国立感染症研究所

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The Topic of This Month Vol.34 No.2 (No.396)

Measles in Japan, 2012

(IASR 34: 21-22, February 2013)

 

WHO Western Pacific Region to which Japan belongs targeted measles elimination by 2012 (see p. 24 of this issue).  The current verification criterion of measles elimination of the Region is “the absence of endemic measles transmission* of endemic virus for more than three years in the presence of a well performing surveillance system, which is supported by genotype analysis of the isolates.” 

*Endemic measles transmission is defined as “the existence of continuous transmission of indigenous or imported measles virus that persists for ≥12 months in any defined geographic area” (WHO, WER, 85: 490-495, 2010). 

Measles incidence under the National Epidemiological Surveillance of Infectious Diseases: Infectious Diseases Control Law requests notification of all measles cases since January 2008 (IASR 29: 179-181, 2008 & 29: 189-190, 2008).  From week 1 to week 52 of 2012, total 293 cases were reported, among which 216 cases including 75 “modified” measles were supported by laboratory diagnosis but 77 cases were supported by clinical diagnosis (as of January 8, 2013).  In 2012, measles cases were reduced to 2/3 of those in 2011 (from 434 cases or 3.58 per million population in 2011 to 293 cases or 2.32 per million population in 2012) (Fig. 1). 

In 2012, the largest number of measles cases were reported from Tokyo (84 cases) followed by Aichi (39 cases), Saitama (32 cases), Kanagawa (29 cases) and Chiba (23 cases).  The total cases in four prefectures within the metropolitan area, Tokyo, Saitama, Kanagawa and Chiba, occupied 57% of all the reported cases. Twenty-one prefectures reported zero cases (Fig. 2 in p. 23), among which 12 prefectures reported zero cases in successive two years (see p. 37 of this issue).  In 2012, 32 prefectures, in contrast to 19 prefectures in 2011, reported <1/million population, the target as a measure of near measles elimination (WHO, WER 85: 490-495, 2010).

The sex ratio was 158 males vs. 135 females.  As for age distribution (Fig. 3), one year olds were the highest in number (29 cases) followed by zero year olds (16 cases).  The teens that occupied 43% of the total in 2008 occupied only 13% in 2012.  In contrast, 20s and 30s increased in proportion, and as a consequence adults occupied 58% of the total measles cases in 2012.

Among the measles patients, 84 had received no dose, 78 only one dose and 17 two doses.  The vaccination history of the remaining 114 was unknown.  The all 16 zero-year-old cases had received no vaccination.  Among 29 one-year-old cases, 15 had received no dose and 13 only one dose.  Among the 132 cases in their 20s and 30s, 22 had received no dose, 35 only one dose and 3 two doses.Two schools, a primary school and a secondary school, temporarily closed in September 2012 in Miyazaki Prefecture on account of measles outbreaks (see p. 33 of this issue).

Isolation and detection of measles virus: The measles virus genotype D5 that had been endemic in Japan during 2006-2008 has not been detected later than May 2010.  Since 2009, measles viruses whose genotypes are those of foreign-origin were detected (Table 1 and Table 2 in p. 23).  In 2012, 45 D8 strains were isolated, among which 24 were derived from an outbreak in Aichi (IASR 33: 66, 2012) and 8 were from an outbreak in Miyazaki (see p. 33 of this issue). Other isolates were 10 D9 strains, among which 5 were from an outbreak in Okayama (IASR 33: 166-167, 2012); 7 H1 strains, among which 5 were from an outbreak in Fukushima (IASR 33: 242-244, 2012); and 6 D4 strains, which were all from sporadic cases.

The National Epidemiological Surveillance of Vaccine-Preventable Diseases (see p. 25 of this issue): WHO considers that measles elimination requires 95% population immunnity against measles virus in each birth cohort.  In Japan, gelatin particle agglutination (PA) assay is conducted and the titers above 1:16 are considered positive.  In 2012, the antibody-positive rate became ≥95% in all the age groups ≥2 years for the first time, which proved effectiveness of the two routine doses (Fig. 4).  However, as the antibody-positive rate in 1-year age group was 67%, earliest vaccination after attaining 12 months of age is desired.

It has been considered that protection of individuals from symptomatic measles infection requires titer 1:128 or higher.  However, the antibody titer of more than 15% of age groups of 0, 1, 4 and 5 years was less than 1:128.

Vaccination rate (see p. 28 of this issue): Since FY2006, routine immunization in Japan has adopted measles-rubella combined vaccine, which is administered in two doses, the first dose to children of one year (1st vaccination) and the second dose to children preceding one year before the school entry (2nd vaccination)(IASR 27: 85-86, 2006).  In addition, from 2008 to 2012, supplementary vaccination was conducted to children whose age corresponds to the age of the first year class of the secondary school (3rd vaccination) and to those whose age corresponds to the age of the third year class of the high school (4th vaccination) to ensure two doses in these age groups too (IASR 29: 189-190, 2008).

The vaccination rate of measles-containing vaccines (M, MR) in FY2011 was 95% for the 1st (96% in 2010), 93% for the 2nd (92% in 2010), 88% for the 3rd (87% in 2010) and 81% for the 4th (79% in 2010).  The coverage of the 1st vaccination exceeded 95% (targeted coverage rate) successively in 2011 and in 2012.

For further increase of vaccination coverage: Consequent to the introduction of the 3rd and 4th vaccinations, there was a great reduction of measles cases under 20 years of age (Fig. 3).  So as to achieve the measles elimination, local governments are requested to make further efforts to attain ≥95% vaccine coverage not only for 1st but also for 2nd, 3rd and 4th vaccination.  According to the questionnaire-based survey destined to municipalities, towns and villages, which was conducted by a research group supported by Ministry of Health Labour and Welfare (MHLW), factors that played an important role in attaining coverage ≥95% were (1) timely reporting on the vaccine coverage in the community level, (2) identification of unimmunized children so as to recommend each unvaccinated child to go to vaccination by mail and (3) preparatory health check conducted in October and November in previous year of the school entry, where immunization is recommended to children with insufficient vaccine doses (see p. 31 of this issue).

Unvaccinated persons belonging to target cohorts of the 2nd, 3rd and 4th vaccinations in FY2012 are advised to be vaccinated before March 31, 2013, as public expense will not cover the vaccination after this date.  During “the Children’s Immunization Week”, from March 1 (Friday) to March 7 (Thursday) in 2013, some local medical association will open clinics on Saturday, Sunday and evenings for vaccination.  The eligible persons are advised to be vaccinated at the earliest occasion before the end of March this year.

Importance of laboratory diagnosis: In 2012, one fourth of the notified cases were diagnosed by symptoms without laboratory confirmation.  More than half of the laboratory diagnosis was based on IgM tests.  Measles cases weakly positive for IgM or clinically suspected measles are often cases infected by rubella virus, B19 virus, HHV-6, HHV-7, enteroviruses, etc, which occasionally develop skin rash (see p. 34 of this issue).  Therefore, direct detection of measles virus genome, such as by PCR or virus isolation, is important.  Prefectural and municipal public health institutes (PHIs) and National Institute of Infectious Diseases (NIID) have established the collaboration network for laboratory diagnosis based on PCR testing.  In 2011-2012, 40% of the laboratory-diagnosed specimens were PCR-tested by PHIs (see p. 36 of this issue).  Physicians are requested to obtain clinical specimens in appropriate timing and the person in charge of transportation should keep the samples under the appropriate temperature.  The PHIs should observe the required temperature control of the received specimens during the storage and testing (IASR 33: 309-310, 2012).

Measures to be taken from now: In 2012, the “foreign strains” were isolated not only from the imported cases but also from sporadic cases without history of overseas travel (Table 2 in p. 23, see p. 36 of this issue and http://www.niid.go.jp/niid/en/iasr-measles-e.html).  For measles elimination, important are maintenance of high vaccine coverage and a system that allows tracing of an outbreak back to the infection source and immediate interruption of virus transmission.  The principle of “immediate response to any one measles-suspected case” should be applied to all the cases.  The response includes active epidemiological investigation supported by laboratory and prompt measures against virus spread, which requires coordination between medical facilities, health centers, PHIs and NIID.  So as to prevent importation, people including adults are advised to complete measles vaccination before going abroad.  It is also important to conduct a vaccination campaign to those going abroad.

Japanese government recently revised the “Special Infectious Disease Prevention Guidelines on Measles (MHLW, December 28, 2007)”.According to the revised guidelines adopted in April 2013, Japan targets elimination of measles by FY2015 to obtain WHO’s certificate of measles elimination and projects maintenance of the measles elimination status thereafter.  According to the Guidelines, a measles elimination verification committee will be established (see p. 39 of this issue).  Cases notified by a physician will be examined for clinical symptoms, laboratory findings, vaccine histories, and possibility of contact with measles patients.  If the possibility of measles is excluded as a consequence, the doctor in charge will be requested retraction of the notification.  In order to prove measles elimination status, it is imperative to obtain clinical specimens in timely manner and to examine the possibility of endemic circulation through genotyping.

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The Topic of This Month Vol.34 No.1 (No.395)

Mycoses in Japan as of 2012

(IASR 34: 1-2, January 2013)

 

Mycoses and responsible pathogens
Mycoses, diseases caused by pathogenic fungi, are classified into two categories depending upon the site of lesion: “superficial mycosis” affecting epidermal or mucosal tissues and “systemic mycosis” producing pathological changes which are disseminated in the whole body or localized to some internal organs.  Though allergenic diseases or poisoning caused by fungi (e.g., aflatoxin) are sometimes included in the category of mycosis, this article principally deals with systemic mycosis, which is often fatal.

Fungi causing systemic mycosis are largely divided into two categories, those causing diseases among normal population, such as, genus Coccidioides, genus Histoplasma and genus Cryptococcus, and those causing diseases only among immunodeficient people, such as, genus Candida and genus Aspergillus.  Among systemic mycosis, cryptococcosis is found in Japan, but coccidioidosis, histoplasmosis and some other mycoses, such as paracoccidioidosis, can be acquired only abroad, which are categorized as imported mycoses (IASR 23: 55-56, 2002).

Coccidioidomycosis is a category IV infectious disease in the scheme of National Epidemiological Surveillance of Infectious Diseases under the Law Concerning the Prevention of Infectious Diseases and Medical Care for Patients of Infections (Infectious Diseases Control Law, in short), which obliges doctors who made diagnosis of this infection to notify every case (See http://www.mhlw.go.jp/bunya/kenkou/kekkaku-kansenshou11/01-04-12.html for criteria of notification).

From April 1999 to December 2012, 31 cases were reported (Table 1 & Fig. 1); 23 cases were male and 8 were female, and those in their 30’s were the most frequent (13 cases) (Fig. 2).  Infection of 27 cases among the total 31 cases was suspected to have occurred in the United States of America (14 in Arizona State).

Another member of the imported mycosis, histoplasmosis, is increasing in number though its frequency still remains in the single digits (see p. 3 of this issue).

Cryptococcus can infect healthy people.  Once the pathogen invades the central nervous system, it may cause fatal consequence.  According to the clinical laboratory data compiled for year 2011 within the framework of Japan Nosocomial Infections Surveillance (JANIS) sponsored by the Ministry of Health Labour and Welfare (MHLW), Cryptococcus occupied 2.8% of all the pathogens isolated from cerebrospinal fluids of encephalomeningitis patients (including both immunologically normal and compromised cases).  The frequency was comparable to those of pneumococci, enterococci, and Escherichia coli.

Mycoses most frequently observed among immunocompromised patients are opportunistic infections by genus Candida and genus Aspergillus.  While in clinical setting, candidiasis was preeminently frequent (Horn DL, et al., Clin Infect Dis. 48: 1695-1703, 2009), in the autopsy data from the Annual of Pathological Autopsy Cases in Japan, candidiasis and aspergillosis were equally frequent (2% of all the autopsied cases, respectively) (Kume H, et al. Med Mycol J 52: 117-127, 2011).  It is probably because aspergillosis was more difficult to treat and more fatal than candidiasis.

Diagnosis and laboratory examinations
Isolation and identification of pathogenic fungi usually depend on morphological and biochemical characters, but for definitive identification, genetic methods are often used.  Laboratory handling of pathogenic fungi requires special attention, as the fungal spores, particularly those of Coccidioides spp., which are dispersed from colonies developing on agar plates, may cause laboratory infection.  Culture of Coccidioides spp. requires the biosafety level 3 facilities (BSL3) (see p. 3 of this issue).  Therefore, whenever coccidioidomycosis is suspected, such as, from patient’s overseas travel history or residential place abroad, it is preferable to ask National Institute of Infectious Diseases or Medical Mycology Research Center, Chiba University, for advice on laboratory diagnosis.

Even when fungi cannot be isolated, diagnosis is possible based on the specific patho-histological characteristics of different mycoses.

As auxiliary methods, antigen detection can be used.  Highly reliable are detection of glucuronoxylomannan antigen of genus Cryptococcus from sera or cerebrospinal fluids.  Detection of galactomannan antigen of genus Aspergillus in sera is highly sensitive for patients with hematologic malignancies.  Increase of antibody titer over clinical course will be an additional infection indicator.

Therapy of mycosis and development of drug resistance
Owing to availability of new generation antifungal drugs that effectively control the systemic mycoses (see p. 4 of this issue) and based on accumulation of clinical experiences, the standard treatment protocol has now been established.  Even under the standard regimen, administration of antifungal agents may last from months to years, which increases the risk of appearance of drug resistant fungi. Actually, among fungi causing systemic mycosis, genetic mutations responsible for the drug resistance, though rare, have been reported, such as azole antifungal drug resistance mutations among Candida and Aspergillus (Tashiro M, et al., Antimicrob Agents Chemother. 56: 4870-4875, 2012) and echinocandin antifungal drug resistance mutation among Candida (Inui S, et al., J Jpn Assoc Infect Dis 85: 49-53, 2011).

Mycosis of public health importance
Other mycoses of public health importance are Cryptococcus gattii, a mycosis with high fatality, which is increasing in the Northern American Continent (see p. 4 of this issue) and Trychophyton tonsurans causing tinea capitis (see p. 5 of this issue) that is increasing among young adults in Japan.  The issues are under investigation by research groups supported by the MHLW so as to establish appropriate countermeasures.

Note: Coccidioides immitis is regulated by Infectious Diseases Control Law as group 3 pathogen.  When it is isolated, it should be reported to the MHLW within 7 days and when the isolates are to be transported it should be notified to Public Safety Commission.

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The Topic of This Month Vol. 33, No. 12 (No. 394)


Pertussis, Japan, 2008-2011
(IASR 33: 321-322, December 2012)

 

Pertussis is caused by Bordetella pertussis.  It is an acute respiratory infection mainly affecting children.  The main symptom is protracted cough.  In Japan, children are recommended to receive four shots (including one supplementary injection) of pertussis-containing vaccine in their infancy.  Instead of “adsorbed diphtheria-tetanus-acellular pertussis (DTaP) combined vaccine”, inactivated poliovirus vaccine (IPV)-containing DTaP, DTaP-IPV, was introduced since November 2012 (see p. 323 of this issue).  It has been found recently that acquired immunity wanes in 4-12 years after vaccination, which permits infection among children and adults who were already vaccinated.  As being often asymptomatic, the infected adolescent and adults transmit the bacteria to unvaccinated infants whose infection tends to become severe.  This trend is a challenge to many developed countries. 

Incidence: Pertussis is a category V infectious disease to be reported by sentinel clinics under the National Epidemiological Surveillance of Infectious Diseases (NESID).  Clinical cases are reported every week from approximately 3,000 pediatric sentinels all over the country (criteria for reporting: http://www.mhlw.go.jp/bunya/kenkou/kekkaku-kansenshou11/01-05-23.html).  While weekly incidence was low during 2001-2007 (<0.040/sentinel), it increased in 2008 with a peak (0.115/sentinel) in week 20/May (Fig. 1).  Pertussis epidemic is known to occur at an interval of about four years (IASR 26: 61-62, 2005).  Year 2008 corresponded the epidemic year as the previous epidemics occurred in 1999-2000 and 2004.  The epidemic started in 2008 continued for three years until 2010.  

The 2008-2010 epidemic was nationwide (Fig. 2).  In 2007 one year before the epidemic, prefectures reporting ≥2.00 cases/sentinel/year were only two, Chiba and Tochigi.  After the onset of the epidemic, prefectures reporting ≥2.00 cases/sentinel/year increased to 16 in 2008, 7 in 2009 and 11 in 2010.  

Age distribution: Adult cases increased from 0.019 cases/sentinel in 2002 to 0.861 cases/sentinel in 2010.  They accounted for 48% of all the cases in 2010 (Fig. 3).  Later than 2007, patients in their teens too, particularly in 10-14 years of age, increased.  Similar phenomenon has been observed in European countries, the United States and Australia (see p. 323 of this issue).  Number of the zero year patients became below 0.400 cases/sentinel in 2001, which level has been maintained till now (Fig. 4).  

Immunological status of Japanese population: National Epidemiological Surveillance of Vaccine-Preventable Diseases (NESVPD) conducted sero-prevalence of anti-pertussis antibodies (anti-pertussis toxin and anti-filamentous hemagglutinin antibodies) among people in all age groups in 2003 and 2008.  In 2008, antibody-positive rate was about 80% among children aged 6 months to 2 years, which was higher than in 2003, and early acquisition of immunity among this age group was confirmed (Fig. 5).  Meanwhile, sero-prevalence rates among other age groups remained as low as 50% from 2003 to 2008. 

Outbreaks: Japan experienced large scale pertussis outbreaks in universities and other facilities in 2007, which reconfirmed the easiness of pertussis transmission in enclosed spaces occupied by people for a long time (IASR 29: 65-66, 2008).  Later than 2008, outbreaks continued to occur in nursery schools and junior high schools (IASR 29: 201-202, 2008, and see pp. 325 & 326 of this issue).  In addition, local epidemics involving mainly primary and junior high school children occurred (IASR 32: 340-341, 2011, and see pp. 327 & 329 of this issue). 

Pathogens that cause pertussis-like clinical symptoms:B. pertussis-related microorganisms that cause cough and other pertussis-like symptoms are B. parapertussis and B. holmesii.  B. holmesii is a new species identified by US CDC in 1995.  In Japan, B. holmesii has been isolated since late 2000’s from pericarditis and “pertussis” patients (IASR 33: 15-16, 2012 and see pp. 329 & 332 of this issue).  

Microorganisms other than Bordetella that cause pertussis-like symptoms are Mycoplasma pneumoniae, Chlamydia pneumoniae and human bocavirus.  Rhinovirus primarily responsible of common cold was detected from a suspected pertussis outbreak in a medical college and its affiliated hospital in Japan, which warned necessity of differential diagnosis between B. pertussis and rhinoviruses (IASR 32: 234-236, 2011).  From a pertussis outbreak in a nursery school in 2012, rhinovirus and coxsackievirus A9 were detected together with B. pertussis, which indicates occasional double infection of these pathogens in children (see p. 326 of this issue).  

Laboratory diagnosis of pertussis: For laboratory diagnosis of pertussis, bacterial isolation, serological test, and gene detection are applicable.  In Japan, the bacterial agglutination test is widely used as a simple serological test.  However, it is of low precision, and its application to adult or vaccinated child cases is not always appropriate (IASR 32: 236-237, 2011).  Titration of anti-pertussis toxin IgG antibody can be used but is not useful as a rapid test, because IgG increases one week or later after the onset of cough.  Bacterial isolation is extremely difficult particularly from adolescent or adult patients whose bacterial load is low, on account of limited bacterial growth.  The genetic testing can detect B. pertussis genome with a high sensitivity and widely being used as rapid detection method in the United States and European countries.  In Japan, the loop-mediated isothermal amplification (LAMP) is only used by the prefectural and municipal public health institutes (PHIs) and some medical institutions for research purposes (IASR 33: 104-105, 2012).  

For B. holmesii, both bacterial isolation and genetic testing are feasible (see p. 330 of this issue), but only genome sequencing can give definitive diagnosis of the pathogen.  Therefore, its presence may have been overlooked in clinical settings.  National Institute of Infectious Diseases Japan (NIID) is currently developing a LAMP method specifically detecting B. holmesii as a part of its NIID-PHI joint activities in strengthening national laboratory pathogen surveillance system.

Additional comments: Pertussis cases are increasing among adults in developed countries including Japan.  In Japan, pertussis epidemic still persists among secondary school children and also in communities.  As clinical diagnosis of pertussis particularly among adolescents and adults is difficult, genetic testing instead of bacterial culture should be used more widely as in the United States and European countries.  Introduction of simple genetic testing with high accuracy is needed not only for surveillance but also for evaluating vaccine efficacy in Japan. 

 

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The Topic of This Month Vol. 33, No. 11 (No. 393)


2011/12 influenza season, Japan
(IASR 33: 285-287, November 2012)

 

The 2011/12 season's influenza epidemic (from week 36/September of 2011 to week 35/August of 2012) was caused mainly by subtype AH3 and to lesser extent by influenza virus type B.  Influenza A(H1N1)pdm09 that dominated in the 2009/10 epidemic and occupied about a half of the influenza virus isolates in 2010/11 season was rare after April 2011.

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 at weekly basis.  In the 2011/12 season, the epidemic index (number of cases/sentinel) became above 1.0 in week 49 nationwide, and the level was maintained for 22 weeks till week 18 of 2012.  The epidemic attained its peak in week 5 of 2012 with the incidence of 42.7 cases/sentinel (Fig. 1), which was the second highest in the past 10 seasons following the peak observed in 2004/05 season (50.1 cases/sentinel) (http://www.niid.go.jp/niid/en/10/2096-weeklygraph/2572-trend-week-e.html).  The cumulative number of cases per sentinel of this season, 342.5, was also the second highest in the past 10 seasons following 415.4 in 2009/10 season.

At prefecture levels, the epidemic index exceeded 10.0 first in Miyagi and Aichi in week 50 of 2011.  The number of prefectures with the epidemic index exceeding 10.0 increased to 12 in week 2 of 2012 and then to 42 in week 3 resulting in the nationwide influenza epidemic (https://nesid3g.mhlw.go.jp/Hasseidoko/Levelmap/flu/index.html).

The total number of patients who visited medical institutions, which was estimated from sentinel site reports, was about 16,480,000 from week 36 of 2011 to week 18 of 2012 (September 6, 2011-May 6, 2012).  According to the hospitalization surveillance that started in September 2011, total 11,118 patients were hospitalized in the “designated sentinel hospitals” (about 500 hospitals with more than 300 beds), among which 1,487 were clinically severe (http://www.mhlw.go.jp/bunya/kenkou/kekkaku-kansenshou04/pdf/120525-01.pdf).

Isolation/detection of influenza virus: In 2011/12 season, the prefectural and municipal public health institutes isolated total 5,457 influenza viruses (as of October 18, 2012, Table 1).  In addition, there were 1,799 influenza virus detections by PCR alone.  Among the total 7,256 isolated/PCR-detected viruses, 5,755 were derived from influenza sentinels and 1,501 from elsewhere (Table 2).

Influenza viruses of the 2011/12 season consisted mainly of subtype AH3 (71%) and type B (28%).  AH1pdm09 were few (0.2%).  Former seasonal AH1 subtype virus has not been isolated since week 36 of 2009.  Influenza B viruses consisted of Victoria and Yamagata lineages, whose isolation/detection ratio was 2:1.  Viruses isolated/detected from overseas travelers were subtype AH3 (25 cases), type B (5 cases) and AH1pdm09 (2 cases) (Table 2).

Nationwide, subtype AH3 was predominant among the isolates from the beginning till week 9 of 2012, well after the epidemic peak, when type B influenza started to exceed subtype A (Fig. 1 and Fig. 2).  In Okinawa Prefecture, however, the epidemic did not fade; the patients further increased from week 26 of 2012.  The AH3 epidemic in this region lasted from June to September of 2012 (IASR 33: 242, 2012).

As for age distribution of the patients, the peak age was invariably 5-9 years for subtype AH3, B/Victoria and B/Yamagata lineages (Fig. 3 and Fig. 4).

Antigenic characteristics of the 2011/12 season isolates and their drug resistance (see p. 288 of this issue): Of the eight AH1pdm09 isolates tested, six were antigenically similar to A/California/7/2009, the vaccine strain for 2009/10-2012/13 seasons.  Subtype AH3 isolates was antigenically similar to A/Victoria/361/2011 (the 2012/13 season vaccine strain), whose antigenicity was slightly changed from that of A/Victoria/210/2009 (the 2010/11-2011/12 season vaccine strain used in Japan).  Antigenicity of Victoria lineage isolates that occupied 2/3 of all the type B isolates was similar to that of B/Brisbane/60/2008 (the 2009/10-2011/12 season vaccine strain), and that of Yamagata lineage that occupied 1/3 of the type B isolates was similar to that of B/Wisconsin/1/2010 (2012/13 season vaccine strain).

None of the nine AH1pdm09 isolates tested had the H275Y mutation implicated in the oseltamivir resistance, while 2.0% of the tested 2010/11 season isolates had the H275Y mutation.  Among 278 subtype AH3 isolates tested, only one had R292K mutation attributable to oseltamivir/peramivir resistance (http://www.niid.go.jp/niid/en/iasr-inf-e.html#Antiviral).

Immunological status of Japanese population: According to the data of National Epidemiological Surveillance of Vaccine-Preventable Diseases (see p. 294 of this issue) that was obtained with serum samples collected from July to September in 2011, frequency of anti-A/California/7/2009pdm09 HI antibody positives (titer higher than 1:40) was average 49%.  The antibody positive rate was relatively high for 5-24 years of age (64-78%).  For age groups 0-4 years and 50 years or older, positive rates were 24-38%, which were higher than in 2010 (blood samples collected during July-September).  Antibody positive populations for subtype AH3 and B/Victoria lineage were average 50% and 45%, respectively, and were highest among age group of 15-19 years (68% and 57%, respectively).  Antibody positive rate for B/Yamagata lineage was generally low, 18% in average and highest (38%) in age group 15-19 years.

Influenza vaccine: The quantity of trivalent vaccines produced in 2011/12 season was 28,880,000 vials (calculated for 1mL/vial), of which estimated 25,100,000 vials were used for vaccination.  The vaccination coverage of the elderly (older than 65 years) in compliance with the Preventive Vaccination Law was 53.3% (53.1% in 2010/11 season).

The vaccine strain selected for 2012/13 season for AH1 was A/California/7/2009pdm09 which is the same as for 2010/11 and 2011/12 seasons, whereas the vaccine strains for AH3 and type B were changed to A/Victoria/361/2011 and B/Wisconsin/1/2010 (Yamagata lineage), respectively (see p. 297 of this issue).

Avian influenza virus A(H5N1) and swine-origin A(H3N2) variant: From November 2010 to March 2011, highly pathogenic avian influenza (HPAI) virus subtype A(H5N1) spread among wild birds and domestic fowl in various places in Japan.  Epidemic of the virus among birds has been continuously reported from Indonesia, Vietnam and Egypt before and after 2011 and human cases of A(H5N1) infection, too.  More recently in September 2012, HPAI among birds was reported from China and Nepal (http://www.maff.go.jp/j/syouan/douei/tori/index.html).

Since July 2012, United States has reported more than 300 human cases of A(H3N2) variant influenza virus infections that occurred through exposure to pigs.

Act on Special Measures For Pandemic Influenza, etc. Preparedness and Response: In preparation for the case of rapid spread of the novel influenza and other emerging/re-emerging infectious diseases of similar public health concern, and based on the experience of pandemic (H1N1)2009, “Act on Special Measures For Pandemic Influenza etc. Preparedness and Response” was issued on May 11 of 2012 (http://www.cas.go.jp/jp/influenza/120511houritu.html).

Additional comments: Trends of outbreaks should be monitored continuously by sentinel surveillance, school outbreak surveillance, hospitalization surveillance and other possibilities.  The virus isolation should be conducted throughout the year and the antigenic and genetic changes of the epidemic strains should be monitored so as to secure vaccine candidate strains.  Monitoring of the resistance to anti-influenza drugs among isolates should be continued.  These measures are all important for future risk management measures.

Flash reports on the isolation and detection of influenza viruses in 2012/13 season are found in p. 300 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. 33, No. 10 (No. 392)


Mycoplasmal pneumonia as of September 2012, Japan
(IASR 33: 261-262, October 2012)

 

Mycoplasmal pneumonia is a category V infectious disease in the National Epidemiological Surveillance of Infectious Diseases (NESID) under the Law Concerning the Prevention of Infectious Diseases and Medical Care for Patients of Infections (the Infectious Diseases Control Law) enforced on April 1, 1999.  Sentinel hospitals* regularly report the weekly number of mycoplasmal pneumonia patients (total of outpatients and inpatients).  In addition to isolation of Mycoplasma pneumoniae or detection of serum antibody to M. pneumoniae, detection of M. pneumoniae genome by PCR or LAMP has been included in the notification criteria (http://www.mhlw.go.jp/bunya/kenkou/kekkaku-kansenshou11/01-05-38.html) since its modification in April 2011.  Recently, the reported number of mycoplasmal pneumonia patients is increasing (Fig. 1).

*There are about 500 sentinel hospitals in Japan, which are selected from those equipped with departments of pediatrics and internal medicine and with more than 300 beds.

Periodicity of mycoplasmal pneumonia epidemics and the epidemic that started in 2011: Periodicity of mycoplasmal pneumonia epidemic at a 3-8 year interval has been observed worldwide.  It is presumably brought about by the herd immunity vs. pathogen interaction but its exact mechanism is unknown.  Seasonally, mycoplasmal pneumonia is prevalent from autumn to winter, and occasionally also in early summer (Fig. 1).

In Japan, the large-scale atypical pneumonia epidemics occurred at four-year intervals from the late 1970s through the 1980s coinciding Olympic years.  Under the former NESID system (July 1981-March 1999), number of “clinically-diagnosed atypical pneumonia” cases peaked in 1984 and 1988 (IASR 28: 31-32, 2007) and it was probably epidemics of mycoplasmal pneumonia, because major cause of atypical pneumonia is M. pneumoniae.  Though almost absent since 1990s (except the epidemic in 2006), mycoplasmal pneumonia cases increased in autumn of 2010 (Fig. 1).  In 2011, number of the reports increased from summer and reached its peak in winter, which was more than twice as high as the past peaks in 2006 and 2010.  The number of the reports per week in 2012 is continuously higher than in 2011.  Since 2010, mycoplasmal pneumonia epidemic is found worldwide, such as, in United Kingdom, France, Northern European countries and Israel.

Age and geographical distribution of mycoplasmal pneumonia patients: Children aged 1-14 years occupied 80% of the patients. Among them, since 2011, age group 10-14 years increased and that below 4 years decreased in proportion (Fig. 2).  As such age group shift has been observed in the past (IASR 28: 31-32, 2007), the present resurgence of mycoplasmal pneumonia may not be related to the age shift.

Regionally, since 2007, Aomori, Miyagi, Fukushima, Gunma, Saitama and Okinawa sentinel points have reported larger number of mycoplasmal pneumonia cases, and since 2010, Iwate, Tochigi, Toyama, Aichi, Gifu, Osaka, Ehime and Saga also do so (Fig. 3).  Since 2011, other prefectures with fewer cases started to report larger number of cases than before.

Mycoplasma pneumoniae: Among species of Mycoplasma of human origin, clear pathogenicity has been found only in Mycoplasma pneumoniae.  M. pneumoniae belongs genus Mycoplasma of class Mollicutes.  Its genome is 800kb and the smallest among organisms that grow in artificial media.  It is entirely devoid of peptide glycan cell wall, and β-lactam antibiotics are ineffective.  It is rod-shaped and 0.3 × 2 µm in size.  It has a cytoplasmic protrusion on one end of the body; it is an organelle used for adherence to the surface of respiratory epithelial cells thus contributing to the bacteria’s pathogenicity (see p. 263 of this issue).  On its surface clustered is a large number of cytadhesin protein P1 (molecular weight 170kDa).  P1 protein is polymorphic, which allows classification of M. pneumoniae into type 1 and 2 and their subtypes by genome sequencing.  So far, type 1, 2, 2a, 2b and 2c have been identified among the Japanese clinical isolates.  Though the type does not affect the pathogenicity, the frequency of the prevalent types is variable from year to year and from region to region.  Recently, multiple-locus variable-number tandem repeat analysis (MLVA) is used for epidemiological investigation in the US and European countries.  So far, more than 30 MLVA types have been reported.

Increase of macrolide resistance: Macrolide antibiotics are used for treatment of mycoplasmal pneumonia.  However, since 2000 when the macrolide-resistant M. pneumoniae was first reported in Japan, macrolide-resistant strains are found continuously increasing in Asia and nearby regions (IASR 32: 337-339, 2011).  Now, more than 50% of clinical isolates in Japan are estimated to be macrolide resistant (see pp. 264, 265 & 267 of this issue).  However, European countries experiencing mycoplasmal pneumonia epidemic similarly as Japan report the macrolide resistance rate below 10%.  Macrolide-resistant strains are more often isolated from pediatric patients rather than adults.  Macrolide resistance itself does not significantly affect the sequel as most cases recover without chemotherapy.  When the patients received chemotherapy, feverish phase may prolong in case of macrolide-resistant M. pneumoniae infection than in case of macrolide-susceptible one (IASR 28: 41-42, 2007 and see p. 266 of this issue).  Macrolide-resistant M. pneumoniae infection can be effectively treated with quinolone and tetracycline antibiotics, and no resistant clinical isolates have been reported in the world including Japan.  However, their use for children should be limited to really serious cases on account of their potential side effects (see p. 268 of this issue).

Laboratory diagnosis of mycoplasmal pneumonia: Culture, serodiagnosis and gene amplification methods are available.  Isolation of M. pneumoniae is the most reliable, but 1-4 weeks are required for obtaining the final data.  PA, EIA and other serodiagnostic kits are preferentially used in clinical settings for the rapid test.  However, it is useful only when the paired serum antibody titers of the patients were obtained.  The current most reliable rapid diagnosis is PCR, LAMP and other gene amplification methods (see p. 268 of this issue).  LAMP method has been covered by the health insurance since October 2011.

Final Comments: The progressing mycoplasmal pneumonia epidemic in Japan (http://www.niid.go.jp/niid/ja/10/2096-weeklygraph/1659-18myco.html) necessitates continued surveillance of patients and continued monitoring of drug-resistance and pathogenicity of the bacterial isolates.

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The Topic of This Month Vol. 33, No. 9 (No. 391)


HIV/AIDS in Japan, 2011
(IASR 33: 229-230, September 2012)

 

HIV/AIDS surveillance in Japan had been conducted in compliance with the AIDS Prevention Law from 1989 to March 1999.  Since April 1999, however, it has been conducted in compliance with the Infectious Diseases Control Law that obliges doctors to notify all the diagnosed cases (criteria of reporting are found in http://www.mhlw.go.jp/bunya/kenkou/kekkaku-kansenshou11/01-05-07.html).  The data presented below are derived from the final version (March 28, 2012) of the annual report of the National AIDS Surveillance Committee for year 2011 released by the Specific Disease Control Division, the Ministry of Health, Labour and Welfare (MHLW) (http://api-net.jfap.or.jp/status/2011/11nenpo/nenpo_menu.htm).   It is important to note that the HIV surveillance in Japan counts as an “HIV case” an infected case that is detected by laboratory diagnosis before development of AIDS, and as an “AIDS case” an infected case detected by the manifestation of AIDS symptoms.   An HIV infected case once registered as an HIV case is not registered as AIDS case even if he/she subsequently develops AIDS.

1. Trend of HIV and AIDS cases reported during 1985-2011: The number of reported HIV cases in 2011 was 1,056 (994 males and 62 females), which was the fourth highest since start of the surveillance, following 1,126 in 2008, 1,082 in 2007 and 1,075 in 2010.   The number of reported AIDS cases was 473 (440 males and 33 females), which was the highest since the start of the surveillance (Fig. 1).   Cumulative number of HIV since 1985 to 2011 (excluding infections through administration of coagulants) amounts to 13,704 (11,564 males and 2,140 females) and that of AIDS to 6,272 (5,604 males and 668 females), which are equivalent to 10.723 and 4.908 per 100,000 population, respectively.   HIV cases that later developed AIDS symptoms or deceased are reported as “change in clinical condition*.”  Number of cases reported as such to Specific Disease Control Division, MHLW in 2011 was 6 for the former category and 16 for the latter category.   They were all Japanese males.   The “Nationwide Survey of Blood Coagulation Anomalies” has additionally identified total 1,439 coagulation factor products-related HIV infections (no increase since 2008), which includes 164 AIDS patients alive and 674 cases deceased (as of May 31, 2011). 

Nationality and gender: In 2011, 923 in total 1,056 HIV cases and 419 in total 473 AIDS cases were Japanese males (87% and 89%, respectively) (Figure).   These figures were slightly less than in 2010, which were 956 and 421, respectively.   HIV cases other than Japanese males were 42 Japanese females, 71 non-Japanese males and 20 non-Japanese females.   AIDS cases other than Japanese males were 16 Japanese females, 21 non-Japanese males and 17 non-Japanese females. 

Infection route and age distribution: Among Japanese male HIV and AIDS cases, infection through homosexual (including bisexual) contact was the most frequent (Fig. 2).   In 2011, 74% of Japanese male HIV cases (686/923) were through this route.   As for age distribution of this group, the most frequent was 30’s followed by 20’s (249 and 246, respectively); those in their 30’s have been continuously decreasing with the peak in 2008 (290 cases), and those in their 20’s have never exceeded the peak level of 2008 (252 cases) (Fig. 3a).   In 2011, however, a male homosexual HIV case in age group of 10-14 years was reported for the first time in Japan, which may be an alarming sign of spread of HIV to younger generation.   Among Japanese male AIDS cases, infection through the homosexual route occupied 61% (255/419), and such cases were frequent among 30’s (85 cases) and 40’s (79 cases); those in their 30’s decreased in the past two successive years, but those in their 40’s increased remarkably since 2009 (Fig. 3b).   Majority of Japanese female HIV and AIDS cases acquired infection through heterosexual contact.   There were 5 HIV/AIDS cases related to intravenous drug abuse (3 Japanese and 2 non-Japanese) in 2011 (7 cases in 2010), and additional 9 cases (all Japanese) having equal chance of infection through intravenous drug abuse and sexual contact (12 cases in 2010).   Though mother-to-child infection was not reported in 2007-2009, 3 cases were reported in 2010 and 1 case in 2011.

Suspected place of infection: For Japanese, in 2011, 91% of HIV cases (92% for male and 81% for female) and 81% of AIDS cases (81% for male and 75% for female) were presumably infected in Japan.   For non-Japanese HIV males, number of HIV infection in Japan exceeded that of the infection outside Japan in 2001.   Since then, this situation has remained unchanged.   In 2011, 51% of non-Japanese HIV males were infected in Japan. 

Districts where doctors made notification: Generally speaking, Kanto-Koshinetsu, Tokai, and Kinki areas reported larger numbers of HIV and AIDS cases compared with other regions.   Reports from Kanto-Koshinetsu (except Tokyo), Tokai and Kyushu increased.   When prefectures are compared for incidences of HIV and AIDS cases (Table 1), Tokyo, Osaka and Aichi continued to be the top three though they reported less numbers of cases in 2011 than 2010.   It should be noted that less populated prefectures began to report more HIV and AIDS cases in recent years (see incidence per 100,000 population). 

2. HIV-antibody-positive rates among blood donors: In 2011, there were 89 HIV-positives among 5,252,182 donated blood specimens (81 from males and 8 from females), which were equivalent to 1.695 positives (2.251 for males and 0.484 for females, respectively) per 100,000 blood donations, slightly exceeding the level of 2010 (1.617) (Fig. 4). 

3. HIV antibody tests and consultation provided by the local governments: The number of people receiving the HIV tests at health centers and other facilities provided by the local governments decreased in 2009-2010.   The number in 2011 was 131,243, maintaining the same level of 2010 (130,939) (Fig. 5).   There were 462 HIV positives corresponding to 0.35% of the tested samples (0.36% in 2010).   While the HIV positive rate among samples tested in health centers was 0.27% (281/102,946), the positive rate among samples from facilities other than the health centers, to which the risk groups are more accessible, was 0.64% (181/28,297), significantly higher than in health centers.   The number of counseling provided by the local governments has decreased in successive 3 years (163,006 in 2011 in contrast to 164,264 in 2010).

Conclusion: The number of AIDS cases reported in 2011 was the largest since the HIV/AIDS surveillance started.   Most HIV/AIDS cases are Japanese male homosexuals who were infected in Japan.   The age group with highest incidence for HIV cases is 20-30 year olds, and that for AIDS cases is 30-40 year olds.   Geographically, Tokyo, Osaka, Aichi and their surrounding areas continue to report large number of HIV/AIDS cases and more recently other areas including Kyushu area started to report increasingly.   In spite of these alarming situations, the number of people using the testing supported by local governments is declining since 2008.   Based on the current trend of HIV/AIDS epidemic, the central and local governments should take effective measures for preventing further spread of HIV and for detecting patients in early phase of infection so as to make possible early start of HIV therapy.   Effective preventive measures may include providing HIV testing and medical consultations more accessible in time and place to male homosexuals (particularly, in their 20’s-40’s) and other risk groups (young people, commercial sex workers and their clients, etc).   It is advised to consider possible collaboration with appropriate partners, such as, companies, NGOs, and educational and/or medical staff.   Ethical consideration is important for some of such activities. 

 
*“Change in clinical condition” includes development of AIDS symptoms among those once reported as HIV case and fatal consequence among those who had been reported as HIV case or as AIDS case.   They are reported to the MHLW on voluntary basis.
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The Topic of This Month Vol. 33, No. 8 (No. 390)


Streptococcal infections in Japan, April 2006-2011
(IASR 33: 209-210, August 2012)

Suppurative infection-causing hemolytic streptococci include Streptococcus pyogenes  (group A, or Group A streptococci; GAS), S. agalactiae (GBS) (group B) and S. dysgalactiae subsp. equisimilis (SDSE) (group C or G; IASR 25: 257-258, 2004).  GAS causes suppurative infections, such as, acute pharyngitis, scarlet fever, erysipelas, cellulitis, and streptococcal toxic shock syndrome (STSS), and post-streptococcal infection sequelae, such as, rheumatic fever and acute glomerulonephritis.  GBS causes septicemia or meningitis in neonates and sepsis or pneumonia in adults.  SDSE causes septicemia and STSS in adults.

STSS and GAS pharyngitis are Category V notifiable diseases under the Law Concerning the Prevention of Infectious Diseases and Medical Care for Patients of Infections (Infectious Diseases Control Law).  For the former, physicians are under obligation of notifying all the cases which they diagnosed, and for the latter, pediatric sentinel clinics are under obligation of reporting (for reporting criteria, go to http://www.mhlw.go.jp/bunya/kenkou/kekkaku-kansenshou11/01-05-06.html and to http://www.mhlw.go.jp/bunya/kenkou/kekkaku-kansenshou11/01-05-17.html, respectively). 

Severe invasive streptococcal infections with toxic shock syndrome (STSS): The previous issue of this topic (IASR 25: 252-253, 2004) indicated that the criteria of STSS notification should be revised.  Based on this recommendation, the criteria were modified and implemented in 2006.  The reporting criteria of STSS (revised on April 1, 2006) include 1) detection of group A or other β-hemolytic streptococcus as a causative agent, 2) manifestation of toxic shock symptoms, and 3) at least two of the following, i.e., liver failure, renal failure, acute respiratory distress syndrome, disseminated intravascular coagulation, soft tissue inflammation (including necrotic fasciitis), generalized erythrodermatous exanthema, and convulsion, syncope and other central nervous system symptoms.

Under the National Epidemiological Surveillance of Infectious Diseases (NESID), total 698 STSS cases including 248 deaths were reported from April 2006 to the end of 2011.  There was a sharp increase in 2011 (Table 1).  Half of the fatal cases died within 3 days after clinical onset.

Seasonally, STSS tends to be more frequent from January to June (Fig. 1).  All the 47 prefectures reported STSS cases, whose incidence was below 1/100,000 population (Fig. 5) except Toyama (1.29) and Shimane (1.26).  The sex ratio of the patients was 1.21 (male 382 and female 316).  There was a broad age peak in 60-64 years for males and 75-79 years for females (Fig. 2).

Of the etiological agents, group A has been the most frequent isolate (Fig. 1) occupying 65-80% of the total isolates every year (Table 1).

Since the first report in 1992 of typical STSS cases in Japan, infectious agent surveillance has been conducted at the Streptococcus Reference Center (SRC) of the Associations of Public Health Laboratories for Microbiological Technology (see IASR 18: 25-26, 1997 and p. 211 of this issue) by monitoring of T serotyping, genotyping of the M protein gene (emm), and drug resistance.  Of 280 isolates, the most frequent one was T1 (148 isolates; 53%), which has been increasing since 2010 (35% in 2009; 61% in 2010; 71% in 2011) (Fig. 3a) (p. 212 of this issue).

With modified reporting criteria of STSS from April 2006, various β-hemolytic streptococci were found to cause STSS.  Among recent isolates sent to SRC, new anginosus groups, such as group C, group F or unclassifiable group, are found (http://www.niid.go.jp/niid/images/lab-manual/reference/13_streptococii.pdf).

Combined administration of penicillin antibiotic at high doses and clindamycin is currently recommended for treating STSS.  According to SRC, to ampicillin and penicillin G, all the tested 280 isolates were susceptible, but not necessarily to clindamycin.  While 5% of the isolates has been resistant in most recent years, in 2009 as high as 15% of the isolates were found resistant to clindamycin (p. 213 of this issue).  To erythromycin, almost all the T1 isolates, which increased in 2011, were resistant (p. 213 of this issue).

Group A streptococcal pharyngitis: Numbers of cases of GAS pharyngitis reported from the sentinel clinics under NESID in 2006-2011 was 202,579-278,990 per year.  Every year, the epidemic follows a characteristic seasonal fluctuation with a dip in summer (Fig. 4) and 70% of the patients are under 7 years of age (majority in 4-7 years).

During 2006-2011, annual report of GAS T-serotyping from prefectural and municipal public health institutes to SRC was 1,002-2,188.  From 2006 to 2008, T1, T12 and T4 were dominant, but in 2010 T4 decreased.  T25  and TB3264 increased in 2009 and 2010, respectively, and in 2011 T1 became more conspicuous as a dominant type (Fig. 3b).

As for antibiotic resistance, the pharyngitis-derived isolates tested by SRC were generally susceptible to ampicillin, but nearly 50% of such isolates were resistant to erythromycin and other macrolide antibiotics (p. 214 & 215 of this issue).

In recent years, pharyngitis outbreaks attributable to GAS-carrier cooks have been reported in Japan and abroad.  In July 2005, 298 GAS pharyngitis patients were reported among 461 people who consumed a boxed lunch served in a university in Kanagawa Prefecture (Eur J Clin Microbiol Infect Dis 28: 305-306, 2009), and in June 2010, 21 GAS pharyngitis patients were reported among 78 people who shared the same food in a dormitory in Saitama Prefecture.  In Denmark, in June 2006, 200-250 persons who used a staff canteen developed GAS pharyngitis (Epidemiol Infect 136: 1165-1171, 2008).  For preventing such incidents, cooks are advised to use a mask and gloves routinely during food handling.  In case of pharyngitis outbreak, it is also important to suspect food-borne GAS infection and, where necessary, conduct appropriate food consumption investigation and throat cultures of the cooks and other employees.

Conclusion: The reported number of STSS increased by two-fold from 2006-2009 to 2011 (Table 1).  It is important to note, however, that SRC obtained streptococcus isolates from only 40% of the total notified STSS patients.  As the trends of circulating pathogen types and their antibiotic resistance in the infectious agents surveillance under NESID are important information for assessing patient’s condition and early commencement of the therapy, the information should be fed back correctly to clinicians and public health servants.  In order to know the whole picture of causative agents of STSS and GAS pharyngitis, the current isolate collection system should be further strengthened.

Data obtained for 2012, preliminary report: As of week 28 of 2012, 146 STSS cases have been notified (127 cases as of week 28 of 2011) (Fig.1).  At the present pace, total number of STSS in 2012 may exceed 200.

In recent years, invasive infections of humans by Streptococcus suis have been reported in significant numbers from China, Vietnam and Thailand, and in very small numbers from Japan (IASR 26: 241 & 242, 2005 and p. 217 of this issue).  Further investigation on this matter is needed.

 

 

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 The Topic of This Month Vol. 33, No. 7 (No. 389)


 Brucellosis in Japan, April 1999-March 2012
(IASR 33: 183-185, July 2012)

Brucellosis, known as “undulant fever” or “Malta fever”, is a zoonotic disease caused by Brucella  spp.  Brucellosis is a category IV notifiable infectious disease under the Law Concerning Prevention of Infectious Diseases and Medical Care for Patients of Infections (Infectious Diseases Control Law) enforced on April 1, 1999 (http://www.mhlw.go.jp/bunya/kenkou/kekkaku-kansenshou11/01-04-28.html).  It is designated also as domestic animal infectious disease under the Act on Domestic Animal Infectious Diseases Control.

Brucella  spp. is an aerobic Gram-negative coccobacillus, but the fresh isolate is more like a Gram-negative coccus in shape (Fig. 1).  It has no flagella, does not form spore and is a facultative intracellular parasite.nbsp;nbsp;Species pathogenic to humans are, in descending order of pathogenicity, B. melitensis , B. suis , B. abortus  and B. canis  (Table 1), among which B. melitensis , B. abortus  and B. suis  are livestock pathogens.

On account of their potential use for bioterrorism, B. melitensis , B. suis , B. abortus  and B. canis  are in the list of the group 3 select agents* under Infectious Diseases Control Law in Japan (IASR 28: 185-188, 2007).  B. melitensis , B. suis  and B. abortus  are also in the list of US CDC/USDA's overlap select agents (http://www.cdc.gov/phpr/documents/DSAT_brochure_July2011.pdf).  It is important to note that B. melitensis , B. suis  and B. abortus  are under strict regulation so as to prevent misuse for terrorism not only against humans but also against livestock.

Infection Route and Symptoms: Main route of human infection is ingestion of milk and milk products derived from infected animals, and sometimes ingestion of meat.  Contact with infected animals, their carcasses, aborted fetuses and placentas, as well as, inhalation of bacteria are alternative routes of infection.  Very rarely, infection through sexual contact with infected persons and through breastfeeding may occur (see p. 186 of this issue).  Incubation period is generally 1-3 weeks but can be as long as months.  Clinical symptom includes flu-like symptoms, i.e., general aching, fatigue, chills and sweats, associated with continued, intermittent or irregular fever of variable duration.  However, osteoarticular complications are the most frequent.  Complications of gastrointestinal tract, respiratory tract, central nervous system and cardiovascular system are also known (see p. 187 of this issue).  Endocarditis is the main cause of the death due to brucellosis.  The disease may last for several days, months or even years.  Infection caused by B. canis  is generally mild, and the patients often do not notice the infection.

Incidence: Every year, around 500,000 new patients are reported in the world, mainly from China, India, West Asia, Middle East, Mediterranean Region, Africa and Latin America.  Increase of patients is the current trend; the recent increase of brucellosis caused by B. melitensis  in China is remarkable (see p. 192 of this issue).  In countries that successfully controlled livestock brucellosis, brucellosis is found among those who visited or returned from abroad (see pp. 187 and 193 of this issue), those who consumed imported contaminated milk products, and those in high risk groups, such as, dairy farmers, veterinarians, butcheries, and laboratory technicians.

In Japan, the first brucellosis case was reported in 1933 (see p. 186 of this issue for the situation before 1999).  Since April 1999 when brucellosis became a notifiable disease, 19 brucellosis cases have been reported (Table 2 ).  Among them, seven were due to livestock Brucella  spp. (B. melitensis , 5 cases; B. abortus , 2 cases), which are considered imported cases (Table 2a) as there is no endemic circulation of livestock Brucella  spp. now in Japan (see p. 191 of this issue).  Among recent cases of them, foreigner residents in Japan were found infected after temporary stay in the brucellosis-endemic mother country (see p. 187 of this issue and IASR 33: 101-102, 2012).

Remaining twelve brucellosis cases were due to B. canis  (Table 2b) whose prevalence in dogs in Japan is currently ≈3%.  Diagnosis was based mostly on positive detection of antibody.  Bacteria were successfully isolated from patients in acute phase among employees of a dog breeding facility affected by the brucellosis epidemic (see p. 189 of this issue).

Clinical and Laboratory Diagnosis: Clinical symptom of brucellosis is uncharacteristic and brucellosis is often found among “fever of unknown origin”.  Therefore, if brucellosis is suspected, it is important to ask the patients about possible chance of Brucella  infection, such as, their history of travel to endemic countries, consumption of foods abroad and contact with animals.  As Brucella spp. is notorious for the past history of laboratory infection, physicians should warn the clinical laboratory against the potential danger of the specimens (see p. 187 of this issue).  Notification of brucellosis requires isolation/identification of Brucella  spp. or detection of antibody by in vitro agglutination test (http://www.mhlw.go.jp/bunya/kenkou/kekkaku-kansenshou11/01-04-28.html).

1) Antibody Test: Brucellosis usually follows chronic course.  Therefore symptomatic cases are usually positive for the antibody.  In addition, on account of intracellular parasitic nature of the bacteria, antibody-positive cases are very often pathogen carriers.  Therefore, the diagnostic value of the serum antibody test is very high.  Usually, the serum antibody test is the tube agglutination test using killed whole bacteria as antigen.  It should be taken into account that antibodies against Francisella tularensis (causative agent of tularemia), Yersinia enterocolitica  and Vibrio cholerae  sometimes show cross-reaction with Brucella  antigen.  The serum test can be conducted in commercial laboratories, whose expense is covered by public medical insurance.

2) Isolation and Identification of Bacteria: Culture for at least 21 days using blood culture bottles, with subculture onto the blood agar twice a week, is recommended.  Bacterial growth is very slow and the colony size is small at most 2 mm after 3 days of culture.  Suspected colonies are further tested for Gram staining and for motility and biochemical characters.  PCR gene amplification is useful for identification.  The target gene for amplification is most frequently a gene encoding cell surface BCSP31 protein, which is conserved in all the Brucella spp.  16S rRNA and IS711 genes are also used as target.  National Institute of Infectious Diseases is conducting differential diagnosis of the above four human pathogen Brucella  spp. using combinatorial-PCR method (http://www.niid.go.jp/niid/images/lab-manual/brucellosis_2012.pdf).

Therapy: As therapy with one antibiotic easily results in therapeutic failure, combination of two or more antibiotics is recommended.  The 1986 WHO Expert Consultation recommends combination of doxycycline (DOXY) and rifampicin (RFP).  However, as RFP increases clearance of DOXY from circulating blood, combination of DOXY and streptomycin (SM) is recommended for treatment of patients with myelitis and other complications.  More recently, combination with gentamycin (GM) whose side effect is lower than SM, i.e., combination of DOXY and GM or that of DOXY, GM and RFP is recommended (http://www.who.int/csr/resources/publications/deliberate/WHO_CDS_EPR_2006_7/en and EJ Young. Brucella species. In: Principles and Practice of Infectious Diseases Seventh edition, Mandell GL, Bennet JE, Dolin R eds, Churchill Livingstone, 2010).  For infants, combination of sulfamethoxazole-trimethoprim (ST) and RFP (or GM) and for pregnant women, combination of ST and RFP are used.

Prevention: For consumer protection, appropriate pasteurization of milk and milk products is the most essential.  From the public health viewpoint, veterinary measures for elimination of carrier animals by vaccination and “test and slaughter” measures are the most effective (see p. 191 of this issue and IASR 16: 127, 1995).  Many countries and regions have successfully reduced human brucellosis by these measures.  No effective vaccine for human use has been developed. 

Additional Comments: B. canis  infection is limited almost to persons who have higher chance of contacting infected dog blood, placenta or aborted pups, i.e., dog breeder, veterinarians and related professions.  As for the livestock brucellosis, Japan has already eradicated them.  However, it is one of the serious zoonotic diseases abroad needing preventive actions against “importation”.  Those who visit brucellosis endemic countries should be aware of the risk of Brucella  infection through ingestion of insufficiently pasteurized milk or milk products and undercooked meat and also through contact with infected animals.


 *Note: Group 3 select agent: Its possession requires notification to and approval by Minister of Health Labour and Welfare as well as a laboratory facility that satisfies the condition required for use of group 3 select agents.  For hospital or other diagnostic laboratories, when they happened to possess a group 3 select agent during their professional practice, they should stop the possession within 10 days; they should destroy the agent by sterilization or transfer the agent to a laboratory, which is authorized to possess the group 3 agents (http://www.mhlw.go.jp/bunya/kenkou/kekkaku-kansenshou17/03.html).


 

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The Topic of This Month Vol. 33, No. 6 (No. 388)


 Kudoa and Sarcocystis Food Poisoning in Japan
(IASR 33: 147-148, June 2012)

Recent four-five years experienced increase of clinical complaints consisting of transient vomiting and diarrhea, which set on a few hours (2 hours in the shortest) after food consumption and disappear without sequelae.  Causative agents could not be identified, but consumption of fresh market foods, such as, raw flatfish and raw horsemeat, was commonly observed.  Ministry of Health, Labour and Welfare (MHLW) started an organized nationwide investigation to identify the causative agent(s) and to find preventive measures.  In June 2011, Food Poisoning Division and Milk, Meat and Aquatic Product Division of Pharmaceutical Affairs and Food Sanitation Council (MHLW) announced, based on the results of the investigation, that Kudoa septempunctata and Sarcocystis fayeri, both parasites, were responsible for food poisonings caused respectively by consumption of flatfish and raw horsemeat.  MHLW issued a notice to prefectures instructing that clinical complaints potentially attributable to the above two parasites should be treated as food poisoning (Syokuan-hatsu number 0617-3, June 17, 2011; http://www.mhlw.go.jp/topics/bukyoku/iyaku/syoku-anzen/gyousei/dl/110617_02.pdf).

During June-December 2011, total 60 parasite-related food poisonings including those caused by K. septempunctata (33 incidents), Anisakis (25 incidents), and S. fayeri (2 incidents), were reported.  The parasite-related food poisoning is now the third most frequent food poisoning following Campylobacter  and norovirus-related ones.

 

1. Kudoa
Food poisoning outbreaks: By June-December 2011, 33 incidents involving 473 cases had been reported. K. septempunctata-related food poisoning was frequent in August-November with a peak in September in 2011 (Fig. 1), and the data in the past two years indicated the high season is September-October.  Outbreaks in September 2011 in Mie and Hokkaido respectively involved 94 and 50 cases (see Table 1 in p. 149 of this issue).

The parasite and/or parasite-specific genome was detected from conserved foods in the Mie incident (see p. 150 of this issue), from remaining raw flatfish sashimi in the Kurashiki (IASR 33: 102-103, 2012) and Hokkaido (see p. 150 of this issue) incidents, from remaining food and stool specimens in Nara incident (see p. 152 of this issue) and from vomits of patients in Hyogo incident (IASR 32: 369-370, 2011).

Prevention: Food poisoning associated with flatfish consumption can be prevented by freezing at –16 ~–20°C for 4 hours or heating at 90°C for 5min, which inactivates K. septempunctata.  However, in view of high market value of live flatfish, Fishery Agency is taking measures towards Kudoa-free flatfish aquaculture, such as, elimination of Kudoa-carrying flatfish fry, cleaning of aquaculture environment of flatfish, and pre-market monitoring of aquacultured flatfish (see p. 155 of this issue).

On June 7, 2012, MHLW sent directors of quarantine stations a notice entitled “On prevention of food poisoning caused by Kudoa” requesting monitoring of flatfish for fresh market (shokuan-hatsu number 0607-9; http://www.mhlw.go.jp/topics/yunyu/other/2012/dl/120607-01.pdf).

Laboratory diagnosis: The notice issued by MHLW issued on July 11, 2011 (Syokuankan-hatsu number 0711-1; http://www.mhlw.go.jp/topics/bukyoku/iyaku/syoku-anzen/gyousei/dl/110711_01.pdf) provisionally recommended combination of real time PCR and microscopic examination for laboratory diagnosis.  The criteria of positive diagnosis is detection of >107 Kudoa rDNA copies per gram specimen (for screening) and microscopic detection of spores with 6-7 polar capsules, which is characteristic to K. septempunctata.  Alternatively, if PCR could not be done, specimens positive for K. septempunctata bodies under microscope are considered K. septempunctata positive (See Fig. 2, which shows a pseudocyst containing spores).  The current real time PCR method is made cross-reactive with other Kudoa species because the Kudoa toxicity may not be restricted to K. septempunctata.  Therefore, it reacts with Kudoa species parasitic to tunnya tuna fish, for example.  A method modified for specific detection of K. septempunctata is now available (see p. 155 of this issue).  The laboratory diagnosis method is placed in e-learning of National Epidemiological Surveillance of Foodborne Disease (NESFD), which can be used by person in charge.

Future challenge: Food poisoning quite similar to the K. septempunctata-related one has been reported after consumption of raw young tuna and ocean bonito in Tokyo and nearby communities (see p. 153 of this issue).  Further research is necessary as regards potential health adverse effect of Kudoa species other than K. septempunctata.

 

2. Sarcocystis
Before issuance of the June 2011 MHLW notice, 37 clinical complaints related to consumption of fresh market horsemeat were reported mainly from the producing centers, such as, Kumamoto and surrounding prefectures in Kyushu and, to the less extent, from Fukushima, Yamanashi, Aomori and other prefectures in eastern Japan.  After release of the MHLW notice, two incidents involving 11 cases were reported in September 2011, but no other cases in Japan since October 2011.  S. feyeri was detected from refrigerated horsemeat, such as, those implicated in the incidents in Fukuoka (IASR 33: 44-45, 2012) and in Okayama (see p. 158 of this issue).  In the both incidents, the implicated horsemeat was purchased from Kumamoto, and at least the one implicated in the Fukuoka incident was derived from the horse imported from Canada.  The S. fayeri-related food poisoning has been decreasing after release of the MHLW notice probably owing to successful implementation of freezing of fresh market horsemeat (a condition that inactivates the parasite) in producer prefectures. 

Prevention: Horsemeat for fresh market should be processed by freezing at –20°C for ≥48 hours.  Sarcocystis -related food poisoning has been always associated with consumption of unfrozen or refrigerated horsemeat.  Inspection of fresh market horsemeat to be consumed in Japan revealed high infestation rate among horsemeat that was imported from Canada.  As distribution channel and consumption pattern of horsemeat in Japan are complex and variable, freezing of fresh market horsemeat should be strictly implemented.

Laboratory diagnosis: S. fayeri laboratory diagnosis, which was announced on August 23, 2011 (Syokuankan-hatsu number 0823-1, http://www.mhlw.go.jp/topics/bukyoku/iyaku/syoku-anzen/gyousei/dl/110823_01.pdf), consists of detection of parasite DNA and microscope detection of parasite body.  The principle of detection is microscopic detection of sarcocysts and bradyzoits in horsemeat.  However, sarcocysts in horsemeat are at most several millimeters in size and are difficult to be distinguished from the fat tissues (Fig. 3).  In addition, depending upon the specimen, they are uneven in size and distribution and are present as scattered minute cysts, which makes their detection all the more difficult.  As a consequence, to increase the diagnostic accuracy, microscopic examination combined with genetic testing is applied.  The criterion of positive detection is confirmation by microscope of both sarcocysts and bradyzoits in horsemeat or detection of amplified specific DNA sequence together with microscopic detection of bradyzoits.  As detection of the parasite from stool specimens or vomits allows the diagnosis, a new genetic testing applicable to stool specimens is being developed for the case from which remaining meat specimens are unavailable (see p. 159 of this issue).

Future challenge: Consumption of horsemeat sashimi has been a local food culture.  The recent preference for fresh market foods and healthy foods added with the gourmet tendency, however, are bringing the fresh market horsemeat into the nation wide market.  Horsemeat is now available through the internet even outside of the producing centers.  Reflecting such a situation, importation from abroad of horsemeat is increasing.  As freezers for household use are inappropriate for killing the parasite, implementation of freezing at –20°C for ≥48 hours at the production or pre-market level is imperative.

 

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(IASR 33: 55-56, March 2012)

Hand, foot and mouth disease (HFMD) is characterized by vesicular exanthema of the oral mucosa and peripheral extremities. It predominately affects young children during the summer season. Common enterovirus isolates from HFMD cases are coxsackievirus A type 16 (CVA16) and enterovirus 71 (EV71), both belonging to human enterovirus species A (IASR 19: 150-151, 1998 & 25: 224-225, 2004). The year 2011 experienced the largest HFMD epidemic since the start of National Epidemiological Surveillance of Infectious Diseases (NESID) (July 1981). The most frequent type isolated from the 2011 epidemic was coxsackievirus A type 6 (CVA6), which had ever been one of the main causative agents of herpangina. This special issue summarizes incidence of HFMD and virus isolation in the past 10 years.

Trends of HFMD epidemics and virus isolation/detection: Weekly reports of NESID (Fig. 1) demonstrate that the peak of HFMD epidemic occurs in the summer. However, epidemics may also occur in the autumn and winter.

The monthly reports from prefectural and municipal public health institutes (PHIs) on EV71, CVA16, CVA10 and CVA6 (Fig. 2) indicate that there have been three large HFMD epidemics since 2002, the first in 2003 (total 172,659 cases; 56.78 per sentinel), the second in 2010 (total 151,021; 49.87 per sentinel), and the last in 2011 (total 347,362; 110.91 per sentinel). The former two epidemics were caused by EV71 and the last one, which was the largest, by CVA6 and CVA16. EV71 epidemics have occurred at 3-4 year intervals since 1994 (IASR 25: 224-225, 2004).

As for age distribution in 2002-2011 (Fig. 3), similarly as in the preceding years, ninety percent of the reported cases were under five. However, exact number of adult cases is obscure as the present surveillance is based on pediatric sentinels. Most EV71, CVA16, CVA10 and CVA6 isolates were from children under seven years (Fig. 4). Among EV71-positive cases in the 2010 epidemic, cases with aseptic meningitis were found in two peak age groups, 0 year and 3-5 years (61/880). In the 2011 epidemic, aseptic meningitis cases were found only in seven among 1,187 CVA6-positive cases (IASR 32: 228-230, 2011), though severe skin symptoms were reported from the adult CVA6-positive cases (IASR 32: 231, 2011). No aseptic meningitis case was reported among 528 CVA16-positive cases in 2011.

Data on the isolation frequencies by prefecture of EV71, CVA16, CVA10 and CVA6 in 2011 are shown in Fig. 5 together with the data of EV71 in 2010. In 2011, more than one type among CVA16, CVA10 and CVA6 caused the HFMD epidemic in various parts of Japan (IASR 32: 232-233, 2011), and some patients experienced multiple infections with different enterovirus serotypes (see p. 59 of this issue). Interestingly, prefectures that reported EV71 in 2010 reported no EV71 in 2011.

Complications of HFMD: Since the late 1990's, a large number of severe, occasionally fatal, central nervous complications associated with large scale HFMD outbreaks have been reported from the East Asia and nearby regions. More recently, many fatal cases have been reported from China (2008-2010; 905 fatal cases in 2010) and Vietnam (2011) (http://www.wpro.who.int/topics/hand_foot_mouth/en/). Most such severe cases are related to EV71-associated acute encephalitis and other central nervous system complications (IASR 30: 9-10, 2009). Taiwan, China and other Asian countries are now developing EV71 vaccines for clinical use in near future (see p. 65 of this issue).

Japan has not yet experienced large-scale HFMD epidemic accompanying high frequency of fatal cases, though sudden deaths associated with severe EV71 infection have been reported sporadically (IASR 19: 55, 1998). The questionnaire-based studies (2000-2002) indicated an increase of severe cases of HFMD when the epidemic was caused by EV71 (2000) (Pedriatr International 52: 203-207, 2010). For epidemiological comparison with other countries, a nationwide investigation on complications associated with the HFMD epidemic mainly due to EV71 in 2010 has been undertaken using WHO's case definitions (http://www.wpro.who.int/publications/PUB_9789290615255/en/) (see p. 63 of this issue).

CVA6, together with other CVAs, had been a major cause of herpangina; since the 2009 HFMD epidemic, however, it started to be isolated more frequently from HFMD (Fig. 2). Clinical picture of CVA6-associated HFMD is characterized by larger blisters, which extend to legs and buttocks (IASR 32: 230-231, 2011). Cases of onychomadesis has been reported after recovery from HFMD (see pp. 59 and 62 of this issue and Emerg Infect Dis 18: 337-339, 2012), and CVA6 was detected from the nail that dropped off (IASR 32: 339-340, 2011). CVA6-related HFMD and onychomadesis had been reported in Europe and Asia since 2008, and molecular analysis revealed phylogenetic relatedness of the above Japanese isolates to the recent European isolates (see p. 60 of this issue). Future evolution of CVA6's pathogenicity including onychomadesis should be followed.

Laboratory diagnosis of HFMD: Laboratory diagnosis consists of virus isolation, viral gene detection and typing (see pp. 57 and 58 of this issue), using throat swab or stool specimens during the clinical phase. The major causative agents of HFMD, EV71 and CVA16 can be isolated by using RD-A, Vero and other cultured cell lines. The isolates are identified by neutralization tests or by sequencing analysis. As some CVAs do not grow well in cultured cells (IASR 32: 196, 2011), isolation by suckling mice has been conventionally used (IASR 32: 195-196, 2011). While CVA6 reported in 2011 was directly detected/identified from the clinical specimens by using CODEHOP VP1 RT-seminested PCR (IASR 30: 12-13, 2009), successful isolations of the virus by using RD-A cell cultures or suckling mouse method have been reported (see pp. 57, 58 and 59 of this issue). The information on virus isolation trends is crucial for efficient laboratory diagnosis of HFMD-related enteroviruses (see p. 61 of this issue).

Infectious agent surveillance on HFMD in Japan is conducted by PHIs and National Institute of Infectious Diseases through collaboration of Enterovirus Reference Centers, which should be further fortified by strengthening of laboratory capacity as regards virus isolation, culture and other necessary practices.

Copyright 1998 National Institute of Infectious Diseases, Japan

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