Antibiotics for prolonged wet cough in children

Antibiotics for prolonged wet cough in children.1 Julie M Marchant, Helen L Petsky, Peter S Morris, Anne B Chang https://doi.org/10.1002/14651858.CD004822.pub3 This is a review about the clinical efficacy and risk of harm of antibiotics in treating children with prolonged wet cough who do not have a chronic respiratory condition. The findings are based on an update of a review published in 20052 including one Australian3 and two Swedish randomised controlled trials4, 5 (see Table 1). Open randomised trial Cough >10 days n = 88 >75% with wet cough >50% with cough >3 weeks Erythromycin, 25 mg/kg BD for 7 days Oxymetazoline nasal drops Salbutamol (oral) allowed Nasopharyngeal swab at baseline and F/U Adverse events (assume no adverse events in control group as not reported): 3.52 (0.14–88.76)†† Outcome used in meta-analysis. % needing additional antibiotics: 0.06 (0.01–0.29)†† Outcome used in meta-analysis. Clinical symptom score (parents) Nasal pathogen elimination Double-blind randomised controlled trial Cough >10 days Cough score ≥8 n = 52 >75% with wet cough Median duration cough 3–4 weeks Amoxicillin/Clavulanic acid, 20 mg/kg/day for 7 days Nasopharyngeal swabs and serology (pertussis and mycoplasma) at baseline and F/U Adverse events: 1.0 (0.18–5.48)†† Outcome used in meta-analysis. % needing additional antibiotics: 0.31 (0.03–3.34)†† Outcome used in meta-analysis. Parental assessment of recovery Number of coughing attacks/day until D8 Parallel double-blind randomised controlled trial Wet cough >3 weeks n = 50 Median duration cough 11–15 weeks Amoxicillin/Clavulanic acid, 22.5 mg/kg BD for 14 days Bronchoscopy and lavage prior End of trial = Days 15–16 End of study = Day 28 Adverse events: 2.88 (0.5–16.48)†† Outcome used in meta-analysis. Mean absolute change in cough score Change in score at end of study Of 190 randomised children, 171 (90%) completed the three trials. All participants were children <18 years old, with mean age for the studies ranging from 21 months to 6 years. In the two Swedish studies,4, 5 prolonged cough was defined as cough lasting >10 days: in one study, 50% of children had cough >3 weeks,4 and in the other, mean cough duration was 3–4 weeks.5 In the Australian study,3 the median length of cough was approximately 3 months (11–15 weeks). The two Swedish studies did not mention the quality of the cough in their publications, but contact by the review authors confirmed that at least 75% of children had wet cough.4, 5 Two studies were classified as low risk of bias.3, 5 One was at risk of detection bias due to inadequate blinding of personnel, participants and outcome assessors.1, 4 The open randomised study compared 1 week of erythromycin with a ‘no treatment’ group. The two other trials compared amoxicillin/clavulanic acid (Augmentin) and placebo. There were important differences to usual practice and between studies. There were also differences in outcome assessment, with clinical assessment being the primary outcome for two studies and a validated cough diary for one (Table 1). The primary outcome for the meta-analysis was children ‘not cured’ or ‘not substantially improved’ at follow-up and resulted in a pooled odds ratio of 0.15 (95% CI 0.07–0.31) (Fig. 1). Based on these results, one child would be cured for every three treated with antibiotics (NNTB = 3, 95% CI 2–4). Progression of disease resulting in additional medical therapy was available for two studies,4, 5 with an overall need for antibiotics for 36% of controls compared to 5% requiring further antibiotics in the treatment group (OR 0.10; 95% CI 0.03–0.34; NNTB = 4; 95% CI 3–5). Adverse events monitoring varied between studies as shown in Table 1. The available evidence suggests that a short course of oral antibiotics for children presenting with prolonged cough is efficacious in eliminating cough symptoms. However, for clinical care, chronic cough is defined as cough lasting more than 4–8 weeks, and treatment with antibiotics is not recommended in the setting of subacute cough (cough <4 weeks) as it is important that children are not treated with antibiotics unnecessarily. Children included in this meta-analysis may have experienced spontaneous cough resolution and may not have had wet cough as the quality of the cough was not specifically defined. ‘Wet’ or ‘productive cough’ is caused by an abnormal increase in airway secretions. A wet cough can be caused by infection, including pneumonia or upper respiratory tract viral infection (URTI), protracted bacterial bronchitis, suppurative lung disease or bronchiectasis. The ‘wet’ characteristic helps differentiate the cough from alternative diagnoses such as asthma, which is classically dry, episodic and usually associated with wheeze.6 Studies have shown that parents, as well as physicians, are able to accurately differentiate between wet and dry cough.7 The most frequent cause of wet cough in children is acute viral URTI. It is now generally accepted that acute cough may last up to 4 weeks but usually begins to abate by the second or third week.8, 9 When the cough does not fit this classic URTI pattern, the child should be assessed for chronic wet cough. The definition of chronic cough varies between guidelines but includes persistent cough lasting greater than 4 weeks, the definition used in the Australian Cough in Children and Adults: Diagnosis and Assessment (CICADA) guidelines.10, 11 The British Thoracic Society guidelines written in 2008 defined chronic cough as cough lasting longer than 8 weeks8 to clearly differentiate it from acute cough. Most children with chronic wet cough will have protracted bacterial bronchitis,12 which is a chronic wet cough without specific signs and symptoms of an alternative diagnosis. The condition is caused by a bronchial infection with common respiratory pathogens, typically Haemophilus influenzae, Streptococcus pneumoniae or Moraxella catarrhalis.13 Antibiotics effective against these pathogens treat the condition through bacterial eradication. An assessment needs to be undertaken to differentiate post-viral or subacute cough from protracted bacterial bronchitis and other more serious causes of cough, including bronchiectasis, cystic fibrosis, recurrent aspiration and infection due to immunodeficiency or inhaled foreign body.1 Signs that suggest an alternate diagnosis include persistent chest signs on auscultation, recurrent sinopulmonary infections, haemoptysis, failure to thrive, clubbing, nasal polyps or chest wall deformity. Protracted bacterial bronchitis classically responds to 2 weeks of oral antibiotics. However, due to the limited evidence, the recommended duration of the course and the class of antibiotic recommended varies between guidelines.8, 10, 11 Protracted bacterial bronchitis may lie within the same disease spectrum as bronchiectasis, the latter occurring in the setting of delayed antibiotic therapy and resulting in significant morbidity and mortality. The authors of this Cochrane review1 noted that the studies included in this meta-analysis included participants whose symptomatology did not meet the current definition of chronic cough. As the studies were performed when the definition of chronic cough was of shorter duration, a decision was made by the Cochrane authors to include these studies in the meta-analysis. Children enrolled in these early studies may have been treated with antibiotics unnecessarily. Indigenous children of Australia, New Zealand and Canada have been shown to have much higher rates of bronchiectasis than the non-indigenous population.14-16 It is particularly important to recognise protracted bacterial bronchitis in this cohort and commence treatment to try to prevent chronic lung disease. Unfortunately, none of the three studies included in the meta-analysis described the frequency and outcomes of indigenous participants. Cough is one of the most common acute presentations to doctors and leads to significant parental stress and financial burden.17, 18 Appropriate cough treatment also improves quality of life.17 Persistent bacterial bronchitis is a simple clinical diagnosis if wet cough has not resolved spontaneously and has lasted more than 4 weeks with no sign of improvement. Once recognised, evidence-based antibiotic therapy should be commenced. Of equal importance is the reduction of inappropriate treatment with antibiotics for subacute cough to prevent patient harm and risk of increased incidence of antimicrobial resistance in the community.

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