The Topic of This Month Vol.26 No.9(No.307)

Herpangina as of July 2005, Japan

(IASR 2005; 26 : 235-236)

Herpangina is a typical enterovirus infection that, similarly to hand, foot and mouth disease (HFMD), occurs annually among infants and young children mainly during the summer season. Surveillance for herpangina as one of the sentinel reportable diseases began in 1981 among approximately 2,500 pediatric and internal medicine sites under the National Epidemiological Surveillance of Infectious Diseases (NESID). Herpangina has been classified as a Category IV infectious disease under the Infectious Diseases Control Law since April 1999. Approximately 3,000 pediatric sentinel clinics report weekly cases by gender and age group to local government health centers and, through prefectural municipalities, the central infectious disease surveillance center (Infectious Disease Surveillance Center, National Institutes of Infectious Diseases). Herpangina was reclassified as a Category V infectious disease subsequent to the implementation of the revised Infectious Diseases Control Law in November 2003. Reporting is based on clinical diagnoses by physicians of "sudden onset with high fever" and "vesicles, ulcer and redness around the uvula". Approximately 10% of pediatric sentinel clinics serve as infectious agent's surveillance sentinels for herpangina, while prefectural and municipal public health institutes (PHIs) conduct pathogen laboratory testing and report positive cases to the central infectious disease surveillance center.

Incidence: Annual case counts from 1982-2004 (Fig. 1) reveal that 1984 experienced the largest number of cases with 204,555 (97.51 cases per sentinel), followed by 70,000-120,000 cases per year until 1998. After the enactment of the Infectious Diseases Control Law, annual cases have increased to 100,000-150,000, although cases per sentinel have remained similar to figures prior to the enactment at 30-50, indicating the occurrence of epidemics of similar magnitudes.

Weekly reported cases from the most recent six seasons are shown in Fig. 2. After the standard epidemic level of 1.0 case per sentinel clinic is exceeded during weeks 22-23 every year (end of May- beginning of June), cases increase rapidly and peak during weeks 27-29 (July). Post-peak decreases to less than 1.0 per sentinel usually occurred between weeks 31-38 (August-September), although in some years this decrease was not seen until autumn. However, as compared with HFMD (see IASR 25:224-225, 2004) the occurrence of herpangina clearly concentrated in the summer.

The age of cases has not changed appreciably over the last 20 years; 70% of cases were 1-4 years of age (Fig. 3). In looking at each age group after 1998, children 1 year of age accounted for the largest number of cases (22-25%), while the proportion of cases decreased with increasing age among those older than 2 years; cases were few among those older than 6 years. The proportion of cases 0 years of age has been decreasing, and is thought to be associated with the decreasing number of births as similarly seen for chickenpox and exanthem subitum.

According to results of a questionnaire survey by the study group on severe enterovirus infections (response rate: 2000 & 2001- 41%, 2002- 32%), the number of cases of herpangina that clinically worsened during the course of illness and required hospitalization was 309 in 2000, 294 in 2001, and 200 in 2002 (see IASR 25:226-227, 2004). The occurrence of complications among patients with herpangina and HFMD should be monitored.

Virus isolations/detections: The principal etiologic agent of herpangina is group A coxsackievirus (CA). CA is most often isolated from nasopharyngeal swabs, followed by stool samples. The most common CA serotypes detected in herpangina cases during 1997-2004 (Table 1) were CA4, CA10, CA2, CA6, and CA5, in the descending order of frequency. CA4 was most prevalent in 1997, 1999, 2001, 2002 and 2004, as was CA10 in 1998, 2000, and 2003. Changes in circulating serotypes from year to year, a characteristic of enteroviruses, was observed during 1982-1996 (see IASR 17:212-213, 1996; 21:212-213, 2000; and A few enteroviruses such as CA16, enterovirus 71, group B coxsackievirus, and echovirus, as well as non-enteroviruses such as adenovirus and herpes simplex virus, were detected.

Virus identification method: Utilization of animals (e.g. suckling mice, especially newborn mice), a more sensitive method of CA virus isolation than cultured cells, has accounted for more than 50% of CA virus isolation reports. However, since the addition of PCR as a reporting item for virus detection in 2000, the proportion of CA detections by PCR has been increasing every year (Fig. 4). This increase stems from the fact that virus isolation involves time and labor, with fewer PHIs using suckling mice. Although pan-entero primers are utilized for detection of enteroviruses by PCR, pathogen confirmation should be performed by virus isolation, the gold standard. Recently, nucleotide sequence analysis has been increasingly used for serotyping virus isolates. However, because various difficulties with nucleic acid analysis have been identified, neutralization or complement fixation (CF) assays are the preferred methods of serotype testing, with genetic analysis used as a supplementary method at the present time (see p. 237 of this issue). In addition, enteroviruses other than CA have been reported that are difficult to identify with antiserum prepared for enterovirus identification and distributed to PHIs (see p. 238 of this issue). Cases in which viruses are difficult to isolate or identify should be referred to NIID, Department of Virology II, Laboratory II.

Trend in 2005: Weekly reports of herpangina exceeded 1.0 per sentinel in week 23 (June 6-12) as seen every year, and peaked at 6.0 per sentinel in week 28 (July 18-24), equivalent to the peak in 2000 and the second highest figure next to 2001. As of week 35 (August 29-September 4), 1.02 cases per sentinel were reported (Fig. 2). Most of the viruses detected were CA6 (148 cases), followed by CA10 (20 cases) (Table 1, as of September 9). Although there were few reports of CA6 in the summer of 2004, CA6 detections were reported in the winter (Fig. 5) and subsequently increased after week 11 of 2005 (March 14-20), not only from cases of herpangina but also from those with HFMD, upper respiratory inflammation, and fever (see p. 238 of this issue and IASR 26:178 & 222, 2005). The number of reports of CA6 isolation from 26 PHIs in 2005 has already surpassed figures from each of the years during 2000-2004.

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