Managing an adult CF population in the COVID-19 pandemic-1 year on.

BACKGROUND: The advent of the COVID-19 pandemic in 2020 required an alteration in the routine care of people with CF (pwCF), deemed to be extremely vulnerable. AIM: We wished to report the alterations in clinical practice, including the introduction of remote video-assisted clinics, made to manage the adult pwCF attending our large centre. METHODS: We studied clinical records over a period of 2 years (March 2019 to February 2021) by comparing 19th March to 20th February (Y1) with 20th March to 21st February (Y2). RESULTS: We have shown out of hospital Multi Disciplinary Team (MDT) support increased and a greater proportion of IV therapy was administered at home. The VAC model of care increased clinical activity while reducing clinic non-attendance rates, suggesting more individuals engage with their carers. CONCLUSIONS: This new model of care has allowed greater engagement with pwCF.

Loss of incretin effect contributes to postprandial hyperglycaemia in cystic fibrosis-related diabetes.

AIM: To investigate the incretin axis in people with cystic fibrosis. METHODS: Adults with cystic fibrosis-related diabetes, cystic fibrosis without diabetes, and controls (adults without cystic fibrosis and without diabetes) underwent an oral glucose tolerance test and then a closely matched isoglycaemic i.v. glucose infusion. On each occasion, glucose, insulin, C-peptide, total and active glucagon-like peptide-1 and gastric inhibitory polypeptide responses were recorded and incremental areas under curves were calculated for 60 and 240 min. RESULTS: Five adults with cystic fibrosis-related diabetes, six with cystic fibrosis without diabetes and six controls, matched for age and BMI, completed the study. Glucose during oral glucose tolerance test closely matched those during isoglycaemic i.v. glucose infusion. The calculated incretin effect was similar in the control group and the cystic fibrosis without diabetes group (28% and 29%, respectively), but was lost in the cystic fibrosis-related diabetes group (cystic fibrosis-related diabetes vs control group: -6% vs 28%; p=0.03). No hyposecretion of glucagon-like peptide-1 or gastric inhibitory polypeptide was observed; conversely, 60-min incremental area under the curve for total glucagon-like peptide-1 was significantly higher in the cystic fibrosis-related diabetes group than in the control group [1070.4 (254.7) vs 694.97 (308.1); p=0.03] CONCLUSIONS: The incretin effect was lost in cystic fibrosis-related diabetes despite adequate secretion of the incretin hormones. These data support the concept that reduced incretin hormone insulinotropic activity contributes significantly to postprandial hyperglycaemia in cystic fibrosis-related diabetes.

Evidence summary: the relationship between oral health and pulmonary disease.

Introduction This paper is the second of four reviews exploring the relationships between oral health and general medical conditions, in order to support teams within Public Health England, health practitioners and policymakers.Aim This review aimed to explore the most contemporary evidence on whether poor oral health and pulmonary disease occurs in the same individuals or populations, to outline the nature of the relationship between these two health outcomes, and discuss the implication of any findings for health services and future research.Methods The work was undertaken by a group comprising consultant clinicians from medicine and dentistry, trainees, public health, and academics. The methodology involved a streamlined rapid review process and synthesis of the data.Results The results identified a number of systematic reviews of medium to high quality which provide evidence that oral health and oral hygiene habits have an impact on incidence and outcomes of lung diseases, such as pneumonia and chronic obstructive pulmonary disease in people living in the community and in long-term care facilities. The findings are discussed in relation to the implications for service and future research.Conclusion The cumulative evidence of this review suggests an association between oral and pulmonary disease, specifically COPD and pneumonia, and incidence of the latter can be reduced by oral hygiene measures such as chlorhexidine and povidone iodine in all patients, while toothbrushing reduces the incidence, duration, and mortality from pneumonia in community and hospital patients.

A microRNA-based prediction algorithm for diagnosis of non-small lung cell carcinoma in minimal biopsy material.

BACKGROUND: Diagnosis is jeopardised when limited biopsy material is available or histological quality compromised. Here we developed and validated a prediction algorithm based on microRNA (miRNA) expression that can assist clinical diagnosis of lung cancer in minimal biopsy material to improve clinical management. METHODS: Discovery utilised Taqman Low Density Arrays (754 miRNAs) in 20 non-small cell lung cancer (NSCLC) tumour/normal pairs. In an independent set of 40 NSCLC patients, 28 miRNA targets were validated using qRT-PCR. A prediction algorithm based on eight miRNA targets was validated blindly in a third independent set of 47 NSCLC patients. The panel was also tested in formalin-fixed paraffin-embedded (FFPE) specimens from 20 NSCLC patients. The genomic methylation status of highly deregulated miRNAs was investigated by pyrosequencing. RESULTS: In the final, frozen validation set the panel had very high sensitivity (97.5%), specificity (96.3%) and ROC-AUC (0.99, P=10(-15)). The panel provided 100% sensitivity and 95% specificity in FFPE tissue (ROC-AUC=0.97 (P=10(-6))). DNA methylation abnormalities contribute little to the deregulation of the miRNAs tested. CONCLUSION: The developed prediction algorithm is a valuable potential biomarker for assisting lung cancer diagnosis in minimal biopsy material. A prospective validation is required to measure the enhancement of diagnostic accuracy of our current clinical practice.

Comparison of real time diagnostic chemistries to detect Pseudomonas aeruginosa in respiratory samples from cystic fibrosis patients.

BACKGROUND: Early eradication therapy is key to keeping the airways Pseudomonas aeruginosa infection-free and rapid identification is essential. METHODS: We used rapid DNA extraction and qPCR assays to detect bacterial, P. aeruginosa and strain-specific targets in samples using two qPCR chemistries. Using 459 respiratory samples from adult and children CF patients, we compared two qPCR methods to culture-based methods in terms of sensitivity and time to result. RESULTS: For adult samples, there was 100% concordance between methods. There was no clear pattern in fluctuations in P. aeruginosa number during exacerbation. In child samples, qPCR methods identified additional P. aeruginosa positive samples. The time-to-result was reduced by over 24h and copy number and colony forming unit could differ dramatically in some samples. CONCLUSION: If adopted, these methods could significantly improve early P. aeruginosa detection in diagnostic laboratories and therefore play a pivotal role in prolonging infection-free airways in CF patients.

Mechanisms of glucose intolerance in cystic fibrosis.

AIMS: Although cystic fibrosis-related diabetes (CFRD), a poor prognostic factor in cystic fibrosis (CF), is characterized by insulinopenia, the role of insulin resistance is unclear. Using a prospective study design, we measured insulin resistance, pancreatic beta-cell function and correlated glycaemic status with clinical parameters. METHODS: Oral glucose tolerance test was performed in 60 stable adult CF patients. Insulin sensitivity and beta-cell function were measured using the homeostatic model assessment (HOMA2), Stumvoll and oral glucose insulin sensitivity (OGIS) indices. RESULTS: Forty-two (70%) had normal glucose tolerance (NGT), 10 (17%) impaired glucose tolerance (IGT) and eight (13%) CFRD. There was no difference in insulin sensitivity among the three groups (HOMA2: NGT 280, IGT 250, CFRD 339, P = 0.42; Stumvoll: NGT 0.128, IGT 0.126, CFRD 0.129, P = 0.76; and OGIS: NGT 515, IGT 472, CFRD 472, P = 0.12). Pancreatic beta-cell function (CFRD 50% vs. NGT 67%; P < 0.05) and first-phase insulin secretion were reduced in CFRD (250 vs. NGT 509; P = 0.004). First-phase insulin secretion was inversely correlated with 1-h (r = -0.74; P < 0.0001) and 2-h glucose levels (r = -0.34; P < 0.05). There was no difference in body mass index or poor lung function (forced expiratory volume in 1 s: CFRD 54% vs. NGT 65%; P = 0.43). However, there were more hospital admissions in the CFRD group (three vs. NGT one per patient per year; P < 0.05). CONCLUSIONS: CFRD is characterized by qualitative and quantitative defects in insulin secretion, but not insulin resistance, and is associated with increased hospital admissions for pulmonary exacerbations.

Transmission of Pseudomonas aeruginosa epidemic strain from a patient with cystic fibrosis to a pet cat.

Chronic infection with Pseudomonas aeruginosa is common in cystic fibrosis (CF) and certain strains are more transmissible and virulent than others. Of these, the Liverpool Epidemic Strain (LES) is highly transmissible and cross infection has been reported between patients with CF and healthy non-CF relatives. However, the risk of transmission from humans to animals is unknown. The first report of interspecies transmission of the LES strain of P aeruginosa from an adult patient with CF to a pet cat is described. This development further complicates the issue of infection control policies required to prevent the spread of this organism.

Does breastfeeding method influence infant weight gain?

OBJECTIVE: To compare the effect of traditional and "baby-led" breastfeeding advice on early infant weight gain and exclusive breastfeeding rates. DESIGN: Longitudinal cohort study: part prospective, part retrospective. SETTING: One UK general practice. PARTICIPANTS: 63 exclusively breastfed infants in two cohorts: 32 babies born before and 31 babies born after a change in breastfeeding advice. INTERVENTION: A change from baby-led to traditional breastfeeding advice. MAIN OUTCOME MEASURES: Primary analysis: comparison of the effectiveness of the intervention (ie, weight gain expressed as standard deviation score gain (SDSG) between birth and 6-8 weeks) and exclusive breastfeeding rates between babies whose mothers received traditional advice and those whose mothers received baby-led advice. Secondary analysis: relevance of feed length (ie, weight gain expressed as SDSG between birth and 6-8 weeks in babies feeding for 10 min or less from the first breast and those feeding for longer than 10 min). RESULTS: The two groups were equivalent with respect to birth weight, gestational age, and parity. PRIMARY OUTCOME: babies whose mothers received the traditional advice were more likely to be exclusively breast fed up to 12 weeks (log rank chi2 = 9.68, p = 0.002) and gained more weight up to 6-8 weeks than those given baby-led advice (mean SDSG 0.41 (95% CI 0.13 to 0.69) vs -0.23 (95% CI -0.72 to 0.27)). Secondary outcome: irrespective of feeding advice given, babies feeding for 10 min or less from the first breast gained more weight by 6-8 weeks than babies feeding for longer than 10 min (mean SDSG 0.42 (95% CI 0.11 to 0.73) vs -0.19 (95% CI -0.64 to 0.26)). CONCLUSIONS: In this study, traditional breastfeeding advice resulted in increased weight gain and increased exclusive breastfeeding rates compared with baby-led advice. Exclusively breastfed babies who had shorter feeds (10 min or less from the first breast) gained more weight.

Comparison of methods of assessment of renal function in cystic fibrosis (CF) patients.

Renal failure is increasingly being recognised in CF patients, usually as a consequence of long-term nephrotoxic therapy. There is a need for a simple method of assessment of renal function in this patient group. We compared measured creatinine clearance from validated timed urine collections (the generally accepted practical test of glomerular filtration) with 10 formulae used to estimate creatinine clearance in a group of 74 CF adult patients and 29 matched normal controls. Compared to direct measurement, formulae gave a range of values (95% CI for mean bias -13 to +27.9 ml/min). Even those with the best correlation (r=0.7) gave wide error ranges (limits of agreement: -42.3 to 45.9 ml/min). The most commonly used formulae (Cockroft-Gault [CGF] and abbreviated Modification of Diet in Renal Disease [aMDRD]) were not superior to most other formulae tested. Both CGF and aMDRD-derived estimates compared less favourably in CF patients than controls (mean bias: 9.7 vs 3.4 ml/min (p<0.05) and 4.9 vs 1.4 (p<0.05) respectively; 78% vs 95% (p<0.01) and 77% vs 97% (p<0.01) of estimates within 33% of measurement respectively). In particular, both CGF and aMDRD grossly overestimated renal function (mean bias 18.3 and 15.8 ml/min respectively, p<0.001) in CF patients with reduced creatinine clearance (<80 ml/min). CGF, aMDRD and other formulae cannot be used to reliably assess renal function in CF patients, since they will fail to detect those with renal impairment. Some form of carefully supervised direct measurement is still required.

Environmental contamination with an epidemic strain of Pseudomonas aeruginosa in a Liverpool cystic fibrosis centre, and study of its survival on dry surfaces.

We conducted an environmental survey in the Liverpool adult cystic fibrosis (CF) centre in order to determine the extent of environmental contamination with an epidemic strain of Pseudomonas aeruginosa that colonizes most CF patients in Liverpool, and to identify possible reservoirs and routes of cross-infection. In addition, we studied the survival of this strain on dry surfaces, compared with that of other CF P. aeruginosa strains, to explore factors that might contribute to its high transmissibility. Samples were collected from staff, patients and the environment (drains, bath tubs, showers, dry surfaces, respiratory equipment and air) in the inpatient ward and outpatient clinic. P. aeruginosa strains were tested using a new polymerase chain reaction amplification assay specific for the Liverpool epidemic strain (LES). LES was isolated from patients' hands, clothes and bed linen. Environmental contamination with LES was only detected in close proximity to colonized patients (external surfaces of their respiratory equipment, and spirometry machine tubing and chair) and was short-lived. No persistent environmental reservoirs were found. LES was detected in the majority of air samples from inside patients' rooms, the ward corridor and the outpatient clinic. Survival of LES on dry surfaces was significantly longer than that for some other strains tested, but not compared with other strains shown not to be transmissible. Improved environmental survival on its own, therefore, cannot explain the high transmissibility of this epidemic strain. Our study suggests that airborne dissemination plays a significant role in patient-to-patient spread of LES, and confirms the need to segregate those patients colonized by epidemic P. aeruginosa strains from all other CF patients.

Renal impairment in cystic fibrosis patients due to repeated intravenous aminoglycoside use.

Although there are reports of cases of acute renal failure occurring in cystic fibrosis (CF) patients, usually in association with the use of nephrotoxic antibiotic therapy, there have been no studies of renal function in this patient group. We hypothesized that long-term use of intravenous (IV) nephrotoxic antibiotics (aminoglycosides and colistin sulphomethate) may contribute to renal disease in CF patients. In a prospective study, we assessed creatinine clearance as an index of renal function with two techniques (24-hr urine collections and the Cockroft-Gault formula) in a group of 80 stable adult CF outpatients chronically infected with Pseudomonas aeruginosa but with no history of preceding renal disease. Using a multiple linear regression model, we evaluated their renal function in terms of their lifetime IV use of aminoglycosides and colistin. Between 31% (Cockroft-Gault formula method) and 42% (24-hr urine collection method) of patients had a creatinine clearance below normal range. Using either method, there was a strong correlation between aminoglycoside use and diminishing renal function (r=- 0.32, P=0.0055), which was potentiated by the coadministration of colistin (r=- 0.42, P <0.0002). However, there was no correlation with colistin when used in combination with other antibiotics alone (r=0.18, P=NS). Repeated IV aminoglycoside use in CF is associated with long-term renal damage. Although this effect is potentiated by colistin, colistin on its own in moderate doses does not appear to be nephrotoxic. IV aminoglycosides should be used cautiously in CF patients, with regular monitoring of renal function.

Increased morbidity associated with chronic infection by an epidemic Pseudomonas aeruginosa strain in CF patients.

BACKGROUND: Chronic pulmonary infection with transmissible Pseudomonas aeruginosa strains in individuals with cystic fibrosis (CF) has been reported, raising issues of cross infection and patient segregation. The first such strain to be described (the Liverpool epidemic strain, LES) is now widespread in many UK CF centres. However, whether such infection carries a worse prognosis is unknown. To address this, the clinical course of a group of CF patients chronically infected by LES was compared with that in patients harbouring unique strains. METHODS: Using P aeruginosa strain genotyping, two cohorts of CF patients attending the Liverpool CF service were identified who were LES positive or negative in 1998 and remained so until 2002. From these, two groups of 12 patients were matched in 1998 for age, spirometric parameters, and nutritional state and their clinical course was followed for 5 years. Patients chronically infected with Burkholderia cepacia were excluded. RESULTS: Patients chronically infected with LES had a greater annual loss of lung function than those not chronically infected by LES (mean difference between groups -4.4% (95% CI -8.1 to -0.9; p<0.02)), and by 2002 their percentage predicted forced expiratory volume in 1 second (FEV1) was worse (mean 65.0% v 82.6%, p<0.03). Their nutritional state also deteriorated over the study period (mean difference between groups in body mass index -0.7 (95% CI -1.2 to -0.2; p<0.01)), such that by 2002 they were malnourished compared with LES negative patients (mean BMI 19.4 v 22.7, p<0.02). CONCLUSIONS: Chronic infection with the Liverpool epidemic P aeruginosa strain in CF patients confers a worse prognosis than infection with unique strains alone, confirming the need for patient segregation. Since this strain is common in many CF units, strain identification in all CF centres is essential. This can only be carried out using genomic typing methods.

Bronchoscopic insertion of Gianturco stents for the palliation of malignant lung disease: 10 year experience.

Malignant large airway obstruction is life threatening and may not be amenable to urgent radiotherapy. Palliative airway stenting is difficult and traditionally carried out under general anaesthesia and fluoroscopy. We have shown that self expanding Gianturco metal stents can be placed under local anaesthesia using fibreoptic bronchoscopy and direct vision for the treatment of malignant airway tumours, and report our 10 year experience. All referrals for stenting referred to our unit between 1990 and 1999 were included, looking for histological type, number and site of stents, complications of the procedure, other interventions, and survival. One hundred and sixty two patients (average age 64 years, (range 21-89)) had 307 stents inserted during 167 procedures (144 primary lung tumours, 18 secondary malignancy). There were no operative deaths, but three patients developed a pneumothorax, one requiring intercostal drain insertion. Average survival following stent insertion was less for primary lung cancer than for secondary disease (103 vs. 431 days, P<0.001). There were no excess complications in a subgroup of 64 patients treated locally by oncologists, even when stenting was the primary procedure. This technique is useful in palliating life threatening airway obstruction, particularly for secondary cancer, and can be used in any centre undertaking fibreoptic bronchoscopy.

Bacterial diversity in cases of lung infection in cystic fibrosis patients: 16S ribosomal DNA (rDNA) length heterogeneity PCR and 16S rDNA terminal restriction fragment length polymorphism profiling.

The leading cause of morbidity and mortality in cystic fibrosis (CF) patients stems from repeated bacterial respiratory infections. Many bacterial species have been cultured from CF specimens and so are associated with lung disease. Despite this, much remains to be determined. In the present study, we characterized without prior cultivation the total bacterial community present in specimens taken from adult CF patients, extracting DNA directly from 14 bronchoscopy or sputum samples. Bacterial 16S ribosomal DNA (rRNA) gene PCR products were amplified from extracted nucleic acids, with analyses by terminal restriction fragment length polymorphism (T-RFLP), length heterogeneity PCR (LH-PCR), and sequencing of individual cloned PCR products to characterize these communities. Using the same loading of PCR products, 12 distinct T-RFLP profiles were identified that had between 3 and 32 T-RFLP bands. Nine distinct LH-PCR profiles were identified containing between one and four bands. T-RFLP bands were detected in certain samples at positions that corresponded to pathogens cultured from CF samples, e.g., Burkholderia cepacia and Haemophilus influenzae. In every sample studied, one T-RFLP band was identified that corresponded to that produced by Pseudomonas aeruginosa. A total of 103 16S rRNA gene clones were examined from five patients. P. aeruginosa was the most commonly identified species (59% of clones). Stenotrophomonas species were also common, with eight other (typically anaerobic) bacterial species identified within the remaining 17 clones. In conclusion, T-RFLP analysis coupled with 16S rRNA gene sequencing is a powerful means of analyzing the composition and diversity of the bacterial community in specimens sampled from CF patients.