Post-acute COVID-19 outcomes in children requiring hospitalisation.

Post-acute COVID-19 causes long term sequalae in adults. This is less well described in children. We performed clinical assessments on a large cohort of children and young people admitted with a positive SARS-CoV-2 RNA swab. We assessed for symptoms of post-acute COVID-19 syndrome after 4 weeks or more. We found that most (85%) of children made a full recovery following SARS-CoV-2 infection. A small number had symptoms which lasted for more than 4 weeks, most of which had resolved at 3 months. Symptoms included dry cough, fatigue and headache. One patient suffered from anosmia. We conclude that most children and young people do not suffer from past-acute COVID-19 syndrome, and make a full recovery from infection.

Smartphone videos to predict the severity of obstructive sleep apnoea.

OBJECTIVE: Diagnosis of obstructive sleep apnoea (OSA) is made on overnight polysomnography (PSG). Given the widespread availability of smartphone video technology, we aimed to develop and test a standardised scoring system for smartphone videos and compare these scores to PSG results. METHODS: Children aged 1-16 years undergoing PSG for suspected OSA were included. Parents were asked to take 1-2 min videos of the breathing they were concerned about. Videos were scored using a newly developed and tested tool on five components: inspiratory obstructive noises (1-4), presence of obstructive events (0-1), increased work of breathing (0-1), mouth breathing (0-1) and neck extension (0-1). Video scores and the Obstructive Apnoea Hypopnoea Index (OAHI) were compared using Spearman correlation. Sensitivity, specificity, positive predictive value and negative predictive value were calculated for different cut-off scores to achieve the best results. RESULTS: Videos from 43 children (28 men (65.1%), median age 5.7 years (range 2.6-14.0 years), median OAHI 3.8/hour (range 0-82 events/hour) were included. Nine children (20.9%) had a video score of <3, all of whom had an OAHI of ≤5 events/hour. For a video score of ≥3, sensitivity was 100%; specificity was 36%; positive predictive value was 53%; and negative predictive value 100% for moderate to severe OSA (OAHI>5 events/hour) . CONCLUSION: We have developed and validated a simple clinical tool (the Monash Obstructive Sleep Apnoea Video Score) to quantify abnormalities in breathing seen on short video recordings made on a smartphone. A low score rules out moderate-severe OSA and may be valuable in the triage of children with symptoms of OSA.

Primary Ciliary Dyskinesia.

Primary ciliary dyskinesia (PCD) is an inherited cause of bronchiectasis. The estimated PCD prevalence in children with bronchiectasis is up to 26% and in adults with bronchiectasis is 1 to 13%. Due to dysfunction of the multiple motile cilia of the respiratory tract patients suffer from poor mucociliary clearance. Clinical manifestations are heterogeneous; however, a typical patient presents with chronic productive cough and rhinosinusitis from early life. Other symptoms reflect the multiple roles of motile cilia in other organs and can include otitis media and hearing loss, infertility, situs inversus, complex congenital heart disease, and more rarely other syndromic features such as hydrocephalus and retinitis pigmentosa. Awareness, identification, and diagnosis of a patient with PCD are important for multidisciplinary care and genetic counseling. Diagnosis can be pursued through a multitest pathway which includes the measurement of nasal nitric oxide, sampling the nasal epithelium to assess ciliary function and structure, and genotyping. Diagnosis is confirmed by the identification of a hallmark ultrastructural defect or pathogenic mutations in one of > 45 PCD causing genes. When a diagnosis is established management is centered around improving mucociliary clearance through physiotherapy and treatment of infection with antibiotics. The first international randomized controlled trial in PCD has recently been conducted showing azithromycin is effective in reducing exacerbations. It is likely that evidence-based PCD-specific management guidelines and therapies will be developed in the near future. This article examines prevalence, clinical features, diagnosis, and management of PCD highlighting recent advances in basic science and clinical care.

COVID-19 Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in children and adolescents: a systematic review of critically unwell children and the association with underlying comorbidities.

Data show that children are less severely affected with SARS-Covid-19 than adults; however, there have been a small proportion of children who have been critically unwell. In this systematic review, we aimed to identify and describe which underlying comorbidities may be associated with severe SARS-CoV-2 disease and death. The study protocol was in keeping with Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines. A total of 1726 articles were identified of which 28 studies fulfilled the inclusion criteria. The 28 studies included 5686 participants with confirmed SARS-CoV-2 infection ranging from mild to severe disease. We focused on the 108 patients who suffered from severe/critical illness requiring ventilation, which included 17 deaths. Of the 108 children who were ventilated, the medical history was available for 48 patients. Thirty-six of the 48 patients (75%) had documented comorbidities of which 11/48 (23%) had pre-existing cardiac disease. Of the 17 patients who died, the past medical history was reported in 12 cases. Of those, 8/12 (75%) had comorbidities.Conclusion: Whilst only a small number of children suffer from COVID-19 disease compared to adults, children with comorbidities, particularly pre-existing cardiac conditions, represent a large proportion of those that became critically unwell. What is Known: • Children are less severely affected by SARS-CoV-2 than adults. • There are reports of children becoming critically unwell with SARS-CoV-2 and requiring intensive care. What is New: • The majority of children who required ventilation for SARS-CoV-2 infection had underlying comorbidities. • The commonest category of comorbidity in these patients was underlying cardiac disease.

Multi-system inflammatory syndrome in children & adolescents (MIS-C): A systematic review of clinical features and presentation.

Multisystem Inflammatory Syndrome in Children (MIS-C) is a new phenomenon reported worldwide with temporal association with Covid-19. The objective of this paper is to evaluate reported cases in children and adolescents. From 1726 papers, 35 documented papers related to MIS-C cases identified 783 individual cases of MIS-C between March-June 2020; with 55% being male (n = 435) and a median age of 8.6 years (IQR, 7-10 years; range 3 months-20 years). Patients with MIS-C were noted to have a high frequency of gastrointestinal symptoms (71%) including abdominal pain (34%) and diarrhea (27%). Cough and respiratory distress were reported in 4.5% and 9.6% cases respectively. Blood parameters showed neutrophilia in 345/418 (83%) of cases and a high CRP in 587/626 (94%). 362/619 (59%) cases were SARS-CoV-2 infection positive (serology or PCR) however only 41% demonstrated pulmonary changes on chest imaging. Severity of illness was high with 68% cases requiring intensive care admission; 63% requiring inotropic support; 244/783 (28%) cases needing some form of respiratory support (138 mechanically ventilated), and 31 required extra-corporeal membrane oxygenation. Treatment strategies included intravenous immunoglobulin (63%) and intravenous steroids (44%). 29 cases received Infliximab, 47 received IL1 (interleukin) receptor antagonist, and 47 received IL6-receptor antagonist. 12/783 (1.5%) children died. In summary, a higher incidence of gastrointestinal symptoms were noted in MIS-C. In contrast to acute Covid-19 infection in children, MIS-C appears to be a condition of higher severity with 68% of cases having required critical care support.

Proceedings of the 3rd BEAT-PCD Conference and 4th PCD Training School.

Primary ciliary dyskinesia (PCD) is a chronic suppurative airways disease that is usually recessively inherited and has marked clinical phenotypic heterogeneity. Classic symptoms include neonatal respiratory distress, chronic rhinitis since early childhood, chronic otitis media, recurrent airway infections leading to bronchiectasis, chronic sinusitis, laterality defects with and without congenital heart disease including abnormal situs in approximately 50% of the cases, and male infertility. Lung function deteriorates progressively from childhood throughout life. 'Better Experimental Approaches to Treat Primary Ciliary Dyskinesia' (BEAT-PCD) is a network of scientists and clinicians coordinating research from basic science through to clinical care with the intention of developing treatments and diagnostics that lead to improved long-term outcomes for patients. BEAT-PCD activities are supported by EU funded COST Action (BM1407). The third BEAT-PCD conference and fourth PCD training school were held jointly in February 2018 in Lisbon, Portugal. Presentations and workshops focussed on advancing the knowledge and skills relating to PCD in: basic science, epidemiology, diagnostic testing, clinical management and clinical trials. The multidisciplinary conference provided an interactive platform for exchanging ideas through a program of lectures, poster presentations, breakout sessions and workshops. Three working groups met to plan consensus statements. Progress with BEAT-PCD projects was shared and new collaborations were fostered. In this report, we summarize the meeting, highlighting developments made during the meeting.

Disease-modifying drug therapy in cystic fibrosis.

Whilst substantial progress has been made in the treatment of cystic fibrosis, the disease still carries a significant burden in terms of symptoms, requirement for treatment and early mortality. The last decade has witnessed a new era in the development of small molecule drugs targeting the CFTR protein, which for the first time may provide a truly disease-modifying approach to treatment. This article reviews progress and highlights some of the current and future challenges in CFTR modulator therapies.

Repeated nebulisation of non-viral CFTR gene therapy in patients with cystic fibrosis: a randomised, double-blind, placebo-controlled, phase 2b trial.

BACKGROUND: Lung delivery of plasmid DNA encoding the CFTR gene complexed with a cationic liposome is a potential treatment option for patients with cystic fibrosis. We aimed to assess the efficacy of non-viral CFTR gene therapy in patients with cystic fibrosis. METHODS: We did this randomised, double-blind, placebo-controlled, phase 2b trial in two cystic fibrosis centres with patients recruited from 18 sites in the UK. Patients (aged ≥12 years) with a forced expiratory volume in 1 s (FEV1) of 50-90% predicted and any combination of CFTR mutations, were randomly assigned, via a computer-based randomisation system, to receive 5 mL of either nebulised pGM169/GL67A gene-liposome complex or 0.9% saline (placebo) every 28 days (plus or minus 5 days) for 1 year. Randomisation was stratified by % predicted FEV1 (<70 vs ≥70%), age (<18 vs ≥18 years), inclusion in the mechanistic substudy, and dosing site (London or Edinburgh). Participants and investigators were masked to treatment allocation. The primary endpoint was the relative change in % predicted FEV1. The primary analysis was per protocol. This trial is registered with ClinicalTrials.gov, number NCT01621867. FINDINGS: Between June 12, 2012, and June 24, 2013, we randomly assigned 140 patients to receive placebo (n=62) or pGM169/GL67A (n=78), of whom 116 (83%) patients comprised the per-protocol population. We noted a significant, albeit modest, treatment effect in the pGM169/GL67A group versus placebo at 12 months' follow-up (3.7%, 95% CI 0.1-7.3; p=0.046). This outcome was associated with a stabilisation of lung function in the pGM169/GL67A group compared with a decline in the placebo group. We recorded no significant difference in treatment-attributable adverse events between groups. INTERPRETATION: Monthly application of the pGM169/GL67A gene therapy formulation was associated with a significant, albeit modest, benefit in FEV1 compared with placebo at 1 year, indicating a stabilisation of lung function in the treatment group. Further improvements in efficacy and consistency of response to the current formulation are needed before gene therapy is suitable for clinical care; however, our findings should also encourage the rapid introduction of more potent gene transfer vectors into early phase trials. FUNDING: Medical Research Council/National Institute for Health Research Efficacy and Mechanism Evaluation Programme.