Results
A total of 35 patients presenting with FN and culture confirmed
bacteremia, as well as, 35 matched controls (sex, age, category of
malignancy and degree of neutropenia) with negative blood cultures were
included in the study (70 total presentations of FN). Controls did not
demonstrate diagnostic tests concerning for either a non-hematogenous
bacterial infection or fungal infection. Nine of the 35 controls (26%)
had a positive respiratory viral panel which was considered to be the
cause of their fever, while the remaining 26 (74%) were considered to
have FN of an unknown cause. All controls experienced spontaneous
resolution of symptoms with symptomatic treatment and were discharged
home without complications (development of healthcare-associated
infection, sepsis, need for ICU admission, or death).
Patient demographic data and the frequency of presenting signs/symptoms
often used for FN risk stratification are included in Table 2. Overall
age ranged between 1.4 and 18.8 years old. Average age was 10.7 (± 6.3)
and 10.0 (± 5.9) years for the cohort and control groups respectively.
Twenty patients were female (57%) and 34 (97%) had presenting ANC’s
< 500 cells/µL. Absolute monocyte count (AMC) was <
100 cells/µL in 24 of the controls (69%) and 22 (63%) of the cohort
patients. Twenty-three matched cohort-control patient pairs (66%) were
categorized as having Leukemia/Lymphoma, 8 (23%) as having a solid
tumor and 4 (11%) as being status-post HSCT.
There was no statistically significant difference in peak temperature
(Tmax), pre-acetaminophen temperature, or the total number of days of
fever between the two groups (p = 0.080, 0.71 and 0.20 respectively).
Temperatures 1-hour after acetaminophen administration were
significantly different between the cohort and controls (p = 0.040).
Patients in the cohort were found to have a higher mean temperature 1-hr
after acetaminophen administration (101.2°F/38.4°C vs. 100.0°F/37.8°C
for the controls). Additionally, presence of a pre-acetaminophen
temperature ≥ 39°C was significantly more common among culture positive
patients (p = 0.044). Despite these distinctions, no significant
relationship was seen between the presence of a fever (temperature ≥
100.4°F/38.0°C) 1-hour after acetaminophen and bacteremia (p = 0.16).
Temperatures 2- and 6-hours after acetaminophen administration were not
significantly different between the groups (p = 0.35 and 0.15
respectively). Changes in patient temperatures between the
pre-acetaminophen,1-, 2- and 6-hour time points were also not
significantly different between the groups. Mean mg/kg dosing of
acetaminophen was not significantly different between groups (p = 0.35).
Details regarding average values and significance of different
temperature endpoints is detailed in Table 3.
Data regarding the timing of antibiotic administration was collected for
both groups to account for possible impacts of early antibiotic
administration on temperature among patients with bacteremia. Analysis
showed no difference between the groups in duration of antibiotic
coverage (hours) at the 1-hr post-acetaminophen time point (p = 0.14).
Additionally, linear regression analysis demonstrated that duration of
antibiotic coverage (hours) at the 1-hr post-acetaminophen time point
was not predictive of patient temperatures among those patients with
positive blood cultures (p = 0.22). Two patients in the study cohort
were on prophylactic levofloxacin at time of presentation; however,
administration of prophylactic levofloxacin was not found to differ
significantly between the groups (p = 0.49).
Given the significant relationship seen between patients with culture
confirmed bacteremia and temperatures 1-hour after initial acetaminophen
administration, pre-acetaminophen temperature ≥ 39°C, evidence of focal
infection and hypotension, a stepwise binary logistic regression was
performed to assess the ability of these variables to predict bacteremia
in this patient population. Regression modeling demonstrated that
temperature 1-hour after acetaminophen was the only variable with
significant predictive value for bacteremia (p = 0.011). A receiver
operating characteristic (ROC) curve was generated using this regression
model (Figure 1) and demonstrated an area under the cure (AUC) of 0.70.
Characterization and regression tree (CART) analysis was also performed
to construct an additional model and identify optimal breakpoints in
temperature 1-hr after acetaminophen administration. Modeling was again
performed with inclusion of pre-acetaminophen temperature ≥ 39°C,
evidence of focal infection and hypotension variables. An optimal
decision tree for determination of bacteremia was constructed and is
detailed in Figure 2. Sensitivity and specificity for the CART model
were 62.9% and 74.3% respectively. The AUC-ROC of the CART model for
the test arm was 0.71 (Figure 3). Examination of the CART decision tree
breakpoints demonstrated that 12 of 14 patients (85.7%) with
temperature ≤ 99.2°F/37.3°C 1-hr after acetaminophen were blood culture
negative. Likewise, 4 of 5 patients (80%) with temperatures
> 102.5°F/39.2°C 1-hr after acetaminophen were culture
positive. All patients with hypotension or evidence of focal infection
displayed positive blood culture results. Relative variable importance
(defined as % improvement with respect to the CART model’s top
predictor) demonstrated temperature 1-hr after acetaminophen as the
models most important variable for predicting bacteremia (Figure 4).