HFMD is a common acute infectious disease caused by enteroviruses that can be transmitted through the digestive tract and respiratory tract, mostly in children under 5 years of age. The causes of HFMD are mainly enterovirus type 71 (Entervirus, 71EV71) and Coxsackievirus group A type 1 (Coxsackievirus A16, CA16), and critical cases are mainly caused by EV71 infection. Most patients have a good prognosis, and severe cases are mainly seen in children under 3 years of age, which can be complicated by encephalitis, encephalomyelitis, pulmonary edema, and circulatory failure. Once brainstem encephalitis occurs, the case fatality rate increases significantly, and effective treatment methods are lacking.
Pathogenesis of severe hand-foot-and-mouth disease The causes of death in critical cases of hand-foot-and-mouth disease are mainly brainstem encephalitis and neurogenic pulmonary edema, which are clinically characterized by severe dyspnea, respiratory distress, coughing up pink foamy sputum, and respiratory and circulatory failure. In the 1997 outbreak of hand-foot-and-mouth disease in Malaysia, 35 cases (88%) died of neurogenic pulmonary edema; in 1998, the outbreak of hand-foot-and-mouth disease or herpetic angina in Taiwan, the main cause of death of patients was pulmonary edema or pulmonary hemorrhage secondary to nervous system damage; since 2008, hand-foot-and-mouth disease has been endemic in some parts of China, and the deaths are mainly cerebral stem encephalitis complicated by pulmonary edema, pulmonary hemorrhage and cardiopulmonary failure. Patients with acute pulmonary edema and pulmonary hemorrhage are generally normal in the heart and lungs, and the virus can be isolated from brain tissue, but the viral content of lung tissue is low, and there is no obvious inflammatory response to the myocardium or only mild monocyte infiltration. Chinese scholar Nong Guangmin and others found that there was brain especially brain stem damage in 14 patients who died of hand-foot-and-mouth disease, 11 patients had pulmonary edema or pulmonary hemorrhage, and 14 patients had a large amount of pink foam in the alveoli, but the lung tissue of patients with pulmonary hemorrhage did not find diffuse lung damage, which was different from the case realization of pulmonary edema secondary to influenza and pulmonary hemorrhage patient tissue in 2009. EV71 is a highly neurotropic virus that primarily invades the brainstem and can cause neurological pathologies such as brainstem encephalitis, encephalomyelitis, aseptic meningitis, and polio-like syndrome. After the virus invades the central nervous system, due to the destruction of the inhibitory center of the sympathetic nerve, the increase in intracranial pressure causes the body's stress response, which together leads to the overexcitement of the sympathetic nervous system, initiates the sympathetic waterfall response, and the patient's heart rate and blood pressure are progressively increased. FU et al. modeled patients with neurogenic pulmonary edema and heart failure using a model of cats, and confirmed that a significant increase in the content of kelpamines in the blood is the main mechanism leading to pulmonary edema and heart failure. Chinese scholars have also confirmed that in patients with hand-foot-and-mouth disease in all stages, the level of thermophenolic substances has increased, and the increase in stages 3 and 4 is more obvious than that in stages 1 and 2. Therefore, most scholars agree that the mechanism of the disease is that under the effect of constrictive vascular cut-off, the systemic circulation resistance increases after the constriction of blood vessels, the blood output of the left ventricle is relatively reduced, resulting in congestion in the pulmonary circulation, the effective filtration pressure of the pulmonary capillary bed is sharply increased, and a large amount of fluid is trapped in the space of pulmonary tissue, resulting in pulmonary edema and pulmonary hemorrhage. However, some scholars have found that there is no significant increase in systemic circulation and pulmonary circulation vascular resistance through invasive hemodynamic observations, so it is believed that the disease may be similar to acute respiratory distress syndrome, which is caused by increased pulmonary tube permeability due to pulmonary edema, rather than increased hydrostatic pressure in the lung capillaries. Kao et al. found that the expression of inducible nitric oxide synthase (iNOS) mRNA in lung tissues of patients with pulmonary edema increased, and iNOS can catalyze the synthesis of nitric oxide (NO), NO can improve the permeability of the pulmonary microcirculation system, increase the filtration coefficient of lung capillaries, resulting in worsening of pulmonary edema, so NPE caused by EV71 infection may be related to iNOS and NO.
2. Treatment
Treatment needs to be based on the patient's disease stage to take different strategies, mainly including antiviral therapy for the pathogen and the treatment after cardiopulmonary function involvement, for patients with cardiopulmonary function involvement, the previous intravenous fluids for patients with decreased blood pressure often lead to the aggravation of pulmonary edema, so the clinical gradual use of vasoactive drugs to maintain blood pressure stability on the basis of limiting fluid intake. According to the central venous pressure, cardiac function, invasive arterial pressure to monitor the amount of circulating fluid, the use of phased management method to treat patients with cardiopulmonary dysfunction, compared with the traditional strategy can significantly reduce the mortality rate of patients with cardiopulmonary failure, but for patients with only nervous system involvement and no cardiopulmonary dysfunction after healing.
2.1. Antiviral therapy In the "Expert Consensus on the Clinical Treatment of Severe Cases of Enterovirus Type 71 (EV71) Infection" issued by the Clinical Expert Group of Hand-Foot-and-Mouth Disease of the Former Ministry of Health, ribavirin is recommended as an antiviral drug for the treatment of hand-foot-and-mouth disease. Studies have reported that ribavirin has shown anti-EV71 effects in both in vitro and in vivo trials, and the incidence of sequelae such as case fatality, morbidity and paralysis rate of infected EV71 mice after the application of ribavirin has decreased. Clinicians in China mostly use ribavirin and traditional Chinese medicine preparations for treatment, which can shorten the duration of fever and rash, but there are fewer reports of ribavirin efficacy in the treatment of severe hand-foot-and-mouth disease.
Some studies have found that interferon can be increased by interferon inducers in test mice, thereby inhibiting the replication of EV71, and the case fatality rate of laboratory mice can be reduced accordingly after the viral load is reduced, which proves that interferon has a protective effect on infected EV71 mice. However, the role of interferons in inhibiting viruses is not ideal, interferon regulator 9 (IRF9) is an important regulator on interferon signaling channels, EV71 encoded 3C protease can lyse IRF9, which may be one of the reasons why interferons have poor anti-EV71 effects.
AG7088 is a 3C protease inhibitor of the virus, originally developed for the treatment of colds caused by human rhinoviruses, and studies have confirmed that it has an inhibitory effect on EV71. According to the AG7088 development of the antiviral drug Lupintrivir (Rupintrivir) has been confirmed to inhibit the EV71 3C protease activity, thereby inhibiting viral replication, Chinese scholar Zhang Xiaonan and others in the study of suckling mice and computer models found that Lupin dianvir can reduce the mortality rate and incidence of limb paralysis in suckling mice infected with EV71, further immunohistochemical detection and quantitative RT-PRC detection showed that Lupin dianvir can reduce the occurrence of necrotizing myositis caused by EV71 , which can also inhibit viral RNA-assisted disease-blocking expression of VP1 in infected tissues.
From the characteristics of the role of interferon and lupin dianvir, if the two are used in combination, they should have a synergistic effect, and there have been in vitro cell experiments to prove that good drugs have obvious synergistic effects, and more clinical trials may be carried out in the future to confirm their effect. However, because as with many critical cases caused by viral infections, complications may mainly stem from SIRS, antiviral therapy needs to be used in the early stage of the disease to avoid the occurrence of critical cases, and many critical cases are in the early stages of the disease cardiopulmonary involvement, how to rationally use antiviral drugs is worth further clinical exploration.
2.2. Fluid management and dehydration treatment Due to the possibility of pulmonary edema and cerebral edema at any time in severe cases, China's hand-foot-and-mouth disease treatment guidelines and expert consensus recommend controlling blood intake under the premise of maintaining blood pressure stability, and it is recommended to use central venous pressure (cvP), invasive arterial blood pressure (ABP), pulse index continuous cardiac output monitoring (PICCO) to know the rehydration. Patients with neurologic involvement should actively control intracranial hypertension, and mannitol or glycerol fructose, diuretic dehydration, and cranial pressure reduction therapy should be given, and human blood proteins can also be given to increase blood colloidal osmolality and reduce cerebral edema. Saline resuscitation is recommended after shock, and colloidal fluid resuscitation may be given when it is still not correctable. In the new pediatric advanced life support (PALS) view, it is also supported that the administration of crystalloid in the early stages of shock, and the administration of human blood albumin or other colloidal fluids during the progression of shock or when the crystalloid recovery effect is not satisfactory, compared with normal saline, human blood albumin can reduce the mortality rate of shock patients without increasing kidney or other organ damage.
2.3. Glucocorticoid therapy Due to the important role of inflammatory factors in the course of the disease, inhibition of inflammatory response can theoretically improve the condition, glucocorticoids can reduce microvascular permeability, promote the synthesis and secretion of alveolar surface substances, reduce alveolar surface tension, promote pulmonary edema absorption, but also effectively prevent cerebral edema, block pulmonary edema - cerebral edema vicious circulation process. It is recommended in the expert consensus in stage 3 of severe cases. Chinese scholars have found that patients with severe hand-foot-and-mouth disease caused by EV71 are more likely to have adrenal dysfunction, and the proportion of adrenal dysfunction in children who die from hand-foot-and-mouth disease is higher than that in the surviving group. Domestic treatment experience also suggests that high-dose shock therapy in severe cases is beneficial for improving prognosis. However, some scholars believe that the dose of glucocorticoids cannot effectively alleviate the clinical symptoms of severe cases of EV71 infection, nor can it significantly reduce white blood cells, blood sugar, and platelets. In ARDS patients with influenza A(H1N1) in 2009, some studies believe that patients who have no benefit after early hormone therapy are more likely to have lung infections and have a prolonged mechanical ventilation time, so the timing and effect of glucocorticoid therapy in such critically ill patients deserve further study.
2.4 Intravenous immunoglobulin humans have the effect of neutralizing the virus to inhibit the non-specific inflammatory response of the lungs, and in the previous outbreaks of hand-foot-and-mouth disease, it has been confirmed that the use of immunoglobulin therapy for critical cases with neurological and cardiopulmonary function involvement can reduce the case fatality rate and improve the prognosis. China's expert consensus recommends that it be used in the third stage of severe cases, and studies have confirmed that the cytokine level of patients with pulmonary edema and nervous system dysfunction after intravenous administration of human immunoglobulin is significantly reduced, which may be one of the mechanisms of human immunoglobulin treatment in critically ill patients with hand-foot-and-mouth disease, but the efficacy of immunoglobulin has been controversial due to the low level of evidence. Immunoglobulins have long been thought to inhibit the release of inflammatory mediators in infected people, reduce the inflammatory response, and improve prognosis in patients with concentration disorders, but a large 2011 study showed that immunoglobulin therapy failed to benefit severely infected newborns. Chinese scholars have reported that high-dose immunoglobulin (1g/kg.d) can rapidly improve clinical symptoms, shorten the course of disease, prevent disease progression and reduce the incidence of critical complications.
2.5. Respiratory support treatment: keep the airway open and inhale oxygen. Respiratory dysfunction makes. Timely endotracheal intubation uses positive pressure mechanical ventilation. General ventilator support is indicated by changes in respiratory rhythm (apnea, double inhalation, sobbing breathing, sighing oxygen breathing); increased or shallow breathing at rest that is not related to body temperature; frequent convulsions; nystagmus; short-term rales in the lungs; exudative changes in the chest x-ray lungs; pallor and humor; wet, cold, and pale extremities. Because delayed intubation can lead to a poor prognosis, doctors have suggested that a ventilator-assisted ventilation should be considered once a patient has frequent muscle clonus. In the ventilator-assisted ventilation phase, the parameters of the ventilator need to be adjusted at any time according to the results of blood gas and chest X-ray. If there is pulmonary edema, pulmonary hemorrhage, in order to control alveolar exudation, PEEP should be increased, in practical applications, PEEP can reach 12-18cmH20 or even higher, the general clinical to ensure oxygen saturation in more than 93% and no pink secretion in the airway is appropriate. Based on this principle, Kang Jie et al. reported treatment of 16 cases of hand-foot-and-mouth disease complicated by neurogenic pulmonary edema, 12 cases improved (2 cases abandoned treatment due to multi-organ dysfunction after improvement), and 4 cases died (25%).
2.6 Vasoactive drug therapy: Millinon makes phosphodiesterase inhibitors, the drug of choice for the treatment of congestive failure, which can slow down heart rate by influencing the regulatory ability of the sympathetic nerve, improve symptoms, etc. The application of milli-lys to treat patients with neurogenic pulmonary edema associated with EV71 infection has been confirmed to be safe and effective. Another retrospective study confirmed that patients in the Millinan group improved tachycardia and reduced mortality compared with the unapplied group, and that the survival rate in the Millinon group was significantly higher in both the acute and later follow-up periods, so the researchers believed that millinon made positive inotropic drugs that improved cardiac function effective. Wang et al. also found that the concentration of leukocytes, platelets and interleukin 13 (IL-13) in plasma after the application of Millinon decreased, suggesting that Millinon may also have immunomodulatory effects. Team doctor heart rate increased, blood pressure increased cardiorespiratory function affected by its patients, expert consensus also recommended nipuna, China has doctors using millinon combined with nipuna treatment, compared to the use of millinon alone can significantly reduce the heart rate and blood pressure level, increase ejection fraction and left cardiac output.
For the onset of blood pressure in the stage of cardiopulmonary failure, expert consensus recommends dopamine, dobutamine, epinephrine and norepinephrine, but studies have found that the use of dopamine before the onset of hypotension can not avoid the appearance of hypotension.
Although the 2012 Rescue Sepsis Campaign Guidelines still cite dobutamine as the preferred inotrope for patients with sepsis, a new meta-analysis notes that dobutamine increases the risk of death in patients with severe cardiac insufficiency due to how to add myocardial oxygen consumption. Wu Jie and other studies believe that low blood pressure in the heart and lung failure stage of hand-foot-and-mouth disease, the above-mentioned vasoactive drugs are not ideal for the treatment effect of maintaining blood pressure. Expert consensus mentions that for patients with poor efficacy of the above vasoactive drugs, levosimendan therapy, a new positive inotropic drug, is widely used in the treatment of patients with heart failure. A meta-analysis of 45 randomized controlled trials showed that levosimendan reduced case fatality and length of hospital stay in patients with severe cardiac insufficiency compared with placebo and dobutamine. Despite this, there are currently no reports at home and abroad on the treatment of patients with severe hand-foot-and-mouth disease.
2.7. Others: Xiong Xiaoyu et al. carried out blood purification treatment for 9 of the 22 critically ill patients due to persistent coma and severe infection, and died 1 case (11.1%); 4 cases (30.8%) of the 13 patients who did not undergo blood purification treatment died, suggesting that the critically ill HFMD cleared the inflammatory mediator and harmful substances through blood purification, which may reduce the deterioration of the patient's condition to a certain extent and reduce the case fatality rate, which may be related to reducing the inflammatory mediator in the blood. In the 2013 critical cases of human infection with H7N9 avian influenza in China, Li Lanjuan et al. found that the increase in cytokine levels such as IL-6 led to one of the critical factors that led to the patient's disease, and the use of plasma exchange to reduce the cytokine level improved the prognosis of patients, providing a new treatment idea for the treatment of critically ill patients related to "cytokine storm" after viral infection. China's hand-foot-and-mouth disease guidelines and expert consensus do not recommend blood purification for the treatment of severe cases of hand-foot-and-mouth disease, but a 2012 pediatric expert consensus pointed out that blood purification treatment can effectively regulate the concentration of inflammatory and anti-inflammatory mediators and downgrade the inflammatory response. It is believed that there will be more reports of blood purification treatment of severe hand-foot-and-mouth disease cases in the future.
Extracorporeal membrane oxygenation ECMO has been successful in treating many patients with cardiopulmonary failure in adults, and there are more and more cases of ARDS use in children, and expert consensus recommends mechanical ventilation when severe cases of EV71 infection are transmitted. Treatments such as vasoactive drugs and liquid therapy have not improved, and ECMO can be considered, but there are no cases of related treatments in China at present.
3. Prognosis
Most children gradually reduce and heal as they recover from neurological damage, and a few critical cases may have sequelae. Long-term follow-up outcomes were good for children with aseptic meningitis, but 20 percent of children were reported with attention-deficit ADHD-like symptoms, compared with only 3 percent in the control group. One in five children with hand-foot-and-mouth disease with serious neurological complications such as encephalitis, polio paralysis and encephalomyelitis present with sequelae, most commonly resulting in limb weakness and muscle atrophy. Taiwan Chang et al. reported that there are moderate degree of neurological damage of the hand, foot and mouth disease patients, 10% of patients with sequelae of ataxia, the use of stage management treatment strategy, although significantly reduced the case fatality rate, but neurological complications of children after 2.9 (1.0-7.4) years of follow-up found that 28 cases of neurogenic cardiopulmonary failure 18 cases (64%) left limb weakness and muscle atrophy sequelae, 17 cases (61%) require nasal feeding, 16 cases (57% of patients) Long-term respiratory support is required. 5% of patients with simple neurological impairment experience neurodevelopmental delay, while 75% of children with complicated cardiopulmonary failure have neurodevelopmental delay (P<0.001< SPAN="">).