Hand, foot, and mouth disease (HFMD) is a common infectious disease in childhood caused by an enterovirus (EV), and which is principally seen in children under 5 years of age. To promote diagnostic awareness and effective treatments, to further standardize and strengthen the clinical management and to reduce the mortality of HFMD, the guidelines for diagnosis and treatment have been developed.
National Health Commission of China assembled an expert committee for a revision of the guidelines. The committee included 33 members who are specialized in diagnosis and treatment of HFMD.
Early recognition of severe cases is utmost important in diagnosis and treatment of patients with HFMD. The key to diagnosis and treatment of severe cases lies in the timely and accurate recognition of stages 2 and 3 of HFMD, in order to stop progression to stage 4. Clinicians should particularly pay attention to those EV-A71 cases in children aged less than 3 years, and those with disease duration less than 3 days. The following indicators should alert the clinician of possible deterioration and impending critical disease: (1) persistent hyperthermia; (2) involvement of nervous system; (3) worsening respiratory rate and rhythm; (4) circulatory dysfunction; (5) elevated peripheral WBC count; (6) elevated blood glucose and (7) elevated blood lactic acid. For treatment, most mild cases can be treated as outpatients. Patients should be isolated to avoid cross-infection. Intense treatment modalities should be given for those severe cases.
The guidelines can provide systematic guidance on the diagnosis and management of HFMD.
Hand, foot, and mouth disease (HFMD) is a common infectious disease in childhood caused by an enterovirus (EV), and which is principally seen in children under 5 years of age; HFMD is encountered across the globe. It is prevalent in all parts of China, where the disease is perennial with an incidence rate varying between 37/100,000 and 205/100,000 while mortality in recent years has ranged between 6.5/100,000 and 51/100,000. With a view to promoting diagnostic awareness and effective treatments, and to further standardize and improve HFMD clinical management and reduce mortality, new guidelines have been developed. The current guidelines are based upon and incorporate the most recent advances in HFMD diagnosis and management.
HFMD is caused by an enterovirus infection. Enteroviruses belong to enterovirus genus of the picornavirus (“small RNA virus”) family. The main serotypes responsible for the disease include enteroviruses in the coxsackievirus (CV) group A, type 4–7, 9, 10, and 16 as well as group B types 1–3, and 5, some echovirus serotypes, and enterovirus A71 (EV-A71). The most commonly encountered are CV-A16 and EV-A71, with the latter accounting for the majority of severe and fatal cases of HFMD. CV-A6 and CV-A10 case burden has increased significantly in some areas in recent years. There is no protective cross immunity between the different enteroviruses types [1,2,3,4,5,6].
Children are the main source of infection. Infection may be overt, subclinical or latent. The latent infection rate of HFMD is high. Enterovirus can survive in hydrothermal conditions. The virus is transmitted via the feces, throat secretions, saliva and potentially other bodily fluids of infected individuals .
Route of transmission
Close contact is usually required for transmission. The infection can be contracted by contact with virus-contaminated hands, towels, handkerchiefs, dental cleaning paraphernalia, toys, tableware, bedding and underwear amongst others. It can also be transmitted via contaminated respiratory droplets, water, and food .
Infants and children are generally considered the most susceptible, especially the children less than 5 years of age .
Pathogenesis and pathological changes
At the initiation of infection, an enterovirus binds to virus receptor on the surface of pharyngeal and intestinal epithelial cells. The main virus receptors of EV-A71 and CV-A16 include human scavenger receptor class B2 (SCARB2) and P-selectin glycoprotein ligand-1 (PSGL-1). The virus is absorbed into the cell via endocytosis after receptor binding. The viral genome is released, replicated, transcribed and translated to produce viral proteins. The newly formed viral genome and proteins are assembled into virus particles in the cytoplasm [10, 11]. Enterovirus replicates mainly in the lymph nodes of the tonsils, pharynx and intestine. It is then released into the bloodstream and spread to skin, mucous membranes, the nervous system, the respiratory tract, heart, liver, pancreas, adrenal gland among other sites, etc. An inflammatory response in infected organs may cause clinical symptoms and organ-related complications. In rare cases, it may lead to organ system failure, e.g., cardiopulmonary failure occasioned by vasomotor dysfunction following nervous system injury [12, 13], or massive release of inflammatory mediators such as containing interleukin (IL)-10, IL-13 and interferon (IFN)-γ. Neurogenic pulmonary edema and circulatory failure are the main causes of death in children with HFMD. The precise pathophysiological mechanisms at play in such cases are complex and multifactorial [14, 15].
Autopsy with histopathological examination may display evidence of lymphocyte degeneration and necrosis, especially in gastrointestinal and mesenteric lymph nodes. The main pathological features observed in nervous tissue include various degree of inflammatory response with a neurotropic pattern showing evidence of neuronal apoptosis, nodular hyperplasia of monocytes and microglia, vascular cuffing, cerebral edema and cerebellar tonsil hernia. The main observation in lung includes pulmonary edema, congestion, and hemorrhage with inflammatory cellular infiltration. Myocardial rupture and edema, necrotizing enteritis, and the severe degeneration and necrosis of kidney, adrenal, spleen and liver can also occur [16,17,18,19,20,21].
Incubation period is typically 2–10 days, with an average of 3–5 days .
Clinical symptoms and signs
Clinical staging is as below:
Stage 1: Eruption
The main symptoms include fever and eruption on the hands, feet, mouth, and buttocks. The oral rash is an enanthem and may be isolated, constituting herpangina. Symptoms may include cough, rhinorrhea, anorexia, and non-specific systemic symptoms. In some cases, the infection may manifest only with a rash or as herpangina. A rash is not inevitable and is not seen in all cases.
The typical rash is maculo-papular and may be vesicular. An inflammatory cuff may surround the vesicles, which may contain little fluid. The rash may be non-pruritic and painless. Resolution, which occurs without scab formation, does not lead to scarring. Atypical rash appearance may occur, being generally less severe, with smaller lesions that are somewhat indurated. Occasionally petechiae and ecchymoses may be evident. Some types of enterovirus, such as CV-A6 and CV-A10, may cause severe skin lesions, with bullous change accompanied by pain and pruritis with extension beyond the hand, foot, and mouth .
This stage represents the commonest clinical picture seen in HMFD. Most such cases resolve of their own accord at this stage.
Stage 2: Nervous system involvement
Central nervous system (CNS) injury and complications may occur. This is typically seen 1–5 days after infection; symptoms include lethargy, sucking weakness, ease of being startled, headache, vomiting, irritability, limb tremors, myopathy, and nuchal rigidity, etc. Some cases may display signs of more extensive or severe neurological injury. The above clinical picture represents the classic image of severe HFMD, although most cases will resolve.
Stage 3: Early cardiopulmonary failure
This usually occurs within the first 5 days of the illness with increased heart and respiratory rates, cold sweats, cold extremities, mottled skin, and increased blood pressure. This stage represents the critical stage of HFMD. The key to reduce mortality is recognition with early diagnosis and appropriate management.
Stage 4: Cardiopulmonary failure
HFMD may progress rapidly from stage 3 to 4. Symptoms include tachycardia (bradycardia is also occasionally seen), tachypnea, cyanosis, cough with pink foamy or even bloody sputum, hypotension and ultimately cardiovascular collapse. Some cases may exhibit severe encephalopathy; convulsions and coma may supervene. This stage constitutes critical HFMD and is accompanied by high mortality.
Stage 5: Recovery
Fever gradually subsides and dependence on cardiovascular support recedes. CNS and cardiopulmonary function gradually recover, although neurological sequelae may remain in some cases. Piptonychia may follow some cases of HFMD (especially those due to CV-A6 and CV-A10), typically 2–4 weeks after infection, with new nails emerging 1–2 months thereafter.
Most infected children enjoy a favorable prognosis and recovery without sequelae, generally within 1 week. With rapid progression and severe disease, a small minority of children may suffer CNS injury; such children may present with signs and symptoms of brainstem encephalitis, encephalomyelitis, cerebrospinal meningitis, or other severe neurological disorder. Mortality rate is high in such children, typically from circulatory failure or neurogenic pulmonary edema .
Diagnostic tests 
Routine blood tests and C-reactive protein (CRP)
The white blood cell count is normal in most cases. In some cases, a leukocytosis with neutrophilia may be observed. CRP elevation may be seen.
Blood biochemical examination
Mild elevations of alanine aminotransferase (ALT), aspartate aminotransferase (AST), and creatine kinase isoenzyme MB (CK-MB) may occur in some cases. In severe cases, elevations in troponin, blood glucose and lactic acid are seen.
Cerebrospinal fluid (CSF) analysis
Cerebrospinal fluid changes will accompany CNS involvement and injury. CSF pressure is typically increased with an elevated WBC count (mainly monocytic but multinucleate in early stages). Normal or slightly increased protein, normal glucose and chloride are seen which is consistent with viral meningitis and/or encephalitis.
Blood gas analysis
Arterial oxygen partial pressure decreases when the respiratory system is involved and in severe cases, decreased blood oxygen saturation and increased partial carbon dioxide pressure with acidosis are seen.
Virologic and serologic examination
Specific enterovirus nucleic acid detection may be conducted on clinical specimens: throat swab, stool, anal swab, and blood. Enterovirus may also be isolated and cultured. IgM-specific antibody should be positive during the acute phase; during the recovery phase neutralizing antibody directed against CV-A16, EV-A71 and other HFMD-relevant enteroviruses should exhibit at least a fourfold magnitude increase in titre compared with the titer obtained during the acute stage.
No obvious abnormality in lungs of children is likely to be seen in mild cases. Severe and critical cases complicated by neurogenic pulmonary edema are likely to show decreased radiolucency with ground-glass opacities in both lung fields; patchy change may show limited or extensive distribution. Pulmonary lesions may progress rapidly.
Cerebral CT and/or MRI
Cerebral CT imaging may be used to identify intracranial hemorrhage, cerebral hernia, and intracranial lesions. Abnormal MRI changes may be seen in patients with CNS involvement. Patients with brainstem encephalitis can be identified by spotty or patchy T1 and T2 signals in the pons, medulla oblongata and midbrain. Patients with acute flaccid paresis show spotty symmetric or asymmetric T1 and T2 signals in the anterior horn of the involved segments of the spinal cord.
Generally, this will show sinus tachycardia or bradycardia, Q–T interval prolongation, and ST–T segment change.
Those patients with nervous system involvement generally show diffuse slow waves, while some may show spikes, or sharp slow waves.
Severely ill patients may demonstrate myocardial systolic and/or diastolic dysfunction, regional wall motion abnormalities, and decreased ejection fraction amongst other abnormalities.
Diagnosis can be made based on current epidemiology, clinical manifestation and virological investigation.
Clinically diagnosed cases
These are common in preschoolers, especially in infants. During epidemics, increased incidence may be detected in local nurseries and the children’s contacts. A history of either direct or indirect contact with infected persons prior to illness onset may be ascertained.
This will largely conform to the clinical descriptions provided above, in the clinical staging section. In rare cases, the rash will have an atypical appearance, while some cases will present with either encephalitis or meningitis. In these atypical cases, the diagnosis will need to be confirmed by virological or serological means.
On the basis of clinical diagnosis, the infection can be confirmed if it meets one of the following criteria: (1) detection of specific enterovirus nucleic acid sequences (CV-A16, EV-A71, etc). (2) Isolation and identification of enterovirus such as CV-A16, EV-A71 or other type that could cause HFMD; (3) presence of IgM antibody against disease-related virus during the acute stage; (4) presence of neutralizing antibody titer against the relevant enterovirus in the recovery phase is at least four times higher than that in the acute stage.
Other childhood exanthemata
HFMD should be differentiated from other exanthemata seen in childhood. This may include papular urticaria, sand rash, chicken pox, atypical measles, exanthema subitum, herpes zoster, rubella and Kawasaki disease. Bullous rashes caused by CV-A6 or CV-A10 should be differentiated from chickenpox. HFMD should be differentiated from herpes simplex when perioral lesions are present. The differential diagnosis is guided by investigation, including virology and serology .
Encephalitis or meningitis caused by other viruses
The clinical manifestation of encephalitis or meningitis caused by viruses such as herpes simplex virus, cytomegalovirus (CMV) and Epstein–Barr virus (EBV) is likely to be similar to those seen in severe cases of HFMD with CNS involvement. For patients with atypical rash, diagnosis can be assisted by the history and early virological investigation for the presence of enterovirus, especially EV-A71. Diagnosis should be made based on the results of virological or serological investigations.
When the severe case of HFMD is complicated with acute flaccid paralysis, it needs to be differentiated from poliomyelitis. The latter mainly manifested as bimodal fever and flaccid paralysis occurs in the process of defervescence at the second week or before. The condition gets the worst after fever and there is no rash .
The neurogenic pulmonary edema which may accompany severe HFMD should be differentiated from pneumonia. Children with pneumonia generally do not exhibit a rash. Chest radiography examination may show consolidation, atelectasis, and pleural effusion, with gradual evolution of the image .
The key to diagnosis and treatment of severe cases lies in the timely and accurate recognition of stages 2 and 3 of HFMD, in order to combat progression to stage 4. Clinicians should be especially concerned by EV-A71 cases in children aged less than 3 years, and cases of less than 3 days duration.
The following indicators should alert the clinician of possible deterioration and impending critical disease: (1) persistent hyperthermia: fever greater than 39 °C with poor response to antipyretics; (2) involvement of nervous system: symptoms may include headache, nystagmus or upward gaze diversion, vomiting, lethargy, ease of being startled, limb tremor, sucking weakness, and instability of posture, e.g., standing or sitting, amongst others; (3) abnormal respiratory rate and rhythm: rapid, slow, or irregular breath. The respiratory rate may exceed 30–40/min in the resting state; (4) circulatory dysfunction: increased heart rate (> 160 times/minute), cold sweats, cold extremities, mottled skin, elevated blood pressure, prolonged capillary filling time (> 2 seconds); (5) elevated peripheral WBC count: peripheral WBC count may exceed 15 × 109/L in the absence of any other infectious etiology; (6) elevated blood glucose: stress hyperglycemia may be evident, with blood glucose > 8.3 mmol/L; (7) elevated blood lactic acid: blood lactic acid is generally ≥ 2.0 mmol/L when circulatory dysfunction exists. Increased levels are of worse prognostic significance.
Most HFMD cases can be treated as outpatients. Patients should be isolated to avoid cross-infection. Attention to nutrition as well as oral and skin care is recommended.
Fever should be actively managed. Physical cooling, e.g., warm water sponge baths, fever cooling patches, fanning and antipyretics are appropriate for children whose temperature exceeds 38.5 °C. Commonly used drugs include: ibuprofen 5–10 mg/kg, acetaminophen 10–15 mg/kg. The minimum interval between two doses is 6 hours.
Keep the children in a quiet and restful state. Seizures should be controlled immediately. Commonly used drugs are as follows: if no venous access is available, the first choice is intramuscular midazolam, 0.1–0.3 mg/kg. The maximum single dose is 5 mg in patients > 40 kg while administration of 10 mg is recommended for those with body weight > 40 kg. Another option is the slow intravenous injection of diazepam at 0.3–0.5 mg/kg with the maximum single dose being 10 mg; the injection rate should be 1–2 mg/minute. One should monitor vital signs closely and prepare for respiratory support. Chloral hydrate may also be used, and maintain a patent airway and administer oxygen if necessary. Pay attention to nutritional support to maintain fluid and electrolyte balance.
There is no specific anti-enterovirus drug available. Studies have shown that interferon alpha spray or atomization treatment, and ribavirin administrated intravenously may have some effect in the management of HFMD in the early stage. Close attention should be paid to ribavirin’s adverse reactions including reproductive toxicity. Acyclovir, ganciclovir, and monosodium phosphate vidarabine have no place in the management of HFMD.
Cerebral edema, pulmonary edema and heart failure may appear in severe cases of HFMD, and fluid intake should be rigorously controlled. Physiological fluid requirement is 60–80 mL/kg/day in the absence of deliberate diuresis. Fluid should be infused at a constant rate of 2.5–3.3 mL/kg/hour, in the meantime to maintain perfusion. In cases with circulatory shock, resuscitate with normal saline 5–10 mL/kg/time over 15–30 minutes while using vasoactive agents; following initial administration, fluid therapy should be carefully managed to avoid overload. Colloidal fluid should be used if circulatory shock is not adequately controlled; examples include albumin or plasma.
Healthcare institutions may monitor indicators such as central venous pressure (CVP) and invasive arterial blood pressure (ABP) to guide fluid therapy.
Decreased intracranial pressure
20% mannitol is commonly used in 0.25–1.0 g/kg, q4h–q8h, as a rapid intravenous injection over 20–30 minutes to reduce increased intracranial pressure. The frequency may be increased to q2h–q4h in the case of severe intracranial hypertension or cerebral herniation.
Treatment in combination with hypertonic saline (3% sodium chloride) may be considered for patients with severe intracranial hypertension or hyponatremia. Diuretics may be used in patients with cardiac overload, e.g., intravenous furosemide at 1–2 mg/kg.
The hemodynamic change typically observed in stage 3 is that of high dynamic and high resistance, and mostly vasodilators should be considered in this period. Milrinone can be used with a loading dosage of 50–75 μg/kg, and the infusion should be completed within 15 minutes . The maintenance dose starts from 0.25 μg/kg/min, and may be gradually adjusted up to 1 μg/kg/min. The total duration of infusion period should in general not exceed 72 hours. Blood pressure should be controlled to a level below that of constituting severe hypertension at the corresponding age (specific blood pressure values are shown in Table 1). Phentolamine (1–20 μg/kg/min) or sodium nitroprusside (0.5–5 μg/kg/min) can be initiated at a low dose and gradually increased to an appropriate dose level. Vital signs including blood pressure should be closely monitored during this period.
Hypotension may manifest in stage 4, in which case positive inotropic agents and vasopressors, such as dopamine at 5–20 μg/kg/min, norepinephrine at 0.05–2 μg/kg/min, adrenaline at 0.05–2 μg/kg/minute and dobutamine at 2.5–20 μg/kg/min may be used. The drug should be initiated at a low dose and gradually increased to the dose which supports adequate pressure and perfusion.
If the above drugs prove ineffective, vasopressin or levosimendan can be considered. Vasopressin, at 20 μg/kg, q4h, can be slowly administered intravenously; the duration of drug use depends on the hemodynamic improvement. Levosimendan’s loading dose is at 6–12 μg/kg intravenously and the maintenance dose is 0.1 μg/kg/min.
Intravenous immunoglobulin (IVIG)
Intravenous immunoglobulin is not recommended for routine use in stage 2 disease. Patients with encephalomyelitis and persistent high fever, and critical cases, may be considered for IVIG treatment. Dosage is at 1.0 g/kg/day for 2 days .
Patients with encephalomyelitis and persistent high fever, as well as critical cases, may be considered for treatment with corticosteroids: methylprednisolone at 1–2 mg/kg/day, or hydrocortisone at 3–5 mg/kg/day, or dexamethasone 0.2–0.5 mg/kg/day may be used for 3–5 days .
Indications: when the following clinical manifestations occur, tracheal intubation and mechanical ventilation may be initiated: (1) shortness of breath, deceleration or rhythm changes; (2) reddish or bloody airway secretion; (3) rapid development of moist rales; (4) obvious pulmonary exudative lesions on chest X-ray examination; (5) decrease in SpO2 or PaO2; (6) pallor, cyanosis, low skin temperature, mottled skin, decreased blood pressure; (7) frequent seizures or coma.
Mechanical ventilation mode: pressure control ventilation is commonly selected but other modes may also be selected. High frequency ventilation (HFV) could be considered in patients with inadequate aeration or refractory hypoxemia.
Target of mechanical ventilation parameter adjustment: maintain PaO2 above 60–80 mmHg, SaO2 above 92–97%. Control pulmonary edema and pulmonary hemorrhage.
For patients with pulmonary edema or pulmonary hemorrhage or central respiratory failure, parameters should be adjusted according to the initial parameters table for mechanical ventilation (Table 2). If pulmonary hemorrhage is not controlled or blood oxygenation is not improved, PEEP can be increased to 1–2 cmH2O each time, but generally not to exceed 20 cmH2O. PIP should be adjusted at the same time to ensure normal oxygenation. Ventilator parameters should be gradually reduced once pulmonary edema and hemorrhage have been controlled.
Mechanical ventilation management: (1) analgesia and sedation: sufficient sedation and analgesia should be administered before tracheal intubation. Drugs include midazolam (intravenous injection at 0.1–0.3 mg/kg/hour), fentanyl (intravenous injection at 1–2 μg/kg, injection time > 60 seconds, with intravenous maintenance pump injection l–4 μg/kg/hour); (2) to avoid frequent and prolonged suction during mechanical ventilation, which will reduce the airway pressure. Keep the airway open and prevent the endotracheal tube from being obstructed by blood clot.
Withdrawal indications: (1) spontaneous breathing returns to normal with a good cough reflex; (2) when oxygenation index (PaO2/FiO2) ≥ 200 mmHg and PEEP < 10 cmH2O, weaning assessment should be started; (3) improved blood gas analysis and improvement of pulmonary effusion and edema on chest X-ray; (4) improved level of consciousness; (5) stable circulation.
(1) Hemodialysis: continuous hemodialysis may be considered in critical cases, but there are no specific recommendations. Hemodialysis as an adjunctive treatment may help to reduce catecholamine storm and inflammation, assist fluid balance and replace kidney function. It is suitable for patients at stage 3 and 4 of HFMD; (2) extracorporeal life support: including extracorporeal membrane oxygenation (ECMO), extracorporeal left ventricular support (ECLVS), or ECMO + left ventricular decompression (LV vent). Extracorporeal life support is suitable for patients with severe heart failure who have failed routine treatment. ECMO + LV vent is suitable for critical cases with severe pulmonary edema and left heart failure. It is not recommended for children with severe encephalopathy.
Treatment during recovery phase
Rehabilitation and nursing care for patients in the recovery phase can promote the early recovery of organ function, especially of the nervous system.
Traditional Chinese medicine treatment
Based on the theory of traditional Chinese medicine (TCM), HFMD belongs to the category of “plague warm and clip wet”. The characteristics of HFMD transmutation have the law of “defensive energy nutrients and blood”, so it should be treated according to the disease progression stages.
Eruption stage: to damp the heat syndrome of spleen and lung.
(1) Symptoms: papules and vesicles appear on hand and foot, in mouth, on buttocks and on other parts, with or without fever, burn-out, salivation, sore throat, anorexia, constipation. For some severe cases, big blisters and piptonychia can be seen; (2) tongue picture, pulse condition and fingerprint: the tongue has a pink or red color, greasy fur, rapid pulse, red or purple fingerprint; (3) treatment: heat-clearing, detoxification, and clearing dampness and evil; (4) basic prescription: Ganlu Xiaodu Micropill; (5) common drugs: Radix Scutellariae, Herba Artemisiae, Capillariae, Herba Pogostemonis, Fructus Forsythiae, Flos Lonicerae, Talcum, Fructus Arctii, Rhizoma Imperatae, Peppermint and Rhizoma Belamcanda; (6) usage: one prescription per day, decoct with 100–150 mL water, 3–4 times orally. Enema prescription also could be taken with decoction of 50–100 mL at 1 enema/day; (7) change of prescription: if there is a continuous high fever, irritability, halitosis, thirsty, constipation, it is possible to add Gypsum Fibrosum, golden thread, herbataching on the above prescriptions; (8) processed TCM drugs: additional processed TCM drugs that have been clinically studied and reported, can be used for the effect of heat-clearing, detoxicating and dissipating dampness and rash.
Wind syndrome stage: heat shock in the liver.
(1) Symptoms: high fever, skittishness, muscle movement, infantile convulsions, or limb flaccidity, weakness, vomiting, somnolence, even confusion and coma; (2) tongue picture, pulse condition and fingerprint: dark red or deep red tongue, yellow or yellow greasy dry, stringy thin rapid pulse, fingerprint purple and stagnant; (3) treatment: cool blood for calming endogenous wind, clear away heat, dampness and toxic material; (4) basic prescription: antipyretic and antitoxic decoction with Cornus Antelopis and Uncariae Decoction; (5) commonly used drugs: antelope horn powder, gambir plant, gypsum, rhubarb root and rhizome, golden thread, tall gastrodia tuber, scorpion, stiff silkworm, Cortex Moutan Radicis, Redroot gromwell root and dried rehmannia root; (6) added or reduced TCM medicine: if a patient has a continuous high fever with loss of consciousness, it is necessary to add Angong Niuhuang Wan on the above prescriptions. If with constipation, add Zixue Powder; (7) usage: one prescription/day, decoct with 100–150 ml water, 3–4 times orally. Enema prescription also could be used, decoction with 50–100 ml at one enema/day; (8) processed TCM drugs: it is recommended to treat with processed Chinese herbal medicine with the effect of heat-clearing, detoxicating and extinguishing wind to arrest convulsion if it has been clinically studied and reported.
Dyspnea collapse stage: evil influence into the heart and lung syndrome, deficiency of vital energy and yang exhausted.
(1) Symptoms: high fever, dyspnea and tachypnea, coma, acrohypothermy, profuse perspiration, pale face, cyanosis of lips; (2) tongue picture, pulse condition and fingerprint: dyspnea, dark purple tongue, rapid pulse or sink and delayed pulse, dark purple fingerprint; (3) treatment: fixation, inducing resuscitation, and clear heat and detoxicate; (4) basic prescription: ginseng and Aconiti decoction, Sheng Mai powder and An Gong Niu Huang Wan; (5) common TCM drugs: ginseng, prepared common monkshood branched root, liriope root tuber, pulp of cornus, artificial bezoar, antelope horn powder, rhizoma coptis, curcuma aromatica, acorus gramineus soland, and curcuma aromatic; (6) usage: one prescription/day, decoct with 100–150 mL water, 3–4 times orally. Enema prescription also could be used with decoction of 50–100 mL at one enema/day; (7) processed TCM drugs: it is recommended that Chinese herbal medicine with effect of heat-clearing, nourishing Qi and warming Yang to solid off which must be clinically studied and reported.
Convalescence stage: Qi and Yin deficiency, collaterals obstruction.
(1) Symptoms: fatigue, anorexia, or with limb flaccidity, or with limb numbness; (2) tongue picture, pulse condition and fingerprint: pale tongue, thin and greasy fur, thready pulse, and light or purple fingerprints; (3) treatment: tonifying Qi, nourishing Yin, and invigorating the spleen; (4) basic prescription: Sheng Mai powder and Qiwei Baizhu powder; (5) common drugs: Codonopsis pilosula, Schisandra chinensis, liriope root tuber, rhizoma atractylodes, poriacocos, polygonatum odoratum, Agastache rugosus, costus root and the root of kudzu vine; (6) usage: one prescription a day orally; decoct with 100–150 mL water, 3–4 times orally; (7) processed TCM drugs: Chinese herbal medicines with tonifying Qi, nourishing Yin and freeing channels can be used for treatment if their efficacy have been clinically studied and reported; (8) non-drug treatment: point massage and others help functional recovery.
The prescription drugs should be used according to patients’ age, and only for treatment of HFMD, not for prevention.
Good personal hygiene habit is the key to prevent HFMD. Wash hands frequently, and prevent children from drinking unpurified water, and eating raw and cold food. Toys and other frequently contacted items should be cleaned and disinfected regularly. Keep children from contact with HFMD patients.
EV-A71 inactivated vaccine is available for children from 6 months to 5 years of age, to prevent HFMD caused by EV-A71. The basic immunization regimen is to administer two doses 1 month apart. Children are encouraged to complete vaccination before 12 months of age [47,48,49,50,51,52].
Hospital infection control
Healthcare institutions should be pro-active in the prevention and control of infection. Healthcare settings at all levels should rigorously identify and isolation of infected patients. There should be a special consulting room for suspected cases of HFMD. Whenever a hospital receives an HFMD case, standard preventive measure should be taken, by strictly following good hand hygiene and disinfection of the facility and related items. Effective disinfectants containing chlorine (bromine) should be selected. General disinfection with 75% ethanol or 5% lysol is ineffective against enterovirus.
Zhang SB, Liao H, Huang CH, Tan QY, Zhang WL, Huang Y, et al. Serum types of enterovirus and clinical characteristics of 237 children with hand, foot and mouth disease in Shenzhen. Chin J Contemp Pediatr. 2008;10:38–41 (in Chinese).
Song Y, Zhang Y, Ji T, Gu X, Yang Q, Zhu S, et al. Persistent circulation of Coxsackievirus A6 of genotype D3 in mainland of China between 2008 and 2015. Sci Rep. 2017;7:5491 (in Chinese).
Tan XJ, Huang XY, Zhu SL, Chen H, Yu QL, Wang HY, et al. The persistent circulation of enterovirus 71 in People’s Republic of China: causing emerging nationwide epidemics since 2008. PLoS One. 2011;6:e25662.
Zhou HT. Epidemiological and clinical characteristics of hand, foot and mouth disease in Guangdong Province during 2009–2013. South Med Univ. 2014.
Yang YP, Chen MM, Ju Y, Wang J, Huang J, Tan Y. Epidemiology and pathogen distribution of hand-foot-mouth disease in Guangxi, 2008–2014. Appl Prev Med. 2015;21:365–8.
Chen GP, Shi YL, Zhang J, Cao MH, Wu JB, Hu WF, et al. Analysis of the epidemiological characteristics of hand-foot-and-mouth disease in Anhui Province between 2008 and 2014. Mod Prev Med. 2016;43:588–90.
Bo YC, Song C, Wang JF, Li XW. Using an autologistic regression model to identify spatial risk factors and spatial risk patterns of hand, foot and mouth disease (HFMD) in Mainland China. BMC Public Health. 2014;14:1–13.
Zhang C. The study of epidemiology and influencing factors of hand, foot and mouth disease in Guangxi Province from, 2008 to 2015. Guangxi Med Univ J. 2016:1–69 (in Chinese).
Zhao J, Jiang F, Zhong L, Sun J, Ding J. Age patterns and transmission characteristics of hand, foot and mouth disease in China. BMC Infect Dis. 2016;16:691.
Yu P, Bao L, Xu L, Li F, Lv Q, Deng W, et al. Neurotropism in vitro and mouse models of severe and mild infection with clinical strains of enterovirus 71. Viruses. 2017;9:351.
Xing J, Liu D, Shen S, Su Z, Zhang L, Duan Y, et al. Pathologic studies of fatal encephalomyelitis in children caused by enterovirus 71. Am J Clin Pathol. 2016;146:95–106.
Wu J, Cheng YB, Li ZF, Li YF, Li YP, Xu HM, et al. Evaluation of adrenocortical function in children with severe and critical enterovirus 71 infection. Chin J Pediatr. 2012;50:249–54 (in Chinese).
Chen YC, Yu CK, Wang YF, Liu CC, Su IJ, Lei HY. A murine oral enterovirus 71 infection model with central nervous system involvement. J Gen Virol. 2004;85:69–77.
Solomon T, Lewthwaite P, Perera D, Cardosa MJ, McMinn P, Ooi MH. Virology, epidemiology, pathogenesis, and control of enterovirus 71. Lancet Infect Dis. 2010;10:778–90.
Yan JJ, Wang JR, Liu CC, Yang HB, Su IJ. An outbreak of enterovirus 71 infection in Taiwan 1998: a comprehensive pathological, virological, and molecular study on a case of fulminant encephalitis. J Clin Virol. 2000;17:13–22.
Hu J, Shi XH, Tang Y, Ge XH, Yu Y, Yang J, et al. Analysis of course of 94 cases of severe hand, foot and mouth disease complicated with viral meningitis encephalitis. Acta Univ Med Nanjing (Nat Sci). 2009;29:1616–8 (in Chinese).
Chen HI, Liao JF, Kuo L, Ho ST. Centrogenic pulmonary hemorrhagic edema induced by cerebral compression in rats. Mechanism of volume and pressure loading in the pulmonary circulation. Circ Res. 1980;47:366–73.
Maron MB, Holcomb PH, Dawson CA, Rickaby DA, Clough AV, Linehan JH. Edema development and recovery in neurogenic pulmonary edema. J Appl Physiol. 1994;77:1155–63.
Malik AB. Mechanisms of neurogenic pulmonary edema. Circ Res. 1985;57:1–18.
Wu JM, Wang JN, Tsai YC, Liu CC, Huang CC, Chen YJ, et al. Cardiopulmonary manifestations of fulminant enterovirus 71 infection. Pediatrics. 2002;109:E26.
Fu YC, Chi CS, Chiu YT, Hsu SL, Hwang B, Jan SL, et al. Cardiac complications of enterovirus rhombencephalitis. Arch Dis Child. 2004;89:368–73.
Clinical Experts Group of the Ministry of Health for Hand, Foot and Mouth Disease. Experts consensus on rescue and treatment of severe cases with enterovirus 71 (EV71) infection. Zhonghua Er Ke Za Zhi. 2011;49:675–8 (in Chinese).
Wang XW, Zhong TY, Tian Y. Analysis of myocardial zymogram in children with severe hand, foot and mouth disease. Med J Nat Defending Forces Southwest China. 2009;19:1001–2 (in Chinese).
National Health and Family Planning Commission of the People's Republic of China. Guideline for the diagnosis and treatment of hand, foot and mouth disease (2010 Edition). http://www.nhfpc.gov.cn/yzygj/s3593g/201306/6d935c0f43cd4a1fb46f8f71acf8e245.shtml. Accessed 15 Apr 2017.
Gmitterová K, Heinemann U, Krasnianski A, Gawinecka J, Zerr I. Cerebrospinal fluid markers in the differentiation of molecular subtypes of sporadic Creutzfeldt-Jakob disease. Eur J Neurol. 2016;23:1126–33.
Wu YD, Shang SQ, Chen ZM, Yang ZH. Analysis of the epidemic characteristics of the etiological agents in children with hand, foot and mouth disease and its clinical significance. Zhonghua Er Ke Za Zhi. 2010;48:535–9 (in Chinese).
Jin L, Huang XM. HFMD rash and the identification. Med Recapitulate. 2012;18:1680–3.
Wang J, Campbell IL, Zhang H. Systemic interferon-a regulates interferon-stimulated genes in the central nervous system. Mol Psychiatry. 2008;13:293–301.
Qiu J, Lu XL, Liu X, Zhang P, Zhao W, Liu P, et al. Derivation and validation of a mortality risk score for severe hand, foot and mouth disease in China. Sci Rep. 2017;7:3371.
Lu GP. Diagnosis and treatment of neurogenic pulmonary edema in children with severe hand, foot and mouth disease. Chin Pediatr Emerg Med. 2011;18:8–10 (in Chinese).
Mao YY, Yao JH, Cao LF, Wang QL, Chen LH, Si MQ. Analysis of the treatment response and prognosis of severe hand-foot-mouth disease. Chin J Infect Dis. 2009;27:35–8 (in Chinese).
Huang T, Li QF, Shen XL, Fu XQ, Cun JP. Analysis of the risk factors for severe hand-foot-and-mouth disease (HFMD) in Yunnan Province. Mod Prev Med. 2017;44:1115–9.
Sasaki O, Karaki T, Imanishi J. Protective effect of interferon on infections with hand, foot, and mouth disease virus in newborn mice. J Infect Dis. 1986;153:498–502.
Huang Y. Curative effect observation on recombinant human interferon α2b Spray in hand-foot-and-mouth disease. China Pract Med. 2014;9:47–8 (in Chinese).
Lin H, Huang L, Zhou J, Lin K, Wang H, Xue X, et al. Efficacy and safety of interferon-α2b spray in the treatment of hand, foot, and mouth disease: a multicenter, randomized, double-blind trial. Adv Virol. 2016;161:1–8.
Cao L, Zhang L, Tian L, Deng J. Antivirus effects and clinical evaluation of recombinant human interferon α2b spray. Chin Med Biotechnol. 2011;6:334–6 (in Chinese).
Wei CH. Clinical and Virological Efficacy of Recombine Human Interferon α-2b for Hand-foot-mouth Disease in Children. Eval Anal Drug-use Hosp China. 2013;13:1018–20 (in Chinese).
Zong WY. Observation of the effects of adjunctive therapy of recombinant human interferon α2b Spray on hand, foot and mouth disease. Hebei Med J. 2011;33:2808–9 (in Chinese).
Huang X, Zhang X, Wang F, Wei H, Ma H, Sui M, et al. Clinical efficacy of therapy with recombinant human interferon α1b in hand, foot, and mouth disease with enterovirus 71 infection. PLoS One. 2016;11:e0148907.
Tan J, Wang WM, Lei KJ. Gamma globulin intravenous drip combined with interferon aerosol inhalation on severe hand, foot and mouth disease in children. J Pediatr Pharm. 2017;23:21–3.
Zhang XD, Tian YK, Xiong F, Mou DL, Wang W. Clinical observation of recombinant human interferon α-2b injection by aerosol inhalation in treatment of hand-foot-mouth disease of children. Drugs Clin. 2014;29:404–7 (in Chinese).
Zeng JS, Qian SY. Characteristics and diagnosis and treatment for severe hand foot and mouth disease. Chin J Crit Care Med. 2008;28:752–3 (in Chinese).
Li YL, Wang WH, Yang HR. Efficacy observation on the treatment of hand foot mouth disease by Multi-channel application of interferon α-2b. Tianjin Med J. 2013;41:78–9 (in Chinese).
Xu Y, Li Y, Chen Y, Xin S, Xie L, Liang Y, et al. A multicenter and contrasted clinical study on efficacy and safety of recombinant human interferon α2b spray in the treatment of hand-foot-and-mouth disease in kids. Chin J Infect Dis. 2018;36:101–7 (in Chinese).
Chi CY, Khanh TH, le Thoa PK, Tseng FC, Wang SM, le Thinh Q, et al. Milrinone therapy for enterovirus 71-induced pulmonary edema and/or neurogenic shock in children: a randomized controlled trial. Crit Care Med. 2013;41:1754–60.
Wang SM, Lei HY, Huang MC, Su LY, Lin HC, Yu CK, Wang JL, Liu CC. Modulation of cytokine production by intravenous immunoglobulin in patients with enterovirus 71-associated brainstem encephalitis. J Clin Virol. 2006;37:47–52.
Ye N, Gong X, Pang LL, Gao WJ, Zhang YT, Li XL, et al. Cytokine responses and correlations thereof with clinical profiles in children with enterovirus 71 infections. BMC Infect Dis. 2015;15:225.
Zeng M, Zheng X, Wei R, Zhang N, Zhu K, Xu B, et al. The cytokine and chemokine profiles in patients with hand, foot and mouth disease of different severities in Shanghai, China, 2010. PLoS Negl Trop Dis. 2013;7:e2599.
Zhu F, Xu W, Xia J, Liang Z, Liu Y, Zhang X, et al. Efficacy, safety, and immunogenicity of an enterovirus 71 vaccine in China. N Engl J Med. 2014;370:818–28.
Hu YM, Wang X, Wang JZ, Wang L, Zhang YJ, Chang L, et al. Immunogenicity, safety, and lot consistency of a novel inactivated enterovirus 71 vaccine in Chinese children aged 6–59 months. Clin Vaccine Immunol. 2013;12:1805–11.
Zhu FC, Meng FY, Li JX, Li XL, Mao QY, Tao H, et al. Efficacy, safety, and immunology of an inactivated alum-adjuvant enterovirus 71 vaccine in children in China: a multi centre, randomised, double-blind, placebo-controlled, phase 3 trial. Lancet. 2013;381:2024–32.
Li R, Liu L, Mo Z, Wang X, Xia J, Liang Z, et al. An inactivated enterovirus 71 vaccine in healthy children. N Engl J Med. 2014;370:829–37.
The Chinese version of this Guideline was published in the June issue of Chin J Infect Dis in 2018. We acknowledge the editing assistance of the English version of HFMD guidelines from Stephen Toovey, MD, PhD, and Jim Wu PhD, and also thank Mi Yao and Zhi-Jie Xu for translation support.
The National Clinical Key Department of Infectious Diseases; The Key Medical Specialty Program of Sailing Plans organized by Beijing Municipal Administration of Hospitals (No. ZYLX201602)
Conflict of interest
No financial or nonfinancial benefits have been received or will be received from any party related directly or indirectly to the subject of this article.
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Li, X., Ni, X., Qian, S. et al. Chinese guidelines for the diagnosis and treatment of hand, foot and mouth disease (2018 edition). World J Pediatr 14, 437–447 (2018). https://doi.org/10.1007/s12519-018-0189-8