Clinical characteristics and treatment of severe encephalitis associated with neurogenic pulmonary edema caused by enterovirus 71 in China

Abstract

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 fluid 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.

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, pulmonary edema or pulmonary 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 medical teams were responsible for the 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 refilling 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 refilling 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 FiO₂ was set at 0.6-1.0, positive end expiratory pressure (PEEP) 8-15 cmH₂O, peak inspiratory pressure (PIP) 15-20 cmH₂O (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 milrinone was administered at a dose of 0.3-1 μg/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.

Table 1.

The main signs and symptoms in the 36 children with severe EV71 infection

Laboratory finding

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 (12-800×10⁶/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 finding

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).

Figure 1.

MR images of the brain and spinal cord in patients with EV71 encephalitis.

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 opacification of the right lung, which rapidly progressed to bilateral large shadows (Figure 2).

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.

Encountered problems and therapeutic interventions

Respiratory support

The mean PaO₂/FiO₂ 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, TcSO₂, showed SpO₂ values higher than 90%. Ventilation settings were variable. Appropriate PEEP was 6 to 10 cmH₂O in 15 patients (42.9%), 11 to 15 cmH₂O in 13 (36.1%), and >15 cmH₂O 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 μg/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.

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 first 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 significant short-term sequelae.

DISCUSSION

EV71 as a tiny RNA virus was first isolated from stool specimen of patients with disease of the central nervous system in 1969 in California, USA. Epidemiological studies then confirmed 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 SpO₂ 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 didn’t show obvious evidence of myocarditis. The findings 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 PaO₂/FiO₂ 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 difficult 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 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 important. Tracheal intubation and mechanical 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 significant 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.