SERENITY: SEveRE Neurological Impairment and children with medical complexiTY

Abstract

Background and aims Children with Severe Neurological Impairment (SNI) have a significant disability as a result of a global impairment of the nervous system. They may be considered to be a subgroup of children with more general medical complexity but have unique challenges. There is no accepted definition of SNI and therefore a paucity of research into the medical and social needs of these children and their families. There is evidence to suggest that children with SNI may have an altered inflammatory state and immune function, but there is the potential for dysfunction in almost every organ system. Extra healthcare needs may place additional pressures on the families of children with SNI, for example, financial stress and mental health difficulties. We aim to create a consensus-based definition of SNI, quantify multi-system involvement in these children, with a particular focus on inflammation and immunity, and examine their wellbeing and that of their families.

Methods The Delphi method was used to reach a consensus-based definition of SNI over 3 rounds of questionnaires with feedback to the multi-national and multi-disciplinary participants between each round. Cytokines were measured using ELISA at baseline and following stimulation with lipopolysaccharide (LPS). Flow cytometry was performed to assess the proportions and activation in response to LPS of lymphocytes, neutrophils and monocytes. Real-time PCR was used to measure expression of components of the NLRP-3 inflammasome. Blood samples were collected to assess biomarkers of cardiac and renal dysfunction, and multi-organ dysfunction was quantified using clinical outcome measures. The Pediatric Quality of Life and Caregiver Priorities & Child Health Index of Life with Disabilities questionnaires were used to assess wellbeing of the child with SNI and their families. A focus was placed on the effect on siblings of living with a brother or sister with SNI through the use of a focus group with teenage siblings

Results Thirty-four multi-disciplinary expert panellists from 5 countries participated in the Delphi process. Six items reached the 70% threshold for consensus and were included in a finalised definition of SNI. Children with SNI had alterations in several cytokine responses to LPS, with GM-CSF and IL-6 showing relative hyporesponsiveness and EPO being relatively hyperresponsive. Children with SNI had lower proportions of T cells, in particular those which were CD8+, and monocytes. Children with SNI exhibited CD66b hyporesponsiveness in neutrophils and TLR-4 hyper-responsiveness in monocytes. Children with SNI exhibited trained immunity with reduced expression of NLRP-3 and IL1 genes in response to stimulation with LPS. Creatinine was significantly lower in children with SNI than controls, reflecting their lower muscle mass. Other markers of renal function were not significantly different to controls. Troponin T and NT-proBNP were not significantly different in children with SNI. The children who participated had a median of 4 systems involved and were exposed to polypharmacy with a mean number of medications of almost 7. Families of children with SNI are significantly impacted by their child s disability. Sibling questionnaires did not show differences in markers of wellbeing but a teenage focus group exhibited the complexities of living with a brother or sister with SNI.

Conclusion We have created a consensus-based definition of SNI which we believe will improve consistency and quality of research for this group of children. Children with SNI exhibit alterations in cytokine and immune cell responses to stimulation with LPS. This raises the possibility of targeting various cytokines to improve neurological outcomes or reduce infection-related morbidity and mortality in this population. Children with SNI do not exhibit biochemical markers of renal or cardiac dysfunction but they have multi-organ dysfunction with considerable healthcare needs. We propose a multi-organ dysfunction scoring system to assist with clinical monitoring and objective measurement of outcomes in research. An understanding of the impact of caring for a child with SNI on families and their unmet needs may allow for more holistic care of these children. Siblings are also impacted by their brother s or sister s disability. Interventions to improve communication and facilitate peer support may help them to deal with the extra challenges they experience.