BACKGROUNDInvasive pneumococcal disease (IPD), pneumonia (PNE), and otitis media (OM) are significant causes of morbidity among children in the United States (US). While studies have evaluated the economic burden of these conditions, recent data on episodic costs of IPD, PNE, and OM requiring hospitalization or ambulatory care only among US children by age and comorbidity profile are currently not available. This study was undertaken to address this evidence gap.METHODSA retrospective observational cohort design and data (2015-2019) from Optum's de-identified Clinformatics® Data Mart Database were employed. Episodes of IPD, all-cause PNE, and all-cause OM were ascertained on a monthly basis during the follow-up period and stratified by care setting (hospital vs. ambulatory); all-cause OM was alternatively stratified by disease severity (acute, persistent, tympanostomy tube placement) and, for acute/persistent, by complexity (simple, complex). Mean episodic costs of disease were estimated for children aged <1, 1-<2, 2-<6, and 6-<18 years, respectively, overall and by comorbidity profile (with vs. without ≥1 medical condition).RESULTSMean age-specific cost of IPD hospitalization ranged from $40,575-$95,607; IPD requiring care in an emergency department (ED), from $2,013-$5,606; and IPD requiring care in other ambulatory settings, from $619-$1,103. Mean cost of all-cause PNE ranged from $16,631-$21,429 for hospitalized cases; $2,462-$2,685 for ED cases; and $424-$473 for other ambulatory cases. Corresponding ranges for all-cause OM were $14,599-$16,341; $1,190-$2,083; and $253-$514. Children with (vs. without) comorbidities had higher mean costs of PNE episodes across all ages and care settings; mean cost of all-cause OM was largely invariant by comorbidity profile and was highest for episodes involving TTP.CONCLUSIONSCosts of IPD, all-cause PNE, and all-cause OM are high, particularly in the hospital setting. All-cause PNE, one of the most common causes of hospitalization for children, is particularly costly for children with comorbidities.