Codeine versus placebo for chronic cough in children (Review)

Background: Cough in children is a commonly experienced symptom that is associated with increased health service utilisation and burden to parents. The presence of chronic (equal to or more than four weeks) cough in children may indicate a serious underlying condition such as inhaled foreign body or bronchiectasis. Codeine (and derivative)-based medications are sometimes used to treat cough due to their antitussive properties. However, there are inherent risks associated with the use of these medications such as respiratory drive suppression, anaesthetic-induced anaphylaxis, and addiction. Metabolic response and dosage variability place children at increased risk of experiencing such side effects. A systematic review evaluating the quality of the available literature would be useful to inform management practices. Objectives: To evaluate the safety and efficacy of codeine (and derivatives) in the treatment of chronic cough in children. Search methods: We searched the Cochrane Airways Group Register of Trials, Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE (1946 to 8 June 2016), EMBASE (1974 to 8 June 2016), the online trials registries of the World Health Organization and ClinicalTrials.gov, and the bibliographic references of publications. We imposed no language restrictions. Selection criteria: We considered studies eligible for analysis when: the participant population included children aged less than 18 years with chronic cough (duration equal to or more than four weeks at the time of intervention); and the study design evaluated codeine or codeine-based derivatives against placebo through a randomised controlled trial. Data collection and analysis: Two review authors independently screened the search results to determine eligibility against a standardised criteria, and we had a pre-planned method for analysis. Main results: We identified a total of 556 records, of which 486 records were excluded on the basis of title and abstract. We retrieved the remaining 70 references in full to determine eligibility. No studies fulfilled the inclusion criteria of this review, and thus we found no evidence to support or oppose the use of codeine or derivatives as antitussive agents for chronic cough in children. While chronic cough is not the same as acute cough, systematic reviews on the use of codeine efficacy for acute cough in children conclude an overall lack of evidence to support or oppose the use of over-the-counter cough and cold medications containing codeine (or derivatives) for treatment of acute cough in children. The lack of sufficient evidence to support the use of these medications has been consistently reaffirmed by medical experts in international chronic cough guidelines and by governing medical and pharmaceutical authorities in the USA, Europe, Canada, New Zealand, and Australia. Due to the lack of sufficient evidence to support efficacy, and the known risks associated with use - in particular the increased risks for children - these medications are now not recommended for children less than 12 years of age and children between 12 to 18 years with respiratory conditions. Authors' conclusions: This review has highlighted the absence of any randomised controlled trials evaluating codeine-based medications in the treatment of childhood chronic cough. Given the potential adverse events of respiratory suppression and opioid toxicity, national therapeutic regulatory authorities recommend the contraindication of access to codeine in children less than 12 years of age. We suggest that clinical practice adhere to clinical practice guidelines and thus refrain from using codeine or its derivatives to treat cough in children. Aetiological-based management practices continue to be advocated for children with chronic cough

Methylxanthines for prolonged non-specific cough in children

Background: Non-specific cough is defined as non-productive cough in the absence of identifiable respiratory disease or known aetiology. It is commonly seen in paediatric practice. These children are treated with a variety of therapies including a variety of asthma medications. Methylxanthines, the main medication used for paediatric asthma for many decades in Western countries, is still widely used in non-Western countries. Also, methylxanthines have other pharmacological properties and their bronchodilator effect is only modest

Inhaled corticosteroids for bronchiectasis (review)

Background: Bronchiectasis is being increasingly diagnosed and recognised as an important contributor to chronic lung disease in both adults and children in high- and low-income countries. It is characterised by irreversible dilatation of airways and is generally associated with airway inflammation and chronic bacterial infection. Medical management largely aims to reduce morbidity by controlling the symptoms, reduce exacerbation frequency, improve quality of life and prevent the progression of bronchiectasis. This is an update of a review first published in 2000. Objectives: To evaluate the efficacy and safety of inhaled corticosteroids (ICS) in children and adults with stable state bronchiectasis, specifically to assess whether the use of ICS: (1) reduces the severity and frequency of acute respiratory exacerbations; or (2) affects long-term pulmonary function decline. Search methods: We searched the Cochrane Register of Controlled Trials (CENTRAL), the Cochrane Airways Group Register of trials, MEDLINE and Embase databases. We ran the latest literature search in June 2017. Selection criteria: All randomised controlled trials (RCTs) comparing ICS with a placebo or no medication. We included children and adults with clinical or radiographic evidence of bronchiectasis, but excluded people with cystic fibrosis. Data collection and analysis: We reviewed search results against predetermined criteria for inclusion. In this update, two independent review authors assessed methodological quality and risk of bias in trials using established criteria and extracted data using standard pro forma. We analysed treatment as 'treatment received' and performed sensitivity analyses. Main results: The review included seven studies, involving 380 adults. Of the 380 randomised participants, 348 completed the studies. Due to differences in outcomes reported among the seven studies, we could only perform limited meta-analysis for both the short-term ICS use (6 months or less) and the longer-term ICS use (> 6 months). During stable state in the short-term group (ICS for 6 months or less), based on the two studies from which data could be included, there were no significant differences from baseline values in the forced expiratory volume in the first second (FEV1) at the end of the study (mean difference (MD) -0.09, 95% confidence interval (CI) -0.26 to 0.09) and forced vital capacity (FVC) (MD 0.01 L, 95% CI -0.16 to 0.17) in adults on ICS (compared to no ICS). Similarly, we did not find any significant difference in the average exacerbation frequency (MD 0.09, 95% CI -0.61 to 0.79) or health-related quality of life (HRQoL) total scores in adults on ICS when compared with no ICS, though data available were limited. Based on a single non-placebo controlled study from which we could not extract clinical data, there was marginal, though statistically significant improvement in sputum volume and dyspnoea scores on ICS. The single study on long-term outcomes (over 6 months) that examined lung function and other clinical outcomes, showed no significant effect of ICS on any of the outcomes. We could not draw any conclusion on adverse effects due to limited available data. Despite the authors of all seven studies stating they were double-blind, we judged one study (in the short duration ICS) as having a high risk of bias based on blinding, attrition and reporting of outcomes. The GRADE quality of evidence was low for all outcomes (due to non-placebo controlled trial, indirectness and imprecision with small numbers of participants and studies). Authors' conclusions: This updated review indicates that there is insufficient evidence to support the routine use of ICS in adults with stable state bronchiectasis. Further, we cannot draw any conclusion for the use of ICS in adults during an acute exacerbation or in children (for any state), as there were no studies

Protracted bacterial bronchitis in children: natural history and risk factors for bronchiectasis

BACKGROUND: Protracted bacterial bronchitis (PBB) and bronchiectasis are distinct diagnostic entities that share common clinical and laboratory features. It is postulated, but remains unproved, that PBB precedes a diagnosis of bronchiectasis in a subgroup of children. In a cohort of children with PBB, our objectives were to (1) determine the medium-term risk of bronchiectasis and (2) identify risk factors for bronchiectasis and recurrent episodes of PBB. METHODS: One hundred sixty-one children with PBB and 25 control subjects were prospectively recruited to this cohort study. A subset of 106 children was followed for 2 years. Flexible bronchoscopy, BAL, and basic immune function tests were performed. Chest CT was undertaken if clinical features were suggestive of bronchiectasis. RESULTS: Of 161 children with PBB (66% boys), 13 were diagnosed with bronchiectasis over the study period (8.1%). Almost one-half with PBB (43.5%) had recurrent episodes (> 3/y). Major risk factors for bronchiectasis included lower airway infection with Haemophilus influenzae (recovered in BAL fluid) (P ¼ .013) and recurrent episodes of PBB (P ¼ .003). H influenzae infection conferred a more than seven times higher risk of bronchiectasis (hazard ratio, 7.55; 95% CI, 1.66-34.28; P ¼ .009) compared with no H influenzae infection. The majority of isolates (82%) were nontypeable H influenzae. No risk factors for recurrent PBB were identified. CONCLUSIONS: PBB is associated with a future diagnosis of bronchiectasis in a subgroup of children. Lower airway infection with H influenzae and recurrent PBB are significant predictors. Clinicians should be cognizant of the relationship between PBB and bronchiectasis, and appropriate follow-up measures should be taken in those with risk factors.No Full Tex

A multicenter study on chronic cough in children: Burden and etiologies based on a standardized management pathway

Background: While the burden of chronic cough in children has been documented, etiologic factors across multiple settings and age have not been described. In children with chronic cough, we aimed (1) to evaluate the burden and etiologies using a standar

Clinical Utility of Exhaled Nitric Oxide

Lower airway inflammation is generally classified as eosinophilic or neutrophilic. In conditions where eosinophilic inflammation predominates such as asthma in children, corticosteroids are usually beneficial. Traditionally, lower airway eosinophilia is measured using cellular count (through bronchoalveolar lavage or induced sputum). Both methods have limited applicability in children. When instruments to measure fractional exhaled nitric oxide (FeNO) became available, it presented an attractive option as it provided a non-invasive method of measuring eosinophilic inflammation suitable for children and adult. Not surprisingly, proposals have been made that FeNO measurement can be clinically used in many scenarios including monitoring the response to anti-inflammatory medications, to verify the adherence to treatment, and to predict upcoming asthma exacerbations.\ud \ud This thesis addresses the utility of FeNO levels in various scenarios, specifically in relation to asthma control and cough, a contentious aspect of the diagnosis of asthma. The thesis consists of a series of systematic reviews (related to the main question) and original studies in children. The over-arching aim of the thesis is to determine if FeNO is a clinically useful tool in the management of asthma and common asthma symptoms.\ud \ud The specific aims of the thesis were, to:\ud \ud 1. Determine if children with asthma have more severe acute respiratory symptoms at presentation with an asthma exacerbation and at days 7, 10 and 14 using validated scales. We also examined if children with asthma were more likely to have a persistent cough on day 14 than children with protracted bronchitis and/or controls.\ud \ud 2. Evaluate the efficacy of tailoring asthma interventions based on sputum analysis in comparison to clinical symptoms (with or without spirometry/peak flow) for asthma related outcomes in children and adults.\ud \ud 3. Evaluate the efficacy of tailoring asthma interventions based on exhaled nitric oxide in comparison to clinical symptoms (with or without spirometry/peak flow) for asthma related outcomes in children and adults.\ud \ud 4. Determine if adjustment of asthma medications based on FeNO levels (compared to management based on clinical symptoms) reduces severe exacerbations in children with asthma.\ud \ud 5. Examine the relationship between FeNO and exercise induced broncho-constriction and cough in children\ud \ud The aims above are addressed in respective chapters and all but one has been published/submitted. A synopsis of the findings are:\ud \ud In study-1 (Aim 1), we found that children with protracted bronchitis had the most severe acute respiratory infection symptoms and higher percentage of respiratory morbidity at day 14 in comparison to children with asthma and healthy controls.\ud \ud The systematic review of study-2 (Aim 2) included 246 randomised adult participants (no children) with 221 completing the trials. In the meta-analysis, a significant reduction in number of participants who had one or more asthma exacerbations occurred when treatment was based on sputum eosinophils in comparison to clinical symptoms.\ud \ud In the systematic review of study-3 (Aim 3), we found no significant difference between the intervention group (treatment adjusted based on FeNO) and control group (treatment adjusted based on clinical symptoms) for the primary outcome of asthma exacerbations or for the other outcomes (clinical symptoms, FeNO level and spirometry). In post-hoc analysis, a significant reduction in mean final daily dose ICS per adult was found in the group where treatment was based on FeNO in comparison to clinical symptoms. In contrast, in the paediatric studies, there was a significant increase in ICS dose in the FeNO strategy arm.\ud \ud Thus, controversy remains of the benefit or otherwise of utilising exhaled nitric oxide (FeNO) in routine clinical practice. FeNO levels are dependent on atopy and none of the 7 published trials have considered atopic status in FeNO levels when medications were adjusted.\ud \ud In study-4 (Aim 4), 64 children with asthma were recruited. Their asthma medications were adjusted according to either FeNO levels or usual clinical care utilising a management hierarchy taking into account atopy. It was concluded that tailoring of asthma medications in accordance to FeNO levels (compared to usual management), taking into account atopy status, reduced the number of children with severe exacerbations. However, a FeNO-based strategy resulted in higher daily ICS doses and had no benefit on asthma control.\ud \ud In study-5 (Aim 5), 33 children with cough and 17 controls were recruited. They were randomised to undertake an exercise challenge on day 1, or dry powder mannitol challenge on day 1 (with alternative challenge being done on day 2). In addition, a 24 hour cough meter, skin prick test, capsaicin cough sensitivity test and cough diary were undertaken. The change in cough frequency post exercise was significantly increased in the children with cough. FeNO decreases post exercise regardless of whether EIB is present or not.\ud \ud Limitations in the studies were addressed in the respective chapters. In summary, the studies from this thesis have provided new information on:\ud \ud • The severity of respiratory symptoms was increased in the early phase of the asthma exacerbation but not in the later recovery phase when compared with controls.\ud \ud • The utility of FeNO in the management of children with asthma.\ud \ud • The relationship of FeNO, cough and EIB in children.\ud \ud • Systematic reviews on the efficacy of tailoring asthma interventions based on eosinophilic inflammatory markers (sputum analysis and FeNO) in comparison to clinical symptoms

Letter in response to: Stark P et al Amoxycillin-clavulanate for chronic wet cough in children: cautious interpretation of study findings warranted

We thank Stark and colleagues1 for comments on our paper and their interest in our recent randomised controlled trial (RCT) of amoxycillin-clavulanate compared with placebo for children with chronic wet cough,2 which as they state are a ‘group of patients that often present paediatricians with a management dilemma’ and which ‘represents a valuable contribution to the literature’. We feel it is important to clarify a few points raised. First, the criteria used for defining chronic cough in children (>3 weeks) was at the time of the study commencement the definition of chronic childhood cough. We acknowledge following the study completion (enrolment between 2004 and 2006) that the 2006 American College of Chest Physicians (ACCP) clinical practice guidelines in paediatrics changed the cough definition to >4 weeks and the reasons for this are discussed in the ACCP guidelines.3 Irrespective of this the median duration of cough in the treatment and placebo groups were 15 and 11 weeks respectively at enrolment, making a discussion of 3 versus 4 weeks of cough as inclusion criteria irrelevant. Stark and colleagues argue that the verbal category descriptive score (VCD) is not the correct outcome measure to use and that cough resolution would be more appropriate. The VCD score has been used extensively in children of all ages and has been previously validated.4 As stated in the article, and shown in figure 3 and table 2, the children who improved had a cough score of 0.0 which indicates total cough resolution. The definition of primary outcome was cough resolution defined as >75% reduction in cough score for at least 3 days. While this may be argued as incomplete resolution, our a priori definition (as previously used5) is far better than just using a reduction in cough score. Further, a VCD score of 1 represents ‘cough for one or two periods only’ without any effect on daytime function. As stated in the manuscript ‘follow-up over a period of months’ was not available in this cohort as it was not study design. Children can always have another episode of coughing illness and the issue of recurrent protracted bacterial bronchitis (PBB) should indeed be examined. We have since begun following a similar group of patients, with PBB, prospectively over a number of years and look forward to being able to shed further light on the long-term outcome of these children. We agree with Stark et al that antibiotic therapy is not without implications. This manuscript is a RCT specifically designed to assess the efficacy of short-term antibiotic therapy in children with chronic wet cough. Current therapeutic guidelines recommend antibiotic treatment based on Cochrane review, prospective6 and retrospective7 observational studies. This study is the first double-blind RCT to support these recommendations and provides the first high-level evidence for the inclusion of antibiotics in paediatric cough-specific guidelines as treatment for chronic wet cough and PBB