Epidemic hand, foot and mouth disease caused by human enterovirus 71, Singapore - Research

Emerging Infectious Diseases, Jan, 2003 by Kwai Peng Chan, Kee Tai Goh, Chia Yin Chong, Eng Swee Teo, Gilbert Lau, Ai Ee Ling

Until this epidemic occurred, no deaths had been associated with HFMD in Singapore, although HEV71-related deaths from encephalitis (15-17), pulmonary edema, and hemorrhage (8,18) have occurred elsewhere since the virus was first isolated in 1969 (15). In this epidemic in Singapore, the case-fatality rate among all reported HFMD case-patients was 0.08%, which is similar to the rate of 0.06% experienced in the 1998 Taiwanese outbreak (9).

Four deaths (two HFMD and two non-HFMD cases) were associated with HEV71. All occurred rapidly despite intensive care, within a day of the patient's hospital admission, and after an average of 3.4 days of illness. The circumstances of these deaths were reminiscent of recent HEV71 deaths in the region (10,18-20). Of these four case-patients, three were autopsied, including a pair of siblings with HFMD and a patient with non-HFMD encephalitis. Their postmortem findings were similar, with HEV71 isolated from the brains of two case-patients and from the tonsils and intestines of the third. Whether HEV71 caused the death of the patient with myocarditis who was not autopsied is less clear since HEV71 was isolated from nonsterile sites (the throat and rectum), although the illness and epidemiology suggest the possibility.

During the epidemic, a fifth death occurred involving a boy with HFMD on whom an autopsy was conducted. No virus was cultured from him, possibly because of the advanced postmortem degradation of his tissues. However, HEV71 was likely also to have been the cause of death on the basis of the similarity of his clinical and postmortem findings to those of the siblings who died, as well as the epidemiologic links to age, time, and place.

Like other fatal HEV71 cases reported elsewhere (7,16,20,21), the primary pathologic changes found at autopsy of four case-patients in this study were in the brain, including the brainstem, which showed extensive inflammatory cell infiltrate and focal necrosis. In addition, pneumonitis was found in all the case-patients and myocarditis in two. In the Malaysian and Taiwanese outbreaks (7,18,20), however, no significant inflammation was found in the lungs of patients with fatal cases. Notably, the myocardium of 10 Malaysian patients was described as normal (7), whereas autopsy reports of 2 patients from the Taiwanese outbreak described mild myocarditis in 1 (20) and no myocarditis in the other (18).

HEV71 was cultured from the brain specimens of two of our autopsied case-patients, but viral cultures of the lung and heart were negative. Similarly, no HEV71 was isolated from 34 CSF samples studied, notwithstanding the diagnosis of aseptic meningitis. Besides encephalitis and death, other complications (such as aseptic meningitis and acute flaccid paralysis) have also been reported in other HFMD outbreaks (7,9). However, other than the three fatal cases and one case of aseptic meningitis, all HFMD cases in the Singapore epidemic were uncomplicated, despite the large number of patients.