This review concluded that outpatient and oral antibiotic management of low-risk febrile neutropenia was effective in children. This conclusion reflects the data presented but should be interpreted cautiously due to the possibility of missed studies and a lack of information on the methodological quality of the included studies.

To assess the effectiveness of outpatient versus in-patient management and oral versus parenteral antibiotics in children with low-risk febrile neutropenia.

MEDLINE, EMBASE and Cochrane Central Register of Controlled Trials (CENTRAL) were searched from 1980 to March 2011 for studies published in English; search terms were reported. Conference proceedings were excluded.

Prospective studies that compared initial or step-down outpatient management and in-patient management and/or initial or stepdown oral antibiotic therapy and parenteral therapy in children with low-risk febrile neutropenia were eligible for inclusion. Studies could examine any infection outcome of a homogeneous initial empiric regimen. Studies in mixed populations were included if separate data could be extracted for children with low-risk febrile neutropenia.

Where reported, the mean or median age of study participants range from 4.7 to 10.8 years, 25 to 97% had unexplained fever, 3% to 100% had leukaemia or lymphoma and zero to 65% had a neutrophil count of <100/μL at presentation. Antibiotic regimens varied and included combinations of ceftriaxone, ceftazidime, amikacin, ciprofloxacin, ofloxacin and amoxicillin-clavulanate.

The primary outcome measure was treatment failure at 30 days, when antibiotic modification was included in the definition. Definitions of treatment failure varied and most included persistence, recurrence or worsening of fever/infecting organisms, new infections, any modification of antibiotics, readmission or death during treatment. Secondary outcome measures were 30-day overall and infection-related mortality, treatment failure excluding antibiotic modification, fever duration, recurrent infection, sepsis, secondary infection, adverse events leading to antibiotic discontinuation and readmission.

One reviewer assessed titles and abstracts identified by the search strategy. Any potentially relevant publication was retrieved in full. Two reviewers independently assessed full publications for inclusion and any disagreements were resolved by discussion.

Methodological quality of included studies was assessed using a published instrument for assessment of quality in studies of prognosis. The instrument assessed study participation, study attrition, confounding variables and measurement of outcomes. Each element was rated as low, medium or high risk of bias.

It appeared that two reviewers independently assessed study quality.

For dichotomous outcomes, numbers of regimens and episodes and percentages of patients with the outcome were extracted for each study and comparison; data were extracted for mean duration of fever.

Data were independently extracted by two reviewers using a standardised form.

Pooled estimates of event rates for each dichotomous outcome and mean duration of fever were calculated using a random-effects model. A test for heterogeneity across subgroup results was used to determine whether outcomes were modified based upon treatment setting (in-patient versus outpatient) or route of administration (parenteral versus oral); statistical significance was defined as p<0.10.

Sixteen studies were included in the review: eight RCTs and eight prospective non-randomised studies. The total number of study participants was unclear. The results of methodological quality assessment were not reported.

Outpatient versus in-patient management: Sixteen outpatient regimens were evaluated in 1,078 febrile neutropenic episodes and eight in-patient regimens were evaluated in 317 episodes.

Treatment failure (including modification of antibiotics) was less likely in the outpatient (treatment failure rate 14.93%, 95% CI 9.55 to 20.31%; seven studies) than in the in-patient setting (treatment failure rate 27.50%, 95% CI 16.61 to 38.39%; eight studies; Ι²=75.7%). There were no significant differences in overall and infection-related mortality or treatment failure (excluding antibiotic modification) between patients treated in in-patient and outpatient settings. There were two infection-related deaths in in-patient settings.

None of the studies reported data on recurrent infection, sepsis, secondary infection or readmission.

Oral versus parenteral antibiotics: Eleven oral regimens were evaluated in 785 febrile neutropenic episodes and 13 parenteral regimens were evaluated in 610 episodes.

There were no significant differences in treatment failure (including or excluding antibiotic modification), duration of fever, recurrent infection, sepsis, secondary infection, adverse events or readmission between patients treated with oral antibiotics and those treated with parenteral antibiotics. There were two infection-related deaths in total; both had been treated with parenteral antibiotics.

Based on the results of this review, outpatient and oral antibiotic management of low-risk febrile neutropenia was effective in children.

This review assessed the effectiveness of lower intensity management strategies in children with low-risk febrile neutropenia. Appropriate inclusion criteria were defined and several sources were searched for relevant studies. The restriction to articles in English may have resulted in relevant studies being omitted. The authors reported measures to minimise error and bias in the review process. The initial stage of study selection was undertaken by one reviewer and this may have introduced error and/or bias. There was an assessment of the methodological quality of included studies but the results were not reported so it not possible to assess the impact of primary study quality on the review findings. Relevant details of included studies were reported and the meta-analytic methods used were broadly appropriate.

The authors' conclusions reflect the data presented but should be interpreted cautiously due to the possibility of missed studies and a lack of information on the methodological quality of the included studies.

Practice: The authors stated that centres should adopt lower-intensity strategies (outpatient and oral antibiotic treatment) for low-risk paediatric febrile neutropenia patients where the infrastructure to safely manage outpatients can be established.

Research: The authors stated that future research should focus on knowledge translation and effectiveness analysis of large numbers of patients treated outside of research protocols as more centres begin to adopt lower-intensity strategies.

One author was supported by a New Investigator Award from the Canadian Institutes of Health Research.

This is a critical abstract of a systematic review that meets the criteria for inclusion on DARE. Each critical abstract contains a brief summary of the review methods, results and conclusions followed by a detailed critical assessment on the reliability of the review and the conclusions drawn.