The key mechanisms of multi-system responses triggered by central nervous system damage in hand, foot, and mouth disease severity

Fig. 1. The time course, diagnosis, and treatment of HFMD. The data were collected and summarized according to “A Guide to Clinical Management and Public Health Response for Hand, Foot and Mouth Disease (HFMD)” from the World Health Organization; “Management of Hand Foot Mouth Disease (HFMD) in Health Care Settings (May 2007)” formulated by the Centre for Health Protection, Hong Kong, China; as well as Chinese guidelines for the diagnosis and treatment of hand, foot, and mouth disease (2018 edition). Notably, severe patients with encephalomyelitis and persistent high fever and critical cases might be considered for IVIG treatment (1.0 g/kg/day for 2 days). Autonomic nervous system, ANS; intravenous immunoglobulin, IVIG. Created with BioRender.com.

Fig. 2. Cytokine storm in HFMD pathogenesis. (A) The time-changing trend diagram illustrates the fluctuations in the serum cytokines, angiotensin (Ang) II, and noradrenaline (NA) as HFMD progresses. The dashed line denotes mild cases, and the solid line denotes severe cases. (B) If the initial immune response fails to prevent viral replication, the viruses spread throughout the body in a secondary viremia. The inflammatory response further prompts the activation of immune cells. Once the virus invades the CNS, activated glial cells, catecholamine storm, and excessive Ang II are subsequently involved with the dysregulation of cytokine expression. The extensive cytokine storm leads to incalculable damage to the body. Created with BioRender.com.

Fig. 3. Pathogenic mechanisms of PE in the progression of HFMD severity. (A) Hemodynamic changes and damage to the vascular endothelial barrier are the two primary factors contributing to pulmonary edema. Increased volume of pulmonary blood circulation; elevated pulmonary microvascular pressure resulting from pulmonary venous constriction; left heart insufficiency; and a combination of these factors cause a dramatic increase in intrathoracic blood volume with excessive hydrostatic pulmonary pressure. (B) Mechanical stress, overproduction of some hydrolases. (C) Circulating and local cytokines, ROS, and chemokine-mediated migratory infiltration of immune cells can damage the alveolar microvascular barrier, causing leakage. Inducible nitric-oxide synthase, iNOS; Intercellular cell adhesion molecule, ICAM. Created with BioRender.com.

Fig. 4. Pathways by which HEVs invade the CNS. (A) The viruses replicate rapidly in intestinal epithelial cells and then invade the CNS through retrograde axonal transport along the nerve axis, or across the BBB. (B) The viruses could cross the BBB via a paracellular or transcellular pathway. Potentially, viruses can hitch-hike across the BBB in immune cells in a “Trojan horse” fashion. Created with BioRender.com.

Fig. 5. Theoretical hypothesis diagram: multi-system dysfunction resulting from systemic hyperinflammatory response contributes to HFMD severity. HEVs invade the CNS through multiple routes, leading to the activation of glial cells. Lesions in the brainstem, thalamus, and medulla oblongata, as well as other CNS tissues, stimulate sympathetic nerves and release large amounts of neuroactive substances, such as catecholamines. Excessive catecholamines have a direct impact on related receptors, resulting in hemodynamic changes that can lead to cardiopulmonary dysfunction. Catecholamines further affect cardiopulmonary function by interacting with the RAS, exacerbating cytokine storms and aggravating regional immunity. A variety of harmful factors combine to disrupt vascular endothelial barrier function. Created with BioRender.com.