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org
108 World J Emerg Med, Vol 1 No.2, 2010 Zhang et al
Clinical characteristics and treatment of severe
encephalitis associated with neurogenic pulmonary
edema caused by enterovirus 71 in China
Yu-cai Zhang, Xing-wang Li , Xiao-dong Zhu, Su-yun Qian, Yun-xiao Shang, Bi-ru Li, Xiao-lin Liu
Children's Hospital, Shanghai Jiaotong University, Shanghai 200040, China (Zhang YC); Beijing Ditan Hospital, Beijing
100010, China (Li XW); Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200092, China
(Zhu XD); Beijing Children's Hospital, Beijing 100045, China (Qian SY); Shengjing Hospital, China Medical University,
Shenyang 110004, China (Shang YX); Children Medical Center, Shanghai Jiaotong University School of Medicine,
Shanghai 200127, China (Li BR); People's Hospital of Fuyang City , Fuyang 236004, China (Liu XL)
Corresponding Author: Yu-cai Zhang, Email:zyucai2005@hotmail.com
BACKGROUND: Hand-foot-mouth disease has become a major public health issue in children
in China. In the present prospective study we investigated the clinical characteristics and emergency
management of children with severe encephalitis associated with NPE caused by enterovirus 71.
METHODS: The study was conducted in 2 pediatric intensive care units (PICUs) over a 2-month
period. Clinical records were reviewed of critically ill children with severe encephalitis associated with
NPE caused by EV71 who were admitted to PICUs during the period of May to June 2008 in Fuyang.
RESULTS: We reviewed the complete records of 36 children, of whom 23 (63.9%) were male and
13 (36.1%) female. Their age ranged from 4 to 48 months, with an average of 15.8 months. All children
except one were under 3 years of age. The overall mortality in these children was 19.4%. The average
duration of critical life threatening signs and symptoms was 2.1 days (12 hours-5 days). Nervous system
diseases included brainstem encephalitis in 27 children (75%), brainstem encephalitis associated with
myelitis in 6 children (16.7%), and general encephalitis in 3 chidren (8.3%), respectively. In 12 patients
of NPE (33.3%) pink or bloody bubble sputum and asymmetric pulmonary edema or hemorrhage was
the primary manifestation but no typical exanthema was observed. Five children died of acute onset of
NPE and / or pulmonary hemorrhage with rapid progression of cardiopulmonary failure within hours after
admission. Therapeutic management consisted of mechanical ventilation and administration of mannitol,
methylprednisolone, intravenous immunoglobulin (IVIG) and vasoactive drugs, associated with the need
of uid volume resuscitation in 9 (25%) of the 36 children.
CONCLUSIONS: In children less than 3 years of age found to be affected by severe EV71
encephalitis associated with NPE, one fifth may die. The major organ systems infected by severe
EV71 include the central nervous system, the respiratory system, and the cardiovascular system. Early
diagnosis and evaluation, respiratory support, treatment of intracranial hypertension, and mainttenance
of function of the cardiovascular system are the most important therapeutic measures.
KEY WORDS: Enterovirus71 (EV71); Encephalitis; Neurogenic pulmonary edema; Hand-foot-
mouth disease; Child
World J Emerg Med 2010;1(2):108-113
Original Article
2010 World Journal of Emergency Medicine
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109 World J Emerg Med, Vol 1 No.2, 2010
INTRODUCTION
There were several large outbreaks of hand-foot-
mouth disease (HFMD) affecting infants and young
children around the world. In recent years, HFMD has
become a major public health issue in children in China.
Enterovirus 71 (EV71) is a major pathogen of HFMD,
which manifests itself most frequently as the childhood
exanthema. Its main characteristics are blister-like rash
in the oral mucosa and the end of the limbs (hands and
feet). A remarkable feature of this disease is the high
mortality due to brainstem encephalitis and pulmonary
edema in children under age of 3 years. The children
develop rapidly progressing sympathetic hyperactivity,
pulmonar y edema or pulmonar y hemorrhage, and
cardiopulmonary failure.
[1,2]
In 2008, an outbreak of EV71
infection occurred in Fuyang City of Anhui Province
in China. Some of these patients with this infection had
severe encephalitis, fulminant pulmonary hemorrhage
or pulmonary edema and cardiovascular system failure.
The Ministry of Health of the Chinese government sent
medical teams to immediately control the disease. We
participated in the management of 36 patients with severe
EV71 encephalitis associated with neurogenic pulmonary
edema (NPE) and investigated the clinical characteristics,
therapeutic management and outcome of the patients.
METHODS
Patients and data collection
Thirty-six patients were diagnosed with severe EV71
encephalitis associated with neurogenic pulmonary
edema (NPE) at the pediatric intensive care units (PICUs)
at People's Hospital and Second People's Hospital of
Fuyang City from May to June 2008. The data collected
included 1) general information: age, gender, disease
course before admission to PICU, and signs of early
re-performance; 2) clinical features: involvement of
the nervous system, signs of pulmonary edema, and
dysfunction of other organs; 3) therapeutic interventions;
and 4) prognosis.
The medi cal t eams were responsi bl e for t he
management of severe EV71 infection in the two
hospitals during this period. The patients with critical
EV71 encephalitis were evaluated according to the
criteria formulated by medical experts from the Ministry
of Health in 2008. The criteria for clinical evaluation of
children with encephalitis in HFMD included serious
disturbance of consciousness or coma, central respiratory
failure, cerebral edema, cerebral hernia, frequent seizures
or encephalitis associated wth unstable vital signs,
or at least one of the following signs: 1) respiratory
system: breathing difficulties, abnormal shallow and
slow breathing rhythm, pink or bloody bubble sputum,
chest X-ray with opacification due to exudations,
need of mechanical ventilation or oxygen therapy; 2)
cardiovascular system: pale face, rapid heart rate, faint
and speed pulse, marmorated skin, cold extremities,
cyanosis, hypertension or hypotension, significantly
decreased urine output, capillary relling time (CRT)2
seconds; 3) gastro-intestinal system: apparent abdominal
distention, stress ulcer bleeding; 4) hematology: a
high-clotting or bleeding tendency according to DIC
diagnostic standards. Multiple organ dysfunction
(MODS) /organ failure (MOF) criteria were as follows:
two or more systems or organ dysfunction / failure within
24 hours after onset of the illness. Organ dysfunction
was assessed according to the criteria recommended
by the 4th Symposium on Pediatric Emergency of
the Chinese Medical Association held in 1995.
[3]
The
diagnostic criteria for NPE included encephalitis with
sudden shortness of breath, sigh-like breathing, pink or
bloody bubble sputum, and chest X-ray changes. All
of the patients underwent at least one chest radiograph
everyday during the mechanical ventilation.
Treatment strategy and evaluation
Vital signs were continuously monitored and evaluated
in the 36 critically ill children after admission to the PICU
with regard to consciousness, respiratory status, heart rate,
blood pressure, body temperature, urine output as well as
capillary relling time (CRT). 1) Basic and advanced life-
support was given to the patients with central respiratory
failure or pulmonary edema who were tracheally intubated
and mechanically ventilated. Ventilation variables were
set according to the initial conditions of the patients.
In general, initial FiO
2
was set at 0.6-1.0, positive end
expiratory pressure (PEEP) 8-15 cmH
2
O, peak inspiratory
pressure (PIP) 15-20 cmH
2
O (pressure above the baseline
of PEEP), tidal volume (Vt) 6-8 ml/kg. 2) Intracranial
hypertension and cerebral edema were treated with 20%
mannitol 2-5 ml/kg for 4-6 hours or combined with 10%
glycerol fructose 2-5 ml/kg for 4-6 hours, or furosemide
1-2 mg/kg if necessary. 3) Fluid administration was 60-
80 ml/kg per day in patients with the normal circulatory
system. In children with relative or absolute hypovolemia
associated with NPE, fluid resuscitation was needed
in monitoring. In selective cases vasoactive drugs
were administered such as dopamine, dobutamine, and
adrenaline. In children with cardiac failure associated
with tachycardia 180/min, phosphodiesterase inhibitor
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110 World J Emerg Med, Vol 1 No.2, 2010 Zhang et al
milrinone was administered at a dose of 0.3-1 g/kg
per minute. 4) Intravenous immunoglobulin (IVIG)
was given at a dose of 1 g/kg per day for 2 days. 5)
Corticosteroid such as methylprednisolone was given at
a dose of 10-20mg/kg per day for 2-3 days, then the dose
was reduced to 2-4 mg/kg per day for 3-7 days. 6) Other
drugs such as VitC were prescribed at a high dose of 100-
300 mg/kg per day. 7) Solutions were given to maintain
the balance of electrolyte, glucose, and acid-base.
RESULTS
Clinical features of EV71 encephalitis and NPE
In the 36 consecutive patients, who had EV71 infection
involving the central nervous system (CNS) associated
with NPE requiring mechanical ventilation and had the
complete records, 23 (63.9%) were male and 13 (36.1%)
female. Their age ranged from 4 months to 48 months
(mean 15.8 months). Fifteen patients (41.7%) were less
than 1 year old, 20 patients (55.6%) were 1 to 3 years old,
and only one patient (2.8%) was more than 3 years old.
The course of the disease before admission was 3.2 days
on average and ranged from 1 to 6 days (less than 3 days
in 22 of the 36 patients).
Life threatening signs and symptoms emerged
between 12 hours to 5 days (average 2.1 days) after the
onset of the disease. The aura signs of NPE included high
fever (> 39 C ) in 18 patients (50%), severe malaise in 36
(100%), vomiting in 22 (60.1%), tachypnea, retraction or
shallow breathing rhythm in 36 (100%), tachycardia in 19
(52.8%), and cool extremities in 33 (91.7%). All patients
developed NPE associated with tachypnea with pink
or bloody bubble sputum. Neurological manifestations
included brain stem encephalitis in 27 patients (75%),
brain stem encephalitis associated with transverse
myelitis in 6 (16.7%) and aseptic meningitis in 3(8.3%).
The clinical signs and symptoms of the patients are
summarized in Table 1.
Laboratory nding
EV71-specific RNA was detected by PCR in probes
of sputum and stool, and confirmed the infection caused
by EV71. Cerebrospinal fluid (CSF) examination was
performed in 19 patients after or on admission, of whom 15
(78.9%) were abnormal. Thirteen patients had an increased
CSF WBC count (12-80010
6
/L), and 12 patients had an
elevated level of CSF protein (600-1163 g/L) but normal
CSF glucose level. CK-MB was elevated mildly to
moderately in 15 (62.5%) of 24 patients, ranging from
27 to 265 ng/L (normal< 25 ng/L). Autopsy of 5 deaths
revealed edema in the brain stem and spinal cord. Neuron
degeneration, nerounophagia and satellite phenomenon
were observed under a microscope. No obvious evidence
of myocarditis was revealed by heart autopsy.
Image nding
Head CT or MRI showed damage in the brain stem,
the thalamus, and basal ganglia lesions (Figure 1) but no
obvious effect on the cerebral cortex (gray matter).
Chest radiograph
In early phase, chest X-ray examination showed mild
interstinal edema including increased hazy lung marking,
septal lines and inceased opacity. The typical image of
NPE was asymmetric pulmonary diffuse alveolar density
without distinct cardiomegaly. Twenty-five patients
(69.4%) initially showed opacication of the right lung,
which rapidly progressed to bilateral large shadows
(Figure 2).
Encountered problems and therapeutic
interventions
Respiratory support
The mean PaO
2
/FiO
2
of all 36 patients was 135.2 on
admission. After mechanical ventilation for 30 minutes
to 1 hour, surviving children using a transcutaneous pulse
oxymeter, TcSO
2
, showed SpO
2
values higher than 90%.
Ventilation settings were variable. Appropriate PEEP was
6 to 10 cmH
2
O in 15 patients (42.9%), 11 to 15 cmH
2
O
in 13 (36.1%), and >15 cmH
2
O in 8 (22.2%). In some
patients the tidal volume had to be increased to 8 to 12
ml/kg for appropriate ventilation and oxygenation. In
the majority of the patients ventilation settings could be
reduced after ventilation for 2 to 3 hours.
Cardiopulmonary support
Eleven patients (30.6%) presented with cardiac arrest
or heart rate <60/min. After CPR, 2 of these patients
relapsed and required CPR for cardiac arrest repeatedly
because continuous infusion of epinephrine had not
been started at the initial arrest, and 9 were not subjected
to repeated CPR at the time of continuous infusion of
adrenaline (0.05 to 0.2 g/kg per minute) for 6 to 24
hours. Nine (25%) patients with shock required volume
resuscitation administered as normal saline ( 10-20 ml/kg)
in 10-30 minutes by pump infusion. All patients were given
vasoactive drugs, and in some of them combined milrinone
and dopamine.
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111 World J Emerg Med, Vol 1 No.2, 2010
Signs and symptoms Number (n)
Present time (d)
Proportion (%)
Median (M) Range
Exanthem hands and feet rash 24 1.2 1-3 66.7
herpangina 18 1.2 1-2 50
no rash 12 33.3
High fever >39 C 18 1.2 1-3 50
CNS weakness 36 1.5 1-4 100
vomiting 22 1.7 1-4 61.1
lethargic or drowsy 24 2.2 1-6 66.7
comatose 11 2.5 2-3.5 30.6
seizure 11 2.4 1.5-3.5 30.6
combative 11 2.0 1-4 30.6
rigid neck 6 1.9 1-4 16.7
pupil change 17 3.1 2-4 47.2
Respiratory system tachypnea 36 2.0 1-6 100
retractions 32 2.0 1-6 88.9
cyanosis 27 2.3 2-4 75
rales 31 2.2 2-6 86.1
bubble/bloody sputum 25 2.3 2-4 69.4
pulmonary edema or hemorrhage 36 2.5 2-6 100
Cardiovascular system pale face 29 2.2 1-4 80.6
tachycardia >180/min 19 2.4 1.5-5 52.8
mottled skin 9 2.6 2-4 25
cool extremities 33 2.3 1-4 91.7
delayed capillary relling time (CRT) 22 2.0 1-4 61.1
hypotension 11 2.0 1-4 30.6
hypertension 13 2.9 1-4 36.1
Gastrointestinal system distended 13 3.4 2~6 36.1
bloody stool/bleeding 6 4 2-6 16.7
Liver elevated ALT 3 4 3-6 8.3
Kidney elevated Cr or BUN 3 3.9 3-6 8.3
anuria 2 3 3-6 5.6
DIC abnormal* 7 3.5 2-6 19.4
Blood glucose >5.6 mmol/L 33 15.6 6-36 91.7
Electrolyte hypokalemia 7 3.5 - 19.4
hyponatrimia 8 4 - 22.2
Table 1. The main signs and symptoms in the 36 children with severe EV71 infection
*: platelet count <10010
9
/L, prothrombin time more than three seconds or APTT time more than 45 seconds.
Figure 1. MR images of the brain and spinal cord in patients with EV71 encephalitis.
Outcome
Seven of the 36 patients died, giving a mortality rate of
19.4%. They suffered from encephalitis complicated with
NPE and died within the rst 24 hours after admission to
the PICU. According to diagnostic criteria for irreversible
organ failure as the direct cause of death, NPE in 4 of the 7
patients was the most dominating cause of death, followed
by circulatory failure (2 patients) and brain edema (1
patient). The majority of the 36 patients were discharged
home without signicant short-term sequelae.
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112 World J Emerg Med, Vol 1 No.2, 2010 Zhang et al
DISCUSSION
EV71 as a tiny RNA virus was rst isolated from stool
specimen of patients with disease of the central nervous
system in 1969 in California, USA. Epidemiological
studies then conrmed that EV71 is the main pathogen of
HFMD in children. Many countries and regions including
the United States , Bulgaria, Hungary, Australia, Sweden,
Japan, Malaysia, Singapore as well as Taiwan and Hong
Kong of China reported the EV71 epidemic.
[4,5]
EV71
can cause serious neurological complications such as
meningitis, brain stem encephalitis, polio-like paralysis,
and susceptibility to neurogenic pulmonary edema or
pulmonary hemorrhage. A distinct pattern of EV71
infection characterized by fever, exanthem, NPE, and
involvement of the central nervous system affects infants
and young children. Such patients may die in a few hours
to several days after infection. These complications
frequently occur in children under 3 years of age, and
infants under 1 year of age. During the 1998 EV71
epidemic in Taiwan of China, almost all the patients with
cardiopulmonary failure died. This outcome might be due
to the lack of experience in managing such patients or
delayed parental or medical recognition of how critical
the patients were at that time.
[5-9]
In our study, the 36
patients were similar to those reported previously that all
the patients were less than 3 years old with the exception
of one 4-year-old patient.
In NPE not complicated with any diseases of the
heart, lung and kidney, a sudden increased intracranial
pressure due to injury of the central nervous system
results in pulmonary edema,known as central pulmonary
edema.
[1,5,6]
The mechanisms of NPE have to do with vocal
cord paralysis, which causes negative intrapulmonary
pressure for the occurrence of edema. Autopsy and
pathological studies in EV71 endemic regions have
also shown that EV71-induced pulmonary edema is
neurogenic.
[4,5]
In our patients, clinical manifestations
caused by viral myocarditis were questioned in the early
stage of EV71 infection outbreak. Some patients exhibited
increased CK-MB and ECG T-wave changes, but no
diseases of the heart, lung and kidney. X-ray examination
showed no appearance of cardiomegaly. EKG findings
showed normalization of pulmonary hypoxemia and SpO
2

values. Pulmonary edema or hemorrhage mainly occurred
on asymmetrical alteration. The patients who underwent
Doppler ultrasound examination of the heart showed
ejection fraction >60%. Autopsy didnt show obvious
evidence of myocarditis. The ndings indicat that sudden
changes in the lungs are not related to cardiac factors.
Why our patients developed right pulmonary effusion is
still not clear.
In our study, the features of NPE were acute
dyspneic breathing and acute hypoxemia. The ratio of
PaO
2
/FiO
2
was 135.2 on average, which is similar to
that of acute respiratory distress syndrome (ARDS).
The signs observed early were non-specific. Mildly to
moderately elevated heart rate, elevated blood pressure,
and mild short breath occurred in the early period.
X-ray examination showed normality or thickening of
interstitinal pattern. Thus it is difcult to diagnose NPE
in its early stage. In the phase of hemodynamic instability
(pale and cooler extremities), pink bubble sputum or
severe hypoxemia shown as chest infiltration or large
shadows is seen on X-ray. In the terminal phase with a
low chance of therapeutic success and a high mortality,
the severely ill patients may have a lot of bloody liquid
emerged or suctioned from the tracheal tube. Therefore,
this is a key observation of NPE for early detection and
early intervention.
There are a variety of methods for the treatment of
severe cardiovascular disorders due to EV71 infection.
Wang and colleagues
[11]
used milrinone in patients with
EV71 infection and pulmonary edema. They found
that milrinone can regulate and control the sympathetic
Figure 2. Chest X-ray examination for severe EV71 infection. A: 4 hours after dyspnea; B: 8 hours after dyspnea; C: 16 hours after dyspnea; D:
40 hours after dyspnea.
A B C D
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113 World J Emerg Med, Vol 1 No.2, 2010
nervous system and reduces the formation of IL-13,
thus significantly lowering the heart rate and reducing
the WBC count and platelet level. All our patients were
treated with vasoactive drugs including milrinone and
dopamine or both in combination. In some patients with a
low heart rate, adrenalin and dopamine were administered
to counteract it. Vasoactive drugs like milrinone should
be assessed for side-effects, and their administration if
necessary should be stopped in time.
There is no special treatment or cure for EV71
encephalitis accompanied with pulmonary edema.
According to our clinical experience, life-support
therapy i.e. support of organ functions is particularly
i mport ant . Tracheal i nt ubat i on and mechani cal
ventilation by selecting a relatively high PEEP can
prevent bloody spill-over from the tracheal tube. It is
necessary to control the high intracranial pressure, and
fluid administration is restricted for the patients with
stable circulation at a volume of 60-80 ml/kg per day,
while using a higher volume to counteract hemodynamic
shock due to capillary leakage. Although positive
liquid balance within 24 hours is likely to increase the
mortality rate,
[12]
9 patients in our study had a signicant
improvement after fluid resuscitation without worsening
of pulmonary edema. In patients without a low heart rate,
phosphodiesterase inhibitors such as milrinone should be
added. Intravenous administration of immunoglobulin
and methylprednisolone is recommended by some
researchers, but evidence is lacking at present. There are
different opinions on the use of corticosteroids in NPE.
Corticosteroids may reduce capillary leakage, alleviate the
edema of the lung and brain, and stablize hemodynamics.
In conclusion, our study provides clinical diagnostic
characteristics of EV71 infection and demonstrates that
vigorous life support therapy can improve the outcome
of patients with severe EV71 encephalitis complicated
with NPE in children.
Funding: None.
Ethical approval: Not needed.
Competing interest: No benefits in any form have been received
or will be received from a commercial party related directly or
indirectly to the subject of this article.
Contributors: Zhang YC proposed the study, analyzed the data
and wrote the rst drafts. All authors contributed to the design and
interpretation of the study and to further drafts.
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Received April 10, 2010
Accepted after revision July 20, 2010