Purpose of review
To describe the current global burden of respiratory syncytial virus (RSV) in infants and its implications for morbidity, health resources and economic costs.
Recent findings
New ...prophylactic therapies are on the horizon for RSV in the form of long-acting monoclonal antibodies suitable for healthy infants and maternal immunizations.
Summary
Despite being responsible for significant global infant morbidity and mortality, until recently there have been no effective therapeutics available for healthy infants to protect them from RSV. Several new drugs are likely to be available within the next few years which could help relieve a huge burden on healthcare systems over the coming winters.
BACKGROUND:Recent advances in outpatient parenteral antibiotic therapy (OPAT) have largely focused on adult practice, and there are few published data on the safety and effectiveness of pediatric ...OPAT (p-OPAT).
METHODS:During a 3-year period (2012 to 2015), data were prospectively collected on patients managed within the p-OPAT service at Southampton Children’s Hospital, a tertiary pediatric hospital in the South of England.
RESULTS:A total of 130 p-OPAT episodes were managed during this period. The most frequently managed pathologies were bone and joint infections (44.6%), followed by ear, nose and throat (10.7%), respiratory (10.0%) and central nervous system (10.0%) infections. The most frequently used antimicrobial agent was ceftriaxone (n = 103; 79.2%). For the majority of p-OPAT episodes, antimicrobials were delivered in prefilled syringes (n = 109; 83.8%); 24-hour infusions administered by elastomeric devices were used less commonly (n = 16; 12.3%). The median duration of p-OPAT treatment was 9.2 days (interquartile range7.6–19.0 days). With regard to patient outcomes, 113 (86.9%) p-OPAT episodes resulted in cure and 12 (9.2%) in improvement; treatment failure occurred in 5 (3.9%) episodes. Intravenous catheter–related complications were rare. A total of 1683 bed days were saved over the 3-year period.
CONCLUSIONS:Our data suggest that p-OPAT is safe and effective, with the potential to offer considerable savings for the healthcare economy through reduced length of inpatient stay.
The current methods for diagnosis of acute and chronic infections are complex and skill-intensive. For complex clinical biofilm infections, it can take days from collecting and processing a patient’s ...sample to achieving a result. These aspects place a significant burden on healthcare providers, delay treatment, and can lead to adverse patient outcomes. We report the development and application of a novel multi-excitation Raman spectroscopy-based methodology for the label-free and non-invasive detection of microbial pathogens that can be used with unprocessed clinical samples directly and provide rapid data to inform diagnosis by a medical professional. The method relies on the differential excitation of non-resonant and resonant molecular components in bacterial cells to enhance the molecular finger-printing capability to obtain strain-level distinction in bacterial species. Here, we use this strategy to detect and characterize the respiratory pathogens Pseudomonas aeruginosa and Staphylococcus aureus as typical infectious agents associated with cystic fibrosis. Planktonic specimens were analyzed both in isolation and in artificial sputum media. The resonance Raman components, excited at different wavelengths, were characterized as carotenoids and porphyrins. By combining the more informative multi-excitation Raman spectra with multivariate analysis (support vector machine) the accuracy was found to be 99.75% for both species (across all strains), including 100% accuracy for drug-sensitive and drug-resistant S. aureus. The results demonstrate that our methodology based on multi-excitation Raman spectroscopy can underpin the development of a powerful platform for the rapid and reagentless detection of clinical pathogens to support diagnosis by a medical expert, in this case relevant to cystic fibrosis. Such a platform could provide translatable diagnostic solutions in a variety of disease areas and also be utilized for the rapid detection of anti-microbial resistance.
Background. The novel influenza vaccine MVA-NP+M1 is designed to boost cross-reactive T-cell responses to internal antigens of the influenza A virus that are conserved across all subtypes, providing ...protection against both influenza disease and virus shedding against all influenza A viruses. Following a phase 1 clinical study that demonstrated vaccine safety and immunogenicity, a phase 2a vaccination and influenza challenge study has been conducted in healthy adult volunteers. Methods. Volunteers with no measurable serum antibodies to influenza A/Wisconsin/67/2005 received either a single vaccination with MVA-NP+M1 or no vaccination. T-cell responses to the vaccine antigens were measured at enrollment and again prior to virus challenge. All volunteers underwent intranasal administration of influenza A/Wisconsin/67/2005 while in a quarantine unit and were monitored for symptoms of influenza disease and virus shedding. Results. Volunteers had a significantly increased T-cell response to the vaccine antigens following a single dose of the vaccine, with an increase in cytolytic effector molecules. Intranasal influenza challenge was undertaken without safety issues. Two of 11 vaccinees and 5 of 11 control subjects developed laboratory-confirmed influenza (symptoms plus virus shedding). Symptoms of influenza were less pronounced in the vaccinees and there was a significant reduction in the number of days of virus shedding in those vaccinees who developed influenza (mean, 1.09 days in controls, 0.45 days in vaccinees, P = .036). Conclusions. This study provides the first demonstration of clinical efficacy of a T-cell-based influenza vaccine and indicates that further clinical development should be undertaken. Clinical Trials Registration. NCT00993083.
Data are limited regarding the optimal dose and duration of amoxicillin treatment for community-acquired pneumonia in children.
To determine the efficacy, safety and impact on antimicrobial ...resistance of shorter (3-day) and longer (7-day) treatment with amoxicillin at both a lower and a higher dose at hospital discharge in children with uncomplicated community-acquired pneumonia.
A multicentre randomised double-blind 2 × 2 factorial non-inferiority trial in secondary care in the UK and Ireland.
Paediatric emergency departments, paediatric assessment/observation units and inpatient wards.
Children aged > 6 months, weighing 6-24 kg, with a clinical diagnosis of community-acquired pneumonia, in whom treatment with amoxicillin as the sole antibiotic was planned on discharge.
Oral amoxicillin syrup at a dose of 35-50 mg/kg/day compared with a dose of 70-90 mg/kg/day, and 3 compared with 7 days' duration. Children were randomised simultaneously to each of the two factorial arms in a 1 : 1 ratio.
The primary outcome was clinically indicated systemic antibacterial treatment prescribed for respiratory tract infection (including community-acquired pneumonia), other than trial medication, up to 28 days after randomisation. Secondary outcomes included severity and duration of parent/guardian-reported community-acquired pneumonia symptoms, drug-related adverse events (including thrush, skin rashes and diarrhoea), antimicrobial resistance and adherence to trial medication.
A total of 824 children were recruited from 29 hospitals. Ten participants received no trial medication and were excluded. Participants median age 2.5 (interquartile range 1.6-2.7) years; 52% male were randomised to either 3 (
= 413) or 7 days (
= 401) of trial medication at either lower (
= 410) or higher (
= 404) doses. There were 51 (12.5%) and 49 (12.5%) primary end points in the 3- and 7-day arms, respectively (difference 0.1%, 90% confidence interval -3.8% to 3.9%) and 51 (12.6%) and 49 (12.4%) primary end points in the low- and high-dose arms, respectively (difference 0.2%, 90% confidence interval -3.7% to 4.0%), both demonstrating non-inferiority. Resolution of cough was faster in the 7-day arm than in the 3-day arm for cough (10 days vs. 12 days) (
= 0.040), with no difference in time to resolution of other symptoms. The type and frequency of adverse events and rate of colonisation by penicillin-non-susceptible pneumococci were comparable between arms.
End-of-treatment swabs were not taken, and 28-day swabs were collected in only 53% of children. We focused on phenotypic penicillin resistance testing in pneumococci in the nasopharynx, which does not describe the global impact on the microflora. Although 21% of children did not attend the final 28-day visit, we obtained data from general practitioners for the primary end point on all but 3% of children.
Antibiotic retreatment, adverse events and nasopharyngeal colonisation by penicillin-non-susceptible pneumococci were similar with the higher and lower amoxicillin doses and the 3- and 7-day treatments. Time to resolution of cough and sleep disturbance was slightly longer in children taking 3 days' amoxicillin, but time to resolution of all other symptoms was similar in both arms.
Antimicrobial resistance genotypic studies are ongoing, including whole-genome sequencing and shotgun metagenomics, to fully characterise the effect of amoxicillin dose and duration on antimicrobial resistance. The analysis of a randomised substudy comparing parental electronic and paper diary entry is also ongoing.
Current Controlled Trials ISRCTN76888927, EudraCT 2016-000809-36 and CTA 00316/0246/001-0006.
This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in
; Vol. 25, No. 60. See the NIHR Journals Library website for further project information.
Just say NO to biofilms: NO‐donors are used to disperse a bacterial biofilm so that co‐administered antibiotics will kill the more susceptible unattached cells. The chemically stable ...cephalosporin‐3′‐diazeniumdiolate NO‐donor prodrug (see scheme) is activated by bacterial β‐lactamases and facilitates this two‐step biofilm erradication.
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).
To estimate the clinical effectiveness and cost-effectiveness of amoxicillin for uncomplicated lower respiratory tract infections in children both overall and in clinical subgroups.
Placebo-controlled trial with qualitative, observational and cost-effectiveness studies.
UK general practices.
Children aged 1-12 years with acute uncomplicated lower respiratory tract infections.
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.
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.
A total of 432 children were randomised (antibiotics,
= 221; placebo,
= 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 (
= 317) and per-protocol (
= 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.
The study was underpowered to detect small benefits in key subgroups.
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.
The data can be incorporated in the Cochrane review and individual patient data meta-analysis.
This trial is registered as ISRCTN79914298.
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
; Vol. 27, No. 9. See the NIHR Journals Library website for further project information.
Isolated congenital asplenia (ICA) is characterized by the absence of a spleen at birth in individuals with no other developmental defects. The patients are prone to life-threatening bacterial ...infections. The unbiased analysis of exornes revealed heterozygous mutations in RPSA in 18 patients from eight kindreds, corresponding to more than half the patients and over one-third of the kindreds studied. The clinical penetrance in these kindreds is complete. Expression studies indicated that the mutations carried by the patients—a nonsense mutation, a frameshift duplication, and five different missense mutations—cause autosomal dominant ICA by haploinsufficiency. RPSA encodes ribosomal protein SA, a component of the small subunit of the ribosome. This discovery establishes an essential role for RPSA in human spleen development.
The COVID-19 pandemic poses many direct and indirect consequences for children's health and associated research. Direct consequences include participation of children in COVID-19 research trials, ...pausing other research in children and the potential implications of a global economic downturn on future research funding. Collaborative and networked research together with streamlined research processes and use of remote technology have been central to efforts by clinicians and scientists around the world and have proved essential for reducing COVID-19 morbidity and mortality. IMPACT: Maintain streamlined and efficient approaches to research governance and data sharing to facilitate high-quality collaborative research. Ensure early inclusion of children in trials of therapies for diseases that affect all age groups. Paediatric Research Societies should co-ordinate effective processes to define key research questions and develop multinational clinical trials for diagnostics, therapeutics and preventative strategies for infants, children and young people.
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