Invasive Haemophilus influenzae infections in Japan
(IASR 34: 185-186, July 2013)
Haemophilus influenzae is a small Gram-negative bacillus. It is carried by many infants in their nasopharyngeal cavities (see p. 193 of this issue). There are two clinical types; the one is systemic invasive type and the other is localized non-invasive type. The systemic invasive type is generally severe and the bacteria can be found in otherwise aseptic sites, such as, blood, cerebrospinal fluid, etc. Haemophilus influenzae is classified into the encapsulated strains and the non-typable strains. Haemophilus influenzae with capsular type b (Hib) is the major cause of the infantile invasive H. influenzae infections (see p. 187 of this issue). Non-typable H. influenzae (NTHi) is a major cause of non-invasive bacterial infections among infants and adults (e.g. otitis media and exacerbation of chronic obstructive pulmonary diseases, etc.).
Capsular type and Hib vaccine: Encapsulated strains are classified into 6 capsular types from a to f. Capsular type is determined by bacterial agglutination test using capsular antigen-specific antibodies or by capsular type-specific gene amplification using polymerase chain reaction (PCR) (see p. 192 of this issue) (see Laboratory Manual for Bacterial Meningitis in Pathogen Detection Manual, http://www.niid.go.jp/niid/images/lab-manual/hib-meningitis.pdf).
In Japan, a tetanus toxoid conjugated Hib vaccine (Hib vaccine in short) has been used since December 2008. Since November 2010, the Hib vaccine to children of less than 5 years of age has been paid by the public under the "Program of accelerated vaccination with cervical cancer and other vaccines". In April 2013, the immunization act was revised to include Hib vaccine in the routine immunization. The routine vaccination consists of three shots to children aged two months to less than seven months, which is followed by the fourth booster shot one year after the third shot (see p.199 of this issue).
The antigen determinants are capsular polysaccharides (polyribosylribitol phosphate: PRP) present on the bacterial surface. Protection from infection is mediated by antibodies against serotype-specific PRP. The immunogenicity of Hib vaccine is evaluated by ELISA titration of serum anti-PRP IgG or by serum bactericidal assay (SBA), which measures bactericidal activity of serum by using Hib as a target (see p.190 of this issue).
Epidemiological situation: Until April 2013 when the Enforcement Regulations for the Infectious Diseases Control Law were revised, meningitis caused by H. influenzae had been reported as "bacterial meningitis" together with other bacterial meningitis. They were reported from about 500 sentinel hospitals in Japan. Total 347-477 bacterial meningitis cases were reported annually from 2006 to 2010, among which 56-83 were due to H. influenzae (Table 1). Among the total 400 H. influenzae meningitis cases reported in 2006-2012, 372 cases (93%) were patients younger than 5 years. Thanks to the public payment of Hib vaccine, the frequency of H. influenzae meningitis decreased to 49 cases in 2011 and to 14 cases in 2012. The reduction was found mainly among patients younger than 2 years of age (Fig. 1).
After the revision of the Enforcement Regulations for the Infectious Diseases Control Law, invasive infections by H. influenzae, Neisseria meningitidis and Streptococcus pneumoniae became category V infectious diseases, which require reporting of all the cases. Accordingly, these infections are now excluded from the category of “bacterial meningitis”.
The notification criterion for “invasive H. influenzae infection” (including Hib meningitis) is the case, from whose cerebrospinal fluid or blood H. influenzae is detected by isolation of bacteria or by detection of bacterial DNA (http://www.niid.go.jp/niid/images/iasr/34/401/de4011.pdf).
Table 2 lists 31 invasive H. influenzae infection cases notified under the National Epidemiological Surveillance of Infectious Diseases (NESID) since April 2013 (14th to 23rd week). In Fig. 2 that shows the age distribution, there are two peaks, the one in young children and the other in adults above 60 years of age. Most cases in the aged group were H. influenzae pneumonia associated with bacteremia. Three among them died.Capsular type was determined only in one case, which was capsular type b.
According to the data from 10 prefectures in Japan (Ihara-Kamiya Research Group: “Research on evidence and recommended policies on better use of vaccinations” started in 2007), the frequency of invasive H. influenzae infection per 100,000 population under 5 years of age was 7.7 for meningitis type and 5.1 for non-meningitis type in 2008-2010. In 2012 the frequency went down to 0.6 for meningitis type (reduction by 92%) and to 0.9 (reduction by 82%) for non-meningitis type (see p. 194 & 195 of this issue). The similar tendency was noted in the nation-wide surveillance data obtained by Japan Nosocomial Infections Surveillance: JANIS (see p. 197 of this issue).
Emergence of drug-resistant strain: There are two types of drug resistant H. influenzae strains known, β-lactamase producers and β-lactamase non-producers. The frequency of the β-lactamase-non-producing ampicillin-resistant (BLNAR) isolate is increasing in recent years (see p. 192 & 195 of this issue), which should be further monitored (see IASR 31: 92-93, 2010; https://idsc.niid.go.jp/iasr/31/362/tpc362.html & IASR 23: 31-32, 2002; https://idsc.niid.go.jp/iasr/23/264/tpc264.html).
Measures to be taken: Increase of invasive H. influenzae infection caused by non-b type H. influenzae (including NTHi) after introduction of Hib vaccine has been reported in abroad. In Japan, a meningitis case of H. influenzae capsular type f was reported among those who had received three Hib vaccine shots (see p. 195 of this issue). Invasive NTHi infections have been reported among infants and adults (see p. 188 & 189 of this issue). Accordingly, surveillance of invasive H. influenzae infections after introduction of routine immunization of Hib vaccine should be directed not only to Hib itself but also to H. influenzae of other capsular types and NTHi. Pathogen surveillance of H. influenzae, including capsular type analysis, is planned as an activity of the National Epidemiological Surveillance of Vaccine Preventable Diseases infection source investigation from 2013FY.
The statistics in this report are based on 1) the data concerning patients and laboratory findings obtained by the National Epidemiological Surveillance of Infectious Diseases undertaken in compliance with the Law Concerning the Prevention of Infectious Diseases and Medical Care for Patients of Infections, and 2) other data covering various aspects of infectious diseases. The prefectural and municipal health centers and public health institutes (PHIs), the Department of Food Safety, the Ministry of Health, Labour and Welfare, and quarantine stations, have provided the above data.