Neutropenic fever during treatment of hematological malignancy : etiology and diagnostics

Abstract

Fever is the principal and sometimes the only manifestation of serious infection in the neutropenic patient because signs of inflammation may be minimal or absent in this group of patients. The aim of this thesis was to improve the clinical management of the febrile neutropenic patient. All positive blood cultures (274 episodes) collected from patients with acute myeloid leukemia during 2 7years periods (1980-86 and 1990-96) were evaluated. During the later period prophylaxis with ciprofloxacin and fluconazol was introduced as well as more frequent use of central venous catheters. The incidence of bacteremia due to viridans streptococci and coagulase-negative staphylococci increased from the first period to the second, whereas the incidence of Enterobacteriaceae decreased. In neutropenic patients treated prophylactically with fluoroquinolone during the period 1990-96, viridans streptococci accounted for 33% of the isolates. The mortality related to bacteremia during the later period was 13%.

Coagulase-negative staphylococci (CNS) are the most commonly pathogens (30-50%) from bloodstream infections in patients with hematological malignancies. We investigated 82 episodes of true CNS bacteramias and 47 blood contaminant isolates of CNS both phenotypically and genotypically. No difference was seen between the 2 groups regarding clinical symptoms, complications, and level of absolute neutrophil count or C-reactive protein (CRP) concentration. Most prevalent species, in both groups was Stapbylococcus epidermidis (80%). Two major genotypic groups of S. epidermidis were found in both groups, showing corresponding pulsotypes. The prevalence of icaAB genes did not discriminate between true bacteremias and contaminants of S. epidermidis.

Discrimination between serious infections and harmless fever episodes in neutropenic patients is difficult. Five inflammatory markers; procalcitonin (PCT), CRP, serum amyloid A (SAA), interleukin-6 (IL-6) and IL8 were evaluated as a screening test for bacteremia (other than CNS) during the 2 initial days of fever in neutropenic patients. Low positive predictive values for bacteremia were seen in all analyzed markers during the 2 days. However, a specificity of > 80% and a negative predictive value (to exclude a bacteremia) of > 85% were seen for PCT, CRP and IL-6. In the majority of neutropenic fever episodes causative infectious agents cannot be identified. After 3-5 days of fever it has been recommended to reassess anti-microbial therapy. We studied the value of determining plasma levels of PCT, CRP, SAA and IL-6 daily throughout the fever episode in neutropenic patients in order to predict clinical outcome. No marker could predict deterioration, however, daily low concentration of PCT (< 0.4 ng/ml) or IL-6 (< 50 pg/ml) 3 days after fever onset were found to be a good predictor of no subsequent complications during the fever course and therefore could be a helpful tool for limiting antimicrobial therapy.

Almost all patients with severe neutropenia (neutrophil count < 0.1 x 109/L) develop fever. Twenty (10 bacteremia and 10 fever of unknown origin (FUO)), severe neutropenic, patients were investigated whether any of 3 different herpesvirus (Cytomegalovirus (CMV), human herpesvirus-6 (HHV-6) and HHV-7) were reactivated as a possible cause of fever in FUO patients. CMV-DNA was detected in 2 of 10 FUOpatients in samples drawn during fever. However, neither of the 2 patients had symptoms of ongoing CMV infection. DNA from HHV-6 and HHV-7 was not detected in any of the febrile episodes.