Imidazoquinoline Toll-like receptor 8 agonists activate human newborn monocytes and dendritic cells through adenosine-refractory and caspase-1-dependent pathways.

BACKGROUND: Newborns have frequent infections and manifest impaired vaccine responses, motivating a search for neonatal vaccine adjuvants. Alum is a neonatal adjuvant but might confer a T(H)2 bias. Toll-like receptor (TLR) agonists are candidate adjuvants, but human neonatal cord blood monocytes demonstrate impaired T(H)1-polarizing responses to many TLR agonists caused by plasma adenosine acting through cyclic AMP. TLR8 agonists, including imidazoquinolines (IMQs), such as the small synthetic 3M-002, induce adult-level TNF from neonatal monocytes, but the scope and mechanisms of IMQ-induced activation of neonatal monocytes and monocyte-derived dendritic cells (MoDCs) have not been reported. OBJECTIVE: We sought to characterize IMQ-induced activation of neonatal monocytes and MoDCs. METHODS: Neonatal cord and adult peripheral blood monocytes and MoDCs were cultured in autologous plasma; levels of alum- and TLR agonist-induced cytokines and costimulatory molecules were measured. TLR8 and inflammasome function were assayed by using small interfering RNA and Western blotting/caspase-1 inhibitory peptide, respectively. The ontogeny of TLR8 agonist-induced cytokine responses was defined in rhesus macaque whole blood ex vivo. RESULTS: IMQs were more potent and effective than alum at inducing TNF and IL-1ß from monocytes. 3M-002 induced robust TLR pathway transcriptome activation and T(H)1-polarizing cytokine production in neonatal and adult monocytes and MoDCs, signaling through TLR8 in an adenosine/cyclic AMP-refractory manner. Newborn MoDCs displayed impaired LPS/ATP-induced caspase-1-mediated IL-1ß production but robust 3M-002-induced caspase-1-mediated inflammasome activation independent of exogenous ATP. TLR8 IMQs induced robust TNF and IL-1ß in whole blood of rhesus macaques at birth and infancy. CONCLUSIONS: IMQ TLR8 agonists engage adenosine-refractory TLR8 and inflammasome pathways to induce robust monocyte and MoDC activation and represent promising neonatal adjuvants.

Parental Perspectives on Continuous Pulse Oximetry Use in Bronchiolitis Hospitalizations.

BACKGROUND: Because of the impact of continuous pulse oximetry (CPOX) on the overdiagnosis of hypoxemia in bronchiolitis, the American Academy of Pediatrics and the Choosing Wisely campaign have issued recommendations for intermittent monitoring. Parental preferences for monitoring may impact adoption of these recommendations, but these perspectives are poorly understood. METHODS: Using this cross-sectional survey, we explored parental perspectives on CPOX monitoring before discharge and 1 week after bronchiolitis hospitalizations. During the 1-week call, half of the participants were randomly assigned to receive a verbal statement on the potential harms of CPOX to determine if conveying the concept of overdiagnosis can change parental preferences on monitoring frequency. An aggregate variable measuring favorable perceptions of CPOX was created to determine CPOX affinity predictors. RESULTS: In-hospital interviews were completed on 357 patients, of which 306 (86%) completed the 1-week follow-up. Although 25% of parents agreed or strongly agreed that hospital monitors made them feel anxious, 98% agreed that the monitors were helpful. Compared to other vital signs, respiratory rate (87%) and oxygen saturation (84%) were commonly rated as "extremely important." Providing an educational statement on CPOX comparatively decreased parental desire for continuous monitoring (40% vs 20%; P < .001). Although there were no significant predictors of CPOX affinity, the effect size of the educational intervention was higher in college-educated parents. CONCLUSIONS: Parents find security in CPOX. A brief statement on the potential harms of CPOX use had an impact on stated monitoring preferences. Parental perspectives are important to consider because they may influence the adoption of intermittent monitoring.