国立感染症研究所

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The Topic of This Month Vol.35 No.4 (No.410)

Measles in Japan, as of March 2014

(IASR 35: 93-95, April 2014)

Measles is characterized by high fever, general exanthema and prodromal catarrh symptoms (notification criteria http://www.niid.go.jp/niid/images/iasr/35/410/de4101.pdf).  Severe com-plications include pneumonia and encephalitis.

In response to the massive outbreak in 2007 that mainly affected those aged 10-20 years, the Ministry of Health, Labour and Welfare announced the “Special Infectious Disease Prevention Guidelines on Measles” (Prevention Guideline in short) on December 28, 2007 (see p. 96 of this issue).  In April 2013, the Prevention Guideline was revised to include an objective, “accomplishing measles elimination by 2015 to obtain measles elimination verification from WHO and maintaining the elimination status thereafter”.

Measles incidence under the National Epidemiological Surveillance of Infectious Diseases:  Largely owing to the catch-up immunization conducted in 2008-2012 targeting age groups corresponding to children in the 1st year of junior high school and those in the 3rd year of high school (IASR 33: 27-29, 2012), measles incidence decreased steadily (Fig. 1) (see also https://idsc.niid.go.jp/iasr/33/384/graph/f3841.gif).  In 2013, despite the large measles outbreak in China and other Western Pacific countries (see p. 97 of this issue), the incidence in Japan was the lowest since the start of notification of all measles cases (Fig. 2), i.e., 232 in total or 1.8 per million population.

Since October 2013, however, measles incidence has been increasing in various locations in Japan.  Most cases were imported from or associated with cases from the Philippines (see pp. 98, 102 & 103 of this issue).  In 2014, the total number of patients notified from week 1 to week 12 was 206 (as of March 26, 2014), which was the highest number of reported cases for the same corresponding period during the past 6 years (Fig. 2).  Suspected nosocomial transmissions have been reported in various locations (see pp. 105, 107 & 108 of this issue).  Owing to prompt measures including vaccinations, large-scale measles outbreaks have been avoided so far.

As for measles encephalitis, a one-year-old case was reported in 2013 and an adult case (30’s) case has been reported in 2014 as of the 12th week.

In 2013, notifications from the Tokyo metropolitan area, Saitama, Kanagawa and Chiba prefectures occupied 64% of all notified cases; the largest number of cases were reported from Tokyo (67 cases) followed by Kanagawa (34 cases), Saitama (27 cases), Aichi (24 cases) and Chiba (20 cases) prefectures.  In 2013, 35 prefectures (in contrast to 32 prefectures in 2012, 19 prefectures in 2011) reported less than one case per million population (WHO’s measles elimination indicator, IASR 32: 34-36, 2011), among which 28 prefectures reported no case.  As of week 12 of 2014, Tokyo has reported 34 cases, Shizuoka 23 cases, Chiba 22 cases, Kyoto 21 cases and Saitama 18 cases.

As for age distribution (Fig. 3 in p. 95), those older than 20 years occupied nearly 70% of the reported cases; those aged 10-19 years, who made up 43% of reported cases in 2008, was reduced to 6%, indicating the likely success of the vaccination program in recent years.  From the beginning of 2014, however, patients <20 years of age have been increasing, and, as of the 12th week, 57% of reported cases were of this age group.  The male-to-female ratio so far in 2014 is 1:1 in contrast to 3:2 in 2013.

Among the 232 measles patients notified in 2013, 52 (22%) had received no vaccination, 51 (22%) one dose and 9 (4%) two doses.  The vaccination status of the remaining 120 cases (52%) was unknown.  All cases less than one year of age had not received vaccination.  Among 163 cases older than 20 years of age, 21 (13%) had received no vaccination and the vaccination status for the 111 (68%) were unknown.

Among the 206 measles cases notified up to week 12 of 2014, there were 113 unvaccinated cases (55%), 31 cases with one dose, 13 cases with two doses and 49 cases with unknown vaccination status.  So far in 2014, the proportion unvaccinated among measles cases, has been the highest since 2008 (Fig. 4 in p. 95).

As for school closure due to measles, while there were none in 2013, in 2014 a high school and a primary school were closed in January and in February, respectively.

Isolation and detection of measles virus:  The measles virus genotype D5 that had been endemic in Japan during 2006-2008 has not been detected in Japan since May 2010.  Thereafter, all isolates had genotypes of foreign origin, such as D9, G3, D8, D4 and H1 (Fig. 5 in p. 95).  In 2013, a B3 strain was isolated for the first time in Japan from a patient who returned from Thailand (IASR 34: 201-201, 2013).  In 2013, genotype B3 was the most frequent genotype detected (n=26), followed by D8 (14 cases), H1 (5 cases) and D9 (5 cases).  Although direct epidemiological links could not be identified, multiple genotype D8 cases were reported from several prefectures from July to August, and were believed to have been part of the same outbreak (see p. 100 of this issue).

From the beginning of 2014, genotype B3 has been increasingly detected from those who returned from the Philippines (see pp. 98 & 102 of this issue), and as of April 1, 139 cases have been notified.  Other genotypes detected so far are D8 (9 cases), D9 (6 cases) and H1 (2 case), with 3 cases unknown.

Laboratory diagnosis and its importance:  The Prevention Guideline recommends i) earliest notification possible, followed by ii) prompt laboratory diagnosis, and iii) withdrawal of the notification if measles is denied by laboratory tests.  It is thus possible that some of the 61 clinically diagnosed cases in 2013 were those whose laboratory test had not yet been completed.  New IgM test kits commercialized in 2014 show little false positivity to the acute phase of erythema infectiosum (a human parvovirus B19 infection) and other exanthema diseases.  Importantly, measles virus infection can be detected by PCR or virus isolation only within 7 days after rash appearance (though measles virus may persist in urine longer than 7 days and can be detected by PCR; see “Principles of Laboratory Diagnosis, revised in 2014) and by IgM from 4 to 28 days after rash appearance.  Results need to be interpreted with caution as specimens collected too early or too late can falsely show negative results. 

The National Epidemiological Surveillance of Vaccine-Preventable Diseases (see p. 109 of this issue):  WHO considers that measles elimination requires 95% population immunity against measles virus in every birth cohort.  In FY2012, the antibody-positivity level  (gelatin particle agglutination (PA) assay>1:16) became ≥95% in all age groups aged 2 years or above, and similarly in FY2013, levels were maintained  for majority of age groups 2 years or older (Fig. 6 in p. 95).  Seventy-six percent of one year old children were antibody positive in FY2013 (67% in FY2012). 

Vaccination coverage:  Since FY2006, routine immunization policy in Japan has adopted measles-rubella combined vaccine (MR), which has been administered in two doses, the first dose at one year of age (1st vaccination) and the second dose to children the year prior to elementary school attendance (2nd vaccination) (IASR 27: 85-86, 2006).  In addition, from FY2008 to FY2012, supplementary vaccination was conducted to children whose age corresponded to the age of the first year of junior high school (3rd vaccination) and third year of high school (4th vaccination) to also ensure two doses in these age groups (IASR 29: 189-190, 2008).

For FY2012, the vaccination coverage of measles-containing vaccines (M, MR) (the denominator for the 1st vaccination: number of 1-year-old babies as of October 1, 2012; the denominator for the 2nd-4th vaccinations: respective number of eligible age groups as of April 1, 2012) was 98% (95% in FY2011), 94% (93% in FY2011), 89% (88% in FY2011), and 83% (81% in FY2011) respectively for the 1st, 2nd, 3rd and 4th vaccinations.  The 1st vaccination covered ≥95% of the eligible children, fulfilling the target of sustaining this level for three successive years.  However, the coverage of the 2nd vaccination in the first half of FY2013 was lower than that in FY2012 in 36 prefectures.

Measures to be taken:  Since the end of 2013, small-scale outbreaks due to imported measles, mainly of genotype B3, have been increasing, involving medical facilities or families in various parts of Japan.  More than 50% of the patients were unvaccinated children under 10 years of age.  Medical practitioners should include measles in the differential diagnosis even during influenza or rubella seasons.  They should pay attention to travel history abroad and vaccination history.  Once measles infection is suspected, immediate infection control measures should be taken.  Healthcare workers should ensure that they have received two doses of measles-containing vaccine.

Since early March this year, measles cases without history of travel abroad are increasing in number.  In order to contain measles  which historically peak from spring to summer, all patients suspected of measles should be epidemiologically investigated with laboratory follow-up.  To this end, medical facilities should closely coordinate with health centres, prefectural and municipal public health institutes and the National Institute of Infectious Diseases.  So as not to import measles from abroad, vaccination should be completed before travelling overseas.

In order to interrupt measles transmission in Japan, high vaccination coverage should be maintained so transmission would not be sustained even if there is importation of the virus.  And, active epidemiological investigation and appropriate preventive measures should be taken following the “one suspected case, immediate response” principle.

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The Topic of This Month Vol.35 No.3 (No.409)

Rotavirus, 2010-2013, Japan

(IASR 35: 63-64, March 2014)

Rotavirus belongs to the family Reoviridae, whose genome consists of 11 segments of double-stranded RNA.  Rotavirus is classified into groups A-G according to the inner core protein’s antigenicity, among which groups A-C are detected from humans. Group A rotavirus is often referred to simply as “rotavirus” since this group makes up most of the circulating rotavirus in the world.  Rotavirus is a major cause of acute viral gastroenteritis among infants, and majority of the people are believed to have experienced infection at least once by 5 years of age (see p. 65 of this issue).  The virus is transmitted by the fecal-oral route, and after an incubation of 1-4 days, clinical manifestations consisting of diarrhea, vomiting and fever appear.  Treatment is oral or intravenous rehydration, as no specific treatment is available.  While patients usually recover within a week, dehydration is often more severe compared with other viral gastroenteritis.  Complications include seizures, which, if sustained, are associated with poor prognosis and increased risk of sequelae.  Less frequent complications include renal or hepatic failures and encephalitis/encephalopathy.  Although rare in developed countries, much of pediatric diarrheal deaths in developing countries is attributed to rotavirus infection (estimated 450,000 deaths/year) (Lancet Infect Dis 12: 136-141, 2012).

Infectious gastroenteritis under the National Epidemiological Surveillance of Infectious Diseases (NESID) system: Under the Infectious Diseases Control Law, rotavirus infection is included under “infectious gastroenteritis” (notification criteria in http://www.niid.go.jp/niid/images/iasr/35/409/de4091.pdf), a Category V infectious disease to be reported from approximately 3,000 nationwide pediatric sentinel clinics.  An amendment on 14 October 2013 introduced an additional reporting system; approximately 500 select key medical institutions (sentinel hos-pitals) in Japan are requested to notify patients of “gastroenteritis specifically caused by rotavirus infection” (notification criteria in http://www.niid.go.jp/niid/images/iasr/35/409/de4092.pdf).  If a pediatric sentinel clinic is selected as a key medical institution, the clinic is requested to notify a rotavirus gastroenteritis patient as “infectious gastroenteritis” and also as “infectious gastro-enteritis specifically caused by rotavirus infection”.  With these measures, it is believed that epidemio-logic features of rotavirus infection (particularly those of severe cases) will become clearer.

Every year, “infectious gastroenteritis” in-creases sharply during November/December with a wide peak in February/March to May followed by a decline (Fig. 1).  The February-May peak of in-fectious gastroenteritis overlaps with the rotavirus detection peak and the Novem-ber/December peak overlaps with the norovirus detection peak (https://nesid4g.mhlw.go.jp/Byogentai/Pdf/data11e.pdf).

Reports of rotavirus detection from public health institutes:  Prefectur-al and municipal public health institutes (PHIs) conduct laboratory diagnosis of infectious gastroenteritis cases based on fecal specimens sent from approximately 10% of the pediatric sentinel clinics and also from specimens collected from out-breaks.  During the past 4 years from 2010 to 2013, 60 PHIs reported group A and 8 PHIs reported group C rotavirus detections.  During 2005/06-2009/10 seasons, 700-800 rotavirus detections/year were reported, but increased during 2010/11 (Table 1, Fig 2). Group A rotavirus has been the majority with few group C detections (0.1-2.2% since 2010/11 season).  Group B rotavirus has not been reported in Japan.

Genotyping of group A rotavirus:  Group A rotavirus is classified according to combination of serotype-related G and P genotypes, which are respectively determined by the genetic sequences of the outer-layer capsid proteins VP7 and VP4 (neutral-izing antibody epitopes).  Most human isolates are currently G1P[8], G2P[4], G3P[8], G4P[8], and G9P[8] (see p. 66 of this issue).  Currently, some PHIs are conducting G genotyping (see pp. 67-71 of this issue).

Among 3,302 patients from whom group A rotavirus were detected during 2010-2013, 38% were 1 year of age, 16% <1 year of age, and 16% 2 years of age; children under 2 years of age comprised 70% of the patients whose age was known (Fig. 3).  Among those <1 year, those aged 6 months or older composed the majority.  The same age distribution was observed across genotypes G1, G3 and G9.  Genotype G2 had a slightly different age distribution; following those aged 1 year (28%), those aged ≥15 years were frequent (21%).  Of the 27 group C rotavirus-detected cases, 18 were children aged 5-9 years and 5 were children aged 10-14 years.

Complications: During 2010-2013, rotavirus was detected in 22 cases of encephalitis/encephalopathy and 4 cases of meningitis had rotavirus detection.  Additionally, group A rotavirus was detected from 4 cases of intussusception.

Outbreak incidents: Rotavirus outbreaks occur frequently in nurseries and in kindergartens, but also occasionally in primary schools, junior high schools, nursing homes for the elderly, and welfare facilities (IASR 33: 13-14, 2012; ibid. 33: 197-198, 2012; ibid. 33: 271, 2012; ibid. 34: 69-79, 2013; ibid. 34: 264-265, 2013) (Table 2).  Among rotavirus gastroenteritis outbreaks in 2010-2013, 105 were group A and 3 group C (Table 2).  Majority of these incidents were attributable to person-to-person transmission except for two food poisoning outbreaks caused by group A rotavirus.  Five outbreaks involved more than 50 patients (4 outbreaks due to group A and 1 outbreak due to group C); two were in April-May 2011 and three March-April 2012.

Prevention: Rotavirus’s infectivity is very high and 10-100 virions are sufficient in establishing infection.  An infected patient’s stool contains as many as 1010-1011 virions per gram, making rotavirus prevention difficult even in developed countries where sanitation and hygiene are well developed.  Currently two oral attenuated live vaccines, G1P[8] monovalent vaccine and a pentavalent vaccine containing G1-G4 and P[8] antigens, have been approved and used in more than 130 countries for preventing severe outcomes and introduced as a routine immunization in 53 countries (see p. 71 of this issue).  The vaccines are available on a voluntary basis since November 2011 and July 2012, respectively, in Japan.  The estimated vaccine coverage among the target age population was 35% in July 2012, and 45% in April 2013 (see p. 73 of this issue).

Challenges: Japan is currently evaluating incorporation of rotavirus vaccine as a routine immunization.  Studies from abroad have indicated that rotavirus vaccine can prevent an estimated 90% of severe outcomes due to rotavirus infection in developed countries (The Immunization and Vaccine Committee of the Health Science Council, Basic Direction of Immunization Policy Subcommittee, Rotavirus Vaccine Task Force Interim Report, 18 November 2013).  If rotavirus vaccination is to be introduced in Japan, its effectiveness and safety must be evaluated by: 1) monitoring trends in rotavirus cases, particularly of severe ones; 2) with regards to safety, given the slight increase in the incidence of intussusception reported from countries that have implemented rotavirus immunization, there is a need for careful monitoring of the occurrence of intussusception (see p.74 of this issue); and 3) to monitor the virus populations in circulation, considering vaccination’s potential selection pressure on circulating rotaviruses.  Rotavirus surveillance should thus be further strengthened and coordinated between the National Institute of Infectious Diseases and partners such as PHIs and universities.

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The Topic of This Month Vol.35 No.2 (No.408)

Severe fever with thrombocytopenia syndrome (SFTS) in Japan, 2013

(IASR 35: 31-32, February 2014)

Severe fever with thrombocytopenia syndrome (SFTS) is a tick-borne systemic infectious disease.  It is caused by SFTS virus (SFTSV), a novel virus belonging to Genus Phlebovirus, Family Bunyaviridae (Fig. 1), which was first reported from China in 2011 (see p. 33 of this issue).  Latency is 6-13 days and the main symptoms are fever and gastrointestinal symptoms, such as nausea, vomiting, abdominal pain, diarrhea, and melena.  Hematuria and proteinuria are frequently observed.  Leukopenia and thrombocytopenia are usually seen in peripheral blood, and hemophagocytosis with cellular hypoplasia are also demonstrated in the bone marrow.  Blood biochemistry shows elevation of AST, ALT and LDH.  Neurological symptoms, such as disturbed consciousness, are often associated with poor prognosis.  SFTS has been reported from China since 2011 and from Japan and the Republic of Korea since 2013.

Natural history of SFTSV and transmission to humans: In nature, SFTSV is maintained through vertical transmission from adult ticks to their offspring through transovarial transmission (tick-tick cycle) and also by transmission from infected mammals to ticks and vice versa (tick-mammal cycle).  Two tick species, Haemaphysalis longicornis and Rhipicephalus microplus, frequently found in areas inhabited by humans in China, are considered to be the natural reservoir of SFTSV; 5.0% and 0.6% of these two species, respectively, were found to harbor SFTSV or its genome.  In Japan, the ticks responsible for SFTSV transmission to humans are probably H. longicornis and Amblyomma testudinarium (Fig. 2), because these ticks were found on the patients’ body surface.

The infection route to humans is mainly tick bite; transmission to family members or to medical providers, mediated by blood and other body fluids, have also been reported from China.  No air-borne or droplet-borne infection has been reported so far.

Identification of SFTS patient in Japan and retrospective clinical and epidemiological studies: An adult with no history of travel abroad developed fever, vomiting and bloody diarrhea in autumn of 2012, and died of systemic organ failure.  SFTSV was isolated from the patient’s blood and pathological examinations revealed SFTSV antigens in various affected organs.  This was the first patient diagnosed as having SFTS in Japan (IASR 34: 40-41, 2013).

The Ministry of Health, Labour and Welfare (MHLW) issued a case definition for the surveillance of SFTS on January 30, 2013 (http://www.niid.go.jp/niid/images/iasr/rapid/graph/pt39811.gif) so as to effectively collect information on SFTS patients in Japan.  Retrospective studies using the MHLW’s case definition identified 8 patients with severe SFTS in or before 2012 (including the first clinical case) (IASR 34: 110, 2013).  Subsequently, 3 additional severe or fatal cases before 2013 were also identified, bringing the total number to 11.  Among the 11 patients, 6 died and all the patients were reported from western Japan.  Among 5 patients in whom bone marrow was examined, all exhibited the findings characteristic to the hemophagocytic syndrome, and many of the patients suffered from blood coagulation abnormality and/or systemic organ failure.  SFTSV was isolated from 8 patients.  Phylogenetic analysis revealed that Japanese strains formed an independent cluster from those of the Chinese strains, indicating that Japanese strains are indigenous to Japan and evolved independently from Chinese strains (see p. 35 of this issue).

Japanese SFTS patients reported in 2013: On March 4, 2013, SFTS was designated as a category IV infectious disease, requiring notification to the designated public health center (see http://www.niid.go.jp/niid/images/iasr/35/408/de4081.pdf for notification criteria), and SFTSV as a biosafety level group 3 pathogen (IASR 34: 110-111, 2013) (see p. 34 & 37 of this issue).  Physicians, who have treated a patient diagnosed virologically as SFTS, must notify the information to the designated public health center within 24 hours.

The number of SFTS patients reported in compliance with the Infectious Diseases Control Law under the National Epidemiological Surveillance of Infectious Diseases was 48 until the end of 2013; 40 were developed in 2013 (see p. 38 of this issue), and 8 in or before 2012 (2 cases in 2005; 1 case in 2010; 5 cases in 2012; IASR 34: 110, 2013).  The seasonal peak was in May (Fig. 3).  Patients were reported from 13 prefectures in Kyushu, Shikoku and Chugoku regions (Fig. 4).  Twenty-two cases were males and 26 females. Patients’ ages ranged from 48 to 95 years (median 72 years) (Fig. 5).  Seventeen of 48 had died.

With increased recognition of SFTS, mild SFTS cases were discovered (see p. 39 of this issue; IASR 34: 207-208, 2013).  Tick-bites were not always found on the body surface of the patients.  It is, therefore, advised to conduct laboratory diagnosis if a patient is suspected of having SFTS, even if the clinical pictures, including presence of bites, do not fit perfectly to the previous case definitions (see p. 38 of this issue).

Laboratory diagnosis available in Japan: Virological diagnosis includes detection/isolation of SFTSV from acute phase patients’ blood and other body fluids (throat swab, urine), and/or the demonstration of a significant rise in IgG antibody titers in paired sera between acute and convalescent phases.  Diagnosis using RT-PCR detection of SFTSV genome is available within the network of prefectural and municipal public health institutes (PHIs).  Furthermore, indirect fluorescent antibody test using the SFTSV-infected cells and IgG-ELISA using the SFTSV antigen are also available in the National Institute of Infectious Disease (NIID), Department of Virology I (see p. 40 of this issue).  Methods for the detection of SFTSV genome in ticks inhabiting Japan and antibody detection methods in mammals have been developed and the surveillance of SFTSV genome prevalence in some species of ticks and antibody levels in wild animals are being conducted (IASR 34: 303-304, 2013).

Measures to be taken: An SFTS patient was first reported in January 2013 in Japan.  Subsequent retrospective and prospective surveillance has revealed the existence of SFTS in western Japan.  PHIs and NIID established a laboratory diagnosis system, which should be maintained and developed further.  In 2013, an MHLW-funded 3-year project “Comprehensive research on control of SFTS” (chief investigator T. Kurata) started.  The project includes 1) detailed epidemiological and clinical studies on SFTS to elucidate the clinical and pathological characteristics; 2) development of rapid SFTSV detection kit; 3) basic research for vaccine development; 4) assessment of risk of SFTSV infection and risk communication on SFTS; and 5) elucidation of SFTSV prevalence among ticks inhabiting Japan, geographical distribution of SFTSV-positive ticks, sero-epidemiology of wild animals, and geographical spread of SFTSV in Japan.

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The Topic of This Month Vol.35 No.1 (No.407)

Hepatitis E, 2005-2013, Japan

(IASR 35: 1-2, January 2014)

Hepatitis E is an acute hepatitis caused by infection with hepatitis E virus (HEV), which belongs to the family Hepeviridae, genus Hepevirus.  It shares many clinical characteristics with hepatitis A including jaundice.  Asymptomatic infection is quite common as in hepatitis A.  The incubation period is average 6 weeks; the prodromal symptoms are systemic and quite variable depending upon the case, include anorexia, nausea, vomiting, fatigue, malaise and low grade of fever.  The case fatality rate is found in 1-2% of HEV cases, which is 10 times higher than in HAV (0.1%).  Though HEV infection rarely becomes chronic, chronic conversion was reported among immunocompromised individuals recently (see pp. 3 & 13 of this issue).  HEV infection has been identified as an important zoonotic infection in the world including in Japan (see p. 4 of this issue).  In developing countries where HEV is endemic and water-mediated large-scale outbreaks are common, however, feco-oral infection through drinking of water contaminated by HEV patients’ feces is an important infection route.

There are four known HEV genotypes (G1-G4) all belonging to one serotype.  In developing countries, G1 is the major genotype detected in the local epidemics.  In developed countries, G3 and G4 from pigs and wild boars are commonly detected though G3 and G4 are detected from sporadic HEV cases.

In April 1999, HEV was classified as category IV infectious disease under the Infectious Diseases Control Law, and notification became mandatory as “acute hepatitis” of all the cases within 7 days after diagnosis.  Subsequently, with the law amendment in November 2003, “hepatitis E” became one of the independent category IV notifiable infectious diseases that mandates immediate reporting after diagnosis (reporting criteria are found in http://www.niid.go.jp/niid/images/iasr/35/407/de4071.pdf).

Incidence:  From January 2005 to November 2013, 626 cases were reported under the National Epidemiological Surveillance of Infectious Diseases (as of 27 November, 2013, Table 1).  While 42-71 cases were reported annually in 2005-2011, more than 100 cases have been reported since 2012 (the increase being attributable to IgA test added to the notification criteria in 2013; see below).  The domestic cases occupied 71-79% of all the cases in 2005-2008, while 86-94% since 2009 (Fig. 1).

Age and gender:  As in previous years (IASR 26: 261-262, 2005), male patients outnumbered female patients irrespectively of place of infection.  There were 502 male cases (infection in Japan: 425 cases, infection abroad: 68 cases; place of infection unknown: 9 cases) in contrast to 124 female cases (infection in Japan 107: cases; infection abroad: 13 cases; place of infection unknown: 4 cases). 

As for age distribution, among those infected in Japan, the most frequent age was middle-aged and older, while the ages of those infected abroad varied widely (Fig. 2).

The laboratory diagnostic methods and genotypes (see p. 3 of this issue):  Of the 626 cases reported in 2005-2013, 303 cases (48%) were laboratory diagnosed by RT-PCR; 228 cases (36%) and 171 cases (27%), respectively, by IgM and IgA antibody detections using ELISA (the above figures include overlaps due to use of more than one diagnostic methods in a single case) (Table 1).  In October 2011, medical insurance started covering diagnosis based on the IgA tests.  The rate of diagnosis based on the IgA test was increased since 2012.  IgA positive was added to the notification criteria in 2013.

Virus genotypes were identified for 86 cases; there were 2 G1 cases (1 domestic; 1 abroad); 39 G3 cases (36 domestic; 3 unknown for place of infection); 45 G4 cases (40 domestic; 5 abroad) and zero G2 case.

Suspected places of infection:  From 2005 to November 2013, 42 prefectures reported HEV cases, whose distribution are shown in Fig. 3.  Hokkaido, reporting every year, reported the largest number of cases, about 34% of all the domestic cases (see pp. 5 & 7 of this issue), which was followed by Tokyo (14%).  The place of infection abroad were mainly Asia, China being the top (42%) followed by India (17%) and Nepal (9.9%) (Table 2). 

Infection routes:  Of 626 cases reported from 2005 to November 2013, information on the infection routes was available for 250 cases infected in Japan and 17 cases infected abroad.  Among the 250 domestic cases, 88 cases (35%) consumed pork (including liver), 60 cases (24%) wild boar meat, 33 cases (13%) deer meat, 10 cases (4.0%) horse meat, 11 cases (4.4%) shellfish (including oyster) and 37 cases (15%) meat and 24 cases (9.6%) liver of unidentified animals (raw or grilled) (figures include overlaps of counting).  There were 4 cases without history of meat consumption that appeared to have been infected through dissection, burial, preparation or cooking.  Among the 17 cases infected abroad, 6 cases (35%) were attributable to drinking of unboiled water, 4 cases (24%) to consumption of pork, and 4 other cases (24%) to consumption of meat of unknown animals.  

HEV infections among animals:  High prevalence of HEV infection in pigs has been reported from many countries including Japan.  In Japan, HEV genes have been detected at high frequencies from feces of pigs 2-3 months of age, and more than 90% of pigs 6 months of age placed on market had anti-HEV antibody.  HEV gene was detected from pig livers placed on the market (see pp. 4 & 8 of this issue).  While the antibody prevalence being reportedly lower than that in pigs, HEV is widely distributed among wild boars throughout the country (34%). 

While deer has been claimed to be infected by HEV, Kumamoto Prefectural Public Health Institute was unable to find any deer whose liver, blood or muscle specimens were HEV genome positive (see p. 9 of this issue).  As also for cattle, sheep and goats, HEV-genome positive cases have not been reported (see p. 10 of this issue).  More recently, several novel HEV variants have been detected in rats, rabbits, bats, and ferrets, but its infectivity to humans is unknown (see p. 10 of this issue).  

Prevention of HEV infection:  As HEV infection due to consumption of raw animal liver and meat continues, the Ministry of Health, Labour and Welfare (MHLW) has published a “Case study of hepatitis E virus infection through consumption of meat (hepatitis E Q&A)” on its homepage to promote awareness of HEV (Notice by the Inspection and Safety Division, Department of Food Safety, Pharmaceutical and Food Safety Bureau, November 29, 2004: http://www.mhlw.go.jp/topics/syokuchu/kanren/kanshi/041129-1.html).  MHLW continuously recommends hunters, meat handlers and consumers to avoid eating raw meat or liver of pigs or other wild animals, and to consume these foods only after thorough cooking. 

When traveling to endemic areas in abroad, as in case of hepatitis A, drinking of unboiled water and eating of undercooked food should be avoided.  The Japanese public should be more aware of the risks of HEV infections.  Vaccines for hepatitis E are currently under development in Japan.

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The Topic of This Month Vol.34 No.12 (No.406)

Meningococcal infection, 2005-October 2013, Japan

(IASR 34: 361-362, December 2013)

Neisseria meningitidis, or meningococcus, is a gram-negative diplococcus that colonizes the nasopharynx of humans and spreads as respiratory droplets.  Four invasive types are known: bacteraemia without causing sepsis, sepsis unassociated with meningitis (IASR 30: 158-159, 2009), meningitis (IASR 25: 207, 2004; IASR 27: 276-277, 2006) and meningoencephalitis.  Prognosis of sepsis is poorer.  Waterhouse-Friderichsen syndrome is an acute fulminant type of meningococcal infection accompanying adrenal bleeding and systemic shock.  Noninvasive meningococcal infection includes pneumonia (see p. 368 of this issue), urethritis (see p. 370 of this issue), etc.

History of surveillance for meningococcal infections:  Among meningococcal infections, “epidemic cerebrospinal meningitis” had been notified since before the World War II under the Communicable Diseases Prevention Law (Table 1).  The epidemic peaked around 1945 amounting annually more than 4,000 cases.  It subsided gradually; annual cases dropped to less than 100 cases in 1969, to less than 30 cases in 1978 and less than 10 in 1990s.  The Infectious Diseases Control Law implemented in April 1999 classified meningococcal meningitis as a Category IV notifiable disease that needs notification of all the cases (Table 1).  Since 1999, 7-21 cases were notified annually till March 2013 (Fig 1 & 2).  In May 2011, there was a meningitis outbreak in a senior high school dormitory in Miyazaki Prefecture that included multiple non-meningitis infections, such as sepsis (IASR 32: 298-299, 2011; p. 367 of this issue).  As a consequence, in April 2012, the School Health and Safety Act was modified to classify meningococcal meningitis as a category II school infectious disease under the Act. 

Trends of invasive meningococcal infections (since April 2013):  In April 2013, meningococcal meningitis and meningococcal sepsis together was classified as “invasive meningococcal infection”, a Category V notifiable disease under the Infectious Diseases Control Law that needs notifica-tion of all the cases (http://www.niid.go.jp/niid/images/iasr/34/406/de4061.pdf).  Since April 2013, 18 cases of invasive meningococcal infection have been notified; no infant case has been included (as of 15 November 2013, Table 2).  The causative agents were detected from cerebrospinal fluid (2 cases), from blood (13 cases) and from the both (3 cases).  Thirteen cases were notified from Kanto district, and ten of them were from Tokyo.  There were no epidemiological links between them and none of them had travelled abroad.  Three cases, 32-, 39- and 70-years old patients, died of septic shock.  The calculated case-fatality rate was 17% (3/18).

Gender and age distributions (Fig. 3):  Male to female ratio of patients reported from 2005 to October 2013 was 7:5.  In 2005-2013 period, number of patients tended to be high among 20s and 50s-60s, while in 1999-2004 period it tended to be high in infants less than 4 years of age and people of 15-19 years of age (IASR 26: 33-34, 2005).  

Incidence according to serogroups:  N. menin-gitidis species are classified into 13 serogroups based on differences in their capsular polysaccharides.  Serogrouping provides important epidemiological information for vaccine planning in endemic areas.  Among 115 cases that consisted of meningococcal meningitis reported from 2005 to March 2013 and invasive meningococcal infection reported from April to October of 2013 (Fig. 4), serogroup information was obtained from 50 cases.  The most frequent was serogroup B (22 cases), followed by serogroup Y (18 cases), serogroup C (2 cases) and serogroup W-135 (3 cases); there were 5 cases indiscernible as to serogroup Y or serogroup W-135 (Fig. 4).  Department of Bacteriology I, National Institute of Infectious Diseases (NIID) has been conducting molecular epidemiological analysis using the multilocus sequence typing (MLST) to make international database referencing possible.  Analysis of 18 isolates obtained during 2005-2012 revealed that the Japanese isolates belonged to ST-23 complex, ST-41/44 complex and other known genotypes; there were small number of isolates of new ST types (see p. 363 of this issue).

Treatment and vaccines:  The primary choice of treatment is intravenous administration of penicillin G or the third generation cephem antibiotics.  To contacts, oral administration of rifampicin or new quinolone is recommended for prevention of further spread (see pp. 364, 365 & 366 of this issue), though guidelines for preventive administration is not yet ready. Currently, capsular antigen-specific vaccines against serogroups A, C, Y and W-135 are available, but they are not yet approved in Japan (see p. 371 of this issue).

Epidemics abroad:  Meningococcal epidemics are reported continuously from the “Meningitis belt” in sub-Saharan Africa. Elsewhere, while it was mostly sporadic, outbreaks, such as, those in schools in the United States (IASR 33: 138 & 142, 2012), those among male homosexuals in Germany (IASR 34: 240, 2013) and those associated with Muslim pilgrimage to Mecca have been reported.  International Health Regulation lists meningococcal disease in Annex 2 as an infection which is generally localized but has a potential of international spread (http://whqlibdoc.who.int/publications/2008/9789241580410_eng.pdf).

Most epidemics have been due to serogroups A, B, C, Y and W-135, and among some of the developed countries serogroup B was dominant.  More recently a new type serogroup X was reported from the meningitis belt (see p. 372 of this issue).

As most meningococcal patients notified in recent years have had no history of travelling abroad, public should be informed not only of infection risk abroad but also infection risk in Japan.  Prompt notification, epidemiological investigation without delay and taking prompt countermeasures are required for preventing spread of infection, particularly when an outbreak is in dormitories or other places for communal life.  Analysis of bacterial isolates is indispensable for finding routes of importation or domestic spread and for planning of countermeasures.  Collaborations and networks between clinics, local governments, prefectural and municipal public health institutes and NIID should be further strengthened. 

 

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The Topic of This Month Vol.34 No.6 (No.400)

Legionellosis, January 2008-December 2012

(IASR 34: 155-157, June 2013)

 

Legionellosis is an infectious disease caused by Gram-negative bacteria belonging to the genus Legionella.  It is a respiratory tract infection and the bacteria multiply within alveolar macrophages.  There are two clinical types, severe form of pneumonia called Legionnaires’ disease and flu-like Pontiac fever.  As the symptoms of Legionella pneumonia are not unique, differentiation from other pneumonias by symptoms alone is difficult.  The first choices for chemotherapy are quinolones and macrolides.  Sudden worsening of the general condition may occur among patients, who were not treated with appropriate antibiotics.  Pontiac fever is a less severe form of infection and the symptom is like common cold.  Elderlies, newborns and immunocompromised persons constitute high-risk groups of legionellosis.

Legionella bacilli live within protozoa (amoeba) that inhabit water, moist soil, etc.  Optimum growth temperature is 36°C with permissive range of 20-45°C.

Incidence of legionellosis: Legionellosis is a category IV notifiable infectious disease in the National Epidemiological Surveillance of Infectious Diseases (NESID) under the first Diseases Control Law (http://www.niid.go.jp/niid/images/iasr/34/400/de4001.pdf).  Physicians who have made diagnosis of legionellosis are obliged to notify all the cases.

From January 2008 to December 2012, 4,081 legionellosis patients (including 31 asymptomatic carriers) were reported (as of May 15, 2013) (Table 1).  The peak season of legionellosis was mostly July (Fig. 1).  More patients were reported from more populated prefectures as expected (http://www.niid.go.jp/niid/images/iasr/34/400/graph/f4002a.gif).  Number of patients per 100,000 was high in Toyama, Ishikawa, Okayama and Tottori Prefectures (Fig. 2).  The average patients’ age was 67.0 years, 65.7 years in males and 72.5 years in females.  While the patients’ ages were distributed widely from 0 year to 103 years, patients younger than 30 years were few (1.0%) (Fig. 3).  Males occupied 81% of the patients.  According to MMWR 60: 1083-1086, 2011, males were 64% of the patients in USA.  Occupations at high risk were reported to be mining and construction, manufacturing of metal materials, assembly and/or repair of transportation machines, and car driving, etc.  Symptoms are fever (92%), pneumonia (90%), cough (48%), dyspnea (44%), disturbance of consciousness (17%), diarrhea (9.8%), multiple organ failure (8.5%), and abdominal pain (2.5%) (percentage in parenthesis indicates percentage among the notified patients having the symptom indicated).  As for the location of infection, 3,962 cases (97%) were infected in Japan, 95 cases (2.3%) abroad and 24 cases (0.6%) unknown.

Methods of diagnosis: Of 4,081 cases, 3,928 (96%) were diagnosed by antigen detection in urine, 113 cases (2.8%) by bacterial culture, 69 (1.7%) by titration of serum antibody, 62 (1.5%) by PCR (including LAMP method), and 8 (0.2%) by the indirect fluorescent antibody method or by the enzyme-linked antibody method (Table 2 on p.157 of this issue).

While antigen detection in urine was used in a great majority, it can detect only Legionella pneumophila serogroup (SG) 1.  The LAMP assay that can detect a wide range of genus Legionella started to be covered by the medical insurance since October 2011.  In 2012, 5 cases were diagnosed by this method.

The number of deaths among the total cases was 134 (3.3%) for 2008-2012.  Among 4,023 patients having the record of the first medical consultation, there were 129 deaths.  It was noted that the longer was the delay from the first consultation to the definitive diagnosis, the higher was the fatality rate, i.e., 2.8% for 0-3 day delay, 4.2% for 4-6 day delay and 5.3% for ≥7 day delay.  Early diagnosis is important for saving lives of the patients.

Species of Legionella isolated by culture: In addition to the above 113 culture-positive cases, reported were additional 148 cases that included isolates provided to the Legionella Reference Center after the notification (see p. 161 of this issue).  Thus Legionella was isolated from total 261 cases.  Among them, there were 216 cases attributable to infection of L. pneumophila SG1.  Some such cases of infection with L. pneumophila SG1 were infected additionally with other Legionella species or serogroups, such as, L. feeleii (one case), L. rubrilucens (one case), L. pneumophila SG6 (two cases), and L. pneumophila SG6 and SG9 and untypable (one case).  There were 24 cases due to L. pneumophila other than L. pneumophila SG1; six cases each due to infection with SG2 and SG3, four cases due to infection with SG6, two cases each due to infection with SG5, SG10 and SG12, and one case each due to infection with SG9 and SG15.  Furthermore, there were one case of L. londiniensis, one case of L. longbeachae, and 19 cases of Legionella whose species were not identified. 

Outbreaks: Outbreaks that occurred in Japan during 2008-2012 involved 2 cases at a public bathing facility in Kobe City in January 2008 (IASR 29: 329-330, 2008); 2 cases at a welfare facility for the elderly in Okayama Prefecture in July 2008 (IASR 29: 330-331, 2008); 8 cases attributable to a bathing facility in a hotel in Gifu Prefecture in October 2009 (IASR 31: 207-209, 2010); 9 cases attributable to a bathing facility of a sports club in Yokohama City in September 2011; 3 cases attributable to a bathing facility in a hotel in Yamagata Prefecture in November 2012 (see p. 159 of this issue); and 9 cases attributable to a “one-day-trip hot spring” in Saitama Prefecture in November to December 2012 (see p. 157 of this issue).  There were 13 suspected clusters, each reporting 2-5 legionellosis patients that were found among those who used the same facilities or toured together.  In addition, after the tsunami associated with the Great East Japan Earthquake, legionellosis was reported among those who were rescued from drowning or engaged in debris processing (see p. 160 of this issue).

Control measures: Legionella infection occurs through inhalation of aerosols or dusts contaminated by Legionella.  The infection source includes spa pools, cooling towers, showers (IASR 31: 331-332, 2010 & 31: 332-333, 2010), hot water supply system, landscaping water, humidifiers (see p.169 of this issue), solar water-heaters (IASR 32: 113-115, 2011) and leaf molds (IASR 26: 221-222, 2005).  Biofilm growing on porous natural stones in a bath sometimes becomes a hotbed of Legionella (IASR 29: 193-194, 2008).

Principles of prevention of legionellosis include 1) prevention of microbial growth and biofilm formation, 2) removal of biofilm formed on equipments and facilities, 3) minimizing aerosol splash, and 4) minimizing of bacterial contamination from external sources.  For this, following measures should be taken.  Firstly, water should be disinfected (see p.168 of this issue), which should be checked by culture of microbes or by rapid tests (see p.165 of this issue).  The current hygienic standard of bath water that may pose risk of aerosol inhalation is Legionella counts less than 10 cfu per 100 ml (below the detection limit).  Secondly, the wall of bath rooms and inner surface of water tanks should be cleaned.  Removal of the biofilm can be checked by measuring adenosine-tri-phosphate (ATP) (see p.167 of this issue).  Thirdly, equipments and facilities should be designed so as not to splash aerosols.  Fourthly, those who clean the wall of bathrooms or hand leaf molds should wear a dust mask.

Hygienic control for prevention of legionellosis should follow guidelines, such as Legionella Control Measures (Ministry of Health, Labour and Welfare: MHLW), Building Hygiene (MHLW), Guidelines for prevention of legionellosis (3rd Ed., Building Management Education Center), Introduction to hygienic maintenance of storage-type hot-water supply equipment (1st Ed., Japan Water Facilities Environmental Hygiene Association).

For prevention of legionellosis, infection sources should be identified by analyzing the data obtained from the pulsed-field gel electrophoresis and sequence-based typing using Legionella obtained from both patients and environment (see p.161 of this issue).  With such information, disinfection and/or removal of Legionella can be effectively onducted.

 


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

 

 
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The Topic of This Month Vol.34 No.11 (No.405)

2012/13 influenza season, Japan

(IASR 34: 325-327, November 2013)

 

The 2012/13 season’s influenza epidemic in Japan (from week 36/September of 2012 to week 35/August of 2013) was caused mainly by subtype AH3, and to a lesser extent by type B and to a very limited extent by A(H1N1)pdm09 (AH1pdm09).  The peak season was January as in the previous years.

Incidence of Influenza:  Under the National Epidemiological Surveillance of Infectious Diseases (NESID), 5,000 influenza sentinels (3,000 pediatric and 2,000 internal medicine clinics) report diagnosed influenza cases weekly (http://www.niid.go.jp/niid/images/iasr/34/405/de4051.pdf).  The number of patients/week/sentinel (http://www.niid.go.jp/niid/en/10/2096-weeklygraph/2572-trend-week-e.html) exceeded 1.0, an index of influenza epidemic, in week 50 of 2012, and peaked in week 4 of the new year as usual (average 36.4 patients/week/sentinel in contrast to 42.6 in 2011/12 season).  The epidemic continued for 24 weeks until week 21 of 2013 (Fig. 1). 

At the prefecture level, influenza incidence >10.0 patients/week/sentinel was first reported from Gunma Prefecture in week 51 of 2012, then from 20 prefectures in week 2 and from 47 prefectures in week 3 of 2013 (https://nesid3g.mhlw.go.jp/Hasseidoko/Levelmap/flu/index.html).  The Okinawa’s summer influenza epidemic annually observed since 2005 was smaller than previous years.

Based on number of reports from influenza sentinels, total number of influenza patients who visited medical institutions from week 36 of 2012 to week 21 of 2013 (September 3, 2012-May 26, 2013) was about 13,700,000.  According to the hospitalization surveillance aiming at monitoring of severe influenza cases, which started in September 2011, there were 10,370 admissions including 1,552 patients in serious states requiring head computed tomography, electroencephalography, MRI scan, ventilator, and treatment in ICU.

Isolation/detection of influenza virus:  Total 4,910 influenza virus strains were isolated by the prefectural and municipal public health institutes (PHIs) in 2012/13 season (as of October 17, 2013, Table 1 ), and 1,673 strains were detected by PCR alone.  Among the total 6,583 isolated/PCR-detected viruses, 5,462 were derived from influenza sentinels and 1,121 from elsewhere (Table 2 ).

Influenza viruses isolated/detected in 2012/13 season consisted of types AH3 (76%), type B (21%) and AH1pdm09 (2%).  No former seasonal AH1 subtype virus has been detected since week 36 of 2009.  Type B isolates were mostly of Yamagata and Victoria lineages with an isolation ratio of 7:3.  Viruses Isolated/detected from overseas travelers included subtype AH3 (33 cases), AH1pdm09 (21 cases) and type B (9 cases) (Table 2).  The 2012/13 influenza season started with subtype AH3, which remained predominant till week 12 of 2013, when AH3 was replaced by type B (Fig. 1; Fig. 2 ).

The highest influenza patient frequency was found among 5-9 year olds for all the influenza types/subtypes, particularly in type B cases (Fig. 3).

Antigenic characteristics of 2012/13 isolates and their drug resistance (see p. 328 of this issue):  Ninety percent of the 94 AH1pdm09 isolates from Japan and abroad tested in National Institute of Infectious Diseases, were similar to A/California/7/ 2009 (2009/10-2012/13 vaccine strain) in the antigenicity.  The remaining 10% were variants with reduced reactivity (≥8-fold lower in HI titer) to the A/California/7/2009 antiserum.  Ninety-nine percent of 236 AH3 isolates (most isolated in Japan and a very few in abroad) similar to A/Victoria/361/2011 (2012/13 vaccine strain).  Among type B isolates, 96% of 120 Yamagata lineage isolates similar to B/Wisconsin/1/2010 (2012/13 vaccine strain) in antigenicity, while 99% of 95 Victoria lineage isolates had antigenically similar to that of B/Brisbane/60/2008 (2009/10-2011/12 season vaccine strain).

The oseltamivir resistance-related mutation, H275Y, was observed in 2 out of 103 AH1pdm09 Japanese isolates (1.9%), which was not found in the 2011/12 season.  Twenty subtype AH3 isolates tested were all sensitive to oseltamivir, zanamivir, peramivir, and laninamivir.

Immunological status of Japanese population (See p. 334 of this issue):  According to the data of the National Epidemiological Surveillance of Vaccine-Preventable Diseases obtained with serum samples (n=6,794) collected from July to September in 2012 in various parts of Japan, frequency of anti-A/California/7/2009 HI antibody positives (titer higher than 1:40) was 51%; and the positive frequency was the highest (60-80%) among age groups of 5-24 years.  To subtype AH3, percentages of antibody positives were 30-40% except 50% level in the age groups of 5-24 years.  The frequency of anti-type B Victoria positives, though above 40% in most age groups, was higher among 35-39 years differently from the case of anti-type A positives.  To type B Yamagata, 31% were antibody positive (65% among 20-24 years; <20% among people younger than 10 years or older than 55 years). 

Vaccines for 2012/13 and 2013/14 seasons:  The quantity of trivalent vaccines produced in 2012/13 season was 32,620,000 vials (by a calculation of 1ml/vial), of which 25,210,000 vials have been used for vaccination. 

Vaccine strains selected for 2013/14 season were A/California/7/2009 (X-179A) (H1N1)pdm09 for AH1, A/Texas/50/2012 (X-223) (H3N2) for AH3 and B/Massachusetts/2/2012 (BX-51B) (Yamagata lineage) for type B (see pp. 336 and 339 of this issue). 

Avian influenza A(H7N9):  Since the first report in February 19, 2013 total 136 laboratory confirmed cases including 45 deaths have been reported from the mainland China and Taiwan (as of October 16, 2013).  The most recent report was the report from Zhejiang province in October after long silence since July (see p. 342 of this issue).  

A(H7N9) was categorized as “designated infectious disease” under the Infectious Diseases Control Law on April 26, 2013.  Manual for detection of A(H7N9) influenza virus is now widely available, and 74 PHIs and 16 quarantine stations in Japan constituting the national laboratory diagnosis network have already received the test reagents, PCR primer and probe set, and positive controls. 

Avian influenza A(H5N1):  In 2013, as of October 8, Bangladesh, Cambodia, China, Egypt, Indonesia, and Vietnam have reported total 31 A(H5N1) cases including 20 deaths (20 cases including 11 deaths from Cambodia) (http://www.who.int/entity/influenza/human_animal_interface/EN_GIP_20131008CumulativeNumberH5N1cases.pdf).

Act on Special Measures for Pandemic Influenza and New Infectious Diseases Preparedness and Response: For protecting life and health of the nation while minimizing adverse effects on daily life and economy that could be incurred by highly virulent new strains of influenza and other dangerous infections, “Act on Special Measures for Pandemic Influenza and New Infectious Diseases Preparedness and Response” was issued on May 11 of 2012 and enforced on April 13, 2013 (http://www.cas.go.jp/jp/influenza/120511houritu.html); in addition, the government’s action plan was adopted in June 2013. 

Additional comments:  To implement prompt and adequate measures in case of outbreaks, sentinel surveillance, school outbreak surveillance, and hospitalization surveillance should be continued and further strengthened.  The virus isolation should be conducted throughout the year to monitor antigenic and genetic changes of viruses so as to secure vaccine candidate strains and to check possible occurrence of resistance to anti-influenza drugs.  The antibody positive rates against influenza viruses should be monitored nationwide.  

Flash reports on the isolation and detection of influenza viruses in 2013/14 season are found in pp. 343 and 345 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.39 No.4(No.458)

Measles in Japan, as of February 2018

(IASR Vol. 39 p49-51: April, 2018)

Measles is an acute infectious viral disease characterized by three main clinical manifestations of fever, rash, and catarrh.  The measles virus, the causative agent of measles, is transmitted as an aerosol, droplet, or via contact and is highly infectious.  As it also transiently suppresses the host’s immune function, approximately 30% of measles case patients suffer from complications, and those who develop pneumonia or encephalitis can have fatal outcomes.  In 2016, an estimated 89,780 persons, mainly children in developing countries, died of measles (http://www.who.int/mediacentre/factsheets/fs286/en/).

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The Topic of This Month Vol.34 No.10 (No.404)

Chickenpox/varicella zoster and vaccine in Japan

(IASR 34: 287-289, October 2013)

 

Chickenpox is caused by the primary infection of varicella-zoster virus (VZV).  It is category V infectious disease under the Law Concerning the Prevention of Infectious Diseases and Medical Care for Patients of Infections (Infectious Diseases Control Law) (http://www.niid.go.jp/niid/images/iasr/34/404/de4041.pdf) and category II school infectious disease under the School Health and Safety Act.  VZV latently infects nerve ganglia, and is reactivated by immunosuppression causing herpes zoster.

Incidence of chickenpox:  Number of cases increases from winter to spring, and then gradually decreases towards the autumn.  Estimatedly about 1,000,000 chickenpox patients, mostly infants, occur every year, though the overall incidence is decreasing (though slightly) in the recent three years (Fig. 1).  While 80% of the patients used to be under 4 years of age, since 2010 the percentage of this age group has been decreasing possibly owing to the increased vaccination coverage of this age group (Fig. 2).  When chickenpox and rubella, both sentinel reportable infectious diseases, are compared, however, while rubella decreased dramatically after starting of rubella routine vaccination to infants of the both genders in 1995, the incidence of chickenpox, to which immunization has been conducted on voluntary basis, remained continuously high. 

Severe cases:  Transmissibility of VZV is strong.  It spreads by the air-borne infection, and subclinical infection is very rare.  On estimation, one in 400 natural chickenpox infections among unvaccinated children require hospitalization, and nearly 20 in 1,000,000 infections are fatal (Chickenpox fact sheet, National Institute of Infectious Diseases).  The incidence of deaths due to chickenpox is the highest among all the deaths caused by vaccine preventable diseases including measles, rubella, mumps and chickenpox that have been reported since 2004.

Hospital infection of chickenpox is a serious problem in pediatric hospitals in Japan.  It cannot be prevented even in hospitals using aggressive infection control, and it sometimes results in ward closure (http://www.theidaten.jp/journal_cont/20130328J-41-2.htm).

As chickenpox infection can be fatal to infants who are under immune-suppression, infection control including outpatient services should be further strengthened.  Currently, utility of post-operative varicella vaccination to infant organ recipients is under study (see p.289 of this issue). Very often, among immune-compromised individuals with leukemia and other malignancies, etc., the first sign of chickenpox infection is abdominal or back or low back pain in place of rash, and may follow poor clinical consequence like multiple organ failure, disseminated intravascular coagulation, etc.  (see p.290 of this issue).  Adults as well as infants at high risk tend to follow severe clinical course, such as, pneumonia (see pp. 292 & 293 of this issue).

If a mother is infected during the first 20 weeks of gestation, infection causes in 1-2% of the cases serious damages to the fetus, which is known as congenital varicella syndrome.  Stillbirth, though rare, may also occur (see p. 294 of this issue).  When a mother catches chickenpox within 5 days before or 2 days after delivery, trans-placental infection occurs and the infected newborn often follows a serious consequence due to the lack of maternal antibody.

Prevention and therapy:  Varicella vaccine is the best for prevention of chickenpox.  When a person without immunization or infection history is exposed to varicella, immediate vaccination within 3 days after exposure can prevent disease onset or aggravation of symptoms.  As a post-exposure treatment, anti-herpes drugs, such as, acyclovir (ACV) and valacyclovir (VCV), or anti-chickenpox/varicella zoster immunoglobulin (VZIG) is administered.  ACV and VCV are not covered by the health insurance in Japan, and VZIG is primarily used abroad.  As treatment of infants at high risk needs VZIG, clinicians request its approval and supply in Japan.

Varicella vaccine:  The Oka strain varicella live vaccine is recognized by WHO as the most desirable varicella vaccine.  In Japan, vaccination targets are people older than 12 months who have no history of chickenpox, people having risk of developing severe form of chickenpox, people having risk individuals in their family, or health care providers.  As the vaccination has been conducted on the voluntary basis, exact coverage rate is unknown; so far, coverage rate has been calculated on the basis of number of shipped lots and number of births, which was 30-40%.  From 2009 to 2012, the vaccine production doubled probably thanks to increased public recognition and local governments’ expanded subsidy to vaccination (Fig. 3).  The vaccination dose, which used to be one dose, is now becoming two doses under the influence of the world trend.  Therefore, the increased shipment can’t be translated directly into increased number of children receiving the vaccine.  A system of more precise estimation of vaccine coverage is needed.  The amount of the vaccine shipped dose 1-year-old children population is quite variable among prefectures in Japan (Fig. 4).

Safety and efficacy of vaccine:  No serious side effects have been observed among the healthy vaccinees since gelatin, an allergen, was removed from vaccine in 2000.  Secondary infection of vaccine strain is very rare; so far only 10 cases have been reported in the world.  Its efficacy is evidenced by the drastic decrease of patients, hospitalizations and deaths in the United States, which adopted routine immunization of chickenpox in 1995 (see p. 295 of this issue).  For those having received one dose, the probability of reinfection during an epidemic is 15-20%, and that of acquiring moderate to severe chickenpox is <5%.  As the reinfection can be prevented by two doses (see p. 296 of this issue), implementation of two vaccine doses is desirable from the public health viewpoint.  Comparison of costs of vaccination and patient care including burden on patient’s family has indicated the cost-effectiveness of routine varicella vaccination.  Currently, Vaccine Panel established by Health Science Council is working on incorporation of varicella vaccine into the routine immunization.

Varicella zoster (VZ):  According to a survey in Miyazaki prefecture (see p. 298 of this issue), one in three persons acquires VZ if they live for 80 years.  The risk of developing VZ can be assessed by an intradermal skin test (see p. 300 of this issue).  VZ reduces quality of life on account of the skin rash and prodromal pain as well as postherpetic neuralgia.  Ramsay Hunt syndrome occasionally observed is refractory to therapeutic intervention (see p.301 of this issue).  Though early clinical intervention can alleviate associated complications, varicella control by vaccine is of prime importance.

As VZ development and decreased host cellular immunity are closely correlated, the United States considered use of varicella vaccine for control of VZ reactivation by taking advantage of its capacity to augment cellular immunity, and the FDA approved an Oka strain based VZ vaccine in 2006.  Clinical trials in the United States revealed that incidence of VZ, postherpetic neuralgia and severe cases were decreased by more than 50% each. 

As Japan’s VZV vaccine for routine immunization has titer comparable to that of the United States’ VZ vaccine, since 2004 the VZV vaccines sold in Japan have been attached with a package insert informing that, under “pharmacology”, the vaccine can enhance cellular immunity to VZ when applied to persons with decreased immunity due to aging and other reasons.

Diagnosis:  Clinical diagnosis of chickenpox and VZ is easy.  Laboratory diagnosis using antibody test is available in the commercial laboratories, and is used as a confirmatory test.  Virus genome can be detected from vesicles as they contain large amount of virus particles, but the test is not covered by the health insurance.  Pathological characteristics of severe VZV infection cases are detailed in p. 302 of this issue. 

For monitoring of efficacy and safety of varicella vaccine, a VZV pathogen surveillance system should be established. Differential diagnosis of wild type VZV and vaccine type VZV that is required for the surveillance is described in the “Pathogen Detection Manual: National Institute of Infectious Diseases”.

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The Topic of This Month Vol.37 No.4(No.434)

Measles and Rubella/Congenital Rubella Syndrome in Japan, as of March 2016

(IASR 37: 59-61, April 2016)

The World Health Organization (WHO) proposed to achieve regional measles and rubella/congenital rubella syndrome (CRS) elimination goals by the end of 2015, and achieve measles and rubella elimination in at least five of the six WHO regions by 2020 (Global Measles and Rubella Strategic Plan, WHO, 2012).  These measles and rubella elimination goals were included in the global vaccine action plan (GVAP) endorsed at the 65th World Health Assembly in 2012.  Here, “elimination” is defined as the absence of endemic transmission of measles or that of rubella/CRS in a defined geographical area (e.g. region or country) for ≥12 months in the presence of a well performing surveillance system.  WHO’s Western Pacific Regional Office started the measles elimination program in 2003, and verified the elimination status of Australia, Macao SAR (China), Mongolia and the Republic of Korea in 2014, and that of Brunei Darussalam, Cambodia and Japan in 2015 (see p. 62 of this issue).  Japan, while maintaining measles elimination status under the “Guidelines for the Prevention of Specific Infectious diseases: Measles (Ministry of Health, Labour and Welfare notice No. 442, December 28, 2007; http://www.mhlw.go.jp/bunya/kenkou/kekkaku-kansenshou21/dl/241214a.pdf)”, now targets attaining rubella elimination status by FY2020 under the “Guidelines for the Prevention of Specific Infectious diseases: Rubella (Ministry of Health, Labour and Welfare notice No. 122, March 28, 2014; http://www.mhlw.go.jp/file/06-Seisakujouhou-10900000-Kenkoukyoku/0000041928.pdf.pdf)”(see p. 81 of this issue).

Copyright 1998 National Institute of Infectious Diseases, Japan

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