Research progress on pathogenic and therapeutic mechanisms of Enterovirus A71.

In recent years, enterovirus A71 (EV-A71) infection has become a major global public health problem, especially for infants and young children. The results of epidemiological research show that EV-A71 infection can cause acute hand, foot, and mouth disease (HFMD) and complications of the nervous system in severe cases, including aseptic pediatric meningoencephalitis, acute flaccid paralysis, and even death. Many studies have demonstrated that EV-A71 infection may trigger a variety of intercellular and intracellular signaling pathways, which are interconnected to form a network that leads to the innate immune response, immune escape, inflammation, and apoptosis in the host. This article aims to provide an overview of the possible mechanisms underlying infection, signaling pathway activation, the immune response, immune evasion, apoptosis, and the inflammatory response caused by EV-A71 infection and an overview of potential therapeutic strategies against EV-A71 infection to better understand the pathogenesis of EV-A71 and to aid in the development of antiviral drugs and vaccines.

The fluid management and hemodynamic characteristics of PiCCO employed on young children with severe hand, foot, and mouth disease-a retrospective study.

BACKGROUND: Hand, foot, and mouth disease (HFMD) is an acute infectious disease caused by human enterovirus 71 (EV71), coxsackievirus, or echovirus, which is particularly common in preschool children. Severe HFMD is prone to cause pulmonary edema before progressing to respiratory and circulatory failure; thus hemodynamic monitoring and fluid management are important to the treatment process. METHODS: We did a review of young patients who had been successfully treated in our department for severe HFMD, which had been caused by EV71. A total of 20 patients met the inclusion criteria. Eight cases were monitored by the pulse indicator continuous cardiac output (PiCCO) technique, and fluid management was administered according to its parameters. With regard to the treatment with PiCCO monitoring, patients were divided into two groups: the PiCCO group (8 patients) and the control group (12 patients). The groups were then compared comprehensively to evaluate whether PiCCO monitoring could improve patients' clinical outcomes. RESULTS: After analysis, the findings informed that although PiCCO failed to shorten the length of ICU stay, reduce the days of vasoactive drug usage, or lower the number of cases which required mechanical ventilation, PiCCO did reduce the incidence of fluid overload (p = 0.085) and shorten the days of mechanical ventilation (p = 0.028). After effective treatment, PiCCO monitoring indicated that the cardiac index (CI) increased gradually(p < 0.0001), in contrast to their pulse (P, p < 0.0001), the extra vascular lung water index (EVLWI, p < 0.0001), the global end diastolic volume index (GEDVI, p = 0.0043), and the systemic vascular resistance index (SVRI, p < 0.0001), all of which decreased gradually. CONCLUSION: Our study discovered that PiCCO hemodynamic monitoring in young children with severe HFMD has some potential benefits, such as reducing fluid overload and the duration of mechanical ventilation. However, whether it can ameliorate the severity of the disease, reduce mortality, or prevent multiple organ dysfunction remain to be further investigated.

Continuous hemodiafiltration as a rescue therapy for patients with cardiopulmonary failure caused by enterovirus-71: a retrospective observational study in a PICU.

BACKGROUND: Hand, foot and mouth disease (HFMD) remains a burdensome health issue in mainland China. Enterovirus71 (EV-A71) is the main pathogen of severe HFMD. Continuous hemofiltration improves fluid overload, restores kidney function and alleviates inflammatory reactions. The aim of the present study was to evaluate the effects of continuous veno-venous hemodiafiltration (CVVHDF) on severe HFMD caused by EV-A71(EV-A71-HFMD) in a pediatric intensive care unit (PICU). METHODS: A retrospective observational study was performed in a tertiary university PICU from January 2012 to December 2016. Children with severe EV-A71-HFMD complicated by cardiopulmonary failure were included. The patients were divided into a CVVHDF group and a conventional therapy (control) group (non-CVVHDF). The demographics, characteristics, and outcomes between the groups were collected and analyzed. RESULTS: Twenty-nine patients with severe EV-A71-HFMD were enrolled. The 28-day mortality was 17.6% (3/17) in the CVVHDF group and 33.3% (4/12) in the non-CVVHDF group, with no statistical significance between the two groups (P = 0.403). The median interval between CVVHDF initiation and PICU admission was 6 (4,8.5) hrs, and the median duration of CVVHDF was 48 (36, 64) hrs. The left ventricular ejection fraction (LVEF) and cardiac index (CI) in the CVVHDF group were improved after treatment. The plasma levels of catecholamines and renin-angiotensin-aldosterone system (RAAS) substances in the CVVHDF group were significantly decreased after treatment. The decreased catecholamines and RAAS substances included adrenalin (169.8 [145.5, 244.6] vs. 148.0 [109.0, 208.1] ng/L, P = 0.033), dopamine (152.7 [97.0, 191.1] vs. 96.0 [68.0, 160.9] ng/L, P = 0.026), angiotensin II (185.9 [125.2, 800.0] vs. 106.0 [90.8, 232.5] ng/L, P = 0.047), aldosterone (165.7 [94.0, 353.3] vs. 103.3 [84.3, 144.3] ng/L, P = 0.033), and renin (1.12 [0.74, 3.45] vs. 0.79 [0.52, 1.25] µg/L/h, P = 0.029), CONCLUSIONS: CVVHDF reduced the levels of catecholamines and RAAS substances and improved cardiovascular function. Continuous hemodiafiltration may represent a potential therapy in patients with severe EV-A71-HFMD complicated with cardiopulmonary failure.

Clinical characteristics and managements of severe hand, foot and mouth disease caused by enterovirus A71 and coxsackievirus A16 in Shanghai, China.

BACKGROUND: Hand, foot and mouth disease (HFMD) is a transmissible infectious disease caused by human enteroviruses (EV). Here, we described features of children with severe HFMD caused by EV-A71 or coxsackievirus A16 (CV-A16) in Shanghai, China. METHODS: Severe EV-A71 or CV-A16 caused HFMD children admitted to the Xinhua Hospital from January 2014 and December 2016, were recruited retrospectively to the study. Symptoms and findings at the time of hospitalization, laboratory tests, treatments, length of stay and residual findings at discharge were systematically recorded and analyzed. RESULTS: Of 19,995 children visited clinic service with probable HFMD, 574 children (2.87%) were admitted, 234 children (40.76%) were confirmed with EV-A71 (90/574) or CV-A16 (144/574) disease. Most (91.02%) of the patients were under 5 years. Initial clinical symptoms of EV-A71 and CV-A16 cases were: fever > 39 °C in 81 (90%) and 119 (82.63%), vomiting in 31 (34.44%) and 28 (19.44%), myoclonic twitching in 19 (21.11%) and 11(7.64%), startle in 21 (23.33%) and 20 (13.69%), respectively. Serum levels of interleukin-1ß (IL-1ß), IL-2, IL-6, IL-8, interferon-γ (IFN-γ), tumor necrosis factor-α (TNF-α) were significantly upregulated in severe HFMD subjects. Forty-seven children (20.08%) treated with intravenous gamma globulin (IVIG) showed decreased duration of illness episodes. All children were discharged without complications. CONCLUSIONS: EV-A71 and CV-A16 accounted 40.76% of admitted HFMD during 2014 to 2016 in Xinhua Hospital. IVIG appeared to be beneficial in shortening the duration of illness episodes of severe HFMD.

Nationwide Survey of Pediatric Inpatients With Hand, Foot, and Mouth Disease, Herpangina, and Associated Complications During an Epidemic Period in Japan: Estimated Number of Hospitalized Patients and Factors Associated With Severe Cases.

BACKGROUND: Severe pediatric cases of hand, foot, and mouth disease (HFMD), herpangina (HA), and associated complications caused by enterovirus 71 (EV71) infection have brought substantial public health impact in Asia. This study aimed to elucidate the epidemiology of these pediatric cases in Japan. METHODS: A nationwide survey was conducted using stratified random sampling of hospital pediatric departments. We estimated the number of inpatients with HFMD, HA, and associated complications between April 1 and September 30, 2010, during which EV71 was circulating predominantly. Factors associated with severe cases with ≥7 days of admission, sequelae, or outcome of death were analyzed using multivariate logistic regression. RESULTS: During the 6-month epidemic period, the number of pediatric inpatients aged <15 years was about 2,900 (estimated cumulative incidence of hospitalized cases: 17.0 per 100,000 population). Severe cases were significantly associated with younger age. Compared to patients ≥5 years of age, the odds ratios (ORs) for <1 year of age and 1 to <3 years of age were 5.74 (95% confidence interval [CI], 2.14-15.4) and 2.94 (95% CI, 1.02-8.51), respectively. Elevated ORs for hyperglycemia (plasma glucose level of ≥8.3 mmol/L) on admission (OR 3.60; 95% CI, 0.94-13.8) were also observed. CONCLUSIONS: Disease burden of pediatric inpatients with HFMD, HA, and associated complications in Japan was described for the first time. During an EV71 epidemic, younger age and, suggestively, hyperglycemia may have been critical factors requiring more careful treatment.

Hand-Foot-and-Mouth Disease: Rapid Evidence Review.

Hand-foot-and-mouth disease is caused by human enteroviruses and coxsackieviruses. Outbreaks can occur in the spring to fall and are common in North America, and most cases occur in patients younger than 10 years. Hand-foot-and-mouth disease is transmitted by fecal-oral, oral-oral, and respiratory droplet contact. Patients present with a low-grade fever, a maculopapular or papulovesicular rash on the hands and soles of the feet, and painful oral ulcerations. Lesions usually resolve in seven to 10 days; however, in rare cases, patients may have neurologic or cardiopulmonary complications. The differential diagnosis for childhood rashes and oral enanthems is broad and includes erythema multiforme, herpes, measles, and varicella. Treatment is supportive and directed toward hydration and pain relief as needed with acetaminophen or ibuprofen. Oral lidocaine is not recommended, and antiviral treatment is not available. The best methods to prevent the spread of hand-foot-and-mouth disease are handwashing and disinfecting potentially contaminated surfaces and fomites.

The Effectiveness of Different Doses of Intravenous Immunoglobulin on Severe Hand, Foot and Mouth Disease: A Meta-Analysis.

OBJECTIVE: To conduct a meta-analysis of evidence from randomized controlled trails (RCTs) of different doses of intravenous immunoglobulin (IVIG) in children with severe hand, foot and mouth disease (HFMD) to provide the scientific basis for clinical practice. METHODS: A search of PubMed-Medline, CNKI, Wanfang, and VIP database (until June 30, 2017) was performed and Software RevMan5.3 was used to evaluate the effect of different doses of IVIG on HFMD in RCTs. We used random-effects models (or fixed-effects models) and generic inverse variance methods to process quantitative data, followed by a leave-one-out method for sensitivity analysis. RESULTS: From a total of 420 entries identified via searches, 8 RCTs involving 1,450 patients were included in the final analysis. The results of the meta-analysis showed that compared with conventional therapy alone, conventional therapy combined with IVIG had shorter fever clearance time, shorter rash regression time, and shorter clinical cure time. Subgroup analyses showed that the high-dose group (1 g/kg/day) had shorter fever clearance time (p < 0.05), shorter rash regression (p< 0.05), shorter remission time of neurological symptoms (p < 0.05), but longer clinical cure time (p > 0.05). CONCLUSION: The high-dose group has a better prognosis; however, the advantages and disadvantages should be carefully considered when deciding the doses in the treatment of severe HFMD.

Hand-foot-mouth disease and use of steroids, intravenous immunoglobulin, and traditional Chinese herbs in a tertiary hospital in Shantou, China.

BACKGROUND: In contrast to the guidelines of World Health Organization (WHO) and United States-Centers for Disease Control and prevention (US-CDC), the Chinese national guidelines recommend the use of steroids, intravenous immunoglobulin (IVIG), or traditional Chinese herbs (TCHs) in hand-foot-mouth disease (HFMD) management. Their use and therapeutic efficacies are, however, unclear. We aimed to describe their use in and the clinical outcomes of hospitalized HFMD cases. METHODS: A retrospective review of hospital medical records for HFMD cases during 2008-2016 was conducted in a medical school-affiliated tertiary hospital in Shantou, Guangdong, China. RESULTS: Hospitalized children with the discharge diagnosis of HFMD (n = 3778), comprising mild (58.4%), severe (41.5%), and very severe (0.1%) cases, were enrolled in the study. Steroids, IVIG, and antiviral TCH Lan-Qin were respectively prescribed in 60.5, 37.1, and 71.0% of cases. Most cases (99.8%) recovered and six died. Recovery rate was lower with the use of IVIG and higher with Lan-Qin (alone or in combination with steroid) in the mild cases (Ps < 0.05). Longer hospital stay was observed with steroid/IVIG with or without Lan-Qin in the severe cases (Ps < 0.05). CONCLUSIONS: This nine-year retrospective review shows 1) an increase in the incidence of HFMD as well as the use of steroids, IVIG, and TCH over time, 2) no significant advantage of using steroids and IVIG, either alone or in combination, in the management of mild HFMD cases, and 3) a higher recovery rate in mild HFMD cases with the use of antiviral TCH (Lan-Qin). Our findings need verification in a larger prospect study with cases from hospitals in other regions of China. Lan-Qin efficacy should be evaluated in randomized trials. Meanwhile, caution should be exercised in the extensive use of steroids and IVIG in HFMD management.

Best practices to prevent transmission and control outbreaks of hand, foot, and mouth disease in childcare facilities: a systematic review.

INTRODUCTION: Hand, foot, and mouth disease continues to cause seasonal epidemics in the Asia-Pacific Region. Since the current Enterovirus 71 vaccines do not provide cross-protection for all Enterovirus species that cause hand, foot, and mouth disease, there is an urgent need to identify appropriate detection tools and best practice to prevent its transmission and to effectively control its outbreaks. This systematic review aimed to identify characteristics of outbreak and assess the impact and effectiveness of detection tools and public health preventive measures to interrupt transmission. The findings will be used to recommend policy on the most effective responses and interventions in Hong Kong to effectively minimise and contain the spread of the disease within childcare facilities. METHODS: We searched the following databases for primary studies written in Chinese or English: MEDLINE, EMBASE, Global Health, WHO Western Pacific Region Index Medicus database, China National Knowledge Infrastructure Databases, and Chinese Scientific Journals Database. Studies conducted during or retrospective to outbreaks of hand, foot, and mouth disease caused by Enterovirus 71 from 1980 to 2012 within childcare facilities and with a study population of 0 to 6 years old were included. RESULTS: Sixteen studies conducted on outbreaks in China showed that hand, foot, and mouth disease spread rapidly within the facility, with an outbreak length of 4 to 46 days, especially in those with delayed notification (after 24 hours) of clustered outbreak (with five or more cases discovered within the facility) to the local Center for Disease Control and Prevention and delayed implementation of a control response. The number of classes affected ranged from 1 to 13, and the attack rate for children ranged from 0.97% to 28.18%. CONCLUSIONS: Communication between key stakeholders about outbreak confirmation, risk assessment, and surveillance should be improved. Effective communication facilitates timely notification (within 24 hours) of clustered outbreaks to a local Center for Disease Control and Prevention. Timely implementation of a control response is effective in minimising incidence and length of an outbreak in childcare facilities. The government should provide incentives for childcare facilities to train infection control specialists who can serve as the first contact, knowledge, and communication points, as well as facilitate exchange of information and provision of support across stakeholders during a communicable disease epidemic.

Coxsackievirus A6 Polymorphic Exanthem in Israeli Children.

Hand foot and mouth disease (HFMD) is an acute childhood viral exanthem usually associated with coxsackievirus A16 or enterovirus 71. Atypical HFMD associated with coxsackievirus A6 was reported recently. The aim of the current study was to describe coxsackievirus A6-associated atypical HFMD in a series of 8 toddlers who were referred with idiopathic extensive eruptions. Demographic and clinical characteristics, Reverse transcriptase-real-time PCR (RT-PCR) results for enterovirus and phylogenetic analysis for the coxsackievirus A6 strains were recorded. Morphologically polymorphous (vesicular, erosive, papular, desquamative or purpuric) and extensive eruptions were found. One patient had delayed nail shedding. Enterovirus was positive in all patients. Genotype analysis confirmed coxsackievirus A6 in 6 patients and 5 sequences underwent phylogenetic analysis. This is the first such report in Israeli children. In conclusion, coxsackievirus A6 atypical HFMD should be regarded as a novel childhood viral exanthem. We suggest the term "coxsackievirus A6 polymorphic exanthem" due to the extensive and variable nature of this eruption.

[Effect of continuous hemofiltration on inflammatory mediators and hemodynamics in children with severe hand, foot and mouth disease].

OBJECTIVE: To investigate the effect of continuous veno-venous hemofiltration (CVVH) on inflammatory mediators in children with severe hand, foot and mouth disease (HFMD), and to investigate its clinical efficacy. METHODS: A total of 36 children with stage IV HFMD were enrolled and randomly divided into conventional treatment group and CVVH group (n=18 each). The children in the CVVH group were given CVVH for 48 hours in addition to the conventional treatment. The levels of interleukin-2 (IL-2), interleukin-6 (IL-6), interleukin-10 (IL-10), tumor necrosis factor-α (TNF-α) and lactic acid in peripheral venous blood, heart rate, blood pressure, and left ventricular ejection fraction were measured before treatment and after 24 and 48 hours of treatment. RESULTS: After 24 hours of treatment, the conventional treatment group had a significantly reduced serum IL-2 level (P<0.01), and the CVVH treatment group had significantly reduced serum levels of IL-2, IL-6, IL-10, and TNF-α (P<0.05). After 48 hours of treatment, both groups had significantly reduced serum levels of IL-2, IL-6, IL-10, and TNF-α (P<0.01), and the CVVH group had significantly lower levels of these inflammatory factors than the conventional treatment group (P<0.01). After 48 hours of treatment, heart rate, systolic pressure, and blood lactic acid level were significantly reduced, and left ventricular ejection fraction was significantly increased in both groups, and the CVVH group had significantly greater changes in these indices except systolic pressure than the conventional treatment group (P<0.01). CONCLUSIONS: CVVH can effectively eliminate inflammatory factors, reduce heart rate and venous blood lactic acid, and improve heart function in children with severe HFMD.

[Clinical characteristics and prognostic factors of children with critical hand-foot-mouth disease treated with mechanical ventilation].

OBJECTIVE: To investigate the clinical characteristics of children with critical hand-foot-mouth disease (HFMD) who were treated with mechanical ventilation and to explore the risk factors for poor prognosis. METHODS: The clinical data of 63 children with critical HFMD who were admitted to the pediatric intensive care unit between April 2012 and September 2013 and needed mechanical ventilation were retrospectively analyzed. RESULTS: Among the 63 children, 43 were boys and 20 were girls, and their mean age was 25 ± 18 months, with 81% under 3 years old. The four death cases were all under three years old. Compared with the cured cases, the death cases had a significantly lower mean age (8 ± 3 months vs 25 ± 18 months; P<0.05). Poor peripheral circulation above the elbow or knee joint, pulmonary edema involving at least two thirds of the lung field, and pulmonary hemorrhage were all closely related to death (P<0.01). The death cases and cured cases had significantly different peripheral white blood cell counts, blood lactic acid, and blood glucose (24 ± 11× 109/L vs 12 ± 5×109/L; 6.6 ± 1.8 mmol/L vs 3.6 ± 1.7 mmol/L; 16.4 ± 2.5 mmol/L vs 10.0 ± 3.0 mmol/L). The cases with critical illness score <90 had a significantly higher death risk (P<0.01). CONCLUSIONS: Children with critical HFMD are mainly under 3 years old. The children face extremely high risk of death when they suffer from poor peripheral circulation above the elbow or knee joint, pulmonary edema involving at least two thirds of the lung field, and pulmonary hemorrhage. Significant increases in peripheral white blood cell counts, blood lactic acid, and blood glucose are risk factors for poor prognosis. Critical illness score is also related to poor prognosis.

Extracorporeal life support and continuous renal replacement therapy in a patient with Enterovirus A71 associated cardiopulmonary failure: A case report.

RATIONALE: Hand-foot-mouth disease (HFMD) caused by Enterovirus A71, complicated by cardiopulmonary failure, is associated with a high mortality rate despite intensive treatment. To date, there is a paucity of clinical management data, regarding the use of extracorporeal life support (VA-ECMO) for Enterovirus-A71 associated cardiopulmonary failure reported. PATIENT CONCERNS: The patient in this study presented with severe HFMD complicated by cardiopulmonary failure, polymorphic ventricular tachycardia, and cardiac arrest. DIAGNOSES: Clinical presentations, laboratory data, and polymerase chain reaction (PCR) results from rectal swabs were used to confirm the diagnosis of severe HFMD caused by Enterovirus A71. INTERVENTIONS: The patient was managed with chest compression and an automatic external defibrillator, mechanical ventilation, intravenous immunoglobulin (IVIG), continuous renal replacement therapy (CRRT) and inotrope (milrinone). The patient did not respond to these interventions and subsequently required further management with VA-ECMO. OUTCOMES: The patient achieved a favorable outcomes. LESSONS: Our study highlights that extracorporeal membrane oxygenation and CRRT can enhance the survival outcomes of patients with severe HFMD with cardiopulmonary failure complications. Furthermore, we propose specific indications for the initiation of VA-ECMO.

Clinical features and management outcomes of severe hand, foot and mouth disease.

OBJECTIVE: This study was designed to describe the clinical features and management outcomes of severe hand, foot and mouth disease (HFMD). SUBJECTS AND METHODS: Data on 147 severe HFMD patients during an outbreak in 2009 were analyzed. RESULTS: Most patients were under 3 years of age; 102 (69.4%) were boys. All had skin rashes and fever of ≥38°C. All (n = 147, 100%) showed signs of central nervous system involvement, such as lethargy (n = 124, 84.4%), myoclonic jerks (n = 76, 51.7%), or drowsiness (n = 34, 23.1%). Respiratory symptoms were mainly tachypnea (n = 112, 76.2%) or bradypnea (n = 21, 14.3%). Common cardiovascular symptoms included tachycardia (n = 134, 91.2%) and hypertension (n = 23, 15.5%). Chest X-ray showed increased markings in 76 (51.7%) or consolidation in 44 (29.9%). Hyperglycemia and elevated blood lactic acid levels were found in 127 (86.4%) and 130 (88.4%), respectively. Positive enterovirus EV71-PCR was found in 113 (76.9%). All patients were treated with mechanical ventilation for 61.2 ± 12.8 h (range, 40-96 h), as well as mannitol, dexamethasone, gamma globulin and ribavirin. Dopamine, dobutamine or amrinone was administered in 58.5, 51.0 and 21.8%, respectively. Three patients (2%) died during hospitalization. All others had a full recovery and were discharged after 14.2 ± 1.6 days (range, 12-17 days). CONCLUSION: Central nervous and cardiorespiratory systems were involved in the patients with severe HFMD. Fasting blood glucose and lactic acid levels increased in the majority of patients. Mechanical ventilation and supportive pharmacotherapy were associated with a good clinical outcome in these patients.

[Clinical application of cardiac output monitoring in children with severe hand-foot-mouth disease].

OBJECTIVE: Significant cardiac dysfunction has been found in children with severe hand-foot-mouth disease and heart failure is the major cause of death in these patients. Evaluation of cardiac function is essential for the treatment of severe cases. This study evaluated the clinical value of cardiac output monitoring in children with severe hand-foot-mouth disease. METHODS: A total of 107 children with severe hand-foot-mouth disease admitted to the pediatric intensive care unit from April 2011 to September 2011 were enrolled and divided into three groups by clinical stage: 73 cases in stage 2, 23 cases in stage 3 and 11 cases in stage 4. Cardiac output and stroke volume were measured by ultrasonic cardiac output monitors (USCOM). Ninety-five children received MRI scanning and were grouped according to the results of MRI: 41 cases (medulla oblongata involvements in 9 cases) in abnormal MRI group and 54 cases in normal MRI group. Cardiac output was compared between the children in different clinical stages and between different MRI results. RESULTS: Compared with children in clinical stages 2 and 3, cardiac output in children in clinical stage 4 decreased significantly (P<0.05). There was no differences in cardiac output between the normal and abnormal MRI groups, however cardiac output was significantly lower in children with medulla oblongata involvement than in those with other involvements and normal MRI. CONCLUSIONS: Significant decrease in cardiac output suggests critical conditions and medulla oblongata cardiovascular center involvement in children with severe hand-foot-mouth disease. Dynamic measurement of cardiac output is valuable for treatment of the disease.

Letter: an adult case of hand-foot-mouth disease showing severe mucous involvement.

Hand-foot-mouth disease is a common childhood viral infection. Generally, small vesicles and erosions occur on the hands, feet and oral mucosa. We report an unusual case of this disease that occurred in an immunocompent adult and resulted in severe erosion on the lips and mucous membranes.