Summa ry Ba c k ground In Taiwan, from April to July, 1998, an epidemic of hand, foot, and mouth disease associated with enterovirus 71 (EV71) occurred with fatal complications. We did a clinical study of EV71-related diseases in Taiwan. M e t hods We studied 154 childre n with virus -c ulture - confirmed EV71 infection. Children were divided into three groups: 11 patients with pulmonary oedema; 38 patients with central nervous system (CNS) involvement and no pulmonary oedema; and 105 children without complications. We compared the clinical features, laboratory findings, risk factors, and outcome among these three groups. Findings Nine children with pulmonary oedema had hand, foot, and mouth disease, one had herpangina, and one had febrile illness with eight children with limb weakness and one with limb hypesthesia. All children had had sudden onset of tachycardia, tachypnoea, and cyanosis 1–3 days after onset of the disease. Nine of 11 children died within 12 h of intubation; one child was braindead within 15 h and died 17 days after intubation; one child was in deep coma and died 3 months later. In children with CNS complication and no pulmonary oedema, one child died of pneumonia after 4 months of ventilator support and four children had sequelae. All 105 children without complications recovered. The re was a significant association between CNS involvement and pulmonary oedema (odds ratio 12·4 [95% CI 2·6–60·1], p=0·001). Risk factors for pulmonary oedema after CNS involvement were hyperglycaemia, leucocytosis, and limb we a kne s s . Hyperglycaemia was the most significant prognostic factor for pulmonary oedema (odds ratio 21·5 [3–159], p=0·003). Interpretation EV71 can cause hand, foot, and mouth disease, CNS involvement with severe sequelae, and fatal pulmonary oedema. Hyperglycaemia is the most important prognostic factor. L a nc e t 1999; 3 5 4 : 1 6 8 2 –8 6 I nt roduct ion Hand, foot, and mouth disease (HFMD), usually caused by coxsackievirus A, is a common disease in children, almost all of whom recover within 4–6 days. 1 From April to July, 1998, an epidemic of HFMD caused mainly by enterovirus 71 (EV71) occurred in Taiwan. 2 EV71, first described in 1974 after specimens were isolated from patients in California, 3 has been associated with sporadic cases or outbreaks of a wide spectrum of diseases including HFMD, herpangina, aseptic meningitis, encephalitis, cerebellar ataxia, and poliomyelitis-like syn d r o m e. 4 –1 0 Fatal cases are rarely reported, except for 44 cases of bulbar encephalitis in Bulgaria in 1975, 5 4 7 deaths in Hungary in 1978, 6 and other sporadic cases. Because of a shortage of adequate viral diagnostic laboratories and difficulty in virus isolation of some strains, reports of EV71 infection may represent only the tip of the iceberg. 1 1 According to the Taiwan official data, up to 78 children with preceding HFMD or herpangina died, mainly from pulmonary oedema, about 400 children were admitted to hospital with central nervous system (CNS) involvement (Department of Health, Taiwan), and about 90 000 cases of HFMD without complications were reported by sentinel physicians during the HFMD epidemic in Taiwan. 2 Most of the viruses isolated during the epidemic were EV71. 1 2 The pathogenesis of acute fatal pulmonary oedema after EV71 infection was still unknown, and until this outbreak only one case here and four cases in Malaysia had been reported. 1 3 –1 5 Beca u se EV71 can spread worldwide and can cause severe neurological complications and acute fatal pulmonary oedema, we did a clinical study of EV71-related diseases at the Chang Gung Children’s Hospital in Taiwan. M e t hods Patie nts , cas e de finition, and gro uping Between April and July, 1998, 154 patients with virus-culture- confirmed EV71 infection were enrolled. 11 patients with preceding HFMD, herpangina, or febrile illness plus subsequent pulmonary oedema were included. EV71 infection was defined as acute illness plus the isolation and typing of EV71 from rectal swab, throat swab, vesicular fluid, cerebrospinal fluid, or necropsy tissue. Pulmonary oedema was defined as alveolar congestion on chest radiography and pink frothy fluid from the endotracheal tube. Herpangina included oral ulceration on anterior tonsillar pillars, soft palate, buccal mucosa, or uvula. HFMD patients had mouth ulcers plus vesicular rash on the hands, feet, knees, or buttocks. 38 patients with EV71 infection and CNS involvement but without pulmonary oedema were included. CNS involvement included aseptic meningitis, encephalitis, poliomyelitis-like syndrome, or encephalomyelitis. Aseptic meningitis was defined as a clinically compatible illness, with cerebrospinal fluid pleocytosis (leucocytes >5/μL if the patient was aged older than 1 month, >25/μL if the patient was newly born) plus negative bacterial culture or EV71 isolated from cerebrospinal fluid. Patients with encephalitis showed an altered level of consciousness, and those with poliomyelitis-like syndrome had 1682 THE LANCET • Vol 354 • November 13, 1999 Clinical features and risk factors of pulmonary oedema after ent erovirus-71-related hand, foot , and mouth disease Luan-Yin Chang, Tzo u-Yie n Lin, Kuang-Hung Hs u, Yhu-Che ring Huang, Kuang-Lin Lin, Chue n Hs ue h, Shin-Ru Shih, Hs iao -Che n Ning, Mao -She ng Hwang, Hue i-Shyo ung Wang, Chin-Yun Le e Division of Pediatric Infectious Disease (L-Y Chang MD, T-Y Lin MD, Y-C Huang MD, C-Y Lee MD), Division of Pediatric Neurology (K-L Lin MD, H-S Wang MD), Division of Pediatric Cardiology (M-S Hwang MD), Department of Pediatrics, Chang Gung Children’s Hospital, Kweishan, Taoyuan, Taiwan; Department of Pathology, Chang Gung Children’s Hospital, and Chang Gung University, College of M edicine, Kweishan, Taoyuan (C Hsueh MD); School of M edical Technology, Chang Gung University, and Clinical Virology Laboratory, Chang Gung M emorial Hospital, Kweishan, Taoyuan (S-R Shih PhD, H-C Ning MS); and Laboratory for Epidemiology and Department of Health Care Management, Chang Gung University, Kweishan, Taoyuan (K-H Hs u PhD) Correspondence to: Dr Tzou-Yien Lin, Division of Pediatric Infectious Disease, Department of Pediatrics, Chang Gung Children’s Hospital and Chang Gung University, College of Medicine, 5 Fu-Hsing Street, Kweishan, Taoyuan, Taiwan (e-mail: pidlin@adm.cgmh.com.tw)