Review question
To systemically review, critically appraise, and synthesise information on the use of serum markers for the prediction of the outcome of febrile neutropenic episodes in children/young adults with cancer.

Search strategy
Relevant electronic sources will be searched for clinically relevant prediction studies. Reference lists of relevant systematic reviews and included articles will also be reviewed. Authors of relevant studies may be contacted as time allows to seek further studies, as this is likely to be a poorly indexed area of biomedical research. Published and unpublished studies will be sought and no language restrictions applied. Non-English language studies will be translated if time permits. Two reviewers will independently screen the title and abstract of studies for inclusion. Disagreements will be resolved by consensus, or if this proves impossible, by recourse to an independent adjudicator.

Types of study to be included
Studies will be included in the review if they meet the following criteria.

Population
Children or young adults (aged 0 – 18y) who are receiving treatment for cancer or leukaemia (including extra-cranial and intra-cranial tumours) presenting with febrile neutropenia. Studies of adults which report data for patients <18y will be included, if outcome data for children are reported separately.

Predictor variables Serum inflammatory/infectious markers (for example including, but not limited to, C-reactive protein (CRP), procalcitonin or interleukin levels) measured within the first 12 hours where timing of samples is reported.

Outcomes (any of) Survival, need for intensive care, need for high-dependency care, single organ impairment (oxygen requirement, renal impairment, hepatic impairment), invasive bacterial or fungal infection, any documented infection (including radiologically confirmed pneumonia), duration of admission.

Study design Cohort studies (both prospective and retrospective) will be sought. Studies which compare marker levels in cases with known infection/sepsis and ‘well’ controls will not be included, as they are known to exaggerate the benefits of ‘diagnostic’ markers

Strategy for data synthesis
Key study characteristics, the accuracy of predictor variables and study quality will be summarised in narrative and tabular forms.

If it is considered appropriate (based on clinical and statistical homogeneity and the necessary data being available) appropriate meta-analytical methods will be used. These may include the use of pooled likelihood ratios and hierarchical summary receiver operator characteristic (HSROC) curve modelling with binary data. Data which are adjusted for other known prognostic markers (for example, clinical features suggestive of poor clinical outcome) will be pooled separately from unadjusted estimates.

Heterogeneity will be explored through consideration of study populations, study quality, and predictor variables assessed and in statistical terms using the I2 statistic.