B-type brain natriuretic peptide as a measure of the severity of hand-foot-mouth disease: a case-control study

Hand-foot-mouth disease (HFMD) is an acute infectious disease caused by various enteroviruses, and the most common pathogens are Coxsackievirus A16 (CA16) and Enterovirus 71 (EV71). Preschool children are easily infected, and the clinical characteristics of ordinary HFMD are fever along with flat discolored spots and bumps on the hands, feet, and mouth. In severe cases of HFMD, varying degrees of neurological complications (such as encephalitis and neurogenic pulmonary edema) and circulatory complications can occur. This severe form of HFMD has a high mortality rate, and survivors often suffer from long-term sequelae [1, 2].

HFMD is an epidemic disease in most parts of the world, and the incidence of HFMD has remained high in recent years, presenting a bimodal distribution status over the course of the year [3, 4]. According to the 2011 version of the Expert Consensus of Clinical Treatment in Severe Cases of Enterovirus 71 Infection in China [5], HFMD cases are classified into two types, common and severe, and the severe type is further divided into severe HFMD and critical HFMD. The clinical progression of HFMD is described in five clinical phases: foot and mouth eruption (phase I), nervous system involvement (phase II), early cardiopulmonary failure (phase III), cardiopulmonary failure (phase IV), and recovery (phase V). Most cases of death occur in patients who reach Phases III and IV, and thus, these two phases represent the crucial period for treating severe HFMD. However, the diagnosis and prognosis of HFMD mainly rely on the patients’ clinical manifestations and signs. Therefore, the identification of objective experimental and biochemical indicators would be valuable for the prevention and clinical treatment of HFMD. Because cardiopulmonary failure is the major cause of death among HFMD patients [6], the primary goal in treating severe HFMD is to maintain the stability of cardiopulmonary circulation function.

Given that B type natriuretic peptide (BNP) is widely applied in monitoring cardiovascular disorders [7–9], we hypothesized that introduction of this index into HFMD management could be helpful in the diagnosis and prognosis of severe HFMD. BNP is mainly secreted by the ventricular myocardium, which has many physiopathological functions, such as diuresis through the natriuretic process, blood vessel dilation, lowering peripheral vascular resistance, reducing the activity of rennin-angiotensin-aldosterone, and decreasing adrenaline and the endothelial response, thereby regulating the blood volume, blood pressure, and salt balance within the human body [10]. Once myocardial cells are subjected to stretching or the myocardial wall is exposed to increased pressure, the original BNP stored in myocardial cells is released quickly and broken down into active BNP and inactive NT-proBNP [11]. Numerous studies have demonstrated that BNP is an important and valuable biomarker in the diagnosis, prognosis, and risk evaluation of conditions such as acute and chronic heart failure, sepsis, and respiratory failure due to cardiac diseases [12].

To test our hypothesis in the present study, we analyzed the data of 83 HFMD patients with or without severe complications treated in our hospital from April 2014 to March 2015 according to the severity of HFMD (common, severe, and critical; with and without complications; and survivors and non-survivors). The clinical value of BNP in relation to the clinical symptoms of HFMD was estimated and discussed.

As a viral-infection disease, HFMD has no specific treatment. Prevention, early diagnosis, respiratory support, and treatment of brain injury are the key measures to reducing the mortality of severe HFMD [5]. For prevention of HFMD, Zhu et al. performed phase III clinical trial studies with an EV71-inactivated vaccine in China [13, 14] and reported satisfactory results in terms of the protective effect and safety of the vaccine. The vaccine received a new drug certificate from the Chinese National Food Drug Administration on December 3, 2015.

For clinical treatment of severe HFMD, limiting the fluid volume and actively controlling intracranial pressure are recommended [5]; however, other opinions suggest the use of glucocorticoids and intravenous immunoglobulin [6]. Some scholars believe that early application of glucocorticoids provides an anti-inflammatory effect to reduce capillary permeability, effectively promoting recovery from pulmonary edema and brain edema [15]. Here, we studied potential indexes for the early diagnosis of severe HFMD and showed that the serum BNP level combined with other HFMD symptoms could be a biochemical indicator for complications (BNP >8.4 pmol/L), critical disease (BNP >38.8 pmol/L), and death (BNP >41.1 pmol/L) HFMD patients.

The pathological mechanism of HFMD has been a topic of research for decades. Some studies have focused on central nervous system complications in HFMD. Enterovirus was found to invade the central nervous system through lymphatic channels or peripheral sympathetic nerve channels located in the hypothalamus, dorsal nucleus, and the ventral brainstem, medial brainstem, and tail of the brainstem to cause hyperfunction of the sympathetic nervous system [16]. Pulmonary vascular permeability in severe HFMD has also been a research focus. The involvement of the central nervous system causes sympathetic nerve excitement, which leads to imbalance between beta adrenergic receptor and alpha adrenaline receptor levels in the lung, resulting in an increase in the proportion of alpha adrenaline receptor. These alterations directly increase blood capillary permeability in the lungs and plasma extravasation and cause pulmonary edema [17].

Another severe pathological effect in HFMD is immune inflammation. The complications of brain stem encephalitis and pulmonary edema caused by EV71 virus in HFMD patients are always accompanied by significant increases in serum interleukin (IL)-13, IL-10, IL-8, interferon gamma (IFN-γ), monocyte chemotactic factor 1 cytokine, natural killer (NK) cells, CD4⁺ T lymphocytes, and CD8⁺ T lymphocytes [18]. Chang et al. found that the human leukocyte antigen serotype (HLA) genes A33 and HLA-A2 are susceptibility genes [19]. The occurrence of neurogenic pulmonary edema is caused by the nervous, immune, and endocrine systems together, and as the result of comprehensive shaping by many factors, its mechanism is not fully clear.

BNP and natriuretic peptide receptors play roles in several physiological processes, such as diuresis, dilation of blood vessels, and inhibition of the rennin angiotensin-aldosterone system [10]. Recently, studies concerning BNP have greatly enriched the field of cardiac marker detection [20]. Troponin, CK-MB, and myoglobin are traditional myocardial markers of myocardial injury, whereas BNP reflects the ventricular function, and thus, is a predictor of impaired ventricular function [21, 22]. In 2008, a consensus of experts on BNP affirmed the application value of blood BNP detection in the adult cardiovascular system [12]. In a study of heart failure in children, Auerbach et al. [9] found that an elevated BNP level is an independent risk factor for prognosis in children with heart failure.

Because severe HFMD is often accompanied by obvious cardiopulmonary dysfunction, we examined the clinical value of the serum BNP level in the diagnosis and prognosis of HFMD. Our results show that the mean serum BNP level in 24 critical HFMD patients was sharply increased to an median concentration of 38.83 pmol/L, with the peak volume even reaching as high as 343.99 pmol/L. This index was significantly higher in the critical HFMD group than in the other groups (p˂0.01). However, the serum BNP levels did not differ significantly among the severe HFMD, common HFMD, and control groups. The mechanism of the BNP elevation in critical HFMD is not yet clear. A possible mechanism could be abnormal sympathetic hyperfunction in children with critical HFMD, as such hyperfunction stimulates catecholamine release into the blood, causing an increase in blood flow to the heart to increase ventricular load [6, 13, 14]. Meanwhile, increased resistance in the peripheral vasculature results in increased ventricular afterload to trigger BNP secretion. In addition, under the stress of viral toxins, some inflammatory cytokines can be released, resulting in myocardial damage to induce the release of BNP. These comprehensive factors may result in critical HFMD in pediatric patients with an abnormally increased plasma BNP level. Next, we compared the indexes between patient groups with complications and without complications as well as between survivors and non-survivors group and found that BNP is a risk factor for complications and death in HFMD patients. Its sensitivity and specificity for detecting HFMD were higher. The corresponding optimal threshold values were 8.4 pmol/L for predicting complications and 41.1 pmol/L for predicting death. However, as in common HFMD, BNP alone has a lower specificity. Because BNP is an indicator of heart ventricle injury, for use in the diagnosis of HFMD, it should be considered in combination with other HFMD symptoms and Glu and PaO₂/FiO₂ data.

WBC and Glu were found to early warning indicators of severe HFMD [5]. Overall, 22 of 24 HFMD patients (91.7%) with complications had a Glu level greater than 6.1 mmol/L, and the Glu levels in the other two cases (8.3%) were 3.9–6.1 mmol/L. No significant differences were observed between the other three indexes. Overall, our results show that a Glu level of 6.1 mmol/L could be an indicator for complications in HFMD. Lac levels were significantly greater in the critical HFMD group compared with levels in other groups, which reflects the presence of hypoxic injury. Similarly, the patient groups that experienced complications or death presented Glu levels higher than those of patients without complications and survivor. This hypoxic injury could be caused by cardiopulmonary dysfunction and failure.

The oxygenation index is important for monitoring clinical respiratory function, and was assessed in terms of the PaO₂/FiO₂ ratio among the different groups of HFMD patients in this study. The normal level is around 400–500 mmHg. A PaO₂/FiO₂ less than 300 mmHg is suggestive of respiratory dysfunction. Our results showed that the PaO₂/FiO₂ levels were significantly decreased in the critical HFMD group, the group with complications, and the group that died, indicating a dysfunctional state of the respiratory system. However, since mechanical ventilation therapy is an ordinary measure for severe HFMD patients clinically, the exact level of mechanical ventilation in patients with severe HFMD should be carefully planned and controlled. In addition, our results suggest that this index could not be used as an indicator of severe HFMD due to the possible interference of artificial ventilation.

In this study, we enrolled 83 HFMD patients with or without severe complications treated in our hospital from April 2014 to March 2015. The serum BNP level and other common clinical biochemical indexes were examined and analyzed according to the severity of HFMD (common, severe, and critical; with and without complication; and survivors and non-survivors). The results indicated that the serum BNP level could be a useful biochemical indicator for severe (critical) disease, complications, and death among HFMD patients. When used in combination with Glu and PaO₂/FiO₂ measurements as well as HFMD clinical symptoms, the new indicator (BNP) becomes more precise and specific. Our results may provide another valuable biochemical indicator for the clinical diagnosis and prognosis of severe HFMD.