Antibiotics for chronic pulmonary infection in children with a neurodisability (neurodevelopmental disorder)

Abstract

Background

'Neurodisability' refers to a group of conditions that result primarily from a neurological problem (e.g. cerebral palsy), neuromuscular problem (e.g. a muscular dystrophy) or developmental problems (e.g. developmental impairment, Down syndrome). Children and young people with these conditions may have similar problems with mobility, feeding and airway clearance. Chest and breathing problems (including pulmonary infections) are commonly experienced by children and young people with neurodisabilities and are often a cause for them requiring hospital care.

For those who are unable to completely clear their airway of secretions, or have frequent infections, pulmonary infections may not be able to be completely eradicated and therefore become chronic. It is unclear what treatment is best for children and young people in this position.

Objectives

To assess the effectiveness and adverse effects of antibiotic treatment for chronic pulmonary infection in children and young people living with a neurodisability, including quality‐of‐life measures, effects on hospitalisation and healthcare contacts.

Search methods

We searched the Cochrane Airways Trials Register, Cochrane Acute Respiratory Infections Group Register of Trials (CARIGRT), Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE (Ovid), Embase (Ovid), Cumulative Index to Nursing and Allied Health Literature (CINAHL), OpenGrey (www.opengrey.eu) and three trials registries up to 8 February 2022. Additionally, we identified related systematic reviews through Epistemonikos.org (8 February 2022) and searched reference lists of these.

Selection criteria

All randomised controlled trials of antibiotic therapy for chronic pulmonary infection in children and young people up to the age of 18 living with a neurodisability were eligible.

Data collection and analysis

Two independent review authors screened results of the searches against predetermined inclusion criteria, resolving any discrepancies by discussion.

Main results

We identified a total of 1968 independent records through our searches, of which we assessed six full‐text articles for eligibility. We identified one ongoing study as well as one related substudy but did not identify any completed studies eligible for inclusion in this systematic review.

Authors' conclusions

The findings of this systematic review highlight a lack of evidence in the antibiotic treatment of chronic pulmonary infection in children and young people up to the age of 18 living with a neurodisability. Further research examining this topic is therefore required.

Plain language summary

Antibiotics for children with a neurodisability and long‐term lung infection

'Neurodisability' refers to a group of conditions that result primarily from a neurological problem (e.g. cerebral palsy), neuromuscular problem (e.g. a muscular dystrophy) or developmental problems (e.g. developmental impairment, Down syndrome). Children and young people with these conditions may have similar problems with mobility, feeding and coughing. Chest and breathing problems (including lung infections) are commonly experienced by children and young people with neurodisabilities and are often a cause for them needing hospital care.

For those who are unable to completely clear their chests of secretions, or have frequent infections, lung infections may not be able to be completely cleared ‐ they become 'chronic infections'. It is unclear what treatment is best for children and young people in this position.

We sought to systematically review all the clinical trials looking at the antibiotic treatment of lung infection for children and young people with chronic lung infection. We reviewed a total of 1968 published studies up to February 2022, from a number of different online databases, but none were relevant to be included in this review. Two studies were ongoing and as such could not be included in this current version.

We are disappointed that we did not find any clinical trials to answer this important question. This is a key focus for future work so that children and young people in this position can receive the best possible treatment.

Background

Description of the condition

Neurodisability in childhood is an umbrella term used to describe a group of individuals living with long‐term conditions who have similar health and educational needs (Morris 2013). It is often characterised by a primarily neurological condition (e.g. cerebral palsy) or a neuromuscular problem (e.g. a muscular dystrophy).

Neurodisability has been defined as "a group of congenital or acquired long‐term conditions that are attributed to impairment of the brain and/or neuromuscular system and create functional limitations. A specific diagnosis may not be identified. Conditions may vary over time, occur alone or in combination, and include a broad range of severity and complexity. The impact may include difficulties with movement, cognition, hearing and vision, communication, emotion, and behaviour" (Morris 2013). Whilst the conditions that can be classified under this umbrella term may be rare individually, grouped together, they are more common. Up to 8% of children in the UK live with any form of disability (Family Resources Survey 2016). Furthermore, it has been estimated that 3% to 4% of children in high‐income countries are affected by intellectual and developmental disabilities (Emerson 2012).

For children and young people living with a neurodisability, respiratory complications are a major cause of morbidity and mortality. In 2018, the National Confidential Enquiry into Patient Outcome and Death (NCEPOD) published a comprehensive review of cerebral palsy (CP) as an example of conditions causing neurodisability in those under 25 years of age in the UK (NCEPOD 2018). For this report, the cerebral palsies were chosen as the exemplar neurodisabling condition as they are the most common cause of physical disability in childhood, affecting 3 per 1000 live births (NCEPOD 2018). In addition, the cerebral palsies comprise a wide spectrum of severity, and can frequently be associated with a range of co‐existing impairments. The enquiry found that respiratory conditions made up a significant proportion of healthcare utilisation for children and young people living with CP. Respiratory problems were the most common cause of primary care attendance, emergency hospitalisation and admission to paediatric intensive care units. In addition, respiratory issues were recorded as the primary cause of death in 51% of children and young people with CP who died (NCEPOD 2018). Improving the treatment of respiratory problems is key to improving quality of life (QoL) and survival of such individuals.

While neurodisability may be due to a range of heterogeneous conditions, the mechanisms by which pulmonary (lung) complications result are often common to all, i.e. impaired airway clearance due to a weak or poorly co‐ordinated cough and aspiration of orogastric secretions provoking inflammation. Clearance of the infected thickened secretions is more difficult and lung infection can result. Persistence of these factors can cause repeated or chronic pulmonary infections, resulting in parenchymal lung damage (Fitzgerald 2009; Hurley 2015). High antibiotic consumption in these children may predispose them to antimicrobial resistance (Chang 2015).

Apart from impact on the quality of life of the child or young person, there is often a significant impact on families and carers. In addition to direct healthcare‐associated costs, there is a larger societal cost due to the potential loss of earnings of carers, in addition to the costs for potential special educational needs as well as additional factors. A study from England and Wales estimates that neurodevelopmental impairment during mid‐childhood equates to an annual economic burden of approximately GBP 1990 million to the broader public services, as well as GBP 333 million to health and social services (Petrou 2013).

As mentioned above, children and young people living with a neurodisability represent a heterogenous group, with different needs. For the purpose of this systematic review and meta‐analysis, we are dividing children and young people into four broad categories. Whilst the cerebral palsies in themselves represent a broad spectrum of disease, these are considered to be 'non‐progressive' in origin and are used in the literature as a representative of conditions resulting in neurodisability; we are therefore assessing these on their own. Neuromuscular disorders (such as Duchenne muscular dystrophy or spinal muscular atrophy) are well known to have pulmonary implications, often due to progressive respiratory muscle weakness; these form a second group in our review. Neurodegenerative causes of neurodisability form a third group, including conditions such as Batten disease and some metabolic conditions. The final group includes all other causes of neurodisability (including acquired brain injury) and may include those children and young people without a specific diagnosis (including Syndromes Without a Name (SWAN)). Furthermore, we will only include chronic respiratory infections, as defined in the methodology section.

Description of the intervention

Antibiotics are a class of medication that kill bacteria (bacteriocidal) or inhibit bacterial growth (bacteriostatic). Antibiotics can be administered by a variety of routes (treatment of pulmonary infection is commonly via oral, intravenous or nebulised routes) and these considerations can impact on the setting in which care is provided. The duration of antibiotic usage can be a few days in the case of acute infections, or long‐term in the case of chronic infection. Multiple subclasses of antibiotics exist, including beta‐lactams, tetracyclines, macrolides and aminoglycosides, amongst others. Usage of these agents in isolation or combination for pulmonary infections can be influenced by local prevalence, resistance patterns, patient factors and availability.

Despite widespread use, the consumption of antibiotics is accompanied by risk and adverse effects. Side effects of antibiotic usage are commonplace depending on the type of antibiotic used (Gleckman 2000). These side effects can range from relatively mild (e.g. diarrhoea in 2.2% to 18.9% of children and generalised rash in 1.4% to 6.5% of children (Hum 2019)) through to nephrotoxicity/hepatotoxicity and rare but potentially life‐threatening events such as anaphylaxis (Cunha 2001). Antibiotic use also drives antibiotic resistance, both within patients and within communities.

How the intervention might work

Managing chronic infection may improve general health by reducing respiratory exacerbations and lung damage. The mechanism of antibiotic actions can broadly be divided into two categories: bacteriostatic antibiotics work by slowing the growth of bacteria and therefore rely on the host organism's defence mechanisms, whereas bacteriocidal antibiotics lead to or induce bacterial cell death (Kohanski 2010). In order to effectively treat bacterial infections, combinations of antibiotics from various classes may be used.

Why it is important to do this review

There are several uncertainties regarding the treatment of chronic pulmonary infection for children and young people living with a neurodisability. Currently, clinical decisions are often informed by extrapolating information from other conditions, such as cystic fibrosis or bronchiectasis. An awareness of respiratory complications in various causes of neurodisability exists, with multiple papers describing the problem, potential physiological causes and management considerations (Boel 2019; Dohna‐Schwake 2006; Kansra 2016; Proesmans 2016). Whilst a recent systematic review has highlighted a limited to absent evidence base for the prevention and management of respiratory disease in children and young people living with CP (Blackmore 2019), this review is looking to assess the evidence base across of wider range of conditions resulting in neurodisability.

Whilst timely prescription of antibiotics is important for the effective management of bacterial infections, antibiotic resistance is a growing problem and inappropriate use of antibiotics can result in increased antibiotic resistance. In 2015 alone, resistant bacteria resulted in an estimated 671,689 infections and 33,110 attributable deaths across all ages in the European Union and European Economic Area (Cassini 2019). With this in mind, a robust evidence base is required to guide clinicians in their decision‐making when prescribing antibiotics, to enable the targeted and effective treatment of bacterial infections whilst minimising risks to individuals and populations.

With respiratory complications being a significant cause of illness and mortality for children and young people living with a neurodisability, effective treatment to improve quality of life is required. When considering antibiotic treatment, the route of administration is a factor of particular importance as this can directly affect the burden of treatment on children and young people and their families/carers. This systematic review therefore set out to be used to understand the evidence base for antibiotic treatment of chronic pulmonary infections in children and young people living with different types of neurodisability.

Objectives

To assess the effectiveness and adverse effects of antibiotic treatment for chronic pulmonary infection in children and young people living with a neurodisability, including quality‐of‐life measures, effects on hospitalisation and healthcare contacts.

Methods

Criteria for considering studies for this review

Types of studies

We planned to include randomised controlled trials (RCTs) only. We planned to also include trials with a cross‐over design, but to restrict the analysis to the first phase of the study only as a significant carry‐over effect was expected (Elbourne 2002). We planned to include studies reported in full text, those published as an abstract only and unpublished data. We had furthermore planned to include studies in all languages, where interpretation was possible. However, we did not identify any studies for inclusion in this review.

Types of participants

Had we been able to include studies, we planned to include children and young people up to 18 years of age living with a neurodisability, who have been diagnosed with chronic pulmonary infection. There were no restrictions on the care setting. For the purpose of this review, we defined neurodisability according to the Delphi survey by Morris 2013, as quoted in the Background section. For the purpose of analysis, we set out to group the underlying conditions into the following categories:

• cerebral palsy (as this is frequently used as a representative of conditions resulting in neurodisability);

• neuromuscular causes (e.g. spinal muscular atrophy, Duchenne muscular dystrophy);

• neurometabolic causes (e.g. Batten disease, Krabbe disease);

• other complex neurodisability (including children and young people with conditions not falling under the other categories, such as trisomy 21 and including acquired brain injury).

Chronic pulmonary infection would have been defined according to the trialist, but was likely to include one or more of the following:

• the presence of clinical features of pulmonary infection (such as a chronic wet cough or persistent need for airway clearance) for a minimum of six months;

• positive microbiology (more than 50% of respiratory samples positive over 12 months);

• radiological features in keeping with chronic respiratory infection (such as persistently abnormal chest X‐rays on two or more occasions in 12 months, or evidence of bronchiectasis on computerised tomography (CT)).

Where studies included a proportion of trial participants not meeting the inclusion criteria (e.g. participants aged 18 years or over), we aimed to only analyse those meeting our predefined criteria. If this was not obvious from the publication, we planned to contact the study authors for the data of those participants of interest only. If no response was received to a further reminder email, we would have included the trial in the summary of findings table as well as the narrative synthesis if it was clear that more than 75% of trial participants met our predefined inclusion criteria. However, we would not have included such trials in a meta‐analysis.

Types of interventions

We planned to include studies comparing antibiotics of any group, administered by any route (e.g. oral/intravenous/nebulised) with placebo or standard care (or both). We planned to analyse primarily based on the route of administration and secondarily by antibiotic group. We planned to include comparative effectiveness trials as well as studies assessing single antibiotics or combinations of antibiotics as the intervention or comparator (or both).

We planned to include the following co‐interventions, provided they were not part of the randomised treatment:

• standard care;

• physiotherapy (including respiratory physiotherapy);

• other antimicrobials (such as antifungals).

Types of outcome measures

We planned to analyse the following outcomes in the review, but we did not use them as a basis for including or excluding studies. We planned to consider outcome measures reported over the period of one year following randomisation and would have extracted data at three, six and 12 months when available.

Primary outcomes

1. Cumulative number of days of hospital admission secondary to respiratory causes per child or young person within one year

2. Quality‐of‐life measures as validated patient‐reported or parent/carer‐reported outcomes (such as DISABKIDS‐CP (Baars 2005), CP QOL Child (Waters 2006)) or CP QOL Teen (Davis 2013)

3. Average time to next pulmonary exacerbation (defined according to the trialist or by the provision of additional antibiotics) within one year

Secondary outcomes

1. Respiratory symptom scores (such as the Liverpool Respiratory Symptom Questionnaire ‐ Neuro (Trinick 2015))

2. Requirement of new respiratory support (invasive or non‐invasive ventilation or high‐flow nasal cannula) within one year

3. Number of critical care admissions (including high‐dependency units) within one year

4. Number of emergency medical visits (including emergency department visits and out‐of‐hours care) within one year

5. Adverse events and serious adverse events (including new development of antimicrobial resistance)

6. Survival

Search methods for identification of studies

Electronic searches

We identified studies from searches of the following databases and trial registries:

• Cochrane Airways Trials Register (Cochrane Airways 2019), via the Cochrane Register of Studies, all years to 8 February 2022;

• Cochrane Acute Respiratory Infections Group Register of Trials (CARIGRT), all years to 8 February 2022;

• Cochrane Central Register of Controlled Trials (CENTRAL), via the Cochrane Register of Studies, all years to 8 February 2022;

• MEDLINE (Ovid) ALL 1946 to 8 February 2022;

• Embase (Ovid) 1974 to 8 February 2022;

• Cumulative Index to Nursing and Allied Health Literature (CINAHL), 1937 to 8 February 2022;

• OpenGrey (www.opengrey.eu) to 8 February 2022;

• US National Institutes of Health Ongoing Trials Register ClinicalTrials.gov (www.clinicaltrials.gov) to 8 February 2022;

• International Standard Randomised Controlled Trials Number (ISRCTN) registry to 8 February 2022.

The database search strategies are listed in Appendix 1. The search was designed in MEDLINE and adapted for use in the other databases. The search strategy was developed by the Cochrane Airways Information Specialist in collaboration with the authors, and was peer‐reviewed by another Cochrane Information Specialist using the Peer Review of Electronic Search Strategies (PRESS) checklist (McGowan 2016). Of note, the search strategy included some older descriptive terms (such as mental retardation) that are no longer in use. Whilst we do not advocate the use of these terms, we felt it necessary to utilise them to comprehensively identify older studies.

All databases and trials registries were searched from their inception to 8 February 2022, with no restriction on language or type of publication. We identified handsearched conference abstracts and grey literature through the Cochrane Airways Trials Register and the CENTRAL database.

Searching other resources

We searched Epistemonikos.org, a database of systematic reviews relevant for health decision‐making, to identify relevant systematic reviews; we then handsearched the references of relevant systematic reviews.

Furthermore, we would have handsearched the reference lists of all included primary studies for additional references. Additionally, we would have used Google Scholar for forward citation searches of all included studies.

Similarly, we had also planned to search for errata or retractions from included studies published in full text on PubMed, and report the date this was done within the review.

Data collection and analysis

Selection of studies

We used Cochrane’s Screen4Me workflow to help assess the search results. Screen4Me comprises three components:

• known assessments (a service that matches records in the search results to records that have already been screened in Cochrane Crowd and been labelled as 'RCT' or as 'not an RCT');

• the RCT classifier (a machine learning model that distinguishes RCTs from non‐RCTs); and

• Cochrane Crowd (Cochrane’s citizen science platform where the Crowd help to identify and describe health evidence), if appropriate.

More detailed information about the Screen4Me components can be found in the following publications: Marshall 2018; McDonald 2017; Noel‐Storr 2018; Thomas 2017.

Following this initial assessment, two out of three review authors (JS, KJ, MH) screened the titles and abstracts of the remaining search results independently and coded them as 'retrieve' (eligible or potentially eligible/unclear) or 'do not retrieve'. We retrieved the full‐text study reports of all potentially eligible studies and two out of three review authors (JS, KJ, MH) independently screened them for inclusion, recording the reasons for exclusion of ineligible studies. We resolved any disagreement through discussion. We identified and excluded duplicates and planned to collate multiple reports of the same study so that each study, rather than each report, was the unit of interest in the review. We recorded the selection process in sufficient detail to complete a PRISMA flow diagram and 'Characteristics of excluded studies' table (Moher 2009). We used Covidence to assist title and abstract screening and full‐text screening stages of the systematic review. We did not plan to include any new studies once the data extraction phase had started.

Data extraction and management

We were planning to use a data collection form for study characteristics and outcome data, which would have been piloted on at least one study in the review. Had we identified any studies for inclusion, two out of three review authors (JS, KJ, MH) would have independently extracted the following study characteristics from included studies:

• methods: study design, total duration of study, details of any 'run‐in' period, number of study centres and location, study setting, withdrawals and date of study;

• participants: number (N), mean age, age range, gender, severity of condition, diagnostic criteria, baseline lung function, smoking history, inclusion criteria and exclusion criteria;

• interventions: intervention, comparison, concomitant medications and excluded medications;

• outcomes: primary and secondary outcomes specified and collected, and time points reported;

• notes: funding for studies and notable conflicts of interest of trial authors.

We would have noted in the 'Characteristics of included studies' table if outcome data were not reported in a usable way. Had there been any disagreements in the data extraction phase, we would have resolved them by consensus. One review author (JS) would have transferred the data into the Review Manager file (Review Manager 2020). We would have double‐checked that data were entered correctly by comparing the data presented in the systematic review with the study reports. A second review author (MH or KJ) would have spot‐checked study characteristics for accuracy against the study report.

Assessment of risk of bias in included studies

Two out of three review authors (JS, KJ, MH) would have assessed risk of bias independently for each study using the criteria outlined in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2017). We would have resolved any disagreements by discussion. We planned to assess the risk of bias according to the following domains:

• random sequence generation;

• allocation concealment;

• blinding of participants and personnel;

• blinding of outcome assessment;

• incomplete outcome data;

• selective outcome reporting;

• other bias (including, but not limited to, study funding and declaration of interest conflicts).

We set out to judge each potential source of bias as high, low or unclear and provide a quote from the study report together with a justification for our judgement in the risk of bias table. We aimed to summarise the risk of bias judgements across different studies for each of the domains listed. We would have considered blinding separately for different key outcomes where necessary (e.g. for unblinded outcome assessment, risk of bias for survival may be very different to a patient‐reported outcome). If risk of bias was initially unclear from the available data, we would have contacted the trial’s contact author via email to gain further information about the risk of bias. If we received no reply to the initial email, we would have sent two reminder emails. If we received no response, we would have highlighted the impact of this in the review. Where information on risk of bias had related to unpublished data or correspondence with a trialist, we would have noted this in the risk of bias table. When considering treatment effects, we would have taken into account the risk of bias for the studies that contributed to that outcome.

Assessment of bias in conducting the systematic review

We conducted the review according to the published protocol. We have justified any deviations in the Differences between protocol and review section of this systematic review.

Measures of treatment effect

We planned to analyse dichotomous data as odds ratios (ORs) and continuous data as the mean difference (MD) or standardised mean difference (SMD). If data from rating scales had been combined in a meta‐analysis, we planned to ensure they were entered with a consistent direction of effect (e.g. lower scores always indicate improvement). We would have undertaken meta‐analyses only where this was meaningful; that is, if the treatments, participants and the underlying clinical question were similar enough for pooling to make sense. We planned to describe skewed data narratively (for example, as medians and interquartile ranges for each group).

If multiple trial arms were reported in a single study, we would have included only the relevant arms. If two comparisons (e.g. drug A versus placebo and drug B versus placebo) had been combined in the same meta‐analysis, we would have either combined the active arms or halved the control group to avoid double‐counting.

If adjusted analyses had been available (analysis of variance (ANOVA) or analysis of covariance (ANCOVA)), we would have used these as a preference in our meta‐analyses. If both change‐from‐baseline and end‐point scores had been available for continuous data, we planned to use change‐from‐baseline unless there was low correlation between measurements in individuals. If a study reported outcomes at multiple time points, we aimed to extract data at one year.

We planned to use intention‐to‐treat (ITT) or 'full analysis set' analyses where they were reported (i.e. those where data had been imputed for participants who were randomly assigned but did not complete the study) instead of completer or per‐protocol analyses.

Unit of analysis issues

For continuous outcomes, we planned to use participants, rather than events, as the unit of analysis (i.e. number of children admitted to hospital, rather than number of admissions per child). However, if rate ratios had been reported in a study, we would have analysed them on this basis. We planned to only meta‐analyse data from cluster‐RCTs if the available data had been adjusted (or could be adjusted), to account for the clustering.

Dealing with missing data

We would have contacted investigators or study sponsors in order to verify key study characteristics and obtain missing numerical outcome data where possible (e.g. when a study is identified as an abstract only). Where this would not have been possible, and the missing data were thought to introduce serious bias, we would have taken this into consideration in the GRADE rating for affected outcomes. We planned to use an imputation method if possible, as detailed in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2020). Where this would not have been possible, we planned to perform a sensitivity analysis including only studies with complete data to assess the effect of missing data upon the final result.

Assessment of heterogeneity

We planned to use the I² statistic to measure heterogeneity among the studies in each analysis. If we had identified substantial heterogeneity, we would have reported it and explored the possible causes by prespecified subgroup analysis. The thresholds for interpretation of the I² value according to the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2020) would have been:

• 0% to 40%: might not be important;

• 30% to 60%: may represent moderate heterogeneity;

• 50% to 90%: may represent substantial heterogeneity;

• 75% to 100%: considerable heterogeneity.

Assessment of reporting biases

Had we found any studies for inclusion, we planned to contact the authors of studies published as abstract only or registered clinical trials to ask for further information. We planned to include data from unpublished trials in the analysis, but unpublished status would have been highlighted.

In order to reduce the risk of outcome reporting bias, we planned to compare the outcomes in protocols, where available, to the outcomes reported.

If we had been able to pool more than 10 studies, we planned to create and examine a funnel plot to explore possible small‐study and publication biases.

Data synthesis

We planned to use a random‐effects model and perform a sensitivity analysis using a fixed‐effect model. We would have combined outcomes and calculated effect estimates using the software Review Manager 5.4 (Review Manager 2020), in accordance with guidelines in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2020). If heterogeneity had been substantial, we would not have performed a meta‐analyses and instead completed a narrative, qualitative summary.

We planned to provide a systematic narrative synthesis with information presented in the text and tables to summarise and explain the characteristics and findings of any studies included. We would have used narrative synthesis to explore the relationship and findings within and between studies.

Subgroup analysis and investigation of heterogeneity

We planned to carry out the following subgroup analyses, if appropriate:

• grading of cerebral palsy as defined by the Gross Motor Function Classification System (GMFCS): grading at GMFCS level 4 and 5 compared to levels 1, 2 and 3;

• microbiological evidence of isolation of Pseudomonas aeruginosa: comparing children and young people who have ever had Pseudomonas aeruginosa confirmed on microbiological testing to those who have not;

• diagnosis of bronchopulmonary dysplasia (BPD): children and young people with a diagnosis of BPD compared to those without.

We set out to use the following outcomes in subgroup analyses:

• cumulative number of days of hospital admission secondary to respiratory causes per child or young person within one year;

• quality‐of‐life measures as validated patient‐reported or parent/carer‐reported outcomes (such as DISABKIDS‐CP (Baars 2005), CP QOL Child (Waters 2006)) or CP QOL Teen (Davis 2013);

• average time to next pulmonary exacerbation (defined according to the trialist or by the provision of additional antibiotics) within one year;

• number of critical care admissions (including high‐dependency units) within one year;

• adverse events and serious adverse events (including new development of antimicrobial resistance).

We planned to use the formal test for subgroup interactions in Review Manager (Review Manager 2020).

Sensitivity analysis

In order to determine whether the results were affected by arbitrary decisions made in the protocol writing stage, we would have to carried out the following sensitivity analyses for the primary outcomes:

• excluding trials at high risk of bias in any of the domains;

• excluding trials with missing data.

We also planned to compare the results from a fixed‐effect model with the random‐effects model.

Summary of findings and assessment of the certainty of the evidence

We would have created a summary of findings table using the following outcomes:

• cumulative number of days of hospital admission secondary to respiratory causes per child or young person within 12 months;

• quality‐of‐life measures as validated patient‐reported or parent/carer‐reported outcomes;

• average time to next pulmonary exacerbation (defined according to the trialist or by the provision of additional antibiotics) within one year;

• requirement of new respiratory support (invasive or non‐invasive ventilation including high‐flow nasal cannula) within one year;

• number of critical care admissions (including high‐dependency units) within one year;

• number of emergency medical visits (including emergency department visits and out‐of‐hours care) within one year;

• adverse events and serious adverse events (including new development of antimicrobial resistance).

We planned to use the five GRADE considerations (risk of bias, consistency of effect, imprecision, indirectness and publication bias) to assess the quality of the body of evidence as it relates to the studies that contributed data for the prespecified outcomes. We planned to use the methods and recommendations described in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2020), using GRADEpro GDT software (GRADEpro GDT). We would have justified all decisions to downgrade the quality of the evidence using footnotes and would have made comments to aid the reader's understanding of the review where necessary.

Results

Description of studies

Results of the search

The PRISMA flow chart can be found in Figure 1.

1.

PRISMA Flow Chart

The searches identified a total of 2091 records before removing duplicates. Of those, 1881 came from searches of CENTRAL (including Airways & ARI registers), MEDLINE, Embase, CINAHL and CT.gov; we identified 10 through ISRCTN and 52 through OpenGrey. Additionally, we identified 148 references by searching the references of two relevant systematic reviews (Blackmore 2019; Onakpoya 2015), which we had in turn identified through Epistemonikos.org.

We removed 123 duplicates, leaving a total of 1968 unique references that were eligible for title and abstract screening.

As specified in our protocol, we used the Screen4Me tool to initially screen 1761 of those records. This rejected 1008 records (983 by RCT classifier and 25 known assessments). We manually screened the remaining 753 records not rejected through Screen4Me, as well as the 210 records identified through other sources.

We identified six records that were eligible for full‐text review. Of these, we excluded four due to ineligible trial design or participant population.The other two were ongoing studies (ISRCTN71955516 and ACTRN12621001486819). We did not identify any completed studies that met our inclusion criteria.

Included studies

We did not identify any completed studies that were eligible for inclusion. One ongoing RCT (ISRCTN71955516) and an associated substudy (ACTRN12621001486819) met our inclusion criteria and will likely be eligible for inclusion in future updates of this review, once results are available.

Excluded studies

We excluded a total of four studies at the full‐text review stage for not being of eligible trial design or participant population, as highlighted in the Excluded studies section of this review.

Risk of bias in included studies

This review did not identify any studies for inclusion, and we are therefore unable to complete the risk of bias tool.

Effects of interventions

We did not include any studies in this review.

Discussion

Summary of main results

Out of the 1968 unique records identified through our searches, none met criteria for inclusion in this review. We identified one ongoing study (PARROT Trial; ISRCTN71955516), alongside a planned associated substudy (PARROT‐Junior; ACTRN12621001486819). Future updates of this review may incorporate results of these, but care will need to be taken to avoid double counting of participants should both studies be eligible for inclusion in future versions of this review.

Our findings highlight a current lack of RCTs to provide evidence for or against the use and choice of antibiotics for chronic pulmonary infection in children and young people living with a neurodisability. The question of antibiotic treatment choices remains clinically important, both due to impact on the child or young person but also due to the growing issue of antibiotic resistance.

Overall completeness and applicability of evidence

In the absence of published RCT results, discussion of bias within the literature is limited. Whilst the lack of results may itself represent publication bias, with negative studies remaining unpublished, we only identified one ongoing study through trial registries. We were unable to formally assess publication bias using a funnel plot due to the lack of identified studies.

Quality of the evidence

Due to a lack of completed studies eligible for inclusion, it was not possible to assess the quality of evidence.

Potential biases in the review process

We used a thorough search strategy and accessed multiple databases in order to comprehensively identify eligible studies, with no restriction on language. Furthermore, two independent review authors assessed resulting searches against predefined inclusion and exclusion criteria in order to improve reliability and minimise false rejection of eligible studies. Our definition of chronic pulmonary infection was purposefully kept pragmatic in the absence of an international consensus for this cohort. The review protocol was published prior to commencing the systematic review (Sanner 2020).

As handsearching of references took place as part of the review process, we are unable to exclude citation bias. It is also important to note that our search was likely narrowed by the selection of RCTs only. We acknowledge the difficulties in RCTs design and set‐up for this cohort, complicated by the significant heterogeneity within different neurodisabilities. However, inclusion of multiple study types would have yielded results with significant bias and low clinical applicability. The strength of RCTs therefore resulted in the decision to restrict this review to RCTs.

Agreements and disagreements with other studies or reviews

A related systematic review by Blackmore 2019 has previously assessed all interventions for respiratory disease in children and young people with CP only. Whilst CP has been used as a surrogate for neurodisabilities, we opted to assess the wider range of neurodisabilities. The Blackmore 2019 review found absent or weak evidence for most respiratory interventions in children and young people with CP. On the topic of antibiotics, the review authors identified one case series of nebulised tobramycin for three young people between the ages of 13 and 24, inhabiting a residential centre for children with severe cerebral palsy (Plioplys 2011). However, this study did not identify any RCTs either.

Authors' conclusions

Implications for practice.

Clinically, this systematic review is unable to contribute to the understanding of the effect of antibiotics in chronic pulmonary infection in children with a neurodisability due to a lack of evidence. It is important to highlight that this current absence of evidence is not equivalent to evidence of absence of effect. Therefore, until further evidence becomes available, clinicians may want to continue to use antibiotics empirically and based on clinical experience, but should be aware that there is currently no available randomised controlled trial (RCT)‐based evidence to best guide the use, selection or administration route of antibiotics in chronic pulmonary infection in children and young people living with a neurodisability. Potential adverse effects of antibiotic usage on an individual level as well as risks on a population level will continue to need to be considered clinically.

Implications for research.

Antibiotic treatment for chronic pulmonary infection in children and young people living with a neurodisability is an important topic due not only to the associated morbidity and mortality related to pulmonary infection in this group, but also due to wider societal issues around impact on families and rising antimicrobial resistance. High‐quality, multicentre RCTs are therefore urgently needed to determine the utility and necessity of antibiotics in this setting.

When designing RCTs, provision of antibiotics as an intervention will need to be assessed in a multi‐faceted approach involving careful consideration of medication class, administration method, dosage and duration of treatment. A holistic approach should be used, and outcomes to assess the impact on the child’s health should include not only measures of healthcare utilisation, but importantly also patient‐reported outcome measures (PROMs), quality of life measures and an assessment of the impact on families/carers.

History

Protocol first published: Issue 12, 2020

Appendices

Appendix 1. Database search strategies

Database/search platform/date of last search	Search strategy	Results
Airways Register+Acute Respiratory Infections Register (via Cochrane Register of Studies) Date of most recent search: 8 February 2022	#1 MESH DESCRIPTOR Neurodevelopmental Disorders EXPLODE ALL AND ARI:INREGISTER #2 MESH DESCRIPTOR Developmental Disabilities EXPLODE ALL AND ARI:INREGISTER #3 MESH DESCRIPTOR Intellectual Disability EXPLODE ALL AND ARI:INREGISTER #4 MESH DESCRIPTOR Child Development Disorders, Pervasive AND ARI:INREGISTER #5 MESH DESCRIPTOR Learning Disabilities AND ARI:INREGISTER #6 MESH DESCRIPTOR Communication Disorders EXPLODE ALL AND ARI:INREGISTER #7 MESH DESCRIPTOR Disabled Children EXPLODE ALL AND ARI:INREGISTER #8 MESH DESCRIPTOR Muscular Diseases EXPLODE ALL AND ARI:INREGISTER #9 MESH DESCRIPTOR Neuromuscular Diseases EXPLODE ALL AND ARI:INREGISTER #10 MESH DESCRIPTOR Cerebral Palsy AND ARI:INREGISTER #11 MESH DESCRIPTOR Muscular Dystrophies EXPLODE ALL AND ARI:INREGISTER #12 ((neurodevelopment* OR development*) NEAR3 (delay* OR disorder* OR disabilit* OR impair* OR condition*)):ti,ab AND ARI:INREGISTER #13 neurodisabilit*:ti,ab AND ARI:INREGISTER #14 (multiple NEAR3 disabilit*):ti,ab AND ARI:INREGISTER #15 (neuromuscular* NEAR3 (disease* OR disorder* OR disabilit* OR impair* OR condition*)):ti,ab AND ARI:INREGISTER #16 myopath*:ti,ab AND ARI:INREGISTER #17 cerebral palsy:ti,ab AND ARI:INREGISTER #18 (muscular NEAR3 dystroph*):ti,ab AND ARI:INREGISTER #19 handicap*:ti,ab AND ARI:INREGISTER #20 (mental* NEAR3 retard*):ti,ab AND ARI:INREGISTER #21 (neurological disabilit*):ti,ab AND ARI:INREGISTER #22 #1 OR #2 OR #3 OR #4 OR #5 OR #6 OR #7 OR #8 OR #9 OR #10 OR #11 OR #12 OR #13 OR #14 OR #15 OR #16 OR #17 OR #18 OR #19 OR #20 OR #21 AND ARI:INREGISTER #23 MESH DESCRIPTOR Respiratory Tract Infections EXPLODE ALL AND ARI:INREGISTER #24 MESH DESCRIPTOR Respiratory Tract Diseases EXPLODE ALL AND ARI:INREGISTER #25 MESH DESCRIPTOR Sputum AND ARI:INREGISTER #26 MESH DESCRIPTOR Mucus AND ARI:INREGISTER #27 MESH DESCRIPTOR Cough AND ARI:INREGISTER #28 ((respiratory OR airway* OR pulmonary OR chest* OR lung*) NEAR3 (problem* OR infection* OR condition* OR disease* OR disorder*)):ti,ab AND ARI:INREGISTER #29 ((respiratory OR airway* OR pulmonary OR chest* OR lung*) NEAR3 (morbidit* OR complication*)):ti,ab AND ARI:INREGISTER #30 MESH DESCRIPTOR Pseudomonas aeruginosa AND ARI:INREGISTER #31 Pseudomonas:ti,ab AND ARI:INREGISTER #32 (secretion* OR sputum OR mucus):ti,ab AND ARI:INREGISTER #33 (chronic* NEAR3 infection*):ti,ab AND ARI:INREGISTER #34 bronchiectasis:ti,ab AND ARI:INREGISTER #35 MESH DESCRIPTOR Bronchiectasis EXPLODE ALL AND ARI:INREGISTER #36 MESH DESCRIPTOR Pneumonia EXPLODE ALL AND ARI:INREGISTER #37 pneumonia:ti,ab AND ARI:INREGISTER #38 #37 OR #36 OR #35 OR #34 OR #33 OR #32 OR #31 OR #30 OR #29 OR #28 OR #27 OR #26 OR #25 OR #24 OR #23 AND ARI:INREGISTER #39 MESH DESCRIPTOR Anti‐Bacterial Agents EXPLODE ALL AND ARI:INREGISTER #40 antibiotic*:ti,ab AND ARI:INREGISTER #41 MESH DESCRIPTOR Macrolides EXPLODE ALL AND ARI:INREGISTER #42 (macrolide* OR azithromycin OR clarithromycin OR erythromycin OR roxithromycin OR spiramycin):ti,ab AND ARI:INREGISTER #43 (penicillin OR amoxicillin OR amoxycillin OR ampicillin OR benzylpenicillin OR cloxacillin OR dicloxacillin OR flucloxacillin OR piperacillin OR ticarcillin OR sulbactam):ti,ab AND ARI:INREGISTER #44 (cephalosporin* OR cephalexin OR cephaclor OR cefaclor OR cefepime OR cefotaxime OR cephamycin* OR cefotetan OR cefoxitin OR cefmetazole OR cefpirome OR cefpodoxime OR ceftazidime OR ceftriaxone OR cephamandole OR cephazolin):ti,ab AND ARI:INREGISTER #45 (fluoroquinolone* OR ciprofloxacin OR enoxacin OR norfloxacin OR ofloxacin OR pefloxacin OR fleroxacin OR levofloxacin OR moxifloxacin):ti,ab AND ARI:INREGISTER #46 (tetracycline* OR doxycycline OR methacycline OR minocycline):ti,ab AND ARI:INREGISTER #47 (amikacin OR gentamicin OR neomycin OR netilmicin):ti,ab AND ARI:INREGISTER #48 (clindamycin OR lincomycin):ti,ab AND ARI:INREGISTER #49 (chloramphenicol OR amantadine OR cotrimoxazole OR trimethoprim):ti,ab AND ARI:INREGISTER #50 (tobramycin* OR co‐amoxiclav* OR Augmentin OR cotrimoxazole OR Sulfamethoxazole OR trimethoprim OR Spetra OR Bactrim OR Clavulin*):ti,ab AND ARI:INREGISTER #51 colistin*:ti,ab AND ARI:INREGISTER #52 #50 OR #51 OR #49 OR #48 OR #47 OR #46 OR #45 OR #44 OR #43 OR #42 OR #41 OR #40 OR #39 AND ARI:INREGISTER #53 #52 AND #38 AND #22 AND ARI:INREGISTER	November 2020 = 6 February 2022 = 0
CENTRAL (via Cochrane Register of Studies) Date of most recent search: 8 February 2022	#1 MESH DESCRIPTOR Neurodevelopmental Disorders EXPLODE ALL AND CENTRAL:TARGET #2 MESH DESCRIPTOR Developmental Disabilities EXPLODE ALL AND CENTRAL:TARGET #3 MESH DESCRIPTOR Intellectual Disability EXPLODE ALL AND CENTRAL:TARGET #4 MESH DESCRIPTOR Child Development Disorders, Pervasive AND CENTRAL:TARGET #5 MESH DESCRIPTOR Learning Disabilities AND CENTRAL:TARGET #6 MESH DESCRIPTOR Communication Disorders EXPLODE ALL AND CENTRAL:TARGET #7 MESH DESCRIPTOR Disabled Children EXPLODE ALL AND CENTRAL:TARGET #8 MESH DESCRIPTOR Muscular Diseases EXPLODE ALL AND CENTRAL:TARGET #9 MESH DESCRIPTOR Neuromuscular Diseases EXPLODE ALL AND CENTRAL:TARGET #10 MESH DESCRIPTOR Cerebral Palsy AND CENTRAL:TARGET #11 MESH DESCRIPTOR Muscular Dystrophies EXPLODE ALL AND CENTRAL:TARGET #12 ((neurodevelopment* OR development*) NEAR3 (delay* OR disorder* OR disabilit* OR impair* OR condition*)):ti,ab AND CENTRAL:TARGET #13 neurodisabilit*:ti,ab AND CENTRAL:TARGET #14 (multiple NEAR3 disabilit*):ti,ab AND CENTRAL:TARGET #15 (neuromuscular* NEAR3 (disease* OR disorder* OR disabilit* OR impair* OR condition*)):ti,ab AND CENTRAL:TARGET #16 myopath*:ti,ab AND CENTRAL:TARGET #17 cerebral palsy:ti,ab AND CENTRAL:TARGET #18 (muscular NEAR3 dystroph*):ti,ab AND CENTRAL:TARGET #19 handicap*:ti,ab AND CENTRAL:TARGET #20 (mental* NEAR3 retard*):ti,ab AND CENTRAL:TARGET #21 (neurological disabilit*):ti,ab AND CENTRAL:TARGET #22 #1 OR #2 OR #3 OR #4 OR #5 OR #6 OR #7 OR #8 OR #9 OR #10 OR #11 OR #12 OR #13 OR #14 OR #15 OR #16 OR #17 OR #18 OR #19 OR #20 OR #21 #23 MESH DESCRIPTOR Respiratory Tract Infections EXPLODE ALL AND CENTRAL:TARGET #24 MESH DESCRIPTOR Respiratory Tract Diseases EXPLODE ALL AND CENTRAL:TARGET #25 MESH DESCRIPTOR Sputum AND CENTRAL:TARGET #26 MESH DESCRIPTOR Mucus AND CENTRAL:TARGET #27 MESH DESCRIPTOR Cough AND CENTRAL:TARGET #28 ((respiratory OR airway* OR pulmonary OR chest* OR lung*) NEAR3 (problem* OR infection* OR condition* OR disease* OR disorder*)):ti,ab AND CENTRAL:TARGET #29 ((respiratory OR airway* OR pulmonary OR chest* OR lung*) NEAR3 (morbidit* OR complication*)):ti,ab AND CENTRAL:TARGET #30 MESH DESCRIPTOR Pseudomonas aeruginosa AND CENTRAL:TARGET #31 Pseudomonas:ti,ab AND CENTRAL:TARGET #32 (secretion* OR sputum OR mucus):ti,ab AND CENTRAL:TARGET #33 (chronic* NEAR3 infection*):ti,ab AND CENTRAL:TARGET #34 bronchiectasis:ti,ab AND CENTRAL:TARGET #35 MESH DESCRIPTOR Bronchiectasis EXPLODE ALL AND CENTRAL:TARGET #36 MESH DESCRIPTOR Pneumonia EXPLODE ALL AND CENTRAL:TARGET #37 pneumonia:ti,ab AND CENTRAL:TARGET #38 #37 OR #36 OR #35 OR #34 OR #33 OR #32 OR #31 OR #30 OR #29 OR #28 OR #27 OR #26 OR #25 OR #24 OR #23 #39 MESH DESCRIPTOR Anti‐Bacterial Agents EXPLODE ALL AND CENTRAL:TARGET #40 antibiotic*:ti,ab AND CENTRAL:TARGET #41 MESH DESCRIPTOR Macrolides EXPLODE ALL AND CENTRAL:TARGET #42 (macrolide* OR azithromycin OR clarithromycin OR erythromycin OR roxithromycin OR spiramycin):ti,ab AND CENTRAL:TARGET #43 (penicillin OR amoxicillin OR amoxycillin OR ampicillin OR benzylpenicillin OR cloxacillin OR dicloxacillin OR flucloxacillin OR piperacillin OR ticarcillin OR sulbactam):ti,ab AND CENTRAL:TARGET #44 (cephalosporin* OR cephalexin OR cephaclor OR cefaclor OR cefepime OR cefotaxime OR cephamycin* OR cefotetan OR cefoxitin OR cefmetazole OR cefpirome OR cefpodoxime OR ceftazidime OR ceftriaxone OR cephamandole OR cephazolin):ti,ab AND CENTRAL:TARGET #45 (fluoroquinolone* OR ciprofloxacin OR enoxacin OR norfloxacin OR ofloxacin OR pefloxacin OR fleroxacin OR levofloxacin OR moxifloxacin):ti,ab AND CENTRAL:TARGET #46 (tetracycline* OR doxycycline OR methacycline OR minocycline):ti,ab AND CENTRAL:TARGET #47 (amikacin OR gentamicin OR neomycin OR netilmicin):ti,ab AND CENTRAL:TARGET #48 (clindamycin OR lincomycin):ti,ab AND CENTRAL:TARGET #49 (chloramphenicol OR amantadine OR cotrimoxazole OR trimethoprim):ti,ab AND CENTRAL:TARGET #50 (tobramycin* OR co‐amoxiclav* OR Augmentin OR cotrimoxazole OR Sulfamethoxazole OR trimethoprim OR Spetra OR Bactrim OR Clavulin*):ti,ab AND CENTRAL:TARGET #51 colistin*:ti,ab AND CENTRAL:TARGET #52 #50 OR #51 OR #49 OR #48 OR #47 OR #46 OR #45 OR #44 OR #43 OR #42 OR #41 OR #40 OR #39 #53 #52 AND #38 AND #22	November 2020 = 59 February 2022 = 5
MEDLINE (Ovid) ALL Date of most recent search: 8 February 2022	1 exp Neurodevelopmental Disorders/ 2 Developmental Disabilities/ 3 exp Intellectual Disability/ 4 Child Development Disorders, Pervasive/ 5 exp Learning Disorders/ 6 exp Communication Disorders/ 7 Disabled Children/ 8 exp Muscular Diseases/ 9 exp Neuromuscular Diseases/ 10 Cerebral Palsy/ 11 exp Muscular Dystrophies/ 12 ((neurodevelopment$ or development$) adj3 (delay$ or disorder$ or disabilit$ or impair$ or condition$)).tw. 13 neurodisabilit$.tw. 14 neurological disabilit$.tw. 15 (multiple adj3 disabilit$).tw. 16 (neuromuscular$ adj3 (disease$ or disorder$ or disabilit$ or impair$ or condition$)).tw. 17 myopath$.tw. 18 cerebral palsy.tw. 19 (muscular adj3 dystroph$).tw. 20 handicap$.tw. 21 (mental$ adj3 retard$).tw. 22 or/1‐21 23 exp Respiratory Tract Infections/ 24 exp Respiratory Tract Diseases/ 25 Sputum/ 26 Mucus/ 27 Cough/ 28 ((respiratory or airway$ or pulmonary or chest$ or lung$) adj3 (problem$ or infection$ or condition$ or disease$ or disorder$)).tw. 29 ((respiratory or airway$ or pulmonary or chest$ or lung$) adj3 (morbidit$ or complication$)).tw. 30 Pseudomonas aeruginosa/ 31 Pseudomonas.tw. 32 (secretion$ or sputum or mucus).tw. 33 (chronic$ adj3 infection$).tw. 34 bronchiectasis.tw. 35 exp Bronchiectasis/ 36 exp Pneumonia/ 37 pneumonia.tw. 38 or/23‐37 39 22 and 38 40 exp Anti‐Bacterial Agents/ 41 antibiotic$.tw. 42 exp Macrolides/ 43 (macrolide$ or azithromycin or clarithromycin or erythromycin or roxithromycin or spiramycin).tw. 44 (penicillin or amoxicillin or amoxycillin or ampicillin or benzylpenicillin or cloxacillin or dicloxacillin or flucloxacillin or piperacillin or ticarcillin or sulbactam).tw. 45 (cephalosporin$ or cephalexin or cephaclor or cefaclor or cefepime or cefotaxime or cephamycin$ or cefotetan or cefoxitin or cefmetazole or cefpirome or cefpodoxime or ceftazidime or ceftriaxone or cephamandole or cephazolin).tw. 46 (fluoroquinolone$ or ciprofloxacin or enoxacin or norfloxacin or ofloxacin or pefloxacin or fleroxacin or levofloxacin or moxifloxacin).tw. 47 (tetracycline$ or doxycycline or methacycline or minocycline).tw. 48 (amikacin or gentamicin or neomycin or netilmicin).tw. 49 (clindamycin or lincomycin).tw. 50 (chloramphenicol or amantadine or cotrimoxazole or trimethoprim).tw. 51 (tobramycin$ or co‐amoxiclav$ or Augmentin or cotrimoxazole or Sulfamethoxazole or trimethoprim or Spetra or Bactrim or Clavulin$).tw. 52 colistin$.tw. 53 or/40‐52 54 39 and 53 55 (controlled clinical trial or randomized controlled trial).pt. 56 (randomized or randomised).ab,ti. 57 placebo.ab,ti. 58 dt.fs. 59 randomly.ab,ti. 60 trial.ab,ti. 61 groups.ab,ti. 62 or/55‐61 63 Animals/ 64 Humans/ 65 63 not (63 and 64) 66 62 not 65 67 54 and 66	November 2020 = 696 February 2022 = 29
Embase (Ovid) Date of most recent search: 8 February 2022	1 exp developmental disorder/ 2 intellectual impairment/ 3 exp learning disorder/ 4 exp communication disorder/ 5 handicapped child/ 6 exp neuromuscular disease/ 7 cerebral palsy/ 8 exp muscular dystrophy/ 9 ((neurodevelopment$ or development$) adj3 (delay$ or disorder$ or disabilit$ or impair$ or condition$)).tw. 10 neurodisabilit$.tw. 11 neurological disabilit$.tw. 12 (multiple adj3 disabilit$).tw. 13 (neuromuscular$ adj3 (disease$ or disorder$ or disabilit$ or impair$ or condition$)).tw. 14 myopath$.tw. 15 cerebral palsy.tw. 16 (muscular adj3 dystroph$).tw. 17 handicap$.tw. 18 (mental$ adj3 retard$).tw. 19 or/1‐18 20 exp respiratory tract infection/ 21 exp respiratory tract disease/ 22 sputum/ 23 mucus/ or bronchus mucus/ or nose mucus/ or trachea mucus/ 24 chronic cough/ 25 ((respiratory or airway$ or pulmonary or chest$ or lung$) adj3 (problem$ or infection$ or condition$ or disease$ or disorder$)).tw. 26 ((respiratory or airway$ or pulmonary or chest$ or lung$) adj3 (morbidit$ or complication$)).tw. 27 exp Pseudomonas aeruginosa/ 28 Pseudomonas.tw. 29 (secretion$ or sputum or mucus).tw. 30 (chronic$ adj3 infection$).tw. 31 bronchiectasis.tw. 32 exp bronchiectasis/ 33 exp pneumonia/ 34 pneumonia.tw. 35 or/20‐34 36 exp antibiotic agent/ 37 antibiotic$.tw. 38 (macrolide$ or azithromycin or clarithromycin or erythromycin or roxithromycin or spiramycin).tw. 39 (penicillin or amoxicillin or amoxycillin or ampicillin or benzylpenicillin or cloxacillin or dicloxacillin or flucloxacillin or piperacillin or ticarcillin or sulbactam).tw. 40 (cephalosporin$ or cephalexin or cephaclor or cefaclor or cefepime or cefotaxime or cephamycin$ or cefotetan or cefoxitin or cefmetazole or cefpirome or cefpodoxime or ceftazidime or ceftriaxone or cephamandole or cephazolin).tw. 41 (fluoroquinolone$ or ciprofloxacin or enoxacin or norfloxacin or ofloxacin or pefloxacin or fleroxacin or levofloxacin or moxifloxacin).tw. 42 (tetracycline$ or doxycycline or methacycline or minocycline).tw. 43 (amikacin or gentamicin or neomycin or netilmicin).tw. 44 (clindamycin or lincomycin).tw. 45 (chloramphenicol or amantadine or cotrimoxazole or trimethoprim).tw. 46 (tobramycin$ or co‐amoxiclav$ or Augmentin or cotrimoxazole or Sulfamethoxazole or trimethoprim or Spetra or Bactrim or Clavulin$).tw. 47 colistin$.tw. 48 or/36‐47 49 19 and 35 and 48 50 Randomized Controlled Trial/ 51 randomization/ 52 controlled clinical trial/ 53 Double Blind Procedure/ 54 Single Blind Procedure/ 55 Crossover Procedure/ 56 (clinica$ adj3 trial$).tw. 57 ((singl$ or doubl$ or trebl$ or tripl$) adj3 (mask$ or blind$ or method$)).tw. 58 exp Placebo/ 59 placebo$.ti,ab. 60 random$.ti,ab. 61 ((control$ or prospectiv$) adj3 (trial$ or method$ or stud$)).tw. 62 (crossover$ or cross‐over$).ti,ab. 63 or/50‐62 64 exp animals/ or exp invertebrate/ or animal experiment/ or animal model/ or animal tissue/ or animal cell/ or nonhuman/ 65 human/ or normal human/ or human cell/ 66 64 and 65 67 64 not 66 68 63 not 67 69 49 and 68	November 2020 = 951 February 2022 = 102
CINAHL (Ebsco) Date of most recent search: 8 February 2022	S71 S54 AND S70 S70 S55 OR S56 OR S57 OR S58 OR S59 OR S60 OR S61 OR S62 OR S63 OR S64 OR S65 OR S66 OR S67 OR S68 OR S69 S69 (MH "Randomized Controlled Trials") S68 (MH "Double‐Blind Studies") S67 (MH "Single‐Blind Studies") S66 (MH "Random Assignment") S65 (MH "Pretest‐Posttest Design") S64 (MH "Cluster Sample") S63 TI (randomised OR randomized) S62 AB (random*) S61 TI (trial) S60 MH ("sample size") AND AB (assigned OR allocated OR control) S59 (MH "Placebos") S58 PT (Randomized Controlled Trial) S57 AB (control W5 group) S56 MH (crossover design) OR MH (comparative studies) S55 AB (cluster W3 RCT) S54 S23 AND S39 AND S53 S53 S40 OR S41 OR S42 OR S43 OR S44 OR S45 OR S46 OR S47 OR S48 OR S49 OR S50 OR S51 OR S52 S52 (TI colistin* OR AB colistin*) S51 ((TI tobramycin* OR AB tobramycin*) OR (TI co‐amoxiclav* OR AB co‐amoxiclav*) OR (TI Augmentin OR AB Augmentin) OR (TI cotrimoxazole OR AB cotrimoxazole) OR (TI Sulfamethoxazole OR AB Sulfamethoxazole) OR (TI trimethoprim OR AB trimethoprim) OR (TI Spetra OR AB Spetra) OR (TI Bactrim OR AB Bactrim) OR (TI Clavulin* OR AB Clavulin*)) S50 ((TI chloramphenicol OR AB chloramphenicol) OR (TI amantadine OR AB amantadine) OR (TI cotrimoxazole OR AB cotrimoxazole) OR (TI trimethoprim OR AB trimethoprim)) S49 ((TI clindamycin OR AB clindamycin) OR (TI lincomycin OR AB lincomycin)) S48 ((TI amikacin OR AB amikacin) OR (TI gentamicin OR AB gentamicin) OR (TI neomycin OR AB neomycin) OR (TI netilmicin OR AB netilmicin)) S47 ((TI tetracycline* OR AB tetracycline*) OR (TI doxycycline OR AB doxycycline) OR (TI methacycline OR AB methacycline) OR (TI minocycline OR AB minocycline)) S46 ((TI fluoroquinolone* OR AB fluoroquinolone*) OR (TI ciprofloxacin OR AB ciprofloxacin) OR (TI enoxacin OR AB enoxacin) OR (TI norfloxacin OR AB norfloxacin) OR (TI ofloxacin OR AB ofloxacin) OR (TI pefloxacin OR AB pefloxacin) OR (TI fleroxacin OR AB fleroxacin) OR (TI levofloxacin OR AB levofloxacin) OR (TI moxifloxacin OR AB moxifloxacin)) S45 ((TI cephalosporin* OR AB cephalosporin*) OR (TI cephalexin OR AB cephalexin) OR (TI cephaclor OR AB cephaclor) OR (TI cefaclor OR AB cefaclor) OR (TI cefepime OR AB cefepime) OR (TI cefotaxime OR AB cefotaxime) OR (TI cephamycin* OR AB cephamycin*) OR (TI cefotetan OR AB cefotetan) OR (TI cefoxitin OR AB cefoxitin) OR (TI cefmetazole OR AB cefmetazole) OR (TI cefpirome OR AB cefpirome) OR (TI cefpodoxime OR AB cefpodoxime) OR (TI ceftazidime OR AB ceftazidime) OR (TI ceftriaxone OR AB ceftriaxone) OR (TI cephamandole OR AB cephamandole) OR (TI cephazolin OR AB cephazolin)) S44 ((TI penicillin OR AB penicillin) OR (TI amoxicillin OR AB amoxicillin) OR (TI amoxycillin OR AB amoxycillin) OR (TI ampicillin OR AB ampicillin) OR (TI benzylpenicillin OR AB benzylpenicillin) OR (TI cloxacillin OR AB cloxacillin) OR (TI dicloxacillin OR AB dicloxacillin) OR (TI flucloxacillin OR AB flucloxacillin) OR (TI piperacillin OR AB piperacillin) OR (TI ticarcillin OR AB ticarcillin) OR (TI sulbactam OR AB sulbactam)) S43 ((TI macrolide* OR AB macrolide*) OR (TI azithromycin OR AB azithromycin) OR (TI clarithromycin OR AB clarithromycin) OR (TI erythromycin OR AB erythromycin) OR (TI roxithromycin OR AB roxithromycin) OR (TI spiramycin OR AB spiramycin)) S42 (MH "Macrolides+") S41 (TI antibiotic* OR AB antibiotic*) S40 (MH "Anti‐Bacterial Agents+") S39 S24 OR S25 OR S26 OR S27 OR S28 OR S29 OR S30 OR S31 OR S32 OR S33 OR S34 OR S35 OR S36 OR S37 OR S38 S38 (TI pneumonia OR AB pneumonia) S37 (MH "Pneumonia+") S36 (MH "Bronchiectasis+") S35 (TI bronchiectasis OR AB bronchiectasis) S34 ((TI chronic* OR AB chronic*) N3 (TI infection* OR AB infection*)) S33 ((TI secretion* OR AB secretion*) OR (TI sputum OR AB sputum) OR (TI mucus OR AB mucus)) S32 (TI Pseudomonas OR AB Pseudomonas) S31 (MH "Pseudomonas aeruginosa") S30 (((TI respiratory OR AB respiratory) OR (TI airway* OR AB airway*) OR (TI pulmonary OR AB pulmonary) OR (TI chest* OR AB chest*) OR (TI lung* OR AB lung*)) N3 ((TI morbidit* OR AB morbidit*) OR (TI complication* OR AB complication*))) S29 (((TI respiratory OR AB respiratory) OR (TI airway* OR AB airway*) OR (TI pulmonary OR AB pulmonary) OR (TI chest* OR AB chest*) OR (TI lung* OR AB lung*)) N3 ((TI problem* OR AB problem*) OR (TI infection* OR AB infection*) OR (TI condition* OR AB condition*) OR (TI disease* OR AB disease*) OR (TI disorder* OR AB disorder*))) S28 (MH "Cough") S27 (MH "Mucus") S26 (MH "Sputum") S25 (MH "Respiratory Tract Diseases+") S24 (MH "Respiratory Tract Infections+") S23 S1 OR S2 OR S3 OR S4 OR S5 OR S6 OR S7 OR S8 OR S9 OR S10 OR S11 OR S12 OR S13 OR S14 OR S15 OR S16 OR S17 OR S18 OR S19 OR S20 OR S21 OR S22 S22 ((TI mental* OR AB mental*) N3 (TI retard* OR AB retard*)) S21 (TI handicap* OR AB handicap*) S20 ((TI muscular OR AB muscular) N3 (TI dystroph* OR AB dystroph*)) S19 TI "cerebral palsy" OR AB "cerebral palsy") S18 (TI myopath* OR AB myopath*) S17 ((TI neuromuscular* OR AB neuromuscular*) N3 ((TI disease* OR AB disease*) OR (TI disorder* OR AB disorder*) OR (TI disabilit* OR AB disabilit*) OR (TI impair* OR AB impair*) OR (TI condition* OR AB condition*))) S16 ((TI multiple OR AB multiple) N3 (TI disabilit* OR AB disabilit*)) S15 (TI "neurological disabilit*" OR AB "neurological disabilit*") S14 (TI neurodisabilit* OR AB neurodisabilit*) S13 (((TI neurodevelopment* OR AB neurodevelopment*) OR (TI development* OR AB development*)) N3 ((TI delay* OR AB delay*) OR (TI disorder* OR AB disorder*) OR (TI disabilit* OR AB disabilit*) OR (TI impair* OR AB impair*) OR (TI condition* OR AB condition*))) S12 (MH "Muscular Dystrophies+") S11 (MH "Cerebral Palsy") S10 (MH "Neuromuscular Diseases+") S9 (MH "Muscular Diseases+") S8 (MH "Disabled Children") S7 (MH "Communication Disorders+") S6 (MH "Learning Disabilities+") S5 (MH "Learning Disabilities+") S4 (MH "Child Development Disorders, Pervasive") S3 (MH "Intellectual Disability+") S2 (MH "Developmental Disabilities") S1 (MH "Neurodevelopmental Disorders+")	November 2020 = 22 February 2022 = 4
ClinicalTrials.gov Date of most recent search: 8 February 2022	Study type: Interventional Condition: (respiratory OR airways OR pulmonary OR chest OR lung OR bronchiectasis OR pneumonia OR Pseudomonas OR chronic infection) AND (Neuromuscular OR Neurodevelopmental OR Developmental OR Intellectual Disability OR Cerebral Palsy OR Muscular Dystrophies) Intervention: Antibiotic Age: Child	November 2020 = 7 February 2022 = 0
WHO trials portal Date of most recent search: 8 February 2022	Condition: (respiratory OR airways OR pulmonary OR chest OR lung OR bronchiectasis OR pneumonia OR Pseudomonas OR chronic infection) AND (Neuromuscular OR Neurodevelopmental OR Developmental OR Intellectual Disability OR Cerebral Palsy OR Muscular Dystrophies) Intervention: Antobiotic	November 2020 = searched via CENTRAL February 2022 = 0
ISCTRN Date of most recent search: 8 February 2022	Search terms: antibiotic* Condition category: Nervous System Diseases	November 2020 = 10 February 2022 = 0
OpenGrey Date of most recent search: 8 February 2022	#1 (respiratory OR airways OR pulmonary OR chest OR lung OR bronchiectasis OR pneumonia OR Pseudomonas OR chronic infection) AND (Neuromuscular OR Neurodevelopmental OR Developmental OR Intellectual Disabilit* OR Cerebral Palsy OR Muscular Dystroph*) #2 (respiratory OR airways OR pulmonary OR chest OR lung OR bronchiectasis OR pneumonia OR Pseudomonas OR chronic infection) AND (Neuromuscular OR Neurodevelopmental OR Developmental OR Intellectual Disability OR Cerebral Palsy OR Muscular Dystrophies) AND (antibiotic OR macrolide* OR azithromycin OR clarithromycin OR erythromycin OR roxithromycin OR spiramycin OR penicillin OR amoxicillin OR amoxycillin OR ampicillin OR benzylpenicillin OR cloxacillin OR dicloxacillin OR flucloxacillin OR piperacillin OR ticarcillin OR sulbactam OR cephalosporin* OR cephalexin OR cephaclor OR cefaclor OR cefepime OR cefotaxime OR cephamycin* OR cefotetan OR cefoxitin OR cefmetazole OR cefpirome OR cefpodoxime OR ceftazidime OR ceftriaxone OR cephamandole OR cephazolin OR fluoroquinolone* OR ciprofloxacin OR enoxacin OR norfloxacin OR ofloxacin OR pefloxacin OR fleroxacin OR levofloxacin OR moxifloxacin OR tetracycline* OR doxycycline OR methacycline OR minocycline OR amikacin OR gentamicin OR neomycin OR netilmicin OR clindamycin OR lincomycin OR chloramphenicol OR amantadine OR cotrimoxazole OR trimethoprim OR tobramycin* OR co‐amoxiclav* OR Augmentin OR cotrimoxazole OR Sulfamethoxazole OR trimethoprim OR Spetra OR Bactrim OR Clavulin* OR colistin*)	November 2020 = 52 February 2022 = 0

Characteristics of studies

Characteristics of excluded studies [ordered by study ID]

Study	Reason for exclusion
Gleason 2007	Opinion piece ‐ not describing a primary study
Greenberg 1974	Not a clinical trial
Nydahl‐Persson 1995	Ineligible patient population
Reinert 2004	Not a clinical trial

Characteristics of ongoing studies [ordered by study ID]

ACTRN12621001486819.

Study name	Effect of prophylactic azithromycin on chest infections in children with neurological and neuromuscular impairment
Methods	Randomised, triple‐blinded, placebo‐controlled trial comparing 26 weeks of azithromycin to placebo in children with neurological/neuromuscular impairment.  Triple‐blinded trial so the parent/child, research/treating clinical team and statistical analysis will be blinded to treatment allocation. There will be a designated unblinding team (usually pharmacy) at each centre who will be unblinded to treatment allocations. Randomisation will occur via a randomisation system and there will be back‐up randomisation envelopes. Only the unblinded team will receive information regarding the unblinded treatment allocation.
Participants	Inclusion Criteria  Children and young people who are aged between 0.5 and 3 years (inclusive) at randomisation Written informed consent from legal guardian Diagnosed with non‐progressive neurological impairment (includes stable neuromuscular abnormalities), AND One or more of the following: received at least 2 courses of oral antibiotics for LRTI in 26 weeks prior to eligibility; have been hospitalised with an LRTI within 52 weeks prior to eligibility and completed; prescribed prophylactic antibiotics for LRTIs and undergone a 4‐week ‘washout’ period'. Exclusion Criteria  Progressive neuromuscular disorders, such as Duchenne muscular dystrophy etc., or neurological disorders in which progressive deterioration in neurological condition are known to occur (e.g. Rett syndrome, some neurometabolic syndromes) Pre‐existing non‐neurological conditions that impact on respiratory function, such as cystic fibrosis (CF), immunodeficiency etc. Children with neurological impairment known to have bronchiectasis will not be excluded. Known contra‐indication to using (e.g. prolonged QT syndrome) or hypersensitivity to: azithromycin, erythromycin, any macrolide or ketolide antibiotic or to any of the excipients contained in the study drug Use of macrolide antibiotics within 90 days prior to eligibility Known significant hepatic disease (hepatic impairment per Child‐Pugh classification C) Treatment with ergot derivatives (dihydroergocristine, dihydroergotamine, dihydroergotoxine, nicergoline or a combination of dihydroergocryptine with caffeine); OR Recruited to another investigation medical product (IMP) trial and continuing to administer the IMP.
Interventions	Intervention Azithromycin 10 mg/kg rounded, administered as an oral suspension 3 times weekly (Mon/Wed/Fri) for 26 weeks Comparison  Placebo matching azithromycin as powder for oral suspension.
Outcomes	Primary outcome measure Rate of LRTIs measured in child‐months, assessed by both parent self‐report and medical reports. Time point: 6 months from commencement of trial medications given Secondary outcome measures Proportion of children with LRTI over the 26‐weeks intervention period, assessed by both parent self‐report and medical reports. Time point: 6 months from time trial medications commenced. Adverse events assessed by both parent self‐report (on diaries) and medical reports. These include, but are not restricted to, mild diarrhoea, abdominal pains, nausea or vomiting, headache and dizziness. Time point: during the 6 months of the intervention period. Quality‐adjusted life years (QALY) assessment (composite outcome). CHU9D and EQ‐5D‐Y are used to evaluate the outcome measure for QALY. However, as not all the questions are applicable for the young children, only applicable questions (for age) will be used. Time point: baseline and at 6 months from commencement of trial medications. Change in health‐related QoL of parent/carer using Parent QoL assessment (Warwick‐Edinburgh). Time point: baseline and at 6 months from commencement of trial medications. Respiratory symptom questionnaire. Time point: baseline and at 6 months from commencement of trial medications.
Starting date	Registered 2021
Contact information	kidslungresearch@qut.edu.au
Notes	This trial (PARROT‐Junior) is a substudy of a parent study (PARROT) ‐ ACTRN1261900159718.  For the analysis, results from PARROT‐Junior will be combined with data from the children recruited from Brisbane/Darwin in the parent study (PARROT). Target sample size thus includes the subset of Brisbane/Darwin‐enrolled children from PARROT.

ISRCTN71955516.

Study name	Joint UK and Australia multicentre, randomised, double‐blind, placebo‐controlled pragmatic trial comparing 52 weeks of azithromycin to placebo in children with neurological impairment at risk of lower respiratory tract infection (the PARROT trial)
Methods	Randomised Controlled Trial  Randomised participants will receive 52 weeks of treatment with either azithromycin or placebo, randomised in a 1:1 ratio. Both participants and their healthcare teams will be blinded to treatment allocation.  All participants will be followed up for 52 weeks from randomisation. If trial recruitment is ongoing at 78 weeks, participants will also be followed up at this time point.
Participants	Inclusion criteria Children and young people who are aged between 3 and 17 years (inclusive) at randomisation Written informed consent from participant (or appropriate person if incapacitated/minor) Participant (or appropriate person if incapacitated/underage) and caregiver have a good understanding of the English language Diagnosed with non‐progressive, non‐neuromuscular neurological impairment* Persistent respiratory symptoms** One or more of the following: received at least 2 courses of oral antibiotics for LRTI in 52 weeks prior to eligibility have been hospitalised with a LRTI within 52 weeks prior to eligibility and completed 13‐week ‘washout’ period (where applicable)*** prescribed prophylactic antibiotics for LRTIs and undergone a 13 week ‘washout’ period***. * Most will likely have cerebral palsy. However, some children may have no formal diagnosis to account for their symptoms. ** Persistent respiratory symptoms defined by LRSQ‐Neuro score of >= 95% CI for age. *** Must have undergone a 13‐week ‘washout’ period where administered IV antibiotics during hospitalisation or have been previously prescribed and administered prophylactic or nebulised antibiotics. Exclusion criteria Any neuromuscular disorders including spinal muscular atrophy (SMA), Duchenne muscular dystrophy etc., or neurological disorders in which progressive deterioration in neurological condition are known to occur (e.g. Rett syndrome, some neurometabolic syndromes) Pre‐existing non‐neurological conditions that impact respiratory functions such as cystic fibrosis (CF), immunodeficiency etc. Note: Children with neurological impairment known to have bronchiectasis will not be excluded Known contra‐indication to using or hypersensitivity to: azithromycin, erythromycin, macrolide or ketolide antibiotic, or to any of the excipients contained in the study drug Use of macrolide antibiotics within 90 days prior to eligibility  Known significant hepatic disease (hepatic impairment per Child‐Pugh classification C) Treatment with ergot derivatives (dihydroergocristine, dihydroergotamine, dihydroergotoxine, nicergoline or a combination of dihydroergocryptine with caffeine) Child/young person already taking prophylactic antibiotics for non‐respiratory causes (e.g. urinary tract infections) Previously randomised in PARROT Recruited to another IMP trial and continuing to administer the IMP
Interventions	Intervention  Powder formulation of azithromycin reconstituted and administered as an oral suspension. The dosing regimen will be based on body weight (10 mg/kg rounded) and will be given 3 times a week (Mon/Wed/Fri). Control  Matched reconstituted powder formulation of placebo.
Outcomes	Primary Outcome Measure Proportion of children and young people (3 to 17 years) hospitalised at their recruiting or designated centre with LTRI over the 52‐week intervention period, recorded at 4, 8, 13, 17, 21, 26, 30, 34, 39, 43, 47 and 52 weeks. Secondary Outcome Measures Health‐related QoL of child and parent/carer measured using parent QoL assessment (Warwick‐Edinburgh Mental Wellbeing Scale) and patient QoL assessment (DISABKIDS) at baseline, 13, 26, 39 and 52 weeks. Safety events, tolerability and adherence measured by the assessment of adverse events and withdrawals from study treatment at 4, 13, 17, 21, 26, 30, 34, 39, 43, 47 and 52 weeks, and treatment diary at 13, 26, 39 and 52 weeks. Respiratory medication usage assessed by reviewing concomitant medication which could impact the respiratory system at baseline, 4, 8, 13, 17, 21, 26, 30, 34, 39, 43, 47 and 52 weeks, and vaccinations at baseline and 52 weeks. Weight based on World Health Organisation Z‐scores using WHO Anthro calculator (www.who.int/growthref/tools/en), assessed at baseline, 13, 26, 39 and 52 weeks. Quality/amount of parent and child/young person’s sleep, measured using the primary caregiver sleep actigraphy and corresponding primary caregiver sleep log (UK only), the Child’s Sleep Habits Questionnaire and 1‐week patient sleep diary, at baseline and 52 weeks. Respiratory symptoms measured using LRSQ‐Neuro score and the respiratory symptom questionnaire at baseline, 13, 26, 39 and 52 weeks, and changes to respiratory treatments/support and surgical/other interventions at 13, 26, 39 and 52 weeks. Number, duration and severity of LRTI; time to first LRTI is measured by reviewing the occurrence of chest infection and LRTI, changes to respiratory treatments/support and the assessment of adverse events at 4, 8, 13, 17, 21, 26, 30, 34, 39, 43, 47 and 52 weeks; by using the resource use questionnaire at baseline, 13, 26, 39 and 52 weeks and documenting length of stay in hospital, admission to critical care and changes to respiratory treatments/support for any unscheduled visits. Unscheduled medical presentations (general practice visits and emergency department attendances) for LRTI measured by reviewing medical history at baseline; reviewing the occurrence of chest infections and LRTIs and the assessment of adverse events at 4, 8, 13, 17, 21, 26, 30, 34, 39, 43, 47 and 52 weeks, and using the resource use questionnaire at baseline, 13, 26, 39 and 52 weeks. Use of other health and social care services, school attendance and indirect costs measured using the resource use questionnaire at baseline, 13, 26, 39 and 52 weeks and Hospital Episode Statistics (HES) at 52 weeks. Number of courses of ‘rescue’ antibiotics prescribed for LRTI measured by reviewing concomitant medications which could impact the respiratory system at baseline, 4, 8, 13, 17, 21, 26, 30, 34, 39, 43, 47 and 52 weeks. Quality‐adjusted life years (QALY) measured using CHU9D and EQ‐5D‐Y at baseline, 13, 26, 39 and 52 weeks. Nasal swab for microbiology and resistance profiling taken at baseline, 26 and 52 weeks, and for unscheduled visits (for Australian participants only until UK contractual arrangements are in place). Nasal swab/nasopharyngeal aspirate to investigate viral causes of acute LRTI (as defined by the protocol) and cough swab/sputum collection to investigate bacterial causes of acute LRTI (as defined by the protocol) taken at unscheduled visits (for Australian participants only until UK contractual arrangements are in place). Residual impact of 52 weeks' antibiotic prophylaxis assessed at 78 weeks, using the following measures: respiratory symptoms measured by assessing LRSQ‐Neuro score, respiratory symptom questionnaire, changes to respiratory treatments/support and surgical and other interventions weight based on World Health Organisation Z‐scores using WHO Anthro calculator (www.who.int/growthref/tools/en) nasal swab for microbiology and resistance profiling changes in respiratory medication usage measured by reviewing concomitant medications which could impact the respiratory system and vaccinations number, duration and severity of LRTI; time to first LRTI measured using the resource use questionnaire and reviewing the occurrence of chest infection and LRTI, changes to respiratory treatments/support and the collection of adverse events QALY measured using the CHU9D and EQ‐5D‐Y use of other health and social care services, school attendance and indirect costs measured using HES health‐related QoL of child and parent/carer measured using the patient QoL assessment (DISABKIDS) and parent QoL assessment (Warwick‐Edinburgh Mental Well‐being Scale) unscheduled medical presentations (GP visits and A&E attendances) for LRTI measured by reviewing the occurrence of chest infection and LRTI, the collection of adverse events and the resource use questionnaire number of courses of ‘rescue’ antibiotics prescribed for LRTI measured by reviewing concomitant medications which could impact the respiratory system safety events measured using the assessment of adverse events
Starting date	1 March 2019
Contact information	Helen Eccleson parrot@liverpool.ac.uk
Notes

Abbreviations: IMP: investigation medical product; IV: intravenous; LRSQ: Liverpool Respiratory Symptom Questionnaire; LRTI: lower respiratory tract infection; QoL: quality of life;

If results of this trial are appropriate for inclusion in future reviews, it will be important to avoid overestimating the treatment effect due double counting participants from PARROT and PARROT‐Junior in the analysis.

Differences between protocol and review

We planned to search the WHO International Clinical Trials Registry Platform (ICTRP); however, this was not available at the time of running the searches due heavy traffic as a result of the Covid‐19 outbreak. ICTRP records were, however, searched indirectly through CENTRAL instead.

There were technical difficulties uploading the references obtained through OpenGrey onto Covidence for screening. In order to ensure independent assessment by two separate review authors, a spreadsheet of those 52 references was created by JS and sent to KJ and MNH. A second password‐protected version of JS's screening assessment was sent in addition and the password was only shared after the second author had completed screening, to ensure the assessments were completed independently of each other.

Due to a lack of published studies meeting our inclusion criteria, we were unable to complete a risk of bias assessment or complete a quantitative synthesis/meta‐analysis.

In a change from our published protocol, for future updates we will perform meta‐analysis using a random‐effects model and perform sensitivity analyses using a fixed‐effect model. We will not choose the model based on the level of heterogeneity observed in the analysis.

Contributions of authors

MNH conceived the idea and JS drafted the review. All authors critically reviewed the review prior to publication. JS, KJ and MNH screened articles for inclusion. JW provided neurodisability expertise. JS and MNH wrote the review.

Contributions of editorial team

Sally Spencer (Co‐ordinating Editor) edited the review; advised on methodology, interpretation and content; approved the review prior to publication.

Iain Crossingham (Contact Editor): edited the review; advised on methodology, interpretation and content.

Emma Dennett (Deputy Co‐ordinating Editor): advised on methodology, interpretation and content; edited the review.

Emma Jackson (Managing Editor): co‐ordinated the editorial process; conducted peer review; edited the references and other sections of the review. 

Elizabeth Stovold (Information Specialist): designed the search strategy; ran the searches; edited the search methods section.

Sources of support

Internal sources

• Nottingham University Hospitals NHS Trust, UK

  Employer of JS, JW and MH

• University Hospitals of Leicester NHS Trust, UK

  Employer of KJ

External sources

• National Institute for Health and Care Research, UK

  JS was undertaking this review as part of an NIHR funded Academic Clinical Fellowship

• National Institute for Health and Care Research, UK

  Cochrane Infrastructure funding for Cochrane Airways

Declarations of interest

JS: salary part‐funded by NIHR Academic Clinical Fellowship.

KJ: none known.

JW: none known.

MNH: site Principal Investigator for the PARROT trial.

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