We conducted a cluster randomised controlled trial comparing CRP testing in all children with clinically-guided CRP testing. Practices were randomised to undertake point-of-care CRP testing in all children or only children assessed as being at higher risk by a validated clinical decision rule.
Children aged 1 month to 16 years presenting with an acute illness for a maximum of 5 days were recruited consecutively from February 15, 2013, to February 28, 2014, in 78 general practices across Flanders, involving 133 general practitioners (GPs). Children were excluded if the acute illness was caused by purely traumatic or neurological conditions, intoxication, a psychiatric problem, or an exacerbation of a known chronic condition. When the same child was recruited twice within 5 days, we considered the second registration to be part of the same illness episode and excluded the second registration from the analyses. If a physician recruited fewer than five children over the 1-year study period, consecutive inclusion was assumed to be violated, leading to the exclusion of that physician from the analysis.
In the “CRP for all” group, each child had a CRP test. In the “CRP only if at clinical risk” group, CRP testing was dependent on the presence of at least one of the following clinical features: breathlessness, body temperature of at least 40 °C, diarrhoea in children 12–30 months of age, and clinician concern . “Breathlessness” was defined as difficult or laboured breathing. “Body temperature” was defined as the highest body temperature measured during the illness episode by the parents or the physician according to their usual practice. Before analysis, 0.5 °C was added to temperatures measured under the axilla or with a tympanic thermometer [13, 14]. “Diarrhoea” was defined as loose or watery stools, increased in frequency and volume . “Clinician concern” was defined as a subjective feeling of the physician that something was out of the ordinary.
We used the Afinion™ CRP Test Cartridge, which has a measuring range for CRP of 5–200 mg/L  and requires 1.5 μL of blood obtained by finger prick, providing a result within 4 minutes. We trained all physicians to perform the CRP test. Internal quality control was performed according to the manufacturer’s instructions.
Randomisation was performed at the practice level to avoid contamination and stratified by practice type (solo, duo, group) before randomisation. The intervention-specific protocols were briefed during a face-to-face meeting at each practice, differing primarily in the indication to test for CRP.
The primary outcome of the study was hospital admission (> 24 hours) for a serious infection within 5 days after initial presentation. Hospital admission was verified by a search of the electronic medical records of all hospitals in the practices’ catchment area, an interview with each participating GP and a diary completed by parents. Serious infections were defined as:
sepsis (including bacteraemia): pathogenic bacteria isolated from blood culture
meningitis: pleocytosis or identification of bacteria or a virus in cerebrospinal fluid
pneumonia: infiltrate on chest X-ray
osteomyelitis: pathogens from bone aspirate or a MRI or bone scan suggestive for osteomyelitis
cellulitis: acute suppurative inflammation of the subcutaneous tissues
bacterial gastroenteritis: pathogen isolated from stool culture
complicated urinary tract infection: > 105/mL pathogens of a single species isolated from urine culture and systemic effects such as fever
In cases where no definitive adjudication could be made based on the above criteria, an adjudication committee, consisting of clinicians with expertise in acute paediatric care, assigned outcome by consensus, using all available information.
Secondary outcomes were referrals (immediate or delayed) to secondary care (hospital-based paediatricians) and the ordering of additional testing (including blood and urine tests, and imaging) at the initial presentation as recorded by the GP.
Sample size calculation was described previously , and is based on the assumptions that prevalence would be 0.8 % and sensitivity and specificity of CRP would be 75 %, as found in a recent meta-analysis, using bivariate random effects meta-analysis across a range of CRP cut-off values . Differences in baseline characteristics and clinical features were analysed through χ2 testing and nonparametric equality-of-medians testing to assess potential recruitment bias. We calculated accuracy of CRP in both groups for the following pre-determined thresholds: 5 and 200 mg/L which are the lower and upper limit of the point-of-care CRP test, and 20 and 80 mg/L which have been identified as ‘ruling out’ and ‘ruling in’ thresholds, respectively, in secondary care . We examined whether time from onset of fever (in days) influenced the level of CRP using non-parametric equality-of-medians tests . The 4.2 % missing values for CRP in those patients that should have had a CRP test were assigned to either side of the optimal split for this continuous predictor, defined as the split resulting in the smallest P value through χ2 testing for the difference between both sides of the split .
To test whether there were any differences in timely diagnosis, referrals to secondary care or additional testing between the two groups, we conducted a mixed-effects logistic regression analysis to account for the clustering at practice level, and other potential interaction terms, such as the child’s age, using the xtmelogit function in Stata . All analyses were performed with Stata software (version 11.2; Stata Corp., USA), and JMP Statistical Discovery (version Pro 12.1.0; SAS Institute Inc., USA).