CRP for Respiratory Diagnosis in Kyrgyz Pediatric Practice
Condition: Antibiotic Resistance; Respiratory Tract Infections; Pediatric Infectious Disease; CRP
MeSH terms: Infections; Communicable Diseases; Respiratory Tract Infections
Study type: Interventional

Summary: 
      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.
    

Detailed description: 
      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.
    

Intervention name(s): CRP POCT (C-reactive protein point of care test)
Intervention type(s): Diagnostic Test
Intervention description(s): 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.
Allocation: Randomized
Intervention model: Parallel Assignment
Intervention model description: 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.
Masking: None (Open Label)
Primary purpose: Prevention
Keywords: antibiotic resistance; respiratory tract infections; crp; respiratory symptoms; acute respiratory tract infections; CRP POCT; Pediatrics