This review found limited data on the value of initial serum biomarkers for predicting adverse outcomes for children with febrile neutropenia. This meant that firm conclusions could not be reached, but interleukin-6, interleukin-8 and procalcitonin required further investigation.

To review the evidence on the ability of initial serum biomarkers to predict adverse outcomes from febrile neutropenia in children and young people with cancer.

Nine databases, including DARE and MEDLINE, were searched up to February, 2009 for cohort studies of the diagnostic ability of serum biomarkers, taken within 12 hours of the onset of febrile neutropenia, in children up to 18 years old. Case-control studies were excluded.

The adverse outcomes assessed were bacteraemia, invasive fungal infection, significant or documented bacterial infection, sepsis and death. The diagnostic performance of each biomarker was compared with a reference standard: survival, need for intensive or high-dependency care, single organ impairment, invasive bacterial or fungal infection, presence of documented infection, or time in hospital. The data were combined in random-effects meta-analyses, where possible, otherwise a narrative synthesis was reported.

Two reviewers independently screened studies for inclusion. Quality was assessed using 11 of the 14 QUADAS criteria, and the data were extracted by one researcher and confirmed by a second. Disagreements were resolved by consensus. Foreign-language papers were processed by a reviewer and a translator together.

Twenty-five studies (2,089 patients; 3,585 episodes of febrile neutropenia) were included; they assessed 14 biomarkers. Quality varied; most studies did not report blind interpretation of the test and outcome.

In the meta-analysis of seven studies (731 episodes), C-reactive protein (>50mg/dL) for documented infection had a sensitivity of 0.65 (95% CI 0.41 to 0.84), and a specificity of 0.73 (95% CI 0.63 to 0.82).

In the meta-analysis of three studies (216 episodes), procalcitonin (>0.2mg/mL) for documented infection had a sensitivity of 0.96 (95% CI 0.05 to 0.99), and a specificity of 0.85 (95% CI 0.53 to 0.97).

In the meta-analysis of three studies (457 episodes), interleukin-6 (>235 picograms/mL) for documented infection had a sensitivity of 0.68 (95% CI 0.15 to 0.96), and a specificity of 0.94 (95% CI 0.84 to 0.98). In the meta-analysis of two studies (166 episodes), interleukin-6 (>1,000 picograms/mL) for gram negative bacteraemia had a sensitivity of 0.78 (95% CI 0.57 to 0.91), and a specificity of 0.96 (95% CI 0.92 to 0.99).

There was significant heterogeneity for almost all analyses. The predictive values for the nine other biomarkers varied greatly, and were subject to bias.

The limited data on the predictive value of biomarkers for children with febrile neutropenia meant that firm conclusions could not be reached. Interleukin-6, interleukin-8 and procalcitonin as biomarkers of adverse outcomes required further investigation.

Support received from the Medical Research Council, UK.