Striving for perfection, accepting the reality: A reflection on adherence to airway clearance and inhalation therapy for paediatric patients with chronic suppurative lung disease.

Non-adherence to prescribed treatment is considered the foremost cause of treatment failure in chronic medical conditions. Airway clearance techniques (ACT) play a key role in the management of chronic suppurative lung disease yet, along with inhaled therapies such as nebulised antibiotics, adherence to these is often lower than to other treatments. In this review we discuss methods of monitoring adherence to these therapies and potential barriers and outline suggestions for improving adherence in the paediatric population.

Screening for sleep-disordered breathing with Pediatric Sleep Questionnaire in children with underlying conditions.

The Pediatric Sleep Questionnaire described by Chervin et al. (Sleep Medicine, 2000, 1, 21-32) was originally validated for children with obstructive sleep apnoea syndrome but without other disorders. The aim of our study was to check the applicability of this questionnaire in children with underlying chronic medical conditions. Children aged 2-18 years who underwent a diagnostic sleep study at Great Ormond Street Hospital were recruited over a 10-month period. The Pediatric Sleep Questionnaire completed by their parents and cardiorespiratory polygraphy were scored. Sensitivities and specificities of the Pediatric Sleep Questionnaire were calculated using a Pediatric Sleep Questionnaire score of 0.33 as being indicative of sleep-disordered breathing. A total of 561 patients were reviewed. Neuromuscular disorders (n = 108), craniofacial anomalies (n = 58) and the obstructive sleep apnea syndrome control group (n = 155) were best represented. The sensitivity for patients with isolated obstructive sleep apnoea syndrome was 76.5% when using an apnoea-hypopnoea index ≥ 5, but this was much lower when looking at specific sub-groups such as neuromuscular patients (25%) or patients with Trisomy 21 (36.7%). Sensitivities remained unchanged for patients with obstructive sleep apnoea syndrome (77.3%) when an apnoea-hypopnoea index of ≥ 1 was used, but improved for neuromuscular disorders sub-groups (36.7%) and Trisomy 21 (84%). In conclusion, the Pediatric Sleep Questionnaire is not a good screening tool for obstructive sleep apnoea syndrome in children with complex underlying disorders when a cut-off apnoea-hypopnoea index of ≥ 5 is used, and it cannot replace cardiorespiratory polygraphy recording.

Antipseudomonal Bacteriophage Reduces Infective Burden and Inflammatory Response in Murine Lung.

As antibiotic resistance increases, there is a need for new therapies to treat infection, particularly in cystic fibrosis (CF), where Pseudomonas aeruginosa is a ubiquitous pathogen associated with increased morbidity and mortality. Bacteriophages are an attractive alternative treatment, as they are specific to the target bacteria and have no documented side effects. The efficacy of phage cocktails was established in vitro. Two P. aeruginosa strains were taken forward into an acute murine infection model with bacteriophage administered either prophylactically, simultaneously, or postinfection. The infective burden and inflammation in bronchoalveolar lavage fluid (BALF) were assessed at various times. With low infective doses, both control mice and those undergoing simultaneous phage treatment cleared P. aeruginosa infection at 48 h, but there were fewer neutrophils in BALF of phage-treated mice (median, 73.2 × 10(4)/ml [range, 35.2 to 102.1 × 10(4)/ml] versus 174 × 10(4)/ml [112.1 to 266.8 × 10(4)/ml], P < 0.01 for the clinical strain; median, 122.1 × 10(4)/ml [105.4 to 187.4 × 10(4)/ml] versus 206 × 10(4)/ml [160.1 to 331.6 × 10(4)/ml], P < 0.01 for PAO1). With higher infective doses of PAO1, all phage-treated mice cleared P. aeruginosa infection at 24 h, whereas infection persisted in all control mice (median, 1,305 CFU/ml [range, 190 to 4,700 CFU/ml], P < 0.01). Bacteriophage also reduced CFU/ml in BALF when administered postinfection (24 h) and both CFU/ml and inflammatory cells in BALF when administered prophylactically. A reduction in soluble inflammatory cytokine levels in BALF was also demonstrated under different conditions. Bacteriophages are efficacious in reducing both the bacterial load and inflammation in a murine model of P. aeruginosa lung infection. This study provides proof of concept for future clinical trials in patients with CF.

Severe pulmonary exacerbation in cystic fibrosis caused by cat allergy.

This paper describes a preschool child who had persistent symptoms suggestive of significant cystic fibrosis lung disease over a period of eighteen months following first isolation of Pseudomonas aeruginosa. Despite vigorous anti-infective treatment and extensive investigations seeking undetected infection, improvement only occurred once severe cat allergy was diagnosed and cats were removed from the household. Whilst infection is the most common cause of respiratory exacerbations in cystic fibrosis, this article serves as a reminder that it is important to consider non-infective pathologies when the response to anti-infective treatment is unexpectedly poor.

COVID-19 in patients with pulmonary alveolar proteinosis: a European multicentre study.

Adult PAP patients experience similar #COVID19 rates to the general population, and high rates of hospitalisation and deaths, underscoring their vulnerability and the need for measures to prevent infection. The impact of iGM-CSF must be considered. https://bit.ly/3M0wKnZ.

Feasibility and efficacy of active remote monitoring of home ventilation in pediatrics.

BACKGROUND: Non-invasive positive airway pressure (PAP) therapy is used to treat children with sleep-disordered breathing. Effective management requires good adherence. In response to the problem of reduced adherence over time, a pilot study using ventilators equipped with technology to remotely monitor home adherence was undertaken. METHODS: From July 2019, children requiring PAP therapy consented for remote monitoring. Data collected included ventilator usage, apnea-hypopnea index (AHI), and mask leak. Parents were contacted on Days 14, 42, and 90 post-establishment. A proforma was used to assess parental understanding and ways to improve therapy adherence. A parental feedback questionnaire was completed on Day 90 of the study. RESULTS: Median nightly PAP usage over 90-day post-establishment was 6.58 h (interquartile range: 2.47-8.62); 60% of patients met criteria for good adherence (>4 h for >70% of nights). There was a decrease in median nightly usage in Week 1 (6.92 h) versus Week 12 (6.15 h), p = 0.04. Mask leak was higher in Week 1 (17.7 L/min) versus Week 12 (14.7 L/min), p = 0.053. There was no significant difference in AHI between Week 1 (2.7/h) versus Week 12 (2.3/h), p = 0.75. 45% of questionnaire respondents felt active remote monitoring positively influenced PAP usage, whilst 84% reported overall satisfaction with PAP therapy. CONCLUSIONS: Remote monitoring technology has the potential to guide adjustments in PAP therapy, monitor and improve adherence in children, and reduce the burden of hospital-based review. Preliminary work shows high approval from parents.

Pulmonary alveolarproteinosis in children.

Pulmonary alveolar proteinosis (PAP) is an umbrella term for a wide spectrum of conditions that have a very characteristic appearance on computed tomography. There is outlining of the secondary pulmonary lobules on the background of ground-glass shadowing and pathologically, filling of the alveolar spaces with normal or abnormal surfactant. PAP is rare and the common causes in children are very different from those seen in adults; autoimmune PAP is rare and macrophage blockade not described in children. There are many genetic causes of PAP, the best known of which are mutations in the genes encoding surfactant protein (SP)-B, SP-C, thyroid transcription factor 1, ATP-binding cassette protein 3, and the granulocyte-macrophage colony-stimulating factor (GM-CSF) receptor α- and ß- chains. PAP may also be a manifestation of rheumatological and metabolic disease, congenital immunodeficiency, and haematological malignancy. Precise diagnosis of the underlying cause is essential in planning treatment, as well as for genetic counselling. The evidence base for treatment is poor. Some forms of PAP respond well to whole-lung lavage, and autoimmune PAP, which is much commoner in adults, responds to inhaled or subcutaneous GM-CSF. Emerging therapies based on studies in murine models of PAP include stem-cell transplantation for GM-CSF receptor mutations. EDUCATIONAL AIMS: To understand when to suspect that a child has pulmonary alveolar proteinosis (PAP) and how to confirm that this is the cause of the presentation.To show that PAP is an umbrella term for conditions characterised by alveolar filling by normal or abnormal surfactant, and that this term is the start, not the end, of the diagnostic journey.To review the developmental differences in the spectrum of conditions that may cause PAP, and specifically to understand the differences between causes in adults and children.To discuss when to treat PAP with whole-lung lavage and/or granulocyte-macrophage colony-stimulating factor, and review potential promising new therapies.

Interstitial lung disease in infancy.

There is a wide differential diagnosis of early onset respiratory distress especially in term babies, and interstitial lung disease (chILD) is a rare but important consideration in this context. chILD manifesting immediately after birth is usually related to mutations in surfactant protein genes, or conditions related to the Congenital Acinar Dysplasia -Alveolar capillary dysplasia - Congenital Alveolar Dysplasia (CAD-ACD) spectrum. There is currently no specific treatment for these conditions, and management is supportive. Prognosis is very poor in most of these babies if onset is early, with relentless respiratory deterioration unless transplanted. Ideally, the diagnosis is made on genetic analysis, but this may be time-consuming and complex in CAD-ACD spectrum, so lung biopsy may be needed to avoid prolonged and futile treatment being instituted. Milder forms with prolonged survival have been reported. Early onset, less severe chILD is usually related to neuroendocrine cell hyperplasia of infancy (NEHI), pulmonary interstitial glycogenosis (PIG) and less severe disorders of surfactant proteins. PIG and NEHI are not specific entities, but are pulmonary dysmaturity syndromes, and there may be a number of underlying genetic and other cause. If the child is stable and thriving, many will not be subject to lung biopsy, and slow improvement and weaning of supplemental oxygen can be anticipated. Where possible, a precise genetic diagnosis should be made in early onset cHILD allow for genetic counselling. chILD survivors and their families have complex respiratory and other needs, and co-ordinated, multi-disciplinary support in the community is essential.

Pooling of bronchoalveolar lavage in children with cystic fibrosis does not adversely affect the microbiological yield or sensitivity in detecting pulmonary inflammation.

BACKGROUND: Bronchoalveolar lavage (BAL) is a potentially useful outcome measure for clinical trials in children with CF but its use is limited by variations in approach internationally. We sought to determine if pooling adversely affected the diagnostic properties of BAL. METHODS: Children undergoing bronchoscopy for clinical reasons were included. A multi-step study protocol ensured BAL was collected and analysed both separately and as a pooled fluid. RESULTS: Eighty-five children (53 CF, 32 control) were recruited. There was a high level of concordance between pooled and non-pooled samples in terms of organism identification (76%). There was good agreement (Bland Altman) between the two methods in terms of detection of inflammation independent of centre, microbiological concordance or disease status. Bi-directional variability in IL-8 levels between pooled and non-pooled samples was seen. Free neutrophil elastase (NE) was detected in 4 cases in pooled lavage when absent in non-pooled lavage. Levels of interleukin-8 (IL-8) were similar between the two groups with pooled samples showing a greater spread of values. CONCLUSIONS: Pooling of BAL in children does not negatively impact on either the detection of pulmonary infection or inflammation or the observed relationship between infection and inflammation. Intra-patient variability in BAL IL-8 levels suggests regional differences in inflammation.

Pseudomonas aeruginosa infection in cystic fibrosis: pathophysiological mechanisms and therapeutic approaches.

Pseudomonas aeruginosa is a remarkably versatile environmental bacterium with an extraordinary capacity to infect the cystic fibrosis (CF) lung. Infection with P. aeruginosa occurs early, and although eradication can be achieved following early detection, chronic infection occurs in over 60% of adults with CF. Chronic infection is associated with accelerated disease progression and increased mortality. Extensive research has revealed complex mechanisms by which P. aeruginosa adapts to and persists within the CF airway. Yet knowledge gaps remain, and prevention and treatment strategies are limited by the lack of sensitive detection methods and by a narrow armoury of antibiotics. Further developments in this field are urgently needed in order to improve morbidity and mortality in people with CF. Here, we summarize current knowledge of pathophysiological mechanisms underlying P. aeruginosa infection in CF. Established treatments are discussed, and an overview is offered of novel detection methods and therapeutic strategies in development.