LETTER
Over 3.4 million cases of hand, foot, and mouth disease (HFMD), including over 1,000 deaths, have been reported in China since March 2008. HFMD is caused mainly by enterovirus 71 (EV71) and coxsackievirus A16 (CA16), while EV71 contributes to severe and fatal cases (3, 5). Both viruses, like poliovirus (PV), belong to the Enterovirus genus of the Picornaviridae family. Previous studies have revealed that poliovirus is cross-reactive with other enteroviruses in antibody and cellular immune responses in humans (1, 6). Almost every human being has been immunized with poliovirus vaccine in early childhood. However, how this specific vaccination influences the pathogenesis of other enteroviral infections and their clinical outcomes remains elusive. A retrospective study from the 1970s in Kuala Lumpur, Malaysis, revealed that the prevalence of total enteroviruses, besides poliovirus per se, sharply decreased shortly after a mass poliovirus vaccination campaign (8). Similarly, a coincidence of poliovirus vaccination and decline of HFMD occurred during the Bulgarian HFMD epidemic in 1978, suggesting a possible protective role of poliovirus vaccination against HFMD (5).
Ineffective immunization in children receiving fewer than five doses of oral poliovirus vaccine (OPV) frequently occurs in developing countries. Therefore, 10 to 15 doses of OPV are given to young children in some countries (4). While only three doses of OPV are administered to children from 2 months old over consecutive months in China, an additional dose is given when children reach the age of 4 years. Interestingly, about 90% of HFMD patients are within this age range (9). Furthermore, poor administration of PV vaccination in rural areas of China occurs frequently for various reasons (2, 7). We questioned whether there is a connection between OPV immunization and this HFMD epidemic.
To study the hypothesis, we carried out a retrospective case-controlled study of the HFMD outbreak in the city of Fuyang. We investigated 153 patients and 447 age- and neighborhood-matched healthy controls from the Fuyang HFMD outbreak in 2008 after receiving consent from family or guardians. Cases were further divided into two groups, based on whether the child had HFMD with or without pulmonary edema. As shown in Table 1, the proportions of children who had followed the recommended OPV immunization schedule were 70.9%, 62.4%, and 41.7% for healthy controls, HFMD patients without pulmonary edema, and HFMD patients with pulmonary edema, respectively. The remaining subjects did not follow the recommended schedule, had fewer than three doses, or had received an OPV 2 to 10 months following the preceding dose. We defined all three conditions as an irregular OPV vaccination. There was a significant difference in the proportions of children who had received the recommended OPV immunization between the group with edema and the controls (P < 0.001). The odds ratio was 0.293 (0.146 to 0.586, 95% confidence interval [CI]). In addition, there was a significant difference between the patients with edema and those without (P = 0.028). These data suggest that the irregularity of OPV vaccination correlates to HFMD severity, particularly pulmonary edema, implying that additional doses of OPV or effective PV immunization likely has a beneficial role in mitigating the severity of HFMD. The implication and its immunological mechanisms merit being further investigated clinically and experimentally.
Table 1.
Differences in the proportions of regular OPV vaccination between healthy controls and HFMD cases with or without edema from the 2008 HFMD outbreak in Fuyang City
| Group | No. with regular vaccination (%) | Odds ratio (95% CI) | P value |
|---|---|---|---|
| Controls (n = 447) | 317 (70.9) | ||
| All cases (n = 153)a | 88 (57.5) | 0.555 (0.380-0.812) | 0.0023 |
| Without edema (n = 117)a | 73 (62.4) | 0.680 (0.444-1.042) | 0.075 |
| With edema (n = 36)a | 15 (41.7) | 0.293 (0.146-0.586) | <0.001 |
| With edema vs without edema | 0.431 (0.201-0.921) | 0.028 |
Odds ratios and P values were calculated against the controls. The chi-square test was used to calculate P values.
Acknowledgments
We thank Nevine El Khatib and International Science Editing for their excellent editorial contributions.
This work was supported by grants from the Knowledge Innovation Program of the Chinese Academy of Sciences (KSCX2-YW-R-204) and 100 Talent Program of CAS.
Footnotes
Published ahead of print on 13 July 2011.
Contributor Information
Chunfu Yang, Key Laboratory of Molecular Virology and Immunology, Institut Pasteur of Shanghai, Shanghai Institutes of Biological Science, Chinese Academy of Sciences, 225 South Chongqing Road, Shanghai 200025, People's Republic of China.
Liye Zhu, Center for Disease Control of Fuyang City, 19 Zhongnan Avenue, Fuyang City, Anhui Province, People's Republic of China.
Qibin Leng, Key Laboratory of Molecular Virology and Immunology, Institut Pasteur of Shanghai, Shanghai Institutes of Biological Science, Chinese Academy of Sciences, 225 South Chongqing Road, Shanghai 200025, People's Republic of China.
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