A review of post COVID syndrome pathophysiology, clinical presentation and management in children and young people.

Post Covid Syndrome (PCS) is a complex multi-system disorder with a spectrum of presentations. Severity ranges from mild to very severe with variable duration of illness and recovery. This paper discusses the difficulties defining and describing PCS. We review the current understanding of PCS, epidemiology, and predisposing factors. We consider potential mechanisms including viral persistence, clotting dysfunction and immunity. We review presentation and diagnosis and finally consider management strategies including addressing symptom burden, rehabilitation, and novel therapies.

Case-based discussion: neonates on extracorporeal membrane oxygenation for undiagnosed recalcitrant pulmonary hypertension-management challenges.

We present two neonates requiring extracorporeal membrane oxygenation for undiagnosed recalcitrant pulmonary hypertension, highlighting the clinical and ethical dilemmas in management of very rare diseases.

Exercise induced laryngeal obstruction (EILO) in children and young people: Approaches to assessment and management.

Exercise Induced Laryngeal Obstruction (EILO) is characterised by breathlessness, cough and/or noisy breathing particularly during high intensity exercise. EILO is a subcategory of inducible laryngeal obstruction where exercise is the trigger that provokes inappropriate transient glottic or supraglottic narrowing. It is a common condition affecting 5.7-7.5% of the general population and is a key differential diagnosis for young athletes presenting with exercise related dyspnoea where prevalence rates go as high as 34%. Although the condition has been recognised for a long time, little attention, and awareness of the condition results in many young people dropping out of sporting participation due to troublesome symptoms. With evolving understanding of the condition, diagnostic tests and interventions, this review looks to present the current available evidence and best practice when managing young people with EILO.

Disparities in pulmonary function in healthy children across the Indian urban-rural continuum.

RATIONALE: Marked socioeconomic health-care disparities are recognized in India, but lung health inequalities between urban and rural children have not been studied. OBJECTIVES: We investigated whether differences exist in spirometric pulmonary function in healthy children across the Indian urban-rural continuum and compared results with those from Indian children living in the UK. METHODS: Indian children aged 5 to 12 years were recruited from Indian urban, semiurban, and rural schools, and as part of the Size and Lung Function in Children study, London. Anthropometric and spirometric assessments were undertaken. MEASUREMENTS AND MAIN RESULTS: Acceptable spirometric data were obtained from 728 (58% boys) children in India and 311 (50% boys) UK-Indian children. As an entire group, the India-resident children had significantly lower z FEV1 and z FVC than UK-Indian children (P < 0.0005), when expressed using Global Lung Function Initiative-2012 equations. However, when India-resident children were categorized according to residence, there were no differences in z FEV1 and z FVC between Indian-urban and UK-Indian children. There were, however, significant reductions of ∼ 0.5 z scores and 0.9 z scores in both FEV1 and FVC (with no difference in FEV1/FVC) in Indian-semiurban and Indian-rural children, respectively, when compared with Indian-urban children (P < 0.0005). z Body mass index, socioeconomic circumstances, tobacco, and biomass exposure were individually significantly associated with z FEV1 and z FVC (P < 0.0005). CONCLUSIONS: The presence of an urban-rural continuum of lung function within a specific ethnic group emphasizes the impact of environmental factors on lung growth in emerging nations such as India, which must be taken into account when developing ethnic-specific reference values or designing studies to optimize lung health.

How "healthy" should children be when selecting reference samples for spirometry?

How "healthy" do children need to be when selecting reference samples for spirometry? Anthropometry and spirometry were measured in an unselected, multi-ethnic population of school children aged 5-11 years in London, UK, with follow-up assessments 12 months later. Parents provided information on children's birth data and health status. Forced expiratory volume in 1 s (FEV1) and forced vital capacity (FVC) were adjusted for sex, age, height and ethnicity using the 2012 Global Lungs Initiative equations, and the effects of potential exclusion criteria on the z-score distributions were examined. After exclusions for current and chronic lung disease, acceptable data were available for 1901 children on 2767 occasions. Healthy children were defined as those without prior asthma or hospitalisation for respiratory problems, who were born at full-term with a birthweight ≥2.5 kg and who were asymptomatic at testing. Mean±sd z-scores for FEV1 and FVC approximated 0±1, indicating the 2012 Global Lungs Initiative equations were appropriate for this healthy population. However, if children born preterm or with low birthweight, children with prior asthma or children mildly symptomatic at testing were included in the reference, overall results were similar to those for healthy children, while increasing the sample size by 25%. With the exception of clear-cut factors, such as current and chronic respiratory disease, paediatric reference samples for spirometry can be relatively inclusive and hence more generalisable to the target population.

Lung function in children in relation to ethnicity, physique and socioeconomic factors.

Can ethnic differences in spirometry be attributed to differences in physique and socioeconomic factors?Assessments were undertaken in 2171 London primary schoolchildren on two occasions 1 year apart, whenever possible, as part of the Size and Lung function In Children (SLIC) study. Measurements included spirometry, detailed anthropometry, three-dimensional photonic scanning for regional body shape, body composition, information on ethnic ancestry, birth and respiratory history, socioeconomic circumstances, and tobacco smoke exposure.Technically acceptable spirometry was obtained from 1901 children (mean (range) age 8.3 (5.2-11.8) years, 46% boys, 35% White, 29% Black-African origin, 24% South-Asian, 12% Other/mixed) on 2767 test occasions. After adjusting for sex, age and height, forced expiratory volume in 1 s was 1.32, 0.89 and 0.51 z-score units lower in Black-African origin, South-Asian and Other/mixed ethnicity children, respectively, when compared with White children, with similar decrements for forced vital capacity (p<0.001 for all). Although further adjustment for sitting height and chest width reduced differences attributable to ethnicity by up to 16%, significant differences persisted after adjusting for all potential determinants, including socioeconomic circumstances.Ethnic differences in spirometric lung function persist despite adjusting for a wide range of potential determinants, including body physique and socioeconomic circumstances, emphasising the need to use ethnic-specific equations when interpreting results.

Increased airway smooth muscle in preschool wheezers who have asthma at school age.

BACKGROUND: Increased airway smooth muscle (ASM) is a feature of established asthma in schoolchildren, but nothing is known about ASM in preschool wheezers. OBJECTIVE: We sought to determine endobronchial biopsy specimen ASM area fraction in preschool wheezers and its association with asthma at school age. METHODS: ASM area, reticular basement membrane thickness, and mucosal eosinophil and ASM mast cell values were quantified in endobronchial biopsy specimens previously obtained from preschool children undergoing clinically indicated bronchoscopy: severe recurrent wheezers (n=47; median age, 26 months) and nonwheezing control subjects (n=21; median age, 15 months). Children were followed up, and asthma status was established at age 6 to 11 years. Preschool airway pathology was examined in relation to asthma at school age. RESULTS: Forty-two (62%) of 68 children had 1 or more evaluable biopsy specimens for ASM. At school age, 51 of 68 children were followed up, and 15 (40%) of 37 preschool wheezers had asthma. Children who had asthma and an evaluable biopsy specimen had increased preschool ASM area fraction (n=8; median age, 8.2 years [range, 6-10.4 years]; median ASM, 0.12 [range, 0.08-0.16]) compared with that seen in children without asthma (n=24; median age, 7.3 years [range, 5.9-11 years]; median ASM, 0.07 [range, 0.02-0.23]; P=.007). However, preschool reticular basement membrane thickness and mucosal eosinophil or ASM mast cell values were not different between those who did or did not have asthma at school age. CONCLUSION: Increased preschool ASM is associated with those children who have asthma at school age. Thus a focus on early changes in ASM might be important in understanding the subsequent development of childhood asthma.

Repeatability and bronchodilator reversibility of lung function in young children.

Knowledge of short- and longer-term repeatability of lung function in health and disease is essential to determine bronchodilator reversibility thresholds and to recognise if changes in lung function represent disease progression, therapeutic intervention or normal variability. Multiple-breath washout indices (lung clearance index, conductive ventilation inhomogeneity (Scond)) and specific airway resistance (sRaw) were measured in healthy children and stable wheezers. Measurements were performed at baseline and after 20 min without intervention to assess repeatability and determine bronchodilator reversibility thresholds. Bronchodilator reversibility was assessed by repeating baseline measurements 20 min after inhaled salbutamol. 28 healthy controls, mean±sd age 6.1±0.7 years and 62 wheezers 5.4±0.6 years were tested. Baseline variability in multiple-breath washout indices and sRaw was not significantly different between wheezers and healthy controls. Significant bronchodilator reversibility was only observed in wheezers for Scond (16%), but in both wheezers (37%) and healthy controls (20%) for sRaw. Some wheezers and healthy controls demonstrated increases in multiple-breath washout indices post-bronchodilator. Lung clearance index and sRaw demonstrate low baseline variability in healthy and diseased subjects. Neither multiple-breath washout indices nor sRaw are ideal for assessing bronchodilator reversibility in young children with stable wheeze. These findings will help to interpret the effect of therapeutic interventions in children with respiratory diseases.

Age and height dependence of lung clearance index and functional residual capacity.

The lung clearance index (LCI) is more sensitive than spirometry in detecting abnormal lung function in children with cystic fibrosis. LCI is thought to be independent of age, but recent evidence suggests that the upper limit of normal is higher in infants and preschool children than in older subjects. This study examines whether LCI remains independent of body size throughout childhood. Multiple-breath washout data from healthy children and adolescents were collated from three centres using the mass spectrometer system and the inert gas sulfur hexafluoride. Reference equations for LCI and functional residual capacity (FRC) were constructed using the LMS (lambda-mu-sigma) method. Data were available from 497 subjects (2 weeks to 19 years of age) tested on 659 occasions. LCI was dependent on body size, decreasing in a nonlinear pattern as height increased. Changes were particularly marked in the first 5 years of life. Height, age and sex were all independent predictors of FRC. Minimal between-centre differences allowed unified reference equations to be developed. LCI is not independent of body size. Although a constant upper normal limit would suffice for cross-sectional clinical assessments from 6 years of age, appropriate reference equations are essential for accurate interpretation of results during early childhood.

Consensus statement for inert gas washout measurement using multiple- and single- breath tests.

Inert gas washout tests, performed using the single- or multiple-breath washout technique, were first described over 60 years ago. As measures of ventilation distribution inhomogeneity, they offer complementary information to standard lung function tests, such as spirometry, as well as improved feasibility across wider age ranges and improved sensitivity in the detection of early lung damage. These benefits have led to a resurgence of interest in these techniques from manufacturers, clinicians and researchers, yet detailed guidelines for washout equipment specifications, test performance and analysis are lacking. This manuscript provides recommendations about these aspects, applicable to both the paediatric and adult testing environment, whilst outlining the important principles that are essential for the reader to understand. These recommendations are evidence based, where possible, but in many places represent expert opinion from a working group with a large collective experience in the techniques discussed. Finally, the important issues that remain unanswered are highlighted. By addressing these important issues and directing future research, the hope is to facilitate the incorporation of these promising tests into routine clinical practice.

Advances in the pathogenesis and personalised treatment of paediatric asthma.

The diversity of pathology of severe paediatric asthma demonstrates that the one-size-fits-all approach characterising many guidelines is inappropriate. The term "asthma" is best used to describe a clinical syndrome of wheeze, chest tightness, breathlessness, and sometimes cough, making no assumptions about underlying pathology. Before personalising treatment, it is essential to make the diagnosis correctly and optimise basic management. Clinicians must determine exactly what type of asthma each child has. We are moving from describing symptom patterns in preschool wheeze to describing multiple underlying phenotypes with implications for targeting treatment. Many new treatment options are available for school age asthma, including biological medicines targeting type 2 inflammation, but a paucity of options are available for non-type 2 disease. The traditional reliever treatment, shortacting ß2 agonists, is being replaced by combination inhalers containing inhaled corticosteroids and fast, longacting ß2 agonists to treat the underlying inflammation in even mild asthma and reduce the risk of asthma attacks. However, much decision making is still based on adult data extrapolated to children. Better inclusion of children in future research studies is essential, if children are to benefit from these new advances in asthma treatment.

Evaluation and use of childhood lung function tests in cystic fibrosis.

PURPOSE OF REVIEW: Lung disease begins early in life in cystic fibrosis (CF), yet our understanding of CF lung abnormalities in the first years of life remains limited. By facilitating earlier diagnosis, newborn screening for CF provides the opportunity to understand and characterize presymptomatic lung disease in infants and young children. This could lead to earlier interventions to mitigate disease progression at a time when therapeutic intervention or prevention may be most effective. This article reviews lung function tests that can be used during the first 5 years of life and discusses their potential applications as objective outcomes for clinical monitoring or research. RECENT FINDINGS: During the past decade, commercial equipment for assessing a wide range of lung function tests in infants and preschool children has become available together with international guidelines and improved reference equations with which to interpret results. The lung clearance index, derived from multiple breath washout, has been shown to be far more sensitive to early CF lung disease than conventional spirometric assessments. SUMMARY: Although limited evidence exists as to whether incorporating lung function tests into routine clinical care can improve patient outcomes during the early years, this is likely to be helpful in preschool children if more sensitive tests such as the multiple breath washout become more widely available. There is an urgent need to assess which infant and preschool lung function outcomes will provide the most robust outcome measures in collaborative multicenter studies, so that they can be incorporated into early therapeutic intervention studies.

Frontiers Review: Severe Asthma in Adolescents.

Asthma remains the most prevalent chronic respiratory disease of childhood. Severe asthma accounts for a minority group of patients but with substantial morbidity burden. It may reflect disease which is resistant to treatment or that which is difficult to treat, or a combination of both. The adolescent patient cohort denote a unique group and are the focus of this review. This group of patients embody transitioning priorities and evolving health beliefs, all of which may influence the management and burden of disease. Factors of importance include the influence of physiological parameters such as sex and race, which have confer implications for medical management and non-physiological factors, such as adherence, risk-taking behavior, and vaping. The holistic approach to management of severe asthma within this group of patients must acknowledge the evolving patient independence and desire for autonomy and strive for a collaborative, patient tailored approach. This review will focus on the factors that may pose a challenge to the management of severe adolescent asthma whilst offering suggestions for changes in practice that might harness patient priorities and shared clinical decision-making.

COVID-19 and delivery of difficult asthma services.

The COVID-19 pandemic necessitated an urgent reconfiguration of our difficult asthma (DA) service. We rapidly switched to virtual clinics and rolled out home spirometry based on clinical need. From March to August 2020, 110 patients with DA (68% virtually) were seen in clinic, compared with March-August 2019 when 88 patients were seen face-to-face. There was DA clinic cancellation/non-attendance (16% vs 43%; p<0.0003). In patients with home spirometers, acute hospital admissions (6 vs 26; p<0.01) from March to August 2020 were significantly lower compared with the same period in 2019. There was no difference in the number of courses of oral corticosteroids or antibiotics prescribed (47 vs 53; p=0.81). From April to August 2020, 50 patients with DA performed 253 home spirometry measurements, of which 39 demonstrated >20% decrease in forced expiratory volume in 1 s, resulting in new action plans in 87% of these episodes. In our DA cohort, we demonstrate better attendance rates at virtual multidisciplinary team consultations and reduced hospital admission rates when augmented with home spirometry monitoring.

Symptom-pattern phenotype and pulmonary function in preschool wheezers.

BACKGROUND: Pulmonary function in preschool wheezing phenotypes based on wheeze onset and duration and atopic status has been extensively described but has not been studied in symptom-pattern phenotypes of episodic (viral) and multiple-trigger wheeze. OBJECTIVE: We investigated whether multiple-trigger wheezers were more likely to have abnormal pulmonary function and increased fraction of exhaled nitric oxide (FeNO) than episodic (viral) wheezers and whether multiple-breath wash-out was more sensitive at detecting abnormal pulmonary function than specific airways resistance (sR(aw)) in preschool wheezers. METHODS: FeNO, multiple-breath wash-out indices (lung clearance index [LCI] and conductive airways ventilation inhomogeneity [S(cond)]) and sR(aw) were measured in healthy children and those with recurrent wheeze aged 4 to 6 years. Subgroup analysis was performed according to current symptom-pattern (multiple-trigger vs episodic [viral]), atopic status (atopic vs nonatopic), and wheeze status (currently symptomatic vs asymptomatic). RESULTS: Seventy-two control subjects and 62 wheezers were tested. Multiple-trigger wheezers were associated with an average increase of 11% (95% CI, 7% to 18%; P < .001) in LCI, 211% (95% CI, 70% to 470%; P < .001) in S(cond), and 15% (95% CI, 3% to 28%; P = .01) in sR(aw) compared with episodic (viral) wheezers. Pulmonary function in episodic (viral) wheezers did not differ significantly from control subjects. The presence of current atopy or wheeze was associated with higher FeNO (P = .05) but did not influence pulmonary function significantly. On average, LCI was abnormal in 39% (95% CI, 32% to 45%), S(cond) was abnormal in 68% (95% CI, 61% to 74%), and sR(aw) was abnormal in 26% (95% CI, 16% to 35%) of multiple-trigger wheezers. CONCLUSIONS: Multiple-trigger wheeze is associated with pulmonary function abnormalities independent of atopic and current wheeze status. S(cond) is the most sensitive indicator of abnormal pulmonary function in preschool wheezers.

Paediatric severe asthma biologics service: from hospital to home.

Children with severe asthma may be treated with biologic agents normally requiring 2-4 weekly injections in hospital. In March 2020, due to COVID-19, we needed to minimise hospital visits. We assessed whether biologics could be given safely at home. The multidisciplinary team identified children to be considered for home administration. This was virtually observed using a video link, and home spirometry was also performed. Feedback was obtained from carers and young people. Of 23 patients receiving biologics, 16 (70%) families agreed to homecare administration, 14 administered by parents/patients and 2 by a local nursing team. Video calls for omalizumab were observed on 56 occasions, mepolizumab on 19 occasions over 4 months (April-July). Medication was administered inaccurately on 2/75 occasions without any adverse events. Virtually observed home biologic administration in severe asthmatic children, supported by video calls and home spirometry, is feasible, safe and is positively perceived by children and their families.