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.

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.

Cystic fibrosis co-existing with trisomy 21.

Previous reports of children with co-existence of cystic fibrosis and full trisomy 21 suggest a very poor prognosis, with the majority of cases dying in infancy and the oldest reported survivor being 6 years of age. We report the case of a young man with genetically confirmed trisomy 21 and homozygous for the F508del cystic fibrosis mutation. Despite the diagnosis of cystic fibrosis being delayed until the age of 2 years he has transitioned to adult services and is now 25 years of age. Currently he has poor lung function and a continuous ambulatory oxygen requirement.

Serum tobramycin levels following delivery of tobramycin (Tobi) via eFlow advanced nebuliser in children with cystic fibrosis.

BACKGROUND: Safety and toxicity data for nebulised tobramycin are mainly derived from use of the Pari LC Plus nebuliser, yet many centres are now using advanced nebulisers, such as the eFlow. METHODS: Ten children (ages 2-16years) receiving 300mg TOBI via eFlow for clinical reasons participated. Serum tobramycin levels were obtained 1h post nebulisation. Nine provided samples for urinary NAG, and 10 underwent audiology. RESULTS: Tobramycin levels were >1mg/L in 3 children (maximum 3.8, 2 children aged 2years). Urine NAG/creatinine levels were raised (>0.94micromol/min/mmol) in 5 children, 1 of these had a tobramycin level of >1mg/L. One patient had high frequency hearing loss. CONCLUSION: Serum tobramycin levels over 1mg/L can occur 1h post 300mg TOBI delivered by eFlow. Raised urinary NAG levels suggest that some children may have some associated early renal toxicity.

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.

Respiratory exacerbations in childhood associated with compound heterozygosity Phe508del/Arg117His-7T of the cystic fibrosis transmembrane regulator gene.

UNLABELLED: Debate continues regarding the clinical implications for compound heterozygotes identified with Phe508del and Arg117His-7T mutations of the cystic fibrosis transmembrane regulator (CFTR) gene. We report respiratory exacerbations and airway culture of Staphylococcus aureus and Pseudomonas aeruginosa in a child with this genotype. CONCLUSION: The compound heterozygote cystic fibrosis (CF) mutation Phe508del with Arg117His-7T should not necessarily be considered benign in childhood.

Successful liver retransplantation for recurrent hepatopulmonary syndrome.

HPS is defined as arterial hypoxemia because of pulmonary vasodilation as a result of cirrhotic or non-cirrhotic portal hypertension. This report describes a teenager with HPS because of primary sclerosing cholangitis/autoimmune hepatitis overlap syndrome requiring OLT. HPS resolved completely within three months of OLT, but recurred again at 12 months post-OLT following liver dysfunction secondary to a biliary stricture. She underwent a second OLT successfully and remains well two yr and three months post-second OLT. Recurrent HPS after OLT may occur because of graft dysfunction and as this novel case illustrates, retransplantation may lead to a successful outcome.

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.

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.

Testosterone and endurance exercise: development of the "exercise-hypogonadal male condition".

During the last 30 years a large number of research studies have been conducted examining reproductive endocrine dysfunction in exercising women. The number of similar studies examining men is still relatively small. Nevertheless, an increasing amount of research studies in men indicate endurance exercise training has significant effects upon the major male reproductive hormone, testosterone, and the hypothalamic-pituitary-testicular axis that regulates reproductive hormones. This review article addresses one reproductive endocrine dysfunction found in exercising men, what has been deemed the "exercise-hypogonadal male condition". Specifically, men with this condition exhibit basal (resting-state) free and total testosterone levels that are significantly and persistently reduced. The exact physiological mechanism inducing the reduction of testosterone is currently unclear, but is postulated to be a dysfunction (or perhaps a readjustment) within the hypothalamic-pituitary-testicular regulatory axis. The time course for the development of the "exercise-hypogonadal condition" or the threshold of exercise training necessary to induce the condition remains unresolved. The potential exists for these reduced testosterone levels within the exercise-hypogonadal male to disrupt and be detrimental to some anabolic or androgenic testosterone-dependent physiological processes. Unfortunately, extremely few research studies have addressed whether such processes are affected, and thus findings are inconclusive. Conversely, the alterations in testosterone levels brought about by endurance exercise training have the potential for cardiovascular protective effects and thus could be beneficial to the health of these men. Current evidence suggests this condition is limited to men who have been persistently involved in chronic endurance exercise training for extended periods of time (i.e., years). Many questions, however, regarding the male reproductive endocrine adaptive process to exercise and exercise training remain unanswered, necessitating the need for further research on this topic.

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.

Are there gender differences in the prescribing of hypnotic medications for insomnia?

Gender differences in the prescribing patterns of general classes of medications for insomnia were examined. The classes of medications included: zopiclone, antidepressants, benzodiazepines, antihistamines and no medication. The sample comprised a sub-set of respondents from 2620 questionnaires of the Canadian Multicentre Sleep Database. Respondents for this database were contacted through physicians, announcements in the media and local pharmacies. The results indicated that gender alone was not associated with differential prescribing for insomnia, nor was gender associated with patterns of medication use such as frequency of taking medication, length of use, taking more or less medication than prescribed or attempts to stop taking medication. Demographic factors were included in the analysis and age and marital status were associated with different prescribing patterns for men and women with insomnia. It is possible that physicians refer to stereotypic expectations when prescribing hypnotics.

Antibiotic treatment of multidrug-resistant organisms in cystic fibrosis.

Respiratory tract infection with eventual respiratory failure is the major cause of morbidity and mortality in cystic fibrosis (CF). Infective exacerbations need to be treated promptly and effectively to minimize potentially accelerated attrition of lung function. The choice of antibiotic depends on in vitro sensitivity patterns. However, physicians treating patients with CF are increasingly faced with infection with multidrug-resistant isolates of Pseudomonas aeruginosa. In addition, innately resistant organisms such as Burkholderia cepacia complex, Stenotrophomonas maltophilia and Achromobacter (Alcaligenes) xylosoxidans are becoming more prevalent. Infection with methicillin-resistant Staphylococcus aureus (MRSA) is also a problem. These changing patterns probably result from greater patient longevity and increased antibiotic use for acute exacerbations and maintenance care. Multidrug-resistant P. aeruginosa infection may be treated successfully by using two antibiotics with different mechanisms of action. In practice antibiotic choices have usually been made on a best-guess basis, but recent research suggests that more directed therapy can be achieved through the application of multiple-combination bactericidal testing (MCBT). Aerosol delivery of tobramycin for inhalation solution achieves high endobronchial concentrations that may overcome bacterial resistance as defined by standard laboratory protocols. Resistance to colistin is rare and this antibiotic should be seen as a valuable second-line drug to be reserved for multidrug-resistant P. aeruginosa. The efficacy of new antibiotic groups such as the macrolides needs to be evaluated.CF units should adopt strict segregation policies to interrupt person-to-person spread of B. cepacia complex. Treatment of panresistant strains is difficult and often arbitrary. Combination antibiotic therapy is recommended, usually tobramycin and high-dose meropenem and/or ceftazidime, but the choice of treatment regimen should always be guided by the clinical response.The clinical significance of S. maltophilia, A. xylosoxidans and MRSA infection in CF lung disease remains uncertain. If patients show clinical decline and are chronically colonized/infected with either of the former two pathogens, treatment is recommended but efficacy data are lacking. There are defined microbiological reasons for attempting eradication of MRSA but there are no proven deleterious effects of this infection on lung function in patients with CF. Various treatment protocols exist but none has been subject to a randomized, controlled trial. Multidrug-resistant microorganisms are an important and growing issue in the care of patients with CF. Each patient infected with such strains should be assessed individually and antibiotic treatment planned according to in vitro sensitivity, patient drug tolerance, and results of in vitro studies which may direct the physician to antibiotic combinations most likely to succeed.