C-reactive protein in critically ill cancer patients with sepsis: influence of neutropenia

The present study is a secondary analysis of a matched case-control study performed in the ICU of Instituto Nacional de Câncer (INCa), Rio de Janeiro, Brazil. Details of the study design, definitions and data collection are provided elsewhere [10]. Briefly, during the study period (January 2003 to July 2007), every adult cancer patient (≥ 18 yrs) that required ICU admission due to life-threatening complications was consecutively enrolled. Patients in complete remission of more than 5 yrs, those with an ICU stay less than 24 hrs and readmissions were not considered. The ICU is a 10-bed medical-surgical unit specialized in the care of patients with cancer [11, 12], with the exception of bone marrow transplant patients.

This study was supported by institutional funds and did not interfere with clinical decisions related with patient care. The Local Ethics Committee approved the study (N° 10/2003) and the need for informed consent was waived.

Infection was defined as the presence of a pathogenic microorganism in a sterile milieu (such as blood or cerebrospinal fluid) and/or clinically suspected infection that justified the administration of antibiotics [13, 14]. Sepsis severity was classified according to the consensus conference definitions [15].

Neutropenia was defined as a neutrophil count below 500/mm³[2]. Neutropenia was further classified as chemotherapy related or unrelated. During the study period, from a prospective cohort of 1,332 consecutive cancer patients, 94 patients with neutropenia and well-matched controls without neutropenia, in a 1:1 ratio, were compared [10]. For the present study, cancer patients with sepsis were segregated, 86 neutropenic and 68 non-neutropenic. Empiric antibiotic therapy was started in all septic cancer patients upon ICU admission according to to local guidelines and in accordance with the Infectious Diseases Society of America guidelines [2]. The prescription was not delayed by the collection of appropriate samples for microbiological cultures. At least two blood cultures were performed from independent venipunctures in each newly admitted patient. Additional samples for microbiological cultures were collected according to the suspected primary focus of infection.

Demographic, clinical and laboratory data were collected using standardized case report forms during the first day of ICU stay including main diagnosis for admission, the Simplified Acute Physiology Score (SAPS) II [16], the Sequential Organ Failure Assessment (SOFA) score [17], comorbidities, and cancer- and treatment-related data. For the purpose of the present study, individual organ failures were diagnosed in case of a SOFA score ≥ 2 points in each domain [14]. In addition, patients receiving dialysis in the context of acute kidney injury and invasive mechanical ventilation (MV) on the first day of ICU were considered as having renal and respiratory failures regardless the SOFA score, respectively. The ICU and hospital mortality rates were also assessed.

Blood samples were obtained via an arterial line on admission and, subsequently, every morning at 07:00 hrs. Measurement of CRP was performed by means of an immunoturbidimetric method using a commercially available kit (Tina-quant CRP; Roche Diagnostics, Mannheim, Germany). The precision of the assay measured by means of the intra- and inter-assay coefficient of variation was < 7%, the sensitivity 0.1 mg/dL and the detection limit 0.3 mg/dL. C-reactive protein was measured during the first week of ICU stay at Day 1 (D1), D3, D5 and D7.

CRP concentrations at ICU admission and during the first week of sepsis course were analysed, comparing neutropenic with non-neutropenic septic critically ill cancer patients.

Data entry was performed by a single investigator (MS) and consistency was assessed with a rechecking procedure of a 10% random sample of patients. Data were screened in detail by three investigators (MS, JIFS, VCSD) for missing information, implausible and outlying values.

Continuous variables were reported as mean ± standard deviation or median (25% to 75% interquartile range, IQR) according to data distribution. Comparisons between groups were performed using the parametric unpaired and paired t-test, or the nonparametric Mann-Whitney U test and Wilcoxon signed-rank test for continuous variables according to data distribution. The Chi-square test was used to carry out comparisons between categorical variables. Correlations were calculated by the Spearman's rank correlation. Time-dependent analysis of CRP was performed via General Linear Model univariate repeated-measures analysis using a split-plot design approach.

In all cases, statistical significance was defined as a two-tailed test with an alpha of 0.05. All statistical calculations were preformed using the PASW v. 18.0 for MAC (SPSS, Chicago, IL, USA).

A total of 154 critically ill septic cancer patients were included in the present study, 86 with neutropenia, that represents all neutropenic septic cancer patients admitted in the ICU during the study period, and the remainder without neutropenia (N = 68). The patients' main characteristics are depicted in Table 1. The sources of ICU admission were the operating room (10.4%), emergency department (16.9%) and wards (72.7%) (P = 0.238, comparing neutropenic vs. non-neutropenic patients). There were 105 (68.2%) patients with hematological malignancies and 49 (31.8%) with solid tumors (P = 0.569). The most frequent underlying malignancies were lymphomas (N = 59, 38.3%), leukemias (N = 32, 20.8%), gastrointestinal (N = 13, 8.4%), multiple myeloma (N = 9, 5.8%), urogenital (N = 8, 5.2%) and others (N = 33, 21.4%). Previous anticancer treatments included surgery for tumor resections (3.9%), chemotherapy (72.7%) and radiation therapy (23.4%). Comorbidities were indentified in 129 (83.8%) patients and the most frequent were immunosuppression (40.3%), arterial hypertension (20.4%), acquired immunodeficiency syndrome (8.4%), diabetes mellitus (6.5%) and chronic obstructive pulmonary disease (6.5%).

The length of ICU and hospital stay were (median (IQR)) 7.0 (10.3) days and 18.5 (23.6) days, respectively, without significant differences between neutropenic and non-neutropenic patients (P = 0.699 and P = 0.111, respectively). The overall ICU and hospital mortality rates were 72.1% and 79.2%, respectively, without significant differences between study groups (P = 0.472 and P = 0.211, respectively).

Most of the patients were admitted in the ICU in severe sepsis/septic shock (93.5%) as well as with a severe degree of organ failure/dysfunction (SOFA at D1, 11.4 ± 3.9 points).

Almost two-thirds of the infections were microbiologically proven infections (65.1%). As expected, the most frequent sites of infection were the lungs, abdomen and bloodstream infection. Gram-negative bacteria were responsible for 72.2% of the infection episodes and 26 (36.6%) patients had polymicrobial (more than one infectious agent) infections.

At ICU admission, temperature in septic critically ill cancer patients was not significantly different in those presenting neutropenia in comparison with non-neutropenic patients (37.2 ± 1.5°C vs. 36.8 ± 1.5°C, respectively, P = 0.119) (Figure 1). Concerning CRP (Figure 1), we found that neutropenic septic cancer patients showed a significantly higher concentration, 25.9 ± 11.2 mg/dL, in comparison with CRP concentration from non-neutropenic patients, 19.7 ± 11.4 mg/dL (P = 0.009). Additionally, among neutropenic patients CRP concentrations at ICU admission were not influenced by the severity of neutropenia (< 100/mm³ vs. ≥ 100/mm³ neutrophils), 25.1 ± 11.6 mg/dL vs. 26.9 ± 10.9 mg/dL, respectively (P = 0.527).

We also assessed the correlation between WCC and CRP concentration. We found a poor, whilst significant, correlation between these two variables (r _s = -0.252, P = 0.012).

Time dependent analysis of CRP (Figure 2) from D1 to D7 of antibiotic therapy showed an almost parallel course in both groups (P = 0.335), with almost no change from D1 to D3, followed by a significant decrease from D3 onwards; though the CRP concentration of neutropenic patients was, on average, higher in comparison to that of non-neutropenic patients. From D1 to D7, CRP concentration of neutropenic and non-neutropenic patients decreased from 25.9 ± 11.2 mg/dL and 19.7 ± 11.4 mg/dL at D1 to 14.1 ± 9.1 mg/dL and 13.1 ± 10.8 mg/dL at D7 (P < 0.001 and P = 0.009, respectively).