Characterization of Fever in Pediatric Patients at First Presentation of Acute Leukemia

Newly diagnosed children with leukemia commonly present with fever at the time of diagnosis; however, the cause of fever is not always clear, and differentiating between infection-related fever and fever due to other leukemia-related factors is critical for optimal patient management. Additionally, some patients present with fever despite substantial numbers of residual neutrophils, which may indicate decreased neutrophil function and reserve. We hypothesized that review of a large cohort of children presenting with leukemia could elucidate the causes of fever in this population and dictate evidence-based antibiotic guidelines.

In this study, features of patients ages 0 to 21 years presenting with leukemia at Children's Hospital Los Angeles between January 2017 and January 2022 were analyzed through retrospective chart review. Relapsed and transferred patients were excluded. Fever was documented as well as microbiological infection and complete blood count (CBC) with differential parameters from within 24 hours of the febrile episode. Differences between groups were assessed via Wilcoxon/Kruskal-Wallis rank sum tests and Fisher's exact tests, as appropriate, and p < 0.05 was considered statistically significant.

Of 336 patients in the study cohort, 180 (53.6%) presented with fever prior to initiation of chemotherapy. The majority of patients were male (58%), Hispanic/Latino (63%) and diagnosed with B-ALL (65%). Median [interquartile range (IQR)] age at diagnosis was significantly lower in febrile patients than non-febrile patients (6.6 [3.4, 12.4] vs 9.2 [3.9, 14.9] years, respectively; p=0.028). The febrile group also had a higher proportion of male patients (63% vs 51%; p=0.027); however, there were no differences in race/ethnicity (64% vs 62% Hispanic, p=0.7) or leukemia subtype (p=0.6). Of the 180 febrile patients, 114 (63%) were diagnosed with B-ALL, 15 (8.3%) with T-ALL, 39 (22%) with AML, and 12 (6.7%) with mixed-phenotype or undifferentiated acute leukemia. Patients with T-ALL had the highest median [IQR] WBC (K/uL) compared to the other groups (T-ALL: 147.7 [97.3, 315.4], AML: 17.0 [5.9, 79.3], B-ALL: 5.1 [2.7, 46.9], other: 31.9 [2.7, 95.9]; p < 0.001), as well as the lowest proportion of neutropenic patients (T-ALL: 13%, AML: 44%, B-ALL: 61%, other: 58%; p = 0.002). The majority of the febrile cohort (175 patients, 97.2%) received antibiotics. A total of 17 (9.4%) of the febrile patients had positive blood (14) or urine (3) cultures. Positive cultures included the following organisms: blood - 7 coagulase-negative Staphylococci, 2 Streptococcus mitis/oralis, 1 S. aureus, 1 P. aeruginosa, 1 Fusobacterium spp., 1 Moraxella spp., 1 Bacillus spp., and urine - 2 E. coli, 1 S. aureus; 9 of these 17 patients were not neutropenic. Although T-ALL patients showed the highest infection incidence (T-ALL: 27%, AML: 7.7%, B-ALL: 8.2%, other: 9.1%), these differences were not statistically significant (p = 0.2).

These data suggest that the incidence of fever at diagnosis of pediatric leukemia at our institution supports previous literature, and that documented infection is rare in children presenting with leukemia. In this study, we determined for the first time that younger patients and male patients were more likely to be febrile. In addition, similar numbers of neutropenic and non-neutropenic patients were found to have an infection, leading to the interpretation that some patients may have a functional neutropenia. A limitation of this study is that functional neutropenia could not be determined, since functional assays were not employed at this institution. In addition, two of the five years of the study were conducted during the COVID-19 pandemic, which could have impacted the incidence of infections due to isolation measures. Future directions of this study include examination of subsequent fate of febrile patients to determine if fever at diagnosis could be predictive of future fever and infection during treatment.

No relevant conflicts of interest to declare.