Hand, foot and mouth disease is an acute infectious disease caused by an enterovirus.
I. Clinical stages
According to the pathogenesis and clinical manifestations, EV71 infection is divided into 5 phases.
Phase 1 (hand-foot-mouth rash phase).
The main manifestations are fever, rash (maculopapular rash, papule, small herpes) on the hands, feet, mouth and buttocks, which may be accompanied by cough, runny nose, loss of appetite and other symptoms. Some cases may present only with a rash or herpetic pharyngitis, and some cases may have no rash. The majority of cases in this stage are ordinary cases of HFMD, and the majority of cases are cured in this stage.
Phase 2 (neurological involvement phase).
Central nervous system damage may occur in a small number of EV71-infected cases, mostly within 1-5 days of illness, manifesting as poor mental health, drowsiness, easy startle, headache, vomiting, irritability, limb tremors, acute limb weakness, cervical ankylosis, and other signs and symptoms of meningitis, encephalitis, polio-like syndrome, and encephalomyelitis. Cerebrospinal fluid examination is aseptic meningitis changes. CT scan of the cerebrospinal cord may have no positive findings, and MRI examination may show abnormalities. Cases in this stage are heavy cases of HFMD and most cases can be cured.
Stage 3 (pre-cardiopulmonary failure).
It mostly occurs within 5 days of the disease. It is thought that it may be related to post-inflammatory vegetative dysfunction or sympathetic hyperfunction in the brainstem, and it is also thought that immune damage after EV71 infection is one of the pathogenic mechanisms. Cases in this phase show increased heart rate and respiration, cold sweats, skin pattern, chilled extremities, elevated blood pressure, elevated blood glucose, elevated peripheral blood white blood cells (WBC), and abnormal heart ejection fraction may be observed. Cases at this stage belong to the critical type of severe cases of HFMD. Timely detection of the above-mentioned manifestations and proper treatment are the keys to reduce the morbidity and mortality rate.
Stage 4 (cardiopulmonary failure stage).
The disease continues to progress and cardiopulmonary failure will occur, which may be related to neurogenic pulmonary edema and circulatory failure due to brainstem encephalitis. It occurs mostly within 5 days of the disease and is predominantly aged 0-3 years. Clinical manifestations include tachycardia (individual children are bradycardic), shortness of breath, cyanosis of the lips and mouth, coughing up pink frothy sputum or bloody fluid, and sustained blood pressure reduction or shock.
There are also cases with severe cerebral failure as the main manifestation, pulmonary edema is not obvious, frequent convulsions, severe consciousness impairment and central respiratory and circulatory failure. Cases in this stage belong to the critical type of severe cases of HFMD and have a high morbidity and mortality rate.
Phase 5 (recovery period).
Body temperature gradually returns to normal, dependence on vasoactive drugs gradually decreases, symptoms of neurological involvement and cardiopulmonary function gradually recover, and a small number of neurological sequelae can be left behind.
Early identification of severe cases
The key to the diagnosis and treatment of severe cases of EV71 infection lies in timely and accurate screening to confirm stage 2 and stage 3.
The following indicators suggest the possibility of developing into critical cases of severe disease.
1. Persistent hyperthermia.
Body temperature (axillary temperature) is greater than 39℃, and conventional antipyretic effect is not effective.
2. Neurological manifestations.
Mental depression, vomiting, easily startled, shaking limbs, weakness, unstable standing or sitting, etc., and in rare cases, hyperphagia.
3. Respiratory abnormalities.
Respiration is faster, slower, or irregularly rhythmic. If the respiratory rate in the quiet state exceeds 30-40 breaths/min (according to age), neurogenic pulmonary edema should be alerted.
4. Circulatory dysfunction.
Cold sweating, cold extremities, skin pattern, increased heart rate (>140-150 beats/min, by age), elevated blood pressure, and prolonged capillary refill time (>2 seconds).
5. Elevated peripheral blood WBC count.
Peripheral blood WBC over 15×109/L, except other infectious factors.
6.Elevated blood glucose.
Presence of stress hyperglycemia with blood glucose >8.3 mmol/L.
Early cerebrospinal fluid examination should be performed in cases with suspected neurological involvement. the key to screening severe cases of EV71 infection is to closely observe the mental status of the child, the presence of limb tremors, easy startle, skin temperature, as well as respiration, heart rate and blood pressure, and to record them in a timely manner.
III. Treatment points
Serious cases of EV71 infection develop from stage 2 to stage 3 mostly within 1 day, occasionally 2 days or more. The progression from stage 3 to stage 4 is sometimes only a few hours. Therefore, appropriate treatment measures should be taken according to the different pathophysiological processes in each clinical stage.
Stage 1: No hospitalization is required and symptomatic treatment is the mainstay. Outpatient physicians should inform the parents of the child to observe carefully and to seek immediate medical attention in case of early manifestations of severe EV71 infection.
Phase 2: Use dehydrating diuretics such as mannitol to reduce intracranial hypertension; control fluid intake appropriately; apply gammaglobulin as appropriate for cases with persistent high fever, spinal cord involvement or rapid disease progression. Closely observe the temperature, respiration, heart rate, blood pressure and changes in skin temperature of the extremities and other high-risk factors that may develop into the critical type, especially in cases within 3 years of age and within 5 days of the course of the disease.
Stage 3: Should be admitted to ICU for treatment. Based on stage 2 treatment, block sympathetic excitability and apply vasoactive drugs such as milrinone and phentolamine in a timely manner, along with oxygen therapy and respiratory support. Apply gammaglobulin and glucocorticoids as appropriate, and prophylactic application of antibacterial drugs is not recommended.
Stage 4: Based on the treatment in stage 3, early application of ventilator with positive pressure ventilation or high frequency ventilation. In cases of pulmonary edema and pulmonary hemorrhage, positive end-expiratory pressure (PEEP) should be increased appropriately; frequent aspiration is not recommended. Dopamine, dobutamine, epinephrine and norepinephrine can be applied in patients with hypotensive shock. In cases of severe cardiopulmonary failure, extracorporeal membrane oxygenation therapy may be considered.
Phase 5: Give supportive therapy to promote the recovery of organ functions; give rehabilitation therapy to those with limb dysfunction; individual cases need long-term mechanical ventilation therapy to maintain life.
IV. Treatment measures
1.General treatment.
Pay attention to isolation to avoid cross-infection; light diet, good oral and skin care; medication and physical cooling to reduce fever; keep the child quiet; use diazepam, midazolam, phenobarbital and other anticonvulsants in cases of convulsions; administer oxygen and keep the airway unobstructed; pay attention to nutritional support and maintain water and electrolyte balance.
2. Fluid therapy.
In severe cases of EV71 infection, cerebral edema, pulmonary edema and cardiac failure can occur, so fluid intake should be controlled appropriately.
Restrict fluid intake while lowering cranial pressure by dehydration. Give the physiological requirement of 60-80 ml/(kg・d) (dehydrating agent is not counted), and it is recommended to give evenly, i.e. 2.5-3.3 ml/(kg・h). Pay attention to maintaining stable blood pressure.
Phase 4: In shock cases, 10-20 ml/kg of saline is given for fluid resuscitation while vasoactive drugs are applied, which is administered within 30 minutes, after which fluid can be rehydrated as appropriate to avoid massive volume expansion in the short term. Those who still cannot be corrected are given colloidal fluid infusion.
Medical institutions with conditions can use central venous pressure (CVP), invasive arterial blood pressure (ABP), pulse index continuous cardiac output monitoring (PICCO) to guide rehydration.
3. Application of dehydrating drugs.
Dehydrating drugs should be used under close monitoring. In patients with encephalitis and pulmonary edema without hypotension and circulatory disorders, fluid management is based on dehydrating agents and fluid restriction; if the patient develops shock and circulatory failure, dehydrating drugs should be used under the premise of correcting shock and replenishing circulating blood volume. Commonly used dehydration drugs include.
(1) Hypertonic dehydration agents.
a, 20% mannitol 0.5-1.0 g/(kg・time), q4-8h, 20-30min rapid intravenous injection, intravenous injection 10min can play a dehydrating effect, the effect can be maintained for 3-6h. In severe intracranial hypertension or brain herniation, the dose can be increased to 1.5-2 g/(kg・time), 2-4h once.
b. 10% glycerol fructose 0.5-1.0 g/(kg・time), q4-8h, rapid intravenous drip, diuretic effect starts 10-30min after injection, the strongest effect at 30min, the effect can be maintained for 24h. critical cases can use the above two drugs alternately, 3-4h use once.
(2) Diuretics.
For those with cardiac dysfunction, tachypnea 1-2 mg/kg can be injected first, and then the use of dehydrating drugs and other rescue measures (such as tracheal intubation with ventilator) can be determined after evaluation.
(3) Human albumin.
Human albumin reduces cerebral edema by increasing blood colloid osmotic pressure, and has a long half-life and long duration of action. Usage: 0.4 g/(Kg・time), often used in combination with diuretics.
V. Intravenous gammaglobulin (IVIG) application.
The application of IVIG in the treatment of viral infections is mainly for severe sepsis. From the pathogenesis of severe cases of EV71 infection, there is evidence to support that damage to the hypothalamus and/or medulla oblongata leads to sympathetic nervous system excitation, neurogenic pulmonary edema and cardiac damage, but it is not clear whether EV71 infection can lead to severe sepsis, and there is a lack of sufficient evidence-based medical evidence for the exact efficacy of IVIG in treating severe cases of EV71 infection. Based on literature reports and the experience of most clinical experts, IVIG is not recommended for routine use in phase 2, and may be considered in cases with severe toxic symptoms such as encephalomyelitis and hyperthermia. Phase 3 application of IVIG may play a certain role in blocking the disease. Suggested indications for application are: mental depression, frequent limb tremors; acute limb paralysis; respiratory rate exceeding 30-40 breaths/min (by age) in the quiet state; cold sweats, cold extremities, skin pattern, and increased heart rate >140-150 breaths/min (by age). It can be applied at 1.0 g/(kg・d) (2 consecutive days of application). The efficacy of IVIG in phase 4 is limited.
At present, domestic enterprises have produced specific EV71 immunoglobulin and IVIG containing EV71 neutralizing antibodies, but they have not been applied to clinical use.
Sixth, glucocorticoid application.
Glucocorticoids help to inhibit inflammatory response, reduce microvascular permeability, stabilize cell membranes and restore sodium pump function, and prevent or attenuate lipid peroxidation caused by free radicals. Most experts believe that glucocorticoids can help reduce brain edema and pulmonary edema caused by EV71 infection, but there is a lack of sufficient evidence-based medical evidence to support this.
The use of glucocorticoids is generally not advocated in stage 2. Stage 3 and 4 may be treated with glucocorticoids as appropriate. Methylprednisolone 1-2 mg/(kg・d), hydrocortisone 3-5 mg/(kg・d) and dexamethasone 0.2-0.5 mg/(kg・d) can be used. Discontinue as soon as possible after the disease is stabilized. Whether to apply high-dose glucocorticoid shock therapy is still controversial.
Antiviral drug application.
There are no effective anti-EV71 drugs. Ribavirin in vitro tests have confirmed the inhibition of EV71 replication and partial inactivation of the virus, can be considered for use, the use of 10-15 mg/(kg・d), divided into two intravenous drips, the course of treatment 3-5 days.
Eight, mechanical ventilation application.
1, the timing of mechanical ventilation.
Early tracheal intubation with mechanical ventilation, especially PEEP, is crucial to reduce pulmonary exudation, stop the development of pulmonary edema and pulmonary hemorrhage, improve ventilation and increase oxygen saturation.
The indications for mechanical ventilation are.
(1) shortness of breath, slowing down or change in rhythm.
(2) Pale red or bloody airway secretions.
(3) Wet sounds in the lungs over a short period of time.
(4) Chest x-ray suggestive of exudative lung lesions.
(5) Significant decrease in pulse volume oxygen saturation (SpO2) or arterial partial pressure of oxygen (PaO2).
(6) Frequent convulsions with deep coma.
(7) Pallor and cyanosis; decreased blood pressure.
2. Mechanical ventilation mode.
Pressure-controlled ventilation is commonly used, but other modes are also available. High frequency oscillatory ventilation can be used for those with air leak or intractable hypoxemia.
Nine, extracorporeal membrane oxygenation application.
Although extracorporeal membrane oxygenation has successfully treated many patients with cardiopulmonary failure, there is little experience in treating severe cases of EV71 infection.
ECMO can be considered when EV71 infection is not improved by mechanical ventilation, vasoactive drugs and fluid therapy, while extracorporeal membrane oxygenation should not be applied to patients with brain failure.