO regions, and the Americas region was the first to attain this goal, in April 2015.

There are currently 13 known genotypes for rubella virus.  From 2011 to June 2015, globally circulating genotypes were 1a, 1E, 1G, 1J and 2B; notably, genotype 2B had spread globally since 2006.  Genotypes prevalent in the WHO’s Western Pacific and Southeast Asian Regions are 1E and 2B.  As the number of circulating genotypes has recently declined, phylogenetic analysis of the isolates is becoming necessary for tracing the movement of rubella virus (see p. 135 of this issue).

Challenges and next steps:  Japan aims to eliminate rubella by 2020 and achieve zero CRS cases.  Special guidelines outlining the necessary activities are now available (see p. 133 of this issue).  The 2013 rubella epidemic (IASR 34: 348-349, 377-378, 2013 & 35: 17-19, 2014), however, revealed the persistence of large number of susceptible male adults in Japan.  Thus, without intervention in this population, achieving such goals will be difficult.  As the most frequent place for rubella transmission was the workplace during the 2013 epidemic, the role of companies, particularly their occupational physicians at the workplace, needs to be emphasized (see p. 128 of this issue).  The Day Care Division of Equal Employment, Children and Families Bureau, MHLW, recommends conducting rubella antibody tests or vaccination to trainees at nursing training facilities who do not have a history of rubella infection or vaccination (see p. 134 of this issue).

The National Institute of Infectious Diseases has produced guidelines on i) rubella prevention in the workplace, ii) rubella prevention in medical settings, iii) local government’s response to rubella outbreaks, iv) establishment of committees and other measures for rubella control at the prefectural level, and v) guidelines for the notification of rubella and CRS for medical doctors.

Elimination of rubella by 2020 requires the concerted efforts of relevant stakeholders, and each and every person should work towards this goal.  The following measures should be taken:

1.   Communicate that the risk of CRS can be prevented by vaccination not only to women expecting pregnancy and their family but also to unmarried men and women. Higher accessibility to antibody testing and MR vaccination to this population should be attained (see pp. 120, 122 & 129 of this issue).

2.  Consultation services concerning CRS should be provided to physicians in primary obstetric facilities; currently 16 secondary obstetric facilities in the nine prefectural blocks in Japan provide such services (see p. 122 of this issue).

3.  Post-delivery vaccination to women with rubella HI antibody ≤16.

4.  In the case of an outbreak involving a company, there should be cooperation between the affected company and regulators. In fact, when rubella emerged in a company that had branches in Asian countries, collaboration between the company, the local health centers, and the local government successfully prevented further expansion of the outbreak in 2015 (see p. 126 of this issue).   

It should be reminded that MR vaccination without prior antibody testing does not cause any harm.  What should be avoided is to neglect follow-up of people found to lack antibody against rubella.

 

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The topic of This Month Vol.36 No.6(No.424)

Ebola hemorrhagic fever in West Africa, as of May 2015

(IASR 36: 93-94, June 2015)

Ebola hemorrhagic fever is one of the viral hemorrhagic fevers that include Lassa fever, Marburg disease and Crimean-Congo hemorrhagic fever.  More recently, it is being called Ebola virus disease (EVD), as it is not always associated with hemorrhage.  Ebola virus’s genome is a single-stranded RNA with negative polarity.  It belongs to the genus Ebolavirus, family Filoviridae; five species, Zaire, Sudan, Bundibugyo, Taï Forest, and Reston are known, among which Zaire ebolavirus is considered the most virulent and a causative agent of the present Ebola hemorrhagic fever outbreak in West Africa (see pp. 96 & 100 of this issue).

Ebola hemorrhagic fever was first reported from Sudan and the Democratic Republic of Congo (former Zaire) in 1976.  The natural reservoir of Ebola virus is wild animals, such as bats.  Human outbreaks begin with the index case having contact with the infected animals’ body fluids, subsequently spreading from person to person through the patients’ blood or body fluids.  Incubation period is 2-21 days.  Cases remain non-infectious during the incubation period.  Typically, the disease starts with sudden fever, profound malaise, myalgia, headache and throat pain, which is followed by vomiting, diarrhea, rash, liver and renal dysfunctions, with a bleeding tendency.  Treatment is supportive, such as provision of intravenous fluids (see pp. 98, 101 & 108 of this issue).

Ebola hemorrhagic fever outbreaks in Africa
Since 1976, nearly 30 Ebola hemorrhagic fever outbreaks have been reported, mostly from Central Africa, such as Uganda and the Democratic Republic of Congo.  During 1976-2013, the median number of patients per outbreak was 44 (range 1-425) and that of deaths 29 (range 1-280).  The duration of the epidemics was from several weeks to ~4 months (see p. 96 of this issue).

Since cases of Ebola hemorrhagic fever from Guinea in West Africa were reported to the World Health Organization (WHO) in March 2014, the outbreak expanded to neighboring Sierra Leone and Liberia, and became the largest Ebola hemorrhagic fever outbreak ever experienced (see p. 96 of this issue).  The index case is believed to have been a two-year-old child that became ill in December 2013.  As of 20 May 2015, a total of 26,969 patients (including probable and suspected cases) and 11,135 deaths were reported to WHO; 3,635 (2,407 deaths) were from Guinea, 10,666 (4,806 deaths) from Liberia, and 12,632 (3,907 deaths) from Sierra Leone.  The number of new infections peaked in the latter half of 2014 and have declined in 2015 (Figure).  As of 20 May 2015, Guinea and Sierra Leone reported around 10 new cases per week, considerably lower than 100 cases per week during the peak period.  Liberia was declared free of Ebola transmission on 9 May 2015 (see p. 96 of this issue).

Suspected transmission route: As with previous Ebola hemorrhagic fever outbreaks, the 2014 epidemic likely began with animal-to-human transmission.  The virus then spread to multiple persons through infected patients’ blood and body fluids, infected corpses and the water used for cleansing corpses during traditional burial rituals.  Through repetition of such practices, transmission was amplified (see pp. 96, 99 & 100 of this issue).  In addition, in the three West Africa countries, medical facilities also became sites of transmission, as implementing sufficient infection prevention and control measures were challenging (see pp. 98 & 99 of this issue).  Importations of Ebola hemorrhagic fever patients from West Africa have been reported from Nigeria, Senegal, Mali, the USA, Spain, UK and Italy, as of 14 May 2015.  However, all of them were able to break the transmission chain by implementing appropriate measures, such as isolation of confirmed or suspected Ebola hemorrhagic fever patients and quarantine of those who had history of contact with Ebola hemorrhagic fever patients (see p. 104 of this issue).

Sex and age: Majority of patients were 15-44 years of age in all three West African countries.  Incidence per 100,000 population within the age groups of 0-14 years, 15-44 years and ≥45 years were, respectively, 11, 39 and 53 in Guinea; 33, 120 and 132 in Liberia; and 79, 211 and 279 in Sierra Leone.  Sex differences were not observed (see p. 96 of this issue).

Prevention and control measures
Given the transmission route of Ebola hemorrhagic fever, standard prevention and control measures against contact infections are important.  Minimizing contact with infected corpses, appropriate isolation and care of Ebola hemorrhagic fever patients, tracing contacts of confirmed Ebola hemorrhagic fever patients and their quarantine can break the transmission chain (see p. 103 of this issue).  Vaccines and therapeutics are under development but none of them have been approved for clinical use (see p. 101 of this issue). 

The international community, in coordination with the three affected West African countries, took systematic actions to prevent the spread of the Ebola epidemic.  WHO declared a “Public Health Emergency of International Concern” and played a leading role in public health actions against Ebola.  Many countries, including Japan, dispatched experts to the three African countries via WHO (see pp. 98, 99, 108 & 111 of this issue).  In September 2014, the United Nations launched the UN Mission for Ebola Emergency Response (UNMEER) and coordinated the support activities of UN agencies and partners (see p. 103 of this issue).

Laboratory Diagnosis in Japan
In Japan, Ebola hemorrhagic fever is a category I infectious disease under the Infectious Diseases Control Law (see pp. 95 & 106 of this issue).  Physicians who have made the diagnosis of Ebola hemorrhagic fever shall immediately notify the case (see http://www.niid.go.jp/niid/images/iasr/36/424/de4241.pdf for notification criteria).

 

“Suspected cases” are defined as “cases diagnosed as such by physicians based on such information as clinical manifestations, travel history to Ebola virus endemic countries, and contact history with Ebola hemorrhagic fever patients”. Suspected cases are sent to medical institutions designated for specified infectious diseases (see pp. 106 & 108 of this issue) for isolation.  The blood specimens are immediately sent to the National Institute of Infectious Diseases (NIID) for Ebola virus genome detection.  NIID conducts several Ebola virus genome tests at the same time: real-time PCR & conventional PCR targeting at the L gene and the conventional PCR targeting at the NP gene (see p. 109 of this issue).  As of May 2015, those with high fever (≥38ºC) who have stayed in Guinea or Sierra Leone in the past 21 days or those who are feverish with a history of contact with viral hemorrhagic fever patients’ body fluids in the past 21 days, are defined as viral hemorrhagic fever-suspected patients (Notice by Director, Tuberculosis and Infectious Diseases Control Division, Health Service Bureau, Ministry of Health, Labour and Welfare [Ken-kan-hatsu 0511 No.2]).  From 27 October 2014 to 19 May 2015, seven suspected cases were reported; all of them were negative for Ebola virus genome test (see pp. 108 & 109 of this issue).

Measures to be taken
Although incident cases of Ebola hemorrhagic fever patients in the three West African countries have been decreasing as of May 2015, the three West African countries and the international community need to maintain their vigilance until the end of the outbreak is definitively confirmed.  In addition, to be better prepared for cases of viral hemorrhagic fever, including Ebola hemorrhagic fever, there is a need to maintain laboratory diagnostics and infrastructure (see p. 109 of this issue).

 

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The topic of This Month Vol.36 No.5(No.423)

Enterohemorrhagic Escherichia coli infection as of April 2015

(IASR 36: 73-74, May 2015)

Enterohemorrhagic Escherichia coli (EHEC) infection is a systemic infection of pathogenic E. coli that produces Verotoxin/Shiga toxin (VT/Stx) or possesses the VT encoding genes.  Main symptoms consist of abdominal pain, watery diarrhea, bloody diarrhea and occasional high fever (38ºC) and/or vomiting.  Hemolytic uremic syndrome (HUS), which can be fatal among the elderly and children, is attributed to VT that causes thrombocytopenia, hemolytic anaemia and/or acute renal failure.

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).  A physician who has made the diagnosis of EHEC infection shall notify all such cases to a health center (HC), who then transmits the information to the National Epidemiological Surveillance of Infectious Diseases (NESID) system (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 HC, 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.  Prefectural and municipal public health institutes (PHIs) conduct isolation of EHEC, serotyping of the isolates and typing of VT; the obtained data are sent to NESID (see p. 75 of this issue).  The Department of Bacteriology I of the National Institute of Infectious Diseases (NIID), meanwhile, conducts molecular epidemiological analysis of outbreaks using pulsed-field gel electrophoresis (PFGE) or multiple-locus variable-number tandem-repeat analysis (MLVA) methods and, where necessary, confirmatory tests of the isolates sent from PHIs (see p. 83 of this issue).  The NIID’s analysis results are fed back to PHIs and to local governments through the National Epidemiological Surveillance of Foodborne Disease (NESFD) system.

Cases notified under NESID:  In 2014, a total of 4,153 EHEC cases were reported; 2,839 were symptomatic cases and 1,314 were asymptomatic cases (detected during active surveillance of outbreaks or routine stool specimen screening of food handlers) (Table 1).  Owing to multiple large-scale food poisoning incidents, the number of notified cases in 2014 was highest since 2009.  Weekly number of reported cases in 2014 was largest during summer as usual (Fig. 1).  Reports from Shizuoka, Tokyo, Kanagawa, Saitama, Hokkaido and Osaka prefectures occupied 41% of all nortified cases.  The notification rate (cases per 100,000 population) was highest in Shizuoka prefecture (10.26), which experienced a large-scale food poisoning outbreak, followed by Nagasaki (10.24) and Iwate prefecture (10.19) (Fig. 2).  Notification rates within the 0-4 year old population were high in Nagasaki, Iwate and Kumamoto prefectures, where nursery school outbreaks occurred (Fig. 2).  A large proportion of symptomatic cases were among those <30 years and ≥60 years of age, as in previous years (Fig. 3).

A total of 102 HUS cases (3.6% of symptomatic cases) were reported in 2014, and among them EHEC was isolated from 70 cases: their O-serogroup were O157 (56 isolates), O26 (3 isolates), O121 (3 isolates), O111 (2 isolates), O165 (2 isolates), O115 (1 isolate) and the remaining 3 cases were untypable/unknown (see p. 84 of this issue).  Sixty-one isolates were positive for VT2 alone or VT2&VT1, five were positive for VT1 alone, and the remaining four were unknown for VT-type.  Two fatal cases were reported. Among symptomatic EHEC cases, HUS was highest among those <5 years of age (7.2%).

EHEC isolated by PHIs:  In 2014, PHIs reported 2,289 EHEC isolations, much less than the reported number of EHEC cases (Table 1).  This discrepancy is due to the current situation where not all isolates from clinical or commercial settings are sent to PHIs.  The most frequent O-serogroup was O157 (59%), followed by O26 (22%), O145 (4.1%) and O103 (4.1%) (see p. 75 of this issue).  Those positive for VT1&VT2 genes or their toxin products occupied 76% of all O157 isolates as in previous years.  Among O26, O145 and O103, those positive for VT1 alone occupied 97%, 67%, and 100%, respectively.  Information on clinical signs and symptoms was obtained from 1,244 cases among a total of 1,355 O157 cases; the majority were abdominal pain (62%), diarrhea (62%), bloody diarrhea (47%), and fever (22%).

Outbreaks:  Among EHEC outbreaks reported by PHIs to NESID in 2014, Table 2 shows key outbreaks consisting of 10 or more EHEC positives and notable food poisoning outbreaks.  Fifteen outbreaks were suspected to be transmitted person-to-person in nursery schools (see p. 81 of this issue).

Under the Food Sanitation Law, 25 EHEC food poisoning incidents, comprising 766 cases (cases without isolation included) were reported in 2014 (see p. 76 of this issue).  Notable incidents include: O157 food poisoning outbreak attributed to the consumption of contaminated raw horse meat, which spread to 11 prefectures in late March-April (see p. 76 of this issue); O26 food poisoning due to contaminated processed meat in a restaurant chain in 3 prefectures in May-June (see p. 79 of this issue); O157 food poisoning in a restaurant in Chiba prefecture in July (see p. 77 of this issue); and O157 food poisoning of 510 cases, who consumed contaminated lightly pickled cucumbers sold at food stands during a fireworks display in Shizuoka prefecture in August (see p. 80 of this issue).  In addition to these cases, the Department of Bacteriology I, NIID, which conducts molecular epidemiologic analysis, identified identical PFGE and MLVA patterns among EHEC isolates obtained from several sporadic cases without known epidemiological linkage, indicating the possible presence of unrecognized widespread diffuse EHEC outbreaks (see p. 83 of this issue).

Prevention and measures to be implemented:  In response to food poisonings caused by raw beef, MHLW revised the standards of the beef marketed for raw consumption (MHLW notice No. 321, October 2011).  Further, upon the detection of EHEC O157 in the inner part of marketed cattle liver, MHLW banned marketing of cattle liver for raw consumption (notice No. 404 in July 2012) (IASR 34: 123-124, 2013).  The number of reported O157 cases related to consumption of raw beef or raw cattle liver has been declining since.  However, the total number of EHEC cases has not declined, and for reducing the number of EHEC cases it is important to follow safe food handling practices and avoid consumption of insufficiently cooked meat.

EHEC establishes infection even at a dose as low as ~100 bacteria.  It can easily spread from an infected person to other persons directly or indirectly through foods or food material.  In 2014, as in 2013, there were several EHEC outbreaks in nursery schools (Table 2 & see p. 81 of this issue).  Preventing such outbreaks requires appropriate hygienic practice, such as routine hand washing and sanitary use of children’s pools (see “Infection Control Guidelines for Nurseries” revised in November 2012).  In case a member in a family or a welfare facility is infected by EHEC, the health center should give full instructions to the family or the facility on the preventive measures to be taken for preventing secondary infections.

 

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The topic of This Month Vol.36 No.4(No.422)

Measles in Japan, as of March 2015

(IASR 36: 51-53, April 2015)

Measles is an acute infectious disease caused by the highly infectious measles virus.  Main clinical manifestations are fever, rash and catarrh.  Pneumonia and encephalitis are major complications that may lead to death.  Subacute sclerosing panencephalitis (SSPE) is a rare complication of measles.  The encephalitis develops several years after infection, and its prognosis is extremely poor.  No effective cure is presently available (see p. 67 of this issue).

Japan has been making progress towards measles elimination using the guidelines of Ministry of Health, Labour and Welfare (MHLW), “Special infectious disease prevention guidelines for measles” (MHLW Notice 442 issued on 28 December 2007; MHLW Revised Notice 126 issued on 30 March 2013).  The elimination target year was fiscal year (FY) 2015.  In 2014, Japan’s National Verification Committee for Measles Elimination announced that Japan was free of the endemic strain D5 for three years in the presence of a well performing surveillance system (see p. 65 of this issue).  On 27 March 2015, the Regional Verification Commission for Measles Elimination in the Western Pacific Region verified that Brunei Darussalam, Cambodia and Japan have interrupted endemic transmission of measles and confirmed that Australia, Macao (China), Mongolia and the Republic of Korea have maintained interruption of endemic measles transmission since the last verification in 2014 (http://www.wpro.who.int/mediacentre/releases/2015/20150327/en/).

Measles incidence under the National Epidemiological Surveillance of Infectious Diseases:  Since January 2008, the Infectious Diseases Control Law requests notification of all measles cases (IASR 34: 21-22, 2013).  As shown in Fig. 1, the number of measles cases started increasing towards the end of 2013 and the trend continued well into 2014.  The outbreak was initiated by measles imported from the Philippines and other Asian countries (see p. 57 of this issue).  The outbreaks involved medical facilities (see p. 54 of this issue) and nursery schools (IASR, 35: 278-280, 2014).  The outbreak waned around week 18 of 2014, thanks to response activities, including active surveillance (see pp. 54 & 55 of this issue), aimed at preventing further transmission (Fig. 2).  As for the period from January to March, the year 2015 recorded the lowest number of cases in the past 7 years (Fig. 2). 

As for age distribution (Table 1 in p. 53), cases in their 10’s have decreased drastically owing to successful catch-up immunization, which started in 2008 as a limited 5 year measure (target populations were 13 year old 1st grade junior high school and 18 year old 3rd grade senior high school students).  The proportion of adult cases (≥20 years of age) was 33% in 2008, 36% in 2009, 37% in 2010, 48% in 2011, 58% in 2012, 70% in 2013 and 47% in 2014.  In 2014, among 462 cases, there were 216 (47%) measles cases without any vaccination, 87 (19%) with 1 dose, 32 (7%) with 2 doses, and 127 (27%) with unknown vaccination status (Fig. 3 in p. 53).  Infants (0-1 year of age) occupied 20% of the cases (93/462), 83% of whom were unimmunized, and among 142 of 6-24 year old cases that should have received 2 MCV doses, 70 were not vaccinated (49%).

Isolation and detection of measles virus:  The measles virus genotype D5 that had been endemic in Japan has not been detected for 4 years and 10 months (i.e., not reported since May 2010) (Fig. 4 in p. 53).  In 2014, a total of 366 measles strains were isolated or detected (Table 2 in p. 53).  The largest number of cases were of genotype B3 (261 cases; of 63 derived from the Philippines), followed by D8 (57 cases), D9 (22 cases) and H1 (15 cases).  Eleven cases had undetermined virus genotype(s).  After detection of a single case, all outbreaks were subjected to active surveillance and laboratory investigation.  In 2015, genotype H1 was detected from 1 case (returnee from China) and D8 genotype was detected from 2 cases (one with travel history to Indonesia) (Fig. 4 in p. 53, as of 31 March, 2015).

Laboratory diagnosis:  Laboratory diagnosis is essentially required for all suspected measles cases by law (notification criteria: http://www.niid.go.jp/niid/images/iasr/35/410/de4101.pdf).  Once measles infection is suspected clinically, the case shall be notified to the nearby health centres (HC), whenever possible, within 24 hours.  The HC arranges shipping of the acute phase clinical specimens (a set of EDTA-treated blood specimen, throat swab and urine specimen obtained within 1 week after onset of rash) from medical institutions to prefectural and municipal public health institutes (PHIs) for virus isolation/detection/genotyping.  The medical institution also sends the clinical specimens to a commercial laboratory for IgM testing (covered by national medical insurance).  Once a definitive diagnosis is made by the clinical and laboratory findings, the notified “clinically-diagnosed measles” is reclassified as “laboratory-confirmed measles”; if the laboratory results are negative, the notification is retracted. 

While only 38% of notified cases in 2008 were laboratory-confirmed cases, the proportion was ≥90% in 2014.  In 2014, 78% of the reported cases were confirmed by PCR and genotyped in PHIs.  The information collected through these activities supported the conclusion of the ≥12 months interruption of endemic measles transmission in Japan (see p. 59 of this issue).  In March 2015, the section on measles in the laboratory manual for pathogen detection was revised; the current version, 3rd edition, is now available.

The National Epidemiological Surveillance of Vaccine-Preventable Diseases:  In 2014, 23 PHIs in Japan conducted particle agglutination (PA) assay from serum obtained from 6,785 persons, such as healthy blood donors and those receiving health-checks (see p. 60 of this issue).  Overall, PA antibody positivity (defined as ≥ 1:16 titers) has been ≥95% in the past 4 years since FY2011.  The positivity was 73% among 0-5 month old infants (mainly attributable to maternal antibody) and 12% in 6-11 month old infants.  After reaching 12 months of age, the antibody level increases through routine immunization.  All age groups 2 years and above have maintained ≥95% positivity (Fig. 5).

Vaccination rate:  Since FY2006, routine immunization in Japan has adopted measles-rubella combined vaccine, administered as two doses, the first to children aged one year (1st vaccination) and the second to children one year before school entry (2nd vaccination).  In addition, from FY2008 to FY2012, supplementary vaccination was conducted for children whose age corresponded to those of the first grade of junior high school (3rd vaccination) and to those whose age corresponded to those of the third grade of high school (4th vaccination) to ensure two doses in these age groups as well.

The 1st vaccination covered ≥95% of the target population for 4 consecutive years from FY2010 to FY2013 (see p. 62 of this issue). The 2nd vaccination was 93% in FY2013, 2% short of the 95% target.  The vaccination rates of the 1st and 2nd vaccinations in FY2013 were lower than those in FY2012.  To stop the declining trends, it has been advised to promote the first immunization (1st vaccination) immediately after attaining 1 year of age and the second immunization (2nd vaccination) during April to June, early in the fiscal year, in the year preceding school entry. 

Further measures to be taken:  In compliance with the “Special infectious disease prevention guidelines for measles”, coverage of the 1st and 2nd vaccination should be maintained at or above 95% so as to maintain population immunity sufficiently high enough to prevent measles transmission, even in case of importation.  As many countries are measles endemic (see p. 68 & 70 of this issue), vaccination is recommended for those going to measles-endemic countries.  Active surveillance should be conducted even if only a single case is detected and preventive measures should be taken immediately so as to interrupt endemic transmission.  The notification format for clinicians was revised to include the patient’s name and address, which is indispensable for rapid investigation and response (to be enforced on 21 May 2015).

 
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The topic of This Month Vol.36 No.3(No.421)

Dengue fever and dengue hemorrhagic fever, 2011-2014

(IASR 36: 33-35, March 2015)

Dengue virus is a member of the flavivirus family with four known serotypes, type 1-4.  It is transmitted to humans by mosquitoes Aedes aegypti and Aedes albopictus, via the human to mosquito to human cycle.  Ae. aegypti are often found in urban areas while Ae. albopictus is found in both urban and rural areas, including in much of Japan.  Persons bitten by infected mosquitoes develop clinical signs or symptoms, such as fever, exanthema and pain (mainly arthralgia), 3-7 days later (see pp.35, 38 & 41 of this issue, IASR 35: 241-242, 2014).  Dengue fever is endemic in many tropical/sub-tropical areas of the world (see p. 46 of this issue).  No commercialized vaccine or specific therapies are available (see p. 44 of this issue), and patients are treated symptomatically with rehydration and/or antipyretic analgesics.  Hemorrhage or shock syndrome, though rare, may occur; fatality can be reduced by appropriate treatments. 

1. National Epidemiological Surveillance of Infectious Diseases (NESID)
   Dengue fever is a Category IV infectious disease under the Infectious Diseases Control Law.  Physicians who have made a diagnosis of dengue fever must notify the cases immediately (see http://www.niid.go.jp/niid/images/iasr/36/421/de4211.pdf for notification criteria). 

During 2007-2009, 89-105 dengue cases were reported annually.  From 2010 to 2013, during each year, 244, 113, 221, and 249 cases were reported, respectively (Fig. 1 and Table 1).  In 2014, a total of 341 cases were notified, which included 179 imported cases and 162 autochthonous cases; it had been nearly 70 years since the last confirmed autochthonous dengue case was reported in Japan (see pp.35, 37& 38 of this issue).  In recent years, the majority of dengue virus serotypes detected among imported cases were type 1 (Table 2).  Among autochthonous cases detected in 2014, only serotype 1 was detected (see pp. 35, 37, 38 &40 of this issue). 

Seasonality: Historically, the number of reported dengue cases has been highest during August-September, including in 2011- 2014 (IASR 32: 159-160, 2011) (Fig. 1).  The trend is likely attributable to seasonality of travelers going abroad and the dengue activity level at their destinations (see p. 46 of this issue).  Among autochthonous cases in 2014, the majority (133 of 162 cases) were also diagnosed in September (Fig. 1).

Suspected place of infection: During 2011-2014, suspected place of infection included at least 37 countries/areas (Table 3).  During 2011-2013, 554 of 583 cases (95%) had visited Southeast and other Asian countries, such as Indonesia, the Philippines, Thailand, India, Cambodia, and Malaysia. There were also cases who had traveled to Central and South America, Oceania or Africa. Similarly, in 2014, 165 of 179 imported cases (92%) were suspected to have been infected in the Asian region. Among 162 autochthonous cases, 159 were suspected to be infected in Tokyo (see pp. 35 & 37 of this issue).

Gender and age: Among 762 imported cases reported in 2011-2014, 471 were male (62%) and 291 female (38%) . There were 218 cases in their 20s (29%), 201 cases in their 30s (26%) and 126 cases in their 40s (17%) (Fig. 2). Among 162 autochthonous cases in 2014, similarly, 95 (59%) were male. While the median age among autochthonous cases was 27 years, age distribution varied widely, from 4 to 77 years (Fig. 2). 

Dengue hemorrhagic fever: About 5% of all imported dengue cases in recent years were dengue hemorrhagic fever (DHF) cases [4/133 (4%) in 2011, 13/221 (6%) in 2012, 11/249 (4%) in 2013, and 8/179 (4%) in 2014)] (Table 1).  The median age among DHF cases was 32 years (range: 3-64 years).  There was no gender difference in the proportion of dengue cases that were DHF, with 23 DHF among 471 dengue cases (5%) in males and 13 DHF among 291 dengue cases (4%) in females. Among 162 autochthonous cases in 2014, there was only one DHF case (1%).  No fatal cases were reported during 2011-2014.  

2. Laboratory diagnosis
Prefectural and municipal public health institutes (PHIs) and the National Institute of Infectious Diseases (NIID) conduct laboratory diagnosis of dengue fever including virus isolation, viral genome detection by RT-PCR, and serological tests (e.g. IgM antibody detection and neutralization test) (see p. 40 of this issue).  Amendment of the Quarantine Law in November 2003 included dengue fever in the list of quarantine-authorized infectious diseases; enabling quarantine stations to offer medical examinations and laboratory testing to travelers coming from dengue fever endemic areas (IASR 35: 112-114, 2014).  The detection of the non-structural protein NS1 antigen was added to the notification criteria of dengue fever in April 2013, and during the domestic dengue fever epidemic in 2014, the rapid diagnostic kits based on NS1 antigen detection were distributed to the PHIs (see pp. 40 & 41 of this issue).  Since 2013, majority of laboratory diagnoses for dengue were RT-PCR  for viral genome detection, IgM antibody detection and NS1 antigen detection (Table 4).

3. Countermeasures in Japan
As Ae. albopictus, a dengue fever vector, inhabits Japan (see p. 42 of this issue), and as the number of imported cases coming from dengue endemic countries continue to increase, there is an ongoing concern for potential dengue outbreaks in Japan.  In 2014, dengue cases infected in Japan were also reported from abroad (see p. 39 of this issue). Prevention and countermeasures against dengue fever are important not only domestically but also internationally, given the ever increasing globalization of human travel.  For preventing the spread of mosquito-borne infectious diseases, such as dengue fever and chikungunya fever (see pp. 47 & 48 of this issue), the Ministry of Health, Labour and Welfare is planning to release the guidelines specific for mosquito-borne infectious diseases in April 2015.  The guidelines recommend, as necessary measures, (i) routine, ongoing implementation of control measures against mosquitoes that transmit infectious diseases, (ii) rapid detection of human cases of mosquito-borne infectious diseases, (iii) implementation of prompt and appropriate measures against mosquitoes in case of outbreaks, and (iv) provision of appropriate medical care to patients.  For combatting dengue fever, not only government and medical personnel but each and every citizen must actively participate.  

 

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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.

 

Copyright 1998 National Institute of Infectious Diseases, Japan

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