Use of Interleukin 6, High Sensitivity CRP, TNFα and Procalcitonin as Early Markers of Sepsis in Febrile Neutropenic Children.

Objective: Children with cancer often develop febrile illnesses after cytotoxic chemotherapy. It is of paramount importance to determine which children have serious bacterial infections in this vulnerable period. We studied the ability of interleukin 6 (IL-6), high sensitivity C-Reactive Protein (hsCRP), tumor necrosis factor alpha (TNFα) and procalcitonin (PCT) to act as a sensitive diagnostic marker for bacterial sepsis in febrile neutropenic children and their utility as a predictive marker for serious infections.

Design: Prospective cohort study.

Setting: Sir Ganga Ram Hospital.

Patients: Sixty-two episodes in children (aged 5 months to 17 yrs) with a known malignancy/aplastic anemia who presented with fever and neutropenia.

Interventions: Serial blood samples were obtained (admission, and 48 hrs), and concentrations of PCT, IL-6, TNF α and hsCRP were determined. Demographic and laboratory data from the patients were collected from the medical records.

Measurements and Main Results: Out of 62 episodes of febrile neutropenia, fifteen (24%) of the children had proven sepsis (13 positive blood cultures, 1 invasive aspergillosis and 1 local abscess with fever). Plasma levels of IL-6, hsCRP, TNFα and PCT were increased at all time points in children with sepsis compared with those without sepsis. In culture positive patients the value of TNF-alpha was higher but statistically not significant. No major differences were found in hsCRP concentrations. IL-6 at 0 and 48 hrs were reliable markers for sepsis (area under the curve 0.73 and 0.77, respectively). Using cutoff values of IL-6 > 137.5 pg/mL at 0 hrs and >69 pg/mL at 48 hrs of admission produced a screening test for sepsis with 67% sensitivity, 75% specificity at 0 hrs and 75% sensitivity and 78% specificity at 48 hrs respectively. Also using the cutoff values of 1.73ng/ml for procalcitonin at 0 hrs was a good screening test with 73%sensitivity and 70% specificity. When IL-6 cutoff was brought down to 20pg/ml at 0 hr then sensitivity increased to 100%. 42/62 children with febrile neutropenia had IL6 >20 which included all 15 proven sepsis cases and all 6 deaths. Rest of 20 patients all had negative cultures and no deaths. PCT value of >1 ng/ml was seen in 39/62 and included 12 of 15 cases of proven sepsis. PCT was < 1ng/ml in a case of invasive aspergillosis and another case of candida line infection and a case of local abscess with fever.

Conclusions: Our data shows the utility of a rapid and sensitive assay for interleukin-6 along with procalcitonin as a sensitive diagnostic marker of bacterial sepsis in febrile neutropenic children. The use of these markers as a clinical tool may allow for early discharge on oral antibiotics or no antibiotics in patients with IL6 less than 20 pg/ml and PCT less than 1 ng/ml.