Antibiotics for lower respiratory tract infection in children presenting in primary care: ARTIC-PC RCT.

Background: Antimicrobial resistance is a global health threat. Antibiotics are commonly prescribed for children with uncomplicated lower respiratory tract infections, but there is little randomised evidence to support the effectiveness of antibiotics in treating these infections, either overall or relating to key clinical subgroups in which antibiotic prescribing is common (chest signs; fever; physician rating of unwell; sputum/rattly chest; shortness of breath). Objectives: To estimate the clinical effectiveness and cost-effectiveness of amoxicillin for uncomplicated lower respiratory tract infections in children both overall and in clinical subgroups. Design: Placebo-controlled trial with qualitative, observational and cost-effectiveness studies. Setting: UK general practices. Participants: Children aged 1-12 years with acute uncomplicated lower respiratory tract infections. Outcomes: The primary outcome was the duration in days of symptoms rated moderately bad or worse (measured using a validated diary). Secondary outcomes were symptom severity on days 2-4 (0 = no problem to 6 = as bad as it could be); symptom duration until very little/no problem; reconsultations for new or worsening symptoms; complications; side effects; and resource use. Methods: Children were randomised to receive 50 mg/kg/day of oral amoxicillin in divided doses for 7 days, or placebo using pre-prepared packs, using computer-generated random numbers by an independent statistician. Children who were not randomised could participate in a parallel observational study. Semistructured telephone interviews explored the views of 16 parents and 14 clinicians, and the data were analysed using thematic analysis. Throat swabs were analysed using multiplex polymerase chain reaction. Results: A total of 432 children were randomised (antibiotics, n = 221; placebo, n = 211). The primary analysis imputed missing data for 115 children. The duration of moderately bad symptoms was similar in the antibiotic and placebo groups overall (median of 5 and 6 days, respectively; hazard ratio 1.13, 95% confidence interval 0.90 to 1.42), with similar results for subgroups, and when including antibiotic prescription data from the 326 children in the observational study. Reconsultations for new or worsening symptoms (29.7% and 38.2%, respectively; risk ratio 0.80, 95% confidence interval 0.58 to 1.05), illness progression requiring hospital assessment or admission (2.4% vs. 2.0%) and side effects (38% vs. 34%) were similar in the two groups. Complete-case (n = 317) and per-protocol (n = 185) analyses were similar, and the presence of bacteria did not mediate antibiotic effectiveness. NHS costs per child were slightly higher (antibiotics, £29; placebo, £26), with no difference in non-NHS costs (antibiotics, £33; placebo, £33). A model predicting complications (with seven variables: baseline severity, difference in respiratory rate from normal for age, duration of prior illness, oxygen saturation, sputum/rattly chest, passing urine less often, and diarrhoea) had good discrimination (bootstrapped area under the receiver operator curve 0.83) and calibration. Parents found it difficult to interpret symptoms and signs, used the sounds of the child's cough to judge the severity of illness, and commonly consulted to receive a clinical examination and reassurance. Parents acknowledged that antibiotics should be used only when 'necessary', and clinicians noted a reduction in parents' expectations for antibiotics. Limitations: The study was underpowered to detect small benefits in key subgroups. Conclusion: Amoxicillin for uncomplicated lower respiratory tract infections in children is unlikely to be clinically effective or to reduce health or societal costs. Parents need better access to information, as well as clear communication about the self-management of their child's illness and safety-netting. Future work: The data can be incorporated in the Cochrane review and individual patient data meta-analysis. Trial registration: This trial is registered as ISRCTN79914298. Funding: This project was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 27, No. 9. See the NIHR Journals Library website for further project information.

Children are commonly prescribed antibiotics for chest infections, but such infections are becoming resistant to antibiotics, and it is not clear if antibiotics work in treating them. A total of 432 children who saw their general practitioner with a chest infection were given either an antibiotic (amoxicillin) or a placebo (no antibiotic) for 7 days. Symptom diaries documented the infection's duration and its side effects. Children not in the placebo study were able to participate in another study that documented the same outcomes (an 'observational study'). We interviewed parents, doctors and nurses about their observations and concerns. Our patient and public involvement and engagement work with parents indicated that a 3-day symptom reduction was required to justify giving antibiotics. After seeing the doctor, parents whose children received antibiotics rated infective symptoms as moderately bad or worse for 5 days, and parents whose children received the placebo rated these for 6 days. Side effects and complications were similar in the two groups. Findings were similar when including the results of the observational study, and for children in whose chest the doctor could hear wheeze or rattles; who had fever; who were rated by the doctor as more unwell, who were short of breath, or who had had bacteria detected in the throat. The costs to the NHS per child were similar (antibiotics, £29; placebo, £26), and the wider costs to society were the same (antibiotics, £33; placebo, £33). Parents found it difficult to interpret their child's symptoms, and commonly used the sound of the cough to judge severity. Parents commonly consulted to receive an examination and reassurance, and accepted that antibiotics should be used only when 'necessary'. Clinicians noted a reduction in parents' expectations for antibiotics. Amoxicillin for chest infections in children is unlikely to be effective. General practitioners should support parents to self-manage at home and give clear communication about when and how to seek medical help if they continue to be concerned.

Immediate oral versus immediate topical versus delayed oral antibiotics for children with acute otitis media with discharge: the REST three-arm non-inferiority electronic platform-supported RCT.

BACKGROUND: Acute otitis media is a painful infection of the middle ear that is commonly seen in children. In some children, the eardrum spontaneously bursts, discharging visible pus (otorrhoea) into the outer ear. OBJECTIVE: To compare the clinical effectiveness of immediate topical antibiotics or delayed oral antibiotics with the clinical effectiveness of immediate oral antibiotics in reducing symptom duration in children presenting to primary care with acute otitis media with discharge and the economic impact of the alternative strategies. DESIGN: This was a pragmatic, three-arm, individually randomised (stratified by age < 2 vs. ≥ 2 years), non-inferiority, open-label trial, with economic and qualitative evaluations, supported by a health-record-integrated electronic trial platform [TRANSFoRm (Translational Research and Patient Safety in Europe)] with an internal pilot. SETTING: A total of 44 English general practices. PARTICIPANTS: Children aged ≥ 12 months and < 16 years whose parents (or carers) were seeking medical care for unilateral otorrhoea (ear discharge) following recent-onset (≤ 7 days) acute otitis media. INTERVENTIONS: (1) Immediate ciprofloxacin (0.3%) solution, four drops given three times daily for 7 days, or (2) delayed 'dose-by-age' amoxicillin suspension given three times daily (clarithromycin twice daily if the child was penicillin allergic) for 7 days, with structured delaying advice. All parents were given standardised information regarding symptom management (paracetamol/ibuprofen/fluids) and advice to complete the course. COMPARATOR: Immediate 'dose-by-age' oral amoxicillin given three times daily (or clarithromycin given twice daily) for 7 days. Parents received standardised symptom management advice along with advice to complete the course. MAIN OUTCOME MEASURE: Time from randomisation to the first day on which all symptoms (pain, fever, being unwell, sleep disturbance, otorrhoea and episodes of distress/crying) were rated 'no' or 'very slight' problem (without need for analgesia). METHODS: Participants were recruited from routine primary care appointments. The planned sample size was 399 children. Follow-up used parent-completed validated symptom diaries. RESULTS: Delays in software deployment and configuration led to small recruitment numbers and trial closure at the end of the internal pilot. Twenty-two children (median age 5 years; 62% boys) were randomised: five, seven and 10 to immediate oral, delayed oral and immediate topical antibiotics, respectively. All children received prescriptions as randomised. Seven (32%) children fully adhered to the treatment as allocated. Symptom duration data were available for 17 (77%) children. The median (interquartile range) number of days until symptom resolution in the immediate oral, delayed oral and immediate topical antibiotic arms was 6 (4-9), 4 (3-7) and 4 (3-6), respectively. Comparative analyses were not conducted because of small numbers. There were no serious adverse events and six reports of new or worsening symptoms. Qualitative clinician interviews showed that the trial question was important. When the platform functioned as intended, it was liked. However, staff reported malfunctioning software for long periods, resulting in missed recruitment opportunities. Troubleshooting the software placed significant burdens on staff. LIMITATIONS: The over-riding weakness was the failure to recruit enough children. CONCLUSIONS: We were unable to answer the main research question because of a failure to reach the required sample size. Our experience of running an electronic platform-supported trial in primary care has highlighted challenges from which we have drawn recommendations for the National Institute for Health Research (NIHR) and the research community. These should be considered before such a platform is used again. TRIAL REGISTRATION: Current Controlled Trials ISRCTN12873692 and EudraCT 2017-003635-10. FUNDING: This project was funded by the NIHR Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 25, No. 67. See the NIHR Journals Library website for further project information.

Ear infections are common in childhood. Some are complicated by a burst eardrum, followed by discharge from the ear. The usual treatment for this is a short course of antibiotics taken by mouth. However, alternative treatment using antibiotic drops, or a 'wait and see' policy before starting antibiotics, would result in less antibiotic use and reduce the subsequent risk of antibiotic resistance, which is bad for both patients and the environment. This study set out to see if these alternative treatments were as effective as the usual treatment for children with ear discharge. Although ear infections are common, only one in six children develops ear discharge, so only a few children might be available to take part at each general practice. We planned to use an electronic recruitment system to help us to gather enough patients. The system [called the 'TRANSFoRm' (Translational Research and Patient Safety in Europe) platform] was designed to remind busy general practitioners and nurses about the study and take them through the recruitment process step by step, as well as to support trial processes. Although the TRANSFoRm platform had been developed and tested, it had not been used in general practices before. We were surprised to find that there were many technical problems in setting up the TRANSFoRm platform in general practices, and staff were too busy and/or did not have the skills to overcome the technical issues. As a result, recruiting patients was slow and the study was halted before we had enough children to answer the main research question. In total, we managed to get 44 general practices and 22 children, but this was not enough. We still think that this kind of research and electronic trial platforms are important. We have noted many system and technical issues that need to be solved to enable funders and researchers to use this recruitment approach in the future.

Antibiotics for lower respiratory tract infection in children presenting in primary care in England (ARTIC PC): a double-blind, randomised, placebo-controlled trial.

BACKGROUND: Antibiotic resistance is a global public health threat. Antibiotics are very commonly prescribed for children presenting with uncomplicated lower respiratory tract infections (LRTIs), but there is little evidence from randomised controlled trials of the effectiveness of antibiotics, both overall or among key clinical subgroups. In ARTIC PC, we assessed whether amoxicillin reduces the duration of moderately bad symptoms in children presenting with uncomplicated (non-pneumonic) LRTI in primary care, overall and in key clinical subgroups. METHODS: ARTIC PC was a double-blind, randomised, placebo-controlled trial done at 56 general practices in England. Eligible children were those aged 6 months to 12 years presenting in primary care with acute uncomplicated LRTI judged to be infective in origin, where pneumonia was not suspected clinically, with symptoms for less than 21 days. Patients were randomly assigned in a 1:1 ratio to receive amoxicillin 50 mg/kg per day or placebo oral suspension, in three divided doses orally for 7 days. Patients and investigators were masked to treatment assignment. The primary outcome was the duration of symptoms rated moderately bad or worse (measured using a validated diary) for up to 28 days or until symptoms resolved. The primary outcome and safety were assessed in the intention-to-treat population. The trial is registered with the ISRCTN Registry (ISRCTN79914298). FINDINGS: Between Nov 9, 2016, and March 17, 2020, 432 children (not including six who withdrew permission for use of their data after randomisation) were randomly assigned to the antibiotics group (n=221) or the placebo group (n=211). Complete data for symptom duration were available for 317 (73%) patients; missing data were imputed for the primary analysis. Median durations of moderately bad or worse symptoms were similar between the groups (5 days [IQR 4-11] in the antibiotics group vs 6 days [4-15] in the placebo group; hazard ratio [HR] 1·13 [95% CI 0·90-1·42]). No differences were seen for the primary outcome between the treatment groups in the five prespecified clinical subgroups (patients with chest signs, fever, physician rating of unwell, sputum or chest rattle, and short of breath). Estimates from complete-case analysis and a per-protocol analysis were similar to the imputed data analysis. INTERPRETATION: Amoxicillin for uncomplicated chest infections in children is unlikely to be clinically effective either overall or for key subgroups in whom antibiotics are commonly prescribed. Unless pneumonia is suspected, clinicians should provide safety-netting advice but not prescribe antibiotics for most children presenting with chest infections. FUNDING: National Institute for Health Research.

Activity and intracellular localization of the human cytomegalovirus protein pp71.

The human cytomegalovirus (HCMV) tegument phosphoprotein pp71 activates viral immediate early (IE) transcription and thus has a role in initiating lytic infection. Protein pp71 stimulates expression from a range of promoters in a sequence-independent manner, and in this respect behaves similarly to the herpes simplex virus type 1 (HSV-1) IE protein ICP0. The intracellular localization of pp71 was investigated after its expression from transfected plasmids or from HSV-1 mutants constructed to produce pp71 transiently. The protein colocalized with the cell promyelocytic leukaemia (PML) protein at nuclear domain 10 (ND10) structures but, unlike ICP0, pp71 did not induce disruption of ND10. The activity of pp71 in mouse sensory neurons in vivo was investigated after co-inoculation of animals with pairs of HSV-1 mutants, one expressing pp71 and the second containing the E. coli lacZ gene controlled by various promoters. In this system, pp71 stimulated beta-galactosidase expression from a range of viral IE promoters when mice were analysed at 4 days postinoculation. At later times, expression of pp71 resulted in a reduction in numbers of neurons containing beta-galactosidase, indicating cytotoxicity or promoter shutoff. The HSV-1 latency-active promoter was not responsive to pp71, demonstrating specificity in the activity of the protein. Pp71 was as active in mice lacking both copies of the PML gene (PML-/-) as in control animals, and in PML-/- fibroblasts pp71 stimulated gene expression as effectively as in other cell types. Therefore, neither the PML protein nor the normal ND10 structure is necessary for pp71 to stimulate gene expression.

Isolation and characterization of a transfectant influenza B virus altered in RNA segment 6.

This report describes the successful generation of an influenza B transfectant virus altered in RNA segment 6, which encodes the neuraminidase (NA) protein. The procedure for selection of the transfectant virus relies on the use of strain-specific anti-NA monoclonal antibodies to inhibit growth of the helper virus within the system. A transfectant virus has been engineered which has a coding change in the NA protein. This change resulted in attenuated growth in vitro that could be rescued by addition of exogenous bacterial NA. The mutant virus-associated NA activity was unstable as a result of the engineered changes. The ability to genetically manipulate influenza B virus segment 6 will allow us to assess the function of both NA and the small protein NB, also coded from this RNA, within the context of the virus infectious cycle.