HFMD outbreaks in Xiangyang had gone through four stages in 6 years: sudden outbreak in 2008, then quickly aggravation year by year, but morbidity sharp fall after 2012 and then low-level tailing for several years. Our investigation shows that EV71 is the main virus that cause serious epidemics, severe morbidity and mortality of HFMD, and EV71 positive rate of severe HFMD cases had decreased coincident with the decrease of HFMD prevalence.
Our investigation reveals that age (<3 years), ANS dysregulation, pulmonary edema/haemorrhage, CRP (>40mg/L) and cTnI (>0.04 ng/mL) are all fatality risk factors for severe HFMD. Thus elevated CRP, cTnI levels have been shown to be useful laboratory signals that may help doctors identify children at risk of systemic complication several hours before the onset of overt signs of disease progression. Hyperglucose and leukocytosis are not risk factors for poor prognosis, which is inconsistent with the report from Hainan, China . Another study identified female sex, light-reflex insensitivity, tachycardia and higher serum lactate levels as independent risk factors; and longer onset-to-hospitalization time as an independent protective factor for death in children with critical and severe HFMD .
Our investigation revealed that IVIG and mechanic ventilation application as soon as possible to severe HFMD at early stage III had significantly improved pulmonary edema or haemorrhage, and had decreased mortality. Protective-ventilation strategy might outweigh other ventilation strategies in maintaining normal blood pressure, but no mortality difference between ventilation strategies was found. High airway pressure and PEEP may have extrapulmonary effects such as reducing the volume of venous return, increasing the afterload in the right atrium, decreasing cardiac output, decreasing visceral venous return, impairing renal function, and altered hormonal levels. PIP and PEEP should be regulated according to lower inflection point and upper inflection point on the static pressure-volume curve.
Milrinone is effective in bring down hypertension and sympathetic tachycardia, and methylprednisolone can exactly decrease high body temperature, which had been proved by many cases, but both had not contributed to the survival rate in our data. A study in Taiwan (China) found that a milrinone-treated group was associated with reduced mortality corresponding to attenuated sympathetic activity and cytokine production in comparison with a non-treated group , but there is no significant difference in mortality in our data. We assumed that significant decrease in mortality in the study might derive from comparison with historical cases.
We also found that there are no enough evidences that urge us to use methylprednisolone, or large doses instead of small doses of IVIG in any stage, nor should we perform mechanic ventilation or IVIG early at stage I or II of severe HFMD.
Elevated serum levels of inflammatory cytokines, including IL-3, IL-6, IL-12p40 and TNF-α, and decreased levels of serum biomarkers, including IL-1Ra, IL-8, IL-16, soluble ICAM-1, CXCL-1 and CCL27 were found in HFMD cases, which suggests systemic inflammation is involved in the etiology of HFMD. In contrast, the associated biomarkers had not made any difference in these patients treated with methylprednisolone , and methylprednisolone even had been associated with an increased risk of severe HFMD development . Therefore further investigations are needed to associate the usefulness of steroid treatment on HFMD.
It usually takes 2 to 4 hours for severe HFMD to deteriorate from stage II to stage III, but less than one hour left at stage III for us to take action as quickly as possible. Severe cases should be thus monitored closely for signs indicative of CNS involvement, ANS dysregulation and the development of cardiopulmonary failure, and timely intervention or even mechanic ventilation is the key to reducing mortality associated with severe HFMD. Persistent high fever, vomiting, lethargy, agitation and irritability are indications of CNS involvement [8,17]. More specific neurological signs, such as myoclonic jerk (usually observed during the early stage of sleep, but also seen in severe cases when patients are awake), truncal ataxia and “wandering eyes” (rotary eye movement without fixation) are commonly observed in children in the severe cases . With disease progression or increased severity affecting the ANS and leading to cardiopulmonary failure, signs such as mottled skin and dyspnea/tachypnea may also be evident at the stage III. We found that patients bringing up by grandparents especially by those too old to be alert or poor education is a risk factor of fatality, which due to delay in early recognition of severe case and loss of timely intervention.
Fatality cases of HFMD are the commonest cause that result in medical disputes and medical compensation in China in recent years. Our investigation found that 78% fatality cases before 2011 occurred on the way of, or within 12 hours after transfer to higher grade hospital, which was attributed largely to delay in applying mechanic ventilation. These cases might have deteriorated too fast or it was too late to have the opportunity to transfer to higher grade hospital. After recognition the truth, local Health Bureau had quickly equipped all paediatric departments with mechanical ventilators for all county-level and district hospitals, and emphasized early recognition of severe cases, compliance with indication and contraindication to transfer, and had held comprehensive trainings on mechanic ventilation management. Experts were dispatched to county-level or district hospital when there was severe HFMD who lost transfer opportunity. The fatality has decreased significantly when new policy being enforced in later years after 2011.
It is puzzling that the outbreaks of HFMD had been so severe in Xiangyang for several years, whereas adjacent areas had less impact, and severe morbidity and mortality among districts, county-level cities and counties were very different in Xiangyang. A study in Shandong province, China also showed spatiotemporal difference on HFMD prevalence . We cannot convincingly interpret the difference are the results of climate, bad environment, insalubrity, large floating population and/or poor education.
IVIG and methylprednisolone had been used in many countries and districts on a presumptive basis, and had been demonstrated inconsistent results for efficacy on severe HFMD [8,20,21]. The efficacy of IVIG had been proved differ when medication in different stage of severe cases in our data, and no significant difference were found when analysis the efficacy of IVIG or methylprednisolone without staging, which may interpret the cause of inconsistent results above.
There are no fatality case at stage I and only 2 at stage II on admission, when more severe cases and fatalities being enrolled, and design of a randomized, double-blind, placebo-controlled trial being adopted, we presume that efficiency of IVIG and methylprednisolone administered at stage I or II on holding stage III at bay might appear. Studies also need be done to understand why these outbreaks occur and why some people have severe disease in the future.