Protein Energy Malnutrition Significantly Increases Mortality and Adverse Outcomes in Acute Myelogenous Leukemia (AML) Patients with Neutropenic Fever: Findings of a Nationwide Inpatient Sample Analysis

Introduction: Neutropenic fever is a major cause of morbidity and mortality in all malignancies, especially acute leukemia. Protein energy malnutrition (PEM) is also a well-established risk factor for overall cancer related mortality. Acute myelogenous leukemia (AML) patients are frequently afflicted with neutropenic fever due to protracted neutropenia and community acquired, nosocomial, and opportunistic infections. They are also commonly malnourished due to poor oral intake, cachexia from underlying disease, and the toxicity of chemotherapy. To date, few studies have attempted to link neutropenic fever and PEM outcomes in AML. We thus aim to explore the prevalence and outcome of PEM in patients with AML and neutropenic fever.

Methods: The Nationwide Inpatient Sample (NIS) database for 2016 and 2017 was searched for patients with primary discharge diagnosis of AML who had NF. This group was divided based on the presence or absence of PEM. The primary outcome was a comparison of inpatient mortality between the groups. Secondary outcomes included diagnosis of sepsis, mean total hospital charges (THC) and mean length of hospital stay (LOS). Outcomes were compared using multivariate regression analysis adjusting for sociodemographic and hospital characteristics and Charlson comorbidity index as a marker of severity.

Results: A total of 10145 admissions met the inclusion criteria with AML and NF. Among the included patients, 1700 (16.7%) had PEM. Patient with PEM were significantly older (58.1 vs 55.2 years of age, p<0.001) but had no significant difference in sex (52.0 vs 55.0% females, p=0.308) and racial distribution, compared with patients without PEM. Overall, 825 (8.1%) hospitalizations had inpatient mortality. Patients with PEM had significantly higher adjusted odds ratio (aOR) of mortality (aOR: 2.00, 95% CI 1.335 - 2.998), developing sepsis (aOR: 2.06, 95% CI 1.514 - 2.812), as well as increase mean difference in LOS(8.6 days, 95% CI 5.77 - 11.37) and THC (105,600 USD 95% CI 57,000 - 154,000), compared to patients without PEM.

Conclusion: PEM is associated with a significantly adverse outcome in patients with febrile neutropenia-- an almost double mortality rate and increased risk of complications like sepsis, increased LOS, and hospital costs. Neutropenic patients are markedly susceptible to fulminant systemic infections from various sources. PEM furthers this risk via weakening of host defenses including natural barriers and both innate and acquired immunity. Furthermore, in neutropenic patients with systemic infections, malnutrition may delay and impede wound healing along with immune responses which often contributes to a protracted course and adverse outcome.

Nutrition in neutropenia has garnered limited attention, with some randomized trials showing limited to no benefit of the "neutropenic diet" in patients while depriving them of essential macro- and micronutrients. Nonetheless, current management guidelines for malnutrition in malignancies, particularly acute leukemias, are sparse. The profound impact of malnutrition in febrile neutropenia patients warrants further study, and we thus recommend further attention to screening practices and management strategies alongside primary treatment for malignancy and infection.