Chinese guidelines for the diagnosis and treatment of hand, foot and mouth disease (2018 edition).

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSION: The guidelines can provide systematic guidance on the diagnosis and management of HFMD.

Gene sequencing and variable site analyzing of coding region of two enterovirus A71 isolates with different clinical phenotypes.

Currently, it is still controversial that if the pathogenicity of EV-A71 causing severe or mild hand, foot, and mouth disease (HFMD) is associated with viral nucleotide or amino acid sequence(s). In this study, 19 clinical strains were detected in samples from diagnosed patients of EV-A71-caused HFMD with mild or severe symptoms. Then, VP1-2A fragment sequences of 19 EV-A71 isolates were determined, the phylogenetic analysis, based on VP1 sequences of 19 EV-A71 stains in this study and which of 62 EV-A71 strains with different clinical phenotypes reported before, were carried out. Our results showed that no difference in the genotype and evolution distribution was observed among the EV-A71 strains mentioned above. Furthermore, two EV-A71 isolates, which with much close evolutionary relationship but different clinical manifestations, were purified by plaque assay, the complete genome sequencing was done, and deduced amino acid sequence analysis of 11 proteins coded by EV-A71 was carried out. Eight variable amino acid sites were found and further verified with those of 62 strains reported before. Our study provides further evidence that the potential pathogenicity of EV-A71 causing severe or mild HFMD seems not to be associated with viral genotype and even the amino acid substitution.

[Evaluation of adrenocortical function in children with severe and critical enterovirus 71 infection].

OBJECTIVE: To evaluate the adrenocortical function in children with severe and critical enterovirus 71 infection by using a high-dose (250 µg) adrenocorticotropic hormone (ACTH) stimulation test. And to at provide experimental basis for glucocorticoid in the treatment of hand-foot-and-mouth disease (HFMD). METHOD: This was a prospective multi-center study which was carried out in PICUs of Beijing Children's Hospital, Zhengzhou Children's Hospital, Kaifeng Children's Hospital and Linyi People's Hospital in Shandong province. Children with severe and critical hand-foot-mouth disease admitted to PICUs of the four hospitals from June 2009 to April 2010 were enrolled in this study, and EV71 virus nucleic acid test and high-dose (250 µg) ACTH stimulation started at the same time. EV71 virus nucleic acid positive 51 cases were eventually enrolled in the study. Cortisol test was performed at baseline (T0) and after high-dose (250 µg) ACTH stimulation at 30 minutes (T30), 60 minutes (T60) in the first 6 hours after admission, but before glucocorticoid was given. The adrenocortical function was evaluated according to ΔTmax [ΔTmax=(T30, T60 maximum)-T0]. Diagnostic criteria of adrenal insufficiency (AI) is increment (ΔTmax)≤9 µg/dl. RESULT: The incidence of AI in 51 cases was 52.94% (27/51). The incidence of AI in severe group was 44.74% (17/38), which was significantly higher in critical group 76.92% (10/13), P<0.05. Of the cases with a pediatric critical illness score (PCIS)≤70, 81.82% (9/11) had adrenal insufficiency, and it was 28.57% (4/14) when PCIS≥90. The incidence of AI was 75% (6/8) and 48.84% (21/43) in death and survivor group respectively, but there were no significant difference between the two groups (P>0.05). Baseline (T0) cortisol in death group was higher than survivor group (P<0.05). CONCLUSION: AI may occur in children with enterovirus 71 infection. The critical enterovirus 71 infection had a high incidence of AI. AI may affect the prognosis of patients with severe and critical enterovirus 71 infection. Exogenous glucocorticoids administration may be considered when AI is identified or highly suspected. The timing, dosage and regimen of glucocorticoid are still unclear. Further animal experiments and clinical trials are needed.

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

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.