Drugs for paediatric hyperinflammatory syndromes

Abstract

Background: Many syndromes are associated with exaggerated inflammation. Children with hyperinflammatory syndromes often present with vague and non-specific symptoms that pose diagnostic and management challenges. The recent literature seems biased towards referring these syndromes only to the multisystem inflammatory syndrome in children (MIS-C) that is associated with COVID-19. The purpose of this paper is to provide an updated narrative review on the pathophysiology, manifestations and management approaches for common hyperinflammatory syndromes.

Methods: An extensive PubMed search of all publications in the English literature was performed with Clinical Queries for various hyperinflammatory syndromes and conditions using the undermentioned Medical Subject Headings: "hyperinflammation", "hyperinflammatory syndromes", "sepsis syndrome", "severe inflammatory response syndrome" and "acute respiratory distress syndrome". Categories were limited to reviews and clinical trials for the age range from birth to 18 years.

Results: The criteria, presentation and management of these hyperinflammatory syndromes are described. Hyperinflammatory syndromes refer to a basket of inflammatory syndromes often associated with multisystem involvement and aberrant cytokine release and should be differentiated from autoinflammatory, autoimmune and hyperimmune syndromes. The major subtypes of hyperinflammatory syndromes, including macrophage activation syndrome, haemophagocytic lymphohistiocytosis, cytokine release syndrome and cytokine storm syndrome, are described. MIS-C associated with SARS-CoV-2 represents the latest addition. It must be understood that the syndrome is not exclusive to COVID-19 but could be caused by various viral infections. Early recognition, prompt and proactive treatment can reduce potential complications and improve outcomes and survival rates in paediatric patients. Anti-inflammatory medications for the management of these syndromes are described.

Conclusion: The incidence of these hyperinflammatory conditions is generally low in comparison to other disease conditions. Except for paediatric inflammatory multisystem syndrome/MIS-C, the mortality is high and the hospital stay is prolonged in affected patients. Acute and critical care physicians must be aware of these conditions and their initial management. Corticosteroids are often used in the initial phrase but various disease-specific drugs and biologics are needed in subsequent management and expert management of these often-difficult conditions is crucial.

Keywords: COVID-19; cytokine release syndrome; cytokine storm syndrome; haemophagocytic lymphohistiocytosis; hyperinflammatory syndromes; macrophage activation syndrome; multisystem inflammatory syndrome in children.

Figure 1

Classification of the inflammatory conditions. ARDS, acute respiratory distress syndrome; CRS, cytokine release syndrome; CSS, cytokine storm syndrome; HLH, haemophagocytic lymphohistiocytosis; MAS, macrophage activation syndrome; MODS, multiorgan dysfunction syndrome; SIRS, systemic inflammatory syndrome.

Figure 2

Two models of classification of the inflammatory conditions based on cytokines. ARDS, acute respiratory distress syndrome; CRS, cytokine release syndrome; CSS, cytokine storm syndrome; HLH, haemophagocytic lymphohistiocytosis; MAS, macrophage activation syndrome; MIS-C, multisystem inflammatory syndrome in children; MODS, multiorgan dysfunction syndrome; SJIA, systemic juvenile idiopathic arthritis; SIRS, systemic inflammatory syndrome.