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.

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, 3^rd 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.