The Topic of This Month Vol. 31, No. 4 (No. 362)

Invasive Haemophilus influenzae type b Infection and Hib vaccine, Japan
(IASR 31: 92-93, April 2010)

Haemophilus influenzae is a gram-negative coccobacillus/bacillus.  For H. influenzae having capsule, there are six serotypes, from a to f, which are determined by the structure of the capsular sugar chain.  Strains devoid of capsule are classified as non-typable, which are commensal to the human nose cavity.  Highly invasive H. influenzae has capsule of type b, and is called Hib.  It causes septicemia, meningitis, acute pharyngitis and other severe invasive infections in newborns and infants (see p. 94 of this issue).

In December 2008, Hib vaccine was finally introduced to Japan as a voluntary immunization, and epidemiological investigation on invasive Hib infection has started as a research project of Ministry of Health Labour and Welfare (MHLW).  This article, dealing with H. influenzae for the first time in the Topic of the Month of IASR, reviews the current situation of Hib infection in Japan using the data obtained through the MHLW and other projects.

Epidemiology: Currently no national infectious disease surveillance focuses on the H. influenzae infection, though its epidemiology can be glimpsed in the bacterial meningitis data that are collected from 500 designated sentinel hospitals based on National Epidemiological Surveillance of Infectious Diseases (NESID) under the Infectious Disease Control Law.

1. Bacterial meningitis under NESID: In 2006-2009, 350-484 bacterial meningitis cases were reported annually, and the cases tended to increase in recent years (Fig. 1 and Table 1).  The most frequent ages of the patients were zero and one year, and the frequency gradually decreases to the school entry year.  The frequency increases again after thirty years of age (Fig. 2).  The causative agents were known only for half of the bacterial meningitis cases.  Among cases whose causative agents were identified, H. influenzae and Streptococcus pneumoniae were prominent (Fig. 1 and Table 1).  H. influenzae was dominant among patients younger than 5 years, but rare among those older than 6 years of age (Fig. 2).  Among zero year-old patients, H. influenzae meningitis starts to increase after 2 months of age (Fig. 3).

2. Invasive bacterial infections among young children: According to the Japan-wide multi-facility joint study (Hokkaido and nine other Prefectures) conducted in 2007-2009 (see p. 95 of this issue), the frequency of Hib meningitis was 5.6-8.2 per 100,000 population under 5 years of age, and invasive Hib infections other than meningitis was 1.4-5.4.  Yearly occurrence of childhood Hib meningitis is estimated to be slightly more than four hundred.

3. Hib infection database: Since May 2009, all the hospitals in Japan having pediatric beds are invited to register, on voluntary basis, hospitalized Hib infection cases among 0-15 year olds to the home page of Infectious Disease Surveillance Center, National Institute of Infectious Diseases (NIID) ( (see p. 97 of this issue).  In nine months from May 2009 to January 2010, 103 medical facilities registered total 200 cases.  Of these, 84% were 0-2-year-olds (36% for 0-year, 31% for 1-year, and 17% for 2-year), and among 0-year-old children 70% were older than 7 months of age.  The most frequent was meningitis (128 cases) followed by bacteremia (77 cases), septicemia (26 cases), pneumonia (20 cases) and acute pharyngitis (12 cases), etc. There were five cases with severe sequelae, such as developmental, mental and motor disturbances and six cases with impaired otological function.  There were three fatal cases and the case-fatality rate was 1.5% among the registered cases.

Treatment and antimicrobial resistance: For invasive Hib infection, ceftriaxone (CTRX), cefotaxime (CTX), meropenem (MEPM) or CTX+MEPM is used in recent years.  Analysis of H. influenzae isolated from purulent meningitis cases in recent 10 years (see p. 98 of this issue) revealed that â└-lactamase—nonproducing ampicillin resistance (BLNAR) reached 60% of the cases in 2009, and, BLNAR and other â└-lactamase—producing amoxicillin/clavulanic acid resistance (BLPACR II) combined, 90% of the isolates were drug resistant.

Hib vaccine: Hib vaccine started to be used from 1980s abroad.  To enhance immunogenicity, capsule polysaccharide antigen is conjugated to carrier protein, i.e., a conjugate vaccine is currently used.  Further improvement of Hib vaccine is ongoing.  In December 2008, Hib vaccine produced by a foreign manufacturer was introduced to Japan and the vaccination was started on voluntary basis.  The imported vaccine was controlled for the quality by NIID according to the Quality Control Standards in compliance with the Standards of Biological Products; the laboratory tests include tests of polysaccharide content, endotoxin content, and abnormal toxicity.  Only lots that passed the National Quality Control are provided to the medical institutions.  Currently, on account of the limited capacity of the manufacturer, the supply of the vaccine hardly satisfies the consumersüf demand, but enough quantity of vaccine will be provided before 2011 (see p. 100 of this issue).

In foreign countries that incorporated Hib vaccine in the vaccine program for children, incidence of Hib infection has decreased dramatically.  The effect of Hib vaccine introduced in Japan is yet to be seen.  According to the survey of the health status and side-effect among those receiving Hib vaccines, of the 1,768 individuals vaccinated at 750 locations in Japan from April 1, 2009 to February 9, 2010, 1,088 were aged under 1 year (419 were 0-6 months and 669 were 7-11months), 676 were 1-5 years, 2 were 6 years or over, and 2 were age unknown; 1,269 (72%) had no systemic side effects and 1,184 (67%) had no local reactions (see p. 99 of this issue).

Summary: Though the frequency of Hib meningitis and other Hib-related invasive infections is 7.0-12.8 per year in 100,000 population under age of five (see p. 95 of this issue), the treatment is sometimes difficult.  Those who survived the infection may often suffer from severe residual symptoms.  Increasing incidence of the antimicrobial resistant strains makes the treatment more difficult.  Some prefectures are providing the vaccine to children on the public expense (see p. 102 of this issue), but vaccine coverage remains low (see p. 101 of this issue).  As the severe invasive type of Hib infection can be prevented by the vaccine, measures should be taken so that more children in Japan are accessible to safe Hib vaccines.

For more appropriate evaluation of the vaccine efficacy, the surveillance of Hib infection has to be intensified.  For correct therapeutic choice, the patientsüf blood should be routinely cultured for the bacteria before administration of antibiotics.

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