Background: Improvements in neonatal and paediatric care in recent decades have increased the survival of children with non-progressive neurological impairment. Respiratory disease in children with neurological impairment is common, with symptoms difficult to manage and lower respiratory tract infection occurring frequently. To reduce these, prophylactic antibiotics are being increasingly used, but the type, duration and dose of antibiotics can vary considerably, and there is limited evidence about their effectiveness in children and young people. A joint United Kingdom and Australia multicentre, randomised, double-blind, placebo-controlled trial comparing 52 weeks of azithromycin to placebo in children and young people with neurological impairment at risk of lower respiratory tract infection (PARROT) was planned to address this gap. PARROT was a multicentre, parallel group, blinded, pragmatic randomised controlled trial of 52-week duration with a planned sample size of 500 (250 in each arm) participants with neurological impairment. The primary outcome was the proportion of children and young people hospitalised with lower respiratory tract infection over the 52-week period.
Results: In total, 90 children and young people (62 in Australia, 28 in the United Kingdom) aged 3-17 years, with a diagnosed non-progressive, non-neuromuscular neurological impairment, who had persistent respiratory symptoms were randomised (1 : 1) to receive azithromycin or placebo. Baseline demographic and clinical characteristics were relatively well balanced across the two treatment groups and countries. Overall, mean (standard deviation) age was 9.2 (4.4) years, with 64% of participants having cerebral palsy, 67% being non-ambulant and 54% being totally tube-fed. At baseline, mean (standard deviation) numbers of hospital admissions with lower respiratory tract infection in the preceding year were 1.8 (2.0)/year, and general practitioner attendances 3.3 (3.0)/year. The PARROT trial was closed early to recruitment due to challenges arising from the COVID-19 pandemic. Sixty-five (72%) participants (azithromycin n = 30, placebo n = 35) completed 52 weeks of treatment and were not withdrawn early from the trial. Regarding the primary outcome, 11 (36.7%) in the azithromycin group were hospitalised with lower respiratory tract infection and 9 (25.7%) in the placebo group [absolute risk reduction 0.11 (95% confidence interval -0.12 to 0.33), relative risk 1.43 (95% confidence interval 0.68 to 2.97)]. Analysis of secondary outcome data was limited by the number of missing data, but parent-reported quality of life for young person and parent, sleep amount/quality for young person and parent, and respiratory symptoms were similar between groups and countries.
Limitations: As PARROT was stopped early and was consequently underpowered, it is not possible to say whether azithromycin prophylaxis is any more effective than placebo in reducing the proportion of children admitted to hospital with lower respiratory tract infection after a 52-week period.
Conclusions and future work: Although we cannot comment on the effectiveness of prophylactic antibiotics in this context, we can draw some useful conclusions from this trial. Thus, the importance placed by families on hospitalisation and its prevalence in both treatment groups, even during the pandemic, would suggest that this is an appropriate primary outcome measure for future trials in this high-risk group of children and young people. Furthermore, the high attrition rate and large numbers of missing data, specifically for questionnaire-based outcomes at later follow-up points, should encourage researchers to be mindful of minimising trial burden to families for any future trials wherever possible.
Funding: This synopsis presents independent research funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme as award number 16/17/01.
Keywords: AZITHROMYCIN; CEREBRAL PALSY; DISABLED CHILDREN; LOWER RESPIRATORY TRACT INFECTION; RANDOMISED CONTROLLED TRIAL.
Many more children and young people are now living with neurological conditions, such as cerebral palsy, because of improvements in neonatal and paediatric care. Respiratory disease and, particularly, chest infections are common causes of hospitalisation in this group and can be very difficult to manage. Therapy with long-term antibiotic treatments is sometimes used to prevent chest infections, but we do not know whether this approach is effective. We undertook a clinical trial in the United Kingdom and Australia to find out whether this preventative therapy works. We wanted to compare a year’s treatment with an antibiotic called azithromycin to a placebo (an inactive treatment) to see whether azithromycin reduced the number of children admitted to hospital with chest infections. This was our primary outcome. We also collected lots of other secondary outcome data. We had planned to include 500 children and young people aged 3–17 years in our trial, but regrettably, we had to end the trial early because of difficulties associated with the COVID-19 pandemic. By the end of the prophylactic antibiotics to prevent chest infections in children with neurological impairment trial, we had recruited 90 participants (most with severe cerebral palsy), with 65 completing a year’s treatment with either azithromycin or placebo. Regarding our primary outcome, similar numbers in the azithromycin (11) and placebo (9) groups were admitted to hospital with a chest infection. Analysis of secondary outcome information was limited by the amount of missing data, but family quality of life and sleep amount/quality and respiratory symptoms were similar between the two groups and countries. Importantly, azithromycin was as safe as placebo and was not associated with any particular side effects. Unfortunately, while this is one of the biggest trials in this group of children and young people with neurological impairment, it was not large enough to answer the question as to whether azithromycin reduces hospital admissions with chest infections. However, we can draw some conclusions from this trial. Prophylactic antibiotics to prevent chest infections in children with neurological impairment confirmed that hospitalisation continues to be an appropriate key outcome measure for future trials in this high-risk and vulnerable group of children and young people. Furthermore, the high attrition rate and large amounts of missing data, specifically for questionnaire-based outcomes at later follow-up points, should encourage researchers to be mindful of minimising trial burden to families for any future trials wherever possible.