A systematic review of antimicrobial therapy in children with tracheostomies.

Tracheostomies are indicated in children to facilitate long-term ventilatory support, aid in the management of secretions, or manage upper airway obstruction. Children with tracheostomies often experience ongoing airway complications, of which respiratory tract infections are common. They subsequently receive frequent courses of broad-spectrum antimicrobials for the prevention or treatment of respiratory tract infections. However, there is little consensus in practice with regard to the indication for treatment/prophylactic antimicrobial use, choice of antimicrobial, route of administration, or duration of treatment between different centers. Routine antibiotic use is associated with adverse effects and an increased risk of antimicrobial resistance. Tracheal cultures are commonly obtained from pediatric tracheostomy patients, with the aim of helping guide antimicrobial therapy choice. However, a positive culture alone is not diagnostic of infection and the role of routine surveillance cultures remains contentious. Inhaled antimicrobial use is also widespread in the management of tracheostomy-associated infections; this is largely based on the theoretical benefits of higher airway antibiotic concentrations. The role of prophylactic inhaled antimicrobial use for tracheostomy-associated infections remains largely unproven. This systematic review summarizes the current evidence base for antimicrobial selection, duration, and administration route in pediatric tracheostomy-associated infections. It also highlights significant variation in practice between centers and the urgent need for further prospective evidence to guide the management of these vulnerable patients.

Unsupervised home spirometry is not equivalent to supervised clinic spirometry in children and young people with cystic fibrosis: Results from the CLIMB-CF study.

BACKGROUND: Handheld spirometry allows monitoring of lung function at home, of particular importance during the COVID-19 pandemic. Pediatric studies are unclear on whether values are interchangeable with traditional, clinic-based spirometry. We aimed to assess differences between contemporaneous, home (unsupervised) and clinic (supervised) spirometry and the variability of the former. The accuracy of the commercially available spirometer used in the study was also tested. METHODS: Data from participants in the Clinical Monitoring and Biomarkers to stratify severity and predict outcomes in children with cystic fibrosisc (CLIMB-CF) Study aged ≥ 6 years who had paired (±1 day) clinic and home forced expiratory volume in 1 s (FEV1 ) readings were analyzed. Variability during clinical stability over 6-months was assessed. Four devices from Vitalograph were tested using 1 and 3 L calibration syringes. RESULTS: Sixty-seven participants (median [interquartile range] age 10.7 [7.6-13.9] years) provided home and clinic FEV1 data pairs. The mean (SD) FEV1 % bias was 6.5% [±8.2%]) with wide limits of agreement (-9.6% to +22.7%); 76.2% of participants recorded lower results at home. Coefficient of variation of home FEV1 % during stable periods was 9.9%. Data from the testing of the handheld device used in CLIMB-CF showed a potential underread. CONCLUSION: In children and adolescents, home spirometry using hand-held equipment cannot be used interchangeably with clinic spirometry. Home spirometry is moderately variable during clinical stability. New handheld devices underread, particularly at lower volumes of potential clinical significance for smaller patients; this suggests that supervision does not account fully for the discrepancy. Opportunities should be taken to obtain dual device measurements in clinic, so that trend data from home can be utilized more accurately.

Tracheostomy in children is associated with neutrophilic airway inflammation.

BACKGROUND: Tracheostomies in children are associated with significant morbidity, poor quality of life, excess healthcare costs and excess mortality. The underlying mechanisms facilitating adverse respiratory outcomes in tracheostomised children are poorly understood. We aimed to characterise airway host defence in tracheostomised children using serial molecular analyses. METHODS: Tracheal aspirates, tracheal cytology brushings and nasal swabs were prospectively collected from children with a tracheostomy and controls. Transcriptomic, proteomic and metabolomic methods were applied to characterise the impact of tracheostomy on host immune response and the airway microbiome. RESULTS: Children followed up serially from the time of tracheostomy up to 3 months postprocedure (n=9) were studied. A further cohort of children with a long-term tracheostomy were also enrolled (n=24). Controls (n=13) comprised children without a tracheostomy undergoing bronchoscopy. Long-term tracheostomy was associated with airway neutrophilic inflammation, superoxide production and evidence of proteolysis when compared with controls. Reduced airway microbial diversity was established pre-tracheostomy and sustained thereafter. CONCLUSIONS: Long-term childhood tracheostomy is associated with a inflammatory tracheal phenotype characterised by neutrophilic inflammation and the ongoing presence of potential respiratory pathogens. These findings suggest neutrophil recruitment and activation as potential exploratory targets in seeking to prevent recurrent airway complications in this vulnerable group of patients.

Providing care for children with tracheostomies: a qualitative interview study with parents and health professionals.

OBJECTIVES: To explore the experience of caring for children with tracheostomies from the perspectives of parents and health professional caregivers. DESIGN: Qualitative semistructured interview study. SETTING: One region in England covered by a tertiary care centre that includes urban and remote rural areas and has a high level of deprivation. PARTICIPANTS: A purposive sample of health professionals and parents who care for children who have, or have had, tracheostomies and who received care at the tertiary care centre. INTERVENTION: Interviews undertaken by telephone or video link. PRIMARY AND SECONDARY OUTCOME MEASURES: Qualitative reflexive thematic analysis with QSR Nvivo 12. RESULTS: This paper outlines key determinants and mediators of the experiences of caregiving and the impact on psychological and physical health and quality of life of parents and their families, confidence of healthcare providers and perceived quality of care. For parents, access to care packages and respite care at home as well as communication and relationships with healthcare providers are key mediators of their experience of caregiving, whereas for health professionals, an essential influence is multidisciplinary team working and support. We also highlight a range of challenges focused on the shared care space, including: a lack of standardisation in access to different support teams, care packages and respite care, irregular training and updates, and differences in health provider expertise and experiences across departments and shift patterns, exacerbated in some settings by limited contact with children with tracheostomies. CONCLUSIONS: Understanding the experiences of caregiving can help inform measures to support caregivers and improve quality standards. Our findings suggest there is a need to facilitate further standardisation of care and support available for parent caregivers and that this may be transferable to other regions. Potential solutions to be explored could include the development of a paediatric tracheostomy service specification, increasing use of paediatric tracheostomy specialist nurse roles, and addressing the emotional and psychological support needs of caregivers.

Automatic oxygen control for reducing extremes of oxygen saturation: a randomised controlled trial.

OBJECTIVE: The objective of this study was to evaluate the efficacy of the automatic oxygen control (A-Fio2) in reducing the percentage of time spent in severe hypoxaemia (Spo2 <80%) in preterm infants for the time period on invasive ventilation and/or nasal continuous positive airway pressure (NCPAP) delivered by AVEA ventilator. DESIGN: A parallel arm randomised controlled trial. SETTING: A level-III neonatal intensive care unit. PATIENTS: Preterm infants (<33 weeks birth gestation) who received invasive ventilation or NCPAP in the first 72 hours of age. INTERVENTIONS: A-Fio2 vs manual (M-Fio2) oxygen control. OUTCOMES: The primary outcome of the study was percentage of time spent in severe hypoxaemia (Spo2 <80%). RESULTS: 44 infants were randomised to either A-Fio2 or M-Fio2 arm and continued in the study for the period of respiratory support (invasive ventilation and/or NCPAP). The total number of study days in A-Fio2 and M-Fio2 arm were 194 and 204 days, respectively. The percentage of time spent in Spo2 <80% was significantly lower with A-Fio2 compared with M-Fio2 (median of 0.1% (IQR: 0.07-0.7) vs 0.6% (0.2-2); p=0.03). The number of prolonged episodes (>60 s) of Spo2 <80% per day was also significantly lower in A-Fio2 (0.3 (0.0-2) vs 2 (0.6-6); p=0.02). CONCLUSION: A-Fio2 was associated with statistically significant reduction in the percentage of time spent in severe hypoxaemia when compared with M-Fio2 in preterm infants receiving respiratory support. TRIAL REGISTRATION NUMBER: NCT04223258.

Diaphragm electrical activity during weaning of nasal high-flow therapy in preterm infants.

OBJECTIVE: To determine whether electrical activity of the diaphragm (Edi) changes with weaning nasal high-flow (HF) therapy in preterm infants according to a standardised protocol. DESIGN: Prospective observational cohort study. SETTING: Neonatal intensive care unit. PATIENTS: Preterm infants born at <32 weeks gestation, receiving nasal HF as part of routine clinical care. INTERVENTIONS: Infants recruited to the study had their HF weaned according to set clinical criteria. Edi was measured using a modified gastric feeding tube serially from baseline (pre-wean) to 24-hours post-wean. MAIN OUTCOME MEASURES: Change in Edi from baseline was measured at four time points up to 24 hours after weaning. Minimum Edi during expiration, maximum Edi during inspiration and amplitude of the Edi signal (Edidelta) were measured. Clinical parameters (heart rate, respiratory rate and fraction of inspired oxygen) were also recorded. RESULTS: Forty preterm infants were recruited at a mean corrected gestational age of 31.6 (±2.7) weeks. Data from 156 weaning steps were analysed, 91% of which were successful. Edi did not change significantly from baseline during flow reduction steps, but a significant increase in diaphragm activity was observed when discontinuing HF (median increase in Edidelta immediately post-discontinuation 1.7 µV (95% CI: 0.6 to 3.0)) and at 24 hours 1.9 µV (95% CI: 0.7 to 3.8)). No significant difference in diaphragm activity was observed between successful and unsuccessful weaning steps. CONCLUSIONS: A protocolised approach to weaning has a high probability of success. Edi does not change with reducing HF rate, but significantly increases with discontinuation of HF from 2 L/min.

Exploring the impact of elexacaftor-tezacaftor-ivacaftor treatment on opinions regarding airway clearance techniques and nebulisers: TEMPO a qualitative study in children with cystic fibrosis, their families and healthcare professionals.

BACKGROUND: Cystic fibrosis (CF) is a genetic condition caused by variants in the cystic fibrosis transmembrane conductance regulator (CFTR) gene that primarily impacts the lungs. Treatments historically have been symptomatic to improve airway clearance and treat infection. However, CFTR modulator drugs have recently been developed that target the underlying defect. The triple combination of elexacaftor-tezacaftor-ivacaftor (ETI) was approved in 2020 in England for over 80% of people with CF aged over 12 years and in 2022 extended to those over 6 years. ETI treatment is associated with substantial improvements in lung function. The experience of children with CF starting on ETI or their views regarding future treatments have not been well studied. This study aimed to explore the opinions of children with CF, their parents/carers and healthcare professionals (HCPs) on the impact of ETI, airway clearance techniques (ACTs) and nebulised treatments. METHODS: Semistructured qualitative interviews were performed with 10 children with CF, 7 parents/carers and 10 HCPs. Audio recordings were transcribed and analysed using reflexive thematic analysis. RESULTS: Four main themes were identified: 'Kaftrio changed my life', 'Your entire life is dictated by the CF timetable', 'Simplifying treatment-hopes and fears' and 'Kaftrio is a game-changer' along with several subthemes and an overarching theme of 'I still can't get my head around how three tablets can do what Kaftrio done'. CONCLUSIONS: Despite the highly positive impact of ETI on the health of children with CF some concerns remain about the longer-term outcomes of reducing ACTs or nebulised treatments. ETI has prompted a shift in treatment for many and offers an opportunity to personalise approaches.

Exposure to bile and gastric juice can impact the aerodigestive microbiome in people with cystic fibrosis.

Studies of microbiota reveal inter-relationships between the microbiomes of the gut and lungs. This relationship may influence the progression of lung disease, particularly in patients with cystic fibrosis (CF), who often experience extraoesophageal reflux (EOR). Despite identifying this relationship, it is not well characterised. Our hypothesis is that the gastric and lung microbiomes in CF are related, with the potential for aerodigestive pathophysiology. We evaluated gastric and sputum bacterial communities by culture and 16S rRNA gene sequencing in 13 CF patients. Impacts of varying levels of bile acids, pepsin and pH on patient isolates of Pseudomonas aeruginosa (Pa) were evaluated. Clonally related strains of Pa and NTM were identified in gastric and sputum samples from patients with symptoms of EOR. Bacterial diversity was more pronounced in sputa compared to gastric juice. Gastric and lung bile and pepsin levels were associated with Pa biofilm formation. Analysis of the aerodigestive microbiomes of CF patients with negative sputa indicates that the gut can be a reservoir of Pa and NTM. This combined with the CF patient's symptoms of reflux and potential aspiration, highlights the possibility of communication between microorganisms of the gut and the lungs. This phenomenon merits further research.

Conjunctival epithelial cells resist productive SARS-CoV-2 infection.

Conjunctival epithelial cells, which express viral-entry receptors angiotensin-converting enzyme 2 (ACE2) and transmembrane protease serine type 2 (TMPRSS2), constitute the largest exposed epithelium of the ocular surface tissue and may represent a relevant viral-entry route. To address this question, we generated an organotypic air-liquid-interface model of conjunctival epithelium, composed of basal, suprabasal, and superficial epithelial cells, and fibroblasts, which could be maintained successfully up to day 75 of differentiation. Using single-cell RNA sequencing (RNA-seq), with complementary imaging and virological assays, we observed that while all conjunctival cell types were permissive to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) genome expression, a productive infection did not ensue. The early innate immune response to SARS-CoV-2 infection in conjunctival cells was characterised by a robust autocrine and paracrine NF-κB activity, without activation of antiviral interferon signalling. Collectively, these data enrich our understanding of SARS-CoV-2 infection at the human ocular surface, with potential implications for the design of preventive strategies and conjunctival transplantation.

Diagnosis and management of asthma in children.

Asthma is the the most common chronic respiratory condition of childhood worldwide, with around 14% of children and young people affected. Despite the high prevalence, paediatric asthma outcomes are inadequate, and there are several avoidable deaths each year. Characteristic asthma features include wheeze, shortness of breath and cough, which are typically triggered by a number of possible stimuli. There are several diagnostic challenges, and as a result, both overdiagnosis and underdiagnosis of paediatric asthma remain problematic.Effective asthma management involves a holistic approach addressing both pharmacological and non-pharmacological management, as well as education and self-management aspects. Working in partnership with children and families is key in promoting good outcomes. Education on how to take treatment effectively, trigger avoidance, modifiable risk factors and actions to take during acute attacks via personalised asthma action plans is essential.This review aimed to provide an overview of good clinical practice in the diagnosis and management of paediatric asthma. We discuss the current diagnostic challenges and predictors of life-threatening attacks. Additionally, we outline the similarities and differences in global paediatric asthma guidelines and highlight potential future developments in care. It is hoped that this review will be useful for healthcare providers working in a range of child health settings.

Elexacaftor-Tezacaftor-Ivacaftor improve Gastro-Oesophageal reflux and Sinonasal symptoms in advanced cystic fibrosis.

Upper gastrointestinal and upper airway disease are common in cystic fibrosis (CF) and may contribute to lower airway infection and inflammation. In a longitudinal cohort study of 32 patients (23 men; median age 32.5 years) with advanced CF lung disease (median FEV1 24.8% predicted) starting elexacaftor-tezacaftor-ivacaftor, the reflux symptom index score fell from a pre-treatment median (IQR) of 15 (11-23) to 5 (2.8-7.3) (p<0.001), the Hull airway reflux score fell from a median of 26.5 (16.3-39) to 7.5 (4-12) (p<0.001), and the sinonasal outcome score from a median of 36.5 (22-24) to 20 (10-32) (p<0.001) at 6 months on treatment. Mean FEV1% predicted rose by 9.2 points, the median respiratory domain score of the CF Questionnaire-Revised rose by 27.8 points and mean body mass index rose by 2.6 kg/m2. In addition to improving lung function and weight, CFTR modulators improve upper airway and gastro-oesophageal reflux symptoms in advanced CF.

Precision Medicine Based on CFTR Genotype for People with Cystic Fibrosis.

Cystic fibrosis (CF) is an autosomal recessive genetic condition that is caused by variants in the cystic fibrosis transmembrane conductance regulator gene. This causes multisystem disease due to dysfunction of the cystic fibrosis transmembrane conductance regulator (CFTR) ion channel at the apical surface of epithelia. Until recently, treatment was directed at managing the downstream effects in affected organs, principally improving airway clearance and treating infection in the lungs and improving malabsorption in the gastrointestinal tract. Care delivered by multidisciplinary teams has yielded incremental improvements in outcomes. However, the development of small-molecule CFTR modulator drugs over the last decade has heralded a new era of CF therapeutics. Modulators target the underlying defect and improve CFTR function. Either monotherapy or a combination of modulators is used depending on the specific genotype and class of CFTR disease-causing variants that an individual has. Both ivacaftor and the ivacaftor/tezacaftor/elexacaftor combination have been demonstrated to be associated with clinically very significant benefits in randomised trials and have rapidly been made available as part of standard care in many countries. CFTR modulators represent one of the best examples of precision medicine to date. They are expensive, however, and equity of access to them worldwide remains an issue. Studies and approvals are also ongoing for children under the age of 6 years for ivacaftor/tezacaftor/elexacaftor. Furthermore, no modulators are available for around 10% of the people with CF. In this review, we firstly summarise the genetics, pathophysiology and clinical problems associated with CF. We then discuss the development of CFTR modulators and key clinical trials to support their use along with other potential future therapeutic approaches.

Protocol for CLASSIC PBB: comparison of lower airway sampling strategies in children with protracted bacterial bronchitis.

BACKGROUND: Protracted bacterial bronchitis (PBB) is an endobronchial infection and a the most common cause of chronic wet cough in young children. It is treated with antibiotics, which can only be targeted if the causative organism is known. As most affected children do not expectorate sputum, lower airway samples can only be obtained by bronchoalveolar lavage (BAL) samples taken during flexible bronchoscopy (FB-BAL). This is invasive and is therefore reserved for children with severe or relapsing cases. Most children with PBB are treated empirically with broad spectrum antibiotics. CLASSIC PBB will compare the pathogen yield from two less invasive strategies with that from FB-BAL to see if they are comparable. METHODS: 131 children with PBB from four UK centres referred FB-BAL will be recruited. When attending for FB-BAL, they will have a cough swab and an induced sputum sample obtained. The primary outcome will be the discordance of the pathogen yield from the cough swab and the induced sputum when compared with FB-BAL. Secondary outcomes will be the sensitivity of each sampling strategy, the success rate of the induced sputum in producing a usable sample and the tolerability of each of the three sampling strategies. DISCUSSION: If either or both of the two less invasive airway sampling strategies are shown to be a useful alternative to FB-BAL, this will lead to more children with PBB having lower airway samples enabling targeted antibiotic prescribing. It would also reduce the need for FB, which is known to be burdensome for children and their families. TRIAL REGISTRATION NUMBER: ISRCTN79883982.

Impact of COVID-19 on carers of children with tracheostomies.

OBJECTIVES: To explore the impact of the COVID-19 pandemic on the experiences of caregivers of children with tracheostomies. DESIGN: Qualitative semistructured interviews. SETTING: All participants were currently, or had previously cared for, a tracheostomised child who had attended a tertiary care centre in the North of England. Health professionals were purposively sampled to include accounts from a range of professions from primary, community, secondary and tertiary care. PARTICIPANTS: Carers of children with tracheostomies (n=34), including health professionals (n=17) and parents (n=17). INTERVENTIONS: Interviews were undertaken between July 2020 and February 2021 by telephone or video link. MAIN OUTCOME MEASURE: Qualitative reflexive thematic analysis with QSR NVivo V.12. RESULTS: The pandemic has presented an additional and, for some, substantial challenge when caring for tracheostomised children, but this was not always felt to be the most overriding concern. Interviews demonstrated rapid adaptation, normalisation and varying degrees of stoicism and citizenship around constantly changing pandemic-related requirements, rules and regulations. This paper focuses on four key themes: 'reconceptualising safe care and safe places'; 'disrupted support and isolation'; 'relationships, trust and communication'; and 'coping with uncertainty and shifting boundaries of responsibility'. These are described within the context of the impact on the child, the emotional and physical well-being of carers and the challenges to maintaining the values of family-centred care. CONCLUSIONS: As we move to the next phase of the pandemic, we need to understand the impact on vulnerable groups so that their needs can be prioritised.

Treating nontuberculous mycobacteria in children with cystic fibrosis: a multicentre retrospective study.

BACKGROUND: Respiratory infection with nontuberculous mycobacteria (NTM) in children with cystic fibrosis (CF) has increased in prevalence. The condition is difficult to diagnose and treatments are complex with limited evidence to guide practice. This study describes the approaches to diagnosis, management and consequences of treatment in a multicentre cohort of children with CF in the UK. METHODS: Retrospective data were collected from 11 CF specialist centres from patients less than 17 years old, treated for NTM infection between 2006 and 2017. Descriptive statistics were used to describe the clinical characteristics of children treated. Treatment regimens, adverse events and success of treatment, with respect to lung function and culture conversion, were evaluated. RESULTS: Data from 70 patients treated for NTM pulmonary disease were collated (60 Mycobacterium abscessus complex (MABSC); 10 M. avium complex (MAC)). Older age and previous diagnosis of allergic bronchopulmonary aspergillosis were all significantly associated with NTM. There was a wide variance in drug choice and side effects were reported with all agents. NTM eradication occurred in 80% of patients with MAC and 48% with MABSC, with variable outcomes on lung function. CONCLUSIONS: Diagnosis and treatment of NTM infection in children with CF is challenging. Treatment success is not guaranteed, particularly for MABSC. Large clinical trials are urgently required to evaluate treatment regimes and their suitability and efficacy in children.

Characterising the allergic profile of children with cystic fibrosis.

BACKGROUND: Cystic fibrosis (CF) is a genetic condition that affects multiple organ systems. Allergic bronchopulmonary aspergillosis (ABPA) is a well-recognised problem but other allergic conditions are less well documented in CF. OBJECTIVE: To characterise the allergic profile of a cohort of children with CF, with a focus on those with ABPA. METHODS: A cohort of children with CF were interviewed and retrospective data were collected regarding their allergic histories and other relevant clinical features. RESULTS: The cohort included 37 children with median age of 9 years (interquartile range: 6-12). There was a history of ≥1 allergic condition(s) in 28/37 children (76%). The most common allergic condition was allergic rhinitis (AR) in 21/37 (57%) and 16 of these 21 children (76%) had another allergic condition. All children with ABPA (8) had another allergic condition. In some children ABPA exacerbations appeared to be seasonal, suggesting possible cross-sensitisation between Aspergillus fumigatus and aeroallergens associated with seasonal AR. Allergic conditions were also common in children with Pseudomonas aeruginosa infection.

Delayed induction of type I and III interferons mediates nasal epithelial cell permissiveness to SARS-CoV-2.

The nasal epithelium is a plausible entry point for SARS-CoV-2, a site of pathogenesis and transmission, and may initiate the host response to SARS-CoV-2. Antiviral interferon (IFN) responses are critical to outcome of SARS-CoV-2. Yet little is known about the interaction between SARS-CoV-2 and innate immunity in this tissue. Here we apply single-cell RNA sequencing and proteomics to a primary cell model of human nasal epithelium differentiated at air-liquid interface. SARS-CoV-2 demonstrates widespread tropism for nasal epithelial cell types. The host response is dominated by type I and III IFNs and interferon-stimulated gene products. This response is notably delayed in onset relative to viral gene expression and compared to other respiratory viruses. Nevertheless, once established, the paracrine IFN response begins to impact on SARS-CoV-2 replication. When provided prior to infection, recombinant IFNß or IFNλ1 induces an efficient antiviral state that potently restricts SARS-CoV-2 viral replication, preserving epithelial barrier integrity. These data imply that the IFN-I/III response to SARS-CoV-2 initiates in the nasal airway and suggest nasal delivery of recombinant IFNs to be a potential chemoprophylactic strategy.