Comorbidity of Neurally Mediated Syncope and Allergic Disease in Children

Abstract

Neurally mediated syncope (NMS) is the most common underlying disease of pediatric syncope, which generally includes vasovagal syncope (VVS), postural tachycardia syndrome (POTS), and situational syncope. Allergic diseases involving the respiratory system, digestive system, skin, and other systems are prevalent in children. In recent years, increasing attention has been paid to children with the comorbidity of NMS and allergic diseases. This article reviews the featured clinical manifestations and pathogenesis of the comorbidity according to the progress of related studies. Clinical studies have shown that the comorbidity rate of pediatric VVS and/or POTS with allergic diseases amounts to ~30-40%, referring to the whole population of children with VVS and/or POTS. Additionally, children with the comorbidity present some relatively special clinical characteristics. A series of mechanisms or regulatory factors relating to allergies, such as the imbalance of vasoactive elements, dysfunction of the autonomic nervous system (ANS), and autoimmunity may play a role in the development of the comorbidity. Moreover, 90% of children with cough syncope, a type of situational syncope, have a history of asthma, indicating a potential relationship between asthma and NMS. Further studies exploring the clinical characteristics and pathogenesis of the comorbidity are still needed to aid in the diagnosis and treatment of children with NMS.

Keywords: allergic diseases; asthma; comorbidity; neurally mediated syncope; postural tachycardia syndrome; vasovagal syncope.

Figure 1

The production of vasoactive inflammatory mediators in type I anaphylaxis of airway. Inspiratory allergens, such as pollens, enter through the damaged airway epithelial cells. Then, DCs capture the allergens, present the antigens to Th0, and promote cell differentiation from Th0 to Th2. Th2 then produces cytokines, such as IL-4, IL-5, and IL-13. IL-5 can induce the aggregation of eosinophils, and IL-4 and IL-13 not only promote the production of NO by activating iNOS, but also stimulate Beff to produce IgE. The combination between antigen and antibody causes effector cells (e.g., MC, BAS) to produce and release histamine, leukotriene, etc., by degranulating, thus acting on peripheral blood vessels to mediate vasodilation and increase vascular permeability and resulting in relative central hypovolemia. DC, Dendritic cell; Th0, naive CD4+T cells; Th2, T cell type 2; Beff, Effector B cell; MC, Mast cell; BAS, Basophil; IL-4, Interleukin-4; IL-5, Interleukin-5; IL-13, Interleukin-13; iNOS, Inducible nitric oxide synthase; IgE, Immunoglobulin E.

Figure 2

Bidirectional regulatory mechanisms between LT and other inflammatory mediators. ET-1 and TNF-α can induce the production of LTC₄ by acting on the mast cells as well as eosinophils. Conversely, studies in vitro have shown that LTD₄ can induce the production of TNF by stimulating the high-affinity receptor on macrophages, and LTC₄ can also regulate the production of ET-1. NO can increase the production of LT through human mast cells, and LTB₄, LTC₄, and LTD₄ can also promote NO release by activating the polymorphonuclear granulocyte surface receptors. LTB₄, Leukotriene B₄; LTC₄, Leukotriene C₄; LTD₄, Leukotriene D₄; LT, Leukotriene; ET, Endothelin; TNF, Tumor necrosis factor; NO, Nitric oxide.

Figure 3

Summary of the underlying mechanisms of the comorbidity of allergic diseases and NMS. The underlying mechanisms of the comorbidity of allergic diseases and VVS and/or POTS involve vasoactive factors associated with allergy, dysfunction of ANS, and autoimmunity. The comorbidity of allergic diseases and cough syncope is supposed to be related to changes in thoracic compliance and autonomic nervous reflex. VVS, Vasovagal syncope; POTS, Postural tachycardia syndrome; ANS, Autonomic nervous system.