Idiopathic pulmonary haemosiderosis.

In this paper, we report the case of a boy in early childhood who presented with iron-deficiency anaemia, initially thought to be nutritional, who had a subsequent diagnosis of idiopathic pulmonary haemosiderosis (IPH). This is a slowly progressive and life-threatening disorder and is of paramount importance that this is identified early and treated appropriately. His first chest CT was not typical for IPH, and this appearance should be highlighted (small cystic changes alone initially). He also had focal disease, which allowed us to make the diagnosis using CT-guided biopsy. During his treatment, he experienced an uncommon side effect to a commonly prescribed medication (bradycardia with methylprednisolone). Since starting azathioprine as a steroid-sparing agent, he has been doing well.

Levelling the playing field through the London Network of the UK clinical trials accelerator platform.

Cystic fibrosis (CF) is a multisystem, genetic disease with a significantly reduced life expectancy. Despite substantial progress in therapies in the last 10-15 years, there is still no cure. There are dozens of drugs in the development pipeline and multiple clinical trials are being conducted across the globe. The UK Cystic Fibrosis Trust's (CFT) Clinical Trials Accelerator Platform (CTAP) is a national initiative bringing together 25 UK based CF centres to support the CF community in accessing and participating in CF clinical trials. CTAP enables more CF centres to run a broader portfolio of trials and increases the range of CF studies available for UK patients. There are four large specialist CF centres based in London, all within a small geographical region as well as two smaller centres which deliver CF care. At the launch of CTAP, these centres formed a sub-network in a consortium-style collaboration. The purpose of the network was to ensure equity of access to trials for patients across the UK's capital, and to share experience and knowledge. Four years into the programme we have reviewed our practices through working group meetings and an online survey. We sought to identify strengths and areas for improvement. We share our findings here, as we believe they are relevant to others delivering research in regions outside of London and in other chronic diseases.

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

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

Promoting smoking cessation in the paediatric respiratory clinic.

Exposure to tobacco smoke is harmful to children and young people (CYP). There is, to our knowledge, no published evidence quantifying the success of smoking cessation interventions targeted at both CYP and their parents or guardians in paediatric respiratory clinics. We offered 102 participants smoking cessation advice, using motivational interviewing and exhaled carbon monoxide measurements to help them quit smoking. In total, 16 of 102 participants quit smoking, with 4 lost to follow-up. A further 40 participants cut down on how much they smoked. CONCLUSION: Formal screening questions on smoking and the provision of smoking cessation advice should form a regular part of all respiratory clinics where CYP and their parents are seen. Simple smoking cessation interventions can lead to reduced smoking in this population. WHAT IS KNOWN: • Tobacco smoking is strongly associated with significant morbidity and mortality. • Adolescents with chronic respiratory diseases may themselves smoke, or may have parents who do so. WHAT IS NEW: • Smoking cessation interventions are well received in paediatric respiratory clinic by patients and their families. • Simple smoking cessation interventions can help young people and their parents to stop smoking or cut down on smoking.

Beneficial effects of adenotonsillectomy in children with sickle cell disease.

Tonsillectomy and adenoidectomy (T&A) is frequently performed in children with sickle cell disease (SCD). Our aim was to evaluate the impact of this surgery on overnight oxygenation and rates of complications in these patients. Children with SCD who underwent T&A between 2008 and 2014 in two tertiary hospitals were retrospectively evaluated. Overnight oximetry and admission rates due to vaso-occlusive pain episodes (VOEs) and acute chest syndrome (ACS) in the year preceding and following the surgery were compared. 19 patients (10 males, 53%) with a median age of 6 years (range 3.5-8) were included. A significant increase of mean overnight arterial oxygen saturation measured by pulse oximetry (S pO2 ) (from 93±3.6% to 95.3±2.8%, p=0.001), nadir S pO2 (from 83.0±7.1% to 88±4.1%, p=0.004) and a reduction of 3% oxygen desaturation index (from a median value of 5.7 to 1.8, p=0.003) were shown. The mean annual rate of ACS decreased from 0.6±1.22 to 0.1±0.2 events per patient-year (p=0.003), while the mean cumulative rate of hospitalisations for all causes and the incidence of VOEs were not affected. T&A improved nocturnal oxygenation and was also associated with a reduction in the incidence of ACS at 1-year follow-up after surgery.

Comparison of pulse oximetry and earlobe blood gas with CO-oximetry in children with sickle cell disease: a retrospective review.

OBJECTIVES: To investigate the agreement between pulse oximetry (SpO2) and oxygen saturation (SaO2) measured by CO-oximetry on arterialised earlobe blood gas (EBG) in children and adolescents with sickle cell disease (SCD). DESIGN AND SETTING: We retrospectively reviewed 39 simultaneous and paired SaO2 EBG and SpO2 measurements from 33 ambulatory patients with SCD (32 subjects with Haemoglobin SS and one with Haemoglobin Sß+, 52% male, mean±SD age 11.0±3.6, age range 5-18). Measurements were performed between 2012 and 2015 when participants were asymptomatic. Hypoxaemia was defined as SaO2 ≤93%. A Bland-Altman analysis was performed to assess the accuracy of SpO2 as compared with EBG SaO2. RESULTS: The mean±SD SpO2 and SaO2 values in the same patients were, respectively, 93.6%±3.7% and 94.3%±2.9%. The bias SpO2-SaO2 was -0.7% (95% limits of agreement from -5.4% to 4.1%) and precision was 2.5%. In 9/39 (23%) cases, the difference in SpO2-SaO2 was greater than the expected error range ±2%, with SaO2 more often underestimated by SpO2 (6/9), especially at SpO2values ≤93%. Thirteen participants (33%) were hypoxaemic. The sensitivity of SpO2 for hypoxaemia was 100%, specificity 85% and positive predictive value 76%. CONCLUSIONS: Pulse oximetry was inaccurate in almost a quarter of measurements in ambulatory paediatric patients with SCD, especially at SpO2values ≤93%. In these cases, oxygen saturation can be confirmed through EBG CO-oximetry, which is easier to perform and less painful than traditional arterial blood sampling.

Lung clearance index and steroid response in pediatric severe asthma.

INTRODUCTION: Lung clearance index (LCI) is a measure of airway disease that has been shown to be abnormal in asthma. We hypothesized that LCI would be higher (worse) in children with severe therapy-resistant asthma (STRA) compared with difficult asthma (DA) and healthy controls and that LCI would fall in response to parenteral steroids in STRA. METHODS: Sixty-four children with asthma who were prescribed high-dose asthma therapy (GINA steps 4 or 5) performed LCI and spirometry. Forty-three had STRA and 21 DA. Thirty-nine of forty-three STRA patients attended for a clinically indicated bronchoscopy during which an intramuscular injection of triamcinolone was given. LCI, spirometry, and fractional exhaled nitric oxide (FeNO) were performed on the day of the bronchoscopy and repeated 4 weeks later. RESULTS: LCI was more abnormal in STRA (median: 7.40, range: 5.58-12.34) than in DA (6.55, 5.77-7.75), P = .0006, and healthy controls (6.53, 5.57-7.35), P = .005. In contrast to the first second forced expired volume (FEV1 ), LCI improved following systemic steroids; of 20 STRA patients with an abnormal LCI at baseline, 13 improved following triamcinolone. LCI and FeNO responses were concordant. CONCLUSIONS: There is a subgroup of children with STRA in whom LCI is elevated who improve following parenteral steroids. LCI may be a valuable additional domain in assessing steroid response in pediatric asthma.

Higher oxygen saturation with hydroxyurea in paediatric sickle cell disease.

INTRODUCTION: Sickle cell disease (SCD) is one of the most common inherited diseases worldwide. It is associated with lifelong morbidity and reduced life expectancy. Hydroxyurea (HU) has been shown to reduce the frequency and severity of vaso-occlusive episodes in SCD. Hypoxaemia and intermittent nocturnal oxygen desaturations occur frequently in children with SCD and contribute to the associated morbidity, including risk of cerebrovascular disease. OBJECTIVE: To evaluate the effect of HU on oxygen saturation (SpO2) overnight and on daytime SpO2 spot checks in children with SCD. METHODS: A retrospective review of children with SCD and respiratory problems who attended two UK tertiary sickle respiratory clinics and were treated with HU. Longitudinal data were collected from 2 years prior and up to 3 years after the commencement of HU. RESULTS: Forty-three children, 23 males (53%) with a median age of 9 (range 1.8-18) years were included. In the 21 children who had comparable sleep studies before and after starting HU, mean SpO2 was higher (95.2% from 93.5%, p=0.01) and nadir SpO2 was higher (87.2% from 84.3%, p=0.009) when taking HU. In 32 of the children, spot daytime oxygen saturations were also higher (96.3% from 93.5%, p=0.001). CONCLUSION: Children with SCD had higher oxygen saturation overnight and on daytime spot checks after starting HU. These data suggest HU may be helpful for treating persistent hypoxaemia in children with SCD pending more evidence from a randomised clinical trial.

A mysterious cause of chronic cough.

This case alerts professionals to take a broad approach when considering childhood chronic cough in sickle cell disease. Certain respiratory conditions are difficult to recognise in childhood, with many children suffering from delayed diagnosis. https://bit.ly/2GZAgmE.

Nutritional status and pulmonary outcome in children and young people with cystic fibrosis.

BACKGROUND: Nutrition is closely related to mortality and pulmonary and respiratory muscle function in cystic fibrosis (CF) patients. We initially validated results from a bioelectrical impedance device against dual energy x-ray absorptiometry (DEXA). We then determined whether fat free mass assessed by a portable impedance device rather than body mass index (BMI) better correlated with pulmonary function, respiratory muscle strength and exercise capacity in CF patients. METHODS: Eighteen young people and adults (median age 19, range 12-39 years) with CF had dual energy X-ray absorptiometry and direct segmental multi-frequency impedance analysis. Body composition, pulmonary function, respiratory muscle function and exercise tolerance using the impedance device were measured in 29 young people with CF with median age 15 (range 12-19) years. MAIN FINDINGS: There was a significant correlation between impedance and absorptiometry results (r2 = 0.947). Fat free mass correlated with the forced vital capacity z-score (r = 0.442, p = 0.016), maximal inspiratory pressure (r = 0.451, p = 0.014) and exercise tolerance (r = 0. 707, p < 0.001). BMI z-scores did not significantly correlate with pulmonary or respiratory muscle function. Subjects with a fat free mass z-score of ≤2 had a lower forced expiratory volume in 1 s z-score (p = 0.007), lower forced vital capacity z-score (p = 0.001), higher residual volume z-score (p = 0.042), lower maximal inspiratory pressure (p = 0.039), more days of intravenous antibiotics per year (p = 0.016) and a higher rate of chronic infections (p = 0.006). PRINCIPAL CONCLUSIONS: Fat-free mass measured by impedance correlated better with pulmonary and respiratory muscle function and exercise capacity than BMI.

A meta-analysis of montelukast for recurrent wheeze in preschool children.

There is conflicting evidence of the effectiveness of montelukast in preschool wheeze. A recent Cochrane review focused on its use in viral-induced wheeze; however, such subgroups are unlikely to exist in real life and change with time, recently highlighted in an international consensus report. We have therefore sought to investigate the effectiveness of montelukast in all children with preschool wheeze (viral-induced and multiple-trigger wheeze). The PubMed, Cochrane Library, Ovid Medline and Ovid EMBASE were screened for randomised controlled trials (RCTs), examining the efficacy of montelukast compared with placebo in children with the recurrent preschool wheeze. The primary endpoint examined was frequency of wheezing episodes. Five trials containing 3960 patients with a preschool wheezing disorder were analysed. Meta-analyses of studies of intermittent montelukast showed no benefit in preventing episodes of wheeze (mean difference (MD) 0.07, 95% confidence interval (CI) -0.14 to 0.29; mean for montelukast 2.68 vs placebo 2.54 (p = 0.5)), reducing unscheduled medical attendances (MD -0.13, 95% CI -0.33 to 0.07; mean for montelukast 1.62 vs placebo 1.78 (p = 0.21)) and reducing oral corticosteroids (MD -0.06, 95% CI -0.16 to 0.02; mean for montelukast 0.35 vs placebo 0.36 (p = 0.25)). The pooled results of the continuous regimen showed no significant difference in the number of wheezing episodes between the montelukast and placebo groups (MD -0.40, 95% CI -1.00 to 0.19; mean for montelukast 2.05 vs placebo 2.37 (p = 0.18)). CONCLUSIONS: This review highlights that the currently available evidence does not support the use of montelukast in preschool children with recurrent wheeze. We recommend further studies to investigate if a 'montelukast responder' phenotype exists, and how these can be easily identified in the clinical setting. What is Known: • Current guidelines recommend montelukast use in preschool children with recurrent wheeze. • A recent Cochrane review has found montelukast to be ineffective at reducing courses of oral corticosteroids for viral-induced wheeze. What is New: • This meta-analysis has examined all children with preschool wheeze and found that montelukast was not effective at preventing wheezing episodes or reducing unscheduled medical attendances. • A specific montelukast responder phenotype may exist, but such patients should be sought in larger multicentre RCTs.

Intraepithelial neutrophils in pediatric severe asthma are associated with better lung function.

BACKGROUND: Neutrophils and IL-17A have been linked mechanistically in models of allergic airways disease and have been associated with asthma severity. However, their role in pediatric asthma is unknown. OBJECTIVES: We sought to investigate the role of neutrophils and the IL-17A pathway in mediating pediatric severe therapy-resistant asthma (STRA). METHODS: Children with STRA (n = 51; age, 12.6 years; range, 6-16.3 years) and controls without asthma (n = 15; age, 4.75 years; range, 1.6-16 years) underwent clinically indicated fiberoptic bronchoscopy, bronchoalveolar lavage (BAL), endobronchial brushings, and biopsy. Neutrophils, IL-17A, and IL-17RA-expressing cells and levels of IL-17A and IL-22 were quantified in BAL and biopsies and related to clinical features. Primary bronchial epithelial cells were stimulated with IL-17A and/or IL-22, with and without budesonide. RESULTS: Children with STRA had increased intraepithelial neutrophils, which positively correlated with FEV1 %predicted (r = 0.43; P = .008). Neutrophilhigh patients also had better symptom control, despite lower dose maintenance inhaled steroids. Submucosal neutrophils were not increased in children with STRA. Submucosal and epithelial IL-17A-positive cells and BAL IL-17A and IL-22 levels were similar in children with STRA and controls. However, there were significantly more IL-17RA-positive cells in the submucosa and epithelium in children with STRA compared with controls (P = .001). Stimulation of primary bronchial epithelial cells with IL-17A enhanced mRNA expression of IL-17RA and increased release of IL-8, even in the presence of budesonide. CONCLUSIONS: A proportion of children with STRA exhibit increased intraepithelial airway neutrophilia that correlated with better lung function. STRA was also characterized by increased airway IL-17RA expression. These data suggest a potential beneficial rather than adverse role for neutrophils in pediatric severe asthma pathophysiology.

Assessment of corticosteroid response in pediatric patients with severe asthma by using a multidomain approach.

BACKGROUND: There is no agreed upon definition of systemic corticosteroid response in asthmatic children. Moreover, pediatric severe therapy-resistant asthma (STRA) is heterogeneous, and thus response to steroids is unlikely to be uniform in all patients. OBJECTIVE: We sought to evaluate the utility of a multidomain approach incorporating symptoms, lung function, and inflammation to determine steroid responsiveness in pediatric patients with STRA. METHODS: Eighty-two children (median age, 12 years) with STRA received a clinically indicated dose of intramuscular steroid. Changes in 4 separate domains were assessed 4 weeks after intramuscular triamcinolone acetonide: normalization of (1) symptoms (Asthma Control Test score, >19/25 or 50% increase), (2) spirometric results (FEV1 ≥80% of predicted value or ≥15% increase), (3) fraction of exhaled nitric oxide levels (<24 ppb), and (4) sputum eosinophil counts (<2.5%). Fifty-four of 82 children had complete data in all 4 domains. RESULTS: Twenty-three (43%) of 54 children had a symptom response, 29 (54%) of 54 had a lung function response, 28 (52%) of 54 had a fraction of exhaled nitric oxide response, and 29 (54%) of 54 had a sputum eosinophil response. Although a similar proportion of children responded to systemic corticosteroids in each domain, there were no reliable predictors of a response pattern. Seven (13%) of 54 were complete responders (response in all domains), 8 (15%) of 54 were nonresponders (no response in any domain), and 39 (72%) of 54 were partial responders (response in ≥1 domain). CONCLUSIONS: A multidomain evaluation of systemic steroid responsiveness using pragmatic clinical assessments confirms childhood STRA is heterogeneous and that a complete response in symptoms and inflammatory and physiologic parameters is rare. Individual response patterns to systemic steroids might be useful in guiding the choice of add-on therapies in each child as a step toward achieving personalized medicine.

Ethnic Variation in Response to IM Triamcinolone in Children With Severe Therapy-Resistant Asthma.

BACKGROUND: Although ethnicity may influence response to treatment of patients with asthma, this approach is controversial. The objective of this study was to determine if ethnicity influences the response to IM steroid use (eliminating adherence as an issue). METHODS: Children with severe therapy-resistant asthma who had previously undergone a detailed assessment (including a nurse-led hospital and home visit in which potentially modifiable factors had been identified and addressed) were admitted for further evaluation; this evaluation included assessment of steroid response. Children were classified as white, black, Asian, or mixed white/black. Steroid responsiveness was defined according to symptoms (Asthma Control Test), inflammation (sputum eosinophil count and exhaled nitric oxide), and spirometry (FEV1); these variables were measured before and 4 weeks after IM triamcinolone use. Data were collected regarding exacerbations. Fractional exhaled nitric oxide (Feno) response was defined as a decrease to < 24 parts per billion (ppb). RESULTS: Seventy-nine subjects were identified (white, n = 54 [68%]; black, n = 16 [20%]; Asian, n = 5 [6%]; and mixed white/black, n = 4 [5%]). After administration of triamcinolone, there was a significant drop in median Feno in white children (46.8 to 23.1 ppb; P < .001) but not in black children (52.2 to 34.5 ppb; P = .58). More black children than white children (86.7%) were Feno nonresponders (86.7% vs 45.3%; P < .05), and more black children had exacerbations compared with white children (61% vs 17%; P < .05). CONCLUSIONS: Black children with asthma were less likely to report an Feno response and had more exacerbations 4 weeks after administration of triamcinolone than white children. Further research is needed to understand the mechanisms of these differences, but they cannot be due to differences in adherence or access to care.

Pediatric severe asthma with fungal sensitization is mediated by steroid-resistant IL-33.

BACKGROUND: The mechanism underlying severe asthma with fungal sensitization (SAFS) is unknown. IL-33 is important in fungus-induced asthma exacerbations, but its role in fungal sensitization is unexplored. OBJECTIVE: We sought to determine whether fungal sensitization in children with severe therapy-resistant asthma is mediated by IL-33. METHODS: Eighty-two children (median age, 11.7 years; 63% male) with severe therapy-resistant asthma were included. SAFS (n = 38) was defined as specific IgE or skin prick test response positivity to Aspergillus fumigatus, Alternaria alternata, or Cladosporium herbarum. Clinical features and airway immunopathology were assessed. Chronic exposure to house dust mite and A alternata were compared in a neonatal mouse model. RESULTS: Children with SAFS had earlier symptom onset (0.5 vs 1.5 years, P = .006), higher total IgE levels (637 vs 177 IU/mL, P = .002), and nonfungal inhalant allergen-specific IgE. Significantly more children with SAFS were prescribed maintenance oral steroids (42% vs 14%, P = .02). SAFS was associated with higher airway IL-33 levels. In neonatal mice A alternata exposure induced higher serum IgE levels, pulmonary IL-33 levels, and IL-13(+) innate lymphoid cell (ILC) and TH2 cell numbers but similar airway hyperresponsiveness (AHR) compared with those after house dust mite exposure. Lung IL-33 levels, IL-13(+) ILC numbers, TH2 cell numbers, IL-13 levels, and AHR remained increased with inhaled budesonide during A alternata exposure, but all features were significantly reduced in ST2(-/-) mice lacking a functional receptor for IL-33. CONCLUSION: Pediatric SAFS was associated with more oral steroid therapy and higher IL-33 levels. A alternata exposure resulted in increased IL-33-mediated ILC2 numbers, TH2 cell numbers, and steroid-resistant AHR. IL-33 might be a novel therapeutic target for SAFS.

Increased nuclear suppressor of cytokine signaling 1 in asthmatic bronchial epithelium suppresses rhinovirus induction of innate interferons.

BACKGROUND: Rhinovirus infections are the dominant cause of asthma exacerbations, and deficient virus induction of IFN-α/ß/λ in asthmatic patients is important in asthma exacerbation pathogenesis. Mechanisms causing this interferon deficiency in asthmatic patients are unknown. OBJECTIVE: We sought to investigate the expression of suppressor of cytokine signaling (SOCS) 1 in tissues from asthmatic patients and its possible role in impaired virus-induced interferon induction in these patients. METHODS: We assessed SOCS1 mRNA and protein levels in vitro, bronchial biopsy specimens, and mice. The role of SOCS1 was inferred by proof-of-concept studies using overexpression with reporter genes and SOCS1-deficient mice. A nuclear role of SOCS1 was shown by using bronchial biopsy staining, overexpression of mutant SOCS1 constructs, and confocal microscopy. SOCS1 levels were also correlated with asthma-related clinical outcomes. RESULTS: We report induction of SOCS1 in bronchial epithelial cells (BECs) by asthma exacerbation-related cytokines and by rhinovirus infection in vitro. We found that SOCS1 was increased in vivo in bronchial epithelium and related to asthma severity. SOCS1 expression was also increased in primary BECs from asthmatic patients ex vivo and was related to interferon deficiency and increased viral replication. In primary human epithelium, mouse lung macrophages, and SOCS1-deficient mice, SOCS1 suppressed rhinovirus induction of interferons. Suppression of virus-induced interferon levels was dependent on SOCS1 nuclear translocation but independent of proteasomal degradation of transcription factors. Nuclear SOCS1 levels were also increased in BECs from asthmatic patients. CONCLUSION: We describe a novel mechanism explaining interferon deficiency in asthmatic patients through a novel nuclear function of SOCS1 and identify SOCS1 as an important therapeutic target for asthma exacerbations.

Passive smoking impairs histone deacetylase-2 in children with severe asthma.

BACKGROUND: Parental smoking is known to worsen asthma symptoms in children and to make them refractory to asthma treatment, but the molecular mechanism is unclear. Oxidative stress from tobacco smoke has been reported to impair histone deacetylase-2 (HDAC2) via phosphoinositide-3-kinase (PI3K)/Akt activation and, thus, to reduce corticosteroid sensitivity. The aim of this study was to investigate passive smoking-dependent molecular abnormalities in alveolar macrophages (AMs) by comparing passive smoke-exposed children and non-passive smoke-exposed children with uncontrolled severe asthma. METHODS: BAL fluid (BALF) was obtained from 19 children with uncontrolled severe asthma (10 non-passive smoking-exposed subjects and nine passive smoking-exposed subjects), and HDAC2 expression/activity, Akt/HDAC2 phosphorylation levels, and corticosteroid responsiveness in AMs were evaluated. RESULTS: Parental smoking reduced HDAC2 protein expression by 54% and activity by 47%, with concomitant enhancement of phosphorylation of Akt1 and HDAC2. In addition, phosphorylation levels of Akt1 correlated positively with HDAC2 phosphorylation levels and negatively with HDAC2 activity. Furthermore, passive smoke exposure reduced the inhibitory effects of dexamethasone on tumor necrosis factor-α-induced CXCL8 release in AMs. There were relatively higher neutrophil counts and CXCL8 concentrations in BALF and lower Asthma Control Test scores compared with non-passive smoke-exposed children with uncontrolled severe asthma. CONCLUSIONS: Passive smoking impairs HDAC2 function via PI3K signaling activation, which could contribute to corticosteroid-insensitive inflammation in children with severe asthma. This novel mechanism will be a treatment target in children with severe asthma and stresses the need for a smoke-free environment for asthmatic children.