ECFS standards of care on CFTR-related disorders: Identification and care of the disorders.

This is the third paper in the series providing updated information and recommendations for people with cystic fibrosis transmembrane conductance regulator (CFTR)-related disorder (CFTR-RD). This paper covers the individual disorders, including the established conditions - congenital absence of the vas deferens (CAVD), diffuse bronchiectasis and chronic or acute recurrent pancreatitis - and also other conditions which might be considered a CFTR-RD, including allergic bronchopulmonary aspergillosis, chronic rhinosinusitis, primary sclerosing cholangitis and aquagenic wrinkling. The CFTR functional and genetic evidence in support of the condition being a CFTR-RD are discussed and guidance for reaching the diagnosis, including alternative conditions to consider and management recommendations, is provided. Gaps in our knowledge, particularly of the emerging conditions, and future areas of research, including the role of CFTR modulators, are highlighted.

Assessing the effects of transient weather conditions on airborne transmission risk in naturally ventilated hospitals.

BACKGROUND: Many UK hospitals rely heavily on natural ventilation as their main source of airflow in patient wards. This method of ventilation can have cost and energy benefits, but it may lead to unpredictable flow patterns between indoor spaces, potentially leading to the unexpected transport of infectious material to other connecting zones. However, the effects of weather conditions on airborne transmission are often overlooked. METHODS: A multi-zone CONTAM model of a naturally ventilated hospital respiratory ward, incorporating time-varying weather, was proposed. Coupling this with an airborne infection model, this study assessed the variable risk in interconnected spaces, focusing particularly on occupancy, disease and ventilation scenarios based on a UK respiratory ward. RESULTS: The results suggest that natural ventilation with varying weather conditions can cause irregularities in the ventilation rates and interzonal flow rates of connected zones, leading to infrequent but high peaks in the concentration of airborne pathogens in particular rooms. This transient behaviour increases the risk of airborne infection, particularly through movement of pathogens between rooms, and highlights that large outbreaks may be more likely under certain conditions. This study demonstrated how ventilation rates achieved by natural ventilation are likely to fall below the recommended guidance, and that the implementation of supplemental mechanical ventilation can increase ventilation rates and reduce the variability in infection risks. CONCLUSION: This model emphasises the need for consideration of transient external conditions when assessing the risk of transmission of airborne infection in indoor environments.

Changes in liver biochemistry and tacrolimus levels following the introduction of elexacaftor/tezacaftor/ivacaftor in patients with cystic fibrosis and liver transplant.

INTRODUCTION: Elevated liver function tests (LFTs) are reported in individuals with cystic fibrosis (CF) starting elexacaftor/tezacaftor/ivacaftor (ETI). We report our experience with ETI in CF liver transplant patients. METHOD: All CF liver transplant patients under the care of the Leeds CF team were commenced on ETI. Liver biopsies were performed when ALT >3 times upper limit of normal with or without bilirubin elevation. Treatment was guided by transplant hepatology and CF teams. Clinical data including lung function, LFTs and tacrolimus levels were collected. RESULTS: Four patients (3 male, 1 female) on tacrolimus were commenced on ETI. Median time post liver transplantation was 6.5 years. Three patients underwent liver biopsy. One biopsy was abnormal with immune-mediated liver injury, which responded to increased immunosuppression. Management of tacrolimus levels proved straightforward. CONCLUSION: ETI therapy in CF post liver transplant recipients was encouraging. Normal liver biopsy provides re-assurance to continue treatment despite elevated LFTs.

The gut microbiota in adults with cystic fibrosis compared to colorectal cancer.

BACKGROUND: Gut dysbiosis is implicated in colorectal cancer (CRC) pathogenesis. Cystic fibrosis (CF) is associated with both gut dysbiosis and increased CRC risk. We therefore compared the faecal microbiota from individuals with CF to CRC and screening samples. We also assessed changes in CRC-associated taxa before and after triple CF transmembrane conductance regulator (CFTR) modulator therapy. METHODS: Bacterial DNA amplification comprising V4 16S rRNA analysis was conducted on 84 baseline and 53 matched follow-up stool samples from adults with CF. These data were compared to an existing cohort of 430 CRC and 491 control gFOBT samples from the NHS Bowel Cancer Screening Programme. Data were also compared to 26 previously identified CRC-associated taxa from a published meta-analysis. RESULTS: Faecal CF samples had a lower alpha diversity and clustered distinctly from both CRC and control samples, with no clear clinical variables explaining the variation. Compared to controls, CF samples had an increased relative abundance in 6 of the 20 enriched CRC-associated taxa and depletion of 2 of the 6 taxa which have been reported as reduced in CRC. Commencing triple modulator therapy had subtle influence on the relative abundance of CRC-associated microbiota (n = 23 paired CF samples). CONCLUSIONS: CF stool samples were clearly dysbiotic, clustering distinctly from both CRC and control samples. Several bacterial shifts in CF samples resembled those observed in CRC. Studies assessing the impact of dietary or other interventions and the longer-term use of CFTR modulators on reducing this potentially pro-oncogenic milieu are needed.

Body mass index and nutritional intake following Elexacaftor/Tezacaftor/Ivacaftor modulator therapy in adults with cystic fibrosis.

BACKGROUND: Elexacaftor/Tezacaftor/Ivacaftor (ETI) modulator therapy is often associated with increased body mass index (BMI) in people with cystic fibrosis (CF). This is thought to reflect improved clinical stability and increased appetite and nutritional intake. We explored the change in BMI and nutritional intake following ETI modulator therapy in adults with CF. METHODS: Dietary intake, measured with myfood24®, and BMI were collected from adults with CF at baseline and follow-up as part of an observational study. Changes in BMI and nutritional intake in participants who commenced ETI therapy between time points were assessed. To contextualize findings, we also assessed changes in BMI and nutritional intake between study points in a group on no modulators. RESULTS: In the pre and post ETI threapy group (n = 40), BMI significantly increased from 23.0 kg/m2 (IQR 21.4, 25.3) at baseline to 24.6 kg/m2 (IQR 23.0, 26.7) at follow-up (p<0.001), with a median of 68 weeks between time points (range 20-94 weeks) and median duration of ETI therapy was 23 weeks (range 7-72 weeks). There was a significant decrease in energy intake from 2551 kcal/day (IQR 2107, 3115) to 2153 kcal/day (IQR 1648, 2606), p<0.001. In the no modulator group (n = 10), BMI and energy intake did not significantly change between time points (p>0.05), a median of 28 weeks apart (range 20-76 weeks). CONCLUSIONS: These findings tentatively suggest that the increase in BMI with ETI therapy may not simply be attributable to an increase in oral intake. Further exploration into the underlying aetiology of weight gain with ETI therapy is needed.

Cystic Fibrosis-Related Gut Dysbiosis: A Systematic Review.

BACKGROUND AND AIMS: Cystic Fibrosis (CF) is associated with gut dysbiosis, local and systemic inflammation, and impaired immune function. Gut microbiota dysbiosis results from changes in the complex gut milieu in response to CF transmembrane conductance regulator (CFTR) dysfunction, pancreatic malabsorption, diet, medications, and environmental influences. In several diseases, alteration of the gut microbiota influences local and systemic inflammation and disease outcomes. We conducted a systematic review of the gut microbiota in CF and explored factors influencing dysbiosis. METHODS: An electronic search of three databases was conducted in January 2019, and re-run in June 2021. Human, animal, and in vitro studies were included. The primary outcome was differences in the gut microbiota between people with CF (pwCF) and healthy controls. Secondary outcomes included the relationship between the gut microbiota and other factors, including diet, medication, inflammation, and pulmonary function in pwCF. RESULTS: Thirty-eight studies were identified. The literature confirmed the presence of CF-related gut dysbiosis, characterized by reduced diversity and several taxonomic changes. There was a relative increase of bacteria associated with a pro-inflammatory response coupled with a reduction of those considered anti-inflammatory. However, studies linking gut dysbiosis to systemic and lung inflammation were limited. Causes of gut dysbiosis were multifactorial, and findings were variable. Data on the impact of CFTR modulators on the gut microbiota were limited. CONCLUSIONS: CF-related gut dysbiosis is evident in pwCF. Whether this influences local and systemic disease and is amenable to interventions with diet and drugs, such as CFTR modulators, requires further investigation.

Diabetes is associated with increased burden of gastrointestinal symptoms in adults with cystic fibrosis.

BACKGROUND: Individuals with diabetes mellitus (DM) are known to frequently experience gastrointestinal (GI) symptoms. In contrast, the impact of cystic fibrosis-related diabetes (CFRD) on accentuating GI symptoms in people with cystic fibrosis (pwCF) is unknown. We sought to examine this. METHODS: Abdominal symptoms were measured using the validated CF-specific GI symptom questionnaire - CFAbd-Score© - as part of a multicentre cohort study in pancreatic insufficient adults with CF, not on cystic fibrosis transmembrane conductance regulator (CFTR) modulators. The CFAbd-Score total score (0-100pts), its 5 domains, alongside nine specific GI symptoms associated with DM, were compared between the CFRD and non-CFRD groups. RESULTS: 27 (31%) and 61 (69%) participants with CF were recruited in the CFRD and non-CFRD groups respectively. Total CFAbd-Score and the two domains: gastroesophageal reflux disease and disorders of appetite were significantly higher in the CFRD group compared to the non-CFRD group (p<0.05), with the mean total CFAbd-Score being 25.4 ± 2.5 and 18.4 ± 1.5 in the CFRD and non-CFRD groups respectively. Among the nine GI symptoms commonly reported as elevated in DM, bloating and nausea were significantly more common in individuals with CFRD compared to those without (p<0.05). CONCLUSIONS: Individuals with CFRD overall, have a higher GI symptom burden, according to CFAbd-Scores. Specifically, they experience significantly more bloating and nausea. Close monitoring and further research is needed to better understand and manage GI symptoms in this group.

Dose adjustments of Elexacaftor/Tezacaftor/Ivacaftor in response to mental health side effects in adults with cystic fibrosis.

INTRODUCTION: Deterioration in mental health has been reported in a minority of individuals with cystic fibrosis starting elexacafor/tezacaftor/ivacaftor (ELX/TEZ/IVA). We report our experience of using sweat chloride and markers of clinical stability to titrate dose reduction with the aim of minimising adverse events and maintaining clinical stability. METHOD: Adults (n = 266) prescribed ELX/TEZ/IVA, were included. Adverse events, sweat chloride, lung function and clinical data were collected. RESULTS: Nineteen (7.1%) individuals reported anxiety, low mood, insomnia and "brain fog" with reduced attention and concentration span. Thirteen underwent dose reduction with sweat chloride remained normal (<30 mmol l-1) or borderline (30-60 mmol l-1) in six (46.2%) and seven (53.2%) cases respectively. Improvement or resolution of AEs occurring in 10 of the 13 cases. CONCLUSION: Dose adjustment of ELX/TEZ/IVA was associated with improvement in mental health AEs without significant clinical deterioration. Sweat chloride concentration may prove useful as a surrogate marker of CFTR function.

Average rate of lung function decline in adults with cystic fibrosis in the United Kingdom: Data from the UK CF registry.

BACKGROUND: Rate of change in lung function is used as a measure of disease progression and a predictor of mortality in individuals with cystic fibrosis (CF). The aim of this study was to determine the national rate of decline in percent predicted Forced Expiratory Volume in 1 second (ppFEV1) in adults in the UK accounting for age, sex and pancreatic status. METHODS: Data on ppFEV1 for adults with CF, excluding those post lung transplantation, was extracted from the UK CF registry between 2015 and 2017. Multilevel modelling was conducted to calculate the annual rate of change in ppFEV1 accounting for age, sex and pancreatic status. RESULTS: Overall annual ppFEV1 decline was -1.52% (95% CI: -1.66 to -1.38%) and -0.55% (95% CI: -0.86 to -0.23%) in pancreatic insufficient (PI) and sufficient (PS) adults respectively. In PI individuals, females had a greater rate of decline in ppFEV1. There were differences between age groups. The fastest rate of decline was observed in the 18-28 years group, declining -1.76% (95% CI: -2.06 to -1.46) and -1.61% (95% CI: -1.91 to -1.31) per year in PI females and males respectively. The pattern between the sexes and age categories was more inconsistent in the PS group. CONCLUSIONS: The average annual rates of decline in lung function in adults with CF in the UK are similar to reports from other large international cohorts. Pancreatic status has a marked impact on average rate of decline. Younger adults, especially females, have a faster rate of decline and need close monitoring.

Why is mock care not a good proxy for predicting hand contamination during patient care?

BACKGROUND: Healthcare worker (HCW) behaviours, such as the sequence of their contacts with surfaces and hand hygiene moments, are important for understanding disease transmission. AIM: To propose a method for recording sequences of HCW behaviours during mock vs actual procedures, and to evaluate differences for use in infection risk modelling and staff training. METHODS: Procedures for three types of care were observed under mock and actual settings: intravenous (IV) drip care, observational care and doctors' rounds on a respiratory ward in a university teaching hospital. Contacts and hand hygiene behaviours were recorded in real-time using either a handheld tablet or video cameras. FINDINGS: Actual patient care demonstrated 70% more surface contacts than mock care. It was also 2.4 min longer than mock care, but equal in terms of patient contacts. On average, doctors' rounds took 7.5 min (2.5 min for mock care), whilst auxiliary nurses took 4.9 min for observational care (2.4 min for mock care). Registered nurses took 3.2 min for mock IV care and 3.8 min for actual IV care; this translated into a 44% increase in contacts. In 51% of actual care episodes and 37% of mock care episodes, hand hygiene was performed before patient contact; in comparison, 15% of staff delivering actual care performed hand hygiene after patient contact on leaving the room vs 22% for mock care. The number of overall touches in the patient room was a modest predictor of hand hygiene. Using a model to predict hand contamination from surface contacts for Staphylococcus aureus, Escherichia coli and norovirus, mock care underestimated micro-organisms on hands by approximately 30%.

Use of ceftazidime/avibactam for the treatment of MDR Pseudomonas aeruginosa and Burkholderia cepacia complex infections in cystic fibrosis: a case series.

BACKGROUND: The efficacy of antibiotic treatment in pulmonary and systemic infections in cystic fibrosis (CF) is limited by the increased prevalence of MDR strains of Pseudomonas aeruginosa and Burkholderia cepacia complex. Ceftazidime/avibactam is a new combination which, in vitro, appears to have good activity against MDR strains of P. aeruginosa and B. cepacia complex. METHODS: A retrospective analysis was performed including adult patients with CF who received at least one course of ceftazidime/avibactam owing to pulmonary exacerbations not responding to conventional antibiotic treatment. RESULTS: Treatment with ceftazidime/avibactam was associated with reduction in inflammatory markers and improvement in lung function. No episodes of acute kidney injury or elevation in transaminase were observed. CONCLUSIONS: Ceftazidime/avibactam appeared to be well tolerated and improved patients' outcomes. Further studies are needed to better assess the role of this new combination in CF.

Intravenous fosfomycin for pulmonary exacerbation of cystic fibrosis: Real life experience of a large adult CF centre.

BACKGROUND: The increased prevalence of multi-drug resistant strains of P.aeruginosa and allergic reactions among adult patients with cystic fibrosis (CF) limits the number of antibiotics available to treat pulmonary exacerbations. Fosfomycin, a unique broad spectrum bactericidal antibiotic, might offer an alternative therapeutic option in such cases. AIM: To describe the clinical efficacy, safety and tolerability of intravenous fosfomycin in combination with a second anti-pseudomonal antibiotic to treat pulmonary exacerbations in adult patients with CF. METHOD: A retrospective analysis of data captured prospectively, over a 2-years period, on the Unit electronic medical records for patients who received IV fosfomycin was performed. Baseline characteristics in the 12 months prior treatment, lung function, CRP, renal and liver function and electrolytes at start and end of treatment were retrieved. RESULTS: 54 patients received 128 courses of IV fosfomycin in combination with a second antibiotic, resulting in improved FEV1 (0.94 L vs 1.24 L, p < 0.01) and reduced CRP (65 mg/L vs 19.3 mg/L, p < 0.01). Renal function pre- and post-treatment remained stable. 4% (n = 5) of courses were complicated with AKI at mid treatment, which resolved at the end of the course. Electrolyte supplementation was required in 18% of cases for potassium and magnesium and 7% for phosphate. Nausea was the most common side effect (48%), but was well controlled with anti-emetics. CONCLUSION: Antibiotic regimens including fosfomycin appear to be clinically effective and safe. Fosfomycin should, therefore, be considered as an add-on therapy in patients who failed to respond to initial treatment and with multiple drug allergies.

Real-time transmission of 16 Tb/s over 1020km using 200Gb/s CFP2-DCO.

We demonstrate real-time transmission of 16 Tb/s (80x200Gb/s) over 1020km TeraWave ULL fiber with 170km span length using the world's first 200Gb/s CFP2-DCO module with a record low power consumption less than 0.1W/Gbps.

Detection of drug-responsive B lymphocytes and antidrug IgG in patients with ß-lactam hypersensitivity.

BACKGROUND: Delayed-type ß-lactam hypersensitivity develops in subset of patients. The cellular immunological processes that underlie the drug-specific response have been described; however, little is known about involvement of the humoral immune system. Thus, the aim of this study was to utilize piperacillin hypersensitivity as an exemplar to (i) develop cell culture methods for the detection of drug-specific B-cell responses, (ii) characterize drug-specific IgG subtypes and (iii) assess reactivity of IgG antibodies against proteins modified to different levels with piperacillin haptens. METHODS: IgG secretion and CD19+ CD27+ expression on B cells were measured using ELISPOT and flow cytometry, respectively. A piperacillin-BSA adduct was used as an antigen in ELISA antibody binding studies. Adducts generated using different ratios of drug to protein were used to determine the degree of conjugation required to detect IgG binding. RESULTS: B cells from hypersensitive patients, but not controls, were stimulated to secrete IgG and increase CD27 expression when cultured with soluble piperacillin. A piperacillin-BSA adduct with cyclized and hydrolysed forms of the hapten bound to eight lysine residues was used to detect hapten-specific IgG 1-4 subclasses in patient plasma. Hapten inhibition and the use of structurally unrelated hapten-BSA adducts confirmed antigen specificity. Antibody binding was detected with antigens generated at piperacillin/BSA ratios of 10:1 and above, which corresponded to a minimum epitope density of 1 for antibody binding. CONCLUSION: These data show that antigen-specific B lymphocytes and T lymphocytes are activated in piperacillin-hypersensitive patients. Further work is needed to define the role different IgG subtypes play in regulating the iatrogenic disease.

800Gb/s (8x128Gb/s) unrepeatered transmission over 515-km large-area ultra-low-loss fiber using 2nd-order Raman pumping.

We demonstrate unrepeatered transmission of 8x128Gb/s PDM-QPSK signals over a 515k-m fiber link. This ultra-long distance of 800 Gb/s unrepeatered transmission in a single fiber configuration is achieved by employing enabling techniques such as large-effective-area ultra-low-attenuation fibers, co-propagating and counter-propagating 2nd-order-pumped distributed Raman amplification, and remote optically pumped amplifier (ROPA). The ROPA itself is also counter-propagating 2nd-order Raman pumped. The designs and characteristics of the ROPA and 2nd-order pumped distributed Raman amplification are described, and optimization of the transmission performance of this ultra-long reach 800Gb/s unrepeatered transmission fiber link is discussed in this paper.

Requirements and access needs of patients with chronic disease to their hospital electronic health record: results of a cross-sectional questionnaire survey.

OBJECTIVES: To identify patient's views on the functionality required for personalised access to the secondary care electronic health record (EHR) and their priorities for development. DESIGN: Quantitative analysis of a cross-sectional self-complete survey of patient views on required EHR functionality from a secondary care EHR, including a patient ranking of functionality. SETTING: Secondary care patients attending a regional cystic fibrosis unit in the north of England. PARTICIPANTS: 201 adults (106 (52.7%) males), median age 29 years (range 17-58 years), entered and completed the study. Inclusion criteria are as follows: a confirmed diagnosis of cystic fibrosis, aged 16 years and over, at the time of clinical stability. OUTCOME MEASURES: Quantitative responses within 4 themes; (1) value placed on aspects of the EHR; (2) access requirements to functions of the EHR; (3) views on information sent to the EHR and (4) patient feedback entered into the EHR. A ranked score for 15 functions of the EHR was obtained. RESULTS: Highest ratings (% reporting item as very important/important) were reported for access to clinical measures (lung function (94%), C reactive protein (84%), sputum microbiology (81%) and blood results (80%)), medication changes (82%) and lists (83%) and sending repeat prescription (83%) and treatment requests (80%), while sending symptom diaries was less so (62%). Email contact with clinicians was the most valuable communication element of the EHR (84% very important/important). Of 15 features of the EHR (1=most desirable to 15=least desirable), patients identified 'clinical measures' (2.62 (CI 2.07 to 3.06)), and 'access to medication lists' (4.91 (CI 4.47 to 5.44)), as highest priority for development and the ability to comment on errors/omissions (11.0 (CI 10.6 to 11.5)) or experience of care (11.8 (CI 11.4 to 12.2)) as lowest. CONCLUSIONS: Patients want extensive personal access to their hospital EHR, placing high importance on the viewing of practical clinical measures and medication management. These influence routine day-to-day care and are priorities for development.

Ultrasound and magnetic resonance imaging assessment of joint disease in symptomatic patients with cystic fibrosis arthropathy.

OBJECTIVES: Cystic fibrosis arthropathy (CFA) is a term commonly used for joint pain with and without swelling seen in some patients with CF. Early studies into CFA focused on the presence of rheumatoid factor and immunological changes on synovial biopsy, with parallels drawn between respiratory and joint activity. Identification of anti-cyclic citrullinated peptide antibodies (anti-CCP) as a marker of rheumatoid arthritis (RA), along with increased access to sensitive imaging techniques including ultrasound (US) and magnetic resonance imaging (MRI), offer great potential to investigate and more accurately understand the type(s) of inflammatory arthritis that may underlie CFA. The aim of this study was to phenotype an active CFA cohort using serology and imaging, as a basis for further work in this understudied area. METHODS: This was a prospective observational cohort study of symptomatic CFA patients presenting with joint pain. Participants underwent serological testing, clinical and US joint and entheseal assessment, as well as MRI of the most symptomatic joint/joint area. RESULTS: Ten symptomatic patients were studied with 9/10 having positive clinical findings. Inflammatory changes on US were seen in 8/10 cases. Five patients had positive findings on MRI (3 of whom had received IV gadolinium contrast). This included patients with significant erosive changes. One patient was anti-CCP positive suggestive of RA, and two were anti-nuclear antibody positive. CONCLUSION: Imaging, and to a lesser extent serology, identified inflammatory joint pathology in a proportion of cases, providing important data to explore in a large CFA cohort examining the clinical and imaging phenotype of this group.

Fungal contamination of nebuliser devices used by people with cystic fibrosis.

BACKGROUND: Poor nebuliser hygiene can result in bacterial contamination and risk of infections. The aim of this study was to assess the prevalence of fungal contamination of nebulisers used by adults with cystic fibrosis. METHODS: A total of 170 nebulisers from 149 subjects were screened by wetting a sterile cotton swab with sterile water and swabbing each drug chamber. The swab was then plated out on Sabouraud and on Scel+agar and incubated at 27 °C for up to 2 weeks. RESULTS: Fungal cultures were positive in 86 (57.7%) patient's devices. In 28/149 (18.8%), 39/149 (26.2%), 47/149 (31.5%) and 20/149 (13.4%) of subjects Aspergillus species, yeasts, moulds and both yeasts and moulds were isolated respectively. There was no difference in contamination rates between different devices. CONCLUSION: Nebuliser devices are frequently contaminated by moulds and yeasts and emphasis should be placed on ensuring adequate nebuliser hygiene.