Outcome of severe infections in afebrile neutropenic cancer patients

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 coagulase-negative staphylococci or other potential skin contaminants (e.g. Corynebacterium spp., Propionibacterium spp., Bacillus spp.) were isolated. Polymicrobial bacteremia was defined as more than one organism isolated from blood culture specimens obtained within 24 hours of the first positive blood culture specimen in a single patient.¹⁸

We calculated the Multinational Association for Supportive Care in Cancer (MASCC) Risk Index score for each patient as described by Klastersky et al.¹⁹ Comorbidities were evaluated using the adult comorbidity evaluation-27 index (ACE-27) and Charlson comorbidity index (CCI).^20,21 Severe sepsis and septic shock were defined according to the established 2001 International Sepsis Definitions Conference criteria.²²

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 et al.²³ Association between the outcome and different prognostic factors and comparison of different characteristics between febrile and afebrile patients were evaluated using Chi-square or Fisher’s exact test as appropriate. To compare mean time from the diagnosis of neutropenic infection to the ICU admission between afebrile and febrile patients we used independent-samples t-test. Due to the small number of events a multivariate analysis was not feasible. All significance tests were two-sided using an alpha level of 0.05. No correction was applied for multiple statistical testing.

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% (E.coli in eight, Pseudomonas aeruginosa in three, Stenotrophomonas maltophilia in three, Klebsiella pneumoniae in two, Acinetobacter baumannii in one and unidentified non-fermenting gram-negative bacteria in one episode). Gram-positive bacteria were isolated from three out of 25 positive blood cultures (Enterococcus faecalis, Streptococcus pneumoniae and methicillin-resistant Staphylococcus aureus). In one case anaerobic bacteremia was identified (Clostridium tertium). There were two cases of polymicrobial blood infection (with E.coli, Enterococcus faecalis and Candida albicans in one, and Enterobacter asburiae, Proteus mirabilis and Enterococcus faecalis in the other). Candidemia with Candida albicans was seen in one case.

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.

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).

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% vs. 10.3%, respectively, p = 0.72).

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 E.coli, one Klebsiella pneumoniae, one Pseudomonas aeruginosa), two had polymicrobial peritonitis, one had a gram-positive pneumonia and one had a gram-negative urinary tract infection but without blood culture drawn. One patient had a radiologically documented pneumonia.

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 Pseudomonas aeruginosa bacteremia.

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% vs. 52%, p = 0.17). MASCC score < 15 (71% vs. 38%, p = 0.006), lactic acidosis (100% vs. 53%, p = 0.04) and use of mechanical ventilation (87% vs. 31%, p < 0.001) were all associated with significantly higher 30-day in-hospital mortality rates. We did not find any significant association between the mortality and age, cancer type, comorbidities as assessed by the two different comorbidity indexes, presence of bloodstream infection, use of G-CSF and time period of ICU admission.