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.

ALPINE2: Efficacy and safety of 14-day vs 28-day inhaled aztreonam for Pa eradication in children with cystic fibrosis.

BACKGROUND: Antibiotic eradication therapies recommended for newly isolated Pseudomonas aeruginosa (Pa) in people with cystic fibrosis (pwCF) can be burdensome. ALPINE2 compared the efficacy and safety of a shortened 14-day course of aztreonam for inhalation solution (AZLI) with 28-day AZLI in paediatric pwCF. METHODS: ALPINE2 (a double-blind, phase 3b study) included children aged 3 months to <18 years with CF and new-onset Pa infection. Participants were randomized to receive 75 mg AZLI three times daily for either 28 or 14 days followed by 14 days' matched placebo. The primary endpoint was rate of primary Pa eradication (no Pa detected during the 4 weeks post AZLI treatment). Non-inferiority was achieved if the lower 95% CI bound of the treatment difference between the two arms was above -20%. Secondary endpoints included assessments of Pa recurrence during 108 weeks of follow-up after primary eradication. Safety endpoints included treatment-emergent adverse events (TEAEs). RESULTS: In total, 149 participants were randomized (14-day AZLI, n = 74; 28-day AZLI, n = 75) and 142 (95.3%) completed treatment. Median age: 6.0 years (range: 0.3-17.0). Baseline characteristics were similar between treatment arms. Primary Pa eradication rates: 14-day AZLI, 55.9%; 28-day AZLI, 63.4%; treatment difference (CI), -8.0% (-24.6, 8.6%). Pa recurrence rates at follow-up end: 14-day AZLI, 54.1% (n = 20/37); 28-day AZLI, 41.9% (n = 18/43). TEAEs were similar between treatment arms. No new safety signals were observed. CONCLUSIONS: Non-inferiority of 14-day AZLI versus 28-day AZLI was not demonstrated. Both courses were well tolerated, further supporting AZLI short-term safety in paediatric and adolescent pwCF. CLINICALTRIALS: GOV: NCT03219164.

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.

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.

Minimal change in structural, functional and inflammatory markers of lung disease in newborn screened infants with cystic fibrosis at one year.

BACKGROUND: With the widespread introduction of newborn screening for cystic fibrosis (CF), there has been considerable emphasis on the need to develop objective markers of lung health that can be used during infancy. We hypothesised that in a newborn screened (NBS) UK cohort, evidence of airway inflammation and infection at one year would be associated with adverse structural and functional outcomes at the same age. METHODS: Infants underwent lung function testing, chest CT scan and bronchoscopy with bronchoalveolar lavage (BAL) at 1 year of age when clinically well. Microbiology cultures were also available from routine cough swabs. RESULTS: 65 infants had lung function, CT and BAL. Mean (SD) lung clearance index and forced expiratory volume in 0.5 s z-scores were 0.9(1.2) and -0.6(1.1) respectively; median Brody II CF-CT air trapping score on chest CT =0 (interquartile range 0-1, maximum possible score 27). Infants isolating any significant pathogen by 1 yr of age had higher LCI z-score (mean difference 0.9; 95%CI:0.4-1.4; p = 0.001) and a trend towards higher air trapping scores on CT (p = 0.06). BAL neutrophil elastase was detectable in 23% (10/43) infants in whom BAL supernatant was available. This did not relate to air trapping score on CT. CONCLUSIONS: In this UK NBS cohort at one year of age, lung and airway damage is much milder and associations between inflammation, abnormal physiology and structural changes were at best weak, contrary to our hypothesis and previously published reports. Continued follow-up will clarify longer term implications of these very mild structural, functional and inflammatory changes.

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.

Fifteen-minute consultation: A structured approach to the management of chronic cough in a child.

Coughing is a primary pulmonary defence mechanism that enhances clearance of secretions and particles from the airways and protects against aspiration of foreign materials. Coughing may affect 30% of children at any given time (1). Many are healthy children but some may have serious underlying disease. Childhood cough accounts for a large number of consultations and 80% of families who are referred to a paediatric respiratory clinic for chronic cough have sought medical advice five times or more (2). The majority of childhood coughs are secondary to an acute respiratory tract infection and will improve once the infection resolves, usually within 1 to 3 weeks. With pre-school children who may experience between 6 and 10 respiratory infections a year differentiating acute recurrent cough from chronic cough is key (Table 1). Chronic cough can significantly impact a family's quality of life, as it affects the child's sleep, school attendance and play. Parents experience distress and anxiety, worrying that the cough may lead to long-term chest damage or even death (3). This article aims to guide clinicians through the assessment of the child with a chronic cough. It will discuss identifying causes, use of first line investigations, initiating appropriate management and addressing parental anxiety and exacerbating factors (4,5).

Cystic fibrosis newborn screening: outcome of infants with normal sweat tests.

Newborn babies positively screened for cystic fibrosis (CF) (high serum immunoreactive trypsin (IRT) with DNA analysis) are referred for a diagnostic sweat test, which may be normal (sweat chloride <30 mmol/L). Unless two gene mutations are identified during Newborn screening (NBS), the babies are discharged from follow-up. We wished to check that none had subsequently developed symptoms suggestive of CF. We retrospectively reviewed patient notes and contacted general practitioners of all babies with a negative sweat test, conducted in one of the four paediatric specialist CF centres in London, over the first 6 years of screening in South East England.Of 511 babies referred, 95 (19%) had a normal sweat test. Five (5%) had CF diagnosed genetically, two of them on extended genome sequencing after clinical suspicion. Eleven (12%) were designated as CF screen positive inconclusive diagnosis (CFSPID); one of the five CF children was originally designated as CFSPID. Seventy-nine (83%) were assumed to be false-positive cases and discharged; follow-up data were available for 51/79 (65%); 32/51 (63%) had no health issues, 19/51 (37%) had other significant non-CF pathology.These results are reassuring in that within the limitations of those lost to follow-up, CF symptoms have not emerged in the discharged children. The high non-CF morbidity in these children may relate to known causes of high IRT at birth. Clinicians need to be aware that a child can have CF despite a normal sweat test following NBS, and if symptoms suggest the diagnosis, further testing, including extended genome sequencing, is required.

Intravenous and Intracavitary Use of Contrast-Enhanced Ultrasound in the Evaluation and Management of Complicated Pediatric Pneumonia.

Pediatric pneumonia can be complicated by necrotizing pneumonia or a parapneumonic effusion either in the form of an empyema or a clear effusion. Ultrasonography (US) and computed tomography represent well-established modalities for evaluation of complicated pediatric pneumonia. Contrast-enhanced ultrasound (CEUS) was recently introduced and is gaining increasing acceptance in pediatric imaging. In this case series, we present our initial experience with both intravenous and intracavitary use of CEUS in children with complicated pneumonia. Intravenous CEUS accurately and confidently showed necrotizing pneumonia and delineated pleural effusions, whereas intracavitary CEUS accurately identified the chest catheter location and patency and showed the presence of loculations, suggesting the use of fibrinolytics.

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.

Prevalence of nontuberculous mycobacteria in cystic fibrosis clinics, United Kingdom, 2009.

Incidence of pulmonary infection with nontuberculous mycobacteria (NTM) is increasing among persons with cystic fibrosis (CF). We assessed prevalence and management in CF centers in the United Kingdom and found 5.0% of 3,805 adults and 3.3% of 3,317 children had recently been diagnosed with NTM. Of those, 44% of adults and 47% of children received treatment.

Kawasaki disease presenting with intussusception: a case report.

A 3 yr old boy presented with abdominal pain, fever and red jelly stools. Intussusception was diagnosed and effectively reduced with air insufflation. However, despite an improvement in his clinical condition, the child remained febrile and miserable; 5 days later he developed characteristic signs of Kawasaki disease and was treated with intravenous immunoglobulin and high dose aspirin with good results. Intussusception prior to the typical features of Kawasaki disease has not been described previously in the English literature. This case illustrates a novel presentation of Kawasaki disease.

Feeding intolerance due to connatal tuberculosis in a prematurely born infant.

A prematurely born infant had three episodes of feeding intolerance in the first three weeks after birth. In the post-partum period, his mother, who was from the Ukraine, had a respiratory arrest; unusually, a high-resolution computerised tomograph demonstrated miliary tuberculosis (TB). As a consequence, and due to the continuing ill health of the infant, gastric aspirates were sent from the infant. Acid fast bacilli were seen on microscopy. Variable nucleotide tandem repeat analysis of acid fast bacilli facilitated the rapid diagnosis of connatal TB. We conclude that connatal TB should be considered in a prematurely born infant poorly responsive to standard management and whose mother falls into a high-risk group.