The Impact of C-reactive Protein Testing

This is a multi-centre, individually randomized-controlled, three-armed pragmatic trial comparing CRP guided antibiotic prescription in febrile patients to the current standard prescribing systems. The study will be implemented in low and middle-income countries in tropical settings, including Myanmar and Thailand in the first instance.

As participation in the study itself may raise awareness amongst the health centre staff and local community, current antibiotic prescribing rates will be assessed in an observational run-in period before the intervention. Health workers will be asked to complete case record forms (CRF) for patients presenting to their health centre with current or recent fever. This aims to capture current antibiotic prescribing habits before the study is launched.

During the intervention phase, patients fulfilling the inclusion criteria and who consent to participate in the study will be randomised to one of the three arms, as follows:

• Control group: The health care provider will manage the patient using standard guidelines. No CRP will be measured onsite
• Group A: CRP will be measured by a study nurse and the result will be communicated to the health care provider as "High-CRP" or "Low-CRP" using a low CRP cut-off of 20mg/L.
• Group B: CRP will be measured by a study nurse and the result will be communicated to the health care provider as "High-CRP" or "Low-CRP" using the higher CRP cut-off, of 40mg/L.

For the two intervention arms, the following guidance will be given to the health care provider: if the CRP test is reported as 'high', antibiotic treatment is recommended, following local guidelines, and if it is reported as 'low' antibiotics are not recommended. In either case the information provided by the CRP test should be interpreted alongside their clinical judgement.

A second CRP will be sampled at day 5 of the follow-up (+/- 1 day) for all the patients, using capillary blood from a finger prick.

The investigators will use the NycoCard Reader II (Axis Shield, Norway or equivalent) to measure CRP levels.

A venous blood sample and a nasopharyngeal swab will be taken in the control group at enrolment and sent to a central laboratory in order to detect the presence of the following key pathogens by real-time polymerase chain reaction (PCR):

• Flavivirus
• Alphavirus
• Influenza A & B
• Rickettsia including typhus group and spotted fever group
• Leptospirosis
• PCR 16s for the detection of any bacteria.
• Malaria

CRP will also be retrospectively measured in these blood samples to validate its ability to distinguish between viral and bacterial infections.

A urine sample will be collected to detect the presence of antimicrobials at day 0 and day 5. This procedure will ascertain pre-study antibiotic intake, as well as the patient's compliance to the health care worker's prescription or advice that antibiotics are not required, during their participation in the study. The urine samples will be collected at the sites, divided into aliquots and frozen to -80°c to be stored on site. Monthly shipments will be made to the laboratory at Mahidol Oxford Tropical Research Medicine Unit in Thailand for analysis.

The investigators aim to follow-up every patient face to face on day 5 (+/-1 day), and either by phone or face-to-face interviews 14 days (+/-2 days) after the initial visit.

Inclusion criteria

• Patients aged ≥1 year presenting to selected primary healthcare centres
• Tympanic temperature >37.5°c or history of fever ≤ 14 days.

Exclusion criteria

• Patients that in view of the study nurse are in need of emergency referral to a higher-level facility, as indicated by either 1) impaired consciousness or 2) inability to take oral medication.
• In sites that routinely test for malaria, patients with a positive malaria rapid diagnostic test or microscopy will be excluded
• The main complaint is a trauma and/or injury
• Suspicion of tuberculosis (any medical history and/or physical examination suggesting tuberculosis)
• Suspicion of Urinary Tract Infections (any medical history and/or physical examination suggesting urinary tract infections)
• Suspicion of local skin/dental abscess (any medical history and/or physical examination suggesting a local skin/dental abscess
• Any presenting symptom present for more than 14 days
• Bleeding, including otorrhagia, haematemesis, haemoptysis, haemorrhagic petechiae, haematuria, bloody diarrhoea.
• Not able to comply with the follow-up at Day 5 (+ / - 1 day).