国立感染症研究所

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The topic of This Month Vol.38 No.11(No.453)

Influenza 2016/17 season, Japan

(IASR Vol. 38 p209-211: November, 2017)

The 2016/17 influenza season (from week 36 in September 2016 to week 35 in August 2017) was characterized by the predominance of the A/H3 subtype, with a smaller contribution by both the Yamagata and Victoria lineages of influenza type B.

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The topic of This Month Vol.38 No.10(No.452)

Hand, foot, and mouth disease and herpangina, 2007 to September 2017 (week 38), Japan

(IASR Vol. 38 p191-193: October, 2017)

Hand, foot, and mouth disease (HFMD) and herpangina are pediatric enteroviral diseases that often occur in the summer.  Both are category V infectious diseases under the Infectious Diseases Control Law, notifiable based on clinical diagnosis from ~3,000 pediatric sentinel sites.  Reporting requires the following clinical manifestations: “2-5mm-sized blisters appearing on the palm, plantar, dorsum of foot or oral mucosa” that “heal without crust formation” for HFMD, and “sudden onset of high fever” and “vesicular rash, ulcers or reddening of the uvula” for herpangina.  Causative agents are mostly viruses belonging to Enterovirus A.

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The topic of This Month Vol.38 No.9(No.451)

HIV/AIDS in Japan, 2016

(IASR Vol. 38 p177-178: September, 2017)

HIV/AIDS surveillance in Japan started in 1984.  It was conducted under the AIDS Prevention Law from 1989 to March 1999 and since April 1999, has been operating under the Infectious Diseases Control Law.  Physicians are required to notify all the diagnosed cases (see http://www.niid.go.jp/niid/images/iasr/34/403/de4031.pdf for the reporting criteria).  The data in this article were derived from the annual report of the National AIDS Surveillance Committee for the year 2016 (reported by the Tuberculosis and Infectious Diseases Control Division, the Ministry of Health, Labour and Welfare (MHLW), http://api-net.jfap.or.jp/status/2016/16nenpo/16nenpo_menu.html).  HIV/AIDS cases are classified into two categories: as an “HIV case” if HIV infection was detected before clinical manifestation of AIDS, and as an “AIDS case” if the infection was detected after manifestation of AIDS symptoms*.

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The topic of This Month Vol.38 No.8(No.450)

Japanese encephalitis, Japan, 2007-2016

(IASR Vol. 38 p151-152: August, 2017)

Japanese encephalitis (JE) is caused by JE virus (JEV) transmitted by Culex tritaeniorhynchus.  Most infections are asymptomatic, but when symptomatic, after 1-2 weeks of incubation, case fatality can be 20-40% and half of the survivors will have sequelae.  JE is a category IV notifiable infectious disease under the Infectious Diseases Control Law and all diagnosed cases shall be notified immediately (see http://www.nih.go.jp/niid/images/iasr/38/450/de4501.pdf for notification criteria).  Prefectural public health institutes (PHIs) measure JEV antibody levels among humans and JEV infection levels among farmed pigs on a periodic basis, annually or once every few years, under the National Epidemiological Surveillance of Vaccine-Preventable Diseases (NESVPD) system.  The collected data are collated and summarized at the National Institute of Infectious Diseases.  This article describes the trends in JE from 2007-2016 (see IASR 30: 147-148, 2009 for data prior to 2008).

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The topic of This Month Vol.38 No.7(No.449)

Adenovirus infections, 2008 to June 2017, Japan

(IASR Vol. 38 p133-135: July, 2017)

Adenovirus (human mastadenovirus: Ad), is a physicochemically stable non-enveloped double-stranded DNA virus.  Over 80 types have been described, and are currently grouped into 7 species from A to G.  Ads have been reported as serotypes up to Ad51 (denoted as, for example, Ad1), but Ads discovered later (i.e. Ad52 or greater) have been reported based on the whole genome sequencing (see p. 136 of this issue).

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The topic of This Month Vol.38 No.2(No.444)

Pertussis in Japan, as of January 2017

(IASR Vol. 38 p23.-24: February, 2017)

Pertussis is defined as “acute respiratory tract infection caused by Bordetella pertussis” in the Infectious Diseases Control Law (see http://www.niid.go.jp/niid/images/iasr/38/444/de4441.pdf for the notification criteria).  The main symptom is a prolonged cough.  As severity may be greater among neonates and infants, vaccination is important.

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The topic of This Month Vol.38 No.1(No.443)

Norovirus trends in Japan, 2015/16 season

(IASR Vol.38: 1-3, January, 2017)

Norovirus (NoV) is a single stranded RNA virus.  It is classified into genogroups GI-GVII, and human infection is primarily associated with GI and GII.  Since the 2015/16 season, a new coding system based on the nucleotide sequence of the VP1 region has been used replacing the previous one, which was based on the nucleotide sequence of the capsid N/S region (see the comparison table; http://www.niid.go.jp/niid/images/iasr/rapid/graph/Vol.36/graph/pt4274a.gif).

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The Topic of This Month Vol.37 No.3(No.433)

Severe fever with thrombocytopenia syndrome (SFTS) in Japan, as of February 2016

(IASR 37: 39-40, March 2016)

Severe fever with thrombocytopenia syndrome (SFTS) is a tick-borne systemic infection caused by SFTS virus (SFTSV), which belongs to Genus Phlebovirus, Family Bunyaviridae.  SFTS was first reported from China in 2011 as a novel bunyavirus infection. Since then, SFTS has also been reported from Japan and South Korea.  Incubation period is 5-14 days.  The signs/symptoms in the early phase of the disease are fever, gastrointestinal symptoms (anorexia, nausea, vomiting, etc.), headache and myalgia, followed by neurological symptoms (impaired consciousness) and bleeding (gingival oozing, bloody diarrhea, hematuria) in the later phase of the disease.  Other somatic signs such as lymph nodes enlargement and epigastric tenderness are commonly observed.  Laboratory findings include lymphopenia and thrombocytopenia in total blood cell counts (TBC), and increased level of AST, ALT and LDH in the serum chemistry.  Among survivors, TBC begins to improve 1 week after onset, and becomes normal within approximately 2 weeks after onset.  In severe cases, however, no recovery signs are observed in the later stage of the disease and signs/symptoms such as impaired consciousness and bleeding tendency appear.  The pathophysiology of fatal SFTS patients are a combination of the disseminated intravascular coagulation and multiple organ failure.  So far, the case fatality rate of notified SFTS patients in Japan has been approximately 30% at the time of notification.

Life cycle in nature and transmission route of SFTSV to humans:  In nature, SFTSV is maintained in ticks and mammals through the tick-tick cycle (vertical transmission from adult ticks to their offspring through transovarial transmission) and tick-mammal cycle (transmission from infected ticks to mammals and then from mammals to ticks).  SFTSV genome has been detected in several tick species in Japan, i.e., Takasago testudinarium (Amblyomma testudinarium), Haemaphysalis longicornis, Haemaphysalis flava, Haemaphysalis megaspinosa, and Haemaphysalis kitaokai.  High prevalence of SFTSV seropositivity has also been demon-strated among deer, wild boars, dogs, and raccoon dogs (see pp. 50 & 51 of this issue), and indicates that the tick-mammal infection cycle is already established in Japan.  While the main infection route of SFTSV to humans is via SFTSV-carrying tick-bite, transmission through direct contact with blood and/or body fluid of the SFTS patient to the patient’s family members or medical providers has been reported in China and South Korea (see p. 48 of this issue).

Molecular epidemiology: SFTSV isolates in Japan, China, and South Korea are classified into two major clades, i.e., a Chinese clade consisting of 5 genotypes, C1 to C5, and a Japanese clade consisting of 3 genotypes, J1 to J3. In Japan, majority of the Japanese SFTSV isolates detected belonged to genotype J1.  However, genotypes C3 to C5 have been detected from some Japanese SFTSV isolates on rare occasions, and conversely, genotype J3 has been detected from some Chinese and South Korean SFTSV isolates (see p. 44 of this issue).

SFTS patients in Japan: Since March 4, 2013, SFTS has been designated as a category IV infectious disease under the Infectious Diseases Control Law in Japan (see http://www.niid.go.jp/niid/images/iasr/35/408/de4081.pdf for notification criteria). Therefore, a physician, who diagnoses a patient as having SFTS, must notify the case within 24 hours to a local health center. SFTSV must be handled as a class III pathogen under the Infectious Diseases Control Law.

A total of 170 SFTS patients have been notified in Japan as of February 24, 2016 (Table).  Among them, 162 had onset in 2013 or afterwards (Fig. 1), while 8 had onset before 2013 (2, 1, and 5 cases in 2005, 2010, and 2012, respectively).  Majority of patients were reported during May to August (Fig. 1) and were from 20 prefectures located mostly in western Japan (Fig. 2).  Among 162 patients reported since 2013, 77 (45%) were male and 93 (55%) were female.  The majority were older than 60 years of age (range 5-95 years; median 74 years) (Fig. 3).  A pediatric case was reported in 2015 for the first time in Japan (see p. 42 of this issue).  Forty-six patients (27%) were fatal at the time of notification (Fig. 3).  Majority of patients had fever (168 cases, 99%) and gastrointestinal symptoms including abdominal pain, diarrhea, vomiting, and anorexia (150 cases, 88%). Thrombocytopenia and leukopenia were found in 162 (95%) and 150 (88%) patients, respectively (see p. 41 of this issue).

SFTS in other countries (China and South Korea) (see p. 47 of this issue): In China, approximately 3,500 SFTS patients have been reported through 2014, with the case fatality rate ranging from 7.8-12.2%.  In South Korea, since a fatal SFTS patient was confirmed in August 2012, 36 cases (17 fatal) and 55 cases (15 fatal) have been reported in 2013 and 2014, respectively.  The estimated case fatality rate in South Korea ranged from 27-47%.

Laboratory diagnosis in Japan: Virological tests for SFTS include detection/isolation of SFTSV from patients’ blood or other body fluids (throat swab, urine, etc.), and/or demonstration of a significant rise in IgG antibody titer against SFTSV in paired sera.  Prefectural and municipal public health institutes (PHIs) conduct the conventional one-step RT-PCR (see p. 43 of this issue), while the National Institute of Infectious Diseases (NIID) conducts the quantitative one-step RT-PCR upon request (see p. 45 of this issue).  Physicians who are concerned regarding laboratory tests should consult their local health center.

Challenges for the future: The first SFTS patient in Japan was reported in January 2013, and SFTS infections are expected to continue to occur.  Studies such as those conducted by NIID and PHIs and the Ministry of Health, Labour and Welfare-funded program, “Comprehensive studies for the control of SFTS”, have increased our knowledge and understanding of the SFTS patients’ geographical distribution, clinical picture, and pathology, and also regarding the lifecycle of SFTSV in nature, transmission route(s), and risk factors of SFTSV infection.

The most important preventive measure against SFTS is avoidance of tick-bite.  During spring to autumn when ticks are most active, exposed areas of the skin should be minimized when entering areas inhabited by ticks.  Repellents containing DEET are effective to some extent.  Other information regarding tick-bite prevention is available at http://www.niid.go.jp/niid/ja/sfts/2287-ent/3964-madanitaisaku.html

No vaccines or specific therapeutics against SFTS are currently available.  While there has been progress in developing therapeutics against SFTSV (see p. 49 of this issue), as the prognosis of SFTSV infection is quite poor, further research is imperative.

 

 

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The Topic of This Month Vol.37 No.2(No.432)

Poliomyelitis as of 2016

(IASR 37: 17-18, February 2016)

Poliomyelitis, also known as infantile paralysis, is caused by poliovirus that infects the central nervous system. Typically, the infection irreversibly damages motor neurons causing acute flaccid paralysis (AFP).  As no specific therapeutic is available, vaccination is the basic strategy for preventing polio disease occurrence and epidemic.  Acute poliomyelitis is a notifiable Category II infectious disease under the Law Concerning the Prevention of Infectious Diseases and Medical Care for Patients of Infections (the Infectious Diseases Control Law); physicians who have diagnosed symptomatic or asymptomatic cases (excluding vaccine strain carriers) must notify the case immediately (see http://www.niid.go.jp/niid/images/iasr/37/432/de4321.pdf for clinical characteristics and notification criteria).  Vaccine-associated paralytic polio (VAPP) and those caused by secondary transmission of vaccine strain(s) derived from vaccinees are also notifiable.  As AFP can be caused by causes other than polio, confirmation of poliovirus by isolation from stool specimens, identification and genetic analysis of the isolates are indispensable for polio surveillance.

Current situation of the global polio eradication program
Since WHO launched the global polio eradication initiative in 1988, the total number of reported polio cases and areas considered endemic steadily decreased.  Globally, wild poliovirus (WPV) type 2 has not been isolated since the last detection in India in 1999 and the Global Commission for the Certification of the Eradication of Poliomyelitis declared eradication of WPV type 2 in September 2015.  WPV type 3 has not been reported for ≥3 years since the last detection in Nigeria in 2012.  The remaining WPV circulating in the world is poliovirus type 1; while still circulating in Pakistan and Afghanistan (Figure, see p. 19 of this issue), it is likely no longer circulating in the African continent after the last detection in Nigeria in July 2014, a country where polio had been endemic for a long time (see p. 29 of this issue).  In 2015, 72 wild polio cases were reported globally, a considerable decline from 359 cases in 2014 (Table).  As the remaining polio-endemic countries are afflicted by numerous social problems, however, polio eradication in the near future will not be easy.

The Western Pacific Region (WPR) of WHO declared eradication of indigenous WPV in 2000.  Since then, it has not experienced an epidemic of WPV except the WPV type 1 epidemic in Xinjiang province in China, which was imported from Pakistan.  More recently, however, vaccine-derived poliovirus (VDPV) epidemics have been reported from various parts of the world, and in the WPR, a type 1 VDPV epidemic was reported from Laos in 2015 (see pp. 20 & 24 of this issue).

VDPV has thus become an impediment to the completion of global polio eradication (see p. 24 of this issue). In addition to VDPV, VAPP has also been a public health concern; approximately 40% of the 250-500 VAPP cases reported annually from countries that use oral polio vaccine (OPV) have been caused by type 2 OPV (http://www.who.int/immunization/diseases/poliomyelitis/inactivated_polio_vaccine/learn/en/index2.html).  Accordingly, WHO requested all countries to stop using trivalent OPV (tOPV) within the period of 17 April - 1 May of 2016, and it further requested for countries that will continue to use OPV that they should be prepared to replace tOPV with type 1 and type 3 bivalent OPV (bOPV).  After replacement of tOPV with bOPV, however, risk of poliomyelitis due to type 2 VDPV may increase.  In order to minimize such a consequence, at least one dose of the trivalent inactivated polio vaccine (IPV) should be incorporated into routine vaccination, which necessitates manufacturing a larger supply of IPV (see pp. 19, 20 & 30 of this issue). 

Introduction of IPV and polio surveillance in Japan
In September 2012, Japan replaced tOPV with tIPV for routine immunization, and two months later, ahead of other countries, it introduced DPT-IPV into routine immunization, which included Sabin-derived tIPV and diphtheria-pertussis-tetanus antigens.  Though vaccine coverage and seropositivity were low in 2011-2012 when OPV was still used (for infants 1 year old and younger, vaccine coverage was 76%, and seropositivity for type 1, type 2, and type 3 were 80%, 78% and 48%, respectively), high levels of vaccine coverage (≥95% among children under 5 years of age) and high seropositivity (≥95% among children under 5 years of age for both type 1 and type 2 antigens) were obtained after switching to IPV-DPT, which has been maintained since then (see p. 26 of this issue).

Reporting under the Infectious Disease Control Law and surveillance activities under the National Epidemiological Surveillance of Vaccine-Preventable Diseases (NESVPD) ensured absence of importation and/or circulation of WPV and VDPV.  To complement disease surveillance, infectious agent surveillance under the NESVPD has been examining stool specimens from healthy children for the presence of poliovirus.  This system was replaced by the more sensitive environmental surveillance system in 2014, and in October 2014, Sabin type 3 poliovirus strain was isolated from concentrated sewage water (see p. 27 of this issue).

Laboratory diagnosis of poliovirus
Laboratory diagnosis consists of isolation of poliovirus in cultured cells.  According to WHO’s standard recommendations, intratypic differentiation should be conducted by real time RT-PCR.  All isolates identified as non-Sabin-like by intratypic differentia-tion should be sequenced for the whole VP1 region to differentiate between WPV, VDPV and vaccine types.  Isolates with nucleotide substitutions in ≥1% of the VP1 gene for types 1 and 3 and ≥0.6% of the VP1 gene for type 2 are classified as VDPV, which should be reported immediately to WHO (see p. 24 of this issue).

Biorisk management of poliovirus
WHO, in its Global Action Plan, 3rd edition (GAPIII), requests Member States to limit the use of poliovirus to the diagnosis, research and vaccine production conducted in certified facilities, where poliovirus is handled according to the Biorisk Management Standards delineated in GAPIII.  In addition, GAPIII requests that the Sabin type 2 OPV strains be destroyed or handled under biosafety conditions designated for wild type poliovirus within three months after the global introduction of bOPV (see p. 22 of this issue).

Accordingly, the Ministry of Health, Labour and Welfare (MHLW) issued a national announcement requesting the destruction of unnecessary poliovirus and requested institutions that will continuously retain poliovirus materials to notify the Tuberculosis and Infectious Diseases Control Division of MHLW (Ken-kan-hatsu 1211 No.1) (see p. 22 of this issue).

Issues to be considered
WHO deems the global polio eradication program as the number one priority among public health programs, and is striving to interrupt the spread of WPV type 1 in endemic countries.  As an endgame strategy, WHO is planning to replace tOPV with bOPV globally within the first half of year 2016.

As high vaccine coverage has been maintained after introduction of IPV, the occurrence of polio and the risk of transmission is believed be low in Japan.  However, as IPV does not confer mucosal immunity sufficient enough for preventing the intestinal replica-tion of the virus, importation of WPV or VDPV should be vigilantly monitored.  As the Sabin type 2 strain will be controlled from the second half of 2016, MHLW is taking the necessary measures regarding further use or destruction of the poliovirus specimens in biomedical research facilities and other institutions.

 

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The Topic of This Month Vol.37 No.1(No.431)

Erythema infectiosum (Human parvovirus B19 infection)

(IASR 37: 1-3, January 2016)

Erythema infectiosum is a contagious exanthematous disease affecting mainly infants and young children.  The causative agent is human parvovirus B19 (PVB19), a single-stranded DNA virus, which belongs to the genus Erythrovirus, the subfamily Parvovirinae, the family Parvoviridae.  It is known to infect only humans.  It infects the erythroid precursor cells through specific binding to the P antigen present on these cells and destroys the cells through apoptosis.  The typical manifestation is butterfly-shaped erythema on the cheeks, and is thus called “apple disease” in Japan.  However, the erythema, often taking lacy, mesh-like form, may extend to the extremities and the trunk (see p. 3 of this issue). 

National Epidemiological Surveillance of Infectious Diseases (NESID)
Erythema infectiosum is a category V infectious disease (notification criteria are found in http://www.niid.go.jp/niid/images/iasr/37/431/de4311.pdf), and approximately 3,000 pediatric sentinel sites report patients diagnosed as erythema infectiosum on a weekly basis.  The reported number of erythema infectiosum cases shows a seasonal trend in epidemic years, with a peak in June-July (Fig. 1).  The annual number of patients reported from 2010 to 2014 was 50,061, 87,010, 20,966, 10,118 and 32,352, respectively. In the 2015 season, a total of 92,625 patients were reported as of week 50 (Table 1), the highest in the last ten years.  Since the current national surveillance system was established, epidemic years (years where the peak in the weekly number of reported cases per sentinel site exceeded one) occurred in 2001, 2007, 2011, and 2015; epidemic years occurred every 4 to 6 years (Fig. 2, IASR 19: 50-51, 1998; https://idsc.niid.go.jp/iasr/19/217/tpc217.html).  In the 2015 season, the epidemic that started in the Kanto region spread nationwide and peaked in week 28 (Fig. 3).  It then subsided but the patient number has again been increasing since autumn (Fig. 1). 

Among reported cases through week 50 of 2015, those 9 years of age or under occupied 93%, and those aged 5 years made up the highest proportion (17% of total cases) (Fig. 4).  Though the epidemiology of erythema infectiosum among adults is unclear as surveillance is based on the pediatric sentinel notifications, local epidemics among adults have been reported (see p. 5 of this issue).  Information on the epidemiological situation abroad is limited, but outbreaks and fatal fetal cases have been reported (see p. 11 of this issue).

Transmission route and clinical picture
The incubation period of PVB19 is 4-15 days. It is transmitted through droplet or contact infection and is transmissible before clinical onset, but generally noninfectious post onset of the typical erythema (see p. 3 of this issue).  As the blood derived from PVB19-infected patients pre-onset poses a risk for infection, raw plasma materials have been all screened for PVB19 by the agglutination method (receptor-mediated hemagglutination assay) since 1997 (IASR 19: 52, 1998).  During the 11 year period till 2007, 9 infections due to transfusion blood-derived prod-ucts were reported.  In 2008, the CLEIA method (chemiluminescent enzyme immunoassay), whose sensitivity was as high as 106 copies/ml, was introduced, and since 2008 to 2015, only one blood product-derived infection was reported (see p. 9 of this issue).

One in four PVB19 infection cases is asymptomatic.  While PVB19 infection confers lifelong immunity, the virus may cause persistent infection among immunocompromised persons.

Among adults, differential diagnosis is difficult due to variety of manifestations.  In one study, about 30% of measles-suspected cases older than 20 years of age were found positive for the PVB19 genome (see p. 4 of this issue).  Among adults (particularly women), PVB19 infection frequently manifests as arthritis.  Other complications include transient aplastic crisis among hemolytic anemia patients and chronic anemia among immunocompromised persons.

When pregnant women are infected with PVB19, transplacental infection occurs in about 20% of the cases (see p. 7 of this issue), and about 10% of them experience miscarriage or stillbirth.  Fetal hydrops is a frequent complication when mothers are infected before 20 weeks of gestation (particularly 9 to 16 weeks), but the risk decreases after 28 weeks of gestation.  As transplacental infection can occur from asymptomatic cases, pregnant women who have frequent contact with children (such as those with young children or in occupational settings that involve children) should take particular care to reduce the chance of infection.

Laboratory diagnosis of PVB19
Routine laboratory diagnosis includes the titration of IgM and IgG antibodies using enzyme immunoassay and the detection of PVB19 DNA by PCR test.  In case of primary infection, IgM antibody can be detected about 2 weeks post infection, when the erythema appears.  IgM remains positive for about 3 months.  IgG antibody is detectable a few days after the appearance of the IgM antibody, and is maintained lifelong.  To determine whether an infection is primary or not, one needs to take into account the clinical picture, the PVB19 IgM antibody data and PVB19 DNA data (see p. 9 of this issue).  

The real-time PCR test can be used for estimating the clinical stage or the time course of infection.  Utilization of a laboratory test for a “pregnant woman with erythema, who is strongly suspected of PVB19 infection” is covered by the national health insurance. 

Measures to be taken against erythema infectiosum
Erythema infectiosum is generally a pediatric disease with good prognosis.  However, PVB19 infection may become serious among immunocompromised persons and may cause fetal infection with serious outcome.  It is important to note that preventing disease spread is challenging due to several reasons, e.g. differential diagnosis is difficult due to diverse manifestations, asymptomatic cases are infectious, and the virus is shed 1 week before the appearance of symptoms.  In epidemic seasons and epidemic areas, special measures, such as intensified hospital infection control and hygienic practices in the family setting, should be implemented so as to protect persons at risk.

 
 

Copyright 1998 National Institute of Infectious Diseases, Japan

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