- Journal Details
- Format
- Journal
- eISSN
- 1581-3207
- First Published
- 30 Apr 2007
- Publication timeframe
- 4 times per year
- Languages
- English
Infections are important cause of morbidity and mortality in cancer patients.1 Neutropenia is a major risk factor for the development of infection in cancer patients undergoing treatment with chemotherapy.2,3 Fever remains the most prevalent and evident sign of infection in neutropenic cancer patients and early initiation of broad-spectrum antibiotic therapy significantly reduces mortality in these patients.4–7
Fever is a phylogenetically ancient host defense response to variety of infectious and non-infectious triggers. It is a result of upregulation of the hypothalamic thermostatic set point due to the complex interplay between endogenous and exogenous pyrogens, enzymatic and neuronal pathways and endogenous antipyretic neuropeptides and hormones.8–11 Pyrogenic cytokines concurrently trigger production of acute phase reactants and stimulate activation of various metabolic, endocrinologic and immunologic systems.12 Data from clinical observations and observational studies show that fever may have a beneficial effect on morbidity and mortality caused by the non-life-threatening infections.8,11,12 However, in some neutropenic cancer patients fever may be absent despite microbiologically and/or clinically confirmed infection.5 According to the Infectious Disease Society of America (IDSA) and some other guidelines afebrile neutropenic patients with new signs or symptoms of infection are considered to be at high-risk for complications and therefore prompt use of empirical antimicrobial agents is recommended.13–15 Nevertheless, the level of evidence for this recommendation is weak (B-III) and is based on the extensive clinical experience of the Panel members.13
Afebrile infections are not unique to neutropenic cancer patients. Even more, published data shows that non-neutropenic patients with afebrile severe infections, especially those with hypothermia, have higher mortality rates compared to febrile non-neutropenic patients.8,16,17
We conducted a retrospective study to evaluate the incidence and characteristics of severe infections in afebrile neutropenic cancer patients undergoing treatment with chemotherapy at our cancer center. Furthermore, we hypothesized that afebrile neutropenic cancer patients with severe infections have worse outcome as compared to cancer patients with febrile neutropenia.
We performed an electronic database search to identify all adult cancer patients, who were transferred from the Department of Medical Oncology to the Intensive Care Unit (ICU) at the Institute of Oncology Ljubljana due to the severe neutropenic infection between January 2000 and December 2011. All eligible patients for this study were required to have a severe infection due to a chemotherapy-induced neutropenia. Multiple episodes of neutropenic infections in one patient were considered as separate events. All information on relevant patients’ characteristics, cancer treatment and episodes of infections were retrieved retrospectively from patients’ charts. All data were extracted by a single author.
Febrile neutropenic infections were defined as at least one axillary body temperature measurement of ≥ 38°C in the presence of neutropenia (absolute neutrophil count < 1 × 109/l at the time of diagnosis of infection with further decline to < 0.5 × 109/l during the following days). Afebrile neutropenic infections were defined as a maximum axillary body temperature < 38°C within 72 hours of diagnosis of neutropenic infection, which had to be micro-biologically and/or clinically documented. Severe neutropenia was defined as an absolute neutrophil count ≤ 0.1 × 109/l.
Infection was considered microbiologically documented when a positive culture was yielded from the site of infection, and clinically documented when there were clinical and/or radiological signs of infection without microbiological confirmation. Characteristics of organisms isolated from blood cultures were recorded. At least two positive blood culture sets were required when
We calculated the Multinational Association for Supportive Care in Cancer (MASCC) Risk Index score for each patient as described by Klastersky
Our retrospective study was approved by the Institutional Review Board and Ethics Committee (#ERID-KESOPKR/74).
We used descriptive statistics to describe relevant patients’ characteristics. The outcome of interest was 30-day in-hospital mortality rate, as proposed by Feld
We identified 69 episodes of neutropenic infections in 65 cancer patients treated with chemotherapy, who required admission to the ICU during the 11-year period. Four patients had two separate episodes of febrile neutropenic infection. Baseline patients’ characteristics, cancer type and treatment are summarized in Table 1.
Patients received a median of one cycle (range 1–9 cycles) of treatment with chemotherapy prior to the episode of neutropenic infection. Median overall length of hospitalization and hospitalization in the ICU were 14 days (range 1–52 days) and 5 days (range 1–34 days), respectively.
A median MASCC score was 14 (range 0–21). Only two episodes were considered low-risk according to the MASCC score. In the remaining 67 high-risk episodes, 35 had the MASCC score < 15. Thirty patients (43.5%) had severe neutropenia at the onset of neutropenic infection. In 21 (30.4%) and 19 (27.5%) episodes patients received either prophylactic or therapeutic granulocyte-colony stimulating factors (G-CSF), respectively.
Infections were microbiologically documented in 53 (76.8%) episodes. Out of the remaining 16 clinically documented infections, 13 were confirmed radiologically or with ultrasound (12 pneumonias and one cholecystitis), two patients had fever with clinical signs of septic shock and one had cellulitis. Details about the sites of infection are listed in Table 1.
Bloodstream and lower respiratory tract were the most common sites of infection. The most common microbiological isolates from blood cultures were gram-negative bacteria in 72% (
Median time from the diagnosis of neutropenic infection to the ICU admission was 10 hours (range 0 hours – 27 days). Reasons for ICU admission were septic shock in 39 (56.5%) patients, severe sepsis in 20 (29%) patients, pulmonary thromboembolism in three patients and seven patients were already in the ICU at the onset of neutropenic infection. In 61 (88.4%), 30 (43.5%), 6 (8.7%) and 11 (15.9%) episodes vasopressors and/or inotropes, mechanical ventilation, dialysis and surgery were required, respectively.
Baseline patients’ characteristics, cancer type and treatment
| Characteristics | N (%) (n = 69) | |
|---|---|---|
| Median age (range) | Elderly (> 65 years) | 58 years (31–86) 28 (40.6%) |
| Sex | Male | 42 (60.9%) |
| Female | 27 (39.1%) | |
| Cancer type | Lymphoma | 52 (75.4%) |
| Solid tumors | 17 (24.6%) | |
| Chemotherapy treatment intent | Neo/adjuvant solid or 1st-line lymphoma | 35 (50.7%) |
| 1st-line solid or 1st-relaps lymphoma | 13 (18.8%) | |
| 2nd-line solid or 2nd-relaps lymphoma | 12 (17.4%) | |
| ≥ 3rd-line solid or ≥ 3rd-relaps lymphoma | 9 (13.1%) | |
| CCI | Low (0) | 28 (40.6%) |
| Medium (1–2) | 30 (43.5%) | |
| High (3–4) | 8 (11.6%) | |
| Very high (≥ 5) | 3 (4.3%) | |
| ACE-27 | None (G0) | 17 (24.6%) |
| Mild (G1) | 16 (23.2%) | |
| Moderate (G2) | 13 (18.9%) | |
| Severe (G3) | 23(33.3%) | |
| WHO performance status | 0–2 | 54 (78.3%) |
| 3–4 | 15 (21.7%) | |
| Bone marrow infiltration | Yes | 22 (31.9%) |
| No | 29 (42.0 %) | |
| Unknown | 18 (26.1%) | |
| Previous neutropenic infection | Yes | 24 (34.8%) |
| No | 45 (65.2%) | |
| Site of infection Includes 53 episodes of microbiologically documented infection (MDI) and 16 episodes of clinically documented infection (CDI) | Bloodstream | 25 (36.2%) |
| Lower respiratory tract Pneumonias with 13 cases of MDI and 12 cases of CDI with radiological signs only | 25 (36.2%) | |
| Gastrointestinal tract Includes cases of cholecystitis, peritonitis, neutropenic enterocolitis | 13 (18.8%) | |
| Upper respiratory tract | 2 (2.9%) | |
| Urinary tract | 1 (1.5%) | |
| Skin and soft tissue | 1 (1.5%) | |
| Unexplained fever CDI with fever and signs of septic shock | 2 (2.9%) | |
| Time period of ICU admission (year) | 2000–2003 | 8 (13.6%) |
| 2004–2011 | 51 (86.4%) |
ACE-27 = adult comorbidity evaluation-27 index; CCI = Charlson comorbidity index; ICU = Intensive Care Unit; WHO = World Health Organization
Sixty (87%) episodes of neutropenic infections were febrile and only 9 (13%) episodes, which occurred in 9 patients, were afebrile. Median age of patients with afebrile infection was 56 years (range 41–82 years). All were considered high-risk with a median MASCC score of 13 (range 7–18). There were no differences between patients with afebrile and febrile neutropenic infection with regard to age, sex, comorbidities, status at the time of diagnosis of neutropenic infection, MASCC score, severity of neutropenia, type of infection, rate of Gram negative or polymicrobial bacteremias and time to the ICU admission. However, patients with afebrile neutropenic infection were more likely to have solid tumors (Table 2).
Comparison between patients with afebrile and febrile neutropenic infection
| Characteristics | Afebrile (n = 9) | Febrile (n = 60) | p-value | |
|---|---|---|---|---|
| Age (years) | < 65 | 4 | 24 | 1.0 |
| ≤ 65 | 5 | 36 | ||
| Sex | Male | 4 | 38 | 0.28 |
| Female | 5 | 22 | ||
| Cancer type | Lymphoma | 3 | 49 | 0.005 |
| Solid tumors | 6 | 11 | ||
| CCI | Low (0) | 5 | 23 | 0.47 |
| Medium - very high (≥ 1) | 4 | 37 | ||
| ACE-27 | None - mild (G0–1) | 5 | 28 | 0.73 |
| Moderate - severe (G2–3) | 4 | 32 | ||
| Status at diagnosis | Inpatient | 3 | 34 | 0.29 |
| Outpatient | 6 | 26 | ||
| MASCC score | < 15 | 5 | 30 | 1.0 |
| ≥ 15 | 4 | 30 | ||
| Severe neutropenia | Yes | 3 | 27 | 0.72 |
| No | 6 | 33 | ||
| Type of infection | MDI | 8 | 45 | 0.33 |
| CDI | 1 | 15 | ||
| Bloodstream infection n = 25 | Gram negative also includes polymicrobial bacteremias with at least one Gram negative bacteria | 4 | 16 | 0.55 |
| non-Gram negative | 0 | 5 | ||
| Mean time to the ICU (hours) | 41 | 54 | 0.73 |
ACE-27 = adult comorbidity evaluation-27 index; CCI = Charlson comorbidity index; CDI = clinically documented infection; ICU = Intensive Care Unit; MASCC = Multinational Association for Supportive Care in Cancer; MDI = microbiologically documented infection
Five patients were afebrile throughout the episode of infection, in two patients there was a history of fever at home, and two patients developed fever on the 5th and 7th day of hospitalization, respectively, due to a secondary, health care-associated infection. The highest recorded temperature within 72 hours of diagnosis of neutropenic infection was 37.2°C or lower in five patients, and between 37.4 and 37.8°C in the remaining four patients.
Six patients (66.7%) received drugs with potential antipyretic effect (non-steroidal anti-inflammatory drugs, paracetamol, corticosteroids, meta-mizole) at least once within 48 hours prior and 72 hours after the diagnosis of neutropenic infection, five intermittently and only one continuously. Similarly, 56.7% of patients with febrile neutropenic infection received drugs with potential antipyretic effect (p = 0.73). There was no difference in the rate of afebrile neutropenic infections in patients who received drugs with antipyretic effect compared to patients who did not (15%
Presenting clinical signs and symptoms of infection in afebrile neutropenic patients were hypo-tension, severe fatigue with inappetence, shaking chills, altered mental state and cough, in descending order of frequency. All of them eventually deteriorated to severe sepsis or septic shock.
Eight patients (89%) had microbiologically documented infections: four had gram-negative bacteremias (two
In all patients with severe neutropenic infection 30-day in-hospital mortality rate was 55.1%. In four patients, who experienced two separate episodes of severe neutropenic infection, two survived both episodes and two had fatal outcome during the second episode. Thirty (79%) deaths occurred in the ICU and the remaining deaths occurred after the ICU discharge. Cause of death was attributed to the uncontrolled infection in 31 patients, pulmonary thromboembolism in three, comorbidities in two, and cancer progression in two patients. In patients with afebrile neutropenic infection episode 30-day in-hospital mortality rate was 78%. While in six patients death occurred due to the uncontrolled infection, one patient died due to the cancer progression. The remaining two patients who survived had radiologically documented pneumonia and
Prognostic factors associated with 30-day inhospital mortality are listed in Table 3. Patients with afebrile neutropenic infection had a trend for a higher 30-day in-hospital mortality rate as compared to patients with febrile neutropenic infection (78%
Prognostic factors associated with 30-day in-hospital mortality
| Prognostic factors | Died (n = 38) | Survived (n = 31) | p-value | |
|---|---|---|---|---|
| Age (years) | >65 | 17 | 11 | 0.44 |
| ≤ 65 | 21 | 20 | ||
| Cancer type | Lymphoma | 29 | 23 | 0.84 |
| Solid tumors | 9 | 8 | ||
| CCI | Low (0) | 17 | 11 | 0.44 |
| Medium - very high | 21 | 20 | ||
| (≥1) | ||||
| ACE-27 | None - mild (G0-1) | 20 | 13 | 0.38 |
| Moderate - severe | 18 | 18 | ||
| (G2-3) | ||||
| G-CSF prophylactic | Yes | 14 | 7 | 0.2 |
| No | 24 | 24 | ||
| G-CSF therapeutic | Yes | 12 | 7 | 0.41 |
| No | 26 | 24 | ||
| Fever status | Febrile | 31 | 29 | 0.17 |
| Afebrile | 7 | 2 | ||
| MASCC score | < 15 | 25 | 10 | 0.006 |
| ≥ 15 | 13 | 21 | ||
| Bloodstream infection | Yes | 15 | 10 | 0.54 |
| No | 23 | 21 | ||
| Mechanical ventilation | Yes | 26 | 4 | P < 0.001 |
| No | 12 | 27 | ||
| Lactic acidosisa | Yes | 7 | 0 | 0.04 |
| No | 31 | 27 | ||
| Time period of ICU admission (year) | 2000–2003 | 4 | 4 | 1.0 |
| 2004–2011 | 34 | 27 |
ACE-27 = adult comorbidity evaluation-27 index; CCI = Charlson comorbidity index; G-CSF = granulocyte-colony stimulating factors; ICU = Intensive Care Unit; MASCC = Multinational Association for Supportive Care in Cancer;
n = 65
Fever in neutropenic cancer patients with infections is only rarely absent and may predict worse outcome.13–15 In our study we identified 69 episodes of severe neutropenic infection in 65 cancer patients, among which 9 (13%) episodes were afebrile. All afebrile neutropenic infection episodes were either microbiologically and/or radiologically documented and all progressed to severe sepsis or septic shock. Patients with afebrile neutropenic infection had a trend for a higher 30-day in-hospital mortality rate as compared to patients with febrile neutropenic infection (Table 3).
Majority of published studies to date, which evaluated cancer patients with neutropenic infections, included only patients with febrile neutropenia. Sickles
Published data show that 18–40% and 10–20% of non-neutropenic patients develop normothermia or hypothermia, respectively, despite infection with severe sepsis or septic shock.9,16,24–29 However, definitions of fever, normothermia and hypothermia differed in published studies. Recently published study by Weinkove
According to our results, overall mortality rate in the ICU was 55.1% and was in line with published results of other studies.31–35 Lower MASCC score (MASCC score <15), need for mechanical ventilation and lactic acidosis at the time of the ICU admission were associated with significantly higher 30-day in-hospital mortality (Table 3). These observations are in line with previously reported studies in patients with severe infections.32,34,36–39 Although studies have reported improved survival rates of critically ill cancer patients during the past decade as compared to later time periods, in part due to implementation of the Surviving Sepsis Campaign guidelines, we did not find any significant difference in mortality rates between patients treated in the ICU before and after 2004 (50
Furthermore, reported mortality rates in this sub-population are consistently higher compared to normothermic or febrile patients, and are in range between 50–80%.24–29,42 In contrast, data on patients with normothermic response to severe infection are inconsistent.24–28 Results of recently published large multicentric retrospective registry study, which included 4027 patients with neutropenic sepsis, showed that patients with neutropenic sepsis and peak temperature below 36.5°C (hypothermia) within the first 24 hours of admission to the ICU had approximately two-fold higher risk for in-hospital death as compared to normothermic (defined as temperatures between 36.5 and 37.4°C) patients. They did not observe any significant difference in mortality between normothermic and febrile (peak temperature of ≥ 37.5°C) patients. Similar was observed in a subgroup of patients with neutropenic sepsis and hematological malignancy.30 Due to the retrospective nature of our study and due to the small number of patients with afebrile infections further subset-analyses (hypothermic
Use of drugs with antipyretic effect (e.g. some drugs used for the management of pain, corticosteroids) could potentially block the development of fever, which may delay presentation of these patients with serious infections to medical services. However, in our study there were no differences in the use of drugs with antipyretic effect in the febrile and afebrile subgroups of patients. Also, we did not find any differences in the rate of afebrile neutropenic infections in patients who received drugs with antipyretic effect and those who did not. Results of recently published study showed that feeling unwell in the absence of fever, which is a key marker of neutropenic sepsis, might discourage patients from contacting a doctor.43 Delay of treatment with effective antimicrobial therapy in patients with severe neutropenia and bacteremia or septic shock is associated with increased mortality rates
Our study has several limitations. First, this was a retrospective, single center study with a small sample size of heterogeneous patient population and therefore our findings are only hypothesis-generating. Only patients with solid tumors and lymphomas are treated at our center; patients with acute leukemias who frequently experience neutropenic infections were thus excluded from our analysis. Second, due to the small number of patients with afebrile infection a multivariate analysis as well as further subset comparisons (e.g. hypothermic
In conclusion, afebrile infections in neutropenic cancer patients are rare. However, in cancer patients with chemotherapy-induced neutropenia and severe infections, afebrile patients might be at higher risk of death due to the complications of infection as compared to patients with febrile neutropenia. In addition, we identified lower MASCC score (MASCC score < 15), need for mechanical ventilation and lactic acidosis at the time of the ICU admission as negative prognostic factors for outcome. Patients on potentially myelosuppressive systemic cancer treatment should be informed that occasionally fever may be absent during the episode of neutropenic infection, and that they should immediately seek medical attention if signs or symptoms suggestive of infection occur, even in the absence of fever.
Prognostic factors associated with 30-day in-hospital mortality
| Prognostic factors | Died (n = 38) | Survived (n = 31) | p-value | |
|---|---|---|---|---|
| Age (years) | >65 | 17 | 11 | 0.44 |
| ≤ 65 | 21 | 20 | ||
| Cancer type | Lymphoma | 29 | 23 | 0.84 |
| Solid tumors | 9 | 8 | ||
| CCI | Low (0) | 17 | 11 | 0.44 |
| Medium - very high | 21 | 20 | ||
| (≥1) | ||||
| ACE-27 | None - mild (G0-1) | 20 | 13 | 0.38 |
| Moderate - severe | 18 | 18 | ||
| (G2-3) | ||||
| G-CSF prophylactic | Yes | 14 | 7 | 0.2 |
| No | 24 | 24 | ||
| G-CSF therapeutic | Yes | 12 | 7 | 0.41 |
| No | 26 | 24 | ||
| Fever status | Febrile | 31 | 29 | 0.17 |
| Afebrile | 7 | 2 | ||
| MASCC score | < 15 | 25 | 10 | 0.006 |
| ≥ 15 | 13 | 21 | ||
| Bloodstream infection | Yes | 15 | 10 | 0.54 |
| No | 23 | 21 | ||
| Mechanical ventilation | Yes | 26 | 4 | P < 0.001 |
| No | 12 | 27 | ||
| Lactic acidosisa | Yes | 7 | 0 | 0.04 |
| No | 31 | 27 | ||
| Time period of ICU admission (year) | 2000–2003 | 4 | 4 | 1.0 |
| 2004–2011 | 34 | 27 |
Baseline patients’ characteristics, cancer type and treatment
| Characteristics | N (%) (n = 69) | |
|---|---|---|
| Median age (range) | Elderly (> 65 years) | 58 years (31–86) 28 (40.6%) |
| Sex | Male | 42 (60.9%) |
| Female | 27 (39.1%) | |
| Cancer type | Lymphoma | 52 (75.4%) |
| Solid tumors | 17 (24.6%) | |
| Chemotherapy treatment intent | Neo/adjuvant solid or 1st-line lymphoma | 35 (50.7%) |
| 1st-line solid or 1st-relaps lymphoma | 13 (18.8%) | |
| 2nd-line solid or 2nd-relaps lymphoma | 12 (17.4%) | |
| ≥ 3rd-line solid or ≥ 3rd-relaps lymphoma | 9 (13.1%) | |
| CCI | Low (0) | 28 (40.6%) |
| Medium (1–2) | 30 (43.5%) | |
| High (3–4) | 8 (11.6%) | |
| Very high (≥ 5) | 3 (4.3%) | |
| ACE-27 | None (G0) | 17 (24.6%) |
| Mild (G1) | 16 (23.2%) | |
| Moderate (G2) | 13 (18.9%) | |
| Severe (G3) | 23(33.3%) | |
| WHO performance status | 0–2 | 54 (78.3%) |
| 3–4 | 15 (21.7%) | |
| Bone marrow infiltration | Yes | 22 (31.9%) |
| No | 29 (42.0 %) | |
| Unknown | 18 (26.1%) | |
| Previous neutropenic infection | Yes | 24 (34.8%) |
| No | 45 (65.2%) | |
| Site of infection Includes 53 episodes of microbiologically documented infection (MDI) and 16 episodes of clinically documented infection (CDI) | Bloodstream | 25 (36.2%) |
| Lower respiratory tract Pneumonias with 13 cases of MDI and 12 cases of CDI with radiological signs only | 25 (36.2%) | |
| Gastrointestinal tract Includes cases of cholecystitis, peritonitis, neutropenic enterocolitis | 13 (18.8%) | |
| Upper respiratory tract | 2 (2.9%) | |
| Urinary tract | 1 (1.5%) | |
| Skin and soft tissue | 1 (1.5%) | |
| Unexplained fever CDI with fever and signs of septic shock | 2 (2.9%) | |
| Time period of ICU admission (year) | 2000–2003 | 8 (13.6%) |
| 2004–2011 | 51 (86.4%) |
Comparison between patients with afebrile and febrile neutropenic infection
| Characteristics | Afebrile (n = 9) | Febrile (n = 60) | p-value | |
|---|---|---|---|---|
| Age (years) | < 65 | 4 | 24 | 1.0 |
| ≤ 65 | 5 | 36 | ||
| Sex | Male | 4 | 38 | 0.28 |
| Female | 5 | 22 | ||
| Cancer type | Lymphoma | 3 | 49 | 0.005 |
| Solid tumors | 6 | 11 | ||
| CCI | Low (0) | 5 | 23 | 0.47 |
| Medium - very high (≥ 1) | 4 | 37 | ||
| ACE-27 | None - mild (G0–1) | 5 | 28 | 0.73 |
| Moderate - severe (G2–3) | 4 | 32 | ||
| Status at diagnosis | Inpatient | 3 | 34 | 0.29 |
| Outpatient | 6 | 26 | ||
| MASCC score | < 15 | 5 | 30 | 1.0 |
| ≥ 15 | 4 | 30 | ||
| Severe neutropenia | Yes | 3 | 27 | 0.72 |
| No | 6 | 33 | ||
| Type of infection | MDI | 8 | 45 | 0.33 |
| CDI | 1 | 15 | ||
| Bloodstream infection n = 25 | Gram negative also includes polymicrobial bacteremias with at least one Gram negative bacteria | 4 | 16 | 0.55 |
| non-Gram negative | 0 | 5 | ||
| Mean time to the ICU (hours) | 41 | 54 | 0.73 |
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