CRP for Respiratory Diagnosis in Kyrgyz Pediatric Practice (COORDINATE)

National Center of Maternity and Childhood Care, National Center of Cardiology and Internal Medicine named after academician M.Mirrakhimov, The Research Unit for General Practice, Copenhagen School of Global Health, Unit of Global Health, The Juliane Marie Center, Rigshospitalet, Kyrgyz Thoracic Society

Rationale: Overuse of antibiotics globally is leading to increasing rates of antibiotic resistance and may lead to a 'post-antibiotic' era. Case fatality rates for pneumonia in children remain high in Central Asia and there is a lack of knowledge of which viruses and bacteria cause the disease. Antibiotic resistance patterns of common bacteria remain largely unknown in Central Asia which makes it challenging for clinicians to choose the right antibiotic to treat children with suspected bacterial pneumonia and sometimes healthcare workers overuse an antibacterial therapy even when the child does not need it. Randomised trials of using CRP point of care test (POCT) to guide antibiotic prescription for respiratory tract infections has been successful in lowering unnecessary antibiotic prescriptions in adults in high income countries but left a small concern for safety in the form of possibly slightly increased risk of hospitalisation in the CRP group. Objective: This study seeks to gain evidence on whether use of C-reactive protein point-of-care test can safely decrease prescription of antibiotics for children under 12 with acute respiratory symptoms in primary level healthcare centres in Kyrgyzstan. Study design: Multicentre, open-label, individual randomised controlled clinical trial with 14 days blinded follow-up in rural Chui and Naryn regions of Kyrgyz Republic. Healthcare workers from ten selected healthcare centres will be trained in the CRP POCT and in interpreting the results in the field. Study population: Children aged from 6 month to 12 years attending the primary level healthcare centres during normal business hours with acute respiratory symptoms. Main study parameters: The proportion of patients in the two groups prescribed an antibiotic within 14 days of index consultation; length of disease, antibiotics given at index consultation, admissions and vital status. Nature and extent of the burden and risks associated with participation, benefit and group relatedness: Risks, inconvenience and burden associated with participating in this observational study are low. As part of the inclusion children in the CRP cluster group will have a finger-prick test performed. This may be unpleasant and course transient discomfort but poses no risks to the child. Follow-up will be three short phone calls day 3, 7 and 14 after inclusion. Risks includes possible undertreatment of serious disease, however previous studies have not found safety issues with CRP testing in children. There is no direct benefit to participants, but side effects and non-necessary medications are likely minimised.

INTRODUCTION AND RATIONALE Respiratory tract infections are the most common cause of contact to the health system and are the main reason for antibiotic overuse at the primary care level globally. At the same time, acute lower respiratory infections (ALRI) are the most common cause of death among children under 5 globally, costing the lives of almost 1 million children annually. Unfortunately, there is substantial overlap in the presentation of different causes of acute lower respiratory illness in young children, including bacterial pneumonia, viral infections and wheezing and with increasing coverage of pneumococcal and Haemophilus influenza type b vaccination, only a smaller proportion of these need antibiotics. At the same time, globally, most children are diagnosed and treated at a primary care clinic, primarily by mid-level providers with only limited access to diagnostic equipment. To assist healthcare providers in diagnosing under these conditions, various algorithms have been used, e.g. WHO's Integrated Management of Childhood Illness, which bases diagnosis of respiratory diseases in children mainly on presence of cough and elevated respiratory rate. This approach has been shown to severely over-diagnose pneumonia and thus result in unnecessary prescription of antibiotics. Therefore, new approaches to diagnosing and treating respiratory infections in children are urgently needed. Concurrently, antimicrobial resistance is now what WHO calls a global health emergency and warns that 'A post-antibiotic era - in which common infections and minor injuries can kill - far from being an apocalyptic fantasy, is instead a very real possibility for the 21st century. Unnecessary prescription of antibiotics is extensive globally and most healthcare providers are aware of the global threat of antimicrobial resistance but express the need for support for prescribing differently, such as knowledge of local resistance patterns of pathogens and better diagnostics to support a decision not to treat with an antibiotic. C-reactive protein (CRP) is an acute phase reactant produced by the liver which can be used as a marker of serious infection. Randomised trials of using CRP point of care test (POCT) to guide antibiotic prescription for respiratory tract infections has been successful in lowering unnecessary antibiotic prescriptions in adults in high income countries but left a small concern for safety in the form of possibly slightly increased risk of hospitalisation in the CRP group. Trials of CRP POCT in children have been performed in Tanzania as part of an intervention package with a strict prescription limit of > 80 mg/L CRP with a reduction in antibiotic prescriptions from 40% to 2%. In South-East Asia with a small but statistically significant effect (5% reduction) when used as either above or below a certain threshold (40 mg/L) in Thailand and Myanmar. In a sub-group analysis from a trial in Vietnam with both children and adults where the numeric value of CRP was used after a short training in CRP interpretation along with clinical evaluation resulted in a 20% reduction from 64% to 44%. A cross-cutting qualitative study of the above-mentioned studies in Thailand, Myanmar, and Vietnam showed that lack of non-antibiotic alternatives to prescribe led to lower adherence to the CRP POCT result. As the intervention of supplying CRP POCT to healthcare providers is more a behavioural than biomedical, previous trials have recommended that further trials are done in different contexts and that qualitative studies of reasons for success or failure. Central Asian countries have been underrepresented in health science, especially in primary care research. The clinical context of primary care in South-East Asian countries, like Vietnam, Thailand, and Myanmar, and Central-Asian countries, like Kyrgyzstan, are vastly different with different caseloads, different human resources, and varying time for consultations available. At the same time, case fatality rates for pneumonia in children remain high in Central Asia and there is a lack of knowledge of which viruses and bacteria cause the disease. Antibiotic resistance patterns of common bacteria remain largely unknown in Central Asia, which makes it challenging for clinicians to choose the right antibiotic to treat children with suspected bacterial pneumonia. Kyrgyz Republic with respiratory diseases being the most common (49,7%). Among all acute respiratory diseases in children, upper respiratory tract infections are the most common. The number of cases per 100,000 population seems to de-crease by 2020, but it is still quite high. OBJECTIVES The aim of this project is to find out if the overuse of antibiotics in children with acute respiratory symptoms can be reduced by effectively identifying children at increased risk of infections who require antibiotic therapy and children who will not benefit from antibiotics. This is done by implementing CRP POCT at the primary healthcare level. Hypotheses: Supplying CRP POCT equipment to primary healthcare providers will help them identify the majority of children who suffer from viral infections and assist in withholding antibiotic treatment when no benefit can be expected and will help identify the severely sick children in need of urgent referral, thus lowering unnecessary use of antibiotics and improving primary care management by studying supplying supportive medication for those not in need of antibiotics. It will be an individually randomised clinical trial where CRP POCT is supplied to approximately 14 healthcare centres. All children up to 12 years with respiratory symptoms have basic clinical data recorded as well as data needed to classify according to WHO IMCI pneumonia diagnostic criteria. CRP POCT is used at intervention sites and CRP results, diagnosis, and treatment is recorded. Follow-up phone calls will be made 3, 7 and 14 days after the health centre visit to record recovery, antibiotics use, hospitalisation and vital status of the participating children. Ethics and dissemination: The study was approved 25/06/2021 by National center of Maternity and Childhood Care Ethics Committee (ref: no. 1). Study results will be disseminated through appropriate peer-reviewed journals, national and international respiratory conferences, social media, and through patient and public involvement events in Kyrgyzstan and in Denmark.

antibiotic resistance, respiratory tract infections, crp, respiratory symptoms, acute respiratory tract infections, CRP POCT, Pediatrics

Individually randomized clinical trial The children will be randomized into two groups. Randomization will be stratified by male/female as well as age <5 years and >5 years.

Participants assigned to Group A will take C-reactive protein (CRP) point of care test (POCT) during a check-up with their healthcare worker (HCW). The assistant investigator will attend the child's consultation with the local HCW and complete the case report form (CRF). Consequently, the CRP result will be recorded in the CRF, which will be the basis for choosing a treatment, depending on its result.

HCWs will also consult children who have been randomised to Group B. The assistant investigator will complete the CRF for these children, but the CRP POCT will not test them. They will receive the treatment prescribed by the HCW as usual care

CRP POCT equipment will be supplied at healthcare centers, along with a short training in use and interpretation supporting the clinical evaluation of the child. It will be communicated that CRP levels less than 10 indicate that the disease is not severe, and antibiotics is most likely not needed, if between 10 and 50, that antibiotics might be needed, and if more than 50 that it is likely that they are needed. With CRP between 10-50 the HCW are instructed to take the clinical picture into account together with the value of the test. The training will also include knowledge of CRP pharmacodynamics and cases where a low CRP might need to be interpreted cautiously, e.g. a history of fever lasting less than 24 hrs. HCWs will be instructed to use CRP POCT for all patients in the intervention group and use the information to guide diagnosis and treatment choice. We will use Aidian (Copenhagen, Denmark) QuickRead go CRP POCT set-up.

The primary study outcome is the proportion of included children in each study arm that are prescribed an antibiotic within 14 days from the index consultation (superiority analysis).

The second primary study outcome is patient safety measured as the number of days until recovery (non-inferiority analysis).

Inclusion Criteria: Between 6 month and 12 years of age; Parents/caregivers of a child are able and willing to comply with all study requirements; Parents/caregivers of a child is able and willing to give Informed Consent; Having at least one of the following focal symptoms lasting for less than 2 weeks (cough; fast/difficult breathing; dore throat; shortness of breath; wheezing) Exclusion Criteria: Severely ill and in need of urgent referral where measurement of CRP POCT would delay the process; Terminally ill patients; Patients with ear ache only; Patients with known immunosuppression or severe chronic disease (HIV, liver disease, history of neoplastic disease, long term systemic steroid use or similar conditions as assessed by the health worker or AI); Parents/caregivers who are not able to participate in follow-up procedures (lack of telephone etc); Haven taken antibiotics within 24 hours before the index consultation

Republican Research Centre of Pulmonology and Rehabilitation the Ministry of Health of the Kyrgyz Republic

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