Objectives:

To determine whether CRP-guided antibiotic treatment for managing AECOPD in adult patients attending Emergency Departments leads to reduced antibiotic duration, without non-inferior COPD health status with usual care.

Hypothesis to be tested:

(i) The antibiotic duration in AECOPD patients will be significantly lower for CRP-guided antibiotic discontinuation than usual care; and (ii) COPD health status as measured by the Clinical COPD Questionnaire has no statistically significant difference between two groups.

Design and subjects:

Multi-center, single-blind, open-label, randomized, combined superiority (antibiotic duration) and non-inferiority (COPD health status) trial in 1,184 adult AECOPD patients presented to A&E.

Instruments:

Clinical COPD Questionnaire and EuroQol-5D

Interventions:

Both intervention and control groups follow usual care with GOLD strategy. The intervention group will be recommended to test for serum CRP daily. Antibiotic prescription is considered when CRP >5mg/dL. Once CRP has declined to <5mg/dL and the patient was afebrile for past 48 hours, antibiotic discontinuation will be considered.

Communication with Receiving Ward Staffs:

Participants in the study may transfer to another departments after treatment/ care in A&E. The following communication would be conducted:

• A handover note that informs the receiving ward staffs about patients' enrolment to the trial, group assignment, and previous treatments given in A&E. The note would also suggest the investigations for the receiving ward staffs.
• Telephone handover about intervention group and investigations of the study, and treatments given in A&E to ward.

Main outcome measures:

The antibiotic duration (total number of antibiotic days) within 28 days and recovery in terms of COPD health status (Clinical COPD Questionnaire total scores) within 14 days from randomisation.

Data analysis:

Intention-to-treat and cost-effectiveness analyses will be performed. The outcome assessors and data analysts will be blinded to group allocation.

Expected results:

The intervention group will exhibit reduction in antibiotic duration at 4-weeks, without negatively impacting on COPD health status, compared with the control group.

Introduction

Multiple small successes against antimicrobial resistance are urgently needed. The Global Action Plan in 2015 reiterated the importance of tackling antimicrobial abuse and bacterial resistance, which is jeopardizing our ability to manage infectious diseases. Antimicrobial resistance is predicted to cause catastrophic economic impacts in the next 10 years by putting 24 million people into extreme poverty, and will lead to an estimated 10 million deaths annually by 2050. Evidence has shown that an extended course of antibiotics is by no means superior to a shorter one. The over-prescription of broad-spectrum antibiotics in both hospitals and primary care has become a global concern and has driven initiatives to safeguard patient safety through the responsible use of antibiotics as treatments and prophylaxis. In a recent analysis, 55% of pathogenic bacteria identified in sputum culture from AECOPD patients in Hong Kong has demonstrated resistance to at least one antibiotic. Even relatively small changes in prescribing are likely to have beneficial effects on resistance at a population level.

There is a need for improved decision-making for antibiotic prescription in AECOPD. International Guideline (GOLD strategy) recommends empirical broad-spectrum antibiotics covering common respiratory pathogens for acute management, based on self-reported subjective AECOPD features, and the risk of bacterial infection. Evidence for the optimal duration of antibiotic treatment is unclear. Antibiotics are reportedly used in 87% of AECOPD patients in US, 74% in UK, and 96% in Hong Kong. AECOPD contributes 21,000 episodes of local hospital admission and readmission in 2019. AECOPD is triggered by infectious and non-infectious precipitants, although 30% are undetermined. Bacterial infection accounts for only 35%-57% among the infected. Inappropriate antibiotic usage may increase the risks of adverse events such as Clostridioides difficile colitis. Moreover, this confers a predisposition to airway colonization by multidrug-resistant bacteria, increasing COPD patients' risk of carrying resistant organisms in their lungs and then exacerbation or progression of pneumonia. The investigators have found that 55% of pathogenic bacteria identified from sputum culture among AECOPD patients were resistant to 1 or more antibiotics.

C-Reactive Protein (CRP) may help physicians make more appropriate antibiotic decisions. C-Reactive Protein (CRP) is an acute-phase reactant secreted by the liver in response to bacterial infections. It is synthesized within 4 to 6 hours after tissue injury/inflammation, and levels double every 8 hours, peaking at about 36 hours. CRP is significantly elevated in patients with bacterial infection, representing better treatment effect with antibiotics at elevated CRP values. CRP has been shown to be highly selective for AECOPD and it has excellent diagnostic accuracy when interpreted together with AECOPD symptomatology. Elevated CRPs (>5 mg/dL) in hospitalised AECOPD patients are associated with chest infections, implying a treatment role for antibiotics in this group. Yet antibiotics did not offer higher benefit over placebo among those with normal CRP level.

Work done by others

CRP-guided antibiotic prescription is effective and safe. In hospitalised AECOPD patients with CRP-guided prescriptions (antibiotic treatment if CRP ⩾50 mg/L, i.e. 5mg/dL) versus a control group with standard GOLD treatment fewer patients in the CRP group were prescribed with antibiotics compared to the GOLD group (31.7% versus 46.2%, p=0.028; adjusted odds ratio (OR) 0.178, 95% CI 0.077-0.411, p=0.029), without a significant difference in the treatment effects between both groups. Yet, the discontinuation of antibiotics in both groups was guided by clinical judgment. The 30-day treatment failure rate was nearly equal in CRP and control groups (44.5% vs. 45.5%, p=0.881), the time to next exacerbation was comparable (32 days vs. 28 days, p=0.713), and the length of hospital stay was also similar (7 days vs. 6 days, p=0.206). On day 30, there was no difference in the symptoms score and quality of life, and no serious adverse events were detected.

CRP-guided antibiotic discontinuation is also safe. Whether antibiotic therapy with CRP-guided duration or fixed 7-day duration were clinically non-inferior to fixed 14-day duration in patients with uncomplicated gram-negative bacteraemia was determined in a multicentre trial involved 504 adults. The main outcome was the rate of clinical failure at 30 days, which was 2.4% in CRP-guided patients who experienced recurrent bacteraemia, local suppurative complications, distant complications, re-initiation of antibiotic therapy due to clinical deterioration, or any-cause mortality, compared with a failure rate of 6.6% in the 7-day group and 5.5% in the 14-day group. The CRP-guided treatment met the 10% margin for inferiority.

Work done by the research team

The team is experienced to conduct trials on antibiotic stewardship with AECOPD. Professor Butler and his research team studied whether point-of-care CRP laboratory testing could be used to safely guide (and perhaps reduce) antibiotic prescribing for AECOPD in primary care practices in the UK. In this multi-centre, open-label, randomised controlled trial, 653 AECOPD patients were randomised to either the CRP-guided treatment group or the usual (GOLD strategy) care group. The results showed that patients in the CRP group reported less antibiotic use within 28 days of randomisation (57.0% vs. 77.4%, adjusted OR 0.31, 95% CI 0.20 to 0.47) and mildly lower (better) clinical COPD questionnaire scores at 2 weeks (adjusted mean difference -0.19 points, 90% CI -0.33 to -0.05). Antibiotics were prescribed less frequently at the initial consultation in the CRP-guided group compared with the usual care group (47.7% vs. 69.7%, adjusted OR 0.31, 95% CI 0.21 to 0.45). There was no evidence of harm to patients, including no differences in diagnosis of pneumonia at the 4-week follow-up and no differences in adverse events related to antibiotics. Both Prins' study and this study provide evidence of the benefits of CRP-guided antibiotic prescription in regard to less antibiotic use, and non-inferiority on the clinical outcomes in AECOPD patients including 30-day treatment failure, length of stay, symptoms score, diagnosis of pneumonia, quality of life, and adverse events.

In the previous study antibiotics were found to be prescribed in 33% of patients who had low CRP levels, even though guidance indicated that antibiotics likely would not be of benefit. Patient factors such as expectations for antibiotics, access to antibiotics before consultation with the clinician, and lack of clear guidelines can influence clinicians' antibiotics prescribing behaviour for acute respiratory symptoms. Previous reports also suggested that risk aversion and long turnaround time for CRP resulted in driving them to prescribe antibiotics.

Local situation has been well studied. Professor Hui (co-applicant) and Dr. Ko (collaborator) found that an infectious aetiology could be established in only 48.7% of the AECOPD patients. 40.8% of sputum culture was positive. The commonest bacteria identified were Streptococcus pneumoniae, Pseudomonas aeruginosa, and Haemophilus influenza.

A&E is an ideal location to start antibiotic stewardship for AECOPD. Prior work has also been conducted by the research team in Hong Kong to ensure the significance of the problem, the feasibility of data collection, and the preliminary results relevant to AECOPD patients with available CRP levels. 21,129 patients were admitted to emergency medicine wards and medical wards through A&E in 2019 (mean age 79 years (IQR 71-86)). Elevated CRP was associated with doubled odds ratio of ICU admission or death (Odds ratio 2.06, 95%CI 1.75 - 2.43). Analysis reveals that 96% of patients with a normal CRP were given antibiotics. Among those with normal CRP, unadjusted statistics suggested those without antibiotics did not have lower odds ratios for deterioration requiring ICU admission and for death (p<0.01). Overall, AECOPD patients were prescribed antibiotics for a mean of 9.4 days (SD 10.3) but the mean duration of an elevated CRP was 6.4 days (SD 6.8). There is an opportunity to shorten antimicrobial regimen for some AECOPD patients. As personalised antibiotic treatments may reduce healthcare resource utilisation, the investigators sought to determine the optimal antibiotics therapy duration for AECOPD patients based on clinical decision-making and CRP results.

Research Gaps

1. Antibiotic stewardship involves both appropriate prescription and timely discontinuation of an antibiotic treatment. Limited evidence informs antibiotic prescription practice for AECOPD in A&E. Information on CRP-guided antibiotic discontinuation is absent.
2. Previous studies with hospitalized AECOPD patients with severe symptoms and severe outcomes was insufficient in power.
3. Cost-effectiveness analyses on CRP-guided antibiotic treatment in AECOPD patients are lacking.

Clinical Question

In adult AECOPD patients in Emergency Departments, does CRP-guided antibiotic treatment, compared with usual care, lead to shorter antibiotic duration without negatively impact on clinical COPD-health status?

Aims and Hypotheses to be tested:

The present study seeks to establish whether serial CRP level guided clinical judgment can safely and cost-effectively be used to better target antibiotic treatment (include both treatment and discontinuation) for AECOPD in emergency departments to those that are most likely to benefit, so that overall antibiotic exposure duration is decreased without compromising COPD-related health status.

The primary objective is to determine whether the addition of a serial CRP levels to usual care for AECOPD leads to shorter antibiotic duration, The co-primary objective is to determine whether the addition of a serial CRP levels to usual care for AECOPD is non-inferior to usual care alone, on COPD health status as measured by CCQ.

The secondary objectives are the effectiveness of the addition of serial CRP levels to usual care in AECOPD patients on:

• General health status as measured by EQ-5D-5L
• Adverse effects of antibiotics
• Cost-effectiveness of individualised CRP-guided antibiotic treatments.

The investigators hypothesise that:

(i) antibiotic duration (defined as 'the number of days of antibiotic treatment') in 28 days among AECOPD patients will be significantly lower for CRP-guided antibiotic treatment (including prescription and discontinuation) than usual care

(ii) COPD health status as measured by the Clinical COPD Questionnaire (CCQ) has no statistically significant difference between two groups;

(iii) general health status of AECOPD patients as measured by EQ-5D-5L will not be significantly different between the two groups

(iv) adverse effects of antibiotic treatment in AECOPD patients will not be significantly different between the two groups

(v) CRP-guided antibiotic treatment will be more cost-effective than usual care

Inclusion Criteria:

1. Being diagnosed with active AECOPD (AECOPD is defined as an event in the natural course of a disease characterized by a change in baseline dyspnoea, cough, and/or sputum that is beyond the normal day-to-day variations with acute onset, which may warrant a change in regular medication in patients with underlying COPD).
2. Known COPD in their medical records.
3. Age 40 years or older.
4. Able to provide informed consent in Cantonese, Mandarin, or English
5. Able to complete the questionnaires during the study period (i.e. 6 months after randomisation)

Exclusion Criteria:

Patients will be excluded if any ONE of the following are present:

1. Pre-treatment with systemic corticosteroids for the present exacerbation.

2. Pre-treatment with any antibiotics for the present exacerbation, any concurrent infection or prophylaxis.

3. Known clinical stroke in past 6 months

4. Patients with high suspicion of active AECOPD mimics:

   1. Pneumonia
   2. Congestive heart failure
   3. Bronchiectasis
   4. Pulmonary embolism
   5. Pneumothorax
   6. Atrial fibrillation / flutter

5. Lung comorbidities:

   1. Cystic fibrosis
   2. Tuberculosis
   3. Unresolved lung malignancy

6. Progression or new radiographic abnormalities on the chest X-ray.

7. Immunodeficiency disorders such as AIDS, humoral immune defect, ciliary dysfunction etc., and the use of immunosuppressive drugs for more than 28 days.

8. Active inflammatory condition (e.g. flare up of rheumatoid arthritis, gout or polymyalgia rheumatica) or concurrent infection at another site (e.g. UTI, cellulitis) that is likely to produce a systemic response

9. Currently pregnant

10. NEWS2 score of ≥3