Neutrophils constitute the main mechanism of host defense against infection and serve as an essential component of innate immunity. The degree and duration of neutropenia were identified as key factors related to the risk and outcome of infection in 1979 [
However, patients with febrile neutropenia may be a heterogeneous group in terms of medical complications and mortality, with a limited number of patients developing serious medical complications [
This study aimed to identify the prognostic factors predicting poor outcome in patients with cancer who presented with febrile neutropenia at the ED. Moreover, the characteristics and outcomes in these patients were retrospectively analyzed, and the independent variables that can be easily assessed and used at the ED to predict patients who are at risk of developing potentially serious complications were identified.
This was a single-center retrospective study that investigated the prognostic factors predicting poor outcome in patients with cancer who presented with febrile neutropenia at the ED from January 2014 to December 2017. This study was conducted in a university hospital in Korea, which is a tertiary hospital with 60,000 patients according to an annual census of ED visits, and was approved by the institutional review board of the hospital (IRB no. 2018-05-004). The need for informed consent was waived.
The medical records of patients diagnosed with febrile neutropenia at the ED during the 5-year study period were reviewed from the computer database. Patients with malignancies and those who were older than 18 years were included. Febrile neutropenia was defined as an absolute neutrophil count (ANC) < 1,000/mm3 with a temperature greater than 38°C. Only the first episode of febrile neutropenia in a patient during the study period was considered.
Patients were divided into two groups: those who were admitted at the intensive care unit (ICU) or those who died during hospitalization (case group) and those who were admitted at general wards and were discharged (control group). The two groups were compared to determine the factors associated with poor prognosis.
The following information on the case and control groups was obtained by reviewing the medical charts: age, sex, comorbidities, clinical manifestations (ED visit on weekends, change in mental status, duration of fever [> 24 h], presence of central venous catheter, and hospital-acquired infection), type and origin of malignancy, and history of chemotherapy. Vital signs at triage and laboratory results, including microbiologic test results, were recorded, and the quick sequential (sepsis-related) organ failure assessment (qSOFA) score was calculated. The presumed source of infection, empirical antimicrobial therapy, time from ED visit to the administration of antibiotics, appropriateness of the empirical therapy, and use of granulocyte colony-stimulating factor were identified. Clinical outcome variables, such as vasopressor use, need for mechanical ventilation, ICU admission, do not resuscitate (DNR) order, and duration of hospitalization, were also documented.
The time from fever onset to ED admission was defined as the time from the onset of subjective symptoms (based on patient history) to ED visit. Central venous catheter included medication ports and peripherally inserted central catheters. The qSOFA score included a systolic blood pressure (BP) ≤ 100 mmHg, RR ≥ 22/minute, and altered mental status [
When focal infection could not be identified, the source was categorized as undetermined. The time from ED visit to the administration of antibiotics is defined as the time in minutes from presentation to triage to the first dose of parental antibiotics and is considered as a continuous variable. The initial empirical antimicrobial therapy was considered appropriate if the initial antibiotics included at least one antibiotic that was active in vitro and if the dosage was in accordance with current medical standards. Otherwise, initial antimicrobial therapy was considered inappropriate.
Data with a normal distribution were expressed as mean ± standard deviation and were analyzed using the independent samples t-test. Data with a skewed distribution were expressed as medians and interquartile ratios and were analyzed using the Mann–Whitney U test. Categorical variables were compared using
We identified 104 patients with cancer who presented with febrile neutropenia at the ED during the study period. The case group consisted of 25 patients who were admitted at the ICU or those who died during hospitalization, whereas the control group included the remaining 79 patients who were admitted at general wards and were discharged. Demographic and clinical data comparing the groups are presented in Table
Comparison of clinical characteristics of 104 cancer patients presented with febrile neutropenia to the emergency department including 25 case patients who admitted to the intensive care unit or died in the hospital and 79 control patients who admitted to general wards and discharged.
Characteristics | Total (n = 104) | Case (n = 25) | Control (n = 79) | P value |
---|---|---|---|---|
Age | 60.8 ± 13.6 | 63.6 ± 12.9 | 61 (51-69) | 0.255 |
Male, no. (%) | 41 (39) | 14 (56) | 27 (34) | 0.052 |
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Comorbid conditions, no. (%) | ||||
Diabetes mellitus | 14 (13) | 5 (20) | 9 (11) | 0.316 |
Cardiovascular disease | 6 (6) | 1 (4) | 5 (6) | 1.0 |
Respiratory disease | 5 (8) | 1 (4) | 4 (5) | 1.0 |
Chronic renal failure | 8 (8) | 3 (12) | 5 (6) | 0.394 |
Liver cirrhosis | 3 (3) | 1 (4) | 2 (3) | 0.565 |
Rheumatologic disease | 1 (1) | 1 (4) | 0 | 0.240 |
Neurodegenerative disease | 6 (6) | 2 (8) | 4 (5) | 0.628 |
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Clinical manifestation | ||||
ED visits on weekends | 36 (35) | 9 (36) | 27 (34) | 0.868 |
Mental change | 6 (6) | 3 (12) | 3 (4) | 0.148 |
Fever > 24 hr | 33 (32) | 4 (16) | 27 (34) | 0.343 |
Presence of central venous catheter | 17 (16) | 4 (16) | 13 (16) | 1.0 |
Hospital-acquired type | 9 (9) | 2 (8) | 7 (9) | 1.0 |
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Solid tumor, no. (%) | 69 (66) | 14 (56) | 55 (70) | 0.211 |
Breast | 34 (33) | 5 (20) | 29 (37) | 0.146 |
Gastrointestinal tract | 14 (13) | 4 (16) | 10 (13) | 0.738 |
Lung | 7 (7) | 0 | 7 (9) | 0.191 |
Hepatobiliary tract | 6 (6) | 2 (8) | 4 (5) | 0.628 |
Ovary | 3 (3) | 0 | 3 (4) | 1.0 |
Others | 5 (5) | 3 (12) | 2 (3) | 0.088 |
Stage IV | 34 | 10 | 24 | 0.712 |
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Hematological malignancy, no. (%) | 35 (34) | 11 (44) | 24 (30) | |
Leukemia | 11 (11) | 5 (20) | 6 (8) | 0.211 |
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History of Chemotherapy | ||||
none | 3 | 1 | 2 | |
oral chemotherapy | 5 | 3 | 2 | |
Intravenous chemotherapy | 96 | 21 | 75 | |
Latency > 2 months | 7 | 3 | 4 | |
< 2months, days | 12.5 (10-15) | 11 (7.7-13.0) | 12.5 (10-15) | 0.043∗ |
ED: emergency department.
The mean age of the participants was 61 years, and diabetes mellitus was the most frequent comorbidity (18%). Approximately 35% of the patients visited the ED during weekends, and 32% had fever for more than 24 h prior to their visit. Moreover, 16% of the patients had central venous line in place, and 9% presented with hospital-acquired infection. No statistical difference was observed between the groups in terms of comorbidities, ED visit during weekends, duration of fever, presence of a central venous line, and hospital-acquired infection.
Of the 104 patients, 69 had a solid tumor, and 35 presented with hematological malignancies. Among the solid tumors, the most frequent origin was the breast, followed by the gastrointestinal tract and the lungs. Around 49% (34 out of 69) of the patients presented with stage IV solid tumor. Leukemia occurred in 11% of the patients.
Approximately 89 patients (18 and 71 from the case and control groups, respectively) received chemotherapy within 2 months, and the median delay between chemotherapy and ED visit was 12.5 days, ranging from 10 to 15 days.
Table
Comparison of vital signs and laboratory findings of 25 case patients and of 79 control patients with neutropenic fever in the emergency department.
Characteristics | Total (n = 104) | Case (n = 25) | Control (n = 79) | P value |
---|---|---|---|---|
Vital signs on presentation | ||||
SBP, mm Hg | 119.1 ± 21.6 | 106.7 ± 24.6 | 122 (110-135) | 0.001∗∗ |
DBP, mm Hg | 70.8 ± 14.3 | 62.0 ± 14.1 | 73.6 ± 13.3 | 0.0003∗∗∗ |
PR, beats/min | 110 (92-128) | 119.7 ± 18.9 | 106.0 (88.5-124.7) | 0.013∗ |
RR, breaths/min | 18 (18-20) | 20 (18-24) | 18 (18-20) | 0.252 |
Body temperature, °C | 38.4 (38-38.9) | 38.5 (38.0-38.1) | 38.3 (38.0-38.7) | 0.649 |
Saturation, % | 97 (96-98) | 96.0 (93.1-97.0) | 97 (96-98) | 0.001∗∗ |
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qSOFA | 0.49 ± 0.63 | 0.88 ± 0.78 | 0.36 ± 0.53 | 0.0003∗∗∗ |
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Complete blood cell counts | ||||
Leukocyte count, x109cells/mL | 1120(615-1570) | 710 (462-1473) | 1170 (702-1625) | 0.056 |
ANC | 205 (84-567) | 174 (67-335) | 222 (101-666) | 0.087 |
Profound neutropenia, no. (%) | 29 (28) | 10 (25) | 19 (24) | 0.123 |
Hemoglobin, g/dL | 9.6 ± 2.1 | 8.1 ± 2.2 | 10.3 (9.1-11) | < 0.0001∗∗∗ |
Platelet, x103/ | 95 (52-178) | 52 (27-114) | 123 (68-188) | 0.002∗∗ |
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Other laboratory findings | ||||
CRP, mg/dL | 5.5 (3-12.6) | 10.2 (6.5-17.7) | 4.0 (2.2-9.5) | < 0.0001∗∗∗ |
Lactic acid, mmol/L | 1.9 (1.4-2.5) | 2.15 (1.4-5.0) | 1.75 (1.4-2.35) | 0.126 |
Glucose, mg/dL | 131 (112-161) | 159 ± 55.4 | 129 (112-147) | 0.106 |
Total bilirubin, mg/dL | 0.7 (0.5-1.1) | 0.9 (0.5-1.2) | 0.6 (0.4-0.9) | 0.029∗ |
Creatinine, mg/dl | 0.77 (0.62-0.96) | 0.97 (0.74-2.01) | 0.72 (0.62-0.89) | 0.001∗∗ |
Albumin, g/dL | 3.5 (3.2-3.8) | 3.1 ± 0.4 | 3.7 (3.3-3.8) | 0.0004∗∗∗ |
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Arterial blood gas | ||||
pH | 7.47 (7.44-7.49) | 7.46(7.43-7.49) | 7.47 ± 0.03 | 0.124 |
PCO2, mm Hg | 31.5 ± 5.7 | 30.6 ± 8.1 | 31.9 ± 4.6 | 0.334 |
PO2, mm Hg | 81.2 (73.7-94.8) | 78.7 (69.6-95.9) | 81.6 (78.8 -91.4) | 0.402 |
HC | 22.7 (20.8-24.9) | 20.2 ± 4.8 | 23.4 ± 2.8 | 0.0002∗∗∗ |
SpO2, mm Hg | 96.7 (95.3-97.7) | 96.2 (94-97.5) | 96.8 (95.5-97.7) | 0.150 |
qSOFA: quick sepsis-related organ failure assessment; ANC: absolute neutrophil count; CRP: C-reactive protein.
The presumed source of infection and the results of the microbiologic study are summarized in Table
Comparison of source of infection and treatment outcome of 25 case patients and of 79 control patients with neutropenic fever in the emergency department.
Characteristics | Total (n = 104) | Case (n = 25) | Control (n = 79) | P value |
---|---|---|---|---|
Source of infection, no. (%) | 26 (25) | 13 (52) | 13 (16) | 0.0004∗∗∗ |
Respiratory tract | 9 (9) | 3 (12) | 6 (8) | 0.446 |
Urinary tract | 6 (6) | 1 (4) | 5 (6) | 1.0 |
Gastrointestinal tract | 2 (2) | 1 (4) | 1 (1) | 0.424 |
Hepatobiliary tract | 3 (3) | 1 (4) | 2 (3) | 0.565 |
Skin and soft tissue | 58 (26) | 6 (24) | 52 (66) | 0.0003∗∗∗ |
Unknown | ||||
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Bacteremia, no (%) | 12 (12) | 6 (24) | 6 (8) | 0.035∗ |
Combination therapy, no (%) | 21 (20) | 8 (32) | 13 (16) | 0.093 |
Time from ED visit to antibiotics, min | 107 (83-135) | 101 (85-119) | 110.5 (83-139) | 0.324 |
Inappropriateness of antibiotics, no (%) | 1 out of 7 | 1 out of 11 | 1.0 | |
Use of G-CSF, no. (%) | 58 (56) | 14 (56) | 44 (56) | 0.978 |
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Use of vasopressor, no. (%) | 16 (15) | 14 (56) | 2 (3) | < 0.0001∗∗∗ |
Intubation, no. (%) | 6 (6) | 6 (24) | 0 | |
ICU care, no. (%) | 20 (19) | 20 (80) | 0 | |
DNR order, no. (%) | 7 (28) | 0 | ||
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Hospital days | 7 (5-12) | 11 (6.7-22) | 7 (4-10.7) | 0.010∗ |
In-hospital death, no (%) | 12 (12) | 12 (48) | 0 |
ED: emergency department; G-CSF: granulocyte-colony stimulating factor; ICU: intensive care unit; DNR: do not resuscitate.
Bacteremia was more frequently observed in the case group than in the control group (24% vs. 8%, respectively; p=0.035). Among the case patients, 6 had bacteremia; 2 presented with
Table
With regard to clinical outcomes, vasopressor was used in 15% of the patients and in 6% of the patients who were intubated at the ED. Moreover, 20 out of the 104 (20%) patients were admitted at the ICU. The in-hospital mortality rate was 12% (12 out of 104 patients), and 5 patients with DNR order were not admitted at the ICU and then died within 24 hours of ED visit.
Table
Logistic regression analysis of prognostic factors in cancer patients with febrile neutropenia in the emergency department.
Characteristics | Simple logistic analysis | Multiple logistic analysis | ||
---|---|---|---|---|
OR (95% CI) | P value | OR (95% CI) | P value | |
Vital signs on presentation | ||||
SBP, mm Hg | 0.95 (0.93-0.98) | 0.0005∗∗∗ | ||
DBP, mm Hg | 0.94 (0.90-0.97) | 0.0003∗∗∗ | ||
PR, beats/min | 1.02 (1.00-1.05) | 0.011∗ | ||
Saturation, % | 0.84 (0.71-1.00) | 0.002∗∗ | ||
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qSOFA | 4.62 (1.17-18.22) | 0.285∗ | ||
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Laboratory findings on presentation | ||||
Hemoglobin, g/dL | 0.51 (0.33-0.78) | 0.002∗∗ | ||
Platelet, x103/ | 0.99 (0.98-0.99) | 0.002∗∗ | ||
CRP, mg/dL | 1.09 (1.03-1.15) | 0.0006∗∗∗ | ||
Total bilirubin, mg/dL | 7.69 (1.29-45.8) | 0.025∗ | ||
Creatinine, mg/dl | 3.52 (1.48-8.37) | 0.0004∗∗∗ | ||
Albumin, g/dL | 0.17 (0.06-0.50) | 0.0004∗∗∗ | ||
Bacteremia, no (%) | 3.84 (1.11-13.2) | 0.036∗ | ||
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Arterial blood gas | ||||
HC | 0.77 (0.66-0.90) | 0.0002∗∗∗ | ||
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Infection focus, no. (%) | ||||
Respiratory tract | 29.65 (3.81-230.7) | 0.0012∗∗ |
CI: confidence interval; OR: odds ratio.
Two models were used to predict the outcome of febrile neutropenic episode. Talcott et al. [
To the best of our knowledge, only a few studies [
The second difference is that our study did not only focus on chemotherapy-induced neutropenia. In fact, it included all causes of neutropenia in patients with cancer. Neutropenia can develop in patients with cancer because of the disease itself that involves the bone marrow. However, severe infection can also cause neutropenia. Because the present study aimed to identify the prognostic factors of febrile neutropenia, which were generally applicable to patients with cancer who visit the ED, we included all causes of neutropenic episodes. In fact, 15 out of 104 patients in our study presented with neutropenia despite the absence of recent chemotherapy within 2 months, of which 8 patients were either admitted at the ICU or died. Consequently, the possibility of febrile neutropenia and the subsequent development of complications should still be considered in patients with cancer even without the history of recent chemotherapy.
Based on our study, the independent predictors significantly correlated with ICU admission, and in-hospital mortality was associated with the qSOFA score, hemoglobin level, total bilirubin, and respiratory tract infection. The qSOFA is a new screening tool for sepsis that has a prognostic performance equal to the full SOFA for patients with suspected infection outside the ICU [
This study has several limitations. First, this is single-center retrospective study. Moreover, it is possible that the significant prognostic factors related to ICU admission or in-hospital mortality were not identified due to the small sample size of the study. For instance, other studies have identified chronic obstructive pulmonary disease (COPD) [
Emergency physicians must identify patients who are at risk because the prognosis of patients with severe infection depends on their initial management. The qSOFA and the presence of pneumonia can be a useful bedside tool for patients with cancer who present with febrile neutropenia in the ED. The results of the present study may help emergency physicians identify high-risk patients, thus preventing the development of complications by ordering prompt blood culture and subsequently administering broad-spectrum antibiotics.
The data used to support the findings of this study are available from the corresponding author upon request.
The authors of this study have no conflicts of interest to report.