Influence of air quality on clinical acuity at presentation in pediatric patients with newly diagnosed Acute Myeloid Leukemia

Abstract

Abstract Introduction: Clinical acuity at presentation is a predictor of mortality and a mediator of racial disparities in early mortality in pediatric acute myeloid leukemia (AML). However, the drivers of acuity at presentation are largely unknown. Ambient air pollutants such as ozone (O3) and fine particulate matter (PM2.5) have been linked to exacerbations of cardiopulmonary disease and sepsis severity in adults but have not been evaluated in pediatric cancer. The exposome is an emerging concept which considers the cumulative influence of internal and external factors on health, providing a novel lens to examine environmental exposures. Leveraging georeferenced census-tract-level data and an exposome framework, we assessed air quality as a previously unstudied risk factor for acuity at presentation. Methods: This was a retrospective cohort analysis of the multi-institutional REAL-AML cohort, which includes patients <19 years with newly diagnosed AML treated at 17 U.S. institutions from 2011 onward. Residential addresses at the time of diagnosis were geocoded to the 2010 Census tract designation and linked with Environmental Protection Agency (EPA) air quality data and area-level metrics from the American Community Survey. Ambient PM2.5(µg/m3) and O3(ppb) were summarized in accordance with EPA standards, averaged over the three-years preceding diagnosis. Air quality measures were analyzed dichotomously based on compliance with EPA thresholds and as standardized continuous measures. Inclusion criteria included initial presentation to the frontline treating institution and a verified geocoded address with three years of available air quality data. Intensive care unit (ICU) resource utilization was obtained via linkage to the Pediatric Health Information System (PHIS) database. The primary outcome was ICU resource use within 72 hours of presentation. Secondary outcomes were organ-specific (cardiovascular, respiratory, renal) ICU support and high acuity designation (ICU support for ≥ 2 organ systems). Modified Poisson regression with robust standard errors was performed to estimate relative risks (RR) and 95% confidence intervals (CI). Models were adjusted for age, sex, race/ethnicity, insurance type, body mass index, and neighborhood-level disadvantage (National Disorganization Index score). Results: Of 902 REAL-AML patients with verified addresses and available air quality data, 815 with complete covariates and PHIS linkage comprised the analytic cohort (median age 8.8 years; 49% female; 16% non-Hispanic Black; 25% Hispanic; 50% public-only insurance). Median PM2.5was 9.5 µg/m3 with a standard deviation (SD) of 1.38, and median O3 was 66.5 ppb (SD 7.16). Seventy percent of patients resided in census tracts which were nonadherent to EPA standards for at least one air quality measure. Non-Hispanic Black and Hispanic patients were disproportionally represented in noncompliant areas compared to non-Hispanic White patients (p <0.001). Noncompliant O3 exposure was associated with increased ICU utilization (RR 1.42, 95% CI: 1.11-1.83) and respiratory ICU support (RR 1.36, 95% CI: 1.04-1.77) within the first 72 hours. While PM2.5noncompliance alone was not linked to early ICU use, higher PM2.5levels were associated with high acuity at presentation (RR 1.44 per SD, 95% CI: 1.05-1.99) and cardiovascular ICU support (RR 1.51 per SD, 95% CI: 1.08-2.11). Concurrent noncompliance for both pollutantsdemonstrated higher risks for ICU use (RR 1.57, 95% CI: 1.12-2.20) as well as respiratory and cardiovascular ICU support. Renal replacement therapy was rare, precluding multivariate analyses. Conclusion: To our knowledge, this is the first study to evaluate the influence of ambient air quality on clinical acuity outcomes in pediatric AML. Elevated ozone exposure was associated with increased respiratory ICU needs, while higher PM2.5levels were linked to multi-organ, and particularly cardiovascular, ICU support. These associations persisted after accounting for demographic variables, proxied socioeconomic status, and neighborhood-level factors. Ongoing work will evaluate the influence of air quality exposure on treatment-related toxicities and overall survival. Beyond the broader implications for policy, we aim to understand how modifiable environmental exposures may impact these clinical outcomes in order to mitigate disparities and improve outcomes in pediatric AML.