The feasibility of home monitoring of young people with cystic fibrosis: Results from CLIMB-CF.

BACKGROUND: CF is traditionally assessed in clinic. It is unclear if home monitoring of young people with CF is feasible or acceptable. The COVID-19 pandemic has made home monitoring more of a necessity. We report the results of CLIMB-CF, exploring home monitoring's feasibility and potential obstacles. METHODS: We designed a mobile app and enrolled participants with CF aged 2-17 years and their parents for six months. They were asked to complete a variety of measures either daily or twice a week. During the study, participants and their parents completed questionnaires exploring depression, anxiety and quality of life. At the end of the study parents and participants completed acceptability questionnaires. RESULTS: 148 participants were recruited, 4 withdrew prior to starting the study. 82 participants were female with median (IQR) age 7.9 (5.2-12 years). Median data completeness was 40.1% (13.6-69.9%) for the whole cohort; when assessed by age participants aged ≥ 12 years contributed significantly less (15.6% [9.8-30%]). Data completeness decreased over time. There was no significant difference between parental depression and anxiety scores at the start and the end of the study nor in CFQ-R respiratory domain scores for participants ≥ 14 years. The majority of participants did not feel the introduction of home monitoring impacted their daily lives. CONCLUSIONS: Most participants felt home monitoring did not negatively impact their lives and it did not increase depression, anxiety or decrease quality of life. However, uptake was variable, and not well sustained. The teenage years pose a particular challenge and further work is required.

Optimising equity of access: how should we allocate slots to the most competitive trials in Cystic Fibrosis (CF)?

BACKGROUND: Trial participation can allow people with CF early access to CFTR modulator therapies, with high potential for clinical benefit. Therefore, the number of people wishing to participate can substantially exceed the number of slots available. We aimed to understand how the CF community thinks slots to competitive trials should be allocated across the UK and whether this should be driven by clinical need, patients' engagement/adherence or be random. For the latter, we explored site-level versus registry-based, national randomisation processes. METHODS: We developed an online survey, recruiting UK-based stakeholders through social media, newsletters and personal contacts. Closed questions were analysed for frequencies and percentages of responses. Free-text questions were analysed using thematic analysis. RESULTS: We received 203 eligible responses. Overall, 75% of stakeholders favoured allocation of slots to individual sites based on patient population size, although pharma favoured allocation based on previous metrics. Currently, few centres have defined strategies for allocating slots locally. At face-value, stakeholders believe all eligible participants should have an equal chance of getting a slot. However, further questioning reveals preference for prioritisation strategies, primarily perceived treatment adherence, although healthcare professionals were less likely to favour this strategy than other stakeholder groups. The majority of stakeholders would prefer to allocate slots and participate in trials locally but 80% said if necessary, they would engage in a system of national allocation. CONCLUSIONS: Fair allocation to highly competitive trials does not appear to have a universally acceptable solution. Therefore, transparency and empathy remain critical to negotiate this uncertain territory.

Isolation of the fungus Geosmithia argillacea in sputum of people with cystic fibrosis.

We report the repeated isolation of the fungus Geosmithia argillacea from sputum samples of people with cystic fibrosis. Identification was based on morphology and DNA sequence analysis. Isolation of G. argillacea did not appear to be associated with clinical deterioration. The pathogenic potential of G. argillacea is discussed.

A European consensus for the evaluation and management of infants with an equivocal diagnosis following newborn screening for cystic fibrosis.

Screening newborns for cystic fibrosis (CF) is considered to be an ethical undertaking in regions with a significant incidence of the condition. Current screening protocols result in recognition of infants with an equivocal diagnosis. A survey of European practice suggested inconsistencies in the evaluation and management of these infants. We have undertaken a consensus process using a modified Delphi method. This has enabled input of CF specialists from a wide geographical area to a rigorous process that has provided a clear pathway to a consensus statement. A core group produced 21 statements, which were modified over a series of three rounds (including a meeting arranged at the European CF Conference). A final document of 19 statements was produced, all of which achieved a satisfactory level of consensus. The statements cover four themes; sweat testing, further assessments and investigations, review arrangements and database. This consensus document will provide guidance to CF specialists with established screening programmes and those who are in the process of implementing newborn screening in their region.

Low gammaglobulin subclass 2 levels in paediatric cystic fibrosis patients followed over a 2-year period.

The aim of this study was to relate serum immunoglobulin G2 subclass levels in a large paediatric population with cystic fibrosis, to clinical status and antibody levels to Haemophilus influenzae type b and Streptococcus pneumoniae and to observe any changes over a 2-year period. IgG subclasses were measured in 131 patients. Results were compared with levels from age-related normal population data. The following clinical data were collected at baseline and 2 years later; genotype: height, weight, and BMI z-scores: FEV1 (as percent predicted): Shwachman-Kulczcyki and Northern chest X-ray scores: Pseudomonas aeruginosa status. Antibody levels to H. influenzae type b and S. pneumoniae measured at baseline were related to IgG2 level. There was a reduction in the prevalence of low levels of IgG2 from 29% to 10% over the 2-year period. Low levels of IgG2 were not associated with any decline in clinical well-being. Low levels of IgG2 alone were associated with low antibody levels to S. pneumoniae. Low levels of IgG2 and low levels of antibody to H. influenzae and S. pneumoniae were not associated with any decline in clinical well-being. Children with high levels of IgG2 had worse lung function, worse Shwachman-Kulczcyki and Northern chest X-ray scores and higher levels of P. aeruginosa infection. Children with low IgG2 levels were not worse clinically compared to those with normal or high IgG2 levels. High IgG2 levels were associated with a worse clinical status.

Longitudinal analysis of FEV1 changes related to antibiotic therapy in children with cystic fibrosis.

The measurement of FEV1 in children with cystic fibrosis has been shown to be the most important objective measurement for survival. It has been observed that children receiving intravenous antibiotics usually show a significant improvement in FEV1 with therapy in the short term. We hypothesized that the FEV1 measured pre-antibiotic therapy and followed longitudinally would show a greater rate of decline and may be a better prognostic indicator than the FEV1 post antibiotic therapy. The study cohort consisted of 60 children with cystic fibrosis who attended the St. James' Hospital cystic fibrosis unit between 1993 and 1999. Mixed model regression analysis provided estimates of the average rate of change of the pre-FEV1, post-FEV1 and FEV1 difference in subgroups based on survival, sex and pseudomonas status. There was no significant difference seen in the rate of decline of the FEV1 difference when comparing those who died and those who survived (p = 0.93). This was also the case when males were compared to females (p = 0.09). Both pre-antibiotic FEV1 and post-antibiotic FEV1 measurements showed a significant difference in rate of decline when comparing those who died (FEV1 slope = -6.4, -6.3) to those who survived (FEV1 slope = -1.9, -1.7) [p = 0.001, p = 0.0005] and when males (FEV1 slope = -0.6, -0.03) were compared to females (FEV1 slope = -3.3, -3.5) [p = 0.03, p = 0.002]. Our study demonstrated that there was no additional value in measuring FEV1 pre-antibiotic therapy compared to the FEV1 post antibiotic therapy in improving the sensitivity of FEV1 as a marker of decline. This study confirms that the rate of decline in FEV1 is a strong predictor of mortality and that females in this age group decline faster than their male counterparts.

Immunoglobulin and IgG subclass levels in a regional pediatric cystic fibrosis clinic.

The aim of this study was to report serum immunoglobulin (Ig) and IgG subclass levels in a large pediatric population with cystic fibrosis, and relate these to measures of disease severity. Total immunoglobulin levels were measured in 154 patients, and IgG subclass levels were measured in 136 patients and compared to age-related normal population data and to levels reported in previously published studies of children with cystic fibrosis. Clinical data were also collected: genotype; height, weight, and BMI standard deviation scores; FEV(1) (as percent predicted); Shwachmann-Kulczycki (S-K) and Northern chest X-ray scores; and Pseudomonas aeruginosa infection status. The clinical well-being of patients with hypo- or hyper-gammaglobulinemia was compared with age- and sex-matched control patients who had normal levels of gammaglobulin. IgG subclass levels were measured, and the results were compared with previous studies. Eleven patients had hypergammaglobulinemia (7.8% compared with 0-69% in the published literature). Patients with hypergammaglobulinemia had lower FEV(1) percent-predicted values, and worse S-K and Northern chest X-ray scores than controls. Three patients had hypogammaglobulinemia (1.9% compared with 0-10.8% in the published literature). There was no difference in any clinical parameter between controls and those with hypogammaglobulinemia. Nineteen patients (14%) had low levels of IgG1, and 40 patients (29%) had low levels of IgG2. The low percentage of patients with abnormally high immunoglobulin levels probably reflects the improved respiratory status of today's children with CF. The low percentage of those with low IgG probably reflects better nutritional status. The finding of worse lung function and clinical scores in patients with hypergammaglobulinemia agrees with the published literature. The high percentage of patients with low IgG2 was unexpected and was not previously reported. The clinical significance of this in patients with CF is unknown.

'Cepacia syndrome' with Burkholderia multivorans, 9 years after initial colonization.

A 16-year-old boy with cystic fibrosis developed 'cepacia syndrome' 9 years after the first isolation of Burkholderia multivorans. It is important to recognise that 'cepacia syndrome' is not restricted to those infected with genomovar type III strains and that rapid, irreversible clinical decline can occur many years after the 1st isolation of Burkholderia cepacia complex (Bcc).

Clinical value of obtaining sputum and cough swab samples following inhaled hypertonic saline in children with cystic fibrosis.

Prompt detection and treatment of lower respiratory tract infection are essential in the management of patients with cystic fibrosis (CF), who often have signs or symptoms of respiratory infection without any pathogens being isolated from sputum or cough swab specimens. The aims of this study were to assess the efficacy and clinical value of obtaining sputum and oropharyngeal cough swab samples following induction with hypertonic saline (HS) in this group of patients. Forty-three outpatients with CF, mean age 7.2 years (range, 1.8-12.9 years), were recruited over a 2-year period. Nebulized salbutamol was administered, followed by 6% HS. Sputum was preferentially obtained before and after HS induction if possible. If the patient was not able to expectorate, oropharyngeal cough swabs were taken instead. Four patients were able to expectorate sputum before and 19 after HS induction. The procedure was tolerated in 41 of 43 patients. Pathogens were isolated from 13 patients' HS-induced samples, but not from their corresponding preinduced specimens, and 4 patients' preinduced specimens cultured organisms which were not identified from their HS-induced samples. Significant changes were made in the management of 13 (30.2%) patients directly resulting from the positive culture of pathogens only from HS-induced samples. Cultures from oropharyngeal cough swab or expectorated sputum specimens following inhalation of HS provide additional microbiological information which is of clinical value and may lead to changes in patient management.

Transmission of colistin-resistant Pseudomonas aeruginosa between patients attending a pediatric cystic fibrosis center.

We report on an outbreak of colistin-resistant Pseudomonas aeruginosa (CRPA) that occurred in a United Kingdom pediatric cystic fibrosis (CF) unit and involved six children over a period of 5 years. All CRPA-positive children had received aerosolized colistin therapy before first isolation of resistant organisms (mean duration, 3.1 years). Four of the 6 had also received courses of intravenous colistin in the year before the first isolation of CRPA. No impact of CRPA acquisition on respiratory function, clinical condition, or radiological parameters could be demonstrated. Four of the 6 children carried isolates of CRPA indistinguishable on genotyping. Two of these 4 children were sisters. The other 2 were on the same ward together at time of first isolation, and subsequently shared overlapping admissions with one of the sisters. While there is no conclusive evidence for the route of transmission, the frequency of overlapping in-patient admissions between 3 of these patients is suggestive of patient-to-patient transfer in the nosocomial setting.CF clinicians should be aware that colistin resistance can occur in P. aeruginosa, and some of these strains are capable of spread within CF units.

Evaluation of fecal pancreatic elastase-1 as a measure of pancreatic exocrine function in children with cystic fibrosis.

Pancreatic elastase-1 (EL-1) is a specific human protease synthesised by the acinar cells. It is stable, unaffected by exogenous pancreatic enzyme treatment, and correlates well with stimulated pancreatic function tests. We report our experience of EL-1 measurements in 142 patients from a large cystic fibrosis (CF) clinic. The median patient age was 7.7 years (range, 0.1-20.8 years), 93 were homozygous and 38 heterozygous for DeltaF508, and 11 had other or unidentified mutations. There were 85 non-CF control subjects. Seven were pancreatic sufficient (PS). The median (quartile 1-quartile 3) fecal EL-1 of the 135 pancreatic insufficient (PI) patients was 10 microg/g stool (2.5-33); of the 7 PS patients, 698 microg/g stool (400.5-824.5), and of the non-CF controls, 615 microg/g stool (420-773). Using the Mann-Whitney U test, there was a statistically significant difference for fecal EL-1 activity between the PS and PI patients (P = 0.0001) and the PI and control group (P < 0.0001), but not between the control and PS groups (P = 0.63). Median (quartile 1-quartile 3) fecal EL-1 in the pancreatic insufficient DeltaF508 homozygotes was 10 microg/g stool (2-33), and in the heterozygotes 12 microg/g stool (4-39) (not significant, P = 0.62). We now use fecal EL-1 as evidence of PI in screened CF infants (reliable over the age of 2 weeks); in older CF patients at diagnosis; for confirming the need for pancreatic enzymes in patients referred to the clinic already taking enzymes; for annual monitoring of PS patients to detect the onset of PI; and as supporting evidence when excluding the diagnosis of CF in patients attending the pediatric gastroenterology clinic. The low values in the first 2 weeks in some normal and premature infants, and the persisting normal values in PS infants, make the fecal EL-1 test unsuitable for neonatal CF screening.

To PEEP or not to PEEP?

It is well recognised that reducing positive end expiratory pressure (PEEP) leads to an increase in the tidal volume and minute volume in ventilated neonates. The magnitude of this effect is perhaps not commonly appreciated, however. Effectively, PEEP is four times as potent as peak inflation pressure (PIP) in bringing about changes in tidal volume. The influence of changes in PEEP and PIP on tidal volume and the relative magnitude of each are considered. Twenty one preterm infants were studied on 38 separate occasions. All were sedated, paralysed, and ventilated, 19 for hyaline membrane disease. A 1 cm H2O reduction in PEEP was twice as potent as a 2 cm H2O increase in PIP in achieving an increase in tidal volume (14 v 7%). Similarly, increasing PEEP by 1 cm H2O was twice as effective as a 2 cm H2O decrease in PIP in reducing tidal volume (13 v 6%). Small (0.5-1 cm H2O) changes in PEEP can often be used to improve ventilation and carbon dioxide elimination. Levels of PEEP of 4-5 cm H2O may, at times, impair gas exchange and contribute to overdistension.

Role of epidermal growth factor and transforming growth factor alpha in the developing stomach.

AIMS: To determine whether epidermal growth factor (EGF) or the related transforming growth factor alpha (TGF alpha) may have a role in the developing human stomach; to substantiate the presence of EGF in human liquor in the non-stressed infant and whether EGF in amniotic fluid is maternally or fetally derived. METHODS: The temporal expression and localisation of EGF, TGF alpha, and their receptors during fetal and neonatal life were examined in 20 fetal and five infant stomachs. Simultaneously, samples of amniotic fluid and fetal urine from 10 newborn infants were collected and assayed for EGF by radioimmunoassay. RESULTS: EGF immunoreactivity was not noted in any of the specimens examined. In contrast, TGF alpha immunoreactivity was shown in mucous cells from 18 weeks of gestation onwards. EGF receptor immunoreactivity was seen on superficial mucous cells in gastric mucosa from 18 weeks of gestation onwards. The median concentration of EGF was 30 and 8.5 pg/ml in amniotic fluid and fetal urine, respectively, suggesting that EGF is not produced by the fetus. CONCLUSIONS: This study adds weight to the hypothesis that swallowed EGF, probably produced by the amniotic membranes, and locally produced TGF alpha, may have a role in the growth and maturation of the human stomach.

Gastric secretory function in the developing human stomach.

Little data exists regarding the activity of gastric parietal cells in the very immature infant. Therefore we have examined the developing human stomach for the presence and location of parietal cells, using both standard histological methods and antibodies to the H+/K+ ATPase (proton pump) and intrinsic factor, in 35 fetuses (ranging from 13-28 weeks) and in five infants (2-21 weeks). Parietal cell activity was noted in the body, antrum and pyloric regions in all the fetal specimens examined. However, this activity was much more limited in the infant specimens. We have noted that from the end of the first trimester parietal cells are present in a mature, functional form with the potential to secrete both gastric acid and intrinsic factor.

Gastric acid secretion in preterm infants.

Little is known about the ontogeny of gastric acid secretion in the very preterm infant. In order to study this we recorded intragastric pH continuously for 24 h on 71 occasions in 22 enterally starved preterm infants. Infants ranged from 24 to 29 weeks' gestation and were studied in the first 5 days, and in the third week, of life. As the infants became more mature, both in terms of gestation and postnatal age, there was a decrease in intragastric pH from median (range) 3.7, 2.5 (0.6-3.9) and 1.8 (1.3-2.6) for infants of 24-25, 26-27 and 28-29 weeks' gestation, respectively on the first day of life to 1.8 (1.7-1.9), 2.0 (1.8-2.3) and 1.7 (1.5-2.0) on day 16. All the infants were able to maintain a gastric pH of below 4 from the first day of life. Our data lay to rest the suggestion that the preterm infant is incapable of hydrogen ion secretion. Gastric acid secretion in the newborn preterm infant should allow normal proteolytic activity and the well recognised clinical problems of intragastric bleeding, gastritis or oesophagitis may be attributable to intragastric acid.

Peripherally inserted central catheters in children with cystic fibrosis. Eight cases of difficult removal.

Peripherally inserted central catheters (PICCs) are widely used in the management of cystic fibrosis (CF) in children and adults. The authors present a collection of eight case reports of patients with CF in whom removal of PICCs was difficult, including two PICCs that required surgical removal. The cases were observed in a regional pediatric CF unit in the United Kingdom. Possible etiology and strategies that can be used to achieve catheter removal are discussed.

Choice of add-on therapy in asthma - another inhaler or a tablet/syrup? A survey of 1415 UK asthmatics.

OBJECTIVES: To determine preferences for asthma treatment given as inhaled therapy or as a tablet / syrup, to identify factors that influence this choice, and to assess how many patients would sacrifice greater efficacy of therapy in order to use the delivery route of their choice. DESIGN: Postal Questionnaire to patients with an active diagnosis of asthma aged less than 60 years under the care of general practitioners, paediatricians or adult respiratory physicians. MAIN OUTCOME MEASURE: Patient preference for inhaled therapy or tablet/syrup. RESULTS: 715 replies were analysed (93% Caucasian). 58% (417) preferred tablets (p<0.01) based on an equal chance of symptom improvement. There was no sex difference, but more children aged 6-10 and parents of under 6 year olds preferred tablets or syrup than adults (65% vs. 54%, p=0.03). Preference for tablets increased with number of current inhalers (p<0.05) but there was no correlation with total number of puffs per day or numbers of existing tablets taken. 238 (36%) opted for their preferred route of delivery in preference to greater efficacy. CONCLUSION: More asthmatics would choose a tablet or syrup than another inhaler as add-on therapy for their asthma. This preference was more marked in children and in patients already taking several inhalers. 36% of patients are prepared to sacrifice greater efficacy in favour of their choice of route of delivery.

An expert system to assist neonatal intensive care.

An expert system for neonatal intensive care (ESNIC) for the management of mechanically ventilated neonates on intermittent positive pressure ventilation (IPPV) has been developed. The system uses the rule based expert system shell XiPlus (Inference Inc.) and runs on an IBM-compatible PC. The rules have been derived from the knowledge of two consultant paediatricians. The inputs to the system are the current ventilator settings, blood gas tensions and pH. The output of the system is a set of suggested new ventilator settings. The aim of the system is to provide ventilator settings which will maintain the arterial blood gas tensions within an acceptable range, reducing pressures whenever feasible and increasing pressures only as a last resort. In addition, ESNIC provides data archiving, graphical displays of all parameters, ventilation and discharge summaries. With the 63 patients in the study ESNIC was consulted for 76% of all ventilator adjustments and the advice given was accepted on 83% of these occasions.

The development and deployment of integrated electronic care records in a regional adult and paediatric cystic fibrosis unit.

BACKGROUND: Electronic care records (ECRs) for cystic fibrosis (CF) provide a basis for accurate, reliable capture of clinical measures and interventions, and epidemiological trends, providing the basis for improved efficiency and patient safety. METHODS: A primary care system was modified for hospital use and clinical codes devised for all aspects of CF care. Performance and usability were assessed. RESULTS: Of a total of 620 patients 619 consented to their data being recorded in the system. Five hundred and twenty three new codes were created and embedded behind 60 new templates. Following introduction of ECR, completion of annual assessments increased from 43% to 92%, retrieval of drug costs rose significantly and time to correspondence with primary care fell from 34days to <2days. Staff satisfaction was high. CONCLUSION: The system is fully operational allowing the unit to function as a paperless service. Efficiencies of staffing activity, process management and cost retrievals are evident. Sharing of coding structures is important in future care.

Lung clearance index: evidence for use in clinical trials in cystic fibrosis.

The ECFS-CTN Standardisation Committee has undertaken this review of lung clearance index as part of the group's work on evaluation of clinical endpoints with regard to their use in multicentre clinical trials in CF. The aims were 1) to review the literature on reliability, validity and responsiveness of LCI in patients with CF, 2) to gain consensus of the group on feasibility of LCI and 3) to gain consensus on answers to key questions regarding the promotion of LCI to surrogate endpoint status. It was concluded that LCI has an attractive feasibility and clinimetric properties profile and is particularly indicated for multicentre trials in young children with CF and patients with early or mild CF lung disease. This is the first article to collate the literature in this manner and support the use of LCI in clinical trials in CF.