CFTR modulator therapies - Effect on life expectancy in people with cystic fibrosis.

CFTR modulators have dramatically changed the clinical course of CF in those fortunate enough to receive them. Inevitably, randomised controlled trials during the development of these drugs are too short to use mortality as an outcome. Evidence for their effect on life expectancy are best gained from real world registry studies specifically looking at mortality, but these are only available for ivacaftor to date. Therefore, indirect evidence must be obtained by looking at outcomes known to affect mortality and seeing the effect of these drugs on those outcomes.

Revisiting a diagnosis of cystic fibrosis - Uncertainties and considerations.

There is now increased knowledge and experience of newborn screening around the world. There is also a better understanding of CF gene analysis, informed by international databases. This has resulted in a small number of children and adults having their diagnosis of CF reversed. This article illustrates this issue with three cases. It considers how best to tell children and adults with their families, and the reactions that may be encountered. It also discusses practical issues of removing the diagnosis.

Initiating home spirometry for children during the COVID-19 pandemic - A practical guide.

The COVID-19 pandemic has led to a rapid escalation in use of home monitoring and video consultations in children with a variety of chronic respiratory conditions. Our department set up a home spirometry service from scratch once it became evident that we needed to keep patients away from hospital clinics whenever possible. We faced a number of challenges but now have around 400 children using home spirometers. There are a number of portable spirometers available, some with online platforms. The technology, particularly the software/apps interface, has been improved by the companies in response to issues that have arisen. We believe the use of home monitoring is here to stay.

Communicating cystic fibrosis newborn screening results to parents.

The way results of cystic fibrosis (CF) newborn screening are communicated to parents is critical yet is done differently across the globe. We surveyed parents of 101 children in our tertiary London paediatric centre with a 48% response rate. Parental responses were as follows: 40/42 (95%) said the information could not have been given over the phone and 39/43 (91%) said they wanted both partners present; 27/42 (64%) said it was helpful having the health visitor also present; and 37/40 (92%) felt it was acceptable to wait until the next day for the sweat test. We have reduced the time from first contact to arriving in the home to 2-3 h.Conclusion: We believe that this survey backs up our approach of a home visit by a CF nurse specialist with the family's health visitor to break the news. This is challenging in the current COVID-19 pandemic. What is Known: • Breaking bad news can have a lasting impact on parents when not done the right way. • Giving results of cystic fibrosis (CF) newborn screening is done differently within the UK and around the world. What is New: • Our parental survey revealed that the majority (92%) believed this should be done face to face and not over the telephone. • There was a mixed response to whether the parents should be told the genotype (assuming the CF centre knew), and thus the CF diagnosis before the confirmatory sweat test was carried out.

Clinical papers of the year 2018 - Cystic fibrosis.

This paper reviews the most important clinical papers in cystic fibrosis published in 2018, having searched all the literature on Pubmed. Focus is on CFTR modulator therapy, randomised controlled trials, and infection/microbiology issues.

European and United Kingdom COVID-19 pandemic experience: The same but different.

The global healthcare landscape has changed dramatically and rapidly in 2020. This has had an impact upon paediatricians and in particular respiratory paediatricians. The effects in Europe, with its mature healthcare system, have been far faster and greater than most authorities anticipated. Within six weeks of COVID-19 being declared a public health emergency by the World Health Organisation [WHO] in China, Europe had become the new epicentre of disease. A pandemic was finally declared by the WHO on March 11th 2020. Continued international travel combined with the slow response of some political leaders and a variable focus on economic rather than health consequences resulted in varying containment strategies in response to the threat of the initial wave of the pandemic. It is likely that this variation has contributed to widely differing outcomes across Europe. Common to all countries was the stark lack of preparations and initial poor co-ordination of responses between levels of government to this unforeseen but not unheralded global health crisis. In this article we highlight the impact of the first wave of the COVID-19 pandemic in Italy, Austria, Germany, and the United Kingdom.

Impact of elexacaftor/tezacaftor/ivacaftor on fat-soluble vitamin levels in children with cystic fibrosis.

BACKGROUND: Children with cystic fibrosis are at risk of fat-soluble vitamin deficiency. CFTR modulators positively effect nutritional status. This study aimed to assess changes in serum vitamins A, D & E after starting ETI therapy to ensure levels were not abnormally high. METHODS: Retrospective review of annual assessment data over 3½ years, before and after starting ETI in a specialist paediatric CF centre, including vitamin levels. RESULTS: 54 eligible patients were included, aged 5-15 yrs (median age 11.5). Median time to post measurements was 171 days. Median vitamin A was increased (1.38 to 1.63 µmol/L, p<0.001). Three patients (6%) had high vitamin A post-ETI, compared with none at baseline; and 2 (4%) had low levels compared to 4 (8%) at baseline. No changes in vitamins D&E. CONCLUSIONS: This study found increased vitamin A, sometimes to high levels. We recommend testing levels within 3 months of starting ETI.

Environmental risks of Pseudomonas aeruginosa-What to advise patients and parents.

Pseudomonas aeruginosa (PsA) is commonly found in soil and water so is impossible to avoid completely. Parents/carers of children with cystic fibrosis (CF) are concerned about them acquiring PsA from the environment, and different families view risk differently. Our ethos is to enable children with CF to take part as much as possible in educational and fun home activities, in order to maintain their quality of life (and their family's), and not have them feel different from other children. This review presents advice for families as to what they must definitely avoid, what they must take precautions with but can allow, and what they must not avoid. It is mostly evidence-based, but where evidence is lacking it a consensus view from the Paediatric CF Unit at the Royal Brompton Hospital.

Corticosteroid responsiveness and clinical characteristics in childhood difficult asthma.

This study describes the clinical characteristics and corticosteroid responsiveness of children with difficult asthma (DA). We hypothesised that complete corticosteroid responsiveness (defined as improved symptoms, normal spirometry, normal exhaled nitric oxide fraction (F(eNO)) and no bronchodilator responsiveness (BDR <12%)) is uncommon in paediatric DA. We report on 102 children, mean+/-sd age 11.6+/-2.8 yrs, with DA in a cross-sectional study. 89 children underwent spirometry, BDR and F(eNO) before and after 2 weeks of systemic corticosteroids (corticosteroid response study). Bronchoscopy was performed after the corticosteroid trial. Of the 102 patients in the cross-sectional study, 88 (86%) were atopic, 60 (59%) were male and 52 (51%) had additional or alternative diagnoses. Out of the 81 patients in the corticosteroid response study, nine (11%) were complete responders. Of the 75 patients with symptom data available, 37 (49%) responded symptomatically, which was less likely if there were smokers in the home (OR 0.31, 95% CI 0.02-0.82). Of the 75 patients with available spirometry data, 35 (46%) had normal spirometry, with associations being BAL eosinophilia (OR 5.43, 95% CI 1.13-26.07) and high baseline forced expiratory volume in 1 s (FEV(1)) (OR 1.08, 95% CI 1.02-1.12). Of these 75 patients, BDR data were available in 64, of whom 36 (56%) had <12% BDR. F(eNO) data was available in 70 patients, of whom 53 (75%) had normal F(eNO). Airflow limitation data was available in 75 patients, of whom 17 (26%) had persistent airflow limitation, which was associated with low baseline FEV(1) (OR 0.93, 95% CI 0.90-0.97). Only 11% of DA children exhibited complete corticosteroid responsiveness. The rarity of complete corticosteroid responsiveness suggests alternative therapies are needed for children with DA.

Incidence and outcome of scoliosis in children with pleural infection.

AIMS: To ascertain the incidence and outcome of secondary scoliosis associated with parapneumonic effusions/empyema. METHODS: Retrospective review of case notes of children with pleural effusions over a 3-year period. Review of digitalized erect chest radiographs by two observers with serial measurements of Cobb angles. Scoliosis defined as lateral curvature of the spine > or = 10 degrees. RESULTS: Of 122 children (median age 4.3 years), 103 (84%) required chest drains of whom 83/103 (81%) received urokinase; 5 (4%) required surgical decortication. On admission, 56 (46%) had a scoliosis, 68 (62%) on the 2nd radiograph, and 68 (59%) at discharge; overall 87 (71%) had a scoliosis at some stage. In all cases, there was a single thoracic curve with the direction towards the side of the effusion. There was no association between scoliosis and size or type of effusion, nor inflammatory markers. There was a statistically significant but small effect from duration of illness prior to admission. At follow-up, 6 (5%) had a mild residual scoliosis but all subsequently resolved. Intraobserver variability for measurement of Cobb angles was +/-4.6 degrees and interobserver variability was +/-5.8 degrees. CONCLUSIONS: Scoliosis was common but always resolved so therapy is unnecessary; follow up is recommended to exclude coincidental idiopathic scoliosis.

A comparison of the prevalence of urinary incontinence in girls with cystic fibrosis, asthma, and healthy controls.

Urinary incontinence (UI) is recognized as a significant problem in adult females with cystic fibrosis and can often have a marked impact on day-to-day activities. The prevalence and severity of UI in the pediatric cystic fibrosis (CF) female population is less clear and there are no comparative data with healthy children or children with other respiratory disorders. An anonymous self-completed semi-structured questionnaire was used to study the prevalence rates of UI in girls with CF aged between 11 and 17 and compared it to age-matched asthmatic and healthy girls. The prevalence of UI in girls with CF was significantly higher (17/51, 33%) than the asthmatic (4/25, 16%) and healthy girls (2/27, 7%) (P = 0.02). It may manifest as early as 11 years of age and is associated with increasing lung disease. Surprisingly it is perceived as a relatively minor problem in terms of the distress it causes. Pediatric CF clinics should be routinely addressing UI as a potential problem in all girls from the age of 11 years.

Thrombophilia in children with cystic fibrosis.

In some children with cystic fibrosis (CF), percutaneous long lines occlude sooner than expected (due to thrombophlebitis or thrombosis), and many have a totally implantable venous access device (TIVAD), a recognized complication of which is thrombosis. This complication is more likely if the child has an underlying thrombotic tendency, which may be enhanced in the presence of inflammatory lung disease. There are no reports of an identified association of heritable thrombophilia with CF, although individual cases have been recognized. Our aim was to determine the incidence of thrombophilia in children with CF. In a tertiary pediatric CF center, blood was screened for thrombophilia at annual review, and retested if abnormal. A thrombotic abnormality was found in 41/204 (20%) patients. These included activated protein C resistance (10/204, 5%) with a prevalence similar to that expected, but the following abnormalities had an increased prevalence: antithrombin deficiency (2/204, 1%), protein S deficiency (11/204, 5%), protein C deficiency (8/204, 4%), and lupus anticoagulant (18/204, 9%). There were no differences found in those with thrombophilia for the following parameters: age, gender, genotype, lung function, presence of Pseudomonas aeruginosa, prothrombin time, serum IgE, aspergillus-specific IgE, liver function, and blood inflammatory markers. Fifteen children had TIVADs, 4 of whom had evidence of thrombophilia. In conclusion, a significant proportion of patients had a thrombophilic abnormality. We recommend that thrombophilia screening be performed prior to insertion of a TIVAD, and also in those with a history of venous thrombosis, blocked TIVADs, or recurring problems with long lines.

Fifteen-count breathlessness score: an objective measure for children.

Breathlessness is an important symptom of respiratory disease and its quantification is useful, especially during exercise testing. However, measures of perceived breathlessness are not readily understood by children and are somewhat subjective. We studied an objective score: the 15-count breathlessness score, in which subjects take a deep breath and then count out loud to 15; the number of breaths taken to complete the count is the score. Fifty-four children with cystic fibrosis (CF) performed a standard 6-min walk and 3-min step test (30 steps/min for 3 min). The 15-count score was compared with the modified Borg scale after exercise. A further 45 children with CF and 33 healthy schoolchildren underwent an incremental step test (20, 30, and then 40 steps/min for 2 min each), using the 15-count score, then the Borg scale, and then a standard visual analogue score between increments. The 15-count score was significantly increased after both the walk and the step test (P < 0.0001), although the step test made children significantly more breathless than the walk test (P < 0.0001). At baseline, there were no differences in any of the breathlessness scores between the CF and normal children. After the full 6 min of the incremental step test, CF children were significantly more breathless than the normal children, as measured by 15-count (P < 0.0001), Borg (P < 0.0005), and visual analogue scores (P < 0.0005). All scores increased significantly as exercise intensity increased over time, but the slope estimates were significantly greater for CF patients than for normal children (P < 0.0005). The 15-count score has been evaluated as an objective measure of breathlessness. It is easy to explain and perform, and can be used by any child capable of counting fluently to 15 in any language. It is best used in conjunction with a subjective score, and either the Borg scale or a visual analogue score is appropriate.

Effect of intravenous antibiotics on exercise tolerance (3-min step test)) in cystic fibrosis.

Most children with cystic fibrosis (CF) feel better and display more energy after a course of intravenous antibiotics (IVABs), but this is not always reflected by a satisfactory improvement in lung function. We assessed the change in exercise tolerance after treatment with IVABs using the 3-min step test, and compared it with changes in spirometric lung function and arterial oxygen saturation (SaO(2)). Thirty-six children (mean age, 13.8 years) were enrolled from two tertiary CF centers during an inpatient stay for IVABs. After 10-14 days of treatment, there was a significant improvement in median FEV(1) from 43% to 57% of predicted values (P < 0.0001), and median FVC from 66% to 73% of predicted values (P < 0.0001), while median SaO(2) significantly increased from 95% to 96.5% (P < 0.05). This was accompanied by a reduction in resting heart rate (median 118 bpm to 109 bpm, P < 0.005) and subjective breathlessness at rest (median visual analogue score 2.2 to 0.8, P < 0.005). All outcomes of exercise tolerance were improved after IVABs. There was a reduction in maximum heart rate (median 156 bpm to 150 bpm, P < 0.05) and an increase in minimum SaO(2) (median 93.5% to 94.5%, P = 0.08) measured during the step test. There was also a reduction in subjective breathlessness (median visual analogue score of 5.5 to 4.2, P < 0.005) and objective breathlessness (median 15-count score of 3 to 2, P < 0.0001) measured immediately after the step test. Exercise testing was a useful outcome measure for monitoring effectiveness of inpatient therapy, and complemented spirometry and SaO(2) monitoring. The simple ward-based 3-min step test was found to be a particularly suitable method for measuring changes in exercise tolerance in children with CF.

Three-minute step test to assess exercise capacity in children with cystic fibrosis with mild lung disease.

The information obtained from a simple submaximal test (the 3-min step test) was compared with that from a maximal cycle ergometry study, in a group of children with CF with relatively mild abnormalities of lung function (FEV(1) > 50% predicted). Nineteen subjects with CF undertook both exercise tests on the same day. Measurements included heart rate (HR), oxygen saturations (SaO(2)), visual analogue score of perceived breathlessness (VAS), 15-count breathlessness score (15c), and peak oxygen consumption (VO(2)). There were significant differences in the median changes in HR and VAS during the cycle test compared to the step test, 78 vs. 46 beats per minute (P < 0.05) and 51 mm vs. 42 mm (P < 0.05), respectively. There were no differences between median changes in 15c and SaO(2), but 3 subjects had significant desaturations (>4%) during the cycle test only. Significant exercise desaturations may occur in mild CF lung disease and will not be detected by a 3-min step test. The 15c did not discriminate between a maximal and a submaximal test, and was less useful than VAS. Important information may be missed by the step test which is detected by more complex exercise tests.

A step in the right direction: assessing exercise tolerance in cystic fibrosis.

Exercise tolerance may be reduced in patients with cystic fibrosis, but it is not always possible to predict this from standard lung function measurements. Formal exercise testing may, therefore, be necessary, and the test should be simple and readily available. We have developed a "3-minute step test" and compared it with the standard 6-minute walking test. Subjects stepped up and down a 15-cm-high single step at a rate of 30 steps per minute for 3 minutes. The effect of the step test on spirometry was tested first in 31 children with CF (mean age, 12.0 years), who had a mean (range) baseline forced expired volume in 1 second (FEV1) of 64% (18-94%) of predicted values. The step test was then compared with the standard 6-minute walk in a further 54 patients with cystic fibrosis (mean age, 12.5 years), with mean (range) baseline FEV1 of 61% (14-103%) of predicted values. Outcome measures were minimum arterial oxygen saturation (SaO2), maximum pulse rate, and the modified Borg dyspnea score. Post-step test spirometry showed mean (95% CI) changes of -1.1% (-6.0 + 3.9%) for forced vital capacity, of -1.6% (-4.2 + 1.1%) for FEV1, and +0.25% (-2.8 + 3.3%) for peak expiratory flow, although 5/31 children showed >15% drop in one or more parameters. The step and walk tests both produced significant changes (P < 0.0001) in all outcomes, with a mean (range) minimum SaO2 of 92% (75-98%) versus 92% (75-97%), a maximum pulse rate of 145 b.p.m. (116-189) versus 132 (100-161), and a Borg score of 2.5 (0-9) versus 1.0 (0-5), respectively. Comparison of the two tests showed that the step test increased breathlessness (mean change Borg score, 2.3 vs. 0.8; P < 0.0001) and pulse rate (mean change, 38% vs. 24%, P < 0.0001) significantly more than the walk, whereas the decrease in SaO2 was similar (mean change, -2.9% vs. -2.6%; P = 0.12). Some patients with a significant drop in SaO2 (>4%) would not have the decrease predicted from their baseline lung function. Reproducibility for the two tests was similar. The step test is quick, simple and portable, and is not dependent on patient motivation. Although the step test is more tiring, its effect on SaO2 is similar to the 6-minute walking test. It is a safe test that may prove to be a valuable measure of exercise tolerance in children with pulmonary disease, although longitudinal studies are now needed.

Inflammatory endobronchial polyps in childhood: clinical spectrum and possible link to mechanical ventilation.

Inflammatory polyps of the airways are now regarded as histopathologically distinct nonneoplastic endobronchial lesions, which in adults are associated with a variety of chronic inflammatory insults. However, their clinical presentation in the pediatric population is extremely rare, with the etiology of such polyps poorly defined. The clinical and histopathological data from four pediatric patients, identified in the histopathology files of the Royal Brompton Hospital, were retrospectively reviewed. Three out of 4 patients had a history of mechanical ventilation in the neonatal period. In these 3 patients, the polyps were all situated in the proximal airways on the right side. These 3 patients presented at 6 weeks, 7 weeks, and 2 years, respectively, and were successfully treated by polypectomy at rigid bronchoscopy, with subsequent return to normality. One patient, presenting at 12 years of age without history of iatrogenic intervention, underwent a left lower lobectomy for a polyp sited in a segmental bronchus. Presentation in 3 of the 4 patients was with lobar collapse. The fourth patient presented with hyperinflation. We conclude that inflammatory endobronchial polyps may be associated with a history of mechanical ventilation in the neonatal period, polyp formation perhaps being secondary to airway trauma. The small caliber of the main airways in neonates may also be a contributory factor in presentation.

Production of the potent neutrophil chemokine, growth-related protein alpha (GROalpha), is not elevated in cystic fibrosis children.

Progressive neutrophil-mediated lung damage causes much of the morbidity and mortality in cystic fibrosis (CF). Neutrophil chemoattractants implicated in CF include interleukin (IL-)8, tumour necrosis factor (TNFalpha) and leukotriene (LT)B4, but growth-related protein alpha (GROalpha), a highly potent neutrophil chemokine, has not been investigated. Atopic status has been considered to contribute to the marked heterogeneity of pulmonary disease in CF. We hypothesized that GROalpha may be produced in biologically-significant amounts in the CF lung, and that enhanced production of GROalpha, IL-8 or LTB4 may contribute to the poorer lung function seen in atopic CF patients compared to non-atopic CF patients. GROalpha, IL-8 and LTB4 levels in the sputum of atopic and non-atopic CF patients were assessed by immunoassays, and GROalpha and IL-8 levels were also assessed in the plasma of CF patients and normal controls. As expected, there were high levels of IL-8 and LTB4 in most CF sputum samples, and IL-8 levels were higher in CF plasma than in control plasma (P=0.02). In contrast, GROalpha was undetectable (< 5 pg ml(-1)) in the sputum of 21 out of 25 CF patients, with low levels (range 144-825 pg ml(-1)) in the remainder, and median levels of GROalpha in CF plasma (33 pg ml(-1), n=24) were not significantly different from controls (34 pg ml(-1), n=25). Lung function [forced expiratory volume in 1 sec (FEV1) and forced vital capacity (FVC)] was significantly poorer in atopic CF compared to non-atopic CF patients (P<0.02), but sputum levels of GROalpha, IL-8 and LTB4 were not different between the subgroups. Our results suggest that unlike LTB4 and IL-8, GROalpha does not contribute to neutrophilic inflammation in the CF lung, and other factors must determine the impaired lung function observed in atopic CF patients. These results may have important implications in the development of chemokine receptor antagonists as novel anti-inflammatory agents in CF.