Luan-Yin Chang

Clinical features and risk factors of pulmonary oedema after enterovirus-71-related hand, foot, and mouth disease

BACKGROUND 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. METHODS We studied 154 children with virus-culture 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. There 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 weakness. 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.

Proinflammatory cytokine reactions in enterovirus 71 infections of the central nervous system

Enterovirus 71 (EV71) infection can lead to devastating clinical outcomes. An appreciation of the scientific relationship between cytokine response and patient mortality may help limit the risks posed by this deadly illness. We present the results of a study that compared the cerebrospinal fluid (CSF) and serum levels of interleukin-6 (IL-6) and interleukin-1beta (IL-1beta) in 24 patients with EV71 infection. Cases in this study involved diverse manifestations or complications, including encephalitis, poliomyelitis-like syndrome, meningitis, and pulmonary edema. CSF levels of IL-6 in study patients were found to be consistently higher during the first 2 days of central nervous system (CNS) involvement than afterward. Compared with patients who did not have pulmonary edema, patients who experienced pulmonary edema had dramatically varied blood values, including IL-6, white blood cell counts, and glucose levels. Our findings suggest that the combination of CNS and systemic inflammatory response may trigger EV71-related cardiopulmonary collapse.

Comparison of enterovirus 71 and coxsackievirus A16 clinical illnesses during the Taiwan enterovirus epidemic, 1998

OBJECTIVES To compare enterovirus 71 (EV 71) with coxsackievirus A16 (Cox A16) clinical illness in patients at Chang Gung Childrens Hospital during Taiwans enterovirus epidemic of 1998. METHODS With the use of the immunofluorescence assay and neutralization test, 177 cases of EV 71 and 64 cases of Cox A16 illness were confirmed from April to September, 1998. The clinical signs and symptoms, complications and case fatality rates were compared. RESULTS Three-fourths of the cases were younger than 3 years of age, and the ratio of males to females was 1.3 in the EV 71 group and 1.2 in the Cox A16 group. In the EV 71 group 120 (68%) cases were uncomplicated, including 94 cases of hand, foot and mouth disease and 15 cases of herpangina, and 57 (32%) cases had complications, including 13 (7.3%) cases of aseptic meningitis, 18 (10%) cases of encephalitis, 4 (2.3%) cases of polio-like syndrome, 8 (4.5%) cases of encephalomyelitis and 12 (6.8%) cases of fatal pulmonary edema. Fourteen (7.9%) patients died, including 12 cases of pulmonary edema and 2 cases of encephalitis; seven (4%) patients had sequelae. By contrast, 60 (94%) of the 64 cases of Cox A16 infection were uncomplicated and only 4 (6.3%) cases were complicated by aseptic meningitis; no fatalities or sequelae were observed. By multivariate analysis vomiting (P = 0.01) and fever higher than 39 degrees C plus lasting longer than 3 days (P = 0.02) were significantly more frequent in the EV 71 group. CONCLUSION EV 71 illness is more severe with significantly greater frequency of serious complications and fatality than is illness caused by Cox A16.

Pyogenic Liver Abscess as Endemic Disease, Taiwan

Increasing incidence and microbiologic shift might have changed the manifestation of this condition.

Enterovirus 71 Outbreaks, Taiwan: Occurrence and Recognition

Enterovirus 71 (EV71) caused a large outbreak in Taiwan in 1998 with 78 deaths, and smaller outbreaks recurred in 2000 and 2001. The outbreak was recognized because of a large number of hand, foot, and mouth disease cases and the rapid deaths of children with the disease. Virologic and pathologic studies indicated that EV71 was the most important agent related to severe and fatal cases and that a neurogenic inflammatory response was involved in the pathogenesis of cardiopulmonary collapse resulting from fulminant EV71 infection. Seroepidemiologic study suggested that EV71 had circulated for at least 16 years and that the accumulation of susceptible hosts might have triggered the 1998 outbreak. However, a change in EV71 neurovirulence and host genetic susceptibility may also have affected the clinical outcome. The Taiwan outbreak shows that worldwide attention should be paid to such outbreaks, new antiviral drugs should be developed, and that vaccination of children under 5 years of age may be warranted.

Fulminant neurogenic pulmonary oedema with hand, foot, and mouth disease

An 8-year-old girl was admitted with fever, oral ulcers, constipation, headache, and vomiting for 2 days. She had a rash on the soles of both feet, and had not urinated for a day. She was alert and not cyanosed, with a heart rate of 114/min, body temperature 37·2°C, and blood pressure 114/64 mm Hg. Her neck was stiff; breath sounds were clear; her heart beat was regular without gallop; her bladder was distended; and several small pink vesicles were found on both soles. There were no focal neurological signs. White blood cell count was 14·310 9 /L, blood sugar was 7·4 mmol/L, and creatine kinase MB fraction was 2 U/L. In cerebrospinal fluid, white cell count was 15310 6 /L with 70% neutrophils; glucose 4·2 mmol/L, and protein 43 mg/dL. The first chest radiograph was normal (figure A). Abdominal radiograph showed dilated loops of bowel and a distended bladder. Brain computed tomography was normal. Intravenous penicillin was given. 2 h after lumbar puncture, she complained of itching followed by pain in her right arm and then in her right forearm. Her muscle power was unimpaired. 1 h later, she had a severe headache and vomited bile. She became sweaty, with cold hands and feet, tachypnoeic (48/min), and had a heart rate up to 170/min. A second chest radiograph showed bilateral alveolar congestion. She coughed up pink frothy sputum and became cyanosed. She was intubated. Pink frothy fluid, followed by fresh blood, came from the endotracheal tube. She had increased leucocytosis (31·810 9

The 1998 Enterovirus 71 Outbreak in Taiwan: Pathogenesis and Management

The most recently discovered enterovirus, enterovirus 71 (EV71), is neurotropic and may cause severe disease and sudden death in children. In 1998, a large outbreak of enterovirus infection occurred in Taiwan that resulted in 405 severe cases in children and 78 deaths. Of the 78 children who died, 71 (91%) were <5 years old. EV71 was the primary agent in fatal cases of infection. Most of these patients died within 1-2 days of admission to the hospital. We hypothesize that EV71 directly attacks the central nervous system and causes neurogenic pulmonary edema and cardiac decompensation through the mechanism of sympathetic hyperactivity and inflammatory responses. Early recognition of risk factors and intensive care are crucial to successful treatment of this fulminant infection. After poliovirus is eradicated, EV71 will become the most important enterovirus that affects children, and development of a vaccine may be the only effective measure against it.

Epidemiologic Features of Kawasaki Disease in Taiwan, 2003–2006

OBJECTIVE. Kawasaki disease is the leading cause of acquired heart disease in children worldwide. This study characterizes the epidemiology of Kawasaki disease in Taiwan between 2003 and 2006. METHODS. Using Taiwans 2003–2006 national health insurance claims, we investigated the epidemiologic features of Kawasaki disease (ICD-9-CM code 446.1) and coronary artery aneurysm formation (International Classification of Diseases, Ninth Revision, Clinical Modification code 414.11) and compared the incidences of these diseases with those occurring between 1996 and 2002 in Taiwan and those reported by other countries. RESULTS. During our 4-year study period, 3877 children and adolescents <20 years of age were hospitalized for Kawasaki disease. Ninety percent of these children were <5 years of age, and the male/female ratio was 1.62:1. The annual incidence of Kawasaki disease was 153 in 100000 children <1 year of age, 111 in children 1 year of age, 58 in children 2 years of age, 30 in children 3 years of age, 19 in children 4 years of age, and 5.2 in children 5 to 9 years of age. The overall incidence was 69 cases per 100000 for children <5 years of age. Kawasaki disease recurred in 1.5% of all cases. Kawasaki disease occurred most frequently in the summer and least frequently in the winter. Coronary artery aneurysm occurred in 7.2% (279 of 3877) of all Kawasaki disease cases. CONCLUSIONS. The overall incidence of Kawasaki disease was 69 in 100000 children <5 years of age between 2003 and 2006 in Taiwan, comparable with the incidence of 66 in 100000 children between 1996 and 2002. Taiwan has the third highest incidence of Kawasaki disease in the world, after Japan and Korea. In Taiwan, it occurs more frequently during the summer.

Humoral and Cellular Immune Responses to a Hepatitis B Vaccine Booster 15–18 Years after Neonatal Immunization

BACKGROUND Whether hepatitis B (HB) vaccine-conferred immunity persists into adulthood is unknown. We aimed to investigate long-term HB immunity in adolescents. METHODS In 2004-2005, 6156 high school students (15-21 years old) who had been vaccinated with plasma-derived HB vaccine as infants were recruited for HB seromarker screening. The immune response to an HB vaccine booster was evaluated in 872 subjects who were seronegative. HB surface antibody (anti-HBs) titers and levels of HB surface antigen (HBsAg)-specific interferon (IFN)-gamma- or interleukin (IL)-5-secreting peripheral blood mononuclear cells (PBMCs; measured by enzyme-linked immunospot assay) were determined 4 weeks later. RESULTS Although the vaccine remained highly efficacious in reducing the HBsAg positivity rate, 63.0% of the vaccinees had no protective anti-HBs. After the booster, anti-HBs remained undetectable in 28.7% (158/551) of the subjects who had received complete HB vaccination (4 doses) during infancy. We estimated that 10.1% of the total population had lost their HB vaccine-conferred booster response. HBsAg-specific IFN-gamma- or IL-5-secreting PBMCs remained negative in 27.2% (25/92) of subjects after the booster. CONCLUSIONS A notable proportion of fully vaccinated adolescents had lost immune memory conferred by a plasma-derived HB vaccine 15-18 years later. This decay of immune memory may raise concerns about the need for a booster vaccine for high-risk groups in the long run.

An outbreak of coxsackievirus A6 hand, foot, and mouth disease associated with onychomadesis in Taiwan, 2010

BackgroundIn 2010, an outbreak of coxsackievirus A6 (CA6) hand, foot and mouth disease (HFMD) occurred in Taiwan and some patients presented with onychomadesis and desquamation following HFMD. Therefore, we performed an epidemiological and molecular investigation to elucidate the characteristics of this outbreak.MethodsPatients who had HFMD with positive enterovirus isolation results were enrolled. We performed a telephone interview with enrolled patients or their caregivers to collect information concerning symptoms, treatments, the presence of desquamation, and the presence of nail abnormalities. The serotypes of the enterovirus isolates were determined using indirect immunofluorescence assays. The VP1 gene was sequenced and the phylogenetic tree for the current CA6 strains in 2010, 52 previous CA6 strains isolated in Taiwan from 1998 through 2009, along with 8 reference sequences from other countries was constructed using the neighbor-joining command in MEGA software.ResultsOf the 130 patients with laboratory-confirmed CA6 infection, some patients with CA6 infection also had eruptions around the perioral area (28, 22%), the trunk and/or the neck (39, 30%) and generalized skin eruptions (6, 5%) in addition to the typical presentation of skin eruptions on the hands, feet, and mouths. Sixty-six (51%) CA6 patients experienced desquamation of palms and soles after the infection episode and 48 (37%) CA6 patients developed onychomadesis, which only occurred in 7 (5%) of 145 cases with non-CA6 enterovirus infection (p < 0.001). The sequences of viral protein 1 of CA6 in 2010 differ from those found in Taiwan before 2010, but are similar to those found in patients in Finland in 2008.ConclusionsHFMD patients with CA6 infection experienced symptoms targeting a broader spectrum of skin sites and more profound tissue destruction, i.e., desquamation and nail abnormalities.