Hand, foot and mouth disease (HFMD) is usually caused by the coxsackievirus (CoX) and is common in children. 1 Since 1998 we have observed fatal cases of enterovirus infection in Taiwan mainly involving enterovirus 71 (EV71) in infants. 2 EV71 infection has become an endemic disease in this region with occasional spikes in incidence. Based on an outbreak in Taiwan in 1998, CoX A16 infection is usually self-limited without associated fatality. Only two fatal cases have been reported in the literature since 1960. 3, 4 We report here a fatal case of CoX A16 infection in a 15-month-old boy.
A 15-month-old boy was admitted to National Taiwan University Hospital because of seizures with shock. Intermittent high spiking fever associated with poor oral intake was noted for 3 days. Many small ulcers and vesicles over his posterior pharyngeal wall were noted by a local medical doctor on the second day. Meanwhile, small vesicles were found on his hands, feet and buttocks. His physician diagnosed hand, foot and mouth disease and prescribed symptomatic medication. Nevertheless poor activity, appetite and fever persisted. Sudden loss of consciousness, upward gazing and tonic convulsions were noted on the third day of illness. On admission weak pulses and lip cyanosis were observed. He was intubated and transferred to our pediatric intensive care unit for further care.
On admission his pulse rate was 187 beats/min and his blood pressure was 64/32 mm Hg. His consciousness level deteriorated gradually. Fine rales and wheezing were audible at both lung bases. His liver and spleen were not palpable.
The routine laboratory studies were normal including: serum sodium, 132 mmol/l; potassium, 5.09 mmol/l; chloride, 104 mmol/l; and normal urinalysis except that the urine protein was 100 mg/dl; urine sugar was 0.25 g/dl. Abnormalities on blood tests were elevated white blood cell counts of 21 540/μl with band cells of 8%, segment cells of 40% and lymphocytes of 48%. Blood glucose was 390 mg/dl. The initial creatine kinase was 183 units/l; creatine kinase-myocardial band was 34.5 units/l and troponin-I was 16.2 ng/ml. Poor cardiac contractivity was detected by cardiac echography. Severe myocarditis was suspected. Lumbar puncture showed pleocytosis. Cell counts of cerebrospinal fluid were 158, and lymphocyte/neutrophil counts were 111/47. His blood and cerebrospinal fluid cultures were sterile. A roentgenogram of the chest showed borderline cardiomegaly with perihilar congestion of the lung fields.
He was given inotropic agents (dopamine, dobutamin, norepinephrine, epinephrine) and frequent fluid challenge, but his blood pressure remained low (mean arterial pressure ∼40 mm Hg) and unresponsive to these medications. Follow-up chest radiographs revealed progressive cardiomegaly and congestion in the lung fields. The child received extracorporeal membrane oxygenation on the fourth day of illness. Intravenous immunoglobulin was given for 2 days (1 g/kg/day). Progressive dilated pupils and oliguria were noted. He died on the sixth day of illness.
Both throat and rectal viral cultures yielded enterovirus. This strain was confirmed to be coxsackievirus A16 by monoclonal antibody fluorescence and a standard neutralization test. 5
HFMD is a common illness in children and may be related to coxsackie viruses A16, A5, A9, A10, B2, B5 and enterovirus 71. 1, 6–12 CoX A16 is a frequently encountered pathogen in cases of HFMD, and its clinical course is usually uneventful, with full recovery. 6 Most cases occur in the summer and fall, and the incubation period is 4 to 6 days. Infection is highly contagious. 13 A literature search revealed only two fatal cases in infants since 1963. 3, 4
In 1963 Wright et al. 3 presented a fatal case of a 10-month-old girl with respiratory infection, culminating in severe cardiac failure. The CoX A16 was isolated from the intestines but not from the myocardium. A severe inflammatory process in the myocardium was documented from microscopic sections at autopsy. The second case involved a 7-month-old boy with grunting and tongue ulcers. 4 The patient died 4 days after onset of clinical manifestations of irritability, respiratory distress, tachycardia, cyanosis and convulsion. Gross pathology suggested encephalitis and myocarditis, and CoX A16 was isolated from the myocardium, blood and bowel contents.
The clinical manifestations of fatal CoX A 16 infection as seen in our patient and the two cases from the medical literature are similar to those of coxsackievirus B infection, 14 occurring mainly in newborns. Fatal cases of coxsackievirus A infection in infants is rare.
Since the outbreak in Taiwan in 1998, EV71 has been the single most prominent pathogen associated with severe morbidity or mortality. 2 Among the enterovirus isolates, EV 71 and CoX A16 were the two most prevalent at that time, and they were associated with similar symptoms and signs. 15 However, EV71 illness was more severe and had serious complications including death, whereas CoX A16 infection was self-limited. 1, 15
Myocarditis caused by coxsackievirus group B is well-established. 16 Since 1954 coxsackievirus group A viruses, such as A1, A4 and A9, have been associated with myocarditis. 17–19 echovirus, group B coxsackievirus and CoX A16 have been reported to cause fatalities in the neonatal period. 20 Most CoX A16 infections are uncomplicated or involve only aseptic meningitis. 9 Our case presented as fulminant myocarditis with intractable shock, a rare condition. The possible cause of our patient’s death was myocardial failure.
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