Association between socioeconomic deprivation, ethnicity and health outcomes in preschool children with recurrent wheeze in England: a retrospective cohort study.

BACKGROUND: Preschool-aged children have among the highest burden of acute wheeze. We investigated differences in healthcare use, treatment and outcomes for recurrent wheeze/asthma in preschoolers from different ethno-socioeconomic backgrounds. METHODS: Retrospective cohort study using data from the Clinical Practice Research Datalink linked to Hospital Episode Statistics in England. We reported number of acute presentations and hospitalisations stratified by index of multiple deprivation (IMD) and ethnicity; and factors associated with treatment non-escalation, and hospitalisation rates using multivariable logistic and Poisson regression models. RESULTS: 194 291 preschool children were included. In children not trialled on asthma preventer medications, children from the most deprived IMD quintile (adjusted OR 1.67; 95% CI 1.53 to 1.83) and South Asian (1.77; 1.64 to 1.91) children were more likely to have high reliever usage and where specialist referral had not occurred, the odds of referral being indicated was higher in the most deprived quintile (1.39; 1.28 to 1.52) and South Asian (1.86; 1.72 to 2.01) children compared with the least deprived quintile and white children, respectively.Hospitalisation rates for wheeze/asthma were significantly higher in children from the most deprived quintile (adjusted IRR 1.20; 95% CI 1.13 to 1.27) compared with the least, and in South Asian (1.57; 1.44 to 1.70) and black (1.32; 1.22 to 1.42) compared with white children. CONCLUSIONS: We identified inequalities in wheeze/asthma treatment and morbidity in preschool children from more deprived, and non-white backgrounds. A multifaceted approach to tackle health inequality at both the national and local levels, which includes a more integrated and standardised approach to treatment, is needed to improve health outcomes in children with preschool wheeze/asthma.

Development of Core Outcome Measures sets for paediatric and adult Severe Asthma (COMSA).

BACKGROUND: Effectiveness studies with biological therapies for asthma lack standardised outcome measures. The COMSA (Core Outcome Measures sets for paediatric and adult Severe Asthma) Working Group sought to develop Core Outcome Measures (COM) sets to facilitate better synthesis of data and appraisal of biologics in paediatric and adult asthma clinical studies. METHODS: COMSA utilised a multi-stakeholder consensus process among patients with severe asthma, adult and paediatric clinicians, pharmaceutical representatives, and health regulators from across Europe. Evidence included a systematic review of development, validity and reliability of selected outcome measures plus a narrative review and a pan-European survey to better understand patients' and carers' views about outcome measures. It was discussed using a modified GRADE (Grading of Recommendations Assessment, Development and Evaluation) Evidence to Decision framework. Anonymous voting was conducted using predefined consensus criteria. RESULTS: Both adult and paediatric COM sets include forced expiratory volume in 1 s (FEV1) as z-scores, annual frequency of severe exacerbations and maintenance oral corticosteroid use. Additionally, the paediatric COM set includes the Paediatric Asthma Quality of Life Questionnaire and Asthma Control Test or Childhood Asthma Control Test, while the adult COM set includes the Severe Asthma Questionnaire and Asthma Control Questionnaire-6 (symptoms and rescue medication use reported separately). CONCLUSIONS: This patient-centred collaboration has produced two COM sets for paediatric and adult severe asthma. It is expected that they will inform the methodology of future clinical trials, enhance comparability of efficacy and effectiveness of biological therapies, and help assess their socioeconomic value. COMSA will inform definitions of non-response and response to biological therapy for severe asthma.

Rhinovirus persistence during the COVID-19 pandemic-Impact on pediatric acute wheezing presentations.

Rhinoviruses have persisted throughout the COVID-19 pandemic, despite other seasonal respiratory viruses (influenza, parainfluenza, respiratory syncytial virus, adenoviruses, human metapneumovirus) being mostly suppressed by pandemic restrictions, such as masking and other forms of social distancing, especially during the national lockdown periods. Rhinoviruses, as nonenveloped viruses, are known to transmit effectively via the airborne and fomite route, which has allowed infection among children and adults to continue despite pandemic restrictions. Rhinoviruses are also known to cause and exacerbate acute wheezing episodes in children predisposed to this condition. Noninfectious causes such as air pollutants (PM2.5 , PM10 ) can also play a role. In this retrospective ecological study, we demonstrate the correlation between UK national sentinel rhinovirus surveillance, the level of airborne particulates, and the changing patterns of pediatric emergency department presentations for acute wheezing, before and during the COVID-19 pandemic (2018-2021) in a large UK teaching hospital.

Sputum biomarkers during acute severe asthma attacks in children-a case-control study.

AIM: To study sputum mediator profiles pattern in children with acute severe asthma, compared with stable asthma and healthy controls. The mechanisms of acute severe asthma attacks, such as biomarkers cascades and immunological responses, are poorly understood. METHODS: We conducted a prospective observational case-control study of children aged 5 to 17 years, who presented to hospital with an asthma attack. Children with stable asthma were recruited during outpatient asthma clinic visits. Control children without an asthma diagnosis were recruited from surgical wards. Sputum mediator profiles were measured, and sputum leukocyte differential cell counts were generated. RESULTS: Sputum data were available in 48 children (acute asthma; n = 18, stable asthma; n = 17, healthy controls; n = 13). Acute-phase biomarkers and neutrophil attractants such as IL-6 and its receptor, IL-8 and cytokines linked with bacterial signals, including TNF-R1 and TNF-R2, were elevated in asthma attacks versus stable asthma and healthy controls. T-cell attractant cytokines, associated with viral infections, such as CCL-5, CXCL-10 and CXCL-11, and CXCL-9 (secreted from eosinophils after a viral trigger) were also raised. CONCLUSION: Mediator profiles consistent with bacterial and viral respiratory infections, and T2 inflammation markers co-exist in the sputum of children with acute severe asthma attacks.

European Respiratory Society clinical practice guidelines for the diagnosis of asthma in children aged 5-16†years.

BACKGROUND: Diagnosing asthma in children represents an important clinical challenge. There is no single gold-standard test to confirm the diagnosis. Consequently, over- and under-diagnosis of asthma is frequent in children. METHODS: A task force supported by the European Respiratory Society has developed these evidence-based clinical practice guidelines for the diagnosis of asthma in children aged 5-16 years using nine Population, Intervention, Comparator and Outcome (PICO) questions. The task force conducted systematic literature searches for all PICO questions and screened the outputs from these, including relevant full-text articles. All task force members approved the final decision for inclusion of research papers. The task force assessed the quality of the evidence using the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach. RESULTS: The task force then developed a diagnostic algorithm based on the critical appraisal of the PICO questions, preferences expressed by lay members and test availability. Proposed cut-offs were determined based on the best available evidence. The task force formulated recommendations using the GRADE Evidence to Decision framework. CONCLUSION: Based on the critical appraisal of the evidence and the Evidence to Decision framework, the task force recommends spirometry, bronchodilator reversibility testing and exhaled nitric oxide fraction as first-line diagnostic tests in children under investigation for asthma. The task force recommends against diagnosing asthma in children based on clinical history alone or following a single abnormal objective test. Finally, this guideline also proposes a set of research priorities to improve asthma diagnosis in children in the future.

Fungal sensitization and positive fungal culture from sputum in children with asthma are associated with reduced lung function and acute asthma attacks respectively.

BACKGROUND: Sensitization to thermotolerant fungi, including filamentous fungi and Candida albicans, is associated with poor lung function in adults with severe asthma. Data in children are lacking. Environmental exposure to fungi is linked with acute severe asthma attacks, but there are few studies reporting the presence of fungi in the airways during asthma attacks. METHODS: We investigated the association between fungal sensitization and/or positive fungal sputum culture and markers of asthma severity in children with chronic and acute asthma. Sensitization was determined using serum-specific IgE and skin prick testing against a panel of five fungi. Fungal culture was focused towards detection of filamentous fungi from sputum samples. RESULTS: We obtained sensitization data and/or sputum from 175 children: 99 with chronic asthma, 39 with acute asthma and 37 controls. 34.1% of children with chronic asthma were sensitized to thermotolerant fungi compared with no children without asthma (p =< 0.001). These children had worse pre-bronchodilator lung function compared with asthmatics without sensitization including a lower FEV1 /FVC ratio (p < .05). The isolation rate of filamentous fungi from sputum was higher in children with acute compared with chronic asthma. CONCLUSIONS: Fungal sensitization is a feature of children with chronic asthma. Children sensitized to thermotolerant fungi have worse lung function, require more courses of systemic corticosteroids and have greater limitation of activities due to asthma. Asthma attacks in children were associated with the presence of filamentous fungi positive sputum culture. Mechanistic studies are required to establish whether fungi contribute directly to the development of acute asthma.

Ventilation heterogeneity in children with severe asthma.

Small airway disease, characterised by ventilation heterogeneity (VH), is present in a subgroup of patients with asthma. Ventilation heterogeneity can be measured using multiple breath washout testing. Few studies have been reported in children. We studied the relationship between VH, asthma severity, and spirometry in a cross-sectional observational cohort study involving children with stable mild-moderate and severe asthma by GINA classification and a group of healthy controls. Thirty-seven participants aged 5-16 years completed multiple breath nitrogen washout (MBNW) testing (seven controls, seven mild-moderate asthma, 23 severe asthma). The lung clearance index (LCI) was normal in control and mild-moderate asthmatics. LCI was abnormal in 5/23 (21%) of severe asthmatics. The LCI negatively correlated with FEV1 z-score.Conclusion: VH is present in asthmatic children and appears to be more common in severe asthma. The LCI was significantly higher in the cohort of children with severe asthma, despite no difference in FEV1 between the groups. This supports previous evidence that LCI is a more sensitive marker of airway disease than FEV1. MBNW shows potential as a useful tool to assess children with severe asthma and may help inform clinical decisions. What is Known: • Increased ventilation heterogeneity is present in some children with asthma • Spirometry is not sensitive enough to detect small airway involvement in asthma What is New • Lung clearance index is abnormal in a significant subgroup of children with severe asthma but rarely in children with mild-moderate asthma • Our data suggests that LCI monitoring should be considered in children with severe asthma.

LabPipe: an extensible bioinformatics toolkit to manage experimental data and metadata.

BACKGROUND: Data handling in clinical bioinformatics is often inadequate. No freely available tools provide straightforward approaches for consistent, flexible metadata collection and linkage of related experimental data generated locally by vendor software. RESULTS: To address this problem, we created LabPipe, a flexible toolkit which is driven through a local client that runs alongside vendor software and connects to a light-weight server. The toolkit allows re-usable configurations to be defined for experiment metadata and local data collection, and handles metadata entry and linkage of data. LabPipe was piloted in a multi-site clinical breathomics study. CONCLUSIONS: LabPipe provided a consistent, controlled approach for handling metadata and experimental data collection, collation and linkage in the exemplar study and was flexible enough to deal effectively with different data handling challenges.

Lung function and asthma control in school-age children managed in UK primary care: a cohort study.

BACKGROUND: Spirometry and fraction of exhaled nitric oxide (FeNO) are commonly used in specialist centres to monitor children with asthma. The National Institute for Health and Care Excellence recommends spirometry for asthma monitoring from 5 years in all healthcare settings. There is little spirometry and FeNO data in children managed for asthma in UK primary care to support their use. OBJECTIVES: To study the prevalence of abnormal spirometry and FeNO in children with asthma managed in primary care and to explore their relationship with asthma control and unplanned healthcare attendances (UHA). METHODS: Prospective observational cohort study in children aged 5-16 years with suspected or doctor-diagnosed asthma attending an asthma review in UK general practice. Spirometry, FeNO, asthma control test (ACT) scores and number of UHAs were studied. RESULTS: Of 612 children from 10 general practices, 23.5% had abnormal spirometry, 36.0% had raised FeNO ≥35 parts per billion and 41.8% reported poor control. Fifty-four per cent of children reporting good asthma control had abnormal spirometry and/or raised FeNO. At follow-up, the mean number of UHAs fell from 0.31/child in the 6 months preceding review to 0.20/child over the 6 months following review (p=0.0004). Median ACT scores improved from 20 to 22 (p=0.032), and children's ACT from 21 to 23 (p<0.0001). CONCLUSIONS: Abnormal lung function and FeNO are common in children attending for asthma review in primary care and relate poorly to symptom scores. A symptoms-based approach to asthma monitoring without objective testing is likely to miss children at high risk of future severe asthma attacks.

Posaconazole therapy in children with cystic fibrosis and Aspergillus-related lung disease.

There is emerging evidence for the role of posaconazole in the management of Aspergillus-related cystic fibrosis (CF) lung disease. The tolerability and efficacy of posaconazole in paediatric CF is not well established. We report a prospective study over a fifty-three month period evaluating the safety, tolerability, and efficacy of posaconazole in pediatric CF. Fourteen children (seven males, median age 13 years, range 3-17 years) received a total of twenty-three courses of posaconazole (13 oral suspension and 10 tablet formulation). Of these patient episodes, nine received posaconazole for emerging or active allergic bronchopulmonary aspergillosis (ABPA) and two required a combination of posaconazole and systemic corticosteroids for difficult-to-treat ABPA. A subgroup of patients (n = 12) with persistent isolates of Aspergillus fumigatus, in the absence of serological markers of ABPA, received posaconazole monotherapy for pulmonary exacerbations not responding to conventional broad-spectrum antibiotic treatment. Posaconazole levels, full blood count, electrolytes, and liver function were monitored on day 7 of treatment and then monthly. Posaconazole was well tolerated in all but three patients. Therapeutic plasma levels >1 mg/l were achieved in all receiving the tablet formulation in comparison to 60% on the liquid preparation. There was a modest but significant improvement in FEV1 (% predicted) demonstrated for the cohort as a whole (p = 0.015) following posaconazole therapy. Posaconazole is well tolerated in children as young as six years old, improvements in lung function are observed, and therapeutic plasma levels are readily achieved in patients taking the tablet formulation and in adherent patients taking the liquid formulation.

The role of objective tests to support a diagnosis of asthma in children.

In many healthcare settings asthma in children is a clinical diagnosis based on parental reported symptoms. These include intermittent episodes of wheezing, breathlessness and periodic nocturnal dry cough. Increased symptoms often coincide with colds. Confirming a diagnosis of asthma in children can be difficult and recent reports highlight that misdiagnosis, including over- and under-diagnosis of asthma are common. Recent UK National Institute of Health and Care Excellence guidelines recommend diagnostic algorithms for children from five years and adults to support a clinical suspicion of asthma. Spirometry, bronchodilator reversibility and fractional exhaled nitric oxide testing are the first line tests to diagnose asthma in children. The introduction of these tests across all healthcare settings has the potential to reduce misdiagnosis, improve asthma management and reduce healthcare spending for asthma.

Processing small sputum samples: a method validation study.

Background: Eosinophilia is frequently a feature of asthma. Sputum analysis can help with the diagnosis and phenotyping of asthma. The current gold standard method is unsuitable for samples <100 mg. However, children frequently produce samples below this threshold.Aim: To compare and validate our modified, small sample (>10 mg and <100 mg) sputum processing method (which omits sample filtering), with the current gold standard. Method: Prospective study of 32 adults with severe asthma providing sputum samples of sufficient size for dual processing. Results: The median (IQR) sample weight was 211.0 (162.4-185.5) mg and 57.5 (22.0-61.6) mg for standard, and small sputum sample processing respectively. There was no statistically significant difference in the median (IQR) cell counts between Method A and B, respectively: eosinophils 3.8% (1.5-14.0) versus 4.9% (1.3-15.5); neutrophils 78.1% (46.5-92.4) versus 65.0% (48.3-86.6). Conclusion: The small sputum sample processing is feasible and reliable, and yields similar results to standard processing.

High prevalence of bronchiectasis on chest CT in a selected cohort of children with severe Asthma.

BACKGROUND: Chest computed tomography (CT) scans have a recognised role in investigating adults with severe asthma to exclude alternative diagnoses, but its role in children is less clear. The objective of this study was to review the CT findings of our local cohort of children with severe asthma and to explore whether clinical or pathobiological parameters predicted CT changes. METHODS: Retrospective observational single centre study including all children attending the Leicester difficult asthma clinic (DAC) who underwent a chest CT from 2006 to 2011. Additionally, we recruited eight age-matched, non-asthmatic controls to compare differences in CT findings between asthmatic and non-asthmatic children. All CT images were independently scored by two radiologists. The DAC patients were sub-divided into binary groups for each abnormality identified so that comparisons could be made against recorded clinical variables including age, lung function, serum total IgE levels, and sputum leukocyte differential cell counts. RESULTS: Thirty DAC patients (median 12 yrs., range 5-16) were included. The most common abnormalities were bronchial wall thickening (BWT) and air trapping (AT), observed in 80 and 60% of DAC patients. Bronchiectasis (BE) was identified in 27% of DAC patients. DAC patients with evidence of BE on CT images were older than those without BE (13.9 ± 0.67 vs 11.5 ± 0.61, p = 0.038). We also identified a positive correlation between increasing BE severity and extent with age (r = 0.400, p = 0.028). CONCLUSION: Abnormal CT findings were highly prevalent in our cohort of children with severe asthma, with bronchiectasis identified in approximately one third of children. We found no alternative diagnoses that resulted in a change in clinical management.

Severe exacerbations in moderate-to-severe asthmatics are associated with increased pro-inflammatory and type 1 mediators in sputum and serum.

BACKGROUND: Asthma is a heterogeneous disease and understanding this heterogeneity will enable the realisation of precision medicine. We sought to compare the sputum and serum inflammatory profiles in moderate-to-severe asthma during stable disease and exacerbation events. METHODS: We recruited 102 adults and 34 children with asthma. The adults were assessed at baseline, 3, 6, and 12-month follow-up visits. Thirty-seven subjects were assessed at onset of severe exacerbation. Forty sputum mediators and 43 serum mediators were measured. Receiver-operator characteristic (ROC) curves were constructed to identify mediators that distinguish between stable disease and exacerbation events. The strongest discriminating sputum mediators in the adults were validated in the children. RESULTS: The mediators that were significantly increased at exacerbations versus stable disease and by ≥1.5-fold were sputum IL-1ß, IL-6, IL-6R, IL-18, CXCL9, CXCL10, CCL5, TNFα, TNF-R1, TNF-R2, and CHTR and serum CXCL11. No mediators decreased ≥1.5-fold at exacerbation. The strongest discriminators of an exacerbation in adults (ROC area under the curve [AUC]) were sputum TNF-R2 0.69 (95% CI: 0.60 to 0.78) and IL-6R 0.68 (95% CI: 0.58 to 0.78). Sputum TNF-R2 and IL-6R were also discriminatory in children (ROC AUC 0.85 [95% CI: 0.71 to 0.99] and 0.80 [0.64 to 0.96] respectively). CONCLUSIONS: Severe asthma exacerbations are associated with increased pro-inflammatory and Type 1 (T1) immune mediators. In adults, sputum TNF-R2 and IL-6R were the strongest discriminators of an exacerbation, which were verified in children.

Case presentation: persistent adenovirus B3 infections associated with bronchiolitis obliterans treated with cidofovir in a child with mosaic tetrasomy 9p.

BACKGROUND: Adenoviruses (AdV) are non-enveloped, double-stranded DNA viruses with multiple serotypes, which cause a variety of end-organ disease in both immunocompetent and immunocompromised individuals. Some adenoviruses can become latent in the mucosa-associated lymphoid tissue (e.g. adenoids and tonsils), with the potential to reactivate sporadically, leading to upper or lower respiratory tract infection and disease. Bronchiolitis Obliterans (BO) is a rare chronic lung disorder which usually follows a severe insult to the respiratory tract. In children, it is a complication of severe infections (as post-infectious BO), typically manifesting after a severe respiratory infection, in previously healthy pre-school children. Symptoms and signs of air trapping (hyperinflated chest, expiratory wheeze) with persistent oxygen requirement are characteristic. The presence of the unusual mosaic tetrasomy 9p genotype in this case, despite standard cidofovir therapy for persistent or chronic adenovirus infection, may have impacted on the child's long-term clinical outcomes. CASE PRESENTATION: We present a case of persistent AdV B3 infection in a 14-month old boy with mosaic tetrasomy 9p, which persisted for 10 weeks, resulting in radiologically-confirmed BO, requiring cidofovir to control the persistent AdV B3 infection and standard therapy with pulsed steroids. We argue that in the presence of the mosaic tetrasomy 9p, earlier antiviral therapy may have decreased the severity of BO, as this mutation is known to be associated with some degree of immune dysregulation. CONCLUSIONS: Adenovirus infections are common in children and may persist as latent infections, with subsequent reactivations during loss of immune control, related to systemic illness arising from other causes. In chronic, reactivated AdV infection with pneumonia, BO is a recognised complication. However, in this case, with the presence of the mosaic tetrasomy 9p mutation, earlier antiviral therapy may have reduced such longer term complications, due to the immune dysregulatory nature of this mutation.

Temporal stability of multitrigger and episodic viral wheeze in early childhood.

The distinction between episodic viral wheeze (EVW) and multitrigger wheeze (MTW) is used to guide management of preschool wheeze. It has been questioned whether these phenotypes are stable over time. We examined the temporal stability of MTW and EVW in two large population-based cohorts.We classified children from the Avon Longitudinal Study of Parents and Children (n=10 970) and the Leicester Respiratory Cohorts ((LRCs), n=3263) into EVW, MTW and no wheeze at ages 2, 4 and 6 years based on parent-reported symptoms. Using multinomial regression, we estimated relative risk ratios for EVW and MTW at follow-up (no wheeze as reference category) with and without adjusting for wheeze severity.Although large proportions of children with EVW and MTW became asymptomatic, those that continued to wheeze showed a tendency to remain in the same phenotype: among children with MTW at 4 years in the LRCs, the adjusted relative risk ratio was 15.6 (95% CI 8.3-29.2) for MTW (stable phenotype) compared to 7.0 (95% CI 2.6-18.9) for EVW (phenotype switching) at 6 years. The tendency to persist was weaker for EVW and from 2-4 years. Results were similar across cohorts.This suggests that MTW, and to a lesser extent EVW, tend to persist regardless of wheeze severity.

Chronic Aspergillus fumigatus colonization of the pediatric cystic fibrosis airway is common and may be associated with a more rapid decline in lung function.

Filamentous fungi are commonly isolated from the respiratory tract of CF patients, but their clinical significance is uncertain and the reported incidence variable. We report on the degree of Aspergillus fumigatus airway colonization in a tertiary pediatric CF cohort, evaluate the sensitivity of routine clinical sampling at detecting A. fumigatus, and compare lung function of A. fumigatus-colonized and non-colonized children.We carried out an 8-year retrospective cohort analysis using local databases, examining 1024 respiratory microbiological specimens from 45 children. Nineteen (42%) had a positive A. fumigatus culture at least once during the 8-year period, with 10 (22%) children persistently colonized. Overall, 29% of 48 bronchoalveolar lavage (BAL) samples tested positive for A. fumigatus, compared with 14% of 976 sputum samples. Of 33 children for whom lung function data were available during the study period, seven were classed as having severe lung disease, of whom four (57%) were persistently colonized with A. fumigatus.We conclude that chronic A. fumigatus colonization of the CF airway is common, and may be associated with worse lung function. In our practice, BAL appears superior at detecting lower airway A. fumigatus compared to sputum samples.

A simple asthma prediction tool for preschool children with wheeze or cough.

BACKGROUND: Many preschool children have wheeze or cough, but only some have asthma later. Existing prediction tools are difficult to apply in clinical practice or exhibit methodological weaknesses. OBJECTIVE: We sought to develop a simple and robust tool for predicting asthma at school age in preschool children with wheeze or cough. METHODS: From a population-based cohort in Leicestershire, United Kingdom, we included 1- to 3-year-old subjects seeing a doctor for wheeze or cough and assessed the prevalence of asthma 5 years later. We considered only noninvasive predictors that are easy to assess in primary care: demographic and perinatal data, eczema, upper and lower respiratory tract symptoms, and family history of atopy. We developed a model using logistic regression, avoided overfitting with the least absolute shrinkage and selection operator penalty, and then simplified it to a practical tool. We performed internal validation and assessed its predictive performance using the scaled Brier score and the area under the receiver operating characteristic curve. RESULTS: Of 1226 symptomatic children with follow-up information, 345 (28%) had asthma 5 years later. The tool consists of 10 predictors yielding a total score between 0 and 15: sex, age, wheeze without colds, wheeze frequency, activity disturbance, shortness of breath, exercise-related and aeroallergen-related wheeze/cough, eczema, and parental history of asthma/bronchitis. The scaled Brier scores for the internally validated model and tool were 0.20 and 0.16, and the areas under the receiver operating characteristic curves were 0.76 and 0.74, respectively. CONCLUSION: This tool represents a simple, low-cost, and noninvasive method to predict the risk of later asthma in symptomatic preschool children, which is ready to be tested in other populations.

Carbon in airway macrophages from children with asthma.

BACKGROUND: Airway macrophage (AM) phagocytosis is impaired in severe asthma. Prostaglandin (PG) E2 and D2 are increased in severe asthma and suppress AM phagocytic function in vitro. In this study, we sought evidence for PG-mediated impairment of phagocytosis of inhalable carbonaceous particulate matter (PM) by AM in children with severe asthma compared with mild asthmatics and healthy controls. METHODS: AM were obtained from children with asthma and healthy controls using induced sputum. AM carbon area (µm(2)) was assessed by image analysis. In a subgroup of asthmatics, urinary PGE2 and PGD2 metabolites were measured by high-performance liquid chromatography, and PM exposure at the home address was modelled. Phagocytosis of PM by human monocyte-derived macrophages and rat AM was assessed in vitro by image analysis. RESULTS: AM carbon was 51% lower in children with moderate-to-severe asthma (n=36) compared with mild asthmatics (n=12, p<0.01) and healthy controls (n=47, p<0.01). There was no association between modelled PM exposure and AM carbon in 33 asthmatics who had a urine sample, but there was an inverse association between AM carbon and urinary metabolites of PGE2 and D2 (n=33, rs=-0.40, p<0.05, and rs=-0.44, p<0.01). PGE2 10(-6) M, but not PGD2 10(-6) M, suppressed phagocytosis of PM10 by human macrophages in vitro (p<0.05 vs control). PGE2 10(-6) M also suppressed phagocytosis of PM10 by rat AM in vitro (p<0.01 vs control). CONCLUSIONS: Phagocytosis of inhaled carbonaceous PM by AMs is impaired in severe asthma. PGE2 may contribute to impaired AM phagocytic function in severe asthma.

Classification and pharmacological treatment of preschool wheezing: changes since 2008.

Since the publication of the European Respiratory Society Task Force report in 2008, significant new evidence has become available on the classification and management of preschool wheezing disorders. In this report, an international consensus group reviews this new evidence and proposes some modifications to the recommendations made in 2008. Specifically, the consensus group acknowledges that wheeze patterns in young children vary over time and with treatment, rendering the distinction between episodic viral wheeze and multiple-trigger wheeze unclear in many patients. Inhaled corticosteroids remain first-line treatment for multiple-trigger wheeze, but may also be considered in patients with episodic viral wheeze with frequent or severe episodes, or when the clinician suspects that interval symptoms are being under reported. Any controller therapy should be viewed as a treatment trial, with scheduled close follow-up to monitor treatment effect. The group recommends discontinuing treatment if there is no benefit and taking favourable natural history into account when making decisions about long-term therapy. Oral corticosteroids are not indicated in mild-to-moderate acute wheeze episodes and should be reserved for severe exacerbations in hospitalised patients. Future research should focus on better clinical and genetic markers, as well as biomarkers, of disease severity.