Status: Funded - Closed
Katherine Bline, MD
BACKGROUND: Children with critical illness due to viral several lower respiratory tract infections (LRTI) often have evidence of a diminished immune response, which is associated with an increased risk of death. Myeloid-derived suppressor cells (MDSCs) are a population of immune cells known to expand under conditions of critical illness that potently suppress the adaptive immune system, specifically the ability of T cells to proliferate and produce cytokines. GAP: Our understanding of why some previously healthy children become critically ill when infected with a respiratory virus while others have only mild symptoms is limited. One area where the knowledge gap is significant relates to the factors that determine outcomes in children with severe LRTI. HYPOTHESIS: We hypothesize that MDSCs are increased in frequency in children with viral severe LRTI and contribute to immune suppression and poor outcomes. METHODS: This is a single-center prospective, observational study that will be conducted in a 54-bed pediatric intensive care unit and involve sequential blood sampling of subjects with the primary measured outcome being MDSC frequencies and subtypes. The study population includes children less than 18 years with confirmed viral lower respiratory tract infection that are not known to have immunosuppression or a chronic condition, although children with mild asthma and not on an inhaled corticosteroid will be included. RESULTS: To date, we have enrolled subjects with 21 RSV (42% male, median age 6.3 [2.2,13] months, and 28 COVID-19 ( 60% male, median age 8.8 [1.0, 22.3 years]). Of the subjects with RSV, 19 required admission to the ICU while 10 of the subjects with COVID required ICU care. Children with RSV or COVID-19 had increased percentages MDSC of PBMC compared to HC (11% [5.6,20] vs 9.9% [5.2, 23] vs 0.95% [0.34, 2.8] respectively). Compared to children with COVID-19, those with RSV had higher %M-MDSC of total MDSC (96% [90,98] vs 45% (8.4, 71], p< 0.0001) and lower G-MDSC (1.3% [0.61,2] vs 38% [17,90], p<0.0001). Those with RSV also had higher % CD4+ T regulatory cells of total CD4+ T cells (7.8% [6.5, 9.0] vs 4.3% [3.3, 5.8], p=0.004), lower CD8+ T cells (21% [17,25] vs 28% [21,43], p=0.04) and lower NK cells (4% [2.4, 5.6] vs 7.7% [3.2, 22], p=0.04) and were more likely to require positive pressure ventilation (PPV) (75% vs 30%, p=0.017). IMPACT: The findings of this proposal have the potential to provide a fresh approach to identify novel therapeutic targets for children with severe LRTI, stratifying by MDSC subset predominance and associated primary mechanism of action mediating T cell suppression. Targeting MDSCs unlocks immunotherapies as a new therapeutic paradigm for children with severe LRTI.